Diagnostic Pathology: Familial Cancer Syndromes [1 ed.] 193188496X, 9781931884969

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Nosé SECOND EDITION

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Second Edition

Vania Nosé, MD, PhD Associate Chief of Pathology Director of Anatomic and Molecular Pathology Massachusetts General Hospital Professor of Pathology Harvard Medical School Boston, Massachusetts

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Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

DIAGNOSTIC PATHOLOGY: FAMILIAL CANCER SYNDROMES, SECOND EDITION Copyright © 2020 by Elsevier. All rights reserved.

ISBN: 978-0-323-71204-0 Inkling: 978-0-323-71206-4

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous edition copyrighted 2013. Library of Congress Control Number: 2019956687

Printed in Canada by Friesens, Altona, Manitoba, Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

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Dedication Developing a comprehensive book like this could only be accomplished with high levels of amazing teamwork. I would like to acknowledge and thank so many remarkable people for their support and contributions to this book. I will start with my parents, Dalva and Antonio Nosé, for their support, invaluable teaching and guidance, and for being my life examples. To my wonderful sons and best friends, Gustave, Erick, and Phillip, and their wives, Carla, Suzana, and Bianca, and to my grandsons, Nicolas, Leonardo, and Lucas Antonio, you all make my life so lovely and complete. To my brothers, Dalton and Walton, and their families for their love and continuous support. To the outstanding and dedicated contributing authors of this book for their hard work and contributions to this unique project. To the wonderful Elsevier team for their extraordinary work in making this book a reality. My final thanks are to all my family, friends, residents, fellows, colleagues, and everyone who shares our love and commitment to a better understanding of familial cancer diseases. VN

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Contributing Authors Ying-Hsia Chu, MD

Clinical Fellow Department of Pathology Massachusetts General Hospital Boston, Massachusetts

Daniel C. Chung, MD

Medical Co-Director, Center for Cancer Risk Assessment MGH Cancer Center and Division of Gastroenterology Director, High-Risk GI Cancer Clinic Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Vikram Deshpande, MD Pathologist Department of Pathology Massachusetts General Hospital Professor of Pathology Harvard Medical School Boston, Massachusetts

Alexander J. Gallan, MD

Renal and Genitourinary Pathologist Assistant Professor Department of Pathology Medical College of Wisconsin Milwaukee, Wisconsin

David G. Hicks, MD

Professor and Director of IHC-ISH Laboratory and Breast Subspecialty Service University of Rochester Medical Center Rochester, New York

Mai P. Hoang, MD

Professor of Pathology Harvard Medical School Director, Dermatopathology Services Massachusetts General Hospital Boston, Massachusetts

Yin Rex Hung, MD, PhD Assistant in Pathology Department of Pathology Massachusetts General Hospital Boston, Massachusetts

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Jochen K. Lennerz, MD, PhD

Medical Director Center for Integrated Diagnostics Associate Chief, Department of Pathology Massachusetts General Hospital Associate Professor Harvard Medical School Boston, Massachusetts

Susan C. Lester, MD, PhD Associate Pathologist Breast Pathology Services Brigham and Women’s Hospital Assistant Professor Harvard Medical School Boston, Massachusetts

Alexander Craig MacKinnon, MD, PhD Director Division of Genomics, Diagnostics, and Bioinformatics Professor Department of Pathology University of Alabama at Birmingham Birmingham, Alabama

Fabiola Medeiros, MD

Director of Gynecologic, Placental and Perinatal Pathology Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles, California

Mari Mino-Kenudson, MD

Pathologist, Department of Pathology Director, Pulmonary Pathology Massachusetts General Hospital Professor of Pathology Harvard Medical School Boston, Massachusetts

Michelle Menon Miyake, MD Otolaryngologist Research Fellow Department of Otolaryngology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, Massachusetts

Valentina Nardi, MD

Assistant Professor of Pathology Harvard Medical School Assistant in Pathology Massachusetts General Hospital Boston, Massachusetts

G. Petur Nielsen, MD

Professor of Pathology Harvard Medical School Pathologist, Department of Pathology Director of Bone & Soft Tissue Pathology Director of Electron Microscopy Unit Massachusetts General Hospital Boston, Massachusetts

Patricia Nogueira de Sa, MD Internal Medicine Residency Program Rochester General Hospital Rochester, New York

Additional Contributing Authors Carla Martins Alberti, MD Lori A. Erickson, MD Larissa V. Furtado, MD Joel K. Greenson, MD Julie Guilmette, MD Gregory Y. Lauwers, MD M. Beatriz S. Lopes, MD, PhD Alexandros D. Polydorides, MD, PhD Von Samedi, MD, PhD Karen S. Thompson, MD Arthur S. Tischler, MD

Gladell P. Paner, MD, (BS) MT

Associate Professor of Pathology and Surgery, Section of Urology Director of Genitourinary Pathology Fellowship Director of Point of Care Testing Associate Director UC Medlabs The University of Chicago Medical Center Chicago, Illinois

Fausto J. Rodríguez, MD

Associate Professor of Pathology, Oncology and Ophthalmology Johns Hopkins University School of Medicine Baltimore, Maryland

Amitabh Srivastava, MD

Associate Professor of Pathology Harvard Medical School Chief, GI Pathology Associate Director, Surgical Pathology Director, Surgical Pathology Fellowship Program Brigham and Women’s Hospital Boston, Massachusetts

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Preface Welcome to the second edition of Diagnostic Pathology: Familial Cancer Syndromes! The expanding use of gene sequencing (as NGS) technologies and our insight in neoplasmpredisposing genes has greatly impacted our understanding of cancer initiation and progression. Neoplasms that were formerly considered sporadic have been now redefined as part of novel hereditary cancer predisposition syndromes. The proportion of tumors with a hereditary background, and the list of hereditary cancer syndromes and cancer-predisposing genes, has been steadily increasing. Presently, at least 10% of all tumors develop in the setting of germline predispositions. Diagnostic Pathology: Familial Cancer Syndromes, second edition, features a comprehensive review of the top inherited tumor syndromes. It is becoming increasingly well recognized that a given familial tumor syndrome may be very heterogeneous in clinical appearance, where patients may present initially with an apparently isolated tumor. It is crucial for clinicians, oncologists, and surgical pathologists to be aware of the specific clinical and morphological findings that suggest a possible syndromic association. A significant number of the hereditary neoplasms have distinct and reproducible morphological and immunophenotypic, as well as molecular, findings. Written by clinicians, molecular pathologists, and subspecialty pathology experts focused on familial diseases, this book’s 166 chapters will help clinicians, oncologists, surgical pathologists, fellows, and residents understand the critical aspects of diagnosing familial tumors and differentiating these from their sporadic counterparts. The book is organized into three parts. The first part, “Diagnoses Associated With Syndromes by Organ,” discusses in detail the diseases encompassing the syndromes, highlighting the characteristics of the tumors in each organ across the different syndromes. The book points out some of the distinct characteristics of tumors found in inherited tumor syndromes that distinguish these tumors from tumors in a sporadic setting. This part also contains tables that can be used as a quick tumor classification reference. The second part, “Overview of Syndromes,” has detailed descriptions of the major syndromes, including genes involved, associated tumors, and diagnostic criteria. We have also included several newly defined cancer syndromes. Finally, the third part, “Reference,” offers a detailed index of each gene referenced in the book and in which chapters each gene appears. We hope that this second edition of Diagnostic Pathology: Familial Cancer Syndromes will guide you to master diagnostic criteria when diagnosing tumors associated with inherited tumor syndromes.

Vania Nosé, MD, PhD Associate Chief of Pathology Director of Anatomic and Molecular Pathology Massachusetts General Hospital Professor of Pathology Harvard Medical School Boston, Massachusetts

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Acknowledgments LEAD EDITOR

Arthur G. Gelsinger, MA TEXT EDITORS

Nina I. Bennett, BA Rebecca L. Bluth, BA Terry W. Ferrell, MS Megg Morin, BA Kathryn Watkins, BA IMAGE EDITORS

Jeffrey J. Marmorstone, BS Lisa A. M. Steadman, BS MEDICAL EDITORS

Daniel C. Chung, MD Jochen K. Lennerz, MD, PhD Alexander Craig MacKinnon, MD, PhD ILLUSTRATIONS

Richard Coombs, MS Lane R. Bennion, MS Laura C. Wissler, MA ART DIRECTION AND DESIGN

Tom M. Olson, BA PRODUCTION COORDINATORS

Emily C. Fassett, BA John Pecorelli, BS

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Sections PART I: Diagnoses Associated With Syndromes by Organ SECTION 1: Blood and Bone Marrow SECTION 2: Bone and Soft Tissue SECTION 3: Breast SECTION 4: Endocrine SECTION 5: Gastrointestinal SECTION 6: Genitourinary SECTION 7: Gynecology SECTION 8: Head and Neck SECTION 9: Nervous System SECTION 10: Pulmonary SECTION 11: Skin

PART II: Overview of Syndromes SECTION 1: Introduction SECTION 2: Syndromes

PART III: Reference SECTION 1: Molecular Factors

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TABLE OF CONTENTS

Part I: Diagnoses Associated With Syndromes by Organ 4

6

14 18 22 28 32 36

92

Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma Valentina Nardi, MD Blood and Bone Marrow Table Valentina Nardi, MD

104

Chondrosarcoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Chordoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Malignant Peripheral Nerve Sheath Tumor G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Osteosarcoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Rhabdomyosarcoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Schwannoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Bone and Soft Tissue Table G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD

SECTION 3: BREAST 46 54

88

SECTION 1: BLOOD AND BONE MARROW

SECTION 2: BONE AND SOFT TISSUE 10

ADRENAL MEDULLA AND PARAGANGLIA

Breast Carcinoma Susan C. Lester, MD, PhD and David G. Hicks, MD Breast Table David G. Hicks, MD and Susan C. Lester, MD, PhD

114

PANCREAS 118 128

58 62 70 78 84

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Adrenal Cortical Adenoma Vania Nosé, MD, PhD Adrenal Cortical Carcinoma Vania Nosé, MD, PhD and Julie Guilmette, MD Adrenal Cortical Neoplasms in Children Vania Nosé, MD, PhD Primary Pigmented Nodular Adrenocortical Disease Vania Nosé, MD, PhD Adrenal Cortex Table Vania Nosé, MD, PhD

Pancreatic Neuroendocrine Neoplasms Vania Nosé, MD, PhD Endocrine Pancreas Table Vania Nosé, MD, PhD

PARATHYROID 130 136 142 152

Parathyroid Adenoma Vania Nosé, MD, PhD and Lori A. Erickson, MD Parathyroid Carcinoma Vania Nosé, MD, PhD and Lori A. Erickson, MD Primary Parathyroid Hyperplasia Lori A. Erickson, MD and Vania Nosé, MD, PhD Parathyroid Table Vania Nosé, MD, PhD

PITUITARY 158 164 166

SECTION 4: ENDOCRINE ADRENAL CORTEX

Adrenal Medullary Hyperplasia Vania Nosé, MD, PhD Neuroblastic Tumors of Adrenal Gland Vania Nosé, MD, PhD Pheochromocytoma and Paraganglioma Vania Nosé, MD, PhD and Arthur S. Tischler, MD Adrenal Medulla and Paraganglia Table Vania Nosé, MD, PhD

Pituitary Adenoma M. Beatriz S. Lopes, MD, PhD and Vania Nosé, MD, PhD Pituitary Hyperplasia M. Beatriz S. Lopes, MD, PhD Pituitary Table Vania Nosé, MD, PhD

THYROID, MEDULLARY 170 176 186

C-Cell Hyperplasia Vania Nosé, MD, PhD Medullary Thyroid Carcinoma Vania Nosé, MD, PhD Thyroid, Medullary Carcinoma Table Vania Nosé, MD, PhD

THYROID, NONMEDULLARY 188 200

Familial Thyroid Carcinoma Vania Nosé, MD, PhD Follicular Thyroid Carcinoma Vania Nosé, MD, PhD

TABLE OF CONTENTS 208

Thyroid, Nonmedullary Carcinoma Table Vania Nosé, MD, PhD

308

SECTION 5: GASTROINTESTINAL HEPATOBILIARY AND PANCREAS 212 218 222 226

Hepatoblastoma Larissa V. Furtado, MD and Karen S. Thompson, MD Hepatocellular Carcinoma Amitabh Srivastava, MD Pancreatic Adenocarcinoma Amitabh Srivastava, MD and Von Samedi, MD, PhD Biliary Tract/Liver/Pancreas Table Amitabh Srivastava, MD

312

320

PROSTATE 326 338

TUBULAR GUT 228 234 236 238 244 252 262 268 270

Colonic Adenomas Ying-Hsia Chu, MD and Vikram Deshpande, MD Esophageal Adenocarcinoma Ying-Hsia Chu, MD and Vikram Deshpande, MD Esophageal Squamous Cell Carcinoma Ying-Hsia Chu, MD and Vikram Deshpande, MD Gastric Adenocarcinoma Ying-Hsia Chu, MD and Vikram Deshpande, MD Gastrointestinal Stromal Tumor Ying-Hsia Chu, MD and Vikram Deshpande, MD Hamartomatous Polyposis Syndromes Vania Nosé, MD, PhD and Amitabh Srivastava, MD Small Bowel Adenocarcinoma Ying-Hsia Chu, MD and Vikram Deshpande, MD Colon/Rectum Table Joel K. Greenson, MD and Amitabh Srivastava, MD Esophagus/Stomach/Small Bowel Table Ying-Hsia Chu, MD and Vikram Deshpande, MD

274 282

Bladder Urothelial Carcinoma Gladell P. Paner, MD, (BS) MT Bladder Table Gladell P. Paner, MD, (BS) MT

348 350

358 362

290 294

296

300 304

Germ Cell Tumor Gladell P. Paner, MD, (BS) MT Sertoli Cell Neoplasms Gladell P. Paner, MD, (BS) MT Testicle Table Gladell P. Paner, MD, (BS) MT

SECTION 7: GYNECOLOGY 370 372 374 380 384

Angiomyolipoma Gladell P. Paner, MD, (BS) MT Clear Cell Renal Cell Carcinoma Gladell P. Paner, MD, (BS) MT Cystic Nephroma Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT HLRCC Syndrome-Associated Renal Cell Carcinoma Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Papillary Renal Cell Carcinoma Gladell P. Paner, MD, (BS) MT Renal Oncocytoma, Chromophobe, and Hybrid Tumors Gladell P. Paner, MD, (BS) MT

Renal Urothelial Carcinoma Gladell P. Paner, MD, (BS) MT Ureter Urothelial Carcinoma Gladell P. Paner, MD, (BS) MT Renal Pelvis and Ureter Table Gladell P. Paner, MD, (BS) MT

TESTICLE 352

KIDNEY 286

Prostate Carcinoma Gladell P. Paner, MD, (BS) MT Prostate Table Gladell P. Paner, MD, (BS) MT

RENAL PELVIS AND URETER 344

SECTION 6: GENITOURINARY BLADDER

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Wilms Tumor Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Kidney Table Gladell P. Paner, MD, (BS) MT

Cervical Carcinoma Fabiola Medeiros, MD Fallopian Tube Carcinoma Fabiola Medeiros, MD Ovarian Tumors Fabiola Medeiros, MD Endometrial Carcinoma Fabiola Medeiros, MD Gynecologic Tumors Fabiola Medeiros, MD

SECTION 8: HEAD AND NECK 390 394 400 404

Endolymphatic Sac Tumor Vania Nosé, MD, PhD Head and Neck Squamous Cell Carcinoma Vania Nosé, MD, PhD Head and Neck Table Vania Nosé, MD, PhD Salivary Glands Table Vania Nosé, MD, PhD

SECTION 9: NERVOUS SYSTEM 412

Central Nervous System Fausto J. Rodríguez, MD

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TABLE OF CONTENTS 416 420

Eye Fausto J. Rodríguez, MD Peripheral Nervous System Fausto J. Rodríguez, MD

SECTION 10: PULMONARY 426 432

434 438 442 444

Adenocarcinoma, Lung Mari Mino-Kenudson, MD Adenocarcinoma With Lepidic (Bronchioloalveolar) Predominant Pattern Mari Mino-Kenudson, MD Lymphangioleiomyomatosis Mari Mino-Kenudson, MD Neuroendocrine Tumor, Lung Mari Mino-Kenudson, MD and Yin Rex Hung, MD, PhD Pleuropulmonary Blastoma Mari Mino-Kenudson, MD and Yin Rex Hung, MD, PhD Lung Table Mari Mino-Kenudson, MD

522 524 528 536 540 542

546 548 556 560

SECTION 11: SKIN 448 450 456 460 466 472

BAP1-Inactivated Melanocytic Tumor Mai P. Hoang, MD Basal Cell Carcinoma Mai P. Hoang, MD Cutaneous Melanoma Mai P. Hoang, MD Cutaneous Squamous Cell Carcinoma Mai P. Hoang, MD Sebaceous Carcinoma Mai P. Hoang, MD Skin Table Mai P. Hoang, MD

Part II: Overview of Syndromes SECTION 1: INTRODUCTION 476 484

494

502 504 506 510 518

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Pathology of Familial Tumor Syndromes Vania Nosé, MD, PhD Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes Vania Nosé, MD, PhD and Daniel C. Chung, MD Molecular Aspects of Familial/Hereditary Tumor Syndromes Alexander Craig Mackinnon, MD, PhD

564

568

576 578 584 586 590 596

600 602 604

SECTION 2: SYNDROMES

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Ataxia Telangiectasia Fausto J. Rodríguez, MD BAP1 Tumor Predisposition Syndrome Mai P. Hoang, MD Basal Cell Nevus Syndrome/Gorlin Syndrome Mai P. Hoang, MD Beckwith-Wiedemann Syndrome Vania Nosé, MD, PhD and Patricia Nogueira de Sa, MD Birt-Hogg-Dubé Syndrome Mai P. Hoang, MD

608 610 616 620

Bloom Syndrome Valentina Nardi, MD Brooke-Spiegler Syndrome Mai P. Hoang, MD Carney Complex Vania Nosé, MD, PhD Colonic Carcinoma Syndromes Joel K. Greenson, MD and Amitabh Srivastava, MD Costello Syndrome Mai P. Hoang, MD Denys-Drash Syndrome Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Diamond-Blackfan Anemia Valentina Nardi, MD DICER1 Syndrome Vania Nosé, MD, PhD and Michelle Menon Miyake, MD Down Syndrome Valentina Nardi, MD Dyskeratosis Congenita Mai P. Hoang, MD Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome Valentina Nardi, MD Familial Adenomatous Polyposis Alexandros D. Polydorides, MD, PhD and Vania Nosé, MD, PhD Familial Chordoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Familial Gastrointestinal Stromal Tumor Vania Nosé, MD, PhD and Daniel C. Chung, MD Familial Infantile Myofibromatosis G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Familial Isolated Hyperparathyroidism Vania Nosé, MD, PhD Familial Nonmedullary Thyroid Carcinoma Vania Nosé, MD, PhD Familial Paraganglioma Pheochromocytoma Syndrome Vania Nosé, MD, PhD and Arthur S. Tischler, MD Familial Testicular Tumor Gladell P. Paner, MD, (BS) MT Familial Uveal Melanoma Fausto J. Rodríguez, MD Familial Wilms Tumor Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Fanconi Anemia Valentina Nardi, MD Glucagon Cell Hyperplasia and Neoplasia Vania Nosé, MD, PhD Breast/Ovarian Cancer Syndrome: BRCA1 Susan C. Lester, MD, PhD and David G. Hicks, MD Breast/Ovarian Cancer Syndrome: BRCA2 David G. Hicks, MD and Susan C. Lester, MD, PhD Hereditary Diffuse Gastric Cancer Joel K. Greenson, MD and Daniel C. Chung, MD

TABLE OF CONTENTS 624

628 630 632 636 640 642

650 652 656 658 660

662 668

674 680

686 692 696 704 712 718 720 728 734 736

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Hereditary Mixed Polyposis Syndrome Joel K. Greenson, MD Multiple Osteochondromas G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Hereditary Neuroblastoma Vania Nosé, MD, PhD Hereditary Pancreatic Cancer Syndrome Daniel C. Chung, MD and Vania Nosé, MD, PhD Hereditary Papillary Renal Cell Carcinoma Gladell P. Paner, MD, (BS) MT Hereditary Paraganglioma/Pheochromocytoma Syndromes Vania Nosé, MD, PhD Hereditary Prostate Cancer Gladell P. Paner, MD, (BS) MT Hereditary Renal Epithelial Tumors, Others Gladell P. Paner, MD, (BS) MT Hereditary Retinoblastoma Fausto J. Rodríguez, MD Hereditary SWI/SNF Complex Deficiency Syndromes Fausto J. Rodríguez, MD Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer Mai P. Hoang, MD Hyperparathyroidism-Jaw Tumor Syndrome Vania Nosé, MD, PhD Juvenile Polyposis Syndrome Daniel C. Chung, MD, Gregory Y. Lauwers, MD, and Amitabh Srivastava, MD Li-Fraumeni Syndrome David G. Hicks, MD and Susan C. Lester, MD, PhD Lynch Syndrome Joel K. Greenson, MD, Daniel C. Chung, MD, and Vania Nosé, MD, PhD McCune-Albright Syndrome Vania Nosé, MD, PhD Melanoma/Pancreatic Carcinoma Syndrome Mai P. Hoang, MD Multiple Endocrine Neoplasia Type 1 (MEN1) Vania Nosé, MD, PhD Multiple Endocrine Neoplasia Type 2 (MEN2) Vania Nosé, MD, PhD and Michelle Menon Miyake, MD Multiple Endocrine Neoplasia Type 4 (MEN4) Vania Nosé, MD, PhD and Michelle Menon Miyake, MD MUTYH-Associated Polyposis Vania Nosé, MD, PhD Neurofibromatosis Type 1 Vania Nosé, MD, PhD and Michelle Menon Miyake, MD Neurofibromatosis Type 2 Fausto J. Rodríguez, MD Nijmegen Breakage Syndrome Valentina Nardi, MD Pancreatic Neuroendocrine Tumor Syndromes Vania Nosé, MD, PhD

744 750 758 762 766 770 772 774 780 782 790 794

796 798

Hamartomatous Polyps, Peutz-Jeghers Gregory Y. Lauwers, MD and Amitabh Srivastava, MD PTEN-Hamartoma Tumor Syndromes Vania Nosé, MD, PhD RASopathies: Noonan Syndrome Valentina Nardi, MD Rhabdoid Predisposition Syndrome Fausto J. Rodríguez, MD Schwannomatosis Fausto J. Rodríguez, MD Shwachman-Diamond Syndrome Valentina Nardi, MD Steatocystoma Multiplex Mai P. Hoang, MD Tuberous Sclerosis Complex Fausto J. Rodríguez, MD Tumor Syndromes Predisposing to Osteosarcoma G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD von Hippel-Lindau Syndrome Vania Nosé, MD, PhD and Carla Martins Alberti, MD Werner Syndrome/Progeria Mai P. Hoang, MD Wilms Tumor-Associated Syndromes Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) MT Wiskott-Aldrich Syndrome Valentina Nardi, MD Xeroderma Pigmentosum Mai P. Hoang, MD

Part III: Reference SECTION 1: MOLECULAR FACTORS 804

Molecular Factors Index Vania Nosé, MD, PhD

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Nosé SECOND EDITION

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PART I SECTION 1

Blood and Bone Marrow Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma Blood and Bone Marrow Table

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Diagnoses Associated With Syndromes by Organ: Blood and Bone Marrow

Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma KEY FACTS

CLINICAL ISSUES • Acute lymphoblastic leukemia (ALL) ○ Not exclusively sporadic disease ○ Risk of developing B-acute lymphoblastic leukemia (BALL) is 2-4x increased among siblings of affected children • Number of genetic alterations that predispose individuals to development of ALL is growing • Children with ALL should have thorough history and focused physical exam or be referred to screen for potential familial syndrome • Implications for preimplantation genetic diagnosis, management of patient and relatives, screening of related stem cell donors

DIAGNOSTIC CHECKLIST • Familial B-ALL due to ○ Germline PAX5 mutations ○ Germline ETV6 mutations or deletions ○ Germline SH2B3 mutations

○ Germline IKZF1 mutations • ALL as manifestations of genetic syndromes ○ Li-Fraumeni syndrome ○ Down syndrome ○ Wiskott-Aldrich syndrome ○ Bloom syndrome ○ Ataxia telangiectasia syndrome ○ Constitutional mismatch repair syndrome ○ Nijmegen breakage syndrome ○ Familial platelet disorder due to RUNX1 mutations ○ Fanconi anemia ○ Neurofibromatosis type 1 ○ Noonan syndrome • Genetic predisposition to lymphoma ○ No known syndromes predisposing exclusively to lymphomas ○ Syndromes leading to immunodeficiency can predispose to NHL

B-ALL/Lymphoma in Bone Marrow

B-ALL/Lymphoma Morphology

B-ALL/Lymphoma in Bone Marrow Aspirate

B-ALL/Lymphoma in Lymph Node

(Left) Bone marrow is 100% cellular. Hematopoietic marrow is replaced by blasts with high nuclear:cytoplasmic ratio conferring the blue appearance at low power. (Right) Lymphoid blasts can have irregular nuclear contours mimicking myeloid blasts. The chromatin is vesicular, and distinct nucleoli can be seen.

(Left) High-power view shows bone marrow involved by BALL. The cellularity consists of sheets of small- to mediumsized blasts, with scant cytoplasm, slightly indented, irregular nuclei, fine chromatin, and occasional distinct nucleoli. (Right) Sheets of immature cells with open chromatin and distinct nucleoli consistent with blasts are filling the sinuses and replacing the parenchyma.

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Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

Abbreviations • Acute lymphoblastic leukemia (ALL) • Non-Hodgkin lymphoma (NHL)

ETIOLOGY/PATHOGENESIS ALL as Manifestation of Genetic Syndromes • Li-Fraumeni (pediatric hypodiploid B-ALL) • Down syndrome (often characterized by somatic CRLF2 rearrangements) • Wiskott-Aldrich syndrome • Bloom syndrome • Ataxia telangiectasia: T-ALL > B-ALL • Constitutional mismatch repair syndrome • Nijmegen breakage syndrome: T-ALL > B-ALL • Familial platelet disorder with predisposition to myeloid malignancy due to RUNX1 mutations (T-ALL) • Fanconi anemia • Neurofibromatosis type I • Noonan syndrome

Familial B-ALL Secondary to Germline Mutations in Genes Somatically Mutated in ALL • • • •

PAX5 ETV6 SH2B3 IKZF1

Genetic Predisposition to Lymphoma • Currently no known syndromes predisposing exclusively to lymphomas (mostly NHL) • Syndromes leading to immunodeficiency can predispose to NHL ○ Ataxia telangiectasia (also at risk for Hodgkin lymphoma) ○ Bloom syndrome ○ Nijmegen breakage syndrome ○ Wiskott Aldrich syndrome ○ Constitutional mismatch repair syndrome

CLINICAL ISSUES Familial B-ALL Due to Germline PAX5 Mutations • B-cell transcription factor paired box protein PAX5 is essential for normal B-cell development • PAX5 is somatically deleted, rearranged, or otherwise mutated in ~ 30% of sporadic B-ALL • Heterozygous hypomorph germline mutations (i.e., p.Gly183Ser) need somatic loss of wild-type PAX5 allele to be leukemogenic

Familial B-ALL Due to Germline ETV6 Mutations or Deletions • ETV6 is ETS family transcriptional repressor essential for bone marrow haematopoiesis • Many germline ETV6 variants have dominant negative effect on transcriptional repression mediated by wild-type protein • Heterozygous germline mutations in ETV6 are associated with thrombocytopenia and predisposition to B-ALL with hyperdiploid karyotype

• 25-30% of patients with germline ETV6 mutations will develop B-ALL; in addition some may develop solid tumors &/or myeloid malignancies

Familial B-ALL Due to Germline SH2B3 Mutations • SH2B adaptor protein 3 (SH2B3) gene (a.k.a. LNK) encodes negative regulator of cytokine signaling and tyrosine kinases • SH2B3 plays critical role in development and function of hematopoietic stem cells and lymphoid progenitors • Biallelic germline loss of function mutations in SH2B3 are associated with familial developmental delay, autoimmunity, and B-ALL • ALL with sporadic or germline SH2B3 mutations, may be sensitive to kinase inhibitors or agents inhibiting activated JAK-STAT pathway

Familial B-ALL Due to Germline IKZF1 Mutations • IKZF1 encodes zinc finger transcription factor IKAROS, critical regulator of lymphoid development • ~ 0.9% of presumed sporadic pediatric B-ALL will have germline IKZF1 variants • Germline IKZF1 variants tend to cluster outside known annotated functional domains • Germline IKZF1 alterations predispose to ALL, with variable penetrance, and potentially reduce response to chemotherapy and kinase inhibitors • Some patients with germline IKZF1 variants have B lymphopenia

Diagnoses Associated With Syndromes by Organ: Blood and Bone Marrow

TERMINOLOGY

MICROSCOPIC Histologic Features • Histologically indistinguishable from pediatric sporadic acute lymphoblastic leukemia/lymphoma and from sporadic Hodgkin and non-Hodgkin lymphomas

ANCILLARY TESTS Genetic Testing • Targeted gene sequencing to detect point mutations, insertions and deletions • Microarrays, multiplex ligation-dependent probe amplification-based (MLPA), or next-generation sequencing assays to detect large-scale genomic rearrangements &/or deletions • Preferred tissue for germline genetic testing in patients with hematologic malignancy are cultured skin fibroblasts

SELECTED REFERENCES 1. 2. 3. 4. 5.

Pui CH et al: Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nat Rev Clin Oncol. 16(4):227-40, 2019 Rampersaud E et al: Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood Adv. 3(7):1039-46, 2019 Churchman ML et al: Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell. 33(5):937-48.e8, 2018 Auer F et al: Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia. 28(5):1136-8, 2014 Perez-Garcia A et al: Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood. 122(14):2425-32, 2013

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Diagnoses Associated With Syndromes by Organ: Blood and Bone Marrow

Blood and Bone Marrow Table Germline Mutations and Conditions Associated With Increased Risk of Hematological Malignancies Disorder

Genes

Inheritance

Hematologic Malignancy

Nonhematological Malignancies

Additional Clinical Findings

Fanconi anemia

FANCA, FANCB*, AR FANCC, FANCD1 * X-linked (BRCA2), FANCD2, ** AD FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1/BACH1), FANCL, FANCM, FANCN (PALB2), FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4), FANCR (RAD51)**, FANCS (BRCA1), FANCT (UBE2T), FANCU (XRCC2), FANCV (MAD2L2/REV7)

MDS, AML, [ALL Squamous cell with FANCD1 carcinomas of head and (BRCA2)] neck, vulva, GI tract; liver tumors; brain tumors and Wilms tumor [FANCD1 (BRCA2)]

Short stature, skin pigmentation, skeletal and thumb abnormalities, facial dysmorphisms, renal, gonadal, cardiac, GI, and CNS abnormalities

Diamond-Blackfan anemia

RPL5, RPL11, RPL15, AD RPL23, RPL 26, RPL27, RPL31, RPL35A, RPL36, RPS7, RPS10, RPS15, RPS17, RPS19, RPS24, RPS26, RPS27, RPS27A, RPS28, RPS29, GATA1   TSR2

MDS, AML

Osteosarcoma, soft tissue sarcomas

Macrocytic anemia, short stature, thumb abnormalities, facial dysmorphisms, cleft lip/palate, Pierre Robin syndrome, cardiac and genitourinary abnormalities

X-linked X-linked

6

Dyskeratosis congenita

DKC1 TERC TERT NOLA3/NOP10 NOLA2/NHP2 TINF2 WRAP53/TCAB1 CTC1 RTEL1 ACD/TPP1 PARN NAF1 STN1

X-linked AD AD, AR AR AR AD AR AR AD, AR AD, AR AD, AR AD AD

MDS, AML, AA

Squamous cell carcinomas of head and neck, GI tract

Nail dystrophy, rash, leukoplakia, short stature, pulmonary fibrosis, vascular anomalies, early graying of hair, hair loss; dental, CNS, GI and GU abnormalities

Shwachman-Diamond syndrome

SBDS

AR

MDS, AML

-

Short stature, steatorrhea, metaphyseal dysostosis

Severe congenital neutropenia

ELANE HAX1

AD AR

MDS, AML

-

Neurological abnormalities

Familial MDS/AML with mutated GATA2

GATA2

AD

MDS, AML, CMML

-

Warts, atypical mycobacteria, lymphedema, deafness, pulmonary alveolar proteinosis, arteriovenous malformations

MIRAGE syndrome

SAMD9

AD

MDS, AML

-

Short stature, adrenal hypoplasia, infections; CNS, GI, GU, and skeletal abnormalities

Ataxia-pancytopenia syndrome

SAMD9L

AD

MDS, AML

-

Ataxia (variable)

Myeloid neoplasm with mutated

SRP72

AD

MDS

-

Sensorineural hearing loss

Blood and Bone Marrow Table

Disorder

Genes

Inheritance

Hematologic Malignancy

Nonhematological Malignancies

Additional Clinical Findings

Familial MDS/AML with mutated DDX41

DDX41

AD

MDS, AML

-

-

Familial platelet disorder with propensity to myeloid malignancy

RUNX1

AD

MDS, AML, ALL

-

Thrombocytopenia and abnormal platelet function

Thrombocytopenia 2

ANKRD26

AD

MDS, AML

-

Thrombocytopenia and abnormal platelet function

Thrombocytopenia 5

ETV6

AD

ALL, MDS, AML

-

Thrombocytopenia and abnormal platelet function

Familial AML with CEBPA mutation

CEBPA

AD

AML

-

-

Li-Fraumeni

TP53

AD

ALL, MDS, AML

Breast, soft tissue sarcomas, brain, adrenocortical carcinoma, lung, colon, pancreas, Wilms, prostate

-

Susceptibility to ALL3  

PAX5

AD

ALL

-

-

Constitutional mismatch repair deficiency syndrome

MLH1 PMS2 MSH2 MSH6

AR AR AR AR

Lymphoma, ALL, AML

CNS, GI tract, other

Café au lait spots, axillary freckling, Lisch nodules, neurofibromas, intestinal adenomas

Wiskott Aldrich

WAS

X-linked

Lymphoma, leukemia

Nijmegen breakage syndrome

NBN

AR

Lymphoma

Gliomas, rhabdomyosarcoma, medulloblastoma

Severe microcephaly, abnormal facies, other malformations

Bloom syndrome

BLM

AR

Lymphoma, MDS, ALL

Colon, skin cancer, squamous cell carcinomas of head and neck, Wilms tumor,  and others, at early age

Facial rash with butterfly distribution, other dermatologic manifestations, chronic obstructive lung disease, endocrine abnormalities

Ataxia telangiectasia

ATM

AR

Lymphoma, leukemia

Solid tumors

-

Noonan syndrome

PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1

AD

JMML

Rhabdomyosarcoma, neuroblastoma

Short stature, macrocephaly, feeding difficulty, cardiac defects, other

SRP72 

Diagnoses Associated With Syndromes by Organ: Blood and Bone Marrow

Germline Mutations and Conditions Associated With Increased Risk of Hematological Malignancies (Continued)

Thrombocytopenia, neutropenia, eczema, infections, autoimmune disorders

AD = autosomal dominant; AR = autosomal recessive; A 90% of all chondrosarcomas • Atypical cartilaginous tumor can be treated conservatively with curettage

MACROSCOPIC

• > 90% of cases sporadic ○ Somatic mutations in IDH1/IDH2 in 50-60% and COL2A1 in 20-40% of tumors • Secondary cases associated with enchondromatosis/osteochondromatosis ○ Enchondromatosis

• Permeation of medullary cavity, scalloping of endosteal surface, cortical thickening

MICROSCOPIC • Infiltration of preexisting trabecular bone is single most important histologic criterion • Histologic grading (grades 1, 2, and 3) is prognostic

Pelvic Chondrosarcoma

Pelvic Chondrosarcoma

Chondrosarcoma

Conventional Chondrosarcoma in Proximal Tibia

(Left) Axial CT shows a large chondrosarcoma ﬊ arising from the left iliac wing with scattered ring and arc mineralization st. (Right) Gross photograph shows pelvic chondrosarcoma in the same patient. The tumor is lobulated with a blue-gray cut surface ſt; adjacent residual normal bone can be seen ﬇.

(Left) Radiograph shows a chondrosarcoma in the proximal tibia with ill-defined border and characteristic ring and arc mineralization ﬉. (Right) Gross photograph shows conventional chondrosarcoma with a bluegray cut surface in the same patient.

10

Chondrosarcoma

Definitions • Malignant cartilaginous matrix-producing tumor of bone ○ Primary chondrosarcoma: Arises in medullary cavity (conventional type) or on bone surface (periosteal/juxtacortical type) ○ Secondary chondrosarcoma: Arises from preexisting benign tumor (e.g., enchondroma, osteochondroma) or diseased bone (e.g., radiation, Paget disease) ○ Atypical cartilaginous tumor: Low-grade cartilaginous tumor in appendicular skeleton with microscopic appearance identical to grade 1 chondrosarcoma ○ Dedifferentiated chondrosarcoma: High-grade nonchondrogenic sarcoma juxtaposed to areas of lowgrade cartilaginous tumor

ETIOLOGY/PATHOGENESIS Sporadic • > 90% of cases • Rarely arise associated with solitary sporadic/nonsyndromic osteochondroma • 50-60% of cases harbor somatic mutations in isocitrate dehydrogenase IDH1 or IDH2 • 20-40% of cases harbor somatic mutations in major cartilage collagen gene COL2A1

Hereditary Multiple Exostosis/Osteochondromatosis • Autosomal dominant ○ Mutations in EXT1 (8q24) or EXT2 (11p11) ○ As part of trichorhinophalangeal syndrome type 2 (Langer-Giedion syndrome) – Disruption/microdeletion of genes including EXT1 ○ As part of Potocki-Schaffer syndrome – Disruption/microdeletion of genes including EXT2 • Develop multiple exostoses/osteochondromas often by 2nd decade of life • Risk of malignant transformation 2-25%

Enchondromatosis • Sporadic (Ollier disease, Maffucci syndrome) or familial (metachondromatosis) ○ Ollier disease and Maffucci syndrome – Somatic postzygotic mutation in isocitrate dehydrogenase genes IDH1 or IDH2 – Maffucci syndrome differs from Ollier disease with additional development of vascular tumors (spindle cell hemangiomas) – Risk of malignant transformation up to 35-40% ○ Metachondromatosis – Autosomal dominant – Develops multiple enchondromas and osteochondromas – Germline PTPN11 loss-of-function mutation – Risk of malignant transformation unclear

CLINICAL ISSUES Site • Arise in bone derived from endochondral ossification

• Most commonly pelvis (especially ilium), followed by proximal/distal femur, proximal humerus, and ribs ○ In long bones, chondrosarcoma usually involves metaphysis or diaphysis • Rarely (< 1%) develops in small bones of hands and feet • Chondrosarcomas of cranium usually involve skull base • Secondary chondrosarcomas: Arise in association with preexisting osteochondromas/enchondromas

Presentation • Pain, enlarging mass, &/or pathologic fracture • Skull-based tumors: Headache, cranial nerve palsies • Abrupt mass enlargement and worsening of clinical symptoms in preexisting osteochondromas/enchondromas

Treatment • Curettage for atypical cartilaginous tumor • Wide surgical resection for grade 1 chondrosarcomas arising in axial skeleton and high-grade chondrosarcoma • Adjuvant chemotherapy considered in dedifferentiated chondrosarcomas • Radiation considered in surgically unresectable tumors

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

TERMINOLOGY

Prognosis • Histologic grade is single most important prognostic factor • Atypical cartilaginous tumors show excellent prognosis with conservative surgical curettage treatment • Grade 1 chondrosarcomas are locally aggressive ○ 5-year survival ~ 80-85% • Grades 2-3 chondrosarcomas show worse prognosis ○ 5-year survival ~ 50% • Dismal prognosis in dedifferentiated chondrosarcomas ○ Median survival < 1-2 years, frequent metastases

IMAGING Radiographic Findings • Lytic with irregular spiculations and radiodensities caused by matrix calcification • Densities often in "rings and arcs" configuration indicative of endochondral ossification and reactive bone formation • Low-grade tumors often show mineralization, bone expansion, endosteal scalloping, and thickening of cortex • High-grade tumors often show large radiolucency, cortical destruction/permeation, frequently accompanied by soft tissue extension

MR Findings • • • •

Helpful in visualizing tumor extent, particularly in soft tissue Dark on T1WI Bright on T2WI Cartilage cap of > 2 cm in osteochondroma may raise concern for malignant transformation but not entirely sufficient • Contrast enhancement may aid in distinguishing secondary chondrosarcoma from preexisting osteochondroma/enchondroma

CT Findings • Unmineralized and mineralized components of tumor delineated in medullary or cortical lesion

11

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Chondrosarcoma

MACROSCOPIC General Features • Low-grade tumors permeate medullary cavity, scallop endosteal surface, and produce cortical thickening • High-grade tumors destroy cortex and extend into soft tissue, frequently associated with elevated periosteum • Neoplastic hyaline cartilage appears gray-blue and glistening • Mineralized matrix appears as punctate, chalk-like deposits • Myxoid matrix appears translucent, gray, mucoid-to-watery • Chondrosarcoma arising in osteochondroma shows thick cartilage cap and frequent cystic changes • Areas of dedifferentiation appear firm and fleshy

MICROSCOPIC Histologic Features • Infiltrative growth pattern encasing preexisting trabecular bone is single most important diagnostic criterion • Diverse histologic subtypes: Conventional (hyaline or myxoid), clear cell, dedifferentiated, mesenchymal • Conventional hyaline type ○ Hyaline cartilaginous matrix: Homogeneous, pink ○ Neoplastic chondrocytes vary in size with moderate eosinophilic-to-vacuolated cytoplasm in lacunar spaces • Conventional myxoid type ○ Myxoid cartilaginous matrix frothy, bubbly, basophilic ○ Bipolar-to-stellate cells singly or in cords and strands • Clear cell ○ Low-grade subtype, abundant clear cytoplasm • Mesenchymal ○ Sheets of round to spindled cells with scant cytoplasm admixed with nodules of hyaline cartilage ○ Recurrent HEY1-NCOA2 fusion • Dedifferentiated ○ Transition from typically low-grade cartilaginous tumor to high-grade nonchondrogenic sarcoma • Infiltration of preexisting bony trabeculae most helpful clue in recognizing malignant transformation • Histologic grading (grades 1, 2, and 3) important prognostic factor ○ Based on cellularity and degree of cytologic atypia

DIFFERENTIAL DIAGNOSIS

• Recurrent GRM1 gene rearrangement in subset of tumors

Chondroid Chordoma • Usually arises in skull base • Can be difficult to differentiate from low-grade chondrosarcoma • Expresses both keratin and T-brachyury (not expressed by chondrosarcoma)

Chondroblastic Osteosarcoma • Osteoid deposition • Chondrogenic component is typically high grade • Lacks mutations in IDH1/IDH2 (whereas 50-60% of chondrosarcomas harbor IDH1/IDH2 mutations)

Fracture Callus • Small nodules of cartilages often with pronounced endochondral ossification • May simulate malignancy based on histologic appearance • Correlation with radiologic features aids recognition

SELECTED REFERENCES 1. 2. 3.

4. 5.

6. 7. 8.

9.

10.

11. 12.

13.

Enchondroma • No infiltrative pattern or extension into soft tissue • Relatively paucicellular and lacks significant cytologic atypia

14.

Osteochondroma

15.

• No infiltrative pattern or extension into soft tissue • Characteristic stalk with cortical and medullary continuity • Thin cartilaginous cap, typically < 2 cm

16.

Chondromyxoid Fibroma

17.

• Radiographically and histologically nonaggressive and wellcircumscribed • Fibromyxoid stroma with conspicuous small staghorn blood vessels • Spindled-shaped cells and frequent osteoclast-type giant cells 12

18.

de Andrea CE et al: Integrating morphology and genetics in the diagnosis of cartilage tumors. Surg Pathol Clin. 10(3):537-52, 2017 Andreou D et al: Metastatic potential of grade I chondrosarcoma of bone: results of a multi-institutional study. Ann Surg Oncol. 23(1):120-5, 2016 DeLaney TF et al: Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. 110(2):115-22, 2014 Nord KH et al: GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nat Genet. 46(5):474-7, 2014 Kerr DA et al: Molecular distinction of chondrosarcoma from chondroblastic osteosarcoma through IDH1/2 mutations. Am J Surg Pathol. 37(6):787-95, 2013 Tarpey PS et al: Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat Genet. 45(8):923-6, 2013 Vanel D et al: Enchondroma vs. chondrosarcoma: a simple, easy-to-use, new magnetic resonance sign. Eur J Radiol. 82(12):2154-60, 2013 Yang W et al: Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature. 499(7459):491-5, 2013 de Andrea CE et al: Interobserver reliability in the histopathological diagnosis of cartilaginous tumors in patients with multiple osteochondromas. Mod Pathol. 25(9):1275-83, 2012 Amary MF et al: IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 224(3):334-43, 2011 Amary MF et al: Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. 43(12):1262-5, 2011 Pansuriya TC et al: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 43(12):1256-61, 2011 Verdegaal SH et al: Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist. 16(12):1771-9, 2011 Lin PP et al: Secondary chondrosarcoma. J Am Acad Orthop Surg. 18(10):608-15, 2010 Eefting D et al: Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol. 33(1):50-7, 2009 Porter DE et al: Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 86(7):1041-6, 2004 Bovée JV et al: Chondrosarcoma of the phalanx: a locally aggressive lesion with minimal metastatic potential: a report of 35 cases and a review of the literature. Cancer. 86(9):1724-32, 1999 Rosenberg AE et al: Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma. Am J Surg Pathol. 23:1370-8, 1999

Chondrosarcoma Chondrosarcoma Arising in Association With Enchondromatosis (Left) Radiograph shows the proximal femur in a patient with Ollier disease, with multiple intramedullary cartilaginous lesions in the form of ring and arc mineralization ſt, associated with an adjacent large chondrosarcoma ﬇. (Right) Gross photograph of proximal femur in the same patient shows multiple blue-gray intramedullary nodules st, consistent with Ollier disease. An expansile, fleshy chondrosarcoma ﬊ is also present.

Chondrosarcoma With Permeative Pattern

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Chondrosarcoma With Enchondromatosis

Clear Cell Chondrosarcoma (Left) A helpful histologic clue to the diagnosis of chondrosarcoma is the presence of permeation. Chondrosarcoma shows infiltration of normal trabecular bone ﬊. (Right) Clear cell chondrosarcoma is a histologic subtype with prominent clear-cell changes with abundant clear cytoplasm and variably hyperchromatic nuclei.

Dedifferentiated Chondrosarcoma

Mesenchymal Chondrosarcoma (Left) Dedifferentiated chondrosarcoma comprises a high-grade sarcoma ﬊ juxtaposed to a low-grade cartilaginous tumor st. Here, both components infiltrate among preexisting bony trabeculae ﬈. (Right) Mesenchymal chondrosarcoma characteristically shows sheets-to-nodules of small blue cells ſt intermixed with small aggregates of cartilaginous nodules ﬊.

13

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Chordoma KEY FACTS

TERMINOLOGY

IMAGING

• Primary malignant tumor of bone that shows notochordal differentiation and usually arises within axial skeleton

• Destructive lytic lesion • Invariably extends into soft tissues

ETIOLOGY/PATHOGENESIS

MACROSCOPIC

• Benign notochordal cell tumor (BNCT) thought to be precursor lesion to chordoma • Mutation in TBXT implicated in both somatic and familial chordomas

• Gelatinous, lobulated, and well delineated • Solid and fish flesh-like in dedifferentiated chordomas

CLINICAL ISSUES • Accounts for ~ 1-3% of primary malignant bone tumors • Usually diagnosed in patients 30-70 years old, rarely children or infants • Primarily involves axial skeleton with soft tissue extension • Treated by surgery &/or radiotherapy, generally with limited role for chemotherapy • Median overall survival 5-7 years for most chordomas but < 1 year for dedifferentiated chordomas

MICROSCOPIC • Histologically classified into 4 groups: Conventional, chondroid, dedifferentiated, and poorly differentiated • Conventional chordomas show epithelioid cells with vacuolated bubbly "physaliferous" cells in myxoid stroma • Chondroid chordomas have areas that mimic hyaline-type chondrosarcomas • Dedifferentiated chordomas contain areas of high-grade sarcoma and portend worst prognosis • Poorly differentiated chordomas defined by loss of SMARCB1/INI1 expression

Sacrococcygeal Chordoma

Sacrococcygeal Chordoma

Conventional Chordoma With Physaliferous Cells

T-Brachyury Expression in Chordoma

(Left) Chordomas most commonly involve the sacrococcygeal region ﬇ in the distal coccyx with considerable soft tissue extension. (Right) Sagittal section of the same tumor in the distal coccyx demonstrates a well-circumscribed, gelatinous mass with multinodular architecture and a patchy red-brown area, consistent with hemorrhage.

(Left) Tumor cells in conventional chordoma often show prominent intracytoplasmic, pale to clear vacuoles, which give rise to a bubbly appearance (so-called physaliferous cells). (Right) Chordomas express Tbrachyury, a transcription factor involved in notochord development and regulation. While nuclear staining ﬈ is seen in chordoma cells, background inflammatory and endothelial cells are negative ﬊.

14

Chordoma

Definitions • Chordoma: Primary malignant tumor of bone showing notochordal differentiation and arising usually in axial skeleton • Chondroid chordoma: Showing areas of hyaline matrix, resembling low-grade hyaline-type chondrosarcoma • Dedifferentiated chordoma: Showing areas of high-grade sarcoma juxtaposed to conventional chordoma • Poorly differentiated chordoma: Showing loss of SMARCB1/INI1 expression

ETIOLOGY/PATHOGENESIS Sporadic • Thought to arise from notochordal remnants • Benign notochordal cell tumor (BNCT) may be precursor lesion to chordoma • Associated with somatic TBXT duplication &/or mutations in growth factor signaling pathways • Poorly differentiated chordoma with SMARCB1 deletion &/or mutation

Familial • Associated with germline TBXT duplication • Chordoma of childhood/infancy reported in tuberous sclerosis complex (germline mutations in TSC1/TSC2) • Germline mutations in DNA repair machinery BRCA2, NBN, or CHEK2

CLINICAL ISSUES Epidemiology • Incidence ○ < 1 per 1 million ○ 1-3% of primary malignant bone tumors • Age ○ Median 60 years, range usually 30-70 years ○ Earlier in familial chordomas (30-50 years) ○ 5% of chordomas seen in patients < 20 years ○ Chordomas in children/infancy often in skull base, occasionally in setting of tuberous sclerosis complex • Sex ○ Slight male predominance for sacral chordoma ○ Slight female predominance for skull base chordoma

Treatment • Surgery and preoperative/postoperative radiotherapy • No established role for chemotherapy in conventional or chondroid chordomas ○ Chemotherapy may be used in managing dedifferentiated or poorly differentiated chordomas

Prognosis • Depends on histology ○ Best prognosis in conventional and chondroid chordomas – Median overall survival 5-7 years ○ Poorly differentiated chordomas show median survival of 4.4 years ○ Worst prognosis in dedifferentiated chordoma – Median overall survival < 1 year, usually rapidly fatal with disseminated disease • Depends on tumor location, size, and resectability ○ Best prognosis seen in sacral chordomas with complete resection and negative margin • Metastatic chordoma seen in < 5-40% of patients ○ Commonly to lung, skin, and bone

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

○ Mobile spine: Pain, neurologic symptoms, compression fracture ○ Sacrum: Pain, constipation, incontinence, bladder dysfunction

TERMINOLOGY

IMAGING Radiographic Findings • • • •

Lytic and destructive Extends into adjacent soft tissue Calcifications may be seen In sacrococcygeal chordomas, soft tissue component is usually anterior ○ May displace rectum and extend along sacral nerve roots into sciatic notch

MR Findings • Bright, lobulated-appearing on T2WI • Foci of calcification are frequent • Soft tissue extension is better delineated

CT Findings • Destructive and radiolucent bone lesion • Calcifications may be seen

Site • Primarily arises within axial skeleton ○ ~ 60% in sacrococcygeal region ○ ~ 30% in skull base ○ ~ 10% in cervical, lumbar, or thoracic spine ○ Rarely reported outside axial skeleton • Chondroid chordoma predominantly in skull base • Dedifferentiated chordoma usually in sacrococcygeal region • Poorly differentiated chordoma most often in skull base

Presentation • Depends on tumor site ○ Skull base: Headache, diplopia, cranial nerve defects

MACROSCOPIC General Features • Soft, lobulated, tan-gray, gelatinous to mucoid • Well delineated from surrounding tissues • Dedifferentiated chordoma appears variegated with solid, fish flesh-like appearance similar to soft tissue sarcomas • Poorly differentiated chordoma lacks mucoid areas but instead often shows hemorrhage and necrosis

Size • Skull-base tumors typically small (< 5 cm) • Sacrococcygeal tumors often large (up to > 20 cm)

15

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Chordoma

MICROSCOPIC Histologic Features • 4 histologic types: Conventional, chondroid, dedifferentiated, and poorly differentiated ○ Similar histologic appearance in familial and sporadic chordomas • Conventional chordoma shows lobular pattern, infiltrates marrow space, encases preexisting bony trabeculae, and usually breaches cortex, forming demarcated soft tissue mass ○ Composed of large epithelioid cells arranged in cohesive nests and cords ○ Nuclei are of moderate size and may contain small nucleolus or pseudoinclusions ○ Moderate eosinophilic to clear cytoplasm ○ Physaliferous cells with numerous small, intracytoplasmic vacuoles that impart bubbly appearance – Physaliferous cells not pathognomonic of chordoma, as other tumor types may have similar-appearing cells and some chordomas lack them ○ One tumor cell may wrap or "hug" another ○ Pleomorphism and spindling of tumor cells may be present ○ Basophilic and myxoid extracellular matrix ○ Mitotic activity usually limited ○ Foci of necrosis common, especially in large tumors • Chondroid chordoma contains chondroid component and areas of conventional chordoma ○ Chondroid component composed of hyaline matrix, with similar appearance to hyaline cartilage, containing neoplastic cells in lacunar-like spaces ○ Chondroid component abruptly abuts or merges with conventional component ○ Quantity of chondroid component variable – Chondroid areas may predominate in some chordomas, thus difficult to distinguish from chondrosarcomas • Dedifferentiated chordoma shows biphasic appearance with high-grade sarcoma juxtaposed to conventional chordoma ○ High-grade sarcoma may show diverse histology: Pleomorphic, osteosarcomatous, rhabdomyosarcomatous, or fibrosarcoma-like • Poorly differentiated chordoma shows epithelioid tumor cells with eccentric nuclei ○ Myxoid matrix is absent ○ Lack of SMARCB1/INI1 expression with presence of brachyury expression is diagnostic • BNCT may be seen adjacent to chordoma, suggesting malignant transformation

○ T-brachyury expression absent in high-grade component of dedifferentiated chordoma • Poorly differentiated chordoma shows loss of SMARCB1/INI1 expression in addition

DIFFERENTIAL DIAGNOSIS Metastatic Adenocarcinoma • Mucinous adenocarcinoma mimic chordoma on small biopsy sample • Mucinous adenocarcinoma is negative for T-brachyury and S100 protein; these markers are positive in chordoma

Chondrosarcoma • Distinction between chordoma and chondrosarcoma can be difficult on small biopsies, especially from skull base • Chondrosarcoma is negative for T-brachyury and cytokeratins; these markers are positive in chordoma

Benign Notochordal Cell Tumor • Generally confined to bone with no soft tissue involvement • Radiographically sclerotic with no contrast enhancement; whereas chordoma appears lytic • Lacks extracellular myxoid matrix, which is present in conventional chordoma • Cells with abundant clear (adipocyte-like) to eosinophilic cytoplasm • Identical immunohistochemical profile as chordoma

Ecchordosis Physaliphora • Proliferation of fetal notochordal remnants • Circumscribed, generally < 3 cm, mostly in retroclival region • Shows epithelioid vacuolated cells and myxoid stroma, microscopically almost identical to chordoma • Identical immunohistochemical profile as chordoma • Distinction relies on radiologic correlation

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5.

6. 7. 8.

9.

ANCILLARY TESTS

10.

Immunohistochemistry • Consistent expression of cytokeratins and epithelial membrane antigen • Variable expression of S100 protein • Consistent expression of T-brachyury

16

11. 12. 13.

Gröschel S et al: Defective homologous recombination DNA repair as therapeutic target in advanced chordoma. Nat Commun. 10(1):1635, 2019 Shih AR et al: Clinicopathologic characteristics of poorly differentiated chordoma. Mod Pathol. 31(8):1237-45, 2018 Tarpey PS et al: The driver landscape of sporadic chordoma. Nat Commun. 8(1):890, 2017 Rotondo RL et al: High-dose proton-based radiation therapy in the management of spine chordomas: outcomes and clinicopathological prognostic factors. J Neurosurg Spine. 23(6):788-97, 2015 Choy E et al: Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 9(7):e101283, 2014 Le LP et al: Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 6(5):e18846, 2011 Yang XR et al: T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet. 41(11):1176-8, 2009 Deshpande V et al: Intraosseous benign notochord cell tumors (BNCT): further evidence supporting a relationship to chordoma. Am J Surg Pathol. 31(10):1573-7, 2007 Vujovic S et al: Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 209(2):157-65, 2006 Rosenberg AE et al: Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma. Am J Surg Pathol. 23:1370-8, 1999 O'Connell JX et al: Base of skull chordoma. A correlative study of histologic and clinical features of 62 cases. Cancer. 74(8):2261-7, 1994 Coffin CM et al: Chordoma in childhood and adolescence. A clinicopathologic analysis of 12 cases. Arch Pathol Lab Med. 117(9):927-33, 1993 Meis JM et al: "Dedifferentiated" chordoma. A clinicopathologic and immunohistochemical study of three cases. Am J Surg Pathol. 11(7):516-25, 1987

Chordoma

Conventional Chordoma (Left) Chordomas generally involve midline bony structures. A typical location for chordoma (~ 30% of cases) is at the base of skull in the region of clivus ﬊. (Right) On low power, conventional chordoma shows a lobulated growth pattern, with fibrous band ﬊ and epithelioid tumor cells amidst prominent myxoid stroma ﬊.

Chondroid Chordoma

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Skull Base Chordoma

Dedifferentiated Chordoma (Left) Chondroid chordoma most often arises in the skull base and shows areas of hyaline-type chondroid matrix, which can be a histologic mimic of chondrosarcoma. (Right) Dedifferentiated chordoma, characterized by a high-grade sarcoma ﬊ juxtaposed to areas of conventional chordoma ﬊, is highly aggressive.

Poorly Differentiated Chordoma

Loss of INI1 Expression in Poorly Differentiated Chordoma (Left) Poorly differentiated chordoma shows sheets of epithelioid cells with abundant cytoplasm. Necrosis is often present ﬈. Unlike conventional chordoma, myxoid stroma is not a feature. Poorly differentiated chordoma expresses Tbrachyury (not shown). (Right) Poorly differentiated chordoma characteristically shows loss of INI1 expression with lack of nuclear staining in the tumor cells ﬊, whereas intact expression can be seen in the control stromal and inflammatory cells ﬈.

17

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Malignant Peripheral Nerve Sheath Tumor KEY FACTS

TERMINOLOGY • Sarcoma arising from nerve or benign nerve sheath tumor or showing nerve sheath cellular differentiation

ETIOLOGY/PATHOGENESIS • 50% associated with neurofibromatosis type 1 (NF1) • 10% associated with radiation • Mutations in polycomb complex (EED, SUZ12) or tumor suppressors (CDKN2A, TP53)

CLINICAL ISSUES • • • • •

Mostly adults, younger in NF1-associated cases Most arise in major nerve trunks 5-year survival 15-40% Local recurrence > 40% Metastasis 30-60%, commonly to lungs and bones

MICROSCOPIC • Spindle-cell MPNST (80%)

○ Alternating hypercellular/hypocellular areas ("marbled") ○ Fascicles of spindle cells, variable pleomorphism ○ Perivascular accentuation of tumor cells around vessels • Heterologous differentiation (15%) • Epithelioid MPNST (5%)

ANCILLARY TESTS • Immunohistochemistry: Focal S100, SOX10, GFAP • Loss of H3K27Me3 in ~ 50% of conventional MPNST • Loss of SMARCB1 in ~ 70% of epithelioid MPNST

TOP DIFFERENTIAL DIAGNOSES • • • • • •

Synovial sarcoma Malignant melanoma Clear cell sarcoma Cellular schwannoma Atypical neurofibroma Atypical neurofibromatous neoplasm of uncertain biologic potential

MPNST Arising in Plexiform Neurofibroma

Radiation-Associated MPNST

MPNST With "Marbled" Pattern

Spindle Cells in Conventional MPNST

(Left) Grossly, malignant peripheral nerve sheath tumor (MPNST) shows a yellow-tan, fleshy cut surface, often with necrosis and hemorrhage ﬉. This MPNST arises in a plexiform neurofibroma ſt in a patient with neurofibromatosis type 1 (NF1). (Right) About 10% of MPNST arises in patients with history of prior therapeutic radiation. This radiationassociated MPNST involves the sciatic nerve ﬇.

(Left) MPNST often shows fascicles of spindle cells in alternating hypercellular and hypocellular areas within the tumor, giving a "marbled" histologic appearance. (Right) MPNST typically shows fascicles of spindle cells with variably hyperchromatic nuclei in a myxoid-to-collagenous stromal background. Conspicuous mitoses may be seen.

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Malignant Peripheral Nerve Sheath Tumor

Abbreviations • Malignant peripheral nerve sheath tumor (MPNST)

Synonyms • Neurofibrosarcoma, neurogenic sarcoma, malignant schwannoma

Definitions • Diagnostic criteria (1 of following) ○ Sarcoma arising from nerve or benign nerve sheath tumor (e.g., neurofibroma) ○ Sarcoma with histologic features of nerve sheath differentiation in patients with neurofibromatosis type 1 (NF1) ○ Sarcoma with histologic and immunophenotypic or ultrastructural evidence of nerve sheath differentiation in patients without NF1

ETIOLOGY/PATHOGENESIS Genetic Predisposition • 50% of tumors associated with NF1 ○ Lifetime incidence of MPNST in NF1 patients: 8-15% • 40% of tumors sporadic

Environmental Exposure • 10% of tumors associated with radiation exposure

Molecular Pathogenesis • NF1 characterized by germline mutation in NF1 ○ MPNST tumorigenesis accelerated by somatic loss of 2nd NF1 allele • Recurrent mutations in polycomb repressive complex 2 (PRC2) components: EED or SUZ12 ○ Subsequent loss of histone 3 lysine 27 trimethylation marks (H3K27Me3) • Recurrent mutations in tumor suppressors CDKN2A (p16) &/or TP53 (p53) • Inactivating mutation in SMARCB1 in ~ 70% of epithelioid MPNST

CLINICAL ISSUES Epidemiology • Rare, 3-10% of soft tissue sarcomas • Mostly adults ○ Wide age range: ~ 10-70 years ○ Average age in NF1 patients: ~ 30 years (vs. ~ 40 years in sporadic cases) • No sex predilection

Site • Most commonly deep-seated soft tissue: Thigh, buttock, trunk, upper extremities, followed by retroperitoneum, head and neck • Most arise in major nerves: Sciatic nerve, followed by brachial plexus, sacral plexus, and paraspinal nerves

Presentation • Painful mass • Neurological deficit

Treatment • Surgical approaches ○ Wide excision/resection or amputation • Adjuvant therapy ○ Radiation ○ Chemotherapy, though generally less effective

Prognosis • Depends on age, tumor location, size, and histologic grade ○ Superior survival in pediatric and intracranial MPNST ○ Worse survival in central and head/neck MPNST (more common in NF1 patients) • 5-year overall survival 15-40% • Local recurrence > 40% • Metastasis 30-60% ○ Most commonly to lungs, bones, &/or pleura

IMAGING General Features

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

TERMINOLOGY

• Large, heterogeneous, fusiform mass associated with major nerve trunk • Tumor necrosis seen on MR suggests MPNST rather than neurofibroma in NF1 patients

MACROSCOPIC General Features • Fusiform or eccentric mass associated with major nerve or nerve trunk • Color/consistency similar to other soft tissue sarcomas ○ Gray-tan, firm to fleshy ○ Necrosis and hemorrhage common

Size • Usually > 5 cm, sometimes massive > 20 cm

MICROSCOPIC Histologic Features • Mostly high grade, < 20% low grade • Some arising from preexisting benign nerve sheath tumor ○ Most commonly from neurofibroma (usually NF1 patients), rarely schwannoma, ganglioneuroma, and others • Histologic types: Conventional/spindle cell (80%), heterologous differentiation (15%), and epithelioid (5%) ○ Conventional/spindle-cell MPNST – Alternating hypercellular and hypocellular areas ("marbled" pattern) – Fascicles of spindle cells, variable pleomorphism – Perivascular accentuation of tumor cells around small vessels – Extensive necrosis common, mitoses frequent ○ MPNST with heterologous differentiation – Rhabdomyosarcomatous (malignant triton tumor) – Osteosarcomatous, chondrosarcomatous, angiosarcomatous, etc. ○ Epithelioid MPNST – Lobules of large epithelioid cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli 19

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Malignant Peripheral Nerve Sheath Tumor – Associated with schwannomatosis and germline SMARCB1 mutation

ANCILLARY TESTS Immunohistochemistry • Conventional MPNST ○ Positive for S100, typically focal, in 20-60% of cases ○ Positive for SOX10 &/or GFAP in 20-60% of cases ○ Complete loss of H3K27Me3 in ~ 50% of cases • Epithelioid MPNST ○ Diffusely positive for S100 in all cases ○ Complete loss of SMARCB1/INI1 nuclear staining in ~ 70% of cases

DIFFERENTIAL DIAGNOSIS

Atypical Neurofibromatous Neoplasm of Uncertain Biologic Potential • Schwann cell neoplasm with at least 2 of following ○ Cytologic atypia ○ Loss of neurofibroma architecture ○ Hypercellularity ○ Mitotic activity > 1/50 HPF to < 3/10 HPF

SELECTED REFERENCES 1.

2.

3.

Synovial Sarcoma • Usually uniformly hypercellular (rather than "marbled" pattern with alternations of cellularity in MPNST) • Immunohistochemistry ○ Usually positive for cytokeratin, EMA, and TLE1 ○ Generally negative for S100 and SOX10 • Gene fusion between SS18 (formerly SYT) and SSX1, SSX2, or SSX4 in nearly all cases

4.

5.

6.

Malignant Melanoma • Typically superficial dermal tumors ○ Sometimes metastasize/involve deep-seated locations • Presence of melanoma in situ component or melanin pigments can be helpful clues • Immunohistochemistry ○ Diffusely positive for S100 ○ Positive for melanocytic markers HMB45, Melan-A, and MiTF • BRAF V600E mutation in some cases

7. 8.

9.

10.

Clear Cell Sarcoma

11.

• Predilection for acral sites • Nests of uniform epithelioid-to-spindly cells, prominent nucleoli, rare scattered multinucleated giant cells • Immunohistochemistry ○ Diffusely positive for S100 ○ Positive for HMB45 • EWSR1-ATF1 or EWSR1-CREB1 gene fusion in most cases

12.

Cellular Schwannoma

16.

• Common locations: Retroperitoneum, pelvis, posterior mediastinum, or gastrointestinal tract • Dominated by Antoni A (cellular) areas • May show focal necrosis, mitosis, &/or degenerative atypia with smudgy nuclei • Immunohistochemistry ○ Diffusely positive for S100 and SOX10

13. 14. 15.

17.

18.

19.

Atypical Neurofibroma • Cytologic atypia ("ancient neurofibroma") or hypercellularity • Retain neurofibroma architecture with characteristic collagen bundles ("shredded carrots" pattern)

20

20.

Martin E et al: Treatment and survival differences across tumor sites in malignant peripheral nerve sheath tumors: a SEER database analysis and review of the literature. Neurooncol Pract. 6(2):134-43, 2019 Schwabe M et al: How effective are noninvasive tests for diagnosing malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1? Diagnosing MPNST in NF1 patients. Sarcoma. 2019:4627521, 2019 Yan P et al: Nomograms for predicting the overall and cause-specific survival in patients with malignant peripheral nerve sheath tumor: a populationbased study. J Neurooncol. 143(3):495-503, 2019 Makise N et al: Clarifying the distinction between malignant peripheral nerve sheath tumor and dedifferentiated liposarcoma: a critical reappraisal of the diagnostic utility of MDM2 and H3K27me3 Status. Am J Surg Pathol. 42(5):656-64, 2018 Le Guellec S et al: Loss of H3K27 trimethylation is not suitable for distinguishing malignant peripheral nerve sheath tumor from melanoma: a study of 387 cases including mimicking lesions. Mod Pathol. 30(12):1677-87, 2017 Miettinen MM et al: Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in neurofibromatosis 1 patients - a consensus overview. Hum Pathol. 67:1-10, 2017 Pekmezci M et al: Significance of H3K27me3 loss in the diagnosis of malignant peripheral nerve sheath tumors. Mod Pathol. 30(12):1710-9, 2017 Cleven AH et al: Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol. 29(6):582-90, 2016 Le Guellec S et al: Malignant peripheral nerve sheath tumor is a challenging diagnosis: a systematic pathology review, immunohistochemistry, and molecular analysis in 160 patients from the French Sarcoma Group Database. Am J Surg Pathol. 40(7):896-908, 2016 Prieto-Granada CN et al: Loss of H3K27me3 expression is a highly sensitive marker for sporadic and radiation-induced MPNST. Am J Surg Pathol. 40(4):479-89, 2016 Röhrich M et al: Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 131(6):877-87, 2016 Schaefer IM et al: Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 29(1):413, 2016 Jo VY et al: Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases. Am J Surg Pathol. 39(5):673-82, 2015 Lee W et al: PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 46(11):1227-32, 2014 Zhang M et al: Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet. 46(11):1170-2, 2014 Rahrmann EP et al: Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat Genet. 45(7):756-66, 2013 Carter JM et al: Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with "neuroblastoma-like" schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol. 36(1):154-60, 2012 Terry J et al: TLE1 as a Diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies. Am J Surg Pathol. 31(2):240-6, 2007 Birindelli S et al: Rb and TP53 pathway alterations in sporadic and NF1related malignant peripheral nerve sheath tumors. Lab Invest. 81(6):833-44, 2001 Perry A et al: NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J Pathol. 159(1):57-61, 2001

Malignant Peripheral Nerve Sheath Tumor Focal S100 Expression in Conventional MPNST (Left) The tumor cells in conventional MPNST show spindle morphology and tapered nuclei, suggestive of neural differentiation. (Right) S100 expression is often focal in conventional MPNST and is only seen in 20-60% of cases. This is in contrast to schwannoma, which shows strong, diffuse nuclear staining for S100 in all cases.

MPNST With Heterologous Differentiation

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Spindle Cells in Conventional MPNST

Rhabdomyoblasts in Malignant Triton Tumor (Left) MPNST can show heterologous elements, such as this example with osteosarcomatous and chondrosarcomatous differentiation. (Right) A subset of MPNSTs harbors heterologous elements such as rhabdomyoblasts, which are tumor cells with abundant eosinophilic cytoplasm showing skeletal muscle differentiation; these are known as malignant triton tumors.

Epithelioid MPNST

Loss of INI1 in Epithelioid MPNST (Left) Epithelioid MPNST shows nodules to sheets of epithelioid tumor cells with prominent nucleoli. Diffuse S100 expression (not shown) is seen in epithelioid MPNST but not in most conventional MPNST. (Right) Epithelioid MPNST shows loss of SMARCB1/INI1 expression in 70% of cases. This example shows loss of INI1 nuclear staining in the tumor cells, whereas the stromal and inflammatory cells retain INI1 expression.

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Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Osteosarcoma KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• High-grade malignant tumor in which neoplastic cells produce bone

• Most patients are young, between 10 and 20 years • Distal femur > proximal tibia > proximal humerus

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• Primary osteosarcomas arise de novo without known predisposing condition • Secondary osteosarcomas arise within diseased bone ○ Paget disease of bone ○ Radiation exposure ○ Chemotherapy ○ Trauma ○ Foreign body • Hereditary syndromes ○ Hereditary retinoblastoma: RB1 mutation ○ Li-Fraumeni syndrome: TP53 mutation ○ Rothmund-Thomson syndrome: RECQL4 mutation ○ Bloom syndrome: BLM mutation ○ Werner syndrome: WRN mutation

• Admixture of 2 elements in varying proportions ○ High-grade sarcoma with epithelioid, plasmacytoid, fusiform, ovoid, small-round, spindle, or clear cells; sometimes with multinucleated giant cells ○ Bone produced directly by tumor cells • Conventional osteosarcoma ○ Histologic variants: Osteoblastic, chondroblastic, fibroblastic, telangiectatic, giant cell, small cell, osteoblastoma-like, chondroblastoma-like, chondromyxoid fibroma-like • Other variants with distinct biological/clinical behavior ○ Parosteal osteosarcoma, periosteal osteosarcoma, welldifferentiated intramedullary osteosarcoma, osteosarcoma of craniofacial bones  

Osteosarcoma in Distal Femur

Osteosarcoma commonly arises in the region of the knee. Radiograph of an osteosarcoma in the distal femur demonstrates a destructive, bone-forming tumor ﬇ associated with pathologic fracture ſt.

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Osteosarcoma in Distal Femur

Gross photograph of the same patient shows a tan-yellow, fleshy mass involving the distal femur and adjacent soft tissue. A pathologic fracture is apparent ſt.

Osteosarcoma

Synonyms • Osteogenic sarcoma

Definitions • High-grade malignant tumor in which tumor cells produce bone

ETIOLOGY/PATHOGENESIS Neoplastic Process • Primary osteosarcomas arise de novo without known predisposing condition • Secondary osteosarcomas arise within diseased bone ○ Paget disease of bone ○ Radiation exposure ○ Chemotherapy ○ Trauma ○ Foreign body (e.g., orthopedic implants)

Genetic Susceptibility • Hereditary retinoblastoma: Germline mutation in RB1 • Li-Fraumeni syndrome: Germline mutation in TP53 • Rothmund-Thomson syndrome: Germline mutation in RECQL4 • Bloom syndrome: Germline mutation in BLM • Werner syndrome: Germline mutation in WRN

Molecular Pathogenesis • Frequent TP53 mutations • Subsets harbor amplification of PDGFRA, KDR, or VEGFA • Subsets harbor mutations in cell cycle/DNA repair regulators: RB1, BRCA2, or BAP1 • Genomic instability signature reminiscent of BRCA1/BRCA2deficient tumors

CLINICAL ISSUES Epidemiology • Incidence ○ Most common primary malignant tumor of bone, exclusive of hematopoietic malignancies – Accounts for ~ 20% of primary bone sarcomas ○ ~ 800 cases each year in USA • Age ○ Most patients are young, between 10 and 20 years – Females usually younger than males, probably due to earlier skeletal development ○ 2nd peak occurs in patients > 50 years (often secondary osteosarcoma) • Sex ○ M:F = 1.3:1.0

Site • Most commonly arises in long tubular bones ○ Distal femur > proximal tibia > proximal humerus – 50% of cases located in knee region • In older individuals, pelvis and axial skeleton are most common locations • < 10% occur in mandible and craniofacial bones

Presentation • Progressively enlarging, painful mass ○ Pain deep-seated and frequently noted months prior ○ Pain intensity increases over time, eventually unremitting • May appear as visible and palpable mass • Overlying skin may be warm, erythematous, edematous, and cartographed by prominent, engorged veins ○ Skin ulceration secondary to pressure ischemia can occur • Restricted range of motion in those with large tumors • Joint effusions when tumor involves epiphysis or periarticular structures • Weight loss and cachexia in patients with advanced disease • Pathologic fracture as heralding event in 5-10% of cases

Laboratory Tests • Elevated serum alkaline phosphatase

Treatment • Surgical approaches ○ Limb salvage; complete excision with wide negative margins is optimal – Biopsy tract often removed with tumor ○ Amputation necessary if major vessels and nerves compromised, if tumor involves region that cannot be reconstructed, or if large volumes of tissue contaminated by fracture or prior surgical intervention • Adjuvant therapy ○ Neoadjuvant &/or adjuvant chemotherapy often administered – Tumor may diminish in size – Tumor often undergoes extensive mineralization and develops pseudocapsule facilitating excision – Chemotherapeutic efficacy determined by histologic assessment of amount of induced tumor necrosis □ Induced tumor necrosis of ≥ 90% considered good response, important prognostic indicator • Drugs ○ High-dose methotrexate, doxorubicin, and cisplatin, &/or others • Radiation ○ Used for unresectable tumors because of size &/or site ○ Used in patients considered incurable with widely metastatic disease ○ Adjuvant radiation if excision associated with positive margins

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

TERMINOLOGY

Prognosis • Relapse-free survival rates 50-80% (median ~ 70%) • May vary by subtypes of conventional osteosarcoma ○ Chondroblastic variant associated with poor response to chemotherapy

IMAGING Radiographic Findings • Permeative and destructive • Centered around metaphysis of long bones ○ < 10% diaphyseal ○ Rarely epiphyseal • Poorly defined, lack of sclerotic rim • Mixed lytic and blastic mass transgressing cortex and forming large soft tissue components 23

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Osteosarcoma ○ 90% extend into soft issue • Matrix visible in 90% of cases ○ Periphery usually less mineralized than central area • Soft tissue components may have fine "cloud-like" pattern of radiodensity • Entirely lytic or sclerotic in some instances ○ Entirely lytic appearance characteristic of telangiectatic variant • Lower grade lesions tend to be more mineralized • Periosteal reaction ○ Appears as multiple layers (onion skin) or radiating (sunburst) appearance ○ Codman triangle: Periosteal reaction at diaphyseal end of tumor at angle created by cortex and elevated periosteum • Rarely, imaging appears deceptively benign

MR Findings • • • •

Heterogeneous metaphyseal mass Osteoid shows low signal on all sequences Helpful in detecting skip lesions in same or adjacent bone T1WI: Nonosteoid portions of tumor near isointense to skeletal muscle • Fluid-sensitive sequences: Appears heterogeneous

CT Findings • Useful in defining bone matrix • Useful in delineating tumor extent and surgical planning

Bone Scan • Increased activity in primary tumor and metastasis

MACROSCOPIC General Features • Intramedullary • Usually centered in metaphysis, but can involve any portion of bone • Tumors with abundant mineralized bone are tan-white and hard • Nonmineralized components are glistening and gray ○ May be mucinous if matrix is myxoid, or more rubbery if hyaline in nature • Areas of hemorrhage and cystic change ○ Can be extensive and produce friable, bloody, and spongy mass (telangiectatic osteosarcoma) • Usually destroys overlying cortex and forms eccentric or circumferential soft tissue component displacing periosteum peripherally • Dislodged periosteum becomes sharp interface between mass and bordering skeletal muscle and fat • Layer of reactive bone at proximal and distal regions where periosteum lifted from cortex • May grow into joint space ○ Growth may occur through synovium, via extension along cortical surface, or through tendoligamentous and joint capsule insertion sites • Open growth plates often function as effective barriers to advancing tumors ○ Penetration of physis and invasion through epiphysis to base of articular surface occurs in some cases 24

• Skip metastases appear as intramedullary firm, ovoid, tanwhite nodules located adjacent to or far from main mass • Variants of osteosarcoma confined to surface of bone uncommon

MICROSCOPIC Histologic Features • Admixture of 2 elements in varying proportions ○ High-grade sarcoma with epithelioid, plasmacytoid, fusiform, ovoid, small-round, spindle, or clear cells; sometimes with multinucleated giant cells ○ Bone matrix produced directly by tumor • Nuclei hyperchromatic, central or eccentric in position ○ Brisk mitotic activity, prominent nucleoli ○ Degree of atypia variable but frequently severe ○ Numerous mitoses, including atypical forms • Eosinophilic cytoplasm, variable in volume • Tumor cells intimately related to surface of neoplastic bone ○ Tumor cells diminish in size and appear less atypical as they are surrounded and imprisoned by matrix – In heavily mineralized portions, tumor cells lack atypia – This phenomenon is referred to as normalization • Neoplastic bone varies in quantity ○ Deposited as primitive disorganized trabeculae producing coarse lace-like pattern, or broad large sheets ○ Frequently mineralized ○ Neoplastic lamellar bone is very rare ○ Preexisting bony trabeculae function as scaffold for tumor growth in some cases • Bone is eosinophilic or basophilic and may have pagetoid appearance caused by haphazardly deposited cement lines • Histologic variants ○ Osteoblastic osteosarcoma ○ Chondroblastic osteosarcoma – Neoplastic cartilage is usually hyaline, but may be myxoid, particularly in tumors arising in jaw bones – Malignant chondrocytes demonstrate severe cytologic atypia ○ Fibroblastic osteosarcoma ○ Telangiectatic osteosarcoma ○ Giant cell-rich osteosarcoma ○ Small-cell osteosarcoma ○ Osteoblastoma-like osteosarcoma ○ Chondroblastoma-like osteosarcoma ○ Chondromyxoid fibroma-like osteosarcoma

DIFFERENTIAL DIAGNOSIS Fracture Callus • Bone rimmed by osteoblasts • Distribution zonal rather than haphazard • Fracture site shows fibrocartilage, finding not seen in either osteosarcoma or chondrosarcoma • Atypical mitotic figures not seen • Radiographic correlation essential

Osteoblastoma • Shows interconnecting trabeculae of tumor bone lined by plump osteoblasts

Osteosarcoma

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Delicate lace-like deposition of unmineralized eosinophilic matrix (osteoid) • At least focal bone production by malignant cells is necessary to render diagnosis of osteosarcoma • Ancillary tests do not help in identifying bone

Myositis Ossificans

Assessment of Chemotherapy Effect

• Both soft tissue and parosteal myositis ossificans may be mistaken for osteosarcoma • Distinct zonal pattern characteristic of myositis ossificans and not seen in osteosarcoma ○ Radiologically and grossly, center lacks mineralization, whereas periphery is mineralized ○ Microscopically, center shows granulation tissue/nodular fasciitis-like appearance, whereas periphery shows woven bone lined by osteoblasts with outermost layer of lamellar bone in mature lesions • Recently described to harbor USP6 rearrangement

• Complete or near-complete response (> 90% necrosis) associated with better survival • Assessment of necrosis should be performed by histologically evaluating central slice of tumor and sampling remaining halves • Extent of necrosis on preoperative chemotherapy may be used to alter postoperative regimen

Aneurysmal Bone Cyst

2.

• May mimic telangiectatic osteosarcoma • Cells in cyst wall not severely atypical • Presence of USP6 rearrangements may support aneurysmal bone cyst

Giant Cell Tumor of Bone • May show reactive woven bone formation in periphery • Bone lined by osteoblasts and not atypical tumor cells as in osteosarcoma • Most harbor histone H3F3A/H3F3B G34W mutation

Chondrosarcoma • Distinction from chondroblastic osteosarcoma can be challenging ○ Bone may be scarce in chondroblastic osteosarcomas and some gnathic osteosarcomas ○ Extensive sampling may reveal diagnostic foci of osteoid deposition or immature bone for osteosarcoma ○ Cartilaginous tumor with marked atypia, particularly in 2nd-3rd decades of life, is suspicious for osteosarcoma • Presence of IDH1 or IDH2 mutations favors chondrosarcoma rather than osteosarcoma

Dedifferentiated Chondrosarcoma • Characterized by low-grade cartilage juxtaposed to highgrade sarcoma (dedifferentiated component) ○ Dedifferentiated component may be osteosarcoma • Presence of IDH1 or IDH2 mutations favors chondrosarcoma rather than osteosarcoma

Ewing Sarcoma

SELECTED REFERENCES 1.

3.

4. 5. 6.

7.

8.

9.

10. 11. 12. 13. 14. 15. 16. 17.

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

• Distinction between osteoblastoma-like osteosarcoma and aggressive osteoblastoma can be challenging ○ Radiographic correlation essential ○ Features supporting diagnosis of osteosarcoma – Infiltration of preexisting bony trabeculae – Large size (> 5 cm) – Atypical mitotic figures – Prominent abundant lace-like bone deposition

Baumhoer D et al: An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 58(2):88-99, 2019 Suehara Y et al: Clinical genomic sequencing of pediatric and adult osteosarcoma reveals distinct molecular subsets with potentially targetable alterations. Clin Cancer Res. ePub, 2019 Švajdler M et al: Fibro-osseous pseudotumor of digits and myositis ossificans show consistent COL1A1-USP6 rearrangement: a clinicopathological and genetic study of 27 cases. Hum Pathol. 88:39-47, 2019 Hameed M et al: Tumor syndromes predisposing to osteosarcoma. Adv Anat Pathol. 25(4):217-22, 2018 Kovac M et al: Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 6:8940, 2015 Behjati S et al: Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013 Dec;45(12):1479-82. Epub 2013 Oct 27. Erratum in: Nat Genet. 46(3):316, 2014 Perry JA et al: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A. 111(51):E5564-73, 2014 Kerr DA et al: Molecular distinction of chondrosarcoma from chondroblastic osteosarcoma through IDH1/2 mutations. Am J Surg Pathol. 37(6):787-95, 2013 Deyrup AT et al: Sarcomas arising in Paget disease of bone: a clinicopathologic analysis of 70 cases. Arch Pathol Lab Med. 131(6):942-6, 2007 Mankin HJ et al: Survival data for 648 patients with osteosarcoma treated at one institution. Clin Orthop Relat Res. (429):286-91, 2004 Ozaki T et al: Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer. 102(4):355-65, 2002 Bridge JA et al: Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature. Cancer Genet Cytogenet. 95(1):74-87, 1997 Chow LT et al: Chondromyxoid fibroma-like osteosarcoma: a distinct variant of low-grade osteosarcoma. Histopathology. 29(5):429-36, 1996 Glasser DB et al: Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience. Cancer. 69(3):698-708, 1992 Unni KK et al: Osteosarcoma: pathology and classification. Semin Roentgenol. 24(3):143-52, 1989 Rosen G et al: Primary osteogenic sarcoma: eight-year experience with adjuvant chemotherapy. J Cancer Res Clin Oncol. 106 Suppl:55-67, 1983 Dahlin DC et al: Osteosarcoma of bone and its important recognizable varieties. Am J Surg Pathol. 1(1):61-72, 1977

• Small cell variant of osteosarcoma mimic Ewing sarcoma • Presence of EWSR1 rearrangements (present in ~ 95% of cases) supports Ewing sarcoma

Metastatic Carcinoma • Metastatic carcinoma from breast or prostate may evoke robust osteoblastic reaction, mimicking osteosarcoma

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Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Osteosarcoma

Osteosarcoma in Proximal Humerus

Osteosarcoma

Osteosarcoma in Proximal Humerus

Treated Osteosarcoma With Necrosis

Osteosarcoma Encasing Preexisting Bone

Sclerotic Osteosarcoma With Permeative Growth Pattern

(Left) Radiograph of an osteosarcoma in the proximal humerus illustrates ill-defined central densities ſt corresponding to the calcifications present in this tumor. Codman triangle ﬇ indicative of a prominent periosteal reaction and soft tissue extension by tumor is present. (Right) Axial STIR MR in the same osteosarcoma in the proximal humerus illustrates a tumor forming a circumferential soft tissue mass.

(Left) Gross photograph shows osteosarcoma involving the proximal humerus in the same patient. The raised periosteum ﬇ corresponds to the radiographic findings of the Codman triangle. (Right) After treatment, this osteosarcoma in the proximal femur shows residual bone ﬊. The tumor demonstrates an infiltrative growth pattern, encasing preexisting bony trabeculae ſt. Treatment effect is present, with extensive tumor necrosis ﬉.

(Left) In osteosarcoma, tumor cells occasionally grow in sheets st, infiltrating among preexisting trabecular bone ﬊. (Right) In osteosarcoma, neoplastic bone st can sometimes be seen being built along preexisting native trabecular bone ﬊ as scaffolds, giving rise to the permeative pattern.

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Osteosarcoma

Chondroblastic Osteosarcoma (Left) In conventional osteosarcoma, tumor cells show plump epithelioid cytomorphology and variably prominent nucleoli; these cells can be seen producing bone ﬈. (Right) Chondroblastic osteosarcoma demonstrates extensive cartilaginous differentiation. Bone formation ﬈ can be variable and may be focal. The cartilage ﬊ in chondroblastic osteosarcoma is usually high grade.

Fibroblastic Osteosarcoma

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Conventional Osteosarcoma

Giant Cell-Rich Osteosarcoma (Left) Fibroblastic osteosarcoma, a histologic subtype of osteosarcoma, shows fascicles of spindle tumor cells; bone formation can be variable and subtle ﬊. (Right) Giant cell-rich osteosarcoma is a subset of osteosarcoma that histologically contains numerous prominent osteoclast-like giant cells ﬈, mimicking other giant cell-rich tumors of bone.

Telangiectatic Osteosarcoma

Telangiectatic Osteosarcoma (Left) Gross photograph shows a telangiectatic osteosarcoma involving the distal tibia. The tumor shows blood-filled cystic spaces ﬈. (Right) Telangiectatic osteosarcoma is a histologic subtype that shows extensive cystic changes accompanied by hemorrhage, mimicking other tumors such as aneurysmal bone cyst.

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Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Rhabdomyosarcoma KEY FACTS ○ ○ ○ ○

TERMINOLOGY • Malignant mesenchymal tumor that shows skeletal muscle differentiation • Subtypes include embryonal, alveolar, spindle cell, sclerosing, and pleomorphic

ETIOLOGY/PATHOGENESIS • Genetic events ○ Fusions in subsets of alveolar rhabdomyosarcoma (RMS) ○ No consistent translocations described in embryonal RMS • Inherited/imprinted diseases increase risk for RMS ○ Li-Fraumeni syndrome ○ Neurofibromatosis type 1 ○ Costello syndrome ○ Noonan syndrome ○ DICER1 syndrome ○ Hereditary retinoblastoma ○ Mosaic variegated aneuploidy syndrome 1

Nijmegen breakage syndrome Rubinstein-Taybi syndrome Werner syndrome Beckwith-Wiedemann syndrome

CLINICAL ISSUES • RMS are most frequent soft tissue sarcomas in children and young adults • Multimodality therapy: Surgery, chemotherapy, radiation • Main prognostic parameters: Histologic type, stage, site

ANCILLARY TESTS • Immunohistochemistry ○ Desmin diffusely positive in most RMS ○ Positive for MYOD1 &/or myogenin • Molecular or cytogenetics testing ○ Alveolar RMS: PAX7-FOXO1 or PAX3-FOXO1 fusion ○ Spindle cell/sclerosing RMS: MYOD1 mutation or rearrangements in VGLL2, NCOA2, or TFCP2

Boytroid Embryonal RMS

Cambium Layer in Embryonal RMS

Embryonal RMS

Alveolar RMS

(Left) Boytroid variant of embryonal rhabdomyosarcoma (RMS) characteristically shows a pedunculated polypoid gross appearance, as in this example involving urinary bladder. (Right) Embryonal RMS, including boytrioid variant in this example, often shows a cambium layer ﬊, characterized by subepithelial condensation or clustering of ovoid to spindly tumor cells in a myxoid background.

(Left) Embryonal RMS typically shows more polymorphous histology with variably hyperchromatic spindle to ovoid tumor cells, in a myxoid to collagenous background. (Right) Alveolar RMS displays nests of hobnail tumor cells showing characteristic dyscohesion within fibrous septae, leading to a histologic appearance reminiscient of alveoli in the lung.

28

Rhabdomyosarcoma

Abbreviations • Rhabdomyosarcoma (RMS)

Definitions • Malignant mesenchymal tumor that shows skeletal muscle differentiation • Subtypes include embryonal, alveolar, spindle cell, sclerosing, and pleomorphic

ETIOLOGY/PATHOGENESIS Genetic Events • No consistent translocations described in embryonal RMS • Fusions in subsets of alveolar RMS ○ PAX7-FOXO1 fusion: t(1;13)(p36;q14) ○ PAX3-FOXO1 fusion: t(2;13)(q35;q14) • Alterations in subsets of spindle cell/sclerosing RMS ○ MYOD1 mutation ○ Rearrangement in VGLL2 (6q22), NCOA2 (8q13), or TFCP2 (12q13) ○ Activating mutations in PI3K pathway

Genetic Associations • Inherited/imprinted diseases increase risk for RMS ○ Li-Fraumeni syndrome: TP53 ○ Neurofibromatosis type 1: NF1 ○ Costello syndrome: HRAS ○ Noonan syndrome: PTPN11, SOS1, KRAS, RAF1 ○ DICER1 syndrome: DICER1 ○ Hereditary retinoblastoma: RB1 ○ Mosaic variegated aneuploidy syndrome 1: BUB1B ○ Nijmegen breakage syndrome: NBN ○ Rubinstein-Taybi syndrome: CREBBP, EP300 ○ Werner syndrome: WRN ○ Beckwith-Wiedemann syndrome: Aberrant imprinting

• Alveolar RMS ○ Most commonly deep soft tissue of extremities ○ Other sites: Head/neck, trunk, pelvis, retroperitoneum • Spindle cell RMS ○ Most commonly head and neck (50% of cases) ○ Paratesticular, retroperitoneum, extremities, vulva ○ Rare primary intraosseous RMS (usually of spindle cell type) described • Sclerosing RMS ○ Most commonly extremities, head and neck • Pleomorphic RMS ○ Deep soft tissues of extremities (particularly thigh) ○ Other sites: Abdomen, retroperitoneum

Presentation • Rapidly enlarging mass ○ Symptoms pertaining to tumor site (e.g., proptosis in head and neck, urinary retention in genitourinary sites) • Most are painful, but may be painless

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

TERMINOLOGY

Treatment • Multimodality approach • Complete surgical resection, if possible • Childhood RMS generally responds to chemoradiation

Prognosis • Major parameters: Histologic type, disease stage, site • Embryonal RMS shows better prognosis than other subtypes ○ Botryoid and spindle cell RMS in children and adolescents have better prognosis – Spindle cell RMS in adults clinically more aggressive ○ Sclerosing RMS shows poor prognosis ○ Pleomorphic RMS aggressive with frequent metastases • Favorable site: Orbit, head and neck (nonparameningeal), genitourinary (except bladder/prostate), and biliary tree

MACROSCOPIC CLINICAL ISSUES Epidemiology • Incidence ○ RMS is most frequent soft tissue sarcoma in children and young adults – Embryonal RMS is most common subtype (60-70%) – Alveolar RMS is 2nd most common subtype (30%) – Spindle cell, sclerosing, and pleomorphic RMS are rare • Age ○ Mostly children and adolescents – Embryonal RMS generally affects younger population than alveolar RMS ○ Most adult RMS are pleomorphic, spindle cell, or sclerosing • Sex ○ M=F – Pleomorphic RMS more common in men

Site • Embryonal RMS ○ Head and neck: Orbital, parameningeal sites ○ Genitourinary region: Bladder, prostate, paratesticular ○ Other sites: Vagina, retroperitoneum, pelvis, biliary tract

General Features • • • • •

Size variable (usually large) Cut surface tan-white fleshy to firm fibrous Margins usually infiltrative May contain hemorrhage, cystic degeneration, necrosis Botryoid RMS (variant of embryonal RMS) ○ Exophytic, polypoid, arising beneath mucosal surface ○ Margins more circumscribed

MICROSCOPIC Histologic Features • Embryonal RMS ○ Loose fascicles or sheets of spindled, stellate, or ovoid cells with hyperchromatic or vesicular nuclei ○ Variable cellularity, myxoid stroma ○ Rhabdomyoblasts variable in number – Cells with eccentric nuclei, variable eosinophilic cytoplasm – Cytoplasmic cross-striations may be visible – Various shapes: Strap cells, tadpole cells, spider cells ○ Cambium layer: Tightly packed cellular layer of tumor cells closely abutting overlying epithelial surface 29

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Rhabdomyosarcoma

•

•

•

•

•

○ Anaplastic variant of embryonal RMS – Sheets of anaplastic cells with marked atypia – Associated with worse prognosis Alveolar RMS ○ Small round blue cell tumor, relatively monomorphic ○ Wreath-like multinucleated giant cells may be seen ○ Rhabdomyoblasts may be present but infrequent ○ Nests to sheets of tumors cells separated by variably thick fibrous septae – Loss of cellular cohesion in tumor nests gives alveolar appearance – Solid variant of alveolar RMS lacks alveolar pattern Spindle cell RMS ○ Fascicles of spindle cells, variable intervening collagen – Nuclei vesicular or hyperchromatic – Variable number of rhabdomyoblasts Sclerosing subtype ○ Stroma hyalinized to sclerotic ○ Small round to spindle cells, scant eosinophilic to clear cytoplasm Pleomorphic RMS ○ Showing morphology of nondescript pleomorphic sarcoma – Marked pleomorphism, anaplasia, mitotic, necrotic ○ Pleomorphic rhabdomyoblasts may be present Postchemotherapy RMS ○ Tumor cells appear more differentiated after therapy – Larger, mature-appearing rhabdomyoblasts ○ Fibrosis, necrosis, myxoid changes common

ANCILLARY TESTS Immunohistochemistry • Desmin ○ Diffuse positivity in most if not all RMS – Expression less diffuse in pleomorphic RMS ○ Perinuclear dot-like staining in some sclerosing RMS • Myogenin and MYOD1 ○ Transcription factor markers, nuclear expression specific for RMS ○ Cytoplasmic staining (nonspecific) should be ignored ○ Diffuse staining in alveolar RMS, focal in other subtypes ○ MYOD1 more often positive than myogenin in sclerosing RMS

Genetic Testing • Alveolar RMS: PAX7-FOXO1 or PAX3-FOXO1 fusion • Spindle cell/sclerosing RMS: MYOD1 mutation or rearrangements in VGLL2, NCOA2, or TFCP2 in some cases • Embryonal RMS: Frequent loss of heterozygosity in Chr 11p15.5 ○ Genes located in 11p15.5 region include those encoding proteins involved in growth regulation – IGF2 (paternally expressed), CDKN1C (maternally expressed)

DIFFERENTIAL DIAGNOSIS Embryonal RMS • Malignant peripheral nerve sheath tumor (MPNST)

30

○ Desmin, myogenin, and MYOD1 staining (if present) limited to rhabdomyosarcomatous component ○ Variably positive for S100 protein &/or SOX10 • Infantile fibrosarcoma ○ Occurs mostly within first 2 years of life ○ Negative for desmin, myogenin, and MYOD1 ○ Harbors ETV6-NTRK3 fusion in most cases

Alveolar RMS • Ewing sarcoma ○ Diffuse CD99 staining, NKX2.2 expression ○ Negative for desmin, myogenin, MYOD1 ○ Harbors EWSR1-FLI1, rarely EWSR1-ERG or other fusion • Desmoplastic small round cell tumor ○ Polyphenotypic: Variable keratin, desmin, NSE ○ Harbors EWSR1-WT1 fusion

Spindle Cell/Sclerosing RMS • Monophasic synovial sarcoma ○ Positive for TLE1, EMA, keratin AE1/AE3 ○ Negative for desmin, myogenin, MYOD1 ○ Harbors SYT1-SSX2, rarely SYT1-SSX1 or SYT1-SSX4 fusion • Sclerosing epithelioid fibrosarcoma ○ Positive for MUC4; negative for desmin, myogenin, MYOD1 ○ Harbors EWSR1-CREB3L1, EWSR1- or FUS-CREB3L2 fusion

Pleomorphic RMS • Pleomorphic leiomyosarcoma ○ Fascicular bundles, cigar-shaped nuclei ○ Negative for myogenin or MYOD1 • Undifferentiated pleomorphic sarcoma ○ Lacks expression of myogenic markers

SELECTED REFERENCES 1.

Agaram NP et al: Expanding the spectrum of intraosseous rhabdomyosarcoma: correlation between 2 distinct gene fusions and phenotype. Am J Surg Pathol. 43(5):695-702, 2019 2. Agaram NP et al: MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification. Mod Pathol. 32(1):27-36, 2019 3. Alaggio R et al: A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol. 40(2):224-35, 2016 4. Hawkins DS et al: Children's oncology group's 2013 blueprint for research: soft tissue sarcomas. Pediatr Blood Cancer. 60(6):1001-8, 2013 5. Mosquera JM et al: Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer. 52(6):538-50, 2013 6. Williamson D et al: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol. 28(13):2151-8, 2010 7. Ognjanovic S et al: Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer. 115(18):4218-26, 2009 8. Nascimento AF et al: Spindle cell rhabdomyosarcoma in adults. Am J Surg Pathol. 29(8):1106-13, 2005 9. Folpe AL et al: Sclerosing rhabdomyosarcoma in adults: report of four cases of a hyalinizing, matrix-rich variant of rhabdomyosarcoma that may be confused with osteosarcoma, chondrosarcoma, or angiosarcoma. Am J Surg Pathol. 26(9):1175-83, 2002 10. Gaffney EF et al: Pleomorphic rhabdomyosarcoma in adulthood. Analysis of 11 cases with definition of diagnostic criteria. Am J Surg Pathol. 17(6):601-9, 1993 11. Galili N et al: Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet. 5(3):230-5, 1993

Rhabdomyosarcoma

Diffuse Desmin Staining in Alveolar RMS (Left) Alveolar RMS can show a solid pattern and histologically mimics other small round blue cell tumors, such as Ewing sarcoma and neuroblastoma. (Right) RMS, such as this alveolar RMS, shows diffuse desmin immunoreactivity.

Diffuse Myogenin Staining in Alveolar RMS

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Alveolar RMS With Solid Pattern

Spindle Cell RMS (Left) Alveolar RMS characteristically shows diffuse expression of MYOD1 and myogenin. (Right) Spindle cell RMS is characterized by sheets to fascicles of overlapping monomorphic spindle cells.

Pleomorphic RMS

Pleomorphic RMS (Left) Pleomorphic RMS shows a fleshy, heterogeneous, tanyellow to gray cut surface, a gross finding that is commonly seen in many high-grade tumors. (Right) Pleomorphic RMS is characterized by sheets of markedly pleomorphic tumor cells with bizarreappearing hyperchromatic nuclei and abundant eosinophilic cytoplasm.

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Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Schwannoma KEY FACTS ○ 5% with multiple meningiomas ○ Rarely associated with neurofibromatosis type 1 (NF1) ○ Melanotic psammomatous schwannoma often associated with Carney complex

TERMINOLOGY • Benign peripheral nerve sheath tumor composed predominantly of Schwann cells

ETIOLOGY/PATHOGENESIS • Somatic NF2 gene mutations present in most tumors • Bilateral vestibular schwannomas occur in setting of germline NF2 mutations • Schwannomatosis associated with germline SMARCB1 or LZTR1 mutations

CLINICAL ISSUES • Common between 20-50 years of age • Can involve diverse sites, most commonly nervous system and somatic soft tissue • 90% sporadic • 10% syndromic ○ 3% with neurofibromatosis type 2 (NF2) ○ 2% with schwannomatosis

MICROSCOPIC • Hallmark: Variable amounts of cellular Antoni A and hypocellular Antoni B areas • Spindle cells in short fascicles in Antoni A areas • Loose matrix with cystic change in Antoni B areas • Bland nuclear features in most instances • Plexiform schwannoma usually subcutaneous, seen in children • Schwannomas in NF2 and schwannomatosis similar to sporadic tumors

ANCILLARY TESTS • Diffuse strong positivity for S100 protein and SOX10 is characteristic

Gross Photograph of Schwannoma

Verocay Bodies in Schwannoma

Plexiform Schwannoma

Melanotic Psammomatous Schwannoma

(Left) Grossly, schwannoma is typically circumscribed with a yellow-tan color and variable areas of hemorrhage and cystic degeneration. Association with nerve ſt can occasionally be seen. (Right) Verocay bodies, characterized by palisading rows of nuclei ſt juxtaposed to anuclear zone of cytoplasmic processes ﬊, can be seen in some schwannomas, although Verocay bodies alone are not specific for the diagnosis.

(Left) Plexiform schwannoma is characterized by a multinodular arrangement with tumor nodules separated by fibrous stroma. Unlike plexiform neurofibroma, plexiform schwannoma is not known to be associated with neurofibromatosis. (Right) Melanotic psammomatous schwannoma is characterized by spindle cells, variably prominent nucleoli, and extensive melanin deposition. Concentric laminated psammoma bodies ſt are occasionally seen; some cases are associated with Carney complex.

32

Schwannoma

Definitions • Benign peripheral nerve sheath tumor composed predominantly of Schwann cells

ETIOLOGY/PATHOGENESIS Molecular Aberrations • Somatic NF2 mutations present in most tumors • Bilateral vestibular schwannomas occur in setting of germline NF2 mutations • Schwannomatosis associated with germline SMARCB1 or LZTR1 mutations

CLINICAL ISSUES Epidemiology • Incidence ○ 90% sporadic ○ 10% syndromic – 3% with neurofibromatosis type 2 (NF2) – 2% with schwannomatosis – 5% with multiple meningiomas – Rarely associated with neurofibromatosis type 1 (NF1) • Age ○ All ages ○ Common between 20-50 years • Sex ○ No sex predilection

Site • Central nervous system (CNS) and peripheral nervous system • Somatic soft tissue in upper and lower extremities • Head and neck • Deep-seated tumor(s) in mediastinum and retroperitoneum

Presentation • Slow growing • Painless mass ○ Large tumors may be painful • Cystic tumors may fluctuate in size

Treatment • Surgical excision curative

Prognosis • Excellent

Multiple Schwannoma Syndromes • NF2 ○ Autosomal dominant ○ Incidence: ~ 1:30,000-40,000 ○ Inactivating germline mutations of NF2 on chromosome 22 ○ Bilateral vestibular schwannomas are characteristic ○ Schwannomas may involve other cranial nerves ○ CNS tumors, such as meningioma, ependymoma, and gliomas, are also part of disease spectrum ○ Schwannomas in NF2 resemble sporadic counterparts • Schwannomatosis ○ Germline mutations in SMARCB1 or LZTR1

MACROSCOPIC General Features • • • •

Surrounded by true capsule consisting of epineurium Eccentric mass loosely attached to underlying nerve Small tumors may be fusiform in shape Tumors in vertebral canal or posterior mediastinum may be dumbbell in shape • Pink to white-yellow cut surface • Cystic change, hemorrhage, or calcifications in large tumors

Size

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

○ Not associated with germline mutations in NF1 or NF2 ○ Autosomal dominant inheritance with incomplete penetrance ○ Both sexes affected equally ○ Patients do not develop bilateral vestibular schwannomas or CNS tumors as seen in NF2 ○ Morphology similar to sporadic schwannomas

TERMINOLOGY

• Variable; small or large

MICROSCOPIC Histologic Features • Hallmark: Variable amounts of Antoni A and Antoni B areas ○ Antoni A – Cellular area with short fascicles of spindle cells – Plump nuclei, indistinct cytoplasmic borders – Nuclear palisading or whorling ○ Antoni B – Hypocellular area with spindle or oval cells – Loose matrix with cystic change and inflammatory cells • Verocay bodies ○ Compact rows of palisaded nuclei separated by fibrillary processes • Large vessels with thick, hyalinized walls and luminal thrombi • Encapsulation and peripheral cuff of lymphocytes may be helpful diagnostic clues

Cytologic Features • Bland nuclear features in most instances

Variants • "Ancient" schwannoma ○ Marked nuclear atypia of degenerative type ○ Usually seen in deep-seated large tumors of long duration ○ Cystic change, hemorrhage, calcifications, and hyalinization ○ Lacks mitotic activity ○ Behavior similar to ordinary schwannoma • Cellular schwannoma ○ Composed almost exclusively of cellular Antoni A areas ○ Common in mediastinum and retroperitoneum ○ Encapsulated; some may be multinodular or plexiform in architecture ○ Long sweeping fascicles of spindle-shaped cells ○ Small foci of necrosis may be present 33

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Schwannoma

•

•

•

•

○ Diffuse strong positivity for S100 protein and SOX10 distinguishes cellular schwannoma from malignant peripheral nerve sheath tumors (MPNSTs) Plexiform schwannoma ○ Usually subcutaneous, infrequently in deeper locations ○ Encapsulated with multinodular or plexiform architecture ○ Often more cellular than conventional schwannoma ○ Weak association with NF (unlike plexiform neurofibroma, which is almost pathognomonic of NF1) Melanotic psammomatous schwannoma ○ Distinctive tumor of adults that often arises in spinal or autonomic nerves near midline ○ Associated with Carney complex in 50% of patients ○ Multiple tumors may be present in 20% of patients ○ Heavy pigmentation may mask underlying tumor morphology ○ Syncytial arrangement of spindle to ovoid cells with prominent nucleoli and intranuclear inclusions ○ Psammoma bodies are present in most cases ○ Tumors express S100 protein and HMB-45 ○ Negative for PRKAR1A expression in subset of cases ○ Difficult to predict behavior since bland-appearing tumors have been known to metastasize ○ Metastasis occurs in ~ 25% of cases Epithelioid schwannoma ○ Small round Schwann cells with eosinophilic cytoplasm and sharp cell borders ○ Arranged in clusters, cords, or as single cells ○ Foci of typical schwannoma may be present ○ Degenerative nuclear atypia may be seen ○ Lacks mitotic activity ○ Positive for S100 protein and SOX10 ○ Loss of SMARCB1/INI1 expression in 40-50% of cases Malignant transformation in schwannomas ○ Extremely rare ○ Rare sarcomas reported in association with schwannomas includes epithelioid MPNST and angiosarcoma

DIFFERENTIAL DIAGNOSIS

• MPNST shows greater degree and extent of nuclear atypia, necrosis, and only focal positivity for S100 protein and SOX10, unlike benign schwannoma variants, which are diffusely positive for S100 protein and SOX10

Malignant Melanoma • Melanotic schwannomas may be mistaken for melanoma due to coexpression of S100 and HMB-45 • Melanotic schwannomas do not have degree of nuclear atypia or mitotic activity seen in malignant melanoma • Psammoma bodies are present in melanotic schwannoma but not in malignant melanoma

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Encapsulated tumor with alternating hypercellular and hypocellular areas • Degenerate atypia in "ancient change" can be mistaken for malignancy • Diffuse positivity for S100 protein and SOX10

SELECTED REFERENCES 1.

2.

3.

4.

5. 6. 7.

8.

9.

Leiomyoma • Nuclear palisading is also seen in smooth muscle tumors and may mimic schwannoma • Leiomyomas lack Antoni A and Antoni B areas • Leiomyomas are positive for desmin and smooth muscle actin and are negative for S100 protein and SOX10

10.

Solitary Fibrous Tumor

13.

• Bland spindle cells and hyalinized vessels in schwannoma may mimic solitary fibrous tumor • Solitary fibrous tumors are positive for STAT6 and negative for S100 protein and SOX10 • Solitary fibrous tumors harbor NAB2-STAT6 fusion, which is absent in schwannoma

14.

Malignant Peripheral Nerve Sheath Tumor • Cellular schwannomas may be mistaken for MPNST • Plexiform schwannomas are often cellular and may be mistaken for MPNST arising in plexiform neurofibroma 34

11. 12.

15. 16.

Jo VY et al: SMARCB1/INI1 loss in epithelioid schwannoma: a clinicopathologic and immunohistochemical study of 65 cases. Am J Surg Pathol. 41(8):1013-22, 2017 Hutter S et al: Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants. Acta Neuropathol. 128(3):449-52, 2014 Piotrowski A et al: Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 46(2):182-7, 2014 Torres-Mora J et al: Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma". Am J Surg Pathol. 38(1):94-105, 2014 Liegl B et al: Microcystic/reticular schwannoma: a distinct variant with predilection for visceral locations. Am J Surg Pathol. 32(7):1080-7, 2008 Hulsebos TJ et al: Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 80(4):805-10, 2007 Woodruff JM et al: Congenital and childhood plexiform (multinodular) cellular schwannoma: a troublesome mimic of malignant peripheral nerve sheath tumor. Am J Surg Pathol. 27(10):1321-9, 2003 McMenamin ME et al: Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma: a study of 17 cases. Am J Surg Pathol. 25(1):13-25, 2001 Antinheimo J et al: Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology. 54(1):71-6, 2000 Kirschner LS et al: Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 26(1):89-92, 2000 Kindblom LG et al: Benign epithelioid schwannoma. Am J Surg Pathol. 22(6):762-70, 1998 Chan JK et al: Pseudoglandular schwannoma. Histopathology. 29(5):481-3, 1996 Goldblum JR et al: Neuroblastoma-like neurilemoma. Am J Surg Pathol. 18(3):266-73, 1994 Carney JA: Psammomatous melanotic schwannoma. A distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol. 14(3):206-22, 1990 Fletcher CD et al: Cellular schwannoma: a distinct pseudosarcomatous entity. Histopathology. 11(1):21-35, 1987 Fletcher CD et al: Benign plexiform (multinodular) schwannoma: a rare tumour unassociated with neurofibromatosis. Histopathology. 10(9):971-80, 1986

Schwannoma

Schwannoma With Edema (Left) Many cellular schwannomas (including visceral ones, such as gastric schwannoma, as in this case) demonstrate a lymphocytic cuff ſt at the periphery, which can be a helpful diagnostic clue. (Right) Characteristic histologic features of schwannoma include stromal edema, prominent vessels, and fascicles of spindle cells with varying cellularity.

Hyalinized Vessels in Schwannoma

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Peripheral Lymphocytic Cuff in Schwannoma

Ancient Change in Schwannoma (Left) Schwannoma often shows stromal edema, vascular congestion, and hemosiderin deposition near hyalinized vessels, some of which may show thrombosis. (Right) Degenerate hyperchromatic nuclei ﬊ can occasionally be seen in schwannoma (so-called "ancient" schwannoma). Awareness of this phenomenon would avoid the diagnostic pitfall of misdiagnosing this tumor as malignant.

S100 Protein Expression in Schwannoma

SOX10 Expression in Schwannoma (Left) Diffuse S100 protein immunoreactivity (with both nuclear ﬈ and cytoplasmic staining) is characteristic of schwannoma and not seen in most malignant peripheral nerve sheath tumors. (Right) Diffuse SOX10 immunoreactivity is also characteristic of schwannoma.

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Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Bone and Soft Tissue Table Familial Cancer Syndromes With Bone and Soft Tissue Tumors Bone and Soft Tissue Tumor

Familial Cancer Syndromes

Genes Involved

Chondrosarcoma

Hereditary multiple exostosis

EXT1, EXT2

Hereditary retinoblastoma

RB1

Li-Fraumeni syndrome

TP53

Chordoma

Familial chordoma

TBXT

Tuberous sclerosis

TSC1, TSC2

Giant cell tumor of bone

Noonan syndrome

PTPN11, SOS1, KRAS, RAF1

Malignant peripheral nerve sheath tumor

Neurofibromatosis type 1

NF1

Neurofibromatosis type 2

NF2

Familial melanoma

CDKN2A

Multiple endocrine neoplasia 1

MEN1

Li-Fraumeni syndrome

TP53

Werner syndrome

WRN

Ossifying fibroma

Hyperparathyroidism-jaw tumor syndrome

CDC73 (HRPT2)

Osteosarcoma

Li-Fraumeni syndrome

TP53

Bloom syndrome

BLM

Hereditary retinoblastoma

RB1

Rothmund-Thomson syndrome

RECQL4

Rhabdomyosarcoma

Other soft tissue tumors and sarcoma

36

Werner syndrome

WRN

Li-Fraumeni syndrome

TP53

Rubinstein-Taybi syndrome

CREBBP, EP300

DICER1 syndrome

DICER1

Mosaic variegated aneuploidy syndrome 1

BUB1B

Costello syndrome

HRAS

Nijmegen breakage syndrome

NBN

Neurofibromatosis type 1

NF1

Noonan syndrome

PTPN11, SOS1, KRAS, RAF1

Hereditary retinoblastoma

RB1

Werner syndrome

WRN

Beckwith-Wiedemann syndrome

Aberrant imprinting in chromosome 11

Li-Fraumeni syndrome

TP53

Proteus syndrome

AKT1

Familial adenomatous polyposis

APC

Familial melanoma

CDKN2A

Rubinstein-Taybi syndrome

CREBBP, EP300

Multiple hereditary exostosis

EXT1, EXT2

Hereditary leiomyomatosis and renal cell carcinoma (Reed syndrome)

FH

Lynch syndrome

MLH1, MSH2, MSH6, PMS2

Carney complex

PRKAR1A

Basal cell nevus syndrome (Gorlin syndrome)

PTCH1

Hereditary retinoblastoma

RB1

Rhabdoid tumor predisposition syndrome

SMARCB1

von Hippel-Lindau syndrome

VHL

Werner syndrome

WRN

Bone and Soft Tissue Table

Tumor

Translocation or Other Features Gene Fusion or Other Features Frequency

Aggressive angiomyxoma

t(12q15)

HMGA2 rearrangement

Occasional

Alveolar soft part sarcoma

t(X;17)(p11;q25)

ASPSCR1-TFE3 fusion

Frequent

Aneurysmal bone cyst

t(17p13)

USP6 rearrangement-promoter swapping

Frequent

Angiofibroma of soft tissue

t(8q13)

NCOA2 rearrangement

Occasional

Angiomatoid fibrous histiocytoma

t (2;22)(q33;q12)

EWSR1-CREB1 fusion

Occasional

t(12;22)(q13;q12)

EWSR1-ATF1 fusion

Rare

t(12;16)(q13;p11)

FUS-ATF1 fusion

Rare

Angiosarcoma

Mutation in VEGF pathway

Occasional

t(19q13)

CIC rearrangement

Rare

Biphenotypic sinonasal sarcoma

t(2;4)(q35;q31)

PAX3-MAML3 fusion

Frequent

Bizarre parosteal osteochondromatous proliferation

t(1;17)(q32;q21)

Unknown

Unknown

Calcifying aponeurotic fibroma

ins(2;4)(q35;q25)

FN1-EGF fusion

Frequent

Cellular angiofibroma

Deletion of 13q14

RB1 inactivation

Frequent

Clear cell sarcoma of kidney

Xp11

BCOR internal tandem duplication

Frequent

t(10;17)(q22;p13)

YWHAE-NUTM2A/B fusion

Rare

inv(X)(p11.4p11.22) 

BCOR-CCNB3 fusion

Rare

t(12;22)(q13;q12)

EWSR1-ATF1 fusion

Frequent

t(2;22)(q33;q12)

EWSR1-CREB1 fusion

Rare

t(2;22)(q33;q12)

EWSR1-CREB1 fusion

Frequent

t(12;22)(q13;q12)

EWSR1-ATF1 fusion

Rare

Chondroblastoma

H3-3B K36M mutation (rarely H33A K36M)

Occasional

Chondroma of bone (central, periosteal)

Mutation in IDH1, IDH2

Occasional

t(12q15)

HMGA2 rearrangement

Occasional

t(2q34-36)

FN1 rearrangement

Occasional

t(6q24)

GRM1 rearrangement-promoter swapping

Frequent

Mutation in IDH1, IDH2

Occasional

6q27

TBXT duplication

Occasional

22q11

SMARCB1 inactivation

Frequent

Dermatofibrosarcoma protuberans

t(17;22)(q22;q13)

COL1A1-PDGFB fusion

Frequent

Desmoplastic fibroblastoma (collagenous fibroma)

t(11q12)

FOSL1 rearrangement

Occasional

Desmoplastic small round cell tumor

t(11;22)(p13;q12)

EWSR1-WT1 fusion

Frequent

t(7;17)(p15;q21)

JAZF1-SUZ12 fusion

Occasional

t(6;7)(p21;p15)

JAZF1-PHF1 fusion

Occasional

t(10;17)(q22;p13)

YWHAE-NUTM2A/B fusion

Occasional

t(X,22)(p11;q13)

ZC3H7B-BCOR fusion

Rare

Xp11

BCOR internal tandem duplication

Rare

t(1;3)(p36;q25)

WWTR1-CAMTA1 fusion

Frequent

t(X;11)(p11;q22)

YAP1-TFE3 fusion

Rare

Epithelioid hemangioma

t(14q21), t(19q13)

Rearrangement in FOS or FOSB

Occasional

Epithelioid sarcoma

Deletion of 22q11

SMARCB1 inactivation

Frequent

Clear cell sarcoma of soft part Clear cell sarcoma-like tumor of gastrointestinal tract (gastrointestinal neuroectodermal tumor)

Chondroma of soft tissue Chondromyxoid fibroma Chondrosarcoma (including conventional and dedifferentiated types) Chordoma Poorly differentiated

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Molecular and Cytogenetic Findings in Bone and Soft Tissue Tumors

Endometrial stromal sarcoma Low grade High grade

Epithelioid hemangioendothelioma

37

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Bone and Soft Tissue Table Molecular and Cytogenetic Findings in Bone and Soft Tissue Tumors (Continued) Tumor

Translocation or Other Features Gene Fusion or Other Features Frequency

Ewing sarcoma

t(11;22)(q24;q12)

EWSR1-FLI1 fusion

Frequent

t(21;22)(q12;q12)

EWSR1-ERG fusion

Rare

t(7;22)(p22;q12)

EWSR1-ETV1 fusion

Rare

t(17;22)(q21;q12)

EWSR1-ETV4 fusion

Rare

t(2;22)(q33;q12)

EWSR1-FEV fusion

Rare

t(16;21)(p11;q22)

FUS-ERG fusion

Rare

t(4;19)(q35;q13) or  t(10;19)(q26;q13)

CIC-DUX4 fusion

Occasional

t(X;19)(q13;q13)

CIC-FOXO4 fusion

Rare

inv(X)(p11.4p11.22) or Xp11 internal tandem duplication

BCOR-CCNB3 fusion or BCOR internal tandem duplication

Occasional

t(9;22)(q22;q12)

EWSR1-NR4A3 fusion

Occasional

t(9;17)(q22;q11)

TAF15-NR4A3 fusion

Occasional

Ewing sarcoma-like round cell sarcomas

Extraskeletal myxoid chondrosarcoma

t(9;15)(q22;q21)

TCF12-NR4A3 fusion

Rare

Fibroma of tendon sheath

t(17p13)

USP6 rearrangement

Occasional

Fibromatosis, extraabdominal/desmoid

5q21, 3p22

Inactivation of APC or CTNNB1

Occasional

Fibroosseous pseudotumor of digit

t(17p13)

USP6 rearrangement

Occasional

GNAS mutation

Occasional

EGFR exon 20 indel mutation

Unknown

MALAT1-GLI1 fusion

Unknown

Fibrous dysplasia Fibrous hamartoma of infancy Gastroblastoma

t(11;12)(q11;q13)

Gastrointestinal stromal tumor Giant cell fibroblastoma

Mutation in KIT, PDGFRA, NF1, SDHB

Occasional

t(17;22)(q22;q13)

COL1A1-PDGFB fusion

Frequent

H3-3A G34W mutation

Occasional

t(1p13), t(9q34)

MIR143-NOTCH1/2 fusion

Occasional

BRAF V600E mutation

Rare

Giant cell tumor of bone Glomus tumor Hemangioma

Mutation in GNA14, GNAQ, GNA11

Occasional

Hemosiderotic fibrolipomatous tumor

t(1;10)(p22;q24), 3p12 amplification

TGFBR3-OGA fusion, VGLL3 amplification

Occasional

Hibernoma

t(11q13-21)

Unknown

Unknown

Infantile fibrosarcoma

t(12;15)(p13;q25)

ETV6-NTRK3 fusion

Frequent

t(2;15)(p21;q25)

EML4-NTRK3 fusion

Rare

t(2p23)

ALK rearrangement

Occasional

t(6q22)

ROS1 rearrangement

Rare

t(5q32)

PDGFRB rearrangement

Rare

t(15q25)

NTRK3 rearrangement

Rare

Inflammatory myofibroblastic tumor

Leiomyosarcoma Uterine leiomyosarcoma

Complex

Unknown

t(8q12), t(11q22)

Rearrangement in PLAG1, PGR

Rare

Lipoblastoma

t(8q12)

PLAG1 rearrangement

Frequent

Lipofibromatosis

ins(2;4)(q35;q25), others

FN1-EGF fusion or rearrangement of BRAF, EGFR, HBEGF, PDGFRB, RET, ROS1

Unknown

Lipofibromatosis-like neural tumor

t(1q21)

NTRK1 rearrangement

Occasional

Chondroid lipoma

t(11;16)(q13;p13)

C11orf95-MRTFB fusion

Occasional

Spindle cell/pleomorphic lipoma

Deletion of 13q14

RB1 inactivation

Frequent

Typical lipoma

t(12q15), t(6p21)

Rearrangement of HMGA2, HMGA1 

Occasional

12q ring/giant marker chromosomes

Amplification ofMDM2 (and

Frequent

Lipoma

Liposarcoma Well differentiated and

38

Bone and Soft Tissue Table

Tumor

Translocation or Other Features Gene Fusion or Other Features Frequency

dedifferentiated

(12q13-q15 amplification)

CDK4, HMGA2)

Spindle cell

Deletion of 13q14

RB1 inactivation

Occasional

t(5p15; intrachromosomal)

TRIO-TERT fusion

Rare

Myxoid/round cell

t(12;16)(q13;p11)

FUS-DDIT3 fusion

Frequent

t(12;22)(q13;q12)

EWSR1-DDIT3 fusion

Rare

Pleomorphic

Complex

Leiomyoma (uterine, cutaneous, soft tissue) Leiomyosarcoma Inflammatory Low-grade fibromyxoid sarcoma

Unknown FH inactivation

Complex

Rare Unknown

Near haploid

Rare

t(7;16)(q32-34;p11)

FUS-CREB3L2 fusion

Occasional

t(11;16)(p11;p11)

FUS-CREB3L1 fusion

Rare

t(11;22)(p11;q12)

EWSR1-CREB3L1 fusion

Rare

Complex

Inactivation of NF1, CDKN2A, SUZ12

Occasional

22q11

INI1 inactivation

Occasional

Mammary-type myofibroblastoma

Deletion of 13q14

RB1 inactivation

Frequent

Mesenchymal chondrosarcoma

t(8;8)(q13;q21)

HEY1-NCOA2 fusion

Frequent

Myoepithelioma, benign/malignant

t(1;22)(q23;q12)

EWSR1-PBX1 fusion

Unknown

t(6;22)(p21;q12)

EWSR1-POU5F1 fusion

Unknown

t(9;22)(q33;q12)

EWSR1-PBX3 fusion

Unknown

t(19;22)(q13;q12)

MPNST Epithelioid MPNST

EWSR1-ZNF444 fusion

Unknown

Myofibroma/myofibromatosis

PDGFRB mutation

Unknown

Myopericytoma

PDGFRB mutation

Unknown

SRF-RELA fusion

Unknown

t(6;11)(p21;q13) Myxofibrosarcoma

Complex

Myositis ossificans

t(17p13)

USP6 rearrangement

Unknown

Myxoinflammatory fibroblastic sarcoma

t(1;10)(p22;q24), 3p12 amplification

TGFBR3-MGEA5 fusion, VGLL3 amplification

Occasional

7q34

BRAF  rearrangement or amplification

Occasional

GNAS mutation

Unknown

PRKAR1A mutation

Occasional

Myxoma, intramuscular or cellular Myxoma, cardiac

Unknown

Neurofibroma

17q11

NF1 inactivation

Occasional

Nodular fasciitis

t(17p13)

USP6 rearrangement-promoter swapping

Frequent

Mutation in MAP kinase pathway (KRAS, FGFR1, NF1)

Occasional

t(6p21)

PHF1 rearrangement

Occasional

t(Xp11)

BCOR rearrangement

Rare

t(Xq26)

BCORL1 rearrangement

Rare

t(3;11)(q25;q13)

KDM2A-WWTR1 fusion

Rare

Osteoblastoma

t(14q21), t(19q13)

Rearrangement in FOS or FOSB

Frequent (FOS), rare (FOSB)

Osteochondroma

8q24

EXT1 inactivation

Occasional

11p11-12

EXT2 inactivation

Occasional

Conventional

Complex

Inactivation of RB1 and TP53

Frequent

Parosteal/low-grade central

12q ring/giant marker chromosomes

Amplification of MDM2 (and CDK4) 

80% (parosteal), 30% (low-grade central)

Nonossifying fibroma of bone Ossifying fibromyxoid tumor

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Molecular and Cytogenetic Findings in Bone and Soft Tissue Tumors (Continued)

Osteosarcoma

39

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Bone and Soft Tissue Table Molecular and Cytogenetic Findings in Bone and Soft Tissue Tumors (Continued) Tumor

Translocation or Other Features Gene Fusion or Other Features Frequency

Pericytoma

t(7;12)(p22;q13)

ACTB-GLI1 fusion

Unknown

Perineurioma

22q11

NF2 inactivation

Unknown

Phosphaturic mesenchymal tumor

t(2;8)(q35;p11)

FN1-FGFR1 fusion

Occasional

t(2;5)(q35;q31)

FN1-FGF1 fusion

Rare

Pleomorphic hyalinizing angiectatic tumor

t(1;10)(p22;q24), 3p12 amplification

TGFBR3-MGEA5 fusion, VGLL3 amplification

Occasional

Plexiform fibromyxoma

t(11;12)(q11;q13), 12q13

MALAT1-GLI1 fusion, GLI1 upregulation

Occasional

Primitive myxoid mesenchymal tumor of infancy

Xp11

BCOR internal tandem duplication

Frequent

Pseudomyogenic hemangioendothelioma

t(19q13)

FOSB rearrangement

Frequent

Alveolar

t(1;13)(p36;q14)

PAX7-FOXO1 fusion

Occasional

t(2;13)(q35;q14)

PAX3-FOXO1 fusion

Rare

Embryonal

Complex

Spindle cell/sclerosing

t(6q22), t(8q13)

Rhabdomyosarcoma

Schwannoma Schwannomatosis

Rearrangement in VGLL2, NCOA2

Occasional

MYOD1 mutation

Occasional

Deletion of 22q11

NF2 inactivation

Occasional

22q11

SMARCB1 inactivation

Unknown

PRKAR1A mutation

Occasional

t(11;22)(p11;q12)

EWSR1-CREB3L1 fusion

Occasional

t(7;22)(q32-34;q12)

EWSR1-CREB3L2 fusion

Occasional

Melanotic schwannoma Sclerosing epithelioid fibrosarcoma

t(7;16)(q32-34;p11)

FUS-CREB3L2 fusion

Rare

Solitary fibrous tumor

t(12q15)

NAB2-STAT6 fusion

Frequent

Subungual exostosis

t(X;6)(q13-14;q22)

Unknown

Unknown

Synovial sarcoma Tenosynovial giant cell tumor

t(X;18)(p11;q11)

SYT with SSX1, SSX2, or SSX4 fusion

Frequent

t(X;20)(p11;q13)

SS18L1-SSX1 fusion

Rare

t(1;2)(p13;q37), t(1p13)

COL6A3-CSF1 fusion or other CSF1 rearrangement

Occasional

MPNST = malignant peripheral nerve sheath tumor.

40

Occasional

Bone and Soft Tissue Table

1.

2.

3.

4. 5.

6.

7.

8.

9. 10. 11.

12.

13.

14. 15.

16. 17.

18.

19.

20.

21.

22. 23.

24. 25.

26.

27.

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28. Carter JM et al: USP6 genetic rearrangements in cellular fibroma of tendon sheath. Mod Pathol. 29(8):865-9, 2016 29. Huang SC et al: Recurrent CIC gene abnormalities in angiosarcomas: a molecular study of 120 Cases with concurrent investigation of PLCG1, KDR, MYC, and FLT4 gene alterations. Am J Surg Pathol. 40(5):645-55, 2016 30. Lee JC et al: Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod Pathol. 9(11):1335-46, 2016 31. Park JY et al: EGFR exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol. 40(12):1713-8, 2016 32. Puls F et al: FN1-EGF gene fusions are recurrent in calcifying aponeurotic fibroma. J Pathol. 238(4):502-7, 2016 33. Spans L et al: Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 upregulation define a subset of plexiform fibromyxoma. J Pathol. 239(3):33543, 2016 34. Yamamoto H et al: ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology. 69(1):72-83, 2016 35. Cleven AH et al: Mutation analysis of H3F3A and H3F3B as a diagnostic tool for giant cell tumor of bone and chondroblastoma. Am J Surg Pathol. 39(11):1576-83, 2015 36. Huang SC et al: Frequent FOS gene rearrangements in epithelioid hemangioma: a molecular study of 58 cases with morphologic reappraisal. Am J Surg Pathol. 39(10):1313-21, 2015 37. Lee JC et al: Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol. 235(4):539-45, 2015 38. Prieto-Granada C et al: A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low-grade fibromyxoid sarcoma: a pathologic and molecular study of 18 cases. Genes Chromosomes Cancer. 54(1):28-38, 2015 39. Ueno-Yokohata H et al: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet. 47(8):861-3, 2015 40. Antonescu CR et al: ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features. Genes Chromosomes Cancer. 53(11):951-9, 2014 41. Carter JM et al: TGFBR3 and MGEA5 rearrangements in pleomorphic hyalinizing angiectatic tumors and the spectrum of related neoplasms. Am J Surg Pathol. 38(9):1182-992, 2014 42. Lee W et al: PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 46(11):1227-32, 2014 43. Lovly CM et al: Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov. 4(8):889-95, 2014 44. Maleszewski JJ et al: PRKAR1A in the development of cardiac myxoma: a study of 110 cases including isolated and syndromic tumors. Am J Surg Pathol. 38(8):1079-87, 2014 45. Nord KH et al: GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nat Genet. 46(5):474-7, 2014 46. Wang X et al: Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet. 46(7):666-8, 2014 47. Zhang M et al: Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet. 46(11):1170-2, 2014 48. Antonescu CR et al: Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 52(8):775-84, 2013 49. Behjati S et al: Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013 Dec; 45(12):1479-82. Epub 2013 Oct 27. Erratum in: Nat Genet. 46(3):316, 2014 50. Chmielecki J et al: Whole-exome sequencing identifies a recurrent NAB2STAT6 fusion in solitary fibrous tumors. Nat Genet. 45(2):131-2, 2013 51. Mosquera JM et al: Novel MIR143-NOTCH fusions in benign and malignant glomus tumors. Genes Chromosomes Cancer. 52(11):1075-87, 2013 52. Robinson DR et al: Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet. 45(2):180-5, 2013 53. Walther C et al: A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol. 232(5):534-40, 2014 54. Bridge JA et al: Pericytoma with t(7;12) and ACTB-GLI1 fusion arising in bone. Hum Pathol. 43(9):1524-9, 2012 55. Gebre-Medhin S et al: Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumors. Am J Pathol. 181(3):1069-77, 2012 56. Jin Y et al: Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes. Genes Chromosomes Cancer. 51(5):510-20, 2012 57. Lee CH et al: 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. Proc Natl Acad Sci U S A. 109(3):929-34, 2012 58. Lessnick SL et al: Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol. 7:145-59, 2012

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

SELECTED REFERENCES

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Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Bone and Soft Tissue Table

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59. Macchia G et al: FOSL1 as a candidate target gene for 11q12 rearrangements in desmoplastic fibroblastoma. Lab Invest. 92(5):735-43, 2012 60. O’Meara E et al: Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol. 227(1):72-80, 2012 61. Pierron G et al: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet. 44(4):461-6, 2012 62. Amary MF et al: IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 224(3):334-43, 2011 63. Erickson-Johnson MR et al: Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest. 91(10):1427-33, 2011 64. Errani C et al: A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 50(8):644-53, 2011 65. Flucke U et al: Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma. Mod Pathol. 24(1):82-9, 2011 66. Tanas MR et al: Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med. 3(98):98ra82, 2011 67. Antonescu CR et al: EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosomes Cancer. 49(12):1114-24, 2010 68. Huang D et al: C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma. Genes Chromosomes Cancer. 49(9):810-8, 2010 69. Delaney D et al: GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma. Mod Pathol. 22(5):718-24, 2009 70. Hallor KH et al: Two genetic pathways, t(1;10) and amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions. J Pathol. 217(5):716-27, 2009 71. Brandal P et al: Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepithelioma. Genes Chromosomes Cancer. 47(7):558-64, 2008 72. Hisaoka M et al: Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 32(3):452-60, 2008 73. Sukov WR et al: Frequency of USP6 rearrangements in myositis ossificans, brown tumor, and cherubism: molecular cytogenetic evidence that a subset of "myositis ossificans-like lesions" are the early phases in the formation of soft-tissue aneurysmal bone cyst. Skeletal Radiol. 37(4):321-7, 2008 74. Antonescu CR et al: EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosom Cancer. 46(12):105160, 2007 75. Idowu BD et al: A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone. Histopathology. 50(6):691-704, 2007 76. Medeiros F et al: Frequency and characterization of HMGA2 and HMGA1 rearrangements in mesenchymal tumors of the lower genital tract. Genes Chromosomes Cancer. 46(11):981-90, 2007 77. Rossi S et al: EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res. 13(24):7322-8, 2007 78. Antonescu CR et al: EWS-CREB1: a recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. 12(18):5356-62, 2006 79. Kawamura-Saito M et al: Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet. 15(13):2125-37, 2006 80. Micci F et al: Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Res. 66(1):107-12, 2006 81. Storlazzi CT et al: Rearrangement of the COL12A1 and COL4A5 genes in subungual exostosis: molecular cytogenetic delineation of the tumorspecific translocation t(X;6)(q13-4;q22). Int J Cancer. 118(8):1972-6, 2006 82. West RB et al: A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A. 103(3):690-5, 2006 83. Hallor KH et al: Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 44(1):97-102, 2005 84. Modena P et al: SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 65(10):4012-9, 2005 85. Oliveira AM et al: Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene. 24(21):3419-26, 2005

86. Nilsson M et al: Molecular cytogenetic characterization of recurrent translocation breakpoints in bizarre parosteal osteochondromatous proliferation (Nora's lesion). Hum Pathol. 35(9):1063-9, 2004 87. Coindre JM et al: Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: a review of 25 cases initially diagnosed as malignant fibrous histiocytoma. Mod Pathol. 16(3):25662, 2003 88. Dahlén A et al: Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol. 16(11):1132-40, 2003 89. Storlazzi CT et al: A novel fusion gene, SS18L1/SSX1, in synovial sarcoma. Genes Chromosomes Cancer. 37(2):195-200, 2003 90. Storlazzi CT et al: Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma. Hum Mol Genet. 12(18):2349-58, 2003 91. Tomlinson IP et al: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 30(4):406-10, 2002 92. Koontz JI et al: Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 98(11):6348-53, 2001 93. Ladanyi M et al: The der (17) t(X; 17) (p11; q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 20(1):48-57, 2001 94. Hibbard MK et al: PLAG1 fusion oncogenes in lipoblastoma. Cancer Res. 60(17):4869-72, 2000 95. Kirschner LS et al: Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 26(1):89-92, 2000 96. Lawrence B et al: TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol. 157(2):377-84, 2000 97. Sjögren H et al: Fusion of the NH2-terminal domain of the basic helix-loophelix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21). Cancer Res. 60(24):6832-5, 2000 98. Bovée JV et al: EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 65(3):689-98, 1999 99. Sciot R et al: Collagenous fibroma (desmoplastic fibroblastoma): genetic link with fibroma of tendon sheath? Mod Pathol. 12(6):565-8, 1999 100. Sjögren H et al: Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid chondrosarcoma. Cancer Res. 59(20):5064-7, 1999 101. Wunder JS et al: Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas. Oncogene. 18(3):783-8, 1999 102. Kazmierczak B et al: HMGIY is the target of 6p21.3 rearrangements in various benign mesenchymal tumors. Genes Chromosomes Cancer. 23(4):279-85, 1998 103. Knezevich SR et al: A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 18(2):184-7, 1998 104. O'Brien KP et al: Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas. Genes Chromosomes Cancer. 23(2):187-93, 1998 105. Alman BA et al: Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol. 151(2):329-34, 1997 106. Dal Cin P et al: Lesions of 13q may occur independently of deletion of 16q in spindle cell/pleomorphic lipomas. Histopathology. 31(3):222-5, 1997 107. Simon MP et al: Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 15(1):95-8, 1997 108. Clark J et al: Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma. Oncogene. 12(2):229-35, 1996 109. Ashar HR et al: Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell. 82(1):57-65, 1995 110. Crew AJ et al: Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma. EMBO J. 14(10):2333-40, 1995 111. Fligman I et al: Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript. Am J Pathol. 147(6):1592-9, 1995 112. Gerald WL et al: Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proc Natl Acad Sci U S A. 92(4):1028-32, 1995 113. Davis RJ et al: Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res. 54(11):2869-72, 1994 114. Mertens F et al: Hibernomas are characterized by rearrangements of chromosome bands 11q13-21. Int J Cancer. 58(4):503-5, 1994 115. Pedeutour F et al: Complex composition and co-amplification of SAS and MDM2 in ring and giant rod marker chromosomes in well-differentiated liposarcoma. Genes Chromosomes Cancer. 10(2):85-94, 1994

Bone and Soft Tissue Table

Schwannoma (Left) Graphic shows a chordoma of the clivus extending into the sphenoid sinus. The tumor has a gray, translucent appearance and expands and erodes the bone, causing focal destruction of the bony cortex. These tumors may be associated with familial chordoma or with tuberous sclerosis. (Right) Bilateral schwannomas involving the vestibular branch of CN VIII are a hallmark of neurofibromatosis type 2, present as a cerebropontine angle mass ﬉, and may be multiple.

Chondrosarcoma

Diagnoses Associated With Syndromes by Organ: Bone and Soft Tissue

Chordoma

Neurofibromas (Left) Chondrosarcoma with a tan-gray glistening appearance fills the medullary cavity of the proximal diaphysis, greater trochanter, and base of the femoral neck. It can be present in hereditary multiple exostosis, Li-Fraumeni syndrome, and hereditary retinoblastoma. (Right) Graphic shows bilateral spinal nerve roots and branchial plexus neurofibromas in NF1. There is lobulated tortuous expansion of the cervical nerve roots with widening of the neural foramina.

Nonossifying Fibroma

Osteosarcoma (Left) Graphic shows a nonossifying fibroma in a patient with hyperparathyroidism-jaw tumor syndrome, presenting as a large maxillary mass. The mass obstructs one side of the nose and compresses the eye. (Right) Graphic shows osteosarcoma arising from the lateral aspect of C5. The firm, pink, solid mass has transgressed the cortex and extended into the soft tissues. These tumors may be associated with hereditary retinoblastoma, Li-Fraumeni, Rothmund-Thomson, Bloom, and Werner syndromes.

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PART I SECTION 3

Breast Breast Carcinoma Breast Table

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Diagnoses Associated With Syndromes by Organ: Breast

Breast Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS • Long recognized that many women with breast cancer also have affected relatives • ~ 10-25% of women with breast cancer have 1st-degree relative (parent, sister, daughter) with breast cancer • Increased risk is associated with families with premenopausal breast cancer, multiple affected individuals, individuals with multiple cancers, and certain types of breast and other cancers • Familial cancers associated with germline mutations: ~ 1/2 of familial cases or 5-10% of all breast cancers ○ 15 major germline mutations that contribute to breast cancer risk – High-risk genes (≥ 4x increased risk): BRCA1, BRCA2, TP53, CDH1, PALB2, PTEN, STK11 □ Together, these genes account for ~ 20% of familial risk – Moderate-risk genes (2-4x increased risk): ATM, CHEK2

□ Together, these genes account for ~ 5% of familial risk – Low-risk genes (differing results in studies): BARD1, BRIP1, NBN, RAD51C, RAD51D, NF1 □ These genes and numerous other low-risk genes (> 170) account for ~ 18% of familial risk ○ Features in common – Autosomal dominant inheritance □ Inherited via females and males – Majority of genes are associated with DNA repair pathways – Breast cancers occur at earlier ages compared to sporadic cancers and are often multiple and bilateral – Risk of some nonbreast cancers increased • Familial cancers not associated with identified germline mutations: ~ 1/2 of familial cases or 5-10% of all breast cancers ○ Source of risk in these families has not yet been identified

Familial Breast Cancer

Family history is a powerful tool for detecting highly penetrant genes responsible for breast cancer susceptibility. This pedigree is very suggestive of a germline mutation due to the presence of multiple affected family members and the development of cancers at a young age. Genetic testing could determine whether any of the currently recognized mutations are present or establish the significance of a yet undescribed mutation if it consistently maps to individuals with cancer.

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Breast Carcinoma

Hereditary Breast Cancer • Long recognized that many women with breast cancer also have affected relatives ○ ~ 10-25% of women with breast cancer have 1st-degree relative (parent, sister, daughter) with breast cancer – Having affected 1st-degree relative increases risk by 23x ○ Increased risk is associated with families with premenopausal breast cancer, multiple affected individuals, individuals with multiple cancers, and certain types of breast and other cancers – However, most common family history is mother developing breast cancer after menopause □ Sporadic breast cancer in this age group is very common □ Does not increase risk of breast cancer for daughter • Familial cancers associated with germline mutations: ~ 1/2 of familial cases or 5-10% of all breast cancers ○ 15 major germline mutations that contribute to breast cancer risk – High-risk genes (≥ 4x increased risk): BRCA1, BRCA2, TP53, CDH1, PALB2, PTEN, STK11 □ Together, these genes account for ~ 20% of familial risk – Moderate-risk genes (2-4x increased risk): ATM, CHEK2 □ Together, these genes account for ~ 5% of familial risk – Low-risk genes (differing results in studies): BARD1, BRIP1, NBN, RAD51C, RAD51D, NF1 □ These genes and numerous other low-risk genes (> 170 genes) account for ~ 18% of familial risk ○ Many of these genes are functionally related to each other – Genes functionally related to BRCA1 and BRCA2: BARD1, CHEK2, NBN, RAD51D – Genes in Fanconi anemia pathway: PALB2, RAD51C (FANCO), BRIP1, RAD51B ○ Features common to all major germline mutations – Autosomal dominant inheritance □ Normal protein function is lost when remaining wild-type allele is rendered nonfunctional or abnormal; however, in some cases mutated protein interferes with function of normal protein (dominant negative mutations) □ Specific mutations may vary in degree of risk: Truncating mutations (in general) confer greater risk than missense mutations □ Inherited via both females and males: Multiple individuals in family are usually affected – Majority of identified genes are associated with DNA repair pathways □ Act as tumor suppressor genes in normal cells to maintain DNA integrity and control proliferation □ Relative tissue specificity for breast cancer has not been explained – Breast cancers occur at earlier ages compared to sporadic cancers and are often multiple and bilateral □ 1st mutation present at birth

□ Destabilization of genome increases likelihood of additional mutations – Risk of some nonbreast cancers is also increased ○ Features specific to certain germline mutations – Type of breast carcinoma □ BRCA1: Negative for estrogen receptor (ER), progesterone receptor (PR), and HER2 with basallike gene expression pattern (~ 90%) □ BRCA2: ER positive, HER2 negative, high-grade, luminal B-type gene expression pattern □ TP53: ER positive, HER2 positive (~ 40-50%) □ CDH1: Lobular carcinomas □ ATM: ER positive, HER2 negative (~ 80%), ER positive, HER2 positive (~ 15%) □ Specific tumor types have not been reported for other mutations – Risk of male breast cancer □ 15-20% of males with breast cancer have family history of breast or ovarian cancer □ Increased risk for some mutations (BRCA2 lifetime risk 7%; BRCA1 lifetime risk 1.8%; PTEN lifetime risk unknown) – Penetrance (% of carriers who develop cancer) □ > 95% lifetime risk for some mutations □ Other genes have lower penetrance (20% or lower lifetime risk) – Spectrum of nonbreast cancers □ Types of other cancers vary according to gene and sometimes are different for specific mutations – Founder mutations in ethnic populations □ Some populations have very high incidences of specific mutations – Homozygosity □ Homozygosity for some mutations confers disease (e.g., BRCA2 and BRIP1: Fanconi anemia; ATM: Ataxia-telangiectasia) □ Homozygosity for other mutations is likely lethal (e.g., BRCA1) ○ Role of somatic mutations in genes responsible for hereditary breast cancer – TP53 is frequently mutated in sporadic carcinomas – BRCA1 and BRCA2 mutations are rare □ Genes may be inactivated by other mechanisms such as methylation – CDH1 is inactivated by somatic mutations in lobular cancers • Familial cancers not associated with identified germline mutations: ~ 1/2 of familial cases or 5-10% of all breast cancers ○ Source of risk in these families has not yet been identified

Diagnoses Associated With Syndromes by Organ: Breast

ETIOLOGY/PATHOGENESIS

CLINICAL ISSUES BRCA1 (Hereditary Breast and Ovarian Cancer Syndrome) • Function ○ BReast CAncer 1 (BRCA1) encodes for protein with central role in DNA repair, regulation of cell cycle checkpoints in response to DNA damage, and transcription 47

Diagnoses Associated With Syndromes by Organ: Breast

Breast Carcinoma

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– Required for error-free DNA double-strand break repair ○ BRCA1 function is required for transactivation of ER gene promoter – May explain why 90% of BRCA1-associated carcinomas are negative for ER Incidence: 0.1-0.3% ○ More common in some ethnic groups: Ashkenazi Jews, Finns, French Canadians ○ Mean age of onset is 44 years, but age can vary with specific mutations ○ Mutation can be suspected in young patients (35% risk for patients < 30 years of age with ER-negative poorly differentiated cancer) Lifetime risk of breast cancer (F): 40-90% (relative risk 11.4) ○ Magnitude of risk can vary for different mutations and for different types of cancers ○ Responsible for ~ 1/2 of cancers known to be due to germline mutation (~ 2% of all breast cancers) Breast cancer ○ ~ 70-80% of BRCA1 cancers share same gene expression pattern with basal-type carcinomas defined by gene expression profiling – Basal-type carcinomas overlap with triple-negative breast cancer (TNBC) (lack expression of hormone receptors and HER2) by ~ 80% – 10-25% of women < 50 years of age with TNBC have BRCA1 mutation – Majority have somatic mutations in p53 – Majority positive for basal markers such as EGFR (HER1) and high molecular weight cytokeratins (e.g., 5/6, 14) ○ Majority (~ 80%) of invasive carcinomas have distinctive morphology – Circumscribed growth pattern with pushing borders, dense lymphocytic infiltrate – High nuclear grade and high proliferative rate ○ ~ 20-30% of BRCA1 cancers are ER positive and HER2 negative – More common in women developing cancer at age > 50 years – ~ 85% show loss of wild-type BRCA1 allele supporting that these are not sporadic cancers Other associated cancers ○ Ovarian, fallopian tube, primary peritoneal (40-50% lifetime risk) – Usually high-grade serous carcinomas – ~ 80% of women with both breast and ovarian cancer have BRCA mutation – Average age of onset: 49-53 years (compared to 63 years in general population) ○ Male breast cancer (1-5% lifetime risk, but ~ 1/2 risk of BRCA2) ○ Possibly pancreatic cancer, colon cancer, and others

BRCA2 (Hereditary Breast and Ovarian Cancer Syndrome) • Function

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○ BReast CAncer 2 (BRCA2) is not structurally related to BRCA1, but both genes have very similar functions and regulatory roles Incidence: 0.1-0.7% ○ More common in some ethnic groups: Ashkenazi Jews, Icelandic populations ○ Mean age of onset is 47 years, but can vary with specific mutations Lifetime risk of breast cancer (F): 45-85% (relative risk 11.7) ○ Magnitude of risk can vary for different mutations and for different types of cancers ○ Responsible for ~ 1/2 of cancers known to be due to germline mutation (~ 2% of all breast cancers) Breast cancer ○ Group with luminal A or B by gene expression profiling – Positive for hormone receptors and negative for HER2 ○ Majority are high grade Other associated cancers and diseases ○ Ovary, fallopian tube, primary peritoneal (10-20% lifetime risk) – Usual age of onset is 55-58 years (compared to 63 years in general population) ○ Male breast cancer: 5-10% lifetime risk; ~ 5-15% of cases are associated with BRCA2 – Also increased risk of early-onset aggressive prostate cancer ○ Pancreatic cancer, prostate cancer ○ Homozygous BRCA2 mutations cause rare form of Fanconi anemia

TP53 (Li-Fraumeni Syndrome) • Function ○ Tumor Protein 53 (TP53) encodes for protein with central role in cell cycle control, DNA replication, DNA repair, and apoptosis • Incidence: 0.0025% ○ Population in southeastern Brazil has 1/300 incidence – Early onset: Average age at diagnosis is 33 years – ~ 55% of women will develop breast cancer by age 45 – ~ 2-7% of women with breast cancer were diagnosed at < 30 years of age – Rare for breast cancer to be diagnosed after age 50 • Lifetime risk of breast cancer (F): > 90% (relative risk ~ 60-165) ○ Penetrance varies for different mutations • Breast cancer ○ 1/3 of malignancies in affected families ○ Most common type is ER positive and HER2 positive (~ 55%) ○ Male breast cancer is rare • Other associated cancers ○ Sarcomas: Most occur in children < 10 years of age ○ Adrenal cortical carcinoma: Most occur in children ~ 3 years of age ○ Brain tumors: Occur in children or in 4th-5th decades ○ Leukemia

CDH1 (Familial Gastric Cancer and Lobular Breast Cancer Syndrome) • Function

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Breast Carcinoma

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PTEN (Cowden Syndrome) • Function ○ Phosphatase and TENsin homolog (PTEN) encodes for dual specificity phosphatase gene involved in control of proliferation signals and apoptosis • Incidence: 0.0005% ○ Early onset; most women diagnosed between 38-46 years of age • Lifetime risk of breast cancer (F): 25-85% • Breast cancer ○ Men also at increased risk for breast cancer; magnitude of risk not yet determined ○ Other breast lesions include fibroadenomas and hamartomas • Other associated tumors ○ Multiple hamartomas (including trichilemmomas) ○ Thyroid and endometrial cancer

STK11/LKB1 (Peutz-Jeghers Syndrome) • Function ○ Serine/Threonine Kinase 11 (a.k.a. Liver Kinase B1) encodes serine/threonine kinase involved in cell cycle regulation and mediation of apoptosis • Incidence: 0.001% ○ Early onset: 8% by age 40 and 32% by age 60 • Lifetime risk of breast cancer (F): ~ 40% • Breast cancer

○ No reported specific histologic types • Other associated lesions ○ Hamartomatous gastrointestinal polyps (including small intestine) ○ Mucocutaneous pigmentation (lips and buccal mucosa) ○ Ovarian cancer (sex cord stromal tumors are most common): ~ 20% risk ○ Increased risk of cancer of colon, pancreas, small intestine, thyroid, lung, uterus, ovary, and cervix (adenoma malignum)

PALB2 • Function ○ Partner And Localizer of BRCA2 (PALPB2) encodes for protein that binds to BRCA2 protein and is part of complex responsible for homologous recombination and double-strand DNA break repair • Incidence: 0.1% • Lifetime risk of breast cancer (F): 35-60% (relative risk ~ 5) • Breast cancer ○ May increase risk of TNBC • Other associated diseases ○ Possibly pancreatic cancer and ovarian cancer ○ Fanconi anemia when homozygous (PALB2 is also termed FANCN)

Diagnoses Associated With Syndromes by Organ: Breast

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○ CaDHerin 1 (CDH1) encodes for epithelial cadherin (Ecadherin), which is cell adhesion molecule ○ Mutations interfere with function – 75-80% are truncating mutations, 20-25% are missense mutations, and 7% are large deletions – Loss of protein results in cells rounding up and singlecell infiltrative pattern due to lack of adhesion to adjacent cells □ Cytoplasmic mucin creates appearance of signet ring cells Incidence: 0.005% Lifetime risk of breast cancer (F): ~ 40-55% (relative risk ~ 7) Breast cancer ○ Women are at increased risk for lobular carcinoma – However, majority of women with lobular carcinomas do not have CDH1 germline mutations Other associated cancers ○ 70-85% lifetime risk of developing gastric signet ring cell carcinoma in majority of families – Gastric carcinomas are more common than breast carcinomas in most affected families – Families developing only breast cancer have also been identified ○ Gastric signet ring cell carcinomas morphologically resemble breast lobular carcinomas – These cancers can be distinguished by protein expression □ Gastric carcinomas are typically ER positive, PR negative, GCDFP-15 negative, and MUC1 negative, while typically CDX-2 positive and Hep-Par1 positive □ Breast carcinomas are typically ER positive, PR positive, GCDFP-15 positive, and MUC1 positive

ATM (Ataxia-Telangiectasia Carriers) • Function ○ Ataxia-Telangiectasia Mutated (ATM) codes for serine threonine kinase that phosphorylates p53 and BRCA1 in response to DNA double-strand breaks • Incidence: 0.5% • Lifetime risk of breast cancer (F): 25-40% (relative risk ~ 3) ○ Varies with specific mutation ○ Earlier onset than sporadic breast cancer • Breast cancer ○ Majority intermediate to high grade ○ ~ 80% positive for ER and negative for HER2 and ~ 15% positive for both ER and HER2 – < 5% are negative for ER and positive for HER2 or negative for both • Other associated lesions ○ Heterozygotes may be more susceptible to DNA damage from radiation ○ Possibly pancreatic cancer ○ Homozygosity results in ataxia-telangiectasia

CHEK2 • Function ○ CHEckpoint Kinase 2 (CHEK2) encodes for serine threonine kinase that phosphorylates p53 and BRCA1 to halt cell division in response to DNA damage • Incidence: 0.2-0.3% ○ 0.5-1% in eastern and northern European populations ○ Later onset of breast cancer • Lifetime risk of breast cancer (F): ~ 30% (relative risk ~ 2) ○ Varies depending on specific mutation and whether or not there is family history of breast cancer • Breast cancer ○ Increased risk for males 49

Diagnoses Associated With Syndromes by Organ: Breast

Breast Carcinoma

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○ Cancers are usually ER positive • Other associated cancers ○ May be linked to prostate, lung, colon, kidney, and thyroid cancer but degree of risk is unclear

REPORTING Genetic Testing • Population to be tested ○ National Comprehensive Cancer Network (NCCN), U.S. Preventative Services Task Force, National Institute for Health and Care Excellence, and other organizations recommend testing individuals at high risk for having pathogenic mutation in breast cancer predisposition gene – NCCN version 3.2019 is available at www.nccn.org – In general, high risk is defined as > 10% likelihood of having mutation □ However, up to 50% of women with germline mutations (particularly in lower risk/lower penetrance genes) may not fulfill criteria for testing □ In addition, some individuals may lack family history due to adoption, sperm donation, very small family size, or other reasons ○ Criteria to identify high-risk individuals generally include (but are not limited to) – Personal history of breast cancer at < 50 years, TNBC at < 60 years, multiple breast cancers – 1st-degree relatives with known germline mutation, breast cancer at < 50 years, male breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer with Gleason score ≥ 7 – Relatives with nonbreast cancers associated with specific germline mutations □ Male breast cancer for BRCA2 and BRCA1 □ Ovarian, fallopian tube, or primary peritoneal cancers for BRCA1 and BRCA2 □ Sarcomas for TP53 – Membership in groups at high risk for certain mutations (e.g., Ashkenazi Jewish heritage) – Relatives with diseases due to homozygous mutations □ Ataxia-telangiectasia for ATM □ Fanconi anemia for BRCA2 and BRIP1 ○ For family, it is most useful to begin testing 1 individual with cancer – If multiple affected individuals are present within kindred, testing can establish linkage between cancer(s) and mutation – Once mutation is detected, other family members without cancer may choose testing ○ Counseling should occur before testing to ensure patient is aware of possible implications for individual and family • Classification of results ○ Mutations are classified into 5 groups – Benign or likely benign: Both are considered negative result – Pathogenic or likely pathogenic: Both are considered positive result – Variants of unknown significance (VUS): Should not be used for patient management □ Genetic polymorphism that has not yet been associated with increased risk of cancer

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•

•

□ Found in 3-7% of individuals tested for BRCA1 and BRCA2 □ > 1,500 identified □ More frequent in minority ethnic populations because they are underrepresented in genetic databases □ Must be identified in multiple individuals to determine clinical significance Extent of testing ○ Full genome sequencing is required to detect all mutations – May become feasible in near future – Does not detect all genetic alterations ○ Limited sequence analysis can be used to detect most likely mutation – Common mutations found in ethnic groups, e.g., 2 BRCA1 and 1 BRCA2 mutations comprise 90% of mutations found in Ashkenazi Jewish population – Hotspots for mutations within gene – Detection of known mutation in family ○ Duplications, inversions, large deletions, and mutations in noncoding regions may not be detected by standard sequence analysis – 18% of genetic changes in BRCA1 and BRCA2 are not detected by standard testing – Also underlie pathogenic variants in other breast cancer predisposition mutations – BRACAnalysis Large Rearrangement Test (BART) detects some rearrangements – Account for 17% of deleterious mutations in individuals from Near East/Middle East and 22% of deleterious mutations in individuals from Latin America/Caribbean Single gene testing ○ Useful when relative has known germline mutation, individual belongs to group with founder mutation of high frequency, or family history is highly suggestive of mutation in specific gene – However, mutations in other genes may be missed ○ Of all individuals meeting recommended criteria for testing for BRCA1/BRCA1, ~ 10% will be found to have germline mutation – However, in only ~ 1/3 will mutation be in BRCA1/BRCA1 – In addition, ~ 6% of individuals who have BRCA1/BRCA1 germline mutation do not meet criteria for testing for these genes – Therefore, multigene testing is required to detect majority of germline mutations Multigene panel testing ○ Currently most common method of testing ○ Companies offer different sets of panels and extent of testing – Can offer results on from 5-50 or more genes – May or may not offer evaluation of deletions and duplications ○ Increases number of VUSs detected Direct to consumer testing ○ Typically only includes most common mutations

Breast Carcinoma

Medical Care of Individuals With Germline Mutations • Overview ○ Identification of pathogenic germline mutation may modify medical care in multiple areas – Notification of relatives at possible risk – Chemoprevention – Prophylactic surgery – Screening – Alterations in cancer therapy targeted to mutation for patients who have cancer – Assisted reproduction to avoid passing mutation to next generation ○ Benefit of interventions is greatest for individuals with high-risk mutations and less certain for those with moderate-risk mutations • Chemoprevention ○ Tamoxifen reduces risk of ER-positive cancer for women with family history of breast cancer – However, risk of endometrial cancer and thrombosis is increased ○ Benefit of chemoprevention for primary prevention of breast cancer for individuals with germline mutations is not yet clear • Screening ○ Clinical breast examination 2x yearly starting at age 25 is recommended – Patient self-breast awareness with periodic breast examinations ○ Mammography at earlier age (10 years before age at which youngest relative with cancer was diagnosed) or more frequently ○ MR screening more sensitive than mammography in young women with dense breasts – However, lower specificity leads to greater numbers of biopsies for benign lesions ○ Screening by mammography and MR may be staggered every 6 months to decrease screening interval • Prophylactic surgery ○ Bilateral mastectomy reduces risk of breast cancer by 97% – Not all breast tissue can be removed in all patients with acceptable cosmetic results

– Major benefit to women prior to development of breast cancer; limited or no benefit after breast cancer diagnosis with possible distant metastases ○ Bilateral salpingo-oophorectomy reduces risk of ovarian and fallopian tube cancer by 70-95% – Relevant for mutations that increase risk of both breast and ovarian cancer – Women remain at risk for primary peritoneal cancers – Reduces risk of breast cancer by 50% in premenopausal women, presumably due to decrease in hormone production – Reduces risk of ER-negative breast cancers for BRCA1 patients to lesser degree; mechanism is unknown • Alterations in recommendations for systemic therapy ○ For patients with advanced breast cancer, presence of germline mutation may alter type of therapy – BRCA1/BRCA1: Platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors (olaparib or talazoparib) – BRCA1/BRCA1-associated TNBC: Carboplatin • Childbearing ○ Assisted reproduction can be used to prevent germline mutation being passed on to children

Diagnoses Associated With Syndromes by Organ: Breast

– If negative result is obtained, and there is strong likelihood of germline mutation due to personal or family history, more comprehensive testing by certified laboratory should be pursued – If positive result is obtained, result should be confirmed by certified laboratory □ In one study, 40% of positive results obtained by direct to consumer testing could not be confirmed by certified laboratory • Polygenic risk scores (PRS) ○ Common (> 1% incidence) single nucleotide polymorphisms can slightly increase risk of breast cancer – > 170 genes with mutations conferring low risk of breast cancer have been identified ○ Although of little significance alone, multiple polymorphisms can be combined into PRS to modify risk estimates for individuals with germline mutations ○ In combination, these low-risk genes may account for ~ 18% of familial risk of breast cancer

SELECTED REFERENCES 1.

LaDuca H et al: A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med. ePub, 2019 2. Wendt C et al: Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer. Acta Oncol. 58(2):135-46, 2019 3. Yadav S et al: Germline genetic testing for breast cancer risk: the past, present, and future. Am Soc Clin Oncol Educ Book. 39:61-74, 2019 4. Hoang LN et al: Hereditary breast and ovarian cancer syndrome: moving beyond BRCA1 and BRCA2. Adv Anat Pathol. 25(2):85-95, 2018 5. Ibrahim M et al: Male BRCA mutation carriers: clinical characteristics and cancer spectrum. BMC Cancer. 18(1):179, 2018 6. Renault AL et al: Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers. Breast Cancer Res. 20(1):28, 2018 7. Tandy-Connor S et al: False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 20(12):1515-21, 2018 8. Michailidou K et al: Association analysis identifies 65 new breast cancer risk loci. Nature. 551(7678):92-4, 2017 9. Drohan B et al: Hereditary breast and ovarian cancer and other hereditary syndromes: using technology to identify carriers. Ann Surg Oncol. 19(6):1732-7, 2012 10. Xie ZM et al: Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer. 117(14):3112-7, 2011 11. Vargas AC et al: The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 9(4):545-53, 2010 12. Gorski JJ et al: The complex relationship between BRCA1 and ERalpha in hereditary breast cancer. Clin Cancer Res. 15(5):1514-8, 2009

51

Diagnoses Associated With Syndromes by Organ: Breast

Breast Carcinoma Familial Breast Cancer: Multiple Invasive Cancers

BRCA1: Screening MR

BRCA1: T-Cell Lymphocytic Lobulitis

BRCA1: Ductal Carcinoma In Situ

BRCA1: Invasive Breast Cancer

BRCA1: Invasive Breast Cancer

(Left) Patients with germline mutations are more likely to develop multiple breast cancers ﬇, either synchronously or metachronously, either ipsilateral or contralateral. Cancers typically occur in younger individuals. (Right) MR can be a useful technique for screening young, high-risk women with dense breasts. This woman with a BRCA1 mutation has an area of clumped linear enhancement on MR ſt that proved to be ductal carcinoma in situ (DCIS) that was not detected by screening mammography.

(Left) Perilobular lymphocytic lobulitis can be seen in the breast tissue of women with BRCA1 mutations. The lymphocytes are predominantly T cells, as are the lymphocytes associated with carcinomas. Benign inflammatory lesions of the breast are associated with B cells. (Right) DCIS associated with BRCA1 mutations can be very subtle histologically. It often has a clinging pattern of cells with high-grade nuclei and is associated with a lymphocytic infiltrate. DCIS is negative for ER, PR, and HER2.

(Left) BRCA1-associated breast cancers typically have circumscribed borders and a prominent lymphocytic infiltrate ﬈. These cancers can be mistaken for benign lesions or lymph node metastases. (Right) BRCA1 carcinomas have high-grade nuclei and the cells grow in a sheet-like pattern. There is typically a dense lymphocytic infiltrate. Almost all carcinomas are negative for ER, PR, and HER2. 10-25% of women under the age of 50 with this type of carcinoma will have a germline mutation.

52

Breast Carcinoma

BRCA2: Male Breast Cancer (Left) The majority of hereditary breast cancer genes are tumor suppressors. Proteins, such as BRCA2, are expressed in normal cells ﬈. When the normal allele is mutated, expression is lost ﬊, resulting in genomic instability and the formation of tumors, such as this invasive breast cancer. (Right) BRCA2 mutations confer a higher risk of male breast cancer over BRCA1 mutations. Cancers are usually ER positive. This BRCA2-associated lobular carcinoma in a male patient has high-grade nuclei ﬉ and is negative for E-cadherin.

CDH1: Invasive Lobular Carcinoma

Diagnoses Associated With Syndromes by Organ: Breast

BRCA2: Invasive Breast Cancer

CDH1: Invasive Lobular Carcinoma (ECadherin) (Left) Germline CDH1 mutations increase the risk of lobular carcinomas. Due to the loss of cell adhesion, the cells are rounded and infiltrate as single cells. Many lobular carcinomas form signet ring cells that typically have a single vacuole with a mucin droplet ﬈. (Right) A germline mutation in CDH1 (coding for E-cadherin), combined with somatic silencing or mutation of the normal allele, generally results in the absence of expression in lobular carcinomas ﬈. Adjacent normal ducts are positive ﬊.

TP53: Invasive Breast Cancer (HER2)

TP53: Invasive Breast Cancer (p53) (Left) From 40-50% of TP53associated breast carcinomas are positive for ER and HER2 (shown here). In contrast, this type of carcinoma comprises only 10% of sporadic cancers. (Right) TP53 mutations can cause either loss of function or gain of function. Many mutated forms fail to be degraded, resulting in protein accumulation in the nucleus ﬊. Loss-of-function mutations result in complete absence of p53, which is also an abnormal pattern.

53

Diagnoses Associated With Syndromes by Organ: Breast

Breast Table

54

Germline Mutations Associated With Increased Risk of Breast Cancer Gene

Population Frequency

% of Breast Cancers

Risk of Breast Cancer by Age 70

Type of Breast Cancer

Other Cancers

Involvement in Sporadic Cancers

Comments

BRCA1 (17q21) Hereditary breast/ovarian cancer syndrome

0.1-0.3%

~ 2% of all cancers; ~ 50% of germlineassociated cancers

40-90%

Majority ER/PR/HER2 negative (TNBC); basal-like by mRNA profiling

Male breast (1-5% risk), ovary, fallopian tube, peritoneal, possibly pancreas or prostate

Mutations are rare; gene may be inactivated by methylation 

Somatic TP53 mutations common

BRCA2 (13q12.3) Hereditary breast/ovarian cancer syndrome

0.1-0.7%

~ 2% of all cancers; ~ 50% of germlineassociated cancers

~ 45-85%

Majority ER positive, PR/HER2 negative, luminal B/HER2 negative

Male breast (7% Mutations and risk), ovary, loss of expression fallopian tube, rare peritoneal, pancreas, prostate

Homozygous germline mutations cause rare form of Fanconi anemia

TP53 (17p13.1) Li-Fraumeni syndrome

0.005-0.020%

< 1% of all breast cancers; ~ 3% of germlineassociated cancers (~ 6% if diagnosed at < 31 years)

> 90%

~ 40-50% ER/HER2 positive (luminal B/HER2); ~ 40% ER positive/HER2 negative (luminal); ~ 15% ER negative/HER2 positive (HER2 enriched)

Sarcoma, adrenal cortical carcinoma, CNS tumors, leukemia, others

TP53 is most commonly mutated gene in sporadic cancers

Individuals are at increased risk of different types of tumors throughout life; breast cancer is most common malignancy in affected women

CDH1 (16q22.1) 0.005% Familial gastric cancer and lobular breast cancer syndrome

< 1% of all breast cancers; ~  0.2-1% of germlineassociated cancers

~ 40-55%

Lobular, ER positive/HER2 negative (luminal)

Signet ring cell gastric cancer

Sporadic lobular carcinomas have somatic CDH1 mutations

Very few women with lobular carcinoma have germline mutations

PTEN (10q23.3) Cowden syndrome

0.0005%

< 1% of all breast cancers: ~  0.3% of germlineassociated cancers

25-85%

No special features Male breast, reported thyroid, endometrial cancer

STK11/LKB1 (19p13.3) Peutz-Jeghers syndrome

0.001%

< 1% of all breast cancers; ~  0.6% of germlineassociated cancers

~ 40%

No special features Colon, pancreas, reported small intestine, thyroid, lung, endometrial cancer, ovary, cervix

PALB2/FANCN (16p12.1)

0.1%

< 1% of all breast cancers; < 1% of germlineassociated cancers

~ 35-65%

May increase risk of TNBC

Possibly pancreas and ovary

Homozygosity results in Fanconi anemia

ATM (11q22q23) Ataxiatelangiectasia heterozygotes

0.5%

< 1% of all breast cancers; < 1% of germlineassociated cancers

~ 25-40%

~ 80% ER positive/HER2 negative (luminal); ~ 15% ER/HER2 positive (luminal B/HER2)

Possibly pancreas

Homozygosity results in ataxiatelangiectasia

CHEK2 (22q12.1)

0.5%

< 1% of all breast cancers; < 1% of germlineassociated cancers

30%

Usually ER positive Male breast cancer; possibly colon, prostate, thyroid, kidney 

Men are also at increased risk of breast cancer (magnitude of risk uncertain)

Mutations rare; loss of expression by unknown mechanisms

May increase risk of breast cancer after radiation exposure

Breast Table

Feature

BRCA1

BRCA2

Chromosome

17q21

13q12.3

Gene size

81 kb

84 kb

Protein size

1,863 amino acids

3,418 amino acids

Function

Tumor suppressor: Role in double-stranded DNA repair, transcriptional regulation (e.g., estrogen receptor)

Tumor suppressor: Role in double-stranded DNA repair, transcriptional regulation

Mutations

> 1,000

> 1,000

Incidence of mutations in population

~ 0.1-0.3%

~ 0.1-0.7%

Groups with increased incidence

Ashkenazi Jews (2 mutations), Finns, French Canadians, families in Sweden, Iceland, others

Ashkenazi Jews (1 mutation), families in Iceland, others

Risk of breast cancer by age 70

40-90%

45-85%

Risk of ovarian cancer (including fallopian tube and peritoneum)

40-50%

11-18%

Risk of male breast cancer

1-5%

7%

Age of onset of female breast cancer

44 years

47 years

Age of onset of ovarian cancer

49-53 years

55-58 years

Proportion of families with breast cancer due to single gene

~ 50%

~ 50%

Proportion of families with breast and ovarian cancer

80%

15%

Proportion of families with female and male breast cancer

< 4%

60-75%

Other associated cancers

Possibly pancreas and prostate (but risk lower than for BRCA2)

Prostate, pancreas, stomach, gallbladder, bile duct, gallbladder

Alterations in sporadic breast cancer

Mutations very rare (< 5%) inactivation may occur by methylation

Mutations very rare (< 5%)

Diagnoses Associated With Syndromes by Organ: Breast

BRCA1 and BRCA2

Pathologic Features of Breast Cancers Histologic type

Many with circumscribed borders, sheet-like growth pattern, and lymphocytic infiltrate; described as having medullary features

Majority of no special type (ductal), but percent of cancers with lobular pattern may be relatively increased

DCIS

Absent or scant

Common

Grade

> 95% poorly differentiated

Majority moderately to poorly differentiated

Hormone receptors

70-80% negative

> 80% positive (but may be at low levels)

HER2

> 95% negative

> 95% negative

TP53 mutations

> 90% of cancers

30-65% of cancers

Molecular type by mRNA gene expression profiling 

Majority basal-like

Majority luminal B/HER2 negative

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PART I SECTION 4

Endocrine Adrenal Cortex Adrenal Cortical Adenoma Adrenal Cortical Carcinoma Adrenal Cortical Neoplasms in Children Primary Pigmented Nodular Adrenocortical Disease Adrenal Cortex Table

58 62 70 78 84

Adrenal Medulla and Paraganglia Adrenal Medullary Hyperplasia Neuroblastic Tumors of Adrenal Gland Pheochromocytoma and Paraganglioma Adrenal Medulla and Paraganglia Table

88 92 104 114

Pancreas Pancreatic Neuroendocrine Neoplasms Endocrine Pancreas Table

118 128

Parathyroid Parathyroid Adenoma Parathyroid Carcinoma Primary Parathyroid Hyperplasia Parathyroid Table

130 136 142 152

Pituitary Pituitary Adenoma Pituitary Hyperplasia Pituitary Table

158 164 166

Thyroid, Medullary C-Cell Hyperplasia Medullary Thyroid Carcinoma Thyroid, Medullary Carcinoma Table

170 176 186

Thyroid, Nonmedullary Familial Thyroid Carcinoma Follicular Thyroid Carcinoma Thyroid, Nonmedullary Carcinoma Table

188 200 208

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Adenoma KEY FACTS

TERMINOLOGY • Benign neoplasm arising from adrenal cortical cells

ETIOLOGY/PATHOGENESIS • Associated with syndromes ○ Multiple endocrine neoplasia 1 (MEN1) ○ McCune-Albright syndrome ○ Carney complex ○ Beckwith-Wiedemann syndrome ○ Congenital adrenal hyperplasia ○ Familial adenomatous polyposis ○ Neurofibromatosis type 1 ○ von Hippel-Lindau syndrome ○ Carney triad • Sporadic

MICROSCOPIC • Smooth, pushing borders without well-defined fibrous capsule

• Clear cytoplasm that is finely vacuolated due to intracytoplasmic lipid droplets • Cells are larger than in normal adrenal and have pleomorphic nuclei • Nuclei are single, round/oval, with chromatin margination and single dot-like nucleolus • Mixed pattern with oxyphilic and clear cells • Mixed composition of pale-staining, lipid-rich cells and cells with lipid-poor compact cytoplasm

ANCILLARY TESTS • Positive for adrenal cortical markers, such as inhibin, MART1, calretinin, SF1, CD56, and Melan-A

TOP DIFFERENTIAL DIAGNOSES • Adrenal cortical carcinoma • Pheochromocytoma • Metastatic renal cell carcinoma

Adrenal Cortical Adenoma Cut Surface

This well-circumscribed adenoma has a homogeneous yellow cut surface, and there is marked atrophy of the attached adrenal cortex ſt. Adrenal cortical adenomas can be seen in patients with multiple endocrine neoplasia 1 (MEN1) syndrome, McCune-Albright syndrome, Carney complex, Beckwith-Wiedemann syndrome, familial adenomatous polyposis, neurofibromatosis 1, von Hippel-Lindau syndrome, Carney triad, and congenital adrenal hyperplasia.

58

Adrenal Cortical Adenoma

Abbreviations • Adrenal cortical adenoma (ACA)

Treatment • Surgical unilateral adrenalectomy

IMAGING

Synonyms

MR Findings

• • • •

• Homogeneous • Signal intensity less than fat but greater than muscle • Similar intensity to liver on T1 and T2

Cortisol-producing adrenocortical adenoma Aldosterone-producing adrenal adenoma Cushing syndrome Functional and nonfunctional adrenal adenoma

Definitions • Benign epithelial tumor arising from adrenal cortical cells ± hormone hypersecretion

ETIOLOGY/PATHOGENESIS Syndromes Associated With Adrenal Cortical Adenoma • • • • • • • • •

Multiple endocrine neoplasia 1 (MEN1) McCune-Albright syndrome Carney complex Beckwith-Wiedemann syndrome Familial adenomatous polyposis Neurofibromatosis type 1 Congenital adrenal hyperplasia von Hippel-Lindau syndrome Carney triad

CT Findings • Well defined with smooth borders, homogeneous • Attenuation values less than normal adrenal tissue • May enhance after contrast administration

MACROSCOPIC General Features • Generally solitary, unilateral, and unicentric • Rarely bilateral (contralateral adenoma is sometimes nonhyperfunctional) • Cross section: Yellow, golden yellow, or brown • Geographic or mottled zones of dark pigmentation may be present ○ Due to lipid depletion of neoplastic cells as well as lipofuscin accumulation

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Size • Average diameter: 3.6 cm (range: 1.5-6.0 cm); 50 g

Sporadic • Most ACA cases are considered sporadic

CLINICAL ISSUES Epidemiology • Incidence ○ True incidence is unknown • Age ○ Can occur in any age group • Sex ○ Slight female predilection

Presentation • Nonfunctional, detected more often by imaging studies • Most common presentation is associated with hormonal production ○ Glucocorticoid – Weight gain (central obesity) – Supraclavicular and dorsocervical fat pads – Facial rounding (moon face) and plethora – Easy bruising and poor wound healing – Purple striae and hirsutism – Proximal muscle weakness – Osteoporosis ○ Mineralocorticoid – Hypertension and hypokalemia ○ Androgens – Virilization in women – Excess testosterone in men ○ Estrogens – Gynecomastia in men – Menstrual irregularities in women

MICROSCOPIC Histologic Features • Smooth, pushing borders without well-defined fibrous capsule • Broad fields of pale-staining, lipid-rich, or oncocytic cells with uniform nuclei • Architectural patterns are cells in nesting or alveolar arrangement with delicate intersecting vasculature and areas of short cords • May have areas of lipomatous or myelolipomatous metaplasia • Some may have degenerative features: Fibrosis, organizing fibrin-rich thrombi within sinusoids, dystrophic calcification, or even metaplastic bone

ANCILLARY TESTS Genetic Profile • Recent studies have elucidated molecular pathogenesis of adrenal cortical tumors, leading to molecular classification ○ Improving our knowledge on pathophysiology and tumorigenesis of these tumors • Genomic (exome and chromosome alteration profiles), epigenomic (micro-RNAs expression and methylation profiles), and transcriptomic (gene expression profiles) studies pointed out roles of ○ Intracellular calcium signaling in aldosterone-producing adenomas ○ Protein kinase A (PKA)/cAMP pathway – Somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for catalytic α-subunit of PKA, are found in cortisol-secreting adenomas 59

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Adenoma Mutations in Adrenal Cortical Adenomas Adrenal Lesion

Gene

Location

Protein

Aldosterone excess

KCNJ5

11q24

GIRK4

Aldosterone excess

ATP1A1

1p21

ATP1A1

Aldosterone excess

ATP2B3

Xq28

PMCA3

Aldosterone excess

CACNA1D

3p14.3

Cav1.3

ACTH-independent Cushing syndrome

PRKACA

10p13.1

PKAC-α

Carney complex

PRKAR1A

17q24.2

PRKAR1A

Syndromes Associated With Adrenal Cortical Adenoma Multiple endocrine neoplasia 1 McCune-Albright syndrome Beckwith-Wiedemann syndrome Congenital adrenal hyperplasia Carney complex Familial adenomatous polyposis Neurofibromatosis 1 von Hippel-Lindau syndrome Carney triad

○ Wnt/β-catenin pathway in nonsecreting tumors • Exome sequencing revealed new major drivers in all tumor types, including ○ KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CACNA1H mutations in aldosterone-producing adenomas ○ PRKACA mutations in cortisol-producing adenomas ○ ARMC5 mutations in primary macronodular adrenocortical hyperplasia (PMAH) – Identification of genetic syndromes, such as germline ARMC5 mutations in PMAH • There is also molecular evidence of adenoma-carcinoma progression

• Immunohistochemistry differentiates these tumors

Immunohistochemistry

6.

• Used to confirm diagnosis, to differentiate from pheochromocytoma, or when tumors occur in unusual locations in abdomen or spinal canal • Positive for adrenal cortical markers, such as inhibin, synaptophysin, NSE, MART-1, calretinin, SF1, CD56, and Melan-A

SELECTED REFERENCES 1. 2. 3.

4.

5.

7. 8.

9. 10.

DIFFERENTIAL DIAGNOSIS Adrenal Cortical Carcinoma • Differentiation is based on numerous morphologic criteria ○ Capsular invasion, lymphovascular invasion, invasion into adjacent structures, presence of necrosis, mitosis, and metastases

12. 13.

Pheochromocytoma

14.

• Negative for inhibin and Melan-A and positive for chromogranin

15.

Metastatic Carcinoma • Metastases from lung or kidney 60

11.

Gazzin A et al: Phenotype evolution and health issues of adults with Beckwith-Wiedemann syndrome. Am J Med Genet A. 179(9):1691-702, 2019 Jouinot A et al: Genomics of benign adrenocortical tumors. J Steroid Biochem Mol Biol. 193:105414, 2019 Kamilaris CDC et al: Multiple endocrine neoplasia type 1 (MEN1): an update and the significance of early genetic and clinical diagnosis. Front Endocrinol (Lausanne). 10:339, 2019 Osswald A et al: Long-term outcome of primary bilateral macronodular adrenocortical hyperplasia after unilateral adrenalectomy. J Clin Endocrinol Metab. 104(7):2985-93, 2019 Palui R et al: Adrenal adenoma in von Hippel-Lindau syndrome: a case report with review of literature. J Cancer Res Ther. 15(Supplement):S163-6, 2019 Faillot S et al: Endocrine tumours: the genomics of adrenocortical tumors. Eur J Endocrinol. 174(6):R249-65, 2016 Nanba K et al: Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations. Eur J Endocrinol. 175(2):K1-6, 2016 Ronchi CL et al: Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation. J Clin Endocrinol Metab. 101(9):3526-38, 2016 Giordano TJ: Genetics: Pinpointing a hotspot in adrenal Cushing syndrome. Nat Rev Endocrinol. 10(8):447-8, 2014 Carney JA et al: Adrenal cortical adenoma: the fourth component of the Carney triad and an association with subclinical Cushing syndrome. Am J Surg Pathol. 37(8):1140-9, 2013 Assie G et al: Gene expression profiling in adrenocortical neoplasia. Mol Cell Endocrinol. 351(1):111-7, 2012 Yaneva M et al: Genetics of Cushing's syndrome. Neuroendocrinology. 92 Suppl 1:6-10, 2010 Stratakis CA: Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin- independent Cushing syndrome). Endocr Dev. 13:117-32, 2008 Giordano TJ: Molecular pathology of adrenal cortical tumors: separating adenomas from carcinomas. Endocr Pathol. 17(4):355-63, 2006 Sidhu S et al: Comparative genomic hybridization analysis of adrenocortical tumors. J Clin Endocrinol Metab. 87(7):3467-74, 2002

Adrenal Cortical Adenoma

Cortisol-Producing Adrenal Adenoma (Left) This large adrenal cortical adenoma has a bright yellow cut surface, is well circumscribed, and compresses the residual adrenal gland ſt at the periphery. (Right) Gross photo of adrenal cortical adenoma highlights the mottled zones of dark pigmentation st. These areas are composed of lipid-depleted cells and cells with accumulation of lipofuscin pigment. Note the marked atrophy of the residual adrenal cortex ﬇.

Morphologic Features of Adenoma

Diagnoses Associated With Syndromes by Organ: Endocrine

Aldosterone-Producing Adrenal Adenoma

Patchy Synaptophysin (Left) The tumor cells in cortisol-producing adrenal adenomas are arranged in a solid pattern with cytoplasmic lipofuscin pigment ﬊, gradation in cell size, and a varying amount of lipid. (Right) Positivity for synaptophysin is one of the characteristics of adrenal cortical neoplasms. There is positive cytoplasmic staining in this case of sex-steroidproducing adrenal cortical adenoma. Other markers are inhibin, MART-1, Melan-A, calretinin, NSE, and SF1.

Negative Chromogranin Staining

Low Proliferative Index (Left) IHC for chromogranin is characteristically negative in adrenal cortical adenoma. The tumor cells in these tumors are also negative for CK7, CK20, AE1/AE3, S100, and CD10, aiding in the differential diagnosis with other epithelial neoplasms. (Right) IHC for Ki67 reveals a low proliferative index in benign, cortisolsecreting adrenal cortical adenoma. These findings correlate with a very low mitotic index.

61

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Carcinoma KEY FACTS ○ High grade: > 20 mitoses/50 HPF

TERMINOLOGY • Adrenal cortical carcinomas (ACC): Malignant epithelial neoplasm of adrenal cortical cells

ETIOLOGY/PATHOGENESIS • Adrenal cortical neoplasms are thought to arise through acquired genetic mutations in driver genes • Associated with diverse familial cancer syndromes ○ Li-Fraumeni syndrome ○ Beckwith-Wiedemann syndrome ○ Lynch syndrome ○ Multiple endocrine neoplasia 1 ○ Familial adenomatous polyposis ○ Carney complex ○ Neurofibromatosis type 1

MICROSCOPIC • ACCs subdivided on basis of mitotic frequency ○ Low grade: ≤ 20 mitoses/50 HPF

ANCILLARY TESTS • Positive for synaptophysin, inhibin, Melan-A/Mart-1, calretinin, CD56, and SF1 stains • High prevalent role of IGF2 overexpression • TP53 mutation and its dominant frequency in pediatric ACC and association with aggressive behavior • Frequent and diversity of WNT pathway defects: CTNNB1 point mutations and ZNRF3 deletions • Copy number alterations and whole-genome doubling • Important role of telomeres and telomerase reactivation • Relative lack of targetable hotspot mutations • Expression of DLGAP5 (previously called DLG7) and PINK1 identify carcinomas and tumors within borderline Weiss criteria

TOP DIFFERENTIAL DIAGNOSES • Adrenal cortical adenoma, pheochromocytoma, renal cell carcinoma, metastases

Large Adrenal Mass

Atypical Mitosis

Melan-A Immunoreactivity in ACC

High Proliferative Index

(Left) Most adrenal carcinomas are large, solitary, and circumscribed tumors. The cut surface of this tumor shows a pale-yellow variegated appearance with areas of necrosis and hemorrhage. (Right) The growth pattern in adrenal cortical carcinoma (ACC) is usually a solid pattern, broad trabecular pattern, or large nested pattern. The finding of atypical mitosis is one of the Weiss criteria for malignancy. This tumor, present in a patient with Li-Fraumeni syndrome, shows numerous atypical mitosis.

(Left) ACC in a child with steroid-producing tumor shows patchy and variably focal staining for Melan-A. These tumors are also positive for SF1, synaptophysin, and inhibin-α stains. (Right) ACC in a patient with virilization syndrome shows a high proliferative index. The diagnostic evaluation of adrenal cortical tumors incorporate mitotic rate. ACC can be subdivided based on mitotic activity into low or high grade.

62

Adrenal Cortical Carcinoma

Abbreviations • Adrenal cortical carcinoma (ACC)

Definitions • Malignant epithelial tumor of adrenal cortical cells

ETIOLOGY/PATHOGENESIS Possible Multistep Process • Adrenal cortical neoplasms are thought to arise through acquired genetic mutations in driver genes, with activation of key cellular signaling pathways • Adrenal cortical hyperplasia and adenoma may represent precursor lesions • Cumulative chromosomal alterations toward malignant transformation

Syndrome Association • • • • • • • •

Li-Fraumeni syndrome (autosomal dominant) Lynch syndrome Multiple endocrine neoplasia 1 Familial adenomatous polyposis Carney complex Beckwith-Wiedemann syndrome (autosomal dominant) Neurofibromatosis type 1 Congenital adrenal hyperplasia

CLINICAL ISSUES Epidemiology • Incidence ○ 1 in every 4,000 adrenal tumors ○ 0.5-2.0 cases per million per year ○ ~ 3% of endocrine neoplasms • Age ○ Bimodal distribution – 60-70 years □ Peak in 5th decade – Early childhood □ 0.21 per million per year □ 0.3-0.4% of all neoplasms in this age group • Sex ○ F > M (2.5:1.0) – More often have functional tumors

Presentation • 42-57% are hormonally functional • Nonfunctional tumors are detected more often as radiographic techniques improve • Most common presentation is associated with hormone oversecretions ○ Glucocorticoid – Cushing syndrome – Central obesity – Moon facies – Protein wasting, striae, and skin thinning – Muscle atrophy, osteoporosis – Diabetes, hypertension, gonadal dysfunction – Psychiatric disorders ○ Mineralocorticoid

– Hypertension and hypokalemia ○ Androgens – Virilization in women – Excess testosterone in men ○ Estrogens – Very rare, yielding gynecomastia and testicular atrophy in men – Menstrual irregularities in women • Mass ○ Flank pain due to compressive symptoms • In children ○ Usually functional ○ May present virilization, precocious puberty, Cushing syndrome, or feminization

Laboratory Tests • Serum or urinary hormone quantification ○ Hormones may not be bioactive ○ Deoxycorticosterone, hydroxyprogesterone ○ Androstenedione, estrogens ○ Urine 17-ketogenic steroids or 17-ketosteroids may be elevated ○ Dehydroepiandrosterone sulfate (DHEAS) • Dexamethasone suppression test

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Treatment • Options, risks, complications ○ Complications due to pituitary-hypothalamus-adrenal axis suppression • Surgical approaches ○ Complete, radical surgical resection is treatment of choice • Drugs ○ Mitotane – May help prolong recurrence-free survival after radical surgery – Can be used after incomplete resection or for metastatic disease – In patients not eligible for surgery ○ Chemotherapy regimens reported – Etoposide, doxorubicin, cisplatin, and mitotane – Streptozotocin and mitotane – Failure possibly due to high rate of multidrug resistance protein 1 (MDR1) gene expression • Radiation ○ Radiotherapy can help control residual disease

Prognosis • Aggressive disease with dismal prognosis • Overall 5-year survival: 37-47% • Key prognostic factors ○ Clinically relevant hypercortisolism ○ Resection margin status ○ Tumor stage correlates with survival ○ Tumor grade ○ Age > 50 years ○ Mitotic rate: Low grade (≤ 20/50 HPF) and high grade (> 20/50 HPF) ○ Ki-67 proliferative index: Significant prognostic and predictive power ○ High expression of SF1 correlates with poorer outcome 63

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Carcinoma ○ Biomarkers TOP2A, EZH2, and BARD1 might provide additional prognostic information ○ Expression of genes BUB1B and PINK1 predicts prognosis ○ Carcinomas classified into 2 main molecular subgroups with distinct genomic alterations: C1A and C1B • Nearly 40% have distant metastases at presentation ○ Most common metastases to lymph nodes, lung, liver, and bone ○ Rarely metastasizes to brain

IMAGING Radiographic Findings • Inhomogeneous masses with irregular borders and necrosis • Usually show low tumor fat content ○ Distinctly different from adenomas, which have high fat content

MR Findings • • • • •

Carcinoma tends to be large (> 5 cm) Irregular or invasive borders Decreased intracellular lipid and macroscopic fat Signal heterogeneity and necrosis Vena cava extension/invasion may be seen

Degenerative changes are usually focally identified Myxoid change may be present Capsular and lymphovascular invasion is usually identified Mitoses are strong predictors of ACC ○ Diagnostic evaluation of adrenal cortical tumors incorporates mitotic rate ○ ACC subdivided on basis of mitotic frequency – Low grade: ≤ 20 mitoses/50 HPF – High grade: > 20 mitoses/50 HPF • In children, these features may not indicate malignancy • Benign cortical tumors with oncocytic change can have some of these features

Cytologic Features • Cells have clear to eosinophilic cytoplasm • Nuclei range from bland to highly atypical • Variable mitotic rate

ANCILLARY TESTS Immunohistochemistry • Positive for ○ Synaptophysin, Melan-A, inhibin, calretinin, SF1, CD56, and keratin stains

CT Findings

Genetic Testing

• Heterogeneous, enhancing, large mass • Typically > 5 cm • Frequently with displacement or invasion of adjacent organs • Calcifications present in 30% of cases

• Numerous studies have elucidated molecular pathogenesis of adrenal cortical tumors ○ Leading to molecular classification ○ Molecular evidence for adenoma to carcinoma progression • Gene expression profiling ○ Overexpression of IGF2 is one of most highly expressed in carcinomas ○ Expression of DLGAP5 (previously called DLG7) and PINK1 identify carcinomas and tumors within borderline Weiss criteria ○ Somatic mutations of TP53, CTNNB1, or RB • MicroRNA expression profiling ○ MicroRNAs were shown to be deregulated in adrenocortical carcinoma – High miR-210 is associated with aggressiveness and poor prognosis • Integrated genomic characterization ○ High prevalent role of IGF1 overexpression ○ TP53 mutation and its dominant frequency in pediatric ACC and association with aggressive behavior ○ Frequency and diversity of WNT pathway defects: CTNNB1 point mutations and ZNRF3 deletions – Present in ~ 50% of ACC ○ Copy number alterations and whole-genome doubling – Complex pattern of chromosomal aberrations □ Multiple regions of gains and losses ○ Important role of telomeres and telomerase reactivation ○ Relative lack of targetable hotspot mutations

MACROSCOPIC General Features • Bulky tumors with red-brown and fleshy, firm appearance • Typically unilateral ○ If bilateral, consider contralateral metastasis • Large, solitary, circumscribed tumors • Tan-yellow cut surface with areas of necrosis and hemorrhage

Size • Often large (10-14 cm) ○ Can range 1-25 cm

Weight • Usually > 200 g • Can be 10-5,000 g

MICROSCOPIC Histologic Features • Patternless sheets or nests of cells, solid arrangement • Broad trabeculae and large nested • Tumor encapsulation is rule; thick fibrous capsule is associated with carcinoma • May have ○ High nuclear grade ○ High mitotic counts ○ Bizarre mitotic figures ○ Venous invasion • Necrosis may be abundant, especially in high-grade tumors 64

• • • •

Electron Microscopy • Features of steroidogenesis ○ Abundant rough and smooth endoplasmic reticulum ○ Many mitochondria ○ Intracytoplasmic lipid droplets

Adrenal Cortical Carcinoma

SELECTED REFERENCES

Adrenal Cortical Adenoma

1.

• Tends to be smaller and weigh less than carcinoma • Often lacks mitotic figures, necrosis, and invasion

2.

Hepatocellular Carcinoma

3.

• Trabecular pattern, bile pigment, glandular arrangement • Positive keratin, CEA, and Hep-Par1 stains

4.

Metastatic Tumors

5.

• More likely to be bilateral • Glandular, squamous, or small cell histology • Often metastasizes to adrenal gland ○ Breast and lung carcinomas ○ Melanoma

Renal Cell Carcinoma • Pseudoalveolar pattern • Clear cytoplasm, prominent cell borders • Positive for keratin, CD10, and EMA stains

Pheochromocytoma • Different radiographic appearance, especially with scintigraphic studies • Nested and zellballen pattern • Basophilic cytoplasm; bizarre, isolated, atypical nuclei • Positive for chromogranin, synaptophysin, and CD56 stains in paraganglia cells • S100 protein positive sustentacular cells

6.

7.

8. 9. 10.

11. 12. 13.

14.

15.

DIAGNOSTIC CHECKLIST Distinction Between Benign and Malignant Adrenal Cortical Neoplasms • No single feature is diagnostic of carcinoma • Weiss criteria for malignancy in adrenal cortical tumors: Presence of ≥ 3 criteria correlates with malignant behavior ○ High nuclear grade (Fuhrman grade IV) ○ > 5 mitotic figures/50 HPF ○ Atypical mitotic figures ○ < 25% of tumor cells with clear/vacuolated cytoplasm ○ Diffuse architecture (> 1/3 of tumor) ○ Confluent tumor necrosis ○ Venous invasion (of smooth muscle-walled vessels) ○ Sinusoidal invasion (no smooth muscle in vessel wall) ○ Capsular invasion

16. 17. 18. 19. 20.

21. 22. 23.

24.

Assessment of Biological Aggression in ACC • Mitotic grade ○ Low-grade carcinoma: ≤ 20 mitoses/50 HPF ○ High-grade carcinoma: > 20 mitoses/50 HPF

STAGING European Network for Study of Adrenal Tumors • Stage I: Confined to gland, ≤ 5 cm • Stage II: Confined to gland, > 5 cm • Stage III: Extends beyond gland, into surrounding tissues but not into adjacent organs; positive regional lymph nodes or involvement of regional veins • Stage IV: Distant metastases or adjacent organ involvement

25. 26.

27.

28.

29. 30. 31.

Ferreira AM et al: Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumenilike syndrome in Brazilian individuals with the TP53 p.R337H mutation. J Steroid Biochem Mol Biol. 190:250-5, 2019 Gimenez-Roqueplo AP: Adrenal tumors: when to search for a germline abnormality? Curr Opin Oncol. 31(3):230-5, 2019 Harada K et al: A novel case of myxoid variant of adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Endocr J. 66(8):739-44, 2019 Jasim S et al: Management of adrenocortical carcinoma. Curr Oncol Rep. 21(3):20, 2019 Kaur RJ et al: Adrenal cortical carcinoma associated with Lynch syndrome: a case report and review of literature. J Endocr Soc. 3(4):784-90, 2019 Łebek-Szatańska A et al: Adrenocortical carcinoma associated with giant bilateral myelolipomas in classic congenital adrenal hyperplasia. Pol Arch Intern Med. 129(7-8):549-50, 2019 Murray KS et al: Li-Fraumeni syndrome-related malignancies involving the genitourinary tract: review of a single-institution experience. Urology. 119:55-61, 2018 Palui R et al: Adrenal adenoma in von Hippel-Lindau syndrome: A case report with review of literature. J Cancer Res Ther. 15(Supplement):S163-6, 2019 Pittaway JFH et al: Pathobiology and genetics of adrenocortical carcinoma. J Mol Endocrinol. 62(2):R105-19, 2019 Poli G et al: Fascin-1 is a novel prognostic biomarker associated with tumor invasiveness in adrenocortical carcinoma. J Clin Endocrinol Metab. 104(5):1712-24, 2019 Pons Fernández N et al: Familial hyperaldosteronism type III a novel case and review of literature. Rev Endocr Metab Disord. 20(1):27-36, 2019 Wang W et al: Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature. Endocr Connect. 8(3):230-8, 2019 Agarwal S et al: Incidentally detected adrenocortical carcinoma in familial adenomatous polyposis: an unusual presentation of a hereditary cancer syndrome. BMJ Case Rep. 2018, 2018 Amadou A et al: Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 30(1):23-9, 2018 Gupta N et al: Adrenocortical carcinoma in children: a clinicopathological analysis of 41 patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr. 90(1):8-18, 2018 Petr EJ et al: Adrenocortical carcinoma (ACC): when and why should we consider germline testing? Presse Med. 47(7-8 Pt 2):e119-25, 2018 Sharma E et al: The characteristics and trends in adrenocortical carcinoma: a United States population based study. J Clin Med Res. 10(8):636-40, 2018 Shiroky JS et al: Characteristics of adrenal masses in familial adenomatous polyposis. Dis Colon Rectum. 61(6):679-85, 2018 Tatsi C et al: Neonatal Cushing syndrome: a rare but potentially devastating disease. Clin Perinatol. 45(1):103-18, 2018 Brown RE et al: Metformin and melatonin in adrenocortical carcinoma: morphoproteomics and biomedical analytics provide proof of concept in a case study. Ann Clin Lab Sci. 47(4):457-65, 2017 Else T et al: Adrenocortical carcinoma and succinate dehydrogenase gene mutations. Eur J Endocrinol. 177(5);439-44, 2017 Jonker PKC et al: Epigenetic dysregulation in adrenocortical carcinoma, a systematic review of the literature. Mol Cell Endocrinol. 469:77-84, 2017 Kallenberg FGJ et al: Adrenal lesions in patients with (attenuated) familial adenomatous polyposis and MUTYH-associated polyposis. Dis Colon Rectum. 60(10):1057-64, 2017 Macedo GS et al: p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers. Fam Cancer. 17(2): 26974, 2017 Challis BG et al: Familial adrenocortical carcinoma in association with Lynch syndrome. J Clin Endocrinol Metab. 101(6):2269-72, 2016 Drelon C et al: EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression. Hum Mol Genet. 25(13):2789-800, 2016 Else T et al: 5th International ACC symposium: hereditary predisposition to childhood ACC and the associated molecular phenotype: 5th International ACC Symposium Session: Not Just for Kids! Horm Cancer. 7(1):36-9, 2016 Liu-Chittenden Y et al: Serum RARRES2 Is a prognostic marker in patients with adrenocortical carcinoma. J Clin Endocrinol Metab. 101(9):3345-52, 2016 Malkin D: Li-Fraumeni syndrome and p53 in 2015: celebrating their silver anniversary. Clin Invest Med. 39(1):E37-47, 2016 Papathomas TG et al: An international Ki67 reproducibility study in adrenal cortical carcinoma. Am J Surg Pathol. 40(4):569-76, 2016 Petr EJ et al: Genetic predisposition to endocrine tumors: diagnosis, surveillance and challenges in care. Semin Oncol. 43(5):582-90, 2016

Diagnoses Associated With Syndromes by Organ: Endocrine

DIFFERENTIAL DIAGNOSIS

65

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Carcinoma Hereditary Syndromes Associated With Adrenal Cortical Carcinoma Syndrome

Gene(s) Involved

Prevalence Among Patients With ACC

Li-Fraumeni syndrome*

TP53

3-5% (adults) 50-80% (children)

Multiple endocrine neoplasia type 1

MEN1

1-2% (adults)

Lynch syndrome

MSH2, MSH6, MLH1, PMS2

3% (adults)

Familial adenomatous polyposis

APC

< 1%

Neurofibromatosis type 1

NF1

< 1%

Beckwith-Wiedemann syndrome

IGF2, H19 at 11p15 locus

< 1%

Carney complex

PRKAR1A

< 1%

* Li-Fraumeni syndrome: There is  an excess of adrenocortical tumors in carriers of germline p53 mutations in comparison to their rate in the general population. ACCs comprise 11.9% of all tumors, while in the general population, ACCs represent < 1% of diagnosed cancers. The age of diagnosis of adrenocortical carcinomas in the general population follows a bimodal distribution with peaks in the 1st and 57th decades of life. By contrast, ACC among individuals with p53 germline mutations follows a unimodal distribution with 68% presenting in the first 4 years of life and 92% presenting in the pediatric age group. The diagnosis of ACC alone, in the absence of a family cancer history, constitutes sufficient indication for germline p53 testing. The prevalence of p53 germline variation among the adult population with ACC is less clear.

Immunohistochemistry Antibody

Reactivity

Staining Pattern

Vimentin

Positive

Cytoplasmic

Inhibin

Positive

Cytoplasmic

Nondiscriminating between adenoma and carcinoma

Melan-A103

Positive

Cytoplasmic

Nondiscriminating between adenoma and carcinoma

Calretinin

Positive

Nuclear & cytoplasmic

SF1

Positive

Nuclear

CK-PAN

Equivocal

Cytoplasmic

< 5% of tumor cells reactive

Synaptophysin

Positive

Cytoplasmic

Frequently expressed

CD56

Positive

Cytoplasmic

CEA-M

Negative

Chromogranin-A

Negative

32. Zheng S et al: Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 29(5):723-36, 2016 33. Asare EA et al: A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage I/II disease. Surgery. 156(6):1378-86, 2014 34. De Martino MC et al: Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors. Endocr Relat Cancer. 21(4):60113, 2014 35. Lerario AM et al: Genetics and epigenetics of adrenocortical tumors. Mol Cell Endocrinol. 386(1-2):67-84, 2014 36. Sasano H et al: Roles of the pathologist in evaluating surrogate markers for medical therapy in adrenocortical carcinoma. Endocr Pathol. 25(4):366-70, 2014 37. Raymond VM et al: Adrenocortical carcinoma is a Lynch syndromeassociated cancer. J Clin Oncol. 31(24):3012-8, 2013 38. de Krijger RR et al: Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants. Virchows Arch. 460(1):9-18, 2012 39. Giordano TJ et al: Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res. 15(2):66876, 2009 40. Volante M et al: Pathological and molecular features of adrenocortical carcinoma: an update. J Clin Pathol. 61(7):787-93, 2008 41. Gross MD et al: PET in the diagnostic evaluation of adrenal tumors. Q J Nucl Med Mol Imaging. 51(3):272-83, 2007 42. Abiven G et al: Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 91(7):2650-5, 2006 43. Sasano H et al: Recent advances in histopathology and immunohistochemistry of adrenocortical carcinoma. Endocr Pathol. 17(4):345-54, 2006

66

Comment

Generally negative

44. Wieneke JA et al: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol. 27(7):867-81, 2003 45. Stratakis CA: Genetics of adrenocortical tumors: Carney complex. Ann Endocrinol (Paris). 62(2):180-4, 2001 46. Weiss LM et al: Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 13(3):202-6, 1989 47. Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 8(3):163-9, 1984 48. Macfarlane DA: Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl. 23(3):15586, 1958

Adrenal Cortical Carcinoma

Large ACC (Left) Radiologic image shows a large left adrenal gland mass ﬇ pushing the kidney down and compressing the adjacent spleen. The interior is mottled and shows mixed intensity. (Right) This ACC presented as a large, irregularly shaped, bulky, unilateral mass and has a light brown variegated color. The cut surface shows extensive regressive changes, necrosis st, hemorrhage ﬇, fibrosis and degeneration ſt, and calcification.

ACC With Necrosis

Diagnoses Associated With Syndromes by Organ: Endocrine

Radiologic Image

Cellular Characteristics (Left) This ACC shows extensive necrosis and hemorrhage with only small areas of viable tumor. This gross appearance is characteristic of carcinoma. (Right) High-power view of ACC shows a tumor composed by slightly pleomorphic round cells with eosinophilic ample cytoplasm. There is mild nuclear pleomorphism and multinucleated tumor giant cells.

Calretinin Immunostain in ACC

Lung With Metastatic Focus of ACC (Left) Strong calretinin immunoreactivity is shown in ACC in a patient with LiFraumeni syndrome. This stain is usually patchy. The tumors in these patients usually also stain positive for p53. (Right) ACC metastatic to lung exhibits tumor cells ſt with abundant, granular, oncocytic cytoplasm with round, uniform, hyperchromatic nuclei. Nuclear pleomorphism can be seen among tumor cells. The compressed adjacent lung parenchyma is seen ﬈.

67

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Carcinoma

Pleomorphic Cell

Areas of Necrosis

Foci of Necrosis in ACC

Myxoid Stromal Changes

Focal Necrosis

Degenerative Changes

(Left) This steroid-producing ACC in a child is composed of cells with ample eosinophilic cytoplasm. Occasional markedly enlarged multinucleated cells are identified. (Right) This adrenal carcinoma in a patient with virilization is composed of large cells with eosinophilic cytoplasm and shows multifocal areas of necrosis. The cells have irregular nuclei with prominent nucleoli.

(Left) This tumor, present in a patient with Li-Fraumeni syndrome, shows multifocal areas of tumor necrosis. Necrosis is one of the Weiss criteria for distinguishing benign from malignant cortical tumors. In higher grade tumors, necrosis may be abundant. (Right) Myxoid changes may be present in ACCs and carcinomas, although these changes are more commonly seen in the latter.

(Left) The growth pattern in ACC is usually solid, broad trabecular, or large nested. H&E shows a tumor with broad trabecula composed of cells with ample eosinophilic cytoplasm and focal necrosis ﬊. (Right) H&E shows an ACC composed of large eosinophilic cytoplasm with pleomorphic nuclei and prominent nucleoli. This area of the tumor shows dyscohesive cells with edematous stroma with degenerative changes.

68

Adrenal Cortical Carcinoma

Vascular Invasion (Left) Low-power view shows an area of juxtaposition between ACC composed of small, uniform cells ﬈ and the residual normal adrenal tissue ﬊. Tumor invasion of a large intraparenchymal vessel is shown ſt. (Right) This tumor invades a vessel wall ſt and is composed of small, uniform cells with clear cytoplasm. Atypical cells with large irregular nuclei and a large, bizarre, multinucleated cell ﬊ are also shown.

Distinct Cell Morphology

Diagnoses Associated With Syndromes by Organ: Endocrine

Lymphovascular Invasion

Metastases to Lung (Left) H&E shows the interface between 2 distinct areas of ACC. One area of tumor is made up of sheets of small, compact round cells with scant cytoplasm ſt. There is a sharp contrast in the cell size of this component compared to the other component ﬈. (Right) H&E shows metastatic ACC ſt to lung parenchyma. The tumor mass is composed of small, compact eosinophilic cells and is surrounded by lung parenchyma ﬈.

Patchy Expression of Synaptophysin

Cytoplasmic Synaptophysin Reactivity (Left) This ACC has a membranous and cytoplasmic patchy immunoexpression of synaptophysin. (Right) Strong synaptophysin immunoreactivity is shown in ACC in a patient with LiFraumeni syndrome. This stain is usually patchy. The tumors in these patients also stain positive for p53.

69

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Neoplasms in Children KEY FACTS

ETIOLOGY/PATHOGENESIS • Li-Fraumeni syndrome ○ Accounts for most pediatric cases of adrenal cortical carcinoma (ACC) – ~ 50% of very early-onset ACCs occur in children with germline TP53 mutations ○ TP53 R337H mutation • Beckwith-Wiedemann syndrome ○ Characterized by adrenal cytomegaly ○ Associated with adrenal cortical neoplasms • Multiple endocrine neoplasia type 1 • Lynch syndrome • Carney complex • Familial adenomatous polyposis • Neurofibromatosis type 1 • Hemihypertrophy ○ Adrenal cortical neoplasms have been associated with hemihypertrophy in children

• Congenital adrenal hyperplasia ○ Adrenal cortical adenoma and ACC have been associated with adrenogenital syndrome • McCune-Albright syndrome

CLINICAL ISSUES • Females have higher incidence until 5 years of age, after which sex difference disappears • > 90% of children with adrenal cortical neoplasms present with symptoms of endocrine syndrome ○ Most common presentation is virilization • Adrenal cortical tumors in children more frequently show adverse histologic features in clinically benign tumors as compared to adult tumors

MICROSCOPIC • Different architectural patterns are seen • Confluent necrosis is histologic feature; adverse prognostic finding if > 25%

Variegated Gross Cut Surface

Large Eosinophilic Cells

Large Multinucleated Cells

Melan-A Immunoreactivity

(Left) Adrenal cortical carcinoma (ACC) cut surface shows a variegated appearance. This markedly enlarged adrenal gland is completely replaced by an irregularly shaped, bulky mass with a pale-brown cut surface. Multiple areas of yellow necrotic foci are identified. (Right) H&E shows an adrenal tumor in a child with sexhormone-producing ACC. The cells are large with ample eosinophilic cytoplasm and marked variation in nuclear size and shape.

(Left) H&E shows a large, multinucleated tumor cell in an adrenal tumor from a child with sex-hormone-producing ACC. (Right) Melan-A shows the variable staining in the cytoplasm of the tumor cells in this tumor from a child with sex-hormone-producing ACC.

70

Adrenal Cortical Neoplasms in Children

Abbreviations • Adrenal cortical neoplasm (ACN)

Synonyms • Adrenal cortical adenoma (ACA) • Adrenal cortical carcinoma (ACC) • Adrenal cortical tumor

Definitions • Neoplasms arising from adrenal cortical cells • Adrenal cortical carcinoma is malignant epithelial tumor of adrenal cortical cells • ACA is benign epithelial tumor of adrenal cortical cells

ETIOLOGY/PATHOGENESIS Sporadic • Rare cases in children are nonsyndromic • Wide variety of syndromes are associated with adrenal cortical tumors ○ > 50% of early-onset ACCs occur in children with germline TP53 mutations

Li-Fraumeni Syndrome • a.k.a. SBLA syndrome: Sarcoma; breast and brain tumors; leukemia, laryngeal carcinoma, and lung cancer; adrenal cortical carcinoma • Li-Fraumeni syndrome accounts for most pediatric ACC cases ○ ~ 50% of very early-onset ACCs occur in children with germline TP53 mutations • Endometrial carcinoma • Autosomal dominant mode of inheritance • Alterations in TP53 tumor suppressor gene • Most common associated neoplasms are soft tissue sarcomas, bone sarcomas, and breast carcinoma

Beckwith-Wiedemann Syndrome • Involves chromosome 11p15.5 in ~ 80% of cases ○ IGF2 and KCNQ1OT1 are normally expressed from paternal allele ○ H19, CDKN1C, and KCNQ1 are normally expressed from maternal allele • Characterized by adrenal cytomegaly • Associated with adrenal cortical neoplasms • Characterized by embryonal tumor in childhood ○ Main tumors associated with Beckwith-Wiedemann syndrome are nephroblastoma, ACC, and hepatoblastoma • Characteristic facies in early childhood (often normal by adulthood) • Somatic overgrowth • Classic triad ○ Exomphalos ○ Gigantism ○ Macroglossia

Congenital Adrenal Hyperplasia • ACA and ACC have been associated with congenital adrenal hyperplasia (adrenogenital syndrome) • Associated with testicular tumors of adrenal cortical type

Hemihypertrophy • Adrenal cortical neoplasms have been associated with hemihypertrophy in children • Adrenal neoplasms are not necessarily located ipsilateral to hemihypertrophy • Other associated tumors are Wilms tumor, hepatoblastoma, and pheochromocytoma

Other Syndromes • • • • • • • •

MEN1 Carney complex McCune-Albright syndrome Neurofibromatosis type 1 Familial adenomatous polyposis Lynch syndrome Hereditary nonpolyposis colorectal cancer Hereditary leiomyomatosis renal cell carcinoma syndrome

CLINICAL ISSUES

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Epidemiology • Incidence ○ Annual incidence is 3:1 million patients < 20 years old ○ Females have higher incidence until 5 years of age, after which sex difference disappears • Age ○ Average at presentation: 8 years – Most cases occur in patients < 5 years old

Presentation • > 90% of children with adrenal cortical neoplasms present with symptoms of endocrine syndrome • Functionally active tumors account for > 80% • Most common presentation is virilization ○ Expressed in females – Increased muscle mass, clitoromegaly, facial hair, pubic hair, deepening of voice ○ Expressed in males – Penile enlargement, pubic hair • May present with Cushing syndrome ○ If so, syndrome is usually associated with virilization

Prognosis • Adrenal cortical tumors in children more frequently show adverse histologic features in clinically benign tumors vs. adult tumors • Histopathological examination and molecular findings in pediatric adrenal cortical tumors have not produced relevant prognostic categories or novel treatment approaches • Adverse prognostic factors in pediatric tumors ○ Older age at diagnosis: > 5 years of age ○ Average tumor size: 12 cm ○ Tumor weight: > 400 g ○ Mitotic count: > 30 per 50 HPF ○ Average tumor necrosis: 60% ○ Vascular &/or capsular invasion ○ Tumor ploidy has been shown not to correlate with outcome • Tumors with both germline TP53 and somatic ATRX mutations are significantly associated with high tumor weight, advanced disease, and poor event-free survival 71

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Neoplasms in Children • Pediatric TP53-associated tumors arise from simpler genomic background (adenoma) and progress to acquire complex and unstable genomic aberrations (carcinoma) • Cluster of ACTs arising from founder TP53  mutation (R337H) in southern Brazil allowed biologic, prognostic, and therapeutic studies in large group of cases with common predisposing factor • Children with advanced-stage disease have very poor overall survival • Most frequent sites of metastases are lung and liver; other sites include peritoneum, pleura/diaphragm, abdominal lymph nodes, and kidneys

MACROSCOPIC General Features • Mostly unilateral; bilateral tumors are extremely rare

Size • Wide range: 2.5-20.0 cm • Tumors with better prognosis have average size of 6 cm, whereas those with worse prognosis have average size of 12 cm

MICROSCOPIC Histologic Features • Pediatric tumors differ from adult adrenal cortical neoplasms in that those features associated with malignancy in adults can sometimes be seen in clinically benign tumors in children ○ Capsular invasion ○ Confluent necrosis (adverse prognostic finding if > 25%) ○ Vascular invasion • Different architectural patterns are seen ○ Alveolar pattern is most common pattern in ACA ○ Trabecular (commonly seen in malignant neoplasms) ○ Solid • Mitotic grading of ACC divides tumors into 2 prognostically significant groups ○ Low-grade carcinomas: < 20 mitosis per 50 HPF ○ High-grade carcinomas: > 20 mitosis per 50 HPF

Cytologic Features • • • •

Nuclear pleomorphism Some can have oncocytic features Nuclear hyperchromasia Mitosis: Few figures can be seen in clinically benign tumors; sign of malignancy if numerous (> 30 per 50 HPF) • Intracytoplasmic hyaline globules

ANCILLARY TESTS Genetic Testing • Most cases of adrenal cortical tumor have loss of heterozygosity (LOH) of chromosome 11p • IGF2 on chromosome 11p is overexpressed in 100% of tumors • TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 76% • Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumor-driver events 72

• Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p

DIFFERENTIAL DIAGNOSIS Pheochromocytoma • Positive for chromogranin • Negative for inhibin and MART-1

Renal Cell Carcinoma • Negative for chromogranin

Primary Bilateral Macronodular Adrenocortical Hyperplasia • Large adrenals with large, yellow nodules • May be associated with familial adenomatous polyposis, McCune-Albright syndrome, MEN1, and hereditary leiomyomatosis renal cell carcinoma • In PBMAH patients with AMRC5 mutations (± associated with meningiomas), genetic screening can be proposed to relatives ○ Genetic screening is important because long-term consequences of hypercortisolism, progressively starting subclinical, should be prevented in AMRC5 mutations carriers

Other Primary or Metastatic Neoplasms • Neuroblastoma, Wilms tumor, hepatoblastoma

DIAGNOSTIC CHECKLIST Genetic Susceptibility • Childhood adrenal cortical tumor is often associated with germline TP53 mutations (Li-Fraumeni syndrome) and with Beckwith-Wiedemann syndrome • Given wide variety of syndromes, it has been recommended that patients with ACC be screened for hereditary diseases associated with TP53 mutation

SELECTED REFERENCES 1.

Wang Z et al: Clinical characteristics and prognosis of adrenocortical tumors in children. Pediatr Surg Int. 35(3):365-71, 2019 2. Gupta N et al: Adrenocortical carcinoma in children: a clinicopathological analysis of 41 patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr. 90(1):8-18, 2018 3. Babińska A et al: Diagnostic and prognostic role of SF1, IGF2, Ki67, p53, adiponectin, and leptin receptors in human adrenal cortical tumors. J Surg Oncol. 116(3):427-33, 2017 4. Bulzico D et al: A novel TP53 mutation associated with TWIST1 and SIP1 expression in an aggressive adrenocortical carcinoma. Endocr Pathol. 28(41):326-31, 2017 5. Lodish M: Genetics of adrenocortical development and tumors. Endocrinol Metab Clin North Am. 46(2):419-33, 2017 6. Macedo GS et al: p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers. Fam Cancer. 17(2):269274, 2017 7. Achatz MI et al: The inherited p53 mutation in the brazilian population. Cold Spring Harb Perspect Med. 6(12), 2016 8. Challis BG et al: Familial adrenocortical carcinoma in association with Lynch syndrome. J Clin Endocrinol Metab. 101(6):2269-72, 2016 9. Das S et al: Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: Is there a correlation? J Pediatr Surg. 51(11):17951800, 2016 10. Else T et al: 5th International ACC Symposium: hereditary predisposition to childhood ACC and the associated molecular phenotype: 5th International ACC Symposium Session: Not Just for Kids! Horm Cancer. 7(1):36-9, 2016

Adrenal Cortical Neoplasms in Children

Syndrome

Gene(s)

Adrenal Pathology

Prevalence Among Patients With Adrenal Cortical Carcinoma

Li-Fraumeni syndrome

TP53

Adrenal cortical carcinoma

3-5% in adults 50-80% in children

HNPCC (Lynch syndrome)

MLH1, MSH2, MSH6, PMS2

Adrenal cortical carcinoma

~ 3% in adults

Multiple endocrine neoplasia 1

MEN1

Adrenal cortical adenoma and carcinoma

1-2% in adults

Beckwith-Wiedemann syndrome

CDKN1C, NSD1

Adrenal cortical carcinoma, adenoma, and hyperplasia

< 1%

Carney complex

PRKAR1A

Primary pigmented adrenal nodular disease (hyperplasia)

< 1%

Neurofibromatosis 1

NF1

Adrenal cortical carcinoma

< 1%

Familial adenomatous polyposis

APC

Adrenal cortical adenoma and carcinoma

< 1%

McCune-Albright syndrome

GNAS1

Adrenal nodular hyperplasia, adenoma, and carcinoma

Congenital adrenal hyperplasia

CYP21

Adrenal nodular hyperplasia; adrenal cortical adenoma and carcinoma

Hereditary leiomyomatosis renal cell carcinoma

FH

Primary bilateral macronodular adrenal hyperplasia

11. Papathomas TG et al: Sarcomatoid adrenocortical carcinoma: a comprehensive pathological, immunohistochemical, and targeted nextgeneration sequencing analysis. Hum Pathol. 58:113-22, 2016 12. Zheng S et al: Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 29(5):723-36, 2016 13. Pinto EM et al: Genomic landscape of paediatric adrenocortical tumours. Nat Commun. 6:6302, 2015 14. Adachi H et al: Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome. Endocr J. 60(4):403-8, 2013 15. Choufani S et al: Molecular findings in Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 163(2):131-40, 2013 16. Custódio G et al: Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol. 31(20):2619-26, 2013 17. Jacob K et al: Beckwith-Wiedemann and Silver-Russell syndromes: opposite developmental imbalances in imprinted regulators of placental function and embryonic growth. Clin Genet. 84(4):326-34, 2013 18. Kantaputra PN et al: A novel mutation in CDKN1C in sibs with BeckwithWiedemann syndrome and cleft palate, sensorineural hearing loss, and supernumerary flexion creases. Am J Med Genet A. 161A(1):192-7, 2013 19. Raymond VM et al: Adrenocortical carcinoma is a Lynch syndromeassociated cancer. J Clin Oncol. 31(24):3012-8, 2013 20. Sidhu A et al: Infantile adrenocortical tumor with an activating GNAS1 mutation. J Clin Endocrinol Metab. 98(1):E115-8, 2013 21. Carney JA et al: Massive neonatal adrenal enlargement due to cytomegaly, persistence of the transient cortex, and hyperplasia of the permanent cortex: findings in Cushing syndrome associated with hemihypertrophy. Am J Surg Pathol. 36(10):1452-63, 2012 22. Malkin D: Li-fraumeni syndrome. Genes Cancer. 2(4):475-84, 2011 23. Pinto EM et al: TP53-associated pediatric malignancies. Genes Cancer. 2(4):485-90, 2011 24. Pianovski MA et al: Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer. 47(1):56-60, 2006 25. Michalkiewicz E et al: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 22(5):838-45, 2004 26. Ribeiro RC et al: Childhood adrenocortical tumours. Eur J Cancer. 40(8):1117-26, 2004 27. Hertel NT et al: Late relapse of adrenocortical carcinoma in BeckwithWiedemann syndrome. Clinical, endocrinological and genetic aspects. Acta Paediatr. 92(4):439-43, 2003 28. Wieneke JA et al: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol. 27(7):867-81, 2003

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Tumor as Part of Inherited Tumor Syndromes

29. Ribeiro RC et al: An inherited p53 mutation that contributes in a tissuespecific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A. 98(16):9330-5, 2001 30. Teinturier C et al: Clinical and prognostic aspects of adrenocortical neoplasms in childhood. Med Pediatr Oncol. 32(2):106-11, 1999 31. Bugg MF et al: Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian Group for Treatment of Childhood Adrenocortical Tumors. Am J Clin Pathol. 101(5):625-9, 1994 32. Lack EE et al: Adrenal cortical neoplasms in the pediatric and adolescent age group. Clinicopathologic study of 30 cases with emphasis on epidemiological and prognostic factors. Pathol Annu. 27 Pt 1:1-53, 1992 33. Medeiros LJ et al: New developments in the pathologic diagnosis of adrenal cortical neoplasms. A review. Am J Clin Pathol. 97(1):73-83, 1992 34. Li FP et al: A cancer family syndrome in twenty-four kindreds. Cancer Res. 48(18):5358-62, 1988 35. Neblett WW et al: Experience with adrenocortical neoplasms in childhood. Am Surg. 53(3):117-25, 1987 36. Cagle PT et al: Comparison of adrenal cortical tumors in children and adults. Cancer. 57(11):2235-7, 1986 37. Lynch HT et al: The sarcoma, breast cancer, lung cancer, and adrenocortical carcinoma syndrome revisited. Childhood cancer. Am J Dis Child. 139(2):1346, 1985 38. Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 8(3):163-9, 1984 39. Hough AJ et al: Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data. Am J Clin Pathol. 72(3):390-9, 1979 40. Lynch HT et al: Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer. 41(5):2055-64, 1978 41. Li FP et al: Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 71(4):747-52, 1969 42. Fraumeni JF Jr et al: Primary carcinoma of the liver in childhood: an epidemiologic study. J Natl Cancer Inst. 40(5):1087-99, 1968 43. Fraumeni JF Jr et al: Adrenocortical neoplasms with hemihypertrophy, brain tumors, and other disorders. J Pediatr. 70(1):129-38, 1967 44. Fraumeni JF Jr et al: Wilms' tumor and congenital hemihypertrophy: report of five new cases and review of literature. Pediatrics. 40(5):886-99, 1967

73

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Neoplasms in Children

Beckwith-Wiedemann Syndrome

Omphalocele in Beckwith-Wiedemann Syndrome

Adrenal Carcinoma Cut Surface

Extensive Necrosis

Adrenal Carcinoma With Liver Metastases

Adrenal Cortical Carcinoma

(Left) This term infant with Beckwith-Wiedemann syndrome (BWS) has a protuberant abdomen, secondary to enlarged liver and kidneys, and a large mouth with macroglossia. (Courtesy J.L.B. Byrne, MD.) (Right) This fetus with BWS shows abdominal wall defects with umbilical hernia and diastasis recti exposing intraabdominal organs. (Courtesy J. Hetch, MD.)

(Left) Gross photograph shows a cross section of a large adrenal mass replacing the adrenal parenchyma in a young child. This ACC is yellow-tan, has irregular borders and necrosis, and weighs > 100 g. (Right) ACCs tend to appear grossly as large, solid masses in the suprarenal region, typically measuring > 5 cm. Focal areas of necrosis and hemorrhage are usually present.

(Left) Coronal graphic shows primary ACC with invasion into adjacent kidney. N1 and M1 disease is illustrated via an involved paraaortic lymph node st and multifocal hepatic metastases ﬇. (Right) Axial graphic demonstrates T4 right-sided ACC invading adjacent organs, including the right kidney, the liver, and the inferior vena cava.

74

Adrenal Cortical Neoplasms in Children Adrenal Cytomegaly in BeckwithWiedemann Syndrome (Left) H&E from a newborn with BWS shows adrenal cortical cell cytomegaly. The large nuclei can be identified at this low magnification. (Right) There are numerous enlarged and bizarre polyhedral cells ﬉ with eosinophilic granular cytoplasm and large hyperchromatic nuclei in the adrenal cortex in patients with BWS.

Marked Cytomegaly in BeckwithWiedemann Syndrome

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal of Newborn With BeckwithWiedemann Syndrome

Adrenal Cortical Carcinoma Pleomorphic Cells in Beckwith-Wiedemann Syndrome (Left) H&E shows adrenal cortical cytomegaly, a characteristic finding in BWS. There are large polyhedral cells with hyperchromatic nuclei. (Courtesy D. Roberts, MD.) (Right) High-power view shows ACC in a patient with BWS. In these patients, the adrenal neoplasms are usually associated with pleomorphism.

Synaptophysin Pattern in Adrenal Tumors

High Proliferative Index (Left) ACCs usually have immunopositivity for synaptophysin, calretinin, Melan-A, SF-1, and inhibin-α. Synaptophysin is present in these tumors in the cytoplasm and in cellular membranes and can be very weak in some tumors. (Right) High Ki-67 proliferative index is shown. ACCs are associated with a high proliferative rate and can be divided on the basis of mitotic activity into low grade or high grade.

75

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Neoplasms in Children

Encapsulated Tumor

Focal Pleomorphism in Adrenal Cortical Carcinoma

Atypical Mitosis in Adrenal Carcinoma

Tumor Necrosis in Li-Fraumeni Syndrome

Eosinophilic Granules

Myxoid Component

(Left) This tumor from a 6year-old girl with virilizing ACC shows a well-circumscribed mass; however, the tumor also had multiple atypical mitoses and necrosis (not shown). All these features are suggestive of ACC. (Right) Higher power view of virilizing ACC shows the residual adrenal gland ﬊. There are numerous bizarre and multinucleated giant cells ﬈, some with intranuclear inclusions. This lesion has several features of malignancy.

(Left) This ACC has a diffuse growth pattern and is composed by cells with eosinophilic cytoplasm. Note atypical mitosis ﬊ and scattered pleomorphic cells. (Right) The presence of adrenal necrosis is one of the Weiss criteria for malignancy in adrenal cortical tumors. This tumor from a patient with LiFraumeni syndrome and TP53 mutation shows multifocal areas of necrosis.

(Left) H&E of an unusual adrenal cortical neoplasm shows numerous giant eosinophilic granules and a large hyaline globule ﬇. (Right) Some adrenal cortical tumors may have focal areas with a myxoid stroma. ACCs more frequently have myxoid stroma than adrenal cortical adenomas. These changes also can occur in pediatric adrenal tumors.

76

Adrenal Cortical Neoplasms in Children

Encapsulated Adrenal Carcinoma (Left) H&E shows a moderately well-circumscribed, solid lesion with areas of necrosis and multiple enlarged cells with atypical nuclei ﬊ in a 20-dayold boy with an adrenal mass. (Right) Higher power view of ACC shows the interface ﬊ between the tumor and the fibrous capsule. The tumor has a predominantly trabecular and solid pattern and is composed of compact cells with nuclear atypia and focal nuclear pleomorphism.

Necrosis and Pleomorphism

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Carcinoma in Newborn

Tumor Cell Characteristics (Left) H&E shows an area of ACC with focal necrosis ﬊. The tumor cells have an eosinophilic cytoplasm with nuclear pleomorphism, atypia, and mitosis. Some of the cells are multinucleated ﬉. (Right) Higher power view of ACC shows a predominantly solid pattern to this tumor composed of compact eosinophilic cells with nuclear atypia and focal nuclear pleomorphism.

Lung Metastases

Oncocytic Carcinoma in Lung (Left) H&E shows lung metastasis from an ACC in a 6year-old girl who presented with multiple lesions in her lungs a few months after the diagnosis of ACC. Biopsy of those lesions showed metastatic carcinoma that was morphologically and immunophenotypically similar to the originally diagnosed ACC. (Right) Higher power view shows a metastatic ACC ﬈ in the lung of a 6-year-old girl. Note the adjacent normal lung parenchyma ﬊.

77

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Pigmented Nodular Adrenocortical Disease KEY FACTS

TERMINOLOGY

MICROSCOPIC

• Rare cause of adrenocorticotropic hormone (ACTH)independent Cushing syndrome that may occur sporadically or in autosomal dominant familial form associated with Carney complex • Characterized by bilateral adrenocortical hyperplasia

• Nodules are composed of cells with compact eosinophilic cytoplasm & abundant brown, granular pigment (lipofuscin)

ANCILLARY TESTS

• Familial as part of Carney complex • Sporadic • Autoimmune origin

• Most patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) have inactivating mutations in PRKAR1A ○ Nonsense mutations, splice-site mutations, and loss of heterozygosity of PRKAR1A • Mutations of PDE11A and PDE8B

CLINICAL ISSUES

TOP DIFFERENTIAL DIAGNOSES

• Corticotropin-independent Cushing syndrome • Treatment: Bilateral adrenalectomy for Cushing syndrome

• Cushing syndrome caused by primary cortisol-producing adrenocortical adenoma • Cushing disease • Corticotropin (ACTH)-independent bilateral macronodular adrenal hyperplasia • Malignant melanoma

ETIOLOGY/PATHOGENESIS

MACROSCOPIC • Small to normal-sized adrenal glands with multiple small, pigmented nodules

Numerous Pigmented Nodules

These bilateral adrenal glands show pigmented nodules that are jet black to gray-brown ﬇. These nodules are usually small; however, some are macronodules resulting from a confluence of smaller nodules ſt.

78

Primary Pigmented Nodular Adrenocortical Disease

Abbreviations • Primary pigmented nodular adrenocortical disease (PPNAD)

Synonyms • Primary pigmented nodular adrenal disease • Isolated or sporadic primary pigmented nodular adrenocortical disease (iPPNAD) • PPNAD associated with Carney complex (CNC)

Definitions • Rare form of primary bilateral adrenal disease that is often associated with adrenocorticotropic hormone (ACTH)independent Cushing syndrome (CS) • PPNAD is most common endocrine manifestation in CNC ○ Detected in 25-60% of patients • Characterized by bilateral micronodular adrenocortical hyperplasia • Can be inherited in autosomal dominant manner associated with CNC • Nonfamilial or isolated or sporadic (iPPNAD) form

ETIOLOGY/PATHOGENESIS Etiology • Unknown • Sporadic ○ Can occur as nonfamilial isolated or sporadic (iPPNAD) form • Autoimmune origin ○ May result from adrenal-stimulating antibodies, which stimulate corticotropin receptor sites in adrenal cortex • Familial ○ Can occur in familial form, inherited as autosomal dominant trait when associated with CNC – Known genetic heterogeneity in CNC – PPNAD is most frequent endocrine manifestation of CNC, occurring in ~ 1/4 of patients

Genetic Abnormality • Disorder has been mapped to genomic loci on chromosomes 2q15-16 and 17q22-24 • Inactivating mutations of PRKAR1A on 17q22-24 have been reported in most patients with CNC • Inactivating mutations of phosphodiesterase 11A (PDE11A) located at 2q31-2q35 have been identified in sporadic PPNAD • Despite known genetic heterogeneity in CNC, in most cases, PPNAD in its sporadic or isolated forms (iPPNAD) is caused by inactivating heterozygous mutations of PRKAR1A ○ Polypyrimidine tract mutation of PRKAR1A leading to probable mild alteration of PRKAR1A mRNA splicing ○ Compared with mutations described for PRKAR1A, exon 7 intervening sequence (IVS) del[(-)7 → (-)2] has low penetrance and is almost exclusively associated with iPPNAD • > 140 PRKAR1A molecular defects have been reported in patients with CNC • Certain genotype-phenotype correlations have been noted in patients with CNC

○ Patients with PRKAR1A mutation are more likely to have pigmented skin lesions, myxomas, pigmented melanotic schwannomas (PMSs), and thyroid and gonadal tumors ○ Patients harboring mutations located in exons develop acromegaly, myxomas, lentigines, and PMSs more frequently ○ c.491-492delTG mutation is more often associated with lentigines, cardiac myxomas, and thyroid tumors when compared to all other PRKAR1A defects • > 80% of patients with CNC and PPNAD have germline inactivating mutations in PRKAR1A • Strong genotype-phenotype correlation in CNC &/or PPNAD for PRKAR1A mutation

Pathogenesis • All genetic events lead to constitutive activation of cAMP/protein kinase A (PKA) pathway, which results in hyperglucocortisolism and adrenocortical hyperplasia

CLINICAL ISSUES

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Epidemiology • Age ○ Patients with PPNAD in both sporadic and familial forms usually present in late childhood/early adulthood • Sex ○ ~ 70% of patients are women

Presentation • Most patients with PPNAD also have multiple neoplasia syndrome within CNC • PPNAD in its sporadic or isolated form is rare • Familial form as part of CNC: Autosomal dominant ○ PPNAD is most common endocrine manifestation in CNC and detected in 25-60% of patients ○ In ~ 1/2 of patients with CNC, PPNAD causes ACTHindependent CS ○ In addition to PPNAD, which is most common endocrine manifestation, CNC patients have – Myxomas – Spotty skin pigmentation – Cutaneous abnormalities – Schwannomas – Testicular tumors, including Leydig cell tumor and large-cell calcifying Sertoli cell tumors – Mammary myxoid fibroadenoma – Pituitary macroadenoma – Psammomatous melanotic schwannoma • Sporadic or isolated corticotropin-independent CS (iPPNAD) ○ Establishing diagnosis of PPNAD can be challenging, particularly when PPNAD is only manifestation of disease; some signs are – Weight gain – Fatigue – Muscle weakness – Moon face – Facial flushing – Buffalo hump – Striae marks – Bruises – Depression, anxiety, and irritability 79

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Pigmented Nodular Adrenocortical Disease – Irregular or absent menstrual periods in women

Laboratory Tests • Plasma cortisol is usually moderately elevated without diurnal rhythm • Plasma ACTH is low or undetectable • Hypercortisolism is resistant to high-dose dexamethasone suppression test (HDDST), metyrapone stimulation, and corticotropin-releasing hormone stimulation

Treatment • Surgical approaches ○ Bilateral adrenalectomy is treatment of choice for PPNAD in patients with CS

Prognosis • Life span is decreased in patients with CNC due to increased incidence of sudden death caused by heart myxoma or its complications • Genetic screening and long-term follow-up • 90% of patients with CNC will develop other endocrine &/or nonendocrine tumors over time

IMAGING CT Findings • Subtle adrenal contour abnormality and bilateral micronodules, which are small, round, well delineated, and hypodense ○ Nodules best seen when CT slices are ≤ 3 mm in thickness • Size of adrenal can be normal

MACROSCOPIC General Features • Small to normal-sized adrenal glands • Multiple small cortical nodules 0.1-0.3 cm in diameter involving both glands • Nodules may be pigmented, either brown or black ○ Some nodules may be pale to bright yellow

MICROSCOPIC Histologic Features • Nodules composed of cells with compact eosinophilic cytoplasm and abundant brown, granular pigment (lipofuscin) • Cell nuclei are vesicular and may contain prominent eosinophilic nucleoli • Intervening cortical tissue is atrophic

ANCILLARY TESTS Serologic Testing • Elevated basal cortisol and low ACTH • High 24-hour urinary-free cortisol • Nonsuppressed cortisol after HDDST suggests ACTHindependent CS

Immunohistochemistry • Increased expression of glucocorticoid receptor

80

Genetic Testing • PPNAD in its sporadic or isolated forms (iPPNAD) is caused by inactivating heterozygous mutations of PRKAR1A, encoding regulatory subunit type I-α of cAMP-dependent PKA ○ Compared with other mutations described for PRKAR1A, exon 7 IVS del[(-)7 → (-)2] has low penetrance and is almost exclusively associated with iPPNAD • Most patients with CNC and PPNAD have inactivating mutations in PRKAR1A ○ Nonsense mutations, splice-site mutations, and loss of heterozygosity of PRKAR1A ○ Because disease-associated mutations result in complete loss of function, there is generally poor correlation between phenotype and genotype • Mutations of PDE11A and PDE8B

DIFFERENTIAL DIAGNOSIS Cushing Syndrome Caused by Primary CortisolProducing Adrenocortical Adenoma • • • •

Patient presents with CS Lab: High cortisol, low ACTH Well-demarcated tumor lesion inside adrenal gland Gross: Single tumor nodule with expansile appearance, adjacent to grossly normal adrenal gland • Tumor cells arranged in short cords or alveoli

Cushing Disease • ACTH-dependent hypercortisolism caused by pituitary adenoma • Lab: High cortisol, high ACTH • MR shows mass in anterior pituitary gland • Diffuse enlargement of adrenal cortex • Grossly, diffuse adrenocortical hyperplasia • Microscopically, diffuse adrenocortical hyperplasia without pigment deposition

Corticotropin (ACTH)-Independent Bilateral Macronodular Adrenal Hyperplasia • Associated with tumefactive enlargement of both adrenal glands • Also associated with bilateral adrenocortical nodules, but nodules are much larger • On imaging, there is marked asymmetric nodularity throughout most of adrenal glands • Associated with markedly enlarged adrenal glands • Marked distortion of cortical architecture composed of lipid-rich cells with some lipid-depleted cells showing atrophy between nodules

Metastatic Malignant Melanoma • Both diseases involve both adrenal glands ○ Immunohistochemistry for S100, HMB-45, and Melan-A can readily separate from PPNAD

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Adrenal glands usually normal in size • Scattered small pigmented nodules ranging from light gray, gray-brown, dark brown, to jet black

Primary Pigmented Nodular Adrenocortical Disease

Immunostain

Cortical Nodules

Cortical Atrophy

Cortical Extrusions

Synaptophysin

Positive

Negative

Positive

Calretinin

Positive

Variably positive

Positive

SF1

Positive

Positive

Positive

Inhibin-α

Positive

Variably positive

Positive

MART-1

Positive

Variably positive

Variably positive

Melan-A

Positive

Variably positive

Variably positive

Vimentin

Negative

Variably positive

Variably positive

CD56

Negative

Variably positive

Variably positive

NSE

Positive

Variably positive

Variably positive

β-catenin

Positive

Positive

Positive

Ki-67

Positive

Negative

Positive

PPNAD = primary pigmented nodular adrenocortical disease. Modified from Carney et al, 2014.

• Histologically, pigmented nodules are round or oval; sporadic and familial forms have similar findings • Unencapsulated nodules of mixed lipid-rich and lipiddepleted adrenocortical cells with expansile borders • Intracytoplasmic pigment is lipofuscin

SELECTED REFERENCES 1. 2.

3. 4. 5. 6.

7.

8.

9.

10.

11. 12. 13.

14.

15.

16.

Kamilaris CDC et al: Carney complex. Exp Clin Endocrinol Diabetes. 127(203):156-64, 2019 Memon SS et al: Primary pigmented nodular adrenocortical disease (PPNAD): single centre experience. J Pediatr Endocrinol Metab. 32(4):391-7, 2019 Zhang CD et al: Cushing syndrome: uncovering Carney complex due to novel PRKAR1A mutation. Endocrinol Diabetes Metab Case Rep, 2019 Bosco Schamun MB et al: Carney complex review: genetic features. Endocrinol Diabetes Nutr. 65(1):52-9, 2018 Tirosh A et al: Genetics of micronodular adrenal hyperplasia and Carney complex. Presse Med. 47(7-8 Pt 2):e127-37, 2018 Kiefer FW et al: PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex. Eur J Endocrinol. 177(2):K7-12, 2017 Lowe KM et al: Cushing syndrome in Carney complex: clinical, pathologic, and molecular genetic findings in the 17 affected Mayo Clinic patients. Am J Surg Pathol. 41(2):171-81, 2017 Wagner-Bartak NA et al: Cushing syndrome: diagnostic workup and imaging features, with clinical and pathologic correlation. AJR Am J Roentgenol. 209(1):19-32, 2017 Bram Z et al: PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease. JCI Insight. 1(15):e87958, 2016 Mineo R et al: A novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) in a Cushing's syndrome patient with primary pigmented nodular adrenocortical disease. Intern Med. 55(17):2433-8, 2016 Schernthaner-Reiter MH et al: MEN1, MEN4, and Carney complex: pathology and molecular genetics. Neuroendocrinology. 103(1):18-31, 2016 Stratakis CA: Carney complex: a familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab Disord. 17(3):367-71, 2016 Carney JA et al: Primary pigmented nodular adrenocortical disease: the original 4 cases revisited after 30 years for follow-up, new investigations, and molecular genetic findings. Am J Surg Pathol. 38(9):1266-73, 2014 Carney JA et al: Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. Hum Pathol. 46(1):40-9, 2014 Anselmo J et al: A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab. 97(2):351-9, 2012 da Silva RM et al: Children with Cushing's syndrome: primary pigmented nodular adrenocortical disease should always be suspected. Pituitary. 14(1):61-7, 2011

Diagnoses Associated With Syndromes by Organ: Endocrine

Immunohistochemistry in PPNAD

17. Almeida MQ et al: Carney complex and other conditions associated with micronodular adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab. 24(6):907-14, 2010 18. Carney JA et al: Familial micronodular adrenocortical disease, Cushing syndrome, and mutations of the gene encoding phosphodiesterase 11A4 (PDE11A). Am J Surg Pathol. 34(4):547-55, 2010 19. Courcoutsakis N et al: CT findings of primary pigmented nodular adrenocortical disease: rare cause of ACTH-independent Cushing syndrome. AJR Am J Roentgenol. 194(6):W541, 2010 20. Peck MC et al: A novel PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease and the Carney complex. Endocr Pract. 16(2):198-204, 2010 21. Pereira AM et al: Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. J Clin Endocrinol Metab. 95(1):338-42, 2010 22. Bertherat J et al: Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab. 94(6):2085-91, 2009 23. Stratakis CA: New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Mol Cell Endocrinol. 300(12):152-7, 2009 24. Tadjine M et al: Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin Endocrinol (Oxf). 69(3):367-73, 2008 25. Stratakis CA: Adrenocortical tumors, primary pigmented adrenocortical disease (PPNAD)/Carney complex, and other bilateral hyperplasias: the NIH studies. Horm Metab Res. 39(6):467-73, 2007 26. Cazabat L et al: PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary. 9(3):211-9, 2006 27. Groussin L et al: A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab. 91(5):1943-9, 2006 28. Horvath A et al: Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J Clin Endocrinol Metab. 91(2):584-96, 2006 29. Groussin L et al: Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab. 87(9):4324-9, 2002 30. Carney JA: Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol. 14(2):90-8, 1995 31. Sasano H et al: Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases. Mod Pathol. 5(1):23-9, 1992 32. Carney JA et al: The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). 64(4):270-83, 1985 33. Shenoy BV et al: Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome. Am J Surg Pathol. 8(5):335-44, 1984

81

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Pigmented Nodular Adrenocortical Disease Characteristic Pigmentation in Carney Complex

Multinodular Adrenal Gland With Pale Nodules

Multiple Adrenocortical Nodules

Lipomatous Foci

Hyperplastic Enlarged Adrenal Gland

Adrenal Cortical Hyperplasia

(Left) In addition to PPNAD, which is the most common endocrine manifestation, Carney complex patients have the characteristic findings of spotty skin pigmentation in the mucocutaneous regions around eyes and lips. (Courtesy J. A. Carney, MD.) (Right) Sections of adrenal gland from a patient with PPNAD are studded with micronodules and rare macronodules that are due to the confluence of smaller nodules. The outer surface has an irregular micronodular contour.

(Left) The microscopic evaluation of primary PPNAD is less obvious than the gross examination. The pigmented nodules are small, round or oval, and may have irregular contours. The adjacent adrenal cortical tissue shows atrophy and lipomatous metaplasia. (Right) Low-power view of an adrenal gland from a patient with PPNAD shows a nodule composed of cells with lipid-depleted cytoplasm ﬊ containing a small amount of finely granular lipofuscin pigment. Lipomatous metaplasia ﬉ is also present.

(Left) Gross photo shows a cross section of an enlarged adrenal gland with cortical hyperplasia. This differs grossly from PPNAD, which is characterized by normal-sized adrenal glands with bilateral pigmented adrenocortical nodules, < 1 cm in diameter. (Right) As a differential diagnosis from PPNAD, this markedly enlarged adrenal gland shows cortical hyperplasia with a homogeneous yellow surface and without small nodules.

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Primary Pigmented Nodular Adrenocortical Disease

Clear Cytoplasm With Pigment (Left) Cytologically, the cells are uniform, although occasional binucleated or cells with enlarged nuclei and prominent nucleoli can be seen. The lipid-poor eosinophilic cytoplasm may contain a finely granular, orange-brown lipofuscin pigment. (Right) High-power view of a PPNAD nodule shows cells with abundant lipid-rich, foamy, and clear cytoplasm ﬇ intermixed with cells that contain eosinophilic cytoplasm with finely granular orange-brown pigment (lipofuscin). Note slight nuclear pleomorphism.

Extensive Pigment Deposition

Diagnoses Associated With Syndromes by Organ: Endocrine

Lipid-Depleted Cells

Lipofuscin Accumulation (Left) In some areas of the adrenal with PPNAD, there is extensive pigment deposition. The pigment often accumulates in the cytoplasm of the cells occupying the entire cytoplasm. (Right) The nodules are composed of enlarged globular cortical cells with granular eosinophilic cytoplasm with lipochrome pigment. The pigment often accumulates in the cytoplasm of the cells, forming a pigmented globule ﬊.

Adrenal Malignant Melanoma

Cell Morphology in Melanoma (Left) Within the differential diagnosis of PPNAD is primary adrenal melanoma, which shows pleomorphic cells and irregular nuclei ﬇ with abundant brown granular pigment (melanin) ﬊. The color of the pigment and immunohistochemistry will help in the diagnosis. (Right) Within the differential diagnosis of PPNAD is primary adrenal melanoma, which shows pleomorphic cells with irregular nuclei ﬇ and abundant dark brown, coarsely granular melanin pigment st.

83

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortex Table Clinical Features Suggesting Familial Adrenal Cortical Carcinoma Personal History

Family History

Metachronous ACC

Family history of ACC

Bilateral ACC

Family history of known hereditary cancer susceptibility syndromes

Multiple primary tumors in other organs

Unusually high number of family members affected with cancer

Other rare cancers

Family history of other rare cancers

ACC diagnosed in childhood Development of ACC from precursor lesion Other endocrine diseases Cutaneous lesions associated with hereditary cancer susceptibility Other congenital defects ACC = adrenal cortical carcinoma.

Adrenal Cortical Tumor as Part of Inherited Tumor Syndromes Syndrome

Gene

Chromosomal Location

Adrenal Pathology

% Adrenal Involvement

Prevalence Among Patients With ACC

Li-Fraumeni syndrome

TP53

17p13

ACC

6.5-9.9%

3-5% in adults; 50-80% in children

Beckwith-Wiedemann syndrome

CDKN1C/NSD1

11p15.5

ACA, ACC, NH

1.0%

< 1%

Multiple endocrine neoplasia type 1 (MEN1)

MEN1

11q13

ACA, ACC

45-55%

1-2%

Carney complex

PRKAR1A

2p16

PPNAD, ACA

~ 100%

< 1%

McCune-Albright syndrome

GNAS1

20q13.2

NH, ACA

Congenital adrenal hyperplasia CYP21

6p21.3

NH, ACA, ACC

Familial adenomatous polyposis (FAP)

APC

5q21-22

ACA (functional or nonfunctional); ACC

7.4-13%

< 1%

Neurofibromatosis type 1 (NF1)

NF1

17

ACC

< 1%

Lynch syndrome

MLH1 MSH2 MSH6 PMS2

Multiple

ACC

3%

Hereditary leiomyomatosis FH renal cell carcinoma syndrome 

Primary bilateral macronodular hyperplasia

ACA = adrenal cortical adenoma; ACC = adrenal cortical carcinoma; NH = nodular hyperplasia; PPNAD = primary pigmented nodular adrenal disease.

Clinical Settings Associated With Cytomegalic Cells Focal Cytomegalic Cells (Variably Present)

Diffusely Scattered Cytomegalic Cells

Extensive hemolysis

Beckwith-Wiedemann syndrome

Rhesus isoimmunization

X-linked congenital adrenal hypoplasia

Congenital Lupus erythematosus Erythropoietic purpura Nonimmune hydrops Trisomy 13 and 18 Diaphragmatic hernia Ectopic adrenal tissue Intrauterine viral infection

84

Adrenal Cortex Table Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortical Lesions Associated With Syndromes  Adrenal Pathology

Syndrome Associated

Adrenal cortical adenoma

Multiple endocrine neoplasia 1 Familial adenomatous polyposis McCune-Albright syndrome Beckwith-Wiedemann syndrome Congenital adrenal hyperplasia Carney complex Familial adenomatous polyposis

Adrenal cortical carcinoma

Li-Fraumeni syndrome Beckwith-Wiedemann syndrome Multiple endocrine neoplasia 1 Lynch syndrome Familial adenomatous polyposis Neurofibromatosis type 1 Congenital adrenal hyperplasia

Primary bilateral macronodular adrenal hyperplasia

Multiple endocrine neoplasia 1 McCune-Albright syndrome Beckwith-Wiedemann syndrome Congenital adrenal hyperplasia Hereditary leiomyomatosis renal cell carcinoma syndrome

Primary pigmented adrenal cortical disease

Carney complex

Criteria for Differentiation Between Adenoma and Carcinoma Criteria

Adenoma

Carcinoma

Hormone production

Often functional

Usually nonfunctional

Gross

Weight < 50 g

Weight > 100 g

Tumor gross color

Variable

Variable; does not differentiate

Circumscription

Well circumscribed

Invasive

Hemorrhage

Absent

Frequent

Necrosis

Absent

Frequent

Capsular invasion

Absent

Usually present

Invasion into adjacent tissues

Absent

Usually present

Intratumoral fibrosis

May be present

May be present

Myxomatous degeneration

May be present

May be present

Cytology

May have cytologic atypia

Cytologic atypia present

Histology

Atypia may be present

Atypia present

Necrosis

Necrosis absent

Present; confluent necrosis

Mitosis

Rare

> 5/50 HPF

Venous invasion

Absent

Present

HPF = high-power field.

Differential Diagnosis of Adrenal Cortical Adenoma Neoplasm

Inhibin

Melan-A

Chromogranin

Synaptophysin

Hep-Par1

CD10

Calretinin

Adrenal cortical adenoma

Positive

Positive

Negative

Positive (57%)

Negative

Negative

Positive

Pheochromocytoma

Negative

Negative

Positive

Positive

Negative

Negative

Negative

Hepatocellular carcinoma

Negative

Negative

Negative

Negative

Positive

Positive (61%)

Negative

Renal cell carcinoma

Negative

Negative

Negative

Negative

Negative

Positive

Negative

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Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Cortex Table

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Immunohistochemistry of Adrenal Cortical Tumors Antibody

Reactivity

Staining Pattern

Inhibin

Positive (~ 85%)

Cytoplasm

Mart-1

Positive (~ 95%)

Cytoplasm

Melan-A103

Positive (~ 85%)

Cytoplasm

SF1

Positive (~ 90%)

Nucleus

Comment

Negative in renal cell carcinoma and pheochromocytoma

NSE

Positive (~ 90%)

Cytoplasm

Synaptophysin

Positive (~ 65%)

Cytoplasm

CD56

Positive (~ 90%)

Membrane

BCL-2

Positive (~ 25%)

Membrane and cytoplasm

CAM5.2

Positive (~ 30%)

Cytoplasm

EGFR

Positive (~ 50%)

Membrane

GATA3 

Positive (~ 10%)

Nucleus

CD10

Positive (~ 10%)

Membrane

PanKeratin

Positive (~ 15%)

Cytoplasm

Calretinin

Positive (~ 30%)

Nucleus and cytoplasm

Chromogranin-A

Negative

Helps to differentiate from pheochromocytoma

CK7

Negative

Helps to differentiate from other epithelial tumors

AE1/AE3

Negative

Helps to differentiate from other epithelial tumors

CK20

Negative

Helps to differentiate from other epithelial tumors

EMA

Negative

Helps to differentiate from other epithelial tumors

CD10

Negative

Helps to differentiate from renal cell carcinoma

Hep-Par1

Negative

Helps to differentiate from hepatocellular carcinoma

HMFG

Negative

RCC

Negative

HMB-45

Negative

Helps to differentiate from renal cell carcinoma

Adrenal Cortex Table

Diffuse Hyperplasia (Left) Sections of the adrenal gland are studded with pigmented micronodules and occasional macronodules that are due to confluence of smaller nodules. The outer surface has an irregular micronodular contour. (Right) Cross section reveals a diffusely enlarged adrenal gland with diffuse adrenal cortical hyperplasia.

Macronodular Adrenal Cortical Hyperplasia

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Pigmented Nodular Adrenocortical Disease in Carney Complex

Adrenal Cortical Adenoma (Left) Markedly enlarged adrenal gland shows a pale yellow cut surface with a dominant 3.8-cm nodule as well as 2 smaller 1.3- and 1.1cm nodules. Such lesions may be seen in hereditary leiomyomatosis renal cell carcinoma syndrome. (Right) Well-circumscribed adrenal cortical adenoma demonstrates a mottled appearance with dark discoloration due to lipid depletion and increased lipofuscin pigment. Adenomas may be present in a variety of familial syndromes.

Adrenal Cortical Carcinoma

Pediatric Adrenal Cortical Carcinoma (Left) Adrenal cortical carcinoma presented as an irregular-shaped, bulky, unilateral mass and has a light-brown variegated cut surface. Note also extensive necrosis, degenerative changes, hemorrhage, and calcification. (Right) Pediatric adrenal cortical carcinoma has a yellow, pink to light-brown variegated cut surface with extensive areas of necrosis ﬇, degenerative changes, and hemorrhagic areas ſt.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Medullary Hyperplasia KEY FACTS

• Adrenal medullary hyperplasia (AMH): Increase in mass of adrenal medullary cells and expansion of these cells into areas of gland where they are not normally present

• Patients with MEN2 syndromes, SDHB-related tumors, and MAX-related disease usually have diffuse and nodular hyperplasia involving both glands • Nodules are gray to tan and may compress adjacent cortex

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• AMH is precursor of pheochromocytomas (PCCs) in MEN2 syndromes, SDHB- and MAX-related tumors  • AMH common in MEN2A and MEN2B ○ Very rare in other PCC/paraganglioma syndromes • Bilateral diffuse AMH in patients with SDHB and MAX mutation

• Nodules can occur with little or no diffuse hyperplasia • Histology shows medullary hyperplasia composed of proliferation of cells containing normal cellular architecture ○ As opposed to nests of cytologically atypical polygonal cells that characterize PCC

MACROSCOPIC

• Distinction between AMH and PCC can be challenging • Cutoff of 1 cm to differentiate PCC from hyperplastic nodule is arbitrary • Presence of unilateral vs. bilateral disease may be helpful in distinguishing AMH from PCC • Unilateral AMH has been reported in isolated and familial AMH

TERMINOLOGY

• Adrenal medulla normally confined to central region (body) of gland ○ Medullary hyperplasia often identifiable by gross extension of gray medullary tissue into alae and tail

TOP DIFFERENTIAL DIAGNOSES

Adrenal Medullary Expansion in MEN2

Hyaline Granules in MEN2

SDHB Preservation Within Medulla

SDHB Loss

(Left) Adrenal gland from a patient with multiple endocrine neoplasia type 2A (MEN2A) shows diffuse medullary expansion st, characteristic of adrenal medullary hyperplasia (AMH), and a well-defined nodule ﬇. (Right) AMH in a patient with MEN2 syndrome shows medullary cells ﬉ within the adrenal cortex ﬇. Hyaline granules st are usually present in MEN2.

(Left) SDHB immunostain shows granules within the medullary cells, indicating wild-type SDHB. (Right) Endothelial cells ﬈ with granular immunopositivity for SDHB serve as intrinsic controls to indicate wild-type SDHB. Tumor cells ﬈ with mutation of SDHB show no immunoreactivity. Immunohistochemistry might also be useful screening for MAX mutations.

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Adrenal Medullary Hyperplasia

Abbreviations • Adrenal medullary hyperplasia (AMH)

Definitions • Increase in mass of adrenal medullary cells and expansion of these cells into areas of gland where they are not normally present • Benign change in adrenal gland characterized by disproportionate enlargement of medulla compared with cortex ○ Considered adrenal cortex to medulla ratio of < 10:1 • Arbitrarily, lesions < 1 cm in diameter are called AMH ○ Expected that majority of these are early lesions and, if left in situ, would grow to pheochromocytoma (PCC) • Increased cell number in sympathoadrenal or parasympathetic paraganglia

ETIOLOGY/PATHOGENESIS Familial Medullary Hyperplasia • Best known to be precursor lesion of MEN2 syndromes • Identification of AMH used to be considered diagnostic of MEN2 syndrome • Bilateral diffuse AMH in patient with SDHB mutation • Familial PCC with germline mutations in MAX (MYCassociated factor X) gene ○ Both nodular and diffuse AMH belong to spectrum of MAX-related disease • Other predisposing genetic syndromes not typically associated with AMH

Hyperplasia Associated With Genetic Disorders • Bilateral AMH 1st described in 1966 ○ Significance was not understood until identification of RET protooncogene – Now, association of AMH and MEN2 syndromes well established ○ AMH is precursor of PCCs in MEN2 syndrome – Common in MEN2A and MEN2B • AMH known to be very rare in other PCC/paraganglioma syndromes ○ Report of bilateral diffuse AMH in patient with SDHB mutation ○ Nodular and diffuse AMH belongs to spectrum of MAXrelated disease • AMH and hyperplasia of extraadrenal sympathetic paraganglia in Beckwith-Wiedemann syndrome (BWS) noted by Beckwith in 1969 description ○ Now seems less consistent than cortical abnormalities • Mature chromaffin cell nodules (sometimes present in fetuses with BWS) suggest extraadrenal paraganglia developing within adrenals

As Precursor Lesion • Because of link between RET mutations and AMH, it is hypothesized that medullary hyperplasia is precursor lesion that will eventually develop into PCC given enough time ○ Similar pattern of progression from hyperplasia to malignancy seen in other endocrine tumors, such as medullary thyroid cancer and adrenal cortical tumors

Sporadic Adrenal Medullary Hyperplasia • Sporadic AMH reported in different settings ○ Patients with cystic fibrosis ○ Infants dying of sudden infant death syndrome (SIDS) ○ Cushing syndrome ○ Sporadic forms of BWS ○ Other rare causes

Compensatory Physiological Hyperplasia • Extensively documented in parasympathetic paraganglia; mostly carotid body, sometimes vagal ○ Presumed association with hypoxia: Occurs in humans and animals living at high altitude; also reported in lung disease, cystic fibrosis, and cyanotic heart disease ○ Controversial association of hyperplastic paraganglia with SIDS

CLINICAL ISSUES Presentation

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

• AMH may present with signs of catecholamine excess or be discovered incidentally after adrenalectomy for PCC • Hyperplasia of extraadrenal paraganglia usually studied in autopsy series of patients dying from other causes

MACROSCOPIC General Features • Patients with some syndromes usually have diffuse and nodular hyperplasia involving both glands ○ Characteristically in these patients, medullary hyperplasia involves tail • Nodules gray to tan and may compress adjacent cortex • Adrenal medulla normally confined to central region (body) of gland ○ AMH often identifiable by gross extension of gray medullary tissue into alae and tail ○ Nodules often superimposed on diffuse hyperplasia ○ Mild diffuse hyperplasia may require morphometry for confirmation (usually not done in practice) • On gross examination, as well as radiologic imaging, medullary hyperplasia has poorly defined nodules ○ Unlike PCC, which usually presents as enlarged adrenal nodule arising from medulla • Hyperplasia of other paraganglia usually not identifiable macroscopically

Size • Morphometrically calculated weight of 1 normal adrenal medulla: 0.3-0.5 g (~ 10% of total adrenal weight) ○ AMH often begins as diffuse ↑ in volume and weight • Carotid body weight ↑ with age ○ Average normal combined weight in adults: < 15 mg (> 30 mg suggests hyperplasia)

MICROSCOPIC Histologic Features • Shows medullary hyperplasia composed by proliferation of cells containing normal cellular architecture ○ As opposed to nests of cytologically atypical polygonal cells that characterize PCC 89

Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Medullary Hyperplasia

• • • •

•

○ In MEN2-associated medullary hyperplasia, hyaline globules may be present ○ Hyperplastic medullary cells may show various growth patterns: Alveolar, diffuse or solid, and trabecular ○ Sometimes, hyperplastic cells are arranged in small nests separated by thin fibrous tissue Presence of adrenal medullary tissue in tail indicates presence of AMH Classic AMH shows diffuse medullary expansion with increasing atypia and superimposed nodules Adrenal medullary nodules can occur with little or no diffuse hyperplasia Medulla does not represent > 1/3 of gland thickness, with cortex on each side comprising other 2/3 ○ However, significant cortical atrophy, usually due to exogenous steroid administration, alters ratio and can mimic medullary hyperplasia – Careful evaluation of cortical anatomy and cytology required before diagnosis of AMH Normal carotid body divided by thick fibrous septa into variable number of lobes ○ Lobes further divided by thin septa into lobules – Lobules contain clusters (zellballen) of chief cells with peripheral sustentacular cells ○ Carotid body hyperplasia at high altitude – ↑ number of lobes and larger lobes with ↑ cellularity caused by chief cell hyperplasia ○ Studies variably report proportionate or disproportionate ↑ of sustentacular cells, especially in hyperplasia unrelated to high altitude

ANCILLARY TESTS Immunohistochemistry • Neuroendocrine markers highlight medullary cells ○ Chromogranin-A ○ Synaptophysin ○ NSE ○ CD56 ○ S100 identifies sustentacular cells • SDHA and SDHB immunostains help identify SDHxassociated inherited cases

• PCCs have characteristic alveolar pattern (zellballen) with variably sized nests of tumor cells surrounded by thinwalled vessels and thin bands of fibrous tissue • Some PCCs lack organoid pattern and instead may show diffuse growth pattern • Some PCCs show mosaic-like pattern of often large cells with granular basophilic cytoplasm admixed with cells that have amphophilic to slightly eosinophilic cytoplasm • Some PCCs formed by small cells with ample eosinophilic cytoplasm with occasional bizarre cells

Metastatic Carcinoma • Can be distinguished by characteristic morphological features • Distinguished by immunohistochemical profile ○ Positivity for chromogranin, synaptophysin, NSE, and CD56 in AMH ○ Characteristic positivity for S100 in sustentacular cells, when present, helps identify AMH

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Adrenals removed for PCC should be carefully examined for additional nodules as clue to presence of MEN2, SDHBand MAX-related diseases

SELECTED REFERENCES 1. 2. 3.

4.

5. 6. 7. 8. 9.

DIFFERENTIAL DIAGNOSIS

10.

Pheochromocytoma • Distinction between AMH and PCC can be challenging ○ Cutoff of 1 cm to differentiate PCC from hyperplastic nodule is arbitrary – Some PCCs may be < 1 cm – Benign adrenal nodules in patients with MEN2B can be monoclonal – Both AMH and PCC often monoclonal – Best to consider nodular hyperplasia and small PCCs as part of continuum of same disease process • Presence of unilateral vs. bilateral disease may be helpful in distinguishing AMH from PCC ○ Unilateral AMH has been reported in isolated and familial AMH • Altered macroscopic appearance and histology probably more meaningful 90

11. 12.

13.

14.

Nishimura Y et al: A case of juvenile hypertension suggestive of adrenomedullary hyperplasia. Intern Med. 58(2):311, 2019 Gupta L et al: Adrenal medullary hyperplasia with coexistent cerebral angiomas. Indian J Pathol Microbiol. 61(4):587-9, 2018 Falhammar H et al: Frequency of Cushing's syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center. Endocrine. 55(1):296-302, 2017 Romanet P et al: Pathological and genetic characterization of bilateral adrenomedullary hyperplasia in a patient with germline MAX mutation. Endocr Pathol. 28(4):302-7, 2017 Huang Z et al: [Diagnosis and treatment of adrenal medullary hyperplasia.] Zhonghua Yi Xue Za Zhi. 94(18):1413-5, 2014 Korpershoek E et al: Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome. Neoplasia. 16(10):868-73, 2014 Yang L et al: Diagnosis and treatment of adrenal medullary hyperplasia: experience from 12 cases. Int J Endocrinol. 2014:752410, 2014 Mete O et al: Precursor lesions of endocrine system neoplasms. Pathology. 45(3):316-30, 2013 Grogan RH et al: Bilateral adrenal medullary hyperplasia associated with an SDHB mutation. J Clin Oncol. 29(8):e200-2, 2011 Berthon A et al: Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet. 19(8):1561-76, 2010 Powers JF et al: Ret protein expression in adrenal medullary hyperplasia and pheochromocytoma. Endocr Pathol. 14(4):351-61, 2003 Diaz-Cano SJ et al: Clonal patterns in phaeochromocytomas and MEN-2A adrenal medullary hyperplasias: histological and kinetic correlates. J Pathol. 192(2):221-8, 2000 Carney JA et al: Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Pathol. 66(2):27990, 1976 DeLellis RA et al: Adrenal medullary hyperplasia. A morphometric analysis in patients with familial medullary thyroid carcinoma. Am J Pathol. 83(1):17796, 1976

Adrenal Medullary Hyperplasia

Alveolar Architecture (Left) Familial medullary hyperplasia is most commonly present in patients with MEN2A and MEN2B and associated with pheochromocytoma. The involvement is usually bilateral, diffuse, and nodular, and often extends to both alae and the tail of the adrenal gland. (Right) Hyperplastic medullary cells may show various growth patterns: Alveolar, solid, or trabecular. This example of AMH shows an alveolar growth pattern.

Alveolar and Trabecular Architecture

Diagnoses Associated With Syndromes by Organ: Endocrine

Gross Cut Surface

Distinct Cell Morphology (Left) AMH in a patient with MEN2 shows a mixed alveolartrabecular growth pattern. Note hyaline granules st, usually present in MEN2. (Right) In areas of AMH, the hyperplastic cells may be arranged in small nests of cells, or as single cells, separated by thin fibrous tissue.

Intermixed Adrenal Cortical Cells

Scattered Hyaline Globules (Left) Patients with MEN2 syndrome may have diffuse and nodular AMH. Note medullary cells ﬉ within the adrenal cortex ﬊. Hyaline granules ﬈ are usually present in MEN2. (Right) Diffuse AMH has cells arranged in cords and is composed of medullary cells with ample granular basophilic cytoplasm and small nuclei. There is mild nuclear pleomorphism. Rare hyaline globules st are noted.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Neuroblastic Tumors of Adrenal Gland KEY FACTS

TERMINOLOGY • Neuroblastic tumors of adrenal gland: Group of tumors arising from sympathoadrenal lineage of neural crest during development (WHO 2017)

MICROSCOPIC • International Neuroblastoma Pathology Committee (INPC) classification • Neuroblastoma (NB) (schwannian stroma poor) ○ Cellular neuroblastic tumor without prominent schwannian stroma – Undifferentiated: No identifiable neuropil formation and supplementary diagnostic techniques required – Poorly differentiated: Diagnosis can be made by pure morphological criteria; differentiating neuroblasts < 5%; characteristic neuropil present – Differentiating: Usually abundant neuropil; differentiating neuroblasts > 5%

• Ganglioneuroblastoma (GNB), intermixed (schwannian stroma rich) ○ Intermingled microscopic foci of neuroblastic elements in expanding schwannian stroma, constituting > 50% of tumor volume • GNB, nodular (composite, schwannian stroma rich/dominant and schwannian stroma poor) ○ Grossly identifiable neuroblastic nodular (stroma-poor) component coexisting with intermixed GNB (stromarich) or ganglioneuroma (GN) (stroma-dominant) component • GN (schwannian stroma dominant) ○ Predominantly composed of schwannian stroma without individually distributed neuronal elements – Maturing GN: Both maturing and mature ganglion cells – Mature GN: Exclusively mature ganglion cells in schwannian stroma

MYCN FISH Amplification

Fluorescence in situ hybridization (FISH) of neuroblastoma (NB) shows marked amplification of MYCN (multiple confluent green dots). The degree of MYCN amplification, higher or lower, is not correlated with a worse outcome.

92

Neuroblastic Tumors of Adrenal Gland

Abbreviations • Neuroblastoma (NB) • Ganglioneuroblastoma (GNB) • Ganglioneuroma (GN)

Synonyms • Peripheral neuroblastic tumor

Definitions • Neuroblastic tumors of adrenal gland: Group of tumors arising from sympathoadrenal lineage of neural crest during development (WHO 2017) ○ Included within broader classification of peripheral neuroblastic tumors • International Neuroblastoma Pathology Classification (INPC) defines 4 categories of peripheral neuroblastic tumors ○ NB (schwannian stroma-poor) ○ GNB, intermixed (schwannian stroma-rich) ○ GNB, nodular (composite, schwannian-rich/dominant) ○ GN (schwannian stroma-dominant)

ETIOLOGY/PATHOGENESIS Developmental Anomaly • Neuroblastic tumors arise from sympathoadrenal lineage of neural crest during development ○ Derived from primordial neural crest cells – These cells migrate from spinal cord to adrenal medulla and sympathetic ganglia ○ ~ 70% abdominal, most located in adrenal glands ○ Other locations include abdominal ganglia, thoracic ganglia, pelvic ganglia, cervical sympathetic ganglia, and paratesticular region • Caused by transformation of neural crest cells secondary to genetic or epigenetic events • Events leading to tumorigenesis remain poorly understood • May be preconception or gestational factors; some tumors congenital • No definitive factors accepted to increase incidence

Genetic Susceptibility • 1-2% of affected individuals have familial NB ○ Autosomal dominant inheritance pattern with incomplete penetration ○ Patients with hereditary predisposition to NB are diagnosed at earlier age (mean age: 9 months)  – Patients with sporadic NB are diagnosed at later age (mean age: 17 months) ○ > 20% have bilateral adrenal disease or multifocal primaries • Gene identified on familial NB linked to 16p12-13 • Germline mutations reported in familial cases are located in 2p12 (PHOX2B) and 2p23 (ALK) ○ Inherited changes in ALK oncogene are observed in most hereditary NB cases ○ PHOX2B mutations have been identified in few inherited cases

Ganglioneuroma • Believed that all GNs were once NBs in early stage of tumor development • Developmental anomaly ○ Postulated that tumor cells derived from neuroblasts in adrenal medulla ○ Most develop de novo • Associated conditions ○ Polypoid GNs in GI tract associated with tumor syndromes – PTEN-hamartoma tumor syndrome (Cowden disease), MEN2B, NF1, juvenile polyposis, and tuberous sclerosis ○ Most adrenal GNs sporadic – Some cases have been associated with Turner syndrome and MEN2

CLINICAL ISSUES Epidemiology

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

• Incidence ○ Peripheral neuroblastic tumors 3rd most common childhood neoplasm – After leukemias and brain tumors ○ Most common neoplasms during 1st year of life ○ Most common extracranial solid tumors during 1st 2 years of life ○ Prevalence: 1/7,000 live births • Age ○ 40% of patients diagnosed < 1 year of age ○ ~ 90% diagnosed < 5 years of age ○ ~ 20-30% congenital (some detected on US during pregnancy) • Sex ○ M:F = 1.2:1.0 • Ethnicity ○ Less common in African Americans; very low incidence in Burkitt lymphoma belt in Africa • GN ○ Age – 7 years or older ○ Sex – No predilection

Site • Primary site reflects migration pattern of neural crest cells during fetal development and follows distribution of sympathetic ganglia ○ Abdomen (54%) – Adrenal (40%) – Abdominal ganglia (25%) ○ Thoracic ganglia (15%) ○ Cervical sympathetic ganglia (3-5%) ○ Pelvic ganglia (5%) ○ Rare tumors occur in paratesticular region • GN ○ Most found in posterior mediastinum and retroperitoneum ○ 20-30% of all GNs occur in adrenal

93

Diagnoses Associated With Syndromes by Organ: Endocrine

Neuroblastic Tumors of Adrenal Gland Presentation

Prognosis

• Usually sporadic ○ Some autosomal dominant familial cases have been seen • Depends on age of patient, location of tumor, and associated clinical syndromes • Most have nonspecific symptoms ○ Fever, weight loss, diarrhea, anemia, hypertension • Fetuses may have hydrops • Palpable mass • ~ 2/3 have metastasis on presentation • "Blueberry muffin" baby ○ Blue-red cutaneous lesions in infants • Opsoclonus/myoclonus syndrome (dancing eyes, dancing feet) • Complex and heterogeneous disease ○ Many factors, such as age at diagnosis and stage of disease, in addition to molecular, cellular, and genetic features of tumor, determine whether it will spontaneously regress or metastasize and become refractory to therapy • GN ○ Asymptomatic; incidental, painless mass ○ Most tumors hormone silent – Up to 37% can produce catecholamine, testosterone, and other hormones

• International Neuroblastoma Staging System (INSS) and International Neuroblastoma Risk Group (INRG) used to predict prognosis of patients with NB • INSS ○ Molecular facts – MYCN status □ MYCN amplification, detected by FISH or IHC, present in ~ 25% of NB – DNA index: Ploidy ○ Patient age ○ INPC histology groups – Favorable – Unfavorable □ Based on age of patient, histological type, and mitosis-karyorrhexis index (MKI) (defined as number of cells undergoing mitosis or karyorrhexis per 5,000 cells) ○ Clinical parameters • INGR ○ Patient age ○ Histological category ○ Grade of tumor differentiation ○ Molecular factors – MYCN status – Ploidy – Presence of unbalanced 11q aberration □ High risk with aberration • 5-year survival based on stage at time of diagnosis ○ Stage I: > 90% ○ Stage II: 70-80% ○ Stage III: 40-70% ○ Stage IV – < 1 year old: > 60% – 1-2 years old: 20% – > 2 years old: 10% ○ Stage IV-S: > 80% • Patient age at diagnosis, stage of disease, and presence of MYCN amplification in NB cells are 3 strongest determinants of clinical outcome • Adverse factors ○ Older age at diagnosis ○ Advanced stage of disease (except IV-S) ○ High histologic grade of tumor ○ Diploid DNA value ○ MYCN (v-myc myelocytomatosis viral related oncogene, NB derived) oncogene amplification and loss of chromosome 11q heterozygosity have been known to be indicative of poor prognosis – MYCN expression profile still one of most robust and significant prognostic markers for NB outcome ○ Cytogenetic abnormalities of chromosomes 1 and 17 ○ Pattern of urinary catecholamine excretion ○ Increased levels of ferritin, NSE, LDH, creatine kinase BB, or chromogranin-A ○ Abnormalities in ganglioside composition ○ Lack of high affinity nerve growth factor receptors

Laboratory Tests • Urine catecholamine metabolites and dopamine have been used for screening • Lactate dehydrogenase ○ > 1,500 IU/L associated with worse clinical outcome • Ferritin ○ > 142 ng/mL associated with worse clinical outcome • NSE ○ > 100 ng/mL associated with worse clinical outcome

Natural History • Some cases undergo spontaneous regression, including stage IV-S ○ Most in children under 1 year of age

Treatment • Low risk ○ Surgery or observation alone • Intermediate risk ○ Surgery and adjuvant chemotherapy • High risk ○ Induction chemotherapy ○ Delayed tumor resection ○ Radiation of primary site ○ Myeloablative chemotherapy with stem cell recovery • Metastases ○ Bone ○ Lymph nodes ○ Liver ○ Skin • GN ○ Definitive treatment: Surgical excision

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Neuroblastic Tumors of Adrenal Gland

• Excellent; few cases reported of malignant transformation of GNs into malignant schwannoma and malignant peripheral nerve sheath tumor (MPNST)

IMAGING General Features • Extensive radiographic evaluation required to determine extent of disease and identify metastatic foci • Calcifications often seen in central portion of tumor • GN imaging ○ MR – Low nonenhanced T1-weighted signal, slightly high and heterogeneous T2-weighted signal, and late and gradual enhancement on dynamic MR ○ CT – Well-defined, sometimes encapsulated, solid mass inside adrenal gland – Punctuate or discrete calcifications seen in almost 1/2 of GNs

Bone Scan • Radiolabeled metaiodobenzylguanidine (MIBG) incorporates into catecholamine-secreting cells and can detect NB

MACROSCOPIC General Features • Color and consistency depends on amount of stroma present (stroma-poor vs. stroma-rich tumors), hemorrhage, and necrosis • Usually solitary masses • NB (schwannian stroma poor): Reach 10 cm and form soft, gray-pale mass with areas of hemorrhage • GNB, nodular type: Soft, hemorrhagic nodules intermixed with tan-white tumor tissue • GNB, intermixed type: Tan-white cut surface • NB (schwannian stroma poor): Well-circumscribed, firm, multinodular mass with gray-white cut surface • Cystic degeneration, hemorrhage, necrosis, and calcification can be seen

MICROSCOPIC Histologic Features • Histopathological classification: INPC defines 4 categories of neuroblastic tumors (NB, intermixed GNB, nodular GNB, and GN) and delineates distinction between them • Cytological features ○ Neuroblasts – Small round blue cells with very scant cytoplasm ○ Homer Wright rosettes or pseudorosettes (uncommon) – Nuclei grouping in ring-like structures around central cores of tangled neuritic cell processes ○ Ganglionic differentiation – Cells enlarged – Increased eosinophilic or amphophilic cytoplasm – Nuclear chromatin pattern becomes vesicular – Must have synchronous differentiation of cytoplasm and nucleus

○ Neuropil – Fibrillar eosinophilic matrix ○ MKI, applicable for stroma-poor tumors – Count of cells undergoing mitosis or karyorrhexis (per 5,000 cells) □ Low: < 100 cells □ Intermediate: 100-200 cells □ High: > 200 cells ○ Schwann cells with spindled cytoplasm, wavy dark nuclei, and inconspicuous nucleoli admixed with ganglion cells ○ Ganglion cells exhibit abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli

INPC Classification • NB (Schwannian stroma poor) ○ Cellular neuroblastic tumor without prominent schwannian stroma – No ganglionic differentiation – No neuropil – No or minimal schwannian stroma – Often requires IHC for accurate diagnosis ○ 3 subtypes included – Undifferentiated □ No identifiable neuropil formation and supplementary diagnostic techniques required – Poorly differentiated □ Diagnosis can be made by pure morphological criteria □ Characteristic neuropil present □ Differentiating neuroblasts < 5% – Differentiating □ Usually abundant neuropil □ Differentiating neuroblasts > 5% • GNB, intermixed (schwannian stroma rich) ○ Intermingled microscopic foci of neuroblastic elements in expanding schwannian stroma, constituting > 50% of tumor volume – Neuroblastic foci microscopic without grossly visible nodular formation – Neuroblastic foci composed of mixture of neuroblastic cells in various stages of differentiation – Neuropil background • GNB, nodular (composite, schwannian stroma rich/dominant and schwannian stroma poor) ○ Grossly identifiable neuroblastic nodular (stroma-poor) component coexisting with intermixed GNB (stromarich) or GN (stroma-dominant) component – Proportion of component varies – Abrupt demarcation between stroma-poor NB and stroma-rich component – Fibrous pseudocapsule often seen surrounding NB component – > 50% schwannian stroma • GN (schwannian stroma dominant) ○ Predominantly composed of schwannian stroma without individually distributed neuronal elements ○ Neuritic processes produced by ganglion cells enveloped by cytoplasm of Schwann cells ○ Characterized by presence of ganglion cells individually distributed in schwannian stroma ○ 2 subtypes

Diagnoses Associated With Syndromes by Organ: Endocrine

Ganglioneuroma

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Diagnoses Associated With Syndromes by Organ: Endocrine

Neuroblastic Tumors of Adrenal Gland – Maturing GN: Both maturing and mature ganglion cells – Mature GN: Exclusively mature ganglion cells in schwannian stroma □ Composed of mature ganglion cells, Schwann celllike spindle cells, and nerve fibers □ Variable size and number of intermixed ganglion cells in uniform spindle cell matrix □ May show calcification, cystic change, and hemorrhage □ Rare mixed composite NB and pheochromocytoma • Do not classify posttreatment resections ○ "Neuroblastoma with treatment effect" is sufficient • May classify metastatic disease if resection/biopsy pretreatment

ANCILLARY TESTS Immunohistochemistry • Tumor cells variably positive for neuronal markers • Panel approach more appropriate, including synaptophysin, chromogranin, PGP9.5, CD56, NFP • Tumor cells positive for neural crest markers, such as tyrosine hydroxylase and PHOX2B, and NB marker NB84 • NSE ○ Most sensitive but least specific ○ Found at least focally even in very undifferentiated NBs • NB84(+) in almost all NBs ○ Not specific; occasionally positive in other small round cell tumors • S100 protein ○ Mature Schwann cells S100 positive in intermixed GNB and in GN ○ Positive in schwannian stroma • PHOX2B ○ Highly sensitive and specific IHC marker for peripheral neuroblastic tumors, including NB ○ Reliably distinguishes NB from histologic mimics: Wilms tumor, Ewing sarcoma, and round cell sarcoma

Genetic Testing • MYCN ○ Amplification associated with worse prognosis ○ Usually seen in advanced disease ○ MYCN is transcription factor that belongs to family of MYC oncoproteins, comprising c-MYC and MYCL genes – Can repress at least as many genes as it activates, thus proposing novel function of this protein in NB biology • ALK and PHOX2B germline mutations in hereditary NB • Common genetic variation in chromosome 6p22 is associated to sporadic NB • DNA ploidy ○ Near-diploidy or tetraploidy associated with worse prognosis ○ Hyperdiploidy associated with better prognosis • Loss of heterozygosity of 1p and 11q ○ Both associated with worse prognosis • TrkA (high-affinity nerve growth factor receptor) ○ Increased expression associates with better prognosis

Electron Microscopy • Wide range of cytologic differentiation 96

• Dense core of neurosecretory granules ○ Found in elongated cell processes ○ 100 nm in diameter ○ Dense core surrounded by clear halos and delicate outer membranes

Genetic Events • By definition, this disease is caused by transformation of neural crest cells secondary to genetic and epigenetic events • Tumorigenesis still poorly understood • Young age of patients at onset of disease suggests role of preconceptional or gestational factors • Neuroblastic tumors present as congenital tumors

Genetic Susceptibility: Familial Neuroblastoma • Familial NB is rare (1-2% of all NBs) • Autosomal dominant inheritance pattern with incomplete penetration • Usually diagnosed at earlier age than patients with sporadic cases (mean: 9 months vs. 17 months) • ~ 20% have bilateral adrenal tumors and multifocal tumors • Mutations in some signaling pathways important for development of sympathoadrenal lineage are associated with familial genetic syndromes • Characterized by defects in development and predisposition to NB • Germline mutations reported in familial NB located in PHOX2B and ALK • 1st predisposition mutation identified in NB was in pairedlike homeobox 2b (PHOX2B) ○ Encodes homeodomain transcription factor that promotes cell cycle exit and neuronal differentiation – Plays crucial part in development of neural crestderived autonomic neurons ○ Perturbations in PHOX2B-regulated differentiation pathway in sympathoadrenal lineage of neural crest may contribute to NB tumorigenesis • More common lesion associated with familial NB is in anaplastic lymphoma receptor tyrosine kinase (ALK) gene ○ Known natural ligands of ALK include pleiotrophin and midkine; ALK is expressed in developing sympathoadrenal lineage of neural crest – May regulate balance between proliferation and differentiation through multiple cellular pathways, including MAPK and RAS-related protein 1 (RAP1) signal transduction pathways • PHOX2B can directly regulate ALK gene expression, providing connection between these 2 pathways that are mutated in familial NB

Sporadic Neuroblastoma • ~ 6-10% of sporadic NBs carry somatic ALK-activating mutations; additional 3-4% have high frequency of ALK gene amplification ○ These findings in familial and sporadic NB suggest that ALK is oncogenic driver in NB – Activating ALK mutations or amplifications, especially in presence of MYCN amplification, associated with lethal disease – ALK is promising target for molecular therapy in preclinical studies and clinical trials for NB

Neuroblastic Tumors of Adrenal Gland

DIFFERENTIAL DIAGNOSIS Alveolar Rhabdomyosarcoma • Cells with more pleomorphism and abundant cytoplasm • Immunoreactivity for muscle markers (desmin, myogenin) • t(1;13) or t(2;13) with PAX-FOXO1 fusion

○ N-myc amplification associated with worse prognosis ○ Loss of heterozygosity of 1p and 11q associated with worse prognosis

SELECTED REFERENCES 1.

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8. 9.

10.

11.

Lymphoma • Lymphoid immunomarkers (CD45, CD3, CD20)

12.

Ganglioneuroma

13.

• Differs from intermixed GNB in having single cells instead of nests of cells within schwannian stroma • Schwannoma ○ Strong S100 positivity; ganglion cells absent • GNBs ○ Presence of neuroblasts

14.

Ewing Sarcoma/Primitive Neuroectodermal Tumor • Usually older patients • Cells have finely stippled chromatin and glycogen-filled cytoplasm • CD99 positivity • Specific gene fusions, most commonly EWSR1-FLI1

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Gross appearance ○ Cystic degeneration and calcification can be seen • Microscopy ○ Small round blue cells with very scant cytoplasm ○ Homer Wright rosettes or pseudorosettes ○ Ganglionic differentiation • MKI applicable for stroma-poor tumors ○ Count of cells undergoing mitosis or karyorrhexis (per 5,000 cells)

Pathologic Interpretation Pearls • To assess classification based on degree of tumor differentiation • High importance of cytogenetics

15. 16. 17.

18. 19.

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21. 22. 23. 24. 25. 26. 27.

28. 29. 30.

Applebaum MA et al: 5-Hydroxymethylcytosine profiles are prognostic of outcome in neuroblastoma and reveal transcriptional networks that correlate with tumor phenotype. JCO Precis Oncol. 3, 2019 Bahmad HF et al: Cancer stem cells in neuroblastoma: expanding the therapeutic frontier. Front Mol Neurosci. 12:131, 2019 Calvo C et al: Metastatic neuroblastoma in a patient with ROHHAD: a new alert regarding the risk of aggressive malignancies in this rare condition. Pediatr Blood Cancer. e27906, 2019 Chami R et al: Immunohistochemistry for ATRX can miss ATRX mutations: lessons from neuroblastoma. Am J Surg Pathol. 43(9):1203-11, 2019 Georgantzi K et al: Synaptic vesicle protein 2 and vesicular monoamine transporter 1 and 2 are expressed in neuroblastoma. Endocr Pathol. 30(3):173-9, 2019 Golan-Tripto I et al: Congenital neuroblastoma in a neonate with hypoparathyroidism-retardation-dysmorphism syndrome. Clin Dysmorphol. ePub, 2019 Koshy A et al: Cytopathological spectrum of peripheral neuroblastic tumours in fine needle aspiration cytology and categorization as per International Neuroblastoma Pathology Classification. Cytopathology. ePub, 2019 Mohlin S et al: Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma. EMBO Mol Med. 11(8):e10058, 2019 Sznewajs A et al: Congenital malformation syndromes associated with peripheral neuroblastic tumors: a systematic review. Pediatr Blood Cancer. 66(10):e27901, 2019 He WG et al: Clinical and biological features of neuroblastic tumors: a comparison of neuroblastoma and ganglioneuroblastoma. Oncotarget. 8(23):37730-9, 2017 Hung YP et al: PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumors. Histopathology. 71(5):786-94, 2017 Iacobone M et al: Adrenal ganglioneuroma: The Padua Endocrine Surgery Unit experience. Int J Surg. 41 Suppl 1:S103-8, 2017 Lam AK: Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocr Pathol.28(3):213-27, 2017 Shimada H et al: Neuroblastic tumors of the adrenal gland. In Lloyd RV et al: WHO Classification of Tumors of the Endocrine Organs. 196-203, 2017 Decarolis B et al: Treatment and outcome of ganglioneuroma and ganglioneuroblastoma intermixed. BMC Cancer. 16:542, 2016 Lee JH et al: Clinicopathological features of ganglioneuroma originating from the adrenal glands. World J Surg. 40(12):2970-5, 2016 Newman EA et al: Recent biologic and genetic advances in neuroblastoma: implications for diagnostic, risk stratification, and treatment strategies. Semin Pediatr Surg. 25(5):257-64, 2016 Louis CU et al: Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med. 66:49-63, 2015 Abu-Arja R et al: Neuroblastoma in monozygotic twins with distinct presentation pathology and outcome: is it familial or in utero metastasis. Pediatr Blood Cancer. 61(6):1124-5, 2014 Barco S et al: Urinary homovanillic and vanillylmandelic acid in the diagnosis of neuroblastoma: report from the Italian Cooperative Group for Neuroblastoma. Clin Biochem. 47(9):848-52, 2014 Beltran H: The N-myc oncogene: maximizing its targets, regulation, and therapeutic potential. Mol Cancer Res. 12(6):815-22, 2014 Jrebi NY et al: Review of our experience with neuroblastoma and ganglioneuroblastoma in adults. World J Surg. 38(11):2871-4, 2014 Li L et al: Adrenal ganglioneuromas: experience from a retrospective study in a Chinese population. Urol J. 11(2):1485-90, 2014 Murga-Zamalloa C et al: ALK-driven tumors and targeted therapy: focus on crizotinib. Pharmgenomics Pers Med. 7:87-94, 2014 Murphy JM et al: Advances in the surgical treatment of neuroblastoma: a review. Eur J Pediatr Surg. 24(6):450-6, 2014 Shawa H et al: Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre. Clin Endocrinol (Oxf). 80(3):342-7, 2014 Shawa H et al: Clinical and radiologic features of pheochromocytoma/ganglioneuroma composite tumors: a case series with comparative analysis. Endocr Pract. 20(9):864-9, 2014 Waters AM et al: The interaction between FAK, MYCN, p53 and Mdm2 in neuroblastoma. Anticancer Agents Med Chem. 14(1):46-51, 2014 Williams P et al: Outcomes in multifocal neuroblastoma as part of the neurocristopathy syndrome. Pediatrics. 134(2):e611-6, 2014 Barone G et al: New strategies in neuroblastoma: therapeutic targeting of MYCN and ALK. Clin Cancer Res. 19(21):5814-21, 2013

Diagnoses Associated With Syndromes by Organ: Endocrine

• Mutations in α-thalassemia/intellectual disability syndrome X-linked (ATRX) among most common lesions in sporadic NB ○ ATRX encodes SWI/SNF chromatin-remodeling ATPdependent helicase – ATRX mutations associated with X-linked intellectual disability (XLMR) and α-thalassemia, suggesting that ATRX functions in various developmental processes – Important association between ATRX mutations and age at diagnosis of NB □ Very young children (< 18 months of age) with stage IV disease tend to have better prognosis than their older counterparts, and no ATRX mutations have been identified in this age group □ ATRX mutations occur in 17% of children aged between 18 months and 12 years with stage IV disease and in 44% of patients > 12 years who uniformly have very poor prognosis □ Relationship between age at diagnosis and ATRX mutations significant

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Neuroblastic Tumors of Adrenal Gland INPC of Favorable and Unfavorable Histological Groups in Neuroblastic Tumors Age at Diagnosis

Favorable Histology Group

Unfavorable Histology Group

Any age

-Ganglioneuroblastoma, intermixed (schwannian stroma rich) -Ganglioneuroma (schwannian stroma dominant) of either subtype (maturing or mature)

- Neuroblastoma (schwannian stroma poor) of undifferentiated subtype - Neuroblastoma (schwannian stroma poor) of any subtype with high MKI

< 18 months (< 548 days)

-Neuroblastoma (schwannian stroma poor) of poorly differentiated subtype with low or intermediate MKI -Neuroblastoma (schwannian stroma poor) of differentiating subtype with low to intermediate MKI

16-60 months (548 days to 5 years)

-Neuroblastoma (schwannian stroma poor) of differentiating subtype, with low MKI

> 60 months (> 5 years)

- Neuroblastoma (schwannian stroma poor) of poorly differentiated subtype - Neuroblastoma (schwannian stroma poor) of differentiating subtype with intermediate MKI - Neuroblastoma (schwannian stroma poor) of any subtype

Modified from Shimada et al, Neuroblastic tumors of the adrenal, WHO 2017. 31. Castel V et al: Emerging drugs for neuroblastoma. Expert Opin Emerg Drugs. 18(2):155-71, 2013 32. Cheung NK et al: Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 13(6):397-411, 2013 33. Gherardi S et al: MYCN-mediated transcriptional repression in neuroblastoma: the other side of the coin. Front Oncol. 3:42, 2013 34. Mei H et al: The mTOR signaling pathway in pediatric neuroblastoma. Pediatr Hematol Oncol. 30(7):605-15, 2013 35. Morgenstern DA et al: Current and future strategies for relapsed neuroblastoma: challenges on the road to precision therapy. J Pediatr Hematol Oncol. 35(5):337-47, 2013 36. Nonaka D et al: A study of gata3 and phox2b expression in tumors of the autonomic nervous system. Am J Surg Pathol. 37(8):1236-41, 2013 37. Schulte JH et al: Targeted therapy for neuroblastoma: ALK inhibitors. Klin Padiatr. 225(6):303-8, 2013 38. Sridhar S et al: New insights into the genetics of neuroblastoma. Mol Diagn Ther. 17(2):63-9, 2013 39. Navarro S et al: New prognostic markers in neuroblastoma. Expert Opin Med Diagn. 6(6):555-67, 2012 40. Capasso M et al: Genetics and genomics of neuroblastoma. Cancer Treat Res. 155:65-84, 2010 41. Maris JM: Recent advances in neuroblastoma. N Engl J Med. 362(23):220211, 2010 42. Matthay KK et al: Criteria for evaluation of disease extent by (123)Imetaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Br J Cancer. 102(9):1319-26, 2010 43. Rondeau G et al: Clinical and biochemical features of seven adult adrenal ganglioneuromas. J Clin Endocrinol Metab. 95(7):3118-25, 2010 44. Allende DS et al: Ganglioneuroma of the adrenal gland. J Urol. 182(2):714-5, 2009 45. Ambros PF et al: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 100(9):1471-82, 2009 46. Cohn SL et al: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 27(2):289-97, 2009 47. Esiashvili N et al: Neuroblastoma. Curr Probl Cancer. 33(6):333-60, 2009 48. Okamatsu C et al: Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG. Pediatr Blood Cancer. 53(4):563-9, 2009 49. De Bernardi B et al: Retrospective study of childhood ganglioneuroma. J Clin Oncol. 26(10):1710-6, 2008 50. Lack E: Tumors of the adrenal glands and extraadrenal paraganglia. In AFIP Atlas of Tumor Pathology Series 4, Fascicle 8. Washington, DC: American Registry of Pathology, 2007 51. Tornóczky T et al: Pathology of peripheral neuroblastic tumors: significance of prominent nucleoli in undifferentiated/poorly differentiated neuroblastoma. Pathol Oncol Res. 13(4):269-75, 2007

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52. Sano H et al: International neuroblastoma pathology classification adds independent prognostic information beyond the prognostic contribution of age. Eur J Cancer. 42(8):1113-9, 2006 53. Peuchmaur M et al: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer. 98(10):2274-81, 2003 54. Shimada H: The International Neuroblastoma Pathology Classification. Pathologica. 95(5):240-1, 2003 55. Ambros IM et al: Morphologic features of neuroblastoma (schwannian stroma-poor tumors) in clinically favorable and unfavorable groups. Cancer. 94(5):1574-83, 2002 56. Goto S et al: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer. 92(10):2699-708, 2001 57. Shimada H et al: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer. 92(9):2451-61, 2001 58. Shimada H et al: Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer. 86(2):349-63, 1999 59. Shimada H et al: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer. 86(2):364-72, 1999 60. Brodeur GM et al: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol. 6(12):1874-81, 1988 61. Fletcher CD et al: Malignant nerve sheath tumour arising in a ganglioneuroma. Histopathology. 12(4):445-8, 1988

Neuroblastic Tumors of Adrenal Gland

Clinical and Imaging Features (Left) Graphic shows the anatomic extent of the sympathetic chain ſt (including adrenal gland) from cervical region through mediastinum and abdomen to the inferior pelvis. NB can arise anywhere along the sympathetic chain. (Right) Child with bilateral orbital masses ſt clinically presents with proptosis and ecchymosis.

Metastatic Neuroblastoma to Liver

Diagnoses Associated With Syndromes by Organ: Endocrine

Sympathetic Chain

Adrenal Tumor and Metastases to Liver (Left) This specimen of liver shows diffuse involvement and extensive replacement by multiple deposits of metastatic NB. There are several foci of hemorrhage. (Right) Axial T2-weighted MR shows a left adrenal mass ﬇, which proved to be NB. It was widely metastatic; the liver was filled with multiple highsignal nodular lesions ſt with little normal remaining hepatic parenchyma.

Mediastinal Tumor

Adrenal Neuroblastoma (Left) Coronal T2-weighted MR in a patient with ganglioneuroblastoma (GNB) shows a mildly hyperintense posterior mediastinal mass ſt with no abnormality in the adjacent osseous marrow signal. (Right) Coronal T2weighted MR shows NB ﬈ of the left adrenal gland with an area of central necrosis ﬉.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Neuroblastic Tumors of Adrenal Gland

Characteristic Gross Appearance of GNB

Homogeneous Cut Surface of Ganglioneuroma

Cytomorphological Features

Characteristic Histopathological Findings

Round Cells and Neuropil

Areas of Necrosis

(Left) This is a typical appearance of a nodular GNB. The hemorrhagic nodule ﬇ is stroma-poor NB, whereas the tan, fleshy rim ﬊ is either ganglioneuroma (GN) or intermixed GNB. The diagnosis of nodular GNB requires gross visible nodules. (Right) Gross photograph of the cut surface of GN shows a wellcircumscribed mass with a yellow and whorled appearance. This appearance resembles a leiomyoma.

(Left) In NB (schwannian stroma poor), undifferentiated subtype, the cells have scant cytoplasm and rounded, deeply staining nuclei. On H&E, this could be mistaken for Ewing sarcoma, alveolar rhabdomyosarcoma, or lymphoma. (Right) H&E shows the typical low-power appearance of NB (schwannian stroma poor), poorly differentiated. Small strips of schwannian stroma ﬈ separate the neuroblasts and neuropil, imparting a nested or multinodular appearance.

(Left) NB (schwannian stroma poor), poorly differentiated subtype shows sheets of small round cells ﬈ in aggregates within a background of neuropil ﬊. (Right) NBs are commonly hemorrhagic with areas of necrosis ﬊. These changes can also be seen after treatment. NBs that have undergone treatment should not be classified in the International Neuroblastoma Pathology Classification (INPC) system.

100

Neuroblastic Tumors of Adrenal Gland

Schwannian Stroma (Left) This GNB, nodular (composite, NB schwannian stroma rich/dominant and stroma poor) shows the pushing border between the stroma-poor NB component ﬈ and the intermixed GNB ﬈. A grossly visible nodule is required to diagnose nodular GNB. (Right) At least 50% of the tumor must be composed of schwannian stroma to make the diagnosis of GNB, intermixed (schwannian stroma rich). This is characterized by spindled, wavy cells in bundles of varying cellularity.

Prominent Stroma

Diagnoses Associated With Syndromes by Organ: Endocrine

Nodular Areas

Neuroblasts and Ganglion Cells (Left) This field of a GNB, intermixed could be mistaken for neurofibroma (spindled wavy cells in a myxoid background). Adequate sampling, generally 1 section per centimeter of tumor, is required to make an accurate diagnosis. (Right) Higher magnification of GNB, intermixed (schwannian stroma rich) shows details of neuroblasts ﬈, maturing neuroblasts ﬈, and ganglion cells ﬉ blending into the schwannian stroma ﬊.

Mixed Cell Population With Neuropil and Schwannian Stroma

Clusters of Ganglion Cells (Left) Low magnification of GNB, intermixed (schwannian stroma rich) shows clusters of maturing neuroblasts and ganglion cells ﬊, foci of neuropil ﬈, and areas of schwannian stroma ﬈. (Right) The neuroblastomatous component of this GNB, intermixed (schwannian stroma rich) is predominantly made up of mature ganglion cells ﬊. The ganglion cells are present in clusters in this tumor, differing from the pattern in maturing GN in which they are present as single cells.

101

Diagnoses Associated With Syndromes by Organ: Endocrine

Neuroblastic Tumors of Adrenal Gland

Characteristics of Ganglion Cells

Neuroblastic Cells and Schwannian Stroma

Neuropil Characteristics

Ganglion Cells

Diffuse Bone Marrow Involvement

Focal Marrow Involvement

(Left) Mature ganglion cells ﬈ are characterized by abundant eosinophilic to amphophilic cytoplasm, eccentric nuclei, and prominent nucleoli. Nissl substance may or may not be present. These cells are admixed with a schwannian stroma. (Right) This section of GNB, intermixed (schwannian stroma rich) could be mistaken for a maturing GN. In maturing GN, the tumor is mainly composed of schwannian stroma, and individual neuroblastic cells merge into the schwannian stroma instead of forming distinct nests.

(Left) High-power view of GNB highlights the maturing ganglion cells ﬊ in a background of neuropil. The neuropil is composed of a dense tangle of fibrillary, eosinophilic cytoplasmic processes. (Right) GN (schwannian stroma dominant) have a variable number of ganglion cells. This image shows numerous fully differentiated mature ganglion cells ﬊ in a paucicellular spindle Schwann cell-like stroma.

(Left) Core biopsy specimen of bone shows a focus of metastatic NB. The marrow has been extensively replaced by sheets of metastatic small round cell tumor ﬇ and shows no areas with normal trilineage hematopoiesis. (Right) Core biopsy specimen of bone marrow shows normal marrow ﬉ in the lower part of the field and a focus of metastatic NB ﬈ in the upper part. The normal bone marrow architecture is destroyed in the focus of metastatic tumor.

102

Neuroblastic Tumors of Adrenal Gland

Characteristic Immunoreactivity (Left) NB with MYCN amplification by FISH using a MYCN probe (red) and a chromosome 2 reference probe (green). The presence of N-myc amplification predicts poor prognosis and is present in advanced disease. (Courtesy L. McGavran, PhD and K. Swisshelm, PhD.) (Right) NSE of NB shows strong diffuse cytoplasmic positivity. NSE is a sensitive marker for NB, although nonspecific.

Interface of Adrenal Cortex and Ganglioneuroma

Diagnoses Associated With Syndromes by Organ: Endocrine

Neuroblastoma With MYCN Amplification

Marker of Neuroblastoma (Left) Melan-A highlights the normal adrenal cells, while the neoplastic cells are negative for this and other adrenal cortical markers, such as inhibin. GNs are usually positive for S100, NSE, NFP, synaptophysin, and chromogranin. (Right) In this bone marrow trephine specimen, there is diffuse immunoreactivity for NB antigen (NB84) in metastatic deposits of NB ﬊ that extend between bony trabeculae ﬈.

Synaptophysin Stain

Pattern of ALK Staining (Left) Synaptophysin shows membranous staining. Although not specific, this can be used for the differential diagnosis of other small round blue cell tumors, such as lymphoma, rhabdomyosarcoma, or Ewing sarcoma. These tumors are also positive for chromogranin and CD56. (Right) ALK1 in NB shows strong membranous staining. Activating mutations in ALK have been reported in NB and provide a potential therapeutic target.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Pheochromocytoma and Paraganglioma KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• Catecholamine-secreting tumors from adrenal medulla or extraadrenal sympathetic and parasympathetic paraganglia • Malignancy defined by documentation of metastases to sites where normal paraganglia not present ○ "Metastatic" preferred to "malignant" to avoid ambiguity

• Identification of patients with hereditary PCC involves clinical assessment, biochemical testing, and pathology leading to genetic testing

ETIOLOGY/PATHOGENESIS • ~ 40% of PCC hereditary; at least 20 susceptibility genes have been discovered • Most attributable to mutations in RET, VHL, NF1, SDHB, SDHD, SDHC, SDHA, SDHAF2, TMEM127, MAX, FH, EPAS1, EGLN2, EGLN1, MDH2, KIF1B, and MEN1 • SDHx mutations account for up to 80% of familial PCC/PGL aggregations, 30% of pediatric tumors, and > 40% of tumors that metastasize ○ SDHB mutation associated with extraadrenal abdominal location, high probability of metastasis, and poor prognosis

MICROSCOPIC • Classic pattern is small nests (zellballen) of neuroendocrine cells with interspersed small blood vessels

ANCILLARY TESTS • Germline mutation testing vital for individual patient care and allows screening and early detection of disease in atrisk family members • Immunohistochemistry for SDHB, SDHA, and MAX can serve as adjuncts to genetic testing

TOP DIFFERENTIAL DIAGNOSES • Adrenal cortical carcinoma • Other neuroendocrine tumors

Pheochromocytoma and Paraganglioma Genetic Classification

Recent data from the Cancer Genome Atlas (TCGA) revealed clinically relevant prognostic and predictive biomarkers and stratified pheochromocytomas and paragangliomas into 3 main groups: Pseudohypoxic, Wnt-signaling, and kinase-signaling clusters. The pseudohypoxia group can be divided into at least 2 subgroups: TCA cycle-related and VHL/EPAS1-related. Each subgroup has a distinct molecular/biochemical/imaging signature.

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Pheochromocytoma and Paraganglioma

Abbreviations • Pheochromocytoma (PCC) • Paraganglioma (PGL)

Definitions • Normal paraganglia consist of neural crest-derived neuroendocrine cells associated with sympathetic and parasympathetic nerves ○ Sympathetic (sympathoadrenal) paraganglia – Paraxial distribution in or near sympathetic ganglia and along branches of sympathetic nerves, predominantly those innervating pelvic and abdominal organs – Adrenal medulla in adults and organ of Zuckerkandl in fetuses are major sympathetic paraganglia; others microscopic ○ Parasympathetic (head and neck paraganglia) – Predominantly located along cranial and cervical branches of glossopharyngeal and vagus nerves – Carotid bodies are major parasympathetic paraganglia; others microscopic • PCC and PGL are neuroendocrine tumors of neural crest origin that arise from adrenal medulla or extraadrenal paraganglia, respectively; PCC is intraadrenal sympathetic PGL ○ WHO definitions arbitrarily established terminology for tumors of paraganglia to eliminate previous inconsistent usage – By definition, PCC is neuroendocrine tumor arising from chromaffin cells of adrenal medulla; similar tumors in other locations are extraadrenal PGL, now abbreviated to just PGL □ Sympathetic (sympathoadrenal) PGLs arise in vicinity of sympathetic chains and along sympathetic nerve branches in pelvic organs and retroperitoneum, sometimes mediastinum □ Parasympathetic PGL arise mainly from branches of vagus and glossopharyngeal nerves in head and neck, sometimes mediastinum

ETIOLOGY/PATHOGENESIS Hereditary Pheochromocytoma/Paraganglioma • PCCs/PGLs have greatest degree of hereditary susceptibility of any human tumor ○ ~ 40% of PCCs/PGLs are hereditary – Occult germline mutations of hereditary susceptibility genes common in patients with apparently sporadic tumors ○ Striking genetic diversity; > 20 susceptibility genes now established – Up to ~ 32% of all patients with PCC/PGL harbor germline mutation in 1 of 5 major susceptibility genes: VHL (~ 13%), SDHB (~ 8%), RET (~ 5%), SDHD (~ 5%), and NF1 (~ 3%) – Less commonly in TMEM127 (~ 1-2%), MAX and SDHC (~ 1%), and SDHA (< 1%) • Different PPC/PGL molecular subgroups have corresponding driver mutations and proportion of hereditary disease in respective cluster

○ Tumors with VHL, FH, EPAS1, or SDHx mutations have hypoxia-associated gene expression profile ○ Tumors with RET, NF1, MAX, HRAS, or TMEM127 mutations characterized by expression of genes that mediate kinase signaling profile ○ Tumors with CSDE1 mutation and MAML3-fusion have Wnt signaling profile • Genotype-phenotype correlations affect tumor location, multiplicity, biochemical phenotype, risk of metastasis, and syndromic associations

Sporadic Pheochromocytoma/Paraganglioma • Majority of PCCs appear to arise sporadically ○ Germline mutations in known susceptibility genes may be seen in up to 16% of sporadic-appearing cases • Somatic mutations of hereditary susceptibility genes relatively uncommon except for NF1 ○ NF1 mutated in > 25% of sporadic tumors, VHL ~ 9%, RET ~ 5% • Somatic mutations of common cancer driver genes occasionally present (HRAS, ATRX, VHL, EPAS1, TP53) • New class of Wnt-altered PCCs/PGLs driven by MAML3 fusions and CSDE1 somatic mutations reported in 2017 Cancer Genome Atlas (TCGA) study

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Environmental Influences • High-altitude PGL in people and cattle living in mountainous areas of some countries ○ Possible modifier effect in genetically predisposed individuals

CLINICAL ISSUES Epidemiology • Incidence ○ Precise incidence and prevalence not available because of varied reporting and occult cases; all current figures are estimates ○ Combined annual incidence of PCC and sympathetic PGL in all sites is ~ 0.4-9.5/million – < 3,000 cases each year in United States ○ Head and neck PGL (HNP) much rarer (~ 0.5-2.0/million) • Age and sex ○ Most PCC and PGL present in 4th-5th decades; ~ equal sex distribution – HNP shows female predominance □ F:M ratio most pronounced in populations at high altitudes (up to 8:1) ○ Presentation in childhood strongly suggests hereditary susceptibility ○ Hereditary disease usually presents before age 40 but can present in elderly

Site • Abdomen and pelvis: ~ 80-85% of all PGLs, ~ 98% of all sympathetic PGLs ○ ~ 90% adrenal, 10% extraadrenal PGL – Extraadrenal abdominal and pelvic PGL ~ 1/10 as common as PCC in adults, up to 1/3 as common in children • Head and neck: ~ 3% of all PGLs, ~ 100% of parasympathetic PGLs 105

Diagnoses Associated With Syndromes by Organ: Endocrine

Pheochromocytoma and Paraganglioma ○ Most are carotid (60%), followed by jugular (23%), vagal (~ 13%), and tympanic (~ 6%) ○ Head and neck sites account for ~ 0.6% of all tumors

Presentation • Depends on tumor location ○ Sympathoadrenal PCCs/PGLs usually cause signs and symptoms of catecholamine excess – Tumors with SDHB mutation more likely than other sympathoadrenal PCCs/PGLs to be clinically silent ○ Parasympathetic PGLs usually clinically silent mass lesions • Affected by genotype ○ Sporadic tumors solitary, usually in adults ○ Multiple tumors or tumors presenting in children suggest hereditary disease ○ Tumors with RET or NF1 mutations almost always intraadrenal ○ Abdominal PGL or combination of sympathetic and parasympathetic PCC/PGL suggests SDHx mutation • Confounded by complexity of tumor syndromes ○ Often highly varied penetrance and manifestation ○ Hereditary PCC/PGL syndromes may be found only after other stigmata point to hereditary basis (MEN2, VHL, NF1, SDH related) – New syndromic associations include gastrointestinal stromal tumors with NF1 or SDHx mutations, renal cell CA with VHL or SDHx – Some patients develop only these tumors ○ Patients with occult germline mutations can present with apparently sporadic PCC/PGL ○ Mutations of some genes (e.g., TMEM127) cause hereditary but usually nonsyndromic PCC/PGL (no associated abnormalities) ○ SDHD-, SDHAF2-, and MAX-related PGL show parent-oforigin dependent penetrance; tumor development only with paternal inheritance ○ Some PGL syndromic but not hereditary, e.g., Carney triad

Laboratory Tests • Biochemical profile correlates with tumor genotype and location • O-methylated metabolites more sensitive than corresponding catecholamines for tumor detection ○ PCC: Metanephrine &/or normetanephrine ○ Extraadrenal sympathetic PGL: Almost always normetanephrine &/or dopamine metabolite methoxytyramine ○ HNP can lack ability for catecholamine biosynthesis or produce only methoxytyramine ○ Noradrenergic PCC raises suspicion of VHL disease ○ Dopamine/methoxytyramine: Sometimes produced by clinically nonfunctional tumors, especially with SDHx mutations, and tumors that metastasize

Treatment • Complete surgical excision only cure • Unresectable primary tumors and metastases can have long doubling time; active surveillance often viable option, especially to avoid complications in head and neck 106

• Potential new modalities target metabolic vulnerabilities caused by SDHx mutations

Prognosis • Most patients with metastases eventually die from complications of excess catecholamines or destructive local growth

Malignancy • WHO 2017 defined malignancy by presence of metastasis ○ Term "metastatic" preferred to "malignant" to avoid ambiguity ○ Must be to sites where normal paraganglia not present to avoid confusion with new primary tumor • Currently, no generally accepted histological criteria to predict whether primary PCC or PGL will metastasize ○ Extensive local invasion alone poor predictor of metastasis • Risk of metastasis and prognosis varies with tumor location and genotype ○ ~ 10% metastasis for PCC, ~ 40% for abdominal PGL ○ Best predictor of metastasis is presence of SDHB mutation (> 30%) – After metastases occur, worst prognosis for tumors caused by SDHB mutation • Staging system introduced in 8th edition of AJCC staging manual ○ Size > 5 cm or extraadrenal abdominal location automatically T2 ○ Does not account for SDHB mutation • Metastases can develop years or decades after resection of primary tumor ○ Currently recommended that no PCC/PGL be signed out as benign; all patients receive lifelong follow-up

IMAGING General Features • Anatomic imaging ○ MR: Very intense T2-weighted image (light bulb sign) classic but not always present ○ Contrast-enhanced CT • Functional imaging ○ More specific because based on specific aspects of tumor phenotype ○ More sensitive for small tumors or metastases in bone ○ Efficacy of different functional imaging techniques varies according to tumor genotype and function ○ Somatostatin receptor imaging by PET/CT using recently developed DOTA; conjugated somatostatin analogs most sensitive modality

MACROSCOPIC General Features • Cut surface usually pink-gray to tan, distinguishes PCCs from yellow-gold of most adrenal cortical tumors • Occasional tumors show patchy or diffuse brown pigmentation • Hemorrhage and necrosis sometimes present • Medullary hyperplasia, when present, may indicate hereditary form of disease

Pheochromocytoma and Paraganglioma

DIFFERENTIAL DIAGNOSIS

Histologic Features

Adrenal Cortical Carcinoma

• Classic pattern is small nests (zellballen) of neuroendocrine cells (chief cells) with interspersed small blood vessels • Numerous variant and combined patterns exist, including diffuse growth, large zellballen, spindle cells, cell cords • Sustentacular cells variably present, best seen with IHC ○ Possibly nonneoplastic cell type induced or attracted by tumor-derived factors • Cavernous blood vessels sometimes prominent, especially in HNP

• Synaptophysin immunoreactivity present in both cortical and medullary tumors and should not be used in this differential diagnosis • Chromogranin (-), TH (-), melan A (+), calretinin (+)

Cytologic Features • Tumor cells often smaller or larger than normal chromaffin cells, inconspicuous or large nucleoli • Nuclear pseudoinclusions, embracing cells, extracellular hyaline globules variably present • Basophilic, amphophilic, or clear cytoplasm • Extreme pleomorphism and hyperchromasia can be seen in benign tumors • Mitoses usually rare

ANCILLARY TESTS Immunohistochemistry • Generic neuroendocrine markers chromogranin (CgA or CgB) and synaptophysin usually positive in chief cells; keratins usually negative ○ Can be expressed in patchy distribution and Golgi dotlike distribution in minimally functional or nonfunctional tumors ○ Parasympathetic PGL can be negative for CgA and positive for CgB • Sustentacular cells stain for S100 • Tyrosine hydroxylase (TH) identifies ability to synthesize catecholamines • SDHB and SDHA important new markers for multiple purposes: Triage for genetic testing or surrogate test where testing not available; validate genetic sequence variants of unknown significance (VUS); assess whether any particular tumor part of syndrome or coincidental in patient with known or suspected SDHx mutation ○ SDHB protein lost in PCC/PGL with SDHA, SDHB, SDHC, or SDHD mutations; SDHA protein lost only when SDHA mutated ○ Endothelial cells serve as intrinsic positive controls • MAX protein may similarly be lost in tumors with MAX mutations

Genetic Testing • Germline mutation testing ○ Vital for individual patient care ○ Initiates screening and early detection of disease in atrisk family members • Major genes causing hereditary PCCs/PGLs are RET (causes MEN2A and MEN2B), VHL, NF1, and SDHx • Caveat is that testing only detects abnormalities in genes added to testing panels, can fail to identify hereditary cases with mutations of uncommon susceptibility genes

Other Neuroendocrine Tumors • Carcinoids, pancreatic endocrine tumors, and medullary thyroid carcinoma • Chromogranin and keratins positive • Tissue-specific hormones (e.g., calcitonin in medullary thyroid carcinoma, serotonin in intestinal neuroendocrine tumors) helpful, but some can be produced ectopically in PCC/PGL

Hepatocellular Carcinomas • Absence of neuroendocrine markers, presence of keratins &/or tissue-specific markers

Diagnoses Associated With Syndromes by Organ: Endocrine

MICROSCOPIC

Renal Cell Carcinoma • Absence of neuroendocrine markers, presence of keratins &/or CD10, RCC, and other tissue-specific markers

Alveolar Soft Part Sarcomas • Absence of neuroendocrine markers, presence of soft tissue-specific marker: TFE3

Glomus Tumors and Glomangiomas • Location: Outside distribution of paraganglia • Presence of smooth muscle actin and muscle-specific actin

SELECTED REFERENCES 1.

2. 3.

4. 5.

6. 7.

8. 9. 10.

11.

12.

13.

Bayley JP et al: Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma. J Med Genet. ePub, 2019 Crona J et al: Genotype-phenotype correlations in pheochromocytoma and paraganglioma. Endocr Relat Cancer. ePub, 2019 Koopman K et al: Pheochromocytomas and paragangliomas: New developments with regard to classification, genetics, and cell of origin. Cancers (Basel). 11(8), 2019 Neumann HPH et al: Pheochromocytoma and paraganglioma. N Engl J Med. 381(6):552-65, 2019 Ong RKS et al: A unique case of metastatic, functional, hereditary paraganglioma associated with an SDHC germline mutation. J Clin Endocrinol Metab. 103(8):2802-6, 2018 Crona J et al: New perspectives on pheochromocytoma and paraganglioma: Toward a molecular classification. Endocr Rev. 38(6):489-515, 2017 Currás-Freixes M et al: PheoSeq: A targeted next-generation sequencing assay for pheochromocytoma and paraganglioma diagnostics. J Mol Diagn. 19(4):575-88, 2017 Fishbein L et al: Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 31(2):181-93, 2017 Gasparotto D et al: Quadruple-negative GIST is a sentinel for unrecognized neurofibromatosis type 1 syndrome. Clin Cancer Res. 23(1):273-82, 2017 NGS in PPGL (NGSnPPGL) Study Group. et al: Consensus Statement on nextgeneration-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol. 13(4):23347, 2017 Rednam SP et al: von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: Clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(12):e6875, 2017 Korpershoek E et al: Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis. J Clin Endocrinol Metab. 101(2):453-60, 2016 Toledo RA et al: Next-generation sequencing for the diagnosis of hereditary pheochromocytoma and paraganglioma syndromes. Curr Opin Endocrinol Diabetes Obes. 22(3):169-79, 2015

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Diagnoses Associated With Syndromes by Organ: Endocrine

Pheochromocytoma and Paraganglioma Tumor Distributions in Major Familial Paraganglioma Syndromes Syndrome

Gene (Chromosome)

Adrenal

Other Sympathetic

Head & Neck

Other Tumors

MEN2A and MEN2B

RET (10q11)

(+++)

(+/-)

(+/-)

Medullary thyroid carcinoma, parathyroid adenoma (MEN2A only)

VHL

VHL (3p25-26)

(+++)

(++)

(+/-)

RCC, clear cell type, hemangioblastoma, endolymphatic sac tumor, pancreatic and intestinal NETs, epididymal papillary cystadenoma; cysts in liver, kidneys, and pancreas

NF1

NF1 (17q11.2)

(+++)

(+/-)

(+/-)

Neurofibroma, MPNST, CNS gliomas, duodenal NET (typically somatostatinoma), GIST (typically small bowel, spindle cell type)

Familial paraganglioma syndromes, SDH related (PGL 1-5)

SDHD (11q23.1) SDHAF2 (11q12.2) SDHC (1q23.3) SDHB (1p36.13) SDHA (5p15.33)

(-/+)

(-/+++)

(++)

RCC, SDH-deficient type, GIST, SDHdeficient type (typically gastric, epithelioid type), pituitary adenoma

No formal syndrome

TMEM127 (2q11.2) (membrane protein involved in protein trafficking)

(+/++)

(+/-)

(+/-)

RCC (clear cell type)

No formal syndrome

MAX (14q23.3)

(+)

(+)

(+)

Renal oncocytoma

GIST = gastrointestinal stromal tumor; MPNST = malignant peripheral nerve sheath tumor; NET = neuroendocrine tumor; RCC = renal cell carcinoma.

Somatic Mutations in Sporadic Pheochromocytoma and Paraganglioma Mutated Gene

Frequency

NF1

Up to 40%

ATRX

~ 13%

VHL

Up to 10%

HRAS

Up to 10%

TP53

Up to 10%

EPAS (HIF2A)

~ 7.5%

CDKN2A

~ 7%

RET

~ 5%

SDHx gene family

Rare

Adapted from WHO classification of tumors of endocrine organs, 2017. 14. Brito JP et al: Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. Clin Endocrinol (Oxf). 82(3):338-45, 2015 15. Dahia PL: Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. 14(2):108-19, 2014 16. Evenepoel L et al: Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 17(8):61020, 2015 17. King EE et al: Integrity of the pheochromocytoma susceptibility TMEM127 gene in pediatric malignancies. Endocr Relat Cancer. 22(3):L5-7, 2015 18. Korpershoek E et al: Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome. Neoplasia. 16(10):868-73, 2014 19. Lefebvre M et al: Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol. 21(1):e8-17, 2014 20. Rattenberry E et al: A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 98(7):E1248-56, 2013

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21. Burnichon N et al: MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 18(10):2828-37, 2012 22. Janeway KA et al: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 108(1):314-8, 2011 23. Wu D et al: Observer variation in the application of the pheochromocytoma of the adrenal gland scaled score. Am J Surg Pathol. 33(4):599-608, 2009

Pheochromocytoma and Paraganglioma

Large Cystic PCC (Left) Axial CECT shows a large, well-circumscribed, moderately enhancing right adrenal PCC with a hypodense area of necrosis ﬊. (Right) This 14-cm PCC contains a cyst formed by resorption of an old hemorrhagic infarct ſt. Recent areas of liquefactive degeneration and hemorrhage are also present.

Carotid Body PGL

Diagnoses Associated With Syndromes by Organ: Endocrine

Necrosis in PCC

Gross Cut Surface of PCC (Left) Gross photo shows a carotid body paraganglioma (PGL) encasing the carotid bifurcation ﬊ and extensively invading the surrounding soft tissue. (Right) Gross photo shows the cut surface of a wellcircumscribed adrenal PCC with an area of hemorrhage. The gross appearance of PCCs is variable and may mimic other tumors. Small residual adrenal cortex is present st.

Jugular PGL

PCC With Capsular Invasion (Left) This jugular PGL grew as a finger-like projection into the lumen of the internal jugular vein. The pink-gray cut surface is typical of most PGL. (Right) The cut surface of this PCC shows extensive areas of degenerative changes ﬇ and areas of necrosis and hemorrhage. Also noted is the focal capsular invasion st.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Pheochromocytoma and Paraganglioma

Adrenal Medullary Hyperplasia and PCC

Typical PCC

MEN2-Associated PCC

Unusual Architecture in MEN2A Tumors

VHL Syndrome

PCC in VHL

(Left) Adrenal gland shows both MEN2-associated adrenal medullary hyperplasia ﬇ and a microPCC ſt. Adrenal medullary hyperplasia is characteristic of MEN2. (Right) Typical pheochromocytoma (PCC) has a gray-pink cut surface with areas of hemorrhage that distinguish it from the yellow-brown adrenal cortex ſt.

(Left) Hyaline globules ﬊ are present in some PCC/PGL but may also be seen in some adrenal cortical neoplasms. They tend to be particularly conspicuous in PCCs of patients with MEN2. (Right) This unusual PCC from a patient with MEN2A shows individual zellballen with degenerative changes ﬈, prominent thick-walled blood vessels ﬉, and scattered pigmented tumor cells ﬊.

(Left) Graphic of abdominal lesions in VHL syndrome shows multiple bilateral renal cysts ſt, renal tumors st, pancreatic cysts ﬇, and PCC ﬊. PCC or PGL occurs in ~ 1026% of VHL patients. (Right) PCC from a patient with VHL shows a pattern of small cells with clear or slightly myxoid cytoplasm forming small zellballen with interspersed small blood vessels. This pattern is reported but inconsistently present in VHL disease.

110

Pheochromocytoma and Paraganglioma

PCC, Small Cell Type (Left) Some PCC/PGL, particularly if they are well fixed, show a mosaic-like pattern of often large cells with granular basophilic cytoplasm admixed with cells that have amphophilic to slightly eosinophilic cytoplasm. The basophilia is probably caused by abundant granin proteins, which are very acidic. (Right) Some PCC/PGL lack the typical pattern of small nests (zellballen) of neuroendocrine cells with interspersed small blood vessels and instead may show a diffuse growth pattern, as in this case.

PCC, Spindle Cell Type

Diagnoses Associated With Syndromes by Organ: Endocrine

PCC, Mosaic-Like Pattern

PGL, Sclerosing Type (Left) Some tumors are composed entirely of spindle cells, as in this example, and no classic pattern (zellballen) may be evident. (Right) Head and neck PGL, sclerosing type, is shown in a child with SDHB mutation, metastatic PGL to lymph nodes, and a strong family history of carotid body PGL.

Mitosis in PCC

Pleomorphic Cells in PCC (Left) A mitotic figure ﬊ is present in this PCC with a diffuse pattern, lacking the classic zellballen pattern. This tumor is composed of compact eosinophilic cells, which may be associated with more aggressive behavior. (Right) The growth of this PCC is patternless with thin, fibrous septa but lacking the zellballen cellular arrangement. There is marked variability in cell size with scattered pleomorphic cells surrounded by tumor cells with clear cytoplasm.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Pheochromocytoma and Paraganglioma

Metastatic PGL to Lymph Node

Metastatic PGL to Lymph Node

SSTR2 Somatostatin Receptor Expression in PGL

Tyrosine Hydroxylase in PCC

SDHB Loss in PGL

SDHB Loss in PGL

(Left) This child with SDHB mutation and a carotid body PGL had metastatic PGL to lymph nodes. SDHB-associated tumors are associated with a more aggressive behavior and ~ 60% have metastases. (Right) SDHB mutationassociated PGL has a higher metastatic potential. This lymph node from a patient with SDHB mutation shows a subcapsular focus of metastatic tumor.

(Left) SDHB-mutated PGL shows typical strong membranous staining for somatostatin receptor expression. This finding is consistent with the high sensitivity of somatostatin receptor by PET/CT. (Right) TYH is variably positive in PCC, and most extraadrenal sympathetic PGL, and is necessary for synthesis of catecholamines.

(Left) PCC and other PGLs with mutations of SDHx genes show loss of immunoreactivity of tumor cell cytoplasm for SDHB protein. The staining is present in the endothelial cells as coarsely granular as the protein is localized to mitochondria. (Right) Tumor cells in PCC/PGL with mutations of SDHA, SDHB, SDHC, or SDHD are negative for SDHB protein, while endothelial cells ﬉ serve as intrinsic positive controls.

112

Pheochromocytoma and Paraganglioma

Carotid Body PGL (Left) IHC for Ki-67 usually shows a low proliferative labeling index ﬈, often < 23%, in both primary and metastatic PCC and PGL, consistent with the usual slow doubling time of these tumors. (Right) A high Ki-67 labeling index is unusual in PCC/PGL and, when present, is sometimes associated with aggressive tumor behavior. This carotid PGL showed angioinvasion and extensive soft tissue infiltration.

Carotid Body PGL

Diagnoses Associated With Syndromes by Organ: Endocrine

Ki-67

S100 in PGL (Left) Chromogranin-A shows granular immunoreactivity in the neuroendocrine cell nests between cavernous blood vessels in a carotid PGL. Note the negativity of the endothelial cells for this marker. (Right) S100 in PGL shows nuclear and cytoplasmic staining of sustentacular cells, which sometimes have conspicuous cytoplasmic processes. The chief cells are usually negative for this marker but sometimes show weak staining.

Metastatic PGL to Lymph Node

Carotid Body PGL (Left) SDHB-mutated PGLs show a metastatic potential in ~ 60% of cases. The small focus of tumor cells present in a neck lymph node is highlighted by synaptophysin. (Right) TYH can be negative in parasympathetic PGL ﬊, which can be both clinically and biochemically nonfunctional. The adjacent nerve ﬈ is positive.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Adrenal Medulla and Paraganglia Table Genes Involved in Pheochromocytoma and Paraganglioma Pathogenesis Gene

Frequency of Mutations Detected

ATRX

< 5% somatic

BRAF

< 2% somatic

CDKN2A

< 2% somatic

EGLN1/PHD2

< 1% germline or somatic

EPAS1

6-12% mosaic or somatic

FGFR1

~ 1% somatic

FH

1-2% germline

H3F3A

< 2% mosaic

HRAS

7-8% somatic

IDH2

< 0.5% somatic

KIF1B

< 5% germline or somatic

KMT2D

< 2% germline or somatic

MAX

1-2% germline or somatic

MDH2

< 2% germline

MERTK

< 2% germline

MET 

< 2% germline or 2-10% somatic

NF1

3% germline or 20-25% somatic

RET

5-6% germline or somatic

SDHA

< 1% germline or somatic

SHDAF2

< 1%

SDHB

5-10% germline 

SDHC

1-2% germline 

SDHD

5-7% germline 

TMEM127

1-2% germline 

TP53

< 5% somatic

VHL

7-10%  germline or somatic

Adapted from NGS in PPGL (NGSnPPGL) Study Group et al: Consensus statement on NGS-based diagnostic testing of hereditary pheochromocytomas and paragangliomas. Nat Rev Endocrinol. 13(4):233-247, 2017.

Tumor Types Associated With SDH-Related Syndromes Tumor and Location

Carney Triad

SDHA; PGL5/CSS

SDHB; PGL4/CSS

SDHC; PGL3/CSS

SDHD; PGL1/CSS

SDHAF2; PGL2

Pheochromocytoma

-

+

+

+/-

+

+/-

Abdominal PGL

+++

++

++++

+/-

+

+/-

Head and neck PGL

++

+

++

++

+++

+

Thoracic PGL

+

+/-

++

+

++

+/-

SDH-deficient gastrointestinal stromal tumor 

++++

+++

+

+

+

+/-

SDH-deficient renal cell carcinoma 

-

+

+++

++

+/-

+/-

SDH-deficient pituitary adenoma 

-

++

+

+

+/-

+/-

Pulmonary chondroma

++++

-

-

-

-

-

PGL = paraganglioma; PGL1-5 = paraganglioma syndrome types 1-5;  CSS = Carney-Stratakis syndrome. Adapted from Lloyd RV et al: WHO Classification of Tumours of Endocrine Organs. 4th ed. Paris: IARC Press, 2017

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Adrenal Medulla and Paraganglia Table

Syndrome

Gene

Tumors in Paraganglia

Associated Neoplasms

Relative Frequency of PCC/PGL (%)

Familial PGL type 1, CarneyStratakis syndrome

SDHD

Multiple H&N PGL

Thyroid, GIST

5-6

Familial PGL type 2

SDHAF2

Multiple H&N PGL

Unknown

50% gastrinoma; 20% insulinoma; rare glucagonoma and VIPoma) – Associated with microadenomatosis, neuroendocrine hyperplasia, and dysplasia ○ VHL: Benign cysts and adenomas; seen in ~ 35-70% – Clinically nonfunctioning with hormonal expression – Up to 60% of tumors contain clear cells or multivacuolated foamy lipid-rich cells ○ Neurofibromatosis type 1: Pancreatic somatostatinoma (rare), duodenal (common), gastrinoma (rare) ○ Tuberous sclerosis: Rare PNETs (Insulinoma, gastrinoma)

○ MEN4: Decreased penetrance of PNETs when compared to MEN1 ○ Glucagon cell hyperplasia and neoplasia: Unrelated to MEN1 and VHL

DIAGNOSTIC CHECKLIST • Morphological perspective ○ Identification of multifocal microadenomas, neuroendocrine hyperplasia, foamy clear cells, and PNETs are features suggesting inherited tumors – Should prompt attention to possibility of underlying genetic susceptibility • Clinical perspective ○ In contrast with sporadic counterparts, MEN1-related PNETs are characterized by early onset, multiplicity of lesions, variable expression of tumors, and propensity for malignant degeneration

PNET Diagnostic Algorithm

The diagnostic algorithm for pancreatic neuroendocrine neoplasms/tumors helps classify these according to the 2017 WHO classification. (Modified from Guilmette and Nosé, 2019.)

118

Pancreatic Neuroendocrine Neoplasms

Abbreviations • Pancreatic neuroendocrine neoplasm (PNEN) • Pancreatic neuroendocrine tumor (PNET) • Pancreatic neuroendocrine carcinoma (PNEC)

Definitions • PNENs have significant neuroendocrine differentiation, with expression of synaptophysin and chromogranin (WHO 2017), including ○ Malignant well-differentiated neuroendocrine neoplasms, which are called PNETs ○ Poorly differentiated neuroendocrine neoplasms, which are called PNECs • PNET ○ Well-differentiated neuroendocrine neoplasms of low, intermediate, and high grade, composed of cells showing minimal to moderate atypia, displaying organoid patterns, and lacking necrosis – Expressing general markers of neuroendocrine differentiation: Diffuse and intense synaptophysin and (usually) chromogranin staining – Expressing hormones: Usually intense, but not diffuse, either orthotopic or ectopic to pancreas • PNEC ○ Poorly differentiated high-grade neuroendocrine neoplasms composed of highly atypical small cells or intermediate to large cells – Expressing general markers of neuroendocrine differentiation: Diffuse or faint synaptophysin and focal to faint chromogranin-A staining – Rarely hormones; lacking expression of trypsin or chymotrypsin, markers of exocrine pancreas • Neuroendocrine-nonneuroendocrine neoplasm (MiNEN) ○ Mixed neoplasm with neuroendocrine component combined with nonneuroendocrine component: Typically ductal adenocarcinoma or acinar cell carcinoma

Classification • PNETs can be classified as sporadic or inherited ○ In ~ 20% of cases, well-differentiated PNETs are associated with hereditary syndromes – Multiple endocrine neoplasia type 1 (MEN1) – von Hippel-Lindau (VHL) syndrome – Neurofibromatosis – Tuberous sclerosis – MEN4 – Glucagon cell hyperplasia and neoplasia • PNETs divided into functional or nonfunctional ○ Functional: Associated with clinical syndromes caused by abnormal secretion of hormones – Insulinomas – Gastrinomas – Glucagonomas – VIPomas – Serotonin-producing tumors – ACTH-producing tumors ○ Nonfunctional (~ 60% of all PNETs) – Not associated with clinical hormone hypersecretion

– May secrete pancreatic polypeptide and chromogranin; secreted at levels insufficient to cause symptoms • WHO 2017 classifies pancreatic endocrine tumors (PETs) into 3 broad categories ○ PNET – G1: < 2 mitoses/50 HPF, < 3% Ki-67 proliferative index – G2: 2-20 mitoses/50 HPF, 3-20% Ki-67 proliferative index – G3: > 20 mitoses/50 HPF, > 20% Ki-67 proliferative index ○ PNEC – G3: > 20 mitoses/50 HPF, > 20% Ki-67 proliferative index □ Small-cell type □ Large-cell type ○ MiNEN – Tumors with both exocrine and endocrine features in morphologically uniform population, proven by double-labeled immunohistochemistry or EM ○ Other tumors – PNET with ductules – Neuroendocrine microadenoma: < 0.5 cm □ Nonfunctional, discovered incidentally (surgery, radiography, autopsy) □ Pancreatic head affected most commonly □ Often coexpress > 1 peptide □ Multiple microadenomas present in MEN1 syndrome

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

ETIOLOGY/PATHOGENESIS Precursor Lesions • Although no precursor lesions have so far been described in sporadic PNETs, there is evidence of neuroendocrine cell proliferations in both ducts and islets as precursor lesions of familial PNETs in patients with MEN1 and VHL • Pancreatic neuroendocrine cell ductular proliferations, distinct phenomenon called nesidioblastosis or ductuloinsular complexes, are seen in both MEN1 and VHL • Alterations in islets of Langerhans, including islet hyperplasia and islet dysplasia, are seen only in setting of inherited pancreatic PNETs • Islet dysplasia: Slightly enlarged islets (< 0.5 mm) that contain neuroendocrine cells arranged in trabeculae that display mild atypia and show loss of normal spatial and quantitative arrangement of normal 4 main cell types ○ Islet dysplasia most frequently associated with MEN1 • Pancreatic neuroendocrine microadenoma: Islet cell dysplasia attains size > 5 mm • Microadenoma > 5 mm classified as PNET • Pancreatic microadenomatosis, or presence of multiple pancreatic neuroendocrine microadenomas, is linked to MEN1 syndrome and is also seen in association with glucagon cell hyperplasia and neoplasia syndrome (GCHN) and VHL disease • Ductuloinsular complexes and islet hyperplasia/dysplasia are precursor premalignant lesions since they may give rise to development of pancreatic neuroendocrine microadenomas and NETs in setting of familial disease

119

Diagnoses Associated With Syndromes by Organ: Endocrine

Pancreatic Neuroendocrine Neoplasms

120

Syndromic PNET • Spectrum of inherited PNETs is larger than previously anticipated (~ 20% of overall presentations) • Associated with MEN1, VHL, tuberous sclerosis (TS), NF1, MEN4, and GCHN syndromes • PETs associated with syndromes are associated with characteristic genetic abnormalities • MEN1 ○ MEN1 gene ○ Patients with MEN1 have unique profile of hormonal function: 50% are gastrin-producing tumors (typically in duodenum), and 20% are insulin-producing tumors ○ MEN1 involvement of pancreas initially involves development of multiple small PETs, often microadenomas, associated with foci of nesidioblastosis or ductuloinsular complexes ○ In contrast with sporadic counterparts, MEN1-related PETs are characterized by early onset, multiplicity of lesions, variable expression of tumors, and propensity for malignant degeneration ○ MEN1 diagnosed in ~ 25% of patients who have gastrinoma and in ~ 5% of those who have insulinproducing PET ○ In contrast to sporadic PETs, those associated with MEN1 tend to present at earlier age (30-50 years), have higher rate of postoperative recurrence, and are common cause of death in these patients ○ MEN1-associated PETs display wide variety of molecular abnormalities, including chromosomal loss, chromosomal loss with duplication, mitotic recombination, or point mutation of wild-type MEN1 allele • VHL ○ VHL gene ○ Pancreatic pathology in VHL usually takes form of benign cysts and microcystic or serous adenomas – Occur in 35-70% of VHL patients – Occur in young patients; multiple and located anywhere in pancreas – Tumors said to be functionally inactive, although immunohistochemistry shows focal positivity for pancreatic polypeptide (PP), somatostatin, glucagon, &/or insulin in 30-40% – Initially reported not to be associated with either microadenomas (endocrine cell foci, 0.5 cm in diameter) or nesidioblastosis; however, there is association of these findings with VHL ○ Endocrine pancreatic tumors in VHL patients are nonfunctioning tumors ○ Characteristically, VHL-related PNETs contain clear cells or multivacuolated lipid-rich cells in varying proportions • Tuberous sclerosis (TS) ○ TSC1 and TSC2 genes ○ Patients with TS complex also have increased incidence of PNETs ○ PNETs are most common pancreatic lesion in patients with TSC – Nonsecretory PNET cases associated with TSC – 1/3 cystic – Average age at resection: 26 years

– Functional PETs reported to produce both insulin and gastrin • NF1 ○ NF1 gene ○ Somatostatinomas of pancreas are rarer than those of duodenal origin – 16x less common than duodenal somatostatinomas ○ Duodenal somatostatinomas occur in NF1 patients – NF1 accounted for 48% of duodenal somatostatinomas reported in literature • MEN4 ○ Germline CDKN1B gene mutations ○ Phenotype similar to that of MEN1 ○ PNETs, usually nonfunctioning • GCHN syndrome ○ Germline GCGR mutation ○ Development of islet glucagon cell hyperplasia and glucagon cell microtumors and macrotumors

CLINICAL ISSUES Epidemiology • Incidence ○ 2-5% of clinically detected pancreatic neoplasms – 1 per 100,000 per year in USA – 2-4 per million per year for insulinoma ○ ~ 20% of PNETs are MEN1-associated • Age ○ Peak: 30-60 years (mean: 50 years) ○ Syndrome-associated tumors (MEN1) tend to occur earlier (10-30 years) • Sex ○ Equal distribution – Exception for somatostatinoma: F > M (2:1) – Exception for gastrinoma: M > F (1.2:1)

Presentation • Functional PNET: Clinical syndromes related to excessive or inappropriate hormone or biogenic amine production ○ ~ 60% ○ Ectopic hormone: Gastrin, VIP, PP, ACTH, serotonin, and neurotensin ○ Pancreatic hormone: Insulin, glucagon, somatostatin, VIP ○ Insulinoma syndrome (~ 20%) – Whipple triad includes □ Symptoms of hypoglycemia □ Plasma glucose levels < 3.0 mmol/L □ Relief of symptoms with administration of glucose ○ Glucagonoma syndrome – Glucagonoma is functioning, well-differentiated pancreatic neuroendocrine neoplasm composed of glucagon-producing and pre-proglucagon-derived peptide-producing cells with uncontrolled glucagon secretion causing glucagonoma syndrome (WHO 2017) – Skin rash (necrolytic migratory erythema) in 70% of patients – Rash usually starts in groin/perineum and migrates to distal extremities

Pancreatic Neuroendocrine Neoplasms

Treatment • Options, risks, complications ○ Multidisciplinary approach mandatory ○ Before surgery, important to separate MEN1-associated tumors from solitary, nonsyndrome-associated, and malignant tumors ○ Pre- and intraoperative localization critical for management ○ Management of hormone production critical ○ Hormone replacement therapy if pancreatectomy performed ○ Observation and surveillance can be considered for small (< 1-2 cm), nonfunctional PNET

Prognosis • PNETs generally slow-growing, with overall 5-year survival of 33%, 10-year survival of 17%, and 20-year survival of 10% • Patients with PNECs rarely survive 1 year • Survival depends on tumor size, functional status, and extent of local invasion • Tumor behavior associated with functional status and specific hormone produced ○ Nonfunctional tumors nearly all malignant (90%) ○ Insulinoma – Has best prognosis – Vast majority benign (~ 8% malignant) ○ Glucagonoma

•

•

•

•

– ~ 60-70% have metastases at time of diagnosis – Patients survive for many years due to slow tumor growth ○ Somatostatinoma – ~ 70% have metastases at time of diagnosis – 75% 5-year survival (worse if metastases present) Routine morphologic examination does not always predict behavior ○ Metastatic disease (lymph nodes, liver) clinches malignant diagnosis Up to 30% of patients already have metastatic disease at diagnosis ○ ~ 65% will develop metastatic disease at some point during disease course Adverse prognostic factors ○ Metastasis to regional lymph nodes &/or liver ○ Gross invasion into adjacent organs ○ Angiolymphatic invasion and perineural invasion ○ Rule of 2: > 2 cm, > 2 mitoses/10 HPF, > 2% proliferation index (Ki-67) ○ Necrosis ○ Functioning tumor (except insulinoma) Surgical margin, WHO 2017 grading, and TNM staging systems may all be meaningful prognostic factors impacting long-term survival of patients with PNETs

Diagnoses Associated With Syndromes by Organ: Endocrine

– Associated with angular stomatitis, cheilitis, atrophic glossitis, alopecia, onycholysis, vulvovaginitis, and urethritis – Marked weight loss (65%), mild diabetes mellitus (glucose intolerance) (50%), anemia (33%), diarrhea, depression (20%), deep vein thrombosis (12%) ○ Somatostatinoma syndrome – Nonspecific findings, although diabetes mellitus, hypochlorhydria, gallbladder disease (cholelithiasis), diarrhea, steatorrhea, anemia, and weight loss may be present – Markedly elevated somatostatin serum/tumor levels define syndrome ○ Gastrinoma syndrome (~ 15%) – Zollinger-Ellison syndrome: Increased gastrin results in gastric or duodenal ulcers, reflux esophagitis, and steatorrhea – 25% of patients found to have MEN1 syndrome ○ VIPoma syndrome – a.k.a. Verner-Morrison syndrome – VIP excess produces voluminous watery diarrhea, hypokalemia, achlorhydria, and metabolic acidosis – Accounts for 80% of diarrheogenic tumors ○ Serotonin-producing tumors ○ ACTH-producing tumor with Cushing syndrome • Nonfunctional PNET ○ Also called "inactive," "nonsyndromic," or "incidentally discovered" ○ Increased frequency more recently due to enhanced diagnostic imaging – Now, relative frequency ~ 70-80% of PNETs ○ May have elevated hormone levels but not distinct syndrome

MACROSCOPIC General Features • Vast majority well demarcated, discrete/circumscribed, and solitary ○ Multifocal tumors more common in MEN1 ○ White-gray-yellow, pink-red, or tan-brown

MICROSCOPIC Well-Differentiated Pancreatic Neuroendocrine Neoplasm, G1/G2/G3 • Functioning ○ Insulinoma (most common type): β-cell derived – Nonfunctioning and microtumors not encapsulated – Predominantly solid, ribbon-like, trabecular, gland-like (tubular or acinar) growth – Amyloid unique to this tumor type (islet amyloid polypeptide or amylin) ○ Gastrinoma (2nd most common) – Many times, no primary tumor identified in spite of having lymph node metastases – High risk of malignant behavior, irrespective of size ○ Glucagonoma (3rd most common): α-cell derived – Commonly occur in tail of pancreas or attached to surface of pancreas – Few cells react with glucagon immunohistochemically – Nesidioblastosis may be present ○ VIPoma (4th most common) – Often react with other markers (growth hormone release hormone, α-human chorionic gonadotropin, PP) ○ Somatostatinoma (least common): δ-cell derived – Tend to have glands and psammoma bodies – Synaptophysin usually reactive; chromogranin weak 121

Diagnoses Associated With Syndromes by Organ: Endocrine

Pancreatic Neuroendocrine Neoplasms Poorly Differentiated Neuroendocrine Carcinoma, G3 • Small-cell variant: Diffuse, sheet-like arrangements of cells, geographic necrosis, mitotic figures > 10/10 HPF • Large-cell neuroendocrine

DIFFERENTIAL DIAGNOSIS Solid Pseudopapillary Neoplasm • Lacks clinical hormone syndrome; usually affects young women • Usually large tumor; most often in body and tail but with mostly benign biologic outcome • Broad, hyalinized to myxoid septa • PAS(+) hyaline globules • Positive for CD56, NSE, and synaptophysin, which can cause misdiagnosis for PEN; negative for chromogranin

Ductal Adenocarcinoma • Glandular architecture is prominent but also has single cell infiltration • Mitotic figures usually easily identified, along with perineural invasion • Positive for CEA and MUC1, while lacking neuroendocrine markers

Acinar Cell Carcinoma • Significant granular, eosinophilic cytoplasm surrounding round nuclei with prominent, brightly eosinophilic nucleoli • Positive for trypsin or chymotrypsin

Pathologic Interpretation Pearls • Presence of neuroendocrine hyperplasia and pancreatic microadenomatosis are features suggesting inherited tumors • Variable patterns between and within tumors and architectural appearance • Nuclei show neuroendocrine salt and pepper chromatin • Required to do Ki-67 to document proliferation index • Amyloid seen in insulinoma • Psammoma bodies seen in somatostatinoma • Clear cells seen in VHL syndrome

SELECTED REFERENCES 1.

2. 3. 4. 5. 6.

7.

Pancreatoblastoma

8.

• Tumor of pediatric patients • Small-cell pattern but acinar in structure with eosinophilic, granular cytoplasm, along with squamous morules

9.

Lymphoma/Plasmacytoma

10.

• Dyscohesive cells with high nuclear:cytoplasmic ratio • Positive reactions with CD138, CD79a, κ, or λ light chain restriction

11.

Localized Hyperplasia

12.

• Islet cell hyperplasia or nesidioblastosis can give isletglandular complexes • Normal islets show several hormones in appropriate distribution, while tumors typically show preponderance of one

13.

Epithelioid Gastrointestinal Stromal Tumor

16.

• Strongly positive for CD117 (C-kit) but negative for neuroendocrine markers

17.

Metastatic Tumors to Pancreas

18.

• Metastatic melanoma, renal cell carcinoma, colon adenocarcinoma • Immunohistochemistry usually valuable in differentiating from PEN ○ HMB-45, Melan-A/MART-1, S100, RCC, CD10, CK7, CK20, CDX-2

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Insulinoma: Hypoglycemia 122

• Glucagonoma: Skin rash (necrolytic migratory erythema) • Gastrinoma: Zollinger-Ellison syndrome • VIPoma: Verner-Morrison syndrome

14.

15.

19.

20. 21. 22.

Guilmette JM et al: Neoplasms of the neuroendocrine pancreas: an update in the classification, definition, and molecular genetic advances. Adv Anat Pathol. 26(1):13-30, 2019 Chiloiro S et al: Pancreatic neuroendocrine tumors in MEN1 disease: a monocentric longitudinal and prognostic study. Endocrine. 60(2):362-7, 2018 Carrera S et al: Hereditary pancreatic cancer: related syndromes and clinical perspective. Hered Cancer Clin Pract. 15:9, 2017 Chen L et al: Clinicopathological features and prognostic validity of WHO grading classification of SI-NENs. BMC Cancer. 17(1):521, 2017 Love JE et al: CD200 Expression in neuroendocrine neoplasms. Am J Clin Pathol. 148(3):236-42, 2017 OʼToole SM et al: Response to somatostatin analog therapy in a patient with von Hippel-Lindau disease and multiple pancreatic neuroendocrine tumors. Pancreas. 46(7):e57, 2017 Park JK et al: DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors. Oncotarget. 8(30):49796-806, 2017 Sharma A et al: Clinical profile of pancreatic cystic lesions in von HippelLindau disease: a series of 48 patients seen at a tertiary institution. Pancreas. 46(7):948-52, 2017 Strosberg JR et al: The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. Pancreas. 46(6):707-14, 2017 Falconi M et al: ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and NonFunctional Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 103(2):153-71, 2016 Hackeng WM et al: Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis. Hum Pathol. 56:93-100, 2016 Massironi S et al: Gastrinoma and neurofibromatosis type 2: the first case report and review of the literature. BMC Gastroenterol. 14:110, 2014 Thakker RV: Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 386(1-2):2-15, 2014 McCall CM et al: Serotonin expression in pancreatic neuroendocrine tumors correlates with a trabecular histologic pattern and large duct involvement. Hum Pathol. 43(8):1169-76, 2012 Zhang Y et al: Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 18(3):206-18, 2011 Klöppel G et al: The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch. 456(6):595-7, 2010 Henopp T et al: Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. J Clin Endocrinol Metab. 94(1):213-7, 2009 Capelli P et al: Endocrine neoplasms of the pancreas: pathologic and genetic features. Arch Pathol Lab Med. 133(3):350-64, 2009 Garbrecht N et al: Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocr Relat Cancer. 15(1):229-41, 2008 Lubensky IA et al: Molecular genetic events in gastrointestinal and pancreatic neuroendocrine tumors. Endocr Pathol. 18(3):156-62, 2007 Rindi G et al: TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 449(4):395-401, 2006 Soga J: Carcinoids and their variant endocrinomas. An analysis of 11842 reported cases. J Exp Clin Cancer Res. 22(4):517-30, 2003

Pancreatic Neuroendocrine Neoplasms

Tumor Type

Associated Syndromes

Nonfunctioning

MEN1 (~ 20% by age 3, 34% by age 50, and 53% by age 80)

Insulinoma

MEN1 (~ 15% of cases); tuberous sclerosis type 2 (rare)

Glucagonoma

Most sporadic; MEN1 (rare) and glucagon cell hyperplasia and neoplasia (50%)

Somatostatinoma

NF1 (ampullary); MEN1 (ampullary and pancreatic), HIF2A mutations (duodenal and pancreatic) 

Gastrinoma

Most sporadic; MEN1 (duodenum: 40%), NF1, NF2, tuberous sclerosis 

VIPoma

Most sporadic; MEN1 (rare)

ACTH-producing NET

Most sporadic; MEN1 (rare)

Grading and Clinicopathological Classification of Pancreatic Endocrine Tumors 2017 WHO Tumor Classification

Grading

Well-differentiated endocrine tumor, grade 1 (PNET G1)

< 2 mitoses/50 HPF; < 3% Ki-67 proliferative index

Well-differentiated endocrine tumor, grade 2 (PNET G2)

2-20 mitoses/50 HPF; 3-20% Ki-67 proliferative index

Well-differentiated neoplasm, grade 3 (PNET G3)

> 20 mitoses/50 HPF or Ki-67 proliferative index > 20%

Diagnoses Associated With Syndromes by Organ: Endocrine

PNETs: Tumor Type and Associated Syndromes

Comparison of WHO Classifications of PNENs, 2000-2017 WHO 2000/2004

WHO 2010

WHO 2017

Well-differentiated endocrine tumor/carcinoma Neuroendocrine tumor (NET), G1/G2 (WDET/WDEC)

PNET, G1/G2/G3; well-differentiated neuroendocrine neoplasm (PNEN)

Poorly differentiated endocrine carcinoma (PDEC)

PNEC, G3; large cell or small cell; poorly differentiated PNEN

Neuroendocrine carcinoma (NEC), large cell or small cell

Immunohistochemistry Antibody

Reactivity

Staining Pattern

Comment

Synaptophysin

Positive

Cell membrane and cytoplasm

Nearly every tumor cell positive; both solid pseudopapillary tumor (SPT) and acinar cell carcinoma (ACC) may be focally positive

PGP9.5

Positive

Cytoplasmic

Nearly every tumor cell positive

NSE

Positive

Cytoplasmic

Very low specificity

CD56

Positive

Cell membrane and cytoplasm

Usually accentuated on cell membrane

Chromogranin-A

Positive

Cytoplasmic

Granular reactivity; less staining in less granulated tumors; SPT negative; ACC may be focally positive

E-cadherin

Positive

Cell membrane

SPT negative; ACC positive

CK-PAN

Positive

Cytoplasmic

Nearly all tumors

CK8/18/CAM5.2

Positive

Cytoplasmic

Most tumor cells

CK19

Positive

Cytoplasmic

Expression correlated with outcome

ISL1

Positive

Nuclear

Support pancreatic origin of metastases

CD117

Positive

Cell membrane

Abnormal expression linked to prognosis

PRP

Positive

Nuclear

If progesterone receptor positivity lost, associated with worse prognosis

NFP

Positive

Cytoplasmic

Trypsin

Negative

ACC positive; SPT negative

β-catenin

Negative

SPT positive; ACC negative

Present in few tumor cells

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Diagnoses Associated With Syndromes by Organ: Endocrine

Pancreatic Neuroendocrine Neoplasms

Pancreatic Endocrine Tumor

Pancreatic Endocrine Tumor

Pancreatic Endocrine Tumor

Small PNET

Well-Circumscribed Pancreatic Mass

Nonfunctional PNET

(Left) CT shows a hypervascular mass ſt in the body of the pancreas, a wellcircumscribed lesion. Note that the pancreas shows marked fatty change, a finding more commonly identified in chronic pancreatitis. (Right) There is a complex mass ſt (gastrinoma) in the tail of the pancreas expanding out into the surrounding tissues with increased vascularity. Note the metastatic foci st in the liver, confirming pancreatic endocrine carcinoma.

(Left) Somatostatin receptor scintigraphy helps detect somatostatin receptor-positive lesions, like gastrinomas. They can be targeted by In-111labeled octreotide. There is a large tumor in the head ﬈, another in the body ﬊, and a metastasis to the liver ﬉. (Right) Axial T1 C+ MR shows a 1-cm PNET in the pancreatic head ſt. Note the clear borders and enhancement of the lesion.

(Left) Endoscopic ultrasound (EUS) shows a 4x5-mm PNET in the pancreatic tail. The tumor is characteristically hypoechoic. (Right) CT shows a large, cystic mass involving the head of the pancreas ﬈. This is a nonfunctional tumor. Interestingly, there is no pancreatic ductal dilatation.

124

Pancreatic Neuroendocrine Neoplasms

Cut Surface of PNET (Left) PNET in a patient with Cushing syndrome shows a firm, tan-yellow cut surface. This ACTH-producing tumor metastasized to the liver. (Right) Gross photo of PNET reveals a firm, tan-yellow, well-demarcated cut surface. Histologically, this was a welldifferentiated PNET, intermediate grade.

Well-Circumscribed Pancreatic Mass

Diagnoses Associated With Syndromes by Organ: Endocrine

Pancreatic Tumor With Liver Metastases

Cut Surface of PNET (Left) This 3.5-cm mass in the head of the pancreas in a 26year-old woman with MEN1 syndrome is well circumscribed and shows a pale-pink cut surface with areas of cystic changes and hemorrhage. (Right) The cut surface of this PNET shows poorly defined borders with a firm, graywhite appearance. The tumor was an insulinoma.

Gastrinoma With Duodenal Nodules

Cytology of Pancreatic Endocrine Neoplasm (Left) The duodenum in this patient with a 3-cm pancreatic head gastrinoma shows numerous submucosal nodules ﬈. These nodules have the same immunophenotype as the pancreatic tumor. (Right) H&E-stained smear of PNET shows a uniformly monotonous population of epithelioid-plasmacytoid cells with ample pink cytoplasm. The nuclei are round to oval, uniform, and eccentrically located.

125

Diagnoses Associated With Syndromes by Organ: Endocrine

Pancreatic Neuroendocrine Neoplasms

PNET Cytology

Well-Differentiated PNET

Enlarged Neuroendocrine Islet

Psammoma Bodies in Insulinoma

Clear Cells in VHL

Increased Neuroendocrine Cell Population

(Left) H&E-stained smear shows the characteristic loosely clustered epithelioid cells. The cells are pale-pink and have a small amount of cytoplasm with central nuclear placement. The nuclei have delicate salt and pepper nuclear chromatin. (Right) H&E from a 26-year-old woman with a family history of MEN1 shows a 3.5-cm, welldifferentiated neuroendocrine tumor of the pancreatic head. This tumor, based on the mitotic count and Ki-67 proliferative index, is classified as intermediate grade.

(Left) Islet hyperplasia refers to slightly enlarged islets that contain neuroendocrine cells arranged in trabeculae and show loss of the normal spatial distribution and numbers of the normal main cell types. This is usually present in patients with MEN1, VHL, and glucagon hyperplasia and neoplasia. (Right) High-power view shows the characteristic mediumsized cells with ample eosinophilic cytoplasm and eccentrically located nuclei. There are areas of fibrosis and numerous psammoma bodies.

(Left) High-power view of this well-differentiated neuroendocrine tumor shows uniform cells with pale-clear cytoplasm and round to oval nuclei. The clear cytoplasm is characteristic of VHL tumors. (Right) Chromogranin-A in the pancreas of a patient with VHL syndrome shows an enlarged neuroendocrine cell population in a background of normal pancreas. The pancreas also had microcystic adenomas.

126

Pancreatic Neuroendocrine Neoplasms

Membranous CD117 Expression (Left) This well-differentiated PNET is classified as intermediate grade by WHO 2017, based on the mitotic count and Ki-67 proliferative index. The mitotic count was 2 mitosis per 10 HPF, and the Ki67 proliferative index was 3.4%. (Right) Welldifferentiated PNET, intermediate grade, shows membranous staining for CD117. The immunopositivity for CD117 is related to the prognosis.

Gastrinoma

Diagnoses Associated With Syndromes by Organ: Endocrine

Ki-67 Immunolabeling Index

Immunoexpression of Gastrin (Left) H&E of gastrinoma shows the typical pseudoglandular and tubuloacinar arrangement with areas of fibrosis. (Right) This section is from a gastrinproducing tumor with diffuse immunostaining for gastrin by the tumor cells. The diffuse apical immunostaining is characteristic. These tumors may be found in MEN1, NF1, and TSC.

Somatostatinoma

Somatostatin Expression in PNET (Left) Somatostatin-producing PNETs are usually associated with dense, fibrous tissue intermingled between the tumor cells. The tumor cells are arranged in a microglandular pattern. (Right) The isolated, small, pseudoglandular arrangements of tumor cells show immunopositivity for somatostatin. These tumors may be found in patients with NF1 and MEN1. HIF2A somatic mutation is also present in somatostatinomas.

127

Diagnoses Associated With Syndromes by Organ: Endocrine

Endocrine Pancreas Table Pancreatic Tumor as Part of Inherited Tumor Syndrome Syndrome

Gene

Pancreatic Pathology

MEN1

MEN1

Islet cell hyperplasia, nesidioblastosis, and dysplasia; microadenomatosis; PNETs (e.g., Zollinger-Ellison syndrome, insulinoma, glucagonoma, VIPoma); usually associated with nesidioblastosis and microadenomatosis

VHL

VHL

Pancreatic cysts in ~ 90% of patients with VHL; PNETs in ~ 15% of VHL patients; when present in patients with VHL, PNETs are multiple in 50-60% of cases; usually functionally inactive with 30-40% immunoexpression of somatostatin, glucagon, or insulin; ~ 70% associated with nesidioblastosis or microadenomatosis; presence of foamy and clear cell changes is characteristic of VHL-associated PNET

NF1

NF1

Somatostatinoma (in pancreas, duodenum, and periampullary region)

TSC

TSC1 and TSC2

Benign and malignant PNETs, insulinoma

GCHN

GCGR

Hypertrophic islets distributed between microadenomas and macrotumors

MEN4

CDKN1B

Similar findings as MEN1

MEN1 = multiple endocrine neoplasia type 1; VHL = von Hippel-Lindau syndrome; NF1 = neurofibromatosis type 1; TSC = tuberous sclerosis; GCHN = glucagon cell hyperplasia and neoplasia; PNET = pancreatic neuroendocrine tumor; VIP = vasoactive intestinal peptide.

Genes Involved in Pancreatic Tumorigenesis Gene(s)

Sporadic PNETs With Mutation

MEN1

~ 45% of sporadic PNETs have MEN1 mutation; found in 55% of gastrin-producing tumors, 50% of VIPproducing tumors, and 7% of insulin-producing tumors

DAXX and ATRX

~ 45% of sporadic PNET have mutation in 1 of 2 genes

TSC2, PTEN,  and PIK3CA

15% of PNETs have alterations of mTOR pathway

TP53, RB, and CDKN2A

Genes involved in cell cycle somatically targeted in carcinomas

VHL and HIF1A

Occasionally found to be involved in development of sporadic tumors

NF1

Not found to be involved in development of sporadic tumors

TSC1 

Not found to be involved in development of sporadic tumors

GCGR

Not found to be involved in development of sporadic tumors

PNET = pancreatic neuroendocrine tumor; VIP = vasoactive intestinal peptide.

Immunohistochemistry of PNET

128

Antibody

Reactivity

Staining Pattern

Comments

Synaptophysin

Positive

Cell membrane and cytoplasm

Nearly every tumor cell (+); SPT and ACC may be focally (+)

PGP9.5

Positive

Cytoplasmic

Nearly every tumor cell is positive

NSE

Positive

Cytoplasmic

Very low specificity

CD56

Positive

Cell membrane and cytoplasm

Usually accentuated on cell membrane

Chromogranin-A

Positive

Cytoplasmic

Granular reactivity, a reflection of neurosecretory granules; less staining in less granulated tumors; SPT negative; ACC may be focally positive

E-cadherin

Positive

Cell membrane

SPT negative; ACC positive

CK-PAN

Positive

Cytoplasmic

Nearly all tumors

CK8/18/CAM5.2

Positive

Cytoplasmic

Most tumor cells

CK19

Positive

Cytoplasmic

Expression correlated with outcome

ISL1

Positive

Nuclear

Pancreatic neuroendocrine cells

CD117

Positive

Cell membrane

Abnormal expression linked to prognosis

PRP

Positive

Nuclear

If progesterone receptor positivity is lost, associated with worse prognosis

Trypsin

Negative

Cytoplasm

SPT negative; ACC positive

β-catenin

Positive

Nuclear positivity correlates with SPT positive; ACC negative mutant pattern

Endocrine Pancreas Table

Antibody

Reactivity

DAXX and ARRX

Negative

Staining Pattern

PNETs may show loss of expression 

Comments

p53

Positive

Overexpression in carcinomas or complete loss

RB

Negative

Lost in carcinomas

SMAD4

Negative

Lost in carcinomas

SSTR2A

Negative

Lost in carcinomas

ACC = acinar cell carcinoma; SPT = solid pseudopapillary tumor; PNET = pancreatic neuroendocrine tumor.

Comparison of Nonfunctioning Neuroendocrine Pancreatic Tumors and Differential Diagnoses Clinical Features

Solid Pseudopapillary Neoplasm

Pancreatic Endocrine Neoplasm

Acinar Cell Carcinoma

Pancreatoblastoma

Age

Young adults

50-70 years; younger in MEN1

50-60 years

Children < 10 years

Sex

Female

Equal sex distribution

Slight male predominance

Slight male predominance

Gross

Circumscribed; variegated, hemorrhagic, solid, and cystic

Circumscribed, usually solid

Circumscribed, soft with abundant hemorrhage

Circumscribed and lobulated, soft and fleshy

Microscopic

Pseudopapillae, necrosis, polygonal epithelial cells with eosinophilic to clear cytoplasm, uniform, round to oval nuclei with grooves, intracytoplasmic and extracytoplasmic hyaline globules

Trabecular, nested pattern; densely hyalinized stroma; cells are polygonal with amphophilic cytoplasm; round to oval, uniform in size and shape of nuclei; classic coarsely stippled salt and pepper chromatin; inconspicuous nucleoli

Tumor is arranged in cellular lobules separated by bands of collagenized stroma; acinar formation; granular eosinophilic cytoplasm; uniform and well-polarized nuclei with basal palisading at interface with stroma; prominent nucleoli

Lighter and darker staining cells, reflecting different cell types of pancreatoblastoma; acinar formation and squamoid corpuscles; hypercellular stromal cells

Cytology

Papillary fragments; cytoplasmic vacuoles, hyaline globules, foamy histiocytes, nuclear grooves

Cellular, monotonous, small or medium-sized cells; granular chromatin and plasmacytoid morphology

Prominent acinar formation; cells with granular eosinophilic cytoplasm and prominent nucleoli

Primitive cellular stromal elements, squamoid corpuscles; acinar cytomorphology

Positive IHC markers

Vimentin, CD56, β-catenin, α-1antitrypsin; progesterone receptor, CD10, cyclin-D1; keratin and synaptophysin focal

Chromogranin, synaptophysin, CD56, pancreatic hormones

Trypsin, chymotrypsin, and Bcl- Markers of acinar, endocrine, 10; chromogranin and and ductal differentiation:  synaptophysin may be focal Trypsin, chymotrypsin, and Bcl10; chromogranin and synaptophysin may be focal

Diagnoses Associated With Syndromes by Organ: Endocrine

Immunohistochemistry of PNET (Continued)

129

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Adenoma KEY FACTS

TERMINOLOGY

MACROSCOPIC

• Benign neoplasm of chief, oncocytic, transitional, waterclear, or mixture of cells

• Single enlarged hypercellular parathyroid gland (if multiple, likely hyperplasia or asymmetric hyperplasia)

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• Most are sporadic • ~ 5-10% of cases of primary hyperparathyroidism are associated with familial syndromes • Most common genetic syndromes ○ Hyperparathyroidism-jaw tumor syndrome ○ Familial isolated hyperparathyroidism ○ Multiple endocrine neoplasia types 1, 4, and 2A ○ Familial hypocalciuric hypercalcemia

• Parathyroid adenoma (PTA) is composed of chief, oxyphilic, transitional, clear cells, or mixtures of cell types

CLINICAL ISSUES • Often asymptomatic or vague symptoms, identified with serum calcium screening

ANCILLARY TESTS • Positive for chromogranin, synaptophysin, CAM5.2, and PTH; negative for TTF-1 and thyroglobulin • Complete loss of nuclear or nucleolar parafibromin expression in parathyroid carcinoma is helpful differentiating from PTA, which usually shows intact nuclear and nucleolar parafibromin expression

TOP DIFFERENTIAL DIAGNOSES • Parathyroid hyperplasia, parathyroid carcinoma, thyroid tumor

Parathyroid Adenoma Gross Appearance

Chief Cells in Parathyroid and Adenoma

HPT-JT Parafibromin-Deficient Adenoma

HPT-JT Parafibromin-Deficient Adenoma

(Left) Parathyroid adenoma (PTA) is a single enlarged parathyroid gland, usually 0.2 g to > 1 g and tan to red-tan in color. PTAs are generally smaller than parathyroid carcinomas but can overlap in size. (Right) Chief cell PTA ﬈ shows adjacent rim of normal ﬊ parathyroid tissue, a feature often identified in smaller rather than larger adenomas. The rim is often separated from the adenoma by connective tissue.

(Left) These HPT-JT parathyroid tumors have cells with eosinophilic cytoplasm demonstrating distinctive perinuclear clearing and characteristic nuclear changes. These tumors are usually cystic. (Right) Parafibromindeficient (HPT-JT-type, CDC73-mutated) parathyroid tumors are usually cystic and have a distinct morphology with cells with eosinophilic cytoplasm demonstrating a sheet-like growth pattern with distinctive nuclei as well as loss of parafibromin nuclear staining.

130

Parathyroid Adenoma

Abbreviations • Parathyroid adenoma (PTA)

Definitions • Benign parathyroid neoplasm composed of chief cells, oncocytic cells, transitional cells, water-clear cells, or mixture of these cell types (WHO 2017)

ETIOLOGY/PATHOGENESIS Hereditary PTAs • Hereditary hyperparathyroidism is less common than sporadic hyperparathyroidism • ~ 5-10% of cases of primary hyperparathyroidism are associated with familial syndromes ○ Study of this group has provided insight into genetic and molecular changes that underlie neoplastic transformation of parathyroid tissue • Most common genetic syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia types 1, 4, and 2A (MEN1, MEN4, MEN2A), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial isolated hyperparathyroidism (FIHP), and familial hypocalciuric hypercalcemia • HPT-JT ○ Autosomal dominant ○ Inactivating mutations in CDC73 (HRPT2) (1q21-q31) tumor suppressor gene – 80% mutations are truncating (frameshift and nonsense), and most involve exon 1 ○ CDC73 (HRPT2) encodes parafibromin/CDC73 protein ○ HPT-JT is disorder of hyperparathyroidism, fibroosseous jaw tumors, kidney cysts, hamartomas, and Wilms tumors and endometrial tumors ○ Parathyroid hyperplasia or adenoma and increased risk of parathyroid carcinoma – 15% of patients with HPT-JT develop parathyroid carcinoma ○ Germline CDC73 (HRPT2) mutations identified in subset of patients with mutation-positive carcinomas thought to be sporadic ○ 80% of HPT-JT patients present with hyperparathyroidism – Penetrance of hyperparathyroidism is 80% – Hyperparathyroidism usually develops by late adolescence • FIHP ○ Autosomal dominant, 1% of primary hyperparathyroidism ○ Parathyroid gland is only endocrine organ involved ○ PTA or parathyroid hyperplasia, and increased risk of parathyroid carcinoma ○ Cause unknown in most families, but GCM2 activating mutations identified in ~ 20% of families – CDC73 (HRPT2) involved in 15%; MEN1 and area on chromosome 2 also implicated • MEN1 ○ Autosomal dominant, high-penetrance germline mutation in MEN1 tumor suppressor gene (11q13) encoding menin protein

○ PTAs and parathyroid carcinomas occur in MEN1 but are less common than hyperplasia (multiglandular parathyroid disease) ○ Somatic MEN1 mutations occur in 15-20% of sporadic adenomas and occasionally in sporadic carcinomas ○ Other MEN1 features – Endocrine: Pituitary adenomas; neuroendocrine tumors of pancreas, duodenum, thymus, and lung; gastrinomas; adrenal cortical adenomas and hyperplasia – Nonendocrine: Angiofibromas, collagenomas, café au lait macules, lipomas, gingival papules, meningiomas, ependymomas, leiomyomas • MEN4 ○ Autosomal dominant disease caused by mutations of CDKN1B ○ Phenotype similar to that of MEN1 • MEN2A ○ Autosomal dominant, high-penetrance germline RETactivating protooncogene (10q11.2) mutation ○ 20-30% of MEN2A is associated with parathyroid hyperplasia or adenomas; may also have medullary thyroid carcinoma &/or pheochromocytomas

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Sporadic PTAs • Predisposing factors poorly understood • Possible association with prior ionizing radiation ○ Particularly external ionizing radiation in childhood ○ Persons exposed to nuclear events ○ Diagnostic or therapeutic doses of radioactive iodine does not appear to be significant risk factor • Long-term lithium therapy

CLINICAL ISSUES Epidemiology • Incidence ○ Most common cause of primary hyperparathyroidism (80-85%) – Followed by parathyroid hyperplasia (15%) and carcinoma (1-2%) ○ Incidence has been increasing for 3 decades – Attributable to introduction of automatic serum calcium screening • Age ○ Any age, but most commonly in patients 50-60 years ○ Familial cases occur at younger ages (20-25 years) • Sex ○ F:M = 3:1 (in patients 50-60 years of age) – But F:M = 1:1 in patients < 40 years of age; 5:1 in patients > 75 years of age ○ Females and males equally affected in familial cases

Site • Single parathyroid gland usually involved ○ Lower parathyroid glands involved slightly more often than upper parathyroid glands ○ 10% in other locations: Intrathyroidal, mediastinum, thymus, soft tissue behind esophagus and pharynx ○ Up to 15% have "double adenoma," but asymmetric hyperplasia should be considered 131

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Adenoma – Double adenomas often involve superior parathyroid glands ("4th pouch disease")

Presentation • Usually asymptomatic or vague symptoms of fatigue, weakness, gastrointestinal symptoms, cognitive impairment ○ Most identified by abnormal calcium levels ○ 4-15% may present with nephrolithiasis • Historical symptoms of nephrolithiasis and severe bone disease (osteitis fibrosa cystica) less common today • Risk of bone fractures increased with primary hyperparathyroidism

• Excellent • Incomplete excision or rupture can result in parathyromatosis

IMAGING General • Tc-99m sestamibi and ultrasound are commonly used to localize site of adenoma • May use CT, MR, etc.

MACROSCOPIC

Laboratory Tests

Normal Parathyroid Gland Macroscopic Features

• Elevated intact parathyroid hormone (PTH) with elevated albumen adjusted calcium ○ But some may have normocalcemic primary hyperparathyroidism • Vast majority of primary hyperparathyroidism, metabolic disease resulting from hypersecretion of hormone from parathyroid tumors, is sporadic • Serum calcium levels are elevated but less so than in parathyroid carcinoma in which calcium levels are often > 13 mg/dL • Hypophosphatemia

• Normal parathyroid gland is size and shape of kidney bean (4-6 mm x 2-4 mm), 20-40 mg each • Most people have 4 parathyroid glands; 10% have ≥ 5 glands, and 3% have < 4 glands

Natural History • 25% of asymptomatic patients show disease progression if adenoma is not removed • Chronic hypercalcemia is associated with increased cardiovascular mortality • Increased risk of bone fractures in primary hyperparathyroidism (4-15%)

Treatment • Surgical approaches ○ Bilateral neck exploration with excision of adenoma is classic approach – Although minimally invasive surgery guided by noninvasive imaging and intraoperative PTH monitoring is gaining favor in nonfamilial cases ○ Subtotal parathyroidectomy is indicated in familial syndromes, such as MEN1 and FIHP ○ Using surgical approach in HPT-JT is controversial because of increased risk of parathyroid cancer – But subtotal parathyroidectomy with close postoperative biochemical monitoring for recurrence is currently recommended over prophylactic total parathyroidectomy ○ Resection of single gland (PTA), often with assistance of intraoperative PTH monitoring – ≥ 50% drop in intraoperative PTH from baseline at 10 minutes after gland excision is helpful to ensure that abnormal gland(s) has been removed • Medical therapy with calcimimetics is useful for patients with primary hyperparathyroidism who are poor surgical candidates, or have nonlocalizable tumors or inoperable disease • Clinical follow-up to monitor for recurrent hypercalcemia ○ Asymmetric hyperplasia may present with predominant involvement of 1 gland (mistaken for adenoma) then progress to involve more glands 132

Prognosis

PTA Macroscopic Features • Single enlarged gland: Usually 0.2 g to > 1 g, tan to pink-tan, encapsulated, ± rim of normal tissue • Ovoid, often surrounded by thin capsule • May have rim of normal tissue (pale tan or yellow) • Vary in size: < 1 cm to > 10 cm • PTAs < 0.6 cm and weighing < 100 mg may be referred to as "microadenomas" • Larger adenomas may show fibrosis, hemosiderin, cystic degeneration, calcification • Cystic change may occur in adenomas, particularly larger adenomas, and in those with HPT-JT syndrome • PTA is ectopic in up to 10% (intrathyroidal, mediastinum, thymus, soft tissue behind esophagus and pharynx) • Double adenomas (also consider asymmetric hyperplasia), which often involve upper parathyroid glands ("4th pouch disease")

MICROSCOPIC Histologic Features • PTA histology ○ Proliferation of parathyroid parenchymal chief cells, oxyphil cells, transitional cells, clear cells, or mixtures of cell types ○ May have thin connective tissue capsule ○ 50-60% have rim of normal parathyroid tissue – Rim more often identified in small adenomas – Rim often separated from adenoma by connective tissue capsule, but not always – Parathyroid parenchymal cells within rim are typically smaller than those within adenoma – Suppressed parathyroid parenchymal cells within rim have larger and more fat droplets than in adenoma cells, which have less lipid and more dispersed lipid than cells in rim – Parathyroid hyperplasia can occasionally also have rims of normal tissue ○ Fat cells sparse (scattered or nested) or absent ○ Stroma is sparse but vascular, may be fibrotic with hemosiderin deposition in large adenomas or those with cystic change

Parathyroid Adenoma

ANCILLARY TESTS Immunohistochemistry • Positive for neuroendocrine markers chromogranin and synaptophysin • Positive for keratin (CAM5.2 is most helpful keratin for neuroendocrine tumors) • Negative for TTF-1, thyroglobulin, calcitonin (usually, but calcitonin can be variable in staining, thus panel of immunostains is often helpful) • Positive for PTH but less intense staining in adenomas compared to normal parathyroid or rim of normal parathyroid • Parafibromin/CDC73 (encoded by CDC73/HRPT2) ○ Loss of nuclear parafibromin in CDC73 (HRPT2)associated parathyroid carcinomas and adenomas ○ Sporadic adenomas are usually positive for parafibromin, and many carcinomas show loss of parafibromin ○ Complete loss of nuclear or nucleolar parafibromin expression in parathyroid carcinoma is helpful differentiating from PTA, which usually shows intact nuclear and nucleolar parafibromin expression ○ Caution: Parathyroid carcinomas in hemodialysis patients can show staining in parathyroid carcinomas and metastasis ○ Caution: Parafibromin expression may be lost in PTAs associated with CDC73 (HRPT2) germline mutations ○ Parafibromin is helpful, but requires rigorously controlled testing as variability exists among laboratories • Increased p27 (cyclin-dependent kinase inhibitor protein) in PTAs compared to parathyroid carcinomas • Adenomas are positive for p27, Bcl-2, and MDM2, and have low Ki-67 labeling index (< 4%) • Carcinomas often show low/absent p27, MDM2, and higher Ki-67 labeling index (> 4%) • Positive for GCM2 (transcription factor), regulatory gene in parathyroid development • Positive for GATA3 (transcription factor) • Positive for RB and APC • Positive for combination of CDKN1B (p27), Bcl-2, and MDM12

• Negative for galectin-3 and PGP9.5

Genetic Testing • Study of uncommon familial syndromes has helped to define pathophysiology of both familial and sporadic parathyroid neoplasms, whereas genotyping of sporadic PTAs identified recurrent somatic mutations ○ Tumor suppressor genes MEN1 and CDC73 (HRPT2) were discovered through genetic analysis of kindreds with MEN1 and HPT-JT ○ Somatic mutations in MEN1 and CDC73 (HRPT2) are frequent events in clonal development of sporadic PTAs and parathyroid carcinomas, respectively • CDC73 (HRPT2) mutation (tumor suppressor gene, 1q31.2) ○ CDC73 (HRPT2) encodes parafibromin/CDC73 protein ○ Germline CDC73 (HRPT2)-inactivating mutation in HPTJT syndrome-associated PTA or parathyroid hyperplasia and increased risk of parathyroid carcinoma ○ 20% of sporadic cystic adenomas have CDC73 (HRPT2) mutation; may be HPT-JT related ○ Germline CDC73 (HRPT2) mutations have been identified in subset of patients with mutation-positive carcinomas (consider genetic testing in patients with parathyroid carcinoma) ○ Somatic CDC73 (HRPT2) mutations are common in sporadic parathyroid carcinomas and rare in sporadic adenomas ○ Strong association with CDC73 (HRPT2) mutation and familial and sporadic parathyroid cancer • Cyclin-D1/CCND1 oncogene (11q13.3) ○ 5-8% of PTAs have genetic alterations in cyclinD1/CCND1 (PTA) gene ○ Cyclin-D1/CCND1 encodes cyclin-D1, cell cycle regulator from G1 to S phase transition ○ Cyclin-D1 protein overexpression observed in up to 40% of adenomas • MEN1 mutation (tumor suppressor gene, 11q13.1, results in truncated menin protein) ○ PTAs and parathyroid carcinomas occur in MEN1, but parathyroid hyperplasia occurs more commonly ○ Up to 40% of sporadic PTAs have loss of 1 MEN1 allele, and 1/2 of these have inactivating mutation in 2nd allele • RET mutation (protooncogene, 10q11.21) ○ Germline RET-activating mutation in MEN2A (95% mutation in exon 10 or 11, codon 634) ○ 30% of patients with MEN2A have parathyroid hyperplasia, but adenomas can also occur ○ RET mutation is generally not identified in sporadic parathyroid disease • CASR inactivating mutations (3q13.33) ○ Causes decreased calcium sensitivity of parathyroid and kidney, resulting in PTH-dependent hypercalcemia • CDKN1B mutation (12p13.1) • GCM2 activating mutations (6p24.2) • Chromosome 11: Frequent loss in adenomas and frequent gain in carcinomas

Diagnoses Associated With Syndromes by Organ: Endocrine

○ Adenoma cells may be larger than normal parathyroid cells and have more variably sized nuclei ○ Often mixture of growth patterns: Solid, follicular, acinar, cords, solid, rosette-like, and rarely papillae ○ Nuclear palisading around blood vessels is common ○ Foci of "endocrine atypia" with pleomorphic, hyperchromatic nuclei (up to 25% of cases) ○ Scattered mitoses in up to 80% of adenomas (more in parathyroid carcinoma) – Usually < 1 mitoses/10 HPF ○ No atypical mitoses ○ Cysts and cystic change and degeneration common, especially in large adenomas and HPT-JT cases ○ May have fibrous bands due to degenerative changes, fibrosis, and hemosiderin ○ Fibrous bands and fibrosis common in both PTA and parathyroid carcinoma ○ No angiolymphatic invasion, perineural invasion, or invasion into adjacent structures ○ PTAs in MEN1 are histologically similar to sporadic PTAs

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Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Adenoma

DIFFERENTIAL DIAGNOSIS Parathyroid Carcinoma

3.

• Malignant neoplasm of parathyroid parenchymal cells (chief cells, oxyphilic cells, transitional cells, water-clear cells, or mixture of cell types) • Often symptomatic and higher serum calcium levels (> 13 mg/dL) than in adenomas • Invasion into adjacent structures, capsular invasion, vascular invasion, perineural invasion • Complete loss of nuclear or nucleolar parafibromin expression in parathyroid carcinoma is helpful differentiating from PTA, which usually shows intact nuclear and nucleolar parafibromin expression ○ But parathyroid carcinomas in hemodialysis patients can show staining in parathyroid carcinomas and metastasis ○ Parafibromin expression may be lost in PTAs associated with CDC73 (HRPT2) germline mutations

4.

5. 6. 7.

8.

9.

10. 11.

Atypical PTA • Noninvasive parathyroid neoplasm composed of chief cells with variable oncocytes, transitional cells, and water-clear cells with some features of parathyroid carcinoma • No definitive invasion (no invasion into adjacent structures, no capsular invasion, no vascular invasion, no perineural invasion)

Parathyroid Hyperplasia

12.

13.

14. 15.

• Absolute increase in parathyroid parenchymal mass resulting from proliferation of chief, oxyphil, and transitional cells in multiple parathyroid glands • Distinguishing PTA from parathyroid hyperplasia classically requires examination of at least 1 additional gland • Increased utilization of preoperative imaging and localization and intraoperative PTH monitoring assists in identification and removal of diseased parathyroid gland(s) • Rim of normal tissue seen in 50-60% of PTAs and occasionally in parathyroid hyperplasias

16.

"Double" PTA

21.

• May account for up to 15% of adenomas • Caution: Asymmetric hyperplasia can be easily mistaken for "double" adenoma

Thyroid Follicular Neoplasm • Often shows follicular growth, which can be seen in some PTAs

Medullary Thyroid Carcinoma • Medullary thyroid carcinoma is positive for calcitonin and CEA and negative for PTH

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Often asymptomatic, identified by screening calcium • Serum calcium elevated, but markedly elevated serum calcium (> 13 mg/dL) worrisome for carcinoma

SELECTED REFERENCES 1.

134

2.

Cristina EV et al: Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 32(6):861-75, 2018

17.

18.

19.

20.

22. 23.

Riccardi A et al: Analysis of activating GCM2 sequence variants in sporadic parathyroid adenomas. J Clin Endocrinol Metab. 104(6):1948-52, 2019 Cinque L et al: Molecular pathogenesis of parathyroid tumours. Best Pract Res Clin Endocrinol Metab. 32(6):891-908, 2018 Wei Z et al: Whole-exome sequencing identifies novel recurrent somatic mutations in sporadic parathyroid adenomas. Endocrinology. 159(8):3061-8, 2018 Al-Hraishawi H et al: Intact parathyroid hormone levels and primary hyperparathyroidism. Endocr Res. 1-5, 2017 Arya AK et al: Promoter hypermethylation inactivates CDKN2A, CDKN2B and RASSF1A genes in sporadic parathyroid adenomas. Sci Rep. 7(1):3123, 2017 Guarnieri V et al: Large intragenic deletion of CDC73 (exons 4-10) in a threegeneration hyperparathyroidism-jaw tumor (HPT-JT) syndrome family. BMC Med Genet. 18(1):83, 2017 Hosny Mohammed K et al: Parafibromin, APC, and MIB-1 are useful markers for distinguishing parathyroid carcinomas from adenomas. Appl Immunohistochem Mol Morphol. 25(10):731-5, 2017 Marini F et al: Molecular genetics in primary hyperparathyroidism: the role of genetic tests in differential diagnosis, disease prevention strategy, and therapeutic planning. A 2017 update. Clin Cases Miner Bone Metab. 14(1):60-70, 2017 Jervis L et al: Osteolytic lesions: osteitis fibrosa cystica in the setting of severe primary hyperparathyroidism. BMJ Case Rep. 2017, 2017 Leere JS et al: Contemporary medical management of primary hyperparathyroidism: a systematic review. Front Endocrinol (Lausanne). 8:79, 2017 Marchiori E et al: Specifying the molecular pattern of sporadic parathyroid tumorigenesis-The Y282D variant of the GCM2 gene. Biomed Pharmacother. 92:843-8, 2017 Padinhare-Keloth TNTK et al: Sensitive detection of a small parathyroid adenoma using fluorocholine PET/CT: a case report. Nucl Med Mol Imaging. 51(2):186-9, 2017 World Health Organization. Tumors of Endocrine Organs, 2017 Ruanpeng D et al: Intrathymic parathyroid adenoma. Am J Med Sci. 353(5):506, 2017 Christakis I et al: Parathyroid carcinoma and atypical parathyroid neoplasms in MEN1 patients; a clinico-pathologic challenge. The MD Anderson case series and review of the literature. Int J Surg. 31:10-6, 2016 Kumari N et al: Role of histological criteria and immunohistochemical markers in predicting risk of malignancy in parathyroid neoplasms. Endocr Pathol. 27(2):87-96, 2016 Mathews JW et al: Hyperparathyroidism-jaw tumor syndrome: an overlooked cause of severe hypercalcemia. Am J Med Sci. 352(3):302-5, 2016 Serrano-Gonzalez M et al: A germline mutation of HRPT2/CDC73 (70 G>T) in an adolescent female with parathyroid carcinoma: first case report and a review of the literature. J Pediatr Endocrinol Metab. 29(9):1005-12, 2016 Gill AJ: Understanding the genetic basis of parathyroid carcinoma. Endocr Pathol. 25(1):30-4, 2014 Sadler C et al: Parathyroid carcinoma in more than 1,000 patients: a population-level analysis. Surgery. 156(6):1622-9; discussion 1629-30, 2014 Zhang Y et al: Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 18(3):206-18, 2011 Chow LS et al: Parathyroid lipoadenomas: a rare cause of primary hyperparathyroidism. Endocr Pract. 12(2):131-6, 2006

Parathyroid Adenoma

Follicular Growth Pattern (Left) This chief cell PTA has a nested growth pattern and prominent vascularity. The nuclei are round and dense. The cytoplasm of the chief cells is eosinophilic to amphophilic. The cells do not show significant nuclear pleomorphism or mitotic activity. (Right) This chief cell adenoma has a glandular growth pattern. PTAs may have various growth patterns, while parathyroid carcinomas often have a monotonous or trabecular growth pattern.

Perinuclear Clearing in PTA

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Chief Cell Adenoma

Follicles With Colloid-Like Material (Left) Foci of nuclear pleomorphism ﬊ can be seen in oxyphil cell adenomas. Welldefined cytoplasmic membranes of parathyroid cells and perinuclear halo are usually seen in parafibromindeficient (HPT-JT-type, CDC73-mutated) parathyroid tumors. (Right) Follicular patterns are relatively common in PTA. Occasionally, PTAs may show large, follicular-like spaces with proteinaceous fluid and can be mistaken for thyroid follicles with colloid.

Endocrine Atypia

Cystic Change in PTA (Left) Benign parathyroid lesions can show foci of "endocrine atypia" with pleomorphism and nuclear hyperchromasia. These foci should not be mistaken for the atypia of parathyroid carcinoma. Often, parathyroid carcinomas will show a markedly monotonous growth pattern and cytomorphology. (Right) Chief cell PTA shows an area of cystic change. Cystic change is common in larger PTAs and those associated with HPT-JT.

135

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Carcinoma KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• Malignant parathyroid parenchymal neoplasm

• Markedly elevated serum calcium (> 13 mg/dL), PTH, alkaline phosphatase • CDC73  mutations in familial and some sporadic

ETIOLOGY/PATHOGENESIS • Most parathyroid carcinomas are sporadic, but increased incidence in patients with hyperparathyroidism-jaw tumor syndrome (HPT-JT) • HPT-JT: Autosomal dominant disorder of hyperparathyroidism, fibroosseous jaw tumors, kidney cysts, hamartomas, and Wilms tumors • MEN1: Autosomal dominant; only rare case of parathyroid carcinoma reported in MEN1 • MEN2A: 20-30% have parathyroid hyperplasia or adenoma with only rare reports of carcinoma • FIH: Autosomal dominant, accounts for 1% of primary hyperparathyroidism: Adenoma or hyperplasia • May occur as part of complex hereditary syndrome ○ Or isolated (i.e., nonsyndromic), nonhereditary (i.e., sporadic) endocrinopathy

MICROSCOPIC • Require invasive growth with capsular, vascular, perineural, or invasion into adjacent structures • Histologic features in sporadic and HPT-JT parathyroid lesions similar, but HPT-JT lesions may be cystic

ANCILLARY TESTS • Positive for chromogranin, synaptophysin, CAM5.2, PTH; negative for TTF-1, thyroglobulin, calcitonin • Loss of parafibromin nuclear staining • Loss of expression of RB protein • Strong association with CDC73 mutation in familial and sporadic parathyroid cancer

Molecular Genetic Mechanisms of Parathyroid Carcinoma

Multiple genes are involved in parathyroid carcinogenesis. Familial parathyroid syndromes exhibit Mendelian inheritance patterns, and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT.

136

Parathyroid Carcinoma

Abbreviations • Parathyroid carcinoma (PC)

○ FIHP predisposition for PC is particularly high for CDC73 mutation carriers  ○ CDC73 mutations in 8% ○ MEN1 mutations in 20%

Definitions

Sporadic

• Malignant neoplasm of parathyroid parenchymal cells (chief cells, oxyphilic cells, transitional cells, water/clear cells, or mixtures of cell types)

• Predisposing factors poorly understood; possible association with prior ionizing radiation • Reports of parathyroid carcinoma occurring in setting of secondary parathyroid hyperplasia

ETIOLOGY/PATHOGENESIS Parathyroid Carcinoma  • May occur as part of complex hereditary syndrome ○ Or isolated (i.e., nonsyndromic), nonhereditary (i.e., sporadic) endocrinopathy • Most parathyroid carcinomas are sporadic but increased incidence in patients with hyperparathyroidism-jaw tumor syndrome (HPT-JT)

Inherited • Syndromic and hereditary forms of PC are associated with germline mutations of cell division cycle 73 CDC73, a.k.a. hyperparathyroidism type 2 (HRPT2), MEN type 1 (MEN1), and rearranged during transfection (RET) genes

HPT-JT • Autosomal dominant disorder of hyperparathyroidism, fibroosseous jaw tumors, kidney cysts, hamartomas, and Wilms tumors • Inactivating mutation tumor suppressor gene CDC73 (HRPT2) (1q21-q31) that encodes parafibromin • Parathyroid hyperplasia, adenoma, or carcinoma ○ 15% with HPT-JT develop parathyroid carcinoma • Germline CDC73 mutations identified in subset of patients with CDC73 mutation-positive carcinomas

Multiple Endocrine Neoplasia Type 1 • Autosomal dominant, high penetrance, germline mutation in MEN1 tumor suppressor gene (11q13); results in truncated menin protein • 20% of patients with primary parathyroid hyperplasia have MEN1, but only ~ 15 cases of parathyroid carcinoma reported in MEN1 • Loss of heterozygosity and somatic MEN1 mutations identified in some parathyroid carcinomas • Somatic MEN1 mutations in 15-20% of sporadic adenomas and occasionally in sporadic carcinomas

Multiple Endocrine Neoplasia 2A  • 20-30% have parathyroid hyperplasia or adenoma (only rare reports of carcinoma) ○ To date, 3 PC cases have been reported in association with MEN2A 

Familial Isolated Hyperparathyroidism • Autosomal dominant; accounts for 1% of primary hyperparathyroidism (parathyroid is only endocrine organ involved), adenoma, or hyperplasia • Increased risk of parathyroid carcinoma has been reported but may be due to inclusion of HPT-JT cases • Cause unknown in most families, but CDC73, MEN1, CASR, and GCM2 are possibilities

CLINICAL ISSUES Epidemiology • Incidence ○ 1-2% of primary hyperparathyroidism (parathyroid adenoma: 80-85%; parathyroid hyperplasia: 15%)

Site • Arises in parathyroid gland ○ Similar to parathyroid adenomas, carcinomas can also occur in ectopic sites ○ Slightly more common in lower parathyroid glands

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Presentation • Parathyroid tumors, of which 15% are carcinomas, are generally 1st manifestation and occur in > 90% of HPT-JT cases • Most parathyroid carcinomas are functional and patients are symptomatic, but nonfunctional tumors occur ○ Fatigue, weakness, weight loss, nausea, polyuria, polydipsia, renal disease, bone disease ○ Bone disease (osteitis fibrosa cystica, diffuse osteopenia, subperiosteal resorption, skull involvement) common in parathyroid carcinoma ○ Renal disease (nephrolithiasis, nephrocalcinosis, decreased renal function) common in carcinoma ○ Prominent symptoms, particularly renal and bone involvement, concerning for malignancy ○ Parathyroid adenomas usually asymptomatic or vague, mild symptoms • Palpable neck mass (unusual for adenoma) • Local recurrence of parathyroid adenoma is worrisome for carcinoma but can be parathyromatosis

Laboratory Tests • Extremely high serum calcium levels (> 13 mg/dL) more common in carcinoma • Markedly elevated PTH levels (> 1,000 ng/L) • High serum alkaline phosphatase activity (> 200 IU/L) • CDC73 mutations are major driver mutations in etiology of PCs

Natural History • Usually recurs 1st in neck and then metastasizes to cervical and mediastinal lymph nodes, lung, bone, and liver

Treatment • Surgical approaches ○ 1st-line treatment is en block resection of parathyroid tumor and surrounding structures, usually ipsilateral thyroid lobe at 1st surgery (better local control and disease-free survival) 137

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Carcinoma ○ Risk progression associated with margin status • Drugs ○ Inoperable parathyroid carcinoma management may include calcimimetics to control hypercalcemia and bisphosphonates to control bone resorption ○ Chemotherapy effectiveness unclear ○ Few reports of immunomodulating therapeutic approaches with vaccines • Radiation ○ Patients treated with surgery and postoperative radiation may have lower risk of locoregional progression and improved cause-specific survival

Prognosis • 5-year survival: Up to 85%; 10-year survival: 49% • Best chance for cure is surgical resection en bloc with adjacent tissues, often ipsilateral thyroid lobe ○ Postoperative radiation may be associated with decreased risk progression and improved survival • Tumors treated with extensive surgery associated with improved survival • Significant risk of locoregional disease progression after surgery

IMAGING General Features • Mass noted on CT and MR, often with no specific features • Tc-99m sestamibi scintigraphy or sonography identifies location but does not separate adenoma from carcinoma

MACROSCOPIC General Features • Firm tumors, may be adherent to or invasive into adjacent structures ○ May be grossly encapsulated and resemble adenomas ○ Caution as large parathyroid adenomas, especially with cystic change, can become fibrotic and adhere to adjacent structures

Size • Large tumors (mean: 6.7 g; range: 1.5-27 g); larger than adenomas but overlap in size

MICROSCOPIC Histologic Features • Hypercellular parathyroid with invasive growth (invasion into adjacent structures, capsular, vascular, or perineural invasion) • Capsular invasion of tumor beyond thickened capsule identified in 60% • Fibrous bands common (up to 90%) but not specific • Invasion of vessels in thickened capsule or surrounding soft tissue (most specific feature for carcinoma but seen in 15% of cases) • Perineural invasion • Solid growth pattern with sheets of cells or closely packed nests or trabecular growth but can show follicular or other growth patterns • Cellular monotony is common, but occasional cases are pleomorphic 138

• Mitotic figures identified in at least 80% of carcinomas but also in up to 70% of adenomas • Atypical mitoses limited to parathyroid carcinoma • Suggested that triad of macronucleoli, > 5 mitoses per 50 HPF, and necrosis is associated with aggressive behavior in parathyroid carcinoma • Histologic features in sporadic and HPT-JT parathyroid lesions similar, but HPT-JT lesions may be cystic

ANCILLARY TESTS Immunohistochemistry • Positive for chromogranin and synaptophysin; parathyroid hormone • Positive for keratin (CAM5.2 most helpful keratin for neuroendocrine tumors) • Parafibromin ○ Loss of nuclear parafibromin in CDC73-associated parathyroid carcinomas and adenomas ○ Sporadic parathyroid adenomas are usually positive for parafibromin, whereas many carcinomas show loss of parafibromin • Ki-67 (MIB-1) elevated > 4 (higher than in adenomas) • Carcinomas have higher Ki-67 proliferative index ○ Adenomas often with low Ki-67 proliferative index • Negative for TTF-1, thyroglobulin, calcitonin 

Genetic Testing • CDC73 mutation (tumor suppressor gene, 1q21-q31, encodes parafibromin) ○ Strong association with CDC73 mutation in familial and sporadic parathyroid cancer – CDC73 mutation uncommon in sporadic adenomas but identified in 20% of sporadic cystic adenomas ○ 15% with HPT-JT (caused by germline CDC73 inactivating mutation) develop parathyroid carcinoma   ○ Germline CDC73 mutations identified in subset of patients with mutation-positive carcinomas – Consider genetic testing in patients with parathyroid carcinoma – CDC73 germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC but in only ~ 2% of parathyroid adenomas  – CDC73 germline mutations occur in 20-40% of patients with sporadic PC and may reveal unrecognized HPT-JT – CDC73 mutations are major driver mutations in etiology of PCs • MEN1 mutation (tumor suppressor gene, 11q13, results in truncated menin protein) ○ Somatic MEN1 mutations in 15-20% of sporadic adenomas and some sporadic carcinomas ○ Loss of heterozygosity and somatic MEN1 mutations in some parathyroid carcinomas ○ Only rare case reports of parathyroid carcinoma in setting of MEN1 • RET mutation (proto-oncogene, 10q11.2) ○ Only rare case reports of parathyroid carcinoma in setting of MEN2A • Cyclin-D1/CCND1 (11q13) ○ Genetic alterations in cyclin-D1/CCND1 (parathyroid adenoma), 11q13, in 5-8% of parathyroid neoplasms

Parathyroid Carcinoma

Condition

Gene

Syndromic or Isolated

Primary Hyperparathyroidism Features

Associated Conditions

HPT-JT

CDC73

Syndromic

PA, cystic PC

Ossifying fibroma of jaw

MEN1

MEN1

Syndromic

Hyperplasia/PA/PC

Pituitary and adrenal hyperplasia or adenoma, enteropancreatic tumor

MEN2

RET

Syndromic

Hyperplasia/PA/PC

Medullary thyroid carcinoma and pheochromocytoma

FIHP

CDC73 MEN1

Isolated

Hyperplasia/PA/PC

PA = parathyroid adenoma; PC = parathyroid carcinoma.

○ Loss of chromosome 11 frequent in parathyroid adenomas, and frequent chromosomal gain in parathyroid carcinomas in FISH studies ○ Cyclin-D1/CCND1 encodes cyclin-D1 (regulator of cell cycle progression from G1 to S phase), and cyclin-D1 overexpression observed in neoplastic parathyroid – Lack of definitive genotype-phenotype correlation limits utility Loss of 1p and 13q relatively common in parathyroid carcinomas, whereas loss of 11q (MEN1 location) most common abnormality in parathyroid adenoma Loss of chromosome 11 common in parathyroid adenoma; gain of chromosome 11 in carcinoma, particularly in those who die of disease Loss of heterozygosity on 13q (RB and BRCA2 location) in carcinomas, but specific abnormalities of RB or BRCA2 not identified by sequencing Candidate oncogenes: PRUNE2, PIK3CA, KMT2D, MTOR

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•

•

•

5. 6. 7.

8. 9. 10.

11.

12.

13. 14.

DIFFERENTIAL DIAGNOSIS

15.

Parathyroid Adenoma • May show only scattered mitoses and usually lacks atypical mitoses • No unequivocal invasive growth (no capsular, vascular, or perineural invasion or invasion into adjacent structures)

16.

Atypical Parathyroid Adenoma

18.

• Noninvasive parathyroid neoplasm composed of chief cells with variable oncocytes and transitional oncocytes, with some features of parathyroid carcinoma ○ Adherence to adjacent structures, mitotic activity, fibrous bands, and trabecular growth

19.

17.

Marx SJ et al: Evolution of our understanding of the hyperparathyroid syndromes: A historical perspective. J Bone Miner Res. 34(1):22-37, 2019 Takumi K et al: CT features of parathyroid carcinomas: comparison with benign parathyroid lesions. Jpn J Radiol. 37(5):380-9, 2019 Triggiani V et al: Parathyroid carcinoma causing mild hyperparathyroidism in neurofibromatosis type 1: A case report and systematic review. Endocr Metab Immune Disord Drug Targets. 19(3):382-8, 2019 Bachmeier C et al: Should all patients with hyperparathyroidism be screened for a CDC73 mutation? Endocrinol Diabetes Metab Case Rep. 2018, 2018 Cinque L et al: Molecular pathogenesis of parathyroid tumours. Best Pract Res Clin Endocrinol Metab. 32(6):891-908, 2018 Cristina EV et al: Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-jaw tumour, familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 32(6):861-75, 2018 El Lakis M et al: Probability of positive genetic testing results in patients with family history of primary hyperparathyroidism. J Am Coll Surg. 226(5):933-8, 2018 Mahajan G et al: Previously unreported deletion of CDC73 involving exons 113 was detected in a patient with recurrent parathyroid carcinoma. BMJ Case Rep. 11(1), 2018 Salcuni AS et al: Parathyroid carcinoma. Best Pract Res Clin Endocrinol Metab. 32(6):877-89, 2018 Cardoso L et al: Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. Hum Mutat. 38(12):1621-48, 2017 Wasserman JD et al: Multiple endocrine neoplasia and hyperparathyroid-jaw tumor syndromes: Clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(13):e123-32, 2017 Witteveen JE et al: Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma. Mod Pathol. 24(5):688-97, 2011 Okamoto T et al: Parathyroid carcinoma: etiology, diagnosis, and treatment. World J Surg. 33(11):2343-54, 2009 Delellis RA: Challenging lesions in the differential diagnosis of endocrine tumors: parathyroid carcinoma. Endocr Pathol. 19(4):221-5, 2008 Sandelin K et al: Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg. 16(4):724-31, 1992

Diagnoses Associated With Syndromes by Organ: Endocrine

Hereditary and Syndromic Forms of Parathyroid Carcinoma

Parathyromatosis • Features favoring parathyroid carcinoma over parathyromatosis: Markedly elevated serum calcium, palpable mass, vascular or perineural invasion, infiltrative growth, prominent mitotic activity

SELECTED REFERENCES 1. 2. 3.

4.

Cetani F et al: Parathyroid carcinoma. Front Horm Res. 51:63-76, 2019 Cetani F et al: Familial and hereditary forms of primary hyperparathyroidism. Front Horm Res. 51:40-51, 2019 Juhlin CC et al: Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center. Mod Pathol. ePub, 2019 Kang H et al: Genomic profiling of parathyroid carcinoma reveals genomic alterations suggesting benefit from therapy. Oncologist. 24(6):791-7, 2019

139

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Carcinoma

Large Parathyroid Tumor

Trabecular Growth Pattern

Mitoses and Apoptosis in Parathyroid Carcinoma

Necrosis in Parathyroid Carcinoma

Numerous Mitosis in Oxyphil Carcinoma

Vascular Invasion

(Left) Cut section of a parathyroid carcinoma shows a firm, yellow-gray, nodular cut surface invading into adjacent structures. (Courtesy L. Erickson, MD.) (Right) Parathyroid carcinoma shows a trabecular growth pattern. Parathyroid carcinomas usually have monotonous or trabecular growth. Other patterns of growth (follicular, acinar) are less common. The cytomorphology of the constituent cells is generally monotonous.

(Left) This parathyroid carcinoma with diffuse growth has numerous mitoses ﬈. Mitoses are commonly identified in parathyroid carcinoma but can also be found in adenomas. Apoptosis is also identified ſt. (Right) Diffuse growth is shown in parathyroid carcinoma with a focus of necrosis ﬊. Necrosis in not seen in adenomas.

(Left) Parathyroid carcinoma shows mitotic figures ﬈. Oxyphil carcinomas are usually functional and much larger than oxyphil adenomas. Similar to conventional parathyroid carcinomas, invasion is required to diagnose malignancy. (Right) Vascular invasion ﬈ is one of the most definitive features of malignancy in parathyroid carcinoma but only occurs in about 15% of cases. Vascular invasion is essentially diagnostic of malignancy in parathyroid.

140

Parathyroid Carcinoma Metastases of Parathyroid Carcinoma to Lymph Node (Left) Parathyroid carcinoma ﬈ is shown invading into the perithyroidal tissue (thyroid parenchyma ﬊). Invasive growth, including invasion into adjacent structures, is diagnostic of malignancy in parathyroid carcinoma. (Right) Parathyroid carcinoma metastatic to a lymph node confirms malignancy. The diagnosis of parathyroid carcinoma requires metastases to lymph nodes or other organs and capsular, vascular, or perineural invasion and invasion into adjacent tissues.

Variable Immunoexpression of Chromogranin

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Carcinoma Invading Soft Tissue

Retinoblastoma Loss (Left) High-power view of parathyroid carcinoma shows a variable expression of chromogranin by the tumor cells. This tumor was a highgrade carcinoma with high proliferative index and numerous metastases. (Right) Loss of RB1 immunoexpression by tumor cells is shown. Decrease or loss of retinoblastoma RB1 expression is identified in > 85% of parathyroid carcinomas.

Parafibromin Loss

Strong p53 immunoreactivity (Left) This patient with HPT-JT had parafibromin loss by the parathyroid carcinoma cells. About 15% of patients with HPT-JT with CDC73 mutations or LOH develop parathyroid carcinoma. Parafibromin protein is encoded by CDC73. (Right) High-power view of parathyroid carcinoma shows strong expression of p53 in the tumor cells. The genes involved in parathyroid carcinogenesis include CDC73, MEN1, and RET in the sporadic and hereditary forms, as well as TP53, BRAC2, and RB1 loss of heterozygosity and CCND1 copy number gain.

141

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Parathyroid Hyperplasia KEY FACTS

TERMINOLOGY • Absolute increase in parathyroid parenchymal mass resulting from proliferation of chief cells, oncocytes, and transitional cells in multiple parathyroid glands in absence of recognized stimulus for parathyroid hormone secretion

ETIOLOGY/PATHOGENESIS • Most common hereditary hyperparathyroidism includes ○ Multiple endocrine neoplasia type 1 (MEN1), MEN4, MEN2A, familial hypocalciuric hypercalcemia (FHH), neonatal severe primary hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome, and familial isolated hyperparathyroidism (FIHP) • Primary parathyroid hyperplasia or multiglandular parathyroid tumors is most common manifestation of MEN1 ○ 90% with MEN1 have parathyroid hyperplasia ○ 20% of primary parathyroid hyperplasia cases associated with MEN1 (consider genetic testing)

• MEN4 ○ Primary hyperparathyroidism with enlargement of 3-4 parathyroid glands • MEN2A ○ 20-30% associated with parathyroid hyperplasia • FIHP ○ Parathyroid is only endocrine organ involved • CASR mutation ○ Activating CASR mutations in familial autosomal dominant hypoparathyroidism and familial hypocalcemia • HPT-JT ○ Disorder of hyperparathyroidism, fibroosseous jaw tumors, kidney cysts, hamartomas, and Wilms tumors

TOP DIFFERENTIAL DIAGNOSES • • • •

Secondary or tertiary parathyroid hyperplasia Primary clear cell hyperplasia Normal parathyroid Parathyroid adenoma or carcinoma

Primary Parathyroid Hyperplasia in MEN1

Asymmetric hyperplasia (or pseudoadenomatous variant) shows marked variation in extent of glandular involvement, easily confused with adenoma or multiple adenomas. 4 parathyroid glands from a patient with parathyroid hyperplasia and multiple endocrine neoplasia type 1 (MEN1) show marked asymmetry in size.

142

Primary Parathyroid Hyperplasia

Synonyms • • • •

Multiglandular parathyroid tumors Multiple adenomatosis Nodular hyperplasia Diffuse hyperplasia

•

Definitions • Absolute increase in parathyroid parenchymal mass resulting from proliferation of chief, oxyphil, and transitional cells in multiple parathyroid glands in absence of recognized stimulus for parathyroid hormone (PTH) secretion

•

ETIOLOGY/PATHOGENESIS Familial • Hereditary hyperparathyroidism is less common than primary sporadic hyperparathyroidism ○ 5-25% of cases • Most common hereditary hyperparathyroidism includes ○ Multiple endocrine neoplasia type 1 (MEN1), MEN4, MEN2A, familial hypocalciuric hypercalcemia (FHH), neonatal severe primary hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome, and familial isolated hyperparathyroidism (FIHP) • MEN1 ○ Autosomal dominant, high-penetrance, germline mutation of MEN1 tumor suppressor gene (11q13) – MEN1 encodes menin protein (truncated with MEN1 mutation) – Sporadic MEN1 cases due to new mutations – > 400 distinct germline mutations in MEN1 – Germline inactivation of one allele of MEN1 gene confers tumor susceptibility – Most syndromic tumors have somatic mutation or deletion of 2nd wild-type MEN1 allele ○ MEN1 equally affects female and male patients; no ethnic or geographic differences ○ MEN1 most common familial cause of primary hyperparathyroidism ○ Primary parathyroid hyperplasia (multiglandular parathyroid tumors) is most common manifestation of MEN1 – 90% with MEN1 have parathyroid hyperplasia – In 1-18% of all primary hyperparathyroidism, patients are found to have MEN1 – MEN1-associated hyperparathyroidism has onset of 20-25 years of age and affects male and female patients equally □ Sporadic primary hyperparathyroidism typical age of onset ~ 50-55 years – Parathyroid adenomas and rare report of carcinoma in MEN1 but much less common than hyperplasia ○ Other MEN1 features – Endocrine: Pituitary adenomas; neuroendocrine tumor of pancreas, duodenum, thymus, and lung; gastrinomas; adrenal cortical adenomas; and hyperplasia

•

•

•

– Nonendocrine: Angiofibromas, collagenomas, café au lait macules, lipomas, gingival papules, meningiomas, ependymomas, and leiomyomas MEN4 ○ Predisposed by germline inactivating mutation of CDKN1B ○ Primary hyperparathyroidism with enlargement of 3-4 parathyroid glands ○ Phenotype similar to that of MEN1 MEN2A ○ 20-30% associated with parathyroid hyperplasia (or adenomas, rare report of carcinoma) ○ Diagnosed clinically by occurrence of at least 2 specific endocrine tumors (medullary thyroid carcinoma, pheochromocytoma, or parathyroid hyperplasia/adenoma) in individual or close relatives ○ Autosomal dominant, high-penetrance, germline RET activating protooncogene mutation (10q11.2) FIHP ○ Autosomal dominant ○ 1% of primary hyperparathyroidism – Parathyroid is only endocrine organ involved □ Parathyroid adenoma or hyperplasia and suggested increased risk of parathyroid carcinoma (but may be due to inclusion of HPT-JT cases) ○ GCM2 activating mutations in ~ 20% of families ○ Cause unknown in most families – CDC73 (HRPT2), MEN1, and area on chromosome 2 implicated ○ Minority of kin have germline mutations in MEN1, CDC73 (HRPT2), or CASR ○ Clinically defined diagnosis of exclusion in kin with at least 2 people with hyperparathyroidism but lacking specific features of MEN1, MEN2A, HPT-JT, or FHH CASR mutation ○ Presents in parathyroid, kidney, thyroid C cells, intestine, and bone and detect extracellular calcium levels that regulate PTH release ○ Inactivating CASR (3q13.3-21) mutation causes decreased calcium sensitivity of parathyroid and kidney and results in PTH-dependent hypercalcemia ○ Homozygous inactivating CASR mutations in neonatal severe hyperparathyroidism ○ Life-threatening disorder with markedly hypercellular, hyperplastic parathyroid glands ○ Activating CASR mutations in familial autosomal dominant hypoparathyroidism and familial hypocalcemia ○ Heterozygous inactivating CASR mutations in FHH ○ Hypocalciuric hypercalcemia is caused by autoantibodies directed at CASR and can simulate FHH HPT-JT ○ Autosomal dominant inactivating mutations in putative tumor suppressor gene CDC73 (HRPT2) (1q21-q31) – 80% of mutations are truncated (frameshift and nonsense); most involve exon 1 ○ CDC73 (HRPT2) encodes parafibromin/CDC73 protein ○ Disorder of hyperparathyroidism, fibroosseous jaw tumors, kidney cysts, hamartomas, and Wilms tumors ○ 80% of HPT-JT patients present with hyperparathyroidism ○ Penetrance of hyperparathyroidism is 80%

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

143

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Parathyroid Hyperplasia ○ Parathyroid adenoma or hyperplasia and increased risk of parathyroid carcinoma ○ Hyperparathyroidism usually develops by late adolescence • CDC73-related disorders ○ Inactivating mutation of tumor suppressor gene CDC73 (HRPT2) on 1q21-q31 – CDC73 transcript spans 2.7 kb – CDC73 protein binds RNA polymerase II as part of PAF1 transcriptional regulatory complex, mediates H3K9 methylation that silences expression of cyclinD1 – CDC73 protein regulates gene expression and inhibits cell proliferation

MACROSCOPIC

Sporadic

Normal Parathyroid Gland

• Etiology of sporadic primary hyperplasia is unclear

• Size and shape of kidney bean (4-6 mm x 2-4 mm), 20-40 mg each • Most people have 4 parathyroid glands, 10% have ≥ 5, and 3% have < 4 parathyroid glands

CLINICAL ISSUES Epidemiology • Incidence ○ Primary parathyroid hyperplasia accounts for 15% of primary hyperparathyroidism (parathyroid adenomas = 80-85%; carcinomas = 1%) ○ Parathyroid hyperplasia occurs in 90% of patients with MEN1 and 30% with MEN2A – 20% of patients with primary parathyroid hyperplasia have MEN ○ Incidence increased in past 3 decades with increased calcium screening with multichannel autoanalyzer ○ Prevalence of 7% in autopsy study (patients did have elevated serum calcium but no bone disease) • Age ○ 5th decade but wide range ○ Familial cases occur earlier (often 25 years of age) • Sex ○ F:M = 2:1 in sporadic cases ○ F:M = 1:1 in familial cases

Site • In 50% of cases, all 4 parathyroid glands symmetrically enlarged ○ Caution with asymmetric hyperplasia, as it can be mistaken for adenoma or double adenomas

Presentation • Clinical presentation changed from patients presenting with nephrocalcinosis and osteopenia to those presenting with weakness and lethargy or asymptomatic with elevated screening serum calcium • Clinically similar to parathyroid adenoma • During pregnancy may cause ○ Nephrolithiasis, hypertension, preeclampsia, decreased bone mineral density

Laboratory Tests • Serum calcium elevated but less than in parathyroid carcinoma in which calcium often > 13 mg/dL • Hypophosphatemia

Treatment • Surgical approaches 144

○ Subtotal parathyroidectomy with 3 glands removed, leaving vascularized remnant of 4th gland – Or total parathyroidectomy with autotransplantation of portion of parathyroid gland into neck or forearm ○ Rapid intraoperative PTH measurements decrease risk of missing multiglandular disease and help confirm removal of diseased parathyroid gland(s) ○ Difficult or impossible to differentiate primary hyperplasia from adenoma based only on histologic examination of 1 gland ○ Residual tissue may become hyperplastic, requiring additional surgery

Primary Parathyroid Hyperplasia • 50% show symmetric enlargement of all 4 glands although others report that, in 2/3 of cases, only 2 glands appeared enlarged • Asymmetric hyperplasia or pseudoadenomatous variant of hyperplasia with marked variation in extent of glandular involvement is easily confused with adenoma or multiple adenomas ○ MEN1-associated hyperplasia/multiglandular disease often asymmetric • Surgeons and pathologists must be cautious in evaluating parathyroid glands in relation to size and cellularity, as these parameters can vary greatly within single patient with parathyroid hyperplasia ○ Asymmetrically enlarged gland can be misinterpreted as parathyroid adenoma • Occult pattern of involvement may show subtle enlargement and subtle microscopic features of hyperplasia (difficult to differentiate from normal) • Cystic change not uncommon

MICROSCOPIC Histologic Features • Normal parathyroid gland ○ Can show significant variation in cellularity even in single individual ○ Normal parathyroid cellularity variable, distributed unevenly, high in infants and children, decreases with age ○ Age, sex, constitutional factors (body fat), etc. affect cellularity of normal parathyroid glands ○ Stromal fat constitutes 10-30% of parathyroid, increases with age ○ More stromal fat in polar regions of parathyroid than central regions • Constituent cells of parathyroid gland ○ Parathyroid glands composed of chief, transitional, and oxyphil cells and adipose tissue ○ Chief cells: 10 μm, polyhedral, round central nuclei, eosinophilic to amphophilic cytoplasm, fat droplets (adults), well-defined cytoplasmic membranes

Primary Parathyroid Hyperplasia – Multiple enlarged parathyroid glands associated with hyperplasia, with parenchymal cells having abundant vacuolated, clear cytoplasm – Not known to be associated with MEN syndromes – No malignant potential ○ Lipohyperplasia – Enlarged parathyroid glands with hyperparathyroidism, but abundant stromal fat of lipohyperplasia (or lipoadenoma) can be confused with normal parathyroid tissue

ANCILLARY TESTS Frozen Sections • Assessing cellularity in small biopsies ○ Cellularity variable within parathyroid gland and among glands in single individual ○ Polar regions of parathyroid more cellular than central regions ○ Cellularity increases with age and varies with sex, ethnicity, and body habitus • Differentiating parathyroid from thyroid on small biopsies ○ Parathyroid has well-defined cytoplasmic membranes ○ Cytoplasmic lipid (fat droplets) common in parathyroid parenchymal cytoplasm (not thyroid) ○ Parathyroid cells generally smaller and more vacuolated than thyroid ○ Parathyroid nuclei rounder with denser chromatin than thyroid ○ Parathyroid lacks calcium oxylate crystals of thyroid

Diagnoses Associated With Syndromes by Organ: Endocrine

○ Oxyphil cells: 10-20 μm, abundant eosinophilic cytoplasm, appear at puberty, increase with age, and may form nodules ○ Transitional cells: Smaller parenchymal cells with less cytoplasm ○ Clear/water-clear cells: Parenchymal cells with clear cytoplasm (may be due to increased vacuolization in chief or oxyphilic cells) • Primary parathyroid hyperplasia histology ○ Increase in parenchymal cell mass of multiple parathyroid glands ○ Chief cell is predominant, but oxyphil, transitional, and clear cells may be present ○ Sporadic and hereditary forms of primary hyperplasia histologically indistinguishable – Parathyroid hyperplasia in MEN1 usually involves increased numbers of chief cells that may have nodular or diffuse pattern – MEN1-associated hyperplasia often asymmetric ○ Hyperplastic chief cells arranged in cords, nests, sheets, or follicular structures ○ Cystic change can be seen ○ Nodular or diffuse growth (nodular is most common pattern in primary hyperplasia) – Nodules usually pure populations of chief, oxyphil, or clear cells (less fat in nodules than internodular or diffuse areas) – Caution: As oxyphil cells increase with age, may form nodules (do not confuse with hyperplastic gland) – Study of sporadic hyperplasia found diffuse growth more prevalent in young patients with moderate hypercalcemia and moderately enlarged glands with little variability in gland size or morphologic patterns – Nodular hyperplasia is more frequent in elderly patients and has asymmetric, variable cellularity with more oxyphil cells – MEN1 cases usually show increase in chief cells and may have nodular or diffuse growth pattern (often asymmetric hyperplasia) – Primary water-clear cell hyperplasia shows increase in clear cells and diffuse rather than nodular growth ○ Stromal fat is decreased, but regional variations occur in stromal fat even among glands in single individual (pitfall in evaluating small biopsies) ○ Scattered mitotic figures may be seen, but more mitoses and atypical mitoses are seen in carcinoma ○ Cells show slight variation in size and shape ○ Foci of endocrine atypia with pleomorphism and hyperchromasia (more common in adenomas) ○ Rim of normal parathyroid tissue can be seen although less common than in adenoma ○ Fibrosis and hemosiderin, especially in markedly enlarged glands or glands with cystic degeneration ○ Cystic change uncommon but can be seen in markedly enlarged glands ○ No capsular, vascular, or perineural invasion or invasion into adjacent structures ○ Histologic features in HPT-JT-associated cases similar to sporadic lesions, but HPT-JT cases are often cystic • Primary parathyroid hyperplasia variants ○ Clear (water-clear) cell hyperplasia

Immunohistochemistry • Positive for chromogranin and synaptophysin • Positive for PTH • Positive for keratin (CAM5.2 most helpful keratin for neuroendocrine tumors) • Negative for thyroid transcription factor-1, thyroglobulin, variable calcitonin • p27, cyclin-dependent kinase inhibitor that helps regulate transition from G1 to S phase of cell cycle, is highest normal parathyroid followed by hyperplasia, adenoma, and carcinoma • Ki-67 lower in hyperplasia and adenomas than carcinomas • Loss of parafibromin IHC expression is significantly higher in parathyroid carcinoma than in adenomas and hyperplasia

Genetic Testing • Parathyroid hyperplasia often polyclonal, but monoclonality identified, particularly in nodular areas and in MEN1 (multiglandular parathyroid tumors) • Specific genetic abnormalities in idiopathic primary parathyroid hyperplasia not as well defined as in hereditary forms of hyperparathyroidism • MEN1 mutation (tumor suppressor gene, 11q13, results in truncated menin protein) ○ Primary parathyroid hyperplasia (multiglandular parathyroid tumors) is most common manifestation of MEN1 (90% of MEN1 cases have hyperplasia) – Autosomal dominant, high-penetrance, germline mutation in MEN1 tumor suppressor gene (11q13) encodes menin (truncated with MEN1 mutation) 145

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Parathyroid Hyperplasia

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•

146

– Sporadic MEN1 cases due to new mutations – Although classically referred to as parathyroid hyperplasia, recent studies demonstrate clonality (multiglandular parathyroid tumors) ○ Somatic MEN1 mutations occur in 15-20% of sporadic parathyroid adenomas and some sporadic parathyroid carcinomas ○ Genetic diagnosis to identify germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical, and radiological screening ○ MEN1 mutation detection rate increases with family history of MEN1 ○ MEN1 mutation detection rate increases with number of MEN1-related tumors and in patients with both parathyroid and pancreatic neuroendocrine tumors CDKN1B mutation ○ Germline inactivating mutation of CDKN1B RET mutation (protooncogene, 10q21) ○ RET germline activating protooncogene mutation in MEN2A (autosomal dominant with high penetrance, 95% of patients have mutation in exon 10 or 11, codon 634) – 20-30% of MEN2A cases associated with parathyroid hyperplasia or adenoma ○ RET mutation is generally not identified in sporadic parathyroid disease CDC73 (HRPT2) mutation (tumor suppressor gene, 1q21q31, encodes parafibromin) ○ Germline CDC73 inactivating mutation in HPT-JTassociated hyperplasia, adenoma, and carcinoma ○ Strong association between CDC73 mutations and familial and sporadic parathyroid cancer ○ Germline CDC73 mutations identified in subset of patients with mutation-positive carcinomas FIHP ○ ~ 20% of families have GCM2 activating mutations ○ Cause unknown in most, but CDC73, MEN1, and area on chromosome 2 implicated CASR ○ Inactivating CASR (3q13.3-21) mutation causes decreased calcium sensitivity of parathyroid and kidney, resulting in PTH-dependent hypercalcemia ○ Heterozygous inactivating CASR mutations occur in FHH – Homozygous inactivating mutations occur in neonatal severe hyperparathyroidism – Activating CASR mutations occur in familial autosomal dominant hypoparathyroidism and familial hypocalcemia ○ CASR mutations generally not seen in sporadic parathyroid disease Cyclin-D1/CCND1 ○ Encodes cyclin-D1, cell cycle regulator from G1 to S phase ○ Cyclin-D1 overexpression has been observed in hyperplastic parathyroid glands, but lack of definitive correlation limits utility

DIFFERENTIAL DIAGNOSIS Parathyroid Adenoma • Benign neoplasm composed of chief, oxyphil, transitional, and water-clear cells or mixture of cell types affecting single parathyroid gland • Difficult/impossible to differentiate primary parathyroid hyperplasia from parathyroid adenoma based only on histologic examination of 1 gland ○ Distinguishing parathyroid adenoma from hyperplasia usually requires examination of at least 1 additional gland, which should be normal ○ Hyperplasia shows enlargement of at least 2 glands, while adenoma typically involves single gland • Rim of normal tissue in 50-60% of parathyroid adenomas but can occasionally be seen in hyperplasia

Double or Triple Parathyroid Adenoma • Rare; strongly consider asymmetric hyperplasia before diagnosing multiple adenomas • Occasional glands of parathyroid hyperplasia may show rims of normal parathyroid tissue (rims not specific for adenomas) • Diagnosis requires resolution of hypercalcemia and hyperparathyroidism and long-term follow-up to be certain no other glands involved

Primary Clear Cell Hyperplasia • Diffuse increase in clear cells rather than nodular growth of predominantly chief cells in primary chief cell hyperplasia

Lipohyperplasia • Rare; can occur as sporadic form and with familial benign hypocalciuric hypercalcemia • Increase in adipose tissue and myxoid change in parathyroid glands associated with hyperfunction • Enlarged parathyroid glands with abundant stromal fat can be microscopically confused with normal parathyroid

Secondary Parathyroid Hyperplasia • Secondary increase in PTH due to hypocalcemia and hyperphosphatemia (renal failure, vitamin D deficiency, pseudohypoparathyroidism, etc.) • Increased PTH due to low serum calcium caused by ○ Disorders of vitamin D (rickets, vitamin D deficiency, or malabsorption) ○ Disorders of phosphate metabolism (malnutrition or malabsorption, renal disease, aluminum toxicity) ○ Tissue resistance to vitamin D, hypomagnesemia, pseudohypoparathyroidism, and calcium deficiency • Often, history of chronic renal failure (most common cause of secondary hyperparathyroidism) • Parathyroid glands show more diffusely hyperplastic changes than in primary hyperparathyroidism • Chief cells usually predominate, but chief cells and oxyphil cells can form nodular areas ○ Nodularity may increase with increasing renal failure, making glands indistinguishable from primary or tertiary hyperplasia

Primary Parathyroid Hyperplasia

• Rare condition in which patients with secondary hyperparathyroidism develop autonomously functioning parathyroid gland

Parathyroid Carcinoma • Often symptomatic, high serum calcium (> 13 mg/dL) • Involves 1 parathyroid gland, not multiple (although rare reports of carcinoma arising in setting of hyperplasia, particularly secondary hyperplasia) • Unequivocal invasion (capsular, vascular, perineural, or invasion into adjacent structures)

Parathyromatosis • Recurrent hyperparathyroidism after subtotal parathyroidectomy may result from multiple small nests of parathyroid cells in neck or mediastinum from lesional tissue left behind or from stimulation of embryonic nests of parathyroid cells

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • 20% of primary hyperplasia cases are associated with MEN1 • Mild, nonspecific symptoms or asymptomatic and identified by screening serum calcium

Pathologic Interpretation Pearls • Normal parathyroid has significant variation in cellularity in and among glands (caution: Small biopsies) • Distinguishing parathyroid tissue from thyroid ○ Well-demarcated cytoplasmic membranes, lacks colloid and cytoplasmic lipid, and has rounder nuclei and denser chromatin • Symmetric enlargement of all 4 glands only in subset of cases; many show enlargement of < 4 glands ○ Be very cautious in attempting to diagnose multiple adenomas (most likely asymmetric hyperplasia) • Rims of normal tissue occasionally seen in parathyroid hyperplasia • Be aware of parathyroid hyperplasia variants ○ Lipohyperplasia ○ Clear cell hyperplasia

10. Iacobone M et al: Surgical approaches in hereditary endocrine tumors. Updates Surg. 69(2):181-91, 2017 11. Simonds WF: Genetics of hyperparathyroidism, including parathyroid cancer. Endocrinol Metab Clin North Am. 46(2):405-18, 2017 12. Zanocco KA et al: Primary hyperparathyroidism: effects on bone health. Endocrinol Metab Clin North Am. 46(1):87-104, 2017 13. Wilhelm SM et al: The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 151(10):959-68, 2016 14. Alevizaki M et al: Primary hyperparathyroidism in MEN2 syndromes. Recent Results Cancer Res. 204:179-86, 2015 15. Duan K et al: Clinicopathological correlates of hyperparathyroidism. J Clin Pathol. 68(10):771-87, 2015 16. Lassen T et al: Primary hyperparathyroidism in young people. when should we perform genetic testing for multiple endocrine neoplasia 1 (MEN-1)? J Clin Endocrinol Metab. 99(11):3983-7, 2014 17. Thakker RV: Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 386(1-2):2-15, 2013 18. Williams BA et al: Surgical management of primary hyperparathyroidism in Canada. J Otolaryngol Head Neck Surg. 43(1):44, 2014 19. Ezzat T et al: Primary hyperparathyroidism with water clear cell content: the impact of histological diagnosis on clinical management and outcome. Ann R Coll Surg Engl. 95(3):e60-2, 2013 20. Hibi Y et al: Increased protein kinase A type Iα regulatory subunit expression in parathyroid gland adenomas of patients with primary hyperparathyroidism. Endocr J. 60(2):215-23, 2013 21. DeLellis RA: Parathyroid tumors and related disorders. Mod Pathol. 24 Suppl 2:S78-93, 2011 22. Kauffmann RM et al: Parathyroid carcinoma arising from four-gland hyperplasia. Endocr Pract. 17(2):e37-42, 2011 23. Zhang Y et al: Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 18(3):206-18, 2011 24. Westin G et al: Molecular genetics of parathyroid disease. World J Surg. 33(11):2224-33, 2009 25. DeLellis RA et al: Primary hyperparathyroidism: a current perspective. Arch Pathol Lab Med. 132(8):1251-62, 2008 26. Gill AJ et al: Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol. 30(9):1140-9, 2006 27. DeLellis RA: Tumors of the parathyroid gland. In AFIP Atlas of Tumor Pathology Series 3, Fascicle 6. Washington, DC: American Registry of Pathology, 1-102, 1991 28. Woolner LB et al: Tumors and hyperplasia of the parathyroid glands; a review of the pathological findings in 140 cases of primary hyperparathyroidism. Cancer. 5(6):1069-88, 1952 29. Albright F et al: Hyperparathyroidism due to diffuse hyperplasia of all parathyroid glands rather than adenoma of one. Clinical studies on three such cases. Arch Intern Med. 45:315-29, 1934

Diagnoses Associated With Syndromes by Organ: Endocrine

Tertiary Hyperplasia

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Masi L: Primary hyperparathyroidism. Front Horm Res. 51:1-12, 2019 Pyo JS et al: Diagnostic and prognostic implications of parafibromin immunohistochemistry in parathyroid carcinoma. Biosci Rep. 39(4), 2019 Yu Q et al: Parathyroid neoplasms: immunohistochemical characterization and long noncoding RNA (lncRNA) expression. Endocr Pathol. 30(2):96-105, 2019 Cinque L et al: Molecular pathogenesis of parathyroid tumours. Best Pract Res Clin Endocrinol Metab. 32(6):891-908, 2018 DeLellis RA et al: Heritable forms of primary hyperparathyroidism: a current perspective. Histopathology. 72(1):117-32, 2018 Mizamtsidi M et al: Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks. Endocr Connect. 7(2):R56-68, 2018 Akpinar G et al: Proteomics analysis of tissue samples reveals changes in mitochondrial protein levels in parathyroid hyperplasia over adenoma. Cancer Genomics Proteomics. 14(3):197-211, 2017 Alhefdhi A et al: Intraoperative parathyroid hormone levels at 5 min can identify multigland disease. Ann Surg Oncol. 24(3):733-8, 2017 Boutzios G et al: Primary hyperparathyroidism caused by enormous unilateral water-clear cell parathyroid hyperplasia. BMC Endocr Disord. 17(1):57, 2017

147

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Parathyroid Hyperplasia

Primary Chief Cell Hyperplasia

Diffuse Growth Pattern in Parathyroid Hyperplasia

Nodular Growth in Parathyroid Hyperplasia

Parathyroid Hyperplasia With Nodular Growth

Parathyroid Hyperplasia With Rim-Like Area

Primary Chief Cell Parathyroid Hyperplasia

(Left) Parathyroid hyperplasia shows diffuse increase in chief cells. Diffuse growth can be seen in primary parathyroid hyperplasia but is common in secondary parathyroid hyperplasia. (Right) Diffuse growth can be seen in primary and secondary parathyroid hyperplasia. Scattered single and small nests of fat cells are identified throughout the gland.

(Left) Primary parathyroid hyperplasia with a nodular growth pattern is shown. Diffuse growth can also be seen. The nodules are composed of chief cells ﬊, as well as nodules of oxyphil cells ﬇. (Right) Primary parathyroid hyperplasia with a nodular pattern of growth is shown.

(Left) A rim of normalappearing parathyroid tissue ﬊ is frequently seen in parathyroid adenoma; this can occasionally be seen in hyperplastic glands. (Right) Parathyroid chief cells are the predominant cell type in parathyroid hyperplasia.

148

Primary Parathyroid Hyperplasia

Chief Cell Parathyroid Hyperplasia (Left) Hyperplastic parathyroid with edematous change is shown. (Right) This hyperplastic parathyroid gland is composed predominantly of chief cells, but mixtures of chief, oxyphil, transitional, and clear cell types can occur.

Chief Cell Parathyroid Hyperplasia

Diagnoses Associated With Syndromes by Organ: Endocrine

Hyperplastic Parathyroid With Edematous Change

Primary Parathyroid Hyperplasia (Left) Chief cells are the predominant cell in most primary parathyroid hyperplasias, both with a nodular and with a diffuse growth pattern. (Right) Primary parathyroid hyperplasia with nodular and diffuse growth is shown.

Parathyroid Hyperplasia With Fibrosis and Calcification

Hemosiderin and Fibrosis in Parathyroid Hyperplasia (Left) Hyperplastic parathyroid gland shows fibrosis ﬈ and calcification ﬊, degenerative features that can be seen in hyperplastic parathyroid glands. (Right) Fibrosis ﬊ and hemosiderin deposition ﬈ in parathyroid hyperplasia are shown. Degenerative features can be seen in hyperplastic parathyroid glands, but invasive growth is only seen in parathyroid carcinoma.

149

Diagnoses Associated With Syndromes by Organ: Endocrine

Primary Parathyroid Hyperplasia

Primary Parathyroid Hyperplasia

Chief Cells in Parathyroid Hyperplasia

Chief and Oxyphilic Cells in Parathyroid Hyperplasia

Palisading of Nuclei in Parathyroid Hyperplasia

Parathyroid Hyperplasia With Scattered Adipocytes

Follicular Structures in Parathyroid Hyperplasia

(Left) Parathyroid gland with a nodular growth pattern shows nodules of chief cells ﬈, oxyphil cells ſt, and transitional cells ﬊. (Right) Diffuse growth of chief cells in a parathyroid gland involved by primary parathyroid hyperplasia is shown.

(Left) Chief ﬇ and oxyphilic ﬊ parathyroid cells in a gland involved by primary parathyroid hyperplasia are shown. (Right) Parathyroid gland shows an area of palisading of nuclei around vascular structures.

(Left) Parathyroid hyperplasia shows increase in parathyroid parenchymal cells and scattered single and small groups of adipocytes. (Right) Parathyroid hyperplasia with follicular/glandular structures is shown.

150

Primary Parathyroid Hyperplasia

Chief Cells and Oxyphil Cells (Left) Follicular/glandular growth pattern is shown in a parathyroid gland from a patient with parathyroid hyperplasia. (Right) Chief cells ﬊ and oxyphil cells ﬈ are shown in parathyroid hyperplasia.

Oxyphilic Cells in Parathyroid Hyperplasia

Diagnoses Associated With Syndromes by Organ: Endocrine

Follicular Growth Pattern

Oxyphilic/Oncocytic Cells (Left) Hyperplastic parathyroid gland shows predominantly oxyphilic cells. The nuclei are mildly pleomorphic, but markedly increased nuclear:cytoplasmic ratios and mitotic figures are not identified. (Right) High-power view shows oxyphilic cells in parathyroid hyperplasia.

Clear Cell Parathyroid Hyperplasia

Parathyroid Clear Cells (Left) Clear cell parathyroid hyperplasia shows a diffuse increase in clear (water-clear) cells in multiple parathyroid glands. (Right) Clear cells are identified in this hyperplastic parathyroid gland.

151

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Table Familial and Hereditary Forms of Primary Hyperparathyroidism Familial Syndrome

Clinical-Pathologic Features

Known Genetics

Familial hypocalciuric hypercalcemia (FHH) 

Expresses primary hyperparathyroidism beginning at birth with lifelong hypercalcemia; reflects dysregulation of PTH secretion with little or no parathyroid overgrowth; surgery remains treatment of choice in all familial forms except FHH

Reflects germline heterozygous mutation in CASR, GNA11, or AP2S1

Neonatal severe primary hyperparathyroidism (NSHPT)

This is severest of 6 syndromes; it requires urgent total parathyroidectomy in infancy

Reflects biallelic inactivation of CASR

Multiple endocrine neoplasia type 1 (MEN1) 

Hyperparathyroidism manifests at  younger age Predisposed by germline inactivation of MEN1 and affects both sexes equally; is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroid glands; surgery is treatment of choice

Multiple endocrine neoplasia type 4 (MEN4)

PHPT with enlargement of 3-4 parathyroid glands;  surgery is treatment of choice

Multiple endocrine neoplasia type 2A (MEN2A)

Rarely presents as familial hyperparathyroidism; Predisposed by RET-activating mutation surgery is treatment of choice

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) 

Hyperparathyroidism manifests at younger age and affects both sexes equally; ~ 20% develop parathyroid cancer; surgery is treatment of choice

Predisposed by inactivating mutation in CDC73

Familial isolated hyperparathyroidism (FIHP)

It causes multiple parathyroid tumors; surgery is treatment of choice

In ~ 20% of families. it reflects GCM2-activating mutation; can be incomplete expression of FHH, MEN1, HPT-JT; or even of relatives without shared driver mutation

It is predisposed by germline by inactivation of cyclin-dependent kinase inhibitor CDKN1B

Familial primary hyperparathyroidism occurs in an isolated nonsyndromic form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome. These familial syndromes exhibit Mendelian inheritance patterns.  The causative genes in most families have been identified.   Pathologists play a major role identifying these diseases.  The early diagnosis of these diseases is of major importance for planning surveillance of the carriers and for correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. 

Syndromes Associated With Primary Hyperparathyroidism  Syndrome

152

Gene

Locus

Parathyroid Pathology

Associated Tumors

Multiple endocrine neoplasia type MEN1 1 (MEN1)

11q13

Parathyroid hyperplasia or adenomas

Pituitary adenoma, pancreatic endocrine tumors, duodenal endocrine tumors, adrenal cortical tumors

Multiple endocrine neoplasia type CDKN1B 4 (MEN4)

12p13

Parathyroid hyperplasia or adenoma

Spectrum similar to that of MEN1 in association with tumors of adrenal, kidney, and reproductive organs

Multiple endocrine neoplasia type RET 2A  (MEN2a)

10q11.2

Parathyroid hyperplasia or adenoma

Medullary thyroid carcinoma, pheochromocytoma

Hyperparathyroidism-jaw tumor syndrome (HPT-JT)

CDC73 (HRPT2)

1q25-q32

Parathyroid adenoma, usually cystic or parathyroid carcinoma 

Ossifying fibromas of jaw, renal cysts, and renal and endometrial tumors

Parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors

CDC73 (HRPT2)

1q25-q32

Parathyroid tumor with cells with eosinophilic cytoplasm demonstrating a sheet-like growth pattern with distinctive perinuclear clearing and characteristic nuclear changes

Should be considered likely part of HPT-JT syndrome

Familial benign hypocalciuric hypercalcemia (FBHH)

CASR GNA11 AP2S1

3q13.3-q21

Parathyroid hyperplasia, mild

Parathyroid Table

Syndrome

Gene

Locus

Parathyroid Pathology

Neonatal severe primary hyperparathyroidism (NSHPT)

CASR

3q13.3-q21

Parathyroid hyperplasia

Associated Tumors

Familial isolated hyperparathyroidism (FIHP)

GCM2 Others

6p24.2

Parathyroid hyperplasia; parathyroid carcinoma

Differential Diagnosis: Parathyroid Adenoma and Parathyroid Carcinoma Feature

Parathyroid Adenoma

Parathyroid Carcinoma

Symptoms

Usually vague

Often symptomatic

Serum calcium

Elevated

Markedly elevated (> 13 mg/dL)

Palpable mass

Unusual

Yes

Tumor size

Enlarged

Larger but may overlap

Invasion into adjacent structures

No (but can have irregular growth and cells in capsule due to degenerative features)

Yes

Fibrous bands

Can be present due to degenerative features

Yes

Perineural invasion

No

Yes

Vascular invasion

No

Yes

Growth pattern

Patterns of growth (follicular, acinar, etc.)

Monotonous, sheet-like growth

Cellular features

Often mixed cell types, can show "endocrine atypia"

Often monotonous cytomorphology, prominent nucleoli

Mitoses

Few, scattered

Yes, more mitoses than adenomas

Proliferation markers (Ki-67, MIB1)

Low

Moderate to high

Parafibromin (CDC73) protein expression

Parathyroid adenoma usually shows intact nuclear and nucleolar parafibromin expression

Complete loss of nuclear or nucleolar parafibromin expression in parathyroid carcinoma

Diagnoses Associated With Syndromes by Organ: Endocrine

Syndromes Associated With Primary Hyperparathyroidism  (Continued)

Differential Diagnosis: Parathyroid and Thyroid Immunohistochemistry Tissue

Keratin

Parathyroid cells and tumors

TTF-1

pax-8

PTH

Chromogranin

Synaptophysin

Calcitonin

Positive Negative (particularly low-molecularweight keratins, e.g., CAM5.2)

Negative

Positive but often not overly robust stain

Positive

Positive

Negative

Thyroid follicular cells and neoplasms

Positive

Positive (strong nuclear staining)

Positive

Negative

Negative

Negative

Negative

Medullary thyroid carcinoma

Positive (particularly low-molecularweight keratins, e.g., CAM5.2)

Positive (nuclear Negative staining; may not be as strong as in follicular cells and neoplasms)

Negative

Positive

Positive

Positive

Differential Diagnosis: Parathyroid Carcinoma Tumor

Chromogranin

Synaptophysin

Parathyroid Hormone

Thyroglobulin

TTF-1

Calcitonin

Parathyroid carcinoma

Positive

Positive

Positive

Negative

Negative

Negative

Medullary thyroid carcinoma

Positive

Positive

Negative

Negative

Positive

Positive

Follicular, Hürthle, or papillary thyroid carcinoma

Negative

Negative

Negative

Positive

Positive

Negative

Metastatic carcinoma

Usually negative

Usually negative

Negative

Negative

Positive/negative Negative

153

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Table

154

Differential Diagnosis: Tumors Secondarily Involving Parathyroid Tumor/Tissue

Chromogranin

Synaptophysin

Cytokeratin

Calcitonin

Other

Parathyroid

Positive

Positive

Positive (CAM5.2) Negative

TTF-1

Negative but variable

Parathyroid hormone

Breast carcinoma

Negative

Negative

Variable

Negative

Negative

Mammoglobulin, GCDFP-15, estrogen

Follicular/papillary thyroid

Negative

Positive

Positive

Positive

Negative

Thyroglobulin

Medullary thyroid

Positive

Positive

Positive (CAM5.2) Positive

Positive

CEA

Hepatocellular carcinoma

Negative

Negative

Positive

Negative

Negative

Hep-Par1, albumin

Prostatic adenocarcinoma

Negative

Negative

Positive

Negative

Negative

PSA, PAP

Malignant melanoma

Negative

Negative

Negative

Negative

Negative

S100, Melan-A, HMB-45

Hematolymphoid

Negative

Negative

Negative

Negative

Negative

CD45 (LCA)

Parathyroid Table

Parathyroid Adenoma (Left) Most parathyroid carcinomas (PC) are sporadic, but these may occur as part of a complex hereditary syndrome. Syndromic and hereditary forms of PC are associated with germline mutations of CDC73 (HRPT2), MEN1, and RET. There is an increased incidence of PC in patients with hyperparathyroidism-jaw tumor syndrome. (Right) Graphic shows parathyroid adenoma ﬇ and a normal parathyroid gland ﬊. Parathyroid adenoma is a benign neoplasm and affects a single parathyroid gland.

Parathyroid Adenoma

Diagnoses Associated With Syndromes by Organ: Endocrine

Evaluating Hyperparathyroidism in Young Patients

Enlarged Parathyroid Gland (Left) Parathyroid adenoma is a benign neoplasm usually affecting a single parathyroid gland. Gross photo shows a tan to red-tan tumor covered by a thin capsule. (Right) Cut surface of a parathyroid adenoma shows a homogeneous yellow-orange surface with focal areas of hemorrhage. A small rim of normal parathyroid is appreciated ﬇.

Parathyroid Adenoma With Normocellular Rim

Cellular Morphology (Left) Adenoma usually has an associated rim of normocellular parathyroid. H&E illustrates a chief cell parathyroid adenoma with a rim of normocellular parathyroid tissue ﬈. Parathyroid adenomas are usually composed of chief cells. Cells in the rim are usually smaller than those within the adenoma. (Right) Chief cell adenoma with a nested growth pattern shows prominent vascularity st. The nuclei are small, round, and dense. The cells show no nuclear pleomorphism or mitosis.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Table

Asymmetric Parathyroid Gland Hyperplasia

Nodular Parathyroid Hyperplasia in MEN1

Symmetric Enlargement

Parathyroid Adenoma in HPT-JT

Parafibromin-Deficient Parathyroid Tumor in HPT-JT

Parafibromin-Deficient Parathyroid Tumor

(Left) Parathyroid hyperplasia is characterized by asymmetric hyperplasia with marked variation in extension of glandular involvement (pseudoadenomatous variant). The asymmetric hyperplasia is easily confused with adenoma or multiple adenomas. (Right) Parathyroid hyperplasia in MEN1 usually shows nodular growth pattern. The nodules are composed of populations of chief cells ﬊, which predominate, as well as nodules of oxyphil cells ﬉.

(Left) In primary parathyroid hyperplasia, ~ 50% of patients present with symmetric enlargement of all 4 parathyroid glands, as seen here, which differs from asymmetric hyperplasia. (Right) Cystic change is particularly common in larger parathyroid adenomas and those associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). H&E illustrates a chief cell adenoma with cystic changes in a patient with HPT-JT.

(Left) Parafibromin-negative tumors usually demonstrate distinctive morphology, including extensive sheet-like growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, prominent arborizing vasculature, microcystic change, and, frequently, a thick capsule. (Right) By morphologic features and IHC profile, this tumor can be classified as parafibromindeficient (HPT-JT type, CDC73 mutated) parathyroid tumor.

156

Parathyroid Table

Capsular and Vascular Invasion (Left) Cut surface of a parathyroid carcinoma shows a firm, yellow, nodular surface. Parathyroid carcinomas are usually larger than parathyroid adenoma and show unequivocal capsular invasion, vascular invasion, perineural invasion, or invasion into adjacent structures. (Courtesy L. Erickson, MD.) (Right) Parathyroid carcinoma is characterized by capsular and vascular invasion. H&E illustrates a parathyroid carcinoma tumor invading through the tumor capsule ﬇ into the vascular space ﬊.

Lymphovascular Invasion in Parathyroid Carcinoma

Diagnoses Associated With Syndromes by Organ: Endocrine

Parathyroid Carcinoma: Gross Appearance

Ki-67 Proliferative Index in Parathyroid Carcinoma (Left) Characteristics of carcinoma include hypercellular parathyroid with invasive growth into adjacent structures and capsular, vascular, or perineural invasion. Parathyroid tumors, of which 15% are carcinomas, are generally the 1st manifestation and occur in > 90% of HPT-JT cases. (Right) Parathyroid carcinomas usually have a higher Ki-67 proliferative index than adenomas, including numerous mitoses. Carcinomas have a Ki-67 proliferative index that is usually < 20%.

p53 Immunoexpression in Carcinoma

Loss of Parafibromin in Carcinoma in HPTJT (Left) Immunoexpression of p53 is not seen in adenoma, whereas some parathyroid carcinomas overexpress p53. The tumor cells are positive for p53, while the endothelial cells ﬈ are negative. (Right) Loss of nuclear parafibromin is usually seen in CDC73associated parathyroid carcinoma and adenoma. Sporadic parathyroid adenomas are usually positive for parafibromin, whereas some sporadic carcinomas show loss of parafibromin.

157

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Adenoma KEY FACTS

• Pituitary adenoma (PA) is neoplastic proliferation of anterior pituitary hormone-producing cells (WHO 2017) • Tumors are typically benign but can be aggressive and invasive into adjacent structures

○ Neurofibromatosis type 1 • PAs may occur as isolated PAs ○ Familial isolated PA ○ Isolated familial somatotropinoma syndrome ○ X-linked acrogigantism syndrome

ETIOLOGY/PATHOGENESIS

CLINICAL ISSUES

• PAs may be sporadic: Activating mutations of common oncogenes, including ○ GNAS mutations in ~ 40% of sporadic GH-PAs ○ USP8 mutations in up to 62% of sporadic ACTH-PAs • PAs may be associated with familial syndromes ○ Multiple endocrine neoplasia type 1 ○ Multiple endocrine neoplasia type 4 ○ McCune-Albright syndrome ○ Carney complex ○ DICER1 syndrome ○ SDH-related familial paraganglioma and pheochromocytoma syndromes

• Constitute 15% of all intracranial neoplasms • Hypersecretion of pituitary hormones, including ACTH, PRL, GH, and TSH, leading to endocrine syndromes • Mass effects, including hypopituitarism, especially in clinically nonfunctioning adenomas • Surgery is main modality of treatment for most PAs

TERMINOLOGY

ANCILLARY TESTS • Immunohistochemistry for pituitary hormones, pituitary transcription factors (Pit-1, T-Pit, GATA2, SF1), LMWK, Ki-67 • Total breakdown of normal acinar architecture on reticulin stain is diagnostic of PA

Autopsy of Pituitary Macroadenoma

Papillary Appearance

Chromophobic Appearance

Acidophilic Appearance

(Left) Gross photo shows a pituitary macroadenoma that extends upward into the suprasellar cistern and laterally into the cavernous sinus. (Right) Pituitary adenomas may display several histological arrangements. This adenoma shows papillary formations of chromophobic cells.

(Left) Cytoplasmic granularity gives 3 morphologically distinct cell types: Chromophobic, eosinophilic, and basophilic. H&E shows a chromophobic pituitary adenoma with clear cells arranged in a diffuse, sheetlike pattern. (Right) H&E shows acidophilic pituitary adenoma composed of cells that exhibit bright cytoplasmic eosinophilia.

158

Pituitary Adenoma

Abbreviations • Pituitary adenoma (PA)

Definitions • PA is neoplastic proliferation of anterior pituitary hormoneproducing cells (WHO 2017) • Tumors are typically benign but can be aggressive and invasive into adjacent structures • Usually arise in sella turcica but occasionally seen as ectopic lesion

ETIOLOGY/PATHOGENESIS Etiology • Genetic, epigenetic factors, hormonal stimulation, growth factors, and their receptors implicated in pituitary tumorigenesis

Pathogenesis • Most adenomas are sporadic • Hormone regulatory pathways ○ Hormonal stimulus or impaired feedback inhibition on hypothalamic-pituitary-target organ axes may underlie pathogenesis of PAs – Excess GHRH, CRH, TRH, or GnRH production – Target organ failure resulting in increased stimulation of hypothalamic-pituitary axes • Somatic genetics ○ PAs are rarely affected by activating mutations of common oncogenes ○ Somatic mutations in GNAS have been identified in ~ 40% of sporadic somatotroph adenomas ○ Mutations in USP8 (ubiquitin-specific protease 8) have been identified in ~ 36-62% of sporadic corticotroph adenomas ○ Epigenetically silenced tumor suppressors are found in sporadic PAs

Syndromic Diseases • Multiple endocrine neoplasia type 1 ○ Autosomal dominant disorder associated with germline mutation of MEN1 tumor suppressor gene that encodes menin ○ Affected individuals usually develop growth hormone (GH) &/or prolactin (PRL)-secreting PAs • McCune-Albright syndrome ○ Mosaic mutations of GNAS (Gαs protein; Gsp) ○ Affected patients develop somatotroph hyperplasia or somatotroph PAs • Carney complex ○ Autosomal dominant disorder associated with germline mutations in PRKAR1A that encodes protein kinase-A regulatory subunit 1α • Multiple endocrine neoplasia type 4 ○ Autosomal dominant disorder associated with mutations of CDKN1B ○ Rare reported cases of somatotroph adenoma associated with hyperparathyroidism • SDH-related familial paraganglioma and pheochromocytoma syndromes

○ Associated gene mutations include SDHA, SDHB, SDHC, SDHD, and SDHAF2

Isolated Pituitary Disease • Familial isolated PA (FIPA) ○ Autosomal dominant disease with variable penetrance – 20% of patients affected by germline mutations in tumor suppressor aryl hydrocarbon receptor interacting protein (AIP) – No gene abnormality has been identified to date in majority of FIPA families ○ AIP mutation-positive patients have characteristic clinical phenotype with usually young- or childhood-onset GH &/or PRL-secreting adenomas • Isolated familial somatotropinoma syndrome (IFS) ○ ~ 50% of IFS kindreds exhibit mutations in AIP • X-linked acrogigantism syndrome ○ Genetic defect is microduplication in chromosome Xq26.3 with upregulation of GPR101 ○ Majority of patients < 5 years at diagnosis and present with hypersecretion of GH and PRL ○ Affected patients develop mixed somatotrophlactotroph adenomas or pituitary hyperplasia

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

CLINICAL ISSUES Epidemiology • Incidence ○ Common, occurring in almost 20% of general population ○ Constitute 15% of all intracranial neoplasms • Age ○ Majority of cases arise in 5th-7th decades ○ Uncommon in pediatric population – When present, may suggest familial syndrome ○ Incidence increases with age in autopsy studies

Presentation • Clinically functioning adenomas with hypersecretion of pituitary hormones ○ Adrenocorticotrophic (ACTH) excess presents with Cushing disease or Nelson syndrome ○ GH excess causes acromegaly &/or gigantism ○ PRL excess presents with galactorrhea, amenorrhea, hypogonadism, and infertility ○ Thyrotropin (TSH) excess presents with hyperthyroidism and is sometimes associated with galactorrhea and hyperprolactinemia ○ Gonadotropin (FSH, LH) excess is extremely rare and may present with gonadal dysfunction • Clinically nonfunctioning adenomas with mass effect symptoms ○ Visual disturbances, headaches, hypopituitarism • Hypopituitarism due to compression of nontumorous anterior pituitary parenchyma • Mild hyperprolactinemia may be seeing due to compression of pituitary stalk ("stalk effect")

Treatment • Surgery is main modality of treatment for most PAs • Pharmacotherapy is initial treatment for majority of PRLsecreting adenomas and is used as adjuvant therapy when surgery cannot completely resect functioning adenoma 159

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Adenoma • Radiotherapy is used in treatment of patients with incompletely resected or recurrent aggressive neoplasms

Prognosis • Best prognosticator is classification of PAs based on hormone content and cell structure • Some PA subtypes are usually associated with invasive or aggressive behavior ○ Sparsely granulated somatotroph adenoma ○ Lactotroph adenoma in men ○ Acidophil stem cell adenoma ○ Crooke cell adenoma ○ Plurihormonal PIT-1-positive adenoma (previously called silent subtype 3 adenoma)

IMAGING

Metastatic Neuroendocrine Carcinoma • Negativity for pituitary hormones and transcription factors and positivity for other transcription factors (CDX-2, TTF-1, etc.) favors metastatic neuroendocrine carcinoma

SELECTED REFERENCES 1. 2. 3. 4.

5. 6.

Radiographic Findings

7.

• PAs are classified radiologically based on tumor size and degree of local invasion (Hardy classification)

8.

MACROSCOPIC

9.

General Features • PAs are usually resected as multiple small pieces; majority of PAs exhibit soft, tan gross appearance

10. 11.

MICROSCOPIC Histologic Features • Solid, diffuse, trabecular, sinusoidal, papillary growth patterns are common • Adenoma reveals breakdown of normal acinar architecture on Gordon-Sweet silver stain ○ This distinguishes neoplasia from hyperplasia that retains acinar reticulin pattern • Involvement of bone, posterior lobe, dura mater, or respiratory mucosa in invasive PAs • Invasive PAs exhibiting increased mitotic activity &/or MIB1/Ki-67 proliferative index > 3% should be considered highrisk tumor for recurrence and clinically aggressive behavior

12.

13. 14. 15.

16.

17. 18.

ANCILLARY TESTS

19.

Immunohistochemistry

20.

• Most valuable tool in determination of cellular differentiation and classification of PAs ○ Hormones: GH, PRL, TSH-β, FSH-β, LH-β, ACTH, α-subunit ○ Transcription factors: Pit-1, SF1, and T-Pit; other differentiating factors: ER-α, GATA2 • General neuroendocrine markers (chromogranin-A, synaptophysin, and NSE) • Other markers: LMWK (CAM5.2), MIB-1

21.

22. 23.

24. 25.

DIFFERENTIAL DIAGNOSIS Pituitary Hyperplasia • Adenoma reveals total breakdown of normal acinar architecture on silver stain

Spindle Cell Oncocytoma/Pituicytoma • Positive for TTF-1, vimentin, S100, EMA, and galactin-3; focally for GFAP • Negative for chromogranin-A, synaptophysin, and keratin 160

26.

Chen J et al: Pituitary adenoma in pediatric and adolescent populations. J Neuropathol Exp Neurol. 78(7):626-32, 2019 Cuny T et al: Acromegaly in Carney complex. Pituitary. ePub, 2019 Kamilaris CDC et al: Carney complex. Exp Clin Endocrinol Diabetes. 127(203):156-64, 2019 Lemelin A et al: Pheochromocytoma, paragangliomas, and pituitary adenoma: An unusual association in a patient with an SDHD mutation. Case report. Medicine (Baltimore). 98(30):e16594, 2019 Pepe S et al: Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects. J Endocrinol. 240(2):R21-45, 2019 Yarman S et al: Three novel MEN1 variants in AIP-negative familial isolated pituitary adenoma patients. Pathobiology. 86(2-3):128-34, 2019 Hannah-Shmouni F et al: An update on the genetics of benign pituitary adenomas in children and adolescents. Curr Opin Endocr Metab Res. 1:1924, 2018 Lecumberri B et al: Head and neck manifestations of an undiagnosed McCune-Albright syndrome: clinicopathological description and literature review. Virchows Arch. 473(5):645-8, 2018 Maher M et al: A patient with a germline SDHB mutation presenting with an isolated pituitary macroprolactinoma. Endocrinol Diabetes Metab Case Rep. 2018, 2018 Srichomkwun P et al: Cowden syndrome and pituitary tumours. QJM. 111(10):735-6, 2018 Vega-Arroyo M et al: Gigantism in a McCune-Albright's syndrome with calcified GH-releasing pituitary adenoma: Case report and literature review. Int J Surg Case Rep. 53:61-65, 2018 Kiefer FW et al: PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex. Eur J Endocrinol. 177(2):K7-12, 2017 Marques P et al: Genetic aspects of pituitary adenomas. Endocrinol Metab Clin North Am. 46(2):335-74, 2017 Rostomyan L et al: AIP mutations and gigantism. Ann Endocrinol (Paris). 78(2):123-30, 2017 Salvatori R et al: In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction & stability and is associated with gigantism. Eur J Endocrinol. 177(3):257-66, 2017 Schultz KAP et al: PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(12):e76-82, 2017 Tufton N et al: Pituitary carcinoma in a patient with an SDHB Sutation. Endocr Pathol. 28(4):320-5, 2017 Caimari F et al: Novel genetic causes of pituitary adenomas. Clin Cancer Res. 22(20):5030-42, 2016 Gordon RJ et al: Childhood acromegaly due to X-linked acrogigantism: long term follow-up. Pituitary. 19(6):560-4, 2016 Beckers A et al: X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer. 22(3):353-67, 2015 Hernández-Ramírez LC et al: Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab. 100(9):E1242-54, 2015 Ma ZY et al: Recurrent gain-of-function USP8 mutations in Cushing's disease. Cell Res. 25(3):306-17, 2015 Perez-Rivas LG et al: The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing's disease. J Clin Endocrinol Metab. 100(7):E997-1004, 2015 Alband N et al: Familial pituitary tumors. Handb Clin Neurol. 124:339-60, 2014 Xekouki P et al: Succinate dehydrogenase (SDHx) mutations in pituitary tumors: could this be a new role for mitochondrial complex II and/or Krebs cycle defects? Endocr Relat Cancer. 19(6):C33-40, 2012 DiGiovanni R et al: AIP mutations are not identified in patients with sporadic pituitary adenomas. Endocr Pathol. 18(2):76-8, 2007

Pituitary Adenoma

Adenoma Type

Transcription Factor

Hormones

LMWK

Densely granulated somatotroph adenoma

Pit-1

GH, α-SU

Perinuclear

Sparsely granulated somatotroph adenoma

Pit-1

GH

Fibrous bodies

Mammosomatotroph adenoma

Pit-1, ER-α

GH, PRL, α-SU

Mixed somatotroph and lactotroph adenoma

Pit-1, ER-α

GH, PRL, α-SU

Plurihormonal GH-producing adenoma

Pit-1, ER

GH, PRL, α-SU, TSH-β

Sparsely granulated lactotroph adenoma

Pit-1, ER-α

PRL (Golgi pattern)

Densely granulated lactotroph adenoma

Pit-1, ER-α

PRL (diffuse)

GH-Producing Adenomas

PRL-Producing Adenomas

Acidophilic stem cell adenoma

PRL (diffuse), GH (focal)

Fibrous bodies (few)

TSH-Producing Adenoma Thyrotroph adenoma

Pit-1, GATA2

TSH-β, α-SU

ACTH-Producing Adenomas Densely granulated corticotroph adenoma

T-Pit

ACTH

Diffuse pattern

Sparsely granulated corticotroph adenoma

T-Pit

ACTH

Diffuse pattern

Crooke cell adenoma

T-Pit

ACTH

Ring-like pattern

SF1, ER-α, GATA2

LH-β, FSH-β, α-SU

Plurihormonal Pit-1-positive adenoma (previously called silent subtype 3 adenoma)

Pit-1, other

GH, PRL, TSH-β, α-SU, ACTH (rarely)

Unusual plurihormonal adenoma, not otherwise specified

Multiple: Pit-1 and TPIT

Multiple: Usually PRL and ACTH

Absent

Absent

Diagnoses Associated With Syndromes by Organ: Endocrine

Immunohistochemical Classification of Pituitary Adenomas

Gonadotropin-Producing Adenoma Gonadotroph adenoma Plurihormonal Adenomas

Hormone-Negative Adenoma Null cell adenoma GH = growth hormone; PRL = prolactin.

Genetic Predisposition to Pituitary Adenomas Syndromic and Isolated Diseases

Associated Genes

Multiple endocrine neoplasia 1

MEN1

Multiple endocrine neoplasia 4

CDKN1B

SDH-related familial paraganglioma-pheochromocytoma syndromes

SDHA, SDHB, SDHC, SDHD, SDHAF2

DICER1 syndrome

DICER1

Carney complex

PRKAR1A/CNC1; rarely PRKACA and PRKACB

McCune-Albright syndrome

Mosaic GNAS

Neurofibromatosis

NF1

Familial isolated pituitary adenoma

AIP

Isolated familial somatotropinoma syndrome

AIP

X-linked acrogigantism syndrome

GPR101

Modified from WHO 2017.

161

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Adenoma

Normal Pituitary Gland

Pituitary Microadenoma

Neuroimaging of Macroadenoma

Macroadenoma With Suprasellar Extension

Loss of Normal Acinar Pattern

Loss of Normal Acinar Pattern

(Left) The pituitary is composed of neural tissue forming the posterior pituitary (PL) and pituitary stalk, epithelial neuroendocrine tissue forming the anterior lobe (AL), and the cystic remnants of the intermediate lobe (IL). The anterior pituitary is composed of cells with production of diverse hormones. Normal distribution of cells is shown (inset). (Right) Microadenomas are defined as tumors < 1 cm in the largest dimension.

(Left) MR shows a pituitary macroadenoma with suprasellar extension, sphenoid sinus, and cavernous sinus invasion. (Right) Graphic shows a large pituitary macroadenoma extending superiorly to compress the body of the chiasm, thus compressing the bulk of the crossing nasal retinal fibers.

(Left) Pituitary adenomas demonstrate a breakdown of normal acinar architecture. In this example, a microadenoma ſt shows definitive loss of the normal acinar pattern in comparison with the surrounding normal gland ﬇. (Right) Pituitary adenomas demonstrate a total breakdown of normal acinar architecture, as seen in this example, highlighting the loss of Wilder silver stain.

162

Pituitary Adenoma

ACTH Immunohistochemistry (Left) Immunohistochemical stains for pituitary hormones are essential for the diagnosis of pituitary adenoma. In this example, strong and diffuse cytoplasmic reactivity is seen in a densely granulated somatotroph adenoma. (Right) Corticotroph adenomas most commonly are composed of densely granulated cells with diffuse cytoplasmic ACTH immunoreactivity.

PRL Immunohistochemistry

Diagnoses Associated With Syndromes by Organ: Endocrine

Growth Hormone Immunohistochemistry

LH-β Immunohistochemistry (Left) In comparison to the densely granulated cells of corticotroph and somatotroph adenomas, lactotroph adenomas show sparse PRL reactivity with characteristic perinuclear Golgi-type staining. (Right) Gonadotroph adenomas show only focal and sparse immunoreactivity for the gonadotropins, exemplified here by LH-β immunostaining.

Sinus Mucosa Invasion

Bone Invasion (Left) Some pituitary adenomas may be associated with invasive or aggressive behavior and are called invasive pituitary adenomas. Some pituitary adenomas may grow inferiorly and invade the sphenoid sinus mucosa. (Right) H&E shows an invasive pituitary adenoma st within bone marrow surrounded by bone trabeculae ﬊.

163

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Hyperplasia KEY FACTS

ETIOLOGY/PATHOGENESIS

CLINICAL ISSUES

• Physiological stimulation is best represented by lactotroph hyperplasia secondary to estrogen stimulation during pregnancy • Thyrotroph hyperplasia may occur due to untreated primary hypothyroidism • Ectopic secretion of hypothalamic-releasing hormones by neuroendocrine tumors is most common pathologic cause of pituitary hyperplasia • Corticotroph hyperplasia may rarely be associated with Cushing disease • Genetic syndromes ○ Somatotroph hyperplasia may arise in setting of – Multiple endocrine neoplasia type 1 – Multiple endocrine neoplasia type 4 – McCune-Albright syndrome – Carney complex – X-linked acrogigantism syndromes

• Signs and symptoms of pituitary hormone hypersecretion mimicking secreting pituitary adenoma • Identification of source of hypersecretion is crucial for treatment/management

IMAGING • Diffuse enlargement of gland

MICROSCOPIC • Anterior gland is composed of enlarged acini, which are mostly composed of single cell type with preserved reticulin network • Focal or diffuse expansion of acini with preservation of reticulin pattern (reticulin stain)

ANCILLARY TESTS • IHC for pituitary hormones identifies hyperplastic cell population

Pituitary Hyperplasia During Pregnancy

Lactotroph Hyperplasia During Pregnancy

Expansion of Acinar Structure in Pituitary Hyperplasia

Normal Acinar Structure in Pituitary Gland

(Left) H&E shows pituitary gland from a 27-year-old woman who died of DIC after delivery of a healthy baby. Pituitary was enlarged with diffuse expansion of the acini. The majority of the cells have acidophilic cytoplasm with large nuclei, consistent with lactotroph cells. (Right) Prolactin immunostain from the same patient confirms lactotroph hyperplasia of pregnancy. Note that in addition to PRL(+) cells, several PRL(-) cells st are present in the same acini, ruling out a lactotroph adenoma.

(Left) Reticulin stain is crucial for diagnosis of hyperplasia, which shows expansion of the acini and preservation of the reticulin pattern, and its distinction from an adenoma. In comparison, reticulin stain of a normal adenohypophysis shows a relatively uniform distribution of acini. (Right) Reticulin stain of a normal adenohypophysis shows a relatively uniform distribution of acini surrounded by a reticulin network ﬇.

164

Pituitary Hyperplasia

MACROSCOPIC

Definitions

General Features

• Cell proliferation driven by hormonal stimulus • Rare and constitutes < 1% of sellar region surgical specimens

• Pituitary gland is enlarged and lacks well-defined lesion distinguishable from surrounding normal gland

MICROSCOPIC ETIOLOGY/PATHOGENESIS Physiologic or Pathologic Mechanism • Pituitary hyperplasia occurs secondary to hypersecretion of stimulating hormone by either physiologic or pathological mechanism or in genetic syndromes • Physiologic ○ Stimulation due to estrogen secretion – Lactotroph hyperplasia during pregnancy – Hypertrophy of puberty mainly in females • Pathologic ○ Ectopic secretion of hypothalamic-releasing hormones by neuroendocrine tumors is most common pathologic cause of pituitary hyperplasia – e.g., pancreatic and pulmonary growth hormonereleasing hormone (GHRH)-secreting tumors producing somatotroph hyperplasia and pulmonary corticotropin-releasing hormone (CRH)-secreting tumors producing corticotroph hyperplasia ○ Thyrotroph hyperplasia may occur due to untreated primary hypothyroidism ○ Corticotroph hyperplasia may rarely be associated with Cushing disease • Genetic syndromes ○ Somatotroph hyperplasia may arise in setting of multiple endocrine neoplasia types 1 and 4, Carney complex, McCune-Albright, and X-linked acrogigantism syndromes

CLINICAL ISSUES Presentation • Signs and symptoms of pituitary hormone hypersecretion mimicking secreting pituitary adenoma ○ Acromegaly in cases of somatotroph or mammosomatotroph hyperplasia due to hypersecretion of GHRH ○ Cushing disease in cases of corticotroph hyperplasia due to hypersecretion of CRH ○ Primary hypothyroidism is main clinical presentation in cases of thyrotroph hyperplasia ○ Hyperprolactinemia in rare cases of idiopathic lactotroph hyperplasia

Treatment • Identification of source of hypersecretion is crucial for treatment/management ○ Reversal of pituitary hyperplasia and hormonal imbalance should occur after treatment of primary disease

IMAGING

Histologic Features • Anterior gland is composed of enlarged acini, which are composed mostly of single cell type • Focal or diffuse expansion of acini with preservation of reticulin pattern (reticulin stain) • Hyperplasia may be diffuse within gland or focal with formation of nodules

ANCILLARY TESTS Immunohistochemistry • IHC for pituitary hormones identifies hyperplastic cell population, and other markers (S100, CD34) identify cellular components of pituitary gland intermixed between hyperplastic nodules

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Pituitary Adenoma, Including Corticotroph Cell Adenoma • Reticulin stain helps in differentiating hyperplasia from adenoma ○ Differential diagnosis with adenoma is particularly significant in corticotroph cell hyperplasia

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • In pituitary hyperplasia, there is expansion of acini with preservation of reticulin pattern

SELECTED REFERENCES 1. 2.

Cuny T et al: Acromegaly in Carney complex. Pituitary. ePub, 2019 Kamilaris CDC et al: Carney complex. Exp Clin Endocrinol Diabetes. 127(203):156-64, 2019 3. Kinoshita Y et al: Physiologic pituitary hyperplasia causing visual disturbance during adolescence. J Clin Neurosci. 61:279-81, 2019 4. Shivaprasad KS et al: Pituitary hyperplasia from primary hypothyroidism. N Engl J Med. 380(8):e9, 2019 5. Aquilina K et al: Nonneoplastic enlargement of the pituitary gland in children. J Neurosurg Pediatr. 7(5):510-5, 2011 6. Weiss DE et al: Ectopic acromegaly due to a pancreatic neuroendocrine tumor producing growth hormone-releasing hormone. Endocr Pract. 17(1):79-84, 2011 7. Nasr C et al: Acromegaly and somatotroph hyperplasia with adenomatous transformation due to pituitary metastasis of a growth hormone-releasing hormone-secreting pulmonary endocrine carcinoma. J Clin Endocrinol Metab. 91(12):4776-80, 2006 8. Stefaneanu L et al: Pituitary lactotrophs and somatotrophs in pregnancy: a correlative in situ hybridization and immunocytochemical study. Virchows Arch B Cell Pathol Incl Mol Pathol. 62(5):291-6, 1992 9. Sano T et al: Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev. 9(3):357-73, 1988 10. Scheithauer BW et al: Pituitary gland in hypothyroidism. histologic and immunocytologic study. Arch Pathol Lab Med. 109(6):499-504, 1985

General Features • Diffuse enlargement of gland

165

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Table

166

Pituitary Adenoma as Part of Inherited Tumor Syndromes Syndrome

Gene Involved Pituitary Pathology

Other Pathology

Notes

Multiple endocrine neoplasia type 1 (MEN1)

MEN1 (> 80%)

Prolactin-producing adenoma (66%);  GH-producing adenoma;  nonfunctional adenoma

Primary hyperparathyroidism; enteropancreatic neuroendocrine tumors; facial angiofibromas; collagenomas; lipomas

40% of patients with MEN1 develop PA; MEN1 mutation uncommon in sporadic cases

Multiple endocrine neoplasia type 4 (MEN4)

CDKN1B (> 90%)

GH-producing PA; ACTH-producing PA; nonfunctioning PA

Primary hyperparathyroidism is most frequent manifestation in patients with MEN4-adrenocortical tumors; thyroid tumors; gastrointestinal neuroendocrine tumors; uterine tumors  

Few reported cases and families; patients presenting phenotype suggestive of MEN1 but with no MEN1 mutations should be tested for CDKN1B mutations

Carney complex (CNC)

PRKAR1A (> 70%) GH-producing adenoma characterized by multiple microadenomas and somatomammotrope hyperplasia

Autosomal dominant disorder characterized by complex of myxomas, spotty pigmentation, and endocrine overactivity: Myxomas (cardiac, cutaneous, mammary), lentigenes, psammomatous melanotic schwannomaprimary pigmented nodular adrenal cortical disease (PPNAD), adrenal cortical disease, gonadal tumors, thyroid tumors  

Acromegaly occurs in 10% of patients with Carney complex;  pituitary hyperplasia is characteristic; CNC is, in essence, multiple endocrine neoplasia syndrome, but one that affects number of other tissues; genetic heterogeneity with distinct genes: Mutations of PRKAR1A on chromosome 17 (17q24) and 2 other genetic changes: PRKACA and PRKACB

McCune-Albright syndrome (MAS)

GNAS1 (> 90%)

GH-producing adenoma; somatomammotrope hyperplasia

Polyostotic fibrous dysplasia; café-aulait spots; precocious puberty; thyrotoxicosis;adrenal Cushing syndrome: Hallmark of MAS-related adrenal disease is bilateral nodular hyperplasia; characteristic bilateral primary bimorphic adrenocortical disease  

GNAS1 mutation present in 40% of sporadic; high GH and IGF1 levels; patients with this condition have characteristic lesions that affect predominantly 3 systems: Skin, endocrine system, and skeleton; precocious puberty, Cushing syndrome, hyperthyroidism;  association of polyostotic fibrous dysplasia (POFD) and intramuscular myxomas categorized as Mazabraud syndrome

Familial pheochromocytoma paraganglioma syndrome 

SDHA, SDHB, SDHC, SDHD (~ 40%)

PA

Pheochromocytoma; paraganglioma

SDHB and SDHA important new markers for multiple purposes: Triage for genetic testing or surrogate test where testing not available; validate genetic sequence variants of unknown significance (VUS); assess whether any particular tumor part of syndrome or coincidental in patient with known or suspected SDHx mutation

DICER1 syndrome (pleuropulmonary blastoma familial tumor and dysplasia syndrome)

DICER1 (> 90%)

Pituitary blastoma (associated with infantile-onset Cushing disease); appears to be pathognomonic of DICER1 mutation  

Tumors and dysplasias with onset in childhood, adolescence, or early adulthood, including pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, Sertoli-Leydig cell tumor, juvenile granulosa cell tumor (JGCT), gynandroblastoma, multinodular thyroid hyperplasia, thyroid carcinoma, pinealoblastoma

Germline-inactivating DICER1 mutations are responsible for familial tumor susceptibility syndrome with increased risk of tumors; DICER1 mutations documented in endocrine tumors (thyroid, parathyroid, pituitary, pineal gland, endocrine pancreas, paragangliomas, medullary, adrenocortical, ovarian, and testicular tumors)

Familial isolated pituitary adenoma (FIPA)

AIP (~ 20%) GPR101 duplications

GH-producing adenoma;  prolactin-producing adenoma;  other subtypes of PA

None

AIP mutation is present in 15-20% of FIPAs, in 50% of familial acromegaly, and in a small proportion of sporadic PAs; almost 90% are GH-producing PAs; most patients with AIP mutation are men (70%), have macroadenomas (97%), and are younger at time of diagnosis than patients with other PAs; majority (70-

Pituitary Table

Syndrome

Gene Involved Pituitary Pathology

Other Pathology

Notes 75%) of patients have AIP  and GPR101 mutation negative disease  

Isolated familial somatotropinoma syndrome (IFS)

AIP

GH-producing adenoma

X-linked Xq26.3 (100%) acrogigantism (X-LAG) duplications have been identified in GPR101 

None

GH-producing adenoma; GH-hyperplasia; GH-prolactin adenoma

Early childhood onset; disease usually manifests in 1st year of life (median of 36 months) with predisposition for female sex

Familial genetic disorders of the pituitary account for ~ 5% of all pituitary adenomas and are characterized by genetic mutations present in either one or both parents that are passed on to every generation. FIPA = familial isolated pituitary adenoma; GH = growth hormone; IFS = isolated familial somatotropinoma syndrome; MEN4 = =multiple endocrine neoplasia 4; PA = pituitary adenoma.

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Adenoma as Part of Inherited Tumor Syndromes (Continued)

Genetic Abnormalities in Pituitary Adenomas Gene

Molecular Defect

RB1

Loss of 13q14; promoter methylation

CCND1

Allelic imbalance; overexpression

PTTG

Overexpression

FGFR2

Promoter methylation

EGFR

Overexpression

PTAG

Underexpression; promoter methylation

GNAS

Inactivating mutations

Somatic mutation in this gene accounts for up to 40% of somatotropinomas

MEN1

Inactivating mutations

Prolactin-producing adenoma; GH-producing adenoma; nonfunctional adenoma

CDKN1B

Underexpression; germline nonsense mutation

PRKAR1A

Germline mutations

AIP

Germline mutations and LOH

PKC

Point mutation; overexpression

PKC mutation was found in 4 invasive adenomas in one study

RAS

Point mutation; gene amplification

Only H-RAS is implicated in pituitary adenomas; ~ 8% invasive tumors have RAS mutation

PIK3CA

Somatic mutation; gene amplification

~ 10% of invasive pituitary tumors contain PIK3CA mutation; PIK3CA was amplified in 20-40% of invasive and noninvasive tumors

CCNA1

Overexpression

UPS8

Tumor

Mutations in USP8 always have been found most commonly in ~ 60% of corticotroph adenomas causing Cushing disease; USP8 mutation occurs in 36% of functioning tumors, while mutation was not present in any of silent corticotropinomas

167

Diagnoses Associated With Syndromes by Organ: Endocrine

Pituitary Table

Pituitary Cell Differentiation

Pituitary Macroadenoma

Pituitary Macroadenoma

Macroadenoma With Apoplexy

Acidophil Stem Cell Adenoma

TSH-Producing Adenoma

(Left) Pituitary adenoma arising from PIT-1 lineage adenohypophyseal cells expresses mainly GH, PRL, and TSH and exhibits PRL-, GH-, and TSH-containing secretory granules. The familial pituitary adenomas are more frequently from the somatotrophic lineage. (Right) Graphic shows a pituitary adenoma that enlarges the pituitary gland and occupies the entire sella. There is no extrasellar extension.

(Left) Graphic shows a large pituitary macroadenoma extending superiorly to compress the body of the chiasm, thus compressing the bulk of the crossing nasal retinal fibers ﬉. (Right) Graphic shows a large "figure of 8" sellar/suprasellar pituitary macroadenoma with acute hemorrhage causing pituitary apoplexy.

(Left) Acidophil stem cell adenoma is composed of eosinophilic cells that exhibit cytoplasmic vacuolization ﬉ due to mitochondrial dilatation. These tumors also originate from the PIT-1 line of differentiation. (Right) Immunoreactivity for β-TSH varies from cell to cell in thyrotroph adenomas. The staining pattern allows recognition of the angular cell morphology of the tumor cells. Only rare inherited familial tumors are TSH-producing adenomas.

168

Pituitary Table

Somatotroph Adenoma (Left) Familial densely granulated somatotroph adenomas harbor numerous GH-containing secretory granules that correlate with their eosinophilic, densely granulated cytoplasm on conventional histology. (Right) Regardless of the subtype, all GH-producing pituitary adenomas are strongly positive for PIT-1. PIT-1 is also expressed in PRL- and TSHproducing pituitary adenomas and in silent subtype 3 adenomas (aggressive monomorphous PIT-1 lineage plurihormonal adenomas).

Somatotroph Adenoma

Diagnoses Associated With Syndromes by Organ: Endocrine

Somatotroph Adenoma

Somatotroph and Lactotroph Adenoma (Left) Familial densely granulated somatotroph adenomas are positive for αsubunit; however, sparsely granulated somatotroph adenomas are usually negative for α-subunit. (Right) α-subunit is usually negative in PRL-producing adenomas, as well as sparsely granulated GH-producing adenomas. Among the PIT-1 lineage pituitary adenoma members, α-subunit is usually expressed in densely granulated GH- and TSH-producing adenomas.

Lactotroph Adenomas

Lactotroph Adenomas (Left) Familial sparsely granulated lactotroph adenomas are composed of chromophobic cells that reveal typical Golgi-type staining for PRL. (Right) Unlike sparsely granulated lactotroph adenomas, aggressive variants of PRL-producing adenomas (such as densely granulated lactotroph adenomas and acidophil stem cell adenomas) have diffuse cytoplasmic positivity for PRL and usually lack the characteristic Golgi pattern.

169

Diagnoses Associated With Syndromes by Organ: Endocrine

C-Cell Hyperplasia KEY FACTS

TERMINOLOGY

MICROSCOPIC

• C-cell hyperplasia (CCH): Increase in C-cell population in thyroid due to reactive/physiologic or neoplastic/primary process ○ For practical purposes, if C cells can be seen on H&E and confirmed by IHC, lesion should be reported as CCH • Reactive, sporadic, or physiological CCH ○ Usually difficult to visualize on H&E stains • Primary, hereditary, or neoplastic CCH ○ Considered precursor lesion to familial medullary thyroid carcinomas (MTC)

• Large cell with granular to amphophilic cytoplasm • Round nuclei, coarse, granular, or salt and pepper chromatin • 4 histological patterns ○ Nodular: C-cell clusters between or filling thyroid follicle ○ Diffuse: Cells scattered between follicles ○ Solitary: Single focus of CCH ○ Multifocal: Foci of CCH throughout gland

ANCILLARY TESTS • C cells stain positively for calcitonin, chromogranin, synaptophysin, CRP, and CEA

CLINICAL ISSUES • Reactive CCH unlikely to represent premalignant lesion • Neoplastic CCH is premalignant lesion • ~ 30% of MTC occur in context of MEN2A and MEN2B or familial MTC ○ Prophylactic thyroidectomy appears to offer best chance of cure to patients with MEN2 and familial MTC

TOP DIFFERENTIAL DIAGNOSES • • • •

Medullary thyroid microcarcinoma MTC with intrathyroidal spread Solid cell nests Tangentially cut follicles

Scattered C Cells

Primary C-Cell Hyperplasia

C-Cell Hyperplasia

Calcitonin Immunostain

(Left) Scattered C cells ﬊ can be identified in this field. These cells are within the follicles or in between the follicles and do not form nodules or have a diffuse proliferation pattern. (Right) Primary C-cell hyperplasia in a patient with multifocal medullary thyroid carcinoma associated with multiple endocrine neoplasia 2A (MEN2A) is shown. Primary Ccell hyperplasia has been also referred to as neoplastic C-cell hyperplasia and thyroid intraepithelial neoplasia of C cells.

(Left) The hyperplastic C cells in this photomicrograph surround almost the entire thyroid follicle. The C-cell proliferation has a diffuse pattern, and the C cells have an ample, blue, granular cytoplasm. (Right) The thyroid follicular cells are almost completely replaced by an increased number of C cells, highlighted by calcitonin immunostaining. The C cells surround the thyroid follicle in a diffuse pattern.

170

C-Cell Hyperplasia

Abbreviations • C-cell hyperplasia (CCH)

Synonyms • C-cell proliferation • Parafollicular CCH

Definitions • Calcitonin-producing C cells are believed to be derived from neural crest and descend down into thyroid with ultimobranchial body ○ Habitually associated with ultimobranchial body remnants and solid cell nests ○ C cells are normally found at junction of upper and middle 1/3 of thyroid lobes bilaterally • CCH to neoplasia progression is hallmark of inherited forms of medullary thyroid carcinoma (MTC) • Recent theory from genetic studies in mice indicates that genuine progenitors to C cells arise in endoderm germ layer ○ New indications may suggest that mouse thyroid C cells are endodermal in origin • CCH: Increase in C-cell population in thyroid due to reactive/physiologic or neoplastic process • Proposed diagnostic criteria for diagnosis of CCH include ○ > 50 C cells per low-power field, 100x (WHO 2017) ○ > 50 C cells in 3 low-power fields (100x) ○ > 40 C cells/cm² ○ > 6-8 C cells per cluster ○ For practical purposes, if C cells can be seen on H&E and confirmed by IHC, lesion should be reported as CCH • Neoplastic/primary CCH ○ Considered precursor lesion of familial MTC – Premalignant lesion; therefore, term hyperplasia is misnomer ○ Caused by mutations in RET protooncogene ○ Histopathology – Predominantly nodular or mixed nodular/diffuse hyperplasia – Usually easy to identify on conventional H&E – Cytomorphologically similar to medullary microcarcinomas (MMC) – C-cell quantification not necessary for diagnosis • Reactive/physiologic CCH ○ No clear malignant potential documented ○ Caused by stimuli external to C cell ○ Histopathology – Predominantly diffuse – Usually difficult to visualize on H&E – Calcitonin stain improves detection

CLINICAL ISSUES Presentation • Primary, hereditary, or neoplastic CCH ○ Regarded as precursor of MTC associated with multiple endocrine neoplasia type 2 (MEN2) syndromes ○ 25-30% occur in context of MENs (MEN2A and MEN2B) or familial MTC

○ Incidence rising due to increase in prophylactic thyroidectomies – Patients with family history of MTC and elevated serum calcitonin – Carriers of mutations in RET • Reactive, sporadic, or physiological CCH ○ Most cases sporadic ○ May be associated with – Aging – Hyperparathyroidism – Hypercalcemia – Hypergastrinemia – Hashimoto thyroiditis – PTEN-hamartoma tumor syndrome – Multinodular goiter – Hyperthyroidism – Following subtotal thyroidectomy – Lymphomas ○ Can be seen in vicinity of large tumors of follicular cell origin

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Treatment • Surgical approaches ○ Prophylactic thyroidectomy appears to offer best chance of cure to patients with MEN2 and familial MTC ○ Thyroidectomy recommended to prevent progression to MMC – Recommended age of prophylactic thyroidectomy depends on RET mutation

Prognosis • Neoplastic CCH is premalignant lesion often associated with MMC ○ Generally good prognosis with early detection and thyroidectomy ○ 10-year survival rates of 74-100% reported for MMC • Reactive CCH unlikely to represent premalignant lesion ○ Reports exist of MTC in patients thought to have reactive CCH but with serum calcitonin > 50 pg/mL • CCH, though more common in familial MTC, can also be seen in sporadic tumors • CCH is not associated with patient survival and disease progression

IMAGING General Features • Due to diffuse nature or small size, CCH lesions may be easily overlooked on imaging studies

MACROSCOPIC General Features • CCH not usually grossly identified • Associated MMC or MTC may be present as whitish, firm nodules, typically in upper or middle 1/3 of lobe • In at-risk patients who undergo thyroidectomy, entire gland should be submitted to identify areas of CCH

171

Diagnoses Associated With Syndromes by Organ: Endocrine

C-Cell Hyperplasia

MICROSCOPIC Histologic Features • CCH appears as multifocal areas of increased numbers of amphophilic large cells replacing follicular epithelium and replacing follicles completely forming nodules • 4 histological patterns ○ Nodular: C-cell clusters between or filling thyroid follicle ○ Diffuse: Cells scattered between follicles ○ Solitary: Single focus of CCH ○ Multifocal: Foci of CCH throughout gland • Hereditary, primary, and neoplastic CCH ○ More likely to be nodular, multifocal, and bilateral ○ Usually detectable on H&E sections – Counting is not needed, as it can be recognized on basis of expansile intrafollicular C-cell proliferation with varying degree of dysplasia ○ Presence of cytological atypia ○ Seen adjacent to MTC ○ Usually bilateral ○ Can be nodular or diffuse • Reactive, physiological, and sporadic CCH ○ Tends to be solitary, diffuse, and unilateral ○ No cytologic atypia, not usually detectable on H&Estained sections ○ Usually unilateral and diffuse ○ Seen in association with nodular thyroid disease ○ Does not appear to be precursor of MTC

Cytologic Features • • • •

Round and polygonal cells Slightly larger than adjacent follicular cells Granular to amphophilic cytoplasm Round nuclei, coarse, granular, or salt and pepper chromatin

DIFFERENTIAL DIAGNOSIS

Neoplastic Processes • Intrathyroid spread of MTC, MMC, follicular-derived neoplasms

Medullary Thyroid Microcarcinoma • < 1 cm, loss of organoid arrangement and desmoplastic stromal reaction • Can be sporadic or familial • Incidental finding in patients undergoing thyroidectomies for nodular disease • Detected by routine calcitonin screening in patients with nodular disease

Medullary Thyroid Carcinoma With Intrathyroidal Spread • May be seen multifocally in areas where C cells absent • Present in lymphovascular spaces, most prominent at periphery

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Differentiation of nodular CCH from MMC represents challenge • Demonstration of breach of basement membrane and desmoplasia favor MMC • One of best ways to distinguish CCH is by routine histologic examination ○ CCH associated with familial medullary carcinoma and MEN syndromes is readily observed on routine H&E – Cells often large and show significant nuclear atypia as well as occasional features of medullary carcinoma ○ Secondary CCH often only observed by immunohistochemical staining for calcitonin and quantitative analysis

SELECTED REFERENCES 1.

Benign Entities • Squamous metaplasia, remnants of thymus, solid cell nests, palpation thyroiditis, intrathyroid parathyroid tissue, tangentially cut follicles

Solid Cell Nests • Can be associated with C cells; finding in normal thyroid • Positive for p63, p40, CD5, 34bE12, GATA3, TTF-1, and CEA • Negative for pax-8

Tangentially Cut Follicles • Smaller cells with small, pale cytoplasm • Absence of immunoexpression of chromogranin, synaptophysin, and calcitonin

Intrathyroid Parathyroid Tissue • Small, round nuclei • Positive for PTH and negative for calcitonin and TTF-1

Palpation Thyroiditis • Single or few follicles destroyed • Presence of histiocytes and giant cells • Random distribution throughout gland

172

2. 3.

4.

5. 6. 7. 8. 9. 10. 11. 12. 13.

Censi S et al: Unique case of a large indolent medullary thyroid carcinoma: time to reconsider the medullary thyroid adenoma entity? Eur Thyroid J. 8(2):108-12, 2019 Fuchs TL et al: Revisiting the significance of prominent C cells in the thyroid. Endocr Pathol. 30(2):113-7, 2019 Chorny JA et al: Primary high-grade calcitonin-negative neuroendocrine carcinoma of the thyroid: a very rare cancer. Endocrinol Diabetes Metab Case Rep. 2018, 2018 Gucer H et al: Positivity for GATA3 and TTF-1 (SPT24), and negativity for monoclonal pax8 expand the biomarker profile of the solid cell nests of the thyroid gland. Endocr Pathol. 29(1):49-58, 2018 Yadav M et al: C-cell hyperplasia in sporadic and familial medullary thyroid carcinoma. Indian J Pathol Microbiol. 61(4):485-8, 2018 Nilsson M et al: On the origin of cells and derivation of thyroid cancer: C cell story revisited. Eur Thyroid J. 5(2):79-93, 2016 Parmer M et al: Calcitonin-negative neuroendocrine tumor of the thyroid: follicular or parafollicular cell of origin? Int J Surg Pathol. 25(2):191-4, 2016 Cote GJ et al: Thyroid C-cell biology and oncogenic transformation. Recent Results Cancer Res. 204:1-39, 2015 Johansson E et al: Revising the embryonic origin of thyroid C cells in mice and humans. Development. 142(20):3519-28, 2015 Sakorafas GH et al: Incidental thyroid C cell hyperplasia: clinical significance and implications in practice. Oncol Res Treat. 38(5):249-52, 2015 Schmid KW: Histopathology of C cells and medullary thyroid carcinoma. Recent Results Cancer Res. 204:41-60, 2015 Synoracki S et al: [Thyroid C cells and their pathology: Part 2: Medullary thyroid carcinoma.] Pathologe. 36(3):254-60, 2015 Ting S et al: [Thyroid C cells and their pathology: part 1: normal C cells, - C cell hyperplasia, - precursor of familial medullary thyroid carcinoma.] Pathologe. 36(3):246-53, 2015

C-Cell Hyperplasia

Features

Reactive or Physiological C-Cell Hyperplasia

Neoplastic or Primary C-Cell Hyperplasia

Detectable on H&E stains

No

Yes

Cytologic atypia

No

Yes

Seen adjacent to medullary thyroid carcinoma

No

Yes

Bilaterality

No

Yes

Staining with NCAM

No

Yes

Calcitonin reactivity

Yes

Yes

CEA reactivity

No

Yes/no

Chromogranin reactivity

Yes

Yes

Synaptophysin reactivity

Yes

Yes

Immunohistochemistry Antibody

Reactivity

Staining Pattern

CK-PAN

Positive

Cytoplasmic

TTF-1

Positive

Nuclear

pax-8

Positive

Nuclear

Chromogranin-A

Positive

Cytoplasmic

Synaptophysin

Positive

Cytoplasmic

Calcitonin

Positive

Cytoplasmic

Calcitonin gene-related peptide is also positive

ACTH

Positive

Cytoplasmic

ACTH may be present in some cases

Somatostatin

Positive

Cytoplasmic

Somatostatin may be present in few cases

GastrinRP

Positive

Cytoplasmic

Rare cases may express

CEA-M

Positive

Cytoplasmic

Thyroglobulin

Negative

Collagen IV

Negative

Used to confirm diagnosis of medullary thyroid microcarcinoma: C cells expanding into interstitium

S100

Negative

Positive in sustentacular cells of intrathyroidal paraganglioma

PTH

Negative

Used to differentiate from intrathyroidal parathyroid tissue

p63

Negative

Used in differential diagnosis of solid cell nests

34bE12

Negative

Used in differential diagnosis of solid cell nests

CD5

Negative

Used in differential diagnosis of solid cell nests

14. Bussolati G: C and APUD cells and endocrine tumours. Pearse's laboratory in the years 1965-1969: a personal recollection. Endocr Pathol. 25(2):133-40, 2014 15. Nakazawa T et al: C-cell-derived calcitonin-free neuroendocrine carcinoma of the thyroid: the diagnostic importance of CGRP immunoreactivity. Int J Surg Pathol. 22(6):530-5, 2014 16. Diazzi C et al: The diagnostic value of calcitonin measurement in wash-out fluid from fine-needle aspiration of thyroid nodules in the diagnosis of medullary thyroid cancer. Endocr Pract. 19(5):769-79, 2013 17. Figlioli G et al: Medullary thyroid carcinoma (MTC) and RET proto-oncogene: mutation spectrum in the familial cases and a meta-analysis of studies on the sporadic form. Mutat Res. 752(1):36-44, 2013 18. Cameselle-Teijeiro J et al: C-cell hyperplasia and papillary thyroid carcinoma. Int J Surg Pathol. 20(6):643-4, 2012 19. Pirola S et al: C-cell hyperplasia in thyroid tissue adjacent to papillary carcinoma. Int J Surg Pathol. 20(1):66-8, 2012 20. Laury AR et al: Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 21(2):135-44, 2011 21. Etit D et al: Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Arch Pathol Lab Med. 132(11):1767-73, 2008 22. Ashworth M: The pathology of preclinical medullary thyroid carcinoma. Endocr Pathol. 15(3):227-31, 2004

Comment

Diagnoses Associated With Syndromes by Organ: Endocrine

Reactive/Physiologic vs. Neoplastic C-Cell Hyperplasia

23. Guyétant S et al: C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients. Mod Pathol. 16(8):756-63, 2003 24. Kaserer K et al: Recommendations for reporting C cell pathology of the thyroid. Wien Klin Wochenschr. 114(7):274-8, 2002 25. Baloch ZW et al: Neuroendocrine tumors of the thyroid gland. Am J Clin Pathol. 115 Suppl:S56-67, 2001 26. Krueger JE et al: Inherited medullary microcarcinoma of the thyroid: a study of 11 cases. Am J Surg Pathol. 24(6):853-8, 2000 27. Moline J, Eng C. Multiple Endocrine Neoplasia Type 2. 1993-, 1999 28. de Lellis RA et al: The pathobiology of the human calcitonin (C)-cell: a review. Pathol Annu. 16(Pt 2):25-52, 1981

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Diagnoses Associated With Syndromes by Organ: Endocrine

C-Cell Hyperplasia

C Cells Associated With Solid Cell Nests

C Cells and Solid Cell Nest

Neoplastic C-Cell Hyperplasia

C-Cell Hyperplasia

C-Cell Hyperplasia

Identification of C Cells

(Left) The calcitonin-producing C cells are usually associated with ultimobranchial body remnants/solid cell nests (SCNs). Near the SCNs, numerous C cells ſt can be identified by routine stains. (Right) The thyroid follicular cells are almost completely replaced by an increased number of C cells ﬇, easily identified by H&E staining. The C cells have ample, blue, granular cytoplasm. These are adjacent to a SCN ﬊.

(Left) H&E of thyroid from a patient with MEN2 shows an area of hyperplasia of C cells associated with a SCN ﬊. The C-cell proliferation is easily identified by H&E in MEN2 syndromes and is hardly seen in the thyroid of other syndromes. (Right) An increased number of C cells can be seen adjacent to large thyroid nodules. The reactive C-cell proliferation is usually difficult to identify on H&E.

(Left) C-cell proliferation is easily identified at this magnification. This finding is usually seen in cases of neoplastic C-cell hyperplasia. (Right) High-power view shows a thyroid from a patient with MEN2. The C-cell proliferation ﬊ is easily identified by H&E. In inherited syndromes, the Ccell hyperplasia usually precedes neoplasia.

174

C-Cell Hyperplasia

Medullary Microcarcinoma (Left) Nodular C-cell hyperplasia is a misnomer, as this is considered a precursor lesion of familial medullary thyroid carcinomas in MEN2 syndromes. (Right) Most of the time, the differential diagnosis between C-cell hyperplasia and medullary thyroid microcarcinoma is challenging. The presence of extension of C cells through the basement membranes of expanded C cell-filled follicles into the surrounding thyroid interstitium associated with desmoplasia help in the diagnosis of microcarcinoma.

Normal C-Cell Population as Identified by Calcitonin Stain

Diagnoses Associated With Syndromes by Organ: Endocrine

C-Cell Hyperplasia and Microcarcinoma

Calcitonin(+) C-Cell Hyperplasia (Left) Calcitonin stain highlights the normal C-cell distribution within the junction of the upper and middle 1/3 of the thyroid lobes. Normal C-cell population is characterized by < 50 calcitonin-positive cells per low-power field. (Right) Calcitonin stain shows the marked increase in the number of C cells, which are arranged in small clusters in a nodular ﬊ and diffuse ﬊ pattern.

C-Cell Hyperplasia Associated With Solid Cell Nests

Calcitonin Immunostain (Left) Calcitonin-producing C cells are derived from the neural crest and descend down into the thyroid with the ultimobranchial body/SCNs. Ccell hyperplasia ſt can be located near the SCNs ﬈. Note the group of C cells obscuring a follicle. (Right) Ccell hyperplasia highlighted by calcitonin staining shows the thyroid follicular cells replaced by an increased number of C cells that surround the entire follicle.

175

Diagnoses Associated With Syndromes by Organ: Endocrine

Medullary Thyroid Carcinoma KEY FACTS

TERMINOLOGY • Malignant tumor of thyroid gland composed of cells with evidence of C-cell differentiation

CLINICAL ISSUES • ~ 1/3 of MTC are hereditary ○ MTC is usually 1st clinical manifestation of MEN2 syndromes • Screening ○ Genetic counseling is recommended to assess patientspecific risk ○ Screening and monitoring tests are performed in patients at risk: MEN2 syndrome or family history of MEN2 or FMTC – Universal genetic screening for RET mutations in all diagnoses of MTC is recommended – Annual serum calcitonin screening should begin in children with MEN2B at 6 months, MEN2A at 3-5 years of age

• Treatment ○ Total thyroidectomy offers best chance of cure – Primary preventive measure for individuals with identified germline RET mutation – Thyroidectomy for CCH, before progression to medullary microcarcinoma (MMC) – In families where most aggressive mutations are found (918, 883), prophylactic thyroidectomy in 1st year of life • Generally clear genotype-phenotype correlation between gene mutation and clinical phenotype in MTC

MICROSCOPIC • In MEN2 and FMTC patients who undergo prophylactic thyroidectomy, entire gland should be examined to identify MMC and CCH • Neoplastic/primary CCH is precursor lesion in hereditary MTC • Histological appearance of MTC is variable

RET Gene and RET Point Mutations Associated With MEN2A, MEN2B, and FMTC

There is a well-recognized genotype-phenotype correlation between RET mutation and clinical phenotype in medullary thyroid carcinoma (MTC). Commonly activating point mutations of RET are on exon 10, codons 609, 611, 618, 620, and exon 11, codon 634, which are responsible for the majority of MEN2A and FMTC. The majority of RET mutations associated with MEN2B are associated with exon 16, codon 918 mutation. ATA recommends prophylactic thyroidectomy for MTC during early childhood in patients with MEN2. ATA risk stratification is based on the RET mutation: Highest risk: Codon 918 (red); high risk: Codons 634 and 883 (yellow).

176

Medullary Thyroid Carcinoma

Abbreviations • Medullary thyroid carcinoma (MTC)

Synonyms • Solid carcinoma with amyloid stroma • C-cell carcinoma • Parafollicular cell carcinoma

Definitions • Malignant tumor of thyroid gland composed of cells with evidence of C-cell differentiation (WHO 2017) • MTCs measuring < 1 cm in diameter are called medullary thyroid microcarcinomas (MMC) • C-cell hyperplasia (CCH) is considered precursor lesion for hereditary forms of MTC

ETIOLOGY/PATHOGENESIS Genetic Predisposition • Hereditary MTC represents ~ 1/3 of MTC cases • Hereditary forms of MTC are transmitted as autosomal dominant traits, usually with high penetrance • Hereditary MTC is caused by autosomal dominant gain-offunction mutations in RET protooncogene ○ Rearranged during transfection (RET) protooncogene plays crucial role in MTC development • Multiple endocrine neoplasia type 2 (MEN2) syndrome and familial MTC (FMTC)-only syndrome are caused by mutations in RET ○ 2 clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B ○ Commonly activating point mutations ○ Exon 10 codons 609, 611, 618, 620, and exon 11 codon 634 responsible for majority of MEN2A and FMTC – MEN2A: Majority involve exon 11 codon 634 ○ MEN2B: Majority associated with exon 16 codon 918 mutation ○ Fusion genes with tyrosine kinase domain of RET also occur – RET chromosomal rearrangements also associated with papillary thyroid carcinoma (RET/PTC) ○ Somatic RET mutations also present in ~ 50% of sporadic MTCs • MTC is seen in setting of MEN2 syndromes ○ MEN2A – MTC, parathyroid hyperplasia, pheochromocytoma, and pancreatic endocrine tumors – ~ 100% of individuals with MEN2A develop MTC – Within MEN2A, there are 4 variants □ Classic MEN2A, represented by uniform presence of MTC and less frequent occurrence of pheochromocytoma, or primary hyperparathyroidism, or both □ MEN2A with cutaneous lichen amyloidosis □ MEN2A with Hirschsprung disease □ FMTC, i.e., families or individuals with only MTC ○ MEN2B – MTC, pheochromocytoma, mucosal and soft tissue tumors (notably neuromas), marfanoid body habitus

– Characterized by early development of aggressive form of MTC in ~ 100% of affected patients • Specific RET mutations may suggest predilection toward particular phenotype and clinical course with strong genotype-phenotype correlation • Besides RET, other oncogenes commonly involved in pathogenesis of human cancers ○ Family of human RAS genes includes highly homologous HRAS, KRAS, and NRAS, which encode 3 distinct proteins ○ Recent reports have described HRAS and KRAS mutations in MTC

Precursor Lesions • Neoplastic or primary CCH ○ Precursor lesion in hereditary MTC ○ Recognized on basis of expansile intrafollicular C-cell proliferation with varying degree of dysplasia – C-cell clusters surrounding or invading follicles ○ a.k.a. C-cell carcinoma in situ or medullary carcinoma in situ or thyroid intraepithelial neoplasia of C cells ○ These lesions harbor germline RET mutations ○ Postulated that CCH progresses to MMC and eventually to MTC ○ Found in vicinity of medullary carcinomas ○ Distinguishing CCH from MMC may be difficult – Extension of C cells through basement membranes of expanded C-cell-filled follicles into surrounding interstitium – Loss of organoid arrangement of C-cell-filled follicles – Appearance of desmoplastic stromal reaction surrounding groups of infiltrating tumor cells • Reactive or physiological CCH ○ Increase in number of C cells secondary to associated – Thyroid disorder (nodules, papillary or follicular carcinoma, inflammatory or autoimmune, and PTENhamartoma tumor syndrome) – Hypergastrinemia – Hyperparathyroidism – Hypercalcemic states ○ Clusters should have > 50 C cells per low-power magnification ○ Lacks pleomorphism, amyloid, fibrosis, or invasion of follicles ○ Difficult to visualize on H&E alone; requires calcitonin staining to identify C cells ○ Role of CCH in sporadic MTC remains unknown

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Sporadic MTC • Unknown etiology

CLINICAL ISSUES Epidemiology • Incidence ○ 2-3% of all thyroid malignancies – ~ 70% are sporadic – ~ 30% are hereditary ○ Variable incidence due to calcitonin-screening protocols and RET genetic testing and relative increased incidence of PTC – Increase in prophylactic thyroidectomies – Mostly MMC identified in familial cases 177

Diagnoses Associated With Syndromes by Organ: Endocrine

Medullary Thyroid Carcinoma • Age ○ Sporadic cases: 50-60 years ○ Familial cases can present from early childhood – MTC in MEN2B: ~ 5 years – MTC in MEN2A: 25-30 years – MTC in FMTC: ~ 50 years • Sex ○ M:F = 1:1 in familial cases

Presentation • • • •

Often presents as painless, cold nodule Up to 70% have nodal metastases Up to 10% may present with distant metastases Symptoms of carcinoid and Cushing syndromes may be present (production of ACTH or CRH) • Large tumors may lead to dysphagia and upper airway obstruction • Nonthyroid findings: Mucosal neuromas; parathyroid, adrenal, pituitary, and pancreatic tumors • MTC tends to metastasize early: Liver, lungs, bone, soft tissue outside neck, brain, and bone marrow

Laboratory Tests • Given that inherited MTC can present at any age and is not universally associated with other features, universal screening for genetic mutations in all diagnoses of MTC is recommended • Screening and monitoring tests are performed in patients at risk ○ History or presence of MEN ○ Family history of MEN2 or FMTC ○ Genetic counseling is recommended to assess patientspecific risk ○ Annual serum calcitonin screening should begin in children with MEN2B at 6 months, MEN2A at 3-5 years of age • Increased serum calcitonin and CEA levels ○ Correlate with tumor burden • Abnormal pentagastrin-stimulated calcitonin response • RET molecular genetic testing indicated in all individuals with ○ Diagnosis of MTC ○ Clinical diagnosis of MEN2 ○ Primary CCH • There is generally clear genotype-phenotype correlation between gene mutation and clinical phenotype in MTC • RET mutation analysis ○ Most commonly exons 10, 11, 13, 14, and 16 in hereditary forms ○ Mutations in codons 768, 790, 791, and 804 may predispose to milder form of MTC with low penetrance, late onset, and without family history ○ Most common somatic mutation in sporadic MTC is M918T ○ Mutation in codon 634 is considered to be associated with aggressive clinical course, whereas C634Y mutation may result in more indolent course • MEN2A: ~ 100% of families have RET mutation in exon 10 or 11 • FMTC: Families have almost 100% RET mutation

178

• MEN2B: Individuals with features of this syndrome should have mutation analysis or sequencing of exons 15 or 16 to detect p.M918T and p.A883F mutations • Rarely, germline RET mutation may not be detected in family with clinical diagnosis of MEN2A, MEN2B, or FMTC

Treatment • Surgical approaches ○ Total thyroidectomy offers best chance of cure ○ Associated neck dissections considered for tumors > 1 cm ○ American Thyroid Association Guidelines Task Force has classified mutations based on risk for aggressive MTC – May be used in predicting phenotype and recommendations for age at which to perform prophylactic thyroidectomy and to begin biochemical screening for associated diseases ○ Prophylactic thyroidectomy – Primary preventive measure for individuals with identified germline RET mutation – In families where most aggressive mutations are found (M918 T, A883F), recommendation can be made for prophylactic thyroidectomy as soon as possible and ideally in 1st year of life ○ Prophylactic thyroidectomy recommendations for specific RET germline mutations – Codons 883, 918, or 922: Thyroidectomy by 1 year of age – Codons 609, 611, 618, 620, 630, or 634: Thyroidectomy before 5 years of age – Codons 786, 790, 791, 804, or 891: Consider surgery before age of 5; may delay surgery up to 10 years – Other mutations: Thyroidectomy once stimulated calcitonin screening turns abnormal ○ Thyroidectomy for CCH, before progression to MMC, may allow surgery to be limited to thyroidectomy alone, sparing of lymph nodes • Adjuvant therapy ○ Targeted tyrosine kinase, hormone therapy, chemotherapy, and anti-CEA treatments can be considered • Radiation ○ For residual disease and palliation

Prognosis • Considerable variation • Overall 5- and 10-year survivals of 60-80% and 40-70%, respectively • Wide use of genetic testing for RET mutations has markedly influenced course of hereditary MTC • 10-year survival by tumor stage ○ Stage I: Near 100%; stage II: 98%; stage III: 81%; stage IV: 28% • Better prognostic factors are tumor stage, young age, sex (F), and familial forms ○ Prophylactic thyroidectomy of RET carriers at early age eliminates risk of developing MTC later in life • Poor prognostic factors are necrosis, squamous metaplasia, < 50% calcitonin immunoreaction, and CEA reactivity in absence of calcitonin • Genetic testing of RET is powerful tool in diagnosis and prognosis of MTC

Medullary Thyroid Carcinoma

Scintigraphy • Cold nodule on iodine scan

MACROSCOPIC General Features • Typically at junction of upper and middle 1/3 of lobe • Sporadic tumors tend to present as solitary mass • Hereditary tumors seen in MEN are usually multicentric and bilateral • Usually not encapsulated but well circumscribed • Firm, grayish-tan to yellow-white, gritty cut surface

○ May mimic other thyroid carcinomas (follicular, papillary, poorly differentiated, anaplastic)

Histologic Variants • Rare variants: Papillary, pseudopapillary, tubular/glandular, follicular, spindle cell, clear cell, oncocytic, small cell, giant cell, melanotic, amphicrine, paraganglioma-like, oat cell carcinoma, angiosarcoma-like, and squamous cell variant • Variant patterns of MTC may resemble wide range of thyroid and extrathyroid tumors ○ Staining for calcitonin is helpful in making distinction between MTC and other diverse tumors it may mimic

ANCILLARY TESTS

Size

Cytology

• Ranges from grossly undetectable to large, replacing entire lobe • Small tumors often seen in prophylactic thyroidectomy specimens from MEN2 patients

• Aspirates are hypercellular with loosely cohesive to noncohesive cells • Spindle, polygonal, or bipolar cells, often with eccentric nuclei • Hyperchromatic nuclei with granular chromatin and moderate pleomorphism • Amyloid may be seen in 50-70% of tumors • Multinucleated giant tumor cells are common ○ Despite well-known cytological features, only ~ 45% of cases are diagnosed in clinical practice – Highlighting difficulty in making this diagnosis

Sections to Be Submitted • In high-risk patients (MEN2 and FMTC) who undergo prophylactic thyroidectomy, entire gland should be submitted to identify MMC and CCH ○ Specimen should be serially sectioned and submitted as whole from superior to inferior ○ C cells are normally situated in upper and middle portions of lobes; submit apparently normal thyroid for histological examination – Search for CCH

MICROSCOPIC

Diagnoses Associated With Syndromes by Organ: Endocrine

IMAGING

Histochemistry • Congo red ○ Reactivity: Positive ○ Staining pattern: Amyloid shows light green birefringence with polarization

Histologic Features

Immunohistochemistry

• Tumors from patients with heritable forms and virtually indistinguishable from those occurring sporadically ○ Except for their bilaterality, multicentricity, and association with primary CCH • MTC is diagnosed histologically when nests of C cells appear to extend beyond basement membrane and infiltrate and destroy thyroid follicles ○ Primary CCH can often be recognized by presence of expansile intrafollicular C-cell proliferation with varying degrees of dysplasia – Finding primary CCH may serve as morphological marker for MEN2-associated MTC – In MEN2, age of transformation from CCH to MTC varies with different germline RET mutation • Most common prototypical morphology has solid, trabecular, or insular growth pattern • Cells can be round, polygonal, plasmacytoid, or spindleshaped, separated by thin fibrovascular cores • Cytoplasm can be clear, amphophilic, or eosinophilic • Nuclei are round to oval with small nucleoli • Chromatin is fine, granular and dispersed or coarsely clumped • Vacuoles with mucin have been frequently described • Psammoma-like concretions are occasionally seen • Up to 90% show calcitonin-positive amyloid in stroma • Histological appearance is quite variable and can mimic entire spectrum of thyroid malignancies

• Hallmark of MTC is positivity for calcitonin and calcitonin gene-related peptide ○ Cases with lack of calcitonin expression, may have immunoreactivity for calcitonin-gene-related peptide • Tumor cells are also positive for neuroendocrine markers (chromogranin, synaptophysin) and CEA • TTF-1 and pax-8 are positive but weak • Progesterone receptor and S100 (in sustentacular cells) can be positive • Other peptide products may be present: ACTH, somatostatin, gastrin-releasing peptide, neurotensin • MTC has been shown to express prospero homeobox protein 1 (PROX1), transcription factor whose expression is altered in diverse human tumors

Genetic Testing • RET sequencing is important to determine prognosis and timing of prophylactic thyroidectomy ○ Exons 10, 11, 13, 14, 15, and 16 cover 95% of cases ○ M918T RET mutation in exon 16 is present in 98% of patients with MEN2B ○ MEN2A: 85% carry codon 634 mutation (associated with pheochromocytoma and hyperparathyroidism) • Identify rearrangements involving RET • Somatic RET mutations (M918T) have been reported in 4060% of sporadic tumors • Presence of HRAS and KRAS mutation in 56% and 12% of RET-negative sporadic MTCs, respectively 179

Diagnoses Associated With Syndromes by Organ: Endocrine

Medullary Thyroid Carcinoma

• • • •

○ Mutual exclusivity suggests that RAS activation may constitute alternative molecular pathway for development of MTC MYH13-RET fusion found in sporadic MTC GFPT1-ALK fusion also found in sporadic MTC Programmed cell death 4 (PDCD4) is tumor-suppressor gene involved in tumorigenesis There is difference in miRNA expression pathway between sporadic and hereditary MTCs

Electron Microscopy • Presence of neurosecretory granules confirms neuroendocrine origin of tumor ○ 2 types: 280 nm and 130 nm electron dense, membrane bound • Amyloid material is detected as fine fibrillary material within parenchymal space

DIFFERENTIAL DIAGNOSIS Intrathyroid Tumor • Metastatic neuroendocrine tumors ○ Can be positive for calcitonin and CEA in rare cases ○ Clinical and radiologic correlation may help in differential • Paraganglioma ○ Negative for calcitonin; zellballen with S100-positive sustentacular cells • Follicular carcinoma ○ Thyroglobulin is positive ○ Nuclear features: Neuroendocrine chromatin in MTC compared with dark dense nuclei in follicular carcinoma • Undifferentiated carcinoma ○ Hemorrhage, necrosis, and high mitotic activity seen in undifferentiated carcinoma ○ Negative for calcitonin • PTC ○ Intranuclear inclusions can be seen in both MTC and PTC ○ Nuclear features usually unique to PTC ○ PTC is calcitonin negative and thyroglobulin positive • Hyalinizing trabecular tumor ○ Thyroglobulin positive, calcitonin negative ○ Hyaline material is not amyloid when stained by Congo red under polarized light • Intrathyroid parathyroid tumors ○ Clear cytoplasm, defined cell border ○ PTH positive, calcitonin and thyroglobulin negative

Tumor in Lymph Nodes • MTC metastatic to lymph nodes may be misdiagnosed as melanoma or metastatic neuroendocrine tumors • Calcitonin and CEA immunostains should be performed in any suspicious case

Benign Conditions • Amyloid goiter ○ May infiltrate fat; Congo red positive ○ Involves thyroid gland diffusely ○ Calcitonin stain is negative

Sporadic vs. FMTC • There is only 1 genetic differential diagnosis for MTC: MEN2 180

• Important for medical management of patient and his/her family to distinguish MTC + MEN2 from truly sporadic MTC • Germline mutations in RET in individuals with apparent sporadic MTC: 6.0-9.5% • Sporadic tumors are usually ○ Solitary mass ○ Unilateral ○ Not associated with CCH ○ Histological findings: Same as familial

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • CCH may serve as morphological marker for MEN2associated MTC • Desmoplasia and breakage of follicular basement membrane help differentiate CCH from MMC

SELECTED REFERENCES 1.

2.

3.

4.

5. 6. 7. 8. 9.

10. 11. 12. 13. 14.

15. 16. 17. 18.

19. 20. 21.

22.

Febrero B et al: Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: a long-term follow-up in a large single-center cohort. Eur J Surg Oncol. 45(4):625-30, 2019 Gambardella C et al: Calcitonin negative medullary thyroid carcinoma: a challenging diagnosis or a medical dilemma? BMC Endocr Disord. 19(Suppl 1):45, 2019 Matsushita R et al: Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997-2017. J Pediatr Endocrinol Metab. 32(6):585-95, 2019 Raue F et al: Long-term outcomes and aggressiveness of hereditary medullary thyroid carcinoma: 40 years of experience at one center. J Clin Endocrinol Metab. 104(10):4264-72, 2019 Haddad RI et al: NCCN guidelines insights: thyroid carcinoma, version 2.2018. J Natl Compr Canc Netw. 16(12):1429-40, 2018 Makri A et al: Multiple endocrine neoplasia type 2B presents early in childhood but often is undiagnosed for years. J Pediatr. 203:447-9, 2018 Accardo G et al: Genetics of medullary thyroid cancer: an overview. Int J Surg. 41 Suppl 1:S2-6, 2017 Lloyd RV et al: WHO Classification of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2017 Mathiesen JS et al: Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study. Thyroid. 27(2):21523, 2017 Mohammadi M et al: A brief review on the molecular basis of medullary tyroid carcinoma. Cell J. 18(4):485-92, 2017 Pappa T et al: Management of hereditary medullary thyroid carcinoma. Endocrine. 53(1):7-17, 2016 Parmer M et al: Calcitonin-negative neuroendocrine tumor of the thyroid: follicular or parafollicular cell of origin? Int J Surg Pathol. 25(2):191-4, 2016 Spinelli C et al: Surgical management of medullary thyroid carcinoma in pediatric age. Curr Pediatr Rev. 12(4):280-5, 2016 Mathiesen JS et al: Aggressive medullary thyroid carcinoma in a ten-year-old patient with multiple endocrine neoplasia 2B due to the A883F mutation. Thyroid. 25(1):139-40, 2015 Moura MM et al: RAS proto-oncogene in medullary thyroid carcinoma. Endocr Relat Cancer. 22(5):R235-52, 2015 Pennelli G et al: The PDCD4/miR-21 pathway in medullary thyroid carcinoma. Hum Pathol. 46(1):50-7, 2015 Wells SA Jr et al: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 25(6):567-610, 2015 Jaskula-Sztul R et al: Tumor-suppressor role of Notch3 in medullary thyroid carcinoma revealed by genetic and pharmacological induction. Mol Cancer Ther. 14(2):499-512, 2014 Lyra J et al: mTOR activation in medullary thyroid carcinoma with RAS mutation. Eur J Endocrinol. 171(5):633-40, 2014 Perri F et al: Targeted therapy: a new hope for thyroid carcinomas. Crit Rev Oncol Hematol. 94(1):55-63, 2014 Romei C et al: 20 Years of lesson learning: how does the ret genetic screening test impact the clinical management of medullary thyroid cancer ? Clin Endocrinol (Oxf). 82(6):892-9, 2014 Valdés N et al: RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. Eur J Endocrinol. 172(3):301-7, 2014

Medullary Thyroid Carcinoma

Characteristics

Familial Medullary Thyroid Carcinoma

Sporadic Medullary Thyroid Carcinoma

Gross features

Multicentric and bilateral

Solitary mass; unilateral

Tumor characteristics

Small tumors in prophylactic thyroidectomy specimens

Usually large tumors

Microscopic features

Associated with neoplastic C-cell hyperplasia

Association with C-cell hyperplasia unknown

RET mutation

Present in majority of hereditary forms

May be present in sporadic cases

Differential Diagnosis of Medullary Thyroid Microcarcinoma Characteristics

Familial

Sporadic

Multifocality

Frequent (~ 90%)

Rare (~ 10%)

Bilaterality

Common (~ 70%)

Rare (~ 10%)

Physiologic C-cell hyperplasia

Rare (~ 10%)

Common (~ 55%)

Neoplastic C-cell hyperplasia

Frequent (~ 90%)

Rare (~ 15%)

Diagnoses Associated With Syndromes by Organ: Endocrine

Pathological Features Distinguishing Familial From Sporadic Medullary Thyroid Carcinoma

Differential Diagnosis of Medullary Thyroid Carcinoma by Immunohistochemistry Antibody

MTC

PTC

PDC

ATC

PA/C

Para

Met C

Cytokeratin

+

+

+

+/-

+

-

+

Thyroglobulin

-

+

+

-

-

-

-

TTF-1

+

+

+

-

-

-

-/+

pax-8

+

+

+

+/-

-

-

-/+

Chromogranin

+

-

-

-

+

+

+/-

Synaptophysin

+

-

-

-

+/-

+

+/-

Calcitonin

+

-

-

-

-

-

-

CEA

+

-

-

-

-

-

-

PTH

-

-

-

-

+

-

-

S100

-

-

-

-

-

+

-

MTC = medullary thyroid carcinoma; PTC = papillary thyroid carcinoma; PDC = poorly differentiated carcinoma; ATC = anaplastic thyroid carcinoma; PA/C = parathyroid adenoma/carcinoma; para = paraganglioma; met C = metastatic carcinoma. 23. Viola D et al: Medullary thyroid carcinoma in children. Endocr Dev. 26:202-13, 2014 24. Maliszewska A et al: Differential gene expression of medullary thyroid carcinoma reveals specific markers associated with genetic conditions. Am J Pathol. 182(2):350-62, 2013 25. Wells SA Jr et al: Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 98(8):3149-64, 2013 26. Shankar RK et al: Medullary thyroid cancer in a 9-week-old infant with familial MEN 2B: mplications for timing of prophylactic thyroidectomy. Int J Pediatr Endocrinol. 2012(1):25, 2012 27. Nosé V: Familial thyroid cancer: a review. Mod Pathol. 24 Suppl 2:S19-33, 2011 28. Waguespack SG et al: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol. 7(10):596-607, 2011 29. Pacini F et al: Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol). 22(6):475-85, 2010 30. Phay JE et al: Targeting RET receptor tyrosine kinase activation in cancer. Clin Cancer Res. 16(24):5936-41, 2010 31. Richards ML: Familial syndromes associated with thyroid cancer in the era of personalized medicine. Thyroid. 20(7):707-13, 2010 32. Torino F et al: Medullary thyroid cancer: a promising model for targeted therapy. Curr Mol Med. 10(7):608-25, 2010 33. Cerrato A et al: Molecular genetics of medullary thyroid carcinoma: the quest for novel therapeutic targets. J Mol Endocrinol. 43(4):143-55, 2009 34. Wells SA Jr et al: Targeting the RET pathway in thyroid cancer. Clin Cancer Res. 15(23):7119-23, 2009

35. Etit D et al: Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Arch Pathol Lab Med. 132(11):1767-73, 2008 36. Moline J, Eng C. Multiple Endocrine Neoplasia Type 2. 1993-, 1999

181

Diagnoses Associated With Syndromes by Organ: Endocrine

Medullary Thyroid Carcinoma

PET of Metastatic Carcinoma

FDG PET/CT of Thyroid Tumor

Cut Surface of Both Thyroid Lobes

C-Cell Hyperplasia in MEN2

Calcitonin in Nodular C-Cell Hyperplasia

Medullary Thyroid Microcarcinoma

(Left) Coronal FDG PET shows hypermetabolic foci in an upper lumbar vertebra ﬈, the left sacroiliac region ﬊, and the left lung ﬉ in a patient with metastatic medullary thyroid carcinoma (MTC). Up to 20% of patients may have distant metastases at the time of presentation. (Right) FDG PET/CT shows a focal hypermetabolic mass ſt in the right thyroid lobe in a patient with MTC.

(Left) The right ﬊ and left ﬇ thyroid lobes have firm, wellcircumscribed, white-grayyellow tumors. Serial sections of the right lobe show a larger tumor than the sections on the left lobe in this patient with multiple endocrine neoplasia type 2 (MEN2) syndrome. (Right) H&E shows thyroid from a patient with MEN2. The C-cell hyperplasia is easily identified ﬊. In inherited syndromes, the primary/neoplastic C-cell hyperplasia usually precedes neoplasia.

(Left) In MEN2 patients, foci of C-cell hyperplasia are typically present in the vicinity of the tumor as well as in the contralateral lobe. Calcitonin highlights C-cell hyperplasia adjacent to MTC. (Right) Medullary thyroid microcarcinoma (MMC) is defined as a tumor measuring < 1 cm. Invasion of the adjacent tissue should be present, and desmoplasia may be present.

182

Medullary Thyroid Carcinoma

C Cells Associated With Solid Cell Nests (Left) Total prophylactic thyroidectomy with a portion of thymus from a patient with MEN2B and RET mutation shows a grossly normal thyroid. However, on histological examination, Ccell hyperplasia and bilateral small MTCs were present. (Right) C cells are usually associated with solid cell nests. The prominent C-cell population ﬇ is adjacent to a solid cell nest ﬊.

C-Cell Hyperplasia in MEN2

Diagnoses Associated With Syndromes by Organ: Endocrine

Prophylactic Thyroidectomy Specimen

C-Cell Hyperplasia in MEN2 (Left) H&E shows C-cell hyperplasia in the thyroid lobe of a patient with MTC in the other lobe. Both were associated with MEN2 and RET mutation. Primary C-cell hyperplasia can be easily identified on H&E in heritable cases. (Right) Calcitonin stain shows the thyroid follicular cells replaced by an increased number of C cells.

Medullary Thyroid Microcarcinoma

Medullary Thyroid Microcarcinoma (Left) Unlike sporadic MTC, tumors in patients with MEN syndromes are frequently accompanied by neoplastic/primary C-cell hyperplasia and MMC. (Right) Calcitonin-stained thyroid section from a prophylactic thyroidectomy from a patient with RET mutation and family history of MEN2B shows C-cell hyperplasia and MMC.

183

Diagnoses Associated With Syndromes by Organ: Endocrine

Medullary Thyroid Carcinoma Gross Cut Surface of Medullary Thyroid Microcarcinoma

Gross Cut Surface of Medullary Thyroid Carcinoma

Unusual Gross Appearance of Medullary Thyroid Carcinoma

Dual Stain for Chromogranin and TTF-1

Plasmacytoid and Epithelioid Cells

Spindle Cell Variant

(Left) Gross cut surface of a thyroid lobe shows a large, firm, white-gray thyroid nodule with extensive areas of hemorrhage. The tumor is well circumscribed. (Right) Gross cut surface of a thyroid lobe shows a well-circumscribed, white-gray-yellow thyroid tumor. MTCs are usually firm and gritty. Areas of hemorrhage are present.

(Left) Gross cut surface of a familial MTC (FMTC) in a patient with MEN2A syndrome shows a large, firm, multilobulated, gray-yellow mass. (Right) Dual stain for chromogranin (red) and TTF-1 (brown) marks neuroendocrine-derived cells of MTC ﬉ from normal adjacent TTF-1(+) follicular cells ﬈. MTC cells are TTF-1 and chromogranin (+). Immunophenotypical distinction is key in follicularpatterned MTC morphology.

(Left) This tumor is composed of epithelioid cells in a diffuse pattern. The cells are round to oval with large cytoplasm and nuclei with fine, granular, and dispersed chromatin. Amyloid is focally present ﬊. (Right) The histological appearance of MTC is quite variable. This stain shows a spindle cell variant with characteristic neuroendocrine nuclear features.

184

Medullary Thyroid Carcinoma

Synaptophysin Immunopositivity (Left) Bilateral MTC from a patient with MEN2A shows the characteristic wellcircumscribed cut surface. MEN-associated tumors are usually bilateral and multifocal. (Right) Synaptophysin frequently has strong diffuse cytoplasmic reactivity. This marker and other markers of neuroendocrine lineage can be helpful in establishing the diagnosis.

Chromogranin Staining by Tumor Cells

Diagnoses Associated With Syndromes by Organ: Endocrine

Bilateral Tumors in Heritable Syndromes

Calcitonin Immunostaining (Left) Although calcitonin is the specific stain for MTC, chromogranin, as a neuroendocrine marker, shows usually variable immunopositivity in the tumor cells. (Right) Variable cytoplasmic immunopositivity for calcitonin is present in the tumor cells of MTC. This stain helps differentiate MTC from many mimics.

Congo Red Stain

Polarized Congo Red Stain (Left) Congo red-stained MTC shows extensive deposition of dense amorphous material suggestive of amyloid. Although not essential for the diagnosis of MTC, variable amounts of amyloid are commonly seen in these tumors. (Right) Congo redstained MTC under polarized light reveals the characteristic apple green birefringence ſt, confirming amyloid deposition.

185

Diagnoses Associated With Syndromes by Organ: Endocrine

Thyroid, Medullary Carcinoma Table Familial Syndromes Associated With MTC Characteristics

MEN2B

MEN2A

FMTC*

Incidence of MEN2 syndromes

Comprises ~ 5-10% of cases with MEN2

Makes up 70-80% of MEN2 cases 

Comprises ~ 10-20% of cases of MEN2

Age at diagnosis of MTC

Early development of MTC; usually < 5 years

Usually 25-35 years

Age of onset of MTC is later than other familial cases; usually 45-55 years

Presentation

Aggressive form of MTC; average age of death before early prophylactic thyroidectomy was 21 years

MTC is usually the initial presentation; up to 70% have LN metastases at time of presentation

MTC is only clinical manifestation of FMTC

MTC incidence by syndrome

Most individuals with MEN2B develop MTC

> 90% of individuals with MEN2A develop MTC

MTC is characteristically present

Commonly involved RET codons

~ 95% of individuals with MEN2B have single point mutation at codon 918, 883

634, 609, 611, 618, 620, 630, 631

768, 790, 791, 804, 649, 891, 609, 611, 618, 620, 630, 631

MTC

~ 100%

~ 100%

~ 100%

FMTC = familial medullary thyroid carcinoma-only syndrome; LN = lymph node; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B; MTC = medullary thyroid carcinoma. *FMTC is viewed as a variant of MEN2A with decreased penetrance of pheochromocytoma and hyperparathyroidism, rather than a distinct subtype. The probability of a de novo pathogenic variant is 5% or less in index cases with MEN2A and 50% in index cases with MEN2B. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prevention of primary manifestations: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant. Evaluation of relatives at risk: RET molecular genetic testing should be offered to all at-risk members of kindreds in which a germline RET pathogenic variant has been identified.

Pathologic Features Distinguishing Familial From Sporadic Medullary Carcinoma Pathologic Features

Familial

Sporadic

Gross features

Multicentric

Solitary mass

Laterality

Bilateral

Unilateral

Presence of C-cell hyperplasia

Associated with C-cell hyperplasia

Association with C-cell hyperplasia unknown

Neoplastic C-cell hyperplasia

Frequent (> 90%)

Rare (< 15%)

Microscopic features

No distinct MTC histopathologic features or MTC variants can distinguish from sporadic tumors

No distinct MTC features or MTC variants can distinguish sporadic from inherited forms

Lymph node metastasis

May be present at time of diagnosis

Usually present at time of diagnosis

RET mutation

Present in majority of hereditary forms

May be present in 6.0-9.5% of sporadic cases

RET mutation MEN2A

98% of families have RET mutation

RET mutation MEN2B

~ 100% of families have RET mutation

RET mutation FMTC

~ 95% of families have RET mutation

Incidence of MTC and Associated Diseases in MEN2 Syndrome Findings

FMTC (% Association)

MEN2A (% Association)

MEN2B (% Association)

Medullary thyroid carcinoma

~ 100

~ 100

~ 100

C-cell hyperplasia

100

100

100

Pheochromocytoma

0

~ 50

~ 50

Hyperparathyroidism

0

20-30

0

Lichen amyloidosis

0

0

10-15

Marfanoid habitus

0

0

100

Mucosal neuromas

0

0

99-100

Intestinal ganglioneuromatosis

0

0

90-100

Thick corneal nerves

0

Rare

60-90

FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B.

186

Thyroid, Medullary Carcinoma Table

Features

Reactive C-Cell Hyperplasia

Neoplastic C-Cell Hyperplasia

Detectable on H&E stains

No

Yes

Cytologic atypia

No

Yes

Seen adjacent to MTC

No

Yes, usually found adjacent to MTC

Associated with MTC

No

Precursor lesion of MTC

Bilaterality

No

Yes

Calcitonin reactivity

Yes

Yes

RET mutation

No

These lesions harbor germline RET mutations

Carcinoembryonic antigen (CEA) reactivity

No

Yes/no

Chromogranin reactivity

Yes

Yes

Synaptophysin reactivity

Yes

Yes

Staining with NCAM 

No

Yes

Diagnoses Associated With Syndromes by Organ: Endocrine

Differential Diagnosis Between Reactive/Physiologic and Neoplastic C-Cell Hyperplasia

Relationship of Common RET Mutations to Risk of Aggressive MTC in MEN2A and MEN2B RET Mutation

Exon

MTC Risk Level

G533C

8

Moderate

C609F/G/R/S/Y;  C611F/G/S/Y/W;  C618F/R/S; C620F/R/S

10

Moderate

C630R/Y;  D631Y;  K666E

11

Moderate

C634F/G/R/S/W/Y

11

High

E768D; L790F

13

Moderate

V804M

14

Moderate

A883F

15

High

S891A

15

Moderate

R912P

16

Moderate

M918T

16

Highest

Adapted from Wells SA et al: Thyroid. 25(6): 567–610, 2015.

ATA Age Recommendations for Prophylactic Thyroidectomy Depending on RET Mutation RET Mutation

Recommended Age for Prophylactic Thyroidectomy

Codons 883, 918, 634

Within 1st year of life

Codons 768, 790, 791, 804, 891

Consider surgery < 5 years; may delay surgery up to 10 years if normal serum calcitonin, normal neck ultrasound, family history of less aggressive tumor

Codons 609, 611, 618, 620, 630

Consider surgery < 5 years; may delay surgery up to 10 years if normal serum calcitonin, normal neck ultrasound, family history of less aggressive tumor

ATA = American Thyroid Association.  Table based on 2015 ATA Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer, Medullary Thyroid Cancer: Management Guidelines of the ATA, and Grubbs EG et al: Do the recent ATA Guidelines accurately guide the timing of prophylactic thyroidectomy in MEN2A.

187

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Thyroid Carcinoma KEY FACTS

CLASSIFICATION • Thyroid carcinoma derived from C cells or follicular cells, occurring in familial setting • Familial follicular cell tumors classified in 2 subgroups ○ Familial follicular cell tumors with predominance of nonmedullary thyroid carcinoma (nonsyndromic) – Most tumors are papillary thyroid cancer (PTC) and have no distinct morphologic findings to differentiate them from sporadic counterparts ○ Familial follicular cell tumors with predominance of nonthyroidal tumors (syndromic) – PTEN-hamartoma tumor syndrome – Familial adenomatous polyposis (FAP) – Carney complex – DICER1 syndrome – Werner syndrome • Familial medullary thyroid carcinoma occurs in 3 distinct settings

○ MEN2A ○ MEN2B ○ Medullary thyroid carcinoma only

ANCILLARY TESTS • Patients with FAP-associated PTC have APC germline mutations with aberrant expression of β-catenin • Patients with PHTS have PTEN mutations with loss of PTEN immunoexpression • Germline point mutation in RET in medullary thyroid carcinoma

DIAGNOSTIC CHECKLIST • Familial thyroid carcinoma has been shown to ○ Occur at younger age ○ Be associated with presence of multiple benign nodules ○ Have high incidence of multifocality and bilateral disease ○ Have more aggressive clinical behavior ○ Have worse prognosis than its sporadic counterparts

Familial Thyroid Carcinoma

Familial thyroid cancers are divided according to the cell of origin. Familial medullary thyroid carcinoma represents 25% of all medullary cancers. Familial nonmedullary thyroid carcinoma (FNMTC) constitutes ~ 10% of all thyroid cancers, and only 5%, the syndromic forms, have known driver germline mutations. The susceptibility chromosomal loci and genes of the nonsyndromic FNMTC cases remain to be identified and characterized. Some of the genes on this chart still need to be validated.

188

Familial Thyroid Carcinoma

Abbreviations • Familial nonmedullary thyroid carcinoma (FNMTC) • Familial medullary thyroid carcinoma (FMTC)

Definitions • Thyroid carcinoma occurring in familial setting ○ Can be syndrome associated or nonsyndromic • Familial thyroid carcinomas are divided into 2 subgroups: FNMTC and FMTC • FNMTC or familial follicular cell tumors: Derived from thyroid follicular cells ○ Further subdivided into 2 subgroups – Familial tumor syndromes characterized by predominance of nonthyroidal tumors – Familial tumor syndromes characterized by predominance of nonmedullary thyroid carcinoma • FMTC: Derived from thyroid calcitonin-producing C cells ○ Occurs in 3 distinct settings – FMTC (medullary thyroid carcinoma-only syndrome) – Multiple endocrine neoplasia 2A (MEN2A) – Multiple endocrine neoplasia 2B (MEN2B)

ETIOLOGY/PATHOGENESIS Familial Nonmedullary Thyroid Carcinoma • Constitutes 3-9% of all thyroid cancers • Out of all FNMTC cases, only 5% in syndromic form have well-studied driver germline mutations ○ These associated syndromes include Cowden syndrome (CS), familial adenomatous polyposis (FAP), Gardner syndrome, Carney complex type 1, Werner syndrome, and DICER1 syndrome

Familial Follicular Cell Tumors or Familial Nonmedullary Thyroid Carcinoma • Rare tumors encompassing heterogeneous group of diseases, including both syndrome-associated and nonsyndromic tumors • Familial tumor syndromes characterized by predominance of nonthyroidal tumors ○ PTEN-hamartoma tumor syndrome (PHTS): CS and Bannayan-Riley-Ruvalcaba syndrome are major entities composing PHTS – Characterized by multiple hamartomas involving multiple organs – Caused by germline mutations of PTEN and inherited in autosomal dominant fashion – PTEN (phosphatase and tensin homolog deleted on chromosome 10) is tumor suppressor gene located on 10q23.3 – Can be caused by mutation of other genes: SDH genes, PIK3CA, AKT1, KLLN, SEC23B ○ FAP: Characterized by hundreds to thousands of colorectal adenomas that develop during early adulthood – Inherited autosomal dominant syndrome caused by germline mutations in adenomatous polyposis coli (APC) on chromosome 5q21 ○ Carney complex: Consists of myxomas, spotty pigmentation, and endocrine overactivity

– Autosomal dominant disease – Most cases classified as type 1 and associated with mutation of protein kinase A regulatory subunit type 1α (PRKAR1A), probable tumor suppressor gene on chromosome 17q22-24 – Type 2 patients have mutation on chromosome 2p16, which may be regulator of genomic stability ○ DICER1 syndrome – Autosomal dominant pleiotropic syndrome caused by germline DICER1 mutations – Tumors and dysplasias with early onset □ Pleuropulmonary blastoma □ Cystic nephroma □ Ovarian tumors: Sertoli-Leydig cell tumor, juvenile granulosa cell tumor □ Pituitary blastoma – Multinodular thyroid hyperplasia and carcinoma ○ Werner syndrome: Rare premature aging syndrome that begins in 3rd decade – Autosomal recessive disease – Caused by mutations in WRN on chromosome 8p11p12 ○ Pendred syndrome: Most common hereditary syndrome associated with bilateral sensorineural deafness – Also called deaf-mutism and goiter – Autosomal recessive trait – Result of mutations in SLC26A4 (PDS), which encodes pendrin protein and is located on chromosome 7q2134 – 100 mutations identified in SLC26A4, and most are family specific • Familial tumor syndromes characterized by predominance of nonmedullary thyroid carcinoma ○ Characterized by ≥ 3 1st-degree relatives with follicularderived nonmedullary thyroid carcinoma and occurs regardless of presence of another familial syndrome ○ Includes – Pure familial papillary thyroid carcinoma (PTC) ± oxyphilia: Mapped to chromosomal region 19q13 – Familial PTC (FPTC) with papillary renal cell carcinoma: Mapped to chromosomal region 1q21 – FNMTC type 1: Mapped to chromosome 2q21 – FPTC with MNG: Mapped to chromosomal region 14q ○ Susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized – To date, 4 susceptibility genes have been identified [SRGAP1 (12q14), TTF1/NKX2-1 gene (14q13), FOXE1 (9q22.33), and HABP2 (10q25.3)] □ Out of which only FOXE1 and HABP2 have been validated – Causal genes located at other 7 FNMTC-associated chromosomal loci [TCO (19q13.2), fPTC/PRN (1q21), FTEN (8p23.1-p22), NMTC1 (2q21), MNG1 (14q32), 6q22, 8q24] have yet to be identified – Increasingly, gene regulatory mechanisms (miRNA and enhancer elements) are recognized to affect gene expression and FNMTC tumorigenesis – Novel germline SEC23B variant, SRGAP1, FOXE1, and HABP2 in nonsyndromic FNMTC

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

189

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Thyroid Carcinoma Familial Medullary Thyroid Carcinoma • Refers to those neoplasms arising from calcitoninproducing C cells derived from neural crest • Medullary thyroid carcinomas (MTCs) occur in sporadic or hereditary (25% of cases) forms, as part of MEN2 syndrome, or as MTC-only syndrome ○ MEN2 syndrome consists of 3 variants: MEN2A, MEN2B, and FMTC ○ MEN2A associated with pheochromocytoma and parathyroid hyperplasia ○ MEN2B associated with marfanoid habitus, mucosal neuromas, ganglioneuromatosis, and pheochromocytoma • Germline gain-of-function mutations in RET protooncogene are major molecular drivers in pathogenesis of hereditary forms of MTC ○ ~ 85% of all RET mutations responsible for FMTC are known ○ In majority of MEN2A and FMTC patients, RET mutations clustered in 6 cysteine residues in RET cysteine-rich extracellular domain ○ Mutations detected in ~ 95% of MEN2A and ~ 85% of FMTC families • Somatic RET point mutations identified in ~ 50% of patients with sporadic MTC

CLINICAL ISSUES Epidemiology • Incidence ○ Thyroid cancer accounts for only 1% of all malignant tumors – Advances in molecular genetics have confirmed presence of several familial cancer syndromes that have FNMTCs ○ 5% incidence of FNMTC in 95% of patients with welldifferentiated thyroid cancer ○ Familial forms of follicular cell-derived tumors are rare and encompass heterogeneous group of diseases, including both syndrome-associated and nonsyndromic tumors – Thyroid neoplasms have been reported with increased frequency in familial syndromes, such as FAP, CS/PHTS, Carney complex type 1, Werner syndrome, Pendred syndrome, DICER1 syndrome – Among nonsyndromic tumors, predominant neoplasm is nonmedullary thyroid carcinoma, although other neoplasms may occur with increased frequency ○ Incidence of MTC in patients with familial disease is 25% – This group represents ~ 5% of all thyroid tumors and ~ 15% of all thyroid cancer-related deaths • Age ○ Familial follicular cell tumors or FNMTC – Age of diagnosis varies, but tumors generally occur in younger patients as compared to their sporadic counterparts ○ MTC – MEN2A syndrome or Sipple syndrome: In late adolescence or early adulthood; peak incidence of MTC in these patients is in 3rd decade 190

– MEN2B patients usually develop MTC early in life, diagnosed in infancy or early childhood; male and female patients equally affected – Inherited MTC without associated endocrinopathies: Similar to other types of thyroid cancers; peak incidence ranges from 40-50 years

Presentation: FNMTC • Syndrome-associated group • Has increased prevalence of follicular cell-derived tumors within familial cancer syndrome with preponderance of nonthyroidal tumors ○ PHTS – > 90% of individuals affected with CS manifest phenotype by age 20 years – By end of or during 3rd decade, almost all patients (99%) develop at least pathognomonic mucocutaneous lesions – Affected individuals with CS develop both benign and malignant tumors in variety of organs, such as breast, uterus, and thyroid gland – Individuals with germline PTEN mutation have 35% lifetime risk of thyroid cancer – Thyroid pathologic findings in this syndrome typically involve follicular cells ○ FAP – Extracolonic manifestations include osteomas, epidermal cysts, desmoid tumors, gastrointestinal tract polyps/hamartomas, congenital hypertrophy of retinal pigmented epithelium (CHRPE), hepatoblastomas – PTC in 2-12% of FAP patients – Young women with FAP at particular risk of developing thyroid cancer, ~ 160x that of normal individuals – PTC occurs with frequency of ~ 10x expected for sporadic PTC ○ Carney complex – Characterized by skin and mucosal pigmentation, diverse pigmented skin lesions, nonendocrine and variety of endocrine neoplasias: Pituitary adenoma, pigmented nodular adrenal disease, Sertoli-Leydig cell tumors, and thyroid tumors – Myxomas occur in heart, skin or soft tissue, external auditory canal, and breast ○ Werner syndrome – Elderly appearance with short stature, thin skin, wrinkles, alopecia, and muscle atrophy – Age-related disorders (e.g., osteoporosis, cataracts, diabetes, peripheral vascular disease, or malignancy) are present in these patients – Cardiac disease and cancer are most common causes of death in these patients – Mutations of WRN gene is specifically associated with malignancies such as melanoma, soft tissue sarcoma, osteosarcomas, and well-differentiated thyroid carcinoma ○ DICER1 syndrome: Multinodular goiter (MNG) and carcinoma – It has been associated with both familial MNG and MNG with ovarian Sertoli-Leydig cell tumors, independent of pleuropulmonary blastoma

Familial Thyroid Carcinoma

Presentation: FMTC • MEN2A syndrome or Sipple syndrome has bilateral MTC or primary C-cell hyperplasia, pheochromocytoma, and hyperparathyroidism ○ Inherited in autosomal dominant manner; male and female patients equally affected • MEN2B associated with pheochromocytoma and alterations in nonendocrine tissue ○ Syndrome also has MTC and pheochromocytoma but only rarely hyperparathyroidism ○ Patients have unusual appearance characterized by mucosal ganglioneuromas and marfanoid habitus ○ Inheritance autosomal dominant, as in MEN2A • FMTC or inherited MTC without associated endocrinopathies ○ Least aggressive form of MTC ○ MTC usually develops in patients with no other clinical manifestations

MACROSCOPIC General Features • Familial tumors have high incidence of multifocality, more likely to be bilateral

MICROSCOPIC Histologic Features • Familial tumor syndromes characterized by predominance of nonmedullary thyroid carcinoma ○ Most tumors are PTC and have no distinct morphologic findings to differentiate them from sporadic counterparts ○ Mutations in patients with FNMTC syndromes have not been as well defined as in MTC ○ Familial thyroid cancers more aggressive than sporadic thyroid cancer, with predisposition for lymph node metastasis, extrathyroidal invasion, and younger age of onset • PHTS ○ ~ 2/3 of CS patients develop thyroid tumors; pathologic findings in this syndrome have been described as involving follicular cells ○ Majority of thyroid lesions occurring in PHTS characteristically multicentric and bilateral; benign and malignant thyroid lesions observed in PHTS ○ Multiple adenomatous nodules with multiple distinct well-circumscribed nodules, firm yellow-tan cut surface, diffusely involving thyroid gland ○ Follicular adenomas are very common, occur at earlier age, and usually multicentric ○ Follicular carcinoma is major criterion and important feature in PHTS; these tumors are more frequently multicentric ○ PTC, follicular variant is associated with this syndrome – Cases with mutations of SDH or both SDH and PTEN show predominant classic PTC histology ○ C-cell hyperplasia has been associated with this entity • FAP ○ Thyroid tumors in FAP occur almost exclusively in young female patients; tumors bilateral, multifocal, and well differentiated ○ Among patients with FAP who have synchronous PTC, > 90% exhibit histologic features of cribriform-morular variant (CMV), which focally shows typical nuclear features of PTC ○ Characteristic cribriform pattern with solid areas and spindle cell component, associated with marked fibrosis and morular areas ○ Characteristic PTC morphology associated with follicular, papillary, trabecular, solid, spindle cell, and squamoid areas ○ Tumors with identical histology can occur as sporadic lesions without background of FAP • Carney complex ○ Thyroid is multinodular and has multifocal and bilateral thyroid disease ○ Lymphocytic thyroiditis, multinodular hyperplasia, multiple follicular adenomas, characteristic multiple adenomatous nodules, follicular carcinoma, and PTC usually present in ~ 15% of patients • DICER1 syndrome ○ Multinodular and bilateral thyroid disease • Werner syndrome

Diagnoses Associated With Syndromes by Organ: Endocrine

– Differentiated thyroid cancer (PTC and follicular thyroid carcinoma) is variably observed in DICER1 syndrome ○ Pendred syndrome: Thyroid disease in these patients may range from minimal enlargement to large, MNG – Most patients are euthyroid • Familial tumor syndromes characterized by predominance of nonmedullary thyroid carcinoma (follicular cell-derived tumors) ○ FNMTC associated with multiple benign nodules, multifocality, bilateral disease, more aggressive clinical behavior, and worse prognosis than sporadic nonmedullary thyroid cancer – Diagnosed when ≥ 3 family members have nonmedullary thyroid cancer in absence of other known associated syndromes – Shorter disease-free survival than sporadic disease because of frequent locoregional recurrence – Increased risk of multifocal disease and more likely to have intraglandular dissemination, local invasion, local or regional recurrence, and lymph node metastases ○ Familial multinodular goiter syndrome (mapped to 14q) – Some patients may develop associated PTC ○ FNMTC type 1 syndrome (chromosomal region 2q21) – Characterized by PTC without any distinguishing pathologic features ○ FPTC associated with papillary renal neoplasia syndrome (mapped to chromosomal region 1q21) – Includes not only PTC and expected benign thyroid nodules but also papillary renal neoplasia ○ FPTC (chromosomal region 19p13) – Characterized by multicentric tumors and multiple adenomatous nodules ± oxyphilia

191

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Thyroid Carcinoma ○ Patients present at younger age and have ~ 3x ↑ risk for developing follicular carcinoma, 6x ↑ risk for anaplastic thyroid carcinoma, and slight ↑ risk for PTC • Pendred syndrome ○ Association of thyroid cancer and Pendred syndrome may be related to untreated congenital hypothyroidism and chronic stimulation by thyroid-stimulating hormone ○ Progression from thyroid goiter to cancer uncommon; risk likely related to longstanding untreated hypothyroidism • FMTC ○ Morphologically indistinguishable from sporadic tumor counterpart ○ Associated with C-cell hyperplasia

ANCILLARY TESTS

2.

3. 4.

5. 6.

7. 8.

Immunohistochemistry • CMV-PTC is characterized by aberrant nuclear and cytoplasmic expression of β-catenin • Immunostains of CMV-PTC show positivity for ER and PR, Bcl-2, E-cadherin, and galectin-3 • Immunostain for PTEN is lost in follicular cells of some nodules of PHTS • All other familial tumors have similar immunophenotype to sporadic thyroid tumor counterparts

9.

Genetic Testing

14.

• Germline point mutation in RET on chromosome 10q11.2 responsible for hereditary MTC • Most patients with FAP-associated PTC have APC germline mutations • Most patients with PHTS have germline mutations on gene PTEN • Genetic inheritance of FNMTC remains unknown, believed to be autosomal dominant ○ To date, only 4 susceptibility genes have been identified: SRGAP1, FOXE1, HABP2, TITF1/NKX2-1, and telomeretelomerase complex ○ Causal genes located at other 7 FNMTC-associated chromosomal loci have yet to be identified: 6q22, 8q24, TCO (19q13.2), fPTC/PRN (1q21), FTEN (8p23.1p22), NMTC1 (2q21), MNG1 (14q32)

DIFFERENTIAL DIAGNOSIS Follicular Cell Carcinoma • Sporadic follicular cell neoplasm ○ Usually single and unilateral; ~ 95% cases ○ Morphologically indistinguishable from tumor occurring in familial setting

Medullary Thyroid Carcinoma • Sporadic MTC ○ Accounts for up to 75% of all cases of medullary thyroid cancer ○ Female patients outnumber male patients by 3:2 ○ Peak of onset: 40-60 years of age; mean: 50 years ○ Typically unilateral; not associated with C-cell hyperplasia ○ No associated endocrinopathies (not associated with disease in other endocrine glands)

192

SELECTED REFERENCES 1.

10. 11. 12. 13.

15.

16.

17. 18. 19.

20. 21.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

Zhang YB et al: Familial nonmedullary thyroid carcinoma: a retrospective analysis of 117 families. Chin Med J (Engl). 131(4):395-401, 2018 Dong L et al: [Next generation sequencing technology for susceptible gene screening in familial non-medullary thyroid carcinoma.] Zhonghua Zhong Liu Za Zhi. 39(1):24-8, 2017 Klubo-Gwiezdzinska J et al: Results of screening in familial non-medullary thyroid cancer. Thyroid. 27(8):1017-24, 2017 Marques IJ et al: Identification of somatic TERT promoter mutations in familial nonmedullary thyroid carcinomas. Clin Endocrinol (Oxf). 87(4):394-9, 2017 Oh EJ et al: TERT promoter mutation in an aggressive cribriform morular variant of papillary thyroid carcinoma. Endocr Pathol. 28(1):49-53, 2017 Schultz KAP et al: PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(12):e76-82, 2017 Scognamiglio T: C cell and follicular epithelial cell precursor lesions of the thyroid. Arch Pathol Lab Med. 141(12):1646-52, 2017 Vidinov K et al: Familial papillary thyroid carcinoma (FPTC): a retrospective analysis in a sample of the Bulgarian population for a 10-year period. Endocr Pathol. 28(1):54-9, 2017 Cao J et al: Clinicopathological features and prognosis of familial papillary thyroid carcinoma--a large-scale, matched, case-control study. Clin Endocrinol (Oxf). 84(4):598-606, 2016 Essig GF Jr et al: Multifocality in sporadic medullary thyroid carcinoma: an international multicenter study. Thyroid. 26(11):1563-72, 2016 Nixon IJ et al: The impact of family history on non-medullary thyroid cancer. Eur J Surg Oncol. 42(10):1455-63, 2016 Peiling Yang S et al: Familial non-medullary thyroid cancer: unraveling the genetic maze. Endocr Relat Cancer. 23(12):R577-95, 2016 Valdes-Socin H et al: [A familial non medullary thyroid carcinoma (FNMTC): a clinical and genetic update.] Rev Med Liege. 71(12):557-61, 2016 Chernock RD et al: Molecular pathology of hereditary and sporadic medullary thyroid carcinomas. Am J Clin Pathol. 143(6):768-77, 2015 Dehner LP et al: Pleuropulmonary blastoma: evolution of an entity as an entry into a familial tumor predisposition syndrome. Pediatr Dev Pathol. 18(6):504-11, 2015 Feng X et al: Characteristics of benign and malignant thyroid disease in familial adenomatous polyposis patients and recommendations for disease surveillance. Thyroid. 25(3):325-32, 2015 Gara SK et al: Germline HABP2 mutation causing familial nonmedullary thyroid cancer. N Engl J Med. 373(5):448-55, 2015 Jiwang L et al: Clinicopathologic characteristics of familial versus sporadic papillary thyroid carcinoma. Acta Otorhinolaryngol Ital. 35(4):234-42, 2015 Pereira JS et al: Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC). Endocrine. 49(1):204-14, 2015 Sakorafas GH et al: Incidental thyroid C cell hyperplasia: clinical significance and implications in practice. Oncol Res Treat. 38(5):249-52, 2015 Sung TY et al: Surgical management of familial papillary thyroid microcarcinoma: a single institution study of 94 cases. World J Surg. 39(8):1930-5, 2015 Tomsic J et al: HABP2 Mutation and nonmedullary thyroid cancer. N Engl J Med. 373(21):2086, 2015 Laury AR et al: Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 21(2):135-44, 2011 Nosé V: Familial thyroid cancer: a review. Mod Pathol. 24 Suppl 2:S19-33, 2011 Smith JR et al: Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab. 96(1):34-7, 2011 Zhang Y et al: Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 18(3):206-18, 2011 Almeida MQ et al: Solid tumors associated with multiple endocrine neoplasias. Cancer Genet Cytogenet. 203(1):30-6, 2010 Farooq A et al: Cowden syndrome. Cancer Treat Rev. 36(8):577-83, 2010 Frank-Raue K et al: Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Mol Cell Endocrinol. 322(1-2):2-7, 2010 Khan A et al: Familial nonmedullary thyroid cancer: a review of the genetics. Thyroid. 20(7):795-801, 2010 Nosé V: Familial follicular cell tumors: classification and morphological characteristics. Endocr Pathol. 21(4):219-26, 2010 Nosé V: Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 17(6):428-36, 2010 Richards ML: Familial syndromes associated with thyroid cancer in the era of personalized medicine. Thyroid. 20(7):707-13, 2010

Familial Thyroid Carcinoma

Disease

Histologic Subtype

Syndromic or Familial Tumor Syndrome With Preponderance of Nonthyroidal Tumors PTEN-hamartoma tumor syndrome (Cowden syndrome)

FTC or follicular variant of PTC, associated with follicular adenomas, multiple adenomatous nodules, and C-cell hyperplasia

FAP hamartoma tumor syndrome

PTC with cribriform and morular patterns with sclerosis

Carney complex

FTC associated with follicular adenomas, multiple adenomatous nodules, and PTC

      DICER1 syndrome

Multinodular thyroid hyperplasia and carcinoma

Pendred syndrome

FTC

Werner syndrome

FTC, PTC, and ATC

Nonsyndromic or Familial Tumor Syndrome With Preponderance of Nonmedullary Thyroid Carcinoma Familial papillary thyroid carcinoma

PTC, usual variant

Familial papillary thyroid carcinoma with papillary renal cell neoplasia

PTC, usual variant

Familial nonmedullary thyroid carcinoma type 1

PTC, usual variant

Familial papillary thyroid carcinoma and multinodular goiter

PTC and nodular hyperplasia

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Follicular Cell Carcinoma Classification

ATC = anaplastic thyroid carcinoma; FAP = familial adenomatous polyposis; FTC = follicular thyroid carcinoma; PTC = papillary thyroid carcinoma.

Familial Follicular Cell Cancer in Familial Cancer Syndromes Syndrome

Inheritance

Gene

Gene Location

Thyroid Involvement

PTEN-hamartoma tumor syndrome

Autosomal dominant

PTEN  and other genes (SDH, PIK3CA, AKT1, KLLN, or SEC23B)

10q23.2

50% (thyroid cancer 35%)

Familial adenomatous polyposis

Autosomal dominant

APC

5q21

2-12%

Carney complex

Autosomal dominant

PRKAR1-α

2p12-17q22-24

60; 4%

Pendred syndrome

Autosomal recessive

SLC26A4 (pendrin)

7q21-24

1%

Werner syndrome

Autosomal recessive

WRN

8p11-p12

18%

DICER1 syndrome

Autosomal dominant

DICER1

14q32.13

Most

MEN2 Syndromes Associated With Heritable Medullary Thyroid Carcinoma MEN2A

MEN2B

Familial Medullary Thyroid Carcinoma

Frequency

35-30%

5-10%

50-60%

Mean age at presentation

25-35 years

10-20 years

45-55 years

Presence of C-cell hyperplasia

100%

100%

100%

Medullary thyroid carcinoma

> 90%

> 90%

> 90%

MEN2A = multiple endocrine neoplasia 2A; MEN2B = multiple endocrine neoplasia 2B. 34. Rubinstein WS: Endocrine cancer predisposition syndromes: hereditary paraganglioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, and hereditary thyroid cancer. Hematol Oncol Clin North Am. 24(5):907-37, 2010 35. Wohllk N et al: Multiple endocrine neoplasia type 2. Best Pract Res Clin Endocrinol Metab. 24(3):371-87, 2010 36. Alevizaki M et al: Multiple endocrine neoplasias: advances and challenges for the future. J Intern Med. 266(1):1-4, 2009 37. Dotto J et al: Familial thyroid carcinoma: a diagnostic algorithm. Adv Anat Pathol. 15(6):332-49, 2008 38. Etit D et al: Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Arch Pathol Lab Med. 132(11):1767-73, 2008

39. Nosé V: Familial non-medullary thyroid carcinoma: an update. Endocr Pathol. 19(4):226-40, 2008 40. Yassa L et al: Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer. 111(6):508-16, 2007 41. Zambrano E et al: Abnormal distribution and hyperplasia of thyroid C-cells in PTEN-associated tumor syndromes. Endocr Pathol. 15(1):55-64, 2004 42. DeLellis RA et al: C-cell hyperplasia and medullary thyroid carcinoma in the rat. An immunohistochemical and ultrastructural analysis. Lab Invest. 40(2):140-54, 1979 43. Wolfe HJ et al: Distribution of calcitonin-containing cells in the normal neonatal human thyroid gland: a correlation of morphology with peptide content. J Clin Endocrinol Metab. 41(06):1076-81, 1975

193

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Thyroid Carcinoma

Grossly Normal Thyroid and Thymus

Calcitonin in C-Cell Hyperplasia

PET/CT Imaging

Amyloid Deposition

Bilateral Thyroid Tumors

Variable Calcitonin Stain

(Left) Total prophylactic thyroidectomy and thymectomy from a patient with a family history of MEN2 with RET mutation shows a grossly normal thyroid. The entirely submitted specimen showed C-cell hyperplasia (CCH) and 2 foci of medullary thyroid carcinoma. (Right) Specimen from a patient with MEN2 syndrome who underwent prophylactic thyroidectomy shows CCH with calcitonin-positive C cells surrounding the thyroid follicle. Heritable medullary thyroid carcinoma is preceded by neoplastic CCH.

(Left) Fused transaxial FDG PET/CT shows a focal hypermetabolic mass ſt in the right thyroid lobe in a patient with medullary thyroid cancer. (Right) H&E shows the characteristic histologic appearance of medullary thyroid carcinoma, a highly cellular tumor with a variable amount of fibrosis and amyloid deposition.

(Left) Gross cut surface of both thyroid lobes from a patient with MEN2A shows 2 well-circumscribed whiteyellow thyroid tumor nodules. Medullary thyroid carcinomas are usually firm and gritty, and familial medullary thyroid carcinomas are usually bilateral and have associated CCH. (Right) Medullary thyroid carcinoma from a patient with familial medullary thyroid carcinoma syndrome shows variable cytoplasmic immunostaining for calcitonin.

194

Familial Thyroid Carcinoma

Adenomatous Nodules (Left) Gross cut surface of a thyroid from an 18-year-old woman with Cowden syndrome/PTEN-hamartoma tumor syndrome shows multiple well-circumscribed nodules almost entirely replacing the thyroid parenchyma ﬇. (Right) H&E of the thyroid from an 18year-old woman with Cowden syndrome shows multiple wellcircumscribed adenomatous nodules with a small amount of compressed residual thyroid parenchyma ﬊.

Uniform Microfollicles

Diagnoses Associated With Syndromes by Organ: Endocrine

Multiple Pale Thyroid Nodules

Angioinvasion in Follicular Carcinoma (Left) High-power view of an adenomatous nodule in a patient with Cowden syndrome shows a homogeneous architecture of microfollicles, indistinguishable from their sporadic counterparts. (Right) An encapsulated follicular carcinoma from a 12-year-old girl with Cowden syndrome shows capsular invasion and lymphovascular invasion ﬇. Follicular carcinoma is a major criterion for diagnosis of this syndrome.

Loss of PTEN

Loss of PTEN Stain (Left) Immunohistochemistry for PTEN shows loss of staining of the follicular cells with preservation of staining of the endothelial cells within 1 nodule ﬇ and preservation of PTEN immunostain in the adjacent nodule ﬊. (Right) High-power view shows loss of PTEN staining in the follicular cells. Preservation of PTEN staining of the endothelial cells and smooth muscle cells in a vessel wall ﬈ are well illustrated.

195

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Thyroid Carcinoma

Numerous Colonic Polyps

Eye Lesion in Familial Adenomatous Polyposis

Cut Surface of Large Tumor

Cribriform Arrangement

Encapsulated Microcarcinoma

Nuclear β-Catenin

(Left) Colectomy specimen from a 17-year-old girl with known thyroid tumor and familial adenomatous polyposis shows numerous polyps on the mucosal surface. This patient had multiple foci of cribriform-morular papillary thyroid carcinoma (PTC). (Right) Congenital hypertrophy of the pigmented retinal epithelium is shown. This condition is benign, and it is found in up to 2/3 of patients with familial adenomatous polyposis.

(Left) Gross cut surface of a large PTC, cribriform-morular variant (CMV), shows irregular areas of fibrosis and a pale, soft, and friable tumor mass occupying most of the section. This variant usually has extensive fibrosis and a thick, fibrous capsule. They are usually multiple and bilateral. (Right) Cytologic features of tumor cells typically seen in PTC, CMV are shown. The cells are cuboidal with basophilic cytoplasm and hyperchromatic nuclei. Note the absence of classic PTC nuclei.

(Left) Encapsulation is common in this variant of PTC. This example shows a thick, fibrous band encapsulating the tumor. Note the papillary and cribriform architecture. Also shown are eosinophilic foci of sclerosis/hyalinization ﬈ within the stroma. This focus of tumor was < 1 cm. (Right) β-catenin immunostain shows the characteristic cytoplasmic and nuclear staining ﬊ in PTC, CMV as well as the cytoplasmic membrane staining in the adjacent compressed follicular cells ﬉.

196

Familial Thyroid Carcinoma

Squamous Morules (Left) PTC, CMV highlights the cribriform appearance of these types of tumors. This tumor shows areas of both cribriform pattern and solid pattern; however, this tumor has a predominantly cribriform architecture. (Right) Solid pattern of PTC, CMV is shown. In the center, there are squamous morules with the characteristic peculiar nuclear clearing ﬈.

CD5(+) Squamous Morules

Diagnoses Associated With Syndromes by Organ: Endocrine

Cribriform Arrangement

Keratin in Squamous Morule (Left) Morules in CMV show immunopositivity for CD5 in the cell membranes and focally within cytoplasm. Note that the adjacent T lymphocytes ﬊ demonstrate strong staining for CD5. (Right) Characteristically, the squamous morules are positive for cytokeratin 5/6 and also for CD5. The cribriform component is negative for these markers.

Cribriform Pattern Lacking Colloid

Nuclear β-Catenin (Left) Cribriform pattern tumor with focal solid areas and a spindle cell component ﬈ is shown at high magnification. The cells are spindled with basophilic cytoplasm and hyperchromatic nuclei with absence of typical PTC nuclei. (Right) High-power β-catenin immunostain of PTC, CMV shows characteristic nuclear and cytoplasmic staining resulting from aberrant accumulation within the nucleus. Note that the endothelial cells are negative ﬊.

197

Diagnoses Associated With Syndromes by Organ: Endocrine

Familial Thyroid Carcinoma

Hereditary Renal and Thyroid Carcinoma

Papillary Arrangement

Papillae Formation

TTF-1-Positive Papillary Tumor

Hobnail Variant of Papillary Thyroid Carcinoma

Hobnail Tumor Cells

(Left) Familial PTC associated with renal papillary neoplasia (fPTC/PRN) has been described as a familial association of PTC, thyroid nodules, and PRN. The thyroid of a 26-year-old woman with a family history of hereditary papillary renal cell carcinoma and PTC shows classic features of tumors. (Right) In hereditary papillary renal cell carcinoma and PTC, both tumors of the distinct sites are similar. However, only thyroid carcinoma is positive for TTF1.

(Left) High-power view shows the papillary arrangement of cells around a thin fibrovascular core. The cells have a pale-pink cytoplasm and irregular nuclear membranes. This image shows papillary arrangement with a glomeruloid appearance. A psammoma body is present. (Right) Morphological features of both kidney and papillary thyroid carcinomas are similar. The immunostain for TTF-1 confirms the thyroid origin for thyroid tumor and not metastases from the kidney.

(Left) Thyroid tumor of a young female patient with CHEK2 mutation and a history of breast cancer and ovarian tumor shows a papillary carcinoma composed of cells with hobnail features. These tumors usually occur in older patients as nonsyndromic tumors. (Right) High-power view highlights the cellular characteristics of the hobnail variant of PTC. In this hereditary tumor, the morphologic characteristics are similar. These tumors are known to be aggressive in a sporadic setting.

198

Familial Thyroid Carcinoma

Lymphatic Involvement (Left) Graphics show carcinogenesis model of progression of multinodular hyperplasia to thyroid carcinoma in DICER1 syndrome. (Right) Thyroid of this patient with familial thyroid carcinoma with cell oxyphilia shows marked lymphocytic thyroiditis and numerous foci of tumor cells within intrathyroid vascular channels. Note that psammoma bodies ﬊ are present among the tumor cells.

Lymphovascular Invasion

Diagnoses Associated With Syndromes by Organ: Endocrine

Carcinogenesis Model in DICER1 Syndrome

Squamous Morules (Left) HBME1 highlights the tumor cells within intrathyroid vascular channels in this patient with familial thyroid carcinoma with cell oxyphilia. (Right) This familial PTC with cell oxyphilia shows focal squamous morules. These are highlighted by cytokeratin 5/6 stain.

Familial Papillary Thyroid Carcinoma

Multiple Tumors (Left) Classic features of PTC are shown in a patient with family history of a brother and a sister with numerous thyroid tumors. The morphologic features of this tumor are indistinguishable from sporadic PTC. (Right) PTC is shown in a patient with numerous tumors measuring up to 1.3 cm and a family history of a brother and a sister with numerous thyroid tumors.

199

Diagnoses Associated With Syndromes by Organ: Endocrine

Follicular Thyroid Carcinoma KEY FACTS ○ Up to 3% of patients will have FTC

TERMINOLOGY • Follicular thyroid carcinoma (FTC): Malignant epithelial tumor of thyroid showing evidence of follicular cell differentiation but lacking diagnostic features of papillary thyroid carcinoma

ETIOLOGY/PATHOGENESIS • Iodine deficiency considered important risk factor for development of follicular adenoma and FTC • PTEN-hamartoma tumor syndrome ○ Usually associated with multiple follicular adenomas • Carney complex ○ ~ 75% of patients develop multiple thyroid nodules • McCune-Albright syndrome ○ Associated with FTC and papillary carcinomas • Li-Fraumeni syndrome ○ Unusual thyroid follicular cell tumors with marked nuclear pleomorphism • Werner syndrome

ANCILLARY TESTS • Cytogenetic changes found in ~ 65% of FTC • Most common somatic mutations in FTC: RAS point mutations and PPARG gene fusions • TERT promoter mutations found in ~ 20% of FTC • FTC occurring in familial setting: Mutations in PTEN, PRKAR1A, WRN, GNAS1, and WRN

DIAGNOSTIC CHECKLIST • Pathologist's most important tasks ○ Demonstrate capsular &/or vascular invasion, as diagnosis of FTC rests on identifying these ○ Identify pathological characteristics of inherited tumor syndrome – Usually multifocal and bilateral – Familial cases usually associated with adenomatous nodules, multinodular hyperplasia, follicular adenomas, and lymphocytic thyroiditis

FTC and Hyperplastic Nodules

Gross cut surface of thyroid from a 29-year-old patient with PTEN-hamartoma tumor syndrome/Cowden disease shows a minimally invasive follicular carcinoma ﬇, confirmed by histopathology, adjacent to hyperplastic nodules st.

200

Follicular Thyroid Carcinoma

Abbreviations • Follicular thyroid carcinoma (FTC)

Synonyms • Follicular carcinoma • Familial nonmedullary thyroid carcinoma • Familial FTC

Definitions • FTC: Thyroid malignancy arising from follicular cells in which diagnostic features of papillary thyroid carcinoma (PTC) are absent ○ Lesions usually encapsulated and show invasive growth ○ Occurs in familial setting

ETIOLOGY/PATHOGENESIS Environmental Exposure • Radiation exposure results in 5.2x relative risk for developing FTC • Iodine deficiency associated with higher risk for development of follicular adenoma and follicular carcinoma

Inherited Tumor Syndromes • Account for at least 5% of FTC in USA • PTEN-hamartoma tumor syndrome (PHTS) ○ Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome ○ Germline mutation of PTEN transmitted in autosomal dominant fashion ○ Individuals may also develop multiple hamartomas of breast, colon, endometrium, brain, and ganglioneuromatous proliferations – Trichilemmomas ○ Affected individuals may develop benign and malignant tumors of breast, uterus, and thyroid – Breast cancer: Early onset; most women diagnosed between 38-46 years of age ○ May be associated with multiple follicular adenomas and carcinomas of thyroid – Thyroid tumors associated with multiple thyroid nodules in young patient – FTC major diagnostic criterion for diagnosis of PHTS • Carney complex ○ Autosomal dominant disorder caused by mutations in PRKAR1A ○ Carney complex includes cardiac myxomas, multiple endocrine neoplasms, and spotty cutaneous pigmentation ○ 75% of patients develop multiple thyroid nodules – Patients may present with follicular or papillary carcinoma – Usually tumors arise in background of nodular hyperplasia or multiple adenomatous nodules • McCune-Albright syndrome ○ Patients harbor postzygotic mutations in GNAS1 with mosaic distribution

○ Triad of café au lait skin pigmentation, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies ○ Associated with precocious puberty, hyperthyroidism, GH excess, and Cushing syndrome – Associated with FTC and papillary thyroid carcinomas • Li-Fraumeni syndrome ○ Caused by germline mutation of TP53 ○ Development of diverse sarcomas and carcinomas at young age ○ Unusual thyroid follicular cell tumors with marked nuclear pleomorphism • Werner syndrome ○ Autosomal recessive ○ Caused by mutations in WRN ○ Age-related disorders present early in life, including malignancies – Melanoma, soft tissue sarcoma, osteosarcoma – Up to 3% of patients will have thyroid disease, usually FTC

Diagnoses Associated With Syndromes by Organ: Endocrine

TERMINOLOGY

Preexisting Thyroid Disease • Present in up to 15% of patients with FTC • Dyshormonogenic goiter with chronic TSH stimulation may predispose to follicular neoplasms • Associated with other thyroid tumors, mostly follicular adenoma ○ These tumors are identical histologically ○ Follicular adenoma may be precursor to follicular carcinoma – Both harbor RAS, PTEN, and PIK3CA mutations • Lymphocytic thyroiditis and FTC may coexist • Association between lymphocytic thyroiditis and FTC remains unclear

CLINICAL ISSUES Epidemiology • Incidence ○ 6-10% of thyroid malignancies • Age ○ Inherited syndrome-related FTC affects patients at earlier age than does sporadic FTC – Sporadic cases: 5th decade • Sex ○ More common in women

Presentation • Painless mass • Slow growing • Difficulty swallowing

Prognosis • 70-80% cure rate if disease confined to thyroid • 20-30% recurrence when regional lymph node metastases present • 50-90% of patients who present with distant metastases will die

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Diagnoses Associated With Syndromes by Organ: Endocrine

Follicular Thyroid Carcinoma

IMAGING Ultrasonographic Findings • In minimally invasive disease, usually well-circumscribed nodule (> 1 cm) • Cannot distinguish follicular adenoma from FTC ○ Carcinoma usually associated with microcalcifications, hypoechogenicity, irregular margins or absent halo sign, solid aspect, intranodular vascularization, and shape (taller than wide) • May be helpful in assessing lymph node involvement by thyroid carcinoma

Scintigraphy • Scan shows "cold" nodule

MACROSCOPIC General Features • Round to ovoid encapsulated tumors, tan to light brown • Usually multiple and bilateral in familial setting • Minimally invasive tumors: Thick, irregular, fibrous capsule and grossly similar or indistinguishable from follicular adenoma • Widely invasive carcinomas: Lack of capsule or extensive permeation of capsule

Size • Round to ovoid encapsulated tumors, 1-10 cm in diameter

MICROSCOPIC Histologic Features • Diagnosis of FTC requires demonstration of capsular &/or vascular invasion • FTC subclassified into 3 groups ○ Minimally invasive: Capsular invasion only ○ Encapsulated angioinvasive: Extent of vascular invasion prognostically relevant ○ Widely invasive: Extensive extension into thyroid and extrathyroidal tissues • Cytoarchitectural features of FTC similar to those of follicular adenoma ○ Trabecular, solid, microfollicular, normofollicular, macrofollicular ○ Mixed architectural patterns also occur • Variants ○ Clear cell ○ Signet ring cell type ○ Glomeruloid pattern ○ Spindle cell type • FTC lacks nuclear features of PTC • FTC generally surrounded by thick, irregular, fibrous capsule • Criteria for capsular invasion ○ Tumor bud has invaded beyond outer contour of capsule ○ Tumor bud still clothed by thin capsule; however, it has extended through outer capsular surface ○ Presence of satellite nodule with cytoarchitectural and cellular features identical to those of tumor cells ○ Classic mushroom-like bud that has totally transgressed fibrous capsule • Criteria for vascular invasion 202

○ Blood vessels should be of larger caliber with identifiable wall size of vein, and involved blood vessels must be located within or outside fibrous capsule (i.e., not within tumor) ○ Intravascular polypoid tumor growth must protrude into lumen, be covered by endothelium, and be attached to wall of vessel and associated with thrombus ○ Clusters of epithelial cells floating in vascular lumen and unattached to wall not considered vascular invasion • Nodal status ○ Metastasis present or absent ○ Ipsilateral vs. contralateral ○ Number with metastases ○ Size of largest metastatic deposit ○ Metastases reportedly more frequent in familial cases • Follicular carcinoma in familial diseases may be incidental finding within thyroid with multiple nodules ○ Tumors arise in background of multiple adenomatous nodules, nodular hyperplasia, &/or lymphocytic thyroiditis ○ Follicular carcinoma in inherited syndromes tends to be – Smaller than sporadic tumors – Multiple – Bilateral

Categories of Tumor • Minimally invasive FTC • Encapsulated angioinvasive FTC • Widely invasive FTC

ANCILLARY TESTS Immunohistochemistry • Expression of lineage-specific antigens: pax-8, TTF-1, thyroglobulin • Value of any other markers questionable

Genetic Testing • FTC has significantly higher rate of numerical chromosomal abnormalities and losses and gains of specific chromosomal regions than PTC • Cytogenetic changes found in ~ 65% of FTC • Most common somatic mutation in FTC ○ RAS point mutations in 30-50% of tumors ○ PPARG gene fusions (PAX8-PPARG or CREB3L2-PPARG) that occur in 20-30% of FTC ○ TERT promoter mutations found in ~ 20% of FTC ○ PIK3CA mutations found in up to 10% of FTC ○ Inactivation of PTEN found in up to 10% of FTC • Accumulation of additional mutations, such as TP53, may be associated with progression to poorly differentiated carcinomas • FTC occurring in familial setting ○ PHTS (Cowden disease and other syndromes), Carney complex, Werner syndrome, McCune-Albright syndrome – Mutations in PTEN, PRKAR1A, WRN, and GNAS1 ○ Family history of thyroid carcinoma identified in ~ 4% of patients diagnosed with FTC ○ Testing families with history of cancer – Most useful to begin by testing individual with cancer

Follicular Thyroid Carcinoma

DIFFERENTIAL DIAGNOSIS

• Clinical picture of hyperparathyroidism should raise suspicion • Histological examination will confirm parathyroid tissue

DIAGNOSTIC CHECKLIST

Papillary Thyroid Carcinoma, Follicular Variant

Pathologic Interpretation Pearls

• Follicular pattern of growth, can be encapsulated • Usually shows typical papillary carcinoma features: Groundglass nuclei, intranuclear pseudoinclusions, nuclear grooves, and overlapping nuclei • Immunohistochemistry for HBME-1, galectin-3, and CK19 may help distinguish follicular variant of PTC from FTC

• Pathologist's most important tasks ○ Demonstrate capsular &/or vascular invasion, as diagnosis of FTC rests on identifying these ○ Differentiate between FTC and numerous variants of follicular adenoma and other benign or malignant neoplasms ○ Identify pathological characteristics of inherited tumor syndrome – Thyroid carcinoma in familial setting usually multifocal and bilateral – Familial cases usually associated with other thyroid pathology: Adenomatous nodules, multinodular hyperplasia, follicular adenomas, and lymphocytic thyroiditis

Noninvasive Follicular Tumor With Papillary-Like Nuclear Features • Encapsulated or well-circumscribed follicular neoplasm with papillary-like nuclear features • No capsular or vascular invasion

Follicular Adenoma • Encapsulated benign neoplasm with variable architecture and histologic patterns • Only features to reliably distinguish adenoma from FTC are capsular &/or vascular invasion

Adenomatous Nodule • Frequently multiple, variably sized follicles with no capsule or incomplete capsule • May have abundant edematous or hyalinized stroma

Hyperplastic Nodules in Dyshormonogenetic Goiter • Hypercellular nodules with varied appearances commonly solid and microfollicular • Atypia with bizarre nuclei may be present • Irregular areas of fibrosis at periphery of nodules may simulate capsular invasion

Hyperplastic Nodules in Hashimoto Thyroiditis • Diffusely enlarged and firm thyroid • Lymphocytic infiltration of stroma, formation of large lymphoid follicles • Thyroid follicles often small and atrophic, lined by Hürthle cells

Hyalinizing Trabecular Tumor • Trabecular growth pattern with medium-sized, elongated cells with granular cytoplasm • No follicle formation and absent colloid • PAS(+) basement membrane material • Characteristic cytoplasmic and membranous Ki-67/MIB1 staining pattern

Medullary Thyroid Carcinoma: Glandular, Oxyphil, and Hyalinizing, Trabecular • • • •

Invasive growth pattern Slightly granular cytoplasm Salt and pepper nuclear chromatin Calcitonin, CEA, chromogranin, and synaptophysin positivity

Intrathyroid Parathyroid Tumor • Solitary parathyroid adenomas within thyroid parenchyma may mimic PTC, as they appear as "cold" nodules on imaging studies

Diagnoses Associated With Syndromes by Organ: Endocrine

□ If multiple affected individuals present within kindred, testing can establish linkage between cancer(s) and mutation

SELECTED REFERENCES 1. 2. 3. 4. 5. 6.

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Kamilaris CDC et al: Carney complex. Exp Clin Endocrinol Diabetes. 127(203):156-64, 2019 Papathomas TG et al: New and emerging biomarkers in endocrine pathology. Adv Anat Pathol. 26(3):198-209, 2019 Carney JA et al: The spectrum of thyroid gland pathology in Carney complex: the importance of follicular carcinoma. Am J Surg Pathol. 42(5):587-94, 2018 Guilmette J et al: Hereditary and familial thyroid tumours. Histopathology. 72(1):70-81, 2018 Hattori S et al: Carney complex: a case with thyroid follicular adenoma without a PRKAR1A mutation. Surg Case Rep. 4(1):34, 2018 Vuong HG et al: Pediatric follicular thyroid carcinoma - indolent cancer with low prevalence of RAS mutations and absence of PAX8-PPARG fusion in a Japanese population. Histopathology. ePub, 2017 Stenson G et al: Minimally invasive follicular thyroid carcinomas: prognostic factors. Endocrine. 53(2):505-11, 2016 Mochizuki K et al: Low frequency of PAX8-PPARγ rearrangement in follicular thyroid carcinomas in Japanese patients. Pathol Int. ePub, 2015 Ni Y et al: Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. Endocr Relat Cancer. 22(2):121-30, 2015 Duman BB et al: Evaluation of PTEN, PI3K, MTOR, and KRAS expression and their clinical and prognostic relevance to differentiated thyroid carcinoma. Contemp Oncol (Pozn). 18(4):234-40, 2014 Kakudo K et al: Prognostic classification of thyroid follicular cell tumors using Ki-67 labeling index: Risk stratification of thyroid follicular cell carcinomas [Review]. Endocr J. ePub, 2014 Nikiforov YE et al: Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. ePub, 2014 Son EJ et al: Familial follicular cell-derived thyroid carcinoma. Front Endocrinol (Lausanne). 3(3):61, 2012 Laury AR et al: Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 21(2):135-44, 2011 Nosé V: Familial thyroid cancer: a review. Mod Pathol. 24 Suppl 2:S19-33, 2011 Nosé V: Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 17(6):428-36, 2010 Dotto J et al: Familial thyroid carcinoma: a diagnostic algorithm. Adv Anat Pathol. 15(6):332-49, 2008 Collins MT et al: Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations. J Clin Endocrinol Metab. 88(9):4413-7, 2003 French CA et al: Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol. 162(4):1053-60, 2003 Stratakis CA et al: Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex) J Clin Endocrinol Metab. 82(7):2037-43, 1997

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Diagnoses Associated With Syndromes by Organ: Endocrine

Follicular Thyroid Carcinoma Follicular Thyroid Carcinoma in Familial Setting Syndrome

Common Clinical Findings

PTEN-hamartoma tumor syndrome

Mucocutaneous lesions, breast carcinoma, endometrial Follicular carcinoma associated with multiple carcinoma, thyroid carcinoma, macrocephaly, adenomatous nodules and multiple follicular adenomas gastrointestinal hamartomas, lipomas, and other tumors

Thyroid Pathology Findings

Carney complex

Myxomas, spotty mucocutaneous pigmentation, psammomatous melanotic schwannoma, breast ductal adenoma, multiple endocrine neoplasms including PPNAD, GH-producing adenoma, thyroid carcinoma

Werner syndrome

Bilateral cataracts, characteristic dermatological findings, Small percentage (~ 3%) of patients with this syndrome short stature, osteoporosis, multiple neoplasms at develop follicular carcinoma younger age

McCune-Albright syndrome

Growth hormone excess, Cushing syndrome, precocious puberty

Li-Fraumeni syndrome

Sarcomas, brain tumor, adrenal cortical carcinoma, Patients develop many thyroid nodules with nuclear breast cancer, other tumors at young age; rarely involves pleomorphism and may develop follicular carcinoma thyroid

Small percentage of patients with this syndrome may develop follicular carcinoma, usually associated with other thyroid nodules, as follicular adenomas, nodular hyperplasia, and adenomatous nodules; few patients had associated papillary thyroid carcinoma

Patients may develop follicular carcinoma and papillary thyroid carcinoma

Differential Diagnosis of Follicular Thyroid Carcinoma Lesion

Characteristic Findings

Comments

Dominant nodule in nodular hyperplasia

Follicles have different sizes and shapes; colloid ranges from pale to dark red, and these nodules have irregular fibrosis and pseudocapsule

Capsule in follicular carcinoma is thick and surrounds entire nodule; colloid is homogeneous and dark red in follicular carcinoma

Adenomatous nodule

Usually multiple and nonencapsulated

Follicular carcinoma may occur in association with adenomatous nodules

Follicular adenoma

Usually single and surrounded by thin capsule

Fibrous capsule in follicular adenoma is usually thinner than in follicular carcinoma

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Encapsulated or well-circumscribed follicularpatterned neoplasm with papillary-like nuclear features

Papillary thyroid carcinoma-like nuclear features

Follicular variant of papillary thyroid carcinoma

Follicular-patterned neoplasm with focal nuclear features of papillary thyroid carcinoma

Usually main differential diagnosis with follicular carcinoma

Poorly differentiated thyroid carcinoma

Pattern of follicular cells usually solid, trabecular, and insular, and presents with rare follicles

May show apoptosis, necrosis, and high mitotic rate; has higher Ki-67 proliferative index; some positive for p53

Hyalinizing trabecular tumor

Well-circumscribed benign thyroid tumor but lacks fibrous capsule; has trabecular growth pattern and rarely forms follicles

Positive for TTF-1 and thyroglobulin; however, HTT has characteristic membranous staining for Ki67/MIB1

Medullary thyroid carcinoma, follicular patterned

Tumor cells in medullary thyroid carcinoma have ample eosinophilic granular cytoplasm and salt and pepper nuclei

Both tumors positive for TTF-1; medullary thyroid carcinoma positive for chromogranin, synaptophysin, calcitonin, and CEA

Classification of Follicular Thyroid Carcinoma Traditional

AFIP 2014

WHO 2017

Minimally invasive

Minimally invasive with capsular invasion

Minimally invasive

Minimally invasive

Minimally invasive with limited vascular invasion Encapsulated angioinvasive (< 4 vessels)

Minimally invasive

Minimally invasive with extensive vascular invasion (> 4 vessels)

Encapsulated angioinvasive

Widely invasive

Widely invasive

Widely invasive

AFIP = Armed Forces Institute of Pathology; modified from 2017 WHO classification of tumors of endocrine organs.

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Follicular Thyroid Carcinoma

CECT Findings (Left) Longitudinal grayscale ultrasound shows an illdefined, solid, hypoechoic thyroid nodule ſt. Ill-defined edges and hypoechogenicity should raise suspicion of malignancy. Normal thyroid echogenicity is seen ﬇. (Right) Axial CECT shows a large follicular carcinoma with diffuse thyroid involvement ﬈, compression of the airway ﬊, and extrathyroid spread posteriorly ſt. These features cannot be evaluated by ultrasound.

Doppler Ultrasound Findings

Diagnoses Associated With Syndromes by Organ: Endocrine

Ultrasound Findings

Follicular Carcinoma and Multiple Nodules (Left) Power Doppler ultrasound shows profuse, chaotic intranodular vascularity. FNAC confirmed carcinoma of the thyroid. Such vessels in a thyroid nodule suggest malignancy. (Right) Gross cut surface of thyroid from a 29-year-old patient with PTEN-hamartoma tumor syndrome shows multiple adenomatous nodules st, hyperplastic nodules, and follicular carcinoma ﬇, confirmed by histopathology.

Gross Cut Surface of Sporadic Case

Cold Thyroid Nodule (Left) Gross photo shows a minimally invasive follicular carcinoma presenting as a single nodule in a sporadic setting. The tumor is grossly indistinguishable from a follicular adenoma. Thorough examination of the capsule is crucial to identify foci of capsular invasion. (Right) Anterior planar I-123 nuclear medicine scan shows a "cold" nodule (differentiated thyroid carcinoma) in the right thyroid lobe ﬈. A "cold" nodule has ~ 20% chance of being malignant.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Follicular Thyroid Carcinoma

Criteria for Capsular Invasion

Capsular Invasion

Capsular Invasion

Lymphovascular Invasion

Vascular Invasion

Capsular and Vascular Invasion

(Left) Graphic shows the criteria necessary to interpret and diagnose a follicular neoplasm as follicular carcinoma based on capsular invasion. The follicular neoplasm is surrounded by a thick, fibrous capsule with invasion on A, D, F, and G. (Right) Follicular carcinoma with cytologically identical satellite nodules indicates true capsular invasion, even without demonstration of the point of capsular penetration.

(Left) H&E shows the classic mushroom sign, diagnostic of follicular thyroid carcinoma (FTC). The tumor cells ﬇ invade across the entire thickness of the fibrous capsule ſt. (Right) H&E shows vascular invasion with tumor cells present in a large capsular blood vessel, a hallmark of FTC.

(Left) In this example of vascular invasion, epithelial tumoral cells are present in the lumen of a vessel within the tumoral capsule. Note that the cluster of tumor cells is lined by endothelium ﬈. (Right) High-power view of FTC shows the point of invasion where tumor cells penetrate the capsule ſt and reach a blood vessel ﬉.

206

Follicular Thyroid Carcinoma

PTEN-Associated Thyroid Disease (Left) Serial section of the gross cut surface of thyroid from a patient with Cowden disease/PTEN-hamartoma tumor syndrome shows multiple adenomatous nodules st, hyperplastic nodules, and a follicular carcinoma ﬇, minimally invasive. (Right) Low-power view shows multiple well-circumscribed adenomatous nodules ﬊ and a follicular carcinoma. Fullthickness capsular invasion is easily recognizable ﬈. In this case, the patient has PTENassociated thyroid disease.

Follicular Carcinoma in Familial Syndrome

Diagnoses Associated With Syndromes by Organ: Endocrine

Multiple Thyroid Nodules in Cowden Disease

Follicular Carcinoma in Familial Syndrome (Left) Low-power view shows multiple well-circumscribed adenomatous nodules ﬉ and a follicular carcinoma, minimally invasive. A focus of capsular invasion is easily recognizable. In this case, the patient has PTEN-associated thyroid disease. Patients with Carney complex may show similar findings. (Right) Lowpower view shows the follicular carcinoma has maintained expression of PTEN ﬊, and adenomatous nodules have lost PTEN expression within follicular cells.

FISH for PPRG Gene Rearrangement

PTEN Loss by Follicular Cells (Left) Three cells ﬇ in this thyroid FNA specimen show typical rearrangements of PPAR-γ seen in some FTC. A FISH break-apart probe was used. Normal chromosomes should have green and red signals next to each other ſt. Rearrangement is shown as separate red and green signals st. (Right) Immunohistochemistry for PTEN shows loss of staining of the follicular cells with preservation of staining of the endothelial cells ﬊.

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Diagnoses Associated With Syndromes by Organ: Endocrine

Thyroid, Nonmedullary Carcinoma Table Familial Nonmedullary Thyroid Carcinoma in Familial Cancer Syndromes Syndrome

Inheritance

Gene

Gene Location

Thyroid Involvement

PTEN-hamartoma tumor syndrome

Autosomal dominant

PTEN

10q23.2

> 50%

Familial adenomatous polyposis

Autosomal dominant

APC

5q21

> 12%

Carney complex

Autosomal dominant

PRKAR1A

2p12-17q22-24

> 60%

DICER1 syndrome

Autosomal dominant

DICER1

14q32.13

~ 75%

McCune-Albright syndrome

Random mutation 

GNAS1

20q13.2-q13.3

~ 50%

Werner syndrome

Autosomal recessive

WRN

8p11-p12

~ 18% (Japanese)

Pendred syndrome

Autosomal recessive

SLC26A4 (pendrin)

7q21-24

~ 1%

Li-Fraumeni syndrome

Autosomal dominant

TP53

17p13.1

~ 1%

Familial Nonmedullary Thyroid Carcinoma Classification Disease

Histologic Subtypes and Associated Thyroid Pathology

Syndromic or Familial Tumor Syndrome With Preponderance of Nonthyroidal Tumors PTEN-hamartoma tumor syndrome/Cowden disease

FTC associated with follicular adenomas, multiple adenomatous nodules, follicular adenoma, nodular hyperplasia, and C-cell hyperplasia

Familial adenomatous polyposis syndrome

PTC,  cribriform morular variant, multicentric, bilateral

Carney complex

FTC associated with follicular adenomas, multiple adenomatous nodules, and PTC

DICER1 syndrome

PTC and multinodular hyperplasia

McCune-Albright syndrome

Hyperthyroidism, FTC, and PTC

Werner syndrome

FTC, PTC, and ATC

Pendred syndrome

Anaplastic carcinoma or FTC

Li-Fraumeni syndrome

May develop thyroid carcinoma; multiple adenomatous nodules with atypia

Nonsyndromic or Familial Tumor Syndrome With Preponderance of Nonmedullary Thyroid Carcinoma Familial PTC ± oxyphilia

PTC, usual variant or oncocytic variant

Familial PTC with papillary renal cell neoplasia

PTC, usual papillary variant architecture

Familial nonmedullary thyroid carcinoma type 1

PTC, usual variant

Familial PTC and multinodular goiter

PTC and nodular hyperplasia

ATC = anaplastic thyroid carcinoma; FAP = familial adenomatous polyposis; FTC = follicular thyroid carcinoma; PTC = papillary thyroid carcinoma.

Distinct Characteristics of Familial Thyroid Carcinoma and Sporadic Carcinoma Familial

Sporadic

Gross Characteristics Usually multiple tumors

Usually single

Usually bilateral

Unilateral

Microscopic Characteristics Usually associated with background of lymphocytic thyroiditis &/or multinodular hyperplasia

Background thyroid usually uninvolved

Unique morphology in some familial cases: Cribriform morular thyroid carcinoma in familial adenomatous polyposis

All described variants occur

Unique immunophenotype: PTEN-loss in PHTS; β-catenin cytoplasmic and nuclear stain in FAP-associated tumors Lymph Node Metastases Usually more frequent than sporadic cases FAP = familial adenomatous polyposis; PHTS = PTEN-hamartoma tumor syndrome.

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Thyroid, Nonmedullary Carcinoma Table

Multiple Adenomatous Nodules (Left) Gross cut surface of a cribriform morular variant of papillary thyroid carcinoma in a patient with FAP shows multiple small nodules with pale tan, firm gross appearance. These tumors are usually multiple and bilateral in familial and single in sporadic settings. (Right) Gross cut surface of a thyroid from an 18-year-old woman with PHTS/Cowden disease shows multiple well-circumscribed nodules almost entirely replacing the thyroid parenchyma with a small amount of residual noninvolved thyroid.

Squamous Morules in CMV-PTC

Diagnoses Associated With Syndromes by Organ: Endocrine

Multiple Thyroid Carcinoma Nodules in FAP

Multiple Adenomatous Nodules (Left) High-power view shows the characteristic peculiar nuclear clearing (PNC) ﬇ seen within some of the nuclei in the cribriform morular variant of papillary thyroid carcinoma (CMV-PTC). These PNCs are characteristically found within squamous morules. (Right) H&E of a thyroid from an 18-year-old woman with PTENhamartoma tumor syndrome (PHTS) shows multiple wellcircumscribed, nonencapsulated, adenomatous nodules with a small amount of compressed residual thyroid parenchyma.

Aberrant β-catenin Stain

Follicular Cells With PTEN Loss (Left) High-power β-catenin immunostain of CMV-PTC shows characteristic nuclear and cytoplasmic staining resulting from aberrant accumulation within the nucleus. Note the negativity of endothelial cells for β-catenin ﬊. (Right) Immunohistochemistry for PTEN in a thyroidectomy specimen from an 18-year-old woman with PHTS/Cowden disease shows loss of staining of the follicular cells with preservation of staining of the endothelial cells ﬊.

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PART I SECTION 5

Gastrointestinal Hepatobiliary and Pancreas Hepatoblastoma Hepatocellular Carcinoma Pancreatic Adenocarcinoma Biliary Tract/Liver/Pancreas Table

212 218 222 226

Tubular Gut Colonic Adenomas Esophageal Adenocarcinoma Esophageal Squamous Cell Carcinoma Gastric Adenocarcinoma Gastrointestinal Stromal Tumor Hamartomatous Polyposis Syndromes Small Bowel Adenocarcinoma Colon/Rectum Table Esophagus/Stomach/Small Bowel Table

228 234 236 238 244 252 262 268 270

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hepatoblastoma KEY FACTS

TERMINOLOGY • Primary hepatic malignancy with diverse patterns of differentiation, including epithelial, mesenchymal, and varied combination of them

ETIOLOGY/PATHOGENESIS • As part of Beckwith-Wiedemann syndrome, Li-Fraumeni syndrome, familial adenomatous polyposis, and trisomy 18

CLINICAL ISSUES • Most common pediatric hepatic neoplasm in Western countries • Commonly affects children < 5 years • Right lobe of liver (most common site) • Metastatic disease in ~ 20% of patients at diagnosis, majority to lungs • Elevated serum AFP in most cases

MACROSCOPIC • Usually solitary

• Appearance varies depending on predominant histologic pattern

MICROSCOPIC • Epithelial subtype ○ Fetal pattern ○ Embryonal pattern ○ Combined fetal and embryonal patterns ○ Macrotrabecular pattern ○ Small cell undifferentiated type ○ Cholangioblastic pattern • Mixed epithelial-mesenchymal subtype ○ Nonteratoid, teratoid

DIAGNOSTIC CHECKLIST • Pure fetal epithelial hepatoblastoma (HB) ○ Low-power dark and light appearance • Macrotrabecular HB ○ Broad trabeculae throughout tumor

Pure Fetal Hepatoblastoma

Mixed Epithelial-Mesenchymal Subtype

Fetal Pattern

Embryonal Pattern

(Left) Cut surface of a pure fetal hepatoblastoma is tan and nonlobulated with the appearance of normal liver. The tumor is well demarcated from the surrounding liver ſt. (Right) Gross photograph shows a mixed epithelial and mesenchymal hepatoblastoma treated with preoperative chemotherapy. Cut surface has a variable appearance with lobules of red-tan epithelial tumor tissue ﬈ intermixed with tan fibrousappearing mesenchymal tissue ﬊. Brown-tan uninvolved liver parenchyma is present at the surgical margin ﬉.

(Left) High-power view shows a pure fetal hepatoblastoma, recapitulating fetal hepatocytes. Note the cluster of extramedullary hematopoiesis ﬊ and cholestatic foci ﬈. (Right) H&E shows a hepatoblastoma composed of embryonal epithelial cells with scant basophilic cytoplasm, pleomorphic nuclei, and increased nuclear:cytoplasmic ratio growing in sheets and vague nested structures.

212

Hepatoblastoma

Abbreviations • Hepatoblastoma (HB)

Definitions • Primary pediatric hepatic malignancy composed of cells that resemble developing fetal and embryonic liver

ETIOLOGY/PATHOGENESIS Developmental Anomaly • Arises from pluripotent stem cells that sustain ability of differentiating into both hepatocytes and biliary epithelial cells • Association with several congenital malformations, metabolic, and pathophysiologic abnormalities

Hereditary and Genetics • Association with genetic syndromes, such as familial adenomatous polyposis of colon, Beckwith-Wiedemann syndrome (BWS), Li-Fraumeni syndrome, and trisomy 18 ○ BWS is multisystem human genomic imprinting disorder characterized by – Disorder of growth regulation – Predisposition to embryonal tumors, including hepatoblastoma in ~ 15% – Phenotypic variability that might include macroglossia, abdominal wall defects, lateralized overgrowth, and organomegaly, among other findings • Familial HB cases have been documented • β-catenin mutation-associated Wnt pathway activation in 70-90% of HB • Inactivation of APC (5q21-q22) in 10% of sporadic HBs • Loss of heterozygosity on chromosomes 11p, 1q, and 1p

Environmental Factors • Low birth weight (< 1,000 g)

CLINICAL ISSUES Epidemiology • Most common malignant liver neoplasm in children ○ 88% in children < 5 years and 3% > 15 years • Male predominance (2:1)

Site • Right lobe of liver (most common site)

Laboratory Tests • Increased serum α-fetoprotein (AFP) in 75-96% of patients ○ Useful marker of response to therapy and recurrence ○ Neonates < 6 months of age have normally elevated AFP

Treatment • Surgical approaches ○ Complete resection of tumor is 1st-line treatment – 1/3 to 1/2 have resectable disease at presentation ○ Orthotopic liver transplant (nonmetastatic unresectable neoplasm) • Adjuvant therapy ○ Adjuvant and neoadjuvant combination chemotherapy converts > 50% of inoperable tumors to resectable tumors

– HB is sensitive to cytostatic and cytotoxic drugs

Prognosis • Resectability and tumor stage are most important prognostic factors in survival • Pure fetal HB with low mitotic rate (≤ 2/10 HPF) = favorable prognosis • Small-cell undifferentiated (SCUD) cell pattern confers worse prognosis ○ Some demonstrate loss of INI1 expression and may behave like malignant rhabdoid tumors of liver – Such tumors may benefit from chemotherapy treatment designed for rhabdoid tumors

MACROSCOPIC General Features • Solitary or multifocal heterogeneous mass • Appearance varies depending on predominant histologic pattern ○ Fetal pattern areas resemble normal liver ○ Embryonal and small cell patterns are fleshy to gelatinous, pale pink or gray-tan ○ Mesenchymal, osteoid-like areas are firm, fibrous, or calcified

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

Sections to Be Submitted • At least 1 cassette/centimeter to ensure correct classification of histologic pattern

MICROSCOPIC Histologic Features • Epithelial subtype ○ Fetal pattern – Uniform hepatocytes arranged in trabeculae 2-3 cells thick – Alternating light and dark areas based on cytoplasmic content of glycogen – Extramedullary hematopoiesis ○ Embryonal pattern – Primitive cells arranged in sheets, nests, trabeculae, acinar configuration, or pseudorosettes – Angulated cells with higher nuclear:cytoplasmic ratio than fetal pattern – Increased mitotic activity – ± extramedullary hematopoiesis ○ Macrotrabecular pattern – Cells arranged in trabeculae > 10 cells thick throughout tumor ○ Cholangioblastic pattern – Cholangiocytic differentiation in form of cords of ductal structures ○ SCUD type – Dyscohesive, uniform, round cells arranged in sheets or showing diffuse growth – Scant basophilic cytoplasm, hyperchromatic nuclei, inconspicuous nucleoli – Increased mitotic activity • Mixed epithelial-mesenchymal subtype ○ Variable combination of mesenchymal and epithelial components 213

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hepatoblastoma ○ Nonteratoid mesenchymal elements – Osteoid-like, myxoid, fibrous ○ Teratoid mesenchymal elements – Skeletal muscle, bone – Keratinized squamous epithelium – Neuroid-melanocytic – Intestinal epithelium

DIFFERENTIAL DIAGNOSIS Hepatocellular Carcinoma • Should be differentiated from macrotrabecular HB • HCC most commonly occur in older children (> 5 years) • HCC lacks light and dark appearance and extramedullary hematopoiesis

Hepatic Adenoma

ANCILLARY TESTS Immunohistochemistry • AFP ○ Positive in epithelial areas ○ Not expressed in mesenchymal or SCUD areas • Glypican-3 ○ Positive in epithelial components of HB ○ Negative in normal liver and mesenchymal components of HB ○ Also positive in hepatocellular carcinoma (HCC) • Hep Par-1 ○ Highlights fetal HB ○ May be negative in embryonal areas ○ Negative in mesenchymal and SCUD areas • β-catenin ○ Nuclear staining in epithelial and nonteratoid mesenchymal HB cells • Keratin: Variable staining ○ CK7 and CK19 highlight biliary differentiation in cholangioblastic pattern • Glutamine synthetase ○ Marker for activated Wnt pathway ○ Differentiation marker in HB: More intense staining in fetal component • INI1 ○ Loss of expression may indicate behavior like malignant rhabdoid tumors

• Should be differentiated from epithelial subtype (fetal pattern) • Hepatic adenoma lacks light and dark appearance

Metastatic Hepatic Tumors • Small blue cell tumors (e.g., neuroblastoma, neuroendocrine tumors, lymphoma) should be differentiated from SCUD and embryonal HB

Normal Liver Parenchyma • Nuclear and cytoplasmic immunoreactivity for β-catenin in HB

Rhabdoid Tumor of Liver • Rhabdoid tumor cell morphology • Loss of INI1 expression

SELECTED REFERENCES 1.

2.

3. 4.

5. 6. 7.

Fetal Pattern (Left) Needle core biopsy of a liver mass shows the fetal pattern of hepatoblastoma. Alternating light and dark areas are based on the content of cytoplasmic glycogen. (Right) H&E shows a low-power view of a pure fetal hepatoblastoma with alternating light and dark areas.

214

Lucas DJ et al: Surgical and anesthetic management for hepatectomy in two pediatric patients with trisomy 18, pulmonary hypertension, and hepatoblastoma. Pediatr Blood Cancer. 66(6):e27678, 2019 Morcrette G et al: APC germline hepatoblastomas demonstrate cisplatininduced intratumor tertiary lymphoid structures. Oncoimmunology. 8(6):e1583547, 2019 Skoczen S et al: Genetic profile and clinical implications of hepatoblastoma and neuroblastoma coexistence in a child. Front Oncol. 9:230, 2019 Uppal S et al: Hepatoblastoma and Wilms' tumour in an infant with Beckwith-Wiedemann syndrome and diazoxide resistant congenital hyperinsulinism. Endocrinol Diabetes Metab Case Rep, 2019 Zivot A et al: Congenital hepatoblastoma and Beckwith-Wiedemann syndrome. J Pediatr Hematol Oncol. ePub, 2019 Sumazin P et al: Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. Hepatology. 65(1):104-21, 2017 Aronson DC et al: Malignant tumors of the liver in children. Semin Pediatr Surg. 25(5):265-75, 2016

Fetal Pattern

Hepatoblastoma

Embryonal Pattern (Left) Fetal hepatoblastoma closely resembles the histology of a normal fetal liver. (Right) Embryonal epithelial cells arranged in glandular structures ﬊ are illustrated in this example of a hepatoblastoma. Embryonal hepatoblastoma cells tend to be angular in shape.

Embryonal Pattern

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Fetal Pattern

Small-Cell Undifferentiated Pattern (Left) The primitive cells of the embryonal subtype show increased nuclear:cytoplasmic ratio, angulated nuclei, and increased mitotic activity. Note the pseudorosette formation ﬊. (Right) Embryonal epithelial cells of this hepatoblastoma are seen ﬇ merging into a focus of small undifferentiated cells ﬊, which have a small round blue cell tumor pattern. The presence of foci of small undifferentiated cells grants a poorer prognosis.

Small-Cell Undifferentiated and Fetal Patterns

Mixed Fetal and Embryonal Patterns (Left) Small undifferentiated and dyscohesive cells ﬊ with scant cytoplasm are shown adjacent to more typical fetal epithelial cells with abundant clear cytoplasm ﬊. (Right) Small focus of hepatoblastoma is present on this liver needle core biopsy. This fragment of tumor is composed of a mixed fetal ﬈ and embryonal ﬉ epithelial pattern. Note the tongue of tumor ﬊ pushing toward normal liver.

215

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hepatoblastoma

Macrotrabecular Pattern

Macrotrabecular Pattern

Mixed Epithelial-Mesenchymal Subtype

Mixed Epithelial-Mesenchymal Subtype

Mixed Epithelial-Mesenchymal Subtype

Mixed Epithelial-Mesenchymal Subtype

(Left) Low-power view shows hepatoblastoma with a macrotrabecular pattern of growth. This hepatoblastoma subtype should be differentiated from hepatocellular carcinoma. (Right) High-power view shows a macrotrabecular growth pattern composed of embryonal epithelial cells. Cells arranged in > 10 cellthick trabeculae may be either fetal epithelial or embryonal epithelial and can be seen throughout hepatoblastomas with macrotrabecular growth patterns.

(Left) Low-power view of a mixed epithelial and mesenchymal hepatoblastoma shows an embryonal epithelial pattern ſt, spindled mesenchymal component ﬈, and a focus of an osteoid-like element ﬊. (Right) Higher magnification of mixed epithelial and mesenchymal hepatoblastoma shows focal osteoid-like tissue ﬊ and squamous epithelium ſt within fibrous stroma ﬈.

(Left) In this mixed epithelialmesenchymal subtype of hepatoblastoma, keratinized squamous epithelium is a teratoid element. (Right) This mixed epithelial and mesenchymal hepatoblastoma with teratoid features has neoplastic epithelial cells adjacent to melanin pigment ﬈ and ganglion-like cells st. Teratoid features have no prognostic significance.

216

Hepatoblastoma

Cholangioblastic Differentiation: CK7 Stain (Left) Chords of tumor cells resembling bile ducts ﬈ are seen admixed with fetal hepatoblastoma cells ﬊ in this area of cholangioblastic differentiation. (Right) CK7 (shown here) and CK19 stains highlight biliary differentiation in areas of cholangioblastic differentiation in hepatoblastoma.

Hepatoblastoma With Melanin Pigment

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Cholangioblastic Differentiation

Glypican-3 Stain (Left) Melanin-containing hepatoblastoma tumor cells are classified as a teratoid mesenchymal element. (Right) Glypican-3 is positive in fetal and embryonal components of hepatoblastoma.

Metastatic Hepatoblastoma

Status Post Chemotherapy (Left) Metastatic hepatoblastoma to the lung is shown. Note the relatively well-circumscribed ﬉, hemorrhagic ﬈, perivascular ſt proliferation of heterogeneous neoplastic cells within the lung parenchyma. (Right) Hepatoblastoma shows extensive treatment effect, including fibrosis, hemosiderinladen macrophages ﬉, and necrosis ſt. Note the nodules of viable neoplastic embryonal epithelial cells in an acinar configuration ﬇.

217

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hepatocellular Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS • Cirrhosis is major risk factor for hepatocellular carcinoma (HCC) ○ Alcohol-induced cirrhosis is most common risk factor for HCC in USA and in Western countries ○ Alcohol acts synergistically with other risk factors, such as hepatitis B virus (HBV), hepatitis C virus (HCV), diabetes, obesity, and smoking ○ Some inherited disorders are associated with cirrhosis – Hemochromatosis, hereditary tyrosinemia, Wilson disease, α-1-antitrypsin deficiency ○ Metabolic syndrome is increasingly important risk factor • Hepatitis B is leading cause of HCC globally • Familial clustering of HCC has been frequently reported in east Asian countries ○ Positive family history is associated with earlier appearance and aggressiveness of HCC ○ Hereditary component may act in concert with environmental factors, such as hepatitis B • Associated syndromes: Familial adenomatous polyposis • Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are emerging risk factors of HCC in Western countries • HCV infection • Aflatoxin (fungal mycotoxin) may play causative role in up to 28% of HCC worldwide • Diabetes, obesity, hypertension, and dyslipidemia are associated with elevated risk of HCC

CLINICAL ISSUES • Tumor size, number of lesions, vascular invasion, and tumor spread determine prognosis • Surgery is primary treatment for resectable HCC • Orthotopic liver transplantation is potentially curative treatment for early-stage HCC • Sorafenib may improve survival in advanced HCC • Newer therapies include regorafenib

• Immune-based treatments like nivolumab are undergoing evaluation for HCC treatment

MOLECULAR • HCC tumors are commonly aneuploid • Chromosomal losses include 1p, 4q, 5q, 6q, 8p, 9p, 13q, 16p, 16q, and 17p • Chromosomal gains include 1q, 6p, 8q, and 17q • DNAJB1-PRKACA fusion reported as specific recurrent abnormality in fibrolamellar subtype of HCC • Most commonly mutated genes include TP53, CTNNB1, AXIN1, RB1 • Common gene amplifications include MYC, MET, TERT, and CCND1 • Common gene deletions include CDKN2A and PTEN • Epigenetic alterations in HCC ○ Most common hypermethylated genes include BMP4, CDKN2A, GSTP1, NFATC1 ○ Common hypermethylated genes in HBV-positive HCC include DAB2IP, BMP4, ZFP41, SPDYA, CDKN2A • Major signaling pathways implicated in hepatic carcinogenesis include Wnt-β catenin, Ras signaling, PI3K/Akt/mTOR, Rb, and DLC1/Rho/ROCK pathways • Molecular alterations are not currently in routine use in clinical practice for diagnostic purposes

MICROSCOPIC • Tumor cells of well-differentiated HCC resemble normal liver cells • Mallory-Denk bodies are identified in 20% of tumors • Desmoplastic stroma is commonly sparse or absent • Subset of HCC contains abundant eosinophilic cytoplasm with desmoplastic stroma, which is known as fibrolamellar variant of HCC

ANCILLARY TESTS • Hep-Par1, pCEA, Glypican-3, Arg-1, glutamine synthetase staining by immunohistochemistry

Hepatocellular Carcinoma (Left) Gross photograph shows a large bile-stained tumor nodule in a background of cirrhosis. This is a classic presentation of hepatocellular carcinoma (HCC). The hereditary component may act in concert with environmental factors, such as hepatitis B. (Right) H&E shows the trabecular pattern of HCC. Cord-like proliferation of neoplastic cells with ≥ 3 nuclei in a single cord is evident.

218

Hepatocellular Carcinoma With Trabecular Pattern

Hepatocellular Carcinoma

Abbreviations • Hepatocellular carcinoma (HCC)

Definitions • Primary malignant neoplasm with hepatocellular differentiation

ETIOLOGY/PATHOGENESIS Cirrhosis • Major risk factor for HCC, some inherited disorders associated with cirrhosis ○ Hemochromatosis, hereditary tyrosinemia, Wilson disease, α-1-antitrypsin deficiency

Viral Hepatitis • Chronic hepatitis B virus (HBV) infection ○ Leading cause of HCC in Asia and Africa ○ ~ 80% of HCC cases are due to HBV globally ○ Seropositive HBV patients (HBsAg positive) have 98x increased risk of HCC ○ HBx protein derived from HBV is key mediator of hepatic carcinogenesis through inactivation of TP53 pathway • Hepatitis C virus (HCV) infection ○ Increasing cause of HCC in Western countries ○ ~ 17x increased risk of HCC in chronic HCV carriers ○ Primary mechanism for HCC may be due to inflammatory hepatocyte damage due to oxidative stress

Alcohol-Related Liver Disease • Alcohol-induced cirrhosis is most common risk factor in USA and in Western countries • Alcohol acts synergistically with other risk factors, such as HBV, HCV, diabetes, obesity, and smoking • Heavy alcohol consumption → 6x increased risk for HCC in cirrhotic patients • P450 enzyme encoded by CYP2E1 metabolizes endogenous and exogenous substrates, resulting in production of reactive oxygen species ○ Hypothesized to lead to DNA damage

Hereditary • Familial clustering of HCC has been frequently reported in east Asian countries • Growing evidence suggests that family history of liver cancer significantly increases HCC risk • Hereditary component may act in concert with environmental factors, such as hepatitis B ○ Haplotypes located at GLUL and SLC13A2/FOXN1 suggest different genetic susceptibility between familial and sporadic HBV-related HCC • Multifactorial inheritance, including novel DICER1 germline mutation • Handful of hepatocellular adenomas and carcinomas reported in familial adenomatous polyposis • Positive family history is associated with earlier appearance and aggressiveness of HCC ○ Family history of HCC is associated with decreased overall survival and recurrence-free survival

Environmental Factors • Aflatoxin (fungal mycotoxin) may play causative role in up to 28% of HCC worldwide ○ Present in contaminated foodstuffs, e.g., rice and peanuts ○ Converted by cytochrome P450 system into reactive epoxide intermediate, causing DNA damage in TP53 at codon 249 ○ Acts synergistically with coexisting HBV and HCV infections to triple risk of HCC

Diabetes and Metabolic Factors • Diabetes, obesity, hypertension, and dyslipidemia are associated with elevated risk of HCC ○ 2-3x increased risk of HCC in diabetic patients ○ Lipid peroxidation and free reactive oxygen species generation is implicated in genotoxic damage ○ Obese patients (BMI > 30) have 2-4x increased risk

CLINICAL ISSUES

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

Epidemiology • Incidence ○ ~ 560,000 cases and 550,000 deaths annually worldwide ○ 5th most common malignancy in men and 8th most common malignancy in women worldwide – 3rd leading cause of death in cancer patients worldwide ○ East Asia (China and Japan): As high as 35.5 cases per 100,000 ○ North America: ~ 4 cases per 100,000 – Incidence doubled from 1975 to 1998 in USA • Geographically dependent ○ 7th decade in USA ○ Peak is 5th decade in China – Mainly due to high prevalence of hepatitis B in China ○ Average age is 35 years in South Africa

Presentation • Initial symptoms may include right upper quadrant abdominal pain • Anorexia or early satiety is 2nd most common symptom • Late-stage symptoms include jaundice, fever, bone pain due to metastatic lesions, complications of portal venous hypertension, including esophagogastric varices, ascites, thrombocytopenia, and coagulopathy • Hepatomegaly is seen in 90% of patients • 50% of patients may show hepatic bruit and splenomegaly

Treatment • Surgery is primary treatment for resectable tumors • Orthotopic liver transplantation is potentially curative treatment for early-stage HCC • Highest survival is seen in patients with single lesion < 5 cm with no evidence of gross vascular invasion • Tumor ablation may improve local tumor control and overall survival • Sorafenib may improve survival in advanced HCC

Prognosis • Tumor size, number of lesions, vascular invasion, and tumor spread determine prognosis 219

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hepatocellular Carcinoma • Family history of HCC is associated with worse prognosis • Only 10-23% of HCC patients are eligible for curative resection • Patients with early HCC undergoing liver transplant have 5year overall survival of 44-78%

○ Polyclonal carcinoembryonic antigen (pCEA) and CD10 highlight very distinctive canalicular pattern ○ Hep Par1(+) in ~ 90% of HCC vs. < 4% in other tumors ○ Glypican-3 (GPC-3) expressed in ~ 80% ○ Arg-1 expressed in both normal hepatocytes and ~ 90% of HCC ○ Glutamine synthetase (GS) is diffusely expressed with cytoplasmic pattern in up to 70% of HCC – GS is also expressed in β-catenin-activated hepatic adenomas ○ α-fetoprotein is expressed in 50% of HCC tumors ○ CD34 sinusoidal expression is typically increased in HCC but is not always reliable marker ○ Other immunostains commonly used include HSP70, annexin-A2, CK7, and MOC-31

MACROSCOPIC General Features • Single or multiple masses may be seen • Numerous cirrhotic-appearing nodules may be present in background • Tumor may be encapsulated or diffusely infiltrative ○ Encapsulated HCC often arises in background of cirrhosis

MOLECULAR Cytogenetics • HCC tumors are commonly aneuploid • Chromosomal losses include ○ 1p, 4q, 5q, 6q, 8p, 9p, 13q, 16p, 16q, and 17p • Chromosomal gains include ○ 1q, 6p, 8q, and 17q • DNAJB1-PRKACA fusion reported as specific recurrent abnormality in fibrolamellar subtype

Molecular Genetics • Molecular alterations are complex and occur in multistep progression • Most commonly mutated genes include ○ TP53, CTNNB1, AXIN1, RB1 • Epigenetic alterations in HCC ○ Most common hypermethylated genes include BMP4, CDKN2A, GSTP1, NFATC1 ○ Common hypermethylated genes in HBV-positive HCC include DAB2IP, BMP4, ZFP41, SPDYA, CDKN2A ○ Other reported promoter hypermethylation genes include CDH1, SLC7A10, DLC1, PTEN, SFRP1 • Major signaling pathways implicated in hepatic carcinogenesis ○ Wnt-β catenin, Ras signaling, PI3K/Akt/mTOR, Rb, and DLC1/Rho/ROCK pathways • Molecular alterations are not currently in routine use in clinical practice for diagnostic purposes

DIFFERENTIAL DIAGNOSIS Metastatic Tumor • Typically lack distinct canalicular pattern with polyclonal CEA and CD10 • Arg-1 is expressed in carcinomas with hepatocellular differentiation and is typically absent in carcinomas of metastatic origin

Hepatocellular Adenoma • Mostly in women of childbearing age; strong association with use of contraceptive pills • Intact reticulin pattern of staining in adenoma but decreased and disorganized in HCC • Glypican-3 typically absent • Glutamine synthetase not helpful in separating HCC from βcatenin pathway hepatocellular adenoma (expressed in both diseases)

Cholangiocarcinoma • Markers specific for HCC, including Hep-Par1 and Glutamine synthetase, can prove helpful

Focal Nodular Hyperplasia • May be confused with HCC in small biopsies • Glypican-3 is absent

SELECTED REFERENCES 1.

MICROSCOPIC Histologic Features • Tumor cells of well-differentiated HCC resemble normal liver cells • Prominent nuclei and nucleoli are seen with high N:C ratio and eosinophilic, finely granular cytoplasm • Bile canaliculi are commonly identified in between neoplastic hepatocytes ○ Mallory-Denk bodies are identified in 20% of tumors • Trabecular pattern is often present microscopically with thickened cords of tumor cells and sinuses with dilated canaliculus leading to pseudoglandular pattern formation

ANCILLARY TESTS Immunohistochemistry • Commonly used immunostains in HCC diagnosis 220

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3.

4. 5.

6. 7.

Li ZL et al: Association of family history with long-term prognosis in patients undergoing liver resection of HBV-related hepatocellular carcinoma. Hepatobiliary Surg Nutr. 8(2):88-100, 2019 Weledji EP: Familial hepatocellular carcinoma: 'a model for studying preventive and therapeutic measures'. Ann Med Surg (Lond). 35:129-32, 2018 Lin YY et al: Genome-wide association analysis identifies a GLUL haplotype for familial hepatitis B virus-related hepatocellular carcinoma. Cancer. 123(20):3966-76, 2017 Graham RP et al: DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 28(6):822-9, 2015 Swanson BJ et al: A triple stain of reticulin, glypican-3, and glutamine synthetase: a useful aid in the diagnosis of liver lesions. Arch Pathol Lab Med. 139(4):537-42, 2015 Ma L et al: Epigenetics in hepatocellular carcinoma: an update and future therapy perspectives. World J Gastroenterol. 20(2):333-45, 2014 Turati F et al: Family history of liver cancer and hepatocellular carcinoma. Hepatology. 55(5):1416-25, 2012

Hepatocellular Carcinoma Hepatocellular Carcinoma With 2 Different Patterns of Differentiation (Left) H&E shows a moderately differentiated HCC. The neoplastic cells show variably enlarged, pleomorphic nuclei with irregular nuclear contours. (Right) H&E shows 2 different histologic patterns, including clear cell and sheetlike foci in this case of HCC.

Hepatocellular Carcinoma With Clear Cell Pattern

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Moderately Differentiated Hepatocellular Carcinoma

HSP70 Expression (Left) H&E shows predominance of clear cells with a sheet-like pattern in this case of HCC. (Right) HSP70 highlights neoplastic cells of HCC. HSP70 expression is also seen in other neoplasms, including carcinoma of the breast, lung, and prostate and squamous cell carcinoma.

Glutamine Synthetase Expression

Hep-Par1 Expression (Left) Glutamine synthetase demonstrates cytoplasmic and nuclear staining of neoplastic cells with variable staining pattern in this case of HCC. (Right) Hep-Par1 shows bright cytoplasmic expression by neoplastic cells in this case of HCC.

221

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Pancreatic Adenocarcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS • Multifactorial (environmental, preexisting medical, and hereditary factors) • Precursor lesions ○ Pancreatic intraepithelial neoplasia ○ Intraductal papillary mucinous neoplasm ○ Mucinous cystic neoplasm • Familial pancreatic cancer (FPC) ○ Patients with FPC constitute 8-10% of all pancreatic cancer patients • Increased risk of pancreatic cancer is now known to be associated with inherited syndromes with known germline mutations, including ○ Hereditary breast cancer syndrome (BRCA1, BRCA2) or familial breast cancer (PALB2) ○ Familial atypical multiple mole-melanoma syndrome (CDKN2A) ○ Hereditary pancreatitis (PRSS1 and SPINK2)

○ Peutz-Jeghers syndrome (STK11) ○ Hereditary nonpolyposis colorectal cancer syndrome or Lynch syndrome (MLH1, MSH2, MSH6, PMS2) ○ Fanconi anemia (FA): Mutations in 1 of 15 genes known to encode FA pathway component

CLINICAL ISSUES • Often nonspecific symptoms, such as epigastric pain and weight loss • Painless jaundice and pruritus if common bile duct is obstructed • 5-year survival < 5%

MICROSCOPIC • Proliferation of haphazardly arranged small tubular structures lined by mucinous cells

TOP DIFFERENTIAL DIAGNOSES • Chronic pancreatitis • Neuroendocrine neoplasm

Fine-Needle Aspirate

Perineural Invasion

Mild Nuclear Atypia

Poorly Differentiated Ductal Adenocarcinoma

(Left) Diff-Quik preparation of fine-needle aspirate (FNA) of a pancreatic ductal adenocarcinoma reveals sheets of atypical ductal cells. The ductal cells are disorganized with nuclear pleomorphism st. (Right) H&E of a pancreatic duct adenocarcinoma shows perineural invasion ﬉. This feature is very common in pancreatic ductal adenocarcinoma.

(Left) In well-differentiated ductal adenocarcinomas, the growth pattern and cytologic appearance closely resemble nonneoplastic ductules with mild nuclear variation. Here, mitotic figures are easily identified ſt. (Right) In poorly differentiated ductal adenocarcinomas, the neoplastic cells may not form glands. Here, they are dyscohesive with marked pleomorphic nuclei st.

222

Pancreatic Adenocarcinoma

Abbreviations • Pancreatic ductal adenocarcinoma (PDA)

Synonyms • Pancreatic adenocarcinoma • Pancreatic infiltrating ductal carcinoma

Definitions • Infiltrating epithelial neoplasm of pancreatic ductal origin ○ > 90% of pancreatic neoplasms have ductal origin

ETIOLOGY/PATHOGENESIS

○ Usually between 60-80 years at diagnosis • Sex ○ Slight male predominance • Ethnicity ○ Higher rates seen in African Americans than in Caucasians in USA

Presentation • Painless jaundice and pruritus if common bile duct is obstructed • Often nonspecific symptoms, such as epigastric pain and weight loss

Treatment

• Multifactorial

• Surgical resection if resectable at presentation ○ ~ 20% of patients have resectable tumor • Neoadjuvant therapy prior to resection may be used

Environmental Risk Factors

Prognosis

• Tobacco smoking ○ 2-3x greater risk than nonsmokers • Diet high in saturated fats and low in vegetables/fruits • Heavy consumption of alcohol

• 5-year survival < 5%

Overview

Hereditary Risk Factors • Family history of pancreatic cancer ○ Familial pancreatic cancer (FPC) designates kindreds that contain at least 2 first-degree relatives with PDA ○ Susceptibility genes include BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, PRSS1, SPINK1 • Hereditary breast cancer syndrome ○ Mostly due to BRCA2 mutations • Familial atypical multiple mole-melanoma syndrome ○ Mutations in CDKN2A • Hereditary pancreatitis ○ Due to mutations in PRSS1 • Peutz-Jeghers syndrome ○ Mutations in STK11 • Hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome) ○ Mutations in DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2 • Fanconi anemia ○ Mutations in FANCC and FANCG

Medical Risk Factors • • • •

Chronic pancreatitis Obesity Diabetes mellitus Previous cholecystectomy or partial gastrectomy

Precursor Lesions • Pancreatic intraepithelial neoplasia • Intraductal papillary mucinous neoplasm • Mucinous cystic neoplasm

CLINICAL ISSUES Epidemiology • Incidence ○ 10-12 cases per 100,000 ○ 4th leading cause of death from cancer in USA • Age

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

MACROSCOPIC General Features • • • •

Solid and firm mass with ill-defined borders Adjacent areas of fibrosis secondary to chronic pancreatitis Common bile duct and duodenum invasion are common Focal narrowing of pancreatic and common bile ducts with proximal dilation

MOLECULAR Cytogenetics • Common chromosomal deletions ○ 18q21, 17p13, 9p21, 8p22, 1p36 • Common chromosomal gains ○ 8q24, 20q13, 1q25

Molecular Genetics • KRAS ○ Functions as oncogene ○ Somatic point mutation in ~ 70% of cases – Mutations likely play early role in oncogenesis – Results in constitutive activation of RAS/MAPK signaling pathway ○ Clinical relevance – Mutations are associated with altered sensitivity to trametinib, bleomycin, selumetinib, refametinib, gefitinib • TP53 ○ Functions as tumor suppressor gene ○ Prevents cells with mutated or damaged DNA from dividing ○ Regulates cell division and growth ○ Inactivating mutations in ~ 40% of cases – Prevents tumor cells from apoptosis ○ Clinical relevance – Mutations are associated with altered sensitivity to 5fluororacil, rucaparib, CX-5461, bleomycin, dabrafenib • SMAD4 ○ Involved in signal transduction via TGF-β signaling pathwayβ 223

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Pancreatic Adenocarcinoma ○ Loss of function mutations in ~ 10% – Results in deregulation of TGF-β signaling pathway – Promotes tumor growth ○ Clinical relevance – Inactivation is likely associated with increased metastatic potential and treatment failure • Molecular heterogeneity is common • Worse outcomes are associated with alterations of 3 of 4 main driver genes ○ Patients whose tumors lacked CDKN2A expression had worse disease-free survival (DFS) ○ KRAS mutant tumors have worse DFS ○ TP53 status is associated with shorter DFS ○ SMAD4 status is not associated with pattern of disease recurrence ○ Patients have worse DFS and overall survival if they have greater number of altered driver genes • Other mutated genes ○ Genes mutated with 5% or less frequency in Catalogue of Somatic Mutations in Cancer (COSMIC) data – CDKN2A, LRP1B, KMT2C (MLL3), ARID1A, RNF43, KMT 2D, ATM, PALB2, GNAS, TGFRB2, MAP2K4, NF1, RBM10

MICROSCOPIC Histologic Features • Conventional type ○ Proliferation of haphazardly arranged small tubular structures lined by mucinous cells ○ Perineural invasion and vascular invasion are typical ○ Glands adjacent to muscular blood vessels ○ Neoplastic cells with generous cytoplasm containing mucin or with clear cell change ○ Variation in nuclear shape and size • Histologic variants and patterns ○ Foamy gland pattern – Well-differentiated ductal carcinoma – Foamy, microvesicular cytoplasm ○ Large duct pattern – Infiltrating microcystic (dilated) glands in clusters – Malignant ducts with irregular contours – Intraluminal necrotic debris with neutrophils ○ Vacuolated pattern – Cribriform nests of neoplastic cells – Signet ring-like appearance ○ Lobular carcinoma-like pattern – Reminiscent of lobular breast carcinoma – Conventional tubular-type often present ○ Solid nested pattern (clear cell carcinoma) – Morphologic features of neuroendocrine neoplasm – Prominent gland formation ○ Micropapillary pattern – Neoplastic cells in micropapillary pattern – Clusters of tumor cells in lacunar spaces ○ Mucinous (colloid) carcinoma – Neoplastic cells floating in pools of mucin ○ Medullary carcinoma – Neoplastic cells in syncytial pattern – Lack of desmoplasia – Associated with inflammatory infiltrate 224

○ Adenosquamous carcinoma – Malignant glands and squamous cells ○ Hepatoid carcinoma – Neoplastic cells in nests or trabeculae – Hepatocellular differentiation ○ Undifferentiated carcinoma – Minimal features of epithelial differentiation – Osteoclast-like giant cells can be seen

Cytologic Features • • • • •

Hypercellular aspirate of ductal cells Uneven distribution of ductal cells within sheet Isolated malignant ductal cells Enlarged nuclei with irregular nuclear contours Anisonucleosis (> 4:1 variation in size)

ANCILLARY TESTS Immunohistochemistry • Positive for CK7, CK8, CK18, CK19, EMA, CEA, CA19-9, CA125, B72.3 • Loss of expression of SMAD4 (55%) • Overexpression of TP53 (50-75%) • CK20 and MUC2 positive in mucinous (colloid) carcinoma

DIFFERENTIAL DIAGNOSIS Chronic Pancreatitis • Ductules retain normal lobular configuration • No significant nuclear abnormalities • Clinical history can also prove helpful

Ampullary/Periampullary Carcinomas • Presence of precursor in situ ampullary lesions

Acinic Cell Carcinoma • Neoplastic cells in acinar, trabecular, and solid patterns • Positive for trypsin and chymotrypsin • Negative for CK7

Neuroendocrine Neoplasms • Nuclear features with salt and pepper chromatin • Positive for chromogranin, synaptophysin

SELECTED REFERENCES 1.

2.

3.

4. 5.

Catalogue of Somatic Mutations In Cancer. https://cancer.sanger.ac.uk/cosmic. Published March 2019. Accessed April 2019. Kimura H et al: CKAP4, a DKK1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy. Clin Cancer Res. 25(6):1936-47, 2019 Qian ZR et al: Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncol. 4(3):e173420, 2018 Zhao L et al: Gene expression profiling of 1200 pancreatic ductal adenocarcinoma reveals novel subtypes. BMC Cancer. 18(1):603, 2018 Martinez-Useros J et al: UNR/CDSE1 expression as prognosis biomarker in resectable pancreatic ductal adenocarcinoma patients: a proof-of-concept. PLoS One. 12(8):e0182044, 2017

Pancreatic Adenocarcinoma

Pancreatic Ductal Adenocarcinoma (Left) Pap-stained FNA of a pancreatic duct adenocarcinoma shows single neoplastic cells with nuclear enlargement and increased nuclear:cytoplasmic ratio ﬉. (Right) H&E of a pancreatic duct adenocarcinoma shows distribution of neoplastic glands in close proximity to a thick-walled vessel ﬈. This is a common feature in pancreatic carcinomas.

Colloid (Mucinous) Variant

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Fine-Needle Aspiration

Foamy Gland Pattern (Left) In this example of colloid (mucinous) variant of pancreatic duct adenocarcinoma, neoplastic glands ﬈ are seen floating in large pools of mucin ﬉. (Right) In this foamy gland pattern of pancreatic duct adenocarcinoma, the neoplastic cells exhibit microvesicular cytoplasm ﬈ with raisinoid nuclei ﬊.

Perineural Invasion

Lymph Node Metastasis (Left) H&E demonstrates pancreatic duct adenocarcinoma with perineural invasion. The neoplastic glands ﬈ are surrounding the nerve ﬊. (Right) Low-power H&E of a pelvic lymph node shows metastatic pancreatic ductal adenocarcinoma ﬊ with extensive involvement of the excised lymph node.

225

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Biliary Tract/Liver/Pancreas Table Familial Neoplasia of Biliary Tract, Liver, and Pancreas Type of Tumor

Possible Syndromes

Gene

Ampullary adenoma/carcinoma

FAP, MYH, Lynch, Peutz-Jeghers

APC, MYH, MSH1, MSH2, MLH1, PMS2, LKB1

Pancreaticobiliary adenocarcinoma

FAP, Lynch, Peutz-Jeghers, juvenile polyposis, hereditary breast and APC, MSH1, MSH2, MLH1, PMS2, LKB1, ovarian cancer, familial atypical multiple mole melanoma, SMAD4, BMPR1A, ENG, BRCA2, PALB2, hereditary pancreatitis, Li-Fraumeni BRCA1, P16/CDKN2A, PRSS1, PRSS2, SPINK1, CFTR, TP53, CHEK2

Pancreatic endocrine tumor

Multiple endocrine neoplasia types 1 and 4, von Hippel-Lindau disease, tuberous sclerosis, neurofibromatosis 1, Glucagon cell hyperplasia and neoplasia

MEN1 and CDKN1B, VHL, TSC1, and TSC2, NF1, GCGR

Hepatocellular adenoma/carcinoma

FAP, hemochromatosis, tyrosinemia, citrullinemia, α-1-antitrypsin deficiency, glycogen storage disease, Alagille, progressive familial intrahepatic cholestasis

APC, HFE, FAH, HPD, TAT, SLC25A13, ASS1, SERPINA1, G6PC, AGL, PYGL, JAG1, NOTCH2, ATP8B1, ABCB11, MDR3

Hepatoblastoma

FAP, Li-Fraumeni, Beckwith-Wiedemann, familial hepatoblastoma

APC, TP53, CHEK2

FAP = familial adenomatous polyposis.

Familial Biliary Tract, Liver, and Pancreas Neoplasms by Syndromes

226

Syndrome

Gene(s)

Inheritance Pattern

Tumor

Other Manifestations

FAP

APC

Autosomal dominant

Ampullary adenomas and adenocarcinomas, hepatoblastoma, hepatic adenoma, hepatocellular carcinoma, pancreatic and biliary tract adenocarcinomas

Multiple colonic adenomas and carcinomas, gliomas, desmoids, CHRPE, osteomas and jaw cysts, adrenal cortical neoplasms, papillary thyroid carcinoma, cribriform-morular variant, parathyroid and pituitary adenomas

Peutz-Jeghers

STK11

Autosomal dominant

Ampullary, biliary, and pancreatic adenocarcinomas

Hamartomatous polyps of gastrointestinal tract, adenocarcinoma of colon, ovarian sex cord tumor with annular tubules, adenoma malignum of cervix, mucinous tumors of ovaries and fallopian tubes, breast carcinoma, bronchioalveolar carcinomas of lung, testicular sex cord and Sertoli cell tumors, papillary thyroid carcinoma

Juvenile polyposis

SMAD4, BMPR1A

Autosomal dominant

Pancreatic adenocarcinoma

Hamartomatous polyps of gastrointestinal  tract and adenocarcinoma of stomach, small intestine, and colon

Multiple endocrine neoplasia 1

MEN1

Autosomal dominant

Pancreatic endocrine neoplasms

Endocrine neoplasms of parathyroid and pituitary glands, adrenal cortical neoplasms, thymic and bronchial carcinoids, esophageal leiomyomas, renal angiomyolipomas, GISTs, spinal ependymomas, meningioma, astrocytoma, lipomas, collagenomas, and angiofibromas

von Hippel-Lindau disease

VHL

Autosomal dominant

Pancreatic serous cystadenomas, pancreatic endocrine neoplasms

CNS hemangioblastomas, renal cell carcinomas, pheochromocytomas, café au lait spots

Tuberous sclerosis

TSC1, TSC2

Autosomal dominant

Pancreatic endocrine neoplasms (TSC2 mutations)

Angiomyolipomas, angiofibromas, astrocytomas, lymphangioleiomyomatosis, renal cysts, retinal hamartomas, cardiac rhabdomyoma, hypomelanotic skin macules, periungual fibromas, cortical tubers

Hereditary breast and ovarian cancer

BRCA2, PALB2, BRCA1

Autosomal dominant

Pancreatic and biliary tract adenocarcinomas

Breast, ovarian, fallopian tube, peritoneal, prostate, stomach, cervical, and endometrial carcinomas

Familial atypical multiple mole melanoma

P16/CDKN 2A

Autosomal dominant

Pancreatic adenocarcinoma

Melanomas and dysplastic nevi

Lynch

MLH1, PMS2,

Autosomal dominant

Ampullary, biliary, and pancreatic adenocarcinomas

Colonic adenomas and adenocarcinomas; carcinomas of endometrium, ovaries, adrenal

Biliary Tract/Liver/Pancreas Table

Syndrome

Gene(s)

Inheritance Pattern

Tumor

MSH2, MSH6

Other Manifestations cortex, prostate, bladder, renal pelvis, and ureter; glioblastomas; and sebaceous neoplasms

Hereditary pancreatitis

PRSS1, PRSS2, SPINK1, CFTR

Autosomal dominant

Pancreatic adenocarcinoma

Pancreatitis

Hemochromatosis

HFE

Autosomal recessive

Hepatocellular carcinoma

Iron overload can lead to endocrine dysfunction, heart failure, arthritis, and cirrhosis of liver

Tyrosinemia

FAH, HPD, TAT

Autosomal recessive

Hepatocellular adenoma and carcinoma

Failure to thrive, liver and renal failure, skin and ocular lesions

Citrullinemia

SLC25A13, ASS1

Autosomal recessive

Hepatocellular carcinoma

Liver dysfunction, hyperammonemia

α-1-antitrypsin deficiency

SERPINA1

Autosomal codominant

Hepatocellular carcinoma

Pulmonary disease

Glycogen storage disease

G6PC, AGL, PYGL

Autosomal recessive

Hepatocellular adenoma and carcinoma

Hypoglycemia, muscle disease, liver disease

Li-Fraumeni

TP53, CHEK2

Autosomal dominant

Hepatoblastoma, pancreatic and biliary adenocarcinoma

Breast carcinoma, osteosarcoma, and other soft tissue sarcomas; leukemias; adrenal cortical carcinoma; brain tumors

Alagille

JAG1, NOTCH2

Autosomal dominant

Hepatocellular carcinoma

Bile duct paucity, pulmonic stenosis, butterfly vertebrae, abnormal facial features

Progressive familial intrahepatic cholestasis (Byler disease)

ATP8B1, ABCB11, MDR3

Autosomal recessive

Hepatocellular carcinoma

Cholestatic liver disease

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Familial Biliary Tract, Liver, and Pancreas Neoplasms by Syndromes (Continued)

CHRPE = congenital hypertrophy of retinal pigment epithelium; FAP = familial adenomatous polyposis; GIST = gastrointestinal stromal tumors.

227

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Colonic Adenomas KEY FACTS

TERMINOLOGY • Polypoid or sessile colonic lesions formed by dysplastic epithelial proliferation

ETIOLOGY/PATHOGENESIS • High-fat/low-fiber diet, obesity, smoking, sedentary • Associated syndromes ○ Familial adenomatous polyposis (FAP) ○ Lynch syndrome ○ MUTYH-associated polyposis (MAP) ○ Hereditary mixed polyposis syndrome ○ MSH3-associated polyposis ○ NTHL1-associated polyposis ○ DNA polymerase ε and δ polyposis ○ Li-Fraumeni syndrome • Syndromes associated with increased risk of colorectal carcinoma but are not associated with adenomas ○ Associated with hamartomatous polyps – Peutz-Jeghers syndrome

– Juvenile polyposis syndrome (JPS) – PTEN-hamartoma syndrome ○ Associated with serrated lesions – Serrated polyposis syndrome

MICROSCOPIC • Adenomas are by definition at least low-grade dysplasia • Features of high-grade dysplasia ○ Vesicular nuclei and prominent nucleoli ○ Architectural complexity, cribriform appearance, back-toback glands

TOP DIFFERENTIAL DIAGNOSES • Reactive/regenerative epithelium ○ Epithelium matures toward surface ○ Usually associated with active inflammation • Invasive carcinoma ○ Accompanied by desmoplastic stromal reaction

Familial Adenomatous Polyposis

Gross photograph shows a colectomy specimen with numerous adenomatous polyps ſt from a 14-year-old girl with familial adenomatous polyposis (upper specimen). Years later, the patient developed a large pelvic desmoid tumor abutting the small bowel (lower specimen).

228

Colonic Adenomas

Definitions • Premalignant (dysplastic), clonal (neoplastic) proliferation of colorectal epithelium • Colorectal adenoma is by definition at least low-grade dysplasia

ETIOLOGY/PATHOGENESIS

•

Genetic Syndromes • Familial adenomatous polyposis (FAP) ○ > 700 mutations in APC on chromosome 5q have been implicated ○ APC encodes component protein of degradation complex, which breaks down cytosolic β-catenin ○ APC dysfunction causes intracellular accumulation and nuclear translocation of β-catenin, which activates oncogenes, such as c-Myc and Wnt/β-catenin pathway • Lynch syndrome ○ Associated with mutations in genes involved in DNA mismatch repair pathway (MLH1, PMS2, MSH2, MSH6) ○ Alternative mechanism includes deletions of 3' end of EPCAM, including polyadenylation signal, which causes transcriptional read-through into downstream MSH2 (end product being EPCAMMSH2 fusion transcripts) – And subsequent hypermethylation of MSH2 promoter • MUTYH-associated polyposis (MAP) ○ > 80 mutations have been implicated ○ ~ 1% of general population are heterozygous carriers of MUTYH mutations ○ Autosomal recessive; most clinically affected patients carry biallelic germline mutations ○ MUTYH encodes MYH, DNA glycosylase which excises adenine paired with 8-oxo-7, 8-dihydro-2deoxyguanosine (8-oxoG), product of oxidative DNA damage (base-excision repair) ○ Dysfunctional MYH leads to increased G:C to T:A transversion ○ Consequence is particularly profound for DNA sequences rich in GAA codons, which are prone to be converted to TAA, stop codon ○ APC is rich in GAA sites, which explains attenuated FAPlike phenotype in MAP • Hereditary mixed polyposis syndrome ○ Associated with large duplication in upstream region of GREM1 – Causing GREM1 overexpression in colonic epithelium ○ GREM1 overexpression suppressed BMP pathway [mechanism similar to juvenile polyposis syndrome (JPS)] • MSH3-associated polyposis ○ Rare; reported in 4 affected individuals in 2 families ○ Each affected individual was found to be compound heterozygous carrier of biallelic MSH3 loss-of-function mutations ○ Described mutations include c.1148delA, c.2319−1G>A, c.2760delC, and c.3001−2A>C ○ MSH3 encodes component in DNA mismatch recognition complex

•

•

•

– While MSH2-MSH6 heterodimer repairs single-base mispairs, MSH2-MSH3 heterodimer has higher affinity toward long indels ○ Adenoma-derived DNA from affected individuals shows microsatellite instability of tetranucleotide markers ○ By immunohistochemistry, both normal colonic tissue and adenomas from affected individuals show loss of MSH3 staining NTHL1-associated polyposis ○ a.k.a familial adenomatous polyposis-3 (FAP3) ○ Rare; reported in 8 individuals from 4 families ○ 7 affected individuals from 3 families carried homozygous NTHL1 nonsense mutation c.268C>T ○ 1 affected individual carried 2 NTHL1 mutations in trans (compound heterozygous): c.268C>T (truncating) and c.709+1G>A (causes abnormal splicing) ○ NTHL1 encodes DNA glycosylase essential for baseexcision DNA repair ○ Unlike MAP (in which MYH dysfunction causes increased G:C to T:A transversion), tumors arising in NTHL1associated polyposis syndrome are characterized by increased G:C to A:T transition DNA polymerase ε and δ polyposis ○ Associated with mutations in POLE and POLD1, which encode exonuclease domain of DNA polymerases δ and ε, respectively ○ Exonuclease domain is essential for proofreading and other DNA repair mechanisms Li-Fraumeni syndrome ○ Associated with TP53 mutations ○ TP53 encodes p53, essential protein which regulates cell division, apoptosis, and DNA repair in event of DNA damage Syndromes associated with increased risk of colorectal carcinoma (CRC) but not associated with adenomas ○ Associated with hamartomatous polyps – Peutz-Jeghers syndrome – JPS – PTEN-hamartoma syndrome ○ Associated with serrated lesions – Serrated polyposis syndrome

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

Nutritional Factors • Diet high in animal fat, low in fruits/vegetables/fiber • High caloric intake, obesity, sedentary lifestyle • Smoking, alcohol

CLINICAL ISSUES Natural History • Well-established premalignant (CRC) precursors ○ ~ 1/2 of adenomas increase in size with time ○ Only some (5-10%) adenomas progress to CRC ○ Endoscopic removal: Interruption of this sequence

Treatment • Complete removal (polypectomy) indicated for all ○ Regardless of size, dysplasia degree, villous component ○ Adequate margins evaluated at time of colonoscopy ○ Confirmed by pathology (when not resected piecemeal) • Incomplete removal (advanced adenoma) or invasion (in sessile polyp or with unfavorable histology) 229

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Colonic Adenomas ○ Resection indicated (surgical or endoscopic mucosal) ○ Weigh relative risks: Procedure vs. metastasis • Surveillance (follow-up) intervals after polypectomy ○ Small, left-sided, hyperplastic polyps: 10 years ○ 1-2 low-risk adenomas: 5-10 years ○ Advanced adenomas, family history of CRC: 3 years ○ > 10 adenomas (possible genetic syndrome): < 3 years ○ Invasion in pedunculated adenoma: 0.5-1.0 year – If no unfavorable histologic features ○ Inadequately removed adenoma: 2-6 months ○ Large sessile adenoma: 2-6 months ○ Negative follow-up: May revert to 5-year frequency • Chemoprevention: Indirect, inconclusive evidence ○ Vitamins A, C, D, E, folate, calcium ○ Aspirin, NSAIDs, selective COX-2 inhibitors ○ May reduce incidence of adenomas (mixed results)

•

Prognosis • 5-7% of adenomas: High-grade dysplasia at presentation ○ More if ≥ 1 cm, ≥ 75% villous, age > 60, multiplicity ○ Adenomas < 5 mm: 1% risk of high-grade dysplasia • 3-5% of adenomas contain invasive CRC at diagnosis ○ Size of adenoma: Best predictor of carcinoma risk – > 2 cm: 10-20%; 1-2 cm: 5%; < 1 cm: < 1% ○ High-grade dysplasia and villous component – Both are more likely with increased adenoma size – Unclear if independent prognostic factors – 30% of villous adenomas (VAs) > 5 mm have invasive CRC • Multiplicity of adenomas at colonoscopy ○ 1 adenoma: 30-50% sync-/metachronous adenoma – Increased risk: Larger lesions (advanced adenoma), CRC ○ 10-30% of patients have multiple (≥ 3) adenomas – Prevalence of multiple adenomas increases with age – 2x risk of villous component, high-grade dysplasia

•

Clinical Characteristics by Syndrome • FAP ○ Autosomal dominant ○ Classic FAP is defined clinically as having 100 or more synchronous colorectal adenomas ○ Attenuated FAP is defined as 10-100 synchronous colorectal adenomas – Differential diagnosis include other polyposis syndromes such as MAP; genetic testing of APC and MUTYH is essential for distinction – Associated with mutations upstream of codon 158, downstream of codon 1595 or in codons 312-412 ○ Severe FAP is defined as > 1,000 adenomas and linked to mutations between codons 1250-1464 ○ If untreated, > 90% of patients develop colorectal adenocarcinoma by age 50 ○ Patients also at increased risk for malignancies arising in – Duodenum/periampullary (adenocarcinoma; 3-5% by age 70) – Thyroid (papillary thyroid carcinoma; 1-12%) – Liver (hepatoblastoma; 1.6%) – Pancreas (adenocarcinoma; 1%) – Cerebellum (medulloblastoma; < 1%) 230

•

•

•

○ Other manifestations include adenomatous polyposis of small and large bowels, congenital hypertrophy of retinal pigment epithelium, desmoid tumors, osteoma in face or skull, dental abnormalities, nasopharyngeal angiofibroma, cutaneous epidermoid cyst, and pilomatrixoma Lynch syndrome ○ Autosomal dominant ○ Adenomas are absent or in small number (nonpolyposis or oligopolyposis) ○ Lifetime risk for colorectal adenocarcinoma is 10-53%; mean age at diagnosis is 45-50 years ○ Adenocarcinoma mostly arises in proximal colon ○ Lynch patients also at increased cancer risk in – Colorectum (35% by age 70, mostly adenocarcinoma) – Endometrium (34%, mostly endometrioid adenocarcinoma) – Ovary (8%, mostly endometrioid or clear cell carcinoma) – Urothelium (2%, mostly in upper urinary tract) – Skin (1-9%, sebaceous neoplasms in Muir-Torre syndrome) – Stomach (1-13%) – Brain (1-4%, glioblastoma in Turcot syndrome) MAP ○ Autosomal recessive ○ Associated with colorectal adenomas (typically < 100 adenomas), hyperplastic polyps, and sessile serrated polyps ○ Lifetime risk for colorectal adenocarcinoma is 80-90%; mean age at diagnosis is 45 years ○ Patients also at increased risk for carcinoma arising in – Breast (25%) – Skin (17%) – Ovary (10%) – Urinary bladder (6%) – Duodenum (4%) – Endometrium (3%) ○ Other manifestations include adenomatous or serrated polyposis of large bowel, congenital hypertrophy of retinal pigment epithelium, dental abnormalities, and benign skin tumors (sebaceous adenomas, epidermoid cysts) Hereditary mixed polyposis syndrome ○ Autosomal dominant ○ Rare; reported in few families ○ Polyposis with mixed histology including adenomas, serrated polyps, Peutz-Jeghers-type and juvenile polyps ○ No extracolonic disease MSH3-associated polyposis ○ Autosomal recessive ○ Rare; reported in 4 affected individuals in 2 families ○ Colonic polyposis (> 40 polyps), diagnosed in 3rd decade of life, include tubular or tubulovillous adenomas ○ Small number of hyperplastic polyps can be seen ○ Extracolonic findings include duodenal adenomas, thyroid adenomas, uterine leiomyomas, multiple intraductal papillomas in breast, astrocytoma, cutaneous fibrolipoma, and signet ring cell gastric adenocarcinoma NTHL1-associated polyposis ○ Autosomal recessive

Colonic Adenomas

Colorectal Surveillance Recommendations (American College of Gastroenterology Guidelines) • FAP ○ Classic FAP – Unaffected family members who are tested positive for pathogenic APC mutations are endoscopically followed every 12 months starting at age 10-15 years – Surgery to remove colon is generally recommended in late teens to early twenties with 2 options □ Total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA) followed by ileal pouch surveillance is recommended for cases with high adenoma burden

•

•

•

•

□ Total abdominal colectomy with ileal-rectal anastomosis (TAC-IRA) is less morbid but incurs residual rectal cancer risk  ○ Attenuated FAP – Generally can be endoscopically managed every 1-2 years, starting at age 18-20 – Surgery can be considered for patients who later develop high polyp burden or high-grade dysplasia Lynch syndrome ○ Colonoscopy every 1-2 years starting at age 20-25 years ○ Surgery can be considered for patients whose disease cannot be endoscopically managed MAP ○ Biallelic pathogenic variants – Generally can be endoscopically managed every 1-2 years, starting at age 25-30 – Surgery can be considered for patients who later develop high polyp burden or high-grade dysplasia ○ Heterozygote pathogenic variant (only 1 allele affected) – No clear consensus Li-Fraumeni syndrome (American Association for Cancer Research 2017 guidelines) ○ Colonoscopy every 2-5 years starting at age 25 years or 5 years prior to earliest age of colorectal cancer diagnosis in family NTHL1-associated polyposis and DNA polymerase ε and δ polyposis (European Society for Medical Oncology 2019 guidelines) ○ Colonoscopy every 1-2 years, starting at age 18-20

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

○ Rare; reported in few families ○ All reported cases had multiple colonic adenomas; some had few hyperplastic polyps ○ Extracolonic findings include duodenal adenomas/carcinoma, endometrial hyperplasia/carcinoma, prostate cancer, bladder carcinoma, meningioma, basal cell carcinoma, pancreatic cancer, breast cancer, and non-Hodgkin lymphoma • DNA polymerase ε and δ polyposis ○ Autosomal dominant ○ All 47 reported cases of POLE-associated polyposis had p.L424V mutation – All had 1-68 colorectal adenomas; some had hyperplastic polyps – CRC developed in 63.8%; mean age at diagnosis is 40.7 years – Extracolonic tumors include duodenal adenoma (50%), gastric fundic gland polyp (21%), and jejunal adenoma (7%) – Endometrial cancer (age 50), breast cancer (age 42), ureter cancer (age 46), anaplastic oligodendroglioma (age 30), astrocytoma (age 15), duodenal cancer (age 45), ovarian cancer (age 33), and glioblastoma (age 47) ○ POLD1 mutations (p.S478N, L474P, D316H, V295M, D316G, R409W, L474P) were reported in 22 individuals – Colorectal adenomas were found in 79%; some also had hyperplastic polyps – 1 individual only had gastric hyperplastic polyps without colonic polyps – CRC developed in 59.1%; mean age at diagnosis 35.9 years – Extracolonic tumors include endometrial cancer (57.1% of female patients) and breast cancer (14.3% of female patients) – Astrocytoma (age 26), gastrointestinal stromal tumor (age 36), angiomyolipoma (age 65), and mesothelioma (age 65) • Li-Fraumeni syndrome ○ Autosomal dominant ○ CRC develop in 2.8% of cases; mean age at diagnosis is 33.0-38.5 years ○ Patients can also have colonic adenomas (55%) and hyperplastic polyps (19%) ○ Extracolonic manifestations include breast cancer (31%), various sarcomas (27%), adrenal cortical carcinomas (10%), choroid plexus tumors (6%), and less commonly leukemias, lymphomas, and carcinomas in various organs

MICROSCOPIC Histologic Features • Adenomas are by definition at least low-grade dysplasia ○ Dysplastic epithelium consists of elongated, hyperchromatic nuclei extending to mucosal surface • Features of high-grade dysplasia ○ Nuclei with open chromatin, prominent nucleoli, and increased nuclear:cytoplasmic ratio ○ Loss of nuclear polarity ○ Architectural complexity: Irregular, back-to-back tubules, cribriforming, solid nests

Villous Component • Elongated leaf-like projections of dysplastic epithelium • % of adenoma surface area with villi defines type ○ Tubular adenoma (70-90%): < 25% villous component – 2-3% lifetime malignancy risk ○ Tubulovillous adenoma (10-25%): 25-75% villous component – Intermediate risk of malignant transformation ○ Villous adenoma (~ 5%): > 75% villous component – > 30% have high-grade dysplasia – ~ 2% have invasive CRC at diagnosis (15-25% lifetime)

Pseudoinvasion (Epithelial Misplacement) • • • • •

Misplaced (herniated) epithelium in submucosa Lacks desmoplastic stromal reaction Glands accompanied by lamina propria Hemosiderin deposition Submucosal epithelium resembles mucosal epithelium 231

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Colonic Adenomas

DIFFERENTIAL DIAGNOSIS Reactive/Regenerative Epithelium • Epithelium matures toward surface • Usually associated with active inflammation • Mitoses limited to crypt bases

Invasive Carcinoma • Accompanied by desmoplastic stromal reaction

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Dysplasia (adenomatous change) can also occur in ○ Hamartomatous and hyperplastic polyps ○ Inflammatory bowel disease (ulcerative colitis, Crohn disease) • Multiple adenomas may be part of genetic syndrome

REPORTING Key Elements to Report • Key facts to be included in pathology report ○ Extent of villous component, presence of high-grade dysplasia ○ If multiple pieces of adenoma (piecemeal removal) – Indicate as such (1 or multiple polyps) – Margin cannot be adequately evaluated – Attempt to account for each polyp removed ○ Large pedunculated polyp, removed in single piece – Bisect (or serially section) and properly orient – Comment on dysplasia at cauterized margin – Positive: Further removal &/or close follow-up – Cautery may actually destroy residual adenoma ○ If invasive carcinoma is present (desmoplasia) – Degree of differentiation and direct extension – Perineural and lymphovascular invasion, if present – Margin status, including clearance to submucosal margin – Tumor budding 

SELECTED REFERENCES 1.

2. 3. 4.

5.

6. 7.

8. 9.

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Stjepanovic N et al: Hereditary gastrointestinal cancers: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. ePub, 2019 Rengifo-Cam W et al: Colon pathology characteristics in Li-Fraumeni syndrome. Clin Gastroenterol Hepatol. 16(1):140-1, 2018 Kratz CP et al: Cancer screening recommendations for individuals with LiFraumeni syndrome. Clin Cancer Res. 23(11):e38-e45, 2017 Adam R et al: Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 99(2):337-51, 2016 Bellido F et al: POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 18(4):325-32, 2016 Rivera B et al: Biallelic NTHL1 mutations in a woman with multiple primary tumors. N Engl J Med. 373(20):1985-6, 2015 Syngal S et al: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 110(2):223-62; quiz 263, 2015 Taupin D et al: A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. Hum Genome Var. 2:15013, 2015 Weren RD et al: A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 47(6):668-71, 2015

10. Gala MK et al: Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas. Gastroenterology. 146(2):520-9, 2014 11. Jaeger E et al: Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 44(6):699-703, 2012 12. Gonzalez KD et al: Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 27(8):1250-6, 2009 13. Wong P et al: Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology. 130(1):73-9, 2006 14. Brensinger JD et al: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut. 43(4):548-52, 1998 15. Giardiello FM et al: Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene. Ann Intern Med. 126(7):514-9, 1997 16. Nielsen M et al: MUTYH polyposis. GeneReviews, University of Washington, 1993 17. Nagase H et al: Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res. 52(14):4055-7, 1992

Colonic Adenomas

Villous Adenoma (Left) H&E shows a higher magnification view of a tubular adenoma with lowgrade dysplasia. Note the "picket fence" arrangement of elongated hyperchromatic nuclei. (Right) H&E shows a villous adenoma, almost entirely composed of villi, elongated, leaf-like projections of dysplastic epithelium ﬈ occupying > 75% of the adenoma.

Intramucosal Carcinoma

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Tubular Adenoma

High-Grade Dysplasia (Left) H&E shows an adenoma with intramucosal carcinoma. (Right) H&E shows extensive high-grade dysplasia, which some would classify as intramucosal carcinoma. There is increased architectural complexity with irregular, back-to-back glands, often forming cribriform structures ﬈. There is no difference in the management between high-grade dysplasia or intramucosal adenocarcinoma.

Squamous Metaplasia

Invasive Carcinoma Arising in Adenoma (Left) H&E shows an adenoma with squamous metaplasia. The dysplastic glandular epithelium of the adenoma differentiates into morules of squamous epithelium ﬈. (Right) H&E shows a tubular adenoma giving rise to an invasive adenocarcinoma. Typically arising from the base of the adenoma, invasive tubules elicit a desmoplastic stromal reaction ﬈.

233

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Esophageal Adenocarcinoma KEY FACTS

TERMINOLOGY • Malignant epithelial tumor of esophagus with glandular differentiation

ETIOLOGY/PATHOGENESIS • Genetic predisposition: ~ 7% of BE/EAC cases are familial • Barrett esophagus: 10% lifetime risk for esophageal adenocarcinoma  • Several germline variants were found shared between probands and affected relatives ○ VSIG10L S631G  ○ MSX1 V120G  ○ Concurrent PTEN frameshift mutation and SMAD7 missense mutation  ○ EAC has also been reported in patient with Li-Fraumeni syndrome • Gastroesophageal reflux disease: Risk increases with duration of exposure to gastric/duodenal contents

• Other risk factors: Male, obesity, smoking, alcohol, Caucasian, high socioeconomic status

CLINICAL ISSUES • Increasing incidence in developed western countries since late 20th century • Average age at presentation in 60s; ~ 80% of cases are in men • Endoscopic ablation treatment for early lesions; chemoradiation and surgery for higher stage tumors • Prognosis depends on stage and response to radiochemotherapy

MACROSCOPIC • Arises predominantly in lower 1/3 of esophagus

MICROSCOPIC • Gland forming in tubular &/or papillary patterns

Intestinal Metaplasia, Nondysplastic

Low-Grade Dysplasia

Esophageal Adenocarcinoma

Gross Examination

(Left) H&E shows abrupt transition from squamous epithelium to columnar epithelium with prominent goblet cells ﬈. (Right) H&E shows an area of low-grade dysplasia with focal intestinal metaplasia. Columnar cells with pencil-shaped, hyperchromatic nuclei line the crypts and extend to the surface ﬈. The atypical nuclei are stratified but mostly remain basally polarized.

(Left) H&E shows an adenocarcinoma undermining squamous mucosa in the esophagus. (Right) Gross photo shows an invasive esophageal adenocarcinoma. The velvety background Barrett mucosa is readily identified ſt.

234

Esophageal Adenocarcinoma

DIAGNOSTIC CHECKLIST

Abbreviations

Duplication of Muscularis Mucosae

• Esophageal adenocarcinoma (EAC) • Barrett esophagus (BE)

• Occurs at least focally in > 90% of BE cases • Tumors invading into space between inner and outer MM are still considered intramucosal  • Awareness of potential MM duplication is important for avoiding overstaging in biopsies

Definitions • Malignant epithelial tumor of esophagus with glandular differentiation ○ BE is precursor lesion

ETIOLOGY/PATHOGENESIS Genetic Predisposition • ~ 7% of BE/EAC cases are familial • Segregation analysis reveals polygenic, autosomal dominant inheritance with incomplete penetrance • Several germline variants were found shared between probands and affected relatives ○ VSIG10L S631G  – Found in North American family with 14 members affected by BE/EAC – VSIG10L is highly expressed in normal suprabasal esophageal squamous epithelium; expression is significantly decreased in nondysplastic and dysplastic BE and EAC – Esophageal epithelium of mutant carriers shows enlarged intercellular space and decreased desmosomes – Transfected esophageal squamous cell 3D culture model shows inhibited maturation ○ MSX1 V120G  – Found in Dutch family with 5 members affected by BE/EAC – MSX1 is part of BMP4 signaling pathway, which induces epithelial to mesenchymal transition (EMT) in human embryonogenesis and has also been implicated in pancreatic and esophageal cancers □ BMP4 is significantly upregulated in BE and EAC compared to normal squamous epithelium ○ Concurrent PTEN frameshift mutation c.568_569insC and SMAD7 missense mutation c.115G>A  – Found in North American father-son pair who both had early-onset EAC (father at age 41; son at 33) – Father had gastrointestinal juvenile polyposis, whereas son had ganglioneuromatous polyposis and cutaneous trichilemmoma ○ By linkage analysis, germline mutations in MSR1, ASCC1, and CTHRC1 have been implicated with BE/EAC  • EAC has also been reported in patient with Li-Fraumeni syndrome  • Polymorphisms in genes involved in inflammation (COX-2), xenobiotics/peroxides detoxification (MGST1, GSTM1, GSTT1, NQO1, and GSTP1), extracellular matrix remodeling (MMP1, MMP3, and MMP12), cell cycle regulation (CCND1, EGF) and DNA repair (ERCC1, XPD, ERCC6, XPA, XPC, and XRCC1) have been associated with BE/EAC

Other Risk Factors • Gastroesophageal reflux disease, males, Caucasians, higher socioeconomic status, obesity, smoking, alcohol

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van Nistelrooij AMJ et al: Germline variant in MSX1 identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma. Fam Cancer. 17(3):435-40, 2018 Buas MF et al: Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Gut. 66(10):1739-47, 2017 Diao J et al: Correlation between NAD(P)H: quinone oxidoreductase 1 C609T polymorphism and increased risk of esophageal cancer: evidence from a meta-analysis. Ther Adv Med Oncol. 9(1):13-21, 2017 Fecteau RE et al: Association between germline mutation in VSIG10L and familial Barrett neoplasia. JAMA Oncol. 2(10):1333-9, 2016 Kestens C et al: BMP4 signaling is able to induce an epithelial-mesenchymal transition-like phenotype in Barrett's esophagus and esophageal adenocarcinoma through induction of SNAIL2. PLoS One. 11(5):e0155754, 2016 Sherman SK et al: Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations. Cancer Genet. 208(1-2):41-6, 2015 Richter A et al: BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2. Stem Cells. 32(3):636-48, 2014 Orloff M et al: Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA. 306(4):410-9, 2011 Sun X et al: A segregation analysis of Barrett's esophagus and associated adenocarcinomas. Cancer Epidemiol Biomarkers Prev. 19(3):666-74, 2010 Bradbury PA et al: Matrix metalloproteinase 1, 3 and 12 polymorphisms and esophageal adenocarcinoma risk and prognosis. Carcinogenesis. 30(5):793-8, 2009 Pan J et al: Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. Carcinogenesis. 30(5):785-92, 2009 Ferguson HR et al: Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 17(3):72731, 2008 Lanuti M et al: A functional epidermal growth factor (EGF) polymorphism, EGF serum levels, and esophageal adenocarcinoma risk and outcome. Clin Cancer Res. 14(10):3216-22, 2008 Masciari S et al: F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA. 299(11):1315-9, 2008 Abraham SC et al: Duplication of the muscularis mucosae in Barrett esophagus: an underrecognized feature and its implication for staging of adenocarcinoma. Am J Surg Pathol. 31(11):1719-25, 2007 Hamada S et al: Bone morphogenetic protein 4 induces epithelialmesenchymal transition through MSX2 induction on pancreatic cancer cell line. J Cell Physiol. 213(3):768-74, 2007 Moons LM et al: COX-2 CA-haplotype is a risk factor for the development of esophageal adenocarcinoma. Am J Gastroenterol. 102(11):2373-9, 2007 Casson AG et al: Genetic polymorphisms of microsomal epoxide hydroxylase and glutathione S-transferases M1, T1 and P1, interactions with smoking, and risk for esophageal (Barrett) adenocarcinoma. Cancer Detect Prev. 30(5):423-31, 2006 Chak A et al: Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev. 15(9):1668-73, 2006 Casson AG et al: Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma. Cancer. 104(4):730-9, 2005 Casson AG et al: Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Carcinogenesis. 26(9):1536-41, 2005 van Lieshout EM et al: Polymorphic expression of the glutathione Stransferase P1 gene and its susceptibility to Barrett's esophagus and esophageal carcinoma. Cancer Res. 59(3):586-9, 1999

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

235

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Esophageal Squamous Cell Carcinoma KEY FACTS

TERMINOLOGY

MACROSCOPIC

• Malignant epithelial neoplasm with squamous cell differentiation

• Most common in the middle 1/3 of esophagus

ETIOLOGY/PATHOGENESIS

• Appears as squamous cell carcinoma in other anatomic sites • Morphological variants ○ Verrucous carcinoma: Highly differentiated, keratinized with minimal cytologic atypia; invades in pushing pattern ○ Basaloid: Aggressive, consisted of lobules of hyperchromatic cells with high N:C ratio ○ Spindle cell carcinoma: May show heterologous differentiation

• Environmental risk factors include tobacco, alcohol, thermal or corrosive injuries, pickled vegetables • Genetic predisposition ○ Howel-Evans syndrome ○ Germline BRCA2 mutations ○ Fanconi anemia (FA) ○ Mutations in ethanol metabolizing enzymes ○ Mutations in epidermal growth factor (EGF) and hepatocyte growth factor (HGF) pathways

CLINICAL ISSUES • Varies by geography • Superficial tumors can be treated endoscopically

MICROSCOPIC

TOP DIFFERENTIAL DIAGNOSES • Pseudoepitheliomatous hyperplasia ○ Lacks "paradoxal maturation" ○ Intact basal layer

High-Grade Squamous Dysplasia

Invasive ESCCa With Keratinization

Verrucous Carcinoma

Basaloid Squamous Cell Carcinoma

(Left) H&E shows an area of high-grade squamous dysplasia. Note the lack of epithelial maturation. (Right) H&E shows an esophageal squamous cell carcinoma (ESCCa) with an invasive tumor nest showing abnormal deep keratinization forming a keratin "pearl" ﬊.

(Left) H&E shows a low-power view of a squamous proliferative lesion with broad bands of highly differentiated keratinized squamous cells pushing downward into the underlying stroma. Cytologic atypia is minimal. (Right) H&E shows basaloid tumor cells with a high N:C ratio forming solid nests. Focal gland-like spaces with deposition of basement membrane-like material are noted ﬇.

236

Esophageal Squamous Cell Carcinoma

Abbreviations • Esophageal squamous cell carcinoma (ESCCa)

Definitions • Malignant epithelial neoplasm with squamous cell differentiation

ETIOLOGY/PATHOGENESIS Environmental Exposure • Tobacco, alcohol, thermal or corrosive injuries, pickled vegetables

Infectious Agents • Role of human papillomavirus remains controversial

○ Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are 2 major enzyme groups responsible for ethanol metabolism ○ Polymorphisms of ADH1B and ALDH2 have been linked to increased ESCCa risk • EGF and hepatocyte growth factor (HGF) pathways ○ Germline mutations in STAT3, EGF, MET, AKT1, and GDF15 have been found in ESCCa patients with positive family history

CLINICAL ISSUES Epidemiology • Incidence ○ Varies by geography – Uncommon in USA: 5 per 100,000 men; 1 per 100,000 women

Nutrition Deficiencies • Plummer-Vinson syndrome (sideropenic dysphagia) ○ Severe, long-term iron deficiency anemia with dysphagia due to esophageal webs

Genetic Predisposition • Howel-Evans syndrome ○ Autosomal dominant, manifesting as – Palmoplantar keratoderma (tylosis) – Oral leukoplakia – Increased lifetime risk for ESCCa ○ Associated with missense mutations in RHBDF2 at chromosome 17q25.1 ○ Synonyms: Tylosis esophageal cancer (TOC) syndrome, type A tylosis ○ Oncogenic mechanisms – RHBDF2 encodes intramembranous protease involved in epidermal growth factor receptor (EGFR) signaling pathway – RHBDF2 mutations dysregulate EGFR signaling and result in hyperproliferative and hypermigratory phenotype of keratinocytes • Germline BRCA2 mutations ○ Germline mutations in BRCA2 are found in 8-19% of ESCCa patients, significantly more frequent than in health controls (0-3%) ○ Over 85% of ESCCa patients with germline BRCA2 mutations have family history of ESCCa – However, no family history of breast or ovarian cancers have been reported by these patients ○ BRCA2, a.k.a. FANCD1, is essential member of Fanconi anemia (FA) pathway for homologous recombination repair of DNA damages – K3326X is most common mutation in ESCCa, occurring in RAD51 recombinase-binding TR2 region • FA ○ FA patients have 1,000-fold increased risk for developing squamous cell carcinomas – Head and neck, esophagus, and anogenital regions are most frequent primary sites ○ Germline insertion/deletions in FANCD2, FANCE, and FANCL have been found in Iranian ESCCa families • Ethanol metabolizing enzymes

DIFFERENTIAL DIAGNOSIS Pseudoepitheliomatous Hyperplasia

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

• Reactive to various inflammatory stimuli, such as fungal infections or granular cell tumor • Elongated jagged bands of epithelium extending downward into stroma • No significant cytologic atypia, atypical mitosis, or deep invasion; otherwise, should consider carcinoma

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237

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastric Adenocarcinoma KEY FACTS – – – – – –

TERMINOLOGY • Primary malignant gastric epithelial neoplasm with glandular differentiation

ETIOLOGY/PATHOGENESIS • Diet (preserved foods), smoking, Helicobacter pylori infection, bile reflux • Predisposing hereditary syndromes ○ Hereditary diffuse gastric cancer (HDGC) due to CDH1 or CTNNA1 mutations ○ Peutz-Jeghers syndrome (PJS) ○ Juvenile polyposis syndrome (JPS) ○ Familial adenomatous polyposis (FAP) ○ MUTYH-associated polyposis (MAP) ○ Gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) • Other syndromes with increased gastric cancer risk but lack strong evidence to support surveillance benefit ○ Lynch syndrome

PTEN-hamartoma tumor syndrome Ataxia-telangiectasia Bloom syndrome Hereditary breast and ovarian cancer syndrome Li-Fraumeni syndrome Xeroderma pigmentosum

CLINICAL ISSUES • Recent guidelines recommend surveillance for HDGC, JPS, and PJS due to high gastric cancer risk • Gastric cancer risk appears to be small in FAP and MAP; nevertheless, gastric mucosa is periodically examined during endoscopic surveillance for duodenal disease

TOP DIFFERENTIAL DIAGNOSES • • • •

Gastric dysplasia Gastric lymphoma Gastric xanthoma Whipple disease

HDGC: Gross Examination

HDGC: Precursor Lesion

HDGC: Intramucosal Carcinoma

Diffuse-Type Carcinoma

(Left) This prophylactic gastrectomy specimen from a 51-year-old woman with CDH1 c.2287G>T mutation appears grossly unremarkable. The patient was diagnosed with invasive mammary carcinoma at age 30. (Right) Signet ring cell precursor lesions are noted multifocally. Signet ring cells displace the epithelium away from the basement membrane ﬇ but are still confined by the basement membrane.

(Left) Microscopic foci of intramucosal carcinoma are also noted in the same patient, with confluent sheets of signet ring cells within the lamina propria. Note the monotonous appearance of tumor cells. (Right) In another patient with advanced-stage carcinoma, the signet ring tumor cells are more pleomorphic.

238

Gastric Adenocarcinoma

Definitions • Primary malignant gastric epithelial neoplasm with glandular differentiation

ETIOLOGY/PATHOGENESIS Environmental Exposure • Diet (preserved foods), smoking, Helicobacter pylori infection, bile reflux

Genetic Predisposition to Gastric Adenocarcinoma • Majority of gastric cancers are sporadic, with only 1-3% of cases associated with hereditary syndromes • Hereditary diffuse gastric cancer (HDGC) ○ CDH1 mutations – CDH1 encodes E-cadherin, transmembrane protein essential for cell-cell adhesion □ > 100 pathogenic alterations have been discovered, including point mutations, insertions, deletions, and splicing variants widely distributed throughout gene ○ CTNNA1 mutations – CTNNA1 encodes alpha-Ecatenin, linkage protein that connects E-cadherin to cytoskeleton ○ One proband sequencing study also found germline mutations in BRCA2, PRSS1, ATM, PALB2, SDHB, STK11, and MSR1 in rare cases of CDH1-wild type HDGC • Hereditary gastric polyposis syndromes ○ Associated with intestinal type gastric adenocarcinoma ○ Syndromes with hamartomatous polyposis – Peutz-Jeghers syndrome (PJS) □ Associated with STK11 mutations □ STK11 is tumor suppressor gene that encodes intracellular protein kinase, LKB1, which regulates cell metabolism and growth by activating AMPactivated protein kinase (AMPK) and transforming growth factor-β (TGF-β) signaling pathways – Juvenile polyposis syndrome (JPS) □ Associated with SMAD4 or BMPR1A mutations □ SMAD4 and BMPR1A are tumor suppressor genes involved in BMP and TGF-β signaling pathways ○ Syndromes with fundic gland polyposis – Familial adenomatous polyposis (FAP) □ > 700 mutations in APC have been implicated □ APC encodes component of degradation complex, which breaks down cytosolic β-catenin □ APC dysfunction causes intracellular accumulation and nuclear translocation of β-catenin, which activates oncogenes, such as c-Myc and Wnt/βcatenin pathway – MUTYH-associated polyposis (MAP) □ > 80 mutations in MUTYH have been implicated □ ~ 1% of general population are heterozygous carriers of MUTYH mutations □ MUTYH encodes MYH, DNA glycosylase which excises adenine paired with 8-oxo-7,8-dihydro-2deoxyguanosine (8-oxoG), product of oxidative DNA damage (base-excision repair) □ Dysfunctional MYH leads to increased G:C to T:A conversion

□ Consequence is particularly profound for DNA sequences rich in GAA codons, which are prone to be converted to TAA, stop codon □ APC is rich in GAA sites, which explains FAP-like phenotype in MAP patients – Gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) □ Associated with point mutations in promoter 1B region of APC • Other syndromes with increased gastric cancer risk but lack strong evidence to support surveillance benefit ○ Lynch syndrome ○ PTEN-hamartoma tumor syndrome ○ Ataxia-telangiectasia ○ Bloom syndrome ○ Hereditary breast and ovarian cancer syndrome ○ Li-Fraumeni syndrome ○ Xeroderma pigmentosum

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

CLINICAL ISSUES Presentation • Abdominal pain ○ May mimic symptomatology related to peptic ulcer • Anemia, vomiting, weight loss • Young patients may present with intraabdominal dissemination and ascites ○ Females may present with metastatic ovarian lesions (Krukenberg tumors)

Treatment • Surgical approaches ○ Gastrectomy ○ Associated with neoadjuvant and adjuvant therapies

Clinical Features by Syndrome • CDH1 mutations ○ Autosomal dominant ○ Risk for gastric cancer by age 80: 70% for men and 56% for women ○ Most patients without prophylactic gastrectomy develop gastric cancer before age 40 ○ Women are also at risk for breast lobular carcinoma (42% risk by age 80) • CTNNA1 mutations ○ Autosomal dominant ○ Rare; found in 3 families with clustering of diffuse-type gastric adenocarcinoma while tested negative for CDH1 mutation • PJS ○ Autosomal dominant ○ PJS-type hamartomatous polyps most commonly develop in small bowel ○ Hamartomatous polyposis also affects stomach, colon, renal pelvis, ureter, urinary bladder, gallbladder, nasal cavity, and bronchus ○ 25-50% of patients have gastric polyps ○ Lifetime risk for gastric cancer: 29% ○ Gastric cancer occurs at average age of 30-40 years

239

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastric Adenocarcinoma

•

•

•

• 240

○ PJS patients also at increased risk for carcinoma arising in breast (32-54%), colorectal (39%), pancreas (11-36%), small bowel (13%), lung (7-17%), and uterine cervix (adenoma malignum; 10%) ○ Other manifestations include mucocutaneous melanocytic macules, ovarian sex cord tumors with annular tubules (SCTATs), and intratubular large-cell hyalinizing Sertoli cell tumors of testes JPS ○ Autosomal dominant ○ Juvenile polyps develop in the stomach, small intestine, colon, and rectum ○ 15-25% of patients have gastric polyps ○ Lifetime risk for gastric cancer: 21-73% ○ Gastric cancer occurs at mean age of 41 years ○ Patients also at increased risk for carcinoma arising in colorectal (39%), pancreas, and small bowel (slightly increased) ○ Subset of patients with SMAD4 pathogenic variants may have mucocutaneous telangiectasia and visceral arteriovenous malformation [juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome] ○ Subset of patients with SMAD4 pathogenic variants may also show features of connective tissue disorder, which may include thoracic aortic dilatation, aneurysm, dissection, mitral valve insufficiency, retinal detachment, lax joints and skin FAP ○ Autosomal dominant ○ 33% of patients have gastric polyps ○ Gastric carcinoma is rare with lifetime risk of 0.6% ○ However, recent large registry study has noted incidence surge with most patients presenting at advanced stage despite compliance with regular upper GI endoscopic surveillance ○ Patients also at increased risk for malignancies arising in colorectum (adenocarcinoma; 93% by age 50), small bowel (adenocarcinoma; 4-12%), thyroid (papillary thyroid carcinoma; 1-12%), liver (hepatoblastoma; 1.6%), pancreas (adenocarcinoma; 1%), and cerebellum (medulloblastoma; < 1%) ○ Other manifestations include adenomatous polyposis of small and large bowels, congenital hypertrophy of retinal pigment epithelium, desmoid tumors, osteoma in face or skull, dental abnormalities, nasopharyngeal angiofibroma, cutaneous epidermoid cyst, and pilomatrixoma MAP ○ Autosomal recessive ○ Gastric polyps occur in 10-30% of patients ○ Gastric carcinoma is rare with lifetime risk of 1-2% ○ Patients also at increased risk for carcinoma arising in colorectum (43-100%), small bowel (4%), breast (25%), skin (17%), ovary (10%), endometrium (3%), and urinary bladder (6%) ○ Other manifestations include adenomatous or serrated polyposis of small and large bowel, congenital hypertrophy of retinal pigment epithelium, dental abnormalities, and benign skin tumors (sebaceous adenomas, epidermoid cysts) GAPPS

○ Autosomal dominant ○ Rare, reported in 9 families thus far; lifetime gastric cancer risk undetermined due to case rarity ○ Clinical characteristics include gastric polyposis sparing antrum and pylorus (proximal polyposis) and absence of duodenal/colorectal involvement

Surveillance Recommendations • CDH1 mutation carriers ○ Prophylactic total gastrectomy with intraoperative frozen examination of margins to ensure complete removal of gastric tissue ○ Those who choose not to undergo gastrectomy should undergo annual endoscopic screening • JPS ○ Endoscopic surveillance should start at age 12-15  – Polyps present: Repeat annually – No polyps present: Repeat every 2-3 years • PJS ○ Esophagoduodenoscopy starting at age 8 – Polyps present: Repeat every 3 years – No polyps present: Repeat at age 18 and every 3 years thereafter • FAP and MAP ○ No strong evidence to support surveillance benefit given low gastric cancer risk ○ Nevertheless, gastric mucosa is periodically examined during duodenal surveillance • GAPPS ○ No strong evidence to support surveillance benefit due to case rarity

MICROSCOPIC HDGC Due to CDH1 or CTNNA1 Mutations • Prophylactic gastrectomy specimens, although grossly normal, frequently show microscopic foci of signet ring cell precursor lesions and intramucosal invasive adenocarcinoma • 2 patterns of precursor lesions ○ Signet ring cell carcinoma in situ: Signet ring cells replacing normal epithelium within confinement of basement membrane ○ Pagetoid spread: Epithelium is preserved but lifted away from basement membrane by signet ring cells • Patterns of E-cadherin immunostaining are variable, including absent, weak membranous, cytoplasmic, and dotlike appearance • Early-stage tumors tend to be cytologically monotonous with low Ki-67 index and wild-type p53 expression, whereas advanced tumors tend to be more pleomorphic with increased Ki-67 index and aberrant p53 staining

Hereditary Polyposis Syndromes • Associated with intestinal-type gastric adenocarcinoma • PJS ○ Polyps are characterized by villiform surface, arborizing smooth muscle bundles, foveolar hyperplasia, and cystic gland dilatation ○ Compared to intestinal PJS polyps, smooth muscle bands are less pronounced in gastric polyps, which can therefore resemble hyperplastic polyps

Gastric Adenocarcinoma

•

•

•

Gastric Xanthoma • Foamy cytoplasm may mimic diffuse-type gastric cancer • CD68(+), cytokeratin (-)

Whipple Disease • • • •

May mimic diffuse-type gastric cancer Cytokeratin (-) CD68(+) Bacteria (Tropheryma whipplei) observed on electron microscopy

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6. 7. 8. 9. 10. 11. 12. 13. 14.

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DIFFERENTIAL DIAGNOSIS Gastric Dysplasia

21.

• May be hard to distinguish from early intramucosal adenocarcinoma • Absence of desmoplasia • Limited cytoarchitectural anomalies

22.

Gastric Lymphoma

25.

• May mimic poorly differentiated intestinal and diffuse adenocarcinoma • CD20 and CD45 (+); cytokeratin and CEA (-)

23. 24.

Short E et al: The role of inherited genetic variants in colorectal polyposis syndromes. Adv Genet. 103:183-217, 2019 Terlouw D et al: Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy. Eur J Hum Genet. ePub, 2019 Ishida H et al: Malignant tumors associated with juvenile polyposis syndrome in Japan. Surg Today. 48(3):253-63, 2018 Rudloff U: Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives. Clin Exp Gastroenterol. 11:447-59, 2018 Vanella G et al: Unusual findings in Peutz-Jeghers syndrome: endoscopic and histologic appearance of gastric hamartomatous polyposis with foveolar dysplasia. Gastrointest Endosc. 88(2):399-400, 2018 Kaurah P et al: Hereditary diffuse gastric cancer. GeneReviews. University of Washington,  2018 McGarrity TJ et al: Peutz-Jeghers syndrome. GeneReviews. University of Washington, 2018 Gonzalez RS et al: Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases. Histopathology. 70(6):918-28, 2017 Jasperson KW et al: APC-associated polyposis conditions. GeneReviews. University of Washington, 2017 Lawless ME et al: Massive gastric juvenile polyposis: A clinicopathologic study using SMAD4 immunohistochemistry. Am J Clin Pathol. 147(4):390, 2017 Larsen Haidle J et al: Juvenile polyposis syndrome. GeneReviews. University of Washington, 2017 Mankaney G et al: Gastric cancer in FAP: a concerning rise in incidence. Fam Cancer. 16(3):371-6, 2017 van der Post RS et al: Emerging concepts in gastric neoplasia: Heritable gastric cancers and polyposis disorders. Surg Pathol Clin. 10(4):931-45, 2017 Li J et al: Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant. Am J Hum Genet. 98(5):830-42, 2016 van der Post RS et al: Histopathological, molecular, and genetic profile of hereditary diffuse gastric cancer: Current knowledge and challenges for the future. Adv Exp Med Biol. 908:371-91, 2016 Hansford S et al: Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 1(1):23-32, 2015 Syngal S et al: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 110(2):223-62; quiz 263, 2015 van der Post RS et al: Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 52(6):361-74, 2015 Nielsen M et al. MUTYH-associated polyposis. GeneReviews. University of Washington, 2015 Ma C et al: Upper tract juvenile polyps in juvenile polyposis patients: dysplasia and malignancy are associated with foveolar, intestinal, and pyloric differentiation. Am J Surg Pathol. 38(12):1618-26, 2014 Majewski IJ et al: An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 229(4):621-9, 2013 Langeveld D et al: SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome. Clin Cancer Res. 16(16):4126-34, 2010 Shackelford DB et al: The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 9(8):563-75, 2009 Vogt S et al: Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 137(6):1976-85.e1-10, 2009 Asnani PJ et al: Production and purification of Escherichia coli hemolysin. Folia Microbiol (Praha). 33(5):393-400, 1988

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

•

○ Dysplasia can rarely be seen in PJS-type hamartomatous polyps (2-3%) ○ Lifetime risk for gastric cancer: 29% JPS ○ Polyps are characterized by eroded surface, dilated glands lined by foveolar epithelium, and edematous stroma with inflammatory infiltrates ○ Distinction from hyperplastic polyps can be difficult ○ Low- and high-grade dysplasia seen in 9-18% and 9-14%, respectively ○ Lifetime risk for gastric cancer: 21- 73% ○ Immunohistochemistry for SMAD4 is variable – In polyps arising in setting of germline SMAD4 mutations, 30-45% show complete loss, 15% show attenuated staining, and 55% show retained nuclear staining – Polyps arising in setting of germline BMPR1A mutations all show retained SMAD4 staining FAP ○ Variable number of fundic gland polyps; can be numerous ("carpeting") ○ Detection of fundic gland polyp(s) in children should raise clinical suspicion for FAP ○ Fundic gland polyps are characterized by cystically dilated glands lined by chief cells and parietal cells, with occasional endocrine cells and mucinous cells ○ Dysplasia is common in syndromic fundic gland polyps – 38% show low-grade dysplasia – 3% show high-grade dysplasia – Dysplasia is typically intestinal type with hyperchromatic, elongated nuclei involving surface – In contrast, dysplasia is found in < 1% of sporadic fundic gland polyps, which are often associated with proton pump inhibitor use ○ Progression to adenocarcinoma is very rare (lifetime risk: < 1%) ○ Adenomatous polyps occasionally occur MAP ○ Mostly fundic gland polyps with occasional adenomatous polyps ○ Progression to adenocarcinoma is very rare (lifetime risk: 1-2%) GAPPS ○ Predominantly fundic gland polyps with occasional adenomatous and hyperplastic polyps ○ Antrum and pylorus are spared

241

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastric Adenocarcinoma

Peutz-Jeghers Gastric Polyp

Peutz-Jeghers Gastric Polyp

Juvenile Polyposis Syndrome

Gastric Juvenile Polyp

Gastric Juvenile Polyp

Gastric Juvenile Polyp With SMAD4 Loss

(Left) At low magnification, this polyp is characterized by its villiform surface, prominent foveolar-type epithelial hyperplasia, and arborizing central stroma. (Right) At high magnification of this polyp, smooth muscle bundles are seen within the stromal core.

(Left) This 63-year-old man with SMAD4 c.692dupG mutation had extensive gastric polyposis. The patient initially presented with recurrent epistaxis, multiple mucocutaneous telangiectasis, and visceral arteriovenous malformations. Three years post gastrectomy, the patient underwent repair surgery for ascending aortic dilation and mitral regurgitation. He also had loose joints since childhood and bilateral retinal detachment. (Right) Lowpower view shows dilated gastric glands and edematous stroma.

(Left) At higher magnification, the dilated glands are lined by foveolar type epithelium. The stroma is edematous and infiltrated by lymphocytes, plasma cells, and eosinophils. (Right) By IHC, the dilated glands show loss of SMAD4 staining. Note the strong nuclear staining in the inflammatory and endothelial cells.

242

Gastric Adenocarcinoma Fundic Gland Polyp in Familial Adenomatous Polyposis (Left) At low power, this fundic gland polyp from an familial adenomatous polyposis (FAP) patient shows dilated glands ﬇ and a hyperchromatic surface ﬊. (Right) High magnification of a fundic gland polyp in a patient with FAP shows that the dilated glands are lined by chief cells and parietal cells.

Fundic Gland Polyp in Familial Adenomatous Polyposis

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Stomach in Familial Adenomatous Polyposis

Gastric Dysplasia in Familial Adenomatous Polyposis (Left) On the surface of this gastric fundic gland polyp, there is low-grade dysplasia with hyperchromatic, elongated nuclei showing crowded, pseudostratified appearance. (Right) In this patient with gastric fundic gland polyps with low-grade dysplasia, a random biopsy from nonpolyp gastric mucosa also shows dysplastic features.

Intestinal-Type Gastric Carcinoma

Gastric Intestinal-Type Carcinoma (Left) Gross photo shows a large, fungating, ulcerated mass with focal necrosis. The Borrmann classification divides gastric carcinoma into type 1: Polypoid, type 2: Fungating, type 3: Ulcerated, and type 4: Diffusely infiltrative. (Right) H&E shows a moderately differentiated adenocarcinoma of the stomach. These lesions may be seen in patients with FAP.

243

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastrointestinal Stromal Tumor KEY FACTS

TERMINOLOGY • Most common mesenchymal tumor of GI tract, arising from interstitial cells of Cajal

CLINICAL ISSUES • Majority are sporadic and associated with mutations in KIT (70-85%), PDGFRA (5-10%, mutually exclusive with KIT mutations) and less commonly other genes • ~ 5% are associated with familial syndromes ○ Germline KIT mutations ○ Germline PDGFRA mutations ○ Neurofibromatosis type 1 (NF1 mutations) ○ Carney-Stratakis syndrome (SDHA, SDHB, SDHC, SDHD mutations) • Carney triad is sporadic tumor syndrome associated with gastrointestinal stromal tumors (GISTs) with SDHC epimutation • Uncertain malignancy: Prognosis depends on site, size, mitotic activity, and molecular profile

• Surgery and tyrosine kinase inhibitors (TKIs) are mainstays of treatment • Mutation profiling is essential for predicting response ○ Tumors with KIT exons 9 and 11 mutations and most PDGFRA mutations typically respond to imatinib ○ PDGFRA D842V and KIT/PDGFRA wild-type cases are resistant to imatinib but may respond to other TKIs

MICROSCOPIC • Muscularis propria-based neoplasm • Spindle cells or epithelioid morphology ○ Epithelioid morphology is associated with PDGFRA mutations and succinate dehydrogenase (SDH)-deficient cases including Carney-Stratakis syndrome and Carney triad

ANCILLARY TESTS • Positive for CD117, CD34, and DOG1 • Loss of SDHB expression in SDH-deficient tumors

GIST: Gross Appearance

GIST: Cross Section

Low-Power Microscopic View

Spindle Cell Gastrointestinal Stromal Tumor

(Left) Gross photograph shows a gastrointestinal stromal tumor (GIST) arising in the cecum. The tumor protrudes from the serosal surface. (Right) Cross section of a cecal GIST is shown. The tumor extends from the muscularis propria into the pericecal adipose.

(Left) H&E shows a gastric GIST. The tumor is well demarcated and located in the muscularis propria of the gastric body. (Right) Higher magnification shows a spindle cell gastric GIST with prominent perinuclear vacuoles.

244

Gastrointestinal Stromal Tumor

Abbreviations • Gastrointestinal stromal tumor (GIST)

Synonyms • Gastrointestinal autonomic nerve tumor is now subsumed under GIST

Definitions • Most common mesenchymal tumors of GI tract ○ Arise from interstitial cells of Cajal • Extragastrointestinal GISTs (rare)

Site • Overall, stomach is most common site (60%), followed by jejunum and ileum (30%), duodenum (5%), colon and rectum (< 5%), esophagus and appendix (rare) • Site predilection for syndromic cases ○ Gastric: Germline PDGFRA mutations, Carney-Stratakis syndrome, Carney triad ○ Small bowel: Neurofibromatosis type 1

Presentation • Gastrointestinal pain, bleeding &/or obstruction; other tumor syndrome manifestations

Treatment

ETIOLOGY/PATHOGENESIS Autosomal Dominant Hereditary Syndromes • 5% of cases are associated with autosomal dominant hereditary syndromes ○ Germline KIT mutations ○ Germline PDGFRA mutations ○ Neurofibromatosis type 1 (NF1 mutations) ○ Carney-Stratakis syndrome [succinate dehydrogenase (SDH) complex mutations]

Sporadic Tumor Syndrome • Carney triad (GISTs, paragangliomas, and pulmonary chondromas) ○ Sporadic tumor syndrome ○ GISTs are SDH-deficient but lack SDH complex mutations ○ 40% are associated with promoter hypermethylation of SDHC (SDHC epimutation) ○ However, 9.5% in one recent series showed germline mutations in SDHA, SDHB, or SDHC, which may represent rare hereditary cases – Further research is needed

Sporadic GISTS • Majority are nonsyndromic sporadic GISTs ○ Somatic mutations in KIT (70-85%), PDGFRA (5-10%, mutually exclusive with KIT mutations), NF1, and BRAF ○ Uncommon SDH-deficient cases are associated with SDHC epimutation and somatic SDH mutations

CLINICAL ISSUES Epidemiology • Incidence ○ ~ 5,000 new cases per year in USA • Age ○ Overall median presenting age is 60 years; younger in syndromic cases – Germline KIT mutations: 40-50 years – Germline PDGFRA mutations: 40-50 years – Neurofibromatosis type 1: 40-50 years – Carney-Stratakis syndrome: 20-30 years – Carney triad: Median 22 years • Sex ○ Overall, no sex difference in most series ○ Female predominance reported in cases with germline PDGFRA mutations and in Carney triad, SDHdeficient tumors

• Resectable cases: Complete surgical excision ○ Adjuvant imatinib for high-risk tumors based on size and mitotic activity (SSGXVIII/AIO trial) • Unresectable cases: Tyrosine kinase inhibitors (TKIs) therapy ○ Molecular testing is required for predicting response to imatinib (1st line TKI) – KIT exon 11 mutations: 90% respond to 400 mg/day – KIT exon 9 mutations: 50% respond to 400 mg/day; response rate improves with increased dose – PDGFRA mutations: Generally respond, with exception of D842V ○ Imatinib resistance – Primary resistance: PDGFRA D842V, SDH-deficient cases, mutations in NF1 or BRAF – Secondary mutations during imatinib treatment – May be sensitive to other TKIs (sunitinib, regorafenib, dasatinib)

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

Prognosis • Variable behavior: Majority are benign while subset may recur or metastasize • Prognosticators include location, size, mitotic activity (table) and molecular profile • Resistance to TKIs is associated with poor prognosis

MACROSCOPIC General Features • Typically arises in muscularis propria • Often multifocal in syndromic cases

MICROSCOPIC Histologic Features • Spindle cells (majority) or epithelioid morphology ○ Epithelioid morphology is associated with PDGFRA mutations and SDH-deficient cases including Carney-Stratakis syndrome and Carney triad • Eosinophilic cytoplasm • Paranuclear vacuoles • Minimal inflammation • Inconspicuous vessels • Skeinoid fibers • Occasional multinucleated cells, myxoid or cystic changes • SDH-deficient GISTs show multinodular growth pattern

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Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastrointestinal Stromal Tumor

ANCILLARY TESTS

4.

Immunohistochemistry

5.

• Positive for CD117, CD34, and DOG1 ○ GISTs with PDGFRA gene mutations can be weak or negative for CD117, while DOG1 is usually positive • SDHB loss in cases associated with SDH-deficienct tumors • Smooth muscle actin is positive in 70% • Desmin is positive in < 5%

6.

DIFFERENTIAL DIAGNOSIS

7. 8. 9. 10. 11.

Gastrointestinal Schwannoma • Muscularis propria (MP)-based, prominent lymphoid cuff, most common in stomach • S100(+) • CD117(-)

12.

13. 14.

Leiomyoma • Muscularis mucosae-based for most colonic tumors; esophageal tumors are often MP-based • Desmin (+), actin (+) • Neoplastic cells CD117(-) • Reactive CD117(+) cells can be prominent

Plexiform Fibromyxoma • MP-based, most common in stomach • Micronodules of myxoid stroma containing bland proliferating myofibroblastic cells • Actin (+) • Negative for S100, desmin, CD117, CD34, and DOG1

15.

16.

17.

18.

19.

Clear Cell Sarcoma of GI Tract • MP-based, most common in ileum • Morphology and immunophenotype resembling melanoma • t(12;22), EWS/ATF1 fusion

20.

21.

Inflammatory Fibroid Polyp • Submucosal-based, most common in stomach • Numerous eosinophils; edematous stroma; spindle cells "onion-skinning" around blood vessels • CD34(+) • CD117(-), DOG1(-) • PDGFRA mutations; no KIT mutations

22.

Perineurioma

25.

• Lamina propria-based, most common in colon • EMA(+), GLUT1(+) • S100(-), CD117(-), desmin (-)

26.

Fibromatosis • Mesentery-based, infiltrative growth • Nuclear β-catenin (+), CD34(-/+), S100(-), DOG1(-) • β-catenin and APC mutations (associated with familial adenomatous polyposis)

SELECTED REFERENCES 1. 2.

3.

246

Ibrahim A et al: Succinate dehydrogenase-deficient gastrointestinal stromal tumors. Arch Pathol Lab Med. ePub, 2019 Li GZ et al: Targeted therapy and personalized medicine in gastrointestinal stromal tumors: drug resistance, mechanisms, and treatment strategies. Onco Targets Ther. 12:5123-33, 2019 Gopie P et al: Classification of gastrointestinal stromal tumor syndromes. Endocr Relat Cancer. 25(2):R49-58, 2018

23. 24.

Sanchez-Hidalgo JM et al: Gastrointestinal stromal tumors: a multidisciplinary challenge. World J Gastroenterol. 24(18):1925-41, 2018 Boikos SA et al: Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet. 24(4):569-73, 2016 Forde PM et al: Familial GI stromal tumor with loss of heterozygosity and amplification of mutant KIT. J Clin Oncol. 34(3):e13-6, 2016 Ricci R: Syndromic gastrointestinal stromal tumors. Hered Cancer Clin Pract. 14:15, 2016 Wada R et al: "Wild type" GIST: clinicopathological features and clinical practice. Pathol Int. 66(8):431-7, 2016 Ricci R et al: PDGFRA-mutant syndrome. Mod Pathol. 28(7):954-64, 2015 Voltaggio L et al: Gastrointestinal tract spindle cell lesions-just like real estate, it's all about location. Mod Pathol. 28 Suppl 1:S47-66, 2015 Deshpande A et al: Leiomyoma of the gastrointestinal tract with interstitial cells of Cajal: a mimic of gastrointestinal stromal tumor. Am J Surg Pathol. 38(1):72-7, 2014 Haller F et al: Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 21(4):567-77, 2014 Killian JK et al: Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med. 6(268):268ra177, 2014 Eisenberg BL: The SSG XVIII/AIO trial: results change the current adjuvant treatment recommendations for gastrointestinal stromal tumors. Am J Clin Oncol. 36(1):89-90, 2013 Miettinen M et al: Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 35(11):171221, 2011 Wang JH et al: Succinate dehydrogenase subunit B (SDHB) is expressed in neurofibromatosis 1-associated gastrointestinal stromal tumors (Gists): implications for the SDHB expression based classification of Gists. J Cancer. 2:90-3, 2011 Agaimy A et al: Sporadic segmental Interstitial cell of cajal hyperplasia (microscopic GIST) with unusual diffuse longitudinal growth replacing the muscularis propria: differential diagnosis to hereditary GIST syndromes. Int J Clin Exp Pathol. 3(5):549-56, 2010 Zhang L, et al: Gastric stromal tumors in Carney triad are different clinically, pathologically and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 34:53-64, 2010 Carney JA et al: Stromal, fibrous, and fatty gastrointestinal tumors in a patient with a PDGFRA gene mutation. Am J Surg Pathol. 32(9):1412-20, 2008 Kleinbaum EP et al: Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor. Int J Cancer. 122(3):711-8, 2008 Abraham SC et al: "Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. Am J Surg Pathol. 31(11):1629-35, 2007 Pasini B et al: Multiple gastrointestinal stromal and other tumors caused by platelet-derived growth factor receptor alpha gene mutations: a case associated with a germline V561D defect. J Clin Endocrinol Metab. 92(9):3728-32, 2007 Miettinen M et al: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Sem Diagn Pathol. 23(2):70–83, 2006 Li FP et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol. 23(12):2735-43, 2005 Chompret A et al: PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 126(1): 318-21, 2004 NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma

Gastrointestinal Stromal Tumor

Tumor Syndrome (Inheritance)

Genetic Alterations

Features of GISTs

Other Manifestations

Germline KIT mutations (autosomal Mutations have been reported in dominant) exons 11(most common), 8, 9, 13, 17

Spindle cell morphology; arise anywhere in GI tract without site predilection; background hyperplasia of interstitial cells of Cajal

Lentigines, melanomas, achalasia

Germline PDGFRA mutations  (autosomal dominant)

Exons 12, 14, 18

Epithelioid morphology; preferentially arise in stomach; lymph node metastasis

Gastrointestinal lipomas and fibrous tumors

Neurofibromatosis type 1 (autosomal dominant)

Reported mutations are widely distributed within NF1 

Spindle cell morphology; preferentially arise in small bowel; background hyperplasia of interstitial cells of Cajal

Ampullary somatostatin-producing neuroendocrine tumors, cutaneous neurofibromas, malignant peripheral nerve sheath tumors, pilocytic astrocytomas, optic gliomas, pheochromocytomas

Carney-Stratakis (autosomal dominant)

SDHA, SDHB, SDHC, SDHD

Epithelioid morphology; preferentially arise in stomach; lymph node metastasis

SDH-deficient pheochromocytomas, SDHdeficient paragangliomas, SDHdeficient renal cell carcinomas, SDH-deficient pituitary adenomas

Carney triad (sporadic)

Sporadic, associated with SDHC epimutation (promoter hypermethylation)

Epithelioid morphology; preferentially arise in stomach; lymph node metastasis

Paragangliomas, pulmonary chondromas

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Tumor Syndromes Associated With GIST

GIST = gastrointestinal stromal tumor; SDH = succinate dehydrogenase.

Malignant Potential Based on Location, Size, and Mitotic Activity  Size

Mitoses/50 HPF

Metastases

Risk

≤ 2 cm

≤5

None

None to negligible

≤ 2 cm

>5

None

Low

> 2 and ≤ 5 cm

≤5

2%

Low

> 2 and ≤ 5 cm

>5

16%

Intermediate

> 5 and ≤ 10 cm

≤5

4%

Low

> 5 and ≤ 10 cm

>5

55%

High

> 10 cm

≤5

12%

Intermediate

> 10 cm

>5

88%

High

≤ 2 cm

≤5

None

None to negligible

≤ 2 cm

>5

50%

High

> 2 and ≤ 5 cm

≤5

4%

Low

> 2 and ≤ 5 cm

>5

73%

High

> 5 and ≤ 10 cm

≤5

24%

Intermediate

> 5 and ≤ 10 cm

>5

85%

High

> 10 cm

≤5

52%

High

> 10 cm

>5

90%

High

Gastric GIST

Small Bowel GIST

GIST = gastrointestinal stromal tumor. Miettinen M et al: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Sem Diagn Pathol. 23 (2): 70-83, 2006 and NCCN Clinical Practical Guidelines in Oncology: Soft Tissue Sarcoma.

247

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastrointestinal Stromal Tumor

Paranuclear Vacuoles

Skeinoid Fibers

Tumor Giant Cells

Palisaded Pattern

Immunohistochemistry: CD117

Immunohistochemistry: CD34

(Left) H&E shows a gastric GIST. In addition to prominent paranuclear vacuoles ﬈, note the brightly eosinophilic fibrillary cytoplasm ſt. (Right) Prominent "skeinoid" fibers ﬊ are noted in a small intestinal GIST.

(Left) Peculiar giant tumor cells are occasionally present in GISTs. (Right) Tumor cells are occasionally arranged in a palisaded pattern.

(Left) CD117 shows strong, diffuse labeling in a gastric spindle cell GIST. (Right) CD34 shows cytoplasmic staining in a gastric spindle cell GIST.

248

Gastrointestinal Stromal Tumor

SDH-Deficient GIST (Left) DOG1 shows membranous and cytoplasmic staining in a spindle cell GIST. (Right) Low-power view of an submucosal SDH-deficient GIST shows a multinodular growth pattern.

Epithelioid Gastrointestinal Stromal Tumor

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Immunohistochemistry: DOG1

Epithelioid Gastrointestinal Stromal Tumor: DOG1 (Left) H&E shows an epithelioid gastric GIST. This tumor is composed of round to polygonal tumor cells with cytoplasmic vacuoles. (Right) In this epithelioid GIST, DOG1 shows crisp membranous staining in all tumoral cells.

Epithelioid Gastrointestinal Stromal Tumor: SDHB

Epithelioid Gastrointestinal Stromal Tumor: SDHB (Left) In previous epithelioid GIST, SDHB expression is completely lost by IHC. Preserved staining in the vascular endothelial cells provides internal positive control. Inactivating mutation(s) of any SDH subunit leads to SDHB loss, which therefore serves as a useful marker for SDHdeficient GISTs but is not specific to SDHB gene mutation(s). (Right) In another epithelioid GIST, SDHB expression is preserved in a granular cytoplasmic (mitochondrial) pattern.

249

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastrointestinal Stromal Tumor

Seedling Gastrointestinal Stromal Tumor

Seedling Gastrointestinal Stromal Tumor: CD34

Interstitial Cell of Cajal Hyperplasia

Interstitial Cell of Cajal Hyperplasia

Diagnostic Pitfall: MART-1

Cytology

(Left) H&E shows several tiny ("seedling") GISTs ﬉ around the gastroesophageal junction. Small, clinically silent GIST tumorlets most often occur in proximal stomach and can be seen in up to 10% of esophagogastric carcinoma resections. Most are sporadic and harbor somatic KIT mutations. (Right) CD34 shows strong staining in the small GISTs in the same patient.

(Left) In a patient presenting with a large gastric GIST, multiple microscopic foci of spindle cell proliferation ﬈ were noted scattered within the gastric muscularis propria. (Right) Another focus ﬈ in the same patient is shown. The spindle cells are haphazardly arranged with eosinophilic cytoplasm and elongated nuclei. These lesions are morphologically and immunophenotypically consistent with hyperplasia of the interstitial cells of Cajal.

(Left) MART-1 shows aberrant staining in an epithelioid gastric GIST, a common finding that should not be misinterpreted as melanoma. Of note, melanomas can express CD117, another pitfall in interpreting immunostains. (Right) Fine-needle aspiration biopsy of a malignant gastric GIST shows scattered tumor cells and a fragment of nonneoplastic gastric epithelium ſt.

250

Gastrointestinal Stromal Tumor

Differential Diagnosis: Schwannoma (Left) Gastrointestinal schwannomas are typically muscularis propria-based tumors with a prominent lymphoid cuff ſt, composed of bland spindled cells in collagenous stroma. Palisading is less prominent compared to soft tissue schwannomas. (Right) SOX10 shows nuclear positivity in schwannomas.

Differential Diagnosis: Perineurioma

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Differential Diagnosis: Schwannoma

Perineurioma: Claudin-1 (Left) Perineurioma is typically based in the lamina propria and composed of bland spindle cells in a fibrillary stroma. (Right) By immunohistochemistry, the perineurioma cells are typically positive for Claudin-1.

Perineurioma: GLUT1

Differential: Inflammatory Fibroid Polyp (Left) GLUT1 also highlights the delicate cytoplasmic processes. The immunoprofile in addition morphology allows distinction from GISTs. (Right) Inflammatory fibroid polyps are submucosal lesions composed of spindle cells arranged in edematous stroma. The spindle cells often form a concentric pattern around arterioles. Inflammatory infiltrates are present with abundant eosinophils.

251

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hamartomatous Polyposis Syndromes KEY FACTS

TERMINOLOGY

MACROSCOPIC

• Polypoid lesions with benign epithelial &/or stromal components in abnormal architecture

• May be sessile or pedunculated

ETIOLOGY/PATHOGENESIS

• Juvenile polyp: Expanded and inflamed lamina propria; cystically dilated glands with crypt abscesses • Peutz-Jeghers polyp: Arborizing smooth muscle with distinct epithelial lobules • Cowden polyp: No distinguishing features, high index of suspicion, may resemble sporadic inflammatory or prolapse polyps

• Germline mutations in ○ Juvenile polyposis (JP) – SMAD4 or BMPR1A ○ Peutz-Jeghers polyposis (PJP) – STK11 ○ PTEN-hamartoma tumor syndrome/Cowden syndrome (CS) – PTEN

CLINICAL ISSUES • Hematochezia, anemia, diarrhea, prolapse, abdominal pain, obstruction, or intussusception

MICROSCOPIC

TOP DIFFERENTIAL DIAGNOSES • Inflammatory polyps may be indistinguishable from small JP or CS-associated polyps • Prominent smooth muscle proliferation of prolapse can mimic Peutz-Jeghers polyp • Reactive atypia in hamartomatous polyps may mimic dysplasia arising in JP

Peutz-Jeghers Polyp

PTEN-Hamartoma/Cowden Syndrome Polyp

Juvenile Polyp

Juvenile Polyp

(Left) Low-power view of a Peutz-Jeghers polyp (PJP) shows arborizing smooth muscle bundles ﬈. (Right) H&E shows a small nondistinctive-appearing hamartomatous polyp from a patient with Cowden syndrome. These polyps often look like healed pseudopolyps or mucosal prolapse-type polyps.

(Left) This small hamartomatous polyp has an ulcerated surface ﬉ with benign dilated glands ﬊ typical of a juvenile polyp. Identical findings could be seen in an inflammatory pseudopolyp. (Right) H&E shows a large juvenile polyp with cystically dilated glands ﬈ and an expanded lamina propria ſt.

252

Hamartomatous Polyposis Syndromes

MACROSCOPIC

Definitions

General Features

• Polypoid lesions with benign epithelial &/or stromal components in abnormal architecture • Variable increase in associated risk of intestinal and extraintestinal carcinoma

• Sessile or pedunculated; variable size • May show smooth or multilobulated surface • Large polyps, particularly PJP, may undergo intussusception

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

Syndromes

Histologic Features

• Juvenile polyposis (JP) • Peutz-Jeghers polyposis (PJP) • PTEN-hamartoma tumor syndrome/Cowden syndrome (CS)

• Juvenile polyps (JP) ○ Polyps may be restricted to colon or involve entire gastrointestinal tract – Diagnosis requires > 5 JP in colon or presence of extracolonic JP or positive family history in patients with any number of JP – Disease confined to colon in juvenile polyposis coli – Colonic and extracolonic involvement in generalized juvenile polyposis coli – Juvenile polyposis of infancy and childhood □ Contiguous BMPR1A and PTEN deletions □ Severe symptoms (hemorrhage, malnutrition, diarrhea) □ Other congenital abnormalities □ High mortality with death at young age ○ Eroded or ulcerated surface with expanded and inflamed lamina propria – Large pedunculated polyps may have secondary prolapse change that may mimic Peutz-Jeghers polyps (PJP) ○ Cystically dilated glands with crypt abscesses are typical, but often not present in small polyps ○ May rarely show dysplasia or carcinoma in polyp ○ SMAD4 mutation (in ~ 30% of patients) associated with – Severe gastric polyposis – Higher gastric cancer risk – Higher association with hereditary hemorrhagic telangiectasia ○ BMPR1A mutation (in 20% of patients) associated with – Concurrent cardiac defects • PJP ○ Polyps most common in small intestine but may involve colon or stomach – Syndrome can be diagnosed when 2 PJP are present ○ Polyps show arborizing bands of smooth muscle that enclose sharply demarcated lobules of epithelium – Epithelium may prolapse into submucosa or even deeper, mimicking invasive carcinoma ○ Small bowel polyps, particularly those large in size, are most likely to show characteristic histology ○ Dysplasia is not usually found in PJP – Carcinoma thought to arise via different mechanism (expanded stem cell compartment in nonpolypoid mucosa) ○ STK11 (formerly known as LKB1) mutations present in over 90% of patients • CS polyps ○ No specific features – May resemble sporadic inflammatory or mucosal prolapse polyps or syndromic juvenile polyps

Germline Mutations • SMAD4 or BMPR1A • STK11 • PTEN

CLINICAL ISSUES Epidemiology • JP incidence: 1 per 100,000-160,000 person-years • PJP incidence: 1 per 50,000-200,000 births • CS incidence: 1 in 200,000-250,000 in Europeans

Presentation • Patients typically present with hematochezia, anemia, diarrhea, prolapse, abdominal pain, obstruction, or intussusception

Prognosis • JP ○ Associated with 30-40x increase in relative risk of colorectal cancer ○ Cumulative colon cancer risk 40-68% by 60 years of age; mean age at cancer diagnosis around 44 years ○ Gastric, duodenal, and pancreatic cancers can also occur in JP syndrome – Magnitude of risk not clearly defined • PJP ○ Increased risk of variety of cancers ○ Lifetime risk ~ 80% by 70 years of age ○ Breast and pancreatic cancer most common extraintestinal malignancies ○ Characteristic gonadal tumors include – Sex cord tumor with annular tubules of ovary – Large-cell calcifying Sertoli cell tumor of testis ○ Also associated with adenoma malignum of cervix • CS ○ Mucocutaneous lesions characteristic – Facial trichilemmomas – Acral keratosis – Papillomatous papules ○ Macrocephaly may be present in subset ○ Increased risk of cancer involving multiple sites, including colorectum – Also increased risk of breast, thyroid, endometrial, and renal carcinomas

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

253

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hamartomatous Polyposis Syndromes ○ Mucosal or submucosal lipomas, especially when multiple should, raise suspicion of CS ○ Ganglioneuromas, usually multiple, may be present ○ Esophagus often shows glycogen acanthosis – PAS and PAS-D stains may aid in diagnosis – Reactive change in reflux esophagitis may mimic glycogen acanthosis ○ Benign lymphoid polyps of colorectum also described in CS ○ Gastric and small intestinal polyps may resemble prolapse-type polyps ○ PTEN-hamartoma tumor syndrome is heterogeneous group that also includes – Bannayan-Riley-Ruvalcaba syndrome – Proteus syndrome

DIFFERENTIAL DIAGNOSIS Inflammatory Pseudopolyps • May be indistinguishable from small JP ○ Both may have eroded surface mucosa with inflamed lamina propria • Inflammatory polyps may also resemble CS-associated polyps ○ Presence of glycogen acanthosis and characteristic extraintestinal lesions important to make diagnosis

Polypoid Prolapsing Mucosal Folds (Prolapse-Type Polyps)

SELECTED REFERENCES 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13.

14.

• These benign mucosal polyps are often seen at mouth of diverticulum • Prominent smooth muscle proliferation of prolapse can mimic PJP ○ Distinct lobular configuration of PJP missing in prolapse polyps

15.

Hyperplastic Polyps (Gastric)

18.

• Gastric JP, Cowden, and PJP polyps cannot reliably be differentiated from sporadic hyperplastic polyps, particularly when small in size

19.

Adenoma/Dysplasia

21.

• Reactive atypia in hamartomatous polyps may mimic adenoma/dysplasia, especially in JP ○ JP may have true dysplasia – Abrupt change from surrounding epithelium is helpful in making diagnosis

22.

Invasive Adenocarcinoma • Epithelial misplacement in PJP can mimic invasive adenocarcinoma ○ Misplacement in PJP shows bland monomorphic glands that lack surrounding desmoplastic stroma

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Presence of multiple, inflammatory or prolapse-type polyps should alert pathologist to possibility of inherited polyposis syndrome • Syndromic hamartomatous polyps do not show classic features until they attain large size 254

○ Small polyps impossible to distinguish from sporadic ones

16. 17.

20.

23. 24.

Borowsky J et al: Spectrum of gastrointestinal tract pathology in a multicenter cohort of 43 Cowden syndrome patients. Mod Pathol. ePub, 2019 Busoni VB et al: Successful treatment of juvenile polyposis of infancy with sirolimus. Pediatrics. 144(2), 2019 de Leon MP et al: Massive juvenile polyposis of the stomach in a family with SMAD4 gene mutation. Fam Cancer. 18(2):165-72, 2019 Iwamuro M et al: Long-term outcome in patients with a solitary peutzJeghers polyp. Gastroenterol Res Pract. 2019:8159072, 2019 Short E et al: The role of inherited genetic variants in colorectal polyposis syndromes. Adv Genet. 103:183-217, 2019 Daniell J et al: An exploration of genotype-phenotype link between PeutzJeghers syndrome and STK11: a review. Fam Cancer. 17(3):421-7, 2018 Guilmette J et al: Hereditary and familial thyroid tumours. Histopathology. 72(1):70-81, 2018 Ma H et al: Pathology and genetics of hereditary colorectal cancer. Pathology. 50(1):49-59, 2018 Rosty C: The Role of the surgical pathologist in the diagnosis of gastrointestinal polyposis syndromes. Adv Anat Pathol. 25(1):1-13, 2018 Spoto CPE et al: Hereditary gastrointestinal carcinomas and their precursors: an algorithm for genetic testing. Semin Diagn Pathol. 35(3):170-83, 2018 Tavusbay C et al: The patients with Peutz-Jeghers syndrome have a high risk of developing cancer. Turk J Surg. 34(2):162-4, 2018 Hızarcıoğlu-Gülşen H et al: Polyposis deserves a perfect physical examination for final diagnosis: Bannayan-Riley-Ruvalcaba syndrome. Turk J Pediatr. 59(1):80-3, 2017 Schultz KAP et al: PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(12):e76-82, 2017 Stojcev Z et al: Hamartomatous polyposis syndromes. Hered Cancer Clin Pract. 11(1):4, 2013 Latchford AR et al: Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum. 55(10):1038-43, 2012 Patel SG et al: Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep. 14(5):428-38, 2012 Trufant JW et al: Colonic ganglioneuromatous polyposis and metastatic adenocarcinoma in the setting of Cowden syndrome: a case report and literature review. Hum Pathol. 43(4):601-4, 2012 Arber N et al: Small bowel polyposis syndromes. Curr Gastroenterol Rep. 13(5):435-41, 2011 Brosens LA et al: Juvenile polyposis syndrome. World J Gastroenterol. 28;17(44):4839-44, 2011 Latchford AR et al: Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: clinical aspects. Fam Cancer. 10(3):455-61, 2011 van Lier MG et al: High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome. Gut. 60(2):141-7, 2011 Lam-Himlin D et al: Morphologic characterization of syndromic gastric polyps. Am J Surg Pathol. 34(11):1656-62, 2010 Chen HM et al: Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 24(8):865-74, 2009 Zbuk KM et al: Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol. 4(9):492-502, 2007

Hamartomatous Polyposis Syndromes

Peutz-Jeghers Polyp (Left) Pedunculated PJPs may present with small intestinal obstruction when they undergo intussusception. (Right) Low-power view of a PJP shows arborizing bands of smooth muscle ﬈.

Peutz-Jeghers Polyp Lobular Architecture

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gross Appearance of Peutz-Jeghers Polyps

Desmin in Peutz-Jeghers Polyp (Left) Colonic PJPs are also characterized by branching smooth muscle fibers ﬇ that often reach the surface. Note the distinct lobular configuration of the epithelial component. (Right) The same polyp stained with a desmin immunostain highlights the smooth muscle arborization ﬊, characteristic of both sporadic and syndromic PJPs.

Microscopic Appearance of Peutz-Jeghers Polyps

Endoscopic Appearance of Peutz-Jeghers Polyps (Left) Histologically, PJPs are characterized by tree-like arborizing strands of smooth muscle ﬊ that separate the epithelial component into lobules. (Right) A large, pedunculated ﬊ PJP with a smooth surface ﬈ involving the sigmoid colon is shown.

255

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hamartomatous Polyposis Syndromes

Gastric Peutz-Jeghers Polyps

Small Antral Polyps in PJP

Dysplasia in Peutz-Jeghers Polyps

Mucosal Prolapse Polyp Mimicking PeutzJeghers Polyps

Juvenile Polyp Mimicking Peutz-Jeghers Polyps

Sporadic Juvenile Polyp

(Left) Large, sessile or pedunculated gastric polyps may be seen in patients with Peutz-Jeghers polyposis. The polyp was present in the gastric body. (Right) Small gastric polyps in PJP cannot be recognized as syndromic without knowledge of clinical history and endoscopic findings. These small lesions are indistinguishable from sporadic hyperplastic or mucosal prolapse polyps and from small syndromic polyps in PJS or Cowden syndrome.

(Left) PJP with low-grade dysplasia shows dysplastic change similar to colonic adenomas with elongated, hyperchromatic, and pseudostratified nuclei st. Note the abrupt transition from the nondysplastic epithelium ﬇. (Right) Rectal prolapse with strands of smooth muscle involving the lamina propria ﬊ impart a resemblance to PJPs. The lack of compact, lobular configuration of the glandular component and smooth muscle wrapping around individual crypts ﬊ favors mucosal prolapse.

(Left) Proliferating smooth muscle strands ﬊ in large, multilobulated, and pedunculated juvenile polyps may also mimic PJP. The architectural disarray and cystic dilatation seen here ﬈ is typical of a juvenile polyp. (Right) Sporadic juvenile polyps are usually solitary and may be sessile or pedunculated and show a smooth surface. Syndromic juvenile polyps look similar to sporadic ones on gross and microscopic examination.

256

Hamartomatous Polyposis Syndromes

PJS Ovarian Sex Cord Tumor (Left) Adenoma malignum of the cervix in PJS shows bland infiltrative glands ﬊ without a desmoplastic response. (Courtesy A. Srivastava, MD.) (Right) Ovarian sex cord tumors with annular tubules may be an extraintestinal manifestation of PJPS. Circumscribed nests of tumor cells with tubular configurations are filled with eosinophilic hyaline material ﬊.

Ovarian Sertoli Cell Tumor

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

PJS Cervical Adenoma Malignum

PJS Sex Cord Tumor (Left) Sertoli cell tumor of the testis shows nests and cords of tumor cells with abundant pink cytoplasm and a hyalinized stroma with foci of calcification ﬊. (Courtesy E. Oliva, MD.) (Right) Ovarian sex cord tumor with annular tubules in PJS shows circumscribed nests of tumor cells ﬊ containing hyaline material ﬈.

Juvenile Polyposis Syndrome

Juvenile Polyposis Syndrome (Left) In some patients, a large number of polyps may cluster together in a small segment of the colon. The large, multilobulated polyps ﬊ are sessile and resemble conventional adenomas and must be sampled extensively to rule out dysplasia or carcinoma. (Right) Multiple polyps in a patient with juvenile polyposis syndrome (JPS) are shown. The larger polyps ﬈ are pedunculated and multilobulated, while the smaller ones are sessile and smooth ﬊.

257

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hamartomatous Polyposis Syndromes

Juvenile Polyp

Epithelium-Rich Juvenile Polyp

Juvenile Polyp With Torsion-Related Changes

Juvenile Polyp

Juvenile Polyp Mimicking Mucosal Prolapse Polyp

Juvenile Polyp Mimicking Peutz-Jeghers Polyp

(Left) Juvenile polyps are characterized by marked stromal expansion ﬊ and cystically dilated crypts ﬉. The stroma is loose, edematous, and inflamed, while the cysts are filled with inspissated mucin ſt. (Right) Juvenile polyp from a patient with germline SMAD4 mutation shows architectural disarray ﬊ and cystic dilatation of crypts ﬉ but minimal expansion of lamina propria. Epithelium-rich juvenile polyps are more often seen in BMPR1A germlinemutant JPS patients.

(Left) Juvenile polyps may undergo torsion injury, which results in stromal hemorrhage ﬊ and the presence of hemosiderin-laden macrophages in the lamina propria. The cystically dilated crypts ﬈ are helpful in making the correct diagnosis. (Right) H&E shows a juvenile polyp with marked cystic change and crypt abscess formation ﬊. The stromal inflammation in such polyps may be in the form of neutrophils, lymphoid follicles ﬈, or both.

(Left) Pedunculated juvenile polyp may mimic mucosal prolapse polyp because of fibromuscular proliferation ﬊ and ectatic blood vessels ﬉. (Right) Larger pedunculated juvenile polyps that undergo prolapse often show a prominent smooth muscle proliferation ﬊ that may be mistaken for a PJP.

258

Hamartomatous Polyposis Syndromes Juvenile Polyp Mimicking Mucosal Prolapse Polyp (Left) The stomach may be involved in juvenile polyposis, typically in patients with germline SMAD4 mutations. Classic features are only seen in large polyps. (Right) Architectural disarray ﬉ and cystic dilatation ﬊ are the only clues to the diagnosis of juvenile polyp in this example that otherwise shows features consistent with a mucosal prolapse polyp. The distinction between these 2 diagnoses may not be possible on morphology alone and requires knowledge of clinical and endoscopic findings.

Early Juvenile Polyp

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Gastric Juvenile Polyposis

Early Juvenile Polyp (Left) Random sections from grossly normal mucosa in a colectomy specimen may show "incipient" juvenile polyps. Inflamed lamina propria, as well as long tortuous crypts, some of which show cystic change and rupture ﬊, are typically found in syndromic cases. (Right) Another example of an early, sessile, syndromic juvenile polyp that is rich in epithelium and lacks typical stromal expansion shows a band of increased inflammation in the upper 1/2 of the mucosa ﬊.

Reactive Changes in Juvenile Polyp

Reactive Changes in Juvenile Polyp (Left) Regenerative changes in juvenile polyps with marked inflammation may mimic serrated or adenomatous polyps. Prominent hyperplastic regenerative change ﬉ is present in this juvenile polyp with an inflamed granulation tissue cap ﬊ on the surface. (Right) Adenoma-like regenerative changes ﬊ are seen in this example of a sporadic juvenile polyp in a 4year-old child. Juvenile polyps in syndromic patients may harbor truly dysplastic foci or cancer.

259

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Hamartomatous Polyposis Syndromes

Low-Grade Dysplasia in Juvenile Polyp

Low-Grade Dysplasia in Juvenile Polyp

Gastric Juvenile Polyp

Gastric Juvenile Polyp

Gastric Juvenile Polyp

Gastric Juvenile Polyp

(Left) Syndromic juvenile polyps may show low- or highgrade dysplasia or cancer. The dysplastic lesions may appear as separate polyps or arise within polyps that show a background architecture, consistent with a juvenile polyp. Low-grade dysplastic change is seen in this example involving the crypt bases ﬊, as well as surface epithelium ﬊. (Right) Low-grade dysplasia in juvenile polyps is characterized by pencillate, hyperchromatic nuclei with stratification, similar to nuclear changes seen in conventional adenomas.

(Left) Gastric juvenile polyps typically show marked expansion of the lamina propria ﬊ with variable inflammation and cystic change. The fibromuscular proliferation in the lamina propria st resembles findings seen in mucosal prolapse polyps. (Right) The foveolar and glandular compartments in gastric juvenile polyps may show marked cystic change that makes the distinction from hyperplastic polyps and fundic gland polyps ﬊ difficult without knowledge of clinical history and endoscopic findings.

(Left) Small juvenile polyps are morphologically indistinguishable from sporadic hyperplastic polyps. (Right) The earliest change in gastric juvenile polyps resembles polypoid foveolar hyperplasia. Knowledge of clinical history is essential for making the right diagnosis.

260

Hamartomatous Polyposis Syndromes

PJS Polyp With Low-Grade Dysplasia (Left) Low- or high-grade dysplasia may be seen in gastric juvenile polyps, similar to what is seen in the colon. The round nuclei with loss of polarity, open chromatin, and prominent nucleoli ﬊ seen in this example are consistent with high-grade dysplasia. (Right) PJP with low-grade dysplasia shows dysplastic change similar to colonic adenomas with elongated, hyperchromatic, and pseudostratified nuclei ﬉. Note the abrupt transition from the nondysplastic epithelium ﬊.

Prominent Muscle Bundles

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Dysplasia in Gastric Juvenile Polyp

PJS Polyps (Left) High-power view shows benign glands ﬊ trapped within muscle bundles ﬈. Care must be taken not to overinterpret this as cancer. (Right) Histologically, PJPs are characterized by tree-like arborizing strands of smooth muscle that separate the epithelial component into lobules.

Microscopic Appearance of Peutz-Jeghers Polyps

Peutz-Jeghers Polyp (Left) Colonic PJPs are also characterized by branching smooth muscle fibers ﬇ that often reach the surface. Note the distinct lobular configuration of the epithelial component. (Right) This hamartomatous polyp has abundant smooth muscle bundles ﬈ surrounding benign mucosal islands ﬇. These features are characteristic of PJPs.

261

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Small Bowel Adenocarcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS • Hereditary gastrointestinal polyposis syndromes ○ Familial adenomatous polyposis (FAP) ○ MUTYH-associated polyposis (MAP) ○ Peutz-Jeghers syndrome (PJS) ○ Juvenile polyposis syndrome (JPS) ○ Lynch syndrome • Chronic inflammation ○ Crohn disease ○ Celiac disease

CLINICAL ISSUES • Overall risk for small bowel adenocarcinoma by syndrome ○ PJS: 13% ○ FAP: 3-5% ○ MAP: 4% ○ Lynch syndrome: 4% ○ JPS: 1%

○ Risk may be heterogeneous among patients with same syndrome depending on pathogenic genetic variant • Endoscopic surveillance is recommended for PJS, FAP, and MAP ○ PJS – Full small bowel evaluation (Upper endoscopy + CT or MR enterography or video capsule endoscopy) ○ FAP and MAP – Duodenal surveillance with upper endoscopy • No strong evidence to support surveillance benefit for JPS and Lynch syndrome

TOP DIFFERENTIAL DIAGNOSES • Metastatic adenocarcinoma • Adenoma with high-grade dysplasia • Endometriosis

Peutz-Jeghers Duodenal Polyp

Peutz-Jeghers Colonic Polyp

Peutz-Jeghers Polyp: Desmin

Peutz-Jeghers Polyp: Desmin

(Left) Endoscopic image shows a large duodenal polyp in a 20year-old man with PeutzJeghers syndrome. (Right) A 35-year-old man with PeutzJeghers syndrome was found to have multiple colonic polyps with a villous surface and a central stromal core containing branching smooth muscle ﬇.

(Left) By immunohistochemistry, desmin highlights the arborizing smooth muscle within a Peutz-Jeghers-type colonic polyp. Lobulated configuration is typical of Peutz-Jeghers polyps. (Right) At higher magnification, the smooth muscle fibers arborize between the glands, given the lobulated architecture.

262

Small Bowel Adenocarcinoma

Definitions • Invasive carcinoma with glandular differentiation in small intestine

ETIOLOGY/PATHOGENESIS Risk Factors • Hereditary gastrointestinal polyposis syndromes ○ Familial adenomatous polyposis (FAP) – > 700 mutations in APC on chromosome 5q have been implicated – APC encodes component protein of degradation complex which breaks down cytosolic β-catenin – APC dysfunction causes intracellular accumulation and nuclear translocation of β-catenin, which activates oncogenes, such as c-Myc and Wnt/β-catenin pathway ○ MUTYH-associated polyposis – > 80 mutations have been implicated – ~ 1% of general population are heterozygous carriers of MUTYH mutations – MUTYH encodes MYH, DNA glycosylase which excises adenine paired with 8-oxo-7, 8-dihydro-2deoxyguanosine (8-oxoG), product of oxidative DNA damage (base-excision repair) – Dysfunctional MYH leads to increased G:C to T:A conversion – Consequence is particularly profound for DNA sequences rich in GAA codons, which are prone to be converted to TAA, stop codon – APC is rich in GAA sites, which explains attenuated FAP-like phenotype in MUTYH-associated polyposis ○ Peutz-Jeghers syndrome (PJS) – Associated with STK11 mutations – STK11 is tumor suppressor gene which encodes intracellular protein kinase, LKB1, which regulates cell metabolism and growth by activating AMP-activated protein kinase (AMPK) and transforming growth factor-β (TGF-β) signaling pathways ○ Juvenile polyposis syndrome – Associated with SMAD4 or BMPR1A mutations – SMAD4 and BMPR1A are tumor suppressor genes involved in BMP and TGF-β signaling pathways • Lynch syndrome ○ Associated with mutations in genes involved in DNA mismatch repair pathway (MLH1, PMS2, MSH2, MSH6) ○ Alternative mechanism includes deletions of 3 end of EPCAM including polyadenylation signal, which causes transcriptional read-through into downstream MSH2 (end product being EPCAM-MSH2 fusion transcripts) and subsequent hypermethylation of MSH2 promoter • Germline BRCA1 mutation ○ p.V1234Qfs*8 mutation was reported in patient with ileal mixed neuroendocrine-nonneuroendocrine neoplasm • Chronic inflammation ○ Crohn disease – Genome-wide association studies have identified several genetic susceptibility foci for Crohn disease, implicating genes involved in

□ Innate and adaptive immunity (NOD2, ADCY7, PTK2B, LY75, CD28, CCL20, NFKBIZ, AHR, PDCD1, PTPRC, IRF4, CD27, TNFRSF1A, LTBR, and NFATC1) □ Autophagy (PLA2G4A, ATG16L1, IRGM, ATG4B) □ Epithelial barrier function (LAMB1, HNF4A, OSMR) □ DNA repair (USP1) – Whether any of susceptibility foci may be associated with increased cancer risk remains unclear ○ Celiac disease – Human leukocyte antigen haplotypes DQ2 and DQ8 are associated with increased risk for celiac disease

CLINICAL ISSUES Clinical Presentation by Syndrome • FAP ○ Autosomal dominant ○ > 70% of FAP patients developed duodenal/periampullary adenomatosis – Lifetime risk for developing duodenal/periampullary adenocarcinoma is 3-5% by age 70 – Duodenal involvement is more severe with mutations in exons 10-15 compared to exons 4-9 ○ 50-88% of FAP patients developed jejunal &/or ileal adenomatosis – High incidence was discovered only after video capsule endoscopy (VCE) and balloon-assisted enteroscopy (BAE) became available – However, progression to jejunal/ileal adenocarcinoma is much less common compared to duodenal adenomas; benefit of jejunal/ileal screening is therefore unclear ○ Duodenal/periampullary adenocarcinoma and complications of desmoid tumors are major causes of deaths in FAP patients after prophylactic colectomy ○ Patients also at increased risk for malignancies arising in – Colorectum (adenocarcinoma; 93% by age 50) – Thyroid (papillary thyroid carcinoma; ~ 12%) – Liver (hepatoblastoma; 1.6%) – Pancreas (adenocarcinoma; 1%) – Cerebellum (medulloblastoma; < 1%) ○ Other manifestations include – Adenomatous polyposis of small and large bowels – Congenital hypertrophy of retinal pigment epithelium – Desmoid tumors – Osteoma in face or skull – Dental abnormalities – Nasopharyngeal angiofibroma – Cutaneous epidermoid cyst – Pilomatrixoma • MUTYH-associated polyposis ○ Autosomal recessive ○ Duodenal polyps occur in 17-34% of patients ○ Lifetime risk for duodenal adenocarcinoma is 4% ○ Patients also at increased risk for carcinoma arising in – Colorectum (43-100%) – Breast (25%) – Skin (17%) – Ovary (10%) – Endometrium (3%)

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

TERMINOLOGY

263

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Small Bowel Adenocarcinoma

264

– Urinary bladder (6%) ○ Other manifestations include – Adenomatous or serrated polyposis of large bowel – Congenital hypertrophy of retinal pigment epithelium – Dental abnormalities – Benign skin tumors (sebaceous adenomas, epidermoid cysts) • PJS ○ Autosomal dominant ○ > 90% of patients develop hamartomatous polyps in small bowel, most commonly in jejunum, followed by ileum and duodenum ○ Symptoms such as bowel obstruction, bleeding, and intussusception typically start in childhood ○ LIfetime risk for small bowel cancer is 13%; average age at diagnosis is 37-42 years ○ Hamartomatous polyposis also affects stomach, colon, renal pelvis, ureter, urinary bladder, gallbladder, nasal cavity, and bronchus ○ PJS patients also at increased risk for carcinoma arising in ○ Other manifestations include – Mucocutaneous melanocytic macules – Ovarian sex cord tumors with annular tubules (SCTATs) – Intratubular large-cell hyalinizing Sertoli cell tumors of testes ○ Also included – Breast (32-54%) – Colorectal (39%) – Pancreas (11- 36%) – Stomach (29%) – Lung (7-17%) – Uterine cervix (adenoma malignum; 10%) • Juvenile polyposis syndrome ○ Autosomal dominant ○ Juvenile polyps develop in colorectum (98%), stomach (14%), jejunum and ileum (7%), and duodenum (2%), starting in childhood ○ Bleeding and anemia are most common presentation ○ Small bowel adenocarcinoma is uncommon with approximately 1% risk in most studies ○ Malignancy risk is higher in colorectum (68% by age 60) and stomach (lifetime risk 21%) ○ Subset of patients with SMAD4 pathogenic variants may have – Mucocutaneous telangiectasia and visceral arteriovenous malformation [juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome] ○ Subset of patients with SMAD4 pathogenic variants may also show features of connective tissue disorder – Which may include thoracic aortic dilatation, aneurysm, dissection, mitral valve insufficiency, retinal detachment, and lax joints and skin • Lynch syndrome ○ Autosomal dominant ○ Lifetime risk for small bowel adenocarcinoma is ~ 4% – Median age at diagnosis is 39 years – Most common in duodenum (47%), followed by jejunum (29%) and ileum (12%)

– Risk is higher for MLH1 and MSH2 mutation carriers compared to MSH6 mutation carriers ○ Adenocarcinoma typically arises without or with few adenomas ○ Lynch patients also at increased cancer risk in – Colorectum (35% by age 70, mostly adenocarcinoma) – Endometrium (34%, mostly endometrioid adenocarcinoma) – Ovary (8%, mostly endometrioid or clear cell carcinoma) – Urothelium (2%, mostly in upper urinary tract) – Skin (1-9%, sebaceous neoplasms in Muir-Torre syndrome) – Stomach (1-13%) – Brain (1-4%, mostly glioblastoma in Turcot syndrome)

Surveillance Recommendations (American College of Gastroenterology Guidelines, 2015) • FAP ○ Baseline upper endoscopy at age 25-30 years, including complete visualization of ampulla of Vater ○ Malignancy risk of duodenal polyps can be estimated based on size, number, and histology using modified Spigelman scoring scheme (Table) – Stage 0: No polyp – Stage I: 1-4 points – Stage II: 5-6 points – Stage III: 7-8 points – Stage IV: 9-12 points ○ Follow-up surveillance using side-viewing endoscope based on Spigelman stage – Spigelman stage 0: Repeat endoscopy in 4 years – Spigelman stage I: 1-4 polyps, size 1-4 mm; repeat endoscopy in 2-3 years – Spigelman stage II: 5-19 polyps, size 5-9 mm; repeat endoscopy in 1-3 years – Spigelman stage III: ≥ 20 polyps, size ≥ 1 cm; repeat endoscopy in 0.5-1.0 years – Spigelman stage IV: Dense polyposis or dysplasia; surgical consultation • MUTYH-associated polyposis ○ Baseline upper endoscopy at age 30-35 years including complete visualization of ampulla of Vater ○ Follow-up surveillance using side-viewing endoscope based on Spigelman stage (same as in FAP) • PJS ○ Baseline video capsule endoscopy at age 8 – No polyps: Repeat at age 18 and every 3 years thereafter – Polyps noted: Repeat every 3 years • Juvenile polyposis ○ No strong evidence to support surveillance benefit given small risk • Lynch syndrome ○ No strong evidence to support surveillance benefit

Small Bowel Adenocarcinoma

Factor

1 Point

2 Points

3 Points

Number of polyps

1-4

5-20

> 20

Polyp size in millimeters

1-4

5-10

> 10

Histology

Tubular

Tubulovillous

Villous

Dysplasia

Mild

Moderate

Severe

Brosens LA et al: Prevention and management of duodenal polyps in familial adenomatous polyposis. Gut. 54(7):1034-43, 2005.

MICROSCOPIC

9.

Distinct Immunoprofile

10.

• Although most cases of primary adenocarcinoma of small intestine are histologically similar to colorectal adenocarcinoma, immunoprofile is distinct ○ 50% positive for cytokeratin 7 ○ 40% positive for cytokeratin 20 ○ Negative for AMACR/P504S ○ Immunostains aid in distinction between metastatic colorectal carcinoma and small bowel primary

11.

Adenocarcinoma Arising in Ampulla of Vater • Can be of intestinal type or pancreatobiliary type ○ Intestinal type has better prognosis

DIFFERENTIAL DIAGNOSIS

12. 13. 14. 15. 16. 17. 18.

19.

Metastatic Adenocarcinoma • Presence of preexisting adenoma or dysplasia suggests small bowel primary • Pancreatic adenocarcinoma can grow out from ampulla and mimic duodenal/ampullary primary

Adenoma With High-Grade Dysplasia • Difficult to differentiate prolapse from invasion around ampulla • Desmoplasia is key to diagnosis

20. 21.

22. 23. 24. 25.

Endometriosis • Presence of endometrial stroma help make diagnosis

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3. 4.

5. 6.

7.

8.

Hammoudi N et al: Duodenal tumor risk in Lynch syndrome. Dig Liver Dis. 51(2):299-303, 2019 Quaas A et al: Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma. BMC Gastroenterol. 19(1):21, 2019 Ishida H et al: Malignant tumors associated with juvenile polyposis syndrome in Japan. Surg Today. 48(3):253-63, 2018 Luo Y et al: Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat Genet. 49(2):186-92, 2017 Shenoy S: Genetic risks and familial associations of small bowel carcinoma. World J Gastrointest Oncol. 8(6):509-19, 2016 Walton SJ et al: Frequency and features of duodenal adenomas in patients with MUTYH-associated polyposis. Clin Gastroenterol Hepatol. 14(7):986-92, 2016 Liu JZ et al: Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 47(9):979-86, 2015 Syngal S et al: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 110(2):223-62; quiz 263, 2015

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Ligtenberg MJ et al: EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam Cancer. 12(2):169-74, 2013 Engel C et al: Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol. 30(35):4409-15, 2012 Koornstra JJ: Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome. Best Pract Res Clin Gastroenterol. 26(3):359-68, 2012 Mishra N et al: Identification of patients at risk for hereditary colorectal cancer. Clin Colon Rectal Surg. 25(2):67-82, 2012 Bonadona V et al: Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 305(22):2304-10, 2011 Vogt S et al: Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 137(6):1976-85.e1-10, 2009 Groen EJ et al: Extra-intestinal manifestations of familial adenomatous polyposis. Ann Surg Oncol. 15(9):2439-50, 2008 Watson P et al: The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 123(2):444-9, 2008 Cheadle JP et al: MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing. DNA Repair (Amst). 6(3):274-9, 2007 Rioux JD et al: Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 39(5):596-604, 2007 ten Kate GL et al: Is surveillance of the small bowel indicated for Lynch syndrome families? Gut. 56(9):1198-201, 2007 Brosens LA et al: Prevention and management of duodenal polyps in familial adenomatous polyposis. Gut. 54(7):1034-43, 2005 Chen ZM et al: Differential expression of alpha-methylacyl coenzyme A racemase in adenocarcinomas of the small and large intestines. Am J Surg Pathol. 29(7):890-6, 2005 Chow E et al: A review of juvenile polyposis syndrome. J Gastroenterol Hepatol. 20(11):1634-40, 2005 Schulmann K et al: HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology. 128(3):590-9, 2005 Amos CI et al: Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet. 41(5):327-33, 2004 Chen ZM et al: Alteration of cytokeratin 7 and cytokeratin 20 expression profile is uniquely associated with tumorigenesis of primary adenocarcinoma of the small intestine. Am J Surg Pathol. 28(10):1352-9, 2004 Kadmon M et al: Duodenal adenomatosis in familial adenomatous polyposis coli. A review of the literature and results from the Heidelberg Polyposis Register. Int J Colorectal Dis. 16(2):63-75, 2001 Ogura Y et al: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 411(6837):603-6, 2001 Enomoto M et al: The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis. Jpn J Clin Oncol. 30(2):82-8, 2000 Kohlmann W et al: Lynch Syndrome 1993 Larsen Haidle J et al: Juvenile Polyposis Syndrome 1993 McGarrity TJ et al: Peutz-Jeghers Syndrome in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018 Spigelman AD et al: Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet. 2(8666):783-5, 1989

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Modified Spigelman Scoring Scheme for Duodenal Polyposis in Familial Adenomatous Polyposis

265

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Small Bowel Adenocarcinoma

Familial Adenomatous Polyposis

Duodenal Adenoma in Familial Adenomatous Polyposis

Duodenal Adenoma in Familial Adenomatous Polyposis

Adenocarcinoma Arising in Adenoma

Familial Adenomatous Polyposis

Familial Adenomatous Polyposis

(Left) An 18-year-old woman with known familial adenomatous polyposis (FAP) was found to have multiple sessile duodenal polyps ſt. (Right) At low magnification, the duodenal polyp shows hyperchromatic adenomatous epithelium ﬈.

(Left) At high magnification, the adenomatous epithelium shows elongated dark and crowded nuclei ﬈, in contrast to the well-organized enterocytes in the adjacent villus ﬊. (Right) H&E shows an adenoma ﬈ on the right and an invasive adenocarcinoma ﬊ on the left. Note the presence of a more complex architecture and desmoplastic stroma on the left.

(Left) The same patient was also found to have multiple colonic adenomas, which also show hyperchromatic lesional epithelium extending to the surface ﬇. (Right) Also noted during the same examination were multiple fundic gland polyps in the stomach, which are characterized by dilated glands lined by chief cells and parietal cells ﬊.

266

Small Bowel Adenocarcinoma

Juvenile Polyposis Syndrome (Left) In a patient with known juvenile polyposis syndrome, a colonic polyp was found with markedly inflamed stroma and scattered, dilated glands. (Right) In another patient with juvenile polyposis syndrome, multiple colonic juvenile polyps were found with edematous stroma and dilated glands seen at low magnification.

Juvenile Polyposis Syndrome

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Juvenile Polyposis Syndrome

Duodenal Adenocarcinoma (Left) At higher magnification, the colonic juvenile polyp shows prominent inflammatory infiltrates within the stroma. Glands are dilated and lined by unremarkable colonic epithelium. (Right) Gross photograph of a duodenal adenocarcinoma resection shows a fungating mass with friable surface.

Adenocarcinoma

Adenocarcinoma in Crohn Disease (Left) H&E shows an invasive adenocarcinoma arising in adenoma with high-grade dysplasia. (Right) H&E shows invasive carcinoma ﬈ arising in Crohn disease. Note the hypertrophic nerves ﬊ and fistula tract ſt.

267

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Colon/Rectum Table Familial Syndromes Associated With Colorectal Carcinoma Syndrome

Precursor Lesion

Other Sites of Involvement

Gene(s) Involved

Useful Diagnostic Tests

Lynch (hereditary nonpolyposiscolorectal cancer)

Adenoma

Endometrium, ovary, renal pelvis and ureters, small intestine, biliary tract, skin, brain, adrenal cortex, prostate

MLH1, MSH2, MSH6, PMS2; autosomal dominant

Microsatellite instability, BRAF V600E mutation, immunostains for mismatch repair proteins, sequencing of mismatch repair genes

FAP

Adenomas (> 100 unless attenuated FAP)

Stomach, ampulla, small bowel, liver, mesentery, skin, jaw, brain, retina

APC; autosomal dominant

Protein truncation assay; sequencing APC

MUTYH-associated polyposis

Adenomas (1-100, similar to Stomach, duodenum, skin, attenuated FAP); may also perhaps ovary, thyroid, have serrated polyps breast, and bladder

MUTYH; autosomal recessive

Screen for 2 most common mutations in MUTYH &/or sequence MYH; immunostain for gene product

Hereditary mixed polyposis

Atypical juvenile polyps, adenomas, serrated polyps, mixed polyps

None

GREM1; autosomal dominant

Sequence GREM1

DNA polymerase ε and δ polyposis

Adenoma

Endometrium

DNA polymerase POLE and POLD1

Sequence DNA polymerases; look for DNA transversions

Giant hyperplastic polyposis Serrated polyps, adenomas, None mixed polyps

Unknown

Still trying to define genetic locus

Peutz-Jeghers

Hamartomatous polyps

STK11 (LKB1); autosomal dominant or sporadic

Sequence STK11 (only 60% successful)

Juvenile polyposis

Juvenile polyps, number Stomach, small intestine, needed for diagnosis ranges pancreas from 3-10; fewer if family history

SMAD4 or BMPR1A; autosomal dominant; may arise de novo

Sequence SMAD4 and BMP R1A

PTEN-hamartoma (Cowden/Bannayan-RileyRuvalcaba)

Hamartomatous/juvenile polyps

Breast, thyroid

PTEN; autosomal dominant

Sequence PTEN

Li-Fraumeni

Adenoma

Soft tissue, bone, brain, breast, bone marrow, adrenal cortex, stomach, lung, germ cell, skin

TP53

Sequence TP53

DNA polymerase ε and δ Adenomas and serrated polyposis (POLE and POLD1) polyps

Endometrial, ovarian, brain, pancreas, small intestine, and cutaneous melanoma

POLE and POLD1

Sequence POLE and POLD1

MSH3 polyposis

Adenoma

Stomach, brain

MSH3, autosomal recessive

Sequence MSH3

NTHL1

Adenoma

Endometrium, breast, bladder, small intestine, skin, meninges

NTHL1, autosomal recessive Sequence NTHL1

Pancreas, stomach, breast, ovary, small intestine

FAP = familial adenomatous polyposis.

Familial Neoplasia of Colon and Rectum

268

Colonic Lesion

Possible Syndromes

Genes Involved

Adenoma

FAP MUTYH-associated polyposis Lynch Juvenile polyposis  Hereditary mixed polyposis   Cowden/PTEN-hamartoma Serrated polyposis (previously known as giant hyperplastic polyposis)

APC MUTYH MLH1, PMS2, MSH2, MSH6  SMAD4, BMPR1A GREM1 PTEN Unknown

Colon/Rectum Table

Colonic Lesion

Possible Syndromes

Genes Involved

Li-Fraumeni DNA polymerase ε and δ polyposis MSH3 polyposis NTHL1 polyposis

p53 POLE and POLD1 MSH3 NTHL1

Serrated polyposis (previously known as giant hyperplastic polyposis)  Hereditary mixed polyposis MUTYH-associated polyposis DNA polymerase ε and δ polyposis

Unknown

Adenomas, serrated polyps, and hamartomatous polyps

Hereditary mixed polyposis

SMAD4, BMPR1A, ENG PTEN

Hamartomatous polyps

Peutz-Jeghers Cowden/PTEN-hamartoma

STK11 PTEN

Juvenile polyps

Juvenile polyposis

SMAD4, BMPR1A

Adenocarcinoma

FAP MUTYH-associated polyposis Lynch Juvenile polyposis Hereditary mixed polyposis Cowden/PTEN-hamartoma Serrated polyposis Peutz-Jeghers Li-Fraumeni DNA polymerase ε and δ polyposis

APC MUTYH MLH1, PMS2, MSH2, MSH6 SMAD4, BMPR1A GREM1 PTEN LKB1 STK11 TP53 POLE and POLD1

Serrated polyp

GREM1  MUTYH POLE and POLD1

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Familial Neoplasia of Colon and Rectum (Continued)

FAP = familial adenomatous polyposis.

269

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Esophagus/Stomach/Small Bowel Table

270

Familial Esophageal, Gastric, and Small Intestinal Tumors by Syndrome Syndrome

Gene

Inheritance

Tumors

Other Manifestations

Tylosis esophageal cancer

RHBDF2

Autosomal dominant

Esophagus: SCC

Skin: Palmoplantar keratoderma (tylosis) HN: Oral leukoplakia

Familial Barrett esophagus*

Polygenic*

Autosomal dominant*

Esophagus/GEJ: Barrett esophagus; ACA

Unknown*

FAP

APC

Autosomal dominant

Stomach: Fundic gland polyps, adenomas, ACA Small intestine: Adenomas, ACA

Skin: Epidermoid cyst and pilomatrixoma HN: CHRPE, osteoma in face or skull, dental abnormalities, nasopharyngeal angiofibroma GI: Colorectal adenomas and ACA HP: Hepatoblastoma, hepatic adenoma, pancreatic ACA Endocrine: Adrenal cortical neoplasms, papillary thyroid carcinoma Neuro: Medulloblastoma Soft tissue: Desmoid tumors

MUTYH-associated polyposis 

MUTYH

Autosomal recessive

Similar to FAP 

Similar to FAP but with more attenuated phenotype

Hereditary diffuse gastric CDH1, cancer CTNNA1

Autosomal dominant

Stomach: Diffuse-type ACA

Breast: Lobular carcinoma in women

Germline KIT mutation

KIT

Autosomal dominant

GIST (preferentially spindled, any GI site)

Skin: Lentigines, melanomas GI: Achalasia

Germline PDGFRA mutation

PDGFRA

Autosomal dominant

GIST  (preferentially epithelioid and gastric)

GI: Lipomas and fibrous tumors

NF1

NF1

Autosomal dominant

GIST (preferentially spindled, in small bowel)

Skin: Café au lait spots, axillary or inguinal freckling, juvenile xanthogranulomas, nevus anemicus Soft tissue: Neurofibromas, malignant peripheral nerve sheath tumors Bone: Sphenoid dysplasia, tibial pseudarthrosis Eye: Lisch nodules in iris, optic gliomas, choroidal freckling, retinal vasoproliferative tumors, neovascular glaucoma GI: Periampullary somatostatinproducing neuroendocrine tumors and gangliocytic paraganglioma Neuro: Pilocytic astrocytomas Endocrine: Pheochromocytomas BM: Juvenile myelomonocytic leukemia

Carney-Stratakis

SDHA, SDHB, SDHC, SDHD

Autosomal dominant

GIST (preferentially epithelioid and gastric)

Endocrine: Pheochromocytomas, paragangliomas, SDH-deficient pituitary adenomas GU: SDH-deficient renal cell carcinomas

Lynch

MLH1, MSH2, MSH6, PMS2, EPCAM

Autosomal dominant

ACA of small intestine and stomach (diffuse or intestinal type)

GI: Colonic adenomas and ACA GU: Urothelial carcinoma of upper urinary tract (renal pelvis, ureter) Gyn: Carcinoma of ovary (endometrioid, clear cell) and endometrium (endometrioid) Skin: Sebaceous tumors (Muir-Torre syndrome) Neuro: Glioblastoma (Turcot syndrome)

Peutz-Jeghers

STK11 (LKB1)

Autosomal dominant

Hamartomatous polyps and ACA of stomach and small intestine

Skin: Mucocutaneousmelanocytic macules GI: Colonic ACA GU: Intratubular large-cell hyalinizing Sertoli cell tumors of testes Gyn: Ovarian SCTATs, adenoma malignum of uterine cervix Other: Increased risk for carcinoma in breast, pancreas, and lung

Juvenile polyposis

SMAD4, BMPR1A

Autosomal dominant

Hamartomatous polyps and ACA of stomach and small intestine

GI/HP: ACA of colon and pancreas Subset with SMAD4 pathogenic variants: Mucocutaneous telangiectasia and visceral arteriovenous malformation JPS/HHT, connective tissue disorder (thoracic aortic dilatation,

Esophagus/Stomach/Small Bowel Table

Syndrome

Gene

Inheritance

Tumors

Other Manifestations aneurysm, dissection, mitral valve insufficiency, retinal detachment, lax joints and skin)

Gastric adenocarcinoma and proximal polyposis

APC (promoter 1B region)

Autosomal dominant

Stomach: Fundic gland polyps, adenomas and ACA, sparing antrum and pylorus

None 

POLE exonuclease domain mutation 

POLE

Autosomal dominant

Stomach: Fundic gland polyps  Small intestine: Adenomas

GI: Colorectal adenomas and ACA

ACA = adenocarcinoma; BM = bone marrow; CHRPE = congenital hypertrophy of retinal pigment epithelium; FAP = familial adenomatous polyposis; GEJ = gastroesophageal junction; GIST = gastrointestinal stromal tumor; GU = genitourinary; Gyn = gynecologic organs;  HHT = hereditary hemorrhagic telangiectasia; HN = head and neck region; HP = hepatopancreatic; JPS = juvenile polyposis syndrome; NF1 = neurofibromatosis type 1; SCC = squamous cell carcinoma; SCTAT = sex cord tumor with annular tubules. *Entity under investigation with limited literature.

Familial Neoplasia of Esophagus, Stomach, and Small Intestine Type of Tumor

Syndromes

Gene(s)

Adenocarcinoma of esophagus

Familial Barrett esophagus

Unknown

Squamous cell carcinoma of esophagus

Tylosis esophageal cancer

RHBDF2

Fundic gland polyps ± dysplasia

FAP, MAP, GAPPS, POLE

APC, MUTYH, POLE

Gastric adenoma

FAP, MAP, GAPPS

APC, MUTYH

Diffuse-type gastric adenocarcinoma

HDGC, Lynch

CDH1, MLH1, MSH2, MSH6, PMS2, EPCAM

Intestinal-type gastric adenocarcinoma

FAP, MAP, GAPPS, PJS, JPS, Lynch

APC, MUTYH, STK11, SMAD4, BMPR1A, MLH1, MSH2,  MSH6, PMS2, EPCAM

Gastrointestinal stromal tumor

Carney-Stratakis, NF1, KIT mutation, PDGFRA mutation

KIT, PDGFRA, NF1, SDHA, SDHB, SDHC, SDHD

Small intestinal adenoma

FAP, MAP, POLE

APC, MUTYH, POLE

Small intestinal adenocarcinoma

FAP, MAP, PJS, JPS, Lynch

APC, MUTYH, STK11, SMAD4, BMPR1A, MLH1, MSH2, MSH6, PMS2, EPCAM

Diagnoses Associated With Syndromes by Organ: Gastrointestinal

Familial Esophageal, Gastric, and Small Intestinal Tumors by Syndrome (Continued)

FAP = familial adenomatous polyposis; GAPPS = gastric adenocarcinoma and proximal polyposis syndrome; HDGC = hereditary diffuse gastric cancer; JPS = juvenile polyposis syndrome; MAP = MUTYH-associated polyposis; NF1 = neurofibromatosis type 1; PJS = Peutz-Jeghers syndrome; POLE = POLE exonuclease domain mutation.

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PART I SECTION 6

Genitourinary Bladder Bladder Urothelial Carcinoma Bladder Table

274 282

Kidney Angiomyolipoma Clear Cell Renal Cell Carcinoma Cystic Nephroma HLRCC Syndrome-Associated Renal Cell Carcinoma Papillary Renal Cell Carcinoma Renal Oncocytoma, Chromophobe, and Hybrid Tumors Succinate Dehydrogenase-Deficient Renal Cell Carcinoma Wilms Tumor Kidney Table

286 290 294 296 300 304 308 312 320

Prostate Prostate Carcinoma Prostate Table

326 338

Renal Pelvis And Ureter Renal Urothelial Carcinoma Ureter Urothelial Carcinoma Renal Pelvis and Ureter Table

344 348 350

Testicle Germ Cell Tumor Sertoli Cell Neoplasms Testicle Table

352 358 362

Diagnoses Associated With Syndromes by Organ: Genitourinary

Bladder Urothelial Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• Consensus molecular subtypes of bladder cancer ○ Luminal papillary, luminal nonspecified, luminal unstable, stroma-rich, basal/squamous, and neuroendocrine-like • Dual track pathway of bladder carcinogenesis ○ Hyperplasia/papillary pathway: Linked to mutations in HRAS and FGFR3 ○ Flat pathway: Linked to alterations in TP53 and RB • Lynch syndrome is associated with urologic malignancies with upper tract urothelial carcinoma most common ○ Other urologic malignancy possibly associated with Lynch syndrome includes bladder carcinoma

• Urothelial CIS: Flat urothelial neoplasm with unequivocal high-grade cytology • Low-grade PUCa: Papillae lined by urothelium with mild degree of distortion and low-grade dysplasia • High-grade PUCa: Papillae lined by urothelium with moderate to high-grade cytology • Inverted papillary urothelial carcinoma: Endophytic rounded growth into lamina propria with regular outline and absent stromal reaction • Invasive UCa ○ Irregular jagged nests, single cell infiltration, or tentacular finger-like projections ○ May show ↑ amount of cytoplasm and eosinophilia ○ Stroma may have desmoplasia, retraction artifact, myxoid change, or pseudosarcomatous stroma • Variants include UCa with divergent differentiation, nested UCa, micropapillary UCa, plasmacytoid UCa, and lymphoepithelioma-like UCa, among others

CLINICAL ISSUES • Disease of older adults with peak incidence in 70s; rare in individuals < 45 years old • Mostly presents with hematuria, dysuria, and frequency

Urothelial Carcinoma In Situ

High-Grade Papillary Urothelial Carcinoma

Infiltrating Urothelial Carcinoma

Polypoid Urothelial Carcinoma of Bladder

(Left) High-power view of UCa in situ shows loss of cell polarity, nuclear enlargement, marked pleomorphism, dense clumped chromatin, and prominent nucleoli. Urothelial CIS is defined by high-grade cytomorphology. Urothelial CIS may exhibit diffuse CK20 positivity in contrast to a reactive urothelium, which shows only CK20 staining of umbrella cells. (Right) Highgrade papillary UCa exhibits morphologic analogy to CIS. The papillary fibrovascular core is lined by high-grade pleomorphic cells.

(Left) Low-power view shows UCa extensively infiltrating the lamina propria. The invasive UCa nests are haphazard and show reactive desmoplastic response in the stroma. Assessment of muscularis propria involvement in TUR is important for management. (Right) Gross photograph shows a large polypoid mass of UCa ſt at the posterior bladder wall. Most UCas arise at the trigonal/bladder outlet area. Tumor staging categories of bladder are assessed by the depth of invasion of the bladder wall.

274

Bladder Urothelial Carcinoma

CLINICAL ISSUES

Synonyms

Epidemiology

• Transitional cell carcinoma

• Incidence ○ Bladder cancer is 4th leading cause of cancer morbidity and 8th cause of cancer mortality in USA • Age ○ Disease of older adults with peak incidence in 70s; rare in individuals < 45 years old ○ Urothelial papilloma and PUNLMP relatively more common in patients < 50 years old • Sex ○ 3-4x more common in men than women • Ethnicity ○ ~ 2x more common in whites than blacks

Definitions • In USA, > 90% of bladder carcinomas are urothelial carcinoma (UCa); < 10% are squamous cell carcinoma, adenocarcinoma, and small-cell carcinoma • Flat urothelial neoplasm ○ Urothelial dysplasia – Flat growth by urothelial cells thought to be neoplastic but cytologically falls below threshold for carcinoma in situ (CIS) ○ Urothelial CIS – Flat growth by cytologically malignant urothelial cells that has not invaded through basement membrane • Papillary urothelial neoplasm ○ Urothelial neoplasm with papillary growth on fibrovascular stalk in exophytic or endophytic manner ○ WHO/ISUP 2016 grading for papillary neoplasm – Urothelial papilloma – Papillary urothelial neoplasm of low malignant potential (PUNLMP) – Papillary UCa (PUCa), low grade – PUCa, high grade • Invasive UCa ○ UCa that invades beyond basement membrane

ETIOLOGY/PATHOGENESIS Environmental Exposure • Tobacco smoking: 2.5x higher risk • Chemicals such as arylamines (e.g., aniline, 2naphthylamine, benzidine)

Other Possible Risk Factors • Chronic urinary tract infection, calculi, drugs (e.g., analgesics and cyclophosphamide) • Schistosomiasis is well-established risk factor for squamous cell carcinoma but may also increase risk for UCa

Consensus Molecular Subtypes of Bladder Cancer • Luminal papillary, luminal nonspecified, luminal unstable, stroma-rich, basal/squamous, and neuroendocrine-like

Model of Bladder Cancer Development and Progression (Dual Track Pathway) • Alterations in Chr 9 initiating event to either pathway ○ Hyperplasia/papillary pathway – 70-80% transform to hyperplastic urothelium and progress to low-grade PUCa – Linked to mutations in HRAS and FGFR3 – Most tumors recur as PUCa, and ~ 15% become invasive UCa by alterations in TP53 and RB ○ Flat pathway – 20-30% transform to CIS/dysplasia – Linked to alterations in TP53 and RB – Most tumors progress to invasive UCa

Presentation • Hematuria, dysuria, and frequency • Advanced disease may present with abdominal pain and weight loss

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

Natural History • Most patients present with PUCa before or concurrently with CIS • Primary (de novo) or isolated CIS without prior or concurrent PUCa rare

Prognosis • For noninvasive urothelial neoplasm, dependent on grade ○ Urothelial papilloma: 8-14% recurrence, < 1% progression ○ PUNLMP: 36% recurrence, 4% progression ○ Low-grade PUCa: 50% recurrence, 10% progression ○ High-grade PUCa: 25% progression to invasive UCa ○ CIS: ~ 50% progress to invasive UCa in 5 years • For invasive UCa, dependent on stage • Locally advanced disease, even in absence of lymph node metastasis, is associated with poor prognosis ○ Estimated 5-year overall survival rates for pT3aN0, pT3bN0, and pT4aN0 disease are 64%, 49%, and 44%, respectively • Most variant morphology of UCa presents with higher stage; behavior may be similar to usual UCa when compared stage to stage

MACROSCOPIC General Features • Most common site is trigone/bladder outlet • More often multifocal • Noninvasive PUCa ○ Elevated or papillary lesion, which may increase in size and complexity with increasing grade ○ Inverted growth has more nodular appearance ○ Low- or high-grade PUCa can be small or large; grading based on cytology; urothelial papilloma and PUNLMP generally < 2 cm

MICROSCOPIC Histologic Features • Urothelial CIS 275

Diagnoses Associated With Syndromes by Organ: Genitourinary

Bladder Urothelial Carcinoma

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•

•

•

•

•

•

276

○ Unequivocal high-grade cytology ○ Marked nucleomegaly, irregular nuclei, prominent nucleoli, coarse dark chromatin, and abundant mitosis ○ Cellular crowding and loss of polarity ○ Morphologic variations – Clinging CIS: Denudation with few residual preserved CIS cells – Pagetoid CIS: Individual malignant cells spread in adjacent benign urothelium – Undermining CIS: Clusters of malignant cells covered by benign urothelium – May extend to involve von Brunn nests or cystitis cystica/glandularis in lamina propria PUNLMP ○ Papillae lined by thickened urothelium with normal cytology and maintained polarity ○ Papillae with minimal branching Low-grade PUCa ○ Papillae lined by urothelium with mild degree of architectural distortion and low-grade dysplasia ○ Pleomorphism is random ○ Mitosis may be present at base High-grade PUCa ○ Papillae lined by urothelium with moderate to highgrade cytology ○ Nucleomegaly, irregular nuclei, prominent nucleoli, and coarse dark chromatin ○ Mitosis may be brisk and seen in all layers ○ Papillae exhibit architectural complexities, including branching, confluence, and fusion ○ May have epithelial denudation Inverted papillary urothelial carcinoma ○ Endophytic rounded growth into lamina propria with regular outline and absent stromal reaction ○ Similar to exophytic PUCa, classified as PUNLMP, low or high grade based on cytologic atypia Urothelial proliferation of uncertain malignant potential ○ Thickened urothelium with no or minimal cytologic atypia and no true papillae (WHO 2016) Invasive UCa ○ Invasive epithelial features – Irregular jagged nests, single cell infiltration, or tentacular finger-like projections – May show ↑ amount of cytoplasm and eosinophilia (squamoid change) referred to as "paradoxical differentiation" – Vast majority of invasive UCa exhibits high-grade cytology, notable exception in some variant morphologies ○ Stromal changes – Desmoplasia, retraction artifact, myxoid change, pseudosarcomatous stroma, or no stromal response Variant morphologies of infiltrating UCa ○ UCa with divergent differentiation – UCa may exhibit glandular (i.e., adenocarcinoma), squamous, müllerian, or trophoblastic differentiation – Squamous differentiation with cell bridges, keratinization, and keratin pearl formation – Glandular differentiation includes enteric gland, mucinous gland, or signet ring cell formation

○

○

○

○

○

○

– Divergent differentiation can be extensive; surface CIS or PUCa that can be focal is clue for diagnosis Nested UCa – Invasive UCa with deceptively benign appearance growing as infiltrating nests of bland-appearing malignant urothelial cells – At surface, closely resembles von Brunn nest proliferation – Unlike von Brunn nest, nested UCa shows more irregular nests with confluence, back-to-back pattern, and at least random pleomorphism – Most do not have surface CIS or PUCa component – Most present with (at least) muscle-invasive disease – Lymphovascular invasion common Large-nested UCa – Invasive UCa consisting of large nests with pushing borders – Nests are typically more apart and connect to surface – Cells have low-grade cytology – Most have surface CIS or PUCa component UCa with small tubules – Invasive UCa with predominance of tubular change – Similar to nested variant, composed of blandappearing malignant urothelial cells – Nested UCa may have focal tubular change – May resemble tubular nephrogenic adenoma or Gleason 3 prostatic adenocarcinoma Microcystic UCa – Invasive UCa with small and large cysts (suggested to be at least 25%) – Cysts are lined by transitional or flattened cells and may have eosinophilic luminal secretions – Similar to nested variant, composed of blandappearing malignant cells – Does not contain glandular cells – May resemble cystitis cystica at surface Micropapillary UCa – Small nests or micropapillae in retraction-like spaces – Resembles micropapillary carcinoma of breast or ovary – Most exhibit high-grade cytology – Nuclei polarized exterior of nests – Multiple nests may be seen inside spaces – Surface PUCa may exhibit micropapillations or filiforms in layers of malignant urothelial cells Plasmacytoid UCa – Invasive UCa characterized by infiltrative, dyscohesive cells with eccentric nuclei that resemble plasma cells or poorly differentiated carcinoma – With CDH1 mutation and loss of e-cadherin – Tumor cells express plasma cell-associated marker CD138 (potential pitfall) – Amount of plasmacytoid morphology varies in published series, although most report it to be at least 30%; may also have signet ring cells – Invasive tumor cells in single cells, cords (resembling lobular carcinoma), small nests, or solid sheets – May form mass or widely infiltrative in linitis plasticalike spread – Has propensity to spread or recur in serosal spaces, such as in peritoneum presenting as carcinomatosis

Bladder Urothelial Carcinoma

ANCILLARY TESTS Immunohistochemistry • Urothelial lineage-associated markers uroplakin-2, GATA3, and S100 help confirm UCa ○ GATA3 is also expressed by breast ductal carcinoma, subset of cervical carcinomas, and paraganglioma

○ Uroplakin most specific for urothelial lineage but less sensitive; uroplakin-2 more sensitive than uroplakin-3 • UCa mostly CK7(+), CK20(+/-), HMCK(+), thrombomodulin (+), and p63(+) • Smoothelin shows differential strong expression in muscularis propria vs. muscularis mucosae and can be useful in staging of muscle-invasive disease

DIFFERENTIAL DIAGNOSIS Poorly Differentiated Prostate Carcinoma • May be difficult to distinguish from poorly differentiated UCa • Relatively more monomorphic and does not usually exhibit marked pleomorphism • May have associated glandular growth of cells with prominent nucleoli • PSA, PAP, NKX3.1, PSMA, or P501S (+) • GATA3, p63, or HMWCK (-)

Diagnoses Associated With Syndromes by Organ: Genitourinary

○ Lymphoepithelioma-like carcinoma – Invasive UCa characterized by syncytium of poorly differentiated UCa in background of dense lymphoplasmacytic infiltrates – Resembles undifferentiated nasopharyngeal carcinoma; not Epstein-Barr virus related ○ Lipid-rich UCa – Presence of large cells that contain multiple clear vacuoles, which indent nucleus to resemble lipoblasts or signet ring cells – Almost always admixed with conventional or other variants of UCa – Lipid-rich cells comprise 10-50% of tumor ○ Clear cell (glycogen-rich) UCa – Tumor cells with clear cytoplasm and may show solid alveolar growth, resembling clear cell renal cell carcinoma ○ Sarcomatoid UCa/carcinosarcoma – UCa containing admixture of epithelial and mesenchymal malignancies by morphology or immunophenotype – Epithelial component may include invasive UCa, CIS, or PUCa – Mesenchymal component often malignant spindle cells – Heterologous malignant mesenchymal elements may be present, such as bone (osteosarcoma), cartilage (chondrosarcoma), or skeletal muscles (rhabdomyosarcoma) ○ UCa with trophoblastic cells – UCa may contain trophoblastic cells with associated production of βHCG, confirmed by immunohistochemistry &/or serum or urine assay – ~ 35% of UCa may express βHCG, usually higher grade tumors, with more staining in more undifferentiated or anaplastic cells – "Pure" choriocarcinoma may occur rarely in bladder; may arise from urothelial metaplasia – Prognosis and treatment response to radiation poorer in UCa with βHCG expression ○ UCa with myxoid stroma and chordoid features – UCa with abundant extracellular mucin in absence of glandular differentiation – Tumor cells arranged in microcysts or small, cellular aggregates – Resembles extraskeletal myxoid chondrosarcoma, chordoma, and myxomatous yolk sac tumor ○ UCa with osteoclast giant cells – Solid growth of mononuclear cells with evenly distributed osteoclast giant cells – Mononuclear cells are plump with ovoid to round nuclei with vesicular chromatin, mostly exhibiting mild atypia

Gynecologic Carcinomas Involving Bladder • Cervical squamous carcinoma ○ p63(+), subset GATA3(+) ○ Lacks CIS or PUCa component in bladder surface • Poorly differentiated uterine carcinomas ○ Often WT1(+), GATA3(-)

Pseudocarcinomatous Hyperplasia • May simulate invasive UCa • Often with prior radiotherapy or chemotherapy • Squamoid changes present and associated with blood vessels and fibrin • Mucosal hemorrhage common and diffuse radiationinduced atypia present (if patient has history)

Papillary Nephrogenic Adenoma • May mimic PUCa • Papillae lined by 1 or few layers of cells and with associated tubular proliferations • Cells lack atypia and may exhibit hobnailing • pax-2(+), GATA3(-), or p63(-)

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Histologic type, including presence and amount of variant morphology • Grade, most meaningful in noninvasive UCa • Stage ○ In transurethral resection (TUR) specimens, diagnosis of high-grade UCa requires reporting of presence or absence of muscularis propria and status of involvement – Muscle should be specified if muscularis propria; reporting as "muscle present" is not appropriate – Repeat TUR is required if muscularis propria is not present for sampling adequacy in high-grade UCa • Margin status in cystectomy

SELECTED REFERENCES 1.

Al-Ahmadie H et al: Updates on the genomics of bladder cancer and novel molecular taxonomy. Adv Anat Pathol. ePub, 2019

277

Diagnoses Associated With Syndromes by Organ: Genitourinary

Bladder Urothelial Carcinoma

Urothelial Papilloma

PUNLMP

Low-Grade Papillary Urothelial Carcinoma

High-Grade Papillary Urothelial Carcinoma

Urothelial Carcinoma In Situ

Urothelial Carcinoma In Situ Extending to von Brunn Nests

(Left) Urothelial papilloma shows papillae lined by normal-appearing urothelium, including presence of surface umbrella cells ﬈. The cells lack cellular atypia or mitoses. (Right) PUNLMP, in contrast to urothelial papilloma, shows increased thickness of urothelial cells with bland cytology. Nuclei are oblong, and tumor characteristically exhibits well-maintained cellular polarity from base toward the surface. Papillae with central fibrovascular core are often simple, delicate, and do not exhibit complex branching and fusion.

(Left) Low-grade PUCa shows tumor cells with nuclear rounding and mildly disordered cell polarity. Mitoses can be seen, usually at the base ﬈. (Right) Highgrade PUCa shows tumor cells with unequivocal high-grade cytology. The nuclei are enlarged and more rounded and have irregular outlines and marked nucleomegaly. There is loss of the normal perpendicular arrangement of cells toward the surface. Note that grading of papillary neoplasm is based on cytomorphology of neoplastic cells.

(Left) UCa in situ shows cellular pleomorphism and presence of enlarged, irregular, hyperchromatic nuclei. There is such marked disorganization of the neoplastic cells that, in some places, the nuclei overlap. Note presence of prominent nucleoli and abundant mitoses. (Right) UCa in situ from the surface may extend downward to involve von Brunn nests ﬈. Recognition of this extension is important not to overcall as invasion into the lamina propria, particularly in fragmented specimens.

278

Bladder Urothelial Carcinoma

Infiltrating Urothelial Carcinoma (Left) Low-power view shows UCa with extensive invasion of the lamina propria. Recognition of the depth of invasion in the bladder wall is important for staging of invasive UCa, including in transurethral resection specimens. (Right) These invasive nests of UCa are irregular, variable in size, jagged, and surrounded by desmoplastic reaction. The neoplastic cells have modest eosinophilic cytoplasm and exhibit pleomorphism, enlarged crowded nuclei, and brisk mitotic activity.

Infiltrating Urothelial Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Infiltrating Urothelial Carcinoma

Inverted Papillary Urothelial Carcinoma (Left) Invasive UCa shows some smaller nests and individual infiltrating cells with abundant cytoplasm. This paradoxical differentiation or squamoid change, particularly if appreciated in single cells or small nests, is almost diagnostic for invasion. Note presence of stromal desmoplasia. (Right) Lowpower view shows noninvasive endophytic extension of PUCa into lamina propria. Inverted growth is characterized by rounded contour, sharp epithelial-stromal boundary, and absence of desmoplasia.

Lymphovascular Invasion by Urothelial Carcinoma

GATA3 in Urothelial Carcinoma (Left) UCa exhibits lymphovascular invasion (LVI). The tumor cell clusters follow the contour of blood vessels. Note presence of admixed hematopoietic cells in the lumen. UCa commonly exhibits retraction artifact and should be distinguished from LVI. (Right) GATA3 shows diffuse nuclear staining of UCa and is useful in distinguishing UCa from nonurothelial tumors in bladder and at metastatic sites. Ductal carcinoma of the breast and some visceral squamous cell carcinoma, including from cervix, may also express GATA3.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Bladder Urothelial Carcinoma Muscularis Propria Invasion by Urothelial Carcinoma

Perivesicular Tissue Invasion by Urothelial Carcinoma

CK20 in Urothelial Carcinoma In Situ

Uroplakin-2 in Urothelial Carcinoma

Urothelial Carcinoma With Glandular Differentiation

Urothelial Carcinoma With Squamous Differentiation

(Left) UCa shows invasion into the muscularis propria layer and is considered one of the crossroads for radical management. Identification of the presence of muscularis propria and reporting of status of involvement is warranted for staging adequacy. (Right) Low-power view of invasive UCa shows tumor infiltrating through the muscularis propria layer and into the perivesical soft tissue ﬈. Boundary between muscularis propria and perivesical tissue is often irregular, making staging of microscopic invasion at this site difficult.

(Left) CK20 shows diffuse fullthickness staining of urothelium in UCa in situ. In benign and reactive urothelium, staining is seen only at the surface umbrella cells or is absent. p53 is often used to complement CK20, which shows increased nuclear staining in UCa in situ. Diffuse staining (> 50%) is helpful, but may not always be present, in UCa in situ. (Right) Uroplakin-2 shows cytomembranous staining of UCa. Uroplakin is the most specific urothelial lineage marker and is useful in metastatic setting. (Courtesy S. Smith, MD.)

(Left) Low-power view shows UCa with glandular differentiation. Part of the tumor shows UCa with solid nests of polygonal malignant cells ﬉. In addition, there is adenocarcinoma characterized by glandular structures lined by tall columnar cells ﬈. (Right) Low-power view of invasive UCa with squamous differentiation shows prominent keratin production. Searching for UCa component, particularly at the surface (as in this case), is important to distinguish this tumor from pure squamous cell carcinoma.

280

Bladder Urothelial Carcinoma

Micropapillary Urothelial Carcinoma (Left) Nested UCa shows nests of bland-appearing cells that resemble a von Brunn nest proliferation. Distinction of this variant can be very difficult in superficial biopsy. Compared to von Brunn nests, nested UCa may show more irregular, tightly packed nests with confluence and fusion. Identification of muscularis propria invasion is key in making the diagnosis. (Right) Micropapillary UCa shows small nests of carcinoma cells within lacunar spaces that are often back-to-back. Nuclei often align at the outer portion of the nests.

Plasmacytoid Urothelial Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Nested Urothelial Carcinoma

Sarcomatoid Urothelial Carcinoma (Left) Plasmacytoid UCa shows infiltrating dyscohesive individual tumor cells with abundant cytoplasm and offcentric nuclei mimicking plasma cells. Tumor cells shows CDH1 mutation and loss of e-cadherin. This variant usually presents with higher stage and greater proclivity for extension into serosal surfaces. (Right) Sarcomatoid UCa shows presence of highgrade spindle cells. Heterologous elements (e.g., malignant bone, cartilage, skeletal muscle) may arise from this tumor (a.k.a. carcinosarcoma).

Clear Cell Urothelial Carcinoma

Lymphoepithelioma-Like Urothelial Carcinoma (Left) Clear cell UCa shows neoplastic cells with clear cytoplasm mimicking clear cell renal cell carcinoma. (Right) Lymphoepithelioma-like carcinoma is characterized by presence of syncytium of poorly differentiated UCa cells in a background of dense lymphoplasmacytic infiltrates resembling undifferentiated carcinoma in nasopharynx. Tumor cells may be masked by the background infiltrates and mimic an inflammatory process. Epithelial markers can highlight the UCa cells. Unlike in head and neck, this bladder tumor is not EBV related.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Bladder Table High-Grade Poorly Differentiated Carcinoma Antibody

Urothelial Carcinoma

Prostate Carcinoma

GATA3

80-95%

0-3%

HMWCK (34bE12)

65-97%

2-7%

p63

73-91%

0%

Uroplakin-2

62-72%

0-5%

S100

22-86%

0-3%

PSA

0-11%

68-100%

PAP

0-11%

78-95%

NKX3.1

0-1%

88-94%

P501S (prostein)

0-5%

93-100%

Urothelial Carcinoma-Associated Markers in Metastatic Setting Antibody

Sensitivity for Urothelial Carcinoma

GATA3

67-93%

p63

60-90%

Uroplakin-2

60-80%

S100

78-86%

Thrombomodulin

49-69%

CK7/CK20

65%

8th AJCC Staging for Bladder Cancer Stage

Definition

Primary Tumor (pT) pT0

No evidence of primary tumor

pTa

Noninvasive papillary carcinoma

pTis

Urothelial carcinoma in situ: "Flat tumor"

pT1

Tumor invades lamina propria (subepithelial connective tissue)

pT2

Tumor invades muscularis propria

pT2a pT2b pT3 pT3a pT3b pT4

Tumor invades superficial muscularis propria (inner 1/2) Tumor invades deep muscularis propria (outer 1/2) Tumor invades perivesical soft tissue Microscopically Macroscopically (extravesical mass) Extravesical tumor directly invades any of following: Prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall

pT4a

Extravesical tumor invades directly into prostatic stroma, uterus, vagina

pT4b

Extravesical tumor invades pelvic wall, abdominal wall

Regional Lymph Nodes (pN) N0

No lymph node metastasis

N1

Single regional lymph node metastasis in true pelvis (perivesical, obturator, internal and external iliac, or sacral node)

N2

Multiple regional lymph node metastasis in true pelvis (perivesical, obturator, internal and external iliac, or sacral node)

N3

Lymph node metastasis to common iliac lymph nodes

Distant Metastasis (M)

282

M0

No distant metastasis

M1

Distant metastasis

M1a

Distant metastasis limited to lymph nodes beyond common iliacs

M1b

Non-lymph node distant metastasis

Bladder Table

Muscularis Propria Invasion (pT2) (Left) Graphic shows different pT categories of bladder cancer. Bladder cancer pT is defined by level of invasion of the bladder wall and adjacent structures. In the 8th AJCC system, transmural invasion into prostate ﬈ is considered as pT4a. Transurethral extension into prostate ﬉ is now considered as pT2 by urethral cancer staging. (Right) Infiltrating carcinoma may dissect muscularis propria (MP) bundles ﬉, and smaller bundles ﬈ may mimic superficial muscularis mucosae (MM) that may lead to understaging as pT1.

Microperivesical Tissue Invasion (pT3a)

Diagnoses Associated With Syndromes by Organ: Genitourinary

8th AJCC TNM Staging of Bladder Cancer

Macroperivesical Tissue Invasion (pT3b) (Left) Most experts define the irregular outer MP boundary by drawing a line to interconnect the outermost muscle bundles ﬈. In this case, the tumor is beyond the 2 MP muscle bundles ﬉ and is thus categorized as pT3a (not pT2b). (Right) A large, fungating mass involves the posterior bladder wall ﬈. Accuracy of categorization as pT3b relies on the prosector's gross assessment and documentation of macroscopic perivesical soft tissue invasion and with microscopic confirmation.

High-Stage Bladder Cancer

Transmural Invasion Into Prostate (pT4a) (Left) Graphic shows a tumor arising from the posterior wall of the bladder, invading through the wall and into the right seminal vesicle st. Also shown are hematogenous metastases to the right pubic ramus ﬇ and lymph node metastases ſt. This would be a T4bN1M1 lesion and treated with chemo- or radiation therapy and possibly palliative surgery. (Right) Gross photograph shows bladder cancer with direct extension into the prostate ﬈, which is categorized as pT4a. Prostate invasion from urethra is categorized as pT2.

283

Diagnoses Associated With Syndromes by Organ: Genitourinary

Bladder Table

Pelvic Node Metastasis by Bladder Cancer

Urothelial Carcinoma Lymph Node Metastasis

Metastatic Urothelial Carcinoma

GATA3 in Metastatic Urothelial Carcinoma

Urothelial Carcinoma In Situ

CK20 in Urothelial Carcinoma In Situ

(Left) Axial CECT shows a pelvic lymphadenopathy ſt due to bladder cancer. Solitary regional lymph node metastasis is categorized as N1, and multiple lymph node metastasis is categorized as N2. (Right) H&E shows a pelvic lymph node involved by metastatic urothelial carcinoma. The 8th AJCC added the perivesical node in pN category. It is important to document the number and location of positive nodes for pN categorization. Size of lymph node metastasis is suggested to have prognostic significance.

(Left) Lung core biopsy shows metastasis of urothelial carcinoma. The main differential diagnosis is squamous cell carcinoma from lung or metastasis from another primary. Distinction can be challenging because of the morphologic and immunohistochemical overlap. (Right) Nuclear staining for GATA3 shows lung metastasis of urothelial carcinoma. While the strong and diffuse positivity favors urothelial carcinoma, caution is advised since squamous cell carcinoma of lung or other primaries may also express GATA3.

(Left) H&E shows carcinoma in situ (CIS) with loss of polarity, nuclear crowding, pleomorphism, and prominent nucleoli. In some instances, distinction between CIS and reactive atypia can be difficult, necessitating use of ancillary immunostains (CK20, CD44, and p53). (Right) CK20 shows full-thickness staining of urothelium in CIS. In normal and reactive urothelium, CK20 is expressed only in the surface umbrella cell layer. When interpreting immunoreactivity in CIS, it is crucial to match the exact focus to the corresponding H&E stain.

284

Bladder Table

GATA3 in Urothelial Carcinoma (Left) p63 shows diffuse nuclear staining in urothelial carcinoma. In the GU tract, p63 is helpful when distinguishing urothelial carcinoma from prostate or renal cell carcinomas, which are both p63(-). (Right) GATA3 shows diffuse nuclear staining in urothelial carcinoma. Compared to p63, GATA3 is more urothelial lineage specific and helpful in the metastatic setting. Other GATA3(+) tumors include ductal breast carcinoma, cutaneous basal cell carcinoma, and some squamous cell carcinomas.

HMWCK (34bE12) in Urothelial Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

p63 in Urothelial Carcinoma

S100 in Urothelial Carcinoma (Left) HMWCK shows strong diffuse cytoplasmic staining in a urothelial carcinoma core biopsy. HMWCK is helpful when distinguishing urothelial carcinoma from prostatic carcinoma. In the prostate, HMWCK is typically expressed only by prostatic basal cells, which are lost in prostate carcinoma. (Right) S100 shows nuclear and cytoplasmic positivity in urothelial carcinoma. S100 is generally not expressed in squamous cell carcinoma and, like GATA3, is helpful when making a distinction from urothelial carcinoma.

Uroplakin in Urothelial Carcinoma

Smoothelin in Muscularis Propria (Left) Uroplakin-3 shows some plaque-like positivity in urothelial carcinoma. Uroplakin-3 is a specific marker for urothelial lineage but suffers from poor sensitivity. The new marker uroplakin-2 has a much better sensitivity than uroplakin-3. (Right) Smoothelin shows differential staining between MP (strong and diffuse) ﬈ and hyperplastic MM (weak to absent) ﬉. Smoothelin can be helpful when distinguishing MP from MM in staging invasive carcinoma.

285

Diagnoses Associated With Syndromes by Organ: Genitourinary

Angiomyolipoma KEY FACTS

TERMINOLOGY

MICROSCOPIC

• Angiomyolipoma (AML); classic AML (C-AML); epithelioid AML (E-AML) • C-AML: Renal mesenchymal neoplasm putatively derived from PECs with triphasic components of dysmorphic blood vessels, fat, and spindle cells • E-AML: Renal mesenchymal neoplasm putatively derived from PECs consisting of polygonal cells

• C-AML: Usually triphasic pattern of dysmorphic vessels, fat, and spindle cells in 85% of cases ○ In 15%, fat (lipoma-like) or spindle cells (leiomyoma-like) may predominate (comprises 95% of tumor) ○ Uncommonly, may have epithelial cysts • E-AML: Carcinoma-like or diffuse mixed epithelioid and plump spindle cell growths ○ Nuclei tend to be pleomorphic with brisk mitosis ○ Larger pleomorphic multinucleated cells present

ETIOLOGY/PATHOGENESIS • > 90% of C-AML and ~ 75% of E-AML are sporadic • Up to 75% of TS patients will develop AML • Association of E-AML (~ 25%) to TS stronger

ANCILLARY TESTS • Melanocytic markers (+); epithelial markers (-); pax-8(-)

CLINICAL ISSUES

TOP DIFFERENTIAL DIAGNOSES

• Age: 14-88 years old; median: 50 years • Younger for TS-associated AML (mean: 26 years) • TS-associated AML presents earlier, larger, multifocal or bilateral, and more symptomatic

• C-AML: Sarcomatoid renal cell carcinoma (RCC) or urothelial carcinoma, liposarcoma and smooth muscle tumors • E-AML: RCC

Classic Angiomyolipoma

Epithelioid Angiomyolipoma

Classic Angiomyolipoma

Lipoma-Like Angiomyolipoma

(Left) Classic angiomyolipoma (C-AML) shows triphasic morphology composed of dysmorphic blood vessels ﬈, spindle cells, and fat. Proportion of these components vary so that 1 may predominate (e.g., leiomyoma-like or lipoma-like AML). (Right) E-AML shows diffuse epithelioid and plump spindle cell growth. Tumor cells show eosinophilic granular cytoplasm, and the nuclei exhibit some degree of pleomorphism. E-AML more often shows less prominent vascularity and rare fat cells. E-AML may resemble RCC.

(Left) Gross photograph of partial nephrectomy for CAML shows a variegated appearance because of varying admixture of spindle cells, fat, and vessels. This tumor protrudes into the perinephric fat, which is not uncommon for AML. (Right) Gross photograph shows partial nephrectomy of fatpredominant C-AML with a soft, lobulated fatty surface resembling lipoma. Caution should be exercised in diagnosing lipoma-like C-AML because the neoplastic fat cells with atypia may resemble retroperitoneal liposarcoma.

286

Angiomyolipoma

Abbreviations • Angiomyolipoma (AML)

MACROSCOPIC

Synonyms

General Features

• Classic AML (C-AML): Renal PEComa, triphasic AML

• Solitary in 60% and multifocal in 40% • Up to 100% of familial AMLs are multifocal/bilateral

Definitions • C-AML ○ Renal mesenchymal neoplasm putatively derived from perivascular epithelioid cells (PECs) with triphasic components of dysmorphic blood vessels, fat, and spindle cells • Epithelioid AML (E-AML) ○ Renal mesenchymal neoplasm putatively derived from PECs consisting mainly of polygonal cells • C-AML and E-AML are closely related to family of PECderived visceral and soft tissue tumors ○ e.g., PEComas, lymphangiomyomatosis, "sugar" tumor of lung, and cardiac rhabdomyomas • C-AML and E-AML are often spectrum

ETIOLOGY/PATHOGENESIS Sporadic AML • > 90% of C-AML and ~ 75% of E-AML are sporadic

Size • E-AML larger than C-AML ○ C-AML range from 1-30 cm; mean: 8.6 cm ○ E-AML range from 0.2-35.0 cm; mean: 5.6 cm • Familial larger than sporadic AMLs (mean: 13 vs. 5 cm)

Gross Appearance • C-AML ○ Unencapsulated and may bulge or extend to extrarenal fat (not sign of malignancy) ○ Variable appearance depending on predominance of fat (lipoma-like) or spindle cells (leiomyoma-like) • E-AML ○ Unencapsulated and may extend outside of kidney ○ More solid with variable amount of hemorrhage, necrosis, or cystic degeneration

MICROSCOPIC

Tuberous Sclerosis-Associated Angiomyolipoma 

Histologic Features

• Genetic alterations in TSC1 orhamartin (Chr 9q34) and TSC2 ortuberin (Chr 16p13.3) • Up to 75% of TS patients will develop AML • Association of E-AML (~ 25%) to TS stronger

• C-AML ○ Usually triphasic pattern of dysmorphic vessels, fat, and spindle cells in up to 85% of cases ○ In 15%, fat or spindle cells may predominate ○ Vessels are ectatic, hyalinized with eccentric lumen ○ Spindle cells have granular cytoplasm, bland nuclei, rare mitosis, and appear to radiate from vessels ○ Fat cells are mature and may have nuclear atypia ○ Uncommonly, may have epithelial cysts lined by flat, cuboidal or hobnail cells (AML with epithelial cells) • E-AML ○ Carcinoma-like growth – Cohesive nests, broad alveoli or sheets compartmentalized by vascular septa ○ Diffuse epithelioid and plump spindle cell growth ○ Cells have pale to granular eosinophilic cytoplasm ○ Nuclei tend to be atypical or pleomorphic ○ Brisk mitosis (> 5 per HPF) with atypical forms ○ Larger pleomorphic multinucleated cells present ○ Hemorrhages, necrosis, vascular invasion, and extrarenal extension not uncommon

CLINICAL ISSUES Epidemiology • Incidence: Uncommon; < 0.2% of population • Age: 14-88 years old; median: 50 years ○ Younger for TS-associated AML (mean: 26 years) ○ E-AML younger than C-AML (mean: 39 vs. 52 years) • Sex: F > M incidence shown by most studies ○ C-AML: M:F = 1:1-4 and E-AML: M:F = 1:1.0-6.5

Presentation • ~ 50% are incidental finding • ~ 2/3 show signs of bleeding (e.g., hematuria, retroperitoneal hemorrhage), and ~ 1/5 have flank pain • TS-associated AML presents earlier, larger, multifocal or bilateral, and more symptomatic than sporadic AML

Treatment • Conservative surgery for C-AML • Expectant management suggested for radiographically typical AML ○ Surgical intervention for suspicion of malignancy, large size, hemorrhage, and intractable pain

Prognosis • Contemporary studies with C-AML show benign outcome; retroperitoneal hemorrhage can be fatal • E-AML has malignancy potential ○ Recurrence and metastasis varied from 5-49%

Diagnoses Associated With Syndromes by Organ: Genitourinary

○ Reported mortality rates of 10-33% ○ Differences influenced by varying diagnostic criteria

TERMINOLOGY

ANCILLARY TESTS Immunohistochemistry • Melanocytic markers (HMB-45, MART-1, tyrosinase) (+); rare cells (+) in fat-predominant AML • Epithelial markers (-); pax-8(-); spindle cells actin (+)

SELECTED REFERENCES 1.

Fernández-Pello S et al: Management of sporadic renal angiomyolipomas: a systematic review of available evidence to guide recommendations from the European Association of Urology Renal Cell Carcinoma guidelines panel. Eur Urol Oncol. ePub, 2019

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Angiomyolipoma

Classic Angiomyolipoma Perivascular Cells

Spindle Cell (Fat-Poor) Angiomyolipoma

Spindle Cell (Fat-Poor) Angiomyolipoma

Lipoma-Like Angiomyolipoma

Multifocal Angiomyolipomas

Angiomyolipoma With Epithelial Cells

(Left) Blood vessels in C-AML are abnormal (ectatic, thickened, and hyalinized). The epithelioid and spindle cells appear to arise from around the vessels or from perivascular epithelioid cells ﬈. Spindle cells merge with the fat component, which can be focal. (Right) Gross photograph shows spindle cellpredominant C-AML with a solid, light tan cut surface and foci of hemorrhages st.This tumor projects outward from the renal capsule ſt. Spindle cell C-AML may mimic a capsular leiomyoma.

(Left) C-AML shows predominant spindle cells with absence of fat (leiomyoma-like AML). Spindle cells may exhibit fascicular growth with elongated nuclei ﬈. The spindle cells appear to emanate from the vessel ﬉. These spindle cells are positive for smooth muscle markers. (Right) C-AML shows predominance of fat that may exhibit atypia. Careful search for abnormal vessels with spindle or epithelioid cells should be made. Lipoma-like AML may resemble a welldifferentiated liposarcoma from retroperitoneum.

(Left) Low-power view shows a kidney with 3 microscopic foci of AML ﬈. AML in patients with tuberous sclerosis are usually bilateral and multifocal. Besides AML, RCC with unique histology, such as eosinophilic and cystic features, may also arise in the setting of tuberous sclerosis. (Right) AML shows a cyst lined by flattened to cuboidal cells ﬈ with subjacent dysmorphic blood vessels, spindle cells, and fat cells. AML with epithelial cells may also occur in the setting of tuberous sclerosis and has a benign outcome.

288

Angiomyolipoma Epithelioid Angiomyolipoma Epithelioid and Spindle Cells (Left) E-AML shows carcinomalike growth with epithelioid cells containing clear to granular cytoplasm separated by thin vasculatures ﬈ and with pleomorphic nuclei, which may resemble highgrade clear cell RCC. Unlike RCC, AML is negative for pax-8 and epithelial markers. (Right) E-AML shows admixture of epithelioid ﬊ and plump spindle cells ﬈ with pale eosinophilic cytoplasm in diffuse growth. The nuclei are more variable with obvious nuclear atypia. Adipocytic differentiation can be focal or absent in E-AML.

Epithelioid Angiomyolipoma Cell Pleomorphism

Diagnoses Associated With Syndromes by Organ: Genitourinary

Epithelioid Angiomyolipoma, CarcinomaLike

Epithelioid Angiomyolipoma Giant Cells (Left) E-AML shows plump rhabdoid and spindle cells showing pleomorphism and occasional multinucleated cells. The epithelioid cells are seen emanating from a large blood vessel ﬈. (Right) E-AML shows marked pleomorphism, including multinucleation ﬈. This degree of nuclear atypia is greater than in RCC. This feature should raise suspicion for E-AML. Admixture of spindle cells and, occasionally, focal areas of fat and abnormal vessels may help in diagnosis. Note how the tumor cells appear to emanate from the blood vessel.

HMB-45 in Epithelioid Angiomyolipoma

Mixed Classic and Epithelioid Angiomyolipoma (Left) E-AML with strong, diffuse staining with HMB-45 is shown. Melanocytic markers are positive in the spindle or epithelioid cells of AML. In lipoma-like AML, staining can be patchy, corresponding to the scattered spindle cells within the fat-predominant tumor. (Right) AML shows admixture of epithelioid cells (left) with nuclear atypia and binucleation ﬈ and usual spindle cells ﬊ admixed with fat cells (right). The proportion of epithelioid cells may vary in AML; some experts consider > 80% epithelioid cells to be labeled as E-AML.

289

Diagnoses Associated With Syndromes by Organ: Genitourinary

Clear Cell Renal Cell Carcinoma KEY FACTS

TERMINOLOGY • Renal epithelial neoplasm composed of cells with optically clear cytoplasm in solid alveolar growth

ETIOLOGY/PATHOGENESIS • Mostly sporadic; up to 90% have somatic inactivation of VHL at Chr 3p25-26 • Other mutations: PBRM1 (~ 40%), SETD2 (~ 10%), and BAP1 (10%) • Present in familial syndromes ○ von Hippel-Lindau (VHL) syndrome ○ Constitutional chromosome 3 translocation ○ Familial clear cell renal cell carcinoma (CCRCC) ○ Subset of Birt-Hogg-Dubé syndrome and tuberous sclerosis patients

CLINICAL ISSUES • Most common renal epithelial neoplasm (~ 75%) • 21-89 years (mean: 61); younger in VHL patients

• 5-year disease-specific survival: 76%; poorer behavior than papillary RCC and chromophobe RCC (CHRCC)

MICROSCOPIC • Solid alveoli/nests separated by meshwork of delicate vessels forming characteristic chicken-wire pattern • Occasionally, hemorrhage occurs within alveoli/nests, forming "blood lakes" • Tumor cells typically have optically clear cytoplasm due to intracellular glycogen and lipid • Occasionally, cells have eosinophilic granular cytoplasm; usually have higher grade nuclei • CA9 diffusely (+), CD10(+), pax-2(+), and pax-8(+)

TOP DIFFERENTIAL DIAGNOSES • • • •

CHRCC MITF/TFE translocation carcinomas Clear cell papillary RCC Epithelioid angiomyolipoma

Clear Cell Renal Cell Carcinoma: Cut Surface

Clear Cell Renal Cell Carcinoma: Architecture

Clear Cell Renal Cell Carcinoma With Sarcomatoid Change

Clear Cell Renal Cell Carcinoma With Sarcomatoid Change

(Left) CCRCC shows the typical golden yellow cut surface due to abundant lipid content. This tumor pushes into the renal sinus fat ﬈ and should be sampled thoroughly to search for possible invasion (pT3a). CCRCC may have cystic change ﬉ that can be focal or extensive. (Right) CCRCC consists of optically clear cells arranged in solid alveolar nests surrounded by an intricate vascular meshwork, imparting a chicken-wire appearance ﬊. Occasionally, hemorrhage ﬈ may occur within nests and may cystically dilate these nests.

(Left) CCRCC shows a variegated cut surface consisting of a golden yellow area ſt, hemorrhage ﬇, and a firmer, irregular, white tan area st. Golden yellow area corresponds to usual CCRCC, whereas the white-tan area corresponds to the aggressive sarcomatoid change. (Right) CCRCC shows sarcomatoid spindle cell change ﬈ and coagulative tumor necrosis ﬊. Sarcomatoid change and tumor necrosis are adverse prognostic variables. Sarcomatoid change is considered WHO/ISUP grade 4.

290

Clear Cell Renal Cell Carcinoma

Abbreviations

Prognosis • 5-year disease-specific survival: 76%; poorer behavior compared to papillary RCC and chromophobe RCC (CHRCC)

• Clear cell renal cell carcinoma (CCRCC)

Definitions • Malignant renal epithelial neoplasm composed of cells with optically clear cytoplasm in solid alveolar growth

ETIOLOGY/PATHOGENESIS Sporadic Clear Cell Renal Cell Carcinoma • Vast majority of CCRCC are sporadic tumors • Up to 90% have somatic inactivation of VHL at Chr 3p25-26 by mutation, loss, or DNA methylation ○ Leads to nondegradation of hypoxia-induced factor (HIF); usually degraded by VHL gene products • Other mutations: PBRM1 (~ 40%), SETD2 (~ 10%), and BAP1 (10%) ○ BAP1 mutation often seen in higher grade tumors

Familial Clear Cell Renal Cell Carcinoma • Familial predisposition for CCRCC and no identifiable genetic factor; diagnosis of exclusion • Usually older onset and presents with solitary CCRCC, similar to sporadic CCRCC • von Hippel-Lindau (VHL) disease ○ Virtually all patients have inactivation of VHL ○ CCRCC seen in up to 45% of VHL patients ○ Frequently multifocal and bilateral CRCCs ○ Multiple renal cysts and small "clear cell tumorlets" involve renal parenchyma ○ At risk of developing up to 600 tumors per kidney • Constitutional chromosome 3 translocation ○ Rare hereditary predisposition for bilateral and multifocal CCRCC due to Chr 3 translocation • CCRCC may occur in subset of patients with Birt-HoggDubé syndrome and tuberous sclerosis complex

CLINICAL ISSUES Epidemiology • Most common renal epithelial neoplasm (~ 75%) • 21-89 years (mean: 61 years) • Younger in VHL patients (16-67 years, mean: 39 years)

Presentation • Mostly encountered as incidental radiologic findings • Classic triad of abdominal mass, flank pain, and hematuria seen in only ~ 25% of patients • In VHL, discovered due to extrarenal symptoms

Treatment • Surgical approaches ○ Nephrectomy; partial is preferred, particularly if tumor is < 4 cm and not involving hilum ○ In VHL patients, conservative surgery performed if tumor reaches 3 cm in size • Tyrosine kinase inhibitor &/or immune-checkpoint inhibitors as 1st option

MACROSCOPIC General Features • Usually well circumscribed; can be cystic • Golden yellow cut surface due to lipid content

Size • 1.3-15.0 cm (mean: 6.2)

MICROSCOPIC Histologic Features • Solid alveoli/nests separated by meshwork of delicate vessels forming characteristic chicken-wire pattern • Occasionally, hemorrhage occurs within alveoli/nests, forming "blood lakes" • Tumor cells typically have optically clear cytoplasm due to intracellular glycogen and lipid • Occasionally, cells have eosinophilic granular cytoplasm; usually have higher grade nuclei • True papillae, if present, should be focal; breakdown of alveoli/nests may form pseudopapillae • Graded by ISUP/WHO grades 1-4; grades 1-3 based on nucleolar prominence ○ Grade 4 with marked pleomorphism, tumor giant cells, sarcomatoid and rhabdoid features

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

DIFFERENTIAL DIAGNOSIS Chromophobe Renal Cell Carcinoma • CCRCC with clear and eosinophilic cells mimics classic and eosinophilic CHRCC, respectively • CD117(+), Ksp-cadherin (+), CK7(+), and CA9(-)

MITF/TFE Translocation Carcinomas • Usually younger patients with higher stage disease • TFEB carcinomas: Biphasic with nests of larger clear cells and central smaller cells clustered around hyaline nodules • Epithelial markers focally (+) or (-), cathepsin-K (+), Melan-A (+), TFE3(+) or TFEB(+)

Clear Cell Papillary Renal Cell Carcinoma • Papillary and solid growths containing clear cells with lowgrade nuclei aligned away from basal aspect • CA9 cup-like (+), CK7(+), and AMACR(-)

Epithelioid Angiomyolipoma • Higher grade, abundant mitosis, admixed plump spindle cells, and giant pleomorphic cells • pax-8(-), epithelial markers (-), and melanocytic markers (+) (e.g., HMB-45, MITF, and MART-1)

SELECTED REFERENCES 1.

2. 3.

Yang C et al: Adverse histopathologic characteristics in small clear cell renal cell carcinomas have negative impact on prognosis: a study of 631 cases with clinical follow-up. Am J Surg Pathol. 43(10):1413-20, 2019 Ricketts CJ et al: The Cancer Genome Atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23(12):3698, 2018 Favazza L et al: Renal cell tumors with clear cell histology and intact VHL and chromosome 3p: a histological review of tumors from the Cancer Genome Atlas database. Mod Pathol. 30(11):1603-12, 2017

291

Diagnoses Associated With Syndromes by Organ: Genitourinary

Clear Cell Renal Cell Carcinoma Clear Cell Renal Cell Carcinoma: WHO/ISUP Grade 1

Clear Cell Renal Cell Carcinoma: WHO/ISUP Grade 4

Clear Cell Renal Cell Carcinoma: "Blood Lakes"

Clear Cell Renal Cell Carcinoma With Eosinophilic Cells

Clear Cell Tumorlet in von Hippel-Lindau Kidney

Clear Cell Microcysts in von Hippel-Lindau Kidney

(Left) CCRCC is typically composed of tumor cells with optically clear cytoplasm due to abundant glycogen and fat content that are not preserved with processing. This tumor's nuclei do not show prominent nucleoli on high-power view, consistent with WHO/ISUP grade 1. Prominent nucleoli on high-power view only is considered grade 2. If prominent on low-power view, this is considered grade 3. (Right) CCRCC shows WHO/ISUP grade 4 nuclei, characterized by marked pleomorphism and multinucleation.

(Left) CCRCC shows abundant hemorrhage within the central aspects of alveolar nests, creating multiple lumina or "blood lakes" ﬈. (Right) CCRCC with eosinophilic cytoplasm retains the basic architecture of intricate vessels ﬈ and solid alveolar nests. Cells in CCRCC with eosinophilic cytoplasm usually have higher grade nuclei (commonly WHO/ISUP grade 3). This tumor may resemble other renal tumors with eosinophilic cytoplasm; the intricate vasculature is a helpful distinguishing feature.

(Left) VHL patients' kidneys harbor multiple microscopic "clear cell tumorlets," seen here between normal renal tubules. Cytology of these cells is similar to that of CCRCC. It is debatable if these tumorlets should be considered carcinomas. (Right) A VHL patient's kidney shows microcysts ﬈. These small cysts are lined by 1 or few layers of clear cells with lowgrade nuclei. Management of VHL patients requires regular surveillance and intervention for renal masses that reach 3 cm in size.

292

Clear Cell Renal Cell Carcinoma

DDx: Chromophobe Renal Cell Carcinoma (Left) CCRCC typically shows strong, diffuse, membranous staining with CA9, a helpful marker in the differential diagnosis from most other renal tumors with pale or clear cytoplasm. (Right) CHRCC shows tumor cells with pale or flocculent cytoplasm, prominent cell membrane (plant cell-like), perinuclear halo, koilocytoid nuclear atypia, and common binucleation. Vessels are usually incomplete, and solid growth is broader. Unlike CCRCC, this tumor is diffusely CD117 and Ksp-cadherin (+) and CA9(-).

DDx: TFE3 Translocation Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

CA9 in Clear Cell Renal Cell Carcinoma

DDx: TFEB Carcinoma (Left) TFE3 carcinoma shows clear cells arranged in solid nests ﬈, resembling CCRCC, with psammoma calcifications. This tumor is more common in younger individuals and presents with higher stage. Diagnosis can be confirmed by detecting TFE3 translocation by FISH. (Right) TFEB carcinoma shows a dual population of cells consisting of larger clear cells arranged in nests and with central collections of smaller cells associated with hyaline material ﬈. Diagnosis can be confirmed by detecting TFEB translocation by FISH.

DDx: Clear Cell Papillary Renal Cell Carcinoma

DDx: Epithelioid Angiomyolipoma (Left) CCPRCC may show solid areas that resemble CCRCC. However, CCPRCC shows tubules lined by clear cells with low-grade nuclei lined at the luminal aspect ﬈. This tumor shows CK7(+) and cuplike CA9(+), unlike CCRCC, which shows CK7(-) and circumferential CA9(+). (Right) E-AML may exhibit a carcinoma-like growth with delicate vessels and resemble CCRCC. E-AML usually shows nuclear pleomorphism with multinucleation and abundant mitosis. This tumor is pankeratin (-), pax-8(-), and HMB-45(+), unlike CCRCC.

293

Diagnoses Associated With Syndromes by Organ: Genitourinary

Cystic Nephroma KEY FACTS

TERMINOLOGY • Pediatric: Epithelial-lined cystic neoplasm usually associated with DICER1 syndrome ○ Distinct entity from adult cystic nephroma (CN)/mixed epithelial stromal tumors (MESTs) • Adult: Epithelial-lined cystic neoplasm not associated with underlying DICER1 mutations; represents cystic end of MEST morphologic spectrum

○ CN almost always benign; prognosis in DICER1 syndrome driven by presence of other aggressive lesions ○ Associated tumors: Pleuropulmonary blastoma, pituitary blastoma, differentiated thyroid carcinoma, ovarian sex cord-stromal tumors, embryonal rhabdomyosarcoma, pineoblastoma, nasal chondromesenchymal hamartoma • Adult: F > M; almost exclusively benign

MACROSCOPIC

ETIOLOGY/PATHOGENESIS

• Unilateral, solitary, unencapsulated

• Pediatric: 90% harbor DICER1 mutations and occur as manifestation of DICER1 syndrome • Adult: No underlying germline mutations, may be hormonally driven

MICROSCOPIC

CLINICAL ISSUES • Pediatric: M > F; prompts genetic testing for DICER1 mutation

• Pseudocapsule around tumor • Multicystic mass lined by bland flat to cuboidal cells • Variably cellular septa between cystic spaces

ANCILLARY TESTS • Pediatric: Stromal spindle cells ER/PR(-) ○ Unlike adult CN/MEST, which are usually ER/PR(+)

Multicystic Appearance

Cystic Spaces

Epithelial Lining

Adult Cystic Nephroma/Mixed Epithelial Stromal Tumor

(Left) From low power, cystic nephromas (CNs) appear as a multicystic mass with enlarged cystic spaces. The epithelial lining is not prominent from this magnification. The septa ﬉ can range from very thin to thickened. However, they typically do not appear hypercellular in comparison to mixed epithelial and stromal tumors (MESTs). (Right) Cystic spaces are often irregularly shaped. Compared to the previous image, the epithelial lining of the spaces is more prominent ﬈, even from low power. The septa are paucicellular ﬉.

(Left) Cystic spaces are lined by bland cuboidal epithelial cells. Note the paucicellular stroma. Tubulocystic carcinomas can have similar architecture but are lined by hobnailed cells with highgrade nuclear atypia. (Right) In comparison to pediatric CNs, adult tumors in the CN/MEST spectrum can show expanded septa between the cystic spaces. The stroma is composed of a very cellular population of stubby spindle cells, which appear blue from low power. The spindle cells are reminiscent of ovariantype stroma.

294

Cystic Nephroma

MACROSCOPIC

Synonyms

General Features

• Pediatric: Pediatric cystic nephroma (CN) • Adult: Adult CN; mixed epithelial stromal tumor (MEST) family of tumors

• Unilateral, solitary, encapsulated • Pediatric: Extensively cystic • Adult: Spectrum ranging from extensively cystic (CN) to mostly solid (MEST)

Definitions • Pediatric: Encapsulated, epithelial-lined cystic neoplasm usually associated with germline mutations in DICER1 and representing distinct entity from adult CN/MEST • Adult: Encapsulated, epithelial-lined cystic neoplasm not associated with underlying DICER1 mutations and likely representing cystic end of MEST morphologic spectrum

ETIOLOGY/PATHOGENESIS Pediatric Cystic Nephroma • 90% harbor germline DICER1 mutations, leading to DICER1 syndrome • DICER1 is important in physiologic cleavage of dsRNA into miRNA and resultant proper regulation of gene expression • Germline DICER1 mutation and subsequent loss of heterozygosity (LOH) leads to abnormal regulation of gene expression, leading to tumorigenesis through poorly understood mechanisms

Adult Cystic Nephroma • No underlying DICER1 mutation • Thought to be hormonally regulated: Tumors express ER/PR, occur primarily in women, and can be related to sex steroid use

CLINICAL ISSUES Epidemiology • Pediatric: Typically < 5 years of age ○ M:F = 2:1 • Adult: Typically presents in 6th decade of life (range: 4th to 8th decades) ○ M:F = 1:8 (including MEST)

Presentation • Can be incidentally detected or related to pain/hematuria • Pediatric: Extremely uncommon outside of DICER1 syndrome; identification triggers genetic testing for DICER1 mutation ○ Other manifestations of DICER1 syndrome: Pleuropulmonary blastoma (PPB), pituitary blastoma, ovarian stromal tumors, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma (cervix), ciliary body medulloepithelioma, multinodular goiter, and others

Prognosis • Pediatric: Usually benign; prognosis determined by presence of other lesions ○ High-risk lesions: PPB, pituitary blastoma, rare sarcomas arising from stroma of CN (DICER1 renal sarcoma) – Screening and surveillance aims to detect PPB before clinically advanced • Adult: Almost always benign; rare reports of "malignant MEST": Usually sarcomatous

MICROSCOPIC Histologic Features • Pediatric ○ Tumors surrounded by pseudocapsule ○ Multicystic with variability in size ○ Epithelial cells lining cyst are flat or cuboidal and often hobnailed ○ Septa with bland spindle cells, tend to be less cellular in comparison to adult CN/MEST • Adult ○ Spectrum of morphologic findings – Cystic end of spectrum: Similar to pediatric CN – MEST end of spectrum: More solid with more cellular ovarian stroma-like septa

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

ANCILLARY TESTS Immunohistochemistry • Stromal spindle cells are ER/PR(-) in pediatric CN and typically ER/PR(+) in adult CN/MEST

DIFFERENTIAL DIAGNOSIS Cystic Partially Differentiated Nephroblastoma • Contains some degree of more conventional nephroblastoma component (epithelial, blastemal, stromal)

Multilocular Cystic Renal Neoplasm of Low Malignant Potential • Clear cells lining cyst and clustered clear cells in septa • Cells are CAIX and CD10 positive

Tubulocystic Carcinoma • Cystic spaces lined by malignant cells with high-grade nuclear features • Stroma is typically desmoplastic

SELECTED REFERENCES 1. 2.

3.

4.

5.

6. 7.

Stewart DR et al: Neoplasm risk among individuals with a pathogenic germline variant in DICER1. J Clin Oncol. 37(8):668-76, 2019 Schultz KAP et al: DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res. 24(10):2251-61, 2018 Fernández-Martínez L et al: Identification of somatic and germ-line DICER1 mutations in pleuropulmonary blastoma, cystic nephroma and rhabdomyosarcoma tumors within a DICER1 syndrome pedigree. BMC Cancer. 17(1):146, 2017 Li Y et al: Pediatric cystic nephroma is morphologically, immunohistochemically, and genetically distinct from adult cystic nephroma. Am J Surg Pathol. 41(4):472-81, 2017 Fremerey J et al: Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome. Fam Cancer. 16(3):401-5, 2016 Mehraein Y et al: DICER1 syndrome can mimic different genetic tumor predispositions. Cancer Lett. 370(2):275-8, 2016 Doros LA et al: DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Mod Pathol. 27(9):1267-80, 2014

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Diagnoses Associated With Syndromes by Organ: Genitourinary

HLRCC Syndrome-Associated Renal Cell Carcinoma KEY FACTS

• Inactivating germline mutations in FH • Accumulation of fumarate leads to HIF-1 overexpression and tumorigenesis

○ Areas of tubulocystic architecture with poorly differentiated foci should raise suspicion for diagnosis ○ Other architectures include tubulopapillary, tubular, and solid ○ Papillae often intracystic • Hyalinized papillary cores • Eosinophilic cytoplasm with prominent "CMV viral-like" nucleoli and perinuclear halos

CLINICAL ISSUES

ANCILLARY TESTS

• Aggressive; patients often present with distant metastases • Risk of RCC in FH-mutated patients (penetrance) is ~ 2025% • Other manifestations of syndromes include multiple cutaneous and uterine leiomyomas, which often occur before development of RCC and have higher penetrance

• IHC: Loss of FH expression, nuclear and cytoplasmic expression of 2SC, CK7 negative or focal • Genetics: Germline mutation in FH

TERMINOLOGY • Subtype of RCC arising in patients with autosomal dominant HLRCC syndrome

ETIOLOGY/PATHOGENESIS

MICROSCOPIC • Mixed architecture usually with predominant papillary features

TOP DIFFERENTIAL DIAGNOSES • • • •

Papillary RCC type 2 Tubulocystic RCC Collecting duct carcinoma TFE3 translocation-associated RCC

Mixed Papillary and Tubulocystic Growth

Papillary Architecture

Tubulocystic Growth

Cellular Features

(Left) Low-power view shows mixed architecture including papillary ﬇ and tubulocystic ﬊ growth within the same tumor. The papillary growth often occurs within a cystic space, suggesting that the tubulopapillary architecture could be an early feature with secondary papillary growth within this space ﬉. (Right) Papillary architecture is commonly seen in RCCs associated with HLRCC syndrome. They have distinctly hyalinized cores ﬇ lined by high-grade tumor cells with prominent nucleoli ſt and mitotic activity ﬈.

(Left) Areas of tubulocystic growth are common, demonstrating enlarged cystic spaces lined by hobnailing tumor cells with the same high-grade cytologic features ﬉ seen in papillary areas. (Right) At high power, the characteristic cytologic features of HLRCC syndromeassociated RCC can be appreciated, including eosinophilic cytoplasm, prominent "CMV viral-like" nucleoli ſt and perinuclear halos ﬉. The nuclear features are more striking than would be expected for papillary RCC type 2.

296

HLRCC Syndrome-Associated Renal Cell Carcinoma

Abbreviations • Hereditary leiomyomatosis and renal cell cancer syndromeassociated renal cell carcinoma (HLRCC-associated RCC)

Definitions • Aggressive subtype of RCC arising in patients with autosomal dominant HLRCC syndrome • Germline mutations in fumarate hydratase (FH) gene • Characterized by tubulopapillary architecture and "CMV inclusion-like" nucleoli

ETIOLOGY/PATHOGENESIS Germline Mutations in FH • Located at 1q42.3-q43 ○ Inactivating mutations ○ Most frequently missense mutations • "2nd hit" is loss of remaining FH allele by somatic mutation, leading to tumorigenesis

Metabolomics and Tumorigenesis • FH converts fumarate to malate in Krebs (tricarboxylic acid) cycle • Loss of functional FH causes accumulation of fumarate • Increased fumarate causes inhibition of prolyl hydroxylase domain-mediated degradation of hypoxia inducible factor-1 (HIF-1) • Resulting overexpression of HIF-1 ○ Promotes tumorigenesis leading to manifestations of HLRCC syndrome

CLINICAL ISSUES Presentation • Most present in 4th-5th decades of life ○ But wide age range reported • Risk of RCC in FH-mutated patients (penetrance) is ~ 2025% • Usually unifocal/unilateral ○ Unlike most syndromic RCCs • Other manifestations of syndromes include multiple cutaneous and uterine leiomyomas ○ Much higher penetrance compared to RCC (75-100%) – Cutaneous leiomyoma is often 1st manifestation □ Provides opportunity to detect syndrome and associated RCC risk – Many patients have even had hysterectomy with leiomyomas prior to RCC development ○ Other uncommon associations of unknown causality – Leiomyosarcoma – Basal cell carcinoma – Melanoma – Adrenal adenoma – Breast tumors – Bladder tumors – Brain tumors – Thyroid tumors – Ovarian cystadenomas – Hematopoietic neoplasms

Treatment • No specific targeted therapies currently available • Early studies of combined bevacizumab plus erlotinib after failures of mTOR inhibitor and VEGFR inhibitor have been promising • Inhibition targeting HIF-1 and Krebs cycle components is under investigation

Prognosis • Aggressive behavior with poor outcomes ○ Often nodal or distant metastases at initial presentation • High index of suspicion in younger women with multiple uterine and cutaneous leiomyomas ○ Can lead to improved detection of syndrome and routine screening for development of RCC

MACROSCOPIC General Features • • • •

Solid to partially cystic tumors Occasionally infiltrative gross appearance Common involvement of medulla Primary kidney tumor may be small but presenting with metastatic disease

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

MICROSCOPIC Histologic Features • Mixed architecture patterns within same tumor ○ Papillary – Many tumors mimic type 2 papillary RCC □ Careful assessment is required to identify HLRCC syndrome-associated RCC without knowledge of syndromic features in patient – Often intracystic papillae ○ Tubulopapillary ○ Tubular ○ Solid ○ Tubulocystic – Tumors often associated with poorly differentiated solid areas – Tumors with pure tubulocystic architecture are likely to lack FH mutations □ Most classified as tubulocystic RCC • Infiltrative growth and stromal desmoplasia are common • Even small tumors frequently have advanced pathologic stage &/or present with nodal disease or distant metastases • Papillary and tubulopapillary tumors show prominent hyalinization of papillary cores ○ Similar to clear cell carcinoma in gynecologic tract • Tumors cells are large and typically have eosinophilic cytoplasm ○ Focal areas of clearing within tumor are occasionally present • Most characteristic feature is enlarged "CMV viral-like" nucleoli with perinuclear halo • Mitotic activity is often conspicuous • Absence of psammoma bodies typically seen in TFE3 translocation-associated RCC • Overall histologic spectrum still not known; may have lower grade histologies 297

Diagnoses Associated With Syndromes by Organ: Genitourinary

HLRCC Syndrome-Associated Renal Cell Carcinoma

ANCILLARY TESTS Immunohistochemistry • Complete or near-complete loss of FH expression in tumor cells ○ Loss of FH can be seen in RCCs lacking FH mutation ○ Improved sensitivity and specificity when combined with 2SC stain • Expression of cytoplasmic and nuclear S-(2-succino)cysteine (2SC) in tumor cells ○ Aberrant succination due to fumarate accumulation in tumor cells leads to overexpression of 2SC ○ More sensitive and specific for HLRCC syndrome than FH expression • Typically pax-8 positive • CK7 negative or focal (unlike PRCC), CK20 negative, CD10 negative • TFE3 negative (unlike translocation-associated RCC) • Mucicarmine stain negative (unlike collecting duct carcinoma)

Genetic Testing • Genetic testing of tumor &/or germline for FH mutation • Gold standard for definitive diagnosis of HLRCC syndrome • Recommended even if loss of FH expression by immunohistochemistry

DIFFERENTIAL DIAGNOSIS Papillary RCC Type 2 • Lack perinuclear halos and "CMV viral-like" nucleoli • Usually lack mixed architectural patterns such as tubulocystic, solid, etc. • Lack distinctly hyalinized papillary cores • Retained FH expression, no 2SC expression • No FH mutations

Tubulocystic RCC • Some RCCs originally diagnosed as tubulocystic RCC found to have FH mutations • True tubulocystic RCC typically lacks areas of other architectural patterns such as solid, papillary, tubulopapillary • Often enlarged nucleoli, but lack characteristic "CMV virallike" nucleoli with perinuclear halos • Retained FH expression, no 2SC expression • No FH mutations

Collecting Duct Carcinoma • More often centered on medulla • Varied architectural patterns can overlap with HLRCC syndrome-associated RCC • Prominent intratumoral inflammatory infiltrate • Presence of dysplastic collecting ducts • Mucicarmine stain demonstrates presence of mucin • Retained FH expression, no 2SC expression • No FH mutations

TFE3 Translocation-Associated RCC • Clear or granular eosinophilic cells with voluminous cytoplasm • Psammomatous calcifications 298

• Xp11 translocation and TFE3 expression • Retained FH expression, no 2SC expression • No FH mutations

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Mixed papillary, tubulopapillary, tubulocystic, and solid architecture with "CMV viral-like" nucleoli and perinuclear halos • FH loss, 2SC expression • FH mutation • Concomitant cutaneous or uterine smooth muscle tumors

Pathologic Interpretation Pearls • Features of type 2 papillary RCC with hyalinized cores and intracystic growth and exaggerated nucleoli, especially in younger woman, should prompt assessment for HLRCC • Tubulocystic growth with poorly differentiated foci should be investigated for loss of FH and 2SC overexpression • Multiple cutaneous or uterine leiomyomas in younger woman is suspicious for HLRCC and should prompt genetic testing for FH mutation

SELECTED REFERENCES 1.

Chan E et al: Detailed morphologic and immunohistochemical characterization of myomectomy and hysterectomy specimens from women with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). Am J Surg Pathol. 43(9):1170-9, 2019 2. Gupta S et al: Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol. 91:114-22, 2019 3. Pan X et al: Fumaratehydratase-deficient renal cell carcinoma: a clinicopathological and molecular study of 13 cases. J Clin Pathol. 72(11):748-54, 2019 4. Park I et al: Long-term response of metastatic hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cell carcinoma to bevacizumab plus erlotinib after temsirolimus and axitinib treatment failures. BMC Urol. 19(1):51, 2019 5. Pivovarcikova K et al: Fumarate hydratase deficient renal cell carcinoma: chromosomal numerical aberration analysis of 12 cases. Ann Diagn Pathol. 39:63-8, 2019 6. Rabban JT et al: Prospective detection of germline mutation of fumarate hydratase in women with uterine smooth muscle tumors using pathologybased screening to trigger genetic counseling for hereditary leiomyomatosis renal cell carcinoma syndrome: a 5-year single institutional experience. Am J Surg Pathol. 43(5):639-55, 2019 7. Xu Y et al: Pathologic oxidation of PTPN12 underlies ABL1 phosphorylation in hereditary leiomyomatosis and renal cell carcinoma. Cancer Res. 78(23):6539-48, 2018 8. Smith SC et al: A distinctive, low-grade oncocytic fumarate hydratasedeficient renal cell carcinoma, morphologically reminiscent of succinate dehydrogenase-deficient renal cell carcinoma. Histopathology. 71(1):42-52, 2017 9. Smith SC et al: Tubulocystic carcinoma of the kidney with poorly differentiated foci: a frequent morphologic pattern of fumarate hydratasedeficient renal cell carcinoma. Am J Surg Pathol. 40(11):1457-72, 2016 10. Trpkov K et al: Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol. 40(7):865-75, 2016 11. Chen YB et al: Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 38(5):627-37, 2014

HLRCC Syndrome-Associated Renal Cell Carcinoma

Solid Tubular and Papillary Growth (Left) At low power, these tumors typically demonstrate at least partial papillary architecture, often with hyalinized papillary cores ſt. These papillary projections often occur within a cystic space lined by high-grade tumor cells ﬉. Even from low power, the high-grade nuclear features of the tumor including very prominent nucleoli are evident. (Right) This area of tumor shows tubular growth of tumor cells ﬈ in addition to some vague papillary formation ſt. Mixed architectural feature are characteristic of this entity.

Hyalinized Broad Papillary Cores

Diagnoses Associated With Syndromes by Organ: Genitourinary

Papillary Architecture

Distinctive "CMV Viral-Like" Nucleoli (Left) Classic architectural appearance of RCC associated with HLRCC is shown. There is papillary architecture, and the papillary cores have prominent stromal hyalinization ſt, similar to clear cell carcinoma of the ovary. Nuclear pseudostratification may also be present. The nucleoli are conspicuous ﬈. (Right) The most characteristic feature of HLRCC syndrome-associated RCC is prominent "CMV virallike" nucleoli. The presence of elongated or oval-shaped (vs. dot-like) nucleoli ﬈ is suspicious for HLRCC.

Tubulocystic Architecture

Distinctive Nuclear Features (Left) Tubulocystic architecture is commonly identified as a component of HLRCC-associated RCCs. However, if the tumor is composed purely of tubulocystic architecture, it is unlikely to be associated with HLRCC and is best classified as tubulocystic RCC. (Right) At high power, areas with tubulocystic architecture demonstrate hobnailing of high-grade eosinophilic tumor cells with prominent "CMV viral-like" nucleoli ﬈. Cystic nephromas can have a similar architecture, but the cells are bland and often flatter.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Papillary Renal Cell Carcinoma KEY FACTS

TERMINOLOGY

• Worse prognosis suggested for PRCC type 2 vs. type 1

• Renal epithelial neoplasm predominantly exhibiting papillary or tubulopapillary architectures • Divided into papillary renal cell carcinoma (PRCC) types 1 and 2, which appear to be biologically distinct • PRCC type 2 likely does not constitute single entity; suggested use allows classification by morphology

MACROSCOPIC

ETIOLOGY/PATHOGENESIS

• Distinct papillary architectures with fibrovascular cores, usually with foamy histiocytes within stalk • Tubulopapillary pattern common; ~ 50% with tubules • PRCC type 1: Smaller cells with few or modest amphophilic or basophilic cytoplasm, usually with low-grade nuclei • PRCC type 2: Larger cells with abundant eosinophilic cytoplasm, usually with higher grade nuclei and cell stratification

• Vast majority of PRCCs are sporadic tumors • Majority of PRCCs show Chr +7, +17, and -Y • Hereditary PRCC syndrome is characterized by development of multiple PRCCs type 1 related to germline MET mutation

CLINICAL ISSUES • ~ 10-15% of renal tumors; 2nd most common type • 5-year survival rate is 82-90%; better than clear cell RCC but poorer than chromophobe RCC

• Well circumscribed with fibrous pseudocapsule • ~ 40% multifocal; highest for sporadic renal tumors • Hemorrhage is common

MICROSCOPIC

ANCILLARY TESTS • pax-2/pax-8(+), AMACR(+), CK7(+), and EMA(+)

Papillary Renal Cell Carcinoma Type 1

Papillary Renal Cell Carcinoma Type 2

Papillary Renal Cell Carcinoma

Papillary Renal Cell Carcinoma

(Left) PRCC type 1 shows papillae lined by small cuboidal cells with amphophilic cytoplasm and low-grade nuclei. Papillae can be hyalinized ﬈ but more often contain hemosiderinladen histiocytes. (Right) PRCC type 2 shows papillae lined by cells with abundant eosinophilic cytoplasm and nuclei with prominent nucleoli. Stratification is more common in type 2 ﬈, and cells usually have higher grade nuclei. Foamy histiocytes are common in papillary cores ﬉. Type 2 is suggested to be more aggressive than type 1.

(Left) PRCC shows a wellcircumscribed and welldelineated tumor with a solid, light-tan cut surface. Tumor may show pseudocapsule. Redbrown ſt and yellow discoloration from hemorrhages and histiocytic infiltrates, respectively, are common in PRCC. (Right) PRCC shows a variegated surface due to hemorrhage and necrosis. PRCC usually presents with tumor bilaterality and multifocality, and intervention with partial nephrectomy is suggested if tumor reaches 3 cm in size.

300

Papillary Renal Cell Carcinoma

Abbreviations

• Sarcomatoid change: Firm, white tan with infiltration

MICROSCOPIC

• Papillary renal cell carcinoma (PRCC)

Histologic Features

Definitions

• Distinct papillary architectures with fibrovascular cores, usually with foamy histiocytes within stalk • Tubulopapillary pattern common; ~ 50% with tubules • Tubules may have intratubular cell proliferation (glomeruloid pattern) • Tubular pattern may predominate and can be compacted ("solid variant") • Typing based on cell types ○ PRCC type 1: Smaller cells with few or modest amphophilic or basophilic cytoplasm, usually with lowgrade nuclei ○ PRCC type 2: Larger cells with abundant eosinophilic cytoplasm, usually with higher grade nuclei and cell stratification ○ PRCC mixed types 1 and 2: Mixture of cells seen in 2447% of cases • Psammomatous calcifications are occasionally present • Hemorrhages, hemosiderin pigment deposits, necrosis, and cystic change are occasionally present

• Renal epithelial neoplasm predominantly exhibiting papillary or tubulopapillary architectures • Divided into PRCC types 1 and 2, which appear to be biologically distinct ○ Type 1 associated with MET alterations ○ Type 2 likely does not constitute single entity; suggested use allows classification by morphology

ETIOLOGY/PATHOGENESIS Sporadic Papillary Renal Cell Carcinoma • Vast majority of PRCC are sporadic tumors • Majority show Chr +7, +17, and -Y

Hereditary Papillary Renal Cell Carcinoma Syndrome • Autosomal dominant; characterized by multiple type 1 PRCCs related to germline MET mutation • No associated extrarenal manifestations, unlike other renal tumor syndromes

Molecular Characteristics • PRCC type 1 with alterations in MET (33%), TERT (30%), CDKN2A/CDKN2B (13%), and EGFR (8%) • PRCC type 2 with alterations in CDKN2A/CDKN2B (18%), TERT (18%), NF2 (13%), and FH (13%) ○ Subset of PRCC type 2 with CIMP phenotype has poor survival and is associated with FH mutation

CLINICAL ISSUES

Grading • WHO/ISUP grading applicable

ANCILLARY TESTS Immunohistochemistry • AMACR(+), CK7(+), and EMA(+) • pax-8 or pax-2(+), and CD10 often with luminal (+)

DIFFERENTIAL DIAGNOSIS

Epidemiology

Mucinous Tubular and Spindle Cell Carcinoma

• ~ 10-15% of renal tumors; 2nd most common type • 22-83 years (mean: 62 years) • More common in men (M:F = 1.8:1.0)

• May resemble sarcomatoid PRCC type 1; also expresses AMACR, CK7, and EMA • Contains mucinous stroma; can be abundant • Spindle cells are low grade

Presentation • Majority of tumors detected incidentally (~ 50%) • Hematuria, flank pain, and abdominal mass

Treatment • Nephrectomy, partially preferred if tumor is < 4 cm and does not involve hilum

Prognosis • 5-year survival rate is 82-90%; better than clear cell RCC but poorer than chromophobe RCC • Worse prognosis suggested for PRCC type 2 vs. type 1

MACROSCOPIC

Collecting Duct Carcinoma • Multinodular and infiltrative, centered at medulla • High-grade cells (some hobnail), admixed invasive glands (adenocarcinoma), and desmoplasia

FH-Deficient Renal Cell Carcinoma • With intracystic papillae &/or large inclusion-like nucleoli • FH(-) and 2SC(+)

Metanephric Adenoma • Tumor cells have scant cytoplasm with uniformly low-grade nuclei (primitive-appearing cells) • WT1(+), CD57(+), and AMACR(-)

General Features

Clear Cell Papillary Renal Cell Carcinoma

• • • •

• Papillae lined by low-grade clear cells with nuclei aligned away from cell base • CK7(+), CAIX cup-like (+), and AMACR(-)

Well circumscribed with fibrous pseudocapsule Size range: 1.8-18.0 cm (mean: 6.7 cm) Multifocal in ~ 40%; highest for sporadic renal tumors Homogeneous tan to brown or variegated cut surface ○ Hemorrhage is common and produces red to dark brown discoloration ○ Collections of histiocytes cause yellowish streaks

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

SELECTED REFERENCES 1.

Akhtar M et al: Papillary renal cell carcinoma (PRCC): an update. Adv Anat Pathol. 26(2):124-32, 2019

301

Diagnoses Associated With Syndromes by Organ: Genitourinary

Papillary Renal Cell Carcinoma Papillary Renal Cell Carcinoma With Extensive Necrosis

Papillary Renal Cell Carcinoma Type 1

Papillary Renal Cell Carcinoma Type 1 Solid Growth

Papillary Renal Cell Carcinoma Type 2

Papillary Renal Cell Carcinoma Mixed Types 1 and 2

AMACR in Papillary Renal Cell Carcinoma

(Left) Gross photograph shows extensive tumor necrosis, which may occur in PRCC. In this case, examination of the peripheral aspect may reveal residual viable tumor cells. Likewise, imaging-guided needle core biopsy should also target the periphery. (Right) PRCC type 1 shows wellformed papillary structures, some with foamy histiocytes in the core. Type 1 usually shows a single layer of cells with lower grade nuclei. Grading is by WHO/ISUP criteria; in this case, the tumor is considered grade 2 (nucleoli prominent at 40x).

(Left) PRCC type 1 with predominant tubular growth imparts a solid appearance. Some tubules have a glomeruloid pattern ﬈ due to intratubular cellular proliferation. ~ 50% of PRCCs have tubular growth, and occasionally it is predominate, as in this tumor. Note the foamy histiocytes ﬉. (Right) High-power view of PRCC type 2 shows cells with larger nuclei and more prominent nucleoli than in type 1. PRCC type 2 exhibits relatively more frequent cellular stratification. Papillary cores are thin and contain histiocytes.

(Left) PRCC shows mixed small cuboidal cells (type 1) ﬈ and large eosinophilic cells (type 2) ﬉. Admixtures of these cells are encountered in ~ 1/4 of PRCCs. PRCC type 2 is considered to have worse prognosis than type 1. Behavior of mixed PRCC types 1 and 2 is unclear. (Right) PRCC shows strong diffuse cytoplasmic immunoreactivity to AMACR. This immunostain is expressed in > 95% of PRCC and helps to distinguish it from most other renal tumors with papillary growth. PRCC and papillary adenoma are positive with AMACR.

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Papillary Renal Cell Carcinoma DDx: Mucinous Tubular and Spindle Cell Carcinoma (Left) This PRCC type 1 shows sarcomatoid change characterized by formation of high-grade spindle cells ﬈ adjacent to a welldifferentiated area with papillary structures ﬊. (Right) Mucinous tubular and spindle cell carcinoma (MTSC) may mimic PRCC with sarcomatoid change and shows immunostaining overlap [both AMACR(+), CK7(+), and EMA(+)]. Unlike PRCC, MTSC exhibits stromal mucin ﬈ that can be abundant and lowgrade spindle cells ﬉. Papillary formation in MTSC is only focal.

DDx: Collecting Duct Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Papillary Renal Cell Carcinoma With Sarcomatoid Change

DDx: FH-Deficient Renal Cell Carcinoma (Left) Collecting duct carcinoma (CDC) may exhibit focal papillary growth and mimic PRCC. Unlike PRCC, CDC shows higher grade cells with hobnailing ﬉. Furthermore, CDC also exhibits an infiltrative gland component ﬈ in desmoplastic stroma. (Right) FH-deficient RCC often forms intracystic papillae mimicking PRCC. Unlike PRCC, this tumor is often infiltrative and may show distinctive inclusion-like nucleoli ﬈. FHdeficient RCC shows loss of FH and overexpression of 2SC. Most of these tumors were previously classified as PRCC.

DDx: Metanephric Adenoma

DDx: Clear Cell Papillary Renal Cell Carcinoma (Left) Metanephric adenoma shows papillary, tubulopapillary, and glomeruloid growth ﬈ similar to PRCC. However, tumor cells have minimal cytoplasm (resembling primitive metanephric cells) and intervening paucicellular stroma. (Right) Clear cell papillary RCC is characterized by papillae lined by clear cells with low-grade nuclei linearly placed away from the basal aspect of the cells ﬈. Cystic change is usual, and this tumor may occur in end-stage kidneys or sporadically.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Renal Oncocytoma, Chromophobe, and Hybrid Tumors KEY FACTS

TERMINOLOGY • RO: Benign renal epithelial neoplasm characterized by eosinophilic cells, uniform nuclei, and small nests • Renal oncocytosis: Kidney involved by innumerable oncocytic nodules • CHRCC: Renal epithelial neoplasm characterized by prominent cytoplasmic membrane, flocculent cells, perinuclear clearing, and koilocytoid nuclei • HOCT: Tumor with mixed RO and CHRCC cells

ETIOLOGY/PATHOGENESIS • BHD patients' renal tumors have higher proclivity for HOCT (50%), CHRCC (34%), and oncocytosis (58%)

CLINICAL ISSUES • BHD renal tumors: Younger (37-67 years; mean: 51) • RO: Benign tumor and CHRCC: > 90% 5-year survival

MACROSCOPIC • Multifocality/bilaterality common in familial tumors

• RO: Well circumscribed, mahogany brown, central scar in ~ 50% • CHRCC: Well circumscribed, central scar in ~ 20%; beige or light yellow (classic) or mahogany brown (eosinophilic)

MICROSCOPIC • RO: Small nests, tubulocystic with hyalinized stroma, and cells have eosinophilic granular cytoplasm, uniform nuclei, and occasional prominent nucleoli • CHRCC, classic type: Small/large solid nests and cells with pale cytoplasm, distinct cell membrane, perinuclear halo, binucleation, round to irregular (koilocytoid) nuclei with occasional large nucleoli • CHRCC, eosinophilic type: More dense, eosinophilic granular cytoplasm • CHRCC, mixed type: Mixed pale and eosinophilic cells; pale cells usually at periphery • HOCT: Mixture of RO-like and CHRCC-like cells/areas • RO and CHRCC: CD117(+) and ksp-cadherin (+)

Renal Oncocytoma

Classic Chromophobe RCC

Eosinophilic Chromophobe RCC

Hybrid Oncocytic/Chromophobe Tumor

(Left) RO shows small nested pattern of tumor cells with eosinophilic granular cytoplasm. The small nests at right are tightly packed ﬈, mimicking solid growth, which is not acceptable in RO. Tubular architecture is also focally present ﬉. (Right) Classic CHRCC shows large, solid, alveolar growth partly separated by incomplete vessels. Tumor cells at periphery usually have pale or flocculent cytoplasm ﬈, and those at central aspect have more eosinophilic cytoplasm ﬉. Note the distinctive nuclear features of CHRCC.

(Left) Eosinophilic CHRCC shows nested growth of tumor cells with eosinophilic cytoplasm. Even on low-power view, the distinctive nuclear features of CHRCC, such as perinuclear clearing and koilocytoid change, are noticeable. (Right) HOCT shows admixture of RO-like area (left) consisting of small nests of eosinophilic cells with low-grade nuclei ﬈ and CHRCC-like area (right) consisting of a more solid growth that includes cells with flocculent cytoplasm ﬉. The CHRCC-like area may show greater CK7 positivity.

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Renal Oncocytoma, Chromophobe, and Hybrid Tumors

Definitions • Renal oncocytoma (RO) ○ Benign renal epithelial neoplasm characterized by eosinophilic cells, uniform nuclei, and small nests • Renal oncocytosis ○ Kidney involved by innumerable oncocytic nodules • Chromophobe renal cell carcinoma (CHRCC) ○ Malignant renal epithelial neoplasm characterized by prominent cytoplasmic membrane, flocculent cells, perinuclear clearing, and koilocytoid nuclei • Hybrid oncocytic chromophobe tumor (HOCT) ○ Tumor with mixed RO and CHRCC cells

ETIOLOGY/PATHOGENESIS Sporadic Tumors • Vast majority of RO and CHRCC are sporadic • Cytogenetics ○ RO: Loss of Chr 1 and Y and 11q23 alteration ○ CHRCC: Multiple loss (Chr 1, 6, 10, 13, 17, 21 & Y) • Nonfamilial HOCT uncommon and oncocytosis rare

Birt-Hogg-Dubé Syndrome • Autosomal dominant characterized by tumors of hair follicles, pneumothorax, and renal tumors • Alteration of folliculin (FLCN) at Chr 17p11.2 • 15-30% develop renal tumors with higher proclivity for HOCT (50%), CHRCC (34%), and oncocytosis (58%)

Familial Oncocytomas • Chr 1 loss; has fewer chromosomal instabilities

CLINICAL ISSUES Epidemiology • Incidence ○ RO accounts for 6% of all renal tumors • Age ○ RO: 32-89 years (mean: 67); CHRCC: 27-82 (mean: 59) ○ BHD renal tumors affect younger patients: 37-67 years (mean: 51)

Presentation • Mostly incidental (66-83%)

Prognosis • RO: Benign tumor, no potential for metastasis • CHRCC: 5- and 10-year survival > 90%

MACROSCOPIC General Features • Familial tumors ↑ tendency for multifocality and bilaterality ○ BHD tumors are 73% multifocal, 62% are bilateral, and 57% have associated renal oncocytosis ○ Familial oncocytomas are 67% bilateral

RO • Well circumscribed, homogeneous, mahogany brown, with central scarring in ~ 50%; few may have focal perinephric fat extension (not sign of malignancy)

Oncocytosis • Dominant nodules range 2.0-10.5 cm, with multiple microscopic to small nodules • Gross features depend on type (RO, CHRCC, or HOCT)

CHRCC • • • •

Well circumscribed with central scarring in ~ 20% Classic type: Beige or light yellow Eosinophilic type: Mahogany brown (resemble RO) Sarcomatoid change: Firm, white-tan with infiltration

MICROSCOPIC Histologic Features • RO ○ Small nests, tubulocystic with hyalinized stroma ○ Large nests or diffuse pattern not permissible; "compact small nests" of RO may appear solid ○ Cells have eosinophilic granular cytoplasm, uniform nuclei and occasional prominent nucleoli ○ Some may have degenerate-appearing nuclei and smaller cells with less cytoplasm (oncoblasts) ○ Mitosis rare; high-grade nuclei not allowed • Oncocytosis ○ Dominant/larger tumors are RO, CHRCC, or HOCT ○ Smaller nodules from microscopic collections of few tumor cells to macroscopic visible lesions – Most have cells like RO, few like CHRCC or HOCT – May percolate between tubules and glomeruli as irregular, solid clusters or form tubules and cysts • CHRCC ○ Classic type – Small/large solid nests; rare microcysts or tubules – Cells with flocculent pale cytoplasm and distinct cytoplasmic membrane (plant cell-like) – Perinuclear halo; round to irregular wrinkled dark nuclei (koilocytoid) with occasional large nucleoli – Binucleation common; may have large, degenerative nuclei (like in RO) ○ Eosinophilic type – More dense eosinophilic granular cytoplasm ○ Mixed type (mixed pale and eosinophilic cells) – Pale cells usually at periphery of solid nests • HOCT ○ Mixture of RO-like and CHRCC-like cells/areas ○ RO-like with high-grade nuclei excluded (categorized as unclassified RCC)

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

ANCILLARY TESTS Immunohistochemistry • RO and CHRCC: CD117(+) and ksp-cadherin (+) • RO: CK7(-) or focal (+); classic CHRCC: CK7(+); eosinophilic CHRCC: CK7 focal (+)

Electron Microscopy • Abundant mitochondria; microvesicles in CHRCC

SELECTED REFERENCES 1.

Ruiz-Cordero R et al: Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma. Mod Pathol. ePub, 2019

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Renal Oncocytoma, Chromophobe, and Hybrid Tumors

Rneal Oncocytoma With Central Scar

Renal Oncocytoma Nests and Central Scar

Renal Oncocytoma Compact Nets

Renal Oncocytoma Nuclear Features

Renal Oncocytoma Degenerative Atypia

Renal Oncocytosis

(Left) Gross photograph of RO shows typical central scar, seen in ~ 50% of cases. This finding, however, is not specific and can be seen in ~ 20% of CHRCC, particularly in eosinophilic type. Both RO and eosinophilic CHRCC show mahogany brown appearance. (Right) RO shows central fibrosis and hyalinization surrounded by small nests of eosinophilic tumor cells. Eosinophilic CHRCC may also show small nested growth like in RO. Solid diffuse growth is not acceptable in RO but may occur in eosinophilic CHRCC.

(Left) RO shows small, tightly packed nests mimicking a "solid diffuse" growth. The small nests are occasionally surrounded by delicate vessels. Note the degree of nuclear monotony in this RO that is not typically seen in CHRCC. The vessels are less prominent than in clear cell RCC with eosinophilic cells, a key DDX. (Right) High-power view of RO shows predominance of lowgrade nuclei with regular nuclear membrane. Nuclear features of CHRCC, such as perinuclear clearing, koilocytoid nuclei, and binucleation, are not seen.

(Left) RO shows small foci of enlarged nuclei with smudgy chromatin ﬈, consistent with degenerative (symplastic) atypia. This change usually occurs in clusters or "clones" with abrupt transition to the more typical, low-grade nuclei of RO. Unlike in true highgrade nuclei, degenerative atypia has low Ki-67 staining and no mitosis. (Right) Lowpower view of kidney shows multiple small, oncocytic nodules ﬈, which are usually innumerable in renal oncocytosis. These nodules can be highlighted by CD117 or ksp-cadherin.

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Renal Oncocytoma, Chromophobe, and Hybrid Tumors

Classic Chromophobe RCC Architecture (Left) This bivalved kidney shows classic CHRCC in the renal sinus with a solid, biege cut surface. Eosinophilic CHRCC by contrast has a mahogany brown appearance, sometimes with central scar mimicking RO. (Right) Classic CHRCC shows cells with clearer cytoplasm arranged at the periphery of the large alveolar nests ﬈. Tumor cells have prominent cytoplasmic membrane imparting a "plant cell-like" or "cobblestone" appearance. Note the incomplete blood vessels separating the large nests.

Classic Chromophobe RCC Nuclear Features

Diagnoses Associated With Syndromes by Organ: Genitourinary

Classic Chromophobe RCC

Eosinophilic Chromophobe RCC Architecture (Left) High-power view shows characteristic nuclear features of CHRCC, including perinuclear clearing ﬈, irregular nuclear outline (koilocytoid or raisinoid nuclei) ﬉, and binucleation ﬊. Because of innate nuclear atypia, ISUP/WHO grading is not applicable for CHRCC. (Right) Eosinophilic CRCC with large nested to solid growth is shown. Note absence of "chicken wire" vasculatures seen in clear cell RCC with eosinophilic cells, a key DDx. Eosinophilic CHRCC are CD117(+) and CA9(-), in contrast to clear cell RCC.

Eosinophilic Chromophobe RCC Nuclear Features

Hybrid Oncocytic/Chromophobe Tumor (Left) Eosinophilic CHRCC shows characteristic nuclear features that are more often readily identifiable in classic CHRCC. These nuclear features distinguish eosinophilic CHRCC from RO, especially when it exhibits small nested growth. (Right) HOCT shows a CHRCC-like area (more solid growth of tumor cells with perinuclear clearing, binucleation ﬈, and prominent cytoplasmic membrane) and an RO-like area (small nested and tubulocytic growths of tumor cells with low-grade nuclei ﬈).

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma KEY FACTS

TERMINOLOGY

MICROSCOPIC

• Renal cell carcinoma (RCC) associated with germline mutations in succinate dehydrogenase (SDH) resulting in familial paraganglioma pheochromocytoma syndrome (PGL1-5)

• Nested or sheet-like architecture ○ Looks similar to oncocytoma from low power • Cytologic features ○ Flocculent eosinophilic cytoplasm ○ Most characteristic feature is presence of cytoplasmic inclusions – Most are pale eosinophilic inclusions – Sometimes clear/vacuolated inclusions – Present in most tumor cells – Important diagnostic feature because otherwise show significant overlap with oncocytoma, eosinophilic chromophobe RCC, and eosinophilic clear cell RCC ○ Most tumors show low-grade nuclear atypia – More atypia than expected for oncocytoma – Presence of high-grade atypia is associated with metastatic disease and aggressive clinical behavior

ETIOLOGY/PATHOGENESIS • Germline mutation in one of multiple SDH (SDHx) genes ○ SDHA (PGL5) ○ SDHB (PGL4, most common) ○ SDHC (PGL3) ○ SDHD (PGL1) ○ SDHAF2 (PGL2) ○ Autosomal dominant inheritance • Somatic mutation leads to loss of heterozygosity (LOH) ○ Results in loss of SDH function • SDH protein is integral part of Krebs cycle and electron transport chain • Mutation leads to impaired conversion of succinate to fumarate ○ Leads to accumulation of succinate ○ Causes overexpression of hypoxia inducible factor (HIF) ○ Development of reactive oxygen species ○ Subsequent tumorigenesis

CLINICAL ISSUES • < 0.1% of all RCCs • Typically develops in 4th decade of life ○ Development of RCC frequently preceded by extrarenal manifestations ○ Paragangliomas ○ Pheochromocytomas ○ Carotid body tumors ○ Gastrointestinal stromal tumors • RCC develops in only 15% of syndromic patients ○ Low rate compared to other syndromic RCCs ○ Highest risk with SDHB mutation • RCC metastases in 25-33% of patients

ANCILLARY TESTS • Loss of cytoplasmic SDHB &/or SDHA immunoexpression • CAIX(-), CD117(-), CD7(-), keratin (-)/weak

TOP DIFFERENTIAL DIAGNOSES • Oncocytoma ○ Lack cytoplasmic inclusions, CD117(+), retained SDHB expression, no SDH mutation • Eosinophilic chromophobe RCC ○ Lack cytoplasmic inclusions, CD117(+), CK7(+), retained SDHB expression, no SDH mutation • Eosinophilic clear cell RCC ○ Lack cytoplasmic inclusions, CAIX(+), retained SDHB expression, no SDH mutation • Hereditary leiomyomatosis and RCC-associated RCC (if high grade) ○ Lack cytoplasmic inclusions, have "CMV viral-like" nucleoli and perinuclear halos, retained SDHB expression, no SDH mutation, loss of FH expression, mutation in FH

Solid Nested Growth Pattern (Left) From low power, SDHdeficient RCCs demonstrate nested to sheet-like architecture. The cytoplasm is eosinophilic. From this power, the tumor bears resemblance to oncocytoma. (Courtesy S. Williamson, MD.) (Right) At high power, the characteristic features of SDH-deficient RCC are present. The tumor cells have flocculent eosinophilic cytoplasm with eosinophilic ſt and clear/vacuolated ﬈ cytoplasmic inclusions. Lowgrade nuclear atypia is present. (Courtesy S. Williamson, MD.)

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Characteristic Cytologic Features

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

Abbreviations • Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC)

Synonyms • Familial paraganglioma pheochromocytoma syndromeassociated RCC

Definitions • RCC associated with germline mutations in SDHx genes or SDHAF2 • Results in familial paraganglioma pheochromocytoma syndrome (PGL1-5)

ETIOLOGY/PATHOGENESIS Genetics • Germline mutation in one of multiple SDH (SDHx) genes or SDH assembly factor ○ Loss-of-function mutations – SDHA – SDHB □ Most common – SDHC – SDHD – SDHAF2 • "2nd hit" somatic mutation ○ Causes loss of heterozygosity (LOH) and absence of functional gene copy • Autosomal dominant inheritance

Metabolomics and Tumorigenesis • SDH is key component of Krebs cycle and electron transport chain • Catalyzes oxidation of succinate to fumarate in Krebs cycle • Donates electrons to electron transport chain to power creation of electrochemical proton gradient ○ Facilitates oxidative phosphylation • Functional mutations in SDH prevent conversion of succinate to fumarate • Accumulation of succinate ○ Impairs hydroxylation and leads to overexpression of hypoxia inducible factor (HIF) – Results in creation of reactive oxygen species ○ Subsequent overexpression of protumorigenic molecules leads to tumor growth

CLINICAL ISSUES Epidemiology • Incidence ○ < 0.1% of all RCCs ○ ~ 15% of patients with familial paraganglioma pheochromocytoma syndrome develop RCC – Lower penetrance than most hereditary renal tumors • Age ○ Frequently present in 4th decade of life (range: 2nd-8th decades) – Typically after development of paragangliomas/pheochromocytomas

Presentation • Variable penetrance leads to variable clinical presentations • Typically present at young age with extrarenal manifestations ○ Paragangliomas ○ Carotid body tumors ○ Pheochromocytomas ○ Gastrointestinal stromal tumors • Mostly unilateral renal mass ○ Bilateral renal masses in 25% • Risk of RCC is based on particular SDHx mutation present ○ High risk – SDHB ○ Intermediate risk – SDHD – SDHC ○ Low risk – SDHA • Some patients may present with metastatic RCC at time of diagnosis • Proper identification is important for screening of individual and family members

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

Prognosis • Metastatic disease occurs in 25-33% of cases, higher than originally believed ○ High-grade histologic features correlates with clinical aggressiveness

MACROSCOPIC General Features • Mean tumor size: 4-5 cm • Typically well-circumscribed tumors ○ Presence of infiltrative gross appearance correlates with high-grade cytologic features and aggressive clinical course • Brown cut surface ○ Occasional hemorrhagic or cystic changes

MICROSCOPIC Histologic Features • Well-circumscribed tumor edge in most cases • Tumors typically demonstrate sheets or nests of tumors cells ○ Cystic spaces occasionally present • Flocculent to granular eosinophilic cytoplasm ○ Mimics oncocytoma, eosinophilic chromophobe RCC, and eosinophilic clear cell RCC • Mast cells may be present within tumor, but this is nonspecific finding • Characteristic feature: Cytoplasmic inclusions ○ Very helpful feature – Other features are nonspecific and mimic common renal neoplasms ○ Represent engorged mitochondria – Due to mutation-related impairment of electron transport chain ○ Inclusions can vary in appearance – Pale eosinophilic 309

Diagnoses Associated With Syndromes by Organ: Genitourinary

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma – Clear/vacuolated ○ Typically involve majority of tumor cells ○ Rarely can be inconspicuous or absent • Nuclear features ○ Typically low grade, but small nucleoli can be identified ○ Still more atypia than expected for oncocytoma ○ Rare tumors demonstrate high nuclear grade with prominent nucleoli – Can raise possibility of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated RCC – Sarcomatoid or rhabdoid features and necrosis may be present in these tumors

ANCILLARY TESTS Immunohistochemistry • Loss of cytoplasmic SDHB immunohistochemical staining is excellent marker ○ High sensitivity and specificity for SDHB germline mutations ○ Mutations leading to loss of SDHB staining – SDHB – SDHC – SDHD – SDHAF2 ○ SDHB immunostaining is not consistently lost in SDHA germline mutations ○ SDHA germline mutations also show loss of cytoplasmic SDHA immunohistochemical staining – Retained SDHA staining in other SDH germline mutations • pax-8(+), CAIX(-), RCC(-), CD117(-), CK7(-), keratin(-)/focal

• • • • • •

Prominent "CMV viral-like" nucleoli and perinuclear halo Loss of FH expression 2SC expression SDHB retained Lack germline SDH mutation Demonstrates germline FH mutation

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Differential diagnosis of nested renal tumors with eosinophilic cytoplasm include oncocytoma, eosinophilic variant of chromophobe RCC, eosinophilic variant of clear cell RCC, and SDH-deficient RCC • Tumors with low-power appearance of oncocytoma, especially in young person, should be evaluated for possibility of SDH-deficient RCC • Important features to help screen cases with low-power appearance of oncocytoma ○ Nuclear atypia greater than expected for oncocytoma, but without characteristic features of chromophobe RCC ○ Presence of cytoplasmic inclusions

SELECTED REFERENCES 1.

2.

3. 4.

Molecular Testing

5.

• Germline mutation in one of SDH genes

6.

DIFFERENTIAL DIAGNOSIS Oncocytoma • • • • •

Lack cytoplasmic inclusions Typically lack low-grade nuclear atypia CD117(+) SDHB retained Lack germline SDH mutations by molecular testing

Chromophobe RCC, Eosinophilic Variant • • • •

Lack cytoplasmic inclusions CD117(+), CK7(+) SDHB retained Lack germline SDH mutations by molecular testing

7. 8.

9. 10.

11.

12.

13.

Clear Cell RCC, Eosinophilic Variant • • • • •

Lack cytoplasmic inclusions Rich vascular network CAIX(+) SDHB retained Lack germline SDH mutations by molecular testing

HLRCC-Associated RCC • Lack cytoplasmic inclusions • Typically mixed papillary, tubulopapillary, and tubulocystic architecture, although solid/nested areas can be present 310

14. 15. 16.

17.

Gupta S et al: Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol. 91:114-22, 2019 Oudijk L et al: The role of immunohistochemistry and molecular analysis of succinate dehydrogenase in the diagnosis of endocrine and non-endocrine tumors and related syndromes. Endocr Pathol. 30(1):64-73, 2019 Tsai TH et al: Succinate dehydrogenase-deficient renal cell carcinoma. Arch Pathol Lab Med. 143(5):643-7, 2019 Casey RT et al: Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility. JCO Precis Oncol. 2:112, 2018 Li Y et al: Re-evaluation of 33 "unclassified" eosinophilic renal cell carcinomas in young patients. Histopathology. 72(4):588-600, 2018 McEvoy CR et al: SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response. NPJ Precis Oncol. 2:9, 2018 Laukka T et al: Fumarate and succinate regulate expression of hypoxiainducible genes via TeT Enzymes. J Biol Chem. 291(8):4256-65, 2016 Evenepoel L et al: Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 17(8):61020, 2015 Hoekstra AS et al: Models of parent-of-origin tumorigenesis in hereditary paraganglioma. Semin Cell Dev Biol. 43:117-24, 2015 Kim E et al: Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 22(3):387-97, 2015 Williamson SR et al: Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod Pathol. 28(1):80-94, 2015 Gill AJ et al: Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 38(12):1588-602, 2014 Papathomas TG et al: Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis. Eur J Endocrinol. 170(1):1-12, 2014 Gill AJ: Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology. 44(4):285-92, 2012 Gill AJ et al: Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 35(10):1578-85, 2011 Ricketts CJ et al: Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 31(1):41-51, 2010 Ricketts C et al: Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 100(17):1260-2, 2008

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

Cells With Flocculent Cytoplasm (Left) A high index of suspicion is necessary to consider SDHdeficient RCC when evaluating an eosinophilic RCC with nested architecture. From low power, it bears resemblance to oncocytoma or eosinophilic clear cell RCC. (Courtesy S. Williamson, MD.) (Right) Unlike many oncocytomas with densely eosinophilic cytoplasm, SDH-deficient RCCs often have a granular, flocculent quality. The typical vessels seen in clear cell RCC are absent. Cytoplasmic inclusions are present ﬈. (Courtesy S. Williamson, MD.)

Characteristic Cellular Features

Diagnoses Associated With Syndromes by Organ: Genitourinary

Eosinophilic Cell Predominance

SDHB Immunostain (Left) The tumor demonstrates low-grade atypia that is greater than would be expected for oncocytoma. Cytoplasmic inclusions are characteristic and may be eosinophilic ﬈ or clear/vacuolated ſt. (Courtesy S. Williamson, MD.) (Right) SDHB immunostain shows loss of SDHB cytoplasmic expression by tumor cells. Surrounding normal tubules ﬊ and inflammatory cells show retained staining and act as an internal control. (Courtesy S. Williamson, MD.)

Renal Oncocytoma

Clear Cell RCC With Eosinophilic Cells (Left) Similar to SDH-deficient RCCs, oncocytomas show nested architecture and eosinophilic cytoplasm. However, oncocytomas do not have the characteristic cytoplasmic inclusions seen in SDH-deficient RCCs. (Right) Clear cell RCC frequently demonstrates nested architecture and can have eosinophilic cytoplasm, similar to SDH-deficient RCC. The characteristic cytoplasmic inclusions seen in SDHdeficient RCC are absent. Note the high-grade nuclear features ﬈ and prominent vasculature st.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Wilms Tumor KEY FACTS

TERMINOLOGY

CLINICAL ISSUES

• Malignant tumor of nephrogenic blastemal cell origin that recapitulates renal embryogenesis and may differentiate into epithelial or mesenchymal cells

• Most common renal tumor of pediatric age group, accounting for 95% of tumors • Peak incidence at 2-3 years of age • Clinical outcomes excellent for both COG and SIOP therapies with > 90% overall survival

ETIOLOGY/PATHOGENESIS • Genes altered in Wilms tumor (WT) include WT1, CTNNB1, WTX, IGF2, and TP53 • Mutations in WT1 occur in 15-20% of SWT • WT1 is considered not predisposition gene in most FWT families • WT cases grouped into ○ SWT, comprising 98-99% of cases ○ FWT, comprising 1-2% of cases ○ WT-associated syndromes, which include WT1associated and overgrowth syndromes

MICROSCOPIC • Classic histology of WT is triphasic pattern composed of undifferentiated blastemal cells, epithelial cells, and stromal cells • Diffuse anaplasia considered poor prognostic factor

ANCILLARY TESTS • WT1(+) in blastemal and epithelial but not stromal elements

Wilms Tumor, Organ Confined

Wilms Tumor, Non-Organ Confined

Wilms Tumor Triphasic Histology

Wilms Tumor Epithelial Component

(Left) Wilms tumor (WT) is often unicentric and encapsulated. The border is usually well demarcated from surrounding parenchyma and is circumscribed ﬈; irregular border may represent predominance of blastemal component ﬊. This WT is limited to kidney with intact renal capsule. (Right) WT shows yellow-tan soft cut surface. The tumor shows extension into the renal sinus tissue ſt but is completely resected consistent with stage II. Presence of residual tumor is considered as stage III.

(Left) H&E shows WT with classic triphasic histology consisting of undifferentiated blastemal cells ﬈, epithelial cells in the form of tubules ﬉, and stromal spindle cells ﬊. The proportion of these 3 components in the tumor may vary. (Right) This WT demonstrates predominantly epithelial differentiation in the form of tubules ﬈. Undifferentiated blastemal cells are also focally present between the tubular structures ﬊. The stroma is not prominent in this area of the tumor.

312

Wilms Tumor

Abbreviations • Wilms tumor (WT)

Synonyms • Nephroblastoma

Definitions • Malignant tumor of nephrogenic blastemal cell origin that recapitulates renal embryogenesis and may differentiate into epithelial or mesenchymal cells

ETIOLOGY/PATHOGENESIS Gene Alterations in WT • WT1 ○ Encodes 55 kDa zinc finger transcription factor located at Chr 11p13 containing 4 carboxy-terminal zinc finger domains that mediate DNA binding ○ Transcript plays important role in both early and late stages of genitourinary development ○ Mutations in WT1 common in sporadic WT and germline mutation consistently present in WT1-associated syndromes • IGF2 ○ Encodes embryonic growth factor located at Chr 11p15 ○ Aberrant inactivation of IGF2 due to loss of imprinting (LOI) in ~ 50% of WT ○ LOI found more often in perilobar nephrogenic rests (vs. WT1 mutations, which tend to be associated with intralobar nephrogenic rests) • CTNNB1 ○ Oncogene encoding β-catenin protein, which is located at Chr 3p21 ○ β-catenin is main effector in Wnt/β-catenin signaling pathway ○ Mutations in CTNNB1 are present in ~ 15% of WT and majority are 3 nucleotide deletions or missense mutations that delete or mutate Ser45 • WTX/FAM123B/AMER1 ○ Functions as tumor suppressor gene located at Chr Xq11.1; stabilizes β-catenin ○ Altered in 7-29% of WT, with most (~ 2/3) carrying deletion of entire WTX • TP53 ○ Tumor suppressor gene located at Chr 17p13.1 and is most frequently mutated gene in human cancers ○ ~ 5% of WT contain p53 missense mutation ○ Present in ~ 75% of diffusely anaplastic WT (AWT)

Loss of Heterozygosity in WT • Loss of heterozygosity (LOH) at Chr 1p and 16q are adverse prognostic factors in favorable histology WT (FHWT) ○ Presence in FHWT requires more aggressive chemotherapy ○ Current Children Oncology Group (COG) guideline recommends LOH studies for Chr 1p and 16q in FHWT

Other Significant Gene Abnormalities • Loss of Chr 4q and 14q specific for AWT • Gain of Chr 1q and MYCN, and loss of Chr 16q, common in both AWT and FHWT

Sporadic WT  • Mutations in WT1 occur in 15-20% of sporadic WT (SWT)

Familial WT  • WT1 is not the predisposition gene in most familial WT (FWT) families • FWT1 (WT4), FWT2, CTR9, BRCA2, REST, additional genes likely to exist

WT-Associated Syndromes • ↑ risk for WT in syndromic settings • WAGR syndrome: 30% chance of developing WT ○ Phenotype: Aniridia, ambiguous external genitalia (including cryptorchidism), and intellectual impairment ○ Denys-Drash syndrome: 90% chance of developing WT – Phenotype: Ambiguous genitalia, diffuse mesangial sclerosis, and genitourinary abnormalities in males – Caused by point mutation in zinc finger region of WT1 at Chr 11p13 ○ Frasier syndrome: Low risk of developing WT – Phenotype: Ambiguous genitalia, streak gonads, focal segmental glomerulosclerosis – Caused by point mutation in WT1 intron 9 donor splice site at Chr 11p13 ○ Caused by microdeletions at Chr 11p13 that encompass WT1 and PAX6 • Overgrowth syndromes (OGS) ○ Beckwith-Wiedemann syndrome: 8% chance of developing WT – Phenotype: Organomegaly, macrosomia, macroglossia, omphalocele, hemihypertrophy, ear anomalies, and neonatal hypoglycemia – Most caused by altered expression of imprinted genes (KCNQ1OT1, CDKN1C, LIT1 or H19, and IGF2) located at Chr 11p15.5 ○ Simpson-Golabi-Behmel syndrome: 9% chance of developing WT – Phenotype: Coarse facial features, skeletal and cardiac abnormalities, accessory nipples, and possible intellectual abnormalities – Majority (70%) caused by mutations or deletions of glypican-3 (GPC3) at Chr Xq26 ○ Isolated (idiopathic) hemihypertrophy: 3% chance of developing WT – Phenotype: Asymmetrical growth with one body part larger than contralateral counterpart – Abnormality in Chr 11p15 in 20-35% of cases ○ Perlman syndrome: 64% chance of developing WT – Deletions in DIS3L2, gene for RNA processing – Phenotype: Polyhydramnios, visceromegaly, facial dysmorphism, developmental delay, cryptorchidism, renal dysplasia, WT, and high infant mortality

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

CLINICAL ISSUES Epidemiology • Incidence ○ 5th most common pediatric malignancy accounting for 6% of all pediatric renal cancers – Incidence of ~ 7 per 1 million children < 16 years of age – ~ 650 new cases diagnosed per year in USA 313

Diagnoses Associated With Syndromes by Organ: Genitourinary

Wilms Tumor ○ Most common renal tumor of pediatric age group accounting for 95% of tumors ○ SWT comprises up to 98-99% of cases ○ FWT comprises 1-2% of cases ○ Syndrome diagnosis seen in up to 17% of WT patients and OGS seen in ~ 4% of WT patients • Age ○ Peak incidence at 2-3 years of age ○ ~ 75% occur in children < 5 years of age

Presentation • Most commonly asymptomatic abdominal mass detected by relatives • Other: Abdominal pain; hematuria (20-30%); hypertension from renin overactivity (25%) • Subcapsular hemorrhage of tumor may cause rapidly enlarging abdominal mass, anemia, pain, and fever

Treatment • Surgical approaches ○ Surgeon has to completely remove tumor without spillage and adequately assess extent of spread • Treatment approach differs for COG [includes National Wilms Tumor Study (NWTS)] followed mostly in USA, and Société Internationale d'Oncologie Pédiatrique (SIOP) followed mostly in Europe ○ COG advocates resection 1st, followed by further therapy depending on stage and histology (i.e., favorable or unfavorable) ○ SIOP advocate neoadjuvant therapy followed by resection, and further therapy depends on stage, histology, and treatment response

○ Often have myxoid background that resembles embryonic mesenchyme ○ Rarely, cartilage, bone, adipocytes, or neural elements • Anaplasia ○ Criteria for diagnosis (all 3 are nuclear features) – Markedly enlarged nuclei (at least 3x size of adjacent nuclei) – Nuclear hyperchromasia – Multipolar mitotic figure ○ Present in 5% of WT; more common in older children ○ Focal anaplasia – Well-defined; may be solitary or > 1 focus, but should be completely surrounded on all sides by nonanaplastic foci – Still considered favorable histology; not poor prognostic factor ○ Diffuse anaplasia – Presence of anaplasia above criteria for focal anaplasia – Defines unfavorable histology by COG; poor prognostic factor – Stage IA WT has 69% 10-year relapse-free survival vs. 91% for FWT – Correlates with p53 expression • Teratoid WT ○ Presence of extensive heterologous differentiation in WT, such as mucinous glands, cartilage, skeletal muscle • Tumor necrosis ○ Necrotic WT with < 1/3 viable area is considered completely necrotic; low-risk tumor (by SIOP)

ANCILLARY TESTS

Prognosis

Immunohistochemistry

• Clinical outcomes excellent for both COG and SIOP therapies with > 90% overall survival

• • • •

MACROSCOPIC General Features • Most are unilateral and unifocal tumors

WT1(+) in blastemal and epithelial but not stroma pax-8(+) Cytokeratin, CK7, and CD57(+) in epithelial components Desmin and CD56 may be positive in blastemal component

DIFFERENTIAL DIAGNOSIS Small Round Blue Cell Tumors

MICROSCOPIC Histologic Features • Classic histology is triphasic pattern of undifferentiated blastemal cells, epithelial cells, and stromal cells • Some WTs may have predominance of 2 or 1 components or may only have 2 (biphasic) or 1 (uniphasic) component • Blastemal cells ○ Tightly packed primitive cells with high nuclear:cytoplasmic ratio (round blue cells) ○ Grow in solid nests, often with infiltrative and serpiginous appearance ○ Nuclei with even chromatin and indistinct nucleoli ○ Mitotically active and may show nuclear molding • Epithelial components ○ Variable, includes solid or hollow primitive or mature tubules, glomeruloid structures, and papillae ○ Rarely, focal mucinous or squamous cells present • Stromal components ○ Spindle cells that are commonly nondescript or with fibroblastic, smooth muscle, or skeletal differentiation 314

• Pediatric tumors in this morphologic group may occur in or at vicinity of kidney ○ Neuroblastoma, rhabdomyosarcoma, acute lymphoblastic lymphoma, synovial sarcoma, and primitive neuroectodermal tumor (PNET) ○ Distinction can often be made with use of ancillary immunohistochemistry

Immature Teratoma • May resemble teratoid WT • More organoid structural differentiation (vs. haphazard elements in teratoid WT)

Metanephric Adenoma • Primitive cells with high nuclear:cytoplasmic ratio arranged in papillae, tubules, or glomeruloid structures • Positive for WT1, similar to WT • Unlike WT, nuclei are bland and mitosis is rare; more common in adults

Wilms Tumor

Stage

Tumor Extent

Findings

Frequency

I

Tumor limited to kidney and completely excised

Tumor confined to kidney

40-45%

Renal capsule is intact or tumor not ruptured No invasion of lymphatic or veins of renal sinus Resection margin free of tumor II

Tumor extends beyond kidney but completely excised

Tumor with regional or local extension

20%

Tumor penetrates capsule or perirenal tissue Tumor invades lymphatics or veins outside of kidney Resection margin free of tumor III

Residual nonhematogenous tumor confined to abdomen

Positive lymph node involvement

20-25%

Spillage from rupture before or during surgery Peritoneal implants

Diagnoses Associated With Syndromes by Organ: Genitourinary

WT Staging System (COG)

Gross residual tumor in abdomen Microscopic or gross positive resection margin Previous biopsy IV

Hematogenous metastasis

Tumor deposits beyond stage III (i.e., lungs, liver, brain, or bone or distant lymph nodes)

10%

V

Bilateral renal involvement

Each side substages separately [e.g., stage V, substage II (right), substage I (left)]

5%

Classification of WT After Neoadjuvant Therapy (SIOP) Risk Level

Tumor Histology

Low-risk tumors

Cystic partially differentiated WT; completely necrotic WT

Intermediate-risk tumors

WT, epithelial type; WT, stromal type; WT, mixed type; WT, regressive type; WT, focal anaplasia

High-risk tumors

WT, blastemal type; WT, diffuse anaplasia

Histological Criteria for WT Subtyping After Chemotherapy by SIOP Tumor Type

Chemotherapy-Induced Changes (%)

% Epithelium

% Stroma

% Blastema

Completely necrotic 100

0

0

0

Regressive

> 66

0-33

0-33

0-33

Mixed

< 66

0-65

0-65

0-65

Epithelial

< 66

66-100

0-33

0-10

Stromal

< 66

0-33

66-100

0-10

Blastemal

< 66

0-33

0-33

66-100

Papillary Renal Cell Carcinoma • Papillary and glomeruloid structures of type 1 tumors may resemble epithelial component of WT • AMACR(+), CK7(+), and WT1(-) unlike WT • More common in older patients (peak: 6th-7th decades)

Clear Cell Sarcoma of Kidney • Similar age group to WT and may resemble blastemalpredominant WT • Tumor cells with clearing and percolated by "chicken-wire" vasculatures • CD99(+) and WT1(-), unlike WT

SELECTED REFERENCES 1.

2.

3.

D'Hooghe E et al: "Teratoid" Wilms tumor: the extreme end of heterologous element differentiation, not a separate entity. Am J Surg Pathol. 43(11):1583-90, 2019 Mahamdallie S et al: Identification of new Wilms tumour predisposition genes: an exome sequencing study. Lancet Child Adolesc Health. 3(5):32231, 2019 Treger TD et al: The genetic changes of Wilms tumour. Nat Rev Nephrol. 15(4):240-51, 2019

315

Diagnoses Associated With Syndromes by Organ: Genitourinary

Wilms Tumor

Wilms Tumor Blastemal Component

Wilms Tumor Blastemal Component

Wilms Tumor Epithelial Component

Wilms Tumor Epithelial Component

Wilms Tumor Epithelial Component

Wilms Tumor Epithelial Component

(Left) Low-power view shows large nests of blastemal cells with a serpiginous pattern of growth. These are tightly packed, undifferentiated cells with high nuclear:cytoplasmic ratio. (Right) High-power view shows blastemal cells of WT. These cells typically have large overlapping nuclei, scant cytoplasm, and evenly distributed chromatin. These cells are mitotically active st. Blastemal cells of WT resemble other small round blue cell tumors that may occur in the kidney or extrarenal sites.

(Left) This WT demonstrates predominantly epithelial components in the form of compact tubular structures ſt. However, undifferentiated blastemal cells are present between the tubules ﬇. Epithelial predominant and mixed subtypes are considered intermediate risk (SIOP). (Right) H&E shows discrete, well-differentiated, hollow tubular epithelial structures in WT. Note the presence of abundant mitoses. Increased mitotic activity (excluding multipolar mitosis) is not considered a poor prognostic factor in WT.

(Left) H&E shows epithelial component of WT with rosette-like structures and solid tubulopapillary formations. These structures contain cells with relatively regular hyperchromatic nuclei. Anaplasia is usually not appreciated in the epithelial component of WT. (Right) WT shows the presence of primitive glomeruloid structures consisting of large tubules with intraluminal papillary growth ﬈. There is a background of spindle cells in myxoid stroma ﬊. An adjacent nest of blastemal cells ﬉ is present.

316

Wilms Tumor

Wilms Tumor Rhabdomyoblastic (Left) H&E shows stromal cells ﬈ and blastemal cells in WT ﬊. The stromal component is typically nondescript spindle cells, which lack significant atypia and are surrounded by a fibrous or somewhat myxoid matrix. Sometimes these cells exhibit smooth muscle or skeletal muscle differentiation. (Right) H&E shows WT with rhabdomyoblastic differentiation. The cells are focally spindled and some show dense eosinophilic cytoplasm with eccentric "rhabdoid" nuclei and frequent interspersed apoptotic cells.

Teratoid Wilms Tumor

Diagnoses Associated With Syndromes by Organ: Genitourinary

Wilms Tumor Stromal and Blastemal Cells

Teratoid Wilms Tumor (Left) H&E shows teratoid WT, which is composed of > 50% heterologous elements (tissue types not normally found in the kidney parenchyma). This example shows large nests of squamous epithelium ſt and smooth muscle stroma ﬇, along with blastemal ﬈ and epithelial tubular elements ﬊. (Right) At higher power, it is evident that the stroma is made up of smooth muscle cells in a typical whorled pattern and cigar-shaped nuclei, rather than the nondescript spindle cells typically seen in WT stroma.

Wilms Tumor Anaplasia

Wilms Tumor Anaplasia (Left) H&E shows WT with anaplasia, which is considered an unfavorable histology when diffusely present. Features of anaplasia include markedly enlarged ﬊ nuclei (3x in size compared to the rest of the tumor cells), hyperchromasia, and multipolar mitotic figures. (Right) Multipolar mitotic figures ﬈ are considered a pathognomonic feature of anaplasia in WT. Only diffuse, and not focal, anaplasia is used in guiding therapeutic decision-making in WT. (Courtesy S. Tickoo, MD.)

317

Diagnoses Associated With Syndromes by Organ: Genitourinary

Wilms Tumor

Wilms Tumor, Non-Organ Confined

Wilms Tumor Lymphovascular Invasion

Wilms Tumor With Capsular Rupture

Wilms Tumor Extensive Necrosis

WT1 in Wilms Tumor

pax-8 in Wilms Tumor

(Left) H&E shows WT involving the perinephric fat. This tumor is classified as stage II due to local extension of WT outside of the kidney with complete tumor resection (negative margin). (Right) H&E shows WT seen within a large vessel. Note that the tumor follows the vessel contour. Involvement of a vessel in the renal sinus in a completely resected WT results in this tumor being classified as stage II. Stage and histology after resection are important pathologic variables that dictate subsequent therapy of WT.

(Left) H&E shows WT with capsular rupture demonstrated by a tumor focus involving the inked capsule, which results in residual tumor in the abdomen. Tumor spillage of any degree before or during surgery is considered a stage III tumor. (Right) This WT shows abundant necrosis ﬈ characterized by the presence of tumor ghost cells (coagulative type necrosis). Note focal viable blastemal ﬉ and stromal cells ﬊. Completely necrotic WT after chemotherapy is considered a low-risk tumor (by SIOP).

(Left) WT1 shows diffuse nuclear positivity in WT. Blastemal and epithelial cells, but not the stromal cells, are usually positive for WT1. Beware that metanephric adenoma may also be positive for WT1, which is a potential diagnostic pitfall. (Right) pax-8 shows diffuse nuclear positivity in WT. pax-8 is a nephric-lineage transcription factor crucial for kidney organogenesis. Expression of this protein is helpful in distinguishing WT from other nonrenal tumor mimics, particularly most other small round blue cell tumors.

318

Wilms Tumor

Teratoma With Wilms Tumor (Left) H&E shows neuroblastoma with rosette formations, which have central neuropil surrounded by small round blue neuroblastic tumor cells (Homer Wright rosettes). This is in contrast to pseudorosettes, which have a central blood vessel. Neuroblastoma may exhibit cytoplasmic, but not nuclear, WT1 expression (unlike WT). (Right) Low-power view shows teratoma giving rise to WT ﬈. Adjacent to WT are welldifferentiated glands (including intestinal type glands ﬉), fat cells, and skeletal muscles ﬊.

Metanephric Adenoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Neuroblastoma

Renal Cell Carcinoma, Papillary Type 1 (Left) Metanephric adenoma shows tubulopapillary and glomeruloid growths of primitive-appearing cells with high nuclear:cytoplasmic ratio. Similar to WT, these tumor cells are positive for nuclear WT1. Unlike epithelialpredominant WT, the nuclei are more regular and lack mitotic figures. (Right) Papillary renal cell carcinoma type 1 shows papillae lined by cuboidal cells with amphophilic cytoplasm and low-grade nuclear atypia. These tumors occur mostly in adults and are racemase (+) and WT1(-).

Renal Cell Carcinoma, Papillary Type 1

Clear Cell Sarcoma (Left) H&E shows "solid" variant of papillary renal cell carcinoma type 1 consisting of diffuse glomeruloid growth and may resemble epithelialpredominant WT with primitive glomeruloid bodies. (Right) Clear cell sarcoma of the kidney may resemble the blastemal or stromal component of WT. It occurs in young children, like WT. Clear cell sarcoma typically shows polygonal tumor cells with cytoplasmic clearing and with presence of arborizing vasculature ﬈. Unlike WT, clear cell sarcoma is negative for nuclear WT1.

319

Diagnoses Associated With Syndromes by Organ: Genitourinary

Kidney Table Familial Renal Tumors Conditions

Gene(s)

Renal Tumors

von Hippel-Lindau syndrome

VHL

CCRCC, clear cell PRCC, and clear cell tumorlets and microcysts

Constitutional chromosome 3 translocation

Unknown; candidate genes: FHIT, RNF139, DIRC1, SLC49A4, DIRC3, HSPBAP1, LSAMP, RASSF5, KCNIP4, and FBXW7

CCRCC

Familial clear cell RCC

Unknown

CCRCC

BAP1 tumor syndrome

BAP1

CCRCC

Hereditary papillary RCC

MET

PRCC type 1

PTEN-hamartoma tumor syndrome

PTEN

PRCC, CCRCC, and chromophobe RCC

Papillary thyroid carcinoma with associated renal neoplasia

Unknown; candidate genes: NRAS and NTRK1

PRCC and papillary adenoma; possibly renal oncocytoma

Birt-Hogg-Dubé syndrome

FLCN or BHD

Hybrid oncocytic/chromophobe tumors, renal oncocytoma, renal oncocytosis, chromophobe RCC, and CCRCC

Familial oncocytoma

Unknown

Renal oncocytoma (association with renal oncocytosis or hybrid oncocytic/chromophobe tumors unknown)

Hereditary leiomyomatosis and renal cancer

FH

Hereditary leiomyomatosis and renal cancerassociated RCC, FH-deficient RCC

SDHB-associated hereditary paraganglioma/ pheochromocytoma

SDHA, SDHB, SDHC, SDHD, and SDHAF2 (SDH5)

SDH-deficient RCC

Tuberous sclerosis

TSC1 and TSC2

Angiomyolipoma, CCRCC, eosinophilic solid and cystic RCC, and benign epithelial cyst

Hereditary hyperparathyroidism-jaw tumor syndrome

CDC73 or HRPT2

PRCC, Wilms tumor, cortical adenoma, and benign epithelial cyst

Familial Wilms tumor

WT4, WT2, and at least 1 unknown gene

Wilms tumor

WT1-associated Wilms tumor (WAGR, DDS, and FS)

WT1

Wilms tumor

Overgrowth syndromes (BWS, SGBS, IHH, and PS)

BWS: Most caused by altered expression of Wilms tumor KCNQ1OT1 (LIT1), CDKN1C, or H19, and IGF2 and CDKN1C mutation; SGBS: GPC3; IHH: Subset with Chr 11p15 abnormality; PS: Unknown, but GPC3 suggested

BWS = Beckwith-Wiedemann syndrome; CCRCC = clear cell renal cell carcinoma; DDS = Denys-Drash syndrome; FS = Frasier syndrome; IHH = isolated hemihypertrophy; PRCC = papillary renal cell carcinoma; PS = Perlman syndrome; SDH = succinate dehydrogenase; SGBS = Simpson-Golabi-Behmel syndrome; WAGR = Wilms tumor, aniridia, genitourinary malformations, and intellectual disability syndrome.

Suggested Pathway for Genetic Referral in Suspected Hereditary Renal Cancer Refer for Genetic Testing Any Patient With Presence of malignant tumor with any characteristics below Bilateral Multifocal Age < 45 Any familial carcinomatosis Unusual histological type findings of nonclear cell RCC Any family history of VHL, BHD, TS, HLRCC, HPRCC, hereditary paraganglioma/pheochromocytoma Presence of benign or malignant tumor + 1 of following 1st- or 2nd-degree relative with renal tumor Early age of onset Bilateral or multifocal tumors Pneumothorax Special skin findings (leiomyomas, trichodiscomas, fibrofolliculomas)

320

Kidney Table

Refer for Genetic Testing Any Patient With Other associated tumors (pheochromocytoma, paraganglioma, epididymal cystadenoma) Hemangioblastoma of: Retina, cerebellum, brainstem, or spinal cord Early onset (< 30 years) of multiple uterine fibroids Lymphangiomatosis Childhood seizure disorder Any 1st-degree relative with 1 of above-mentioned findings No presence of tumor and Any family history of VHL, BHD, TS, HLRCC, HPRCC, hereditary paraganglioma/pheochromocytoma BHD = Birt-Hogg-Dubé; HLRCC = hereditary leiomyomatosis and renal cancer; HPRCC = hereditary papillary renal cell carcinoma; RCC = renal cell carcinoma; TS = tuberous sclerosis; VHL = von Hippel-Lindau. From Kallinikas et al. Int Urol Nephrol 2017;49:1507; Based on Canadian guideline on genetic screening for hereditary renal cell cancers and American Society of Clinical Oncology policy statement update.

Diagnoses Associated With Syndromes by Organ: Genitourinary

Suggested Pathway for Genetic Referral in Suspected Hereditary Renal Cancer (Continued)

Renal Tumors With Clear/Light-Staining Cytoplasm Antibody

Clear Cell RCC

Chromophobe RCC

MITF/TFE Family TranslocationAssociated Carcinoma

Clear Cell Papillary RCC

Epithelioid Angiomyolipoma

pax-2/pax-8

(+)

(+)

(+)

(+)

(-)

CA9

(+) (circumferential and diffuse)

(-)

(-) (some focal +)

(+) (basolateral and diffuse)

(-)

CK7

(-)

(+)

(-)

(+) (diffuse)

(-)

CD10

(+) (membranous)

(-) (rarely +)

(+) (but often - in TFEB carcinoma)

(-)

(-)

Vimentin

(+)

(-)

(-/+)

(+)

(-)

Ksp-cadherin

(-)

(+)

(-) (usually)

ND

(-)

CD117

(-)

(+) (diffuse)

(-)

(-)

(-)

AMACR

(-) (rarely focal +)

(-)

(+) (usually)

(-)

(-)

EMA/MUC1

(+)

(+)

(-) (rarely focal +)

(+)

(-)

AE1/AE3

(+)

(+)

(-) (rarely focal +)

(+)

(-)

TFE3/TFEB

(-)

(-)

(+)

(-)

(-)

cathepsin-K

(-)

(-)

(+) in TFEB carcinoma, (+) (-) in ~ 50% TFE3

(-)

Melan-A (MART-1), HMB-45, or MITF

(-)

(-)

(+) in TFEB carcinoma, rarely (+) in TFE3

(-)

(+)

Actin-sm

(-)

(-)

(-)

(-)

(+/-)

ND = no data; RCC = renal cell carcinoma.

Renal Tumors With Papillary or Tubulopapillary Architecture Antibody

Papillary RCC

Collecting Duct Carcinoma

Metanephric Adenoma

Mucinous Tubular and Spindle Cell Carcinoma

Clear Cell Papillary RCC

Hereditary Leiomyomatosis and Renal CancerAssociated RCC

CK7

(+)

(+)

(-/+)

(+)

(+)

(-)

CD10

(+) (often luminal pattern)

(-)

(-)

(-/+) (focal)

(-)

(+)

RCC

(+)

(-)

(-)

V

(-/+)

(-)

AMACR

(+)

(-)

(-/+)

(+)

(-)

(+)

WT1

(-)

(-)

(+)

(-)

(-)

(-)

321

Diagnoses Associated With Syndromes by Organ: Genitourinary

Kidney Table Renal Tumors With Papillary or Tubulopapillary Architecture (Continued) Antibody

Papillary RCC

Collecting Duct Carcinoma

Metanephric Adenoma

Mucinous Tubular and Spindle Cell Carcinoma

Clear Cell Papillary RCC

Hereditary Leiomyomatosis and Renal CancerAssociated RCC

34bE12 (HMWK)

(-)

(+/-)

(-)

(-/+)

(-)

(-)

SNF5 (INI1)

(+)

(+) (lost in renal medullary carcinoma)

(+)

(+)

(+)

(+)

CA9

(-) (+ perinecrotic areas and papillary tips)

(-/+) (perinecrotic area)

ND

ND

(+)

(-)

Epithelioid Angiomyolipoma

SDH-Deficient RCC

ND = no data; RCC = renal cell carcinoma; V = variable.

Renal Tumors With Granular/Eosinophilic Cytoplasm Antibody

Clear Cell RCC, Eosinophilic

Chromophobe RCC, Eosinophilic

Oncocytoma

MITF/TFE Family TranslocationAssociated Carcinoma

CA9

(+)

(-)

(-)

(-) (+ in some cases) (-)

(-)

Vimentin

(+/-)

(-)

(-)

(-/+)

(+)

(+/-)

CD117

(-)

(+)

(+)

(-)

(-)

(-)

pax-2/pax-8

(+)

(+/-)

(+)

V

(-)

(-)

TFE3/TFEB

(-)

(-)

(-)

(+)

(-)

(-)

Melan-A (MART-1), (-) HMB-45, or MITF

(-)

(-)

(+) in TFEB carcinoma, rarely (+) in TFE3

(+)

(-)

Actin-sm

(-)

(-)

(-)

(-)

(+/-)

(-)

SDHB

(+)

(+)

(+)

(+)

(+)

Complete loss

RCC = renal cell carcinoma; SDH = succinate dehydrogenase; V = variable.

8th AJCC Staging System pT Categories for Kidney Cancer Category

Definition

Primary Tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor ≤ 7 cm in greatest dimension, limited to kidney T1a T1b

T2

Tumor > 4 cm but ≤ 7 cm in greatest dimension, limited to kidney Tumor > 7 cm in greatest dimension, limited to kidney

T2a

Tumor > 7 cm but ≤ 10 cm in greatest dimension, limited to kidney

T2b

Tumor > 10 cm, limited to kidney

T3

T4

Tumor ≤ 4 cm in greatest dimension, limited to kidney

Tumor extends into major veins or perinephric tissues but not into ipsilateral adrenal gland and not beyond Gerota fascia T3a

Tumor extends into renal vein or its segmental branches, or invades pelvicalyceal system, or invades perirenal &/or renal sinus fat but not beyond Gerota fascia

T3b

Tumor grossly extends into vena cava below diaphragm

T3c

Tumor grossly extends into vena cava above diaphragm or invades wall of vena cava Tumor invades beyond Gerota fascia (including contiguous extension into ipsilateral adrenal gland)

Adapted from 8th edition AJCC Staging System, 2017.

322

Kidney Table

pT3 and pT4 Categories (Left) Renal cell tumors confined to the kidney and ≤ 7 cm in diameter are assigned category pT1 (up to 4 cm, pT1a; 4-7 cm, pT1b). Tumors > 7 cm and confined to the kidney are regarded as pT2. (Right) The size criterion does not apply to tumors with extrarenal extension. Tumors with renal sinus ﬈, perirenal fat ﬉, or renal vascular st invasion are all assigned stage pT3a. Tumors directly invading the adrenal ﬊ are considered pT4, and those with discontinuous adrenal invasion ﬇ are considered pM1.

Renal Sinus Invasion (pT3a)

Diagnoses Associated With Syndromes by Organ: Genitourinary

pT1 and pT2 Categories

Adrenal Gland Involvement (pT4 or pM1) (Left) Low-power view shows clear cell renal cell carcinoma (CCRCC) invading the renal sinus ﬈ (pT3a). Renal sinus invasion occurs more often via the sinus vessels or by direct infiltration of adipose tissue. Renal sinus should be routinely sampled in nephrectomy specimens to assess for invasion, which significantly upstages small tumors. (Right) This CCRCC involves the adrenal gland. Direct contiguous extension into the adrenal is considered pT4, whereas discontinuous involvement is regarded as metastasis (pM1).

Renal Cancer Extension to Adjacent Organs

Lung Metastasis (Left) Axial CECT shows a large, centrally necrotic mass ſt invading the posterior margin of the liver (T4). The mass completely engulfs the adrenal gland and has invaded the entire perirenal and pararenal spaces. The inferior vena cava ﬇ is not invaded but is displaced anteriorly. (Right) H&E of lung shows metastatic CCRCC. Diagnosis of metastatic CCRCC can often be made by morphology alone. In difficult cases, pax-8 or pax2 is helpful to confirm renal origin. Subtyping of metastatic RCC is important in systemic therapy.

323

Diagnoses Associated With Syndromes by Organ: Genitourinary

Kidney Table

pax-8 in Clear Cell Renal Cell Carcinoma

CA9 in Clear Cell Renal Cell Carcinoma With Eosinophilic Cells

AMACR in Papillary Renal Cell Carcinoma

CA9 in Clear Cell Papillary Renal Cell Carcinoma

CD117 in Chromophobe Renal Cell Carcinoma

CK7 in Eosinophilic Chromophobe Renal Cell Carcinoma

(Left) pax-8 shows diffuse nuclear immunoreactivity in this CCRCC. pax-8 is expressed by most RCC subtypes and is helpful in the metastatic setting. (Right) Needle core biopsy shows CA9 immunoreactivity in this CCRCC with eosinophilic cells. Diffuse CA9 immunoreactivity is helpful in distinguishing CCRCC from its mimics, such as eosinophilic chromophobe RCC and renal oncocytoma, which are usually negative. Clear cell PRCC also exhibits diffuse CA9 positivity but in a "cup-like" cell staining pattern.

(Left) AMACR shows strong diffuse positivity in this papillary RCC. Mucinous tubular and spindle cell carcinoma is diffusely AMACR positive. Other renal tumors with papillae, such as clear cell papillary RCC and collecting duct carcinoma, show absent AMACR staining. Some metanephric adenoma, however, may express AMACR. (Right) CA9 in clear cell PRCC shows diffuse positivity with basolateral or "cup-like" cell staining ﬈. CCRCC will also have diffuse CA9 positivity but in a circumferential cell pattern.

(Left) C-kit (CD117) is diffusely immunoreactive in this chromophobe RCC. Renal oncocytoma is also diffusely positive with C-kit and is not helpful to distinguish this tumor. CCRCC with eosinophilic cytoplasm, however, is typically negative with this marker. (Right) CK7 shows cytoplasmic positivity in some chromophobe RCC cells. CK7 staining in chromophobe RCC can be diffuse or focal; diffuse staining may help distinguish from renal oncocytoma, which usually shows scattered or absent staining.

324

Kidney Table

TFE3 in TFE3 Carcinoma (Left) CK-PAN shows scattered immunoreactivity in this translocation-associated RCC, where staining is often focal or absent. Lack of CK-PAN is helpful when translocationassociated RCC is suspected. CCRCC often shows diffuse staining with CK-PAN. (Right) TFE3 shows diffuse nuclear positivity in this translocationassociated carcinoma. However, specificity of this antibody is in question, and FISH confirmation may be necessary, especially in cases with atypical morphology and immunoprofile.

MART-1 in TFEB Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Pankeratin in TFE3 Carcinoma

GATA3 in Urothelial Carcinoma (Left) This TFEB carcinoma shows diffuse MART-1 staining. Other melanocytic markers, such HMB-45 and MITF, are often positive in this tumor and are helpful when distinguishing from CCRCC, where these are generally negative. (Right) GATA3 shows nuclear positivity in this renal urothelial carcinoma. In contrast, renal carcinomas are often GATA3 negative. Note GATA3 positivity in some collecting tubules ﬈. GATA3 is a good compliment for pax2/pax-8, which are positive in renal carcinoma.

WT1 in Wilms Tumor

MITF in Fat-Poor Angiomyolipoma (Left) WT1 shows diffuse nuclear reactivity in this Wilms tumor. WT1 immunoreactivity is usually seen in blastemal and epithelial components. Metanephric adenoma also exhibits nuclear WT1 positivity. (Right) This fat-poor angiomyolipoma shows diffuse nuclear positivity for MITF. Other melanocytic markers, such as MART-1 and HMB-45, are also expressed by this tumor, which helps confirm the diagnosis. Immunoreactivity is usually present in the spindle cell component.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Carcinoma KEY FACTS

TERMINOLOGY • Prostate carcinoma (PCa): Malignant neoplasm of acinar cell phenotype

ETIOLOGY/PATHOGENESIS • Hereditary: Genetic contribution in ~ 40-50% ○ Genes implicated in hereditary PCa include BRCA1, BRCA2, other DNA repair genes (ATM, CHEK2, RAD51, PALB2, BRIP1, and NBN), HOXB13, DNA MMR genes, and TP53 ○ HOXB13 associated with early-onset familial PCa and lifetime risk of ~ 33-60% • ~ 50% of PCa harbor TMPRSS2 and ETS fusion • SPOP alterations occur mutually exclusive of ETS rearrangements

MICROSCOPIC • Diagnosis based on constellation of architectural, nuclear, cytoplasmic, and intraluminal features

• Crowded uniform glands that infiltrate between preexisting benign glands ○ Small caliber, crowded clusters, rigid or "sharp" lumina, tinctorial staining of cytoplasm distinct from adjacent benign glands • Nuclear enlargement and hyperchromasia with prominently enlarged &/or multiple and peripherally located nucleoli • Luminal features, e.g., mucin, amorphous materials, and crystalloids • Less differentiated tumors have poorly formed, fused, or large cribriform glands • Negative for basal cell markers (e.g., HMWCK, CK5/6, p63); overexpresses AMACR

ANCILLARY TESTS • Prostatic lineage specific markers, such as PSA, PAP, NKX3.1, PSMA and p501S (prostein) helpful for diagnosis at metastatic sites

Gleason Grading System

Diagram shows modified Gleason grading for prostate carcinoma (PCa). The Gleason score (GS) is a powerful prognostic variable in predicting PCa behavior. This grading system is based purely on glandular architectural patterns, divided into 5 histologic categories or grades with decreasing differentiation. First developed in 1966 by Dr. Donald F. Gleason, it underwent refinements in 1974 and 1977 and had its latest modifications by ISUP in 2005 and 2014, and by ISUP and GUPS in 2019. This grading scheme is now universally accepted and recognized by WHO and AJCC. Recently, the GS has been compressed into the more clinically meaningful Grade Group (GG) system.

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Prostate Carcinoma

Abbreviations • Prostate carcinoma (PCa)

Synonyms • Prostatic adenocarcinoma

Definitions • Malignant neoplasm of acinar cell phenotype • ≥ 95% of PCa are acinar adenocarcinomas ○ Basis of epidemiologic, pathogenetic, and clinical features of PCa • < 5% of PCa include urothelial carcinoma, small-cell carcinoma, carcinoma with squamous differentiation, basal cell/adenoid cystic carcinoma, and sarcomatoid carcinoma

ETIOLOGY/PATHOGENESIS Molecular Genetics • TMPRSS2 and ETS fusion ○ ~ 50% of PCa harbor these recurrent gene fusions ○ ETS family of transcription factors include ERG, ETV1, ETV4, ETV5, and FLI1 ○ TMPRSS2-ERG fusion most common (~ 90%) – ERG brought under control of androgen-regulated promoter causing protein overexpression – In ~ 2/3 of cases, fusion results from deletion – Associated with blue-tinged mucin, cribriform pattern, intraductal spread, macronucleoli, and signet ring cells ○ Clinical significance not fully understood • PTEN mutation ○ 15-20% of PCa, more often in advanced stage ○ Loss results to ↑ activity of PI3K and upregulation of Akt/mTOR pathway • SPOP mutation ○ 5-15% of PCa ○ Unlike PTEN, alterations occur mutually exclusive of ETS rearrangements, suggesting different class of PCa • Other genes and molecular alterations ○ Other genes implicated in PCa include FOXA1, IDH1, TP53, MED12, CDKN1B, BRAF, HRAS, AKT1, CTNNB1, ATM, and NKX3-1 ○ Most common chromosomal alterations in prostate cancer are losses at 1p, 6q, 8p, 10q, 13q, 16q, and 18q, and gains at 1q, 2p, 7, 8q, and Xq

Hereditary Prostate Cancer • Genetic contribution in ~ 40-50% of PCa ○ 2x ↑ risk if 1 first-degree relative and 9x ↑ risk if 3 firstdegree relatives diagnosed with prostate cancer • Genes implicated in hereditary PCa ○ BRCA1, BRCA2, DNA repair genes (ATM, CHEK2, RAD51, PALB2, BRIP1, NBN), HOXB13, DNA MMR genes (MLH1, MSH2, MSH6, PMS2) and TP53 • Men with BRCA1/BRCA2 mutations carriers from family with hereditary breast and ovarian cancer syndrome (HBOC) have 5x relative risk for PCa • HOXB13 associated with early-onset (< 55 years) familial PCa and lifetime risk of ~ 33-60%

Risk Factors • Older age, black race, and positive family history well established • Others include red meat diet, obesity, metabolic disease, environmental factors (e.g., exposure to cadmium, pesticides, rubber, textiles, and chemicals), and vitamin D deficiency

CLINICAL ISSUES Epidemiology • Incidence ○ Most common cause of cancer morbidity and 2nd cause of cancer mortality in men in USA ○ Estimated 174,650 new cases of and 31,620 deaths from PCa in USA in 2019 • Age ○ PCa is disease of older men, and incidence increases dramatically with age ○ Incidence is remarkably low in men < 50 years old; ~ 60% of cases occur in men > 65 years old ○ Rate of diagnosis peaks in men 65-74 years old ○ Median age at diagnosis: 67 years old • Ethnicity ○ Incidence highest in higher resource areas, such as USA, Canada, Australia, New Zealand, Western Europe, Scandinavia, and Caribbean ○ In USA, blacks have highest incidence rates, which is ~ 60% higher than in whites – Rates are much lower in Asian Americans, Native Americans, and Alaska Natives ○ Mortality rate is also highest in black Americans (54.9 per 100,000 men) and lowest in Asian Americans and Pacific Islanders

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

Presentation • Majority of PCa in USA asymptomatic • Main indications for needle biopsy are elevated serum PSA level and abnormal digital rectal examination • When symptomatic, presents with obstructive urinary symptoms, pelvic pain from local extension, and bonerelated symptoms from metastasis

Natural History • Latent form of PCa extremely common; up to 80% of PCa in 9th decade ○ Gleason score (GS) 6 PCa unable to metastasize and rarely extends to extraprostatic tissue • Most PCa patients die from other causes, most commonly from cardiovascular disease

Prognosis • Dependent on stage and grade

MACROSCOPIC General Features • Unlike most other visceral organ tumors, PCa often has no reliably distinguishable gross mass lesion ○ Grossly evident tumors are usually pT3, ≥ GS 8, or ≥ 1 cm in size – Indurated, yellow to yellow-tan homogeneous areas 327

Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Carcinoma

328

– More dense or firmer than surrounding benign spongy parenchyma ○ Typically lack necrosis or hemorrhage • Tumors usually in posterior or posterolateral aspect [peripheral zone (PZ)] of gland

Site • 75-80% of PCas arise in PZ, and 15-25% arise in transition zone (TZ) • Multifocal tumors present in > 50% of PCa

MICROSCOPIC Histologic Features • Diagnosis based on constellation of architectural, nuclear, cytoplasmic, and intraluminal features ○ Some individual features may also be seen in benign glands • Architectural features ○ Better differentiated tumors consist of compact or loose collections of well-formed glands – Small, crowded, uniform glands infiltrate between preexisting benign glands ○ Malignant glands usually differ in appearance from surrounding benign glands – Smaller caliber glands, – Crowded or compact gland clusters – Rigid or "sharp" glandular lumina – May have periglandular clefts ○ Malignant glands should lack basal cells ○ Less differentiated tumors consist of poorly formed, fused, or large cribriform glands ○ Poorly differentiated tumors may grow as infiltrative single cells or solid sheets • Nuclear features ○ Nuclear enlargement and hyperchromasia ○ Prominently enlarged nucleoli ○ Single or multiple peripherally located nucleoli ○ Parachromatin clearing ○ Mitoses are rare; highly suggestive of malignancy if present ○ Apoptotic bodies (rare) ○ Nuclei commonly uniform, nonpleomorphic • Cytoplasmic features ○ Typically cuboidal to columnar cells with modest cytoplasm ○ Amphophilic, clear or pale, granular cytoplasm ○ Taller cells with clear to pale pink cytoplasm and basally located nuclei more common in TZ • Intraluminal features ○ Blue mucin – Usually prominent collection of wispy, blue-tinged intracellular mucin ○ Eosinophilic amorphous secretions – Granular eosinophilic luminal material ○ Crystalloids – Geometric bright eosinophilic rhomboid to prismatic structures with sharp edges, usually associated with eosinophilic amorphous secretions – Present in up to 41% of PCa

– Seen in atypical adenomatous hyperplasia and uncommonly in benign glands ○ Corpora amylacea are extremely rare in PCa, should strongly suggest benign glands ○ Intraluminal necrosis may be present in high-grade tumors, highly indicative of malignancy • Pathognomonic features for malignant glands ○ Glomerulations ○ Collagenous micronodules (mucinous fibroplasia) – Hyalinized eosinophilic material usually associated with abundant intraluminal blue mucin ○ Circumferential perineural invasion – Gland should completely surround nerve – Benign glands may focally touch or indent nerve; very rarely may be intraneural ○ Growth within adipose tissue – Intraprostatic fat is exceedingly rare – Indicates extraprostatic extension (EPE)

Morphologic Variants and Variations • Ductal adenocarcinoma ○ Large glandular and papillary architecture lined by tall, columnar cells, often with pseudostratified growth ○ Often occurs admixed with acinar adenocarcinoma; requires > 80% ductal component for diagnosis ○ Graded as Gleason grade 4; if necrosis present, grade 5 • Atrophic variant ○ PCa with glands lined by cells with scant cytoplasm, resembling atrophy ○ Infiltrative growth, cytology of malignancy ○ In contrast, benign atrophic glands typically have dense, hyperchromatic nuclei and lobular growth • Pseudohyperplastic variant ○ Large or dilated glands with branching and papillary infolding, resembling hyperplasia ○ Tall, columnar cells with abundant pale to slightly granular cytoplasm and basally located nuclei ○ Commonly with luminal eosinophilic amorphous secretions and may have crystalloids ○ Diagnostic malignant nuclear features retained, in contrast to benign hyperplastic glands • Foamy gland (xanthomatous) ○ PCa with abundant foamy cytoplasm ○ Malignant nuclear features not always present, as nuclei may be small and pyknotic ○ Presence of infiltrative pattern; may require immunostains • Mucinous (colloid) ○ ≥ 25% of resected tumor shows extracellular mucin ○ Intraluminal mucinous material does not qualify, and extraprostatic origin must be excluded • Signet ring cell ○ ≥ 25% of resected tumor shows signet ring cells (arbitrary definition) ○ Tumor cells contain optically clear vacuoles displacing nuclei and are widely infiltrative ○ May be mucin-producing PCa (mucinous carcinoma with signet ring cells) • Microcystic ○ Cystically dilated glands with rounded contour and flat cell lining

Prostate Carcinoma

Key Elements to Report • GS ○ Provide % of Gleason pattern 4 in GS 7 PCa in biopsy • Tumor quantity ○ Number of cores involved over total biopsy cores ○ Provide tumor % in biopsy ○ Provide length of tumor in mm in biopsy • Perineural invasion • EPE • Margin status • Lymphovascular invasion • Seminal vesicle invasion • In biopsy with no cancer ○ Atypical small acinar proliferation (ASAP) ○ High-grade prostatic intraepithelial neoplasia [multifocal (in > 2 cores)] remains indication for rebiopsy)

ANCILLARY TESTS Immunohistochemistry • PCa should have no basal cells ○ Absent staining for basal cell markers HMWCK, CK5/6, or p63 • Overexpress AMACR, in contrast to benign glands • Prostatic lineage specific marker such as PSA, PAP, NKX3.1, PSMA, and p501S (prostein) helpful for diagnosis at metastatic sites

DIFFERENTIAL DIAGNOSIS General Features • Given broad morphologic spectrum, differential diagnosis for PCa ranges from innocuous benign normal structures to secondary high-grade cancers • PCa most often mimicked by benign prostatic glandular lesions; difficulty enhanced in limited samples (e.g., biopsy) ○ Use of ancillary immunohistochemistry helpful in some scenarios

○ Pattern-based approach facilitates work-up and judicious selection of adjuvant stains

GRADING Gleason Grading System • Assessment of gland architecture at low/intermediate magnification: Classified into 5 basic grades • In resection specimens, GS is sum of primary and secondary Gleason grades ○ Primary grade is most prevalent grade and secondary is 2nd most common grade • International Society of Urological Pathology (ISUP) consensus conference proposed several modifications and guidelines ○ In needle biopsies, include tertiary pattern in GS if higher than secondary grade – In high-grade cancers, ignore lower grade if < 5% (e.g., 4 + 4, if pattern 3 is < 5%) – For cancers with > 1 grade, include higher grade even if < 5% (e.g., 3 + 4, even if grade 4 is < 5%) ○ Assign individual GS to all cores as aggregate if submitted in 1 container; assign GS to each core separately designated (e.g., ink or separately submitted) by urologist ○ In radical prostatectomy, provide GS (primary and secondary grades); separately mention tertiary grade – If tertiary grade 5 is > 5%, should be considered as secondary grade ○ Assign separate GS to dominant tumor(s) for multifocal tumors in radical prostatectomy ○ Individualized Gleason grading approach for some PCa morphologic variants and subtypes • Gleason patterns 1 and 2 ○ Using strict criteria, exceedingly rare, and use is almost completely abandoned in current practice – Most described pre-IHC were likely atypical adenomatous hyperplasia • Gleason pattern 3 ○ Most common pattern ○ Predominantly well-formed, individual glands that infiltrate between benign ducts and acini ○ Includes small (microacini) or large but well-formed glands and branched glands • Gleason pattern 4 ○ Most commonly fused and poorly formed glands – Tangentially sectioned grade 3 glands may mimic fused pattern 4 glands ○ Cribriform considered to have higher risk among pattern 4 ○ Glomeruloid recently added and hypernephromatoid no longer used • Gleason pattern 5 ○ Lacks glandular differentiation: Manifests as solid sheets, cords, or single infiltrative tumor cells ○ Also includes solid or cribriform with central comedotype necrosis, small solid cylinders, and solid medium to large nests with rosette-like spaces

Diagnoses Associated With Syndromes by Organ: Genitourinary

○ Mixed pseudohyperplastic and atrophic features • Pleomorphic giant cell ○ Aggressive, undifferentiated variant characterized by bizarre, anaplastic, and giant tumor cells • PCa with Paneth cell-like differentiation ○ PCa containing neuroendocrine cells with bright eosinophilic cytoplasmic granules resembling Paneth cells of gastrointestinal tract • Other rarer variations ○ Cystadenocarcinoma – Cystic PCa that can be massively enlarged (giant multilocular cystadenocarcinoma) with florid intracystic papillae, ductal morphology, and markedly elevated PSA level in cyst fluid ○ Lymphoepithelioma-like – As in other organs, characterized by syncytial growth amid dense, lymphocytic background ○ PCa with stratified epithelium (PIN-like) – Glands lined by ≥ 2 layers of malignant cells ○ Oncocytic – PCa with abundant granular eosinophilic cytoplasm, and ultrastructurally contains abundant mitochondria

Grade Group System • GS converted into clinically meaningful groups (GG 1-5) 329

Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Carcinoma Differential Diagnosis for Prostate Carcinoma Histologic Pattern

Prostate Carcinoma

Main Differential Diagnoses

Small glandular proliferation

Gleason pattern 3

Crowded benign glands

Atrophic carcinoma variant

Simple atrophy

Posttreatment cancer

Outpouching of high-grade PIN Partial atrophy Postatrophic hyperplasia (PAH) Atypical adenomatous hyperplasia (AAH, adenosis) Sclerosing adenosis Basal cell hyperplasia Seminal vesicle epithelium Ejaculatory duct Cowper glands Mesonephric remnants Nephrogenic adenoma Verumontanum mucosal gland hyperplasia Radiation atypia

Large glandular proliferation

Cribriform Gleason patterns 4 and 5

High-grade PIN

Ductal adenocarcinoma

Urothelial carcinoma involving prostatic ducts and acini

Pseudohyperplastic carcinoma variant

Colorectal carcinoma involving prostate

Intraductal carcinoma

Cribriform hyperplasia Squamous metaplasia Urothelial metaplasia

Infiltrative single cell pattern

Single cell Gleason pattern 5

Dense inflammation

Signet ring cell carcinoma variant

Granulomatous prostatitis

Posttreatment carcinoma

Lymphoma Small-cell carcinoma

Clear cell pattern

Foamy gland carcinoma variant

Prostatic xanthoma

Hypernephromatoid carcinoma Oncocytic pattern

Gleason pattern 4

Paraganglion/paraganglioma

Oncocytic carcinoma variant

Carcinoid tumor

Poorly to undifferentiated carcinoma

Solid Gleason pattern 5

Urothelial carcinoma

Spindle cell pattern

Sarcomatoid carcinoma

Pseudosarcomatous myofibroblastic proliferation Stromal sarcoma Leiomyosarcoma

Small cell pattern

Small-cell carcinoma

Lymphoma Rhabdomyosarcoma

• GG 1 (GS 6), GG 2 (GS 3 + 4 = 7), GG 3 (GS 4 + 3 = 7), GG 4 (GS 8), and GG5 (GS 9-10) ○ Advantage is lowest baseline grade is now 1 and not 6; facilitates counseling in active surveillance • In RP, PSA BCR hazard ratio relative to GG 1 of 1.9, 5.1, 8.0, and 11.7 for GG 2, GG 3, GG 4, and GG 5, respectively

SELECTED REFERENCES 1.

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Paner GP et al: Essential updates in grading, morphotyping, reporting, and staging of prostate carcinoma for general surgical pathologists. Arch Pathol Lab Med. 143(5):550-64, 2019

2.

3.

4. 5.

Epstein JI et al: Contemporary Gleason grading of prostatic carcinoma: an update with discussion on practical issues to implement the 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 41(4):e1-7, 2017 Epstein JI et al: The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 40(2):244-52, 2016 Cancer Genome Atlas Research Network.: The molecular taxonomy of primary prostate cancer. Cell. 163(4):1011-25, 2015 Paner GP et al: Best practice in diagnostic immunohistochemistry: prostate carcinoma and its mimics in needle core biopsies. Arch Pathol Lab Med. 132(9):1388-96, 2008

Prostate Carcinoma

Prostate Carcinoma in Peripheral Zone (Left) Transverse section of prostate shows multifocal PCa predominantly involving the left lobe with a dominant nodule ﬇ at the posterolateral aspect and additional smaller tumor foci ﬉ at the lateral aspect of the peripheral zone. (Right) Transverse section of prostate shows the urethra ſt pushed to the left due to prominent hyperplasia ﬉. The peripheral zone shows evidence of prominent atrophy ﬊ and a carcinoma ﬈ involving the posterolateral aspect.

Nuclear Features

Diagnoses Associated With Syndromes by Organ: Genitourinary

Multifocal Prostate Carcinoma

Nuclear and Cytoplasmic Features (Left) Prominent nucleoli, as seen here, are characteristic of PCa, but they are not always required for the diagnosis. In addition, nuclei larger than the adjacent nuclei of benign glands, and those with double nucleoli and with parachromatin clearing or mitosis, are helpful features. (Right) PCa shows pale granular cytoplasm and monotonous-appearing round nuclei. PCa nuclei are typically homogeneous. Nuclear pleomorphism should suggest the possibility of a nonprostatic lesion.

Nuclear and Intraluminal Features

Nuclear Features (Left) PCa glands commonly show parachromatin clearing in the malignant nuclei. These nuclei also show a mild degree of nuclear variability and crowding not typically seen in PCa. PCa nuclei are usually very round and monotonous. Two carcinoma glands contain intraluminal mucin ﬈. These glands are graded GS 3 + 3 = 6. (Right) PCa shows readily identifiable mitotic figures ﬈ within the malignant glands. Mitotic figures are very rare in PCa; however, their presence is highly suggestive of adenocarcinoma.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Carcinoma

Intraluminal Features

Intraluminal Features

Intraluminal Features

Pathognomonic Features

Pathognomonic Features

Pathognomonic Features

(Left) H&E shows PCa glands with multiple bright eosinophilic crystalloids in the lumina. The nuclei of these glands are enlarged with prominent nucleoli that are occasionally multiple and peripheral ﬉. Crystalloids are common, but not specific, in PCa. (Right) PCa glands contain eosinophilic amorphous secretions in the lumen. Focal crystalloids ﬉ may be seen admixed with the eosinophilic secretions. Presence of these features warrants close examination of the harboring glands.

(Left) PCa glands contain blue mucin in the lumen. Sometimes these mucin may be thin and wispy and may not be easily discernible on scanning magnification. (Right) Collagenous micronodules (mucinous fibroplasia) is a pathognomonic feature of PCa. Early collagenous micronodules consist mostly of mucin with scant fibrous tissue and, with time, the fibrous deposits predominate. Despite the glands assuming a complex architecture, these are typically assigned as GS 3 + 3 = 6.

(Left) H&E shows PCa with glomerulations characterized by intraluminal proliferation of cells that form a cribriform structure attached to 1 pole of the gland. Recent data suggests that glomerulations should be regarded as Gleason grade 4. (Right) Biopsy shows only PCa focus completely surrounding a nerve. Complete circumferential perineural invasion is a pathognomonic feature of PCa. Benign glands can be seen adjacent to a nerve and may resemble partial perineural invasion. Intraneural invasion may rarely occur in benign glands.

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Prostate Carcinoma

Gleason Pattern 3 (Left) This GS 3 + 3 = 6 PCa consists of a circumscribed nodule of slightly irregular medium and large glands (formerly Gleason grade 2, now grade 3) ﬉ and focally infiltrating glands (Gleason grade 3) ﬈. (Right) Lowpower view shows GS 3 + 3 = 6 PCa glands infiltrating between benign glands ﬉. PCa glands are smaller, haphazardly arranged, have different cytoplasmic tincture, and some have rigid lumina ﬈. A well-formed gland should have a complete circumference of cells showing central lumina.

Gleason Pattern 3

Diagnoses Associated With Syndromes by Organ: Genitourinary

Gleason Pattern 3

Gleason Pattern 3 (Left) These GS 3 + 3 = 6 PCa glands have large nuclei and prominent nucleoli that can be multiple and peripheral. Nuclei of benign glands ﬉ are smaller, and the glands have > 1 layer of cells. (Right) H&E shows GS 3 + 3 = 6 PCa composed of individual infiltrating glands and microacini ﬉. One has to take into account that not all lumina may be visible on 1 plane of section. Tangentially sectioned glands (vs. illformed glands) are suggested by being few in number and scattered in between wellformed glands.

Gleason Pattern 3

Gleason Pattern 3 (Left) This GS 3 + 3 = 6 PCa shows periacini retraction spaces, which is a helpful diagnostic feature. The somewhat linear alignment of the PCa glands is also a helpful hint. These PCa glands consist of columnar cells with basally oriented nuclei. PCa nuclei are relatively homogeneous and very rarely exhibit marked pleomorphism. (Right) High-power view of GS 3 + 3 = 6 PCa shows glands with corpora amylacea. These concretions, while common in benign glands, are rare in PCa.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Carcinoma

Gleason Pattern 4

Gleason Pattern 4

Gleason Pattern 4

Gleason Pattern 4

Gleason Pattern 5

Gleason Pattern 5

(Left) High-power view of Gleason grade 4 PCa shows illdefined glands formed by aggregates of tumor cells that are unable to form a complete circumference and central lumina. (Right) These Gleason grade 4 PCa cribriform glands are larger, and central lumina are compartmentalized by multiple cellular bridges. Cribriform PCa glands can be medium or large with an expansile, elongated, or branching shape. Most experts now assign Gleason grade 4 to any cribriform PCa gland that lacks necrosis.

(Left) This GS 4 + 4 = 8 PCa consists of multiple fused glands. Some lumina are separated by a single layer of cellular bridge ﬉ that cannot be traced as an exclusive part of 1 gland. In contrast, tightly packed Gleason grade 3 glands can be individually outlined. (Right) H&E shows Gleason grade 4 PCa consisting of solid growth of cells with clear to foamy cytoplasm that resembles clear cell RCC. The nuclei are often small and dark with inconspicuous nucleoli. The term hypernephromatoid is no longer used.

(Left) H&E shows Gleason grade 5 PCa consisting of cords and single infiltrative tumor cells. These high-grade PCa cells may resemble chronic inflammatory cells. Note that some of the cells exhibit vacuolation ﬉. (Right) This large cribriform PCa gland contains luminal necrosis, and grading is bumped to Gleason grade 5. The lumen should unequivocally demonstrate necrotic tumor ghost cells ﬉. Luminal eosinophilic secretions and inflammatory debris can be mistaken for tumor cell necrosis.

334

Prostate Carcinoma

Gleason Pattern 5 (Left) This Gleason grade 5 PCa gland shows comedonecrosis. The central lumen contains abundant necrotic tumor cells. (Right) This Gleason grade 5 PCa shows solid growth of poorly differentiated cells. This morphology should be distinguished from a poorly differentiated urothelial carcinoma. Morphologic distinction can be very difficult and often necessitates use of immunostains. Beware that poorly differentiated PCa may exhibit weak or absent PSA expression in up to 13% of cases.

HMWCK in PCa

Diagnoses Associated With Syndromes by Organ: Genitourinary

Gleason Pattern 5

AMACR, p63, and HMWCK in PCa (Left) HMWCK shows lack of staining in PCa glands. All atypical glands in a suspicious focus should have complete absence of basal cell staining. Adjacent benign gland shows HMWCK staining of the basal cells ﬉. (Right) This cocktail of AMACR (red) and basal cell markers p63 and HMWCK (brown) shows AMACR overexpression and complete absence of basal cell marker immunoreactivity in PCa glands ﬉. Benign glands in contrast show intact basal cells ﬈ and no AMACR overexpression.

Intraductal Carcinoma

Intraductal Carcinoma (Left) H&E shows intraductal carcinoma consisting of large, expansile cribriform structures that are composed of cells with large nuclei and prominent nucleoli and have an intact basal cell layer ﬉. (Right) Antibody cocktail of AMACR (red) and basal cell markers p63 and HMWCK (brown) shows AMACR overexpression and basal cell marker staining. Intraductal carcinoma more often coexists with invasive glands ﬉ and is considered to be a process succedent to PCa invasion.

335

Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Carcinoma

Ductal Adenocarcinoma Variant

Pseudohyperplastic Carcinoma Variant

Atrophic Carcinoma Variant

Foamy Gland Carcinoma Variant

Mucinous Carcinoma Variant

Prostate Carcinoma With Paneth Cell-Like Differentiation

(Left) Ductal adenocarcinoma shows papillae lined by tall, columnar cells with pale cytoplasm and elongated nuclei exhibiting pseudostratification. Presence of tall, columnar cell is a distinguishing feature. (Right) Pseudohyperplastic PCa shows medium to large dilated glands with papillary infolding, eosinophilic secretions, and few crystalloids ﬈. The cells have abundant cytoplasm, and nuclei are usually aligned basally. This variant architecturally resembles benign hyperplasia.

(Left) Atrophic PCa shows acini lined by cells with attenuated cytoplasm. Features indicative of malignancy include malignant nuclear features (e.g., nucleomegaly, prominent nucleoli), nonlobular growth, luminal features of malignancy, and admixed typical PCa morphology. (Right) Foamy gland PCa shows cells with abundant xanthomatous cytoplasm and small to eosinophilic luminal secretions. Typical malignant nuclear features may not be present, making recognition as PCa difficult.

(Left) Mucinous (colloid) carcinoma is characterized by malignant cells floating in abundant extracellular mucin. This is distinct from the intraluminal mucin seen in more typical forms of PCa. When seen pure in biopsy, confirmation of prostatic origin by immunohistochemistry is necessary. (Right) PCa with Paneth cell-like differentiation shows occasional neuroendocrine cells ﬈ with bright eosinophilic cytoplasmic granules resembling Paneth cells of the gastrointestinal tract.

336

Prostate Carcinoma

DDx: Atrophy (Left) H&E shows partial atrophy with relatively ample amount of pale to clear cytoplasm. In contrast to PCa, these glands are somewhat more lobular, more irregular, and lack nuclear and luminal features of malignancy. (Right) Simple atrophy shows nuclear crowding from loss of cytoplasmic volume. Unlike typical PCa, these atrophic glands are more irregular and angulated. Unlike atrophic PCa, these atrophic glands lack the nuclear and luminal features of malignancy.

DDx: Adenosis

Diagnoses Associated With Syndromes by Organ: Genitourinary

DDx: Partial Atrophy

DDx: Adenosis (Left) Low-power view of adenosis or atypical adenomatous hyperplasia (AAH) shows relatively wellcircumscribed proliferation of variably sized acini. The glands at the central aspect are usually larger than in the periphery. (Right) Intraluminal proteinaceous material and crystalloids may occasionally be seen in AAH. Presence of both of these features in atypical glands compounds the diagnostic difficulty vs. PCa. Immunohistochemistry confirms presence of basal cells in AAH vs. PCa that can be focal or patchy.

DDx: Postatrophic Hyperplasia

DDx: Nephrogenic Adenoma (Left) PAH encountered in needle biopsy is shown. PAH is one of the main differential diagnoses for ASAP in needle biopsy. Diagnosis is relatively less challenging if the entire architecture is appreciated, as in this case. (Right) Nephrogenic adenoma from the prostatic urethra may be sampled in needle biopsy, and its tubules ﬈ may mimic PCa. Distinction is confounded by the similar positivity for AMACR. Attention to single layer of hobnail cells at the surface ﬉ similar to those in tubules is helpful.

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Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Table Significance of Normal Histoanatomic Structures in Prostate Pathology Structures

Remarks

Peripheral zone (PZ)

Most common origin for prostate carcinoma (70-75%) Most susceptible to inflammation and most common to undergo atrophy Uncommon site for benign prostatic hyperplasia (BPH)

Transition zone (TZ)

Most common site for BPH and its myriad morphologic patterns Common site for adenosis (atypical adenomatous hyperplasia) Less commonly, site of origin of prostate carcinoma (15-20%), which tends to be lower grade

Central zone (CZ)

Relatively resistant to prostate carcinoma and inflammation CZ glands mimic glands of BPH and prostatic intraepithelial neoplasia (PIN)

Periurethral gland region Possible origin of uncommon pure primary urothelial carcinoma of prostate Corpora amylacea

Common in benign prostate glands and rarely seen in carcinoma

Intraluminal crystalloids

Common in prostate carcinoma but may also be seen in benign glands Presence in benign glands not risk factor for subsequent diagnosis of prostate carcinoma

Lipofuscin pigment

Not exclusive for seminal vesicle and ejaculatory duct epithelium and may also be seen uncommonly in benign and malignant prostate glands

Striated muscles in anterior fibromuscular stroma (AFS) and apical region

Benign glands may be seen admixed with striated muscles and thus are not necessarily invasive or malignant feature

Adenocarcinoma involving striated muscles at these sites does not constitute extraprostatic extension (EPE) Prostate capsule

Although not true capsule, serves as histoanatomic boundary for organ-confined prostate cancer Absent in base and not clearly defined in apex, complicating interpretation of EPE at these sites

Nerve

Perineural glands not exclusively associated with carcinoma, unless glands completely circle or are present within nerve One of pathways for EPE by carcinoma

Prostatic urethra (PU)

May give rise to urothelial carcinoma (common), squamous carcinoma, adenocarcinoma of prostate, and primary carcinoma of urethra Florid nephrogenic adenoma from this site may extend to prostate and mimic prostate carcinoma Urothelial carcinoma of PU invading prostate may occur in patients with bladder urothelial carcinoma and should not be staged as pT4 bladder cancer

Verumontanum

May undergo florid glandular hyperplasia, which may be confused with prostate carcinoma

Seminal vesicle (SV)

Rare site for primary malignancy Secondary involvement by prostate carcinoma relatively more common and denotes higher tumor stage (pT3b) Pseudomalignant features of epithelium may be confused with malignancy in limited sample

Ejaculatory duct (ED)

Involvement by cancer in needle biopsy should not be confused as SV involvement, which denotes higher tumor stage Pseudomalignant features of epithelium may be confused with malignancy in limited sample Distinction from SV is based on absence of distinct smooth muscle wall

Cowper gland

Resembles minor salivary gland tissue; may mimic low-grade prostate carcinoma

Periprostatic adipose tissue

Involvement by prostate carcinoma constitutes EPE, including needle biopsy specimens May be absent over large areas of prostatic surface in prostatectomy specimen, making evaluation of EPE difficult

Paraganglia

May mimic prostate carcinoma with hypernephroid features Involvement by carcinoma not always equivalent to EPE, since it may be present rarely within prostate

Important Immunohistochemical Stains in Diagnosis of Prostate Carcinoma

338

Immunostain

Rationale

Basal cell-associated markers HMWCK (34bE12), CK5/6, p63, basal cell cocktail

Benign vs. malignant proliferation; complete absence of basal cell layer is defining criterion for invasive prostate carcinoma

Prostate carcinoma-associated marker AMACR (p504S)

Benign vs. malignant proliferation; absence of basal cell-associated markers favors invasive prostate carcinoma

Prostate Table

Immunostain

Rationale

Epithelial lineage PAN-CK(AE1/AE3)

Identification of subtle infiltrating cells in posttreatment setting; in differential diagnosis of carcinoma vs. nonepithelial process or malignancy

Prostate lineage-specific marker PSA, PAP, PSMA, NKX3.1, p501S (prostein)

Prostatic vs. nonprostatic origin, e.g., Cowper gland, mesonephric remnant, nephrogenic adenoma, seminal vesicle vs. prostate cancer or for use in metastatic setting

Benign Mimics of Prostate Carcinoma in Needle Biopsy Antibody

Seminal Vesicle Ejaculatory Duct

Cowper Gland

Mesonephric Remnants

Verumontanum Hyperplasia

Nephrogenic Adenoma

PSA/PAP

-/+

-/+

-

+/-

-/+

Basal cell marker

+ (basal cell)

+

-/+

+ (basal cell)

-/+

AMACR

-/NS

-

-

-

+/-

NS = nonspecific, frequently marks pigment. Mesonephric remnants are also positive for CD10, calretinin, and vimentin.

Diagnoses Associated With Syndromes by Organ: Genitourinary

Important Immunohistochemical Stains in Diagnosis of Prostate Carcinoma (Continued)

Atypical Small Glandular Proliferations in Needle Biopsy Antibody

Benign Glands

Postatrophic Hyperplasia and Atrophy

Prostatic Adenocarcinoma

Basal Cell Hyperplasia

Outpouching of High-Grade PIN

AAH (Adenosis)

Basal cell+ associated markers

+ (patchy)

-

+

+

+/- (patchy)

AMACR

-/+

+ (strong circumferential)

-

+

-/+

-/+ (rare)

AAH = atypical adenomatous hyperplasia; PIN = prostatic intraepithelial neoplasia.

8th AJCC Staging System for Prostate Cancer Stage

Definition

Primary Tumor (pT)* pT2

Organ confined

pT3

Extraprostatic extension

pT3a

Extraprostatic extension (unilateral or bilateral) or microscopic invasion of bladder neck

pT3b pT4

Tumor invades seminal vesicle(s) Tumor is fixed or invades adjacent structures other than seminal vesicles, such as external sphincter, rectum, bladder, levator muscles, &/or pelvic wall

Regional Lymph Nodes (pN) pN0

No positive regional lymph nodes

pN1

Metastasis in regional lymph node(s)

Distant Metastasis (M) M0

No distant metastasis

M1

Distant metastasis

   M1a

Nonregional lymph nodes(s)

   M1b

Bone(s)

   M1c

Other site(s) ± bone disease

*Radical prostatectomy does not have a pT1 category.

339

Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Table

Histoanatomic Zones of Prostate

McNeal's Model for Zones of Prostate

Zones of Prostate at Verumontanum

Prostate "Capsule"

Benign Prostatic Acini

Prostatic Duct

(Left) Prostatic urethra (PU) is divided into proximal PU and distal PU by a mid angulation at the verumontanum where the ED exits ﬇. TZ (blue) and CZ (magenta) encase proximal PU and ED, respectively. PZ (transparent) surrounds CZ and distal PU posteriorly. Nonglandular AFS (yellow) is situated anteriorly. (Right) McNeal's model uses the PU as a key anatomic landmark and divides the prostate glandular component into PZ (green), CZ (orange), TZ (blue), and PUGR (white). The AFS (yellow) comprises the midanterior portion.

(Left) Coronal section of the prostate at the verumontanum ﬇ shows the peripheral zone ﬊ extending from posterior aspect st, surrounding part of transition zone ﬉, and abutting the AFS ſt. The central urethra is enveloped by the transition zone. (Right) The prostate "capsule" ﬈ is not a true capsule but a condensation of fibromuscular tissue that is an inseparable component of the prostatic stroma. Periprostatic adipose tissues and nerves are present. Involvement of adipose tissue by prostatic carcinoma constitutes EPE.

(Left) Typical benign acini show columnar secretory cells with pale cytoplasm and round, regular, basally oriented nuclei with indistinct nucleoli. Basal cells ﬈ are situated internal to glandular basement membrane outline and contain scant cytoplasm. (Right) The lining of the prostatic duct ﬈ is similar to that of adjacent acini. On cross section, ducts and acini are not reliably distinguished unless the longitudinal dimension of the duct is appreciated. Proximal prostatic ducts often show urothelial cells in lining ﬉.

340

Prostate Table

pT2 Prostate Cancer (Left) Graphic shows examples of incidental T1 prostate carcinoma divided into T1a, < 5% tumor in tissue resected (TURP) ſt; T1b, > 5% tumor in tissue resected (TURP) st; and T1c, tumor identified by needle biopsy (e.g., because of elevated PSA) ﬇. If unsuspected prostate carcinoma is identified in tissue submitted and is < 5%, then remainder of tissue should be submitted for histologic evaluation. (Right) pT2 shows organ-confined tumor involving both lobes of the prostate. In 8th AJCC, pT2 is no longer subcategorized.

pT3a Prostate Cancer

Diagnoses Associated With Syndromes by Organ: Genitourinary

cT1 Prostate Cancer in TURP and Biopsy

Extraprostatic Extension With Fat (Left) EPE ﬇ by prostate carcinoma indicates pT3 disease. Detection of EPE is most reliably made by histologic examination. DRE and radiographic studies are not sensitive in detecting EPE. (Right) EPE with tumor extension into periprostatic fat is shown, which is the most objective evidence for EPE. Intraprostatic fat is vanishingly rare; thus, fat involvement by prostate carcinoma is considered diagnostic for EPE. EPE most commonly occurs at the posterior and posterolateral aspects of prostate.

Extraprostatic Extension Without Fat

Lymph Node Metastasis by Prostate Cancer (Left) Low-power view shows high-grade (grade group 5) prostate cancer involving the neurovascular bundle (NVB) area, where fat may not be present ﬈. Experts recommend that tumor involvement of soft tissue within NVB should be considered as EPE. (Right) Lymph node shows metastatic prostate carcinoma (pN1). The metastatic tumor exhibits hint of acini formation and, with nucleomegaly, are helpful morphologic clues in distinguishing from metastatic urothelial carcinomas.

341

Diagnoses Associated With Syndromes by Organ: Genitourinary

Prostate Table Patterns of Seminal Vesicle Involvement by Prostate Cancer (pT3b)

Seminal Vesical Invasion and EPE

pT4 Prostate Cancer

Rectum With Prostate Cancer

Bone and Lymph Node Metastasis by Prostate Cancer

Bone Metastasis by Prostate Cancer

(Left) Mechanisms of SV involvement by prostate cancer include spread via (a) ejaculatory duct tissue into SV (green), (b) direct extra- (blue) or intraprostatic (red) spread into SV, or (c) noncontiguous metastasis to SV (purple). Seminal vesicle invasion is categorized as pT3b. (Right) H&E shows tumor invading into the muscular wall of seminal vesicles ﬈, consistent with pT3b disease. Tumors in soft tissue adjacent to seminal vesicles, without infiltrating the wall, are categorized as EPE only (pT3a).

(Left) pT4 prostate cancer shows tumor invading structures other than SV, such as the bladder, rectum, and anterior pelvic wall. This tumor extent is managed with radiotherapy or hormonal therapy. RP with lymph node dissection may be performed in selected patients (e.g., low volume, no fixation). (Right) Rectal biopsy shows poorly differentiated prostate carcinoma ﬈ involving rectal mucosa. This, the highest pT stage, is confirmed histologically, and criteria for pT staging is fulfilled without removal of the tumor.

(Left) Axial CT shows retroperitoneal lymphadenopathy ﬈ and sclerotic vertebral metastasis by prostate cancer ﬊. Staging pelvic CT or MR is performed for T3 or T4 or in localized prostate cancer with high nomogram probability for lymph node involvement. Due to false positivity, staging MR/CT is usually not performed if GS < 7 or PSA < 20 ng/mL. (Right) Bone metastasis shows acini formation typical for prostate cancer. Confirmation can be performed with prostatespecific IHC markers.

342

Prostate Table

PIN4 in Prostate Cancer (Left) PIN4 dual chromogen immunostain shows overexpression of AMACR (red) in carcinoma glands ﬈ and basal cell markers (HMWCK and p63) (brown) positivity only in benign glands ﬉. AMACR staining in cancer is typically granular and circumferential. (Right) PIN4 dual chromogen immunostain shows overexpression of AMACR (red) and basal cell markers (brown) positivity in atypical cribriform lesions ﬈. Carcinoma glands show AMACR overexpression with no basal cell markers staining ﬉.

PSA in Metastatic Prostate Cancer

Diagnoses Associated With Syndromes by Organ: Genitourinary

PIN4 in Prostate Cancer and Benign Gland

PAP in Metastatic Prostate Cancer (Left) Bone metastasis of prostate cancer shows expression of PSA. Poorly differentiated prostate cancer may lose expression of PSA. Strong cytoplasmic expression, even when focal, should be sufficient for confirmation as prostatic primary. (Right) Bone metastasis of prostate cancer shows diffuse positivity for PAP. It is a good approach to combine PSA and PAP in metastatic setting since poorly differentiated prostate cancer may loss expression of these markers. Other prostatespecific markers include PSMA, NKX3.1, and prostein (p501s).

PSMA in Metastatic Prostate Cancer

AMACR in Tubular Nephrogenic Adenoma (Left) Bone biopsy shows foci of metastatic prostate carcinoma highlighted by PSMA staining. Prostatelineage markers PSMA, PSA, PAP, NKX.3 and prostein have good sensitivity in the metastatic setting. (Right) AMACR immunostain shows strong cytoplasmic staining in tubules of nephrogenic adenoma. Prostatic urethral nephrogenic adenoma may proliferate inward into the prostate parenchyma and mimic a Gleason grade 3 acinar carcinoma, confounded by the similar positive AMACR staining.

343

Diagnoses Associated With Syndromes by Organ: Genitourinary

Renal Urothelial Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS

MACROSCOPIC

• Mutations in FGFR3 (74%; 92% low grade, 60% high grade), KMT2D (44%), PIK3CA (26%), and TP53 (22%) • Familial cases: Lynch syndrome (a.k.a. HNPCC) ○ Associated with inherited mutations in DNA mismatch repair genes, most commonly with MSH2 (~ 90%), but also observed in small numbers of MLH1, MSH6, PMS2, and EPCAM (TACSTD1) ○ ~ 6% lifetime risk for upper urinary tract UCa ○ 22x higher risk than general population ○ Younger patients are more likely to have bilateral disease

• Papillary or polypoid mass involving or filling pelvicalyceal space • Infiltrative mass may extensively involve kidney and mimic primary high-grade renal carcinoma

CLINICAL ISSUES • • • •

Upper tract UCa accounts for ~ 5-10% of all UCa ~ 17% have concurrent bladder cancer 60% are invasive compared to 15-25% of bladder tumors In up to ~ 25% of ureteroscopic biopsy, diagnosis cannot be made due to inadequate sampling

MICROSCOPIC • Histologic classification similar to bladder UCa (WHO 2016) • Higher percentage of non-UCa and variant morphologies (25%) than bladder • Other morphologies may occur, e.g., small cell, micropapillary, plasmacytoid, lymphoepithelioma-like, and sarcomatoid carcinomas • Intratubular growth by UCa (pTis) should not be interpreted as renal parenchymal invasion (pT3)

ANCILLARY TESTS • GATA3, p63, uroplakin-2, HMWCK, and CK7 positive

Pelvicalyceal Urothelial Carcinoma

Renal Pelvis Papillary Urothelial Carcinoma

Renal Pelvis Papillary Urothelial Carcinoma

Renal Infiltrating Urothelial Carcinoma

(Left) Bivalved resected kidney (coronal plane) shows multiple foci of UCa along the mid and upper pole collecting system ﬉ and is invading into the renal parenchyma ﬈ and peripelvic fat ﬊ but with no extension into perinephric fat. Parenchymal or peripelvic fat invasion is considered pT3 disease. (Right) Low-power view shows a papillary UCa involving and filling the renal pelvis lumen. Despite its size and florid growth, this tumor does not show invasion into the underlying renal structures, evident by the regular smooth boundary.

(Left) High-grade papillary UCa consists of papillae lined by a thick layer of neoplastic urothelial cells that exhibit crowding, loss of polarity, nuclear pleomorphism, and mitosis. The tumor is noninvasive showing regular boundary to the subepithelium ﬊. (Right) This UCa from renal pelvis shows infiltration into renal parenchyma. The invasive tumor consists of irregular or jagged nests of cells in a desmoplastic stroma. The irregular boundary to renal parenchyma ﬈ is one key distinction to renal carcinoma.

344

Renal Urothelial Carcinoma

Abbreviations • Urothelial carcinoma (UCa)

Definitions • Carcinoma arising from pelvicalyceal urothelium

ETIOLOGY/PATHOGENESIS

Presentation • Gross or microscopic hematuria (70-80%), flank pain (2040%), and lumbar mass (10-20%) • Systemic symptoms, such as anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough for metastasis • ~ 17% have concurrent bladder cancer • 60% are invasive compared to 15-25% of bladder tumors

Risk Factors

Endoscopic Findings

• Similar to bladder cancer ○ Tobacco exposure increases risk by 2.5-7x ○ Long exposure to aromatic amines (e.g., benzidine, βnaphthalene) ↑ risk by 8.3x – ~ 7 years of exposure with latency of ~ 20 years to develop upper tract UCa

• Papillary or sessile mass; may fill renal pelvic cavity • In up to ~ 25% of ureteroscopic biopsies, diagnosis cannot be made due to inadequate sampling

Molecular Alterations • Mutations in FGFR3 (74%; 92% low grade, 60% high grade), KMT2D (44%), PIK3CA (26%), and TP53 (22%)

Familial Renal UCa • Lynch syndrome a.k.a. hereditary nonpolyposis colorectal cancer (HNPCC) syndrome ○ Autosomal dominant condition with increased risk for cancer of colon (63%), uterus (9%), upper urinary tract, stomach, ovary, biliary tract, pancreas, and brain ○ Lifetime risk of cancer up to 80% by age 70 years ○ Associated with inherited mutations in DNA mismatch repair genes – Most commonly with MSH2 (~ 90%), but also observed in small numbers of MLH1, MSH6, PMS2, and EPCAM (TACSTD1) ○ ~ 6% lifetime risk for upper urinary tract UCa (3rd after colon and endometrial Ca) – 22x higher risk than general population – Younger median age of onset (56 years, or 10-15 years younger than sporadic cases) – More likely to be bilateral than in sporadic cases – Risk is higher for ureter than renal pelvis UCa; risk for bladder UCa not established – UCas have more potential for high grade than in general population ○ Suspect hereditary upper tract UCa if – Patient < 60 years old – History of HNPCC-associated cancer – 1st-degree relative < 50 years of age with HNPCCassociated cancer – 2 first-degree relatives with HNPCC-associated cancer ○ Suspected patients should undergo DNA testing for confirmation

CLINICAL ISSUES Epidemiology • Incidence ○ Upper tract UCa accounts for ~ 5-10% of all UCa ○ Annual incidence of 2 new cases per 100,000 • Age ○ Range: 40s-90s; median: 69 years (similar to bladder UCa) • Sex

Treatment • Surgical approaches ○ Radical nephroureterectomy (RNU) with excision of bladder cuff is gold standard therapy

Prognosis

Diagnoses Associated With Syndromes by Organ: Genitourinary

○ M:F = 2:1

TERMINOLOGY

• Dependent on stage ○ 5-year specific survival is < 50% for pT2/pT3 and < 10% for pT4 • Other important prognostic factors ○ Grade, tumor size, multifocality, lymphovascular invasion, hydronephrosis, and positive margin after RNU • Recurrence in bladder occurs in 22-47% • Recurrence in contralateral upper tract occurs in 2-6%

MICROSCOPIC Histologic Features • Classification similar to bladder UCa (WHO 2016) ○ Papillary urothelial neoplasms – Urothelial papilloma and papillary urothelial neoplasm of unknown malignant potential (PUNLMP) rare in renal pelvis – Papillary UCa, low grade or high grade ○ Flat urothelial neoplasms – Urothelial dysplasia – UCa in situ ○ Invasive conventional UCa and variants morphology – Higher percentage of non-UCa and variant morphologies (25%) than bladder ○ Most common variants: Squamous cell carcinoma (9.9%) and carcinomas with glandular differentiation (4.4%) ○ Other morphologies may occur, e.g., small cell, micropapillary, plasmacytoid, lymphoepithelioma-like, and sarcomatoid carcinomas

ANCILLARY TESTS Immunohistochemistry • GATA3, p63, uroplakin-2, HMWCK, and CK7 positive

SELECTED REFERENCES 1.

2.

Rouprêt M et al: European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 73(1):111-22, 2018 Moss TJ et al: Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 72(4):641-9, 2017

345

Diagnoses Associated With Syndromes by Organ: Genitourinary

Renal Urothelial Carcinoma

Pelvicalyceal Urothelial Carcinoma

Renal Pelvis Low-Grade Papillary Urothelial Carcinoma

Renal Pelvis Low-Grade Papillary Urothelial Carcinoma

Renal Pelvis High-Grade Papillary Urothelial Carcinoma

Renal Pelvis High-Grade Papillary Urothelial Carcinoma

Renal Pelvis High-Grade Papillary Urothelial Carcinoma

(Left) Gross image shows a UCa ſt involving the inferior pelvicalyceal system. At the upper aspect, the tumor shows a relatively regular and distinct boundary ﬇, whereas at the inferior aspect, there is focal infiltration of the renal parenchyma st. Distinction between renal UCa and primary renal cell carcinoma can often be made by gross examination alone. (Right) Low-power view shows a renal pelvis low-grade papillary UCa. It is not uncommon to see large papillary UCa with low-grade cytology in the renal pelvis.

(Left) This renal pelvis lowgrade papillary UCa shows similar histology to low-grade UCa elsewhere in the GU tract. The tumor cells exhibit mild nuclear atypia with oval nuclei, vesicular chromatin, and mild cellular disorganization. (Right) Lowpower view shows a highgrade papillary UCa with necrosis ﬈ in the renal pelvis and extending into the ureteropelvic portion. Note the adjacent peripelvic fat ﬊; infiltration of tumor into this fat is staged similar to renal parenchymal invasion.

(Left) Low-power view shows a high-grade noninvasive papillary UCa in the renal pelvis with delicate exophytic papillae containing fibrovascular cores. Similar to UCa elsewhere, grading of renal UCa is based entirely on cytomorphologic features. (Right) High-grade papillary UCa shows fused papillae containing disorganized, large pleomorphic cells with nuclear rounding and frequent overlap. Nuclear chromatin is dense and mitosis is frequent ﬈. No invasion is present in this tumor.

346

Renal Urothelial Carcinoma Renal Pelvis Noninvasive Papillary Urothelial Carcinoma (Left) Invasive UCa to renal parenchyma is seen infiltrating between glomeruli. There are irregular nests and small cell clusters of high-grade cells ﬈ in a desmoplastic background. (Right) This noninvasive papillary UCa exhibits an endophytic growth characterized by a smooth, regular outline and no desmoplastic response. Inverted growth is suggested to be a feature of renal UCa in Lynch syndrome. Note the artifactual dyscohesion, which is not uncommon in nephrectomy specimens for UCa.

Renal Pelvis Urothelial Carcinoma In Situ

Diagnoses Associated With Syndromes by Organ: Genitourinary

Renal Infiltrating Urothelial Carcinoma

Urothelial Carcinoma Within Collecting Ducts (Left) H&E shows UCa in situ involving the renal pelvis urothelium. There is cellular disorganization with crowding, nuclear pleomorphism, and hyperchromaticity. (Right) Low-power view shows UCa in situ in the renal pelvis urothelium with extension within the collecting ducts. Note the outline of the tumor nests follows the contour of the native tubules with no desmoplastic reaction. This growth remains noninvasive (pTis) and should not be overstaged as renal parenchymal invasion (pT3).

Renal Urothelial Carcinoma With Squamous Differentiation

GATA3 in Renal Urothelial Carcinoma (Left) Low-power view shows a high-grade UCa with squamous differentiation exhibiting abundant keratinization. In terms of proportion, variant morphology of UCa is more frequent (~ 25%) in the renal pelvis than in the bladder. (Right) GATA3 shows diffuse nuclear staining in this invasive renal UCa. GATA3 can be helpful in the distinction of UCa from renal carcinoma. Distinction between renal UCa [GATA3/p63(+)] and renal carcinoma [pax-8/pax-2(+)] has important prognostic and therapeutic implications.

347

Diagnoses Associated With Syndromes by Organ: Genitourinary

Ureter Urothelial Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS

MACROSCOPIC

• Risk factors similar to those in bladder cancer • Familial cases: Lynch syndrome or hereditary nonpolyposis colorectal cancer syndrome ○ ~ 6% lifetime increased risk of upper urinary tract cancer, greater for ureter than renal pelvis

• Papillary or polypoid tumors may fill in and obstruct ureter • Infiltrative tumors may present with higher stage and involvement of surrounding structures

CLINICAL ISSUES • Rare; estimated 3,930 new cases and 980 deaths from ureter and other urinary organ cancer in USA in 2019 • Normal bladder cystoscopy and positive urine cytology suggest upper urinary tract cancer • Distribution of upper urinary tract cancer ○ Renal pelvis (36%), upper ureter (5%), mid ureter (7%), lower ureter (56%), and multifocal (22%) • Up to ~ 6% will have contralateral ureteral cancer, and ~ 17% will have concurrent bladder cancer • Poor survival, similar to pelvicalyceal urothelial carcinoma (UCa)

MICROSCOPIC • Classification similar to bladder or pelvicalyceal UCa (WHO 2016) • Papillary UCa either low or high grade; urothelial papilloma and papillary urothelial neoplasm of unknown malignant potential (PUNLMP) rare in ureter • Invasive conventional UCa and variants morphology • Squamous cell carcinoma, small-cell or neuroendocrine carcinoma, adenocarcinoma, and sarcomatoid carcinoma rarer in ureter

ANCILLARY TESTS • GATA3, p63, uroplakin-2, and CK7 positive

Papillary Urothelial Carcinoma

Papillary Urothelial Carcinoma

Multifocal Urothelial Carcinoma

Infiltrating Urothelial Carcinoma

(Left) Gross photo of a segment of an opened ureter shows an irregular, sessile, polypoid mass ſt almost filling the ureteral lumina. Urothelial carcinoma (UCa) is relatively more common at the lower ureter. (Right) Highgrade ureteral UCa shows a complex papillary growth not invading the underlying stroma. Ureteral UCa may exhibit infiltrative or exophytic growths and cause symptoms related to urinary tract obstruction. Most papillary neoplasms are low- or highgrade UCa; papilloma and PUNLMP are rare in ureter.

(Left) Gross photo of an opened ureter shows an infiltrating UCa ſt distally and an exophytic papillary UCa ﬇ at the more proximal segment. Invasion is relatively more common in ureter UCa than in bladder UCa. (Right) Invasive high-grade UCa shows infiltration into the ureter muscularis propria ﬈, which has smaller caliber bundles than those in the bladder proper. Higher stage presentation is common for ureteral UCa due to its thinner wall. Infiltrating UCa variants and non-UCa types may occur rarely in the ureter.

348

Ureter Urothelial Carcinoma

Synonyms

Prognosis

• Ureter transitional cell carcinoma

• Poor survival, similar to pelvicalyceal UCa • UCa in ureter has worse prognosis than UCa in pelvicalyceal system ○ Some studies, however, showed that after adjustment for tumor stage, location for upper urinary tract cancer is no longer predictor of cancer-specific survival • Up to ~ 6% of patients will have contralateral ureteral cancer, and ~ 17% will have concurrent bladder cancer

Abbreviations

Definitions • Carcinoma arising from ureteral urothelium • Available clinicopathologic data similar with those for renal pelvicalyceal UCa; almost always lumped together in literature as upper urinary tract cancer

ETIOLOGY/PATHOGENESIS Risk Factors • Similar to those in bladder cancer ○ Tobacco, long-term occupational exposure to aromatic amines

Lynch Syndrome • a.k.a. hereditary nonpolyposis colorectal cancer syndrome • Autosomal dominant condition with increased risk of cancers; mainly colon, uterus, and upper urinary tract • Due to inherited mutations in mismatch repair genes, most commonly MSH2 (~ 90%) • ~ 6% lifetime increased risk of upper urinary tract cancer in both ureter and renal pelvis; possibly also risk for bladder UCa ○ Higher incidence of ureter location of UCa (~ 50%) in Lynch syndrome

CLINICAL ISSUES Epidemiology • Incidence ○ Rare; estimated 3,930 new cases and 980 deaths from ureter and other urinary organ cancer in USA in 2019 • Age ○ Range: 40s-90s with peak in 60s-70s; similar to bladder and pelvicalyceal UCa • Sex ○ More common in men, but lesser sex difference than in bladder UCa

Site • Distribution of upper urinary tract cancer ○ Renal pelvis (36%), upper ureter (5%), mid ureter (7%), lower ureter (56%), and multifocal (22%)

IMAGING CT Findings • May present with luminal mass and signs of ureteral obstruction (e.g., hydronephrosis) • Flat tumors may not be easily discernible unless there is wall thickening or mass effect

Diagnoses Associated With Syndromes by Organ: Genitourinary

• Urothelial carcinoma (UCa)

• Drugs ○ Unlike in bladder cancer, intraluminal chemotherapy (e.g., BCG, thiotepa) and immunotherapy are sparsely used in ureter cancer and with no guidelines

TERMINOLOGY

MACROSCOPIC General Features • Papillary or polypoid tumors may fill in and obstruct ureter • Infiltrative tumors may present with higher stage and involvement of surrounding structures

MICROSCOPIC Histologic Features • Classification similar to bladder or pelvicalyceal UCa ○ Papillary urothelial neoplasms – Urothelial papilloma and papillary urothelial neoplasm of unknown malignant potential rare in ureter – Papillary UCa, low or high grade ○ Flat urothelial neoplasms – Urothelial dysplasia – UCa in situ ○ Invasive conventional UCa and variants morphology; relative rates of invasion higher than in bladder ○ Squamous cell carcinoma, small-cell or neuroendocrine carcinoma, adenocarcinoma, and sarcomatoid carcinoma rarer in ureter • Carcinoma may spread/infiltrate through ureteral wall or adventitial tissue without involving overlying ureter mucosa ○ Potential pitfall for false-negative margin, particularly in frozen section ureteral margin

Presentation • Hematuria, flank pain, irritative voiding symptoms, and weight loss • May have symptoms related to urinary tract obstruction

Endoscopic Findings

ANCILLARY TESTS Immunohistochemistry • GATA3, p63, uroplakin-2, and CK7 positive

SELECTED REFERENCES

• Papillary, sessile, or infiltrative tumor • Normal bladder cystoscopy and positive urine cytology suggest upper urinary tract cancer

1.

Treatment

2.

• Surgical approaches ○ Ureterectomy, ± adjuvant therapy depending on stage

Wischhusen JW et al: Clinical factors associated with urinary tract cancer in individuals with Lynch syndrome. Cancer Epidemiol Biomarkers Prev. ePub, 2019 Rouprêt M et al: European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 73(1):111-22, 2018

349

Diagnoses Associated With Syndromes by Organ: Genitourinary

Renal Pelvis and Ureter Table Diagnosis of Lynch (HNPCC) Syndrome Upper Urinary Tract Urothelial Carcinoma Examination

Findings

Clinical

Patient < 60 years old Personal history of HNPCC-associated cancer (e.g., colon cancer, uterine cancer), or 1st-degree relative < 50 years of age with HNPCC-associated cancer, or 2 first-degree relatives with HNPCC-associated cancer

Pathologic

Upper tract UCa more often with inverted growth pattern [sensitivity and specificity of 0.82 for high-frequency MSI (MSI-H)]

Immunohistochemical screening with antibodies against MLH1, MSH2, PMS2, and MSH6

Loss of nuclear staining with normal nuclear staining in internal control cells (such as normal lymphocytes) indicates loss of that protein

MSI testing by PCR using NCI consensus panel of 2 mononucleotide (BAT25 and BAT26) and 3 dinucleotide (D2S123, D5S346, and D17S250) markers

MSI phenotypes: High MSI (MSI-H) if size alterations or shifts observed in ≥ 2 markers or MSI of ≥ 30%, low MSI (MSI-L) if only 1 marker shows instability, and microsatellite stable (MSS) if no markers show instability Other centers test additional markers, such as BAT40 and TGFBR2

HNPCC = hereditary nonpolyposis rectal cancer; MSI = microsatellite instability; NCI = National Cancer Institute; UCa = urothelial carcinoma.

Carcinomas Involving Kidney &/or Renal Pelvis Antibody

Urothelial Carcinoma

Collecting Duct Carcinoma

Renal Cell Carcinoma, NOS

p63

+

- (rarely focal +)

-

GATA3

+

- (rarely focal +)

-

Uroplakin-3/uroplakin-2

+/-

-

-

HMWCK (34bE12)

+

-/+

-

CK7

+

+

-/+

CK20

+/-

- (rarely focal +)

-

Thrombomodulin

+/-

-

-

pax-8/pax-2

- (rarely focal +)

+/-

+

INI1

+

+ (loss in medullary)

+

8th AJCC Staging System for Renal Pelvis and Ureter Cancer Stage

Definition

Primary Tumor (pT) pTX

Primary tumor cannot be assessed

pT0

No evidence of primary tumor

pTa

Papillary noninvasive carcinoma

pTis

Carcinoma in situ

pT1

Tumor invades subepithelial connective tissue

pT2

Tumor invades the muscularis

pT3

For renal pelvis only: Tumor invades beyond muscularis into peripelvic fat or renal parenchyma For ureter only: Tumor invades beyond muscularis into periureteric fat

pT4

Tumor invades adjacent organs or through kidney into perinephric fat

Regional Lymph Nodes (pN) pNX

Regional lymph nodes cannot be assessed

pN0

No regional lymph node metastasis

pN1

Metastasis in single lymph node, ≤ 2 cm in greatest dimension

pN2

Metastasis in single lymph node, > 2 cm in greatest dimension; or multiple lymph nodes

Distant Metastasis (M)

350

M0

No distant metastasis

M1

Distant metastasis

Renal Pelvis and Ureter Table Urothelial Carcinoma Infiltrating Into Renal Parenchyma (Left) Gross photograph shows urothelial carcinoma ﬉ arising from the renal pelvis and filling the pelvicalyceal system. There is focal tumor infiltration into the kidney (pT3) ﬈. Concomitant urothelial carcinoma is present in the ureter ſt. (Right) Lowpower view shows invasive urothelial carcinoma nests ﬈ in between glomeruli. Infiltration into renal parenchyma without involving the perinephric fat is categorized as pT3. Urothelial carcinoma typically shows infiltrative border in contrast to most renal cell carcinomas.

Ureter Urothelial Carcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Concomitant Renal Pelvis and Ureter Urothelial Carcinomas

Ureter Papillary Urothelial Carcinoma (Left) Gross photograph shows a segment of ureter thickened by invasive urothelial carcinoma ſt. Ureteral urothelial carcinoma may present as obstruction that mimics a stricture. In this case, the tumor infiltrates full thickness of the wall and extends into the periureteric fat (pT3). (Right) Low-power view shows papillary urothelial carcinoma filling and distending the ureteral lumen. The wall of ureter is markedly distended ﬈. Unlike in bladder, a smaller focus of invasion may infiltrate into the periureteral tissue.

p63 in Urothelial Carcinoma

pax-8 Negativity in Urothelial Carcinoma (Left) p63 shows nuclear positivity in urothelial carcinoma. A nearby glomerulus ﬈ shows negative staining. (Right) pax-8 shows negative staining of invasive urothelial carcinoma ﬈. The renal tubular cells show immunoreactivity and may serve as internal positive control ﬉. pax-8 should be complemented by p63 &/or GATA3 when distinguishing urothelial carcinoma from renal cell carcinomas. Combination of p63/pax-8 has a slightly better sensitivity and specificity than combination of GATA3/pax-8.

351

Diagnoses Associated With Syndromes by Organ: Genitourinary

Germ Cell Tumor KEY FACTS

TERMINOLOGY • Germ cell tumor (GCT): Group of tumors arising from germ cells that are capable of differentiating into embryonic and extraembryonic elements • Pediatric GCTs: Most are pure GCTs and include mostly pure yolk sac tumor (YST) (~ 75% of childhood GCTs) and pure teratoma (TT) • Postpubertal GCTs: Majority of GCTs arise in men 20-45 years old, with peak incidence in 30s ○ Most are pure seminoma (S) (~ 30-45%), pure embryonal carcinoma (EC) (< 5%), or MGCT (~ 30-40%) • GCNIS: Considered precursor of postpubertal GCTs • Clinically, GCTs are divided into SGCT and NSGCT with differing behavior and therapy

ETIOLOGY/PATHOGENESIS • Familial GCTs: ~ 2% of TGCT patients have positive family history for GCT

○ Affected individuals' siblings have 4-6x higher risk for TGCT, sons have 4x higher risk for TGCT • Postpubertal GCTs typically have 1 or more copies of Chr 12p or other forms of Chr 12 abnormalities

MACROSCOPIC • S typically well circumscribed, homogeneous, devoid of necrosis or hemorrhages; other postpubertal GCTs usually with variegated appearances • Postpubertal NSGCTs usually with variegated appearances

MICROSCOPIC • Distinction of S, EC, YST, TT, CC, ST, and components of MGCT are based mainly on morphologic assessment

ANCILLARY TESTS • SALL4: Positive in all GCT • Helpful immunostains for distinction of GCT components: OCT3/4, CD117, CD30, α-fetoprotein, and Glypican-3

Mixed Germ Cell Tumor

Mixed Germ Cell Tumor

Seminoma

Seminoma

(Left) Gross photograph shows MGCT with typical variegated cut surface. The hemorrhagic area may represent EC ſt, the smoother solid area S st, and the cystic solid area TT ﬇. This tumor is organ-confined. (Right) MGCT shows admixture of TT ﬈ with primitive neuroepithelium, and YST ﬊ with variable patterns, including microcysts and spindle cells, and S ﬉ with sheets and infiltrates of tumor cells with clear cytoplasm. Distinction of MGCT components can often be achieved by pure morphologic examination alone.

(Left) Gross photograph shows typical S devoid of necrosis or frank hemorrhage. The cut surface is solid, gray-white, and slightly lobulated. pT1 category for organ-confined S with no LVI, as in this case, is now subdivided based on tumor size (3-cm cut-off) into pT1a and pT1b. (Right) Lowpower view shows S characterized by solid growth of clear cells with fibrovascular septa ﬈ and occasional lymphoplasmacytic infiltrates ﬉. The tumor cells usually have distinct cytoplasmic membrane and are not overlapping.

352

Germ Cell Tumor

Definitions

Cytogenetic Changes

• GCT ○ Group of tumors arising from germ cells that are capable of differentiating into embryonic and extraembryonic elements • Occurrence of testicular GCTs cluster in 3 age groups ○ Pediatric or prepubertal GCTs – Occur mostly in infants and young children – Most are pure GCTs and include mostly pure yolk sac tumors (YST) (~ 75% of childhood GCTs) and pure teratomas (TTs) ○ Postpubertal GCTs – Majority arise in men 20-45 years of age, with peak incidence in 30s – GCTs in this age group are pure or mixed: Pure seminoma (S, ~ 30-45%), pure embryonal carcinoma (EC, < 5%), or mixed germ cell tumor (MGCT, ~ 3040%) – YST, TT, and choriocarcinoma (CC) are more commonly encountered as component of MGCTs; pure form rare in adults – Described familial GCT cases are mostly in this age group ○ Older adult GCTs – Rare; majority are spermatocytic tumor (ST) in patients with mean age of 53 years • From clinical standpoint, GCTs are divided into 2 groups ○ Seminomatous GCT (SGCT) – Only pure S ○ Nonseminomatous GCT (NSGCT) – Includes pure and mixed NSGCTs ○ Compared to NSGCT, SGCT usually arises in patients older by 10 years, is less likely to metastasize, is sensitive to radiotherapy and chemotherapy – Response of NSGCTs with chemotherapy getting better with platinum-based regimens • Germ cell neoplasia in situ (GCNIS) ○ Uncommitted neoplastic germ cells proliferating peripherally within seminiferous tubules ○ Considered precursor of most GCTs and common in seminiferous tubules of postpubertal GCTs; not seen in pediatric pure YST, pure TT, or ST

• Postpubertal GCTs typically have 1 or more copies of Chr 12p or other forms of Chr 12 abnormalities ○ Most common is isochromosome 12 (i[12p]) seen in ~ 80% of testicular GCTs • Pediatric GCTs are usually diploid • ST often with gain of Chr 9

Abbreviations

ETIOLOGY/PATHOGENESIS Risk Factors • Family history, prior history of GCT, contralateral GCT, cryptorchidism, testicular dysgenesis syndrome, undescended testis (cryptorchidism), Klinefelter syndrome

Familial GCT • ~ 2% of testicular GCT (TGCT) patients have positive family history for GCT • Siblings of TGCT-affected individuals: 4-6x ↑ risk • Sons of TGCT-affected individuals: 4x ↑ risk • Most affected families have 2 members with TGCT

CLINICAL ISSUES Epidemiology • Age ○ Postpubertal GCTs – NSGCT usually occurs in patients aged 25-35 years – S occurs at ages ranging from 35-45 years (10 years older than NSGCT and 5 years older than NSGCT with S) • Ethnicity ○ Occurs 5x more often in white men than black men; 3x more often in white men than Asian men

Diagnoses Associated With Syndromes by Organ: Genitourinary

• Germ cell tumor (GCT)

• No high-penetrance cancer susceptibility gene has been described so far ○ Familial risk of TGCT likely polygenic or due to dosages of multiple genetic factors 

TERMINOLOGY

Presentation • Typically painless testicular mass • ~ 10% present due to symptoms from distant metastasis

Laboratory Tests • α-fetoprotein elevated in YST • Normal α-fetoprotein in S (if elevated categorized clinically as NSGCT) • Borderline elevation of β-HCG in GCT with syncytiotrophoblasts and markedly high in CC (usually > 50,000 mIU/mL) • Serum LDH, α-fetoprotein, and β-HCG levels important in prognosis and are incorporated in AJCC TNM staging • Normal hormone levels in ST

Treatment • Decision is made based on stage and whether tumor is SGCT or NSGCT ○ SGCT: Radical orchiectomy and surveillance for stage I; radiotherapy, cisplatin-based, or multidrug chemotherapy depending on stage ○ NSGCT: Radical orchiectomy and retroperitoneal lymph node dissection for all stages; additional chemotherapy depending on stage

Prognosis • Depends on tumor type, stage, and therapy • In USA, overall survival is good (95%), attributed to advancement in therapy

MACROSCOPIC S • Well-circumscribed, homogeneous, gray-white mass ± lobulations and usually devoid of necrosis or hemorrhages • May have punctate hemorrhages from syncytiotrophoblasts 353

Diagnoses Associated With Syndromes by Organ: Genitourinary

Germ Cell Tumor • Range: < 1-24 cm; mean: 5 cm

EC • Usually poorly circumscribed and with variegated, irregular surface exhibiting abundant necrosis and hemorrhage • Tumor usually presents smaller than S

YST • Homogeneous, gray-white mass with gelatinous surface ± hemorrhage ○ "Pure S-appearing" tumor in infants and young children

T • Often circumscribed, solid &/or cystic mass • Cysts may contain keratinous debris or mucinous fluid • May have hairs, teeth, bone, or cartilage

MGCT • Variegated, solid &/or cystic • Variation depends on components ○ NSGCT components usually associated with necrosis, hemorrhages, and cystic changes

MICROSCOPIC GCNIS • Large, atypical cells with large nucleus, nucleolomegaly, clear cytoplasm, and prominent cytoplasmic membrane within seminiferous tubules usually at periphery • Seminiferous tubules usually with thickened basement membrane, decreased or absent spermatogenesis, and GCNIS cells admixed with mainly Sertoli cells

S • Mainly solid growth but may exhibit interstitial and other rare patterns • Characteristically shows sheets of tumor cells compartmentalized by thin fibroconnective septae with occasional lymphoplasmacytic infiltrates • Tumor cells have clear cytoplasm, prominent cytoplasmic border, slightly irregular nuclei, and large central nuclei; cells typically do not overlap • ~ 30% may have granulomas

EC • Mainly exhibits solid, glandular, or papillary growths • Characterized by large high-grade pleomorphic cells with indistinct cytoplasmic border, modest amphophilic cytoplasm, large nuclei, and prominent irregular nucleoli; cells usually overlap • Hemorrhages and necrosis common

YST • Variable patterns, including reticular (80%, micro- or macrocystic), endodermal sinus pattern (Schiller-Duval bodies), solid, papillary, glandular-alveolar, parietal, enteric, hepatoid, spindled, myxomatous, and mixed • Bland cells with varied shape; can be cuboidal, columnar, flattened, or spindled • Clear to eosinophilic cytoplasm, overlapping border, and relatively regular nuclei with no to mild atypia

T • Mature T 354

○ Mixture of ectodermal (e.g., epidermis, neuronal tissue), endodermal (e.g., gastrointestinal or respiratory mucosa), and mesodermal (e.g., cartilage, bone) tissues • Immature T ○ Presence of primitive endoderm, neuroectoderm, or mesoderm (undifferentiated spindle cells), including blastemal cells

CC • Admixture of syncytiotrophoblasts (often as giant multinucleated cells) and cytotrophoblasts (smaller polygonal cells with prominent membrane and uniform nuclei) • Hemorrhage is invariably present, forming pseudocystic hemorrhagic nodules • Lymphovascular invasion is common • Rare nonchoriocarcinomatous trophoblastic GCTs have also been reported

MGCT • Combination of any S, EC, YST, TT, or CC in varying proportions • Most common combinations are EC + TT and EC + S, but any combination may occur • Usually exhibits hemorrhages and necrosis • YST and EC component are often intermingled (e.g., embryoid bodies, diffuse embryonal pattern) • May have carcinomatous or sarcomatous transformation often from YST

ST • Hallmark is presence of 3 distinct cell types ○ Small lymphocyte-like cells: Scant cytoplasm with dark round nuclei ○ Intermediate cells: Most common, with modest cytoplasm and round nuclei with granular chromatin ○ Large cells: Nuclei with filamentous or "spireme" chromatin

ANCILLARY TESTS Immunohistochemistry • SALL4 and PLAP: Positive in GCT • Important immunostains include OCT3/4, CD117, CD30, αfetoprotein, and Glypican-3 • OCT3/4: Positive in GCNIS, S, and EC • CD117: Positive in GSNIS, S, and ST • CD30 and SOX2: Positive in EC • β-HCG and human placental lactogen: Positive in CC (syncytiotrophoblasts) • Inhibin: Negative in GCT and positive in sex cord-stromal tumors

SELECTED REFERENCES 1.

2.

Ulbright TM: Recently described and clinically important entities in testis tumors: a selective review of changes incorporated into the 2016 Classification of the World Health Organization. Arch Pathol Lab Med. 143(6):711-21, 2019 Williamson SR et al: The World Health Organization 2016 classification of testicular germ cell tumours: a review and update from the International Society of Urological Pathology Testis Consultation Panel. Histopathology. 70(3):335-46, 2017

Germ Cell Tumor Germ Cell Neoplasia In Situ and Intratubular Embryonal Carcinoma (Left) GCNIS shows seminiferous tubules with no spermatogenesis, thickened basement membrane, and containing large atypical cells with abundant clear cytoplasm, prominent cell border, and large nuclei with nucleolomegaly ﬈. GCNIS cells are more often at the periphery, intermingled with residual Sertoli cells ﬉. (Right) Seminiferous tubules with GCNIS ﬉ and seminiferous tubules with intratubular growth of EC ﬈ are shown. GCNIS cells have morphologic and staining pattern overlapping with S.

Seminoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Germ Cell Neoplasia In Situ

Seminoma (Left) The classic histology of S includes solid growth of tumor cells with clear cytoplasm and distinct cytoplasmic membrane ﬈, separated by thin, fibrous septa ﬉, and occasional lymphoplasmacytic infiltrates, usually at the septa ﬊. (Right) This S has solid and focal infiltrative growth. S can be mimicked by solid YST and EC. Unlike S, YST also shows admixed varied patterns and EC shows marked nuclear pleomorphism. If immunostain is necessary, S is CD117(+), whereas YST and EC express glypican-3 and CD30, respectively.

Embryonal Carcinoma

Embryonal Carcinoma (Left) EC with a variegated cut surface, hemorrhage, and necrosis is shown. The tumor is poorly circumscribed. The rete testis and spermatic cord are more commonly involved in EC than in S. (Courtesy S. Shen, MD.) (Right) EC cells are characterized by marked pleomorphism; the extent and degree not typically seen in other GCT components. EC cells are usually crowded and overlapping, with single or multiple nucleoli, and have abundant mitosis and prominent apoptotic bodies ﬈. EC is CD30(+) and SOX2(+).

355

Diagnoses Associated With Syndromes by Organ: Genitourinary

Germ Cell Tumor

Embryonal Carcinoma

Yolk Sac Tumor

Yolk Sac Tumor

Yolk Sac Tumor

Teratoma

Teratoma

(Left) EC often shows solid, glandular or papillary growths. This papillary EC shows tumor cell surrounding a fibrovascular core. Other less common patterns of EC include nested, micropapillary, glandular, sieve-like, and blastocyst-like. (Right) Large YST with a relatively homogeneous, white, mucoid cut surface is shown. Focal hemorrhage is present ﬈. A gelatinous or myxoid appearance is common in pediatric pure YSTs. Postpubertal YST occurs almost always in MGCT. (Courtesy S. Shen, MD.)

(Left) YST has multiple patterns, the most common being microcystic ﬈, characterized by multiple sieve-like spaces. A focal, solid growth is present ﬉. In postpubertal MGCT, YST often intermingles with EC. (Right) H&E shows a Schiller-Duval body in YST characterized by a central vessel surrounded by a layer of tumor cells and a space created by another layer of tumor cells, giving a glomeruloid appearance. This pattern is the most specific pattern for YST. YST cells are typically bland-appearing.

(Left) This mature TT shows a predominantly cystic mass with chalky keratin debris ﬈. Solid mucoid and gelatinous components ﬊ are also present and frequently correlate microscopically with immature teratomatous components. Uninvolved testis is pushed to one side ﬉. (Courtesy S. Shen, MD.) (Right) TT shows squamous epithelium, glands, and focal adipose tissue. Postpubertal TT elements are usually haphazard in contrast to a more organoid arrangement in prepubertal TT.

356

Germ Cell Tumor

Choriocarcinoma (Left) Sarcomatous transformation in TT shows rhabdomyoblasts consisting of plump cells with abundant dense eosinophilic cytoplasm and eccentric atypical nuclei ﬈. (Right) CC is often associated with hemorrhage. Diagnosis as CC requires the presence of both syncytiotrophoblasts ﬈ and cytotrophoblasts ﬉. The smaller cytotrophoblasts are usually arranged in layers. Syncytiotrophoblasts are often multinucleated but can also be mononucleated. CC has proclivity to invade blood vessels.

Choriocarcinoma

Diagnoses Associated With Syndromes by Organ: Genitourinary

Rhabdomyosarcoma in Teratoma

Mixed Germ Cell Tumor (Left) CC shows the typical biphasic pattern consisting of layers of cytotrophoblasts ﬈ and syncytiotrophoblasts ﬉, which usually "cap" the cytotrophoblasts. The syncytiotrophoblasts may also present as thin, elongated cells ﬊. (Right) MGCT consists of YST with polyvesicular vitelline pattern ﬈; EC consists of glands ﬉ and seminoma with clear cells ﬊. Note the abundant hyaline globules associated with YST. In postpubertal GCTs, YST is almost always seen as a component of MGCT.

Embryonal Carcinoma and Yolk Sac Tumor: Polyembryoma

Embryonal Carcinoma and Yolk Sac Tumor: Diffuse Embryoma (Left) High-power view shows an embryoid body in MGCT consisting of a central embryonic disc ﬈ composed of EC cells and surrounded by YST cells creating an amnioticlike cavity ﬊. (Right) MGCT shows diffuse embryoma pattern characterized by intimate admixture of YST and EC components (necklace pattern). YST ﬈ is seen wrapping around EC component ﬊. EC cells are distinguished by the marked pleomorphism. Note the extracellular hyaline globules from YST ﬈.

357

Diagnoses Associated With Syndromes by Organ: Genitourinary

Sertoli Cell Neoplasms KEY FACTS

TERMINOLOGY

MICROSCOPIC

• Group of testicular neoplasms with Sertoli cell differentiation linked to syndromes such as Carney complex and Peutz-Jeghers syndrome  • Most ILCHSCNs described in Peutz-Jeghers syndrome • Most SCTs and ~ 60% of LCCSCTs are sporadic

• ILCHSCN: Seminiferous tubules with thickened basement membrane ○ Expanded by large Sertoli cells with pale to eosinophilic cytoplasm and globular, eosinophilic basement membrane deposits • LCCSCT: Large polygonal cells with abundant eosinophilic ground-glass cytoplasm associated with hallmark irregular or psammomatous calcifications • SCT: Hallmark tubular growth of regular cuboidal or columnar cells with pale to pink cytoplasm that may be vacuolated

CLINICAL ISSUES • Tumors may present with testicular enlargement, hormonal-related symptoms, or syndromic manifestations • High serum estradiol levels • ILCHSCN: Benign course, but subset may transform to invasive SCT or LCCSCT • LCCSCT: Majority benign; malignant cases are mostly sporadic • SCT: Majority benign; ~ 10% are malignant and may metastasize

ANCILLARY TESTS • Inhibin (+), PLAP and OCT3/OCT4(-) • LCCSCT: Positive for SF1, WT1, and S100 • SCT: Positive for SF1, FOXL2, inhibin, and WT1

Intratubular Large-Cell Hyalinizing Sertoli Cell Neoplasia

Large-Cell Calcifying Sertoli Cell Tumor

Sertoli Cell Tumor

Sertoli Cell Tumor

(Left) ILCHSCN composed of intratubular proliferations of large Sertoli cells and dense, eosinophilic basement membrane deposits is shown. The deposits are denser at the peritubular area and may also form globules ﬈. The Sertoli cells ﬉ have abundant eosinophilic cytoplasm, which can be fibrillary. (Right) LCCSCT shows small nests and cords of large, polygonal cells with abundant eosinophilic cytoplasm. Presence of calcifications ﬈ is a hallmark for LCCSCT. These calcifications may make the tumor gritty on sectioning.

(Left) Intermediate-power view shows SCT with small, nested cords and tubular and interanastomosing growths of tumor cells in a fibrous stroma. SCT grows in variable architectural patterns with tubule formation being the most common ﬈. The background stroma is collagenous and hypocellular. (Right) High-power view of SCT shows cuboidal cells with moderate amount of pale to eosinophilic cytoplasm. The nuclei are round to ovoid with occasional nucleoli. Mitosis is usually rare.

358

Sertoli Cell Neoplasms

Definitions • Group of testicular neoplasms with Sertoli cell differentiation linked to syndromes such as Carney complex and Peutz-Jeghers syndrome  ○ Intratubular large-cell hyalinizing Sertoli cell neoplasia (ILCHSCN): Intraseminiferous tubular neoplasia of large Sertoli cells admixed with globular basement membrane deposits – Subset may progress to invasive large-cell calcifying Sertoli cell tumor (LCCSCT) or Sertoli cell tumor (SCT) ○ LCCSCT: Variant of SCT composed of large epithelioid cells with abundant eosinophilic cytoplasm and peculiar calcifications ○ SCT: Sex cord-stromal tumor exhibiting variable patterns and hallmark tubular growth • Most ILCHSCNs described in Peutz-Jeghers syndrome • Vast majority of SCTs and ~ 60% of LCCSCTs encountered as sporadic tumors ○ ~ 40% of LCCSCTs linked to syndromes

ETIOLOGY/PATHOGENESIS Syndromes/Familial Sertoli Cell Neoplasms • Peutz-Jeghers syndrome ○ Mainly caused by mutations in STK11/LKB1 ○ Autosomal dominant disorder characterized by multiple hamartomatous polyps and mucocutaneous pigmentations ○ ILCHSCN, LCCSCT, and SCT described in patients with this syndrome • Carney complex ○ Autosomal dominant multiple neoplasia syndrome ○ Caused by mutations in PRKAR1A (45-80%) ○ LCCSCT is component of this complex

CLINICAL ISSUES Epidemiology • Age ○ ILCHSCN: < 15 years of age; mean: 6.8 years ○ LCCSCT: Mostly prepubertal boys to young adult men; mean: ~ 30 years ○ SCT: ~ 30% occur in 1st decade of life

Presentation • ILCHSCN may exhibit testicular enlargement but no discrete mass • SCT and LCCSCT may present as painless testicular mass or enlargement • Hormone-related symptoms, such as gynecomastia (most common), precocious puberty, or advanced skeletal maturation • Discovery of testicular tumors from other syndromic manifestations ○ Peutz-Jeghers syndrome – Mucocutaneous pigmentations, bowel obstruction, or intussusception from multiple gastrointestinal polyps ○ Carney complex – Spotty pigmentation of skin, cardiac or cutaneous myxomas, endocrinopathy, schwannomas

• Testicular ultrasound of LCCSCT will show characteristic Christmas tree-like appearance

Laboratory Tests • High serum estradiol levels • Serum α-fetoprotein and β-HCG levels not elevated

Prognosis • ILCHSCN: Benign course, but subset may transform to invasive SCT or LCCSCT • LCCSCT: Majority benign; malignant cases are mostly sporadic • SCT: Majority benign; ~ 10% are malignant and may metastasize

MACROSCOPIC General Features • ILCHSCN: Either testicular enlargement with no visible lesion or small, ill-defined, white lesions • LCCSCT: Usually small (< 4 cm), well-circumscribed, homogeneous, gray-white to yellow mass with calcifications • SCT: Small (mean: 3.5 cm), well-circumscribed, homogeneous, gray-white to yellow mass

Diagnoses Associated With Syndromes by Organ: Genitourinary

TERMINOLOGY

MICROSCOPIC Histologic Features • ILCHSCN: Expanded seminiferous tubules with thickened peritubular basement membrane ○ Tubules filled with large Sertoli cells with abundant pale to eosinophilic cytoplasm and globular, eosinophilic basement membrane deposits • LCCSCT: Nest, cords, and trabecular or focal tubular growth ○ Large, polygonal cells with abundant eosinophilic, ground-glass cytoplasm, nuclei with vesicular chromatin and variably prominent nucleoli ○ Hallmark calcifications that may be large, irregular, wavy, laminated, or psammomatous ○ Myxoid or fibromyxoid stroma ○ Malignant LCCSCT with ≥ 2 of following: > 4 cm, > 3 mitosis/10 HPF, significant nuclear atypia, necrosis, LVI, and extratesticular growth • SCT: Tubular (hallmark), microcystic, cords, and nests or solid growths ○ Nodular pattern on low-power view often separated by fibrous or acellular stroma ○ Tubules may be solid, hollow, or dilated ○ Regular cuboidal or columnar cells with bland round nuclei, occasional nucleoli, and pale to pink cytoplasm that may be vacuolated ○ Usually paucicellular, hyalinized, or fibrous stroma

ANCILLARY TESTS Immunohistochemistry • LCCSCT: Positive for SF1, WT1, and S100 • SCT: Positive for SF1, FOXL2, inhibin, and WT1

SELECTED REFERENCES 1.

Mooney KL et al: A contemporary review of common adult non-germ cell tumors of the testis and paratestis. Surg Pathol Clin. 11(4):739-58, 2018

359

Diagnoses Associated With Syndromes by Organ: Genitourinary

Sertoli Cell Neoplasms

ILCHSCN

ILCHSCN and LCCSCT

ILCHSCN and LCCSCT

LCCSCT

LCCSCT

LCCSCT

(Left) High-power view shows ILCHSCN in a Peutz-Jeghers syndrome testis, composed of large Sertoli cells ﬈ with abundant eosinophilic cytoplasm surrounded by thickened basement membrane material. The nuclei are round to ovoid with no detectable mitosis. (Right) Low-power view shows ILCHSCN ﬈ adjacent to LCCSCT ﬊. ILCHSCN is an intratubular process that does not form a mass lesion. A subset of ILCHSCN may become invasive to form LCCSCT or SCT.

(Left) High-power view shows neoplastic Sertoli cells from ILCHSCN that appears to infiltrate into the stroma ﬈. The adjacent cluster of neoplastic Sertoli cells in contrast shows abundant glassy eosinophilic cytoplasm ﬊ seen in LCCSCT. ILCHSCN may give rise to LCCSCT. (Right) LCCSCT shows solid tubules, cords, and small nests of large polygonal cells with abundant eosinophilic cytoplasm in a paucicellular fibromyxoid stroma. Focal calcification is present ﬈. Most LCCSCTs are benign, but malignant cases may occur.

(Left) High-power view of LCCSCT shows the characteristic large, polygonal pink cells with bland nuclei in a paucicellular fibromyxoid stroma. Mitosis is usually rare or absent but can be increased in malignant cases (> 3 mitosis/10 HPF). (Right) LCCSCT shows abundant small and large, irregular calcifications with ossifications. Calcifications in LCCSCT vary and can be psammomatous, wavy, or laminated. The tumor cells with pale eosinophilic cytoplasm are seen adjacent to the calcifications.

360

Sertoli Cell Neoplasms

Sertoli Cell Tumor Architectural Patterns (Left) SCT shows cords and tubules composed of polygonal cells with modest light eosinophilic cytoplasm and regular round to ovoid nuclei in a fibrous background. Note the presence of cytoplasmic vacuolations, which is common in SCT. (Right) SCT is characterized by tubular formations that can be solid ﬈, hollow ﬊, or dilated ﬉. Dilated tubules are occasionally lined by more flattened cells and may ramify to resemble rete testis (retiform pattern). Note the presence of light eosinophilic secretions in tubular lumina.

Sertoli Cell Tumor Cellular Features

Diagnoses Associated With Syndromes by Organ: Genitourinary

Sertoli Cell Tumor

Sertoli Cell Tumor Cell Vacuolations (Left) High-power view shows SCT composed of polygonal cells with a modest amount of pale to light eosinophilic cytoplasm. The nuclei usually do not exhibit prominent nucleoli, and mitosis is rare in > 80% of cases, particularly in the well-differentiated (tubule-forming) tumors. (Right) H&E shows SCT exhibiting a more solid growth. The tumor cells have abundant lipid-filled cytoplasmic vacuoles. Some of the vacuoles are multiple and large, which indents the nuclei.

Sertoli Cell Tumor Architectural Patterns

FOXL2 in Sertoli Cell Tumor (Left) Low-power view of SCT shows mainly cords of tumor cells in a collagenous stroma. Several dilated tubules are also present ﬈. (Courtesy M. Aron, MD.) (Right) SCT shows diffuse nuclear staining with FOXL2, which is positive in ~ 70% of tumors. Other markers that can be positive in SCT include SF1 (~ 65%), inhibin (~ 55%), WT1 (~ 65%), and βcatenin (~ 70%). SCT can be mimicked by yolk sac tumor [SALL4(+)], seminoma [SALL4 or OCT3/4(+)], and adenomatoid tumor [inhibin or SF1(-)]. (Courtesy M. Aron, MD.)

361

Diagnoses Associated With Syndromes by Organ: Genitourinary

Testicle Table Familial Testicular Tumors Conditions

Gene(s)

Familial testicular GCT (female relatives with familial ovarian GCT)

KITLG, SPRY4, BAK1, DAZL, PRDM14, DMRT1, TEX14, GCNIS and GCT (tumors reported are postpubertal CENPE, PMF1, TERT, ATF7IP, and PITX1 by genome-wide types) association studies

Testicular Tumors

Peutz-Jeghers syndrome

STK11/LKB1

ILCHSCN, LCCSCT, and Sertoli cell tumor

Carney complex

PRKAR1A (mutations seen in up to 70%)

LCCSCT is considered major diagnostic criterion of Carney complex

GCT = germ cell tumor; GCNIS = germ cell neoplasia in situ; ILCHSCN = intratubular large-cell hyalinizing Sertoli cell neoplasia; LCCSCT = large-cell calcifying Sertoli cell tumor.

Tumors With Diffuse Arrangement and Pale and Clear Cytoplasm Antibody

Classic Seminoma

Spermatocytic Tumor

Embryonal Carcinoma

Yolk Sac Tumor

Sertoli Cell Tumor

Lymphoma

Renal Cell Carcinoma

Melanoma

PLAP

+

-

+

-/+

-

-

-

-

SALL4

+

+ (weak)

+

+

-

+/-

-

-

CD117

+

+

-

-/+

-

-/+

V

V

OCT3/4

+

-

+

-

-

-

-

-

CD30 (BER-H2)

-/+ (+ rare cells)

-

+

-

-

V

ND

-

SOX2

-

-

+

-

ND

+/-

ND

+

PAN-CK (AE1/AE3)

-

-

+

+

+/-

-

+

-

CK7

V

ND

+

-/+

-

-

V

-

EMA/MUC1

-

-

+

-/+

V

-

+

-

α-fetoprotein

-

-

-

+

-

ND

-

-

Glypican-3

-

-

-

+

-

-

-

-

GATA3

-

-

-/+

+

-

+/-

-

-

Inhibin

- (+ STC)

ND

-

-

+

-

-

-

SF1

-

-

-

-

+

ND

-

ND

β-catenin

-

-

-

-

+

V

-

-

CD45 (LCA)

-

-

-

-

-

+

-

-

S100

-

-

-

-

-/+

-

-

+

RCC

-

ND

V

-

-

-

+

-

ND = no data; STC = syncytiotrophoblast; V = variable.

Tumors With Glandular/Tubular Pattern

362

Antibody

Embryonal Carcinoma

Seminoma

Yolk Sac Tumor

Sertoli Cell Tumor

Rete Testis Tumor

Metastatic Adenocarcinoma

SALL4

+

+

+

-

-

V

OCT3/4

+

+

-

-

-

-

CD30 (BER-H2)

+

-/+ (rare focal cells) + (rare)

-

V

CD117

-

+

-

-

-

V

α-fetoprotein

-

-

+

-

-

-

Glypican-3

-

-

+

-

-

-/+ (+ in hepatocellular carcinoma)

EMA

-

-

-/+

-

V

+

Inhibin

-

-

-

+

-

-

SF1

-

-

-

+

+

-/+ (+ in adrenocortical

Testicle Table

Antibody

Embryonal Carcinoma

Seminoma

Yolk Sac Tumor

Sertoli Cell Tumor

Rete Testis Tumor

Metastatic Adenocarcinoma

β-catenin

-

-

-

+

ND

-/+ (+ in colonic adenocarcinoma)

Calretinin

-

-

-

+

+

-/+

tumors)

ND = no data; V = variable.

Tumors With Oxyphilic Cytoplasm Antibody

Leydig Cell Tumor

Large-Cell Calcifying Sertoli Cell

Sertoli Cell Tumor, NOS

Carcinoid

Plasmacytoma

Inhibin

+

+

V

-

-

Calretinin

+

+/-

+

-

-

Melan A

+

-

V

-

-

WT1

-

+/-

+

-

-

β-catenin

-

+/-

+

-

-

S100

V

+

V

V

V

Synaptophysin

V

ND

V

+

-

PAN-CK (AE1/AE3)

-/+

-/+

+/-

+

-

Diagnoses Associated With Syndromes by Organ: Genitourinary

Tumors With Glandular/Tubular Pattern (Continued)

NOS = not otherwise specified; ND = no data; V = variable.

8th AJCC Staging System for Testicular Cancer Stage

Definition

Primary Tumor (pT) pT0

No evidence of primary tumor

pTis

Germ cell neoplasia in situ

pT1

Tumor limited to testis (including rete invasion) without lymphovascular invasion

     pT1a*

Tumor < 3 cm in size

     pT1b*

Tumor ≥ 3 cm in size

pT2

Tumor limited to testis (including rete testis invasion) with lymphovascular invasion Tumor invading hilar soft tissue, epididymis, or penetrating visceral mesothelial layer covering external surface of tunica albuginea ± lymphovascular invasion

pT3

Tumor invades spermatic cord ± lymphovascular invasion

pT4

Tumor invades the scrotum ± lymphovascular invasion

Regional Lymph Nodes (pN) pN0

No regional lymph node metastasis

pN1

Metastasis with lymph node mass ≤ 2 cm in greatest dimension and ≤ 5 nodes positive, none > 2 cm in greatest dimension

pN2

Metastasis with lymph node mass > 2 cm but not > 5 cm in greatest dimension; or > 5 lymph nodes positive, none > 5 cm; or evidence of extranodal tumor extension

pN3

Metastasis with a lymph node mass > 5 cm in greatest dimension

Distant Metastasis (M) M0

No distant metastasis

M1

Distant metastasis

M1a

Nonretroperitoneal nodal or pulmonary metastases

M1b

Nonpulmonary visceral metastases

*Applies to pure seminoma only; Adapted from 8th edition AJCC Staging System (2017).

363

Diagnoses Associated With Syndromes by Organ: Genitourinary

Testicle Table

Testis and Paratestis Anatomy

Seminiferous Tubules With Spermatogenesis

Seminiferous Tubules With Spermatogenesis

Seminoma on Ultrasound

Seminoma

Embryonal Carcinoma

(Left) Graphic of testis and paratestis is shown. The testicular parenchyma is separated by fibrous septae ﬈. The tubules converge and exit to the rete testis ﬊, efferent ducts ﬇, epididymis st, and vas deferens ſt. (Right) Graphic shows seminiferous tubule (ST) with spermatogenesis (spermatogonia ſt, spermatocytes ﬇, spermatids ﬉, spermatozoa ﬈). Cellular maturation progresses from base to lumina. Sertoli cells st and Leydig cells ﬊ are also shown and have supportive roles in spermatogenesis.

(Left) ST shows spermatogenesis. The largest cell in a normal ST is the primary spermatocyte ﬈, usually situated about halfway toward the lumen. Primary spermatocytes have beaded (spireme) nuclear chromatin. In GCNIS, large atypical cells with nucleoli are seen usually adjacent to basement membrane. Note the Leydig ﬉ and Sertoli cells ﬊. (Right) Longitudinal ultrasound shows a large seminoma ſt. Despite its large size, it remains homogeneous without evidence of necrosis.

(Left) Gross photograph of resected testis shows seminoma ﬈ to be relatively uniform in texture without necrosis and with minimal hemorrhages, resulting in its homogeneous echogenicity on ultrasound. Normal testis parenchyma is softer and more granular ſt. (Right) Embryonal carcinoma (EC) shows circumscribed variegated hemorrhagic tumor. Tumor size is not a variable when staging EC (unlike in seminoma). Staging is based on extent of invasion to surrounding structures and by LVI.

364

Testicle Table

Rete Testis Invasion (Left) This mixed germ cell tumor (GCT) ſt shows a variegated cut surface because of the mixed components. The tumor is organ-confined, and in this case, identification of LVI is crucial for staging. (Right) Low-power view shows seminoma invading the rete testis. Invasion of rete testis is suggested to be an adverse prognostic indicator but is not currently incorporated in staging. GCNIS can also be seen spreading in the rete testis ﬈. Only the invasive tumor is considered for positive rete testis invasion.

Lymphovascular Invasion

Diagnoses Associated With Syndromes by Organ: Genitourinary

Mixed Germ Cell Tumor

Lymphatic Drainage of Testis (Left) Multiple EC emboli are seen inside the vessel lumina. Note the tumor clusters follow the vessel contour. Presence of LVI upstages a testisconfined tumor from pT1 to pT2 and should be diligently searched in orchiectomy specimens. (Right) Graphic shows testicular lymphatic drainage. The primary pathway (yellow) follows the testicular veins. If tumor has invaded through the tunica vaginalis into the scrotal skin, the inguinal nodes may be involved.

Retroperitoneal GCT Metastasis

Retroperitoneal Metastasis of Mixed GCT (Left) Axial CECT in a patient with a right testicular carcinoma shows bulky retroperitoneal adenopathy ſt. The right testis lymphatics drain to the aortocaval nodes just inferior to the right renal hilum. (Right) This mixed GCT has metastasized into a retroperitoneal lymph node. Note presence of extranodal tumor extension ﬈. Size of nodal metastasis (pN1: ≤ 2 cm, pN2: 2-5 cm, and pN3: > 5 cm) and presence of extranodal extension (pN2) are used in subcategorizing pN status.

365

Diagnoses Associated With Syndromes by Organ: Genitourinary

Testicle Table

PLAP in Seminoma and GCNIS

OCT3/4 in Seminoma

CD117 in Seminoma

CD30 in Embryonal Carcinoma

OCT3/4 in Mixed Germ Cell Tumor

GATA3 in Mixed Germ Cell Tumor

(Left) PLAP shows diffuse membranous and cytoplasmic staining of seminoma cells ﬈. GCNIS cells in the STs are also positive for PLAP ﬉. PLAP is considered a pan-GCT marker. (Right) OCT3/4 shows diffuse immunoreactivity in this seminoma. OCT3/4 can be positive in GCNIS, seminoma, and EC. This marker is useful when distinguishing seminoma and EC from other GCTs exhibiting solid growth, such as solid yolk sac tumor and spermatocytic tumor.

(Left) CD117 is diffusely positive in this seminoma. It is also immunoreactive in GCNIS and spermatocytic tumor and is useful when distinguishing seminoma from EC [CD117(-)] and solid yolk sac tumor [usually CD117(-)]. (Right) CD30 shows diffuse membranous immunoreactivity in this EC. CD30 is highly specific for EC and is often done to compliment CD117 when distinguishing EC from seminoma [CD30(-) and CD117(+)]. SOX2 is another marker for EC.

(Left) OCT3/4 highlights the EC elements, whereas the adjacent solid yolk sac tumor is negative ﬈. Distinction of GCT components is mainly based on morphology, and use of IHC should not be frequent. (Right) GATA3 highlights the yolk sac tumor component whereas the adjacent EC cells are negative ﬈. GATA3 can also be useful to distinguish yolk sac tumor from seminoma [GATA3(-)]. The cytotrophoblastic cells in choriocarcinoma are also positive for GATA3.

366

Testicle Table

GATA3 in Choriocarcinoma (Left) Glypican-3 highlights yolk sac element in mixed GCT. Note the EC component is completely negative ﬈. Glypican-3 may also be positive in some teratomas. (Right) GATA3 shows diffuse nuclear staining in the cytotrophoblastic cells component of choriocarcinoma. The syncytiotrophoblasts are negative for GATA3 ﬈. Distinction between cytotrophoblastic cells and solid yolk sac tumor is challenging, compounded by GATA3(+) in both.

Desmin in Rhabdomyosarcoma From GCT

Diagnoses Associated With Syndromes by Organ: Genitourinary

Glypican-3 in Mixed Germ Cell Tumor

Inhibin in Leydig Cell Tumor (Left) Desmin shows cytoplasmic positivity in this rhabdomyosarcoma (RMS) arising from teratoma. Nonsarcomatous myogenic differentiation [desmin (+)] may also occur in teratoma after therapy and should be distinguished morphologically from RMS. (Right) Inhibin shows diffuse positivity in this Leydig cell tumor. Inhibin is expressed by all sex cordstromal tumors (SCSTs) and is often used to complement PLAP or SALL4 when distinguishing SCSTs from GCTs [inhibin(-) and PLAP or SALL4(+)].

Calretinin in Sertoli Cell Tumor

SF1 in Leydig Cell Tumor (Left) Calretinin shows positivity in this Sertoli cell tumor. GCTs that also exhibit tubular features such as seminoma, yolk sac tumor, and EC are negative for calretinin. Beware that calretinin is also expressed by paratesticular adenomatoid tumor. (Right) This Leydig cell tumor shows nuclear reactivity to SF1. Most SCSTs express SF1 and can be used to distinguish from GCTs which are negative for SF1. SF1 is also expressed by normal and neoplastic adrenocortical cells.

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PART I SECTION 7

Gynecology Cervical Carcinoma Fallopian Tube Carcinoma Ovarian Tumors Endometrial Carcinoma Gynecologic Tumors

370 372 374 380 384

Diagnoses Associated With Syndromes by Organ: Gynecology

Cervical Carcinoma KEY FACTS

TERMINOLOGY • Majority of non-HPV-associated cervical adenocarcinomas are gastric-type endocervical adenocarcinoma (GAS) ○ Minimal deviation adenocarcinoma (MDA) represents extremely well-differentiated, rare variant of GAS • Peutz-Jeghers syndrome (PJS) ○ Characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyps ○ Increased cancer risk in multiple sites, including gastrointestinal, pancreas, breast, thyroid, lung, testis, and gynecologic ○ Gynecologic tumors – GAS, including MDA – Sex cord-stromal tumor with annular tubules (SCTAT)

ETIOLOGY/PATHOGENESIS • PJS ○ Germline mutations of STK11 (LKB1) tumor suppressor gene

○ Incidence of GAS in PJS patients is estimated to be 1530%, with mean age at diagnosis of 33 years ○ Among GAS, ~ 10% are associated with PJS

MICROSCOPIC • GAS ○ Irregularly shaped glands that infiltrate cervical wall in haphazard pattern ○ Glands are lined by columnar cells with basal nuclei and abundant apical, pale pink, mucin-rich cytoplasm ○ Most cases of GAS are well differentiated but not to extreme level of prototypic MDA

ANCILLARY TESTS • Negative for HPV by in situ hybridization or other molecular techniques • Great majority of cases are negative for p16 immunohistochemistry

Gastric-Type Endocervical Adenocarcinoma

Gastric-Type Endocervical Adenocarcinoma

Minimal Deviation Adenocarcinoma

Minimal Deviation Adenocarcinoma

(Left) Haphazard infiltration of the cervical wall with marked desmoplastic reaction is shown. (Right) Glands are lined by columnar cells with voluminous, pale pink cytoplasm and show mild to moderate degrees of nuclear atypia.

(Left) Low-power view of minimal deviation adenocarcinoma shows infiltrative glands with irregular outlines in this extremely well-differentiated variant of gastric-type endocervical adenocarcinoma. (Right) Minimal deviation adenocarcinoma is composed of glands lined by tall columnar cells with abundant apical mucin and bland nuclei. Glands are lined by deceptively tall columnar cells with abundant apical, pale pink cytoplasm, well-defined cell membranes, and minimal to no nuclear atypia.

370

Cervical Carcinoma • In some cases, normal-appearing cervix with no discrete lesion

Definitions • Gastric-type endocervical adenocarcinoma (GAS) ○ HPV is implicated in development of 80-90% of endocervical adenocarcinomas ○ Majority of non-HPV-associated cervical adenocarcinomas are GAS ○ Minimal deviation adenocarcinoma (MDA), a.k.a. adenoma malignum, represents extremely welldifferentiated, rare variant of GAS • Peutz-Jeghers syndrome (PJS) ○ Characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyps ○ Increased cancer risk in multiple sites, including gastrointestinal, pancreas, breast, thyroid, lung, testis, and gynecologic ○ Gynecologic tumors – GAS, including MDA – Lobular endocervical glandular hyperplasia (LEGH) – Sex cord-stromal tumor with annular tubules (SCTAT) – Ovarian oxyphilic Sertoli cell tumor – Case report of gastric phenotype ovarian mucinous tumor in patient with PJS

ETIOLOGY/PATHOGENESIS Peutz-Jeghers Syndrome • Autosomal dominant disorder • Caused by germline mutations of STK11 (LKB1) tumor suppressor gene • 25% of cases are de novo

Gastric-Type Endocervical Adenocarcinoma • Not associated with human papillomavirus (HPV) infection, unlike majority of cervical adenocarcinomas • Incidence of GAS in PJS patients is estimated to be 15-30%, with mean age at diagnosis of 33 years • Among GAS, ~ 10% are associated with PJS

CLINICAL ISSUES Presentation • Most patients present with cervical discharge or bleeding • Upon exam, bulky cervix may be detected in some cases

Treatment • Surgery is most important modality of treatment • Chemotherapy and radiation can also be employed

Prognosis • Worse prognosis than HPV-associated endocervical adenocarcinomas • All lesions within GAS spectrum exhibit aggressive behavior, often with advanced stage at presentation compared with HPV-associated adenocarcinomas and propensity for spread to unusual sites, such as peritoneum, omentum, adnexa, liver, brain, and bone

MACROSCOPIC General Features • Enlarged, indurated cervix (barrel-shaped cervix)

MICROSCOPIC Histologic Features • Irregularly shaped glands that infiltrate cervical wall in haphazard pattern with variable stromal reaction (none to desmoplastic) • Morphological resemblance to glandular epithelium seen in foveolar and pyloric gastric glands and pancreaticobiliary tree • Glands are lined by columnar cells with basal nuclei and abundant apical, pale pink, mucin-rich cytoplasm and welldefined cell membranes • Most cases of GAS are well differentiated but not to extreme level of prototypic MDA • Spectrum of differentiation is often seen within individual tumor • Low mitotic rate • Intestinal metaplasia with goblet cells and neuroendocrine cells are present in some cases

Diagnoses Associated With Syndromes by Organ: Gynecology

TERMINOLOGY

ANCILLARY TESTS Histochemistry • Mucin staining patterns [Alcian blue/periodic acid-Schiff (PAS)] may overlap and are not reliable for diagnosis

Immunohistochemistry • Great majority of cases are negative for p16 • Gastric immunophenotype has been demonstrated by MUC6 and HIK1083; however, some cases are focal or negative • Subset with p53 aberrant immunohistochemical patterns, consistent with mutant type, in ~ 40% of cases • Positive for CK7 and CEA, similar to usual-type cervical adenocarcinomas • ~ 70% are positive for pax-8

In Situ Hybridization • Negative for HPV by in situ hybridization or other molecular techniques

Genetic Testing • Germline testing for STK11 mutations for suspected cases of PJS • Somatic mutations of STK11 have been demonstrated in 6 of 11 sporadic cases of MDA

SELECTED REFERENCES 1.

2. 3.

4.

5. 6.

Kim EN et al: A pyloric gland-phenotype ovarian mucinous tumor resembling lobular endocervical glandular hyperplasia in a patient with Peutz-Jeghers syndrome. J Pathol Transl Med. 51(2):159-64, 2017 Talia KL et al: The developing spectrum of gastric-type cervical glandular lesions. Pathology. 50(2):122-33, 2017 Carleton C et al: A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas. Am J Surg Pathol. 40(5):636-44, 2016 Holl K et al: Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: results from a European multinational epidemiological study. Int J Cancer. 137(12):2858-68, 2015 Banno K et al: Hereditary gynecological tumors associated with PeutzJeghers syndrome (review). Oncol Lett. 6(5):1184-8, 2013 Kuragaki C et al: Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix. Lab Invest. 83(1):35-45, 2003

371

Diagnoses Associated With Syndromes by Organ: Gynecology

Fallopian Tube Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS • Hereditary breast and ovarian cancer (HBOC): Germline BRCA1 and BRCA2 mutations • Li-Fraumeni syndrome: Germline TP53 mutations

CLINICAL ISSUES • Most tubal carcinomas are detected at early stages at riskreducing bilateral salpingo-oophorectomy (RRSO)

MACROSCOPIC • Most RRSO specimens do not have visible gross lesion • Sectioning and extensively examining fimbriated end (SEEFIM) protocol describes how to submit fallopian tubes to optimize detection of microscopic carcinomas

MICROSCOPIC • Serous tubal intraepithelial carcinoma (STIC) or invasive tubal carcinoma is detected in ~ 8% of RRSO specimens and < 1% in average-risk women • STIC is characterized by

○ Cellular stratification and pseudostratification with loss of polarity ○ High nuclear:cytoplasmic ratio and loss of cilia ○ Nuclear enlargement and chromatin irregularities ○ No lamina propria invasion • Majority of invasive tubal carcinomas are serous carcinomas ○ Papillary or solid growth with slit-like spaces ○ Invasion into lamina propria or muscularis ○ Marked nuclear atypia with pleomorphism and brisk mitotic activity

ANCILLARY TESTS • p53-aberrant immunostaining indicative of TP53 mutation ○ Strong diffuse nuclear staining is seen in 90% of cases ○ Remaining 10% show complete absence of nuclear staining in tumor cells (null mutation) • Ki-67 (MIB-1) proliferation index is variable but usually > 40%

Invasive Carcinoma and Serous Tubal Intraepithelial Carcinoma

p53 Immunohistochemistry

Serous Tubal Intraepithelial Carcinoma

Invasive Serous Carcinoma

(Left) Risk-reducing bilateral salpingo-oophorectomy (RRSO) of a patient who tested positive for a germline BRCA2 mutation is shown. The fallopian tube infundibulum reveals a focus of invasive high-grade serous carcinoma ﬊ with adjacent serous tubal intraepithelial carcinoma (STIC) ﬈. (Right) p53 immunohistochemistry shows diffuse and strong nuclear staining in both invasive carcinoma and STIC.

(Left) On high magnification, STIC ﬊ reveals stratification, with cellular enlargement and nuclear pleomorphism, compared with the adjacent single-layered, benign fallopian tube epithelium ﬈, which contains orderly, bland nuclei. (Right) High-grade serous carcinoma invades the lamina propria of the fallopian tube in a haphazard growth pattern.

372

Fallopian Tube Carcinoma

MICROSCOPIC

Hereditary Breast and Ovarian Cancer

Histologic Features

• Caused by germline BRCA1 and BRCA2 mutations with increased risk for breast and gynecologic cancers, including ovary, fallopian tube, and peritoneum • Germline mutations in other genes, such as genes involved in Fanconi anemia-BRCA pathway, might be related to development of fallopian tube cancer, but data is limited • p53 signatures are believed to be precursor lesion for development of serous tubal intraepithelial carcinoma (STIC)

• STIC or invasive tubal carcinoma is detected in ~ 8% of RRSO specimens and < 1% in average-risk women • Majority are STIC ○ Cellular stratification and pseudostratification with loss of polarity ○ Marked cytologic atypia when compared with background tubal epithelium ○ High nuclear:cytoplasmic ratio and loss of cilia ○ Nuclear enlargement and chromatin irregularities ○ No lamina propria invasion • Most invasive tumors in tube are high-grade serous carcinomas ○ Papillary or solid growth with slit-like spaces ○ Invasion into lamina propria or muscularis ○ Marked nuclear atypia with pleomorphism and brisk mitotic activity • Some carcinomas show undifferentiated or endometrioid histology

Li-Fraumeni Syndrome • Germline mutations of TP53 gene with increased risk for several cancers, including ovary, fallopian tube, and primary peritoneal

CLINICAL ISSUES Epidemiology • Up to 50% lifetime risk of tubal carcinoma in patients with BRCA1 mutations • Up to 30% of women with unselected fallopian tube carcinoma were found to have germline BRCA1 and BRCA2 mutations in recent study

Presentation • Most tubal carcinomas diagnosed in HBOC patients are detected at early stages at risk-reducing bilateral salpingooophorectomy (RRSO)

Treatment • RRSO is recommended between 35-40 years of age or after childbearing is complete • BRCA1- and BRCA2-related tumors have better response to platinum-based chemotherapy and increased sensitivity to poly ADP-ribose polymerase (PARP) inhibitors compared to sporadic carcinomas

Prognosis • STIC has low risk of pelvic recurrence (~ 3-5%) • Invasive serous carcinoma tends to have extratubal disease at time of diagnosis • As for ovarian carcinomas, HBOC tubal carcinomas have better prognosis than sporadic counterpart

Diagnoses Associated With Syndromes by Organ: Gynecology

ETIOLOGY/PATHOGENESIS

ANCILLARY TESTS Immunohistochemistry • p53-aberrant immunostaining indicative of TP53 mutation ○ Strong diffuse nuclear staining is seen in 90% of cases ○ Remaining 10% show complete absence of nuclear staining in tumor cells (null mutation) • p53 signature ○ Defined as strong and diffuse p53 immunoreaction in 12 or more consecutive tubal secretory cells ○ To be considered p53 signature, focus in question should not demonstrate cytologic atypia ○ p53 signatures have been shown to harbor TP53 mutations by molecular genetic studies

Genetic Testing • DNA sequencing for germline mutations in BRCA1 and BRCA2 genes • Consider BRCA1 and BRCA2 mutational analysis in all patients diagnosed with fallopian tube carcinoma

SELECTED REFERENCES 1.

MACROSCOPIC Gross Findings

2.

• Most RRSO specimens do not have visible gross lesion • Majority of both STIC and invasive tubal carcinomas in RRSO specimens are found in distal tube, particularly fimbriae • Bilateral fallopian tubes received as part of RRSO specimen should be fixed in formalin prior to sectioning • Sectioning and extensively examining fimbriated end (SEEFIM) protocol describes how to submit fallopian tubes to optimize detection of microscopic carcinomas • Frozen section examination of RRSO specimen is not recommended unless grossly visible suspicious lesion is present

3.

4.

5.

Soong TR et al: The fallopian tube, "precursor escape" and narrowing the knowledge gap to the origins of high-grade serous carcinoma. Gynecol Oncol. 152(2):426-33, 2019 Meserve EEK et al: Serous tubal intraepithelial neoplasia: the concept and its application. Mod Pathol. 30(5):710-21, 2017 Howitt BE et al: Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma. Am J Surg Pathol. 39(3):287-93, 2015 Mingels MJ et al: Tubal epithelial lesions in salpingo-oophorectomy specimens of BRCA-mutation carriers and controls. Gynecol Oncol. 127(1):88-93, 2012 Vicus D et al: Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol. 118(3):299302, 2010

373

Diagnoses Associated With Syndromes by Organ: Gynecology

Ovarian Tumors KEY FACTS

ETIOLOGY/PATHOGENESIS • Hereditary breast and ovarian cancer (HBOC) ○ Germline BRCA1 and BRCA2 mutations • Lynch syndrome (LS) ○ Germline mutations of MLH1, MSH2, MSH6, and PMS2 • Peutz-Jeghers syndrome (PJS) ○ Mutations in serine threonine kinase 11 (STK11) • DICER1 syndrome ○ Germline DICER1 mutations usually result in protein truncation followed by somatic missense mutations in tumors • Rhabdoid tumor predisposition syndrome 2 (RTPS2) ○ Germline SMARCA4 (BRG1) mutations, member of SWISNF complex

CLINICAL ISSUES • HBOC ○ Patients are at risk for developing ovarian, fallopian tube, and primary peritoneal carcinomas in addition to breast, pancreatobiliary, and prostate cancer • LS ○ Cancers of gastrointestinal tract, endometrium, ovaries, hepatobiliary, urinary tract, brain, and skin • PJS ○ Hamartomatous gastrointestinal polyps and mucocutaneous pigmentation ○ Increased risk for multiple cancers, including – Gastrointestinal – Pancreas – Breast – Lung ○ Gynecologic tumors include – Cervical gastric-type adenocarcinoma – Ovarian sex cord-stromal tumor with annular tubules (SCTAT) • DICER1 syndrome ○ Highly characteristic rare tumors in children and young adults, including

– Pleuropulmonary blastoma – Cystic nephroma – Thyroid hyperplasia and carcinoma – Pituitary blastoma, pineoblastoma – Ciliary body medulloepithelioma ○ Gynecologic tumors include – Ovarian Sertoli-Leydig cell tumors – Cervical embryonal rhabdomyosarcoma • RTPS2 ○ Poorly differentiated tumors, some with rhabdoid morphology, including – CNS atypical teratoid/rhabdoid tumor – Renal malignant rhabdoid tumor – Small-cell carcinoma of ovary, hypercalcemic type (SCCOHT)

MICROSCOPIC • HBOC ○ Most are high-grade serous carcinomas • LS ○ Characteristically müllerian carcinomas – Various subtypes with predominance of endometrioid adenocarcinomas – Serous, clear cell, and mucinous • PJS ○ SCTAT in PJS tends to be microscopic, bilateral, multifocal, and calcified • DICER1 syndrome ○ Sertoli-Leydig cell tumors seen in DICER1 syndrome are characteristically moderately and poorly differentiated • RTPS2 ○ Small-cell carcinoma, hypercalcemic type (SCCOHT) shows loss of SMARCA4/BRG1 and SMARCA2/BRM nuclear expression by immunohistochemistry

High-Grade Serous Carcinoma (Left) Gross photo shows highgrade serous carcinoma forming a large, solid ovarian mass. (Right) High-grade serous carcinoma typically grows in papillary configurations and forms cleft-like spaces.

374

High-Grade Serous Carcinoma

Ovarian Tumors

Hereditary Breast and Ovarian Cancer • Autosomal dominant • Germline BRCA1 and BRCA2 mutations • BRCA1 and BRCA2 repair DNA damage through homologous recombination

Germline Mutations of Genes in FA-BRCA Pathway • RAD51C, RAD51D, BRIP1, PALB2, ATM, among others • Monoallelic germline mutations of these genes have been identified in highly penetrant breast and ovarian cancer families lacking BRCA1/BRCA2 mutations • FA-BRCA pathway plays role in homologous recombination

Lynch Syndrome • Autosomal dominant • Germline mutations of MLH1, MSH2, MSH6, and PMS2 • DNA mismatch repair genes that excise errors occurring during DNA replication

Peutz-Jeghers Syndrome • Autosomal dominant • Mutations in serine threonine kinase 11 (STK11)

DICER1 Syndrome • Autosomal dominant • Germline DICER1 mutations usually result in protein truncation followed by somatic missense mutations in tumors • Pathomechanism of tumorigenesis in DICER1 syndrome is poorly understood

Rhabdoid Tumor Predisposition Syndrome 2 • Autosomal dominant • Germline SMARCA4 (BRG1) mutations, member of SWI-SNF complex

CLINICAL ISSUES Epidemiology • Hereditary breast and ovarian cancer (HBOC) ○ Account for majority of hereditary ovarian cancers ○ 13-15% of women with invasive ovarian cancer harbor germline mutations of BRCA1 or BRCA2 ○ Proportion of ovarian cancer that is hereditary varies with prevalence of founder mutations in each population ○ In women of Ashkenazi decent, 35-40% of ovarian carcinomas are associated with BRCA1 or BRCA2 mutations ○ Lifetime risk for ovarian cancer – 35-60% for BRCA1 – 11-18% for BRCA2 ○ Average age of ovarian cancer onset – 50 years for BRCA1 mutation – 60 years for BRCA2 mutation – 63 years in general population ○ Women with very early-onset ovarian cancer (< 40 years old) are less likely to harbor BRCA1/BRCA2 mutations, unlike breast cancer • Lynch syndrome (LS) ○ Approximately 2-4% of ovarian cancers are believed to be associated with LS

○ Lifetime risk for ovarian cancer is estimated at 11% ○ Mean age at diagnosis is 45.3 (range: 19-82) years with 1/3 of patients < 40 years old • Peutz-Jeughers syndrome (PJS) ○ Estimated 10x increase cancer incidence compared to general population ○ Lifetime risk for ovarian tumors is estimated at 18-21% ○ 1/2 of patients with ovarian tumors present at ≤ 22 years old ○ Up to 35% of women with sex-cord stromal tumor with annular tubules (SCTATs) are found to have PJS • DICER1 syndrome ○ Ovarian sex-cord stromal tumors tend to occur in patients 10-25 years old with reported range of 2-45 years old • Rhabdoid tumor predisposition syndrome (RTPS2) ○ Average age for presentation of ovarian small-cell carcinoma, hypercalcemic type (SCCOHT) is 24 years old ○ In one recent study, incidence of germline SMARCA4 mutation in SCCOHT was 43%

Diagnoses Associated With Syndromes by Organ: Gynecology

ETIOLOGY/PATHOGENESIS

Presentation • HBOC ○ Patients are at risk for developing ovarian, fallopian tube, and primary peritoneal carcinomas in addition to breast, pancreatobiliary, and prostate cancer • LS ○ Cancers of gastrointestinal tract, endometrium, ovaries, hepatobiliary, urinary tract, brain, and skin ○ Women with synchronous endometrial and ovarian endometrioid adenocarcinomas and with lower uterine segment primaries are more likely to have LS • PJS ○ Hamartomatous gastrointestinal polyps and mucocutaneous pigmentation ○ Increased risk for multiple cancers, including gastrointestinal, pancreas, breast, and lung ○ Gynecologic tumors include – Cervix: Adenocarcinoma, gastric type (including minimal deviation adenocarcinoma), characteristically HPV negative – Ovary: SCTAT – Endometrium: Increased risk for endometrial adenocarcinoma ○ Ovarian sex cord-stromal tumors may lead to abnormal uterine bleeding, precocious puberty, and infertility • DICER1 syndrome ○ Highly characteristic rare tumors in children and young adults, including pleuropulmonary blastoma, cystic nephroma, thyroid hyperplasia and carcinoma, pituitary blastoma, pineoblastoma, ciliary body medulloepithelioma ○ Gynecologic tumors include ovarian Sertoli-Leydig cell tumors and cervical embryonal rhabdomyosarcoma ○ Ovarian Sertoli-Leydig cell tumors are usually associated with androgenic manifestations and less commonly with estrogenic manifestations • RTPS2 ○ Poorly differentiated tumors, some with rhabdoid morphology

375

Diagnoses Associated With Syndromes by Organ: Gynecology

Ovarian Tumors – Central nervous system: Atypical teratoid/rhabdoid tumor – Kidney: Malignant rhabdoid tumor – Ovary: Small-cell carcinoma, hypercalcemic type (SCCOHT) ○ 2/3 of patients with SCCOHT have hypercalcemia

Treatment • HBOC ○ Risk-reducing bilateral salpingo-oophorectomy (RRSO) at age 35-40, or after childbearing is complete ○ After RRSO, patients still have estimated 4% risk of primary peritoneal cancer development ○ Oral contraceptives have been shown to reduce ovarian cancer risk by 50% in patients choosing nonsurgical approach ○ BRCA1/BRCA2-related ovarian cancers have better response to platinum-based agents compared to nonmutation carriers ○ Increased sensitivity to poly ADP-ribose polymerase (PARP) inhibitors compared to sporadic carcinomas • LS ○ Hysterectomy and bilateral salpingo-oophorectomy recommended after childbearing is complete • PJS ○ Tumors arising in PJS setting are treated in same manner as sporadic ovarian tumors of same histologic subtype • DICER1 syndrome ○ Ovarian sex cord-stromal tumors can be treated with fertility-sparing surgery for stage I tumors; more aggressive surgery and chemotherapy are indicated for higher stage tumors • RTPS2 ○ Surgery and aggressive chemotherapy for SCCOHT

Prognosis • HBOC ○ BRCA1/BRCA2-related ovarian cancers have better prognosis than nonmutation carriers • LS ○ There are no prognostic differences between sporadic and hereditary ovarian tumors associated with this syndrome • PJS ○ Behavior of PJS-associated SCTAT tends to be benign with rare exceptions ○ Malignant behavior occurs in 20% of sporadic SCTAT • DICER1 syndrome ○ Ovarian sex cord-stromal tumors in DICER1 syndrome tend to have favorable outcome ○ Up to 10% of poorly differentiated Sertoli-Leydig cell tumors in general can behave in malignant fashion • RTPS2 ○ Most patients with SCCOHT present with advanced stage disease ○ Prognosis is poor for SCCOHT with 5-year survival of 55% for stage I tumors, 32% for stages II and III tumors, and rapidly fatal for stage IV tumors

Surveillance • HBOC 376

○ Transvaginal ultrasound and CA-125 are recommended every 6 months starting at age 30, or 5-10 years before earliest age at onset of ovarian cancer in patient's family • LS ○ No specific recommendations have been outlined for ovarian cancer • PJS ○ Annual pelvic examination starting at age 18-20 • DICER1 syndrome and RTPS2 ○ Surveillance for these syndromes has not been defined

MACROSCOPIC HBOC • 2.5-17.0% of patients undergoing RRSO have occult ovarian, fallopian tube, or peritoneal carcinoma upon pathologic examination • Extensive sampling of RRSO specimens should be performed, including histopathologic examination of entire ovaries and fallopian tubes • Ovaries should be transversely sectioned in 5 mm intervals along greater axis and all cross sections submitted

PJS • PJS-associated SCTAT tends to be bilateral, multifocal, and calcified • Most are incidental microscopic findings but can also present as small yellow parenchymal nodules

DICER1 Syndrome • Sertoli-Leydig cell tumors are typically unilateral, yellow, solid, lobulated ovarian masses; often large tumors

RTPS2 • SCCOHT tend to be unilateral large ovarian tumors, solid, fleshy with areas of necrosis and cystic degeneration

MICROSCOPIC Histologic Features • HBOC ○ Most are high-grade serous carcinomas ○ Solid, endometrioid and transitional (SET) pattern is associated with BRCA-related tumors ○ Borderline tumors and mucinous carcinomas are uncommon ○ Ovaries and fallopian tubes should be scrutinized for occult microscopic carcinoma • LS ○ Characteristically müllerian carcinomas ○ Histologic subtypes include endometrioid, serous, clear cell, and mucinous ○ Higher proportion of endometrioid subtype than nonmutation carriers • PJS ○ Patients are particularly at risk for SCTAT ○ SCTAT are characterized by tumors cells forming tubules, surrounding hyalinized eosinophilic material with antipodal polarization ○ Oxyphilic Sertoli cell tumor has also been described in association with PJS • DICER1 syndrome

Ovarian Tumors

ANCILLARY TESTS Immunohistochemistry and Molecular Genetics • HBOC ○ Germline testing for BRCA1 and BRCA2 ○ Commercially available tests include sequencing of all coding exons and exon-intron boundaries, as well as testing for common gene rearrangements ○ Commercial panels, including other genes associated with HBOC, are available • LS ○ Paraffin-embedded tissue can be evaluated for immunohistochemistry for mismatch repair proteins – MLH1 – MSH2 – MSH6 – PMS2 ○ MLH1 promoter hypermethylation is indicated if loss of MLH1/PMS2 ○ Germline mutation testing for MLH1, MSH2, MSH6, and PMS2 • PJS ○ SCTAT is positive for sex cord-stromal markers by immunohistochemistry, including SF1, inhibin, and calretinin ○ Testing for germline alterations of STK11 ○ STK11 alterations are found in 94% of individuals with clinical diagnosis of PJS ○ Majority of mutations are missense or truncating but up to 30% are large deletions ○ Optimal testing includes both DNA sequencing and analysis for large deletions/duplications • DICER1 syndrome

○ Sertoli-Leydig cell tumor is positive for sex cord-stromal markers by immunohistochemistry, including SF1, inhibin, and calretinin ○ DICER1 mutations, either germline or somatic, are encountered in majority of moderately and poorly differentiated Sertoli-Leydig cell tumors ○ DICER1 immunohistochemistry does not detect protein alterations indicative of mutations in tumors • RTPS2 ○ Like other tumors in RTPS2 spectrum, SCCOHT shows loss of SMARCA4/BRG1 and SMARCA2/BRM nuclear expression by immunohistochemistry – Although highly supportive of diagnosis of SCCOHT in appropriate clinical context, this immunophenotype is not entirely sensitive or specific ○ Other immunohistochemical features of SCCOHT – Positive: WT1, CD10, vimentin, SALL4 – EMA and keratins can be focally positive in large cells – Negative: Sex cord-stromal markers (inhibin, calretinin), CD99 – Neuroendocrine markers tend to be negative but can be focally positive

Diagnoses Associated With Syndromes by Organ: Gynecology

○ Sertoli-Leydig cell tumors are ovarian sex cord-stromal tumors composed of predominantly Sertoli cells with variable component of Leydig cells ○ Sertoli component varies in appearance depending on tumor differentiation from well-formed tubules to cellular nests and cords to solid sheets of cells ○ Sertoli-Leydig cell tumors seen in DICER1 syndrome are characteristically moderately and poorly differentiated ○ No well-differentiated Sertoli-Leydig cell tumors have been described in association with DICER1 syndrome to date ○ Heterologous elements can be seen in Sertoli-Leydig cell tumors, including gastrointestinal-type mucinous epithelium, chondroid and rhabdomyosarcomatous elements ○ Some studies have reported DICER1 mutations in ovarian gynandroblastomas, juvenile granulosa cell tumors, sex cord-stromal tumors with unusual features, and rarely ovarian germ cells tumors • RTPS2 ○ SCCOHT is composed of sheets of monotonous noncohesive small round blue cells punctuated by pseudofollicular spaces ○ 40% of SCCOHT have intermixed larger cells, sometimes with rhabdoid features ○ 10% of cases may show mucinous glands

SELECTED REFERENCES 1.

Samadder NJ et al: Hereditary cancer syndromes-a primer on diagnosis and management: part 1: breast-ovarian cancer syndromes. Mayo Clin Proc. 94(6):1084-98, 2019 2. Garg K et al: Uncommon hereditary gynaecological tumour syndromes: pathological features in tumours that may predict risk for a germline mutation. Pathology. 50(2):238-56, 2018 3. Lim D et al: Ovarian sex cord-stromal tumours: an update in recent molecular advances. Pathology. 50(2):178-89, 2018 4. de Kock L et al: DICER1 mutations are consistently present in moderately and poorly differentiated Sertoli-Leydig cell tumors. Am J Surg Pathol. 41(9):1178-87, 2017 5. Fuller PJ et al: Genetics and genomics of ovarian sex cord-stromal tumors. Clin Genet. 91(2):285-91, 2017 6. Helder-Woolderink JM et al: Ovarian cancer in Lynch syndrome; a systematic review. Eur J Cancer. 55:65-73, 2016 7. Ritterhouse LL et al: Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas. Mod Pathol. 29(8):893-903, 2016 8. Ballinger LL: Hereditary gynecologic cancers: risk assessment, counseling, testing and management. Obstet Gynecol Clin North Am. 39(2):165-81, 2012 9. Pennington KP et al: Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol. 124(2):347-53, 2012 10. Soslow RA et al: Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol. 25(4):625-36, 2012 11. Weissman SM et al: Genetic testing by cancer site: ovary. Cancer J. 18(4):3207, 2012 12. Giardiello FM et al: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 119(6):1447-53, 2000

377

Diagnoses Associated With Syndromes by Organ: Gynecology

Ovarian Tumors

High-Grade Serous Carcinoma

High-Grade Serous Carcinoma, SET Pattern

Endometroid Carcinoma of Ovary

Endometrioid Adenocarcinoma

Sex Cord-Stromal Tumor With Annular Tubules

Sex Cord-Stromal Tumor With Annular Tubules

(Left) H&E shows high-grade serous carcinoma with highgrade nuclear atypia characterized by large, hyperchromatic nuclei ﬉. (Right) Solid, endometrioid, and transitional (SET) patterns are associated with BRCArelated high-grade serous carcinoma. H&E shows an area of solid growth. Mitoses are noted ﬈.

(Left) Gross photo shows endometroid carcinoma of the ovary forming a large mass composed of cystic spaces and solid areas. (Right) Endometrioid adenocarcinoma, FIGO grade 1, is characterized by confluent growth of glands lined by pseudostratified columnar epithelium. This histologic subtype is particularly seen in association with Lynch syndrome.

(Left) H&E shows sex cordstromal tumor with annular tubules (SCTAT). Up to 35% of women with SCTAT are found to have Peutz-Jeghers syndrome. (Right) SCTAT consists of pale Sertoli cells arranged around hyaline bodies. SCTAT in PeutzJeghers syndrome tends to be small, calcified, multifocal, and bilateral.

378

Ovarian Tumors Sertoli-Leydig Cell Tumor, Moderately Differentiated (Left) Sertoli-Leydig cell tumor, moderately differentiated, is often seen in association with DICER1 syndrome. The tumor is characterized by nests and cords of Sertoli cells ﬈ and nests of Leydig cells ﬊. (Right) Sertoli-Leydig cell tumor can show mucinous glandular differentiation ﬊.

Sertoli-Leydig Cell Tumor, Poorly Differentiated

Diagnoses Associated With Syndromes by Organ: Gynecology

Sertoli-Leydig Cell Tumor, Moderately Differentiated

Small-Cell Carcinoma of Ovary, Hypercalcemic Type (Left) Sertoli-Leydig cell tumor, poorly differentiated grows as sheets of spindle cells that are difficult to recognize as representing Sertoli cells. Leydig cells are rare (not shown). (Right) Small-cell carcinomas of the ovary, hypercalcemic type (SCCOHT) are characterized by SMARCA4 mutations. Lowpower view shows sheets, nests, and cords of small, monotonous tumor cells and follicular-like spaces containing fluid ﬊. (Courtesy R. Young, MD.)

Small-Cell Carcinoma of Ovary, Hypercalcemic Type

SCCOHT With Mucinous Elements (Left) The follicle-like spaces ﬊ in SCCOHT are seen in ~ 80% of tumors, vary in size and shape, and are not very numerous. Cells have hyperchromatic nuclei and scant cytoplasm. Mitotic activity is high. (Courtesy R. Young, MD.) (Right) A small proportion of SCCOHT shows glandular mucinous elements ﬊. (Courtesy R. Young, MD.)

379

Diagnoses Associated With Syndromes by Organ: Gynecology

Endometrial Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• Lynch syndrome (LS) ○ Multiple cancer disorder caused by germline mutations of mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 ○ Less common causes for LS are EPCAM deletions and germline MLH1 promoter hypermethylation • PTEN-hamartoma tumor syndrome (PHTS)/Cowden syndrome(CS) ○ Germline-inactivating mutations of PTEN tumor suppression gene • Peutz-Jeghers syndrome (PJS) ○ Mutations in serine/threonine kinase STK11 gene

• LS ○ Both endometrioid and nonendometrioid adenocarcinoma histology ○ Higher incidence of high-grade nonendometrioid types than among general population, particularly with MSH2 mutations

CLINICAL ISSUES • LS ○ Increased risk for cancer of gastrointestinal tract, endometrium, ovaries, pancreatobiliary, urinary tract, brain, and skin ○ In women, lifetime risk for endometrial cancer is similar to colorectal cancer (50-60%) ○ Endometrial carcinoma is 1st sentinel malignancy in > 1/2 of women with LS that develop cancer ○ Patients particularly at risk for LS – Synchronous/metachronous colorectal and endometrial cancer – Synchronous endometrial and ovarian carcinomas – Carcinomas originating in lower uterine segment ○ Most experts recommend hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete ○ Favorable response to immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) • PHTS/CS ○ Recent study showed that PTEN-related endometrial cancer risk begins at age 25 and rises to 30% by age 60 • PJS ○ Estimated 9% risk of endometrial cancer by age 65

ANCILLARY TESTS • LS ○ MMR immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 is screening test of choice in endometrial carcinoma ○ Most professional societies have endorsed universal screening in endometrial carcinoma, independent of patient's age and histologic subtype ○ Microsatellite instability (MSI) can result from sporadic or germline loss of MMR protein function and is not as reliable as MMR immunohistochemistry for LS screening in endometrial carcinoma ○ MLH1 promoter hypermethylation is sporadic cause of loss of MLH1 protein expression, and when found, there is no indication for germline testing ○ Germline testing consists of DNA sequencing of MLH1, MSH2, MSH6, and PMS2 ○ ~ 50% of patients with endometrial carcinoma with MMR deficiency (not due to MLH1 hypermethylation) do not harbor apparent germline mutation • PHTS/CS ○ Germline testing for PTEN mutations, large deletion/duplication • PJS ○ Germline testing for STK11 mutations, large deletion/duplication

Polypoid Endometrial Adenocarcinoma (Left) Gross photograph of an endometrial adenocarcinoma, endometrioid type, shows a sessile polypoid lesion involving most of the endometrial cavity. (Right) Endometrial adenocarcinoma, endometrioid type, FIGO grade 1 shows cribriforming glands lined by columnar cells, similar to normal endometrial glands.

380

Endometrial Adenocarcinoma Morphology

Endometrial Carcinoma

Definitions • Endometrial malignant neoplasms that comprise multiple histologic subtypes ○ Endometrioid carcinoma ○ Serous carcinoma ○ Clear cell carcinoma ○ Mixed endometrial carcinomas ○ Carcinosarcoma (malignant mixed müllerian tumor) ○ Undifferentiated/dedifferentiated carcinoma

○ LS prevalence varies by population with > 50 founder mutations identified in Icelandic, French-Canadian, African American, Polish, and Latin American groups • PHTS/CS ○ Lifetime risk for endometrial cancer has been estimated to range from 5-42%, although it is not well defined ○ Recent study showed that PTEN-related endometrial cancer risk begins at age 25 and rises to 30% by age 60 • PJS ○ Estimated 9% risk of endometrial cancer by age 65

Presentation

• Lynch syndrome (LS) ○ Autosomal dominant ○ Multiple cancer disorder caused by germline mutations of mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 ○ Less common causes for LS are EPCAM deletions and germline MLH1 promoter hypermethylation ○ DNA MMR genes excise errors occurring during DNA replication • PTEN-hamartoma tumor syndrome (PHTS) [a.k.a.Cowden syndrome (CS)] or PHTS/CS ○ Autosomal dominant ○ Germline-inactivating mutations of PTEN tumor suppression gene • Peutz-Jeghers syndrome (PJS) ○ Autosomal dominant ○ Mutations in serine/threonine kinase 11 (STK11) gene, a.k.a. LKB1 gene

• LS ○ Increased risk for cancer of gastrointestinal tract, endometrium, ovaries, pancreatobiliary, urinary tract, brain, and skin ○ Patients particularly at risk for LS – Synchronous/metachronous colorectal and endometrial cancer – Synchronous endometrial and ovarian carcinomas – Carcinomas originating in lower uterine segment • PHTS/CS ○ Multiple cancer syndrome with hamartomatous growths in many organs, particularly skin and mucous membranes ○ Increased cancer risk in multiple sites, including breast, thyroid, endometrium, colorectal, kidney, and melanoma ○ Frequent and multiple uterine leiomyomas • PJS ○ Hamartomatous gastrointestinal polyps and mucocutaneous pigmentation ○ Increased risk for multiple cancers, including gastrointestinal, pancreatic, breast, ovarian, cervical, and endometrial

Sporadic

Treatment

• The Cancer Genome Atlas has identified 4 genetically distinct groups of endometrial cancers ○ Ultramutated DNA polymerase epsilon (POLE) ○ Hypermutated microsatellite instable ○ Copy number low microsatellite stable ○ Copy number high

• Most experts recommend hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete for patients with LS • Favorable response to immune checkpoint inhibitors (antiPD-1, anti-PD-L1) in patients with LS • No specific recommendations have been defined for PHTS/CS and PJS regarding endometrial cancer

ETIOLOGY/PATHOGENESIS Genetic Predisposition

CLINICAL ISSUES Epidemiology • LS ○ Accounts for 2-3% of all endometrial cancers and 10% of endometrial cancers diagnosed before 50 years of age ○ In women, lifetime risk for endometrial cancer is similar to colorectal cancer (50-60%) ○ Endometrial carcinoma is 1st sentinel malignancy in > 1/2 of women with LS that develop cancer ○ Women with endometrial carcinoma before age 50 have higher likelihood of having LS, but tumor may develop later in life ○ Risk of endometrial cancer development varies with genetic alteration – 21-57% for MLH1 and MSH2 – 17-26% for MSH6 – 15% for PMS2 ○ Endometrial:colon cancer ratio is higher for MSH6

Diagnoses Associated With Syndromes by Organ: Gynecology

TERMINOLOGY

Prognosis • Does not seem to differ for endometrial carcinomas arising in familial or sporadic settings

Surveillance • Transvaginal ultrasound and endometrial sampling after age 30 is recommended for patients with familial cancer syndromes with increased risk for endometrial cancer

MACROSCOPIC General Features • Synchronous endometrial and ovarian endometrioid adenocarcinomas • Carcinomas of lower uterine segment

MICROSCOPIC Histologic Features • LS 381

Diagnoses Associated With Syndromes by Organ: Gynecology

Endometrial Carcinoma ○ Both endometrioid and nonendometrioid histology ○ Higher incidence of high-grade nonendometrioid types than among general population, particularly with MSH2 mutations ○ As in colorectal cancer, tumor-infiltrating lymphocytes and peritumoral lymphocytes in endometrial carcinoma appear to be predictors of microsatellite instability (MSI) ○ Undifferentiated tumor histology, unlike colon cancer, has not been consistently associated with LS • PHTS/CS and PJS ○ Data regarding histologic subtypes in PHTS/CS and PJS are limited

ANCILLARY TESTS Immunohistochemistry • LS ○ MMR immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 ○ Most professional societies have endorsed universal screening in endometrial carcinoma, independent of patient's age and histologic subtype; however, this strategy has not yet been widely adopted ○ Screening test of choice in endometrial carcinoma as significant proportion of LS-associated endometrial carcinomas are microsatellite low or microsatellite stable by MSI testing, particularly when MSH6 is mutated ○ Loss of nuclear staining is considered abnormal ○ Background nonneoplastic cells, particularly lymphocytes, are good internal positive controls ○ Concurrent loss of MLH1 and PMS2 expression indicates MLH1 gene abnormalities – When PMS2 mutations are present, only PMS2 expression is lost ○ Concurrent loss of MSH2 and MSH6 expression indicates MSH2 gene abnormalities – When MSH6 mutations are present, only MSH6 expression is lost

Genetic Testing • LS ○ MLH1 promoter hypermethylation – Methylation of MLH1 promoter is sporadic cause of loss of MLH1 protein expression – When MLH1 promoter is methylated, there is no indication for germline testing – Performed in DNA extracted from paraffin-embedded tissues ○ MSI – Hallmark of defective MMR – Can result from sporadic or germline loss of MMR protein function – DNA is extracted from both tumor and nonneoplastic tissue – Normal tissue can be extracted from paraffinembedded tissue or peripheral blood lymphocytes – Significant proportion of LS-associated endometrial carcinomas are microsatellite low or microsatellite stable by MSI testing, particularly when MSH6 is mutated – Less reliable as LS screening test in endometrial carcinoma compared to colorectal cancer 382

○ Germline testing – Mutational analysis by DNA sequencing of MLH1, MSH2, MSH6, and PMS2 – Performed in DNA extracted from peripheral blood lymphocytes – Next-generation sequence (NGS) panels have largely replaced single gene testing done by Sanger sequencing in past – ~ 50% of patients with endometrial carcinoma with MMR deficiency (not due to MLH1 hypermethylation) do not harbor apparent germline mutation □ Most of these cases have been shown to contain biallelic acquired somatic mutations or loss of heterozygosity in MMR genes • PHTS/CS ○ Germline testing – PTEN sequencing analysis, large deletion/duplication analysis – Performed in DNA extracted from peripheral blood lymphocytes • PJS ○ Germline testing – STK11 gene sequencing analysis, large deletion/duplication analysis – Performed in DNA extracted from peripheral blood lymphocytes

DIFFERENTIAL DIAGNOSIS SELECTED REFERENCES 1.

Biller LH et al: Recent advances in Lynch syndrome. Fam Cancer. 18(2):211-9, 2019 2. Cho KR et al: International Society of Gynecological Pathologists (ISGyP) endometrial cancer project: guidelines from the special techniques and ancillary studies group. Int J Gynecol Pathol. 38 Suppl 1:S114-22, 2019 3. Ferriss JS et al: Immunotherapy: checkpoint inhibitors in Lynch-associated gynecologic cancers. Curr Treat Options Oncol. 20(10):75, 2019 4. Wadee R et al: A potpourri of pathogenetic pathways in endometrial carcinoma with a focus on Lynch syndrome. Ann Diagn Pathol. 39:92-104, 2019 5. Garg K et al: Uncommon hereditary gynaecological tumour syndromes: pathological features in tumours that may predict risk for a germline mutation. Pathology. 50(2):238-56, 2018 6. Mester J et al: Cowden syndrome: recognizing and managing a not-so-rare hereditary cancer syndrome. J Surg Oncol. 111(1):125-30, 2015 7. Banno K et al: Hereditary gynecological tumors associated with PeutzJeghers syndrome (Review). Oncol Lett. 6(5):1184-8, 2013 8. Miesfeldt S et al: Management of genetic syndromes predisposing to gynecologic cancers. Curr Treat Options Oncol. 14(1):34-50, 2013 9. Ballinger LL: Hereditary gynecologic cancers: risk assessment, counseling, testing and management. Obstet Gynecol Clin North Am. 39(2):165-81, 2012 10. Tan MH et al: Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 18(2):400-7, 2012 11. Broaddus RR et al: Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer. 106(1):87-94, 2006

Endometrial Carcinoma

Serous Adenocarcinoma (Left) Endometrioid adenocarcinoma shows backto-back glands lined by pseudostratified columnar cells with nuclear atypia. Despite the high frequency of nonendometrioid adenocarcinomas in Lynch syndrome, endometrioid adenocarcinomas are most common in absolute numbers. (Right) Serous adenocarcinoma is composed of papillae with cellular budding into intervening spaces ﬊. The cells are markedly atypical with pleomorphic nuclei and prominent nucleoli.

Clear Cell Adenocarcinoma

Diagnoses Associated With Syndromes by Organ: Gynecology

Lynch Syndrome-Associated Carcinoma

Carcinosarcoma (Left) Clear cell adenocarcinoma shows tubulopapillary growth of polygonal cells with abundant clear cytoplasm and markedly pleomorphic nuclei. Typical of this tumor are nuclei polarized toward the lumen, known as hobnailing. (Right) Carcinosarcoma shows an admixture of carcinomatous gland-forming ﬈ and sarcomatous chondroid ﬊ components.

MSH2 Immunohistochemistry

Microsatellite Instability Testing: Stable and Unstable (Left) MSH2 shows an endometrioid adenocarcinoma in a patient with Lynch syndrome and germline MSH2 mutation. Tumor cell nuclei are negative, and infiltrating lymphocytes serve as an internal positive control. (Right) Microsatellite instability testing using a mononucleotide marker (BAT26) shows that the top tumor sample is microsatellite stable, whereas the bottom tumor sample is microsatellite unstable.

383

Diagnoses Associated With Syndromes by Organ: Gynecology

Gynecologic Tumors

384

Familial Cancer Syndromes With Gynecologic Manifestations Syndrome

Nongynecologic Manifestations

Gene(s)

Lifetime Risk

Gynecologic Manifestations

Gynecologic Tumor Characteristics

Diagnostic Testing

Lynch syndrome

Cancers of gastrointestinal tract, pancreatobiliary tract, genitourinary tract, brain and skin

MLH1, MSH2, MSH6, PMS2  

50-60% for endometrial cancer; 11% for ovarian cancer

Various müllerian subtypes, including endometrioid, serous, clear cell and mixed carcinomas, and carcinosarcoma

Synchronous endometrial and ovarian endometrioid adenocarcinomas, lower uterine segment primaries

IHC for MLH1, MSH2, MSH6, and PMS2; MLH1 promoter hypermethylation;  germline testing for MLH1, MSH2, MSH6, PMS2

Hereditary breast Cancers of prostate, BRCA1, BRCA2 Ovarian and ovarian pancreas, bile duct cancer:  cancer and gallbladder 35-60% for BRCA1,  11-18% for BRCA2

Ovary: Most are high-grade invasive serous carcinomas; fallopian tube: Most are serous intraepithelial carcinomas

Germline testing for BRCA1, BRCA2

Germline mutations of Fanconi anemiaBRCA pathway and others

Limited data

RAD51C, RAD51D, BRIP1,  PALB2, ATM

Limited data Ovary, potentially fallopian tube and peritoneum

High-grade serous carcinoma

Germline testing for suspected genes

Li-Fraumeni syndrome

Breast cancer, CNS tumors, sarcomas, adrenocortical carcinomas, others

TP53

Limited data High-grade serous carcinoma

Early onset of ovarian cancer 

Germline testing for TP53

Peutz-Jeghers syndrome

STK11 Mucocutaneous pigmentation, hamartomatous intestinal polyps, increased cancer risk in breast, gastrointestinal tract, pancreas, and lung

21% of PJS patients develop ovarian tumors and 15-30% develop cervical cancer 9% risk for endometrial cancer by age 65

Ovary: Sex cordstromal tumor with annular tubules (SCTAT), oxyphilic Sertoli cell tumor; cervix: Gastric-type adenocarcinoma; endometrium: Endometrial adenocarcinoma

PJS-associated SCTAT are small, calcified, multifocal, bilateral; cervical gastric-type adenocarcinoma, includes minimal deviation adenocarcinoma and less well-differentiated variants characterized by negative HPV 

Germline testing for STK11 detects mutations in 94% of PJS patients; 25% of PJS cases are de novo; somatic STK11 mutations have been found in cervical minimal deviation adenocarcinoma

PTENhamartoma tumor syndrome (Cowden syndrome)

Hamartomatous PTEN growths, particularly in skin and mucous membranes; increased cancer risk for breast, thyroid, colorectal, kidney, and melanoma

5-42% for endometrial cancer

Uterus: Endometrial Most are grade 1 adenocarcinoma, endometrioid uterine leiomyomas adenocarcinomas

DICER1 syndrome

Pleuropulmonary blastoma, cystic nephroma, thyroid hyperplasia or carcinoma, pineoblastoma, pituitary blastoma

DICER1

Limited data Ovary: Sertoli-Leydig cell tumors, others; cervix: Embryonal rhabdomyosarcoma

Sertoli-Leydig cell tumors are moderately and poorly differentiated; gynandroblastoma and juvenile granulosa cell tumor have been reported

Germline testing for DICER1 Low penetrance with estimated 50% of germline carries developing associated phenotype

Rhabdoid tumor predisposition syndrome 2 (RTPS2)

Poorly differentiated tumors of central nervous system and kidney (rhabdoid tumors) 

SMARCA4

Limited data Ovary: Small-cell carcinoma, hypercalcemic type

Limited data

Loss of SMARCA4/BRG1 and SMARCA2/BRM by immunohistochemistry; germline testing for SMARCA4 

Hereditary leiomyoma renal

Cutaneous and Fumarate Nearly all Uterus: Leiomyomas Large and multiple uterine leiomyomas; hydratase (FH) women with uterine leiomyomas;

Germline testing for PTEN

Loss of FH by immunohistochemistry

Gynecologic Tumors

Syndrome

Nongynecologic Manifestations

Gene(s)

Lifetime Risk

cell carcinoma (HLRCC) syndrome

20% develop renal cell carcinoma

Ollier and Maffucci syndromes

Nonfamilial multiple enchondromas with risk for chondrosarcoma Maffucci syndrome;  hemangiomas 

Suspected Limited data postzygotic IDH1 and IDH2 mutations 

Hereditary esophagealvulvar syndrome

Esophageal leiomyomatosis

Some associated with X-linked Alport syndrome

von HippelLindau (VHL) syndrome

Familial adenomatous polyposis

Gynecologic Manifestations

Gynecologic Tumor Characteristics

Diagnostic Testing

prominent staghornshaped vessels, edema, large eosinophilic macronucleoli  surrounded by a clear halo and eosinophilic cytoplasmic inclusions 

can be seen with both somatic and germline FH  mutations; some germline mutations result in preserved FH immunoexpression; germline testing for FH  for diagnosis of HLRCC syndrome

Limited data

Limited data

Limited data Vulvar leiomyomatosis

Multiple vulvar leiomyomas

Limited data

Hemangioblastoma, VHL clear cell renal cell carcinoma, paraganglioma, pancreatic neuroendocrine tumor

Limited data Clear cell papillary cystadenoma of mesosalpinx and broad ligament

Limited data

Germline testing for VHL 

Numerous colorectal adenomatous polyps, duodenal polyps, desmoid tumors, osteomas, dental abnormalities, hepatoblastoma

APC

Limited data Microcystic ovarian stromal tumor

Limited data

Germline testing for APC 

Tuberous Hamartomatous sclerosis complex neoplasms in skin, (TSC) brain, kidney, heart, lungs and soft tissues

TSC1, TSC2

~ 10% for uterine PEComa

PEComa associated with TSC1/TSC2 abnormalities tend to show focal HMB45 staining and no TFE3 staining; PEComa associated with TFE3 (somatic) translocation tend to show strong  HMB-45 and TFE3 staining

Germline testing for TSC1 and TSC2 detects mutation in 75% of patients that meet clinical criteria for TSC

Nevoid basal cell carcinoma syndrome (NBCCS)/Gorlin syndrome

Early-onset multifocal basal cell carcinomas, odontogenic keratocysts, macrocephaly, skeletal abnormalities

PTCH1

17% of Ovarian fibromas women with NBCCS syndrome develop ovarian fibromas

NBCCS- associated Germline testing for ovarian fibromas tend to PTCH1 be bilateral, multinodular, and heavily calcified

Ovarian dysgenesis

Most are phenotypic Partial or females; association complete Y with Swyer chromosome syndrome

Limited data Gonadoblastoma, malignant germ cell tumors, particularly dysgerminoma

Bilateral and calcified gonadoblastomas; overgrowth of  malignant germ cell tumor

HLRCC syndrome develop uterine leiomyoma

Ovary: Characteristically juvenile granulosa cell tumor; case report of ovarian fibroma

Uterine perivascular epithelioid cell tumor (PEComa) Uterine lymphangioleiomyomatosis

Diagnoses Associated With Syndromes by Organ: Gynecology

Familial Cancer Syndromes With Gynecologic Manifestations (Continued)

Karyotype; chromosome microarray

385

Diagnoses Associated With Syndromes by Organ: Gynecology

Gynecologic Tumors Endometrioid Adenocarcinoma, FIGO Grade 1

High-Grade Serous Carcinoma

Serous Tubal Intraepithelial Carcinoma

Sex Cord-Stromal Tumor With Annular Tubules

Gastric-Type Endocervical Adenocarcinoma, Minimal Deviation Variant

Small-Cell Carcinoma of Ovary, Hypercalcemic Type

(Left) Endometrioid adenocarcinoma shows confluent glands. Lynch syndrome, PTEN-hamartoma tumor syndrome, and PeutzJeghers syndrome are associated with increased risk of endometrial adenocarcinoma. (Right) Highgrade serous carcinoma diffusely infiltrates the peritoneum. Hereditary breast and ovarian cancers lead to the development of serous carcinomas, which can originate in the ovaries, fallopian tubes, or peritoneum.

(Left) 8% of risk-reducing salpingo-oophorectomies in patients with hereditary breast and ovarian cancer reveal serous tubal intraepithelial carcinoma. (Right) Sex cord-stromal tumor with annular tubules is associated with Peutz-Jeghers syndrome.

(Left) Gastric-type endocervical adenocarcinoma is associated with PeutzJeghers syndrome. Welldifferentiated mucinous glands with minimal atypia deeply infiltrate the cervical stroma. (Right) Small-cell carcinoma of the ovary, hypercalcemic type is characterized by SMARCA4 mutations and is associated with rhabdoid tumor predisposition syndrome 2. (Courtesy R. Young, MD.)

386

Gynecologic Tumors

Uterine PEComa (Left) Fumarate hydratasedeficient uterine leiomyoma with characteristic eosinophilic cytoplasmic inclusions is shown. These tumors are associated with hereditary leiomyoma renal cell carcinoma syndrome. (Right) Uterine perivascular epithelioid cell tumor (PEComa) is shown. TSC1/TSC2-associated PEComa tend to have focal HMB-45 positivity and be negative for TFE3 by immunohistochemistry.

Sertoli-Leydig Cell Tumor, Moderately Differentiated

Diagnoses Associated With Syndromes by Organ: Gynecology

Fumarate Hydratase-Deficient Uterine Leiomyoma

Cervical Embryonal Rhabdomyosarcoma (Left) Sertoli-Leydig cell tumor, moderately differentiated is often seen in association with DICER1 syndrome. The tumor is characterized by nests and cords of Sertoli cells ﬈ and nests of Leydig cells ﬊. (Right) Cervical embryonal rhabdomyosarcomas are associated with DICER1 syndrome. This case from a 17year-old girl shows atypical sarcoma cells below the endocervical epithelium ﬈ and chondroid differentiation ﬊.

Ovarian Fibroma

Gonadoblastoma (Left) Nevoid basal cell carcinoma syndrome/Gorlin syndrome can be associated with ovarian fibromas that tend to be bilateral and heavily calcified. (Right) Gonadoblastoma is commonly seen in gonadal dysgenesis. Tumors are composed of nests of smaller sex cord cells ﬈ punctuated by larger germ cells ﬉.

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PART I SECTION 8

Head and Neck Endolymphatic Sac Tumor Head and Neck Squamous Cell Carcinoma Head and Neck Table Salivary Glands Table

390 394 400 404

Diagnoses Associated With Syndromes by Organ: Head and Neck

Endolymphatic Sac Tumor KEY FACTS

TERMINOLOGY • Endolymphatic sac tumor (ELST) is low-grade malignant epithelial tumor arising from endolymphatic sac in temporal bone (WHO 2017) • Rare, slowly growing, locally invasive but nonmetastasizing papillary neoplasm 

CLINICAL ISSUES • ~ 1/3 of cases are associated with von Hippel-Lindau (VHL) disease ○ ~ 10% of patients with VHL develop ELST – From these, ~ 30% are bilateral • Nonspecific presenting symptoms include Meniere-like clinical syndrome of hearing loss, tinnitus, vertigo, aural fullness, and facial nerve dysfunction

ANCILLARY TESTS • Tumor cells are usually positive for keratins • Tumor cells are positive for CAIX, pax-8

• Tumor cells are negative for CD10 and RCC ○ Strong pax-8 and CAIX positivity should be used in conjunction with negative CD10 and RCC to help exclude metastatic renal cell carcinoma

TOP DIFFERENTIAL DIAGNOSES • Middle ear adenoma/neuroendocrine adenoma of middle ear • Meningioma • Paraganglioma • Ceruminous gland adenoma/adenocarcinoma • Heterotopic or primary choroid plexus papillomas of cerebellopontine angle (CPA) • Metastatic carcinoma • Distinct locations and do not involve retrolabyrinthine temporal bone ○ Jugular glomus tumor involve jugular foramen ○ Middle ear paraganglioma involve middle ear ○ Schwannoma is centered in jugular foramen 

Endolymphatic Sac Tumor Location

Papillary Architecture

Papillary Structures

Cellular Morphology

(Left) Axial graphic of temporal bone shows the typical appearance of endolymphatic sac tumor (ELST). The tumor is vascular, shows a tendency to fistulize the inner ear, and contains bone fragments within the tumor matrix. (Right) Lowpower view highlights the papillary architecture of ELST with branching fibrovascular cores and single layer of cuboidal epithelium.

(Left) ELST typically shows a papillary architecture with fibrovascular cores and a single row of eosinophilic cuboidal epithelium. Nuclei are ovoid with fine chromatin. (Right) The papillae of this ELST are lined by columnar epithelium with pale eosinophilic cytoplasm. Mast cells ſt can occasionally be seen in the fibrovascular cores. Nuclei are ovoid with fine chromatin, variably prominent nucleoli, and scattered intranuclear pseudoinclusions ﬊.

390

Endolymphatic Sac Tumor

CLINICAL ISSUES

Abbreviations

Epidemiology

• Endolymphatic sac tumor (ELST)

• Incidence ○ ELST detected by MR or CT in ~ 15% of patients with VHL disease – 60% of VHL patients with vestibulocochlear symptoms may have microscopic ELSTs that are not visible on MR or CT ○ Compared to sporadic cases, ELST in VHL patients associated with – Younger patients – Bilateral tumors (30% of VHL patients with ELST have bilateral tumors) – Less advanced • Age ○ Occurs mostly in adults with wide age range – Rare pediatric cases have been reported • Sex ○ Slight female predominance among VHL patients

Synonyms • Low-grade papillary adenocarcinoma of endolymphatic sac origin • Heffner tumor

Definitions • Endolymphatic sac tumor is low-grade malignant epithelial tumor arising from endolymphatic sac in temporal bone (WHO 2017) • Rare, slowly growing, locally invasive but nonmetastasizing papillary neoplasm 

ETIOLOGY/PATHOGENESIS Genetic Predisposition • ELST is rare neoplasm of temporal bone that can occur sporadically or familially ○ High association with von Hippel-Lindau (VHL) disease • VHL disease ○ Autosomal dominant inheritance ○ Prevalence: 1 in 39,000 ○ Germline mutation in VHL tumor suppressor gene on chromosome 3p25 – VHL protein (pVHL): E3 ubiquitin ligase that marks certain proteins [e.g., α subunits of hypoxia-inducible factors (HIF)] for degradation ○ Somatic inactivation or loss of remaining wild-type VHL allele leads to characteristic manifestations – Pheochromocytoma – Renal cysts and renal cell carcinoma – Pancreatic cysts, cystadenomas, carcinomas, and islet cell tumors – Retinal and central nervous system hemangioblastomas – Epididymal papillary cystadenoma (men) – Female adnexal tumor of probable wolffian origin (FATWO) – ELST ○ 2 types of VHL disease based on absence/presence of pheochromocytoma – Type 1 VHL: Pheochromocytoma absent – Type 2 VHL: Pheochromocytoma present • ~ 10% of patients with ELST have VHL disease ○ Conversely, ~ 15% of patients with VHL disease have radiographically detectable ELST

Histogenesis • Cell of origin is papillary epithelium of endolymphatic sac • Endolymphatic sac ○ Endolymph-filled, neuroectodermally derived, nonsensory component of membranous labyrinth ○ Paddle-shaped structure consisting of complex network of interconnecting tubules ○ Connected to utricular and saccular ducts by endolymphatic duct • Specific precursor lesions for ELST: Not well characterized

Diagnoses Associated With Syndromes by Organ: Head and Neck

TERMINOLOGY

Site • Posteromedial region of petrous portion of temporal bone (site of normal endolymphatic sac)

Presentation • VHL-associated ELSTs can be 1st presentation of syndrome and mimic sporadic tumors ○ Emphasizing need of molecular testing in all presentations of ELST ○ Many hypervascular tumors, such as hemangioblastomas, renal cell carcinomas, pheochromocytomas, and ELST are known to be manifestations of VHL • VHL patients with evidence of ELST by imaging may show following symptoms ○ Meniere-like clinical syndrome of hearing loss in 95%, tinnitus in 92%, and vertigo in 62% – Possible causes of vestibulocochlear symptoms include □ Tumor invasion of inner ear structures (e.g., semicircular canal or cochlea) □ Labyrinthine hemorrhage □ Labyrinthine hydrops (due to excessive fluid production by tumor, blockage of endolymph resorption, &/or inflammation secondary to hemorrhage) □ Cochlear and neuronal degeneration secondary to above changes – Hearing loss: Usually irreversible; mean age of onset: 22 years □ Typically sensorineural rather than conductive hearing loss □ Acute and clinically significant in 43% □ Subacute and progressive (over 3-6 months) in 43% □ Gradual hearing loss in 14% ○ Aural fullness in 29% ○ Facial nerve dysfunction in 8%

391

Diagnoses Associated With Syndromes by Organ: Head and Neck

Endolymphatic Sac Tumor Laboratory Tests

Cytologic Features

• VHL patients should undergo serial audiologic tests and high-resolution imaging studies for early detection of small ELST • Conversely, all patients with ELST should be screened for other signs and symptoms of VHL disease

• Cuboidal to columnar cells with pale eosinophilic to clear cytoplasm • Typically uniform, ovoid nuclei ± intranuclear pseudoinclusions

Treatment • Early and complete surgical resection: Relieves hearing and vestibular symptoms, prevents permanent neurologic deficits ○ Combined transmastoidal-suboccipital approach may allow complete tumor removal, preservation of hearing in affected ear(s)

Prognosis • Slowly growing tumor with potential for local destruction and extension into vital structures • Invasion into posterior cranial fossa and brain can result in meningitis and death

IMAGING CT and MR Findings • As ELST is radiographically hypervascular, preoperative misdiagnoses of paraganglioma, glomus tumor, and other temporal tumors may be seen • Typically 4-6 cm in greatest dimension • Contrast-enhancing lytic lesion • Location: Posteromedial aspect of petrous portion of temporal bone • Radiographic differential diagnosis includes inflammatory, cystic, and neoplastic lesions involving temporal bone

Angiography Findings • Well-vascularized lesion with tumoral blush

MACROSCOPIC Size • Variable; can measure up to several cm

MICROSCOPIC Histologic Features • Architecture is variable with both cystic and papillary components • ELST histologically shows epithelial features, such as papillary architecture, glandular formation, and colloid-like structure ○ Papillary, tubular, and cystic structures lined by single layer of epithelial cells ○ Cystic structures may contain eosinophilic colloid-like fluid, resembling thyroid follicles ○ Variably cellular stroma ± small blood vessels ± fibrosis ○ Hemorrhage, hemosiderin, cholesterol clefts, and chronic inflammatory cells may be present ○ Necrosis and mitosis are not seen • ELST is papillary-cystic neoplasm that frequently raises differential diagnosis with renal cell carcinoma, thyroid or prostatic carcinomas within other metastatic neoplasms, whether in VHL patients or not

392

ANCILLARY TESTS Immunohistochemistry • Tumor cells are usually positive for keratins CAM5.2, CK7, CK8, CK19, AE1/AE3, and 34βE12     • Tumor cells are also positive for EMA, CK7, CAIX, GLUT1, VEGF, and pax-8 • Tumor cells are negative for CEA, GFAP, S100, CK10/13, CK20, CD10, and RCC • Strong pax-8 and CAIX should be used in conjunction with negative CD10 and RCC to help exclude metastatic renal cell carcinoma

DIFFERENTIAL DIAGNOSIS Middle Ear Adenoma/Carcinoid Tumor • Glandular, trabecular, cords • Dual cell population: Luminal and basal cells

Ceruminous Gland Adenoma/Adenocarcinoma • Glandular or cystic • Dual cell population: Luminal and myoepithelial cells

Meningioma • Epithelioid cells in nests

Paraganglioma • Zellballen architecture

Heterotopic or Primary Choroid Plexus Papilloma • Distinguished by IHC

Metastatic Carcinoma • Variable morphology

SELECTED REFERENCES 1.

Le H et al: Clinicoradiologic characteristics of endolymphatic sac tumors. Eur Arch Otorhinolaryngol. ePub, 2019 2. Bellairs JA et al: A histopathological connection between a fatal endolymphatic sac tumour and von Hippel-Lindau disease from 1960. J Laryngol Otol. 132(1):75-8, 2018 3. Ganeshan D et al: Tumors in von Hippel-Lindau syndrome: from head to toecomprehensive state-of-the-art review. Radiographics. 38(3):849-66, 2018 4. Mendenhall WM et al: Current treatment of endolymphatic sac tumor of the temporal bone. Adv Ther. 35(7):887-98, 2018 5. Thompson LDR et al: CAIX and pax-8 commonly immunoreactive in endolymphatic sac tumors: a clinicopathologic study of 26 cases with differential considerations for metastatic renal cell carcinoma in von HippelLindau patients. Head Neck Pathol. 13(3):355-63, 2018 6. Wick CC et al: Case series and systematic review of radiation outcomes for endolymphatic sac tumors. Otol Neurotol. 39(5):550-7, 2018 7. Schnack DT et al: Sporadic endolymphatic sac tumor-A very rare cause of hearing loss, tinnitus, and dizziness. J Int Adv Otol. 13(2):289-91, 2017 8. Zanoletti E et al: Endolymphatic sac tumour in von Hippel-Lindau disease: management strategies. Acta Otorhinolaryngol Ital. 37(5):423-9, 2017 9. Bausch B et al: Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the international ELST registry. Head Neck. 38 Suppl 1:E673-9, 2015 10. Bell D et al: Endolymphatic sac tumor (aggressive papillary tumor of middle ear and temporal bone): sine qua non radiology-pathology and the University of Texas MD Anderson Cancer Center experience. Ann Diagn Pathol. 15(2):117-23, 2011

Endolymphatic Sac Tumor

Tumor

Site

Architecture

Cytology

IHC: Positive

IHC: Negative

ELST

Petrous portion of temporal bone

Papillary, tubular, cystic

Cuboidal to columnar cells; pale eosinophilic to clear cytoplasm; uniform, ovoid nuclei with occasional pseudoinclusions

Various cytokeratins, including CK7 and CAM5.2, vimentin, VEGF, S100, CD34, NSE, GFAP, EMA, CAIX, and pax-8

CK20, chromogranin, synaptophysin

Middle ear adenoma [neuroendocrine adenoma of middle ear (NAME)]

Middle ear cavity of temporal bone

Glandular, trabecular, cords, single cells

Dual cell population of flattened luminal and cuboidal/columnar basal cells; neuroendocrine salt and pepper chromatin pattern

Luminal cells (pankeratin, CAM5.2, CK7); basal cells (pankeratin, CAM5.2, synaptophysin, chromogranin)

S100, GFAP, EMA

Glandular and cystic

Dual cell population with secretory-type luminal cells and basal layer of myoepithelial cells; yellow-brown ceroid pigment in cytoplasm

Luminal cells (pankeratin, EMA, CK7); basal cells (pankeratin, EMA, CK5/6, p63, S100, CD117)

CK20, chromogranin

Epithelioid cells with ill-defined cell borders, ovoid nuclei, fine chromatin, and occasional intranuclear pseudoinclusions

Pankeratin, CAM5.2, EMA, S100 (weak)

Chromogranin, synaptophysin

Pankeratin

Ceruminous adenoma External auditory canal, outer portion

Meningioma

Jugular foramen and Infiltrative lobules and internal auditory canal nests with whorled, region of temporal syncytial pattern bone

Paraganglioma

Middle ear (glomus tympanicum paraganglioma) or jugular foramen (glomus jugulotympanicum paraganglioma) regions of temporal bone

Ball-like clusters of Granular, basophilic cytoplasm, tumor cells (zellballen round nuclei, delicate to coarse architecture) chromatin

Chromogranin, synaptophysin, NSE, CD56; S100 and GFAP positive in sustentacular cells

Choroid plexus papilloma

Extraventricular tumors can occur at cerebellopontine angle

Papillary, tubular, glandular

Cuboidal to columnar cells, eosinophilic to clear cytoplasm, bland nuclear features

Pankeratin, vimentin; variable staining with transthyretin, S100, GFAP, synaptophysin

Metastatic carcinoma

Variable

Variable

Variable

Distinguishing markers include TTF-1 (thyroid or lung), RCC antigen (kidney), and CD10 (kidney)

Diagnoses Associated With Syndromes by Organ: Head and Neck

Differential Diagnosis of Endolymphatic Sac Tumor

ELST = endolymphatic sac tumor. 11. Bisceglia M et al: Endolymphatic sac papillary tumor (Heffner tumor). Adv Anat Pathol. 13(3):131-8, 2006 12. Choo D et al: Endolymphatic sac tumors in von Hippel-Lindau disease. J Neurosurg. 100(3):480-7, 2004 13. Lonser RR et al: Tumors of the endolymphatic sac in von Hippel-Lindau disease. N Engl J Med. 350(24):2481-6, 2004 14. Horiguchi H et al: Endolymphatic sac tumor associated with a von HippelLindau disease patient: an immunohistochemical study. Mod Pathol. 14(7):727-32, 2001 15. Heffner DK: Low-grade adenocarcinoma of probable endolymphatic sac origin A clinicopathologic study of 20 cases. Cancer. 64(11):2292-302, 1989

393

Diagnoses Associated With Syndromes by Organ: Head and Neck

Head and Neck Squamous Cell Carcinoma KEY FACTS

TERMINOLOGY • Malignant neoplasm characterized by squamous cell differentiation arising from squamous epithelium

ETIOLOGY/PATHOGENESIS • Somatic mutation signatures of cutaneous squamous cell carcinoma (SCC) is often dominated by high mutational background from ultraviolet exposure • Well-known cancer-associated genes are often mutated (e.g., TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, KMT2C) • Genetic ○ Dyskeratosis congenita – TERT, TERC, DKC1, TINF2, and other genes involved in telomere maintenance ○ Fanconi anemia – 13 separate genes (FANCx) comprise Fanconi anemia pathway ○ Xeroderma pigmentosum

– Genes involved in nucleotide excision repair of ultraviolet light-induced damage: XPA-XPG ○ Bloom syndrome – BLM: Tumor suppressor gene that belongs to family of RecQ DNA helicase • Iron deficiency (Plummer-Vinson syndrome) associated with elevated risk of SCC • Oncogenic viruses: Human papillomavirus (HPV) and Epstein-Barr virus (EBV) • Relatives of patients with oropharyngeal SCC display elevated risks of oropharyngeal, lung, and cervical cancers among others

MICROSCOPIC • SCC is generally divided into multiple categories ○ Histologic categories: In situ, superficially invasive, or deeply invasive ○ Histologic grade includes well-, moderately, and poorly differentiated SCC

Squamous Cell Carcinoma of Tongue

Coronal view through the mid oral cavity shows a lateral dorsal squamous cell carcinoma (SCC) that has grown into the deep muscles of the tongue and into the cortical bone of the mandible ﬉. SCC of the head and neck may be associated with dyskeratosis congenita (DC) and Fanconi anemia. SCC of the tongue is seen in patients with xeroderma pigmentosum (XP) and DC. XP patients have 100,000x increase in SCC of the tongue, and disease manifests 20 years earlier than in the general population.

394

Head and Neck Squamous Cell Carcinoma

Abbreviations

•

• Squamous cell carcinoma (SCC)

Synonyms • Epidermoid carcinoma (general for head and neck carcinomas) • Sinonasal carcinoma • Transitional carcinoma • Respiratory epithelial carcinoma • Cylindrical cell carcinoma

Definitions • Malignant neoplasm characterized by squamous cell differentiation arising from squamous epithelium

ETIOLOGY/PATHOGENESIS Genetic Predisposition for Head and Neck SCC • Dyskeratosis congenita ○ TERT, TERC, DKC1, TINF2, and other genes involved in telomere maintenance ○ SCC of head and neck and SCC of tongue ○ Other manifestations – Skin cancer, anorectal carcinoma, gastric carcinoma, lung carcinoma, colonic carcinoma, esophageal carcinoma, Hodgkin lymphoma, and retinoblastoma, among others • Fanconi anemia ○ 13 separate genes (FANCx) comprise Fanconi anemia pathway ○ SCC of head and neck ○ Other manifestations – Short stature – Eye abnormalities – Wilms tumor – Hematologic neoplasms: Cumulative incidence of hematologic malignancy is 25% by age 45; predominantly myeloid malignancies, acute myeloid leukemia (AML), and other hematopoietic abnormalities; 600x increased risk of AML, 5,000x increased risk of myeloplastic syndrome (MDS) – Solid tumors as SCC (esophagus, anogenital, and cervix) – Hepatocellular carcinoma – Brain tumors – Breast cancer susceptibility • Xeroderma pigmentosum (XP) ○ Genes involved in nucleotide excision repair of ultraviolet light-induced damage: XPA-XPG ○ SCC of tongue (100,000x increase in XP patients; disease manifests 20 years earlier than in general population) ○ Other manifestations – Carcinomas and sarcomas of skin – Melanomas – Ocular cancer – Brain tumors (medulloblastomas and glioblastomas) – Spinal cord astrocytomas – Carcinomas of lung, uterus, breast, stomach, kidney, and testicular

•

•

•

– Leukemias – Multiple benign tumors Bloom syndrome ○ BLM: Tumor suppressor gene that belongs to family of RecQ DNA helicase ○ SCC of head and neck ○ Other manifestations – Up to 50% of patients will develop malignancy – Hematolymphoid malignancies predominant in first 2 decades of life – Carcinomas predominant after first 2 decades of life and arise in varied sites, including skin, head and neck, lung, uterus, breast, and gastrointestinal tract, including esophagus (both SCC and adenocarcinoma), stomach, and colon – Medulloblastoma – Wilms tumor – Osteosarcoma Relatives of patients with oropharyngeal SCC display elevated risks of oropharyngeal, lung, and cervical cancers, among others Complex array of alterations, including aberrations in PIK3CA, EGFR, CDKN2A, TP53, and NOTCH family and FAT1 genes Other syndromes

Diagnoses Associated With Syndromes by Organ: Head and Neck

TERMINOLOGY

Environmental Exposure • Laryngeal SCC ○ Tobacco use (e.g., cigarette, cigar, pipe, smokeless) ○ Alcohol consumption: Independent of tobacco but multiplicative if both are used – Maté drinking is suggested risk factor ○ Gastroesophageal reflux or laryngopharyngeal reflux (chronic inflammation as mutagen) ○ Radiation exposure (therapeutic and environmental) ○ Occupational factors/exposures ○ Protective effect by high intake of fruits and vegetables • Tongue SCC ○ Tobacco use ○ Alcohol consumption ○ Nutritional deficiencies – Iron deficiency (Plummer-Vinson syndrome) associated with elevated risk of SCC ○ Betel quid (a.k.a. paan): Combination of betel leaf and 1 or more other ingredients (e.g., areca palm nuts, slaked lime, tobacco) ○ Radiation exposure (ultraviolet and therapeutic) • Nasal ○ Nickel exposure ○ Textile dust ○ Tobacco smoking ○ Prior Thorotrast use

Infectious Agents • Tongue SCC ○ Oncogenic virus: Human papillomavirus (HPV), high-risk type associated with development of tonsil and base of tongue cancer – Relationship to oral SCC is not as convincing ○ Can develop from area of leukoplakia or erythroplakia 395

Diagnoses Associated With Syndromes by Organ: Head and Neck

Head and Neck Squamous Cell Carcinoma ○ Malignant transformation of severe dysplasia or carcinoma in situ • Laryngeal SCC ○ HPV, human herpesvirus 8 (HHV-8), Epstein-Barr virus (EBV) may have minor causative role • Nasal and sinonasal SCC ○ HPV

Developmental • Nasal SCC: May develop from sinonasal (schneiderian) papilloma ○ Majority transform to keratinizing SCC ○ Majority arise in association with inverted-type sinonasal papilloma

CLINICAL ISSUES Presentation • Depending on location of head and neck SCC ○ Glottic tumors: Hoarseness is earliest symptom ○ Supraglottic &/or hypopharyngeal tumors: Dysphagia, changes in phonation, foreign body sensation in throat, and odynophagia ○ Subglottic tumors: Dyspnea and stridor most common ○ Tracheal tumors: Dyspnea, stridor, cough, and hemoptysis ○ Neck mass (lymph nodes) more common in transglottic tumors ○ Tongue: Difficulty eating and swallowing, sore that does not heal, dentures that fit poorly, loose teeth ○ Nasal cavity: Unilateral obstruction, nonhealing sore, rhinorrhea, epistaxis, mass, or pain ○ Maxillary sinus: Early symptoms often confused with sinusitis resulting in delay in diagnosis; with progression of disease, grouped in 5 categories – Oral: Referred pain, including upper premolar and molar teeth, ulceration, loosening of teeth, and fistula – Nasal: Nasal obstruction, mass, persistent purulent rhinorrhea, nonhealing sore/ulcer, epistaxis – Facial: Swelling, facial asymmetry – Ocular: Eyelid swelling, proptosis/exophthalmos – Neurologic: Numbness, paraesthesia, pain, cranial neuropathy

MACROSCOPIC General Features • Gross findings vary depending on origin and location of tumor

MICROSCOPIC Histologic Features • SCC is generally divided into multiple categories ○ Histologic categories – SCC in situ – SCC, superficially invasive – SCC, deeply invasive ○ Histologic grade includes well-, moderately, and poorly differentiated SCC – Well differentiated: Resembles normal squamous epithelium but shows invasion 396

– Moderately differentiated: Easily identified nuclear pleomorphism, loss of polarity, disorganization, increased mitotic activity, usually less keratinization – Poorly differentiated: Immature cells predominate, high nuclear:cytoplasmic ratio, limited keratinization, numerous typical and atypical mitoses ○ Keratinization: Absent or present and divided into – SCC, keratinizing – SCC, nonkeratinizing

Variants of Squamous Cell Carcinoma • • • • • • • •

Basaloid SCC Verrucous carcinoma Papillary SCC Spindle cell squamous carcinoma Adenosquamous carcinoma Lymphoepithelial carcinoma Acantholytic SCC (pseudoglandular or adenoid) Carcinoma cuniculatum

DIFFERENTIAL DIAGNOSIS Nasal Cavity Squamous Cell Carcinoma • Schneiderian papillomas • NUT midline carcinoma • Sinonasal undifferentiated carcinoma (SNUC)

Tongue Squamous Cell Carcinoma • Pseudoepitheliomatous hyperplasia (PEH) • Necrotizing sialometaplasia • Radiation changes

Laryngeal Squamous Cell Carcinoma • • • •

PEH Radiation changes Squamous papilloma Necrotizing sialometaplasia

SELECTED REFERENCES 1.

Budach V et al: Novel prognostic clinical factors and biomarkers for outcome prediction in head and neck cancer: a systematic review. Lancet Oncol. 20(6):e313-26, 2019 2. Mann JE et al: The molecular landscape of the University of Michigan laryngeal squamous cell carcinoma cell line panel. Head Neck. 41(9):3114-24, 2019 3. Monroe MM et al: Familial clustering of oropharyngeal squamous cell carcinoma in the Utah population. Head Neck. 40(2):384-93, 2018 4. Mountzios G et al: The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact. Ann Oncol. 25(10):1889-900, 2014 5. Boscolo-Rizzo P et al: New insights into human papillomavirus-associated head and neck squamous cell carcinoma. Acta Otorhinolaryngol Ital. 33(2):77-87, 2013 6. Lin BM et al: Long-term prognosis and risk factors among patients with HPVassociated oropharyngeal squamous cell carcinoma. Cancer. 119(19):346271, 2013 7. McBride SM et al: Mutation frequency in 15 common cancer genes in highrisk head and neck squamous cell carcinoma (HNSCC). Head Neck. 36(8):1181-8, 2013 8. Saba NF et al: Acetylated tubulin (AT) as a prognostic marker in squamous cell carcinoma of the head and neck. Head Neck Pathol. 8(1):66-72, 2013 9. Takahashi Y et al: Comprehensive assessment of prognostic markers for sinonasal squamous cell carcinoma. Head Neck. 36(8):1094-102, 2013 10. Wilson GA et al: Integrated virus-host methylome analysis in head and neck squamous cell carcinoma. Epigenetics. 8(9), 2013

Head and Neck Squamous Cell Carcinoma Precursor Lesion of Squamous Cell Carcinoma (Left) SCC can arise from the nasal cavity and paranasal sinus. This coronal graphic illustrates the anatomic separations of the maxillary sinus from the nasal cavity, ethmoid sinus, and orbit. (Right) Coronal graphic illustrates the presence of a lobular inverted papilloma centered at the middle meatus ﬉. The lesion enters the maxillary sinus st via an enlarged infundibulum. This may be a precursor lesion of SCC.

Larynx

Diagnoses Associated With Syndromes by Organ: Head and Neck

Maxilla and Sinuses

Supraglottic Squamous Cell Carcinoma (Left) Basic anatomic landmarks of the larynx are used in accurate classification and separation of specific tumors into location and stage. The vocal cords are used to separate tumors into supraglottic, glottic, and subglottic regions, one of the most useful staging parameters. Extension into cartilage or across membranes also changes the tumor stage. (Right) A large supraglottic tumor fills the laryngeal side of the epiglottis with expansion into thyroid cartilage and bone ﬉.

Oropharynx

Oropharyngeal Squamous Cell Carcinoma (Left) The oropharynx, highlighted in purple, includes the base of tongue (posterior 1/3), vallecula, tonsil, tonsillar fossa and pillars, inferior surface of the soft palate and uvula, and posterior wall of the pharynx. (Right) This oropharyngeal SCC is large and extends from the base of the tongue to vallecula, involves the oropharynx and nasopharynx, and extends into the posterior nasal cavity. SCC of the tongue may be associated with dyskeratosis congenita and xeroderma pigmentosum.

397

Diagnoses Associated With Syndromes by Organ: Head and Neck

Head and Neck Squamous Cell Carcinoma

Sinonasal Squamous Cell Carcinoma

Nonkeratinizing Squamous Cell Carcinoma

Squamous Cell Carcinoma of Nasal Cavity

p16 Block Positivity in Squamous Cell Carcinoma

Nonkeratinizing Squamous Cell Carcinoma

Sinonasal Squamous Cell Carcinoma Invading Bone

(Left) Coronal graphic demonstrates a tumor involving the maxillary sinus with extension into bone. This SCC may develop from a sinonasal papilloma and be associated with a few familial syndromes. (Right) Patients with hereditary retinoblastoma develop diverse neoplasms and may also develop an SCC of the nasal cavity. This is a typical microscopic feature of nonkeratinizing SCC formed by sheets of basaloid cells with sharply defined borders. No stromal reaction is seen in the tumor.

(Left) Most of the SCCs of the nasal cavity and paranasal sinuses are of the welldifferentiated keratinizing type and may be 1 of the neoplasms occurring in patients with hereditary retinoblastoma. This H&E stain shows widened and downwardly growing rete, marked dysplastic cellular changes, and, focally, violation of the basement membrane by tumor cells. (Right) This slide illustrates p16 positivity in a SCC. Human papillomavirus (HPV), high-risk type, may be associated with development of head and neck SCC.

(Left) Nonkeratinizing SCC originates from the surface epithelium, invades into the submucosa as broad bands of neoplastic epithelium growing down, and very frequently invades adjacent bone ﬉. (Right) Sinonasal, invasive, keratinizing welldifferentiated SCC shows a nest of carcinoma cells ﬉ within the bone and is associated with marked desmoplastic reaction.

398

Head and Neck Squamous Cell Carcinoma

Invasive Squamous Cell Carcinoma (Left) SCC of the head and neck may be associated with dyskeratosis congenita (DC) and Fanconi anemia. SCC of the tongue is seen in patients with xeroderma pigmentosum (XP) and DC. This picture illustrates a keratinizing invasive SCC of the tongue in a patient with DC. (Right) An invasive nonkeratinizing SCC may show only focal keratinization (< 10% of the tumor). Note that the basement membrane is violated and cells ﬉ are present in the lamina propria.

Keratin Pearl in Squamous Cell Carcinoma

Diagnoses Associated With Syndromes by Organ: Head and Neck

Invasive Squamous Cell Carcinoma in Dyskeratosis Congenita

Well-Differentiated Squamous Cell Carcinoma (Left) This invasive, keratinizing, welldifferentiated SCC shows islands of malignant epithelial cells invading into deeper tissues with extensive keratin pearl formation and formation of a large mass of keratin. (Right) Higher magnification of a well-differentiated SCC shows violation of the basement membrane by groups of malignant epithelial cells associated with inflammatory cell infiltrate. Dyskeratotic cells ﬉ are seen throughout. A keratin pearl ﬈ is present.

Dyskeratotic Cells in Squamous Cell Carcinoma

Xeroderma Pigmentosum-Associated Squamous Cell Carcinoma (Left) Higher magnification of SCC shows a large group of malignant epithelial cells with dyskeratotic cells. The tumor cells show nuclear atypia, prominent nucleoli, and mitosis st. XP patients have 100,000x increase in SCC of the tongue, and disease manifests 20 years earlier than in general population. (Right) Invasive SCC of the tongue in a patient with XP shows an island of keratinizing malignant cells infiltrating between the muscle fibers and surrounded by mixed inflammatory infiltrate and mild desmoplastic reaction.

399

Diagnoses Associated With Syndromes by Organ: Head and Neck

Head and Neck Table

400

Familial Cancer Syndromes With Head and Neck Lesions and Neoplasms Syndrome

Gene

Head and Neck Tumors and Lesions

Other Manifestations

PTEN-hamartoma tumor syndrome (Cowden disease)

PTEN

-Typical mucocutaneous manifestations of this syndrome are multiple facial trichilemmomas, acral keratoses, and papillomatous lesions -Skin: Tricholemmomas typically in perinasal and perioral distribution Oral mucosa: Papillomatous papules

-Breast carcinoma -Multiple thyroid nodules, including follicular adenoma, adenomatous nodules, and follicular carcinoma -Endometrial carcinoma -Hamartoma of cerebellum (dysplastic gangliocytoma or Lhermitte-Duclos disease) -Macrocephaly  -Gastrointestinal polyps

Dyskeratosis congenita

TERT, TERC, DKC1, TINF2; other genes involved in telomere maintenance

-SCC of head and neck -SCC of tongue

Skin cancer, anorectal carcinoma, gastric carcinoma, lung carcinoma, colon carcinoma, esophageal carcinoma, Hodgkin lymphoma, retinoblastoma, and others

Tuberous sclerosis complex

TSC2 TSC1

-Skin: Multiple facial angiofibromas occur in most cases particularly around nose -Jaws: Fibrous proliferations described as intraosseous desmoplastic fibromas -Teeth: Enamel pitting

-Highly variable syndrome characterized by benign tumors in multiple organ systems -Within renal system, complex is associated with angiomyolipomas, multiple cysts, and increased risk of carcinoma -Central nervous system: Tumors, cortical dysplasias; learning difficulties; seizures -Lymphangioleiomyomatosis is seen in lungs and rhabdomyoma in heart

Basal cell nevus syndrome (Gorlin syndrome)

PTCH1 PTCH2 (in Japanese and Chinese)

-Jaws: Odontogenic cysts, dentigerous cysts -Odontogenic keratocysts were present in < 70% of patients, were usually multiple, and occurred within first 2 decades of life -Syndromic odontogenic keratocysts have greater propensity for showing epithelial budding, solid epithelial proliferations, and satellite cysts within their walls -Skin: Basal cell carcinomas

-Nevoid basal cell carcinoma syndrome is tumor syndrome characterized by multiple basal cell carcinomas with early age of onset together with development of odontogenic keratocysts  -Triggers that should prompt evaluation for Gorlin syndrome: Odontogenic keratocysts if age < 20 years old, basal cell carcinoma if age < 20 years old, palmar or plantar pits, lamellar calcification of falx cerebri, medulloblastoma, desmoplastic, characteristic facies with broad nasal root (and hypertelorism), numerous tumors, including basal cell carcinoma, medulloblastoma, meningoma, ovarian fibroma, cardiac fibroma -Palmar and plantar pits were seen in 87% of cases

Fanconi anemia

13 separate genes comprising Fanconi anemia pathway: FANCx

-SCC of head and neck

Short stature, eye abnormalities, Wilms tumor and other solid tumors, SCC of cervix; hematologic neoplasms (by age 45, cumulative incidence of hematologic malignancy is 25%; median diagnosis age: 11-14 years); predominantly myeloid malignancies, AML, and other hematopoietic abnormalities (600x increased risk of AML; 5,000x increased risk of MDS); solid tumors, such as SCC (esophageal, anogenital), hepatocellular carcinoma, brain tumors; breast cancer susceptibility

Xeroderma pigmentosum

Genes involved in nucleotide excision repair of ultraviolet light-induced damage (XPA-XPG)

-SCC of tongue (increase 100,000x in xeroderma pigmentosum patients; tumor present < 20 years compared to general population)

Carcinomas and sarcomas of skin, melanomas, ocular cancer, and other internal malignancies, such as brain tumors (medulloblastomas and glioblastomas); spinal cord astrocytomas; carcinomas of lung, uterus, breast, stomach, kidney, and testicles; leukemias; and multiple benign tumors

Bloom syndrome

BLM (tumor -SCC of head and neck suppressor gene belonging to family of RecQ DNA helicase)

Up to 50% of patients will develop malignancy; ~ 10% of patients have ≥ 2 primary cancers with fewer patients reported to have 3, 4, or even 5 primary neoplasms; hematolymphoid malignancies predominant in first 2 decades of life; carcinomas predominant after first 2 decades of life and arise in varied sites, e.g., skin, head and neck, gastrointestinal tract, including esophagus (both squamous cell carcinoma and adenocarcinoma), stomach, and colon, lung, uterus, and breast; medulloblastoma, Wilms tumor, osteogenic sarcoma

Head and Neck Table

Syndrome

Gene

Head and Neck Tumors and Lesions

Other Manifestations

Retinoblastoma

RB

-Carcinoma of nasal cavity

Retinoblastoma; 2nd cancers common in patients with RB mutations (i.e., osteosarcoma, leiomyosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, Ewing sarcoma, melanoma, pinealoblastoma, Hodgkin lymphoma, breast carcinoma)

NF2

NF2

-Vestibular schwannoma: Bilateral Plexiform schwannoma (features occurring more vestibular schwannomas hallmark frequently in NF2-associated schwannomas include of NF2 (90-95% of patients) whorl formation, multiple tumors involving  single nerve, and juxtaposition to meningioma), neurofibroma, meningoma, ependymoma, conventional MPNST and MPNST ex-schwannomas reported in NF2 but are very rare

Hyperparathyroidism: Jaw tumor syndrome

CDC73 (HRPT2)

-Fibroma of jaw, ossifying fibroma Hyperparathyroidism develops late in adolescence in > of jaw 80% of patients: Parathyroid hyperplasia, adenoma, and carcinoma; renal cysts, hamartomas, and cortical adenomas; Wilms tumor; testicular germ cell tumor; papillary thyroid carcinoma, and other neoplasms

Familial adenomatous polyposis

APC

-Juvenile nasopharyngeal angiofibroma

≥ 100 colorectal adenomas (classical familial adenomatous polyposis), fundic gland polyps, antral adenomas, gastric cancer (rare), hepatoblastomas in male infants, hepatic adenomas and hepatocellular carcinomas, pancreatic adenocarcinoma and intraductal mucinous neoplasms of pancreas, adenocarcinoma of gallbladder, fibromatosis, multiple osteomas, congenital hypertrophy of retinal pigmented epithelium, cribriformmorular variant of papillary thyroid carcinoma

Gardner syndrome

APC

-Osteomas in oral and maxillofacial region are typical of Gardner syndrome -These benign tumors commonly develop in paranasal sinuses, mandible, and maxilla -Multiple epidermoid cysts, lipomas and tumors of fibrous tissue, including Gardner fibroma

-Development of < 100 colorectal adenomas during 2nd decade of life -Colorectal adenocarcinoma  -Adenocarcinoma in upper gastrointestinal tract -Patients also carry raised risk of hepatoblastoma, medulloblastoma, and papillary thyroid carcinoma

Muir-Torre syndrome

Mismatch repair genes (MSH2, MLH1, MSH6)

-Sebaceous neoplasms, including sebaceous carcinoma, sebaceous adenomas, and other benign sebaceous tumors -Majority of sebaceous neoplasms occur on head and neck, specifically face and periocular region

-Muir-Torre syndrome is association of dermal sebaceous tumor with internal malignancy and is variant hereditary nonpolyposis colorectal cancer (Lynch syndrome); most commonly associated with colorectal carcinomas as well as urothelial carcinomas and carcinomas of endometrium

Brooke-Spiegler syndrome

CYLD

-Multiple benign skin adnexal tumors, including cylindromas, spiradenomas, and trichoepitheliomas; typically affects head and neck region

-Salivary basal cell adenomas are rarely reported in association with Brooke-Spiegler syndrome

Birt-Hogg-Dubé syndrome

FLCN

Fibrofolliculomas, trichodiscomas, -Multiple typically benign skin tumors, lung cysts, and and acrochordons increased risk of both benign and malignant kidney tumors; lung cysts are seen on imaging, and these are associated with pneumothoraces -Renal carcinomas associated with syndrome are frequently multiple and bilateral, and most common histologic type is chromophobe renal cell carcinoma

Multiple endocrine neoplasia 2B (MEN2B)

RET

-Mucosal neuromas: Mucosal neuromas typically develop on lips, anterior tongue, and other oral sites; also frequently affected are conjunctiva, nasal mucosa, and

Diagnoses Associated With Syndromes by Organ: Head and Neck

Familial Cancer Syndromes With Head and Neck Lesions and Neoplasms (Continued)

-Pheochromocytomas -Medullary thyroid carcinoma -Marfanoid build characterized by thin elongate limbs and muscle wasting, ganglioneuromatosis of digestive tract, thickened corneal nerve fibers, and mucosal

401

Diagnoses Associated With Syndromes by Organ: Head and Neck

Head and Neck Table Familial Cancer Syndromes With Head and Neck Lesions and Neoplasms (Continued) Syndrome

Gene

Head and Neck Tumors and Lesions

Other Manifestations

laryngeal mucosa -Thickened corneal nerve fibers and mucosal neuromas

neuromas

Peutz-Jeghers syndrome

STK11

-Mucocutaneous macules

-Peutz-Jeghers syndrome is hereditary intestinal polyposis syndrome -Hamartomatous polyps have histologically distinct appearance and occur throughout gastrointestinal tract but are most frequent in small bowel -Increased risk of malignancy in upper gastrointestinal tract and lower gastrointestinal tract as well as in pancreas, gynecological tract, and female breast -Also associated with Sertoli cell neoplasia of testes

Paraganglioma syndromes

PGL1: SDHD PGL2: SDHAF2 PGL3: SDHC PGL4: SDHB PGL5: SDHA

-Head and neck paraganglioma occurs in 80-90% of paraganglioma 1 syndrome and 25-60% in paraganglioma 4 syndrome

-Paragangliomas now represent most common hereditary condition known with ~ 40% of paragangliomas, including those arising in head and neck region being familial -Prototypic head and neck paraganglioma is carotid body tumor, where 60% of these tumors occur -SDHB mutation carriers (PGL-4) are more likely to develop extraparaganglial neoplasias, including renal cell and thyroid carcinomas -In contrast with SDHD mutation carriers (PGL-1) who have more frequent multifocal paragangliomas, SDHB mutation carriers (PGL-4) are more likely to develop malignant disease 

AML= acute myeloid leukemia; MDS = myelodysplastic syndrome; MPNST = malignant peripheral nerve sheath tumor; NF2 =  neurofibromatosis type 2; SCC = squamous cell carcinoma. The early diagnosis of these tumor syndromes will allow appropriate screening for and prophylactic or early-stage care of associated malignancies. Patients benefit from appropriate surveillance, and in some cases, prophylactic surgery. Although identification of the defined genetic mutation is the diagnostic gold standard of genetic syndromes, a suspicion is needed to identify carriers of the mutations when index lesions are present. These index lesions in the oral and maxillofacial region include adnexal tumors, angiofibromas, multiple odontogenic keratocysts, odontomas/osteomas, mucosal neuromas, and fibroosseous lesions of the jaws. The identification of one of these should lead to an early diagnosis of these syndromes when evaluated in the proper clinical setting. The pathologist's role is becoming increasing critical for facilitating optimal patient care beyond the initial tissue diagnosis to include screening and documenting potential hereditary tumors requiring further patient counseling and testing.

402

Head and Neck Table

Dyskeratosis Congenita (Left) Bilateral schwannomas involving the vestibular branch of cranial nerve VIII are a hallmark of neurofibromatosis type 2, present as a cerebellopontine angle mass ﬊. These may be multiple ſt. (Right) Squamous cell carcinoma on the posterior lateral border of the tongue in a patient with dyskeratosis congenita presents as an exophytic, firm, indurated mass with rolled borders. (Courtesy S. Muller, DMD.)

Hereditary Retinoblastoma

Diagnoses Associated With Syndromes by Organ: Head and Neck

Schwannomas in Neurofibromatosis Type 2

Nevoid Basal Cell Carcinoma Syndrome (Left) Axial graphic shows retinoblastoma with a lobulated tumor extending through the limiting membrane into the vitreous. Punctate calcifications ﬈ are characteristic. Hereditary retinoblastoma patients may develop carcinoma of nasal cavity. (Right) Lateral graphic of the mandible (buccal cortex removed) illustrates features of a classic keratocytic odontogenic tumor ſt, splaying roots of the 1st and 2nd molar teeth, displacing the inferior alveolar nerve st, in a patient with nevoid basal cell carcinoma syndrome.

Hyperparathyroidism-Jaw Tumor Syndrome

Familial Adenomatous Polyposis Syndrome (Left) Nonossifying fibroma shows a large, welldemarcated maxillary mass with mixed calcification and fibrosis. Note that the mass obstructs 1 side of the nose and compresses the eye in a patient with hyperparathyroidism-jaw tumor syndrome. (Right) Multiple thyroid tumors in a patient with familial adenomatous polyposis show white firm nodules in both thyroid lobes. The patient also had a juvenile nasopharyngeal angiofibroma.

403

Diagnoses Associated With Syndromes by Organ: Head and Neck

Salivary Glands Table Familial Cancer Syndromes With Salivary Gland Neoplasms Syndrome

Gene (Locus)

Inheritance

Salivary Gland Tumor

Other Manifestations

BSS and FC

CYLD (16q12.1)

AD

Basal cell adenoma, membranous type¹

Dermal cylindroma, trichoepithelioma, and eccrine spiradenoma

VHL

VHL (3p25.3)

AD

Mucoepidermoid carcinoma²

Retinal and central nervous system hemangioblastoma; pheochromocytoma; renal cysts and renal cell carcinoma; pancreatic cysts, cystadenoma, carcinoma, and islet cell tumor; hepatic cysts; papillary cystadenoma of epididymis (men) and broad ligament (women); FATWO; endolymphatic sac tumor

AT

ATM (11q22.3)

AR

Mucoepidermoid carcinoma and acinic cell carcinoma³

Cerebellar AT; hematolymphoid malignancies (B-cell lymphoma, ALL, chronic lymphocytic leukemia); gastric cancer (associated with IgA-deficient men); medulloblastoma; basal cell carcinoma; glioma; uterine cancer; ovarian dysgerminoma; heterozygotes show increased risk for breast cancer in younger women, colorectal cancer, gastric cancer, and T-cell ALL

RB

RB1 (13q14.2)

AD

Mucoepidermoid carcinoma⁴

Osteosarcoma; pinealoblastoma; melanoma, nasal cavity cancers; leiomyosarcoma; fibrosarcoma; chondrosarcoma; rhabdomyosarcoma; Ewing sarcoma; leukemia and lymphoma; malignant phyllodes tumor; some tumors may be due in part to radiation therapy for retinoblastoma

Lynch syndrome (HNPCC)

Germline mutations affecting 1 or several mismatch repair genes

AD

Adenocarcinoma, acinic cell carcinoma

Colonic cancer, endometrial cancer, bladder cancer; other cancers are sometimes associated with HNPCC

Gardner syndrome

APC (5q22.2)

AD

Carcinoma,   Gardner syndrome is association of FAP with several extradigestive pleomorphic manifestations: Osteomas, epidermal cysts, and desmoid tumors adenoma, fibromatous tumor of parotid

AD = autosomal dominant; ALL = acute lymphocytic leukemia; AR = autosomal recessive; AT = ataxia-telangiectasia; BSS = Brooke-Spiegler syndrome; FATWO = female adnexal tumor of probable wolffian origin; FC = familial cylindromatosis; RB = retinoblastoma; VHL = von Hippel-Lindau syndrome. HNPCC = hereditary nonpolyposis colorectal cancer; FAP = familial adenomatous polyposis. ¹Strong etiologic association of membranous type of basal cell adenoma with BSS and FC based on multiple reports. ²Etiologic association with VHL disease is unclear; single case from authors' institution. ³Etiologic association with AT is unclear; 2 case reports in literature. ⁴Etiologic association with RB is unclear; 1 case report in literature.

Salivary Gland Neoplasms With Familial Clustering Reports Reference

Affected Family Members (Age in Years at Diagnosis)

Comment

Ahn MS et al (1999)

Sister (51), sister (age N/A)

Sister (51) with bilateral tumors; t(3;12)(p21;q15) identified in 1 of these tumors, presumably involving HMGA2 gene on 12q15

Klausner RD and Handler SD (1993)

Brother (11), sister (15)

Hayter JP and Robertson JM (1990)

Brother (27), brother (29)

Cameron JM (1959)

Father (51), son (21), daughter (21)

Pleomorphic Adenoma

Warthin Tumor Gallego et al (2010)

Twin brothers (45, 47)

Russo et al (1999)

Mother (73), son (51)

Talmi et al (1994)

3 brothers (ages N/A)

Noyek et al (1980)

Mother (76), son (57)

Skerlavay et al (1976)

Brother (69), brother (65)

Acinic Cell Carcinoma Delides et al (2005)

404

Father (89), son (64), daughter (27)

Son (64) with bilateral acinic cell carcinoma; other conditions in family include pituitary adenoma, oncocytic adenoma of parotid, Warthin tumor

Salivary Glands Table

Reference Depowski et al (1999)

Affected Family Members (Age in Years at Diagnosis)

Comment

Father (35), daughter (16)

Mucoepidermoid Carcinoma Newman et al (1981)

Brother (33), sister (32)

Brother (33) with moderately differentiated adenocarcinoma of submandibular gland; sister (32) with mucoepidermoid carcinoma

Low-Grade Neuroendocrine Carcinoma Michaels et al (1999)

Mother (67), sister (46), brother (34), sister (43), brother (33)

Tumors in siblings were composed primarily of cells with neuroendocrine differentiation, admixed with ductal and myoepithelial cells; histology of mother's tumor not reported; other conditions in family include vestibular schwannoma, sensorineural hearing loss, amelogenesis imperfecta

Autio-Harmainen et al (1988)

Mother (64), daughter (43)

Other conditions in family include trichoepitheliomas, eccrine spiradenomas, cylindromas

Merrick et al (1986)

Family 1: Sister (31), sister (34), sister Likely EBV related, but suspect additional genetic predisposition; other (50); family 2: Sister (37), sister (44) conditions in family include uterine cervical cancer, nasopharyngeal carcinoma, malignant neck mass (NOS) in maternal grandfather

Lymphoepithelial Carcinoma

Diagnoses Associated With Syndromes by Organ: Head and Neck

Salivary Gland Neoplasms With Familial Clustering Reports (Continued)

Adenoid Cystic Carcinoma of the Minor Salivary Glands Channir et al (2017)

Father (N/A), daughter (50) 

Both cases harbored the MYB-NFIB gene fusion as demonstrated by FISH and RNA sequencing

EBV = Epstein-Barr virus; N/A = not available; NOS = not otherwise specified. Case reports of salivary gland neoplasms showing familial clustering (without known germline mutation) are summarized in this table.

Molecular Changes Described in Salivary Gland Tumors Tumor

Locus

Implicated Gene(s)

PA

8q12 translocations [t(3;8)p21;q12 is most common]

Fusion transcripts involving PLAG1 or HMGA2

Prevalence

Carcinoma ex-PA

12q14-15 translocations [t(9;12)(p12-22;q13-15) is most common]

Fusion transcripts involving HMGA2 24% (a.k.a. HMGIC); EWSR1 rearrangement (clear cell carcinoma ex-PA)

Secretory carcinoma (ex-MASC)

t(12;15)(p13;q25) t(12;X)

ETV6-NTRK3 fusion ETV6-RET

Mucoepidermoid carcinoma

t(11;19)(q21;p13) t(11;15)(q21;q2 CRTC1-MAML2CRTC36)Losses of 2q, 5p, 12p, 16p MAML2 (CRTC1 a.k.a. MECT1, ORC1, and WAMTP1)

Warthin tumor

Rare cases with t(11;19) reported, No metaplastic WTs showed but larger series have not positivity for fusion transcripts reproduced this finding CRTC1-MAML2 or CRTC3-MAML2, and none showed rearrangement of gene by FISH

Adenoid cystic carcinoma

t(6;9)(q22-23;p23-24);  t(8;9) LOH at 6q23-q25;  Loss of 12q12-q13

Acinic cell carcinoma

Deletions of 6q; loss of Y; trisomy 8; and LOH at 4p, 5q, 6p, 17p

PAC (low grade)

95-98% 2-5% 40-80% 5%

MYB-NFIB fusion MYBL1-NFIB

25-80% 10-20%

14q12 12q12-q13, 12q22, or 12p12.3 translocations

Hotspot-activating PRKD1 somatic point mutation (E710D)

20%

Cribriform adenocarcinoma (or cribriform variant of PAC) (CASG)

t(1;14)(p36.11;q12) t(X;14)(p11.4;q12)

ARID1A-PRKD1-DDX3X-PRKD1PRKD2 and PRKD3 rearrangements

24% 13% 16%

Salivary duct carcinoma

17q21.1

ERBB2 amplification

20-40%

405

Diagnoses Associated With Syndromes by Organ: Head and Neck

Salivary Glands Table Molecular Changes Described in Salivary Gland Tumors (Continued) Tumor

Salivary sialadenoma papilliferum, classic type

Locus

Implicated Gene(s)

Prevalence

3q26.32 inv(10)(q11.21q11.22) LOH at 6q, 17p, 17q Homozygous deletion of locus 9p21 (CDKN2A)

PIK3CA mutation NCOA4-RET Deletion of CDKN2A Mutation of HRAS, TP53, MDM2 amplification

20% < 5%

BRAF V600E 

BRAF V600E mutations

Salivary sialadenoma papilliferum, oncocytic variant 

Negative for BRAF mutations

Clear cell myoepithelial carcinoma of salivary glands

EWSR1

EWSR1 rearrangement**

39% EWSR1 is promiscuous gene with rearrangements involving number of partner genes, such as POU5F1, PBX1, ATF1, CREB1, etc.

Hyalinizing clear cell carcinoma of minor salivary glands

t(12;22)(q13;q12.2-12.3)

EWSR1-ATF1

80-90%

LOH = loss of heterozygosity; MASC = mammary analogue secretory carcinoma; PA = pleomorphic adenoma; PAC = polymorphous adenocarcinoma. This table summarizes cytogenetic changes that have been observed in salivary gland neoplasms. Most of these cases represent somatic mutations in sporadic salivary gland tumors and are included here for reference.  ** Most EWSR1-rearranged carcinomas seem to share phenotypical features in many cases, such as nested appearance divided by hyalinized fibrous septa, focal necrosis, collagenous spherulosis, foci of squamous metaplasia, and particularly clear cell cytomorphology. EWSR1 gene rearrangement has been also demonstrated in 45% of SMET  (soft tissue myoepithelial tumors) with a variety of fusion partners. The tumors harboring EWSR1POU5F1 fusion were composed predominantly of clear cells and had a distinctive nested morphology.

406

Salivary Glands Table

1. 2.

3.

4.

5.

6.

7.

8. 9.

10.

11.

12. 13. 14.

15.

16. 17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

Adkins BD et al: SOX10 and GATA3 in adenoid cystic carcinoma and polymorphous adenocarcinoma. Head Neck Pathol. ePub, 2019 Andersson MK et al: Clinical, genetic and experimental studies of the Brooke-Spiegler (CYLD) skin tumor syndrome. J Plast Surg Hand Surg. 53(2):71-5, 2019 Hsieh MS et al: Salivary sialadenoma papilliferum consists of two morphologically, immunophenotypically, and genetically distinct subtypes. Head Neck Pathol. ePub, 2019 McIntyre JB et al: MYB-NFIB gene fusions identified in archival adenoid cystic carcinoma tissue employing NanoString analysis: an exploratory study. Diagn Pathol. 14(1):78, 2019 Xu B et al: Pan-Trk immunohistochemistry is a sensitive and specific ancillary tool in diagnosing secretory carcinoma of salivary gland and detecting ETV6NTRK3 fusion. Histopathology. ePub, 2019 Feng AL et al: Multiple simultaneous head and neck cancers in Lynch syndrome: Case report and literature review. Laryngoscope. 128(12):275961, 2018 Rijken JA et al: Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations. BJS Open. 2(2):62-9, 2018 Skálová A et al: The role of molecular testing in the differential diagnosis of salivary gland carcinomas. Am J Surg Pathol. 42(2):e11-27, 2018 Udager AM et al: The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes. Hum Pathol. 71:47-54, 2018 Channir HI et al: Genetic characterization of adenoid cystic carcinoma of the minor salivary glands: a potential familial occurrence in first-degree relatives. Head Neck Pathol. 11(4):546-51, 2017 Kennedy RA et al: An overview of autosomal dominant tumour syndromes with prominent features in the oral and maxillofacial region. Head Neck Pathol. 11(3):364-76, 2017 Guignard N et al: Gardner's syndrome presenting with a fibromatous tumour of the parotid. Eur Ann Otorhinolaryngol Head Neck Dis. 133(5):357-9, 2016 Kazakov DV: Brooke-Spiegler syndrome and phenotypic variants: an update. Head Neck Pathol. 10(2):125-30, 2016 Piscuoglio S et al: Lack of PRKD2 and PRKD3 kinase domain somatic mutations in PRKD1 wild-type classic polymorphous low-grade adenocarcinomas of the salivary gland. Histopathology. 68(7):1055-62, 2016 Skálová A et al: Mammary analogue secretory carcinoma of salivary glands: molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6-NTRK3 fusion transcript by standard RT-PCR: report of 4 cases harboring ETV6-X gene fusion. Am J Surg Pathol. 40(1):313, 2016 Guardoli D et al: A novel CYLD germline mutation in Brooke-Spiegler syndrome. J Eur Acad Dermatol Venereol. 29(3):457-62, 2015 Malzone MG et al: Brooke-Spiegler syndrome presenting multiple concurrent cutaneous and parotid gland neoplasms: cytologic findings on fine-needle sample and description of a novel mutation of the CYLD gene. Diagn Cytopathol. 43(8):654-8, 2015 Skálová A et al: Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement: molecular analysis of 94 salivary gland carcinomas with prominent clear cell component. Am J Surg Pathol. 39(3):338-48, 2015 Skálová A et al: Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes. Am J Surg Pathol. 38(1):23-33, 2014 Weinreb I et al: Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands. Nat Genet. 46(11):1166-9, 2014 Weinreb I et al: Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin. Genes Chromosomes Cancer. 53(10):845-56, 2014 Skálová A et al: CRTC1-MAML2 and CRTC3-MAML2 fusions were not detected in metaplastic Warthin tumor and metaplastic pleomorphic adenoma of salivary glands. Am J Surg Pathol. 37(11):1743-50, 2013 Bahrami A et al: PLAG1 alteration in carcinoma ex pleomorphic adenoma: immunohistochemical and fluorescence in situ hybridization studies of 22 cases. Head Neck Pathol. 6(3):328-35, 2012 Clauditz TS et al: 11q21 rearrangement is a frequent and highly specific genetic alteration in mucoepidermoid carcinoma. Diagn Mol Pathol. 21(3):134-7, 2012 Ponti G et al: Brooke-Spiegler syndrome: report of two cases not associated with a mutation in the CYLD and PTCH tumor-suppressor genes. J Cutan Pathol. 39(3):366-71, 2012 West RB et al: MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation. Am J Surg Pathol. 35(1):92-9, 2011

27. Gallego L et al: Familial Warthin tumor: occurrence in monozygotic twins. J Oral Maxillofac Surg. 68(6):1400-1, 2010 28. Mitani Y et al: Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance. Clin Cancer Res. 16(19):4722-31, 2010 29. Seethala RR et al: A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am J Surg Pathol. 34(8):1106-21, 2010 30. Skálová A et al: Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 34(5):599-608, 2010 31. Persson F et al: High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosomes Cancer. 48(1):69-82, 2009 32. Fehr A et al: A closer look at Warthin tumors and the t(11;19). Cancer Genet Cytogenet. 180(2):135-9, 2008 33. Leivo I: Insights into a complex group of neoplastic disease: advances in histopathologic classification and molecular pathology of salivary gland cancer. Acta Oncol. 45(6):662-8, 2006 34. Okabe M et al: MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma. Clin Cancer Res. 12(13):3902-7, 2006 35. Young AL et al: CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 70(3):246-9, 2006 36. Bowen S et al: Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 124(5):919-20, 2005 37. Stenman G: Fusion oncogenes and tumor type specificity--insights from salivary gland tumors. Semin Cancer Biol. 15(3):224-35, 2005 38. Kakagia D et al: Brooke-Spiegler syndrome with parotid gland involvement. Eur J Dermatol. 14(3):139-41, 2004 39. Röijer E et al: Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma. Am J Pathol. 160(2):433-40, 2002 40. Martins C et al: Cytogenetic similarities between two types of salivary gland carcinomas: adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma. Cancer Genet Cytogenet. 128(2):130-6, 2001 41. Ahn MS et al: Familial mixed tumors of the parotid gland. Head Neck. 21(8):772-5, 1999 42. Depowski PL et al: Familial occurrence of acinic cell carcinoma of the parotid gland. Arch Pathol Lab Med. 123(11):1118-20, 1999 43. Michaels L et al: Family with low-grade neuroendocrine carcinoma of salivary glands, severe sensorineural hearing loss, and enamel hypoplasia. Am J Med Genet. 83(3):183-6, 1999 44. Russo F et al: [Cystadenolymphoma of the salivary glands: is there a familial role?.] Ann Ital Chir. 70(2):233-7; discussion 237-8, 1999 45. Antonescu CR et al: Multiple malignant cylindromas of skin in association with basal cell adenocarcinoma with adenoid cystic features of minor salivary gland. J Cutan Pathol. 24(7):449-53, 1997 46. Hoşal AS et al: Ataxia telangiectasia and mucoepidermoid carcinoma of the parotid gland: a case report. Int J Pediatr Otorhinolaryngol. 37(1):79-84, 1996 47. Klausner RD et al: Familial occurrence of pleomorphic adenoma. Int J Pediatr Otorhinolaryngol. 30(3):205-10, 1994 48. Talmi YP et al: Familial occurrence of Warthin's tumour. J Otolaryngol. 23(3):206-7, 1994 49. Bullerdiek J et al: Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas: correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet Cytogenet. 65(1):27-31, 1993 50. Hayter JP et al: Familial occurrence of pleomorphic adenoma of the parotid gland. Br J Oral Maxillofac Surg. 28(5):333-4, 1990 51. Rockerbie N et al: Malignant dermal cylindroma in a patient with multiple dermal cylindromas, trichoepitheliomas, and bilateral dermal analogue tumors of the parotid gland. Am J Dermatopathol. 11(4):353-9, 1989 52. Autio-Harmainen H et al: Familial occurrence of malignant lymphoepithelial lesion of the parotid gland in a Finnish family with dominantly inherited trichoepithelioma. Cancer. 61(1):161-6, 1988 53. Bullerdiek J et al: Translocation t(11;19)(q21;p13.1) as the sole chromosome abnormality in a cystadenolymphoma (Warthin's tumor) of the parotid gland. Cancer Genet Cytogenet. 35(1):129-32, 1988 54. Merrick Y et al: Familial clustering of salivary gland carcinoma in Greenland. Cancer. 57(10):2097-102, 1986 55. Newman AN et al: Familial carcinoma of the submandibular gland. A case report and an epidemiologic review. Arch Otolaryngol. 107(3):169-71, 1981 56. Skerlavay MA et al: Letter: Warthin tumor in two brothers. Arch Pathol Lab Med. 100(9):508, 1976

Diagnoses Associated With Syndromes by Organ: Head and Neck

SELECTED REFERENCES

407

Diagnoses Associated With Syndromes by Organ: Head and Neck

Salivary Glands Table Basal Cell Adenoma in Brooke-Spiegler Syndrome

Basal Cell Adenoma in Brooke-Spiegler Syndrome

Brooke-Spiegler Syndrome-Associated Basal Cell Adenoma

Basal Cell Adenoma in Brooke-Spiegler Syndrome

Brooke-Spiegler Syndrome/Familial Cylindromatosis

Brooke-Spiegler Syndrome/Familial Cylindromatosis

(Left) This basal cell adenoma (BCA), membranous type, was resected from the parotid gland of a patient with multiple dermal cylindromas. The tumor has multinodular architecture and is encased by dense fibrous stroma ﬈. (Right) Another area of the BCA shows dense collagen bands ﬈ and multiple tumor nodules. Within the nodules are nests of basaloid cells that are surrounded by eosinophilic hyaline material ﬊ and arranged in a jigsaw puzzlelike pattern.

(Left) On higher magnification, this membranous-type BCA shows drop-like eosinophilic hyaline material ſt of variable sizes and shapes in addition to the rim of basement membrane-like material ﬇ separating the nests of basaloid cells. (Right) Basaloid cells in the centers of the nests st are larger with fine chromatin; those at the periphery ﬇ appear smaller with hyperchromatic nuclei. There is strong etiologic association of membranoustype BCA with Brooke-Spiegler syndrome (BSS) and familial cylindromatosis (FC).

(Left) In addition to BCA in the parotid gland, this patient had multiple cutaneous cylindromas. This low-power view shows multiple nodules of basaloid cells in the dermis. (Right) This cylindroma shows a typical jigsaw puzzle-like pattern (lower left) in addition to a more diffuse pattern ﬈ seen in BSS and FC.

408

Salivary Glands Table Basal Cell Carcinoma in Brooke-Spiegler Syndrome (Left) This Romanowskystained, air-dried smear from a fine-needle aspiration of BCA shows a sheet of medium-sized basaloid cells with a peripheral rim of hyaline material ﬈. (Right) BCAC is a rare low-grade tumor associated with a good prognosis. This tumor accounts for ~ 3% of all malignant tumors of the salivary glands. BCAC shows nuclear pleomorphism, increased mitotic activity, necrosis, vascular invasion, and lymphatic invasion, the features distinguishing it from BCA.

Mucoepidermoid Carcinoma in von HippelLindau

Diagnoses Associated With Syndromes by Organ: Head and Neck

Cytology of Basal Cell Adenoma

von Hippel-Lindau-Associated Mucoepidermoid Carcinoma (Left) This low-grade mucoepidermoid carcinoma was resected from the parotid gland of a patient with von Hippel-Lindau disease (VHL). On low magnification, a cystic space lined by epidermoid and mucous cells is present. A prominent lymphoid infiltrate is present ſt. Parotid parenchyma is present at the top of the image ﬊. (Right) Multiple mucocytes ﬈ are supported by sheets of epidermoid/intermediate cells ﬇ with a transitional or squamous metaplastic appearance.

Tumor With Molecular Alterations

Molecular Changes in Secretory Carcinoma (Left) Secretory carcinoma of salivary gland is a recently described salivary gland tumor that shares the same histological appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. (Right) Secretory carcinoma is characterized by mammaglobin immunostaining in tumor cells. The presence of an ETV6NTRK3 gene fusion is confirmatory of this tumor. Other ETV6 gene fusion (ETV6-RET) has been described in these tumors.

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PART I SECTION 9

Nervous System Central Nervous System Eye Peripheral Nervous System

412 416 420

Diagnoses Associated With Syndromes by Organ: Nervous System

Central Nervous System Genetic Syndromes Associated With CNS Neoplasms Syndromes

Gene(s)

Gene Regions

Cell Pathways

Neurofibromatosis NF1 type 1

17q11.2

Neurofibromatosis NF2 type 2

von Hippel-Lindau syndrome

Non-CNS Tumors

Nonneoplastic Manifestations

RAS/MAPK/PI3K/ Astrocytic and mTOR/cAMP glioneuronal  tumors

Neurofibromas, MPNST, pheochromocytoma, carcinoid tumors, JMML

Lisch nodules, café au lait spots, skeletal dysplasia, vasculopathy

22q12.2

Integrin, RAC/PAK, WNT, YAP/Hippo, MAPK, PI3K, CRL4

Meningioma, ependymoma, glioma NOS

Schwannoma

Retinal hamartoma, skeletal abnormalities, cataracts

VHL

3p25.3

HIF (angiogenesis)

Hemangioblastoma

RCC, pheochromocytoma, PNET, Cysts of pancreas, endolymphatic sac tumor, kidney, adrenal gland, papillary cystadenoma testis, and ovary

Gorlin syndrome

PTCH1 > > PTCH2, SUFU

9q22.3, Sonic hedgehog 1p34.1, 10q24.32

Medulloblastoma

Basal cell carcinoma

Turcot type 1 (Lynch)

MLH1, MSH2/6, PMS2

3p, 2p, 2p, 7p

Astrocytic tumors (grade II-IV)

GI carcinomas, endometrium, adrenal carcinoma, osteomas, sebaceous neoplasms

Turcot type 2 (familial adenomatous polyposis)

APC

5q21-q22 WNT

Medulloblastoma/ PNET

FAP colorectal cancer, GI polyps, desmoid tumor, papillary thyroid carcinoma (cribriform-morular variant)

Hypertrophy of retinal pigment epithelium, osteomas, teeth impaction

CMMRD

MLH1, MSH2/6, PMS2

3p, 2p, 2p, 7p

Mismatch repair

Astrocytic tumors (grade II-IV)

Lymphoma, cancers associated with Turcot type 1

Café au lait spots

Tuberous sclerosis complex

TSC1, TSC2

9q34, 16p13.3

mTOR

Subependymal giant Angiomyolipoma, cell astrocytoma angioleiomyomatosis, (SEGA) rhabdomyoma, angiofibroma

Li-Fraumeni syndrome

TP53

17p13.1

DNA damage response, apoptosis, cell cycle

Astrocytomas > > medulloblastoma, choroid plexus CA

Sarcomas, osteosarcomas, breast carcinoma, adrenal cortical carcinoma, hematolymphoid

Melanoma, astrocytoma 

CDKN2A

9p21

Cell cycle (CDKs) (p16), DNA damage response (p14)

Astrocytic tumors

Melanoma, pancreatic adenocarcinoma, nevi

Familial uveal melanoma

BAP1

3p21

DNA repair Astrocytic tumors, (BRCA1 pathway) meningioma

Uveal melanoma, RCC, mesothelioma, nevi

Rhabdoid predisposition 

INI1 22q11.23 Chromatin (SMARCB1) dynamics

AT/RT

Renal and extrarenal rhabdoid tumors

Hereditary retinoblastoma

RB1

Cowden/Lhermitte PTEN -Duclos syndrome

412

Mismatch repair

CNS Tumors

13q14.2

Cell cycle (CDKs)

Pineoblastoma, embryonal tumors

Retinoblastoma,  sarcomas

10q23.3

mTOR

Dysplastic gangliocytoma of cerebellum

Breast/endometrial carcinoma, thyroid carcinoma and adenoma, trichilemmomas, RCC

Keratocysts, skeletal anomalies, calcification of falx cerebri, palmar/plantar pits

Cortical tubers, subependymal nodules, ungual fibroma, macules

Acral keratoses, thyroid nodules, GI polyps, intellectual disabilities

Noonan syndrome PTPN11, 12q24 RAS/MAPK NF1, KRAS, (PTPN11 RAF1, SOS1 most common)

Pilocytic None astrocytoma, glioneuronal tumors

Pulmonary valve stenosis, learning disabilities, pectus excavatum, facies

Aicardi syndrome

Unknown

X-linked Unknown dominant

Choroid plexus papilloma

None

Agenesis of corpus callosum, chorioretinal lacunae, spasms

Pleuro-pulmonary blastoma

DICER1

14q32.13 MicroRNA machinery

Pineoblastoma

Pituitary blastoma, medulloepithelioma (eye); Wilms, sex cord-stromal tumors

Lung cysts

Multi meningioma syndromes

INI1, SUFU, SMARCE1

22q, 10q, 17q

Meningiomas, clear cell subtype

Schwannomatosis (INI1)

Chromatin dynamics, Shh

Central Nervous System

Pilocytic Astrocytoma in NF1 (Left) The central nervous system hallmark of NF1 is multiple (bilateral) involvement of the optic pathways by low-grade gliomas. These may affect the optic nerve proper ﬈ as well as the chiasm ſt. (Right) The overwhelming majority of optic pathway gliomas are pilocytic astrocytomas. In this NF1-associated case, areas of tissue compaction, microcysts, and Rosenthal fibers ﬊ are evident. The tumors grow slowly and may even be followed without treatment in most cases.

High-Grade Astrocytoma in NF1

Diagnoses Associated With Syndromes by Organ: Nervous System

Bilateral Optic Gliomas in NF1

Anaplastic Astrocytoma in NF1 (Left) Although pilocytic astrocytoma is the most frequent glioma in patients with NF1, all astrocytic subtypes develop, including high-grade astrocytomas, as seen in this example. Heterogeneous contrast enhancement ſt is evident in this tumor. (Right) High-grade astrocytomas in patients with NF1 are graded using similar criteria as in sporadic tumors. Parenchymal infiltration, atypia, and mitotic activity ſt are present in this anaplastic (WHO grade III) astrocytoma.

Meningiomas in NF2

Meningioma (Left) Meningiomas are the 2nd most common neoplasms in patients with NF2. They are usually dura-based, multiple, and demonstrate strong, homogeneous contrast enhancement after administration of gadolinium on T1-weighted MR sequences ﬇. (Right) The cytologic features of meningiomas are evident in intraoperative smears. Features include "flat" cells with ample eosinophilic cytoplasm containing bland oval nuclei as well as whorls ﬈.

413

Diagnoses Associated With Syndromes by Organ: Nervous System

Central Nervous System

Hemangioblastomas in VHL

Retinal Hemangioblastoma

SEGA in Tuberous Sclerosis

SEGA

Choroid Plexus Carcinoma

Choroid Plexus Carcinoma

(Left) Axial T1-weighted postcontrast MR shows 2 of several cerebellar hemangioblastomas ſt, a finding that is so characteristic as to be diagnostic of VHL syndrome by itself. The presence of multiple cysts and tumors in other organs is also characteristic of this disorder. (Right) The characteristic neoplasm involving the CNS and retina in patients with VHL syndrome is hemangioblastoma, a vascularized tumor containing vacuolated stromal cells ﬈.

(Left) Subependymal giant cell astrocytomas (SEGAs) are typical of tuberous sclerosis complex, characterized by contrast-enhancing intraventricular masses near the foramen of Monro ſt. A subtle cortical tuber is also present ﬇ in this patient with tuberous sclerosis complex. (Right) SEGAs are characterized by colorful, large cells with prominent nucleoli, features particularly recognizable in smear preparations. Variable cytoplasmic processes and pleomorphism may also be present.

(Left) Choroid plexus carcinomas are malignant neoplasms that almost always develop in young children and demonstrate variable contrast enhancement ſt. (Courtesy T. Vanegas, MD.) (Right) Choroid plexus carcinomas usually have a papillary architecture, at least in part, and variable pleomorphism. This young patient developed a rhabdomyosarcoma subsequently, which strongly suggests Li-Fraumeni syndrome.

414

Central Nervous System

AT/RT (Left) The cerebellopontine angle is a classic location for atypical teratoid rhabdoid tumors (AT/RT) ſt. These tumors may form large, heterogeneous masses involving the posterior fossa, but they may also affect other CNS sites. (Courtesy C. Specht, MD.) (Right) AT/RTs contain variable proportions of rhabdoid cells, characterized by eccentric nuclei with nucleoli and eosinophilic cytoplasm. This patient had a constitutional chromosome 22 abnormality and multiple associated congenital anomalies.

Pineoblastoma

Diagnoses Associated With Syndromes by Organ: Nervous System

AT/RT

Pineoblastoma (Left) Pineoblastomas are malignant neoplasms presenting as contrastenhancing masses in the pineal region ſt. Associated hydrocephalus is a frequent finding. Pineoblastomas may occur sporadically or in association with tumor predisposition syndromes, such as familial retinoblastoma. (Right) Pineoblastomas are high-grade neoplasms composed of cells with high nuclear:cytoplasmic ratios. Cell-cell wrapping may be present as in other embryonal neoplasms ﬈.

Lhermitte-Duclos Disease

Lhermitte-Duclos Disease (Left) The hallmark of CNS involvement by Cowden syndrome secondary to constitutional PTEN mutations is Lhermitte-Duclos disease, which has a characteristic gross/radiographic appearance (i.e., asymmetric expansion of cerebellar folia ﬈). (Right) Lhermitte-Duclos (or dysplastic gangliocytoma of the cerebellum) is characterized by replacement of the internal granular layer of the cerebellum by large, dysplastic ganglion cells, with relative architectural preservation.

415

Diagnoses Associated With Syndromes by Organ: Nervous System

Eye Genetic Syndromes and Neoplasms Involving Eye and Ocular Adnexa Syndromes

Gene(s)

Gene Region

Cell Pathways

Eye Tumors

Extraocular Tumors

Nonneoplastic Manifestations

Neurofibromatosis NF1 type 1

17q11.2

RAS/MAPK/ PI3K/mTOR/cA MP

Pilocytic astrocytoma, orbital/intraocular neurofibromas

Gliomas, neurofibromas, MPNST, pheochromocytoma, carcinoid tumors, JMML

Lisch nodules, café au lait spots, skeletal, vasculopathy

Neurofibromatosis NF2 type 2

22q12.2

Integrin, Orbital meningioma, RAC/PAK, WNT, orbital and intraocular YAP/Hippo, schwannoma MAPK, PI3K, CRL4

Meningioma, schwannoma

Retinal hamartoma, skeletal abnormalities, subcapsular cataract

von Hippel-Lindau syndrome

VHL

3p25.3

HIF (angiogenesis)

RCC, pheochromocytoma, PNET, endolymphatic sac tumor, papillary cystadenoma

Cysts of pancreas, kidney, adrenal gland, testis, and ovary

Muir-Torre (Lynch)

MSH2 > MLH1

2p21, 3p21.3

Mismatch repair Sebaceous neoplasms involving eyelid, conjunctiva

Astrocytomas, GI carcinomas, endometrial and adrenal carcinoma, sebaceous neoplasms

Tuberous sclerosis complex

TSC1, TSC2

9q34, 16p13.3

mTOR

Giant cell astrocytoma/astrocytic hamartomas

SEGA, angiomyolipoma, angioleiomyomatosis, rhabdomyoma, angiofibroma

Familial uveal melanoma

BAP1

3p21.31p21.2

DNA repair (BRCA1 pathway)

Uveal melanoma

Astrocytoma, meningioma, RCC, mesothelioma, melanocytic lesions

Hereditary retinoblastoma

RB1

13q14.2

Cell cycle (CDKs)

Retinoblastoma (often bilateral)

Pineoblastoma, CNS-embryonal tumors, retinoblastoma, sarcomas

Pleuro-pulmonary blastoma

DICER1

14q32.13 MicroRNA machinery

Medulloepithelioma

Pineoblastoma, pituitary Lung cysts blastoma, Wilms, sex cord-stromal tumors

Xeroderma pigmentosum

Multiple (XPA-G, POLH)

Multiple

Nucleotide excision DNA repair

SCC, BCC, melanoma 

SCCa of tongue, sarcomas

Norrie disease

NDP

Xp11.4

WNT pathway

Pseudoglioma of retina

Hemangioblastoma

Cortical tubers, subependymal nodules, ungual fibroma

Telangiectasias, cataracts, keratitis, CNS dysfunction Cataracts, eye globe shrinkage; abnormalities of iris, CNS, and hearing

Genetic Tumor Syndromes and Nonneoplastic Ocular Manifestations

416

Syndromes

Gene(s)

Gene Region

Nonneoplastic Ocular Manifestations

Extraocular Neoplasms

Other Nonneoplastic Manifestations

Aicardi syndrome

Unknown

X-linked dominant

Chorioretinal lacunae

Choroid plexus papilloma

Corpus callosum agenesis, infantile spasms

Ataxia-telangiectasia

ATM

11q22-23

Conjunctival telangiectasias

Hematolymphoid neoplasms, ovarian/breast CA, smooth muscle tumors

Progressive ataxia, dermatitis, café au lait spots, hypogonadism, short stature, insulin resistance

WAGR

Multiple

11p

Aniridia

Wilms tumor, gonadoblastoma Genitourinary anomalies, mental retardation

Gorlin syndrome

PTCH1 > > 9q22.3, PTCH2, SUFU 1p34.1, 10q24.32

Microphthalmos, cataracts, glaucoma, coloboma

Basal cell carcinoma, medulloblastoma

Fanconi anemia

Fanconi anemia core complex

Multiple

Microphthalmia

Hematolymphoid, solid tumors Multiple congenital anomalies, (e.g., SCCa) endocrine dysfunction

Werner syndrome/progeria

WRN (RECQL2)

8p12

Cataracts

Epithelial and nonepithelial cancers

Odontogenic keratocysts, skeletal anomalies, calcification of falx cerebri, palmar/plantar pits

Premature aging, short stature, bird-like facies

Eye

Lisch Nodule (Left) A diagnostically important ocular manifestation of neurofibromatosis type 1 (NF1) is the Lisch nodule, an aggregate of pigmented cells in the anterior surface of the iris ﬈. (Right) Lisch nodules are composed of melanincontaining cells that form superficial aggregates in the iris ﬈. They usually do not affect vision and have no malignant potential.

Plexiform Neurofibroma

Diagnoses Associated With Syndromes by Organ: Nervous System

Lisch Nodule

Subcapsular Cataract (Left) Plexiform neurofibroma is a hallmark of NF1 and often affects the eyelid and orbital tissues. This eyelid example demonstrates the characteristic multinodular appearance resulting from multiple nerve fascicle involvement. (Right) Posterior subcapsular cataracts ﬈ represent a hallmark of neurofibromatosis type 2 (NF2) and are incorporated in the clinical diagnostic criteria for the syndrome.

Meningioma in NF2

Glial Hamartoma in NF2 (Left) Meningiomas in NF2 patients are usually multiple and may arise in any anatomic site, including the orbit. Many intraorbital meningiomas develop in close relation to the optic nerve sheath ﬈. (Right) Glial hamartomas are characterized by benign glial proliferations ﬈ involving the retina superficially. They may occur in the setting of NF2 or tuberous sclerosis complex (TSC). This particular example developed in an NF2 patient.

417

Diagnoses Associated With Syndromes by Organ: Nervous System

Eye

Astrocytic Hamartoma/Astrocytoma in TSC

Retinal Astrocytic Lesion

Uveal Melanoma

Uveal Melanoma

Retinoblastoma

Retinoblastoma

(Left) The typical intraocular manifestation of TSC is astrocytic hamartoma/astrocytoma. This proliferation is characterized by slow growth and bland cytology, and it is frequently multiple in TSC but may form a dominant mass ﬈. (Right) Retinal astrocytic lesions in tuberous sclerosis patients are histologically similar to subependymal nodules/subependymal giant cell astrocytoma. Scattered microcalcifications are present in this example ﬈.

(Left) Uveal melanomas arise predominantly in the choroid and form well-circumscribed masses. Most uveal melanomas arise sporadically, but they may also develop in the setting of a tumor predisposition syndrome characterized by BAP1 mutations. (Right) The presence of epithelioid cells in uveal melanoma is a negative prognostic factor and is associated with class 2 (highrisk) tumors and BAP1 mutations. These cells contain ample cytoplasm, round nuclei, and macronuclei.

(Left) Retinoblastoma is a proliferative tumor with frequent necrosis ﬈, centered in the retina. It is the main tumor developing in patients with germline RB1 mutations and may be multiple &/or bilateral in these patients. (Right) Retinoblastoma is histologically a round blue cell tumor, highly cellular, and composed of sheets or nests of proliferative neoplastic cells.

418

Eye

Retinal Hemangioblastoma in VHL (Left) Although named hemangiomas in the past, given their rich vascular supply, retinal tumors afflicting von Hippel-Lindau syndrome (VHL) patients are hemangioblastomas, histologically identical to tumors involving the CNS. (Right) The characteristic neoplasm involving the CNS and retina in patients with VHL syndrome is hemangioblastoma, a vascularized tumor containing vacuolated stromal cells ﬈. This particular example is intraocular.

Squamous Carcinoma in XP

Diagnoses Associated With Syndromes by Organ: Nervous System

Retinal Hemangioblastoma in VHL

Basal Cell Carcinoma in XP (Left) Patients with xeroderma pigmentosum (XP) are predisposed to neoplasms developing in sun-exposed areas. This excision of a bulbar conjunctival lesion in a child with XP demonstrates a welldifferentiated squamous cell carcinoma. (Right) XP patients also develop basal cell carcinomas in a variety of cutaneous sites, including the eyelids ſt.

Sebaceous Carcinoma

Intraocular Medulloepithelioma (Left) Patients with alterations in genes encoding for mismatch repair enzymes are predisposed to a variety of superficial and visceral neoplasms. Sebaceous tumors characterize Muir-Torre syndrome. Sebaceous carcinomas frequently involve the eyelids ﬈. (Right) Medulloepithelioma is a distinct ocular neoplasm arising in the ciliary body. It is a recently recognized component of a tumor predisposition syndrome characterized by DICER1 mutations.

419

Diagnoses Associated With Syndromes by Organ: Nervous System

Peripheral Nervous System

420

DIAGNOSTIC CRITERIA Neurofibromatosis Type 1 • NIH (1991) ○ 2 or more of following features – Café au lait macules (≥ 6) with diameter of 0.5 cm in children or 1.5 cm after puberty – Cutaneous or subcutaneous neurofibromas (≥ 2) or plexiform neurofibroma – Freckling of axillary or groin region – Glioma of optic pathways – Lisch nodules identified by slit lamp examination (≥ 2) – Dysplasias of skeletal system (sphenoid wing, long bone bowing, pseudoarthrosis) – Diagnosis of NF1 in 1st-degree relative

Neurofibromatosis Type 2 • Manchester criteria (1992) ○ Any of following – Bilateral vestibular schwannoma – NF2 in 1st-degree relative plus unilateral vestibular schwannoma or any 2 of following □ Neurofibroma □ Meningioma □ Glioma □ Schwannoma □ Posterior subcapsular lens opacity – Unilateral vestibular schwannoma plus any 2 of following □ Neurofibroma □ Meningioma □ Glioma □ Schwannoma □ Posterior subscapular lens opacity – ≥ 2 meningiomas plus unilateral vestibular schwannoma or any 2 of following □ Neurofibroma □ Glioma □ Schwannoma □ Cataract • Baser criteria additive scoring system ○ Criteria – NF2 in 1st-degree relative → 2 points – Vestibular schwannoma (unilateral) □ If present at age ≤ 30 years → 2 points □ If present at age > 30 years → 1 point – Vestibular schwannoma (2nd) □ If present at age ≤ 30 years → 4 points □ If present at age > 30 years → 3 points – Meningioma(s) □ If present at age ≤ 30 years → 2 points □ If present at age > 30 years → 1 point – Cutaneous schwannoma(s) □ If present at age ≤ 30 years → 2 points □ If present at age > 30 years → 1 point – Neoplasm of cranial nerves □ If present at age ≤ 30 years → 2 points □ If present at age > 30 years → 1 point – Mononeuropathy □ If present at age ≤ 30 years → 2 points

□ If present at age > 30 years → 1 point – Cataract(s) □ If present at age ≤ 30 years → 2 points □ If present at age > 30 years → 0 points ○ Points totaled – ≥ 6: Definite NF2 – 4-5: NF2 mutational analysis required – < 4: NF2 unlikely

Schwannomatosis • Baser et al (2006) ○ Definite schwannomatosis – Age > 30 years plus ≥ 2 schwannomas (not dermal), at least 1 with histologic confirmation – Schwannoma (pathologically confirmed) plus 1stdegree relative who meets above criteria ○ Possible schwannomatosis – Age < 30 years plus ≥ 2 schwannomas (not dermal), at least 1 with histologic confirmation – Age > 45 years plus ≥ 2 schwannomas (not dermal), at least 1 with histologic confirmation – Evidence of schwannoma (by radiology) and 1stdegree relative meeting criteria for definite schwannomatosis ○ Must not have – NF2 by criteria – Vestibular schwannoma (by high-resolution MR) – NF2 in 1st-degree relative – Germline NF2 mutation • International Schwannomatosis Workshop (2011) ○ Molecular diagnosis – Both □ Schwannomas or meningiomas (≥ 2 pathologically proven) □ ≥ 2 tumors with chromosome 22 loss of heterozygosity plus 2 different NF2 mutations – Or schwannoma or meningioma plus germline SMARCB1 mutation ○ Clinical diagnosis – Both □ ≥ 2 schwannomas (not intradermal), 1 pathologically confirmed □ No vestibular schwannomas on high-quality MR – Or either □ Schwannoma, pathologically confirmed □ Intracranial meningioma and 1st-degree relative with schwannomatosis ○ Possible schwannomatosis – ≥ 2 schwannomas (not intradermal) without pathologic confirmation ○ Any of following excludes schwannomatosis – NF2 by criteria – Germline NF2 mutation – 1st-degree relative with NF2 – Multiple schwannomas in prior irradiated field only

Peripheral Nervous System

Feature

NF1

NF2

Schwannomatosis

Carney Complex

Incidence

1 in 2,500-3,000 births

1 in 30,000-40,000 births

1 in 30,000-40,000 births

Very rare

Ethnic predilection None

None

None

None

Inheritance

Familial ≈ sporadic (autosomal dominant)

Familial ≈ sporadic (autosomal dominant)

Sporadic > familial (autosomal dominant)

Familial > sporadic (autosomal dominant)

Gene

NF1

NF2

INI1 (SMARCB1, BAF47, hSNF5)

PRKAR1A

Gene location

17q11.2

22q12.2

22q11.23

17p22-24, 2p16

Protein

Neurofibromin

Merlin

SMARCB1 (SWI/SNF complex), LZTR1

Regulatory R1 α-subunit of protein kinase A (PKA)

Pathway/cellular function

RAS/MAPK/PI3K/mTOR/cAMP

Integrin, RAC/PAK, WNT, YAP/Hippo, MAPK, PI3K, CRL4

SMARCB1: Chromatin remodeling; LZTR1 various functions, but may interact with CUL3-based E3 ubiquitin ligase complex

cAMP

Mosaicism

Yes (segmental)

Yes

Yes (segmental in 1/3)

No

Peripheral nervous Neurofibromas, intestinal system neoplasms ganglioneuromatosis, GI schwannoma, benign hybrid nerve sheath tumor, MPNST

Schwannomas > > neurofibromas (cutaneous), benign hybrid nerve sheath tumor, MPNST (very rare)

Schwannomas, benign hybrid nerve sheath tumor, neurofibromas (very rare)

Melanotic schwannian tumors (psammomatous melanotic schwannoma)

Central nervous system neoplasms

Astrocytomas (grade I-IV), indeterminate astrocytomas, glioneuronal tumors

Ependymomas > meningiomas > > nonependymal gliomas

Meningiomas (rare)

Other neoplasms

Pheochromocytoma, sarcomas (rhabdomyosarcoma), gastrointestinal stromal tumor, carcinoids, glomus tumor, juvenile myelomonocytic leukemia, breast carcinoma

Nonneoplastic nervous system manifestations

Macrocephaly, cognitive disabilities, developmental delays, and behavioral disturbances

Diagnoses Associated With Syndromes by Organ: Nervous System

Syndromes With Genetic Predisposition for Peripheral Nerve Neoplasia

Myxomas (cutaneous, mucosal, cardiac), GH adenoma, blue nevi, breast duct adenoma, breast myxomatosis, osteochondromyxoma, thyroid carcinoma/nodules, large-cell calcifying Sertoli cell tumor, fibromas Meningioangiomatosis, glial microhamartoma, peripheral neuropathy

Neuropathic pain

Eye manifestations Lisch nodules

Posterior subcapsular cataract, retinal hamartoma, epiretinal membranes

Cutaneous manifestations

Café au lait spots, intertriginous skin freckling

Hairy plaques, café au lait spots (rare)

Skeletal manifestations

Scoliosis Sphenoid wing dysplasia/hypoplasia, scoliosis, pseudoarthrosis, bowing of long bones

Endocrine manifestations

↑ catecholamines/hypertension (secondary to pheochromocytoma)

Acromegaly, hyperprolactinemia, pigmented nodular adrenal cortical disease

Cardiovascular manifestations

Cerebral arteriopathy, pulmonary artery stenosis

Cardiomyopathy

Differential diagnosis

Noonan syndrome, Legius syndrome, constitutional mismatch repair syndrome, McCune-Albright syndrome, proteus syndrome, familial café au lait spots, MEN2B

Schwannomatosis, NF1

Spotty skin pigmentation (lips, conjunctiva, inner or outer canthi, vagina, penis), freckling, café au lait spots, pilonidal sinus, skin tags

NF2

Peutz-Jeghers, McCuneAlbright syndrome, LEOPARD, Cowden disease and Bannayan-Ruvalcaba-Riley syndrome (PTEN hamartoma tumor syndromes)

421

Diagnoses Associated With Syndromes by Organ: Nervous System

Peripheral Nervous System

Neurofibromas in NF1

Plexiform Neurofibroma

Neurofibroma

Neurofibroma Involving Sensory Ganglion

MPNST

MPNST

(Left) Expansion of numerous nerve roots by neurofibromas is typical of neurofibromatosis type 1 (NF1). Many of these neurofibromas may be classified as plexiform neurofibromas, defined by involvement of multiple nerve fascicles. (Right) Plexiform neurofibroma is a distinctive subtype defined by architectural features (i.e., involvement of multiple nerve fascicles) and demonstrates a multinodular pattern of growth. When large and deep, plexiform neurofibroma is almost pathognomonic of NF1.

(Left) Neurofibromas of all types may affect NF1 patients. The typical neurofibroma contains wavy neoplastic Schwann cells in a myxoid background and delicate collagen fibers. Mast cells are frequent ﬈. In the context of NF1, mast cells facilitate tumor growth by providing trophic signals to the Schwann cell component. (Right) Spinal neurofibromas often involve sensory ganglia in NF1. These entrapped ganglion cells are distributed singly and contain numerous satellite cells ﬈.

(Left) Malignant peripheral nerve sheath tumors (MPNST) represent the main malignancies afflicting NF1 patients. This large, contrastenhancing mass ſt afflicting a patient with NF1 was characterized by sudden growth, which is a worrisome clinical feature. The histologic features were diagnostic of MPNST. (Right) MPNSTs are characterized by a cellular, fascicular pattern of growth. Mitotic activity is not subtle in this NF1-associated MPNST ﬈.

422

Peripheral Nervous System

Schwannoma in NF2 (Left) Well-circumscribed schwannomas of various sizes are evident in nerve roots in this patient with NF2 at autopsy. These schwannomas stand out as areas of pallor ﬈ in a background of myelinated nerve fibers. (Right) In contrast to neurofibromas, schwannomas form wellcircumscribed masses composed almost exclusively of neoplastic Schwann cells, as in this NF2-associated example. A sharp edge with associated nerve is typical ﬈, which facilitates surgical excision.

Schwannoma in Schwannomatosis

Diagnoses Associated With Syndromes by Organ: Nervous System

Multiple Schwannomas in NF2

Melanotic Schwannian Tumor (Left) Schwannomas characterized by a predominance of myxoid stroma (myxoid schwannomas) are not infrequent in the setting of schwannomatosis. (Right) Melanotic schwannian tumor (melanotic schwannoma) is a distinctive, rare subtype characterized by prominent melanotic content, pleomorphism, and nuclear pseudoinclusions ſt. On isolation, melanotic schwannomas raise an important differential diagnosis with melanocytic neoplasms of various grades.

Melanotic Schwannian Tumor

Pericellular and Perilobular Collagen IV Staining (Left) Patients with melanotic schwannian tumors (melanotic schwannomas) containing microcalcifications and psammoma bodies ﬈ (psammomatous melanotic schwannoma) should be clinically evaluated for the possibility of Carney complex. A significant proportion of such tumors develop in the setting of this rare syndrome. (Right) Pericellular ﬈ and perilobular ﬊ collagen IV staining, identifying basal lamina typical of Schwann cells, is typical of melanotic schwannomas. A perilobular pattern may predominate.

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PART I SECTION 10

Pulmonary Adenocarcinoma, Lung Adenocarcinoma With Lepidic (Bronchioloalveolar) Predominant Pattern Lymphangioleiomyomatosis Neuroendocrine Tumor, Lung Pleuropulmonary Blastoma Lung Table

426 432 434 438 442 444

Diagnoses Associated With Syndromes by Organ: Pulmonary

Adenocarcinoma, Lung KEY FACTS

TERMINOLOGY

MICROSCOPIC

• Malignant epithelial tumor with glandular differentiation, mucin production, &/or pneumocyte maker expression

• 5 conventional patterns and 4 variants ○ Conventional: Lepidic, acinar, papillary, micropapillary, and solid patterns ○ Variant: Invasive mucinous, enteric, colloid, and fetal adenocarcinomas

CLASSIFICATION • Classified according to predominant pattern, after comprehensive histologic subtyping of entire tumor in 510% increments

ANCILLARY TESTS

ETIOLOGY/PATHOGENESIS

• TTF-1 &/or Napsin-A expressions by immunohistochemistry

• Close association with tobacco smoking • Oncogenic driver alterations in majority • Risk of developing lung adenocarcinoma is increased in ○ Peutz-Jeghers syndrome with cumulative risk of 7-17% ○ Li-Fraumeni syndrome ○ Bloom syndrome ○ Hereditary retinoblastoma ○ Germline BRCA2 mutants ○ Xeroderma pigmentosum

TOP DIFFERENTIAL DIAGNOSES • • • • •

Nonkeratinizing squamous cell carcinoma Large-cell carcinoma Large-cell neuroendocrine carcinoma Minimally invasive adenocarcinoma Adenocarcinoma from extrathoracic origin

Chest CT Demonstrating 2 Lesions

Acinar Pattern

Lepidic and Papillary Patterns

Papillary Pattern

(Left) Chest CT in a patient with multiple adenocarcinomas of the lung shows a 3.7-cm, part-solid mass (mass #1) ﬈ and a 2.4cm, ground-glass nodule (mass #2) ﬊, both in subpleural regions. (Courtesy M. Price, MD.) (Right) H&E of mass #1 shows columnar cells forming well-formed glands associated with collagen fibrosis in the background of elastotic stroma, consistent with acinar pattern of invasion. This mass was diagnosed as acinar adenocarcinoma.

(Left) H&E of mass #2 shows both lepidic ſt and papillary ﬇ patterns in the subpleural region. (Right) Higher magnification of the papillary pattern shows cuboidal to low columnar cells lining papillary structures with fibrovascular cores ſt. Mass #2 was diagnosed as papillary adenocarcinoma, histologically distinct from mass #1.

426

Adenocarcinoma, Lung

Definitions • Malignant epithelial tumor with glandular differentiation, mucin production, &/or pneumocyte maker expression • Invasive size > 0.5 cm

Classifications • 70-90% of invasive lung adenocarcinomas show heterogeneous histologic patterns • 5 conventional and 4 variant histologic patterns ○ Conventional: Lepidic, acinar, papillary, micropapillary, and solid adenocarcinomas ○ Variant: Invasive mucinous adenocarcinoma (IMA), enteric, colloid, and fetal adenocarcinomas • Classified according to predominant pattern, after comprehensive histologic subtyping of entire tumor in 510% increments

ETIOLOGY/PATHOGENESIS Environmental Exposure • Close association with tobacco smoking • Radon, occupational agents, air pollution, wood smoke

Genetic Alterations • Association with oncogenic driver alterations in majority ○ Mutations: EGFR, KRAS, BRAF, ERBB2, and MET, among others ○ Fusions: ALK, ROS1, and RET, among others

○ Adjuvant therapy for ≥ stage II tumors, and stage I tumors with aggressive features – Chemotherapy &/or radiation therapy • Advanced-stage tumors (stage IIIB-IV) ○ Targeted therapy, if molecular targets (e.g., EGFR and BRAF mutations, ALK and ROS1 fusions) are present ○ Immunotherapy ○ Chemotherapy &/or radiation therapy

Prognosis • Depends on stage at presentation ○ Stage I tumors – Longer recurrence-free survival (RFS) in lepidic adenocarcinoma – Shorter RFS in solid/micropapillary adenocarcinomas ○ Advanced stage tumors – Patients with molecular targets may have better prognosis • Could be influenced by pulmonary and other comorbidity

IMAGING CT Findings • Solid or part solid ground-glass (GGO) nodule(s) often in lung periphery • Consolidation may be seen in IMA • Low-attenuation density in colloid adenocarcinoma • Multiple nodules not uncommon

MACROSCOPIC

Association With Familial Syndromes

General Features

• Risk of developing lung adenocarcinoma is increased in ○ Peutz-Jeghers syndrome, with cumulative risk of 7-17% ○ Li-Fraumeni syndrome, Bloom syndrome, hereditary retinoblastoma, germline BRCA2 mutants and xeroderma pigmentosum, as compared with general population • Often younger onset than general population

• Commonly present in lung periphery • Gray-white nodules with central scarring fibrosis associated with anthracotic pigments and pleural puckering • Poorly defined border, if peripheral lepidic component is significant • Lepidic tumor components may be difficult to identify in fresh, unfixed specimens

CLINICAL ISSUES Epidemiology • Incidence ○ Most common histologic type of lung cancer worldwide ○ Prevalence varies across countries/regions • Age ○ Average presentation at 6th and 7th decades of life ○ Younger onset in patient with familial syndrome or gene rearrangement

Size • > 0.5 cm, but varies • Frequent small (≤ 2 cm) tumors in resection due to lowdose CT screening

Sections to Be Submitted • Entire tumor submission for small (≤ 3 cm) tumors • At least 1 section/1 cm for larger (> 3 cm) tumors

MICROSCOPIC

Presentation

Histologic Features

• • • •

• Malignant epithelial tumor with glandular differentiation on routine staining &/or by immunohistochemistry • Invasive size (nonlepidic patterns) > 0.5 cm • Classified according to predominant pattern

Cough, dyspnea, wheezing, hemoptysis Chest pain/back pain, pleural effusion Weight loss, loss of appetite, fever Asymptomatic, discovered incidentally or during screening

Diagnoses Associated With Syndromes by Organ: Pulmonary

TERMINOLOGY

Treatment

Lepidic Adenocarcinoma

• Early-stage tumors (stage I-IIIA) ○ Surgical approaches – Sublobar resection, lobectomy, pneumonectomy ○ Neoadjuvant therapy for stage IIIA

• Typically bland pneumocytic cells lining preexisting alveolar walls • Significant (> 0.5 cm) nonlepidic components present

427

Diagnoses Associated With Syndromes by Organ: Pulmonary

Adenocarcinoma, Lung Acinar Adenocarcinoma • Major component exhibits gland formation • Tumor cells &/or glandular spaces may contain mucin • Cribriform, fused are complex acinar patterns considered high-grade features

Papillary Adenocarcinoma • Major component exhibits tumor cell growth along central fibrovascular cores

Micropapillary Adenocarcinoma • Major component shows tumor cells growing in papillary tufts that form florets and lack fibrovascular cores

Solid Adenocarcinoma • Major component exhibits polygonal tumor cells forming sheets without recognizable glandular differentiation • Ancillary tests to differentiate from squamous and largecell carcinomas necessary in pure solid tumors

IMA • Columnar cells with abundant cytoplasmic mucin &/or goblet cells • Lepidic with acinar, papillary, &/or micropapillary patterns • Classified as mixed invasive mucinous and nonmucinous adenocarcinoma, if nonmucinous cells present in ≥ 10% of tumor

Colloid Adenocarcinoma • Abundant extracellular mucin pools distending and destroying alveolar walls • Often banal mucinous cells partially lining &/or free floating in mucin pools or growing in lepidic pattern

Fetal Adenocarcinoma • Complex glandular structures with glycogen-rich, nonciliated cells resembling fetal lung epithelium of pseudoglandular phase; low- and high-grade types • Low-grade fetal adenocarcinoma ○ Low nuclear atypia and morule formation ○ Typically enveloped by loose fibromyxoid stroma • High-grade fetal adenocarcinoma ○ Often mixed with other conventional patterns ○ ≥ 50% of tumor cells exhibit fetal morphology

Enteric Adenocarcinoma • Cytomorphologically resembles colorectal adenocarcinoma • May be mixed with other patterns, but enteric morphology should be seen in ≥ 50% of tumor cells

Cytologic Features • Signet ring, clear, &/or hepatoid cells may be seen • Solid and signet ring cell &/or mucinous cribriform patterns often associated with fusion positive tumors

ANCILLARY TESTS

• Significantly lower expression rates of TTF-1 and Napsin-A in IMA, colloid, and enteric adenocarcinomas • Negative expression of squamous markers (e.g., p40, p63, and CK5/6)

DIFFERENTIAL DIAGNOSIS Nonkeratinizing Squamous Cell Carcinoma • Differentiation from pure solid adenocarcinoma • p40 or p63 labeling typically ≥ 50% of tumor cells, and absent TTF-1 and Napsin-A expression

Large-Cell Carcinoma • Differentiation from pure solid adenocarcinoma • Absent expression of squamous and adenocarcinoma markers

Large-Cell Neuroendocrine Carcinoma • Differentiation from pure solid adenocarcinoma or cribriform pattern • Positive synaptophysin, chromogranin, &/or CD56 expressions • High Ki-67 proliferative index, typically ≥ 50%

Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma • Differentiation from lepidic adenocarcinoma • No or limited (≤ 0.5 cm) nonlepidic components

Adenocarcinoma From Extrathoracic Origin • Clinical correlation is very important for differentiation • Immunohistochemistry panels combining TTF-1/Napsin-A, CK7/CK20 and other organ markers may be helpful ○ Absent expressions of both TTF-1 and Napsin-A in 15% of conventional lung adenocarcinomas and majority of IMA, colloid, and enteric adenocarcinomas

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • After comprehensive histologic subtyping of entire tumor in 5-10% increments, predominant pattern determines diagnosis • Invasive (nonlepidic) patterns ≥ 0.5 cm • Invasive patterns/components often multifocal; total % of nonlepidic patterns x entire tumor size/100 considered as invasive size, if multifocal

SELECTED REFERENCES 1.

2. 3.

4.

Histochemistry • Intracytoplasmic mucicarmine expression often present

5.

Immunohistochemistry

6.

• Nuclear labeling with TTF-1 in 75-80% • Granular cytoplasmic expression of Napsin-A in 80-85% 428

7.

Kadouri L et al: Homologous recombination in lung cancer, germline and somatic mutations, clinical and phenotype characterization. Lung Cancer. 137:48-51, 2019 Yatabe Y et al: Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol. 14(3):377-407, 2019 Ballinger ML et al: Baseline surveillance in Li-Fraumeni syndrome using whole-body magnetic resonance imaging: a meta-analysis. JAMA Oncol. 3(12):1634-9, 2017 Travis WD et al: Adenocarcinoma. In Travis WD et al: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th ed. Lyon: IARC Press, 2015 Moreira AL et al: Cribriform and fused glands are patterns of high-grade pulmonary adenocarcinoma. Hum Pathol. 45(2):213-20, 2014 Yu CL et al: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst. 101(8):581-91, 2009 Giardiello FM et al: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 119(6):1447-53, 2000

Adenocarcinoma, Lung

Lepidic Pattern (Left) Gross photograph of lung adenocarcinoma shows a gray-white nodule with central scarring fibrosis associated with anthracotic pigments ſt and pleural puckering ﬇. (Right) H&E of lung adenocarcinoma with an EGFR mutation shows relatively bland but atypical pneumocytes lining preexisting alveolar walls without invasion, consistent with lepidic pattern.

Solid Pattern

Diagnoses Associated With Syndromes by Organ: Pulmonary

Lung Adenocarcinoma

Solid Pattern (Left) Polygonal tumor cells form sheets/nests without recognizable glandular differentiation, consistent with solid pattern. Tumor necrosis ﬇ is also seen. (Right) H&E of lymph node metastasis consists solely of a solid pattern of tumor growth. In this case, differentiation between adenocarcinoma with solid pattern from nonkeratinizing squamous cell carcinoma or large-cell carcinoma is difficult.

TTF-1 Immunostain

p40 Immunostain (Left) Immunohistochemistry performed on lymph node biopsy shows positive nuclear labeling with TTF-1 in the tumor cells. (Right) The tumor cells are negative for p40 nuclear expression. The positive TTF-1 and negative p40 are consistent with lung adenocarcinoma.

429

Diagnoses Associated With Syndromes by Organ: Pulmonary

Adenocarcinoma, Lung

Micropapillary Pattern

Fused Acinar Pattern

Invasive Mucinous Adenocarcinoma

Enteric Adenocarcinoma

Colloid Adenocarcinoma

Colloid Adenocarcinoma

(Left) Micropapillary pattern exhibits tumor cells growing in papillary tufts that form florets and lack fibrovascular cores ﬇. (Right) In this area, tumor cells form angulated, small glands in an infiltrating pattern, and many of them are fused, consistent with fused acinar pattern. The fused, cribriform, and other complex acinar patterns are considered high grade, while conventional acinar pattern is classified intermediate grade.

(Left) An example of invasive mucinous adenocarcinoma exhibits columnar cells with abundant cytoplasmic mucinforming glands ſt or lining preexisting alveolar walls ﬇. (Right) Enteric adenocarcinoma exhibits tall columnar cells with elongated, hyperchromatic nuclei forming complex glands, and cytomorphologically resembles colorectal adenocarcinoma. A large area of necrosis ﬇ is also seen.

(Left) An example of colloid adenocarcinoma is characterized by abundant extracellular mucin pools, distending and destroying alveolar walls. (Right) Banal mucinous cells partially lining mucin pools are shown at higher power.

430

Adenocarcinoma, Lung β-catenin Nuclear Labeling in Low-Grade Fetal Adenocarcinoma (Left) Low-grade fetal adenocarcinoma exhibits complex glandular structures with glycogen-rich, nonciliated cells with low-grade nuclear atypia resembling fetal lung epithelium of the pseudoglandular phase. A morule formation ﬇ is characteristic. (Courtesy Y. Nakatani, MD.) (Right) Lowgrade fetal adenocarcinoma typically demonstrates aberrant nuclear localization of β-catenin in association with morule formation. (Courtesy Y. Nakatani, MD.)

High-Grade Fetal Adenocarcinoma

Diagnoses Associated With Syndromes by Organ: Pulmonary

Low-Grade Fetal Adenocarcinoma

Mucinous Cribriform Pattern (Left) High-grade fetal adenocarcinoma is characterized by complex glandular structures with glycogen-rich tumor cells exhibiting significant nuclear atypia. High-grade fetal adenocarcinoma is often mixed with other conventional adenocarcinoma patterns, but fetal morphology needs to be seen in ≥ 50% of tumor cells. (Courtesy Y. Nakatani, MD.) (Right) Lung adenocarcinoma with ALK rearrangement exhibits a cribriform pattern of growth with extracellular mucin, consistent with mucinous cribriform pattern.

Solid and Signet Ring Cell Pattern

Positive ALK Expression (Left) The same ALK-positive tumor shows areas with a solid pattern of growth with abundant signet ring cells. Both solid and signet ring cell and mucinous cribriform patterns are often associated with fusion-positive tumors. (Right) Immunohistochemistry for ALK (clone 5A4) highlights cytoplasm of almost all tumor cells, consistent with ALKrearranged tumor. Of note, expression of ALK appears to be weaker in signet ring cells due to abundant intracytoplasmic mucin.

431

Diagnoses Associated With Syndromes by Organ: Pulmonary

Adenocarcinoma With Lepidic (Bronchioloalveolar) Predominant Pattern KEY FACTS

TERMINOLOGY

• Similar to invasive lung adenocarcinoma in sporadic cases

• Lepidic pattern: Neoplastic cells lining preexisting alveolar walls without invasion • Classified into 3 categories ○ AIS: Small (≤ 3 cm), localized adenocarcinoma consisting solely of lepidic pattern ○ MIA: Small (≤ 3 cm), solitary adenocarcinoma with predominantly lepidic pattern and ≤ 5 mm invasion ○ Lepidic adenocarcinoma: Invasive adenocarcinoma with predominantly lepidic pattern • Nonmucinous (vast majority) or mucinous/mixed cytology • No adverse pathologic features in AIS and MIA

MACROSCOPIC

ETIOLOGY/PATHOGENESIS • Risk of developing lung cancer in general is increased in ○ Peutz-Jeghers syndrome, with cumulative risk of 7-17% ○ Li-Fraumeni syndrome and xeroderma pigmentosum, as compared with general population • EGFR T790M germline mutations

• Localized nodule/mass, not infrequently multifocal • AIS and MIA may not be seen grossly

MOLECULAR • EGFR mutants often exhibit predominantly lepidic pattern in resection

TOP DIFFERENTIAL DIAGNOSES • Atypical adenomatous hyperplasia ○ Tumor nodule of ≤ 0.5 cm in greatest dimension • Metastatic mucinous adenocarcinoma ○ Clinicopathologic correlation is important in determining site of origin • Invasive (nonlepidic) adenocarcinomas of lung ○ Majority of tumor cells exhibit nonlepidic patterns

Lepidic Adenocarcinoma

Minimally Invasive Adenocarcinoma

Nonmucinous Lepidic Pattern

Mucinous Lepidic Pattern

(Left) Representative coronal CT from a patient with lepidic adenocarcinoma shows partsolid ground-glass opacity (GGO). In this case, a solid component measuring 1.2 cm in the greatest dimension ﬊ is seen in the background of this 4.1-cm GGO ﬈. (Right) Minimally invasive adenocarcinoma demonstrates a small component of invasive (acinar) pattern ﬇ in the background of nonmucinous lepidic pattern ſt.

(Left) Adenocarcinoma in situ (AIS) in a patient with EGFR T790M germline mutation consists of a cellular proliferation of pneumocytes along the surface of alveolar walls without destruction (invasion). (Right) Mucinous lepidic pattern consists of columnar cells with abundant intracytoplasmic mucin and goblet cells along alveolar walls without destruction. The background alveolar spaces are also filled with mucin.

432

Adenocarcinoma With Lepidic (Bronchioloalveolar) Predominant Pattern

IMAGING

Abbreviations

CT Findings

• Adenocarcinoma in situ (AIS) • Minimally invasive adenocarcinoma (MIA)

• Ground-glass opacity (GGO) or part-solid GGO, not infrequently multifocal

Synonyms • Bronchioloalveolar carcinoma (obsolete)

Definitions • Lepidic pattern: Neoplastic cells lining preexisting alveolar walls without invasion • Classified into 3 categories ○ AIS: Small (≤ 3 cm), localized adenocarcinoma consisting solely of lepidic pattern ○ MIA: Small (≤ 3 cm), solitary adenocarcinoma with predominantly lepidic pattern and ≤ 5 mm invasion ○ Lepidic adenocarcinoma: Invasive adenocarcinoma with predominantly lepidic pattern • AIS and MIA are nonmucinous, mucinous (rare), or mixed (rare); lepidic adenocarcinoma is typically nonmucinous • No evidence of lymphatic, vascular or pleural invasion, airspace invasion or necrosis in AIS and MIA

ETIOLOGY/PATHOGENESIS Environmental Exposure

MACROSCOPIC General Features • Localized nodule/mass, not infrequently multifocal • AIS and MIA may not be seen grossly

MICROSCOPIC Histologic Features • Minor component of nonlepidic patterns in MIA and lepidic adenocarcinoma

Cytologic Features • Nonmucinous type ○ Small and dark tumor cells with hyperchromatic nuclei and scant cytoplasm &/or hobnail appearance ○ Inconspicuous nucleoli and lack of mitotic activity • Mucinous type ○ Mucinous columnar cells &/or goblet cells

DIFFERENTIAL DIAGNOSIS

• Refer to "lung adenocarcinoma" section

Atypical Adenomatous Hyperplasia

Genetic Alterations • EGFR mutants often exhibit lepidic pattern

• Tumor nodule of ≤ 0.5 cm in greatest dimension • Cytomorphology similar to AIS, but less cellular

Association With Familial Syndromes

Metastatic Mucinous Adenocarcinoma

• EGFR T790M germline mutations • Risk of developing lung cancer in general is increased in ○ Peutz-Jeghers syndrome, with cumulative risk of 7-17% ○ Li-Fraumeni syndrome and xeroderma pigmentosum, as compared with general population

• Metastasis from pancreas, colon, ovary, or breast primary may exhibit mucinous lepidic pattern • Immunohistochemical studies may not be so helpful

CLINICAL ISSUES Epidemiology • Unknown incidence of AIS and MIA • Prevalence of lepidic adenocarcinoma in resected stage I adenocarcinomas ranges from < 5% to 25% • Age and gender distributions similar to invasive lung adenocarcinoma • Younger at presentation in those with familial syndromes

Presentation • Often discovered incidentally or during screening • Cough, chest pain, &/or shortness of breath, if symptomatic

Treatment • Surgical approaches ○ Wedge resection, segmentectomy, or lobectomy

Invasive (Nonlepidic) Adenocarcinomas of Lung • Majority of tumor cells exhibit nonlepidic patterns

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Histologic examination of entire tumor and lymph node sampling are required for diagnosis of AIS and MIA ○ Diagnosis of AIS and MIA cannot be rendered in biopsy

Pathologic Interpretation Pearls • Alveolar walls lined by neoplastic cells without invasion • Absence of adverse pathologic features in AIS and MIA

SELECTED REFERENCES 1.

2.

Prognosis • 100% 5-year recurrence-free survival for AIS and MIA; favorable prognosis for lepidic adenocarcinoma

Diagnoses Associated With Syndromes by Organ: Pulmonary

TERMINOLOGY

3. 4. 5.

Jiang L et al: Association between the novel classification of lung adenocarcinoma subtypes and EGFR/KRAS mutation status: A systematic literature review and pooled-data analysis. Eur J Surg Oncol. 45(5):870-6, 2019 Kameda K et al: Implications of the eighth edition of the TNM proposal: Invasive versus total tumor size for the T descriptor in pathologic stage I-IIA lung adenocarcinoma. J Thorac Oncol. 13(12):1919-29, 2018 Zabeck H et al: Molecular signatures in IASLC/ATS/ERS classified growth patterns of lung adenocarcinoma. PLoS One. 13(10):e0206132, 2018 Travis WD et al: Adenocarcinoma. In: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th ed. Lyon: IARC Press, 2015 Gazdar A et al: Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. J Thorac Oncol. 9(4):456-63, 2014

433

Diagnoses Associated With Syndromes by Organ: Pulmonary

Lymphangioleiomyomatosis KEY FACTS

CLASSIFICATION

MICROSCOPIC

• Sporadic form • Tuberous sclerosis complex (TSC)-associated lymphangioleiomyomatosis (LAM) (TSC-LAM)

• Multiple small, thin-walled cysts • Proliferation of atypical smooth muscle-like cells (LAM cells) ○ In walls of cysts, blood vessels, &/or lymphatics ○ 2 types of LAM cells: Vascular smooth muscle-like cells; perivascular epithelioid cells (PECs) ○ Lacking overt atypia or mitotic activity

ETIOLOGY/PATHOGENESIS • Excessive proliferation of LAM cells due to mutations in TSC genes, in particular TSC2 • Aberrant stimulation of LAM cell growth by estrogen and other factors may be involved in sporadic form

CLINICAL ISSUES • Incidence ○ 1 per million in general population and 3-8 per million women; sporadic LAM extremely rare in men ○ 26-50% of women with TSC and 10-38% of men with TSC ○ More common in premenopausal women; prepubertal LAM is rare

ANCILLARY TESTS • LAM cells are positive for melanocyte markers, smooth muscle markers, and ER/PR (in subset)

TOP DIFFERENTIAL DIAGNOSES • • • •

Severe emphysema Pulmonary Langerhans cell histiocytosis (PLCH) Birt-Hogg-Dubé syndrome (BHD) Lymphocytic interstitial pneumonia (LIP)/follicular bronchiolitis (FB)

Representative Chest CT of LAM

Cystic Airspace With Subtle Infiltrate of Lesional Cells

Cystic Changes With Lesional Cells Forming Overt Nodules

High-Power View of Lesional Cells

(Left) Coronal CT from a patient with lymphangioleiomyomatosis (LAM) shows numerous thinwalled cysts of various sizes throughout both lungs. (Courtesy Y. Hung, MD, PhD.) (Right) A thin-walled cyst in a patient with LAM is shown. LAM cells subtly infiltrate the edge of the cystic airspace ﬊.

(Left) In this example of LAM, LAM cells form overt nodules within the wall of cystic airspaces ﬊. (Right) A proliferation of plump spindleshaped myoid cells (LAM cells) focally expands alveolar septae ſt. No mitosis or cytologic atypia is present. Distinguishing between sporadic and TSC-LAM may not be possible on histologic grounds alone.

434

Lymphangioleiomyomatosis

Abbreviations • Lymphangioleiomyomatosis (LAM)

Synonyms • Lymphangiomyomatosis

Definitions • Rare multisystem disorder that belongs to family of neoplasms with perivascular epithelioid differentiation (PEComa) • Diffuse multicystic distortion of lung parenchyma with proliferation of atypical smooth muscle-like cells (LAM cells) • Sporadic form and tuberous sclerosis complex (TSC)associated LAM (TSC-LAM) present

ETIOLOGY/PATHOGENESIS Etiology • Excessive proliferation of LAM cells due to mutations in TSC genes, in particular TSC2 • Aberrant stimulation of LAM cell growth by estrogen, and other factors may be involved in sporadic form

CLINICAL ISSUES Epidemiology • Incidence ○ 1 per million in general population and 3-8 per million women ○ 26-50% of women with TSC and 10-38% of men with TSC • Age ○ Ranging from preadolescence to old age, but more common in premenopausal women ○ Prepubertal LAM is rare • Sex ○ Commonly affects women ○ Sporadic LAM is extremely rare in men

Presentation • • • • •

Fatigue Progressive dyspnea Pneumothorax Pleural effusion Chest pain, cough or phlegm, chyloptysis and hemoptysis are less common

Laboratory Tests • Vascular endothelial growth factor (VEGF)-D level ≥ 800 pg/mL reliably distinguishes LAM from other cystic lung diseases

Treatment • Monitored observation for patients with mild lung function impairment • Sirolimus (mTOR inhibitor) indicated for symptomatic patients with abnormal lung function, evidence of rapidly progressive disease, or problematic chylous accumulations • Everolimus for patients who do not tolerate sirolimus • Lung transplantation or clinical trials for advanced disease or in those refractory to mTOR inhibitors

Prognosis • Rates of progression vary among individuals; serum VEGF-D correlates with disease severity • 10-20% of overall mortality • 2nd most common cause of death in TSC patients; average life expectancy of 63 years for TSC-LAM

IMAGING CT Findings • Multiple bilateral (typically > 10), thin-walled cysts of various sizes (2-40 mm in diameter) • Cysts may be larger and more numerous in women than men with TSC • Pneumothorax as presenting manifestation in 1/3 of sporadic LAM and ultimately seen in > 2/3 of LAM patients • Septal thickening, unilateral or bilateral pleural effusion, and mediastinal lymphadenopathy may be seen • Features of multifocal micronodular pneumocyte hyperplasia (multiple centrilobular, solid or ground-glass nodular opacities ranging in size from 2-10 mm scattered throughout lungs in random distribution) may be present in TSC-LAM • Features of renal angiomyolipomas may be depicted by abdominal CT in 1/3 of sporadic LAM and > 80% of TSCLAM

Diagnoses Associated With Syndromes by Organ: Pulmonary

TERMINOLOGY

MACROSCOPIC General Features • Multiple thin-walled cysts uniformly distributed throughout lungs

MICROSCOPIC Histologic Features • Multiple small, thin-walled cysts • Proliferation of LAM cells ○ In cyst walls – May be overt and nodular – May be subtly infiltrate and require multiple levels examined to identify ○ May infiltrate blood vessels and lymphatics, causing secondary pulmonary hemorrhage ○ May be seen within focally thickened alveolar septae • No difference in histologic features of LAM between sporadic and TSC-associated cases • Multinodular type II pneumocyte hyperplasia may be seen in TSC-LAM

Cytologic Features • 2 types of LAM cells ○ Plump spindle-shaped myoid cells with typically eosinophilic cytoplasm resembling vascular smooth muscle cells ○ More cuboidal cells with features of perivascular epithelioid cells (PECs: Clear to granular, lightly eosinophilic cytoplasm located in perivascular location) • Lacking overt atypia or mitotic activity

435

Diagnoses Associated With Syndromes by Organ: Pulmonary

Lymphangioleiomyomatosis

ANCILLARY TESTS Immunohistochemistry • Cytoplasmic labeling with melanocyte markers (HMG45, melan A, and microphthalmia transcription factor) • Cytoplasmic labeling with smooth muscle markers (smooth muscle actin and desmin) • Nuclear labeling with ER and PR (in subset) • Lack of reactivity to S100 or cytokeratin

Genetic Testing

• Cystic changes seen in perihilar or upper lobe distribution and associated with fibrosis • Bilateral hilar adenopathy common

SELECTED REFERENCES 1. 2. 3.

• Mutations in TSC genes, in particular TSC2

DIFFERENTIAL DIAGNOSIS Severe Emphysema

4. 5.

• Dilated airspaces may contain septae or centrilobular vessels • Often upper lobe predominant with indiscernible borders • History of cigarette smoking and characteristic CT appearance sufficient for diagnosis

6.

Pulmonary Langerhans Cell Histiocytosis

9.

• More bizarre-shaped, peribronchiolar, and thicker walled cysts • Typically upper lobe predominant sparing costophrenic angles • History of cigarette smoking and no female predominance • Association with stellate nodules on CT

Birt-Hogg-Dubé Syndrome • Crescent-shaped or elliptical cysts in basilar, perivascular, &/or subpleural distribution • Frequently present with recurrent spontaneous pneumothoraces • Associated with renal cysts and neoplasms including oncocytomas and cutaneous fibrofolliculomas and trichodiscomas • Mutations in folliculin (FLCN) gene; familial history may or may not be present

7. 8.

10. 11.

12.

13. 14.

15. 16.

17.

Lymphocytic Interstitial Pneumonia/Follicular Bronchiolitis

18.

• Cystic changes can be seen in up to 2/3 of patients • Predilection for lower-lung zone in perivascular distribution • Typically associated with diffuse interstitial infiltration of polymorphous lymphocytes and plasma cells • Usually seen in middle-aged women and in association with autoimmune disorder (e.g., Sjögren syndrome, SLE) or immunodeficiency state • Diffuse, thin-walled cystic changes without interstitial infiltration of polymorphous lymphoplasma cells can be presentation of Sjögren or lupus-associated lymphocytic interstitial pneumonia/follicular bronchiolitis (LIP/FB) and can mimic LAM

19.

Light Chain Deposition Disease

24.

• Emphysematous changes and dilation of small airways • κ-light chain deposition in alveolar walls, small airways, and vessels • Variable cystic changes (multiple small, round cysts in diffuse distribution to large, cystic spaces associated with reticulonodular opacities) on CT 436

Sarcoidosis With Advanced Interstitial Lung Disease

20. 21.

22.

23.

Zak S et al: Lymphangioleiomyomatosis mortality in patients with tuberous sclerosis complex. Ann Am Thorac Soc. 16(4):509-12, 2019 Gupta N et al: Diffuse cystic lung disease as the presenting manifestation of Sjögren syndrome. Ann Am Thorac Soc. 13(3):371-5, 2016 McCormack FX et al: Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 194(6):748-61, 2016 Goldberg HJ et al: Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J. 46(3):783-94, 2015 Gupta N et al: Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 192(1):17-29, 2015 Gupta N et al: Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 191(12):1354-66, 2015 Kristof AS et al: Lymphangioleiomyomatosis and tuberous sclerosis complex in Quebec: prevalence and health-care utilization. Chest. 148(2):444-9, 2015 Travis WD et al: PEComatous tumours in Travis WD et al: WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th ed. Lyon: IARC Press, 2015 Bhardwaj H et al: Differentiating pulmonary lymphangioleiomyomatosis from pulmonary langerhans cell histiocytosis and Birt-Hogg-Dube syndrome. Lung India. 30(4):372-3, 2013 Cudzilo CJ et al: Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest. 144(2):578-85, 2013 Krueger DA et al: Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 49(4):255-65, 2013 Northrup H et al: Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 49(4):243-54, 2013 Ryu JH et al: Cystic lung disease is not uncommon in men with tuberous sclerosis complex. Respir Med. 106(11):1586-90, 2012 Adriaensen ME et al: Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin Radiol. 66(7):625-8, 2011 McCormack FX et al: Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 364(17):1595-606, 2011 Seibert D et al: Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences. Ann Intern Med. 154(12):806-13, W-294, 2011 Hayashi T et al: Loss of heterozygosity on tuberous sclerosis complex genes in multifocal micronodular pneumocyte hyperplasia. Mod Pathol. 23(9):1251-60, 2010 Young LR et al: Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest. 138(3):674-81, 2010 Muzykewicz DA et al: TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet. 46(7):465-8, 2009 Colombat M et al: Pulmonary cystic disorder related to light chain deposition disease. Am J Respir Crit Care Med. 173(7):777-80, 2006 Franz DN et al: Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 164(4):661-8, 2001 Maruyama H et al: Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2. Pathol Int. 51(8):585-94, 2001 Moss J et al: Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 164(4):669-71, 2001 Costello LC et al: High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc. 75(6):591-4, 2000

Lymphangioleiomyomatosis

HMB45 Immunostain (Left) Two types of LAM cells are seen. Plump spindleshaped myoid cells with eosinophilic cytoplasm resembling vascular smooth muscle cells ſt and more cuboidal cells with clear cytoplasm (PECs) ﬇. Both lack mitosis and cytologic atypia. (Right) LAM cells are reactive to HMB45 and other melanocyte markers including melan A and microphthalmia transcription factor (MiTF), but lack reactivity to S100 and cytokeratin.

Smooth Muscle Actin Immunostain

Diagnoses Associated With Syndromes by Organ: Pulmonary

Two Types of Lesional Cells

ER Immunostain (Left) LAM cells are reactive to smooth muscle actin and other smooth muscle markers, including desmin. (Right) A subset of LAM cells exhibit nuclear expression of ER &/or PR.

Abundant Hemosiderin-Laden Macrophages

Micronodular Type II Pneumocyte Hyperplasia (Left) Abundant hemosiderinladen macrophages filling alveolar spaces ſt may be seen in LAM. It is attributed to LAM cells infiltrating blood vessels and lymphatics, causing secondary hemorrhage. (Right) Small, nodular proliferation of type II pneumocytes st may be seen in TSC-LAM. The nodular pneumocyte hyperplasia can mimic atypical adenomatous hyperplasia or adenocarcinoma in situ.

437

Diagnoses Associated With Syndromes by Organ: Pulmonary

Neuroendocrine Tumor, Lung KEY FACTS ○ < 10% for extensive SCLC, 15-40% for LCNEC ○ 50-80% for AC, > 90% for TC

CLASSIFICATION • Based on mitotic activity, necrosis, and cytologic features • High grade: Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) • Intermediate grade: Atypical carcinoid (AC) • Low grade: Typical carcinoid (TC)

ETIOLOGY/PATHOGENESIS

MOLECULAR • SCLC: Frequent mutations in TP53 and RB1 • LCNEC: Multiple genetic subgroups • AC and TC: Mutations in MEN1, ARID1A, and PSIP1

MICROSCOPIC

• SCLC and LCNEC associated with smoking history • SCLC arises de novo or in EGFR-mutant or fusion-positive lung adenocarcinoma resistant to targeted therapy • Patients with hereditary retinoblastoma noted to show increased risks for lung cancer, including SCLC and LCNEC

CLINICAL ISSUES • SCLC and LCNEC often present with bulky disease at presentation with frequent metastases • Paraneoplastic syndromes • 5-year overall survival

• Architecture: Rosettes, nests, trabeculae, sheets • SCLC: Small cell cytomorphology, > 10 mitoses per 2 mm², frequent necrosis • LCNEC: Non-small cell cytomorphology, moderate cytoplasm, > 10 mitoses per 2 mm², comedo necrosis ○ Neuroendocrine differentiation confirmed by immunohistochemical &/or ultrastructural studies • AC: Necrosis &/or 2-10 mitoses per 2 mm² • TC: No necrosis, 0-1 mitosis per 2 mm²

Neuroendocrine Tumor of Lung

CT of Small-Cell Carcinoma

CT of Small-Cell Carcinoma

Small-Cell Carcinoma of Lung

(Left) Graphic of a pulmonary neuroendocrine tumor illustrates one of the most common locations as an endobronchial mass near the hilum. The tumor often produces symptoms due to obstruction of an adjacent bronchial lumen. (Right) Smallcell carcinoma of lung (SCLC) typically presents in smokers and often shows extensive disease at presentation. Coronal CT shows a large hilar tumor ﬉, along with nodular thickening along suture line ﬊ from prior lung adenocarcinoma resection > 10 years ago.

(Left) Rarely, small-cell carcinoma presents as localized disease. Coronal CT shows a solitary ill-defined tumor ﬊ centrally located near the right hilum. (Right) Gross photograph of the same tumor shows a lobulated border and a fleshy appearance ﬉.

438

Neuroendocrine Tumor, Lung

Abbreviations • • • •

Small-cell lung carcinoma (SCLC) Large-cell neuroendocrine carcinoma (LCNEC) Atypical carcinoid (AC) Typical carcinoid (TC)

Definitions • Neuroendocrine tumors of lung classified into 4 categories ○ SCLC: High-grade neuroendocrine carcinoma of lung showing small cell morphology ○ LCNEC: High-grade neuroendocrine carcinoma of lung showing non-small cell morphology ○ AC: Intermediate-grade neuroendocrine tumor of lung showing necrosis &/or 2-10 mitoses per 2 mm² ○ TC: Low-grade neuroendocrine tumor of lung showing no necrosis and 0-1 mitoses per 2 mm² • Neuroendocrine carcinoma: Malignant epithelial tumor showing histologic features &/or evidence of neuroendocrine differentiation ○ Includes SCLC and LCNEC ○ AC and TC are not considered as such

ETIOLOGY/PATHOGENESIS Etiology • SCLC and LCNEC are associated with smoking history • SCLC can arise de novo or as part of resistance mechanism in patients with EGFR-mutant or fusion-positive lung adenocarcinomas treated with targeted therapy • Patients with hereditary retinoblastoma noted to show increased risks for lung cancer, including SCLC and LCNEC • AC and TC hypothesized to originate from Kulchitsky cells ○ Rare AC and TC cases associated with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

Molecular Characteristics • Mutations in tumor suppressor genes TP53 and RB1 are present in most SCLC and subset of LCNEC ○ Genomically, SCLC appears relatively homogeneous – Transcriptionally, SCLC harbors several subgroups with distinct expressions of transcription factors ○ Genomically, LCNEC is heterogeneous with multiple subgroups with distinct mutation patterns ○ Mutations in oncogenic PI3K and MYC signaling pathways are present in subsets of SCLC and LCNEC • Mutations in epigenetic regulators MEN1, ARID1A, and PSIP1 are present in subsets of AC and TC ○ Mutations in TP53 or RB1 are nearly absent in TC or AC

CLINICAL ISSUES Presentation • Cough, dyspnea, hemoptysis • Paraneoplastic syndromes ○ Syndrome of inappropriate antidiuretic hormone (SIADH) seen in some patients with SCLC ○ Cushing syndrome, carcinoid syndrome • Incidental during radiologic work-up for unrelated conditions ○ Less common for high-grade neuroendocrine carcinomas

Treatment • SCLC/LCNEC ○ Chemotherapy (typically including etoposide and platinum for SCLC and SCLC-like LCNEC) ○ Radiotherapy ○ Immunotherapy ○ Surgery considered for resectable/localized tumors • AC/TC ○ Surgery for resectable tumors ○ Nonsurgical therapy for unresectable tumors – Somatostatin analog – Peptide receptor radionuclide therapy – mTOR inhibitor – Chemotherapy – Radiotherapy

Prognosis • SCLC ○ Overall survival < 10% at 5 years for extensive SCLC ○ Overall survival ~ 35% at 5 years for limited SCLC • LCNEC ○ Overall survival 15-40% at 5 years • AC ○ Overall survival 50-80% at 5 years ○ Metastases in ~ 50% of cases • TC ○ Overall survival > 90% at 5 years ○ Metastases in < 10% of cases

Diagnoses Associated With Syndromes by Organ: Pulmonary

TERMINOLOGY

IMAGING Radiographic Findings • Bulky mediastinal disease often seen in SCLC patients ○ Rarely, SCLC present as solitary localized mass • Solitary mass or bulky disease in LCNEC patients • Solitary endobronchial mass in carcinoid patients

MACROSCOPIC General Features • Location: Endobronchial or intraparenchymal/peripheral • High-grade tumor may show extensive necrosis

MICROSCOPIC Histologic Features • SCLC ○ Sheets of small blue tumor cells at low power ○ Small cell cytomorphology – Scant cytoplasm, high nuclear:cytoplasmic ratio – Nucleoli generally inconspicuous ○ Frequent mitoses – Median ~ 70-80 mitoses per 2 mm² ○ Necrosis variable but often present ○ Desmoplastic stroma may be seen • LCNEC ○ Neuroendocrine architecture – Cells arranged in rosettes, trabeculae, nests, or sheets – Organoid-appearing ○ Non-small cell cytomorphology – Moderate eosinophilic-to-amphophilic cytoplasm 439

Diagnoses Associated With Syndromes by Organ: Pulmonary

Neuroendocrine Tumor, Lung – Low nuclear:cytoplasmic ratio – Palisading nuclei often seen – Nucleoli often prominent ○ Frequent mitoses – Median mitoses ~ 60-70 per 2 mm² ○ Necrosis variable, often present in comedo fashion ○ Diagnosis requires demonstration of neuroendocrine differentiation by immunohistochemical &/or ultrastructural studies in addition to histology • AC ○ Circumscribed border ○ Nuclei with salt and pepper chromatin ○ Nucleoli variable, often inconspicuous ○ Mitoses 2-10 per 2 mm² &/or necrosis ○ Pleomorphism in scattered cells (endocrine atypia) • TC ○ Circumscribed border ○ Similar to AC but with 0-1 mitosis per 2 mm² and necrosis is absent

AC and TC • Metastatic low- to intermediate-grade neuroendocrine tumors from extrapulmonary sites ○ TTF-1 expression can be used to favor lung primary • Metastatic medullary thyroid carcinoma ○ Positive for pax-8 and calcitonin • Melanoma ○ Positive for S100 protein, SOX10, other melanocytic markers • Carcinoid tumorlets ○ Size < 0.5 cm ○ Can be multicentric, e.g., in setting of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

SELECTED REFERENCES

ANCILLARY TESTS

1.

Immunohistochemistry

2.

• Markers to support neuroendocrine differentiation ○ Synaptophysin, chromogranin, INSM1, CD56 ○ TTF-1 expression is seen in some SCLC, LCNEC, and subsets of TC and AC – In SCLC and LCNEC, TTF-1 expression is not site specific and does not necessarily indicate lung primary – In TC and AC, TTF-1 expression supports lung primary ○ Keratin expression is sometimes dot-like in SCLC • Markers to exclude mimics ○ p40 (to exclude basaloid squamous cell carcinoma) ○ S100 protein, SOX10, HMB-45 (to exclude melanoma) • Ki-67 proliferation index ○ SCLC: Ki-67 usually > 50% (often 80-90%) ○ LCNEC: Ki-67 usually > 50% (often 50-60%) ○ AC: Ki-67 < 20% ○ TC: Ki-67 < 20% (typically < 5%) • Ki-67 proliferation index technically not required to classify neuroendocrine tumors of lung ○ Helpful in cases with suboptimal histology (e.g., crushed or limited specimens)

DIFFERENTIAL DIAGNOSIS SCLC and LCNEC • Basaloid squamous cell carcinoma ○ Positive for p40, p63, and keratin 5/6 ○ Negative for neuroendocrine markers and TTF-1 • Poorly differentiated adenocarcinoma ○ Cribriform adenocarcinoma can closely mimic LCNEC ○ Positive for TTF-1 and NAPSIN-A in some cases ○ Keratin expression is membranous rather than dot-like • Carcinoid tumors ○ Necrosis, if present, is often focal ○ Mitoses < 11 per 2 mm² ○ Ki-67 proliferation index < 20% • Metastatic neuroendocrine carcinoma from extrapulmonary sites 440

○ TTF-1 expressed in some extrapulmonary neuroendocrine carcinomas, thus not useful for distinction ○ Correlation with clinical history and radiology required

3.

4.

5.

6.

7.

8.

9.

10. 11. 12. 13.

14. 15. 16.

17.

18. 19.

Rudin CM et al: Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 19(5):289-97, 2019 George J et al: Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 9(1):1048, 2018 Park JW et al: Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science. 362(6410):91-5, 2018 Rekhtman N et al: Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations. Mod Pathol. 31(1):111-21, 2018 Lee JK et al: Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 35(26):306574, 2017 Mollaoglu G et al: MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Cancer Cell. 31(2):270-85, 2017 Thunnissen E et al: The use of immunohistochemistry improves the diagnosis of small cell lung cancer and its differential diagnosis. An international reproducibility study in a demanding set of cases. J Thorac Oncol. 12(2):334-46, 2017 Naidoo J et al: Large cell neuroendocrine carcinoma of the lung: clinicopathologic features, treatment, and outcomes. Clin Lung Cancer. 17(5):e121-9, 2016 Rekhtman N et al: Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res. 22(14):3618-29, 2016 George J et al: Comprehensive genomic profiles of small cell lung cancer. Nature. 524(7563):47-53, 2015 Niederst MJ et al: RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 6:6377, 2015 Peifer M et al: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 44(10):1104-10, 2012 Tsuta K et al: Oncocytic neuroendocrine tumors of the lung: histopathologic spectrum and immunohistochemical analysis of 15 cases. Hum Pathol. 42(4):578-85, 2011 Kaltsas G et al: Paraneoplastic syndromes secondary to neuroendocrine tumours. Endocr Relat Cancer. 17(3):R173-93, 2010 Rekhtman N: Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 134(11):1628-38, 2010 Yao JC et al: One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 26(18):3063-72, 2008 Pelosi G et al: Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol. 29(2):179-87, 2005 Kleinerman RA et al: Hereditary retinoblastoma and risk of lung cancer. J Natl Cancer Inst. 92(24):2037-9, 2000 Travis WD et al: Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 22(8):934-44, 1998

Neuroendocrine Tumor, Lung

TTF-1 Expression in Small-Cell Carcinoma (Left) Histologically, small-cell carcinoma shows sheets of tumor cells with scant cytoplasm, inconspicuous nucleoli, and nuclear crowding and molding. Mitoses ﬈ can be seen in noncrushed areas. (Right) TTF-1 expression is often seen in SCLC, though not required for the diagnosis. Since TTF-1 can be expressed in small-cell carcinomas from extrapulmonary sites (such as bladder, prostate, cervix), TTF1 expression is not useful for assessing tumor origin for high-grade neuroendocrine tumors.

Ki-67 Proliferation Index in Small-Cell Carcinoma

Diagnoses Associated With Syndromes by Organ: Pulmonary

Small-Cell Carcinoma

Large-Cell Neuroendocrine Carcinoma of Lung (Left) Ki-67 proliferation index is markedly elevated (> 50%) in high-grade neuroendocrine carcinomas of lung, including small-cell carcinoma (shown here) and large-cell neuroendocrine carcinoma (LCNEC). (Right) LCNEC is characterized by nests or trabeculae of tumor cells with peripherally palisaded nuclei ﬈ and abundant eosinophilic cytoplasm. Frequent mitoses ﬇ and comedonecrosis ﬉ are apparent.

Atypical Carcinoid With Necrosis

Ki-67 Proliferation Index in Carcinoid Tumors (Left) Histologically, atypical carcinoid (AC) demonstrates necrosis &/or 2-10 mitoses per 2 mm². The presence of necrosis st excludes the diagnosis of typical carcinoid (TC). (Right) Ki-67 proliferation index is < 20% in nearly all carcinoid tumors, such as this AC shown here. Though not being part of classification criteria, Ki-67 proliferation index can be helpful in cases with suboptimal histology, in which mitoses can be difficult to assess.

441

Diagnoses Associated With Syndromes by Organ: Pulmonary

Pleuropulmonary Blastoma KEY FACTS

• Primitive tumor of lung (and rarely pleura) presenting as cystic &/or solid sarcoma in infancy or early childhood • Associated with germline and somatic DICER1 mutations

○ Type 1 PPB: 5-year overall survival ~ 90% ○ Type 2 PPB: 5-year overall survival ~ 70% ○ Type 3 PPB: 5-year overall survival ~ 50% • Associated with other DICER1 syndrome-related tumors

CLASSIFICATION

MACROSCOPIC

• Based on histomorphology of pleuropulmonary blastoma (PPB) ○ Type 1 PPB: Purely cystic ○ Type 2 PPB: Cystic and solid ○ Type 3 PPB: Purely solid

• Type 1: Peripheral- and pleural-based cysts, sometimes protruding from pleural surface, no solid nodules • Type 2: Both solid and cystic areas in varying proportions • Type 3: All solid, necrosis and cystic degeneration often present

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• 20% are familial and associated with extrapulmonary lesions in same patient or family members • Heterozygous germline mutations in DICER1 have been identified in familial PPB

• Type 1: Large cysts lined by single layer of cuboidal to flattened benign epithelium; within wall, there are areas of hypercellularity composed of small blue to spindled cells, often forming cambium-like layer • Types 2-3: Partial to all solid areas composed of high-grade sarcomatous components: Undifferentiated, rhabdomyosarcomatous, or chondrosarcomatous

TERMINOLOGY

CLINICAL ISSUES • Prognosis depends on histologic type

Pleuropulmonary Blastoma

Histology of Pleuropulmonary Blastoma

Pleuropulmonary Blastoma With Chondrosarcomatous Component

Pleuropulmonary Blastoma With Rhabdomyosarcomatous Differentiation

(Left) Coronal CT of a pleuropulmonary blastoma (PPB) shows a large, expansile, solid-to-cystic mass in the left lower lobe of lung with discernible internal septation ﬊. (Right) PPB is histologically characterized by a cellular mesenchymal proliferation of ovoid-tospindle cells ﬉, along with a banal-appearing epithelial component ﬈.

(Left) The high-grade component in PPB can show various sarcomatous differentiation, including chondrosarcomatous differentiation ﬊. (Right) Rhabdomyosarcomatous differentiation, as indicated by tumor cells with abundant eosinophilic cytoplasm and diffuse expression of desmin and myogenic markers (not shown), can be seen in a subset of PPB.

442

Pleuropulmonary Blastoma

Abbreviations • Pleuropulmonary blastoma (PPB)

Synonyms • Pulmonary blastoma of childhood, pulmonary blastoma associated with cystic lung disease

Definitions • Primitive tumor of lung (and rarely pleura) presenting as cystic &/or solid sarcoma in infancy or early childhood

ETIOLOGY/PATHOGENESIS Genetic Abnormality • 20% of cases familial, associated with extrapulmonary lesions in same patient or family members • Germline DICER1 mutations identified in familial PPB ○ DICER1: Component in physiologic micro-RNA processing • Biallelic somatic DICER1 mutations in sporadic PPB • Karyotypic abnormalities including trisomy 8 described

CLINICAL ISSUES Epidemiology • Incidence ○ Most common primary lung malignancy in childhood ○ Extremely rare, incidence ~ 1 per 250,000 live births • Age ○ Occurs in children, primarily infants and toddlers – ~ 95% of cases occur in children < 6 years of age

Presentation • Depends on histologic type of PPB ○ PPB type 1: Median age at diagnosis ~ 8 months ○ PPB type 2: Median age at diagnosis ~ 35 months ○ PPB type 3: Median age at diagnosis ~ 41 months • Most commonly respiratory distress, pneumothorax • May be detected incidentally in utero or postnatally • Solitary or multiple synchronous or metachronous lesions

Treatment • Depends on histologic type of PPB ○ PPB type 1: Surgical resection; adjuvant chemotherapy if incomplete resection ○ PPB types 2 and 3: Surgical resection followed by adjuvant chemotherapy &/or radiation therapy • Monitor for recurrence, metastasis, extrapulmonary lesions

Prognosis

• Nasal chondromesenchymal hamartoma • Endocrine: Multinodular hyperplasia of thyroid, SertoliLeydig cell tumor, juvenile granulosa cell tumor

IMAGING General Features • Unilocular or multilocular cyst, mixed cystic-solid lesion, or large solid mass in lung or protruding from pleura

MACROSCOPIC Gross Features • Type 1 PPB: Purely cystic ○ Peripheral- and pleural-based cysts, sometimes protruding from pleural surface, no solid nodules • Type 2 PPB: Mixed cystic and solid ○ Solid and cystic areas are in varying proportions • Type 3 PPB: Purely solid ○ Necrosis and cystic degeneration may be present

MICROSCOPIC Histologic Features • Type 1 PPB: Purely cystic ○ Large cysts lined by single layer of cuboidal to flattened banal-appearing epithelium ○ Cyst wall composed of focally hypercellular areas with small blue to spindled cells ○ Cambium layer: Subepithelial condensation and clustering of tumor cells • Type 2 PPB: Mixed cystic and solid • Type 3 PPB: Purely solid ○ Composed of high-grade primitive sarcomatous component, which can be undifferentiated, rhabdomyosarcomatous, chondrosarcomatous, etc.

ANCILLARY TESTS In Situ Hybridization • Chromosome 8 polysomy in mesenchymal component

Genetic Testing • DICER1 mutation testing

SELECTED REFERENCES 1.

2. 3.

• Depends on histologic type of PPB ○ Type 1 PPB: 5-year overall survival ~ 90% ○ Type 2 PPB: 5-year overall survival ~ 70% ○ Type 3 PPB: 5-year overall survival ~ 50% • Type 1 PPB may subsequently recur as type 2 or 3 PPB • Metastases occur in 30% of types 2 and 3 PPB ○ Commonly to central nervous system and bone

4.

Other Associated Lesions

8.

• Cystic nephroma • Embryonal rhabdomyosarcoma of cervix or ovary

Diagnoses Associated With Syndromes by Organ: Pulmonary

TERMINOLOGY

5. 6. 7.

Messinger YH et al: Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry. Cancer. 121(2):276-85, 2015 Foulkes WD et al: DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer. 14(10):662-72, 2014 Seki M et al: Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma. Cancer Res. 74(10):2742-9, 2014 Stewart DR et al: Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder. Hum Genet. 133(11):1443-50, 2014 Rio Frio T et al: DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 305(1):68-77, 2011 Hill DA et al: DICER1 mutations in familial pleuropulmonary blastoma. Science. 325(5943):965, 2009 Hill DA et al: Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. Am J Surg Pathol. 32(2):282-95, 2008 Vargas SO et al: Gains of chromosome 8 are confined to mesenchymal components in pleuropulmonary blastoma. Pediatr Dev Pathol. 4(5):434-45, 2001

443

Diagnoses Associated With Syndromes by Organ: Pulmonary

Lung Table Familial Cancer Syndromes With Lung Neoplasms Familial Cancer Syndromes

Lung Neoplasms*

Genes Involved

Tuberous sclerosis

Lymphangioleiomyomatosis (LAM)

TSC2 > TSC1

Familial pleuropulmonary blastoma/DICER1 syndrome

Pleuropulmonary blastoma (PPB)

DICER1

Bloom syndrome

Squamous cell carcinoma and adenocarcinoma

BLM

Xeroderma pigmentosum

Squamous cell carcinoma and adenocarcinoma

XPA, ERCC3/XPB, XPC, ERCC2/XPD, DDB2/XPE, ERCC4/XPF, ERCC5/XPG

Peutz-Jeghers syndrome

Adenocarcinoma 

STK11/LKB1

Li-Fraumeni syndrome

Adenocarcinoma

TP53

Hereditary breast ovarian cancer syndrome 

Adenocarcinoma

BRCA1, BRCA2

Hereditary retinoblastoma syndrome

Early onset of small-cell carcinoma; some nonsmall-cell carcinoma

Rb

Multiple endocrine neoplasia type 1 (MEN1)

Carcinoid tumor

MEN1

*Most commonly seen histologic types are listed.

EGFR T790M Germline Mutations and Lung Adenocarcinoma* Case

Family

Ethnicity

Age

Sex

Smoking Status

Histology

2nd EGFR Mutation

Comment

1

1

White

50

M

S

ADC

L858R in 2/5 and exon 19 deletion in 1/5

5 tumors

2

1

White

55

M

N/A

ADC

G719A

Widespread metastases

3

1

White

62

F

N/A

ADC

N/A

T790M germline mutation assumed

4

1

White

72

M

N/A

ADC

N/A

T790M germline mutation assumed

5

2

East Indian

66

F

NS

ADC

L858R

Multiple bilateral nodules

6

2

East Indian

41

F

NS

N/A

N/A

T790M germline mutation assumed

7

3

White

56

M

NS

ADC

L858R

Widespread metastases

8

3

White

72/80

M/F

S

N/A

N/A

T790M germline mutation assumed; either father or mother of case 7

9

4

N/A

72

F

NS

2 ADCs and None in 3 tumors 1 LCNEC

3 tumors

10

4

N/A

N/A

F

N/A

ADC

N/A

T790M germline mutation assumed

11

5

N/A

N/A

F

NS

ADC

L858R

12

6

N/A

N/A

N/A

N/A

ADC

Exon 19 deletion

13

7

N/A

N/A

F

NS

ADC

L858R in 4/6 and exon 19 deletion in 2/6

6 tumors 

14

8

White

72

F

NS

ADC

Exon 19 deletion

Bilateral pulmonary lesions

15

8

White

74

F

NS

NSCLC

None

16

9

White

29

F

S

ADC

L858R

17

9

White

67

F

NS

N/A

N/A

T790M germline mutation assumed

18

9

White

56

M

NS

N/A

N/A

T790M germline mutation assumed

19

9

White

81

F

NS

N/A

N/A

Obligate carrier for T790M germline mutation

*Lung cancer patients with EGFR T790M mutations and family members with lung cancer (mutation status known and assumed). ADC = adenocarcinoma of lung; F = female; LCNEC = large-cell neuroendocrine carcinoma; M = male; N/A = not available; NS = never smoker; NSCLC = non-small-cell lung cancer; S = smoker.  Adapted and modified from Gazdar A et al: Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. J Thorac Oncol. 9(4):456-63, 2014.

444

Lung Table

Clinicopathologic Features

Tuberous SclerosisLymphangioleiomyomatosis

Sporadic Lymphangioleiomyomatosis

Sex

Both male and female

Almost always female

Incidence

26-50% of women with TSC; 10-38% of men with TSC

8 per 1 million women

Age 

Late adolescence to adulthood

Mid 30s to mid 40s (ranging from adolescence to elderly) 

Cysts depicted by imaging studies

May be larger and more numerous in women than in men

May be more numerous than milder disease of TSC-LAM

Renal angiomyolipoma 

Seen in > 80%, often bilateral

Seen in 30%

Multifocal micronodular pneumocyte hyperplasia (MMPH)

Common

Very rare

Other features

Cognitive disability, seizure, and polycystic kidney may be seen

No difference in histologic features of LAM between sporadic and TSC-associated cases. LAM = lymphangioleiomyomatosis; TSC = tuberous sclerosis.

Diagnoses Associated With Syndromes by Organ: Pulmonary

Comparison of Tuberous Sclerosis-Associated and Sporadic Lymphangioleiomyomatosis 

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PART I SECTION 11

Skin BAP1-Inactivated Melanocytic Tumor Basal Cell Carcinoma Cutaneous Melanoma Cutaneous Squamous Cell Carcinoma Sebaceous Carcinoma Skin Table

448 450 456 460 466 472

Diagnoses Associated With Syndromes by Organ: Skin

BAP1-Inactivated Melanocytic Tumor KEY FACTS

TERMINOLOGY • BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome: Tumor suppressor gene located on short arm of chromosome 3

CLASSIFICATION • Appear earlier than other BAP1-associated tumors • Cases with either spitzoid morphology or smaller epithelioid cells • Rhabdoid features can frequently be seen • Loss of BAP1 nuclear expression • Often BRAF V600E mutated • Junctional component with BAP1 nuclear loss is statistically associated with germline mutation • Due to lack of long-term follow-up, malignant potential of BIMT is currently unknown

ETIOLOGY/PATHOGENESIS

○ BAP1-inactivated melanocytic tumors (BIMT) • Autosomal dominant • In patients with BAP1 germline mutation, at least 75% develop at least 1 of following 5 ○ Uveal melanoma (31%), malignant mesothelioma (22%), BAP1-BIMT (18%), cutaneous melanoma (13%), and renal cell carcinoma (10%)

MICROSCOPIC • 2 histopathologic patterns ○ Nodular growth pattern  – Spitzoid tumor cells ○ Nevus with features of congenital-onset pattern – Melanocytes with mildly enlarged nuclei with hyperchromatic nuclei

ANCILLARY TESTS • BAP1 immunohistochemistry

• BAP1 tumor predisposition syndrome

BAP1-Inactivated Melanocytic Tumor

BAP1-Inactivated Melanocytic Tumor

BAP1-Inactivated Melanocytic Tumor

BAP1 Immunostain

(Left) Beneath a dermal nevus is a nodular proliferation of epithelioid melanocytes resembling a proliferative nodule. (Right) While the background nevus cells have scant cytoplasm and appear hyperchromatic, the melanocytes within the nodule possess an epithelioid appearance.

(Left) At high magnification, cytologic atypia and foci of lymphohistiocytic infiltrate are seen. (Right) The lesional cells exhibit loss of BAP1 nuclear staining, while the background nevus cells exhibit nuclear staining.

448

BAP1-Inactivated Melanocytic Tumor

Synonyms • BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome • OMIM #614327

BAP1 Gene • Tumor suppressor gene located on short arm of chromosome 3 (locus 3p21.1) • Encodes nuclear-localized protein that is deubiquitinating enzyme • Important for cell cycle regulation, transcription, DNA damage repair, and chromatin dynamics

CLINICAL ISSUES Presentation • Germline-inactivating mutations in BAP1 causing autosomal dominant tumor predisposition syndrome ○ Uveal melanoma ○ Meningioma ○ Lung adenocarcinoma ○ Mesothelioma ○ Renal cell carcinoma ○ Cutaneous melanoma ○ BAP1-inactivated melanocytic tumors (BIMTs) ○ Basal cell carcinoma ○ Squamous cell carcinoma • BIMTs have highest penetrance and earliest age of presentation among tumors associated with BAP1-tumor predisposition syndrome • Median age of onset of BIMTs in patients with germline BAP1 mutations is 32 years • Patients often begin to have BIMT lesions during 2nd decade and develop more lesions as patients get older • Recognition of BIMTs can result in earlier identification of individuals with BAP1-tumor predisposition syndrome • These lesions can represent sporadic tumors not associated with germline mutations in BAP1 gene

Prognosis • Due to lack of long-term follow-up, malignant potential of BIMT is currently unknown

Indication for Germline Testing • Family history of cutaneous melanoma and uveal melanoma • Personal history of cutaneous melanoma • Histology with extensive junctional involvement in BIMT

MACROSCOPIC Clinical Appearance • • • •

Pink or flesh-colored, dome-shaped papules Circumscribed, raised erythematous papule Average size of 5 mm Variable in number

• Pink-to-tan, structureless areas • Network with raised, structureless, pink-to-tan areas • Globular patterns

MICROSCOPIC Histologic Features • 2 histopathologic patterns • Nodular growth pattern ○ Spitzoid neoplastic cells: Abundant eosinophilic cytoplasm and large nuclei and low nuclear:cytoplasmic ratio ○ Distinct cell membranes and glassy cytoplasm ○ Loss of BAP1 nuclear expression • Nevus with features of congenital-onset pattern ○ Small aggregates of tumor cells that exhibit loss of BAP1 nuclear expression ○ Melanocytes with mildly enlarged nuclei with hyperchromatic nuclei • Other histologic appearance ○ Nuclear pseudoinclusion ○ Multinucleated melanocytes ○ Adipocytic metaplasia ○ Rhabdoid features • Often BRAF V600E mutated • Junctional component with BAP1 nuclear loss is statistically associated with germline mutation

Diagnoses Associated With Syndromes by Organ: Skin

TERMINOLOGY

BAP1 Immunohistochemistry • Strong nuclear staining seen in cells with 2 wild-type copies of BAP1 gene • Loss of nuclear staining, maybe with cytoplasmic staining seen in cells with biallelic inactivation of BAP1

SELECTED REFERENCES 1.

Aung PP et al: Melanoma with loss of BAP1 expression in patients with no family history of BAP1-associated cancer susceptibility syndrome: a case series. Am J Dermatopathol. 41(3):167-79, 2019 2. Garfield EM et al: Histomorphologic spectrum of germline-related and sporadic BAP-1 inactivated melanocytic tumors. J Am Acad Dermatol. 79(3):525-34, 2018 3. Yélamos O et al: Clinical and dermoscopic features of cutaneous BAP1inactivated melanocytic tumors: results of a multicenter case-control study by the International Dermoscopy Society. J Am Acad Dermatol. 80(6):158593, 2018 4. Haugh AM et al: Genotypic and phenotypic features of BAP1 cancer syndrome: a report of 8 new families and review of cases in the literature. JAMA Dermatol. 153(10):999-1006, 2017 5. O'Shea SJ et al: Histopathology of melanocytic lesions in a family with an inherited BAP1 mutation. J Cutan Pathol. 43(3):287-9, 2016 6. Rai K et al: Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 89(3):285-94, 2016 7. Marušić Z et al: Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome. J Cutan Pathol. 42(6):406-12, 2015 8. Mochel MC et al: Loss of BAP1 expression in basal cell carcinomas in patients with germline BAP1 mutations. Am J Clin Pathol. 143(6):901-4, 2015 9. Piris A et al: BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations. Hum Pathol. 46(2):239-45, 2015 10. Busam KJ et al: Combined BRAF(V600E)-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. Am J Surg Pathol. 37(2):193-9, 2013

Dermoscopy • Pink-to-tan, structureless areas with peripheral and eccentric globules • Pink, structureless areas with radial linear vessels 449

Diagnoses Associated With Syndromes by Organ: Skin

Basal Cell Carcinoma KEY FACTS

TERMINOLOGY • Low-grade malignancy of basal keratinocytes

ETIOLOGY/PATHOGENESIS • Chronic sun or UV light exposure • In some instances, associated with radiation, immunosuppression (e.g., organ transplantation), and burn scars • Common in individuals with predisposing hereditary syndrome ○ Basal cell nevus syndrome ○ Bazex-Dupre-Christol syndrome ○ Hereditary infundibulocystic basal cell carcinoma ○ Xeroderma pigmentosum ○ Rombo syndrome

CLINICAL ISSUES • Most common cutaneous malignancy • Curative by local excision with excellent prognosis

• Indolent tumor with low recurrence rate • More aggressive histologic subtypes: Infiltrative, morpheaform, and metatypical/basosquamous • Genetic syndrome should be considered in patients developing multiple basal cell carcinomas and < 20 years

MICROSCOPIC • Proliferation of nests of basaloid cells exhibiting peripheral palisade, stromal retraction artifact, and myxoid stroma • Hyperchromatic tumor cell with scant cytoplasm

TOP DIFFERENTIAL DIAGNOSES • • • • • •

Actinic keratosis Squamous cell carcinoma Trichoepithelioma and trichoblastoma Microcystic adnexal carcinoma Merkel cell carcinoma Sebaceous carcinoma

Ulcerated Basal Cell Carcinoma

Nodular Basal Cell Carcinoma

Morpheaform Basal Cell Carcinoma

Infiltrative Basal Cell Carcinoma

(Left) Clinical photograph shows a large basal cell carcinoma (BCC) on the cheek exhibiting irregular areas of ulceration with surrounding raised border ſt. (Courtesy S. Yashar, MD.) (Right) Nodular BCC is the most common histologic subtype.

(Left) Morpheaform (desmoplastic/sclerosing) BCC exhibits cords of atypical basaloid cells within a dense and sclerotic stroma. (Right) In this aggressive variant of BCC, strands and cords of basaloid tumor cells are seen infiltrating a fibrotic or desmoplastic dermis.

450

Basal Cell Carcinoma

Abbreviations • Basal cell carcinoma (BCC)

ETIOLOGY/PATHOGENESIS Multifactorial • Chronic sun or UV light exposure • In some instances, associated with radiation, immunosuppression (e.g., organ transplantation), and burn scars

Genetics • Constitutive activation of Hedgehog signaling pathway ○ PTCH1, TP53, and SMO are key drivers • Increased risk of developing BCC ○ Skin phenotype: Fair skin, red or blond hair, blue or green eyes, inability to tan, propensity to freckle ○ Predisposing hereditary syndrome – Basal cell nevus syndrome – Bazex-Dupre-Christol syndrome – Hereditary infundibulocystic BCC – Rombo syndrome – Xeroderma pigmentosum ○ Autoimmune conditions: Rheumatoid arthritis ○ Immunosuppression in organ transplant recipients ○ Psoralen plus ultraviolet A phototherapy

CLINICAL ISSUES Epidemiology • Incidence ○ Increased incidence in individuals > 40 years ○ Most common cutaneous malignancy ○ Lifetime risk of developing BCC in United States ~ 2030% for Caucasians • Age ○ Most common in individuals in 6th-8th decades ○ Genetic syndrome should be considered in patients developing multiple BCCs and < 20 years • Ethnicity ○ Light-skinned individuals; rare in darker skin types

Site • Most commonly affected sun-exposed sites but may occur on any skin regions • Head and neck: Most common • Rarely involving lips, breast, inguinal and genital areas • Palms or soles involvement: Genetic syndrome should be considered

Presentation • • • •

Enlarging and nonhealing lesion Size can vary from few millimeters to > 10 centimeters Can present with multiple lesions Pigmented in dark skin individuals

Treatment • Standard excision • Mohs micrographic surgery • Topical imiquimod

• Electrodesiccation/curettage • Vismodegib (SMO inhibitor)

Prognosis • Curative by local excision with excellent prognosis • Indolent tumor with low recurrence rate • Histopathologic subtypes, such as infiltrative and metatypical, which have higher recurrence rate and increased metastatic rate • Although rarely cause death, BCC can cause extensive morbidity via local tissue destruction • Metastasis extremely rare ○ Regional lymph nodes and lungs are most commonly affected sites ○ Patients with BCC with distant metastasis are younger at diagnosis than those with regional metastasis

MICROSCOPIC Histologic Features

Diagnoses Associated With Syndromes by Organ: Skin

TERMINOLOGY

• Perineural invasion is indicative of aggressive biologic behavior; increased rate of local recurrence and metastasis • Many tumors exhibit > 1 histologic pattern

Histopathologic Variants • Superficial ○ 2nd most common subtype ○ Account for 10-30% of cases ○ Nests of basaloid keratinocytes arising from basal layer of epidermis • Nodular ○ Most common subtype ○ Account for 50-80% of cases ○ Predilection for head and neck region ○ Present as smooth and pearly nodule with rolled borders and associated telangiectasia ○ Nodules of basaloid keratinocytes exhibiting peripheral palisade and stromal clefting artifact within myxoid stroma • Infiltrative, sclerosing or morpheaform ○ < 10% of cases ○ Aggressive biologic behavior ○ Higher local recurrence rate ○ Indurated or depressed white patch or plaque ○ Strands and cords of basaloid neoplastic cells within desmoplastic stroma ○ Histopathologic extent of tumor often extends beyond clinical appearance, making surgical treatment challenging • Infundibulocystic ○ Nodule on head and neck ○ Strands of basaloid cells with associated infundibulumlike cystic structures ○ When multiple, infundibulocystic basal cell carcinoma syndrome should be suspected • Basosquamous or metatypical ○ Mostly on head and neck ○ Tumor exhibiting features of both basal cell carcinoma and squamous cell carcinoma ○ Prominent keratin formation • Fibroepithelioma of Pinkus ○ Uncommon subtype 451

Diagnoses Associated With Syndromes by Organ: Skin

Basal Cell Carcinoma ○ Indolent behavior ○ Trunk is most commonly affected site ○ Clinically can be mistaken as acrochordon or nonpigmented seborrheic keratosis ○ Reticulate pattern of basaloid keratinocytes within fibrotic stroma • Rare subtypes ○ Adenoid BCC often mistaken as adenoid cystic carcinoma ○ Adamantinoid BCC resembles ameloblastoma or adamantinoma ○ BCC with sebaceous differentiation ○ BCC with matrical differentiation ○ BCC with glandular or ductal differentiation ○ Clear cell BCC ○ Signet ring cell BCC ○ Sarcomatoid BCC

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Aggressive behavior associated with certain subtypes, deep dermal/subcutaneous invasion, and perineural invasion

SELECTED REFERENCES 1.

2. 3. 4. 5. 6.

ANCILLARY TESTS

7.

Immunohistochemistry • BCC vs. trichoepithelioma and trichoblastoma ○ BCC lacks CK20(+) Merkel cells ○ BCC often stains for androgen receptor, while trichoepithelioma and trichoblastoma are generally negative • BCC vs. SCC ○ BCC is positive for BER-EP4, while SCC is generally negative ○ CK-PAN, HMWCKs, and p63 are positive in both tumor types

8. 9. 10. 11.

12. 13. 14.

DIFFERENTIAL DIAGNOSIS Actinic Keratosis • Can be difficult to distinguish from superficial type of BCC on very superficial shave biopsies ○ Superficial BCC is typically positive for BerEP4, while actinic keratosis is positive for EMA

Squamous Cell Carcinoma • Typically negative for BerEP4

Trichoepithelioma and Trichoblastoma • CK20 highlights intratumoral Merkel cells • Papillary mesenchymal bodies may be evident

Microcystic Adnexal Carcinoma • In differential diagnosis of infiltrative BCC • Majority of tumors would express keratin 15 and keratin 19

Merkel Cell Carcinoma • Perinuclear dot-like staining with CK20, pancytokeratin, and CAM5.2 • Expresses neuroendocrine markers such as chromogranin, synaptophysin, and CD56

Sebaceous Carcinoma • Adipophilin is positive in sebaceous carcinoma and negative in clear cell BCC • Positive for keratin CAM5.2 and 7, which are typically negative in BCC

452

15. 16. 17. 18.

19.

Cameron MC et al: Basal cell carcinoma: Epidemiology; pathophysiology; clinical and histological subtypes; and disease associations. J Am Acad Dermatol. 80(2):303-17, 2019 Work Group. et al: Guidelines of care for the management of basal cell carcinoma. J Am Acad Dermatol. 78(3):540-59, 2018 Pellegrini C et al: Understanding the molecular genetics of basal cell carcinoma. Int J Mol Sci. 18(11), 2017 McCusker M et al: Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 50(4):774-83, 2014 Ferrucci LM et al: Host phenotype characteristics and MC1R in relation to early-onset basal cell carcinoma. J Invest Dermatol. 132(4):1272-9, 2012 Ferrucci LM et al: Indoor tanning and risk of early-onset basal cell carcinoma. J Am Acad Dermatol. 67(4):552-62, 2012 Ostler DA et al: Adipophilin expression in sebaceous tumors and other cutaneous lesions with clear cell histology: an immunohistochemical study of 117 cases. Mod Pathol. 23(4):567-73, 2010 Garcia C et al: Basosquamous carcinoma. J Am Acad Dermatol. 60(1):137-43, 2009 Krokowski M et al: Basal cell carcinoma with neuroendocrine differentiation arising in a scar: a case report. Dermatol Online J. 15(10):4, 2009 Cohen PR et al: Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer. Dermatol Surg. 32(4):542-51, 2006 Farley RL et al: Aggressive basal cell carcinoma with invasion of the parotid gland, facial nerve, and temporal bone. Dermatol Surg. 32(2):307-15; discussion 315, 2006 Tschen JP et al: Pleomorphic basal cell carcinoma: case reports and review. South Med J. 99(3):296-302, 2006 Wadhera A et al: Metastatic basal cell carcinoma: a case report and literature review. How accurate is our incidence data? Dermatol Online J. 12(5):7, 2006 Ackerman AB et al: Fibroepithelial tumor of pinkus is trichoblastic (Basal-cell) carcinoma. Am J Dermatopathol. 27(2):155-9, 2005 Ting PT et al: Metastatic basal cell carcinoma: report of two cases and literature review. J Cutan Med Surg. 9(1):10-5, 2005 Bogdanov-Berezovsky A et al: Risk factors for incomplete excision of basal cell carcinomas. Acta Derm Venereol. 84(1):44-7, 2004 Kim YC et al: Signet ring cell basal cell carcinoma: a basal cell carcinoma with myoepithelial differentiation. Am J Dermatopathol. 23(6):525-9, 2001 Meehan SA et al: Basal cell carcinoma with tumor epithelial and stromal giant cells: a variant of pleomorphic basal cell carcinoma. Am J Dermatopathol. 21(5):473-8, 1999 von Domarus H et al: Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol. 10(6):104360, 1984

Basal Cell Carcinoma

Micronodular Basal Cell Carcinoma (Left) Low magnification shows a large nodular- and micronodular-type BCC with overlying epidermal ulceration and marked inflammatory crust. (Right) Histologic section of a micronodular-type BCC shows a proliferation of small nests of basaloid cells with a prominent retraction artifact ﬊ in a sclerotic stroma.

Basosquamous Basal Cell Carcinoma

Diagnoses Associated With Syndromes by Organ: Skin

Nodular and Micronodular Basal Cell Carcinoma

Basosquamous Basal Cell Carcinoma (Left) Basosquamous-type BCC shows a proliferation of large, squamoid-appearing cells with abundant eosinophilic cytoplasm and focal mucin collections ﬊. (Right) Basosquamous-type BCC shows traditional areas of BCC with peripheral palisading ﬊ surrounding collections of larger, squamoid-appearing cells associated with follicular differentiation and focal keratinization ﬈.

Fibroepithelioma of Pinkus

Clear Cell Basal Cell Carcinoma (Left) Scanning magnification shows a fibroepithelioma of Pinkus-type BCC characterized by numerous small, anastomosing cords of basaloid cells with multiple epidermal connections ﬊. (Right) Clear cell BCC is composed of large cells with abundant clear cytoplasm ﬊ and can mimic clear cell squamous cell carcinoma or sebaceous carcinoma in some cases. However, areas of more conventional-appearing BCC ﬉ are often present, as are seen in the lower aspect of the figure.

453

Diagnoses Associated With Syndromes by Organ: Skin

Basal Cell Carcinoma

Adenoid Basal Cell Carcinoma

Pigmented Basal Cell Carcinoma

Metatypical Basal Cell Carcinoma

Metatypical Basal Cell Carcinoma

Infundibulocystic Basal Cell Carcinoma

Pleomorphic Basal Cell Carcinoma

(Left) Low-power view shows a BCC with adenoid cystic-like features (adenoid BCC) characterized by numerous well-formed cystic spaces containing mucinous material. (Right) Low-power view of a large pigmented nodular BCC shows prominent pigmentation ﬈ throughout the nodule.

(Left) Although keratin pearl formation is seen, nests of basaloid tumor cells exhibiting peripheral palisading and mucin deposition are present, characteristic features of BCC. (Right) Prominent follicular differentiation is seen in this example of metatypical BCC.

(Left) Beneath an unremarkable epidermis are strands of basaloid tumor cells and associated infundibulumlike cystic structures. (Right) High magnification of a nodular BCC shows a rare, markedly enlarged, pleomorphic tumor cell with a macronucleolus ﬊.

454

Basal Cell Carcinoma

BerEP4 Immunostain (Left) Large nodule of basaloid keratinocytes in the dermis exhibits peripheral palisading and retraction artifact. (Right) The majority of BCC is invariably positive for BerEP4, which is typically negative in squamous cell carcinoma.

Trichoblastoma

Diagnoses Associated With Syndromes by Organ: Skin

Basal Cell Carcinoma, Nodular Type

Keratin 20 in Trichoblastoma (Left) Although comprised of basaloid tumor cells exhibiting peripheral palisading, there is no clefting artifact, and tumoral stroma is fibrotic and lacks myxoid appearance. (Right) The presence of keratin 20 (+) Merkel cells helps distinguish trichoblastoma from nodular BCC.

Merkel Cell Carcinoma

Keratin 20 in Merkel Cell Carcinoma (Left) Tumor cells with scant cytoplasm, nuclear molding, and dispersed chromatin pattern are seen in this example of Merkel cell carcinoma. (Right) Perinuclear positivity for keratin 20 is a characteristic feature of Merkel cell carcinoma.

455

Diagnoses Associated With Syndromes by Organ: Skin

Cutaneous Melanoma KEY FACTS

ETIOLOGY/PATHOGENESIS

MICROSCOPIC

• Majority of melanomas are sporadic • Inherited predisposition to melanoma seen in minority of cases; may be associated with ○ Multiple clinically atypical melanocytic nevi (often > 50) ○ Pancreatic cancer ○ Germline mutations in CDKN2A and other genes, MC1R, BAP1 ○ Other syndromes, such as xeroderma pigmentosum, LiFraumeni, Lynch

• Microscopic features are not different in hereditary vs. sporadic melanomas • Common subtypes include superficial spreading, nodular, acral lentiginous and lentigo maligna melanomas • Uncommon subtypes include desmoplastic melanoma and nevoid melanoma • Rare subtypes include animal-type melanoma, myxoid melanoma, and rhabdoid melanoma

CLINICAL ISSUES

• • • • •

• Broad pigmented lesion, variegated colors, irregular borders • Sites vary: Often back in men, legs in women • Prognosis mainly dependent on depth of invasion and presence of ulceration in nonmetastatic lesions

TOP DIFFERENTIAL DIAGNOSES Severely atypical (dysplastic) melanocytic nevus Spitz (spindle or epithelioid) cell nevus Genital nevus Recurrent nevus Nonmelanocytic lesions

Melanoma

Melanoma In Situ

Nodular Melanoma

Epithelioid Cells in Nodular Melanoma

(Left) Clinical photograph shows a large melanoma with variegated color, jagged border, and irregular surface, all of which are concerning clinical signs. (Courtesy J. Hall, MD.) (Right) Multifocal pagetoid scatter of atypical, epithelioid-shaped melanocytes is seen throughout all layers of the epidermis ſt in this melanoma in situ.

(Left) An expansile proliferation of atypical melanocytes fills and expands the papillary dermis, extending to the reticular dermis. (Right) The tumor cells are enlarged and epithelioid with abundant amphophilic cytoplasm and prominent nucleoli.

456

Cutaneous Melanoma Site

Definitions

• Back is common in men, legs common in women • Melanoma subtypes correlate with levels of sun exposure ○ Head and neck region: Lentigo maligna ○ Non-sun-exposed sites: Acral melanomas

• Malignant tumor of melanocytes

Presentation

Synonyms • Malignant melanoma

ETIOLOGY/PATHOGENESIS Pathogenesis • Melanocytes are responsible for production of eumelanin and pheomelanin, which play important role in protection against DNA damage • Environmental ○ Ultraviolet (UV) light radiation is main environmental risk factor ○ UV light-induced BRAF and NRAS mutation in > 85% ○ Intense and intermittent sun exposure has higher risk than chronic continuous pattern ○ History of sunburn in childhood or adolescence ○ > 5 episodes of severe sunburn • Genetics ○ Polymorphisms of melanocortin 1 receptor (MC1R) gene: Individuals with light skin, green or blue eyes ○ Germline CDKN2A mutation in familial melanoma syndrome ○ Melanoma-astrocytoma syndrome ○ Xeroderma pigmentosum: Accumulation of UV lightinduced mutations at young age ○ Lynch syndrome type II ○ Li-Fraumeni cancer syndrome • Genes ○ B-Raf protooncogene (BRAF), neurofibromin 1 (NF1), and NRAS mutations are main genetic drivers ○ RAS/RAF/MEK/ERK signaling cascade (mitogen-activated protein kinase or MAPK pathway) ○ Phosphoinositol-3-kinase (PI3K)/AKT pathway

CLINICAL ISSUES Epidemiology • Age ○ Generally adults – Hereditary melanoma presents at mean age of 34 years • Sex ○ Younger women and older men affected more frequently • Ethnicity ○ Typically affects ethnicities with fairer skin (especially red hair and skin types I/II) • Geographic distribution ○ Incidence varies according to racial skin phenotype and degree of sun exposure ○ Australia has highest incidence • Incidence ○ 232,000 new melanoma cases and 55,000 deaths registered worldwide in 2012 ○ 15th most common malignancy worldwide

• Clinical appearance ○ Often > 6 mm in diameter ○ Variation in color ○ White areas signified zones of regression • Suspect hereditary melanoma in following settings ○ Multiple primary melanomas ○ Multiple atypical nevi, often > 50 ○ > 2 or 3 first-degree relatives with cutaneous melanoma ○ History of melanoma and pancreatic cancer

Treatment • Surgical approaches ○ Complete excision with margins dependent on depth of invasion

Diagnoses Associated With Syndromes by Organ: Skin

TERMINOLOGY

Prognosis • Dependent on variables such as depth of invasion, ulceration

MICROSCOPIC Histologic Features • Melanoma subtypes ○ Melanoma in situ – Limited to epidermis ○ Lentigo maligna melanoma – Predominantly single-cell melanocytic proliferation in epidermis with dermal invasion ○ Superficial spreading melanoma – In situ component extends 3 rete ridges beyond invasive component ○ Nodular melanoma – In situ component does not extend 3 rete ridges beyond invasive component ○ Acral lentiginous melanoma – Melanoma occurring on hands or feet with single melanocytes predominating ○ Desmoplastic melanoma – < 4% of all melanomas – Affects sun-exposed, head and neck skin of elderly men – Slow-growing nodule or plaque – Can be mistaken clinically as well as histopathologically as scar, basal cell or squamous cell carcinoma – Proliferation of spindled melanocytes within desmoplastic stroma and foci of inflammation – Can be pure desmoplastic melanoma or mixed (occurs together with other melanoma types, such as lentigo maligna melanoma, superficial spreading melanoma, etc.) – Associated with lower risk of metastasis than conventional melanoma with similar depth of invasion – Pure desmoplastic melanomas have less aggressive clinical course than mixed desmoplastic melanomas 457

Diagnoses Associated With Syndromes by Organ: Skin

Cutaneous Melanoma – S100 and Sox10 are sensitive diagnostic markers, since majority negative for Melan A, Mart1, and HMB45 ○ Nevoid melanoma – Accounts for < 1% of all melanomas – Diagnostically challenging since it mimics benign melanocytic nevus and lacks in situ component – Presents as black or brown nodule, dome shaped or verrucous, on trunk or extremities – 3 histopathologic patterns □ Nevus-like nevoid melanoma □ Amelanotic nevoid melanoma □ Mixed pattern ○ Amelanotic or hypomelanotic melanoma – Can be clinically mistaken as nevus or nonmelanocytic tumor, resulting in delayed diagnosis – Most commonly affect trunk, head and neck, and lower extremities – 3 histopathologic morphologies □ Epithelioid (72%) □ Spindled (18.7%) □ Desmoplastic (5.3%) ○ Unusual subtypes – Myxoid melanoma – Animal-type melanoma – Rhabdoid melanoma – Signet ring cell melanoma – Chondroid melanoma – Primary dermal melanoma • Up to 1/3 of melanomas may be associated with melanocytic nevus • Regression ○ Absence of melanoma in epidermis or dermis with alteration of dermis (lymphocytic inflammation, melanophages, vascular alteration, fibroplasia)

Acral Nevus

Cytologic Features

1.

• Occasional cytologic features include ○ Balloon cell ○ Small cell size ○ Signet ring cell ○ Rhabdoid ○ Clear cell

DIFFERENTIAL DIAGNOSIS Atypical (Dysplastic) Melanocytic Nevus • Should show symmetry and circumscription • Bridging of nests across rete ridges • Lamellar fibroplasia of papillary dermis

Recurrent Nevus • Usually any irregular junctional component delimited to epidermis above scar

Spitz (Spindle and Epithelioid Cell) Nevus • Composed of epithelioid and spindle-shaped cells, which may be atypical but are often monomorphous • Symmetric with circumscription • Epidermal nests of melanocytes may show clefting • Maturation with depth • If mitoses present, typically located in superficial portion of dermal component 458

• May have upward melanocytic scatter

Genital Nevus • May have similar histopathologic appearance to atypical (dysplastic) melanocytic nevus

Nonmelanocytic Lesions • Lesions with pagetoid tumor cells resembling in situ melanoma ○ Paget  and extramammary Paget disease ○ Merkel cell carcinoma ○ Sebaceous carcinoma ○ Squamous cell carcinoma in situ • Differential diagnosis of invasive melanoma ○ Sarcomatoid squamous cell carcinoma ○ Poorly differentiated carcinoma ○ Atypical fibroxanthoma ○ Merkel cell carcinoma ○ Lymphoma

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • AJCC Melanoma Staging and Classification System evaluates ○ Tumor thickness ○ Ulceration ○ Mitotic figures ○ Microscopic satellites • Case summary also includes Clark level, margin assessment, vascular invasion, perineural invasion, tumor-infiltrating lymphocytes, and regression

SELECTED REFERENCES Cabrera R et al: Unusual clinical presentations of malignant melanoma: a review of clinical and histologic features with special emphasis on dermatoscopic findings. Am J Clin Dermatol. 19(Suppl 1):15-23, 2018 2. Gershenwald JE et al: Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 67(6):472-92, 2017 3. Longo C et al: Morphological features of naevoid melanoma: results of a multicentre study of the International Dermoscopy Society. Br J Dermatol. 172(4):961-7, 2015 4. Vyas R et al: A systematic review and meta-analysis of animal-type melanoma. J Am Acad Dermatol. 73(6):1031-9, 2015 5. Sidiropoulos M et al: Primary dermal melanoma: a unique subtype of melanoma to be distinguished from cutaneous metastatic melanoma: a clinical, histologic, and gene expression-profiling study. J Am Acad Dermatol. 71(6):1083-92, 2014 6. Cheung WL et al: Amelanotic melanoma: a detailed morphologic analysis with clinicopathologic correlation of 75 cases. J Cutan Pathol. 39(1):33-9, 2012 7. Banerjee SS et al: Divergent differentiation in malignant melanomas: a review. Histopathology. 52(2):119-29, 2008 8. de Almeida LS et al: Desmoplastic malignant melanoma: a clinicopathologic analysis of 113 cases. Am J Dermatopathol. 30(3):207-15, 2008 9. Magro CM et al: Unusual variants of malignant melanoma. Mod Pathol. 19 Suppl 2:S41-70, 2006 10. Quinn MJ et al: Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer. 83(6):1128-35, 1998

Cutaneous Melanoma

Nevoid Melanoma (Left) In this example of nevoid melanoma, the invasive melanoma cells are deceptively uniform and small, mimicking nevus cells in the dermis. (Right) At high magnification, the invasive melanoma cells, which are uniform and small, show mitotic figures.

Desmoplastic Melanoma

Diagnoses Associated With Syndromes by Organ: Skin

Nevoid Melanoma

Desmoplastic Melanoma (Left) A proliferation of spindled cells is shown within the dermis with associated foci of inflammation, which can be mistaken for an inflammatory process. (Right) Spindle tumor cells are seen underneath an uninvolved epidermis, raising the differential diagnosis of sarcoma and sarcomatoid carcinoma.

Desmoplastic Melanoma

Desmoplastic Melanoma (Left) At higher magnification, atypical spindle tumor cells are infiltrating the dermis. These atypical spindle cells are small and irregular with focal pleomorphism. (Right) S100 immunostain strongly highlights the spindled tumor cells, confirming the diagnosis of desmoplastic melanoma.

459

Diagnoses Associated With Syndromes by Organ: Skin

Cutaneous Squamous Cell Carcinoma KEY FACTS

ETIOLOGY/PATHOGENESIS

TOP DIFFERENTIAL DIAGNOSES

• • • •

• • • • • • •

Ultraviolet (UV) radiation is responsible for majority of cases Prior radiation therapy HPV infection in tumors on genital sites Genetic predisposition ○ Xeroderma pigmentosum ○ Epidermolysis bullosa

CLINICAL ISSUES • Genetic syndrome should be considered in very young patients • Most often affects sun-exposed sites, such as head and neck, in elderly individuals • Complete surgical excision is treatment of choice • Excellent prognosis in superficial and well-differentiated tumors • Worse prognosis in poorly differentiated or deeply invasive tumors, or those with aggressive histopathologic subtypes

Basal cell carcinoma Sebaceous carcinoma Poorly differentiated carcinoma (including metastatic) Pseudoepitheliomatous hyperplasia Spindle cell melanoma Atypical fibroxanthoma Leiomyosarcoma

DIAGNOSTIC CHECKLIST • Degree of differentiation • Depth of invasion ○ To subcutaneous tissue or underlying bone • Perineural invasion ○ Tumors with perineural invasion have high rates of local recurrence and increased risk of metastasis ○ More concerning if diameter of nerve > 0.1 mm • Location of tumor important (i.e., lip, mucosal lesions more aggressive)

Keratoacanthoma-Type SCCa

Advanced SCCa

Xeroderma Pigmentosum

Burn Injury

(Left) Clinical photograph shows squamous cell carcinoma (SCCa) with raised borders and a central, crateriform keratin-filled defect, suggestive of keratoacanthoma type. (Courtesy S. Yashar, MD.) (Right) A large, ulcerated tumor is shown on the patient's cheek. A prominent nodular component is seen in the preauricular region.

(Left) This child with xeroderma pigmentosum is predisposed to multiple skin cancers, including SCC at a young age. Many lentigines cover the face. (Courtesy, K. Kraemer, MD.) (Right) Clinical photograph shows an extensive SCC arising on the distal foot in a patient with a history of previous burn injury. (Courtesy S. Yashar, MD.)

460

Cutaneous Squamous Cell Carcinoma

Abbreviations • Squamous cell carcinoma (SCCa)

ETIOLOGY/PATHOGENESIS Environmental Exposure • Chronic sun or ultraviolet (UV) radiation • Radiation therapy

Genetic Predisposition • Xeroderma pigmentosum • Epidermolysis bullosa

Infection • Human papillomavirus (HPV)

CLINICAL ISSUES Epidemiology • Incidence ○ 15-35/100,000 persons per year • 2nd most common form of nonmelanoma skin cancer after basal cell carcinoma • Responsible for majority of nonmelanoma skin cancerrelated deaths

Presentation • Affects sun-exposed areas, including head and neck and extremities • Associated with HPV when affecting oral, perianal, and genital sites

○ Invasion to subcutaneous tissue is poor prognostic factor • Tumor grade ○ Differentiation includes well differentiated, moderately differentiated, and poorly differentiated ○ Poorly differentiated tumor is associated with local recurrence, lymph node metastasis, and disease-specific death • Perineural invasion ○ Associated with poor outcome, especially when involving nerve ≥ 0.1 mm in diameter • Growth pattern ○ Desmoplastic (sclerosing) growth pattern is risk factor for recurrence • Association with burns, ulcers, and radiation ○ Cutaneous SCCa developing in association with burns, chronic ulceration, and radiation are high-risk tumors with metastatic potential • Anatomic site ○ Increased risk of recurrence and metastasis observed for tumors affecting lip (vermilion and hair-bearing), ear, temple, and cheeks • Immunosuppression ○ Immunosuppressed patients are predisposed to develop cutaneous SCCa ○ Acantholytic and spindle/sarcomatoid variants are frequent observed in transplanted patients • HPV ○ Vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PeIN), anal intraepithelial neoplasia (AIN), and invasive SCCa of anogenital region are frequently associated with high-risk HPV, including HPV-16 and HPV-18

Diagnoses Associated With Syndromes by Organ: Skin

TERMINOLOGY

Treatment • Surgical approaches ○ Complete excision is main therapy • Drugs ○ Topical chemotherapeutics or immunomodulators in patients who are not surgical candidates • Radiation ○ Radiation in advanced cases in which surgical treatment is not curative

Prognosis • Prognosis is excellent for superficial and well-differentiated tumors after surgical removal • Worse prognosis in poorly differentiated, deeply invasive, or aggressive subtypes • High cure rates when detected and treated early for cutaneous SCCa with lymph node metastasis • Incidences of recurrence, nodal metastasis. and SCCarelated death are estimated at 4.6%, 3.7%, and 2.1%, respectively

Prognostic Factors • Tumor size ○ Increased risk for recurrence and metastasis for tumor with clinical diameter > 2 cm • Tumor thickness ○ Measured from granular layer of adjacent normal skin to deepest tumor cells ○ Thickness > 6 mm is risk factor for local recurrence and metastasis

MACROSCOPIC General Features • Papular to nodular or plaque-like lesion; can be exophytic, ulcerated, or hemorrhagic

Size • Variable; can be small or large

MICROSCOPIC Histologic Features • Proliferation of atypical keratinocytes • Keratinization is evident by keratin pearls and squamous eddies

Histopathologic Variants • Low-risk variants: Well-differentiated SCC, keratoacanthoma, verrucous carcinoma, and clear cell/trichilemmal carcinoma ○ Keratoacanthoma or well-differentiated SCC – Rapidly growing tumor on sun-exposed skin – Typically present as round to oval, umbilicated nodule with central keratin-filled crater – Solitary to multiple in setting of BRAF-kinase inhibitor treatment ○ Verrucous carcinoma – Slow-growing, well-differentiated, exophytic, and papillomatous tumor 461

Diagnoses Associated With Syndromes by Organ: Skin

Cutaneous Squamous Cell Carcinoma Immunohistochemistry in Differential Diagnosis DDx

p40

p63

HMW keratin

BerEP4

Sox10

S100

Desmin

CD10

Spindle SCCa

+

+

+

-

-

-

-

-

Spindle cell melanoma

-

-

-

-

+

+

-

-

Atypical fibroxanthoma

-

-/+

-

-

-

-

-

+

Leiomyosarcoma

-

-

-

-

-

-

+

-

SCCa = squamous cell carcinoma.

– Common locations include scalp, shoulder, and plantar surfaces – Majority of verrucous carcinoma is negative for HPV ○ Clear cell cutaneous SCCa – Differential diagnosis includes clear cell basal cell carcinoma, sebaceous carcinoma, trichilemmal carcinoma, clear cell hidradenocarcinoma • Intermediate-risk variants: Acantholytic (adenoid/pseudoglandular), lymphoepithelioma-like carcinoma ○ Acantholytic/adenoid/pseudoglandular SCC – Typically affecting head and neck ○ Lymphoepithelioma-like cutaneous SCCa – Very rare – Typically present as solitary nodule on head and neck of elderly patients – Very good prognosis with low metastatic potential • High-risk variants: Adenosquamous, desmoplastic, spindle cell/sarcomatoid, and basaloid ○ Adenosquamous/mucoepidermoid carcinoma – Most commonly affecting head and neck – With aggressive behavior – CEA immunostain highlights glandular differentiation ○ Desmoplastic or sclerosing cutaneous SCCa – Perineural invasion is common – Differential diagnosis includes microcystic adnexal carcinoma ○ Sarcomatoid or spindle cell SCCa – Typically occurs on head and neck – Differential diagnosis includes spindle cell melanoma and atypical fibroxanthoma ○ Basaloid SCCa – Aggressive and infiltrative variant that occurs on mucocutaneous and genital regions – Strong association with high-risk HPV

DIFFERENTIAL DIAGNOSIS Basal Cell Carcinoma

Poorly Differentiated Carcinoma (Including Metastatic) • Clinical history and imaging studies are paramount, as immunohistochemistry may not be able to distinguish some cases from primary SCC

Pseudoepitheliomatous Hyperplasia • Can mimic SCC • Deep fungal and leishmaniasis infection • Hypertrophic lichen planus

Spindle Cell Melanoma • Sox10, S100, Melan-A/Mart-1, and HMB-45 to exclude melanoma

Atypical Fibroxanthoma • CD68, CD163, and CD10 are typically positive, while SCC is typically positive for high molecular weight keratin and p40

Leiomyosarcoma • Smooth muscle actin, calponin, and desmin to exclude leiomyosarcoma

SELECTED REFERENCES 1.

2.

3.

4.

5. 6. 7.

• BerEP4 is typically positive

Sebaceous Carcinoma • Adipophilin and androgen receptor to exclude sebaceous carcinoma

462

8.

Cañueto J et al: Comparing the eighth and the seventh editions of the American Joint Committee on Cancer staging system and the Brigham and Women's Hospital alternative staging system for cutaneous squamous cell carcinoma: Implications for clinical practice. J Am Acad Dermatol. 80(1):10613.e2, 2019 von Schuckmann LA et al: Survival of patients with early invasive melanoma down-staged under the new eighth edition of the American Joint Committee on Cancer staging system. J Am Acad Dermatol. 80(1):272-4, 2019 Liu J et al: Predictive value of the 8th edition American Joint Commission Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck. J Surg Oncol. 117(4):765-72, 2018 Ross AS et al: Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study. Dermatol Surg. 35(12):1859-66, 2009 Garcia-Zuazaga J et al: Cutaneous squamous cell carcinoma. Adv Dermatol. 24:33-57, 2008 Ulrich C et al: Skin cancer in organ transplant recipients--where do we stand today? Am J Transplant. 8(11):2192-8, 2008 Renzi C et al: Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature. Eur J Surg Oncol. 33(3):364-9, 2007 Veness MJ et al: High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer. 106(11):2389-96, 2006

Cutaneous Squamous Cell Carcinoma

Keratoacanthoma-Type SCCa (Left) A crateriform proliferation of atypical keratinocytes is typical for keratoacanthoma-type SCC. (Right) Invasive nests of atypical keratinocytes at the periphery of the lesion is a helpful feature in rendering the diagnosis of SCC.

Well-Differentiated SCCa

Diagnoses Associated With Syndromes by Organ: Skin

Keratoacanthoma-Type SCCa

Clear Cell SCCa (Left) Abundant, well-formed keratin pearls are seen in this example of well-differentiated SCC. (Right) Nests of atypical keratinocytes with clear cytoplasm are characteristic of clear cell SCC. The differential diagnosis includes clear cell hidradenocarcinoma and trichilemmal carcinoma.

Verrucous Carcinoma

Verrucous Carcinoma (Left) Prominent hypergranulosis can often be mistaken for warty changes. The histologic diagnosis of verrucous carcinoma is based on the irregular appearance of epidermal proliferation at low magnification. (Right) The tumor cells have ample eosinophilic cytoplasm. There is minimal cytology atypia, and individual cell keratinization is noted at the tip of invading tumor nests.

463

Diagnoses Associated With Syndromes by Organ: Skin

Cutaneous Squamous Cell Carcinoma

Acantholytic SCCa

Acantholytic SCCa

Myxoid SCCa

Poorly Differentiated SCCa

Poorly Differentiated SCCa

Lymphoepithelioma-Like Carcinoma

(Left) Acantholytic (adenoid) type of invasive SCC shows scattered cystic spaces containing dyscohesive squamous cells ﬈. This variant of SCC may mimic adenocarcinoma (pseudoglandular SCC) or even angiosarcoma (pseudovascular SCC). (Right) High-power view of acantholytic SCC shows large epithelioid cells with dense, eosinophilic cytoplasm and scattered dyskeratotic (apoptotic) cells ﬈. There is an associated heavy inflammatory cell infiltrate.

(Left) Higher power view of poorly differentiated myxoid SCC shows epithelioid to signet ring-like, eosinophilicstaining cells with focal extracellular mucin ﬇. (Right) H&E shows poorly differentiated infiltrating SCC forming cords, mimicking ductal structures ﬊. There is an associated dense, desmoplastic stroma.

(Left) Poorly differentiated infiltrating SCC ﬊ associated with a sclerotic (desmoplastic) stroma is shown. This is a high malignant potential variant of SCC. (Right) Heavily inflamed invasive SCC with moderately differentiated tumor islands ﬊ composed of basaloid to squamoid cells is surrounded by a sea of inflammatory cells, features suggestive of lymphoepithelioma-like carcinoma of the skin variant.

464

Cutaneous Squamous Cell Carcinoma

Desmoplastic SCCa (Left) Involvement of peripheral nerve with diameter > 0.1 mm is a poor prognostic indicator. (Right) Infiltrating strands of tumor cells exhibiting keratinization are shown within a desmoplastic or hyalinized stroma. These features are indicative of an aggressive subtype of SCC.

Spindle or Sarcomatoid SCCa

Diagnoses Associated With Syndromes by Organ: Skin

Perineural Invasion

Sarcomatoid SCCa (Left) A proliferation of spindle and atypical tumor cells is seen extending to the subcutaneous tissue. Without immunostains, it would be difficult to distinguish a sarcomatoid SCC from a pleomorphic dermal sarcoma. (Right) Pleomorphic atypical tumor cells are seen at high magnification, indistinguishable from spindle cell melanoma and dermal sarcoma.

High Molecular Weight Keratin

p40 Immunostain (Left) Strong yet patchy staining with high molecular weight keratin, such as CK5/6 or CK903, is a characteristic pattern seen in sarcomatoid SCC. (Right) p40 is a more specific marker for sarcomatoid SCC than p63, which can be focally positive in atypical fibroxanthoma.

465

Diagnoses Associated With Syndromes by Organ: Skin

Sebaceous Carcinoma KEY FACTS

TERMINOLOGY

MICROSCOPIC

• Adnexal carcinoma that exhibits sebaceous differentiation • May be associated with Muir-Torre syndrome ○ Autosomal dominant variant of Lynch syndrome ○ In majority of cases, gene implicated is MSH2

• Nodules of basaloid tumor cells • Sebaceous differentiation is prominent in welldifferentiated tumors and focally seen in moderately to poorly differentiated tumors • Often with squamous or basaloid differentiation • Comedonecrosis and high mitotic rate are common

CLINICAL ISSUES

ANCILLARY TESTS

• Most common sites are periocular and head and neck region • Mohs excision is primary treatment modality for tumor without orbital involvement • Metastasis can occur in up to 30% of cases • Sentinel lymph node biopsy and imaging for tumor staging may be indicated for more aggressive tumors • For advanced tumors: Orbital exenteration, radiation therapy, chemotherapy or combination therapy

• Expression of adipophilin and EMA seen in welldifferentiated cases • Majority of cases expresses AR

ETIOLOGY/PATHOGENESIS

TOP DIFFERENTIAL DIAGNOSES • • • • •

Sebaceoma Clear cell squamous cell carcinoma Clear cell basal cell carcinoma Basal cell carcinoma with sebaceous differentiation Clear cell hidradenocarcinoma

Sebaceous Carcinoma of Eyelid

Large Nodular Tumor

Atypical Clear Cells With Mitotic Figures

Epithelial Membrane Antigen

(Left) A nodular tumor is noted at the inner aspect of the upper eyelid. (Courtesy F.A. Jakobiec.) (Right) Scanning magnification of sebaceous carcinoma shows a very large nodular tumor in the dermis. Note the lack of epidermal attachments; however, there are focal entrapped follicular structures ﬈.

(Left) Higher power view of sebaceous carcinoma shows a proliferation of markedly atypical clear cells with numerous mitotic figures ﬈ and abundant apoptotic cellular debris ﬉. (Right) Strong immunohistochemical staining for EMA, often positive in well- and moderately differentiated tumors, highlights the cytoplasmic membrane and intracytoplasmic vacuoles st.

466

Sebaceous Carcinoma

Synonyms • Sebaceous adenocarcinoma

Definitions • Malignant adnexal tumor of sebaceous cells

ETIOLOGY/PATHOGENESIS

• ~ 10% of patients with poorly or undifferentiated tumors experience nodal metastasis • Tumors of upper eyelid often metastasize to preauricular and parotid lymph nodes ○ Whereas tumors of lower eyelid spread to submandibular and cervical lymph nodes • Distant metastasis is uncommon • 5-year and 10-year survival rates are 78% and 62%, respectively

Unknown in Most Cases

Association With Cancer Syndromes

• Some cases likely due to solar (UV) damage ○ As most occur on sun-damaged skin of elderly • Sporadic tumors may have loss of mismatch repair proteins ○ Suggesting defect in DNA mismatch repair

• Muir-Torre syndrome (OMIM 158320) ○ Autosomal dominant variant of Lynch syndrome, hereditary nonpolyposis colorectal cancer ○ MSH2 and MSH1 are commonly mutated in Muir-Torre syndrome • Mismatch repair protein staining of sebaceous neoplasms has been proposed as screening test • Abnormal IHC results ○ Sensitivity of 85% ○ Specificity of 48% ○ Positive predictive value of 22% ○ Negative predictive value of 95%

Genetics • May be marker of Muir-Torre syndrome (MTS) ○ Genes implicated include MSH2 (majority of cases), MLH1, and MSH6 – Encode mismatch repair proteins – Mutations lead to microsatellite instability (MSI) – MSI assays and immunohistochemistry can be used to screen for MTS

Incidence • 3rd most common eyelid tumor after basal cell carcinoma and squamous cell carcinoma • Elderly patients ○ Median age: 72 years • No sex predilection

Origin • Arising from ocular adnexa ○ Meibomian glands that line eyelid margin ○ Glands of Zeis that line individual eyelashes • Pilosebaceous units of hair follicles • Caruncle

CLINICAL ISSUES Site • Up to 75% of cases ○ Periocular tumor • Remainder of cases ○ Other head and neck sites, followed by trunk, extremities • Nonperiocular sebaceous carcinoma may be more likely than periocular carcinomas to be associated with MTS

Presentation • Hard, painless, or cystic nodule • 1-4 cm, enlarges rapidly

Treatment • Surgical approaches ○ Surgical excision with clear margins ○ Mohs excision can be effective in some settings ○ Sentinel lymph node biopsy can be helpful for staging

Prognosis • Recurrence after wide local excision is variable

Diagnoses Associated With Syndromes by Organ: Skin

TERMINOLOGY

MICROSCOPIC Histologic Features • Basaloid neoplasm comprised of lobules or sheets of cells separated by fibrovascular stroma • Growth patterns ○ Lobular ○ Comedo with central necrosis ○ Papillary and pagetoid growth • Basaloid tumor cells have scant cytoplasm, hyperchromatic nuclei, and prominent nucleoli • Well-differentiated tumors ○ Prominent clear cell changes ○ Multiple cytoplasmic vacuoles with nuclear indentation ○ Enlarged and vesicular nuclei or hyperchromatic nuclei with prominent nucleoli • Moderately to poorly differentiated tumors ○ Comprised predominantly of basaloid or squamoid cells ○ Prominent cytologic atypia and nuclear pleomorphism ○ High mitotic rate • Histologic features of aggressiveness ○ Multifocal tumor origin ○ Poorly differentiated ○ Pagetoid spread ○ Marked infiltrative growth pattern ○ Lymphovascular invasion

ANCILLARY TESTS Immunohistochemistry • Tumor cells positive for ○ Adipophilin ○ EMA ○ Cytokeratin CAM5.2 ○ BerEP4 ○ Androgen receptor • Tumor cells negative for 467

Diagnoses Associated With Syndromes by Organ: Skin

Sebaceous Carcinoma ○ CEA ○ S100 protein ○ GCDFP • ER, PR, and AR expression are noted in 43%, 26%, and 81% of cases, respectively • Loss of nuclear expression of MLH1, MSH2, &/or MSH6 can be seen in sporadic tumors

DIFFERENTIAL DIAGNOSIS

2. 3.

4.

Squamous Cell Carcinoma • SCC with clear cell features can be difficult to distinguish from sebaceous carcinoma in some cases • Often associated with overlying actinic keratosis or SCC in situ (Bowen disease) • Clear cells in SCC are due to either degenerative changes or glycogen accumulation ○ Lack cytoplasmic lipid and nuclear indentations ○ PAS (without diastase) is positive in cases with cytoplasmic glycogen – Negative in sebaceous carcinoma • Areas of squamous eddies and keratinization typically present ○ Only rarely seen in sebaceous carcinoma • Sebaceous carcinoma is usually diffusely positive for EMA and AR ○ EMA is weak or focally positive in SCC ○ AR is negative in SCC

5.

6. 7. 8. 9. 10. 11.

12.

13.

Basal Cell Carcinoma

14.

• Most cases are not difficult to distinguish from sebaceous carcinoma • Some cases are predominantly clear cell ○ Typically show at least focal areas of more conventional BCC with peripheral palisading and mucinous stroma • Usually negative with EMA and only focally positive with AR

15.

Other Primary Cutaneous Adnexal Carcinomas • Porocarcinoma and hidradenocarcinoma with clear cell features • Porocarcinoma shows multiple epidermal attachments ○ Whereas hidradenocarcinoma is dermal-based tumor typically lacking epidermal connections • Both tumors show at least focal ductal differentiation ○ May be highlighted by EMA and CEA • Sebaceous carcinoma is usually diffusely positive for EMA and AR

Metastatic Carcinomas to Skin • Metastatic carcinomas with clear cell features should be considered in differential ○ Especially if no epidermal or follicular connections are identified • Metastatic clear cell renal cell carcinoma (RCC) is most likely consideration ○ Prominent capillary-type vasculature present ○ Cells are typically relatively low grade ○ Uniform cytoplasmic clearing ○ IHC: Positive for RCC antigen, pax-8, CD10 – CD10 is positive in ~ 50% of sebaceous carcinomas – EMA is positive in both RCC and sebaceous carcinoma 468

SELECTED REFERENCES 1.

16. 17. 18.

19.

20.

21.

22. 23. 24. 25. 26. 27. 28. 29.

Bao Y et al: Mutations in TP53, ZNF750, and RB1 typify ocular sebaceous carcinoma. J Genet Genomics. 46(6):315-8, 2019 Coquillard C et al: Muir-Torre syndrome presenting as a sebaceous carcinoma of the nasal ala. Am Surg. 85(3):e115-e117, 2019 Task Force/Committee Members. et al: Muir-Torre syndrome appropriate use criteria: Effect of patient age on appropriate use scores. J Cutan Pathol. 46(7):484-9, 2019 Hsia Y et al: Eyelid sebaceous carcinoma: Validation of the 8th edition of the American Joint Committee on cancer T staging system and the prognostic factors for local recurrence, nodal metastasis, and survival. Eye (Lond). 33(6):887-95, 2019 Sa HS et al: Prognostic factors for local recurrence, metastasis and survival for sebaceous carcinoma of the eyelid: observations in 100 patients. Br J Ophthalmol. 103(7):980-4, 2019 North JP et al: Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma. J Cutan Pathol. ePub, 2019 Knackstedt T et al: Sebaceous carcinoma: A review of the scientific literature. Curr Treat Options Oncol. 18(8):47, 2017 Mahalingam M: MSH6, past and present and Muir-Torre syndromeConnecting the dots. Am J Dermatopathol. 39(4):239-49, 2017 Chang AY et al: Management considerations in extraocular sebaceous carcinoma. Dermatol Surg. 42 Suppl 1:S57-65, 2016 Neelakantan IV et al: Parotid sebaceous carcinoma in patient with Muir Torre syndrome, caused by MSH2 mutation. Head Neck Pathol. 10(3):354-61, 2016 Plocharczyk EF et al: Mismatch repair protein deficiency is common in sebaceous neoplasms and suggests the importance of screening for Lynch syndrome. Am J Dermatopathol. 35(2):191-5, 2013 Roberts ME et al: Screening for muir-torre syndrome using mismatch repair protein immunohistochemistry of sebaceous neoplasms. J Genet Couns. 22(3):393-405, 2013 Tetzlaff MT et al: Distinct biological types of ocular adnexal sebaceous carcinoma: HPV-driven and virus-negative tumors arise through nonoverlapping molecular-genetic alterations. Clin Cancer Res. 25(4):128090, 2019 Takagawa Y et al: Radiotherapy for localized sebaceous carcinoma of the eyelid: a retrospective analysis of 83 patients. J Radiat Res. ePub, 2019 Dasgupta T et al: A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. 115(1):158-65, 2009 Buitrago W et al: Sebaceous carcinoma: the great masquerader: emgerging concepts in diagnosis and treatment. Dermatol Ther. 21(6):459-66, 2008 Singh RS et al: Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol. 32(6):936-42, 2008 Yang HM et al: Immunohistochemical expression of D2-40 in benign and malignant sebaceous tumors and comparison to basal and squamous cell carcinomas. Am J Dermatopathol. 30(6):549-54, 2008 Cabral ES et al: Desmoplastic tricholemmoma of the eyelid misdiagnosed as sebaceous carcinoma: a potential diagnostic pitfall. J Cutan Pathol. 34 Suppl 1:22-5, 2007 Ho VH et al: Sentinel lymph node biopsy for sebaceous cell carcinoma and melanoma of the ocular adnexa. Arch Otolaryngol Head Neck Surg. 133(8):820-6, 2007 Cabral ES et al: Distinction of benign sebaceous proliferations from sebaceous carcinomas by immunohistochemistry. Am J Dermatopathol. 28(6):465-71, 2006 Curry ML et al: Muir-Torre syndrome: role of the dermatopathologist in diagnosis. Am J Dermatopathol. 26(3):217-21, 2004 Nelson BR et al: Sebaceous carcinoma. J Am Acad Dermatol. 33(1):1-15; quiz 16-8, 1995 Cohen PR et al: Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med. 90(5):606-13, 1991 Nakamura S et al: Sebaceous carcinoma--with special reference to histopathologic differential diagnosis. J Dermatol. 15(1):55-9, 1988 Burgdorf WH et al: Muir-Torre syndrome. Histologic spectrum of sebaceous proliferations. Am J Dermatopathol. 8(3):202-8, 1986 Ratz JL et al: Sebaceous carcinoma of the eyelid treated with Mohs' surgery. J Am Acad Dermatol. 14(4):668-73, 1986 Wolfe JT 3rd et al: Sebaceous carcinoma of the eyelid. Errors in clinical and pathologic diagnosis. Am J Surg Pathol. 8(8):597-606, 1984 Russell WG et al: Sebaceous carcinoma of meibomian gland origin. The diagnostic importance of pagetoid spread of neoplastic cells. Am J Clin Pathol. 73(4):504-11, 1980

Sebaceous Carcinoma Poorly Differentiated Sebaceous Carcinoma (Left) Clear tumor cells rich in lipid are abundant in this welldifferentiated sebaceous carcinoma. (Right) In poorly differentiated tumor, welldifferentiated sebocytes are often seen only focally.

Comedonecrosis

Diagnoses Associated With Syndromes by Organ: Skin

Well-Differentiated Sebaceous Carcinoma

Comedonecrosis (Left) Scanning magnification shows an atypical cellular, nodular, basaloid-appearing proliferation with large areas of comedonecrosis ﬇. (Right) High-power view shows an area of comedonecrosis surrounded by atypical clear to basaloid cells with apoptotic bodies ﬈ and mitoses ﬊. Some of the cells show clear cytoplasmic vacuoles ﬉.

Poorly Differentiated Sebaceous Carcinoma

Squamous Differentiation (Left) Invasive poorly differentiated sebaceous carcinoma with squamoid features shows markedly enlarged, atypical, and pleomorphic-appearing cells ﬈. Note the overlying epidermal ulceration with serum crusting and neutrophils ﬊. Scattered cells show nuclear indentations by cytoplasmic vacuoles ﬉. (Right) Sebaceous carcinoma shows areas of squamous differentiation ﬊ adjacent to more typical areas with clear cell differentiation ﬈.

469

Diagnoses Associated With Syndromes by Organ: Skin

Sebaceous Carcinoma

Cytokeratin 7

Keratin CAM5.2

Adipophilin

Androgen Receptor

Sebaceous Carcinoma In Situ

EMA

(Left) The tumor cells are strongly positive for cytokeratin 7, which often show patchy, moderate to strong cytoplasmic staining. (Right) Keratin CAM5.2 strongly highlights the tumor cells. There is a patchy staining for keratins.

(Left) Vesicular staining of the lipid droplets with adipophilin is a characteristic feature of sebaceous carcinoma. (Right) AR immunohistochemistry is positive in most cases and shows moderate, diffuse nuclear staining in the majority of the tumor cells.

(Left) Nests of tumor cells with clear cytoplasm are seen within the epidermis. This pagetoid growth pattern of sebaceous carcinoma in situ can mimic other tumors including melanoma in situ, squamous cell carcinoma in situ, and Paget disease. (Right) The in situ tumor cells are highlighted by EMA. The staining of the underlying normal sebaceous glands serves as an internal positive control.

470

Sebaceous Carcinoma Differential Diagnosis: Sebaceous Adenoma (Left) Low-power view shows a large sebaceous adenoma. The tumor is a wellcircumscribed, fusing lobular proliferation with superficial holocrine necrosis ﬊ (recapitulating normal sebaceous glands), composed of bland clear cells surrounded by a thin layer of basaloid cells ﬉. (Right) High-power view of a sebaceous adenoma shows the bland cytologic appearance of the mature sebocytes and surrounding basaloid cells. Note the prominent intracytoplasmic lipid vacuoles ﬉.

Differential Diagnosis: Sebaceoma

Diagnoses Associated With Syndromes by Organ: Skin

Differential Diagnosis: Sebaceous Adenoma

Differential Diagnosis: Atypical Sebaceoma (Left) Sebaceoma shows wellcircumscribed lobules of predominantly basaloid cells with a smaller population of bland-appearing, mature sebaceous cells ﬇. (Right) High-power view of an atypical sebaceoma shows a predominantly basaloid population of enlarged, moderately atypical cells with nuclear hyperchromasia surrounding several large clear cells ﬇ with abundant, multivacuolated cytoplasm. Several mitotic figures are seen ſt, but these can be quite numerous in some sebaceomas.

Differential Diagnosis: Clear Cell BCC

Hidradenocarcinoma (Left) Clear cell basal cell carcinoma (BCC) shows uniform cytoplasmic clearing without the vacuoles and nuclear indentations seen in sebaceous carcinoma. Note the focal retraction artifact ﬉ and adjacent areas of conventional-type BCC ﬊. (Right) Hidradenocarcinoma is another malignant adnexal tumor that often shows clear cell features. However, the cells lack cytoplasmic vacuoles and nuclear indentations. In addition, a few ductal structures are often seen ﬈, which are rare in sebaceous carcinoma.

471

Diagnoses Associated With Syndromes by Organ: Skin

Skin Table Selected Cutaneous Neoplasms and Associated Hereditary Cancer Syndromes Cutaneous Neoplasm

Hereditary Cancer Syndrome

BAP1-associated melanocytic tumors

BAP1-tumor predisposition syndrome

Basal cell carcinoma

Basal cell nevus syndrome, Bazex-Dupre-Christol syndrome, hereditary infundibulocystic basal cell carcinoma, Rombo syndrome, xeroderma pigmentosum

Cylindromas

Familial cylindromatosis syndrome

Fibrofolliculoma/trichodiscoma

Birt-Hogg-Dubé syndrome

Fibrous papules (angiofibromas)

Birt-Hogg-Dubé syndrome, multiple endocrine neoplasia type 1, tuberous sclerosis

Leiomyomas

Reed syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome

Melanoma

Hereditary multiple melanoma, melanoma/pancreatic carcinoma syndrome, Werner syndrome, xeroderma pigmentosum

Sebaceoma

Lynch syndrome, Muir-Torre syndrome

Sebaceous adenoma

Lynch syndrome, Muir-Torre syndrome

Sebaceous carcinoma

Lynch syndrome, Muir-Torre syndrome

Spiradenomas, spiradenocylindroma, and cylindromas

Brooke-Spiegler syndrome

Squamous cell carcinoma

Xeroderma pigmentosum

Steatocystomas

Steatocystoma multiplex

Trichoepitheliomas

Multiple familial trichoepitheliomas syndrome

Trichilemmomas

Cowden syndrome

Selected Hereditary Cancer Syndromes With Skin Manifestations

472

Syndrome

Common Skin Manifestations

BAP1-tumor predisposition syndrome

BAP1-inactived melanocytic lesions

Basal cell nevus syndrome (Gorlin syndrome)

Basal cell carcinoma

Bazex-Dupre-Christol syndrome

Basal cell carcinoma

Beckwith-Wiedemann syndrome

Nevus flammeus, posterior helical pits

Birt-Hogg-Dubé syndrome

Fibrofolliculoma/trichodiscoma, fibrous papules (angiofibromas)

Brooke-Spiegler syndrome

Cylindromas, spiradenomas, and spiradenocylindroma

Costello syndrome

Papillomas, palmoplantar keratoderma

Cowden syndrome

Trichilemmomas, sclerotic fibroma, oral papilloma

Dyskeratosis congenita

Palmoplantar keratoderma, reticulate hyperpigmentation

Familial cylindromatosis syndrome

Cylindromas

Familial multiple basaloid follicular hamartomas

Basaloid follicular hamartomas

Familial multiple discoid fibromas

Trichodiscomas, angiofibromas

Gardner syndrome/familial polyposis of colon

Epidermoid cyst with matrical differentiation, desmoid tumor, fibroma

Generalized basaloid follicular hamartoma syndrome

Multiple basaloid follicular hamartomas, palmoplantar pitting

Hereditary breast/ovarian carcinoma

Melanoma

Hereditary infundibulocystic basal cell carcinoma

Basal cell carcinoma

Hereditary leiomyomatosis and renal cell carcinoma syndrome

Leiomyomas

Hereditary multiple melanoma

Melanomas

Howel-Evans syndrome

Palmoplantar keratoderma

Legius syndrome (NF1-like syndrome)

Multiple café au lait spots without neurofibromas

Lynch syndrome

Sebaceoma, sebaceous adenoma, sebaceous carcinoma

Melanoma/pancreatic carcinoma syndrome

Melanomas

Muir-Torre syndrome

Sebaceoma, sebaceous adenoma, sebaceous carcinoma

Multiple endocrine neoplasia type 1

Fibrous papules (angiofibromas)

Skin Table

Syndrome

Common Skin Manifestations

Multiple familial trichoepitheliomas syndrome

Trichoepitheliomas

Neurofibromatosis, type I

Neurofibromas, café-au-lait spots

Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome)

Multiple lentigines

Oley syndrome

Basal cell carcinoma

Pachyonychia congenita type 2

Multiple pilosebaceous cysts

Reed syndrome

Leiomyomas

Rombo syndrome

Basal cell carcinoma

Rothmund-Thomson syndrome

Squamous cell carcinoma

Schopf-Schulz-Passarge syndrome

Eyelid cysts, palmoplantar keratoderma

Steatocystoma multiplex

Steatocystomas

Tuberous sclerosis

Fibrous papules (angiofibromas), collagenoma, hypopigmented macule

Xeroderma pigmentosum

Basal cell carcinoma, squamous cell carcinomas, lentigines, melanomas

Werner syndrome

Melanomas

Diagnoses Associated With Syndromes by Organ: Skin

Selected Hereditary Cancer Syndromes With Skin Manifestations (Continued)

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PART II SECTION 1

Introduction Pathology of Familial Tumor Syndromes Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes Molecular Aspects of Familial/Hereditary Tumor Syndromes

476 484 494

Overview of Syndromes: Introduction

Pathology of Familial Tumor Syndromes Hereditary Syndromes: Practical Guide to Pathological Recognition

INTRODUCTION Background • Proportion of cancer cases with hereditary background is increasing steadily • Use of whole-genome sequencing and using nextgeneration sequencing technologies have increased our understanding of molecular biological aspects of familial cancer syndromes • Numerous new genes have been identified as etiology for cancer predisposition, and numerous new familial cancer syndromes are now identified • Over 10% of all malignant tumors develop in setting of germline predisposition • ~ 40% of pediatric malignancies are of hereditary origin • Awareness of important manifestations associated with each syndrome that might provide additional clues to hereditary/familial neoplasia syndrome is important • Recognizing and identifying hereditary diseases during routine medical practice is needed

• Significant proportion of hereditary neoplasia displays distinct/unusual histopathological &/or immunophenotypic features that make pathologists 1st medical specialists to recognize their inherited nature • Role of pathologist resides in suspecting/recognizing inherited tumors and alerting clinicians to possibility of inherited predisposition ○ All patients identified as having familial tumors should then be screened for familial disease's associated mutation ○ Geneticists and clinicians should perform additional clinical and genetic evaluation for confirmation • It is becoming increasingly well recognized that given familial tumor syndrome may be very heterogeneous in clinical appearance • Identification of hereditary cases and early diagnosis makes preventive surgery and adequate treatment possible

Pathology of Familial Cancer Syndromes

Graphic highlights involvement of different organs with distinct pathologies, including typical findings of familial cancer syndromes. Abdominal lesions are seen in patients with von Hippel-Lindau (VHL) syndrome, including bilateral and multiple renal cysts ﬉, renal tumors st, pancreatic cysts ﬈, and pheochromocytoma ſt.

476

Pathology of Familial Tumor Syndromes

• Awareness of pathologic features of neoplasms seen in variety of hereditary/familial neoplasia syndromes is crucial for diagnosis • Pathologic findings suggestive of familial or inherited tumor syndromes or findings specific for syndrome ○ Tumors occurring at younger age than sporadic counterpart ○ Multiple tumors ○ Bilateral tumors ○ Tumors involving multiple organs and systems ○ Tumors associated with multiple lesions ○ Tumors associated with multiple hamartomatous lesions ○ Specific location of tumor ○ Unique morphological features of tumor ○ Presence of precursor lesions ○ Presence of multiple benign lesions • Many surgical specimens are received from patients who have known syndrome diagnosis at time of surgery ○ Pathologist may be 1st physician to suggest possibility of syndromic association based on presence of unique pathologic findings in tumor resection specimen ○ Gross and histological features that are evaluated in routine tumor resection specimens might suggest each individual syndrome ○ In their pathological examinations, it is important for surgical pathologists to be aware of specific gross and microscopic findings that suggest possible syndromic association ○ Some tumors frequently display characteristic clinical, biochemical, and histopathological features that, although not pathognomonic, can be helpful in suggesting inherited disease as underlying etiology and distinguishing these tumors from sporadic cases • Characteristic and distinct pathologic findings in these syndromes should alert pathologist to possible familial cancer syndrome ○ Correct histologic interpretation may lead to further molecular genetic evaluation of patient and family members

Pathology Reporting • If constellation of pathologic findings strongly suggests potential syndromic association ○ Consult medical records for diagnosis of potential syndrome ○ Pathologists should notify clinicians about this possibility, consider appropriate molecular testing • For reporting purposes, diagnosis of lesion or neoplasm should use same criteria and terminology as for sporadic lesions and tumors ○ Comment suggesting possible association with genetic disease is recommended – To document possibility of specific genetic association

HEREDITARY SYNDROMES ASSOCIATED WITH NEOPLASIA Hereditary Syndromes • Some hereditary syndromes are known to be associated with neoplasia and have unique &/or characteristic pathologic features • Characteristic and distinct pathologic findings in these syndromes should alert pathologist to possible familial cancer syndrome

ENDOCRINE SYSTEM Hereditary Syndromes Associated With Thyroid Neoplasia

Overview of Syndromes: Introduction

Recognition of Morphological Characteristics Indicating Familial Tumor Syndromes

• Medullary thyroid carcinoma (MTC) ○ Multiple endocrine neoplasia 2A (MEN2A) ○ Multiple endocrine neoplasia 2B (MEN2B) ○ Familial medullary thyroid carcinoma (FMTC) • Cribriform morular papillary thyroid carcinoma ○ Familial adenomatous polyposis (FAP) syndrome – Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) was described originally as FAPassociated thyroid carcinoma • Numerous adenomatous nodules, multinodular hyperplasia, follicular adenomas, follicular carcinomas, papillary carcinomas ○ PTEN-hamartoma tumor syndrome (PHTS)/Cowden disease – Presence of numerous multiple adenomatous nodules (MANs) or follicular thyroid carcinoma (FC) in younger patients should raise suspicion for diagnosis of PHTS ○ Carney complex ○ DICER1 syndrome • Oncocytic tumors ○ Li-Fraumeni syndrome ○ Familial oncocytic neoplasms ○ McCune-Albright syndrome ○ Tuberous sclerosis complex

Hereditary Syndromes Associated With Adrenal Neoplasia • Adrenal cortical tumors ○ Beckwith-Wiedemann syndrome ○ Li-Fraumeni syndrome ○ Multiple endocrine neoplasia 1 (MEN1) ○ Carney complex ○ Lynch syndrome ○ Congenital adrenal hyperplasia

Hereditary Syndromes Associated With Parathyroid Neoplasia • • • • •

MEN1 Hereditary hyperparathyroidism-jaw tumor syndrome Familial isolated hyperparathyroidism syndrome MEN2A Neonatal severe primary hyperparathyroidism

Hereditary Syndromes Associated With Pituitary Neoplasia • MEN1 477

Overview of Syndromes: Introduction

Pathology of Familial Tumor Syndromes • • • • • •

Familial pituitary adenoma syndrome Familial isolated pituitary adenoma syndrome (FIPA) Carney complex Multiple endocrine neoplasia 4 (MEN4) McCune-Albright syndrome DICER1 syndrome

Hereditary Syndromes Associated With Endocrine Pancreas Neoplasia • • • • • • •

MEN1 von Hippel-Lindau syndrome Tuberous sclerosis complex Neurofibromatosis type 1 (NF1) FAP MEN4 Glucagon cell hyperplasia and neoplasia

Hereditary Syndromes Associated With Paraganglioma/Pheochromocytoma • • • • • • • • • • • • • •

MEN2A MEN2B von Hippel-Lindau syndrome NF1 Familial paraganglioma type 1 (PGL1) Familial PGL2 Familial PGL3 Familial PGL4 Familial PGL5 FH Carney-Stratakis syndrome Familial pheochromocytoma (PCC) 2q MAX related TMEM127 related

GENITOURINARY TRACT Hereditary Syndromes Associated With Renal Neoplasia • • • • • • • • • • • •

von Hippel-Lindau syndrome Hereditary papillary renal cell carcinoma (RCC) Hereditary leiomyomatosis-RCC Birt-Hogg-Dubé syndrome Tuberous sclerosis complex Succinate dehydrogenase (SDH) germline mutation ○ SDH-deficient RCC (High risk: SDHB) Lynch syndrome Heritable sickle cell hemoglobinopathy and medullary carcinoma of kidney Hyperparathyroidism-jaw tumor syndrome PHTS Constitutional chromosome 3 translocation Wilms tumor-associated syndromes ○ Familial Wilms tumor (WT), aniridia, genitourinary malformations, and intellectual disability (WAGR) syndrome, Denys-Drash syndrome, Frasier syndrome, Perlman syndrome, Fanconi anemia, WT1 deletions, Beckwith-Wiedemann syndrome

Hereditary Syndromes Associated With Testicular Neoplasia • Carney complex 478

• • • • •

Li-Fraumeni syndrome Peutz-Jeghers syndrome RCC and leiomyomas Xeroderma pigmentosus Familial testicular germ cell tumor

Hereditary Syndromes Associated With Prostate Neoplasia • • • •

Hereditary breast and ovarian cancer BRCA1 and BRCA2 Lynch syndrome Li-Fraumeni syndrome Hereditary prostate cancer

Hereditary Syndromes Associated With Bladder and Ureter Neoplasia • Lynch syndrome

GASTROINTESTINAL TRACT Hereditary Syndromes Associated With Esophagus, Stomach, and Intestinal Neoplasia • • • • • • • • • • • • • • • • •

FAP Juvenile polyposis Familial gastrointestinal stromal tumor Hereditary diffuse gastric cancer MUTYH-associated polyposis (MAP) DNA polymerase ε and δ polyposis (POLE and POLD1 mutation-associated tumors) MSH3 polyposis NTHL1 polyposis Peutz-Jeghers syndrome Breast/ovarian BRCA1 and BRCA2 PHTS Li-Fraumeni syndrome Bloom syndrome Dyskeratosis congenita Gastrointestinal stromal tumor syndrome NF1 MEN1

Hereditary Syndromes Associated With Pancreas Neoplasia • Endocrine pancreas ○ von Hippel-Lindau syndrome ○ MEN1 ○ MEN4 ○ NF1 ○ Tuberous sclerosis complex ○ Glucagon cell hyperplasia and neoplasia • Ampullary and pancreaticobiliary cancer ○ FAP ○ Lynch syndrome ○ Peutz-Jeghers syndrome ○ Juvenile polyposis ○ Hereditary breast/ovarian BRCA1 and BRCA2 ○ Familial atypical multiple mole melanoma syndrome ○ Li-Fraumeni syndrome ○ Dyskeratosis congenita ○ Carney complex ○ Hereditary pancreatic cancer syndrome

Pathology of Familial Tumor Syndromes

• • • • • • •

FAP Breast/ovarian BRCA2 Li-Fraumeni syndrome PHTS Beckwith-Wiedemann syndrome von Hippel-Lindau syndrome Lynch syndrome

SKIN Hereditary Syndromes Associated With Skin Neoplasia • • • • • • • • • •

Carney complex PHTS Basal cell nevus syndrome Beckwith-Wiedemann syndrome Birt-Hogg-Dubé syndrome Dyskeratosis congenita Hereditary multiple melanoma Howell-Evans syndrome Melanoma pancreatic carcinoma syndrome Werner syndrome

BREAST Hereditary Syndromes Associated With Breast Neoplasia • • • • • • •

BRCA1 hereditary breast &/or ovarian cancer syndrome BRCA2 hereditary breast &/or ovarian cancer syndrome Li-Fraumeni syndrome Familial gastric cancer and breast lobular cancer syndrome PHTS Peutz-Jeghers syndrome Ataxia-telangiectasia syndrome

HEMATOLOGY Hereditary Syndromes Associated With Hematological Neoplasia • • • • • • • • • • • • • • • • •

Congenital amegakaryocytic thrombocytopenia Diamond-Blackfan anemia Dyskeratosis congenita Severe congenital neutropenia Shwachman-Diamond syndrome Fanconi anemia Familial myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML) with mutated GATA2 MIRAGE syndrome Ataxia-pancytopenia syndrome Myeloid neoplasm with mutated SRP72 Familial MDS/AML with mutated DDX41 Familial platelet disorder with propensity to myeloid malignancy Thrombocytopenia 2 and 5 Familial AML with CEBPA mutation Li-Fraumeni syndrome Bloom syndrome Constitutional mismatch repair deficiency syndrome

• Ataxia-telangiectasia syndrome • Noonan syndrome

LUNG Hereditary Syndromes Associated With Lung Neoplasia • • • • • • • • • • •

BRCA2 hereditary breast &/or ovarian cancer syndrome Hereditary retinoblastoma syndrome Familial pleuropulmonary blastoma Tuberous sclerosis complex Carney triad Bloom syndrome Li-Fraumeni syndrome Xeroderma pigmentosum Peutz-Jeghers syndrome Bloom syndrome  Hereditary retinoblastoma 

Overview of Syndromes: Introduction

Hereditary Syndromes Associated With Liver Neoplasia

HEAD AND NECK Hereditary Syndromes Associated With Head and Neck Neoplasia • • • • • • • • • •

Dyskeratosis congenita Fanconi anemia Xeroderma pigmentosum Bloom syndrome Hereditary retinoblastoma Neurofibromatosis type 2 (NF2) Basal cell nevus syndrome/Gorlin syndrome Hyperparathyroidism-jaw tumor syndrome FAP von Hippel-Lindau syndrome

Hereditary Syndromes Associated With Salivary Gland Neoplasia • • • •

von Hippel-Lindau syndrome Ataxia-telangiectasia syndrome Hereditary retinoblastoma syndrome Brooke-Spiegler syndrome and familial cylindromatosis

CENTRAL NERVOUS SYSTEM Hereditary Syndromes Associated With CNS and PNS Neoplasia • • • • • • • • • • • • • • • •

Ataxia-telangiectasia syndrome Familial uveal melanoma Hereditary retinoblastoma NF1 NF2 Rhabdoid predisposition syndrome Schwannomatosis Tuberous sclerosis complex von Hippel-Lindau syndrome Multiple meningoma syndrome FAP Lynch syndrome Gorlin syndrome Li-Fraumeni syndrome PHTS Melanoma astrocytoma syndrome 479

Overview of Syndromes: Introduction

Pathology of Familial Tumor Syndromes Application of Immunohistochemistry Markers Aiding Diagnosis of Syndromes IHC Marker

Gene

Main Application

PTEN

PTEN

Loss of immunostaining aids identifying PTEN-hamartoma tumor syndrome in thyroid nodules, trichilemmomas, Lhermitte-Duclos disease

β-catenin

APC

Nuclear immunostaining confirms unusual papillary thyroid carcinoma, cribriform-morular variant, which is usually associated with FAP

SDHB

SDHx

SDHB loss in pheochromocytomas, paragangliomas, and RCCs serve as screening test to triage patients for further genetic analysis of SDHx subunits on diagnosis of familial paraganglioma pheochromocytoma syndrome

BAP1

BAP1

In patients with clinical features and family history of BAP1-hereditary predisposition syndrome, triaging for genetic testing for patients with BAP1-deficient tumors

FH

FH

Confirming diagnosis of distinct RCC-associated with hereditary leiomyomatosis and RCC

BRAF V600E

BRAF

Serves as screen for papillary thyroid carcinoma, melanoma, and other tumors

MLH1, PMS1,  MSH2, MSH6 

MMR

Loss of 1 marker serves as screening for further genetic testing for Lynch syndrome

Parafibromin

CDC73

Aiding in diagnosis of parathyroid carcinoma or parathyroid tumor associated with hyperparathyroidism-jaw tumor syndrome

Glucagon

GCGR

Pancreatic neuroendocrine tumors with expression of glucagon are highly suggestive of germline GCGR mutation and glucagon cell adenomatosis (Mahvash syndrome)

PRKAR1A

PRKAR1A

IHC in certain tumors (such as thyroid nodules or cardiac myxoma) aids excluding Carney complex

p53

TP53

Abnormal pattern: Complete absence; all cells negative; genomic alterations with absence of p53 expression  Abnormal pattern: Overexpression; diffuse strong positivity; mutations that stabilize protein IHC is not useful for screening for germline mutations as somatic mutations occur in ~ 50% of tumors

FAP = familial adenomatous polyposis; RCC = renal cell carcinoma; IHC = immunohistochemistry.

• DICER1 syndrome

BONE AND SOFT TISSUE Hereditary Syndromes Associated With Bone and Soft Tissue Neoplasia • • • • • • • • • • • • • • • • • • • • • • • •

480

Multiple osteochondromas (hereditary multiple exostoses) Li-Fraumeni syndrome Hereditary retinoblastoma Familial chordoma syndrome Tuberous sclerosis complex Hyperparathyroidism-jaw tumor syndrome Bloom syndrome Werner syndrome Rothmund-Thomson syndrome Basal cell nevus syndrome FAP Rhabdoid tumor predisposition syndrome von Hippel-Lindau syndrome Renal carcinoma with leiomyomas NF1 NF2 Carney complex Beckwith-Wiedemann syndrome Rubinstein-Taybi syndrome DICER1 syndrome Mosaic variegated aneuploidy syndrome 1 Costello syndrome Nijmegen breakage syndrome Noonan syndrome

GYNECOLOGY Hereditary Syndromes Associated With Uterine Neoplasia • • • • • • •

BRCA1 hereditary breast &/or ovarian cancer syndrome BRCA2 hereditary breast &/or ovarian cancer syndrome Lynch syndrome PHTS Peutz-Jeghers syndrome Hereditary leiomyomatosis and RCC von Hippel-Lindau syndrome

Hereditary Syndromes Associated With Ovarian Neoplasia • • • • •

BRCA1 hereditary breast &/or ovarian cancer syndrome BRCA2 hereditary breast &/or ovarian cancer syndrome von Hippel-Lindau syndrome Peutz-Jeghers syndrome Lynch syndrome

SELECTED REFERENCES 1.

2.

3. 4.

Elisei R et al: Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations. Genes (Basel). 10(9), 2019 Gupta S et al: Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol. 91:114-22, 2019 Guilmette J et al: Hereditary and familial thyroid tumours. Histopathology. 72(1):70-81, 2018 Euhus DM et al: Genetic predisposition syndromes and their management. Surg Clin North Am. 93(2):341-62, 2013

Pathology of Familial Tumor Syndromes von Hippel-Lindau-Associated Hemangioblastoma (Left) Graphic shows abdominal lesions seen in patients with VHL syndrome, including bilateral and multiple renal cysts ﬉, renal tumors st, pancreatic cysts ﬈, and pheochromocytoma ſt. (Right) Hemangioblastoma is the most frequently occurring tumor in VHL syndrome patients and is usually multiple. The main locations involved are the cerebellum ﬈ and spinal cord ﬊.

Endolymphatic Sac Tumor in von HippelLindau Syndrome

Overview of Syndromes: Introduction

von Hippel-Lindau-Associated Abdominal Lesions

Renal Cell Carcinoma (Left) The presence of unusual tumors is one of the characteristics of inherited tumor syndromes. Graphic of temporal bone shows the typical appearance of endolymphatic sac tumor seen in VHL patients. When diagnosing this tumor, VHL syndrome should be highly considered. (Right) The presence of renal cell carcinomas ﬉ in a young patient with specific histopathological features should alert the pathologist to the diagnosis of familial renal tumor syndromes.

NF1-Associated Lesions

NF2-Associated Lesions (Left) The presence of multiple lesions, including multiple and bilateral tumors, is a characteristic feature of inherited tumor syndromes. Graphic depicts sphenoid dysplasia with arachnoid cyst ﬇, optic nerve glioma ﬊, buphthalmos st, and multiple plexiform neurofibromas ﬉, features associated with neurofibromatosis type 1 (NF1). (Right) The combination of multiple meningiomas ﬈ and schwannomas ﬊ is characteristic of patients with neurofibromatosis type 2 (NF2).

481

Overview of Syndromes: Introduction

Pathology of Familial Tumor Syndromes Chordoma in Tuberous Sclerosis or Familial Chordoma

Sacrococcygeal Chordoma

Tuberous Sclerosis-Associated Lesions

Atypical Teratoid/Rhabdoid Tumors

Retinoblastoma

Tuberous Sclerosis-Associated Angiomyolipoma

(Left) Chordomas classically occur in the midline of the body, and one of the more common locations is at the base of the skull in the region of the clivus. In familial chordomas, there is an increased incidence of chordoma in patients with tuberous sclerosis or familial chordoma. (Right) Chordomas have a gelatinous, lobulated, and well-delineated gross appearance. These may occur in familial chordoma syndrome and in tuberous sclerosis.

(Left) The characteristic lesions of tuberous sclerosis in the CNS include cortical tubers ﬇, subependymal nodules identifiable in the walls of the lateral ventricles st, and a subependymal giant cell astrocytoma ﬊. (Right) Atypical teratoid/rhabdoid tumors (AT/RT) form variably sized masses that may appear well circumscribed. Multiple foci of necrosis are common in these extremely aggressive pediatric tumors. They occur throughout the neural axis.

(Left) Graphic shows retinoblastoma with lobulated tumor extending through the limiting membrane into the vitreous. Punctate calcifications ﬈ are characteristic. Hereditary retinoblastoma patients may develop carcinoma of the nasal cavity. (Right) Renal manifestations, including bilateral angiomyolipomas, are also typical of tuberous sclerosis complex. These are usually benign, but large tumors st are associated with risk for life-threatening bleeding.

482

Pathology of Familial Tumor Syndromes

Carotid Body Paraganglioma (Left) Graphic depicts a squamous cell carcinoma of the maxillary sinus. These tumors may be present in patients with dyskeratosis congenita, Fanconi anemia, xeroderma pigmentosum, and Bloom syndrome, presenting at an earlier age than the sporadic tumors. (Right) Graphic depicts a carotid body paraganglioma at the carotid bifurcation. The main arterial feeder is the ascending pharyngeal artery. The vagus ﬇ and hypoglossal nerves st are in close proximity.

Succinate Dehydrogenase-Associated Glomus Tympanicum Paraganglioma

Overview of Syndromes: Introduction

Squamous Cell Carcinoma of Maxillary Sinus

Glomus Jugulare Paraganglioma (Left) Graphic shows a highly vascular glomus tympanicum paraganglioma filling a portion of the middle ear cavity. Head and neck paragangliomas are mostly associated with succinate dehydrogenase (SDH) mutation. (Right) Graphic shows a glomus jugulare paraganglioma centered in the jugular foramen with superolateral extension into the middle ear. The ascending parapharyngeal artery st is feeding this vascular tumor.

Hyperparathyroidism-Jaw Tumor Syndrome

Gorlin Syndrome-Associated Keratocystic Odontogenic Tumor (Left) Graphic shows nonossifying fibroma as a large, well-demarcated maxillary mass that obstructs one side of the nose and compresses the eye in a patient with HPT-JT. These patients present with hyperparathyroidism and also have distinct renal tumors. (Right) Graphic of the mandible shows features of classic keratocystic odontogenic tumor (KOT) ſt, displacing the inferior alveolar nerve st. The diagnosis of KOT should prompt evaluation for Gorlin syndrome.

483

Overview of Syndromes: Introduction

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes INTRODUCTION Hereditary Cancer Syndromes • Characterized by germline mutation associated with high probability of cancer development • Most syndromes are autosomal dominant with relatively high penetrance, but there are also several autosomal recessive conditions • Tumors typically develop at younger age compared to sporadic counterparts • Multiple primary tumors can arise in affected organ • Environmental factors can modulate extent of cancer risk • New susceptibility genes continue to be identified, and many of these are lower penetrance • Germline genetic testing is standard of care for establishing diagnosis of most hereditary cancer syndromes

Background • ~ 10% of all cancers are attributable to inherited cancer predisposition gene

• Identifying clinical features that suggest possibility of genetic predisposition to cancer is 1st step to diagnosing these syndromes • Studies of rare familial clusters have been remarkably productive scientific and clinical approach that provided 1st clues about genetics of these syndromes ○ Identification of 1st cancer susceptibility genes (i.e., RB1, APC) ○ Molecular pathogenesis of hereditary tumors informed understanding of more common sporadic counterparts ○ Full spectrum of clinical phenotypes and specific genotype-phenotype correlations were defined • Single-gene hereditary syndromes account for only small fraction of familial clustering on population basis ○ Genetics of many "familial" cases remain undefined • Pathologists can often play important role in recognizing hereditary cancer syndromes ○ Immunohistochemistry for DNA mismatch repair proteins can raise suspicion for Lynch syndrome

Clinical Management of MEN2 Patients With Germline RET Mutations

In patients with multiple endocrine neoplasia type 2 (MEN2) syndrome, genetic testing offers early diagnosis, stratifies the risk of developing medullary thyroid cancer, and informs the timing of thyroidectomy. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma during early childhood in patients with MEN2. ATA risk stratification is based on the RET mutation. Early genetic testing and age-appropriate surgery helps improve outcomes in these patients.

484

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes

Identification of At-Risk Individuals • Accurate identification of patients at increased risk for developing cancer is essential • Obtaining careful family history of cancer is key first step and should be routine part of clinical practice ○ 2-generation pedigree should be obtained as minimum; 3 generations ideal • Now routine to pursue cancer genetics risk assessment, which includes option of germline mutation testing for 1 or more relevant genes • Identification of individuals at risk for cancer has become integral part of medicine ○ Will allow health care providers to intervene with appropriate – Counseling and education – Increased cancer surveillance – Cancer prevention • Genetic risk assessment in context of childhood cancer is specific circumstance and requires participation of all family members • National Comprehensive Cancer Network (NCCN) has established criteria for those individuals who should undergo further genetic risk assessment ○ Multiple algorithmic approach for tumor syndromes available on their website – http://www.nccn.org/professionals/physician_gls/pdf/ genetics_screening • Emerging trend to offer genetic testing to all patients with specific cancers ○ NCCN currently recommends genetic testing for all patients with ovarian cancer and pancreatic cancer ○ Such "universal" approaches reduce burden of remembering clinical criteria for genetics referral

CANCER SUSCEPTIBILITY TESTING ASCO: Indications for Testing • American Society of Clinical Oncology (ASCO) recommends that genetic testing be offered when ○ Individual has personal or family history features suggestive of genetic cancer susceptibility condition ○ Tests can be adequately interpreted ○ Results will aid in diagnosis or influence medical or surgical management of patient or family members at hereditary risk of cancer

• ASCO recommends that genetic testing only be done in setting of pre- and post test counseling, which should include discussion of possible risks and benefits of early cancer detection and prevention modalities

ASCO: Policy Statement • Advent of syndrome-specific germline mutation testing represents major advance in care of cancer-prone individuals • ASCO reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into practice of oncology and preventive medicine ○ Genetic testing for cancer susceptibility has become accepted part of oncologic care – Germline testing for inherited predisposition is well established as part of care of individuals who may be at hereditary risk for cancers of breast, ovary, colon, stomach, uterus, thyroid, and other primary sites – Germline genetic testing is distinct from somatic genetic profiling of cancer tissue to predict prognosis or treatment response – Germline testing involves analysis of DNA from blood or saliva for inherited mutations in specific genes that are associated with type of cancer seen in individual or family seeking assessment – When identified, such high-penetrance mutations usually result in significant alteration in function of corresponding gene product and are associated with large increases in cancer risk – Other mutations result in less dramatic increases in risk (intermediate penetrance) – Identification of high-penetrance mutation often justifies adjustment of clinical care through modification of surveillance or through preventive surgery – Germline testing for certain high-penetrance predispositions is now part of clinical guidelines and is reimbursed by most 3rd-party payers – Impact of low and moderate penetrance mutations on clinical care is less clear

Overview of Syndromes: Introduction

○ Cumulative colon adenoma count over time can raise suspicion for polyposis syndrome • Recognizing hereditary cancer syndromes has several key clinical implications ○ Management of cancer may change – Altered surgical approach (i.e., more extensive colonic resection for colon cancer in Lynch syndrome) – Selection of chemotherapy regimen (i.e., use of PARPinhibitor in BRCA mutation-positive tumor) ○ Cancer screening may be more intensive (higher frequency) and extensive (inclusion of multiple other organ systems) ○ Risk-reducing operations may be option for individuals at high risk for certain cancers ○ Family members are also at risk for these hereditary syndromes and should undergo counseling

ASCO: Clinical Utility of Genetic Testing • Genetic tests may benefit individuals by providing deeper self-knowledge and motivation to pursue healthy behaviors, even if results do not inform clinical decision making • Tests for high-penetrance mutations in appropriate populations have clinical utility, meaning that they inform clinical decision making and facilitate prevention or amelioration of adverse health outcomes • Genetic tests for intermediate-penetrance mutations and genomic profiles of SNPs linked to low-penetrance variants are of uncertain clinical utility

ASCO: Informed Consent • Proposed elements of informed consent related to testing for inherited cancer susceptibility are set forth • Basic elements of informed consent for cancer susceptibility testing ○ Information on specific genetic mutation(s) or genomic variant(s) being tested, including whether range of risk associated with variant will impact medical care 485

Overview of Syndromes: Introduction

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes ○ Implications of positive and negative result ○ Possibility that test will not be informative ○ Options for risk estimation without genetic or genomic testing ○ Risk of passing genetic variant to children ○ Technical accuracy of test including, where required by law, licensure of testing laboratory ○ Fees involved in testing and counseling and, for direct-toconsumer (DTC) testing, whether counselor is employed by testing company ○ Psychological implications of test results (benefits and risks) ○ Risks and protections against genetic discrimination by employers or insurers ○ Confidentiality issues, including, for DTC testing companies, policies related to privacy and data security ○ Possible use of DNA testing samples in future research ○ Options and limitations of medical surveillance and strategies for prevention after genetic or genomic testing ○ Importance of sharing genetic and genomic test results with at-risk relatives so that they may benefit from this information ○ Plans for follow-up after testing

Special Issues Related to Genetic Testing Research • Prospective clinical trials, large registries, and retrospective reviews are most accurate methods for ○ Deriving relative risks of genetic variants ○ Measuring response to and effectiveness of clinical interventions based on genetic cancer risk assessment • Tests with uncertain clinical utility have become commercially available ○ It will be crucial to establish evidence-based algorithm for clinically responsible use of these tests • Wherever possible, genetic tests with uncertain clinical utility should be administered in context of clinical trials • Research should include basic studies of functional significance of genetic variants linked to disease risk as well as prospective, randomized controlled trials of individual genomic markers • At translational level, it is important to establish criteria for technologic assessment of genetic and other diagnostic tests • Research should focus on extent to which personal benefits accrue to individuals who receive tests that have uncertain clinical utility • Establishing evidence-based test for personal utility is particularly important for tests that would not be recommended based on clinical utility • Research is also needed to demonstrate validity and reproducibility of some commercially available tests • Because algorithms used to convert genotypes into absolute risk estimates are empirically derived, prospective research is needed to confirm calibration of these estimates and to measure effectiveness of interventions based on individual genomic profiling • If genetic and genomic tests for cancer risk are going to be offered or justified on basis of personal utility, effort should be made to establish evidence-based tests for these claims

486

Genetic Counseling • Genetic testing should be conducted only in setting of preand post test counseling ○ Pretest counseling – Allows for advance consideration of possible test results, medical options, and impact test results may have on family members – Permits discussion of pros/cons of which genetic test to order □ Single gene analysis □ Analysis of several genes associated with specific syndrome □ Analysis of panel of genes associated with specific tumor type □ Analysis of comprehensive panel of genes associated with multiple tumor types ○ Post test counseling – Provides valuable opportunity for health care providers to interpret test results, recommend appropriate follow-up, and emphasize importance of cancer prevention activities

DIAGNOSIS General • In most cases, positive genetic test is standard for diagnosing hereditary cancer syndrome • Clinical criteria have historically been used and are important adjunct in diagnostic work-up

Diagnostic Criteria for Basal Cell Nevus Syndrome • Caused by PTCH1 mutation • Clinical diagnosis is established if 2 major or 1 major and 2 minor criteria are met • Major criteria ○ Multiple (> 2) basal cell carcinomas, or 1 basal cell carcinoma in patient < 20 years ○ Any odontogenic keratocyst (proven on histology) or polyostotic bone cyst ○ Palmar or plantar pits (≥ 3) ○ Ectopic calcification; lamellar or early (patient < 20 years) falx calcification ○ Family history of basal cell nevus syndrome • Minor criteria ○ Congenital skeletal anomaly: Bifid, fused, splayed, or missing rib; or bifid, wedged, or fused vertebrae ○ Head circumference > 97th percentile, with frontal bossing ○ Cardiac or ovarian fibroma ○ Medulloblastoma (primitive neuroectodermal tumor, most often of desmoplastic histology) ○ Lymphomesenteric or pleural cysts

Diagnostic Criteria for von Hippel-Lindau Syndrome • Caused by VHL mutation • Clinical features that suggest diagnosis include ○ ≥ 2 CNS or retinal hemangioblastomas or ○ Single CNS or retinal hemangioblastoma, plus 1 of following – Multiple renal, pancreatic, or hepatic cysts – Pheochromocytoma (any location) – Renal cancer

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes

Diagnostic Criteria for Carney Complex • Caused by PRKAR1A mutation • Clinical diagnosis can be made if at least 2 of following findings are present ○ Spotty skin pigmentation with typical distribution (often vermilion border of lips, conjunctiva and ocular canthi, vaginal or penile mucosa) ○ Myxoma (cutaneous: Often on the eyelid, external ear, nipple) ○ Cardiac myxoma ○ Breast myxomatosis or fat-suppressed MR findings suggestive of this diagnosis ○ Primary pigmented nodular adrenocortical disease or paradoxical positive response of urinary glucocorticosteroid to dexamethasone administration during Liddle diagnostic test for Cushing syndrome ○ Acromegaly due to GH-producing adenoma (somatotropinomas) ○ Large-cell calcifying Sertoli cell tumor of testis or characteristic calcification on testicular US ○ Thyroid carcinoma or multiple hypoechoic nodules on thyroid US in young patient ○ Psammomatous melanotic schwannoma ○ Blue nevus, epithelioid blue nevus (multiple) ○ Breast ductal adenoma (multiple) (or mammary tumor with intraductal papilloma) ○ Osteochondromyxoma of bone (histological diagnosis) • Diagnostic criteria is also satisfied in patient meeting any of these criteria and having either affected 1st-degree relative or inactivating mutation of PRKAR1A

Diagnostic Criteria for Neurofibromatosis Type 1 • Caused by NF1 mutation • Clinical diagnosis requires 2 or more of following ○ Café au lait macules – In children, ≥ 5 that are ≥ 0.5 cm in diameter – In adults, ≥ 6 that are ≥ 1.5 cm in diameter ○ ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma ○ Multiple axillary or inguinal freckles ○ Sphenoid wing dysplasia or congenital bowing or thinning of long bone cortex (± pseudoarthrosis) ○ Bilateral optic nerve gliomas

○ ≥ 2 iris Lisch nodules (iris hamartomas) ○ 1st-degree relative with NF1 by these criteria

Diagnostic Criteria for Neurofibromatosis Type 2 • Caused by NF2 mutation • Clinical diagnosis requires any 1 of following (Manchester criteria) ○ Bilateral vestibular schwannomas < age 70 years ○ Unilateral vestibular schwannoma < age 70 years and 1stdegree relative with NF2 ○ Any 2 of following (meningioma, cataract, glioma, neurofibroma, schwannoma, cerebral calcification) and 1st-degree relative with NF2 or unilateral vestibular schwannoma and negative LZTR1 testing ○ Multiple meningiomas (2 or more) and any 2 of following (unilateral vestibular schwannoma, cataract, glioma, neurofibroma, schwannoma, cerebral calcification) ○ Constitutional or mosaic pathogenic NF2 mutation in blood or identical mutations in 2 distinct tumors

Overview of Syndromes: Introduction

– Endolymphatic sac tumor of inner ear – Papillary cystadenoma of epididymis or broad ligament – Neuroendocrine tumor of pancreas ○ Definite family history of VHL plus 1 of following – CNS or retinal hemangioblastoma – Multiple renal, pancreatic, or hepatic cysts – Pheochromocytoma – Renal cancer < age 60 years – Epididymal cystadenoma ○ Key diagnostic points – Multiple retinal and CNS hemangioblastomas – Multiple clear cell RCCs (bilateral), multiple renal cysts (bilateral) with clear cell lining, multiple pancreatic and hepatic cysts – May suspect possibility of syndrome based on constellation of pathologic findings

Diagnostic Criteria for Li-Fraumeni Syndrome • Germline mutation in TP53 ○ When strict criteria are met, TP53 mutations are found in 60-80% ○ If less strict criteria are used [Li-Fraumeni-like (LFL)], TP53 mutations are found in up to 40% • Chompret criteria ○ Individual (proband) must have 1 of following tumors before age 46: Sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, adrenal cortical carcinoma, leukemia, or lung bronchoalveolar carcinoma, and – At least one 1st- or 2nd-degree relative with LFS tumor < age 56 or with multiple tumors – Breast cancer is not included if proband has breast cancer ○ Multiple tumors (not including breast cancers), 2 of which belong to LFS tumors and 1st of which occurred < age 46 ○ Adrenal cortical carcinoma or choroid plexus tumor, irrespective of family history ○ 30% of individuals fulfilling these criteria have germline TP53 mutation

Diagnostic Criteria for Lynch Syndrome • Mutations in genes coding for mismatch repair proteins (MLH1, PMS2, MSH2, MSH6) or EPCAM • Clinical features ○ Multiple epithelial cancers occur at average age of ~ 20 years younger than expected ○ Lynch-associated tumors include colorectal, endometrial, gastric, urinary tract, ovarian, and sebaceous • Several guidelines have been proposed to help identify patients who should be tested for Lynch syndrome ○ Amsterdam II criteria – ≥ 3 relatives with Lynch-associated cancer – ≥ 2 successive generations affected – ≥ 1 cancer diagnosed < age 50 – 1 affected individual should be 1st-degree relative of other 2 – Familial adenomatous polyposis must be excluded ○ Revised Bethesda guidelines 487

Overview of Syndromes: Introduction

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes – Colorectal carcinoma (CRC) diagnosed < age 50 – Presence of synchronous or metachronous CRC or other Lynch-associated tumor, regardless of age – CRC with histologic features suggestive of microsatellite instability in patient < age 60 – CRC diagnosed in ≥ 1 1st-degree relative with Lynchassociated tumor, with 1 of cancers diagnosed < age 50 – CRC diagnosed in ≥ 2 1st-degree or 2nd-degree relatives with Lynch-associated tumors, regardless of age • Sensitivity of these criteria are not optimal; hence, many recommend testing all CRCs for Lynch syndrome

4.

Future Perspectives

10.

• Progress of recent years in understanding pathogenesis of familial tumor syndromes is expected to continue ○ Understanding molecular pathogenesis may hopefully offer new insights into diagnostic and therapeutic strategies for these tumors • New hereditary syndromes continue to be identified ○ Recently, germline mutations of DICER1 have been identified in patients with rare neoplasms – DICER1 mutations were identified in patients with familial pleuropulmonary blastoma – Additional manifestations of syndrome have been identified, including cystic nephroma, medulloepithelioma, Sertoli-Leydig cell tumor, and others ○ Familial pheochromocytoma and paraganglioma (PCC/PGL) syndromes form heterogeneous group of tumors – Extensive genetic heterogeneity of these tumors came to light identification of multiple susceptibility genes – At least 13 PPC/PGL syndromes are hereditary – Mutations account for at least 30% of these tumors, highest inheritable proportion of any known human tumor • Recognizing presence of hereditary syndrome is critical for proper patient management ○ Universal testing strategies may become more common in future • Hereditary cancer syndromes in children and adolescents are also recognized in field of pediatric hematology/oncology • Now number of online resources available that provide more comprehensive information about these conditions ○ GeneTests, resource for those seeing individuals with genetic disorders: http://www. genetests.org/ • Pathologists can play crucial role; important for surgical pathologists to be aware of specific pathology findings that suggest possible tumor syndrome

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21. 22. 23.

24. 25. 26. 27. 28.

29. 30.

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Casey RT et al: Fumarate metabolic signature for the detection of Reed syndrome in humans. Clin Cancer Res. ePub, 2019 Ceolin L et al: Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocr Relat Cancer. 26(9):R499-518, 2019 de Jonge MM et al: Germline BRCA-associated endometrial carcinoma is a distinct clinicopathologic entity. Clin Cancer Res. ePub, 2019

Decmann A et al: Overview of genetically determined diseases/multiple endocrine neoplasia syndromes predisposing to endocrine tumors. Exp Suppl. 111:105-27, 2019 Foretová L et al: BAP1 syndrome - predisposition to malignant mesothelioma, skin and uveal melanoma, renal and other cancers. Klin Onkol. 32(Supplementum2):118-22, 2019 Gori S et al: Recommendations for the implementation of BRCA testing in ovarian cancer patients and their relatives. Crit Rev Oncol Hematol. 140:6772, 2019 Hamid RN et al: Hereditary tumor syndromes with skin involvement. Dermatol Clin. 37(4):607-13, 2019 Imbert-Bouteille M et al: Osteosarcoma without prior retinoblastoma related to RB1 low-penetrance germline pathogenic variants: A novel type of RB1-related hereditary predisposition syndrome? Mol Genet Genomic Med. e913, 2019 Kim JY et al: Genetic counseling and surveillance focused on Lynch syndrome. J Anus Rectum Colon. 3(2):60-8, 2019 Knabben L et al: Genetic testing in ovarian cancer - clinical impact and current practices. Horm Mol Biol Clin Investig. ePub, 2019 Lau HD et al: A clinicopathologic and molecular analysis of fumarate hydratase-deficient renal cell carcinoma in 32 patients. Am J Surg Pathol. ePub, 2019 Lopes JL et al: FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer. Cancer Genet. 235-6:57-64, 2019 Mankaney G et al: Enhancing the efficacy of colonoscopy in Lynch syndrome: the search for the holy grail continues. Gastrointest Endosc. 90(4):633-5, 2019 Nazar E et al: The emerging role of succinate dehyrogenase genes (SDHx) in tumorigenesis. Int J Hematol Oncol Stem Cell Res. 13(2):72-82, 2019 Neumann HPH et al: Comparison of pheochromocytoma-specific morbidity and mortality among adults with bilateral pheochromocytomas undergoing total adrenalectomy vs cortical-sparing adrenalectomy. JAMA Netw Open. 2(8):e198898, 2019 Ngeow J et al: PTEN in hereditary and sporadic cancer. Cold Spring Harb Perspect Med. ePub, 2019 Nishimura S et al: Feasibility of identifying patients at high risk of hereditary gastric cancer based on clinicopathological variables. Anticancer Res. 39(9):5057-64, 2019 Parsons MT et al: Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 40(9):1557-78, 2019 Piccinin C et al: An update on genetic risk assessment and prevention: the role of genetic testing panels in breast cancer. Expert Rev Anticancer Ther. 19(9):787-801, 2019 Raue F et al: Long-term outcomes and aggressiveness of hereditary medullary thyroid carcinoma: 40 years of experience at one center. J Clin Endocrinol Metab. ePub, 2019 Shindo T et al: Genomic characterization for familial cases with urothelial carcinoma. Int Cancer Conf J. 8(4):185-9, 2019 Slavin TP et al: Genetics of gastric cancer: what do we know about the genetic risks? Transl Gastroenterol Hepatol. 4:55, 2019 Terlouw D et al: Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy. Eur J Hum Genet. ePub, 2019 Tischler J et al: Cases in precision medicine: The role of tumor and germline genetic testing in breast cancer management. Ann Intern Med. ePub, 2019 Vargas SO et al: Mesenchymal hamartoma of the liver and DICER1 syndrome. N Engl J Med. 381(6):586-7, 2019 Yehia L et al: The clinical spectrum of PTEN mutations. Annu Rev Med. ePub, 2019 Cimino PJ et al: Neurofibromatosis type 1. Handb Clin Neurol. 148:799-811, 2018 Fisher MJ et al: 2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Am J Med Genet A. 176(5):1258-69, 2018 Guilmette J et al: Hereditary and familial thyroid tumours. Histopathology. 72(1):70-81, 2018 Plotkin SR et al: Neurofibromatosis and schwannomatosis. Semin Neurol. 38(1):73-85, 2018

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes

In Patient

In Patient's Family

Young age at diagnosis 

1 first-degree relative with same or related tumor and 1 of individual features listed

Association with other genetic traits

≥ 2 first-degree relatives with neoplasms in same site

Neoplasms with rare morphological features

≥ 2 first-degree relatives with neoplasms belonging to known familial cancer syndrome

Association with congenital defects

≥ 2 first-degree relatives with rare tumors

Multiple primary neoplasms within same organ

≥ 2 relatives in 2 generations with tumors of same site 

Multiple primary neoplasms within different organs and tissues Bilateral primary neoplasms in paired organs or lobes Neoplasms occurring in gender that is not usually affected

Overview of Syndromes: Introduction

General Features Suggesting Presence of Familial Cancer Syndrome

Association with inherited precursor lesion Association with cutaneous lesions known to be related to cancer susceptibility disorders

Known Hereditary Cancer Syndromes Syndrome

Gene(s)

Inheritance Pattern

Characteristic Tumor Spectrum

Familial adenomatous polyposis (FAP)/Gardner

APC

Autosomal dominant

Colorectal adenomas and cancer, duodenal adenomas and cancer, papillary thyroid cancer

Attenuated FAP (AFAP)

APC

Autosomal dominant

Colorectal adenomas and cancer, duodenal adenomas and cancer, papillary thyroid cancer

MUTYH-associated polyposis (MAP) MUTYH  

Autosomal recessive

Colorectal adenomas and cancer, duodenal adenomas and cancer, papillary thyroid cancer

 Juvenile polyposis (JPS)

BMPR1A, SMAD4

Autosomal dominant

 Juvenile-type hamartomatous polyps, colorectal cancer

Polymerase proofreadingassociated polyposis (PPAP)

POLD1, POLE

Autosomal dominant

Colorectal adenomas and cancer, endometrial cancer

Peutz-Jeghers (PJS)

STK11

Autosomal dominant

Hamartomatous (PJS-type) polyps, colorectal cancer, gastric cancer, pancreatic cancer, small bowel cancer, breast cancer

Hereditary mixed polyposis (HMPS) GREM1

Autosomal dominant

Adenomatous polyps, hyperplastic polyps, hamartomatous polyps, colorectal cancer

Serrated polyposis (SPS)

RNF43, others

Autosomal dominant*

Serrated colon polyps, colorectal cancer

Lynch syndrome

MLH1, MSH2, MSH6, PMS2, EPCAM

Autosomal dominant

Colorectal cancer, endometrial cancer, gastric cancer, urinary tract tumors, ovarian cancer, sebaceous skin tumors

Li-Fraumeni (LFS)

TP53

Autosomal dominant

Breast cancer, colon cancer, soft tissue sarcoma, osteosarcoma, brain tumors, leukemias, adrenocortical tumors, colorectal cancer, renal cancer,  pancreatic cancer

Hereditary diffuse gastric cancer (HDGC)

CDH1

Autosomal dominant

Diffuse gastric cancer, lobular breast cancer

Hereditary breast and ovarian cancer (HBOC)

BRCA1, BRCA2, PALB2

Autosomal dominant

Breast cancer, ovarian cancer, prostate cancer, pancreatic cancer

von Hippel-Lindau (VHL)

VHL

Autosomal dominant

Pheochromocytoma, paraganglioma, hemangioblastoma, clear cell renal cancer

Multiple endocrine neoplasia type 1 MEN1 (MEN1)

Autosomal dominant

Parathyroid adenomas, pituitary adenomas, pancreatic neuroendocrine tumors

Multiple endocrine neoplasia type 2A (MEN2A)

RET

Autosomal dominant

Medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia

Multiple endocrine neoplasia type 2B (MEN2B)

RET

Autosomal dominant

Medullary thyroid cancer, pheochromocytoma, mucosal neuromas

Familial atypical mole and melanoma (FAMM)

CDKN2A

Autosomal dominant

Melanoma, pancreatic cancer

Nevoid basal cell carcinoma/Gorlin

PTCH1

Autosomal dominant

Basal cell carcinomas, odontogenic keratocysts, medulloblastoma

489

Overview of Syndromes: Introduction

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes

490

Known Hereditary Cancer Syndromes (Continued) Syndrome

Gene(s)

Inheritance Pattern

Characteristic Tumor Spectrum

Familial paraganglioma

SDHA (PGL5) SDHB (PGL4 most common) SDHC (PGL3) SDHD (PGL1) SDHAF2 (PGL2)

Autosomal dominant

Paraganglioma

Succinate dehydrogenase (SDH)deficient renal cell carcinoma

SDHA (PGL5) SDHB (PGL4 most common) SDHC (PGL3) SDHD (PGL1) SDHAF2 (PGL2)

Autosomal dominant

Development of RCC frequently preceded by extrarenal manifestations: Paragangliomas, pheochromocytomas, carotid body tumors, gastrointestinal stromal tumors

Neurofibromatosis type 1 (NF1)/von Recklinghausen disease

NF1

Autosomal dominant

Café au lait macules, neurofibromas

Neurofibromatosis type 2 (NF2)

NF2

Autosomal dominant

Vestibular schwannomas, meningiomas

Hereditary retinoblastoma

RB1

Autosomal dominant

Retinoblastomas, pineoblastoma, osteosarcoma, sarcoma, melanoma

DICER1 syndrome

DICER1

Autosomal dominant

Pleuropulmonary blastoma, pediatric cystic nephroma, multinodular hyperplasia, thyroid carcinoma, Sertoli-Leydig cell tumor, gynandroblastoma, Juvenile granulosa cell tumor, pituitary blastoma

BAP1 tumor predisposition syndrome

BAP1

Autosomal dominant

Uveal melanoma (31%), malignant mesothelioma (22%), BAP1-inactivated melanocytic tumor (18%), cutaneous melanoma (13%), and renal cell carcinoma (10%)

Ataxia-telangiectasia

ATM

Autosomal recessive

Characterized by cerebellar ataxia, immunodeficiency, oculocutaneous telangiectasia, respiratory failure, and increased risk of malignancies: T-cell and B-cell lineage; myeloid leukemia; ovarian carcinoma, breast carcinoma, thyroid carcinoma, salivary gland tumors, gastric carcinoma, melanoma, and leiomyomas/leiomyosarcomas 

Carney complex

PRKAR1A

Autosomal dominant

Atrial myxoma, pigmented epithelioid melanocytoma, PPNAD, large-cell calcifying Sertoli cell tumor, pituitary adenoma, psammomatous melanotic schwannoma, thyroid carcinoma

Cowden disease and BannayanRuvalcaba-Riley syndrome  (PTENhamartoma tumor syndromes)

PTEN

Autosomal dominant

Breast cancer, thyroid cancer, endometrial cancer, hamartomatous polyps

Rhabdoid predisposition syndrome

INI1 (SMARCB1, hSNF5, BAF47)

Autosomal dominant

Genetic predisposition for development of rhabdoid tumors [atypical teratoid/rhabdoid tumor (AT/RT)] of brain, renal rhabdoid tumors, and extrarenal rhabdoid tumors

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes

Carney Complex (Left) Patients with multiple endocrine neoplasia 2B (MEN2B) develop medullary thyroid carcinoma ﬇, pheochromocytoma, and present with multiple neuromas of the tongue and lips st. (Right) Mucocutaneous involvement in Carney complex is extensive and includes the characteristic pigmented skin lesions around the eye and in the inner canthus ﬈. (Courtesy J. Carney, MD, PhD.)

Multiple Endocrine Neoplasia 2B

Overview of Syndromes: Introduction

Multiple Endocrine Neoplasia 2B

Carney Complex Pigmented Lesions (Left) Patients with MEN2B may present with multiple neuromas of the tongue st and lip &/or pigmented skin lesions ﬉. (Right) Pigmented skin lesions are present in Carney complex and also in McCune-Albright, PeutzJeghers, Birt-Hogg-Dubé, neurofibromatosis, and PTENhamartoma tumor syndromes. (Courtesy J. Carney, MD, PhD.)

Multiple Endocrine Neoplasia 2B

Multiple Basal Cell Carcinomas (Left) Patients with multiple endocrine neoplasia 2B (MEN2B) develop medullary thyroid carcinoma, pheochromocytoma, and present with multiple neuromas of the tongue &/or ganglioneuromatosis of the intestine, a marfanoid habitus, &/or medullated corneal nerve fibers. (Right) Clinical photo shows multiple basal cell carcinomas ﬈ in a patient with NBCCS. These skin lesions are a major component of the syndrome. Treatment of multiple BCC all over the body can lead to considerable cosmetic disfigurement.

491

Overview of Syndromes: Introduction

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes

McCune-Albright Syndrome

Neurofibromatosis Type 2

Hereditary Retinoblastoma

von Hippel-Lindau Syndrome

NBCC Syndrome-Associated Odontogenic Keratocysts

Hyperparathyroidism-Jaw Tumor Syndrome

(Left) McCune-Albright syndrome consists of a triad of polyostotic fibrous dysplasia, pigmented skin lesions, and sexual precocity. These patients may develop hyperplasia and adenomas of endocrine glands. (Right) Bilateral vestibular schwannomas involving the vestibular branch of CN VIII are pathognomonic of NF2. They present as a cerebellopontine angle mass ﬊ and may be multiple ﬈.

(Left) Axial graphic shows retinoblastoma with lobulated tumor extending through the limiting membrane into the vitreous. (Right) The presence of multiple lesions, including multiple and bilateral tumors, is a characteristic feature of inherited tumor syndromes. Graphic of abdominal lesions seen in patients with VHL shows bilateral multiple renal cysts ﬉, renal tumors st, pancreatic cysts ﬈, and adrenal pheochromocytoma ſt.

(Left) Lateral graphic with outer mandibular cortex removed shows the classic appearance of multiple OKCs in nevoid basal cell carcinoma syndrome (NBCCS). Lesions splay teeth roots and displace the inferior alveolar nerve. Tooth resorption is not a common finding. (Right) Nonossifying fibroma shows a large, well-demarcated maxillary mass with mixed calcification and fibrosis. Note that the mass obstructs 1 side of the nose and compresses the eye in this case of hyperparathyroidism-jaw tumor syndrome.

492

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes Pediatric Cystic Nephroma in DICER1 Syndrome (Left) A large, solid and cystic mass was discovered in a child with DICER1 syndrome. This tumor is best classified as type II PPB, which typically occur in children between 18 months and 6 years of age. It retains a grossly visible cystic component and also presents solid components. (Right) This large, multicystic mass in a child was the 1st finding in diagnosing DICER1 syndrome. Pediatric cystic nephroma commonly presents in the first 4 years of life.

Hyperparathyroidism-Jaw Tumor Syndrome

Overview of Syndromes: Introduction

Pleuropulmonary Blastoma in DICER1 Syndrome

VHL-Associated Pancreatic Cystadenoma (Left) Axial bone CT shows a large, well-demarcated left maxillary ossifying fibroma with mixed calcific and soft tissue density components in a patient with hyperparathyroidism-jaw tumor syndrome. (Right) Normal architecture is diffusely replaced by variably sized, thin-walled cysts in this patient with von Hippel-Lindau disease. The presence of multiple cysts and tumors in other organs is also characteristic of this disorder.

Familial Adenomatous PolyposisAssociated Polyps

Carney Complex-Associated Adrenal PPNAD (Left) Gross photo of the colon from a patient with familial adenomatous polyposis (FAP) shows hundreds of small and large, sessile polyps carpeting the mucosal surface. This extent of polyposis is characteristic of classic FAP. (Right) Characteristic small, black-brown and yellow nodules occupying the entire cortical area are shown in this case of primary pigmented nodular adrenocortical disease (PPNAD) associated with Carney complex.

493

Overview of Syndromes: Introduction

Molecular Aspects of Familial/Hereditary Tumor Syndromes

OVERVIEW OF HEREDITARY CANCER Hereditary • ~ 90% of cancer in adults is sporadic and attributed to unrepaired damage to genome caused by environmental exposures, diet, aging, or other influences • ~ 10% of cancer develops in setting of hereditary predisposition and are largely caused by inherited genetic variant in genes that predispose to familial cancer syndromes ○ > 50 Mendelian hereditary cancer syndromes with very high risk of cancer ○ > 100 Mendelian hereditary cancer syndromes with predisposition to cancer • Proportion of cancer cases with hereditary background is steadily increasing • Familial refers to occurrence of cancer (i.e., phenotype) with greater frequencies in families than in general population • "Familial" and "hereditary" are frequently used synonymously

• Occurrence patterns that raise likelihood of familial cancer syndrome ○ Many cases of same type of cancer ○ Cancer occurring at younger age than usual ○ > 1 type of cancer in single person ○ Cancer occurring in both pairs of organ (e.g., both breasts; bilateral distribution) ○ > 1 childhood cancer in siblings ○ Cancer occurring in sex not usually affected (e.g., breast cancer in men) ○ Cancer occurring in many generations • Germline mutation is another way to refer to inherited mutation because these mutations occur in specialized tissues that give rise to germ/sex cells (i.e., sperm or oocytes) and can be transmitted to next generation

Family History • Can help identify individuals at risk for developing cancer

Analysis of Genes and Cancer

Chart shows association of phenotypes with gene, knowledge of gene and disease-specific properties, frequency of variant in the general population, evidence of co-segregation in affected individuals, review of variant, published evidence in model experimental systems, predicted functional effect on protein, and assessing if variant satisfies indication for testing.

494

Molecular Aspects of Familial/Hereditary Tumor Syndromes

GENETICS OF FAMILIAL CANCER

• In AD diseases, risk is increased when 1 pathogenic allele is inherited • Autosomal recessive (AR) inheritance occurs when pathogenic variant is present in both copies of gene (i.e., individual is homozygous for pathogenic variant) • Pathogenic variant present in each gene is not necessarily same variant, and this situation is referred to as compound heterozygosity • In AR disease, 2 pathogenic alleles must be inherited for increased risk of disease

Germline vs. Somatic Variants

Loss of Heterozygosity

• Most germline variants are present in 100% of cells, including both nonmalignant and tumor cells leading to allelic fractions of 0.5 or 1.0 in both tissue components • Somatic variants are acquired after birth and result from either errors in DNA repair or replication, and allelic fractions in tumors are usually < 0.5 due to presence of nonmalignant tissue within tumor • Familial cancer syndromes often present and first come to clinical attention as primary tumor in some families ○ In these instances, genetic analysis of tumor often identifies several pathogenic variants, including variants in known familial cancer syndrome genes (e.g., BRCA1 or TP53) • Laboratories must correctly distinguish somatic variants from germline variants in cancer patients due to serious clinical consequences for patient • Sequencing DNA from patient's paired normal tissue is ideal way to determine if variant is germline, as it will be detected in both tumor and normal tissue, whereas somatic variants will not be detected in normal tissue • Clinical features can also be used to help determine whether origin of variants is germline or somatic

• Represents "2nd hit" of remaining functional allele in patients who inherited defective familial cancer gene • Occurs by interstitial deletion, mitotic recombination, or nondisjunction of remaining functional allele leading its deletion &/or functional inactivation • Represents most common mechanism by which remaining functional allele is disrupted • Alternative mechanisms include somatic mutation or epigenetic alteration of functional allele as 2nd hit • Tumor suppressor genes are frequently inactivated by in familial cancer syndromes

Allele • Humans have 2 copies of each genes at same locus because we inherit 1 copy from each parent ○ Each copy differs in sequence &/or structure and are considered variants of each other • Allele is used to distinguish variant forms of gene, and, accordingly, individuals inherit 2 alleles of each gene ○ Consequently, men have only 1 copy (and therefore 1 allele) of genes on their X and Y chromosomes • Alleles of same gene may be fully functional, completely defective, or functional at some level between these extremes

Variant • "Variant" should be used in place of mutation and polymorphism • "Mutation" and "polymorphism" often lead to confusion because of incorrect assumptions of pathogenic and benign effects, respectively ○ Mutation is permanent change in nucleotide sequence ○ Polymorphism is variant with frequency > 1% in population

Inheritance Patterns • Autosomal dominance (AD) inheritance occurs when pathogenic variant is present in 1 copy of familial cancerassociated gene (i.e., individual is heterozygous for pathogenic variant)

Overview of Syndromes: Introduction

• 1st-degree relatives include individual's parents, children, and brothers and sisters, including half-brothers and halfsisters • 2nd-degree relatives include grandparents, aunts and uncles, nieces and nephews, and grandchildren • 3rd-degree relatives include first cousins, greatgrandparents, great aunts and uncles, and great grandchildren

GENETIC VARIANTS Simple Variants • One nucleotide of DNA code substituted by another • Deletion (del) is when 1 or more nucleotides are deleted (missing) • Duplication (dup) is when 1 or more nucleotides are duplicated (repeated) • Insertion (ins) is when 1 or more new nucleotides are present • Insertion/deletion (indel) is when 1 or more nucleotides are missing and replaced by several new nucleotides

Complex Variants • Copy number variants (CNV) ○ Defined as segment of DNA, at least 1 kb in size, that differs in copy number compared with representative reference genome ○ Losses or gains of chromosomal material alter gene function or expression and underlie disease phenotype ○ Chromosomal areas that house CNVs may include both coding and noncoding regions ○ May affect up to 12% of human genome ○ Both global and targeted approaches for CNV are performed in diagnostic laboratory ○ Assessment of CNVs often takes form of genome-wide scan, e.g., using microarray or karyotype analysis ○ Targeted CNV analysis is also used since particular variants are associated with specific conditions ○ Targeted approaches include qPCR and MLPA and are used for CNV detection in given region of interest ○ Array-based methods are being challenged by NGS technology since NGS permits detection of CNV as well as SNV and indels ○ CNV analysis is frequently performed in parallel to sequence analysis for many familial cancer genes, for example BRCA1, BRCA2, and EPCAM • Structural variants (SV) 495

Overview of Syndromes: Introduction

Molecular Aspects of Familial/Hereditary Tumor Syndromes ○ Complex genetic alteration characterized by chromosomal breakage events followed by reattachment of broken ends to different chromosomal positions ○ Translocations and inversions are 2 examples of SV ○ Can be either balanced or unbalanced – Balanced SV indicates that individual's set of chromosome has normal complement of chromosomal material □ Balanced rearrangements usually do not have associated phenotype because all chromosomal material is present – Unbalanced SV indicates additional or missing chromosomal material in patient's set of chromosomes and are more likely associated with phenotype ○ Inversions describe chromosome that breaks twice and then reconstitutes itself with inversion of intervening segment – Pericentric inversions involve centromere – Paracentric inversions are breaks on 1 arm of chromosome – Small paracentric inversion of exons 1-7 of MSH2 is cause of unexplained Lynch syndrome ○ Translocations involve exchange of chromosome segments between 2 nonhomologous chromosomes ○ Translocations are either reciprocal when broken ends are exchanged between 2 nonhomologous chromosomes or Robertsonian when translocation involves 2 acrocentric chromosomes

CLINICAL TESTING OF GENETIC VARIANTS Mutation Testing Has Major Impact for Patients • • • •

Access to genetic counseling Increases chance of survival Defines prognosis of carriers Identifies most appropriate prophylactic options

Patients Generally Referred for Genetic Carrier Screening Through Various Channels • Strong personal or family history • Molecular profiling of malignant cells uncovers germline variant

Site-Specific Testing • With strong family history or phenotype, single gene is analyzed for pathogenic variant • When pathogenic variant has been identified in family, addition family members are typically tested for only variant that was found • Site-specific testing will miss pathogenic variants present in genes that are not analyzed • Site-specific testing typically utilizes older sequencing technology (i.e., Sanger or dideoxy sequencing), and these tests are relatively expensive

Multigene Panels • Next-generation sequencing (NGS) technology permits simultaneous testing of large set of genes (i.e., multiplex gene panels) associated with familiar cancer phenotype

496

• Patients with personal or family history suggesting single familial cancer syndrome are most appropriately managed by test for that specific syndrome • Expanded, multiplex gene panels are useful when > 1 gene can explain familial cancer syndrome, or as cost-effective and efficient testing strategy • Both content and interpretation of gene panels provided by clinical labs differs, and selecting appropriate panel is important • Most gene panels include both high-risk genes and moderate-risk genes • For moderate-risk genes, there is often limited clinical data &/or no clear guidelines to manage cancer risk • Consequently, not all genes included on multiplex gene panels are clinically actionable, and risk management may not be influenced by results of genetic testing • At present, most commercial labs offer multiplex gene panels that include 15-30 genes on average • Number of genes on multiplex panels continues to grow as clinical knowledge and evidence accumulates

Testing Considerations • Diagnostic performance of multigene panels is roughly 9% in subjects referred for testing • NGS technology is generally suitable for identifying variants that affect 20 or fewer nucleotides ○ Larger variants are at significant risk of not being detected by NGS, and alternative assays need to be used for their identification • Variant detection in some genes, e.g., PMS2 and CHEK2, can be difficult  ○ Reasons include GC-rich areas, pseudogenes, and others ○ Alternative custom analytical workflows are utilized in these instances • Complex genetic variants > 20-30 nucleotides, including genomic rearrangements, are not detected by NGS testing and require supplemental analysis • Since CNV can be difficult to detect using NGS, large-scale genomic alterations are interrogated by microarray in parallel with NGS testing • Confirmation studies using orthogonal method are often performed when sequence variants considered pathogenic or likely pathogenic for familial cancer or syndrome are identified

CLINICAL REPORTING OF GENETIC VARIANTS Overview • Important clinical decisions are based upon findings of genetic testing • Critical that genetic variants are accurately annotated and described • Variants are initially identified by comparing sequencing data obtained from patient sample with reference sequence considered "normal" • All variants are described at DNA level in variant table ○ Size and complexity of variant table is directly related to portion of genome targeted by panel • Variant list is then analyzed and interpreted for clinical significance

Molecular Aspects of Familial/Hereditary Tumor Syndromes

• NCBI Reference Sequence (RefSeq) database is source of annotated and assembled genomic DNA, RNA transcripts, and protein sequences • Sequences relating to genes, transcripts, and proteins are accessioned in RefSeq with 2 characters followed by underscore and their accession number and version number • RefSeq serves as stable reference genome used internationally for precisely identifying and describing genomic variants • RefSeq is continuously updated and annotated to incorporate newly available data

Describing Genetic Variants • Human Genome Variation Society (HGVS) provides recommendations for designating and describing genetic variants • Letter prefix is mandatory to indicate type of reference sequence used • Variant positions should be numbered and described at DNA level using cDNA coordinates defined according to longest known transcript &/or most clinically relevant transcript to allow functional interpretation [e.g., c.1673G>C (NM_007300.4)] • Coding or protein nomenclature is provided to allow functional interpretation (e.g., Trp557Phe) • Only approved HGNC gene symbols should be used to describe genes

SELECTED REFERENCES 1.

2.

3.

4.

5.

6. 7. 8.

9. 10.

11.

12. 13.

Variant Interpretation and Classification

14.

• Clinical report lists variants described using HGVS nomenclature with following modifiers ○ Pathogenic ○ Likely pathogenic ○ Uncertain significance ○ Likely benign ○ Benign • Variant classification should contain evidence supporting variant classification ○ Prevalence of disease phenotypes associated with constituent gene on panel ○ Precurated knowledge of gene and disease-specific properties, including allelic and loss of heterozygosity ○ Frequency of variant in general (unaffected) population using data from Exome Aggregation Consortium (ExAC), Exome Variant Server (EVS), dbSNP, 1,000 genomes, and available literature ○ Evidence of cosegregation in affected individuals ○ Review of published content in variant databases (e.g., HGMD, ClinVar, OMIM, Breast Cancer Information Core, BRCA Share, and InSiGHT) ○ Published evidence in model experimental systems linking variant to mechanisms of disease ○ Predicted functional effect on resultant protein ○ Assessing whether identified variant(s) fully or partially explains  indication for testing • Recommendations to clinician for supplemental clinical testing ○ Variant testing of family members

15. 16.

17.

18.

19.

Gardner SA et al: Evaluation of a 27-gene inherited cancer panel across 630 consecutive patients referred for testing in a clinical diagnostic laboratory. Hered Cancer Clin Pract. 16:1, 2018 Kurian AW et al: Uptake, results, and outcomes of germline multiple-gene sequencing after diagnosis of breast cancer. JAMA Oncol. 4(8):1066-72, 2018 Manchanda R et al: Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women. J Natl Cancer Inst. 110(7):714-25, 2018 Li MM et al: Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 19(1):4-23, 2017 Blazer KR et al: Increased reach of genetic cancer risk assessment as a tool for precision management of hereditary breast cancer. JAMA Oncol. 2(6):723-4, 2016 den Dunnen JT et al: HGVS Recommendations for the description of sequence variants: 2016 Update. Hum Mutat. 37(6):564-9, 2016 Hall MJ et al: Multigene panels to evaluate hereditary cancer risk: Reckless or relevant? J Clin Oncol. 34(34):4186-7, 2016 Susswein LR et al: Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 18(8):823-32, 2016 Tung N et al: Counselling framework for moderate-penetrance cancersusceptibility mutations. Nat Rev Clin Oncol. 13(9):581-8, 2016 van Marcke C et al: Routine use of gene panel testing in hereditary breast cancer should be performed with caution. Crit Rev Oncol Hematol. 108:33-9, 2016 Desmond A et al: Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol. 1(7):94351, 2015 Hall MJ et al: Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw. 12(9):1339-46, 2014 Kurian AW et al: Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 32(19):2001-9, 2014 Rainville IR et al: Next-generation sequencing for inherited breast cancer risk: counseling through the complexity. Curr Oncol Rep. 16(3):371, 2014 Bombard Y et al: Translating genomics in cancer care. J Natl Compr Canc Netw. 11(11):1343-53, 2013 Walsh T et al: Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. 107(28):12629-33, 2010 Chibon F et al: Contribution of PTEN large rearrangements in Cowden disease: a multiplex amplifiable probe hybridisation (MAPH) screening approach. J Med Genet. 45(10):657-65, 2008 Palma MD et al: The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res. 68(17):7006-14, 2008 Walsh T et al: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 295(12):1379-88, 2006

Overview of Syndromes: Introduction

Reference Sequences

497

Overview of Syndromes: Introduction

Molecular Aspects of Familial/Hereditary Tumor Syndromes Hereditary Cancer Syndromes with Autosomal Dominant Inheritance and High Penetrance Syndrome

Gene(s)

Associated Cancers

Breast/ovarian

BRCA1, BRCA2

Breast, ovary, colon, prostate, pancreatic, gallbladder, bile duct, gastric, melanoma

Cowden disease/PTEN-hamartoma tumor syndrome

PTEN

Breast, thyroid, renal cell, uterine fibroid

Familial adenomatous polyposis (Gardner syndrome, Turcot syndrome)

APC

Colon, sebaceous carcinoma, medulloblastoma

Li-Fraumeni syndrome

TP53

Osteosarcoma, sarcoma, breast, brain, adrenocortical carcinoma, acute leukemia

Familial melanoma

CMM1, CDK4, CDKN2A

Melanoma

Lynch syndrome

MLH1, MSH2, MSH6, PMS2, EPCAM

Colon, endometrial, stomach, small intestine, ureter, renal, ovary

Multiple endocrine neoplasia, type 1

MEN1

Parathyroid, pituitary, pancreas

Multiple endocrine neoplasia, type 2

RET

Medullary thyroid carcinoma, pheochromocytoma, parathyroid

Neurofibromatosis, type 1

NF1

Café au lait spots, optic glioma, neurofibrosarcoma, astrocytoma

Neurofibromatosis, type 2

NF2

Spine and skin tumors

Nevoid basal cell carcinoma syndrome

PTC

Basal cell carcinoma, ovarian fibroma, gastric hamartomas

Peutz-Jeghers syndrome

STK11

Gastrointestinal hamartomas, colon, breast, pancreas, uterine, ovary

Familial retinoblastoma

RB1

Retinal tumors, osteosarcomas, Ewing sarcoma, leukemia, lymphoma

von Hippel-Lindau syndrome

VHL1

Clear cell renal carcinoma, pheochromocytoma, retinal angioma, pancreas

Wilms tumor

WT1

Wilms tumor

Selected Genes With Guidelines For Management

498

Gene(s)

Breast Cancer Risk

Ovarian Cancer Risk

Other Cancer Risk

ATM1

Increased

Potential

Unknown/insufficient evidence

APC

Unknown/insufficient evidence

Unknown

Colon

BARD1

Potential

Unknown/insufficient evidence

Unknown/insufficient evidence

BMPR1

Unknown/insufficient evidence

Unknown/insufficient evidence

Gastrointestinal

BRCA1

Increased

Increased

Prostate

BRCA21

Increased

Increased

Pancreas, prostate, melanoma

BRIP11

Unknown/insufficient evidence

Increased

Unknown/insufficient evidence

CDH1

Increased

None

Diffuse gastric cancer

CHEK2

Increased

None

Colon

MLH1, MSH2, MSH6, PMS2, EPCAM

Unknown/insufficient evidence

Increased

Colon, endometrial, others

NBN1

Increased

Unknown/insufficient evidence

Unknown/insufficient evidence

NF1

Increased

None

GIST, MPNST

PALB21

Increased

Unknown/insufficient evidence

Unknown/insufficient evidence

PTEN

Increased

None

Breast, thyroid, renal cell, uterine fibroid (Cowden syndrome)

RAD51C1

Unknown/insufficient evidence

Increased

Unknown/insufficient evidence

RAD51D

Unknown/insufficient evidence

Increased

Unknown/insufficient evidence

STK11

Increased

Increased (nonepithelial ovarian cancer)

Gastrointestinal hamartomas, colon, breast, pancreas, uterine, ovary (Peutz-Jeghers syndrome)

Molecular Aspects of Familial/Hereditary Tumor Syndromes

Gene(s)

Breast Cancer Risk

Ovarian Cancer Risk

Other Cancer Risk

TP53

Increased

None

Osteosarcoma, sarcoma, breast, brain, adrenocortical carcinoma, acute leukemia (Li-Fraumeni syndrome)

GIST = gastrointestinal stromal tumor; MPNST = malignant peripheral nerve sheath tumor. These genes are also associated with autosomal recessive conditions: Ataxia-telangiectasia (ATM); Fanconi anemia (BRCA2, BRIP1, PALB2, RAD51C ); Nijmegen breakage syndrome (NBN).

Reference Sequence Types Source

Sequence

Comment

DNA

g. = linear genomic reference sequence m. = mitochondrial reference (special case of circular genomic reference sequence) c. = coding DNA reference sequence (based on protein coding transcript) n. = non-coding DNA reference sequence

Preferred human mtDNA reference sequence is Homo sapiens mitochondrion, complete genome (GenBank NC_012920.1) Coding DNA reference sequence should be complete, cover major and largest transcript known, and include as many exons as possible, even when this transcript has not been proven to actually exist in nature Refers to transcript not coding for protein

RNA

r. = RNA reference sequence

Nucleotide numbering for RNA reference sequencing follows that of associated coding or non-coding DNA reference sequence, e.g., nucleotide r.123 relates to c.123 or n.123

Protein

p. = protein reference sequence

Overview of Syndromes: Introduction

Selected Genes With Guidelines For Management (Continued)

499

PART II SECTION 2

Syndromes Ataxia Telangiectasia BAP1 Tumor Predisposition Syndrome Basal Cell Nevus Syndrome/Gorlin Syndrome Beckwith-Wiedemann Syndrome Birt-Hogg-Dubé Syndrome Bloom Syndrome Brooke-Spiegler Syndrome Carney Complex Colonic Carcinoma Syndromes Costello Syndrome Denys-Drash Syndrome Diamond-Blackfan Anemia DICER1 Syndrome Down Syndrome Dyskeratosis Congenita Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome Familial Adenomatous Polyposis Familial Chordoma Familial Gastrointestinal Stromal Tumor Familial Infantile Myofibromatosis Familial Isolated Hyperparathyroidism Familial Nonmedullary Thyroid Carcinoma Familial Paraganglioma Pheochromocytoma Syndrome Familial Testicular Tumor Familial Uveal Melanoma Familial Wilms Tumor Fanconi Anemia Glucagon Cell Hyperplasia and Neoplasia Breast/Ovarian Cancer Syndrome: BRCA1 Breast/Ovarian Cancer Syndrome: BRCA2 Hereditary Diffuse Gastric Cancer Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Hereditary Mixed Polyposis Syndrome Multiple Osteochondromas Hereditary Neuroblastoma Hereditary Pancreatic Cancer Syndrome Hereditary Papillary Renal Cell Carcinoma Hereditary Paraganglioma/Pheochromocytoma Syndromes Hereditary Prostate Cancer Hereditary Renal Epithelial Tumors, Others Hereditary Retinoblastoma Hereditary SWI/SNF Complex Deficiency Syndromes

502 504 506 510 518 522 524 528 536 540 542 546 548 556 560 564 568 576 578 584 586 590 596 600 602 604 606 608 610 616 620 624 628 630 632 636 640 642 650 652 656 658

Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer Hyperparathyroidism-Jaw Tumor Syndrome Juvenile Polyposis Syndrome Li-Fraumeni Syndrome Lynch Syndrome McCune-Albright Syndrome Melanoma/Pancreatic Carcinoma Syndrome Multiple Endocrine Neoplasia Type 1 (MEN1) Multiple Endocrine Neoplasia Type 2 (MEN2) Multiple Endocrine Neoplasia Type 4 (MEN4) MUTYH-Associated Polyposis Neurofibromatosis Type 1 Neurofibromatosis Type 2 Nijmegen Breakage Syndrome Pancreatic Neuroendocrine Tumor Syndromes Hamartomatous Polyps, Peutz-Jeghers PTEN-Hamartoma Tumor Syndromes RASopathies: Noonan Syndrome Rhabdoid Predisposition Syndrome Schwannomatosis Shwachman-Diamond Syndrome Steatocystoma Multiplex Tuberous Sclerosis Complex Tumor Syndromes Predisposing to Osteosarcoma von Hippel-Lindau Syndrome Werner Syndrome/Progeria Wilms Tumor-Associated Syndromes Wiskott-Aldrich Syndrome Xeroderma Pigmentosum

660 662 668 674 680 686 692 696 704 712 718 720 728 734 736 744 750 758 762 766 770 772 774 780 782 790 794 796 798

Overview of Syndromes: Syndromes

Ataxia Telangiectasia

TERMINOLOGY

GENETICS

Abbreviations

Autosomal Recessive Disease

• Ataxia-telangiectasia (AT)

• Caused by germline inactivation of ataxia-telangiectasiamutated (ATM) gene • Chromosomal region 11q22-23 • Encodes for ~ 300 kDa serine/threonine protein kinase with sequence homology to PI3K family ○ Predominantly nuclear protein ○ Major function is regulation of DNA repair secondary to double-strand DNA breaks ○ Normally in form of inactive dimers ○ Activated ATM protein monomers recruited to areas of DNA damage ○ MRN (MRE11A/RAD50/NBS1) complex required for optimal activation of ATM in areas of double-stranded DNA breaks ○ Several protein kinases (e.g., CHK2) and p53 key substrates phosphorylated by ATM ○ Other functions include regulation of cell cycle, apoptosis, telomere maintenance, response to oxidative stress, mitochondrial homeostasis, insulin signaling • In classic AT, ATM is almost completely absent secondary to severe/truncating mutations

Definitions • Autosomal recessive multisystem disorder with severe neurological involvement • Neurodegenerative and multisystem disease, characterized by cerebellar ataxia, immunodeficiency, oculocutaneous telangiectasia, respiratory failure, and increased risk of malignancies

EPIDEMIOLOGY Incidence • 1 per 40,000-100,000 • Occurs in all geographic regions with variable local prevalence

Sex • M=F

CLINICAL IMPLICATIONS Clinical Presentation • Ataxia of gait, stance, and trunk most frequent ○ Progresses to affect extremities and eye movements • Dysarthria • Late cerebellar tremor in variant AT rather than profound ataxia • Some patients with variant AT present with milder phenotypes

Imaging Findings • Atrophy of cerebellar vermis and hemispheres in older children (not evident in early childhood)

Heterozygous Carriers of ATM Mutations Predisposed to Cancers • Contribute to small subset of familial breast and ovarian cancer ○ Germline pathogenetic variants in up to 3% of families with hereditary breast and ovarian cancer ○ Breast tumors mostly of luminal B subtype

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Hypersensitivity to Ionizing Radiation • Most characteristic biologic feature

↑ α-Fetoprotein in Serum • Useful biomarker Cerebellar Atrophy in AtaxiaTelangiectasia (Left) Cerebellar atrophy is a hallmark of ataxiatelangiectasia, particularly in the vermis ſt. However, this may not be evident on MR until late childhood. (Right) This diffuse large B-cell lymphoma developed in an ataxia-telangiectasia patient. Ataxia-telangiectasia patients have an increased predisposition to various cancers, particularly of B- and T-cell lineage.

502

Diffuse Large B-Cell Lymphoma in AtaxiaTelangiectasia

Ataxia Telangiectasia

Early Diagnosis • Allows genetic counseling and avoidance of extended medical work-ups

NONNEOPLASTIC MANIFESTATIONS Central Nervous System Degeneration • Progressive ataxia starts early (6-18 months of age) ○ Wheelchair bound by 1st decade of life ○ Cerebellar atrophy, particularly vermis ○ Extensive Purkinje and granule cell loss ○ Cell loss in inferior olives (retrograde) ○ Ectopic Purkinje cells may be found in molecular layer ○ Peripheral nervous system may also be affected and contribute to symptoms • Mental deficiency • Posterior spinal column dysfunction

Skin and Eye

• Ovarian carcinoma, breast carcinoma, thyroid carcinoma, salivary gland tumors, gastric carcinoma, melanoma, and leiomyomas/leiomyosarcomas may develop

CANCER RISK MANAGEMENT Lifetime Cancer Risk • AT patients have risk between 10-38% of developing at least 1 malignancy during their life • Patients with variant AT are at increased risk of developing cancer, mainly solid tumors • Avoid x-ray-based tests if possible, given characteristic radiosensitivity of AT

DIFFERENTIAL DIAGNOSIS Ataxia-Telangiectasia-Like Disorder • Usually caused by hypomorphic mutations in ATM or mutations in genes encoding related proteins (e.g., MRE11A) ○ Missense or splice site rather than truncating mutations in ATM more common than in classic AT ○ Milder phenotype

• Telangiectasias ○ Involve bulbar conjunctivae and eventually bridge of nose ○ Appear between 2-8 years of age • Seborrheic dermatitis common • Cutaneous granulomas • Café au lait spots • Gray hair, skin atrophy

Nijmegen Breakage Syndrome

Deficiency of Cellular Immunity

Disorders Associated With Defects in DNA SingleStrand Break Repair

• Hypoplasia of thymus, tonsil, and adenoids • Lymphopenia • ↓ IgA, IgE, IgG2

Respiratory Infections and Bronchiectasis • Important cause of death in AT in addition to cancer

Endocrine Abnormalities • Hypogonadism/infertility • Insulin resistance/type 2 diabetes • ~ 3/4 of children with classic AT suffer from growth restriction ○ Poor nutritional status and abnormal insulin-like growth factor 1 secretion, possibly caused by pituitary abnormalities, seem to be important causative factors ○ Short stature • Patients with variant AT seem to have normal height, weight, and pubertal development

ASSOCIATED NEOPLASMS Hematolymphoid Malignancies • Predominant neoplasms affecting AT patients (> 100x risk compared to general population) • T-cell and B-cell lineage • Myeloid leukemia very uncommon

Solid Tumors

Overview of Syndromes: Syndromes

• Rising serum levels typical • Not feature of other ataxia and immunodeficiency syndromes in differential diagnosis

• Caused by mutations in NBS1 ○ Encodes for another component of MRN protein complex • Patients also demonstrate immunodeficiency, radiosensitivity, and cancer predisposition • Microcephaly and intellectual disability but lack progressive ataxia and telangiectasias

• Ataxia with oculomotor apraxia types 1 and 2, spinocerebellar ataxia with axonal neuropathy type 1 • Neurodegenerative syndromes and neurologic features overlap with AT • No manifestations outside of nervous system

SELECTED REFERENCES 1.

Amirifar P et al: Ataxia-telangiectasia: a review of clinical features and molecular pathology. Pediatr Allergy Immunol. 30(3):277-88, 2019 2. Renault AL et al: Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers. Breast Cancer Res. 20(1):28, 2018 3. van Os NJH et al: Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Child Neurol. 59(7):680-9, 2017 4. Shiloh Y et al: The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 14(4):197-210, 2013 5. Hoche F et al: Neurodegeneration in ataxia telangiectasia: what is new? What is evident? Neuropediatrics. 43(3):119-29, 2012 6. McKinnon PJ: ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol. 7:303-21, 2012 7. Chiam LY et al: Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation? Dermatology. 223(1):13-9, 2011 8. Vogel CA et al: Chronic noninfectious necrotizing granulomas in a child with Nijmegen breakage syndrome. Pediatr Dermatol. 27(3):285-9, 2010 9. Lavin MF: Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 9(10):759-69, 2008 10. Thorstenson YR et al: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 63(12):3325-33, 2003

• More evident as patients are living longer 503

Overview of Syndromes: Syndromes

BAP1 Tumor Predisposition Syndrome • No clear associations between genotype and phenotype

TERMINOLOGY

BAP1 Gene

Synonyms • BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome • OMIM #614327

GENETICS

• Tumor suppressor gene located on short arm of chromosome 3 (locus 3p21.1) • Encodes nuclear-localized protein that is deubiquitinating enzyme • Important for cell cycle regulation, transcription, DNA damage repair, and chromatin dynamics

Inheritance • Autosomal dominant • 2-hit hypothesis ○ Patient inherits nonfunctional BAP1 allele, and remaining allele is inactivated later in life • Germline mutations in both coding and noncoding regions of BAP1 gene • Majority of mutations result in protein truncation due to frameshift or nonsense mutation of biallelic inactivation of BAP1 • Tumor formation is result of loss of heterozygosity due to 2nd mutation or deletion

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Findings • Germline testing is recommended in patient with BAP1inactivated melanocytic tumor (BIMT) with extensive junctional component or history of prior melanoma or BIMT

Immunohistochemistry • Lesional cells have loss of BAP1

Fundus Examination

Gross Examination of Uveal Melanoma

Uveal Melanoma: Spindle Histology

Uveal Melanoma: Epithelioid Histology

(Left) Posterior uveal melanoma is the most common malignancy to arise in the setting of BAP1-tumor syndrome. The diagnosis can be made clinically when the classic appearance of a pigmented, dome-shaped mass is visualized on a dilated fundus exam. (Courtesy F. A. Jakobiec.) (Right) Posterior uveal melanoma (choroidal and ciliary body melanoma) classically presents as a brown, dome-shaped mass but can be mushroom-shaped, as shown here, or diffuse. (Courtesy F. A. Jakobiec.)

(Left) Fascicles of spindleshaped tumor cells are seen in this example of uveal melanoma. (Courtesy F. A. Jakobiec.) (Right) Epithelioid tumor cells with polygonal shape and oval nuclei are seen in this example of uveal melanoma with epithelioid histology. (Courtesy F. A. Jakobiec.)

504

BAP1 Tumor Predisposition Syndrome

In Patients With BAP1 Germline Mutation • At least 75% develop at least 1 of following 5 neoplasms: Uveal melanoma (31%), malignant mesothelioma (22%), BIMT (18%), cutaneous melanoma (13%), and renal cell carcinoma (10%) ○ Uveal and cutaneous melanomas ○ BIMT – Appear earlier than other BAP1-associated tumors – Cases with either Spitzoid morphology or smaller epithelioid cells – Rhabdoid features can frequently be seen – Loss of BAP1 nuclear expression – Often BRAF V600E mutated – Junctional component with BAP1 nuclear loss is statistically associated with germline mutation – Due to lack of long-term follow-up, malignant potential of BIMT is currently unknown ○ Malignant melanoma ○ Malignant mesothelioma ○ Renal cell carcinoma • Also increased susceptibility to develop ○ Basal cell carcinoma ○ Squamous cell carcinoma ○ Lung adenocarcinoma ○ Meningioma ○ Neuroendocrine tumors ○ Paraganglioma ○ Breast cancer ○ Intrahepatic cholangiocarcinoma ○ Pancreatic cancer ○ Colorectal cancer ○ Prostate cancer ○ Ovarian cancer ○ Thyroid cancer ○ Sarcoma

CANCER RISK MANAGEMENT • Up to 90% of affected patients have at least 2 of main tumors in 1st- or 2nd-degree relatives ○ Uveal melanoma ○ Malignant mesothelioma ○ BIMT ○ Cutaneous melanoma ○ Renal cell carcinoma • Families that carry BAP1-tumor predisposition syndrome should receive genetic counseling and be offered testing for at-risk family members • Genetic testing for BAP1 mutations should be considered in patients with 2 or more tumors &/or 1st- or 2nd-degree relatives • Uveal melanoma ○ Yearly eye exam and imaging starting at 16 years of age ○ 6-month visits from 30 years of age • Malignant mesothelioma ○ Yearly physical examination from 30 years of age ○ Ultrasound, MR (abdomen/chest) every 2 years between 30 and 55 years of age 

○ CT (abdomen/chest) or MR (abdomen/chest), both with contrast and ultrasound (renal/chest) in between • Cutaneous melanoma ○ Annual full skin exam starting at 20 years of age ○ 6-month skin exam after 30 years of age ○ Sequential digital dermatoscopic photographic monitoring • Renal cell carcinoma ○ Yearly physical examination from 30 years of age ○ Ultrasound, MR (abdomen/chest) every 2 years between 30 and 55 years of age ○ CT (abdomen/chest) or MR (abdomen/chest), both with contrast and ultrasound (renal/chest) in between

Overview of Syndromes: Syndromes

ASSOCIATED NEOPLASMS

DIFFERENTIAL DIAGNOSIS Hereditary Melanoma Syndrome • • • •

Numerous nevi Atypical nevi are more likely to transform into melanoma Increased risk of melanoma Family history of melanoma

CRITERIA FOR DIAGNOSIS • At least 1 type of cancer is present in ~ 80% of gene carriers • Because penetrance is variable, there is variability in types of BAP1-related tumors among members of same family

SELECTED REFERENCES 1.

2.

3.

4.

5.

6. 7.

8.

9.

10. 11. 12.

13. 14.

Chau C et al: Families with BAP1-tumor predisposition syndrome in the Netherlands: path to identification and a proposal for genetic screening guidelines. Cancers (Basel). 11(8), 2019 Melzer C et al: Basal cell carcinomas developing independently from BAP1tumor predisposition syndrome in a patient with bilateral uveal melanoma: diagnostic challenges to identify patients with BAP1-TPDS. Genes Chromosomes Cancer. 58(6):357-64, 2019 Yélamos O et al: Clinical and dermoscopic features of cutaneous BAP1inactivated melanocytic tumors: results of a multicenter case-control study by the International Dermoscopy Society. J Am Acad Dermatol. 80(6):158593, 2019 Zauderer MG et al: Prevalence and preliminary validation of screening criteria to identify carriers of germline BAP1 mutations. J Thorac Oncol. S1556-0864(19)30559-3, 2019 Garfield EM et al: Histomorphologic spectrum of germline-related and sporadic BAP-1 inactivated melanocytic tumors. J Am Acad Dermatol. 79(3):525-34, 2018 Masoomian B et al: Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr Ophthalmol. 30(2):102-9, 2018 Star P et al: Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy. Eur J Cancer. 92:48-53, 2018 Walpole S et al: Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J Natl Cancer Inst. 110(12):132841, 2018 Haugh AM et al: Genotypic and phenotypic features of BAP1 cancer syndrome: a report of 8 new families and review of cases in the literature. JAMA Dermatol. 153(10):999-1006, 2017 O'Shea SJ et al: Histopathology of melanocytic lesions in a family with an inherited BAP1 mutation. J Cutan Pathol. 43(3):287-9, 2016 Rai K et al: Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 89(3):285-94, 2016 Marušić Z et al: Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome. J Cutan Pathol. 42(6):406-12, 2015 Mochel MC et al: Loss of BAP1 expression in basal cell carcinomas in patients with germline BAP1 mutations. Am J Clin Pathol. 143(6):901-4, 2015 Piris A et al: BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations. Hum Pathol. 46(2):239-45, 2015

505

Overview of Syndromes: Syndromes

Basal Cell Nevus Syndrome/Gorlin Syndrome ○ Few to numerous ○ On face, neck, and upper trunk Odontogenic keratocysts of jaw ○ Mandible more frequently than maxilla Asymmetrical palmar or plantar pits or both Bifid ribs Lamellar calcification of falx cerebri Other abnormalities ○ Frontal bossing ○ Macrocephaly ○ Hypertelorism ○ Mild mandibular prognathism

TERMINOLOGY Synonyms

•

• • • • •

• • • •

Basal cell nevus syndrome (BCNS) Nevoid basal cell carcinoma syndrome Gorlin-Goltz syndrome Gorlin syndrome OMIM 109400

EPIDEMIOLOGY Age at Presentation • Bony abnormalities ○ From birth • Jaw cysts; odontogenic keratocyst: 1st decade • Palmoplantar pitting: 2nd decade • Basal cell carcinomas: Childhood to adulthood

Incidence • 1 per 50,000 to 1 per 256,000

GENETICS Inheritance • Autosomal dominant

PTCH1 Gene • Human homolog of Drosophila patched-1 gene located on chromosome 9q22.3 • Tumor suppressor gene • Germline mutations in patched or patched-1 (PTCH1) gene • Mutations detected in 60-70% of tested cases ○ Present in ~ 70% of syndromic and sporadic odontogenic keratocysts • No clear genotype and phenotype correlation

CLINICAL IMPLICATIONS AND IMAGING FINDINGS Clinical Findings • Basal cell carcinoma

Imaging Findings • Head: Calcification of falx, tentorium cerebelli, sella turcica ○ Calcification of falx ○ Tentorium cerebelli ○ Sella turcica ○ Jaw cysts ○ Cleft lip or palate • Trunk ○ Bifid ○ Missing or splayed ribs • Spine ○ Scoliosis ○ Vertebral anomalies • Extremities ○ Flame-shaped lucencies of hand or feet ○ Cysts of long bones

ASSOCIATED NEOPLASMS Skin • Basal cell carcinoma on both sun-exposed and nonexposed skin ○ Clinical appearance – Pearly pink – Telangiectatic papules or nodules – Erythematous macules or plaques ○ Histopathology

Scalp Basal Cell Carcinomas (Left) Multiple crusted pink plaques on the scalp represent basal cell carcinomas in this patient with Gorlin syndrome. (Courtesy K. Hoffmann, MD.) (Right) Histologic section shows basaloid neoplastic cells arranged in nests with peripheral palisade, stromal mucin deposition, clefting artifact, and follicular differentiation. All these features are characteristic of basal cell carcinoma.

506

Basal Cell Carcinoma

Basal Cell Nevus Syndrome/Gorlin Syndrome

Musculoskeletal • Odontogenic keratocyst ○ Sites – Mandibular molar/ramus (~ 40%) – Mandibular canine/incisor (~ 20%) – Maxillary molar tuberosity (~ 10%) ○ Uninflamed fibrous wall lined by folded, thin, parakeratinized epithelium – Parakeratin surface is corrugated and basal layer is often palisading □ These findings are characteristic and distinguish keratocysts from other odontogenic cysts

Central Nervous System • Most common ○ Medulloblastoma, often desmoplastic • Others include ○ Meningiomas ○ Craniopharyngiomas

Genitourinary • Bilateral calcified ovarian fibromas

Cardiac • Fibroma

CANCER RISK MANAGEMENT Multidisciplinary Care • Dermatology, surgery, dental or oral medicine, orthopedics, ophthalmology, neurology, genetics • Skin exams ○ Every 4-6 months to 1 year • Medulloblastoma ○ Baseline MR of brain ○ Epilepsy protocol • Avoid ultraviolet light exposure ○ Practice sun protection • PTCH1 gene testing is recommended: Prenatal testing if known mutation within family or cases highly suspicious for syndrome

DIFFERENTIAL DIAGNOSIS Early-Onset Sporadic Basal Cell Carcinomas • Patients are < 40 years

Bazex-Dupré-Christol Syndrome • Triad ○ Hypotrichosis ○ Follicular atrophoderma ○ Basal cell carcinoma syndrome • Onset at birth or during early childhood • Multiple milia and basal cell carcinomas affecting face

• Basal cell carcinomas in 40% during 2nd or 3rd decade of life • Distinguishing features from Gorlin syndrome ○ X-linked dominant inheritance ○ Involved gene locus: Xq24-27.1 ○ Congenital hypotrichosis ○ Follicular atrophoderma – Funnel-shaped follicular depression – On face and dorsal hands ○ Hair shaft abnormality – Pili torti – Trichorrhexis nodosa

Oley Syndrome

Overview of Syndromes: Syndromes

– All subtypes of basal cell carcinoma, including pigmented variant • Palmoplantar pits ○ Clinical appearance – Pink and several millimeters in size ○ Histopathology – Basaloid proliferation • Epidermal inclusion cyst or milium

• Possibly variant of Bazex-Dupré-Christol syndrome • Inheritance ○ Autosomal dominant ○ X-linked dominant • Sparse, coarse scalp hair • Milia on face and limbs • Excessive sweating • Basal cell carcinomas

Rombo Syndrome • Multiple basal cell carcinomas • Inheritance ○ Autosomal dominant • Age of onset ○ 7 to 10 years • Distinguishing features from Gorlin syndrome ○ Vermiculate atrophoderma ○ Milia ○ Hypotrichosis ○ Multiple trichoepitheliomas ○ Follicular atrophodermas on elbows and cheeks ○ Acral cyanosis

Generalized Basaloid Follicular Hamartoma Syndrome • Palmoplantar pitting • Inheritance ○ Autosomal dominant • Distinguishing features from Gorlin syndrome ○ Multiple basaloid follicular hamartomas – Initially on central face – Then spread to scalp, neck, trunk, and upper extremities ○ Absence of basal cell carcinomas and jaw cysts

Familial Multiple Basaloid Follicular Hamartomas • Multiple facial papules ○ Basaloid follicular hamartomas • Presenting in childhood

Hereditary Infundibulocystic Basal Cell Carcinoma • Distinguishing features from Gorlin syndrome ○ Multiple small papules/infundibulocystic basal cell carcinoma on central face ○ Absence of palmar pits and jaw cysts

507

Overview of Syndromes: Syndromes

Basal Cell Nevus Syndrome/Gorlin Syndrome

• Defective DNA repair syndromes (e.g., xeroderma pigmentosum)

CRITERIA FOR DIAGNOSIS

SELECTED REFERENCES 1.

Diagnosis • Diagnosis is based on 2 major criteria, 1 major criterion and 2 minor criteria, or 1 major criterion & genetic confirmation

2.

Major Criteria

3.

• Basal cell carcinomas in excessive number or in patients younger than 20 years • Odontogenic keratocyst of jaw prior to 20 years of age • 3 or more palmar or plantar pits • Lamellar calcification of falx cerebri • Medulloblastoma, typically desmoplastic, in early childhood • 1st-degree relative with BCNS

4.

• Bifid, fused, or markedly splayed ribs • Other specific skeletal malformations and radiologic abnormalities ○ Vertebral anomalies ○ Kyphoscoliosis ○ Short 4th metacarpals ○ Postaxial polydactyly ○ Flame-shaped lucencies of phalanges • Macrocephaly • Congenital malformations ○ Cleft lip or palate ○ Frontal bossing ○ Coarse facies ○ Hypertelorism • Ovarian or cardiac fibroma • Lymphomesenteric cysts • Ocular abnormalities ○ Congenital cataracts ○ Glaucoma ○ Coloboma

Palmar Pittings (Left) This patient had multiple pink 1- to 2-mm depressions on the palm, consistent with palmar pitting characteristic of Gorlin syndrome. (Courtesy K. Hoffmann, MD.) (Right) This biopsy from a palm exhibits the thick stratum corneum typical of acral skin. Abutting the epidermis, a basaloid proliferation of palmoplantar pit composed of interconnecting basaloid nests with associated stromal mucin deposition is shown.

5. 6. 7.

8.

Minor Criteria

508

○ Strabismus ○ Hypertelorism

Other Syndromes With Basal Cell Carcinoma

9.

10. 11.

12.

13.

14. 15. 16. 17. 18.

Reinders MGHC et al: Genetic profiling of basal cell carcinomas detects postzygotic mosaicism in basal cell naevus syndrome. Br J Dermatol. 181(3):587-91, 2019 Akbari M et al: Basal cell nevus syndrome (Gorlin syndrome): genetic insights, diagnostic challenges, and unmet milestones. Pathophysiology. 25(2):77-82, 2018 Alonso N et al: Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome. Br J Dermatol. 178(1):198-206, 2018 Fink AZ et al: Imaging findings in systemic childhood diseases presenting with dermatologic manifestations. Clin Imaging. 49:17-36, 2018 Gielen RCAM et al: PTCH1 isoform 1b is the major transcript in the development of basal cell nevus syndrome. J Hum Genet. 63(9):965-9, 2018 Reinders MGHC et al: New mutations and an updated database for the patched-1 (PTCH1) gene. Mol Genet Genomic Med. 6(3):409-15, 2018 Shevchenko A et al: Generalized basaloid follicular hamartoma syndrome versus Gorlin syndrome: a diagnostic challenge. Pediatr Dermatol. 35(6):e396-7, 2018 Basset-Séguin N et al: Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 86:334-48, 2017 Bree AF et al: Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet A. 155A(9):2091-7, 2011 Jones EA et al: Basal cell carcinomas in gorlin syndrome: a review of 202 patients. J Skin Cancer. 2011:217378, 2011 Tiodorovic-Zivkovic D et al: Clinical and dermatoscopic findings in BazexDupré-Christol and Gorlin-Goltz syndromes. J Am Acad Dermatol. 63(4):7224, 2010 Wheeler CE Jr et al: Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family. J Am Acad Dermatol. 43(2 Pt 1):189-206, 2000 Requena L et al: Multiple hereditary infundibulocystic basal cell carcinomas: a genodermatosis different from nevoid basal cell carcinoma syndrome. Arch Dermatol. 135(10):1227-35, 1999 Hahn H et al: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 85(6):841-51, 1996 Johnson RL et al: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 272(5268):1668-71, 1996 Shanley S et al: Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet. 50(3):282-90, 1994 Brownstein MH: Basaloid follicular hamartoma: solitary and multiple types. J Am Acad Dermatol. 27(2 Pt 1):237-40, 1992 Michaëlsson G et al: The Rombo syndrome: a familial disorder with vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, basal cell carcinomas and peripheral vasodilation with cyanosis. Acta Derm Venereol. 61(6):497-503, 1981

Palmar Basaloid Proliferation

Basal Cell Nevus Syndrome/Gorlin Syndrome

Postodontogenic Keratocyst Removal (Left) CECT demonstrates a well-defined expansile cyst in the angle of the left mandible. Extensive or precocious falx calcification and mandibular cysts (keratocysts) are diagnostic of basal cell nevus syndrome. (Right) This patient with Gorlin syndrome had multiple basal cell carcinomas of the skin as well as several odontogenic jaw cysts. The photograph shows a scar from where one of the jaw cysts was surgically excised. (Courtesy K. Hoffmann, MD.)

Mandible With Odontogenic Keratocyst

Overview of Syndromes: Syndromes

Mandibular Cyst

Odontogenic Keratocyst Epithelium (Left) Lateral graphic of the mandible (buccal cortex removed) illustrates features of a classic odontogenic keratocyst ſt, splaying roots of the 1st and 2nd molar teeth and displacing the inferior alveolar nerve st. (Right) An odontogenic keratocyst is a multiloculated cyst lined by squamous epithelium with a prominent undulating surface. The basal cells are palisading with hyperchromatic nuclei.

Dural Calcification

Medulloblastoma (Left) Axial nonenhanced CT shows beaded calcification of the falx cerebri ﬇. Basal cell nevus syndrome should be suspected when multiple jaw cysts &/or precocious dural calcification is detected. Dural calcification is unusual in patients < 10 years of age. (Right) H&E shows a lowpower view of nodular/desmoplastic medulloblastoma with hypocellular nodules ﬈ against a background of increased cellularity ﬊, giving the appearance of pale islands. (Courtesy A. Polydorides, MD, PhD.)

509

Overview of Syndromes: Syndromes

Beckwith-Wiedemann Syndrome

TERMINOLOGY

EPIDEMIOLOGY

Abbreviations

Incidence

• Beckwith-Wiedemann syndrome (BWS) • Beckwith-Wiedemann spectrum (BWSp)

• ~ 1 in 14,000

Definitions

• M:F = 1:1 ○ Exception is monozygotic twins – F:M = 3:1

• Classic BWS: Multisystem human genomic imprinting disorder characterized by ○ Disorder of growth regulation ○ Predisposition to embryonal tumors ○ Phenotypic variability that might include macroglossia, abdominal wall defects, lateralized overgrowth, and organomegaly, among other findings • BWSp ○ Classic BWS ○ Lateralized overgrowth (hemihypertrophy &/or hemihyperplasia) ○ Atypical BWS: Children with 11p15 anomaly who do not fit into above groups

Sex

Age Range • Increased growth ○ In utero ○ First few years of life • Associated tumors ○ Most tumors occur in first 7 years of life

Other • Associated with assisted reproduction ○ Risk is 1 in 4,000 for in vitro fertilization

Flowchart for Investigation and Diagnosis of Beckwith-Wiedemann Syndrome

Flowchart summarizes the molecular diagnostic pathway for investigation of suspected Beckwith-Wiedemann spectrum (BWSp). Patients with clinical features reaching a score of ≥ 2 should be genetically tested. It is recommended that 1st-line testing should assay the methylation status of H19/IGF2:intergenic (IG) differentially methylated region (DMR) (a.k.a. IC1) and KCNQ1OT1:transcriptional start site (TSS) DMR (a.k.a. IC2). These assays can yield a positive molecular diagnosis of BWSp. (Adapted from Flowchart for investigation and diagnosis of Beckwith-Wiedemann syndrome. Nature 1:2018.)

510

Beckwith-Wiedemann Syndrome • Cardiac defects • Adrenal cysts and masses

Clinical Presentation • Highly variable presentation ○ Ranges from mild to severe • Classic triad ○ Macroglossia (can cause abnormal feeding/breathing/speech) ○ Abdominal wall defects ○ Macrosomia (present in only 1/2 of patients) • Somatic overgrowth ○ Initial increased growth – In utero – Height and weight are often above 90th percentile for age in initial years of life – Normalizes by childhood ○ Overgrowth may be unilateral (hemihyperplasia) ○ Visceromegaly can involve – Liver – Spleen – Pancreas – Adrenals – Heart – Kidneys (may be associated with renal medullary dysplasia, nephrocalcinosis, or medullary sponge kidney) • Characteristic facies in early childhood (often normal by adulthood) ○ Macroglossia ○ Midfacial hypoplasia ○ Prominent mandible ○ Ear creases &/or pits ○ Infraorbital creases ○ Naevus flammeus • Abdominal wall defects ○ Umbilical hernia ○ Diastasis recti ○ Exomphalos • Pregnancy-related findings ○ Polyhydramnios ○ Placentomegaly ○ Prematurity ○ Placental mesenchymal dysplasia ○ Thickened umbilical cord ○ Neonatal hypoglycemia

Clinical Risk Factors • Prognostic factors and risk ○ Worse prognosis with perinatal hypoglycemia – Hypoglycemia in 30-50% of BWS ○ Different molecular subgroups have been shown to be associated with different tumor rates and tumor profiles • Overall risk for tumor development ○ Estimated at ~ 8% ○ Range: 4-21%

Ultrasonographic Findings • Polyhydramnios, placentomegaly • Organomegaly • Urinary tract abnormalities

GENETICS Inheritance • Sporadic: ~ 85% • Familial: ~ 15% ○ Heterogeneous transmission – Sometimes autosomal dominant maternal transmission

Molecular Pathology • Involves chromosome 11p15.5 in ~ 80% of cases ○ Delineation of molecular defects within imprinted 11p15.5 region can predict familial recurrence risks and risk type of embryonal tumor ○ Methylation abnormalities at chromosome 11p15.5 imprinting centers are associated with extremes of cancer risk in BWS – Hypermethylation at imprinting center 1 (IC1) is associated with cancer risk of > 22%, almost exclusively Wilms tumor – Hypomethylation at imprinting center 2 (IC2) is associated with 2-3% overall cancer risk, with risks of specific cancers all below 1% ○ IGF2 and KCNQ1OT1 are normally expressed from paternal allele – KCNQ1OT1-associated imprinting center (IC2) is usually methylated on maternal allele ○ H19, CDKN1C, and KCNQ1 are normally expressed from maternal allele – H19-associated imprinting center (IC1) is usually methylated on paternal allele • Different molecular pathology is associated with different clinical phenotypes ○ Epigenetic – Altered methylation: Loss of methylation at IC2 occurs in 50%; gain of methylation occurs at IC1 in 10% – Loss of methylation at IC2 is associated with decreased risk of renal findings compared with gain of methylation at IC1 ○ Genetic – CDKN1C mutation □ Most prominent cancer risk is neuroblastoma (24%) – Microdeletion – Uniparental disomy of 11p15.5 (~ 10-20% of cases; usually paternal allele) is associated with high risk of Wilms tumor – Duplication, inversion, translocation of 11p15 in < 1% of cases

Overview of Syndromes: Syndromes

CLINICAL IMPLICATIONS

ASSOCIATED NEOPLASMS Embryonal Tumors • Occur in ~ 8% of children with BWSp • Wilms tumor (nephroblastoma) ○ ~ 60% of all tumors ○ Risk of Wilms tumor is significantly increased among patients with hemihyperplasia &/or nephromegaly ○ Histopathology (often characterized by 3 elements) 511

Overview of Syndromes: Syndromes

Beckwith-Wiedemann Syndrome

•

•

•

•

•

– Blastema (embryologic structure related to kidney development) – Mesenchyme (may be composed of striated muscle, bone, cartilage, fat, fibroblastic tissue) – Epithelium Hepatoblastoma ○ ~ 15% of all tumors ○ High levels of α-fetoprotein (100,000-300,000 μg/mL) ○ Different histologic variants – Epithelial (fetal pattern) – Embryonal and fetal pattern – Macrotrabecular pattern – Small cell undifferentiated pattern – Mixed epithelial and mesenchymal pattern ± teratoid features Neuroblastoma ○ 10% of all tumors ○ Round blue cells, sometimes forming rosettes Rhabdomyosarcoma ○ Subtypes reported – Embryonal: Dense foci of rhabdomyoblasts with areas of loose, myxoid stroma – Alveolar: Small blue cells in aggregates floating in spaces lined by fibrous septa Adrenal cortical carcinoma ○ Cells with eosinophilic cytoplasm ○ Often with numerous mitoses and invasive growth pattern Adrenal cytomegaly ○ Hyperplastic adrenal glands ○ Characteristic cytology – Large, polyhedral cells with eosinophilic granular cytoplasm and enlarged nuclei

CANCER RISK MANAGEMENT Cancer Screening for Children With BWS Hereditary Cancer Predisposition Syndrome • Significant proportion of pediatric cancer occurs in children with BWS hereditary cancer predisposition syndrome • Consensus screening recommendations have been evolving in response to new evidence: BWS, Li-Fraumeni syndrome, and constitutional mismatch repair deficiency syndrome ○ Survival may be significantly improved &/or late effects diminished through screening for greatly elevated cancer risks

Tumor Surveillance Protocol • Multiple areas of divergence in surveillance recommendations for children with BWSp ○ Whether and how to screen for hepatoblastoma, neuroblastoma, and adrenal cortical carcinoma ○ Appropriate age at which to discontinue surveillance ○ Cancer screening in BWSp could be differentiated on basis of (epi)genotype and target specific histotypes • Abdominal ultrasound ○ Every 3 months – Until age 7 • Serum levels of α-fetoprotein ○ Every 3 months – Until age 4 512

• Physical examination by specialist twice yearly

DIFFERENTIAL DIAGNOSIS Maternal Diabetes Mellitus • Macrosomia

Isolated Omphalocele • May be associated with normal growth or growth restriction

Hemihypoplasia • Underdevelopment of one side of body ○ Relative to underdeveloped side, normal side may be misdiagnosed as being hyperplastic

Simpson-Golabi-Behmel Syndrome • X-linked recessive, mutations in GPC3 or CXORF5 • High mortality in infancy • Pre- and postnatal overgrowth, macrocephaly, macroglossia, coarse face, polydactyly, cardiac anomalies, abdominal wall defects, organomegaly • Increased risk of tumors (especially Wilms tumor)

Sotos Syndrome • Autosomal dominant, mutation in NSD1 • Overgrowth, macrocephaly, neonatal hypotonia, jaundice and feeding difficulties, intellectual disability, seizures • Cardiac/renal anomalies • Characteristic facies ○ High forehead ○ Inverted pear-shaped head ○ Sparse frontotemporal hair ○ Pointed chin

Perlman Syndrome • • • •

Autosomal recessive, mutation in DIS3L2 High neonatal mortality High risk of Wilms tumor Overgrowth, hypotonia, hyperinsulinism, organomegaly, developmental delay • Characteristic facies ○ High forehead ○ Flat nasal bridge ○ Tented upper lip ○ Deep-set eyes ○ Low-set ears

Weaver Syndrome • Autosomal dominant, mutation in EZH2 • Tall stature, macrocephaly, umbilical hernia, camptodactyly, intellectual disability • Characteristic facies ○ High forehead ○ Pointed chin ○ Hypertelorism ○ Macrotia and retrognathia in early childhood

Marshall-Smith Syndrome • Autosomal dominant, mutation in DNA-binding domain of NFIX • Overgrowth, macrocephaly, hypotonia, brain anomalies, intellectual disability, autism

Beckwith-Wiedemann Syndrome • Typical BWSp tumors (unilateral Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenocortical carcinoma or pheochromocytoma) • Hepatomegaly or nephromegaly • Umbilical hernia &/or diastasis recti

PTEN-Hamartoma Tumor Syndrome

• Clinical diagnosis of classical BWS • This clinical diagnosis does not require molecular confirmation of 11p15 anomaly

• Autosomal dominant • Prenatal overgrowth, macrocephaly, hypotonia, intellectual disability, autism • Dermatologic features: Acral keratosis, genital freckling, papillomatous papules, trichilemmomas • High risk of thyroid, endometrial, and breast cancer

PIK3CA-Related Overgrowth Spectrum • Somatic mosaic • Segmental overgrowth syndromes ○ CLOVES syndrome ○ Hemihyperplasia multiple lipomatosis syndrome ○ Fibroadipose hyperplasia ○ Megalencephaly-capillary malformation

Syndromic Wilms Tumor • Syndromes related to WT1 mutation ○ Examples – WAGR (Wilms tumor, aniridia, genitourinary anomalies, intellectual disability) syndrome – Denys-Drash syndrome (gonadal dysgenesis, nephropathy, Wilms tumor) – Frasier syndrome (pseudohermaphroditism, glomerulonephropathy, gonadoblastoma; rarely Wilms tumor) – Genitourinary anomalies syndrome (abnormal external genitalia, Wilms tumor)

Nonsyndromic Wilms Tumor • Wilms tumor not associated with any syndrome (e.g., BWS, WAGR syndrome, Denys-Drash syndrome, Frasier syndrome)

Score of ≥ 4

Score of ≥ 2 • Including those with classical BWS with score of ≥ 4 • Merit genetic testing for investigation and diagnosis of BWS

Score of < 2 • Does not meet criteria for genetic testing

Score of ≥ 2 With Negative Genetic Testing • Consider alternative diagnosis &/or refer to BWS expert for further evaluation

SELECTED REFERENCES 1.

2.

3.

4.

5.

6.

7. 8.

BECKWITH-WIEDEMANN SPECTRUM SCORING SYSTEM

9.

Cardinal Features (2 Points Feature) • • • •

Macroglossia Lateralized overgrowth Exomphalos Multifocal &/or bilateral Wilms tumor or nephroblastomatosis • Hyperinsulinism (lasting >1 week and requiring escalated treatment) • Pathology findings: Adrenal cortex cytomegaly, placental mesenchymal dysplasia, or pancreatic adenomatosis

Suggestive Features (1 Point Per Feature) • • • • •

Birth weight > 2 standard deviations above mean Polyhydramnios &/or placentomegaly Facial naevus simplex Ear creases &/or pits Transient hypoglycemia (lasting < 1 week)

Overview of Syndromes: Syndromes

• Characteristic facies ○ High forehead ○ Short nose ○ Long philtrum ○ Micrognathia ○ Blue sclerae

10. 11.

12. 13. 14.

15. 16.

Kim EN et al: Adrenal cortical neoplasm with uncertain malignant potential arising in the heterotopic adrenal cortex in the liver of a patient with Beckwith-Wiedemann syndrome. J Pathol Transl Med. 53(2):129-35, 2019 Mussa A et al: Defining an optimal time window to screen for hepatoblastoma in children with Beckwith-Wiedemann syndrome. Pediatr Blood Cancer. 66(1):e27492, 2019 Rednam SP: Updates on progress in cancer screening for children with hereditary cancer predisposition syndromes. Curr Opin Pediatr. 31(1):41-7, 2019 Brioude F et al: Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 14(4):229-49, 2018 Dagar V et al: Genetic variation affecting DNA methylation and the human imprinting disorder, Beckwith-Wiedemann syndrome. Clin Epigenetics. 10(1):114, 2018 Fontana L et al: Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders. Epigenetics. 13(9):897-909, 2018 Shterenshis M et al: The 11p15.5 chromosomal region: when did the instability occur? Med Hypotheses. 121:21-5, 2018 Uk A et al: Assisted reproductive technologies and imprinting disorders: results of a study from a French congenital malformations registry. Eur J Med Genet. 61(9):518-23, 2018 Kalish JM et al: Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 23(13):e115-22, 2017 Kalish JM et al: Tumor screening in Beckwith-Wiedemann syndrome: to screen or not to screen? Am J Med Genet A. 170(9):2261-4, 2016 Chen CP: Prenatal findings and the genetic diagnosis of fetal overgrowth disorders: Simpson-Golabi-Behmel syndrome, Sotos syndrome, and Beckwith-Wiedemann syndrome. Taiwan J Obstet Gynecol. 51(2):186-91, 2012 Mussa A et al: Nephrological findings and genotype-phenotype correlation in Beckwith-Wiedemann syndrome. Pediatr Nephrol. 27(3):397-406, 2012 Weksberg R et al: Beckwith-Wiedemann syndrome. Eur J Hum Genet. 18(1):8-14, 2010 Wangler MF et al: Inheritance pattern of Beckwith-Wiedemann syndrome is heterogeneous in 291 families with an affected proband. Am J Med Genet A. 137(1):16-21, 2005 Halliday J et al: Beckwith-Wiedemann syndrome and IVF: a case-control study. Am J Hum Genet. 75(3):526-8, 2004 Smith AC et al: Association of alveolar rhabdomyosarcoma with the Beckwith-Wiedemann syndrome. Pediatr Dev Pathol. 4(6):550-8, 2001

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Overview of Syndromes: Syndromes

Beckwith-Wiedemann Syndrome Beckwith-Wiedemann Spectrum: Molecular Defect Categories and Recurrence Risk Molecular Defect

Frequency of Molecular Defect

Mosaicism Observed

Risk of Recurrence

Characteristic Clinical Features (Compared With Other Molecular Subgroups)

IC2 LOM

50%

Yes

-If no genetic anomaly identified, < 1% -If cis-acting genetic anomaly present, 50%; dependent on parental origin

-High frequency of exomphalos -Low risk of Wilms tumor

MLID

33% of IC2 LOM cases

Yes

Low unless in trans genetic variant is identified Unclear

upd(11)pat

20% (see also Yes paternal unidiploidy)

< 1%

-High incidence of lateralized overgrowth -Low frequency of exomphalos -High risk of Wilms tumor and hepatoblastoma

Mosaic paternal unidiploidy (genome-wide paternal UPD)

Up to 10% of upd(11)pat

Yes

Low

High frequency of neoplasia

Loss-of-function CDKN1C variants

5% (40% in familial cases)

Usually no but has rarely been reported

50% on maternal transmission

-High frequency of exomphalos -Low risk of Wilms tumor

IC1 GOM

5%

Yes

-If no genetic anomaly present, < 1% -If genetic anomaly (e.g., pathogenic SNV of copy number variant in DMR) present, 50%; dependent on parental origin

-Low frequency of exomphalos -High risk of Wilms tumor

dup(11)(p15.5)pat

~ 2-4%

No

-50% on paternal transmission -Risk of SRS on maternal transmission

-

No

Dependent on extent and position of CNV, and parent of origin

-

Deletions involving 1-2% 11p15

DMR = differentially methylated region; dup(11)(p15.5)pat = duplication of paternal 11p15.5; GOM = gain of methylation; LOM = loss of methylation; MLID = multilocus imprinting disturbance; SNV = single nucleotide variation; SRS = Silver-Russell syndrome; UPD = uniparental isodisomy; upd(11)pat = paternal uniparental isodisomy of 11p15.5. Modified from Brioude F et al: Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 14(4):229-49, 2018.

Clinical Features of Beckwith-Wiedemann Spectrum Cardinal Features (2 Points Per Feature)

Suggestive Features (1 Point Per Feature)

Macroglossia

Birth weight > 2 standard deviations above mean

Lateralized overgrowth

Polyhydramnios &/or placentomegaly

Exomphalos

Facial naevus simplex

Multifocal &/or bilateral Wilms tumor or nephroblastomatosis

Ear creases &/or pits

Hyperinsulinism

Transient hypoglycemia (lasting < 1 week)

Pathology findings: adrenal cortex cytomegaly, placental mesenchymal dysplasia or pancreatic adenomatosis

Hepatomegaly or nephromegaly Typical BWSp tumors (unilateral Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenocortical carcinoma, or pheochromocytoma) Umbilical hernia &/or diastasis recti

For a clinical diagnosis of classic Beckwith-Wiedemann syndrome (BWS), a patient requires a score of ≥ 4. This clinical diagnosis does not require the molecular confirmation of an 11p15 anomaly. Patients with a score of ≥ 2 (including those with classical BWS with a score of ≥ 4) merit genetic testing for investigation and diagnosis of BWS. Patients with a score of < 2 do not meet the criteria for genetic testing. Patients with a score of ≥ 2 with negative genetic testing should be considered for an alternative diagnosis &/or referral to a BWS expert for further evaluation. BWSp = Beckwith-Wiedemann spectrum. Modified from Brioude F et al: Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 14(4):229-49, 2018.

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Beckwith-Wiedemann Syndrome

Protuberant Abdomen and Macroglossia (Left) This fetus with Beckwith-Wiedemann syndrome (BWS) shows abdominal wall defects with umbilical hernia and diastasis recti exposing intraabdominal organs. (Courtesy J. Hetch, MD.) (Right) This term infant with BWS has a protuberant abdomen ﬊, secondary to enlarged liver and kidneys, and a large mouth with macroglossia ﬈. (Courtesy J. Byrne, MD.)

Placental Mesenchymal Dysplasia

Overview of Syndromes: Syndromes

Large Omphalocele

Embryonal Rhabdomyosarcoma Features (Left) This term placenta shows large stem villi with cisternae and peripheralized muscularized vessels with normal tertiary villi, characteristic of placental mesenchymal dysplasia, a feature often seen in BWS. (Courtesy D. Roberts, MD.) (Right) The cells of this embryonal rhabdomyosarcoma have ovoid or spindled nuclei and moderate amounts of eosinophilic cytoplasm. The prominent myxoid stroma, a common feature, imparts a reticular or filigree pattern in this part of the tumor.

Wilms Tumor in Child With BeckwithWiedemann Syndrome

Triphasic Wilms Tumor (Left) Total nephrectomy specimen from a BWS patient with Wilms tumor shows an area of relatively intact residual kidney ﬇ and ureter st. Wilms tumors often weigh > 500 g. (Courtesy L. Erickson, PA.) (Right) Typical triphasic morphology of Wilms tumor is shown. Note the blastemal ſt, epithelial ﬈, and stromal ﬊ components. Wilms tumors (nephroblastoma) represent ~ 60% of all tumors. (Courtesy A. Putnam, MD.)

515

Overview of Syndromes: Syndromes

Beckwith-Wiedemann Syndrome

Adrenal Neuroblastoma

Neuroblastoma Cells

Hepatoblastoma Gross Appearance

Cross Section of Hepatoblastoma

Hep-Par1(+) Hepatoblastoma Cells

Variable β-Catenin Immunoexpression

(Left) Adrenal gland from a patient with BWS shows a medullary mass surrounded by yellow adrenal cortex. This cut surface shows a tumor with a gray-pink appearance. (Right) An adrenal medullary tumor in a patient with BWS is composed of round blue cells, separated by thin fibrovascular stroma.

(Left) Gross photograph shows a liver mass from a 3-year-old child with BWS and a biopsyproven hepatoblastoma. The surface shows a large area of capsular thickening. (Right) Cross section of the liver of a 3-year-old patient with a hepatoblastoma shows an irregular, multilobulated, welldemarcated mass occupying most of the 12-cm resected specimen. There is a large necrotic area. The patient also had lower lobe metastatic hepatoblastoma lesions.

(Left) Hepatoblastoma in this patient with BWS shows diffuse immunopositivity for Hep-Par1 by the tumor cells. These cells are also positive for glypican-3 and INI1. (Right) β-catenin stain shows a membranous pattern within the fetal component ﬇ of this hepatoblastoma, while within the embryonal component ﬊ shows a nuclear pattern.

516

Beckwith-Wiedemann Syndrome

Adrenal Cortical Cytomegaly (Left) Adrenal cortex of a child with BWS shows large polyhedral cells with hyperchromatic nuclei and foci of extramedullary hematopoiesis. (Courtesy D. Roberts, MD.) (Right) Adrenal cortical cytomegaly, a characteristic finding in BWS, is shown. There are large polyhedral cells with hyperchromatic nuclei ﬈. (Courtesy D. Roberts, MD.)

Adrenal Cortex

Overview of Syndromes: Syndromes

Adrenal Cortical Cytomegaly

Adrenal Cortical Adenoma (Left) Adrenal cortical cytomegaly is usually present in children with BWS. The adrenal cortical cells are composed of a mixture of small cells and large polyhedral cells with markedly enlarged nuclei st. (Right) Adrenal cortical adenoma composed of large cells with eosinophilic cytoplasm and enlarged hyperchromatic nuclei is shown. Besides BWS, other syndromes associated with adrenal cortical adenoma include MEN1, McCuneAlbright, Carney complex, congenital adrenal hyperplasia, and Carney triad.

Mitosis in Adrenal Cortical Carcinoma

Pulmonary Metastases of Adrenal Cortical Carcinoma (Left) Adrenal cortical carcinoma in a child with BWS shows that the tumor is composed of large cells with nuclear pleomorphism, prominent nucleoli, and numerous mitotic figures ﬉. This tumor metastasized to the lung within 6 months of diagnosis. (Right) A focus of metastatic adrenal cortical carcinoma to the lung ﬊ is shown in this 6 month old with BWS.

517

Overview of Syndromes: Syndromes

Birt-Hogg-Dubé Syndrome

Age at Presentation

– In flexural areas • Fibrofolliculomas and trichodiscomas present as ○ Multiple skin-colored smooth papules ○ Location – Face – Neck – Upper trunk ○ During 3rd and 4th decades in 80% of affected adults • Pulmonary cysts ○ Rupture can lead to pneumothorax in 80% • Renal tumors ○ 25-35% of patients

• Cutaneous lesions after age 30 years

Imaging Studies

TERMINOLOGY Abbreviations • Birt-Hogg-Dubé syndrome (BHDS)

Synonyms • Hornstein-Knickerberg syndrome • Hornstein-Birt-Hogg-Dubé syndrome • OMIM 135150

EPIDEMIOLOGY

• Chest CT ○ Multiple and bilateral pulmonary cysts ○ In basilar and mediastinal regions of lungs • Abdominal MR or CT ○ For renal tumors

GENETICS Inheritance • Autosomal dominant

Gene Defect • FLCN gene on chromosome 17q11.2 ○ Encodes for folliculin (tumor suppressor gene) • Most germline mutations detected in 84% of affected families involve FLCN gene ○ Frameshift or nonsense mutations ○ Resulting in protein truncation ○ Involved in mTOR signaling pathway • ~ 150 unique mutations in FLCN gene are reported to be associated with BHDS • Specific mutations (exon 9) have been associated with greater number of lung cysts

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Findings • Cutaneous triad ○ Fibrofolliculomas ○ Trichodiscomas – On face and neck ○ Acrochordons

ASSOCIATED NEOPLASMS Skin • Skin manifestations ○ Seen in 58-90% of patients ○ In 3rd or 4th decade • Fibrofolliculomas and trichodiscomas ○ Considered to be tumors within histologic spectrum ○ Tumors of perifollicular mesenchyme • Fibrofolliculoma ○ Interconnecting epithelial strands extending from hair follicles ○ Fibrotic stroma • Trichodiscoma ○ Fascicles of loose connective tissue ○ Admixed myxoid stroma ○ Folliculosebaceous collarette surrounding proliferation • Acrochordons ○ Polypoid growth of skin • Perifollicular fibroma

Clinical Appearance of Fibrofolliculoma (Left) Multiple smooth, skincolored to slightly hypopigmented papules are seen on the cheek and nose in a patient with Birt-Hogg-Dubé syndrome. (Courtesy B. Goldberg, MD.) (Right) This perifollicular fibroma has the same loose stroma as in fibrofolliculoma/ trichodiscoma. The stroma is concentric around hair follicle epithelium, with clefting from the surrounding normal dermis. On step sections, some perifollicular fibromas show changes of fibrofolliculoma, suggesting they are related lesions.

518

Perifollicular Fibroma

Birt-Hogg-Dubé Syndrome • Tumor > 3 cm ○ Nephron-sparing surgery ○ Radiofrequency ablation ○ Cryoablation • After renal surgery, MR each year for 5 years ○ Every 2nd year thereafter

Lung

Colorectal Carcinoma

• Pulmonary cysts ○ In patients > 77 years ○ In 67-90% ○ Usually bilateral ○ Lower lung predominance • 50x increased risk of pneumothorax • 40-75% of patients will experience recurrent spontaneous pneumothorax • Although infrequent, neoplasms include ○ Minimally invasive adenocarcinoma ○ Papillary adenocarcinoma ○ Micropapillary adenocarcinoma ○ Atypical adenomatous hyperplasia ○ Micronodular pneumocyte hyperplasia

• Colonoscopy

Kidney • Renal cell carcinoma ○ Oncocytic (67%) ○ Chromophobe (23%) ○ Clear cell (7%) ○ Oncocytoma (3%) ○ Multifocal ○ Bilateral ○ Slow growing • Histology of renal carcinoma ○ Can be hybrid with > 1 tumor histology • Can be bilateral tumors ○ 56% • Develop multiple tumors ○ 65-77% • Renal cysts • 7x increased risk of developing renal cell carcinoma compared to general population • Risk increases with age

Thyroid • Nodules • Cysts • Carcinoma

Colorectal • Increased risk of colon carcinoma and polyps

Parotid • Oncocytoma

CANCER RISK MANAGEMENT Renal Cell Carcinoma • Annual abdominal MR at age 25 years ○ Every 2nd year thereafter • Tumor > 1 cm and < 3 cm ○ Follow-up with MR every 6 months ○ Or offered ablative therapy

DIFFERENTIAL DIAGNOSIS Familial Multiple Discoid Fibromas • Clinical presentation ○ Multiple ○ Variably sized ○ Telangiectatic facial or ear papules ○ Develop in childhood • Histopathology ○ Similar to trichodiscomas • Distinguishing features from BHDS ○ No association with renal cell carcinoma ○ Low risk of pneumothorax ○ Absence of FLCN mutation

Overview of Syndromes: Syndromes

○ Perifollicular fibrous sheath ○ Surrounds dilated follicular infundibulum • Angiofibroma ○ a.k.a. fibrous papule ○ Vascular telangiectasia ○ Fibrosis with stellate fibroblasts

Tuberous Sclerosis • Clinical presentation ○ Multiple ○ Skin-colored papules ○ On central face • Histopathology ○ Angiofibroma or fibrous papule • Inheritance ○ Autosomal dominant • Distinguishing features from BHDS ○ TSC1 and TSC2 mutations ○ Cutaneous lesions – Hypomelanotic macules – "Confetti" macules – Periungual fibromas – Shagreen patch (connective tissue nevus) ○ Brain – Cortical tubers – Subependymal nodules – Subependymal giant cell astrocytoma ○ Retina – Hamartomas – Achromic patch ○ Kidney – Angiomyolipoma – Cysts ○ Cardiac rhabdomyoma ○ Pulmonary lymphangioleiomyomatosis ○ Hamartomatous rectal polyps

Cowden Syndrome/PTEN-Hamartoma Tumor Syndrome • Inheritance ○ Autosomal dominant • Cutaneous lesions ○ Multiple smooth to verrucous, skin-colored papules 519

Overview of Syndromes: Syndromes

Birt-Hogg-Dubé Syndrome ○ Early-onset (< 50 years) renal cell carcinoma ○ Multiple bilateral renal tumors ○ Renal tumors of chromophobe or oncocytic type

○ On face or ear • Histopathology ○ Trichilemmomas • Distinguishing features from BHDS ○ PTEN mutation ○ Oral papillomatosis ○ Acral keratosis ○ Sclerotic fibroma ○ Tumor of the follicular infundibulum ○ Associated neoplasms – Breast carcinoma – Thyroid carcinoma

SELECTED REFERENCES 1.

2.

3.

4.

Lymphangioleiomyomatosis • Affects women more frequently than men • Recurrent pneumothorax • Distinguishing features from BHDS ○ Renal angiomyolipomas ○ Pulmonary function tests show chronic obstructive pattern, unlike BHD syndrome ○ Cysts are smaller and uniform in size and shape in comparison to those of BHD syndrome ○ Diffuse distribution throughout both lungs

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7. 8.

9. 10.

DIAGNOSIS Criteria • Should fulfill 1 major criterion or 2 minor criteria for diagnosis • Major criteria ○ At least 5 fibrofolliculomas or trichodiscomas, of adultonset (at least 1 histologically confirmed) ○ FLCN mutation • Minor criteria ○ Lung cysts – Multiple – Bilateral – Basal location – ± spontaneous pneumothorax ○ 1st-degree relative with BHDS

Fibrofolliculoma (Left) This fibrofolliculoma shows characteristic reticulated, lace-like, thin strands of epithelium extending away from hair follicles. The reticulated epithelium is embedded in a myxoid stroma. (Right) Highmagnification view shows a typical fibrofolliculoma with a loose stroma in which there are reticulated, thin strands of epithelium.

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12. 13.

14.

15.

Furuya M et al: Pathology of Birt-Hogg-Dubé syndrome: a special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review. Pathol Int. 69(1):1-12, 2019 Johannesma PC et al: Renal imaging in 199 Dutch patients with Birt-HoggDubé syndrome: screening compliance and outcome. PLoS One. 14(3):e0212952, 2019 Park HJ et al: Differentiation between lymphangioleiomyomatosis and BirtHogg-Dubé syndrome: analysis of pulmonary cysts on CT images. AJR Am J Roentgenol. 212(4):766-72, 2019 Freifeld Y et al: Imaging for screening and surveillance of patients with hereditary forms of renal cell carcinoma. Curr Urol Rep. 19(10):82, 2018 Hasumi H et al: BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes. Hum Mol Genet. ePub, 2018 Iwabuchi C et al: Skin lesions of Birt-Hogg-Dubé syndrome: clinical and histopathological findings in 31 Japanese patients who presented with pneumothorax and/or multiple lung cysts. J Dermatol Sci. 89(1):77-84, 2018 Maher ER: Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management. World J Urol. 36(12):1891-8, 2018 Furuya M et al: Pulmonary neoplasms in patients with Birt-Hogg-Dubé syndrome: histopathological features and genetic and somatic events. PLoS One. 11(3):e0151476, 2016 Gupta N et al: Birt-Hogg-Dubé syndrome. Clin Chest Med. 37(3):475-86, 2016 Tobino K et al: Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol. 81(6):13406, 2012 Houweling AC et al: Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer. 105(12):1912-9, 2011 Kluger N et al: Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 162(3):527-37, 2010 Misago N et al: Fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/angiofibroma): a revaluation of the histopathological and immunohistochemical features. J Cutan Pathol. 36(9):943-51, 2009 Toro JR et al: Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med. 175(10):1044-53, 2007 Schulz T et al: Birt-Hogg-Dubé syndrome and Hornstein-Knickenberg syndrome are the same. Different sectioning technique as the cause of different histology. J Cutan Pathol. 26(1):55-61, 1999

Stroma of Fibrofolliculoma

Birt-Hogg-Dubé Syndrome

Spindle Cells in Trichodiscoma (Left) This lesion, previously termed trichodiscoma, has the same loose stroma as fibrofolliculoma, but absent reticulated strands of epithelium, often with a hair follicle bordering the loose stroma. On step sections, reticulated epithelium is often present, evidence that fibrofolliculoma and trichodiscoma are the same lesion. (Right) At high magnification, bland spindle neoplastic cells are seen within a loose and myxoid stroma in the dermis.

Angiofibroma

Overview of Syndromes: Syndromes

Trichodiscoma

Telangiectatic Vessels in Angiofibroma (Left) Angiofibroma (fibrous papule) has ectatic thin-walled vessels st and dense collagenous stroma surrounding adnexal structures. There may be perifollicular fibrosis ﬈. (Courtesy S. Billings, MD.) (Right) Telangiectatic dermal blood vessels and stellate fibroblasts are noted at higher magnification. The overlying epidermis appears unremarkable. (Courtesy S. Billings, MD.)

Chromophobe Renal Cell Carcinoma

Chromophobe Renal Cell Carcinoma (Left) Chromophobe renal cell carcinoma is typically well circumscribed with a tan-gray, multilobulated cut surface. Hemorrhage and necrosis ﬇ are grossly identified in > 25% of cases. (Courtesy S. Tickoo, MD.) (Right) Typically, a chromophobe renal cell carcinoma shows solid sheets of clear and eosinophilic cells, separated by thin and incomplete vascular septations ﬈ that do not completely encircle cell nests.

521

Overview of Syndromes: Syndromes

Bloom Syndrome

TERMINOLOGY

EPIDEMIOLOGY

Abbreviations

Incidence

• Bloom syndrome (BS)

• Exceedingly rare (< 300 individuals in Bloom Syndrome Registry in 2016) • Parental consanguinity common • ~ 1/4 of patients with BS are of Jewish descent, particularly Central and Eastern European (Ashkenazi) Jewish background ○ Seen in 1/48,000 live births in this population

Synonyms • Bloom-Torre-Machacek syndrome • Congenital telangiectatic erythema

Definition • Rare autosomal recessive disorder resulting from mutations in BLM gene; first described by dermatologist Dr. David Bloom in 1954 • Characterized by severe pre- and postnatal growth deficiency, immunodeficiency, increased risk for malignancies, craniofacial dysmorphisms, and typical erythematous sun-sensitive skin lesions

ETIOLOGY/PATHOGENESIS Molecular Pathogenesis • Caused by biallelic mutations in BLM gene, located at 15q26.1 (most commonly homozygous; less frequently compound heterozygous) ○ Described mutations include missense, nonsense, insertions/deletions, and splicing defects due to intronic mutations

Increased Sister Chromatid Exchanges

Sister chromatid exchange (SCE) analysis performed on cells from a Bloom syndrome patient is shown. Note the markedly increased number of SCEs.

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Bloom Syndrome • Lymphoma (predominantly non-Hodgkin lymphoma, less frequently Hodgkin lymphoma)

Carcinomas • Arise in varied sites, including skin, head, neck, lung, uterus, breast, and gastrointestinal tract [including esophagus (both squamous cell carcinoma and adenocarcinoma), stomach, and colon]

Rare Tumor Types

ANCILLARY TESTS

• Medulloblastoma, Wilms tumor, osteogenic sarcoma

Confirmation of Diagnosis

Carriers

• Cytogenetic testing ○ Diagnostic test: Evaluation for increased number of sister chromatid exchanges (SCEs) in any cell (typically peripheral blood lymphocytes) – Cells are cultured for 2 cell cycles in medium containing bromodeoxyuridine (BrDu) and arrested at metaphase – Upon fluorescence-plus-Giemsa coloration, differential staining of 2 sister chromatids is apparent (1 appears dark, 1 appears light) – In BS, sister chromatids show increased number of exchanges [at least 10x increase compared to control, therefore 40-100 SCEs (normal SCEs are < 10 per metaphase)] ○ Increase in random chromosome breakage seen on metaphase spread, including chromatid gaps, breaks and rearrangements, chromatid interchange configurations such as quadriradial interchange configuration, telomeric associations, anaphase bridges, and lagging chromosomal fragments • Molecular testing ○ Targeted mutation analysis (e.g., evaluation of c.2207_2212delinsTAGTTC, present in 93% of patients of Ashkenazi Jewish descent) ○ Sequence analysis of entire coding region ○ Deletion/duplication analysis

• BLM mutation carriers do not have increased cancer risk

Prenatal Testing • Can be performed via SCE analysis or by specific mutation testing if familial mutation is known (chorionic villous sampling or amniocentesis)

CANCER RISK MANAGEMENT Patients With Bloom Syndrome • Markedly increased risk of variety of malignancies, which occur earlier compared to general population, necessitates careful and broad cancer surveillance throughout patient's life • Exposure to radiation or DNA-damaging chemicals should be avoided

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2. 3. 4. 5.

6. 7. 8. 9. 10. 11.

ASSOCIATED NEOPLASMS Increased Cancer Risk • Up to 50% of patients with BS will develop malignancy ○ ~ 10% have ≥ 2 primary cancers, with fewer numbers reported to have 3, 4, or even 5 primary neoplasms • Mean age of cancer diagnosis: ~ 24 years • Hematolymphoid malignancies predominant in first 2 decades of life • Carcinomas predominant after first 2 decades of life • Increased cancer incidence shortens overall lifespan

Hematolymphoid Malignancies

Overview of Syndromes: Syndromes

• BLM is tumor suppressor gene and belongs to family of RecQ DNA helicases ○ RecQ helicases are important for repair of DNA damage ○ Protein product (BLM) permits unwinding of DNA in order to resolve disruptive structures that have developed during replication ○ Mutations in other RecQ helicase genes result in additional DNA repair deficiency syndromes

12. 13.

14.

15.

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Bale TA et al: Financially effective test-algorithm to identify an aggressive, EGFR-amplified variant of IDH-wildtype, lower-grade diffuse glioma. Neuro Oncol. 21(5):596-605, 2019 Bouman A et al: Bloom syndrome does not always present with sunsensitive facial erythema. Eur J Med Genet. 61(2):94-7, 2018 Martin CA et al: Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Hum Genet. 103(3):456, 2018 de Renty C et al: Bloom syndrome: why not premature aging? A comparison of the BLM and WRN helicases. Ageing Res Rev. 33:36-51, 2017 Amor-Guéret: Bloom syndrome. Orphanet encyclopedia. http://www.orpha.net/data/patho/GB/uk-Bloomsyndrome.pdf. Published September 2013. Accessed September, 2013 Weil Cornell Medical College: the Bloom's Syndrome Registry. http://weill.cornell.edu/bsr. Accessed September 17, 2013 Seif AE: Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genet. 204(5):227-44, 2011 German J et al: Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Hum Mutat. 28(8):743-53, 2007 Poppe B et al: Chromosomal aberrations in Bloom syndrome patients with myeloid malignancies. Cancer Genet Cytogenet. 128(1):39-42, 2001 German J: Bloom syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet. 93(1):100-6, 1997 Straughen J et al: Physical mapping of the Bloom syndrome region by the identification of YAC and P1 clones from human chromosome 15 band q26.1. Genomics. 35(1):118-28, 1996 Ellis NA et al: The Bloom syndrome gene product is homologous to RecQ helicases. Cell. 83(4):655-66, 1995 German J et al: Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc Natl Acad Sci U S A. 91(14):6669-73, 1994 McDaniel LD et al: Elevated sister chromatid exchange phenotype of Bloom syndrome cells is complemented by human chromosome 15. Proc Natl Acad Sci U S A. 89(17):7968-72, 1992 Chaganti RS et al: A manyfold increase in sister chromatid exchanges in Bloom syndrome lymphocytes. Proc Natl Acad Sci U S A. 71(11):4508-12, 1974 Bloom D: Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 88(6):754-8, 1954

• Leukemia (both acute myeloid leukemia and acute lymphoblastic leukemia) ○ May be preferential occurrence of monosomy 7 (-7) and deletion of long arm of chromosome 7 (del[7q]) in myelodysplastic syndrome/acute myeloid leukemia in BS patients 523

Overview of Syndromes: Syndromes

Brooke-Spiegler Syndrome

TERMINOLOGY Synonyms • Brooke-Spiegler syndrome (BSS) ○ OMIM 605041 • Multiple familial trichoepitheliomas (MFT) ○ OMIM 601606 • Familial cylindromatosis (FC) ○ OMIM 132700 • Features of BSS, FC, and MFT can occur in same individual or in different individuals within single family

Definitions • All 3 syndromes have overlapping clinical, pathologic, and genetic features • They are now considered to be allelic diseases with same genetic basis ○ Phenotypic variations of same syndrome

EPIDEMIOLOGY Incidence • Estimated prevalence of CYLD mutations is > 1:1,000,000

Age at Presentation • Adolescence • Early adulthood • Women are more often affected

ETIOLOGY/PATHOGENESIS Inheritance • • • •

Autosomal dominant Sporadic cases can occur High penetrance Variable phenotypic expression

Gene • Tumor suppressor gene located on chromosome 16q12q13 • CYLD encodes deubiquitinating enzyme that negatively regulates nuclear factor-κB

• Germline CYLD mutations are detected in ○ 80-85% of BSS patients ○ 40-50% of MFT patients • Most CYLD mutations are ○ Frameshift (50%) ○ Nonsense (25%) ○ Missense (15%) ○ Large genomic deletions (3%)

CLINICAL IMPLICATIONS Clinical Findings • BSS ○ Multiple tumors – Spiradenoma – Cylindroma – Spiradenocylindroma – 10-30 to hundreds – 0.5-3.0 cm in size – On head and neck areas ○ Spiradenomas – Painful – Blue dermal nodules ○ Trichoepitheliomas – Bilateral – Small – Skin-colored papules – On nasolabial folds ○ Rarely with salivary gland tumors – Most commonly parotid gland • MFT ○ Numerous trichoepitheliomas ○ Present as skin-colored papules or firm nodules ○ Symmetrical ○ Bilateral ○ On central face – Especially around nose • FC ○ Numerous cylindromas

Multiple Familial Trichoepitheliomas (Left) A 9-year-old girl with multiple familial trichoepithelioma syndrome presented with many trichoepitheliomas several millimeters in size on her bilateral cheeks, nose, and forehead. Her father also has similar facial lesions. (Courtesy C. Verder, MD.) (Right) Biopsy of several facial lesions on the same patient shows a proliferation of basaloid cells with differentiation toward the follicular germinative epithelium, consistent with trichoepithelioma.

524

Trichoepithelioma in Brooke-Spiegler

Brooke-Spiegler Syndrome

DIFFERENTIAL DIAGNOSIS Neurofibromatosis Type 1

ASSOCIATED NEOPLASMS Skin • Syndrome results from defects in regulation of putative stem cells of folliculo-sebaceous-apocrine unit leading to different skin appendage tumors • Tumors are disfiguring and often painful • Spiradenoma ○ Well-demarcated nodule(s) ○ Encapsulation can be seen ○ Stroma can be vascular and hemorrhage can be prominent ○ Composed of eosinophilic inner cells surrounded by small and dark basaloid cells • Cylindroma ○ Jigsaw puzzle arrangement of multiple lobules of basaloid cells ○ Uniform basaloid cells and larger paler cells ○ Surrounded by eosinophilic basement membrane material ○ Globules of basement membrane material can be seen within tumor nests ○ Ductal differentiation can be focally identified • Spiradenocylindroma ○ Hybrid tumor of spiradenoma and cylindroma • Trichoepithelioma ○ Epithelial structures with differentiation toward follicular germinative epithelium ○ Embedded within fibrotic stroma ○ Papillary mesenchymal bodies • Carcinomas developing from preexisting spiradenoma, cylindroma, and spiradenocylindroma in 5-10% of cases; can exhibit 4 histopathologic patterns ○ Salivary gland-type basal cell adenocarcinoma-like, low grade ○ Salivary gland-type basal cell adenocarcinoma-like, high grade ○ Invasive adenocarcinoma, not otherwise specified ○ Sarcomatoid carcinoma

Salivary Gland • At risk of developing tumors of major and minor salivary glands • Most commonly, membranous basal cell adenoma • Adenocarcinomas of parotid glands and minor salivary glands • Malignant salivary gland tumors are very rare

Breast • Malignant transformation of spiradenoma

CANCER RISK MANAGEMENT • Although malignant transformation is not common, close monitoring for ulceration rapid growth and bleeding is warranted for prompt excision

• Developed in < 90% by puberty ○ Multiple small cutaneous neurofibromas ○ Café au lait spots ○ Iris Lisch nodules • Distinguishing features from BSS ○ Germline mutations of NF1 (neurofibromin 1) ○ Freckling of axilla and inguinal regions ○ Musculoskeletal abnormalities (sphenoid bone dysplasia, congenital hydrocephalus) ○ Iris Lisch nodules ○ Pain &/or paralysis due to peripheral nerve sheath tumor ○ Malignant transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumor

Overview of Syndromes: Syndromes

○ Present as painless, smooth, and pink nodules on scalp ○ Can be confluent ("turban" tumor)

Birt-Hogg-Dubé Syndrome • Cutaneous triad ○ Fibrofolliculomas ○ Trichodiscomas ○ Acrochordons • Distinguishing features from BSS ○ FLCN mutations ○ Pulmonary cysts that can lead to spontaneous pneumothorax ○ Renal tumors in 25-35% of patients

Tuberous Sclerosis • • • •

Multiple, skin-colored papules on central face Histologic features: Angiofibroma or fibrous papule Autosomal dominant inheritance Distinguishing features from BSS ○ TSC1 and TSC2 mutations ○ Skin – Hypomelanotic macules – "Confetti" macules – Periungual fibromas – Shagreen patch (connective tissue nevus) ○ Brain – Cortical tubers – Subependymal nodules – Subependymal giant cell astrocytoma ○ Retina – Hamartomas – Achromic patch ○ Kidney – Angiomyolipoma – Cysts ○ Cardiac rhabdomyoma ○ Pulmonary lymphangioleiomyomatosis ○ Hamartomatous rectal polyps

CRITERIA FOR DIAGNOSIS CYLD Testing via PCR and Sanger Sequencing • Should be performed for patients with ○ Multiple cylindromas, spiradenomas, or trichoepitheliomas

525

Overview of Syndromes: Syndromes

Brooke-Spiegler Syndrome ○ Solitary cylindroma, spiradenoma or trichoepithelioma and affected 1st-degree relative with any of these tumors ○ Asymptomatic family member at 50% risk with known mutation in family

7.

8.

SELECTED REFERENCES 9. 1.

2.

3. 4.

5.

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Parren LJMT et al: CYLD mutations differentially affect splicing and mRNA decay in Brooke-Spiegler syndrome. J Eur Acad Dermatol Venereol. 32(8):e331-3, 2019 Parren LJMT et al: Phenotype variability in tumor disorders of the skin appendages associated with mutations in the CYLD gene. Arch Dermatol Res. 310(7):599-606, 2018 Kazakov DV: Brooke-Spiegler syndrome and phenotypic variants: an update. Head Neck Pathol. 10(2):125-30, 2016 Shiver M et al: A novel CYLD gene mutation and multiple basal cell carcinomas in a patient with Brooke-Spiegler syndrome. Clin Exp Dermatol. 41(1):98-100, 2016 Tantcheva-Poór I et al: Report of three novel germline CYLD mutations in unrelated patients with Brooke-Spiegler syndrome, including classic phenotype, multiple familial trichoepitheliomas and malignant transformation. Dermatology. 232(1):30-7, 2016 Dubois A et al: CYLD genetic testing for Brooke-Spiegler syndrome, familial cylindromatosis and multiple familial trichoepitheliomas. PLoS Curr. 7, 2015

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11.

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Malzone MG et al: Brooke-Spiegler syndrome presenting multiple concurrent cutaneous and parotid gland neoplasms: cytologic findings on fine-needle sample and description of a novel mutation of the CYLD gene. Diagn Cytopathol. 43(8):654-8, 2015 Grossmann P et al: Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens. Am J Dermatopathol. 35(1):34-44, 2013 van den Ouweland AM et al: Identification of a large rearrangement in CYLD as a cause of familial cylindromatosis. Fam Cancer. 10(1):127-32, 2011 Blake PW et al: Update of cylindromatosis gene (CYLD) mutations in BrookeSpiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat. 30(7):1025-36, 2009 Kazakov DV et al: Morphologic diversity of malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma based on the study of 24 cases, sporadic or occurring in the setting of Brooke-Spiegler syndrome. Am J Surg Pathol. 33(5):705-19, 2009 Young AL et al: CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 70(3):246-9, 2006 Zhang G et al: Diverse phenotype of Brooke-Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene. Exp Dermatol. 15(12):966-70, 2006 Bowen S et al: Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 124(5):919-20, 2005

Infiltrative Basal Cell Adenocarcinoma

Salivary Gland Basal Cell Adenocarcinoma

Basal Cell Adenocarcinoma

Basal Cell Adenocarcinoma

(Left) Patients with BrookeSpiegler syndrome are at risk of developing adenocarcinoma of the salivary glands. The infiltrative architecture characterized by extension of small tumor nests into the surrounding fibroadipose tissue and parotid parenchyma is supportive of a low-grade adenocarcinoma. (Courtesy V. Nosé, MD, PhD.) (Right) The tumor nests here are composed of basaloid neoplastic cells separated by fibrous bands with lymphoplasmacytic infiltrate ﬇. (Courtesy V. Nosé, MD, PhD.)

(Left) At higher magnification, eosinophilic basement membrane material ﬊ is seen surrounding these basaloid tumor nests. The basaloid tumor cells are uniform and have scant cytoplasm. (Courtesy V. Nosé, MD, PhD.) (Right) The eosinophilic basement membrane ﬊ is prominent around as well as within the tumor nests. These features are all consistent with a low-grade basal cell adenocarcinoma, membranous type. (Courtesy V. Nosé, MD, PhD.)

526

Brooke-Spiegler Syndrome

Merkel Cells in Trichoepithelioma (Left) This trichoepithelioma in a patient with Brooke-Spiegler syndrome has prominent stromal mucin ﬊, raising the possibility of a basal cell carcinoma. (Right) The presence of intratumoral Merkel cells is supportive of the tumor being a trichoepithelioma rather than a basal cell carcinoma, which typically lacks intratumoral Merkel cells.

Low-Power View of a Cylindroma

Overview of Syndromes: Syndromes

Trichoepithelioma With Mucin

Basement Material in Cylindroma (Left) This jigsaw puzzle appearance at low magnification is very characteristic of cylindroma. (Right) Characteristic of cylindroma are the eosinophilic basement membrane materials. These materials both present as hyaline droplets within the tumor nests ﬊ and surround the tumor nests ﬇.

Well-Demarcated Spiradenoma

Spiradenoma Cellular Composition (Left) Spiradenoma is characterized by a welldemarcated nodule in the dermis. This is often known as "blue ball in the dermis," and the clinical presentation is often a painful nodule. (Right) Spiradenoma is composed of 2 types of cells: Inner eosinophilic cells are surrounded by small and dark basaloid cells. The stromal vasculature can be prominent in some cases.

527

Overview of Syndromes: Syndromes

Carney Complex – Birt-Hogg-Dubé – Neurofibromatosis – Other phacomatoses and hamartomatoses

TERMINOLOGY Abbreviations • Carney complex (CNC)

EPIDEMIOLOGY

Synonyms • LAMB syndrome (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) • NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, and ephelides)

Incidence • > 750 patients have been identified as having CNC • Cardiac myxomas are most common primary cardiac tumor and occur in 7 per 10,000 individuals

Definitions

Age

• Autosomal dominant tumor syndrome caused by PRKAR1A mutations leading to ○ Spotty skin pigmentation with typical distribution (lips, conjunctiva and canthi, and vaginal and penile mucosa) ○ Myxomatosis: Cutaneous, mucosal, breast, and cardiac myxomas ○ Primary pigmented nodular adrenocortical disease (PPNAD) ○ Acromegaly due to growth hormone (GH)-producing adenoma ○ Schwannomas ○ Multiple other endocrine and nonendocrine neoplasms – Nonfunctioning tumors of thyroid, testes, ovary ○ Rarely tumors in liver and pancreas • Other disease-related genes, including PRKACA and PRKACB activating mutations, have also been associated with CNC • May occur sporadically as result of de novo genetic defect • CNC may simultaneously involve multiple endocrine glands, as in classic multiple endocrine neoplasia syndromes 1 and 2 • CNC is in essence multiple endocrine neoplasia syndrome, but one that affects number of other tissues ○ This unique condition has similarities to other syndromes/diseases, such as – McCune-Albright – Peutz-Jeghers – Cowden, Bannayan-Zonana (PTEN-hamartoma tumor syndrome)

• Mean patient age at diagnosis is 20 years

Sex • F:M ~ 2:1

ETIOLOGY/PATHOGENESIS Etiology • Autosomal dominant disorder characterized by complex of myxomas, spotty pigmentation, and endocrine overactivity ○ CNC is not only multiple neoplasia syndrome but also causes variety of pigmented lesions of skin and mucosa – Several patients described in earlier years under acronyms NAME and LAMB probably had CNC • Inactivating mutations in PRKAR1A ○ Located at 17q22-24 ○ PRKAR1A encodes regulatory R1 α-subunit of protein kinase A (PKA) ○ PRKAR1A defects associated with CNC lead to PRKAR1A haploinsufficiency and thus to loss of this regulatory subunit's function ○ 70% of patients with CNC occur in familial setting ○ > 120 different PRKAR1A mutations have been identified to date in CNC patients • Other components of complex have been associated with defects of other PKA subunits ○ Catalytic subunit PRKACA is associated with adrenal hyperplasia; catalytic subunit PRKACB is associated with pigmented spots, myxomas, pituitary adenomas

Inner and Outer Eye Canthi Pigmentation (Left) There is conjunctival and inner ſt and outer canthi pigmentation in Carney complex, usually associated with sooty skin pigmentation, with typical distribution in lips and vaginal and penile mucosa. (Courtesy A. Carney, MD.) (Right) Myxoid lesions associated with Carney complex are located in different sites, including skin, heart, and breast. The cardiac myxomas may occur in any chamber and at any age.

528

Cardiac Myxoma

Carney Complex

Criteria for Diagnosis • Clinical characteristics of CNC have been recently reviewed • Definite diagnosis of CNC is given if ○ 2 or more major manifestations are present ○ 1 major manifestation + 1 supplementary criteria • Major diagnostic criteria for CNC ○ Spotty skin pigmentation with typical distribution (lips, conjunctiva, and inner or outer canthi, vaginal and penile mucosa) ○ Myxomas (cardiac, cutaneous, and mucosal) ○ Breast myxomatosis or fat-suppressed MR findings suggestive of this diagnosis ○ PPNAD or paradoxical positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle test ○ Acromegaly due to GH-producing adenoma ○ Large-cell calcifying Sertoli cell tumor (LCCSCT) or characteristic calcification on testicular ultrasound ○ Thyroid carcinoma or multiple hypoechoic nodules on thyroid ultrasound in prepubertal child ○ Psammomatous melanotic schwannomas ○ Blue nevus, epithelioid blue nevus: Pigmented epithelioid melanocytoma ○ Breast ductal adenomas ○ Osteochondromyxoma • Supplementary criteria ○ Affected 1st-degree relative ○ Inactivating mutation of PRKAR1A ○ Activating pathogenic variants of PRKACA or PRKACB mutation or increased copy number • Findings suggestive of, or possibly associated with, CNC but not diagnostic for disease ○ Intense freckling (without darkly pigmented spots or typical distribution), blue nevus, common type (if multiple) ○ Café au lait spots or other birthmarks ○ Multiple skin tags or other skin lesions and lipomas ○ Elevated IGF-I levels, abnormal GTT, or paradoxical GH response to TRH testing in absence of clinical acromegaly ○ Cardiomyopathy ○ History of Cushing syndrome, acromegaly, or sudden death in extended family ○ Pilonidal sinus ○ Lipomas ○ Colonic polyps; usually in association with acromegaly ○ Hyperprolactinemia; usually mild and almost always combined with clinical or subclinical acromegaly ○ Single, benign thyroid nodule in child; multiple thyroid nodules in > 18 years detected on ultrasound ○ Family history of carcinoma, in particular of thyroid, colon, pancreas, and ovary; other multiple benign or malignant tumors • Cutaneous manifestations constitute 3 of major disease manifestations ○ Spotty skin pigmentation with typical distribution (lips, conjunctiva, and inner or outer canthi, genital mucosa)

•

•

•

•

○ Cutaneous or mucosal myxoma ○ Blue nevi (multiple) or epithelioid blue nevus/pigmented epithelioid melanocytoma Findings that are suggestive of, or associated with, CNC findings but not diagnostic ○ Intense freckling (without darkly pigmented spots or typical distribution) ○ Multiple blue nevi of common type ○ Café au lait spots or other birthmarks ○ Multiple skin tags or other skin lesions, including lipomas and angiofibromas Relationship between cutaneous and noncutaneous manifestations of CNC appears to be essential clue to molecular etiology of disease > 1/2 of CNC patients present with both characteristic dermatologic and endocrine signs ○ Significant number of patients present with skin lesions that are only suggestive and not characteristic of CNC Recent classification based on both dermatologic and endocrine markers has subgrouped CNC patients as ○ Multisymptomatic (with extensive endocrine and skin signs) ○ Intermediate (with few dermatologic and endocrine manifestations) ○ Paucisymptomatic (with isolated PPNAD alone and no cutaneous signs)

Overview of Syndromes: Syndromes

○ Activating mutation or increased copy number of PRKACA or PRKACB

Similar Clinical and Pathologic Features • CNC shares skin abnormalities and some nonendocrine tumors with lentiginoses and certain hamartomatoses ○ Peutz-Jeghers syndrome (PJS), with which it shares mucosal lentiginosis and unusual gonadal tumor, and LCCSCT ○ McCune-Albright syndrome, sporadic condition also characterized by multiple endocrine and nonendocrine tumors

CLINICAL IMPLICATIONS Clinical Presentation • Skin ○ Multiple facial lentigines and mucosal labial pigmentation ○ Subcutaneous myxoid neurofibromas • Atrial myxoma ○ Myxomas are most common primary tumor of heart ○ Majority of tumors arise from left atrial septum near fossa ovalis ○ Lesions arising from right atrium or in young adults are more likely to be associated with familial syndrome ○ May present with tumor emboli • Endocrine organs ○ Thyroid – 75% of patients have multiple thyroid nodules □ Follicular hyperplasia, follicular adenoma, follicular carcinoma, and papillary thyroid carcinoma ○ Adrenal gland – PPNAD with Cushing syndrome • Testis ○ LCCSCT, often bilateral • Gastrointestinal tract 529

Overview of Syndromes: Syndromes

Carney Complex ○ Psammomatous melanotic schwannoma in esophagus and stomach • There are groups of CNC patients who show specific genotype-phenotype correlation, and this also explains CNC heterogeneity • Mutations in c.709-7del6 are present in most patients with isolated PPNAD, and most of remaining were c.1AOG carriers

Treatment • Depends on main pathology • Bilateral adrenalectomy, removal of cardiac myxomas, or removal of testicular tumor or other tumors

Prognosis • Historic adjusted average life span for patients with CNC is 50-55 years ○ With careful surveillance, life expectancy may be normal • Most tumors associated with CNC are slow growing with no malignant potential • Sudden death due to cardiac myxoma may occur ○ Complications: Emboli (strokes), postoperative cardiomyopathy, and cardiac arrhythmias ○ Decreased lifespan expected • Complications of Cushing syndrome or acromegaly

MICROSCOPIC General Features • Pigmented epithelioid melanocytoma/epithelioid blue nevus ○ CNC-associated lesions – Poorly circumscribed, wedge-shaped dermal lesions with heavily pigmented spindle and epithelioid cells containing pale nuclei with prominent nucleoli – 2 types of melanocytes: 1 is heavily pigmented, globular, and fusiform, and other is lightly pigmented, polygonal, and spindled • Cardiac myxoma ○ Composed of plump, stellate, or spindled cells arranged in cords and primitive-appearing vessels in loose, myxoid stroma – Stroma often contains hemorrhage or hemosiderin with variable numbers of inflammatory cells ○ Heterologous elements such as glands or extramedullary hematopoiesis can be found in small minority of cases (2%) • PPNAD ○ Nodules composed of cells with compact eosinophilic cytoplasm with abundant brown granular pigment (lipofuscin) ○ Cell nuclei are vesicular and may contain prominent nucleoli ○ Intervening cortical tissue is atrophic and may present myelolipomatous changes • LCCSCT ○ Tumor has ill-defined periphery ○ Multiple cellular patterns of distribution: Usually solid or trabecular ○ Large tumor cells with abundant granular and eosinophilic cytoplasm ○ Laminated calcospherites are characteristic 530

– May be only few or multiple and often with confluence ○ Mitoses are rare ○ Neutrophilic infiltration is usually present • Pituitary adenoma ○ Adenoma with solid growth pattern ○ Round and polygonal cells with granular eosinophilic cytoplasm with round to oval nuclei ○ Usually GH- &/or prolactin-producing tumors ○ Ultrastructural examination: Large, tightly packed cells with complex interdigitations, abundant rough endoplasmic reticulum, and conspicuous Golgi complexes • Psammomatous melanotic schwannoma ○ Peripheral nerve sheath tumor affecting posterior spinal nerve roots, alimentary tract, bone, and skin ○ Spindle and epithelioid cells intermixed with melanin, psammoma bodies, and adipose tissue ○ Spindle cells are arranged in interlacing fascicles and show whorling and occasionally nuclear palisading ○ ~ 10% are malignant and metastasize ○ Ultrastructural examination: Cells with elongated processes, continuous basal lamina, and melanosomes as well as premelanosomes and intercellular long spacing collagen • Osteochondromyxomas ○ Polymorphic histology, including areas of polygonal, stellate, or bipolar cells ○ Immature osteoid with increased numbers of osteoclasts, indicating rapid bone remodeling

ANCILLARY TESTS Immunohistochemistry • Atrial myxoma ○ Cells stain positive for CD34, CD31, and S100 ○ Calretinin is positive in 74-100% of cases and can be useful to distinguish this lesion from myxoid thrombus • PPNAD ○ Increased expression of glucocorticoid receptor ○ Positive for inhibin-α, Melan-A, and synaptophysin • LCCSCT ○ Positive for vimentin, inhibin-α, NSE, S100, desmin, and smooth muscle actin ○ Negative for α-fetoprotein, HCG, PLAP, podoplanin, OCT3/4, and cytokeratin (may be focally positive) • Psammomatous melanotic schwannoma ○ Positive for S100 protein and vimentin, whereas staining for GFAP, actin, and keratin are negative

Genetic Testing • Genetic heterogeneity with distinct genes ○ Mutations of PRKAR1A on chromosome 17 (17q24) ○ 2 other genetic changes: PRKACA and PRKACB ○ CNC2 on chromosome 2 locus 2p16

DIFFERENTIAL DIAGNOSIS Other Syndromes • Shares clinical features and molecular pathways with other familial lentiginosis syndromes

Carney Complex 2. 3. 4.

McCune-Albright Syndrome • Probably closest to CNC in terms of molecular pathway link • Patients with this condition have characteristic lesions that affect predominantly 3 systems: Skin, endocrine system, and skeleton • Café au lait spots in McCune-Albright syndrome patients are similar to those observed in CNC ○ Tend to be more intensely pigmented • Caused by postzygotic activating mutations of gene encoding adenylate cyclase stimulating G α protein (GNAS1) of heterotrimeric G protein

Peutz-Jeghers Syndrome • Autosomal dominant familial lentiginosis syndrome characterized by melanocytic macules of lips, buccal mucosa, and digits, multiple gastrointestinal hamartomatous polyps, and increased risk of various neoplasms • Lentigines observed in patients with PJS show similar density and distribution to those in CNC • PJS was first mapped to chromosome 19p13.3, and gene encoding serine threonine kinase 11 (STK11 a.k.a. LKB1) was found to be mutated in most patients

Cowden Disease and Bannayan-Riley-Ruvalcaba Syndrome (PTEN-Hamartoma Tumor Syndrome)

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• Cowden disease and Bannayan-Riley-Ruvalcaba syndrome share clinical characteristics such as mucocutaneous lesions, hamartomatous polyps of gastrointestinal tract, and increased risk of developing neoplasms • Both conditions are caused by mutations in PTEN ○ PTEN is located on 10q23.31 and encodes phosphatidylinositol (3,4,5)-triphosphate 3-phosphatase – Tumor suppressor gene that has been found mutated in number of tumors • Thyroid is usually affected by numerous adenomatous nodules, follicular adenomas, and follicular carcinoma ○ Findings are similar to those familial syndromes characterized by predominance of nonthyroidal tumors – PTEN-hamartoma tumor syndrome, CNC, Werner syndrome, and Pendred syndrome

18.

LEOPARD

27.

• Multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness • Allelic to Noonan syndrome: Both diseases are linked to mutations in PTPN11 (12q24), which encodes nonreceptor tyrosine phosphatase Shp-2 • Protein encoded by this gene is member of protein tyrosine phosphatase family, proteins that are known to regulate variety of cellular processes, including cell growth, differentiation, mitotic cycle, and oncogenic transformation

SELECTED REFERENCES 1.

Kamilaris CDC et al: Carney complex. Exp Clin Endocrinol Diabetes. 127(203):156-64, 2019

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31.

32. 33. 34.

Bosco Schamun MB et al: Carney complex review: genetic features. Endocrinol Diabetes Nutr. 65(1):52-9, 2018 Carney JA et al: The spectrum of thyroid gland pathology in Carney complex: the importance of follicular carcinoma. Am J Surg Pathol. 42(5):587-94, 2018 Graham RP et al: Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology. 68(4):14417, 2018 Idrees MT et al: The World Health Organization 2016 classification of testicular non-germ cell tumours: a review and update from the International Society of Urological Pathology Testis Consultation Panel. Histopathology. 70(4):513-21, 2017 Kirschner LS et al: Carney complex. In: WHO. 269-71, 2017 Lowe KM et al: Cushing syndrome in Carney complex: clinical, pathologic, and molecular genetic findings in the 17 affected Mayo Clinic patients. Am J Surg Pathol. 41(2):171-81, 2017 Hannah-Shmouni F et al: Genetics of gigantism and acromegaly. Growth Horm IGF Res. 30-31:37-41, 2016 Schernthaner-Reiter MH et al: MEN1, MEN4, and Carney complex: pathology and molecular genetics. Neuroendocrinology. 103(1):18-31, 2016 Stratakis CA: Carney complex: a familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab Disord. 17(3):367-71, 2016 Stratakis CA: Hereditary syndromes predisposing to endocrine tumors and their skin manifestations. Rev Endocr Metab Disord. 17(3):381-8, 2016 Berthon AS et al: PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors. Front Cell Dev Biol. 3:26, 2015 Salpea P et al: Carney complex and McCune Albright syndrome: an overview of clinical manifestations and human molecular genetics. Mol Cell Endocrinol. 386(1-2):85-91, 2014 Gaal J et al: SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 24(1):147-51, 2011 Janeway KA et al: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 108(1):314-8, 2011 Lodish MB et al: The differential diagnosis of familial lentiginosis syndromes. Fam Cancer. 10(3):481-90, 2011 Nosé V: Familial thyroid cancer: a review. Mod Pathol. 24 Suppl 2:S19-33, 2011 Saggini A et al: Skin lesions in hereditary endocrine tumor syndromes. Endocr Pract. 17 Suppl 3:47-57, 2011 Smith JR et al: Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab. 96(1):34-7, 2011 Horvath A et al: Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update. Hum Mutat. 31(4):369-79, 2010 Kirschner LS: PRKAR1A and the evolution of pituitary tumors. Mol Cell Endocrinol. 326(1-2):3-7, 2010 Lodish MB et al: Rare and unusual endocrine cancer syndromes with mutated genes. Semin Oncol. 37(6):680-90, 2010 Nosé V: Familial follicular cell tumors: classification and morphological characteristics. Endocr Pathol. 21(4):219-26, 2010 Nosé V: Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 17(6):428-36, 2010 Pan L et al: Novel PRKAR1A gene mutations in Carney complex. Int J Clin Exp Pathol. 3(5):545-8, 2010 Storr HL et al: Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation. Horm Res Paediatr. 73(2):115-9, 2010 Vezzosi D et al: Carney complex: clinical and genetic 2010 update. Ann Endocrinol (Paris). 71(6):486-93, 2010 Zhang L, et al: Gastric stromal tumors in Carney triad are different clinically, pathologically and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 34:53-64, 2010 Horvath A et al: Carney complex and lentiginosis. Pigment Cell Melanoma Res. 22(5):580-7, 2009 Stratakis CA: New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Mol Cell Endocrinol. 300(12):152-7, 2009 Stratakis CA et al: The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 266(1):43-52, 2009 Mateus C et al: Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol. 59(5):801-10, 2008 Nosé V: Familial non-medullary thyroid carcinoma: an update. Endocr Pathol. 19(4):226-40, 2008 Horvath A et al: Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J Clin Endocrinol Metab. 91(2):584-96, 2006

Overview of Syndromes: Syndromes

○ In all of these conditions, skin lesions accompany underlying endocrine &/or other abnormalities and, similarly to CNC, are considered important diagnostic sign

531

Overview of Syndromes: Syndromes

Carney Complex Genomic Locus and Genes Associated With Carney Complex Locus/Gene

Chromosomal Locus

Mutation Type

Expression/Protein

PRKAR1A (CNC1)

17q24

Large deletions in ~ 20% of patients thought to be PRKAR1A mutation negative

Almost all mutations generate premature stop codon, leading to nonsense-mediated mRNA decay and absence of R1α protein, although some PRKAR1A mutations in CNC were demonstrated to lead to expressed R1α that had lost its inhibitory effect on PKA signaling

Missense, nonsense, frameshift (< 125 pathogenic mutations)

PRKACA

19p13.1

Large gene amplification

Overexpression

PRKACB

1p31.1

Large gene amplification

Overexpression

CNC2

2p16

N/A

N/A

CNC = Carney complex; PKA = protein kinase A.

Syndromes With Similar Tissue Manifestations as Carney Complex Disease per Organ

Related Disorders

Skin: Lentigines

Familial lentiginosis  Peutz-Jeghers syndrome LEOPARD syndrome Noonan syndrome with lentiginosis Bannayan-Riley-Ruvalcaba syndrome

Skin: Café au lait spots

McCune-Albright syndrome Neurofibromatosis type 1 Neurofibromatosis type 2 Watson syndrome

Skin: Pigmented epithelioid melanocytoma/blue nevus

Sporadic solitary lesions

Heart: Cardiac myxomas

Sporadic myxomas in adults: Most common type of cardiac tumor Sporadic myxomas in children: ~ 30% of cardiac tumors Familial myxomas due to mutation of protein of myosin family

Thyroid: Tumors

Cowden/PTEN-hamartoma tumor syndrome Sporadic thyroid tumor

Thyroid hyperplasia

Cowden/PTEN-hamartoma tumor syndrome Familial multinodular goiter Sporadic 

Adrenals

Sporadic isolated PPNAD Isolated micronodular adrenocortical hyperplasia

Adrenal tumors

Beckwith-Wiedemann syndrome Li-Fraumeni syndrome Multiple endocrine neoplasia type 1 (MEN1) Congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency McCune-Albright syndrome

Pituitary: GH-secreting adenoma

MEN1 IFS Sporadic somatotropinomas

Testes: LCCSCT

Peutz-Jeghers syndrome

Ovary: Tumors

Peutz-Jeghers syndrome

Schwannomas

Neurofibromatosis type 1 Neurofibromatosis type 2 Isolated familial schwannomatosis

GH = growth hormone; IFS = isolated familial somatotropinomas; LCCSCT = large-cell calcifying Sertoli cell tumor; PPNAD = primary pigmented nodular adrenocortical disease.

532

Carney Complex

Vascular Invasion in Follicular Carcinoma (Left) Spotty skin pigmentation is characteristic of Carney complex, with typical distribution in lips ﬈, conjunctiva, inner or outer canthi, and vaginal and penile mucosa. (Courtesy A. Carney, MD.) (Right) Patients with Carney complex have a variety of thyroid findings. The thyroid is usually affected by numerous hyperplastic nodules, follicular adenomas, follicular carcinoma, &/or papillary thyroid carcinoma. Vascular invasion is shown here.

Large Atrial Myxoma

Overview of Syndromes: Syndromes

Skin and Mucosal Pigmentation in Carney Complex

Atrial Myxoma (Left) Lateral radiograph shows densely calcified left atrial myxoma ﬈ in a patient with multiple transient ischemic attacks, a clinical feature associated with cardiac myxoma. (Right) Axial CECT shows myxoma involving the interarterial septum and extending into the right atrium ſt. A tumor embolism is seen in a right lower lobe pulmonary artery branch st. The tumor has a different density than adipose tissue.

Cardiac Myxomas

Hypocellular Cardiac Myxoma (Left) Cardiac myxomas in Carney complex are usually multifocal and found in the atria and in the ventricles. Photographs show intact ﬇ and cut gross surgical specimen ﬊ depicting the redbrown cut surface and adherent right atrial wall. (Courtesy J. Stone, MD.) (Right) Histologically, the cardiac myxomas in Carney complex are hypocellular with only scattered spindle cells, multinucleated cells, and polygonal cells in large pools of myxoid matrix. (Courtesy J. Stone, MD.)

533

Overview of Syndromes: Syndromes

Carney Complex

Adrenal Involvement in Carney Complex

Variable-Sized Pigmented Nodules

Nodular Adrenal Cortex

Enlarged Cortical Cells With Pigment

Pigmented Melanotic Schwannoma

Spindle Cells in Melanotic Schwannoma

(Left) The gross findings of primary pigmented nodular adrenocortical disease (PPNAD) include decreased, normal, or slightly increased weight, the presence of small black-brown ﬇ and yellow nodules, atrophy of the cortex, and loss of normal zonation. (Right) Gross cross section of an adrenal gland from a child with Cushing syndrome is shown. There are multiple dark pigmented nodules, from minute to large. These gross findings are characteristic of Carney complex and PPNAD.

(Left) On low-power magnification, the normal adrenal gland architecture is replaced by multiple nodules, most unencapsulated, but some with a thin fibrous capsule. There is lipomatous metaplasia, and the adjacent adrenal is atrophic. (Right) The adrenal cortex shows loss of zonation and atrophy of cortex adjacent to nodules in PPNAD. The nodules are composed of enlarged globular cortical cells with granular eosinophilic cytoplasm with lipochrome pigment ﬊.

(Left) A well-circumscribed but incompletely encapsulated tumor composed of spindle cells and epithelioid cells, melanin pigment, and psammoma bodies ﬇ is a characteristic feature of a pigmented melanotic schwannoma. (Right) These spindle cells are arranged in interlacing fascicles and show whorling and rare nuclear palisading. These cells are positive for S100 protein and vimentin.

534

Carney Complex Keratin in Sparsely Granulated Growth Hormone Adenoma (Left) Pituitary adenomas, microadenomas ﬇, or macroadenomas, which are usually growth hormone (GH)producing adenomas, are typical findings in Carney complex. (Right) CAM5.2 reveals diffuse paranuclear keratin aggresomes (fibrous bodies) in sparsely granulated somatotroph adenomas. Occasional fibrous bodies can be seen in aggressive acidophil stem cell adenomas as well as in intermediate-type somatotroph adenomas.

Variably Growth Hormone Immunoexpression

Overview of Syndromes: Syndromes

Pituitary Adenoma

Gross Cut Surface of Large-Cell Calcifying Sertoli Cell Tumor (Left) GH shows somatotroph adenomas harboring numerous GH-containing secretory granules with variable staining within the adenomatous cells. (Right) Large-cell calcifying Sertoli cell tumor (LCCSCT) is well circumscribed but not encapsulated. The tumor shows a yellow cut surface. These tumors are usually bilateral and calcified. (Courtesy R. Young, MD.)

Epithelioid Cells and Neutrophils

Calcification and Large Epithelioid Cells (Left) LCCSCT shows cords and small nests of large epithelioid cells embedded in a fibrous background with dense neutrophilic infiltrate. A psammoma body ﬊ is also seen. The neutrophilic background is an important diagnostic feature st. (Right) An LCCSCT is shown with cords of large epithelioid cells containing abundant eosinophilic cytoplasm with irregular nuclei and prominent nucleoli. The hallmark of this tumor is the presence of scattered calcifications.

535

Overview of Syndromes: Syndromes

Colonic Carcinoma Syndromes

TERMINOLOGY Definitions • Colorectal cancer (CRC) is one of most common cancers with diversity of possible pathways of development ○ Despite fact that CRC is histologically homogeneous, each tumor has unique molecular profile, characterized by various genetic and epigenetic changes – It is caused by environmental and genetic factors with > 35% of variation in CRC susceptibility probably explained by inherited causes • Mismatch repair (MMR) genes: Genes that promote genomic stability by initiating DNA repair at time of mitosis • Microsatellites: Short DNA repeats in introns that can be detected as stable or unstable as way of predicting MMR of DNA • Microsatellite instability-high (MSI-H)

Classification of CRC • CRC can be classified as sporadic and familial

• Familial cancer syndromes: Germline mutations associated with increased incidence of specific cancer types ○ Between 20-30% of CRC are familial ○ Many syndromes are related to > 1 cancer type • Set of molecular markers is usually used for CRC classification, helping understanding of causation and facilitating clinical management • Traditional CRC classification ○ Chromosomal instability ○ MSI ○ CpG island methylator phenotype • Jass CRC classification into molecular subtypes (2007) ○ CIMP-H, MSI-H, and BRAF mutation ○ CIMP-H, MSI-L, or MSS/BRAF mutation ○ CIMP-L/MSS or MSI-L/KRAS mutation ○ CIMP-negative/MSS ○ CIMP-negative/MSI-H or Lynch syndrome • Classification system of sporadic CRC based on molecular pathways of its onset and progression (2010) ○ Serrated pathway

Evaluation of Patients With Personal or Familial History of Colonic Polyps/Carcinomas

For patients with a personal or familial history of colonic polyps or colonic carcinoma as part of a familial tumor syndrome, this flow chart guides practitioners toward the proper clinical evaluation depending on the presence or absence of a known pathogenic gene or syndrome.

536

Colonic Carcinoma Syndromes

CRC Characterized by • High frequency of mutations ○ BRAF, APC, TP53, NRAS, KRAS, PIK3CA, SMAD4, SMAD2, SOX9, ARID1A, FBXW7, and AMER1 (FAM123B/WTX) • Methylation status changes ○ MLH1 • Copy number alterations ○ IGF2 and ERBB2 • Impaired expression at mRNA or protein level, and translocations ○ NAV2/TCF7L1

SYNDROMES

• •

•

Familial Adenomatous Polyposis • Autosomal dominant ○ Germline mutation in APC – 1/3 at codon 1061-1309 – Severe polyposis has mutations at codons 1250-1464 – Attenuated polyposis has mutations at 5' and 3' ends of gene – Desmoid tumors associate with mutations at codons 1403-1578 – APC I1307K makes somatic mutations more likely • Incidence: 1 in 5,000 • Hundreds of adenomas in childhood or adolescence • Associated with other tumor formation ○ Gardner syndrome: Osteomas of jaw, epidermoid cysts, thyroid carcinomas, and desmoid tumors ○ Turcot syndrome: Medulloblastoma ○ Periampullary adenoma/carcinoma ○ Desmoid tumors ○ Fundic gland polyps (often with dysplasia) – Despite gastric dysplasia, gastric adenocarcinoma is very uncommon in Western countries

Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) • Autosomal dominant • Germline mutation in DNA MMR genes (MSH2, MLH1, MSH6, PMS2) as well as epithelial cell adhesion molecule (EPCAM) ○ Biallelic mutations lead to multiple cancers at young ages (constitutional MMR deficiency) – Usually PMS2

•

– Café au lait macules similar to neurofibromatosis type 1 ○ Detected by sequelae of MMR; instability in short DNA repeats called MSI-H – 2 of 5 MS regions must be unstable for positive diagnosis ○ IHC for products of MLH1, MSH2, MSH6, and PMS2 can also be performed ○ Specific gene testing may be indicated if either of these tests is positive ○ Next-generation sequencing now able to detect MSI-H as well as identify which, if any, germline mutation is present – Will likely replace IHC screening once price drops Incidence: 1 in 1,000 2-4% of all colorectal carcinoma ○ Lifetime risk of colon cancer is up to 80% – Endometrial cancer: 55% lifetime risk – Ovarian cancer: 15% lifetime risk – Small bowel, stomach, and biliary tract adenocarcinomas, transitional cell carcinomas of renal pelvis and ureter, gliomas, adrenal cortical carcinoma – Sebaceous neoplasms and keratoacanthomas = MuirTorre syndrome – Subset of adenocarcinomas of prostate – Subset of breast carcinomas associated with some MMR gene polymorphisms and biallelic mutations of MMR genes Familial CRC type X is closely related syndrome ○ Patients have appropriate family history without MSI-H tumors ○ As common as hereditary nonpolyposis colorectal cancer (HNPCC) ○ Treated and screened like HNPCC Lynch-like syndrome patients have all features of Lynch but no identifiable mutations

Overview of Syndromes: Syndromes

○ Alternative pathway ○ Traditional pathway • The Cancer Genome Atlas (TCGA) (2012; 2014) ○ 2 major classes of CRC with dramatic difference in gene expression profiles were found – Hypermutated (HM, > 10 nonsilent substitutions per 1 Mb) – Nonhypermutated (non-HM) tumors ○ HM and non-HM tumors revealed following differences in WNT, TGF-β, and RAS – Each group could be subdivided into several subgroups according to alterations in signaling pathways (WNT, TGF-β, RTK/RAS, PI3K, TP53), driver mutations and classical subtyping (CIMP, CIN, MSI)

MUTYH-Associated Polyposis • Autosomal recessive • Biallelic inactivation of MUTYH ○ Normally, this enzyme repairs oxidative damage to guanine ○ Failure of enzyme leads to multiple G-C to T-A transversions in DNA ○ 2 common sites of mutation in gene associated with most cases ○ Immunostain for gene product is now commercially available – Lack of nuclear staining may be potential screening test; needs to be validated ○ Incidence: 1 in 5,000 ○ Clinically and pathologically looks identical to attenuated familial adenomatous polyposis

Serrated (Giant Hyperplastic) Polyposis Syndrome • Genetic basis currently unknown • Incidence: 1 in 100,000 • Initially described as giant hyperplastic polyps, they are now known to be sessile serrated adenomas ○ > 4 proximal serrated polyps of which 2 are > 1 cm or at least 20 pancolonic serrated polyps 537

Overview of Syndromes: Syndromes

Colonic Carcinoma Syndromes ○ Many have adenomas as well ○ Ultimately, this may prove to be several different syndromes with different genetic loci • Risk of tumors outside colon not documented

Hereditary Mixed Polyposis • Autosomal dominant ○ Mutation of GREM1 ○ Incidence unknown • Mixture of adenomas, serrated polyps, mixed polyps, and atypical juvenile polyps • Risk of tumors outside colon not documented

Juvenile Polyposis • Autosomal dominant ○ Mutation of SMAD4 in 30% of cases and BMPR1A in 30% of cases • Incidence: 1 in 100,000 • Multiple hamartomatous polyps (need > 5 unless positive family history) ○ Confined to colon in some patients/families ○ Involves entire GI tract in some patients/families ○ Polyps identical to inflammatory pseudopolyps, especially when small – Larger polyps have dilated cysts characteristic of juvenile polyps ○ Polyps can develop dysplasia/carcinoma • Increased risk of cancer in stomach, small bowel, and pancreas

Peutz-Jeghers Syndrome • Autosomal dominant ○ Mutations in STK11 (a.k.a. LKB1), which encodes serine/threonine kinase • Incidence: 1 in 8,300-120,000 • Multiple hamartomatous polyps throughout GI tract ○ Polyps have characteristic bundles of arborizing smooth muscle – Muscularis mucosae appears hyperplastic – Mimics mucosal prolapse ○ Mucocutaneous pigmentation – Freckles on lips, oral and anal mucosa ○ Increased risk of cancer throughout GI tract, pancreas, ovary, and breast

538

○ Uncertain if risk of stomach and lung cancer is increased

DNA Polymerase ε and δ Polyposis (POLE and POLD1 Mutation-Associated Tumors) • Autosomal dominant inheritance with microsatellite stable tumors • Mutations in proofreading polymerases lead to transversions in DNA • Germline mutations cause predisposition to colorectal multiple polyposis, wide range of neoplasms, and earlyonset CRC • Multiple polyps (10-100): Adenomatous, serrated, or combination of adenomatous and serrated polyps • Other neoplasms ○ POLE: Endometrial, ovarian, brain, pancreas, small intestine, and cutaneous melanoma ○ POLD1: Endometrial and breast cancer

MSH3 Polyposis • Autosomal recessive • MSI-H tumors ○ Colon, stomach, and astrocytomas

NTHL1 Polyposis • Autosomal recessive • Small bowel and colonic adenomas/carcinomas • Endometrial, breast, and bladder carcinomas as well as meningiomas and basal cell carcinomas of skin

SELECTED REFERENCES 1. 2. 3.

4.

5.

6.

7.

PTEN-Hamartoma Syndrome (Cowden/BannayanRiley-Ruvalcaba)

8.

• • • • •

9.

Autosomal dominant; mutation in PTEN Incidence: 1 in 200,000 Multiple hamartomatous polyps throughout GI tract Increased risk of breast and thyroid cancers Increased risk of colon cancer is debatable (only 1 study shows increase)

10. 11. 12.

Li-Fraumeni Syndrome

13.

• Autosomal dominant ○ Mutation in TP53 – Some families have mutation in CHEK2 • Incidence: 1 in 500,000 • Increased risk of soft tissue sarcomas, melanomas, leukemias, brain tumors, and carcinomas of breast, colon, pancreas, and adrenal cortex

14. 15.

16.

Buchanan DD et al: Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. Genet Med. 20(8):890-5, 2018 Fostira F et al: Extending the clinical phenotype associated with biallelic NTHL1 germline mutations. Clin Genet. 94(6):588-9, 2018 Papke DJ Jr et al: Validation of a targeted next-generation sequencing approach to detect mismatch repair deficiency in colorectal adenocarcinoma. Mod Pathol. 31(12):1882-90, 2018 Valle L et al: Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine. J Pathol. 247(5):574-88, 2018 Adam R et al: Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 99(2):337-51, 2016 Shiovitz S et al: Characterisation of familial colorectal cancer Type X, Lynch syndrome, and non-familial colorectal cancer. Br J Cancer. 111(3):598-602, 2014 Valle L et al: New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 23(13):3506-12, 2014 Palles C et al: Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 45(2):136-44, 2013 Patel SG et al: Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep. Oct;14(5):428-38, 2012 Masciari S et al: Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med. 13(7):651-7, 2011 Gatalica Z et al: Pathology of the hereditary colorectal carcinoma. Fam Cancer. 7(1):15-26, 2008 Jass JR: Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract. 204(7):431-47, 2008 Rubio CA et al: Hyperplastic polyposis coli syndrome and colorectal carcinoma. Endoscopy. 38(3):266-70, 2006 Sweet K et al: Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA. 294(19):2465-73, 2005 Rozen P et al: A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol. 98(10):2317-20, 2003 Torem MS: Psychodynamic ego-state therapy for eating disorders. New Dir Ment Health Serv. 99-107, 1986

Colonic Carcinoma Syndromes

Attenuated FAP (Left) Gross photograph of a total colectomy resection specimen from a young patient with familial adenomatous polyposis (FAP) syndrome shows innumerable small (< 5 mm), sessile polyps carpeting the mucosa. This extent of polyposis qualifies as classic FAP. (Right) Gross photograph of a colectomy resection specimen shows only a few colonic polyps in a patient with attenuated FAP.

Larger Polyps in FAP

Overview of Syndromes: Syndromes

Classic FAP With Thousands of Polyps

Colon With Serrated Polyposis (Left) This colon was resected from a patient with FAP, showing numerous polyps on the mucosal surface with variable size, not uniformly distributed. (Right) Gross photograph of a colon shows many polyps, some readily identifiable ﬇ and others that are small st and difficult to identify.

Lynch Syndrome-Associated Colonic Tumor

Juvenile Polyposis (Left) Hereditary colorectal cancer (CRC) syndromes are associated with early onset of CRC and some with risk for extracolonic cancers. Lynch syndrome is characterized by proximally located tumors. Most CRCs are MSI-H with increased intraepithelial lymphocytes and Chron-like reaction. (Right) These colonic polyps have long stalks ﬇ and lobulations st. These findings are characteristic of juvenile polyposis.

539

Overview of Syndromes: Syndromes

Costello Syndrome

TERMINOLOGY

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

RASopathy Family • Group of related genetic disorders due to germline activation of RAS/MAPK pathway • Features include ○ Short stature ○ Heart defects ○ Facial dysmorphism ○ Intellectual disability ○ Cancer predisposition • Costello syndrome (CS, OMIM 218040) • Noonan syndrome (NS, OMIM 163950) • NS with multiple lentigines (LEOPARD syndrome, OMIM 151100) • Noonan-like syndrome with loose anagen hair (OMIM 607721) • Cardiofaciocutaneous syndrome (CFCS, OMIM 115150) • Neurofibromatosis type 1 (OMIM 162200) • Legius syndrome (OMIM 611431)

EPIDEMIOLOGY Incidence • Exceeding rare with 200-300 cases reported worldwide • Estimated prevalence of 1:300,000 to 1.25 million 

Clinical Presentation • Failure to thrive, slow growth, short stature, sparse and fine hair • Characteristic facial features ○ Large mouth ○ Thick lips ○ Low-set ears ○ Epicanthal folds ○ Depressed nose bridge ○ Anteverted nostrils • Redundant skin over neck and hands • Deep palmoplantar creases • Palmoplantar keratoderma • Skeletal abnormalities (short stature, macrocephaly, kyphoscoliosis, positional foot deformity) • Vision problems (nystagmus) • Dental problems • Cardiovascular problems (cardiac hypertrophy, pulmonic stenosis, arrhythmia, aortic dilation) • Chiari 1 malformation • Intellectual disability • Syringomyelia and hydrocephalus

ASSOCIATED NEOPLASMS

GENETICS Inheritance • Autosomal dominant • Almost all reported cases secondary to new mutation

HRAS Mutation • At least 5 different mutations in HRAS, protooncogene on chromosome 11, with p.G12S being most common • H-Ras protein, which helps to control cell growth and division, is overactive in CS • Detected in 80-90% of patients

Skin Papillomas (Most Common Nonmalignant Neoplasm Associated With Costello Syndrome) • Sites of predilection: Perinasal, perioral, perianal • May be seen in children younger than 10 years of age

Rhabdomyosarcoma (Most Common Malignant Neoplasm Associated With Costello Syndrome) • Histopathologic subtypes: Embryonal, alveolar, mixed, pleomorphic, spindle cell type, unclassified

Bladder Carcinoma (Urothelial Carcinoma) • Transitional cell carcinoma: Most common

Clinical Appearance of Costello Syndrome (Left) This young girl with Costello syndrome has the characteristic facies, with thick lips, a large mouth, and prominent epicanthal folds. (Courtesy C. Ko, MD.) (Right) Clinical photograph shows the hand of a patient with Costello syndrome. Deep palmar creases and ulnar deviation are apparent. (Courtesy C. Ko, MD.)

540

Hand Findings in Costello Syndrome

Costello Syndrome

Syndrome

Affected Gene(s)

Mode of Inheritance

Clinical Manifestation

Costello syndrome

HRAS

Autosomal dominant

Coarse facial features Cutaneous defects Papillomas Intellectual disability Malignancy

Noonan syndrome

PTN11, SOS1, RAF1, KRAS, NRAS, SHOC2, BRAF, SOS2, RIT1, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, A2ML1

Autosomal dominant

Webbed or short neck, hypertelorism, downslanting palpebral fissures, ptosis Short stature Mild developmental impairment Malignancy: Neuroblastoma, acute lymphoblastic leukemia, low-grade glioma, rhabdomyosarcoma

Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome)

PTPN11, RAF1, BRAF

Autosomal dominant

Multiple lentigines, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth restriction, sensorineural deafness Electrocardiographic conduction abnormalities

Noonan-like disorder with loose anagen hair

SHOC2, PPP1CB

Autosomal dominant

Hyperactive behavior Macrocephaly, short stature Growth hormone deficiency Loose anagen hair: Easily pluckable, sparse, thin and slow-growing hair with abnormal hair bulb

Noonan-like disorder

CBL

Hyperpigmented cutaneous lesions Microcephaly Developmental delay

Craniofaciocutaneous syndrome

BRAF, MAP2K1, MAP2K2, KRAS Autosomal dominant

Ectodermal abnormalities Intellectual disability Failure to thrive, distinctive facial features, nevi, lentigines, palmar-plantar keratosis, curly hair, intellectual impairment, seizure Associated acute lymphoblastic leukemia, nonHodgkin lymphoma, hepatoblastoma, embryonal rhabdomyosarcoma

Type 1 neurofibromatosis (NF1)

NF1

Autosomal dominant

Multiple café au lait spots, skin-fold freckling, neurofibromas, short stature, macrocephaly, Lisch nodules

Legius syndrome (NF1-like syndrome)

SPRED1

Autosomal dominant

Multiple café au lait spots without neurofibromas Skinfold freckling, macrocephaly, learning disability, lipomas Noonan syndrome-like face

• Low-grade papillary carcinoma

Capillary Malformation-Arteriovenous Malformation

Other Tumors

• Caused by haploinsufficiency of RASA1 (or p120 Ras-GTPase activating protein) • Capillary malformation, arteriovenous malformation

• Neuroblastoma and fibrosarcoma

CANCER RISK MANAGEMENT Rhabdomyosarcoma • Abdominal or pelvic ultrasound every 3-4 months until 8 years of age

SELECTED REFERENCES 1.

2.

Transitional Cell Carcinoma • Annual urinalysis starting at 10 years of age

3. 4.

DIFFERENTIAL DIAGNOSIS Hereditary Gingival Fibromatosis • Mutation in SOS1 • Gingival fibromatosis

Overview of Syndromes: Syndromes

RASopathy Family

5.

6. 7.

Bessis D et al: Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients. Br J Dermatol. 180(1):172-80, 2019 Tajan M et al: The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev. 39(5):676-700, 2018 Altmüller F et al: Genotype and phenotype spectrum of NRAS germline variants. Eur J Hum Genet. 25(7):823-31, 2017 Bertola D et al: Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp. Am J Med Genet A. 173(5):1309-18, 2017 Villani A et al: Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk. Clin Cancer Res. 23(12):e83-90, 2017 Aoki Y et al: Recent advances in RASopathies. J Hum Genet. 61(1):33-9, 2015 Smpokou P et al: Malignancy in Noonan syndrome and related disorders. Clin Genet. 88(6):516-22, 2015

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Overview of Syndromes: Syndromes

Denys-Drash Syndrome ○ C to T transition missense mutation at amino acid 394 in exon 9 involving 3rd zinc finger of WT1 most common ○ Also G to A transition at +5 of splice donor site within intron 9

TERMINOLOGY Abbreviations • Denys-Drash syndrome (DDS)

Definition

GENITALIA

• Disorder characterized by ambiguous genitalia or pseudohermaphroditism, early-onset nephrotic syndrome, and ↑ risk for Wilms tumor (WT)

EPIDEMIOLOGY

External Genitalia • Most are male with pseudohermaphrodism having external female or ambiguous genitalia

Internal Genitalia

Incidence • Very rare, only few hundred cases reported

Gender • Karyotype ○ Most tested are male (46, XY) – Including > 80% of patients with ambiguous external genitalia and > 60% of patients with female external genitalia ○ Few female karyotype probably due to underdiagnosis of DDS in both genotypic and phenotypic females with nephropathy • External genitalia ○ 13% male, 43% female (most are male with pseudohermaphrodism), 44% ambiguous

Age • Onset of nephropathy ○ Typically in 2nd year of life (range: 1 month to 17 years) • Onset of WT ○ Typically in 2nd year of life (range: 1 month to 13 years)

GENETICS WT1 • Located at Chr 11p13 • Critical in early and late stages of genitourinary development • DDS is caused by germline point mutation in zinc finger region of WT1

• Most have dysgenic gonads ○ "Streak gonads" composed of fibrous tissue without epithelial structures ○ Immature, infantile, or rudimentary gonads ○ Wolffian structures present in phenotypic female ○ Both wolffian and müllerian structures present • Less frequently true hermaphrodites: Both testicular and ovarian tissues (ovotestis) present • Only rarely is internal genitalia appropriate to external genitalia

RENAL FEATURES Nephrotic Syndrome • Core feature of DDS, present in 95% of cases • Rapidly progressive to end-stage renal disease (ESRD) at early age (1st or 2nd year of life) • Glomeruli: Diffuse mesangial sclerosis ○ Immature, "fetal-appearing" glomeruli ○ Podocytes – Prominent podocytes with hobnail appearance early in disease process – Proliferation of podocytes forming pseudocrescents, retraction and collapse of glomerular tuft, and glomerular solidification are seen later in disease process – Nuclear expression of WT1 in podocytes absent or decreased, suggesting decreased binding capacity of mutated protein

Male Pseudohermaphrodism (Left) Axial T2 MR of a baby shows the presence of an undescended testis in the right inguinal area ﬈. A vagina is also demonstrated ſt, confirming the presence of internal genital organs of both sexes. (Right) Gonad shows intermingling of both testicular ﬈ and ovarian ﬊ elements. The seminiferous tubule contains mostly Sertoli cells ﬉ and with occasional immature germ cells ﬊. Leydig-like cells are present in interstitium ﬉. Ovarian follicles are present nearby ﬈ with associated spindle cell stroma.

542

Ovotestis

Denys-Drash Syndrome

ASSOCIATED NEOPLASMS WT • Malignant immature tumor of nephrogenic blastemal cell origin that may differentiate into epithelial or mesenchymal cells recapitulating renal embryogenesis • Present in ~ 75% of DDS patients • Age of onset similar to that of nephropathy • May also present as abdominal mass, abdominal pain, or hematuria • ~ 20% of WTs are bilateral ○ Higher than sporadic cases of WT • No distinct histologic features from sporadic WT cases

Gonadal Malignancies • ~ 4% of DDS patients develop gonadal malignancies • Most commonly gonadoblastoma ○ Composed of seminomatous/dysgerminomatous elements and immature sex cord-stromal elements • Juvenile granulosa cell tumor also reported

OTHER ASSOCIATED FINDINGS Structural and Functional Abnormalities • Overall present in 10% of DDS • Can be isolated abnormality (e.g., hernia, contractures) or multiple abnormalities (e.g., cleft palate, intellectual disability, nystagmus) • Renal abnormalities: Unilateral hydronephrosis, renal pelvis or ureter duplication, double kidney, and horseshoe kidney

CANCER RISK MANAGEMENT WT • Bilateral nephrectomy for children with ESRD suggested • For DDS children on dialysis, unilateral nephrectomy suggested, followed by subsequent contralateral nephrectomy at time of kidney transplantation

Gonadal Malignancies • Elective gonadectomy proposed

PROGNOSIS Outcome • With limited cases followed, 32% of patients alive with age range of 3 months to 21 years • 38% of patients died at average age of 2 years (range: 1 month to 7.5 years) • Most common cause of death ○ Renal failure (80%) ○ Sepsis (3.5%) • < 2% of patients died from WT

DIFFERENTIAL DIAGNOSIS WAGR Syndrome

Overview of Syndromes: Syndromes

○ Mesangium – Progressive increase in mesangial matrix with later development of mesangial hypercellularity □ Usually diffuse, but occasionally segmental □ Immunofluorescence negative for immune complex deposition (may have nonspecific trapping in sclerotic areas) ○ Glomerular basement membrane (GBM) – Thickening and multilayering of GBM, few electrondense deposits later in disease process – Can simulate Alport syndrome, but immunofluorescence staining for α-chains of type IV collagen is preserved • Tubulointerstitium ○ Dilated tubules with casts ○ Progressive interstitial fibrosis and tubular atrophy • Vessels: Rare report of associated thrombotic microangiopathy

• Rarely, aniridia and intellectual disability may occur in DDS • WT and genitourinary abnormalities in absence of nephropathy in DDS (~ 5%) can make distinction difficult ○ Diagnosis of DDS made if external genitalia are female and internal genitalia show both wolffian and müllerian structures or karyotype is male

Frasier Syndrome • Phenotype: Ambiguous genitalia, streak gonads, and segmental glomerulosclerosis • Nephropathy similar but usually of later age of onset

Diffuse Mesangial Sclerosis From Other Causes • Without specific phenotypic features of DDS • Can occur as sporadic finding of unknown cause • Can occur in Pierson syndrome, Galloway-Mowat syndrome, Frasier syndrome, congenital nephrotic syndrome of Finnish type, familial steroid-resistant nephrotic syndrome, CoQ deficiency • Rarely due to congenital CMV infection

Nephrotic Syndrome in Infants • Consider congenital nephrosis, idiopathic nephrosis, diffuse mesangial proliferation, minimal change or focal segmental sclerosis, and isolated diffuse mesangial sclerosis

SELECTED REFERENCES 1.

Gariépy-assal L et al: Management of Denys-Drash syndrome: a case series based on an international survey. Clin Nephrol Case Stud. 6:36-44, 2018 2. Hodhod A et al: 46-XY Denys-Drash syndrome. Is there a role for nephronsparing modalities in management of renal masses? A report of 2 cases. Urology. 117:153-5, 2018 3. Alge JL et al: Hemolytic uremic syndrome as the presenting manifestation of WT1 mutation and Denys-Drash syndrome: a case report. BMC Nephrol. 18(1):243, 2017 4. Hashimoto H et al: Denys-Drash syndrome associated WT1 glutamine 369 mutants have altered sequence-preferences and altered responses to epigenetic modifications. Nucleic Acids Res. 44(21):10165-76, 2016 5. Niaudet P et al: WT1 and glomerular diseases. Pediatr Nephrol. 21(11):165360, 2006 6. Breslow NE et al: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol. 174(5):1972-5, 2005 7. Royer-Pokora B et al: Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am J Med Genet A. 127A(3):249-57, 2004 8. Yang AH et al: The dysregulated glomerular cell growth in Denys-Drash syndrome. Virchows Arch. 445(3):305-14, 2004 9. McTaggart SJ et al: Clinical spectrum of Denys-Drash and Frasier syndrome. Pediatr Nephrol. 16(4):335-9, 2001 10. Mueller RF: The Denys-Drash syndrome. J Med Genet. 31(6):471-7, 1994

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Overview of Syndromes: Syndromes

Denys-Drash Syndrome

Mesangial Sclerosis

Mesangial Sclerosis

Nephrogenic Rests

Streak Gonad

Dysgenetic Gonad

Ovotestis

(Left) High-power view shows a glomerulus in DDS with mesangial sclerosis shown by an increase in mesangial matrix and hypercellularity ﬈. (Courtesy S. Meehan, MD.) (Right) PAS stain shows glomeruli with diffuse mesangial sclerosis characterized by an increase in PAS-positive mesangial matrix. Diffuse mesangial sclerosis is a primary feature of DDS, seen in ~ 95% of patients, and eventually causes rapid decline in glomerular filtration rate and progresses to ESRD. (Courtesy S. Meehan, MD.)

(Left) H&E of kidney from a DDS patient shows multiple nephrogenic rests ﬈. Nephrogenic rests are considered to be precursors of WT. DDS increases the risk for WT, which is encountered in 74% of patients. (Courtesy S. Meehan, MD.) (Right) H&E shows a dysgenetic gonad in DDS, composed purely of ovarian-type stroma without any epithelial cells ("streak gonad"). The majority of patients with DDS are karyotypically male (46, XY) and most have female or ambiguous external genitalia.

(Left) H&E shows a dysgenetic gonad containing both müllerian-type structure (fallopian tube) ﬈ and wolffian-type structure (epididymis/ductuli efferentes) ﬊. (Right) H&E shows an ovotestis containing both testicular and ovarian elements. Seminiferous tubules ﬈ containing mostly Sertoli cells are present. In addition, ovarian follicles are clustered nearby ﬊. Note the presence of interstitial steroidproducing cells ﬉. Ovotestis increases the risk for the development of gonadoblastoma.

544

Denys-Drash Syndrome

WT Epithelial Predominant (Left) H&E shows WT with classic triphasic histology consisting of blastemal cells ﬈, epithelial cells ﬊, and stromal cells ﬉. WT may also have biphasic or uniphasic histology. Although DDS has a high risk for WT, only a small subset of patients will die from this malignancy. (Right) H&E shows WT composed of differentiated epithelial cells forming tubules. Predominance of epithelial component in WT may mimic a renal cell carcinoma. Both tumors will express pax-8, but only WT will be positive for WT1 antigen.

WT Glomeruloid Structures

Overview of Syndromes: Syndromes

WT Triphasic Morphology

Gonadoblastoma (Left) H&E shows WT containing some primitive glomeruloid epithelial structures ſt admixed with blastemal cells. Note the presence of mitosis st. WT is a primitive neoplasm that recapitulates renal embryogenesis. (Right) Gonadoblastoma is characterized by nests containing seminomatous germ cells ﬈ located in the center, and sex cord-stromal cells forming rosette-like structures reminiscent of CallExner bodies ﬊ at the periphery of nests. (Courtesy S. Shen, MD, PhD.)

Gonadoblastoma

Juvenile Granulosa Cell Tumor (Left) Gonadoblastoma shows smaller sex cord-stromal cells forming Call-Exner body-like structures ﬈ and large seminomatous cells with abundant clear cytoplasm and prominent nucleoli ſt. Gonadoblastoma usually occurs in dysgenetic gonads such as in DDS. (Courtesy S. Shen, MD, PhD.) (Right) Juvenile granulosa cell tumor is composed of multicystic follicular spaces lined by multilayers of granulosa cells ﬈. The cystic spaces contain basophilic fluid. (Courtesy S. Shen, MD, PhD.)

545

Overview of Syndromes: Syndromes

Diamond-Blackfan Anemia

TERMINOLOGY

ETIOLOGY/PATHOGENESIS

Abbreviations

Genetic Basis

• Diamond-Blackfan anemia (DBA)

• 25-50% tied to sporadic mutation in genes encoding for ribosomal proteins (RPs) resulting in proapoptotic erythropoiesis and erythroid failure ○ 25% have mutations in RPS19 ○ Another 25-35% have mutations in RPL5, RPL11, RPL35A, RPS10, RPS17, RPS24, or RPS26  • Mutations in RP genes have been confirmed to be direct cause of faulty erythropoiesis and consequently anemia • Rare mutations of GATA1, EPO, TSR2 and advanced alternative splicing of gene involved in iron metabolism, FLVCR1 (SLC49A1) have also been associated with DBA

Synonyms • Congenital hypoplastic anemia • Inherited erythroblastopenia • Blackfan-Diamond syndrome

Definitions • DBA: Heterogeneous genetic disorder characterized by red blood cell aplasia in association with skeletal anomalies and short stature that classically appear soon after birth ○ Congenital erythroid aplasia characterized by block in erythropoiesis ○ DBA is inherited anemia with broad spectrum of anomalies that present soon after delivery ○ Although prominent feature of DBA is anemia, clinically is broader disorder and is manifested by – Growth retardation – Congenital malformations of head, heart, neck, upper limbs, and urinary system • ~ 40-45% of DBA hereditary with autosomal dominant inheritance • 55-60% of DBA sporadic, i.e., occur in people who have no family history of disorder ○ Resulted from new aberrations in gene

EPIDEMIOLOGY Age Range • Present at birth or otherwise diagnosed in 1st year of life

Sex • Male and female patients equally affected

Incidence • 1-4 cases per 500,000 live births in 1 year

Pure Red Cell Aplasia (Left) Bone marrow biopsy shows hypercellular marrow with megakaryocytes ﬇, maturing myeloid elements, and virtually absent erythroid precursors. (Right) Bone marrow aspirate smear shows maturing myeloid and an adequate number of megakaryocytes. Nucleated erythroid elements are rare to absent.

546

Inheritance • ~ 55% sporadic, ~ 45% familial with disease inherited mostly in autosomal dominant pattern

CLINICAL IMPLICATIONS Clinical Presentation • Diagnosing DBA is usually problematic due to partial phenotype and wide inconsistency in clinical expression • Profound isolated normocytic or macrocytic anemia (MCV ~ 110-140 fL) with no other significant cytopenias • ~ 50% will have variety of congenital abnormalities, including ○ Craniofacial malformations ○ Thumb or upper limb abnormalities ○ Cardiac defects ○ Urogenital malformations ○ Cleft palate ○ Low birth weight and generalized growth delay • Modest risk of malignancies ○ Associated malignancies include: Acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors (including colon cancer, female genital cancers, and osteogenic sarcoma) ○ Cumulative incidence of solid tumor or leukemia was ~ 20% by 46 years of age

Pure Red Cell Aplasia

Diamond-Blackfan Anemia

Primary and Secondary Etiologies • • • • •

DBA Transient erythroblastopenia of childhood Transient aplastic crisis (parvoivirus B19 infection) Fanconi anemia Red cell aplasia secondary to ○ Malignancies – Thymoma – Carcinoma – T-cell large granular lymphocytic leukemia ○ Autoimmune disorders – Myastenia gravis – Systemic lupus erythematosus – Multiple endocrinopathies ○ Viral infections – Hepatitis – HIV – Epstein-Barr virus ○ Pregnancy ○ Post transplantation of ABO incompatible bone marrow ○ Antibodies to recombinant erythropoietin ○ Drugs – Cytostatics – Antiepilectics – Antirheumatics – Antitubercolar agents – Penicillamine – Cloramfenicol – Cotrimoxazole

Differential Diagnosis • Secondary causes of pure red cell aplasia • Other genetic conditions with bone marrow failure (i.e., Fanconi anemia, Shwachman-Diamond syndrome, Pearson syndrome)

SELECTED REFERENCES 1. 2. 3. 4. 5. 6.

7. 8.

Chai KY et al: Danazol: an effective and underutilised treatment option in Diamond-Blackfan anaemia. Case Rep Hematol. 2019:4684156, 2019 Clinton C et al: Diamond-Blackfan anemia. In Adam MP et al: GeneReviews. University of Washington: Seattle 2019 Engidaye G et al: Diamond Blackfan anemia: genetics, pathogenesis, diagnosis and treatment. EJIFCC. 30(1):67-81, 2019 Ulirsch JC et al: The genetic landscape of Diamond-Blackfan anemia. Am J Hum Genet. 104(2):356, 2019 Foucar K et al:Bone Marrow Pathology Vol 1. ASCP Press, 2010 Vlachos A et al. Participants of sixth annual Daniella Maria Arturi International Consensus Conference. Diagnosing and treating Diamond Blackfan anaemia: Results of an international clinical consensus conference. Br J Haematol. 142(6):859-76, 2008 Draptchinskaia N et al: The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 21(2):169-75, 1999 Clinton C et al: Diamond-Blackfan Anemia, 1993

Overview of Syndromes: Syndromes

PURE RED BLOOD CELL APLASIAS

DIAGNOSIS Blood and Bone Marrow Findings • • • • •

Normocytic or macrocytic anemia Low reticulocyte counts Elevated fetal hemoglobin (HbF) Elevated adenosine deaminase levels in red blood cells Decreased to absent erythroid precursors in normocellular bone marrow • Alterations in RP genes ○ RPS19 was formerly known as mutated small ribosomal protein and is still most frequently mutated gene, ~ 25% of total DBA patients • Although DBA is considered ribosomopathy, it can be also caused by non-RP gene mutations ○ Rarely results from mutation of hematopoietic transcription factor gene, GATA1

Major Supporting Criteria • Gene mutation described in classic DBA • Positive family history

Minor Supporting Criteria • • • •

Elevated erythrocyte adenosine deaminase activity Congenital anomalies described in ''classical'' DBA Elevated HbF No evidence of another inherited bone marrow failure syndrome 547

Overview of Syndromes: Syndromes

DICER1 Syndrome – Endocrine-related lesions □ Multinodular hyperplasia (MNG) □ Thyroid carcinoma □ Sertoli-Leydig cell tumor (SLCT) □ Gynandroblastoma (GAM) □ Juvenile granulosa cell tumor (JGCT) □ Pituitary blastoma (associated with infantile-onset Cushing disease) – DICER1 mutations documented in endocrine tumors (thyroid, parathyroid, pituitary, pineal gland, endocrine pancreas, paragangliomas, medullary, adrenocortical, ovarian, and testicular tumors)

TERMINOLOGY Synonyms • Pleuropulmonary blastoma (PPB) familial tumor and dysplasia syndrome • PPB familial tumor susceptibility syndrome

Definitions • DICER1 syndrome: Pediatric cancer predisposition condition causing variety of tumor types in children and young adults ○ Germline-inactivating DICER1 mutations are responsible for familial tumor susceptibility syndrome with increased risk of tumors • Autosomal dominant pleiotropic tumor syndrome caused by germline DICER1 mutations (WHO 2017) ○ Tumors and dysplasias with onset in childhood, adolescence, or early adulthood, including – PPB – Cystic nephroma (CN) 

EPIDEMIOLOGY Age • Childhood or young adulthood ○ PPBs: Nearly all present by 6 years of age ○ CN: > 90% of cases occur by 4 years of age

Pleuropulmonary Blastoma Imaging

Pleuropulmonary blastoma (PPB) can be solid &/or cystic. The cystic PPB can be unilocular but is often multilocular. This image shows a large cystic mass ﬊ with numerous cysts with thin septa. (Courtesy S. Westra, MD.)

548

DICER1 Syndrome

Prevalence • Must be substantially higher ○ Many carriers go unidentified, and most associated conditions are nonlethal

Incidence • Rare (~ 9:100,000 live births)

ETIOLOGY/PATHOGENESIS Genetics: DICER1 • Chromosomal location: 14q32.13 • DICER1 is multidomain protein ○ 1 copy of altered gene is sufficient to cause increased risk of developing tumors ○ Many individuals who carry mutation in DICER1 gene do not develop abnormal growths ○ During tumorigenesis, patients may acquire 2nd mutation that has potential to affect catalytic activity of enzyme ○ Encodes protein of 1922 amino acids ○ Comprises several structurally distinct domains (from Nterminus to C-terminus) • DICER1 has several known functions ○ Maturation of microRNAs from precursor molecules – Acts as molecular ruler, measuring and then cutting hairpin precursors into mature 5p and 3p forms ○ Chromatin structure remodeling ○ Inflammation and apoptotic DNA degradation • Mutations may alter DICER1 expression &/or resultant protein activity and consequently initiate pathologic processes • DICER1 mutations ○ Germline mutations – Typically result in protein truncation and likely affect global processing – In majority of cases, germline mutations are nonsense, frameshift, or splice-site mutations leading to premature truncation of protein and resulting in loss of RNAse III function ○ 2nd somatic missense mutations – Occur in most tumors studied to date – Occur in metal ion-binding RNase IIIa and IIIb domains; result in reduced 3p and 5p microRNAs, respectively – Commonly result from combination of neomorphic missense mutation at 1 of 5 specific hotspot codons within RNase IIIb domain and complete loss of function (LOF) in other allele ○ Mosaicism for RNase IIIb domain hotspot mutations – Rare individuals carry germline or mosaic mutations of critical metal ion-binding domains – More severe phenotypes in terms of both patient age at onset and number of organs involved – Likely that these RNase III mutations have oncogenic properties ○ ~ 10% of predisposing DICER1 mutations are mosaic rather than germline

• No clear correlation among DICER1 expression, cancer type, and disease progression ○ Significant changes in DICER1 expression have been detected during different stages of lung adenocarcinoma – Early stages: Transient upregulation in expression – More advanced stages: Downregulation in expression ○ Controversial whether DICER1 acts as tumor suppressor or oncogene – Reduced expression may be associated with poor prognosis in some types of lung cancers – Increased expression associated with prostate adenocarcinoma, other cancers, and Burkitt lymphoma • Pathomechanism of DICER1-mutation-mediated diseases still poorly understood • Individuals with 1 of typical DICER1 conditions should be offered DICER1 analysis

Overview of Syndromes: Syndromes

○ Ovarian sex cord-stromal tumors (OSCST): 2-45 years, but most occur in patients aged 10-25 years ○ Pituitary blastoma (very rare): Occurs by 24 months of age

CLINICAL IMPLICATIONS Clinical Presentation • Features number of highly characteristic tumor and tumorlike conditions that generally arise in childhood or young adulthood • Some tumors are either so rare or so characteristic that any affected individual is likely to carry germline DICER1 mutation • PPB ○ Most common neoplasm in DICER1 syndrome – Nearly all PPB present by age of 6 years ○ PPB is childhood cancer arising from pleuropulmonary mesenchyme ○ Mutations in DICER1 gene are found in ~ 50-70% of PPB patients ○ Clinical presentation of PPB varies by age and tumor type – Children < 2 years: Shortness of breath ± pneumothorax secondary to PPB cyst rupture – Older children: Advanced disease often present with shortness of breath, weight loss, and fever ○ Classically, 3 types of PPB based on gross pathology; highly correlated with age at diagnosis and outcome; thought to represent natural history of disease – Type I PPB: Purely cystic □ Present in youngest age group (median: 9 months) □ Has best prognosis – Type II PPB: Cystic and solid □ Typically occur in children between ages 18 months and 6 years (median: 36 months) □ Retains grossly visible cystic component; also presents solid components – Type III PPB: Purely solid □ Typically occur in children between ages of 18 months and 6 years (median: 43 months) ○ This neoplasm is sentinel disease in familial tumor syndrome recently found to be associated with germline mutations in DICER1 • Pediatric cystic nephroma (PCN) ○ 2nd most common neoplasm in DICER1 syndrome – > 90% of cases occurring by age of 4 years 549

Overview of Syndromes: Syndromes

DICER1 Syndrome

550

○ Frequency of DICER1 germline mutations in patients with CN is ~ 73% ○ Most commonly presents in first 4 years of life as painless, enlarging abdominal or flank mass ○ Finding of bilateral tumors rare event, highly suggestive of germline DICER1 pathogenic variant • Ovarian stromal tumors ○ SLCT, JGCT, and GAB ○ Seen in children and young adults ○ Nearly all SLCTs and GAB are DICER1 related ○ Very highly suggestive of germline mutation – > 1/2 of individuals with SLCT have germline DICER1 mutations ○ Typically unilateral but can occur bilaterally; often large (≥ 10 cm) and predominantly solid ○ May present as isolated adnexal mass ± clinical signs or laboratory findings of hormone production ○ Signs of hormone production can include precocious puberty, menstrual irregularities, or signs of virilization, such as hirsutism, acne, or voice changes ○ Primary ovarian neoplasms, particularly OSCST, are manifestation of familial PPB syndrome and may be initial clinical presentation of DICER1 mutations within family ○ Occurrence of ovarian SLCT with thyroid carcinoma is highly suggestive of DICER1 syndrome • Most important endocrine manifestations ○ Nodular thyroid hyperplasia – Can result in MNG ○ 75% of women and 17% of men with DICER1 syndrome were shown to harbor abnormal thyroid growths, such as MNG ○ Recent study indicates correlation between truncating germline DICER1 mutations and familial MNG ○ More rarely differentiated thyroid carcinoma – Women are more likely to develop thyroid cancer than men, regardless of DICER1 variant status ○ OSCSTs – SLCT in particular ○ Co-occurrence of ovarian SLCT with thyroid carcinoma highly suggestive of DICER1 syndrome • Differentiated thyroid carcinoma ○ Association between germline mutations in DICER1 and familial MNG have been reported ○ DICER1-associated thyroid cancer also harbors somatic pathogenic variants in DICER1 hotspot amino acids ○ Individuals with DICER1 syndrome have 16x increased risk of thyroid cancer ○ DICER1 carriers have quantified excess risk of MNG and thyroid cancer – DICER1 carriers have significantly increased risk of MNG compared with family controls and significantly elevated risk of thyroid cancer compared with population ○ DICER1 mutations in pediatric papillary thyroid cancer (PTC) are present at frequency nearly 30x that seen in adult PTC – DICER1 malignancies comprise ~ 17% of tumors in pediatric series – DICER1 as common oncogenic driver in pediatric lowrisk PTC

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○ Early-onset, familial, or male MNG should prompt careful personal and family history focused on DICER1associated tumors (especially PPB, CN, SLCT) Nasal chondromesenchymal hamartoma ○ Presents in nasal cavity or sinuses, commonly as unilateral polyp or mass, or rarely as bilateral ○ Symptoms vary depending on size and location – Persistent nasal drainage/rhinorrhea, nasal obstruction/swelling, and respiratory or feeding difficulties – Bony destruction can be seen Ciliary body medulloepithelioma ○ Primitive neuroepithelial neoplasm; arises in anterior chamber of eye ○ Present ~ 7 years of age with decreased visual acuity and pain ○ Although viewed as malignant neoplasms, distant metastases are rare Pituitary blastoma ○ Rare primitive malignant neoplasm of pituitary gland presenting in first 2 years of life ○ Can present with ophthalmoplegia, proptosis, visual disturbance, &/or clinical endocrinopathy, typically Cushing disease ○ Appears to be pathognomonic of DICER1 mutation Embryonal rhabdomyosarcoma (ERMS) of cervix ○ Older children and young adults ○ Can present with vaginal spotting or passage of myxoid, hemorrhagic solid tissue Pineoblastoma ○ Germline DICER1 mutations make clinically significant contribution to pineoblastoma – Further studies may determine relationship between DICER1 mutations and pineoblastomas ○ Malignant primitive neuroectodermal tumor in region of pineal gland ○ Typically presents with findings of increased intracranial pressure stemming from obstructive hydrocephalus due to compression of cerebral aqueduct by tumor mass ○ Neuroophthalmologic abnormalities, including upgaze paralysis and nystagmus, may be seen ○ Focal neurologic deficits found in 25% of affected individuals Other tumors reported ○ Primitive neuroectodermal tumors at other sites ○ GAB ○ Anaplastic sarcoma of kidney ○ Cerebral sarcoma ○ Seminoma ○ Rare forms of T-cell Hodgkin lymphoma – One patient had 2 DICER1 mutations (c.5299delC and c.4616C>T), and several of his family members shared these mutations ○ Wilms tumor Macrocephaly reported as common finding in DICER1 syndrome Global developmental delay, lung cysts, overgrowth, and Wilms tumor (GLOW)

Treatment • Identification of tumor type and stage

DICER1 Syndrome

Prognosis • Favorable outcome ○ OSCST, CN, ERMS of cervix, MNG, differentiated thyroid carcinoma, nasal chondromesenchymal hamartoma, or ciliary body medulloepithelioma • Low survival rates (50%) ○ PPB type II and III, pituitary blastoma, and anaplastic sarcoma of kidney • Screening DICER1 mutation carriers for cystic PPB at young age may permit early detection of PPB type I ○ Subsequent surgical resection may prevent progression to types II and III with their higher morbidity and mortality

MACROSCOPIC General Features • PPB ○ Type I PPB: Purely cystic – Cysts can be unilocular but are more often multilocular and located in periphery of lung ○ Type II PPB: Cystic and solid – Tumor cells within cyst wall have proliferated, creating grossly visible thickening of septa or formation of solid mass ○ Type III PPB: Purely solid • CN ○ Large, multicystic mass ○ Cysts do not communicate with each other or with renal pelvis ○ Cysts may prolapse into pelvis, resulting in urinary obstruction ○ Have diaphanous capsule and are filled with clear, colorless, watery fluid ○ Cysts are separated by delicate fibrous septa – Septa may contain well-differentiated tubules

MICROSCOPIC General Features • PPB ○ Type I: Purely cystic – Multilocular, thin-walled cyst lined by epithelium – Cyst septa contain variably present, primitive mesenchymal tumor cells beneath epithelium ○ Type II: Cystic and solid ○ Type III: Purely solid – Solid components best characterized as high-grade, multipatterned sarcoma that includes ≥ 2 of following patterns □ ERMS pattern with ovoid, stellate, and spindled cells arranged in myxoid, pale blue background □ Blastemal pattern with cohesive clusters of primitive rounded cells with minimal cytoplasm □ Cartilaginous differentiation with fetal type or highgrade malignant cartilage nodules □ Spindle cell sarcoma

• CN ○ Tumor is well circumscribed and composed of variably sized cysts separated by loose myxoid stroma with associated chronic inflammation ○ Cysts can sometimes be simpler in architecture compared with type I PPB and can resemble dilated tubules with plump, hobnail epithelium ○ In well-developed cystic tumors, delicate septa divide lesion into variably sized locules, much like type I PPB ○ Cyst septa typically contain bland mesenchymal cells in pale, myxoid matrix with variable amount of inflammatory cells ○ No immature nephroblastic elements are identified ○ Entrapped mature tubules are seen • Nasal chondromesenchymal hamartoma ○ Composed of epithelial cysts lined by respiratory epithelium and nodules of immature or mature cartilage surrounded by spindle cell mesenchyme ○ Rest of polyp contains mucoid ground substance containing inflammatory cells, small vessels, and fibrosis – Occasional cases without cartilage nodules have been seen in individuals with DICER1 mutations • Ovarian stromal tumors ○ May be cystic and solid or solid and often containing heterologous epithelial glandular elements ○ Sertoli-cell component staining with inhibin staining invariably present in primary tumors ○ Tumors may also contain sarcomatous components • Pineoblastoma ○ Tumor cells are primitive with high nuclear:cytoplasmic ratio and hyperchromatic nuclei ○ Homer Wright and Flexner-Wintersteiner rosettes may be seen • Pituitary blastoma ○ Combination of Rathke-type epithelial rosettes/glands intermixed with small, primitive-appearing cells with blastemal features and larger secretory cells • ERMS ○ Subepithelial layer of primitive cells beneath intact epithelium (cambium layer), very similar to type I PPB ○ Deeper in polyp, stroma cells better differentiated, often showing tails of eosinophilic cytoplasm with striations ○ Background is pale and mucoid and contains variable number of inflammatory cells ○ Cartilaginous nodules present in 35-40% of cervical ERMS ○ These polyps can be deceptively bland and confused with nonneoplastic polypoid lesions • Ciliary body medulloepithelioma ○ Neuroblastic or embryonic-like neural tubules and Homer Wright rosettes accompanied by hyaluronic, acidrich stroma expanding region of ciliary body ○ Teratoid variant may have cartilage or immature skeletal muscle • Differentiated thyroid carcinoma ○ Associated with MNG ○ Classical PTC

Overview of Syndromes: Syndromes

• Most often treatment involves surgical resection ± chemotherapy • Treatment of PPB may also include use of radiation to treat recurrence or metastases

551

Overview of Syndromes: Syndromes

DICER1 Syndrome

DIFFERENTIAL DIAGNOSIS Cowden Disease and Bannayan-Riley-Ruvalcaba Syndrome (PTEN-Hamartoma Tumor Syndrome) • Share clinical characteristics, such as mucocutaneous lesions, hamartomatous polyps of gastrointestinal tract, and increased risk of developing neoplasms • Both conditions caused by mutations in PTEN gene ○ PTEN located on 10q23.31 and encodes phosphatidylinositol-3,4,5-triphosphate 3-phosphatase ○ Tumor suppressor gene that has been found mutated in number of tumors • Thyroid usually affected by numerous adenomatous nodules, follicular adenomas, and follicular carcinoma • Findings similar to those familial syndromes characterized by predominance of nonthyroidal tumors ○ PTEN-hamartoma tumor syndrome, Carney complex, Werner syndrome, and Pendred syndrome

Carney Complex • Autosomal dominant syndrome ○ Caused by PRKAR1A mutations • Multiple neoplasia syndrome featuring endocrine overactivity, involving diverse endocrine organs, such as adrenal cortex, pituitary, thyroid, ovary, and testes • Presents spotty skin pigmentation, schwannomas, myxomatosis, neural tumors, and, rarely, tumors in liver and pancreas

Congenital Cystic Adenomatoid Malformation • Type I PPB cannot be distinguished radiographically from benign congenital cystic lung malformations ○ Pneumothoraces and presence of multifocal or bilateral cysts more common in PPB than in other conditions ○ Difficulties in distinguishing from PPB have led some pediatric surgeons to advocate excision of all congenital cystic adenomatoid malformations

• Most commonly reported germline variants include WT1 and 11p15.5 locus • Abdominal pain, fever, anemia, hematuria, and hypertension seen in 25-30% of affected children

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Presence of CN, ovarian SLCT, or urogenital ERMS in child should alert clinician to possibility of DICER1 mutation and associated risk of PPB • Occurrence of ovarian SLCT with thyroid carcinoma is highly suggestive of DICER1 syndrome

SELECTED REFERENCES 1. 2. 3. 4.

5. 6.

7.

8.

9.

10.

11.

Lung Cysts and Pneumothoraces

12.

• Multiple inherited and noninherited disorders can present with lung cysts &/or pneumothorax • Many of these can be distinguished from PPB on basis of medical history and physical examination

13.

Mixed Epithelial and Stromal Tumor (So-Called Adult CN)

15.

• CN and mixed epithelial stromal tumor (MEST) of kidney have been considered synonymous terms describing single nosologic entity in adult patients ○ These tumors are negative for mutation in DICER1 hotspot codons • CN in pediatric patients is completely different nosologic entity with presence of DICER1 mutations • Cysts resemble those in DICER1-related PCN but often contain cellular stroma resembling ovarian stroma • PCN is morphologically, immunohistochemically, and genetically distinct from adult CN

14.

16. 17.

18.

19. 20. 21.

Wilms Tumor (Nephroblastoma) • Most common renal tumor of childhood • Usually presents as abdominal mass in otherwise apparently healthy child 552

22. 23.

Wasserman JD et al: DICER1 mutations are frequent in adolescent-onset papillary thyroid carcinoma. J Clin Endocrinol Metab. 103(5):2009-15, 2018 Bueno MT et al: Pediatric imaging in DICER1 syndrome. Pediatr Radiol. 47(10):1292-301, 2017 Cai S et al: Multimorbidity and genetic characteristics of DICER1 syndrome based on systematic review. J Pediatr Hematol Oncol. 39(5):355-61, 2017 Fernández-Martínez L et al: Identification of somatic and germ-line DICER1 mutations in pleuropulmonary blastoma, cystic nephroma and rhabdomyosarcoma tumors within a DICER1 syndrome pedigree. BMC Cancer. 17(1):146, 2017 Khan NE et al: Macrocephaly associated with the DICER1 syndrome. Genet Med. 19(2):244-8, 2017 Khan NE et al: Quantification of thyroid cancer and multinodular goiter risk in the DICER1 syndrome: a family-based cohort study. J Clin Endocrinol Metab. 102(5):1614-22, 2017 Li Y et al: Pediatric cystic nephroma is morphologically, immunohistochemically, and genetically distinct from adult cystic nephroma. Am J Surg Pathol. 41(4):472-81, 2017 Schultz KAP et al: PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(12):e76-82, 2017 Vanecek T et al: Mixed epithelial and stromal tumor of the kidney: mutation analysis of the DICER 1 gene in 29 cases. Appl Immunohistochem Mol Morphol. 25(2):117-21, 2017 Durieux E et al: The co-occurrence of an ovarian Sertoli-Leydig cell tumor with a thyroid carcinoma is highly suggestive of a DICER1 syndrome. Virchows Arch. 468(5):631-6, 2016 Stewart CJ et al: Gynecologic manifestations of the DICER1 syndrome. Surg Pathol Clin. 9(2):227-41, 2016 Kurzynska-Kokorniak A et al: The many faces of Dicer: the complexity of the mechanisms regulating Dicer gene expression and enzyme activities. Nucleic Acids Res. 43(9):4365-80, 2015 Messinger YH et al: Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry. Cancer. 121(2):276-85, 2015 de Kock L et al: Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol. 128(1):111-22, 2014 Klein S et al: Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome. J Med Genet. 51(5):294-302, 2014 Rath SR et al: Multinodular goiter in children: an important pointer to a germline DICER1 mutation. J Clin Endocrinol Metab. 99(6):1947-8, 2014 Schultz KA et al: Judicious DICER1 testing and surveillance imaging facilitates early diagnosis and cure of pleuropulmonary blastoma. Pediatr Blood Cancer. 61(9):1695-7, 2014 Stewart DR et al: Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder. Hum Genet. 133(11):1443-50, 2014 Foulkes WD et al: Extending the phenotypes associated with DICER1 mutations. Hum Mutat. 32(12):1381-4, 2011 Rio Frio T et al: DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 305(1):68-77, 2011 Slade I et al: DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet. 48(4):273-8, 2011 Hill DA et al: DICER1 mutations in familial pleuropulmonary blastoma. Science. 325(5943):965, 2009 Priest JR et al: Pleuropulmonary blastoma: a marker for familial disease. J Pediatr. 128(2):220-4, 1996

DICER1 Syndrome

Cyst Wall in Pleuropulmonary Blastoma (Left) This child with DICER1 syndrome presented with shortness of breath, weight loss, and fever. A large solid and cystic mass was discovered. This tumor is best classified as type II PPB, which typically occur in children between ages 18 months and 6 years. It retains a grossly visible cystic component and also presents solid components ﬈. (Right) Microscopically, the majority of PPBs are characterized as multilocular cysts containing primitive small mesenchymal cells within the cyst walls.

Keratin Expression in Cyst Lining Cells

Overview of Syndromes: Syndromes

Large Multicystic Pulmonary Mass

Cyst Wall in Pleuropulmonary Blastoma (Left) The cystic spaces in type II PPB are lined by keratinpositive cells, whereas the solid components are negative. The solid areas consist of a collage of primitive sarcomatous patterns. (Right) Microscopically, the majority of PPBs are characterized as multilocular cysts containing primitive, small mesenchymal cells within the cyst walls. Three pathologic types or stages in the evolution of PPB have been defined: Type I (purely cystic PPB), type II (cystic/solid PPB), and type III (purely solid PPB).

Pleuropulmonary Blastoma Components

Stromal Cells With Muscle Differentiation (Left) PPB is multiloculated with interconnecting septa of variable thicknesses dividing the mass into multiple cysts. The septa are lined by predominantly flattened or cuboidal alveolar-type epithelium with nuclear pleomorphism ﬊. (Right) The tumor cells in PPB usually show patchy immunopositivity for desmin. Definitive skeletal muscle differentiation characterized by cells with long tails of eosinophilic cytoplasm may be identified. Myogenin and myoD1 stains may show scattered positive cells.

553

Overview of Syndromes: Syndromes

DICER1 Syndrome

Large Cystic Nephroma in Child

Cystic Nephroma in Child

Gross Cut Surface of Cystic Nephroma

Low-Power View of Cystic Nephroma

Cyst Lining Cells Characteristics

Primitive Cells in Pineoblastoma

(Left) Pediatric cystic nephroma commonly presents in the first 4 years of life as a painless, enlarging, wellcircumscribed, multicystic abdominal or flank mass. (Right) This large, multicystic mass in a child was the 1st finding in diagnosing DICER1 syndrome. The cysts do not communicate with each other or with the renal pelvis.

(Left) Pediatric cystic nephroma is a welldemarcated, multicystic kidney mass. The cyst septa are thin and uniform without solid areas or septal nodularity. The cyst walls are smooth and shiny. (Right) Cystic nephromas are tumors that occur in patients with DICER1 syndrome. The tumor is composed of variably sized cysts separated by loose myxoid stroma with focal lymphoplasmacytic infiltration. Immature nephroblastic elements are not identified in these tumors.

(Left) Pediatric cystic nephroma shows large epithelial cells with large, irregular nuclei with nucleoli. The cytoplasm is ample and eosinophilic in smaller cysts, while it tends to be flattened ﬊ in larger cysts. (Right) Pineoblastoma is the most primitive of parenchymal tumors. These tumors are highly cellular and composed of patternless sheets of densely packed small cells with elongated nuclei and scant cytoplasm.

554

DICER1 Syndrome

Synaptophysin in Pineoblastoma (Left) Pineoblastomas are highly cellular with undifferentiated small cell histology and composed of patternless sheets of densely packed small cells and scant cytoplasm with a high nuclear:cytoplasmic ratio. The cell borders are indistinct. The diffuse growth pattern is only interrupted by rare rosettes. (Right) The tumor cells in pineoblastoma show strong immunopositivity for synaptophysin. The tumor cells are also positive for NSE and chromogranin A but negative for GFAP and neurofilaments.

Sertoli-Leydig Cell Tumor

Overview of Syndromes: Syndromes

Patternless Pineoblastoma

Intermediate Sertoli-Leydig Cell Tumor (Left) ~ 50% of patients with DICER1 syndrome develop a Sertoli-Leydig cell tumor (SLCT) by the age of 15. Typically, they are unilateral and are often large and predominantly solid with a multilobulated yellow-brown cut surface. (Courtesy R. Young, MD.) (Right) This ovarian tumor is composed of cords of blue Sertoli cells ﬊ intermixed with Leydig cells. These cells are seen in clusters at bottom left ﬇. DICER1related SLCTs are typically intermediate to poorly differentiated. (Courtesy E. Oliva, MD.)

Carcinogenesis Model in DICER1 Syndrome

Papillary Thyroid Carcinoma (Left) The carcinogenesis model of progression of multinodular hyperplasia to thyroid carcinoma in DICER1 syndrome is shown. (Right) DICER1 mutations in pediatric papillary thyroid cancer (PTC) are present at a frequency nearly 30x that seen in adult PTC. Women are more likely to develop thyroid cancer than men. The variant of carcinoma is usually a solid variant or the usual classic type. A psammoma body ﬊ is seen in this tumor from a child with DICER1 syndrome.

555

Overview of Syndromes: Syndromes

Down Syndrome

TERMINOLOGY

EPIDEMIOLOGY

Abbreviations

Incidence

• Down syndrome (DS)

• ~ 1/700 newborns • Risk of having child with DS increases with maternal age especially after age 35 ○ 1/1,000 maternal age 30 years ○ 9/1,000 maternal age 40 years • Trisomy occurs in at least 0.3% of newborns and in nearly 25% of spontaneous abortions

Synonyms • Trisomy 21 • Chromosome 21 trisomy

Definitions • Genetic disorder originally described in 1866 associated with ○ Intellectual disability ○ Characteristic facial appearance ○ Often cardiac, ophthalmic, skeletal, intestinal, reproductive, endocrine, and growth abnormalities • Most common human aneuploid abnormality in children • One of most important leukemia-predisposing syndromes

ETIOLOGY/PATHOGENESIS Etiology • 95% of time DS is caused by trisomy 21 due to nondisjunction during maternal meiosis I • 3% of children have translocation DS occurring ○ Before conception, inherited from unaffected parent with balanced translocation ○ After conception • ~ 2% of cases of DS are mosaic

Acute Megakaryoblastic Leukemia

TAM in Fetal Capillaries in Term Villi

Megakaryoblasts Detected by Flow Cytometric Analysis

Erythroid Dysplasia

(Left) Bone marrow aspirate smear shows sheets of medium- to large-sized megakaryoblasts with scant cytoplasm, irregular cytoplasmic borders, and cytoplasmic projections (blebs and pseudopods). (Right) The villi contain immature erythroid and myeloid elements and some circulating megakaryoblasts, consistent with diagnosis of TAM in a stillborn fetus with hydrops fetalis and trisomy 21.

(Left) CD45 vs. CD61 staining highlights a large population of blasts [CD45 (dim), CD61 (bright) (gated blue dots)], consistent with megakaryoblasts. (Right) Bone marrow aspirate shows severe dysplasia in the erythroid lineage with nuclear irregularities, and nuclear budding, binucleation in this patient with Down syndrome (DS).

556

Down Syndrome

Clinical Presentation • DS medical abnormalities and severity of symptoms and health problems vary among individuals • Some of more common facial features include ○ Flattened face ○ Short neck ○ Protruding tongue ○ Upward slanting eye lids ○ Poor muscle tone ○ Broad short hands with single palmar crease ○ Short stature ○ Brushfield spots (white spots on iris) ○ Epicanthic folds ○ Abnormal teeth ○ Small low-set ears • Mild to moderate cognitive impairment • Congenital heart defect (50%) • Gastrointestinal tract anomalies (5%) • Ophthalmologic disorders (40-80%) • Hearing loss (30-70%) • Benign skin disorders • Pulmonary disorders (sleep apnea) • Hematologic disorders ○ 65% of DS newborns have polycythemia ○ Macrocytosis is often present in children ○ Leukopenia ○ Transient myeloproliferative disorder (TAM)/transient abnormal myelopoiesis – 10-30% of newborn/infants with DS – Caused by somatic GATA1 mutations resulting in expression of aminoterminally truncated GATA1 resulting in impaired megakaryocytic differentiation and uncontrolled proliferation of blasts – TMD resolves in vast majority of patients within first 3 months of life – 20% of cases of TMD, however are followed by onset of acute myeloid leukemia within first 4 years of life – Characterized by □ Frequent presence of blasts (usually megakaryoblasts) in peripheral blood □ Relatively minor marrow infiltration (disorder of liver hematopoiesis) □ Erythroid and megakaryocytic dysplasia in bone marrow (often) – Patients can present with □ No symptoms (usually) □ Cardiopulmonary symptoms (pericardial effusion, pulmonary edema) □ Liver abnormalities (hepatosplenomegaly, hepatic fibrosis, liver failure, obstructive jaundice) □ Hematological abnormalities (leukocytosis, persistent circulating blasts, abnormal platelet count, abnormal hemoglobin) □ Skin rash – Most definitive test to identify TMD blasts is detection of somatic mutation of GATA1, typically in exon 2 or 3

– 20% of infants with TAM still die of disease (i.e., severe liver disease with fibrosis may not respond to treatment)

Complications • Majority of DS patients develop dementia/Alzheimer disease (54 years is average age of onset) • Increased risk of hematological malignancies ○ 10-20x increased risk of developing acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) – Acute megakaryoblastic leukemia (AMKL) □ ~ 20% of DS infants with TAM develop AMKL (AMLM7) □ Incidence of AMKL is 500x greater in children with than without DS □ Invariably associated with mutations in GATA1, transcription factor that regulates megakaryocyte, erythroid, eosinophil, and mast cell differentiation □ Additional mutations include mutations of cohesin component genes (RAD21, STAG2, SMC3, SMC1A), CTCF, EZH2, KANSL1, JAK2, JAK3, MPL, SH2B3, and RAS pathway genes □ Monosomy 7 and trisomy 8 are most frequent chromosomal abnormalities □ Megakaryoblasts are often CD34(+), usually HLADR(-), CD41(+), CD61(+), MPO(-) – AML □ Risk is 50x higher in children < 5 years with than without DS □ 20% of DS ALL have JAK2 mutation at codon 683 □ AML often follows prolonged myelodysplastic syndrome (MDS)-like phase □ In individuals with DS, there is no biological difference between MDS and overt AML □ AML with GATA1 mutations has more favorable prognosis in DS than in non-DS children – ALL □ Children with DS are 10-20x more likely to develop ALL than children without DS □ Activating JAK2 p.R683 mutations have been found in ~ 18% of DS-ALL patients, mostly in patients with CRLF2 rearrangements □ Rearrangements of CRLF2 occur in ~ 60% of DS-ALL patients and in < 10% of non-DS-ALL patients □ Thus far, CRLF2 rearrangements seem to lack prognostic relevance in DS-ALL, although all series have been small □ Increased sensitivity to chemotherapy and significantly increased risk of treatment-related morbidity and mortality due to infectious complications ○ 10-30% develop TAM • Of note, solid tumors occur significantly less frequently in DS children and adults in comparison with individuals without trisomy 21

Overview of Syndromes: Syndromes

CLINICAL IMPLICATIONS

DIAGNOSIS • Often made by prenatal screening ○ 1st trimester "combined test" – Nucal translucency (NT)

557

Overview of Syndromes: Syndromes

Down Syndrome Age-Specific Hematologic Abnormalities in DS Neonates

Infants and Children

Nonspecific findings associated with intrauterine growth restriction and trisomies      Erythroblastosis, polycythemia, neutropenia, thrombocytopenia

Myelodysplastic syndrome

TAM

Myeloid leukemia of DS

-

Acute lymphoblastic leukemia DS = Down syndrome; TAM = transient abnormal myelopoiesis.

Age-Specific Hematological Malignancies in DS Children and Risk Compared to NonDS Peers Entity

Risk Over Non-DS Children

Age at Presentation

Acute megakaryoblastic leukemia

500x increase

< 4 years 

Acute myeloid leukemia of DS

150x increase in < 5 year age group

1-4 years (median: 1.8 years)

Acute lymphoblastic leukemia

40x increase in < 5 year  age group

Median 5 years (range: 1-18 years)

DS = Down syndrome.

– Determination of biochemical markers associated with aneuploidy: Pregnancy-associated plasma protein-A (PAPP-A) and free β-hCG or total human chorionic gonadotropin hCG ○ 2nd trimester "quadruple test" – Measures level of biochemical markers α-fetoprotein (AFP), unconjugated estriol (uE3), hCG, and dimeric inhibin A (DIA) in maternal serum ○ 2nd trimester "triple test" – Evaluates 3 second-trimester maternal serum markers, typically AFP, free or total hCG, and unconjugated estriol ○ Maternal plasma cell-free DNA testing at > 10 weeks gestation, currently offered as secondary screening test in women in high-risk group • DS is otherwise usually recognized from characteristic phenotypic features present in newborn • Clinical diagnosis of DS should be confirmed by genetic testing whenever possible • Full karyotype should always be performed to detect DS due to translocations (e.g., robertsonian translocations involving chromosome 21) or mosaic DS

SELECTED REFERENCES 1.

2. 3. 4. 5.

6.

558

Taub JW et al: Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood. 129(25):3304-13, 2017 Bhatnagar N et al: Transient abnormal myelopoiesis and AML in Down Syndrome: an update. Curr Hematol Malig Rep. 11(5):333-41, 2016 Asim A et al: "Down syndrome: an insight of the disease". J Biomed Sci. 22:41, 2015 Yoshida K et al: The landscape of somatic mutations in Down syndromerelated myeloid disorders. Nat Genet. 45(11):1293-9, 2013 Gamis AS et al: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood. 118(26):6752-9; quiz 6996, 2011 Hertzberg L et al: Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood. 115(5):1006-17, 2010

7. 8. 9.

10.

11. 12. 13.

14.

Lott IT et al: Cognitive deficits and associated neurological complications in individuals with Down's syndrome. Lancet Neurol. 9(6):623-33, 2010 Xavier AC et al: Acute leukemia in children with Down syndrome. Haematologica. 95(7):1043-5, 2010 Mullighan CG et al: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet. 41(11):12436, 2009 Lightfoot J et al: Distinct gene signatures of transient and acute megakaryoblastic leukemia in Down syndrome. Leukemia. 18(10):1617-23, 2004 Roizen NJ et al: Down's syndrome. Lancet. 361(9365):1281-9, 2003 Wechsler J et al: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 32(1):148-52, 2002 Lange BJ et al: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood. 91(2):608-15, 1998 Pueschel SM: Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet Suppl. 7:52-6, 1990

Down Syndrome

Dysplastic Megakaryocytes in AML (Left) Core biopsy from a 2year-old patient with DS shows left-shifted erythroid and myeloid elements, increased and dysplastic megakaryocytes ﬇, and increased myeloid blasts. (Right) CD61 highlights increased and dysplastic megakaryocytes in this patient with DS.

Increased Myeloid Blasts in AML

Overview of Syndromes: Syndromes

Myeloid Leukemia Associated With Down Syndrome

Morphologic Dysplasia in Erythroid and Megakaryocytic Lineage (Left) CD61 highlights increased and dysplastic megakaryocytes in this patient with DS. (Right) Bone marrow aspirate smear shows an erythroid dominant hematopoiesis. Erythroid elements show prominent dysplastic features including nuclear irregularities, nuclear budding, and binucleation. A small dysplastic megakaryocyte ﬇ is also seen.

B-ALL

Lymph Node Involved by B-ALL/Lymphoma (Left) Core biopsy shows a diffuse infiltrate of Blymphoblasts (based on flow cytometric analysis) comprising virtually 100% of marrow cellularity in this patient with DS. (Right) H&E shows lymphoblasts invading and replacing the lymph node sinuses and parenchyma.

559

Overview of Syndromes: Syndromes

Dyskeratosis Congenita

TERMINOLOGY

GENETICS

Synonyms

Complex Inheritance Pattern

• • • •

• Autosomal dominant ○ TERC or TINF2 mutations • Autosomal recessive ○ CTC1, WRAP53, NHP2, NOP10 • Autosomal dominant or recessive ○ TERT • X-linked recessive ○ DKC1 • De novo/sporadic occurrence ○ TERF1-interacting nuclear factor 2 gene (TINF2) • Telomeres are noncoding sequences at chromosome ends • Telomerase adds repeat nucleotides to 3' end of DNA after replication to prevent shortening of telomeres with each cell division

Zinsser-Cole-Engman syndrome Hoyeraal-Hreidarsson syndrome Revesz syndrome OMIM ○ 127550 ○ 224230 ○ 305000 ○ 613987 ○ 613988 ○ 613989 ○ 613989 ○ 615190 ○ 616353

Definition • Clinical triad ○ Oral leukoplakia (80%) ○ Nail dystrophy (90%) ○ Reticulate hyperpigmentation (80-90%) • Secondary to defective telomere maintenance (premature telomere shortening is proposed underlying mechanism of disease) • Timepoint when telomeres become critically short determines clinical picture

EPIDEMIOLOGY Age at Presentation • M:F = 3:1 for X-linked form • Present with dystrophic nails between ages of 5-13 years • Bone marrow failure in 2nd decade

Incidence • ~ 1 in 1 million

Pathogenic Mutations • DKC1, TERC, TERT, NOP10, and NHP2 ○ DKC1 (dyskeratosis congenita 1, dyskerin) most common ○ TERC (telomerase RNA component) ○ TERT (telomerase reverse transcriptase) ○ NOP10 (NOP10 ribonucleoprotein) ○ NHP2 (NHP2 ribonucleoprotein) ○ DKC1 (dyskerin pseudouridine synthase 1) ○ NAF1 (nuclear assembly factor 1) ○ Encode components of telomerase complex, telomere elongation • TINF2 and ACD ○ TINF2 (TERF1-interacting nuclear factor 2) ○ ACD (adrenocortical dysplasia homolog) ○ Encode components of shelterin complex, telomere protection • CTC1 (CST telomere maintenance complex component 1) ○ Encodes part of CST complex, recruitment and docking of telomerase on to telomere • WRAP53 involves in telomere trafficking ○ WRAP53 or TCAB1 (WD repeat containing antisense to TP53)

Tongue Squamous Cell Carcinoma (Left) Squamous cell carcinoma on the posterior lateral border of the tongue presents as an exophytic, firm, indurated mass with rolled borders. (Courtesy S. Müller, DMD.) (Right) Welldifferentiated squamous cell carcinoma extends from the overlying epithelium into the lamina propria with keratin pearl formation ﬊. (Courtesy S. Müller, DMD.)

560

Squamous Cell Carcinoma, Invasive

Dyskeratosis Congenita

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Telomere Shortening With Subsequent • • • •

Bone marrow failure Malignancy Pulmonary fibrosis Testing of peripheral blood leukocytes would show telomere lengths to be below 1st percentile

Clinical Findings • Triad ○ Oral leukoplakia ○ Nail dystrophy ○ Reticular hyperpigmentation/poikiloderma • Oral leukoplakia ○ Most common on tongue • Nail dystrophy ○ Thin dystrophic nails with longitudinal ridges • Reticular hyperpigmentation ○ Fine, lace-like pattern ○ Frequently on – Face – Upper trunk – Upper arms • Other mucocutaneous findings ○ Adermatoglyphia (no fingerprints) ○ Palmoplantar hyperkeratosis ○ Early graying ○ Scalp or eyelash hair loss ○ Epiphora (watering eyes) • Bone marrow failure ○ 90% of cases • Atrophic wrinkled skin • Eye disease • Bone marrow failure • Increased risk of squamous cell carcinoma ○ Oropharynx ○ Esophagus ○ Bronchus ○ Rectum ○ Cervix and vagina • Increased risk of ○ Myelodysplasia ○ Acute myelogenous leukemia

○ Hodgkin disease

Hoyeraal-Hreidarsson Syndrome • • • • • • •

Cerebellar hypoplasia Microcephaly Severe immunodeficiency Aplastic anemia Enteropathy Intrauterine growth retardation Developmental delay

Revesz Syndrome • Bilateral exudative retinopathy • Developmental delay • Triad ○ Oral leukoplakia ○ Abnormal nails ○ Reticulate hyperpigmentation • Cerebellar hypoplasia • Bone marrow hypoplasia

Overview of Syndromes: Syndromes

• RTEL1 and STN1 involve in telomere replication ○ RTEL1 (regulator of telomere elongation helicase 1) ○ STN1 • PARN involves in control of mRNA stability ○ PARN [poly(A)-specific ribonuclease] • 30-40% of patients clinically diagnosed with dyskeratosis congenita lack germline mutations of above 11 causative genes • Dyskeratosis congenita patients can harbor biallelic variants in USB1, LIG4, and GRHL2 ○ Genes mutated in – Poikiloderma with neutropenia – Dubowitz syndrome – Ectodermal dysplasia/short stature syndrome.

Phenotypic Variability Correlated With Genotype • Severe mucocutaneous phenotypes (triad features plus additional mucocutaneous findings) • Associated with worse overall prognosis • Cancer is more frequent in cases secondary to TERT and TERC mutations • Cancer is less frequent in cases secondary to TINF2 mutations • Disease secondary to TERC mutations is less severe than that of DKC1 mutations • TINF2 mutations cause severe disease with early death

ASSOCIATED NEOPLASMS • Upper aerodigestive tract cancers ○ Esophageal carcinoma ○ Gastric adenocarcinoma ○ 11x increase in comparison to general population • Squamous cell carcinoma of head and neck • Hodgkin lymphoma • Colorectal carcinoma • Anorectal carcinoma • Lung carcinoma • Bronchial and laryngeal carcinoma

CANCER RISK MANAGEMENT • Major cause of death is related to bleeding and opportunistic infections • Avoid sun exposure and smoking • Leukemia ○ Annual complete blood count ○ Annual bone marrow aspirate • Squamous cell carcinoma ○ Monthly self-examination ○ Annual skin and gynecologic examination

561

Overview of Syndromes: Syndromes

Dyskeratosis Congenita

CRITERIA FOR DIAGNOSIS Criteria • At least 2/4 major features and 2 or more of other minor somatic features • 2 or more features seen in dyskeratosis congenital plus very short telomeres ○ < 1st percentile • Major criteria ○ Oral leukoplakia ○ Nail dystrophy ○ Abnormal skin pigmentation ○ Bone marrow failure • Minor criteria ○ Early hair loss or graying ○ Epiphora ○ Esophageal stricture ○ Hyperhidrosis ○ Hypogonadism ○ Undescended testes ○ Urethral stricture/phimosis ○ Liver disease ○ Malignancy ○ Osteoporosis, aseptic necrosis, scoliosis ○ Pulmonary disease ○ Intellectual disability, developmental delay ○ Microcephaly ○ Cerebellar hypoplasia ○ Ataxia ○ Deafness ○ Short stature ○ Intrauterine growth retardation

• • • • •

Sun-sensitive rash with prominent poikiloderma Juvenile cataracts Saddle nose Congenital bone defects Hypodontia

Naegeli-Franceschetti-Jadassohn Syndrome • • • • • • • •

Chromatophore nevus of Naegeli and Naegeli syndrome Autosomal dominant form of ectodermal dysplasia KRT14 (keratin 14) mutation Reticular skin pigmentation Absence of teeth Hyperkeratosis of palms and soles Diminished function of sweat glands Adermatoglyphia (absence of fingerprints)

Dermatopathia Pigmentosa Reticularis • • • •

a.k.a. dermatopathic pigmentosa reticularis Autosomal dominant KRT14 (keratin 14) mutation Triad ○ Generalized reticulate hyperpigmentation ○ Noncicatricial alopecia ○ Onychodystrophy Lack of sweat glands Thin hair Brittle nails Mottled skin Hyperkeratosis of palms and soles Adermatoglyphia (absence of fingerprints)

• • • • • •

SELECTED REFERENCES 1.

DIFFERENTIAL DIAGNOSIS Fanconi Anemia • • • • • • • • • •

Due to chromosomal rearrangement and breakage Pigmentary changes Short stature Eye abnormalities CNS malformation Developmental delay Urogenital, cardiac, gastrointestinal, or oral abnormalities Acute myeloid leukemia Other hematologic malignancies Solid tumors ○ Wilms tumor ○ Squamous cell carcinoma of head and neck

2. 3. 4.

5.

6. 7.

8. 9.

Rothmund-Thomson Syndrome • Poikiloderma atrophicans with cataract or poikiloderma congenitale • Autosomal recessive • Mutations in DNA helicase RECQL4 • Features of accelerated aging ○ Atrophic skin ○ Alopecia ○ Osteopenia ○ Cataracts ○ Increased incidence of cancer 562

10.

11.

12. 13. 14.

Higgs C et al: Understanding the evolving phenotype of vascular complications in telomere biology disorders. Angiogenesis. 22(1):95-102, 2019 Agarwal S: Evaluation and management of hematopoietic failure in dyskeratosis congenita. Hematol Oncol Clin North Am. 32(4):669-85, 2018 Fioredda F et al: Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita. Br J Haematol. 183(1):110-8, 2018 Ward SC et al: Beyond the triad: inheritance, mucocutaneous phenotype, and mortality in a cohort of patients with dyskeratosis congenita. J Am Acad Dermatol. 78(4):804-6, 2018 Bongiorno M et al: Malignant transformation of oral leukoplakia in a patient with dyskeratosis congenita. Oral Surg Oral Med Oral Pathol Oral Radiol. 124(4):e239-42, 2017 Kelmenson DA et al: Dyskeratosis congenita. N Engl J Med. 376(15):1460, 2017 Khincha PP et al: Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders. Eur Respir J. 49(1), 2017 Monoi A et al: Atypical dyskeratosis congenita diagnosed using wholeexome sequencing. Pediatr Int. 59(8):933-5, 2017 Gadalla SM et al: The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita. Mol Genet Genomic Med. 4(4):475-9, 2016 Gadalla SM et al: Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. Biol Blood Marrow Transplant. 19(8):1238-43, 2013 Alter BP et al: Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica. 97(3):353-9, 2012 Mason PJ et al: The genetics of dyskeratosis congenita. Cancer Genet. 204(12):635-45, 2011 Alter BP et al: Cancer in dyskeratosis congenita. Blood. 113(26):6549-57, 2009 Vulliamy T et al: Dyskeratosis congenita. Semin Hematol. 43(3):157-66, 2006

Dyskeratosis Congenita

Invasive Squamous Cell Carcinoma (Left) H&E shows welldifferentiated squamous cell carcinoma. Note the extensive keratin pearls ﬈ and large, pale, eosinophilic carcinoma cells ﬊. (Courtesy S. Owens, MD.) (Right) This invasive squamous cell carcinoma has a broad, pushing border and is adjacent to mucosal epithelium with little cytologic atypia. (Courtesy S. Müller, DMD.)

Acantholytic Squamous Cell Carcinoma

Overview of Syndromes: Syndromes

Well-Differentiated Squamous Cell Carcinoma

Poorly Differentiated Squamous Cell Carcinoma (Left) This squamous cell carcinoma of the lower lip has an acantholytic appearance characterized by tumor nests with a pseudoglandular architecture ﬊. (Courtesy S. Müller, DMD.) (Right) There are few features to distinguish this poorly differentiated squamous cell carcinoma from other poorly differentiated neoplasms. When present, intercellular bridges (desmosomes) ﬈ can be helpful. (Courtesy S. Owens, MD.)

Keratin 5/6 Expression in Squamous Cell Carcinoma

Nuclear p63 Expression in Squamous Cell Carcinoma (Left) CK5/6 stains a squamous cell carcinoma beneath normal squamous mucosa. Note the positivity of the normal squamous cells ﬈ as well as the carcinoma ﬊. (Courtesy S. Owens, MD.) (Right) Positive p63 nuclear staining in this invasive squamous carcinoma nest differentiates squamous cell carcinoma (positive) from other possible neoplasms, including adenocarcinoma and neuroendocrine tumors (negative) in the anal canal. (Courtesy S. Owens, MD.)

563

Overview of Syndromes: Syndromes

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome

TERMINOLOGY Abbreviations • Acute myeloid leukemia (AML) • Myelodysplastic syndromes (MDS)

Definitions, Classification, Distinguishing Features • MDS: Heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, clinical cytopenia(s), dysplasia in 1 or more myeloid lineages, and increased risk of evolution to AML • AML: Heterogeneous group of clonal hematopoietic neoplasms characterized by ≥ 20% blasts or blast equivalents in peripheral blood or bone marrow ○ Exceptions include AML with specific recurrent genetic abnormalities (t[15;17], t[8;21], inv[16]/t[16;16]) • Frequency of familial myeloid neoplasm is unknown but considered rare • Familial MDS/AML syndromes with defined genetic lesions include ○ Myeloid neoplasms with germline predisposition without preexisting disorder or organ dysfunction – AML with germline CEBPA mutation □ Autosomal dominant inheritance (usually frameshift or nonsense mutation in 5' of gene), encoding for transcription factor □ Requires 2nd mutation (usually in 3' of gene) for leukemia to develop □ Near-complete penetrance for development of AML □ Typically results in AML in children or young adults □ AML often has Auer rods, aberrant CD7 expression, and normal karyotype □ Generally favorable prognosis, but allogeneic hematopoietic stem cell transplant (SCT) is often pursued for eligible candidates – Myeloid neoplasms with germline DDX41 mutation □ Autosomal dominant inheritance with frameshift, missense splice site mutations in gene encoding for DEAD box RNA helicase

Peripheral Blood Smear (Left) Peripheral blood smear shows thrombocytopenia with 2 platelets ﬈ per HPF. Thrombocytopenia is characteristic of familial platelet disorder (FDP) with propensity to acute myeloid leukemia (AML). (Right) Bone marrow aspirate smear shows erythroid precursors with dysplastic changes ﬈. Dysplasia in 1 or more myeloid lineages is morphologic hallmark of myelodysplastic syndromes (MDS).

564

□ Most cases of myeloid neoplasms (high-grade MDS, AML, CMML) with germline DDX41 mutation have 2nd somatic (often missense) DDX41 mutation □ Penetrance of disease appears high and latency long (mean age: 62 years) □ Rare cases of Hodgkin and non-Hodgkin lymphoma have been reported □ Leukopenia at presentation is common, as is hypocellular marrow with erythroid dysplasia and normal karyotype □ Prognosis is generally poor and allogeneic SCT is often pursued for eligible candidates – Aplastic anemia (AA)/myelodysplasia with SRP72 mutations □ Autosomal dominant transmission of heterozygous SRP72 mutations in 2 families with AA &/or MDS □ SRP72 encodes for component of signal recognition peptide complex □ Pancytopenia since childhood but MDS in adulthood □ One pedigree had also congenital nerve deafness – Myeloid neoplasms with germline duplications of ATG2B and GSKIP □ Germline duplication of 700 kb region of 14q32.2, including ATG2B and GSKIP genes (4 families, French West Indies) □ Both genes enhance megakaryopoiesis □ 2/3 presented in adulthood with essential thrombocythemia; 50% progressed to AML or myelofibrosis □ Other myeloid malignancies: CMML, CML, and atypical CML □ High penetrance (> 80%) ○ Myeloid neoplasms with germline predisposition and preexisting platelet disorder – Myeloid neoplasms with germline RUNX1 mutation □ Autosomal dominant inheritance (monoallelic germline mutation in RUNX1, which encodes for αsubunit of core binding transcription factor)

Bone Marrow Aspirate Smear

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome – Bone marrow failure syndromes: Diamond-Blackfan anemia, severe congenital neutropenia, ShwachmanDiamond syndrome, Fanconi anemia – DNA damage repair deficiency syndromes: RecQ helicase deficiencies (Bloom syndrome, RothmundThomson syndrome, Werner syndrome) – Cell cycle and cell differentiation defects: Neurofibromatosis type 1, Noonan syndrome, and Noonan-like syndrome (juvenile myelomonocytic leukemia) – Li-Fraumeni syndrome – Telomere biology disorders: Dyskeratosis congenita, syndromes due to TERC or TERT mutations – Myeloid neoplasms with germline GATA2 mutation □ Previously 4 different syndromes: MonoMac syndrome, Emberger syndrome, familial MDS/AML, DCML □ Now considered as single genetic disorder with protean manifestations □ Autosomal dominant inheritance (disease results from monoallelic germline mutation, causing loss of function of mutated allele and haploinsufficiency) □ GATA2 is transcription factor regulating hematopoiesis, autoimmunity, inflammatory and developmental processes □ Heterogeneous clinical presentation □ MDS/AML in ~ 70% of affected individuals (median age of 29 years), often starting with MDS at high risk of evolution to AML or CMML □ Nontuberculous mycobacterial infections, monocytopenia, and predisposition to MDS/AML (previously MonoMac syndrome) □ Dendritic, monocyte, B- and NK-cell deficiency associated with viral infections and pulmonary alveolar proteinosis (HPV) (previously DCML syndrome) □ Primary lymphedema, disseminated cutaneous warts, sensorineural deafness, and predisposition to MDS/AML (previously Emberger syndrome) □ 37% of children with MDS and monosomy 7 harbor germline GATA2 mutations and often no other GATA2-related symptoms □ Bone marrow often hypocellular with dysplastic megakaryocytes and increased reticulin fibrosis □ Monocytopenia, decreased NK and B cells and CD56(+) plasma cells can be seen by flow cytometric analysis □ Monosomy 7 and trisomy 8 are commonly seen in these patients as are ASXL1 mutations at malignant progression □ Many mutations have been described, including large rearrangements and mutations in intron 5 enhancer – MIRAGE and ATXPC/MLSM7 syndromes (SAMD9/SAMD9L mutations) □ Autosomal dominant inheritance (germline mutation in SAMD9 or SAMD9L, located in tandem on chromosome 7) □ Both genes are involved in control of cell proliferation

Overview of Syndromes: Syndromes

□ RUNX1 (a.k.a. AML1, CBFA2) □ RUNX1 mutations (large intragenic deletions, Runt domain mutations) tend to be specific to families; mutational heterogeneity may explain variable phenotype □ Mild to moderate bleeding tendency with mild thrombocytopenia □ Functional, aspirin-like platelet defect (impaired platelet aggregation with collagen and epinephrine) □ Median age at onset of myeloid neoplasms (AML and MDS, rarely CMML) is 33 years, and lifetime risk is estimated at 35-40% □ Rare cases of T-lymphoblastic leukemia/lymphoma and B-cell neoplasms have been reported □ Acquisition of 2nd (somatic) RUNX1 mutation is common but not required □ Anticipation appears to occur (children presenting at earlier age than older generations) – Myeloid neoplasms with germline ANKRD26 mutation □ a.k.a. thrombocytopenia 2 (THC2) □ Autosomal dominant inheritance (mutations in 5' UTR of ANKRD26, which encodes for ankyrin repeat domain 26) □ Mutations cause impaired binding of RUNX1 and FLI1 with signaling through MPL pathway □ Moderate thrombocytopenia with normal platelet size and volume and normal platelet aggregation studies □ Bone marrow can show increased and hypolobated megakaryocytes and dysmegakaryopoiesis □ TPO levels are elevated □ Mild bleeding tendency □ Affected individuals have 30x higher risk of myeloid neoplasms (AML/MDS mostly, but also CMML) or even CLL – Myeloid neoplasms with germline ETV6 mutation □ a.k.a. thrombocytopenia 5 (THC5) □ Autosomal dominant inheritance [germline mutation in ETV6 (usually missense mutations)] □ Mutations disrupt ETV6 nuclear localization with decreased expression of platelet-associated genes □ Moderate thrombocytopenia with normal-sized platelets with mild to moderate bleeding tendency, often in infancy □ Bone marrow with small hyposegmented megakaryocytes and mild dyserythropoiesis □ Associated malignancies include MDS, AML, CMML, B-ALL, plasma cell myeloma, and even early-onset colorectal adenocarcinoma □ Predisposition to ALL is more frequent, especially to childhood B-ALL □ Penetrance of hematological malignancies varies strongly between different affected amino acid residues and between families □ ~ 30% of carriers have been diagnosed with some kind of hematologic malignancy ○ Myeloid neoplasms with germline predisposition associated with other organ dysfunction

565

Overview of Syndromes: Syndromes

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome □ Germline gain of function mutations in SAMD9 cause MIRAGE syndrome □ MIRAGE syndrome: Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy □ Germline gain of function mutations in SAMD9L cause ataxia-pancytopenia syndrome (ATXPC) and myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7) □ Monosomy 7 is common and often results in loss of mutated allele □ In cis mutations and other genetic mechanisms [UPD(7q)], can cause reversion of germline mutations □ Bone marrow failure and cytopenias occur in childhood with frequent dysplastic features, -7 karyotype, and high risk of MDS and AML □ Screening should be considered in pediatric patients with MDS, AML, or JMML and chromosome 7 aberrations □ Analyses should include sequencing of DNA from peripheral blood as well as nonhematopoietic tissue

SELECTED REFERENCES 1. 2. 3.

4. 5.

6.

7. 8. 9.

10. 11.

12.

GENETICS General Points • Underlying genetic cause of many clusters of familial MDS/AML have not yet been elucidated • Given variable penetrance and latency periods, single germline mutations that have been described likely predispose to MDS/AML by rendering families highly susceptible to additional, somatic mutations

13. 14. 15.

16.

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

17.

Familial vs. Sporadic MDS/AML

18.

• Younger age of presentation in some familial MDS/AML • Relatives of AML patients < 21 years old at diagnosis have 6.5x increase risk of MDS/AML and 3x risk of any myeloid malignancy

19.

20.

ASSOCIATED NEOPLASMS FPD/AML • Increased risk for T-acute lymphoblastic leukemia • No increased risk for other nonmyeloid neoplasms

MonoMac • Reported malignancies (some due to HPV infection): Vulvar carcinoma, metastatic melanoma, cervical carcinoma, Bowen disease of vulva, Epstein-Barr virus-positive leiomyosarcoma

CANCER RISK MANAGEMENT Stem Cell Transplantation • Genetic screening is advised when evaluating relatives as potential donors for patients undergoing allogeneic stem cell transplantation

21.

22. 23.

24.

25.

26. 27. 28.

29.

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Churpek JE et al: Transcription factor mutations as a cause of familial myeloid neoplasms. J Clin Invest. 129(2):476-88, 2019 Rampersaud E et al: Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood Adv. 3(7):1039-46, 2019 Tesi B et al: Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 129(16):2266-79, 2017 Chen DH et al: Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 98(6):1146-58, 2016 Narumi S et al: SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 48(7):792-7, 2016 Noetzli L et al: Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 47(5):535-8, 2015 Polprasert C et al: Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 27(5):658-70, 2015 Saliba J et al: Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet. 47(10):1131-40, 2015 Hsu AP et al: GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 121(19):3830-7, S1-7, 2013 Noris P et al: ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 122(11):1987-9, 2013 Pasquet M et al: High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 121(5):822-9, 2013 Bodor C et al: Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica. 97(6):890-4, 2012 Goldin LR et al: Familial aggregation of acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 30(2):179-83, 2012 Holme H et al: Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol. 158(2):242-8, 2012 Kazenwadel J et al: Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood. 119(5):1283-91, 2012 Kirwan M et al: Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am J Hum Genet. 90(5):888-92, 2012 Bigley V et al: The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. J Exp Med. 208(2):227-34, 2011 Calvo KR et al: Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica. 96(8):1221-5, 2011 Dickinson RE et al: Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 118(10):2656-8, 2011 Hahn CN et al: Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 43(10):1012-7, 2011 Hsu AP et al: Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 118(10):2653-5, 2011 Liew E et al: Familial myelodysplastic syndromes: a review of the literature. Haematologica. 96(10):1536-42, 2011 Ostergaard P et al: Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 43(10):929-31, 2011 Vinh DC et al: Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood. 115(8):1519-29, 2010 Kirwan M et al: Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum Mutat. 30(11):1567-73, 2009 Owen C et al: Familial myelodysplasia and acute myeloid leukaemia--a review. Br J Haematol. 140(2):123-32, 2008 Smith ML et al: Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 351(23):2403-7, 2004 Song WJ et al: Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 23(2):166-75, 1999 Weiss HJ et al: A familialdefect in platelet function associated with imapired release of adenosine diphosphate. N Engl J Med. 281(23):1264-70, 1969

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome

Cytogenetics in Familial MDS/AML (Left) Aspirate smear from a patient with AML shows intermediate-sized blasts with slightly irregular nuclear contours, fine chromatin, distinct nucleoli, and 1 cell with distinct Auer rods ﬈. Auer rods are frequently seen in AML with CEBPA mutation. (Right) Patients with familial MDS/AML may also have cytogenetic abnormalities, frequently monosomy 7 ﬈, as depicted in this karyotype. (Courtesy P. Dal Cin, PhD.)

MonoMac Syndrome

Overview of Syndromes: Syndromes

Bone Marrow Aspirate Smear

Urethral Condyloma in MonoMac Syndrome (Left) Bone marrow aspirate smear from a 26-year-old man with MonoMac syndrome shows erythroid hyperplasia, ↑ plasma cells and myelodysplasia in the erythroid (nuclear budding) ﬈, and myeloid (hypogranularity) ſt lineages. (Right) Koilocytes (large squamous cells with pyknotic nuclei and abundant clear cytoplasm) ﬈ are present in this urethral condyloma biopsy from a 26-year-old man with MonoMac syndrome. HPV infection is common in MonoMac.

Lymph Node in MonoMac Syndrome

Mycobacterium in MonoMac Syndrome (Left) Thoracic lymph node biopsy from a 26-year-old man with MonoMac syndrome shows nonnecrotizing granulomatous inflammation. Necrosis was identified in other sections. (Right) Highpower view shows acid-fast bacilli stain of lymph node from a 26-year-old man with MonoMac syndrome. Numerous red-staining mycobacterial organisms are present. PCR studies identified the species as Mycobacterium kansasii.

567

Overview of Syndromes: Syndromes

Familial Adenomatous Polyposis

TERMINOLOGY Abbreviations • Familial adenomatous polyposis (FAP) • Attenuated FAP (AFAP)

Synonyms • • • • • •

Familial polyposis coli Multiple adenomatosis Adenomatous polyposis coli (APC) Hereditary flat adenoma syndrome = AFAP Attenuated APC (AAPC) = AFAP Mesenteric fibromatosis = intraabdominal desmoids

Definitions • FAP: Autosomal dominant inherited syndrome ○ Numerous (> 100 in classic FAP) colorectal adenomas ○ Inevitably progress to adenocarcinoma at young age • Gardner syndrome (Bussey-Gardner polyposis): FAP with (prominent) extraintestinal manifestations (EIMs)

• AFAP: < 100 adenomas, right sided, later age at diagnosis

ETIOLOGY/PATHOGENESIS Genetic Predisposition • Inherited (germline) mutation in APC gene ○ Almost complete (90-100%) penetrance by 40 years • APC tumor suppressor gene (chromosome 5q21-22) ○ Downregulates β-catenin (Wnt signaling pathway) – Blocks transcription (otherwise uncontrolled growth) ○ Controls cell cycle, cell adhesion, enterocyte migration, actin/microtubule networks, chromosome segregation ○ Knudson 2-hit hypothesis: Somatic mutation or loss of heterozygosity at 2nd APC allele → FAP-related tumors • Specific APC mutations correlate with FAP phenotypes ○ Most FAP cases: Truncating mutations on 5q ○ Profuse polyposis (> 1,000 polyps): Mutation hot spots – Especially in exon 15: Mutation cluster region (MCR) – Codon 1061 (11%) and 1309 (13-17%) mutations ○ AFAP: Mutations at more 5' and 3' ends of APC

APC Gene

Graphic shows the location of various mutations along the APC gene and the phenotypic abnormalities that have been associated with each mutation site.

568

Familial Adenomatous Polyposis

CLINICAL ISSUES Epidemiology • Incidence ○ 0.005-0.020% (1 in 5,000-20,000 births) – Most frequent genetic polyposis syndrome ○ FAP accounts for < 1% of colorectal carcinoma (CRC) ○ AFAP comprises ~ 10% of all FAP cases • Age ○ Mean age of 1st adenoma: 10-15 years old – Found on screening flexible sigmoidoscopy ○ Mean age of FAP diagnosis: 35-43 years old – In otherwise unscreened populations ○ Mean age of CRC diagnosis: 40 years old – But can occur as early as teen years – Later in AFAP (CRC diagnosis at mean of 50 years old) • Sex ○ No sex predilection in FAP reported ○ Desmoids more common in women (F:M = 3:1) – Sex hormones (estrogens) may affect growth

Site

•

• • •

○ Single dysplastic colonic crypt, usually incidental ○ Becomes oligocryptal, eventually visible adenoma – Through excessive, asymmetric crypt fission Adenomas increase in number and size with age ○ Polyp count and patient age predict CRC risk ○ Overall, only small % of adenomas progress to CRC Neighboring normal colonic mucosa epithelium ○ ↑ cell proliferation/mitotic activity (controversial) Multiple CRC: Synchronous or metachronous AFAP: Fewer adenomas/CRC, 15 years later than FAP ○ Upper GI lesions almost always present, but EIM rare

Treatment • Options, risks, complications ○ Annual flexible sigmoidoscopy starting at age 10-12 years – Patients with APC mutation or clinical FAP diagnosis ○ Endoscopic evaluation of upper GI tract at age 20 years – Remove adenomas > 1 cm or with high-grade dysplasia (HGD) rather than eradicate all neoplasia □ Progression rate to carcinoma in small bowel is low ○ AFAP: Close endoscopic surveillance, upper/lower GI – Complete colonoscopy (common right-sided lesions) • Surgical approaches ○ Prophylactic colectomy by age 20-25 years – In mutation-positive patients with adenomas ○ Operation: Colectomy and ileorectal anastomosis, or – Proctocolectomy with ileal pouch-anal anastomosis □ Contraindications: Mesenteric desmoids, advanced low rectal cancer, poor anal sphincter function – Screening of rectal stump/ileal pouch after surgery • Drugs: NSAIDs (sulindac) and selective COX-2 inhibitors ○ Reduce rectal adenomas after subtotal colectomy – Do not completely prevent CRC ○ Treatment cessation leads to polyp regrowth ○ Side effects: Cardiovascular/thrombotic events ○ Used in desmoid tumors together with antiestrogens

• FAP adenomas: Similar distribution to sporadic adenomas ○ Mostly in sigmoid colon and rectum • CRC distribution follows adenomas (70-80% left sided) • > 70% of FAP patients develop extracolonic manifestations • Desmoid: In small bowel mesentery (most common site), retroperitoneum, abdomen/abdominal wall, extremities

Prognosis

Presentation

• Small intestine/duodenum ○ Duodenal/ampullary/periampullary adenomas – Possible cocarcinogenic effect of bile ○ Occur 10-15 years later than colorectal adenomas – 30 years earlier than general population ○ 90% of FAP patients on routine screening (50-100%) ○ Cumulative risk of small intestinal carcinoma (1-10%) – Cause of death after prophylactic colectomy (20%) ○ Small intestinal (nonduodenal) adenomas: < 10% of FAP – Small intestinal carcinoma in < 1% of FAP ○ Duodenal polyp classification: 5 Spigelman stages – Based on size, number, dysplasia degree, architecture • Stomach: Up to 85% of FAP patients develop gastric polyps ○ Mostly fundic gland polyps (FGPs) (40-60% of FAP) – More numerous, occur at younger age than sporadic

• • • •

Diarrhea, colicky abdominal pain Rectal bleeding, mucous discharge, intussusception Rarely severe electrolyte depletion (in diffuse polyposis) Acute pancreatitis (adenoma obstructing duct/ampulla)

Endoscopic Findings • Hundreds of small (< 1-cm) polyps carpet entire colon ○ Pedunculated or sessile; some larger (> 1 cm) ○ Rectal sparing has been described (especially in AFAP) ○ 5% can be nonpolypoid, flat adenomas • In severe cases: Thousands of polyps, back to back • AFAP: Fewer, smaller, flatter, more often right-sided polyps

Natural History • Earliest recognizable lesion: Unicryptal adenoma

Overview of Syndromes: Syndromes

○ No detectable APC mutation in some patients – 10-30% of classic FAP, up to 90% of AFAP ○ Mutations at 3' end of APC – Associated with aggressive and atypical desmoids • 20-40% of FAP: New solitary cases (no family history) ○ 10-25% spontaneous, de novo APC mutations – Arise during embryogenesis; no risk for siblings ○ 11-20% parents with somatic or gonadal mosaicism – May present with less severe phenotype • Single nucleotide mutation (APC I1307K) in exon 15 ○ Autosomal dominant but low penetrance – Affects 6% of Ashkenazi Jewish population ○ Renders APC susceptible to further mutations ○ No polyposis or extracolonic FAP manifestations ○ 10-20% lifetime cancer risk; age similar to sporadic

• Patients invariably progress to CRC (100% by 60 years) ○ Cancer risk already 1-6% at age 20-25 years ○ 50-75% of FAP patients have CRC by age 30 years ○ If untreated/unscreened, patients die by 5th decade

Extracolonic Gastrointestinal Lesions

569

Overview of Syndromes: Syndromes

Familial Adenomatous Polyposis ○ Gastric antral adenomas also described (6% of FAP) – ↓ numbers and ↓ frequency than FGPs – May be present diffusely throughout stomach – Rarely may be precursors to malignancy ○ Gastric carcinoma is rare, but cases have been reported – Possibly due to duodenogastric bile reflux – Mostly in Japan (additional environmental role)

Extraintestinal Manifestations • Desmoid tumors of soft tissue ○ Benign (no metastases) but locally aggressive – Recurrence or progression common after excision ○ Intraabdominal desmoids are most frequent in FAP ○ 10-30% of FAP, more in females and after early colectomy – Incidence ↑ during childbearing years, during/after pregnancy, and after oral contraceptive use – Often seen post trauma or post surgery ○ Adverse factors: ↑ complications, tumor recurrence ○ Complications: Obstruction (small bowel or ureters) – Thrombosis/occlusion of mesenteric vessels – Compression of peripheral nerves, perforation – 2nd cause of death in FAP (~ 20%) after CRC • Endocrine system ○ Papillary thyroid carcinoma (1-12%, mostly women) – Characteristic cribriform-morular variant of papillary thyroid carcinoma – Multiple bilateral small thyroid tumors in young females ○ Neoplasia: Pituitary, pancreatic islets, adrenal cortex • Liver, biliary tract, and pancreas ○ ↑ rate of hepatoblastoma (~ 0.5%, male infants) ○ Bile duct/gallbladder dysplasia, adenocarcinoma ○ Pancreas: Adenocarcinoma, intraductal papillary mucinous neoplasm, intraepithelial neoplasia • Bones and teeth (70-80%) ○ Multiple osteomas of skull, long bones, mandible – Benign, asymptomatic, osteosclerotic, radiopaque ○ Impacted, supernumerary/absent teeth, abnormal roots • Eye (75-90%) ○ Congenital hypertrophy of retinal pigment epithelium – Earliest diagnostic stigma of FAP (young infants) □ Especially bilateral pigmented lesions with halo – Large or multiple lesions: 100% specific for FAP • Skin, adnexa, and soft tissue ○ Multiple epidermal inclusion ("epidermoid") cysts – Face, scalp, extremities (vs. non-FAP patients: Back) ○ Lipomas, fibromas, sebaceous cysts – Sebaceous cysts and FAP: Oldfield syndrome • Nasopharyngeal angiofibroma ○ Highly vascular, locally invasive, seen in adolescent boys

Variants of Familial Adenomatous Polyposis • Turcot (Crail) syndrome (glioma-polyposis syndrome) ○ Coexistence: Hereditary colon cancer and brain tumor – FAP patients: Medulloblastomas (APC mutation) – Lynch: Gliomas (DNA mismatch repair mutation) • Hereditary desmoid disease: Multiple, unusual desmoids ○ Autosomal dominant APC mutation, rare colonic lesions

MACROSCOPIC General Features • Hundreds/thousands of colonic polyps, mostly < 1 cm • Duodenal/ampullary/periampullary adenomas ○ Multiple, sessile, and mostly on mucosal folds • Desmoid tumors: Slow-growing, fibrous masses ○ Flat or lobulated, nonencapsulated, may be multiple ○ Intralesional hemorrhage, cystic degeneration

MICROSCOPIC Histologic Features • FAP-associated adenomas/CRC ○ Similar histology to sporadic adenomas/CRC ○ Tubular adenomas, rarely tubulovillous or villous • Desmoid tumors ○ Elongated, highly differentiated myofibroblasts ○ Growth in fascicles or whorls, abundant collagen matrix ○ Variable collagen, numerous small blood vessels • Duodenal/ampullary/periampullary adenomas ○ Similar histology to colonic tubular adenomas – Hyperchromatic, crowded, elongated nuclei – Mostly low-grade dysplasia (retain polarity) ○ Dysplasia also seen in grossly normal duodenal mucosa • Stomach: FGPs ○ Cystic dilatation, irregular budding of fundic glands ○ More often have dysplasia (up to 25%) than sporadic

ANCILLARY TESTS Genetic Testing • APC mutations detected in 60-90% of FAP families ○ Protein truncation testing, DNA sequencing ○ Confirm diagnosis by flexible sigmoidoscopy

DIFFERENTIAL DIAGNOSIS MUTYH-Associated Polyposis • Autosomal recessive inheritance ○ Biallelic germline mutations needed for phenotype ○ Patients' children: Obligate carriers → screen partners • MUTYH (MYH) located on chromosome 1p ○ Involved in base excision repair (oxidative DNA damage) ○ Defect results in APC and KRAS mutations • Multiple adenomas (typically < 100), may have EIM of FAP • ↑ CRC (especially right sided), even in absence of polyps

NTHL1-Associated Adenomatous Polyposis • ↑ CRC risk, autosomal recessive

POLE/POLD1 Mutations • Faulty polymerase proofreading ○ Autosomal dominant oligopolyposis, mimic Lynch

Juvenile Intestinal Polyposis • Rare autosomal dominant syndrome, hundreds of small polyps ○ Branched dilated crypts, inflamed edematous stroma

Hyperplastic Polyposis • Generally < 100 colorectal polyps

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Familial Adenomatous Polyposis □ Annual endoscopic surveillance begins at 10-12 years ○ Inadvisable to test children < 10 years – Emotional stress and family conflicts – Result does not change treatment strategy

Hereditary Mixed Polyposis

Pathologic Interpretation Pearls

• Atypical juvenile polyps, serrated polyps, classic adenomas • Only colon affected; 2 separate loci implicated; ↑ CRC risk

• Duodenal adenomas in FAP ○ More Paneth/endocrine cells per crypt than sporadic

Cronkhite-Canada Syndrome • Rare syndrome, not considered genetic ○ Controversial malignant potential • Diffuse polyposis throughout GI tract (not esophagus) ○ Hamartomatous, juvenile polyps • Alopecia, onychodystrophy, skin hyperpigmentation

SELECTED REFERENCES 1.

2. 3.

Diffuse Lipomatous Polyposis • Rare; diffusely involves small and large intestines • Histologically, multiple benign mature lipomas

Nodular Lymphoid Hyperplasia • Often associated with immunodeficiency • Numerous nodules in small and large intestines • Large lymphoid clusters, prominent germinal centers ○ In lamina propria and superficial submucosa

4. 5.

6. 7.

8.

Lymphomatous Polyposis • Rare form of 1° GI lymphoma (mostly mantle cell) • Widespread lymphomatous polyps, poor prognosis

9. 10.

Inflammatory Polyposis • Mostly in association with inflammatory bowel disease • Regenerating mucosal islands and granulation tissue

11.

MSH3 Mutation

12.

• Autosomal recessive polyposis ○ Duodenal adenomas, gastric signet ring carcinoma, astrocytoma and thyroid neoplasia

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Diagnostic criteria for FAP: Any of following ○ ≥ 100 colorectal adenomas (classic FAP) – < 100 colon adenomas in AFAP (usually 1-50) ○ Germline APC mutation ○ Family history of FAP + at least 1 of following – Epidermoid cyst, osteoma, or desmoid • Suspect and test for FAP when patients present with ○ CRC at age < 45 years or with multiple CRC ○ Adenomatous polyps at age < 40 years ○ > 10 polyps in lifetime with positive family history ○ Family with multiple generations with CRC – And familial clustering of extracolonic cancers • Features of FAP/AFAP but no germline APC mutation ○ Test for MUTYH mutations: 10-20% positive for MYHassociated polyposis (MAP) • Genetic counseling in relatives of newly diagnosed patients ○ If asymptomatic and clearly negative DNA test – No further screening or testing necessary ○ If specific family mutation present is unknown – Negative result is inconclusive; continue screening

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Chenbhanich J et al: Prevalence of thyroid diseases in familial adenomatous polyposis: a systematic review and meta-analysis. Fam Cancer. 18(1):53-62, 2019 Dinarvand P et al: Familial adenomatous polyposis syndrome: An update and review of extraintestinal manifestations. Arch Pathol Lab Med. ePub, 2019 Hyer W et al: Management of familial adenomatous polyposis in children and adolescents: Position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 68(3):428-41, 2019 Khattab A et al: Turcot syndrome. StatPearls Publishing, 2019 Kim B et al: Next-generation sequencing with comprehensive bioinformatics analysis facilitates somatic mosaic APC gene mutation detection in patients with familial adenomatous polyposis. BMC Med Genomics. 12(1):103, 2019 Liu Q et al: Advances in identification of susceptibility gene defects of hereditary colorectal cancer. J Cancer. 10(3):643-53, 2019 Nakano K et al: Phenotypic variations of gastric neoplasms in familial adenomatous polyposis are associated with the endoscopic status of atrophic gastritis. Dig Endosc. ePub, 2019 Rubinstein JC et al: APC mutational patterns in gastric adenocarcinoma are enriched for missense variants with associated decreased survival. Genes Chromosomes Cancer. ePub, 2019 Short E et al: APC transcription studies and molecular diagnosis of familial adenomatous polyposis. Eur J Hum Genet. ePub, 2019 Akaishi J et al: Cribriform-morular variant of papillary thyroid carcinoma: Clinical and pathological features of 30 cases. World J Surg. 42(11):3616-23, 2018 Gutierrez Sanchez LH et al: Upper GI involvement in children with familial adenomatous polyposis syndrome: single-center experience and metaanalysis of the literature. Gastrointest Endosc. 87(3):648-56.e3, 2018 Pouya F et al: A novel large germ line deletion in adenomatous polyposis coli (APC) gene associated with familial adenomatous polyposis. Mol Genet Genomic Med. 6(6):1031-40, 2018 Sarvepalli S et al: Natural history of colonic polyposis in young patients with familial adenomatous polyposis. Gastrointest Endosc. 88(4):726-33, 2018 Trobaugh-Lotrario AD et al: Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening. Pediatr Blood Cancer. 65(8):e27103, 2018 Weren RD et al: NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 244(2):135-42, 2018 Yang A et al: Germline APC mutations in hepatoblastoma. Pediatr Blood Cancer. 65(4), 2018 Rosty C: The role of the surgical pathologist in the diagnosis of gastrointestinal polyposis syndromes. Adv Anat Pathol. 25(1):1-13, 2018 Basso G et al: Hereditary or sporadic polyposis syndromes. Best Pract Res Clin Gastroenterol. 31(4):409-17, 2017 Belhadj S et al: Delineating the phenotypic spectrum of the NTHL1associated polyposis. Clin Gastroenterol Hepatol. 15(3):461-2, 2017 DE Marchis ML et al: Desmoid tumors in familial adenomatous polyposis. Anticancer Res. 37(7):3357-66, 2017 Talseth-Palmer BA: The genetic basis of colonic adenomatous polyposis syndromes. Hered Cancer Clin Pract. 15:5, 2017 Walton SJ et al: Gastric tumours in FAP. Fam Cancer. 16(3):363-9, 2017 Adam R et al: Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 99(2):337-51, 2016 Giglia MD et al: Familial colorectal cancer: Understanding the alphabet soup. Clin Colon Rectal Surg. 29(3):185-95, 2016 Aihara H et al: Diagnosis, surveillance, and treatment strategies for familial adenomatous polyposis: rationale and update. Eur J Gastroenterol Hepatol. 26(3):255-62, 2014 Sereno M et al: MYH polyposis syndrome: clinical findings, genetics issues and management. Clin Transl Oncol. 16(8):675-9, 2014 Yamaguchi S et al: MUTYH-associated colorectal cancer and adenomatous polyposis. Surg Today. 44(4):593-600, 2014

Overview of Syndromes: Syndromes

○ Hyperplastic, serrated, adenomas, and mixed polyps ○ May mimic FAP or AFAP endoscopically • Familial aggregation, no definite genetic association ○ May have underlying defect in DNA methylation ○ Probably at increased risk for CRC

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Overview of Syndromes: Syndromes

Familial Adenomatous Polyposis Variants of Familial Adenomatous Polyposis Variant

Phenotype

Comment

Attenuated familial adenomatous polyposis

Fewer adenomas and later age of onset, lower risk of CRC

Need to exclude autosomal recessive MYHassociated polyposis

Gardner syndrome

FAP with extraintestinal manifestations (desmoids, osteomas, epidermoid cysts)

Significant mortality from extraintestinal lesions, especially after colectomy

Turcot syndrome

FAP with medulloblastoma

CRC with glioma is likely Lynch syndrome, not FAP

CRC  = colorectal carcinoma.

Extraintestinal Features in Familial Adenomatous Polyposis Benign Lesions

Malignant Lesions

CHRPE (75-90%)

Papillary thyroid cancer (> 12%)

Epidermoid cysts (50%)

Brain tumor (medulloblastoma) (< 1%)

Osteoma (50-90%)

Hepatoblastoma (1%)

Desmoid tumor (10-30%)

Hepatocellular carcinoma (< 1%)

Supernumerary teeth (70-80%)

Pancreatic adenocarcinoma (2%)

Adrenal adenomas (7-13%)

Pancreatic islet cell neoplasms (rare)

Lipomas and fibromas (prevalence unknown)

Adrenal cortical carcinoma (rare)

Juvenile angiofibroma (prevalence unknown)

Biliary tract adenocarcinoma (rare)

CHRPE = congenital hypertrophy of retinal pigmented epithelium. 28. Barrow P et al: Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg. 100(13):1719-31, 2013 29. Liang J et al: APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol. 177(11):1169-79, 2013 30. Lynch PM: When and how to perform genetic testing for inherited colorectal cancer syndromes. J Natl Compr Canc Netw. 11(12):1577-83, 2013 31. Lynch PM et al: Global quantitative assessment of the colorectal polyp burden in familial adenomatous polyposis by using a web-based tool. Gastrointest Endosc. 77(3):455-63, 2013 32. Tajika M et al: Risk of ileal pouch neoplasms in patients with familial adenomatous polyposis. World J Gastroenterol. 19(40):6774-83, 2013 33. Koornstra JJ: Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome. Best Pract Res Clin Gastroenterol. 26(3):359-68, 2012 34. Patel SG et al: Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep. 14(5):428-38, 2012 35. Gala M et al: Hereditary colon cancer syndromes. Semin Oncol. 38(4):490-9, 2011 36. Goodenberger M et al: Lynch syndrome and MYHassociated polyposis: review and testing strategy. J Clin Gastroenterol. 45(6):488-500, 2011 37. Kim B et al: Chemoprevention in familial adenomatous polyposis. Best Pract Res Clin Gastroenterol. 25(4-5):607-22, 2011 38. Parc Y et al: Surgical management of the duodenal manifestations of familial adenomatous polyposis. Br J Surg. 98(4):480-4, 2011 39. Jasperson KW et al: Hereditary and familial colon cancer. Gastroenterology. 138(6):2044-58, 2010 40. Mallinson EK et al: The impact of screening and genetic registration on mortality and colorectal cancer incidence in familial adenomatous polyposis. Gut. 59(10):1378-82, 2010 41. Gómez García EB et al: Gardner's syndrome (familial adenomatous polyposis): a cilia-related disorder. Lancet Oncol. 10(7):727-35, 2009 42. Al-Sukhni W et al: Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome. Surg Clin North Am. 88(4):81944, vii, 2008 43. Desai TK et al: Syndromic colon cancer: Lynch syndrome and familial adenomatous polyposis. Gastroenterol Clin North Am. 37(1):47-72, vi, 2008 44. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol. 61(2):153-61, 2007 45. Galiatsatos P et al: Familial adenomatous polyposis. Am J Gastroenterol. 101(2):385-98, 2006

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46. Ionescu DN et al: Attenuated familial adenomatous polyposis: a case report with mixed features and review of genotype-phenotype correlation. Arch Pathol Lab Med. 129(11):1401-4, 2005 47. Jass JR: What's new in hereditary colorectal cancer? Arch Pathol Lab Med. 129(11):1380-4, 2005 48. Cruz-Correa M et al: Familial adenomatous polyposis. Gastrointest Endosc. 58(6):885-94, 2003 49. Hernegger GS et al: Attenuated familial adenomatous polyposis: an evolving and poorly understood entity. Dis Colon Rectum. 45(1):127-34; discussion 134-6, 2002 50. Fodde R et al: Disease model: familial adenomatous polyposis. Trends Mol Med. 7(8):369-73, 2001 51. Lal G et al: Familial adenomatous polyposis. Semin Surg Oncol. 18(4):314-23, 2000 52. Lynch PM: Clinical challenges in management of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. Cancer. 86(11 Suppl):2533-9, 1999 53. Wallace MH et al: Upper gastrointestinal disease in patients with familial adenomatous polyposis. Br J Surg. 85(6):742-50, 1998

Familial Adenomatous Polyposis

Tubular Adenoma (Left) Gross photo of a colectomy resection specimen (fresh) shows hundreds of small, sessile polyps ﬈ almost completely covering the mucosal surface in a patient with known familial adenomatous polyposis (FAP). (Right) High-power view shows a tubular adenoma of the colon with dysplastic crypt epithelium ﬈ in a patient with FAP. The adenoma is mostly flat since the mucosa is not much expanded by proliferating tubules, and there is no protrusion above the colon surface ﬈.

Attenuated Familial Adenomatous Polyposis

Overview of Syndromes: Syndromes

Small, Sessile Polyps

Oligocryptal Tubular Adenoma (Left) Gross photo of a colectomy resection specimen (fresh) shows only a few colonic polyps ﬈ in a patient with attenuated FAP. Compare to the hundreds of polyps seen in classic FAP. (Right) High-power view shows an oligocryptal tubular adenoma in the colon of a patient with FAP. Often incidental, these feature only a few ("oligo") dysplastic crypts ﬈. Compare to the normal epithelium lining nondysplastic crypts nearby ﬈.

Small, Sessile Polyps

Fundic Gland Polyp (Left) Gross photo of a colectomy resection specimen (fresh) shows hundreds of small (< 0.5-cm), sessile polyps ﬈ diffusely present on the mucosa of the colon. The exact number of polyps would determine if this is attenuated or classic FAP. (Right) Highpower view of a fundic gland polyp shows low-grade dysplasia ﬊. The nondysplastic epithelium shows dilated oxyntic glands typical of a fundic gland polyp ﬇.

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Overview of Syndromes: Syndromes

Familial Adenomatous Polyposis

Duodenal Adenoma

Periampullary Adenoma

Fundic Gland Polyp

Fundic Gland Polyp

Classic Familial Adenomatous Polyposis

Oligocryptal Tubular Adenoma

(Left) High-power view of a duodenal polyp shows a duodenal adenoma ﬈ (lowgrade dysplasia) in a patient with FAP. This appears histologically identical to colonic adenomas. (Right) High-power view of endoscopically normal ampullary mucosa in a patient with FAP shows low-grade dysplasia (adenoma) with pseudostratified, elongated, and crowded hyperchromatic nuclei ſt lining the epithelium.

(Left) High-power view shows low-grade dysplasia with darker (hyperchromatic), larger (elongated), and proliferating (crowded) nuclei ﬈ in a fundic gland polyp from a patient with FAP. (Right) High-power view of a stomach section from a patient with FAP shows fundic gland polyp with low-grade dysplasia. Dilated oxyntic glands ﬊, characteristic of these polyps, coexist with lowgrade dysplasia of the foveolar epithelium ﬈.

(Left) Gross photo of a total proctocolectomy resection specimen (fresh) from an adolescent with FAP shows innumerable (thousands) small (< 5-mm), sessile polyps ﬈ carpeting the mucosa. This extent of polyposis qualifies as classic FAP. (Right) Highpower view shows oligocryptal adenoma with low-grade dysplastic ("adenomatous") epithelium spanning 3 crypts ﬊ only. This is the earliest histologically identifiable lesion in the colon of patients with FAP.

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Familial Adenomatous Polyposis Cribriform Pattern in Cribriform-Morular Variant (Left) Gross photo shows multiple thyroid tumor nodules in the papillary thyroid carcinoma (PTC), cribriform-morular variant (CMV), seen in a familial setting. Sporadic thyroid tumors with similar morphology are usually solitary and larger than tumors in FAP patients. (Right) High-power view of CMV-PTC shows the cytological features of the tumor cells typically seen in this variant. Note the absence of classic PTC nuclei and absence of colloid.

Aberrant β-Catenin Expression in Cribriform-Morular Variant

Overview of Syndromes: Syndromes

Multifocal Thyroid Tumors

Desmoid Tumor (Mesenteric Fibromatosis) (Left) Strong nuclear and cytoplasmic staining pattern for β-catenin in CMV-PTC is shown. Note how this differs from the membranous staining pattern seen in the adjacent thyroid follicles ﬊. (Right) Gross photo of an enterectomy resection specimen (fresh) from a patient with FAP shows a desmoid tumor ﬈ in the mesentery, surrounding intestinal muscle ſt, and ureter ﬈. Note the overlying colonic surface with adenomatous polyps ﬇.

Desmoid Tumor (Mesenteric Fibromatosis)

Desmoid Tumor (Left) High-power view shows an example of mesenteric fibromatosis (desmoid tumor) in a patient with FAP. These are relatively hypocellular tumors with abundant collagenous stroma ﬈. (Right) High-power view shows desmoid tumor in FAP. Note the spindle-shaped, welldifferentiated myofibroblasts ﬈, background collagen bundles ﬊, and evenly spaced blood vessels ﬈.

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Overview of Syndromes: Syndromes

Familial Chordoma • Pathogenic germline mutations in DNA repair genes: BRCA2, NBN, or CHEK2

TERMINOLOGY Definition • Chordomas in at least 2 blood relatives

ASSOCIATED NEOPLASMS Chordoma

EPIDEMIOLOGY Incidence • < 0.5% of all chordomas • Extremely rare with few families reported

Age • Wide range (30-50 years most common) • < 10 years rare

Gender • M:F = 2:1

Site • Arise in sacrococcygeal (~ 50%) and clival (~ 45%) locations • Can be multifocal

GENETICS Currently Under Active Investigation • Familial Chordoma Study (National Institute of Health)

Inheritance Pattern • Possible autosomal dominant inheritance pattern ○ Male to male transmission reported in some families

Genetic Alterations • Similar to sporadic cases ○ Duplication of region on chromosome 6q27 containing T-brachyury gene ○ Reports of loss of heterozygosity on 7q33 ○ Putative tumor suppressor gene locus on 1p36

Other Associations • Chordoma of infancy in tuberous sclerosis complex (TSC) ○ Autosomal dominant ○ Mutation in TSC1 on 9q34 or TSC2 on 16p13.3

• Etiology ○ Primary bone tumor arising from notochordal remnants ○ Usually affects midline, axial skeleton • Clinical presentation ○ Cranial tumors – Headache – Visual complaints (e.g., diplopia) – Cranial nerve defects – Evidence of pituitary dysfunction – May present as nasal polyp ○ Sacrococcygeal tumors – Longstanding lower back pain – Regional neurogenic issues (e.g., constipation, bladder dysfunction) ○ Nonsacrococcygeal spinal tumors – Symptoms related to compression of spinal cord or nerve roots – Lumbar vertebrae may show compression fractures • Imaging findings ○ Cranial tumors – Consistent involvement of midline structures – Destructive lesion in clival, sphenooccipital, or hypophyseal region – Mass effect on adjacent brain – May show calcific densities ○ Sacrococcygeal tumors – Lytic, destructive bone tumor – Anterior soft tissue extension common ○ Nonsacrococcygeal spinal tumors – Predominantly lytic, some sclerotic – Most localized to vertebral bodies – Rarely extraosseous with minimal bone involvement • Macroscopic findings ○ Soft, lobulated, translucent

Sacrococcygeal Chordoma (Left) Chordoma of both sporadic and familial cases characteristically involves midline bony structures. MR shows a chordoma involving the sacrum. (Right) Microscopically, chordoma shows epithelioid cells with abundant pink to clear and often multivacuolated cytoplasm ﬉, giving rise to a bubbly "physaliferous" appearance.

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Chordoma Histology

Familial Chordoma ○ Small molecule inhibitors of T-brachyury currently under development

Prognosis • Indolent but locally aggressive ○ Most morbidity due to local recurrence ○ Most mortality due to local extension (brain, upper respiratory tract, genitourinary/gastrointestinal tracts) • Metastases in up to 40% of patients ○ Most commonly to lungs, skin, other bones • Varies by histologic subtypes ○ Similar among conventional and chondroid chordomas ○ Worse in poorly differentiated chordoma ○ Worst in dedifferentiated chordoma • Age < 40 may be good prognostic factor

SELECTED REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

9.

10.

11. 12.

CANCER RISK MANAGEMENT Screening • No established screening protocol currently in place • Detection of germline T-brachyury gene duplication suggests susceptibility to chordoma development • MR of entire craniospinal axis at time family aggregation is identified

13. 14. 15.

16.

Treatment • Complete surgical resection with wide tumor-free margins ○ Depending on site, resection may often be incomplete • Preoperative &/or postoperative radiation • Chemotherapy ○ May be efficacious in dedifferentiated and poorly differentiated chordomas • Investigative therapies ○ Defective homologous recombination DNA repair as targets by immunotherapy &/or poly ADP-ribose polymerase (PARP) inhibitors ○ Discoveries of overexpression of tyrosine kinases (EGFR, PDGFR, VEGFR) and transcriptional regulators suggest potential targets

Overview of Syndromes: Syndromes

○ May appear mucoid ○ Sacrococcygeal chordomas with anterior soft tissue extension often covered by periosteum ○ Multiple nodules occasionally in recurrent tumors • Microscopic findings ○ Characteristically lobulated ○ Conventional chordoma – Physaliferous cells: Vacuolated, clear to eosinophilic cytoplasm – Prominent myxoid stroma ○ Chondroid chordoma – Contain areas of chondroid matrix or frank cartilage – Almost all occur in skull base ○ Dedifferentiated chordoma – Defined as high-grade sarcoma arising in association with or at site of previously documented chordoma – Most occur in sacrococcygeal region ○ Poorly differentiated chordoma – Defined as chordoma with loss of SMARCB1/INI1 expression – Cells with eosinophilic cytoplasm, eccentric nuclei, prominent nucleoli – No physaliferous cells or myxoid stroma – Most occur in skull base • Immunophenotype ○ Strong nuclear expression of T-brachyury ○ Generally strong expression of cytokeratins, epithelial membrane antigen (EMA) ○ Variable expression of S100 protein • Molecular findings ○ Recurrent somatic duplication in T-brachyury ○ Copy number loss of CDKN2A ○ Mutations in lysosomal trafficking regulator LYST ○ Mutations in PI3K-Akt signaling pathway ○ Poorly differentiated chordoma with focal SMARCB1 deletion &/or mutation

17. 18. 19. 20. 21.

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23.

Gröschel S et al: Defective homologous recombination DNA repair as therapeutic target in advanced chordoma. Nat Commun. 10(1):1635, 2019 Sharifnia T et al: Small-molecule targeting of brachyury transcription factor addiction in chordoma. Nat Med. 25(2):292-300, 2019 Shih AR et al: Molecular characteristics of poorly differentiated chordoma. Genes Chromosomes Cancer. 58(11):804-8, 2019 Shih AR et al: Clinicopathologic characteristics of poorly differentiated chordoma. Mod Pathol. 31(8):1237-45, 2018 Dahl NA et al: Chordoma occurs in young children with tuberous sclerosis. J Neuropathol Exp Neurol. 76(6):418-23, 2017 Tarpey PS et al: The driver landscape of sporadic chordoma. Nat Commun. 8(1):890, 2017 Wang KE et al: Familial chordoma: a case report and review of the literature. Oncol Lett. 10(5):2937-40, 2015 Choy E et al: Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 9(7):e101283, 2014 Kelley MJ et al: Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma. Hum Genet. 133(10):128997, 2014 Le LP et al: Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846. doi: 10.1371/journal. pone. PubMed Central PMCID: PMC3094331, 0018, 2013 Yang XR et al: T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet. 41(11):1176-8, 2009 Hallor KH et al: Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation. Br J Cancer. 98(2):434-42, 2008 Bhadra AK et al: Familial chordoma. A report of two cases. J Bone Joint Surg Br. 88(5):634-6, 2006 Larizza L et al: Update on the cytogenetics and molecular genetics of chordoma. Hered Cancer Clin Pract. 3(1):29-41, 2005 Yang X' et al: Corroboration of a familial chordoma locus on chromosome 7q and evidence of genetic heterogeneity using single nucleotide polymorphisms (SNPs). Int J Cancer. 116(3):487-91, 2005 Lee-Jones L et al: Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosomes Cancer. 41(1):80-5, 2004 Kelley MJ et al: Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q33. Am J Hum Genet. 69(2):454-60, 2001 Miozzo M et al: A tumor suppressor locus in familial and sporadic chordoma maps to 1p36. Int J Cancer. 87(1):68-72, 2000 Dalprà L et al: First cytogenetic study of a recurrent familial chordoma of the clivus. Int J Cancer. 81(1):24-30, 1999 Stepanek J et al: Familial chordoma with probable autosomal dominant inheritance. Am J Med Genet. 75(3):335-6, 1998 Eisenberg MB et al: Loss of heterozygosity in the retinoblastoma tumor suppressor gene in skull base chordomas and chondrosarcomas. Surg Neurol. 47(2):156-60; discussion 160-1, 1997 Butler MG et al: Cytogenetic, telomere, and telomerase studies in five surgically managed lumbosacral chordomas. Cancer Genet Cytogenet. 85(1):51-7, 1995 Coffin CM et al: Chordoma in childhood and adolescence. A clinicopathologic analysis of 12 cases. Arch Pathol Lab Med. 117(9):927-33, 1993

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Overview of Syndromes: Syndromes

Familial Gastrointestinal Stromal Tumor • FGISTs tend to occur in younger patients, and there are often synchronous or metachronous tumors

TERMINOLOGY Abbreviations

Age

• Gastrointestinal stromal tumor (GIST) • Familial GIST (FGIST)

Definition • Generally CD117(+), KIT or PDGFR mutation-driven mesenchymal tumors ○ Characteristic histological features: Spindle cells, epithelioid cells, and pleomorphic cells

EPIDEMIOLOGY Incidence • Most common mesenchymal tumor arising in gut ○ 6.8 cases per million per year in USA, 14.5 cases per million per year in Sweden – Vast majority are sporadic, not familial • Sporadic GISTs are typically seen in middle-aged to elderly patients

• Median is 60 years; rare in children and young adults • Familial cases present in middle age, ~ 10 years younger than sporadic cases • Carney triad cases may present in childhood • Mean age for neurofibromatosis type 1 (NF1)-associated lesions is 49 years

Site • Stomach most common site (60%) • Jejunum and ileum (30%) ○ Succinate dehydrogenase (SDH)-deficient cases always in stomach, usually in children ○ NF1-associated lesions tend to occur in small bowel • Duodenum (5%) • Colorectum (< 5%) • Esophagus and appendix (rare)

Gastric GIST

Gastric GIST

Large GIST

Carney Triad GIST

(Left) A large submucosal gastric gastrointestinal stromal tumor (GIST) is evident in the body of the stomach. (Courtesy B. Casey, MGH.) (Right) Gastric GIST in the same patient is hypoechoic by ultrasound criteria, and multiple cystic spaces are present in this tumor. (Courtesy B. Casey, MGH.)

(Left) Radiologic image shows a large GIST ſt. The lesion compresses the liver but arises in association with the gastric wall ﬈. (Right) Low-power view shows 2 epithelioid GIST from a patient with Carney triad. These patients often have multinodular or multifocal gastric GIST.

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Familial Gastrointestinal Stromal Tumor Germline Mutations of KIT

• Surgical approaches ○ Complete resection preferred, though not always achievable in familial cases with multiple tumors • Imatinib mesylate (Gleevec): Inhibits tyrosine kinases (such as C-kit) • Newer drugs used for acquired resistance to imatinib (attributed to secondary KIT or PDGFRA mutations) or initial lack of response ○ Sunitinib malate (Sutent): Used for patients with KIT exon 9 mutations, others ○ Regorafenib (Stivarga)

• Very rare (< 40 kindreds reported) • Patients have multiple GISTs (primarily in small intestine), hyperpigmentation, urticaria pigmentosa, and dysphagia • Autosomal dominant • Most mutations are in exon 11 ○ Mutations in other exons tend not to be associated with hyperpigmentation

SYNDROMES/GENETICS Genetics • GISTs are generally CD117(+) and KIT or PDGFRA mutationdriven mesenchymal tumors • 10-15% of all GISTs lack KIT or PDGFRA mutations ○ These have been classified as KIT/PDGFRA wild-type GIST (a.k.a. KIT/PDGFRA-WT GIST) ○ Recently, molecular analyses have shown that KIT/PDGFRA WT GISTs are heterogeneous group of different diseases rather than one single entity • 20-40% of all KIT/PDGFRA WT GISTs are succinate dehydrogenase (SDH)-complex deficient GISTs, recognized by loss of subunit B (SDHB) protein expression ○ Due to germline &/or somatic loss-of-function mutations in any of 4 SDH subunits (A, B, C, or D) ○ SDH-deficient GISTs are characterized by overexpression of insulin growth factor 1 receptor ○ SDH-deficiency is found in GIST arising as part of nonhereditary Carney triad (including paraganglioma and pulmonary chondroma) and autosomal dominant Carney-Stratakis syndrome (together with paragangliomas) with predisposing germline SDH subunit mutations ○ 88% of GISTs that had been classified as pediatric/WT GISTs were shown to be SDH-complex deficient upon genetic evaluation • Subgroup of remaining KIT/PDGFRA WT GISTs (but not SDH-deficient) have been partially characterized ○ 4-13% carry BRAF V600E mutation, are localized more frequently in small intestine, and have more favorable prognosis ○ Within non-SDH-deficient group, some GISTs have NF1 mutation and show female prevalence, frequent nongastric site, and multifocal localization, often unveiling unrecognized NF1 syndromic condition • 1/2 of KIT/PDGFRA WT GISTs have been identified to be either SDH-deficient or BRAF/RAS/NF1 mutated ○ Other 1/2 of KIT/PDGFRA WT GIST – Named as quadruple WT-GIST – Some have somatic mutations of TP53, MEN1, MAX, FGFR1, CTDNN2, CHD4, CBL, ARID1A, BCOR, and APC – Some of these quadruple WT GISTs have neuroendocrine-like signature – Some have ETV6-NTRK3, FGFR1-HOOK3, FGFR1-ACC1, KIT-PDGFRA, MARK2-PPFIA1, PRKAR1B-BRAF, and SPRED2-NELFCD gene fusions

Germline Mutations of PDGFRA • Very rare (< 5 kindreds reported)  • GISTs are typically epithelioid or mixed • Patients have multiple GISTs (primarily in stomach) without hyperpigmentation, urticaria pigmentosa, and dysphagia ○ 1 kindred also had large hands, associated with multiple GISTs, and intestinal neurofibromatosis ○ 1 patient from different kindred with unique PDGFRA mutation also had multiple lipomas and fibrous tumors of small bowel

Overview of Syndromes: Syndromes

Treatment

Carney Triad • Gastric GIST, paragangliomas, and pulmonary chondromas ○ Also may have adrenal cortical adenomas and esophageal leiomyomas ○ GISTs are typically epithelioid or mixed and are often multinodular ○ Histologically, these GISTs appear malignant with high mitotic rate and increased cellularity, but they often behave in benign fashion – Up to 29% have reported lymph node metastasis (nonsyndromic adult GISTs rarely spread to lymph nodes) – Even with these metastases, patients still have excellent prognosis – Respond to sunitinib much more than imatinib • 85% of patients are young females ○ Originally thought to be X-linked trait, as all patients were initially women, but no longer thought to be familial • Genetic defect unknown ○ SDH complex promoter methylation observed ○ Immunostains for SDH subunits may be negative, but germline mutations are not found in patients with Carney triad ○ No KIT mutations ○ Losses of chromosome 1p have been found in tumors (not germline)

Carney-Stratakis Syndrome • Germline mutations in SDH complex B, C, and D subunits • Patients have dyad of GISTs and paragangliomas ○ Autosomal dominant ○ GISTs are typically epithelioid or mixed and are often multinodular – Histologically, these tumors appear malignant with high mitotic rate and increased cellularity, but they often behave in benign fashion – May have lymph node metastases but still have good prognosis – Respond to sunitinib much more than imatinib ○ Dyad GISTs are wild type for KIT and PDGFRA mutations, also referred to as pediatric GISTs 579

Overview of Syndromes: Syndromes

Familial Gastrointestinal Stromal Tumor ○ SDH-deficient GISTs share pathognomonic profile characterized by – Young age – Female gender predilection – Gastric localization – Mixed epithelioid and spindle cell morpholog – Diffuse KIT and ANO1 (DOG1) IHC positivity – Frequent lymph node metastatic involvement – Often indolent behavior but can be metastatic upfront – Loss of SDH immmunostaining may be used to screen for tumors with SDH mutation – Poor response to imatinib

Neurofibromatosis Type 1 • Autosomal dominant due to mutation in NF1 (tumor suppressor gene) • May have multiple small intestinal GISTs (as well as usual neurogenic tumors and other stigmata of NF1) ○ NF1 patients 150x more likely than general population to develop GIST • Interaction between KIT gene product and NF1 gene product • Tumors have CD117 immunolabeling but no KIT gene mutations • GIST in NF1 often wild type for KIT and PDGFRA ○ Overall good prognosis and respond to sunitinib much better than imatinib

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Unique Features of Syndromic GIST • Presence of synchronous or metachronous stromal tumors or tumors in young patients should alert pathologist to possibility of familial syndromes ○ Epithelioid or mixed histology gastric tumors in young people should prompt work-up for paragangliomas and pulmonary chondromas – Immunostains for SDH subunits may be helpful to triage germline sequencing – Germline sequencing of PDGFRA may also be helpful if family history is positive and no paragangliomas are found ○ Presence of multiple GISTs in patients with hyperpigmented skin should prompt germline KIT sequencing ○ Multiple small bowel GISTs should raise question of NF1

SELECTED REFERENCES 1.

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Heinrich MC et al: Genomic aberrations in cell cycle genes predict progression of KIT-mutant gastrointestinal stromal tumors (GISTs). Clin Sarcoma Res. 9:3, 2019 Li GZ et al: Targeted therapy and personalized medicine in gastrointestinal stromal tumors: drug resistance, mechanisms, and treatment strategies. Onco Targets Ther. 12:5123-33, 2019 Mühlenberg T et al: KIT-dependent and -independent genomic heterogeneity of resistance in gastrointestinal stromal tumors - TORC1/2 inhibition as salvage strategy. Mol Cancer Ther. ePub, 2019 Serrano C et al: Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 120(6):612-20, 2019 Yen CC et al: Identification of phenothiazine as an ETV1targeting agent in gastrointestinal stromal tumors using the Connectivity Map. Int J Oncol. 55(2): 536-46, 2019

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Chen W et al: Dual targeting of insulin receptor and KIT in imatinib-resistant gastrointestinal stromal tumors. Cancer Res. 77(18):5107-17, 2017 Nannini M et al: The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). J Transl Med. 15(1):113, 2017 Schaefer IM et al: What is new in gastrointestinal stromal tumor? Adv Anat Pathol. 24(5):259-67, 2017 Schaefer IM et al: MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun. 8:14674, 2017 Ben-Ami E et al: Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol. 27(9):1794-9, 2016 Boikos SA et al: Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: A report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2(7):922-8, 2016 Huss S et al: Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy. Expert Rev Anticancer Ther. 15(6):623-8, 2015 Pantaleo MA et al: Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways. Cancer Med. 4(1):101-3, 2015 Nannini M et al: Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST). BMC Cancer. 14:685, 2014 Nannini M et al: Expression of IGF-1 receptor in KIT/PDGF receptor-α wildtype gastrointestinal stromal tumors with succinate dehydrogenase complex dysfunction. Future Oncol. 9(1):121-6, 2013 Janeway KA et al: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 108(1):314-8, 2011 Otto C et al: Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. Diagn Pathol. 6:52, 2011 Zhang L et al: Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol. 34(1):53-64, 2010 Thalheimer A et al: Familial gastrointestinal stromal tumors caused by the novel KIT exon 17 germline mutation N822Y. Am J Surg Pathol. 32(10):15605, 2008 Antonescu CR: Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models. Semin Diagn Pathol. 23(2):63-9, 2006 de Raedt T et al: Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology. 131(6):1907-12, 2006 Dahia PL et al: A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1(1):72-80, 2005 O'Riain C et al: Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features. Am J Surg Pathol. 29(12):1680-3, 2005 Yantiss RK et al: Multiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study. Mod Pathol. 18(4):475-84, 2005 Chompret A et al: PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 126(1):318-21, 2004 Robson ME et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res. 10(4):1250-4, 2004 Maeyama H et al: Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology. 120(1):210-5, 2001

Familial Gastrointestinal Stromal Tumor

Syndrome/Disease

Gene Affected

Associated Lesions

Pattern of Inheritance

Carney-Stratakis syndrome

Succinate dehydrogenase (SDH) subunits A, B, C, and D

Paragangliomas, epithelioid GIST

Autosomal dominant

Carney triad

SDHB 

Pulmonary chondromas, paragangliomas, epithelioid GISTs, adrenal cortical adenomas, esophageal leiomyomas

Female predominance raised question of X-linked trait, but ~ 15% of patients are male; no longer thought to be familial

Neurofibromatosis type 1

NF1

Café au lait spots, neurofibromas, neuroendocrine neoplasms of gut, malignant peripheral nerve sheath tumors, GIST, gliomas, pheochromocytomas, rhabdomyosarcomas, leukemias

Autosomal dominant

Familial GIST syndrome

KIT

GIST, hyperpigmentation, dysphagia, urticaria pigmentosa/systemic mastocytosis, nevi

Autosomal dominant

Familial GIST syndrome

PDGFRA

GIST, large hands, small intestinal fibrous tumors

Autosomal dominant

Overview of Syndromes: Syndromes

Genetic Syndromes Associated With GIST

GIST = gastrointestinal stromal tumor.

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Overview of Syndromes: Syndromes

Familial Gastrointestinal Stromal Tumor

Small Intestine GIST

Cecal GIST

Gastric GIST

GIST, Epithelioid Type

GIST, Spindle Cell Type

GIST, Gastric Epithelioid Type

(Left) Gross photo shows a small intestinal GIST. The bulk of the tumor is in the muscularis propria, but the lesion has extended into the submucosa and was diagnosed by mucosal biopsy. Note the overlying mucosa, which is eroded in places. (Right) Gross section of a large, ulcerated cecal tumor shows marked thickening of the submucosa. The mass displays a white, homogeneous, lobulated cut surface and extends into the peritonealized tissue and surrounding fat.

(Left) Cut surface of a tanwhite, fleshy, multilobulated rubbery mass with a smooth outer surface is shown within the stomach wall of a patient with Carney triad. (Right) This high-grade GIST, epithelioid type, involving the musculsris propria and perigastric adipose tissue of the stomach had > 5 mitosis per 21 HPF.

(Left) This spindle cell colonic GIST displays enhanced cellularity. Such appearances are often associated with an unfavorable outcome. Note that the nuclei are not pleomorphic. (Right) This gastric GIST is a multinodular epithelioid tumor with focal areas of interstitial fibrosis in a patient with Carney triad and SDHA mutation.

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Familial Gastrointestinal Stromal Tumor

GIST, Pediatric Type (Left) Low-power view shows a GIST involving the muscularis propria and submucosa of the colonic wall. The lesion is infiltrative and was centered in the muscularis propria. (Right) High-power view shows an epithelioid pediatric-type GIST from a patient with Carney-Stratakis syndrome. Despite the numerous mitoses ﬊, these lesions have a relatively good prognosis.

CD34 in GIST, Epithelioid Type

Overview of Syndromes: Syndromes

Colonic GIST

DOG1 in GIST, Spindle Cell Type (Left) High-power view shows membranous and cytoplasmic CD34 immunostaining in gastric GIST. ~ 80% of gastric GISTs express CD34, whereas small bowel GIST express CD34 in ~ 60%. (Right) DOG1 shows membranous staining, as is frequently the case with CD117 immunolabeling. An important pitfall of DOG1 is that it labels ~ 1/3 of gastric adenocarcinomas.

Membranous and Cytoplasmic Stain in GIST

Preserved SDHB in GIST, Spindle Cell Type (Left) CD117 shows diffuse membranous and cytoplasmic labeling in a gastric epithelioid cell GIST. This is the usual strong staining seen in the majority of such neoplasms. Similar CD117 expression can be encountered in other tumors, however. (Right) Spindle cell-type GIST shows preserved immunoexpression of SDHB. SDH-deficient GIST occurs exclusively in the stomach and shows either epithelioid or mixed morphology but virtually never pure spindle cell morphology.

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Overview of Syndromes: Syndromes

Familial Infantile Myofibromatosis

TERMINOLOGY

GENETICS

Abbreviations

Inheritance Pattern

• Familial infantile myofibromatosis (FIM)

• FIM shows autosomal dominant inheritance

Synonyms

Genetic Alterations

• Congenital generalized myofibromatosis

• Mutations in platelet-derived growth factor receptor (PDGFRB) ○ Sporadic infantile myofibromatosis/myofibroma characterized by somatic mutations in PDGFRB ○ FIM characterized by germline mutations in PDGFRB ○ PDGFRB mutations lead to ligand-independent constitutive activation of receptor and downstream pathways • Mutations in NOTCH3 noted in rare PDGFRB wild-type cases

Definitions • Myofibromas are benign tumors showing perivascular myoid differentiation • Myofibromas can involve infants, children, or adults ○ Myofibromas in infants and children present in 3 forms – Solitary myofibroma – Multicentric myofibroma – Generalized myofibromatosis • FIM is rare familial form of myofibromas with generalized involvement that presents mostly in infancy

EPIDEMIOLOGY Incidence • Infantile myofibroma/myofibromatosis is one of most common soft tissue tumors of infancy and childhood • Generalized infantile myofibromatosis is rare ○ Familial form accounts for subset of generalized cases

Age Range • Most infantile myofibromatosis present before age 2 ○ > 50% of cases present congenitally

Other Associated Conditions With Germline PDGFRB Mutations • Penttinen syndrome ○ Autosomal dominant, phenotype associated with premature aging • Overgrowth syndrome with dysmorphic facies and neurologic deterioration ○ Autosomal dominant • Familial idiopathic basal ganglia calcification ○ Autosomal dominant, associated with both PDGFRB and PDGFB mutations

CLINICAL IMPLICATIONS Clinical Presentation

Sex • Male predilection in infantile myofibromatosis

• Signs and symptoms depend on sites of myofibromas

Clinical Behavior

Site • Solitary and multicentric myofibromas most commonly involve soft tissue (especially head and neck, extremities) and bone • Generalized myofibromatosis involves not only soft tissue and bone but frequently also visceral organs (such as brain and lung)

• Solitary and multicentric myofibromas may regress spontaneously • Generalized myofibromatosis often progresses, leading to death in some cases, and rarely regresses spontaneously

Therapeutic Implications • Presence of PDGFRB mutations suggests use of tyrosine kinase inhibitors, such as imatinib for treatment

Myofibromatosis/Myofibroma (Left) Myofibromatosis is characterized by multiple myofibroma nodules, each of which shows characteristic biphasic histology with peripheral cellular areas ﬊ with bland myofibroblasts and a central, variably hyalinized area st. Peripheral slit-like vessels ﬊ are also characteristic. (Right) The cells in myofibromatosis show myofibroblastic differentiation with expression of smooth muscle actin, as seen here.

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Smooth Muscle Actin Expression in Myofibroma/Myofibromatosis

Familial Infantile Myofibromatosis

MACROSCOPIC

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Gross Features • Well circumscribed • Cut surface tan-red • Variable hemorrhage or vascular congestion

MICROSCOPIC Histology • Biphasic zonal appearance ○ Periphery: Fascicles of spindle cells with moderate eosinophilic cytoplasm ○ Center: Cellular nodules of ovoid to round cells with scant cytoplasm • Peripheral, compressed or slit-like to central staghorn vessels frequently seen • Present in histologic continuum with another related tumor, myopericytoma ○ Myopericytoma shows distinctive concentric perivascular arrangement of spindle to ovoid cells

Differential Diagnosis • Infantile fibrosarcoma ○ Appearance typically monomorphic rather than biphasic ○ Harbors in most cases ETV6-NTRK3 fusion • Desmoid fibromatosis ○ Long, sweeping fascicles of bland spindle cells ○ Harbors in most cases CTNNB1 mutations (which encode β-catenin) • Fibrous hamartoma of infancy ○ Characteristic triphasic histology with 3 components – Nests of primitive ovoid to spindle cells in myxoid background – Fascicles of bland fibroblastic component – Adipose tissue ○ Harbors recurrent insertion/duplication mutations in EGFR exon 20 • Epstein-Barr virus (EBV)(+) leiomyomatosis ○ Disseminated smooth muscle tumors that are driven by EBV – Positive for SMA, desmin – Positive for in situ hybridization for EBV-encoded RNA (EBER) ○ Associated with immunodeficiency – Subset of cases with germline homozygous loss-offunction mutations in CARMIL2, which encodes capping protein regulator and myosin 1 linker 2

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Arts FA et al: PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis. Hum Mol Genet. 26(10):1801-10, 2017 Hung YP et al: Myopericytomatosis: clinicopathologic analysis of 11 cases with molecular identification of recurrent PDGFRB alterations in myopericytomatosis and myopericytoma. Am J Surg Pathol. 41(8):1034-44, 2017 Schober T et al: A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat Commun. 8:14209, 2017 Arts FA et al: PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene. 35(25):3239-48, 2016 Park JY et al: EGFR exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol. 40(12):1713-8, 2016 Johnston JJ et al: A point mutation in PDGFRB causes autosomal-dominant penttinen syndrome. Am J Hum Genet. 97(3):465-74, 2015 Takenouchi T et al: Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB mutation. J Pediatr. 166(2):483-6, 2015 Cheung YH et al: A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am J Hum Genet. 92(6):996-1000, 2013 Keller A et al: Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 45(9):1077-82, 2013 Martignetti JA et al: Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet. 92(6):1001-7, 2013 Nicolas G et al: Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology. 80(2):181-7, 2013 Oudijk L et al: Solitary, multifocal and generalized myofibromas: clinicopathological and immunohistochemical features of 114 cases. Histopathology. 60(6B):E1-11, 2012 Granter SR et al: Myofibromatosis in adults, glomangiopericytoma, and myopericytoma: a spectrum of tumors showing perivascular myoid differentiation. Am J Surg Pathol. 22(5):513-25, 1998 Knezevich SR et al: A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 18(2):184-7, 1998 Chung EB et al: Infantile myofibromatosis. Cancer. 48(8):1807-18, 1981 Stout AP: Juvenile fibromatoses. Cancer. 7(5):953-78, 1954

Overview of Syndromes: Syndromes

• Most, though not all, PDGFRB mutations discovered in infantile myofibromatosis appear sensitive to tyrosine kinase inhibition by imatinib and its analogs

SELECTED REFERENCES 1. 2.

3.

Dachy G et al: Association of PDGFRB mutations with pediatric myofibroma and myofibromatosis. JAMA Dermatol. ePub, 2019 Hung YP et al: Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics. Histopathology. 73(4):634-44, 2018 Linhares ND et al: "Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis (Linhares et al., 2014)" turns out to be EBV+ leiomyomatosis caused by CARMIL2 mutations. Eur J Med Genet. 61(2):106, 2018

585

Overview of Syndromes: Syndromes

Familial Isolated Hyperparathyroidism

TERMINOLOGY Abbreviations • Familial isolated hyperparathyroidism (FIHP) • Familial isolated primary hyperparathyroidism (FIPHT) • Parathyroid hormone (PTH)

○ Remainder of cases are associated with multiple endocrine neoplasia, types 1, 2, and 4 (MEN1/2/4); hyperparathyroidism-jaw tumor syndrome (HPT-JT); and familial hypocalciuric hypercalcemia

GENETICS Autosomal Dominant

Definitions • FIHP is defined as hereditary primary hyperparathyroidism without association of other diseases or tumors ○ Without characteristic extraparathyroidal feature of more complex hyperparathyroid syndrome • Newest concepts of FIHP focus upon kindreds without mutation of either MEN1, CASR, or CDC73 ○ 17% have germline-activating mutation of gene for GCM2 transcription factor • FIHP is inherited condition characterized by overactivity of parathyroid glands ○ 1 or more overactive parathyroid gland releases excess PTH, which causes hypercalcemia • PTH stimulates removal of calcium from bone and absorption of calcium from diet ○ Production of excess PTH is caused by parathyroid glands • FIHP is mainly due to 4-gland hyperplasia or single-gland adenoma

EPIDEMIOLOGY Age Range • Age at which FIHP is diagnosed varies from childhood to adulthood

Gender • F~M

Incidence • 90% of hyperparathyroidism cases are sporadic • 10% of hyperparathyroidism cases are familial ○ In 1% of FIHP cases, parathyroid is only endocrine organ involved

• GCM2 germline-activating mutations ○ Gene required for parathyroid development and likely protooncogene • Mutations in parafibromin gene CDC73 (also HRPT2) on chromosome 1q25 have been found in small proportion of FIHP cases • FIHP phenotypes have been associated with mutant multiple endocrine neoplasia 1 (MEN1) and calcium sensing receptor (CASR) genotypes • Genomic screen of 7 familial hyperparathyroidism families has identified suggestive 1.7 Mb region on chromosome 2 • For majority of cases of FIHP, genetic cause is unknown

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Presentation • 1st indication of condition is elevated calcium levels identified through routine blood test ○ Even though affected individual may not yet have signs or symptoms of hyperparathyroidism or hypercalcemia • Because production of excess PTH is caused by abnormalities of parathyroid glands, FIHP is considered form of primary hyperparathyroidism • Typically, only 1 of 4 parathyroid glands is affected, but in some people, > 1 gland develops tumor ○ Tumors are usually adenomas ○ Rarely, people with FIHP develop parathyroid carcinoma • In contrast to sporadic primary hyperparathyroidism, FIHP is characterized by earlier onset of disease, higher incidence of multiglandular involvement, and higher recurrence rate

Oxyphil Cell Hyperplasia in FIHP (Left) FIHP is an inherited condition characterized by overactivity of parathyroid glands. This hyperplastic parathyroid shows prominent parathyroid oxyphil cells. Oxyphil cells are not normally present in normal parathyroids in children, but occur with increase in age. (Right) FIHP is characterized by 1 or more overactive parathyroid gland releasing excess parathyroid hormone, which causes hypercalcemia. Parathyroid carcinoma can occur in patients with FIHP. An atypical mitosis ﬈ is identified in this field.

586

Parathyroid Carcinoma in FIHP

Familial Isolated Hyperparathyroidism

Treatment • Parathyroid surgery is treatment of choice, especially when disorder is complicated by symptomatic hypercalcemia, bone loss or fractures, hypercalciuria, and nephrolithiasis • Subtotal parathyroidectomy is recommended for multiglandular involvement

ASSOCIATED CONDITIONS Parathyroid Hyperplasia • 4-gland hyperplasia is often seen in FIHP • Hyperplasia may be either chief cell or oxyphil cell variants

Parathyroid Adenoma • Common occurrence in FIHP

Parathyroid Carcinoma • Rare in patients with FIHP • Patients with CDC73 (also HRPT2) mutation have greater risk of developing carcinoma

CANCER RISK MANAGEMENT Screening and Guidelines • There are no published guidelines on surveillance • Based on phenotype, annual screening with serum calcium, phosphorous, and PTH levels • Every 1-2 years, reassessment of renal status • Annual palpation of thyroid and parathyroid glands is recommended beginning at age 10-12 years ○ Adenomas and carcinomas have been reported in adolescents

DIAGNOSIS Clinical • Familial PHPT occurs in isolated nonsyndromal form, termed FIHP, or as part of syndrome, such as MEN1 or HPTJT syndrome • Clinical picture is of familial primary hyperparathyroidism in absence of sufficient clinical, radiological, or biochemical evidence for diagnoses of ○ MEN1 ○ Multiple endocrine neoplasia type 2A (MEN2A) ○ HPT-JT syndrome – 20% of individuals with HPT-JT syndrome have kidney lesions (most commonly cysts), renal hamartomas, and (more rarely) Wilms tumors ○ Familial benign hypocalciuric hypercalcemia (FBHH) • FIHP is essentially diagnosis of exclusion

Laboratory Tests • Elevated PTH in context of hypercalcemia in patient with no renal disease

Genetic Tests • 4 main genes were identified as being mutated in 5 distinct familial syndromes with primary hyperparathyroidism PHPT (MEN1, RET, CASR, and CDC73) ○ Rarer germline mutations in other genes (CDKN1A, CDKN1B, CDKN2B, CDKN2C, SLC12A1, GNA11) also contribute to familial PHPT ○ Gene specific for FIHP has been identified: GCM2 • GCM2 germline-activating mutations: 6p24.2 ○ Located on human chromosome 6p24.2, encodes 506 aa transcription factor ○ Gene encoding transcription factor required for parathyroid development ○ GCM2 is likely parathyroid protooncogene • CDC73 (also HRPT2) mutations: 1q31.2 ○ Tumor suppressor gene located on chromosome 1q31.2, which encodes 531 amino acid protein parafibromin ○ Almost all mutations in this gene inactivate parafibromin expression or function ○ Relatively high incidence of parathyroid carcinoma is described in patients with CDC73 mutations ○ Studies report CDC73 mutations in 0-5.3% of all cases of FIHP • MEN1 mutations (loss-of-function mutation): 11q13 ○ According to current studies, MEN1 mutations have been reported in up to 17.6% of unrelated FIHP families • CDKN1B mutation (loss-of-function mutation): 12p13.1 • CASR mutations (loss-of-function mutation): 3q13.33 ○ Current studies show up to 11.8% detection rate of CASR mutations in FIHP families ○ Rare pancreatitis, relative hypocalciuria ○ Associated with rare neonatal severe primary hyperparathyroidism

Overview of Syndromes: Syndromes

• Disruption of normal calcium balance resulting from overactive parathyroid glands causes many common signs and symptoms of FIHP ○ Kidney stones, nausea, vomiting, hypertension, fatigue, and osteoporosis

DIFFERENTIAL DIAGNOSIS Sporadic Parathyroid Adenomas • Predisposing factors poorly understood; possible association with prior ionizing radiation • Later onset of disease than FIHP • Lower incidence of multiglandular involvement than FIHP • Lower recurrence rate than FIHP

MEN1/4 • Autosomal dominant familial tumor syndrome in which patients develop tumors of parathyroid glands, enteropancreatic neuroendocrine system, pituitary gland, and skin • Primary hyperparathyroidism, caused by adenoma or hyperplasia, is 1st manifestation of MEN1 in > 90% of patients • Parathyroid adenomas occur in ~ 90% of MEN1 patients ○ Cause hyperparathyroidism and hypercalcemia • Patients with MEN1 inherit mutation in tumor suppressor gene MEN1 on chromosome 11q13

HPT-JT Syndrome • Autosomal dominant disorder characterized by adenomatous or carcinomatous parathyroid tumors, fibroosseous tumors of jaw bones, renal tumors and cysts, and uterine tumors 587

Overview of Syndromes: Syndromes

Familial Isolated Hyperparathyroidism Differential Diagnosis of FIHP Syndrome

Gene

Clinical Characteristics

FIHP

GCM2

Autosomal dominant inheritance; elevated serum calcium, elevated Hyperplasia, adenoma, and or unexpectedly "normal" circulating PTH carcinoma

Sporadic parathyroid adenomas

Pathologic Features

No associated findings; later occurrence, low recurrence rate

Parathyroid adenoma

MEN1

MEN1

Autosomal dominant inheritance; > 95% of patients with MEN1 develop hyperparathyroidism; tumors of parathyroids, pancreatic islets, duodenal endocrine cells, anterior pituitary, smooth muscle, and dermis

3-4 glands with tumors; majority are parathyroid adenoma

MEN4

CDKN1B

Autosomal dominant inheritance; tumors of parathyroids, pancreatic islets, duodenal endocrine cells, foregut carcinoids, anterior pituitary

Hyperplasia or adenoma

MEN2A

RET

Autosomal dominant inheritance; parathyroid tumors may be present in up to 50% of patients with MEN2A; medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenomas

Usually all 4 glands are enlarged; hyperplasia or adenoma

HPT-JT

CDC73

Autosomal dominant inheritance; associated with fibroosseous tumors of jaw and renal and endometrial tumors

Usually caused by single parathyroid adenoma; ~ 15%  have parathyroid carcinoma

FBHH

CASR GNA11 AP2S1

Autosomal dominant inheritance; difficult to distinguish from FIHP; Normal parathyroid size, elevated serum calcium, low urinary calcium excretion, normal or weight, and histology; mildly elevated circulating PTH hyperplasia

NSHPT

CASR

Autosomal recessive inheritance; very high serum calcium and PTH, 4 hyperplastic glands skeletal demineralization (in first 6 months of life)

FIHP = familial isolated hyperparathyroidism; PTH = parathyroid hormone; MEN1/2A/4 = multiple endocrine neoplasia types 1, 2A, and 4; HPT-JT = hyperparathyroidism-jaw tumor syndrome; FBHH = familial benign hypocalciuric hypercalcemia; NSHPT = neonatal severe hyperparathyroidism.

○ Penetrance of each of these phenotypic features is variable • Gene responsible for HPT-JT is tumor suppressor gene CDC73 (formerly HRPT2) located on chromosome 1q25

MEN2A • Rare familial tumor syndrome caused by RET protooncogene • Parathyroid tumors are found in 35-50% of affected family members • Virtually all patients develop medullary thyroid carcinoma • ~ 50% of patients develop pheochromocytomas, which are bilateral in 60-80% of cases

FBHH • Most difficult of familial hyperparathyroidism syndromes to distinguish clinically from FIHP • Usually caused by heterozygous inactivating mutations of CASR on chromosome 3q • Atypical presentations with severe hypercalcemia, hypercalciuria, normocalcemia following parathyroidectomy, and pancreatitis have all been described • General recommendation is that if FBHH is suspected, kindred should be investigated to resolve diagnostic uncertainty

SELECTED REFERENCES 1. 2.

588

Cetani F et al: Whole exome sequencing in familial isolated primary hyperparathyroidism. J Endocrinol Invest. ePub, 2019 Bachmeier C et al: Should all patients with hyperparathyroidism be screened for a CDC73 mutation? Endocrinol Diabetes Metab Case Rep. 2018, 2018

3.

Cristina EV et al: Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-jaw tumour, familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 32(6):861-75, 2018 4. Cardoso L et al: Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. Hum Mutat. 38(12):1621-48, 2017 5. Pardi E et al: Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 12(10):e0186485, 2017 6. Guan B et al: GCM2-activating mutations in familial isolated hyperparathyroidism. Am J Hum Genet. 99(5):1034-44, 2016 7. Kong J et al: Familial isolated primary hyperparathyroidism/hyperparathyroidism-jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese. Clin Endocrinol (Oxf). 81(2):222-30, 2014 8. Pontikides N et al: Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature. J Bone Miner Metab. 32(4):351-66, 2014 9. Pepe J et al: Sporadic and hereditary primary hyperparathyroidism. J Endocrinol Invest. 34(7 Suppl):40-4, 2011 10. Masi G et al: Clinical, genetic, and histopathologic investigation of CDC73related familial hyperparathyroidism. Endocr Relat Cancer. 15(4):1115-26, 2008

Familial Isolated Hyperparathyroidism

Single Adenoma in FIHP (Left) Asymmetric hyperplasia or pseudoadenomatous variant of hyperplasia with marked variation in size of each parathyroid gland can be confused with adenoma. (Right) Graphic shows both an enlarged parathyroid gland ﬇ (due to adenoma) and a normal-sized parathyroid gland ﬊. This helps differentiate this from hyperplasia, which usually shows enlargement of all glands.

Chief Cells Parathyroid Adenoma

Overview of Syndromes: Syndromes

4-Gland Hyperplasia in FIHP

Oxyphil Parathyroid Adenoma (Left) Parathyroid chief cells are the predominant cell type in parathyroid adenoma. Parathyroid cells have small amounts of cytoplasm and small, dense nuclei. (Right) This parathyroid shows prominent oxyphil cells, which are not typically present in the normal parathyroid in children but develop with increasing age. One unusual feature in this adenoma is the presence of enlarged nuclei ﬈.

Clear Cells

Vascular Invasion in Parathyroid Carcinoma (Left) Foci of clear cells are identified in this hyperplastic parathyroid. Note the characteristically well-defined cytoplasmic membranes of parathyroid cells. (Right) Vascular invasion may be present in carcinoma. Capsular invasion of tumor beyond thickened capsule is identified in 60% of carcinoma. Fibrous bands are common (up to 90%) but not specific. However, invasion of vessels is the most specific feature for carcinoma, seen in 15% of cases.

589

Overview of Syndromes: Syndromes

Familial Nonmedullary Thyroid Carcinoma

TERMINOLOGY Familial Follicular Cell-Derived Carcinoma or Familial Nonmedullary Thyroid Carcinoma  • Familial nonmedullary thyroid carcinoma (FNMTC) or familial follicular cell tumors derived from thyroid follicular cells can be subdivided into 2 subgroups • Familial tumor syndromes characterized by predominance of nonthyroidal tumors ○ PTEN-hamartoma tumor syndrome (PHTS) – Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are major entities comprising PHTS ○ Familial adenomatous polyposis (FAP): Characterized by hundreds of adenomatous colonic polyps that develop during early adulthood – Develop diverse tumors ○ Carney complex: Consists of myxomas, spotty pigmentation, and endocrine overactivity ○ Werner syndrome: Rare premature-aging syndrome that begins in 3rd decade

○ DICER1 syndrome: Multinodular goiter (MNG) and carcinoma – Differentiated thyroid cancer [papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma] is variably observed in DICER1 syndrome – It has been associated with both familial MNG and MNG with ovarian Sertoli-Leydig cell tumors, independent of pleuropulmonary blastoma ○ Pendred syndrome: Most common hereditary syndrome associated with bilateral sensorineural deafness – Also called deaf-mutism and goiter • Familial tumor syndromes characterized by predominance of nonmedullary thyroid carcinoma (NMTC) ○ Characterized by 3 or more 1st-degree relatives with follicular-derived NMTC and occurs regardless of presence of another familial syndrome ○ Genetic basis for follicular cell tumors is less well established than that of MTC

Follicular Cell-Derived Thyroid Carcinoma/Nonmedullary Thyroid Carcinoma

Follicular cell-derived thyroid carcinoma or nonmedullary thyroid carcinoma can be sporadic or familial. The most common follicular cellderived carcinoma is papillary thyroid carcinoma, and the familial tumors are divided into 2 main groups according to whether thyroid tumors occur within these syndromes or if the thyroid tumor is the predominant finding. Some syndromes, such as Cowden syndrome and Carney complex, have multiple and different tumors within the thyroid lesions seen in these patients.

590

Familial Nonmedullary Thyroid Carcinoma

EPIDEMIOLOGY Syndromes Characterized by Predominance of Nonthyroidal Tumors and Syndromes With Predominance of NMTC • Criterion of FNMTC families is that ≥ 3 first-degree family members are affected with NMTC • Benign thyroid lesions, such as multinodular hyperplasia (MNG) and follicular thyroid adenoma, are associated with FNMTC ○ Personal or family history of benign thyroid conditions is present in ~ 45% of patients with FNMTC • Age range at which each affected individual is diagnosed is broad; but usually < 35 years • F:M reported ratio varies from 2:1 to 12:1 • Constitutes 3-9% of all thyroid cancers ○ Out of all FNMTC cases, only 5% in syndromic form have well-studied driver germline mutations ○ These associated syndromes include PHTS/CS, FAP, Gardner syndrome, Carney complex type 1,  DICER1 syndrome, and Werner syndrome

GENETICS  Syndromes Characterized by Predominance of Nonthyroidal Tumors • PHTS ○ Caused by germline mutations of PTEN and inherited in autosomal dominant fashion ○ PTEN (phosphatase and tensin homolog deleted on chromosome 10) is tumor suppressor gene located on 10q23.3 – Can be caused by mutation of other genes: SDH genes, PIK3CA, AKT1, KLLN, SEC23B ○ > 90% of PHTS patients manifest phenotype by 20 years of age • FAP

•

•

•

•

○ Inherited autosomal dominant syndrome caused by germline mutations in adenomatous polyposis coli (APC) gene on chromosome 5q21 Carney complex ○ Autosomal dominant condition – Most cases are classified as type 1 and are associated with mutation to protein kinase A regulatory subunit type 1-α (PRKAR1A), probable tumor suppressor gene on chromosome 17q22–24 – Type 2 patients have mutation on chromosome 2p16, which may be regulator of genomic stability Werner syndrome ○ Rare premature-aging syndrome that begins in 3rd decade ○ Autosomal recessive disease caused by mutations in WRN on chromosome 8p11-p12  DICER1 syndrome ○ Autosomal dominant pleiotropic syndrome caused by germline DICER1 mutations ○ Tumors and dysplasias with early onset, as pleuropulmonary blastoma, cystic nephroma, multinodular thyroid hyperplasia, and pituitary blastoma Pendred syndrome ○ Most common hereditary syndrome associated with bilateral sensorineural deafness ○ Autosomal recessive trait, result of mutations in SLC26A4 (PDS), which encodes protein pendrin and is located on chromosome 7q21–34

Overview of Syndromes: Syndromes

○ Pure familial PTC ± oxyphilia: Mapped to chromosomal region 19p13 ○ FNMTC type 1: Mapped to chromosome 2q21 ○ Familial papillary thyroid carcinoma (FPTC) with papillary renal cell carcinoma: Mapped to chromosomal region 1q21 ○ FPTC with MNG: Mapped to chromosomal region 14q ○ Causal genes located at 7 FNMTC-associated chromosomal loci have yet to be identified – TCO (19q13.2) – NMTC1 (2q21) – fPTC/PRN (1q21) – FTEN (8p23.1-p22) – MNG1 (14q32), 6q22, 8q24 ○ To date, 4 susceptibility genes have been identified – FOXE1 (9q22.33) – HABP2 (10q25.3) – SRGAP1 (12q14) – TITF-1/NKX2-1 (14q13) □ Only FOXE1 and HABP2 have been validated by separate study groups ○ Most tumors are PTC and indistinguishable from sporadic

Syndromes With Predominance of NMTC • Although NMTC is mostly sporadic, evidence for familial form, which is not associated with other mendelian cancer syndromes, is well documented • Linkage analyses have mapped 6 different chromosomal regions that may harbor FNMTC susceptibility genes ○ Causal genes located at 7 FNMTC-associated chromosomal loci have yet to be identified – TCO (19q13.2) – NMTC1 (2q21) – FPTC/PRN (1q21) – FTEN (8p23.1-p22) – MNG1 (14q32), 6q22, 8q24 • To date, 4 susceptibility genes have been identified ○ FOXE1 (9q22.33) ○ HABP2 (10q25.3) ○ SRGAP1 (12q14) ○ TITF-1/NKX2-1 (14q13) ○ Only FOXE1 and HABP2 have been validated by separate study groups • Important genes reported to have been excluded are RET, NTRK1, MET, APC, PTEN, and TSHR • Although majority of sporadic PTC, and significant proportion of FTA/FTC, harbors activating mutations in genes from RAS/BRAF pathway, no oncogenic germline mutations have been detected in KRAS, NRAS, HRAS, BRAF, MEK1, and MEK2 in FNMTC cases • Based on current evidence, FNMTC is likely to represent polygenic mode of inheritance • Putative susceptibility genes identified appear to account for only minority of FNMTCs

591

Overview of Syndromes: Syndromes

Familial Nonmedullary Thyroid Carcinoma • Identification of genes for FNMTC could be utilized in screening, management, and surveillance of NMTC ○ This could ultimately improve outcomes in FNMTC, which is considered by many to be more aggressive disease

Pure FPTC ± Oxyphilia • Mapped to chromosomal region 19p13 • Thyroid carcinoma with oxyphilia locus (TCO; MIM 603386) was mapped to chromosome 19p13.2 in French family with unusual form of NMTC with cell oxyphilia • Speculated that TCO locus is associated only with this unique form of FNMTC with cell oxyphilia • There are suggestions that TCO might be tumor suppressor gene • TCO locus may account for FNMTC in minority of cases • Rare type of thyroid cancer with distinct morphology • LOH at TCO site in 70 sporadic oxyphilic thyroid tumors

Other Genes • FOXE1 (9q22.33) • HABP2 (10q25.3) • FTEN: Mapped to chromosome 8p23.1-p22 ○ Linkage to 8q23.1-p22 locus was confirmed in family with 11 cases of benign thyroid disease and 5 cases of carcinoma • SRGAP1 (12q14) • TITF-1/NKX2-1 (14q13) • Telomere-telomerase complex ○ Study of telomere-telomerase complex in series of patients with FNMTC revealed significantly shorter telomere lengths, higher telomerase reverse transcriptase (TERT) gene amplification, and TERT mRNA expression in patients with FPTC when compared with sporadic PTCs – This study did not report any mutations of TERT or telomerase RNA component

FPTC With Papillary Renal Cell Carcinoma • Mapped to chromosomal region 1q21 • Locus predisposing to FNMTC was identified on chromosome 1p13.2-1q22 in USA family with recurrent PTC and papillary renal neoplasia (PRN) (FPTC/PRN or PRN1; MIM 605642) • To date, no further families with PTC and PRN association have been reported • 2 studies that performed linkage analysis on total of 29 FNMTC families (without PRN) did not find association between FNMTC and FPTC/PRN locus ○ These findings suggest that FPTC/PRN locus may harbor susceptibility gene for unique FNMTC phenotype where PTC is associated with PRN

FNMTC Type 1 • Mapped to chromosome 2q21 • Susceptibility locus named nonmedullary thyroid carcinoma 1 was mapped to chromosome 2q21 in large Tasmanian family with high frequency of PTC (NMTC1; MIM 606240) • Extensive genome-wide scan followed by haplotype analysis revealed that majority of subjects with PTC shared common haplotype on chromosome 2q21 • Studies suggested that 2q21 locus, NMTC1 locus, has more significant association with familial PTC follicular variant (FV) than with familial PTC ○ NMTC locus is also associated with some oxyphilic tumors

FPTC With MNG • Mapped to chromosomal region 14q • MNG susceptibility locus (MNG1; MIM 138800) was mapped to chromosome 14q32 in large Canadian family with MNG and low occurrence of NMTC • Additional studies failed to find linkage between MNG1 locus and FNMTC ○ MNG1 locus has shown evidence of linkage only to FNMTC in original Canadian kindred with multiple MNGs ○ Linkage analyses in further 124 families have failed to confirm association between MNG1 and FNMTC • Therefore, this locus may not be involved in FNMTC, or it may account for only minority of FNMTC cases with MNG

592

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Syndromes Characterized by Predominance of Nonthyroidal Tumors • Diagnosis of thyroid cancer is usually in younger patients than their sporadic counterpart • Multifocal and bilateral PTC • Thyroid has distinct pathological findings • FNMTC is 1 component of defined cancer susceptibility syndrome with preponderance of nonthyroidal tumors

Syndromes With Predominance of NMTC • FNMTC is clinical entity characterized by earlier age of onset, more frequent multifocal and bilateral disease, and recurrence compared with its sporadic NMTC • Familial cases of PTC are reportedly more aggressive than their sporadic counterparts • 10x increase in risk of thyroid cancer in relatives of patients with thyroid cancer

ASSOCIATED NEOPLASMS Syndromes Characterized by Predominance of Nonthyroidal Tumors • Thyroid carcinoma is usually bilateral and multifocal • FAP ○ FAP, GI manifestations: Colonic polyps, colonic adenocarcinoma, duodenal/ampullary adenomas, fundic gland polyps, liver lesions ○ FAP, extraintestinal manifestations: Desmoid tumors, osteomas, congenital hypertrophy of retinal pigmented epithelium, brain tumors, and PTC cribriform morular variant ○ PTC occurs with frequency of ~ 10x expected for sporadic PTC – Characteristic thyroid tumor: Cribriform morular variant of PTC • PHTS/CS: Breast carcinoma, endometrial carcinoma, renal carcinoma, and multiple other tumors including papillary and follicular thyroid carcinoma

Familial Nonmedullary Thyroid Carcinoma

•

•

•

Syndromes With Predominance of NMTC • Thyroid carcinoma usually bilateral and multifocal • Papillary renal cell carcinoma in association with familial PTC/PRN

SELECTED REFERENCES 1.

2.

3.

4. 5. 6. 7. 8. 9.

10. 11. 12.

13. 14. 15.

16. 17.

18.

CANCER RISK MANAGEMENT Screening • Family history of individuals with FNMTC should be reviewed carefully to rule out syndromes characterized by predominance of nonthyroidal tumors and risk of renal cancer • If familial predisposition exists, annual screening of thyroid by US and physical examination ○ Screening should start no later than age 10 years younger than that of youngest relative diagnosed with either benign or malignant thyroid tumors • Renal imaging is recommended for individuals from families with history of renal cell carcinoma • Surveillance for other cancers according to their syndromes ○ Screening for other tumors is advised by the American Cancer Society

19. 20. 21.

22. 23. 24. 25. 26. 27.

Chenbhanich J et al: Prevalence of thyroid diseases in familial adenomatous polyposis: a systematic review and meta-analysis. Fam Cancer. 18(1):53-62, 2019 Chung JH et al: Multifocality in a patient with cribriform-morular variant of papillary thyroid carcinoma is an important clue for the diagnosis of familial adenomatous polyposis. Thyroid. ePub, 2019 El Lakis M et al: Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? implications for initial surgical treatment. Surgery. 165(1):50-7, 2019 Haley M et al: A family with Sertoli-Leydig cell tumour, multinodular goiter, and DICER1 mutation. Curr Oncol. 26(3):183-5, 2019 Hińcza K et al: Current knowledge of germline genetic risk factors for the development of non-medullary thyroid cancer. Genes (Basel). 10(7), 2019 Papathomas TG et al: New and emerging biomarkers in endocrine pathology. Adv Anat Pathol. 26(3):198-209, 2019 Yuan X et al: GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression. Oncogene. 38(7):965-79, 2019 Carney JA et al: The spectrum of thyroid gland pathology in Carney complex: the importance of follicular carcinoma. Am J Surg Pathol. 42(5):587-94, 2018 de Randamie R et al: Frequent and rare HABP2 variants are not associated with increased susceptibility to familial nonmedullary thyroid carcinoma in the Spanish population. Horm Res Paediatr. 89(6):397-407, 2018 Guilmette J et al: Hereditary and familial thyroid tumours. Histopathology. 72(1):70-81, 2018 Zhang YB et al: Familial nonmedullary thyroid carcinoma: a retrospective analysis of 117 families. Chin Med J (Engl). 131(4):395-401, 2018 Khan NE et al: Quantification of thyroid cancer and multinodular goiter risk in the DICER1 syndrome: a family-based cohort study. J Clin Endocrinol Metab. 102(5):1614-22, 2017 Rutter MM et al: DICER1 mutations and differentiated thyroid carcinoma: evidence of a direct association. J Clin Endocrinol Metab. 101(1):1-5, 2016 Stratakis CA: Carney complex: a familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab Disord. 17(3):367-71, 2016 Pereira JS et al: Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC). Endocrine. 49(1):204-14, 2015 Darrat I et al: Novel DICER1 mutation as cause of multinodular goiter in children. Head Neck. 35(12):E369-71, 2013 Mazeh H et al: In patients with thyroid cancer of follicular cell origin, a family history of nonmedullary thyroid cancer in one first-degree relative is associated with more aggressive disease. Thyroid. 22(1):3-8, 2012 Laury AR et al: Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 21(2):135-44, 2011 Nosé V: Familial thyroid cancer: a review. Mod Pathol. 24 Suppl 2:S19-33, 2011 Smith JR et al: Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab. 96(1):34-7, 2011 Hillenbrand A et al: Familial nonmedullary thyroid carcinoma-clinical relevance and prognosis. a European multicenter study. ESES Vienna presentation. Langenbecks Arch Surg. 395(7):851-8, 2010 Khan A et al: Familial nonmedullary thyroid cancer: a review of the genetics. Thyroid. 20(7):795-801, 2010 Nosé V: Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 17(6):428-36, 2010 Richards ML: Familial syndromes associated with thyroid cancer in the era of personalized medicine. Thyroid. 20(7):707-13, 2010 Vriens MR et al: Clinical features and genetic predisposition to hereditary nonmedullary thyroid cancer. Thyroid. 19(12):1343-9, 2009 Dotto J et al: Familial thyroid carcinoma: a diagnostic algorithm. Adv Anat Pathol. 15(6):332-49, 2008 Nosé V: Familial non-medullary thyroid carcinoma: an update. Endocr Pathol. 19(4):226-40, 2008

Overview of Syndromes: Syndromes

•

○ Thyroid pathologic findings in this syndrome typically involves follicular cells with adenomatous nodules, follicular adenoma, follicular carcinoma, nodular hyperplasia Carney complex: Multiple facial lentigines, myxomas, epithelioid blue nevus, neurofibromas, primary pigmented adrenal cortical nodular disease, atrial myxomas ○ Less common: Large-cell calcifying Sertoli cell tumor, psammomatous melanotic schwannoma, and multiple thyroid nodules and follicular adenoma DICER1: Tumors and dysplasias with early onset ○ Pleuropulmonary blastoma ○ Cystic nephroma ○ Ovarian tumors: Sertoli-Leydig cell tumor, juvenile granulosa cell tumor ○ Pituitary blastoma ○ MNG and carcinoma – Has been associated with both familial MNG and MNG with ovarian Sertoli-Leydig cell tumors; thyroid cancer is rare Werner syndrome: Multiple malignancies occurring at younger age such as melanoma, soft tissue sarcoma, osteosarcoma, and thyroid carcinoma ○ ~ 3x ↑ risk for developing follicular carcinoma, 6x ↑ risk for anaplastic thyroid carcinoma, and slight ↑ risk for papillary thyroid carcinoma Pendred syndrome ○ Association of thyroid cancer and Pendred syndrome may be related to untreated congenital hypothyroidism

Treatment • Because FNMT is more aggressive and has higher rates of intrathyroidal spread and recurrence than sporadic tumors, total thyroidectomy and neck dissection is recommended

Prophylactic Surgery • Role of prophylactic surgery in most of these conditions is still undefined

593

Overview of Syndromes: Syndromes

Familial Nonmedullary Thyroid Carcinoma

Numerous Thyroid Nodules

Adenomatous Nodules in Cowden Disease

PTEN Loss

Capsular and Vascular Invasion

Follicular Adenoma in Carney Complex

Follicular Carcinoma in Carney Complex

(Left) Gross serial sections of both thyroid lobes from a very young patient show numerous distinct nodules. Some of the nodules are adenomatous and hyperplastic nodules, and one is follicular carcinoma. Thyroid tumors in a familial setting are usually multiple and bilateral. (Right) H&E from an 18-yearold woman with PHTS shows multiple well-circumscribed, nonencapsulated adenomatous nodules surrounded by a small residual compressed thyroid parenchyma.

(Left) IHC for PTEN in an adenomatous nodule from a patient with PHTS shows loss of staining of the follicular cells and preservation of staining of the endothelial cells ﬊. (Right) This angioinvasive follicular thyroid carcinoma in a patient with PHTS shows numerous areas with vascular invasion. H&E illustrates both capsular ﬊ and vascular invasion ﬇.

(Left) Patients with Carney complex have a variety of thyroid lesions, including follicular adenoma, follicular carcinoma, papillary carcinoma, multinodular hyperplasia, and adenomatous nodules. Similar findings are present in patients with PHTS. (Right) H&E shows a focus of vascular invasion involving an extracapsular vessel ﬊. This 4-cm follicular carcinoma is from a young patient with Carney complex.

594

Familial Nonmedullary Thyroid Carcinoma

Cribriform-Morular Carcinoma in FAP (Left) Cribriform-morular variant of papillary thyroid carcinoma shows the cribriform appearance of these types of tumors. This tumor has areas of both cribriform pattern and solid pattern; however, it has a predominantly cribriform architecture. (Right) β-catenin shows the characteristic cytoplasmic and nuclear staining ﬊ in PTC, CMV and membranous staining in the adjacent compressed follicular cells ﬈.

Molular Component in CMV-PTC

Overview of Syndromes: Syndromes

Cribriform Architecture in FAP-Associated Thyroid Carcinoma

CD5-Positive Morules in CMV-PTC (Left) Solid pattern of PTC, CMV is shown. In the center, there are squamous morules with characteristic peculiar nuclear clearing. (Right) Small morular components ﬊ can be easily identified by CD5. These morules also stain for keratin 5/6. Note that the T lymphocytes ﬈ are also positive for CD5.

Familial PTC and Papillary Renal Cell Carcinoma

PTC With Oxyphilia (Left) The familial PTC associated with renal papillary neoplasia (FPTC/PRN) has been described as a familial association of PTC, thyroid nodules, and PRN. In this syndrome, both tumors of the distinct sites are morphologically similar; however, only thyroid carcinoma is positive for TTF1. (Right) PTC with oxyphilia is usually present in family members with this familial syndrome. This tumor is characterized by large cells with granular cytoplasm with nuclear features of PTC.

595

Overview of Syndromes: Syndromes

Familial Paraganglioma Pheochromocytoma Syndrome • Carney-Stratakis dyad or syndrome: Not distinct entity; encompasses any combination of PGL and GIST

TERMINOLOGY Abbreviations

ETIOLOGY/PATHOGENESIS

• Paraganglioma (PGL) • Pheochromocytoma (PCC)

Genetics

Synonyms • Succinate dehydrogenase (SDH)-associated paraganglioma

Definitions • PCC and PGL: Catecholamine-producing neuroendocrine tumors arising from adrenal and extraadrenal chromaffin tissues • PGL syndromes 1-5 (PGL 1-5): Hereditary tumor syndromes caused by germline mutations of genes encoding subunits of SDH (SDHA, SDHB, SDHC, SDHD) or SDHAF2, collectively succinate dehydrogenase subunits (SDHx) genes • Carney triad: Nonhereditary combination of PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma

• At least 20 additional susceptibility genes for PCC have been reported • PGL 1-5: Autosomal dominant loss-of-function germline mutation followed by somatic 2nd hit, often large deletion that may involve tumor suppressor genes in addition to specific SDHx allele ○ PGL 1 and PGL 2 show parent of origin effect: Germline mutation transmissible by either parent, disease usually occurs only with paternal transmission – Resultant skipping of generations can obscure family histories ○ SDHD and SDHAF2 are maternally imprinted – Inherited mutation from mother rarely results in tumor development, which explains why one or more generations are skipped

Relationship Between SDH Subunits

SDHB Loss in Paraganglioma

Metastatic SDHB-Mutated PGL

SDH-Deficient Renal Cell Carcinoma

(Left) Graphic of part of the mitochondrial respiratory chain complex II shows the relationship between the succinate ubiquinone oxidoreductase subunits (SDHA → SDHD). Inactivating mutations result in hereditary paraganglioma (PGL). (Right) IHC stain for SDHB in PGL in a patient with SDHB mutation shows absent staining in tumor cells and strong granular staining in endothelial cells ﬉, which are an intrinsic control. A typical nested (zellballen) tumor architecture is also seen.

(Left) Lymph node shows metastatic PGL with SDHB mutation. (Right) SDHBdeficient renal cell carcinoma (RCC) shows typical solid pattern of uniform cuboidal cells with indistinct borders, flocculent and vacuolated ﬉ cytoplasm, and tubules or cystic spaces.

596

Familial Paraganglioma Pheochromocytoma Syndrome ○ Potential new modalities target metabolic vulnerabilities caused by loss of SDH

Postulated Mechanisms of Tumorigenesis

Prognosis

• Pseudohypoxic signaling, genomic hypermethylation, reactive oxygen species (ROS) ○ Normal SDH converts succinate to fumarate in Krebs cycle and functions in mitochondrial electron transport chain as complex ll ○ Loss of activity causes succinate buildup, interruption of oxidative phosphorylation, accumulation of ROS – Succinate inhibits α-ketoglutarate-dependent histone/DNA demethylases and prolyl hydroxylases that control levels of hypoxia-inducible transcription factors

• Staging system introduced in 8th edition of AJCC staging manual ○ Size > 5 cm or extraadrenal abdominal location automatically staged as T2 ○ System does not account for SDHB mutation, which is most significant prognostic factor • High risk of metastasis (> 30%) and poor long-term survival with SDHB mutations ○ Risk might reflect large size and extraadrenal locations of SDHB-mutated tumors, both independent predictors of metastasis ○ Metastases may occur years after primary or be present at initial diagnosis

CLINICAL ISSUES Epidemiology • SDHx mutations account for > 80% of familial groupings of PGLs, 15-25% of all patients, almost 30% of pediatric patients, > 40% of tumors that metastasize, and almost 10% of apparently sporadic tumors • SDHB mutations most common (~ 6-8%) • SDHD (~ 5-6%), SDHC (~ 1-2%), SDHA (~ 1%) • SDHAF2 mutations extremely rare

Presentation • Specific mutated gene determines number and distribution of tumors and risk of metastasis • Penetrance very variable, no predetermined patterns of tumor development in individuals or families ○ Syndromically associated tumors [SDH-deficient GIST, renal cell carcinoma (RCC), or pituitary adenoma] can develop in some patients ± PGL – SDH-deficient GIST: Usually in children or young adults □ 5.0-7.5% of all gastric GISTs in adults; overwhelming majority in children □ ~ 30% of all SDH-deficient GISTs occur in patients with SDHA mutations; ~ 50% in patients with Carney triad – SDH-deficient RCC: Age range: 14-76 years; mean: 37 years with slight male predominance (M:F = 1.7:1.0); bilateral in 26% of patients □ Occurs in up to 14% of patients with SDHB and 8% with SDHD mutations – SDH-deficient pituitary adenomas appear very rare but are possibly underdiagnosed

Treatment • Only surgical excision is curative; no highly effective treatments available for metastases ○ Peptide receptor radionuclide therapy (PRRT): Radiolabeled somatostatin analogs show efficacy in small series – Most PGL strongly express somatostatin receptor SSTR2A ○ Some benefit of temozolomide for tumors with hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter and deficient expression of MGMT

Overview of Syndromes: Syndromes

• Carney triad: Epigenetic silencing, predominantly by promoter methylation of SDHC

IMAGING General Features • Somatostatin receptor imaging by PET/CT using recently developed DOTA ○ Conjugated somatostatin analogs most sensitive modality ○ DOTA peptides can be labeled with PET tracer (Ga-68) for diagnosis or with therapeutic b-emitters (Lu-177) or (Y-90) for follow-up PRRT

MICROSCOPIC Histologic Features • SDH-related PC and PGL have no specific features distinguishing them from other hereditary or sporadic counterparts ○ Varied histologic patterns; classic zellballen architecture not always apparent, especially in small metastatic foci ○ Often small, amphophilic to clear cells ○ Sustentacular cells rare in metastases and in some abdominal primaries • Distinctive features exist for syndromically associated tumors ○ SDH-deficient RCC – Typically uniform cuboidal cells with indistinct borders, flocculent and vacuolated cytoplasm, solid pattern surrounding tubules or cystic spaces – Historically misdiagnosed as clear cell or other RCC types ○ SDH-deficient GIST – Gastric location, predominantly epithelioid, often plexiform and multinodular architecture • SDH-deficient GIST or RCC can be poorly differentiated; IHC for SDHB advisable to rule out SDH deficiency for any morphologically or clinically unusual examples of these tumors

ANCILLARY TESTS Immunohistochemistry • IHC for SDHB should be performed in all PCC/PGL and is crucial for different reasons

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Overview of Syndromes: Syndromes

Familial Paraganglioma Pheochromocytoma Syndrome Familial Paraganglioma Syndromes Syndrome

Gene

Chromosome

PC or PGL Distribution

PGL 1

SDHD

11q23.1

H&N (~ 85%), adrenal gland (~ 10-25%), abdomen, thorax ~ 60% multifocal

PGL 2

SDHAF2

11q12.2

H&N (adrenal gland, abdomen, thorax very rare)

PGL 3

SDHC

1q23.3

H&N, thorax (adrenal gland, abdomen very rare) ~ 15-20% multifocal

PGL 4

SDHB

1p36.13

Abdomen (~ 50%), H&N (~ 20-30%), adrenal gland (~ 20-25%), thorax ~ 20-25% multifocal

PGL 5

SDHA

5p15.33

Abdomen, adrenal gland, H&N (thorax very rare)

○ Assess whether any particular tumor is part of syndrome or coincidental in patient with known or suspected SDHx mutation – Any SDHx mutation causes loss of enzyme activity, destabilization of enzyme complex, and loss of SDHB protein ○ Triage for genetic testing or surrogate where testing not available – Validate genetic sequence variants of unknown significance • SDHA staining is preserved except when SDHA is mutated, can serve as adjunct to SDHB stain

9.

10. 11. 12.

13.

14.

DIFFERENTIAL DIAGNOSIS Paraganglioma Metastasis vs. 2nd Primary • Metastases must be to site where normal paraganglionic tissue not present • Very rare primary PGLs occur in lung and near hilum of liver; especially, solitary lesions in these sites must be interpreted with caution • Only sites that unequivocally qualify are bone and histologically confirmed lymph node

Primary or Metastatic Carcinomas, Especially Those With Small Clear Cells • Differential depends on anatomic location; includes squamous cell carcinoma, prostatic adenocarcinoma, RCC ○ PGLs positive for synaptophysin and chromogranin A, usually negative for keratins ○ Tyrosine hydroxylase shows excellent specificity but often negative in head and neck PGLs

SELECTED REFERENCES 1.

2.

3. 4. 5. 6. 7. 8.

598

Bayley JP et al: Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma. J Med Genet. ePub, 2019 Guerrero-Pérez F et al: 3P association (3PAs): Pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations. Eur J Intern Med. ePub, 2019 Neumann HPH et al: Pheochromocytoma and paraganglioma. N Engl J Med. 381(6):552-65, 2019 Jochmanova I et al: Genomic landscape of pheochromocytoma and Pparaganglioma. Trends Cancer. 4(1):6-9, 2018 Kim E et al: Utility of the succinate: Fumarate ratio for assessing SDH dysfunction in different tumor types. Mol Genet Metab Rep. 10:45-9, 2017 Jochmanova I et al: Pheochromocytoma: The first metabolic endocrine cancer. Clin Cancer Res. 22(20):5001-11, 2016 Laukka T et al: Fumarate and succinate regulate expression of hypoxiainducible genes via TET enzymes. J Biol Chem. 291(8):4256-65, 2016 Pinato DJ et al: Peptide receptor radionuclide therapy for metastatic paragangliomas. Med Oncol. 33(5):47, 2016

15.

16.

17. 18.

19. 20. 21.

22. 23.

Benn DE et al: 15 years of Paraganglioma: Clinical manifestations of paraganglioma syndromes types 1-5. Endocr Relat Cancer. 22(4):T91-103, 2015 Her YF et al: Oxygen concentration controls epigenetic effects in models of familial paraganglioma. PLoS One. 10(5):e0127471, 2015 Hoekstra AS et al: Models of parent-of-origin tumorigenesis in hereditary paraganglioma. Semin Cell Dev Biol. 43:117-24, 2015 Janssen I et al: Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma. Clin Cancer Res. 21(17):3888-95, 2015 Kim E et al: Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 22(3):387-97, 2015 Papathomas TG et al: SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 28(6):807-21, 2015 Tischler AS et al: 15 years of Paraganglioma: Pathology of pheochromocytoma and paraganglioma. Endocr Relat Cancer. 22(4):T12333, 2015 Gill AJ et al: Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 38(12):1588-602, 2014 Gill AJ et al: Succinate dehydrogenase deficiency is rare in pituitary adenomas. Am J Surg Pathol. 38(4):560-6, 2014 Hadoux J et al: SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 135(11):2711-20, 2014 Tischler AS et al: The adrenal medulla and extra-adrenal paraganglia: then and now. Endocr Pathol. 25(1):49-58, 2014 Letouzé E et al: SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 23(6):739-52, 2013 Eisenhofer G et al: Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 48(11):1739-49, 2012 Gill AJ: Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology. 44(4):285-92, 2012 Xiao M et al: Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26(12):1326-38, 2012

Familial Paraganglioma Pheochromocytoma Syndrome

Metastatic Paraganglioma (Left) Carotid body PGL in a patient with SDHB mutation shows a focus of metastatic PGL. The differential diagnosis for this focal lymph node metastasis includes squamous cell carcinoma and other tumors with clear cell features. (Right) IHC for synaptophysin distinguishes this metastatic PGL from tumor types that are not neuroendocrine.

S100(+) Sustentacular Cells

Overview of Syndromes: Syndromes

Metastatic Paraganglioma

SDHB(-) Head and Neck PGL (Left) Carotid body PGL in a young patient with SDHB mutation shows scattered S100(+) sustentacular cells. (Right) IHC for SDHB in this SDH-deficient head and neck PGL shows absent staining in tumor cells and strong granular staining in endothelial cells ﬉.

Somatostatin Receptor SSTR2A

SDHB Maintained in Sporadic PGL (Left) SDHB-mutated PGL shows typical strong membrane staining for SSTR2A, consistent with the high sensitivity of somatostatin receptor imaging by PET/CT. (Right) Tumor cells in this sporadic PGL show preserved granular cytoplasmic staining of the same intensity as in endothelial cells ﬉, consistent with intact SDHB. The granular staining reflects mitochondrial localization of SDHB protein.

599

Overview of Syndromes: Syndromes

Familial Testicular Tumor

FAMILIAL TESTICULAR GERM CELL TUMORS Terminology • Abbreviations ○ Testicular germ cell tumor (TGCT) ○ Familial testicular germ cell tumor (FTGCT) ○ Hereditary testicular germ cell tumor (HTGCT) • Definitions ○ FTGCT – Affected males from families with ≥ 2 cases of TGCT ○ HTGCT – FTGCT with consistent passage of susceptibility gene via Mendelian inheritance □ Several suspected genetic loci reported but so far no definitive human susceptibility gene identified – Existence not firmly established; familial risk of TGCT likely due to varying dosages of multiple minor genetic factors

Epidemiology • Incidence ○ In USA, 9,560 cases of testicular cancers estimated in 2019 ○ Incidence increased 3-6% annually since 1970s ○ 95% of testicular tumors are TGCT ○ ~ 2% of patients with TGCT reported positive family history of TGCT • Age range ○ 3 distinct age groups of TGCT – Mostly young adults (postpubertal) between 20 and 35 years [pure and mixed germ cell tumors (GCTs)] – Neonates and infants or prepubertal (mostly pure teratoma and yolk sac tumor) – Older men (spermatocytic tumor) ○ Most reported FTGCT cases in young adults (1st group) ○ Diagnosis of FTGCT is 2-3 years younger than in usual TGCT

Risk Factors for TGCT • Family history, prior TGCT, cryptorchidism, and testicular microlithiasis • Syndromic associations such as Klinefelter syndrome (47 XXY) and XY gonadal genesis

Family History as Risk for TGCT • 4-6x ↑ risk of TGCT in brothers of affected individuals ○ Higher risk among brothers suggests recessive or Xlinked inheritance • 4.7x ↑ risk of TGCT in sons of affected individuals • TGCT in father 2x ↑ risk of TGCT in son • 88% of FTGCT have 2 affected individuals; highest incidence is up to 5 members ○ Indicates very low penetrance for HTGCT • Risk in twins: 37x higher for dizygotic, 76x higher for monozygotic • Also ↑ risk of ovarian GCT in female family members (familial ovarian GCT) ○ TGCT 15x ↑ than ovarian GCT • Risk of TGCT ↑ in families with diagnosis of breast and nervous system cancers, melanoma, or mesothelioma

Genetic Factors • No definite susceptibility gene identified so far ○ Putative gene mapped to Xq27 is postulated to confer ↑ risk of TGCT and cryptorchidism • Majority of FTGCT suggested to be attributable to enrichment of genes (polygenic) that confer susceptibility to sporadic TGCT • Several candidate genes suggested by genome-wide association studies (GWAS) ○ 39 independent genetic loci identified to date that explain 37% of father to son familial risk ○ KITLG, SPRY4, and BAK1 shown by GWAS

Clinical Implications • Bilaterally in FTGCT slightly ↑ at 6.5-9.8% vs. 2.8% in TGCT with negative family history

Mixed Germ Cell Tumor (Left) Mixed germ cell tumor (GCT) shows admixture of embryonal carcinoma ﬈ (with distinctive pleomorphic nuclei), yolk sac tumor ﬉, & teratoma ﬊. Mixed GCTs almost exclusively occur as postpubertal-type GCT arising from germ cell neoplasia in situ & are malignant. (Right) Large-cell calcifying Sertoli cell tumor (LCCSCT) shows characteristic large polygonal cells with abundant eosinophilic ground-glass cytoplasm & ossified calcifications. LCCSCT is associated with Peutz-Jeghers syndrome & Carney complex.

600

Large-Cell Calcifying Sertoli Cell Tumor

Familial Testicular Tumor

Cytoband

Gene Neighborhood

Cytoband

Gene Neighborhood

1q22

SLC25A44 (KIAA0446)

9p24.3

DMRT1 (SNP rs55873183)

1q24.1

UCK2

10q26.13

LHPP

2q14.2

TFCP2L1

11q14.1

GAB2

3p24.3

DAZL

12p13.1

ATF7IP, PLBD1

3q23

TFDP2, DKFZp434G222

12q21.32

KITLG

3q25.31

Unknown

15q21.3

PRTG

3q26.2

GPR160

15q22.31

MAP2K1, TIPIN

4q22.3

SMARCAD1, HPGDS

16p13.13

BCAR4, CATX-11, RSL1D1

4q24

CENPE

16q12.1

HEATR3, AF086132

4q35.2

ZFP42

16q23.1

RFWD3

5p15.33

TERT

16q24.2

ZFPM1

5p15.33

CLPTM1L

17q12

HNF1B

5q31.1

CATSPER3, PITX1, AK026965

17q22

TEX14

5q31.3

SPRY4

19p12

ZNF728

6p21.31

BAK1, AY383626, C6orf227

19p12

ZNF726

7p22.3

MAD1L1

19p12

ZNF257

7q36.3

NCAPG2

19p12

AK125686

8q13.3

PRDM14

21q22.3

MCM3APAS, MCM3AP

9p24.3

DMRT1 (SNP rs7040024)

Xq28

TKTL1

9p24.3

DMRT1 (SNP rs755383)

-

-

Overview of Syndromes: Syndromes

Genetic Loci Implicated in Familial Testicular Germ Cell Tumors by GWAS

GWAS = genome-wide association studies. Adapted from Wang Z et al. Nat Gen; 49 (7): 1141-1147, 2017.

• Clinical behavior of FTGCT likely similar to usual TGCT, which is dependent on stage, specific GCT component, and treatment type

Pathological Findings • Similar to usual TGCT in younger adult patients ○ TGCT in this age group associated with germ cell neoplasia in situ (GCNIS) • Seminoma and nonseminoma diagnosis at 1:1 ratio in FTGCT

FAMILIAL SEX CORD-STROMAL TUMORS Terminology • Abbreviations ○ Sex cord-stromal tumors (SCST) ○ Familial sex cord-stromal tumors (FSCST)

Epidemiology • < 5% of testicular tumors; most SCST are sporadic • FSCST encountered in Peutz-Jeghers syndrome and Carney complex

Syndromic Associations • Large-cell calcifying Sertoli cell tumor (LCCSCT) and Sertoli cell tumor associated with Peutz-Jeghers syndrome and Carney complex; LCCSCT component of Carney complex ○ Carney complex caused by inherited mutation in PRKAR1A

– Autosomal dominant inheritance characterized by cardiac or cutaneous myxomas, lentiginosis, endocrine tumors or overactivity, and schwannoma – 1/3 develop LCCSCT within 1st decade – Clinical testing available for PRKAR1A ○ Peutz-Jeghers syndrome caused by inherited mutation in STK11 (LKB1) – Autosomal dominant inheritance characterized by gastrointestinal polyposis and oral pigmentations • Intratubular large-cell hyalinizing Sertoli cell neoplasia (ILCHSCN) almost exclusively seen in patients with PeutzJeghers syndrome • Juvenile granulosa cell tumor associated with sex chromosomal abnormalities, ambiguous genitalia, and ipsilateral cryptorchidism

Clinical Implications • Most LCCSCT have benign behavior • ILCHSCN is benign • Juvenile granulosa cell tumor mostly have indolent behavior

SELECTED REFERENCES 1. 2.

Loveday C et al: Large-scale analysis demonstrates familial testicular cancer to have polygenic aetiology. Eur Urol. 74(3):248-52, 2018 Wang Z et al: Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor. Nat Genet. 49(7):1141-7, 2017

601

Overview of Syndromes: Syndromes

Familial Uveal Melanoma

TERMINOLOGY Description • Malignant intraocular neoplasm with melanocytic differentiation arising in choroid, ciliary body, or iris

EPIDEMIOLOGY Uveal Melanoma • Most frequent primary intraocular neoplasm in adults • Annual incidence: 5-6 per 1 million in USA ○ Predominantly disease of adults (mean age ~ 60 years) ○ Predilection for white patients, light-colored eyes ○ No sex predilection

Familial Uveal Melanoma • Families with multiple members with uveal melanoma very rare (< 1%) • If cancers other than uveal melanoma are considered, familial predisposition for uveal melanoma is much higher (~ 10%)

GENETICS BAP1-Associated Tumor Predisposition Syndrome • Autosomal dominant syndrome associated with mutations in BRCA1-associated protein 1 (BAP1) located in chromosome region 3p21.1 • Encodes nuclear ubiquitin carboxy-terminal hydroxylase ○ Binds BRCA1 and ASXL1 ○ Plays role in DNA damage response, apoptosis, senescence, chromatin modulation/stem cell biology, and regulation of cell cycle • Inactivating somatic mutations in 1/2 of uveal melanomas, particularly when metastatic • Inactivating somatic mutations in small subset of lung and breast cancers • Monosomy 3 (containing BAP1) strongly associated with metastatic risk in uveal melanoma

Uveal Melanoma (Left) Axial T1WI C+ MR demonstrates a wellcircumscribed intraocular mass centered in the uveal tract ſt. Histologic examination confirmed the diagnosis of melanoma. (Right) Uveal melanomas arise predominantly in the choroid and form well-circumscribed masses. Serous detachment of overlying/adjacent retina is common ﬈.

602

• Germline mutations associated with increased risk in families for uveal melanoma, cutaneous melanoma, malignant mesothelioma, renal cell carcinoma, and other cancers ○ Frequent epithelioid/rhabdoid cytology ○ Germline mutations in ~ 2% of patients with uveal melanoma and 20% of those with familial cases • Protein loss may be identified by immunohistochemistry in tumor tissues

CDKN2A • Encodes tumor suppressors p14ARF and P16 • Best known high-risk melanoma susceptibility gene • Germline mutations strongly associated with cutaneous melanoma, but rare in uveal melanoma (< 1% of patients)

GNAQ and GNA11 • Somatic mutations frequent in uveal melanoma ○ Early genetic events leading to MAPK pathway activation • Germline mutations not feature of familial uveal melanoma

BRAF • Somatic mutations frequent in cutaneous melanoma but very rare in uveal melanoma • Germline mutations associated with cardiofaciocutaneous syndrome but not with melanoma predisposition

TP53 • Germline mutations characterize Li-Fraumeni syndrome • Germline mutations rarely reported in patients with uveal melanoma

DMPK and Myotonic Dystrophy • Rare reports and small series of patients with myotonic dystrophy, DMPK alterations, and uveal melanoma

ASSOCIATED NEOPLASMS Uveal Melanoma • High propensity for metastases (~ 50%), particularly liver • Composed of 3 main cell types in various proportions ○ Spindle A: Narrow nuclei, inconspicuous nucleoli

Uveal Melanoma

Familial Uveal Melanoma

Cutaneous Melanoma and Atypical Melanocytic Lesions • Melanocytic BAP1-mutated atypical intradermal tumors (MBAIT) or nevoid melanoma-like melanocytic proliferations (NEMMP) ○ Terms proposed for subset of tumors with spitzoid features and high prevalence of somatic BRAF p.V600E mutation in patients with germline BAP1 mutations – Terminology not uniformly accepted ○ Combined somatic BAP1 and BRAF mutations also found in subset of atypical Spitz tumors/nevi

SELECTED REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9.

10. 11. 12. 13.

14.

Astrocytoma • Melanoma-astrocytoma predisposition recognized in rare families • Associated with CDKN2A mutations, particularly when exons coding for p14ARF are involved • Astrocytomas pathologically high grade (i.e., glioblastomas)

15. 16.

Repo P et al: Population-based analysis of BAP1 germline variations in patients with uveal melanoma. Hum Mol Genet. 28(14):2415-26, 2019 Shain AH et al: The genetic evolution of metastatic uveal melanoma. Nat Genet. 51(7):1123-30, 2019 Dalvin LA et al: Uveal melanoma associated with myotonic dystrophy: a report of 6 cases. JAMA Ophthalmol. 136(5):543-7, 2018 Grossniklaus, HE et al: Choroidal and Ciliary Body Melanomas. In: Grossniklaus, HE et al: WHO Classification of Tumours of the Eye. 4th ed. Paris: IARC Press, 87, 2018 Hajkova N et al: Germline mutation in the TP53 gene in uveal melanoma. Sci Rep. 8(1):7618, 2018 Betti M et al: CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma. Cancer Lett. 378(2):120-30, 2016 Turunen JA et al: BAP1 germline mutations in Finnish patients with uveal melanoma. Ophthalmology. 123(5):1112-7, 2016 Gupta mP et al: Clinical characteristics of uveal melanoma in patients with germline BAP1 Mutations. JAMA Ophthalmol. 133(8):881-7, 2015 Hawkes JE et al: Lack of GNAQ and GNA11 germ-line mutations in familial melanoma pedigrees with uveal melanoma or blue nevi. Front Oncol. 3:160, 2013 Murali R et al: Tumours associated with BAP1 mutations. Pathology. 45(2):116-26, 2013 Popova T et al: Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 92(6):974-80, 2013 Carbone M et al: BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 10:179, 2012 Njauw CN et al: Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One. 7(4):e35295, 2012 Abdel-Rahman MH et al: Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma. Fam Cancer. 9(3):431-8, 2010 Harbour JW et al: Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 330(6009):1410-3, 2010 Goldstein AM et al: High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 66(20):9818-28, 2006

Overview of Syndromes: Syndromes

○ Spindle B: Oval, plump nuclei with prominent nucleoli ○ Epithelioid: Abundant cytoplasm, prominent nucleoli, associated with poor prognosis • Gene expression profiles ○ Class 1: Low metastatic risk ○ Class 2: High metastatic risk, frequent monosomy 3 • Other prognostic factors ○ Tumor size ○ Extracellular matrix patterns (i.e., vascular mimicry) ○ Mitotic activity ○ Extraocular extension ○ Necrosis ○ Lymphocytic infiltrates

Mesothelioma • Genetic factors important ○ Some patients develop mesothelioma after short exposure to asbestos whereas others do not, even after heavy exposure • Recognized component of BAP1-associated tumor predisposition syndrome • BAP1 mutations also occur in sporadic mesothelioma (up to 60%) ○ More frequent in tumors with epithelioid morphology

Renal Cell Carcinoma • Recognized component of BAP1-associated tumor predisposition syndrome ○ Clear cell histology • Somatic BAP1 mutations in 8-14% of clear cell renal carcinomas

Others • Meningioma, lung adenocarcinoma, neuroendocrine carcinoma, paraganglioma

CANCER RISK MANAGEMENT Uveal Melanoma Families • Members with uveal melanomas and other possibly related cancers (e.g., cutaneous melanomas and mesotheliomas) should be screened for BAP1 mutations • Ophthalmologic and dermatologic exams; avoid environmental insults (e.g., sun exposure) 603

Overview of Syndromes: Syndromes

Familial Wilms Tumor ○ Average age of diagnosis for bilateral tumors: ~ 16 months

TERMINOLOGY Abbreviations

Sex

• Wilms tumor (WT) • Familial Wilms tumor (FWT)

• Males and females equally affected • No sex bias in obligate carrier parents of children with WT

Definitions • WT: Malignant embryonic neoplasm arising from undifferentiated renal mesenchyme that exhibits triphasic histology of blastemal, epithelial, and stromal elements • FWT: Individuals affected by WT with positive family history of WT ○ WT-associated syndromes due to congenital anomalies, genetic syndromes, or WT1 mutation discussed separately

Synonyms • Familial nephroblastoma

EPIDEMIOLOGY Incidence • WT diagnosed in 1 in 10,000 Caucasian children and comprises ~ 85% of childhood renal malignancies ○ 98-99% of WT are sporadic ○ FWT comprises 1-2% of cases – Very rare cases of familial extrarenal WT cases have been reported

Age Range • Sporadic WT ○ Average age of diagnosis for unilateral tumors: 42-47 months ○ Average age of diagnosis for bilateral tumors: 30-33 months ○ ~ 80% of cases diagnosed before 15 years of age • FWT ○ Younger patients than in sporadic WT ○ Average age of diagnosis for unilateral tumors: ~ 35 months

Imaging Findings (Left) Coronal CT in a child with abdominal pain shows a large, heterogeneously enhancing mass replacing most of the left upper quadrant ﬇ and compressing surrounding structures. A portion of residual left renal parenchyma is present ﬈. The patient also developed pulmonary metastases st. (Right) Gross photograph shows a very large tumor replacing the kidney that was eventually resected from a patient after several rounds of chemotherapy were given to shrink the mass.

604

Site • Sporadic WT ○ Bilateral involvement in 5-10% of cases • FWT ○ Higher rate of bilateral involvement: ~ 16% of cases

ETIOLOGY/PATHOGENESIS Genetics • Etiology of WT is heterogeneous and may vary in sporadic, familial, and WT-associated syndrome settings • Sporadic WT ○ WT1 at Chr 11p13 acts as tumor suppressor gene and is inactivated in individuals with constitutional WT – WT1 is member of zinc finger transcription factors and encodes 449-amino acid protein containing 4 zinger motifs and regulatory domain – Most mutations in WT are deletions or truncation mutations • FWT ○ WT1 mutations are rare in FWT – Not predisposing gene in most WT families ○ Genetic basis very poorly understood, but several genes have been implicated in individual families – WT4 (FWT1) – WT2 (FWT2) – CTR9 – BRCA2 – REST – Other genes likely exist ○ Likely due to autosomal dominant allele with incomplete (25-60%) penetrance ○ Other WT genes

Gross Findings

Familial Wilms Tumor

CLINICAL IMPLICATIONS Clinical Risk Factors • Positive family history ○ Majority of affected families have 2-3 members with WT ○ Hallmark of FWT: Affected individuals are either siblings or cousins – Related through unaffected obligate carrier ○ Recognition of FWT is important for screening and surveillance of additional family members

Clinical Presentation • Abdominal mass detected by parents • Presenting symptoms ○ Abdominal pain ○ Gross hematuria ○ Fever ○ Hypertension • FWT rarely presents with features of genetic syndromes associated with WT [e.g., WT, aniridia, genitourinary anomalies, and mental retardation (WAGR); Denys-Drash, Perlman, Beckwith-Wiedemann syndromes, etc.]

Prognosis • Similar for WT in sporadic, familial, and WT-associated syndromes settings • High cure rate for WT; estimated survival of 90% for localized disease and 70% for advanced disease ○ Recognition of familial association allows for screening and surveillance of family for earlier detection and better outcomes

Treatment • Similar therapeutic approach for WT in sporadic, familial, and WT-associated syndromes setting • Children Oncology Group (COG) and National Wilms Tumor Study (NWTS) advocate primary tumor resection and further chemotherapy &/or radiotherapy determined by stage and histology (favorable or unfavorable)

MACROSCOPIC General Features • Majority of WT are unilateral and solitary, but FWT more likely to be bilateral • Tumor macroscopic findings similar for WT in sporadic, familial, and WT-associated syndromes setting ○ Cut surface usually shows homogeneous, pale, gray-tan appearance ○ May vary in consistency depending on proportion of components; firmer and fleshier with predominance of stromal component

○ Triphasic histology consisting of variable admixture of undifferentiated blastemal cells, epithelial cells, and stromal cells ○ Monophasic or biphasic WT may also occur ○ Blastemal cells – Tightly packed small cells with high nuclear:cytoplasmic ratio, overlapping nuclei, even chromatin, and brisk mitotic activity ○ Epithelial cells – From primitive to well-differentiated tubules and glomeruloid bodies resembling those found in normal kidneys ○ Stromal cells – Most are undifferentiated spindle cells, some have myogenic or fibroblastic differentiation – Occasionally contain ganglion cells, neuroglia, bone, cartilage, or adipocytes • Immunohistochemistry ○ Nuclear immunoreactivity for WT1 of blastemal and epithelial cells ○ CK7 positivity in epithelial cells ○ pax-2 often positive ○ Blastemal cells usually negative for pankeratin and vimentin

Overview of Syndromes: Syndromes

– Mutations in TP53 and β-catenin observed in 5% and 15% of WT cases, respectively – Other genes at Chr 16q, Chr 1p, and Chr 7p – Mainly somatic alterations

CANCER RISK MANAGEMENT Screening for Wilms Tumor • Clinical and genetic testing and surveillance for WT recommended for children in families with FWT • Screening for FWT similar with other conditions considered high (> 20%) or moderate (5-20%) risks for WT, such as WAGR, Denys-Drash, Perlman, and Beckwith-Wiedemann syndromes ○ Renal ultrasound every 3 months

SELECTED REFERENCES 1. 2. 3. 4. 5.

6. 7. 8.

Martins AG et al: Identification of a novel CTR9 germline mutation in a family with Wilms tumor. Eur J Med Genet. 61(5):294-9, 2018 Mahamdallie SS et al: Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat Genet. 47(12):1471-4, 2015 Huff V: Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer. 11(2):111-21, 2011 Scott RH et al: Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet. 43(9):705-15, 2006 Reid S et al: Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet. 42(2):147-51, 2005 Ruteshouser EC et al: Familial Wilms tumor. Am J Med Genet C Semin Med Genet. 129C(1):29-34, 2004 Dome JS et al: Recent advances in Wilms tumor genetics. Curr Opin Pediatr. 14(1):5-11, 2002 Breslow NE et al: Familial Wilms' tumor: a descriptive study. Med Pediatr Oncol. 27(5):398-403, 1996

MICROSCOPIC General Features • Tumor histologic findings similar for WT in sporadic, familial, and WT-associated syndromes setting 605

Overview of Syndromes: Syndromes

Fanconi Anemia – Anemia is often macrocytic – Neutropenia can result in severe bacterial and fungal infections – Increased percentage of Hgb F for age ○ Increased risk of hematologic neoplasms and solid tumors (500-700x that of normal individuals)

TERMINOLOGY Abbreviations • Fanconi anemia (FA)

Definition • Described by pediatrician Dr. Guido Fanconi in 1927 • One of several bone marrow failure syndromes and one of several DNA damage repair deficiency syndromes • Rare, inherited genetic condition that may lead to bone marrow failure, leukemia, &/or solid tumors • Clinically and genetically heterogeneous inherited disorder characterized by ○ Autosomal recessive (majority), X-linked recessive (FANCB), and rarely autosomal dominant [RAD51 (FANCR) mutations] patterns of inheritance ○ Congenital abnormalities in ~ 60% of patients, including VACTERL-H features – Low birth weight/short stature – Classic finding of hypoplastic or absent thumbs &/or radii and deeper cleft between first 2 digits – Pigmentation abnormalities (hyperpigmentation, café au lait spots) – Renal malformations (horseshoe, hypoplastic) – Duodenal atresia or other gastrointestinal malformations – Microcephaly &/or microphthalmia – Congenital heart disease – Ear abnormalities/deafness – Hypogonadism – Neurologic abnormalities – Endocrine dysfunction – 25-40% of patients are phenotypically normal ○ Bone marrow failure presenting in 1st decade of life – Bone marrow failure may begin with one cell line, then pancytopenia develops with marrow aplasia (patients present with sequelae such as anemia, bleeding, and easy bruising) – By 5th decade, cumulative incidence of bone marrow failure is 90%

EPIDEMIOLOGY Incidence • Incidence of 1 in 100,000-250,000 births and carrier frequency of ~ 1:156-209 (North America) • Increased incidence of FA in Ashkenazi Jewish population due to specific FANCC mutations (IVS4 + 4A>T) (carrier frequency of 1.1%) • Accounts for ~ 20% of cases of childhood aplastic anemia

Age • 75% diagnosed between 3-14 years of age • 10% diagnosed at age 16 or older

ETIOLOGY/PATHOGENESIS Molecular Pathogenesis • Mutations, mostly bi-allelic in any of (at least) 21 separate genes composing FA pathway (FANCA-FANCU) • Collectively, proteins encoded by these genes serve to sense DNA damage [interstrand crosslinks (ICLs)] and initiate DNA repair • FA pathway proteins fall into 3 separate groups, encoded by following genes ○ FA core complex – FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM – FANCA is most frequently mutated gene in this complex (mutations account for ~ 65% of FA cases) □ Mostly large intragenic deletions, though point mutations, smaller insertions/deletions, and splicing mutations do occur also frequently

Child With Fanconi Anemia (Left) Clinical photo of a hand of a child with Fanconi anemia (FA) shows the dramatic, classic finding of an absent or hypoplastic thumb. (Courtesy C. Clericuzio, MD.) (Right) Bone marrow biopsy from a patient with FA shows marked hypocellularity with trilineage hematopoietic failure. Stromal elements, lymphocytes, and plasma cells remain. (Courtesy D. Czuchlewski, MD.)

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Bone Marrow in Fanconi Anemia

Fanconi Anemia

ANCILLARY TESTS Confirmation of Diagnosis • Cytogenetic testing ○ Diagnostic test: Chromosomal breakage (typically off peripheral blood T lymphocytes) ○ Cannot detect FA carriers with this test • Molecular testing ○ Sequence analysis and targeted mutation analysis – Initial test should consist of single gene sequencing of FANCA, which is most likely to be affected ○ Carrier and prenatal testing can be performed by specific mutation testing if familial mutation is known

Evaluation for Hematologic Malignancy • Bone marrow biopsy: Morphologic evaluation is gold standard for diagnosis of MDS • Cytogenetic analysis: Clonal amplification of chromosome 3q26-q29 often precedes progression to MDS/AML ○ Most common cytogenetic abnormalities in FA patients with AML are gains of 1q, 3q, or 13q, along with loss of 7q

ASSOCIATED NEOPLASMS Hematologic Neoplasms • By age 45, cumulative incidence of hematologic malignancy is 25% (30% for MDS and 10% for AML); median age at diagnosis: 11-14 years • Predominantly myeloid malignancies (600x increased risk of AML; 5,000x increased risk of MDS) ○ In ~ 25% of cases, leukemia (or cancer) diagnosis precedes recognition of underlying FA • Risk of AML in patients with FA reaches plateau between 30-40 years of age

Overview of Syndromes: Syndromes

□ Founder mutations have been described for specific populations, i.e., p.C295T mutation in Spanish Gypsies, who have highest carrier frequency of FA in world (carrier frequency of 1/6470) □ Patients with 2 mutations leading to null alleles have earlier onset of hematologic abnormalities and shorter survival than patients with at least 1 hypomorphic mutation – FANCC mutations account for 10-15% of FA cases □ Less severe hematologic course except for mutations IVS4+4A>T, p.Arg548Ter, and p.Leu554Pro, which have more congenital anomalies and earlier onset of hematologic abnormalities – FANCG mutations account for ~ 10% of FA cases □ More severe cytopenias and higher rates of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) □ c.637-643delTACCGCC mutation is considered founder mutation responsible for > 80% of FA cases in black South African population ○ ID complex – FANCI, FANCD2 ○ Downstream effectors/DNA repair genes – FANCJ, FANCN (a.k.a. BRIP1 and PALB2, respectively) – FANCD1 (a.k.a. BRCA2) • Functional interactions of FA proteins ○ Core complex detects DNA damage and ubiquitinates ID complex proteins ○ ID complex colocalizes at site of DNA damage with FA downstream effectors and other DNA repair proteins, including – RAD51 protein, which binds and promotes accurate DNA repair via homologous recombination – BRCA1 protein, which binds to facilitate repair and mediate cell cycle checkpoint control • Genotype-phenotype correlations ○ Some FANCC mutations predispose to early-onset bone marrow failure ○ Incidence of AML and severe cytopenias is higher in patients with some FANCG and FANCA mutations ○ Patients with biallelic inactivating mutations in FANCD1 (BRCA2) have 97% cumulative incidence of midline brain tumors, Wilms tumor, and AML (or T-ALL) by age 6

Solid Tumors • Squamous cell carcinoma (head, neck, esophagus, anogenital), hepatocellular carcinoma, brain tumors • By 5th decade, 30% cumulative incidence • Median age of 16 years

Breast Cancer Risk • Heterozygous mutations in downstream effectors FANCJ (a.k.a. BRIP1), FANCN (a.k.a. PALB2), FANCD1 (a.k.a. BRCA2) confer breast cancer susceptibility

CANCER RISK MANAGEMENT Patients With FA • Increased surveillance for commonly associated neoplasms • Exposure to radiation or DNA-damaging chemicals should be avoided ○ Special protocols required for patients undergoing stem cell transplantation

SELECTED REFERENCES 1.

Amenábar JM et al: Two enemies, one fight: An update of oral cancer in patients with Fanconi anemia. Cancer. ePub, 2019 2. Che R et al: Multifaceted Fanconi anemia signaling. Trends Genet. 34(3):17183, 2018 3. Nepal M et al: Fanconi anemia signaling and cancer. Trends Cancer. 3(12):840-56, 2017 4. Malric A et al: Fanconi anemia and solid malignancies in childhood: a national retrospective study. Pediatr Blood Cancer. 62(3):463-70, 2015 5. Alter BP et al: VACTERL-H association and Fanconi anemia. Mol Syndromol. 4(1-2):87-93, 2013 6. Knoch J et al: Rare hereditary diseases with defects in DNA-repair. Eur J Dermatol. 22(4):443-55, 2012 7. Seif AE: Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genet. 204(5):227-44, 2011 8. Green AM et al: Fanconi anemia. Hematol Oncol Clin North Am. 23(2):193214, 2009 9. Moldovan GL et al: How the fanconi anemia pathway guards the genome. Annu Rev Genet. 43:223-49, 2009 10. Pinto FO et al: Diagnosis of Fanconi anemia in patients with bone marrow failure. Haematologica. 94(4):487-95, 2009 11. Callén E et al: A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood. 105(5):1946-9, 2005

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Overview of Syndromes: Syndromes

Glucagon Cell Hyperplasia and Neoplasia

TERMINOLOGY

CLINICAL IMPLICATIONS

Abbreviations

Clinical Presentation

• Glucagon cell hyperplasia and neoplasia (GCHN)

• Patients with GCHN present with acute pancreatitis, abdominal pain, obesity, fatigue, diarrhea, and new-onset type 2 diabetes • Serum glucagon is elevated, and some patients have glucagonoma syndrome • Glucagonoma syndrome ○ Clinical symptoms, including necrotizing migratory erythema (NME), diabetes, weight loss, and anemia • Patients with GCGR mutations are slightly younger (mean age: 41.6 years) than those with wild-type GCGR (mean age: 47.3 years) • Imaging reveals single large tumor or multiple small tumors • Inactivating mutations of glucagon receptor gene lead to nonfunctional hyperglucagonemia and are associated with GCHN ○ Homozygous or compound heterozygous GCGR mutations are associated with α-cell hyperplasia, known precursor to pancreatic neuroendocrine tumors

Synonyms • • • •

Glucagon cell adenomatosis (GCA) Glucagonoma syndrome Mahvash disease Mahvash syndrome

Definitions • GCHN: Rare inherited autosomal recessive syndrome due to mutation of GCGR gene that leads to development of islet glucagon cell hyperplasia and glucagon cell microtumors and macrotumors (WHO 2017) ○ Multifocal hyperplastic and neoplastic disease of glucagon cells – Unrelated to multiple endocrine neoplasia type 1 (MEN1) and von-Hippel-Lindau disease (VHL) • These tumors probably develop via hyperplasia-neoplasia sequence ○ As glucagon cells in islets around tumors outnumber insulin cells with increasing islet diameter

MACROSCOPIC General Features

EPIDEMIOLOGY

• Pancreas may be normal or enlarged • Cut surface: Multiple small, yellow-white nodules with nodules up to 8 cm

Incidence • GCHN is extremely rare disease

ETIOLOGY/PATHOGENESIS

MICROSCOPIC General Features

Inherited • Homozygous mutation of glucagon cell receptor (GCGR) ○ Located on chromosome 17q25 ○ Mutations lead to development of glucagon cell hyperplasia and glucagon cell microtumors and macrotumors

• GCHN is characterized by multifocal, exclusively or predominantly glucagon-expressing, micro- as well as macroadenomas arising on background of glucagon cell hyperplasia of islets • Pancreas shows multiple randomly distributed hyperplastic islets and microtumors (with average numbers between 38) • Islets > 500 μm imperceptibly merged with microtumors

Normal Distribution of Alpha Cells (Left) Normal-sized islets are intermixed with hypertrophic islets, microadenomas, and macrotumors. Immunostain for glucagon reveals normal distribution of the glucagonproducing alpha cells. (Right) Glucagon cell hyperplasia and neoplasia (GCHN) is characterized by numerous hyperplastic islets, microtumors ſt, and macrotumors intermixed with normal islets ﬈.

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Glucagon Microadenoma

Glucagon Cell Hyperplasia and Neoplasia

SELECTED REFERENCES 1.

2. 3.

ANCILLARY TESTS Immunohistochemistry

4.

• Pancreatic tumors are positive for glucagon, either exclusively or predominantly • In addition to tumors, differently sized islets with increased glucagon cells and insulin cells decreased • Some tumors may have isolated insulin cells • Microtumors express pancreatic polypeptide (PP) • Micrometastases may express glucagon in addition to single insulin-positive cells • Density of hyperplastic islets and microtumors is higher in patients harboring mutant GCGR gene compared with wildtype cases ○ Patients with wild-type GCGR had no macrotumors • Proliferation rate (Ki-67) of micro- and macrotumors has been reported < 1%

5. 6. 7.

8. 9.

10. 11.

12.

Genetic Testing • GCGR gene germline mutations • ~ 50% of patients with GCHN have GCGR gene germline mutation ○ Homozygous missense mutation in human GCGR is associated with alpha cell hyperplasia and hyperglucagonemia – This mutation lowers receptor's affinity to glucagon and decreases cyclic adenosine monophosphate production with physiological concentrations of glucagon • GCGR alterations suggest that mutations cause loss of receptor function

Microadenomatosis

13. 14.

15.

16. 17.

Guilmette JM et al: Neoplasms of the neuroendocrine pancreas: an update in the classification, definition, and molecular genetic advances. Adv Anat Pathol. 26(1):13-30, 2019 Lam CJ et al: Glucagon receptor antagonist-stimulated α-cell proliferation is severely restricted with advanced age. Diabetes. 68(5):963-74, 2019 Toberer F et al: Glucagonoma-associated necrolytic migratory erythema: the broad spectrum of the clinical and histopathological findings and clues to the diagnosis. Am J Dermatopathol. 41(3):e29-32, 2019 Gild ML et al: Hypercalcemia in glucagon cell hyperplasia and neoplasia (Mahvash syndrome): a new association. J Clin Endocrinol Metab. 103(9):3119-23, 2018 Ring LL et al: Glucagon like peptide-2 and neoplasia; a systematic review. Expert Rev Gastroenterol Hepatol. 12(3):257-64, 2018 Song X et al: Glucagonoma and the glucagonoma syndrome. Oncol Lett. 15(3):2749-55, 2018 Tamura A et al: Glucagonoma with necrolytic migratory erythema: metabolic profile and detection of biallelic inactivation of DAXX gene. J Clin Endocrinol Metab. 103(7):2417-23, 2018 Yu R: Mahvash disease: 10 years after discovery. Pancreas. 47(5):511-5, 2018 Miller HC et al: Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome. World J Gastrointest Surg. 7(4):606, 2015 Sipos B et al: Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. J Clin Endocrinol Metab. 100(5):E783-8, 2015 Kang H et al: [A case of alpha-cell nesidioblastosis and hyperplasia with multiple glucagon-producing endocrine cell tumor of the pancreas.] Korean J Gastroenterol. 63(4):253-7, 2014 Klöppel G et al: Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. Endocr Pathol. 25(2):181-5, 2014 Henopp T et al: Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. J Clin Endocrinol Metab. 94(1):213-7, 2009 Zhou C et al: Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas. 38(8):941-6, 2009 Yu R et al: Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas: review of the literature. Pancreas. 36(4):428-31, 2008 Saenko VF et al: [Hyperplasia of the glucagon-producing cells of the pancreas (the glucagonoma syndrome).] Klin Khir. 60, 1988 Kheir SM et al: Histologic variation in the skin lesions of the glucagonoma syndrome. Am J Surg Pathol. 10(7):445-53, 1986

Overview of Syndromes: Syndromes

• Patients with GCGR mutations exhibit severe proliferative changes of glucagon cells

• Macrotumors are also present, ranging 5-80 mm in diameter, some cystic • Tumor calcifications may be present • Distribution of tumors in pancreas reveals microadenomas and macrotumors present throughout pancreas • Micrometastases (200-400 μm) and isolated tumor cells in peripancreatic lymph nodes have been reported ○ Findings are unrelated to MEN1 and VHL

Glucagon Macroadenoma (Left) GCHN is characterized by numerous hyperplastic islets, microtumors, and macrotumors. (Right) Highpower view of pancreas reveals glucagon-only immunopositivity. Both the microadenomas and macroadenomas in GCHN are almost exclusively composed of cells that are immunopositive for glucagon.

609

Overview of Syndromes: Syndromes

Breast/Ovarian Cancer Syndrome: BRCA1 ○ Other possibilities are under investigation

TERMINOLOGY Synonyms • • • •

EPIDEMIOLOGY

BRCA1 syndrome Breast cancer 1 syndrome Early-onset breast/ovarian cancer syndrome OMIM 113705

INTRODUCTION Hereditary Breast/Ovarian Cancer Syndrome • BRCA1 and BRCA2 were 1st discovered by Dr. Mary-Claire King and colleagues by recognizing that breast cancers arising in young women were more likely to be associated with germline mutation ○ BRCA1 was localized to chromosomal site in 1990 and BRCA2 in 1994 • These genes confer increased risk for breast cancer as well as other cancers for both women and men • Majority of cancers associated with BRCA1 are both tissue and tumor-type specific ○ Breast: Triple-negative carcinoma (TNBC) [defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER2] – BRCA1 cancers are also typically basal-like carcinomas, which are defined by mRNA expression (this group overlaps with TNBC by ~ 80%) ○ Ovary: High-grade serous carcinoma (majority are thought to arise in cells lining fimbriated end of fallopian tube) ○ Both cancers share similarities in gene expression and mutation profiles (e.g., frequent TP53 mutations, MYC amplification and overexpression, RB1 loss) • This very specific increased risk for these 2 types of cancer is not completely understood ○ One proposal is that higher estrogen levels due to diminished BRCA1 protein (which is negative regulator of estrogen) stimulates growth of progenitor cells – ER-negative progenitor cells in breast may have their growth stimulated due to paracrine effects on other ER-positive epithelial cells

Population Incidence • ~ 1 in 300 (~ 0.1-0.3%) ○ BRCA2 mutations found in ~ 0.1-0.7% • Founder mutations are present at increased frequency in ethnic populations ○ Ashkenazi Jewish population – ~ 2.5% or ~ 1 in 40 individuals carries 1 of 3 BRCA1 or BRCA2 germline mutations □ Account for 95% of BRCA1/BRCA2 mutations in this population – Current Human Genome Variation Society (HGVS) guideline designations □ BRCA1: c.68_69delAG (previously referred to as 185delAG or 187delAG) □ BRCA1: c.5266dupC (previously referred to as 5382insC or 5385insC) □ BRCA2: c.5946delT (previously referred to as 6174delT) ○ Additional founder mutations are present in families in Sweden, Hungary, Iceland, Netherlands, Italy, Quebec (French Canadians), and other locations • ~ 90% of families with both hereditary breast and ovarian cancer have BRCA1/BRCA2 mutation

Modifiers of Risk • Parity decreases risk of breast cancer • Low-dose ionizing radiation to chest before age 20 increases risk

Cancer Incidence • Lifetime risk for women varies depending on specific mutation ○ Ranges from 40-90% ○ Small increased risk for males (1-5%), but lower than risk associated with BRCA2 (7%) • For all breast cancers, ~ 2% occur in women with BRCA1 germline mutations

Mammographic Appearance (Left) BRCA1-related invasive carcinomas often present as circumscribed masses that may be mistaken for benign lesions by imaging. Associated calcifications are unusual. Cancers grow rapidly and can present in the interval between screening. (Right) BRCA1-associated cancers are most often high grade and negative for hormone receptors and HER2. The typical pushing borders and a dense lymphocytic infiltrate can mimic metastases to a lymph node both by imaging and histologically.

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Invasive Breast Cancer

Breast/Ovarian Cancer Syndrome: BRCA1

GENETICS BRCA1 Gene • Located on 17q21 • Large 81 kb gene ○ Does not share sequence homology with BRCA2 or other genes • 24 exons with 22 coding exons • Transcript 7,094 base pairs ○ Protein 1,863 amino acids (210 kDa) ○ No sequence homology with other proteins • Autosomal dominant inheritance • > 1,000 different mutations identified ○ Occur along entire sequence ○ Include single nucleotide changes, small insertions or deletions, and large genomic rearrangements ○ Can affect reading frame, splice sites, binding regions, and other areas ○ Inactivating mutations impair conservative DNA repair and genomic stability functions

Protein Function • Classified as tumor suppressor gene ○ 2nd event involving wild-type allele occurs in tumorigenesis • Central role in DNA repair, regulation of cell cycle checkpoints in response to DNA damage, and transcription ○ Additional functions beyond DNA repair may help explain why cancer risk is greater and cancers occur at younger ages, as compared to BRCA2 • Regulation of repair of DNA damage ○ BRCA1 protein is required for repair of DNA doublestranded breaks by homologous recombination – This repair pathway also requires BRCA2, ATM, CHEK2, BARD1, BRIP1, and other proteins ○ Cells that lack BRCA1 protein rely on other less reliable mechanisms for DNA repair – Increases replication errors and genomic instability ○ Chromosomal instability contributes to tumor formation – BRCA1 protein defects are postulated to be initiating oncogenic event • Cell cycle regulation, checkpoint control ○ Accumulating DNA abnormalities increase likelihood of additional mutations in genes essential to cell cycle checkpoint activation • Transcriptional regulation ○ BRCA1 protein is required for transactivation of ER promoter • Also functional in chromatin remodeling and protein ubiquitination

Immunohistochemistry • Antibodies to BRCA1 protein are available ○ Detected as nuclear immunoreactivity • Carcinomas arising in women with BRCA1 germline mutations are positive or negative for protein in approximately equal proportions ○ Sporadic breast cancers can also be positive or negative for BRCA1 protein

○ Therefore, immunohistochemical studies are not helpful to detect possible germline mutations • Absence of BRCA1 protein in hereditary and sporadic breast cancers has been reported to be poor prognostic factor

ASSOCIATED NEOPLASMS Female Breast Cancer • Risk (penetrance) ○ 40-90% of women with germline mutation will develop breast cancer by age 70 – Varies by mutation ○ After diagnosis of 1st cancer, 40% of women develop contralateral cancer within 20 years • Prognosis ○ Some studies have shown lower survival compared to sporadic carcinomas, but this has not been supported by all studies ○ BRCA1-associated TNBC is more likely to undergo pathologic complete response (pCR) to neoadjuvant chemotherapy (~ 46%) compared to TNBC not associated with BRCA1 (~ 27%) – Patients who achieved pCR had improved survival compared to patients who did not • Precursor lesions ○ Definite precursor lesion has not been identified ○ Proposed (but not proven) possible precursors include – Histologically normal cells with uniform p53 expression (analogous to "p53 signature" associated with fallopian tube serous carcinomas) – Histologically normal cells associated with T-cell lymphocytic infiltrate (T-cell lymphocytic lobulitis) – RANK positive cells susceptible to DNA damage – Microglandular adenosis; however, this is more advanced lesion that lacks myoepithelial cells and has infiltrative pattern • Ductal carcinoma in situ (DCIS) ○ BRCA1-associated DCIS is usually negative for ER, PR, and HER2 and has high nuclear grade ○ Cells may fill acini in clinging pattern without distorting lobule, making DCIS difficult to recognize – Dense lymphocytic infiltrate often surrounds involved lobules ○ May be detected as enhancement seen on screening MR for high-risk patients • Invasive carcinoma: Histologic features ○ Invasive carcinomas typically have pushing circumscribed borders – Can mimic benign lesions of breast or lymph nodes on imaging ○ Predominantly high grade and poorly differentiated – High nuclear grade, high proliferation, foci of geographic tumor necrosis, &/or central fibrotic center ○ Lymphocytic infiltrate common – Many BRCA1-associated cancers are associated with dense lymphocytic infiltrate □ Lymphocytes are predominantly T cells □ Lymphocytic infiltrate is associated with better response to neoadjuvant chemotherapy and improved survival

Overview of Syndromes: Syndromes

○ ~ 50% of all cancers related to germline mutation are due to BRCA1 germline mutations

611

Overview of Syndromes: Syndromes

Breast/Ovarian Cancer Syndrome: BRCA1 – Primary carcinoma can be mistaken for lymph node metastasis microscopically when there is dense lymphocytic infiltrate □ Identification of normal breast tissue or DCIS within carcinoma excludes metastasis □ Lymph node metastasis can be determined with confidence when there is definite lymph node capsule – Combination of circumscribed border, syncytial growth pattern (sheets of cells at least 7 cells across: Not true syncytium), and lymphocytic infiltrate is described as having "medullary features" □ 60% of BRCA1-associated cancers have medullary features (13% fulfill prior criteria for medullary carcinoma) □ In one study, 3 of 18 TNBCs with medullary features were found to have BRCA1 mutations, all thought to be germline mutations • Invasive carcinoma: Biologic type ○ ER-negative/HER2-negative TNBC: 70-80% – Majority of these cancers group with basal-like carcinomas by gene expression profiling (mRNA) – ~ 7% (if > 60 years of age) to 30% (if < 30 years of age) of women with TNBC have BRCA1 germline mutations □ ~ 1-17% of women with TNBC have BRCA2 germline mutations □ Somatic BRCA1 mutations are only detected in ~ 1% of TNBCs – TP53 mutations common (> 90%); ~ 55% positive by immunohistochemistry – > 95% poorly differentiated – 50-80% positive for CK5/6, CK14, or EGFR ○ ER-positive/HER2-negative ("luminal"): 20-30% – ~ 85% show loss of wild-type BRCA1 allele □ This finding supports that these cancers are related to germline mutation and are not incidental sporadic cancers – ~ 45% poorly differentiated – < 20% positive for CK5/6, CK14, or EGFR – ~ 50% positive for p53 ○ HER2-positive: < 5%

Male Breast Cancer • 1-5% lifetime risk (compared to 0.1% risk in general population) ○ 7% lifetime risk for males with BRCA2 mutation ○ ~ 1% of male breast cancer cases are associated with BRCA1 and 8-16% of cases with BRCA2 • Majority are invasive carcinomas that are high grade, ER positive, HER2 negative, and stage 3-4

Ovarian, Fallopian Tube, and Peritoneal Carcinoma • 40-50% lifetime risk ○ Lifetime risk associated with BRCA2 is ~ 11-18% • 60-85% involve fimbriated end of fallopian tube • Precursor lesion ○ Serous tubal intraepithelial carcinoma (STIC) is found in ~ 1-2% of prophylactic surgeries – Entire fimbriated end of fallopian tube should be examined microscopically □ Immunohistochemical studies for p53 and MIB-1 (Ki-67) can be helpful to identify early neoplasia 612

– If no invasion is seen, risk of recurrence in peritoneum is 4-5% ○ Prophylactic surgery is recommended by 35-40 years of age – High-grade serous carcinoma is found in 1-17% (average ~ 2-3%) of prophylactic surgeries and is more common in women > 40 years of age • Invasive carcinoma ○ Majority are high-grade serous carcinomas ○ More likely to have solid, pseudoendometrioid, and transitional-like patterns compared to sporadic carcinomas ("SET" pattern) ○ Better prognosis compared to sporadic carcinomas in first 10 years – May be due to greater response to therapy

Other Cancers • Prostate, pancreas: Possibly increased but lower than for BRCA2

SCREENING FOR BRCA1 Population to Be Tested • Recommendations for persons to be tested have broadened due to importance of identifying germline mutations ○ Affected individuals can take steps to reduce risk of subsequent cancers or to detect them at early stage ○ Carcinomas associated with BRCA1 mutations are being treated with specific therapies ○ Family members may also be at risk ○ Affected individuals can choose to not pass mutation to their offspring with assisted reproduction • Criteria have been developed to identify individuals with increased likelihood of germline mutation using following information ○ Personal history of cancer, age at diagnosis, number of cancers, member of group with known increased incidence (e.g., Ashkenazi Jewish ancestry) ○ Family history of cancer, age at diagnosis, number of cancers, identified germline mutations ○ Pathologic features of cancers (type, presence of BRCA1 mutation) • American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and others have issued recommendations for testing

Genetic Testing • Multigene panel testing has become more common than testing for single genes ○ For women meeting NCCN guidelines for testing for BRCA1/BRCA2, ~ 10% will be found to have germline mutation – However, only ~ 1/3 of tested individuals will mutation be in BRCA1/BRCA2; rest have mutations in other genes – In addition, ~ 6% of individuals with BRCA1/BRCA2 germline mutations do not meet criteria for testing – Thus, multigene testing can be helpful to detect major germline mutations conferring increased risk for breast cancer

Breast/Ovarian Cancer Syndrome: BRCA1

Interpretation of Results • Alterations in BRCA1 may be variant with no increased risk, variant that greatly increases risk, or significance may currently be unknown ○ Ideally, testing includes both pre- and posttest genetic counseling to help determine best type of testing and to interpret results • Pathogenic variants (true positive) ○ Some mutations are well documented to increase cancer risk in multiple members in affected families – It is helpful to test multiple members of families with newly detected variant in order to establish linkage • Nonpathogenic variants (true negative) ○ Results show normal sequence or benign polymorphism – These include point mutations that do not alter type of amino acid • Variants of uncertain significance (VUS) (inconclusive result) ○ Some alterations have not yet been linked to individual with breast or ovarian cancer ○ Detected in 7% of individuals tested (> 1,500 identified) ○ More frequent in populations of non-European origin as fewer individuals have been studied ○ VUS is problematic for individuals without personal or family history of cancer because linkage cannot be determined

○ However, for women with BRCA1/BRCA2 mutations undergoing regular screening, 15% of malignancies can be interval cancers (cancers detected as palpable mass between screens) – Compared to screen-detected cancers, interval cancers are larger, present at higher stage, and are more likely to be associated with positive lymph nodes • Mammography and MR may alternate every 6 months in order to reduce length of interval between screening

Prophylactic Surgery • Bilateral mastectomy reduces breast cancer risk by 97% ○ However, not all breast tissue can be removed and achieve acceptable cosmetic results ○ Greatest benefit for patients before diagnosis of cancer ○ Clinically and radiologically occult carcinoma is found in 1-15% of patients – Cancers are most often DCIS or small invasive carcinomas with negative lymph nodes • Bilateral salpingo-oophorectomy reduces breast and ovarian cancer risk ○ Breast cancer risk reduced by 50% – Mechanism not well understood but may be due to decreased estrogen production ○ Ovarian and fallopian tube cancer risk reduced by 5096% – 4-5% risk of papillary serous carcinoma of peritoneum remains

Systemic Therapy • For patients with advanced cancer, presence of BRCA1 germline mutation may alter type of treatment recommended

Childbearing • With assisted reproduction, individuals can choose to not pass mutation on to their children

SELECTED REFERENCES 1.

2.

MEDICAL CARE OF INDIVIDUALS WITH BRCA1 GERMLINE MUTATIONS

3.

Overview • Identification of BRCA1 germline mutation can have important implications for medical care

4.

Chemoprevention

5.

• Oral contraceptives ○ Reduces risk of ovarian cancer by 50% ○ Breast cancer risk may be increased by some types of oral contraceptives (results of studies have not been consistent) • Tamoxifen ○ Reduces risk ○ Protective effect observed in BRCA1 and BRCA2 carriers

Overview of Syndromes: Syndromes

• Comprehensive testing by certified laboratory is necessary to detect all current gene variants known to increase cancer risk ○ Full sequencing is required to detect all mutations ○ Additional testing required to detect deletions and amplifications • Direct to consumer testing ○ Assays for cancer risk marketed directly to individuals are generally not comprehensive ○ Typically only include most common mutations (e.g., 3 BRCA1/BRCA2 mutations common in Ashkenazi Jewish populations) ○ In one study, 40% of results from direct to consumer testing could not be validated by certified laboratory

6.

LaDuca H et al: A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med. ePub, 2019 Pilewskie M et al: Differences between screen-detected and interval breast cancers among BRCA mutation carriers. Breast Cancer Res Treat. 175(1):1418, 2019 Semmler L et al: BRCA1 and breast cancer: a review of the underlying mechanisms resulting in the tissue-specific tumorigenesis in mutation carriers. J Breast Cancer. 22(1):1-14, 2019 Sønderstrup IMH et al: Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer. Acta Oncol. 58(3):363-70, 2019 Engel C et al: Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history. BMC Cancer. 18(1):265, 2018 Tandy-Connor S et al: False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 20(12):1515-21, 2018

Breast Screening • Annual mammograms, MR imaging, and clinical breast examination are recommended 613

Overview of Syndromes: Syndromes

Breast/Ovarian Cancer Syndrome: BRCA1

Linear Clumped Enhancement

Ductal Carcinoma In Situ

T-Cell Lymphocytic Lobulitis

DCIS With Microinvasion

Invasive Carcinoma

Invasive Breast Cancer: High Molecular Weight Keratin

(Left) Screening by MR is an option for young women. MR detects cancers by vascular uptake, which is not affected by dense breast tissue. A common MR finding for ductal carcinoma in situ (DCIS) is linear clumped enhancement ﬇. (Right) DCIS associated with BRCA1 germline mutations can be very subtle. In this case, tumor cells with highly atypical nuclei line acini associated with a dense lymphocytic infiltrate. DCIS is negative for hormone receptors and HER2.

(Left) T-cell-rich infiltrate is sometimes seen surrounding normal-appearing lobules adjacent to invasive carcinomas and occasionally in the breasts of women with BRCA1/BRCA2 germline mutations undergoing prophylactic mastectomies. This may be an early precursor lesion. (Right) DCIS is negative for hormone receptors, and HER2 is the least common type of DCIS. It is rarely seen in isolation. It is possible that this type of DCIS rapidly transitions to invasive carcinoma. In this example, microinvasion ﬈ is present.

(Left) BRCA1-associated invasive carcinomas have defects in DNA repair, resulting in genomic instability. This is reflected in marked nuclear pleomorphism, enlargement, and irregular nuclear contours, as seen here. (Right) BRCA1associated cancers are usually negative for ER, PR, and HER2. Tumor cells often show strong cytoplasmic expression of basal cytokeratin CK5/6 ﬉. This finding makes it more likely that mRNA profiling would identify this carcinoma as basal-like.

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Breast/Ovarian Cancer Syndrome: BRCA1

Invasive Breast Cancer (Left) The majority of BRCA1 cancers are poorly differentiated and do not express hormone receptors or HER2. Pushing borders and a dense lymphocytic infiltrate are typical. Adjacent DCIS may be scant and consists of a clinging pattern of highly atypical cells in lobules. (Right) Typical BRCA1-related carcinoma has a dense, T-cellrich lymphocytic infiltrate. The presence of a dense lymphocytic infiltrate correlates with a good response to neoadjuvant chemotherapy and a relatively improved prognosis.

Invasive Breast Cancer

Overview of Syndromes: Syndromes

Invasive Breast Cancer

Invasive Breast Cancer: Core Needle Biopsy (Left) BRCA1-associated cancers usually have a high mitotic rate ﬇ and can present as palpable masses between scheduled screening breast imaging (interval cancers). (Right) Core needle biopsy from a palpable breast mass in a 34-year-old woman with a positive family history of breast cancer shows a poorly differentiated cancer that is negative for hormone receptors and HER2. Genetic testing is helpful in this case, as she may choose bilateral mastectomies rather than breast conservation if she has a germline mutation.

Fallopian Tube Carcinoma

Fallopian Tube Carcinoma: p53 (Left) The second most common malignancy associated with BRCA1 germline mutations is highgrade serous carcinoma. The majority of these carcinomas are thought to arise from cells lining the fimbriated end of the fallopian tube. (Right) Breast and ovarian carcinomas associated with germline BRCA1 mutations share many similarities, including gene expression patterns and the types of mutations, such as in TP53. In this fallopian tube carcinoma, p53 is expressed at abnormally high levels.

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Overview of Syndromes: Syndromes

Breast/Ovarian Cancer Syndrome: BRCA2 ○ Genome-wide association studies (GWAS) are investigating possible associations

TERMINOLOGY Synonyms • • • •

BRCA2 syndrome Breast cancer 2 syndrome Early-onset breast-ovarian cancer syndrome Online Mendelian Inheritance in Man (OMIM) I 600185

Definitions • Hereditary breast &/or ovarian cancers resulting from inheritance of germline mutation in BRCA2 ○ Deficient DNA repair leads to genomic instability, accumulating mutations, and tumor development ○ Early-onset and multiple primary breast tumors ○ Family history of breast or ovarian cancer

EPIDEMIOLOGY Population Incidence • 0.1-0.7% of individuals ○ Slightly more common than BRCA1 mutations • Specific mutations are found at increased frequency in ethnic populations ○ Ashkenazi Jewish population – ~ 1-3% of individuals – 6174delT – There are also 2 common BRCA1 mutations ○ Icelandic population – 0.6% of individuals – 999del5 detected in 38% of male patients and 10.4% of female patients with breast cancer – BRCA2 mutations found in 90% of families with male and female breast cancer

Modifiers of Risk • Parity may increase risk (whereas it decreases risk for BRCA1 carriers) • Low-dose ionizing radiation to chest before age 20 increases risk • Mutations in other genes ○ None yet well defined

Cancer Incidence • ~ 2% of breast cancers related to BRCA2 germline mutations ○ ~ 50% of all breast cancers related to germline mutation are due to BRCA2 • ~ 7% of ovarian cancers related to BRCA2 germline mutations ○ ~ 27% of ovarian cancers due to germline mutation are related to BRCA2

GENETICS BRCA2 Gene • Located on 13q13.1 • Large 84 kb gene ○ Does not share sequence homology with BRCA1 or other genes • 27 coding exons • Transcript is 10,930 base pairs ○ Protein is 3,418 amino acids (390 kDa) • Autosomal dominant inheritance ○ De novo mutations are rare • > 1,000 different mutations identified ○ Majority are small deletions or insertions – Results in frameshift mutations, nonsense mutations, or splice site alterations – Protein may be truncated or absent – Less common are full-length proteins with missense mutations ○ Inactivating mutations impair conservative DNA repair and genomic stability functions • Central portion of gene designated "ovarian cancer cluster region" ○ Mutations in this region are 2x as likely to be associated with ovarian cancer as are mutations in 5' or 3' region ○ Risk of breast cancer associated with mutation in this region is lower

BRAC2-Associated Breast Carcinoma (Left) Breast cancers associated with BRCA2 are generally moderately to poorly differentiated with a high mitotic rate ſt. Unlike BRCA1-associated cancers, they do not have a characteristic appearance. (Right) BRCA2-associated breast cancers, in contrast to BRCA1 cancers, usually express hormone receptors (as seen here for estrogen receptor). HER2 overexpression is very rare in either type of cancer.

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BRAC2 Breast Carcinoma ER-Positive

Breast/Ovarian Cancer Syndrome: BRCA2

• Central role in DNA repair, transcription, gametogenesis, and centrosome duplication • Regulation of repair of DNA damage ○ Repair of DNA double-stranded breaks through homologous recombination (HR) • Deficient DNA repair in tumor with BRCA1/2 mutations leads to genomic instability and potential sensitivity to DNA-damaging agents ○ Tumor cells with HR-deficiency; highly dependent on DNA repair pathways for single-stranded breaks – This pathway is regulated by enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) – PARP inhibitors have been developed as anticancer therapies and have been tested in clinical trials for BRCA1/2 mutation tumors

Targeting Cancer Cell Vulnerabilities • Cancer cells with BRCA1/2 mutation are deficient in HR DNA repair • PARP is a family of proteins involved in a number of cellular processes, including DNA repair, genomic stability ○ In cells with BRCA1/2 mutation, inhibition of PARP causes cell death due to accumulation of irreparable DNA damage (synthetic lethality) • In clinical trials, PARP inhibitors demonstrate encouraging efficacy in BRCA-mutated advanced breast cancers

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

○ Genetic risk prediction models – Make assumptions about number of genes and allele frequencies – Include information about relationships among individuals in kindred – Accuracy depends on validity of assumptions – Examples include BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) – BRCAPRO available at http://www4.utsouthwestern.edu/breasthealth/cage ne/ – BOADICEA available at https://ccge.medschl.cam.ac.uk/boadicea/boadiceaweb-application

Genetic Testing • Full sequencing required to detect all mutations • Additional testing required to detect large deletions and amplifications ○ 18% of genetic changes are not detected by standard testing • Testing is performed in reference labs such as Myriad Genetics • Targeted mutation analysis may be population or family specific ○ Individuals of some ethnic backgrounds are at higher risk for certain mutations ○ Specific mutation may be sought if there is affected relative with known mutation

Population To Be Tested

Interpretation of Results

• American Society of Clinical Oncology recommends that patients with > 10% mutation risk undergo testing ○ 85% of mutation carriers will be detected using this 10% cutoff • National Institute for Health and Clinical Excellence in United Kingdom recommends testing individuals with > 20% mutation risk • Counseling should occur before testing to ensure patients are aware of implications for themselves and their families

• Mutation associated with breast cancer in other families ○ Patient classified as having BRCA2 syndrome ○ Testing of additional family members should be considered • Mutation linked to relative with breast cancer ○ Testing of additional individuals in family may be helpful to establish definite linkage • Mutation known to be benign or have low clinical significance ○ Mutations that do not change amino acid type ○ Mutations known to occur in individuals without cancer • Variant of uncertain significance (VUS) ○ Not yet linked to individual with breast cancer ○ Detected in 7% of individuals (> 1,500 identified) ○ More frequent in populations of non-European ancestry

Clinical Criteria • Personal history of breast cancer in women < 40 years of age • Breast cancer in 1st-degree relatives (mother, sister, daughter) ○ Risk increased if cancer diagnosed at young age ○ Risk increased if individuals have multiple cancers • Risk increased if male with breast cancer is in family • Risk increased if ovarian cancers are also present in family • Risk increased if relative has known mutation

Calculating Risk • There are multiple models to predict probability of individual carrying germline BRCA1 or BRCA2 mutation ○ Empiric models – Do not make assumptions about genetic risks (e.g., mutation frequency, mode of inheritance, penetrance) – Examples include Penn II model, Myriad II (Frank) model, and National Cancer Institute model

Overview of Syndromes: Syndromes

Protein Function

ASSOCIATED NEOPLASMS Female Breast Cancer • Risk ~ 45% lifetime risk ○ Germline BRCA mutation carriers usually develop cancer at younger age, more aggressive behavior ○ Varies by mutation, may be modified by mutations in additional genes • Histology ○ Moderately to poorly differentiated ○ No specific histologic type – Pushing margins – Lack of tubule formation 617

Overview of Syndromes: Syndromes

Breast/Ovarian Cancer Syndrome: BRCA2 – Some studies have suggested higher incidence of tubulolobular and pleomorphic lobular carcinomas – Other series have not shown significant differences between BRCA2 carcinomas and sporadic carcinomas • Majority are positive for estrogen receptor ○ HER2 overexpression is rare (< 5%), lower than incidence in sporadic breast cancer • TP53 mutations (30-65%) are less common than in BRCA1associated cancers (> 90%) • Majority classified as luminal B by gene expression profiling

Male Breast Cancer • Risk ~ 7% lifetime risk (compared to 0.07% in general population) ○ 8-16% of male breast cancers are in individuals with BRCA2 mutations – 60-75% chance that BRCA2 mutation exists in families with ≥ male with breast cancer – Association with BRCA1 is less common (< 4% of all male breast cancers)

Ovarian, Fallopian Tube, and Peritoneal Carcinoma • ~ 11-18% lifetime risk ○ Risk for ovarian cancer lower than that observed in BRCA1 mutation carriers (40-50% lifetime risk) • Age ○ Average onset is 55-58 years compared to 63 years in general population ○ Young women (< 40) with ovarian/tubal/peritoneal carcinoma unlikely to have BRCA1 or BRCA2 mutation – These women tend to have borderline tumors and cancers of more favorable histologic types • Fallopian tube ○ Serous tubal intraepithelial carcinoma (80%) and endometrioid tubal carcinoma (20%) are found in ~ 5-7% of prophylactic salpingo-oophorectomies – 60-85% involve fimbriated end of fallopian tube – Entire tube should be examined microscopically – Immunohistochemical studies for p53 and MIB-1 (Ki67) can be helpful • Ovary ○ Carcinomas are usually high-grade serous carcinomas – Only ~ 2% of tumors are mucinous or borderline – Endometrioid, clear cell, and papillary carcinomas occur but are rare • Primary peritoneal carcinoma ○ Women have ~ 4% risk after bilateral prophylactic salpingo-oophorectomy

Other Cancers • Prostate: Relative risk is 4.6% ○ 1-2% of cancers diagnosed before age 65 ○ Increased prostate cancer risk is not consistent finding across all studies • Pancreas, gallbladder, and bile duct: Relative risk is 3.5% ○ Presence of pancreatic cancer in breast cancer family may be predictor of BRCA2 mutation • Gastrointestinal ○ Stomach: Relative risk is 2.6% ○ As with BRCA1, initial reports of increased colon cancer risk have generally not been replicated 618

CANCER RISK MANAGEMENT Chemoprevention • Oral contraceptives ○ Reduce risk of ovarian cancer by 50% ○ Breast cancer risk may be increased by some types of oral contraceptives; studies have not been consistent • Tamoxifen ○ Reduces risk – Evidence derives from observed 50% reduction in risk of contralateral cancer among mutation carriers treated with tamoxifen

Screening • Mammography ○ Should begin at 10 years younger than youngest affected family member ○ May have limited sensitivity as young women often have dense breast tissue • Magnetic resonance (MR) imaging ○ MR detects cancers due to blood flow and is more sensitive in detecting cancer in dense breasts ○ Highly sensitive but not very specific; false-positive results are frequent

Prophylactic Surgery • Bilateral mastectomy reduces breast cancer risk by 97% ○ However, not all breast tissue can be removed and achieve acceptable cosmetic results ○ Greatest benefit for patients prior to cancer diagnosis – After cancer has been diagnosed, there may be no benefit if distant metastases are present • Bilateral salpingo-oophorectomy reduces breast and ovarian cancer risk ○ Breast cancer reduced by 50% – Mechanism not well understood but may be due to decreased estrogen production ○ Ovarian and fallopian tube cancer reduced by 70-96% – There remains 4% risk of papillary serous carcinoma of peritoneum

SELECTED REFERENCES 1.

2. 3. 4.

5.

6.

7. 8.

9.

Turner NC et al: A phase II study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO). Clin Cancer Res. 1; 25(9): 2717-24, 2019 Litton JK et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 379(8):753-63, 2018 Nicolas E et al: Targeting BRCA deficiency in breast cancer: what are the clinical evidences and the next perspectives? Cancers (Basel). 10(12), 2018 Cott Chubiz JE et al: Cost-effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers. Cancer. 119(6):1266-76, 2013 Vencken PM et al: The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers: implications for counseling. Cancer. 119(5):955-62, 2013 Ballinger LL: Hereditary gynecologic cancers: risk assessment, counseling, testing and management. Obstet Gynecol Clin North Am. 39(2):165-81, 2012 Crum CP et al: The oviduct and ovarian cancer: causality, clinical implications, and "targeted prevention". Clin Obstet Gynecol. 55(1):24-35, 2012 Fakkert IE et al: Breast cancer incidence after risk-reducing salpingooophorectomy in BRCA1 and BRCA2 mutation carriers. Cancer Prev Res (Phila). 5(11):1291-7, 2012 Iqbal J et al: The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 107(12):2005-9, 2012

Breast/Ovarian Cancer Syndrome: BRCA2

BRAC2 Loss in Carcinoma (Left) A 70-year-old man was discovered to be a carrier of a BRCA2 mutation after 2 of his daughters were diagnosed with ovarian cancer. He subsequently developed an invasive high-grade lobular carcinoma ﬈. (Right) Tumors arising in BRCA2 mutation carriers exhibit allelic loss of the remaining wild-type BRCA2 gene in their cancer and possible loss of BRCA2 expression. The normal ducts show expression of BRCA2 protein by IHC ﬈, whereas the tumor has lost reactivity ﬉.

BRAC2 Fallopian Tube Carcinoma

Overview of Syndromes: Syndromes

BRAC2-Associated Male Breast Carcinoma

BRAC2 Ovarian Carcinoma (Left) Germline BRCA2 mutations increase the risk of fallopian tube cancers. A high incidence of early neoplastic lesions are found at the fimbriated ends of the tubes. (Right) About 7% of ovarian carcinomas are due to BRCA2 mutations. The majority are high-grade serous carcinomas with psammoma body calcifications ſt. Other types such as endometrioid, clear cell, and papillary occur but are unusual. After oophorectomy, ~ 4% of women develop primary peritoneal carcinomas.

Metastatic Ovarian Carcinoma to Breast

BRAC2 Prostate Carcinoma (Left) It may be difficult to distinguish metastases from primary carcinomas in women at high risk for both breast and ovarian cancers. In this core needle biopsy of a breast mass, the papillary architecture and psammoma bodies ſt favor metastatic ovarian serous carcinoma. A metastasis was confirmed by positivity for pax-8 and WT1. (Right) BRCA2 germline mutations also increase the risk of other types of cancers, such as early-onset (before age 55) prostate cancer, as seen here.

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Overview of Syndromes: Syndromes

Hereditary Diffuse Gastric Cancer

TERMINOLOGY Abbreviations • Hereditary diffuse gastric cancer (HDGC)

Definition • HDGC is autosomal dominant syndrome characterized by early-onset diffuse gastric carcinoma and lobular breast carcinoma in women • Mutations of CDH1 encoding E-cadherin are most common germline mutations detected in gastric cancer and underlie HDGC syndrome

EPIDEMIOLOGY Prevalence • Up to 30% of gastric cancers have familial clustering ○ Of these, 1-3% represent truly HDGC ○ Gastric cancer predisposition has been linked to familial cancer syndromes, including – Lynch syndrome

– – – –

Peutz-Jeghers syndrome Li-Fraumeni syndrome Familial adenomatous polyposis syndrome Recently described gastric adenocarcinoma and proximal polyposis syndrome of stomach • 1st described in Maori families from New Zealand, but syndrome is seen in all ethnic groups ○ Asian countries with high incidence of sporadic gastric carcinoma seem to have low incidence of HDGC • Other associated neoplasms ○ Signet ring cell carcinoma of colon ○ Lobular carcinoma of breast – Female kindreds of HDGC family have increased risk of invasive lobular carcinoma with lifetime risk of 50-60% ○ Prostatic adenocarcinoma ○ CDH1 mutations have also been identified in patients with blepharocheilodontic syndrome, congenital development disorder causing dysmorphic features – Which can be accompanied by imperforate anus, hypothyroidism, and neural tube defect

Gross Specimen With Cassette Map in HDGC

Gross photograph of a gastrectomy specimen shows the intensive blocking technique necessary to identify all foci of carcinoma in a hereditary diffuse gastric cancer (HDGC) resection. The red and green foci depict blocks with signet ring cell carcinoma and signet ring cell carcinoma in situ.

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Hereditary Diffuse Gastric Cancer

CDH1 and HDGC Syndrome • Germline CDH1 mutation carriers are at risk for early-onset HDGC ○ Female carriers have additional risk of lobular breast cancer • Reported literature gastric cancer (GC) risk of 70% has led to recommendation for germline mutation carriers to undergo prophylactic total gastrectomy • HDGCs are pure diffuse type by Lauren classification and are associated with dismal prognosis once tumor invades submucosa

GENETICS E-Cadherin/CDH1 • Mutation in CDH1 (located on 16q22.1) that encodes Ecadherin is identified in 30-40% of patients who fit clinical definition of HDGC ○ Autosomal dominant – Cumulative lifetime risk of diffuse gastric cancer is 4067% for men and 63-83% for women – Lifetime risk of lobular breast carcinoma in women is 39-52% – Increased risk of signet ring cell colorectal cancer in both men and women ○ E-cadherin is cell-cell adhesion protein that acts as tumor suppressor gene ○ 2nd hit that inactivates wild-type copy of gene is often due to promoter methylation – May be important mechanism in sporadic diffuse gastric cancer

α-Catenin/CTNNA1 • Mutations in CTNNA1 identified rarely in HDGC families without CDH1 mutation

CLINICAL ISSUES Clinical Criteria • Phenotype is not correlated with location or type of germline CDH1 mutation • Patients who fulfill these clinical criteria should undergo sequencing of CDH1 ○ Some variability among experts regarding these clinical criteria, as some would test single patient < 45 years with diffuse gastric cancer and no family history ○ > 100 mutations have been reported that lead to HDGC, so entire gene must be sequenced ○ ≥ 1 group of physicians recommends waiting until 16 years of age to test children of affected families

Major Criteria • ≥ 2 cases of gastric cancer in 1st- or 2nd-degree relatives with ≥ 1 diffuse gastric cancer in patient < 50 years of age • ≥ 3 cases of gastric cancer in 1st- or 2nd-degree relatives at any age with ≥ 1 documented case of diffuse gastric cancer ○ Only 30-40% of cases that fulfill these 2 major criteria will have CDH1 mutation, suggesting other genes may cause similar syndrome

Minor or Additional Clinical Criteria • Diffuse gastric cancer in patient < 40 years of age without family history • Diffuse gastric cancer and lobular breast cancer in 1 patient, or 1 patient with diffuse gastric cancer and family member with lobular breast cancer or signet ring colon cancer ○ Patients who fulfill these clinical criteria should undergo sequencing of their CDH1

Ancillary Tests • CDH1, coding for E-cadherin, is located on chromosome 16q22.1 and consists of 16 exons ○ > 100 CDH1 pathogenic germline variants have been described in HDGC families ○ Most common mutations are small insertions and deletions (35%) ○ Other mutations include nonsense mutations (16%), splice site mutations (16%), and large exon deletions and missense mutations (28%) • Mutation in CDH1 in 30-40% of patients who fit clinical definition of HDGC • Reduced or absent E-cadherin expression is seen in both in situ and invasive components of HDGC ○ Suggesting that inactivation of E-cadherin is early event • Endoscopic surveillance ○ Early lesions not evident endoscopically ○ Not very effective as number of biopsies needed to ensure adequate sampling too high

Overview of Syndromes: Syndromes

• Cumulative risk of gastric cancer at age 80 years: 67% for men and 83% for women

MICROSCOPIC General Features • Due to lack of gross lesion, histological examination of entire grossly normal gastric mucosa of prophylactic gastrectomy specimen is still standard practice for asymptomatic CDH1 mutation carriers • All reported gastric cancers identified in HDGC families are pure diffuse type

Endoscopic Biopsies • Classic lesion is presence of signet ring cell carcinoma in situ ○ Signet ring cells within basement membrane of glands with pagetoid spread ○ May also see vacuolization of foveolar epithelium called globoid change – Globoid change by itself is not specific for HDGC • Recent histological studies suggest that HDGC progresses through several stages ○ Even when tumor becomes "invasive" in lamina propria, it may stay indolent for period of time ○ 2 morphological populations of signet ring cells are present in intramucosal carcinoma – "Well-differentiated large cells" are signet ring cells with abundant mucin – "Small cells" are signet ring cells with less mucin and have hyperchromatic and atypical nuclei □ Further classified as well differentiated or poorly differentiated • One study has shown that immunohistochemical staining for E-cadherin is negative in 77% of signet ring cell carcinoma foci in HDGC (some foci do stain positively) 621

Overview of Syndromes: Syndromes

Hereditary Diffuse Gastric Cancer • If unsure about pathology, best to have case reviewed by pathologist who has experience with HDGC cases

Resection Specimens • No gross lesion can be detected in early stages of disease • Advanced HDGC demonstrates linitis plastica (entire wall of stomach is infiltrated, creating thickened and rigid stomach) • Multiple foci of signet ring cell carcinoma ○ Some studies suggest most tumors are found at antral transition zone, but this is not reproducible ○ Careful examination can identify signet ring cell carcinoma (mostly multifocal and intramucosal) as well as signet ring carcinoma in situ in > 90% of these specimens ○ Some patients have hundreds of small in situ lesions whereas others have only 1 or 2 – May need to take hundreds of sections to find small in situ lesions – Nearly all gastrectomy specimens will have microscopic foci of cancer, but there are documented cases of patients with CDH1 mutations whose prophylactic gastrectomy specimen did not show any carcinoma despite totally embedding entire stomach ○ PAS staining is superior to H&E staining for screening prophylactic gastrectomy specimens from CDH1 mutation carriers

Prophylactic Total Gastrectomy • Treatment of choice to reduce risk of mortality from gastric cancer ○ Up to 25% of patients who test positive for CDH1 mutation refuse gastrectomy – Offered endoscopy with biopsy every 6 months ○ Procedure has low mortality rate but high morbidity ○ Timing should be individualized but generally recommended between age 20-30 years in known carriers – Others recommend gastrectomy 5 years earlier than earliest known cancer in individual family – Risk of advanced gastric cancer is < 1% at age 20 years, 4% at age 30 years, and 21-46% at age 50 years ○ Multidisciplinary management (gastroenterology, surgery, nutrition, genetics, psychology) is essential preand postoperatively

SELECTED REFERENCES 1. 2.

3.

4.

ASSOCIATED NEOPLASMS Lobular Carcinoma of Breast

5.

• Lifetime risk in women is 39-52% • Heightened surveillance with MR or prophylactic bilateral mastectomy should be offered

6. 7.

Signet Ring Cell Carcinoma of Colon • Affects both sexes • Uncommon tumor that should raise possibility of Lynch syndrome or HDGC

8. 9. 10.

Prostatic Adenocarcinoma • Weak evidence that suggests association with HDGC ○ Likely unrelated given frequency of prostate cancer

CANCER RISK MANAGEMENT Endoscopic Surveillance • Early lesions are not evident endoscopically ○ Not very effective in detecting signet ring cancer cells as number of biopsies needed to ensure adequate sampling is too high – One study found > 1,750 mucosal biopsies would be needed to have 90% chance of finding in situ lesion ○ Up to 25% of patients who test positive for CDH1 mutation refuse gastrectomy ○ Endoscopy with biopsy can be offered every 6-12 months ○ "Cambridge" protocol recommends endoscopic sampling at 30 sites throughout entire stomach – Abnormalities, such as pale areas, nodules, ulcers, umbilicated lesions, should be sampled

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13. 14.

15.

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Kaurah P et al: Hereditary diffuse gastric cancer: cancer risk and the personal cost of preventive surgery. Fam Cancer. 18(4):429-38, 2019 Kumar S et al: The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome. World J Gastroenterol. 25(23):2878-86, 2019 Fewings E et al: Germline pathogenic variants in PALB2 and other cancerpredisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. Lancet Gastroenterol Hepatol. 3(7):489-98, 2018 Luo W et al: CDH1 gene and hereditary diffuse gastric cancer syndrome: molecular and histological alterations and implications for diagnosis and treatment. Front Pharmacol. 9:1421, 2018 Benusiglio PR et al: Cleft lip, cleft palate, hereditary diffuse gastric cancer and germline mutations in CDH1. Int J Cancer. 132(10):2470, 2013 Carneiro F: Hereditary gastric cancer. Pathologe. 33 Suppl 2:231-4, 2012 Fujita H et al: Endoscopic surveillance of patients with hereditary diffuse gastric cancer: biopsy recommendations after topographic distribution of cancer foci in a series of 10 CDH1-mutated gastrectomies. Am J Surg Pathol. 36(11):1709-17, 2012 Mastoraki A et al: Prophylactic total gastrectomy for hereditary diffuse gastric cancer. Review of the literature. Surg Oncol. 20(4):e223-6, 2011 Pandalai PK et al: Prophylactic total gastrectomy for individuals with germline CDH1 mutation. Surgery. 149(3):347-55, 2011 Carneiro F et al: Pathology and genetics of familial gastric cancer. Int J Surg Pathol. 18(3 Suppl):33S-6S, 2010 Guilford P et al: Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice. Gastric Cancer. 13(1):1-10, 2010 Lee AF et al: Periodic acid-schiff is superior to hematoxylin and eosin for screening prophylactic gastrectomies from CDH1 mutation carriers. Am J Surg Pathol. 34(7):1007-13, 2010 Lynch HT et al: Hereditary diffuse gastric cancer: lifesaving total gastrectomy for CDH1 mutation carriers. J Med Genet. 47(7):433-5, 2010 Oliveira C et al: Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterology. 136(7):2137-48, 2009 Rogers WM et al: Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol. 32(6):799-809, 2008 Oliveira C et al: Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat. 19(5):510-7, 2002

Hereditary Diffuse Gastric Cancer Stomach in Hereditary Diffuse Gastric Cancer (Left) Low-power view shows gastric wall in a patient with family history of HDGC with minimal changes at this magnification. Some prophylactic gastrectomy specimens do not show any evidence of tumor. (Right) High-power view shows disorganized gastric surface epithelium with vacuolated cells. This vacuolization is often seen in HDGC and has been called globoid change.

Signet Ring Cell Carcinoma In Situ

Overview of Syndromes: Syndromes

Gastric Wall in Hereditary Diffuse Gastric Cancer

Signet Ring Cells Surrounding Gland (Left) H&E shows signet ring cells ﬈ surrounding a benign gastric gland ﬊. This signet ring cell carcinoma in situ is diagnostic of HDGC. (Courtesy F. Carneiro, MD.) (Right) Highpower view shows signet ring cells ﬈ surrounding a benign gastric gland ﬊. This signet ring cell carcinoma in situ is diagnostic of HDGC. (Courtesy F. Carneiro, MD.)

Small Focus of Signet Ring Cell Carcinoma

Single Signet Ring Cell in Hereditary Diffuse Gastric Cancer (Left) Medium-power view shows a diffusely infiltrating signet ring cell carcinoma ﬊ within the lamina propria in a patient with HDGC. (Right) High-power view shows a single signet ring cell ﬊ in the lamina propria of a gastrectomy specimen from a patient with HDGC.

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Overview of Syndromes: Syndromes

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome ○ FH-mutated RCC represents ~ 4% of previously unclassified RCC

TERMINOLOGY Abbreviations • Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)

Synonyms • Multiple cutaneous and uterine leiomyomatosis syndrome • Reed syndrome

Definitions • Autosomal inherited disorder characterized by development of multiple cutaneous and uterine smooth muscle tumors and RCC linked to fumarate hydratase (FH) mutation

EPIDEMIOLOGY

CLINICAL IMPLICATIONS Clinical Presentation • Most patients initially present with multiple skin lesions due to smooth muscle tumors ○ Usually multiple, involving limbs and trunk ○ Sometimes itchy, painful; can be disfiguring • Gynecologic symptoms at reproductive age due to uterine smooth muscle tumors ○ Metrorrhagia, menorrhagia, pelvic pain, and fertility problems ○ Younger mean age than sporadic leiomyomas

GENETICS

Age Range

FH Mutation

• Smooth muscle tumors and RCC develop at younger age in patients with HLRCC than in those with sporadic onset ○ Males: By age 35, nearly all will have cutaneous leiomyomas ○ Females: By age 45, risk for cutaneous leiomyomas is > 70% – Uterine leiomyomas: Mean age at diagnosis: 30 years (range: 18-53 years), younger than in sporadic leiomyomas • Median age of patients with RCC: 42-44 years ○ Younger than in sporadic RCCs with papillary or tubulopapillary architectures

• FH in chromosome 1q42-1q44 • FH mutation found in 76-100% of families with clinical manifestation of HLRCC • Heterozygous germline mutation ○ Majority are missense (~ 58%); nonsense (~ 11%) or frameshift (~ 18%) mutations ○ Splice site mutations, in-frame deletions or insertions, exon 7 duplications, exon 1 deletions, and whole-gene deletion also reported • Mutations of 2 alleles seen in associated tumors ("2-hit" hypothesis) ○ FH suggested as tumor suppressor gene • > 100 different FH germline mutations have been reported • FH encodes enzyme in Krebs cycle that catalyzes hydration of fumarate to L-malate ○ Mutation causes accumulation of fumarate and subsequent abnormal succination of 2SC ○ Mutation causes aberrant stabilization and overexpression of hypoxia inducible factor 1 (HIF1) transcription factor

Gender • Risk of disease is greater in men vs. women ○ However, number of cutaneous tumors is more numerous in women ○ Renal tumor: M:F = 1.1:1.0

Incidence • Rare; FH mutation predisposing to HLRCC has been described in ~ 180 families worldwide

Skin Smooth Muscle Tumors (Left) Clinical photograph shows a cluster of leiomyomas in the skin. The nodules are reddish-brown, firm to rubbery, and can be painful. Multiple cutaneous leiomyomas, especially in a young to middle-aged patient, are the most prominent feature of HLRCC. (Courtesy C. Ko, MD.) (Right) H&E shows RCC in HLRCC with papillary architecture, eosinophilic cytoplasm, and high-grade nuclei with prominent "CMV inclusion-like" nucleoli ﬉. These nuclear features are more striking than typically seen in type 2 papillary RCC.

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Renal Cell Carcinoma in HLRCC

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Comparative Genomic Hybridization • 27% of HLRCC renal tumors show gains in Chr 2, 7, and 17 and losses in 13q12.3-q21.1, 14, 18, and X ○ Gains in Chr 7 and 17 are common in sporadic papillary RCC

CLINICAL IMPLICATIONS AND ANCILLARY TESTS FH Mutation Testing • Usually by direct sequencing of FH coding region ○ Reveals genetic alterations in ~ 90% of families suspected for HLRCC • If clinically highly suspicious and initial test is negative, additional methods such as multiplex ligation probe amplification (MLPA) are recommended

ASSOCIATED NEOPLASMS Smooth Muscle Tumors • Cutaneous leiomyomas (piloleiomyomas) ○ High penetrance: With age, eventually up to 100% of men and 80% of women will develop them ○ Originate from hair follicle arrector pili muscles ○ Size range: 2 mm to 4 cm ○ Vast majority are benign, with rare reports of leiomyosarcoma ○ Immunohistochemistry: Loss of cytoplasmic FH expression and positive cytoplasmic 2SC expression is sensitive (70%) and specific (97.6%) • Uterine smooth muscle tumors ○ High penetrance: With age, up to 77% of women will develop uterine leiomyomas ○ Usually numerous tumors (up to 50) ○ Size range: Up to 15 cm ○ Grossly shows firm, solid, white-tan, whorled cut surface; similar in appearance to sporadic tumors ○ Mostly benign (leiomyomas) – Fascicles of spindle cells with elongated, blunt-edged nuclei – Can show increased atypia, multinucleation, &/or mitotic activity (up to 6 per HPF) – "FH-d" morphology suggestive of HLRCC: Macronucleoli with halos, eosinophilic cytoplasmic inclusions, staghorn vessels, alveolar edema, cords or chained arrangement of nuclei – Immunohistochemistry: Loss of cytoplasmic FH expression and positive cytoplasmic 2SC staining ○ Uterine leiomyosarcomas have been reported in 6 cases from HLRCC families

RCC • Variable penetrance: Risk of developing RCC is lower and often manifests later than smooth muscle tumors ○ Seen in ~ 20-25% of FH mutation-positive families

• 6.5x greater risk than general population; higher in younger patients ○ Risk is 230x greater in patients 15-29 years old and 45x greater in patients 30-44 years old ○ Youngest patient reported was 11 years old • When symptomatic, patients with renal tumor present with back pain, fatigue, and weight loss; discovery after work-up for suspicion of HLRCC after cutaneous lesion manifestation is not uncommon • Usually involves 1 person in FH mutation-positive family • Macroscopy ○ Tumors are predominantly unilateral and solitary, unlike other RCCs in hereditary setting • Microscopy ○ Most RCCs in HLRCC were previously classified as papillary RCC (PRCC) type 2 and collecting duct carcinoma (CDC) but now officially considered as different subtype of RCC in 2016 WHO "blue book" ○ Variable and often mixed histologic features – Variable architecture often includes tubulopapillary, papillary, tubulocystic, tubular CDC-like), and solid – Intracystic papillary formation common – May exhibit tubulocystic pattern associated with poorly differentiated foci – Papillae are thick with abundant collagen – Cells are large, high grade with abundant eosinophilic cytoplasm – Nuclei pseudostratification is common and may resemble rosettes – Mitoses common (2-6/10 HPF) – May have focal clear cell area – Histologic hallmark is prominent "CMV viral-like" nucleoli with perinuclear clearing, resembling cytomegalovirus cytopathic effect – Nuclear features are typically widespread, detected in most cells, including in foci of clear cells if present ○ Tumor often exhibits infiltrative growth (~ 50%) ○ Mucicarmine stain is negative for mucin, unlike in CDC • Immunohistochemistry ○ Complete or partial loss of cytoplasmic FH expression in most cases – Some RCCs with loss of FH expression do not have FH mutations ○ 2SC expression in nearly all confirmed cases (including subset with retained FH staining) ○ CK7(-), unlike in most PRCC ○ CD10(-), CK20(-), and TFE3(-) ○ HMWK (34bE12)(-), unlike in CDC • Aggressive, most present with higher stage (≥ pT3a) ○ Frequent metastasis to lymph nodes and involvement of adrenal glands ○ Most aggressive RCC among hereditary renal tumors • Rare reports of concurrent clear cell RCC in bilateral cases; unclear if associated or incidental

Overview of Syndromes: Syndromes

– HIF1 regulates transcription of genes important for vascularization, glucose transport, and glycolysis, all of which are important for tumor growth – Somewhat similar mechanism with inactivation of VHL in hereditary clear cell RCC, which causes nondegradation and accumulation of HIF1

Other Tumors • Rarely reported • Adrenal gland adenomas, breast tumor, bladder tumor, brain tumor, lymphoid malignancy, basal cell carcinomas, melanoma, thyroid tumors, ovarian cystadenomas 625

Overview of Syndromes: Syndromes

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Lehtonen Modified Criteria for Diagnosis of HLRCC Major Criterion

Minor Criteria

Presence of multiple cutaneous leiomyomas (histopathologically confirmed) indicates high likelihood of HLRCC

HLRCC can be suspected when individual meets ≥ 2 of following criteria 1) Surgical treatment of severely symptomatic uterine leiomyomas before age 40 2) Type 2 papillary or collecting duct renal cell carcinoma before age 40 3) 1st-degree family member who meets criteria for number 1 or 2 above 4) Occurrence of severely symptomatic uterine leiomyomas before age 40 in 2nd-degree paternal family members may also be relevant

CANCER RISK MANAGEMENT Diagnosis • Proposed practical criteria for diagnosis • If clinical features are suggestive, genetic counseling and molecular testing should be performed for ○ Individual with multiple cutaneous leiomyomas, ≥ 1 histologically confirmed ○ Individual with leiomyoma and family history of HLRCC ○ Uterine leiomyomas with "FH-d" morphology in young patient ○ Individual with ≥ 1 tubulopapillary RCCs showing large inclusion-like nucleolus and perinucleolar clearing • All family members of person with germline FH mutation should be tested

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Surveillance • Currently, no consensus ○ Lifelong clinical surveillance warranted in individuals who are at risk ○ No established standard for age of surveillance for RCC, but ideally should start at earliest age due to aggressive nature – For renal tumors, baseline renal ultrasound and abdominal CT scan with contrast or MR at age 20 years, then annual MR or semiannual ultrasound – For uterine tumors, annual gynecologic ultrasound at age 20 years – Dermatologic examination for lesions suspicious for cutaneous leiomyomas

Treatment • Smooth muscle tumors ○ Surgical excision for solitary skin tumors ○ Myomectomy desired for smaller uterine tumors to retain fertility • RCCs ○ Radical surgery preferred, even if small in size because of its aggressive nature – This approach is in contrast to renal tumors in other hereditary settings that are usually observed until certain size is reached ○ Chemotherapy using inhibitors for HIF1-activated targets is being tried – LDHA inhibition has been shown to cause increased apoptosis in FH-deficient cells in xenograft mouse model, suggesting possible therapeutic strategy

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Chan E et al: Detailed morphologic and immunohistochemical characterization of myomectomy and hysterectomy specimens from women with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). Am J Surg Pathol. 43(9):1170-9, 2019 Gupta S et al: Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol. 91:114-22, 2019 Ohe C et al: Reappraisal of morphologic differences between renal medullary carcinoma, collecting duct carcinoma, and fumarate hydratasedeficient renal cell carcinoma. Am J Surg Pathol. 42(3):279-92, 2018 Carter CS et al: Immunohistochemical characterization of fumarate hydratase (FH) and succinate dehydrogenase (SDH) in cutaneous leiomyomas for detection of familial cancer syndromes. Am J Surg Pathol. 41(6):801-9, 2017 Smith SC et al: Tubulocystic carcinoma of the kidney with poorly differentiated foci: a frequent morphologic pattern of fumarate hydratasedeficient renal cell carcinoma. Am J Surg Pathol. 40(11):1457-72, 2016 Sommer LL et al: Melanoma and basal cell carcinoma in the hereditary leiomyomatosis and renal cell cancer syndrome. An expansion of the oncologic spectrum. J Dermatol Case Rep. 10(3):53-5, 2016 Trpkov K et al: Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol. 40(7):865-75, 2016 Chen YB et al: Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 38(5):627-37, 2014 Sanz-Ortega J et al: Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 37(1):74-80, 2013 Tolvanen J et al: Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod. 27(6):1865-9, 2012 Gardie B et al: Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet. 48(4):226-34, 2011 Lehtonen HJ: Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer. 10(2):397-411, 2011 Smit DL et al: Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 79(1):49-59, 2011 Alrashdi I et al: Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam Cancer. 9(2):23943, 2010 Ashrafian H et al: Expression profiling in progressive stages of fumaratehydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res. 70(22):9153-65, 2010 Koski TA et al: Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer. Genes Chromosomes Cancer. 48(7):544-51, 2009 Xie H et al: LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther. 8(3):62635, 2009 Lehtonen HJ et al: Conventional renal cancer in a patient with fumarate hydratase mutation. Hum Pathol. 38(5):793-6, 2007 Merino MJ et al: The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 31(10):1578-85, 2007

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Renal Cell Carcinoma in HLRCC (Left) Low-power view shows RCC in HLRCC with predominant papillary architecture. These RCCs were previously classified as papillary RCC type 2 (eosinophilic type) or collecting duct carcinoma but are now considered to be distinct. The neoplastic papillae have thick stalks and are lined by stratified, highgrade tumor cells with eosinophilic cytoplasm. (Right) H&E shows RCC in HLRCC exhibiting tubular growth. The cells in the tubules and papillae have similar cytologic features.

Distinctive Nuclei in Renal Cell Carcinoma in HLRCC

Overview of Syndromes: Syndromes

Renal Cell Carcinoma in HLRCC

Tubulocystic Architecture in Renal Cell Carcinoma in HLRCC (Left) The hallmark feature is presence of large nuclei with inclusion-like orangeophilic nucleolus and perinucleolar clearing, resembling cytomegalovirus cytopathic change, seen diffusely in this tumor. Nuclear stratification is common, and nuclei may form pseudorosettes ﬉. (Right) Tubulocystic architecture is commonly seen in FH-deficient RCC. Note high-grade nuclei lining the cystic spaces ﬉. This pattern is typically seen in combination with papillary or tubulopapillary architectures &/or poorly differentiated solid foci.

Cutaneous Leiomyoma

Uterine Leiomyomas (Left) H&E shows cutaneous leiomyoma consisting of fascicles of smooth muscle cells. These lesions are thought to arise from pili erector muscle of the skin. Eventually, up to 100% of men and 80% of women with HLRCC will develop cutaneous leiomyomas. (Courtesy C. Ko, MD.) (Right) Graphic shows uterus in HLRCC with leiomyomas at submucosal, intramural, and subserosal sites. HLRCC patients are at high risk for early-onset, multiple, atypical, &/or cellular leiomyomas.

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Overview of Syndromes: Syndromes

Hereditary Mixed Polyposis Syndrome □ This in turn leads to ectopic crypt formation and neoplasia

TERMINOLOGY Abbreviations

CLINICAL ISSUES

• Hereditary mixed polyposis syndrome (HMPS)

Definitions

Presentation

• Autosomal dominant polyposis syndrome with adenomas, serrated polyps, and "atypical juvenile polyps" that have mixture of serrated epithelium and inflammatory changes

• Age of presentation: ~ 35 years • Gastrointestinal bleeding or abdominal pain • Patients with HMPS have been difficult to identify due to lack of well-established diagnostic criteria

ETIOLOGY/PATHOGENESIS

Natural History

Genetic Alterations • Duplication in 5' regulatory region of GREM1 gene ○ Vast majority (but not all) have been described in Ashkenazi Jews ○ GREM1 expression disrupts bone morphogenetic protein pathway, which is also important in juvenile polyposis – In animal models, excess GREM1 protein suppresses bone morphogenic protein, leading to retained stem cell properties in epithelial cells

• Patients develop variety of colon polyps with early-onset colorectal carcinoma ○ Polyps and cancers develop in 2nd-5th decades of life – Some data suggests rapid progression from adenoma to carcinoma

Treatment • Surveillance colonoscopy ○ Prophylactic colectomy may be considered

Adenoma

Mixed Serrated/Inflammatory/Juvenile Polyp

Mixed Polyp With Dysplasia

Mixed Polyp With Dysplasia

(Left) Typical-appearing tubular adenoma with lowgrade dysplasia ﬊ is shown. While part of mixed polyposis, there is nothing specific about this lesion that distinguishes it from sporadic adenomas. (Right) This unusual polyp has serrated epithelium on the left ﬈ and the disorganized appearance of an inflammatory/juvenile polyp on the right ﬊. Note the increased stroma in the lamina propria ﬉ that raises the question of a juvenile polyp. These unusual mixed polyps are the distinguishing feature of this syndrome.

(Left) This serrated polyp has lamina propria stroma ﬈ much like a juvenile polyp and low-grade dysplasia on the surface ﬊. (Right) High-power view of a mixed polyp shows an abrupt cutoff ﬊ between the dysplastic epithelium on the surface ﬈ and the nondysplastic mucosa below ﬊.

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Hereditary Mixed Polyposis Syndrome

• High risk of colon cancer at young age • Only one report has described extracolonic tumors ○ One patient had hundreds of colonic polyps, duodenal adenomas, and desmoid tumor – Genetic testing was negative for APC mutations

MICROSCOPIC Histologic Features • Adenomas • Hyperplastic polyps • Adenomas and unique polyps composed of mixture of hyperplastic polyp and inflammatory polyp-type changes are most common findings ○ Other polyps, including hyperplastic, mixed inflammatory polyp/adenoma, inflammatory polyp, prolapse-type polyp, and lymphoid aggregates are seen • Mixed hyperplastic/inflammatory polyps that have been described as atypical juvenile polyps ○ Only few studies describe histology of these mixed polyps in any detail – Mixture of serrated epithelium and changes that resemble inflammatory polyp or juvenile polyp □ May have dysplasia/adenomatous foci within them

ANCILLARY TESTS Genetic Testing • Many commercially available germline genetic testing panels include looking for duplications in GREM1

DIFFERENTIAL DIAGNOSIS

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Combination of adenomas, hyperplastic polyps, and mixed polyps in young patient should prompt genetic testing

Pathologic Interpretation Pearls • SCG5-GREM1 duplication-associated polyposis is characterized by few polyps per endoscopy with mixture of phenotypes, most commonly adenoma and nondysplastic mixed hyperplastic/inflammatory polyps • Presence of colorectal polyps with mixture of serrated and inflammatory features should alert pathologist to possibility of HMPS

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Juvenile Polyposis Syndrome • Can be difficult to differentiate without genetic testing as both syndromes can have adenomas/dysplasia ○ Hyperplastic/serrated polyps typically not seen in juvenile polyposis

Serrated Polyposis Syndrome (Giant Hyperplastic Polyposis) • Multiple sessile serrated adenomas should favor serrated polyposis

Overview of Syndromes: Syndromes

Prognosis

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McKenna DB et al: Identification of a novel GREM1 duplication in a patient with multiple colon polyps. Fam Cancer. 18(1):63-6, 2019 Cox DM et al: Hereditary cancer screening: case reports and review of literature on ten Ashkenazi Jewish founder mutations. Mol Genet Genomic Med. 6(6):1236-42, 2018 Lieberman S et al: Features of patients with hereditary mixed polyposis syndrome caused by duplication of GREM1 and implications for screening and surveillance. Gastroenterology. 152(8):1876-80.e1, 2017 Plesec T et al: Clinicopathological features of a kindred with SCG5-GREM1associated hereditary mixed polyposis syndrome. Hum Pathol. 60:75-81, 2017 Ziai J et al: Defining the polyposis/colorectal cancer phenotype associated with the Ashkenazi GREM1 duplication: counselling and management recommendations. Genet Res (Camb). 98:e5, 2016 Davis H et al: Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med. 21(1):62-70, 2015 Laitman Y et al: GREM1 germline mutation screening in Ashkenazi Jewish patients with familial colorectal cancer. Genet Res (Camb). 97:e11, 2015 Clendenning M et al: Germline mutations in the polyposis-associated genes BMPR1A, SMAD4, PTEN, MUTYH and GREM1 are not common in individuals with serrated polyposis syndrome. PLoS One. 8(6):e66705, 2013 Jaeger E et al: Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 44(6):699-703, 2012 Ibirogba SB et al: Clinical and pathological features of hereditary mixed polyposis syndrome: report on a South African family. S Afr J Surg. 46(3):902, 2008 Rozen P et al: A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol. 98(10):2317-20, 2003 Giardiello FM et al: Hereditary mixed polyposis syndrome: a zebra or a horse dressed in pinstripes. Gastroenterology. 112(2):643-5, 1997 Whitelaw SC et al: Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology. 112(2):327-34, 1997

MUTYH-Associated Polyposis • MUTYH-associated polyposis (MAP) is autosomal recessive disorder characterized by various number of colorectal polyps with different histological phenotypes that have tendency to progress to malignancy • Appearance of MAP adenomas resembles attenuated familial adenomatous polyposis (FAP) • Conventional adenomas associated with serrated polyps, hyperplastic polyps, and sessile serrated adenoma/polyps • MAP carcinomas usually located in right colon

Familial Adenomatous Polyposis Syndrome (Attenuated Form) • Number of polyps and age of patients may be similar to HMPS, but only adenomas are seen in FAP

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Overview of Syndromes: Syndromes

Multiple Osteochondromas

TERMINOLOGY Synonyms • Hereditary multiple exostoses (HME) • Multiple hereditary osteochondromatosis (MHO) • Multiple cartilaginous exostoses

Definitions • Characterized by multiple exostoses/osteochondromas • At least 2 osteochondromas of juxtaepiphyseal region of long bones required for diagnosis • Autosomal dominant • Germline mutations in 1 EXT gene • Rarely seen as part of other autosomal dominant syndromes ○ Trichorhinophalangeal syndrome type 2 (Langer-Giedion syndrome) ○ Potocki-Shaffer syndrome

EPIDEMIOLOGY Age Range • Median age at diagnosis is 3 years • Nearly all affected individuals are identified by 2nd decade of life (~ age 12)

Site • Typically arises in appendicular skeleton ○ Distal femur, proximal tibia, proximal humerus • Can involve flat bones, such as ilium and scapula

• EXT1 (8q24.11-q24.13) ○ Accounts for ~ 60% of cases ○ > 80 different mutations in EXT1 • EXT2 (11p11-p12) ○ Accounts for ~ 30% of cases

Molecular Genetics • Germline inactivating alterations in EXT1 and EXT2 involved in HME ○ Most mutations are predicted to result in truncated or nonfunctional protein • Contiguous gene deletion syndromes ○ Deletion of EXT1 and TRPS1: Langer-Giedion syndrome/trichorhinophalangeal syndrome type 2 – Multiple osteochondromas with craniofacial dysmorphism and intellectual disability ○ Deletion of EXT2, ALX4, and PHF21A: Potocki-Shaffer syndrome – Multiple osteochondromas with enlarged parietal foramina, craniofacial dysostosis, and intellectual disability • Function of gene products of EXT1 and EXT2 ○ Proteins exostosin-1 (EXT1) and exostosin-2 (EXT2) are localized to endoplasmic reticulum and encode glycosyltransferases to catalyze heparan sulphate polymerization – Hypothesized to be essential for fibroblast growth factor and Indian hedgehog signaling within normal growth plate

CLINICAL IMPLICATIONS

Sex • Male predominance

Clinical Presentation

Incidence

• Characterized by multiple osteochondromas near diaphyses of extremities, ribs, scapulae that undergo ossification • Can be diagnosed at birth • 60% of patients with positive family history of multiple osteochondromas • Associated with mild short stature

• Prevalence: ~ 1-2 per 100,000 • Sporadic osteochondromas ≥ 6x more common than HME

ETIOLOGY/PATHOGENESIS Histogenesis • Mutations in 1 EXT gene in 70-95% of cases

Multiple Osteochondromas (Left) Radiograph of a patient with multiple osteochondromas is shown. Multiple osteochondromas are seen involving both femurs and pelvis. (Right) Osteochondroma characteristically shows a cartilaginous cap ﬊ on the bone surface.

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Gross Photograph of Osteochondroma

Multiple Osteochondromas

Diagnosis • Family history • Presence of multiple (average: 6) exostoses in individual • EXT1 phenotype more severe than EXT2 phenotype ○ Patients with EXT1 mutations show more exostoses, more limb malalignment, and more pelvic and flat bone involvement than those with EXT2 mutations

Prognosis • Patients may show deformities of forearm, unequal limb length, varus or valgus knee angulation, ankle deformity, and disproportionate short stature • Increased risk of malignant transformation ○ Malignant transformation of osteochondroma to chondrosarcoma in 0.2-25.0% of patients with HME – Chondrosarcoma has predilection for pelvis or proximal femur □ Mostly occurs in ages 20-40 ○ Malignant transformation of osteochondroma to osteosarcoma or dedifferentiated chondrosarcoma has also been reported

• Arises from surface of bone • Cortices and medullary cavities of osteochondroma and underlying bone are in direct continuity • Outer layer consists of thin sheath of fibrous tissue that overlies pearly gray-white cartilaginous cap ○ Cartilaginous cap is of varying thickness ○ Ranging from < 2.5 cm to several cm in thickness ○ Base of cartilage cap undergoes enchondral ossification and merges with areas that have appearance of cancellous bone

MICROSCOPIC General Features • Overall architecture recapitulates that of disorganized growth plate • Chondrocytes exhibit minimal cytologic atypia and no mitotic activity • Peripheral cap of hyaline cartilage ○ Cellularity of cartilage decreases from deep to superficial layer ○ Chondrocytes arranged in vague columns • Newly formed trabeculae at base of cartilage mimics primary spongiosa of normal growth plate

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Cancer Risk Management • Treated successfully with low morbidity • Baseline radiographs of pelvis and shoulder • Annual MR screening may be of value

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MACROSCOPIC General Features • Generally similar to sporadic osteochondroma

Osteochondroma

Overview of Syndromes: Syndromes

• Growth of new or existing lesions stops with skeletal maturation • Multiple firm, slowly enlarging lesions present for many years • Painful ○ Related to bursitis or impingement upon neurovascular structures • Arises from surface of bone ○ Continuity of cortices and medullary cavities

6. 7.

Pacifici M: The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses. Matrix Biol. 71-72:28-39, 2018 Labonne JD et al: A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies. Am J Med Genet A. 167A(12):3011-8, 2015 Ciavarella M et al: 20 novel point mutations and one large deletion in EXT1 and EXT2 genes: report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis. Gene. 515(2):339-48, 2013 Huegel J et al: Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. Dev Biol. 377(1):100-12, 2013 Nadanaka S et al: EXTL2, a member of the EXT family of tumor suppressors, controls glycosaminoglycan biosynthesis in a xylose kinase-dependent manner. J Biol Chem. 288(13):9321-33, 2013 Munoz J et al: Familial history of bone tumors. JAMA. 308(14):1476-7, 2012 Jennes I et al: Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat. 30(12):1620-7, 2009

Cartilaginous Cap in Osteochondroma (Left) The overall architecture of an osteochondroma recapitulates that of a disorganized growth plate. The cartilage undergoes endochondral ossification. (Right) The cartilaginous cap of an osteochondroma is composed of hyaline cartilage. The cellularity of cartilage decreases from deep to superficial layer.

631

Overview of Syndromes: Syndromes

Hereditary Neuroblastoma ○ Such as family history of NB, bilateral/multifocal primary tumors, and earlier median age of diagnosis • Overall risk to siblings: ~ 0.2% • Familial NBs are thought to have earlier median age at diagnosis than those with sporadic NB • Most cases (> 60%) of hereditary NB are diagnosed before 1 year of age

TERMINOLOGY Abbreviations • Neuroblastoma (NB) • Ganglioneuroblastoma (GNB)

Definitions • Malignant tumor derived from primordial neural crest cells that usually presents in childhood ○ NB is less differentiated ○ GNB is moderately differentiated, showing variable cytodifferentiation into ganglion cells • ~ 2% of patients with NB have underlying genetic predisposition that may have contributed to development of NB

EPIDEMIOLOGY Incidence • Hereditary NB is rare: ~ 2% of individuals with NB exhibit features suggestive of hereditary predisposition

GENETICS Heterogeneous Etiology • Autosomal dominant pattern of inheritance with penetrance of ~ 63% • ~ 2% of individuals with NB exhibit features suggestive of hereditary predisposition ○ Such as family history of NB, bilateral/multifocal primary tumors, and earlier median age of diagnosis ○ Patients with NB have underlying genetic predisposition that may have contributed to development of NB • Germline mutations in ALK and PHOX2B account for most familial NB cases

Neuroblastoma With Homer Wright Rosettes

Strong ALK Expression in Hereditary Neuroblastoma

MYCN Amplification by FISH

PHOX2B Nuclear Immunoexpression

(Left) Homer Wright rosettes ﬉ are composed of neuroblasts surrounding a central core of neurites (cytoplasmic processes). These can be found in varying numbers in poorly differentiated neuroblastomas (NBs) but are not wholly specific. Small foci of schwannian stroma are also seen. (Right) Immunohistochemical staining for ALK1 in NB shows strong membranous staining. Activating mutations in ALK gene are associated with hereditary NB and provide a potential therapeutic target.

(Left) Fluorescence in situ hybridization (FISH) of this neuroblastoma shows low degree of amplification of MYCN, demonstrated by increased numbers of green dots in the NB cells. (Right) Adrenal NB in a child with hereditary NB shows sheets of uniform cells with round to ovoid nuclei with diffuse strong nuclear PHOX2B expression. PHOX2B reliably distinguishes NB among small round blue cell tumors.

632

Hereditary Neuroblastoma

Genetic Changes • Mutations in ALK and PHOX2B genes account for majority of familial NB, and some additional cases may be associated with germline mutations in RAS pathway and other known cancer predisposition genes, such as TP53 and CDKN1C • Hereditary basis and molecular pathogenesis of NB are incompletely understood, and causal gene in small subset of families with NB (~ 15%) remains unknown

ALK • Activating mutations in ALK receptor tyrosine kinase as major familial NB gene • ALK locus, centromeric to MYCN locus, was identified as recurrent target of copy number gain and gene amplification • Germline activating mutations in ALK gene explain most hereditary NBs ○ Activating mutations can also be somatically acquired • DNA sequencing of ALK revealed 8 novel missense mutations in up to ~ 35% of NB • Heritable mutations of ALK are main cause of familial NB • Patients with germline ALK mutations do not appear to develop NB earlier than general population ○ ALK is also commonly activated by somatic mutation or amplification in 8-10% of sporadic NBs without germline mutation – Which further supports biological importance of ALK in NB pathogenesis • Germline or acquired activation of this cell-surface kinase is tractable therapeutic target for this lethal pediatric malignancy

PHOX2B • Heterozygous mutations in PHOX2B found in 1 of 8 families cosegregating for NB • PHOX2B is homeobox gene that is master regulator of autonomic nervous system development • NB can occur in association with disorders related to neural crest development, including congenital central hypoventilation syndrome (CCHS) and Hirschsprung disease • PHOX2B found as candidate gene because of reported increased risk of NB individuals with CCHS (due to de novo PHOX2B mutations) ○ Patients with this syndrome have increased risk (5-10%) of NB, GNB, or ganglioneuroma ○ Very strong genotype-phenotype association exists between type of PHOX2B variant and clinical presentation of child

• Although PHOX2B mutations are most often associated with CCHS &/or Hirschsprung disease, germline PHOX2B mutations have also been observed in some patients with NB in absence of CCHS &/or Hirschsprung disease

RASopathies • In addition to ALK and PHOX2B, NB has been reported in individuals with germline mutations in genes involved in RAS pathway (RASopathies) ○ Costello syndrome, associated with HRAS gene ○ Noonan syndrome, associated with PTPN11, KRAS, NRAS, RAF1, BRAF, SOS1, RIT1, and MEK1 ○ Neurofibromatosis type 1 associated with NF1

Overview of Syndromes: Syndromes

• Other cancer predisposition syndromes, such as LiFraumeni syndrome (LFS), RASopathies, and others, may be associated with increased risk for NB • MYCN amplification • Potential susceptibility loci at 16p12-p31, 4p16,2p21-p25.1, 12p12.1-p13.33 ○ Suggests possible oligogenic model in which 2 loci have synergistic effect on NB • NB harbors variety of genetic changes ○ Gain of genetic material from 17q ○ Loss of heterozygosity at 1p36 and 11q • Anaplastic lymphoma kinase (ALK) is frequent target of genetic alteration in advanced NB

Li-Fraumeni Syndrome and Other Cancer Predisposition Syndromes • Several cases of NB have been reported in patients with LFS and germline mutations of TP53, especially R337H mutation • Patients with Beckwith-Wiedemann syndrome (BWS) due to mutations in CDKN1C have 2-5% risk of developing NB • Somatic and germline mutations in children with cancer identifies germline mutations in several other genes, including SDHB, BRAC1, BRAC2, and APC in children with NB • GALNT14 gene mutations have been associated with NB predisposition in 3 individuals from 2 families

JMJD6 • Recently identified NB tumorigenic factor • Transcriptional super enhancer (jumonji domain-containing 6) at chromosome 17qter • Potential therapeutic target

ASSOCIATED SYNDROMES AND NEOPLASMS Hereditary Neuroblastoma • No specific clinical features characterize individuals with predisposition • Small proportion of patients with NB have clinically recognizable genetic syndrome that has been associated with NB ○ As disorders of neural crest development, including – CCHS – Aganglionosis of colon (Hirschsprung disease) – ROHHAD syndrome (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysfunction) – RASopathies, such as Costello syndrome, Noonan syndrome, and neurofibromatosis type 1 – Epigenetic syndromes, such as BWS, including hemihypertrophy, or 11p overgrowth • NBs have been seen in patients with germline mutations in other cancer predisposition syndromes, such as ○ LFS ○ Hereditary pheochromocytoma/paraganglioma syndrome

Neuroblastoma • Patients with familial NB have 20% risk of developing bilateral adrenal and multifocal primary NBs

633

Overview of Syndromes: Syndromes

Hereditary Neuroblastoma

• Patients with familial NB have increased risk of developing benign tumors as ganglioneuromas

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinically Relevant Pathologic Features • Adverse factors ○ Older age at diagnosis ○ Advanced stage of disease (except IV-S) ○ High histologic grade of tumor ○ Diploid DNA value ○ MYCN oncogene amplification ○ Cytogenetic abnormalities of chromosomes 1 and 17 ○ Pattern of urinary catecholamine excretion ○ Increased levels of ferritin NSE, LDH, creatine kinase BB, or chromogranin-A ○ Abnormalities in ganglioside composition ○ Lack of high-affinity nerve growth factor receptors

Classification • Several coexisting histologic classification systems ○ Shimada classification ○ International Neuroblastoma Pathology Classification (INPC) System • 2 main staging systems ○ International Neuroblastoma Staging System (INSS) – Based on extent of surgical resection ○ International Neuroblastoma Risk Group (INRG) Staging System – Based on clinical features and imaging studies – Presurgical risk assessment tool • Prognostic classification ○ Risk stratification systems ○ Children's Oncology Group – 3 prognostic groups: Low, intermediate, and high risk – Based on INSS stage, age, MYCN status, DNA-ploidy, and INPC histology ○ INRG Criteria – 4 prognostic groups: Very low, low, intermediate, and high risk – IRG stage, age, histology, differentiation/grade, MYCN status, 11q status, ploidy ○ Many other prognostic factors – Favorable: Lymphoid infiltrates, location (neck, thorax, pelvis) – Unfavorable: MYCN amp, ALK amp, 1p del, 11q del, diploid DNA, age

CANCER RISK MANAGEMENT Hereditary Neuroblastoma: Recommended Neuroblastoma Surveillance Protocol • Individuals with highly penetrant, heritable ALK or PHOX2B mutations have significant risk (45-50%) to develop 1 or more tumors, especially in infancy and childhood • Also recommended NB surveillance in individuals with following disorders ○ LFS and germline TP53-R337H mutations ○ BWS with germline CDKN1C mutations 634

○ Costello syndrome with HRAS mutations ○ Those with NB and strong family history of NB, or clearly bilateral/multifocal NB

Ganglioneuroma

Screening • Mass NB screening of normal infants by measuring urinary catecholamine metabolites was shown to be effective for detecting NBs before they produced clinical symptoms • For individuals with mutation in known NB predisposition gene, it is recommend biochemical and radiographic surveillance for early detection of tumors in first 10 years of life • It is recommend to do following tests for individuals who are genetically at increased risk to develop NB ○ Abdominal US ○ Quantitative, normalized assessment of urinary catecholamine metabolites [such as vanillylmandelic acid (VMA) and homovanillic acid (HVA)] by gas chromatography and mass spectroscopy (GC-MS) ○ Chest radiograph as NB surveillance tests: This should begin at birth or at diagnosis of NB predisposition and continued every 3 months until 6 years of age, and then continued every 6 months until 10 years of age (and then stop) • Urinary catecholamines ○ NB could be detected by screening at age of 6 months – Evidence of improvement in survival of children with screen-detected NB – Associated with favorable biological features – Lack of MYCN amplification • Urinary HVA and VMA ○ Increased in > 95% of cases of NB ○ Due to clinical heterogeneity of hereditary NB and possibility of later age at presentation, prolonged period of time screening may be necessary – Patients with Costello syndrome can have elevated urinary VMA and HVA in absence of catecholaminesecreting tumor □ Therefore, only very high levels or significantly rising levels would prompt further investigation beyond abdominal US and chest radiograph

High Importance of Cytogenetics • MYCN amplification is associated with worse prognosis • Loss of heterozygosity of 1p and 11q associated with worse prognosis • Activating mutations of ALK receptor tyrosine kinase confer sensitivity to ALK inhibition with small molecules, providing molecular rationale for targeted therapy of this disease

SELECTED REFERENCES 1. 2. 3.

Wong M et al: JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nat Commun. 10(1):3319, 2019 Aygun N: Biological and genetic features of neuroblastoma and their clinical importance. Curr Pediatr Rev. 14(2):73-90, 2018 Kamihara J et al: Retinoblastoma and neuroblastoma predisposition and surveillance. Clin Cancer Res. 23(13):e98-106, 2017

Hereditary Neuroblastoma

Large Adrenal Neuroblastoma (Left) Coronal T2-weighted MR shows an NB ſt of the left adrenal gland with an area of central necrosis st. This large adrenal mass is compressing the upper pole of the kidney. (Right) Gross image shows a cut surface of a large mass arising from the adrenal gland and compressing the upper pole of the kidney in a child with hereditary NB. NBs are usually hemorrhagic with focal areas of necrosis.

Poorly Differentiated Neuroblastoma

Overview of Syndromes: Syndromes

Adrenal Mass

Strong Synaptophysin Expression (Left) Low-power view of a poorly differentiated NB shows thin septa composed of schwannian stroma. Pale, eosinophilic neuropil is seen in places between the nodules or nests of NB cells. (Right) Synaptophysin immunostain shows a granular pattern. Although synaptophysin is not specific, it can be used for differential diagnosis of other small round blue cell tumors like lymphoma, rhabdomyosarcoma, or Ewing sarcoma. NBs are also positive for chromogranin and CD56.

PHOX2B Immunoexpression in Neuroblastoma

MYCN Amplification (Left) This metastatic NB of a 1-year-old boy shows nests of small round to angulated cells with scant cytoplasm with diffuse and strong nuclear PHOX2B expression. Note that the endothelial cells are negative ſt. (Courtesy Y.O. Hung, MD, PhD.) (Right) FISH of an NB shows marked amplification of MYCN demonstrated by numerous red dots (green dots show chromosome 2). This finding predicts poor prognosis, although the amount of amplification does not relate to outcome.

635

Overview of Syndromes: Syndromes

Hereditary Pancreatic Cancer Syndrome

TERMINOLOGY

EPIDEMIOLOGY

Abbreviations

Prevalence

• • • •

• ~ 10% of pancreatic carcinomas have familial component ○ Known genetic syndromes account for < 15% of this group – Genetic basis of most cases of FPC remains undefined ○ Greater the number of family members affected, higher the relative risk of pancreatic cancer for individuals within that family ○ Cigarette smoking is synergistic environmental cofactor ○ Clinical features in HPC cases are ordinary and their genomic backgrounds are heterogeneous

Familial pancreatic cancer (FPC) Familial atypical multiple mole melanoma (FAMMM) Hereditary pancreatic cancer (HPC)  Familial adenomatous polyposis (FAP)

Definitions • HPC: Well-defined genetic syndromes associated with increased risk of pancreatic cancer ○ Include hereditary breast and ovarian cancer syndrome, FAMMM, Peutz-Jeghers, FAP, Lynch syndrome, and hereditary pancreatitis ○ Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM • FPC is defined as families with 2 or more close relatives with pancreatic cancer that do not meet criteria for known cancer susceptibility syndrome

GENETICS Autosomal Dominant • Most of these syndromes are inherited in autosomal dominant manner

Inherited Pancreatic Cancer Risk Variants

The majority of pancreatic cancer is considered sporadic. ~ 10% of pancreatic cancers are associated with some familial cancer syndromes. Hereditary pancreatic cancers are well-defined genetic syndromes associated with increased risk of pancreatic cancer, such as hereditary breast and ovarian cancer syndrome, FAMMM, Peutz-Jeghers, FAP, Lynch syndrome, and hereditary pancreatitis. The genes that are mutated in familial cancer syndrome are within the rare allele frequencies with high effect. These genes are STK11, BRAC2, PALB2, MSH2, ATM, BRAC1, CDKN2A, APC, TP53, and BRCA1. Low risk of pancreatic cancer risk loci are shown at lower right.

636

Hereditary Pancreatic Cancer Syndrome

ETIOLOGY/PATHOGENESIS

○ Patients with BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, or PMS2 mutation who have 1st- or 2nd-degree relative with pancreatic cancer • Evidence suggesting that pancreatic cancers identified through such screening are more likely to be resectable and are associated with longer 3-year survival

Surgery • Worrisome features including solid mass, dilated main pancreatic duct, mural nodules, multiple cysts, or positive cytology/FNA should prompt surgical evaluation • Total pancreatectomy generally avoided due to significant morbidities (i.e., brittle diabetes)

SELECTED REFERENCES 1.

2.

3.

4. 5.

6.

Histogenesis

7.

• Given wide variety of genes and syndromes involved, there is no consistent correlation between genotype and pancreatic cancer histology ○ Precursor lesions include pancreatic intraepithelial neoplasias (PanINs) or intraductal papillary mucinous neoplasms (IPMNs) • Invasive carcinomas arise at similar age to sporadic cases (> 60 years)

8. 9. 10.

11.

12.

CANCER RISK MANAGEMENT Surveillance • No established consensus on best method to follow highrisk patients ○ Endoscopic ultrasound (with fine-needle aspiration of lesions, if present) and MR cholangiopancreatography thought to be best modalities for screening ○ Screening should start at age 50, or 10 years younger than earliest diagnosis in family – For patients with Peutz-Jeghers syndrome, screening is recommended to start between 25-30, and 35 years is recommended starting age for hereditary pancreatitis ○ Exams should be performed on annual basis ○ CA19-9 is not useful tool • Candidates for screening ○ Risk level of candidate is assessed based on number of affected family members and hereditary syndromes ○ 1st-degree relatives of patients with FPC ○ Patients with Peutz-Jeghers syndrome, regardless of family history of pancreatic cancer ○ Patients with hereditary pancreatitis ○ Patients with FAMMM

13. 14. 15. 16. 17. 18. 19.

Overview of Syndromes: Syndromes

• Genes responsible for FPC include ATM (~ 2.5%), BRAC1 (up to 1%), BRAC2 (8-19%), CHEK2 (~ 3%), and PALB2 (~ 34%) • 4-8% of individuals with pancreatic cancer carry germline mutation associated with pancreatic cancer risk ○ Hereditary breast and ovarian cancer syndrome: BRCA1, BRCA2, PALB2 ○ FAMMM: CDKN2A ○ Lynch syndrome: MLH1, MSH2, MSH6, PMS2 ○ ATM: Increased pancreatic cancer risk in ATM heterozygote carriers; homozygous mutations lead to ataxia-telangiectasia syndrome ○ Peutz-Jeghers syndrome: STK11 – One of highest risk factors for onset of pancreatic cancer ○ Hereditary pancreatitis: PRSS1 (autosomal dominant), SPINK1 (autosomal recessive), CFTR (complex genetics) • Individuals with germline mutation have higher risk of pancreatic cancer (HR 2.85) than FPC kindreds without known mutation ○ However, known germline mutations account for < 20% of FPC cases • Recommended that all patients with pancreatic cancer have genetic testing

Ohmoto A et al: Genomic features and clinical management of patients with hereditary pancreatic cancer syndromes and familial pancreatic cancer. Int J Mol Sci. 20(3), 2019 NCCN Clinical Practice Guidelines. Pancreatic Adenocarcinoma. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed September 11, 2019 Canto MI et al: Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 155(3):740-51.e2, 2018 Matsubayashi H et al: Familial pancreatic cancer: Concept, management and issues. World J Gastroenterol. 23(6):935-48, 2017 Canto MI et al: International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 62(3):339-47, 2013 Potjer TP et al: Variation in precursor lesions of pancreatic cancer among high-risk groups. Clin Cancer Res. 19(2):442-9, 2013 Bartsch DK et al: Familial pancreatic cancer--current knowledge. Nat Rev Gastroenterol Hepatol. 9(8):445-53, 2012 Canto MI et al: Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. Gastroenterology. 142(4):796-804; quiz e14-5, 2012 Roberts NJ et al: ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2(1):41-6, 2012 Sakorafas GH et al: Individuals at high-risk for pancreatic cancer development: management options and the role of surgery. Surg Oncol. 21(2):e49-58, 2012 Segura PP et al: Hereditary pancreatic cancer: molecular bases and their application in diagnosis and clinical management: a guideline of the TTD group. Clin Transl Oncol. 14(8):553-63, 2012 Solomon S et al: Inherited pancreatic cancer syndromes. Cancer J. 18(6):48591, 2012 Solomon S et al: PRSS1-related hereditary pancreatitis. 1993-2013, 2012 Brentnall TA: Pancreatic cancer surveillance: learning as we go. Am J Gastroenterol. 106(5):955-6, 2011 Matsubayashi H et al: Risk factors of familial pancreatic cancer in Japan: current smoking and recent onset of diabetes. Pancreas. 40(6):974-8, 2011 Hruban RH et al: Update on familial pancreatic cancer. Adv Surg. 44:293-311, 2010 Maisonneuve P et al: Epidemiology of pancreatic cancer: an update. Dig Dis. 28(4-5):645-56, 2010 Shi C et al: Familial pancreatic cancer. Arch Pathol Lab Med. 133(3):365-74, 2009 Shi C et al: Increased prevalence of precursor lesions in familial pancreatic cancer patients. Clin Cancer Res. 15(24):7737-43, 2009

637

Overview of Syndromes: Syndromes

Hereditary Pancreatic Cancer Syndrome Hereditary Pancreatic Cancer Syndromes Syndrome

Genes

Adenocarcinoma

Familial atypical multiple mole melanoma syndrome

P16/CDKN2A

Adenocarcinoma

Lynch syndrome

MLH1, PMS2, MSH2, MSH6

Adenocarcinoma

Peutz-Jeghers syndrome

STK11

Adenocarcinoma

Hereditary pancreatitis

PRSS1, PRSS2, SPINK1, CFTR

Adenocarcinoma

Familial adenomatous polyposis

APC, MYH

Adenocarcinoma (ampullary)

Genetic Risks of Pancreatic Cancer Risk Factor

Cumulative Lifetime Risk (%)

Relative Risk Compared to General Population

Family history: 1 first-degree relative affected

4.6x

Family history: 2 first-degree relatives affected

6.4x

Family history: 3 first-degree relatives affected

638

Tumors

Hereditary breast and ovarian cancer syndrome BRCA2, PALB2, BRCA1

17-32x

Hereditary breast and ovarian cancer

1.5% (women), 2-4% (men)

2.4-6x

Peutz-Jeghers syndrome

11-36%

132x

Familial atypical multiple mole melanoma

14-17%

13-39x

Hereditary pancreatitis

40-53%

26-87x

Lynch syndrome

4%

9-11x

Hereditary Pancreatic Cancer Syndrome

Pancreatic Ductal Adenocarcinoma (Left) Pancreatic adenocarcinoma is shown involving the pancreatic head and invading the ampulla and duodenal wall. Up to 8% of those with pancreatic cancer carry a germline mutation associated with this disease. (Right) Several hereditary cancer syndromes have increased risk for pancreatic cancer, including PeutzJeghers, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis (FAP), Lynch, and hereditary breast and ovarian cancer syndrome.

Pancreatic Ductal Adenocarcinoma

Overview of Syndromes: Syndromes

Pancreatic Ductal Adenocarcinoma

Metastases to Peripancreatic Lymph Node (Left) Gross cut surface shows an invasive pancreatic adenonocarcinoma with cystic spaces. This tumor arose in an intraductal papillary mucinous neoplasm (IPMN). (Right) Several genetic syndromes, including Peutz-Jeghers, hereditary pancreatitis, hereditary breast-ovarian cancer (HBOC), Lynch syndrome, and FAP, also have increased risks of pancreatic cancer. Patients are often younger and have worse prognosis with metastases.

Invasion Around Nerve

Perineural Invasion in PJS-Associated Pancreatic Cancer (Left) This invasive adenocarcinoma arose in a patient with IPMN. IPMN as a precursor lesion of pancreatic ductal adenocarcinoma is observed in some patients with Peutz-Jeghers syndrome. (Right) Peutz-Jeghers syndrome increases the incidence of pancreatic cancer by 132x and increases the incidence of gastrointestinal, lung, breast, uterine, and ovarian cancers as well.

639

Overview of Syndromes: Syndromes

Hereditary Papillary Renal Cell Carcinoma Ethnicity Relationship

TERMINOLOGY Abbreviations • Papillary renal cell carcinoma (PRCC) • Hereditary papillary renal cell carcinoma (HPRCC)

Definitions • Autosomal dominant hereditary disease characterized by development of multiple PRCCs type 1 related to germline MET (c-MET) mutation

EPIDEMIOLOGY Age Range • PRCC typically develops between 45-63 years ○ Somewhat late onset for hereditary renal cancer syndrome; however, tumor development as early as 2nd or 3rd decade may occur

• No known ethnic relationship ○ Most cases encountered in Caucasian families; possibly biased by general population ethnic distribution

Incidence • Rare; only ~ 30 families with MET mutation described worldwide ○ 1 study did not find MET mutation in 59 clinic-based PRCC cases, including subset with bilateral &/or multifocal tumors ○ PRCC represents 5% of familial renal cancers in National Institute of Health (NIH) database • Vast majority of PRCC are sporadic tumors; 2nd most common type of renal epithelial tumor ○ MET mutation also uncommonly detected in some PRCC type 1 without known family history of PRCC type 1

ETIOLOGY/PATHOGENESIS

Gender • M:F = 2.4:1.0

Genetics • Mutation in MET protooncogene

Multifocal Papillary RCCs

Papillary RCC Type 1

Multifocal Papillary RCCs

Mutifocal Papillary Adenomas

(Left) Kidney shows multifocal PRCCs. Upper pole PRCC st is dark red-brown due to diffuse hemorrhage, and lower pole PRCC ſt has yellow discoloration due to histiocytic infiltrates. These changes are common in PRCC. (Right) PRCC type 1 shows wellformed papillae lined by cuboidal cells with amphophilic cytoplasm. The papillae are typically lined by single or few layers of tumor cells, and nuclei are usually low grade. Note hemosiderin pigment-laden histiocytes ﬈ in papillary core from hemorrhage.

(Left) Multiple (6) PRCCs resected from a single kidney are shown. The tumors show extensive ſt and focal ﬇ hemorrhages common in PRCC. One tumor grew as exophytic mass from renal capsule st. Observation and conservative excision (at 3 cm size) is considered for HPRCC. (Right) Low-power view shows papillary adenomas lacking capsule ﬈. The tumor cells resemble those in PRCC type 1, are typically low grade, and blend with nonneoplastic tubules at periphery. New 2016 WHO size cut-off for papillary adenoma is 15 mm.

640

Hereditary Papillary Renal Cell Carcinoma

CLINICAL IMPLICATIONS

○ Predominant histology of PRCC type 1 in HPRCC is similar to those in sporadic type – Papillary architecture with fibrovascular core that occasionally contains foamy histiocytes – May also have tubular or tubulopapillary architecture; may impart solid appearance when predominant – Tumor cells are small with scant to modest amount of basophilic or amphophilic cytoplasm ○ Admixed areas of clear cells present in > 90% of tumors, more common than in sporadic PRCCs – Amount of clear cells varies from 1-70% – PRCC lacks delicate vasculature in clear cell RCC – Electron microscopy detects intracytoplasmic lipid and glycogen, unlike in usual PRCC cells • Immunohistochemistry ○ pax-2 or pax-8(+), AMACR(+), CK7(+), and EMA(+)

Clinical Presentation

PRCC Type 2

• Diagnosis in index patients from families with HPRCC not different from sporadic PRCCs ○ Renal cancers often detected incidentally ○ When symptomatic, may present with hematuria, abdominal pain, &/or mass ○ Suspicion for HPRCC raised by history of multiple family members with renal cancers ○ Subsequent radiologic screening may identify affected family members with asymptomatic renal cancers • Renal cancers can be lethal if not detected and treated at early stage • Estimated prevalence of renal tumors is 1,100-1,300 microscopic papillary tumors in kidney

• HPRCC with mixture of PRCC types 1 and 2 reported; association not established as in type 1 • Suggested that some PRCC type 1 classified before 1997 are perhaps type 2

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

Papillary Adenoma • Small (≤ 15 mm) tumor nodule in renal parenchyma with papillary, tubular, or tubulopapillary architectures • Nonencapsulated • Similar cytology to low-grade PRCC type 1 ○ Distinguished from low-grade PRCC type 1 by size and lack of capsule; distinction not possible in needle biopsy • Like PRCC, multiple adenomas are present in kidney • Similar genetic and immunophenotypic profiles to PRCC type 1 • Benign tumor with no metastatic potential

MET Protooncogene Mutation Screening

Other Tumors

• Not advocated to be performed in every case of PRCC, because HPRCC is rare ○ 1 study screened 59 patients with PRCC that included 22% with bilateral &/or multifocal tumors, and no MET mutation was identified • Testing should be performed only if clinical suspicion of disease ○ Unusually young age of onset, positive family history, bilateral &/or multifocal PRCCs • Testing can be performed on blood samples (lymphocytes)

• No known extrarenal manifestations, in contrast to most other hereditary renal cancer syndromes

ASSOCIATED NEOPLASMS PRCC Type 1 • Macroscopy ○ Bilateral and multifocal tumors in > 80% of cases of HPRCC ○ Reported number of PRCCs ranges from 1-26 ○ HPRCC tumors have similar gross appearance to sporadic PRCC – Well circumscribed with fibrous pseudocapsule – Hemorrhages are common and cause red or dark brown discoloration – Intratumoral collections of histiocytes may produce yellow streaks or contrasts • Microscopy

Overview of Syndromes: Syndromes

○ Gene located in Chr 7q31.1-34 ○ MET is receptor for hepatocyte growth factor (HGF) or scatter factor (SF) ○ Most are germline missense mutations ○ Mutation occurs in glycine-rich subdomain adjacent to ATP binding site or in activation loop of tyrosine kinase domain – Results in constitutive activation of receptor ○ MET overexpression is frequently observed in HPRCC – Suggested as potential therapeutic target ○ Penetrance suggested to be high but age of onset varies; 100% by age 80 • HPRCC cytogenetics ○ Chr +7 and +17, similar in sporadic PRCCs

CANCER RISK MANAGEMENT Management • Observation can be performed for smaller tumors ○ No standard size cut-off for therapeutic intervention; some follow 3 cm as cut-off, similar to criterion used for VHL disease • Nephron-sparing surgery prioritized to preserve renal function • Radical surgery if tumor is large or kidney is extensively involved • Treatment with MET inhibitors show promising results

Surveillance • Lifelong clinical surveillance of affected family members should be performed • Baseline radiographic examination of kidneys to detect asymptomatic tumor • Regular follow-up to detect new tumor and careful monitoring for progression of smaller tumors

SELECTED REFERENCES 1.

Akhtar M et al: Papillary renal cell carcinoma (PRCC): An update. Adv Anat Pathol. 26(2):124-32, 2019

641

Overview of Syndromes: Syndromes

Hereditary Paraganglioma/Pheochromocytoma Syndromes

TERMINOLOGY Abbreviations • Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes

Definitions • PCCs and PGLs are neuroendocrine tumors that arise in adrenal medulla or extraadrenal sympathetic and parasympathetic paraganglia ○ Occur sporadically or as part of different hereditary tumor syndromes ○ Tumors arising within adrenal medulla are known as PCCs; histologically identical tumors arising elsewhere are termed PGLs ○ PCC and PGL are amongst tumors most frequently accompanied by germline mutations • Hereditary PGL/PCC syndromes are characterized by presence of PGL &/or PCC that occur as part of familial syndrome

○ > 40% of PCCs and PGLs are currently believed to be caused by germline mutations, and several novel susceptibility genes have recently been discovered ○ RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127, MAX, FH, MDH2, and IDH1/IDH2 have been associated with hereditary PCC &/or PGL • Hereditary PGL/PCC syndromes should be considered in all individuals with PGL or PCC with following findings ○ Multiple tumors, including bilateral tumors ○ Multifocal with multiple synchronous or metachronous tumors ○ Early onset (age < 40 years) ○ Family history of such tumors • "Familial PGL/PCC syndrome" is term restricted to tumors from germline mutations in SDHx genes • Simplex cases: Many individuals with hereditary PGL/PCC syndrome may present with solitary tumor of head or neck, thorax, abdomen, adrenal, or pelvis and no family history of disorder

Approach to Pheochromocytoma and Associated Syndromes by Clinical Scenario

Algorithmic approach to pheochromocytoma in carriers of disease-causing mutation is shown. Depending on the specific mutation, initial biochemical testing and imaging and follow-up should be performed.

642

Hereditary Paraganglioma/Pheochromocytoma Syndromes

Syndromes Characterized by Susceptibility to PCC and PGL • Tumors associated with multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), and neurofibromatosis type 1 (NF1) • Tumors associated with mutations in genes encoding different subunits of succinate dehydrogenase (SDH) complex ○ Familial PGL/PCC syndrome (PGL1, 2, 3, 4, 5) • Small fraction is associated with other syndromes, as Carney triad, Carney-Stratakis syndrome, MEN1 • PCCs and PGLs are currently associated with germline &/or somatic mutations in > 20 genes • These mutations are divided into 3 main clusters based on activation of particular signaling pathway ○ Pseudohypoxic signaling cluster ○ Kinase signaling cluster ○ Wnt signaling cluster ○ Each cluster is associated with unique clinical characteristics of patients with these tumors • Several genes have been added to list (associated with unknown hereditary PGL/PCC) ○ MYC-associated factor X (MAX) ○ Transmembrane protein 127 (TMEM127) ○ Kinesin family member 1B (KIF1B) ○ EGL-9 homolog 1 (EGLN1),also termed PHD2 ○ Fumarate hydratase (FH) ○ Malate dehydrogenase 2 (MDH2) ○ Isocitratedehydrogenase (IDH1/IDH2)

GENETICS MEN2 • Autosomal dominant syndrome caused by mutation of RET protooncogene • Activating RET mutation predisposes to PCC, which is often bilateral and recurrent ○ Low risk of malignancy • Prevalence is estimated at 1:30,000 • Often suspected on basis of family history; patients with PCC infrequently present as simplex cases • Clinically, can be divided into 3 types: MEN2A (55%), MEN2B (5-10%), and familial medullary thyroid carcinoma (FMTC) (35-40%) • MEN2A and MEN2B patients have almost 100% risk of developing medullary thyroid carcinoma • ~ 50% of individuals with MEN2A and MEN2B develop PCC

Familial PGL/PCC Syndromes • Germline mutations in SDHx genes give rise to familial PGL/PCC syndrome • Associated with germline mutations in genes encoding subunits of SDH enzyme complex in context of familial PGL syndromes; PGL1, PGL2, PGL3, PGL4, and PGL5 caused by mutations in SDHD, SDHAF2, SDHC, SDHB, and SDHA genes, respectively • Patients harboring SDHB mutation are at increased risk of malignancy

VHL • Autosomal dominant disorder caused by mutation of VHL • Features include retinal angiomas, central nervous system hemangioblastomas, clear cell renal cell carcinoma, pancreatic endocrine tumors, endolymphatic sac tumors; renal, pancreatic, and epididymal cysts; and PCC • ~ 10-26% of VHL patients develop PCC or PGL, but risk varies between families ○ Frequency of PCC in patients with VHL is 10-20% • Mean age of onset of PCC in VHL is ~ 30 years ○ PCCs occur in only 6-9% of patients with VHL type 1 ○ Prevalence of PCC rises to 40-59% in patients with VHL type 2 ○ In type 2C VHL, PCCs are sole manifestation of syndrome (simplex cases) • VHL mutations predispose to unilateral or bilateral PCCs and, much less frequently, to sympathetic or parasympathetic PGLs ○ ~ 50% of PCCs are bilateral

Overview of Syndromes: Syndromes

• In PGL/PCC that appear to be sporadic based on absence of family history, rate of occult germline mutation is said to be up to 24%

NF1 • Autosomal dominant disorder caused by mutation of NF1 • Major features of NF1 include neurofibromas, café au lait spots, iris hamartomas, and axillary and inguinal freckling • Gastrointestinal stromal tumors (GISTs) and carcinoid tumors may also occur • PCCs and PGLs are not among most common manifestations of NF1 but occur in 0.1-5.7% of patients • PCCs occur in 20-50% of patients with NF1 and hypertension • NF1-associated PCC and PGL typically have characteristics similar to those of sporadic tumors, with relatively late mean age of onset and ~ 10% risk of malignancy • 95% of patients with NF1 had PCC and 6% had PGL; all PGLs were sympathetic • 14% of patients displayed bilateral PCC

Carney Triad • Rare multitumoral syndrome • Usually occurs in young women • Neoplasms affect stomach, lungs, paraganglionic system, adrenal cortex, and esophagus ○ Triad: Gastric stromal tumor, PGL, and pulmonary chondroma ○ PCC, adrenal cortical adenoma, and esophageal leiomyoma are also associated ○ Multifocal tumors develop in affected organs • Mean age at presentation with PGL/PCC is 28 years • 92% present with PGL, including both sympathetic and parasympathetic tumors, and ~ 16% present with PCC • Multiple PGLs are found in 22% of patients and bilateral PCC in 3%

Carney-Stratakis Syndrome • Mutations in SDHB, SDHC, and SDHD can give rise to CarneyStratakis syndrome, characterized by dyad of PGL and GIST • 100% of patients have PGL and rarely PCC • Mean age of 33 years at presentation • PGLs occur in head and neck, thorax, and abdomen • Multiple PGLs, which could be both sympathetic and parasympathetic, seen in 73% of patients 643

Overview of Syndromes: Syndromes

Hereditary Paraganglioma/Pheochromocytoma Syndromes MEN1

Immunohistochemistry

• Caused by mutations in MEN1 • MEN1 is 10-exon gene that encodes 610-amino acid protein, menin • Mutation spectrum ○ > 1,300 different mutations of MEN1 have been characterized ○ Penetrance of MEN1 is high: 45% by age 30, 82% by age 50, and 96% by age 70

• SDHA and SDHB are important surrogate markers to triage patients for genetic testing ○ Identifying > 15% of PGL/PCC associated with mitochondrial complex 2 dysfunction; SDHB is vital tool for triaging genetic testing – Yield is particularly high in extraadrenal PCC/PGL • SDHB immunoexpression is lost in PGL and PCC with SDHA, SDHB, SDHC, and SDHD mutations • Any PGL/PCC should be considered potentially hereditary until this possibility is excluded

Other Genes Involved in PGL/PCC • Several other genes have recently been added to the list (associated with unknown hereditary PGL/PCC) ○ KIF1B, EGLN1 (also termed PHD2), TMEM127, and MAX • No specific syndrome has been attributed yet, but patients with germline KIF1Bβ mutations seem to be predisposed to at least PCCs and neuroblastomas ○ Ganglioneuroma, leiomyosarcoma, and lung adenocarcinoma have also been reported in family with KIF1Bβ mutations • Only 1 PGL patient, suffering from recurrent PGL and erythrocytosis, has been reported to have germline mutation in EGLN1 • So far, no specific syndrome has been described for TMEM127 ○ TMEM127 mutations were identified in 2% of cases considered sporadic, all of which had PCC ○ 96% of patients have PCC and 39% have bilateral PCC • MAX mutations segregate with disease in families with PCC, but no specific syndrome has been described yet ○ Usually bilateral tumors, early age of onset, &/or familial antecedents with disease ○ Notably, 25% of patients showed metastasis at diagnosis, suggesting that MAX mutations are associated with high risk of malignancy ○ Patients rarely may have renal cell carcinoma

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

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Diagnosis • Based on physical examination, family history, imaging studies, and biochemical and molecular genetic testing

ASSOCIATED NEOPLASMS MEN2 • MEN2A: Characterized by medullary thyroid carcinoma, PCC, and hyperparathyroidism • MEN2B: Lacks hyperparathyroidism but includes mucocutaneous neuromas &/or diffuse ganglioneuromatosis of gastroenteric mucosa, slender body habitus, joint laxity, and skeletal malformations

Familial PGL/PCC Syndromes • SDHx mutations are associated with renal cell carcinoma, pituitary adenoma, GIST, and possibly other tumors

VHL Syndrome • Retinal angiomas, central nervous system hemangioblastomas, clear cell renal cell carcinoma, pancreatic endocrine tumors, endolymphatic sac tumors; renal, pancreatic, and epididymal cysts; and PCCs

NF1 • Neurofibromas, café au lait spots, iris hamartomas, and axillary and inguinal freckling • Optic nerve glioma, duodenal neuroendocrine tumors, bone lesions

Clinical Hallmarks

Carney Triad

• In addition to family history, classic hallmarks of hereditary PCC and PGL include early age at onset, extraadrenal and multiple primary tumors, and associated nonparaganglial tumors ○ Age at diagnosis is ~15 years younger for syndromic PCCs and PGLs than for sporadic cases ○ PGL occurring in unusual location, such as organ of Zuckerkandl, thorax, or urinary bladder, suggests possibility of syndrome associated with tumor ○ Anatomical locations of PCC and PGL differ widely among syndromes – Adrenal pheochromocytomas occur almost exclusively in patients with germline mutations in RET – Patients with SDHx mutations frequently have head and neck PGL, but PCC and retroperitoneal PGLs are seen mainly in carriers of SDHD, SDHB, and SDHA mutations – Patients with mutations in NF1, VHL, TMEM127, and MAX have PCC and retroperitoneal PGLs ○ Multiple primary tumors often occur in patients with germline mutations in VHL, RET, SDHD, and MAX

• Extraadrenal sympathetic PGL, GIST, and pulmonary chondroma

Carney-Stratakis Syndrome • Association of PGL and GIST (dyad)

Other Genes Involved In PGL/PCC • Ganglioneuroma, leiomyosarcoma, and lung adenocarcinoma have also been reported in family with KIF1Bβ mutations

CANCER RISK MANAGEMENT RET-Associated PGL/PCC • Activating mutations predispose to PCCs: Bilateral in 63% and only 3% malignant • PGL are rare in MEN2

VHL-Associated PGL/PCC • VHL mutations predispose to unilateral or bilateral PCCs: Bilateral in 44% and only 3% malignant

Hereditary Paraganglioma/Pheochromocytoma Syndromes

NF1-Associated PGL/PCC • PCCs and PGLs not among most common tumors in NF1; occur in up to 6% of patients with NF1 • NF1-associated tumors with similar characteristics as sporadic tumors • ~ 10% are malignant

SDHx-Associated PGL/PCC • • • •

PGL1 (SDHD): Metastases in 1-9% PGL2 (SDHAF2): No metastases PGL3 (SDHC): No metastases PGL4 (SDHB): Metastases in 25-50% ○ Malignancy associated with SDHB mutation ○ Higher morbidity and mortality than mutations in other SDHx genes • PGL5 (SDHA): Metastases in 1-9%

Genetic Counseling • Once diagnosis is established, important to consider when genetic testing in context of genetic counseling should be performed • All patients with PCC or PGL should undergo genetic analysis ○ Evidence to date shows that > 40% of patients presenting with PCC or PGL, irrespective of age at onset and family history, carry germline mutations ○ Hereditary PGL/PCC syndromes are inherited in autosomal dominant manner • After detection of mutation, specific gene guides tailoring of imaging studies and subsequent medical management ○ Imaging studies are performed for medullary thyroid carcinoma if RET is mutated ○ Imaging studies are performed for hemangioblastomas of eyes and CNS and for tumors of ears, kidneys, and pancreas if VHL is mutated ○ Imaging studies are performed for other chromaffin tumors or kidney carcinoma, pituitary adenomas, or GISTs if SDHx, TMEM127, and MAX are mutated • Bilateral adrenal tumors can occur metachronously, especially in patients with RET germline mutations • If patient is found to carry mutation, all 1st-degree relatives should be offered mutation-specific testing ○ Each child of individual with hereditary PGL/PCC syndrome has 50% chance of inheriting disease-causing mutation • Prenatal testing for pregnancies at increased risk is possible for families in which disease-causing mutation is known

Patient Evaluation • Includes detailed family history, including specific knowledge of any relatives with unexplained or incompletely explained sudden death • Personal medical history for following symptoms of catecholamine excess: Sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor, and anxiety ○ Paroxysmal symptoms that may be triggered by changes in body position, increases in intraabdominal pressure, some medications, exercise, or micturition in case of urinary bladder PGL

– Urinary bladder PGL may also be accompanied by painless hematuria • Head and neck PGL may present as enlarging masses that are asymptomatic or associated with symptoms of mass effects from size and location of tumors ○ Associated symptoms may include unilateral hearing loss, pulsatile tinnitus, cough, hoarseness of voice, pharyngeal fullness, swallowing difficulty, pain, and problems with tongue motion

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Fishbein L: Pheochromocytoma/paraganglioma: Is this a genetic disorder? Curr Cardiol Rep. 21(9):104, 2019 Koopman K et al: Pheochromocytomas and paragangliomas: New developments with regard to classification, genetics, and cell of origin. Cancers (Basel). 11(8), 2019 Jochmanova I et al: Genomic landscape of pheochromocytoma and paraganglioma. Trends Cancer. 4(1):6-9, 2018 Udager AM et al: The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes. Hum Pathol. 71:47-54, 2018 Crona J et al: New perspectives on pheochromocytoma and paraganglioma: Toward a molecular classification. Endocr Rev. 38(6):489-515, 2017 Dahia PL: Novel hereditary forms of pheochromocytomas and paragangliomas. Front Horm Res. 41:79-91, 2013 Dwight T et al: Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab. 98(6):E1103-8, 2013 Elston MS et al: Novel mutation in the TMEM127 gene associated with phaeochromocytoma. Intern Med J. 43(4):449-51, 2013 Jafri M et al: Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. Clin Endocrinol (Oxf). 78(6):898-906, 2013 Toledo RA et al: In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr Relat Cancer. 20(3):34959, 2013 Burnichon N et al: MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 18(10):2828-37, 2012 Grogan RH et al: Bilateral adrenal medullary hyperplasia associated with an SDHB mutation. J Clin Oncol. 29(8):e200-2, 2011 Janeway KA et al: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 108(1):314-8, 2011 Jiang S et al: Minireview: the busy road to pheochromocytomas and paragangliomas has a new member, TMEM127. Endocrinology. 152(6):213340, 2011 Barontini M et al: VHL disease. Best Pract Res Clin Endocrinol Metab. 24(3):401-13, 2010 Qin Y et al: Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 42(3):229-33, 2010 Yao L et al: Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 304(23):2611-9, 2010 Yeh IT et al: A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. Hum Genet. 124(3):279-85, 2008 Recasens M et al: Asymptomatic bilateral adrenal pheochromocytoma in a patient with a germline V804M mutation in the RET proto-oncogene. Clin Endocrinol (Oxf). 67(1):29-33, 2007 Dahia PL: Evolving concepts in pheochromocytoma and paraganglioma. Curr Opin Oncol. 18(1):1-8, 2006 Dahia PL et al: A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1(1):72-80, 2005

Overview of Syndromes: Syndromes

• In VHL patients with PGL/PCC, 90% had PCC and 19% had PGL

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Overview of Syndromes: Syndromes

Hereditary Paraganglioma/Pheochromocytoma Syndromes Characteristics of Pheochromocytoma-Associated Syndromes Syndrome

Gene

Adrenal PCC

Head and Neck PGL

Extraadrenal PGL

Multiple PGL

Metastatic PCC and PGL

Nonchromaffin Tumors

von Hippel-Lindau

VHL

> 50%

< 1%

10-24%

> 50%

1-9%

Hemangioblastomas, RCC, PNET, and endolymphatic sac tumor

MEN2

RET

> 50%

< 1%

< 1%

> 50%

< 1%

Medullary thyroid carcinoma and parathyroid hyperplasia &/or adenoma

Neurofibromatosis NF1 type 1

> 50%

< 1%

1-9%

25-50%

< 1%

Neurofibromas, malignant peripheral nerve sheath tumor, breast carcinoma

Familial paraganglioma type 1

SDHD

10-24%

> 50%

10-24%

> 50%

1-9%

RCC, GIST, and pituitary adenomas

Familial paraganglioma type 2

SDHAF2

1-9%

> 50%

-

> 50%

-

-

Familial paraganglioma type 3

SDHC

1-9%

> 50%

< 1%

10-24%

-

GIST and pituitary adenomas

Familial paraganglioma type 4

SDHB

25-50%

25-50%

25-50%

10-24%

25-50%

RCC, GIST, and pituitary adenomas

Familial paraganglioma type 5

SDHA

25-50%

25-50%

25-50%

1-9%

1-9%

RCC, GIST, and pituitary adenomas

FH-related

FH

1-9%

1-9%

1-9%

-

> 50%

HLRCC-associated RCC, cutaneous and uterine leiomyoma

MAX-related

MAX

> 50%

< 1%

1-9%

> 50%

1-9%

RCC

TMEM127-related

TMEM127

> 50%

1-9%

< 1%

25-50%

10-24%

-

GIST = gastrointestinal stromal tumor; HLRCC = hereditary leiomyomatosis and renal cell carcinoma; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma. Modified from Neumann et al, N Engl J Med. 381:552-65, 2019.

Oncogenic Signaling in Pheochromocytoma and Paraganglioma Pseudohypoxic Signaling Cluster*

Kinase Signaling Cluster**

Wnt Signaling Cluster***

 Hypoxia-inducible factor 2 alpha (HIF2A)

 RET protooncogene

Mastermind like transcriptional coactivator 3 (MAML3) fusion genes

Succinate dehydrogenase subunits (SDHx) SDHA, SDHB, SDHC, and SDHD

 Neurofibromin 1 (NF1) tumor suppressor

CSDE1 

Succinate dehydrogenase complex assembly factor2 (SDHAF2)

 H-RAS and K-RAS protooncogenes

von Hippel-Lindau tumor suppresor (VHL)

Ttransmembrane protein 127 (TMEM127)

egl-9 prolyl hydroxylase 1 and 2 (EGLN1 and EGLN2)

 MYC-associated factor X (MAX)

Fumarate hydratase (FH)

Cold shock domain containing E1 (CSDE1)

Malate dehydrogenase 2 (MDH2)

Chromatin remodeler ATRX

 Isocitratedehydrogenase (IDH) *HIF signaling pathway is affected by mutations. **Dysregulation of PI3K/mTOR pathway/receptor kinase signaling results from mutations. ***PHEOs and PGLs overexpressing genes of Wnt and Hedgehog pathways related to somatic mutations. Modified from Jochmanova et al: Trends Cancer. 4(1): 6-9, 2018 and Crona et al: Endocr Rev. 38(6):489-515, 2017.

646

Hereditary Paraganglioma/Pheochromocytoma Syndromes

Head and Neck Paraganglia (Left) Graphic shows paraganglia and neuroendocrine tissues symmetrically distributed along the paravertebral axis in the abdomen, including the organ of Zuckerkandl ſt and the adrenal medulla ﬇. (Right) Graphic shows paraganglia in head, neck, and upper thorax that are associated with arteries or cranial nerves. They include aortic st and carotid bodies ﬇ and jugulotympanic ſt, vagal, and laryngeal ﬈ paraganglia.

Carotid Body PGL

Overview of Syndromes: Syndromes

Distribution of Paraganglia and Neuroendocrine Tissues

Glomus Vagale PGL (Left) Graphic shows a carotid body paraganglioma (PGL) at the carotid bifurcation ſt, splaying the ICA ﬇ and ECA st. The main arterial feeder is the ascending pharyngeal artery ﬈. The vagus ﬊ and hypoglossal ﬉ nerves are in close proximity. (Right) Graphic shows a glomus vagale PGL ﬈ located in the nasopharyngeal carotid space. The mass is seen interposed between and displacing the ICA ﬉ and jugular vein (inset) ﬊.

Glomus Tympanicum PGL

Glomus Jugulare PGL (Left) Graphic shows a vascular glomus tympanicum PGL pedunculating off the cochlear promontory into the inferior middle ear cavity. The bony floor of the middle ear cavity is intact ſt. The pulsatile tumor mass is behind the lower tympanic membrane ﬇. (Right) Glomus jugulare PGL is centered in the jugular foramen with superolateral extension into the middle ear. The main arterial supply for this vascular tumor is the ascending pharyngeal artery ſt.

647

Overview of Syndromes: Syndromes

Hereditary Paraganglioma/Pheochromocytoma Syndromes

Carotid Body PGL

PGL Gross Cut Surface

Metastatic PGL to Liver

Adrenal Medullary Hyperplasia and PCC

PCC Morphology

Metastatic PGL to Lymph Node

(Left) Carotid angiogram shows a tumor at the bifurcation of the carotid body with high uptake of the iodinecontaining contrast medium due to hypervascularization of the tumor. (Right) Gross photo shows the cut surface of a well-circumscribed PGL with a homogeneous appearance and a small area of hemorrhage. The gross appearance of PGL is variable and may mimic other tumors.

(Left) Gross photo of liver from a patient with history of glomus jugulare PGL centered in the jugular foramen shows multiple metastatic nodules of tumor. (Right) Cross section of adrenal gland from a patient with multiple endocrine neoplasia type 2A (MEN2A) reveals diffuse medullary expansion st and a welldefined nodule ﬇ representing a pheochromocytoma (PCC).

(Left) This PCC has the characteristic alveolar pattern (zellballen) with variably sized nests of tumor cells surrounded by thin-walled vessels and thin bands of fibrous tissue. (Right) PGL is present in cervical lymph node from a young patient with head and neck PGL. Only metastases are the proof for malignancy, and the term "malignant PCC" should be replaced with "metastatic PCC".

648

Hereditary Paraganglioma/Pheochromocytoma Syndromes

MEN2-Associated PGL (Left) This highly vascular glomus jugulare PGL is underneath an intact mucosa and shows groups of neoplastic cells interspersed between the vascular channels. (Right) SDHB reveals maintenance of immunoreactivity in PGL in a MEN2-associated hereditary PGL patient, without SDHB or SDHD mutation. The staining is coarsely granular as the protein is localized in the mitochondria.

Morphology of Hereditary PGL

Overview of Syndromes: Syndromes

Morphology of Glomus Jugulare PGL

SDHB Loss in PGL (Left) PGL shows characteristic tumor growth with the socalled zellballen pattern, consisting of well-developed tumor cells with nested growth, with an intervening stromal component of fibrovascular tissue and peripheral sustentacular cells. (Right) Tumor cells in PCC/PGL with mutations of SDHA, SDHB, SDHC, or SDHD show loss of immunoreactivity of tumor cell cytoplasm for SDHB protein, while endothelial cells serve as intrinsic positive controls.

SSTR2 Membranous Staining in PGL

SDHx-Unrelated PGL (Left) Typical strong membranous staining for SSTR2 is shown in SDHBmutated PGL. This finding is consistent with the high sensitivity of somatostatin receptor by PET/CT. (Right) PCCs and PGLs without mutations of SDHx genes show immunoreactivity of tumor cell cytoplasm for SDHB protein. The immunoreactivity is granular because the protein is localized to mitochondria.

649

Overview of Syndromes: Syndromes

Hereditary Prostate Cancer

TERMINOLOGY Abbreviations • Sporadic prostate cancer (SPC) • Familial prostate cancer (FPC) • Hereditary prostate cancer (HPC)

Definitions • FPC ○ 2 first-degree relatives diagnosed with prostate cancer at any age, or ○ 1 first-degree relative and ≥ 2 second-degree relatives diagnosed at any age • HPC ○ Subtype of FPC with consistent passage of susceptibility gene via Mendelian inheritance ○ HOXB13 among prostate cancer susceptibility genes identified ○ Clinical criteria proposed by Carter et al – Family with prostate cancer in ≥ 3 first-degree relatives, or – Family with prostate cancer in 3 successive generations from paternal or maternal side, or – Family with 2 first-degree relatives with prostate cancer at age ≤ 55 years

EPIDEMIOLOGY Incidence • Prostate cancer is leading cause of cancer mortality and 2nd cause of cancer morbidity in men in USA ○ Estimated that there will be 174,650 cases of prostate cancer diagnosed in USA in 2019 • ~ 5-10% of prostate cancer patients can be accounted for by genetic susceptibility • Identification of true prevalence of FPCs or HPCs difficult due to very high occurrence rate of prostate cancer

Family History as Risk Factor • ~ 10-15% of prostate cancer patients have at least 1 relative who also has prostate cancer

• Risk is greater for men with affected brothers than for men with affected fathers • Risk ↑ with number of relatives affected • Concordance between monozygotic twins of 27% vs. 7% between dizygotic twins

Age Range • Peak occurrence of prostate cancer overall is at 65-75 years and median age is 67 years ○ HPC diagnosed ~ 6-7 years earlier than SPC

ETIOLOGY/PATHOGENESIS Risk Factors • Major risk factors for prostate cancer are age, ethnicity (black), and family history

Genetics • Genetic contribution is ~ 40-50% of prostate cancer • BRCA-associated prostate cancer ○ Contribute to small minority of prostate cancer risk with reported prevalence of only < 1-3% ○ BRCA2/BRCA1 are DNA repair genes ○ BRCA2 carriers have cumulative risk for prostate cancer of 16% vs. 3.8% for noncarriers ○ Hereditary breast and ovarian cancer syndrome (HBOC) – Caused by inherited mutation in BRCA2/BRCA1, and manifests clinically with mutation in other allele (Knudson "2-hit" hypothesis) – In women, mutations confer up to 87% lifetime risk of breast cancer and up to 54% risk of ovarian cancer – Men from families with women who had breast and ovarian cancers due to BRCA mutations have 5x relative risk for prostate cancer when they carry germline BRCA2 mutation • HOXB13-associated prostate cancer ○ Early-onset (< 55 years) FPC ○ Lifetime risk for prostate cancer ~ 33-60% ○ Found in 0.2% of population; higher in Europeans (0.8%) • Lynch syndrome has 5x ↑ risk for prostate cancers

Prostate Cancer Gleason Architectures (Left) Prostate cancer shows mixed Gleason patterns, including patterns 3 (wellformed glands ﬈), 4 (fused ﬊ and poorly formed ﬉ glands), and 5 (solid with rosette formation ﬈). This tumor is graded as Gleason score 4+5=9 (grade group 5). (Right) Anterior bone scan shows multiple bony metastases with relative sparing of distal appendicular skeleton. Only < 5% of prostate cancer is diagnosed with metastasis. Germline BRCA1/2 and ATM mutations are associated with higher grade and lethal tumors.

650

Prostate Cancer Bone Metastasis

Hereditary Prostate Cancer

Family History

Relative Risk (%)

Absolute Risk (%)

Negative

1

8

Father with prostate cancer at age ≥ 60 years

1.5

12

1 brother with prostate cancer at age ≥ 60 years

2

15

Father with prostate cancer at age < 60 years

2.5

20

1 brother with prostate cancer at age < 60 years

3

25

2 affected male relatives*

4

30

≥ 3 affected male relatives

5

35-45

*Father and brother, 2 brothers, a brother and a maternal grandfather or uncle, or a father and a paternal grandfather or uncle; from Bratt O et al.

Overview of Syndromes: Syndromes

Prostate Cancer Family History Effects on Lifetime Risk

Genes Associated With Increased Risk for Prostate Cancer Genes

Location

Risk for Prostate Cancer

Syndrome

BRCA1

17q21

1.07-3.81

Hereditary breast and ovarian cancer

BRCA2

13q12

3.18-8.6

Hereditary breast and ovarian cancer

Other DNA repair genes (ATM, CHEK2, RAD51, PALB2, BRIP1, NBN)

11q22, 22q12, 15q15, 8q21

HOXB13 (G84E)

17q21

2.8-8.47

Hereditary prostate cancer

DNA MMR genes (MLH1, MSH2, MSH6, PMS2)

3p21, 2p21, 2p16, 7p22

1.99-3.67

Lynch

TP53

17p13

Li-Fraumeni

2017 Philadelphia Prostate Cancer Consensus: Indications for Genetic Evaluation in Men With Prostate Cancer 1. From families meeting criteria for HBOC, HPC, and Lynch syndrome 2. Have ≥ 2 close blood relatives on same side of family having a cancer in the above syndromes (broader family history) 3. Have metastatic castration-resistant prostate cancer 4. Have tumor sequencing that shows mutations in cancer-susceptible genes

• Other DNA repair genes (e.g., ATM) also with ↑ risk for prostate cancer • Genome-wide association studies also identified ~ 100 loci associated with modest ↑ risk for prostate cancer

CLINICAL IMPLICATIONS Clinical Presentation • Preradical prostatectomy PSA level higher in HPC than in FPC and SPC • Clinical features and long-term oncological outcomes are similar postradical prostatectomy in patients with FPC, HPC, and SPC • Germline BRCA2/BRCA1 mutations confer more aggressive prostate cancer with high chance of nodal and distant metastasis and poor survival • Germline BRCA2/BRCA1 and ATM mutations are significantly higher in lethal (6%) than localized (1.4%) prostate cancer ○ Advanced prostate cancers have 8-12% germline mutations; may have better response to PARP inhibitors

PATHOLOGICAL FEATURES Gross and Microscopic Features • No established differences described in gross or microscopic features of tumors in FPC, HPC, and SPC • Multifocality, common trait for familial tumors in general, is frequent in SPCs

CANCER RISK MANAGEMENT BRCA Mutation • African American men and those with germline BRCA1/2 mutations may consider beginning shared decision-making about PSA screening at age 40 and at annual intervals (NCCN)

SELECTED REFERENCES 1.

2.

Giri VN et al: Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol. 36(4):414-24, 2018 Zhen JT et al: Genetic testing for hereditary prostate cancer: current status and limitations. Cancer. 124(15):3105-17, 2018

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Overview of Syndromes: Syndromes

Hereditary Renal Epithelial Tumors, Others

TERMINOLOGY Abbreviations • • • •

Clear cell renal cell carcinoma (CCRCC) Papillary renal cell carcinoma (PRCC) Chromophobe renal cell carcinoma (CHRCC) Renal oncocytoma (RO)

Definitions • Familial renal tumor ○ Families with ≥ 2 members within 2 generations with renal tumor and no evidence of known hereditary renal tumor syndrome ○ Reported mostly in CCRCC and also in PRCC, CHRCC, ROs, Wilms tumor, and some unique RCC subtypes in hereditary setting

CONSTITUTIONAL CHROMOSOME 3 TRANSLOCATION

Renal Tumor • CCRCC

Definition • Hereditary renal tumor characterized by chromosome (Chr) 3 translocation and predisposition for CCRCC

Synonym

FAMILIAL CCRCC Definition

• Familial non-VHL, nonpapillary, CCRCC

• Familial renal tumor with predisposition for CCRCC and no identifiable genetic factor

General Features

General Features

• Rare; so far 13 different constitutional translocations identified ○ 7 translocations associated with familial disease – t(3;8)(p14;q24), t(2;3)(q35;q21), t(3;6)(q12;q15), t(2;3)(q33;q21), t(1;3)(q32;q13.3), t(3;8)(p13;q24), and t(3;8)(p14;q24.1) – Candidate genes: FHIT, RNF139 (TRC8), DIRC1, DIRC2, DIRC3, HSPBAP1, LSAMP, RASSF5 (NORE1), KCNIP4, and FBXW7 • Affected individuals predisposed to multifocal and bilateral CCRCC • Lifetime risk in some families: > 80%; however, in absence of family history, Chr 3 translocation carriers are not at high risk of developing CCRCC

• Currently, diagnosis of exclusion of other hereditary causes of CCRCC ○ Exclude VHL disease, Chr 3 translocation, Birt-HoggDubé syndrome, and tuberous sclerosis complex • Rare; so far ~ 70 families with familial CCRCC reported with no identifiable genetic factor • May have multigenic inheritance mechanism • More common in males (M:F = 1.9:1.0) • Later onset compared to other familial renal tumors ○ 1 family member develops CCRCC between 50-70 years • Most patients present with solitary tumor • Suggested management dependent on size to renal tumor; observation if < 3 cm (similar to VHL patients)

Multifocal ROs (Left) Kidney shows multiple renal oncocytomas (ROs) st. A possible 4th tumor is encased in the larger RO ſt. RO is characterized by tumor cells with abundant eosinophilic cytoplasm and uniform round nuclei (inset). Multifocal ROs may occur in Birt-Hogg-Dubé syndrome and familial RO. (Right) Kidney shows a large well-circumscribed clear cell renal cell carcinoma (CCRCC) with central necrosis ſt and hemorrhage. Viable tumor at periphery retains the usual golden-yellow color st. The kidney contains smaller CCRCC nodules ﬇.

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• 2-5 affected family members • Patient age: 9-92 years old (median: 54; mean: 53) ○ Younger onset than sporadic CCRCC • M:F = 1.8:1.0 • "3-hit" model of tumorigenesis proposed ○ Germline Chr 3 translocation ○ Nondisjunctional loss of derivative chromosome carrying 3p segment ○ Somatic mutation in remaining 3p allele of ≥ 1 CCRCC tumor suppressor gene (e.g., VHL) • No known extrarenal manifestations, including those encountered in VHL ○ Few affected individuals (3%) also developed breast cancer • Annual surveillance not recommended unless there is personal or family history of CCRCC &/or tumor suppressor gene mutation

Multifocal CCRCCs

Hereditary Renal Epithelial Tumors, Others

Renal Tumor • CCRCC

BAP1 TUMOR PREDISPOSITION SYNDROME Definition • Hereditary autosomal disorder characterized by mutation in BAP1 and increased risks for mesothelioma, melanoma (uveal and cutaneous), renal cancer, possibly other cancers

General Features • Full spectrum still not identified • Risk of RCC ~ 10% • Somatic BAP1 mutation (seen in 8-14% of sporadic CCRCC) associated with higher tumor grade and poorer survival; unclear if also applies to germline BAP1 mutation

Renal Tumor • CCRCC

FAMILIAL NONCLEAR CELL RCC General Features • Familial renal tumor with no identifiable genetic factor, also described with PRCC and CHRCC • One report from NIH of 68 affected individuals with familial renal tumor included ○ 54% CCRCC (familial CCRCC) ○ 16% RO (familial RO) ○ 12% PRCC ○ 4% CHRCC

PTEN-HAMARTOMA TUMOR SYNDROME Definition • Hereditary autosomal disorder characterized by mutation in PTEN and development of hamartomas, macrocephaly, and ↑ risk for breast, endometrial, and thyroid cancers, and dermatologic conditions • Includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteuslike syndrome

General Features • > 70% of patients with Cowden syndrome have germline PTEN mutation • Higher risks for breast (85%) and thyroid cancer (~ 35%) • 34% risk for renal cancer; typical diagnosis ~ 40 years old • Also associated with prostate cancer

Renal Tumor • PRCC, CHRCC, and CCRCC • PTEN expression lost in tumor cells

PAPILLARY THYROID CARCINOMA WITH ASSOCIATED NEOPLASIA Definition • Inherited renal tumor syndrome characterized by papillary thyroid cancer, nodular thyroid disease, and renal tumor

General Features • Rare; ~ 5% of papillary thyroid carcinoma overall has familial association • Autosomal dominant inheritance with age-dependent penetrance • Women more affected than men • Linked to Chr 1q21 • Specific gene not yet identified; potential candidates include NRAS and NTRK1 • No germline mutations in MET protooncogene present

Renal Tumor • PRCC, multifocal papillary adenomas, and possibly renal oncocytoma

Overview of Syndromes: Syndromes

○ Conservative surgery, such as partial nephrectomy or enucleation if amenable

FAMILIAL RENAL ONCOCYTOMA Definition • Familial renal tumor with affected individuals predisposed to develop bilateral and multifocal ROs

General Features • Rare; described in ~ 30 families • 2-4 affected family members • Patient age: 38-83 years old (median: 49; mean: 55) ○ Younger onset than in sporadic renal oncocytoma • More common in males (M:F = 4:1) • Partial or complete loss of Chr 1 most frequent ○ Chromosomal changes less frequently observed compared to sporadic ROs • Most ROs detected incidentally or by screening of affected family members • For unclear reason, some patients develop renal insufficiency that progresses into end-stage kidney disease • Some affected individuals have pulmonary cysts; association unclear

Renal Tumor • Has benign outcome; no reported malignant transformation • Not known if affected individuals have predisposition for renal oncocytosis or hybrid oncocytic/chromophobe tumor

HEREDITARY HYPERPARATHYROIDISM-JAW TUMOR SYNDROME Definition • Hereditary autosomal dominant disorder characterized by functional parathyroid neoplasm and ossifying fibroma of jaw with increased risk for renal and uterine tumors

General Features • Very rare; largest study involved 19 affected family members ○ Patient age range: 3-63 years old • Autosomal dominant inheritance • Tumor suppressor gene identified as CDC73 (HRPT2) at Chr 1q25-31 and encodes for parafibromin protein • No germline mutations in MEN1 • May present with hypercalcemic crises • Parathyroid neoplasm often functional parathyroid adenoma that can be multifocal ○ ~ 15% may have parathyroid carcinoma 653

Overview of Syndromes: Syndromes

Hereditary Renal Epithelial Tumors, Others Hereditary or Familial Renal Tumor Syndromes Syndrome

Gene

Chromosome

Gene Product

Renal Tumor

von Hippel-Lindau

VHL

3p25-26

pVHL

CCRCC, clear cell PRCC, and clear cell tumorlets and microcysts

Constitutional chromosome 3 translocation

Unknown; candidate genes: Chr 3 FHIT, RNF139 (TRC8), DIRC1, DIRC2, DIRC3, HSPBAP1, LSAMP, RASSF5 (NORE1), KCNIP4, and FBXW7

Unknown

CCRCC

Familial CCRCC

Unknown

Unknown

Unknown

CCRCC

BAP1 tumor syndrome

BAP1

3p21

BAP1 proteins

CCRCC

Hereditary papillary RCC

MET

7q31

MET

PRCC type 1

PTEN-hamartoma tumor syndrome

PTEN

10q22-23

PTEN

PRCC, CCRCC, and chromophobe RCC

Papillary thyroid carcinoma with associated neoplasia

Unknown; potential candidate genes: NRAS and NTRK1

1q21

Unknown

PRCC and papillary adenoma; possibly renal oncocytoma

Birt-Hogg-Dubé

FLCN or BHD

17p11.2

Folliculin

Hybrid oncocytic/chromophobe tumor, renal oncocytoma, renal oncocytosis, chromophobe RCC, and CCRCC

Familial oncocytoma

Unknown

Unknown

Unknown

Renal oncocytoma (association with renal oncocytosis or hybrid oncocytic/chromophobe tumor not known)

Hereditary leiomyomatosis and renal cancer

FH

1q42-43

Fumarate hydratase

Hereditary leiomyomatosis and renal cancer-associated RCC or FHdeficient RCC

Succinate dehydrogenase B-associated hereditary paraganglioma/pheochromocytoma

SDHA, SDHB, SDHC, SDHD, and SDHAF2 (SDH5)

1p36

SDHA, SDHB, SDHC, SDHD and SDH AF2 (SDH5)

SDH-deficient RCC

Tuberous sclerosis 1

TSC1

9q34

Hamartin

Angiomyolipoma, CCRCC, eosinophilic solid and cystic RCC, and benign epithelial cyst

Tuberous sclerosis 2

TSC2

16p13.3

Tuberin

Hereditary hyperparathyroidism-jaw tumor syndrome

CDC73 (HRPT2)

1q21-32

Parafibromin

Mixed epithelial and stromal tumor, Wilms tumor, PRCC, renal cortical adenoma, and benign epithelial cysts

CCRCC = clear cell renal cell carcinoma; FH = fumarate hydratase; PRCC = papillary renal cell carcinoma; SDH = succinate dehydrogenase.

• ~ 75% may have uterine neoplasm, such as adenofibromas, leiomyomas or adenomyosis, or adenosarcomas • ~ 15% may have renal tumors • Patients may also have renal hamartomas or polycystic kidney disease

3. 4. 5. 6.

Renal Tumor • Mixed epithelial and stromal tumor, Wilms tumor, PRCC, renal cortical adenoma, benign epithelial cysts

SELECTED REFERENCES 1. 2.

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Carlo MI et al: Familial kidney cancer: implications of new syndromes and molecular insights. Eur Urol. ePub, 2019 Maher ER: Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management. World J Urol. 36(12):1891-8, 2018

7.

8.

Moch H et al: Morphological clues to the appropriate recognition of hereditary renal neoplasms. Semin Diagn Pathol. 35(3):184-92, 2018 Peng YC et al: Recognizing hereditary renal cancers through the microscope: a pathology update. Surg Pathol Clin. 11(4):725-37, 2018 Kallinikas G et al: Renal cell cancers: unveiling the hereditary ones and saving lives-a tailored diagnostic approach. Int Urol Nephrol. 49(9):1507-12, 2017 Adeniran AJ et al: Hereditary renal cell carcinoma syndromes: clinical, pathologic, and genetic features. Am J Surg Pathol. 39(12):e1-18, 2015 Przybycin CG et al: Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens. Adv Anat Pathol. 20(4):245-63, 2013 Shuch B et al: The surgical approach to multifocal renal cancers: hereditary syndromes, ipsilateral multifocality, and bilateral tumors. Urol Clin North Am. 39(2):133-48, v, 2012

Hereditary Renal Epithelial Tumors, Others Multifocal Clear Cell Renal Tumors and Cysts (Left) CCRCC typically shows tumor cells with clear cytoplasm because of lipid and glycogen contents. Tumor cells are arranged in solid nests separated by intricate meshwork of delicate vasculatures imparting a chicken-wire appearance. (Right) Kidney section shows CCRCC ﬈ and smaller clear cell tumors ﬉ and cyst ﬊. Multifocal and bilateral CCRCCs are common in hereditary RCCs such as VHL and in constitutional chromosome 3 translocation patients. Familial CCRCC tends to present with solitary tumor.

Multifocal Papillary RCCs and Adenomas

Overview of Syndromes: Syndromes

CCRCC

Parathyroid Adenoma (Left) Kidney shows a PRCC type 1 ﬈ and several papillary adenomas ﬉. Papillary adenoma is unencapsulated with low-grade nuclei and should not be > 15 mm in size. Multiple adenomas and PRCC type 1 can be seen in papillary thyroid carcinoma with associated neoplasia. (Right) Tc-99m MIBI shows parathyroid adenoma ﬈ inferior to the inferior pole of the right thyroid lobe ﬉. Activity is also evident in salivary glands ﬊. Gross specimen shows encapsulated brown-tan parathyroid adenoma.

Ossifying Fibroma

Thyroid Carcinoma (Left) Coronal bone CT demonstrates a very large, bilobed, ossifying fibroma (OF) with a large maxillary antral portion and smaller component extending into the buccal space ﬇. Peripheral ossification ſt of the maxillary component is noted. OF can occur with renal tumors in hereditary hyperparathyroidism-jaw tumor syndrome. (Right) Coronal graphic illustrates a left thyroid lobe differentiated thyroid carcinoma ﬇ with metastatic nodal disease in the left paratracheal chain ſt and superior mediastinum st.

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Overview of Syndromes: Syndromes

Hereditary Retinoblastoma

TERMINOLOGY Definition • Familial cancer syndrome with predisposition for retinoblastoma development, often multiple, and other cancers resulting from germline mutations in tumor suppressor gene RB1

EPIDEMIOLOGY Retinoblastoma • Most common intraocular malignancy in children ○ Incidence: 1 in 15,000-34,000 births ○ No gender or ethnic predilection • ~ 40% of retinoblastomas are hereditary and due to germline mutations in RB1

GENETICS Germline Mutations in RB1 • Located at chromosomal region 13q14 • 5-10% of retinoblastomas inherited in autosomal dominant fashion • Autosomal dominant inheritance with high penetrance ○ 60-80% of carriers develop retinoblastomas • RB1 encodes for ubiquitously expressed nuclear protein ○ Important role in cell cycle control, cellular differentiation, and survival ○ Undergoes phosphorylation in cell cycle-dependent fashion ○ Regulator of restriction (R) point of cell cycle – Unphosphorylated (active) in G₀ → hypophosphorylated in G₁ → hyperphosphorylated (inactive) as cell passes through R point → dephosphorylated (reactivated) by PP1 phosphatase at M/G₁ transition • 13q-deletion syndrome (< 5% of retinoblastomas) ○ Retinoblastoma in association with moderate growth and intellectual disability, facial abnormalities, microphthalmia, cardiac anomalies, anal atresia, colobomas, cataracts, and muscle hypotonia

• Germline RB1 mutations in 25% of retinoblastoma patients without family history (i.e., new mutations) ○ Progeny may be affected • Polymorphisms in other genes may affect risk for retinoblastoma development (e.g., MDM2, MDM4)

Somatic Mutations in RB1 • Reported in sarcomas, small-cell lung carcinoma, bladder carcinoma, gliomas, and breast carcinoma • Promoter hypermethylation (epigenetic inactivation) in astrocytomas and lymphoma subsets

Knudson "2-Hit" Hypothesis • Model for classic tumor suppressor genes • 2 inactivating mutations required for tumor development • 1st mutation may be either somatic (sporadic) or germinal (inherited) • 2nd mutation is somatic

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Presentation and Complications • Earlier age of presentation for hereditary retinoblastoma ○ Mean age at presentation of sporadic retinoblastoma: 18-24 months ○ Mean age at presentation of hereditary retinoblastoma: 12 months • Sporadic retinoblastoma is usually unilateral, whereas hereditary retinoblastoma is often bilateral (~ 60%) • Increased risk for 2nd primary tumors, particularly craniofacial locations ○ ~ 70% of 2nd primaries develop in irradiation field or at boundary ○ Median age of presentation: 13 years for craniofacial location, but risk continues through life ○ Risk highest for patients receiving external beam radiotherapy in 1st year of life ○ Addition of chemotherapy also increases risk ○ Extent of resection important prognostic factor

Cut Surface of Eye With Retinoblastoma (Left) Retinoblastomas may form large masses and occupy a significant intraocular volume. They classically demonstrate a white reflection on ophthalmologic exam, leading to the classic sign known as leukocoria. (Right) Retinoblastoma is a proliferative tumor with frequent necrosis ﬈, centered in the retina. It is the main tumor developing in patients with germline RB1 mutations.

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Retinoblastoma: Microscopic Overview

Hereditary Retinoblastoma

MICROSCOPIC FINDINGS Retinoblastoma • Small round blue cell tumor ○ Evidence of retinoblastic differentiation: FlexnerWintersteiner rosettes and fleurettes ○ Homer Wright (neuroblastic) rosettes may also be present ○ Necrosis and calcifications common ○ May invade optic nerve and secondarily brain and CSF

• Bone sarcomas: Osteosarcoma (most common), chondrosarcoma, and Ewing sarcoma • Soft tissue tumors ○ Pathologic subtypes include leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, pleomorphic sarcoma, and liposarcoma/lipomatous tumors – Leiomyosarcoma most common pathology in some studies – Majority of leiomyosarcomas in women are uterine (i.e., outside of radiation field) – Most of nonleiomyosarcoma soft tissue tumors in radiation field

Others • Melanoma of skin; carcinomas of bladder, lung, upper respiratory tract, and skin; tumors of central nervous system/meningiomas

Overview of Syndromes: Syndromes

• 2nd primary tumors are leading cause of death in hereditary retinoblastoma patients in developed countries ○ Higher risk of 2nd primary malignancies in patients with recurrent nonsense RB1 mutations compared with low penetrance mutations in some studies ○ No significant increase in mortality due to nonneoplastic disorders

SELECTED REFERENCES ASSOCIATED NEOPLASMS

1.

Retinoma/Retinocytoma • Composed entirely of photoreceptor differentiation ○ Lacks mitotic activity and necrosis • Usually benign, but may develop malignant transformation into retinoblastoma • Inactivation of both RB1 copies, but lacks additional alterations typical of retinoblastoma

Pineoblastoma/CNS PNET • Part of "trilateral" retinoblastoma syndrome (bilateral retinoblastoma + pineoblastoma or suprasellar PNET) • Occurs in < 1% of patients with retinoblastoma • Intracranial tumor frequently (~ 80%) in pineal region = pineoblastoma ("3rd eye")

Soft Tissue and Bone Sarcomas • Susceptibility secondary to germline predisposition (i.e., RB1 mutations) and radiation therapy • Encompass ~ 1/2 of 2nd cancers in survivors of hereditary retinoblastoma

Retinoblastoma: Morphological Appearance

Kleinerman RA et al: Patterns of cause-specific mortality among 2053 survivors of retinoblastoma, 1914-2016. J Natl Cancer Inst. 111(9):961-9, 2019 2. Kamihara J et al: Retinoblastoma and neuroblastoma predisposition and surveillance. Clin Cancer Res. 23(13):e98-106, 2017 3. de Jong MC et al: The incidence of trilateral retinoblastoma: A systematic review and meta-analysis. Am J Ophthalmol. 160(6):1116-26.e5, 2015 4. Wong JR et al: Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol. 32(29):3284-90, 2014 5. Maccarthy A et al: Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer. 108(12):2455-63, 2013 6. Rodjan F et al: Second cranio-facial malignancies in hereditary retinoblastoma survivors previously treated with radiation therapy: clinic and radiologic characteristics and survival outcomes. Eur J Cancer. 49(8):1939-47, 2013 7. Kleinerman RA et al: Sarcomas in hereditary retinoblastoma. Clin Sarcoma Res. 2(1):15, 2012 8. Yu CL et al: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst. 101(8):581-91, 2009 9. Antoneli CB et al: Trilateral retinoblastoma. Pediatr Blood Cancer. 48(3):30610, 2007 10. O'Neill JK et al: An association of multiple well differentiated liposarcomas, lipomatous tissue and hereditary retinoblastoma. Sarcoma. 9(3-4):151-6, 2005

Retinoblastoma: Histological Features (Left) Homer Wright rosettes ſt are characterized by an acellular delicate eosinophilic core and may be encountered in retinoblastomas, although they are not specific. (Right) Retinoblastoma is histologically a round blue cell tumor, highly cellular, and composed of sheets or nests of proliferative neoplastic cells. The tumor is usually solid with multifocal vascular proliferation and focal necrosis.

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Overview of Syndromes: Syndromes

Hereditary SWI/SNF Complex Deficiency Syndromes

TERMINOLOGY

MICROSCOPIC

Genetic Syndromes Resulting From Mutations in Gene-Encoding Protein Members of SWI/SNF Complex • SWI/SNF: "SWitching defective/Sucrose NonFermenting" • SMARCB1, SMARCA4, SMARCA2, SMARCE1, PBRM1

ETIOLOGY/PATHOGENESIS SWI/SNF Complex Alters Chromatin Configuration • Evolutionarily conserved tumor suppressor family • Multiple cell functions, including regulation of chromatin dynamics and gene transcription • Mutations result in profound epigenetic effects • Germline mutations associated with predisposition to variety of neoplasms usually, but not always, with variable rhabdoid components • Predisposition to developmental disorders (Coffin-Siris syndrome)

CLINICAL IMPLICATIONS Clinical Variants of SWI/SNF Complex Deficiency Syndromes • Rhabdoid tumor predisposition syndrome ○ Type 1: Rhabdoid tumors of CNS [atypical teratoid rhabdoid tumor (ATRT)], kidney, and other sites (SMARCB1/INI1 deficiency) ○ Type 2: Rhabdoid tumors of CNS (ATRT), kidney, and other sites, and small-cell carcinoma of ovary, hypercalcemic type (SMARCA4/BRG1 deficiency) • Familial schwannomatosis ○ Germline SMARCB1 mutations ○ Meningiomas may be present • Multiple familial meningiomas ○ Spinal location, clear cell subtype, SMARCE1 loss • Hereditary renal cell carcinoma (RCC) ○ Clear cell RCC, PBRM1 loss

General Features • General unifying features of associated neoplasms ○ Cell monotony, little pleomorphism ○ Variable rhabdoid morphology (but may be absent) ○ Pankeratin- and vimentin-positive inclusions ○ Loss of deficient SWI/SNF protein in neoplastic cells but retained in nonneoplastic elements (vessels, stromal cells) • Specific neoplasms ○ Rhabdoid tumors (kidney, CNS, gastrointestinal tract, soft tissue) ○ Schwannomas, meningiomas ○ Epithelioid malignant peripheral nerve sheath tumor (MPNST) – Somatic inactivating mutations in SMARCB1 in most cases – May develop in schwannoma precursors sporadically or in schwannomatosis patients ○ Small-cell carcinoma of ovary, hypercalcemic type – Most common undifferentiated malignant ovarian tumor in women < 40 years of age – Germline or somatic SMARCA4 mutations in almost all cases – SMARCA4-deficient uterine sarcomas have overlapping features and may develop in families with germline mutations

SELECTED REFERENCES 1.

2. 3.

4.

Lin DI et al: SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association. Mod Pathol. ePub, 2019 Agaimy A et al: Hereditary SWI/SNF complex deficiency syndromes. Semin Diagn Pathol. 35(3):193-8, 2018 Agaimy A et al: SWI/SNF complex-deficient undifferentiated/rhabdoid carcinomas of the gastrointestinal tract: a series of 13 cases highlighting mutually exclusive loss of SMARCA4 and SMARCA2 and frequent coinactivation of SMARCB1 and SMARCA2. Am J Surg Pathol. 40(4):544-53, 2016 Fahiminiya S et al: Molecular analyses reveal close similarities between small cell carcinoma of the ovary, hypercalcemic type and atypical teratoid/rhabdoid tumor. Oncotarget. 7(2):1732-40, 2016

Atypical Teratoid Rhabdoid Tumor (Left) Atypical teratoid rhabdoid tumor (ATRT) is the main CNS manifestation of rhabdoid tumor predisposition syndrome (a SWI/SNF complex deficiency disorder). (Right) Rhabdoid morphology, illustrated here in an ATRT, is a variable feature of the SWI/SNF complex deficiencyassociated tumors. Rhabdoid cells predominate in this example.

658

Rhabdoid Morphology

Hereditary SWI/SNF Complex Deficiency Syndromes

Cellular Schwannoma in Schwannomatosis (Left) Multiple spinal schwannomas ﬇ are frequent in schwannomatosis patients, as in this SMARCB1associated case. (Right) This cellular schwannoma lacking Verocay bodies and an Antoni B pattern contained a SMARCB1 mutation.

Epithelioid Malignant Peripheral Nerve Sheath Tumors

Overview of Syndromes: Syndromes

SMARCB1-Related Schwannomatosis

INI1 Loss in MPNST (Left) Epithelioid malignant peripheral nerve sheath tumors (MPNST) frequently have somatic SMARCB1 mutations. However, this morphology may also be present in schwannomas with malignant transformation, including those developing in schwannomatosis. (Right) Loss of expression of INI1 in neoplastic cells is shown in epithelioid MPNST.

Follicle-Like Spaces

Loss of SMARCA4 Expression (Left) The follicle-like spaces ﬈ in small-cell carcinoma of the ovary, hypercalcemic type, are seen in ~ 80% of tumors, vary in size and shape, and are not very numerous. Granulosa cell tumor, the most common DDx, tends to have more follicles, which are lined by granulosa and often theca cells. (Right) Small-cell carcinoma, hypercalcemic type, is associated with loss of SMARCA4 in the vast majority, and this staining pattern is both sensitive and specific for this diagnosis. Loss of expression correlates with SMARCA4 mutation.

659

Overview of Syndromes: Syndromes

Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer ○ Can be either focal or diffuse • Squamous cell carcinoma

TERMINOLOGY Synonyms • • • • • • •

Howel-Evans syndrome Clarke-Howell-Evans-McConnell syndrome Bennion-Patterson syndrome Tylosis with esophageal cancer Keratosis palmares and plantares with esophageal cancer Palmoplantar keratoderma with esophageal cancer OMIM 148500

EPIDEMIOLOGY Age at Presentation • Cutaneous features are evident by 7-8 years of age • Esophageal cancer presents in mid 50s

Incidence • < 1 in 1 million

GENETICS Inheritance • Autosomal dominant  ○ With complete penetrance • Missense mutation in RHBDF2 (rhomboid family member 2) ○ On 17q25.1 ○ RHBDF2 protein is member of intramembranous serine proteases ○ Regulate secretion of epidermal growth factor receptor  ○ May play role in epithelial response to injury in skin and esophagus

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Cutaneous Findings

Oral Findings • Oral leukoplakia • Teeth ○ Premature loss ○ Poor dental enamel

Classification • Epidermolytic (Vorner type) and nonepidermolytic in one classification • Divided into type A and type B in another classification ○ Type A: Tylosis, affected patients of 5-15 years, strongly associated with esophageal carcinoma ○ Type B: Affected patients during 1st year of life, benign

ASSOCIATED NEOPLASMS Esophageal Cancer • Present at mean age of 45 years • 95% of developing carcinoma by age 65

CANCER RISK MANAGEMENT Esophageal Cancer • Surveillance and early detection of esophageal dysplasia from age 20 • ~ 70% of individuals with palmoplantar keratoderma develop esophageal carcinoma

Acquired Palmoplantar Keratoderma as Paraneoplastic Phenomenon • Negative family history

Plantar Eratoderma

660

• Gastroesophageal reflux disease • 2-5 mm white and polypoid lesions throughout esophagus • Very high lifetime risk of developing esophageal squamous cell carcinoma

DIFFERENTIAL DIAGNOSIS

• Palmoplantar keratoderma ○ Thickening of skin of hands and feet  ○ Over areas of pressure and friction ○ Can affect palms, soles, or both

(Left) Clinical photograph illustrates the skin thickening over the sole, an area of pressure and friction, characteristic of plantar keratoderma. The histopathology of keratoderma is characterized by marked hyperkeratosis. (Courtesy L. Milstone, MD.) (Right) Adjacent to the benign squamous epithelium, a proliferation of atypical keratinocytes is seen within the epithelium and extending into the underlying soft tissue and muscle.

Gastrointestinal Symptoms/Findings

Esophageal Squamous Cell Carcinoma

Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer

Focal Palmoplantar and Oral Mucosa Hyperkeratosis Syndrome • • • •

Autosomal dominant Palmoplantar keratoderma  Oral leukoplakia Absence of association with esophageal carcinoma

Dyskeratosis Congenita • X-linked recessive • Mutation in DKC1 that encodes dyskerin • Triad of ○ Oral leukoplakia ○ Nail dystrophy ○ Reticular hyperpigmentation/poikiloderma • Increased risk of developing squamous cell carcinoma of following organs ○ Oropharynx ○ Esophagus ○ Bronchus ○ Rectum ○ Cervix and vagina • Increased risk of developing following hematologic malignancies  ○ Myelodysplasia ○ Acute myelogenous leukemia ○ Hodgkin disease

Pachyonychia Congenita • • • • • •

Autosomal dominant Mutations in KRT6, KRT16, and KRT17 Palmoplantar keratoderma Oral leukoplakia Thickened nails Some associated with steatocystoma multiplex

Hidrotic Ectodermal Dysplasia • Clouston syndrome • Autosomal recessive • Mutation in GJB6 on 13q12  ○ GJB6 encodes gap junction protein connexin 30 • Triad of ○ Alopecia ○ Nail dystrophy ○ Palmoplantar keratoderma

Nonepidermolytic Palmoplantar Keratoderma • Diffuse nonepidermolytic palmoplantar keratoderma with frequent fungal infection • Autosomal dominant • Mutation in AQP5 (aquaporin 5)

• Palmoplantar keratodermas with other associated findings ○ Olmsted syndrome – Periorificial keratotic plaques and bilateral palmoplantar keratoderma ○ Richner-Hanhart syndrome – Oculocutaneous tyrosinemia – Deficiency of tyrosine aminotransferase enzyme ○ Carvajal syndrome – Striate palmoplantar keratoderma with wooly hair and cardiomyopathy – Defect in desmoplakin gene

Schopf-Schulz-Passarge Syndrome • Autosomal recessive • Associated with WNT10A • a.k.a. eyelid cysts, palmoplantar keratoderma, hypodontia, and hypotrichosis • Punctate symmetric palmoplantar keratoderma • Begin at age 12 • Keratoderma and fragility of nails • Hypodontia, hypotrichosis, nail dystrophies, and eyelid cysts

Overview of Syndromes: Syndromes

• Palmoplantar keratoderma is acquired later in life

CRITERIA FOR DIAGNOSIS Tylosis and Esophageal Cancer • Positive family history of tylosis and esophageal cancer • Onset of cutaneous palmar and plantar hyperkeratosis after birth but before puberty • Esophageal lesions and squamous cell carcinoma of esophagus • Mutation in RHBDF2

SELECTED REFERENCES 1.

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6.

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Jenkins LE et al: A survey study with assessment of esophageal screening and genetic counseling in patients with Howel-Evans syndrome. Dermatol Online J. 24(6), 2018 Ellis A et al: Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms. Orphanet J Rare Dis. 10:126, 2015 Blaydon DC et al: RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet. 90(2):340-6, 2012 Grundmann JU et al: Lung carcinoma with congenital plantar keratoderma as a variant of Clarke-Howel-Evans syndrome. Int J Dermatol. 42(6):461-3, 2003 Kelsell DP et al: Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC). Hum Mol Genet. 5(6):857-60, 1996 Stevens HP et al: Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch Dermatol. 132(6):640-51, 1996 Schöpf E et al: Syndrome of cystic eyelids, palmo-plantar keratosis, hypodontia and hypotrichosis as a possible autosomal recessive trait. Birth Defects Orig Artic Ser. 7(8):219-21, 1971 Howel-Evans W et al: Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis): a study of two families. Q J Med. 27(107):413-29, 1958

Other Palmoplantar Keratodermas • Only inherited palmoplantar keratodermas with no other associated findings ○ Vorner syndrome – Mutation of KRT9 – a.k.a. epidermolytic palmoplantar keratoderma ○ Unna-Thorst syndrome – Diffuse nonepidermolytic palmoplantar keratoderma – Thorst-Unna disease 661

Overview of Syndromes: Syndromes

Hyperparathyroidism-Jaw Tumor Syndrome

TERMINOLOGY

ETIOLOGY/PATHOGENESIS

Abbreviations

Mutation of CDC73 on 1q25-q31

• Hyperparathyroidism-jaw tumor syndrome (HPT-JT)

• Autosomal dominant • Inactivating mutation of tumor suppressor gene CDC73 ○ 80% of mutations are truncating (frameshift and nonsense), most involve exon 1 • CDC73-related disorders ○ CDC73 transcript spans 2.7 kb ○ CDC73 protein binds RNA polymerase II as part of PAF1 transcriptional regulatory complex, mediates H3K9 methylation that silences expression of cyclin-D1 ○ CDC73 mutation present in familial predisposition to parathyroid carcinoma (as with HPT-JT and familial isolated hyperparathyroidism) ○ CDC73 protein regulates gene expression and inhibits cell proliferation ○ Somatic-inactivating CDC73 mutations in some sporadic parathyroid carcinomas

Synonyms • Familial cystic parathyroid adenomatosis

Definitions • Autosomal dominant disorder characterized by parathyroid adenoma or carcinoma, ossifying fibromas of jaw bones, renal cysts and tumors, and hamartomas resulting from inactivating mutations in CDC73 (HRPT2)

EPIDEMIOLOGY Incidence • First described in 1990; only ~ 40 families have been reported to date • Exact incidence unknown

Mitotic Figures in Parathyroid Carcinoma

This parathyroid carcinoma is hypercellular and is formed by solid sheets of cells with round nuclei. Both parathyroid adenoma and carcinoma are hypercellular. Many mitoses ﬈ and atypical mitoses are seen in carcinomas. The diagnosis of parathyroid carcinoma requires invasion (capsular, vascular, perineural, into adjacent structures) or metastases.

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Hyperparathyroidism-Jaw Tumor Syndrome

• • •

CLINICAL IMPLICATIONS Clinical Presentation • Hyperparathyroidism ○ 80% of HPT-JT patients present with hyperparathyroidism ○ Hyperparathyroidism usually develops in late adolescence ○ More aggressive course with severe hypercalcemia and higher incidence of parathyroid carcinoma ○ Penetrance of hyperparathyroidism is 80% ○ Parathyroid adenoma or carcinoma ○ 15% of patients with HPT-JT develop parathyroid carcinoma ○ Germline CDC73 mutations identified in subset of patients with CDC73 mutation-positive carcinomas • Jaw tumors ○ Well-demarcated osseous lesion (ossifying fibroma) of mandible or maxilla • Other features reported include renal cysts, hamartomas, Wilms tumor, and papillary thyroid carcinoma

Treatment • Surgery

Prognosis • Majority of patients with adenoma can be cured by surgery • Guarded once parathyroid carcinoma confirmed 

IMAGING General Features • Parathyroid ○ Tc-99m sestamibi scintigraphy or sonography identifies location but does not separate adenoma from carcinoma ○ Mass noted on CT and MR, often no specific features • Ossifying fibroma ○ Radiography: Well-demarcated, expansile mass with mixed soft tissue density central area surrounded by ossified rim

○ Bone scan: Increased uptake of affected bones

MACROSCOPIC General Features • Parathyroid adenoma or carcinoma usually presents as single enlarged parathyroid gland ○ Parathyroid adenoma is single enlarged gland, tan to pink-tan, encapsulated, ± rim of normal tissue – Vary in size: < 1 cm to > 10 cm; weight: 0.2 g to > 1.0 g – Cystic change may occur in adenomas, particularly larger adenomas, and in those with HPT-JT syndrome – Larger adenomas may show fibrosis, hemosiderin, cystic degeneration, and calcification ○ Parathyroid carcinomas may be large, firm, and variably encapsulated, poorly circumscribed – Large tumors (mean: 6.7 g; range: 1.5 to > 50 g); generally larger than adenomas, but overlap in size – Lobulated appearance due to thick, fibrous bands – May be grossly encapsulated and resemble adenoma – Firm tumors may be adherent to or invasive into adjacent structures – Caution as large parathyroid adenomas, especially with cystic change, can become fibrotic and adhere to adjacent structures • Ossifying fibroma gross pathology shows classic appearance of tumor with central pink-yellow area of fibrous tissue surrounded by pale yellow, dense, peripheral ossified tissue

Overview of Syndromes: Syndromes

•

– Up to 75% CDC73 inactivation, but may be higher as mutations may be outside of coding region sequenced in clinical testing and some research studies – Germline CDC73 mutations present in substantial minority (20%) of clinically sporadic-appearing parathyroid carcinoma – Additional genes may be involved for malignant behavior □ CCND1 overexpressed in many parathyroid carcinomas CDC73 encodes protein known as parafibromin (CDC73) ○ Germline CDC73 mutations identified in subset of patients with mutation-positive carcinomas thought to be sporadic CDC73 has strong association with mutation in familial and sporadic parathyroid carcinoma CDC73 mutation uncommon in sporadic adenomas but identified in 20% of sporadic cystic adenomas HPT-JT associated with parathyroid adenoma or carcinoma, ossifying fibromas of jaw bones, renal cysts and tumors, and hamartoma

MICROSCOPIC General Features • Hyperparathyroidism ○ Caused by adenoma or carcinoma ○ Cystic changes ○ Both parathyroid adenoma and carcinoma are hypercellular – Mitoses may be seen in both adenoma and carcinoma but more mitoses in carcinoma than adenoma – Atypical mitoses generally seen only in carcinoma – Fibrous bands can be seen in both adenoma and carcinoma – Diagnosis of parathyroid carcinoma requires invasion (capsular, vascular, perineural, into adjacent structures) or metastases • Ossifying fibroma of jaw ○ Microscopically, densely cellular, well-defined fibrous tumor that ossifies beginning at periphery ○ Tumor composed of dense, relatively avascular fibroblast-rich stroma and irregular spicules of woven bone with osteoblastic rimming

ANCILLARY TESTS Immunohistochemistry • Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and HPT-JT syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias

Genetic Testing • DNA-based sequencing on CDC73 663

Overview of Syndromes: Syndromes

Hyperparathyroidism-Jaw Tumor Syndrome • CDC73 mutation (tumor suppressor gene, 1q21-q31), encodes CDC73/parafibromin protein ○ Strong association with CDC73 mutation in familial and sporadic parathyroid cancer – 15% of patients with HPT-JT (caused by germine CDC73 inactivating mutation) develop parathyroid carcinoma – Germline CDC73 mutations identified in subset of patients with mutation-positive carcinomas □ Consider genetic testing in patients with parathyroid carcinoma □ Substantial minority of clinically sporadic parathyroid carcinomas may have germline mutation □ Up to 75% of parathyroid carcinomas have CDC73 inactivation □ Clinical testing may not identify all mutations; inactivating CDC73 mutations may be located outside coding region evaluated ○ CDC73 mutation uncommon in sporadic adenomas but identified in 20% of sporadic cystic parathyroid adenoma (possibly HPT-JT related) – Somatic CDC73 mutations are common in sporadic parathyroid carcinomas and rare in sporadic adenomas but can be seen in adenomas in setting of HPT-JT syndrome ○ Complete loss of parafibromin (CDC73) protein expression helpful in separating parathyroid carcinoma from adenoma; however, parafibromin expression may be lost in parathyroid adenomas associated with germline CDC73 mutations

Serologic Testing • Blood test measuring ionized calcium and iPTH

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DIFFERENTIAL DIAGNOSIS Multiple Endocrine Neoplasia Type 1 • Characterized with hyperparathyroidism, pituitary adenoma, and pancreatic endocrine tumors caused by inactivation of MEN1 gene • Hyperparathyroidism in MEN1 is caused by multiglandular parathyroid hyperplasia in contrast to solitary adenoma or carcinoma in HPT-JT syndrome

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Parathyroid Carcinoma  • Hereditary syndromes associated with parathyroid carcinoma include ○ HPT-JT syndrome and MEN1 and MEN2 syndromes ○ Nonsyndromic familial isolated primary hyperparathyroidism, which may be clinically difficult to distinguish from MEN1 and HPT-JT syndromes 

Fibrous Dysplasia • Caused by activating missense mutations of GNAS, which is benign bone tumor composed of woven bone and fibrous tissue in background • In contrast to ossifying fibroma, fibrous dysplasia lacks osteoblastic rimming of woven bone

SELECTED REFERENCES 1.

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Cetani F et al: Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer. ePub, 2019

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Cetani F et al: Parathyroid carcinoma. Front Horm Res. 51:63-76, 2019 Cetani F et al: Familial and hereditary forms of primary hyperparathyroidism. Front Horm Res. 51:40-51, 2019 Gill AJ et al: Parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol. 43(1):35-46, 2019 Marx SJ et al: Evolution of our understanding of the hyperparathyroid syndromes: a historical perspective. J Bone Miner Res. 34(1):22-37, 2019 Vocke CD et al: CDC73 germline mutation in a family with mixed epithelial and stromal tumors. Urology. 124:91-7, 2019 Bachmeier C et al: Should all patients with hyperparathyroidism be screened for a CDC73 mutation? Endocrinol Diabetes Metab Case Rep, 2018 Cristina EV et al: Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 32(6):861-75, 2018 DeLellis RA et al: Heritable forms of primary hyperparathyroidism: a current perspective. Histopathology. 72(1):117-32, 2018 El Lakis M et al: Probability of positive genetic testing results in patients with family history of primary hyperparathyroidism. J Am Coll Surg. 226(5):933-8, 2018 Kapur A et al: A young male with parafibromin-deficient parathyroid carcinoma due to a rare germline HRPT2/CDC73 mutation. Endocr Pathol. 29(4):374-9, 2018 Koikawa K et al: Hyperparathyroidism-jaw tumor syndrome confirmed by preoperative genetic testing. Intern Med. 57(6):841-4, 2018 Salcuni AS et al: Parathyroid carcinoma. Best Pract Res Clin Endocrinol Metab. 32(6):877-89, 2018 Cardoso L et al: Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. Hum Mutat. 38(12):1621-48, 2017 Guarnieri V et al: Large intragenic deletion of CDC73 (exons 4-10) in a threegeneration hyperparathyroidism-jaw tumor (HPT-JT) syndrome family. BMC Med Genet. 18(1):83, 2017 Marx SJ et al: Familial hyperparathyroidism - disorders of growth and secretion in hormone-secretory tissue. Horm Metab Res. 49(11):805-15, 2017 Pandya C et al: Genomic profiling reveals mutational landscape in parathyroid carcinomas. JCI Insight. 2(6):e92061, 2017 Satpathy AS et al: Osteitis fibrosa cystica of mandible in hyperparathyroidism-jaw tumor syndrome: a rare presentation and review of literature. Natl J Maxillofac Surg. 8(2):162-6, 2017 Simonds WF: Genetics of hyperparathyroidism, including parathyroid cancer. Endocrinol Metab Clin North Am. 46(2):405-18, 2017 van der Tuin K et al: CDC73-related disorders: clinical manifestations and case detection in primary hyperparathyroidism. J Clin Endocrinol Metab. 102(12):4534-40, 2017 Chen Y et al: CDC73 gene mutations in sporadic ossifying fibroma of the jaws. Diagn Pathol. 11(1):91, 2016 Thakker RV: Genetics of parathyroid tumours. J Intern Med. 280(6):574-83, 2016 DeLellis RA: Parathyroid tumors and related disorders. Mod Pathol. 24 Suppl 2:S78-93, 2011 Zhang Y et al: Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 18(3):206-18, 2011 Juhlin CC et al: Parafibromin as a diagnostic instrument for parathyroid carcinoma-lone ranger or part of the posse? Int J Endocrinol. 2010:324964, 2010 Wang P et al: Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice. Mol Cell Biol. 28(9):2930-40, 2008 Carpten JD et al: HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 32(4):676-80, 2002 Szabó J et al: Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am J Hum Genet. 56(4):944-50, 1995 Jackson MA et al: CDC73-related disorders, 1993 Jackson CE et al: Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery. 108(6):100612; discussion 1012-3, 1990

Hyperparathyroidism-Jaw Tumor Syndrome

Ossifying Fibroma (Left) Axial bone CT shows a large, well-demarcated left maxillary ossifying fibroma ﬇ with mixed calcific and soft tissue density components. Note that the mass obstructs both sides of the nose. (Right) Gross photo shows the classic appearance of ossifying fibroma with central pink-yellow area of fibrous tissue ſt surrounded by pale yellow, dense, peripheral ossified tissue ﬇.

Ossifying Fibroma

Overview of Syndromes: Syndromes

Ossifying Fibroma

Parathyroid Adenoma (Left) Typical ossifying fibroma exhibits a dense, avascular, fibroblast-rich stroma and irregular spicules of woven bone with osteoblastic rimming. (Right) Hypercellular parathyroid tissue is composed predominantly of parathyroid chief cells in this parathyroid adenoma. ~ 80% of patients with hyperparathyroidism-jaw tumor (HPT-JT) syndrome develop hyperparathyroidism, most by parathyroid adenoma.

Parathyroid Tumor

Parafibromin-Negative Tumor (Left) Parafibromin-negative tumors usually demonstrate distinctive morphology, including extensive sheet-like growth, eosinophilic cytoplasm, nuclear enlargement, perinuclear cytoplasmic clearing, and microcystic changes. (Right) The nuclei show loss of expression for parafibromin. CDC73 mutation/inactivation is also associated with parathyroid carcinoma occurring outside the setting of HPT-JT syndrome. This syndrome should be considered in young patients with hyperparathyroidism.

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Overview of Syndromes: Syndromes

Hyperparathyroidism-Jaw Tumor Syndrome

Necrosis in Parathyroid Carcinoma

Parathyroid Carcinoma Morphology

Parathyroid Carcinoma Invading Skeletal Muscle

Vascular Invasion in Parathyroid Carcinoma

Lymph Node Metastases

Parathyroid Carcinoma Within Lymph Node

(Left) This 4.5-cm parathyroid carcinoma was adherent to, but not invading into, the thyroid gland. Numerous mitoses ﬈ can be seen, and areas of necrosis ﬊ are present. (Right) Parathyroid carcinoma has a solid architecture with groups of cells separated by small fibrovascular cores ﬈. The tumor is composed by cells with clear cytoplasm and round nuclei. Focal apoptotic cells ﬇ and a mitotic figure ſt are present.

(Left) ~ 15% of patients with HTP-JT syndrome develop parathyroid carcinoma, shown here invading skeletal muscle. (Right) The histological criteria for parathyroid carcinoma include capsular invasion, vascular &/or perineural tumor invasion, &/or metastasis. Associated features of malignancy include mitosis > 5/10 HPF, tumor necrosis, diffuse monotonous small cells with high nuclear:cytoplasmic ratio, cellular atypia, and presence of macronuclei.

(Left) This lymph node from a patient with parathyroid carcinoma shows a focus of metastatic parathyroid carcinoma ſt. The cells have a clear cytoplasm and round nuclei. (Right) Tumor in the lymph node ﬈ of a patient with a high-grade parathyroid carcinoma helps to confirm the malignancy. The diagnosis of parathyroid carcinoma requires metastases to lymph nodes or other organs and capsular, vascular, or perineural invasion.

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Hyperparathyroidism-Jaw Tumor Syndrome

p53 Immunoexpression in Carcinoma (Left) This parathyroid tumor shows perinuclear dot-like staining for keratin. (Right) Strong expression of p53 is shown in the parathyroid carcinoma cells. Somatic TP53 missense mutation has been reported in anaplastic parathyroid carcinoma, suggesting an association between TP53 mutation and anaplastic transformation.

Parathormone Immunopositivity

Overview of Syndromes: Syndromes

Keratin Staining Pattern in Parathyroid Tumor

High Proliferative Index (Left) This parathyroid carcinoma shows variably positivity for PTH immunostain by the parathyroid tumor cells. (Right) This parathyroid carcinoma with > 3 mitoses per HPF and multifocal areas of necrosis shows variably high Ki-67 proliferative index, with areas of the tumor approaching 90%.

Parafibromin Loss in Carcinoma

Retinoblastoma Loss in Carcinoma (Left) Parafibromin protein is encoded by CDC73. There is a strong association with CDC73 mutation in familial and sporadic parathyroid carcinoma. ~ 15% of patients with HPT-JT develop parathyroid carcinoma. This patient had parafibromin loss by tumor cells while the endothelial cells ﬊ had retained parafibromin. (Right) Decrease or loss of retinoblastoma RB1 expression is identified in > 85% of parathyroid carcinomas. The RB1 gene has been implicated in the pathogenesis of carcinomas.

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Overview of Syndromes: Syndromes

Juvenile Polyposis Syndrome

TERMINOLOGY Abbreviations • Juvenile polyp (JP) • Juvenile polyposis syndrome (JPS) •

Definitions • Hamartomatous polyp ○ May occur sporadically or as manifestation of inherited familial polyposis syndrome • No increase in cancer risk in sporadic JP • Patients with JPS have increased risk of colorectal carcinoma and other malignancies

• •

•

ETIOLOGY/PATHOGENESIS Genetics • Germline mutations in SMAD4 (DPC4) gene on 18q21 present in ~ 40% of JPS patients ○ 4-bp-deletion(1372-1375delACAG) in exon 9 accounts for 25% of cases

•

○ Patients with SMAD4 germline mutations more likely to have – Polyps in upper GI tract – Positive family history and hemorrhagic telangiectasia (HHT) Germline mutations in BMPR1A gene on 10q23 present in similar proportion of JPS cases ○ Variety of mutations have been identified in JPS families Mutations in SMAD4 and BMPR1A genes interfere with TGFB1 signaling pathway Phosphatase and tensin homologue (PTEN) ○ Chromosomal deletions encompassing BMPR1A and PTEN recognized in juvenile polyposis of infancy PTCH (patched, drosophila, homologue of) ○ Rare families with basal cell nevus syndrome present features of JPS Role of ENG mutations debatable

Sporadic Juvenile Polyp

Juvenile Polyposis Syndrome

Juvenile Polyposis Syndrome

Juvenile Polyp

(Left) Sporadic juvenile polyps are usually solitary and may be sessile or pedunculated (as in this example) and show a smooth surface. Syndromic juvenile polyps look similar to sporadic ones on gross and microscopic examination. (Right) In some patients, a large number of polyps may cluster together in a small segment of the colon. The large ﬊, multilobulated polyps are sessile and resemble conventional adenomas and must be sampled extensively to rule out dysplasia or carcinoma.

(Left) Multiple polyps in a patient with juvenile polyposis syndrome (JPS) are shown. The larger polyps ﬈ are pedunculated and multilobulated, while the smaller ones are sessile and smooth ﬊. (Right) Juvenile polyps are characterized by marked stromal expansion ﬊ and cystically dilated crypts ﬉. The stroma is loose, edematous, and inflamed, while the cysts are filled with inspissated mucin ſt.

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Juvenile Polyposis Syndrome

Epidemiology • Prevalence between 1/100,000 and 1/160,000

Presentation • Hematochezia, anemia, diarrhea, or prolapse • Clinical diagnosis of JPS is made if any of these findings is present ○ ≥ 5 JPs of large bowel ○ Multiple JPs of upper and lower GI tract ○ Any number of JPs with family history of JPS • JPs occur in distinct clinical settings ○ Sporadic JP – 90% of all polyps in children – 20-50% may have more than 1 polyp – No increase in risk of colorectal carcinoma – Polyps histologically identical to those in JPS patients ○ Juvenile polyposis coli – Most common inherited form; presents in 1st decade of life – Polyps confined to colon ○ Generalized juvenile polyposis – Diffuse involvement of GI tract – Colon, stomach, and small intestine involved ○ Gastric juvenile polyposis – Rare form; polyps confined to stomach – Patients may present with protein-losing enteropathy and mimic Cronkhite-Canada syndrome (CCS) ○ Juvenile polyposis of infancy – Rare, autosomal recessive disease; usually associated with death in infancy • Diagnostic criteria for JPS ○ > 5 JPs (most patients have between 50-200) – Any number of polyps in patient with positive family history ○ Extracolonic JPs are almost always syndromic • Extracolonic manifestations present in ~ 2/3 of JPS patients ○ Cardiac – Mitral valve prolapse, ventricular septal defects, bicuspid aortic valve ○ Vascular – Telangiectasia, splenic or iliac artery aneurysm, pulmonary arteriovenous malformation (AVM) ○ Cranial/skeletal – Macrocephaly, hydrocephalus, and intellectual disability – Cleft palate, polydactyly ○ Others – Malrotation and Meckel diverticulum; cryptorchidism • Risk of colorectal cancer ○ Starts around 20 years of age onward and increases in 4th decade – Risk is ~ 68% by 60 years of age ○ Mean age for colon cancer in JPS patients is ~ 35 years

Treatment • Supportive treatment for anemia and diarrhea • Polypectomy in patients with only few polyps • Surgical resection for large polyps or polyps with dysplasia/carcinoma

• Surveillance in JPS patients ○ 1-2 yearly colonoscopy from adolescence until 35 years of age – Interval can be extended after 35 years of age ○ 1-2 yearly upper GI endoscopy from 25 years of age • Cardiovascular examination and evaluation for HHT for SMAD4 mutation carriers

Prognosis • Varies with severity of disease manifestation

MACROSCOPIC General Features • • • •

JPS patients usually have > 50 polyps Variable size; most ~ 1.0 cm Majority of polyps (> 2/3) are pedunculated Sessile polyps are infrequent, usually smaller in size, and often with smooth surface • Larger lesions are multilobulated and ulcerated • Gross appearance may resemble adenomas • Cut surface of larger polyps is soft (gelatinous mucin-filled cysts)

Overview of Syndromes: Syndromes

CLINICAL ISSUES

MICROSCOPIC Histologic Features • Epithelial component in colonic polyps ○ Surface erosion or ulceration with granulation tissue cap may be present ○ Markedly dilated cysts with mucin or crypt abscesses ○ Cyst lining epithelium may be completely flattened ○ Regenerative changes mimicking serrated polyp or adenoma may be present ○ Random sections from grossly normal mucosa in colectomy specimens may show early "incipient" JP with cystically dilated and inflamed crypts ○ Dysplasia or carcinoma may be present • Stromal component in colonic polyps ○ Markedly expanded loose, edematous, variably inflamed (neutrophils or lymphoid follicles) lamina propria ○ Hemorrhage and hemosiderin deposits present in larger polyps with torsion injury ○ Smooth muscle proliferation may be present in larger pedunculated polyps ○ Ganglioneuromatous proliferation may be present (more common in Cowden syndrome) • Gastric polyps ○ Cystic epithelial component lined by foveolar-type epithelium ○ Variable degree of inflammation ○ Small gastric JP indistinguishable from sporadic hyperplastic polyps or other hamartomatous polyps • Dysplastic change or carcinoma ○ Not present in sporadic JPs ○ May be present in larger (> 1.0 cm) polyps in syndromic patients ○ Prevalence varies from 8-20% ○ Dysplasia may be present within JP or occur as separate lesion with no residual JP ○ Adenocarcinoma more common in distal colon and rectum 669

Overview of Syndromes: Syndromes

Juvenile Polyposis Syndrome ○ Rare gastric and small intestine carcinomas (~ 20% risk)

DIFFERENTIAL DIAGNOSIS Familial Adenomatous Polyposis • Rarely presents before puberty; polyps are adenomas • Presence of JP and adenomas in same patient should raise suspicion of hereditary mixed polyposis syndrome

Cronkhite-Canada Syndrome • Polyps may appear histologically similar to JP • Colonic mucosa in between polyps shows nodularity and cystic change in CCS • Ectodermal manifestations (onychodystrophy, alopecia, hyperpigmentation, etc.) diagnostic of CCS

• Dysplastic change or cancer may be present • Gastric polyps in JPS patients may appear similar to sporadic hyperplastic polyp or other hamartomatous polyps

SELECTED REFERENCES 1. 2. 3. 4.

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Cowden/PTEN-Hamartoma Syndrome • Polyps are also stroma rich, but stroma is often fibrotic and less inflamed • Skin, oral cavity, breast, thyroid, and esophageal lesions present in patients with Cowden syndrome • Germline mutations in PTEN gene diagnostic of Cowden syndrome

Hereditary Mixed Polyposis Syndrome • Rare disease with autosomal dominant inheritance • Patients of Ashkenazi-Jewish descent • Adenomas, JPs, and hyperplastic polyps seen in same patient • May be confused with juvenile or hyperplastic polyposis • Difficult to classify polyps with hybrid features often present • Susceptibility locus mapped to chromosome 15q13-q14; increased ectopic expression of GREM1

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Peutz-Jeghers Polyposis • Pedunculated JPs with prolapse-type changes may mimic those seen in Peutz-Jeghers polyposis (PJP) • Epithelial component in PJP is arranged in distinct lobular configuration • Lobules in PJP are separated by compact smooth muscle bundles unlike disarrayed proliferation seen in some JPs • Mucocutaneous manifestations typical of PJP not seen in JPS • Extraintestinal tumors closely associated with PJP include ○ Sex cord tumor with annular tubules ○ Large-cell calcifying Sertoli tumor ○ Adenoma malignum of cervix ○ Pancreatic cancer ○ Breast cancer

Inflammatory Polyposis • Early JPs in JPS patients resemble sporadic inflammatory polyps

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Organ and age distribution

Pathologic Interpretation Pearls • Stromal component predominates in most JPs • Cystically dilated, inflamed crypts in loose edematous stroma are characteristic of JP 670

16. 17. 18. 19. 20.

21. 22.

Busoni VB et al: Successful treatment of juvenile polyposis of infancy with sirolimus. Pediatrics. 144(2), 2019 de Leon MP et al: Massive juvenile polyposis of the stomach in a family with SMAD4 gene mutation. Fam Cancer. 18(2):165-72, 2019 Lecoquierre F et al: Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis. Eur J Med Genet. 103773, 2019 Malandra M et al: Utility of routine colonic biopsies in pediatric colonoscopic polypectomy for benign juvenile hamartomatous polyps. J Pediatr Gastroenterol Nutr. 64(4):555-8, 2017 Brosens LA et al: Syndromic gastric polyps: at the crossroads of genetic and environmental cancer predisposition. Adv Exp Med Biol. 908:347-69, 2016 Shaco-Levy R et al: Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Hum Pathol. 49:39-48, 2016 Syngal S et al: ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 110(2):223-62; quiz 263, 2015 Dahdaleh FS et al: Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet. 81(2):110-6, 2012 Latchford AR et al: Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum. 55(10):1038-43, 2012 Brosens LA et al: Juvenile polyposis syndrome. World J Gastroenterol. 28;17(44):4839-44, 2011 Calva-Cerqueira D et al: The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 75(1):79-85, 2009 Friedl W et al: Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet. 111(1):108-11, 2002 Subramony C et al: Study of a kindred: evolution of polyps and relationship to gastrointestinal carcinoma. Am J Clin Pathol. 102(1):91-7, 1994 Larsen Haidle J et al: Juvenile polyposis syndrome. GeneReviews [Internet]. Seattle: University of Washington, 1993 Prieto G et al: Association of juvenile and adenomatous polyposis with pulmonary arteriovenous malformation and hypertrophic osteoarthropathy. J Pediatr Gastroenterol Nutr. 11(1):133-7, 1990 Bentley E et al: Generalized juvenile polyposis with carcinoma. Am J Gastroenterol. 84(11):1456-9, 1989 Burke AP et al: The pathology of Cronkhite-Canada polyps. A comparison to juvenile polyposis. Am J Surg Pathol. 13(11):940-6, 1989 Grosfeld JL et al: Generalized juvenile polyposis coli. Clinical management based on long-term observations. Arch Surg. 121(5):530-4, 1986 Järvinen H et al: Familial juvenile polyposis coli; increased risk of colorectal cancer. Gut. 25(7):792-800, 1984 Goodman ZD et al: Pathogenesis of colonic polyps in multiple juvenile polyposis: report of a case associated with gastric polyps and carcinoma of the rectum. Cancer. 43(5):1906-13, 1979 Watanabe A et al: Familial juvenile polyposis of the stomach. Gastroenterology. 77(1):148-51, 1979 Sachatello CR et al: Generalized juvenile gastrointestinal polyposis. A hereditary syndrome. Gastroenterology. 58(5):699-708, 1970

Juvenile Polyposis Syndrome Juvenile Polyp With Torsion-Related Changes (Left) Juvenile polyp from a patient with germline SMAD4 mutation shows architectural disarray ﬊ and cystic dilatation of crypts ﬉ but minimal expansion of lamina propria. Epithelium-rich juvenile polyps are more often seen in BMPR1A germlinemutant JPS patients. (Right) Juvenile polyps may undergo torsion injury, which results in stromal hemorrhage ﬊ and the presence of hemosiderinladen macrophages in the lamina propria. The cystically dilated crypts ﬈ are helpful in making the correct diagnosis.

Juvenile Polyp

Overview of Syndromes: Syndromes

Epithelium-Rich Juvenile Polyp

Juvenile Polyp Mimicking Mucosal Prolapse Polyp (Left) H&E shows a juvenile polyp with marked cystic change and crypt abscess formation ﬊. The stromal inflammation in such polyps may be in the form of neutrophils, lymphoid follicles ﬈, or both. (Right) Pedunculated juvenile polyp may mimic mucosal prolapse polyp because of fibromuscular proliferation ﬊ and ectatic blood vessels ﬉.

Juvenile Polyp Mimicking Mucosal Prolapse Polyp

Juvenile Polyp Mimicking Peutz-Jeghers Polyp (Left) Architectural disarray ﬉ and cystic dilatation ﬊ are the only clues to the diagnosis of juvenile polyp in this example that otherwise shows features consistent with a mucosal prolapse polyp. The distinction between these 2 diagnoses may not be possible on morphology alone and requires knowledge of clinical and endoscopic findings. (Right) Larger pedunculated juvenile polyps that undergo prolapse often show a prominent smooth muscle proliferation ﬊ that may be mistaken for a Peutz-Jeghers polyp.

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Overview of Syndromes: Syndromes

Juvenile Polyposis Syndrome

Early Juvenile Polyp

Early Juvenile Polyp

Reactive Changes in Juvenile Polyp

Reactive Changes in Juvenile Polyp

Low-Grade Dysplasia in Juvenile Polyp

Low-Grade Dysplasia in Juvenile Polyp

(Left) Random sections from grossly normal mucosa in a colectomy specimen may show "incipient" juvenile polyps. Inflamed lamina propria, as well as long tortuous crypts, some of which show cystic change and rupture ﬊, are typically found in syndromic cases. (Right) Another example of an early, sessile, syndromic juvenile polyp that is rich in epithelium and lacks typical stromal expansion shows a band of increased inflammation in the upper 1/2 of the mucosa ﬊.

(Left) Regenerative changes in juvenile polyps with marked inflammation may mimic serrated or adenomatous polyps. Prominent hyperplastic regenerative change ﬉ is present in this juvenile polyp with an inflamed granulation tissue cap ﬊ on the surface. (Right) Adenoma-like regenerative changes ﬊ are seen in this example of a sporadic juvenile polyp in a 4year-old child. Juvenile polyps in syndromic patients may harbor truly dysplastic foci or cancer.

(Left) Syndromic juvenile polyps may show low- or highgrade dysplasia or cancer. The dysplastic lesions may appear as separate polyps or arise within polyps that show a background architecture, consistent with a juvenile polyp. Low-grade dysplastic change is seen in this example involving the crypt bases ﬊, as well as surface epithelium ﬊. (Right) Low-grade dysplasia in juvenile polyps is characterized by pencillate, hyperchromatic nuclei with stratification, similar to nuclear changes seen in conventional adenomas.

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Juvenile Polyposis Syndrome

Gastric Juvenile Polyp (Left) The stomach may be involved in juvenile polyposis, typically in patients with germline SMAD4 mutations. The morphology of the polyps varies with polyp size, and classic features are only seen in large polyps. (Right) Gastric juvenile polyps typically show marked expansion of the lamina propria ﬊ with variable inflammation and cystic change. The fibromuscular proliferation in the lamina propria st resembles findings seen in mucosal prolapse polyps.

Gastric Juvenile Polyp

Overview of Syndromes: Syndromes

Gastric Juvenile Polyposis

Gastric Juvenile Polyp (Left) The foveolar and glandular compartments in gastric juvenile polyps may show marked cystic change that makes the distinction from hyperplastic polyps and fundic gland polyps ﬊ difficult without knowledge of clinical history and endoscopic findings. (Right) Small juvenile polyps are morphologically indistinguishable from sporadic hyperplastic polyps.

Gastric Juvenile Polyp

Dysplasia in Gastric Juvenile Polyp (Left) The earliest change in gastric juvenile polyps resembles polypoid foveolar hyperplasia. Knowledge of clinical history is essential for making the right diagnosis. (Right) Low- or high-grade dysplasia may be seen in gastric juvenile polyps, similar to what is seen in the colon. The round nuclei with loss of polarity, open chromatin, and prominent nucleoli ﬊ seen in this example are consistent with high-grade dysplasia.

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Overview of Syndromes: Syndromes

Li-Fraumeni Syndrome

TERMINOLOGY Abbreviations • Li-Fraumeni syndrome (LFS)

Synonyms • Online Mendelian Inheritance in Man (OMIM) 151623

INTRODUCTION Li-Fraumeni Syndrome • In 1969, Frederick Li and Joseph Fraumeni recognized unusual pattern of cancers in 4 families with autosomal dominant transmission ○ Family members developed wide variety of different types of cancers ○ Syndrome-related cancers developed at different ages  – 0-15 years: Sarcomas, adrenal cortical carcinomas, brain tumors, leukemia – 16-50 years: Sarcomas, breast cancers, brain tumors, leukemia

– > 50 years: Breast cancers, sarcomas, lung cancers, prostate cancers • LFS results from pathogenic germline mutations in TP53 ○ Currently, broader genetic testing is identifying individuals with germline TP53 mutations without typical family histories • Li-Fraumeni-like syndrome has been used to refer to individuals who have histories that do not fulfill all criteria for LFS ○ 20-40% have germline TP53 mutations and can be classified as having LFS ○ Other individuals may have germline mutations in genes such as BRCA2, Fanconi genes (BRIP1, PALB2, and RAD51C), and DNA mismatch repair genes

EPIDEMIOLOGY Incidence of TP53 Germline Mutations • ~ 1/5,000 to 1/20,000 individuals have definite pathogenic mutations

Li-Fraumeni-Associated Tumors

Li-Fraumeni syndrome is associated with a wide range of diverse tumors that occur at characteristic ages throughout life. Brain tumors (blue) and soft tissue tumors (red) occur more commonly in childhood and early adulthood, whereas carcinomas (green) occur more commonly in later adulthood. The one exception is adrenal cortical carcinoma. The majority of children with this malignancy have a germline p53 mutation. The width of the lines reflects the relative frequency of the tumor. Overall, the most common cancer associated with this syndrome is breast cancer. (Modified from Amadou A, et al, Cancer Biology, 30;23-29:2018.)

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Li-Fraumeni Syndrome

Modifiers of Risk • Type of TP53 germline mutation alters age of onset ○ Missense mutations may affect all cells from conception – 1st tumor has earlier age of onset □ This type of mutation occurs in majority of pediatric patients except for those developing adrenal cortical carcinoma (many of these children have specific mutation) ○ Loss-of-function mutations (e.g., nonsense mutations, frameshift mutations, genomic rearrangements) likely require 2nd event to alter p53 function – 1st tumor in LFS has later age of onset • Sex ○ Median age of developing 1st cancer is higher in females compared to males (28 years vs. 17 years) due to large number of breast cancers – If breast cancers are excluded, median age of 1st cancer in females is ~ 13 years vs. ~ 17 years for males ○ After age 20, incidence of breast cancer in females results in higher overall cancer rates compared to males ○ Lifetime risk for females is ~ 100%, whereas for males it is ~ 75%

GENETICS TP53 • Located on 17p13.1 ○ 20 kb, 11 coding exons, 393 amino acids • Autosomal dominant inheritance • Types of germline TP53 mutations ○ Missense mutations: Majority of cases (~ 75%)  – Most are within central DNA binding domain: 85% in exons 5-8 – Alter DNA binding capacity or destabilize 3D structure of protein – Altered protein can have dominant-negative effect: Abnormal protein interferes with function of wildtype protein □ Occurs in ~ 1/3 of affected LFS families ○ Null mutations: Minority of cases  – May be due to nonsense mutations, splice mutations, deletions, or insertions – Results in nonfunctional protein – Loss or inactivation of wild-type allele is necessary to alter normal TP53 function – Like other germline tumor suppressor genes, majority of tumors exhibit loss of wild-type allele

Function of p53 Protein • Transcription factor with central role to upregulate genes involved in cell cycle arrest, DNA replication, DNA repair, apoptosis, and senescence, in response to DNA damage ○ Binds to double-stranded DNA ○ Transactivation function for promoter sequences • Activated in response to various stress signals • p53 provides mechanism of protection against accumulation of genetic alterations ○ Activates DNA repair proteins when DNA has been damaged ○ Cell cycle arrest allows repair of genetic damage prior to DNA replication and fixation of mutations ○ Terminally damaged cells undergo apoptosis (programmed cell death)

Overview of Syndromes: Syndromes

○ However, broader screening has identified germline mutations in up to 1/400 to 1/800 individuals – Mutations associated with cancers, but not associated with classic LFS history, show lower penetrance and cancers occur at older age • Population in southeastern Brazil has 1/300 incidence ○ Due to specific mutation R337H (c.1010G > A, p.Arg337His) ○ Lifetime risk for cancer ~ 50-60%  ○ Adrenal cortical carcinoma is most common cancer to be diagnosed 1st in all age groups ○ Adults also develop breast cancer, soft tissue sarcoma, and choroid plexus carcinoma

Immunohistochemistry for p53 • p53 protein degrades rapidly with only 20-minute half-life ○ Some mutant forms of p53 cannot transcriptionally activate MDM2 ○ Loss of this negative feedback loop results in p53 accumulation • Many antibodies to p53 are available ○ Target different epitopes on protein ○ May detect only wild-type protein, mutant protein, or both • Different patterns of positivity are observed in tumors ○ Abnormal pattern; complete absence: All cells negative – May correlate with genomic alterations resulting in absence of p53 expression (e.g., deletions, nonsense, splice site mutations) ○ Wild-type pattern: Mixture of negative cells and weak to strongly staining cells – May correlate with presence of normal TP53 □ However, some splice site mutations or truncating mutations can result in nonfunctional p53 that mimics normal pattern ○ Abnormal pattern; overexpression: Diffuse strong positivity in majority of cells – Often correlates with mutations that stabilize protein (~ 96% of missense mutations) □ Some mutant forms of p53 have half-lives of up to 4 hours • Immunohistochemistry is not useful for screening for germline mutations because somatic mutations occur in ~ 50% of tumors

ASSOCIATED NEOPLASMS All Tumors • Risk for malignancy is 100x greater than for unaffected individuals • Cancers arising in children (affecting ~ 30-40% of LFS patients) ○ Osteosarcoma (~ 30% of affected children) ○ Adrenal cortical carcinoma (~ 25% of affected children) ○ CNS tumor (~ 26% of affected children) ○ Soft tissue sarcoma (~ 23% of affected children) ○ Leukemia (~ 10% of affected children) ○ Lymphoma, nephroblastoma, others (< 5% of affected children) 675

Overview of Syndromes: Syndromes

Li-Fraumeni Syndrome • Cancers arising in adults (affecting > 90% of LFS patients by age 70) ○ Breast cancer (~ 79% of female patients) ○ Soft tissue sarcoma (~ 27%) ○ Lung, prostate, colorectal, renal, pancreatic and prostate cancer, CNS tumors (all < 10%)

• Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) ○ These tumors arise in association with textured breast implants and present as late periimplant effusions ○ 5 cases have occurred in LFS patients

Multiple Tumors

• 2nd most common malignancy in LFS (~ 20-30% of total) ○ Occur in both children and adults – 5-10% of children with sarcomas have germline TP53 mutations • Histologic types ○ Rhabdomyosarcoma [~ 29% of LFS-associated soft tissue sarcomas (STS)] – Most common in individuals < 5 years of age □ ~ 50% of children with rhabdomyosarcoma, but without personal or family history of LFS, have germline mutations in TP53 – Embyronal rhabdomyosarcoma of anaplastic subtype is most common □ 9% of individuals with this sarcoma have LFS ○ Leiomyosarcoma (~ 25% of LFS-associated STS) ○ Liposarcoma (~ 12% of LFS-associated STS) ○ Fibrohistiocytic tumors (~ 11% of LFS-associated STS)

• LFS patients have high risk of developing multiple cancers ○ ~ 40% have multiple cancers – 7-20% of individuals with multiple primary tumors have LFS • Increased risk if 1st cancer occurred at early age • Chemotherapy and radiation treatment for 1st cancer may elevate risk ○ Usually occurs 6 -12 years after 1st cancer ○ 2nd cancer may occur in radiation field

Breast Carcinoma • TP53 is 3rd most common germline mutation associated with breast carcinoma, after BRCA1 and BRCA2 • Most common malignancy in LFS (~ 33% of total) • Increased risk for women starts at age 20 and continues into adulthood ○ ~ 6% of women diagnosed before age 31 have germline TP53 mutation • ~ 55% of women will develop breast cancer by age 45 (average age at diagnosis is 33) ○ ~ 100% lifetime risk for women ○ ~ 2% per year will develop subsequent contralateral breast cancer – Overall, ~ 30% will have multiple breast cancers • Histologic type ○ Ductal (no special type) is most common – Other types (lobular, mucinous, medullary) have been reported – Distribution similar to that for sporadic breast tumors ○ Majority of cancers have high nuclear grade, solid growth pattern, and elevated mitotic rate ○ Not associated with syncytial growth pattern, pushing borders, or prominent lymphocytic infiltrate • Biologic type ○ ER(+)/HER2(+): ~ 40-50% – In contrast, this type is much less common in sporadic cancers (~ 10%) ○ ER(+)/HER2(-) ("luminal"): ~ 40% – "Luminal" type is most common type of sporadic breast cancer (50-65%) ○ ER(-)/HER2(+) ("HER2"): ~ 15% – Similar to frequency in sporadic tumors (15-20%) ○ ER(-)/HER2(-) ("triple-negative breast cancer"): ~ 5% – This type is more frequent in sporadic cancers (~ 15%) ○ Although HER2 positivity is common for LFS-associated breast cancers (~ 55-65%), germline TP53 mutations are rare amongst women ≤ 50 years of age with HER2positive breast cancer (< 2%)

Other Breast Tumors • Phyllodes tumor ○ Increased incidence in LFS compared with general population 676

Soft Tissue Sarcoma 

Osteosarcoma • ~ 15% of LFS tumors ○ 2-3% of persons with osteosarcoma have LFS • Most commonly develop during adolescence • 10% of individuals with osteosarcoma diagnosed before age 20 have germline TP53 mutations

CNS Tumors • ~ 13% of LFS tumors • ~ 80% of LFS-associated CNS tumors occur in childhood ○ 2-10% of children with CNS tumors have LFS • Smaller 2nd peak in incidence in 4th-5th decades • Histologic types ○ Glioblastomas and other gliomas (~ 45%) – Occur in children and adults ○ Choroid plexus tumors (~ 30%) – Occur in infants to young adults – ~ 50% of children with these tumors have germline TP53 mutation ○ Medulloblastoma (~ 20%) – Occur in children

Adrenal Cortical Carcinoma • ~ 13% of LFS tumors • 80% of children with this carcinoma have LFS ○ Median age of onset is 3 years • Cases in adults usually occur before 50 years of age

Hematologic Malignancies • Include both lymphoma and leukemia • Children with germline TP53 mutations with acute lymphoblastic leukemia are older (~ 15 years vs. ~ 7 years), have lower survival, and are at greater risk for 2nd malignancies, compared to children without germline mutations

Li-Fraumeni Syndrome

Population to Be Screened • When strict criteria for LFS are met (e.g., classic or Chompret criteria), TP53 mutations are found in 60-80% of individuals ○ However, ~ 45-60% of individuals with germline TP53 mutations will not fulfill these criteria • Recommendations for germline screening have broadened due to improvements in genetic testing ○ Majority of TP53 mutations are currently detected by multigene testing in patients not fulfilling strict criteria • Classic Criteria for Screening ○ Person must have all 3 of following criteria – Diagnosed with sarcoma at age < 45 – Has 1st-degree relative with cancer at age < 45 – Has additional 1st- or 2nd-degree relative in same lineage with cancer at age < 45 or sarcoma at any age ○ 70-80% of individuals fulfilling these criteria have TP53 germline mutation • Chompret Criteria for Screening (2015) ○ Person to be tested must have 1 or more of following criteria – Familial presentation □ Must have tumor belonging to LFS spectrum before age 46 (including premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, CNS tumor, or adrenal cortical carcinoma) and at least one 1st- or 2nd-degree relative with LFS tumor before age 56 or with multiple tumors (excluding breast cancer if person to be tested has breast cancer) – Multiple primary tumors □ Must have multiple tumors (excluding multiple breast tumors), 2 of which belong to LFS tumor spectrum and 1st of which occurred before age 46 – Rare tumors □ Person to be tested has adrenal cortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history – Early-onset breast cancer □ Person to be tested has breast cancer before age 31 ○ ~ 80-90% of individuals fulfilling first 3 criteria have germline TP53 mutations – Women with breast cancer before age 31 have ~ 14% likelihood of germline TP53 mutation

Genetic Testing • DNA sequencing is gold standard for identifying TP53 mutations ○ Over 200 different pathogenic mutations have been identified ○ Sequence analysis of exons 2-11 detects ~ 95% of mutations ○ Deletions of gene, promoter region, or exon 1 may be present in ~ 1% of families ○ Duplications, inversions, large deletions, and mutations in noncoding regions may not be detected by standard sequence analysis

• De novo germline mutations account for ~ 12% of all germline mutations ○ Pathogenic de novo mutations will not have family history, but person and their children are at high risk • When abnormal results are found in individuals without personal or family history of cancer, not all will be found to be pathogenic germline mutations ○ False-positive results – ~ 40% of results indicating individual has genetic variant associated with cancer risk may be false positives when direct to consumer testing is used – Abnormal result needs to be confirmed by certified laboratory ○ Germline mutations that do not increase risk of cancer – Models are being developed to separate mutations that confer risk from polymorphic variants ○ Somatic mutations in hematopoietic cells – Acquired aberrant clonal expansions (ACEs) due to clonal hematopoiesis of indeterminate potential (CHIP) can occur in hematopoietic cells □ More common in older individuals and after chemotherapy □ Testing of additional tissue samples &/or relatives may be necessary to distinguish ACE from germline mutation □ May account for ~ 20% of TP53 positive tests – Increases risk for hematopoietic malignancy and cardiovascular disease – Relatives and offspring are not at higher risk ○ Somatic mutations in solid tissue – Mutations in solid tissue may occur during embryogenesis and result in mosaicism – May increase individual's risk of primary and secondary tumors □ ~ 5% of patients with tumors characteristic of LFS (adrenal cortical carcinoma, choroid plexus tumor, or breast cancer at < 31 years) are mosaic for somatic TP53 mutation – May increase individual's risk for secondary tumors after chemotherapy or radiation – Relatives and offspring are not at higher risk

Overview of Syndromes: Syndromes

SCREENING FOR LFS

SELECTED REFERENCES 1. 2.

3. 4.

5. 6.

7. 8.

9.

de Andrade KC et al: Variable population prevalence estimates of germline TP53 variants: a gnomAD-based analysis. Hum Mutat. 40(1):97-105, 2019 Ferreira AM et al: Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumenilike syndrome in Brazilian individuals with the TP53 p.R337H mutation. J Steroid Biochem Mol Biol. 190:250-5, 2019 Fortuno C et al: A quantitative model to predict pathogenicity of missense variants in the TP53 gene. Hum Mutat. 40(6):788-800, 2019 Packwood K et al: Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the cohort study of TP53 carrier early onset breast cancer (COPE study). J Pathol Clin Res. 5(3):189-98, 2019 Rana HQ et al: Genotype-phenotype associations among panel-based TP53+ subjects. Genet Med. ePub, 2019 Amadou A et al: Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 30(1):23-9, 2018 MacFarland SP et al: The differential diagnosis of a TP53 genetic testing result. Genet Med. 20(8):806-8, 2018 Tandy-Connor S et al: False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 20(12):1515-21, 2018 Wang X et al: p53 alteration in morphologically normal/benign breast luminal cells in BRCA carriers with or without history of breast cancer. Hum Pathol. 68:22-5, 2017

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Overview of Syndromes: Syndromes

Li-Fraumeni Syndrome

Adrenal Cortical Carcinoma

Adrenal Cortical Carcinoma

Embryonal Rhabdomyosarcoma, Anaplastic Subtype

Radiation-Associated Sarcoma

Osteosarcoma

Phyllodes Tumor

(Left) This adrenal cortical carcinoma ﬊ displaces the normal adrenal gland ﬇. In 80% of children with this tumor, a germline TP53 mutation will be present. The median age of onset is 3 years. These tumors also occur in adults but generally before the age of 50. (Right) Adrenal cortical carcinomas occur in both children and adults, but cause death more often in adults. This tumor is particularly common in Brazilian LFS families with a common founder mutation but is also associated with many other LFS mutations.

(Left) Sarcomas are the 2nd most common tumor in LFS. The most common type is rhabdomyosarcoma, particularly embryonal rhabdomyosarcoma of anaplastic subtype. In this case, large pleomorphic tumor cells and a highly atypical mitotic figure ﬈ are present. (Right) In addition to the risk conferred by the germline TP53 mutation, LFS patients are at increased risk for secondary malignancies due to treatment of the 1st malignancy. This unclassified sarcoma arose in the radiation field.

(Left) ~ 15% of tumors associated with LFS are osteosarcomas. These tumors most commonly develop during adolescence. ~ 2-3% of all patients with osteosarcoma, and 10% of patients < 20 years of age, have LFS. (Right) Phyllodes tumors of the breast are another type of stromal tumor that occurs with higher than average incidence in LFS patients.

678

Li-Fraumeni Syndrome

Choroid Plexus Carcinoma (Left) Central nervous system tumors comprise 13% of tumors occurring in LFS. There are 2 peaks in incidence: Childhood and in the 4th and 5th decades. ~ 1/3 are choroid plexus tumors, as seen here. (Right) ~ 80% of brain tumors in LFS occur in children and ~ 1/3 are choroid plexus carcinomas, as in this example. 1/2 of the children with these tumors have LFS.(Courtesy P. Burger, MD.)

Lung Adenocarcinoma, Lepidic Pattern

Overview of Syndromes: Syndromes

Choroid Plexus Carcinoma

Breast Implant-Associated Anaplastic Large Cell Lymphoma (Left) In addition to the rare types of cancers associated with LFS, some more common types of cancers also occur. Adults with LFS are at increased risk of lung cancer, including lepidic pattern adenocarcinoma. (Right) Very rare anaplastic large cell lymphomas ﬈ arise in the setting of effusions associated with textured breast implants. 5 cases (~ 1% of total) have occurred in women with LFS.

Immunohistochemistry for p53

Immunohistochemistry for p53 (Left) Strong diffuse immunoreactivity for p53 is an abnormal pattern due to mutant forms that do not undergo normal degradation, allowing the protein to accumulate in the nucleus. The majority of missense mutation result in this pattern. (Right) A normal "wild-type" pattern of p53 expression is a mixture of negative cells intermingled with variably positive cells ﬈. An abnormal pattern is the complete absence of immunoreactivity. This pattern is associated with mutant forms that degrade or result in a truncated or absent protein.

679

Overview of Syndromes: Syndromes

Lynch Syndrome Definitions

TERMINOLOGY Abbreviations • Lynch syndrome (LS) • Previously known as "hereditary nonpolyposis colorectal cancer" (HNPCC) syndrome

Synonyms • Muir-Torre syndrome ○ Subset of Lynch patients who also have skin tumors – Sebaceous neoplasms – Keratoacanthomas • Turcot syndrome ○ Subset of LS patients who also have brain tumors, typically gliomas ○ Also encompasses familial adenomatous polyposis (FAP) patients with brain tumors, typically medulloblastomas

• One of most common genetically determined predisposition syndromes, accounting for 2-4% of all colorectal adenocarcinoma (CRC) cases and 2-3% of endometrial cancer cases • Autosomal dominant disorder caused by defect in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2 • LS defined by ○ Presence of pathogenic germline defects in DNA MMR genes ○ Presence of microsatellite instability and absence of expression of DNA MMR proteins in tumors • 1st described by pathologist Aldred Warthin in 1895 • Constitutional MMR deficiency (CMMRD) ○ Rare syndrome in which patients have homozygous germline mutations in 2 copies of DNA MMR genes (often PMS2) – Childhood onset of hematologic, brain, and GI tract malignancies – Café au lait macules resembling neurofibromatosis

Workflow: Lynch Syndrome Screening for Colorectal Cancer

Results of IHC stains show either combined or isolated loss of nuclear immunopositivity in the mismatch repair markers MSH2/MSH6 or PMS2/MLH1. In case of isolated or combined MLH1/PMS2 loss, combined MLH1 promoter methylation and BRAF mutation assessment is added to delineate whether the loss could be of sporadic nature. An unusual pattern is followed up with a repeat, consensus conference, or genetic counseling.

680

Lynch Syndrome

Epidemiology

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• Incidence ○ Most common hereditary colon cancer syndrome ○ 2-4% of all colon cancers in USA ○ Affects male and female patients equally

Presentation • Individuals with LS are at increased risk for metachronous colon cancer • In addition to colon cancer, endometrial and ovarian cancers are most common LS-associated cancers • Less common associated cancers include gastric, small intestine, biliary tract, pancreatic, ureter and renal pelvis, and brain (glioblastoma) • Also, sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas, as seen in Muir-Torre syndrome variant • Different criteria for identification of LS  ○ Amsterdam criteria (I and II) were used to identify individuals who warranted further genetic testing  ○ Bethesda criteria developed to provide broader clinical criteria for screening • Bethesda criteria ○ CRC < 50 years ○ Presence of other CRC or other LS-associated tumors ○ CRC with microsatellite instability-high (MSI-H) phenotype < 60 years ○ Patient with CRC and 1st-degree relative with LSassociated tumor • Amsterdam criteria ○ At least 3 relatives with CRC – 1 should be 1st-degree relative of other 2 ○ At least 2 consecutive generations involved ○ At least 1 CRC before age 50 ○ FAP excluded ○ Tumor histology verified ○ Many patients with LS do not fulfill these criteria – Pathologic features of tumor can help predict LS in these patients □ > 90% of tumors are DNA microsatellite unstable MSI-H ○ Sensitivity of Amsterdam criteria is low for diagnosis of LS • In contrast to colonic polyposis syndromes, polyp burden in LS is minimal • Endometrial cancers may be presenting malignancy in female patients

Laboratory Tests • Universal screening of all CRCs for deficient MMR through MSI testing or IHC is currently recommended • Germline alteration in DNA MMR gene, which leads to mutator phenotype ○ Mutations in MLH1, MSH2, MSH6, or PMS2 account for vast majority of cases ○ Deletions in EPCAM, which lead to hypermethylation of MSH2 promoter, also cause LS – Small subset of cases is caused by mutations in EPCAM, which is located adjacent to MSH2

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– EPCAM mutations lead to epigenetic silencing of MSH2 IHC staining for MMR proteins ○ Antibodies for 4 major MMR gene proteins are commercially available ○ Lack of staining in tumor cells indicative of deficient protein – Always need to compare tumor to adjacent inflammatory cells to make sure stain worked (internal positive control) □ In rare cases of constitutional MMR deficiency, there will be no staining of nonneoplastic cells since both copies are knocked out MSI testing ○ PCR assay performed on paraffin-embedded, formalinfixed tissue – Requires both normal and tumor tissue ○ Most MSI-H tumors will be sporadic tumors – Most of these will be due to somatic methylation of MLH1 promoter – Presence of BRAF V600E mutation excludes LS in MSIH tumors □ This can now be detected using IHC for BRAF V600E – Direct analysis of MLH1 promoter methylation is more accurate ○ Vast majority but not all CRCs in LS are MSI-H (90-95%) Germline sequencing of MMR genes for mutations ○ Once missing protein is determined using immunostains, that gene should be sequenced to identify specific germline mutation ○ In some cases, no germline mutation will be found despite presence of MSI-H tumor with absent MMR protein expression – In some cases, biallelic somatic inactivation may be explanation – This has been termed Lynch-like syndrome ○ Genetic counseling and informed consent are considered standard of care for genetic testing ○ Positive germline genetic test establishes diagnosis of LS – Family members should be offered genetic testing after pathogenic variant is identified (cascade testing) No single test or combination of tests is both cost-effective and sensitive/specific ○ Most laboratories use algorithm starting with either MSI testing by PCR or immunostains Next-generation sequencing can detect MSI-H and identify specific Lynch mutations ○ As price drops, this will likely replace IHC for MMR proteins

Overview of Syndromes: Syndromes

CLINICAL ISSUES

Natural History • Lifetime risk of CRC: ~ 50-60% ○ Average age of CRC diagnosis in 4th decade • Lifetime risk of endometrial cancer in women: ~ 40-50% • Cancer risks are highest with MLH1 and MSH2 mutations and lower with MSH6 and PMS2 mutations • Moderately increased risk of other cancers, including ovarian, gastric, small bowel, renal pelvis, pancreatic, skin, and brain tumors

Treatment • Surveillance and prevention 681

Overview of Syndromes: Syndromes

Lynch Syndrome ○ Patients need annual colonoscopic surveillance or total colectomy – Very few patients without cancer opt for prophylactic colectomy – Extended (total) colectomy recommended instead of segmental resection for cancer ○ Hysterectomy should be considered at time of menopause • Metastatic disease ○ MSI-H tumors respond to checkpoint inhibitor therapy – Likely due to prominent host response in tumor [tumor-infiltrating lymphocyte (TIL) and Crohn-like reaction]

Prognosis • Tumors tend to be faster growing compared to sporadic CRC ○ Evidence suggests that adenomas transition to invasive carcinomas faster than in sporadic cases of CRC – Dwell time for usual adenoma-carcinoma sequence is thought to be 10-15 years, whereas it may only be 2-3 years in LS • Better survival in Lynch CRCs compared to sporadic CRCs ○ May be in part due to prominent host immune response often found in these tumors

MICROSCOPIC Histologic Features • LS CRCs arise from adenomas ○ Adenomas in Lynch have increased TILs and decreased apoptosis compared to sporadic adenomas ○ IHC can be performed on adenomas, though less sensitive than for CRCs • Most CRCs are MSI-H ○ Can arise anywhere throughout colon, though there is slight right-sided predominance ○ Increased TILs (> 2/HPF) and Crohn-like reaction ○ Poorly differentiated, well differentiated, or mucinous • CRCs arising in sessile serrated adenomas may be MSI-H, but they are typically not due to LS

DIFFERENTIAL DIAGNOSIS

• Autosomal dominant • Genetic testing required to make diagnosis ○ G:C to T:A and T:A to G:C transversions in DNA

MSH3 Polyposis • Autosomal recessive inheritance

NTHL1 Polyposis • Autosomal recessive inheritance

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Hereditary cancer risk assessment is essential to identifying individuals and families at risk for developing certain types of cancers and provides targeted surveillance and management for affected individuals • If there is no personal or family history of known pathogenic variant in colorectal polyposis or cancer gene, patient's personal or family history of any of following should trigger evaluation for possible polyposis syndrome ○ > 10 adenomatous polyps in lifetime ○ ≥ 2 hamartomatous polyps ○ ≥ 5 serrated polyps proximal to sigmoid colon • Think of LS when patients are < 50 years &/or tumor morphology suggests MSI-H ○ However, ~ 1/3 of LS patients will present at older ages • MSI testing can be performed on all tumor types, and abnormal result should prompt evaluation for LS regardless of tumor type

SELECTED REFERENCES 1. 2.

3.

4. 5.

6.

Familial Adenomatous Polyposis • Hundreds to thousands of adenomas • Cancers that arise are generally microsatellite stable • Look for APC mutation

MUTYH-Associated Polyposis • Autosomal recessive inheritance of MUTYH • Looks like attenuated FAP ○ Fewer adenomas and older onset • Genetic testing required to make diagnosis ○ G:C to T:A transversions in DNA

7. 8. 9.

10.

11. 12.

Hereditary Mixed Polyposis Syndrome • Adenomas, serrated polyps, juvenile polyps, and CRC

682

13.

Polymerase Proofreading Associated Polyposis (POLE and POLD1)

14.

• Multiple adenomas, colorectal carcinomas, and endometrial carcinomas

15.

Biller LH et al: Recent advances in Lynch syndrome. Fam Cancer. 18(2):211-9, 2019 Chu JN et al: Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Cancer. 125(2):278-89, 2019 Goverde A et al: Yield of Lynch syndrome surveillance for patients with pathogenic variants in DNA mismatch repair genes. Clin Gastroenterol Hepatol. ePub, 2019 Harada S et al: Molecular pathology of colorectal cancer. Adv Anat Pathol. ePub, 2019 Hashmi AA et al: Microsatellite instability in endometrial carcinoma by immunohistochemistry, association with clinical and histopathologic parameters. Asian Pac J Cancer Prev. 20(9):2601-6, 2019 Katabathina VS et al: Hereditary gastrointestinal cancer syndromes: role of imaging in screening, diagnosis, and management. Radiographics. 39(5):1280-301, 2019 Kim JY et al: Genetic counseling and surveillance focused on Lynch syndrome. J Anus Rectum Colon. 3(2):60-8, 2019 Ladabaum U: What is Lynch-like syndrome and how should we manage it? Clin Gastroenterol Hepatol. ePub, 2019 Liccardo R et al: Novel variants of unknown significance in the PMS2 gene identified in patients with hereditary colon cancer. Cancer Manag Res. 11:6719-25, 2019 Papke DJ Jr et al: Validation of a targeted next-generation sequencing approach to detect mismatch repair deficiency in colorectal adenocarcinoma. Mod Pathol. 31(12):1882-90, 2018 Burt RW: Colonic polyps in lynch syndrome. Dis Colon Rectum. 58(4):371-2, 2015 Shia J: Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma. Semin Diagn Pathol. 32(5):352-61, 2015 Botma A et al: Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study. Cancer. 2013 Feb 1;119(3):512-21. Epub 2012 Dec 17. Erratum in: Cancer. 119(12):2358, 2013 Rondagh EJ et al: Nonpolypoid colorectal neoplasms: a challenge in endoscopic surveillance of patients with Lynch syndrome. Endoscopy. 45(4):257-64, 2013 Shia J et al: Lynch syndrome-associated neoplasms: a discussion on histopathology and immunohistochemistry. Fam Cancer. 12(2):241-60, 2013

Lynch Syndrome

Amsterdam II Criteria

Revised Bethesda Criteria

Increased risk for LS in family with proband unaffected by CRC or any other LS-associated cancer, and 3 relatives with LS-associated cancer provided following criteria met

CRC diagnosed before age 50 years

1 relative is first-degree relative of other 2

Synchronous or metachronous colorectal or other LS-associated tumor

At least 2 successive generations affected

CRC with microsatellite instability-high histology, i.e., presence of tumor infiltrating lymphocytes, Chron-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern, diagnosed before age 60 years

At least 1 LS-associated cancer diagnosed before age 50 years

CRC in patient with family history of LS-associated cancer diagnosed before age 50 years

Familial adenomatous polyposis excluded

CRC diagnosed in > 1 relative with LS-associated cancer, regardless of age

Overview of Syndromes: Syndromes

Clinical and Pathologic Criteria for Lynch Syndrome

Tumors verified through pathological examination CRC = colorectal cancer; LS = Lynch syndrome.

Characteristics of Lynch Syndrome-Associated Human DNA Mismatch Repair Genes Gene

Chromosomal Location

Number of Exons

Genomic Size (KB)

MLH1

3p21-p23

19

58-100

MSH2

2p21

16

73

PMS2

7p22

15

16

MSH6

2p21

10

20

IHC Staining Patterns by Mutation Mutation

IHC Staining Pattern of Protein Product

MLH1

Loss of MLH1 and PMS2 (same pattern if there is methylation of MLH1)

PMS2

Loss of PMS2

MSH2

Loss of MSH2 and MSH6 (same pattern if there is EPCAM mutation)

MSH6

Loss of MSH6

16. Vasen HF et al: Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 62(6):812-23, 2013 17. Wei C et al: A pilot study comparing protein expression in different segments of the normal colon and rectum and in normal colon versus adenoma in patients with Lynch syndrome. J Cancer Res Clin Oncol. 139(7):1241-50, 2013 18. Moreira L et al: Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 308(15):1555-65, 2012 19. Edelstein DL et al: Rapid development of colorectal neoplasia in patients with Lynch syndrome. Clin Gastroenterol Hepatol. 9(4):340-3, 2011 20. Goodenberger M et al: Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol. 45(6):488-500, 2011 21. Lynch HT et al: Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 76(1):1-18, 2009 22. Polydorides AD et al: Adenoma-infiltrating lymphocytes (AILs) are a potential marker of hereditary nonpolyposis colorectal cancer. Am J Surg Pathol. 32(11):1661-6, 2008 23. Classics in oncology. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. By Aldred Scott Warthin. 1913. CA Cancer J Clin. 35(6):348-59, 1985

683

Overview of Syndromes: Syndromes

Lynch Syndrome

Endometrial Carcinoma

Endometrial Adenocarcinoma

Workflow: Lynch Syndrome Screening for Uterine Carcinoma

PMS2 and MLH1 Preserved Expression

Algorithmic Approach to Evaluation of Lynch Syndrome

Loss of MSH6 and MSH2 Expression

(Left) A patient with Lynch syndrome (LS) presented with a uterine mass. The endometrial cavity is distorted by an exophytic nodular mass, which occupies most of the cavity. (Right) H&E shows an endometrial adenocarcinoma, endometrioid type, grade 2 or 3. The tumor is invasive through the uterine wall.

(Left) Results of IHC stains show either combined or isolated loss of nuclear immunopositivity in the mismatch repair markers MSH2/MSH6 or PMS2/MLH1. In case of isolated or combined MLH1/PMS2 loss, combined MLH1 promoter methylation assessment is added. An unusual pattern is followed up with a repeat, consensus conference, or genetic counseling. (Right) Mismatch repair proteins show preservation of MLH1 and PMS2 and loss of MSH2 and MSH6 expression.

(Left) Algorithm shows evaluation of LS based on whether the LS pathogenic variant is known or if no known pathogenic variant is present. (Right) This patient with known LS has an endometrial carcinoma with loss of expression of MSH2 and MSH6 and preservation of MLH1 and PMS2. Note the stromal cells have retained expression of MSH6.

684

Lynch Syndrome

Colonic Adenocarcinoma (Left) The most common form of hereditary colorectal cancer (CRC) is LS, which is characterized by right colon tumors with mucinous- and medullary-type histologic features. (Right) Hereditary CRC syndromes are associated with early onset of CRC, some with risk for extracolonic cancers. LS is characterized by proximally located tumors frequently showing mucinousand medullary-type histologic features.

Preserved MSH2 and MSH6 Expression

Overview of Syndromes: Syndromes

Colonic Carcinoma

Adenocarcinoma With Mucinous Features (Left) IHC staining for MMR proteins is shown. (Right) LSassociated colonic carcinomas frequently have mucinous-type histology. The presence of intraepithelial lymphocytes is the single most helpful morphologic feature in identification of CRC caused by deficiency in MMR proteins.

Loss of MLH1 and PMS2 Expression

Loss of MLH1 and PMS2 Expression (Left) IHC staining for MMR proteins shows lack of staining of MLH1 and PMS2 in tumor cells, indicative of deficient protein. The stromal cells are positive. (Right) Loss of MLH1 and PMS2 expression of MMR proteins and preservation of MSH2 and MSH6 are seen in this mucinous-type colonic cancer in a patient with LS.

685

Overview of Syndromes: Syndromes

McCune-Albright Syndrome • Association of polyostotic fibrous dysplasia (POFD) and intramuscular myxomas categorized as Mazabraud syndrome

TERMINOLOGY Abbreviations • McCune-Albright syndrome (MAS)

Synonyms • Mazabraud syndrome • Albright syndrome • Fibrous dysplasia (FD), polyostotic and monostotic

EPIDEMIOLOGY Incidence • Rare disease with estimated prevalence between 1:100,000-1 million

Age

Definitions • MAS: Tumor disorder caused by somatic activating GNAS mutations ○ Resulting in mosaic disease with wide clinical variability and broad spectrum of lesions (WHO 2017) • MAS consists of at least 2 features of triad of polyostotic or monostotic fibrous dysplasia, café au lait pigmented skin lesions, and autonomous endocrine hyperfunction ○ Endocrinopathies leading to hyperfunctioning syndromes: Precocious puberty, Cushing syndrome, hyperthyroidism, growth hormone excess

• Diagnosis often made within 1st decade of life

Sex • Occurs equally in both sexes

ETIOLOGY/PATHOGENESIS Etiology • MAS usually caused by early embryonic postzygotic somatic activating mutations in GNAS1 gene (GNAS locus at 20q13.2-q13.3)

Rib With Variegated Cut Surface in Fibrous Dysplasia

Gross photograph of fibrous dysplasia (FD) of the rib shows an irregularly shaped bone lesion with a thinning of cortex and complete loss of marrow, which is occupied by a mass with a variegated appearance.

686

McCune-Albright Syndrome

CLINICAL IMPLICATIONS Clinical Presentation • Endocrine hyperfunction ○ Precocious puberty – Most common endocrine manifestation in girls □ Accounting for ~ 80% of cases – Caused by gonadotropin-independent secretion of estrogen from large ovarian follicles – Clinical presentation includes vaginal bleeding or spotting, development of breast tissue – Ovarian cysts may be either present or absent due to episodic nature of their development – In boys, testicular and penile enlargement and precocious sexual behavior, ± excess testosterone production – Testicular enlargement often results from maturation and growth of seminiferous tubules ○ Thyroid – Hyperthyroidism is 2nd most common endocrine manifestation □ Due to multinodular hyperplasia □ Hyperthyroidism present in ~ 70% of patients with MAS-related goiter □ ~ 30% of patients with hyperthyroidism do not have enlarged thyroid – Clinical or subclinical hyperthyroidism, ± clinically detectable goiter or thyroiditis – Higher triiodothyronine:thyroxine ratio even in absence of hyperthyroidism (partially explained by cAMP-induced 5'-deiodinase activity) – Rare cases of inflammatory thyroiditis and thyroid carcinomas described ○ Adrenal gland – Hallmark of MAS-related adrenal disease is bilateral nodular hyperplasia (characteristic bilateral primary bimorphic adrenocortical disease) □ Characterized by diffuse nodular hyperplasia juxtaposed with areas of atrophic cortex resulting in bimorphic appearance – Hypercortisolism in MAS always ACTH-independent and leads to Cushing syndrome, often mild and cyclical, but occasionally severe and with significant mortality – Weight gain and decreasing growth velocity: Cushing syndrome in childhood – Adrenal involvements manifests in 1st year of life (1.77.5% of patients affected)

– Rare examples of bilateral adenomas have also been described in MAS ○ Pituitary gland – Acromegaly or gigantism due to pituitary adenoma – MAS-related acromegaly always associated with POFD of skull base – Synchronous hyperprolactinemia occurs in ~ 80% of patients – Acromegaly affects 20-30% of patients with MAS ○ Others – Chronic liver disease, tachycardia, and hypophosphatemia – Hyperphosphaturic hypophosphatemic rickets □ Hypophosphatemia is FGF23 mediated (phosphaturic factor), which is released from FD tissue □ Typically seen in patients with significant skeletal disease – Osteomalacia • Polyostotic fibrous dysplasia ○ Benign fibroosseous bone lesion involving multiple bone sites ○ Clinical presentation includes – Abnormal gait – Visible bony deformities (leg length discrepancy, shepherd's crook deformity, facial asymmetry, or bony enlargement) – Bone pain – Joint stiffness with pain – Pathological fractures – Nerve compression – Rarely undergoes sarcomatous degeneration ○ Location – Most commonly in femur, tibia, humerus, ribs, and craniofacial bones – Craniofacial FD, in particular, can vary widely in severity from asymptomatic to severe disfigurement and functional impairment ○ POFD is thought to be secondary to increased proliferation and decreased osteoblastic differentiation of bone marrow stromal cells • Café au lait pigmented skin lesions ○ Likely result from increased intracellular cAMP in melanocytes, which leads to increased melanin production ○ Flat macules that often follow segmental pattern of distribution of developmental lines of Blaschko ○ Most common locations: Posterior neck, sacrum, head ○ Skin pigmentation often covers large geographic area with irregular border ○ May be present at birth or develop soon after; do not fade with age ○ Often, lesions on same side affected by fibrous dysplasia ○ Pigmentation becomes more obvious with age and may darken after sun exposure • Others ○ Oral pigmentation, gastrointestinal polyps, breast cancer ○ Hepatobiliary and pancreatic neoplasms, hepatobiliary dysfunction, cardiac disease ○ Platelet dysfunction, along with hyperplasia of thymus, spleen, and pancreatic islets

Overview of Syndromes: Syndromes

• Most common mutations are point mutations with Arg201 (most commonly R201H and R201C) • Activating mutations lead to increased cAMP levels, which has multiple effects in different organs • Significant variability observed in extent and severity of clinical presentation due to somatic mosaicism of GNAS1 mutations • Nonmosaic state of activating mutations presumably lethal to embryo • No known genotype-phenotype correlations • Penetrance high and primarily determined by number and location of mutant cells

687

Overview of Syndromes: Syndromes

McCune-Albright Syndrome Genotype-Phenotype Correlations • No known genotype-phenotype correlations • Clinical presentation and disease severity likely determined by mosaicism degree and extent of affected tissues

Treatment • Phenotype reflects distribution of GNAS mutations and role of Gs-α in mutation-bearing tissues • Endocrine hyperfunction ○ Management depends on individual presentation • Fibrous dysplasia ○ Bony disease very difficult to treat and no specific treatments available – Bisphosphonates often used to reduce bone pain, frequency of pathological fractures • Café au lait skin lesions ○ Totally benign and no treatment needed • MAS-related pituitary disease ○ Total hypophysectomy required for surgical cure

Prognosis • Depends on disease site involvement and severity • MAS not associated with significantly increased mortality risk • GNAS mutations in MAS/POFD weakly oncogenic • Radiotherapy and uncontrolled GH excess may increase risk of malignant transformation • Sudden cardiac death has been reported • Endocrinopathies persist throughout childhood and adulthood ○ Exception of FGF23-mediated hypophosphatemia, which may worsen during periods of rapid linear growth and ameliorate in adulthood (FD disease activity wanes) ○ Hypophosphatemia increases fractures and bone pain

Genetic Counseling • MAS results from activating mutations that are always somatic • Germline mutations are likely lethal ○ So, MAS is never inherited • Counseling: Risk of recurrence appears to be same as general population

Complications • • • • • • •

Osteosarcoma in ~ 1% of patients with POFD Females may have greater risk for breast cancer Secondary osteomyelitis Thyroid carcinoma Myositis Compressive neuropathy Sympathetic algodystrophy

IMAGING General Features • Fibrous dysplasia ○ Radiograph: Ground-glass appearance • Precocious puberty ○ Ultrasonography: Ovarian cysts (may be present or absent)

688

– Testicular microlithiasis, hyperechoic and hypoechoic lesions, heterogeneity, and focal calcifications irrespective of precocity • Hyperthyroidism ○ Solitary or multiple functioning nodules that occur in MAS appear warm or hot on scan

MICROSCOPIC General Features • Endocrine hyperfunction ○ Ovary with enlarged follicles lined by granulosa cells – Single case of borderline ovarian serous tumor and another of virilizing sclerosing stromal tumor have been reported in MAS ○ Testicular enlargement results from maturation and growth of seminiferous tubules – Leydig cell hyperplasia indistinguishable from Leydig cell tumors recently reported – Sertoli cells proliferations (including Sertoli cell intraepithelial neoplasia), bilateral testicular cell tumors (including embryonal carcinoma), and testicular adrenal rests ○ Thyroid with multinodular hyperplasia – Multiple nodules with different size □ Regardless of size, such nodules called follicular adenomas with papillary growth (or so-called papillary adenomas) □ Characterized by benign follicular epithelial proliferations with intrafollicular centripetal papillary projections – Sanderson polsters (papillary-type projections into lumina of follicles) – Varying degree of cellularity and colloid ○ Adrenal gland with macronodular hyperplasia/primary bimorphic adrenal cortical disease – Shows multiple macronodules – Macronodules composed of hypertrophied, globoid, lipid-depleted adrenocortical cells – Residual normal gland often atrophic – Bilateral nodular hyperplasia and bilateral primary bimorphic adrenocortical disease □ Diffuse nodular hyperplasia juxtaposed with areas of atrophic cortex, resulting in bimorphic appearance ○ Pituitary gland with pituitary adenoma – Solid, diffuse, trabecular, sinusoidal, and papillary growth patterns common – Tumor cells with typical neuroendocrine cell features – Finely dispersed chromatin with distinct nucleoli – Cytoplasmic granularity gives 3 morphologically distinct cell types: Chromophobic, eosinophilic, and basophilic – Evidence suggests hyperplasia-to-neoplasia progression sequence and multicentric microadenomas • Fibrous dysplasia ○ Composed of fibrous tissue and immature woven bone – Spindle-shaped fibroblasts arranged in parallel arrays or in whorls – Woven bone with Chinese writing pattern

McCune-Albright Syndrome

ANCILLARY TESTS Cytology • Multinodular thyroid hyperplasia with abundant colloid, low cellularity, and benign nuclear features ○ Cellular atypia and oncocytic changes may be present

Genetic Testing • MAS/FD results from postzygotic somatic-activating mutations in Gs-α, one of several transcripts encoded by GNAS • Mutation spectrum ○ Activating mutation of GNAS1 at Arg201 or Gln227 ○ Missense mutations on Arg201, accounting for > 95% of mutations ○ Mutations in Gln227, accounting ~ 5% of mutations

Hyperparathyroidism-Jaw Tumor Syndrome • Caused by mutation of HRPT2 gene, which encodes parafibromin • Hyperparathyroidism often caused by parathyroid adenoma or carcinoma with severe hypercalcemia • Ossifying fibroma in jaw can be confused with fibrous dysplasia clinically, radiographically, and histologically

SELECTED REFERENCES 1. 2.

3. 4.

5. 6.

7.

Serologic Testing • Sexual precocity with increase of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) • Elevated serum alkaline phosphatase • Elevated hormone level (thyroid hormone, cortisone, growth hormone, or estrogen)

DIFFERENTIAL DIAGNOSIS Mazabraud Syndrome • Combination of polyostotic fibrous dysplasia and intramuscular myxomas • Also caused by GNAS1 mutations

8.

9.

10.

11. 12.

13.

Neurofibromatosis

14.

• Café au lait spots also present (autosomal dominant) • Multiple neurofibromas, Lisch nodules often present

15. 16.

Carney Complex • Autosomal dominant disease • Shares some similarities with MAS • Multiple endocrine neoplasia syndrome featuring cardiac, endocrine, cutaneous, and neural tumors • Presence of variety of mucocutaneous pigmented lesions • Involve several endocrine glands simultaneously ○ Adrenal cortex, gonads, pituitary and thyroid

Osteofibrous Dysplasia • Rare, benign, nonneoplastic, self-limited intracortical fibroosseous lesion • Most lesions of osteofibrous dysplasia affect cortex of tibiae and fibulae of children • Radiograph shows that cortex often expanded and thinned with multiple radiolucencies • Microscopically, lesion composed of spindle cell proliferation with production of woven bone trabeculae with prominent osteoblastic rimming

17. 18. 19.

20. 21. 22. 23. 24.

25.

Folpe AL: Phosphaturic mesenchymal tumors: a review and update. Semin Diagn Pathol. 36(4):260-8, 2019 Javaid MK et al: Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis. 14(1):139, 2019 Johansen L et al: Hepatic lesions associated with McCune Albright syndrome. J Pediatr Gastroenterol Nutr. 68(4):e54-7, 2019 Pereira TDSF et al: Fibrous dysplasia of the jaws: integrating molecular pathogenesis with clinical, radiological, and histopathological features. J Oral Pathol Med. 48(1):3-9, 2019 Rajan R et al: McCune Albright syndrome: an endocrine medley. BMJ Case Rep. 12(7), 2019 Lecumberri B et al: Head and neck manifestations of an undiagnosed McCune-Albright syndrome: clinicopathological description and literature review. Virchows Arch. 473(5):645-8, 2018 Tessaris D et al: Growth hormone-Insulin-like growth factor 1 axis hyperactivity on bone fibrous dysplasia in McCune-Albright syndrome. Clin Endocrinol (Oxf). 89(1):56-64, 2018 Boyce AM et al: Improving patient outcomes in fibrous dysplasia/McCuneAlbright syndrome: an international multidisciplinary workshop to inform an international partnership. Arch Osteoporos. 12(1):21, 2017 Itonaga T et al: Three-quarters adrenalectomy for infantile-onset Cushing syndrome due to bilateral adrenal hyperplasia in McCune-Albright syndrome. Horm Res Paediatr. 88(3-4):285-90, 2017 Neyman A et al: Treatment of girls and boys with McCune-Albright syndrome with precocious puberty - update 2017. Pediatr Endocrinol Rev. 15(2):136-41, 2017 Pal R et al: Acromegaly with hypophosphataemia: McCune-Albright syndrome. BMJ Case Rep. 20i7, 2017 Shin SJ et al: Frequency of GNAS R201H substitution mutation in polyostotic fibrous dysplasia: pyrosequencing analysis in tissue samples with or without decalcification. Sci Rep. 7(1):2836, 2017 Wong SC et al: Long-term health outcomes of adults with McCune-Albright syndrome. Clin Endocrinol (Oxf). 87(5):627-34, 2017 Robinson C et al: Fibrous dysplasia/McCune-Albright syndrome: clinical and translational perspectives. Curr Osteoporos Rep. 14(5):178-86, 2016 Brillante B et al: McCune-Albright syndrome: an overview of clinical features. J Pediatr Nurs. 30(5):815-7, 2015 Pichard DC et al: Oral pigmentation in McCune-Albright syndrome. JAMA Dermatol. 150(7):760-3, 2014 Salenave S et al: Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab. 99(6):1955-69, 2014 Elhaï M et al: McCune-Albright syndrome revealed by hyperthyroidism at advanced age. Ann Endocrinol (Paris). 72(6):526-9, 2011 Adegbite NS et al: Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. 146A(14):1788-96, 2008 Chapurlat RD et al: Fibrous dysplasia of bone and McCune-Albright syndrome. Best Pract Res Clin Rheumatol. 22(1):55-69, 2008 Dumitrescu CE et al: McCune-Albright syndrome. Orphanet J Rare Dis. 3:12, 2008 de Sanctis L et al: Genetics of McCune-Albright syndrome. J Pediatr Endocrinol Metab. 19 Suppl 2:577-82, 2006 Tinschert S et al: McCune-Albright syndrome: clinical and molecular evidence of mosaicism in an unusual giant patient. Am J Med Genet. 83(2):100-8, 1999 Riminucci M et al: Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation. Am J Pathol. 151(6):1587-600, 1997 Park YK et al: Osteofibrous dysplasia: clinicopathologic study of 80 cases. Hum Pathol. 24(12):1339-47, 1993

Overview of Syndromes: Syndromes

– Spicules of woven bone surrounded by flat lining cells with retracted cell bodies, forming pseudolacunar spaces • Café au lait skin lesions ○ No change in number of melanocytes but increase in number of melanin-containing pigment melanosomes

689

Overview of Syndromes: Syndromes

McCune-Albright Syndrome

Maxillary Lesion in MAS

Polyostotic Fibrous Dysplasia

Fibrous Dysplasia

Gross Cut Surface

Trabeculae in Fibrous Dysplasia

Woven Bone in Fibrous Dysplasia

(Left) Axial CT shows an expansion of the right anterior maxilla and right pterygoid plate with an internal groundglass density ſt. (Right) Coronal graphic shows polyostotic FD involving the proximal femur and acetabular roof. Cystic changes are shown in red, while the ground-glass appearance is shown in brown.

(Left) Axial graphic shows expansion of the right lateral orbital rim, sphenoid wing, and temporal squamosa by FD. Note the exophthalmos and stretching of the optic nerve on the ipsilateral side. (Right) Gross photograph of a polyostotic FD of the rib shows a bone lesion with a thinning of cortex occupying the entire bone marrow space.

(Left) Irregular, curvilinear trabeculae of woven bone are characteristic of FD. The bone is surrounded by a fibrousappearing stroma that contains scattered, congested blood vessels. The amount of bone in an individual tumor can be very variable. (Right) High-power view of the neoplastic bone in FD shows its composition of woven bone. Sharpey-like collagen fibers of the stroma can be seen extending into the matrix. The fibrous stroma is moderately cellular.

690

McCune-Albright Syndrome

Large Adrenal Nodules in MAS (Left) ACTH-independent diffuse nodular hyperplasia shows multiple adrenal cortical nodules ﬊. The residual overlying and intervening cortex appears atrophic or normal ﬉. A bimorphic adrenocortical disease is a hallmark of MAS. (Right) The cut surface of this adrenal gland shows multiple macronodules ﬊. The residual normal gland ﬇ is often atrophic, resulting in a bimorphic appearance. Hypercortisolism and Cushing syndrome often are a result of nodular cortical hyperplasia.

Primary Bimorphic Adrenocortical Disease

Overview of Syndromes: Syndromes

Primary Bimorphic Adrenal Cortical Disease

Touch Prep of Pituitary Adenoma (Left) Primary bimorphic adrenocortical disease is characterized by diffuse nodular hyperplasia. The nodular compact cell hyperplasia is interspersed with alternating areas of residual gland with cortical atrophy, usually seen in MAS. (Right) Touch prep of a pituitary adenoma shows uniform cells with round to oval nuclei with delicate chromatin. The pituitary tumors in these patients are usually G producing. Acromegaly affects 20-30% of patients with MAS.

Hyperplastic Thyroid Changes

Papillary Growth Pattern in MAS (Left) Section from the thyroid in a patient with MAS shows multinodular hyperplasia with follicular hyperplasia and marked scalloping of colloid ﬇. (Right) Hyperthyroidism is the 2nd most common endocrine manifestation in MAS, occurring in as many as 77% of patients with MASrelated goiter. The functioning thyroid nodules usually show intrafollicular centripetal papillary growth ﬊.

691

Overview of Syndromes: Syndromes

Melanoma/Pancreatic Carcinoma Syndrome

TERMINOLOGY Familial Atypical Multiple Mole Melanoma Syndrome • Familial atypical multiple mole melanoma syndrome (FAMMM) ○ OMIM 155601 • FAMMM-pancreatic cancer (FAMMM-PC) ○ OMIM 606719 • Melanoma-astrocytoma syndrome ○ OMIM 155755

• Individuals with FAMMM-PC have 20-34% relative risk of developing pancreatic carcinoma • Inherited mutations in CDKN2A, CDK4, POT1, and TERT confer 60-90% lifetime risk of melanoma

GENETICS Inheritance • Autosomal dominant

Genes Commonly Implicated in Familial Melanoma and Associated Malignancies

EPIDEMIOLOGY Incidence • Hereditary cutaneous melanoma ○ 7-15% of melanomas occur in patients with family history of melanoma • Hereditary pancreatic cancer ○ 5-10% of pancreatic ductal adenocarcinoma cases have hereditary basis

• CDKN2A/CDK4 ○ Germline mutations of CDKN2A (cyclin-dependent kinase inhibitor 2A) are missense or nonsense mutations that result in impaired functions of p16 &/or p14ARF ○ Pancreatic, breast, cervical, lymphoma, gastrointestinal, and lung cancer • TERT ○ Telomere maintenance ○ Renal, bladder, and myeloproliferative disorders

Melanoma

Clinical photograph of a nodular-type melanoma shows a darkly pigmented elevated lesion with irregular borders on the chest. (Courtesy J. Wu, MD.)

692

Melanoma/Pancreatic Carcinoma Syndrome

Melanoma-Astrocytoma Syndrome • Deletions involving CDKN2A/CDKN2B/CDKN2B-AS1 gene cluster

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Findings • FAMMM ○ Numerous nevi ○ Atypical nevi are more likely to transform into melanoma ○ Increased risk of cutaneous melanoma and pancreatic cancer ○ Family history of melanoma • Some kindreds have cutaneous melanoma and pancreatic cancer without increased numbers of atypical melanocytic nevi

Clinical Risk Factors • Family and personal history of melanoma or pancreatic cancer • CDKN2A mutation carrier • Personal history of melanoma or nonmelanoma skin cancers • Exposure to ultraviolet radiation • Sun sensitivity • Pigmentary characteristics ○ Fair skin with inability to tan ○ Red/blonde hair color ○ Blue eyes • Freckling • Multiple nevi and atypical nevi ○ Especially > 50 years of age

Definition • Presence of 2 or more cases of melanoma in 1st- or 2nddegree relatives • Presence of 2 or more melanomas in same individual (3 or more in areas of high melanoma incidence such as Australia or USA)

ASSOCIATED NEOPLASMS Malignant Melanoma • Cutaneous melanoma

Dysplastic Nevi (Atypical Nevi, Clark Nevi) • Can occur in those with or without increased risk of developing melanoma • Clinical appearance ○ > 6 mm in size ○ Irregular color and borders ○ Asymmetric ○ Recent change in some cases ○ Can have papular or macular components • Histopathology ○ Disordered architecture: Lateral extension of junctional component, bridged rete ridges, fibrolamellar fibrosis, irregular junctional nests ○ Cytologic atypia: Enlarged size and nuclei, prominent nucleoli

Overview of Syndromes: Syndromes

• POT1 ○ Telomere maintenance ○ Glioma, brain, breast, lung, endometrial, and chronic lymphocytic leukemia • ACD and TERF2IP ○ Telomere maintenance ○ Breast, brain, lung, ovarian, cervical, colorectal, prostate, and myeloproliferative disorders • BAP1 ○ Tumor suppressor ○ Uveal melanoma, mesothelioma, renal, meningioma, paraganglioma, and cholangiocarcinoma • PTEN ○ Tumor suppressor ○ Breast, thyroid, endometrium, colorectal, and kidney • MC1R, OCA2, ASIP, and SLC45A2 ○ Melanin production • BRCA2 ○ Tumor suppressor and DNA repair ○ Breast, ovarian, prostate, and pancreatic cancer • MITF ○ Regulates melanocyte development ○ Pancreatic, renal cancer • MGMT ○ DNA repair

Pancreatic Cancer • Lifetime risk: 11-17% • 5.8 years younger than patients affected by sporadic pancreatic cancer

Breast Cancer • Greater risk than those without multiple atypical melanocytic nevi

CANCER RISK MANAGEMENT FAMMM • Should be considered in patients with ○ 2 first-degree relatives with melanoma ○ Multiple primary melanomas even in absence of family history ○ Family history of melanoma, pancreatic cancer, and astrocytoma ○ Individual with 10-100 dysplastic nevi

Avoidance of Other Carcinogens • Increased pancreatic cancer risk with cigarette smoking

Skin Examination • Baseline at 10 years of age • Every 6-12 months • Skin self-examination every 3 months ○ Looking for any changes in color, size, and shape of nevi • Baseline photography • Digital dermoscopy

Screening • The National Comprehensive Cancer Network (NCCN) guidelines recommend annual skin exam in individuals with personal history of melanoma or CDKN2A mutation carriers 693

Overview of Syndromes: Syndromes

Melanoma/Pancreatic Carcinoma Syndrome • Pancreatic cancer screening in high-risk individuals

Sun Protection • Sunscreen

Pancreatic Cancer

Familial adenomatous polyposis Li-Fraumeni syndrome Peutz-Jeghers syndrome Hereditary breast and ovarian cancers

Disorders With Chronic Pancreatitis

• Refer for genetic counseling when ○ Pancreatic cancer diagnosed at any age and – 2 or more close relatives with pancreatic cancer – 2 or more close relatives with breast, ovarian &/or aggressive prostate cancer – Ashkenazi Jewish ancestry ○ Patient with both pancreatic cancer and melanoma ○ Patient with both pancreatic cancer and more than 1 Peutz-Jeghers-type polyp ○ Patient with pancreatic cancer and 2 additional Lynch syndrome-associated cancers ○ 3 or more cases of pancreatic cancer &/or melanoma in close relatives • Initiate screening at 10 years before youngest age of diagnosis of pancreatic cancer in given family or age 50 years • Multimodal screening ○ Endoscopic ultrasound ○ CT ○ MR ○ Endoscopic retrograde cholangiopancreatography

DIFFERENTIAL DIAGNOSIS Hereditary Tumor Syndromes With Increased Melanoma Risk • • • • •

• • • •

BAP1 tumor predisposition syndrome Hereditary breast and ovarian cancers Li-Fraumeni syndrome Xeroderma pigmentosum Cowden syndrome

• Familial pancreatic cancer ○ Not associated with melanoma • Hereditary pancreatitis • Cystic fibrosis

SELECTED REFERENCES 1.

Cremin C et al: CDKN2A founder mutation in pancreatic ductal adenocarcinoma patients without cutaneous features of familial atypical multiple mole melanoma (FAMMM) syndrome. Hered Cancer Clin Pract. 16:7, 2018 2. Signoretti M et al: Results of surveillance in individuals at high-risk of pancreatic cancer: a systematic review and meta-analysis. United European Gastroenterol J. 6(4):489-99, 2018 3. Leachman SA et al: Identification, genetic testing, and management of hereditary melanoma. Cancer Metastasis Rev. 36(1):77-90, 2017 4. Hawkes JE et al: Genetic predisposition to melanoma. Semin Oncol. 43(5):591-7, 2016 5. Jaju PD et al: Familial skin cancer syndromes: increased risk of nonmelanotic skin cancers and extracutaneous tumors. J Am Acad Dermatol. 74(3):437-51; quiz 452-4, 2016 6. Lynch HT et al: Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity. Fam Cancer. 15(3):487-91, 2016 7. Ransohoff KJ et al: Familial skin cancer syndromes: Increased melanoma risk. J Am Acad Dermatol. 74(3):423-34; quiz 435-6, 2016 8. Soura E et al: Hereditary melanoma: update on syndromes and management: emerging melanoma cancer complexes and genetic counseling. J Am Acad Dermatol. 74(3):411-20; quiz 421-2, 2016 9. Soura E et al: Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol. 74(3):395-407; quiz 408-10, 2016 10. Hampel H et al: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 17(1):70-87, 2015

Hereditary Tumor Syndromes With Increased Risk of Pancreatic Cancer • Hereditary nonpolyposis colorectal carcinoma

Nodular Melanoma (Left) An expansile proliferation of atypical melanocytes is seen filling the dermis. A lentiginous and nested proliferation of similarly atypical melanocytes is seen within the overlying epidermis. (Right) The atypical and epithelioid melanocytes exhibit enlarged nuclei with prominent nucleoli and abundant cytoplasm containing fine melanin pigment.

694

Melanoma

Melanoma/Pancreatic Carcinoma Syndrome

Atypical Nevus at Low Magnification (Left) Clinical photograph of an atypical compound nevus shows a central papular ﬈ area surrounded by an irregular macular periphery ﬉. (Courtesy P. Duray, MD.) (Right) At low magnification, features of architectural disorder are seen, including lateral extension of the junctional component beyond the dermal component, bridging of rete ridges, superficial dermal fibrosis, and patchy host response.

Atypical Nevus at High Magnification

Overview of Syndromes: Syndromes

Atypical Nevus

Pancreatic Adenocarcinoma (Left) Concentric or fibrolamellar fibrosis is seen. The melanocytes within the junctional nests exhibit cytologic atypia. (Right) This large tumor in the pancreatic head forms a solid and cystic mass that focally obliterates the pancreatic duct. The bile duct is focally dilated, but not involved by tumor. Individuals with familial atypical multiple mole melanoma syndromepancreatic cancer (FAMMMPC) have a relative risk of 2034% of developing pancreatic carcinoma.

Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma (Left) This pancreas cut surface shows a 1.5-cm tanyellow, ill-defined mass ﬇. This lesion shows an usual gross appearance of pancreatic ductal adenocarcinoma. 5-10% of pancreatic ductal adenocarcinoma cases have a hereditary basis. (Right) In ductal adenocarcinomas, the growth pattern and cytologic appearance closely resemble nonneoplastic ductules with mild/moderate nuclear variation. Perineural invasion is a common feature.

695

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 1 (MEN1)

TERMINOLOGY

CLINICAL IMPLICATIONS

Abbreviations

Clinical Presentation

• Multiple endocrine neoplasia type 1 (MEN1) • Zollinger-Ellison syndrome (ZES)

• Hyperparathyroidism ○ 1st clinical manifestation in most patients ○ Percentage of patients who develop biochemical evidence of hyperparathyroidism increases with age – 43% and 94% at ages 20 and 50 years, respectively ○ Incidence of MEN1 among individuals aged < 40 years with primary hyperparathyroidism: 5-13% ○ Most are asymptomatic; severe cases with "moans, groans, bones, and stones" are hallmarks of hypercalcemia ○ Multiglandular disorder • Pituitary tumors ○ 1st clinical manifestation of MEN1 in 17% (range: 1025%) of patients ○ Prevalence of pituitary tumors in MEN1 ~ 30-40% (range: 10-50%) ○ Suggested penetrance in MEN1 (aged > 16 years) of 38% ○ Patients with MEN1 with pituitary adenomas tend to be younger than patients with sporadic tumors – MEN1 adenomas: Mean patient age ± standard deviation = 35.1 ± 14.8 years – Sporadic tumors: Mean patient age of 40 years ○ Prolactinomas (60%), nonsecreting adenomas (15%), growth hormone-secreting adenoma (9-10%), adrenocorticotrophin-secreting and thyrotroph adenomas (4-5%) ○ GH adenoma: Acromegaly ○ ACTH-secreting adenoma: Cushing disease • Neuroendocrine pancreatic/duodenal tumors ○ Incidence of MEN1-associated duodenal neuroendocrine tumors (NETs) and pancreatic neuroendocrine tumors (PNETs) peaks at 40-60 years ○ Clinical manifestations in ~ 40% of patients with MEN1 ○ In as many as 80% of cases, tumors give rise to large periduodenal &/or peripancreatic lymph node metastases, which were formerly interpreted as gastrinoma primaries

Synonyms • Multiple endocrine adenomatosis type 1 • Wermer syndrome • Familial ZES

Definitions • WHO 2017: MEN1 is autosomal dominant disease caused by germline MEN1 mutations leading to development of multifocal neoplastic endocrine lesions ○ Parathyroid glands, neuroendocrine pancreas, duodenum, and anterior pituitary ○ Less commonly involving stomach, adrenal cortex, thymus, and lung ○ Various nonneuroendocrine lesions occur in skin, soft tissue, and central nervous system

EPIDEMIOLOGY Incidence • 1:20,000-40,000

Age • Penetrance increases with age

ETIOLOGY/PATHOGENESIS Etiology • Caused by mutations in MEN1 gene at 11q13

Pathogenesis • MEN1 gene encodes 610-amino acid protein menin ○ Protein with multitude of functions and interactions and known tumor suppressor

Multiglandular Parathyroid Hyperplasia (Left) Gross pathology from a multiple endocrine neoplasia type 1 (MEN1) patient with parathyroid hyperplasia shows that 3 of the glands are enlarged (each a different size) as compared to a relatively normal parathyroid. (Right) This 3.5-cm mass in the head of the pancreas of a 26year-old woman with MEN1 syndrome shows a pale pink cut surface with areas of cystic change and hemorrhage. Pancreatic neuroendocrine tumors are usually well circumscribed.

696

Cut Surface of Pancreatic Tumor

Multiple Endocrine Neoplasia Type 1 (MEN1) ○ Central nervous system tumors – Spinal ependymomas, meningioma, and astrocytoma have been described in MEN1 cases ○ Soft tissue tumors – Esophageal leiomyoma – Renal angiomyolipoma – Malignant gastrointestinal stromal tumors – Large visceral and intrathoracic lipomas – Aggressive malignant peripheral nerve sheath tumor arising from adrenal ganglioneuroma ○ Breast cancer – Has been found in 6% of female patients with MEN1

Treatment

Overview of Syndromes: Syndromes

– ZES □ Most frequent clinical manifestation related to duodenal &/or pancreatic gastrinoma observed in MEN1 patients □ MEN1-associated ZES accounts for 20-30% of all ZES cases □ Initial symptoms such as abdominal pain or gastroesophageal reflux disease caused by gastric acid hypersecretion □ Source of gastrin excess is multicentric NETs typically in mucosa and submucosa of upper duodenum and sometimes at margin of ulcer □ In 90% of MEN1 patients with ZES, lesions are often multiple, small, and located in duodenum – Insulinomas □ 2nd most frequent pancreatic tumor in setting of MEN1 □ Hypoglycemia – Glucagonoma, VIPoma, and other pancreatic endocrine tumors □ Occur in < 5% of MEN1 patients □ > 70% of glucagonomas and 40% of VIPomas are malignant □ Glucagonomas induce necrolytic migratory erythema associated with diabetes mellitus, which is secondary to abnormal glucagon secretion □ VIPomas induce classic Verner-Morrison syndrome associated with watery diarrhea, hypokalemia, and achlorhydria □ GHRH tumor-causing acromegaly – Nonfunctioning pancreatic endocrine tumors □ 20-40% of MEN1 patients • Others ○ Adrenal cortical lesions – Observed in 20-45% of MEN1 patients – Often hyperplastic, ≤ 3 cm, bilateral, and nonfunctional – Adrenal cortical carcinomas may be found bilaterally – MEN1 cases more often associated with hyperaldosteronism ○ Thymic and bronchial neuroendocrine tumor – Observed in 5-10% of MEN1 patients – Bronchial carcinoids (typical and atypical) are usually nonfunctioning ○ Gastric ECLomas – Thought to originate from proliferation of ECL cells in fundic mucosa – Often small and multiple – Can be treated with endoscopic polypectomy if lesion is < 1 cm – Good prognosis ○ Cutaneous proliferations – Present in 40-80% of MEN1 patients – Variable histologic forms □ Collagenomas □ Angiofibromas are multiple and often on face □ Nodular lipomas are multicentric and show no recurrence after surgery □ Café au lait macules □ Confetti-like hypopigmented macules □ Multiple gingival papules

• Hyperparathyroidism ○ Total parathyroidectomy with autotransplantation or subtotal resection of 3.5 parathyroid glands ○ Prophylactic partial thymectomy is also considered: Mediastinal recurrence due to ectopic or supernumerary parathyroid glands in as many as 12% of cases • Pituitary adenoma ○ Conflicting data on treatment response – Pharmacotherapy &/or surgery: Suboptimal response of functioning pituitary adenomas (earlier reports) – Dopamine agonist therapy: Good response of lactotroph adenomas in adult patients with MEN1 (Netherlands cohort) • Endocrine pancreatic/duodenal tumors ○ Surgery

Prognosis • Same prognosis for pituitary adenoma in MEN1 as in sporadic counterparts • Malignancy of duodenal and pancreatic endocrine tumors ○ Gastrinomas > 40%, glucagonoma > 80%, VIPoma > 40%, nonfunctioning tumor > 70% • Increased risk of premature death, usually related to disease and its complications ○ Main causes of death are thymic tumors, PNETs, along with rare cases of aggressive adrenal tumors ○ Female sex, family history of MEN1, and recent diagnosis are associated with lower risk of death ○ Patients with small duodenal NETs have 15-year survival rate of nearly 100%

Diagnostic Criteria • Criteria related to inherited cancers ○ Age < 50 years ○ Positive family history ○ Multifocal or recurrent neoplasia ○ Presence of ≥ 2 of following – Primary hyperparathyroidism with multiglandular hyperplasia &/or adenoma or recurrent primary hyperparathyroidism – Duodenal &/or pancreatic endocrine tumors, gastric ECL tumors □ Both functioning and nonfunctioning or multisecreting tumor – Anterior pituitary adenoma □ Functioning (GH-secreting tumor or acromegaly, prolactinoma) □ Nonfunctioning or multisecreting 697

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 1 (MEN1) – Adrenocortical tumor □ Both functioning and nonfunctioning – Thymic &/or bronchial tube endocrine tumors (foregut carcinoids) – 1st-degree relative with MEN1 according to above criteria

MACROSCOPIC Hyperparathyroidism • All 4 glands are generally grossly enlarged (> 6-8 mm), increased in weight (> 40-60 mg), and lobulated • MEN1-associated multiglandular parathyroid lesions are composed of multiple monoclonal cell proliferations consisting of multiglandular adenomas

Pituitary Adenoma • Soft, well-circumscribed lesion ○ May be confined to sella turcica ○ Larger lesions extend into suprasellar region and often compress optic chiasm • MEN1-associated adenomas vs. nonassociated are more often to be ○ Multiple (i.e., in 4-5% of cases vs. 0.1%) ○ Multihormonal (i.e., in 10-39% of cases), with prolactin and growth hormone being most frequently detected

Duodenal &/or Pancreatic Endocrine Tumors • Multiple well-circumscribed nodules in mucosa and submucosa of duodenum and within pancreatic parenchyma • Diffuse microadenomatosis associated with 1 or several macrotumors (> 0.5 cm) is distinctive feature of pancreas in MEN1

MICROSCOPIC General Features • Parathyroid hyperplasia ○ Multiglandular parathyroid lesions are suggested to be composed of multiple monoclonal proliferations, constituting multiple multiglandular microadenomas ○ All 4 glands are hypercellular with relative paucity of intraparenchymal fat ○ Architecturally, pattern in hyperplasia consists of cords or nests, or cells in glandular pattern as well as foci of solid sheets (nodular hyperplasia) ○ Predominant cell type is chief cell – Faintly eosinophilic cytoplasm and centrally placed, round, relatively monotonous nucleus without conspicuous nucleoli – Followed by oncocytic &/or clear cells ○ Mostly lack characteristic atrophic rim of nonlesional parathyroid tissue • Pituitary adenoma ○ Composed of uniform, polygonal cells arranged in sheets or cords with absence of reticulin network ○ Cytoplasm can be acidophilic, basophilic, or chromophobic depending on type and amount of secretory product ○ Nuclei of neoplastic cells may be uniform or pleomorphic ○ Macroadenomas (76-85%) vs. sporadic cases – Significantly larger 698

– Often more invasive – Higher Ki-67 proliferation index – More S100(+) folliculostellate cells • Pancreatic &/or duodenal endocrine tumors ○ Pancreatic endocrine tumors – Diffuse microadenomatosis associated with 1 or several macrotumors (> 0.5 cm) is characteristic of pancreas in MEN1 syndrome □ Numerous nonfunctioning microadenomas (< 0.5 cm) distributed throughout pancreas – Distinct trabecular/pseudoglandular pattern with conspicuous connective tissue stroma – Insulinomas with amyloid deposition – Tiny monohormonal glucagon cell proliferations that appear to originate from islets with hyperplastic glucagon cell component are composed of monoclonal cells □ Characterized by loss of heterozygosity of 11q13, which is obviously required to transform hyperplastic cells into neoplastic proliferations – Islet hyperplasia and endocrine cell budding from ducts are not features ○ Duodenal endocrine tumors – Well-circumscribed mucosal or submucosal nodules – Well differentiated (grade 1) – Trabecular to pseudoglandular pattern – Cells have fine chromatin and inconspicuous nucleoli – Stain mainly for gastrin – Associated with focal hyperplastic changes of gastrin and somatostatin cells in duodenal crypts and Brunner glands • Others ○ Adrenal nodular hyperplasia ○ Adrenal cortical carcinoma ○ Thymic and bronchial NETs ○ Gastric ECLomas: Proliferation of ECL cells ○ TSH-producing pituitary carcinoma

ANCILLARY TESTS Immunohistochemistry • Pituitary adenoma can express 1 or several hormones ○ Prolactin, GH, ACTH, LH, FSH, and TSH • Pancreatic endocrine tumor can express 1 or several hormones ○ Glucagon, insulin, pancreatic polypeptide, somatostatin, gastrin, vasointestinal polypeptide, serotonin, and calcitonin

Genetic Testing • MEN1 gene ○ Inherited as autosomal dominant trait or occurs de novo ○ Located on chromosome 11q13 ○ Encodes menin – Protein with multitude of functions and interactions and known tumor suppressor □ Multiple domains and interacting partners, ranging from transcription factors to histone deacetylase complexes

Multiple Endocrine Neoplasia Type 1 (MEN1) • 2 syndromes that should be considered in mutationnegative MEN1 patients: MEN4 and familial isolated pituitary adenomas

DIFFERENTIAL DIAGNOSIS Multiple Endocrine Neoplasia Type 4 • Autosomal dominant disease, caused by germline mutations of CDKN1B • Resulting in phenotype similar to that of MEN1 characterized by neuroendocrine neoplasms, particularly in parathyroid glands and pituitary but rarely pancreas • Compared to MEN1 patients, patients with MEN4 develop tumors at relatively late age with mean age for developing primary hyperparathyroidism ~ 56 years • Patients presenting with MEN1-like changes but lacking germline MEN1 mutation should therefore be tested for CDKN1B mutation ○ ~ 5-25% of clinically diagnosed patients with MEN1 in whom no mutation can be found may have CDKN1B mutation

Familial Isolated Pituitary Adenoma • Defined as occurrence of pituitary adenomas of any type among ≥ 2 related family members in absence of MEN1 or Carney complex • Autosomal dominant disease with low penetrance • Familial isolated pituitary adenoma is syndrome of familial isolated pituitary adenomas caused by mutation in AIP gene, most commonly resulting in prolactin-secreting and GH-secreting pituitary tumors ○ 20% of affected families harbor mutation in AIP gene • Slightly higher prevalence in women

Hyperparathyroidism-Jaw Tumor Syndrome • Autosomal dominant disorder caused by mutation in CDC73 (previously known as HRPT2) • Often is caused by parathyroid adenoma or carcinoma and follows much more aggressive behavior

Multiple Endocrine Neoplasia Type 2

• Serum Ca, PTH: Hyperparathyroidism • PRL, GH, ACTH, others: Pituitary adenoma • Gastrin, insulin, glucagon, pancreatic polypeptide, and serum chromogranin-A: GI NET

• Autosomal dominant tumor syndrome pattern caused by mutations of RET gene • Characterized by various endocrine tumors, such as medullary thyroid carcinoma and adrenal pheochromocytoma • Additional abnormalities affecting nonendocrine tissues may be present • Subdivided into 3 groups ○ Familial medullary thyroid carcinoma, MEN2A, and MEN2B

DIAGNOSTIC CHECKLIST

Carney Complex

• Simultaneous presence of at least 2 of 3 characteristic tumors (pituitary, parathyroid, or pancreatic islets) is still considered pathognomic for MEN1 ○ New clinical practice guidelines describe 3 criteria for diagnosis of MEN1: Genetic, clinical, and familial – Current practice guidelines: Genetic mutation analysis should be offered to all patients meeting familial or clinical criteria for diagnosis of MEN1 and patients presenting with MEN1-related tumor

• Autosomal dominant syndrome caused by PRKAR1A mutations • Multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous, and neural tumors, as well as mucocutaneous pigmented lesions • May involve several endocrine glands (adrenal cortex, pituitary, and thyroid)

Serologic Testing

Overview of Syndromes: Syndromes

– Scaffold protein with crystal structure that may associate with cell membrane and organelles and may be active in nucleus (regulates gene transcription) • Genetic testing has well-established role in confirming diagnosis of MEN1 ○ Identifying family members of index patients with MEN1 mutation who are at risk of developing tumor manifestation ○ Reassuring family members without mutation • Mutation spectrum ○ > 400 different mutations described ○ Spread over entire coding and intronic sequence – 40% frameshift changes, 25% missense, 20% nonsense mutations – No significant genotype-phenotype correlations, with few exceptions ○ All somatic cells have inactivating mutation in one MEN1 allele, predisposing patient to development of tumors associated with condition – But neoplasms do not develop until loss of heterozygosity of normal MEN1 allele occurs at tissue level – Therefore, loss of heterozygosity is essential for tumorigenicity, although other factors are also at play ○ Penetrance of MEN1 is high; > 90% of individuals carrying MEN1 mutation will be affected ○ Tissue-specific factors determine expression of MEN1 mutations in specific organs – Range from menin expression levels and interacting proteins, such as mixed-lineage leukemia protein, to presence (or absence) of other genes that regulate cell growth and proliferation, such as CDKN1B ○ 5-25% of patients clinically diagnosed with MEN1 in whom no mutation can be found – Most common mutation-negative MEN1 phenotype is combination of primary hyperparathyroidism and pituitary adenoma – This phenotype might also be caused by mutations in CDKN1B gene, causing recently described MEN4 syndrome • Testing ○ Sequencing – Genetic counseling useful for individuals and families with nonclassic MEN1 presentations

699

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 1 (MEN1) Frequency and Clinical Features of Various Organ Changes in Multiple Endocrine Neoplasia Type 1 Organ Changes

Frequency

Parathyroid gland

≥ 90%

Clinical Features

Microadenomatosis

Primary hyperparathyroidism

Multiglandular parathyroid disease: Multiple multiglandular microadenomas

Usually 1st manifestation of MEN1 patients

Neuroendocrine pancreas

30-75%

Multiple microadenomas Diffuse microadenomatosis

Distinct feature of pancreas in MEN1

Nonfunctioning macrotumors

Distinctive trabecular/pseudoglandular pattern

Functioning macrotumors Insulinoma

10-30%

Hypoglycemia syndrome

Glucagon

Monoclonal glucagon cell proliferations

Duodenum Multiple gastrinomas

50-80%

ZES

Multicentric NETs in mucosa and submucosa of duodenum

MEN1-associated ZES accounts for 20-30% of all ZES cases

Pituitary gland Adenoma

70%

Clinically silent, local symptoms, pituitary insufficiency

Lactotroph adenoma

Frequent

Amenorrhea, galactorrhea

Somatotroph adenoma

9%

Acromegaly

Corticotroph adenoma

4%

Cushing syndrome

Others

Rare

Other lesions Neuroendocrine tumors (thymus, stomach, lung, intestinal)

5-10%

Skin (facial angiofibromas, collagenoma, pigment lesions)

40-80%

Adrenal cortical hyperplasia/tumor

20-45%

Lipoma

10%

Spinal ependymoma

Rare

Soft tissue tumors

Rare

MEN1 = multiple endocrine neoplasia type 1; NETs = neuroendocrine tumors; ZES = Zollinger-Ellison syndrome.  Modified from: Komminoth P. et al: Multiple endocrine neoplasia type 1. In: WHO; 243, 2017.

SELECTED REFERENCES 1. 2.

3. 4.

5. 6.

7.

8.

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Cetani F et al: Familial and hereditary forms of primary hyperparathyroidism. Front Horm Res. 51:40-51, 2019 Guilmette JM et al: Neoplasms of the neuroendocrine pancreas: an update in the classification, definition, and molecular genetic advances. Adv Anat Pathol. 26(1):13-30, 2019 Pepe S et al: Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects. J Endocrinol. 240(2):R21-45, 2019 Romanet P et al: UMD-MEN1 database: an overview of the 370 MEN1 variants present in 1676 patients from the French population. J Clin Endocrinol Metab. 104(3):753-64, 2019 de Laat JM et al: The importance of an early and accurate MEN1 diagnosis. Front Endocrinol (Lausanne). 9:533, 2018 Marini F et al: Correction to: Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. Endocrine. 62(1):234-41, 2018 Nell S et al: Management of MEN1 related nonfunctioning pancreatic NETs: a shifting paradigm: results from the DutchMEN1 study group. Ann Surg. 267(6):1155-60, 2018 Stevenson M et al: Molecular genetic studies of pancreatic neuroendocrine tumors: new therapeutic approaches. Endocrinol Metab Clin North Am. 47(3):525-48, 2018

9. 10. 11.

12.

13.

14.

15. 16. 17.

van Treijen MJC et al: Diagnosing nonfunctional pancreatic NETs in MEN1: the evidence base. J Endocr Soc. 2(9):1067-88, 2018 Alrezk R et al: MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr Relat Cancer. 24(10):T195-208, 2017 Bartsch DK et al: Bronchopulmonary neuroendocrine neoplasms and their precursor lesions in multiple endocrine neoplasia type 1. Neuroendocrinology. 103(3-4):240-7, 2016 Concolino P et al: Multiple endocrine neoplasia type 1 (MEN1): an update of 208 new germline variants reported in the last nine years. Cancer Genet. 209(1-2):36-41, 2016 Goudet P et al: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab. 100(4):1568-77, 2015 Ito T et al: Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/ZollingerEllison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore). 92(3):135-81, 2013 Thakker RV et al: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 97(9):2990-3011, 2012 Tsukada T et al: MEN1 gene and its mutations: basic and clinical implications. Cancer Sci. 100(2):209-15, 2009 Oberg K et al: Multiple endocrine neoplasia type 1 (MEN-1). Clinical, biochemical and genetical investigations. Acta Oncol. 28(3):383-7, 1989

Multiple Endocrine Neoplasia Type 1 (MEN1)

Multiglandular Parathyroid Disease (Left) The usual finding in specimens from patients with MEN1 and multiglandular parathyroid disease is an uneven enlargement of the parathyroid glands. In this thyroid specimen, 2 attached parathyroid glands show multiglandular parathyroid enlargement ﬇. (Right) H&E of a nodular parathyroid gland shows variable hypercellularity and variably sized nodules. The micronodular adenomatosis of the parathyroid gland is usually seen in patients with MEN1.

Chief Cell Proliferation

Overview of Syndromes: Syndromes

Parathyroid Multiglandular Disease

Parathyroid Clear Cell Component (Left) H&E of a parathyroid from a patient with MEN1 shows a chief cell predominant with focal clear cells. There are only scattered residual adipocytes present. (Right) MEN1-associated multiglandular parathyroid lesions are composed of multiple monoclonal cell proliferations consisting of multiglandular adenomas. Some may have abundant clear cell cytoplasm.

Tumor in Pancreas

Tumor in Pancreatic Head (Left) Graphic shows a small, hypervascular lesion in the pancreatic body with regional lymph node metastases. Note the absence of pancreatic ductal dilatation. (Right) Axial CECT in the arterial phase shows an 8-mm hypervascular insulinoma ſt in the pancreatic head; it was not detected on portal venous phase CT. Note the opacified superior mesenteric artery and unopacified superior mesenteric vein ﬇.

701

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 1 (MEN1)

Irregularly Shaped Pancreatic Islet

Pancreatic Microadenoma

Trabecular Arrangement in Pancreatic Neuroendocrine Tumors

Amyloid in Insulin-Producing Pancreatic Neuroendocrine Tumors

Pancreatic Microadenoma

Glucagon Expression in Pancreatic Neuroendocrine Tumors

(Left) H&E of pancreas from a MEN1 patient shows an irregularly shaped pancreatic islet with increase in the endocrine cell population. Immunohistochemistry for the pancreatic hormones in this pancreas shows multiple nonfunctioning microadenomas. (Right) IHC for chromogranin A of the pancreas from a MEN1 patient highlights the small proliferation of neuroendocrine cells with focal invasion into the adjacent parenchyma.

(Left) At higher magnification, the pancreatic neuroendocrine tumor (PNET) shows a distinct trabecular pattern with conspicuous connective tissue stroma. The nuclei of the cells show the typical salt and pepper pattern. (Right) PNETs may have abnormal amyloid deposition ﬇, as seen in this insulin-producing tumor.

(Left) H&E of pancreas from a MEN1 patient shows a proliferation of endocrine cells with immunohistochemical confirmation of a microadenoma (< 0.5 cm). This is the characteristic microscopic appearance of a patient with MEN1 syndrome, showing microadenoma and associated with islet cell hyperplasia. (Right) PNETs may be hormonally active or nonfunctional. The tumor cells in this example show cytoplasmic reactivity for glucagon.

702

Multiple Endocrine Neoplasia Type 1 (MEN1)

Pituitary Macroadenoma (Left) Gross image shows a pituitary macroadenoma that extends upward into the suprasellar cistern ﬈ and laterally into the cavernous sinus ﬉. Pituitary adenomas are a common finding in MEN1 patients. (Right) Coronal graphic shows a pituitary macroadenoma with suprasellar extension and acute hemorrhage ſt causing pituitary apoplexy.

Touch Preparation of Pituitary Adenoma

Overview of Syndromes: Syndromes

Pituitary Macroadenoma

Microscopic View of Pituitary Adenoma (Left) Touch preparation of pituitary adenoma shows a monotonous population of cells with poorly defined pale cytoplasm and round to oval nuclei with typical salt and pepper chromatin. (Right) Pituitary adenomas are usually arranged in a solid pattern, which is formed by a homogeneous population of cells with no nuclear pleomorphism. The nuclei exhibit neuroendocrine cell features with finely dispersed chromatin and small distinct nucleoli.

Prolactin-Producing Pituitary Adenoma

Prolactin Expression in Sparsely Granulated Lactotroph Adenoma (Left) Diffuse cytoplasmic as well as Golgi-pattern ﬊ immunoreactivity for PRL is usually present in densely granulated pituitary adenomas. (Right) Sparsely granulated lactotroph adenomas are composed of cells with typical Golgi-type ﬊ staining for PRL. There is only focal and faint immunopositivity for prolactin in these tumors.

703

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 2 (MEN2)

TERMINOLOGY Abbreviations • Multiple endocrine neoplasia type 2 (MEN2)

Synonyms • MEN2A (or MEN2) ○ Sipple syndrome • MEN2B (or MEN3) ○ Wagenmann-Froboese syndrome ○ Mucosal neuroma syndrome

Definitions • Autosomal dominant tumor syndrome caused by activating germline mutations in RET • Characterized by coexistence of various endocrine tumors and lesions in nonendocrine organs and tissues • 3 subtypes depending on clinical features and penetrance of RET mutations: MEN2A, MEN2B, familial medullary thyroid carcinoma (FMTC)

EPIDEMIOLOGY Incidence • Estimated 1.25-7.5/10 million per year ○ MEN2A: ~ 1 case per 2 million per year ○ MEN2B: ~ 1 case per 40 million per year ○ Hereditary MTC accounts for 25% of all MTC • F:M = 1:1

Prevalence • ~ 1/30,000 population

Mean Age at Clinical Presentation • MEN2A: 25-35 years • MEN2B: 10-20 years • FMTC: 45-55 years

ETIOLOGY/PATHOGENESIS RET Protooncogene • ~ 98% of MEN2 harbor germline RET mutation

• Maps to 10q11.2 and encodes receptor tyrosine kinase rearranged during transfection protein ○ Tyrosine kinase plays integral role in transducing signals for growth and differentiation in tissues derived from neural crest

CLINICAL IMPLICATIONS Clinical Presentation • MEN2A ○ MTC: ~ 70-95% – Generally 1st manifestation of MEN2A – Neck mass or neck pain in patient < 35 years of age □ Age-related progression of malignant disease, starting with C-cell hyperplasia (CCH) – Clinical disease: Palpable thyroid nodule &/or palpable lymphadenopathy – Subclinical disease: Identified after clinical testing or early thyroidectomy on patient with pathogenic RET mutation – Diarrhea (↑ frequent systemic manifestation; implies poor prognosis) when plasma calcitonin > 10 ng/mL – Metastatic disease: Cervical lymph nodes, lungs, liver, and bone are most common sites □ Up to 70% already have cervical lymph node metastases when diagnosed ○ Pheochromocytoma (PCC): ~ 50% – Usually after MTC (1st symptom in only 13-27%) – Adrenal involvement often diagnosed at 30-40 years of age – 40-60% of patients with MEN2 develop PCC with agerelated and mutation-specific penetrance – Diagnosis of PCC warrants further investigation for MEN2A and other syndromes □ Diagnosed at earlier age, subtler symptoms, and more likely to be bilateral than sporadic tumors – Malignant transformation in ~ 4% of cases – Stroke and myocardial infarction risk – PCCs occurring as part of MEN2 almost always benign, with < 1-2% reported to be malignant

Pheochromocytoma: Gross Cut Surface (Left) The cut surface of a typical pheochromocytoma (PCC) has a gray-pink appearance with areas of hemorrhage. The tumor is distinct from the surrounding bright yellow adrenal cortex ﬇. (Right) Bilateral medullary thyroid carcinoma (MTC) from a patient with multiple endocrine neoplasia type 2A (MEN2A) shows the characteristic wellcircumscribed, tan-pink cut surface.

704

Bilateral Thyroid Tumors in MEN2

Multiple Endocrine Neoplasia Type 2 (MEN2)

RET Mutations ↔ MEN2 Phenotype Correlations • Codon 634 in exon 11 ↔ full-blown phenotype of MEN2A; also CLA

•

• • • •

○ p.C634R ↔ fulminant course (↑ probability of having metastases at diagnosis of MTC) ○ 25% of FMTC harbor mutation in codon 634, but most commonly p.C634Y, p.C634R mutations are virtually absent Germline p.M918T mutations ↔ MEN2B ○ Somatic mutations frequently observed in MTC in individuals with no known family history of MTC ○ Overrepresented in individuals with sporadic MTC who have particular germline RET variant, c.2439C>T Codons 609 and 611 in exon 10 ↔ MTC in 77%, PCC in 17%, and HPT in 3% Cysteine codons 609, 618, and 620 in exon 10 ↔ MEN2A or FMTC cosegregating with HSCR Codons 768, 804, and 891 ↔ FMTC and in rare MEN2A Codons 790 or 804 ↔ PTC as well as MTC ○ 40% of p.V804M mutation had concomitant medullary and PTC

Overview of Syndromes: Syndromes

– High risk of developing hypertensive crisis and stroke or myocardial infarction; must be treated before surgery ○ Hyperparathyroidism (HPT): ~ 15-30% – Typically mild and asymptomatic, may range from single adenoma to marked hyperplasia – Affects adults many years after diagnosis of MTC; average age of onset: 38 years – Hypercalciuria and renal calculi may occur – If longstanding and unrecognized, symptoms may become severe ○ Pruritic cutaneous lichen amyloidosis (CLA): ~ 10% – Intense pruritus and secondary skin changes – Dermal amyloid deposition arises as consequence of repeated scratching – Typically located in interscapular region of back ○ Hirschsprung Disease (HSCR): ~ 7% – Complete absence of neuronal ganglion cells (aganglionosis) in myenteric (Auerbach) and submucosal (Meissner) plexuses in variable lengths of GI tract, primarily rectosigmoid colon • FMTC: ~ 10-20% ○ By definition, MTC as only clinical manifestation – Recent recommendations: Include as variant form within spectrum of MEN2A with ↓ penetrance of PCC and HPT □ Strict criteria should be met before classified as FMTC to avoid assumption of PCC risk • MEN2B ○ MTC: Early-onset of aggressive form of MTC – Individuals who do not undergo thyroidectomy at early age (< 1 year): Likely develop metastatic MTC – Before early prophylactic thyroidectomy, average age of death was 21 years – In patients with de novo MEN2B, MTC is usually diagnosed at more advanced stages ○ PCC: In ~ 50% ; ~ 1/2 multiple; often bilateral – Consistently produce epinephrine or both epinephrine and norepinephrine ○ Mucosal neuromas: Individuals with MEN2B may be identified in infancy or early childhood – Mucosal neuromas on anterior dorsal surface of tongue, palate, or pharynx and distinctive facial appearance – Lips become prominent (or "blubbery") over time – Neuromas of eyelids may cause thickening and eversion of upper eyelid margins – Prominent thickened corneal nerves may be seen by slit lamp examination ○ Ganglioneuromatosis: ~ 98-100% have neuroma and diffuse ganglioneuromatosis of GI tract – Associated symptoms: Abdominal distension, megacolon, constipation, or diarrhea – GI symptoms beginning in infancy or early childhood ○ Marfanoid habitus: ~ 98-100% have kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat ○ Parathyroid disease: Not related to MEN2B

Treatment and Prevention • MTC: Thyroidectomy with regional lymph node dissection ○ Complementary: Small molecule kinase inhibitors of RET (vandetanib and cabozantinib) and other receptors • PCC: Removed by adrenalectomy ○ Detected by biochemical testing and radionuclide imaging ○ Bilateral adrenalectomy indicated at time of demonstration of tumor within gland • Parathyroid lesions: Resection of visibly enlarged parathyroid glands, subtotal or total parathyroidectomy • Prevention of primary manifestations ○ Prophylactic thyroidectomy – Performed in MEN2A associated with high-risk mutations (< 5 years of age) and MEN2B (< 1 year of age) ○ Neck dissection – Central neck dissection: In early thyroidectomy □ Reserved for cases with basal calcitonin > 40 pg/mL □ Recommended for MTC and other cases with suspicion of lymph node metastasis – Lateral neck dissection: Only if radiologically or clinically suspicious for metastasis – Thyroidectomy for CCH, before progression to invasive MTC, may spare lymph nodes ○ Serum calcitonin screening – MEN2B: Annual, starting at 6 months old – MEN2A or FMTC: Annual, starting at 3-5 years of age – Postoperative, if only precursor lesion and no MTC: Every 3-6 months for first 2 years, then every 6 months until 5 years after surgery, and annually thereafter • Prevention of secondary manifestations ○ Before any surgery, presence of functioning PCC should be excluded in any MTC, MEN2A, or MEN2B ○ PCC adrenalectomy should be performed before thyroidectomy (avoid intraoperative catecholamine crisis and hypertensive crisis)

Prognosis • 10-year survival rate ○ 97.4% for patients with MEN2A 705

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 2 (MEN2) ○ 75.5% for patients with MEN2B

IMAGING General Features • Abdominal MR performed when PCC suspected clinically • F-18 fluorodopamine positron emission tomography (PET) best overall imaging modality in localization of PCC • Postoperative parathyroid localizing studies with Tc-99m sestamibi scintigraphy may be helpful if HPT recurs • For preoperative adenoma localization, 3D single-photon emission CT may also be used

MACROSCOPIC MTC • MTCs in MEN2 typically bilateral and multicentric • Tumors well circumscribed but unencapsulated • Smaller tumors located at junction of upper and middle 1/3 of thyroid lobes • Larger tumors can occupy entire lobe

PCC and Adrenomedullary Hyperplasia

• Adrenal medullary hyperplasia to neoplasia progression sequence leading to bilateral and multifocal PCC • Associated with bilateral adrenal medullary hyperplasia, nodular and diffuse (gray to tan) in majority of patients with MEN2A and MEN2B ○ Normal medulla located in apex and corpus of adrenal gland and accounts for < 1/3 of gland thickness ○ Adrenal medullary hyperplasia: Medulla > 1/3 of gland thickness in absence of cortical atrophy &/or medulla noted in tail of gland • Tumors tend to be bilateral and multicentric, gray, usually confined to adrenal medulla

• Mixed pattern of diffuse hyperplasia expanding into tail of gland ○ May be intermingling of medullary and adrenocortical cells ○ Cellular, architectural, and immunohistochemical features of hyperplastic lesions are similar to PCC • Classic pattern is small nests (zellballen) of neuroendocrine cells with interspersed capillaries • Sustentacular cells variably present • PCCs vary in morphology and may have variety of growth patterns ○ Most common are diffuse, large zellballen, cell cords, and cells may be round, oval, or spindled ○ Extreme pleomorphism may be seen in benign tumors • Hyaline globules usually present in PCCs of MEN2 • At molecular level, such lesions do not represent hyperplasia in MEN2 (micropheochromocytoma)

Parathyroid Lesions

Parathyroid Hyperplasia

• All 4 glands enlarged with considerable variation in size of each gland • Multiple enlarged cellular parathyroid glands ○ Individual gland measuring > 6-8 mm and weighing > 4060 mg considered abnormal parathyroid gland

• Intraparenchymal fat content reduced with great variation in this finding • Predominant cell type chief cells arranged in cords and nests or in glandular or follicular pattern • Corresponds to multiglandular adenomas in background of underlying genetic predisposition

PCC

MICROSCOPIC MTC and CCH • Tumors from heritable forms of MTC are virtually indistinguishable from those occurring sporadically, except for their bilaterality, multicentricity, and association with primary CCH ○ Primary CCH – Suggested when > 6-8 C cells per cluster in several foci with > 50 C cells per low-power field are identified – Usually obvious on H&E-stained slides (counting often unnecessary) – Recognized on basis of expansile intrafollicular C-cell proliferation with varying degrees of dysplasia ○ Primary CCH in MEN2 and in some sporadic microcarcinomas constitutes thyroid intraepithelial neoplasia of C cells • CCH to neoplasia progression: Hallmark of inherited forms of MTC 706

○ In MEN2, age of transformation from CCH to MTC varies with different germline RET mutations ○ Earliest manifestation of invasive carcinoma characterized by extension of C cells through basement membrane of expanded C-cell-filled follicles into surrounding thyroid interstitium (confirmed on collagen IV stain) • MTC diagnosed histologically when nests of C cells appear to extend beyond basement membrane and to infiltrate and destroy thyroid follicles • MTC has variable histological appearance ○ Morphology includes sheets, nests, trabeculae, or insular patterns ○ Cells round, polygonal, or spindle-shaped ○ ~ 80% show amyloid in stroma

ANCILLARY TESTS Immunohistochemistry • MTC: Calcitonin, calcitonin gene-related peptide (CGRP), chromogranin, and CEA ○ MTC and CCH suspected in presence of elevated plasma calcitonin concentration (specific and sensitive marker) • PCC: Neuroendocrine markers; RET staining not helpful to distinguish MEN2-associated PCC from sporadic cases

Genetic Testing: RET Protooncogene • RET molecular genetic testing indicated in all individuals with diagnosis of MTC, MEN2, or primary CCH • Gain-of-function mutations affected several hotspot codons, with great majority mutating cysteine residues in exons 10 and 11 • Algorithm for testing summarized in most recent American Thyroid Association MTC Practice Guidelines ○ Young age of onset, significant CCH, &/or multifocal disease suggest inherited disorder

Multiple Endocrine Neoplasia Type 2 (MEN2)

Testing of Relatives at Risk • At-risk relatives should be periodically screened for ○ MTC with neck ultrasound examination, and basal &/or stimulated calcitonin measurements ○ HPT with albumin-corrected calcium or ionized calcium ○ PCC with measurement of plasma or 24-hour urine metanephrine and normetanephrine • American Society of Clinical Oncologists identifies MEN2 as group 1 disorder ○ Genetic testing is considered part of standard management for at-risk family members ○ RET molecular genetic testing should be performed as soon as possible in all children at risk for MEN2B

DIFFERENTIAL DIAGNOSIS Apparently Sporadic Medullary Thyroid Carcinoma • MEN2: Only genetic differential diagnosis for MTC • Germline mutations in RET gene in individuals with simplex MTC: 6.0-9.5%

Physiological C-Cell Hyperplasia • Presence of ≥ 50 C cells per low-power field • C cells (immunoperoxidase staining): Beyond normal geographical distribution or typically clustered in upper 2/3 of lateral lobes • Observed in association with sporadic MTCs and other thyroid tumor types, Hashimoto thyroiditis, hypothyroidism, hypergastrinemic and hypercalcemic states, and PTEN-hamartoma tumor syndrome

Reactive CCH • Not detected on H&E, unilateral, no cytological atypia

Pheochromocytoma • Hereditary PCC: 84% for multifocal (including bilateral) tumors and 59% for tumors with onset ≤ 18 years of age • ~ 25% of individuals with PCC and no known family history may have inherited disease caused by mutation in 1 of 4 genes ○ RET: ~ 5% ○ VHL: ~ 11% – VHL disease: PCC, renal cell carcinoma, cerebellar and spinal hemangioblastoma, and retinal angioma – Some families with apparent autosomal dominant PCC have VHL gene mutations in absence of other clinical manifestations ○ SDHx: ~ 8.5% [SDHD or SDHB, or SDHA (SDHC mutations are rare)] – Genes are associated with familial paragangliomas (extraadrenal PCC or glomus tumors)

○ NF1: Virtually all PCC presentations are accompanied by clinical features of neurofibromatosis type 1 (NF1) • PCCs can sometimes express calcitonin or calcitonin generelated peptide ○ Tyrosine hydroxylase (+), cytokeratin (-), CEA(-): Can be used to distinguish PCC from metastatic medullary carcinoma

Hyperparathyroidism • Rare initial presentation of MEN2, unnecessary formal differential diagnosis • Role of surgical pathologist: Identify tissue as parathyroid and define abnormal gland • MEN2-related HPT associated with benign parathyroid proliferations; few reported cases of parathyroid carcinoma

Overview of Syndromes: Syndromes

○ All individuals with MTC and those with clinical features &/or family history suspicious of MEN2: Germline RET testing for exons 10, 11, and 13-16 • MEN2B detection strategy (detect > 98% of mutations) ○ Mutation analysis of exons 16 and 15 to detect p.M918T and p.A883F mutations ○ If negative: Testing for p.V804M in exon 14 followed by sequencing of entire RET coding region – Isolated p.V804M mutation ↔ FMTC but p.V804M cooccurring with 2nd RET variant ↔ MEN2B • Exon 10 sequencing should be considered in HSCR

Intestinal Ganglioneuromatosis • Germline analysis for RET p.M918T and p.A883F mutations should be offered • Other than MEN2, only other genetic differential diagnoses to consider are Cowden syndrome (more likely) and NF1

Genetically Related Disorder • HSCR ○ Complex genetic disorder characterized by aganglionosis of gut, likely due to absent gut ganglia from premature apoptosis of ganglia anlage – Similar clinical presentation: Careful differentiating constipation/obstipation resulting from ganglioneuromatosis of MEN2B ○ MEN2A and FMTC families segregate HSCR, seemingly unrelated neurocristopathy and developmental disorder ○ Subsets of families and individuals harboring germline RET mutations in exon 10, especially at codons 618 and 620, cosegregate MEN2A/FMTC and HSCR • PTC ○ ~ 20-40% of PTC associated with somatic gene rearrangements that cause juxtaposition of tyrosine kinase domain of RET to various gene partners (RET/PTC)

SELECTED REFERENCES 1.

Elisei R et al: Twenty-five years experience on RET genetic screening on hereditary mtC: an update on the prevalence of germline RET mutations. Genes (Basel). 10(9), 2019 2. McDonnell JE et al: Multiple endocrine neoplasia: an update. Intern Med J. 49(8):954-61, 2019 3. Castinetti F et al: A comprehensive review on MEN2B. Endocr Relat Cancer. 25(2):T29-39, 2018 4. Revised American Thyroid Association Guidelines for the management of medullary thyroid carcinoma. Pediatrics. 142(6), 2018 5. Accardo G et al: Genetics of medullary thyroid cancer: an overview. Int J Surg. 41 Suppl 1:S2-6, 2017 6. Essig GF Jr et al: Multifocality in sporadic medullary thyroid carcinoma: an international multicenter study. Thyroid. 26(11):1563-72, 2016 7. Pappa T et al: Management of hereditary medullary thyroid carcinoma. Endocrine. 53(1):7-17, 2016 8. Frank-Raue K et al: Hereditary medullary thyroid cancer genotypephenotype correlation. Recent Results Cancer Res. 204:139-56, 2015 9. Wells SA Jr et al: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 25(6):567-610, 2015 10. Korpershoek E et al: Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome. Neoplasia. 16(10):868-73, 2014 11. Krampitz GW et al: RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer. 120(13):1920-31, 2014

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Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 2 (MEN2) Components of MEN2 Syndromes Pathology

FMTC

MEN2A

MEN2B

Medullary thyroid carcinoma

> 90%

> 90%

> 90%

C-cell hyperplasia

100%

100%

100%

Pheochromocytoma

0%

30-50%

50%

Hyperparathyroidism

0%

15-30%

0%

Marfanoid habitus

0%

0%

98-100%

Mucosal neuromas

0%

0%

98-100%

Intestinal ganglioneuromatosis

0%

0%

60-90%

Thick corneal nerves

0%

Rare

60-90%

Cutaneous lichen amyloidosis

0%

10-15%

0%

FMTC = familial medullary thyroid carcinoma; MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B.

RET Receptor Mutations Associated With MEN2 Phenotypes and Risk for Thyroidectomy Codon/Mutations

MTC

+PCC

+PHPT

✓ ✓ ✓ ✓

✓ ✓ ✓ ✓

✓ ✓ ✓ ✓

✓ ✓

✓

✓✓

✓ ✓

✓

✓

✓

✓

✓ ✓

✓ ✓

✓

✓

✓

+CLA

+HSCR

MEN2B

ATA Riskⁱ

Exon 10 C609R/G/F/S/Y C611R/G/F/S/W/Y C618R/G/F/S/Y C620R/G/F/S/W/Y

✓ ✓

M M M M

Exon 11 C630R/F/S/Y  C634R/G/F/S/W/Y

✓

M H

Exon 13 E768D L790F

M M

Exon 14 V804L/M

✓

M

Exon 15 A883F S891A

✓

H M

✓

HST

Exon 16 M918T

Risk for thyroidectomy as defined by ATA risk categories: Moderate (M), high (H), and highest (HST)ⁱ; CLA = cutaneous lichen amyloidosis; HSCR = Hirschsprung disease; MTC = medullary thyroid carcinoma; PCC = pheochromocytoma; PHPT = primary hyperparathyroidism. Modified from ATA: American Thyroid Association. Grubbs et al: WHO 2017.

Screening Tests and Surgery for Tumors in MEN2 MTC (ATA Risk Stratification)

Age of RET Testing and 1st Ultrasound

Age of 1st Serum Calcitonin

Age of Prophylactic Thyroidectomy

Highest-risk: Mutation Ex16 (918)

ASAP and within 1st year of life

6 months, if surgery not already done

ASAP and within 1st year of life

High-risk: Mutation Ex11 (634) and Ex15 (883)

< 3-5 years

< 3-5 years

< 5 years

Moderate risk: Mutations Ex10 (609, 611, 618, 620); Ex11 (630); Ex13 (768, 790); Ex14 (804); Ex15 (891)

< 3-5 years

< 3-5 years

Consider surgery before 5 years Delay surgery if stringent criteria met

MTC = medullary thyroid carcinoma. Adapted from Wells et al. and McDonnell et al.

708

Multiple Endocrine Neoplasia Type 2 (MEN2)

Ganglioneuromas (Left) Young patient with multiple endocrine neoplasia type 2B (MEN2B) displays marked thickening of the lips and tongue due to ganglioneuromatosis. This patient also had MTC at young age. (Right) S100 highlights ganglioneuromatosis of the intestine from a patient with MEN2.

Cystic Pheochromocytoma

Overview of Syndromes: Syndromes

Ganglioneuromatosis

Adrenal Medullary Hyperplasia and Tumor (Left) Axial CECT shows a large, well-circumscribed, moderately enhancing right adrenal PCC ſt with a hypodense area of cystic necrosis st. (Right) Adrenal gland shows both MEN2associated PCC and adrenal medullary hyperplasia ﬊, which is characteristic of MEN2. The cut surface is graypink, which distinguishes it from the yellow of the adrenal cortex ﬇ or adrenal cortical tumors.

Hyaline Globules

SDHB Maintained in MEN2 (Left) Hyaline globules ﬊ are present in some PCCs but also may be seen in some adrenal cortical neoplasms. They tend to be particularly conspicuous in PCCs from patients with MEN2. (Right) SDHB reveals maintenance of immunoreactivity in a PCC associated with MEN2. SDHx mutations are seen in patients with hereditary PCC/paraganglioma syndromes.

709

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 2 (MEN2)

Prophylactic Thyroidectomy

MEN2-Associated C-Cell Hyperplasia

C-Cell Hyperplasia in MEN2

C-Cell Hyperplasia in MEN2

Medullary Microcarcinoma

Medullary Thyroid Microcarcinoma

(Left) Total prophylactic thyroidectomy from a patient with family history of MEN2 and mutation of RET shows a grossly normal thyroid. However, on histological examination, C-cell hyperplasia (CCH) and a small medullary carcinoma were present. (Right) C-cell proliferation is easily identified at this magnification by routine H&E. This CCH finding usually precedes medullary carcinoma in MEN2associated tumors.

(Left) In MEN2 thyroid, there are multiple foci of CCH. These areas are present in the vicinity of the tumor as well as in the contralateral lobe. Calcitonin highlights CCH adjacent to MTC. (Right) CCH is usually present adjacent to MTC in MEN2 patients. Lowpower view of the thyroid shows an area of CCH ﬇ in close proximity to a medullary carcinoma ﬊.

(Left) Thyroid section from a patient with family history of MEN2 and mutation of RET shows multiple medullary thyroid microcarcinoma. Note the infiltration by individual cells within the dense stromal fibrosis. (Right) Multiple medullary thyroid microcarcinomas are usually seen in thyroidectomy of MEN2 patients. This tumor is < 0.5 cm and has an infiltrative pattern showing desmoplasia and individual cells infiltrating the stroma.

710

Multiple Endocrine Neoplasia Type 2 (MEN2)

MEN2A-Associated Medullary Carcinoma (Left) Gross cut surface of a thyroid lobe from a patient with MEN2-associated MTC shows a well-circumscribed, firm, white-gray thyroid nodule with hemorrhage. (Right) Thyroid cut surface of a familial MTC in a patient with MEN2A syndrome shows a large, firm, multilobulated, gray-yellow mass. Residual thyroid is seen ﬇.

MTC Cytological Features

Overview of Syndromes: Syndromes

Medullary Thyroid Carcinoma

TTF-1 and Calcitonin Positivity (Left) Fine-needle aspiration from MTC shows the characteristic cellular specimen with clusters of loosely cohesive cells and single cells in the background with the salt and pepper quality of the nuclear chromatin. Many cells have a plasmacytoid appearance. (Right) Dual staining for TTF-1 and calcitonin in MTC shows variable immunopositivity for both TTF-1 (nuclear) and calcitonin (cytoplasmic) in the tumor cells. The endothelial cells are negative.

Cut Surface of Parathyroid

Parathyroid Adenomatosis in MEN2A (Left) Gross cut surface of an enlarged parathyroid shows a pink-yellow, slightly nodular surface with areas of hemorrhage. There is a small area of normal parathyroid st, compressed by this micronodular adenomatosis. (Right) Parathyroid has a nodular growth pattern in primary parathyroid hyperplasia with clear (water clear) cells ﬈, chief cells ſt, oxyphil cells ﬇, and a few scattered fat cells. The quantity of fat cells is highly variable both within a single gland and among glands.

711

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 4 (MEN4) – Demonstrating novel role for CDKN1B as tumor susceptibility gene for endocrine and other neoplasms

TERMINOLOGY Abbreviations • Multiple endocrine neoplasia type 4 (MEN4)

EPIDEMIOLOGY

Synonyms

Incidence

• MEN1-like syndrome

• Extremely low ○ ~ 1.5-3.7% incidence of CDKN1B mutations in patients with MEN1-related phenotype

Definitions • Novel MEN syndrome was recently discovered, initially in rats, then known as MENX, and then in humans, now known as MEN4 • Autosomal dominant disease caused by germline mutations of CDKN1B, resulting in phenotype similar to that of MEN1 ○ Characterized by neuroendocrine neoplasms, particularly in parathyroid glands, pituitary, and pancreas ○ Recently, somatic and germline mutations in CDKN1B were also identified in patients with sporadic primary hyperparathyroidism (PHPT), lymphoma, and breast cancer

Age • PHPT most frequent manifestation in patients with MEN4 ○ Appears to occur later than in MEN1 – Average reported patient age: 56 years (vs. 20-25 years in MEN1)

Penetrance • Has not been reliably calculated (limited data suggesting incomplete penetrance of CDKN1B mutations)

Pancreatic Neuroendocrine Tumor

Patients with MEN4 may have diffuse microadenomas associated with 1 or more macroadenomas. This gross cut surface of the pancreas shows the typical pancreatic neuroendocrine tumor, characterized by a firm, pale-tan surface ſt.

712

Multiple Endocrine Neoplasia Type 4 (MEN4)

Etiology • Caused by mutations in CDKN1B gene at 12p13

○ ○ ○ ○

Stomach Thyroid Breast Duodenum

Pathogenesis

Treatment

• CDKN1B gene encodes p27 ○ p27: Cyclin-dependent kinase inhibitor whose main function is to control progression from G1 phase to S phase • Most of reported CDKN1B mutations in humans are missense • CDKN1B mutations causing MEN4 affect p27's cellular localization, stability, or binding with Cdk2 or Grb2

• Hyperparathyroidism ○ Total parathyroidectomy with autotransplantation or subtotal resection of 3.5 parathyroid glands • Pituitary adenoma ○ Surgery • Tumors at other sites ○ Surgery

CLINICAL IMPLICATIONS Clinical Presentation • Clinical and histologic manifestations seem to be more variable than in MEN1 ○ Small number of patients reported so far; comprehensive phenotype has not yet been established • Wide variety of tumors have been reported in MEN4 • Most common neuroendocrine neoplasms ○ Parathyroid – PHPT seems to have fairly higher penetrance in MEN4 (75%) than in MEN1 – Appears to occur later than in MEN1 ○ Pituitary – Pituitary adenomas in children and adolescents are rare tumors that often result from tumor predisposition syndrome □ MEN1 and 4 □ Carney complex □ Tuberous sclerosis □ DICER1 syndrome □ NF1 □ McCune-Albright syndrome □ Familial isolated pituitary adenoma □ SDH-pituitary adenoma – Pituitary adenomas (37.5%): Corticotropinomas, somatotropinomas, and nonfunctioning pituitary adenomas □ Growth hormone-secreting adenoma: Features of acromegaly □ Adrenocorticotropic hormone-secreting tumors: Cushing disease □ Lactotroph adenoma (suspected): High prolactin blood levels □ Nonfunctioning adenoma ○ Pancreas – It appears that there is decreased penetrance of pancreatic neuroendocrine tumors (PNETs) in MEN4 when compared to MEN1 ○ Adrenal – Adrenal neoplasia is frequent finding in MEN1, but MEN4 data are not available – Only 1 case reported with bilateral adrenal nodules • Other sites ○ Cervix ○ Bronchus

Prognosis

Overview of Syndromes: Syndromes

ETIOLOGY/PATHOGENESIS

• Depends on tumors with which patients present or develop ○ Currently not possible to predict which tumors patients with CDKN1B mutations will develop • Pituitary tumors in MEN4 are present with less aggressiveness than MEN1 • Parathyroid tumors in MEN4 represent overall milder disease spectrum than MEN1 • Poor prognostic factors ○ Functioning hormonal syndromes ○ Local or distant tumor spread ○ Aggressive &/or large tumors ○ Need for multiple surgical resections

Diagnostic Criteria • No specific guidelines for diagnosis ○ CDKN1B-associated tumors have no distinctive features from tumors with other genetic backgrounds ○ Patients presenting phenotype suggestive of MEN1 but with no MEN1 mutations should be tested for CDKN1B mutations

MACROSCOPIC General Features • Clinical and histologic manifestations seem to be more variable than in MEN1, and, due to small number of patients so far reported, comprehensive phenotype has not yet been established

MICROSCOPIC General Features • CDKN1B-associated tumors have no distinctive features from tumors with other genetic backgrounds • NETs have histologic features similar to sporadic and other inherited tumors ○ Parathyroid hyperplasia/adenoma/carcinoma similar to non-MEN4 ○ Types of pituitary adenomas in MEN4 vary: Nonfunctional, somatotropinoma, prolactinoma, or corticotropinoma

Cytologic Features • Neuroendocrine-type cells

713

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 4 (MEN4)

714

ANCILLARY TESTS

DIFFERENTIAL DIAGNOSIS

Immunohistochemistry

Multiple Endocrine Neoplasia Type 1

• Pituitary adenoma can express 1 or several hormones ○ Prolactin ○ ACTH ○ GH ○ LH ○ FSH ○ TSH • Pancreatic endocrine tumor can express 1 or several hormones ○ Pancreatic polypeptide ○ Glucagon ○ Insulin ○ Gastrin ○ Vasointestinal polypeptide ○ Somatostatin ○ Serotonin ○ Calcitonin

• Autosomal dominant disease caused by mutations in MEN1 gene at 11q13 • Characterized by proliferative lesions of multiple endocrine organs involving mainly parathyroid, endocrine pancreas/duodenum, and pituitary glands • Phenotype similar to that of MEN4; appears to occur earlier than in MEN4

Genetic Testing

Hyperparathyroidism-Jaw Tumor Syndrome

• Genetic testing in clinical practice for affected patients and their families with MEN has become routine • CDKN1B gene ○ Located on chromosome 12p13 ○ 2 coding exons resulting in 2.4 kb coding region ○ 16 germline base substitutions in CDKN1B have been identified in association with development of various endocrine tumors – Mutations reduce amount of protein, inhibit its binding to protein partners or mislocalized p27 to cytoplasm, ultimately impairing protein's ability to regulate cell division ○ Encodes p27 – Cyclin-dependent kinase inhibitor whose main function is to control progression from G1 phase to S phase – Activity tightly regulated at transcriptional, translational, and posttranslational levels – Multifunctional protein involved in control of various processes □ Migration and invasion, apoptosis, autophagy, progenitor/stem cell fate and specification, cytokinesis, and transcriptional regulation ○ In clinical practice, if clinician encounters patients with asymptomatic or symptomatic PHPT – In young age (< 30 years old) – With multiglandular disease or – Parathyroid carcinoma or – Atypical adenoma or – Those with family history or evidence of syndromic disease and negative for MEN1 or MEN2 – Genetic testing for CDKN1B should be pursued • Identification of germline CDKN1B mutation should be followed by clinical, biochemical, and radiologic screening for MEN4 • CDKN1B somatic mutations are frequent in NETs and other nonendocrine neoplasms

• Autosomal dominant disorder caused by mutation in CDC73 (previously known as HRPT2) • Known as familial cystic parathyroid adenomatosis • Parathyroid tumors usually single but may be multiple • Often caused by parathyroid adenoma or carcinoma and follows much more aggressive behavior • Parathyroid carcinoma is cause of hypercalcemia in 15-37% of cases ○ Although diagnosis of carcinoma not made until recurrence • Patients with apparently sporadic parathyroid carcinoma; up to 30% in fact have germline mutations in CDC73 ○ Indicating occult syndrome

Multiple Endocrine Neoplasia Type 2 • Autosomal dominant tumor syndrome pattern caused by mutations of RET gene • Characterized by various endocrine tumors involving thyroid, adrenals, and parathyroids • Additional abnormalities affecting nonendocrine tissues may be present • Subdivided into 3 groups ○ Familial medullary thyroid carcinoma, MEN2A, and MEN2B

Carney Complex • Autosomal dominant syndrome ○ Caused by PRKAR1A mutations • Multiple neoplasia syndrome featuring endocrine overactivity involving diverse endocrine organs, such as adrenal cortex, pituitary, thyroid, ovary, and testes, as well as ○ Spotty skin pigmentation, schwannomas, myxomatosis, neural tumors, and (rarely) tumors in liver and pancreas • Tumors and lesions ○ Primary pigmented nodular adrenocortical disease, bilateral adrenal hyperplasia leading to Cushing syndrome ○ Growth hormone-secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly ○ Thyroid and gonadal tumors, including predisposition to thyroid cancer ○ Psammomatous melanotic schwannomas, which can become malignant ○ Myxomas of heart, breast, and other sites

Multiple Endocrine Neoplasia Type 4 (MEN4)

Clinically Relevant Pathologic Features • Most common tumors are parathyroid tumors, pancreatic tumors, and other NETs ○ Parathyroid: PHPT seems to have fairly higher penetrance in MEN4 (75%) than in MEN1 – Appears to occur later than in MEN1; average reported patient age: 56 years (vs. 20-25 years in MEN1)  ○ Pancreas: Similar to sporadic and other hereditary tumors  ○ Pituitary: Adenomas (37.5%): Corticotropinomas, somatotropinomas, and nonfunctioning pituitary adenomas • Wide variety of tumors have been reported in MEN4 

Pathologic Interpretation Pearls • CDKN1B-associated tumors have no distinctive features to distinguish them from tumors of other genetic backgrounds

CDKN1B  • Patients presenting phenotype suggestive of MEN1 but with no MEN1 mutations should be tested for CDKN1B mutations • CDKN1B mutations enable personalized approaches to diagnosis, risk stratification, and appropriate treatment for individuals with MEN and other sporadic tumors

SELECTED REFERENCES 1.

2. 3.

4.

5.

6.

7. 8.

9. 10.

11. 12. 13. 14. 15.

Frederiksen A et al: Clinical features of multiple endocrine neoplasia type 4 novel pathogenic variant and review of published cases. J Clin Endocrinol Metab. ePub, 2019 Marx SJ et al: Evolution of our understanding of the hyperparathyroid syndromes: a historical perspective. J Bone Miner Res. 34(1):22-37, 2019 Cristina EV et al: Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-jaw tumour, familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 32(6):861-75, 2018 Hannah-Shmouni F et al: An update on the genetics of benign pituitary adenomas in children and adolescents. Curr Opin Endocr Metab Res. 1:1924, 2018 Horiuchi K et al: Impact of "tailored" parathyroidectomy for treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1. World J Surg. 42(6):1772-8, 2018 Keutgen XM et al: Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype. Cancer. 124(3):636-47, 2018 Alrezk R et al: MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr Relat Cancer. 24(10):T195-208, 2017 Marx SJ et al: Familial hyperparathyroidism - disorders of growth and secretion in hormone-secretory tissue. Horm Metab Res. 49(11):805-15, 2017 Pellegata NS et al: Multiple endocrine neoplasia type 4. In: WHO; 253-4, 2017 Wasserman JD et al: Multiple endocrine neoplasia and hyperparathyroid-jaw tumor syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(13):e123-32, 2017 Caimari F et al: Novel genetic causes of pituitary adenomas. Clin Cancer Res. 22(20):5030-42, 2016 Pacheco MC: Multiple endocrine neoplasia: a genetically diverse group of familial tumor syndromes. J Pediatr Genet. 5(2):89-97, 2016 Schernthaner-Reiter MH et al: MEN1, MEN4, and Carney complex: pathology and molecular genetics. Neuroendocrinology. 103(1):18-31, 2016 Stratakis CA: Carney complex: a familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab Disord. 17(3):367-71, 2016 Elston MS et al: Early onset primary hyperparathyroidism associated with a novel germline mutation in CDKN1B. Case Rep Endocrinol. 2015:510985, 2015

16. Longuini VC et al: Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. Eur J Endocrinol. 171(3):335-42, 2014 17. Thakker RV: Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 386(1-2):2-15, 2014 18. Tonelli F et al: A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome. Eur J Endocrinol. 171(2):K7K17, 2014 19. Lee M et al: Multiple endocrine neoplasia type 4. Front Horm Res. 41:63-78, 2013 20. Occhi G et al: A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet. 9(3):e1003350, 2013 21. Malanga D et al: Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype. Eur J Endocrinol. 166(3):551-60, 2012 22. Pellegata NS: MENX and MEN4. Clinics (Sao Paulo). 67 Suppl 1:13-8, 2012 23. Tichomirowa MA et al: Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocr Relat Cancer. 19(3):233-41, 2012 24. Costa-Guda J et al: Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab. 96(4):E701-6, 2011 25. Marinoni I et al: p27kip1: a new multiple endocrine neoplasia gene? Neuroendocrinology. 93(1):19-28, 2011 26. Wander SA et al: p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies. Clin Cancer Res. 17(1):12-8, 2011 27. Molatore S et al: A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum Mutat. 31(11):E1825-35, 2010 28. Molatore S et al: Characterization of a naturally-occurring p27 mutation predisposing to multiple endocrine tumors. Mol Cancer. 9:116, 2010 29. Molatore S et al: The MENX syndrome and p27: relationships with multiple endocrine neoplasia. Prog Brain Res. 182:295-320, 2010 30. Agarwal SK et al: Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab. 94(5):1826-34, 2009 31. Chu IM et al: The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 8(4):253-67, 2008 32. Besson A et al: Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev. 21(14):1731-46, 2007 33. Georgitsi M et al: Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab. 92(8):3321-5, 2007 34. Ozawa A et al: The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations. J Clin Endocrinol Metab. 92(5):1948-51, 2007 35. Pellegata NS et al: Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 103(42):15558-63, 2006 36. Philipp-Staheli J et al: p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp Cell Res. 264(1):148-68, 2001 37. Servant MJ et al: Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms. J Cell Biol. 148(3):543-56, 2000 38. Slingerland J et al: Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol. 183(1):10-7, 2000 39. Tomoda K et al: Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature. 398(6723):160-5, 1999 40. Fero ML et al: The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature. 396(6707):177-80, 1998 41. Pagano M et al: Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 269(5224):682-5, 1995

Overview of Syndromes: Syndromes

DIAGNOSTIC CHECKLIST

715

Overview of Syndromes: Syndromes

Multiple Endocrine Neoplasia Type 4 (MEN4) Germline CDKN1B Mutation in MEN4 and Phenotype CDKN1B Germline Mutation

Parathyroid Disease

Pituitary Tumors

-7G>C

PHPT

Bilateral adrenal mass (nonfunctioning)

-456_-453del(cctt)

GH-secreting (acromegaly)

-29_-26del(agag)

GH-secreting (young age)

-32_-29del(gaga)

PHPT

Nonfunctioning pancreatic neuroendocrine tumor Gastric carcinoid tumor

In Coding Sequence G9R

PHPT

K25fs

PHPT

A55T

PHPT

P69L

PHPT

Nonfunctioning

W76X

PHPT

GH-secreting (acromegaly)

P95S

PHPT (2 parathyroid tumors)

Zollinger-Ellison syndrome, mass in duodenum and tail of pancreas

S125X

PHPT (2 parathyroid tumors)

Multiple gastroenteropancreatic tumors

ACTH-secreting (Cushing disease) Zollinger-Ellison syndrome, gastrinoma

K96Q

PRL-secreting (suspected lactotroph adenoma)

I119T

GH-secreting (acromegaly)

E126D

PHPT (young age)

P133T

PHPT

Stop>Q

PHPT (3 parathyroid tumors)

ACTH = adrenocorticotropic hormone; GH = growth hormone; PHPT = primary hyperparathyroidism; PRL = prolactin. Modified from Pellegata NS et al: Multiple endocrine neoplasia type 4. In: WHO; 253-4, 2017.

716

Other Manifestations

In 5 Untranslated Region

Bronchial carcinoids, papillary thyroid carcinoma, bilateral multiple lung metastases

Breast tumor

Multiple Endocrine Neoplasia Type 4 (MEN4)

Parathyroid Adenoma (Left) Multiglandular parathyroid disease is a characteristic finding in patients with MEN4, as seen on this gross photo of an enlarged gland. These lesions are monoclonal proliferations of parathyroid cells, consisting of multiple microadenomas. (Right) High-power view of a parathyroid adenoma shows cells with clear or oxyphilic cytoplasm and focal and mild nuclear pleomorphism. Welldefined cytoplasmic membranes ﬇ are a characteristic of parathyroid cells.

Parathyroid Neoplasia in MEN4

Overview of Syndromes: Syndromes

Enlarged Parathyroid Gland

Pituitary Adenoma (Left) Hyperparathyroidism (PHPT) due to parathyroid neoplasia affects ~ 80% of MEN4 cases. No one with MEN4 had PHPT recurrence after surgical resection, which might indicate that PHPT in MEN4 represents an overall milder disease spectrum than MEN1. (Right) MEN4associated pituitary adenomas are usually functioning adenomas, and, as in MEN1 patients, they may be multiple and most frequently produce prolactin and growth hormone.

Well-Circumscribed Pancreatic Tumor

Glucagon-Producing Pancreatic Neuroendocrine Tumor (Left) The cut surface of this pancreatic neuroendocrine tumor is well circumscribed and shows a firm, tan-yellow, multilobulated ﬇ cut surface. (Right) As with MEN1 patients, MEN4 patients may have multiple pancreatic microadenomas and adenomas, as illustrated here. Glucagon-producing adenomas usually have a trabecular arrangement.

717

Overview of Syndromes: Syndromes

MUTYH-Associated Polyposis

TERMINOLOGY Abbreviations • MUTYH-associated polyposis (MAP) • Mut Y homologue (MUTYH )

EPIDEMIOLOGY Definition • MAP: Autosomal recessive disorder characterized by various number of colorectal polyps with different histological phenotypes that tend to progress to malignancy ○ Polyposis syndrome with recessive mode of inheritance in patients with attenuated polyposis phenotype

Prevalence

– Oxidated guanine binds to adenine instead of cytosine, hence G:C to T:A transversions – Somatic mutations in APC lead to polyposis similar to FAP • Autosomal recessive inheritance ○ 1-2% of population carry single deleterious mutation ○ Parents of affected patient are both carriers ○ Unclear if carriers have increased rate of colon cancer – Some reports have found slightly increased risk (1.52.1 relative risk) of CRC, whereas other studies have failed to show this ○ Patients' children are obligate carriers

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Profile

• 1 in 5,000 population • Mean age at diagnosis is 45 years, with reported age range of 10-70 years ○ Risk of colorectal cancer (CRC) is 80% at age 70 with 50% of patients found to have CRC at time of polyposis diagnosis ○ MAP patients tend to be older than familial adenomatous polyposis (FAP) patients but slightly younger than typical CRC patients – Right-sided CRC in younger patient suggestive of Lynch syndrome

GENETICS MUTYH Gene • Base excision repair gene ○ Located on chromosome 1p ○ Biallelic mutations in MUTYH, located at chromosome locus 1p34.3-p32.1, are responsible for development of these polyps ○ Biallelic germline mutations in MUTYH lead to G:C to T:A transversions in somatic genes (i.e., APC, KRAS) – Oxidation of guanine is normally repaired by MUTYH

• Multiple adenomas, but typically not in overwhelming numbers as seen in FAP ○ ~ 2/3 of patients have < 100 polyps • Due to recessive mode of inheritance, MAP patients are often discovered late in course of their disease, having already developed CRC as compared to FAP patients ○ Easy to miss diagnosis since there is no family history and patients have fewer polyps at older age than typical FAP patients

Genetic Testing • In patients without family history of polyposis, need to test for both FAP and MAP as ~ 30% of FAP cases arise de novo • MAP carcinomas are typically microsatellite-stable (as opposed to Lynch cancers that are unstable) • 2 common mutations in MUTYH account for 80% of cases (especially in people of Northern European descent) ○ Most cost-effective method currently is to sequence APC and test for 2 common MUTYH mutations – If this fails to identify mutations, then sequencing MUTYH will be necessary ○ If patients are not of Northern European descent, may be more cost effective to sequence MUTYH from start

Scattered Colonic Polyps (Left) The diagnosis of MUTYH-associated polyposis (MAP) is suspected when 20 to < 100 adenomatous colonic polyps ﬇ are found. If in association with hyperplastic polyps, sessile serrated adenomas, and mixed polyps, can aid possible diagnosis, differentiating MAP from other polyposis syndromes. (Right) Endoscopic view shows a stomach that is carpeted with fundic gland polyps. Patients with MUTYH can have gastric findings similar to those of patients with familial adenomatous polyposis. (Courtesy E. Stoffel, MD.)

718

Stomach With Fundic Gland Polyps

MUTYH-Associated Polyposis

Immunohistochemistry • Immunostains for gene product MUTYH is available

ASSOCIATED NEOPLASMS

Surgery • When polyps become too numerous, prophylactic colectomy with ileoanal anastomosis is treatment of choice

SELECTED REFERENCES 1.

Identical to FAP • Multiple adenomas and increased risk of CRC ○ Up to ~ 50% of MAP patients have 10-100 polyps, similar to attenuated FAP (AFAP) ○ Up to 29% will have > 100 adenomas and resemble classic FAP ○ May have unicryptal or microadenomas ○ May also have hyperplastic polyps, serrated polyps, sessile serrated adenomas, and mixed polyps – Differentiating MAP from other polyposis syndromes ○ MAP-associated colonic carcinoma has features of microsatellite-unstable cancer – Predilection to right colon – Presence of tumor-infiltrating lymphocytes – Mucinous histotype – Chron-like infiltrate • Extracolonic neoplasms ○ Up to 20% have duodenal adenomas – 4% lifetime risk of duodenal carcinoma ○ Gastric fundic gland polyps similar to FAP in ~ 15% of cases ○ Extraintestinal malignancies: 2x general population; lifetime risk: 40% ○ Congenital hypertrophy of retinal pigment epithelium, dermal cysts, osteomas, dental abnormalities, and desmoids have also been reported – Prevalence of these lesions may be lower than in FAP, but given rarity of syndrome, good data do not exist ○ Ovarian, bladder, and skin cancers have been reported (which can be suggestive of Lynch syndrome) ○ Association with breast and thyroid carcinomas also reported

2. 3. 4.

5.

6. 7.

8.

9. 10.

11.

12. 13.

14.

15. 16.

17. 18.

CANCER RISK MANAGEMENT

19.

Surveillance • If family with AFAP-like syndrome implies recessive inheritance (i.e., 1 or more cases in 1 generation), screening for MUTYH mutations should be performed • Patients with known MUTYH mutations should have colonoscopic surveillance beginning between ages 20-30 ○ If no polyps are found, may continue surveillance every 35 years ○ If polyps are found, may go to annual surveillance • Upper tract endoscopic surveillance is recommended beginning at ages 30-35 ○ If no polyps are found, may continue surveillance every 35 years ○ If polyps are found, annual surveillance may be recommended • Without timely surveillance, colonic carcinoma in MAP confers lifetime risk of ~ 100%

20.

21. 22. 23.

24.

25.

Samadder NJ et al: Hereditary cancer syndromes-a primer on diagnosis and management, part 2: gastrointestinal cancer syndromes. Mayo Clin Proc. 94(6):1099-16, 2019 Short E et al: The role of inherited genetic variants in colorectal polyposis syndromes. Adv Genet. 103:183-217, 2019 Sutcliffe EG et al: Multi-gene panel testing confirms phenotypic variability in MUTYH-associated polyposis. Fam Cancer. 18(2):203-9, 2019 Casper M et al: Phenotypic variability of MUTYH-associated polyposis in monozygotic twins and endoscopic resection of a giant polyp in pregnancy. Am J Gastroenterol. 113(4):625-7, 2018 Hurley JJ et al: The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis. Gastrointest Endosc. 88(4):665-73, 2018 Weren RD et al: NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 244(2):135-42, 2018 Kallenberg FGJ et al: Adrenal lesions in patients with (attenuated) familial adenomatous polyposis and MUTYH-associated polyposis. Dis Colon Rectum. 60(10):1057-64, 2017 Kanth P et al: Hereditary colorectal polyposis and cancer syndromes: a primer on diagnosis and management. Am J Gastroenterol. 112(10):150925, 2017 Kantor M et al: Hereditary colorectal tumors: a literature review on MUTYHassociated polyposis. Gastroenterol Res Pract. 2017:8693182, 2017 Pilati C et al: Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas. J Pathol. 242(1):10-5, 2017 Thomas LE et al: Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis. Clin Cancer Res. 23(21):6721-32, 2017 Grandval P et al: Genomic variations integrated database for MUTYHassociated adenomatous polyposis. J Med Genet. 52(1):25-7, 2015 Cohen SA et al: An individual with both MUTYH-associated polyposis and lynch syndrome identified by multi-gene hereditary cancer panel testing: a case report. Front Genet. 7:36, 2016 Kacerovska D et al: Cutaneous sebaceous lesions in a patient with MUTYHassociated polyposis mimicking Muir-Torre syndrome. Am J Dermatopathol. 38(12):915-23, 2016 McVeigh TP et al: MUTYH-associated polyposis: the Irish experience>. Ir Med J. 109(10):485, 2016 Walton SJ et al: Frequency and features of duodenal adenomas in patients with MUTYH-associated polyposis. Clin Gastroenterol Hepatol. 14(7):986-92, 2016 Castillejo A et al: Recurrent testicular germ cell tumors in a family with MYHassociated polyposis. J Clin Oncol. 30(23):e216-7, 2012 Lefevre JH et al: APC, MYH, and the correlation genotype-phenotype in colorectal polyposis. Ann Surg Oncol. 16(4):871-7, 2009 Terdiman JP: MYH-associated disease: attenuated adenomatous polyposis of the colon is only part of the story. Gastroenterology. 137(6):1883-6, 2009 Boparai KS et al: Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology. 135(6):2014-8, 2008 Castells A: MYH-associated polyposis: adenomas and hyperplastic polyps, partners in crime? Gastroenterology. 135(6):1857-9, 2008 O'Shea AM et al: Pathological features of colorectal carcinomas in MYHassociated polyposis. Histopathology. 53(2):184-94, 2008 Di Gregorio C et al: Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis. Gastroenterology. 131(2):439-44, 2006 Ponti G et al: Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations. Clin Genet. 68(5):442-7, 2005 Al-Tassan N et al: Inherited variants of MYH associated with somatic G:C->T:A mutations in colorectal tumors. Nat Genet. 30(2):227-32, 2002

Overview of Syndromes: Syndromes

• Can measure G:C to T:A transversion in tumor DNA, especially in APC and KRAS

719

Overview of Syndromes: Syndromes

Neurofibromatosis Type 1

TERMINOLOGY

EPIDEMIOLOGY

Abbreviations

Incidence

• Neurofibromatosis type 1 (NF1)

• 1:2,500-3,000

Synonyms

Age

• von Recklinghausen disease • Peripheral neurofibromatosis

• Diagnosis often made in childhood

ETIOLOGY/PATHOGENESIS

Definitions • Autosomal dominant tumor syndrome caused by mutations in NF1 on chromosome 17q11.2, leading to multiple neurofibromas, café au lait spots, freckling of axilla &/or groin, bone dysplasia, brainstem gliomas, malignant peripheral nerve sheath tumors (MPNST), pheochromocytomas, duodenal neuroendocrine tumors, and gastrointestinal stromal tumors (WHO 2017) • NF1 is most common inherited disease associated with neurofibromas

Etiology • Genetic syndrome resulting from germline mutations in NF1 • Inherited as autosomal dominant trait • Result from mutation in or deletion of NF1 encoding neurofibromin • Neurofibromin is tumor suppressor, which downregulates p21-RAS oncoprotein • Little genotype-phenotype correlation among patients with classic NF1 and NF1 mutations (other than chromosomal deletions)

Neurofibromin Pathway

NF1 syndrome is caused by germline mutations in the gene encoding for neurofibromin, a tumor suppressor protein that works by activating RAS GTPase function. Neurofibromin loss leads to constitutive RAS signaling and altered cAMP levels, resulting in a variety of neoplasms and other manifestations, particularly affecting the nervous system.

720

Neurofibromatosis Type 1

CLINICAL IMPLICATIONS Clinical Presentation • Skin lesions ○ Café au lait patches – Can be present at birth, and nearly every affected child has ≥ 6 by age 5 or 6 – Often 1st feature of NF1; > 95% of patients – Patches are usually round to ovoid, light brown in color with smooth borders, located over nerve trunks – Borders of patches are smooth, so-called "coast of California" ○ Plexiform neurofibromas – Pathognomonic for NF1; 40-60% of patients – Cutaneous neurofibromas are soft, sessile, or pedunculated lesions that vary in number – Subcutaneous neurofibromas are often firm, round masses that are painful – Plexiform neurofibromas contain numerous tortuous, thickened nerves □ ~ 30% of patients with NF1 ○ MPNST – Most common frequent malignant neoplasms associated with NF1 (8-13%) – Often large, irregular, painful mass with rapid expansion – Hematogenous metastasis to lung can occur – 50% of MPNSTs are associated with NF1 – All deep-seated sarcomas with clear association to nerve and without clear line of differentiation should be considered MPNSTs ○ Freckling in axillary or inguinal region – > 90% of NF1 patients – Presents by 7 year of age – Freckling occurs in non-sun-exposed skin – Appears later than café au lait spots • CNS lesions ○ Optic nerve glioma – ~ 15-20% of NF1 patients – Presents between birth and 7 years of age – Pilocytic astrocytoma is most common glioma affecting optic nerve – Can cause loss of vision and various visual abnormalities (e.g., strabismus, color vision changes, and proptosis) – May cause acromegaly ○ Macrocephaly ○ Unidentified bright objects – Multiple, bilateral foci on MR, often affecting brainstem as well as cerebellum and deep cerebral gray matter

• Lisch nodules ○ Pigmented hamartomatous nevus of iris ○ Present in > 94% of patients > 6 years of age ○ Clear, yellow-brown, oval to round, dome-shaped papules that project from surface of iris • Endocrine lesions ○ Pheochromocytoma – Occurs in ~ 1% of NF1 patients, usually in 4th or 5th decade – Headache is most common presentation, usually frontal or occipital; starts suddenly and lasts ~ 15 minutes – Present with classic symptoms and signs related to excess release of epinephrine and metanephrine □ Paroxysmal hypertension, palpitations, sweating, nervousness, anxiety, and pallor – Typically located in adrenal glands □ Extraadrenal localization is rare □ ~ 10% of patients have multiple tumors □ Metastases develop in < 5% of cases ○ Duodenal neuroendocrine tumors – 1% of NF1 patients – Most patients presenting with NF1-related duodenal NETs 40-50 years of age – Duodenal somatostatin-producing NETs usually occur at or in ampulla of Vater – Duodenal gangliocytic paragangliomas may coexist – Signs and symptoms are usually related to localization of tumor, including abdominal pain, anemia, melena, jaundice, and weight loss ○ Neuroendocrine tumors – Neuroendocrine tumors of gastrointestinal tract and periampullary region ○ Pituitary adenoma – GH-producing somatotroph adenoma causing acromegaly □ Acromegaly has been reported in patients with NF1 but usually due to optic pathway glioma • Gastrointestinal lesions ○ Gastrointestinal stromal tumor (GIST) – Prevalence rate of GISTs ~ 6.3/100 in NF1 patients – NF1 patients may be predisposed to developing small intestinal GISTs, which may appear as multiple GISTs without KIT and PDGFRA mutations ○ Neuroendocrine tumors of gastrointestinal tract – Coincidence of GIST and NET is almost pathognomonic for NF1 □ Should raise suspicion of this rare disorder in clinical practice • Bone lesions ○ Most common lesions are skeletal dysplasias: Sphenoid wing, orbital bone, long bone dysplasias ○ Rare lesions: Ciliary bone cysts and giant cell granulomas ○ Very rare lesions (but can lead to metastatic disease): Fibrosarcomas and primary neurogenic sarcomas • Neurobehavioral abnormalities ○ Headaches ○ Seizures ○ Learning disabilities occur in 50-75%

Overview of Syndromes: Syndromes

• Genetic counseling; 50% of patients with NF1 are familial while other 50% arise from de novo mutation ○ Neurofibromatosis-Noonan syndrome (NFNS): Rare condition with clinical features of both NF1 and Noonan syndrome (NS) – All 3 syndromes belong to RASopathies □ Major gene involved in NFNS is NF1, but also identified are co-occurring NF1 and PTPN11 mutations

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Overview of Syndromes: Syndromes

Neurofibromatosis Type 1 Treatment

Malignant Peripheral Nerve Sheath Tumor

• Genetic counseling; 50% of NF1 is familial while other 50% arise from de novo mutation • Cutaneous or subcutaneous neurofibromas can be removed surgically or by laser electrocautery • Surgical or radiofrequency therapy for diffuse plexiform neurofibromas or café au lait spots • Chemotherapy is treatment of choice for optic gliomas • Bracing for progressive dystrophic scoliosis • Among NF1-affected children with primary tumor, therapeutic radiation (but not alkylating agents) confers increased risk of subsequent neoplasia

• Huge fusiform mass

Prognosis • Average life expectancy of individuals with NF1 is reduced by 15 years • Wide variability of outcomes, depending on tumor burden

Optic Nerve Glioma • Grows within neural sheath to produce fusiform enlargement • Many low-grade gliomas (e.g., clinically indolent optic pilocytic astrocytoma) in patients with NF1 are not biopsied; therefore, little is known about specific histological features

Duodenal Neuroendocrine Tumor • Neuroendocrine tumors of duodenum in NF1 are usually solitary and often polypoid, with mean diameter of 2 cm • Typically affect major papilla &/or ampulla • Advanced lesions infiltrate sphincter of Oddi, duodenal wall, &/or pancreatic head and are then associated with lymph node metastases

Diagnostic Criteria • Developed by National Institutes of Health (NIH) Consensus Conference in 1987 ○ Presence of ≥ 2 of following – ≥ 6 café au lait macules, greatest diameter of which is > 5 mm in prepubertal patients and > 15 mm in postpubertal patients – ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma – Axillary or inguinal freckling (Crowe sign) – Optic glioma – ≥ 2 Lisch nodules – Distinctive osseous lesion, such as sphenoid dysplasia or pseudoarthrosis – 1st-degree relative with NF1 according to these criteria • By 8 years of age, 97% of children with NF1 clinically fulfill diagnostic criteria; by 20 years of age, rate reaches 100% • NIH 1991 ○ Presence of ≥ 2 of following – Café au lait macules (≥ 6) with diameter of 0.5 cm in children or 1.5 cm after puberty – Cutaneous or subcutaneous neurofibromas (≥ 2) or plexiform neurofibroma – Freckling of axillary or groin region – Glioma of optic pathways – Lisch nodules (≥ 2) identified by slit-lamp examination – Dysplasias of skeletal system (sphenoid wing, long bone bowing, pseudoarthrosis) – Diagnosis of NF1 in 1st-degree relative

MACROSCOPIC Neurofibroma • Benign tumor arising from Schwann cells that surround peripheral nerves of all sizes

Plexiform Neurofibroma • Tortuous proliferation of all components of peripheral nerves including axons, Schwann cells, fibroblasts, and perineurial cells

Café au Lait Spots • Vary in size; flat with smooth border 722

MICROSCOPIC Café au Lait Spots • Basilar hyperpigmentation ± suprabasilar melanosis • Giant melanosomes within melanocytes are characteristic

Neurofibroma • Proliferation of all elements in peripheral nerve, including neuritides, Schwann cells, and fibroblasts in loose, myxoid stroma • Consists mainly of uniform, spindle-shaped Schwann cells with barely discernible processes and delicate elongate or sinuous nuclei • Diffuse cutaneous and subcutaneous neurofibroma is much less common and is characterized by plaque-like tumor, usually in head and neck region • Pseudomeissnerian corpuscles are frequent

Plexiform Neurofibroma • S100 positivity in Schwann cells • Trichrome stains highlight proliferating fibroblasts • Plexiform tumors may undergo malignant transformation to MPNST (risk of progression: 2-5%) • Consists of tumor mass with multinodular and plexiform architecture that imparts bag of worms appearance

Malignant Peripheral Nerve Sheath Tumor • Tumor may show glandular differentiation, skeletal muscle (triton tumor), or epithelioid elements • Cells are pleomorphic with frequent mitotic figures • ~ 50% of MPNSTs express S100 weakly, focal in majority of cases, and minority show perineurial differentiation • Often high grade, poorly differentiated, and aneuploid • MPNSTs with rhabdomyosarcomatous and heterologous epithelial elements (malignant triton tumors) are particularly strongly associated with NF1 • Cutaneous MPNSTs, which are very rare, display fascicles of alternating cellularity, whorls, palisades, or rosette-like arrangements

Optic Nerve Glioma • In children, almost all are pilocytic astrocytomas • Fibrovascular septa within optic nerve are separated by tumor cells

Neurofibromatosis Type 1

Duodenal Carcinoid • Typically exhibit tubuloglandular and pseudoglandular structures • PAS(+) psammoma bodies composed of calcium apatite crystals

• High risk of pheochromocytoma but can be differentiated based on other clinical features

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls • Diagnosis of NF1 is often made in children • Plexiform neurofibromas, which contain numerous tortuous thickened nerves, are pathognomonic for NF1 • 50% of MPNST is associated with NF1

SELECTED REFERENCES

Pheochromocytomas

1.

• NF1-associated pheochromocytomas do not differ from sporadic pheochromocytomas, except that they are more frequently of composite type • NF1 pheochromocytomas lack high microvessel density typical of von Hippel-Lindau syndrome-associated pheochromocytomas

2.

ANCILLARY TESTS

3. 4. 5.

6.

Immunohistochemistry • Duodenal carcinoid ○ All duodenal NETs express synaptophysin, chromogranin A, and somatostatin

Genetic Testing • NF1 was mapped to 17q11.2 ○ Massive gene containing > 300 kilobases of DNA divided into > 50 exons • Most mutations are protein truncating, consisting of nonsense, frameshift, and splicing • NF1 has one of highest mutation rates in human disorders, which may explain outbreak of independent de novo variants in same family • Large gene deletion can be detected by FISH • NF1 abnormalities are currently found in > 90% of patients with clinical diagnosis of NF1

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8.

9. 10.

11.

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13. 14.

DIFFERENTIAL DIAGNOSIS McCune-Albright Syndrome • Consists of polyostotic fibrous dysplasia, café au lait spots, and endocrinopathies caused by GNAS mutation • Café au lait spots are larger than in NF1 and have "coast of Maine" border

15.

16. 17. 18.

Neurofibromatosis Type 2 • Autosomal dominant disorder caused by mutation of NF2, located on chromosome 22q12; encodes merlin • Bilateral vestibular schwannomas, cutaneous schwannomas, meningiomas, and juvenile posterior subcapsular cataracts

Hereditary Nonpolyposis Colon Cancer • Multiple café au lait spots, axillary freckling, and cutaneous neurofibromas are similar to NF1 • Colonic cancer at unusually young age

Multiple Endocrine Neoplasia Type 2B

19.

20. 21. 22. 23. 24. 25.

Ahlawat S et al: Imaging biomarkers for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. Neurology. ePub, 2019 Barnett C et al: Evidence of small fiber neuropathy in neurofibromatosis Type 1. Muscle Nerve. ePub, 2019 Eoli M et al: Neurological malignancies in neurofibromatosis type 1. Curr Opin Oncol. ePub, 2019 Hozumi K et al: Acromegaly caused by a somatotroph adenoma in patient with neurofibromatosis type 1. Endocr J. ePub, 2019 Poredska K et al: Triple malignancy (NET, GIST and pheochromocytoma) as a first manifestation of neurofibromatosis type-1 in an adult patient. Diagn Pathol. 14(1):77, 2019 Kitajima R et al: [Simultaneous occurrence of an ampullary neuroendocrine tumor and multiple duodenal/jejunal gastrointestinal stromal tumors in a patient with neurofibromatosis type 1.] Nihon Shokakibyo Gakkai Zasshi. 116(7):583-91, 2019 Schwabe M et al: How effective are noninvasive tests for diagnosing malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1? Diagnosing MPNST in NF1 patients. Sarcoma. 2019:4627521, 2019 Ylä-Outinen H et al: Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST). Mol Genet Genomic Med. e927, 2019 Al Momani LA et al: Recurrent gastric gastrointestinal stromal tumor in a patient with neurofibromatosis. Cureus. 10(6):e2854, 2018 Blakeley JO et al: The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis. Am J Med Genet A. 173(6):1714-21, 2017 Sites ER et al: Analysis of copy number variants in 11 pairs of monozygotic twins with neurofibromatosis type 1. Am J Med Genet A. 173(3):647-53, 2017 Okumura A et al: Development of a practical NF1 genetic testing method through the pilot analysis of five Japanese families with neurofibromatosis type 1. Brain Dev. ePub, 2014 Abramowicz A et al: Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease. Dev Period Med. 18(3):297-306, 2014 Hirbe AC et al: Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 13(8):834-43, 2014 Pasmant E et al: Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet. ePub, 2014 Yap YS et al: The NF1 gene revisited - from bench to bedside. Oncotarget. 5(15):5873-92, 2014 Takenouchi T et al: Multiple café au lait spots in familial patients with MAP2K2 mutation. Am J Med Genet A. 164A(2):392-6, 2014 Bikowska-Opalach B et al: [Neurofibromatosis type 1 - description of clinical features and molecular mechanism of the disease.] Med Wieku Rozwoj. 17(4):334-40, 2013 Salvi PF et al: Gastrointestinal stromal tumors associated with neurofibromatosis 1: a single centre experience and systematic review of the literature including 252 cases. Int J Surg Oncol. 2013:398570, 2013 Jouhilahti EM et al: The pathoetiology of neurofibromatosis 1. Am J Pathol. 178(5):1932-9, 2011 Upadhyaya M: Genetic basis of tumorigenesis in NF1 malignant peripheral nerve sheath tumors. Front Biosci. 16:937-51, 2011 Ferner RE: The neurofibromatoses. Pract Neurol. 10(2):82-93, 2010 Jett K et al: Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 12(1):1-11, 2010 Lee MJ et al: Recent developments in neurofibromatosis type 1. Curr Opin Neurol. 20(2):135-41, 2007 Pinson S et al: [Neurofibromatosis type 1 or Von Recklinghausen's disease.] Rev Med Interne. 26(3):196-215, 2005

Overview of Syndromes: Syndromes

• Minimal pleomorphism, lack of mitotic activity, and necrosis • Tumor cells are reactive for glial fibrillary acidic protein • 3 major patterns recognized ○ Reticulated pattern ○ Microcystic pattern ○ Fibrillated; spindle-shaped cells form bundle pattern

• Autosomal dominant tumor syndrome pattern caused by mutations of RET gene 723

Overview of Syndromes: Syndromes

Neurofibromatosis Type 1

NF1 Glioma

Asymmetric Deformities

Optic Nerve and Chiasm Glioma

Neurofibromas

Neurofibromas

Café au Lait Spots

(Left) Axial T1WI MR in a young girl with NF1 reveals a massive optic nerve glioma that nearly fills the orbit. Notice the resultant proptosis and remodeling of the posterior orbit. (Right) Axial graphic shows sphenoid dysplasia with arachnoid cyst ﬈, optic nerve glioma ﬇, buphthalmos ſt, and multiple plexiform neurofibromas st.

(Left) The central nervous system hallmark of NF1 is multiple involvement of the optic pathways by low-grade gliomas. These may affect the optic nerve proper ﬈ as well as the chiasm ſt. (Right) Coronal graphic shows bilateral spinal nerve root and brachial plexus neurofibromas. Intramedullary cervical glial tumor produces focal cord expansion and cystic central canal dilatation.

(Left) Numerous cutaneous neurofibromas afflict a significant proportion of patients with NF1, characterized by sessile or pedunculated growths. An associated café au lait spot ﬈ is also present. (Courtesy K. Yohay, MD.) (Right) Multiple café au lait spots represent an important cutaneous manifestation of NF1 ﬈. (Courtesy K. Yohay, MD.)

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Neurofibromatosis Type 1

NF1-Related Tumor (Left) Graphic shows plexiform neurofibromas in NF1 with multilevel, lobulated, tortuous expansion of cervical nerve roots and brachial plexus, with widening of the neural foramina. (Right) Gross cut surface of a large MPNST arising from neurofibroma shows extensive areas of necrosis ﬊.

Plexiform Neurofibroma

Overview of Syndromes: Syndromes

Plexiform Neurofibromas

Neurofibroma (Left) Plexiform neurofibroma consists of multiple huge nerve bundles formed by proliferation of all components of peripheral nerves, including axons, Schwann cells, fibroblasts, and perineurial cells. (Right) Microscopically, neurofibromas reveal proliferation of all of the elements in the peripheral nerve, including neuritides, Schwann cells, and fibroblasts in a loose, myxoid stroma.

Iris Lisch Nodules

Lisch Nodules (Left) Lisch nodules are asymptomatic nodular proliferations of pigmented cells involving the anterior surface of the iris ﬈ in NF1 patients. They represent an important diagnostic criterion that is relatively easy to identify by ophthalmologic examination. (Right) Lisch nodules are composed of melanin-containing cells that form superficial aggregates in the iris. They usually do not affect vision and have no malignant potential.

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Overview of Syndromes: Syndromes

Neurofibromatosis Type 1

Adrenal Mass

Adrenal Pheochromocytoma

NF1-Associated Astrocytoma

Paucicellular Area

Plexiform Neurofibroma

Plexiform Neurofibroma

(Left) Axial CECT in a patient with NF1 shows a right adrenal mass ſt that proved to be a ganglioneuroma, although distinction from a pheochromocytoma is difficult and somewhat semantic. (Right) Both sporadic or NF1associated pheochromocytomas have similar gross as well as histopathologic findings. The cut surface of pheochromocytoma is graypink, which distinguishes it from the yellow adrenal cortex ﬊. This tumor also shows areas of hemorrhage ﬇.

(Left) The majority of optic pathway gliomas are pilocytic astrocytomas. In this NF1associated case, areas of tissue compaction, degenerative atypia ﬈, and Rosenthal fibers ﬊ are evident. (Right) Most neurofibromas are paucicellular tumors characterized by wavy, delicate eosinophilic collagen bundles colorfully referred to as "shredded carrots." A variable myxoid stroma may be identified in almost all neurofibromas.

(Left) The main diagnostic attributes of plexiform neurofibroma are evident on gross examination and low magnification, particularly, a nodular or worm-like pattern of growth imparted by expansion of multiple peripheral nerve fascicles. (Right) Neurofibromas, including the plexiform variant, contain a myxoid stroma stained by Alcian blue. Such tumors also demonstrate cellular complexity, including Schwann cells, perineurial cells, fibroblasts, mast cells, and peripheral nerve axons.

726

Neurofibromatosis Type 1

Large Epithelioid Cells in MPNST (Left) Malignant peripheral nerve sheath tumor (MPNST) is the prototypical malignancy afflicting patients with NF1 syndrome. A suspicious finding on gross examination is the presence of necrosis ſt. MPNST may arise de novo or from a preexisting, usually plexiform neurofibroma. (Right) The morphologic variability of MPNST is wide, and pleomorphism may be marked in some NF1associated and sporadic examples. Some tumors may contain epithelioid cells with well-defined borders ﬈.

Spindle Cells in MPNST

Overview of Syndromes: Syndromes

NF1-Associated MPNST

p53 Immunoexpression in MPNST (Left) MPNSTs are usually high-grade spindle cell malignancies. The neoplastic cells may be arranged in fascicles and resemble fibrosarcoma. Mitotic activity is variable but usually evident ﬈. (Right) Strong nuclear immunoreactivity for p53 in a variable number of neoplastic cell nuclei is frequent in MPNST, in contrast with benign neurofibromas.

Loss of H3K27Me3 in MPNST

Loss of p16 in MPNST (Left) Complete loss of nuclear H3K27Me3 is seen in ~ 50% of MPNSTs. The nuclei with retention of staining are a positive control for stromal/endothelial/inflamma tory cells. (Courtesy Y. Hung, MD, PhD.) (Right) p16 immunoreactivity is frequently lost in MPNST. p16 represents an important tumor suppressor that is frequently inactivated by gene mutations/deletions in MPNST. p16 loss at the gene or protein level may suggest malignant degeneration of neurofibromas in NF1 patients.

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Overview of Syndromes: Syndromes

Neurofibromatosis Type 2 • Vasculopathy: Children may be at increased risk

TERMINOLOGY

Classification Criteria

Abbreviations • Neurofibromatosis type 2 (NF2)

Definitions • Inherited tumor predisposition syndrome caused by germline mutations in NF2 encoding for merlin/schwannomin

EPIDEMIOLOGY Incidence • 1:33,000-40,000 births • Similar proportion of male and female patients

GENETICS AND MOLECULAR BIOLOGY NF2 Encodes Merlin • NF2 mutations inherited in 1/2 of patients and new germline mutation in remaining 1/2 • Located in chromosomal region 22q12.2 • Merlin associates with cell junctional complexes and participates in contact-dependent inhibition • More severe phenotype in patients with frameshift or nonsense mutations • Germline mosaicism occurs in 20-30% of patients without family history ○ Next-generation sequencing platforms sensitive for detecting mosaicism

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Nonneoplastic Manifestations • Ophthalmic: Posterior subcapsular cataracts, retinal hamartomas, and epiretinal membranes • Central nervous system: Glial microhamartomas • Peripheral nervous system: Polyneuropathy • Skin: Café au lait spots but at lesser frequency than NF1; also hairy cutaneous plaques • Musculoskeletal: Scoliosis

• Manchester criteria (1992) ○ Bilateral vestibular schwannoma or ○ NF2 in 1st-degree relative plus unilateral vestibular schwannoma or any 2 of following: Neurofibroma, meningioma, glioma, schwannoma, posterior subcapsular lens opacity, or ○ Unilateral vestibular schwannoma plus any 2 of following: Neurofibroma, meningioma, glioma, schwannoma, posterior subscapular lens opacity, or ○ ≥ 2 meningiomas plus unilateral vestibular schwannoma or any 2 of following: Neurofibroma, glioma, schwannoma, or cataract • Baser criteria (2011) ○ Manifests effort to incorporate genetic information into clinical classifications

ASSOCIATED NEOPLASMS Schwannoma • Similar histologic features as sporadic tumors ○ Compact Antoni A areas alternating with loose Antoni B areas ○ Verocay bodies, hyalinized vessels, hemosiderin deposition ○ S100, SOX10, and pericellular collagen IV immunoreactivity; EMA limited to perineurium and neurofilament protein to rare entrapped axons • Features occurring more frequently in NF2-associated schwannomas include whorl formation, multiple tumors involving single nerve, and juxtaposition to meningioma ○ Mosaic pattern of INI1 immunostaining in majority of syndrome-associated schwannomas • Bilateral vestibular schwannomas are hallmark of NF2 (9095% of patients) • Plexiform schwannomas may occur in NF2 but are not specific to syndrome ○ Nodular Schwann cell proliferation favoring cutaneous and mucosal sites

Bilateral Vestibular Schwannomas (Left) Bilateral schwannomas involving the vestibular branch of CNVIII are a hallmark of neurofibromatosis type 2 (NF2). They present as a cerebellopontine angle mass ﬊ and may be multiple ﬈. (Right) Schwannomas are the most common neoplasms affecting patients with NF2. They are composed of a solid proliferation of neoplastic Schwann cells and may contain characteristic Verocay bodies ﬈.

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Schwannoma With Verocay Bodies

Neurofibromatosis Type 2

Feature

Present Age ≤ 30 Years

Present Age > 30 Years

NF2 in 1st-degree relative

2

2

Vestibular schwannoma (unilateral)

2

1

Vestibular schwannoma (2nd)

4

3

Meningioma

2

1

Meningioma (2nd)

2

1

Cutaneous schwannoma(s)

2

1

Neoplasm of cranial nerves

2

1

Mononeuropathy

2

1

Cataract(s)

2

0

Overview of Syndromes: Syndromes

Baser Criteria for Neurofibromatosis Type 2

Points are added: ≥ 6 = definite NF2; 4-5 = NF2 mutational analysis required for diagnosis; < 4 = NF2 unlikely; NF2 = neurofibromatosis type 2.

○ May be multiple • Some NF2 patients with vestibular schwannoma improve with antiangiogenic therapy (bevacizumab)

Neurofibroma • Relatively rare in NF2 compared to NF1 but may contribute to clinical diagnosis if other criteria present

4.

5. 6.

7.

Meningioma • Intracranial meningiomas found in ~ 1/2 of NF2 patients • Skull base involvement is less frequent than in sporadic tumors • "Saltatory growth": Periods of growth followed by quiescence • Relatively high frequency of fibroblastic, transitional, and grade II meningiomas in NF2 patients but also histologic heterogeneity • Meningioangiomatosis ○ Growth of meningothelial-like cells into superficial cortical vessels and leptomeninges ○ Associated with seizures ○ EMA(+) or EMA(-), collagen rich (Masson trichrome)

8.

Ependymoma

15.

• Cervical cord and cervicomedullary junction are favored sites in NF2 • Majority of NF2-associated ependymomas are low grade and asymptomatic • Associated with relatively high rate of truncating NF2 mutations

Other • Conventional malignant peripheral nerve sheath tumor (MPNST) and MPNST exschwannomas reported in NF2 but very rare • Some malignant neoplasms may be irradiation induced • Nonependymal glial neoplasms may occur

SELECTED REFERENCES 1. 2. 3.

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18. 19.

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Huang V et al: Improvement in patient-reported hearing after treatment with bevacizumab in people with neurofibromatosis type 2. Otol Neurotol. 39(5):632-8, 2018 Lascelles K et al: Cerebral vasculopathy in childhood neurofibromatosis type 2: cause for concern? Dev Med Child Neurol. 60(12):1285-8, 2018 Louvrier C et al: Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis. Neuro Oncol. 20(7):917-29, 2018 Vargas WS et al: Incidental parenchymal magnetic resonance imaging findings in the brains of patients with neurofibromatosis type 2. Neuroimage Clin. 4:258-65, 2014 Aboukais R et al: Intracranial meningiomas and neurofibromatosis type 2. Acta Neurochir (Wien). 155(6):997-1001, 2013 Dirks MS et al: Long-term natural history of neurofibromatosis type 2associated intracranial tumors. J Neurosurg. 117(1):109-17, 2012 Goutagny S et al: Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features. Neuro Oncol. 14(8):1090-6, 2012 Baser ME et al: Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet Med. 13(6):576-81, 2011 Evans DG et al: Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin Cancer Res. 15(16):5032-9, 2009 Baser ME et al: The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 42(7):540-6, 2005 Baser ME et al: Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet. 75(2):231-9, 2004 Kluwe L et al: Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet. 40(2):109-14, 2003 Moyhuddin A et al: Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet. 40(6):459-63, 2003 Perry A et al: Aggressive phenotypic and genotypic features in pediatric and NF2-associated meningiomas: a clinicopathologic study of 53 cases. J Neuropathol Exp Neurol. 60(10):994-1003, 2001 Mérel P et al: Screening for germ-line mutations in the NF2 gene. Genes Chromosomes Cancer. 12(2):117-27, 1995 Rouleau GA et al: Alteration in a new gene encoding a putative membraneorganizing protein causes neuro-fibromatosis type 2. Nature. 363(6429):51521, 1993 Trofatter JA et al: A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993 Mar 12;72(5):791-800. Erratum in: Cell. 75(4):826, 1993 Wiestler OD et al: Distribution and immunoreactivity of cerebral microhamartomas in bilateral acoustic neurofibromatosis (neurofibromatosis 2). Acta Neuropathol. 79(2):137-43, 1989

Coy S et al: An update on the CNS manifestations of neurofibromatosis type 2. Acta Neuropathol. ePub, 2019 Halliday D et al: Neurofibromatosis type 2 and related disorders. Curr Opin Oncol. ePub, 2019 Lu VM et al: Efficacy and safety of bevacizumab for vestibular schwannoma in neurofibromatosis type 2: a systematic review and meta-analysis of treatment outcomes. J Neurooncol. 144(2):239-48, 2019

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Overview of Syndromes: Syndromes

Neurofibromatosis Type 2

Pathways Affected by Merlin

Scoliosis in NF2

Meningioangiomatosis

Meningioangiomatosis

Glial Hamartoma in NF2

Glial Hamartoma in NF2

(Left) NF2 is associated with loss of the tumor suppressor merlin. Merlin has numerous important cellular functions, including participation in intercellular junctions, contact dependent growth inhibition (through integrins, CD44), cytoskeleton dynamics, and modulation of signaling pathways, including those downstream from receptor tyrosine kinases (RTK) and YAP. (Right) In addition to neoplasms, patients with NF2 may develop a variety of nonneoplastic disorders, such as severe scoliosis.

(Left) Meningioangiomatosis afflicts some patients with NF2. It is a hamartomatouslike lesion associated with seizures and is characterized by a cortical proliferation of spindle cells, particularly surrounding small vessels ﬈. An association with an overlying meningioma may be present in some instances. (Right) Perivascular collagen deposition is a diagnostically useful feature of meningioangiomatosis that may be demonstrated with histochemical stains, such as Masson trichrome ﬈.

(Left) Another nonneoplastic brain lesion afflicting patients with NF2 is the glial hamartoma, characterized by clusters of glial-like hyperchromatic cells with nuclear atypia and hyperchromasia ﬈. Multinucleated cells may also be present. They tend to arise in cerebral cortex and basal ganglia and lack mitotic activity and potential for neoplastic change. (Right) Glial hamartomas in NF2 patients show strong S100 labeling ﬈ but lack expression of other neuronal and glial markers.

730

Neurofibromatosis Type 2

Antoni A Pattern in Schwannoma (Left) Bilateral vestibular schwannomas are pathognomonic of NF2, presenting as enhancing masses in the cerebellopontine angle ſt. Age of presentation is variable; candidate patients may be monitored for years before this characteristic manifestation presents. (Right) Compact proliferations of spindle cells characterize the Antoni A pattern of schwannomas. Mitotic activity is usually low, and the potential for spontaneous malignant degeneration is negligible.

NF2-Associated Schwannoma

Overview of Syndromes: Syndromes

Bilateral Vestibular Schwannomas

Antoni B Pattern in Schwannoma (Left) Bland spindle cells represent the main component of sporadic and NF2associated schwannomas. These usually aggregate in compact areas known as Antoni A. Diagnostic Verocay bodies are not always identifiable, and in such instances, immunohistochemistry may be required for confirmation. (Right) Antoni B patterns are relatively paucicellular in contrast to Antoni A patterns. They contain variable mixtures of Schwann cells with clear cytoplasm and foamy histiocytes.

Plexiform Schwannoma in NF2

Whorls in NF2-Associated Schwannoma (Left) Plexiform schwannomas form multinodular masses usually involving superficial locations. Unlike plexiform neurofibromas, which are closely associated with NF1, most plexiform schwannomas are sporadic but may affect NF2 patients, as in this example. (Right) Whorls resembling those encountered in meningiomas may be more frequent in NF2-associated schwannomas than in sporadic tumors. IHC may help in their distinction, particularly in small biopsies.

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Overview of Syndromes: Syndromes

Neurofibromatosis Type 2

Meningioma in NF2

Meningioma Cytology Features

Meningotheliomatous Meningeoma

Mitosis in Meningioma

Meningiomas and Schwannomas in NF2

Schwannoma and Meningioma

(Left) Meningiomas are the 2nd most common neoplasms in patients with NF2. They are usually dural-based and demonstrate strong, homogeneous contrast enhancement after administration of gadolinium in T1-weighted MR sequences ﬇. (Right) The cytologic features of meningiomas are evident in intraoperative smears. They include "flat" cells with ample eosinophilic cytoplasm containing bland, oval nuclei. Intercellular borders are usually indistinct.

(Left) The most frequent meningioma subtype is meningotheliomatous, characterized by bland cells with indistinct borders and oval nuclei. This subtype occurs at a lesser frequency in NF2 patients compared to sporadic tumors. (Right) One of the most useful features for grading meningiomas is the number of mitotic figures ﬈ per 10 HPF. Most meningiomas are low grade (WHO grade I), but the whole grading spectrum (I-III) may affect patients with NF2.

(Left) The combination of multiple meningiomas ﬈ and schwannomas ﬇ is characteristic of patients with NF2. (Right) Juxtaposition of schwannomas and meningiomas (i.e., collision tumors) represents a characteristic feature of patients with NF2. Histologically, these NF2associated tumors may demonstrate morphologic overlap. However, the presence of wavy nuclei and Verocay bodies indicate schwannoma ﬊, whereas psammoma bodies are usually limited to meningiomas ﬈.

732

Neurofibromatosis Type 2

Perivascular Pseudorosettes (Left) The intraparenchymal CNS neoplasm afflicting patients with NF2 is ependymoma, which has a predilection for the cervical cord/cervicomedullary junction st. These tumors are well demarcated and demonstrate contrast enhancement. (Right) Perivascular pseudorosettes are frequent in ependymomas. They are composed of anuclear perivascular zones containing numerous neoplastic glial cell processes ﬈.

Ependymoma in NF2

Overview of Syndromes: Syndromes

Ependymoma in NF2

Perivascular Pseudorosettes (Left) This intramedullary neoplasm in a patient with NF2 contains bland, oval nuclei, but the pseudorosettes are inconspicuous, making identification of ependymoma difficult. A high index of suspicion is required in spinal cord tumors originating in patients with NF2. (Right) In some ependymomas, diagnosis is straightforward and possible at low magnification. In this NF2-associated ependymoma, perivascular pseudorosettes are abundant ﬈.

GFAP Expression in Ependymoma

Dot-Like EMA Positivity in Ependymoma (Left) The glial nature of ependymoma may be confirmed by immunolabeling with anti-GFAP antibodies. Although the reactivity of individual cells varies, pseudorosettes show intense immunoreactivity ﬈. (Right) A dot-like pattern of immunoreactivity for EMA is a diagnostically useful property of ependymoma ﬈. Although it may resemble an artifact at 1st glance, it corresponds to microlumina containing microvilli at the ultrastructural level.

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Overview of Syndromes: Syndromes

Nijmegen Breakage Syndrome

TERMINOLOGY Abbreviations

Clinical Presentation

• Nijmegen breakage syndrome (NBS)

• Microcephaly (present at birth in 75% of cases, and develops in rest of patients during early infancy) • Distinctive facial features (bird-like face, which becomes apparent by 3 years of age) • Recurrent respiratory tract infections • Intellectual disability • Increased risk of cancer ○ 40% of patients develop malignancy before 20 years of age ○ Mostly lymphomas ○ Rare cases of – Glioma – Rhabdomyosarcoma – Medulloblastoma • ~ 50% of patients have additional malformations • Hypergonadotropic hypogonadism with ovarian insufficiency in females

Synonyms • Ataxia-telangiectasia variant 1 (AT-V1) • Berlin breakage syndrome • Microcephaly, normal intelligence, and immunodeficiency syndrome • Seemanova syndrome

Definitions • NBS is autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies • Autosomal recessive condition of chromosomal instability caused by mutations in the NBN (NBS1) gene located in band 8q21, characterized by ○ Microcephaly – Present at birth and progressive with age ○ Distinct facial appearance ○ Short stature ○ Mild growth restriction ○ Combined cellular and humoral immunodeficiency ○ Radiation sensitivity ○ Strong predisposition to lymphoid malignancies ○ Mild to moderate intellectual disability ○ In females, hypergonadotropic hypogonadism • Majority of patients affected are of Slavic origin ○ Patients share same founder mutation of 657del5 within NBN gene-encoding protein involved in DNA doublestrand breaks repair

EPIDEMIOLOGY Incidence • NBS is rare syndrome estimated to affect 1:100,000 newborns worldwide • But is thought to be most common in Slavic populations of Eastern Europe

ETIOLOGY/PATHOGENESIS Genetics and Pathogenesis • Nibrin forms is involved in double-strand DNA break repair, meiotic recombination, telomere maintenance, cell division, and cell growth (proliferation) ○ Nibrin, product of NBN gene, is part of MRE11/RAD50 (MRN) complex • Nibrin (NBN) gene mutations lead to production of short version of protein, which prevents it from efficiently repair DNA breaks • Lack of functional nibrin causes ○ Errors in DNA, increasing risk of cancer ○ Reduced immune cell proliferation and reduced amounting of immunoglobulins

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CLINICAL IMPLICATIONS

Laboratory Findings • Lymphopenia [decreased CD4, CD8, and CD19(+) cells] • Absent or low levels of 1 or more immunoglobulin classes or immunoglobulin G (IgG) subclasses • Radioresistant DNA synthesis

Diagnosis • Absence of full-length nibrin protein • T-cell receptor excision circles (TRECs) assay, as part of many newborn screening panels • Chromosomal hypersensitivity to X-irradiation • Chromosomal (karyotype) instability in PHA-cultured T cells with spontaneous structural chromosomal rearrangements (particularly chromosomes 7 and 14) • Biallelic hypomorphic mutations in NBN gene ○ Identifying mutations in both alleles of NBN gene completes diagnosis of NBS • Genetic counseling should inform parents of affected child of 25% risk for further children to be affected • Prenatal molecular genetic diagnosis is possible if diseasecausing mutations in both alleles of NBN gene are known

Treatment • Anticancer treatment among patients with NBS is challenging because of high risk of life-threatening, therapy-related toxicity, including ○ Severe infections ○ Bone marrow failure ○ Cardio- and nephrotoxicity ○ Occurrence of secondary cancer • Patients with NBS acute lymphoblastic leukemia who suffered from clinically proven severe immunodeficiency are at risk of complications associated with treatment ○ In this group, it advised to reduce chemotherapy up to 50% • Infection prophylaxis with intravenous immunoglobulin supplementation as well as with antifungal and antibacterial agent is recommended

Nijmegen Breakage Syndrome

Disease Name

Gene(s)

Immunodeficiency

Predisposition to Cancer

Cellular Sensitivity

Nijmegen breakage syndrome (NBS)

NBN

Yes; combined

Yes; mainly of lymphoid malignancies

Ionizing radiation, bleomycin, alkylating agents (mild)

NBS-like disorder

RAD50

No

Limited data; unknown

Ionizing radiation, bleomycin

Fanconi anemia

18 genes

No

Yes; acute myeloid leukemia Ionizing radiation (mild), and solid tumors DNA cross-linking/alkylating agents

Ataxia-telangiectasia

ATM

Only in subset of patients

Yes; leukemia, Hodgkin and non-Hodgkin lymphoma

Ionizing radiation, bleomycin, alkylating agents (mild)

Bloom syndrome

BLM (RECQL3)

No

Yes; any cancer, earlier in life, particularly leukemia and osteosarcoma

UV

Nonhomologous end joining factor 1 (NHEJ1 ) syndrome

NHEJ1

Yes; severe, combined

Limited data; unknown

Ionizing radiation (variable)

DIFFERENTIAL DIAGNOSIS Fanconi Anemia • NBS and Fanconi anemia share development delay, microcephaly, cancer predisposition, and immune abnormalities

4. 5.

6.

Ataxia-Telangiectasia • Both ataxia-telangiectasia and NBS share radiation hypersensitivity, microcephaly, and increased risk of hematological malignancies

Nijmegen Breakage Syndrome-Like Disorder (RAD50 Deficiency) • While clinical features are similar, these patient have normal immunoglobulin levels, no history of serious infections, and no early occurrence of malignancies

7.

8. 9. 10.

11.

LIG4 Syndrome • Caused by mutations in the DNA Ligase IV (LIG4) gene • Microcephaly and similar facial features to NBS • Severe radiosensitivity and increased chromosomal breakage • Pancytopenia, growth &/or developmental delay, skin abnormalities, and severe combined immunodeficiency • Predisposition to malignancies, particularly lymphoma and leukemia • Broad clinical presentation and phenotype with some genotype-phenotype correlation

SELECTED REFERENCES 1.

2.

3.

Szeliga A et al: A case of premature ovarian insufficiency in Nijmegen breakage syndrome patient and review of literature. From gene mutation to clinical management. Gynecol Endocrinol. 1-4, 2019 Braitsch K et al: Non-Hodgkin lymphoma secondary to Hodgkin lymphoma in an adult patient with nijmegen breakage syndrome. Hemasphere. 2(5):e140, 2018 Habib R et al: Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome. Mol Cytogenet. 11:17, 2018

12.

13.

14.

15. 16.

17.

18. 19.

20.

Overview of Syndromes: Syndromes

Disorders With Chromosomal Instability in Differential Diagnosis of Nijmegen Breakage Syndrome 

Slack J et al: Outcome of hematopoietic cell transplantation for DNA doublestrand break repair disorders. J Allergy Clin Immunol. 141(1):322-8.e10, 2018 Meijers RWJ et al: Correction to: circulating T cells of patients with Nijmegen breakage syndrome show signs of senescence. J Clin Immunol. 38(4):538, 2018 Deripapa E et al: Prospective study of a cohort of Russian Nijmegen breakage syndrome patients demonstrating predictive value of low kappadeleting recombination excision circle (KREC) numbers and beneficial effect of hematopoietic stem cell transplantation (HSCT). Front Immunol. 8:807, 2017 Maciejczyk M et al: Oxidative stress, mitochondrial abnormalities and antioxidant defense in ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome. Redox Biol. 11:375-83, 2017 Meijers RWJ et al: Circulating T cells of patients with Nijmegen breakage syndrome show signs of senescence. J Clin Immunol. 37(2):133-42, 2017 Altmann T et al: DNA ligase IV syndrome; a review. Orphanet J Rare Dis. 11(1):137, 2016 Halevy T et al: Chromosomal instability and molecular defects in induced pluripotent stem cells from nijmegen breakage syndrome patients. Cell Rep. 16(9):2499-511, 2016 Pastorczak A et al: Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome. Eur J Med Genet. 59(3):12632, 2016 Kuo YC et al: Nijmegen breakage syndrome protein 1 (NBS1) modulates hypoxia inducible factor-1α (HIF-1α) stability and promotes in vitro migration and invasion under ionizing radiation. Int J Biochem Cell Biol. 64:229-38, 2015 Patel JP et al: Nijmegen breakage syndrome detected by newborn screening for T cell receptor excision circles (TRECs). J Clin Immunol. 35(2):227-33, 2015 Wolska-Kuśnierz B et al: Nijmegen breakage syndrome: clinical and immunological features, long-term outcome and treatment options - a retrospective analysis. J Clin Immunol. 35(6):538-49, 2015 Chrzanowska KH et al: Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 7:13, 2012 Dembowska-Baginska B et al: Non-Hodgkin lymphoma (NHL) in children with Nijmegen breakage syndrome (NBS). Pediatr Blood Cancer. 52(2):186-90, 2009 Gładkowska-Dura M et al: Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation. J Pathol. 216(3):337-44, 2008 Antoccia A et al: Nijmegen breakage syndrome and functions of the responsible protein, NBS1. Genome Dyn. 1:191-205, 2006 Carney JP et al: The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell. 93(3):477-86, 1998 Weemaes CM et al: A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand. 70(4):557-64, 1981

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Overview of Syndromes: Syndromes

Pancreatic Neuroendocrine Tumor Syndromes

TERMINOLOGY Abbreviations • Pancreatic neuroendocrine neoplasms (PNENs) • Pancreatic neuroendocrine tumors (PNETs)

Synonyms • Pancreatic endocrine tumors (PETs) or neoplasms (PENs)

Definitions • PNETs have significant neuroendocrine differentiation with expression of synaptophysin and chromogranin A (WHO 2017)

ETIOLOGY/PATHOGENESIS Histogenesis • Well-established syndromes associated with inherited PNETs • ~ 20% of PNETs are associated with hereditary syndromes • PNETs can occur as part of inherited disorders, including ○ Multiple endocrine neoplasia type 1 (MEN1)

○ Neurofibromatosis 1 (NF1) or von Recklinghausen disease ○ von Hippel-Lindau disease (VHL) ○ Tuberous sclerosis complex (TSC) ○ Multiple endocrine neoplasia type 4 (MEN4) ○ Glucagon cell hyperplasia and neoplasia (GCHN) • Underlying genes associated with these conditions are MEN1, NF1, VHL, TSC1/TSC2, CDKN1B, and GCGR, respectively ○ All are autosomal dominant, except GCHN (autosomal recessive)

CLINICAL IMPLICATIONS Clinical Presentation • PNETs can be divided into 2 general groups ○ Nonfunctional PNETs (NF-PNET), which are not associated with clinical syndrome or hormone excess ○ Functional PNETs associated with symptoms due to ectopic secretion of hormones • Nonfunctional PETs (NF-PETs)

MR of Pancreatic Neuroendocrine Tumor

Endoscopic Ultrasound of Pancreatic Neuroendocrine Tumor

Gross Cut Surface of Pancreatic Neuroendocrine Tumor

Cytology of Well-Differentiated Pancreatic Neuroendocrine Tumor

(Left) Pancreatic neuroendocrine tumors (PNETs) are typically T2-bright lesions that are hypervascular and enhance with intravenous contrast. A 1-cm T2-bright lesion ſt is seen in the pancreatic head. (Right) Endoscopic ultrasound (EUS) is a highly sensitive modality used to identify PNETs. This 4x5-mm hypoechoic lesion was identified near the pancreatic tail.

(Left) PNETs are well demarcated with well-defined borders. The tumor shows sharp ﬇ separation from the adjacent pancreatic parenchyma and has a firm, tan-yellow cut surface. (Right) H&E-stained smear of a welldifferentiated PNET shows a monotonous population of epithelioid cells with ample pink cytoplasm and round to oval nuclei.

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Pancreatic Neuroendocrine Tumor Syndromes

•

•

•

•

Syndromes Associated With PNETs • MEN1 ○ MEN1 gene ○ PNETs diagnosed clinically in ~ 80% of patients with MEN1 ○ Most common PNETs in MEN1: Nonfunctional tumors (80-100%), gastrinomas (mean: 54%), insulinomas (mean: 18%), glucagonomas (3%), VIPomas (3%)

•

– Gastrinomas and insulinomas occur at younger ages in MEN1 patients compared to sporadic cases ○ In MEN1, duodenal gastrin-producing NETs are more common than those arising in pancreas ○ MEN1 diagnosed in ~ 25% of patients who have gastrinoma and in ~ 5% of those who have insulinoma ○ Clinical prognostic factors for PNET growth, survival, or development of liver metastases in MEN1 include – Age > 35 years at PNET diagnosis – History of 1st-degree relative with PNET malignancy – Presence of nonfunctional PNET or gastrinoma – Presence of liver metastases – Presence of large PNET (i.e., > 3 cm) – History of unsuccessful curative resection ○ MEN1 is most common hereditary pancreatic NET syndrome VHL ○ VHL gene ○ Pancreatic pathology in VHL usually takes form of benign cysts and microcystic or serous adenomas ○ Occur in 35-70% of VHL patients ○ Occur in young patients, are multiple, and located anywhere in pancreas ○ Tumors clinically inactive, nonfunctioning NF1 ○ NF1 gene ○ Somatostatinomas of pancreas rarer than those of duodenal origin; 16x less common than duodenal somatostatinomas ○ Duodenal somatostatinomas occur in NF1 patients – NF1 accounts for 48% of duodenal somatostatinomas reported in literature TSC ○ TSC1 and TSC2 genes ○ Patients with TSC also have increased incidence of PNETs ○ PNETs are most common pancreatic lesion in patients with TSC – Nonsecretory PNET cases associated with TSC – In children, cystic NF-NETs – Malignant PNETs described in children ○ TSC1 (hamartin) highly expressed in normal islet cells; loss of this tumor suppressor speculated to have etiologic role in these lesions MEN4 ○ CDKN1B gene ○ Phenotype similar to that of MEN1 ○ Wide variety of tumors have been reported in MEN4 ○ Primary hyperparathyroidism is primary clinical manifestation ○ Pituitary adenomas (37.5%) ○ PNETs – Decreased penetrance of PNETs in MEN4 when compared to MEN1 GCHN ○ Rare inherited recessive syndrome with germline GCGR mutation ○ Development of islet glucagon cell hyperplasia and glucagon cell microtumors and macrotumors ○ Only ~ 10 cases reported to date

Overview of Syndromes: Syndromes

○ Most frequent type in syndromic PNETs ○ NF-PNETs occur histologically in 80-100% of MEN1 pancreata as multiple microadenomas (< 0.5 cm), with ~ 82% of patients also having macroadenomas (> 1 cm) ○ Term NF-PNET is misnomer in that these neuroendocrine tumors (NETs) usually produce multiple peptides by immunohistochemistry – By immunohistochemistry, these adenomas show multiple hormone production in 38-100% with PP (2075%), glucagon (24-52%), insulin (15-42%), somatostatin (3-58%), gastrin (4-33%), and VIP, neurotensin (< 1-8%) ○ PNETs in VHL are usually nonfunctional (~ 98%) and asymptomatic; some may cause pancreatitis or mass effect ○ PNETs in patients with tuberous sclerosis are usually nonfunctional • Functional PNETs include ○ Insulinomas: Secrete insulin that causes hypoglycemia in ~ 18% MEN1 patients and may occur in patients with tuberous sclerosis – Insulinomas in MEN1 patients, similar to patients with sporadic insulinomas, have low rate of malignancy ○ Gastrinomas: Ectopically release gastrin, causing Zollinger-Ellison syndrome (ZES); characterized by refractory peptic ulcer disease – Gastrinomas are most common functional PNETs occurring in MEN1 patients (~ 54%) and occur 3x as frequently as insulinomas – MEN1 is cause of ZES in 20-25% of all ZES patients □ Gastrinomas are primarily in duodenum (65-100%), multiple, small (usually < 1 cm), and most common in 1st and 2nd parts of duodenum – Gastrinomas may occur also in patients with tuberous sclerosis ○ Somatostatinomas: Secrete somatostatin, causing diabetes, steatorrhea, and gallstones; seen in NF1 patients ○ Vipomas (Verner-Morrison syndrome; watery diarrhea, hypokalemia, and achlorhydria syndrome; pancreatic cholera): Secrete vasoactive intestinal peptide, causing severe secretory diarrhea; occur rarely in MEN1 (~ 3%) ○ Glucagonomas: Cause hyperglycemia, diabetes, and necrolytic migratory erythema in patients with GCHN ○ Serotonin-producing tumors ± carcinoid syndrome ○ ACTH-producing tumor with Cushing syndrome ○ GRFomas: Secrete growth hormone-releasing factor (GRF), causing acromegaly • Sporadic PNETs are typically solitary lesions ○ Patients with PNET syndrome typically present with multiple distinct PNETs that are both functional and nonfunctional

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Overview of Syndromes: Syndromes

Pancreatic Neuroendocrine Tumor Syndromes

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MICROSCOPIC General Features • MEN1 ○ Most characteristic MEN1 pancreatic lesion is presence of diffuse microadenomatosis and neuroendocrine hyperplasia ○ MEN1-associated PNETs are usually nonfunctional – However, insulinomas, gastrinomas, glucagonomas, and rarely VIPomas and somatostatinomas also occur ○ In contrast with sporadic counterparts, MEN1-related PNETs are characterized by early onset, multiplicity of lesions, variable expression of tumors, and lower propensity for malignant degeneration – Once islet dysplasia attains size of 0.5 mm, it is classified as microadenoma; islet dysplasia most frequently associated with MEN1 ○ In patients with ZES/MEN1, duodenal gastrinomas are present in 80-100% and pancreatic gastrinomas in ~ 25% ○ Except for gastrinomas and rare somatostatinoma, all other classes of PNETs in MEN1 occur exclusively within pancreas – Display trabecular or mixed trabecular growth pattern surrounded by or interspersed with dense connective tissue ○ Most of micro- and macroadenomas produce multiple hormones/peptides on immunohistochemical staining with 100% positivity for generic neuroendocrine markers • VHL ○ Pancreatic involvement in VHL disease is common, with prevalence ~ 88% ○ PNETs develop in 10-17% of VHL patients ○ VHL is characterized by multifocal lesions dispersed along pancreas as multicentric microcystic adenomas ○ VHL-associated PNETs tend to be arranged in trabeculae, glandular configurations, and solid foci ○ Clear cell PNETs, closely mimicking renal cell carcinoma, are distinctive neoplasms of VHL – Identification of PNET with clear cells points to VHL – PNET component of clear cells is arranged in nests, cords, and tubules separated by thin-walled vessels, resembling renal cell carcinoma ○ VHL-associated PNETs are usually nonfunctional – Tumors said to be functionally inactive, although immunohistochemistry shows focal positivity for pancreatic polypeptide (PP), somatostatin, glucagon, &/or insulin in 30-40% of cases • NF1 ○ NF1 patients may have pancreatic somatostatinoma and less frequently gastrinoma, insulinoma, and nonfunctioning PNET ○ PNETs demonstrate glandular architecture and scattered psammoma bodies ○ NF1-associated somatostatinomas differ from sporadic tumors: Less likely to cause hypersecretory state, smaller, and less likely to be malignant ○ Somatostatinomas of pancreas rarer than those of duodenal origin – 16x less common than duodenal somatostatinomas • TSC ○ Patients with TSC also have increased incidence of PNETs

○ PNETs are most common pancreatic lesion in patients with TSC – Nonsecretory PNET cases associated with TSC – 1/3 were cystic – Functional PNETs reported to produce both insulin and gastrin • MEN4 ○ Decreased penetrance of PNETs in MEN4 when compared to MEN1 ○ NETs have histologic features similar to sporadic and other inherited tumors • GCHN ○ Development of islet glucagon cell hyperplasia and glucagon cell microtumors and macrotumors ○ Well-differentiated PNET morphology with occasional cystic changes and calcifications in larger tumors ○ Positive expression for glucagon immunohistochemistry

SELECTED REFERENCES 1.

2.

3. 4.

5. 6.

7.

8. 9. 10.

11.

12.

13.

14.

15.

16.

Guilmette JM et al: Neoplasms of the neuroendocrine pancreas: an update in the classification, definition, and molecular genetic advances. Adv Anat Pathol. 26(1):13-30, 2019 Hechtman JF et al: Performance of DAXX immunohistochemistry as a screen for DAXX mutations in pancreatic neuroendocrine tumors. Pancreas. ePub, 2019 Crespigio J et al: Von Hippel-Lindau disease: a single gene, several hereditary tumors. J Endocrinol Invest. 41(1):21-31, 2018 Rindi G et al: A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 31(12):1770-86, 2018 Chou A et al: ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors. Hum Pathol. 82:249-257, 2018 Lee L et al: Imaging of pancreatic neuroendocrine tumors: recent advances, current status, and controversies. Expert Rev Anticancer Ther. 18(9):837860, 2018 Singhi AD et al: Well-differentiated pancreatic neuroendocrine tumours (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs): concepts, issues and a practical diagnostic approach to highgrade (G3) cases. Histopathology. 72(1):168-77, 2018 Park JK et al: DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors. Oncotarget. 8(30):49796-806, 2017 Scarpa A et al: Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 543(7643):65-71, 2017 Rindi G et al: Competitive testing of the WHO 2010 versus the WHO 2017 grading of pancreatic neuroendocrine neoplasms: data from a large international cohort study. Neuroendocrinology. 107(4):375-86, 2018 Scoazec JY et al: [Classification of pancreatic neuroendocrine tumours: changes made in the 2017 WHO classification of tumours of endocrine organs and perspectives for the future.] Ann Pathol. 37(6):444-56, 2017 Sharma A et al: Clinical profile of pancreatic cystic lesions in von HippelLindau disease: a series of 48 patients seen at a tertiary institution. Pancreas. 46(7):948-52, 2017 Woo CG et al: Clear cell neuroendocrine tumor of the pancreas in von Hippel-Lindau disease: a case report and literature review. Neuro Endocrinol Lett. 38(2):83-6, 2017 Kakkar A et al: Pancreatic mixed serous neuroendocrine neoplasm with clear cells leading to diagnosis of von Hippel Lindau disease. Pathol Res Pract. 212(8):747-50, 2016 de Wilde RF et al: Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol. 9(4):199-208, 2012 Jensen RT et al: Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 113(7 Suppl):1807-43, 2008

Pancreatic Neuroendocrine Tumor Syndromes

Syndrome

Gene

Pancreatic Pathology

MEN1

MEN1

Diffuse microadenomatosis and neuroendocrine hyperplasia; PNETs (e.g., ZollingerEllison syndrome, insulinoma, glucagonoma, VIPoma); usually associated with hyperplasia and microadenomas

VHL

VHL

VHL is characterized by multicentric microcystic adenomas; cysts and PNETs with clear cell phenotype; presence of foamy and clear cell changes is characteristic of VHLassociated PNETs; usually functionally inactive with 30-40% with immunoexpression of somatostatin, glucagon, or insulin; usually not associated with hyperplasia or microadenomas; nuclear atypia common

NF1

NF1

Multifocal; glandular architecture; somatostatinoma (in pancreas, duodenum, and periampullary region); pancreatic less common than duodenal somatostatinomas

TSC

TSC1 and TSC2

Nonsecretory PNETs; 1/3 were cystic; benign and malignant PNETs; insulinomas and gastrinoma

MEN4

CDKN1B

Decreased penetrance of PNETs in MEN4 when compared to MEN1; neuroendocrine tumors have histologic features similar to sporadic and other inherited tumors

GCHN

GCGR

Neuroendocrine hyperplasia and microadenomas; some with concomitant macroadenomas; micro- and macroadenomas immunopositive for glucagon

Overview of Syndromes: Syndromes

Inherited Tumor Syndromes Associated With Pancreatic Neuroendocrine Tumors

GCHN = glucagon cell hyperplasia and neoplasia; MEN1 = multiple endocrine neoplasia 1; MEN4 = multiple endocrine neoplasia type 4; NF1 = neurofibromatosis type 1; PNET = pancreatic neuroendocrine tumor; TSC = tuberous sclerosis complex; VHL = von Hippel-Lindau syndrome.

Genes Involved in Pancreatic Tumorigenesis Gene

% of Sporadic Pancreatic Neuroendocrine Tumors With Mutation

MEN1

~ 30% of sporadic PNETs have MEN1 mutation; found in 55% of gastrin-producing tumors, 50% of VIPproducing tumors, and 20% of insulin-producing tumors

NF1, TSC1, CDKN1B, GCGR

Not found to be involved in development of sporadic tumors

DAXX and ATRX

45% of cases have mutation in 1 of 2; DAXX mutations tended to be mutually exclusive with ATRX mutations; DAXX mutations were associated with TSC2 mutations

VHL and HIF1A

Rare tumors may show mutations

PTEN, TSC2, PIK3CA

15% of PNETs have alterations in mTOR pathway

YY1

30% sporadic insulinomas

EPAS1 (HIF2A)

Activating mutations in some somatostatinomas

PNET = pancreatic neuroendocrine tumor.

Grading and Clinicopathologic Classification of Tumors of Endocrine Pancreas 2017 WHO Tumor Classification

Grading

Well-differentiated endocrine tumor, grade 1 (PNET G1)

< 2 mitoses/50 HPF; < 3% Ki-67 proliferative index

Well-differentiated endocrine tumor, grade 2 (PNET G2)

2-20 mitoses/50 HPF; 3-20% Ki-67 proliferative index

Well-differentiated neoplasm, grade 3 (PNET G3)

> 20 mitoses/50 HPF or Ki-67 proliferative index > 20%

Source: 2017 WHO Histological Classification of Tumours of Endocrine Organs.

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Overview of Syndromes: Syndromes

Pancreatic Neuroendocrine Tumor Syndromes Large Neuroendocrine Tumor in Tail of Pancreas

Pancreatic Neuroendocrine Tumor

Pancreatic Neuroendocrine Microadenoma

Pancreatic Microadenomatosis in MEN1

Glandular Architecture in Neurofibromatosis Type 1

Rare Psammoma Body in Somatostatinoma

(Left) There is a complex mass in the tail of the pancreas expanding out into the surrounding tissues. There are also metastatic foci ﬇ in the liver, confirming that this pancreatic endocrine tumor is malignant. (Right) This gross cut surface of a PNET reveals a large, gray-white, firm, welldemarcated mass ﬇. In contrast with the sporadic counterparts, MEN1-related PNETs are characterized by an early-onset multiplicity of lesions and propensity for malignant degeneration.

(Left) In the pancreas of patients with MEN1, there are usually multiple (> 5) small neuroendocrine cell proliferations and tumors, a finding that has been referred to as microadenomatosis. Note the irregular borders of the neuroendocrine components. (Right) Pancreatic microadenomatosis, the presence of multiple pancreatic neuroendocrine microadenomas, is linked to MEN1, VHL, and GCHN. Pancreatic microadenoma is when an islet cell dysplasia attains a size > 0.5 mm.

(Left) PNETs in NF1 account for ~ 10% of cases, are somatostatin-producing tumors, and often demonstrate a glandular architecture. NF1-associated neuroendocrine tumors are less likely to cause a hypersecretory state and are smaller than the sporadic tumors. (Right) Somatostatinproducing PNETs occurring in NF1 patients have no distinctive histologic features in common with other PNETs, except that they have a paraganglioma-like pattern. Rarely, they show a psammoma body ﬇.

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Pancreatic Neuroendocrine Tumor Syndromes

Pancreatic Neuroendocrine Tumor (Left) Axial CECT in the arterial phase shows an 8-mm hypervascular insulinoma ﬊ in the pancreatic head; it was not detected on portal venous phase CT. (Right) This pancreatic tumor in an MEN1 patient shows a firm, graypink cut surface with less welldefined borders. Histologically, this was a PNET grade 2 (WHO 2017).

MEN1-Associated Pancreatic Neuroendocrine Tumor

Overview of Syndromes: Syndromes

Tumor in Pancreatic Head

Insulinoma in MEN1 Syndrome (Left) This 3.5-cm pancreatic mass in a 26-year-old woman with MEN1 is well circumscribed ﬇ and shows a pale cut surface with areas of cystic change and hemorrhage. (Right) Insulinomas are β-cell derived and have a predominantly solid, ribbon-like, trabecular, gland-like growth pattern. Amyloid deposition is unique to this tumor type.

Pancreatic Endocrine Cell Proliferation

Pancreatic Microadenoma and Hyperplasia (Left) Two distinct pancreatic endocrine cell proliferations are shown in a case of MEN1. The lesion on the left ﬊ has irregular borders, and the lesion on the right ﬇ is well demarcated and larger. (Right) The smaller pancreatic endocrine lesion ﬊ is uniformly positive for glucagon (microadenoma), whereas the larger lesion ﬇ shows a pattern of distribution of glucagon similar to a normal islet, indicating hyperplasia.

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Overview of Syndromes: Syndromes

Pancreatic Neuroendocrine Tumor Syndromes Chromogranin in MEN1-Associated Pancreatic Neuroendocrine Tumor

Insulin Immunoexpression in Nonfunctional PNET

Neuroendocrine Hyperplasia in von HippelLindau Disease

Neuroendocrine Hyperplasia in von HippelLindau Disease

Glucagon Cell Distribution

Glucagon Microadenoma

(Left) Patients with MEN1, VHL, and GCHN usually have neuroendocrine hyperplasia and microadenomas in their pancreas, with neuroendocrine cells arranged in trabeculae with loss of spatial distribution and number of normal main cell types. (Right) Multiple pancreatic microadenomas (< 5 mm) seen in patients with MEN1 and NF are often accompanied by 1 or more macroadenomas (diameter > 5 mm), some of which may become insulinomas, as seen in this image.

(Left) A stained section of pancreas near a pancreatic neuroendocrine neoplasm shows an increased number of chromogranin-positive neuroendocrine cells in clusters and forming ductuloinsular complexes. (Right) A section of pancreas near a pancreatic neuroendocrine neoplasm shows increased number of synaptophysin-positive cells in clusters and forming ductuloinsular complexes ﬊. Ductuloinsular complexes are precursor lesions of PNETs in the setting of familial disease.

(Left) This glucagon-stained pancreas shows the usual neuroendocrine pancreas with normal glucagon cell distribution. (Right) The microadenoma present in a patient with GCHN shows intense and exclusive immunostain for glucagon ﬇. Note the normal neuroendocrine pancreas ﬊ with normal glucagon cell distribution.

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Pancreatic Neuroendocrine Tumor Syndromes von Hippel-Lindau Disease-Associated Pancreatic Cystadenoma (Left) This image shows a cystic lesion of the pancreatic head and corpus in a patient with VHL. The cystic component was large (6 cm) with a 2-cm solid component. (Courtesy F. Fedeli, MD.) (Right) Pancreas from a VHL patient shows a multicystic lesion with thin-walled cysts containing clear fluid.

von Hippel-Lindau Disease-Associated PNET and Cystadenoma

Overview of Syndromes: Syndromes

Multicystic Pancreatic Mass

Pancreatic Neuroendocrine Tumor and Cystadenoma in von Hippel-Lindau Disease (Left) Gross cut surface of a large pancreatic cystic mass in a patient with VHL shows both a pancreatic cystadenoma and a PNET. (Courtesy F. Fedeli, MD.) (Right) This pancreatic lesion in a VHL patient demonstrates numerous cysts lined by cells with clear cytoplasm with uniform nuclei adjacent to a mass with cells arranged in nests, cords, and sheets of cells with pale, faintly eosinophilic cytoplasm.

Clear Cells in von Hippel-Lindau DiseaseAssociated PNET

Clear Cells in von Hippel-Lindau DiseaseAssociated PNET (Left) VHL-associated PNETs tend to be arranged in trabeculae with glandular configurations and solid foci. Characteristically, the tumors contain clear cells or multivacuolated lipid-rich cells in varying proportions. (Right) VHL-associated PNETs are characteristically composed of clear cells. They are functionally inactive, although immunohistochemistry may show focal positivity for pancreatic polypeptide, somatostatin, glucagon, &/or insulin.

743

Overview of Syndromes: Syndromes

Hamartomatous Polyps, Peutz-Jeghers

TERMINOLOGY Abbreviations • Peutz-Jeghers polyp (PJP) • Peutz-Jeghers polyposis syndrome (PJPS)

•

Definitions • PJP may occur sporadically or as part of inherited polyposis syndrome • PJPS is characterized by ○ Pigmented melanotic lesions around mouth, lips, and oral cavity ○ Hamartomatous polyposis involving GI tract ○ Increased risk of cancer of GI tract, pancreas, and breast

ETIOLOGY/PATHOGENESIS

• • • •

○ 80-94% of patients with PJP have identifiable mutations in STK11 ○ 25% of new diagnoses represent de novo mutations STK11 encodes protein that localizes to nucleus and cytoplasm and is postulated to be involved in ○ Cell polarity ○ Chromatin remodeling ○ Cell cycle arrest ○ Wnt signaling Mutations in STK11 (LKB1) lead to dysregulation of mTOR pathway More severe phenotype with truncating mutations No LKB1/STK11 genotype-phenotype correlations reported Rare cases not related to LKB1/STK11 recognized

CLINICAL ISSUES

Genetics of PJPS

Epidemiology

• Autosomal dominant inheritance pattern • Germline protein mutation of STK11 (LKB1) on chromosome 19p13.3

• Incidence ○ Exact incidence uncertain; estimates range from 1/50,000 to 1/200,000

Endoscopic Appearance of PJP

Macroscopic Appearance of PJP

Microscopic Appearance of PJP

Microscopic Appearance of PJP

(Left) Endoscopic image shows a large, pedunculated ﬊ Peutz-Jeghers polyp (PJP) with a smooth surface ﬈ involving the sigmoid colon. (Right) Pedunculated PJPs may present with small intestinal obstruction when they undergo intussusception.

(Left) Histologically, PJPs are characterized by tree-like arborizing strands of smooth muscle ﬊ that separate the epithelial component into lobules. (Right) Colonic PJPs are also characterized by branching smooth muscle fibers ﬇ that often reach the surface. Note the distinct lobular configuration of the epithelial component.

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Hamartomatous Polyps, Peutz-Jeghers

Presentation • Pigmented melanotic lesions ○ In infancy and early childhood ○ Lips most common site (> 95%) ○ Buccal mucosa involved in ~ 94% of patients ○ Other sites include – Area around mouth and nose – Hands and feet ○ Pigmented spots may fade with age • Abdominal pain ○ Obstruction is most common presentation – Usually secondary to intussusception of polyp • Anemia ○ Due to occult GI bleeding • Hematochezia • Hematemesis ○ In patients with gastric and duodenal polyposis • Prolapse of rectal polyps • Other associated anomalies ○ Polyps may also be present in – Bladder – Renal pelvis – Bronchus – Nose – Gallbladder ○ Skeletal anomalies – Club foot – Scoliosis • Neoplastic lesions associated with PJPS ○ Colon cancer ○ Pancreatic cancer ○ Small intestinal and gastric cancer ○ Breast cancer ○ Distinctive tumors of genital tract – Sex cord tumor with annular tubules (SCTAT) of ovary – Large-cell calcifying Sertoli tumor of testis □ Feminization reported in some cases – Adenoma malignum of cervix ○ Risk of thyroid carcinoma uncertain

Treatment • Screening/surveillance of all 1st-degree relatives ○ For melanosis ○ For testicular or ovarian tumors, which may cause precocious puberty ○ Upper endoscopy, colonoscopy, and small bowel (video capsule) starting at age 8 – Repeated every 3 years if polyps are detected ○ Endoscopic ultrasound to evaluate pancreas ○ Breast mammograms starting at age 18 ○ Pelvic examination and Pap smears for cervical tumors ○ Annual CA-125 measurement for ovarian and uterine tumors starting at age 25 • Genetic testing of all asymptomatic 1st-degree relatives • Removal of small polyps by polypectomy • Surgical intervention for cases of

Intestinal obstruction, intussusception Large polyps with bleeding or prolapse Polyps with dysplastic change Intestinal or extraintestinal malignancies

Prognosis • Colon cancer ○ Cumulative risk for developing colon cancer: ~ 39% ○ Mean age of diagnosis: ~ 46 years • Stomach and small intestine ○ Cumulative risk for gastric cancer: 29% ○ Cumulative risk for small intestinal cancer: 13% • Pancreas ○ > 100x increase in risk for pancreatic cancer (cumulative risk: 11-36%) • Breast cancer ○ Absolute risk of developing breast cancer: 24-54% • Other organs ○ Absolute risk of ovarian cancer (21%), cervical cancer (1023%), uterine and testicular cancer (9% each) • Risk of cancer may also increase in patients with sporadic PJP ○ Number of cases reported so far too small to draw definite conclusions • Chemoprevention approaches are being evaluated ○ COX-2 inhibitors; everolimus (inhibiting rapamycin)

Overview of Syndromes: Syndromes

○ ○ ○ ○

• Age ○ 2/3 of PJPS patients present in 2nd-3rd decades of life ○ ~ 1/3 present in 1st decade

MACROSCOPIC General Features • • • •

Solitary or multiple Size is variable Small polyps are sessile Large polyps are usually pedunculated and may lead to intussusception • Multilobulated architecture ○ May resemble juvenile polyps (JPs) or tubulovillous adenoma on gross examination • Sites of involvement ○ Most common in jejunum and ileum ○ Less common in stomach and duodenum ○ Colon involved to variable degree in most patients • Diagnosis of PJPS can be made if ○ > 2 PJPs are present ○ Any number of PJPs are present in patient with mucocutaneous pigmentation around lips, nose, and oral cavity ○ Either PJP or pigmentation in patient with family history of PJPS

MICROSCOPIC Histologic Features • Colon and small intestine ○ Frequency of small bowel polyps: 96% ○ Frequency of colonic polyps: 27% ○ Papillary architecture ○ Arborizing compact bundles of smooth muscle ○ Epithelial component arranged in distinct lobular configuration ○ Lobules separated by smooth muscle 745

Overview of Syndromes: Syndromes

Hamartomatous Polyps, Peutz-Jeghers

•

•

•

•

•

○ Secondary erosion, ulceration may be present ○ Dysplastic change or cancer may occur within polyp ○ Submucosal misplacement common in pedunculated polyps and may be mistaken for invasive cancer Stomach ○ Frequency of gastric polyps: 24% ○ Large polyps show typical appearance (i.e., lobules of glandular epithelium and arborizing smooth muscle bands) – Smooth muscle commonly less prominent ○ Small polyps cannot be recognized as PJP unless clinical and endoscopic context is known – May resemble hyperplastic or JPs □ Foveolar hyperplasia with cystic dilatation □ Edematous and inflamed stroma – May resemble mucosal prolapse polyps □ Frayed muscularis mucosae □ Fibromuscular proliferation in lamina propria □ Both foveolar and glandular compartment are part of polypoid proliferation Mucocutaneous lesions ○ May appear in neonatal period or after detection of GI polyps ○ Lentiginous macules ○ Acanthosis with prominent melanin in basal layer SCTAT ○ Present in 1/3 of PJPS patients; usually small and found incidentally ○ Often bilateral and multiple ○ Tubular formations with nuclei arranged at periphery with central clear zone ○ Tubules filled with eosinophilic hyaline material Sertoli cell tumors ○ In young boys with PJPS ○ May be estrogenic and bilateral ○ Large-cell calcifying Sertoli cell tumor may be associated with PJPS or other endocrinopathies ○ Intratubular large-cell hyalinizing Sertoli cell tumor is seen primarily in PJPS patients ○ May also occur in setting of Carney syndrome ○ Large tumor cells in sheets, nest, cords, or trabeculae ○ Abundant eosinophilic granular cytoplasm ○ Large, laminated calcific deposits – Psammoma body-like calcification may be present ○ Myxoid or collagenous stroma ○ Neutrophilic infiltrate may be seen in some cases Adenoma malignum of cervix ○ a.k.a. minimal deviation mucinous adenocarcinoma ○ Small, tubular, deeply infiltrating glands ○ Minimal or no desmoplastic stromal reaction ○ Minimal nuclear atypia ○ Poor prognosis despite bland morphologic appearance

DIFFERENTIAL DIAGNOSIS

• Smooth muscle wrapping around individual crypts favors mucosal prolapse • Distinction important since apparently sporadic PJP may be associated with increased cancer risk

Juvenile Polyposis Syndrome • May appear similar on gross examination • Loose, edematous, and inflamed lamina propria is characteristic feature of JP • Marked cystic dilatation of epithelial component in JP • Smooth muscle arborization not prominent feature of juvenile polyposis • Epithelial component organized in lobular configuration in PJP • Genetic testing may be helpful (SMAD4 and BMPR1A germline mutations in JPS)

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features • Organ distribution • Age distribution

Pathologic Interpretation Pearls • Tree-like arborization of smooth muscle present in PJP • Smooth muscle bands divide epithelial component into lobules • Submucosal misplacement (pseudoinvasion) of epithelial component may mimic invasive carcinoma • Mucosal prolapse polyps contain smooth muscle and can be mistaken for PJP • Diagnosis of solitary PJP should be made only if "classic" histologic features present ○ Risk of cancer in solitary PJP (if strictly defined) may be similar to that in syndromic cases ○ Number of such cases reported thus far is too small to recommend routine surveillance • Gastric polyps in PJP may mimic hyperplastic or juvenile or mucosal prolapse polyps ○ Typical features of PJP are visible only in large gastric polyps

SELECTED REFERENCES 1.

2.

3. 4.

5.

6. 7.

Mucosal Prolapse Polyp • More common in rectosigmoid colon • Smooth muscle component shows disarray and is not as compact as in PJP

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8.

9.

Jiang YL et al: Early screening the small bowel is key to protect PeutzJeghers syndrome patients from surgery: a novel mutation c.243delG in STK11 gene. BMC Gastroenterol. 19(1):70, 2019 Latchford A et al: Management of Peutz-Jeghers syndrome in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 68(3):442-52, 2019 Sengupta S et al: Peutz-Jeghers syndrome. N Engl J Med. 380(5):472, 2019 Shen N et al: Early genetic testing of STK11 is important for management and genetic counseling for Peutz-Jeghers syndrome. Dig Liver Dis. 51(9):1353-5, 2019 Zhao HM et al: Clinical and genetic study of children with Peutz-Jeghers syndrome identifies a high frequency of STK11 de novo mutation. J Pediatr Gastroenterol Nutr. 68(2):199-206, 2019 Campos FG et al: Colorectal cancer risk in hamartomatous polyposis syndromes. World J Gastrointest Surg. 7(3):25-32, 2015 Syngal S et al: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 110(2):223-62; quiz 263, 2015 Ngeow J et al: Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. Gastroenterology. 144(7):1402-9, 1409.e1-5, 2013 Kuwada SK et al: A rationale for mTOR inhibitors as chemoprevention agents in Peutz-Jeghers syndrome. Fam Cancer. 10(3):469-72, 2011

Hamartomatous Polyps, Peutz-Jeghers

Cancer Site

Cumulative Risk of Cancer

All sites

1% by age 20, 19% by age 40, and 81% by age 70

Colorectal

39%

Gastric

29%

Small intestine

13%

Pancreas

11-36%

Breast

24-54%

Ovarian

21%

Cervix

10-23%

Uterine

9%

Testicular

9%

Lung

7-17%

10. Latchford AR et al: Peutz-Jeghers syndrome: intriguing suggestion of gastrointestinal cancer prevention from surveillance. Dis Colon Rectum. 54(12):1547-51, 2011 11. Latchford AR et al: Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: clinical aspects. Fam Cancer. 10(3):455-61, 2011 12. Triggiani V et al: Papillary thyroid carcinoma in Peutz-Jeghers syndrome. Thyroid. 21(11):1273-7, 2011 13. van Lier MG et al: High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines? Am J Gastroenterol. 106(5):940-5, 2011 14. van Lier MG et al: High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome. Gut. 60(2):141-7, 2011 15. Beggs et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 59(7):975-86, 2010 16. Udd L et al: Impaired gastric gland differentiation in Peutz-Jeghers syndrome. Am J Pathol. 176(5):2467-76, 2010 17. van Lier MG et al: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 105(6):1258-64; author reply 1265, 2010 18. Kopacova M et al: Peutz-Jeghers syndrome: diagnostic and therapeutic approach. World J Gastroenterol. 15(43):5397-408, 2009 19. Suzuki S et al: Three cases of Solitary Peutz-Jeghers-type hamartomatous polyp in the duodenum. World J Gastroenterol. 14(6):944-7, 2008 20. Burkart AL et al: Do sporadic Peutz-Jeghers polyps exist? Experience of a large teaching hospital. Am J Surg Pathol. 31(8):1209-14, 2007 21. de Leng WW et al: Peutz-Jeghers syndrome polyps are polyclonal with expanded progenitor cell compartment. Gut. 56(10):1475-6, 2007 22. de Leng WW et al: Nasal polyposis in Peutz-Jeghers syndrome: a distinct histopathological and molecular genetic entity. J Clin Pathol. 60(4):392-6, 2007 23. Mehenni H et al: Molecular and clinical characteristics in 46 families affected with Peutz-Jeghers syndrome. Dig Dis Sci. 52(8):1924-33, 2007 24. Giardiello FM et al: Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol. 4(4):408-15, 2006 25. Hearle N et al: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 12(10):3209-15, 2006 26. Amos CI et al: Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet. 41(5):327-33, 2004 27. Hearle N et al: Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases. Genes Chromosomes Cancer. 41(2):163-9, 2004 28. Mangili G et al: An unusual admixture of neoplastic and metaplastic lesions of the female genital tract in the Peutz-Jeghers Syndrome. Gynecol Oncol. 92(1):337-42, 2004 29. Entius MM et al: Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J Clin Pathol. 54(2):126-31, 2001 30. Petersen VC et al: Misplacement of dysplastic epithelium in Peutz-Jeghers polyps: the ultimate diagnostic pitfall? Am J Surg Pathol. 24(1):34-9, 2000 31. Su GH et al: Germline and somatic mutations of the STK11/LKB1 PeutzJeghers gene in pancreatic and biliary cancers. Am J Pathol. 154(6):1835-40, 1999

Overview of Syndromes: Syndromes

Cancer Risk in Peutz-Jeghers Polyp Syndrome

32. Wang ZJ et al: Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma(adenoma)-carcinoma sequence. J Pathol. 188(1):9-13, 1999 33. Ylikorkala A et al: Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet. 8(1):45-51, 1999

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Overview of Syndromes: Syndromes

Hamartomatous Polyps, Peutz-Jeghers

Desmin Immunostain of PJP

Dysplasia in PJP

Mucosal Prolapse Polyp Mimicking PJP

Juvenile Polyp Mimicking PJP

Endoscopic Appearance of Gastric PJP

Microscopic Appearance of Gastric PJP

(Left) The same polyp stained with a desmin highlights the smooth muscle arborization ﬊, characteristic of both sporadic and syndromic PJPs. (Right) PJP with low-grade dysplasia shows dysplastic change similar to colonic adenomas with elongated, hyperchromatic, and pseudostratified nuclei st. Note the abrupt transition from the nondysplastic epithelium ﬇.

(Left) Rectal prolapse with strands of smooth muscle involving the lamina propria ﬊ impart a resemblance to PJPs. The lack of compact, lobular configuration of the glandular component and smooth muscle wrapping around individual crypts ﬊ favors mucosal prolapse. (Right) Proliferating smooth muscle strands ﬊ in large, multilobulated, and pedunculated juvenile polyps may also mimic PJP. The architectural disarray and cystic dilatation ﬈ is typical of juvenile polyp.

(Left) Large, sessile, or pedunculated gastric polyps may be seen in patients with PJP. The polyp seen here was present in the gastric body. (Right) Similar to what is seen in the small intestine and colon, typical gastric polyps in Peutz-Jeghers syndrome (PJS) show arborizing bands of smooth muscle ﬊ that divide the epithelial compartment into compact lobules.

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Hamartomatous Polyps, Peutz-Jeghers

Gastric PJP Mimicking Mucosal Prolapse (Left) Small gastric polyps in PJS cannot be recognized as syndromic without knowledge of clinical history and endoscopic findings. These lesions are indistinguishable from sporadic hyperplastic or mucosal prolapse polyps and from small syndromic polyps in PJS or Cowden syndrome. (Right) Gastric polyp (same patient) with germline STK11 mutation shows foveolar hyperplasia ﬊, fibromuscular proliferation in lamina propria ﬈. Compact lobular configuration of glands typically seen in PJS is not discernible in this small polyp.

Gastric PJP Mimicking Hyperplastic Polyp

Overview of Syndromes: Syndromes

Small Antral Polyps in PJS

Ovarian Sex Cord Tumor With Annular Tubules (Left) Marked foveolar hyperplasia and edematous stroma is reminiscent of a hyperplastic polyp in this small antral polyp from a PJS patient. (Right) Ovarian sex cord tumors with annular tubules may be an extraintestinal manifestation of Peutz-Jeghers polyposis syndrome (PJPS). Circumscribed nests of tumor cells with tubular configurations are filled with eosinophilic hyaline material ﬊.

Adenoma Malignum Cervix in PJPS

Large-Cell Calcifying Sertoli Cell Tumor (Left) Adenoma malignum of the cervix may also be an extraintestinal manifestation of PJPS. Glands lined by cells with bland nuclei and abundant pale cytoplasm ﬊ infiltrate deep into the cervix without inciting a desmoplastic stromal response. (Right) Large-cell calcifying Sertoli cell tumor in a male patient with PJPS shows nests and cords of tumor cells with abundant eosinophilic cytoplasm and a hyalinized stroma with foci of calcification ﬊. (Courtesy E. Oliva, MD.)

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Overview of Syndromes: Syndromes

PTEN-Hamartoma Tumor Syndromes

TERMINOLOGY Abbreviations • Phosphatase and tensin homolog (PTEN) deleted on chromosome 10 • PTEN-hamartoma tumor syndrome (PHTS)

Definition • PHTS is primarily composed of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) ○ Several other syndromes have been linked with PTEN mutations, including PTEN-related Proteus syndrome (PRPS), Proteus-like syndrome, and autism with macrocephaly • CS ○ Clinical manifestations of CS include hamartomatous tumors in multiple organ systems and increased risk for malignancy ○ Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules present by late 20s ○ Multiple hamartoma syndrome with high risk for benign and malignant tumors of thyroid, breast, and endometrium ○ ~ 50% of women have benign breast conditions: Ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, fibrocystic change, &/or densely fibrotic hyalinized nodules – Increased incidence of both multifocality and bilateral involvement has been observed for both benign and malignant breast disorders ○ ~ 67% of CS patients develop thyroid lesions involving follicular cells – Includes multinodular goiter, multiple adenomatous nodules, follicular adenoma, follicular carcinoma, and, less frequently, papillary thyroid carcinoma – ~ 70x increased incidence of nonmedullary thyroid cancer relative to general population ○ Risk for endometrial cancer, although not well defined, may approach ~ 13-28% • BRRS

○ Congenital disorder characterized by macrocephaly, lipomas, intestinal hamartomatous polyposis, vascular hamartomatous lesions, and pigmented macules of glans penis ○ Although diagnostic criteria for CS have been established for more than decade, there are no agreed-upon international criteria for diagnosis of BRRS ○ Rate of occurrence and histologic types of thyroid lesions in BRRS have not been widely reported but have appeared similar to those seen in CS, suggesting single entity • PRPS ○ Complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues as well as connective tissue nevi, epidermal nevi, and hyperostoses ○ There have been reports of PTEN mutations in some patients with phenotypic similarities to Proteus syndrome (PS) – Somatic activating mutations in AKT1 oncogene have been delineated as genetic cause of PS • Proteus-like syndrome ○ Undefined but refers to individuals with significant clinical features of PS who do not meet diagnostic criteria for PS

EPIDEMIOLOGY Incidence • Estimated at ~ 1 in 200,000-250,000 people

Familial • Only 10-50% of individuals with CS have affected parent • Each child of affected individual has 50% chance of inheriting mutation and developing PHTS

Lifetime Risk of Developing Cancer • Lifetime risks for variety of cancers are increased in patients with PTEN mutations ○ Thyroid: ~ 35% ○ Breast: ~ 85% ○ Endometrium: ~ 28%

Nodular Thyroid Cut Surface (Left) This gross cut surface of a thyroid from a young patient with Cowden disease, or PHTS, shows multiple pale, wellcircumscribed nodules ſt surrounded by a compressed pale parenchyma ﬉. A small amount of residual brown thyroid is focally seen. (Right) Immunohistochemistry for phosphatase and tensin homolog (PTEN) in thyroid adenomatous nodules in patients with PHTS usually shows loss of immunoreactivity of the follicular cells. Endothelial cells maintain immunopositivity ﬈.

750

PTEN Loss by Follicular Cells

PTEN-Hamartoma Tumor Syndromes

GENETICS General • PTEN is tumor suppressor gene located on 10q23.3 • Up to ~ 80% of cases that meet criteria for CS and small percentage of cases of Cowden-like syndrome result from mutations in PTEN gene ○ In PTEN sequencing-negative and clinically positive CS, ~ 10% have large deletions, and ~ 10% have promoter mutations • PTEN mutation ○ Initially reported that up to 83% of individuals meeting clinical criteria for CS had detectable PTEN mutation – Overestimate attributable to highly selected nature of earlier CS cohorts ○ More recent estimates are that germline PTEN mutations are found in ~ 20-34% of individuals who meet clinical criteria for CS or who meet criteria for genetic testing • Function of PTEN is not entirely understood, but it is major phosphatase for phosphoinositide-3,4,5-triphosphate • By downregulating levels of phosphoinositide-3,4,5triphosphate, PTEN produces inhibitory (tumor suppressor) effect on PI3P/Akt pathway, important carcinogenesis pathway • Loss of PTEN function results in escape from programmed cell death and G1 arrest in cell cycle • Proposed that PTEN has important activity both in cytoplasm and nucleus ○ Nuclear PTEN might be required for cell cycle arrest by downregulating cyclin-D1 and preventing phosphorylation of mitogen-activated protein kinase pathway ○ Cytoplasmic PTEN seems to be required for apoptosis by downregulating phosphorylation of Akt and upregulating p27 • Protein produced from PTEN gene is tumor suppressor, which means that it normally prevents cells from growing and dividing (proliferating) too rapidly or in uncontrolled way • Mutations in PTEN gene prevent protein from regulating cell proliferation effectively, leading to uncontrolled cell division and formation of hamartomas and cancerous tumors

Other Loci • In some patients who lack PTEN mutations, hypermethylation of promoter of KLLN (killin) gene, leading to reduced expression of KLLN, has been described ○ KLLN gene, which is located on chromosome 10q23 and functions as p53-regulated inhibitor of DNA synthesis, shares same transcription site as PTEN gene • Other patients have been reported with mutations in succinate dehydrogenase (SDH) gene, subunits B and D • Tumor suppressor PTEN classically counteracts PI3K/AKT/mTOR signaling cascade ○ Germline pathogenic PTEN mutations cause PHTS

○ Germline and somatic mosaic mutations in genes encoding components of PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed PTENopathies ○ Germline PIK3CA and AKT1 mutations have also been reported in phenotypic CS patients without PTEN, SDH, or KLLN mutations • 8% of CS/CS-like and BRRS so-called PTEN-wild-type patients; other gene alterations were reported with MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2, and HRAS

Diagnosis • Up to 85% of individuals who meet diagnostic criteria for CS and 65% of individuals with clinical diagnosis of BRRS have detectable PTEN mutations • Preliminary data suggest that up to 50% of individuals with Proteus-like syndrome and up to 20% of individuals with PRPS have PTEN mutations • PTEN sequence analysis, deletion/duplication testing, and FISH testing are available on clinical basis • CS ○ Consensus diagnostic criteria for CS have been developed and are updated each year by National Comprehensive Cancer Network (NCCN) ○ Clinical criteria have been divided into 3 categories: Pathognomonic, major, and minor ○ Pathognomonic criteria – Adult Lhermitte-Duclos disease (LDD) defined as presence of cerebellar dysplastic gangliocytoma ○ Mucocutaneous lesions – Acral keratoses – Papillomatous lesions – Mucosal lesions – Trichilemmomas (facial) ○ Major criteria – Epithelial thyroid cancer (nonmedullary), especially follicular thyroid cancer – Macrocephaly (occipital frontal circumference ≥ 97th percentile) – Endometrial carcinoma – Breast cancer ○ Minor criteria – Other thyroid lesions (e.g., adenoma, adenomatous nodules, multinodular goiter) – Hamartomatous intestinal polyps – Fibrocystic disease of breast – Lipomas – Fibromas – Genitourinary tumors (especially renal cell carcinoma) – Genitourinary malformation – Uterine fibroids – Intellectual disability ○ Operational diagnosis of CS: Made if individual meets any of following criteria – Pathognomonic mucocutaneous lesions combined with 1 of following – ≥ 6 facial papules, of which ≥ 3 must be trichilemmoma – Cutaneous facial papules and oral mucosal papillomatosis

Overview of Syndromes: Syndromes

○ Now extending to – Colorectal cancer: 9-13% – Kidney cancer: 13-34% – Melanoma: 6%

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Overview of Syndromes: Syndromes

PTEN-Hamartoma Tumor Syndromes – ≥ 6 palmoplantar keratoses – Oral mucosal papillomatosis and acral keratoses – ≥ 4 minor criteria – 1 major and ≥ 3 minor criteria – ≥ 2 major criteria • BRRS ○ Diagnostic criteria for BRRS have not been set ○ Based heavily on presence of cardinal features – Macrocephaly – Hamartomatous intestinal polyposis – Lipomas – Pigmented macules of glans penis ○ ~ 60% of patients with BRRS have detectable PTEN mutation • PRPS ○ Highly variable and appears to affect individuals in mosaic distribution – Somatic activating mutations in AKT1 oncogene have been delineated as genetic cause of PS ○ It is frequently misdiagnosed despite development of consensus diagnostic criteria ○ Mandatory general criteria for diagnosis include mosaic distribution of lesions, progressive course, and sporadic occurrence ○ Rapidly progressive, asymmetric postnatal overgrowth of tissues, with hyperostoses, vascular malformations, dysregulation of fatty tissues (both atrophy and overgrowth), and skin manifestations, such as verrucous epidermal nevi or cerebriform connective tissue nevi ○ Specific criteria for diagnosis include connective tissue nevi (pathognomonic) ○ 2 of following – Epidermal nevus – Disproportionate overgrowth (≥ 1) – Limbs: Arms/legs; hands/feet/digits – Skull: Hyperostoses – External auditory meatus: Hyperostosis – Vertebrae: Megaspondylodysplasia – Specific tumors before end of 2nd decade – Bilateral ovarian cystadenomas – Parotid monomorphicadenoma ○ 3 of following – Dysregulated adipose tissue: Lipomas or regional absence of fat – Vascular malformations (≥ 1): Capillary, venous, lymphatic – Facial phenotype: Dolichocephaly, long face, minor downslanting of palpebral fissures &/or minor ptosis, low nasal bridge, wide or anteverted nares, open mouth at rest • Proteus-like syndrome ○ Exceedingly rare asymmetric overgrowth syndrome ○ Undefined but describes individuals with significant clinical features of PS yet who do not meet diagnostic criteria

Genetic Counseling • PHTS is inherited in autosomal dominant manner • Majority of CS cases are simplex (defined as individuals with no obvious family history) 752

• Because CS is likely underdiagnosed, actual proportion of simplex cases and familial cases (defined as ≥ 2 related affected individuals) cannot be determined • Perhaps 10-50% of individuals with CS have affected parent • Each child of affected individual has 50% chance of inheriting mutation and developing PHTS • Prenatal testing for pregnancies at increased risk is possible if disease-causing mutation in family is known

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Testing • Relevant to clinical practice, identification of PTEN mutations in patients not only establishes PHTS molecular diagnosis but also informs on more accurate cancer risk assessment and medical management of those patients and affected family members • Treatment of manifestations ○ Treatment for benign and malignant manifestations of PHTS is same as for their sporadic counterparts ○ Topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may alleviate mucocutaneous manifestations of CS ○ Cutaneous lesions should be excised only if malignancy is suspected or symptoms (e.g., pain, deformity) are significant • Sequence analysis ○ Virtually all missense mutations in PTEN are believed to be deleterious ○ Early studies suggest that up to 85% of individuals who meet diagnostic criteria for CS and 65% of individuals with clinical diagnosis of BRRS have detectable PTEN mutation ○ More recently, it was found that ~ 25% of individuals who meet strict diagnostic criteria for CS have pathogenic PTEN mutation, including large deletions ○ Data suggest that up to 50% of individuals with Proteuslike syndrome and up to 20% of individuals with PS have PTEN mutations • Deletion/duplication analysis ○ Southern blotting, real-time PCR, MLPA, and other methods of detecting gene copy number variation can each be used to detect large PTEN deletions and rearrangements that are not detectable by PCR-based sequence analysis

Management • Surveillance ○ To detect tumors at earliest, most treatable stages – For children (< 18 years): Yearly thyroid ultrasound and skin check with physical examination – For adults: Yearly thyroid ultrasound and dermatologic evaluation – For men and women: Colonoscopy beginning at age 35-40 years with frequency dependent on degree of polyposis identified; biennial (every 2 years) renal imaging (CT or MR preferred) beginning at age 40 years – For women beginning at age 30 years: Monthly breast self-examination

PTEN-Hamartoma Tumor Syndromes

ASSOCIATED LESIONS AND BENIGN NEOPLASMS Skin • Multiple trichilemmomas, usually on face, are cutaneous hallmark of disease ○ Trichilemmomas show differentiation toward hair follicle infundibulum • Mucocutaneous fibromas and neuromas • Acral and palmoplantar keratoses • Oral papillomas involving lips, gums, and tongue

Breast • Benign lesions are often bilateral and multiple ○ Fibroadenoma ○ Adenosis ○ Apocrine cysts ○ Hamartomas • Breast cancer risk estimates (~ 85%) for women with germline PTEN mutations are similar to those quoted for patients with BRCA1/2 germline mutations

Thyroid • Thyroid disease is even more common in children with PHTS (75%) than previously expected • Multiple adenomatous nodules are hallmark of disease • Lymphocytic thyroiditis • Multinodular hyperplasia • C-cell hyperplasia

• • • • •

○ Intramucosal lipomas are easily overlooked by pathologists despite their diagnostic significance for CS Hamartomatous stroma-rich polyps with cystically dilated glands Ganglioneuromatous polyps with proliferation of Schwann cells and ganglion cells in lamina propria Inflammatory polyps that may mimic juvenile polyps Lymphoid polyps with prominent mucosal or submucosal reactive lymphoid aggregates Colon adenomas may occur in patients with CS at young age ○ Isolated polyps in rectosigmoid colon may mimic mucosal prolapse

Brain • Dysplastic gangliocytoma of cerebellum or adult LDD ○ Refers to hamartomatous tumor of cerebellar cortex that can occur in setting of PTEN mutation • Cavernous hemangioma

Soft Tissue • Characteristic disorganized overgrowth of mesenchymal elements (PTEN hamartoma of soft tissue) • Vascular proliferations • Hamartomas

ASSOCIATED MALIGNANT NEOPLASMS Breast Carcinoma • Increased risk of female breast cancer: 25-50% lifetime risk; reports up to 85% • Age of diagnosis: 38-46 years ○ Occurs 10 years younger than general population ○ Male breast cancer also occurs

Follicular Thyroid Carcinoma • Increased risk of thyroid cancer: 3-35% lifetime risk ○ Risk increased in both female and male patients • Predominant thyroid tumor in PHTS

Papillary Thyroid Carcinoma • Also reported to have greater risk than general population

Esophagus

Endometrial Carcinoma

• Esophageal glycogen acanthosis is hallmark of CS ○ Abundant glycogen demonstrated on PAS stain ± diastase treatment ○ Pale, ballooned, and vacuolated squamous cells ○ Multiple nodular foci of squamous cell proliferation

• Increased risk of endometrial adenocarcinoma: 13-28% lifetime risk

Stomach

Colorectal Adenocarcinoma

• Most often resemble hyperplastic polyps with prominent foveolar hyperplasia ○ Stromal smooth muscle proliferation may be prominent and mimic Peutz-Jeghers polyps ○ Distinction from gastric polyps in juvenile polyposis difficult ○ Polyps may appear virtually identical to those described in patients with Cronkhite-Canada syndrome

• Risk of colorectal cancer was estimated at 10x higher than general population

Colon • Variable manifestations: Multiple gastrointestinal hamartomas, especially 2 or more hamartoma types, and any intramucosal lipomas or ganglioneuromas

Overview of Syndromes: Syndromes

– Annual breast screening (at minimum mammogram; MR may also be incorporated) and transvaginal ultrasound or endometrial biopsy – For those with family history of particular cancer type at early age: Consider initiating screening 5-10 years prior to youngest age of diagnosis in family • Testing of relatives at risk ○ When PTEN mutation has been identified in proband, molecular genetic testing of asymptomatic at-risk relatives can identify those who have family-specific mutation and warrant ongoing surveillance

Renal Cancer • Increased risk of renal cancer

Other Cancers Associated With PHTS • • • • • • • • •

Glioblastoma Melanoma Merkel cell carcinoma Retinal glioma Lung cancer Liver cancer Pancreatic cancer Ovarian cancer Bladder cancer 753

Overview of Syndromes: Syndromes

PTEN-Hamartoma Tumor Syndromes • Liposarcoma

Other Cancers Rarely Associated With PHTS • • • •

Ependymoma Medullary thyroid carcinoma Granulosa cell tumor Lipoblastoma

CANCER RISK MANAGEMENT

8.

9. 10. 11.

Breast • Breast awareness, including prompt reporting to physicians of any changes • Periodic breast self-exams starting at age 18 years • Clinical breast exam every 6-12 months starting at age 25 years or individualized based on earliest known onset of breast cancer in family • Annual mammography and breast MR screening starting at age 30-35 years ○ Or 5-10 years before earliest known breast cancer in family ○ MR screening as adjunct to mammography

12.

13. 14.

15. 16.

17.

Thyroid

18.

• Baseline thyroid ultrasound at 18 years and consideration of repeating annually thereafter • Monthly thyroid examination and palpation starting in adolescence

19.

20.

Uterus

21.

• Surveillance for endometrial cancer starting at age 35-40 years ○ Or 5 years younger than earliest familial endometrial cancer diagnosis

22.

Kidney

24.

• Annual urinalysis with cytology and renal ultrasound

25.

Colon • Consideration of baseline colonoscopy at age 35 years ○ Then every 5-10 years or more frequently if patient is symptomatic or polyps are noted

23.

26. 27.

Other Tumors

28.

• Given high risk of malignancy, cancer surveillance is major focus of medical management as per American Cancer Society guidelines ○ Annual comprehensive physical exam, starting at 18 years of age

29.

SELECTED REFERENCES 1.

2. 3.

4. 5. 6.

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7.

Sloot YJE et al: Effect of PTEN inactivating germline mutations on innate immune cell function and thyroid cancer-induced macrophages in patients with PTEN hamartoma tumor syndrome. Oncogene. ePub, 2019 Yehia L et al: PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 129(2):452-64, 2019 Bouron-Dal Soglio D et al: A case report of syndromic multinodular goitre in adolescence: exploring the phenotype overlap between Cowden and DICER1 syndromes. Eur Thyroid J. 7(1):44-50, 2018 Byrd V et al: The microbiome in PTEN hamartoma tumor syndrome. Endocr Relat Cancer. 25(3):233-43, 2018 Caliskan A et al: Intramucosal lipomas of the colon implicate Cowden syndrome. Mod Pathol. 31(4):643-51, 2018 Habeshian K et al: Segmental storiform collagenomas: expanding the spectrum of PTEN hamartoma tumor syndrome in children. Pediatr Dermatol. 35(4):e253-4, 2018

30.

31. 32.

33. 34. 35. 36. 37.

Lopez C et al: Novel germline PTEN mutation associated with Cowden syndrome and osteosarcoma. Cancer Genomics Proteomics. 15(2):115-20, 2018 Mester JL et al: Gene-specific criteria for PTEN variant curation: recommendations from the ClinGen PTEN expert panel. Hum Mutat. 39(11):1581-92, 2018 Plamper M et al: Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS). Eur J Pediatr. 177(3):429-35, 2018 Tosur M et al: Considerations for total thyroidectomy in an adolescent with PTEN mutation. Ther Adv Endocrinol Metab. 9(9):299-301, 2018 Yehia L et al: Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLoS Genet. 14(4):e1007352, 2018 Yehia L et al: 65 years of the double helix: one gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocr Relat Cancer. 25(8):T121-40, 2018 Chen HJ et al: Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome. Hum Mutat. 38(10):1372-7, 2017 Jiang T et al: Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) and Cowden syndrome: clinical experience from a single institution with long-term follow-up. World Neurosurg. 104:398-406, 2017 Ngeow J et al: Clinical implications for germline PTEN spectrum disorders. Endocrinol Metab Clin North Am. 46(2):503-17, 2017 Schultz KAP et al: PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23(12):e76-82, 2017 Shaco-Levy R et al: Gastrointestinal polyposis in Cowden syndrome. J Clin Gastroenterol. 51(7):e60-7, 2017 Ngeow J et al: Germline PTEN mutation analysis for PTEN hamartoma tumor syndrome. Methods Mol Biol. 1388:63-73, 2016 Shaco-Levy R et al: Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Hum Pathol. 49:39-48, 2016 Agarwal R et al: Targeted therapy for genetic cancer syndromes: von HippelLindau disease, Cowden syndrome, and Proteus syndrome. Discov Med. 19(103):109-16, 2015 Ngeow J et al: Detecting germline PTEN mutations among at-risk patients with cancer: an age- and sex-specific cost-effectiveness analysis. J Clin Oncol. 33(23):2537-44, 2015 Nizialek EA et al: KLLN epigenotype-phenotype associations in Cowden syndrome. Eur J Hum Genet. 23(11):1538-43, 2015 Al-Zaid T et al: Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors. J Cutan Pathol. 39(5):493-9, 2012 Hobert JA et al: Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals. Genet Med. 14(6):616-9, 2012 Kurek KC et al: PTEN hamartoma of soft tissue: a distinctive lesion in PTEN syndromes. Am J Surg Pathol. 36(5):671-87, 2012 Mester JL et al: Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 79(5):1187, 2012 Ngeow J et al: Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes. J Clin Endocrinol Metab. 97(12):E2320-7, 2012 Son EJ et al: Familial follicular cell-derived thyroid carcinoma. Front Endocrinol (Lausanne). 3:61, 2012 Laury AR et al: Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 21(2):135-44, 2011 Ngeow J et al: Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab. 96(12):E2063-71, 2011 Nosé V: Familial thyroid cancer: a review. Mod Pathol. 24 Suppl 2:S19-33, 2011 Pilarski R et al: Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet. 48(8):505-12, 2011 Smith JR et al: Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab. 96(1):34-7, 2011 Lam-Himlin D et al: Morphologic characterization of syndromic gastric polyps. Am J Surg Pathol. 34(11):1656-62, 2010 Nosé V: Familial follicular cell tumors: classification and morphological characteristics. Endocr Pathol. 21(4):219-26, 2010 Nosé V: Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 17(6):428-36, 2010 Eng C et al: PTEN hamartoma tumor syndrome, updated June 12, 2016, in Adam MP, et al: GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2018

PTEN-Hamartoma Tumor Syndromes Thyroid Carcinoma and Adenomatous Nodule (Left) Anterior planar I-123 nuclear medicine scan shows a cold nodule ﬊, indicating a thyroid carcinoma in the right thyroid lobe. A cold nodule has ~ 20% chance of being malignant. (Right) Gross photograph of thyroid carcinoma ﬇ arising in a background of multiple adenomatous nodules in a patient with PHTS is shown. The tumor is well circumscribed and invades st the adjacent adenomatous nodule ﬊.

Intervening Thyroid Parenchyma

Overview of Syndromes: Syndromes

Cold Thyroid Nodule

Microfollicular Pattern (Left) Adjacent adenomatous nodules ſt compress the adjacent thyroid parenchyma with atrophic follicles and dilated spaces. Note the focus of a small adenomatous nodule ﬈. These nodules are unencapsulated. (Right) This high-power view of an adenomatous nodule in a patient with PHTS shows a uniform population of follicular cells with pale pink cytoplasm with round and uniform nuclei.

Capsular Invasion in Follicular Carcinoma

Capsular Invasion in Thyroid (Left) One of the major criteria for the diagnosis of PHTS is the presence of follicular carcinoma. A follicular cell proliferation present in this young patient with Cowden syndrome shows capsular invasion ﬊. (Right) This photomicrograph shows a follicular thyroid carcinoma with a proliferation of small follicles invading the fibrous capsule ﬊ and forming separated tumor nodules outside the capsule ﬇.

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Overview of Syndromes: Syndromes

PTEN-Hamartoma Tumor Syndromes

Adjacent Adenomatous Nodules

PTEN Loss in Follicular Cells

High Power of Dysplastic Gangliocytoma

PTEN Loss in Tumor Cells

Invasive Breast Carcinoma

Ductal Carcinoma in PHTS

(Left) This photomicrograph shows 2 adjacent unencapsulated adenomatous nodules with minimal residual intervening thyroid parenchyma ſt between them. The nodules have homogeneous uniform microfollicles with pale-pink cytoplasm and small round nuclei. (Right) Immunohistochemistry for PTEN in thyroid adenomatous nodules in patients with PHTS usually shows loss of immunoreactivity of the follicular cells. Endothelial cells maintain immunopositivity ﬈.

(Left) Dysplastic gangliocytoma of the cerebellum, or adult Lhermitte-Duclos disease, is a hamartomatous tumor of the cerebellar cortex that can occur in PHTS. (Right) PTEN immunostaining is lost in the proliferating ganglion cells ſt in dysplastic gangliocytoma of the cerebellum, or adult Lhermitte-Duclos disease, in patients with PHTS. The endothelial cells retain PTEN expression.

(Left) Patients with PHTS may develop invasive breast carcinoma. These typically form firm-to-hard radiodense white masses ﬇ that replace radiolucent yellow adipose tissue. (Right) Invasive ductal carcinomas present in patients with PHTS may demonstrate tubules and have intermediate- to high-grade nuclei or a prominent component of well-formed tubules and may have rare or absent mitoses.

756

PTEN-Hamartoma Tumor Syndromes

Ganglioneuromatous Colonic Polyp (Left) A submucosal expansion is seen in a PHTS endoscopy. There are different types of polyps in Cowden disease/PHTS, including hamartomatous polyps, ganglioneuromatous polyps, inflammatory polyps, and colonic adenomas. (Right) H&E shows ganglioneuromatous polyps, which may be seen in juvenile polyposis and Cowden syndrome. Schwann cell proliferation ﬉ and numerous ganglion cells st are present in the lamina propria in this polyp. (Courtesy J. Greenson, MD.)

Colonic Hamartomatous Polyp

Overview of Syndromes: Syndromes

Colonic Polyps in PHTS

Esophagus With Acanthosis (Left) H&E shows hamartomatous colon polyps usually present in Cowden syndrome. Disarray of normal crypt architecture and fibromuscular proliferation may mimic mucosal prolapse polyps. (Right) Glycogen acanthosis involving the esophagus in Cowden syndrome shows a polypoid benign proliferation of large, ballooned, and vacuolated st squamous cells. A normal mucosa for comparison is seen on the right ﬇. (Courtesy J. Greenson, MD.)

Facial Trichilemmoma in PHTS

Trichilemmoma in PHTS (Left) Multiple facial trichilemmomas are common and clinically significant when seen in multiplicity with at least 1 lesion biopsy proven. Well-circumscribed epidermal proliferation with pale clear cells are reminiscent of the hair follicle infundibulum. (Right) Multiple facial trichilemmomas are common in patients with Cowden disease/PHTS. Wellcircumscribed ﬇ epidermal proliferation with pale clear cells is reminiscent of the hair follicle infundibulum.

757

Overview of Syndromes: Syndromes

RASopathies: Noonan Syndrome

TERMINOLOGY

EPIDEMIOLOGY

Definitions

Incidence

• RASopathies or RAS-/mitogen-activated protein kinase (MAPK) syndromes are group of phenotypically overlapping neurodevelopmental syndromes caused by germline mutations in components of RAS/MAPK signaling pathway • These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), NS with multiple lentigines (formerly LEOPARD syndrome), Costello syndrome (CS), cardiofaciocutaneous (CFC) syndrome, and Legius syndrome • NS is "prototype" of these developmental syndromes • NS is heterogeneous disorder caused by activating mutations in RAS-MAPK signaling pathway ○ It is associated with variable clinical expression, including short stature, congenital heart defect, unusual pectus deformity, and typical facial features ○ Autosomal dominant inheritance

• NS is most common RASopathy with prevalence of 1:1,0002,500, followed by NF1 with prevalence of 1:2,000-5,000

ETIOLOGY/PATHOGENESIS Genetic Basis • RASopathies, which are caused by dysregulation of RASMAPK pathway • Germline mutations in genes that encode components or regulators of RAS/MAPK pathway • Mutations in different genes can result in NS, more commonly affecting ○ PTPN11 (~ 50%) ○ SOS1 (~ 10%) ○ RAF1 (~ 10%) ○ Less commonly in other genes of RAS/MAPK signaling pathway, such as

Dysplastic Megakaryocyte in JMML

Bone marrow buffy coat shows maturing myelomonocytic forms and a small dysplastic megakaryocyte ﬇.

758

RASopathies: Noonan Syndrome KRAS NRAS MAP2K1 BRAF SHOC2 CBL SOS2

CLINICAL IMPLICATIONS

– Ptosis – Downslanting palpebral fissures – Low-set posteriorly rotated ears – Short/webbed neck • Heterogeneity among patients with NS and redundancy with other RASopathies can make early diagnosis with certainty difficult

DIAGNOSIS

Clinical Presentation

Clinical and Molecular Diagnosis

• NS, heterogeneous developmental disorder associated with variable clinical expression, including short stature, congenital heart defect, unusual pectus deformity, and typical facial features • Each RASopathy exhibits unique phenotype but shares many overlapping characteristics, owing to common mechanisms of RAS/MAPK pathway dysregulation, including ○ Craniofacial dysmorphology ○ Cardiac malformations ○ Cutaneous, musculoskeletal, and ocular abnormalities – 50% of NS patients with NRAS mutation present with lentigines &/or café au lait spots □ This demonstrates predisposition to hyperpigmented lesions in NRAS-positive NS patients ○ Neurocognitive impairment ○ Increased cancer risk – 8x increased cancer risk in NS with increased childhood cancers, including □ Gliomas (dysembryoplastic neuroepithelial tumors), acute lymphoblastic leukemia, neuroblastoma (NBL), and rhabdomyosarcoma □ Specific mutations of PTPN11 (i.e., at codon 61 or T73I) or KRAS (T58I) are associated with myeloproliferative disorder (NS/MPD) resembling juvenile myelomonocytic leukemia (JMML) □ NS/MPD occurs in neonates and young infants, starts as polyclonal disease, and typically resolves over time, although could become aggressive monoclonal disease – CS has highest cancer risk among RASopathies, with cumulative 15% incidence of tumors, including rhabdomyosarcoma and, less frequently, NBL and bladder carcinoma – CBL syndrome also carries high JMML risk • Severity of phenotype varies widely, from presentations that are lethal prenatally to mildly affected individuals with normal lifespan and minimal morbidity • NS formal diagnostic criteria include ○ Short stature (< 3rd percentile) ○ Cardiac defects, particularly pulmonary stenosis, hypertrophic obstructive cardiomyopathy, &/or typical ECG changes ○ Pectus carinatum/excavatum ○ Mild developmental delay, cryptorchidism, and lymphatic dysplasia ○ 1st-degree relative with confirmed NS ○ Typical facial features (most striking from newborn period until middle childhood) – Hypertelorism

• Clinical diagnosis can be made when typical constellation of features are present and recognized • Molecular confirmation of clinical diagnosis through genetic testing using NS or RASopathy panel test • Neurofibromatosis-NS (NFNS) is rare condition with clinical features of both NF1 and NS ○ Due to phenotypic overlap between NFNS and NS, screening for NF1 mutations in NS patients should be performed – Preferentially when café au lait spots are present

Overview of Syndromes: Syndromes

– – – – – – –

SELECTED REFERENCES 1.

Li X et al: Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 96(4):290-9, 2019 2. Tajan M et al: The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev. 39(5):676-700, 2018 3. Aoki Y et al: Recent advances in RASopathies. J Hum Genet. 61(1):33-9, 2015 4. Chang TY et al: Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia. Blood. 124(16):2487-97, 2014 5. Ekvall S et al: Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 164A(3):579-87, 2014 6. Niemeyer CM: RAS diseases in children. Haematologica. 99(11):1653-62, 2014 7. Rauen KA: The RASopathies. Annu Rev Genomics Hum Genet. 14:355-69, 2013 8. Ekvall S et al: Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 155A(6):1217-24, 2011 9. Komatsuzaki S et al: Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 55(12):801-9, 2010 10. Schubbert S et al: Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar;38(3):331-6. Epub 2006 Feb 12. Erratum in: Nat Genet. 38(5):598, 2006

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Overview of Syndromes: Syndromes

RASopathies: Noonan Syndrome Clinical Features and Genetics of RASopathies Disease

Inheritance

Clinical Features

Genes

Noonan syndrome

Autosomal dominant

Facial dysmorphic features, congenital heart defects, skeletal abnormalities, short stature, developmental delay, easy bruising, and increased risk of JMML

PTPN11 (50%), SOS1 (10%), RAF1 (10%),  KRAS, NRAS, MAP2K1, BRAF, SHOC2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1

CBL syndrome

Autosomal dominant

NS-like dysmorphic features, congenital heart defect (less often), delayed brain myelination, hypoplasia of cerebellar vermis, café au lait spots, vasculopathy, and increased risk of JMML

CBL

NS-like disorder with loose anagen hair

Autosomal dominant

NS-like dysmorphic features, hairless and darkly pigmented skin with eczema or ichthyosis

SHOC2

NS-ML (formerly LEOPARD syndrome)

Autosomal dominant

Facial dysmorphic features, congenital heart defects, skeletal abnormalities, short stature, mild intellectual disability, ML, and deafness (20%)

PTPN11 (90%), RAF1 (5%), BRAF, MAP2K1

Costello syndrome

Autosomal dominant

Coarse facial features, congenital heart defects, short stature, ocular abnormalities, failure to thrive, deep palmar and plantar creases, papillomas, intellectual disability, and increased risk of solid tumors (rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma)

HRAS (80-90%)

NF1

Autosomal dominant

Multiple café au lait spots, neurofibromas, optic glioma, Iris Lisch nodules, mild learning disability, and increased risk of cancer (astrocytoma, JMML, peripheral nerve-sheath tumor, rhabdomyosarcoma, neuroblastoma, breast cancer, GI stromal tumor)

 NF1 (> 90%)

Cardiofaciocutaneous syndrome

Autosomal dominant

Congenital heart defects, short stature, ectodermal abnormalities (sparse, slow-growing, curly scalp hair that is abnormally dry and brittle; absent or sparse eyebrows and eyelashes), and intellectual disability

BRAF (75%), MEK1 (10%), MEK2 (10%), KRAS (< 2-3%)

Legius syndrome 

Autosomal dominant

Multiple café au lait spots, mild learning disability

SPRED1 (98%)

JMML = juvenile myelomonocytic leukemia; ML = myelomonocytic leukemia; NS = Noonan syndrome.

Genotype-Phenotype Correlation in Juvenile Myelomonocytic Leukemia Genetic Subtype

Age at Presentation

Clinical Features

JMML in children with NF1

Older age (often > 5 years)

Fatal in absence of allogeneic HSCT Higher percentage of bone marrow blasts Higher platelet count

JMML in children with  germline CBL mutation

Frequent spontaneous regression of myeloproliferation e persistence of clonal hematopoiesis Frequent occurrence of mixed chimerism after allogeneic HSCT Loss of CBL heterozygosity in hematopoietic cells

Somatic PTPN11 mutation

Rapidly fatal in absence of allogeneic HSCT High probability of relapse Frequent acquisition of NF1 haploinsufficiency

Somatic NRAS mutation

Variable

Variable course Indolent course with spontaneous regression, typically in infants or in cases with G12S mutation Rapid progression with high relapse rate after allogeneic HSCT, typically in older children with high levels of HbF

Somatic KRAS mutation

Mostly infants

Frequent concomitant monosomy  Aggressive at presentation but low risk of relapse after allogeneic HSCT

HSCT = hematopoietic stem cell transplant.

760

RASopathies: Noonan Syndrome JMML With Increased and Dysplastic Megakaryocytes (Left) Bone marrow buffy coat shows 2 blasts ﬇ with monocytic features amid maturing myeloid and lymphoid elements in a patient with juvenile myelomonocytic leukemia (JMML) and neurofibromatosis type 1 (NF1). (Right) Core biopsy shows a hypercellular marrow with numerous small, dysplastic megakaryocytes and left-shifted myeloid elements.

JMML With Dysplastic Megakaryocytes

Overview of Syndromes: Syndromes

Increased Blasts at Diagnosis in JMML and NF1

Increased Blasts at Diagnosis in JMML (Left) CD61 highlights increased and dysplastic megakaryocytes, which are small and hypolobated. (Right) CD34 highlights increased myeloid blasts at presentation in a case of JMML arising in a patient with NF1.

JMML With Increased Reticulin Fibrosis

Increased Blasts at Diagnosis in JMML (Left) Reticulin stain highlights increased reticulin fibrosis in a patient with JMML and NF1. (Right) Bone marrow aspirate shows a myeloid blast ﬇ amid maturing myeloid, monocytic, and lymphoid elements in this case of JMML presenting with increased blasts at diagnosis.

761

Overview of Syndromes: Syndromes

Rhabdoid Predisposition Syndrome • Few, if any, additional somatic genetic alterations in rhabdoid tumors other than SMARCB1 alterations

TERMINOLOGY Synonyms • Formerly called familial posterior fossa brain tumor syndrome, though not all tumors arise in posterior fossa

Definition • Genetic predisposition for development of rhabdoid tumors [atypical teratoid/rhabdoid tumor (AT/RT)] of brain, renal rhabdoid tumors, and extrarenal rhabdoid tumors

Relatively Rare • AT/RT represents 1-2% of pediatric brain tumors; 10% of brain tumors in infants with M:F 1.6-2:1 • Rhabdoid tumors represent < 3% of pediatric renal tumors • Median age at diagnosis of rhabdoid tumors is 6 months in patients with germline mutations vs. 18 months sporadically

GENETICS Germline Mutations in SMARCB1

• • • •

•

• Reported in rare family with rhabdoid predisposition syndrome • Encodes another protein member of SWI/SNF chromatinremodeling complex • Loss of heterozygosity in 2 sisters with rhabdoid tumors, INI1 protein preservation

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

EPIDEMIOLOGY

• • • •

Germline Mutations in SMARCA4/BRG1

Occur in ~ 1/3 of patients with rhabdoid tumors a.k.a. INI1, hSNF5, BAF47 Located in chromosome region 22q11.2 Encodes for protein component of ATP-dependent SWISNF chromatin-remodeling complex ○ Protein product interacts with HIV-1 integrase Classic tumor suppressor gene (i.e., inactivation through 2 hits leads to tumor formation) Frequency of germline mutations is highest in patients with multiple primary sites (~ 100%) Gonadal mosaicism in subset ○ Multiple affected siblings, unaffected parents Most mutations in rhabdoid tumors are deletions, nonsense, or frameshift and lead to complete gene inactivation Rarely present in > 1 generation given high penetrance and high mortality of disease

Genetic Testing • Germline mutation testing and genetic counseling recommended in any patient/families with rhabdoid tumors/neoplasms associated with INI1 protein loss • Irrespective of age: Patients with germline mutations as old as 22 years at presentation have been reported • Prenatal DNA testing may be offered in families with documented mutation

ASSOCIATED NEOPLASMS Atypical Teratoid/Rhabdoid Tumor • Highly malignant neoplasm corresponding to WHO grade IV • Composed of large cells with eccentric nuclei and macronucleoli arranged in nests or sheets • Brisk mitotic activity and necrosis • Variable small round blue cell component ○ May predominate in younger patients • Mesenchymal differentiation, arrangement in cords, myxoid stroma in subset of cases • Epithelial morphology with papillae and gland-like areas is rare • Immunohistochemistry highlights polyphenotypic pattern of staining

Cerebellopontine Angle Tumor (Left) The cerebellopontine angle is a classic location for atypical teratoid/rhabdoid tumor (AT/RT) ſt. This patient had a constitutional chr 22 abnormality with multiple congenital anomalies in addition to AT/RT. (Courtesy C. Specht, MD.) (Right) Cytologic features of rhabdoid tumors at all sites include the presence of large, variably dyscohesive cells with eosinophilic cytoplasm ﬈ and eccentric nuclei with prominent nucleoli.

762

Cytological Features of Rhabdoid Tumor

Rhabdoid Predisposition Syndrome

•

•

•

•

•

Malignant Rhabdoid Tumors • Renal ○ Most frequent organ affected outside of CNS ○ Germline SMARCB1 mutations in almost all bilateral cases ○ Sheets of rhabdoid cells with extensive infiltration of renal parenchyma ○ Brisk mitotic activity, necrosis, vascular invasion, and extrarenal extension are common ○ Gene expression studies suggest origin from early progenitors with repression of neural development ○ Differential diagnosis includes renal medullary carcinoma, cellular mesoblastic nephroma, and clear cell sarcoma of kidney • Extrarenal ○ May occur in deep soft tissue, skin, and viscera ○ Differential diagnosis includes melanoma, proximal variant of epithelioid sarcoma, rhabdomyosarcoma, extraskeletal myxoid chondrosarcoma, soft tissue myoepithelioma, and carcinoma

Schwannoma • Germline mutations in SMARCB1 are also responsible for subset of patients with schwannomatosis ○ Mainly multiple schwannomas but also meningiomas in rare occasions

○ Mosaic pattern of INI1 protein loss by immunohistochemistry in syndrome-associated schwannomas suggests milder phenotype compared to rhabdoid tumors ○ Mutations more likely to be nontruncating (e.g., splice site) • Rare families characterized by both rhabdoid tumors and schwannomatosis in different family members

Others • Choroid plexus carcinomas and medulloblastomas have been reported in setting of rhabdoid predisposition syndrome, but morphologic and immunophenotypic features overlap with AT/RT, and diagnosis questionable in presence of INI1 loss • Loss of SMARCB1 protein expression also described in epithelioid sarcoma, renal medullary carcinoma, pediatric sarcomas, hepatoblastomas, epithelioid malignant peripheral nerve sheath tumor, and soft tissue myoepithelioma

Overview of Syndromes: Syndromes

•

○ EMA expression is most frequent, but cytokeratin, GFAP, neurofilament protein, and smooth muscle actin may also be expressed Cytoplasmic aggregates of intermediate filaments by electron microscopy Very few genetic alterations other than SMARCB1 mutation ○ Loss of INI1 nuclear protein by immunohistochemistry with preservation in nonneoplastic elements is almost diagnostic Differential diagnosis includes choroid plexus carcinoma, CNS-PNET/medulloblastoma, epithelioid/rhabdoid glioblastoma, metastasis (melanoma, carcinoma) ○ Cribriform neuroepithelial tumor: Rare, nonrhabdoid intracranial tumor that also demonstrates INI1 protein loss but with relatively favorable prognosis 3 different molecular subtypes of AT/RT identified by global methylation and gene expression analysis (Johann PD et al) ○ ATRT-TYR: Mostly infratentorial, broad SMARCB1 deletions ○ ATRT-SHH: Supra- and infratentorial, focal SMARCB1 aberrations ○ ATRT-MYC: Mostly supratentorial, focal SMARCB1 deletions 3 different molecular subgroups by integrated molecular analysis (Torchia J et al), different sensitivities to specific inhibitors ○ Neurogenic (1): Supratentorial ○ Mesenchymal (2A): Infratentorial ○ Mesenchymal (2B): Spinal Predilection for pituitary in adult women; may represent distinct entity ○ Poor prognosis but rare patients with extended survival

CANCER RISK MANAGEMENT Established Guidelines for Tumor Screening in Affected Families • Routine imaging (CNS MR, renal ultrasound) and feasible screening approaches in 1st few years of life for mutation carriers

SELECTED REFERENCES 1.

2.

3.

4.

5. 6. 7. 8.

9. 10.

11.

12.

13.

14. 15.

16.

Johann PD et al: sellar region atypical teratoid/rhabdoid tumors (ATRT) in adults display DNA methylation profiles of the ATRT-MYC subgroup. Am J Surg Pathol. 42(4):506-11, 2018 Johann PD et al: Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 29(3):379-93, 2016 Torchia J et al: Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell. 30(6):891-908, 2016 Plotkin SR et al: Update from the 2011 International Schwannomatosis Workshop: from genetics to diagnostic criteria. Am J Med Genet A. 161(3):405-16, 2013 Lee RS et al: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest. 122(8):2983-8, 2012 Bourdeaut F et al: Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res. 17(1):31-8, 2011 Eaton KW et al: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer. 56(1):7-15, 2011 Hasselblatt M et al: Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol. 35(6):933-5, 2011 Gadd S et al: Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab Invest. 90(5):724-38, 2010 Schneppenheim R et al: Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 86(2):279-84, 2010 Hasselblatt M et al: Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis. J Neuropathol Exp Neurol. 68(12):1249-55, 2009 Swensen JJ et al: Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. J Med Genet. 46(1):68-72, 2009 Ammerlaan AC et al: Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome. Br J Cancer. 98(2):474-9, 2008 Hulsebos TJ et al: Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 80(4):805-10, 2007 Judkins AR et al: Atypical teratoid/rhabdoid tumour. In Louis DN, et al: WHO Classification of Tumours of the Central Nervous System. IARC Press. 147-9, 2007 Taylor MD et al: Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. Am J Hum Genet. 66(4):1403-6, 2000

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Overview of Syndromes: Syndromes

Rhabdoid Predisposition Syndrome Supratentorial Atypical Teratoid/Rhabdoid Tumors

Atypical Teratoid/Rhabdoid Tumors Architecture

Large Cells With Eccentric Nuclei

Hight Proliferative Index

Poorly Differentiated Areas

Areas of Necrosis

(Left) AT/RTs form variably sized masses that may appear well circumscribed. Multiple foci of necrosis are not uncommon in these highgrade, extremely aggressive pediatric tumors. Despite their genetic predisposition being ascribed to the posterior fossa in early reports, they occur throughout the neural axis, including the supratentorial compartment. (Right) AT/RT architecture is variable and may demonstrate sheet-like arrangements of rhabdoid cells.

(Left) Rhabdoid tumors at all sites contain variable numbers of large eosinophilic cells with eccentric nuclei and macronucleoli. Cell borders are usually distinct. Single cell necrosis may be a feature ﬈. (Right) Mitotic activity is usually not subtle in AT/RT ﬈. These tumors are characterized by high proliferative rates and are among the most aggressive human malignancies. Cell to cell wrapping ﬊ raises the differential with anaplastic medulloblastoma in the CNS.

(Left) Rhabdoid tumors may contain poorly differentiated areas of closely packed cells with high nuclear:cytoplasmic ratios lacking overt rhabdoid cytologic features, particularly when involving the CNS. A high index of suspicion is required when encountering a primitive neoplasm in a very young child. Careful searching for rare rhabdoid cells and immunostaining documenting INI1 loss is helpful in the diagnosis. (Right) Necrosis is almost always present in rhabdoid tumors.

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Rhabdoid Predisposition Syndrome Smooth Muscle Actin in Atypical Teratoid/Rhabdoid Tumors (Left) Rhabdoid tumors typically label with numerous immunohistochemical markers. Epithelial membrane antigen (EMA) is one of the most frequently expressed antigens in such tumors. (Right) Smooth muscle actin expression occurs in a subset of cases of AT/RT and other rhabdoid tumors, although with less frequency than EMA.

Loss of INI1 Immunoexpression

Overview of Syndromes: Syndromes

Rhabdoid Tumors EMA Immunopositivity

Chromosome 22 Loss by FISH (Left) One of the most diagnostically useful immunohistochemical findings in malignant rhabdoid tumors is the loss of INI1 expression in neoplastic cells. Preservation of reactivity in nonneoplastic elements, including stromal and endothelial cells ﬈, is essential for interpretation. (Right) Whole chr 22 loss/22q deletion occurs in a variety of neoplasms, particularly rhabdoid tumors (BCR = green, NF2 = red). (Courtesy A. Perry, MD.)

SMARCA4 Rhabdoid Tumor Morphology

Preserved SMARCB1 in SMARCA4-Mutated Tumor (Left) Rarely, AT/RTs may lack SMARCB1 mutations and instead have mutations in associated proteins such as SMARCA4. As this example demonstrates, histologic and other immunophenotypic findings are identical to SMARCB1 (INI1) mutant tumors. (Courtesy C. Giannini, MD.) (Right) Retained SMARCB1 (INI1) in an AT/RT containing a SMARCA4 mutation is shown, although this tumor demonstrated classic histologic and immunohistochemical features of AT/RT. (Courtesy C. Giannini, MD.)

765

Overview of Syndromes: Syndromes

Schwannomatosis

EPIDEMIOLOGY Incidence • Affects ~ 1 in 40,000 [similar incidence as neurofibromatosis type 2 (NF2)] in some studies ○ Frequency may be actually lower than NF2 with increased recognition of mosaic NF2 by high-resolution techniques (NGS) • Similar incidence in males and females

ETIOLOGY/PATHOGENESIS Inheritance Pattern • 75-85% sporadic, 15-25% inherited

Germline Mutations in SMARCB1 Tumor Suppressor Gene • Germline mutations of either SMARCB1 or LZTR1 tumor suppressor genes have been identified in ~ 85% of familial and 40% of sporadic schwannomatosis patients • 4-hit hypothesis: (1) germline SMARCB1 mutation → loss of Chr 22 with remaining (2) SMARCB1 allele and (3) NF2 → loss of remaining (4) NF2 allele • Tumorigenesis in schwannomatosis must involve mutation of at least 2 different tumor suppressor genes ○ Occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harboring not only SMARCB1 and LZTR1 but also NF2

• Mood disorders, including depression and anxiety, are frequent • Lack of family history in majority of patients • Meningiomas occur at low frequency in schwannomatosis patients (~ 5%) ○ Rare families with schwannomatosis, multiple meningiomas, and germline SMARCB1 mutation ○ Preferential location in falx cerebri ○ Usually solitary rather than multiple in schwannomatosis (in contrast to NF2) • Ependymoma not feature • Ophthalmologic manifestations not present at higher frequency in schwannomatosis (in contrast to NF2)

Imaging Findings • Peripheral schwannoma location (89%) ○ Arms and legs most common • Spinal schwannomas (74%) • Intracranial schwannoma (nonvestibular) (9%) • Unilateral vestibular schwannoma may develop, particularly in LZTR1 germline variants

Diagnostic Criteria • Several clinical criteria proposed to distinguish schwannomatosis from NF2 ○ Lack of bilateral vestibular schwannoma; lack of NF2 in 1st-degree relative; lack of germline NF2 mutation • Recent proposals incorporate molecular testing

Proposed Criteria for Schwannomatosis (2011 International Schwannomatosis Workshop)

CLINICAL IMPLICATIONS Clinical Presentation • Onset is usually in 2nd and 3rd decades ○ Wide range of ages at initial presentation (children < 10 years through senior patients) • Multiple schwannomas, usually sparing vestibular nerve ○ Restricted to 1 anatomical region in 1/3 of patients ○ Unilateral vestibular schwannomas may occur at low frequency and do not exclude diagnosis • Chronic pain is most common symptom, often debilitating ○ No clear relationship to tumor size, location, or burden

• Molecular diagnosis ○ Schwannomas or meningiomas (≥ 2 pathologically proven) and ○ ≥ 2 tumors with chromosome 22 loss of heterozygosity + 2 different NF2 mutations or schwannoma or meningioma + germline SMARCB1 mutation • Clinical diagnosis ○ ≥ 2 schwannomas (not intradermal), 1 pathologically confirmed; no vestibular schwannomas on high-quality MR study or

Multiple Schwannomas (Left) Multiple schwannomas are the hallmark of schwannomatosis ſt. The spinal nerves are frequently involved in these patients. (Courtesy J. Blakeley, MD.) (Right) Many schwannomas in patients with schwannomatosis have features similar to sporadic tumors, including circumscription and a biphasic architecture of Antoni A and Antoni B areas.

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Schwannoma

Schwannomatosis

MICROSCOPIC Schwannomas • Histologic features similar to sporadic tumors ○ Compact Antoni A areas alternating with loose Antoni B areas, Verocay bodies, hyalinized vessels, and wellformed capsule • Myxoid changes (myxoid schwannoma), intraneural growth, and peritumoral edema overrepresented in schwannomatosis-associated cases • Nerve edema • Rare schwannoma variants reported in schwannomatosis patients include plexiform, cellular, and neuroblastoma-like • S100 and collagen IV (pericellular) positive by immunohistochemistry; EMA(-) • Mosaic pattern of INI1 immunostaining (i.e., loss in subset of neoplastic cells) in most schwannomatosis-associated schwannomas • Malignant transformation into MPNST rare but documented

Neurofibromas • Neurofibromas, in addition to schwannomas, are recognized feature of NF2 • Not usually feature of schwannomatosis, but previously reported in at least 2 patients

Germline Mutations in SMARCB1 • Nontruncating, missense, or splice site in familial schwannomatosis (unlike atypical teratoid rhabdoid tumor) • Mutations usually located at ends of SMARCB1 • Inherited in autosomal dominant fashion, incomplete penetrance

Germline Mutations in LZTR1 • Adaptor of cullin 3-containing E3 ubiquitin ligase complex • Located in chromosome arm 22q (3 Mb centromeric to SMARCB1) • Autosomal dominant inheritance

SELECTED REFERENCES 1. 2. 3.

4.

5.

6. 7.

8.

9.

10.

11.

Hybrid Tumors • Tumors with hybrid neurofibroma/schwannoma features overrepresented in syndrome-associated peripheral nerve tumors, particularly in schwannomatosis • Neurofilament (+) axons in neurofibroma-like component in 1/2 of cases • GLUT1/EMA(+) perineurial-like cells in neurofibroma-like areas • CD34(+) in Antoni B and neurofibroma-like areas, negative in Antoni A areas

12. 13. 14.

15.

16.

Other Tumors

17.

• Malignant sarcomas rare but reported in schwannomatosis patients

18.

GENETICS AND MOLECULAR BIOLOGY

19.

SMARCB1 Function • Tumor suppressor gene • Other synonyms include INI1, BAF47, hSNF5 • Encodes component of SWI/SNF protein complex ○ Chromatin-remodeling complex, ATP dependent ○ Interacts with HIV-1 integrase

20.

Overview of Syndromes: Syndromes

○ Schwannoma, pathologically confirmed, or intracranial meningioma and 1st-degree relative with schwannomatosis • Possible schwannomatosis ○ ≥ 2 nonintradermal schwannomas without pathologic confirmation • Excludes schwannomatosis ○ Patient with diagnostic criteria for NF2, germline NF2 mutation, 1st-degree relative with NF2, or multiple schwannomas in prior irradiated field only

Alaidarous A et al: Segmental schwannomatosis: characteristics in 12 patients. Orphanet J Rare Dis. 14(1):207, 2019 Evans DG et al: Schwannomatosis: a genetic and epidemiological study. J Neurol Neurosurg Psychiatry. 89(11):1215-9, 2018 Louvrier C et al: Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis. Neuro Oncol. 20(7):917-29, 2018 Kehrer-Sawatzki H et al: The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet. 136(2):129-48, 2017 Paganini I et al: Broadening the spectrum of SMARCB1-associated malignant tumors: a case of uterine leiomyosarcoma in a patient with schwannomatosis. Hum Pathol. 46(8):1226-31, 2015 Smith MJ et al: Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology. 84(2):141-7, 2015 Hutter S et al: Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants. Acta Neuropathol. 128(3):449-52, 2014 Piotrowski A et al: Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 46(2):182-7, 2014 Plotkin SR et al: Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am J Med Genet A. 161(3):405-16, 2013 Carter JM et al: Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with "neuroblastoma-like" schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol. 36(1):154-60, 2012 Harder A et al: Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients. Am J Surg Pathol. 36(5):702-9, 2012 Merker VL et al: Clinical features of schwannomatosis: a retrospective analysis of 87 patients. Oncologist. 17(10):1317-22, 2012 Smith MJ et al: Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics. 13(2):141-5, 2012 Smith MJ et al: Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis. Am J Med Genet A. 158A(1):215-9, 2012 Rodriguez FJ et al: Superficial neurofibromas in the setting of schwannomatosis: nosologic implications. Acta Neuropathol. 121(5):663-8, 2011 Boyd C et al: Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin Genet. 74(4):358-66, 2008 Patil S et al: Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol. 18(4):517-9, 2008 Sestini R et al: Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum Mutat. 29(2):22731, 2008 Baser ME et al: Increasing the specificity of diagnostic criteria for schwannomatosis. Neurology. 66(5):730-2, 2006 MacCollin M et al: Diagnostic criteria for schwannomatosis. Neurology. 64(11):1838-45, 2005

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Overview of Syndromes: Syndromes

Schwannomatosis

Schwannoma

Schwannoma

Verocay Body

Antoni B Area

Collagenous Capsule in Schwannoma

Myxoid Schwannoma

(Left) Classic schwannoma features that may be present in tumors from patients with schwannomatosis include a circumscribed architecture, a collagenous capsule of variable thickness ﬈, and microcysts ﬊. (Right) Syndrome-associated and sporadic schwannomas are characterized by the presence of compact areas rich in neoplastic Schwann cells (Antoni A areas) ﬈, alternating with loose, macrophage-rich regions (Antoni B areas). Microcysts may be frequent ﬊.

(Left) One of the diagnostic hallmarks of schwannoma is the Verocay body ﬈. This anuclear, process-rich, elongated structure is bordered by palisades of neoplastic Schwann cells. (Right) Antoni B areas in schwannomas are characterized by a loose stroma containing lipidized cells as well as macrophages. Delicate wisps of bland spindle cells are variably present ﬈, suggesting the schwannian nature of the neoplasm.

(Left) A collagenous capsule is typical of most schwannomas ﬈, including schwannomatosis-associated cases. However, capsule thickness is variable and may be altogether absent in areas. (Right) Conspicuous myxoid change (i.e., myxoid schwannoma) is seen at an increased frequency in schwannomatosis-associated tumors. Compact Antoni A areas ﬈ may represent a minor component of these tumors.

768

Schwannomatosis

Neurofibroma-Like Area (Left) Many schwannomas in schwannomatosis patients contain classic features. However, the presence of benign nerve sheath tumors with mixed features, including compact Antoni A areas typical of schwannoma ﬈ and juxtaposed to neurofibromalike areas ﬊, occur at a relatively higher frequency in syndrome-associated tumors. (Right) Neurofibroma-like area in a schwannomatosisassociated benign nerve sheath tumor contains wavy nuclei in a loose stroma with associated collagen.

S100 Expression

Overview of Syndromes: Syndromes

Hybrid Features

Mosaic INI1 Loss (Left) The immunohistochemical hallmark of schwannoma is the expression of S100 protein in a strong, diffuse pattern. (Right) A mosaic pattern of INI1 immunostaining is found in most syndrome-associated schwannomas, including in schwannomatosis. Immunonegative cells ﬈ alternate with immunopositive cells ﬊. This finding suggests that INI1 protein loss is partial in these tumors, compared with the uniform INI1 loss present in rhabdoid tumors.

MPNST Arising in Schwannoma

MPNST Arising in Schwannoma (Left) Although most nerve sheath tumors in schwannomatosis patients are benign, MPNST ﬊ may rarely develop in schwannomatosisassociated schwanomas. (Right) MPNST developing in schwannomas are frequently of the epithelioid subtype. This example developed in a schwannoma from a schwannomatosis patient.

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Overview of Syndromes: Syndromes

Shwachman-Diamond Syndrome • SDS patients negative for SBDS mutations may have more severe hematological failure and milder pancreatic disease

TERMINOLOGY Abbreviations • Shwachman-Diamond syndrome (SDS)

CLINICAL IMPLICATIONS

Synonyms

Clinical Presentation

• Shwachman-Bodian-Diamond syndrome • Shwachman-Diamond-Oski syndrome • Shwachman syndrome

• Triad of ○ Pancreatic exocrine insufficiency – Noted as early as 2 weeks of age – Deficiency of fat-soluble vitamins, causing failure to thrive – Fat replacement of pancreas on imaging or biopsy (lipomatosis) – Many patients spontaneously improve over time with almost 1/2 of patients no longer requiring supplemental pancreatic enzyme therapy – Loose, foul-smelling stools – Decreased isoamylase and serum trypsinogen ○ Bone marrow dysfunction – Cytopenias (2 occasions, at least 2 months apart) □ Neutropenia [absolute neutrophil count (ANC) < 1,500/ul], often intermittent, is most classic finding □ Other cytopenias can occur, particularly over time ○ Skeletal abnormalities (metaphyseal dysostosis) • In addition, can present with ○ Dental abnormalities ○ Liver abnormalities (elevated liver enzymes, hepatomegaly) ○ Endocrine dysfunction (diabetes mellitus, growth hormone deficiency) • In North American SDS registry, only 51% (19 of 37) of those with biallelic SBDS mutations presented with classic findings of neutropenia with steatorrhea

Definitions • Inherited bone marrow failure disorder with pancreatic exocrine dysfunction and diverse clinical phenotype

EPIDEMIOLOGY Age Range • Typically manifests in 1st year of life (neutropenia, pancreatic dysfunction)

Incidence • True incidence of SDS is unknown • In Italy, incidence of biallelic mutation-positive patients with SDS is 1:168,000

ETIOLOGY/PATHOGENESIS Molecular Genetics • 90% of patients have biallelic mutations in SBDS, leading to impaired ribosomal assembly • Many mutations appear to result from gene conversion between SBDS and adjacent, nonfunctional pseudogene with similar sequence, SBDSP • Autosomal recessive transmission ○ Affected individuals are either homozygous or compound heterozygous for SBDS mutations • SBDS protein has been implicated in ribosome biogenesis and mitotic spindle function • Mutations in other SDS-associated genes (DNAJC21, SRP54, EFL1) have been recently identified, leading to SDS-like phenotype

Risk of Malignancy • 8-33% of patients will develop myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), typically during adulthood and associated with TP53 mutations

Hypocellular Marrow With Neutropenia and Thrombocytopenia (Left) Bone marrow biopsy shows a hypocellular erythroid dominant marrow for age (patient was 1 year old) with decreased maturing myeloid elements and decreased megakaryocytes ﬊, consistent with suspected bone marrow failure syndrome. (Right) Peripheral smear shows neutropenia and, to a lesser degree, thrombocytopenia (note platelet ﬊) and anemia.

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Pancytopenia in Setting of Bone Marrow Failure Syndrome

Shwachman-Diamond Syndrome

Diagnostic Criteria of SDS • Hematologic abnormality ○ Cytopenias (present on at least 2 occasions, at least 2 months apart) – Neutropenia (absolute neutrophil count < 1,500) – Anemia or macrocytosis – Thrombocytopenia (platelet count < 150,000) ○ Bone marrow findings – Hypocellularity – MDS, AML – Cytogenetic abnormalities □ del(20) (q11) □ Isochromosome  7q • Pancreatic insufficiency ○ Reduced level of pancreatic enzymes relevant to age ○ Low levels of fecal elastase ○ Low levels of serum lipase – Trypsinogen (< 3 years) – Isoamylase  (> 3 years) • Additional supportive features ○ Skeletal abnormalities ○ Neurocognitive/behavioral problems ○ Short stature (< 3rd percentile) ○ 1st-degree family member with SDS

○ Aplastic anemia

SELECTED REFERENCES 1.

Nelson AS et al: Diagnosis, treatment, and molecular pathology of Shwachman-Diamond syndrome. Hematol Oncol Clin North Am. 32(4):687700, 2018 2. Dhanraj S et al: Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. Blood. 129(11):1557-1562, 2017 3. Stepensky P et al: Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome. J Med Genet. 54(8):558566, 2017 4. Tummala H et al: DNAJC21 mutations link a cancer-prone bone marrow failure syndrome to corruption in 60S ribosome subunit maturation. Am J Hum Genet. 99(1):115-24, 2016 5. Minelli A et al: Incidence of Shwachman-Diamond syndrome. Pediatr Blood Cancer. 59(7):1334-5, 2012 6. Dror Y et al: Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci. 1242:40-55, 2011 7. Hashmi SK et al: Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Clin Genet. 79(5):448-58, 2011 8. Cesaro S et al: Haematopoietic stem cell transplantation for ShwachmanDiamond disease: a study from the European Group for blood and marrow transplantation. Br J Haematol. 131(2):231-6, 2005 9. Donadieu J et al: Hematopoietic stem cell transplantation for ShwachmanDiamond syndrome: experience of the French neutropenia registry. Bone Marrow Transplant. 36(9):787-92, 2005 10. Boocock GR et al: Mutations in SBDS are associated with ShwachmanDiamond syndrome. Nat Genet. 33(1):97-101, 2003 11. Shwachman H et al: The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr. 65:645-63, 1964

Overview of Syndromes: Syndromes

• Hematopoietic stem cell transplant remains only curative therapy for SDS patients with severe aplastic anemia or malignant transformation with overall survival at 1 year ~ 65%

Diagnosis • Often by classic criteria of failure to thrive, steatorrhea, and feeding difficulties, along with cytopenias and recurrent infections • Laboratory testing ○ CBC with differential and platelet count – Peripheral blood smear review will reveal neutropenia/multiple cytopenias and no significant morphologic dysplasia ○ Testing for pancreatic dysfunction • Bone marrow evaluation ○ Hypocellular marrow per age (normal if very early in disease course) ○ Granulocytic hypoplasia with left-shifted granulopoiesis ○ Multilineage dysplasia is unusual, and, if present, disease may be evolving toward MDS • Genetic testing for biallelic SDBS mutations

Differential Diagnosis • Pearson syndrome (defect of mitochondrial DNA) ○ Pancytopenia ○ Pancreatic insufficiency with pancreatic fibrosis ○ Lactic acidosis ○ Failure to thrive ○ Normocellular marrow with vacuoles in myeloid precursors and ring sideroblasts • Cystic fibrosis • Other causes of bone marrow failure ○ Fanconi anemia ○ Dyskeratosis congenita ○ Severe congenital neutropenia 771

Overview of Syndromes: Syndromes

Steatocystoma Multiplex

TERMINOLOGY

CLINICAL IMPLICATIONS

Synonyms

Clinical Findings

• • • • •

• 100-2,000 asymptomatic, skin-colored papules or cysts widespread on ○ Back ○ Anterior trunk ○ Arms ○ Scrotum ○ Thighs ○ Face ○ Scalp • According to sites of involvement, disease can be classified as following types ○ Localized ○ Generalized ○ Facial ○ Acral ○ Suppurative • Hereditary steatocystoma multiplex typically presents in adolescence ○ Trunk is most common site • Sporadic steatocystoma simplex presents in adults ○ Commonly affected sites include – Face – Neck – Chest – Axillae • Hair abnormality ○ Pili torti ○ Pili canaliculi • Nail changes can be seen in some patients • Steatocystoma multiplex suppurativa ○ Inflammatory variant

Sebocystomatosis Epidermal polycystic disease Multiple sebaceous cysts Multiple steatocystoma OMIM 184500

EPIDEMIOLOGY Incidence • Disease is rare with unknown prevalence

Age at Presentation • Adolescence • Early adulthood

Criteria for Diagnosis • Numerous cysts • On trunk &/or extremities

ETIOLOGY/PATHOGENESIS Genetics • Autosomal dominant • Mutations in helix initiation domain (1A domain) of KRT17 gene • There is no family history in individuals who do not harbor KRT17 mutations • Might be variant of pachyonychia congenital type 2 (OMIM 167210) ○ Due to mutations in identical areas of KRT17 • Defective gene responsible for disorder is located on autosome ○ Therefore, only 1 defective gene copy is sufficient • Keratin 17 is differentiation-specific keratin expressed in ○ Nail bed ○ Hair follicle ○ Sebaceous gland ○ Other epidermal appendages

ASSOCIATED NEOPLASMS Skin • Hamartomatous malformation of pilosebaceous duct junction

Sebaceous Glands and Lack of Hair (Left) The presence of sebaceous glands in steatocystoma can be prominent; therefore, the cyst can be mistaken for a dermoid cyst. However, insertion of hair follicles into the cyst wall and presence of hair shafts, features of a dermoid cyst, are not seen in steatocystoma. (Right) Sebaceous glands are seen inserting directly into the wall of the cyst. The cyst is typically filled with clear fluid rather than holocrine secretion seen in sebaceous neoplasms.

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Sebaceous Glands in Cyst Wall

Steatocystoma Multiplex

DIFFERENTIAL DIAGNOSIS Eruptive Vellus Hair Cyst • Follicular developmental abnormality of vellus hair follicles • Inheritance can be either ○ Autosomal dominant – Mutation of KRT17 gene ○ Sporadic • Clinical presentation ○ Hyperpigmented ○ 1-5 mm and smooth papules ○ On chest, extremities, and abdomen • Histology ○ Cyst wall comprised of either stratified or trichilemmal epithelium ○ Numerous vellus hairs • Cyst wall of eruptive vellus hair cyst expresses only keratin 17 ○ On contrary, cyst wall of steatocystoma multiplex express both keratins 10 and 17

Pachyonychia Congenital Type 2 • • • •

Autosomal dominant Focal plantar keratoderma Hypertrophic nail dystrophy Multiple pilosebaceous cysts

Epidermoid Cyst • Simple cyst lined by infundibular epithelium containing granular layer • Loose keratins as cyst content

Pilar or Trichilemmal Cyst • Simple cyst lined by isthmic epithelium lacking granular layer • Compact and laminated keratins often with dystrophic calcification as cyst content

SELECTED REFERENCES 1.

Anand P et al: Eruptive vellus hair cyst: an uncommon and underdiagnosed entity. Int J Trichology. 10(1):31-3, 2018 2. Georgakopoulos JR et al: Numerous asymptomatic dermal cysts: diagnosis and treatment of steatocystoma multiplex. Can Fam Physician. 64(12):892-9, 2018 3. Liu Q et al: Steatocystoma multiplex is associated with the R94C mutation in the KRTl7 gene. Mol Med Rep. 12(4):5072-6, 2015 4. Ofaiche J et al: Familial pachyonychia congenita with steatocystoma multiplex and multiple abscesses of the scalp due to the p.Asn92Ser mutation in keratin 17. Br J Dermatol. 171(6):1565-7, 2014 5. Kamra HT et al: Steatocystoma multiplex-a rare genetic disorder: a case report and review of the literature. J Clin Diagn Res. 7(1):166-8, 2013 6. Torchia D et al: Eruptive vellus hair cysts: a systematic review. Am J Clin Dermatol. 13(1):19-28, 2012 7. Kanda M et al: Morphological and genetic analysis of steatocystoma multiplex in an Asian family with pachyonychia congenita type 2 harbouring a KRT17 missense mutation. Br J Dermatol. 160(2):465-8, 2009 8. Covello SP et al: Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol. 139(3):475-80, 1998 9. Smith FJ et al: Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol. 108(2):220-3, 1997 10. Tomková H et al: Expression of keratins (K10 and K17) in steatocystoma multiplex, eruptive vellus hair cysts, and epidermoid and trichilemmal cysts. Am J Dermatopathol. 19(3):250-3, 1997 11. NOOJIN RO et al: Familial steatocystoma multiplex; 12 cases in three generations. Arch Derm Syphilol. 57(6):1013-8, 1948

Overview of Syndromes: Syndromes

• Steatocystoma is characterized histologically by ○ Multiloculated dermal cyst ○ Lined by stratified squamous epithelium ○ Sebaceous glands inserting directly into cyst wall ○ Eosinophilic and hyaline inner cuticle ○ Filled with translucent fluid • These cysts derive from sebaceous duct

Dermoid Cyst • Occurs at skin developmental lines • Epithelial lining with granular layer rather than eosinophilic cuticle of steatocystoma

Epithelium With Thick Eosinophilic Cuticle

PAS-Positive Cuticle (Left) Thick eosinophilic cuticle ﬇ is seen lining the inner aspect of the cyst. Note the direct insertion of the sebaceous gland into the wall of the cyst. (Right) Periodic acid-Schiff stain highlights the thick cuticle ﬇ that lined the inner aspect of the cyst. This feature is very characteristic of steatocystoma since it is a cyst derived from the sebaceous duct.

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Overview of Syndromes: Syndromes

Tuberous Sclerosis Complex

TERMINOLOGY Abbreviations • Tuberous sclerosis complex (TSC)

Definitions • Inherited tumor predisposition syndrome resulting from mutations in TSC1 or TSC2 leading to mTOR pathway activation and dysfunction of hamartin or tuberin, respectively

EPIDEMIOLOGY

○ Effective pharmacologic inhibition by rapamycin and analogs • Majority of patients (70-80%) have new "spontaneous" mutations and lack family history ○ TSC1 and TSC2 mutation frequency similar in familial cases ○ Mutations in TSC2 more frequent than TSC1 in nonfamilial cases • Germline mosaicism increasingly detected by highresolution techniques (e.g., next-generation sequencing)

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

Incidence • ~ 1:5,000-10,000 ○ 2nd most common hereditary tumor syndrome involving CNS [after neurofibromatosis type 1 (NF1)]

GENETICS Germline Mutations in TSC1 or TSC2 • Encode tumor suppressor part of protein complex that inhibits RHEB and regulates mTOR activation ○ TSC1 located in chromosome region 9q34 (encodes for hamartin) ○ TSC2 located in chromosome region 16p13.3 (encodes for tuberin) ○ RHEB is small GTPase/homolog of RAS and is kept in inactive state by TSC1/TSC2 complex • mTOR is key downstream mediator of PI3K/AKT activation • Protein mTOR exists as part of 2 different multiprotein complexes ○ mTORC1 contains PRAS40, RAPTOR, and mLST8/GBL – Increases protein translation, cell growth, and survival ○ mTORC2 contains RICTOR, mSIN1, PROTOR, and mLST8 – Functional role less understood than mTORC1 complex – Regulates metabolism and survival through activation of AKT – Plays role in cytoskeletal organization ○ Activation leads to increased protein translation

Diagnostic Criteria • Specific guidelines for diagnosis, surveillance, and management have been proposed by International Tuberous Sclerosis Complex Consensus Group • Definite TSC: 2 major features or 1 major + 2 minor • Probable TSC: 1 major + 1 minor • Possible TSC: 1 major or > 1 minor • Major features: Cortical tuber, subependymal nodule, subependymal giant cell astrocytoma (SEGA), facial angiofibroma/forehead plaque, ungual/periungual fibroma, > 3 hypomelanotic macules, Shagreen patch, multiple retinal hamartomas, cardiac rhabdomyoma, renal angiomyolipoma/lymphangioleiomyomatosis (LAM) • Minor features: White matter migration lines, transmantle cortical dysplasia, retinal patch, hamartomatous rectal polyps, gingival fibroma, dental pits, hypomelanotic clustered skin lesions, bone cysts, renal cysts, nonrenal hamartomas

NONNEOPLASTIC MANIFESTATIONS Skin • Hypomelanotic macules ("ash leaf spot") • Shagreen patch

Nervous System • Epilepsy and intellectual disability • Cortical tubers

SEGA: Intraventricular Masses (Left) Subependymal giant cell astrocytomas (SEGAs) are characteristic of tuberous sclerosis complex, forming contrast-enhancing intraventricular masses ſt near the foramen of Monro. A subtle cortical tuber ﬇ is also present. (Right) SEGAs are characterized by eosinophilic, large cells with prominent nucleoli, features particularly recognizable in smear preparations. Variable cytoplasmic processes are also present.

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SEGA: Smear Findings

Tuberous Sclerosis Complex • Progressive pulmonary disorder involving lung • Cystic changes, respiratory failure • Lung biopsies demonstrate smooth muscle cells involving lymphatics, vessels, airways, and alveolar septa • SMA(+), HMB-45(+) • Majority of cases associated with tuberous sclerosis have TSC2 mutations (rather than TSC1) and loss of heterozygosity • Loss of heterozygosity in TSC2 also frequent in sporadic LAM

Retinal Hamartoma/Astrocytoma

• ~ 50% of patients with TSC • Most frequent initial imaging finding in TSC patients • May cause cardiac arrhythmias but also may regress with age

• Small lesions involving nerve fiber layer of retina in ~ 50% of TSC patients • Larger lesions may grow and cause retinal detachment • Histologically similar to SEGA

Renal Cysts • Usually asymptomatic • TSC2/PKD1 contiguous gene syndrome: Coexisting TSC and autosomal dominant polycystic kidney disease (severe)

Micronodular Pneumocyte Hyperplasia

Cardiac Rhabdomyoma

Overview of Syndromes: Syndromes

○ Localized cortical areas with abnormal development – Abnormal lamination, dysmorphic neurons, microcalcifications ○ Giant/balloon cells: Pale cytoplasm, variably immunoreactive with glial (S100, GFAP) and neuronal markers (synaptophysin, neurofilament) • Cortical cytoarchitectural abnormalities may also be present outside tubers • Subependymal nodules ("candle guttering lesions") ○ Giant cells arranged in clusters and fascicles with mixed glial/neuronal phenotype

Pancreatic Neuroendocrine Tumor • Not part of diagnostic criteria but recognized in rare TSC patients

Fibroma-Like PEComa • Rare soft tissue neoplasm with morphology of fibroma but immunophenotype of PEComa

• Small nodules of bland type II pneumocytes

SELECTED REFERENCES ASSOCIATED NEOPLASMS

1.

Cutaneous Angiofibroma • • • • •

Previously known by misnomer adenoma sebaceum Dermal sclerosis Dilatation/proliferation of small vessels Stellate fibroblasts/multinucleated cells UV-induced mutations implicated in pathogenesis

2. 3. 4. 5.

Subependymal Giant Cell Astrocytoma • • • • • • •

• •

Slow growth WHO grade I Mitotic activity rare to absent Microcalcifications in subset; necrosis rare Pseudorosettes may be present and simulate ependymal neoplasms Composed of large cells with eosinophilic cytoplasm and macronucleoli Evidence of glial and neuronal differentiation by immunohistochemistry and electron microscopy ○ Consistent S100 expression, GFAP variable ○ Variable expression of synaptophysin, chromogranin, and neurofilament protein ○ TTF-1 expression Excellent response to mTOR inhibitors in clinical trials SEGA-like tumors may develop in NF1 patients

6. 7. 8.

9.

10.

11. 12.

13. 14.

Angiomyolipoma • Usually benign, but large tumors associated with risk for life-threatening bleeding • Most common cause of mortality in TSC adult patients • May be classic or epithelioid subtype • May be cause of LAM • Partial response to mTOR inhibitors in some studies

15.

16. 17.

Jansen AC et al: Newly diagnosed and growing subependymal giant cell astrocytoma in adults with tuberous sclerosis complex: results from the international TOSCA study. Front Neurol. 10:821, 2019 Treichel AM et al: Phenotypic distinctions between mosaic forms of tuberous sclerosis complex. Genet Med. ePub, 2019 Wan MJ et al: Neuro-ophthalmological manifestations of tuberous sclerosis: current perspectives. Eye Brain. 11:13-23, 2019 Larque AB et al: Fibroma-like PEComa: a tuberous sclerosis complex-related lesion. Am J Surg Pathol. 42(4):500-5, 2018 Bissler JJ et al: Everolimus long-term use in patients with tuberous sclerosis complex: four-year update of the EXIST-2 study. PLoS One. 12(8):e0180939, 2017 Hodgson N et al: Ophthalmic manifestations of tuberous sclerosis: a review. Clin Exp Ophthalmol. 45(1):81-6, 2017 Lam HC et al: New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex. J Pathol. 241(2):219-225, 2017 Hewer E et al: Consistent nuclear expression of thyroid transcription factor 1 in subependymal giant cell astrocytomas suggests lineage-restricted histogenesis. Clin Neuropathol. 34(3):128-31, 2015 Tyburczy ME et al: Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum Mol Genet. 23(8):2023-9, 2014 Kocabaş A et al: Cardiac rhabdomyomas associated with tuberous sclerosis complex in 11 children: presentation to outcome. Pediatr Hematol Oncol. 30(2):71-9, 2013 Krueger DA et al: Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 80(6):574-80, 2013 Arva NC et al: Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis--case report and review of the literature. Am J Surg Pathol. 36(1):149-53, 2012 Budde K et al: Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis. 59(2):276-83, 2012 Yates JR et al: The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management. Arch Dis Child. 96(11):1020-5, 2011 Kacerovska D et al: TSC2/PKD1 contiguous gene syndrome: a report of 2 cases with emphasis on dermatopathologic findings. Am J Dermatopathol. 31(6):532-41, 2009 Shields JA et al: Aggressive retinal astrocytomas in 4 patients with tuberous sclerosis complex. Arch Ophthalmol. 123(6):856-63, 2005 Lopes MB et al: Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol. 91(4):368-75, 1996

Lymphangioleiomyomatosis • Occurs in 30% of women with tuberous sclerosis 775

Overview of Syndromes: Syndromes

Tuberous Sclerosis Complex

Cortical Tuber

Cortical Tuber

Cortical Tuber

Cortical Tuber

Dysplastic Neuron

Gliosis in Cortical Tuber

(Left) Numerous cortical abnormalities characterize the tuberous sclerosis complex. In this example, cortical disarray ﬈ is present in a cortical tuber. (Right) Numerous abnormal pale cells are evident in this field ﬈. They have an ambiguous phenotype. A distinct cortical neuron is also present in this field, which serves as a morphologic comparison ﬊.

(Left) Large, pale balloon cells ﬈ are typical of cortical tubers associated with tuberous sclerosis and are present in variable numbers. Fine, particulate calcifications are also present in this example ﬊. (Right) Cortical tubers are distinctive lesions associated with tuberous sclerosis complex containing enlarged pale cells (giant/balloon cells) ﬈ with an ambiguous, variable phenotype along glial and neuronal lines.

(Left) Dysplastic neurons are also frequent in tubers ﬈. In this example, there is abnormal pallor and uneven distribution of Nissl substance. Prominent gliosis, including Rosenthal fibers, was also present ﬊. (Right) In addition to abnormal neurons and pale cells, tubers are characterized by frequent gliosis. An immunohistochemical stain for GFAP is useful in highlighting reactive astrocytes and their characteristic stellate cytoplasmic processes ﬈.

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Tuberous Sclerosis Complex

SEGA: Smear Findings (Left) The characteristic lesions of tuberous sclerosis in the CNS include cortical tubers ſt, subependymal nodules identifiable in the walls of the lateral ventricles ﬈, and the low-grade neoplasm known as SEGA ﬊. (Right) SEGAs may be identified on smear preparations during intraoperative evaluations. They are characterized by large, eosinophilic cells with round/oval nuclei and macronucleoli.

SEGA: Large Cells

Overview of Syndromes: Syndromes

Brain Lesions in Tuberous Sclerosis Complex

SEGA: Eosinophilic Cells (Left) The large cells of SEGA may contain voluminous eosinophilic cytoplasm with a "glassy" quality. Mitotic activity in these tumors is rare to absent, in keeping with their low-grade nature. (Right) Aggregates of eosinophilic cells in a fibrillar stroma characterize this SEGA.

SEGA: Spindle Cells

SEGA: Calcifications (Left) Not infrequently, SEGAs may contain fields of spindle cells arranged in loose fascicles. Whorling may be present at low-power magnification. (Right) Coarse calcifications may be a feature of some SEGAs, as in other CNS lesions associated with tuberous sclerosis.

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Overview of Syndromes: Syndromes

Tuberous Sclerosis Complex

S100 Expression in SEGA

GFAP Expression in SEGA

Synaptophysin Expression in SEGA

Low Proliferation in SEGA

Mast Cells in SEGA

Mast Cells in SEGA

(Left) A glial phenotype was ascribed early on to SEGA, which is reflected in its name. The most consistent glial marker in these tumors is S100, which typically demonstrates diffuse staining. However, this marker is not entirely specific for glial differentiation. (Right) GFAP, a more specific marker of glial differentiation, is usually positive in SEGA, although it is more variable in frequency and intensity.

(Left) In addition to glial markers, SEGA also labels with markers of neuronal differentiation, such as synaptophysin. Therefore, these tumors demonstrate differentiation along glial and neuronal lines. (Right) SEGAs usually have very low proliferative rates. In this example, the Ki-67 proliferation index is < 1%.

(Left) SEGA is a tumor of the nervous system that is characterized by varying numbers of mast cells ﬈. Other tumors with increased number of mast cells include hemangioblastoma and neurofibroma. (Right) Mast cells may be identified by expression of KIT on immunohistochemical preparations ﬈.

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Tuberous Sclerosis Complex Retinal Astrocytic Lesion in Tuberous Sclerosis Complex (Left) Astrocytic hamartomas represent the typical intraocular manifestation in tuberous sclerosis patients. They are characterized by slow growth and bland spindle cell cytology. They are frequently multiple in tuberous sclerosis complex. (Right) Histologic similarities with subependymal nodules/SEGA are a feature of retinal astrocytic lesions in tuberous sclerosis patients. Scattered microcalcifications ﬈ were present in this example.

Renal Manifestations of Tuberous Sclerosis Complex

Overview of Syndromes: Syndromes

Astrocytic Hamartomas of Eye

Renal Angiomyolipoma (Left) Renal manifestations are also typical of tuberous sclerosis complex, including numerous cysts as well as bilateral neoplasms ſt that, in this case, were interpreted radiologically as probable angiomyolipomas. (Right) The prototypical neoplasm involving the kidney in tuberous sclerosis patients is angiomyolipoma, which contains spindle/eosinophilic cells as well as variable amounts of adipose tissue ﬈.

Cutaneous Angiofibroma

Cutaneous Angiofibroma (Left) Tuberous sclerosis patients also frequently develop cutaneous angiofibromas. As the name implies, these benign growths contain variable amounts of small vessels and collagen deposition. (Right) Numerous thin-walled vessels are evident in cutaneous angiofibromas. Multinucleated stromal cells ﬈ are also frequent and, despite their pleomorphic nature, should not be a cause for alarm in these benign tumors.

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Overview of Syndromes: Syndromes

Tumor Syndromes Predisposing to Osteosarcoma

LI-FRAUMENI SYNDROME

HEREDITARY RETINOBLASTOMA

Molecular Alteration

Molecular Alteration

• Germline mutation in TP53 (17p13) ○ p53 is one of major tumor suppressors in cell cycle regulation and other signaling pathways

• Germline mutation in RB1 (13q14) ○ RB1 is one of major tumor suppressors in cell cycle regulation and other signaling pathways

Clinical Manifestations

Clinical Manifestations

• Autosomal dominant inheritance ○ Subset of mutations occurs de novo during embryonic development and may be mosaic • High lifetime risk for various types of cancers ○ Osteosarcoma – Most common sarcoma in patients with Li-Fraumeni syndrome – Risk increase: ~ 100x as compared to general population – Prevalence: 5% of women and 11% of men with LiFraumeni syndrome – Most cases appear in young adulthood (median age ~ 16) – Histology similar to those in sporadic cases □ Osteoblastic, chondroblastic, fibroblastic types described ○ Soft tissue sarcomas ○ Breast cancer ○ Adrenocortical carcinoma ○ Brain tumors, including choroid plexus tumors ○ Leukemia ○ Lung carcinoma • Increased risks for osteosarcoma are multifactorial ○ Germline TP53 mutations in patients with osteosarcoma are most commonly missense mutations – Hotspot missense mutation at codon 282, 273, 248, 220, or 175 in DNA-binding domains – Rarely frameshift, splice site, or nonsense mutation ○ Correlation of genotype (TP53 mutation status) with outcome unclear

• Autosomal dominant inheritance • Increased risks for tumors ○ Osteosarcoma – 25-30% of all secondary malignancies in hereditary retinoblastoma patients – Most commonly involves skull, followed by lower limbs and trunk – Typically occurs within prior radiation field – Histology similar to those in sporadic cases □ Histologic types include osteoblastic, chondroblastic, fibroblastic, telangiectatic, etc. □ Uncommon (nonosteoblastic) subtype of osteosarcoma in young patients may raise possibility of familial syndromes, including hereditary retinoblastoma ○ Retinoblastoma ○ Soft tissue sarcomas ○ Melanoma ○ Carcinomas from lung, bladder, breast • Increased risks for osteosarcoma are multifactorial ○ Contributed by prior history of treatment (radiation &/or chemotherapy) and germline predisposition ○ Greatest risk increase in hereditary retinoblastoma patients with radiation exposure: ~ 400x as compared to general population ○ Correlation of genotype (RB1 mutation status) with outcome and risks of secondary malignancies unclear

WERNER SYNDROME Molecular Alteration • Germline mutation in WRN (8p12)

Orbital Osteosarcoma in Patient With Prior Retinoblastoma (Left) Coronal CT of a patient with prior left retinoblastoma status post enucleation ﬊ shows an osteosarcoma involving the right orbital bone st. (Right) Gross photograph of the same orbital/maxillary osteosarcoma shows an aggressive, tan-white to yellow, bone-forming tumor.

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Orbital Osteosarcoma in Patient With Prior Retinoblastoma

Tumor Syndromes Predisposing to Osteosarcoma

Clinical Manifestations • Rare; incidence ~ 1:400,000 to 1:1 million • Autosomal recessive inheritance • Premature aging and age-related disease (e.g., cardiovascular disease) • Bilateral cataracts • Short stature • Increased risk for tumors ○ Osteosarcoma – Prevalence: ~ 8% of patients with Werner syndrome ○ Soft tissue sarcoma ○ Melanoma ○ Thyroid cancer ○ Meningioma ○ Leukemia

ROTHMUND-THOMSON SYNDROME Molecular Alteration • Germline mutation in RECQL4 (8q24) ○ RECQL4 is one of RecQ helicase family members involved in DNA repair ○ Mutations in RECQL4 associated 2 additional recessive disorders – RAPADILINO (radial hypoplasia, patella hypoplasia and cleft or arched palate, diarrhea and dislocated joints, little size and limb malformation, slender nose and normal intelligence) – Baller-Gerold syndrome ○ All RECQL4 mutations described in Rothmund-Thomson syndrome patients lead to partial but not complete functional loss of RECQL4 activity, since complete functional loss is lethal in humans

Clinical Manifestations • • • • •

Rare; < 300 cases reported worldwide circa 2019 Autosomal recessive inheritance Short stature, distinctive facies, photosensitive skin rash Infertility in men and subfertility in women Increased risk for tumors ○ Osteosarcoma ○ Carcinoma ○ Lymphoma, leukemia

SELECTED REFERENCES 1. 2.

3. 4. 5. 6.

7. 8. 9. 10.

11. 12.

13. 14.

Clinical Manifestations • Rare; < 500 cases reported worldwide circa 2019 • Autosomal recessive inheritance • Genodermatosis with characteristic facial rash (poikiloderma) • Increased risk for tumors ○ Osteosarcoma – Prevalence: ~ 30% of patients with RothmundThomson syndrome – Histology and outcome similar to sporadic cases – Median age of diagnosis ~ 10 years – Occasionally show multicentric presentation – Limited data on correlation between genotype and osteosarcoma risk ○ Skin tumors (squamous cell carcinoma, basal cell carcinoma)

15. 16. 17. 18. 19.

20.

21.

22.

23.

BLOOM SYNDROME Molecular Alteration • Germline mutation in BLM (15q26) ○ BLM is one of RecQ helicase family members involved in DNA repair

24. 25.

26.

Taylor AMR et al: Chromosome instability syndromes. Nat Rev Dis Primers. 5(1):64, 2019 Amadou A et al: Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 30(1):23-9, 2018 Hameed M et al: Tumor syndromes predisposing to osteosarcoma. Adv Anat Pathol. 25(4):217-22, 2018 Renaux-Petel M et al: Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet. 55(3):173-80, 2018 Gnoli M et al: Tumor syndromes that include bone tumors: an update. Surg Pathol Clin. 10(3):749-64, 2017 Mai PL et al: Prevalence of cancer at baseline screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort. JAMA Oncol. 3(12):1640-5, 2017 Walsh MF et al: Recommendations for childhood cancer screening and surveillance in DNA repair disorders. Clin Cancer Res. 23(11):e23-31, 2017 Yokote K et al: WRN mutation update: mutation spectrum, patient registries, and translational prospects. Hum Mutat. 38(1):7-15, 2017 Bouaoun L et al: TP53 variations in human cancers: new lessons from the IARC TP53 Database and Genomics Data. Hum Mutat. 37(9):865-76, 2016 Mai PL et al: Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 122(23):3673-81, 2016 Zils K et al: Osteosarcoma in patients with Rothmund-Thomson syndrome. Pediatr Hematol Oncol. 32(1):32-40, 2015 Dommering CJ et al: RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients. J Med Genet. 51(6):366-74, 2014 Lauper JM et al: Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 8(4):e59709, 2013 Ognjanovic S et al: Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer. 118(5):1387-96, 2012 Larizza L et al: Rothmund-Thomson syndrome. Orphanet J Rare Dis. 5:2, 2010 Siitonen HA et al: The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 17(2):151-8, 2009 Marees T et al: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst. 100(24):1771-9, 2008 Hicks MJ et al: Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol. 25(4):370-5, 2007 Kleinerman RA et al: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 23(10):2272-9, 2005 Hauben EI et al: Multiple primary malignancies in osteosarcoma patients. Incidence and predictive value of osteosarcoma subtype for cancer syndromes related with osteosarcoma. Eur J Hum Genet. 11(8):611-8, 2003 Olivier M et al: Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 63(20):664350, 2003 Wang LL et al: Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 95(9):669-74, 2003 Wang LL et al: Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 102(1):11-7, 2001 Wong FL et al: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA. 278(15):1262-7, 1997 Malkin D et al: Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 326(20):1309-15, 1992 Toguchida J et al: Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med. 326(20):1301-8, 1992

Overview of Syndromes: Syndromes

○ WRN is one of RecQ helicase family members involved in DNA repair

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Overview of Syndromes: Syndromes

von Hippel-Lindau Syndrome

TERMINOLOGY Abbreviations • von Hippel-Lindau (VHL) syndrome

Synonyms • von Hippel-Lindau disease • Familial cerebelloretinal angiomatosis

Definitions • Rare autosomal dominant genetic disease resulting from mutation in VHL tumor suppressor gene on chromosome 3p25.3 • Characterized by retinal and CNS hemangioblastomas, pheochromocytomas, pancreatic serous cystadenoma, café au lait spots, and renal cell carcinoma (RCC) ○ If no family history, diagnosis requires 2 cardinal manifestations – Including retinal and CNS involvement – Excluding cysts ○ With positive family history – 1 cardinal manifestation, excluding cysts • Member of phacomatosis familial cancer syndromes

○ Major regulator of hypoxic response by targeting transcription factor hypoxia inducible factor (HIF) for degradation • VHL disease demonstrates marked phenotypic variability and age-dependent penetrance ○ Genotype-phenotype associations in VHL disease form basis of clinical classification • Presumed that clinical presentation reflects quantitative or qualitative altered VHL protein function

Molecular Genetics • Autosomal dominant • Germline mutation of VHL gene (3p25.3) ○ VHL mutation in 50% of sporadic RCC ○ 2nd inactivating event predisposes to neoplasms • VHL protein ○ Promotes destruction of HIF 1 α (HIF-1-α) via ubiquitin pathway – Loss of function leads to increased levels of vascular endothelial growth factor (VEGF) ○ HIF-independent regulation of primary cilium and apoptosis via NF-κB pathway – Loss of function promotes renal cysts

Subtypes

EPIDEMIOLOGY Incidence • 1 case per 36,000 newborns • 6,000-7,000 patients in United States

Age • Age at diagnosis varies from infancy to 60-70 years

Sex • No predilection is noted

GENETICS AND MOLECULAR BIOLOGY Tumorigenesis • VHL gene encodes VHL protein, which is E3 ubiquitin ligase

• Classification ○ Type 1: Caused by deletions or truncating mutations of VHL gene ○ Types 2A, B, C: Caused by missense point mutations • Genotype-phenotype correlations ○ Type 1 VHL (truncating and exon deletions): Hemangioblastoma and renal cell carcinoma – Low risk of pheochromocytoma ○ Type 2 VHL (missense mutations) – High risk of pheochromocytoma – Type 2A: Low risk of RCC – Type 2B: High risk of RCC – Type 2C: Familial pheochromocytoma without hemangioblastoma or RCC

Abdominal Lesions in VHL Syndrome (Left) Abdominal lesions in von Hippel-Lindau (VHL) syndrome are varied and include bilateral renal cysts ﬈, renal tumors, particularly renal cell carcinoma (RCC) ﬉, pancreatic cysts ſt, and pheochromocytoma ﬊. (Right) The characteristic neoplasm involving the CNS and retina in patients with VHL syndrome is hemangioblastoma, a vascularized tumor containing vacuolated stromal cells ﬈.

782

Hemangioblastoma

von Hippel-Lindau Syndrome

von Hippel-Lindau Development in Children and Adolescents • ~ 70% develop manifestations before 18 years • ~ 30% develop > 1 manifestation type ○ Most frequent were retinal (34%) and CNS (30%) hemangioblastomas • Patients have their 1st CNS hemangioblastomas at median age of 13-14 years

Surgical Approaches • • • •

Nephron-sparing surgery Tumor resection when other organs affected Surgery for > 3-cm endocrine pancreatic tumor Adrenalectomy for pheochromocytoma

Prognosis • Death due to RCC in 50% ○ Metastases to liver, lung, and bone • Pheochromocytoma is cured after surgery ○ Metastatic pheochromocytoma has not been reported

– Glioma-like areas expressing GFAP – Less reticulin ○ Nuclear pleomorphism may be present ○ Extramedullary hematopoiesis ○ Cystic changes and sclerosis variable ○ Metastatic RCC to hemangioblastoma very rare but reported • Histochemistry and immunohistochemistry ○ Lipid in stromal cells may be highlighted by oil red O in frozen sections ○ Reticulin helpful in highlighting small lobules and individual cells in reticular type ○ Immunophenotype typically inhibin (+), NSE(+), GFAP(+/-) ○ EMA usually negative (very rarely positive), CD10(-), CK(-) ○ Low Ki-67 labeling index • Molecular cytogenetics ○ Different cytogenetic profiles in reticular and cellular subtypes of hemangioblastoma by comparative genomic hybridization – Loss of chromosome 6 associated with cellular subtype – Loss of 19/19p more frequent in reticular variant

Overview of Syndromes: Syndromes

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

Renal Cell Carcinoma

ASSOCIATED NEOPLASMS Hemangioblastoma • Most common neoplasm associated with VHL disease • Clinical, radiologic, and pathologic features similar in sporadic and VHL-associated tumors • Cerebellum and spinal cord tumors are major CNS manifestations ○ Affect 60-84% of patients • Benign vascular tumor, but may cause significant morbidity due to neurologic deficits • Clinically, patient can present with headaches, numbness, dizziness, weakness, pain in arms and legs, incontinence, or ataxia • Retinal hemangioblastomas are typical ocular lesions of VHL disease ○ Previously referred to as hemangiomas, but histologically identical to CNS counterparts ○ Usually multifocal and bilateral ○ Clinically, patients present with painless loss of visual acuity or visual field ○ In advanced cases, can present with hemorrhage, leading to secondary glaucoma and loss of vision • Histologic features ○ Well-circumscribed tumors ○ Piloid gliosis with Rosenthal fibers common in adjacent CNS parenchyma ○ Highly vascular with large and small thin-walled vessels ○ Absent to rare mitotic activity ○ Reticular type – Composed of small nests/sheets of vacuolated cells known as stromal or interstitial – Reticulin abundant and highlights small lobules and individual cells ○ Cellular type – Architecture characterized by larger lobules – Increased cytoplasm, vacuolation inconspicuous

• Patients with VHL disease are at high risk of developing multiple renal cysts and RCC, affecting 2/3 of VHL patients • RCC is clear cell type, often multicentric &/or bilateral • Histology ○ Sporadic and VHL-associated clear cell tumors are often indistinguishable ○ Tumors are usually surrounded by thick fibrous capsule ○ Tumors in VHL patients are usually multicystic &/or solid ○ Typically VHL tumors have microcystic growth pattern ○ Early lesion: Intratubular proliferation of clear cells

Pheochromocytoma • Catecholamine-producing neuroendocrine tumor related to chromaffin cells from adrenal medulla or extraadrenal chromaffin tissue (paraganglia) • Pheochromocytoma associated with VHL is usually asymptomatic • Hallmark of type 2 VHL disease • Patients with VHL disease are often very young (< 40 years) • Tumor is usually bilateral, multiple, or extraadrenal ○ Hypertension with headache and sweating is most common presentation • Histology ○ VHL pheochromocytomas have distinct pathologic features from multiple endocrine neoplasia type 2 (MEN2) pheochromocytomas – Presence of thick fibrous capsule – Myxoid and hyalinized stroma – Small to medium-sized tumor cells – Absence of cytoplasmic hyaline globules – Lack of nuclear atypia

Pancreatic Endocrine Tumor and Pancreatic Cysts • Tumors present in 10% of VHL patients are usually multiple and well circumscribed • Tumors in VHL patients are usually nonsecretory

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Overview of Syndromes: Syndromes

von Hippel-Lindau Syndrome • Endocrine pancreatic tumors are characterized by solid, trabecular, &/or glandular architecture • Stromal collagen is usually present • Most tumors have clear cells • Marked nuclear atypia may be present

Endolymphatic Sac Tumor • Slowly growing, locally invasive but nonmetastasizing papillary neoplasm arising from endolymphatic sac within temporal bone • Endolymph-filled, neuroectodermally derived, nonsensory component of membranous labyrinth • Connected to utricular and saccular ducts by endolymphatic duct • Endolymphatic sac tumors (ELSTs) are detected by MR or CT in ~ 15% of patients with VHL disease • ~ 10% of patients with ELSTs have VHL disease ○ Conversely, ~ 15% of patients with VHL disease have radiographically detectable ELSTs ○ 30% of VHL patients with ELSTs have bilateral tumors • Symptoms: Meniere-like clinical syndrome of hearing loss in 95%, tinnitus in 92%, and vertigo in 62% • All patients with ELSTs should be screened for other signs and symptoms of VHL disease • Recent studies highlight some immunophenotypic and genetic similarities with RCC ○ Loss of 3p (VHL), CAIX, and pax-8 positivity ○ CD10 and RCC negative (in contrast to RCC)

Other Associated Lesions • Papillary cystadenoma of epididymis • Papillary cystadenoma of broad ligament and mesosalpinx • Cysts of pancreas, kidney, adrenal, testis, and ovary

DIFFERENTIAL DIAGNOSIS Cystic Renal Diseases Associated With Renal Neoplasms • Acquired cystic kidney disease ○ Cyst frequency proportional to duration of ESRD ○ Diverse array of RCCs • Tuberous sclerosis complex/autosomal dominant polycystic kidney disease (ADPKD) contiguous gene syndrome ○ Diffusely cystic kidneys identical to ADPKD ○ Multiple and bilateral angiomyolipomas ○ Rarely, clear cell RCC • ADPKD ○ Risk of RCC may be increased but controversial ○ Far more numerous cysts than in VHL

Tuberous Sclerosis Complex • • • •

Angiomyolipomas common Renal cancer and renal cysts rare Rare pancreatic lesions Calcified cortical lesions (i.e., tubers), subependymal nodules, and subependymal giant cell astrocytoma

CANCER RISK MANAGEMENT Early Diagnosis • Improves prognosis of most VHL manifestations ○ Comprehensive screening program starting in childhood ○ Lifelong routine screening for hemangioblastomas (CNS and retinal), RCCs, and pheochromocytomas ○ Current guidelines suggest that retinal surveillance be performed from birth • Individuals who are affected with VHL, individuals at risk of VHL, and VHL-mutation carriers ○ Are advised to follow surveillance program that consists of regular prophylactic examinations relevant to different age groups

SELECTED REFERENCES 1.

2.

3.

4. 5. 6.

7. 8.

9.

10.

11. 12. 13. 14. 15. 16.

17. 18.

19. 20.

Neurofibromatosis Type 1 • May develop multiple pheochromocytomas, but CNS lesions are astrocytomas rather than hemangioblastomas

21.

22.

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Chen X et al: Early detection of retinal hemangioblastomas in von HippelLindau disease using ultra-widefield fluorescein angiography. Retina. 38(4):748-54, 2018 Jester R et al: Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls. Acta Neuropathol Commun. 6(1):107, 2018 Thompson LDR et al: CAIX and pax-8 commonly immunoreactive in endolymphatic sac tumors: a clinicopathologic study of 26 cases with differential considerations for metastatic renal cell carcinoma in von HippelLindau patients. Head Neck Pathol. ePub, 2018 Launbjerg K et al: von Hippel-Lindau development in children and adolescents. Am J Med Genet A. 173(9):2381-94, 2017 varshney N et al: A review of von Hippel-Lindau syndrome. J Kidney Cancer VHL. 4(3):20-9, 2017 Binderup ML et al: Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition. Dan Med J. 60(12):B4763, 2013 Maher ER et al: von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 19(6):617-23, 2011 Padhi S et al: A 10-year retrospective study of hemangioblastomas of the central nervous system with reference to von Hippel-Lindau (VHL) disease. J Clin Neurosci. 18(7):939-44, 2011 Rechsteiner MP et al: VHL gene mutations and their effects on hypoxia inducible factor HIFα: identification of potential driver and passenger mutations. Cancer Res. 71(16):5500-11, 2011 Rohan SM et al: Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol. 24(9):1207-20, 2011 Traen S et al: Central nervous system lesions in Von Hippel-Lindau syndrome. JBR-BTR. 94(3):140-1, 2011 Zhang Y et al: Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 18(3):206-18, 2011 Ellison J: Novel human pathological mutations. Gene symbol: VHL. Disease: von Hippel-Lindau syndrome. Hum Genet. 127(4):477, 2010 Kaelin WG Jr: New cancer targets emerging from studies of the Von HippelLindau tumor suppressor protein. Ann N Y Acad Sci. 1210:1-7, 2010 Safo AO et al: Pancreatic manifestations of von Hippel-Lindau disease. Arch Pathol Lab Med. 134(7):1080-3, 2010 Tamura K et al: Diagnosis and management of pancreatic neuroendocrine tumor in von Hippel-Lindau disease. World J Gastroenterol. 16(36):4515-8, 2010 Shehata BM et al: Von Hippel-Lindau (VHL) disease: an update on the clinicopathologic and genetic aspects. Adv Anat Pathol. 15(3):165-71, 2008 Nakamura E et al: Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von Hippel-Lindau tumor suppressor protein. Am J Pathol. 168(2):574-84, 2006 Rickert CH et al: Cellular and reticular variants of hemangioblastoma differ in their cytogenetic profiles. Hum Pathol. 37(11):1452-7, 2006 Hasselblatt M et al: Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases. Neuropathol Appl Neurobiol. 31(6):618-22, 2005 Jung SM et al: Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear cell renal cell carcinoma. Mod Pathol. 18(6):788-94, 2005 Lonser RR et al: von Hippel-Lindau disease. Lancet. 361(9374):2059-67, 2003

von Hippel-Lindau Syndrome

Cysts in Pancreas and Kidney (Left) Axial T1WI C+ MR shows 2 of several cerebellar hemangioblastomas ſt, a finding that is so characteristic as to be diagnostic of VHL syndrome by itself. The presence of multiple cysts and tumors in other organs is also characteristic of this disorder. (Right) Axial CT shows innumerable pancreatic and renal cysts ſt. Either the CNS or abdominal findings would be considered diagnostic of this disorder. A patient's family history is also useful for corroboration.

Pancreatic and Renal Cysts

Overview of Syndromes: Syndromes

Cerebellar Tumor

Renal Cell Carcinoma and Renal Cysts (Left) Axial T2WI MR in a young man with multiorgan manifestations of VHL syndrome shows multiple pancreatic ſt and renal cysts st. (Right) Kidney from a patient with VHL syndrome shows multiple renal cysts st within the renal parenchyma. There is a yellow, wellcircumscribed RCC ﬇ with extensive hemorrhage.

Numerous Thin-Walled Pancreatic Cysts

Numerous Cysts Filled With Clear Fluid (Left) This cut surface of a pancreas from a patient with VHL syndrome shows diffuse replacement of the normal architecture by variably sized cysts. The cysts are thin walled and have clear contents. (Right) Pancreas from a patient with VHL syndrome shows a multicystic lesion with a cystadenoma. The cysts are derived from the pancreatic duct system, have a thin capsule, and are lined by a simple epithelium.

785

Overview of Syndromes: Syndromes

von Hippel-Lindau Syndrome

Clear Cells in Renal Cell Carcinoma

Cystic Renal Cell Carcinoma

Clear Cells in Cystic Renal Carcinoma

Solid and Cystic Renal Cell Carcinoma

Clear Cells in Renal Cell Carcinoma

Decreased Clusterin Expression in Renal Cell Carcinoma

(Left) H&E shows an RCC in a patient with VHL syndrome with a predominantly solid component of the tumor. The tumor is composed of clear cells and is morphologically indistinguishable from sporadic RCC. (Right) RCC with a cystic component is usually present in patients with VHL syndrome. The tumor is predominantly cystic, and the cysts are lined by cells with clear cytoplasm ﬊ and lowgrade nuclei.

(Left) The cyst lining from a renal cyst in a patient with VHL syndrome is composed of clear cells with ample cytoplasm ﬊ and irregular grade 2 nuclei. The cyst is surrounded by a thick fibrous capsule. (Right) Most of the RCCs in VHL syndrome patients are solid and cystic. The solid component is composed of cells with similar appearance to the cells lining the cystic spaces.

(Left) RCC in a patient with VHL syndrome shows a solid component of the tumor. The tumor cells are arranged in cords or trabeculae and are separated by thin fibrovascular stroma ﬊. The tumor cells are round to oval with irregular nuclei. (Right) RCC in patients with VHL syndrome shows decreased clusterin staining in comparison with RCC in nonVHL syndrome patients.

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von Hippel-Lindau Syndrome

Decreased Clusterin in Pheochromocytoma (Left) Pheochromocytoma in association with VHL syndrome shows tumor cells arranged in a nested and trabecular arrangement. Tumor cells have ample cytoplasm and irregular nuclei. Note the absence of intracytoplasmic eosinophilic granules. (Right) Decreased clusterin staining in VHL syndrome pheochromocytoma is similar to the findings of decreased expression seen in VHL syndrome-associated RCC.

Immunopositivity for SDHA

Overview of Syndromes: Syndromes

Pheochromocytoma

Loss of SDHB Immunoexpression (Left) SDHA immunostain reveals preservation of the staining of the pheochromocytoma cells in VHL syndrome-associated tumors. (Right) SDHB staining in VHL-associated pheochromocytoma may show loss of immunostaining, which is accompanied by preservation of SDHA. This finding is similar to the immunoexpression of these antigens in familial paragangliomapheochromocytoma syndromes (SDHB- and SDHDassociated pheochromocytomas).

Cut Surface of Pancreatic Cysts

Pancreatic Cysts (Left) Pancreas from a patient with VHL syndrome shows multiple thin-walled cysts of variable sizes. The cysts are filled with clear fluid, and there is extensive fibrosis of the pancreas. (Right) H&E in a patient with VHL syndrome shows multiple cysts lined by a single layer of cuboidal clear cells surrounded by thick fibrous bands. There is residual pancreatic parenchyma ﬊.

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Overview of Syndromes: Syndromes

von Hippel-Lindau Syndrome

Hemangioblastomas

Retinal Hemangioblastoma

Hemangioblastoma With Vacuoles

Cellular Hemangioblastoma

Hematopoesis in Hemangioblastoma

Multinucleated Cell

(Left) Hemangioblastoma is the most frequently occurring tumor in patients with VHL syndrome. Although they may also arise sporadically, the presence of multiple tumors is essentially pathognomonic of the disorder. The main locations involved are the cerebellum ﬈ and spinal cord ﬊. (Right) Although named hemangiomas in the past given their rich vascular supply, retinal tumors afflicting patients with VHL syndrome are hemangioblastomas, histologically identical to tumors involving the CNS.

(Left) The reticular variant of hemangioblastoma is characterized by variable numbers of stromal cells containing prominent cytoplasmic microvacuoles ﬊. (Right) This hemangioblastoma developed in a VHL syndrome patient and demonstrates some attributes of the cellular variant, particularly a paucity of vacuolated cells and larger lobules. There are no significant clinical or pathologic differences between VHL syndromeassociated and sporadic hemangioblastomas.

(Left) An interesting histologic finding in a minority of hemangioblastomas is the presence of extramedullary hematopoiesis. This is characterized by variable clusters of large cells with prominent nucleoli and frequent mitotic figures ſt. (Right) Hemangioblastomas contain a rich vascular supply and are not uncommonly grossly mistaken for blood clots or vascular malformations. This particular example demonstrates congestion as well as a multinucleated megakaryocyte ﬈.

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von Hippel-Lindau Syndrome

Immunopositivity for Inhibin (Left) Stromal cells contain variable amounts of intracytoplasmic lipid ﬈. In a frozen section, an oil red O special stain may be particularly useful since the characteristic microvacuolation of stromal cells may not be evident. (Right) A positive immunohistochemical reaction for inhibin is one of the most useful diagnostic features of hemangioblastoma since most entities in the differential diagnosis are almost always negative.

GFAP Immunoexpression

Overview of Syndromes: Syndromes

Intracellular Fat

Reticulin Pattern in Hemangioblastomas (Left) A subset of hemangioblastomas may contain areas of glial differentiation and demonstrate overt immunoreactivity in neoplastic cells for glial markers such as GFAP. (Right) Reticulin stain is useful in the evaluation of hemangioblastomas since it highlights small lobules ﬊ and even individual cells. This pattern is particularly characteristic of the reticular variant.

Endolymphatic Sac Tumor Location

EMA in Endolymphatic Sac Tumor (Left) Axial graphic of the temporal bone shows the typical appearance of an endolymphatic sac tumor. The tumor is vascular, shows a tendency to fistulize the inner ear, and contains bone fragments within the tumor matrix. (Right) Endolymphatic sac tumors are recognized by their epithelial cytologic and architectural features. Their epithelial phenotype may also be confirmed by immunohistochemistry. Strong EMA immunopositivity is present in this example.

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Overview of Syndromes: Syndromes

Werner Syndrome/Progeria ○ Turkish ○ Dutch

TERMINOLOGY Synonyms

Inheritance

• Progeria of adults • Adult premature aging syndrome • OMIM 277700

• Autosomal recessive • Heterozygote relatives of affected individuals may have very mild findings

Definitions

CLINICAL IMPLICATIONS AND ANCILLARY TESTS

• Premature aging after puberty • Predisposition to malignancy

Clinical Findings

EPIDEMIOLOGY Natural History • • • •

Adult-onset accelerated aging  Patients affected as they reach adolescence Median survival: 54 years Death most commonly due to cancer and myocardial infarction

• • • •

•

Incidence • More common in Japanese, although all races are affected • Japan ○ 1 in 20,000-40,000 •  United States ○ 1 in 200,000 to 1 million

• •

GENETICS Mutation • Null mutation of WRN gene on chromosome 8  ○ Encodes member of RECQ family of DNA helicases • WRN gene participates in ○ DNA replication and repair ○ Telomere maintenance ○ Apoptosis • Ethnicity-specific WRN mutations ○ Japanese ○ Sardinian ○ Indian/Parkistani ○ Moroccan

•

Werner Syndrome: Age 15 (Left) This is a patient with Werner syndrome at age 15. Her face has a normal appearance without premature aging, and her hair is not yet gray. (Courtesy International Registry of Werner Syndrome.) (Right) The same patient with Werner syndrome is shown at age 49. Her hair is gray, and she has prematurely aged facies. (Courtesy International Registry of Werner Syndrome.)

790

Lack of pubertal growth spurt in teenage years Short stature as adults Low body weight Aged appearance  ○ Skin atrophy ○ Loss of subcutaneous fat ○ Graying and loss of hair Bird-like facial appearance  ○ Thin limbs ○ Truncal obesity ○ Flat feet Bilateral cataracts by late 20s and early 30s Age-related diseases ○ Type 2 diabetes mellitus ○ Hypogonadism ○ Osteoporosis ○ Atherosclerosis ○ Malignancies Cutaneous findings ○ Deep ulcerations around Achilles tendons and elbows pathognomonic ○ Hyperkeratoses  – Soles of feet – Fingers – Toes – Ankles – Elbows – Sometimes ears

Werner Syndrome: Age 49

Werner Syndrome/Progeria

• • •

Imaging Findings • Calcification of Achilles tendon

ASSOCIATED NEOPLASMS Risk of Malignancy • 2-60x higher than normal population ○ Frequent neoplasms – Thyroid follicular carcinoma (most common) – Melanoma – Meningioma – Soft tissue sarcomas – Primary bone tumors – Hematolymphoid ○ Less common neoplasms – Nonmelanoma skin cancer □ Squamous cell carcinoma □ Basal cell carcinoma – Gastrointestinal carcinoma □ Esophageal □ Gastric □ Pancreatic – Uterus/ovary – Hepatobiliary – Genitourinary – Head and neck neoplasm – Breast carcinoma – Lung carcinoma – Central nervous system □ Astrocytoma – Adrenocortical carcinoma – Pheochromocytoma

• Growth impairment • Distinguishing features from Werner syndrome ○ Aging develops as early as infancy ○ Autosomal dominant ○ LMNA mutation resulting in abnormal lamin A or progerin ○ Lacks following features – Cataracts – Hyperkeratosis – Skin ulcers – Diabetes mellitus ○ Death at age 13 due to myocardial infarction or stroke

Atypical Werner Syndrome • Wild-type WRN • LMNA (lamin A) mutation • Although similar, phenotype may be more severe than Werner syndrome

Acrogeria • Marked atrophy of skin of hands/feet • Dystrophic nails • Distinguishing features from Werner syndrome ○ Onset from birth ○ Autosomal dominant or recessive ○ Normal scalp hair

Metageria • • • •

Poikiloderma Atrophic extremities Early-onset diabetes mellitus and atherosclerosis Distinguishing features from Werner syndrome ○ Onset from birth ○ Autosomal recessive

Rothmund-Thomson Syndrome

Screening

Cataracts Short stature Hypogonadism Poikiloderma ○ Telangiectasias of skin • Increased risk of developing  ○ Osteosarcoma ○ Squamous cell carcinoma • Distinguishing features from Werner syndrome ○ Autosomal recessive ○ RECQL4 mutation ○ Lacks following features – Premature graying – Sclerodermoid skin changes – Osteoporosis – Arterioclerosis

• As clinically indicated

Cockayne Syndrome

CANCER RISK MANAGEMENT

DIFFERENTIAL DIAGNOSIS Hutchinson-Gilford Progeria • • • •

Severe atherosclerosis Sclerotic skin Joint contractures Alopecia

Overview of Syndromes: Syndromes

• • •

○ Extensive subcutaneous calcifications  – Resulting in amputation of feet or lower extremities ○ Skin ulcers ○ Soft tissue calcifications ○ Nail dystrophies ○ Clavus/callus Premature and severe atherosclerosis Abnormal voice Abnormal laboratory level of ○ Glucose ○ Lipid panel  ○ Uric acid level Hypogonadism Atherosclerosis Osteoporosis

• • • •

• • • • •

Autosomal recessive Short stature  Bird-like facies Poikiloderma Distinguishing features from Werner syndrome ○ ERCC8 or ERCC6 mutation ○ Onset after 1st year 791

Overview of Syndromes: Syndromes

Werner Syndrome/Progeria ○ No increased risk of malignancy ○ Photosensitivity ○ Neurologic degeneration

DIAGNOSTIC CRITERIA Cardinal Signs and Symptoms • • • •

Develop when patients > 10 years Premature graying &/or hair thinning (100%) Bilateral cataracts (99%) Cutaneous findings (96%) ○ Tight and atrophic skin ○ Pigmentary alterations ○ Ulceration ○ Hyperkeratosis ○ Regional subcutaneous atrophy ○ Characteristic bird-like facies • Soft tissue calcification • Voice changes

Other Signs and Symptoms • • • • • • •

Short stature (95%) and low body weight Abnormal glucose &/or lipid metabolism Hypogonadism Osteoporosis Osteoclerosis of distal phalanges of fingers &/or toes Premature atherosclerosis Mesenchymal neoplasms, rare neoplasms or multiple neoplasms • Flat feet • Parental consanguinity

Genetic Testing • WRN mutation

Confirmed Diagnosis • All cardinal signs or WRN gene mutation and > 3 cardinal signs

Suspected Diagnosis • > 2 cardinal signs or 1-2 cardinal signs and other signs

Exclusion • Onset of signs before puberty (excluding short stature)

SELECTED REFERENCES 1.

2. 3. 4. 5.

6.

7. 8. 9.

792

University of Washington School of Medicine, Department of Pathology: Werner syndrome. www.wernersyndrome.org. Updated Jan 4, 2019. Accessed Jan 8, 2019 Mukherjee S et al: Werner syndrome protein and DNA replication. Int J Mol Sci. 19(11): pii: E3442, 2018 Oshima J et al: Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 33:105-14, 2017 Tokita M et al: Werner syndrome through the lens of tissue and tumour genetics. Sci Rep. 6: 32038, 2016 Takemoto M et al: Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int. 13(2):47581, 2013 Takemoto M et al: Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int. 13(2):47581, 2013 Lauper JM et al: Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 8(4):e59709, 2013 Merideth MA et al: Phenotype and course of Hutchinson-Gilford progeria syndrome. N Eng J Med. 358(6):592-604, 2008 Huang S et al: The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat. 27(6):558-67, 2006

10. Chen L et al: LMNA mutations in atypical Werner's syndrome. Lancet. 362(9382):440-5, 2003 11. Eriksson M et al: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 423(6937):293-8, 2003 12. Chen L et al: LMNA mutations in atypical Werner's syndrome. Lancet. 362(9382):440-5, 2003 13. Epstein CJ et al: Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore). 45(3):177-221, 1966

Werner Syndrome/Progeria

Werner Syndrome: Age 21 (Left) This is a patient with Werner syndrome at age 13. Her appearance is normal. (Courtesy J. Oshima, PhD.) (Right) The same patient with Werner syndrome is shown at age 21. She does not yet have premature gray hair but does have short stature. (Courtesy J. Oshima, PhD.)

Werner Syndrome: Age 36

Overview of Syndromes: Syndromes

Werner Syndrome: Age 13

Werner Syndrome: Age 40 (Left) The same patient with Werner syndrome is shown at age 36. She has a prematurely aged appearance with gray hair. (Courtesy J. Oshima, PhD.) (Right) The same patient with Werner syndrome is shown at age 40.

Werner Syndrome: Age 48

Werner Syndrome: Age 54 (Left) The same patient with Werner syndrome is shown at age 48. (Right) The same patient with Werner syndrome is shown at age 54.

793

Overview of Syndromes: Syndromes

Wilms Tumor-Associated Syndromes

TERMINOLOGY Abbreviations • Wilms tumor (WT)

Definitions • WT arising in setting of genetic syndromes associated with WT1 and childhood overgrowth syndromes

EPIDEMIOLOGY Incidence • WT diagnosed in ~ 1 in 10,000 white children ○ 98-99% of WTs are sporadic ○ Familial WT comprises ~ 2% of cases ○ Congenital anomalies seen in up to 9% with syndrome diagnosis in up to 17% of WT patients ○ Childhood overgrowth syndrome seen in ~ 4% of WT patients

CLINICAL IMPLICATIONS Prognosis of WT • High cure rate ○ Localized disease: 90% survival ○ Advanced disease: 70% survival • Screening syndromic patients for WT results in earlier detection ○ Reduced complications from extensive therapy of higher stage diseases

Screening of WT • Genetic testing and surveillance recommended for children with > 5% risk for WT • Screening up to age 5 years expected to detect up to 95% of tumors in patients with WT1 mutations

WT1-ASSOCIATED SYNDROMES General Features • Syndromic patients develop WT at younger age than sporadic cases

Wilms Tumor Imaging (Left) Coronal CT of the abdomen shows a large, heterogeneously enhancing mass in the left kidney ﬊. Fluid surrounding perinephric space and paracolic gutter suggests tumor rupture st. Multiple masses are also scattered throughout the right kidney ﬇. (Right) H&E shows classic triphasic histology of Wilms tumor. It recapitulates renal embryogenesis and is composed of an admixture of blastemal ﬉, epithelial tubular ﬊, and stromal spindle cells ﬈. Blastemal cells are crowded small cells with abundant mitosis.

794

○ ~ 1 year vs. 3-4 years • Higher likelihood for bilateral WT ○ 38% vs. 5% for sporadic cases • Screening for WT performed by renal ultrasound every 3 months until 5 years of age • WT frequently contains intralobar nephrogenic rests and often stromal predominant

WT Aniridia Genitourinary Malformations and Mental Retardation Syndrome • Phenotype: Aniridia, ambiguous external genitalia (including cryptorchidism), and intellectual impairment • High risk for renal failure, affecting ~ 40% by age 20 years • Caused by microdeletions at Chr 11p13 that encompass WT1 and PAX6 • ~ 30% risk for WT

Denys-Drash Syndrome • Phenotype: Ambiguous genitalia, diffuse mesangial sclerosis, and genitourinary abnormalities in males ○ Nephropathy presents as hypertension and proteinuria • Caused by point mutation in zinc finger region of WT1 at Chr 11p13 • ~ 90% risk for WT

Frasier Syndrome • Phenotype: Ambiguous genitalia, streak gonads, focal segmental glomerulosclerosis • Caused by point mutation in WT1 intron 9 donor splice site at Chr 11p13 • Low risk for WT

OVERGROWTH SYNDROMES General Features • Heterogeneous, poorly defined, and overlapping group of genetic conditions with manifestations of overgrowth ○ Fetal macrosomia, macrocephaly, excessive growth or rapid increase in weight or length • Risk for WT evaluated per syndrome rather than on collective basis

Wilms Tumor Histology

Wilms Tumor-Associated Syndromes

Condition

Level of Risk

WT1 deletions (including WAGR syndrome)

High

Truncating and pathogenic missense WT1 mutations (including Denys-Drash syndrome)

High

Familial Wilms tumor

High

Perlman syndrome

High

Mosaic variegated aneuploidy

High

Fanconi anemia D1/biallelic BRCA2 mutation

High

WT1 intron 9 splice mutations (Frasier syndrome)

Moderate

Beckwith-Wiedemann syndrome caused by 11p15 uniparental disomy, isolated H19 hypermethylation or of unknown cause

Moderate

Simpson-Golabi-Behmel syndrome caused by GPC3 mutations/deletions

Moderate

Isolated hemihypertrophy

Low

Bloom syndrome

Low

Li-Fraumeni syndrome/Li-Fraumeni-like syndrome

Low

Hereditary hyperparathyroidism-jaw tumor syndrome

Low

Mulibrey nanism

Low

Trisomy 18

Low

Trisomy 13

Low

2q37 deletions

Low

Overview of Syndromes: Syndromes

Conditions With Increased Risk of Wilms Tumor

High risk (> 20%); moderate risk (5-20%); low risk (< 5%); screening for WT recommended for moderate- and high-risk conditions.

• Screening for WT in Beckwith-Wiedemann syndrome (BWS) and isolated (idiopathic) hemihypertrophy (IHH) performed by renal ultrasound every 3 months until age 8 years (older than in WT1-associated syndromes due to later age of onset)

• Hemihypertrophy can be associated with other syndromes such as BWS ○ Majority are isolated finding • Abnormality in Chr 11p15 in 20-35% of cases • ~ 3% develop WT

BWS

Perlman Syndrome

• Phenotype: Organomegaly, macrosomia, macroglossia, omphalocele, hemihypertrophy, ear anomalies, and neonatal hypoglycemia • Renal abnormalities such as nephromegaly, renal cysts, medullary sponge kidney, medullary dysplasia, hydronephrosis, and calculi formation • Genomic imprinting disorder ○ Involves KCNQ1OT1, CDKN1C, LIT1, or H19 and IGF2 genes located at Chr 11p15.5 • < 10% results from germline CDKN1C mutation • ~ 7-14% develop cancer, greatest risk at 1st decade of life ○ Most frequent is WT affecting up to 8% of cases • Higher risk for bilateral WT (17%) and perilobar nephrogenic rest (60%) than in sporadic WT

• Phenotype: Polyhydramnios, visceromegaly, facial dysmorphism, developmental delay, cryptorchidism, renal dysplasia, WT, and high infant mortality • Deletions in DIS3L2, gene important for RNA processing • ~ 64% develop WT • Nephroblastomatosis also common

Simpson-Golabi-Behmel Syndrome • Phenotype: Coarse facial features, skeletal and cardiac abnormalities, accessory nipples, and possible intellectual abnormalities • ~ 30% have renal abnormalities • Majority (70%) caused by mutations or deletions of Glypican-3 (GPC3) at Chr Xq26 • ~ 9% develop WT

IHH • Phenotype: Asymmetrical growth with one body part larger than contralateral counterpart

SELECTED REFERENCES 1.

Mussa A et al: The effectiveness of Wilms tumor screening in BeckwithWiedemann spectrum. J Cancer Res Clin Oncol. ePub, 2019 2. Han Q et al: Clinical features, treatment, and outcomes of bilateral Wilms' tumor: a systematic review and meta-analysis. J Pediatr Surg. 53(12):2465-9, 2018 3. Morris MR et al: Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2. Am J Med Genet C Semin Med Genet. 163C(2):106-13, 2013 4. Astuti D et al: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet. 44(3):277-84, 2012 5. Huff V: Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer. 11(2):111-21, 2011 6. Rao A et al: Genetic testing and tumor surveillance for children with cancer predisposition syndromes. Curr Opin Pediatr. 20(1):1-7, 2008 7. Scott RH et al: Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet. 43(9):705-15, 2006 8. Ruteshouser EC et al: Familial Wilms tumor. Am J Med Genet C Semin Med Genet. 129C(1):29-34, 2004 9. Dome JS et al: Recent advances in Wilms tumor genetics. Curr Opin Pediatr. 14(1):5-11, 2002 10. Breslow NE et al: Familial Wilms' tumor: a descriptive study. Med Pediatr Oncol. 27(5):398-403, 1996

795

Overview of Syndromes: Syndromes

Wiskott-Aldrich Syndrome

TERMINOLOGY

ETIOLOGY/PATHOGENESIS

Abbreviations

Histogenesis

• Wiskott-Aldrich syndrome (WAS) • X-linked thrombocytopenia (XLT)

• Syndrome caused by mutations in WAS gene that encodes WAS protein (WASP), located on chromosome X • WASP, expressed exclusively in hematopoietic cells, plays crucial role in actin cytoskeleton remodeling, which also affects cell migration, adhesion, and homing • Pathogenic loss-of-function WAS gene mutations lead to ○ Decreased or lack of any functional WASP resulting in – Defective T-cell function and B-cell homeostasis and impaired phagocytosis and chemotaxis of myeloid cells • Of note, gain-of-function mutations that impair autoinhibitory conformation of molecule result in ○ Increased actin polymerization and X-linked congenital neutropenia (XLN) • There is genotype/phenotype correlation in that absence of, or truncated, WASP causes WAS

Synonyms • Eczema-thrombocytopenia-immunodeficiency syndrome • Immunodeficiency 2 • Wiskott syndrome

EPIDEMIOLOGY Incidence • Rare syndrome with estimated incidence of ~ 1:100,000 live births • Seen almost exclusively in males as it is X-linked disorder • 50% of patients with WAS mutations

WASP Domains

Wiskott-Aldrich syndrome protein (WASP) domains are shown. WH1 = WASP homology 1; GBD = GTPase-binding domain; PP = prolinerich domain; and VCA = verprolin-cofilin-acidic (a.k.a. WA) region.

796

Wiskott-Aldrich Syndrome

Disease

Gene

Immunodeficiency

Thrombocytopenia

Eczema

Predisposition to Malignancy

Idiopathic thrombocytopenic purpura (ITP)

Unknown

No

Yes; increased platelet size and increased reticulated platelet count

No

No

Wiskott-Aldrich syndrome 2 (WAS2)

WIPF1 

Yes; low numbers of B Yes; but normal and T cells, defective platelet volume T-cell proliferation and chemotaxis, low NK-cell function

Yes

Unknown

○ While mutated, nonfunctional protein, although often in reduced quantities and of normal size, causes XLT • 6 hotspot mutations have been described, 3 in coding regions (T45M; R86C/H/L/S; R211X) and 3 involving splice sites (c.559+5G>A; c.777+1G>N; c.777+1 to +6 del GTGA)

CLINICAL IMPLICATIONS

• Sequence analysis of WAS gene with identification of deleterious mutation is used for confirmation • Flow cytometric analysis of lymphocytes looking for presence/absence of WASP using anti-WASP antibody (misses patients with nonfunctional but expressed protein)

PROGNOSIS

Wiskott-Aldrich Syndrome

Prognostic Adverse

• Also called "classic" (severe) WAS • Bleeding since early childhood due to severe congenital thrombocytopenia • Immunodeficiency, resulting in severe, mostly bacterial infections • Eczema resembling classic atopic dermatitis in ~ 50% of patients and since 1st year of life • Autoimmune manifestations (due to autoantibodies) (i.e., hemolytic anemia, neutropenia, vasculitis) • Malignancies (most frequently in adolescents and young adults) consisting of B-cell lymphomas [often EBV(+)] and leukemia

• Reduced life expectancy due to infections, hemorrhage, autoimmune diseases and malignancies

SELECTED REFERENCES 1.

2.

3.

4.

X-Linked Thrombocytopenia

5.

• Congenital thrombocytopenia • Lower risk for infections, eczema, and malignancies

6.

MICROSCOPIC

7.

Laboratory Findings • Abnormal immunologic findings ○ Decreased number and function of T cells ○ Abnormal immunoglobulin levels (decreased IgM, increased IgA and IgE) ○ Often decreased number of B cells • Thrombocytopenia (platelets usually 20,000-50,000/mm³) and usually decreased platelet volume

Histopathology • Decreased number of follicles and "burned-out" germinal centers • Small or atrophic thymus • Some degree of T-cell zone depletion in spleen and lymph nodes

Overview of Syndromes: Syndromes

Differential Diagnosis for Wiskott-Aldrich Syndrome

8. 9. 10. 11.

12. 13. 14.

Cheminant M et al: Lymphoproliferative disease in patients with WiskottAldrich syndrome: analysis of the French Registry of Primary Immunodeficiencies. J Allergy Clin Immunol. 143(6):2311-5.e7, 2019 Fernández-Calleja V et al: CRISPR/Cas9-mediated deletion of the WiskottAldrich syndrome locus causes actin cytoskeleton disorganization in murine erythroleukemia cells. PeerJ. 7:e6284, 2019 Jin YY et al: When WAS gene diagnosis is needed: seeking clues through comparison between patients with Wiskott-Aldrich syndrome and idiopathic thrombocytopenic purpura. Front Immunol. 10:1549, 2019 Candotti F: Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J Clin Immunol. 38(1):13-27, 2018 Albert MH et al: X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood. 115(16):3231-8, 2010 Thrasher AJ: New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. Dec:132-8, 2009 Jin Y et al: Mutations of the Wiskott-Aldrich syndrome protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 104(13):4010-9, 2004 Shcherbina A et al: High incidence of lymphomas in a subgroup of WiskottAldrich syndrome patients. Br J Haematol. 121(3):529-30, 2003 Notarangelo LD et al: Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood. 99(6):2268-9, 2002 Devriendt K et al: Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 27(3):313-7, 2001 Villa A et al: X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet. 9(4):414-7, 1995 Derry JM et al: Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell. 78(4):635-44, 1994 Cotelingam JD et al: Malignant lymphoma in patients with the WiskottAldrich syndrome. Cancer Invest. 3(6):515-22, 1985 ALDRICH RA et al: Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 13(2):133-9, 1954

DIAGNOSIS Diagnostic Clues • Family history, physical examination, and laboratory investigation are often sufficient to reach diagnosis 797

Overview of Syndromes: Syndromes

Xeroderma Pigmentosum

TERMINOLOGY

GENETICS

Abbreviations

Inheritance

• Xeroderma pigmentosum (XP)

• Autosomal recessive

Synonyms

Mutations

• DeSanctis-Cacchione syndrome • OMIM 278700, 278720, 278730, 278740, 278750, 610651

• In genes involved in nucleotide excision repair ○ Results in high number of UV signature mutations (C to T or CC to TT) • XP-C clinical syndrome ○ Photosensitivity ○ Poikiloderma ○ Lentigines skin cancer ○ XPC encoding protein recognizing global genome defects • XP-A, XP-B, XP-E, XP-G clinical syndromes ○ Photosensitivity ○ Poikiloderma ○ Lentigines and skin cancer ○ Neurodegeneration ○ XPA encoding protein that assists with DNA unwinding ○ ERCC3/XPB encoding helicase involved with DNA unwinding ○ DDB2/XPE encoding protein that recognizes global genome defects ○ ERCC5/XPG encoding endonuclease that incises damaged DNA • XP-D, XP-F clinical syndromes ○ Photosensitivity ○ Poikiloderma ○ Lentigines and skin cancer ○ Neurodegeneration and brain tumors ○ ERCC2/XPD encoding helicase involved with DNA unwinding ○ ERCC4/XPF forms endonuclease together with ERCC1 that incises damaged DNA for repair   • XP variant ○ Milder photosensitivity ○ Poikiloderma ○ Intact DNA excision repair capability

Definitions • Inherited disorder of nucleotide excision repair • XP cells cannot effectively clear UV photoproducts and are not able to use excision repair to mend UV radiation damage to DNA

EPIDEMIOLOGY Incidence • • • •

1 per million in United States 2.3 per million in Western Europe 45 per million in Japan XP-A, XP-C, and XP-D make up 90% of XP patients worldwide

Age Range • Freckling before age 2 • Early development of skin cancer ○ Nonmelanoma: Median age of 9 years (1-32 years) ○ Melanoma: Median age of 22 years (2-47 years) • Median age of hearing loss: 19 years

Natural History • Median age at death ○ 29 years with neurologic degeneration ○ 37 years without neurologic degeneration

ETIOLOGY/PATHOGENESIS Ultraviolet Light Action Spectrum • Inflammatory erythema of skin ○ 290-340 nm

Sun-Exposed Lentigines (Left) Extensive lentigines are shown on sun-exposed areas in a patient with xeroderma pigmentosum. (Courtesy K. Kraemer, MD.) (Photo in public domain. Originally published in Kraemer KH et al., Neuroscience 2007;145:1388.) (Right) Extensive lentigines are shown on sun-exposed areas in a patient with xeroderma pigmentosum. (Courtesy K. Kraemer, MD.) (Photo in public domain. Originally published in Kraemer KH et al., Neuroscience 2007;145:1388.)

798

Sun-Exposed Lentigines

Xeroderma Pigmentosum

CLINICAL IMPLICATIONS AND ANCILLARY TESTS Clinical Findings • Skin ○ Congenital extreme sensitization of skin to UV light ○ Solar lentigines or freckles on face before 2 years of age ○ Severe sunburn following minimal sun exposure ○ Premature aging – Progressive atrophy – Dryness – Telangiectasias – Atypical lentiginous proliferation – Admixed hyperpigmented and hypopigmented areas ○ Developing skin cancer before age 10 – Either metastatic melanoma or invasive squamous cell carcinoma – Most common cause of death ○ Patients with XP-C are at risk of developing desmoplastic melanomas • Eyes ○ Photophobia ○ Severe keratitis ○ Increased pigmentation of eyelids ○ Loss of eyelashes ○ Conjunctivitis ○ Conjunctival melanosis ○ Cataracts • Central nervous system ○ Neurodegeneration ○ Loss of intellectual functioning ○ Deterioration of neurologic status ○ Impaired hearing ○ Abnormal speech ○ Areflexia ○ Ataxia ○ Peripheral neuropathy ○ Loss of ability to walk and talk • Lungs ○ Lung cancer

Imaging Findings • Brain imaging studies show enlarged ventricles and cortical thinning

ASSOCIATED NEOPLASMS Skin Cancer • > 10,000x risk of developing nonmelanoma skin cancer ○ Basal cell carcinoma ○ Squamous cell carcinoma • > 2,000x risk for melanoma

Internal Malignancy • 1,000x risk for ocular cancer • 50x increased risk of developing brain tumors ○ Medulloblastoma ○ Glioblastoma

○ Spinal cord astrocytoma ○ Schwannoma • In patients who smoke, risk of lung cancer is higher than that of general population • Carcinomas ○ Uterus ○ Breast ○ Stomach ○ Kidney ○ Testis

CANCER RISK MANAGEMENT Ultraviolet Light Protection (From Sunlight and Artificial Light)

Overview of Syndromes: Syndromes

○ POLH/XPV encoding DNA-polymerase eta (pol-eta), which performs translesion DNA synthesis past UV

• Minimize sun exposure • Protect all body surfaces and eyes • Oral vitamin D and calcium supplementation

Regular Examination • Comprehensive dermatologic examination at least every 3 months • Close monitoring by ophthalmology for ocular disease

DIFFERENTIAL DIAGNOSIS Cockayne Syndrome • • • • • • • • •

Mutation in ERCC6/CSA or ERCC8/CSB genes Autosomal recessive Short stature with microcephaly Pigmentary retinal degeneration Kyphoscoliosis Gait defects Sensorineural deafness Prominent ears and wizened appearance Type I ○ Moderate phenotype with symptoms manifested in first 2 years of life ○ Death occurred during 1st or 2nd decade • Type II ○ Severe phenotype with growth failure at birth ○ Death in 1st decade of life • Type III ○ Milder symptoms or later onset

Xeroderma Pigmentosum/Cockayne Syndrome Overlap • Mutations in ERCC3/XPB, ERCC2/XPD, and ERCC5/XPG genes • Solar lentigines • Increased skin cancers • Pigmentary retinal degeneration • Basal ganglion calcification

Ultraviolet Light Sensitive Syndrome • • • • •

Mutation in ERCC6/CSA or ERCC8/CSB genes Autosomal recessive Possibly mild variant of Cockayne syndrome Photosensitivity Solar lentigines

799

Overview of Syndromes: Syndromes

Xeroderma Pigmentosum Cerebrooculofacial-Skeletal Syndrome

Rothmund-Thomson Syndrome

• • • • • • • • •

• • • • • • • • •

Autosomal recessive Microcephaly Congenital cataracts Microphthalmia Arthrogryposis Severe developmental delay Severe postnatal growth failure Photosensitivity Facial dysmorphism

Trichothiodystrophy • Associated with ERCC3/XPB, ERCC2/XPD, GTF2H5/TTDA gene mutations • Autosomal recessive • Photosensitivity • Differences from XP ○ Abnormal hair – Brittle hair is sulfur deficient and exhibits striped light and dark pattern with polarizing light microscopy ○ Intellectual impairment ○ Decreased fertility ○ Short stature ○ Ichthyosis ○ Absent lentigines ○ No increased risk of internal cancer or skin cancer

Bloom Syndrome • • • • • • • • • • •

Mutation in BLM/RECQL3 gene Autosomal recessive Malar erythema and telangiectasias Café au lait macules Long face with prominent nose Short stature Diabetes mellitus Normal intelligence Reduced/absent fertility Recurrent respiratory and gastrointestinal infections Malignancies including leukemia, lymphoma, and gastrointestinal adenocarcinoma

Malignant Melanoma (Left) The lesion labeled 15 is a malignant melanoma with a depth of 0.55 mm on the leg of this patient with xeroderma pigmentosum. There are numerous surrounding lentigines. (Courtesy K. Kraemer, MD.) (Right) This melanoma in situ in a patient with xeroderma pigmentosum demonstrates a proliferation of atypical melanocytes arranged in irregular nests at the basal aspect of the epidermis ﬊ as well as single cells migrated toward the granular layer (i.e., pagetoid spread).

800

Mutations in RECQL4 gene Autosomal recessive Facial erythema, edema, and vesicles Sparse hair Hypoplastic nails Acral keratoses Short stature Normal intelligence Malignancies ○ Osteosarcoma ○ Squamous cell carcinoma

SELECTED REFERENCES 1.

Lehmann J et al: Xeroderma pigmentosum - facts and perspectives. Anticancer Res. 38(2):1159-64, 2018 2. Weon JL et al: Novel therapeutic approaches to xeroderma pigmentosum. Br J Dermatol. ePub, 2018 3. Natale V et al: Xeroderma pigmentosum-Cockayne syndrome complex. Orphanet J Rare Dis. 12(1):65, 2017 4. Walsh MF et al: Recommendations for childhood cancer screening and surveillance in DNA repair disorders. Clin Cancer Res. 23(11):e23-31, 2017 5. Black JO: Xeroderma pigmentosum. Head Neck Pathol. 10(2):139-44, 2016 6. Kraemer KH et al: Forty years of research on xeroderma pigmentosum at the US National Institutes of Health. Photochem Photobiol. 91(2):452-9, 2015 7. Hadj-Rabia S et al: Unexpected extradermatological findings in 31 patients with xeroderma pigmentosum type C. Br J Dermatol. 168(5):1109-113, 2013 8. Kashiyama K et al: Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and fanconi anemia. Am J Hum Genet. 92(5):807-19, 2013 9. Laugel V et al: Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation. J Med Genet. 45(9):564-71, 2008 10. Kraemer KH et al: Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience. 145(4):1388-96, 2007 11. Cleaver JE: Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 5(7):564-73, 2005 12. Kraemer KH et al: Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 123(2):24150, 1987

Melanoma

Xeroderma Pigmentosum

Lentigo (Left) A 17-year-old girl with xeroderma pigmentosum presents with multiple tumors on her scalp, ear, and nose. (Courtesy S. Demehri, MD, PhD.) (Right) This xeroderma pigmentosum patient has numerous lentigines. A skin biopsy, as demonstrated here, shows hyperpigmentation of basal keratinocytes and no significant increase in the number of melanocytes within the epidermis.

Squamous Cell Carcinoma

Overview of Syndromes: Syndromes

Scalp Tumor

Squamous Cell Carcinoma (Left) A biopsy of the scalp tumor of a patient with xeroderma pigmentosum shows an invasive squamous cell carcinoma in the dermis extending to the deep aspect of the biopsy. The tumor is infiltrative despite the welldifferentiated morphology of the tumor cells. (Right) The tumor of the patient's left nasal sidewall is also a welldifferentiated squamous cell carcinoma. Infiltrative nests and strands of atypical keratinocytes exhibiting keratinization are seen within an elastotic dermis.

Basal Cell Carcinoma

Basal Cell Carcinoma (Left) A biopsy of the tumor on the patient's right posterior ear shows a nodular and infiltrative basal cell carcinoma. Melanin pigment is focally noted, consistent with a pigmented basal cell carcinoma. (Right) High-power view of the same tumor demonstrates nests of basaloid tumor cells exhibiting a peripheral palisade within a mucinous stroma.

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PART III SECTION 1

Molecular Factors Molecular Factors Index

804

Reference: Molecular Factors

Molecular Factors Index

804

Molecular Factors Discussed Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

ABCB11

2q24

ABCB11; ATP-binding cassette, sub-family B (MDR/TAP), member 11

Biliary Tract/Liver/Pancreas Table

AGL

1p21

AGL; amylo-alpha-1, 6-glucosidase, 4-alphaglucanotransferase

Biliary Tract/Liver/Pancreas Table

AIP

11q13.3

AIP; aryl hydrocarbon receptor interacting protein

Multiple Endocrine Neoplasia Type 1 (MEN1); Pituitary Adenoma; Pituitary Table

AKT1

14q32.32

AKT1; v-akt murine thymoma viral oncogene homolog 1

Bone and Soft Tissue Table; Esophageal Squamous Cell Carcinoma; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Prostate Carcinoma; PTENHamartoma Tumor Syndromes

ALDH2

12q24.2

ALDH2; aldehyde dehydrogenase 2 family (mitochondrial)

Esophageal Squamous Cell Carcinoma

ALK

2p23

ALK; anaplastic lymphoma receptor tyrosine kinase

Adenocarcinoma, Lung; Bone and Soft Tissue Table; Hereditary Neuroblastoma; Medullary Thyroid Carcinoma; Neuroblastic Tumors of Adrenal Gland

ALX4

11p11.2

ALX4; ALX homeobox 4

Multiple Osteochondromas

AML1

21q22.3

RUNX1; runt-related transcription factor 1

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome

APC

5q21

APC; adenomatosis polyposis coli

Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Adrenal Cortex Table; Biliary Tract/Liver/Pancreas Table; Bone and Soft Tissue Table; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Colon/Rectum Table; Esophagus/Stomach/Small Bowel Table; Familial Adenomatous Polyposis; Familial Gastrointestinal Stromal Tumor; Gynecologic Tumors; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Gastric Adenocarcinoma; Gastrointestinal Stromal Tumor; Head and Neck Table; Hepatoblastoma; Hereditary Mixed Polyposis Syndrome; Hereditary Neuroblastoma; Hereditary Pancreatic Cancer Syndrome; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; MUTYH-Associated Polyposis; Parathyroid Adenoma; Pathology of Familial Tumor Syndromes; Salivary Glands Table; Small Bowel Adenocarcinoma; Thyroid, Nonmedullary Carcinoma Table

ASIP

20q11.2-q12

ASIP; agouti signaling protein

Melanoma/Pancreatic Carcinoma Syndrome

ASS1

9q34.1

ASS1; argininosuccinate synthase 1

Biliary Tract/Liver/Pancreas Table

ATM

11q22.3

ATM; ataxia telangiectasia mutated

Ataxia Telangiectasia; Blood and Bone Marrow Table; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Breast Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Eye; Gynecologic Tumors; Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Pancreatic Adenocarcinoma Gastric Adenocarcinoma; Prostate Carcinoma; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Nijmegen Breakage Syndrome; Ovarian Tumors; Salivary Glands Table

ATP8B1

18q21.31

ATP8B1; ATPase, aminophospholipid transporter, class I, type 8B, member 1

Biliary Tract/Liver/Pancreas Table

BACH1

21q22.11

BACH1; BTB and CNC homology 1, basic leucine zipper transcription factor 1

Blood and Bone Marrow Table

BAK1

6p21.3

BAK1; BCL2-antagonist/killer 1

Familial Testicular Tumor; Testicle Table

BAP1

3p21.31-p21.2

BAP1; BRCA1 associated protein-1 (ubiquitin BAP1-Inactivated Melanocytic Tumor; BAP1 Tumor carboxy-terminal hydrolase) Predisposition Syndrome; Central Nervous System; Clear Cell Renal Cell Carcinoma; Clinical Diagnosis and

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Management of Familial/Hereditary Tumor Syndromes; Cutaneous Melanoma; Eye; Familial Uveal Melanoma; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Melanoma/Pancreatic Carcinoma Syndrome; Osteosarcoma; Pathology of Familial Tumor Syndromes; Skin Table

BARD1

2q34-q35

BARD1; BRCA1 associated RING domain 1

Adrenal Cortical Carcinoma; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Molecular Aspects of Familial/Hereditary Tumor Syndromes

BHD

17p11.2

FLCN; folliculin

Birt-Hogg-Dubé Syndrome; Brooke-Spiegler Syndrome; Head and Neck Table; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Lymphangioleiomyomatosis; Renal Oncocytoma, Chromophobe, and Hybrid Tumors

BLM

15q26.1

RECQL3; Bloom syndrome, RecQ helicaselike

Blood and Bone Marrow Table; Bloom Syndrome; Bone and Soft Tissue Table; Head and Neck Table; Lung Table; Nijmegen Breakage Syndrome; Osteosarcoma; Squamous Cell Carcinoma; Tumor Syndromes Predisposing to Osteosarcoma; Xeroderma Pigmentosum  

BMPR1A

10q22.3

BMPR1A; bone morphogenetic protein receptor, type IA

Biliary Tract/Liver/Pancreas Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Carcinoma Syndromes; Colon/Rectum Table; Esophagus/Stomach/Small Bowel Table; Gastric Adenocarcinoma; Hamartomatous Polyps, PeutzJeghers; Hamartomatous Polyposis Syndromes; Juvenile Polyposis Syndrome; Small Bowel Adenocarcinoma

BRAF

7q34

BRAF; v-raf murine sarcoma viral oncogene homolog B

Adenocarcinoma, Lung; Adrenal Medulla and Paraganglia Table; BAP1-Inactivated Melanocytic Tumor; Pathology of Familial Tumor Syndromes; BAP1 Tumor Predisposition Syndrome; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Colon/Rectum Table; Colonic Carcinoma Syndromes; Costello Syndrome; Cutaneous Melanoma; Cutaneous Squamous Cell Carcinoma; Familial Gastrointestinal Stromal Tumor; Familial Nonmedullary Thyroid Carcinoma; Familial Uveal Melanoma; Gastrointestinal Stromal Tumor; Hereditary Neuroblastoma; Lynch Syndrome; Malignant Peripheral Nerve Sheath Tumor; Prostate Carcinoma; RASopathies: Noonan Syndrome; Salivary Glands Table

BRCA1

17q21

BRCA1; breast cancer 1, early onset

BAP1-Inactivated Melanocytic Tumor; BAP1 Tumor Predisposition Syndrome; Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Breast/Ovarian Cancer Syndrome: BRCA2; Breast Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Eye; Fallopian Tube Carcinoma; Familial Uveal Melanoma; Fanconi Anemia; Gynecologic Tumors;  Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Osteosarcoma;  Li-Fraumeni Syndrome; Lung Table; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Pathology of Familial Tumor Syndromes; PTEN-Hamartoma Tumor Syndromes; Prostate Carcinoma; Small Bowel Adenocarcinoma  

BRCA2

13q12.3

BRCA2; breast cancer 2, early onset

Adenocarcinoma, Lung; Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Breast/Ovarian Cancer Syndrome: BRCA2; Breast Table; Chordoma; Clinical Diagnosis and Management of

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

805

Reference: Molecular Factors

Molecular Factors Index

806

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Familial/Hereditary Tumor Syndromes; Esophageal Squamous Cell Carcinoma; Fallopian Tube Carcinoma; Familial Chordoma; Gastric Adenocarcinoma; Familial Wilms Tumor; Fanconi Anemia; Gynecologic Tumors; Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Li-Fraumeni Syndrome; Lung Table; Melanoma/Pancreatic Carcinoma Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Osteosarcoma; Ovarian Tumors; Pancreatic Adenocarcinoma; Parathyroid Carcinoma; Pathology of Familial Tumor Syndromes; PTEN-Hamartoma Tumor Syndromes; Prostate Carcinoma; Wilms Tumor; Wilms Tumor-Associated Syndromes  

BRIP1

17q22.2

BRIP1; BRCA1 interacting protein C-terminal helicase 1

Blood and Bone Marrow Table; Breast Carcinoma;  Breast/Ovarian Cancer Syndrome: BRCA1; Fanconi Anemia; Gynecologic Tumors; Hereditary Prostate Cancer; Li-Fraumeni Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Prostate Carcinoma

CASR

3q13.3-21

CASR; calcium-sensing receptor

Familial Isolated Hyperparathyroidism; Parathyroid Adenoma; Parathyroid Carcinoma; Parathyroid Table; Primary Parathyroid Hyperplasia

CBFA2

21q22.3

RUNX1; runt-related transcription factor 1

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome

CBL

11q23.3

CBL; Cas-Br-M (murine) ecotropic retroviral transforming sequence

Costello Syndrome; Familial Gastrointestinal Stromal Tumor; RASopathies: Noonan Syndrome

CCNA1

13q12.3-q13

CCNA1; cyclin-A1

Pituitary Table

CCND1

11q13

CCND1; cyclin-D1

Esophageal Adenocarcinoma; Hepatocellular Carcinoma; Hyperparathyroidism-Jaw Tumor Syndrome; Parathyroid Adenoma; Parathyroid Carcinoma; Pituitary Table; Primary Parathyroid Hyperplasia

CDC73/HRPT2

1q25

CDC73; cell division cycle 73

Parathyroid Adenoma

CDH1

16q22.1

CDH1; cadherin 1, type 1

Bladder Urothelial Carcinoma; Breast Carcinoma; Breast Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Gastric Adenocarcinoma; Esophagus/Stomach/Small Bowel Table; Hepatocellular Carcinoma; Hereditary Diffuse Gastric Cancer

CDK4

12q14

CDK4; cyclin-dependent kinase 4

Bone and Soft Tissue Table; Melanoma/Pancreatic Carcinoma Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes

CDKN1B

12p13.1-p12

CDKN1B; cyclin-dependent kinase inhibitor 1B

Biliary Tract/Liver/Pancreas Table; Endocrine Pancreas Table; Familial Isolated Hyperparathyroidism; Multiple Endocrine Neoplasia Type 1 (MEN1); Multiple Endocrine Neoplasia Type 4 (MEN4); Pancreatic Neuroendocrine Neoplasms; Pancreatic Neuroendocrine Tumor Syndromes; Parathyroid Adenoma; Parathyroid Table; Pituitary Adenoma; Primary Parathyroid Hyperplasia; Prostate Carcinoma

CDKN1C

11p15.5

CDKN1C; cyclin-dependent kinase inhibitor 1C

Adrenal Cortical Neoplasms in Children; Rhabdomyosarcoma

CDKN2A/P16

9p21

CDKN2A; cyclin-dependent kinase inhibitor 2A

Astrocytoma; Biliary Tract/Liver/Pancreas; Central Nervous System; Cutaneous Melanoma; Cutaneous Melanoma; Familial Plasma Cell Myeloma; Familial Uveal Melanoma; Follicular Lymphoma; Hereditary Multiple Melanoma; Hereditary Pancreatic Cancer Syndrome; Melanoma/Pancreatic Carcinoma Syndrome; Neurofibromatosis Type 1; Pancreatic Endocrine Tumor; Squamous Cell Carcinoma, Head and Neck Bone and Soft

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Tissue

CEBPA

19q13.1

CEBPA; CCAAT/enhancer binding protein (C/EBP), alpha

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome; Pathology of Familial Tumor Syndromes

CFTR

7q31.2

CFTR; cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)

Biliary Tract/Liver/Pancreas Table; Hereditary Pancreatic Cancer Syndrome

CHEK2

22q12.1

CHEK2; checkpoint kinase 2

Biliary Tract/Liver/Pancreas Table; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Breast Table; Chordoma; Colonic Carcinoma Syndromes; Familial Chordoma; Familial Thyroid Carcinoma; Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Prostate Carcinoma

COL1A1-PDGFB

t(17;22)(q21;q13)

COL1A1-PDGFB

Bone and Soft Tissue Table

COL6A3-CSF1

t(1;2)(p13;q37)

COL6A3-CSF1

Bone and Soft Tissue Table

CTC1

17p13

CTC1; CTS telomere maintenance complex component 1

Blood and Bone Marrow Table; Dyskeratosis Congenita

CTNNB1

3p21

CTNNB1; catenin (cadherin-associated protein), beta 1

Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Bone and Soft Tissue Table; Familial Infantile Myofibromatosis; Hepatocellular Carcinoma; Prostate Carcinoma; Wilms Tumor

CXORF5

Xp22

OFD1; oral-facial-digital syndrome 1

Beckwith-Wiedemann Syndrome

CYLD

16q12.1

CYLD; cylindromatosis (turban tumor syndrome)

Brooke-Spiegler Syndrome; Head and Neck Table; Salivary Glands Table

CYP21

6p21.3

CYP21A2; cytochrome P450, family 21, subfamily A, polypeptide 2

Adrenal Cortex Table; Adrenal Cortical Neoplasms in Children

DICER1

14q32.13

DICER1; dicer 1, ribonuclease type III

Bone and Soft Tissue Table; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Cystic Nephroma; DICER1 Syndrome; Eye; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Gynecologic Tumors; Hamartomatous Polyposis Syndromes; Hepatocellular Carcinoma; Lung Table; Multiple Endocrine Neoplasia Type 4 (MEN4); Ovarian Tumors; Pathology of Familial Tumor Syndromes; Pituitary Adenoma; Pituitary Table; Pleuropulmonary Blastoma; PTEN-Hamartoma Tumor Syndromes; Rhabdomyosarcoma; Thyroid, Nonmedullary Carcinoma Table

DIRC1

2q33

DIRC1; disrupted in renal carcinoma 1

Hereditary Renal Epithelial Tumors, Others; Kidney Table

DIRC2

2q33

DIRC2; disrupted in renal carcinoma 1

Hereditary Renal Epithelial Tumors, Others

DIRC3

2q35

DIRC3; disrupted in renal carcinoma 3

Hereditary Renal Epithelial Tumors, Others; Kidney Table

DIS3L2

2q37.1

DIS3L2; DIS3 mitotic control homolog (S. cerevisiae)-like 2

Beckwith-Wiedemann Syndrome; Wilms TumorAssociated Syndromes

DKC1

Xq28

DKC1; dyskeratosis congenita 1, dyskerin

Blood and Bone Marrow Table; Dyskeratosis Congenita; Head and Neck Table; Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer; Squamous Cell Carcinoma

DOG1

11q13.3

ANO1; anoctamin 1, calcium activated chloride channel

Familial Gastrointestinal Stromal Tumor; Gastrointestinal Stromal Tumor

EGFR

7p12

EGFR; epidermal growth factor receptor

Adenocarcinoma, Lung; Adenocarcinoma With Lepidic (Bronchioloalveolar) Predominant Pattern; Adrenal Cortex Table; Bone and Soft Tissue Table; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Esophageal Squamous Cell Carcinoma; Familial Chordoma; Familial Infantile Myofibromatosis; HLRCC Syndrome-Associated Renal Cell Carcinoma; Lung Table;

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

807

Reference: Molecular Factors

Molecular Factors Index

808

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Neuroendocrine Tumor, Lung; Papillary Renal Cell Carcinoma; Pituitary Table; Squamous Cell Carcinoma

EGLN1/PHD2

1q42.1

EGLN1; egl-9 family hypoxia-inducible factor 1

Adrenal Medulla and Paraganglia Table

ELAC2

17p11.2

ELAC2; elaC ribonuclease Z 2

Hereditary Prostate Cancer; Prostate Carcinoma

ELANE

19p13.3

ELANE; elastase, neutrophil expressed

Blood and Bone Marrow Table

ENG

9q34.11

ENG; endoglin

Biliary Tract/Liver/Pancreas Table; Colon/Rectum Table; Juvenile Polyposis Syndrome  

EPCAM

2p21

EPCAM; epithelial cell adhesion molecule

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Endometrial Carcinoma; Esophagus/Stomach/Small Bowel Table; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Renal Urothelial Carcinoma; Small Bowel Adenocarcinoma  

ERCC6

10q11.23

ERCC6; excision repair cross-complementing Esophageal Adenocarcinoma; Werner rodent repair deficiency, complementation Syndrome/Progeria; Xeroderma Pigmentosum group 6

ERCC8

5q12.1

ERCC8; excision repair cross-complementing Werner Syndrome/Progeria; Xeroderma Pigmentosum rodent repair deficiency, complementation group 8

ERG

21q22.3

ERG; v-ets erythroblastosis virus E26 oncogene homolog

Bone and Soft Tissue Table; Prostate Carcinoma; Wilms Tumor-Associated Syndromes

ETS

11q23.3

ETS; v-ets avian erythroblastosis virus E26 oncogene homolog 1

Prostate Carcinoma

ETV1

7p21.3

ETV1; ets variant 1

Bone and Soft Tissue Table; Prostate Carcinoma

ETV4

17q21

ETV4; ets variant 4

Bone and Soft Tissue Table; Prostate Carcinoma

ETV5

3q28

ETV5; ets variant 5

Prostate Carcinoma

ETV6-NTRK3

t(12;15)(p13;q25)

ETV6-NTRK3

Bone and Soft Tissue Table; Familial Gastrointestinal Stromal Tumor; Familial Infantile Myofibromatosis Rhabdomyosarcoma; Salivary Glands Table

EWSR1/EWS

22q12

EWSR1; EWS RNA-binding protein 1

Bone and Soft Tissue Table; Neuroblastic Tumors of Adrenal Gland; Osteosarcoma; Rhabdomyosarcoma; Salivary Glands Table

EWSR1ATF1/EWS-ATF1

t(12;22)(q13;q12)

EWSR1-ATF1

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor; Salivary Glands Table

EWSR1CREB1/EWSCREB1

t(2;22)(q34;q12)

EWSR1-CREB1

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor

EWSR1DDIT3/EWSCHOP

t(12;22)(q13;q12)

EWSR1-DDIT3

Bone and Soft Tissue Table

EWSR1-E1AF

t(17;22)(q21;q12)

EWSR1-ETV4

Bone and Soft Tissue Table

EWSR1-ERG

t(21;22)(q22;q12)

EWSR1-ERG

Bone and Soft Tissue Table; Rhabdomyosarcoma

EWSR1-ETV1

t(7;22)(p21.3;q12)

EWSR1-ETV1

Bone and Soft Tissue Table

EWSR1-FEV

t(2;22)(q36;q12)

EWSR1-FEV

Bone and Soft Tissue Table

EWSR1-FLI1

t(11;22)(q24;q12)

EWSR1-FLI1

Bone and Soft Tissue Table; Neuroblastic Tumors of Adrenal Gland; Rhabdomyosarcoma

EWSR1-NR4A3

t(9;22)(q22;q12)

EWSR1-NR4A3

Bone and Soft Tissue Table

EWSR1-PBX1

(1;22)(q23;q12)

EWSR1-PBX1

Bone and Soft Tissue Table

EWSR1-WT1

t(11;22)(p13;q12)

EWSR1-WT1

Bone and Soft Tissue Table; Rhabdomyosarcoma

EWSR1-ZNF444

t(19;22)(q13;q12)

EWSR1-ZNF444

Bone and Soft Tissue Table

EXT1

8q24.11

EXT1; exostosin 1

Bone and Soft Tissue Table; Chondrosarcoma; Multiple Osteochondromas

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

EXT2

11p12-p11

EXT2; exostosin 2

Bone and Soft Tissue Table; Chondrosarcoma; Multiple Osteochondromas

FAH

15q25.1

FAH; fumarylacetoacetate hydrolase (fumarylacetoacetase)

Biliary Tract/Liver/Pancreas Table

FANCA

16q24.3

FANCA; Fanconi anemia, complementation group A

Blood and Bone Marrow Table; Fanconi Anemia

FANCB

Xp22.2

FANCB; Fanconi anemia, complementation group B

Blood and Bone Marrow Table; Fanconi Anemia

FANCC

9q22.3

FANCC; Fanconi anemia, complementation group C

Blood and Bone Marrow Table; Fanconi Anemia; Pancreatic Adenocarcinoma

FANCD1

13q12.3

BRCA2; breast cancer 2, early onset

Blood and Bone Marrow Table; Esophageal Squamous Cell Carcinoma; Fanconi Anemia

FANCD2

3p26

FANCD2; Fanconi anemia, complementation group D2

Blood and Bone Marrow Table; Esophageal Squamous Cell Carcinoma; Fanconi Anemia

FANCE

6p22-p21

FANCE; Fanconi anemia, complementation group E

Blood and Bone Marrow Table; Esophageal Squamous Cell Carcinoma; Fanconi Anemia

FANCF

11p15

FANCF; Fanconi anemia, complementation group F

Blood and Bone Marrow Table; Fanconi Anemia

FANCG

9p13

FANCG; Fanconi anemia, complementation group G

Blood and Bone Marrow Table; Fanconi Anemia; Pancreatic Adenocarcinoma

FANCI

15q26.1

FANCI; Fanconi anemia, complementation group I

Blood and Bone Marrow Table; Fanconi Anemia

FANCJ

17q22.2

BRIP1; BRCA1 interacting protein C-terminal helicase 1

Blood and Bone Marrow Table; Fanconi Anemia

FANCL

2p16.1

FANCL; Fanconi anemia, complementation group L

Blood and Bone Marrow Table; Esophageal Squamous Cell Carcinoma; Fanconi Anemia

FANCM

14q21.2

FANCM; Fanconi anemia, complementation group M

Blood and Bone Marrow Table; Fanconi Anemia

FANCN

16p12.2

PALB2; partner and localizer of BRCA2

Blood and Bone Marrow Table; Breast Carcinoma; Breast Table; Fanconi Anemia

FANCx

Multiple

Fanconi anemia, complementation groups

Head and Neck Table; Squamous Cell Carcinoma

FBXW7

4q31.3

FBXW7; F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase

Colonic Carcinoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table

FGFR2

10q26

FGFR2; fibroblast growth factor receptor 2

Pituitary Table

FGFR3

4p16.3

FGFR3; fibroblast growth factor receptor 3

Bladder Urothelial Carcinoma; Renal Urothelial Carcinoma

FH

1q42.1

FH; fumarate hydratase

Adrenal Cortical Carcinoma; Adrenal Cortex Table; Adrenal Cortical Neoplasms in Children; Adrenal Medulla and Paraganglia Table; Bone and Soft Tissue Table; Gynecologic Tumors; Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndromes; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; HLRCC Syndrome-Associated Renal Cell Carcinoma; Kidney Table; Papillary Renal Cell Carcinoma; Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma; Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

FHIT

3p14.2

FHIT; fragile histidine triad

Hereditary Renal Epithelial Tumors, Others; Kidney Table

FLCN

17p11.2

FLCN; folliculin

Birt-Hogg-Dubé Syndrome; Brooke-Spiegler Syndrome; Hereditary Renal Epithelial Tumors, Others; Head and Neck Table; Kidney Table; Lymphangioleiomyomatosis; Renal Oncocytoma, Chromophobe, and Hybrid Oncocytic Tumors

FLI1

11q24.3

FLI1;  a.k.a. BDPLT21, EWSR2, SIC-1; Fli-1 protooncogene, ETS transcription factor

Prostate Carcinoma

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

809

Reference: Molecular Factors

Molecular Factors Index

810

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

FOXA1

14q21.1 

FOXA1; a.k.a. HNF3A, TCF3A; forkhead box A1

Prostate Carcinoma

FUS-ATF1

t(12;16)(q13;p11.2)

FUS-ATF1

Bone and Soft Tissue Table

FUS-CREB3L1

t(11;16)(p11.2;p11.2)

FUS-CREB3L1

Bone and Soft Tissue Table

FUS-CREB3L2

t(7;16)(q34;p11.2)

FUS-CREB3L2

Rhabdomyosarcoma; Bone and Soft Tissue

FUS-DDIT3

t(12;16)(q13;p11.2)

FUS-DDIT3

Bone and Soft Tissue Table

FUS-ERG

t(16;21)(p11.2;q22.3)

FUS-ERG

Bone and Soft Tissue Table

FWT1

17q12-q21

WT4; Wilms tumor 4

Familial Wilms Tumor; Wilms Tumor

G6PC

17q21

G6PC; glucose-6-phosphatase, catalytic subunit

Biliary Tract/Liver/Pancreas Table

GATA2

3q21.3

GATA2; GATA binding protein 2

Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome; Pathology of Familial Tumor Syndromes; Pituitary Adenoma

GATA3

10p15

GATA3; GATA binding protein 3

Bladder Table; C-Cell Hyperplasia; Parathyroid Adenoma; Renal Pelvis and Ureter Table; Testicle Table

GJB6

13q12

GJB6; gap junction protein, beta 6, 30kDa

Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer

GNA11

19p13.3

GNA11; guanine nucleotide binding protein (G protein), alpha 11 (Gq class)

Bone and Soft Tissue Table; Familial Isolated Hyperparathyroidism; Familial Uveal Melanoma; Parathyroid Table

GNAQ

9q21

GNAQ; guanine nucleotide binding protein (G protein), q polypeptide

Bone and Soft Tissue Table; Familial Uveal Melanoma

GNAS/GNAS1

20q13.3

GNAS; GNAS complex locus

Bone and Soft Tissue Table; Adrenal Cortex Table; Adrenal Cortical Neoplasms in Children; Carney Complex; Follicular Thyroid Carcinoma; Hyperparathyroidism-Jaw Tumor Syndrome; McCune-Albright Syndrome; Neurofibromatosis Type 1; Pancreatic Adenocarcinoma; Pituitary Adenoma; Pituitary Table; Thyroid, Nonmedullary Carcinoma Table

GPC3

Xq26.1

GPC3; Glypican 3

Beckwith-Wiedemann Syndrome; Kidney Table; Wilms Tumor; Wilms Tumor-Associated Syndromes

GSTM1

1p13.3

GSTM1; glutathione S-transferase mu 1

Esophageal Adenocarcinoma

GSTP1

11q13

GSTP1; glutathione S-transferase pi 1

Esophageal Adenocarcinoma; Hepatocellular Carcinoma

H19

11p15.5

H19; imprinted maternally expressed transcript (non-protein coding)

Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Beckwith-Wiedemann Syndrome; Kidney Table; Wilms Tumor; Wilms Tumor-Associated Syndromes

HAX1

1q21.3

HAX1; HCLS1 associated protein X-1

Blood and Bone Marrow Table

HER2

17q12

ERBB2; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2

Adenocarcinoma, Lung; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Breast/Ovarian Cancer Syndrome: BRCA2; Breast Table; Colonic Carcinoma Syndromes; Salivary Glands Table

HFE

6p21.3

HFE; hemochromatosis

Biliary Tract/Liver/Pancreas Table

HMGA2/HMGIC

12q15

HMGIC; high mobility group AT-hook 2

Bone and Soft Tissue Table; Salivary Glands Table

HMGA2-LPP

t(3;12)(q28;q15)

HMGIC-LPP

Bone and Soft Tissue Table

HPD

12q24.31

HPD; 4-hydroxyphenylpyruvate dioxygenase

Biliary Tract/Liver/Pancreas Table

HRAS

11p15.5

HRAS; v-Ha-ras Harvey rat sarcoma viral oncogene homolog

Adrenal Medulla and Paraganglia Table; Bladder Urothelial Carcinoma; Bone and Soft Tissue Table; Costello Syndrome; Familial Nonmedullary Thyroid Carcinoma; Medullary Thyroid Carcinoma; Hereditary Neuroblastoma; Pheochromocytoma and Paraganglioma; Pituitary Carcinoma; PTEN-Hamartoma Tumor Syndromes; Prostate Carcinoma; RASopathies: Noonan Syndrome; Rhabdomyosarcoma; Salivary Glands Table; Squamous Cell Carcinoma

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

HRPT2

1q25

CDC73; cell division cycle 73

Bone and Soft Tissue Table; Head and Neck Table; Familial Isolated Hyperparathyroidism; Hyperparathyroidism-Jaw Tumor Syndrome; Hereditary Renal Epithelial Tumors, Others; Kidney Table; McCuneAlbright Syndrome; Multiple Endocrine Neoplasia Type 1 (MEN1); Multiple Endocrine Neoplasia Type 4 (MEN4); Parathyroid Adenoma; Parathyroid Carcinoma; Parathyroid Table; Primary Parathyroid Hyperplasia

HSPBAP1

3q21.1

HSPBAP1; HSPB (heat shock 27kDa) associated protein 1

Hereditary Renal Epithelial Tumors, Others; Kidney Table

IDH1

2q33.3

IDH1; isocitrate dehydrogenase 1 (NADP+), soluble

Bone and Soft Tissue Table; Chondrosarcoma; Gynecologic Tumors; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Osteosarcoma; Prostate Carcinoma

IDH2

15q26.1

IDH2; isocitrate dehydrogenase 2 (NADP+), mitochondrial

Adrenal Medullary and Paraganglia Table; Bone and Soft Tissue Table; Chondrosarcoma; Gynecologic Tumors; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Osteosarcoma

IGF2

11p15.5

IGF2; insulin-like growth factor 2

Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Beckwith-Wiedemann Syndrome; Colonic Carcinoma Syndromes; Kidney Table; Rhabdomyosarcoma; Wilms Tumor; Wilms TumorAssociated Syndromes

JAG1

20p12.1-p11.23

JAG1; jagged 1

Biliary Tract/Liver/Pancreas Table

JAK2

9p24

JAK2; Janus kinase 2

Down Syndrome

JAZF1-JJAZ1

t(7;17)(p15;q11)

JAZF1-JJAZ1

Bone and Soft Tissue Table

JAZF1-PHF1

t(6;7)(p21;p15)

JAZF1-PHF1

Bone and Soft Tissue Table

KCNIP4

4p15.32

KCNIP4; Kv channel interacting protein 4

Hereditary Renal Epithelial Tumors, Others; Kidney Table

KCNQ1

11p15.5

KCNQ1; potassium voltage-gated channel, KQT-like subfamily, member 1

Adrenal Cortical Neoplasms in Children; BeckwithWiedemann Syndrome

KCNQ1OT1/LIT1

11p15

KCNQ1OT1; KCNQ1 opposite strand/antisense transcript 1 (non-protein coding)

Adrenal Cortical Neoplasms in Children; BeckwithWiedemann Syndrome; Kidney Table; Wilms Tumor; Wilms Tumor-Associated Syndromes;

KIF1B

1p36.2

kinesin family member 1B

Adrenal Medulla and Paraganglia Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Pheochromocytoma and Paraganglioma

KIT

4q11-q12

KIF1B; v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

Bone and Soft Tissue Table; Esophagus/Stomach/Small Bowel Table; Familial Gastrointestinal Stromal Tumor; Familial Testicular Tumor; Gastrointestinal Stromal Tumor; Neurofibromatosis Type 1; Pheochromocytoma and Paraganglioma; Tuberous Sclerosis Complex

KITLG

12q22

KITLG; KIT ligand

Familial Testicular Tumor; Testicle Table

KLLN

10q23

KLLN; killin, p53-regulated DNA replication inhibitor

Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; PTEN-Hamartoma Tumor Syndromes

KMT2D

12q13.12

KMT2D; lysine methyltransferase 2D

Bladder Urothelial Carcinoma

KRAS

12p12.1

KRAS; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

Adenocarcinoma, Lung; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Central Nervous System; Colonic Carcinoma Syndromes; Costello Syndrome; Familial Adenomatous Polyposis; Familial Nonmedullary Thyroid Carcinoma; Hereditary Neuroblastoma; Medullary Thyroid Carcinoma; MUTYH-Associated Polyposis; Pancreatic Adenocarcinoma; RASopathies: Noonan Syndrome; Rhabdomyosarcoma

KRT16

17q21.2

KRT16; keratin 16

Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer

KRT17

17q21.2

KRT17; keratin 17

Howel-Evans Syndrome/Keratosis Palmares and

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

811

Reference: Molecular Factors

Molecular Factors Index

812

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Plantares With Esophageal Cancer; Steatocystoma Multiplex

KRT6

12q13.13

KRT72; keratin 72

Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer

LMNA

1q22

LMNA; lamin A/C

Werner Syndrome/Progeria

LSAMP

3q13.2-q21

LSAMP; limbic system-associated membrane protein

Hereditary Renal Epithelial Tumors, Others; Kidney Table

MAX

14q23

MAX; MYC-associated factor X

Adrenal Medulla and Paraganglia Table; Adrenal Medullary Hyperplasia; Familial Gastrointestinal Stromal Tumor; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma

MC1R

16q24.3

MC1R; melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)

Cutaneous Melanoma; Melanoma/Pancreatic Carcinoma Syndrome

MDM2

12q15

MDM2; MDM2 oncogene, p53 E3 ubiquitin protein ligase homolog

Bone and Soft Tissue Table; Hereditary Retinoblastoma; L-Fraumeni Syndrome; Parathyroid Adenoma; Salivary Glands Table

MDM4

1q32

MDM4; Mdm4 p53 binding protein homolog Hereditary Retinoblastoma

MDR1

7q21.12

ABCB1; ATP-binding cassette, sub-family B (MDR/TAP), member 1

Adrenal Cortical Carcinoma

MDR3

7q21.1

ABCB4; ATP-binding cassette, sub-family B (MDR/TAP), member 4

Biliary Tract/Liver/Pancreas Table

MECT1

19p13

MECT1; mucoepidermoid carcinoma translocated 1

Salivary Glands Table

MECT1-MAML2

t(11;19)(q21-22;p13)

MEK1

15q22.1-q22.33

MAP2K1; mitogen-activated protein kinase kinase 1

Familial Nonmedullary Thyroid Carcinoma; Hereditary Neuroblastoma; RASopathies: Noonan Syndrome

MEK2

19p13.3

MEK2; mitogen-activated protein kinase kinase 2

Familial Nonmedullary Thyroid Carcinoma; RASopathies: Noonan Syndrome

MEN1

11q13

MEN1; multiple endocrine neoplasia I

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Bone and Soft Tissue Table; Biliary Tract/Liver/Pancreas Table; Endocrine Pancreas Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Familial Gastrointestinal Stromal Tumor; Familial Isolated Hyperparathyroidism; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Lung Table; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Multiple Endocrine Neoplasia Type 1 (MEN1); Multiple Endocrine Neoplasia Type 4 (MEN4); Neuroendocrine Tumor, Lung; Pancreatic Neuroendocrine Tumor Syndromes; Pancreatic Neuroendocrine Neoplasms; Parathyroid Table; Parathyroid Adenoma; Parathyroid Carcinoma; Pituitary Table; Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Primary Parathyroid Hyperplasia

MET

7q31

MET; met protooncogene (hepatocyte growth factor receptor)

Adenocarcinoma, Lung; Adrenal Medulla and Paraganglia Table; Esophageal Squamous Cell Carcinoma; Familial Nonmedullary Thyroid Carcinoma; Hepatocellular Carcinoma; Hereditary Papillary Renal Cell Carcinoma; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Papillary Renal Cell Carcinoma

MLH1

3p21.3

MLH1; mutL homolog 1

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma

Salivary Glands Table

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Syndromes; Colon/Rectum Table; Endometrial Carcinoma; Esophagus/Stomach/Small Bowel Table; Eye; Gynecologic Tumors; Hereditary Pancreatic Cancer Syndrome; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Pathology of Familial Tumor Syndromes; Renal Pelvis and Ureter Table; Renal Urothelial Carcinoma; Sebaceous Carcinoma; Small Bowel Adenocarcinoma

MLK1

14q24.2

MLK1; a.k.a. MEKK9, MLK1, PRKE1; MAP3K9, mitogen-activated protein kinase 9; MLK1 myosin light chain kinase

Prostate Carcinoma

MPL

1p34

MPL; myeloproliferative leukemia virus oncogene

Down Syndrome

MRE11A

11q21

MRE11A; MRE11 meiotic recombination 11 homolog A

Ataxia-Telangiectasia

MSH2

2p21

MSH2; mutS homolog 2

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Colon/Rectum Table; Endometrial Carcinoma; Esophagus/Stomach/Small Bowel Table; Eye; Gynecologic Tumors; Hereditary Pancreatic Cancer Syndrome; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Pathology of Familial Tumor Syndromes; Prostate Carcinoma; Renal Pelvis and Ureter Table; Renal Urothelial Carcinoma; Sebaceous Carcinoma; Small Bowel Adenocarcinoma; Ureter Urothelial Carcinoma

MSH6

2p16

MSH6; mutS homolog 6

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Colon/Rectum Table; Endometrial Carcinoma; Esophagus/Stomach/Small Bowel Table; Eye; Gynecologic Tumors; Hereditary Pancreatic Cancer Syndrome; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Pathology of Familial Tumor Syndromes; Prostate Carcinoma; Renal Pelvis and Ureter Table; Renal Urothelial Carcinoma; Sebaceous Carcinoma; Small Bowel Adenocarcinoma  

MSR1

8p22

MSR1; macrophage scavenger receptor 1

Esophageal Adenocarcinoma; Gastric Adenocarcinoma

MUTYH/MYH

1p34.1

MUTYH; mutY homolog

Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Colon/Rectum Table; Esophagus/Stomach/Small Bowel Table; Familial Adenomatous Polyposis; Gastric Adenocarcinoma; Hereditary Mixed Polyposis Syndrome; Lynch Syndrome; MUTYH-Associated Polyposis; PTENHamartoma Tumor Syndromes; Small Bowel Adenocarcinoma

MYB-NFIB

t(6;9)(q22-23;p24)

MYB-NFIB

Salivary Glands Table

MYC

8q24

MYC; v-myc myelocytomatosis viral oncogene homolog

Adrenal Medullary Hyperplasia; Adrenal Medulla and Paraganglia Table; Breast/Ovarian Cancer Syndrome:

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

813

Reference: Molecular Factors

Molecular Factors Index

814

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced BRCA1; Hepatocellular Carcinoma; Neuroendocrine Tumor, Lung; Rhabdoid Predisposition Syndrome; Wilms Tumor

MYCN

2p24.3

MYCN; v-myc myelocytomatosis viral related oncogene, neuroblastoma derived

Hereditary Neuroblastoma; Neuroblastic Tumors of Adrenal Gland

NBN/NBS1

8q21

NBN; nibrin

Blood and Bone Marrow Table; Bone and Soft Tissue Table; Breast Carcinoma; Chordoma; Familial Chordoma; Hereditary Prostate Cancer; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Nijmegen Breakage Syndrome; Rhabdomyosarcoma

NDP

Xp11.4

NDP; Norrie disease (pseudoglioma)

Eye

NF1

17q11.2

NF1; neurofibromin 1

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Adrenal Medulla and Paraganglia Table; Biliary Tract/Liver/Pancreas Table; Bone and Soft Tissue Table; Breast Carcinoma; Brooke-Spiegler Syndrome; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Cutaneous Melanoma; Endocrine Pancreas Table; Esophagus/Stomach/Small Bowel Table; Eye; Familial Gastrointestinal Stromal Tumor; Gastrointestinal Stromal Tumor; Hereditary Neuroblastoma; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Kidney Table; Malignant Peripheral Nerve Sheath Tumor; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Multiple Endocrine Neoplasia Type 2 (MEN2); Myeloid Neoplasms; Neuroblastic Tumors of Adrenal Gland; Neurofibromatosis Type 1; Pancreatic Adenocarcinoma; Pancreatic Neuroendocrine Neoplasms; Pancreatic Neuroendocrine Tumor Syndromes; Peripheral Nervous System; Pheochromocytoma and Paraganglioma; RASopathies: Noonan Syndrome; Rhabdomyosarcoma; Schwannoma

NF2

22q12.2

NF2; neurofibromin 2

Bone and Soft Tissue Table; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Eye; Head and Neck Table; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Neurofibromatosis Type 1; Neurofibromatosis Type 2; Papillary Renal Cell Carcinoma; Peripheral Nervous System; Schwannoma; Schwannomatosis

NHP2

5q35.3

NHP2; NHP2 ribonucleoprotein

Blood and Bone Marrow Table; Dyskeratosis Congenita

NKX3-1

8p21.2

NKX3-1; NK3 homeobox 1

Prostate Carcinoma

NMTC1

2q21

NMTC1; Nonmedullary thyroid carcinoma 1

Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma

NOLA2

5q35.3

NHP2; NHP2 ribonucleoprotein

Blood and Bone Marrow Table

NOLA3

15q14-q15

NOP10; NOP10 ribonucleoprotein

Blood and Bone Marrow Table

NORE1

1q32.1

RASSF5; Ras association (RalGDS/AF-6) domain family member 5

Hereditary Renal Epithelial Tumors, Others

NOTCH1

9q34.3

NOTCH1; notch 1

Blood and Bone Marrow Table; Squamous Cell Carcinoma

NOTCH2

1p13-p11

NOTCH2; notch 2

Biliary Tract/Liver/Pancreas Table

NRAS

1p13.2

NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog

Blood and Bone Marrow Table; Colonic Carcinoma Syndromes; Costello Syndrome; Cutaneous Melanoma; Familial Nonmedullary Thyroid Carcinoma; Hereditary Neuroblastoma; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Medullary Thyroid Carcinoma; RASopathies: Noonan Syndrome

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

NSD1

5q35

NSD1; nuclear receptor binding SET domain protein 1

Adrenal Cortex Table; Adrenal Cortical Neoplasms in Children; Beckwith-Wiedemann Syndrome

NTRK1

1q22

NTRK1; neurotrophic tyrosine kinase, receptor, type 1

Bone and Soft Tissue Table; Familial Nonmedullary Thyroid Carcinoma; Hereditary Renal Epithelial Tumors, Others; Kidney Table

NTRK3-ETV6

t(12;15)(p13;q25)

NTRK3-ETV6

Bone and Soft Tissue Table; Familial Gastrointestinal Stromal Tumor; Familial Infantile Myofibromatosis; Rhabdomyosarcoma; Salivary Glands Table

NUT

15q14

NUTM1; NUT midline carcinoma, family member 1

Bone and Soft Tissue Table; Squamous Cell Carcinoma

OCA2

15q

OCA2; oculocutaneous albinism II

Melanoma/Pancreatic Carcinoma Syndrome

P14/ARF

9p21

CDKN2A; cyclin-dependent kinase inhibitor 2A

Adrenal Medulla and Paraganglia Table; Biliary Tract/Liver/Pancreas Table; Bone and Soft Tissue Table; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Cutaneous Melanoma; Endocrine Pancreas Table; Familial Chordoma; Familial Uveal Melanoma; Hepatocellular Carcinoma; Hereditary Pancreatic Cancer Syndrome; Malignant Peripheral Nerve Sheath Tumor; Melanoma/Pancreatic Carcinoma Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Pancreatic Adenocarcinoma; Papillary Renal Cell Carcinoma; Pheochromocytoma and Paraganglioma; Salivary Glands Table; Squamous Cell Carcinoma  

P15

9p21

CDKN2B; cyclin-dependent kinase inhibitor 2B

Familial Isolated Hyperparathyroidism; Melanoma/Pancreatic Carcinoma Syndrome; Papillary Renal Cell Carcinoma

P57KIP2

11p15.5

CDKN1C; cyclin-dependent kinase inhibitor 1C

Adrenal Cortex Table; Adrenal Cortical Neoplasms in Children; Beckwith-Wiedemann Syndrome; Hereditary Neuroblastoma; Kidney Table; Rhabdomyosarcoma; Wilms Tumor; Wilms Tumor-Associated Syndromes

PALB2

16p12.2

PALB2; partner and localizer of BRCA2

Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Breast Table; Breast Carcinoma; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Gastric Adenocarcinoma; Gynecologic Tumors; Fanconi Anemia; Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Li-Fraumeni Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Prostate Carcinoma

PAX3

2q35

PAX3; paired box 3

Bone and Soft Tissue Table; Rhabdomyosarcoma

PAX3/7-FOXO1

t(2;13)(q35;q14) or t(1;13)(p36;q14)

PAX3-FOXO1; PAX7-FOXO1

Bone and Soft Tissue Table; Rhabdomyosarcoma

PAX3FOXO1/PAX3FKHR

t(2;13)(q35;q14)

PAX3-FOXO1

Bone and Soft Tissue; Rhabdomyosarcoma

PAX5

9p13

PAX5; paired box 5

Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma; Blood and Bone Marrow Table

PAX6

11p13

PAX6; paired box 6

Wilms Tumor; Wilms Tumor-Associated Syndromes

PAX7FOXO1/PAX7FKHR

t(1;13)(p36;q14)

PAX7-FOXO1

Bone and Soft Tissue Table; Rhabdomyosarcoma

PBRM1

3p21

PBRM1; polybromo 1

Clear Cell Renal Cell Carcinoma; Hereditary SWI/SNF Complex Deficiency Syndromes

PDE11A

2q31-2q35

PDE11A; phosphodiesterase 11A

Primary Pigmented Nodular Adrenocortical Disease

PDE8B

5q13.3

PDE8B; phosphodiesterase 8B

Primary Pigmented Nodular Adrenocortical Disease

PDGFRA

4q12

PDGFRA; platelet-derived growth factor

Bone and Soft Tissue Table; Carney Complex;

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

815

Reference: Molecular Factors

Molecular Factors Index

816

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

receptor, alpha polypeptide

Esophagus/Stomach/Small Bowel Table; Familial Gastrointestinal Stromal Tumor; Gastrointestinal Stromal Tumor; Neurofibromatosis Type 1; Osteosarcoma

PDS

7q31

SLC26A4; solute carrier family 26 (anion exchanger), member 4

Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma

PHD2

1q42.1

EGLN1; egl-9 family hypoxia-inducible factor 1

Adrenal Medulla and Paraganglia Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes

PHOX2B

4p12

PHOX2B; paired-like homeobox 2b

Hereditary Neuroblastoma; Neuroblastic Tumors of Adrenal Gland

PIK3CA

3q26.3

PIK3CA; phosphatidylinositol-4,5bisphosphate 3-kinase, catalytic subunit alpha

Beckwith-Wiedemann Syndrome; Colonic Carcinoma Syndromes; Endocrine Pancreas Table; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Follicular Thyroid Carcinoma; Pancreatic Neuroendocrine Tumor Syndromes; Parathyroid Carcinoma; Pituitary Table; PTEN-Hamartoma Tumor Syndromes; Renal Urothelial Carcinoma; Salivary Glands Table; Squamous Cell Carcinoma

PKC

16p11.2

PKC; proline-rich transmembrane protein 2

Pituitary Table

PLAG1

8q12

PLAG1; pleomorphic adenoma gene 1

Bone and Soft Tissue Table; Salivary Glands Table

PMS1

2q31.1

PMS1; PMS1 postmeiotic segregation increased 1

Pathology of Familial Tumor Syndromes

PMS2

7p22.2

PMS2; PMS2 postmeiotic segregation increased 2

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Biliary Tract/Liver/Pancreas Table; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Colon/Rectum Table; Endometrial Carcinoma; Esophagus/Stomach/Small Bowel Table; Gynecologic Tumors; Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Prostate Carcinoma; Renal Pelvis and Ureter Table; Renal Urothelial Carcinoma; Small Bowel Adenocarcinoma

POLH

6p21.1

POLH; polymerase (DNA directed), eta

Eye; Xeroderma Pigmentosum

PRKAR1A

17q23-q24

PRKAR1A; protein kinase, cAMP-dependent, regulatory, type I, alpha

Adrenal Cortex Table; Adrenal Cortical Adenoma; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Bone and Soft Tissue Table; Carney Complex; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; DICER1 Syndrome; Familial Nonmedullary Thyroid Carcinoma; Familial Testicular Tumor; Familial Thyroid Carcinoma; Follicular Thyroid Carcinoma; Multiple Endocrine Neoplasia Type 1 (MEN1); Multiple Endocrine Neoplasia Type 4 (MEN4); Pathology of Familial Tumor Syndromes; Peripheral Nervous System; Pituitary Adenoma; Pituitary Table; Primary Pigmented Nodular Adrenocortical Disease; Schwannoma; Sertoli Cell Neoplasms; Testicle Table; Thyroid, Nonmedullary Carcinoma Table

PRSS1

7q34

PRSS1; protease, serine, 1 (trypsin 1)

Biliary Tract/Liver/Pancreas; Pancreatic Adenocarcinoma

PRSS2

7q34

PRSS2; protease, serine, 2 (trypsin 2)

Biliary Tract/Liver/Pancreas Table; Gastric Adenocarcinoma; Hereditary Pancreatic Cancer Syndrome

PTAG

22q12.2

RHBDD3; rhomboid domain containing 3

Pituitary Table

PTCH1

9q22.3

PTCH1; patched 1

Basal Cell Carcinoma; Basal Cell Nevus Syndrome/Gorlin Syndrome; Bone and Soft Tissue Table; Central Nervous System; Clinical Diagnosis and Management of

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Familial/Hereditary Tumor Syndromes; Eye; Gynecologic Tumors; Head and Neck Table

PTCH2

1p34.1

PTCH2; patched 2

Central Nervous System; Eye; Head and Neck Table

PTEN

10q23.31

PTEN; phosphatase and tensin homolog

Birt-Hogg-Dubé Syndrome; Breast Carcinoma; Breast Table; Carney Complex; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Carcinoma Syndromes; Colon/Rectum Table; DICER1 Syndrome; Endocrine Pancreas Table; Endometrial Carcinoma; Esophageal Adenocarcinoma; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Follicular Thyroid Carcinoma; Gynecologic Tumors; Hamartomatous Polyposis Syndromes; Head and Neck Table; Hepatocellular Carcinoma; Hereditary Renal Epithelial Tumors, Others; Juvenile Polyposis Syndrome; Kidney Table; Melanoma/Pancreatic Carcinoma Syndrome; Pancreatic Neuroendocrine Tumor Syndromes; Pathology of Familial Tumor Syndromes; Prostate Carcinoma; PTEN-Hamartoma Tumor Syndromes; Thyroid, Molecular Aspects of Familial/Hereditary Tumor Syndromes; Nonmedullary Carcinoma Table

PTPN11

12q24

PTPN11; protein tyrosine phosphatase, nonreceptor type 11

Blood and Bone Marrow Table; Bone and Soft Tissue Table; Carney Complex; Central Nervous System; Chondrosarcoma; Costello Syndrome; Hereditary Neuroblastoma; Neurofibromatosis Type 1; RASopathies: Noonan Syndrome; Rhabdomyosarcoma

PTTG

5q35.1

PTTG1; pituitary tumor-transforming 1

Pituitary Table

PYGL

14q21-q22

PYGL; phosphorylase, glycogen, liver

Biliary Tract/Liver/Pancreas Table

RAD50

5q31

RAD50; RAD50 homolog

Ataxia Telangiectasia; Nijmegen Breakage Syndrome

RAD51B

14q23-q24.2

RAD51B; RAD51 paralog B

Breast Carcinoma, Female

RAD51C

17q22

RAD51C; RAD51 paralog C

Breast Carcinoma

RAD51D

17q11

RAD51D; RAD51 paralog D

Breast Carcinoma; Gynecologic Tumors; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Prostate Carcinoma

RAF1

3p25

RAF1; v-raf-1 murine leukemia viral oncogene homolog 1

Blood and Bone Marrow Table; Bone and Soft Tissue Table; Central Nervous System; Costello Syndrome; Hereditary Neuroblastoma; RASopathies: Noonan Syndrome; Rhabdomyosarcoma

RAS

Multiple

RAS; Rat sarcoma oncogene

Adrenal Medulla and Paraganglia Table; Central Nervous System; Colonic Carcinoma Syndromes;  Costello Syndrome; Cutaneous Melanoma; Down Syndrome; Eye; Familial Gastrointestinal Stromal Tumor; Familial Nonmedullary Thyroid Carcinoma; Follicular Thyroid Carcinoma; Hereditary Neuroblastoma; Medullary Thyroid Carcinoma; Neuroblastic Tumors of Adrenal Gland; Neurofibromatosis Type 1; Pancreatic Adenocarcinoma; Peripheral Nervous System; Pituitary Table; RASopathies: Noonan Syndrome; Tuberous Sclerosis Complex

RB1/RB

13q14.2

RB1; retinoblastoma 1

Bladder Urothelial Carcinoma; Bone and Soft Tissue Table; Breast/Ovarian Cancer Syndrome: BRCA1; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Eye; Hepatocellular Carcinoma; Hereditary Retinoblastoma; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Neuroendocrine Tumor, Lung; Pituitary Table; Parathyroid Carcinoma; Osteosarcoma; Salivary Glands Table; Tumor Syndromes Predisposing to Osteosarcoma

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

817

Reference: Molecular Factors

Molecular Factors Index

818

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

RECQL4

8q24.3

RECQL4; RecQ protein-like 4

Bone and Soft Tissue Table; Dyskeratosis Congenita; Osteosarcoma; Tumor Syndromes Predisposing to Osteosarcoma; Xeroderma Pigmentosum

RET

10q11

RET; rearranged during transfection

Adenocarcinoma, Lung; Adrenal Medulla and Paraganglia Table; Adrenal Medullary Hyperplasia; Bone and Soft Tissue Table; C-Cell Hyperplasia; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Familial Isolated Hyperparathyroidism; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Head and Neck Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Medullary Thyroid Carcinoma; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Parathyroid Adenoma; Multiple Endocrine Neoplasia Type 1 (MEN1); Multiple Endocrine Neoplasia Type 2 (MEN2); Multiple Endocrine Neoplasia Type 4 (MEN4); Parathyroid Carcinoma; Parathyroid Table; Pheochromocytoma and Paraganglioma; Primary Parathyroid Hyperplasia; PTEN-Hamartoma Tumor Syndromes; Salivary Glands Table; Thyroid, Medullary Carcinoma Table

RHBDF2

17q25.1

RHBDF2; rhomboid 5 homolog 2

Esophageal Squamous Cell Carcinoma; Esophagus/Stomach/Small Bowel Table; Howel-Evans Syndrome/Keratosis Palmares and Plantares With Esophageal Cancer

RPS19

19q13.2

RPS19; ribosomal protein S19

Blood and Bone Marrow Table; Diamond-Blackfan Anemia

RTEL1

20q13.3

RTEL1; regulator of telomere elongation helicase 1

Blood and Bone Marrow Table; Dyskeratosis Congenita

RUNX1

21q22.3

RUNX1; runt-related transcription factor 1

Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma; Blood and Bone Marrow Table; Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome

SBDS

7q11.21

SBDS; Shwachman-Bodian-Diamond syndrome

Blood and Bone Marrow Table; Shwachman-Diamond Syndrome

SDH/SDHx

Multiple

Succinate dehydrogenase complex

Adrenal Medulla and Paraganglia Table; Adrenal Medullary Hyperplasia; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Esophagus/Stomach/Small Bowel Table; Familial Gastrointestinal Stromal Tumor; Familial Nonmedullary Thyroid Carcinoma; Familial Paraganglioma Pheochromocytoma Syndrome; Head and Neck Table; Familial Thyroid Carcinoma; Hereditary Renal Epithelial Tumors, Others; Gastrointestinal Stromal Tumor; Multiple Endocrine Neoplasia Type 2 (MEN2); Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Pituitary Table; PTEN-Hamartoma Tumor Syndromes; Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

SDHA

5p15

SDHA; succinate dehydrogenase complex, subunit A, flavoprotein

Adrenal Medulla and Paraganglia Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Esophagus/Stomach/Small Bowel Table; Familial Gastrointestinal Stromal Tumor; Familial Paraganglioma Pheochromocytoma Syndrome; Gastrointestinal Stromal Tumor; Head and Neck Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Multiple Endocrine Neoplasia Type 2 (MEN2); Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Pituitary Table; Succinate DehydrogenaseDeficient Renal Cell Carcinoma; von Hippel-Lindau

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Syndrome

SDHAF2

11q12.2

SDHAF2; succinate dehydrogenase complex assembly factor 2

Adrenal Medulla and Paraganglia Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Familial Paraganglioma Pheochromocytoma Syndrome; Head and Neck Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Multiple Endocrine Neoplasia Type 2 (MEN2); Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Pituitary Table; Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

SDHB

1p36

SDHB; succinate dehydrogenase complex, subunit B, iron sulfur

Adrenal Medulla and Paraganglia Table; Adrenal Medullary Hyperplasia; Bone and Soft Tissue Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Esophagus/Stomach/Small Bowel Table; Familial Gastrointestinal Stromal Tumor; Familial Paraganglioma Pheochromocytoma Syndrome; Gastric Adenocarcinoma; Gastrointestinal Stromal Tumor; Head and Neck Table; Hereditary Neuroblastoma; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Multiple Endocrine Neoplasia Type 2 (MEN2); Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Pituitary Table; Succinate DehydrogenaseDeficient Renal Cell Carcinoma; von Hippel-Lindau Syndrome

SDHC

1q21-23

SDHC; succinate dehydrogenase complex, subunit C, integral membrane protein

Adrenal Medulla and Paraganglia Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Esophagus/Stomach/Small Bowel Table; Familial Paraganglioma Pheochromocytoma Syndrome; Gastrointestinal Stromal Tumor; Head and Neck Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Multiple Endocrine Neoplasia Type 2 (MEN2); Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Pituitary Table; Succinate DehydrogenaseDeficient Renal Cell Carcinoma

SDHD

11q23

SDHD; succinate dehydrogenase complex, subunit D, integral membrane protein

Adrenal Medulla and Paraganglia Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Esophagus/Stomach/Small Bowel Table; Familial Paraganglioma Pheochromocytoma Syndrome; Gastrointestinal Stromal Tumor; Head and Neck Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Multiple Endocrine Neoplasia Type 2 (MEN2); Pheochromocytoma and Paraganglioma; Pituitary Adenoma; Pituitary Table; Succinate Dehydrogenase-Deficient Renal Cell Carcinoma; von Hippel-Lindau Syndrome

SERPINA1

14q32.1

SERPINA1; serpin peptidase inhibitor, clade A Biliary Tract/Liver/Pancreas Table (alpha-1 antiproteinase, antitrypsin), member 1

SHH

7q36

SHH; sonic hedgehog

Rhabdoid Predisposition Syndrome

SHOC2

10q25

SHOC2; soc-2 suppressor of clear homolog

Costello Syndrome; RASopathies: Noonan Syndrome

SLC25A13

7q21.3

SLC25A13; solute carrier family 25 (aspartate/glutamate carrier), member 13

Biliary Tract/Liver/Pancreas Table

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

819

Reference: Molecular Factors

Molecular Factors Index

820

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced

SLC26A4

7q31

SLC26A4; solute carrier family 26, member 4

Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Thyroid, Nonmedullary Carcinoma Table

SMAD4

18q21.1

SMAD4; SMAD family member 4

Biliary Tract/Liver/Pancreas Table; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Carcinoma Syndromes; Colon/Rectum Table; Endocrine Pancreas Table; Esophagus/Stomach/Small Bowel Table; Gastric Adenocarcinoma; Hamartomatous Polyps, Peutz-Jeghers; Hamartomatous Polyposis Syndromes; Juvenile Polyposis Syndrome; Pancreatic Adenocarcinoma; Small Bowel Adenocarcinoma

SMARCA4/BRG1

19p13.2

SMARCA4; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4

Gynecologic Tumors; Hereditary SWI/SNF Complex Deficiency Syndromes; Ovarian Tumors; Rhabdoid Predisposition Syndrome

SMARCB1/INI1/B 22q11 AF47/hSNF5

SMARCB1; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1

Bone and Soft Tissue Table; Central Nervous System; Chordoma; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Familial Chordoma; Hereditary SWI/SNF Complex Deficiency Syndromes; Malignant Peripheral Nerve Sheath Tumor; Peripheral Nervous System; Rhabdoid Predisposition Syndrome; Schwannoma; Schwannomatosis

SMARCE1

17q21.2

SMARCE1; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1

Central Nervous System; Hereditary SWI/SNF Complex Deficiency Syndromes

SMO

7q32.3

SMO; smoothened, frizzled family receptor

Basal Cell Carcinoma

SOS1

2p21

SOS1; son of sevenless homolog 1

Blood and Bone Marrow Table; Bone and Soft Tissue Table; Central Nervous System; Costello Syndrome; Hereditary Neuroblastoma; RASopathies: Noonan Syndrome; Rhabdomyosarcoma

SOX9

17q23

SOX9; SRY (sex determining region Y)-box 9

Colonic Carcinoma Syndromes

SPINK1

5q32

SPINK1; serine peptidase inhibitor, Kazal type Adrenal Cortical Carcinoma; Biliary Tract/Liver/Pancreas 1 Table; Hereditary Pancreatic Cancer Syndrome; Pancreatic Adenocarcinoma

SPOP

17q21.33

SPOP; speckle-type POZ protein

Prostate Carcinoma

SPRED1

15q14

SPRED1; sprouty-related, EVH1 domain containing 1

Costello Syndrome; RASopathies: Noonan Syndrome

SPRY4

5q31.3

SPRY4; sprouty homolog 4

Familial Testicular Tumor; Testicle Table

SRP72

4q11

SRP72; signal recognition particle 72kDa

Blood and Bone Marrow Table; Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome; Pathology of Familial Tumor Syndromes

SS18/SYT

18q11.2

SS18; synovial sarcoma translocation, chromosome 18

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor

SS18L1-SSX1

t(X;20)(p11.23;q13.3)

SS18L1-SSX1

Bone and Soft Tissue Table

SSX

Multiple

Synovial sarcoma, X

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor; Rhabdomyosarcoma

SSX1

Xp11.23

SSX1; synovial sarcoma, X breakpoint 1

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor; Rhabdomyosarcoma

SSX2

Xp11.22

SSX2; synovial sarcoma, X breakpoint 2

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor; Rhabdomyosarcoma

SSX4

Xp11.23

SSX4; synovial sarcoma, X breakpoint 4

Bone and Soft Tissue Table; Malignant Peripheral Nerve Sheath Tumor; Rhabdomyosarcoma

STK11/LKB1

19p13.3

STK11; serine/threonine kinase 11

Biliary Tract/Liver/Pancreas Table; Breast Carcinoma; Carney Complex; Breast Table; Cervical Carcinoma; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Carcinoma Syndromes; Colon/Rectum Table; Endometrial Carcinoma; Esophagus/Stomach/Small

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Bowel Table; Familial Testicular Tumor; Gastric Adenocarcinoma; Gynecologic Tumors; Hamartomatous Polyposis Syndromes; Hamartomatous Polyps, PeutzJeghers; Head and Neck Table; Hereditary Pancreatic Cancer Syndrome; Lung Table; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Ovarian Tumors; Pancreatic Adenocarcinoma; Testicle Table; Sertoli Cell Neoplasms; Small Bowel Adenocarcinoma

SUFU

10q24.32

SUFU; suppressor of fused homolog

Central Nervous System; Eye

TACSTD1

2p21

EPCAM; epithelial cell adhesion molecule

Colonic Adenomas; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Carcinoma Syndromes; Endometrial Carcinoma; Esophagus/Stomach/Small Bowel Table; Lynch Syndrome; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Renal Urothelial Carcinoma; Small Bowel Adenocarcinoma

TAT

16q22.1

TAT; tyrosine aminotransferase

Biliary Tract/Liver/Pancreas Table

TCAB1

17p13.1

WRAP53; WD repeat containing, antisense to TP53

Blood and Bone Marrow Table; Dyskeratosis Congenita

TCF12-NR4A3

t(9;15)(q22;q21)

TERC

3q26

TERC; telomerase RNA component

Blood and Bone Marrow Table; Dyskeratosis Congenita; Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome; Head and Neck Table; Squamous Cell Carcinoma

TERT

5p15.33

TERT; telomerase reverse transcriptase

Blood and Bone Marrow Table; Bone and Soft Tissue Table; Dyskeratosis Congenita; Familial Acute Myeloid Leukemia and Myelodysplastic Syndrome; Familial Nonmedullary Thyroid Carcinoma; Familial Testicular Tumor; Follicular Thyroid Carcinoma; Head and Neck Table; Hepatocellular Carcinoma; Melanoma/Pancreatic Carcinoma Syndrome; Papillary Renal Cell Carcinoma; Squamous Cell Carcinoma; Testicle Table

TGFBR3-MGEA5

t(1;10)(p22;q24)

TINF2

14q12

TINF2; TERF1 (TRF1)-interacting nuclear factor 2

Blood and Bone Marrow Table; Dyskeratosis Congenita; Head and Neck Table; Squamous Cell Carcinoma

TMEM127

2q11.2

TMEM127; transmembrane protein 127

Adrenal Medulla and Paraganglia Table; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma

TMPRSS2

21q22.3

TMPRSS2; transmembrane protease, serine 2 Prostate Carcinoma

TP53

17p13.1

TP53; tumor protein p53

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

Bone and Soft Tissue Table

Bone and Soft Tissue Table

Adrenal Cortex Table; Adrenal Cortical Carcinoma; Adrenal Cortical Neoplasms in Children; Adrenal Medulla and Paraganglia Table; Basal Cell Carcinoma; Biliary Tract/Liver/Pancreas Table; Bladder Urothelial Carcinoma; Blood and Bone Marrow Table; Bone and Soft Tissue Table; Breast Carcinoma; Breast/Ovarian Cancer Syndrome: BRCA1; Breast/Ovarian Cancer Syndrome: BRCA2; Breast Table; Central Nervous System; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Colonic Adenomas; Colonic Carcinoma Syndromes; Colon/Rectum Table; Dyskeratosis Congenita; Fallopian Tube Carcinoma; Familial Uveal Melanoma; Familial Wilms Tumor; Follicular Thyroid Carcinoma; Gynecologic Tumors; Hepatocellular Carcinoma; Hereditary Neuroblastoma; Hereditary Pancreatic Cancer Syndrome; Hereditary Prostate Cancer; Hyperparathyroidism-Jaw Tumor Syndrome; Li-Fraumeni Syndrome; Lung Table; Malignant Peripheral Nerve

821

Reference: Molecular Factors

Molecular Factors Index

822

Molecular Factors Discussed (Continued) Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Sheath Tumor; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Neuroendocrine Tumor, Lung; Osteosarcoma; Pancreatic Adenocarcinoma; Pathology of Familial Tumor Syndromes; Pheochromocytoma and Paraganglioma; Renal Urothelial Carcinoma; Salivary Glands Table; Shwachman-Diamond Syndrome; Squamous Cell Carcinoma; Thyroid, Nonmedullary Carcinoma Table; Prostate Carcinoma; Wilms Tumor; Tumor Syndromes Predisposing to Osteosarcoma  

TRC8

8q24

TRC8; RNF139; ring finger protein 139

Hereditary Renal Epithelial Tumors, Others

TRPS1

8q24.12

TRPS1; trichorhinophalangeal syndrome I

Multiple Osteochondromas

TSC1

9q34

TSC1; tuberous sclerosis 1

Angiomyolipoma; Biliary Tract/Liver/Pancreas Table; BirtHogg-Dubé Syndrome; Bone and Soft Tissue Table; Brooke-Spiegler Syndrome; Central Nervous System; Chordoma; Endocrine Pancreas Table; Eye; Familial Chordoma; Gynecologic Tumors; Head and Neck Table; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Lung Table; Pancreatic Neuroendocrine Neoplasms; Pancreatic Neuroendocrine Tumor Syndromes; Tuberous Sclerosis Complex

TSC2/PKD1

16p13.3

TSC2; tuberous sclerosis 2

Angiomyolipoma; Biliary Tract/Liver/Pancreas Table; BirtHogg-Dubé Syndrome; Bone and Soft Tissue Table; Brooke-Spiegler Syndrome; Central Nervous System; Chordoma; Endocrine Pancreas Table; Eye; Familial Chordoma; Gynecologic Tumors; Head and Neck Table; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Lung Table; Pancreatic Neuroendocrine Neoplasms; Pancreatic Neuroendocrine Tumor Syndromes; Tuberous Sclerosis Complex

TSHR

14q31

TSHR; thyroid stimulating hormone receptor Familial Nonmedullary Thyroid Carcinoma

TYR

11q14.3

TYR; tyrosinase

Rhabdoid Predisposition Syndrome;

USB1/C16orf57

16q21

USB1; U6 snRNA biogenesis 1

Dyskeratosis Congenita

USP6

17p13

USP6; ubiquitin specific peptidase 6 (Tre-2 oncogene)

Bone and Soft Tissue Table; Osteosarcoma

VHL

3p25.3

VHL; von Hippel-Lindau tumor suppressor

Adrenal Medulla and Paraganglia Table; Biliary Tract/Liver/Pancreas Table; Bone and Soft Tissue Table; Central Nervous System; Clear Cell Renal Cell Carcinoma; Clinical Diagnosis and Management of Familial/Hereditary Tumor Syndromes; Endocrine Pancreas Table; Endolymphatic Sac Tumor; Eye; Gynecologic Tumors; Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome; Hereditary Paraganglioma/Pheochromocytoma Syndromes; Hereditary Renal Epithelial Tumors, Others; Kidney Table; Multiple Endocrine Neoplasia Type 2 (MEN2); Molecular Aspects of Familial/Hereditary Tumor Syndromes; Pancreatic Neuroendocrine Neoplasms; Pancreatic Neuroendocrine Tumor Syndromes; Pheochromocytoma and Paraganglioma; Salivary Glands Table; von Hippel-Lindau Syndrome

WAS

Xp11.4-p11.21

WAS; Wiskott-Aldrich syndrome

Blood and Bone Marrow Table; Wiskott-Aldrich Syndrome

WNT

Multiple

Wingless-type family

Adrenal Cortical Carcinoma; Central Nervous System; Colonic Carcinoma Syndromes; Eye; Peripheral Nervous System

WRN/RECQL2

8p12

WRN; Werner syndrome, RecQ helicase-like

Bone and Soft Tissue Table; Eye; Familial Nonmedullary Thyroid Carcinoma; Familial Thyroid Carcinoma; Follicular Thyroid Carcinoma; Osteosarcoma; Rhabdomyosarcoma; Thyroid, Nonmedullary Carcinoma Table; Tumor

Molecular Factors Index

Gene

Gene Location

Official Gene Symbol and Name

Chapter(s) Referenced Syndromes Predisposing to Osteosarcoma; Werner Syndrome/Progeria  

WT1

11p13

WT1; Wilms tumor 1

Beckwith-Wiedemann Syndrome; Bone and Soft Tissue Table; Denys-Drash Syndrome; DICER1 Syndrome; Familial Wilms Tumor; Kidney Table; Molecular Aspects of Familial/Hereditary Tumor Syndromes; Pathology of Familial Tumor Syndromes; Rhabdomyosarcoma; Wilms Tumor; Wilms Tumor-Associated Syndromes

WT2

19q13.4

Genetic linkage region (no specific gene identified)

Familial Wilms Tumor; Kidney Table; Wilms Tumor

WTX/FAM123B

Xq11.2

AMER1; APC membrane recruitment protein Colonic Carcinoma Syndromes; Wilms Tumor 1

XPA

9q22.3

XPA; xeroderma pigmentosum, complementation group A

Esophageal Adenocarcinoma; Eye; Head and Neck Table; Lung Table; Squamous Cell Carcinoma; Xeroderma Pigmentosum

XPA-XPG

Multiple

Xeroderma pigmentosum, complementation group A through G

Head and Neck Table; Squamous Cell Carcinoma

XPB

2q21

ERCC3; excision repair cross-complementing Lung Table; Xeroderma Pigmentosum rodent repair deficiency, complementation group 3

XPC

3p25

XPC; xeroderma pigmentosum, complementation group C

XPD

19q13.3

ERCC2; excision repair cross-complementing Esophageal Adenocarcinoma; Lung Table; Xeroderma rodent repair deficiency, complementation Pigmentosum group 2

XPE

11q12-q13

DDB1; damage-specific DNA binding protein Lung Table; Xeroderma Pigmentosum 1

XPF

16p13.12

ERCC4; excision repair cross-complementing Lung Table; Xeroderma Pigmentosum rodent repair deficiency, complementation group 4

XPG

13q33

ERCC5; excision repair cross-complementing Head and Neck Table; Lung Table; Squamous Cell rodent repair deficiency, complementation Carcinoma; Xeroderma Pigmentosum group 5

Reference: Molecular Factors

Molecular Factors Discussed (Continued)

Esophageal Adenocarcinoma; Lung Table; Xeroderma Pigmentosum

823

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INDEX

A

ABCB11 gene, 804–823 Abdominal pain - familial Wilms tumor, 605 - Peutz-Jeghers polyposis syndrome, 745 Acantholytic SCC, head and neck squamous cell carcinoma, 396 ACD gene, melanoma/pancreatic carcinoma syndrome, 692 Acinar adenocarcinoma, lung adenocarcinoma vs., 428 Acinar cell carcinoma, 129 - pancreatic neuroendocrine neoplasms vs., 122 Acinic cell carcinoma - familial cancer syndromes with salivary gland neoplasms, 404 - molecular changes described in salivary gland tumors (table), 405–406 - pancreatic adenocarcinoma vs., 224 - salivary gland neoplasms with familial clustering (table), 404 Acquired cystic kidney disease, von Hippel-Lindau (VHL) syndrome vs., 784 Acquired palmoplantar keratoderma, as paraneoplastic phenomenon, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 Acral nevus, cutaneous melanoma vs., 458 Acrochordons, associated with Birt-Hogg-Dubé syndrome, 518 Acrogeria, Werner syndrome/progeria vs., 791 Acromegaly - multiple endocrine neoplasia type 4, 713 - pituitary hyperplasia, 165 ACTH-producing NET, pancreatic neuroendocrine tumor, 121, 123 Actinic keratosis, basal cell carcinoma vs., 452 Acute lymphoblastic leukemia (ALL), 4–5 - age-specific hematologic abnormalities in Down syndrome, 558 - age-specific hematological malignancies in DS children and risk compared to non-DS peers, 558 - due to germline ETV6 mutations, 5 - due to germline IKZF1 mutations, 5 - due to germline PAX5 mutations, 5 - due to germline SH2B3 mutations, 5 - genetic testing, 5 Acute megakaryoblastic leukemia, age-specific hematological malignancies in DS children and risk compared to non-DS peers, 558

Acute myeloid leukemia (AML). See also Familial acute myeloid leukemia. - age-specific hematological malignancies in DS children and risk compared to non-DS peers, 558 Adenocarcinoma - endolymphatic sac tumor vs., 392 - of esophagus, familial neoplasia of esophagus, stomach, and small intestine (table), 271 - from extrathoracic origin, lung adenocarcinoma vs., 428 - familial colon and rectum tumors by syndrome, 268–269 - lung, 426–431 association with familial syndromes, 427 diagnostic checklist, 428 differential diagnosis, 428 environmental exposure, 427 genetic alterations, 427 prognosis, 427 - metastatic chordoma vs., 16 small bowel adenocarcinoma vs., 263 - pancreatic, 222–225 cytogenetics, 223–224 differential diagnosis, 224 molecular genetics, 223–224 prognosis, 223 - polymorphous low-grade, molecular changes described in salivary gland tumors (table), 405–406 - small bowel, 262–267 differential diagnosis, 265 Adenocarcinoma in situ (AIS). See also Adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern. - lung adenocarcinoma vs., 428 Adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern, 432–433 - diagnostic checklist, 433 - differential diagnosis, 433 - environmental exposure, 433 - familial syndromes associated, 433 - genetic alterations, 433 - prognosis, 433 Adenoid cystic carcinoma, molecular changes described in salivary gland tumors (table), 405–406 Adenoma - ceruminous, endolymphatic sac tumor vs., 393 - corticotroph cell, pituitary hyperplasia vs., 165 - familial isolated pituitary, multiple endocrine neoplasia type 1 vs., 699 - familial neoplasia colon and rectum (table), 268–269 - hepatic, hepatoblastoma vs., 214 - multiple endocrine neoplasia type 1, 700 i

INDEX - parathyroid, 130–135 diagnostic checklist, 134 differential diagnosis, 134 double, primary parathyroid hyperplasia vs., 146 genetic testing, 134 hereditary, 131 primary parathyroid hyperplasia vs., 146 sporadic, 131 triple, primary parathyroid hyperplasia vs., 146 - pituitary, 158–163 differential diagnosis, 160 genetic predisposition, 161 immunohistochemical classification, 161 pituitary hyperplasia vs., 165 prognosis, 160 Adenoma malignum of cervix. See also Cervical carcinoma. - Peutz-Jeghers polyposis syndrome, 746 Adenoma with high-grade dysplasia, small bowel adenocarcinoma vs., 263 Adenomas - colonic, 228–233 diagnostic checklist, 232 differential diagnosis, 232 prognosis, 230 - hamartomatous polyps of GI tract vs., 254 - pituitary genetic abnormalities, 167 inherited tumor syndrome, 166–167 Adenomatous hyperplasia, atypical, adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern vs., 433 Adenomatous nodule, follicular thyroid carcinoma vs., 203 Adenomatous polyposis coli (APC). See Familial adenomatous polyposis (FAP). Adenosquamous carcinoma, head and neck squamous cell carcinoma, 396 Adnexal carcinoma - microcystic, basal cell carcinoma vs., 452 - other primary cutaneous, sebaceous carcinoma vs., 468 Adolescents, von Hippel-Lindau (VHL) syndrome, 783 Adrenal cortex neoplasms - adrenal cortical adenoma, 58–61 differential diagnosis, 60 genetic profile, 59–60 mutations in, 60 syndromes associated with, 59, 60 - adrenal cortical carcinoma, 62–69 diagnostic checklist, 65 differential diagnosis, 65 genetic testing, 64 hereditary syndromes associated with, 66 immunohistochemistry, 66 prognosis, 63–64 staging, 65 - adrenal cortical neoplasms in children, 70–77 diagnostic checklist, 72 differential diagnosis, 72 genetic testing, 72 as part of inherited tumor syndromes, 73 prognosis, 71–72 ii

- primary pigmented nodular adrenocortical disease, 78––83 diagnostic checklist, 80–81 differential diagnosis, 80 genetic abnormality, 79 genetic testing, 80 immunohistochemistry, 81 prognosis, 80 - table, 84–87 Adrenal cortical adenoma, 58–61. See also Adrenal cortical neoplasms, in children. - adrenal cortical carcinoma vs., 65 - adrenal cortical lesions associated with syndromes, 85 - differential diagnosis, 60, 85 - genetic profile, 59–60 - mutations in, 60 - syndromes associated with, 59, 60 Adrenal cortical carcinoma, 62–69. See also Adrenal cortical neoplasms, in children. - adrenal cortical adenoma vs., 60 - adrenal cortical lesions associated with syndromes, 85 - Beckwith-Wiedemann syndrome associated, 512 - clinical features suggesting familial adrenal cortical carcinoma, 84 - clinical settings associated with cytomegalic cells, 84 - criteria for differentiation between adenoma and carcinoma, 85 - diagnostic checklist, 65 - differential diagnosis, 65 - genetic testing, 64 - hereditary syndromes associated with, 66 - immunohistochemistry, 66, 86 - Li-Fraumeni syndrome, 676 - as part of inherited tumor syndromes, 84 - pheochromocytoma/paraganglioma vs., 107 - prognosis, 63–64 - staging, 65 Adrenal cortical hyperplasia, multiple endocrine neoplasia type 1, 700 Adrenal cortical lesions, multiple endocrine neoplasia type 1, 697 Adrenal cortical neoplasms, in children, 70–77 - diagnostic checklist, 72 - differential diagnosis, 72 - genetic testing, 72 - as part of inherited tumor syndromes, 73 - prognosis, 71–72 Adrenal cortical tumor. See Adrenal cortical neoplasms, in children. Adrenal cytomegaly, Beckwith-Wiedemann syndrome associated, 512 Adrenal gland, neuroblastic tumors of, 92–103 - diagnostic checklist, 97 - differential diagnosis, 97 - familial neuroblastoma, 96 - favorable and unfavorable histological groups, 98 - genetic events, 96 - genetic testing, 96 - INPC classification, 95 - natural history, 94

INDEX - prognosis, 94 - sporadic neuroblastoma, 96 Adrenal gland adenomas, hereditary leiomyomatosis and renal cell carcinoma, 625 Adrenal hyperplasia, corticotropin (ACTH)-independent bilateral macronodular, primary pigmented nodular adrenocortical disease vs., 80 Adrenal medullary hyperplasia (AMH), 88–91 - associated with genetic disorders, 89 - diagnostic checklist, 90 - differential diagnosis, 90 - as precursor lesion, 89 - sporadic, 89 Adrenal neoplasia, hereditary syndromes associated, 477 Adrenocortical adenoma, Cushing syndrome caused by, primary pigmented nodular adrenocortical disease vs., 80 Adrenocortical disease, primary pigmented nodular. See Primary pigmented nodular adrenocortical disease. Adult cystic nephroma (CN). See also Cystic nephroma. - DICER1 syndrome vs., 552 Adult premature aging syndrome. See Werner syndrome/progeria. Advanced interstitial lung disease, sarcoidosis with, lymphangioleiomyomatosis vs., 436 Aggressive angiomyxoma, molecular and cytogenic findings, 37–40 Aggressive malignant peripheral nerve sheath tumor, multiple endocrine neoplasia type 1, 697 AGL gene, 804–823 Aicardi syndrome - genetic syndromes associated with CNS neoplasms, 412 - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 AIP gene, 804–823 AJCC Staging for Bladder Cancer, 282 AKT1 gene, 804–823 Alagille syndrome, familial biliary tract, liver, and pancreas neoplasms, 226–227 Albright syndrome. See McCune-Albright syndrome. Alcohol-related liver disease, hepatocellular carcinoma, 219 ALDH2 gene, 804–823 Aldosterone-producing adrenal adenoma. See Adrenal cortical adenoma. ALK gene, 804–823 - mutations, hereditary neuroblastoma and, 633 ALL. See Acute lymphoblastic leukemia. Alveolar rhabdomyosarcoma, 29 - differential diagnosis, 30 - genetic testing, 30 - molecular and cytogenic findings, 37–40 - neuroblastoma vs., 97 Alveolar soft part sarcoma - molecular and cytogenic findings, 37–40 - pheochromocytoma/paraganglioma vs., 107 ALX4 gene, 804–823 AMER1 gene mutations, Wilms tumor, 313 American Society of Clinical Oncology (ASCO) - clinical utility of genetic testing, 485

- indications for testing, 485 - informed consent, 485–486 - policy statement, 485 AMH. See Adrenal medullary hyperplasia. AML. See Angiomyolipoma. AML1 gene, 804–823 Ampullary adenoma/carcinoma, familial neoplasia of biliary tract, liver, and pancreas, 226 Ampullary/periampullary carcinomas, pancreatic adenocarcinoma vs., 224 Amsterdam criteria, Lynch syndrome, 681, 683 Amyloid goiter, medullary thyroid carcinoma vs., 180 Anaplasia, Wilms tumor, 314 "Ancient" schwannoma, 33 Anemia - Fanconi, genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 - glucagonoma syndrome and, 608 - Peutz-Jeghers polyposis syndrome, 745 Aneurysmal bone cyst - molecular and cytogenic findings, 37–40 - osteosarcoma vs., 25 Angiofibroma - Birt-Hogg-Dubé syndrome associated, 519 - of soft tissue, molecular and cytogenic findings, 37–40 Angiomatoid fibrous histiocytoma, molecular and cytogenic findings, 37–40 Angiomyolipoma (AML), 286–289 - differential diagnosis, 286 - epithelioid, clear cell renal cell carcinoma, 291 - prognosis, 287 - sporadic AML, 287 - tuberous sclerosis associated, 287 - tuberous sclerosis complex, 775 Angiosarcoma, molecular and cytogenic findings, 37–40 Anomalies, Peutz-Jeghers polyposis syndrome, 745 Anorectal carcinoma, dyskeratosis congenita associated, 561 α-1-antitrypsin deficiency, familial biliary tract, liver, and pancreas neoplasms, 226–227 APC gene, 804–823 APC germline mutations - familial adenomatous polyposis associated, 568 - familial thyroid carcinoma, 192 Aplastic anemia, Shwachman-Diamond syndrome vs., 771 ARF gene, 804–823 ASIP gene, 804–823 ASS1 gene, 804–823 Astrocytoma - familial uveal melanoma, 603 - pilocytic, neurofibromatosis type 1, 721 - tuberous sclerosis complex (TSC), 775 AT. See Ataxia-telangiectasia (AT). Ataxia-pancytopenia syndrome, associated with increased risk of hematological malignancies, 6–7 Ataxia-telangiectasia (AT), 502–503 - acute lymphoblastic leukemia, 5 - associated with increased risk of hematological malignancies, 6–7 - differential diagnosis, 503 iii

INDEX - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 - genetics, 502 - known hereditary cancer syndromes, 489–490 - neoplasms associated, 503 - Nijmegen breakage syndrome vs., 735 Ataxia-telangiectasia-like disorder, ataxia-telangiectasia vs., 503 Ataxia-telangiectasia mutated (ATM) gene - germline inactivation, 502 - heterozygous carriers of mutations predisposed to cancers, 502 - mutations, breast carcinoma, 49, 54 Ataxia-telangiectasia syndrome, familial cancer syndromes with salivary gland neoplasms, 404 Ataxia-telangiectasia variant 1 (AT-V1). See Nijmegen breakage syndrome. ATM gene, 804–823 ATP8B1 gene, 804–823 Atrophic variant, prostate carcinoma, 328 ATRT-MYC, rhabdoid predisposition syndrome, 763 ATRT-SHH, rhabdoid predisposition syndrome, 763 ATRT-TYR, rhabdoid predisposition syndrome, 763 Attenuated APC (AAPC). See Familial adenomatous polyposis (FAP). Attenuated FAP (AFAP). See also Familial adenomatous polyposis (FAP). - known hereditary cancer syndromes, 489–490 - as variant of familial adenomatous polyposis, 572 Atypical adenomatous hyperplasia, adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern vs., 433 Atypical carcinoid (AC). See also Neuroendocrine tumors, of lung. - neuroendocrine tumor of lung vs., 440 Atypical cartilaginous tumor, 11 Atypical fibroxanthoma - cutaneous melanoma vs., 458 - cutaneous squamous cell carcinoma vs., 462 Atypical neurofibroma, malignant peripheral nerve sheath tumor vs., 20 Atypical neurofibromatous neoplasm of uncertain biologic potential, malignant peripheral nerve sheath tumor vs., 20 Atypical nevi, melanoma/pancreatic carcinoma syndrome, 693 Atypical parathyroid adenoma - parathyroid adenoma vs., 134 - parathyroid carcinoma vs., 139 Atypical teratoid/rhabdoid tumor (AT/RT), rhabdoid predisposition syndrome, 762–763 Atypical Werner syndrome, Werner syndrome/progeria vs., 791 Autism with macrocephaly, 750 Autosomal dominant polycystic kidney disease (ADPKD), von Hippel-Lindau (VHL) syndrome vs., 784 Autosomal recessive inheritance, MUTYH-associated polyposis, 718

iv

B

BACH1 gene, 804–823 BAF47 gene, 804–823 BAK1 gene, 804–823 Bannayan-Riley-Ruvalcaba syndrome (BRRS), 538, 750 - Carney complex vs., 531 - diagnosis, 752 - DICER1 syndrome vs., 552 - known hereditary cancer syndromes, 489–490 BAP1-associated melanocytic tumors, selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 BAP1-associated tumor predisposition syndrome, familial uveal melanoma and, 602 BAP1 gene, 804–823 - BAP1-inactivated melanocytic tumor associated, 449 - BAP1 tumor predisposition syndrome, 504 - melanoma/pancreatic carcinoma syndrome, 692 BAP1 germline mutation, BAP1 tumor predisposition syndrome, 505 BAP1-inactivated melanocytic tumor, 448–449 - prognosis, 449 BAP1 tumor predisposition syndrome, 504–505 - criteria for diagnosis, 505 - differential diagnosis, 505 - genetics, 504 - known hereditary cancer syndromes, 489–490 - neoplasm associated, 505 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 BAP1 tumor syndrome, familial renal tumors in (table), 320 BARD1 gene, 804–823 Barrett esophagus, 235 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Basal cell carcinoma (BCC), 450–455 - basal cell nevus syndrome/Gorlin syndrome associated, 506–507 - cutaneous squamous cell carcinoma vs., 462 - diagnostic checklist, 452 - differential diagnosis, 452 - early-onset sporadic, basal cell nevus syndrome/Gorlin syndrome vs., 507 - genetics, 451 - hereditary infundibulocystic basal cell nevus syndrome/Gorlin syndrome vs., 507 selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - hereditary leiomyomatosis and renal cell carcinoma, 625 - other syndromes with, basal cell nevus syndrome/Gorlin syndrome vs., 508 - prognosis, 451 - sebaceous carcinoma vs., 468

INDEX Basal cell nevus syndrome/Gorlin syndrome, 506–509 - bone and soft tissue tumors associated with, 36 - criteria for diagnosis, 508 - diagnostic criteria, 486 - differential diagnosis, 507–508 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - genetic syndromes associated with CNS neoplasms, 412 - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 - genetics, 506 - neoplasms associated, 506–507 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Basaloid squamous cell carcinoma - head and neck squamous cell carcinoma, 396 - neuroendocrine tumor of lung vs., 440 Baser criteria, neurofibromatosis type 2, 728, 729 Bazex-Dupré-Christol syndrome - basal cell nevus syndrome/Gorlin syndrome vs., 507 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 BCC. See Basal cell carcinoma (BCC). BE. See Barrett esophagus. Beckwith-Wiedemann spectrum (BWSp). See BeckwithWiedemann syndrome (BWS). Beckwith-Wiedemann syndrome (BWS), 510–517 - adrenal cortical adenoma, 59 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - associated neoplasms, 511–512 - bone and soft tissue tumors associated with, 36 - clinical features, 514 - differential diagnosis, 512–513 - familial renal tumors in (table), 320 - genetics, 511 - hepatoblastoma, 213 - hereditary neuroblastoma and, 633 - molecular defect categories and recurrence risk, 514 - selected hereditary cancer syndromes with skin manifestations, 472–473 - Wilms tumor, 313 Benign notochordal cell tumor, chordoma vs., 16 Bennion-Patterson syndrome. See Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer. Berlin breakage syndrome. See Nijmegen breakage syndrome. Bethesda criteria, Lynch syndrome, 681, 683 BHD gene, 804–823 BHDS. See Birt-Hogg-Dubé syndrome (BHDS). Bilateral nodular hyperplasia, McCune-Albright syndrome, 687

Bile duct cancer, breast/ovarian cancer syndrome (BRCA2), 618 Biliary tract/liver/pancreas table, 226–227 - familial neoplasia, 226 - syndromes, 226–227 Biliary tract neoplasms, familial adenomatous polyposis associated, 570 Biphenotypic sinonasal sarcoma, molecular and cytogenic findings, 37–40 Birt-Hogg-Dubé syndrome (BHDS), 518–521 - associated neoplasms, 518–519 - Brooke-Spiegler syndrome vs., 525 - colorectal carcinoma, 519 - diagnostic criteria, 520 - differential diagnosis, 519–520 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial renal tumors in (table), 320 - genetics, 518 - hereditary or familial renal tumor syndrome, 654 - lymphangioleiomyomatosis vs., 436 - renal cell carcinoma, 519 - renal oncocytoma, chromophobe, and hybrid oncocytic tumors, 305 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Bizarre parosteal osteochondromatous proliferation, molecular and cytogenic findings, 37–40 Blackfan-Diamond syndrome. See Diamond-Blackfan anemia (DBA). Bladder carcinoma - Costello syndrome associated, 540–541 - hereditary retinoblastoma, 657 - MUTYH-associated polyposis, 719 Bladder neoplasms - AJCC Staging for Bladder Cancer, 282 - bladder table, 282–285 - hereditary syndromes associated, 478 - high-grade poorly differentiated carcinoma (table), 282 - urothelial carcinoma-associated markers in metastatic setting, 282 Bladder table, 282–285 Bladder tumor, hereditary leiomyomatosis and renal cell carcinoma, 625 Bladder urothelial carcinoma, 274–281 - diagnostic checklist, 277 - differential diagnosis, 277 - prognosis, 275 Blastemal cells, Wilms tumor, 314 BLM gene, 804–823 - mutations, Bloom syndrome associated, 522 BLM mutation, Bloom syndrome, 781 Blood and bone marrow neoplasms - acute lymphoblastic leukemia (ALL), 4–5 due to germline ETV6 mutations, 5 due to germline IKZF1 mutations, 5 due to germline PAX5 mutations, 5 due to germline SH2B3 mutations, 5 v

INDEX genetic testing, 5 - germline mutations and conditions associated with increased risk of hematological malignancies, 6–7 - non-Hodgkin lymphoma (NHL), 4–5 genetic testing, 5 Bloom syndrome (BS), 522–523 - acute lymphoblastic leukemia, 5 - associated neoplasms, 523 - associated with increased risk of hematological malignancies, 6–7 - bone and soft tissue tumors associated with, 36 - cytogenetic testing, 523 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial cancer syndromes with lung neoplasms, 444 - genetic predisposition for squamous cell carcinoma of head and neck, 395 - increased cancer risk, 523 - lung adenocarcinoma associated, 427 - Nijmegen breakage syndrome vs., 735 - osteosarcoma, 781 - xeroderma pigmentosum vs., 800 Bloom-Torre-Machacek syndrome. See Bloom syndrome (BS). BMPR1A gene, 804–823 - germline mutations, juvenile polyposis syndrome, 668 BMPR1A germline mutations, hamartomatous polyposis syndromes, 253 Bone and soft tissue neoplasms - chondrosarcoma, 10–13 differential diagnosis, 12 prognosis, 11 - chordoma, 14–17 differential diagnosis, 16 familial, 15 prognosis, 15 sporadic, 15 - familial cancer syndromes with, 36 - hereditary syndromes associated, 480 - malignant peripheral nerve sheath tumor, 18–21 differential diagnosis, 20 genetic predisposition, 19 prognosis, 19 - molecular and cytogenic findings, 37–40 - osteosarcoma, 22–27 diagnostic checklist, 25 differential diagnosis, 24–25 genetic susceptibility, 23 prognosis, 23 - rhabdomyosarcoma, 28–31 differential diagnosis, 30 genetic associations, 29 genetic events, 29 genetic testing, 30 prognosis, 29 - schwannoma, 32–35 diagnostic checklist, 34 differential diagnosis, 34 prognosis, 33 Bone disease, parathyroid carcinoma, 137 Bone lesions, neurofibromatosis type 1, 721 vi

Bone manifestations, familial adenomatous polyposis, 570 Bone marrow dysfunction, Shwachman-Diamond syndrome, 770 Bone marrow failure syndromes, predisposition to myelodysplastic syndromes/acute myeloid leukemia, 565 Bone sarcomas, hereditary retinoblastoma, 657 BRAF gene, 804–823 - familial uveal melanoma, 602 B-Raf protooncogene (BRAF) mutations, cutaneous melanoma associated, 457 Brain lesions, PTEN-hamartoma tumor syndromes, 753 Brain tumor - Fanconi anemia, 607 - hereditary leiomyomatosis and renal cell carcinoma, 625 BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome. See BAP1-inactivated melanocytic tumor; BAP1 tumor predisposition syndrome. BRCA1 gene, 611, 804–823 - mutations breast carcinoma, 47–48, 54, 55 fallopian tube carcinoma, 373 hereditary prostate cancer, 651 - protein function, 611 BRCA1 syndrome - associated neoplasms, 611–612 - genetics, 611 - prognosis, 611 BRCA2 gene, 616, 804–823 - melanoma/pancreatic carcinoma syndrome, 692 - mutations breast carcinoma, 48, 54, 55 fallopian tube carcinoma, 373 hereditary prostate cancer, 650, 651 pancreatic adenocarcinoma, 223 - protein function, 616 BRCA2 syndrome. See Breast/ovarian cancer syndrome (BRCA2). Breast cancer - female breast/ovarian cancer syndrome (BRCA1), 611 breast/ovarian cancer syndrome (BRCA2), 617–618 - male breast/ovarian cancer syndrome (BRCA1), 612 breast/ovarian cancer syndrome (BRCA2), 618 - McCune-Albright syndrome, 687 - melanoma/pancreatic carcinoma syndrome, 693 - multiple endocrine neoplasia type 1, 697 - Peutz-Jeghers polyposis syndrome, 745 - risk, Fanconi anemia, 607 Breast cancer 1 syndrome. See Breast/ovarian cancer syndrome (BRCA1). Breast cancer 2 syndrome. See Breast/ovarian cancer syndrome (BRCA2). Breast carcinoma, 46–53 - ATM (ataxia-telangiectasia carriers), 49 - BRCA1 (hereditary breast and ovarian cancer syndrome), 47–48

INDEX - BRCA2 (hereditary breast and ovarian cancer syndrome), 48 - CDH1 (familial gastric cancer and lobular breast cancer syndrome), 48–49 - CHECK2, 49–50 - differential diagnosis of tumors secondarily involving parathyroid, 154 - familial cancers associated with germline mutations, 47 - familial cancers not associated with germline mutations, 47 - genetic testing, 50 - germline mutations associated with increased risk of, 54 - hereditary, 47 - Li-Fraumeni syndrome, 676 - lobular, hereditary diffuse gastric cancer, 622 - MUTYH-associated polyposis, 719 - PALB2, 49 - pathologic features, 54 - PTEN (Cowden syndrome), 49 - PTEN-hamartoma tumor syndromes, 753 risk management, 754 - STK11/LKB1 (Peutz-Jeghers syndrome), 49 - TP53 (Li-Fraumeni syndrome), 48 Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), Li-Fraumeni syndrome, 675 Breast lesions, PTEN-hamartoma tumor syndromes, 753 Breast neoplasms - Brooke-Spiegler syndrome associated, 525 - hereditary syndromes associated, 479 Breast/ovarian cancer syndrome (BRCA1), 610–615 - associated neoplasms, 611–612 - genetics, 611 - prognosis, 611 Breast/ovarian cancer syndrome (BRCA2), 616–619 - associated neoplasms, 617–618 - cancer risk management, 618 chemoprevention, 618 prophylactic surgery, 618 screening, 618 Breast/ovarian syndrome, hereditary cancer syndromes associated, 498 Breast tumor, hereditary leiomyomatosis and renal cell carcinoma, 625 BRG1 gene, 804–823 BRIP1 gene, 804–823 - hereditary prostate cancer, 651 Bronchial carcinoma, dyskeratosis congenita associated, 561 Bronchial neuroendocrine tumor, multiple endocrine neoplasia type 1, 697 Bronchiectasis, ataxia-telangiectasia, 503 Bronchiolitis, follicular, lymphangioleiomyomatosis vs., 436 Bronchioloalveolar carcinoma. See Adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern. Brooke-Spiegler syndrome (BSS), 524–527 - associated neoplasms, 525 - criteria for diagnosis, 525–526 - differential diagnosis, 525

- familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial cancer syndromes with salivary gland neoplasms, 404 - gene, 524 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 BS. See Bloom syndrome (BS). BSS. See Brooke-Spiegler syndrome (BSS). Burns, cutaneous squamous cell carcinoma associated, 461 BWS. See Beckwith-Wiedemann syndrome (BWS). Byler disease, familial biliary tract, liver, and pancreas neoplasms, 226–227

C

C16orf57 gene, 804–823 Café au lait patches, neurofibromatosis type 1, 721 Café au lait pigmented skin lesions, McCune-Albright syndrome, 687 Café au lait spots - neurofibromatosis type 2, 728 - Noonan syndrome, 759 Calcifying aponeurotic fibroma, molecular and cytogenic findings, 37–40 Cancer - Nijmegen breakage syndrome, 734 - Noonan syndrome, 759 - PTEN-hamartoma tumor syndromes, 753–754 Cancer susceptibility testing, 485–486 Capillary malformation-arteriovenous malformation, Costello syndrome vs., 541 Carcinoid tumor - endolymphatic sac tumor vs., 392 - neuroendocrine tumor of lung vs., 440 Carcinoid tumorlets, neuroendocrine tumor of lung vs., 440 Carcinoids - pheochromocytoma/paraganglioma vs., 107 - tumors with oxyphilic cytoplasm (table), 363 Carcinoma - acinic cell, pancreatic adenocarcinoma, 224 - ampullary/periampullary, pancreatic adenocarcinoma, 224 - basal cell, 450–455 diagnostic checklist, 452 differential diagnosis, 452 genetics, 451 prognosis, 451 sebaceous carcinoma vs., 468 - cervical, 370–371 genetic testing, 371 prognosis, 371 - colon, invasive, colonic adenoma vs., 232 - colorectal, colonic adenoma, 229 vii

INDEX - familial thyroid, 188–199 diagnostic checklist, 188 differential diagnosis, 192 familial follicular cell carcinoma classification, 193 genetic testing, 192 - follicular, medullary thyroid carcinoma vs., 180 - follicular thyroid, 200–207 classification, 204 diagnostic checklist, 203 differential diagnosis, 203, 204 familial setting, 204 genetic testing, 202–203 prognosis, 201 - hepatocellular, 218–221 cytogenetics, 220 differential diagnosis, 220 hepatoblastoma vs., 214 molecular genetics, 220 prognosis, 219–220 - medullary thyroid, 176–185 diagnostic checklist, 180 differential diagnosis, 180 familial, 181 genetic predisposition, 177 genetic testing, 179–180 immunohistochemistry, 181 with intrathyroidal spread, C-cell hyperplasia vs., 172 prognosis, 178 sporadic, 181 - Merkel cell, basal cell carcinoma vs., 452 - metastatic, to skin, sebaceous carcinoma vs., 468 - metastatic clear cell renal cell, sebaceous carcinoma vs., 468 - microcystic adnexal, basal cell carcinoma vs., 452 - other primary cutaneous adnexal, sebaceous carcinoma vs., 468 - papillary thyroid, medullary thyroid carcinoma vs., 180 - parathyroid, 136–141 differential diagnosis, 139 genetic testing, 138 primary parathyroid hyperplasia vs., 147 prognosis, 138 - primary or metastatic, familial paraganglioma pheochromocytoma syndrome vs., 598 - sebaceous, 466–471 basal cell carcinoma vs., 452 cancer syndromes associated, 467 differential diagnosis, 468 genetics, 467 prognosis, 467 - sporadic medullary thyroid, medullary thyroid carcinoma vs., 180 - squamous cell basal cell carcinoma vs., 452 sebaceous carcinoma vs., 468 - in varied sites, Bloom syndrome associated, 523 - xeroderma pigmentosum, 799 Carcinoma cuniculatum, head and neck squamous cell carcinoma, 396 Carcinoma ex pleomorphic adenoma, molecular changes described in salivary gland tumors, 405–406 viii

Carcinoma table, thyroid - medullary, 186–187 familial from sporadic medullary carcinoma, 186 familial syndromes, 186 MEN2 syndrome, 186 MEN2A and MEN2B, RET mutations to risk of aggressive MTC, 187 prophylactic thyroidectomy depending on RET mutation, ATA age recommendations, 187 reactive/physiologic and neoplastic C-cell hyperplasia, 187 - nonmedullary, 208–209 distinct characteristics of familial thyroid carcinoma and sporadic carcinoma, 208 familial nonmedullary thyroid carcinoma classification, 208 familial nonmedullary thyroid carcinoma in familial cancer syndromes, 208 Carcinosarcoma, endometrial carcinoma, 381 Cardiac fibroma, basal cell nevus syndrome/Gorlin syndrome, 507 Cardiac rhabdomyoma, tuberous sclerosis complex (TSC), 775 Carney complex (CNC), 528–535 - adrenal cortical adenoma, 59 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - atrial myxoma, 529 - bone and soft tissue tumors associated with, 36 - criteria for diagnosis, 529 - diagnostic criteria, 487 - DICER1 syndrome vs., 552 - differential diagnosis, 530–531 - familial cancer syndromes, 208 - familial follicular cell carcinoma, 193 - familial nonmedullary thyroid carcinoma, 190, 593 - familial sex cord-stromal tumors, 601 - familial testicular tumors (table), 362 - familial thyroid carcinoma, 189 - follicular thyroid carcinoma, 201, 204 - genetic testing, 530 - genetics, 591 - genomic locus and genes associated, 532 - including Lamb syndrome, testicular Sertoli cell neoplasms, 359 - known hereditary cancer syndromes, 489–490 - large-cell calcifying Sertoli cell tumor, 530 - McCune-Albright syndrome vs., 689 - multiple endocrine neoplasia type 1 vs., 699 - multiple endocrine neoplasia type 4 vs., 714 - part of inherited tumor syndrome, 166 - pituitary adenoma, 159 - primary pigmented nodular adrenocortical disease, 530 - prognosis, 530 - psammomatous melanotic schwannoma, 530 - syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 - syndromes with similar tissue manifestations, 532 Carney-Stratakis dyad, familial paraganglioma pheochromocytoma syndrome, 596

INDEX Carney-Stratakis syndrome - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 - familial gastrointestinal stromal tumor associated, 579–580 - gastrointestinal stromal tumor, 247 - hereditary paraganglioma/pheochromocytoma syndromes, 643 - pheochromocytoma/paraganglioma associated with, 115 Carney triad - adrenal cortical adenoma, 59 - familial gastrointestinal stromal tumor associated, 579 - familial paraganglioma pheochromocytoma syndrome, 596 - gastrointestinal stromal tumor, 247 - hereditary paraganglioma/pheochromocytoma syndromes, 643 Carvajal syndrome, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 661 CASR gene, 804–823 - mutations genetic testing, 587 parathyroid hyperplasia, 146 Cataract(s), 420 α-catenin, hereditary diffuse gastric cancer and, 621 β-catenin mutation, Wnt pathway activation, hepatoblastoma, 213 CBFA2 gene, 804–823 CBL gene, 804–823 C-cell carcinoma. See Medullary thyroid carcinoma. C-cell hyperplasia, 170–175 - diagnostic checklist, 172 - differential diagnosis, 172 - immunohistochemistry, 173 - multiple endocrine neoplasia type 2, 708 - physiologic, multiple endocrine neoplasia type 2 vs., 707 - prognosis, 171 - reactive/physiologic and neoplastic, 187 - reactive/physiologic vs. neoplastic, 173 C-cell proliferation. See C-cell hyperplasia. CCH. See C-cell hyperplasia. CCNA1 gene, 804–823 CCND1 gene, 804–823 - abnormalities parathyroid adenoma, 133 parathyroid hyperplasia, 146 - parathyroid carcinoma, 138–139 CCRCC. See Clear cell renal cell carcinoma. CDC73 gene, 804–823 - mutations familial isolated hyperparathyroidism associated, 586 genetic testing, 587 hyperparathyroidism-jaw tumor syndrome, 662 CDH1 gene, 804–823 - mutations breast carcinoma, 48–49, 54 gastric adenocarcinoma, 239 hereditary diffuse gastric cancer and, 621

CDK4 gene, 804–823 - melanoma/pancreatic carcinoma syndrome, 692 CDKN1B gene, 804–823 CDKN1B germline mutation, multiple endocrine neoplasia type 4 (MEN4), 716 CDKN1C gene, 804–823 - mutation, Beckwith-Wiedemann syndrome associated, 511 CDKN2A gene, 804–823 - familial uveal melanoma, 602 - melanoma/pancreatic carcinoma syndrome, 692 - mutation, cutaneous melanoma associated, 457 CEBPA gene, 804–823 - mutation, familial CEBPA mutation, 564 Celiac disease, risk factor for small bowel adenocarcinoma, 263 Cell cycle and cell differentiation defects, associated with myelodysplastic syndromes/acute myeloid leukemia, 565 Cellular angiofibroma, molecular and cytogenic findings, 37–40 Cellular immunity deficiency, ataxia-telangiectasia, 503 Cellular schwannoma, 33–34 - malignant peripheral nerve sheath tumor vs., 20 Central nervous system, 412–415 - degeneration, ataxia-telangiectasia, 503 - genetic syndromes associated with CNS neoplasms, 412 - xeroderma pigmentosum, 799 Central nervous system neoplasms - basal cell nevus syndrome/Gorlin syndrome, 507 - hereditary syndromes associated, 479–480 - pineoblastoma, hereditary retinoblastoma, 657 - retinoblastoma familial cancer syndromes with head and neck lesions and neoplasms, 400–402 familial cancer syndromes with salivary gland neoplasms, 404 Central nervous system tumors, multiple endocrine neoplasia type 1, 697 Central zone (CZ), significance of normal histoanatomic structures in prostate pathology (table), 338 Cerebrooculofacial-skeletal syndrome, xeroderma pigmentosum vs., 800 Ceruminous gland adenoma, endolymphatic sac tumor vs., 392, 393 Cervical carcinoma, 370–371 - genetic testing, 371 - prognosis, 371 Cervical squamous carcinoma, bladder carcinoma vs., 277 CFTR gene, 804–823 Charcot-Marie-Tooth disease, pheochromocytoma/paraganglioma associated with, 115 CHEK2 gene, 804–823 - hereditary prostate cancer, 651 - mutations, breast carcinoma, 49–50, 54 Children, von Hippel-Lindau (VHL) syndrome, 783 Cholangiocarcinoma, hepatocellular carcinoma vs., 220 Cholecystectomy, previous, pancreatic adenocarcinoma, 223 ix

INDEX Chompret Criteria for Screening, Li-Fraumeni syndrome, 677 Chondroblastic osteosarcoma, chondrosarcoma vs., 12 Chondroblastoma, molecular and cytogenic findings, 37–40 Chondroid chordoma, 15, 16 - chondrosarcoma vs., 12 - familial chordoma associated, 577 Chondroma, molecular and cytogenic findings, 37–40 Chondromesenchymal hamartoma, nasal, DICER1 syndrome, 550 Chondromyxoid fibroma - chondrosarcoma vs., 12 - molecular and cytogenic findings, 37–40 Chondrosarcoma, 10–13 - chordoma vs., 16 - differential diagnosis, 12 - familial cancer syndromes with bone and soft tissue tumors, 36 - molecular and cytogenic findings, 37–40 - osteosarcoma vs., 25 - prognosis, 11 Chordoma, 14–17 - chondroid, chondrosarcoma vs., 12 - differential diagnosis, 16 - familial, 15 - familial cancer syndromes with bone and soft tissue tumors, 36 - familial chordoma associated, 576–577 - molecular and cytogenic findings, 37–40 - prognosis, 15 - sporadic, 15 Choriocarcinoma (CC), germ cell tumor, 353, 354 Choroid plexus carcinomas, rhabdoid predisposition syndrome, 763 Choroid plexus papilloma, endolymphatic sac tumor vs., 393 Choroidal lipoma, molecular and cytogenic findings, 37–40 Chromophil renal cell carcinoma. See Papillary renal cell carcinoma. Chromophobe renal cell carcinoma (CHRCC), 305 - eosinophilic variant, succinate dehydrogenase-deficient renal cell carcinoma vs., 310 - with granular/eosinophilic cytoplasm, 322 Chromosomal region 11q22-23, of ataxia-telangiectasiamutated (ATM) gene, 502 Chromosome 1 loss, renal oncocytoma, 305 Chromosome 1p - loss of heterozygosity, Wilms tumor, 313 - losses, prostate carcinoma, 327 Chromosome 1q losses, prostate carcinoma, 327 Chromosome 2p - gains, prostate carcinoma, 327 - losses, prostate carcinoma, 327 Chromosome 3 translocation, constitutional - clear cell renal cell carcinoma, 291 - familial renal tumors in (table), 320 - hereditary renal epithelial tumors, 652 Chromosome 4q, Wilms tumor, 313

x

Chromosome 6 loss, chromophobe renal cell carcinoma, 305 Chromosome 6q losses, prostate carcinoma, 327 Chromosome 7 gains, prostate carcinoma, 327 Chromosome 8 polysomy, pleuropulmonary blastoma associated, 443 Chromosome 8p losses, prostate carcinoma, 327 Chromosome 8q gains, prostate carcinoma, 327 Chromosome 10 loss, chromophobe renal cell carcinoma, 305 Chromosome 10q gains, prostate carcinoma, 327 Chromosome 11p15.5, Beckwith-Wiedemann syndrome, 511 Chromosome 11q23 alteration, renal oncocytoma, 305 Chromosome 13 loss, chromophobe renal cell carcinoma, 305 Chromosome 13q gains, prostate carcinoma, 327 Chromosome 16q losses - prostate carcinoma, 327 - Wilms tumor, 313 Chromosome 17 loss, chromophobe renal cell carcinoma, 305 Chromosome 18q losses, prostate carcinoma, 327 Chromosome 19p13.2, pure familial papillary thyroid carcinoma associated, 592 Chromosome 21 loss, chromophobe renal cell carcinoma, 305 Chromosome 21 trisomy. See Down syndrome (DS). Chromosome Xq gains, prostate carcinoma, 327 Chromosome Y loss, renal oncocytoma, 305 Chronic inflammation, risk factor for small bowel adenocarcinoma, 263 Chronic pain, schwannomatosis, 766 Chronic pancreatitis, disorders with, melanoma/pancreatic carcinoma syndrome vs., 694 Chronic sun, cutaneous squamous cell carcinoma associated, 461 Ciliary body medulloepithelioma, DICER1 syndrome, 550 Cirrhosis, hepatocellular carcinoma, 219 Citrullinemia, familial biliary tract, liver, and pancreas neoplasms, 226–227 Clark nevi, melanoma/pancreatic carcinoma syndrome, 693 Clarke-Howell-Evans-McConnell syndrome. See HowelEvans syndrome/keratosis palmares and plantares with esophageal cancer. Classic angiomyolipoma. See Angiomyolipoma. Clear cell carcinoma, endometrial carcinoma, 381 Clear cell myoepithelial carcinoma, molecular changes described in salivary gland tumors (table), 405–406 Clear cell papillary renal cell carcinoma - clear cell renal cell carcinoma vs., 291 - papillary renal cell carcinoma vs., 301 Clear cell renal cell carcinoma (CCRCC), 290–293 - differential diagnosis, 291 - eosinophilic variant, succinate dehydrogenase-deficient renal cell carcinoma vs., 310 - familial hereditary or familial renal tumor syndrome, 654 hereditary renal epithelial tumors, 652

INDEX -

familial renal tumors in (table), 320 with granular/eosinophilic cytoplasm, 322 metastatic to skin, sebaceous carcinoma vs., 468 with papillary or tubulopapillary architecture (table), 321 - prognosis, 291 - tumors with clear/light-staining cytoplasm (table), 321 Clear cell sarcoma - gastrointestinal, molecular and cytogenic findings, 37–40 - kidney molecular and cytogenic findings, 37–40 Wilms tumor vs., 315 - malignant peripheral nerve sheath tumor vs., 20 - soft part, molecular and cytogenic findings, 37–40 Clear cell (glycogen-rich) urothelial carcinoma, bladder carcinoma and, 277 Clinical diagnosis and management of familial/hereditary tumor syndromes, 484–493 - cancer susceptibility testing, 485–486 American Society of Clinical Oncology (ASCO), 485–486 genetic counseling, 486 special issues related to genetic testing research, 486 - diagnosis, 486–488 - diagnostic criteria basal cell nevus syndrome, 486 Carney complex, 487 Li-Fraumeni syndrome, 487 Lynch syndrome, 487–488 neurofibromatosis type 1, 487 neurofibromatosis type 2, 487 von Hippel-Lindau syndrome, 486–487 - features suggesting presence of familial cancer predisposition, 489 - future perspectives, 488 - identification of at-risk individuals, 485 - known hereditary cancer syndromes, 489–490 CNC. See Carney complex. CNS tumors, Li-Fraumeni syndrome, 676 CNS-PNET, hereditary retinoblastoma, 657 Cockayne syndrome - Werner syndrome/progeria vs., 791–792 - xeroderma pigmentosum vs., 799 COL1A1-PDGFB gene, 804–823 COL6A3-CSF1 gene, 804–823 Collecting duct carcinoma - carcinomas involving kidney &/or renal pelvis, 350 - HLRCC syndrome-associated renal cell carcinoma vs., 298 - with papillary or tubulopapillary architecture (table), 321 - papillary renal cell carcinoma vs., 301 Colloid adenocarcinoma, lung adenocarcinoma vs., 428 Colon carcinoma - invasive, colonic adenoma vs., 232 - lobular, hereditary diffuse gastric cancer, 622 - Peutz-Jeghers polyposis syndrome, 745 Colon/rectum - familial neoplasia of, 268–269

- lesions, PTEN-hamartoma tumor syndromes, 753 - Peutz-Jeghers polyposis syndrome, 745–746 - table, 268–269 Colonic adenomas, 228–233 - diagnostic checklist, 232 - differential diagnosis, 232 - prognosis, 230 Colonic carcinoma syndromes, 536–539 - DNA polymerase ε and δ polyposis (POLE and POLD1 mutation-associated tumors), 538 - familial adenomatous polyposis, 537 - hereditary mixed polyposis, 538 - juvenile polyposis, 538 - Li-Fraumeni syndrome, 538 - Lynch syndrome (hereditary nonpolyposis colorectal cancer), 537 - MSH3 polyposis, 538 - MUTYH-associated polyposis, 537 - NTHL1 polyposis, 538 - Peutz-Jeghers syndrome, 538 - PTEN-hamartoma syndrome (Cowden/Bannayan-RileyRuvalcaba), 538 - serrated (giant hyperplastic) polyposis syndrome, 537–538 Colorectal adenocarcinoma, PTEN-hamartoma tumor syndromes, 753 - risk management, 754 Colorectal carcinoma - Birt-Hogg-Dubé syndrome, 519 - colonic adenoma, 229 - dyskeratosis congenita associated, 561 - familial colon and rectum tumors by syndrome (table), 268 - juvenile polyposis syndrome, 669 Comparative genomic hybridization, hereditary leiomyomatosis and renal cell carcinoma, 625 Compensatory physiological hyperplasia, 89 Compressive neuropathy, McCune-Albright syndrome, 687 Congenital adrenal hyperplasia - adrenal cortical adenoma, 59 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 Congenital cystic adenomatoid malformation, DICER1 syndrome vs., 552 Congenital generalized myofibromatosis. See Familial infantile myofibromatosis (FIM). Congenital hypoplastic anemia. See Diamond-Blackfan anemia (DBA). Congenital telangiectatic erythema. See Bloom syndrome (BS). Constitutional chromosome 3 translocation - clear cell renal cell carcinoma and, 291 - familial renal tumors in (table), 320 - hereditary or familial renal tumor syndrome, 654 - hereditary renal epithelial tumors, 652 Constitutional mismatch repair deficiency syndrome - associated with increased risk of hematological malignancies, 6–7 - genetic syndromes associated with CNS neoplasms, 412 xi

INDEX Constitutional mismatch repair syndrome, acute lymphoblastic leukemia, 5 Constitutional MMR deficiency (CMMRD), 680 Conventional chordoma, familial chordoma associated, 577 Corpora amylacea, significance of normal histoanatomic structures in prostate pathology (table), 338 Cortical carcinoma, adrenal, Beckwith-Wiedemann syndrome associated, 512 Corticotroph cell adenoma - multiple endocrine neoplasia type 1, 700 - pituitary hyperplasia vs., 165 Corticotropin (ACTH)-independent bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease vs., 80 Cortisol-producing adrenocortical adenoma. See Adrenal cortical adenoma. Costello syndrome, 540–541 - associated neoplasms, 540–541 - bone and soft tissue tumors associated with, 36 - differential diagnosis, 541 - genetics, 540 - hereditary neuroblastoma and, 633 - RASopathy family, 541 - rhabdomyosarcoma, 541 - selected hereditary cancer syndromes with skin manifestations, 472–473 - transitional cell carcinoma, 541 Cowden disease - Carney complex vs., 531 - DICER1 syndrome vs., 552 - hereditary cancer syndromes associated, 498 - known hereditary cancer syndromes, 489–490 Cowden/Lhermitte-Duclos syndrome, genetic syndromes associated with CNS neoplasms, 412 Cowden syndrome (CS), 538, 750 - Birt-Hogg-Dubé syndrome vs., 519–520 - breast carcinoma, 49, 54 - diagnosis, 751–752 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - hamartomatous polyposis syndromes, 253 - juvenile polyposis syndrome vs., 670 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Cowper gland, significance of normal histoanatomic structures in prostate pathology (table), 338 Craniofaciocutaneous syndrome, Costello syndrome, 541 Cribriform adenocarcinoma, molecular changes described in salivary gland tumors (table), 405–406 Cribriform morular papillary thyroid carcinoma, hereditary syndromes associated, 477 Crohn disease, risk factor for small bowel adenocarcinoma, 263 Cronkhite-Canada syndrome - familial adenomatous polyposis vs., 571 - juvenile polyposis syndrome vs., 670 CS. See Cowden syndrome. xii

CTC1 gene, 804–823 - dyskeratosis congenita associated, 560 CTNNA1 mutations - gastric adenocarcinoma, 239 - hereditary diffuse gastric cancer and, 621 CTNNB1 gene, 804–823 - mutations, Wilms tumor, 313 Cushing disease - multiple endocrine neoplasia type 4, 713 - pituitary hyperplasia, 165 - primary pigmented nodular adrenocortical disease vs., 80 Cushing syndrome. See also Adrenal cortical adenoma. - caused by primary cortisol-producing adrenocortical adenoma, primary pigmented nodular adrenocortical disease vs., 80 Cutaneous adnexal carcinomas, other primary, sebaceous carcinoma vs., 468 Cutaneous angiofibroma, tuberous sclerosis complex (TSC), 775 Cutaneous leiomyomas (piloleiomyomas), hereditary leiomyomatosis and renal cell carcinoma, 625 Cutaneous lichen amyloidosis, multiple endocrine neoplasia type 2, 708 Cutaneous melanoma, 456–459 - AJCC Melanoma Staging and Classification System, 458 - atypical melanocytic lesions, familial uveal melanoma, 603 - diagnostic checklist, 458 - differential diagnosis, 458 - genetics, 457 - prognosis, 457 Cutaneous schwannoma(s), 420 Cutaneous squamous cell carcinoma, 460–465 - differential diagnosis, 462 - environmental exposure, 461 - genetic predisposition, 461 - immunohistochemistry, 462 - prognosis, 461 CXORF5 gene, 804–823 CYLD gene, 804–823 - mutations, Brooke-Spiegler syndrome, 524 Cylindrical cell carcinoma. See Head and neck neoplasms, squamous cell carcinoma. Cylindroma - Brooke-Spiegler syndrome associated, 525 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 CYP21 gene, 804–823 Cystadenocarcinoma, prostate carcinoma, 329 Cystic adenomatoid malformation, congenital, DICER1 syndrome vs., 552 Cystic fibrosis - melanoma/pancreatic carcinoma syndrome vs., 694 - Shwachman-Diamond syndrome vs., 771 Cystic nephroma, 294–295 - adult, DICER1 syndrome vs., 552 - differential diagnosis, 295 - pediatric, DICER1 syndrome, 549–550 - pleuropulmonary blastoma associated, 443

INDEX - prognosis, 295 Cystic partially differentiated nephroblastoma, cystic nephroma vs., 295 Cystic renal diseases associated with renal neoplasms, von Hippel-Lindau (VHL) syndrome vs., 784 Cysts - lung, DICER1 syndrome vs., 552 - pulmonary cysts, associated with Birt-Hogg-Dubé syndrome, 519 - renal cysts, associated with Birt-Hogg-Dubé syndrome, 519 - thyroid cysts, Birt-Hogg-Dubé syndrome associated, 519 Cytomegaly, adrenal, Beckwith-Wiedemann syndrome associated, 512 Cytopenias, Shwachman-Diamond syndrome, 771 Cytoplasmic PTEN, 751

D

DDS. See Denys-Drash syndrome (DDS). Dedifferentiated chondrosarcoma, 11 - osteosarcoma vs., 25 Dedifferentiated chordoma, 15, 16 - familial chordoma associated, 577 Dedifferentiated liposarcoma, molecular and cytogenic findings, 37–40 Deletion/duplication analysis, PTEN-hamartoma tumor syndromes, 752 Denys-Drash syndrome (DDS), 542–545, 794 - associated neoplasms, 543 - differential diagnosis, 543 - familial renal tumors in (table), 320 - genetics, 542 - prognosis, 543 - structural and functional abnormalities, 543 - Wilms tumor, 313 Dermatofibrosarcoma protuberans, molecular and cytogenic findings, 37–40 Dermatopathia pigmentosa reticularis, dyskeratosis congenita vs., 562 Dermoid cyst, steatocystoma multiplex vs., 773 DeSanctis-Cacchione syndrome. See Xeroderma pigmentosum. Desmoid fibromatosis, familial infantile myofibromatosis vs., 585 Desmoplastic fibroblastoma, molecular and cytogenic findings, 37–40 Desmoplastic small round cell tumor - alveolar rhabdomyosarcoma vs., 30 - molecular and cytogenic findings, 37–40 Diabetes mellitus - glucagonoma syndrome and, 608 - hepatocellular carcinoma, 219 - maternal, Beckwith-Wiedemann syndrome vs., 512 - pancreatic adenocarcinoma, 223 Diamond-Blackfan anemia (DBA), 546–547 - associated with increased risk of hematological malignancies, 6–7

- differential diagnosis, 547 - genetic basis, 546 DICER1 gene, 804–823 - mutations DICER1 syndrome associated, 549 pleuropulmonary blastoma associated, 443 DICER1 syndrome, 548–555 - bone and soft tissue tumors associated with, 36 - diagnostic checklist, 552 - differential diagnosis, 552 - familial cancer syndromes, 208 with gynecologic manifestations (table), 384–385 with lung neoplasms, 444 - familial follicular cell carcinoma, 193 - familial nonmedullary thyroid carcinoma, 190–191, 593 - familial thyroid carcinoma, 189 - genetics, 549, 591 - known hereditary cancer syndromes, 489–490 - multiple endocrine neoplasia type 4, 713 - ovarian tumors, 375 - part of inherited tumor syndrome, 166 - prognosis, 376, 551 Differentiated thyroid carcinoma, DICER1 syndrome, 550 Diffuse gastric cancer, hereditary. See Hereditary diffuse gastric cancer. Diffuse hyperplasia. See Primary parathyroid hyperplasia. Diffuse lipomatous polyposis, familial adenomatous polyposis vs., 571 Diffuse mesangial sclerosis, Denys-Drash syndrome vs., 543 Diffuse microadenomatosis, multiple endocrine neoplasia type 1, 700 Diffuse-type gastric adenocarcinoma, familial neoplasia of esophagus, stomach, and small intestine (table), 271 DIRC1 gene, 804–823 DIRC2 gene, 804–823 DIRC3 gene, 804–823 Divergent differentiation, urothelial carcinoma with, bladder carcinoma and, 276 DKC1 gene, 804–823 - mutations dyskeratosis congenita associated, 560 head and neck squamous cell carcinoma, 395 DNA damage repair deficiency syndromes, predisposition to myelodysplastic syndromes/acute myeloid leukemia, 565 DNA polymerase ε and δ polyposis (POLE and POLD1 mutation-associated tumors), 538 - colonic adenoma, 229 - familial syndromes associated with colorectal carcinoma (table), 268 DNA single-strand break repair defects, disorders associated with, ataxia-telangiectasia vs., 503 DOG1 gene, 804–823 Double, parathyroid adenoma, primary parathyroid hyperplasia vs., 146 "Double" PTA, parathyroid adenoma vs., 134 Down syndrome (DS), 556–559 - acute lymphoblastic leukemia, 5 - age-specific hematologic abnormalities, 558 xiii

INDEX - age-specific hematological malignancies in children and risk compared to non-DS peers, 558 DS. See Down syndrome (DS). Ductal adenocarcinoma - pancreatic neuroendocrine neoplasms vs., 122 - prostate carcinoma, 328 Ductal carcinoma in situ (DCIS), breast/ovarian cancer syndrome (BRCA1), 612 Duodenal neuroendocrine tumors, neurofibromatosis type 1, 721 Duodenal polyposis, familial adenomatous polyposis, 265 Dyshormonogenetic goiter, hyperplastic nodules, follicular thyroid carcinoma vs., 203 Dyskeratosis congenita, 560–563 - associated neoplasms, 561 - associated with increased risk of hematological malignancies, 6–7 - diagnostic criteria, 562 - differential diagnosis, 562 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - genetic predisposition for squamous cell carcinoma of head and neck, 395 - genetics, 560–561 - Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 - selected hereditary cancer syndromes with skin manifestations, 472–473 - Shwachman-Diamond syndrome vs., 771 Dysplasia - fibrous, hyperparathyroidism-jaw tumor syndrome vs., 664 - hamartomatous polyps of GI tract vs., 254 - osteofibrous, McCune-Albright syndrome vs., 689 Dysplasia syndrome. See DICER1 syndrome. Dysplastic melanocytic nevus (atypical melanocytic nevus), atypical, cutaneous melanoma vs., 458 Dysplastic nevi, melanoma/pancreatic carcinoma syndrome, 693

E EAC. See Esophageal adenocarcinoma. Early-onset breast/ovarian cancer syndrome. See Breast/ovarian cancer syndrome (BRCA1). EC. See Embryonal carcinoma. E-cadherin, hereditary diffuse gastric cancer and, 621 Ecchordosis physaliphora, chordoma vs., 16 Eczema-thrombocytopenia-immunodeficiency syndrome. See Wiskott-Aldrich syndrome. EGFR gene, 804–823 EGFR T790M germline mutations, 444 EGL-9 homolog 1 (EGLN1), hereditary paraganglioma/pheochromocytoma syndromes and, 643 EGLN1 gene, 804–823

xiv

Ejaculatory duct (ED), significance of normal histoanatomic structures in prostate pathology (table), 338 ELAC2 gene, 804–823 ELANE gene, 804–823 ELST. See Endolymphatic sac tumor. Emberger syndrome, recently described GATA2 mutation, 565 Embryonal carcinoma (EC) - germ cell tumor, 353, 354 - tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 - tumors with glandular/tubular pattern (table), 362–363 Embryonal rhabdomyosarcoma (ERMS), 29 - of cervix DICER1 syndrome, 550 or ovary, pleuropulmonary blastoma associated, 443 - differential diagnosis, 30 - genetic testing, 30 - molecular and cytogenic findings, 37–40 Embryonal tumors, Beckwith-Wiedemann syndrome, 511–512 Emphysema, severe, lymphangioleiomyomatosis vs., 436 Enchondroma, chondrosarcoma vs., 12 Enchondromatosis, chondrosarcoma, 11 Endocrine abnormalities, ataxia-telangiectasia, 503 Endocrine hyperfunction, McCune-Albright syndrome, 687 Endocrine lesions, neurofibromatosis type 1, 721 Endocrine pancreas neoplasia, hereditary syndromes associated, 478 Endocrine pancreas table, 128–129 - inherited tumor syndrome, 128 - nonfunctioning neuroendocrine pancreatic tumors and differential diagnoses, comparison, 129 - pancreatic neuroendocrine tumor, immunohistochemistry, 128–129 - pancreatic tumorigenesis, 128 Endocrine pancreas tumors, grading and classification, 739 Endocrine system manifestations, familial adenomatous polyposis, 570 Endolymphatic sac tumor (ELST), 390–393 - differential diagnosis, 392, 393 - prognosis, 392 - von Hippel-Lindau (VHL) syndrome, 784 Endometrial carcinoma, 380–383 - differential diagnosis, 382 - prognosis, 381 - PTEN-hamartoma tumor syndromes, 753 Endometrial stromal sarcoma, molecular and cytogenic findings, 37–40 Endometrioid carcinoma, endometrial carcinoma, 381 Endometriosis, small bowel adenocarcinoma vs., 263 Endoscopic surveillance, for hereditary diffuse gastric cancer, 622 ENG gene, 804–823 Enteric adenocarcinoma, lung adenocarcinoma vs., 428 Eosinophilic RCC, with granular/eosinophilic cytoplasm, 322 EPCAM gene, 804–823 EPCAM mutation, Lynch syndrome, 683

INDEX Ependymoma, neurofibromatosis type 2, 729 Epidermal polycystic disease. See Steatocystoma multiplex. Epidermoid carcinoma. See Head and neck neoplasms, squamous cell carcinoma. Epidermoid cyst, steatocystoma multiplex vs., 773 Epithelial components, Wilms tumor, 314 Epithelioid AML (E-AML), 287 Epithelioid angiomyolipoma - clear cell renal cell carcinoma, 291 - with granular/eosinophilic cytoplasm, 322 - tumors with clear/light-staining cytoplasm (table), 321 Epithelioid gastrointestinal stromal tumor, pancreatic neuroendocrine neoplasms vs., 122 Epithelioid hemangioendothelioma, molecular and cytogenic findings, 37–40 Epithelioid hemangioma, molecular and cytogenic findings, 37–40 Epithelioid malignant peripheral nerve sheath tumor - hereditary SWI/SNF complex deficiency syndrome, 658 - rhabdoid predisposition syndrome, 763 Epithelioid sarcoma - molecular and cytogenic findings, 37–40 - rhabdoid predisposition syndrome, 763 Epithelioid schwannoma, 34 EPO genes mutations, Diamond-Blackfan anemia, 546 Epstein-Barr virus (EBV)(+) leiomyomatosis, familial infantile myofibromatosis vs., 585 ERCC6 gene, 804–823 ERCC8 gene, 804–823 ERG gene, 804–823 Eruptive vellus hair cyst, steatocystoma multiplex vs., 773 Erythroblastosis, age-specific hematologic abnormalities in Down syndrome, 558 ESCa. See Esophageal squamous cell carcinoma. Esophageal adenocarcinoma, 234–235 - diagnostic checklist, 235 - genetic predisposition, 235 Esophageal cancer, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 660 Esophageal carcinoma, dyskeratosis congenita associated, 561 Esophageal leiomyoma, multiple endocrine neoplasia type 1, 697 Esophageal neoplasia - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 271 - hereditary syndromes associated, 478 Esophageal squamous cell carcinoma, 236–237 - differential diagnosis, 237 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 271 - genetic predisposition, 237 Esophagus - adenocarcinoma of, 271 - lesions, PTEN-hamartoma tumor syndromes, 753 - table, 270–271 ETS gene, 804–823 ETV1 gene, 804–823 ETV4 gene, 804–823

ETV5 gene, 804–823 ETV6-NTRK3 gene, 804–823 Ewing sarcoma - alveolar rhabdomyosarcoma vs., 30 - molecular and cytogenic findings, 37–40 - neuroblastoma vs., 97 - osteosarcoma vs., 25 Ewing sarcoma-like round cell sarcomas, molecular and cytogenic findings, 37–40 EWS gene, 804–823 EWS-ATF1 gene, 804–823 EWS-CHOP gene, 804–823 EWS-CREB1 gene, 804–823 EWSR1 gene, 804–823 EWSR1-ATF1 gene, 804–823 EWSR1-CREB1 gene, 804–823 EWSR1-DDIT3 gene, 804–823 EWSR1-E1AF gene, 804–823 EWSR1-ERG gene, 804–823 EWSR1-ETV1 gene, 804–823 EWSR1-FEV gene, 804–823 EWSR1-FLI1 gene, 804–823 EWSR1-NR4A3 gene, 804–823 EWSR1-PBX1 gene, 804–823 EWSR1-WT1 gene, 804–823 EWSR1-ZNF444 gene, 804–823 EXT1 gene, 804–823 - mutations of, multiple osteochondromas, 630 EXT2 gene, 804–823 - mutations of, multiple osteochondromas, 630 Extracolonic neoplasms, MUTYH-associated polyposis, 719 Extramammary Paget disease, cutaneous melanoma vs., 458 Extrarenal malignant rhabdoid rumors, rhabdoid predisposition syndrome, 763 Extraskeletal myxoid chondrosarcoma, molecular and cytogenic findings, 37–40 Eye, 416–419 - manifestations, ataxia-telangiectasia, 503 - xeroderma pigmentosum, 799 Eye and ocular adnexa, genetic syndromes and neoplasms involving (table), 416

F FA. See Fanconi anemia. FAH gene, 804–823 Fallopian tube carcinoma, 372–373 - breast/ovarian cancer syndrome (BRCA1), 611 - breast/ovarian cancer syndrome (BRCA2), 618 - genetic testing, 373 - hereditary breast/ovarian cancer, 373 - prognosis, 373 FAM123B gene, 804–823 - mutations, Wilms tumor, 313 Familial acute myeloid leukemia, 564–567 - associated neoplasms, 566

xv

INDEX - associated with increased risk of hematological malignancies, 6–7 - genetics, 566 Familial adenomatous polyposis (FAP), 537, 568–575 - adrenal cortical adenoma, 59 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - bone and soft tissue tumors associated with, 36 - colonic adenoma, 229 - diagnostic checklist, 571 - differential diagnosis, 570–571 - duodenal polyposis, 265 - extraintestinal features, 572 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial cancer syndromes, 208 with gynecologic manifestations (table), 384–385 with head and neck lesions and neoplasms, 400–402 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 - familial follicular cell carcinoma, 193 - familial nonmedullary thyroid carcinoma, 190, 592 - familial syndromes associated with colorectal carcinoma (table), 268 - familial thyroid carcinoma, 189 - genetic predisposition, 568–569 - genetic syndromes associated with CNS neoplasms, 412 - genetic testing, 570 - hepatoblastoma, 213 - hepatocellular carcinoma, 219 - hereditary cancer syndromes associated, 498 - hereditary pancreatic cancer syndrome, 637 - juvenile polyposis syndrome vs., 670 - known hereditary cancer syndromes, 489–490 - Lynch syndrome vs., 682 - melanoma/pancreatic carcinoma syndrome vs., 694 - prognosis, 569 - risk factor for small bowel adenocarcinoma, 263 - variants, 572 Familial adenomatous polyposis syndrome (attenuated form), hereditary mixed polyposis syndrome vs., 629 Familial atypical mole and melanoma (FAMM), known hereditary cancer syndromes, 489–490 Familial atypical multiple mole melanoma, familial biliary tract, liver, and pancreas neoplasms, 226–227 Familial atypical multiple mole melanoma syndrome - hereditary pancreatic cancer syndrome, 637 - pancreatic adenocarcinoma, 223 Familial Barrett esophagus, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Familial benign hypocalciuric hypercalcemia (FBHH) - familial isolated hyperparathyroidism vs., 588 - primary hyperparathyroidism, 152–153 Familial cerebelloretinal angiomatosis. See von HippelLindau (VHL) syndrome. Familial chordoma, 15, 576–577 - associated neoplasms, 576–577 - bone and soft tissue tumors associated with, 36 xvi

- genetics, 576 - prognosis, 577 Familial clear cell renal cell carcinoma - clear cell renal cell carcinoma, 291 - as familial renal tumors (table), 320 - hereditary or familial renal tumor syndrome, 654 - hereditary renal epithelial tumors, 652 Familial cylindromatosis (FC). See also Brooke-Spiegler syndrome (BSS). - familial cancer syndromes with salivary gland neoplasms, 404 Familial cylindromatosis syndrome - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Familial cystic parathyroid adenomatosis. See Hyperparathyroidism-jaw tumor syndrome. Familial erythrocytosis type 4, pheochromocytoma/paraganglioma associated with, 115 Familial esophageal tumors, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Familial follicular cell carcinoma - classification, 193 - familial cancer syndromes, 193 Familial follicular cell-derived carcinoma, 590–591 Familial follicular cell tumors, familial thyroid carcinoma, 189 Familial FTC. See Follicular thyroid carcinoma. Familial gastric cancer and lobular breast cancer, breast carcinoma, 54 Familial gastric cancer and lobular breast cancer syndrome, 48–49 Familial gastrointestinal stromal tumor, 578–583 - genetic syndromes associated, 581 - syndromes/genetics, 579–580 Carney-Stratakis syndrome, 579–580 Carney triad, 579 KIT germline mutations, 579 neurofibromatosis type 1, 580 PDGFRA germline mutations, 579 Familial GIST (FGIST). See Familial gastrointestinal stromal tumor. Familial hypocalciuric hypercalcemia, primary hyperparathyroidism, 152 Familial idiopathic basal ganglia calcification, familial infantile myofibromatosis associated, 584 Familial infantile myofibromatosis (FIM), 584–585 - differential diagnosis, 585 - genetics, 584 Familial isolated hyperparathyroidism (FIHP), 586–589 - associated conditions, 587 - differential diagnosis, 587–588 - genetic tests, 587 - genetics, 586 - parathyroid carcinoma, 137, 139 - parathyroid hyperplasia, 143 - primary hyperparathyroidism, 152–153

INDEX Familial isolated pituitary adenoma - multiple endocrine neoplasia type 1 vs., 699 - multiple endocrine neoplasia type 4, 713 - part of inherited tumor syndrome, 166 - pituitary adenoma, 159 Familial isolated primary hyperparathyroidism (FIPHT). See Familial isolated hyperparathyroidism (FIHP). Familial medullary thyroid carcinoma, 189 Familial melanoma - bone and soft tissue tumors associated with, 36 - hereditary cancer syndromes associated, 498 Familial multiple basaloid follicular hamartomas - basal cell nevus syndrome/Gorlin syndrome vs., 507 - selected hereditary cancer syndromes with skin manifestations, 472–473 Familial multiple discoid fibromas, selected hereditary cancer syndromes with skin manifestations, 472–473 Familial nephroblastoma. See Familial Wilms tumor. Familial neuroblastoma, 96 Familial nonclear cell renal cell carcinoma, hereditary renal epithelial tumors, 653 Familial nonmedullary thyroid carcinoma, 189, 590–595. See also Follicular thyroid carcinoma. - associated neoplasms, 592–593 - classification, 208 - familial cancer syndromes, 208 - genetics, 591–592 familial papillary thyroid carcinoma with multinodular goiter, 592 familial papillary thyroid carcinoma with papillary renal cell carcinoma, 592 pure FPTC ± oxyphilia, 592 syndromes characterized by predominance of nonthyroidal tumors, 591 syndromes with predominance of nonmedullary thyroid carcinoma, 591–592 type 1 familial nonmedullary thyroid carcinoma, 592 Familial oncocytoma - familial renal tumors (table), 320 - hereditary or familial renal tumor syndrome, 654 - renal oncocytoma, chromophobe, and hybrid oncocytic tumors, 305 Familial ovarian germ cell tumor, familial testicular germ cell tumors, 600 Familial papillary thyroid carcinoma (FPTC) - with multinodular goiter, 592 - with papillary renal cell carcinoma, 592 - pure familial papillary thyroid carcinoma, 592 Familial paraganglioma, known hereditary cancer syndromes, 489–490 Familial paraganglioma pheochromocytoma syndrome, 596–599 - differential diagnosis, 598 - genetics, 596–597 - prognosis, 597 Familial paraganglioma pheochromocytoma syndromeassociated RCC. See Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC). Familial paraganglioma type 2, pheochromocytomaassociated syndromes (table), 646

Familial paraganglioma type 3, pheochromocytomaassociated syndromes (table), 646 Familial paraganglioma type 4, pheochromocytomaassociated syndromes (table), 646 Familial paraganglioma type 5, pheochromocytomaassociated syndromes (table), 646 Familial PGL/PCC syndromes, hereditary paraganglioma/pheochromocytoma syndromes, 643 Familial pheochromocytoma paraganglioma syndrome, part of inherited tumor syndrome, 166 Familial platelet disorder - associated with increased risk of hematological malignancies, 6–7 - with predisposition to myeloid, malignancy due to RUNX1 mutations, acute lymphoblastic leukemia, 5 Familial platelet disorder/acute myeloid leukemia (FPD/AML), familial acute myeloid leukemia associated, 566 Familial pleuropulmonary blastoma, familial cancer syndromes with lung neoplasms, 444 Familial polyposis coli. See Familial adenomatous polyposis (FAP). Familial posterior fossa brain tumor syndrome. See Rhabdoid predisposition syndrome. Familial renal oncocytoma, hereditary renal epithelial tumors, 653 Familial renal UCa, renal urothelial carcinoma, 345 Familial retinoblastoma, hereditary cancer syndromes associated, 498 Familial schwannomatosis, hereditary SWI/SNF complex deficiency syndrome, 658 Familial sex cord-stromal tumors, 601 Familial somatotropinoma syndrome, isolated, pituitary adenoma, 159 Familial syndromes, medullary thyroid carcinoma, 186 Familial testicular germ cell tumors, 600, 601 - familial testicular tumors (table), 362 Familial testicular tumor, 600–601 - genetic factors, 600 - genetic loci implicated, 601 Familial thyroid carcinoma, 188–199 - diagnostic checklist, 188 - differential diagnosis, 192 - familial follicular cell carcinoma classification, 193 - genetic testing, 192 - sporadic carcinoma and, 208 Familial tumor syndromes, pathology, 476–483 - bone and soft tissue-related hereditary syndromes, 480 - gynecology, 480 - head and neck, 479 - hematologic, 479 - immunohistochemistry, 480 - lung, 479 - practical guide to pathological recognition, 476 - recognition of morphological characteristics, 477 - syndromes known to be associated with neoplasia, 477 breast, 479 central nervous system, 479–480 endocrine system, 477–478 gastrointestinal tract, 478–479 xvii

INDEX genitourinary tract, 478 skin, 479 Familial uveal melanoma, 602–603 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - genetics, 602 Familial Wilms tumor (FWT), 313, 604–605 - familial renal tumors (table), 320 - genetics, 604 - prognosis, 605 Familiar medullary hyperplasia, 89 FANCA gene, 804–823 - Fanconi anemia, 606 FANCB gene, 804–823 - Fanconi anemia, 606 FANCC gene, 804–823 - Fanconi anemia, 606 FANCD1 gene, 804–823 FANCD2 gene, 804–823 FANCE gene, 804–823 - Fanconi anemia, 606 FANCF gene, 804–823 - Fanconi anemia, 606 FANCG gene, 804–823 - Fanconi anemia, 606 FANCI gene, 804–823 FANCJ gene, 804–823 FANCL gene, 804–823 - Fanconi anemia, 606 FANCM gene, 804–823 - Fanconi anemia, 606 FANCN gene, 804–823 Fanconi anemia, 606–607 - acute lymphoblastic leukemia, 5 - associated with increased risk of hematological malignancies, 6–7 - Diamond-Blackfan anemia vs., 547 - dyskeratosis congenita vs., 562 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - genetic predisposition for squamous cell carcinoma of head and neck, 395 - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 - Nijmegen breakage syndrome vs., 735 - pancreatic adenocarcinoma, 223 - Shwachman-Diamond syndrome vs., 771 FANCx gene, 804–823 FAP. See Familial adenomatous polyposis. Fatigue, parathyroid carcinoma, 137 FBHH. See Familial benign hypocalciuric hypercalcemia. FBXW7 gene, 804–823 Fetal adenocarcinoma, lung adenocarcinoma vs., 428 α-Fetoprotein in serum, biomarker for ataxiatelangiectasia, 502–503 Fever, familial Wilms tumor and, 605 FGFR2 gene, 804–823 FGFR3 gene, 804–823

xviii

FH-deficient renal cell carcinoma, papillary renal cell carcinoma vs., 301 FH gene, 804–823 - mutation, hereditary leiomyomatosis and renal cell carcinoma, 625 FHH. See Familial hypocalciuric hypercalcemia. FHIT gene, 804–823 Fibrofolliculoma/trichodiscoma - associated with Birt-Hogg-Dubé syndrome, 518 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Fibrohistiocytic tumors, Li-Fraumeni syndrome, 676 Fibroma - cardiac, basal cell nevus syndrome/Gorlin syndrome, 507 - familial multiple discoid fibromas, Birt-Hogg-Dubé syndrome vs., 519 - ovarian fibroma, basal cell nevus syndrome/Gorlin syndrome, 507 - perifollicular, associated with Birt-Hogg-Dubé syndrome, 518–519 - tendon sheath, molecular and cytogenic findings, 37–40 Fibroma-like PEComa, tuberous sclerosis complex (TSC), 775 Fibromatosis - extraabdominal/desmoid, molecular and cytogenic findings, 37–40 - gastrointestinal stromal tumor vs., 246 Fibroosseous pseudotumor, molecular and cytogenic findings, 37–40 Fibrous dysplasia (FD). See also McCune-Albright syndrome. - hyperparathyroidism-jaw tumor syndrome vs., 664 - molecular and cytogenic findings, 37–40 Fibrous hamartoma of infancy, familial infantile myofibromatosis vs., 585 Fibrous papules (angiofibromas), selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Fibroxanthoma, atypical, cutaneous squamous cell carcinoma vs., 462 FIHP. See Familial isolated hyperparathyroidism; Familial isolated hyperparathyroidism (FIHP). FIM. See Familial infantile myofibromatosis (FIM). FIPA. See Familial isolated pituitary adenoma. Flat pathway, bladder carcinoma and, 275 Flat urothelial neoplasms, renal urothelial carcinoma, 345 FLCN gene, 804–823 - mutations, Birt-Hogg-Dubé syndrome associated, 518 FLI1 gene, 804–823 FMTC. See Familial medullary thyroid carcinoma. FNMTC. See Familial nonmedullary thyroid carcinoma. Foamy gland (xanthomatous) variant, prostate carcinoma, 328 Focal nodular hyperplasia, hepatocellular carcinoma vs., 220 Focal palmoplantar and oral mucosa hyperkeratosis syndrome, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661

INDEX Follicular, Hürthle, or papillary thyroid carcinoma, parathyroid carcinoma vs., 154 Follicular adenoma, follicular thyroid carcinoma vs., 203 Follicular bronchiolitis, lymphangioleiomyomatosis vs., 436 Follicular carcinoma. See also Follicular thyroid carcinoma. - medullary thyroid carcinoma vs., 180 Follicular cell carcinoma, familial - classification, 193 - familial cancer syndromes, 193 - thyroid carcinoma vs., 192 Follicular cell-derived carcinoma, familial, 590–591 Follicular/papillary thyroid, differential diagnosis of tumors secondarily involving parathyroid, 154 Follicular thyroid carcinoma, 200–207 - classification, 204 - diagnostic checklist, 203 - differential diagnosis, 203, 204 - familial setting, 204 - genetic testing, 202–203 - prognosis, 201 - PTEN-hamartoma tumor syndromes, 753 FOXA1 gene, 804–823 Fracture callus - chondrosarcoma vs., 12 - osteosarcoma vs., 24 Frasier syndrome, 794 - Denys-Drash syndrome vs., 543 - familial renal tumors (table), 320 - Wilms tumor, 313 FTC. See Follicular thyroid carcinoma. Fumarate hydratase (FH), 643 - hereditary paraganglioma/pheochromocytoma syndromes and, 643 - pheochromocytoma-associated syndromes (table), 646 Functional and nonfunctional adrenal adenoma. See Adrenal cortical adenoma. Functioning macrotumors, multiple endocrine neoplasia type 1, 700 Fundic gland polyps ± dysplasia, familial neoplasia of esophagus, stomach, and small intestine (table), 271 FUS-ATF1 gene, 804–823 FUS-CREB3L1 gene, 804–823 FUS-CREB3L2 gene, 804–823 FUS-ERG gene, 804–823 FWT. See Familial Wilms tumor. FWT1 gene, 804–823 - mutations, familial Wilms tumor and, 604 FWT2 mutations, familial Wilms tumor and, 604

G

G6PC gene, 804–823 Gall bladder cancer, breast/ovarian cancer syndrome (BRCA2), 618 GALNT14 gene mutations, hereditary neuroblastoma and, 633 Ganglioneuroblastoma, 95

Ganglioneuroma, 93, 95 - hereditary neuroblastoma and, 633 - hereditary paraganglioma/pheochromocytoma syndromes and, 644 - neuroblastoma vs., 97 Ganglioneuromatosis, multiple endocrine neoplasia type 2, 705 Gardner syndrome - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial cancer syndromes with salivary gland neoplasms, 404 - hereditary cancer syndromes associated, 498 - as variant of familial adenomatous polyposis, 572 Gardner syndrome/familial polyposis of colon, selected hereditary cancer syndromes with skin manifestations, 472–473 Gastrectomy, prophylactic total, for hereditary diffuse gastric cancer, 622 Gastric adenocarcinoma, 238–243 - differential diagnosis, 241 - dyskeratosis congenita associated, 561 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Gastric adenoma, familial neoplasia of esophagus, stomach, and small intestine (table), 271 Gastric cancer, hereditary diffuse. See Hereditary diffuse gastric cancer. Gastric carcinomas, juvenile polyposis syndrome, 670 Gastric dysplasia, gastric adenocarcinoma vs., 241 Gastric juvenile polyposis, 669 Gastric lymphoma, gastric adenocarcinoma vs., 241 Gastric tumors, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Gastric-type endocervical adenocarcinoma (GAS), cervical carcinoma, 371 Gastric xanthoma, gastric adenocarcinoma vs., 241 Gastrinoma syndrome - pancreatic neuroendocrine tumor, 121, 123 - well-differentiated pancreatic neuroendocrine neoplasm, 121 Gastrinomas, 737 Gastroblastoma, molecular and cytogenic findings, 37–40 Gastrointestinal autonomic nerve tumor. See Gastrointestinal stromal tumor. Gastrointestinal cancer, breast/ovarian cancer syndrome (BRCA2), 618 Gastrointestinal lesions, familial adenomatous polyposis associated, 569 Gastrointestinal neoplasms - esophageal adenocarcinoma, 234–235 diagnostic checklist, 235 genetic predisposition, 235 - esophageal squamous cell carcinoma, 236–237 differential diagnosis, 237 genetic predisposition, 237 - gastrointestinal stromal tumor, 244–251 differential diagnosis, 246 prognosis, 245 xix

INDEX - hamartomatous polyposis syndromes, 252–261 diagnostic checklist, 254 differential diagnosis, 254 prognosis, 253 - hereditary syndromes associated, 478–479 Gastrointestinal stromal tumor (GIST), 244–251. See also Familial gastrointestinal stromal tumor. - associated with SDH-related syndromes, 114 - differential diagnosis, 246 - familial, 578–583 - familial neoplasia of esophagus, stomach, and small intestine (table), 271 - molecular and cytogenic findings, 37–40 - neurofibromatosis type 1, 721 - prognosis, 245 GATA1 genes mutations, Diamond-Blackfan anemia, 546 GATA2 gene, 804–823 - mutation, 565 Emberger syndrome, 565 MonoMAC syndrome, 565 GATA3 gene, 804–823 GCCR, mutations of, glucagon cell hyperplasia and neoplasia and, 608 GCHN. See Glucagon cell hyperplasia and neoplasia. GCHN syndrome, pancreatic neuroendocrine neoplasms, 120 GCNIS. See Germ cell neoplasia in situ. GCT. See Germ cell tumor. Generalized basaloid follicular hamartoma syndrome - basal cell nevus syndrome/Gorlin syndrome vs., 507 - selected hereditary cancer syndromes with skin manifestations, 472–473 Generalized juvenile polyposis, 669 Genetic counseling - for McCune-Albright syndrome, 688 - PTEN-hamartoma tumor syndromes, 752 Genetic risk assessment of at-risk individuals, 485 Genetic syndrome, colonic adenoma, 229 Genetic testing - American Society of Clinical Oncology (ASCO) clinical utility of genetic testing, 485 indications for testing, 485 - familial adenomatous polyposis, 570 - familial isolated hyperparathyroidism associated, 587 - genetic counseling, 486 - special issues related to genetic testing research, 486 Genital nevus, cutaneous melanoma vs., 458 Genitalia, Denys-Drash syndrome, 542 Genitourinary neoplasms - basal cell nevus syndrome/Gorlin syndrome, 507 - germ cell tumor. See Germ cell tumor. - hereditary syndromes associated, 478 - prostate carcinoma, 326–337 differential diagnosis, 329, 330 Gleason Grading System, 329 prognosis, 327 - ureter urothelial carcinoma, 348–349 prognosis, 349 Germ cell neoplasia in situ (GCNIS), 353, 354 Germ cell tumor (GCT), 352–357 - older adult, 353 xx

- pediatric or prepubertal, 353 - postpubertal, 353 - prognosis, 353 Germline BRCA2 mutants, lung adenocarcinoma associated, 427 Germline KIT mutation, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Germline mutations of Fanconi anemia-BRCA pathway, familial cancer syndromes with gynecologic manifestations (table), 384–385 Germline mutations of genes in Fanconi anemia-BRCA pathway, ovarian tumors, 375 Germline NF2 mutation, schwannomatosis associated, 420 Germline PDGFRA mutation, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Giant cell fibroblastoma, molecular and cytogenic findings, 37–40 Giant cell tumor - familial cancer syndromes with bone and soft tissue tumors, 36 - molecular and cytogenic findings, 37–40 - osteosarcoma vs., 25 Giant hyperplastic polyposis, familial syndromes associated with colorectal carcinoma (table), 268 Gingival fibromatosis, hereditary, Costello syndrome vs., 541 GIST. See Gastrointestinal stromal tumor. GJB6 gene, 804–823 Gland adenoma, ceruminous, endolymphatic sac tumor vs., 392 Glial microhamartomas, neurofibromatosis type 2, 728 Glioblastoma, Lynch syndrome, 681 Gliomas, Noonan syndrome, 759 Glomangiomas, pheochromocytoma/paraganglioma vs., 107 Glomus tumors - molecular and cytogenic findings, 37–40 - pheochromocytoma/paraganglioma vs., 107 Glucagon, multiple endocrine neoplasia type 1, 700 Glucagon cell adenomatosis. See Glucagon cell hyperplasia and neoplasia. Glucagon cell hyperplasia, 608–609 Glucagon cell hyperplasia and neoplasia (GCHN) - pancreatic neuroendocrine tumors, 737, 738 - part of inherited tumor syndromes, 128 Glucagon cell neoplasia, 608–609 Glucagonoma syndrome. See also Glucagon cell hyperplasia and neoplasia. - pancreatic neuroendocrine tumor, 120–121, 123 - prognosis, 121 - well-differentiated pancreatic neuroendocrine neoplasm, 121 Glucagonomas, 737 Glycogen storage disease, familial biliary tract, liver, and pancreas neoplasms, 226–227 GNA11, familial uveal melanoma, 602 GNA11 gene, 804–823 GNAQ, familial uveal melanoma, 602 GNAQ gene, 804–823

INDEX GNAS gene, 804–823 GNAS1 gene, 804–823 - mutations, follicular carcinoma, 201 Gonadal malignancies, Denys-Drash syndrome, 543 Gonadoblastoma, Denys-Drash syndrome associated, 543 Gorlin-Goltz syndrome. See Basal cell nevus syndrome/Gorlin syndrome. GPC3 gene, 804–823 GREM1 gene, hereditary mixed polyposis syndrome, 628 GRFomas, 737 GSTM1 gene, 804–823 GSTP1 gene, 804–823 Gynecologic carcinomas involving bladder, bladder carcinoma vs., 277 Gynecologic neoplasms - cervical carcinoma, 370–371 genetic testing, 371 prognosis, 371 - endometrial carcinoma, 380–383 differential diagnosis, 382 genetic testing, 382 prognosis, 381 - fallopian tube carcinoma, 372–373 genetic testing, 373 hereditary breast/ovarian cancer, 373 prognosis, 373 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - hereditary syndromes associated, 480 Gynecologic tumors, 384–387 Gynecological neoplasms, ovarian tumors, 374–379 - prognosis, 376

H

H19 gene, 804–823 - abnormalities, Beckwith-Wiedemann syndrome, 511 Hamartoma - hyperparathyroidism-jaw tumor syndrome, 663 - nasal chondromesenchymal, pleuropulmonary blastoma associated, 443 Hamartomatous polyposis syndromes, gastrointestinal tract, 252–261 - diagnostic checklist, 254 - differential diagnosis, 254 - prognosis, 253 Hamartomatous polyps - familial neoplasia colon and rectum (table), 268–269 - Peutz-Jeghers, 744–749. See also Peutz-Jeghers polyposis syndrome. Hashimoto thyroiditis, hyperplastic nodules, follicular thyroid carcinoma vs., 203 HAX1 gene, 804–823 HB. See Hepatoblastoma. HCC. See Hepatocellular carcinoma. HDGC. See Hereditary diffuse gastric cancer. Head and neck neoplasms - endolymphatic sac tumor, 390–393

- familial cancer syndromes with head and neck lesions and neoplasms, 400–403 - hereditary syndromes associated, 479 - salivary glands (table), 404–409 - squamous cell carcinoma, 394–399 differential diagnosis, 396 Heffner tumor. See Endolymphatic sac tumor (ELST). Hemangioblastoma, von Hippel-Lindau (VHL) syndrome, 783 Hemangioma, molecular and cytogenic findings, 37–40 Hematemesis, Peutz-Jeghers polyposis syndrome, 745 Hematologic malignancies, Li-Fraumeni syndrome, 676 Hematologic neoplasms, Fanconi anemia, 607 Hematological malignancies. See Blood and bone marrow neoplasms. Hematolymphoid malignancies - ataxia-telangiectasia, 503 - Bloom syndrome associated, 523 - differential diagnosis of tumors secondarily involving parathyroid, 154 Hematuria, familial Wilms tumor and, 605 Hemihyperplasia, Beckwith-Wiedemann syndrome vs., 513 Hemihypertrophy - adrenal cortical neoplasms in children, 71 - isolated (idiopathic) familial renal tumors (table), 320 Wilms tumor, 313 Hemihypoplasia, Beckwith-Wiedemann syndrome vs., 512 Hemochromatosis, familial biliary tract, liver, and pancreas neoplasms, 226–227 Hemosiderotic fibrolipomatous tumor, molecular and cytogenic findings, 37–40 Hepatic adenoma, hepatoblastoma vs., 214 Hepatobiliary and pancreas - biliary tract/liver/pancreas table, 226–227 familial neoplasia, 226 syndromes, 226–227 - hepatoblastoma, 212–217 differential diagnosis, 214 genetics, 213 prognosis, 213 - hepatocellular carcinoma, 218–221 cytogenetics, 220 differential diagnosis, 220 molecular genetics, 220 prognosis, 219–220 - pancreatic adenocarcinoma, 222–225 cytogenetics, 223–224 differential diagnosis, 224 molecular genetics, 223–224 prognosis, 223 Hepatoblastoma, 212–217 - adrenal cortical neoplasms in children vs., 72 - Beckwith-Wiedemann syndrome, 512 - differential diagnosis, 214 - familial neoplasia of biliary tract, liver, and pancreas, 226 - genetics, 213 - prognosis, 213 - rhabdoid predisposition syndrome, 763 xxi

INDEX Hepatocellular adenoma/carcinoma - familial neoplasia of biliary tract, liver, and pancreas, 226 - hepatocellular carcinoma vs., 220 Hepatocellular anemia, Fanconi anemia, 607 Hepatocellular carcinoma, 218–221 - adrenal cortical adenoma vs., 85 - adrenal cortical carcinoma vs., 65 - cytogenetics, 220 - differential diagnosis, 220 tumors secondarily involving parathyroid, 154 - hepatoblastoma vs., 214 - molecular genetics, 220 - pheochromocytoma/paraganglioma vs., 107 - prognosis, 219–220 HER2 gene, 804–823 Hereditary breast, familial biliary tract, liver, and pancreas neoplasms, 226–227 Hereditary breast and ovarian cancer (HBOC), known hereditary cancer syndromes, 489–490 Hereditary breast cancer syndrome, pancreatic adenocarcinoma, 223 Hereditary breast/ovarian cancer syndrome (BRCA1), 47–48, 54, 610–615 - associated neoplasms, 611–612 - fallopian tube carcinoma, 373 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with lung neoplasms, 444 - genetics, 611 - hereditary pancreatic cancer syndrome, 637 - ovarian tumors, 375 - prognosis, 376, 611 Hereditary breast/ovarian cancer syndrome (BRCA2), 48, 54 - fallopian tube carcinoma, 373 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with lung neoplasms, 444 - hereditary pancreatic cancer syndrome, 637 - ovarian tumors, 375 - prognosis, 376 Hereditary breast/ovarian carcinoma, selected hereditary cancer syndromes with skin manifestations, 472–473 Hereditary diffuse gastric cancer (HDGC), 620–623 - associated neoplasms, 622 - cancer risk management, 622 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 - gastric adenocarcinoma, 239 - genetics, 621 - known hereditary cancer syndromes, 489–490 Hereditary esophageal-vulvar syndrome, familial cancer syndromes with gynecologic manifestations (table), 384–385 Hereditary flat adenoma syndrome. See Familial adenomatous polyposis (FAP). Hereditary gastric polyposis syndrome, gastric adenocarcinoma, 239

xxii

Hereditary gastrointestinal polyposis syndromes, risk factor for small bowel adenocarcinoma, 263 Hereditary gingival fibromatosis, Costello syndrome vs., 541 Hereditary hyperparathyroidism-jaw tumor - parathyroid adenoma, 131 - parathyroid carcinoma, 137, 139 Hereditary hyperparathyroidism-jaw tumor syndrome - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial renal tumors (table), 320 - hereditary or familial renal tumor syndrome, 654 - hereditary renal epithelial tumors, 653 - parathyroid hyperplasia, 143–144 Hereditary infundibulocystic basal cell carcinoma - basal cell nevus syndrome/Gorlin syndrome vs., 507 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Hereditary leiomyoma renal cell carcinoma, pheochromocytoma/paraganglioma associated with, 115 Hereditary leiomyomatosis - with papillary or tubulopapillary architecture (table), 321 - and renal cell carcinoma, familial renal tumors (table), 320 Hereditary leiomyomatosis and renal cell carcinoma - familial cancer syndromes with gynecologic manifestations (table), 384–385 - hereditary or familial renal tumor syndrome, 654 Hereditary leiomyomatosis and renal cell carcinoma syndrome, 624–627 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - associated neoplasms, 625 - genetics, 626 - Lehtonen Modified Criteria for diagnosis of, 626 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Hereditary melanoma syndrome, BAP1 tumor predisposition syndrome vs., 505 Hereditary mixed polyposis syndrome (HMPS), 538, 628–629 - colonic adenoma, 229 - differential diagnosis, 629 - familial adenomatous polyposis vs., 571 - familial syndromes associated with colorectal carcinoma (table), 268 - juvenile polyposis syndrome vs., 670 - known hereditary cancer syndromes, 489–490 - Lynch syndrome vs., 682 - prognosis, 629 Hereditary multiple exostoses (HME). See also Multiple osteochondromas. - bone and soft tissue tumors associated with, 36 - chondrosarcoma, 11

INDEX Hereditary multiple melanoma - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Hereditary neuroblastoma, 632–635 - classification of, 634 - prognostic classification, 634 Hereditary nonpolyposis colon cancer, neurofibromatosis type 1 vs., 723 Hereditary nonpolyposis colorectal cancer, 537. See also Lynch syndrome. - adrenal cortical neoplasms in children, 71, 73 - familial syndromes associated with colorectal carcinoma (table), 268 Hereditary nonpolyposis colorectal cancer syndrome, pancreatic adenocarcinoma, 223 Hereditary nonpolyposis colorectal carcinoma, melanoma/pancreatic carcinoma syndrome vs., 694 Hereditary pancreatic cancer syndrome, 636–639 - genetics, 636, 637 - histogenesis, 637 Hereditary pancreatitis - familial biliary tract, liver, and pancreas neoplasms, 226–227 - hereditary pancreatic cancer syndrome, 637 - melanoma/pancreatic carcinoma syndrome vs., 694 - pancreatic adenocarcinoma, 223 Hereditary papillary renal cell carcinoma (HPRCC), 640–641 - familial renal tumors (table), 320 - genetics, 640 - hereditary or familial renal tumor syndrome, 654 Hereditary papillary renal cell carcinoma syndrome, papillary renal cell carcinoma and, 301 Hereditary paraganglioma/pheochromocytoma syndromes, 642–649 - genetics, 643 Hereditary prostate cancer, 650–651 - genetics, 650 - indications, 651 - lifetime risk, 651 - prostate carcinoma, 327 Hereditary PTAs, 131 Hereditary renal cell carcinoma, hereditary SWI/SNF complex deficiency syndrome, 658 Hereditary renal epithelial tumors, others, 652–655 - constitutional chromosome 3 translocation, 652 - familial clear cell renal cell carcinoma, 652 - familial nonclear cell renal cell carcinoma, 653 - familial renal oncocytoma, 653 - hereditary hyperparathyroidism-jaw tumor syndrome, 653 - hereditary or familial renal tumor syndrome, 654 - papillary thyroid carcinoma with associated neoplasia, 653 Hereditary retinoblastoma, 656–657 - associated neoplasms, 657 - bone and soft tissue tumors associated with, 36

- genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - genetics, 656 - known hereditary cancer syndromes, 489–490 - Knudson 2-hit hypothesis, 656 - lung adenocarcinoma associated, 427 - osteosarcoma, 780 Hereditary retinoblastoma syndrome, familial cancer syndromes associated with lung neoplasms, 444 Hereditary syndromes associated with neoplasia, 477 - bone and soft tissue-related hereditary syndromes, 480 - breast, 479 - central nervous system, 479–480 - endocrine system, 477–478 - gastrointestinal tract, 478–479 - genitourinary tract, 478 - gynecology, 480 - head and neck, 479 - hematologic, 479 - lung, 479 - skin, 479 Hereditary tumor syndromes - with increased melanoma risk, melanoma/pancreatic carcinoma syndrome vs., 694 - with increased risk of pancreatic cancer, melanoma/pancreatic carcinoma syndrome vs., 694 Heterotopic or primary choroid plexus papilloma, endolymphatic sac tumor vs., 392 HFE gene, 804–823 Hibernoma, molecular and cytogenic findings, 37–40 Hidradenocarcinoma, sebaceous carcinoma vs., 468 Hidrotic ectodermal dysplasia, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 High-grade papillary urothelial carcinoma, bladder carcinoma and, 276 High-grade poorly differentiated carcinoma (table), 282 Hirschsprung disease - multiple endocrine neoplasia type 2, 705 - multiple endocrine neoplasia type 2 vs., 707 Histiocytosis, pulmonary Langerhans cell, lymphangioleiomyomatosis vs., 436 HLRCC syndrome-associated renal cell carcinoma (HLRCCassociated RCC), 296–299 - diagnostic checklist, 298 - differential diagnosis, 298 - genetic testing, 298 - prognosis, 297 - succinate dehydrogenase-deficient renal cell carcinoma vs., 310 HMGA2 gene, 804–823 HMGA2-LPP gene, 804–823 HMGIC gene, 804–823 HMPS. See Hereditary mixed polyposis syndrome. Hodgkin lymphoma, dyskeratosis congenita associated, 561 Hornstein-Birt-Hogg-Dubé syndrome. See Birt-Hogg-Dubé syndrome (BHDS).

xxiii

INDEX Hornstein-Knickerberg syndrome. See Birt-Hogg-Dubé syndrome (BHDS). Howel-Evans syndrome, selected hereditary cancer syndromes with skin manifestations, 472–473 Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 660–661 - classification, 660 - differential diagnosis, 660 - genetics, 660 HOXB13, hereditary prostate cancer, 651 Hoyeraal-Hreidarsson syndrome. See Dyskeratosis congenita. HPD gene, 804–823 HPRCC. See Hereditary papillary renal cell carcinoma (HPRCC). HPT-JT. See Hyperparathyroidism-jaw tumor syndrome. HRAS gene, 804–823 HRAS mutation, Costello syndrome associated, 540 HRPT2 gene, 804–823 HRPT2 gene mutations - 1q25-q31, hyperparathyroidism-jaw tumor syndrome, 662 - familial isolated hyperparathyroidism associated, 586 - genetic testing, 587 - parathyroid adenoma, 133 - parathyroid carcinoma, 137 - parathyroid hyperplasia, 146 hSNF5 gene, 804–823 HSPBAP1 gene, 804–823 Human papillomavirus (HPV), cutaneous squamous cell carcinoma associated, 461 Hutchinson-Gilford progeria, Werner syndrome/progeria vs., 791 Hyalinizing clear cell carcinoma of minor salivary glands, molecular changes described in salivary gland tumors (table), 405–406 Hyalinizing trabecular tumor - follicular thyroid carcinoma vs., 203 - medullary thyroid carcinoma vs., 180 Hybrid oncocytic chromophobe tumor (HOCT), 305 Hybrid tumors, schwannomatosis, 767 Hyperkeratoses, Werner syndrome/progeria, 790–791 Hyperparathyroidism - familial isolated, 586–589 - hyperparathyroidism-jaw tumor syndrome, 663 - multiple endocrine neoplasia type 1, 696 - multiple endocrine neoplasia type 2, 705, 708 - multiple endocrine neoplasia type 2 vs., 707 Hyperparathyroidism-jaw tumor syndrome (HPT-JT), 662–667 - bone and soft tissue tumors associated with, 36 - differential diagnosis, 664 - familial isolated hyperparathyroidism vs., 587–588 - McCune-Albright syndrome vs., 689 - multiple endocrine neoplasia type 1 vs., 699 - multiple endocrine neoplasia type 4 vs., 714 - primary hyperparathyroidism, 152 - prognosis, 663 Hyperplasia, pseudoepitheliomatous, cutaneous squamous cell carcinoma vs., 462 xxiv

Hyperplasia/papillary pathway, bladder carcinoma and, 275 Hyperplastic nodules - dyshormonogenetic goiter, follicular thyroid carcinoma vs., 203 - Hashimoto thyroiditis, follicular thyroid carcinoma vs., 203 Hyperplastic polyposis, familial adenomatous polyposis vs., 570–571 Hyperplastic polyps (gastric), hamartomatous polyps of GI tract vs., 254 Hyperprolactinemia, pituitary hyperplasia, 165 Hypertension, familial Wilms tumor and, 605 Hyperthyroidism, McCune-Albright syndrome, 687

I

Identification of at-risk individuals, 485 IDH1 gene, 804–823 IDH2 gene, 804–823 Idiopathic thrombocytopenic purpura (ITP), WiskottAldrich syndrome vs., 797 IFS. See Isolated familial somatotropinoma syndrome. IGF2 gene, 804–823 - abnormalities Beckwith-Wiedemann syndrome, 511 Wilms tumor, 313 ILCHSCN. See Intratubular large-cell hyalinizing Sertoli cell neoplasia. Immature teratoma - germ cell tumor, 354 - Wilms tumor vs., 314 Immunodeficiency 2. See Wiskott-Aldrich syndrome. Infantile fibrosarcoma - embryonal rhabdomyosarcoma vs., 30 - familial infantile myofibromatosis vs., 585 - molecular and cytogenic findings, 37–40 Inflammatory fibroid polyp, gastrointestinal stromal tumor vs., 246 Inflammatory leiomyosarcoma, molecular and cytogenic findings, 37–40 Inflammatory myofibroblastic tumor, molecular and cytogenic findings, 37–40 Inflammatory polyposis - familial adenomatous polyposis vs., 571 - juvenile polyposis syndrome vs., 670 Inflammatory pseudopolyps, hamartomatous polyps of GI tract vs., 254 Inherited erythroblastopenia. See Diamond-Blackfan anemia (DBA). Inherited tumor syndrome, pancreatic tumor, 128 INI1 gene, 804–823 Insulinoma, 737 - multiple endocrine neoplasia type 1, 700 - pancreatic neuroendocrine tumor, 120, 123 - prognosis, 121 - well-differentiated pancreatic neuroendocrine neoplasm, 121

INDEX Internal malignancy, xeroderma pigmentosum, 799 International Neuroblastoma Risk Group (INRG) Staging System, for hereditary neuroblastoma, 634 International Neuroblastoma Staging System (INSS), for hereditary neuroblastoma, 634 Interstitial pneumonia, lymphocytic, lymphangioleiomyomatosis vs., 436 Intestinal ganglioneuromatosis - multiple endocrine neoplasia type 2, 708 - multiple endocrine neoplasia type 2 vs., 707 Intestinal neoplasia, hereditary syndromes associated, 478 Intestinal tumors, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Intestinal-type gastric adenocarcinoma, familial neoplasia of esophagus, stomach, and small intestine (table), 271 Intraductal papillary mucinous neoplasm, pancreatic adenocarcinoma, 223 Intraluminal crystalloids, significance of normal histoanatomic structures in prostate pathology (table), 338 Intrathyroid parathyroid tissue, C-cell hyperplasia vs., 172 Intrathyroid parathyroid tumor - follicular thyroid carcinoma vs., 203 - medullary thyroid carcinoma vs., 180 Intrathyroid tumor, medullary thyroid carcinoma vs., 180 Intratubular large cell hyalinizing Sertoli cell neoplasia (ILCHSCN), 359 - familial sex cord-stromal tumors, 601 Invasive adenocarcinoma, hamartomatous polyps of GI tract vs., 254 Invasive (nonlepidic) adenocarcinomas of lung, adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern vs., 433 Invasive carcinoma, breast/ovarian cancer syndrome (BRCA1), 611, 612 Invasive colon carcinoma, colonic adenoma vs., 232 Invasive mucinous adenocarcinoma (IMA), lung adenocarcinoma vs., 428 Invasive papillary urothelial carcinoma, bladder carcinoma and, 276 Inverted papillary urothelial carcinoma, bladder carcinoma and, 276 Ionizing radiation, hypersensitivity to, ataxiatelangiectasia, 502 Islet dysplasia, pancreatic neuroendocrine neoplasms, 119 Isocitratedehydrogenase (IDH1/IDH2), hereditary paraganglioma/pheochromocytoma syndromes and, 643 Isolated familial somatotropinoma syndrome - part of inherited tumor syndrome, 167 - pituitary adenoma, 159 Isolated (idiopathic) hemihypertrophy (IHH), 795 - Wilms tumor, 313 Isolated omphalocele, Beckwith-Wiedemann syndrome vs., 512

J JAG1 gene, 804–823 JAK2 gene, 804–823 Jaw tumors, hyperparathyroidism-jaw tumor syndrome, 663 JAZF1-JJAZ1 gene, 804–823 JAZF1-PHF1 gene, 804–823 JMJD6 gene, hereditary neuroblastoma and, 633 JP. See Juvenile polyposis. JPS. See Juvenile polyposis syndrome. Juvenile granulosa cell tumor - familial sex cord-stromal tumors, 601 - pleuropulmonary blastoma associated, 443 Juvenile intestinal polyposis, familial adenomatous polyposis vs., 570 Juvenile polyposis, 538 - known hereditary cancer syndromes, 489–490 Juvenile polyposis coli, 669 Juvenile polyposis of infancy, 669 Juvenile polyposis syndrome (JPS), 668–673 - diagnostic checklist, 670 - differential diagnosis, 670 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 - familial neoplasia colon and rectum (table), 268 - genetics, 668 - hamartomatous polyposis syndromes, 253 - hereditary mixed polyposis syndrome vs., 629 - Peutz-Jeghers polyposis syndrome vs., 746 - prognosis, 669 - risk factor for small bowel adenocarcinoma, 263 Juvenile polyps, familial colon and rectum tumors by syndrome (table), 268–269

K

KCNIP4 gene, 804–823 KCNQ1 gene, 804–823 - abnormalities, Beckwith-Wiedemann syndrome, 511 KCNQ1OT1 gene, 804–823 - abnormalities, Beckwith-Wiedemann syndrome, 511 Keratoacanthoma - cutaneous squamous cell carcinoma, 461 - Lynch syndrome, 681 Keratosis, actinic, basal cell carcinoma vs., 452 Keratosis palmares and plantares with esophageal cancer. See Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer. KIF1B gene, 804–823 - hereditary paraganglioma/pheochromocytoma syndromes, 644 xxv

INDEX KIT gene, 804–823 - mutations, gastrointestinal stromal tumor vs., 245, 247 KIT germline mutations, familial gastrointestinal stromal tumor associated, 579 KITLG gene, 804–823 KLLN gene, 804–823 KMT2D gene, 804–823 Knudson 2-hit hypothesis, hereditary retinoblastoma, 656 KRAS gene, 804–823 - mutations, Noonan syndrome, 759 KRT6 gene, 804–823 KRT16 gene, 804–823 KRT17 gene, 804–823

L

Lactotroph adenoma, multiple endocrine neoplasia type 1, 700 LAM. See Lymphangioleiomyomatosis (LAM). LAMB syndrome (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi). See Carney complex (CNC). Langerhans cell histiocytosis, pulmonary, lymphangioleiomyomatosis vs., 436 Large-cell calcifying Sertoli cell tumor (LCCSCT), 359 - familial sex cord-stromal tumors, 601 - tumors with oxyphilic cytoplasm (table), 363 Large cell carcinoma, lung adenocarcinoma vs., 428 Large-cell neuroendocrine carcinoma (LCNEC). See also Neuroendocrine tumors, of lung. - lung adenocarcinoma vs., 428 - neuroendocrine tumor of lung vs., 440 Large-nested urothelial carcinoma, bladder carcinoma and, 276 Laryngeal carcinoma, dyskeratosis congenita associated, 561 Laryngeal squamous cell carcinoma, 395 - head and neck squamous cell carcinoma vs., 396 LCCSCT. See Large-cell calcifying Sertoli cell tumor. Legius syndrome (NF1-like syndrome) - Costello syndrome, 541 - selected hereditary cancer syndromes with skin manifestations, 472–473 Leiomyoma - gastrointestinal stromal tumor vs., 246 - molecular and cytogenic findings, 37–40 - schwannoma vs., 34 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Leiomyomatosis and renal cell carcinoma, hereditary. See Hereditary leiomyomatosis and renal cell carcinoma syndrome. Leiomyosarcoma - cutaneous squamous cell carcinoma vs., 462 - hereditary paraganglioma/pheochromocytoma syndromes and, 644 - Li-Fraumeni syndrome, 676 - molecular and cytogenic findings, 37–40 xxvi

Lentigines, Noonan syndrome, 759 LEOPARD syndrome - Carney complex vs., 531 - Costello syndrome, 541 Lepidic adenocarcinoma, lung adenocarcinoma vs., 427 Leukemia - Bloom syndrome associated, 523 - dyskeratosis congenita, cancer risk management, 561 - familial acute myeloid leukemia, 564–567 - familial platelet disorder/acute myeloid leukemia (FPD/AML), familial acute myeloid leukemia associated, 566 - hereditary syndromes associated, 479 Leydig cell tumor, tumors with oxyphilic cytoplasm (table), 363 LFS. See Li-Fraumeni syndrome. Li-Fraumeni syndrome (LFS), 538, 674–679 - acute lymphoblastic leukemia, 5 - adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern associated, 433 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - associated with increased risk of hematological malignancies, 6–7 - bone and soft tissue tumors associated with, 36 - breast carcinoma, 48, 54 - colonic adenoma, 229 - diagnostic criteria, 487 - fallopian tube carcinoma, 373 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial cancer syndromes, 208 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with lung neoplasms, 444 - familial syndromes associated with colorectal carcinoma (table), 268 - follicular thyroid carcinoma, 201, 204 - genetic syndromes associated with CNS neoplasms, 412 - genetics, 675 - hepatoblastoma, 213 - hereditary cancer syndromes associated, 498 - hereditary neuroblastoma and, 633 - known hereditary cancer syndromes, 489–490 - lung adenocarcinoma associated, 427 - melanoma/pancreatic carcinoma syndrome vs., 694 - myelodysplastic syndromes/acute myeloid leukemia associated, 565 - osteosarcoma, 780 LIG4 syndrome, Nijmegen breakage syndrome vs., 735 Light chain deposition disease, lymphangioleiomyomatosis vs., 436 Lipid-rich urothelial carcinoma, bladder carcinoma and, 277 Lipoblastoma, molecular and cytogenic findings, 37–40 Lipofibromatosis, molecular and cytogenic findings, 37–40 Lipofibromatosis-like neural tumor, molecular and cytogenic findings, 37–40

INDEX Lipofuscin pigment, significance of normal histoanatomic structures in prostate pathology (table), 338 Lipohyperplasia, primary parathyroid hyperplasia vs., 146 Lipoma - molecular and cytogenic findings, 37–40 - multiple endocrine neoplasia type 1, 700 Liposarcoma - Li-Fraumeni syndrome, 676 - molecular and cytogenic findings, 37–40 Lisch nodules, neurofibromatosis type 1, 721 LIT1 gene, 804–823 Liver - parenchyma, hepatoblastoma vs., 214 - rhabdoid tumor, hepatoblastoma vs., 214 Liver neoplasia, hereditary syndromes associated, 479 Liver neoplasms, familial adenomatous polyposis associated, 570 LKB1 gene, 804–823 LMNA gene, 804–823 Lobular carcinoma of breast - familial gastric cancer and, 48–49 - hereditary diffuse gastric cancer, 622 Localized hyperplasia, pancreatic neuroendocrine neoplasms vs., 122 Loss of heterozygosity, Wilms tumor, 313 Low-grade fibromyxoid sarcoma, molecular and cytogenic findings, 37–40 Low-grade neuroendocrine carcinoma, salivary gland neoplasms with familial clustering (table), 405–406 Low-grade papillary adenocarcinoma of endolymphatic sac origin. See Endolymphatic sac tumor (ELST). Low-grade papillary urothelial carcinoma, bladder carcinoma and, 276 LS. See Lynch syndrome. LSAMP gene, 804–823 Lung, neuroendocrine tumor of, 438–441 - differential diagnosis, 440 - prognosis, 439 Lung adenocarcinoma, 426–431, 444 - association with familial syndromes, 427 - diagnostic checklist, 428 - differential diagnosis, 428 - environmental exposure, 427 - familial uveal melanoma, 603 - genetic alterations, 427 - hereditary paraganglioma/pheochromocytoma syndromes and, 644 - prognosis, 427 Lung carcinoma, dyskeratosis congenita associated, 561 Lung cysts, DICER1 syndrome vs., 552 Lung neoplasia, hereditary syndromes associated, 479 Lung neoplasms, familial cancer syndromes with lung neoplasms, 444 Lymph nodes, tumor, medullary thyroid carcinoma vs., 180 Lymphangioleiomyomatosis (LAM), 434–437 - Birt-Hogg-Dubé syndrome vs., 520 - differential diagnosis, 436 - genetic testing, 436 - prognosis, 435 - tuberous sclerosis complex (TSC), 775

Lymphangiomyomatosis. See Lymphangioleiomyomatosis (LAM). Lymphocytic interstitial pneumonia, lymphangioleiomyomatosis vs., 436 Lymphoepithelial carcinoma - head and neck squamous cell carcinoma, 396 - salivary gland neoplasms with familial clustering reports, 405 Lymphoepithelioma-like carcinoma, bladder carcinoma, 277 Lymphoepithelioma-like variant, prostate carcinoma, 329 Lymphoma - Bloom syndrome associated, 523 - cutaneous melanoma vs., 458 - gastric, gastric adenocarcinoma vs., 241 - genetic predisposition, 5 - neuroblastoma vs., 97 - pancreatic neuroendocrine neoplasms vs., 122 - testicular tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 Lymphomatous polyposis, familial adenomatous polyposis vs., 571 Lynch syndrome (LS), 537, 680–685 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - bone and soft tissue tumors associated with, 36 - clinical and pathologic criteria, 683 - colonic adenoma, 229 - diagnosis of Lynch syndrome upper urinary tract urothelial carcinoma, 350 - diagnostic checklist, 682 - diagnostic criteria, 487–488 Amsterdam II criteria, 487 revised Bethesda guidelines, 487–488 - differential diagnosis, 682 - endometrial carcinoma, 381 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with salivary gland neoplasms, 404 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 - familial syndromes associated with colorectal carcinoma (table), 268 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - hereditary cancer syndromes associated, 498 - hereditary pancreatic cancer syndrome, 637 - known hereditary cancer syndromes, 489–490 - MUTYH-associated polyposis, 719 - ovarian tumors, 375 - pancreatic adenocarcinoma, 223 - prognosis, 375, 682 - renal urothelial carcinoma, 345 - risk factor for small bowel adenocarcinoma, 263

xxvii

INDEX - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 - ureter urothelial carcinoma, 349

M Macrocephaly, neurofibromatosis type 1, 721 Maffucci syndrome, chondrosarcoma, 11 Mahvash disease. See Glucagon cell hyperplasia and neoplasia. Mahvash syndrome. See Glucagon cell hyperplasia and neoplasia. Malate dehydrogenase 2 (MDH2), hereditary paraganglioma/pheochromocytoma syndromes and, 643 Malignancy, Werner syndrome/progeria, 791 Malignant gastrointestinal stromal tumors, multiple endocrine neoplasia type 1, 697 Malignant melanoma. See also Cutaneous melanoma. - differential diagnosis of tumors secondarily involving parathyroid, 154 - malignant peripheral nerve sheath tumor vs., 20 - melanoma/pancreatic carcinoma syndrome, 693 - schwannoma vs., 34 Malignant peripheral nerve sheath tumor (MPNST), 18–21 - differential diagnosis, 20 - embryonal rhabdomyosarcoma vs., 30 - familial cancer syndromes with bone and soft tissue tumors, 36 - genetic predisposition, 19 - molecular and cytogenic findings, 37–40 - neurofibromatosis type 1, 721 - neurofibromatosis type 2, 729 - prognosis, 19 - schwannoma vs., 34 Malignant sarcomas, schwannomatosis, 767 Malignant schwannoma. See Malignant peripheral nerve sheath tumor. Mammary analogue secretory carcinoma, molecular changes described in salivary gland tumors, 405–406 Mammary-type myofibroblastoma, molecular and cytogenic findings, 37–40 Manchester criteria, neurofibromatosis type 2, 728 Marfanoid habitus, multiple endocrine neoplasia type 2, 705, 708 Marshall-Smith syndrome, Beckwith-Wiedemann syndrome vs., 512–513 MAS. See McCune-Albright syndrome. Maternal diabetes mellitus, Beckwith-Wiedemann syndrome vs., 512 MAX gene, 804–823 Mazabraud syndrome, McCune-Albright syndrome vs., 689 MC1R gene, 804–823 McCune-Albright syndrome (MAS), 686–691 - adrenal cortical adenoma, 59 - adrenal cortical neoplasms in children, 71, 73 xxviii

- adrenal cortical tumor as part of, 84 - Carney complex vs., 531 - differential diagnosis, 689 - familial cancer syndromes, 208 - follicular thyroid carcinoma, 201, 204 - multiple endocrine neoplasia type 4, 713 - neurofibromatosis type 1 vs., 723 - part of inherited tumor syndrome, 166 - pituitary adenoma, 159 - prognosis, 688 MDM2 gene, 804–823 MDM4 gene, 804–823 MDR1 gene, 804–823 MDR3 gene, 804–823 MDS. See Myelodysplastic syndrome (MDS). MECT1 gene, 804–823 MECT1-MAML2 gene, 804–823 Medullary hyperplasia, adrenal, 88–91 - associated with genetic disorders, 89 - diagnostic checklist, 90 - differential diagnosis, 90 - as precursor lesion, 89 - sporadic, 89 Medullary thyroid carcinoma, 176–185 - diagnostic checklist, 180 - differential diagnosis, 180 tumors secondarily involving parathyroid, 154 - familial, 181 - familial thyroid carcinoma vs., 192 - follicular thyroid carcinoma vs., 203 - genetic predisposition, 177 - genetic testing, 179–180 - hereditary syndromes associated, 477 - immunohistochemistry, 181 - with intrathyroidal spread, C-cell hyperplasia vs., 172 - metastatic, neuroendocrine tumor of lung vs., 440 - multiple endocrine neoplasia type 2, 708 - parathyroid adenoma vs., 134 - parathyroid carcinoma vs., 154 - pheochromocytoma/paraganglioma vs., 107 - prognosis, 178 - sporadic, 181 Medullary thyroid microcarcinoma - C-cell hyperplasia vs., 172 - differential diagnosis, 181 Medulloblastoma - basal cell nevus syndrome/Gorlin syndrome, 507 - Bloom syndrome associated, 523 - rhabdoid predisposition syndrome, 763 Medulloepithelioma, ciliary body, DICER1 syndrome, 550 MEK1 gene, 804–823 MEK2 gene, 804–823 Melanocytic tumor, BAP1-inactivated, 448–449 - prognosis, 449 Melanoma - familial, bone and soft tissue tumors associated with, 36 - familial uveal. See Familial uveal melanoma. - hereditary leiomyomatosis and renal cell carcinoma, 625

INDEX - hereditary multiple selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 selected hereditary cancer syndromes with skin manifestations, 472–473 - malignant, schwannoma vs., 34 - neuroendocrine tumor of lung vs., 440 - of skin, hereditary retinoblastoma, 657 - spindle cell, cutaneous squamous cell carcinoma vs., 462 Melanoma astrocytoma, genetic syndromes associated with CNS neoplasms, 412 Melanoma-astrocytoma syndrome, melanoma/pancreatic carcinoma syndrome, 692 Melanoma/pancreatic carcinoma syndrome, 692–695 - differential diagnosis, 694 - genetics, 692 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Melanoma syndrome - familial atypical multiple mole hereditary pancreatic cancer syndrome, 637 pancreatic adenocarcinoma, 223 - hereditary, BAP1 tumor predisposition syndrome vs., 505 Melanotic psammomatous schwannoma, 34 Melanotic schwannoma, molecular and cytogenic findings, 37–40 MEN1. See Multiple endocrine neoplasia type 1. MEN1 gene, 804–823 - mutations genetic testing, 587 pancreatic neuroendocrine neoplasms, 118 parathyroid adenoma, 133 parathyroid carcinoma, 138 parathyroid hyperplasia, 145–146 MEN1-like syndrome. See Multiple endocrine neoplasia type 4. MEN2 syndrome, MTC and associated disease, 186 MEN4. See Multiple endocrine neoplasia type 4. Meningiomas, 420 - basal cell nevus syndrome/Gorlin syndrome, 507 - endolymphatic sac tumor vs., 392, 393 - familial uveal melanoma, 603 - hereditary retinoblastoma, 657 - hereditary SWI/SNF complex deficiency syndrome, 658 - neurofibromatosis type 2, 729 - schwannomatosis, 766 Mental retardation syndrome, Wilms tumor, 794 Merkel cell carcinoma - basal cell carcinoma vs., 452 - cutaneous melanoma vs., 458 Mesangial sclerosis, diffuse, Denys-Drash syndrome vs., 543 Mesenchymal chondrosarcoma, molecular and cytogenic findings, 37–40 Mesenteric fibromatosis. See Familial adenomatous polyposis (FAP).

Mesothelioma, familial uveal melanoma, 603 MET gene, 804–823 MET protooncogene, mutations - hereditary papillary renal cell carcinoma, 640 - screening for, 641 Metachondromatosis, chondrosarcoma, 11 Metageria, Werner syndrome/progeria vs., 791 Metanephric adenoma - with papillary or tubulopapillary architecture (table), 321 - papillary renal cell carcinoma vs., 301 - Wilms tumor vs., 314 Metastatic adenocarcinoma - chordoma vs., 16 - small bowel adenocarcinoma vs., 263 - testicular tumors with glandular/tubular pattern (table), 362–363 Metastatic carcinoma - adrenal cortical adenoma vs., 60 - adrenal medullary hyperplasia vs., 90 - cutaneous squamous cell carcinoma vs., 462 - endolymphatic sac tumor vs., 392, 393 - osteosarcoma vs., 25 - parathyroid carcinoma vs., 154 - to skin, sebaceous carcinoma vs., 468 Metastatic clear cell renal cell carcinoma (RCC), sebaceous carcinoma vs., 468 Metastatic hepatic tumors, hepatoblastoma vs., 214 Metastatic malignant melanoma, primary pigmented nodular adrenocortical disease vs., 80 Metastatic medullary thyroid carcinoma, neuroendocrine tumor of lung vs., 440 Metastatic mucinous adenocarcinoma, adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern vs., 433 Metastatic neuroendocrine carcinoma - neuroendocrine tumor of lung vs., 440 - pituitary adenoma vs., 160 Metastatic neuroendocrine tumors, medullary thyroid carcinoma vs., 180 Metastatic tumor - adrenal cortical carcinoma vs., 65 - hepatocellular carcinoma vs., 220 - pancreatic neuroendocrine neoplasms vs., 122 MGCT. See Mixed germ cell tumor. MGMT gene, melanoma/pancreatic carcinoma syndrome, 692 Microadenomatosis, multiple endocrine neoplasia type 1, 700 Microcephaly, normal intelligence, and immunodeficiency syndrome. See Nijmegen breakage syndrome. Microcystic adnexal carcinoma, basal cell carcinoma vs., 452 Microcystic urothelial carcinoma, bladder carcinoma and, 276 Microcystic variant, prostate carcinoma, 328–329 Micronodular pneumocyte hyperplasia, tuberous sclerosis complex (TSC), 775 Micropapillary adenocarcinoma, lung adenocarcinoma vs., 428 xxix

INDEX Micropapillary urothelial carcinoma, bladder carcinoma and, 276 Microsatellite instability (MSI), endometrial carcinoma, 382 Middle ear adenoma, endolymphatic sac tumor vs., 392, 393 MiNEN. See Neuroendocrine-nonneuroendocrine neoplasm. Minimal deviation adenocarcinoma (MDA), cervical carcinoma, 371 Minimally invasive adenocarcinoma (MIA). See also Adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern. - lung adenocarcinoma vs., 428 MIRAGE syndrome, associated with increased risk of hematological malignancies, 6–7 MITF gene, melanoma/pancreatic carcinoma syndrome, 692 MITF/TFE family translocation-associated carcinoma, with granular/eosinophilic cytoplasm, 322 MiTF/TFE translocation carcinomas - clear cell renal cell carcinoma vs., 291 - tumors with clear/light-staining cytoplasm (table), 321 Mixed endometrial carcinomas, endometrial carcinoma, 381 Mixed epithelial and stromal tumor, DICER1 syndrome vs., 552 Mixed epithelial stromal tumor (MEST) family of tumors. See Cystic nephroma. Mixed germ cell tumor (MGCT), 353, 354 Mixed polyposis syndrome, hereditary - juvenile polyposis syndrome vs., 670 - Lynch syndrome vs., 682 MLH1 gene, 804–823 - hereditary prostate cancer, 651 - mutations Lynch syndrome, 683 sebaceous carcinoma associated, 467 MLH1 promoter hypermethylation, endometrial carcinoma, 382 MLK1 gene, 804–823 Molecular aspects of familial/hereditary tumor syndromes, 494–499 - genetic variants, 495–497 - genetics, 495 - hereditary cancer syndromes with autosomal dominant inheritance and high penetrance, 498 - reference sequence types, 499 - selected genes with guidelines for management, 498–499 Molecular factors index, 804–823 MonoMAC syndrome - familial acute myeloid leukemia associated, 566 - GATA2 mutation, 565 Mononeuropathy, 420 Monophasic synovial sarcoma, spindle cell rhabdomyosarcoma vs., 30 Monosomy 7, myelodysplastic syndromes/acute myeloid leukemia associated, 565 Mood disorders, schwannomatosis, 766 xxx

Mosaic variegated aneuploidy syndrome 1, bone and soft tissue tumors associated with, 36 MPL gene, 804–823 MPNST. See Malignant peripheral nerve sheath tumor. MRE11A gene, 804–823 MRE11A/RAD50/NBS1 complex, required for activation of ataxia-telangiectasia, 502 MSH2 gene, 804–823 - hereditary prostate cancer, 651 - mutations Lynch syndrome, 683 sebaceous carcinoma associated, 467 MSH3-associated polyposis, colonic adenoma, 229 MSH3 mutation, familial adenomatous polyposis vs., 571 MSH3 polyposis, 538 - Lynch syndrome vs., 682 MSH3 polyposis syndrome, familial syndromes associated with colorectal carcinoma (table), 268 MSH6, hereditary prostate cancer, 651 MSH6 gene, 804–823 - mutations Lynch syndrome, 683 sebaceous carcinoma associated, 467 MSR1 gene, 804–823 MTC. See Medullary thyroid carcinoma. Mucinous (colloid) adenocarcinoma - chordoma vs., 16 - metastatic, adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern vs., 433 - prostate carcinoma, 328 Mucinous cystic neoplasm, pancreatic adenocarcinoma, 223 Mucinous tubular and spindle cell carcinoma, papillary renal cell carcinoma vs., 301 Mucinous tubular carcinoma, with papillary or tubulopapillary architecture (table), 321 Mucocutaneous lesions, Peutz-Jeghers polyposis syndrome, 746 Mucoepidermoid carcinoma - molecular changes described in salivary gland tumors (table), 405–406 - salivary gland neoplasms with familial clustering reports, 405 Mucosal neuroma syndrome. See Multiple endocrine neoplasia type 2. Mucosal neuromas, multiple endocrine neoplasia type 2, 705, 708 Mucosal prolapse polyp, Peutz-Jeghers polyposis syndrome vs., 746 Muir-Torre syndrome. See also Lynch syndrome. - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - sebaceous carcinoma associated, 467 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473

INDEX Multi meningioma syndromes, genetic syndromes associated with CNS neoplasms, 412 Multiglandular parathyroid disease, multiple endocrine neoplasia type 1, 700 Multiglandular parathyroid tumors. See Primary parathyroid hyperplasia. Multilocular cystic renal neoplasm of low malignant potential, cystic nephroma vs., 295 Multinodular hyperplasia, of thyroid, pleuropulmonary blastoma associated, 443 Multiple adenomatosis. See Familial adenomatous polyposis; Primary parathyroid hyperplasia. Multiple cartilaginous exostoses. See Multiple osteochondromas. Multiple cutaneous and uterine leiomyomatosis syndrome. See Hereditary leiomyomatosis and renal cell carcinoma syndrome. Multiple endocrine adenomatosis type 1. See Multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 (MEN1), 696–703 - adrenal cortical adenoma, 59 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - diagnostic checklist, 699 - differential diagnosis, 699 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial cancer syndromes with lung neoplasms, 444 - hereditary cancer syndromes associated, 498 - hyperparathyroidism-jaw tumor syndrome vs., 664 - known hereditary cancer syndromes, 489–490 - multiple endocrine neoplasia type 4 vs., 714 - pancreatic neuroendocrine neoplasms, 118 - pancreatic neuroendocrine tumors, 737, 738 - parathyroid adenoma, 131 - parathyroid carcinoma, 137, 139 - parathyroid hyperplasia, 143 - part of inherited tumor syndrome, 128, 166 - pituitary adenoma, 159 - primary hyperparathyroidism, 152–153 - prognosis, 697 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Multiple endocrine neoplasia type 1/4, familial isolated hyperparathyroidism vs., 587 Multiple endocrine neoplasia type 2 (MEN2), 704–711 - differential diagnosis, 707 - familial medullary thyroid carcinoma presentation, 191 - familial thyroid carcinoma, 189 - hereditary cancer syndromes associated, 498 - hereditary paraganglioma/pheochromocytoma syndromes, 643 - multiple endocrine neoplasia type 1 vs., 699 - multiple endocrine neoplasia type 4 vs., 714 - parathyroid adenoma, 131 - parathyroid hyperplasia, 143 - pheochromocytoma-associated syndromes (table), 646

- pheochromocytoma/paraganglioma associated with, 115 - prognosis, 705 - screening (table), 708 Multiple endocrine neoplasia type 2A (MEN2A) - familial isolated hyperparathyroidism vs., 588 - familial medullary thyroid carcinoma presentation, 191 - known hereditary cancer syndromes, 489–490 - medullary thyroid carcinoma, 177 - parathyroid carcinoma, 137, 139 - primary hyperparathyroidism, 152 Multiple endocrine neoplasia type 2B (MEN2B) - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial medullary thyroid carcinoma presentation, 191 - known hereditary cancer syndromes, 489–490 - medullary thyroid carcinoma, 177 - neurofibromatosis type 1 vs., 723 Multiple endocrine neoplasia type 4 (MEN4), 712–717 - diagnostic checklist, 715 - differential diagnosis, 714 - multiple endocrine neoplasia type 1 vs., 699 - pancreatic neuroendocrine tumors, 737, 738 - part of inherited tumor syndrome, 166 - pituitary adenoma, 159 - primary hyperparathyroidism, 152 - prognosis, 713 Multiple familial meningiomas, hereditary SWI/SNF complex deficiency syndrome, 658 Multiple familial trichoepitheliomas (MFT). See BrookeSpiegler syndrome (BSS). Multiple familial trichoepitheliomas syndrome - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Multiple gastrinomas, multiple endocrine neoplasia type 1, 700 Multiple hereditary osteochondromatosis (MHO). See Multiple osteochondromas. Multiple microadenomas, multiple endocrine neoplasia type 1, 700 Multiple osteochondromas, 630–631 - genetics, 630 - prognosis, 631 Multiple sebaceous cysts. See Steatocystoma multiplex. Multiple steatocystoma. See Steatocystoma multiplex. Multiple tumors, Li-Fraumeni syndrome, 676 Musculoskeletal manifestations, neurofibromatosis type 2, 728 Musculoskeletal neoplasms, basal cell nevus syndrome/Gorlin syndrome, 507 Mutation, Werner syndrome/progeria, 790 MUTYH gene, 804–823 - MUTYH-associated polyposis, 718 MUTYH-associated polyposis (MAP), 537, 718–719 - colonic adenoma, 229 - familial adenomatous polyposis vs., 570

xxxi

INDEX - familial esophageal, gastric, and small intestinal tumors by syndrome (table)mors by syndrome (table), 270–271 - familial syndromes associated with colorectal carcinoma (table), 268 - genetics, 718 - hereditary mixed polyposis syndrome vs., 629 - known hereditary cancer syndromes, 489–490 - Lynch syndrome vs., 682 - small bowel adenocarcinoma, 263 MYB-NFIB gene, 804–823 MYC-associated factor X (MAX) - hereditary paraganglioma/pheochromocytoma syndromes and, 643 - pheochromocytoma-associated syndromes (table), 646 MYC gene, 804–823 MYCN gene, 804–823 - gain, Wilms tumor, 313 Myelodysplastic syndrome (MDS), 564–567 - age-specific hematologic abnormalities in Down syndrome, 558 - associated neoplasms, 566 - familial, associated with increased risk of hematological malignancies, 6–7 - genetics, 566 Myeloid leukemia, age-specific hematologic abnormalities in Down syndrome, 558 Myeloid neoplasms, with mutated SRP72, associated with increased risk of hematological malignancies, 6–7 MYH gene, 804–823 Myoepithelioma, molecular and cytogenic findings, 37–40 Myofibroma, molecular and cytogenic findings, 37–40 Myopericytoma, molecular and cytogenic findings, 37–40 Myositis, McCune-Albright syndrome, 687 Myositis ossificans - molecular and cytogenic findings, 37–40 - osteosarcoma vs., 25 Myxofibrosarcoma, molecular and cytogenic findings, 37–40 Myxoid/round cell liposarcoma, molecular and cytogenic findings, 37–40 Myxoid stroma and chordoid features, urothelial carcinoma with, bladder carcinoma and, 277 Myxoinflammatory fibroblastic sarcoma, molecular and cytogenic findings, 37–40 Myxoma, molecular and cytogenic findings, 37–40

N Naegeli-Franceschetti-Jadassohn syndrome, dyskeratosis congenita vs., 562 NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, and ephelides). See Carney complex (CNC). Nasal cavity squamous cell carcinoma, head and neck squamous cell carcinoma vs., 396 Nasal chondromesenchymal hamartoma - DICER1 syndrome, 550 xxxii

- pleuropulmonary blastoma associated, 443 Nasal squamous cell carcinoma, 395 Nausea, parathyroid carcinoma, 137 NBCSS. See Nevoid basal cell carcinoma syndrome. NBN gene, 804–823 - hereditary prostate cancer, 651 NBS. See Nijmegen breakage syndrome. NBS1 gene, 804–823 NDP gene, 804–823 Necrotizing migratory erythema, glucagonoma syndrome and, 608 Necrotizing sialometaplasia - laryngeal squamous cell carcinoma vs., 396 - tongue squamous cell carcinoma vs., 396 Neonatal severe primary hyperparathyroidism, primary hyperparathyroidism, 152–153 Neoplasms - bladder AJCC Staging for Bladder Cancer, 282 bladder table, 282–285 high-grade poorly differentiated carcinoma (table), 282 urothelial carcinoma-associated markers in metastatic setting, 282 - cranial nerves, 420 - peripheral nervous system, 420–423 syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 - von Hippel-Lindau (VHL) syndrome, 783–784 Neoplastic lesions, Peutz-Jeghers polyposis syndrome, 745 Neoplastic processes, C-cell hyperplasia vs., 172 Nephroblastoma. See also Wilms tumor (WT). - Beckwith-Wiedemann syndrome, 511–512 - DICER1 syndrome vs., 552 Nephroma, cystic, 294–295 - differential diagnosis, 295 - prognosis, 295 Nephrotic syndrome - Denys-Drash syndrome, 542–543 - in infants, Denys-Drash syndrome vs., 543 Nerve, significance of normal histoanatomic structures in prostate pathology (table), 338 Nervous system - central, 412–415 genetic syndromes associated with CNS neoplasms, 412 - eye, 416–419 - peripheral nervous system neoplasms, 420–423 syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 - tuberous sclerosis complex (TSC), 774–775 Nested urothelial carcinoma, bladder carcinoma and, 276 Neurobehavioral abnormalities, neurofibromatosis type 1, 721 Neuroblastic tumors of adrenal gland, 92–103 - diagnostic checklist, 97 - differential diagnosis, 97 - familial neuroblastoma, 96 - favorable and unfavorable histological groups, 98

INDEX - genetic events, 96 - genetic testing, 96 - INPC classification, 95 - natural history, 94 - prognosis, 94 - sporadic neuroblastoma, 96 Neuroblastoma - adrenal cortical neoplasms in children vs., 72 - Beckwith-Wiedemann syndrome, 512 - Costello syndrome associated, 541 - hereditary, 632–635 - hereditary neuroblastoma, 633 Neuroendocrine carcinoma - familial uveal melanoma, 603 - large cell, lung adenocarcinoma vs., 428 - low-grade salivary gland neoplasms with familial clustering reports, 405 Neuroendocrine duodenal tumors, multiple endocrine neoplasia type 1, 696 Neuroendocrine neoplasms, pancreatic adenocarcinoma vs., 224 Neuroendocrine-nonneuroendocrine neoplasm, 119 Neuroendocrine pancreatic tumors, multiple endocrine neoplasia type 1, 696 Neuroendocrine tumors - of gastrointestinal tract, neurofibromatosis type 1, 721 - of lung, 438–441 differential diagnosis, 440 prognosis, 439 - multiple endocrine neoplasia type 1, 700 - neurofibromatosis type 1, 721 - pheochromocytoma/paraganglioma vs., 107 Neurofibroma - atypical, malignant peripheral nerve sheath tumor vs., 20 - molecular and cytogenic findings, 37–40 - neurofibromatosis type 2, 729 - plexiform, neurofibromatosis type 1, 721 - schwannomatosis, 767 Neurofibromatosis, McCune-Albright syndrome vs., 689 Neurofibromatosis type 1, 720–727 - acute lymphoblastic leukemia, 5 - adrenal cortical adenoma, 59 - adrenal cortical carcinoma, 63 - adrenal cortical neoplasms in children, 71, 73 - adrenal cortical tumor as part of, 84 - bone and soft tissue tumors associated with, 36 - Brooke-Spiegler syndrome vs., 525 - Costello syndrome, 541 - diagnostic checklist, 723 - diagnostic criteria, 420, 487, 722 - differential diagnosis, 723 - familial gastrointestinal stromal tumor associated, 580 - genetic counseling for, 721 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - hereditary cancer syndromes associated, 498 - hereditary neuroblastoma and, 633

- hereditary paraganglioma/pheochromocytoma syndromes, 643 - known hereditary cancer syndromes, 489–490 - multiple endocrine neoplasia type 4, 713 - pancreatic neuroendocrine neoplasms, 120 - pancreatic neuroendocrine tumors, 737, 738 - part of inherited tumor syndromes, 128 - pheochromocytoma-associated syndromes (table), 646 - pheochromocytoma/paraganglioma associated with, 115 - selected hereditary cancer syndromes with skin manifestations, 472–473 - syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 - von Hippel-Lindau (VHL) syndrome vs., 784 Neurofibromatosis type 2, 728–733 - bone and soft tissue tumors associated with, 36 - classification criteria, 728 - diagnostic criteria, 420, 487 Baser criteria additive scoring system, 420 Manchester criteria, 420 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetics, 728 - hereditary cancer syndromes associated, 498 - known hereditary cancer syndromes, 489–490 - neurofibromatosis type 1 vs., 723 - schwannoma, 33 - syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 Neurofibromatosis-NS (NFNS), Noonan syndrome, 759 Neurofibromin 1 (NF1) mutations, cutaneous melanoma associated, 457 Neurofibrosarcoma. See Malignant peripheral nerve sheath tumor. Neurogenic sarcoma. See Malignant peripheral nerve sheath tumor. Neutropenia, age-specific hematologic abnormalities in Down syndrome, 558 Nevoid basal cell carcinoma/Gorlin, known hereditary cancer syndromes, 489–490 Nevoid basal cell carcinoma syndrome (NBCCS). See also Basal cell nevus syndrome/Gorlin syndrome. - familial cancer syndromes with gynecologic manifestations (table), 384–385 - hereditary cancer syndromes associated, 498 Nevus - acral, cutaneous melanoma vs., 458 - atypical (dysplastic) melanocytic, cutaneous melanoma vs., 458 - genital, cutaneous melanoma vs., 458 - recurrent, cutaneous melanoma vs., 458 - Spitz (spindle and epithelioid cell), cutaneous melanoma vs., 458 NF1 gene, 804–823 - germline mutations, neurofibromatosis type 1, 720 NF1 syndrome, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 xxxiii

INDEX NF2 gene, 804–823 - encodes for Merlin, 728 NHL. See Non-Hodgkin lymphoma. NHP2 gene, 804–823 Nibrin forms, Nijmegen breakage syndrome, 734 Nibrin (NBN) gene mutations, Nijmegen breakage syndrome, 734 Nijmegen breakage syndrome (NBS), 734–735 - acute lymphoblastic leukemia, 5 - associated with increased risk of hematological malignancies, 6–7 - ataxia-telangiectasia vs., 503 - bone and soft tissue tumors associated with, 36 - differential diagnosis, 735 - genetics, 734 Nijmegen breakage syndrome-like disorder (RAD50 deficiency), Nijmegen breakage syndrome vs., 735 NKX3-1 gene, 804–823 NMTC1 gene, 804–823 Nodular fasciitis, molecular and cytogenic findings, 37–40 Nodular hyperplasia. See Primary parathyroid hyperplasia. Nodular lymphoid hyperplasia, familial adenomatous polyposis vs., 571 NOLA2 gene, 804–823 NOLA3 gene, 804–823 Nonependymal glial neoplasms, neurofibromatosis type 2, 729 Nonepidermolytic palmoplantar keratoderma, HowelEvans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 Nonfunctioning adenoma, multiple endocrine neoplasia type 4, 713 Nonfunctioning macrotumors, multiple endocrine neoplasia type 1, 700 Non-Hodgkin lymphoma (NHL), 4–5 - genetic testing, 5 Nonhomologous end joining factor 1 (NHEJ1) syndrome, Nijmegen breakage syndrome vs., 735 Noninvasive follicular tumor with papillary-like nuclear features, follicular thyroid carcinoma vs., 203 Nonkeratinizing squamous cell carcinoma, lung adenocarcinoma vs., 428 Nonmelanocytic lesions, cutaneous melanoma vs., 458 Nonossifying fibroma, molecular and cytogenic findings, 37–40 Nonseminomatous GCT (NSGCT), 353 Nonsyndromic Wilms tumor, Beckwith-Wiedemann syndrome vs., 513 Noonan-like disorder - Costello syndrome, 541 - with loose anagen hair, Costello syndrome, 541 Noonan syndrome (NS), 758–761 - acute lymphoblastic leukemia, 5 - associated with increased risk of hematological malignancies, 6–7 - bone and soft tissue tumors associated with, 36 - Costello syndrome, 541 - diagnostic criteria, 759 - genetic basis, 758–759, 760 - genetic syndromes associated with CNS neoplasms, 412 xxxiv

- genotype-phenotype correlation in juvenile myelomonocytic leukemia, 760 - hereditary neuroblastoma and, 633 - with multiple lentigines, Costello syndrome, 541 Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome), selected hereditary cancer syndromes with skin manifestations, 472–473 NORE1 gene, 804–823 Norrie disease, genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 NOTCH1 gene, 804–823 NOTCH2 gene, 804–823 Notochordal cell tumor, benign, chordoma vs., 16 NRAS gene, 804–823 NRAS mutations, cutaneous melanoma associated, 457 NS. See Noonan syndrome. NSD1 gene, 804–823 NSGCT. See Nonseminomatous GCT. NSHPT. See Neonatal severe primary hyperparathyroidism. NS/MPD, Noonan syndrome, 759 NTHL1-associated polyposis, colonic adenoma, 229 NTHL1 polyposis, 538 - Lynch syndrome vs., 682 NTHL1 syndrome, familial syndromes associated with colorectal carcinoma (table), 268 NTRK1 gene, 804–823 NTRK3-ETV6 gene, 804–823 Nuclear PTEN, 751 NUT gene, 804–823 NUT midline carcinoma, nasal cavity squamous cell carcinoma vs., 396

O Obesity, pancreatic adenocarcinoma, 223 OCA2 gene, 804–823 Ocular manifestations - familial adenomatous polyposis, 570 - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 Odontogenic keratocyst, basal cell nevus syndrome/Gorlin syndrome, 507 Older adult, germ cell tumor, 353 Oley syndrome - basal cell nevus syndrome/Gorlin syndrome vs., 507 - selected hereditary cancer syndromes with skin manifestations, 472–473 Ollier and Maffucci syndrome, familial cancer syndromes with gynecologic manifestations (table), 384–385 Ollier disease, chondrosarcoma, 11 Olmsted syndrome, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 661 Omphalocele, isolated, Beckwith-Wiedemann syndrome vs., 512 Oncocytic variant, prostate carcinoma, 328 Oncocytoma - familial hereditary or familial renal tumor syndrome, 654

INDEX renal oncocytoma, chromophobe, and hybrid oncocytic tumors, 305 - familial renal tumors (table), 320 - with granular/eosinophilic cytoplasm, 322 - succinate dehydrogenase-deficient renal cell carcinoma vs., 310 Online Mendelian Inheritance in Man (OMIM) - OMIM 113705. See Breast/ovarian cancer syndrome (BRCA1). - OMIM 184500. See Steatocystoma multiplex. - OMIM 277700. See Werner syndrome/progeria. - OMIM 278700. See Xeroderma pigmentosum. - OMIM 278720. See Xeroderma pigmentosum. - OMIM 278730. See Xeroderma pigmentosum. - OMIM 278740. See Xeroderma pigmentosum. - OMIM 278750. See Xeroderma pigmentosum. - OMIM 610651. See Xeroderma pigmentosum. - OMIM I 600185. See Breast/ovarian cancer syndrome (BRCA2). Ophthalmic manifestations, neurofibromatosis type 2, 728 Optic nerve glioma, neurofibromatosis type 1, 721 Ossifying fibroma, familial cancer syndromes with bone and soft tissue tumors, 36 Ossifying fibromyxoid tumor, molecular and cytogenic findings, 37–40 Osteoblastoma - molecular and cytogenic findings, 37–40 - osteosarcoma vs., 24–25 Osteochondroma - chondrosarcoma vs., 12 - molecular and cytogenic findings, 37–40 - multiple, 630–631 genetics, 630 prognosis, 631 Osteochondromatosis, chondrosarcoma, 11 Osteoclast giant cells, urothelial carcinoma with, bladder carcinoma and, 277 Osteofibrous dysplasia, McCune-Albright syndrome vs., 689 Osteogenic sarcoma. See also Osteosarcoma. - Bloom syndrome associated, 523 Osteosarcoma, 22–27 - chondroblastic, chondrosarcoma vs., 12 - diagnostic checklist, 25 - differential diagnosis, 24–25 - familial cancer syndromes with bone and soft tissue tumors, 36 - genetic susceptibility, 23 - Li-Fraumeni syndrome, 676 - McCune-Albright syndrome, 688 - molecular and cytogenic findings, 37–40 - prognosis, 23 Ovarian cancer - breast/ovarian cancer syndrome (BRCA2), 618 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - MUTYH-associated polyposis, 719 Ovarian carcinoma, breast/ovarian cancer syndrome (BRCA1), 611

Ovarian cystadenomas, hereditary leiomyomatosis and renal cell carcinoma, 625 Ovarian dysgenesis, familial cancer syndromes with gynecologic manifestations (table), 384–385 Ovarian fibroma, basal cell nevus syndrome/Gorlin syndrome, 507 Ovarian neoplasia, hereditary syndromes associated, 480 Ovarian stromal tumors, DICER1 syndrome, 550 Ovarian tumors, 374–379 - DICER1 syndrome ovarian tumors, 375 prognosis, 376 - hereditary breast/ovarian cancer syndrome ovarian tumors, 375 prognosis, 376 - Lynch syndrome ovarian tumors, 375 prognosis, 375 - Peutz-Jeghers syndrome ovarian tumors, 375 prognosis, 376 - prognosis, 376 - rhabdoid tumor predisposition syndrome 2 ovarian tumors, 375 prognosis, 376 Overgrowth syndrome (OGS) - with dysmorphic facies and neurologic deterioration, familial infantile myofibromatosis associated, 584 - Wilms tumor, 313

P P14 gene, 804–823 P15 gene, 804–823 P16 gene, 804–823 P53 gene abnormalities, Wilms tumor, 313 P57KIP2 gene, 804–823 PA. See Pituitary adenoma. PAC (low grade), molecular changes described in salivary gland tumors (table), 405–406 Pachyonychia congenita - Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 - type 2 selected hereditary cancer syndromes with skin manifestations, 472–473 steatocystoma multiplex vs., 773 Paget disease, cutaneous melanoma vs., 458 PALB2, hereditary prostate cancer, 651 PALB2 gene, 804–823 - mutations, breast carcinoma, 49 PALB2/FANCN gene mutations, breast carcinoma, 54 Palmoplantar keratoderma with esophageal cancer. See Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer. Palmoplantar keratodermas, other, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 xxxv

INDEX Palpation thyroiditis, C-cell hyperplasia vs., 172 Pancreas, Peutz-Jeghers polyposis syndrome, 745 Pancreas cancer, breast/ovarian cancer syndrome (BRCA2), 618 Pancreas neoplasms - endocrine pancreas table, 128–129 comparison of nonfunctioning neuroendocrine pancreatic tumors and differential diagnoses, comparison, 129 inherited tumor syndrome, 128 pancreatic neuroendocrine tumor, immunohistochemistry, 128–129 pancreatic tumorigenesis, 128 - familial adenomatous polyposis associated, 570 - hereditary syndromes associated, 478 - pancreatic neuroendocrine neoplasms, 118–127 diagnostic checklist, 122 differential diagnosis, 118, 122 grading and clinicopathological classification, 119, 123 immunohistochemistry, 123 prognosis, 120 Pancreatic adenocarcinoma, 222–225 - cytogenetics, 223–224 - differential diagnosis, 224 - molecular genetics, 223–224 - prognosis, 223 Pancreatic cancer - genetic risk, 638 - melanoma/pancreatic carcinoma syndrome, 693 Pancreatic cancer syndrome, hereditary, 636–639 Pancreatic cysts, von Hippel-Lindau (VHL) syndrome, 783–784 Pancreatic ductal adenocarcinoma, 223. See also Pancreatic adenocarcinoma. Pancreatic endocrine neoplasms (PENs), 129. See also Pancreatic neuroendocrine neoplasms. Pancreatic endocrine tumors (PETs). See also Pancreatic neuroendocrine tumors. - familial neoplasia of biliary tract, liver, and pancreas, 226 - pheochromocytoma/paraganglioma vs., 107 - von Hippel-Lindau (VHL) syndrome, 783–784 Pancreatic exocrine insufficiency, Shwachman-Diamond syndrome, 770, 771 Pancreatic infiltrating ductal carcinoma. See Pancreatic adenocarcinoma. Pancreatic intraepithelial neoplasia, pancreatic adenocarcinoma, 223 Pancreatic neuroendocrine carcinoma, 119 Pancreatic neuroendocrine cell ductular proliferation, pancreatic neuroendocrine neoplasms, 119 Pancreatic neuroendocrine microadenoma, pancreatic neuroendocrine neoplasms, 119 Pancreatic neuroendocrine neoplasms (PNENs), 118–127, 736 - diagnostic checklist, 122 - differential diagnosis, 118, 122 - grading and clinicopathological classification, 119, 123 - immunohistochemistry, 123 xxxvi

- prognosis, 120 Pancreatic neuroendocrine tumor, 119 - immunohistochemistry, 128, 128–129 - tuberous sclerosis complex (TSC), 775 Pancreatic neuroendocrine tumor syndromes, 736–743 Pancreatic neuroendocrine tumors (PNETs), 736 - functional, 737 - inherited tumor syndromes associated, 739 - multiple endocrine neoplasia type 4, 713 - nonfunctional, 736–737 - sporadic, 737 - syndromes associated, 737 Pancreatic tumorigenesis, 128 - genes, 739 Pancreaticobiliary adenocarcinoma, familial neoplasia of biliary tract, liver, and pancreas, 226 Pancreatitis - chronic pancreatic adenocarcinoma, 223 pancreatic adenocarcinoma vs., 224 - hereditary hereditary pancreatic cancer syndrome, 637 melanoma/pancreatic carcinoma syndrome vs., 694 Pancreatoblastoma, 129 - pancreatic neuroendocrine neoplasms vs., 122 Papillary adenocarcinoma, lung adenocarcinoma vs., 428 Papillary adenoma - hereditary papillary renal cell carcinoma, 641 - nephrogenic, bladder carcinoma vs., 277 Papillary renal cell carcinoma (PRCC), 300–303 - clear cell clear cell renal cell carcinoma vs., 291 papillary renal cell carcinoma vs., 301 - differential diagnosis, 301 - grading, 301 - hereditary, 640–641 familial renal tumors (table), 320 genetics, 640 hereditary or familial renal tumor syndrome, 654 - prognosis, 301 - type 1, 301 - type 2, 301 hereditary papillary renal cell carcinoma, 641 HLRCC syndrome-associated renal cell carcinoma vs., 298 - types 1 and 2, mixed, 301 - Wilms tumor vs., 315 Papillary SCC, head and neck squamous cell carcinoma, 396 Papillary thyroid carcinoma - with associated neoplasia familial renal tumors in (table), 320 hereditary or familial renal tumor syndrome, 654 hereditary renal epithelial tumors, 653 - familial with multinodular goiter, 592 pure familial papillary thyroid carcinoma, 592 - follicular variant, follicular thyroid carcinoma vs., 203 - hyperparathyroidism-jaw tumor syndrome, 663 - medullary thyroid carcinoma vs., 180 - PTEN-hamartoma tumor syndromes, 753

INDEX Papillary urothelial neoplasm of low malignant potential (PUNLMP), bladder carcinoma and, 276 Papillary urothelial neoplasms, renal urothelial carcinoma, 345 Parafollicular CCH. See C-cell hyperplasia. Parafollicular cell carcinoma. See Medullary thyroid carcinoma. Paraganglia, significance of normal histoanatomic structures in prostate pathology (table), 338 Paraganglioma - associated with SDH-related syndromes, 114 - endolymphatic sac tumor vs., 392, 393 - familial paraganglioma pheochromocytoma syndrome, 596–599, 598 differential diagnosis, 598 genetics, 596–597 prognosis, 597 - familial uveal melanoma, 603 - genetics, 115 - hereditary paraganglioma/pheochromocytoma syndromes, 642–649 genetics, 643 - hereditary syndromes associated, 478 - medullary thyroid carcinoma vs., 180 Paraganglioma metastasis, vs. 2nd primary, familial paraganglioma pheochromocytoma syndrome vs., 598 Paraganglioma syndromes, familial cancer syndromes with head and neck lesions and neoplasms, 400–402 Parasympathetic paraganglia, 105 Parathyroid adenoma, 130–135 - diagnostic checklist, 134 - differential diagnosis, 134 - double, primary parathyroid hyperplasia vs., 146 - familial isolated hyperparathyroidism associated, 587 - genetic testing, 134 - hereditary, 131 - parathyroid carcinoma vs., 139 - primary parathyroid hyperplasia vs., 146 - sporadic, 131 familial isolated hyperparathyroidism vs., 587 - triple, primary parathyroid hyperplasia vs., 146 Parathyroid carcinoma, 136–141 - differential diagnosis, 139 - familial isolated hyperparathyroidism associated, 587 - genetic testing, 138 - hyperparathyroidism-jaw tumor syndrome, 662 - hyperparathyroidism-jaw tumor syndrome vs., 664 - parathyroid adenoma vs., 134 - primary parathyroid hyperplasia vs., 147 - prognosis, 138 Parathyroid disease, multiple endocrine neoplasia type 2, 705 Parathyroid hormone (PTH). See Familial isolated hyperparathyroidism (FIHP). Parathyroid hyperplasia - familial isolated hyperparathyroidism associated, 587 - parathyroid adenoma vs., 134 - primary, 142–151 diagnostic checklist, 147 differential diagnosis, 146–147

genetic testing, 145–146 Parathyroid neoplasms - hereditary syndromes associated, 477 - parathyroid adenoma, 130–135 diagnostic checklist, 134 differential diagnosis, 134 genetic testing, 134 hereditary, 131 sporadic, 131 - parathyroid carcinoma, 136–141 differential diagnosis, 139 genetic testing, 138 prognosis, 138 - parathyroid table, 152–157 familial and hereditary forms of primary hyperparathyroidism, 152 parathyroid adenoma and parathyroid carcinoma, 153 parathyroid and thyroid immunohistochemistry, 153 parathyroid carcinoma, 154 syndromes associated with primary hyperparathyroidism, 152–153 tumors secondarily involving, 154 - primary parathyroid hyperplasia, 142–151 diagnostic checklist, 147 differential diagnosis, 146–147 genetic testing, 145–146 Parathyroid table, 152–157 - familial and hereditary forms of primary hyperparathyroidism, 152 - parathyroid adenoma and parathyroid carcinoma, 153 - parathyroid and thyroid immunohistochemistry, 153 - parathyroid carcinoma, 154 - syndromes associated with primary hyperparathyroidism, 152–153 - tumors secondarily involving, 154 Parathyromatosis - parathyroid carcinoma vs., 139 - primary parathyroid hyperplasia vs., 147 Parotid neoplasms, associated with Birt-Hogg-Dubé syndrome, 519 Parotid oncocytoma, associated with Birt-Hogg-Dubé syndrome, 519 PAX3 gene, 804–823 PAX3/7-FOXO1 gene, 804–823 PAX3-FKHR gene, 804–823 PAX3-FOXO1 gene, 804–823 PAX5 gene, 804–823 PAX6 gene, 804–823 PAX7-FKHR gene, 804–823 PAX7-FOXO1 gene, 804–823 PBRM1 gene, 804–823 - hereditary SWI/SNF complex deficiency syndrome, 658 - mutations, clear cell renal cell carcinoma, 291 PC. See Parathyroid carcinoma. PCa with Paneth cell-like differentiation, prostate carcinoma, 329 PCa with stratified epithelium (PIN-like), prostate carcinoma, 329 PCC. See Pheochromocytoma/paraganglioma. xxxvii

INDEX PDA. See Pancreatic ductal adenocarcinoma. PDE8B gene, 804–823 PDE11A gene, 804–823 PDGFRA gene, 804–823 PDGFRA germline mutations, familial gastrointestinal stromal tumor associated, 579 PDGFRA mutations, gastrointestinal stromal tumor vs., 245, 247 PDS gene, 804–823 Pearson syndrome - Diamond-Blackfan anemia vs., 547 - Shwachman-Diamond syndrome vs., 771 Pediatric cystic nephroma (PCN). See also Cystic nephroma. - DICER1 syndrome, 549–550 Pediatric germ cell tumor, 353 Pediatric sarcomas, rhabdoid predisposition syndrome, 763 Pendred syndrome - familial cancer syndromes, 208 - familial follicular cell carcinoma, 193 - familial nonmedullary thyroid carcinoma, 191, 593 - familial thyroid carcinoma, 189 - genetics, 591 Penttinen syndrome, familial infantile myofibromatosis associated, 584 Pericytoma, molecular and cytogenic findings, 37–40 Perifollicular fibroma, associated with Birt-Hogg-Dubé syndrome, 518–519 Perineurioma - gastrointestinal stromal tumor vs., 246 - molecular and cytogenic findings, 37–40 Peripheral nerve sheath tumor, malignant, 18–21 - differential diagnosis, 20 - familial cancer syndromes with bone and soft tissue tumors, 36 - genetic predisposition, 19 - molecular and cytogenic findings, 37–40 - prognosis, 19 - schwannoma vs., 34 Peripheral nervous system manifestations, neurofibromatosis type 2, 728 Peripheral nervous system neoplasms, 420–423 - hereditary syndromes associated, 479–480 - syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 Peripheral neurofibromatosis. See Neurofibromatosis type 1. Peripheral zone (PZ), significance of normal histoanatomic structures in prostate pathology (table), 338 Periprostatic adipose tissue, significance of normal histoanatomic structures in prostate pathology (table), 338 Peritoneal carcinoma - breast/ovarian cancer syndrome (BRCA1), 611 - breast/ovarian cancer syndrome (BRCA2), 618 Periurethral gland region, significance of normal histoanatomic structures in prostate pathology (table), 338 Perlman syndrome, 795 - Beckwith-Wiedemann syndrome vs., 512 xxxviii

- familial renal tumors in (table), 320 - Wilms tumor, 313 Peutz-Jeghers polyp (PJP), 744 Peutz-Jeghers polyposis - hamartomatous polyposis syndromes, 253 - juvenile polyposis syndrome vs., 670 Peutz-Jeghers polyposis syndrome (PJPS), 744 - cancer risk, 747 - diagnostic checklist, 746 - differential diagnosis, 746 - genetics, 744 - prognosis, 745 Peutz-Jeghers syndrome (PJS), 538 - adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern associated, 433 - breast carcinoma, 49, 54 - Carney complex vs., 531 - cervical carcinoma, 371 - endometrial carcinoma, 381 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial cancer syndromes with lung neoplasms, 444 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 - familial sex cord-stromal tumors, 601 - familial syndromes associated with colorectal carcinoma (table), 268 - familial testicular tumors (table), 362 - hereditary cancer syndromes associated, 498 - hereditary pancreatic cancer syndrome, 637 - known hereditary cancer syndromes, 489–490 - lung adenocarcinoma associated, 427 - melanoma/pancreatic carcinoma syndrome vs., 694 - ovarian tumors, 375 - pancreatic adenocarcinoma, 223 - prognosis, 376 - risk factor for small bowel adenocarcinoma, 263 - testicular Sertoli cell neoplasms, 359 PGL. See Paraganglioma. PHD2 gene, 804–823 Pheochromocytoma/paraganglioma, 104–113 - adrenal cortical adenoma vs., 60, 85 - adrenal cortical carcinoma vs., 65 - adrenal cortical neoplasms in children vs., 72 - adrenal medullary hyperplasia vs., 90 - associated with SDH-related syndromes, 114 - differential diagnosis, 107 - familial paraganglioma pheochromocytoma syndrome, 596–599 - genes involved in, 114 - genetic testing, 107 - hereditary, 105 - hereditary paraganglioma/pheochromocytoma syndromes, 642–649 genetics, 643 - hereditary syndromes associated, 478

INDEX -

multiple endocrine neoplasia type 2, 704, 708 multiple endocrine neoplasia type 2 vs., 707 neurofibromatosis type 1, 721 prognosis, 106 sporadic, 105 somatic mutations in, 108 - tumor distributions in major familial paraganglia syndromes, 108 - von Hippel-Lindau (VHL) syndrome, 783 Phosphatase tensin homolog (PTEN), 750 Phosphaturic mesenchymal tumor, molecular and cytogenic findings, 37–40 PHOX2B gene, 804–823 - mutations, hereditary neuroblastoma and, 633 PHTS. See PTEN-hamartoma tumor syndrome. Phyllodes tumor, Li-Fraumeni syndrome, 676 Pigmented melanotic lesions, Peutz-Jeghers polyposis syndrome, 745 PIK3CA gene, 804–823 PIK3CA-related overgrowth spectrum, BeckwithWiedemann syndrome vs., 513 Pilar cyst, steatocystoma multiplex vs., 773 Pilocytic astrocytoma, neurofibromatosis type 1, 721 Pineoblastoma - of cervix, DICER1 syndrome, 550 - hereditary retinoblastoma, 657 Pituitary adenoma, 158–163 - associated with SDH-related syndromes, 114 - differential diagnosis, 160 - genetic abnormalities, 167 - genetic predisposition, 161 - immunohistochemical classification, 161 - multiple endocrine neoplasia type 4, 713 - neurofibromatosis type 1, 721 - part of inherited tumor syndrome, 166–167 - pituitary hyperplasia vs., 165 - prognosis, 160 Pituitary blastoma, DICER1 syndrome, 550 Pituitary hyperplasia, 164–165 - diagnostic checklist, 165 - differential diagnosis, 165 - genetic syndromes, 165 - pituitary adenoma vs., 160 Pituitary neoplasms - hereditary syndromes associated, 477–478 - pituitary adenoma, 158–163 differential diagnosis, 160 genetic abnormalities, 167 genetic predisposition, 161 immunohistochemical classification, 161 part of inherited tumor syndrome, 166–167 prognosis, 160 - pituitary hyperplasia, 164–165 diagnostic checklist, 165 differential diagnosis, 165 genetic syndromes, 165 - pituitary table, 166–169 Pituitary tumors, multiple endocrine neoplasia type 1, 696 PJP. See Peutz-Jeghers polyp. PJPS. See Peutz-Jeghers polyposis syndrome. PJS. See Peutz-Jeghers syndrome.

PKC gene, 804–823 PKD1 gene, 804–823 PLAG1 gene, 804–823 Plasmacytoid urothelial carcinoma, bladder carcinoma and, 276 Plasmacytoma - pancreatic neuroendocrine neoplasms vs., 122 - testicular tumors with oxyphilic cytoplasm (table), 362 Platelet-derived growth factor receptor (PDGFRB), familial infantile myofibromatosis associated, 584 Pleomorphic adenoma - molecular changes described in salivary gland tumors, 405–406 - salivary gland neoplasms with familial clustering (table), 404 Pleomorphic giant cell, prostate carcinoma, 329 Pleomorphic hyalinizing angiectatic tumor, molecular and cytogenic findings, 37–40 Pleomorphic leiomyosarcoma, pleomorphic rhabdomyosarcoma vs., 30 Pleomorphic liposarcoma, molecular and cytogenic findings, 37–40 Pleomorphic rhabdomyosarcoma, 29 - differential diagnosis, 30 Pleuropulmonary blastoma (PPB), 442–443 - associated lesions, 443 - DICER1 syndrome, 549 - genetic abnormality, 443 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - genetic testing, 443 - prognosis, 443 Pleuropulmonary blastoma (PPB) familial tumor. See DICER1 syndrome. Plexiform fibromyxoma - gastrointestinal stromal tumor vs., 246 - molecular and cytogenic findings, 37–40 Plexiform neurofibromas, neurofibromatosis type 1, 721 Plexiform schwannoma, 34 PMS1 gene, 804–823 PMS2 gene, 804–823 - hereditary prostate cancer, 651 - mutations, Lynch syndrome, 683 PNEC. See Pancreatic neuroendocrine carcinoma. PNENs. See Pancreatic neuroendocrine neoplasms. PNETs. See Pancreatic neuroendocrine tumors. Pneumonia, lymphocytic interstitial, lymphangioleiomyomatosis vs., 436 Pneumothoraces, DICER1 syndrome vs., 552 POLE and POLD1 mutation-associated tumors, 538 POLE exonuclease domain mutation, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 POLE/POLD1 mutations, familial adenomatous polyposis vs., 570 POLH gene, 804–823 Polycythemia, age-specific hematologic abnormalities in Down syndrome, 558 Polydipsia, parathyroid carcinoma, 137 xxxix

INDEX Polymerase proofreading-associated polyposis (PPAP) - known hereditary cancer syndromes, 489–490 - Lynch syndrome vs., 682 Polyneuropathy, neurofibromatosis type 2, 728 Polyostotic fibrous dysplasia, McCune-Albright syndrome, 687 Polyp, serrated, familial colon and rectum tumors by syndrome (table), 268–269 Polypoid prolapsing mucosal folds (prolapse-type polyps), hamartomatous polyps of GI tract vs., 254 Polyposis - familial adenomatous hereditary pancreatic cancer syndrome, 637 Lynch syndrome vs., 682 - hereditary mixed polyposis, familial colon and rectum tumors by syndrome (table), 268 - hereditary mixed polyposis syndrome, 628–629 - juvenile polyposis syndrome, 668–673 diagnostic checklist, 670 differential diagnosis, 670 genetics, 668 prognosis, 669 Polyuria, parathyroid carcinoma, 137 Poorly differentiated adenocarcinoma, neuroendocrine tumor of lung vs., 440 Poorly differentiated carcinoma - cutaneous melanoma vs., 458 - cutaneous squamous cell carcinoma vs., 462 Poorly differentiated chordoma, 15, 16 - familial chordoma associated, 577 - molecular and cytogenic findings, 37–40 Poorly differentiated prostate carcinoma, bladder carcinoma vs., 277 Porocarcinoma, sebaceous carcinoma vs., 468 Posterior subcapsular cataracts, neurofibromatosis type 2, 728 Postpubertal germ cell tumor, 353 POT1 gene, melanoma/pancreatic carcinoma syndrome, 692 PPB. See Pleuropulmonary blastoma (PPB). PPB familial tumor susceptibility syndrome. See DICER1 syndrome. PPNAD. See Primary pigmented nodular adrenocortical disease. PRCC. See Papillary renal cell carcinoma. Prepubertal germ cell tumor, 353 Primary bilateral macronodular adrenal hyperplasia, adrenal cortical lesions associated with syndromes, 85 Primary bilateral macronodular adrenocortical hyperplasia, adrenal cortical neoplasms in children vs., 72 Primary chondrosarcoma, 11 Primary clear cell hyperplasia, primary parathyroid hyperplasia vs., 146 Primary cutaneous adnexal carcinomas, other, sebaceous carcinoma vs., 468 Primary hypothyroidism, pituitary hyperplasia, 165 Primary parathyroid hyperplasia, 142–151 - diagnostic checklist, 147 - differential diagnosis, 146–147 - genetic testing, 145–146 xl

Primary pigmented adrenal cortical disease, adrenal cortical lesions associated with syndromes, 85 Primary pigmented nodular adrenocortical disease (PPNAD), 78––83 - diagnostic checklist, 80–81 - differential diagnosis, 80 - genetic abnormality, 79 - genetic testing, 80 - immunohistochemistry, 81 - prognosis, 80 Primitive myxoid mesenchymal tumor of infancy, molecular and cytogenic findings, 37–40 Primitive neuroectodermal tumor, neuroblastoma vs., 97 PRKAR1A gene, 804–823 - mutations Carney complex associated, 528 follicular carcinoma, 201 Progeria - of adults. See Werner syndrome/progeria. - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 Progressive familial intrahepatic cholestasis, familial biliary tract, liver, and pancreas neoplasms, 226–227 Prophylactic surgery - breast/ovarian cancer syndrome (BRCA1) and, 613 - breast/ovarian cancer syndrome (BRCA2) and, 618 Prophylactic total gastrectomy, for hereditary diffuse gastric cancer, 622 Prostate cancer - hereditary, 650–651 genetics, 650 indications, 651 lifetime risk, 651 - hereditary diffuse gastric cancer, 622 Prostate capsule, significance of normal histoanatomic structures in prostate pathology (table), 338 Prostate carcinoma (PCa), 326–337 - benign mimics of (table), 339 - differential diagnosis, 329 table, 330 - Gleason Grading System, 329 grades 1 and 2, 329 grades 3, 329 grades 4, 329 grades 5, 329 - high-grade poorly differentiated carcinoma (table), 282 - important immunohistochemical stains in diagnosis of (table), 338–339 - prognosis, 327 - staging, AJCC Pathologic Staging of Prostate Cancer, 339 - table, 338–343 Prostate gland - atypical small glandular proliferations, 339 - significance of normal histoanatomic structures in prostate pathology (table), 338 Prostate neoplasia, hereditary syndromes associated, 478

INDEX Prostatic adenocarcinoma. See also Prostate carcinoma (PCa). - differential diagnosis of tumors secondarily involving parathyroid, 154 - hereditary diffuse gastric cancer, 622 Prostatic urethra (PU), significance of normal histoanatomic structures in prostate pathology (table), 338 Proteus-like syndrome, 750 - diagnosis, 752 Proteus syndrome, bone and soft tissue tumors associated with, 36 Proximal polyposis syndrome, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 PRSS1 gene, 804–823 PRSS2 gene, 804–823 Pruritic cutaneous lichen amyloidosis, multiple endocrine neoplasia type 2, 705 Pseudocarcinomatous hyperplasia, bladder carcinoma and, 277 Pseudoepitheliomatous hyperplasia (PEH) - cutaneous squamous cell carcinoma vs., 462 - laryngeal squamous cell carcinoma vs., 396 - tongue squamous cell carcinoma vs., 396 Pseudohyperplastic variant, prostate carcinoma, 328 Pseudomyogenic hemangioendothelioma, molecular and cytogenic findings, 37–40 PTA. See Parathyroid adenoma. PTAG gene, 804–823 PTCH1 gene, 804–823 - basal cell nevus syndrome/Gorlin syndrome associated, 506 - mutations, basal cell carcinoma associated, 451 PTCH2 gene, 804–823 PTEN. See Phosphatase tensin homolog. PTEN gene, 804–823 - melanoma/pancreatic carcinoma syndrome, 692 - mutations breast carcinoma, 49, 54 familial nonmedullary thyroid carcinoma associated, 591 familial thyroid carcinoma, 192 hamartomatous polyposis syndromes, 253 prostate carcinoma, 327 PTEN-hamartoma syndrome (Cowden/Bannayan-RileyRuvalcaba), 538 - familial syndromes associated with colorectal carcinoma (table), 268 - juvenile polyposis syndrome vs., 670 PTEN-hamartoma tumor syndrome (PHTS), 750–757 - associated lesions, 753 - associated neoplasms benign, 753 malignant, 753–754 - Beckwith-Wiedemann syndrome vs., 513 - Birt-Hogg-Dubé syndrome vs., 519–520 - Carney complex vs., 531 - diagnosis, 751–752 - DICER1 syndrome vs., 552

- endometrial carcinoma, 381 - familial cancer syndromes, 208 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial follicular cell carcinoma, 193 - familial nonmedullary thyroid carcinoma, 190, 592–593 - familial thyroid carcinoma, 189 - follicular thyroid carcinoma, 201, 204 - genetic counseling, 752 - genetics, 591, 751–752 - hamartomatous polyposis syndromes, 253 - hereditary cancer syndromes associated, 498 PTEN-related Proteus syndrome (PRPS), 750 - diagnosis, 752 PTPN11 gene, 804–823 - mutations, Noonan syndrome, 759 - neurofibromatosis type 1, 721 PTTG gene, 804–823 Pulmonary blastoma associated with cystic lung disease. See Pleuropulmonary blastoma (PPB). Pulmonary blastoma of childhood. See Pleuropulmonary blastoma (PPB). Pulmonary chondroma, associated with SDH-related syndromes, 114 Pulmonary cysts, associated with Birt-Hogg-Dubé syndrome, 519 Pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis vs., 436 Pulmonary neoplasms - adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern, 432–433 diagnostic checklist, 433 differential diagnosis, 433 environmental exposure, 433 familial syndromes associated, 433 genetic alterations, 433 prognosis, 433 - lung adenocarcinoma, 426–431 association with familial syndromes, 427 diagnostic checklist, 428 differential diagnosis, 428 environmental exposure, 427 genetic alterations, 427 prognosis, 427 - lymphangioleiomyomatosis, 434–437 differential diagnosis, 436 genetic testing, 436 prognosis, 435 - neuroendocrine tumor of lung, 438–441 differential diagnosis, 440 prognosis, 439 - pleuropulmonary blastoma, 442–443 associated lesions, 443 genetic abnormality, 443 genetic testing, 443 prognosis, 443 Pure familial papillary thyroid carcinoma, genetics, 592 Pure red cell aplasia, Diamond-Blackfan anemia vs., 547 xli

INDEX PYGL gene, 804–823

R

RAD50 gene, 804–823 RAD51, hereditary prostate cancer, 651 RAD51D gene, 804–823 Radiation, ionizing, hypersensitivity to, ataxiatelangiectasia, 502 Radiation changes - laryngeal squamous cell carcinoma and, 396 - tongue squamous cell carcinoma and, 396 Radiation therapy, cutaneous squamous cell carcinoma associated, 461 RAF1 gene, 804–823 RAS gene, 804–823 RASopathies, hereditary neuroblastoma and, 633 RASopathies or RAS-/mitogen-activated protein kinase (MAPK) syndromes, 758–761 RB gene, 804–823 RB1 gene, 804–823 - mutations, hereditary retinoblastoma, 656, 780 Reactive/regenerative epithelium, colonic adenoma vs., 232 RECQL2 gene, 804–823 RECQL4 gene, 804–823 - mutation, Rothmund-Thomson syndrome, 781 Recurrent nevus, cutaneous melanoma vs., 458 Reed syndrome. See also Hereditary leiomyomatosis and renal cell carcinoma syndrome. - bone and soft tissue tumors associated with, 36 - selected hereditary cancer syndromes with skin manifestations, 472–473 Reference: molecular factors, index, 804–823 Remnants of thymus, C-cell hyperplasia vs., 172 Renal angiomyolipoma, multiple endocrine neoplasia type 1, 697 Renal cancer, PTEN-hamartoma tumor syndromes, 753 - risk management, 754 Renal cancer-associated RCC, with papillary or tubulopapillary architecture (table), 321 Renal cell carcinoma - adrenal cortical adenoma vs., 85 - adrenal cortical carcinoma vs., 65 - adrenal cortical neoplasms in children vs., 72 - associated with SDH-related syndromes, 114 - Birt-Hogg-Dubé syndrome, 519 - carcinomas involving kidney &/or renal pelvis, 350 - familial nonclear cell renal cell carcinoma, hereditary renal epithelial tumors, 653 - familial uveal melanoma, 603 - hereditary leiomyomatosis and renal cell carcinoma and, 625 - HLRCC syndrome-associated, 296–299 diagnostic checklist, 298 differential diagnosis, 298 genetic testing, 298 prognosis, 297 xlii

- pheochromocytoma/paraganglioma associated with, 115 - pheochromocytoma/paraganglioma vs., 107 - succinate dehydrogenase-deficient, 308–311 - tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 - von Hippel-Lindau (VHL) syndrome, 783 Renal cysts - associated with Birt-Hogg-Dubé syndrome, 519 - hyperparathyroidism-jaw tumor syndrome, 663 - tuberous sclerosis complex (TSC), 775 Renal disease - HLRCC syndrome-associated renal cell carcinoma, 296–299 diagnostic checklist, 298 differential diagnosis, 298 genetic testing, 298 prognosis, 297 - parathyroid carcinoma, 137 Renal features, Denys-Drash syndrome, 542–543 Renal malignant rhabdoid rumors, rhabdoid predisposition syndrome, 763 Renal medullary carcinoma, rhabdoid predisposition syndrome, 763 Renal neoplasms - AJCC Staging System for Kidney Cancer, 322 - angiomyolipoma. See Angiomyolipoma. - clear cell renal cell carcinoma, 290–293 differential diagnosis, 291 prognosis, 291 - cystic nephroma, 294–295 differential diagnosis, 295 prognosis, 295 - hereditary syndromes associated, 478 - kidney (table), 320–325 - papillary renal cell carcinoma, 300–303 clear cell, papillary renal cell carcinoma vs., 301 differential diagnosis, 301 grading, 301 prognosis, 301 type 1, 301 type 2, 301 types 1 and 2, mixed, 301 - renal oncocytoma, chromophobe, and hybrid oncocytic tumors, 304–307 - renal tumors familial renal tumors in (table), 320 with granular/eosinophilic cytoplasm (table), 322 with papillary or tubulopapillary architecture (table), 321 - renal urothelial carcinoma, 344–347 classification similar to bladder UCa, 345 prognosis, 345 - succinate dehydrogenase-deficient renal cell carcinoma, 308–311 diagnostic checklist, 310 differential diagnosis, 310 genetics, 309 prognosis, 309 - Wilms tumor. See Wilms tumor.

INDEX Renal oncocytoma, chromophobe, and hybrid oncocytic tumors, 304–307 - chromophobe renal cell carcinoma, clear cell renal cell carcinoma vs., 291 - prognosis, 305 - tumors with clear/light-staining cytoplasm (table), 321 Renal oncocytoma (RO), 305 Renal oncocytosis, 305 Renal PEComa. See Angiomyolipoma. Renal pelvis and ureter - carcinomas involving kidney &/or renal pelvis, 350 - diagnosis of Lynch syndrome upper urinary tract urothelial carcinoma, 350 - staging, AJCC Staging System for Renal Pelvis and Ureter Cancer, 350 - table, 350–351 Renal transitional carcinoma. See Renal urothelial carcinoma. Renal urothelial carcinoma, 344–347 - classification similar to bladder UCa, 345 - prognosis, 345 Respiratory epithelial carcinoma. See Head and neck neoplasms, squamous cell carcinoma. Respiratory infections, ataxia-telangiectasia, 503 RET gene, 804–823 - mutations ATA age recommendations for prophylactic thyroidectomy, 187 MTC in MEN2A and MEN2B, 187 parathyroid carcinoma, 138 parathyroid hyperplasia, 146 testing, medullary thyroid carcinoma, 177 RET receptor mutations, multiple endocrine neoplasia type 2, 708 Rete testis tumor, tumors with glandular/tubular pattern (table), 362–363 Retinal hamartomas - neurofibromatosis type 2, 728 - tuberous sclerosis complex (TSC), 775 Retinal hemangioblastomas, von Hippel-Lindau (VHL) syndrome, 783 Retinoblastoma - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - hereditary bone and soft tissue tumors associated with, 36 genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 lung adenocarcinoma associated, 427 Retinoma/retinocytoma, hereditary retinoblastoma, 657 Revesz syndrome. See Dyskeratosis congenita. Rhabdoid predisposition, genetic syndromes associated with CNS neoplasms, 412 Rhabdoid predisposition syndrome, 762–765 - associated neoplasms, 762–763 - genetics, 762 - known hereditary cancer syndromes, 489–490 Rhabdoid tumor - of liver, hepatoblastoma vs., 214 - malignant, rhabdoid predisposition syndrome, 763

Rhabdoid tumor predisposition syndrome, bone and soft tissue tumors associated with, 36 Rhabdoid tumor predisposition syndrome 2 (RTPS2) - familial cancer syndromes with gynecologic manifestations (table), 384–385 - ovarian tumors, 375 - prognosis, 376 Rhabdoid tumors, hereditary SWI/SNF complex deficiency syndrome, 658 Rhabdomyosarcoma, 28–31 - alveolar, neuroblastoma vs., 97 - Beckwith-Wiedemann syndrome, 512 - Costello syndrome, 540 cancer risk management, 541 - differential diagnosis, 30 - embryonal, of cervix, DICER1 syndrome, 550 - familial cancer syndromes with bone and soft tissue tumors, 36 - genetic associations, 29 - genetic events, 29 - genetic testing, 30 - Li-Fraumeni syndrome, 676 - molecular and cytogenic findings, 37–40 - prognosis, 29 RHBDF2 gene, 804–823 - mutations, esophageal squamous cell carcinoma, 237 Richner-Hanhart syndrome, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 661 Rombo syndrome - basal cell nevus syndrome/Gorlin syndrome vs., 507 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Rothmund-Thomson syndrome - bone and soft tissue tumors associated with, 36 - dyskeratosis congenita vs., 562 - osteosarcoma, 781 - selected hereditary cancer syndromes with skin manifestations, 472–473 - Werner syndrome/progeria vs., 791 - xeroderma pigmentosum vs., 800 RP genes mutations, Diamond-Blackfan anemia, 546 RPS19 gene, 804–823 RTEL1 gene, 804–823 - dyskeratosis congenita associated, 561 Rubinstein-Taybi syndrome, bone and soft tissue tumors associated with, 36 RUNX1 gene, 804–823 - mutations, familial acute myeloid leukemia associated, 565

xliii

INDEX

S

Salivary duct carcinoma, molecular changes described in salivary gland tumors (table), 405–406 Salivary gland neoplasms - Brooke-Spiegler syndrome associated, 525 - familial cancer syndrome with, 404 - with familial clustering reports, 404 - hereditary syndromes associated, 479 - salivary glands (table), 404–409 Salivary sialadenoma papilliferum, molecular changes described in salivary gland tumors (table), 405–406 Sarcoidosis, with advanced interstitial lung disease, lymphangioleiomyomatosis vs., 436 Sarcoma - bone, hereditary retinoblastoma, 657 - clear cell gastrointestinal stromal tumor vs., 246 kidney, Wilms tumor vs., 315 malignant peripheral nerve sheath tumor vs., 20 - neurogenic. See Malignant peripheral nerve sheath tumor. - soft tissue and bone, hereditary retinoblastoma, 657 - synovial, malignant peripheral nerve sheath tumor vs., 20 Sarcomatoid squamous cell carcinoma, cutaneous melanoma vs., 458 Sarcomatoid urothelial carcinoma/carcinosarcoma, bladder carcinoma and, 277 SBDS gene, 804–823 - mutation, Shwachman-Diamond syndrome, 770 SCCa. See Squamous cell carcinoma (SCC). Schneiderian papillomas, nasal cavity squamous cell carcinoma vs., 396 Schopf-Schulz-Passarge syndrome - Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer vs., 661 - selected hereditary cancer syndromes with skin manifestations, 472–473 Schwannoma, 32–35 - cellular, malignant peripheral nerve sheath tumor vs., 20 - cutaneous, 420 - diagnostic checklist, 34 - differential diagnosis, 34 - gastrointestinal stromal tumor vs., 246 - hereditary SWI/SNF complex deficiency syndrome, 658 - malignant. See Malignant peripheral nerve sheath tumor. - molecular and cytogenic findings, 37–40 - neurofibromatosis type 2, 728 - prognosis, 33 - rhabdoid predisposition syndrome, 763 - schwannomatosis, 767 - vestibular, 420 Schwannomatosis, 33, 766–769 - diagnostic criteria, 420, 766 Baser et al (2006), 420 xliv

International Schwannomatosis Workshop (2011), 420 - genetics, 767 - molecular and cytogenic findings, 37–40 - proposed criteria for, 766–767 - syndromes with genetic predisposition for peripheral nerve neoplasia (table), 421 Sclerosing epithelioid fibrosarcoma - molecular and cytogenic findings, 37–40 - spindle cell rhabdomyosarcoma vs., 30 Scoliosis, neurofibromatosis type 2, 728 SCT. See Sertoli cell tumor. SDH gene, 804–823 SDHA gene, 804–823 SDHAF2 gene, 804–823 SDHB gene, 804–823 SDHC gene, 804–823 SDHD gene, 804–823 SDH-deficient RCC, with granular/eosinophilic cytoplasm, 322 SDH-pituitary adenoma, multiple endocrine neoplasia type 4, 713 SDH-related familial paraganglioma and pheochromocytoma syndromes, pituitary adenoma, 159 SDHx gene, 804–823 - mutations, familial hereditary paraganglioma/pheochromocytoma syndromes, 642 SDS. See Shwachman-Diamond syndrome. Sebaceoma - sebaceous carcinoma vs., 466 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Sebaceous adenocarcinoma. See Sebaceous carcinoma. Sebaceous adenoma - Lynch syndrome, 681 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Sebaceous carcinoma, 466–471 - basal cell carcinoma vs., 452 - cancer syndromes associated, 467 - cutaneous melanoma vs., 458 - cutaneous squamous cell carcinoma vs., 462 - differential diagnosis, 468 - genetics, 467 - Lynch syndrome, 681 - prognosis, 467 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Sebocystomatosis. See Steatocystoma multiplex. Secondary osteomyelitis, McCune-Albright syndrome, 687 Secondary parathyroid hyperplasia, primary parathyroid hyperplasia vs., 146 Seemanova syndrome. See Nijmegen breakage syndrome. Seminal vesicle (SV), significance of normal histoanatomic structures in prostate pathology (table), 338 Seminoma - classic germ cell tumor, 353, 354 tumors with diffuse arrangement and pale and clear cytoplasm (table), 362

INDEX tumors with glandular/tubular pattern (table), 362–363 - spermatic, tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 Seminomatous GCT (SGCT), 353 Sequence analysis, PTEN-hamartoma tumor syndromes, 752 Serous carcinoma, endometrial carcinoma, 381 SERPINA1 gene, 804–823 Serrated polyposis (SPS) - familial neoplasia colon and rectum (table), 268–269 - known hereditary cancer syndromes, 489–490 Serrated (giant hyperplastic) polyposis syndrome, 537–538 - hereditary mixed polyposis syndrome vs., 629 Sertoli cell neoplasms, 358–361 - prognosis, 359 - syndromes/familial Sertoli cell neoplasms, 359 Sertoli cell tumor (SCT), 359 - Peutz-Jeghers polyposis syndrome, 746 - tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 - tumors with glandular/tubular pattern (table), 362–363 - tumors with oxyphilic cytoplasm (table), 363 Sertoli-Leydig cell tumor, pleuropulmonary blastoma associated, 443 Severe congenital neutropenia - associated with increased risk of hematological malignancies, 6–7 - Shwachman-Diamond syndrome vs., 771 Severe emphysema, lymphangioleiomyomatosis vs., 436 Sex cord tumor with annular tubules (SCTAT), PeutzJeghers polyposis syndrome, 746 SGCT. See Seminomatous GCT. SHH gene, 804–823 SHOC2 gene, 804–823 Shwachman syndrome. See Shwachman-Diamond syndrome. Shwachman-Bodian-Diamond syndrome. See ShwachmanDiamond syndrome. Shwachman-Diamond syndrome (SDS), 770–771 - associated with increased risk of hematological malignancies, 6–7 - diagnostic criteria, 771 - Diamond-Blackfan anemia vs., 547 - differential diagnosis, 771 Shwachman-Diamond-Oski syndrome. See ShwachmanDiamond syndrome. Signet ring cell carcinoma of colon, hereditary diffuse gastric cancer, 622 Signet ring cell variant, prostate carcinoma, 329 Significant gene abnormalities, others, Wilms tumor, 313 Simpson-Golabi-Behmel syndrome, 795 - Beckwith-Wiedemann syndrome vs., 512 - familial renal tumors in (table), 320 - Wilms tumor, 313 Sinonasal carcinoma. See Head and neck neoplasms, squamous cell carcinoma. Sinonasal undifferentiated carcinoma (SNUC), nasal cavity squamous cell carcinoma vs., 396

Sipple syndrome. See Multiple endocrine neoplasia type 2. Skeletal anomalies, Peutz-Jeghers polyposis syndrome, 745 Skin - melanoma, hereditary retinoblastoma, 657 - tuberous sclerosis complex (TSC), 774 - xeroderma pigmentosum, 799 Skin cancer - MUTYH-associated polyposis, 719 - xeroderma pigmentosum, 799 Skin lesions - neurofibromatosis type 1, 721 - PTEN-hamartoma tumor syndromes, 753 Skin manifestations - ataxia-telangiectasia, 503 - familial adenomatous polyposis, 570 - neurofibromatosis type 2, 728 Skin neoplasms - associated with Birt-Hogg-Dubé syndrome, 518–519 - BAP1-inactivated melanocytic tumor, 448–449 prognosis, 449 - basal cell carcinoma, 450–455 diagnostic checklist, 452 differential diagnosis, 452 genetics, 451 prognosis, 451 - basal cell nevus syndrome/Gorlin syndrome, 506–507 - Brooke-Spiegler syndrome associated, 525 - cutaneous melanoma, 456–459 AJCC Melanoma Staging and Classification System, 458 diagnostic checklist, 458 differential diagnosis, 458 genetics, 457 prognosis, 457 - cutaneous squamous cell carcinoma, 460–465 differential diagnosis, 462 environmental exposure, 461 genetic predisposition, 461 immunohistochemistry, 462 prognosis, 461 - hereditary syndromes associated, 479 - sebaceous carcinoma, 466–471 cancer syndromes associated, 467 differential diagnosis, 468 genetics, 467 prognosis, 467 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Skin papillomas, Costello syndrome associated, 540 SLC25A13 gene, 804–823 SLC26A4 gene, 804–823 SMAD4 (DPC4) gene, 804–823 - germline mutations, juvenile polyposis syndrome, 668 - mutations hamartomatous polyposis syndromes, 253 small bowel adenocarcinoma, 263 Small bowel adenocarcinoma, 262–267 - differential diagnosis, 265 xlv

INDEX Small bowel neoplasms - familial adenomatous polyposis associated, 570 - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Small cell lung carcinoma (SCLC). See also Neuroendocrine tumors, of lung. - neuroendocrine tumor of lung vs., 440 Small intestinal adenocarcinoma, familial neoplasia of esophagus, stomach, and small intestine (table), 271 Small intestinal adenoma, familial neoplasia of esophagus, stomach, and small intestine (table), 271 Small intestine - carcinomas, juvenile polyposis syndrome, 670 - familial neoplasia of, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 271 - Peutz-Jeghers polyposis syndrome, 745–746 Small round blue cell tumors, Wilms tumor vs., 314 Small tubules, urothelial carcinoma with, bladder carcinoma and, 276 SMARCA2, hereditary SWI/SNF complex deficiency syndrome, 658 SMARCA4 gene, 804–823 - hereditary SWI/SNF complex deficiency syndrome, 658 SMARCA4/BRG1 gene, germline mutations, rhabdoid predisposition syndrome, 762 SMARCB1 gene, 804–823 - germline mutations, rhabdoid predisposition syndrome, 762 - hereditary SWI/SNF complex deficiency syndrome, 658 - schwannomatosis function, 767 germline mutations, 766, 767 SMARCE1 gene, 804–823 - hereditary SWI/SNF complex deficiency syndrome, 658 SMO gene, 804–823 - mutations, basal cell carcinoma associated, 451 Smooth muscle tumors, hereditary leiomyomatosis and renal cell carcinoma, 625 SNF complex deficiency syndrome, hereditary, 658–659 Soft tissue lesions, PTEN-hamartoma tumor syndromes, 753 Soft tissue manifestations, familial adenomatous polyposis, 570 Soft tissue myoepithelioma, rhabdoid predisposition syndrome, 763 Soft tissue neoplasia, hereditary syndromes associated, 480 Soft tissue sarcomas - hereditary retinoblastoma, 657 - Li-Fraumeni syndrome, 676 Soft tissue tumors, multiple endocrine neoplasia type 1, 697, 700 Solid adenocarcinoma, lung adenocarcinoma vs., 428 Solid carcinoma with amyloid stroma. See Medullary thyroid carcinoma. Solid cell nests, C-cell hyperplasia vs., 172 Solid pseudopapillary neoplasm, 129 - pancreatic neuroendocrine neoplasms vs., 122 Solid tumors - ataxia-telangiectasia, 503 xlvi

- Fanconi anemia, 607 Solitary fibrous tumor - molecular and cytogenic findings, 37–40 - schwannoma vs., 34 Somatostatinoma syndrome - pancreatic neuroendocrine tumor, 123 - prognosis, 121 - well-differentiated pancreatic neuroendocrine neoplasm, 121 Somatostatinomas, 737 Somatotroph adenoma, multiple endocrine neoplasia type 1, 700 Somatotropinoma syndrome, isolated familia, pituitary adenoma, 159 SOS1 gene, 804–823 Sotos syndrome, Beckwith-Wiedemann syndrome vs., 512 SOX9 gene, 804–823 Spermatic seminoma, tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 Spinal ependymoma, multiple endocrine neoplasia type 1, 700 Spindle cell carcinoma, with papillary or tubulopapillary architecture (table), 321 Spindle cell liposarcoma, molecular and cytogenic findings, 37–40 Spindle cell melanoma, cutaneous squamous cell carcinoma vs., 462 Spindle cell oncocytoma/pituicytoma, pituitary adenoma vs., 160 Spindle cell/pleomorphic lipoma, molecular and cytogenic findings, 37–40 Spindle cell/sclerosing rhabdomyosarcoma, 29 - differential diagnosis, 30 - genetic testing, 30 - molecular and cytogenic findings, 37–40 Spindle cell squamous carcinoma, head and neck squamous cell carcinoma, 396 SPINK1 gene, 804–823 Spiradenocylindroma - Brooke-Spiegler syndrome associated, 525 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Spiradenoma - Brooke-Spiegler syndrome associated, 525 - malignant transformation of, Brooke-Spiegler syndrome associated, 525 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Spitz (spindle and epithelioid cell) nevus, cutaneous melanoma vs., 458 SPOP gene, 804–823 - mutation, prostate carcinoma, 327 Sporadic adrenal medullary hyperplasia, 89 Sporadic carcinoma, 381 Sporadic chondrosarcoma, 11 Sporadic chordoma, 15 Sporadic clear cell renal cell carcinoma, clear cell renal cell carcinoma, 291 Sporadic follicular cell neoplasm, familial thyroid carcinoma vs., 192

INDEX Sporadic lymphangioleiomyomatosis, comparison of tuberous sclerosis-associated lymphangioleiomyomatosis, 445 Sporadic medullary thyroid carcinoma - familial thyroid carcinoma vs., 192 - medullary thyroid carcinoma vs., 180 - multiple endocrine neoplasia type 2 vs., 707 Sporadic neuroblastoma, 96 Sporadic papillary renal cell carcinoma, papillary renal cell carcinoma and, 301 Sporadic parathyroid adenoma, familial isolated hyperparathyroidism vs., 587 Sporadic pheochromocytoma/paraganglioma, 105 - somatic mutations in, 108 Sporadic PJP, 745 Sporadic PTAs, 131 Sporadic tumors, renal oncocytoma, chromophobe, and hybrid oncocytic tumors, 305 Sporadic Wilms tumor, 313 SPRED1 gene, 804–823 SPRY4 gene, 804–823 Squamous cell carcinoma (SCC) - basal cell carcinoma vs., 452 - basaloid, neuroendocrine tumor of lung vs., 440 - cutaneous, 460–465 differential diagnosis, 462 environmental exposure, 461 genetic predisposition, 461 immunohistochemistry, 462 prognosis, 461 - dyskeratosis congenita, cancer risk management, 561 - esophageal, 236–237 differential diagnosis, 237 genetic predisposition, 237 - of esophagus, familial neoplasia of esophagus, stomach, and small intestine (table), 271 - Fanconi anemia, 607 - head and neck, 394–399 differential diagnosis, 396 - of head and neck, dyskeratosis congenita associated, 561 - nonkeratinizing, lung adenocarcinoma vs., 428 - sebaceous carcinoma vs., 468 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Squamous cell carcinoma in situ, cutaneous melanoma vs., 458 Squamous metaplasia, C-cell hyperplasia vs., 172 Squamous papilloma, laryngeal squamous cell carcinoma vs., 396 SRP72 gene, 804–823 - mutations, aplastic anemia/myelodysplastic associated, 564 SS18 gene, 804–823 SS18L1-SSX1 gene, 804–823 SSX gene, 804–823 SSX1 gene, 804–823 SSX2 gene, 804–823 SSX4 gene, 804–823

Steatocystoma multiplex, 772–773 - associated neoplasms, 772–773 - differential diagnosis, 773 - genetics, 772 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Steatocystomas, selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 STK11 gene, 744, 804–823 - mutations, 744 hamartomatous polyposis syndromes, 253 STK11/LKB1 gene mutations, breast carcinoma, 49, 54 Stomach - familial neoplasia of, 271 - lesions, PTEN-hamartoma tumor syndromes, 753 - Peutz-Jeghers polyposis syndrome, 745, 746 - table, 270–271 Striated muscles, significance of normal histoanatomic structures in prostate pathology (table), 338 Stromal components, Wilms tumor, 314 Subependymal giant cell astrocytoma, tuberous sclerosis complex (TSC), 775 Subungual exostosis, molecular and cytogenic findings, 37–40 Succinate dehydrogenase (SDH)-associated paraganglioma. See familial paraganglioma pheochromocytoma syndrome. Succinate dehydrogenase B-associated hereditary paraganglioma/pheochromocytoma - hereditary or familial renal tumor syndrome, 654 - tumors with clear/light-staining cytoplasm (table), 320 Succinate dehydrogenase (SDH)-deficient renal cell carcinoma, known hereditary cancer syndromes, 489–490 Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC), 308–311 - diagnostic checklist, 310 - differential diagnosis, 310 - genetics, 309 - prognosis, 309 SUFU gene, 804–823 Suspected hereditary renal cancer, pathway for genetic referral in, 320 SWI complex deficiency syndrome, hereditary, 658–659 Sympathetic algodystrophy, McCune-Albright syndrome, 687 Sympathetic (sympathoadrenal) paraganglia, 105 Syndromes - ataxia-telangiectasia, 502–503 differential diagnosis, 503 genetics, 502 neoplasms associated, 503 - BAP1 tumor predisposition syndrome, 504–505 criteria for diagnosis, 505 differential diagnosis, 505 genetics, 504 neoplasm associated, 505

xlvii

INDEX - basal cell nevus syndrome/Gorlin syndrome, 506–509 criteria for diagnosis, 508 differential diagnosis, 507–508 genetics, 506 neoplasms associated, 506–507 - Beckwith-Wiedemann syndrome, 510–517 associated neoplasms, 511–512 differential diagnosis, 512–513 genetics, 511 - Birt-Hogg-Dubé syndrome, 518–521 associated neoplasms, 518–519 colorectal carcinoma, 519 diagnostic criteria, 520 differential diagnosis, 519–520 genetics, 518 renal cell carcinoma, 519 - Bloom syndrome, 522–523 associated neoplasms, 523 cytogenetic testing, 523 increased cancer risk, 523 - Brooke-Spiegler syndrome, 524–527 associated neoplasms, 525 criteria for diagnosis, 525–526 differential diagnosis, 525 gene, 524 - Carney complex, 528–535 atrial myxoma, 529 criteria for diagnosis, 529 differential diagnosis, 530–531 genetic testing, 530 genomic locus and genes associated, 532 large-cell calcifying Sertoli cell tumor, 530 primary pigmented nodular adrenocortical disease, 530 prognosis, 530 psammomatous melanotic schwannoma, 530 syndromes with similar tissue manifestations, 532 - colonic carcinoma syndromes, 536–539 DNA polymerase ε and δ polyposis (POLE and POLD1 mutation-associated tumors), 538 familial adenomatous polyposis, 537 hereditary mixed polyposis, 538 juvenile polyposis, 538 Li-Fraumeni syndrome, 538 Lynch syndrome (hereditary nonpolyposis colorectal cancer), 537 MSH3 polyposis, 538 MUTYH-associated polyposis, 537 NTHL1 polyposis, 538 Peutz-Jeghers syndrome, 538 PTEN-hamartoma syndrome (Cowden/BannayanRiley-Ruvalcaba), 538 serrated (giant hyperplastic) polyposis syndrome, 537–538 - Denys-Drash syndrome, 542–545 associated neoplasms, 543 differential diagnosis, 543 genetics, 542 prognosis, 543 structural and functional abnormalities, 543 xlviii

- Diamond-Blackfan anemia, 546–547 differential diagnosis, 547 genetic basis, 546 - DICER1 syndrome, 548–555 diagnostic checklist, 552 differential diagnosis, 552 genetics, 549 prognosis, 551 - Down syndrome, 556–559 age-specific hematologic abnormalities, 558 age-specific hematological malignancies in children and risk compared to non-DS peers, 558 - dyskeratosis congenita, 560–563 associated neoplasms, 561 diagnostic criteria, 562 differential diagnosis, 562 genetics, 560–561 - familial acute myeloid leukemia and myelodysplastic syndrome, 564–567 associated neoplasms, 566 genetics, 566 - familial adenomatous polyposis, 568–575 diagnostic checklist, 571 differential diagnosis, 570–571 extraintestinal features, 572 genetic predisposition, 568–569 genetic testing, 570 prognosis, 569 variants, 572 - familial chordoma, 576–577 associated neoplasms, 576–577 genetics, 576 prognosis, 577 - familial gastrointestinal stromal tumor, 578–583 Carney-Stratakis syndrome, 579–580 Carney triad, 579 genetic syndromes associated, 581 KIT germline mutations, 579 neurofibromatosis type 1, 580 PDGFRA germline mutations, 579 syndromes/genetics, 579–580 - familial infantile myofibromatosis, 584–585 differential diagnosis, 585 genetics, 584 - familial isolated hyperparathyroidism, 586–589 associated conditions, 587 differential diagnosis, 587–588 genetic tests, 587 genetics, 586 - familial nonmedullary thyroid carcinoma, 590–595 associated neoplasms, 592–593 familial papillary thyroid carcinoma with multinodular goiter, 592 familial papillary thyroid carcinoma with papillary renal cell carcinoma, 592 genetics, 591–592 pure FPTC ± oxyphilia, 592 syndromes characterized by predominance of nonthyroidal tumors, 591 syndromes with predominance of nonmedullary thyroid carcinoma, 591–592

INDEX type 1 familial nonmedullary thyroid carcinoma, 592 - with fundic gland polyposis, gastric adenocarcinoma, 239 - hereditary retinoblastoma, 656–657 - hereditary SWI/SNF complex deficiency syndrome, 658–659 - Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 660–661 - overview hamartomatous polyps, Peutz-Jeghers, 744–749 Nijmegen breakage syndrome, 734–735 pancreatic neuroendocrine tumor syndromes, 736–743 PTEN-hamartoma tumor syndromes, 750–757 RASopathies: Noonan syndrome, 758–761 rhabdoid predisposition syndrome, 762–765 schwannomatosis, 766–769 Shwachman-Diamond syndrome, 770–771 steatocystoma multiplex, 772–773 tuberous sclerosis complex, 774–779 tumor syndromes predisposing to osteosarcoma, 780–781 von Hippel-Lindau syndrome, 782–789 Werner syndrome/progeria, 790–793 Wilms tumor-associated syndromes, 794–795 Wiskott-Aldrich syndrome, 796–797 xeroderma pigmentosum, 798–801 Syndromic Wilms tumor, Beckwith-Wiedemann syndrome vs., 513 Synovial sarcoma - malignant peripheral nerve sheath tumor vs., 20 - molecular and cytogenic findings, 37–40 SYT gene, 804–823

T TACSTD1 gene, 804–823 Tamoxifen, for breast/ovarian cancer syndrome (BRCA1), 613 Tangentially cut follicles, C-cell hyperplasia vs., 172 TAT gene, 804–823 TCAB1 gene, 804–823 - dyskeratosis congenita associated, 560 TCF12-NR4A3 gene, 804–823 Teeth manifestations, familial adenomatous polyposis, 570 Tenosynovial giant cell tumor, molecular and cytogenic findings, 37–40 Teratoid Wilms tumor, 314 Teratoma, immature, Wilms tumor vs., 314 Teratoma (T), germ cell tumor, 353, 354 TERC gene, 804–823 TERC gene mutations - dyskeratosis congenita associated, 560 - familial acute myeloid leukemia associated, 565 - head and neck squamous cell carcinoma, 395 TERF2IP gene, melanoma/pancreatic carcinoma syndrome, 692

TERT gene, 804–823 - melanoma/pancreatic carcinoma syndrome, 692 - mutations dyskeratosis congenita associated, 560 familial acute myeloid leukemia associated, 565 head and neck squamous cell carcinoma, 395 Tertiary hyperplasia, primary parathyroid hyperplasia vs., 147 Testicle, table, 362–367 Testicular neoplasms - germ cell tumor, 352–357 older adult, 353 pediatric or prepubertal, 353 postpubertal, 353 prognosis, 353 - hereditary syndromes associated, 478 - Sertoli cell, 358–361 prognosis, 359 syndromes/familial Sertoli cell neoplasms, 359 Testicular tumors. See also Familial sex cord-stromal tumors; Familial testicular germ cell tumors; Familial testicular tumor. - AJCC Staging System for Testicular Cancer, 363 - familial testicular tumors (table), 362 - tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 - tumors with glandular/tubular pattern (table), 362–363 - tumors with oxyphilic cytoplasm (table), 363 TFE3 translocation-associated RCC, HLRCC syndromeassociated renal cell carcinoma vs., 298 TGFBR3-MGEA5 gene, 804–823 Thick corneal nerves, multiple endocrine neoplasia type 2, 708 Thrombocytopenia, age-specific hematologic abnormalities in Down syndrome, 558 Thrombocytopenia 2, associated with increased risk of hematological malignancies, 6–7 Thrombocytopenia 5, associated with increased risk of hematological malignancies, 6–7 Thymic and bronchial neuroendocrine tumor, multiple endocrine neoplasia type 1, 697 Thyroid, medullary - carcinoma, 176–185 diagnostic checklist, 180 differential diagnosis, 180 familial, 181 genetic predisposition, 177 genetic testing, 179–180 immunohistochemistry, 181 prognosis, 178 sporadic, 181 - carcinoma table, 186–187 familial from sporadic medullary carcinoma, 186 familial syndromes, 186 MEN2 syndrome, 186 MEN2A and MEN2B, RET mutations to risk of aggressive MTC, 187 prophylactic thyroidectomy depending on RET mutation, ATA age recommendations, 187

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INDEX reactive/physiologic and neoplastic C-cell hyperplasia, 187 - C-cell hyperplasia, 170–175 diagnostic checklist, 172 differential diagnosis, 172 immunohistochemistry, 173 prognosis, 171 reactive/physiologic vs. neoplastic, 173 Thyroid, nonmedullary - carcinoma table, 208–209 distinct characteristics of familial thyroid carcinoma and sporadic carcinoma, 208 familial nonmedullary thyroid carcinoma classification, 208 familial nonmedullary thyroid carcinoma in familial cancer syndromes, 208 - familial thyroid carcinoma, 188–199 diagnostic checklist, 188 differential diagnosis, 192 familial follicular cell carcinoma classification, 193 genetic testing, 192 - follicular thyroid carcinoma, 200–207 classification, 204 diagnostic checklist, 203 differential diagnosis, 203, 204 familial setting, 204 genetic testing, 202–203 prognosis, 201 Thyroid carcinoma - cribriform morular papillary, hereditary syndromes associated, 477 - differentiated, DICER1 syndrome, 550 - familial, 188–199 diagnostic checklist, 188 differential diagnosis, 192 familial follicular cell carcinoma classification, 193 genetic testing, 192 - McCune-Albright syndrome, 687 - MUTYH-associated polyposis, 719 - with oxyphilia, genetics, 592 - PTEN-hamartoma tumor syndromes, risk management, 754 - pure familial papillary thyroid carcinoma, genetics, 592 Thyroid cysts, Birt-Hogg-Dubé syndrome associated, 519 Thyroid follicular neoplasm, parathyroid adenoma vs., 134 Thyroid lesions, PTEN-hamartoma tumor syndromes, 753 Thyroid neoplasms - Birt-Hogg-Dubé syndrome associated, 519 - hereditary syndromes associated, 477 Thyroid nodules, Birt-Hogg-Dubé syndrome associated, 519 Thyroid tumors, hereditary leiomyomatosis and renal cell carcinoma, 625 Thyroiditis, palpation, C-cell hyperplasia vs., 172 TINF2 gene, 804–823 - mutations dyskeratosis congenita associated, 560 head and neck squamous cell carcinoma, 395 TMEM127 gene, 804–823 TMPRSS2 and ETS gene fusion, prostate carcinoma, 327 l

TMPRSS2 gene, 804–823 TMPRSS2-ERG gene fusion, prostate carcinoma, 327 Tongue squamous cell carcinoma, 395 - head and neck squamous cell carcinoma vs., 396 TP53 - familial uveal melanoma, 602 - hereditary prostate cancer, 651 TP53 gene, 804–823 - Li-Fraumeni syndrome, 675 - mutations basal cell carcinoma associated, 451 breast carcinoma, 48, 54 follicular carcinoma, 201 Wilms tumor, 313 TP53 mutation, Li-Fraumeni syndrome, 780 Transient abnormal myelopoiesis, age-specific hematologic abnormalities in Down syndrome, 558 Transition zone (TZ), significance of normal histoanatomic structures in prostate pathology (table), 338 Transitional carcinoma. See Head and neck neoplasms, squamous cell carcinoma. - renal. See Renal urothelial carcinoma. Transitional cell carcinoma. See Bladder urothelial carcinoma; Ureter urothelial carcinoma. Transmembrane protein 127 (TMEM127), hereditary paraganglioma/pheochromocytoma syndromes and, 643 TRC8 gene, 804–823 Trichilemmal cyst, steatocystoma multiplex vs., 773 Trichilemmomas, selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Trichoblastoma, basal cell carcinoma vs., 452 Trichodiscomas, associated with Birt-Hogg-Dubé syndrome, 518 Trichoepithelioma - basal cell carcinoma vs., 452 - Brooke-Spiegler syndrome associated, 525 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 Trichothiodystrophy, xeroderma pigmentosum vs., 800 Triphasic angiomyolipoma. See Angiomyolipoma. Triple parathyroid adenoma, primary parathyroid hyperplasia vs., 146 Trisomy 18, hepatoblastoma, 213 Trisomy 21. See Down syndrome (DS). Trophoblastic, urothelial carcinoma with, bladder carcinoma and, 277 TRPS1 gene, 804–823 TSC. See Tuberous sclerosis complex. TSC1 and TSC2 genes, pancreatic neuroendocrine neoplasms, 120 TSC1 gene, 804–823 - germline mutations, tuberous sclerosis complex (TSC), 774 TSC2 gene, 804–823 - germline mutations, tuberous sclerosis complex (TSC), 774 TSHR gene, 804–823 TSR2 genes mutations, Diamond-Blackfan anemia, 546

INDEX Tuberous sclerosis - Birt-Hogg-Dubé syndrome vs., 519 - bone and soft tissue tumors associated with, 36 - Brooke-Spiegler syndrome vs., 525 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - familial cancer syndromes with lung neoplasms, 444 - hereditary or familial renal tumor syndrome, 654 - multiple endocrine neoplasia type 4, 713 - pancreatic neuroendocrine neoplasms, 120 - part of inherited tumor syndromes, 128 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Tuberous sclerosis-associated angiomyolipoma, 287 Tuberous sclerosis complex (TSC), 774–779 - associated neoplasms, 775 - diagnostic criteria, 774 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial renal tumors in (table), 320 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - genetics, 774 - pancreatic neuroendocrine tumors, 737, 738 - von Hippel-Lindau (VHL) syndrome vs., 784 Tuberous sclerosis complex/autosomal dominant polycystic kidney disease (ADPKD) contiguous gene syndrome, von Hippel-Lindau (VHL) syndrome vs., 784 Tubular gut - colonic adenomas, 228–233 diagnostic checklist, 232 differential diagnosis, 232 prognosis, 230 - esophageal adenocarcinoma, 234–235 diagnostic checklist, 235 genetic predisposition, 235 - esophageal squamous cell carcinoma, 236–237 differential diagnosis, 237 genetic predisposition, 237 - gastric adenocarcinoma, 238–243 differential diagnosis, 241 - gastrointestinal stromal tumor, 244–251 differential diagnosis, 246 prognosis, 245 - hamartomatous polyposis syndromes, 252–261 diagnostic checklist, 254 differential diagnosis, 254 prognosis, 253 - small bowel adenocarcinoma, 262–267 differential diagnosis, 265 Tubular gut neoplasms - colon/rectum table, familial colon and rectum tumors by syndrome (table), 268–269

- esophagus/stomach/small bowel table, familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Tubulocystic carcinoma, cystic nephroma vs., 295 Tubulocystic RCC, HLRCC syndrome-associated renal cell carcinoma vs., 298 Tumor necrosis, Wilms tumor, 314 Tumor syndromes predisposing to osteosarcoma, 780–781 - Bloom syndrome, 781 - hereditary retinoblastoma, 780 - Li-Fraumeni syndrome, 780 - Rothmund-Thomson syndrome, 781 - Werner syndrome, 780–781 Tumorigenesis, von Hippel-Lindau (VHL) syndrome, 782 Turcot syndrome. See also Lynch syndrome. - hereditary cancer syndromes associated, 498 - as variant of familial adenomatous polyposis, 572 Turcot type 1, genetic syndromes associated with CNS neoplasms, 412 Turcot type 2. See also Familial adenomatous polyposis. - genetic syndromes associated with CNS neoplasms, 412 Tylosis esophageal cancer. See also Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer. - familial esophageal, gastric, and small intestinal tumors by syndrome (table), 270–271 Typical carcinoid (TC). See also Neuroendocrine tumors, of lung. - neuroendocrine tumor of lung vs., 440 TYR gene, 804–823 Tyrosinemia, familial biliary tract, liver, and pancreas neoplasms, 226–227

U UCa. See Urothelial carcinoma. Ulcers, cutaneous squamous cell carcinoma associated, 461 Ultraviolet light action spectrum, xeroderma pigmentosum, 798 Ultraviolet light sensitive syndrome, xeroderma pigmentosum vs., 799 Ultraviolet (UV) radiation, cutaneous squamous cell carcinoma associated, 461 Undifferentiated carcinoma, medullary thyroid carcinoma vs., 180 Undifferentiated/dedifferentiated carcinoma, endometrial carcinoma, 381 Undifferentiated pleomorphic sarcoma, pleomorphic rhabdomyosarcoma vs., 30 Unna-Thorst syndrome, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 661 Upper aerodigestive tract cancers, dyskeratosis congenita associated, 561 Ureter neoplasia, hereditary syndromes associated, 478 Ureter transitional cell carcinoma. See Ureter urothelial carcinoma. li

INDEX Ureter urothelial carcinoma, 348–349 - prognosis, 349 Urothelial carcinoma (UCa) - bladder, 274–281 diagnostic checklist, 277 differential diagnosis, 277 prognosis, 275 - carcinomas involving kidney &/or renal pelvis, 350 - Costello syndrome associated, 540–541 - with divergent differentiation, bladder carcinoma and, 276 - high-grade poorly differentiated carcinoma (table), 282 - with myxoid stroma and chordoid features, bladder carcinoma and, 277 - with osteoclast giant cells, bladder carcinoma and, 277 - renal. See Renal urothelial carcinoma. - with small tubules, bladder carcinoma and, 276 - with trophoblastic, bladder carcinoma and, 277 - ureter, 348–349 prognosis, 349 Urothelial carcinoma-associated markers in metastatic setting, bladder neoplasm and, 282 Urothelial proliferation of uncertain malignant potential, bladder carcinoma and, 276 USB1 gene, 804–823 USP6 gene, 804–823 Uterine cancer, PTEN-hamartoma tumor syndromes, risk management, 754 Uterine carcinoma, poorly differentiated, bladder carcinoma vs., 277 Uterine leiomyosarcoma, molecular and cytogenic findings, 37–40 Uterine neoplasia, hereditary syndromes associated, 480 Uterine smooth muscle tumors, hereditary leiomyomatosis and renal cell carcinoma, 625 Uveal melanoma, 602 - familial, 602–603 genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 genetic syndromes associated with CNS neoplasms, 412 genetics, 602

V

Vasoactive intestinal peptide, part of inherited tumor syndromes, 128 Verrucous carcinoma, head and neck squamous cell carcinoma, 396 Verumontanum, significance of normal histoanatomic structures in prostate pathology (table), 338 Vestibular schwannoma, 420 VHL. See von Hippel-Lindau syndrome. VHL disease, endolymphatic sac tumor, 391 VHL gene, 804–823 - mutations, pancreatic neuroendocrine neoplasms, 120 VHL protein, 782 VHL syndrome. See von Hippel-Lindau (VHL) syndrome. lii

VIPoma syndrome - pancreatic neuroendocrine tumor, 121, 123 - well-differentiated pancreatic neuroendocrine neoplasm, 121 VIPomas, 737 - multiple endocrine neoplasia type 1, 697 Viral hepatitis, hepatocellular carcinoma, 219 von Hippel-Lindau (VHL) disease. See also von HippelLindau (VHL) syndrome. - clear cell renal cell carcinoma, 291 - familial biliary tract, liver, and pancreas neoplasms, 226–227 - hereditary or familial renal tumor syndrome, 654 - hereditary paraganglioma/pheochromocytoma syndromes, 643 - pancreatic neuroendocrine tumors, 737, 738 - pheochromocytoma-associated syndromes (table), 646 von Hippel-Lindau (VHL) syndrome, 782–789 - adrenal cortical adenoma, 59 - bone and soft tissue tumors associated with, 36 - diagnostic criteria, 486–487 - differential diagnosis, 784 - familial cancer syndromes with gynecologic manifestations (table), 384–385 - familial cancer syndromes with salivary gland neoplasms, 404 - familial renal tumors in (table), 320 - genetic predisposition to endolymphatic sac tumor, 391 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetic syndromes associated with CNS neoplasms, 412 - genetics, 782 - hereditary cancer syndromes associated, 498 - known hereditary cancer syndromes, 489–490 - pancreatic neuroendocrine neoplasms, 119 - part of inherited tumor syndromes, 128 - pheochromocytoma/paraganglioma associated with, 115 - prognosis, 783 - subtypes, 782 - type 1, 782 - type 2, 782 von Recklinghausen disease. See also Neurofibromatosis type 1. - known hereditary cancer syndromes, 489–490 Vorner syndrome, Howel-Evans syndrome/keratosis palmares and plantares with esophageal cancer, 661

W Wagenmann-Froboese syndrome. See Multiple endocrine neoplasia type 2. WAGR syndrome - Denys-Drash syndrome vs., 543 - familial renal tumors in (table), 320 - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 - Wilms tumor, 313

INDEX Warthin tumor - familial cancer syndromes with salivary gland neoplasms, 404 - molecular changes described in salivary gland tumors (table), 405–406 WAS. See Wiskott-Aldrich syndrome. WAS gene, 796, 804–823 Weakness, parathyroid carcinoma, 137 Weaver syndrome, Beckwith-Wiedemann syndrome vs., 512 Weight loss, parathyroid carcinoma, 137 Well-differentiated liposarcoma, molecular and cytogenic findings, 37–40 Werner syndrome/progeria, 790–793. See also Multiple endocrine neoplasia type 1. - bone and soft tissue tumors associated with, 36 - diagnostic criteria, 792 - differential diagnosis, 791–792 - familial cancer syndromes, 208 - familial follicular cell carcinoma, 193 - familial nonmedullary thyroid carcinoma, 190, 593 - familial thyroid carcinoma, 189 - follicular thyroid carcinoma, 201, 204 - genetic testing, 792 - genetic tumor syndromes and nonneoplastic ocular manifestations (table), 416 - genetics, 591, 790 - osteosarcoma, 780–781 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Whipple disease, gastric adenocarcinoma vs., 241 Wilms tumor (WT), 312–319 - adrenal cortical neoplasms in children vs., 72 - aniridia genitourinary malformations, 794 - associated syndromes, 794–795 - Beckwith-Wiedemann syndrome, 511–512 - Bloom syndrome associated, 523 - classification after neoadjuvant therapy (SIOP), 315 - conditions with increased risk, 795 - Denys-Drash syndrome, 543 - DICER1 syndrome vs., 552 - differential diagnosis, 314–315 - familial, 604–605 familial renal tumors (table), 320 genetics, 604 prognosis, 605 - hereditary cancer syndromes associated, 498 - histological criteria for subtyping after chemotherapy by SIOP, 315 - hyperparathyroidism-jaw tumor syndrome, 663 - nonsyndromic, Beckwith-Wiedemann syndrome vs., 513 - overgrowth syndromes, 794–795 - prognosis, 314, 794 - staging system (COG), 315 - syndromic, Beckwith-Wiedemann syndrome vs., 513 Wiskott syndrome. See Wiskott-Aldrich syndrome. Wiskott-Aldrich syndrome (WAS), 796–797 - acute lymphoblastic leukemia, 5

- diagnostic clues in, 797 - differential diagnosis, 797 - prognosis, 797 Wiskott-Aldrich syndrome 2 (WAS2), Wiskott-Aldrich syndrome vs., 797 WNT gene, 804–823 Wnt pathway activation, β-catenin mutation, hepatoblastoma, 213 WRAP53 gene mutations, dyskeratosis congenita associated, 560 WRN gene, 804–823 - mutations, follicular carcinoma, 201 WRN mutation, Werner syndrome, 780–781 WT. See Wilms tumor. WT1 gene, 804–823 - mutations Denys-Drash syndrome, 542 familial Wilms tumor and, 604 Wilms tumor, 313 WT2 gene, 804–823 WTX gene, 804–823 - mutations, Wilms tumor, 313

X

Xeroderma pigmentosum (XP), 798–801 - adenocarcinoma with lepidic (bronchioloalveolar) predominant pattern associated, 433 - differential diagnosis, 799–800 - familial cancer syndromes with head and neck lesions and neoplasms, 400–402 - familial cancer syndromes with lung neoplasms, 444 - genetic predisposition for squamous cell carcinoma of head and neck, 395 - genetic syndromes and neoplasms involving eye and ocular adnexa (table), 416 - genetics, 798–799 - lung adenocarcinoma associated, 427 - selected cutaneous neoplasms and associated hereditary cancer syndromes, 472 - selected hereditary cancer syndromes with skin manifestations, 472–473 Xeroderma pigmentosum/Cockayne syndrome overlap, xeroderma pigmentosum vs., 799 X-LAG. See X-linked acrogigantism. X-linked acrogigantism, part of inherited tumor syndrome, 167 X-linked acrogigantism syndrome, isolated familia, pituitary adenoma, 159 X-linked thrombocytopenia, 797 XP. See Xeroderma pigmentosum. XP-A clinical syndrome, 798 XP variant, 798–799 XPA gene, 804–823 XPA-XPG gene, 804–823 XP-B clinical syndrome, 798 XPB gene, 804–823 XP-C clinical syndrome, 798 liii

INDEX XPC gene, 804–823 XP-D clinical syndrome, 798 XPD gene, 804–823 XP-E clinical syndrome, 798 XPE gene, 804–823 XP-F clinical syndrome, 798 XPF gene, 804–823 XP-G clinical syndrome, 798 XPG gene, 804–823

Y

Yolk sac tumor (YST) - germ cell tumor, 353, 354 - tumors with diffuse arrangement and pale and clear cytoplasm (table), 362 - tumors with glandular/tubular pattern (table), 362–363 YST. See Yolk sac tumor.

Z Zinsser-Cole-Engman syndrome. See Dyskeratosis congenita.

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