Gattuso's Differential Diagnosis in Surgical Pathology [4 ed.] 0323661653, 9780323661652

Citation preview

FOURTH EDITION

Gattuso’s Differential Diagnosis in Surgical Pathology Vijaya B. Reddy, MD, MBA The Harriet Blair Borland Chair of Pathology Professor and Chairperson Department of Pathology Rush University Medical Center Chicago, Illinois United States

Odile David, MD

Associate Professor and Director of Cytopathology University of Illinois at Chicago Chicago, Illinois United States

Daniel J. Spitz, MD

Chief Medical Examiner Macomb and St. Clair Counties, Michigan Clinical Assistant Professor of Pathology Wayne State University School of Medicine Detroit, Michigan United States

Meryl H. Haber, MD

Borland Professor and Chairman of Pathology, Emeritus Rush Medical College of Rush University Chicago, Illinois United States

iii Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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

GATTUSO’S DIFFENENTIAL DIAGNOSIS IN SURGICAL PATHOLOGY, FOURTH EDITION Copyright © 2022 by Elsevier, Inc. All rights reserved.

ISBN: 978-­0-­323-­66165-­2

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).

Notice 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 c­ ontributors 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 editions copyrighted 2015, 2010, 2002. Library of Congress Control Number: 2020949417

Executive Content Strategist: Michael Houston Senior Content Development Specialist: Ann Ruzycka Anderson Publishing Services Manager: Catherine Jackson Senior Project Manager: Sharon Corell Design Direction: Ryan Cook Printed in the United States. Last digit is the print number: 9 8 7 6 5 4 3 2 1

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Contributors

SYLVIA ASA, MD, PhD Professor Pathology Case Western Reserve University Consultant in Endocrine Pathology Pathology University Hospitals Cleveland Cleveland, Ohio United States Consultant in Endocrine Pathology Pathology University Health Network Toronto, Ontario Canada

BYRON CRAWFORD, MD Professor and Chair Pathology LSU School of Medicine Shreveport, Louisiana United States

ELIZAVETA BELYAEVA, MD Assistant Professor of Pathology and Laboratory Medicine Tulane University School of Medicine New Orleans, Louisiana United States

VIRGINIA E. DUNCAN, MD, MS Assistant Professor Pathology University of Alabama at Birmingham Birmingham, Alabama United States

PINCAS BITTERMAN, MD Professor Emeritus Departments of Pathology and Obstetrics and Gynecology Rush University Medical Center Chicago, Illinois United States

ADEL K. EL-­NAGGAR, MD Professor pathology The University of Texas MD Anderson Cancer Center Houston, Texas United States

KOSSIVI DANTEY, MD Assistant Professor Drexel University College of Medicine Pathology Allegheny Health Network Pittsburgh, Pennsylvania United States

DUSTIN E. BOSCH, MD, PhD Fellow Department of Laboratory Medicine and Pathology University of Washington School of Medicine Seattle, Washington United States

MARK F. EVANS, PhD Assistant Professor Pathology and Laboratory Medicine Larner College of Medicine University of Vermont Burlington, Vermont United States

ELIZABETH J. COCHRAN, MD Professor Department of Pathology Medical College of Wisconsin Milwaukee, Wisconsin United States

HUMA FATIMA, MD Associate Professor Pathology University of Alabama at Birmingham Birmingham, Alabama United States

KUMARASEN COOPER, MBChB, DPhil Professor of Pathology Department of Pathology Hospital of University of Pennsylvania (HUP) Philadelphia, Pennsylvania United States

vii

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

viii

Contributors

SANDRA E. FISCHER, MD Associate Professor Laboratory Medicine and Pathobiology University of Toronto Staff Pathologist Laboratory Medicine Program University Health Network Clinician Investigator Princess Margaret Cancer Centre University Health Network Toronto, Ontario Canada JULIA T. GEYER, MD Associate Professor of Pathology and Laboratory Medicine Weill Cornell Medicine New York, New York United States

CRISTINA MAGI-­GALLUZZI, MD, PhD Director Anatomic Pathology Department of Pathology Professor of Pathology Pathology University of Alabama at Birmingham Section Head Genitourinary Pathology Director Genitourinary Pathology Fellowship Program The C. Bruce Alexander Endowed Professorship in Pathology Birmingham, Alabama United States

RICHARD J. GROSTERN, MD Section Director Ophthalmic Pathology Department of Ophthalmology Rush Medical College of Rush University Chicago, Illinois United States

MEERA MAHALINGAM, MD, PhD, FRCPath Professor of Dermatology Tufts University School of Medicine Senior Lecturer Pathology Harvard Medical School Dermatopathology Section Chief Department of Pathology and Laboratory Medicine VA Integrated Service Networks (VISN1), New England West Roxbury, Massachusetts United States

RALPH H. HRUBAN, MD Professor Pathology and Oncology The Johns Hopkins University School of Medicine Baltimore, Maryland United States

MARIA J. MERINO, MD Chief Translational Surgical Pathology NCI Bethesda, Maryland United States

ALIYA N. HUSAIN, MBBS Professor Pathology University of Chicago Chicago, Illinois United States

IRA MILLER, MD, PhD Director of Orthopedic Pathology Department of Pathology Rush University Medical Center Chicago, Illinois United States

ALEXANDRA N. KALOF, MD Associate Professor Pathology and Laboratory Medicine Larner College of Medicine University of Vermont Burlington, Vermont United States

ATTILIO ORAZI, MD, FRCPath Pofessor of Pathology Department of Pathology TexasTech University Health Sciences Center El Paso, Texas United States

NIKOLAJ P. LAGWINSKI, MD Associate Pathologist GI Insitute Ameripath Cleveland Oakwood Village, Ohio United States

HREEM N. PATEL, MD Assistant Professor Ophthalmology Rush University Medical Center Chicago, Illinois United States

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Contributors

SUNNY B. PATEL, BS, MD† Resident Physician Department of Ophthalmology Rush University Medical Center Chicago, Illinois United States ROBERT E. PETRAS, MD Associate Clinical Professor of Pathology Northeast Ohio Medical University Rootstown, Ohio United States MICHAEL R. PINS, MD Professor and Chair of Pathology Pathology Chicago Medical School of Rosalind Franklin University of Medicine and Science North Chicago, Illinois United States Chairman of Pathology Pathology Advocate Lutheran General Hospital and Advocate Children’s Hospital Park Ridge, Illinois United States SONAM PRAKASH, MBBS Clinical Professor Laboratory Medicine University of California San Francisco San Francisco, California United States VIJAYA B. REDDY, MD, MBA The Harriet Blair Borland Chair of Pathology Professor and Chairperson Department of Pathology Rush University Medical Center Chicago, Illinois United States E. RENE RODRIGUEZ, MD Professor Cleveland Clinic Lerner College of Medicine of Case Western University Cleveland, Ohio United States JOHN J. SCHMIEG, MD, PhD Staff Hematopathologist The Joint Pathology Center Silver Spring, Maryland United States

ix

JEFREE SCHULTE, MD Assistant Professor Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public Health Madison, Wisconsin United States DAVID SUSTER, MD Assistant Professor Pathology Rutgers University New Jersey Medical School Newark, New Jersey United States SAUL SUSTER, MD Professor and Chairman Emeritus Department of Pathology Medical College of Wisconsin Milwaukee, Wisconsin United States PAUL E. SWANSON, MD Professor Department of Laboratory Medicine and Pathology University of Washington School of Medicine Seattle, Washington United States CARMELA D. TAN, MD Associate Professor Cleveland Clinic Lerner College of Medicine of Case Western University Cleveland Clinic Cleveland, Ohio United States ELIZABETH THOMPSON, MD, PhD Assistant Professor Pathology The Johns Hopkins University School of Medicine Baltimore, Maryland United States MICHELLE D. WILLIAMS, MD Professor Pathology The University of Texas MD Anderson Cancer Center Houston, Texas United States LEI YAN, MD, PhD Assistant Professor Department of Pathology Rush University Medical Center Chicago, Illinois United States

†Deceased

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

x

Contributors

MATTHEW M. YEH, MD, PhD Professor Department of Laboratory Medicine and Pathology University of Washington School of Medicine Adjunct Professor Department of Medicine University of Washington School of Medicine Seattle, Washington United States

MING ZHOU, MD, PhD Chair and Pathologist-­in-­Chief Pathology and Laboratory Medicine Tufts Medical Center Tufts University School of Medicine Boston, Massachusetts United States

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

To Swathi, my shining star VIJAYA B. REDDY

To my wife, Nancy, and my children, Vincent and Francesca PAOLO GATTUSO

To my family, to whom I owe my appreciation of life and learning ODILE DAVID

To my parents, for setting me on the right track, and to my wife, Jodi, for her continuous support and encouragement DANIEL J. SPITZ

To all of my former students, residents, fellows, and physician associates from whom I have always learned more than I have been able to teach MERYL H. HABER

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Acknowledgments

We thank all our contributors for their expertise, knowledge, and invaluable role in the continued success of this book. The editors also gratefully acknowledge the work of authors who have contributed to this book in its previous editions. We thank Irma Parker for her assistance and persistence in contacting the contributors and ensuring the timely submissions. We are thankful to our publisher,

Elsevier, and Michael Houston, Executive Content Strategist, for his support and encouragement in the production of a fourth edition. A special thanks to Ann Ruzycka Anderson, Senior Content Development Specialist, and Sharon Corell, Senior Project Manager, for their patience and competence in keeping the book on course over the past year.

Vijaya B. Reddy, MD

xiii

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Preface

The concept of this textbook was conceived just over 20 years ago by attending pathologists and residents in the Department of Pathology of Rush Medical Center in Chicago. This, the fourth edition, has gradually evolved into a widely used textbook for practicing surgical pathologists, residents, and others of the medical field interested in diagnostic pathology. Conceptually, it began as and remains a nonencyclopedic compendium of a wide variety of surgical pathology specimens with which pathologists are confronted daily. No attempt was made to copy or emulate already existing textbooks of pathology. Instead, the author’s goals were to produce a usable text in outline format with succinct text discussions and clear descriptions of differential diagnoses of pathologic entities. A “Pearls” line or two is included to facilitate prompt and accurate diagnosis. Each discussed entity is accompanied by numerous carefully selected high-quality color photographs, both macro and microscopic, of commonly encountered specimens surgically removed. These images

illustrating particular diagnostic characteristics continue to be a hallmark. In this current edition, 5 years since the previous, each section has been reviewed and revised especially with the application of diagnostic biomarkers. As in the third edition, Dr. Vijaya Reddy oversaw these additions and revisions, monitored the selection of new authors, prompted previous authors, added photomicrographs, and pursued overall development. This volume is now more encompassing than before. It includes new and valuable diagnostic findings and, even though we have attempted to make it more concise, it remains more than a thousand pages. We are gratified that over the past score of years this textbook has been a helpful aid to pathologists in surgical pathology laboratories around the world. Selected updated references remain included, as are the many “Pearl” paragraphs. Meryl H, Haber, MD

xi

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1

Special Diagnostic Techniques in Surgical Pathology ALEXANDRA N. KALOF  •  MARK F. EVANS  •  KOSSIVI DANTEY  •  KUMARASEN COOPER

Chapter Outline Light Microscopy  1 Tissue Processing Overview  1 Fixation  1 Histologic Stains  3 Fluorescence Microscopy  6 Electron Microscopy  7 Technical Overview  7 Ultrastructure of a Cell  7 Immunohistochemistry  9 Introduction  9 Technical Overview  9 Flow Cytometry  11 Introduction  11 Technical Overview  11

LIGHT MICROSCOPY TISSUE PROCESSING OVERVIEW • Fixation • Preserves tissues in situ as close to the lifelike state as possible • Ideally, fixation will be carried out as soon as possible after removal of the tissues, and the fixative will kill the tissue quickly, thus preventing autolysis • Dehydration • Fixed tissue is too fragile to be sectioned and must be embedded first in a nonaqueous supporting medium (e.g., paraffin) • The tissue must first be dehydrated through a series of ethanol solutions • Clearing • Ethanol is not miscible with paraffin, so nonpolar solvents (e.g., xylene, toluene) are used as clearing agents; this also makes the tissue more translucent • Embedding • Paraffin is the usual embedding medium; however, tissues are sometimes embedded in a plastic resin, allowing for thinner sections (required for electron microscopy [EM]) •  This embedding process is important because the tissues must be aligned, or oriented, properly in the block of paraffin

Cytogenetic Analysis  12 Molecular Pathology Methods  17 Introduction  17 Nucleic Acid Extraction Methods  17 Tissue Microdissection Methods  23 Gel Electrophoresis Methods  26 Blot Hybridization Methods  27 Amplification Methods  29 Nanostring Technology  33 Microarray Technology  34 Nucleic Acid Sequencing  35 In Situ Hybridization  36 Protein Analytic Methods  37 Emerging Developments  39 Resources  40

• Sectioning • Embedded in paraffin, which is similar in density to tissue, tissue can be sectioned at anywhere from 3 to 10 μm (routine sections are usually cut at 6 to 8 μm) • Staining • Allows for differentiation of the nuclear and cytoplasmic components of cells as well as the intercellular structure of the tissue • Cover-­slipping • The stained section on the slide is covered with a thin piece of plastic or glass to protect the tissue from being scratched, to provide better optical quality for viewing under the microscope, and to preserve the tissue section for years 

FIXATION •  There are five major groups of fixatives, classified according to mechanism of action: aldehydes, mercurials, alcohols, oxidizing agents, and picrates • Aldehydes • Formalin • Aqueous solution of formaldehyde gas that penetrates tissue well but relatively slowly; the standard solution is 10% neutral buffered formalin • A buffer prevents acidity that would promote autolysis and cause precipitation of formol-­ heme pigment in the tissues

1

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

2

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

• Tissue is fixed by cross-­linkages formed in the proteins, particularly between lysine residues • This cross-­linkage does not harm the structure of proteins greatly, preserving antigenicity, and is therefore good for immunoperoxidase techniques • Glutaraldehyde • The standard solution is a 2% buffered glutaraldehyde and must be cold, buffered, and not more than 3 months old • Fixes tissue quickly and therefore is ideal for EM • Causes deformation of α-­helix structure in proteins and therefore is not good for immunoperoxidase staining • Penetrates poorly but gives best overall cytoplasmic and nuclear detail • Tissue must be as fresh as possible and preferably sectioned within the glutaraldehyde at a thickness of no more than 1 mm to enhance fixation • Mercurials • B-­5 and Zenker • Contain mercuric chloride and must be disposed of carefully • Penetrate poorly and cause tissue hardness but are fast and give excellent nuclear detail • Best application is for fixation of hematopoietic and reticuloendothelial tissues • Alcohols •  Methyl alcohol (methanol) and ethyl alcohol (ethanol) • Protein denaturants • Not used routinely for tissue because they dehydrate, resulting in the tissues becoming brittle and hard • Good for cytologic smears because they act quickly and give good nuclear detail • Oxidizing agents •  Permanganate fixatives (potassium permanganate), dichromate fixatives (potassium dichromate), and osmium tetroxide cross-­link proteins • Cause extensive denaturation • Some of these have specialized applications but are used infrequently • Picrates • Bouin solution has an unknown mechanism of action • It does almost as well as mercurials with nuclear detail but does not cause as much hardness • Picric acid is an explosion hazard in dry form • Recommended for fixation of tissues from testis, gastrointestinal tract, and endocrine organs • Factors affecting fixation • Buffering • Penetration • Volume • Temperature • Concentration • Time interval • Fixation is optimal at a neutral pH, in the range of 6 to 8 • Hypoxia of tissues lowers the pH, so there must be buffering capacity in the fixative to prevent excessive acidity; acidity causes formation of

formalin-­ heme pigment that appears as black, polarizable deposits in tissue • Common buffers include phosphate, bicarbonate, cacodylate, and veronal • Fixative solutions penetrate at different rates, depending on the diffusibility of each individual fixative • In order of decreasing speed of penetration: formaldehyde, acetic acid, mercuric chloride, methyl alcohol, osmium tetroxide, and picric acid • Because fixation begins at the periphery, thick sections sometimes remain unfixed in the center, compromising both histology and antigenicity of the cells (important for immunohistochemistry [IHC]) • It is important to section the tissues thinly (2 to 3 mm) • Should be at least a 10:1 ratio of fixative to tissue • Increasing the temperature, as with all chemical reactions, increases the speed of fixation • Hot formalin fixes tissues faster, and this is often the first step on an automated tissue processor • Formalin is best at 10%; glutaraldehyde is generally made up at 0.25% to 4% • Formalin should have 6 to 8 hours to act before the remainder of the processing is begun • Decalcification • Tissue calcium deposits are extremely firm and do not section properly with paraffin embedding because of the difference in densities between calcium and paraffin • Strong mineral acids such as nitric and hydrochloric acids are used with dense cortical bone because they remove large quantities of calcium at a rapid rate • These strong acids also damage cellular morphology and thus are not recommended for delicate tissues such as bone marrow • Organic acids such as acetic and formic acid are better suited to bone marrow because they are not as harsh; however, they act more slowly on dense cortical bone • Formic acid in a 10% concentration is the best all-­ around decalcifier PEARLS • P  rolonged fixation can affect immunohistochemical results owing to alcohol precipitation of antigen at the cell surface; to optimize antigenicity of the tissue for IHC, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend fixation of tissue destined for IHC in neutral buffered formalin for a minimum of 6 hours and a maximum of 48 hours (see Wolff et al., 2007) • Urate crystals are water soluble and require a nonaqueous fixative such as absolute alcohol • If tissue is needed for immunofluorescence (e.g., kidney or skin biopsies) or enzyme profiles (e.g., muscle biopsies), the specimen must be frozen without fixative; enzymes are rapidly inactivated by even brief exposure to fixation • For rapid intraoperative analysis of tissue specimens, tissue can be frozen, and frozen sections can be cut with a special freezing microtome (“cryostat”); the pieces of tissue to be studied are snap-­frozen in a cold liquid or cold environment (−20°C to −70°C); freezing makes the tissue solid enough to section with a microtome 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

3

Figure 1.2  Masson trichrome stain.  Cirrhosis of the liver characterized by bridging fibrosis (blue) and regenerative nodule formation (red). Figure 1.1  Elastin/Alcian blue stain.  Aortic cystic medial degeneration in Marfan syndrome. Elastin stain highlights fragmentation of elastic fibers (brown-­black) and pooling of mucopolysaccharides (blue) within the media.

HISTOLOGIC STAINS • The staining process makes use of a variety of dyes that have been chosen for their ability to stain various cellular components of tissue • Hematoxylin and eosin (H&E) stain • The most common histologic stain used for routine surgical pathology • Hematoxylin, because it is a basic dye, has an affinity for the nucleic acids of the cell nucleus •  Hematoxylin does not directly stain tissues but needs a “mordant” or link to the tissues; this is provided by a metal cation such as iron, aluminum, or tungsten • The hematoxylin-­metal complex acts as a basic dye, and any component that is stained is considered to be basophilic (i.e., contains the acid groups that bind the positively charged basic dye), appearing blue in tissue section • The variety of hematoxylin stains available for use is based partially on choice of metal ion used, which can vary the intensity or hue • Conversely, eosin is an acid aniline dye with an affinity for cytoplasmic components of the cell •  Eosin stains the more basic proteins within cells (cytoplasm) and in extracellular spaces (collagen) pink to red (acidophilic)

Connective Tissue • Elastin stain •  Elastin van Gieson (EVG) stain highlights elastic fibers in connective tissue •  EVG stain is useful in demonstrating pathologic changes in elastic fibers, such as reduplication, breaks or splitting that may result from episodes of vasculitis, or connective tissue disorders such as Marfan syndrome (Figure 1.1)

• Elastic fibers are blue to black; collagen appears red; and the remaining connective tissue is yellow • Masson trichrome stain •  Helpful in differentiating between collagen fibers (blue staining) and smooth muscle (bright red staining) (Figure 1.2) • Reticulin stain •  A silver impregnation technique stains reticulin fibers in tissue section black • Particularly helpful in assessing for alteration in the normal reticular fiber pattern, such as can be seen in some liver diseases or marrow fibrosis • Jones silver stain •  A silver impregnation procedure that highlights basement membrane material; used mainly in kidney biopsies (Figure 1.3A) 

Fats and Lipids • Oil red O stain • Demonstrates neutral lipids in frozen tissue • Sudan black stain • Demonstrates neutral lipids in tissue sections •  Mainly used in hematologic preparations such as peripheral blood or bone marrow aspirations for demonstration of primary granules of myeloid lineage 

Carbohydrates and Mucoproteins • Congo red stain • Amyloid is a fibrillar protein with a β pleated sheet structure •  Amyloid deposits in tissue exhibit a deep red or salmon color, whereas elastic tissue remains pale pink (Figure 1.4A) • When viewed under polarized light, amyloid deposits exhibit apple-­green birefringence (Figure 1.4B) • The amyloid fibril–Congo red complex demonstrates green birefringence owing to the parallel alignment of dye molecules along the β pleated sheet • The thickness of the section is critical (8 to 10 μm)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

4

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

A A

B B

C C Figure 1.3  Membranous glomerulopathy.  A, Jones silver stain highlighting basement membrane “spikes” (arrow) along glomerular capillary loops corresponding to basement membrane material surrounding intramembranous immune complexes. B, Direct immunofluorescence showing diffuse, granular staining of the glomerular capillary basement membranes with goat antihuman immunoglobulin G. This technique requires fresh-­frozen tissue sections. C, Electron microscopy showing intramembranous electron-­dense immune complexes within the glomerular capillary basement membranes. (Courtesy of Pamela Gibson, MD, University of Vermont/Fletcher Allen Health Care, Department of Pathology, Burlington, VT.)

Figure 1.4  Alzheimer disease.  A, Congo red–positive core of Alzheimer disease plaque. B, Apple-­green birefringence of amyloid core under polarized light. C, Bielschowsky stain highlighting Alzheimer disease plaque (arrow) and neurofibrillary tangle within neuronal cell bodies (arrowhead).

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

• Mucicarmine stain • Demonstrates epithelial mucin in tissue sections •  Also highlights mucin-­ rich capsule of Cryptococcus species • Periodic acid–Schiff (PAS) stain • Glycogen, neutral mucosubstances, basement membranes, and fungal walls exhibit a positive PAS (bright rose) • PAS with diastase digestion: diastase and amylase act on glycogen to depolymerize it into smaller sugar units that are then washed out of the section •  Digestion removes glycogen but retains staining of other substances attached to sugars (i.e., mucopolysaccharides) • Alcian blue stain • May be used to distinguish various glandular epithelia of the gastrointestinal tract and in the diagnosis of Barrett epithelium • pH 1.0: acid sulfated mucin positive (colonic-­like) • pH 2.5: acid sulfated mucin (colonic-­like) and acid nonsulfated mucin (small intestine–like) positive • Neutral mucins (gastric-­like) negative at pH 1.0 and 2.5 

5

Figure 1.5  Luxol fast blue stain.  Demyelination in multiple sclerosis (colorless regions).

Pigments and Minerals • Ferric iron (Prussian blue), bilirubin (bile stain), calcium (von Kossa), copper (rhodanine), and melanin (Fontana-­Masson) are the most common pigments and minerals demonstrated in surgical pathology specimens 

Nerves and Fibers • Bielschowsky stain • A silver impregnation procedure that demonstrates the presence of neurofibrillary tangles and senile plaques in Alzheimer disease (Figure 1.4C) • Axons stain black • Luxol fast blue stain • Demonstrates myelin in tissue sections • Loss of staining indicates myelin breakdown secondary to axonal degeneration • Gray matter and demyelinated white matter should be almost colorless and contrast with the blue-­ stained myelinated white matter (Figure 1.5) 

Hematopoietic and Nuclear Elements • Toluidine blue stain • Demonstrates mast cells in tissue • Giemsa, Wright, and May-­Grünwald stains • For cellular details, including hematopoietic (peripheral blood or bone marrow) and cytology preparations • Leder stain (chloracetate esterase) •  Identification of cytoplasmic granules of granulocytes and myeloid precursors 

Microorganisms: Bacteria, Fungi, Parasites • Brown and Brenn Gram stain •  Demonstration of gram-­ negative (red) and gram-­ positive (blue) bacteria in tissue • Giemsa stain •  Demonstration of bacteria, rickettsia, and Toxoplasma gondii in tissue sections

Figure 1.6  Aspergillus organisms in the lung stained by Grocott methenamine silver stain.

• Grocott methenamine silver (GMS) stain • Demonstration of fungi or Pneumocystis organisms (fungi may also be demonstrated by PAS-­ amylase stain) (Figure 1.6) • Warthin-­Starry and Steiner stains • Silver impregnation technique for spirochetes (e.g., Borrelia burgdorferi, Treponema pallidum) in tissue sections • Note: all bacteria are nonselectively blackened by silver impregnation methods such as the Warthin-­ Starry and Steiner stains • These methods are more sensitive for small gram-­ negative bacteria (e.g., Legionella species, Helicobacter pylori, and Bartonella species) than tissue Gram stain • Ziehl-­Neelsen method for acid-­fast bacteria (AFB) • Detect the presence of acid-­fast mycobacteria (bright red) in tissue sections (background light blue) (Figure 1.7) • Fite method should be used to demonstrate Mycobacterium leprae or Nocardia species, both of which are weakly acid fast

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

6

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Selected References

FLUORESCENCE MICROSCOPY

Bancroft JD, Gamble M. Theory and Practice of Histochemical Techniques. 5th ed. Philadelphia: Elsevier; 2001. Carson FL. Histotechnology: A Self-­Instructional Text. 2nd ed. Chicago: American Society for Clinical Pathology (ASCP) Press; 1997. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18–43.

•  Tissue is exposed to short-­ wavelength ultraviolet (UV) light (2500 to 4000 angstroms) through a mercury or halogen lamp; the energy is absorbed by molecules that then release the energy as visible light (4000 to 8000 angstroms) •  In immunofluorescence techniques, antibodies are labeled with a fluorescent dye such as fluorescein isothiocyanate (FITC) • Direct immunofluorescence •  Fluorescein-­ labeled antihuman globulin primary antibodies are applied to frozen, unfixed tissue sections to locate and combine with antibodies, complement, or antigens deposited in tissue • Indirect immunofluorescence • Unlabeled primary antibody is applied to the tissue section, followed by application of an FITC-­labeled antibody that is directed against a portion of the unlabeled primary antibody • More sensitive and more expensive • Primary application in surgical pathology is detection of autoimmune diseases involving the skin and kidney (Table 1.1)

Selected References

Figure 1.7  Ziehl-­Neelsen stain for acid-­fast bacilli.  Abundant Mycobacterium avian intracellulare organisms (red) within macrophages in the lung.

D’Agati VD, Jennette JC, Silva FG. Non-­neoplastic kidney diseases. In: AFIP Atlas of Nontumor Pathology. Vol. 4. Washington, DC: Armed Forces Institute of Pathology; 2005. Kalaaji AN, Nicolas MEO. Mayo Clinic Atlas of Immunofluorescence in Dermatology: Patterns and Target Antigens. New York, NY: Informa Healthcare; 2006.

TABLE 1.1   IMMUNOFLUORESCENCE PATTERNS AND DISEASE ASSOCIATIONS Disease

Antibodies

Pattern

Histologic Manifestation

Skin Pemphigus vulgaris

Antidesmosomal

Intercellular chicken-­wire IgG in epidermis Linear IgG along BM; in salt-­split skin, reactivity along roof

Suprabasal vesiculation

Linear IgG along BM; in salt-­split skin, reactivity along floor Granular IgA, especially in tips of dermal papillae

Subepithelial vesiculation

Linear GBM staining for IgG, corresponding granular staining for C3 Diffuse, granular GBM staining for IgG and C3

Crescentic GN

IgA ± IgG, IgM, and C3 in mesangium

Focal proliferative GN; mesangial widening

Type I: IgG + C3; C1q + C4 Type II: C3 ± IgG; no C1q or C4

Mesangial proliferation; GBM thickening; splitting

Bullous pemphigoid

Epidermolysis bullosa acquisita (EBA) Dermatitis herpetiformis Kidney Anti–glomerular basement membrane (anti-­GBM) disease Membranous glomerulopathy

IgA nephropathy

Membranoproliferative glomerulonephritis

Antiepithelial BM; anti-­ hemidesmosome (collagen XVII [BP180]) EBA Ag Antigluten

Anti-­GBM COL4-­A3 antigen

Subepithelial deposits secondary to in situ immune complex formation (antigen unknown; associated with lupus nephritis, hepatitis B, penicillamine, gold, malignancy) Deposited IgA polyclonal: possible increased production in response to exposure to environmental agents (e.g., viruses, bacteria, food proteins such as gluten) Type I: immune complex Type II: autoantibody to alternative complement pathway

Subepithelial vesiculation

Subepithelial vesiculation

Diffusely thickened glomerular capillary loops with lacelike splitting and “spikes” identified on Jones silver stain

BM, Basement membrane; GBM, glomerular basement membrane; GN, glomerulonephritis; Ig, immunoglobulin.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

ELECTRON MICROSCOPY • The electron microscope has a magnification range of 1000 to 500,000 diameters (×) (the upper limit of light microscopy is approximately 1000 diameters), thereby allowing for analyzing the ultrastructure of a cell • There are two types of EM: • Transmission EM • Scanning EM • Two-­dimensional (2D) black-­and-­white image is produced •  Tissue either transmits electrons (producing “lucent” or clear areas in the image) or deflects electrons (producing electron “dense” or dark areas in the image) • Useful in the diagnosis of nonneoplastic diseases of the kidney • Three-­dimensional (3D) black-­and-­white image results as an electron beam sweeps the surface of the specimen and releases secondary electrons • Lower resolution than transmission EM and used primarily in the research setting to study cell surface membrane changes •  Application in surgical pathology: EM is a useful diagnostic technique to supplement morphologic, immunohistochemical, cytogenetic, and molecular analysis of tissues • Immunoperoxidase techniques have largely replaced EM for tumor diagnosis in surgical pathology • EM is useful in • Renal, skin, myocardial, nerve, and muscle biopsies • Undifferentiated or poorly differentiated neoplasms • Diagnosis of lysosomal storage disorders • Ciliary dysmorphology • Visualization of infectious agents

TECHNICAL OVERVIEW • The main fixative used for EM is glutaraldehyde, which penetrates tissues more slowly than formalin; cubes of tissue 1 mm or smaller are needed • Processing post fixation with osmium tetroxide, which binds to lipids in membranes for better visualization; dehydration with graded alcohols; infiltration with propylene oxide and epoxy resin; embedding in epoxy resin • 1-­μm sections (semithin) are cut and stained with toluidine blue to verify that the area of interest has been selected for EM • 100-­nm sections (ultrathin) are cut and collected on copper grids • Tissues are stained with heavy metals (uranyl acetate and lead citrate) • Electron dense: darker in color as a result of heavy impregnation with heavy metal • Electron lucent: lighter in color 

ULTRASTRUCTURE OF A CELL Nucleus • Nuclear membrane • Nuclear pore

7

• Nucleolus • Dense, rounded basophilic structure that consists of 80% to 90% protein • Produces most of the ribosomal RNA (rRNA) • Mitotically or metabolically active cells have multiple nucleoli • Chromatin •  Heterochromatin: stainable, condensed regions of chromosomes seen as intensely basophilic nuclear material in light microscopy • Euchromatin: nonstainable, extended portions of the chromosomes that consist of genetically active DNA 

Cytoplasm • Plasma membrane • Appears as two electron-­dense (dark) layers with an intervening electron-­lucent (light) layer • Basement membrane = basal lamina (lamina densa + lamina lucida) + lamina reticularis + anchoring fibrils + microfibrils • Lamina densa •  Electron-­ dense membrane made up of type IV collagen fibers coated by a heparan sulfate proteoglycan • Approximately 30 to 70 nm thick with an underlying network of reticular collagen (type III) fibrils, which average 30 nm in diameter and 0.1 to 2 μm in thickness • Mitochondria • The energy-­producing component of the cell; these membrane-­bound organelles undergo oxidative reactions to produce energy • Energy generation occurs on the cristae, which are composed of the inner mitochondrial membrane • Most cells contain shelflike mitochondrial cristae • Steroid-­producing cells (i.e., adrenal cortex) contain tubular cristae • Mitochondrial crystals are always pathologic • Hürthle cell change occurs when the cytoplasm of a cell becomes packed with mitochondria • Ribosomes • Sites of protein synthesis • Usually responsible for the basophilic staining of the cytoplasm on H&E-­stained sections • Endoplasmic reticulum • Membrane-­bound channels responsible for the transport and processing of secretory products of the cell • Granular or rough endoplasmic reticulum is abundant in cells that actively produce secretory products (e.g., plasma cells producing immunoglobulin [Ig] and pancreatic acinar cells producing digestive enzymes); the granular appearance is due to attached ribosomes • Smooth endoplasmic reticulum is abundant in cells that synthesize steroids (i.e., adrenal cortex, Sertoli-­ Leydig cells) and in tumors derived from these types of cells • Golgi apparatus •  Concentrates and packages proteins into secretory vesicles for transport to the cell surface • Prominent in cells that secrete proteins 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

8

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

TABLE 1.2   CYTOPLASMIC GRANULES Type

Size

Morphology

Product

Cell Type/Tumor

Mucigen Serous, zymogen

0.7–1.8 μm 0.5–1.5 μm

Electron lucent Electron dense

Glycoprotein Proenzyme/enzyme

Neuroendocrine

100–300 nm

Dense core

Example: biogenic amines

Mucin secreting Example: acinar cells of pancreas Neuroendocrine cells

Figure 1.8  Electron microscopy.  Neuroendocrine granules in small cell carcinoma of the lung.

Single Membrane–Bound Structures • Cytoplasmic granules are classified based on size and morphology (Table 1.2) • Lysosomes • Contain enzymes that assist in digesting material to be disposed of in the cell •  Endogenous and exogenous pigments can be collected in lysosomes; can be large and filled with undigested cellular components in lysosomal storage disorders • Dense core granules: seen in cells and tumors with neuroendocrine differentiation (Figure 1.8) • Melanosomes and premelanosomes are specific single membrane–bound structures • Weibel-­Palade bodies are specific for endothelial cells • Birbeck granules are seen in Langerhans cell histiocytosis (Figure 1.9) 

Filaments and Tubules • Filaments are classified based on size (Table 1.3) • Microtubules are seen in association with the mitotic spindle and in cells or tumors of neural origin (e.g., neuroblastoma) 

Cell Surface • Cell processes are seen in cells that are capable of movement; some tumors, such as schwannomas and meningiomas, demonstrate interdigitating processes • Villi are prominent and regular in cells or tumors of glandular origin (Figure 1.10)

Figure 1.9  Electron microscopy.  Birbeck granules (arrow) in Langerhans cell histiocytosis. (Photo courtesy of Janet Schwarz, Senior Research Technician, Microscopy Imaging Center, University of Vermont, Burlington, VT.)

TABLE 1.3   FILAMENTS AND TUBULES Component

Diameter

Microfilaments (actin, 6–8 nm nonmuscle myosin) Intermediate filaments 10 nm Cytokeratin >19 proteins 40–68 kD Glial fibrillary acid 55 kD protein Neurofilament 68, 160, 200 kD Vimentin 57 kD Desmin 53 kD Microtubules 25 nm

Location Cytoskeleton of all cells Epithelial cells Astrocytes Neural tissue Mesenchymal tissues Muscle Neural derivatives (e.g., neuroblastoma)

kD, kilodaltons; nm, nanometers; 50 kD = ∼4 nm.

• Terminal web and rootlets in villi are seen in foregut derivatives (e.g., colon) • Junctions are seen in virtually all cells except those of hematopoietic origin • Basal lamina is seen surrounding all endodermal and ectodermal derivatives; cells with muscle differentiation also may have a basal lamina, which may be incomplete 

Extracellular Matrix • Collagen shows a regular structure amyloid • Fibrils measuring approximately 10 nm in diameter, with an electron-­lucent core

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Figure 1.10  Electron microscopy.  Short villi lining an intracytoplasmic lumen in adenocarcinoma of the breast.

•  Fibrils are straight, nonbranching, and arranged randomly

Selected References Ghadially FN. Diagnostic Electron Microscopy of Tumors. Boston: Butterworth-­Heinemann; 1986. Ghadially FN. Diagnostic Ultrastructural Pathology. 2nd ed. Boston: Butterworth-­Heinemann; 1998. Ghadially FN. Ultrastructure of the Cell and Matrix. 4th ed. Boston: Butterworth-­Heinemann; 1997.

IMMUNOHISTOCHEMISTRY INTRODUCTION IHC combines anatomic, immunologic, and biochemical techniques to identify specific tissue components using a specific antigen-­antibody reaction labeled with a visible reporter molecule. This binding is then visualized through the use of various enzymes that are coupled to the antibodies being used. The enzyme acts on a chromogenic substrate to cause deposition of a colored material at the site of antibody-­antigen bindings. Hence IHC permits the visualization and localization of specific cellular components within a cell or tissue while importantly preserving the overall morphology and structure of the tissue section. Key improvements in protein conjugation, antigen preservation and antigen retrieval methods, and enhanced immunodetection systems have enshrined IHC as a major adjunctive investigative tool for both surgical and cytopathology. IHC is not only critical for the accurate diagnosis of malignancies but also plays a pivotal role in prognostic evaluation (e.g., estrogen and progesterone receptors in breast cancer) and treatment strategies (e.g., c-­kit protein for gastrointestinal stromal tumors and HER-­ 2-­neu in certain breast cancers). 

TECHNICAL OVERVIEW •  Formalin cross-­ links proteins in tissues; success of immunohistochemical staining depends on the availability of an antigen after fixation

9

•  Various techniques may unmask antigens, such as digestion by enzymes (e.g., trypsin) or antigen retrieval using heat, metallic mordants, or alkaline buffers • Commonly used enzymes include peroxidase, alkaline phosphatase, and glucose oxidase •  Most commonly used chromogen substrates produce brown 3,3’-Diaminobenzidine (DAB), or red 3-Amino-9-Ethylcarbazole (AEC) reaction products • Definition of terms • Polyclonal antibody: conventional antiserum produced by multiple plasma cells of an animal that had been injected with an antigen; a polyclonal antibody may have multiple determinants (binding sites) • Monoclonal antibody: produced by fusion of a malignant cell with a plasma cell producing antibody to a specific epitope; antibodies may be grown in tissue culture • Antibodies for the detection of cellular components • Intermediate filaments (see Table 1.3) •  Other cellular and tissue components: (e.g., α1-­ antitrypsin, myeloperoxidase, synaptophysin and chromogranin, myoglobin) • Leukocyte antigens and Ig components commonly used in paraffin-­embedded tissues • T-­cell • CD1a: thymocyte; also marks Langerhans cells • CD3: Pan–T-­cell marker that shows cytoplasmic and membrane staining • CD5: Pan–T-­cell marker also expressed by some B-­cell lymphomas •  CD43: Pan–T-­ cell marker also expressed by some B-­cell lymphomas • CD45RO (UCHL-­1), CD4, CD8: T-­cell markers • B-­cell • CD20: Pan–B-­cell marker • Ig heavy and light chains: used for demonstration of clonality in B-­cell neoplasms • Myeloid • CD15 (Leu-­M1): pan-­myeloid antigen that also marks Reed-­Sternberg cells of Hodgkin lymphoma • Monocyte and histiocyte • CD163, CD68 • Natural killer cell • CD57 (Leu-­7) •  CD56 (neural cell adhesion molecules, NCAM, Leu-­19) • Megakaryocyte • CD41 • Factor VIII–von Willebrand factor (vWF) • Ulex europaeus agglutinin-­1 (UEA-­1) • Hormones and hormone receptors • Presence may have prognostic significance •  Estrogen and progesterone receptors in breast carcinomas • Androgen receptors • Infectious agents • Oncogenes and oncogene products • May correlate with prognosis • bcl-­1, bcl-­2, bcl-­6 in lymphoid neoplasms • HER-­2-­neu and C-­erbB2 in breast carcinomas (Figure 1.11) • p53 tumor suppressor gene: mutations are seen in a variety of malignant tumors 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

10

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Figure 1.11  Immunohistochemistry for HER-­2-­neu in a breast adenocarcinoma showing (3+) membranous staining.

Figure 1.12  Immunohistochemistry for HepPar-­1 highlighting strong cytoplasmic staining of normal hepatic parenchyma.

GROUND RULES FOR QUALITY APPLICATION OF IMMUNOHISTOCHEMISTRY IN SURGICAL PATHOLOGY

• Avoid preordering an IHC panel of antibodies before previewing the morphology; remember that IHC is an ancillary or adjunctive technique to the quality practice of surgical pathology and not vice versa • Interpretation • Interpretation of IHC should always be made in the context of the known subcellular localization or distribution of the targeted antigen (e.g., membranous, cytoplasmic, nuclear, or perinuclear “Golgi pattern” of immunoreactivity) (Figures 1.12 and 1.13) • Controls •  Finally, the importance of adequate incorporation of appropriate tissue and reagent (both positive and negative) controls in every run of IHC cannot be overemphasized; this is ultimately the highest form of quality control of the IHC assay and should be reviewed daily to avoid false-­positive and false-­ negative interpretation 

• Technique •  It is imperative that the pathologist work closely with the immunohistotechnologist to optimize, validate, and interpret the IHC assay for any particular antibody reagent •  Adequate fixation of tissue or specimen in 10% buffered formalin is essential to high-­quality IHC; it is probably better to overfix (because modern antigen retrieval systems can unmask epitopes) rather than underfix (because inadvertent alcohol fixation during tissue processing precipitates and masks epitopes) • It is best to use a polymer-­based detection system, which has the advantage of being avidin-­ biotin free, thereby avoiding false immunoreactivity with endogenous biotin •  Appropriate antigen retrieval systems should be optimized for each antibody (noting that different antibodies require unique systems, and some require none) • Antibody choice • A generic screening panel of antibodies should be chosen initially, followed algorithmically by a specific panel to further characterize a neoplasm • Avoid using a single antibody in isolation (because this may result in a potentially erroneous diagnosis), and always use more than one antibody to target a specific antigen • The choice of a panel of antibodies to target a specific antigen should always be made in the context of the morphology and clinical presentation of any neoplasm; avoid use of the “buckshot” approach in hope that an IHC assay returns a positive reaction

A PRACTICAL TABULAR APPROACH TO USING IMMUNOHISTOCHEMISTRY FOR COMMON DIAGNOSTIC PROBLEMS • Because a complete technical overview of IHC and comprehensive listing of available antibodies is beyond the scope of this chapter, our goal is to provide a practical approach to IHC application in surgical pathology; the following tables are presented as guidelines to assist with the choice of an antibody panel when confronted with certain differential diagnoses (Tables 1.4 through 1.36) PEARLS • T  umors are not 100% specific or sensitive to a particular immunoreagent; interpretation of these tables should be used in this context to avoid diagnostic pitfalls • Always target the IHC panel in the context of the ­morphologic differential diagnosis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Selected References

11

FLOW CYTOMETRY

Dabbs D. Diagnostic Immunohistochemistry. 2nd ed. Philadelphia: Churchill Livingstone; 2006. Jagirder J. Immunohistochemistry: then and now. Arch Pathol Lab Med. 2008;132:323–509. Leong AS-­Y, Leong TY-­M. Newer developments in immunohistology. J Clin Pathol. 2006;59:1117–1126. Yaziji H, Barry T. Diagnostic immunohistochemistry: what can go wrong? Adv Anat Pathol. 2006;13:238–246.

INTRODUCTION • Flow cytometry is widely used to immunophenotypically detect clonal hematopoietic populations (e.g., leukemia and lymphoma) • When performed on peripheral blood, bone marrow, and lymph nodal tissue, single-­ cell suspensions are required •  Manipulation of solid tissue samples into single-­ cell suspensions can sometimes compromise the integrity of the cell surface 

TECHNICAL OVERVIEW

A

B Figure 1.13  Immunohistochemistry for TTF-­1.  A, Nuclear immunoreactivity in normal thyroid parenchyma. B, Nuclear immunoreactivity in pulmonary adenocarcinoma.

• Single-­cell suspension is split into multiple tubes •  Various fluorescent-­ labeled antibodies against different cell surface antigens (each with a different attached fluorochrome) are added to each tube • One by one, the cells are run through the flow cytometer; as the cells pass through the counting chamber, multiple data points are collected • Degree of forward light scatter (FSC): indicator of cell size • Degree of 90-­degree light scatter or side scatter (SSC): indicator of nuclear complexity and cytoplasmic granularity • Intensity of fluorochrome on the cell surface: detects expression of cell surface antigens (e.g., CD45, leukocyte common antigen) • Gating: the cells of interest are digitally selected for interpretation; for example, if lymphocytes are to be examined, one would “gate” around the cells that exhibit low side scatter (SSC) (little cytoplasmic granularity) and strong CD45 (leukocyte common antigen) expression (Figure 1.15) •  Typical findings in mantle cell lymphoma would include a CD20-­positive population (B-­cells) exhibiting coexpression of CD19 and CD5 (narrowing the differential to small lymphocytic lymphoma and mantle cell lymphoma), with light chain restriction supporting clonality. Lack of CD23 expression helps to exclude small lymphocytic lymphoma, which would have an immunophenotype similar to that of mantle cell lymphoma, except for CD23 expression and dimmer light chain expression. Follicular lymphoma would also consist of a population of CD20-­positive B-­cells that express CD10 and lack CD5

TABLE 1.4   IMMUNOHISTOCHEMISTRY APPROACH TO UNDIFFERENTIATED TUMORS Carcinoma Melanoma Germ cell Lymphoma Anaplastic plasmacytoma/ myeloma

Pan-­CK

EMA

S-­100

SALL4

LCA

CD138

+ −/v v − −

+ − − − +

− + − − −

−/v − + − −

− − − + −/+

− − − − +

EMA, Epithelial membrane antigen; LCA, leukocyte common antigen; Pan-­CK, pan-­cytokeratin; SALL4, sal-­like4; v, variable; +, positive; −, negative; −/+, rarely positive.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

12

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Selected Reference Carey JL, McCoy P, Keren DF. Flow Cytometry in Clinical Diagnosis. 4th ed. Chicago: ASCP Press; 2007.

CYTOGENETIC ANALYSIS • Technical overview • Fresh tissue is incubated in short-­term culture, and metaphase chromosomes are spread on glass slides TABLE 1.5    IMMUNOPHENOTYPIC DISTRIBUTION OF CYTOKERATINS 7 AND 20 Carcinoma Typea

CK7

CK20

Colorectal and Merkel cell Hepatocellular Salivary gland Lung, non–small cell carcinoma Lung, neuroendocrine carcinoma Breast, ductal Ovarian, serous, and endometrioid Endometrial and endocervical Renal cell Prostatic Urothelial Pancreas Mesothelioma

− − + + − + + + − − + +/− +

+ − − − − − − − − − + +/− −

CK, Cytokeratin; +, positive; −, negative; +/−, variably positive. aOnly approximately 70% to 90% of these tumors follow the given CK7/20 immunoprofile; therefore reliance solely on this profile to ­determine the primary site of carcinomas is not recommended.

• After staining of the chromosomes, specific chromosomal abnormalities can be detected • In surgical pathology practice at University of Vermont Medical Center we routinely submit fresh tissue in Hanks solution for cytogenetics in the following cases • All renal tumors (except for urothelial carcinomas of the renal pelvis) • Any soft tissue tumor larger than 5 cm (including adipocytic neoplasms) (Figure 1.16) • In addition, a portion of fresh tissue (1 cm3, if available) is snap-­frozen for potential molecular analyses for tumor-­specific translocations or for potential treatment protocols • Oncogenes (Table 1.37) and tumor suppressor genes (Table 1.38) of importance in surgical pathology •  Cytogenetic abnormalities of importance in surgical pathology (Table 1.39)

Selected References Gersen SL, Keagle MB. The Principles of Clinical Cytogenetics. 2nd ed. Totowa: Humana Press; 2004. Korf B. Molecular medicine: molecular diagnosis (part I). N Engl J Med. 1995;332:1218–1220. Korf B. Molecular medicine: molecular diagnosis (part II). N Engl J Med. 1995;332:1499–1502. Richmond JA, Tang M, Cooper K. Cytogenetic and clinicopathologic analysis of benign lipomatous tumors. Arch Pathol Lab Med. 2005;129:553.

TABLE 1.6   SPECIFIC ANTIBODY REAGENTS TO IDENTIFY PRIMARY SITE OF METASTATIC CARCINOMA Carcinoma Type

Antibody

Signal Localization

Other Tumors Identified

Breast Breast Breast Colon Hepatocellular

GCDFP-­15 Mammaglobin GATA3 CDX2 HepPar-­1 Ag

Cytoplasmic Cytoplasmic Nuclear Nuclear Cytoplasmic

Hepatocellular Hepatocellular

pCEA or CD10 GPC-­3

Lung and thyroid except mucinous adenocarcinoma in situ (formerly mucinous BAC) Lung squamous cell carcinoma Ovarian serous Prostate Prostate Squamous, urothelial, thymic

TTF-­1

Bile canaliculi Membranous and cytoplasmic Nuclear

Salivary, sweat gland Salivary, sweat gland Urothelial, Salivary glands Subset of pancreas, gastric Hepatoid carcinomas of stomach, ovary Hepatoid carcinomas Melanoma, a subset of chronic active hepatitis Neuroendocrine carcinoma extrapulmonary

p40 WT-­1, p16 NKX3.1 PSA, PAP p63

Nuclear Nuclear Nuclear Cytoplasmic Nuclear

Thyroid Urothelial Renal, clear

Thyroglobulin Uroplakin III RCC

Cytoplasmic Membranous Membranous

— Mesothelioma (WT-­1)

Salivary gland, neuroendocrine, subset prostate — —

BAC, Bronchoalveolar carcinoma; GATA3, GATA Binding Protein 3; GCDFP-­15, gross cystic disease fluid protein-­15; GPC-­3, glypican 3; NKX3.1, NK3 Homeobox 1; PAP, prostatic acid phosphatase; pCEA, polyclonal carcinoembryonic antigen; PSA, prostate-­specific antigen; RCC, renal cell carcinoma; TTF-­1, thyroid transcription factor-­1; WT-­1, Wilms tumor gene protein 1. Modified from Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma versus metastatic neoplasms. Arch Pathol Lab Med. 2007;131:1648–1654; Bishop JA, Teruya-­Feldstein J, Westra WH, et al. p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2012;25:405–415. From Conner JR, Hornick JL. Metastatic carcinoma of unknown primary: diagnostic approach using immunohistochemistry. Adv Anat Pathol. 2015;22(3):149–167. From Miettinen M, McCue PA, Sarlomo-­Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systemic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38(1):13–22.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

13

TABLE 1.7    IMMUNOHISTOCHEMISTRY PANEL FOR INTERPRETATION OF LUNG MESOTHELIOMA AND ADENOCARCINOMA Antibody Epithelial Marker Naspin A mCEA Ber-­Ep4 B72.3 CD15 (Leu-­M1) MOC-­31 TTF-­1 Mesothelial Marker Cytokeratin 5/6 Calretinin WT-­1 D2-­40 Mesothelin BAP1 (loss of nuclear expression)

Epithelioid Mesothelioma (Percentage Positive)

Sarcomatoid Mesothelioma (Percentage Positive)

Adenocarcinoma (Percentage Positive)

Negative 3 10 7 7 7 Negative

Negative — 0 0 0 0 0

83 (lung) 81 80 80 72 93 72 (lung)

83 82 77 86–100 100 55.4

13 88 13 0 0 41.7

15 15 4 36 (weak) — __

BAP1, BRCA1-­associated protein 1; mCEA, monoclonal carcinoembryonic antigen; TTF-­1, thyroid transcription factor-­1; WT-­1, Wilms tumor gene protein 1. Modified from Marchevsky AM. Application of immunohistochemistry to the diagnosis of malignant mesothelioma. Arch Pathol Lab Med. 2008;132:397– 401; Bishop JA, Sharma R, Illei PB: Naspin A and thyroid transcription factor-­1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol. 2010;41:20–25. From Erber R, Warth A, Muley T, et al. BAP1 loss is a useful adjunct to distinguish malignant mesothelioma including the adenomatoid-­like variant from benign adenomatoid tumors. Appl Immunohistochem Mol Morphol. 2019 Jan 11. doi: 10.1097 [Epub ahead of print].

TABLE 1.8    IMMUNOHISTOCHEMISTRY PANEL FOR LUNG ADENOCARCINOMA AND BREAST ADENOCARCINOMA Immunostain

Lung Adenocarcinoma (Percentage Positive)

Breast Adenocarcinoma (Percentage Positive)

TTF-­1 Naspin A Mammaglobin GCDFP-­15 ER

77 83 17 2 4

0 0 85 53 72

ER, Estrogen receptor; GCDFP-­15, gross cystic disease fluid protein-­15; TTF-­1, thyroid transcription factor-­1. Data from Takeda Y, Tsuta K, Shibuki Y, et al. Analysis of expression patterns of breast cancer-­specific markers (mammaglobin and gross cystic disease fluid protein 15) in lung and pleural tumors. Arch Pathol Lab Med. 2008;132:239; Striebel JM, Dacic S, Yousem SA. Gross cystic disease fluid protein (GCDFP-­15): expression in primary lung adenocarcinoma. Am J Surg Pathol. 2008;32:426; Bishop JA, Sharma R, Illei PB. Naspin A and thyroid transcription factor-­1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol. 2010;41:20–25.

TABLE 1.9    IMMUNOHISTOCHEMISTRY COMPARISON OF SPINDLE CELL AREAS IN METAPLASTIC CARCINOMA, PHYLLODES TUMOR, AND FIBROMATOSIS OF THE BREAST Metaplastic carcinoma Phyllodes Fibromatosis Myofibroblastoma Myoepithelial tumor

CD34

SMA

34βe12

Pan-­CK

β-­catenin

Desmin

p63

− +/− − + −

+/− +/− +/− +/− +/−

+/− − − − +/−

−/+ − − − +

− − + − −

−/+ −/+ − + −/+

+ − − − +/−

Pan-­CK, Pan-­cytokeratin; SMA, smooth muscle actin; +, positive; −, negative; +/−, often positive; −/+, rarely positive. Modified from Dunne B, Lee AH, Pinder SE, et al. An immunohistochemical study of metaplastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast. Hum Pathol. 2003;34:1009–1015.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

14

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

TABLE 1.10    USEFUL ANTIBODY PANEL TO DEMONSTRATE MYOEPITHELIAL AND BASAL CELLS IN BREAST LESIONS TO DISTINGUISH BENIGN (+) FROM INVASIVE (−) CARCINOMA Smooth muscle heavy-­chain myosin p63 α-­SMA S-­100 Calponin D2-­40a

Myoepithelial/Basal Cells

Stromal Myofibroblasts

+ (Cytoplasmic) + (Nuclear) + (Cytoplasmic) + (Nuclear and cytoplasmic) + (Cytoplasmic) −/+

−/+ − +/− v −/+ −

SMA, Smooth muscle actin; v, variable; +, positive; −, negative; −/+, rarely positive. aD2-­40 is a useful marker to highlight lymphatic endothelium in lymphovascular invasion (LVI) by carcinoma but may in addition occasionally stain myoepithelial and basal cells—hence the use of D2-­40 to demonstrate that LVI should always be accompanied by p63/SMHCM immunohistochemistry. Modified from Rabban JT, Chen YY. D2-­40 expression by breast myoepithelium: potential pitfalls in distinguishing intralymphatic carcinoma from in situ carcinoma. Hum Pathol. 2008;39:175–183.

TABLE 1.11    IMMUNOHISTOCHEMICAL PANEL APPROACH TO DIFFERENTIAL DIAGNOSIS OF HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma Cholangiocarcinoma Metastatic adenocarcinoma Colon Thyroid, lung Tumors with polygonal cells RCC Adrenocortical carcinoma Neuroendocrine tumorsb Hepatoid carcinoma (e.g., gastric, ovary)

Arginase-1 HepPar-­1

CK19

MOC-­31

GPC-­3

pCEA

CDX-­2

TTF-­1

RCC

Inhibin/ Melan-­A/D2-­40

+ −/+

− +/−

−/+ +/−

+ −

+ −

−

−a −

− −

− −

− −

− −

+ −

− +

− −

− −

− − −

− −

− − v

+

− +

+ − − − −

− − − − − − −

− − − +

+ +

CK, Cytokeratin; p-­CEA, canalicular pattern of staining; RCC, renal cell carcinoma; TTF-­1, thyroid transcription factor-­1; v, variable; +, positive; −, negative; +/−, often positive; −/+, rarely positive. aCertain TTF-­1 antibody reagents may highlight the cytoplasm of liver cells (only nuclear immunoreactivity should be interpreted as being of thyroid or lung origin in the correct clinical setting). bStrong synaptophysin and chromogranin support neuroendocrine tumor; TTF-­1 may notoriously highlight extrapulmonary neuroendocrine tumors. Modified from Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma versus metastatic neoplasms. Arch Pathol Lab Med. 2007;131:1648–1654; Yan BC, Gong C, Song J, et al. Arginase-­1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms. Am J Surg Pathol. 2010;34:1147–1154.

TABLE 1.12    IMMUNOHISTOCHEMISTRY PANEL INTERPRETATION FOR GASTROINTESTINAL AND ABDOMINAL SPINDLE CELL TUMORS ALK

WT-­1

Leiomyoma Leiomyosarcoma (LMS)a Inflammatory myofibroblastic tumor Inflammatory fibroid polyp Solitary fibrous tumor Desmoid fibromatosis Gastrointestinal schwannoma Metastatic melanoma Desmoplastic small round cell tumor GIST

+

+

DOG1

CD117

CD34

−/+

−

+/− − − − − − − − +

− − − − − − +/− − +

STAT6

SMA

Desmin

S-­100 Protein

−

+

+

−

−/+a − + + − − − − +

+ +/− +/− − + − − − +/−

+ − − − −/+ − − + −/+

− − − − − + + − −/+

+

β-­Catenin

+ (Nuclear)

ALK, Anaplastic lymphoma kinase; GIST, gastrointestinal stromal tumor; SMA, smooth muscle actin; STAT6, Signal transducer and activator of transcription (STAT) 6; +, positive; −, negative; +/−, often positive; −/+, rarely positive. aRetroperitoneal LMS may be positive. Modified from Miettinen M, Sobin LH, Sarlomo-­Rikala M. Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol. 2000;13:1134–1142; Sah SP, McCluggage WG. DOG1 immunoreactivity in uterine leiomyosarcomas. J Clin Pathol. 2013;66:40–43; Hill DA, Pfeifer JD, Marley EF, et al. WT1 staining reliably differentiates desmoplastic small round cell tumor from Ewing sarcoma/primitive neuroectodermal tumor: an immunohistochemical and molecular diagnostic study. Am J Clin Pathol. 2000;114:345–354. From Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007;31(4):509–520. Doyle LA, Vivero M, Fletcher CD, et al. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol. 2014;27(3):390–395.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

15

TABLE 1.13   IMMUNOPHENOTYPE OF PRIMARY OVARIAN AND METASTATIC COLORECTAL ADENOCARCINOMA Mucinous Ovarian Tumors CK7 CK20 mCEA STAB2 CDX2 ER

Intestinal Type

Endocervical Type

Endometrioid Adenocarcinoma

Metastatic Colorectal Adenocarcinoma

+++/+ −/+/+++ +

+++ − −

+++ − −

+ −

− +

−/+ +

− +++ ++ +++ ++ −

ER, Estrogen receptor; mCEA, monoclonal carcinoembryonic antigen; STAB2, Special AT-­rich sequence binding-­protein 2 (SATB2); +++, diffusely positive; +, focally positive; −, negative. Modified from McCluggage WG: My approach to and thoughts on the typing of ovarian carcinomas. J Clin Pathol. 2008;61:152–163. From Conner JR, Hornick JL. Metastatic carcinoma of unknown primary: diagnostic approach using immunohistochemistry. Adv Anat Pathol. 2015;22(3):149–167.

TABLE 1.14    IMMUNOHISTOCHEMISTRY PANEL FOR PRIMARY AND METASTATIC ADENOCARCINOMA OF THE OVARY Primary mucinous, intestinal type Primary endometrioid Metastatic colorectal Metastatic pancreas Metastatic thyroid Metastatic renal Metastatic thymic

PAX2

PAX8

CK7

CK20

CDX2

DPC4

− + − −

− + − − + + +

+ + − +/−

+ − + +/−

+/− − + −

+ + + −

CK, Cytokeratin; DPC, deleted in pancreatic carcinoma; +, positive; −, negative; +/−, often positive. Modified from Ji H, Isacson C, Seidman JD, et al. Cytokeratins 7 and 20, Dpc4, and MUC5AC in the distinction of metastatic mucinous carcinomas in the ovary from primary ovarian mucinous tumors: Dpc4 assists in identifying metastatic pancreatic carcinomas. Int J Gynecol Pathol. 2002;21:391–400; Ozcan A, Liles N, Coffey D. PAX2 and PAX8 expression in primary and metastatic müllerian epithelial tumors: a comprehensive comparison. Am J Surg Pathol. 2011;35:1837–1847.

TABLE 1.15    IMMUNOHISTOCHEMISTRY: HIGH-­GRADE SEROUS CARCINOMA AND POORLY DIFFERENTIATED ENDOMETRIOID ADENOCARCINOMA OF THE OVARY AND ENDOMETRIUM Serous Endometrioid

WT-­1

p53

p16

β-­Catenin

+++ −/+

+++ −/+/+++a

+++ −/+

Membranous Membranous/nuclear

WT-­1, Wilms tumor gene protein 1; +++, diffusely positive; +, focally positive; −, negative. aThe +++ expression corresponds to some high-­grade carcinomas. Data from McCluggage WG. My approach to and thoughts on the typing of ovarian carcinomas. J Clin Pathol. 2008;61:152–163.

TABLE 1.16    IMMUNOHISTOCHEMISTRY APPROACH TO OVARIAN SEX CORD–STROMAL TUMORS AND ENDOMETRIOID ADENOCARCINOMA Granulosa cell tumor Sertoli-­Leydig cell tumor Endometrioid adenocarcinoma

FOXL2

Inhibin

Calretinin

CD99

EMA

Pan-­cytokeratin

+ +/−

+ + −

+ + −

+ + −

− − +

−/+ +/− +

EMA, Epithelial membrane antigen; +, positive; −, negative; +/−, often positive; −/+, rarely positive. Modified from Mount SL, Cooper K. Tumours with divergent müllerian differentiation of the uterine corpus. Curr Diagn Pathol. 2005;11:349–355; Al-­Agha OM, Huwait HF, Chow C, et al: FOXL2 is a sensitive and specific marker for sex cord-­stromal tumors of the ovary. Am J Surg Pathol. 2011;35:484-­494.

TABLE 1.17    IMMUNOHISTOCHEMISTRY APPROACH TO ENDOCERVICAL ADENOCARCINOMA AND ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA Endocervical Endometrial

mCEA

Vimentin

ER/PR

p16

HPV DNA

+ −

− +

− +

+ −/+

+ −

ER/PR, Estrogen/progesterone receptor; HPV, human papillomavirus; mCEA, monoclonal carcinoembryonic antigen; +, positive; −, negative; −/+, rarely positive. Modified from Staebler A, Sherman ME, Zaino RJ, Ronnett BM. Hormone receptor immunohistochemistry and human papillomavirus in situ hybridization are useful for distinguishing endocervical and endometrial adenocarcinomas. Am J Surg Pathol. 2002;26:998–1006.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

16

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

TABLE 1.18    IMMUNOHISTOCHEMISTRY IN THE DIFFERENTIAL DIAGNOSIS OF SQUAMOUS AND GLANDULAR LESIONS OF THE UTERINE CERVIX LSIL (CIN I) HSIL (CIN II-­III) Adenocarcinoma in situ Atypical immature metaplasia Reactive squamous or glandular atypia Tubal metaplasia

p16a

MIB-­1 (Ki-­67)

+/− + + − − +/−

Increased Increased (full thickness) + −/+ + −

CIN, Cervical intraepithelial neoplasia; HSIL, high-­grade squamous intraepithelial neoplasia; LSIL, low-­grade squamous intraepithelial neoplasia; +, positive; −, negative; +/−, often positive; −/+, rarely positive. MIB-­1, monoclonal antibody directed against the Ki-­67 antigen, a nuclear antigen expressed by all human proliferating cells. aExpression of p16 (nuclear and cytoplasmic) is a surrogate marker for high-­risk human papillomavirus (HPV), for example, HPV-­16 and HPV-­18. In LSIL, the p16 expression may be confined to the lower one third or one half of the squamous epithelium or show focal immunoreactivity (the latter being a pattern of expression, albeit cytoplasmic only, that may be seen in reactive squamous epithelia). HSIL p16 immunoexpression usually involves two-­ thirds or full thickness of the squamous epithelium. Modified from Kalof AN, Cooper K. p16INK4a immunoexpression: surrogate marker of high-­risk HPV and high-­grade cervical intraepithelial neoplasia. Adv Anat Pathol. 2006;13:190–194.

TABLE 1.19   P57KIP2 IMMUNOREACTION AND HER-­2 FLUORESCENCE IN SITU HYBRIDIZATION (FISH) ANALYSIS IN MOLAR PREGNANCY Complete hydatidiform molar pregnancy Partial hydatidiform molar pregnancy Hydropic abortion

Villous Cytotrophoblasts

Villous Stroma

Syncytiotrophoblasts

HER-­2 FISH Analysis

−

−

+

Diploid

+

+

+

Triploid

+

+

+

Diploid

Note: p57KIP2 is a paternally imprinted, maternally expressed gene protein. Hence, complete moles comprising only paternal genes will not express this protein. Modified from Hoffner L, Dunn J, Esposito N, et al. p57KIP2 Immunostaining and molecular cytogenetics: combined approach aids in diagnosis of morphologically challenging cases with molar phenotype and in detecting androgenetic cell lines in mosaic/chimeric conceptions. Hum Pathol. 2008;39:63; and LeGallo RD, Stelow EB, Ramirez NC, et al. Diagnosis of hydatidiform moles using p57 immunohistochemistry and her2 fluorescent in situ hybridization. Am J Clin Pathol. 2008;129:749.

TABLE 1.20   IMMUNOHISTOCHEMICAL APPROACH FOR TROPHOBLASTIC LESIONS Trophoblastic Lesion

CK18

p63

hPL

MIB-­1 LI (%)

Exaggerated placental site Placental site trophoblastic tumor Placental site nodule Epithelioid trophoblastic tumor Choriocarcinoma

+++ +++ +++ +++ +++

− − +++ +++ −/+

+++ +++ −/+ −/+ ++

1 10

Note: Expression of p63 highlights mononucleated trophoblasts corresponding to cytotrophoblasts, and human chorionic gonadotropin selectively stains syncytiotrophoblasts; this combination is indicative of choriocarcinoma. CK, Cytokeratin; hPL, human placental lactogen; LI, labeling index; MIB-­1, Ki-­ 67 proliferation marker; +++, diffusely positive; ++, focally positive; −, negative; −/+, rarely positive. Modified from Shih IM, Kurman RJ. p63 Expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations. Am J Surg Pathol. 2004;28:1177–1183.

TABLE 1.21   IMMUNOHISTOCHEMISTRY FOR SELECTED GERM CELL TUMORS Germinoma Embryonal carcinoma Yolk sac tumor Choriocarcinoma

SOX2

SALL4

c-­kit

OCT3/4

CD30

AFP

GPC-­3

D2-­40

β-­hCG

− + − −

+ + + +/−

+ − − −

+ + − −

− + − −

− − v −

− − + −

+ − − −

−a v − +

AFP, α-­fetoprotein; β-­hCG, β-­human chorionic gonadotropin; GPC-­3, glypican-­3; SALL4, sal-­like4; SOX2 (also known as SRY [sex determining region Y]­box2); v, variable; +, positive; −, negative; +/−, often positive. Cao D, Li J, Guo CC. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol. 2009;33:1065–1077; Gopalan A, Dhall D, Olgac S, et al. Testicular mixed germ cell tumors: a morphological and immunohisto­ chemical study using stem cell markers, OCT3/4, SOX2 and GDF3, with emphasis on morphologically difficult-­to-­classify areas. Mod Pathol 2009;22: 1066–1074. aExcept for syncytiotrophoblastic giant cells in seminoma. Modified from Ulbright TM. The most common, clinically significant misdiagnoses in testicular tumor pathology, and how to avoid them. Adv Anat Pathol. 2008;15:18–27; and Young RH. Testicular tumors: some new and a few perennial problems. Arch Pathol Lab Med. 2008;132:548–564.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

17

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology TABLE 1.22   IMMUNOHISTOCHEMISTRY PANEL TO DISTINGUISH RENAL CELL NEOPLASMS

Clear cell carcinoma Chromophobe carcinoma Papillary carcinoma Oncocytoma Xp11/TFE3 translocation renal carcinoma RCC with t(6,11)

Melan A or HMB45

RCC

CD10

CK7

AMACR

CA IX

TFE3

CD117

PAX2

PAX8

+/− −

+ −

− +/−

− −

+ −

− −

− +

+ −

+ +

+/− −

−/+ − +

+/− −/+ −

+ − +

− −

− − +

− +/− −

−/+ −

+ +

+

TFEB

+

AMACR, α-­methylacyl coenzyme A racemase (P504S); CA IX, carbonic anhydrase 9; CK, cytokeratin; PAX2, paired box gene-­2; PAX8, paired box gene-­8; RCC, renal cell carcinoma; TFE3, transcription factor E3; +, positive; −, negative; +/−, often positive; −/+, rarely positive. Modified from Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med. 2011;135:92–109; Ozcan A, de la Roza G, Ro JY, et al. PAX2 and PAX8 expression in primary and metastatic renal tumors: a comprehensive comparison. Arch Pathol Lab Med. 2012;136:151–154; Suárez-­Vilela D, Izquierdo-­García F, Méndez-­Álvarez JR, et al. Renal translocation carcinoma with expression of TFEB: presentation of a case with distinctive histological and immunohistochemical features. Int J Surg Pathol. 2011;19:506–509.

TABLE 1.23    SELECTED IMMUNOHISTOCHEMISTRY TO DISTINGUISH VASCULAR NEOPLASM Neoplasm

IHC

Angiosarcomaa

CD31, CD34, ERG CD31, CD34, ERG, CAMTA1

Epithelioid hemangioendothelioma Pseudomyogenic hemangioendothelioma Kaposi sarcoma Epithelioid hemangioma

AE1/AE3, FLI1, FOSB (96%) HHV8, CD31, CD34, ERG CD31, CD34, ERG, FOSB (54%)

CAMTA1, Calmodulin binding transcription activator 1; ERG, ERG (Erythroblast transformation-specific [ETS]-related gene); FLI1, Friend leukemia integration-­1; FOSB, FBJ Murine Osteosarcoma Viral Oncogene Homolog B; IHC, immunohistochemistry. aAngiosarcoma is also cytokeratin and EMA positive (+). Al-­Abbadi MA, Almasri NM, Al-­Quran S, Wilkinson EJ. Cytokeratin and epithelial membrane antigen expression in angiosarcomas: an immunohistochemical study of 33 cases. Arch Pathol Lab Med. 2007;131:288–292. Miettinen M, Wang ZF, Paetau A, et al. ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol. 2011;35:432–441. Doyle LA, Fletcher CD, Hornick JL. Nuclear expression of CAMTA1 distinguishes epithelioid hemangioendothelioma from histologic mimics. Am J Surg Pathol. 2016;40(1):94–102. Hung YP, Fletcher CD, Hornick JL. FOSB is a useful diagnostic marker for pseudomyogenic hemangioendothelioma. Am J Surg Pathol. 2017;41(5):596–606.

MOLECULAR PATHOLOGY METHODS INTRODUCTION Molecular tests are widely relied upon as standard of care assays in the diagnosis of a wide variety of pathologic conditions. Ongoing advances in molecular pathology, genomics, epigenetics, proteomics, and infectious diseases research, as well as technological developments continue to expand the potential of molecular assays to improve disease characterization and patient care. This section provides an overview of the molecular techniques applicable to pathology practice. 

TABLE 1.24   IMMUNOHISTOCHEMISTRY APPROACH TO ATYPICAL GLANDULAR PROLIFERATIVE LESION IN THE PROSTATEa

Lesion Atrophic glands Post–atrophic hyperplasia Basal cell hyperplasia Atypical adenomatous hyperplasia (adenosis) Prostatic intraepithelial neoplasia Prostate carcinoma

Basal Cell Markers (HMWCK 34βE12, CK5/6, p63)

AMACR (p504S)

+ + + +/− (patchy)

− − − −/+

+

+

−a,b

+

AMACR, α-­methylacyl coenzyme A racemase; CK, cytokeratin; HMWCK, high-­molecular-­weight cytokeratin; +, positive; −, negative; +/−, often positive; −/+, rarely positive. aSee Figure 1.14. bRarely, p63 may demonstrate immunoreactivity in prostate carcinoma (see Ali TZ, Epstein JI. False positive labeling of prostate cancer with high molecular weight cytokeratin: p63 a more specific immunomarker for basal cells. Am J Surg Pathol. 2008;32:1890–1895). Modified from Paner GP, Luthringer DJ, Amin MB. Best practices in diagnostic immunohistochemistry: prostate carcinoma and its mimics in needle core biopsies. Arch Pathol Lab Med. 2008;132:1388–1396.

NUCLEIC ACID EXTRACTION METHODS Background • The extraction of nucleic acids from pathology samples involves cell lysis followed by selective DNA or RNA isolation, and a quantity and quality assessment relative to the requirements of the end-­ diagnostic test • Pathology samples: biopsy or surgical material (fresh or formalin-­ fixed, paraffin-­ embedded [FFPE] tissue), body fluids (amniotic, saliva, stools, urine), buccal cell scrapes, cervical scrapes, fine-­ needle aspiration, hair root, peripheral blood, primary cell culture.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

18

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

TABLE 1.25   IMMUNOHISTOCHEMISTRY PANEL TO DISTINGUISH PROSTATE AND UROTHELIAL CARCINOMAS Prostate carcinoma Urothelial carcinoma

GATA3

CK7

CK20

NKX3.1

PSA

Uroplakin

p63

− +

−/+ +/−

−/+ +/−

+ −

+ −

− +/−

−/+ +

Notes: Only CK7/20 negativity (prostate carcinoma) and CK7/20 positivity (urothelial carcinoma) reliably distinguish between these two carcinomas. Any other permutation is unreliable. Uroplakin is highly specific for urothelial carcinoma but has a low sensitivity, being focally present in approximately 50% to 60% of tumors. Expression of p63 is used more often to highlight basal cells in benign prostate glands but may rarely be positive in the prostate carcinoma itself (see Ali TZ, Epstein JI. False positive labeling of prostate cancer with high molecular weight cytokeratin: p63 a more specific immunomarker for basal cells. Am J Surg Pathol. 2008;32:1890–1895). CK, Cytokeratin; PSA, prostate-­specific antigen; +, positive; −, negative; +/−, often positive; −/+, rarely positive. GATA3, GATA binding protein 3. Modified from Hammerich AH, Ayala GE, Wheeler TM. Application of immunohistochemistry to the genitourinary system (prostate, urinary bladder, testis, and kidney). Arch Pathol Lab Med. 2008;132:432–440; Chang A, Amin A, Gabrielson E, et al. Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung. Am J Surg Pathol. 2012;36:1472–1476.

TABLE 1.26    RECOMMENDED ANTIBODY PANEL FOR COMMON PLEOMORPHIC CUTANEOUS SPINDLE CELL TUMORS

Sarcomatoid squamous cell carcinoma Melanoma Atypical fibroxanthoma Leiomyosarcoma Angiosarcoma

CD10

p63

Cytokeratins (Pan, HMW, CK5/6)

−

+

+

−

−

−

−

−

− + − −

− −/+ − −

−/+ −

+ − −/+ −

+/− − − −

− −/+ + −

−/+ − +/− −

− − −/+ +

−/+

S-­100 Protein

Melanocytic (HMB-­45, Melan-­A)

Smooth Muscle Actin

Desmin

Endothelial (CD31, CD34)

+, positive; −, negative; +/−, often positive; −/+, rarely positive. Modified from Folpe AL, Cooper K. Best practices in diagnostic immunohistochemistry: pleomorphic cutaneous spindle cell tumors. Arch Pathol Lab Med. 2007;131:1517; Hultgren TL, DiMaio DJ. Immunohistochemical staining of CD10 in atypical fibroxanthomas. J Cutan Pathol. 2007;34:415–419; Dotto JE, Glusac EJ. p63 is a useful marker for cutaneous spindle cell squamous cell carcinoma. J Cutan Pathol. 2006;33:413–417.

TABLE 1.27   MIB-­1(KI-­67) MEMBRANOUS AND CYTOPLASMIC STAINING MIB-­1 (Ki-­67); Clone MIB-­1, 1:700; Dako, Glostrup, Denmark Staining Pattern Cytoplasmic staininga Membrane and cytoplasmic stainingb

Hyalinizing trabecular tumor of the thyroid Pulmonary sclerosing hemangiomas aFrom

Hirokawa M, Carney JA. Cell membrane and cytoplasmic staining for MIB-­1 in hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol. 2000;24:575–578. bFrom Kim BH, Bae YS, Kim SH, et al. Usefulness of Ki-­67 (MIB-­1) immunostaining in the diagnosis of pulmonary sclerosing hemangiomas. APMIS. 2013;121:105–110.

TABLE 1.28A    IMMUNOHISTOCHEMISTRY PANEL FOR THE INTERPRETATION OF LOW-­GRADE (SMALL) B-­CELL LYMPHOMA SLL/chronic lymphocytic leukemia Mantle Marginal zone Lymphoplasmacytic Follicular Extranodal marginal

CD23 (%)

CD5 (%)

Cyclin D1 (%)

CD10 (%)

LEF1 (%)

85

80

0

0

92

2 8 0–30 0–25 0

80 0 5 0 0

75–100 0 0 0 0

2 2 3 85 0

SOX11 (%)

94

SLL, Small lymphocytic lymphoma; LEF1, lymphocyte enhancer-­binding factor 1; SOX11, SRY (sex-­determining region Y)–box 11. Modified from http://surgpathcriteria.stanford.edu. Ek S, Dictor M, Jerkeman M, et al. Nuclear expression of the non B-­cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008;111(2):800–805. Menter T, Dirnhofer S, Tzankov A. LEF1. A highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol. 2015;68(6):473–478.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

19

TABLE 1.28B    BASIC IMMUNOPHENOTYPIC APPROACH TO LYMPHOMAS OF SMALL B-­CELL TYPE (CD20+ AND LOW KI-­67) CD5

+

–

CD23/FMC-7

CD10

+/–

–/+

–

+

Chronic lymphocytic leukemia/Small lymphoblastic lymphoma (LEF1+)

Mantle cell lymphoma (Cyclin D1+, SOX11+)

Marginal zone lymphoma/ lymphoplasmacytic lymphoma

Follicular lymphoma

TABLE 1.29   ANTIBODY PANEL FOR DIFFERENTIAL DIAGNOSIS OF HODGKIN LYMPHOMA NLPHL (Nodular lymphocyte predominant Hodgkin lymphoma) ALCL DLBCL

CD30

CD15

CD20

CD45 (LCA)

ALK

−

−

+

+

−

+ −/+

− −

− +

−/+ +

+ −

ALCL, Anaplastic large cell lymphoma; ALK, alkaline kinase; DLBCL, diffuse large B-­cell lymphoma; LCA, leukocyte common antigen; +, positive; −, negative; −/+, rarely positive.

• There is increasing interest in the potential of liquid biopsy (blood/plasma/serum) samples for use in molecular diagnostics. Diagnostic signals may be shed into the circulation in the form of cell-­free DNA or RNA (cfDNA/cfRNA) of diseased/normal tissue origin; cell-­ free fetal DNA (cffDNA); circulating tumor cells (CTCs)/ circulating tumor DNA (ctDNA)/coding or noncoding circulating tumor RNA (ctRNA), in particular RNA associated with exosomes 

TABLE 1.30    IHC CLASSIFICATION OF DIFFUSE LARGE B-­CELL LYMPHOMAS INTO GERMINAL CENTER B-­LIKE CELL (GCB) AND NON-­GCB CD 10

+

–

GCB

BCL6

DNA Extraction Methods

+

–

MUM 1

NON–GCB

+

–

NON–GCB

GCB

Modified from Hans CP, Weisenburger DD, Greiner TC. Confirmation of the molecular classification of diffuse large B-­cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–282.

• Classical methods were time consuming (∼3 days) and required relatively large quantities of tissues (100 mg to >1 g) •  Extraction kits are now available that use glass-­ fiber filters that selectively bind DNA following tissue treatments with a protease and chaotropic buffers (which disrupt protein and DNA secondary structures); the glass fibers, typically loaded in mini-­ columns, are washed and centrifuged to rinse away cellular debris, extraction solution reagents, and pathology tissue processing chemicals; the DNA is then recovered from the resin/glass-­fiber by low-­salt buffer rinses and centrifugation; pure DNA recovery from diverse pathology samples is possible within several hours by these procedures.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

20

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

TABLE 1.31   IMMUNOPROFILE OF SMALL ROUND CELL TUMORS Ewing sarcoma, primitive neuroectodermal tumor Rhabdomyosarcoma Poorly differentiated synovial sarcomaa Desmoplastic small round cell tumor Neuroblastoma Lymphoblastic lymphomab Wilms tumor

FLI-­1

NKX2-­2

Pan-­CK

CD99

Desmin

Myogenin

WT-­1

CD56

+

+

v

+

−

−

−

v

− −

− −

− +

v +

+ −

+ −

− −

+ +

+

−

+

v

+

−

+

v

− +

− −

− −

− +

− −

− −

− −

+ −

+

−

v

v

+

vc

+

+

FLI-­1, Friend leukemia virus integration-­1; NKX2-­2, Homeobox protein Nkx-­2.2; Pan-­CK, pan-­cytokeratin; WT-­1, Wilms tumor gene protein 1; +, positive; −, negative; v, variable. Folpe AL, Hill CE, Parham DM, et al. Immunohistochemical detection of FLI-­1 protein expression: a study of 132 round cell tumors with emphasis on CD99-­positive mimics of Ewing’s sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol. 2000;24:1657–1662. aEpithelial membrane antigen is frequently positive. bFrequently leukocyte common antigen negative. cIn rhabdomyomatous Wilms tumor. Modified from Barami A, Truong LD, Ro JY. Undifferentiated tumor: true identity by immunohistochemistry. Arch Pathol Lab Med. 2008;132:326–348. From Hung YP, Fletcher CD, Hornick JL. Evaluation of NKX2-­2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma. Mod Pathol. 2016;29(4):370–380.

TABLE 1.32    IMMUNOHISTOCHEMISTRY PANEL TO DISTINGUISH FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA FROM FOLLICULAR ADENOMA FVPTC FA

HBME1 (%)

CK19 (%)

Galectin-­3 (%)

96 7–11

91–100 44–68

98 30

Note: The combination of HBME1 and CK19 has the greatest utility in differentiating FVPTC from benign follicular lesions. FA, Follicular adenoma; FVPTC, follicular variant of papillary thyroid carcinoma. Data from Erickson LA, Lloyd RV. Utility of a panel of immunohistochemical markers in the diagnosis of follicular variant of papillary thyroid carcinoma. Adv Anat Pathol. 2008;15:59–60.

• Inclusive nucleic acid extraction is a feature of most automated molecular diagnostic platforms. 

RNA Extraction Methods •  Classical methods required the rapid homogenization of large quantities of fresh tissues in protease/ guanidinium thiocyanate solution to denature ubiquitous endogenous RNases that otherwise degrade cellular RNA • Current methods allow the relatively rapid (1-­day) recovery of RNA again following tissue homogenization in a chaotropic guanidinium salt solution that leaves RNA contained in an aqueous phase and protein and DNA in an organic phase. Admixture of the aqueous phase with nucleic acid binding glass filters allows the recovery of pure total RNA by elution from the glass filters with a low-­salt buffer. Total RNA can be used for mRNA isolation (purification by passage through oligo[dT] cellulose spin columns) or mRNA assays (polymerase chain reaction [PCR], microarray, sequencing, etc.) and long noncoding RNA (lncRNA; >200 nucleotides) assays (PCR, microarray, sequencing, etc.). MicroRNA (mRNA) species are approximately 18 nucleotides in length and

TABLE 1.33    IMMUNOHISTOCHEMISTRY TO DETECT THE GAIN OR LOSS OF PROTEIN EXPRESSION Loss of SMARCB1 (INI-­1) Expression (%) Medullary carcinoma of kidney Malignant rhabdoid tumor (Glypican 3+)a Epithelioid sarcoma (classic and proximal type) Epithelioid MPNST

100 98 90 50 Loss of Succinate Dehydrogenase B (SDHB) Expressionb

Succinate dehydrogenase-­deficient wildtype GISTs, paragangliomas, and pheochromocytomas Sporadic GISTs (association with KIT or PDGFRA mutations)

− (no expression)

+ (expression)

Kohashi K, Nakatsura T, Kinoshita Y, et al. Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression. Hum Pathol. 2013;44:526–533. GIST, Gastrointestinal stromal tumor; MPNST, myxoid malignant peripheral nerve sheath tumor. aGlypican 3 positive in malignant rhabdoid tumor and negative in epithelioid sarcoma. bBarletta JA, Hornick JL. Succinate dehydrogenase-­deficient tumors: diagnostic advances and clinical implications. Adv Anat Pathol. 2012;4:193–203. Modified from Hollmann TJ, Hornick JL. INI1-Deficient Tumors: Diagnostic Features and Molecular Genetics. Am J Surg Pathol. 2011; 35(10):e47–e63.

require dedicated extraction reagents for extraction from tissue or plasma/serum/exome sources 

DNA and RNA Quantification, Purity, and Integrity Assay • High-­integrity nucleic acids are best extracted from fresh tissue specimens. Extraction from tissues preserved in liquid nitrogen is the next best option. Commercially

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

21

TABLE 1.34   IMMUNOHISTOCHEMISTRY TO DETECT THE GAIN OR LOSS OF PROTEIN EXPRESSION Tumor positive for microsatellite instability (highly suspicious for Lynch syndrome); germline mutation of MSH6 Tumor positive for microsatellite instability (highly suspicious for Lynch syndrome); germline mutation of MSH2 Tumor positive for microsatellite instability (highly suspicious for Lynch syndrome); germline mutation of PMS2 Tumor positive for microsatellite instability; majority of colon cancers with this pattern of protein loss are associated with somatic changes (not inherited mutation); follow-­up testing should include a BRAF mutational analysis or methylation of MLH-­1 testing —Presence of the BRAF V600E mutation and MLH1 promoter hypermethylation provide confirmation of a sporadic MSI tumor (loss of MLH1 secondary to promoter hypermethylation, not due to inherited mutation) —Absence of BRAF V600E and negative MLH1 promoter hypermethylation is highly suggestive of a germline mutation of MLH1 Tumor negative for microsatellite instability; germline mutation unlikely (however, up to 10% of Lynch syndrome patients may have retained expression of these 4 MMR proteins)

MSH2

MSH6

MLH1

PMS2

Present

Loss

Present

Present

Loss

Loss

Present

Present

Present

Present

Present

Loss

Present

Present

Loss

Loss

Present

Present

Present

Present

Loss, negative nuclear staining; Present, positive nuclear staining. Courtesy of Rebecca Wilcox, MD, University of Vermont/Fletcher Allen Health Care.

TABLE 1.35    IMMUNOHISTOCHEMISTRY FOR GENE PRODUCTS DETECTION FROM SPECIFIC MUTATIONS Antibodies Against Gene Products from Specific Mutations Gene

Malignancy

BRAF V600E

Melanoma (37/38)a Hairy cell leukemia (32/32)b Papillary thyroid carcinoma (72/144)c Non–small cell lung cancerd

EGFR aFrom

Long GV, Wilmott JS, Capper D, et al. Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol. 2013;37:61–65. bFrom Andrulis M, Penzel R, Weichert W, et al. Application of a BRAF V600E mutation-­specific antibody for the diagnosis of hairy cell leukemia. Am J Surg Pathol. 2012;36:1796–1800. cFrom Koperek O, Kornauth C, Capper D, et al. Immunohistochemical detection of the BRAF V600E-­mutated protein in papillary thyroid carcinoma. Am J Surg Pathol. 2012;36:844–850. dFrom Hasanovic A, Ang D, Moreira AL, Zakowski MF. Use of mutation specific antibodies to detect EGFR status in small biopsy and cytology specimens of lung adenocarcinoma. Lung Cancer. 2012;77:299–305.

available storage reagents (e.g., RNAlater, Ambion, Inc., Foster City, CA) preserve tissue morphology and nucleic acids integrity. Disaggregated cells/cell cultures can be stored at −20°C in 70% ethanol with efficient nucleic acid preservation. DNA and RNA extracts from FFPE tissues tend to be degraded. In general, the quality of nucleic acids extractable from FFPE blocks decreases with block age • The concentration of extracted nucleic acids is assessed spectrophotometrically. Both DNA and RNA absorb UV light with peak absorbance at a wavelength of 260 nm; an absorbance (A260) reading of 1.0 demonstrates a DNA concentration of 50 μg/mL or an RNA concentration of 40 μg/mL • The purity of extracted DNA or RNA is also determined spectrophotometrically. Readings taken at A230 and at

A270 are indicators of contamination with organics (e.g., guanidinium salts) or phenol, respectively. Contamination with proteins can be inferred from an A280 reading, whereat peak protein absorbance occurs. Particulate matter contamination can be gauged from an A320 reading. Typically, an A(260–320): A(280–320) ratio is calculated; a value of 1.7 to 2 indicates pure DNA or RNA • Nucleic acid integrity can be estimated by comparing nucleic acid fragment size against a molecular weight ladder following agarose gel electrophoresis. High-­ integrity genomic DNA extracted from fresh or frozen tissues or cultured cells demonstrates a band greater than 30 to 40 kilobase pairs (kb) in size. The presence of a smear extending to smaller sized fragments indicates degraded DNA. DNA extracted from FFPE tissues typically appears as a smear extending from approximately 1 kb to less than 100 base pairs (bp). Total RNA integrity is gauged in terms of the presence of 28S (∼5 kb) and 18S (∼2 kb) rRNA. Discrete 28S and 18S bands, with minimal smearing, indicate intact RNA species, whereas partial or absent bands and smeared rRNA indicate a degraded sample • Instruments such as the Agilent 2100 Bioanalyzer (Agilent Technologies, Inc., Santa Clara, CA) and Qubit Fluorimeter (Thermo Fisher Scientific, Waltham, MA) have facilitated rapid DNA and RNA quantitation and purity analyses, and RNA integrity assays 

Nucleic Acids Storage • DNA is generally stored at 4°C for assays performed within 1 week to 1 month of extraction, and in aliquots at −20°C or −80°C for longer-­ term storage; repeated freeze-­thawing may lead to DNA degradation • RNA is more labile than DNA and is susceptible to degradation by RNases that are a pervasive laboratory hazard. For short-­term use, RNA is stored at −20°C, and at −80°C or under liquid nitrogen for longer-­term storage 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

22

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

TABLE 1.36    SELECTED SOFT TISSUE TUMORS WITH CORRESPONDING IMMUNOHISTOCHEMISTRY CD34+ Spindle Cell Tumors Cellular angiofibroma (ER/PR +) Angiomyofibroblastoma (ER/PR +) Superficial myofibroblastoma (ER/PR +) Solitary fibrous tumor (CD99 +, STAT6 +) Spindle cell lipoma (Rb IHC, loss of nuclear expression) Dermatofibrosarcoma protuberans Kaposi sarcoma (HHV8 +) IHC for Liposarcomas (LPSs) Myxoid LPS S-­100 protein + (mature fat cells and lipoblasts) Well-­differentiated/atypical MDM2 + lipomatous tumor CDK4 + p16 + Dedifferentiated liposarcoma MDM2 + CDK4 + IHC for Myxoid Spindle Cell Tumors Myxofibrosarcoma Vimentin + Low-­grade fibromyxoid MUC4 + sarcoma Vimentin + Myxoid LPS S-­100 protein + (mature fat cells and lipoblasts) Extraskeletal myxoid S-­100 protein + (17%)a chondrosarcoma Vimentin + Chordoma Brachyury + CK + EMA + S-­100 protein + Myxoid leiomyosarcoma Desmin + h-­Caldesmon + DOG1 −/+ Myxoid malignant peripheral SMA + (50%) nerve sheath tumor (MPNST) S-­100 + (50%) focal CD34 +/− Myxoid dermatofibrosarcoma CD34 + protuberans (DFSP) Apolipoprotein D + Myxoid solitary fibrous tumor STAT6+ (SFT) CD99 + CD34 + Myxoid monophasic synovial Keratin + sarcoma CD99 + TLE1 + +, positive; −, negative; +/−, often positive; −/+, rarely positive. MUC4 (mucin 4 gene): Doyle LA, Möller E, Dal Cin P, et al. MUC4 is a highly sensitive and specific marker for low-­grade fibromyxoid sarcoma. Am J Surg Pathol. 2011;35:733–741. MDM2, CDK4, and p16: Thway K, Flora R, Shah C, et al. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-­differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol. 2012;36:462–469. Apolipoprotein D: West RB, Harvell J, Linn SC, et al. Apo D in soft tissue tumors: a novel marker for dermatofibrosarcoma protuberans. Am J Surg Pathol. 2004;28:1063–1069. TLE1 (transducer-­like enhancer of split 1): Foo WC, Cruise MW, Wick MR, Hornick JL. Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics. Am J Clin Pathol. 2011;135:839–844. aOliveira AM, Sebo TJ, McGrory JE, et al. Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and ploidy analysis of 23 cases. Mod Pathol. 2000;13:900–908. From Chen BJ, Mariño-­Enríquez A, Fletcher CD, Hornick JL. Loss of retinoblastoma protein expression in spindle cell/pleomorphic lipomas and cytogenetically related tumors: an immunohistochemical study with diagnostic implications. Am J Surg Pathol. 2012 Aug;36(8):1119–1128. From Jambhekar NA, Rekhi B, Thorat K, et al. Revisiting chordoma with brachyury, a “new age” marker: analysis of a validation study on 51 cases. Arch Pathol Lab Med. 2010;134:1181–1187.

A

B

C Figure 1.14  Immunohistochemistry in prostate adenocarcinoma.  Both p63 (A) and 34βE12 (B) highlight an intact basal cell layer surrounding benign glands and loss around small acini of invasive adenocarcinoma. C, P504S immunohistochemistry shows strong, granular luminal staining in invasive adenocarcinoma and prostatic intraepithelial neoplasia. Normal glands are negative.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

23

1023

CD45 Pos Grans CD45 Neg

SS Lin

Monos

Other

0

Lymphs 100

101

F1

103

F2

A1

103

A2

CD19

101

F3

100

B

101 CD5

102

103

C2

C3

C4

102

101

100

F4

C1

FMC7

102 Kappa

102

100

103

CD45 PC7

A 103

102

101

A3

100

A4

100

101 Lambda

102

103

100

101 CD23

102

103

Figure 1.15  Flow cytometry.  A, Gating for lymphocytes (CD45 versus side scatter, linear scale [SS Lin]) shows the relative locations of granulocytes (Grans), monocytes (Monos), and lymphocytes (Lymphs) (arrow). B, Mantle cell lymphoma. Flow cytometric analysis of a lymph node specimen shows that nearly all of the lymphocytes express CD19, CD5, and kappa immunoglobulin light chains. A subset coexpresses FMC7, whereas the cells are negative for CD23. Expression of CD20 is not dim (data not shown). This immunophenotypic profile fits with involvement by mantle cell lymphoma. (Courtesy of Michael R. Lewis, MD, MBA, Department of Pathology, University of Vermont Medical Center Burlington, VT.)

TISSUE MICRODISSECTION METHODS Background • Microdissection allows the targeted collection of minimal numbers of cells or tissues from slide mounted cytologic specimens, or frozen or FFPE tissue sections. Sample tissues may be treated for nucleic acids or protein extraction 

Methods • In manual microdissection, lightly stained tissue sections are viewed by dissecting microscope and dampened with 70% ethanol; targeted tissues are selectively

scraped off the slides using a syringe needle. DNA/RNA extraction is by mini-­column applications • Laser capture microdissection (LCM) (Figure 1.17) uses specialized microscopy apparatus such as the ArcturusXT system (Thermo Fisher Scientific, Waltham, MA) • The procedure involves overlaying the tissue of interest with a thermoplastic film contained in a cap. LCM can be applied to frozen or FFPE tissues, or to blood smears, or cytologic or cell culture samples. Tissues can be unstained or histochemically or immunohistochemically stained (chromogenic or fluorescence). A pulsed laser beam is targeted against the selected cells, which fuses them to the thermoplastic film. The cap is then

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1

2

6

7

13

Figure 1.16  Well-­differentiated liposarcoma.  Karyotype analysis of a deep retroperitoneal lesion revealed a giant ring chromosome. (Courtesy of Mary Tang, MD, Cytogenetic Laboratory, University of Vermont/Fletcher Allen Heath Care, Burlington, VT.)

3

8

14

19

20

4

9

10

15

21

5

11

16

22

17

X

12

18

Y

ring chromosome A

TABLE 1.37   ONCOGENES OF IMPORTANCE IN SURGICAL PATHOLOGY Category

Proto-­Oncogene

Mode of Activation/ Location (Chromosome)

Signal Transduction Proteins Nonreceptor tyrosine kinase

ABL

Translocation/9q34

KRAS NRAS HRAS BRAF Beta-­catenin bcl-­1 (PRAD-­1)

Point mutation/12p12 Point mutation/1p22 Point mutation/11p15 Point mutation/7q34 Point mutation 11q13

bcl-­2

18q21

bcl-­6

3q27

erbA erbB1 (EGFR) neu (erbB2, HER-­2)

17 Overexpression/7p11-­12 Overexpression/17q11-­12

KIT

Point mutation

PDGFRB Ret FLT3

Overexpression, translocation 10q11.2 Amplification

Erythroleukemia Squamous cell carcinoma of lung, gliomas Breast carcinoma, gastric and esophageal carcinoma Gastrointestinal stromal tumors, seminomas, leukemias Gliomas, leukemias Medullary and papillary thyroid carcinomas Breast and ovarian carcinomas

L-­MYC N-­MYC C-­MYC

Amplification/1p32 Amplification/2p23-­24 Translocation/8q24

Small cell carcinoma of lung Neuroblastoma, small cell carcinoma of lung Burkitt lymphoma

Cell Cycle Regulators Cyclins

Cyclin D

Cyclin-­dependent kinase

Cyclin E CDK4

Translocation Amplification Overexpression Amplification or point mutation

Mantle cell lymphoma Breast and esophageal carcinomas Breast carcinoma Glioblastoma, melanoma, sarcoma

GTP-­binding

RAS signal transduction WNT signal transduction

Association Chronic myeloid leukemia/acute lymphoblastic leukemia. t(9;22)(q34;q11) (Philadelphia chromosome) forming bcr-­abl fusion protein Colon, lung, pancreatic carcinomas Melanomas, hematologic malignancies Bladder and kidney tumors Melanoma Hepatoblastomas, hepatocellular carcinoma Parathyroid adenomatosis; mantle zone lymphomas with translocation to 14q32 Block of apoptosis; translocation to 14q in follicular lymphomas Diffuse large cell lymphoma

Growth Factor Receptors

Nuclear-­Regulatory Proteins Transcriptional activators

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

TABLE 1.38   TUMOR SUPPRESSOR GENES OF IMPORTANCE IN SURGICAL PATHOLOGY Gene

Location (Chromosome)

Association

RB (retinoblastoma) p53

13q14 17p13.1

WT-­1 EWS

11p13 22q12

BRCA1 and BRCA2 APC/B-­Catenin PTEN NF1 NF2

17q21 5q21 10q23 17q11 22q12

Retinoblastoma, childhood osteosarcoma Mutations in cancers of colon, breast, lung, leukemia, sarcoma; progression to diffuse large cell lymphoma (germline mutation of p53 forms the basis for Li-­Fraumeni syndrome) Wilms tumor; desmoplastic small round cell tumor Ewing/primitive neuroectodermal tumor, soft tissue clear cell sarcoma, desmoplastic small round cell tumor, myxoid liposarcoma, acute myelogenous leukemia Breast and ovarian carcinomas Familial adenomatous polyposis coli; carcinomas of colon, stomach, pancreas Endometrial and prostate cancers/Cowden syndrome Schwannomas, neuroblastomas, neurogenic sarcomas Central schwannomas, meningiomas

TABLE 1.39   CYTOGENETIC ABNORMALITIES OF IMPORTANCE IN SURGICAL PATHOLOGY Tumor Hematopoietic Neoplasms Acute myelogenous leukemia (AML) —AML-­M1 —AML-­M2 —AML-­M3 —AML-­M4eo Chronic myelogenous leukemia B-­cell acute lymphoblastic leukemia Chronic lymphocytic leukemia Burkitt lymphoma Follicular lymphoma Mantle zone lymphoma Primitive Precursor Cell Neoplasms Ewing sarcoma/primitive neuroectodermal tumor CIC-­Rearranged Sarcoma BCOR-­Rearranged Sarcoma Medulloblastoma Neuroblastoma Retinoblastoma Wilms tumor Epithelial Neoplasms Colorectal carcinoma Mesothelioma Renal cell carcinoma (RCC) Clear cell carcinoma Papillary RCC Chromophobe RCC Oncocytoma Small cell carcinoma Soft Tissue Neoplasms Alveolar soft part sarcoma Chondrosarcoma, extraskeletal myxoid Clear cell sarcoma Desmoplastic small round cell tumor Dermatofibrosarcoma protuberans Fibrosarcoma, infantile Hibernoma Inflammatory myofibroblastic tumor Leiomyoma Leiomyosarcoma Lipoma Liposarcoma (myxoid) Liposarcoma (well differentiated) Rhabdoid tumor Rhabdomyosarcoma (alveolar) Rhabdomyosarcoma (embryonal) Synovial sarcoma Central Nervous System Neoplasms Atypical teratoid rhabdoid tumor Oligodendroglioma Schwannoma

Chromosomal Abnormality

Fusion Transcript, Involved Genes

t(9;22) t(8;21) (favorable) t(15;17) inv(16) (favorable) t(9;22)(q34;q11) t(12;21) Trisomy 12, deletions of 11q, 13q and 17p t(8;14), t(8;22), t(4;8) t(14;18) t(11;14)

BCR-­ABL CBFα-­ETO RARα/PML CBFβ/MYH11 BCR-­ABL CBFα-­ETV6

t(11;22)(q24;q12) t(4;19)(q35;q13.1) inv(X)(p11p11) del 17q del 1p (poor prognosis); double minute chromosomes del 13q (band q14) del 11p (band p13)

EWS-­FLI1 (or EWSR1-­ERG, EWSR1-­PATZ1, FUS-­ERG) CIC-­DUX4 (CIC-­DUX4L or CIC-­FOX04) BCOR-­CCNB3 (BCOR-­MAML3 or ZC3H7B-­BCOR)

Involving c-­myc and immunoglobulin (Ig) loci BCL2 gene BCL1 (cyclin D1) and IgH

N-­myc amplification

del 17p del of 1p, 3p, 22p del 3p Trisomy 7 and 17 Loss of chromosome 1, 2, 6, or 10 Loss of chromosome 1; translocation involving 11q13 del 3p t(X;17)(p11;q25) t(9;22)(q22;q12) t(12;22)(q13;q12) t(11;22)(q24;q12) Ring form of chromosomes 17 and 22 t(12;15)(p13;q26) Translocation at 11q13 t(1;2)(q22;p23) t(12;14), del 7q del 1p Rearrangement of 12q15 t(12;16)(q13;p11) Ring chromosome 12 Deletion of 22q t(2;13)(q35;q14) Trisomies 2q, 8, and 20 t(X;18)(p11;q11)

TFE3-­ASPL fusion EWS-­NR4A3 fusion EWSR1-­ATF1 fusion EWSR1-­WT-­1 fusion COL1A1-­PDGFB fusion ETV6-­NTRK3 fusion

Deletion of 22q del 1p, 19q (improved response to chemotherapy) Deletion of 22q

INI1 inactivation

TPM3-­ALK fusion

HMGIC fusion TLS/CHOP INI1 inactivation PAX3-­FKHR SYT-­SSX1/SYT-­SSX2

NF-­2 inactivation

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

26

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Place cap on tissue

Figure 1.17  Laser capture technology.  Target tissues are overlaid with a cap using microscope guidance. Cells are adhered to the thermoplastic film of the cap by laser pulsing. Lifting the cap removes the target cells for nucleic acids or protein extraction. (Courtesy of Molecular Devices, Sunnyvale, CA.)

Extract molecules from target cells

removed from the tissue section surface and nucleic acids are recoverable from the cells adhered thereto after cell lysis treatments applied directly to the cap film 

Applications • LCM it is useful in surgical pathology practice when there is a suspicion of patient sample cross-­ contamination. PCR-­based microsatellite sequence identity testing comparing the known patient sample with the queried tissue supports verification of patient identity 

GEL ELECTROPHORESIS METHODS Background • Gel electrophoresis, as a method for separating, identifying, or purifying nucleic acids • Nucleic acids are negatively charged at neutral pH due to the phosphate in the sugar-­phosphate backbone of DNA or RNA. Accordingly, in the presence of an electric field, nucleic acids will migrate from the cathode to the anode; migration through a sieving matrix (gel) depends on the size of the nucleic acid molecule, its conformation (secondary folding), net charge (dependent on the pH of the gel buffer), and gel pore size •  Agarose gel and polyacrylamide gel are the basic forms of electrophoresis. Variations on these methods include pulsed-­field gel electrophoresis (PFGE), capillary gel electrophoresis (CGE), denaturing gradient gel electrophoresis (DGGE), and temperature gradient gel electrophoresis (TGGE) 

Agarose Gel Electrophoresis • Agarose is manufactured from seaweed such as Rhodophyta. It consists of multiple linked repeat units of the disaccharide agarobiose (D-­ galactose and 3,6-­anhydro-­L-­galactose) •  Agarose gel is prepared by heating agarose powder to near boiling in electrophoresis buffer. The

Pulse laser at target cells

Remove cap with adhered target cells

concentration of the agarose determines the gel pore size, which in turn determines the size range of DNA fragments that can be resolved. The higher the agarose concentration, the smaller the pore size. At low agarose concentrations, small DNA fragments pass rapidly through the gel and cannot be resolved, whereas large DNA molecules are size sorted; at high agarose concentrations, the mobility of large DNA molecules through the gel is limiting and large fragment sizes cannot be resolved, whereas the resistance to the passage of smaller fragments is sufficient for their resolution (e.g., 0.5% agarose gel resolves DNA fragment sizes in the range ∼0.7 to 25 kb; a 2% agarose gel resolves DNA fragment sizes in the range ∼0.05 to 2 kb) • The gel is poured into a horizontal casting tray, and a comb is inserted at one end to mold wells • When set, the “slab” gel is placed in an electrophoresis tank and immersed under electrophoresis buffer • DNA sample is combined with a gel-­loading dye. The loading dye (typically bromophenol blue containing sucrose and/or glycerol) ensures the DNA sample sinks into the well and indicates how far the samples have migrated during electrophoresis. Electrophoresis is generally conducted at 5 V/cm measured as the distance between the negative and positive electrodes • A DNA ladder is also run so that sample DNA fragment sizes can be estimated • DNA is most commonly visualized in agarose gels by staining with ethidium bromide, which intercalates double-­ stranded DNA and fluoresces under UV illumination. Less toxic (noncarcinogenic) alternatives to ethidium bromide, such as SYBR, EvaGreen, or GelStar dyes, stain DNA and with higher sensitivity • Applications •  Agarose gel electrophoresis is commonly used for the analysis of end-­point PCR/reverse transcription (RT)-­ PCR assays where the presence or absence of amplicons defines the interpretation of the test; for example, the detection of a fusion transcript or a pathogen

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

•  The analysis of restriction fragment length polymorphism (RFLP) assays (see RFLP section) generally requires agarose gel electrophoresis • The technique is used routinely in molecular biology for the analysis of recombinant DNA experiments and can be used for the purification of probes for in situ hybridization (ISH) and blot hybridization by excision of DNA fragments from a gel followed by mini-­column purification 

Pulsed-­Field Gel Electrophoresis • PFGE is an electrophoretic method for the improved resolution of high-­ molecular-­ weight DNA. Standard agarose gel electrophoresis separates DNA under a constant and uniform electric field. Under these conditions, DNA greater than 50 kb is poorly distinguished from DNA in the size range of 30 to 50 kb • The improved resolution of PFGE is accomplished by alternating the direction of the electrical field. In the simplest approach, the direction of field is constantly reversed so that the DNA spends some time moving backward. More refined techniques alternate the field so that the DNA moves through the gel in a zigzag pattern • Applications • PFGE can be used for the identification of microorganismal strains such as Escherichia coli O157:H7, Salmonella, Shigella, Listeria, or Campylobacter. High-­ molecular-­ weight DNA extracts (from culture) are digested with a restriction enzyme (RE) (see the Southern blotting section). The PFGE electrophoretic DNA “fingerprint” helps to identify the infective strain. The Centers for Disease Control and Prevention (CDC) maintains databases of PFGE standardized molecular subtypes for the identification of microorganisms • In combination with Southern blot analysis, PFGE can be used in the evaluation of autosomal dominant ataxia 

Polyacrylamide Gel Electrophoresis • Polyacrylamide is produced from monomers of acrylamide in a reaction initiated by free radicals generated by reduction of ammonium persulfate by TEMED (N,N,N′,N′-­ tetramethylene diamine). These linear strands of polyacrylamide form into a gel after cross-­ linkage by N,N′-­ methylenebisacrylamide. The higher the concentration of acrylamide the finer the resolution of DNA fragments. The advantage of polyacrylamide over agarose is that size differences at the base pair bases can be distinguished (e.g., 5% polyacrylamide gel resolves DNA fragment sizes in the range ∼80 to 500 bp; a 15% polyacrylamide gel resolves DNA fragment sizes in the range ∼25 to 150 bp) • Polyacrylamide “slab” gels are set between glass plates and run under a buffer in a vertical gel apparatus. Samples and DNA ladder plus loading dye, are loaded into wells and DNA fragment progression is estimated from the dye migration • Polyacrylamide gels may be stained for DNA with ethidium bromide, SYBR dyes and the like, or silver nitrate. PCR amplicons can be detected by autoradiography

27

when one primer is labeled with a radioisotope; the gel is dried then fastened with an x-­ray film in a cassette. Gel/image analysis apparatuses fitted with a laser-­ induced fluorescence (LIF) detector can be used to analyze PCR amplicons that include a fluorophore-­ labeled primer • Applications •  End-­ point PCR fragment analysis where fragment size differences are slight • The discrimination of PCR fragments of identical size (bp) but containing different sequences (mutations or variants) can be performed by several polyacrylamide gel–based techniques, including single-­ stranded conformational polymorphism (SSCP) analysis, and DGGE •  Polyacrylamide slab gels are used for sequencing assays and for microsatellite marker-­ based assays using autoradiography or fluorescently labeled fragments 

Capillary Gel Electrophoresis • CGE supports automated DNA sequencing and fragment analyses •  The technique involves the electrophoresis of DNA molecules through a solution phase polyacrylamide-­ based gel matrix contained within a 20-­to 50-­ inch silica capillary with a 25-­to 100-­μm bore • Proximal to the anode end of the capillary is a LIF detector. The light emissions from fluorescence labeled DNA fragments (e.g., by way of PCR using a fluorescence-­ labeled primer) are registered by the LIF detector, which can detect up to four different emission wavelengths •  Given the LIF detector location, all DNA fragments are sieved through the complete length of gel prior to detection. This supports the accumulation of data having high resolution; single base differences can be distinguished. Emission data are recorded using dedicated computer software that integrates the data collected during the time course of the electrophoresis. The final data are presented in terms of peak heights and areas (relative to a fluorescence emissions scale [representing DNA amplicons/fragments]) and with reference to a DNA size marker • Applications • CGE is widely used for sequencing and microsatellite assay data analyses 

BLOT HYBRIDIZATION METHODS Southern Blotting • Background • Dr. E.M. Southern developed the Southern blot technique in 1975 as a method for transferring DNA out of an agarose slab gel onto a solid support (a nitrocellulose or nylon membrane) •  The method involves the use of restriction endonucleases to cut (restrict) genomic DNA into differently sized fragments that are size-­ fractionated by gel electrophoresis. After transfer, the membrane is hybridized with a labeled probe specific to the target sequence of interest

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

28

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology Genomic DNA

 Large

1

2

3

Membrane Gel

Restriction enzyme digest

Figure 1.18  Southern blot analysis.  Following agarose gel electrophoresis of restriction endonuclease-­treated genomic DNA, alkali-­denatured DNA is transferred onto a nylon membrane by capillary action. The recovered membrane is screened for target sequences by hybridization with a labeled probe. (Modified from Leonard DGB, ed. Diagnostic Molecular Pathology. Philadelphia: WB Saunders; 2003.)

Gel electrophoresis

DNA transfer to membrane

Small 

Membrane (blot) 1 2 3

Salt solution 1 2

3

Hybridization with labeled probe

• Can be used to detect chromosomal rearrangements, DNA amplifications, deletions, and loss of heterozygosity and to assess clonal status • The technique (Figure 1.18) generally requires relatively large quantities of high-­ molecular-­ weight DNA (5 to 10 μg per restriction endonuclease-treated sample) • Applications • The Southern blot method is widely used in RFLP applications. The number of restriction sites for a given restriction endonuclease in the site of a gene may vary because of normal (polymorphic) variation between individuals or due to sequence mutations. These differences can result in altered restriction fragment patterns. Altered fragment sizes between individuals may also result when the restriction fragment contains a variable number of tandem repeat (VNTR) sequences. VNTR regions contain microsatellite or minisatellite repeats comprising approximately less than 6 bp or approximately 10 to 100 bp repeat sequences, respectively. Differences in the number of these repeat units may be detectable as altered fragment sizes (see Figure 1.18). The size differences may be simple polymorphisms or can reflect a disease condition. For example, the (CGG)n microsatellite trinucleotide in the FMR1 gene is repeated approximately 5 to 44 times among normal individuals, whereas in patients with fragile X syndrome the number of repeats is expanded more than 230 up to thousands of times. The detection of this expansion by Southern blot analysis also involves the use of a methylation-­sensitive restriction endonuclease that fails to cut a restriction site that is unmethylated in normal individuals but methylated in fragile X syndrome patients • Despite the requirement for relatively large quantities of DNA and time-­consuming procedures, Southern blotting may have advantages over PCR in certain applications. For example, when available sequence data are insufficient to design PCR primers specific to the site of a chromosomal rearrangement or where

Stack of paper towels

Bands represent gene location

Wash Probe detection

Film

competition from normal cells in a sample will mask the detection of an anomaly by PCR •  The detection of clonality by Ig gene rearrangements in B-­cell lymphoproliferative disorders can aid the diagnosis of minimal residual disease. PCR tests for B-­cell clonality may have a false-­negative rate of up to 30%, and the “gold standard” test for the detection of Ig clonal rearrangements may be Southern blot analysis. Clonality can be inferred from a comparison of normal and B-­ cell tumor tissue restriction fragment sizes following hybridization with a region of the Ig gene. The normal sample will demonstrate a single band representing the germline Ig gene, whereas a B-­cell tumor also demonstrates a unique band size as a consequence of gene rearrangement and altered restriction site position(s) • Southern blotting can also have an advantage over PCR in the detection of fragile X syndrome. PCR can be used in this diagnosis by designing primers that include the (CGG)n repeat unit within the amplicon. However, especially when the expansion involves hundreds to thousands of (CGG) repeats, PCR amplification can be problematic and may fail •  Southern blotting can be combined with PCR. Hybridization with a target-­ specific probe can be used to confirm. PCR amplicons represent the target and are not anomalous products resulting from incidental primer annealing events. PCR amplicon RFLP analyses may also be performed by Southern blotting 

Northern Blotting •  Northern blotting is used in the analysis of mRNA expression. mRNA constitutes up to 5% of the total cellular RNA. Extracted mRNA is denatured with formaldehyde or glyoxal to prevent the formation of secondary RNA structures. Digestion of the RNA into smaller fragments is not required as native mRNA fragment sizes range from approximately 300 to 12,000 nucleotides; the average size is 1000 to 3000 nucleotides. Following

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

Dot Blotting •  Dot blot hybridization involves spotting denatured DNA or RNA onto a membrane for hybridization with a labeled probe. The method allows confirmation that a genomic DNA or RNA sample or a PCR product is positive for the probe target. The method can also be used semiquantitatively to assess or compare target sequence load within a sample • Reverse-­line dot blot hybridization • An alternative approach to the standard dot-­blot is to fix an array of unlabeled probes onto the membrane and hybridize this with labeled nucleic acids/ PCR products • Applications • A variety of “line probe assays” (LiPAs) have been developed. These include screening tests for ApoE mutations, cystic fibrosis mutations, hepatitis B virus (HBV) and human papillomavirus (HPV) genotyping, human leukocyte antigen (HLA) typing, and mycobacteria detection • Outside the United States, Conformité Européenne (CE)-­marked LiPA tests are available for PCR-­based HPV clinical screening • The SPF10-­INNO LiPA HPV Genotyping Test (Innogenetics, Ghent, Belgium) allows the specific genotyping of 25 different HPV types • The Roche Linear Array (LA) HPV genotyping test (Roche Molecular Systems, Inc., Branchburg, NJ) detects 37 different HPV types • With both systems, biotinylated PCR product is hybridized with a membrane strip affixed with a line of HPV genotype-­ specific probes. Detection of the PCR product label indicates the HPV genotype(s) for which the patient is positive 

AMPLIFICATION METHODS The Polymerase Chain Reaction • Background • PCR (Figure 1.19) is a method for the in vitro amplification of DNA involving automated cycles of denaturation, annealing, and extension/synthesis performed in a thermocycler • End-­point PCR (first-­generation PCR) consists of performing 30 to 50 cycles of amplification followed by analysis of the PCR product • In real-­time quantitative (q) PCR (second-­generation PCR) continuous cycle-­by-­cycle monitoring of product accumulation is performed by measuring fluorescent signal generated from the amplicons

5 3

3 5 DNA denaturation (95°C)

5 3 5 5 Primer 1 3 3 5 3 5 3

Primer 1

3

5 Primer annealing (40°−60°C) 3 3 5 Primer 2 5 DNA synthesis (72°C) 3 5 Primer 2 3 5 Repeat cycle 30−50 times

Cycle 1

agarose gel electrophoresis, RNA is transferred to a membrane by a capillary, vacuum, or electrotransfer process and the membrane is hybridized with a labeled probe to the gene target. The resulting data indicate whether the gene is overexpressed or underexpressed, or if an abnormally sized transcript is expressed. The method requires relatively large amounts of high integrity RNA, is time consuming, and requires a high level of laboratory skill, all of which limits the clinical utility of northern blotting 

29

109 −1015 PCR products

Cycle 2

Cycle 3

30−50 cycles

Figure 1.19  Polymerase chain reaction (PCR).  A PCR cycle consists of denaturation, primer annealing, and DNA synthesis or extension steps. Following the first PCR cycle, there is (theoretically) a per-­cycle doubling in the number of copies of the PCR product. (Modified from Leonard DGB, ed: Diagnostic Molecular Pathology. Philadelphia: WB Saunders; 2003.)

• In digital PCR (dPCR; third-­generation PCR), approximately 40 cycles of PCR are performed on a reaction tube containing 20,000 droplet partitioned reactions; each droplet is then assessed individually for fluorescent signal generated from PCR amplicons • Basic PCR method •  During the denaturation stage, sample specimen DNA is rendered to a single-­stranded form by heating to 94°C to 98°C •  In the annealing step, oligonucleotide primers hybridize with the target sequences they have been designed to complement. The annealing temperature depends on the deoxyribonucleoside triphosphate (dNTP) composition of the primers and is typically in the 40° to 60°C range •  During the extension step (72°C), the annealed primer/target DNA seeds the (5′ → 3′) synthesis by thermostable DNA polymerase of a new DNA strand • DNA amplification is accomplished by repetition of the denaturation, annealing, and extension cycle, 30 to 50 more times • The time period for each of the denaturation, annealing, and extension steps can vary from 10 seconds to greater than 1 minute and depends on reaction volume size, amplicon base composition and length, thermostable DNA polymerase activity (∼1000 bp are extended per minute), and thermal cycler hardware specifications •  The essential ingredients in a PCR include the following: • DNase/RNase free pure water: final PCR reaction volumes typically vary from 10 μL to 50 μL

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

30

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology



• Buffer: pH is typically maintained using a TRIS-­HCl– based buffer. Other ingredients include KCl, which can aid primer template annealing (K+ ions offset the repulsive force between negatively charged DNA strands), nonionic detergents, and bovine serum albumin (BSA) to aid Taq DNA polymerase enzyme stability • Magnesium cations: Mg2+ is an essential ingredient and stabilizes the interaction between the oligonucleotide primer, template DNA, and Taq DNA polymerase enzyme • dNTPs: 2′-­deoxyadenosine 5′-­triphosphate (dATP), 2′-­deoxycytidine 5′-­ triphosphate (dCTP), 2′-­ deoxyguanosine 5′-­triphosphate (dGTP), and thymidine 5′-­triphosphate (TTP also referred to as dTTP) • Oligonucleotide primers: typically 18 to 25 bases in length • Template DNA: the amount of sample in a reaction can range from 1 ng to 1 μg, with approximately 100 ng representing a standard quantity for many applications •  Thermostable DNA polymerase enzymes such as Taq DNA polymerase extracted from Thermus aquaticus isolated from a hot springs–dwelling bacterium of the Deinococcus-­Thermus phylum • PCR efficiency •  Optimization experiments are required to ensure PCR test efficiency approaches ideal efficiency and to avoid false-­negative data. Potentially, each component of the PCR setup can be manipulated for improved PCR sensitivity and specificity 

Polymerase Chain Reaction Contamination Control • The sensitivity of PCR incurs the potential defect of false-­ positive data due to the amplification of cross-­ contaminating DNA from an exogenous source. Strict measures are required from patient sample collection through to PCR assay to ensure authentic data and to avoid false-­positive data • Ideally, laboratory space should be arranged such that DNA sample extraction, PCR setup, and post-­ PCR manipulations all occur in physically distinct areas, and using PCR-­grade reagent aliquots, dedicated equipment, and laboratory coats specific for each area. PCR products from previous rounds of PCR represent the major potential source for contamination • Substituting dTTP with dUTP results in PCR amplicons that are degraded by uracil N-­glycosylase (UNG) allows the inclusion of a pre-­PCR incubation step with UNG. This prevents carry-­over of PCR amplicons from prior PCR assays (the major source of contamination) leading to false-­positive data 

Polymerase Chain Reaction Method Variations •  PCR technique is a highly adaptable technique, enabling its applicability in a wide range of research and clinical niches • Modifications centered on primer design/usage: • Multiplex PCR supports the simultaneous detection of more than one target by the use of multiple primer pair sets

• Consensus PCR can be used to amplify a single target that has variable sequences or multiple targets that have similar (common) sequences • Degenerate PCR is also used in the amplification of a variable sequence target and involves a primer design that incorporates alternative sequences at a particular primer base sequence • Nested PCR is a method for improved PCR sensitivity and specificity. Standard PCR is performed; the PCR product obtained is then used as DNA template for a second round of PCR with nested primers •  Amplification refractory mutation system (ARMS)/ allele-­specific PCR (AS-­PCR)/PCR amplification of specific alleles (PASA) supports sequence-­specific PCR by designing the 3′-­base at the end of a primer to match critical target • LA PCR stands for long and accurate PCR and allows the amplification of sequences 5 to greater than 20 kb in length 

Reverse Transcription Polymerase Chain Reaction • RT-­PCR (Figure 1.20) allows the investigation of RNA expression via PCR. Thermostable DNA polymerases require DNA as a substrate; the first step in RT PCR is thus the conversion of (DNA-­free) total RNA or mRNA into single-­ stranded complementary DNA (cDNA). The two most commonly used reverse transcriptase enzymes are the avian myeloblastoma virus (AMV) or Moloney murine leukemia virus (M-­MuLV) reverse transcriptases • In addition to the general determinants of standard PCR success, RT-­PCR efficiency depends on RNA sample quality and the effectiveness of the reverse transcriptase step 

Real-­Time Quantitative Polymerase Chain Reaction • In end-­point PCR, the final product obtained after 30 to 50 PCR cycles is the object of data interpretation. Although end-­point PCR can be semiquantitative, it is essentially a qualitative assay. qPCR/qRT-­PCR is used for the accurate quantification of a DNA or RNA (via cDNA) target in a sample •  Fluorescent DNA-­ binding dyes (e.g., SYBR green) or amplicon-­specific probes that hybridize to accumulating PCR product are used to monitor amplicon accumulation at each cycle of PCR; these strategies involve the use of TaqMan, Molecular Beacons, or Scorpions probes 

Digital Polymerase Chain Reaction • dPCR or droplet digital PCR (ddPCR) allows absolute quantification of a target sequence. This is in contrast to qPCR, where the quantification is relative to standard curve data derived from assays performed using known amounts of target copies • The procedure involves setting up a 20-­μL PCR, which is then partitioned into 20,000 droplets (i.e., 20,000 self-­contained individual PCRs in one tube). Target and nontarget sequences are randomly distributed among the droplets. After 40 cycles of PCR, droplets are analyzed one by one for the detection of fluorescence

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology 3

Primer 1

5

5

3 RNA

Reverse transcription

cDNA synthesis by reverse transcriptase

5

3 5

5

3 5

Primer 2

RNA:cDNA hybrid

cDNA

3 Denature Anneal Synthesize

5

3 PCR Cycle 2

3

Primer 1

Denature RNA : cDNA hybrid Anneal primer Synthesize second cDNA strand

PCR Cycle 1

31

5

3

3

5

5 3

30−50 PCR cycles

3 5 3 5

5 3 5 3

released by an amplicon. The fraction of fluorescence positive droplets supports quantification calculation based on Poisson distribution analyses •  The technique enables the highest analytic sensitivity of any molecular method, allowing the detection of rare targets in a complex background with sensitivity down to one target copy in 1015 bases. The method can be used to investigate gene copy number variation, mutation detection, gene expression, and viral load 

Polymerase Chain Reaction Tests in Pathology Practice • PCR is highly adaptable for use in a wide variety of clinical applications including the following: • Infectious pathogens detection • Genetic diseases diagnosis • Hematologic diseases diagnosis (e.g., chimeric RNA transcripts detection such as the bcr-­abl translocation pro­ duct characteristic of chronic myelogenous leukemia) • Sarcoma diagnosis by signature gene fusion detection (e.g., EWS/FLI1 in Ewing sarcoma/peripheral neuroectodermal tumor) •  Solid tumor characterization (e.g., hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome mutation analyses) • Identity testing • Detection of circulating tumor or pathogen nucleic acid signatures • PCR-­based tests that have been approved and cleared by the US Food and Drug Administration (FDA) include numerous microbial assays (e.g., avian flu [qRT-­PCR], Bacillus anthracis [qPCR], Chlamydia trachomatis, warfarin sensitivity [qPCR], enteroviral meningitis

Figure 1.20  Reverse transcription polymerase chain reaction (RT-­PCR).  Complementary DNA (cDNA) is synthesized from an RNA sample by a reverse transcriptase enzyme; thereafter the cDNA is available for PCR amplification. (Modified from Leonard DGB, ed. Diagnostic Molecular Pathology. Philadelphia: WB Saunders; 2003.)

[qRT-­PCR], Francisella tularensis [qPCR], HBV, hepatitis C virus (HCV), HPV, methicillin-resistant Staphylococcus aureus (MRSA) screening [qPCR], West Nile virus [qPCR], and Yersinia pestis [qPCR]) and a number of genetic tests including BRAC1 and BRAC2 mutation screening in ovarian cancer, BRAF V600E mutation screening in melanoma, EGFR gene deletion an mutation screening in non–small cell lung cancer, and KRAS mutation screening in colorectal cancer patients • ddPCR clinical applications include newborn screening for severe combined immunodeficiency syndrome (SCID), and spinal muscular atrophy carrier screening • Non–FDA-­approved tests are also in widespread clinical diagnostics usage including: • Infectious pathogen detection • Genetic diseases diagnosis • Bloom syndrome mutation analysis, Fabry disease, Factor IX gene, familial amyloidosis, familial factor IX gene familial amyloidosis, familial dysautonomia, fragile X syndrome, Gaucher disease, Fanconi anemia, galactosemia hemochromatosis, Prader Willi/Angelman, spinobulbar muscular atrophy, Tay-­Sachs disease • Tumor characterization/diagnosis • Adenovirus (qPCR), Bartonella henselae, BK virus, cytomegalovirus (CMV), enterovirus, HBV, Human Herpesvirus 6 (HHV-6), human metapneumovirus (hMPV), JC virus, Legionella RNA, Lyme disease, malaria, parvovirus B19, varicella-­ zoster virus •  BCR/ABL (qRT-­ PCR), desmoplastic small-roundcell tumor (DSRCT) (RT-­ PCR), Ewing sarcoma (RT-­ PCR), HNPCC, JAK2 V617F mutation detection,

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

32

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

microsatellite instability, PML/RARA (qPCR), RET/PTC rearrangements (RT-­PCR), synovial sarcoma (RT-­PCR) • The Oncotype DX breast cancer assay is a qRT-­PCR array test that screens 21 genes (16 tumor-­related genes, 5 reference genes). The test is applicable to patients with stage I, II, or IIIa invasive breast cancer that is estrogen receptor positive (ER+) and human epidermal growth factor receptor negative (HER2−). Based on the gene expression profile, a recurrence score (RS) is calculated indicating prognosis and treatment path. The Oncotype DX DCIS test screens for seven cancer-­related and five reference genes • Several automated platforms incorporate PCR amplification steps •  Roche COBAS 4800 system performs automated DNA extraction and is capable of multiplex PCR (using TaqMan fluorescent probes); for example, the FDA-­approved COBAS HPV test performs a threefold screening assay: HPV-­16, HPV-­18, and 12 other high-­ risk HPV types; in addition, a β-­globin PCR assay is performed to confirm amplifiable quality DNA was extracted from a patient sample. COBAS platforms are also available for HBV, HCV, and human immunodeficiency virus (HIV) detection • Luminex xTAG technology combines multiplex PCR, followed by multiplexed primer extension assays that incorporates labeled dNTPs. The extended products are captured on fluorescent microspheres. Coincident dual detection of the microsphere and extension product fluorescent signatures confirms detection of a given target in a specimen. The methodology is FDA cleared for screening cystic fibrosis, respiratory viruses, gastrointestinal pathogens and for polymorphisms associated with CYP2D6 drug metabolism and has also been developed for numerous other applications • AutoGenomics’ BioFilmChip microarray assay multiplexes ARMS-­type PCR of target sequences. Fluorescent dCTP is incorporated into PCR amplicons. A successfully amplified target is immobilized by sequence-­ specific capture probes embedded in a fluorescent-­labeled hydrogel matrix. Coincident dual detection of the hydrogel and amplicon fluorescent signatures confirms detection of a given target in a specimen. The assay is FDA-­cleared for CYP2C19 and warfarin metabolism sensitivity, as well as for coagulation factor (factor II, factor V Leiden) assessments •  The GenMark Dx eSensor XT-­ 8 assay involves multiplex PCR of target sequences followed by incubation with exonuclease III, which results in single-­ stranded amplicon DNA. A hybridization reaction is then performed with a ferrocene labeled probe; hybridization occurs if the target sequence has been amplified from the patient specimen. Next, the hybrid solution is pumped through a microfluidics cartridge containing a series of gold disk electrodes. Each electrode is tagged with a unique capture probe. Voltage is applied to the cartridge; a current will be detected at the electrode at which probe-­ hybridized-­ amplicon has been immobilized by the capture probe. The assay is FDA cleared for investigation of cystic fibrosis, respiratory viruses, thrombophilia, and warfarin sensitivity

•  Several assays combine PCR with other molecular manipulations •  Multiplex ligation-­ dependent probe amplification (MLPA) is a proprietary technology of MRC-­Holland, Amsterdam, The Netherlands, which allows multiplex assaying of disease biomarkers • The technique involves two steps: ligation followed by PCR. First, denatured specimen DNA is hybridized overnight with multiple target-­specific primer pairs; for example, primers could be specific for a variety of alternative mutations. If two oligonucleotides hybridize directly adjacent to each other, they can be ligated to form one continuous DNA molecule by the enzyme DNA ligase. At the 5′ end of the forward oligonucleotide is a universal PCR primer sequence “X” that does not hybridize to specimen DNA sequences. At the 3′ end of the reverse oligonucleotide is a second universal primer sequence “Y.” This second primer also contains a nonhybridizing “stuffer sequence” of variable length intermediate between “Y” and the 5′ sequence that binds to target. The length of the “stuffer sequence” is linked to the specific target that the oligonucleotide can hybridize with. The total length of the first oligonucleotide is 50 to 60 bp and the second oligonucleotide is 60 to 450 bp in length; PCR amplified products range from 130 to 450 bp in length • PCR is then performed on the ligation product using two primers complementary to X and Y. The length of the PCR product will depend on which (if any) oligonucleotide pairs initially hybridized and were ligated; that is, the length of the “stuffer sequence” indicates which bio-target was present in the sample • Applications • MLPA is applicable for the detection of mutations/ SNPs, deletions, and amplifications. Nonamplification with a particular probe indicates the presence of a mutation, Single nucleotide polymorphism (SNP), or deletion; “excess” amplification demonstrates an amplification event •  MLPA tests (none are currently FDA cleared/ approved) are available for the diagnosis of a large variety of pathologic conditions including these: • Familial cancers: ataxia telangiectasia, BRCA1 and BRCA2 testing, colon polyposis (APC), MLH1/ MSH1/MSH2/MSH6/PMS2 testing, Li-­ Fraumeni syndrome, multiple endocrine neoplasia, neurofibromatosis types 1 and 2, Peutz-­ Jeghers syndrome, retinoblastoma, von Hippel-­ Lindau syndrome, Wilms tumor •  Tumor analyses: melanoma (uveal), mismatch repair genes, neuroblastoma, oligodendroma, PTEN, rhabdoid tumors, tumor suppressor genes • Phosphatase and tensin homolog (PTEN) Prenatal and postnatal screening: aneuploidy (Down, Edwards, Patau), mental retardation syndromes, microdeletion syndromes (Prader-­ Willi/Angelman; RETT/Xq28 duplication and others) • Pharmacogenetics: DPYD deficiency • Specific syndromes: cystic fibrosis, Turner/Klinefelter, typical uremic, Wilson disease • PCR/oligonucleotide ligation assay (OLA) • MLPA involves an oligonucleotide ligation step followed by rounds of PCR, whereas PCR/OLA involves

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 1  —  Special Diagnostic Techniques in Surgical Pathology

multiplex PCR (up to 40 cycles) followed by cycles (up to 10) of multiplex ligation amplification of oligonucleotides to PCR product • PCR/OLA is FDA cleared for cystic fibrosis gene mutation panel screening (CELERA, Alameda, CA) 

33

infections. FDA-­approved TMA assays for high-­risk type HPV E6/E7 RNA, for HCV, and for gastrointestinal infectious agents have also been developed. There is also an FDA-­approved test for prostate cancer gene 3 (PROGENSA PCA3) mRNA detected from urine samples 

NANOSTRING TECHNOLOGY

Nucleic Acid Sequence-­Based Amplification

•  NanoString technology (NanoString Technologies, Seattle, WA) is used for RNA expression analyses. Total RNA (extracted from >10,000 cells) is mixed with two DNA oligonucleotide probes: a 3′ biotin end–labeled target-­ specific capture probe, and a target-­ specific reporter probe labeled at the 5′ end with a series of differently colored fluorescent tags; the tag color order acts as a “bar code” target-­specific identifier of the sequence detected by the probe. If the target sequence is present in the RNA extract, both probes will hybridize. •  The tripartite probes/target complex is purified and then passed across a NanoString cartridge coated with streptavidin. Streptavidin has a high affinity for biotin and immobilizes hybrid targets. A voltage is applied across the cartridge and causes the negatively charged nucleic acid hybrids to linearize over the cartridge surface. The detected fluorescent tag codes allow quantification of gene target expression in the sample. • The assay is highly multiplexable and can screen for the detection of up to 800 targets. The assay need not include amplification steps; if specimen is limiting (3 months duration for DLE • Well-­defined lesions of DLE occur in 15% of patients with subacute lupus erythematosus

Selected References Arps DP, Patel RM. Lupus profundus (panniculitis): a potential mimic of subcutaneous panniculitis-­like T-­cell lymphoma. Arch Pathol Lab Med. 2013;137:1211–1215. Biazar C, Sigges J, Patsinakidis N, Ruland V, et al. Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev. 2013;12:444–454. Jerdan MS, Hood AF, Moore GW, et al. Histopathologic comparison of the subsets of lupus erythematosus. Arch Dermatol. 1990;126:52–55.

Dermatomyositis Clinical Features  •  Connective tissue disease characterized by inflammatory myositis involving the proximal muscles and cutaneous lesions consisting of a heliotrope rash (violaceous, slightly edematous periorbital patches involving the eyelids), Gottron papules (discrete red-­purple papules over bony prominences of knuckles, knees, and elbows), and photodistributed erythematous-­ edematous lesions over the upper chest and back • The disease has two peaks, one in childhood and one between the ages of 45 and 65 years  Histopathology  •  Histopathologic changes of the erythematous-­ edematous lesions of the skin include epidermal atrophy, vacuolar interface change with scattered individually necrotic keratinocytes, a sparse superficial perivascular lymphocytic infiltrate (Figure 2.9) • Mild increase in interstitial mucin • Subepidermal fibrin deposits can be seen • Gottron papules—epidermal hyperplasia in addition to mild interface change • Panniculitis and calcification of the subcutaneous tissue may be seen at a later stage  Special Stains and Immunohistochemistry  • PAS stain confirms interface change and a thickened basement membrane zone  Other Techniques for Diagnosis  • DIF—may show complement (C5b-­C9) around blood vessels 

Figure 2.9  Dermatomyositis.  Vacuolar alteration of the basal cell layer, epidermal atrophy, and a mild perivascular inflammatory cell infiltrate are seen.

Differential Diagnosis  • Subacute Cutaneous Lupus Erythematosus • Histopathologic features identical to those of dermatomyositis, clinical correlation including evaluation for myositis critical • Positive lupus band test helpful (especially in early stages of dermatomyositis when the muscular weakness is not apparent) PEARLS • P  auci-­inflammatory interface dermatitis with a minimal increase in dermal mucin • Histopathologic reaction pattern that of a subtle interface dermatitis and is therefore not diagnostic • Clinicopathologic correlation key to making the histopathologic diagnosis

Selected References Callen JP. Dermatomyositis. Lancet. 2000;355:53–57. Mendese G, Mahalingam M. Histopathology of Gottron’s papules— utility in diagnosing dermatomyositis. J Cutan Pathol. 2007;34:793– 798. Sontheimer RD. Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol. 1999;11:475– 482.

Epidermal Spongiosis Spongiotic Dermatitis Clinical Features  • Spongiotic dermatitis refers to reaction pattern characterized histologically by the presence of intercellular edema (spongiosis) in the epidermis • Group includes allergic contact dermatitis, photoallergic dermatitis, nummular dermatitis, atopic dermatitis, dyshidrotic dermatitis, and Id reaction • Allergic Contact Dermatitis • Most commonly caused by poison ivy, nickel, and rubber compounds, presents with pruritic, edematous, erythematous papules and occasional vesicles usually within 1-­3 days of exposure

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

50

Chapter 2  —  Skin and Adnexal Structures

• Photoallergic Dermatitis • Due to topical application (photocontact) or ingestion of an allergen • Presents with pruritic and erythematous papulovesicular lesions on sun-­exposed skin; usually on face, arms, and neck • Nummular Dermatitis • Disease of unknown etiology characterized by coin-­ shaped, pruritic, erythematous, scaly, crusted plaques on the exterior aspects of extremities • Atopic Dermatitis • Inherited chronic, pruritic, scaly eruption affecting face and extensor aspects of extremities in children • Dyshidrotic Dermatitis

•  Characterized by numerous pruritic vesicles along sides of fingers and toes and palms and soles • Autoeczematization or Id Reaction • Sudden localized or generalized eruption of pinhead-­ sized vesicles developing in association with a defined local dermatitis or with infection • Most common cause is a remote dermatophyte infection  Histopathology  • Three distinct reaction patterns—acute, subacute, and chronic • Acute spongiotic dermatitis • Spongiotic vesicles with minimal acanthosis (Figure 2.10A)

A

B

C

D

Figure 2.10  Spongiotic dermatitis.  A, Marked epidermal spongiosis with formation of spongiotic vesicles and a superficial perivascular mixed inflammatory cell infiltrate are seen. B, Higher-­power view shows abundant eosinophils within the spongiotic vesicle, which favors a diagnosis of contact dermatitis. C, Seborrheic dermatitis. Follicle-centered, “shoulder” parakeratosis [arrow]. D, Pityriasis rosea. “Mound­like” parakeratosis and a mild superficial perivascular lymphoid cell infiltrate and extravasated red cells.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

51

•  In allergic contact dermatitis, eosinophils may be present in the vesicles (Figure 2.10B) • Mild papillary dermal edema and a superficial perivascular lymphohistiocytic inflammation are present • Subacute spongiotic dermatitis • Parakeratosis with plasma, mild to moderate spongiosis, epidermal hyperplasia, and superficial perivascular lymphohistiocytic infiltrate • Chronic Spongiotic Dermatitis •  Hyperkeratosis, acanthosis with hypergranulosis, minimal spongiosis, and papillary dermal fibrosis  Special Stains and Immunohistochemistry  •  PAS stain useful in excluding dermatophytosis with spongiosis  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Seborrheic Dermatitis • Histopathology varies with age of the lesion, follicle-­ centered, “shoulder” parakeratosis (Figure 2.10C) and a mild superficial perivascular lymphoid cell infiltrate with admixed neutrophils • Pityriasis Rosea •  “Moundlike” parakeratosis (Figure 2.10D), mild spongiosis (only in the “herald patch”), mild superficial perivascular lymphoid cell infiltrate, and extravasated red cells • Identical changes may be seen in superficial form of erythema annulare centrifugum • Spongiotic Drug Eruptions and Insect Bite Reactions • Deeper extension of the inflammatory infiltrate with admixed eosinophils • Psoriasis •  Chronic spongiotic dermatitis (lichen simplex chronicus) may resemble psoriasis but lacks confluent parakeratosis with neutrophils and thinning of suprapapillary plates PEARLS • E czema is a nonspecific term used clinically to describe erythematous vesicular lesions with scaly crust that show spongiotic dermatitis on histology • Three distinct reaction patterns—acute, subacute, and chronic • Histopathology typically varies with age of the lesion • Several entities can exhibit the same reaction pattern

Figure 2.11  Incontinentia pigmenti.  Intraepidermal spongiosis, dyskeratosis, and collections of eosinophils both within the epidermis and in the dermal inflammatory cell infiltrate are seen.

Incontinentia Pigmenti Clinical Features  • An X-­linked–dominant dermatosis that affects mostly females • Characteristic cutaneous manifestations seen at birth include crops of vesicles and bullae on extremities arranged in a linear or whorled pattern •  Lesions heal with hyperkeratosis and verrucous epidermal hyperplasia; the verrucous lesions heal with streaks and whorls of hyperpigmentation that are later replaced by faint hypochromic patches  Histopathology  •  Vesicular stage—characterized by marked epidermal spongiosis with eosinophils, individually dyskeratotic keratinocytes, and whorls of squamous cells with central keratinization (Figure 2.11) • Verrucous stage—characterized by hyperkeratosis, verrucous epidermal hyperplasia, individually dyskeratotic keratinocytes, and occasional eosinophils •  Hyperpigmented stage—characterized by numerous melanophages in the superficial dermis •  Hypopigmented stage—characterized by epidermal atrophy, decreased melanin in the basal cell layer, and absence of adnexae  Special Stains and Immunohistochemistry  • Noncontributory 

Selected References

Other Techniques for Diagnosis  • Noncontributory 

Ackerman AB, Chongchitnant N, Sanchez J, et al. Histologic Diagnosis of Inflammatory Skin Diseases. Baltimore: Williams & Wilkins; 1997. Ackerman AB, Ragaz A. A plea to expunge the word “eczema” from the lexicon of dermatology and dermatopathology. Am J Dermatopathol. 1982;4:315. Weedon D. Skin Pathology. 2nd ed. New York: Churchill Livingstone; 2002:112.

Differential Diagnosis  • Eosinophilic Spongiosis • Seen in a spectrum of unrelated entities that include allergic contact dermatitis, precursor lesions of pemphigus and bullous pemphigoid; clinical history essential in differentiation

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

52

Chapter 2  —  Skin and Adnexal Structures

• Epidermal Nevus •  Verrucous stage of incontinentia pigmenti may resemble epidermal nevus • Postinflammatory Pigmentary Alterations • Hyper-­and hypopigmented stages of incontinentia pigmenti resemble postinflammatory pigmentary changes PEARLS • H  istopathology typically varies with age of the lesion with four distinct histopathologic reaction patterns • Several entities can exhibit the same reaction pattern, clinicopathologic correlation essential in making a conclusive diagnosis • Eosinophilic chemotactic activity has been shown in the blister fluid of patients with incontinentia pigmenti • In up to 80% of patients, systemic findings with involvement of the central nervous system and eye may be seen; teeth abnormalities may be present • Extent of systemic involvement determines the clinical course • The genetic defect in the familial form has been traced to a mutation in the IKBKG-­gene (called NEMO) localized to Xq28 region

Selected References Ackerman AB, Chongchitnant N, Sanchez J, et al. Histologic Diagnosis of Inflammatory Skin Diseases. Baltimore: Williams & Wilkins; 1997. Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002;47:169–187. Ehrenreich M, Tarlow MM, Godlewska-­Janusz E, Schwartz RA. Incontinentia pigmenti (Bloch-­Sulzberger syndrome): a systemic disorder. Cutis. 2007;79:355–362.

Psoriasiform Dermatitis Psoriasis Clinical Features  • Chronic dermatosis of unknown etiology affecting up to 2% of the population • Males and females affected equally •  Variably sized, well-­ demarcated plaques covered by thick, silvery white scale that have a predilection for areas with trauma, including scalp, lumbosacral skin, and extensor surfaces of elbows and knees • Several manifestations that include localized or generalized pustular psoriasis, eruptive or guttate psoriasis, and erythrodermic psoriasis •  Involvement of nails, oral mucosa, and tongue can occur  Histopathology  • Confluent parakeratosis with neutrophils and neutrophilic microabscesses (intracorneal-­ Munro microabscesses and intraspinous-­spongiform pustule of Kogoj) • Hypogranulosis corresponding to zones of parakeratosis •  Regular (psoriasiform) epidermal hyperplasia with elongation of rete ridges and thinning of suprapapillary plates (Figure 2.12A)

• Dilated tortuous blood vessels in the dermal papillae • Mild superficial perivascular lymphocytic infiltrate • Pustular psoriasis—Exhibits the above but has in addition prominent Munro microabscesses and spongiform pustules of Kogoj (Figure 2.12B) • Guttate psoriasis—psoriasiform epidermal hyperplasia not as pronounced • Erythrodermic psoriasis-­histopathologic changes may be nonspecific • AIDS-­associated psoriasiform dermatitis • Distinguishing features from psoriasis include individually necrotic/dyskeratotic keratinocytes, absence of thinning of the suprapapillary plates, and presence of plasma cells (Figure 2.12C-­a,b)  Special Stains and Immunohistochemistry  •  PAS stain helpful in excluding dermatophytic infections (which also exhibit neutrophils in the stratum corneum)  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Subacute/Chronic Spongiotic Dermatitis Such As Allergic Contact or Nummular Dermatitis •  Presence of spongiosis and eosinophils helpful in differentiation • Dermatophyte Infection •  Presence of superficial fungal spores and hyphal forms diagnostic (typically evident in PAS stained sections) • Bacterial Impetigo •  Subcorneal pustule diagnostic of an early lesion (rarely biopsied) • Gram stain may demonstrate the bacteria • Pityriasis Rubra Pilaris • Alternating ortho and para-­keratotic scale, psoriasiform epidermal hyperplasia, follicular plugging with “shoulder” parakeratosis diagnostic • Contrasting features with psoriasis include absence of neutrophils in the stratum corneum and retention of the granular cell layer PEARLS • “ Dry” horn typical-­scale crust with neutrophils but no inspissated serum • Intraepidermal pustule not specific for psoriasis—can be seen in Reiter syndrome, AIDS-­associated psoriasiform dermatitis, acrodermatitis enteropathica, and glucagonoma syndrome • Basal keratinocyte atypia not uncommon and related to etiopathogenesis • Psoriatic arthritis is seen in about 15% of patients with psoriasis and characteristically involves terminal interphalangeal joints • Severe expression of psoriasis is seen in patients with AIDS who may present with extensive erythroderma, inverse psoriasis, and palmoplantar psoriasis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

A

53

B

Ca

100 µm

Cb

20 µm

Figure 2.12  A, Psoriasis. Confluent parakeratosis with collections of neutrophils, diminished granular layer, regular (psoriasiform) epidermal hyperplasia with thinning of suprapapillary plates, dilated blood vessels in the papillary dermis, and mild superficial perivascular inflammation are seen. B, Pustular psoriasis. Prominent Munro microabscess. C, AIDS-associated psoriasis. Scale crust with neutrophils, psoriasiform epidermal hyperplasia, absence of thinning of the suprapapillary plate [a], and numerous plasma cells [b].

Selected References De Mozzi P, Johnston GA, Alexandroff AB. Psoriasis. An evidence-­based update. Report of the 9th evidence-­based update meeting, 12 May 2011, Loughborough, UK. Br J Dermatol. 2012;166:252–260. Nestle FO. Psoriasis. Curr Dir Autoimmun. 2008;10:65–75. Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of psoriasis. Am J Dermatopathol. 1979;1:199.

Pityriasis Rubra Pilaris Clinical Features  •  Chronic follicular-­ based erythematous papular eruption of unknown etiology that progresses to form orange-­red scaly plaques containing islands of normal-­ appearing skin • Generalized erythroderma may occur with progression • Palmoplantar keratoderma and scales on the face and scalp not uncommon  Histopathology  •  Alternating orthokeratosis and parakeratosis in horizontal and vertical directions (“checkerboard pattern”) (Figure 2.13A and B)

• Psoriasiform epidermal hyperplasia with short rete and thick suprapapillary plates •  Follicular papules demonstrate “shoulder” parakeratosis and dilated follicular infundibula with follicular plugging • Acantholysis restricted to adnexal epithelium  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Psoriasis • Confluent parakeratosis with neutrophils and neutrophilic microabscesses, psoriasiform epidermal hyperplasia with hypogranulosis (granular cell layer is retained in pityriasis rubra pilaris) and basal keratinocyte atypia, thinning of suprapapillary plates (suprapapillary plates are thick in pityriasis rubra pilaris), and papillary dermal telangiectases are diagnostic features

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

54

Chapter 2  —  Skin and Adnexal Structures

A

B

Figure 2.13  Pityriasis rubra pilaris.  A, Alternating layers of hyperkeratosis and parakeratosis in both vertical and horizontal patterns, psoriasiform epidermal hyperplasia, and mild superficial perivascular inflammation are seen. B, High-­power view shows alternating hyperkeratosis and parakeratosis with a normal granular layer.

PEARLS “ •  Checkerboard” cornified layer distinctive • Acantholysis not uncommon but restricted to adnexal epithelium when present • “Shoulder” parakeratosis not specific to pityriasis rubra pilaris and can also be seen in seborrheic dermatitis

Selected References Barr RJ, Young EM Jr. Psoriasiform and related papulosquamous disorders. J Cutan Pathol. 1985;12:412–425. Mobini N, Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. In: Elder DE, Elenitsas R, Johnson BL Jr, et al., eds. Lever’s Histopathology of Skin. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:169. Piamphongsant T, Akaraphant R. Pityriasis rubra pilaris: a new proposed classification. Clin Exp Dermatol. 1994;19:134–138.

SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS Dermatitis With Minimal Epidermal Changes Lymphocytes Predominant Polymorphous Light Eruption Clinical Features  •  Recurrent pruritic papules and plaques that typically occur in young women mostly during summer, induced by ultraviolet radiation (UVR) • Eruption starts a few minutes to a few hours after exposure and lasts for hours to days • Extensor aspects of arms and upper chest are most frequently involved • Despite the diverse clinical presentation, within any one patient, only one clinical form is consistently manifested  Histopathology  • Epidermis is mostly unremarkable •  Prominent papillary dermal edema with occasional subepidermal separation and extravasated red cells • Superficial and deep perivascular, predominantly lymphocytic infiltrate (Figure 2.14A) 

Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Sweet Syndrome • Superficial and deep perivascular and interstitial predominantly neutrophilic infiltrate with abundant leukocytoclasia, prominent papillary dermal edema, and extravasated erythrocytes • Sweet Syndrome-­Like Arthropod Bite Reaction • Superficial and deep dermal inflammation with numerous eosinophils and prominent papillary dermal edema • Pernio • Interface change, superficial and deep dermal perivascular and periadnexal inflammation, increased dermal mucin, prominent papillary dermal edema and extravasated erythrocytes (Figure 2.14B) • Pityriasis Lichenoides, Acute Form • Parakeratosis with neutrophils, interface change with numerous individually necrotic keratinocytes, papillary dermal edema and extravasated erythrocytes • Cutaneous Lupus Erythematosus • Typically the subacute and tumid forms should be considered in the differential diagnosis •  Polymorphous light eruption lacks changes at the dermoepidermal junction, has less prominent periadnexal infiltrate, and lacks interstitial mucin deposits, features typically seen in cutaneous lupus • Papillary dermal edema is more prominent in polymorphous light eruption than in SCLE PEARLS • E xtravasated erythrocytes and prominent papillary dermal edema helpful histopathologic features but not specific for polymorphous light eruption • Extravasated erythrocytes and papillary dermal edema, also observed in pityriasis lichenoides acuta, pernio, Sweet syndrome

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

55

Chapter 2  —  Skin and Adnexal Structures

A

B

200 µm

Figure 2.14  A, Polymorphous light eruption. A superficial and deep perivascular lymphocytic infiltrate is associated with marked papillary dermal edema. B, Pernio. Interface change, superficial and deep dermal perivascular and periadnexal inflammation, increased dermal mucin, prominent papillary dermal edema, and extravasated erythrocytes.

Selected References Boonstra HE, van Weelden H, Toonstra J, van Vloten WA. Polymorphous light eruption: a clinical, photobiologic, and follow-­up study of 110 patients. J Am Acad Dermatol. 2000;42:199–207. Gruber-­Wackernagel A, Byrne SN, Wolf P. Polymorphous light eruption: clinic aspects and pathogenesis. Dermatol Clin. 2014;32:315– 334. Hasan T, Ranki A, Jansen CT, Karvonen J. Disease associations in polymorphous light eruption: a long-­term follow-­up study of 94 patients. Arch Dermatol. 1998;134:1081–1085.

Eosinophils Predominant Insect Bite Reaction (Papular Urticaria) Clinical Features  •  Allergic reaction induced by bites from mosquitoes, fleas, and bedbugs • Papules and papulovesicular lesions that are intensely pruritic and often excoriated  Histopathology  • Focal epidermal ulceration/excoriation, epidermis, and cornified layer may show changes of excoriation • A superficial and deep, V-­or wedge-­shaped, perivascular and interstitial, mixed inflammatory cell infiltrate containing numerous eosinophils characteristic (Figure 2.15A and B) • Chronic lesions—characterized by an exuberant inflammatory infiltrate with reactive follicles  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  •  Immunohistochemistry for B- and T-cell lymphoid markers helpful in confirming a reactive process in chronic lesions  Differential Diagnosis  • Eosinophilic Cellulitis/Wells Syndrome •  Pandermal, predominantly eosinophil-­ rich inflammatory infiltrate with “flame figures” (eosinophilic debris as a result of degranulating eosinophils) (Figure 2.15C)

• Dermal Hypersensitivity Reaction • Hypersensitivity reaction due to drugs while histopathologically indistinguishable from papular urticaria often tends to have an inflammatory infiltrate that is less dense and deep •  B-­ Cell Lymphoproliferative Disease/Follicle Center Lymphoma • Poorly defined follicles with aberrant expression of lineage-­specific immunohistochemical markers PEARLS • P  resence of a deep, predominantly eosinophil-­rich inflammatory infiltrate helpful but not diagnostic • Identification of foreign body material reminiscent of arthropod parts superficially or within the dermis diagnostic • Reactive lymphoid follicles may be a feature of chronic lesions (persistent arthropod bite reaction)

Selected References Ackerman AB, Chongchitnant N, Sanchez J, et al. Histologic Diagnosis of Inflammatory Skin Diseases: An Algorithmic Method Based on Pattern Analysis. 2nd ed. Baltimore: Williams & Wilkins; 1997:202. Gilliam AC, Wood GS. Cutaneous lymphoid hyperplasias. Semin Cutan Med Surg. 2000;19:133–141. Howard R, Frieden IJ. Papular urticaria in children. Pediatr Dermatol. 1996;13:246–249.

Interface Dermatitis Pityriasis Lichenoides Clinical Features  • Self-­limited cutaneous eruption of unknown cause that affects young adults and children • Two forms: • Acute or pityriasis lichenoides et varioliformis acuta (PLEVA), more severe form common in children and young adults

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

56

Chapter 2  —  Skin and Adnexal Structures

A

B

C

50 μm

Figure 2.15  Insect bite reaction.  A, A superficial and deep perivascular and interstitial infiltrate is arranged in a wedge shape. B, High-­power view shows frequent eosinophils within the infiltrate. C, Wells syndrome. Dense dermal infiltrate composed predominantly of eosinophils and “flame figures.”

• Chronic or pityriasis lichenoides chronica (PLC), the milder form more common in adults •  Transitional forms with changes between the two extremes occur •  In PLEVA, a papular, papulonecrotic, and occasionally vesiculopustular eruption occurs on the trunk and proximal extremities, usually resolves in a few weeks; crops of new lesions can continue to appear, and the disease process itself may have a chronic course • In PLC, recurrent crops of reddish-­brown papules with adherent scales occur on the trunk and extremities and resolve in a few weeks  Histopathology  • PLEVA • Parakeratosis and scale crust with neutrophils, vacuolar interface change, and individually necrotic keratinocytes (Figure 2.16A) •  Superficial and deep perivascular and lichenoid, predominantly lymphocytic infiltrate with atypical CD30+ lymphocytes • Lymphocytic vasculitis (especially in the ulceronecrotic variant)

• Papillary dermal edema and extravasated erythrocytes • PLC • Hyperkeratosis, parakeratosis, mild epidermal hyperplasia, interface change •  Superficial perivascular lymphohistiocytic infiltrate with extravasated erythrocytes (Figure 2.16B)  Special Stains and Immunohistochemistry  • Lymphocytes predominantly of the cytotoxic/suppressor T-­cell phenotype, presence of CD8+ T lymphocytes confirmed by immunohistochemistry • Immunohistochemical stain for CD30 may reveal scattered CD30+ cells in PLEVA  Other Techniques for Diagnosis  • DIF may reveal IgM and C3 deposits along the basement membrane zone  Differential Diagnosis  • Lymphomatoid Papulosis • Histopathologic features overlap with PLEVA • Wedge-­shaped inflammatory cell infiltrate composed of clusters of atypical CD30+ lymphocytes with admixed eosinophils

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

A

57

B

Figure 2.16  A, Pityriasis lichenoides acuta. Parakeratosis containing collections of neutrophils, vacuolar alteration of the basal cell layer, and patchy lichenoid and perivascular lymphocytic inflammation are seen. Scattered necrotic keratinocytes and extravasated red cells are present. B, Pityriasis lichenoides chronica. Hyperkeratosis, parakeratosis, mild epidermal hyperplasia, interface change, and a superficial perivascular lymphohistiocytic infiltrate with extravasated erythrocytes

• Vesicular Insect Bite Reactions • Superficial and deep dermal infiltrate with numerous eosinophils, papillary dermal edema and extravasated erythrocytes helpful histopathologic clues PEARLS D •  ensity of infiltrate in PLC is less than that observed in PLEVA • Despite the unifying presence of CD30+ lymphocytes in PLEVA and lymphomatoid papulosis they are pathogenetically distinct entities

Selected References Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad Dermatol. 2006;55:557–572. Ersoy-­Evans S, Greco MF, Mancini AJ, et al. Pityriasis lichenoides in childhood: a retrospective review of 124 patients. J Am Acad Dermatol. 2007;56:205–210. Kempf W, Kazakov DV, Palmedo G, et al. Pityriasis lichenoides et varioliformis acuta with numerous CD30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol. 2012;36:1021–1029.

FIXED DRUG ERUPTION Clinical Features  • Well-­defined, circumscribed patches occur at the same site in response to repeated intake of the drug • Lesions are slightly edematous and erythematous and may develop dusky centers and become bullous and heal with pigmentation • Increasing number of lesions can occur with each successive administration of the offending drug  Histopathology  • Interface dermatitis with scattered individually necrotic keratinocytes, (changes identical to those seen in EM) (Figure 2.17A) • Superficial and deep perivascular and lichenoid inflammatory cell infiltrate composed of lymphocytes, eosinophils, and occasional neutrophils

• Prominent pigment incontinence • Bullous variant resulting from more extensive epidermal necrosis has been described  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Erythema Multiforme •  Interface dermatitis with scattered individually necrotic keratinocytes and a predominantly superficial perivascular and patchy lichenoid lymphoid cell infiltrate •  Erythema Dyschromicum Perstans/Lichen Planus Pigmentosus •  Interface dermatitis with scattered individually necrotic keratinocytes; prominent pigment incontinence may be the only feature in older lesions (Figure 2.17B) PEARLS • H  istopathologic reaction pattern of interface dermatitis not specific or diagnostic and can be exhibited by several unrelated entities • Clinicopathologic correlation key to rendering correct diagnosis • Fixed drug eruptions occur most commonly with trimethoprim-­sulfamethoxazole, acetylsalicylic acid, and phenolphthalein

Selected References Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin. 1999;17:537–560, viii. Gru AA, Salavaggione AL. Lichenoid and interface dermatoses. Semin Diagn Pathol. 2017;34:237–249. Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006;45:897–908.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

58

Chapter 2  —  Skin and Adnexal Structures

A

B

Figure 2.17  A, Fixed drug eruption. Necrotic keratinocytes in the epidermis, vacuolar alteration of the basal cell layer, and patchy lichenoid inflammatory cell infiltrate that obscures the dermoepidermal junction are seen. Histologic changes are similar to those seen in erythema multiforme. B, Erythema dyschromicum perstans. Interface change with prominent underlying pigment incontinence.

Special Stains and Immunohistochemistry  • Immunohistochemical stain CD30 highlights the presence of clusters of CD30+ atypical lymphocytes  Other Techniques for Diagnosis  • Clonal rearrangement of T-­cell receptor gene may be present 

Figure 2.18  Lymphomatoid papulosis.  Dense perivascular and interstitial infiltrate consisting predominantly of lymphocytes. A significant number of the lymphocytes are large and contain enlarged hyperchromatic and irregular nuclei.

Differential Diagnosis  • Insect Bite Reaction • Superficial and deep perivascular and interstitial lymphoid cell infiltrate with numerous eosinophils • While reactive CD30+ lymphocytes can be seen these are typically single cells and not clustered • PLEVA • Histologic pattern of interface and lichenoid dermatitis similar to lymphomatoid papulosis •  Reactive CD30+ lymphocytes can be seen, however, these are typically scattered single cells and not clustered PEARLS

LYMPHOMATOID PAPULOSIS Clinical Features  • Multiple, small papules that are most often short lived, heal leaving oval scars, and are usually recurrent  Histopathology  •  Wedge-­ shaped superficial and deep perivascular and lichenoid lymphoid cell infiltrate with admixed eosinophils and scattered large and small atypical lymphocytes • Surface ulceration may be present • Reed Sternberg–like cells (in type A) and atypical lymphocytes with cerebriform nuclei resembling mycosis fungoides (in type B) are occasionally seen •  Rarely, a dense monomorphous infiltrate of atypical lymphocytes resembling anaplastic large cell lymphoma (type C) can be seen in association with typical clinical features of lymphomatoid papulosis (Figure 2.18) 

• P  resence of scattered CD30 positive cells not diagnostic of lymphomatoid papulosis as these may be present in reactive conditions • Presence of clusters of CD30 positive atypical lymphoid cells and a wedge-­shaped inflammatory infiltrate diagnostic for lymphomatoid papulosis • Clinical correlates of histopathologic subtypes of lymphomatoid papulosis are of no known relevance • Progression of lymphomatoid papulosis to large cell anaplastic lymphoma (CD30 positive) can occur, suggesting that lymphomatoid papulosis may represent the benign end in the spectrum of CD30-­positive T-cell lymphoproliferative disorders

Selected References Cerroni L. Lymphomatoid papulosis, pityriasis lichenoides et varioliformis acuta, and anaplastic large-­cell (Ki-­1+) lymphoma. J Am Acad Dermatol. 1997;37:287. Guitart J, Querfeld C. Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue. Semin Diagn Pathol. 2009;26:131–140.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

A

59

B

Figure 2.19  Secondary syphilis.  A, Parakeratosis with neutrophils, epidermal hyperplasia, and a dense bandlike inflammatory cell infiltrate that obscures the dermoepidermal junction. B, On high-­power view, the infiltrate contains a large number of plasma cells. LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma. Am J Dermatopathol. 1996;18:221–235. Werner B, Massone C, Kerl H, Cerroni L. Large CD30-­positive cells in benign, atypical lymphoid infiltrates of the skin. J Cutan Pathol. 2008;35:1100–1107.

Psoriasiform Dermatitis Secondary Syphilis Clinical Features  •  Hematogenous dissemination of causative organism, Treponema pallidum, results in a cutaneous eruption that can be macular, papular, papulosquamous, or, rarely, pustular • Associated constitutional symptoms such as fever and lymphadenopathy may be present; other manifestations include condyloma lata, syphilis cornee, lues maligna, and alopecia  Histopathology  • Patchy/confluent parakeratosis containing neutrophils • Regular psoriasiform epidermal hyperplasia (minimal in macular lesions, prominent in condylomata lata) with focal spongiosis (Figure 2.19A) • Interface change with scattered individually necrotic keratinocytes and papillary dermal edema •  Superficial and deep perivascular, periadnexal, and lichenoid lymphoplasmacytic infiltrate; plasma cells may be present around nerves (Figure 2.19B) • Infiltrate can be lymphocytic, lymphoplasmacytic, or lymphohistiocytic with rare granuloma formation  Special Stains and Immunohistochemistry  •  Silver stain (Warthin-­ Starry) may show spirochetes within the epidermis in one third of cases (not used anymore because of high background associated with this stain) • Immunohistochemistry with a monoclonal antibody to T. pallidum yields better detection rates (organisms are more often found in the dermis compared to the epidermis)  Other Techniques for Diagnosis  • Molecular detection of T. pallidum using PCR the gold standard 

Differential Diagnosis  • Mycosis Fungoides •  Shows psoriasiform lichenoid pattern similar to syphilis; however, in mycosis fungoides, atypical lymphoid cells are present within the dermal infiltrate and in the mildly spongiotic epidermis • Plasma cells are not frequent • Subacute and Chronic Spongiotic Dermatitis, Including Photoallergic Dermatitis •  May show some psoriasiform hyperplasia and spongiosis • In general, plasma cells are not prominent • Pityriasis Lichenoides • Can simulate secondary syphilis but shows predominantly a lymphocytic infiltrate without plasma cells •  Psoriasis and Psoriasiform Drug Eruption and AIDS-­ Associated Psoriasiform Dermatitis • Inflammatory infiltrate is typically not deep as in secondary syphilis and plasma cells not prominent • Suprapapillary plate thinning is not a feature of secondary syphilis • Sarcoid and Other Conditions With a Prominent Granulomatous Pattern • May appear similar to the granulomatous pattern of secondary syphilis •  Clinical correlation and serologic studies are necessary PEARLS • Increased plasma cells in the inflammatory infiltrate not a constant histopathologic feature • The organism is more commonly seen in the dermis and best detected with immunohistochemistry or PCR-­based techniques • Interface change with a perineural plasma cell-­rich infiltrate highly suggestive of secondary syphilis • An unusual variant of secondary syphilis is lues maligna, an ulcerative form characterized by thrombotic endarteritis of vessels in the deep dermis resulting in ischemic necrosis • Serologic tests are the most common method of diagnosing syphilis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

60

Chapter 2  —  Skin and Adnexal Structures

Selected References Hoang MP, High WA, Molberg KH. Secondary syphilis: a histologic and immunohistochemical evaluation. J Cutan Pathol. 2004;31:595–599. Jeerapaet P, Ackerman AS. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373. Müller H, Eisendle K, Bräuninger W, et al. Comparative analysis of immunohistochemistry, PCR and focus-­floating microscopy for the detection of T. pallidum in mucocutaneous lesions of primary, secondary and tertiary syphilis. Br J Dermatol. 2011;165:50–60.

NODULAR AND DIFFUSE DERMATITIS Neutrophils Predominant Sweet Syndrome Clinical Features  • Characterized clinically by fever, arthralgia, leukocytosis, and a cutaneous eruption of painful violaceous plaque­like or nodular lesions involving the extremities and face; truncal lesions are uncommon • Affects adults mainly • An underlying myeloproliferative disorder, most commonly acute myeloid leukemia or inflammatory disease and rarely solid tumors may be present •  Sweet syndrome–like eruption reported with many drugs  Histopathology  •  Dense, diffuse, upper dermal predominantly neutrophilic infiltrate, abundant leukocytoclasia, scattered lymphocytes, histiocytes, and eosinophils (Figure 2.20) • Marked papillary dermal edema, reactive endothelial cell atypia, and extravasated erythrocytes. Fibrinoid necrosis of vessel walls is not typically seen • Histiocytoid variant-­infiltrate composed of immature myeloid cells; lesional cells are not neoplastic  Special Stains and Immunohistochemistry  • Gram stain useful in excluding an infectious etiology such as cellulitis  Other Techniques for Diagnosis  • Noncontributory 

Figure 2.20  Sweet syndrome.  Diffuse dermal infiltrate consisting predominantly of neutrophils and extravasated red blood cells. Intact blood vessels help to differentiate this from leukocytoclastic vasculitis.

Differential Diagnosis  • Leukocytoclastic Vasculitis • Vascular damage with fibrin deposition in the vessel wall seen in leukocytoclastic vasculitis is not a feature of Sweet syndrome • Pyoderma Gangrenosum • Inflammatory infiltrate (predominately neutrophilic) is deeper and denser than in Sweet syndrome • Surface ulceration, foci of folliculitis, and secondary vasculitis may be evident • Other Neutrophilic Dermatoses •  Behçet disease (pathergic lesion), bowel-­ associated dermatosis-­ arthritis syndrome, rheumatoid neutrophilic dermatosis—all characterized by a superficial and deep, predominantly neutrophil-­rich inflammatory cell infiltrate without vasculitis and minimal papillary dermal edema PEARLS • N  eutrophil-­rich inflammatory infiltrate, leukocytoclasia but NOT vasculitis and marked papillary dermal edema characteristic • Histiocytoid variant of Sweet syndrome is not a variant of leukemia cutis • Potential infectious etiology should be considered and excluded in all cases of neutrophilic dermatoses

Selected References Buck T, González LM, Lambert WC, Schwartz RA. Sweet’s syndrome with hematologic disorders: a review and reappraisal. Int J Dermatol. 2008;47:775–782. Raza S, Kirkland RS, Patel AA, et al. Insight into Sweet’s syndrome and associated-­malignancy: a review of the current literature. Int J Oncol. 2013;42:1516–1522. Sweet RD. Acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;74:349–356.

Pyoderma Gangrenosum Clinical Features  •  Idiopathic ulceronecrotic skin disease that begins as follicular papules and pustules that eventually ulcerate • Lower extremities and trunk are often involved • Fully developed lesions show a necrotic center with a raised, undermined border with a dusky-­purple hue • Pyoderma gangrenosum may be the cutaneous manifestation of underlying systemic diseases such as inflammatory bowel disease, connective tissue disease, hematopoietic malignancies, and liver diseases  Histopathology  •  Histologic features are nonspecific and not diagnostic—vary according to the age of the lesion and the area biopsied • Area biopsied: • Center of the lesion shows ulcer with necrosis, dense diffuse neutrophilic infiltrate, and occasionally secondary vasculitis (Figure 2.21) •  Undermined border shows a mixed inflammatory cell infiltrate in addition to neutrophils • Periphery of the ulcer shows a lymphocytic and histiocytic inflammatory infiltrate • Age of the lesion

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

Figure 2.21  Pyoderma gangrenosum.  Dense diffuse dermal infiltrate of predominantly neutrophils. Blood vessels show plump endothelial lining. The infiltrate is generally denser than that seen in Sweet syndrome.

• Early lesions show an intradermal microabscess • A  dvanced lesions show a perivascular lymphoplasmacytic infiltrate, reactive endothelial cell atypia and secondary vasculitis  Special Stains and Immunohistochemistry  • Special stains and microbiologic cultures help exclude an infectious etiology  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Sweet Syndrome • Neutrophilic infiltrate that is typically more superficial, leukocytoclasia and marked papillary dermal edema • Bacterial Cellulitis • Requires demonstration of bacteria by Gram stain or microbiologic cultures PEARLS • H  istopathology nonspecific and varies with age of the lesion and area biopsied • Clinicopathologic correlation important in making the diagnosis and excluding other ulceronecrotic inflammatory disorders of the skin

Selected References Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients. Br J Dermatol. 2011;165:1244. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol. 2009;23:1008. Su WP, Schroeter AL, Perry HO, et al. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol. 1983;13:323.

Eosinophils Predominant Eosinophilic Cellulitis/Wells syndrome Clinical Features  •  Relatively rare, recurrent dermatosis of uncertain pathogenesis, characterized by sudden onset of erythematous patches that evolve into painful plaques

61

• May be idiopathic or associated with insect bites, parasitosis, infections, myeloproliferative disorders, and drug reactions • Associated with peripheral eosinophilia in at least 50% of the patients  Histopathology  • Spongiotic intraepidermal vesicles may be present •  Dense diffuse dermal infiltrate composed predominantly of eosinophils and occasionally extending into the subcutaneous tissue • “Flame figures” (eosinophilic debris caused by degranulating eosinophils and may impregnate the collagen bundles) more prominent in older lesions (Figure 2.15C) • Palisading histiocytes with central necrobiosis may be seen in florid lesions  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  •  Dermal hypersensitivity reactions (to drugs or an arthropod bite)—similar histopathology PEARLS • F lame figures although a helpful diagnostic clue not specific for Wells syndrome • Eosinophilic cellulitis most likely represents an exaggerated dermal hypersensitivity reaction rather than a specific disease, and a search for inciting stimuli is warranted

Selected References Brasileiro LG, Abreu MAMM, Paschoal RS. Wells’ syndrome: the importance of differential diagnosis. An Bras Dermatol. 2019;94:370–372. Caputo R, Marzano AV, Vezzoli P, Lunardon L. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157. Fujii K, Tanabe H, Kanno Y, et al. Eosinophilic cellulitis as a cutaneous manifestation of idiopathic hypereosinophilic syndrome. J Am Acad Dermatol. 2003;49:1174–1177.

Scabies Clinical Features  • Contagious, pruritic, papulovesicular, and pustular eruption most pronounced on the abdomen, buttocks, and anterior axillary folds caused by the mite Sarcoptes scabiei • Eruption believed to be a hypersensitivity reaction •  Burrows, produced by the female mite, typically involve the palms, web spaces between fingers, and male genitalia •  Persistent pruritic nodules/nodular scabies involving most commonly the scrotum can be seen up to several months after treatment  Histopathology  • Sections taken from the burrow show a tunnel-­like space (“molting pouches”) between layers of parakeratosis containing the mite/larvae/ova/feces (Figure 2.22). •  Spongiosis and vesiculation may be present in the epidermis • Superficial and deep dermal infiltrate containing varying numbers of eosinophils • Persistent nodular lesions show dense, diffuse, mixed inflammatory cell infiltrate containing eosinophils,

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

62

Chapter 2  —  Skin and Adnexal Structures

Figure 2.22  Scabies.  Parakeratotic burrow containing body parts of the mite of scabies. The dermal inflammatory cell infiltrate typically contains frequent eosinophils.

thick-­ walled blood vessels, and occasionally atypical mononuclear cells, “pseudolymphomatous” pattern may also be seen. Mite is generally absent in these lesions  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • A suspected burrow can be shaved, placed on a glass slide, and examined under oil immersion  Differential Diagnosis  • In the absence of the mite or its products in the cornified layer, the histologic changes cannot be distinguished from other hypersensitivity reactions such as those caused by arthropod bites PEARLS • N  orwegian scabies is a rare variant in which an immeasurable number of mites is present within the cornified layer; generally seen in immunocompromised patients or patients with poor hygiene • Scabetic by-­product or “feces” in the stratum corneum may be the only clue • Pink “pigtails” in the stratum corneum representing egg fragments or casings left behind after the mite hatches may be the only clue

Selected References Brites C, Weyll M, Pedroso C, et al. Severe and Norwegian scabies are strongly associated with retroviral (HIV-­ 1/HTLV-­ 1) infection in Bahia, Brazil. AIDS. 2002;16:1292. Chosidow O. Scabies and pediculosis. Lancet. 2000;355:819–826. Fernandez N, Torres A, Ackerman AB. Pathological findings in human scabies. Arch Dermatol. 1977;113:320.

Histiocytes Predominant Xanthogranuloma Clinical Features  •  Benign non-­ Langerhans cell histiocytosis that most commonly occurs during infancy (within first 6 months of life) but can be seen occasionally in adults (adult xanthogranuloma)

Figure 2.23  Xanthogranuloma.  Dermal infiltrate of predominantly histiocytes, including multinucleated histiocytes containing foamy cytoplasm and nuclei arranged at the periphery in a wreathlike pattern (Touton giant cells). Lymphocytes are present in the background.

• About 20% are congenital • Usually presents as single or multiple tan to pink-­red nodules that almost always regress over time to a tan macule or depression • Occasionally found in the deep soft tissue • Eye, particularly the uveal tract, most frequent site of extracutaneous involvement  Histopathology  • Distinctive architecture—exophytic lesion with a well-­ defined epidermal collarette • Lesional cells—uniform-­appearing histiocytes with an eosinophilic, vacuolated, or xanthomatous cytoplasm, • Touton giant cells are typically seen (Figure 2.23) • Admixture of neutrophils, eosinophils, and lymphocytes • Resolving lesion resembles dermatofibroma  Special Stains and Immunohistochemistry  • Oil red O highlights intracytoplasmic neutral lipids • CD68 and factor XIIIa positive • CD1a negative; S-­100 protein usually negative  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Langerhans Cell Histiocytosis (Eosinophilic Granuloma) • Presence of histiocytes positive for CD1a and S-­100 protein and admixed eosinophils, electron microscopy demonstrates Birbeck granules • Fibrous Histiocytoma (Dermatofibroma) • Spindled fibroblasts and histiocytic cells arranged in a storiform pattern • Peripheral collagen entrapment and overlying epidermal hyperplasia with pigmentation of basal keratinocytes • Xanthoma • Composed of sheets of histiocytes containing abundant intracytoplasmic lipid • Cholesterol clefts and multinucleate giant cells are typical

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

63

PEARLS • P  athogenesis remains uncertain; believed to be a reactive rather than neoplastic process • Not associated with a lipid abnormality • Skin lesions almost always regress with time and ultimately appear as a slight depression on the skin surface • Overall prognosis is excellent • Distinctive architecture with epidermal collarette Touton giant cells not specific for juvenile xanthogranuloma—can also be seen in dermatofibroma and xanthoma

Selected References Burgdorf WH, Zelger B. JXG, NF1, and JMML: alphabet soup or a clinical issue? Pediatr Dermatol. 2004;21:174–176. Dehner LP. Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations. Am J Surg Pathol. 2003;27:579. Freyer DR, Kennedy R, Bostrom BC, et al. Juvenile xanthogranuloma: forms of systemic disease and their clinical implications. J Pediatr. 1996;129:227–237.

Reticulohistiocytic Granuloma Clinical Features  • Typically occurs in adults • Most frequently presents as a well-­circumscribed red-­ brown cutaneous nodule with a red-­brown to yellow cut surface • May present as localized (giant cell reticulohistiocytoma) or systemic disease (multicentric reticulohistiocytosis) • Cutaneous reticulohistiocytoma (localized form)—may present as single or multiple skin lesions with clinical features similar to xanthogranuloma •  Multicentric reticulohistiocytosis (systemic form)— rare, may involve lymph nodes, heart, bone, and joints in addition to widespread skin involvement, may present with progressive erosive arthritis, fever, and weight loss, association with hyperlipidemia, internal malignancies, and autoimmune diseases  Histopathology  • Essentially similar features in both localized and systemic forms •  Well-­ defined infiltrate of multinucleate, uniform epithelioid histiocytes with abundant eosinophilic (“oncocytic”) cytoplasm, multinucleate giant cells with “ground-­glass” cytoplasm (Figure 2.24) • Infrequent mitotic activity • Scattered chronic inflammatory cells  Special Stains and Immunohistochemistry  • Lesional cells are CD68 positive and S-­100 protein and CD1a negative  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Langerhans Cell Histiocytosis • Infiltrate of large histiocytoid CD1a and S100 protein positive cells with nuclear grooves • Juvenile Xanthogranuloma •  Distinctive architecture, polymorphous infiltrate, presence of Touton giant cells diagnostic

Figure 2.24  Reticulohistiocytic granuloma.  The dense dermal infiltrate consists of lymphocytes and histiocytes. The cytoplasm of the histiocytes shows characteristic ground-­glass appearance.

PEARLS • S olitary and disseminated form of reticulohistiocytoma exhibit identical histopathology and cytomorphology • Predominant population of oncocytic histiocytes and multinucleate giant cells with “ground glass” cytoplasm distinctive • Occasional histiocytes with “ground glass” cytomorphology can be seen in other histiocyte rich entities • Disseminated reticulohistiocytosis is associated with various malignancies (carcinoma of the breast, colon, or lung) or systemic disease (tuberculosis, diabetes, hypothyroidism) • Polyarthritis seen in the disseminated form is due to infiltrate of similar histiocytic cells found in skin around the joints

Selected References Jung HD, Kim HS, Lee JY, et al. Multicentric reticulohistiocytosis. Acta Derm Venereol. 2013;93:124–125. Miettinen M, Fetsch JF. Reticulohistiocytoma (solitary epithelioid histiocytoma): a clinicopathologic and immunohistochemical study of 44 cases. Am J Surg Pathol. 2006;30:521. Snow JL, Muller SA. Malignancy-­associated multicentric reticulohistiocytosis: a clinical, histological, and immunophenotypic study. Br J Dermatol. 1995;133:71–76.

Palisading and Necrobiotic Granulomas Granuloma Annulare Clinical Features  • Benign granulomatous process of unknown etiology • Occurs most commonly in children and young adults; females more commonly affected than males • Predilection for areas of trauma and exposure, typically the dorsal surface of the hands and feet, ankles, knees, and elbows • Single or multiple annular dermal plaques with central clearing and raised erythematous borders • Spontaneously regress but can recur  Histopathology  •  Diagnostic histopathologic triad—palisaded lymphohistiocytic infiltrate with occasional multinucleate giant cells (some of which can demonstrate

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

64

Chapter 2  —  Skin and Adnexal Structures

Selected References Barren DF, Cootauco MH, Cohen BA. Granuloma annulare: a clinical review. Prim Care Pract. 1997;1:33–39. Güneş P, Göktay F, Mansur AT, et al. Collagen-­elastic tissue changes and vascular involvement in granuloma annulare: a review of 35 cases. J Cutan Pathol. 2009;36:838. Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol. 1996;27:50–56.

Necrobiosis Lipoidica

Figure 2.25  Granuloma annulare.  Palisade of histiocytes surrounding zones of myxoid degeneration of collagen. The granulomas are typically located in the upper dermis.

elastophagocytosis) minute foci of necrobiosis (mucinous degeneration of the collagen) and increased dermal mucin (Figure 2.25) • Typically involves upper and middle dermis, occasionally only the upper or deep dermis • Deep variant (subcutaneous granuloma annulare) typically found in a pediatric population • Perivascular infiltrates of lymphocytes; eosinophils in varying numbers may be present • Occasional neutrophils and nuclear fragmentation in areas of mucinous degeneration • Classified as a “blue granuloma” because of the presence of mucinous necrobiosis  Special Stains and Immunohistochemistry  • Colloidal iron stain highlights mucin  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis  • Rheumatoid Nodule • Characterized by a deeply eosinophilic homogenous foci of fibrinoid degeneration of collagen surrounded by a palisade of lymphohistiocytic infiltrate • Typically seen in the deep dermis or subcutis • Necrobiosis Lipoidica • Biopsy specimens are usually rectangular •  Foci of basophilic degeneration of collagen stratified between layers of an inflammatory cell infiltrate (“sandwich appearance”) that typically contains plasma cells • Involvement of deep dermis is typical PEARLS • D  iagnostic histopathologic triad (palisaded lymphohistiocytic infiltrate, necrobiosis and increased dermal mucin) • Subcutaneous variant of granuloma annulare (pseudorheumatoid nodule) typically presenting in children with deep-­seated nodules in the dermis or subcutaneous fat may be difficult to distinguish from rheumatoid nodule • A well-­known diagnostic pitfall is diagnosing epithelioid sarcoma as granuloma annulare, and vice versa

Clinical Features  • Degenerative cutaneous disease of unknown etiology • More common in women than men • Characteristically affects the anterior tibial surface but also has a predilection for the thighs, popliteal areas, and dorsum of the feet and arms • Indurated yellow-­brown oval plaques with a violaceous border • Center of the plaque may later become atrophic with a distinctive yellow waxy hue • Very small proportion occur in patients with diabetes mellitus  Histopathology  • Rectangular contour of biopsy sample, alternating horizontal layers of basophilic degeneration of collagen and an inflammatory infiltrate of histiocytes, lymphocytes, and plasma cells (Figure 2.26) diagnostic (“sandwich” or tiered appearance at scanning magnification) • Vascular changes (reactive endothelial cell atypia and thickened vessel walls) are features shared with diabetic microangiopathy • Zones of dermal sclerosis • Sarcoidal type granulomas are seen on occasion  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • DIF may reveal IgM, IgA, C3 and fibrinogen in thickened vessels  Differential Diagnosis  • Rheumatoid Nodule •  Deeply eosinophilic homogenous foci of fibrinoid degeneration of collagen surrounded by a palisade of lymphohistiocytic infiltrate typically seen in the deep dermis or subcutis • Granuloma Annulare •  Demarcated zones of necrobiosis with mucin surrounded by a palisade of lymphohistiocytic infiltrate, typically involving the upper half of the dermis • Necrobiotic Xanthogranuloma •  Atrophic epidermis, granulomatous inflammation with Touton giant cells of the deep dermis and subcutis, necrobiosis with cholesterol clefts PEARLS • C  haracteristic tiered appearance at scanning magnification—zones of necrobiosis alternating with layers of an inflammatory infiltrate

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 2  —  Skin and Adnexal Structures

A

65

B

Figure 2.26  Necrobiosis lipoidica.  A, Low-­power view shows zones of granulomas alternating with those of fibrosis and extending into deep dermis. B, High-­power view shows histiocytes, including multinucleated giant cells surrounding zones of collagen degeneration in the deep dermis.

• P  resence of plasma cells in the inflammatory infiltrate a helpful clue • Less than 1% of the patients with diabetes develop necrobiosis lipoidica

Selected References Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991;25:735–748. Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol. 1996;27:50–56. O’Toole EA, Kennedy U, Nolan JJ, et al. Necrobiosis lipoidica: only a minority of patients have diabetes mellitus. Br J Dermatol. 1999;140:283–286.

Rheumatoid Nodule Clinical Features  • Chronic deep-­seated inflammatory nodule that occurs in patients with rheumatoid arthritis and occasionally in patients with SLE • Seen during the course of the disease in 30% to 40% of patients with rheumatoid arthritis •  Predilection for areas subject to mechanical trauma, typically in para-­articular locations, including metacarpophalangeal and proximal interphalangeal joints •  Solitary or multiple, firm, nontender, freely mobile, large subcutaneous nodules  Histopathology  • Central areas of homogeneous eosinophilic degeneration of collagen surrounded by a peripheral palisade of histiocytes and lymphocytes (Figure 2.27), located in the subcutaneous tissue and deep dermis • Classified as a “red granuloma” because of the central homogenous eosinophilic areas  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Serologic evaluation for rheumatoid factor, which is nonspecific (may be elevated in a number of autoimmune disease; with age; and in females, particularly elderly females) 

Figure 2.27  Rheumatoid nodule.  Palisading granulomas surrounding zones of fibrinoid degeneration of collagen are present within the subcutaneous tissue.

Differential Diagnosis  • Subcutaneous Granuloma Annulare •  Palisaded lymphohistiocytic infiltrate with mucinous degeneration of collagen • Necrobiosis Lipoidica • Typically seen on the anterior tibial surface • Layers of necrobiosis are stratified with layers of an inflammatory cell infiltrate PEARLS • D  eep-­seated nodule with no connection to the overlying epidermis/dermis • Central area of homogeneous eosinophilic degeneration of collagen surrounded by a peripheral palisade of histiocytes and lymphocytes • Rheumatoid nodules are almost always associated with high titer of rheumatoid factor

Selected References Dubois EL, Friou GJ, Chandor S. Rheumatoid nodules and rheumatoid granulomas in systemic lupus erythematosus. JAMA. 1972; 220:515.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

66

Chapter 2  —  Skin and Adnexal Structures

• Foam cells not prominent • Xanthomas • Xanthomatized histiocytes, without necrobiosis • Juvenile Xanthogranuloma • Epidermal collarette at scanning magnification, polymorphous infiltrate, Touton giant cells, no necrobiosis PEARLS

Figure 2.28  Necrobiotic xanthogranuloma.  Dense dermal infiltrate composed of histiocytes and lymphocytes associated with degenerated collagen. Many of the histiocytes have foamy cytoplasm, and some are multinucleated.

Sayah A, English JC 3rd. Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol. 2005;53:191.  Veys EM, De Keyser F. Rheumatoid nodules: differential diagnosis and immunohistological findings. Ann Rheum Dis. 1993;52:625.

Necrobiotic Xanthogranuloma Clinical Features  • Relatively uncommon disorder often associated with paraproteinemia and seen in middle-­ aged/elderly patients • Presents as discrete papules and large, yellow indented nodular plaques with atrophy •  Most commonly involves the periorbital region but may also occur on trunk, neck, and extremities  Histopathology  • Granulomatous inflammation in the deep dermis and subcutis composed of lymphocytes, histiocytes, foam cells, Touton giant cells (Figure 2.28) • Intervening broad zones of necrobiosis containing cholesterol clefts • Lymphoid follicles are sometimes present  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Serum protein electrophoresis shows an IgG monoclonal gammopathy in most patients  Differential Diagnosis  • Necrobiosis Lipoidica •  Characteristically affects the anterior tibial surface but also has a predilection for the thighs, popliteal areas, and dorsum of the feet and arms • Tiered appearance at scanning magnification due to alternating horizontal layers of basophilic degeneration of collagen and palisades consisting of histiocytes, lymphocytes, and plasma cells • Foam cells not prominent • Subcutaneous Granuloma Annulare • Mucinous degeneration of collagen surrounded by lymphohistiocytic infiltrate

• T  outon giant cells not specific for necrobiotic xanthogranuloma—can also be seen in dermatofibroma, juvenile xanthogranuloma, and xanthoma • Monoclonal gammopathy not specific for necrobiotic xanthogranuloma—can be seen in erythema elevatum diutinum, scleromyxedema, plane xanthomas, and subcorneal pustular dermatosis

Selected References Finan MC, Winkelmann RK. Histopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol. 1987;14:92–99. Mehregan DA, Winkelmann RK. Necrobiotic xanthogranuloma. Arch Dermatol. 1992;128:94–100. Wood AJ, Wagner MV, Abbott JJ, Gibson LE. Necrobiotic xanthogranuloma: a review of 17 cases with emphasis on clinical and pathologic correlation. Arch Dermatol. 2009;145:279–284.

Sarcoidal Granulomas Sarcoidosis Clinical Features  • Relatively uncommon systemic granulomatous disease of unknown etiology • Usually seen in females living in the north temperature zone (e.g., Scandinavians); more common in blacks in the United States • Cutaneous involvement seen in approximately 25% of patients with systemic disease and as the only manifestation in about 25% •  Maculo-­ papular eruption with a predilection for the face, posterior neck and shoulders, and extensor surfaces of extremities • Lesions typically appear as small (15 eosinophils/hpf) usually indicates eosinophilic esophagitis • Eosinophilic esophagitis often responds to asthma therapy (steroid treatment, fluticasone, which is often swallowed especially by children and oral viscous budesonide) • Esophagitis with >15 eosinophils/hpf responsive to proton pump inhibitors (PPIs) (formerly called PPI-­responsive esophageal eosinophilia) is now called eosinophilic esophagitis and PPIs now considered a therapeutic option

• One third of patients have normal or slightly erythematous mucosa on endoscopy • Subset of patients has glandular metaplasia, erosions, or ulcers • About 30% of patients with documented abnormal histology have no endoscopic lesion •  Endoscopic grading system (Los Angeles Classification) often used to document severity of esophageal damage • Uses four letter (A, B, C, and D) grades: A (the least change) through D (the most severe endoscopic changes) 

Selected References

Histopathology

Dellon ES, Liacouras CA, Molina-­Infante J, et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference. Gastroenterol. 2018;155:1022–1033. Mahajau L, Wyllie R, Petras R, et al. Idiopathic eosinophilic esophagitis with stricture formation in a patient with longstanding eosinophilic gastroenteritis. Gastrointest Endosc. 1997;46:557–560. O’Shea KM, Aceves SS, Dellon ES, et al. Pathophysiology of eosinophilic esophagitis. Gastroenterol. 2018;154:333–345. Vanderheyden AD, Petras RE, DeYoung BR, Mitros FA. Emerging eosinophilic (allergic) esophagitis: increased incidence or increased recognition? Arch Pathol Lab Med. 2007;131:777–779. Walsh SV, Antonioli DA, Goldman H, et al. Allergic esophagitis in children: a clinicopathologic entity. Am J Surg Pathol. 1999;23:390–396.

• Characteristic histologic changes involving squamous mucosa (Figure 6.5) •  Hyperplasia with elongated or lengthened lamina propria papillae (more than two thirds of thickness of epithelium) • Thickened basal layer (more than 15% of epithelial thickness) •  Increased intraepithelial lymphocytes and eosinophils; neutrophils may also be present but occur only in severe reflux • Dilatation of intercellular spaces

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

• Erosive and ulcerated lesions show neutrophilic and eosinophilic exudate over a granulation tissue base •  Barrett esophagus with intestinal metaplasia (goblet cell metaplasia) may be present •  Inflammation of gastric cardia–type mucosa with or without intestinal metaplasia may also be present 

Special Stains and Immunohistochemistry • Combined Alcian blue and PAS staining with hematoxylin counterstain: serves four purposes •  Defines the relatively PAS-­ negative, glycogen-­ free basal layer of the esophagus •  Detects dark-­ blue intestinal mucus in goblet cells when intestinal metaplasia is present • Identifies fungi, if present • Good screening stain for signet cell adenocarcinoma • Stains for H. pylori (Warthin-­Starry, Diff-­Quik, Giemsa, immunohistochemistry) may be helpful when differential includes chronic gastritis 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Infectious Esophagitis  •  May resemble reflux esophagitis endoscopically, but usually more focal • Differentiated by the presence of characteristic organisms or cytopathic changes • Most common organisms: • HSV • CMV • Candida species  Helicobacter pylori Gastritis of Cardia (Carditis) With or Without Intestinal Metaplasia  •  Can be histologically indistinguishable from reflux-­ related inflammation of gastric cardia type mucosa; H. pylori infection typically causes more chronic and active inflammatory cells; H. pylori seen on hematoxylin and eosin (H&E) or special stain • Most cases of chronic inflammation of gastric cardia– type mucosa at the gastroesophageal junction or in lower esophagus are examples of reflux  Eosinophilic Esophagitis  • Typically in children or young men with an allergic history • Characterized by numerous intraepithelial eosinophils (>15 eosinophils/hpf) • Many cases cannot be reliably separated from reflux esophagitis without clinical history and response to therapy  Pill Esophagitis  • Typically associated with odynophagia (painful swallowing), lump in the throat sensation, and history of consuming oral medications with inadequate amounts of water • Occurs more proximally in esophagus than do changes caused by reflux • Nonspecific histology with ulcer 

315

Squamous Dysplasia, Squamous Cell Carcinoma  • Less likely than reflux-­associated regenerative changes because incidence of esophageal squamous cell carcinoma is declining in the United States • Dysplasia and carcinoma show •  Less papillomatosis versus reflux-­ related squamous changes • Overlapping, pleomorphic nuclei with high nuclear-­ to-­cytoplasmic ratio • Atypical mitoses • Single-­cell necrosis • Paradoxical maturation • Squamous pearl formation PEARLS • Gastroesophageal reflux: classic histologic changes • Thickened basal layer • Elongated papillae • Intraepithelial inflammatory cells, including some eosinophils (generally 2 per 10 high magnification fields); however, the only definite criterion is metastasis 

Special Stains and Immunohistochemistry • Cytoplasmic positivity for PAS and immunostain positive for CD68 and S-­100 protein • TFE3 positivity mimics alveolar soft parts sarcoma 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Squamous Cell Carcinoma  • Especially on small biopsies, granular cell tumors have many times been misdiagnosed as squamous cell carcinoma because of the pseudoepitheliomatous hyperplasia that accompanies the tumor PEARLS • B  iopsy and observation may be employed; typically slow growing and cured by local surgical excision; malignant granular cell tumors with metastases have been reported

Squamous Papilloma  • More common in males (male-­to-­female ratio is 2.5:1) • Occurs throughout life • Two types of squamous papilloma • Human papillomavirus (HPV) associated • May coexist with laryngeal papillomatosis; associated with HPV-­6 and HPV-­11 infections • Not HPV associated • Majority of esophageal papillomas • May be related to reflux esophagitis, eosinophilic esophagitis, or trauma • Patients typically present with dysphagia and heartburn  Squamous Cell Carcinoma  • About 1% of all cancers in the United States • Risk factors include the following: • Male gender (male-­to-­female ratio is 5:1) • Black race • Tobacco and ethanol use • Low socioeconomic status • Diet low in trace elements, minerals, and vitamins or high in hot liquids • Premalignant conditions include chronic esophagitis, squamous dysplasia, and carcinoma in situ and are typically asymptomatic • Dysphagia is the most common symptom associated with invasive carcinoma; cancer is often advanced at presentation •  Complications of invasive carcinoma include the following: • Invasion into adjacent structures (major blood vessel, trachea, laryngeal nerve), causing hemorrhage, aspiration, and hiccups • More than half of all patients have positive lymph nodes at diagnosis; many are unresectable • Most common metastatic sites are liver and lung • Several variants of squamous cell carcinoma exist (see below). 

Gross and Endoscopic Pathology Squamous Papilloma  • Exophytic, partially pedunculated, soft, pink-­tan mass • About 95% occur in mid-­or lower esophagus • Typically smaller than 1 cm • Can see endoscopic evidence of coexisting eosinophilic esophagitis (e.g., corrugations)  Squamous Cell Dysplasia • Dysplasia

and

Carcinoma 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

322

Chapter 6  —  Gastrointestinal System

Figure 6.16  Squamous carcinoma of the esophagus characterized by an infiltrative growth pattern and marked cellular atypia.

Figure 6.15  Resection specimen of esophageal squamous carcinoma.  Note the ulcerated mass lesion.

• Often multifocal • D  ysplastic lesions vary widely in size and may be extensive • Most are at least focally erosive • Most involve mid-­to lower esophagus • Invasive carcinoma • Most (90%) occur in mid-­and lower esophagus •  Most tumors are large, discrete masses projecting into the lumen with variable intramural extension • Ulcerating tumors are less common and are typically erosive with infiltration and expansion of esophageal wall (Figure 6.15) • Least common is an infiltrating tumor with similar intramural invasion but little or no ulceration • Polypoid tumors have better survival than ulcerative and infiltrative tumors • Early lesions (T1) may be multifocal and combined with dysplasia of varying degrees and carcinoma in situ over a wide area 

Histopathology Squamous Papilloma  •  Exophytic and endophytic proliferations of benign squamous epithelium • Papillary proliferation with fibrovascular core; koilocytosis, hyperkeratosis, and hypergranulosis may occur • Patterns are often mixed • Intraepithelial eosinophils sometimes seen  Squamous Cell Dysplasia and Carcinoma  • Dysplasia and carcinoma in situ • Variable combination of nuclear anaplasia (hyperchromasia, pleomorphism) and disordered maturation •  As in the cervix, dysplastic lesions are defined as those showing some evidence of maturation and are graded in tiers

• Full-­thickness atypia without superficial maturation is termed carcinoma in situ • Dysplastic cells may extend into metaplastic submucosal glands • Invasive squamous carcinoma (Figure 6.16) • Low-­grade carcinomas are characterized by obvious recapitulation of benign counterpart and are composed of syncytial nests of cells with abundant pink cytoplasm, intercellular bridges, and keratin pearls • High-­grade carcinomas may show only solid nests of cells with pleomorphic nuclei and vague pink cytoplasm • Necrosis is often seen in high-­grade carcinomas • Infiltration is often marked by paradoxical maturation of invading cells with squamous pearl formation and stromal desmoplasia •  Effects of preoperative radiation include the following: • Marked atypia of stromal, endothelial, and squamous metaplasia in the submucosal glandular cells with atypia • Postradiation changes include foci of calcified keratinized cells and foreign-­body giant cell reaction 

Special Stains and Immunohistochemistry Squamous Papilloma  • Noncontributory  Squamous Cell Carcinoma  •  Cytokeratin immunostain is positive in virtually all squamous cell carcinomas; exceptions include a minority of high-­grade carcinomas; 50% of sarcomatoid carcinomas (sarcomatoid areas may react focally with cytokeratin and generally are reactive with vimentin antibodies; antibodies to desmin and muscle-­specific actin may be positive) 

Other Techniques for Diagnosis Squamous Papilloma  • In situ hybridization and PCR to detect and classify HPV; not performed routinely 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

Squamous Cell Carcinoma  • Proliferative index with Ki-­67 and ploidy status may correlate with prognosis; usually not routinely performed 

323

Torres CM, Wang HH, Turner JR, et al. Pathologic prognostic factors in esophageal squamous cell carcinoma: a follow-­up study of 74 patients with or without preoperative chemoradiation therapy. Mod Pathol. 1999;12:961–968.

Differential Diagnosis Ulcerative Esophagitis  • Usually recognizable endoscopically and typically covers a wide area of distal esophagus •  Biopsies demonstrate regenerative squamous epithelium characterized by basal cell hyperplasia and orderly superficial maturation without significant nuclear pleomorphism • Keratinization is usually absent  Infectious Esophagitis  • Similar histology to ulcerative esophagitis with detection of responsible organism  Barrett Esophagus  •  Many show inflamed, regenerating squamous epithelium adjacent to diagnostic columnar glands with intestinal metaplasia (goblet cells)  Esophageal Leukoplakia/Epidermoid Metaplasia  • White to tan patches of villiform or plaquelike mucosa • Sharply demarcated area of acanthosis with prominent granular layer and hyperorthokeratosis • Associated with tobacco smoking, alcohol intake • Adjacent squamous dysplasia can be seen PEARLS • E xtensive, diffusely ulcerated, flat lesions by endoscopy are most likely benign esophagitis with regenerative atypia • Most squamous cell carcinomas form an exophytic mass with ulceration • Keratinization or keratin pearls, particularly those containing hyperchromatic and atypical cells, are highly suggestive of infiltrating squamous carcinoma • Five-­year survival with carcinoma is dictated largely by depth of invasion and lymph node status • Use CAP cancer protocols to ensure proper staging and grading • Tylosis is an autosomal dominant condition consisting of hyperkeratosis of the palms and soles and oral leukoplakia and is associated with squamous cell carcinoma of the esophagus

Selected References Blot W. Esophageal cancer trends and risk factors. Semin Oncol. 1994;21:403–410. Iezzoni JC, Mills SE. Sarcomatoid carcinomas (carcinosarcomas) of the gastrointestinal tract: a review. Semin Diagn Pathol. 1993;10:176–187. Montgomery E, Field JK, Boffetta P, et al. Squamous cell carcinoma of the oesophagus. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. World Health Organization Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010:18–24. Odze R, Antonioli D, Shocket D, et al. Esophageal squamous papillomas: a clinicopathologic study of 38 lesions and analysis for human papillomavirus by the polymerase chain reaction. Am J Surg Pathol. 1993;17:803–812. Singhi AD, Arnold CA, Crowder CD, et al. Esophageal leukoplakia or epidermoid metaplasia: a clinicopathological study of 18 patients. Modern Pathol. 2014;27:38–43.

SQUAMOUS CELL CARCINOMA VARIANTS Clinical Features Undifferentiated Carcinoma  • About 20% of esophageal malignancies • Highly aggressive  Verrucous Carcinoma  • Considered a well-­differentiated variant of squamous cell carcinoma • Slow growing but often recurs; low metastatic risk • Some cases reported after acid ingestion or with achalasia  Sarcomatoid Carcinoma  • Represents a carcinoma with mesenchymal differentiation • Rare (25 per 100 gastric foveolar cells) (Figure 6.27)  Ménétrier Disease Versus Gastric Polyps  •  Can be histologically indistinguishable from gastric hyperplastic polyp, juvenile polyp, Cronkhite-­ Canada polyp, or reactive gastropathy in small biopsy specimens • Careful attention to exact clinical setting and status of adjacent mucosa is critical to accurate diagnosis  Gastritis Glandularis et Cystica Profunda  • Synonyms include diffuse cystic glandular malformation and diffuse cystic malformation • Mucosal and submucosal cysts lined by mucus cells, pyloric or Brunner-­type glands, or rarely gastric body– type glands enveloped by smooth muscle • Rare but may be associated with increased risk for gastric carcinoma 

Figure 6.26  Resection specimen of Ménétrier disease with large cerebriform gastric rugae.

Zollinger-­Ellison Syndrome Versus Peptic Ulcer Disease  • Peptic ulcer disease may have surface foveolar hyperplasia but no parietal cell hyperplasia

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

334

Chapter 6  —  Gastrointestinal System

Figure 6.28  Endoscopic photograph of fundic gland polyposis in a patient with familial adenomatous polyposis. Note the small hemispheric polyps on the summit of rugae.

Figure 6.27  Lymphocytic gastritis associated with Ménétrier disease-­ like gastropathy. Note the foveolar hyperplasia with numerous (>25 per 100 gastric foveolar cells) intraepithelial lymphocytes.

PEARLS • H  ypertrophic gastropathy is characterized by giant cerebriform enlargement of the gastric rugae (see Figure 6.26) • Ménétrier disease and Zollinger-­Ellison syndrome are the most common causes; large folds are less commonly seen with H. pylori infection • Most common complication is peptic ulcer, which may cause gastrointestinal hemorrhage; rarely, the hyperplastic mucosa becomes metaplastic and may subsequently undergo malignant transformation

Selected References Haot J, Bogomoletz WV, Jouret A, et al. Ménétrier’s disease with lymphocytic gastritis: an unusual association with possible pathogenic implications. Human Pathol. 1991;22:379–386. Komorowski RA, Caya JG. Hyperplastic gastropathy: clinicopathologic correlation. Am J Surg Pathol. 1991;15:577–585. Qualman SJ, Hamoudi AB. Pediatric hypertrophic gastropathy (Ménétrier’s disease). Pediatr Pathol. 1992;12:263–268.

NON-­NEOPLASTIC GASTRIC POLYPS Clinical Features Fundic Gland Polyp  • Most common gastric polyp • May occur sporadically, can be part of familial adenomatous polyposis (FAP) syndromes (FAP, attenuated FAP, MUTYH-­associated polyposis syndrome, and polymerase proofreading associated polyposis), and is a common polyp type seen in patients taking proton pump inhibitors

•  FAP-­ associated fundic gland polyps affect one third to one half of all FAP patients and typically occur at a young age (10 to 30 years) •  Sporadic fundic gland polyps are typically found in older women  Hyperplastic Polyp  • Second most common gastric polyp • Most common in older adults • Generally occurs in body or antrum •  Associated mainly with chronic gastritis, but also occurs in reactive gastropathy adjacent to ulcers, surgical anastomosis, or gastrostomy sites • Low malignant potential, but hyperplastic polyps may coexist with adenomas and carcinoma  Inflammatory Fibroid Polyp  • Occurs throughout GI tract • Identical to those described in esophagus • Typically occurs in adults between 50 and 60 years of age • Often asymptomatic (incidental finding); large polyps may cause abdominal pain or obstructive symptoms 

Gross and Endoscopic Pathology Fundic Gland Polyp  • Small (0.1 to 0.5 cm), nonpedunculated mucosal nodules (Figure 6.28) • Most involve the fundic mucosa • Sporadic polyps • May be multiple but generally fewer than 20 • Fundic gland polyposis associated with FAP syndromes • Characterized by hundreds of polyps covering the gastric mucosa; often many more polyps than in non-­ FAP–associated fundic gland polyposis; concentrate on greater curvature and usually spares the antrum

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

Figure 6.29  Hyperplastic polyp of the stomach showing edematous and inflammatory expansion of the lamina propria associated with mucosal microcyst formation.

• Gastric Adenocarcinoma and Proximal Polyposis syndrome (GAPPS) •  Autosomal dominant; mutation in adenomatous polyposis coli (APC) promoter • Numerous polyps concentrated in body and fundus; no polyps in colon or duodenum  Hyperplastic Polyp  • Typically small and sessile with a smooth, bosselated surface • Generally less than 2 cm •  About one third of affected patients have multiple polyps • Most occur in patients with chronic gastritis or reactive gastropathy  Inflammatory Fibroid Polyp  • Most occur in the antrum • Most are small (2 cm) • Numerous subtypes • Tubular, villous, tubulovillous most common •  Antral-­ foveolar type, pyloric type much less common • Progression from dysplasia to carcinoma is thought to be slow, and dysplasia may remain stable for years • Ulcers • Although one fourth of all gastric carcinomas contain a discrete ulcer, less than 1% arise in a preceding, documented benign ulcer • In most cases, it is difficult to determine whether the cancer arose in an ulcer or whether a cancer ulcerated • About 5% of clinically and endoscopically presumed benign ulcers are eventually proved to be carcinoma • Partial gastrectomy •  Patients who have undergone resection have a slightly elevated risk of developing adenocarcinoma in the gastric stump or in the area of the stoma • Occurs more than 15 years after surgery  Gastric Carcinoma  •  Common symptoms include early satiety, anorexia, and weight loss • Like the epithelium from which it arises, gastric carcinoma is a heterogeneous tumor • Fundamental differences in characteristics of two types of gastric carcinoma • Intestinal type • More common in elderly men • Seen in countries with high gastric cancer risk •  Associated with dietary and environmental substances

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System



337

• Associated with H. pylori infection and intestinal metaplasia • Arises in a dysplasia precursor • Expands centripetally into gastric lumen and wall • Better prognosis than diffuse-­type carcinoma • Diffuse type • Younger patients and more common in women • No identifiable nutritional risk factor • May also be associated with H. pylori infection • Thought to arise from undifferentiated neck cells • Type seen with familial cases associated with germline E-­cadherin (CDH1) gene mutations; these demonstrate a subtle precursor lesion • Infiltrates into and expands gastric wall • Poor prognosis 

Early Gastric Carcinoma  • Superficial malignant tumor that invades the mucosa and submucosa but has not invaded the muscularis propria • In large-­scale screening programs in countries with a high incidence of gastric carcinoma (Japan), early gastric carcinoma is frequently diagnosed • Distinct from other entities, such as high-­grade dysplasia, an incipient malignancy still confined within its original glandular basement membrane • Curable, with a 5-­year survival rate of 95% 

Gross and Endoscopic Pathology Precursor Lesions  • Flat dysplasia •  Often associated with chronic gastritis, which is endoscopically diffuse • Mucosa may be hyperemic or eroded •  Usually, flat dysplasia is not endoscopically discernible • Adenoma •  Sessile or pedunculated polyp; may be endoscopically indistinguishable from a hyperplastic polyp • Ulcer • Benign form characteristically has discrete, smooth, flat margins and a clean base  Gastric Carcinoma  • May be raised, flat, or ulcerated (Figure 6.31) • Some tumors are minute (20 mitoses per 10 high magnification field and percentage of Ki-­67 positive nuclei >20 •  Neuroendocrine carcinomas predominantly show a solid growth pattern as well as nuclear anaplasia, necrosis, and higher mitotic rates • Large cell neuroendocrine carcinoma is most common; tumor cells are polygonal-­shaped with abundant cytoplasm, vesicular nuclei, and prominent nucleoli •  Small cell carcinoma shows cells with scant cytoplasm, high nuclear:cytoplasmic ratios, and nuclear molding 

Special Stains and Immunohistochemistry • Immunoreactive with antibodies to chromogranin and synaptophysin help verify neuroendocrine differentiation and help classify tumors as sporadic (no hyperplasia or dysplasia of ECL cells) or hypergastrinemia related •  Adjacent mucosa in hypergastrinemia-­ related neuroendocrine tumors can show linear hyperplasia (five or more endocrine cells in a line), nodular hyperplasia (clusters of five or more endocrine cells smaller than 150 μm), endocrine cell dysplasia (growths larger than 150 μm but smaller than 0.5 mm), or neuroendocrine tumors (growths larger than 0.5 mm) • Classification of gastric endocrine cell proliferations is only applied to nonantral mucosa; an immunostain for gastrin should be performed to prove that the tissue specimen is not derived from the gastric antrum 

Other Techniques for Diagnosis • Noncontributory  Figure 6.36  Intramucosal gastric carcinoid tumor arising in association with atrophic gastritis and intestinal metaplasia.

•  Hypergastrinemia-­ associated and sporadic neuroendocrine tumors (carcinoids) can be histologically indistinguishable • Typically arise in the deep mucosa and are covered by intact superficial epithelium; can invade the gastric wall and produce desmoplastic reaction •  Tumors show variety in growth pattern, including monomorphic nests, trabeculae, festoons, solid island, and/or glandlike formations

Differential Diagnosis Gastric Adenocarcinoma  • Typically forms recognizable glandular elements with a destructive and invasive growth pattern •  Mixed adenocarcinoma—neuroendocrine carcinoma (MANEC) exist, but are rare in the stomach  Lymphoma  • Particularly in small biopsies, the small, monomorphic lymphoid cells may superficially resemble those of a neuroendocrine tumor • Lymphocytic infiltrate is positive for LCA and other lymphoid markers

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

341

PEARLS • In tumors associated with chronic atrophic (autoimmune) gastritis, lymph node metastases are extremely rare and generally occur only in tumors larger than 1 cm • Some sporadic neuroendocrine tumors and high-­grade carcinomas can behave in a more aggressive manner and may prompt more aggressive surgery (complete or partial gastrectomy with lymph node resection) • Remember to exclude melanoma if a tumor resembling a neuroendocrine tumor demonstrates a high Ki-­67 labeling index

Selected References Odze R, Montgomery E, Wang H, et al. Gastric Neuroendocrine Neoplasms. Atlas of Tumor Pathology, Fourth Series, Fascicle 28. Washington, DC: Armed Forces Institute of Pathology; 2019. Thomas RM, Baybick JH, Elsayed AM, et al. Gastric carcinoids: an immunohistochemical and clinicopathologic study of 104 patients. Cancer. 1994;73:2053–2058. Washington MK, Tang LH, Berlin J, et al. Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the stomach. Arch Pathol Lab Med. 2010;134:187–191. Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology. 2007;50:30–41.

GASTRIC LYMPHOMA Clinical Features •  Gastric lymphoma accounts for over half of all GI lymphomas • Diffuse large B-­cell lymphoma is most common • Many gastric lymphomas are derived from MALT • Generally affects patients over 40 • May be asymptomatic or present with an abdominal mass, abdominal pain (related to gastritis or ulcer), weight loss, or less commonly, bleeding • Clear association between gastric marginal zone B-­cell lymphoma of MALT type and H. pylori infection (92% to 100% of cases); treatment of H. pylori induces regression in 77% of early lesions (Figure 6.37) • Indolent behavior and generally an excellent prognosis with marginal zone B-­cell lymphoma of MALT type 

Gross and Endoscopic Pathology • Most arise in the antrum • Early lesions typically form a plaque or small mucosal erosions •  Advanced lesions cause ulcers, diffuse thickening of mucosal folds, or obvious masses 

Histopathology • Marginal zone B-­cell lymphoma of MALT type (see Figure 6.37) • Heterogeneous infiltrate of neoplastic lymphocytes •  Centrocyte-­ like cells: small lymphocytes with irregular nuclear contours and pale cytoplasm •  Monocytoid B-cells: medium-­ sized lymphocytes with abundant clear cytoplasm •  Large cells resembling centroblasts or immunoblasts are present, but rare • Three additional characteristic features: •  Classic feature is the lymphoepithelial lesion (caused by invasion and destruction of gland or

Figure 6.37  Extranodal marginal zone B-­cell lymphoma of the mucosa-­associated lymphoid tissue involving the stomach. A destructive lymphoepithelial lesion is associated with a proliferation of marginal zone lymphoma cells within the lamina propria.

cyst by aggregates of neoplastic lymphocytes, with eosinophilic epithelial change) • Lymphoid follicles often with germinal centers •  “Follicular colonization” occurs when MALT lymphoma infiltrates the germinal center • Neoplastic plasma cells (present in up to one third of cases) • Diffuse large B-­cell lymphoma •  Confluent, sheetlike proliferations of large transformed cells which can infiltrate glandular structures • Centroblasts: vesicular chromatin and two or more eccentric nuclei •  Immunoblasts: more prominent cytoplasm and single large, central nucleolus • May represent transformation from marginal zone B-­cell lymphoma of MALT type; this is suggested by a mixture of low-­and high-­grade histology in the same tumor and presence of same genotype 

Special Stains and Immunohistochemistry • Large cell lymphoma; confirm B-­cell lineage with CD20 immunostain • Differentiate germinal center from nongerminal center type using immunostains for CD10, BCL-­6, and MUM-­1 • Gastric marginal zone B-­cell lymphoma of MALT type • Workup includes immunostains that should be positive, such as CD20, BCL-­2, and CD79a as well as negative staining for CD3, CD5, CD10, CD23, and cyclin D1 • Aberrant expression of CD43 and CD-­5 supports the diagnosis • Immunostains for kappa and lambda light chains are only helpful when extensive plasmacytic differentiation is present 

Other Techniques for Diagnosis • PCR for B-­cell clonality is supportive (with appropriate histology) but may be positive in some cases of gastritis • Cytogenetics: t(11;18), trisomy 3 and 18 may be seen • t(11;18) predicts resistance to H. pylori therapy • Flow cytometry positive for CD19, CD20, CD21; negative for CD5, CD10, and CD23 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

342

Chapter 6  —  Gastrointestinal System

Differential Diagnosis Lymphoid Hyperplasia Versus Mucosa-­Associated LymphoidTissue Lymphoma  • Hyperplasia lacks lymphoepithelial lesions and epithelial eosinophilia, lymphocytes with irregular nuclear contours, plasma cells with Dutcher bodies, and monocytoid cells Immunostains are helpful; hyperplasia shows organized CD20-­positive B-cells and numerous CD3-­positive T-cells in interfollicular areas

• Up to 50% of affected infants have additional anomalies, including malrotation, Meckel diverticulum, imperforate anus, and cardiovascular defects 

PEARLS

Gastroschisis  • Uncommon overall, but more common in males • Incidence is estimated at 1 to 2 cases per 100,000 births •  Presumed to be due to a vascular accident in early embryogenesis (before 12 weeks) • Results from a defect in the anterior abdominal wall that permits extrusion of the abdominal viscera • No membranous sac surrounds the extruded viscera 

• M  ALT lymphomas have an excellent prognosis and typically remain confined to the stomach for many years; early lesions often improve with treatment for H. pylori • Biopsy fragments showing diffuse sheets of lymphoplasmacytic cells with lymphoepithelial lesions, particularly in an older patient, suggest MALT lymphoma • Immunohistochemistry is helpful to distinguish MALT lymphoma from reactive lymphoid proliferations as well as other small B-­cell lymphomas

Atresia and Stenosis  • Rare conditions; found in 1 in 2000 to 1 in 6000 live births •  Duodenal atresia is most common and is associated with other anomalies in 35% of cases • Higher incidence in twin gestations and in infants of mothers using cocaine • Colonic atresia virtually never occurs • Atresia presents in early neonatal period with bilious vomiting 

Selected References

Meckel Diverticulum  • Failure of the vitelline duct (connects the lumen of the bowel to the yolk sac) to involute produces a Meckel diverticulum • Generally found within 85 to 100 cm of the ileocecal valve in adults • About 1% to 4% prevalence • No gender predilection • Complications include hemorrhage, peptic ulceration, intussusception, and diverticulitis 

Banks PM. Gastrointestinal lymphoproliferative disorders. Histopathology. 2007;50:42–54. Foukas PG, de Leval L. Recent advances in intestinal lymphomas. Histopathol. 2015;66:112–136. Isaacson PG. Gastric lymphoma and Helicobacter pylori. N Engl J Med. 1994;330:1310–1311. Katzin WE. Lymphoproliferative and related disorders of the gastrointestinal tract. In: Noffsinger A, ed. Fenoglio-­Preiser’s Gastrointestinal Pathology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2017:1069–1140.

LOWER GASTROINTESTINAL TRACT (SMALL AND LARGE INTESTINE) CONGENITAL ANOMALIES Clinical Features Malrotation  • Varying degrees of malrotation or malfixation are not uncommon • Results from disturbance of normal counterclockwise rotation of bowel around the superior mesenteric artery • Occurs in 1 in 6000 live births • Presenting symptoms are volvulus, obstruction, bilious vomiting, abdominal distention, steatorrhea, and failure to thrive  Omphalocele  • Affects about 1 in 6000 to 1 in 10,000 births •  Results from failure of the intestines to return to the abdominal cavity during the 10th week of development •  May occur as a result of incomplete closure of the abdominal wall during the fourth week of development, which produces a large defect in the anterior abdominal wall (as a result, most of the abdominal viscera remain outside the embryo) •  In both situations, the herniated intestines are contained within a thin membranous sac (composed of peritoneal lining and amnion)

Intussusception  • Telescoping of one intestinal segment into another • Affects about 2 to 4 per 1000 live births • Twice as common in males • Symptoms include abdominal pain, bloody diarrhea, and obstruction • Complications include bowel infarction and peritonitis • Children usually have no underlying anatomic abnormalities; intussusception in adults is typically associated with an intraluminal mass  Volvulus  • Twisting of a bowel segment around mesentery • Thought to cause about 10% of all bowel obstructions • Occurs with or without predisposing causes, including • Congenitally long mesentery • Meckel diverticulum • Congenital band • Most commonly occurs with redundant loops of sigmoid colon; less common in small intestine, and rarely involves the stomach or transverse colon •  Patients generally present with abdominal pain and obstruction • Occurs acutely and may produce bowel infarction and peritonitis 

Gross and Endoscopic Pathology Malrotation  • Intestines occupy abnormal positions

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

• Generally small bowel appears as a coiled mass of intestine pushed to one side of the abdomen • Cecum may be on left side of the abdomen •  Fixation band may cause intestinal torsion and infarction  Omphalocele  • Extra-­abdominal viscera are covered by a thin membranous sac composed of peritoneum and amnion •  Herniated viscera typically includes intestines; may involve stomach and liver • Umbilical cord arises from the center of the overlying sac  Gastroschisis  •  Abdominal viscera herniate through a defect in the abdominal wall • Extruded viscera do not have an overlying thin membranous sac • No involvement of the umbilical cord  Atresia and Stenosis  • Multiple types of atresias exist and may coexist • Imperforate septum across intestinal lumen • Bowel segment replaced by a fibrotic cord • Bowel segment and associated mesentery completely absent • Intestinal stenosis is similar to atresia; has a variable reduction of the lumen diameter over a long segment or contains a septum with a central communication; bowel wall layers generally intact  Meckel Diverticulum  See Figure 6.38. • Antimesenteric ileum is the most common location • Located 30 cm from ileocecal valve in infants and 85 to 100 cm from the ileocecal valve in adults • Usually 2 to 15 cm in length 

343

Intussusception  • Invagination or telescoping of proximal small or large bowel (intussusceptum) into the adjacent distal bowel that encircles it  Volvulus  • Segment of bowel may twist around its mesentery • Involved bowel is ischemic or frankly infarcted (35% to 40% of cases) • Associated fibrous band or adhesion may be found 

Histopathology Malrotation, Omphalocele, and Gastroschisis  • Normal bowel histology unless complicated by ischemia or peritonitis  Atresia and Stenosis  • Bowel proximal to the atretic or stenotic area may show ischemic or gangrenous changes (due to dilation of bowel) • Villous blunting, ulceration, and granulation tissue can be seen; with time, marked submucosal fibrosis and muscularis propria hypertrophy occur • Blind segment contains meconium, lanugo hair, and mucin  Meckel Diverticulum  • Usually lined by normal small intestinal mucosa • May contain ectopic pancreatic or gastric tissue  Intussusception  • Ischemic changes are common •  Vascular proliferation in lamina propria and deeper bowel layers develops in recurrent cases and can mimic vascular tumors  Volvulus  • Variable degrees of ischemia 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis • Malrotation, atresia, Meckel diverticulum, intussusception, and volvulus all are considered in the differential diagnosis in patients with bowel obstruction symptoms •  Combination of clinical, radiographic, and surgical findings is usually diagnostic PEARLS

Figure 6.38  Meckel diverticulum (autopsy photograph).

• M  eckel diverticulum may contain heterotopic rests of gastric or pancreatic tissue (80% of cases); complications include peptic ulceration, hemorrhage, and diverticulitis • Omphalocele is characterized by a central protrusion of abdominal contents, directly beneath (and with attachment to) the umbilical cord; protruding abdominal organs are covered by a membrane • Omphalocele is typically due to failure of abdominal wall to form rather than to a focal abdominal wall defect, as in gastroschisis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

344

Chapter 6  —  Gastrointestinal System

Selected References Dillon PW, Cilley RE. Newborn surgical emergencies: gastrointestinal anomalies, abdominal wall defects. Pediatr Surg. 1993;40:1289–1314. Dimmick JE, Kalousek DK. Developmental Pathology of the Embryonal Fetus. Philadelphia: JB Lippincott; 1992:526. Rescorla FJ, Shedd FK, Grosfeld JL, et al. Anomalies of intestinal rotation in childhood: analysis of 447 cases. Surgery. 1990;108:710–715.

ENTERIC INFECTIONS IN IMMUNOCOMPETENT HOSTS Clinical Features • Populations affected are generally those from underdeveloped countries and immunologically naive travelers to these areas • Associated with poor sanitation in industrialized nations • Food-­and water-­borne illnesses also occur after ingestion of large amounts of bacteria owing to contamination by food handlers or improper preparation or refrigeration and in institutionalized settings Escherichia coli Infection  • Pathologic subtypes may not be routinely differentiated from nonpathogenic forms in culture • May cause prolonged diarrhea; some E. coli elaborate an enterotoxin after the bacteria colonize the intestinal epithelium, leading to watery diarrhea and dehydration • Enterohemorrhagic E. coli (e.g., E. coli O157:H7) produces a Shiga toxin; this infection is becoming increasingly prevalent in the United States (8% of routine stool cultures); generally occurs in the summer months; severe infection occurs in very young or very old patients who eat contaminated food • Most infections are mild and self-­limited, but hemolytic-­ uremic syndrome and thrombocytopenic purpura may occur • At least five other categories of E. coli pathogens are recognized • Enteroinvasive E. coli are associated with a dysentery-­ like clinical picture •  Enterotoxigenic, enteropathogenic, enteroaggregative, and diffusely adherent E. coli may cause traveler’s diarrhea and diarrhea in children  Shigellosis  • Shigella species are virulent invasive gram-­ negative bacilli that cause bloody diarrhea • Shigella dysenteriae is most common, but infections with Shigella sonnei and Shigella flexneri are reported • Associated with fecal contamination of water supply • Most severe infection seen in infants and children, men who have sex with men (MSM), and malnourished and debilitated individuals  Salmonellosis  • Produces several distinct disease states; the two with primary GI involvement are typhoid fever and salmonella gastroenteritis • Organisms replicate within intracellular vacuoles in enterocytes and macrophages and disseminate systemically • Typhoid fever • Caused by consumption of contaminated food or water

• Fecal-­oral transmission occurs • O  ne case per 500,000 people in United States • Causes a systemic febrile and diarrheal illness following a 1-­week incubation period • Complications include massive hemorrhage, peritonitis, and perforation • About 15% mortality rate in untreated patients • Salmonella gastroenteritis •  Produces febrile diarrheal illness within hours of consumption of food contaminated by one of several types of Salmonella; can mimic appendicitis • Causes 80% of food poisoning incidents • Strains resistant to multiple antibiotics have arisen as a result of agricultural practices (feed with antibiotic-­ supplemented grains)  Campylobacteriosis  • Causes both enteritis and colitis • Common stool pathogen in infants, teens, and young adults •  Common cause of traveler’s diarrhea and illness in hikers who consume untreated mountain water; three times more common than giardiasis in the Rocky Mountains • Campylobacter fetus is a cause of severe systemic illness • Produces bloody diarrhea up to 1 week after infection •  Complications include meningitis, pseudomembranous colitis, arthropathy, and Guillain-­Barré syndrome  Cholera  • Produces massive watery diarrhea due to antiabsorptive effect of endotoxin on small intestinal villi • Incubation period ranges from a few hours to 2 days • Recovery takes up to 1 week • Untreated mortality rate of 50% to 75% • Losses of 15 to 20 L of fluid per day reported (when fluid replacement provided)  Yersiniosis  • Can clinically mimic Crohn disease • Aerobic bacteria present in contaminated food or blood products • Enterocolitis is the most common clinical manifestation and usually affects young children • Often associated with mesenteric lymphadenitis • Fatal infections occur in immunosuppressed patients and patients with iron overload 

Gross and Endoscopic Pathology Escherichia coli O157:H7 (Enterohemorrhagic E. coli)  See Figure 6.39. • Hemorrhagic, oozing mucosa, sometimes with ulceration • Pseudomembranes may be present but are rare • Generally affects the right side of the colon • Other E. coli pathogens may cause edema or patchy erythema of colon  Shigellosis  • Typically affects large bowel • Can see mucosal hemorrhage, ulcer, and occasionally pseudomembranes • Typical cases show patchy erythema of colonic mucosa 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

345

Figure 6.39  Escherichia coli infection.  A linear shallow ulcer is surrounded by patchy erythematous mucosa.

Salmonellosis  • Typhoid fever or Salmonella enteritis • Longitudinal oval ulcers with elevated edges • Ulcers are typically on top of Peyer patches in the terminal ileum • Nontyphoidal species may cause edema or patchy erythema of colon 

Figure 6.40  Enterohemorrhagic Escherichia coli infection showing the infectious pattern of injury with neutrophils loose within the lamina propria.

Campylobacteriosis  • Diffuse, hemorrhagic, and focally ulcerative enterocolitis • Often near ileocecal valve with involvement of Peyer patches  Cholera  •  Edematous small bowel mucosa; biopsy rarely done because it adds little to diagnosis or management  Yersiniosis  • Diffuse and focal ulcerations and edema in the ileum and colon • Enlarged mesenteric lymph nodes with foci of necrosis • Hyperplastic lymphoid follicles in mucosa often with overlying aphthous ulcers 

Histopathology Escherichia coli Infection Including E. coli O157:H7 (Enterohemorrhagic E. coli)  See Figures 6.40 and 6.41. • Enterohemorrhagic E. coli produces both ischemic and infectious colitis (toxin interferes with protein synthesis, causing epithelial and endothelial cell damage) • Mucosal hemorrhage, infarct, and pseudomembranes can occur • Focal neutrophilic infiltrates, cryptitis, and crypt abscesses may be present • Adherent bacteria can be seen in some cases of infection with adherent E. coli pathogens 

Figure 6.41  Acute ischemic colitis pattern of injury in a patient with enterohemorrhagic Escherichia coli infection. There is superficial coagulative necrosis and hemorrhage of the colonic mucosa associated with inflammatory pseudomembrane formation. There is preservation of the deep colonic crypts.

Shigellosis  •  Infective-­ type pattern of colitis (focal active colitis) characterized by • Limited areas of increased inflammatory cells; sometimes seen with focal architectural changes • Some areas of biopsy specimen maintain an essentially normal appearance • Inflammation is typically acute with patchy cryptitis and neutrophils within the lamina propria without lamina propria plasmacytosis 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

346

Chapter 6  —  Gastrointestinal System

Salmonellosis  • Typhoid fever or salmonella enteritis • Hyperplastic lymphoid follicles with adjacent mucosal hemorrhage, neutrophilic infiltrates, and atrophy and regeneration • Progressive hemorrhage and inflammation may produce perforation • Can cause focal active colitis pattern of injury  Campylobacteriosis  •  Focal active colitis with neutrophilic infiltrates with cryptitis, hemorrhage, and necrosis  Cholera  • Intact mucosa with minimal changes  Yersiniosis  • Hyperplastic lymphoid follicles with large germinal centers • Punctate ulcers with neutrophilic fissures over hyperplastic lymphoid follicles (similar to Crohn disease) • Suppurative epithelioid granulomas in bowel wall and regional lymph nodes • Acute cryptitis occurs in colon 

Special Stains and Immunohistochemistry •  Organisms are not reliably detected with histologic stains; Gram-­ negative organisms can sometimes be seen with yersiniosis 

Other Techniques for Diagnosis • Pathogenic Escherichia coli •  Requires sophisticated techniques such as a serotyping, PCR, or DNA hybridization for diagnosis, although E. coli O157:H7 can be detected from stool culture using selective growth media and serologic techniques • Pathogenic bacteria are best characterized using microbiologic techniques, serum antibody assays, or occasionally PCR in biopsy specimens 

Differential Diagnosis Enterohemorrhagic Escherichia coli, Campylobacter Species, and Salmonella Species Infection Versus Inflammatory Bowel Disease, Ischemic Colitis, and Pseudomembranous Colitis  • Inflammatory bowel disease • Characterized by a similar neutrophilic infiltrate but distinguished by a more diffuse involvement, less mucosal hemorrhage, basal plasmacytosis, and greater glandular changes (mucin depletion, gland distortion) • Giant cells may be present in any infection, but not the well-­formed non-­necrotizing granulomas seen in Crohn disease • Suppurative granulomas may be seen with Campylobacter species infection • Ischemic colitis • Characterized by superficial necrosis and less acute inflammation than infectious enterocolitis • Clinical history and symptoms are often suggestive of ischemia • Pseudomembranous colitis (Clostridium difficile–associated colitis)

• May be histologically indistinguishable from other causes of infectious colitis •  Pseudomembrane is composed of desquamated epithelial cells, inflammatory cells, and fibrin material • Requires clinical history (i.e., previous antibiotic use) and diagnostic tests for identification • Diagnosis is based on detection of toxins (toxin A and toxin B) or nucleic acid amplification tests; culture is not helpful  Yersinia Species Infection Versus Crohn Disease  • Similar clinical involvement of the terminal ileum with aphthous ulcers • Crohn disease typically does not produce the extensive suppurative granulomas seen with Yersinia species PEARLS • C  ampylobacter species infection may be complicated by meningitis, Guillain-­Barré syndrome, and pseudomembranous colitis • Yersinia species infection is generally associated with mesenteric lymphadenitis • Aeromonads, Klebsiella species, and mycobacterial infection can cause enterocolitis

Selected References Griffin P, Olmstead L, Petras R. Escherichia coli O157:H7-­associated colitis: a clinical and histologic study of 11 cases. Gastroenterology. 1990;99:142–149. Lamps LW. Infective disorders of the gastrointestinal tract. Histopathology. 2007;50:55–63. Nataro JP, Kaper JB. Diarrheogenic Escherichia coli. Clin Microbiol Rev. 1998;11:142–210. Norstrant TT, Kumar NB, Appelman HD. Histopathology differentiates acute self-­limited colitis from ulcerative colitis. Gastroenterology. 1987;92:318–328. Petras R. Non-­neoplastic intestinal diseases. In: Mills SE, ed. Sternberg’s Diagnostic Surgical Pathology. 6th ed. Philadelphia: Wolters Kluwer; 2015:1447–1504.

INFECTIONS IN IMMUNOCOMPROMISED PATIENTS Clinical Features •  Enteric infections are common in immunocompromised patients, particularly patients with AIDS; other causes include the following: • Transplantation (solid organ and bone marrow) • Cancer chemotherapy • Autoimmune diseases (treated with steroids) • Advanced age • Diabetes • Long-­term antibiotic use • Hemodialysis • Postoperative complications • Indwelling vascular devices • Infection may occur at any level of the GI tract, and symptoms depend on level infected •  Esophageal infections: dysphagia, odynophagia, chest pain • Gastric infections: nausea, vomiting, abdominal pain • Intestinal infections: diarrhea

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

•  Complications include bleeding, obstruction, and perforation • In AIDS patients, about one half of all diarrheal episodes are due to infections; some of the remaining episodes are due to AIDS enteropathy (syndrome characterized by chronic diarrhea, malnutrition, and wasting without evidence of GI infection) • Fungal, parasitic, bacterial, and viral infections are all common in untreated AIDS and immunocompromised patients 

Gross and Endoscopic Pathology Viral Infections  •  CMV: variable, often discrete, ulcers affecting the esophagus, stomach, or intestines (Figure 6.42) • HSV: painful ulcers or vesicles, often in esophagus, low rectum and anus, and perianal skin • Adenovirus: nonspecific appearance  Parasitic Infections  • Giardiasis (Giardia intestinalis): nonspecific changes • Coccidiosis (Cryptosporidium parvum, Isospora belli, and Cyclospora cayetanensis) • Cryptosporidium and Isospora species are most commonly found in patients with AIDS • Cyclosporidiosis is more commonly traveler’s diarrhea or associated with contaminated food (e.g., imported fruit) • All show mild, nonspecific features • Microsporidiosis (Enterocytozoon bieneusi and Encephalitozoon intestinalis): mild, nonspecific abnormalities in small bowel  Fungal Infections  • Candidiasis • Most common cause of esophagitis in AIDS patients • Esophagus is most common site (affects small bowel in disseminated disease)

Figure 6.42  Endoscopic photograph of cytomegalovirus-­associated colitis showing three well-­circumscribed “punched-­out” ulcers.

347

• Forms adherent, white-­brown plaques with mucosal hyperemia and ulceration • May completely denude esophagus • Aspergillosis •  Typically involves esophagus, although rare in GI tract • Often produces necrotic ulcers (due to angioinvasive properties resulting in ischemia) • Mucormycosis • Often produces extensive necrosis (due to angioinvasive properties resulting in ischemia); rarely in GI tract • Histoplasmosis • May spread to esophagus and elsewhere from lung •  Rarely causes esophageal perforation or esophagobronchial fistula  Bacterial Infections  • Bacterial pathogens common to the immunocompromised host include Salmonella, Shigella, and Campylobacter species (may be difficult to eradicate in AIDS patients) • Intestinal spirochetosis typically involves the colon diffusely, usually with no endoscopic abnormality; more often seen in immune competent individuals in whom it may be considered a commensal • Tuberculosis causes shallow ulcers with confluent granulomas; most commonly involves ileocecal region (90%) • Mycobacterium avium-­intracellulare (MAI): causes poorly delineated, often plaquelike lesions anywhere in GI tract  Noninfectious AIDS-­Related Enteropathy  • Often has minimal changes at endoscopy 

Histopathology Viral Infections  • CMV • Variable, but often mild mixed inflammation with ulceration and characteristic nuclear or cytoplasmic inclusions typically in endothelial or mesenchymal cells (Figure 6.43) • Rarely causes severe disease with vasculitis and intestinal perforation • HSV • In esophageal and perianal lesions, acute inflammation, and necrosis predominate; classic multinucleated cells, acantholysis, and nuclear inclusions in squamous epithelium may be observed • Adenovirus • Mild, nonspecific chronic inflammation in colon with dystrophic goblet cells containing amorphic nuclei and rarely containing diagnostic inclusion bodies  Parasite Infections  • Giardiasis • Pear-­shaped organism similar in size to an enterocyte nucleus (Figure 6.44) • Trophozoite has two symmetrical nuclei (“monkey face”) •  Organisms are generally found along the luminal border and induce a variable mucosal inflammatory infiltrate

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

348

Chapter 6  —  Gastrointestinal System

Figure 6.45  Cryptosporidiosis showing developmental forms attached to cell surfaces. Figure 6.43  Cytomegalovirus-­associated colitis showing infected stromal cells with cytomegaly, cytoplasmic inclusions, and prominent intranuclear inclusions with surrounding halo.

Figure 6.44  Giardiasis.  Giardia lamblia organisms en face appear pear shaped with paired nuclei.

• Coccidial infections • Cryptosporidium parvum (Figure 6.45) • Isospora belli • Cyclospora cayetanensis • Basophilic dotlike organisms (1 to 3 μm) attached to luminal border (brush border) of small intestinal or colonic epithelial cells • Usually minimal associated chronic inflammation and variable villous abnormalities; mild villous shortening may be seen



• Coccidia are tiny ovoid structures within the epithelial cells of the intestinal villi (may be difficult to detect); merozoites are banana shaped • Tiny ovoid structures (2 to 3 μm) in enterocytes (similar to Isospora species) • Microsporidiosis • Two forms • Mature spores appear as a cluster of dotlike structures (1.5 μm) in the apical cytoplasm of epithelial cell in the small bowel or colon (often difficult to detect) • Larger nucleated sporont (3 to 5 μm) is a basophilic structure in epithelial cells near the villus tips; may cause nuclear indentation  Fungal Infections  • Candidiasis •  Acantholysis with superficial neutrophils within squamous epithelium; can be associated with focal squamous epithelial lymphocytosis •  Mucosal ulceration with neutrophilic infiltrates in severe cases • Yeast and pseudohyphae form within necrotic debris • Invasion of submucosa verifies significant disease • Invasive disease is characterized by mixture of dimorphic forms, including the 3-­to 5-­μm blastoconidia (budding oval yeasts) and pseudohyphae (elongated blastoconidia with indentation at pseudosepta representing several separate yeast organisms) •  True hyphae may form (one elongated organism with parallel walls and no indentation at true septa); branching is absent • Aspergillosis •  Often admixed with necrotic or infarcted debris owing to ischemia caused by the angioinvasive properties of the fungus • Dichotomous branching at 45-­degree angles; 2-­to 4-­μm-­wide hyphae with parallel walls and true septa • Rarely seen in surgical or biopsy specimens

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

Figure 6.46  Intestinal spirochetosis showing numerous organisms attached to the brushed border.

• Mucormycosis • Wide (10 to 20 μm) aseptate hyphae that are irregularly branched and often create folded, ribbon-­like structures • Rarely seen in surgical or biopsy specimens • Histoplasmosis •  May cause granuloma formation or diffuse collections of histiocytes in the lamina propria • Intracellular organisms are 2 to 3 μm • Granulomatous inflammation can mimic Crohn disease  Bacterial Infections  • Syphilis and lymphogranuloma venereum • Usually a proctitis or anorectal inflammation; can mimic inflammatory bowel disease or neoplasia clinically • Associated with intense lymphohistiocytic infiltrate, prominent plasma cells, and lymphoid aggregates without architectural distortion or marked acute inflammation • Silver stains and immunohistochemistry for Treponema pallidum not sensitive • Diagnosis requires serum testing or special studies on rectal swabs • Spirochetosis • Organisms form a basophilic haze on the luminal surface of colonic biopsy specimens (Figure 6.46) •  Can be verified with silver stains (e.g., Warthin-­ Starry) or immunostains for Treponema species • Tuberculosis • Ulceration and necrotizing granulomas with Langhans giant cells • MAI •  Lamina propria contains foamy histiocytes stuffed with acid-­ fast bacilli (AFB; modified AFB) (Figures 6.47 and 6.48)  AIDS-­Related Enteropathy  • Nonspecific apoptosis, chronic inflammation, and villous atrophy due to HIV infections of enterocytes and other cells

349

Figure 6.47  Mycobacterium avium-­intracellulare complex infection involving proximal small intestine. The lamina propria is variably expanded with foamy macrophages.

Figure 6.48  Mycobacterium avium-­intracellulare complex infection (acid-­fast stain).

• Regenerating immature cells have no microvilli • Noninfectious esophageal ulcers •  Range of histologic features, including focal edema, apoptotic cells, and dense neutrophilic inflammation with erosion • Erosion may produce large ulcers that are potentially life threatening • Electron microscopy reveals viral particles, presumed to be HIV, in mononuclear cells •  Rarely seen since advent of aggressive antiretroviral therapy 

Special Stains and Immunohistochemistry • PAS and GMS: fungal structures are highlighted (best used to detect fungi within ulcerated or necrotic tissue in esophageal and gastric biopsy specimens)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

350

Chapter 6  —  Gastrointestinal System

• Giemsa: highlights Cryptosporidium, Isospora, and Microsporidium species •  Trichrome: helps differentiate Giardia species from mucus • Modified AFB: detects MAI infection • Warthin-­Starry or Dieterle: highlights spirochetes • Immunostains available for CMV (useful), HSV, Cryptosporidium and Microsporidia species (immunofluorescence), adenovirus, and Cyclospora species 

and common variable immunodeficiency disease (CVID); look for plasma cells and nodular lymphoid hyperplasia; giardiasis can be found in ileal biopsy specimens • Mentally rule out infection in every small bowel biopsy specimen • Consider immunostain for CMV, AFB, and PAS or GMS for gastrointestinal biopsies (unless the tissue is perfectly normal and the endoscopy detected no lesions) in immunocompromised patients

Other Techniques for Diagnosis

Selected References

• PCR available for numerous microorganisms, including CMV and Microsporidia species; may work in paraffin blocks •  Diagnosis of parasitic infections is readily made by detecting oocytes or cyst forms in stool specimens; AFB stain detects oocyst of Cryptosporidia species in stool samples (not in histologic sections) • Electron microscopy: may be helpful to identify and speciate some microorganisms (e.g., Microsporidium species) 

Differential Diagnosis •  Gastrointestinal infection is the foremost consideration in immunocompromised hosts Kaposi Sarcoma  • Prevalent in AIDS patients; relatively common in GI tract • Characterized by macular red lesions, composed of a spindle cell proliferation in the lamina propria containing extravasated red blood cells in slitlike spaces • Immunohistochemistry for HHV-­8 diagnostic  Whipple Disease  •  Closely simulates MAI with PAS-­ positive foamy histiocytes • Lacks fat vacuoles and AFB positivity characteristic of MAI infection PEARLS • E ven though the patient is immunocompromised, there is usually some inflammation • Consider an opportunistic infection when you see inflammation that you are unable otherwise to account for (even if the patient is not known to be immunocompromised) • Small blue dots in a row on the surface of enterocytes: think of cryptosporidiosis • Small blue dots in the enterocyte: think of microsporidiosis • Blue haze on surface of colonic cells: think of spirochetosis • When mesenchymal cells look too big or there are subtle erosions or inflammation, check mesenchymal cells—particularly endothelial cells—for CMV inclusions • Do not confuse luminal mucin globules for Cryptosporidium species (C. parvum are deeper blue on H&E stain, and generally there are many organisms of equal size along the luminal surface) or for Giardia species (trichrome stain can help) • Giardiasis is common in immune competent patients and is also associated with selective IgA immunodeficiency

Arnold CA, Limketkai BN, Illei PB, et al. Syphilitic and lymphogranuloma venereum (LGV) proctocolitis. Am J Surg Pathol. 2013;37:38–46. Calderaro A, Bommezzadri S, Gorrini C, et al. Infective colitis associated with human intestinal spirochetosis. J Gastroenterol Hepatol. 2007;22:1772–1779. Greenberg PD, Koch J, Cello JP. Diagnosis of Cryptosporidium parvum in patients with severe diarrhea and AIDS. Dig Dis Sci. 1996;41: 2286–2290. Greenson JK, Belitos PC, Yardley JH, Bartlett JG. AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhea. Ann Intern Med. 1991;114:366–372. Gutierrez Y. Diagnostic Pathology of Parasitic Infections with Clinical Correlations. Philadelphia: Lea & Febiger; 1990. Orenstein JM, Chlang J, Steinberg W, et al. Intestinal microsporidiosis as a cause of diarrhea in human immunodeficiency virus-­infected patients. Hum Pathol. 1990;21:475–481. Petras R. Non-­neoplastic intestinal diseases. In: Mills SE, ed. Sternberg’s Diagnostic Surgical Pathology. 6th ed. Philadelphia: Wolters Kluwer; 2015:1447–1504. Strom RL, Gruninger RP. AIDS with Mycobacterium avium-­intracellulare lesions resembling those of Whipple’s disease. N Engl J Med. 1983;309:1324. Varma M, Hester JD, Schaefer FW 3rd, et al. Detection of Cyclospora cayetanensis using a quantitative real-­time PCR assay. J Microbiol Methods. 2003;53:27–36.

WHIPPLE DISEASE Clinical Features •  Rare (approximately 30 cases per year worldwide), chronic systemic illness with prominent GI symptoms •  Commonly affects white adults between 40 and 60 years of age; strong male predominance • More common in people of North American and European ancestry • May involve any organ of the body, most commonly the GI tract, joints, and central nervous system •  Symptoms include malabsorption and diarrhea, abdominal pain, weight loss, polyarthralgia, and cardiac dysfunction • Characteristically responsive to antibiotics; often fatal without treatment 

Gross and Endoscopic Pathology • Yellowish mucosal plaques in small bowel • Occasional shallow ulcers and hemorrhage • Thickened bowel wall • Enlarged mesenteric and retroperitoneal lymph nodes • Hepatosplenomegaly • Mesenteric fat and peritoneal plaques 

Histopathology • Lamina propria, muscularis mucosae, and superficial submucosa infiltrated by foamy histiocytes, which contain the Whipple bacillus (Figure 6.49)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

351

Figure 6.49  Whipple disease within duodenum biopsy specimen.  Histologic section shows flattening of the villi and an expansion of the lamina propria by foamy macrophages with fat vacuoles. Figure 6.50  Whipple disease.  Periodic acid-­Schiff stain shows brightly staining, coarsely granular intracytoplasmic inclusions.

• Intestinal villi are blunted by histiocytic infiltrate other than the histiocytes • Typically minimal or no associated inflammatory infiltrate • Characteristic large open round spaces in mucosa and submucosa (so-­called fat vacuoles), although some represent dilated lymphatics • Regional lymph nodes may contain foamy histiocytes • Foreign-­body epithelioid granulomas and lipogranulomas are sometimes seen in GI mucosa, lymph nodes, spleen, muscles, lung, kidney, and brain • May simulate organizing fat necrosis in retro­per­itoneum 

Special Stains and Immunohistochemistry • Diastase-­resistant PAS stain: Whipple bacilli within histiocytes are strongly positive; stain is coarsely granular, and bacillary structure cannot be seen (Figure 6.50) • AFB stain negative • A specific immunohistochemical stain is available but not widely used 

Other Techniques for Diagnosis • PCR: used to sequence the bacterial 16 s ribosomal gene •  Electron microscopy: demonstrates bacterial rods in macrophage cytoplasm • Has been cultured using special techniques 

Differential Diagnosis MAI Infection  •  Similar histologic profile with sheets of foamy histiocyte-­like cells in the lamina propria • Differs in the conspicuous absence of fat vacuoles and dilated lymphatics • Is faintly PAS positive; bacillary shape can still be seen • More commonly seen in immunocompromised patients  Histoplasmosis  •  Characterized by presence of well-­ formed granulomas and infiltrates of histiocytes with less “foamy” cytoplasm

• Intracellular, 2-­to 3-­μm organisms seen with PAS or silver stain  Waldenstrom Macroglobulinemia  • Foamy macrophages in lamina propria • Differs in lack of robust granular staining of macrophages by PAS • Differs from Whipple disease by showing dilated lymphatics filled with eosinophilic material PEARLS • W  hipple disease is caused by Tropheryma whipplei, a gram-­positive bacillus.

Selected References Arnold CA, Moreira RK, Lam-­Himlin D, et al. Whipple disease a century after the initial description: increased recognition of unusual presentations, autoimmune comorbidities, and therapy effects. Am J Surg Pathol. 2012;36:1066–1073. Dolmans RAV, Boel CHE, Lacle MM, et al. Clinical manifestations, treatment and diagnosis of Tropheryma whipplei infections. Clin Microbiol Rev. 2017;30:529–555. Dobbins WO III. Whipple’s Disease. Springfield, IL: Charles C. Thomas; 1987. Relman DA, Schmidt TM, MacDermott RP, et al. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med. 1992;327:293–301.

CELIAC SPRUE Clinical Features •  Also called gluten-­ sensitive enteropathy or celiac disease • Malabsorptive disorder related to immunologic reaction to the toxic component of cereal grains, the gliadin-­related proteins in wheat, rye, and barley • Genetic predisposition in people of Irish and Northern European descent; much more common in whites; prevalence in the United States could be as high as 1%

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

352

Chapter 6  —  Gastrointestinal System

Figure 6.51  Endoscopic photograph of duodenum showing scalloped valvulae conniventes of celiac sprue.

• Classic presentation includes diarrhea, steatorrhea, flatulence, weight loss, and fatigue; failure to thrive may be seen in infants •  Numerous disease manifestations due to both malabsorption (anemia, neuropathies) and associated autoimmune conditions (dermatitis herpetiformis, diabetes, autoimmune thyroiditis, Sjögren syndrome, and rheumatoid arthritis). • Strong association with HLA-­DQ2 (more than 98% of cases) and HLA-­DQ8 (the other 2%) 

Figure 6.52  Celiac sprue.  Histologic section shows a diffuse severe villous abnormality with crypt hyperplasia and epithelial lymphocytosis. The lamina propria is expanded by chronic inflammatory cells, including plasma cells.

Gross and Endoscopic Pathology •  Flattened mucosa typically most prominent in the proximal small intestine; may show scalloping of the valvulae conniventes (Figure 6.51) 

Histopathology See Figures 6.52 and 6.53. • Characteristic features include shortening of villi and intraepithelial lymphocytes (>40 per 100 enterocytes or >12 in villous tips) •  Surface epithelium shows loss of brush border, and crypts typically show increased mitotic activity •  Secondary features include crypt elongation and hyperplasia • May see a thickened subepithelial collagen band (collagenous sprue); typically in patients refractory to treatment 

Special Stains and Immunohistochemistry • Immunostain for CD3 can be used to evaluate intraepithelial component and may be helpful in recognizing epithelial lymphocytosis; immunostaining for CD3 is not recommended • Alcian blue/PAS with a hematoxylin counterstain can be useful to exclude Whipple disease and to detect foveolar metaplasia

Figure 6.53  Celiac sprue at high magnification emphasizing the intraepithelial lymphocytosis.

• Immunostaining for CD3, CD5, and CD8 should be considered in patients with refractory sprue 

Other Techniques for Diagnosis • Serologic testing includes IgA antiendomysial and anti-­ tissue transglutaminase antibody test; both are sensitive

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

353

and specific; the latter is considered the screening test of choice • Detecting antibodies against deaminated gliadin peptides (DGP) can help detect celiac sprue in otherwise seronegative patients, especially those with low IgA levels •  Molecular evaluation (e.g., T-cell gene rearrangement) should be considered in patients with refractory sprue or in celiac sprue patients developing small intestinal ulcers 

Differential Diagnosis Normal Mucosa  • Malabsorption can be seen with normal small bowel histology (e.g., disaccharidase deficiency) • Normal villous to crypt ratio of 3:1 to 5:1 •  Up to 30 intraepithelial lymphocytes are considered normal  Lymphocytic Enterocolitis  •  Coexisting lymphocytic colitis and celiac spruelike lesion of the proximal small bowel that is not responsive to gluten withdrawal  Refractory or Unclassified Sprue  • Refractory to gluten withdrawal for 12 months • Refractory sprue type I • No atypical lymphocytes • Normal surface CD3, CD5, and CD8 intraepithelial lymphocytes • Polyclonal T-­cell receptor •  Many respond to azathioprine, prednisone, budesonide, or mesalamine • Low rate of progression to enteropathy-­associated T-­cell lymphoma • Refractory sprue type II • May have scattered atypical lymphocytes • Loss of surface CD3 or CD8 (>50% of CD3 +/CD8 −) intraepithelial lymphocytes); aberrant loss of CD5 expression •  Monoclonal T-­ cell receptor gene rearrangement (cryptic T-­cell lymphoma) •  Not responsive to azathioprine, prednisone, or interleukin-­10 (IL-­10) • May respond to cladribine, anti-­CD52, chemotherapy, and stem cell transplantation • About 50% fatality rate, with most cases developing enteropathy-­associated T-­cell lymphoma • Allergic reaction to protein other than gluten  Entities Associated With Variable Villous Abnormality With Intraepithelial Lymphocytosis (>30 Lymphocytes per 100 Enterocytes)  See Figure 6.54. • Latent or partially treated celiac sprue (about 10% of patients) • Tropical sprue (2% of patients) Occurs in natives and naive visitors to specific tropical locations (e.g., India, Africa, Southeast Asia, Central America, West Indies) • Treated with broad-­spectrum antibiotics (believed to be infectious etiology) and vitamins • IgA deficiency

Figure 6.54  Duodenal intraepithelial lymphocytosis.  This variable villous abnormality shows villi of near-­normal length with increased (>30 per 100 enterocytes) intraepithelial lymphocytes.

• Infectious gastroenteritis and stasis • Peptic ulceration/H. pylori infection •  Although the most sensitive site for diagnosis of celiac sprue is the duodenal bulb, specimens from this area must be interpreted with caution because the area is prone to peptic injury • Alcian Blue/PAS stain with a hematoxylin counterstain can be useful in detecting foveolar metaplasia seen in peptic duodenitis • Autoimmune diseases (e.g., rheumatoid arthritis, Graves disease, Crohn disease) • Drug-­related lesions (e.g., NSAIDs, olmesartan) • Autoimmune enteritis • X-­linked severe form due to germline mutation of FOXP3 gene can be associated with immune dysregulation and polyendocrinopathy • Can have circulating antibodies to enterocytes, goblet cells, parietal cells, and smooth muscle cells • Absence of goblet cells and/or Paneth cells, lack of intraepithelial lymphocytosis coupled with a nonresponsiveness to a gluten-­free diet can be clues to the diagnosis  Entities Associated With Severe Villous Abnormality and Crypt Hypoplasia  • Kwashiorkor, marasmus • Megaloblastic anemia • Radiation and chemotherapy effect • Microvillus inclusion disease 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

354

Chapter 6  —  Gastrointestinal System

Entities Associated With Variable Villous Abnormality That Contain Specific Diagnostic Changes  • Collagenous sprue • Increased subepithelial collagen plate (>10 μm) • Often refractory to gluten withdrawal • Can be associated with drugs (e.g., olmesartan) • Common variable immune deficiency and selective IgA immunodeficiency • Reduced numbers of plasma cells within the lamina propria +/− nodular lymphoid hyperplasia • Increased apoptotic bodies • May have comorbid giardiasis • Eosinophilic gastroenteritis • Parasitic infestation • Waldenstrom macroglobulinemia •  Lymphangiectasia with intralymphatic amorphous eosinophilic material • Foamy macrophages in lamina propria • Lymphangiectasia • Abetalipoproteinemia • Enterocytes with intracytoplasmic vacuoles PEARLS • D  iagnosis is best made by correlation of clinical history with serology and histologic features (documentation of malabsorption, characteristic histologic features, and improvement of symptoms and resolution of histologic abnormalities on removal of gluten from the diet) • Removal of gluten from the diet is typically curative • Withdrawal of gluten causes a return to normal that progresses from distal to proximal (i.e., duodenum is the last to recover); must consider where biopsy is taken from when evaluating recovery • Always consider T-­cell lymphoma in patients who present with refractory sprue or in celiac sprue patients who have developed small intestinal ulcers (perform immunohistochemistry or PCR)

Selected References Bao F, Green PHR, Bhagat G. An update on celiac disease histopathology and the road ahead. Arch Pathol Lab Med. 2012;136:735–745. Cellier C, Cerf-­Bensussan N. Treatment of clonal refractory celiac disease or cryptic intraepithelial lymphoma: a long road from bench to bedside. Clin Gastroenterol Hepatol. 2006;4:1320–1321. Greenson JK. The biopsy pathology of non-­coeliac enteropathy. Histopathol. 2015;66:29–36. Husby S, Murray JA, Katzka DA. AGA clinical practice update on diagnosis and monitoring of celiac disease—changing utility of serology and histologic measures: expert review. Gastroenterol. 2019;156: 885–889. Lockyer MG, Petras R. Small Intestine. In: Mills SE, ed. Histology for Pathologists. 5th ed. Philadelphia: Wolters Kluwer; 2020:615–639. Petras R. Non-­neoplastic intestinal diseases. In: Mills SE, ed. Sternberg’s Diagnostic Surgical Pathology. 6th ed. Philadelphia: Wolters Kluwer; 2015:1447–1504. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1981– 2002. Rubio-­Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656–676.

SMALL INTESTINAL ADENOMA AND ADENOCARCINOMA Clinical Features • Can be sporadic and proximal in older patients •  Primary adenomas and adenocarcinomas that occur in the small intestine, especially in younger patients, can be associated with underlying conditions such as the FAP syndromes (FAP, attenuated FAP, MUTYH-­ associated polyposis syndrome, polymerase proofreading associated polyposis) and Lynch syndrome •  Adenocarcinoma of the distal small bowel can be a complication of Crohn disease • More common small bowel malignancies are metastases, lymphoma, and neuroendocrine tumors Adenoma  • Small intestinal adenomas are extremely rare (10), may indicate a genetic syndrome (e.g., FAP, attenuated FAP, MUTYH-­associated polyposis syndrome, and polymerase proofreading associated polyposis) • Generally exhibit slow growth with 10-­year doubling time • Prevalence is thought to be around 35% in Western civilizations • Prevalence increases dramatically after 40 years of age (peak, 60 to 70 years) • Presence of one adenoma is associated with a 40% to 55% risk for additional adenomas • Risk for presence of villous architecture and for higher-­ grade dysplasia increases with multiple adenomas and increasing size • Risk for new adenomas is 20% to 60% within 3 to 10 years after initial polypectomy • Symptoms include the following: • Bleeding; however, adenomas smaller than 1 cm are usually asymptomatic, except those in the rectosigmoid area, which may bleed •  Larger and villous lesions may produce mucinous diarrhea or constipation •  Ominous signs are obstruction and abdominal pain • Detection of small sigmoid or rectal adenomas is indication for full colonoscopy 

Figure 6.87  Endoscopic view of hyperplastic polyp.  Hyperplastic polyps are typically small (1 cm) stalks; thought to arise following torsion resulting in hemorrhage, inflammation, fibrosis, or increased pressure causing herniation of the adenomatous epithelium through defects in the muscularis mucosae •  Pseudoinvasion is recognized by the following conditions: •  Presence of lamina propria around adenomatous glands or by identifying direct connection to mucosa •  Hemosiderin deposits and fibrosis rather than desmoplasia • Lack of malignant cytology • Rounded contours to malpositioned glands without infiltration • Traditionally defined serrated adenoma •  True adenoma (with epithelial dysplasia) characterized by serration; nature of the epithelial atypia is controversial with some experts believing it to be a type of “senescence” rather than true dysplasia (Figure 6.91) • Usually left sided and pedunculated • Ectopic crypt formation in which there is budding of proliferating crypts situated perpendicular to the long axis of a filiform or villous structure is touted as the most characteristic histologic feature •  Lining cells are less mature than in hyperplastic polyps often showing eosinophilic cytoplasm or gastric foveolar metaplasia, and they show superficial mitotic figures, intact nuclear polarity, a high nuclear-­to-­cytoplasmic ratio, and nuclear pleomorphism; however, the cells have abundant mucin

Figure 6.91  Traditionally defined serrated adenoma.  These polyps are typically pedunculated, left sided, and demonstrate epithelial dysplasia. The serration imparts a resemblance to hyperplastic polyp. Serrated adenoma typically shows gastric foveolar change and eosinophilic cytoplasmic changes.

• May be admixed with areas of hyperplastic polyp, sessile serrated polyp, and classic adenoma 

Special Stains and Immunohistochemistry •  Stromal cells (including bizarre stromal cells) in an inflammatory polyp are carcinoembryonic antigen (CEA), cytokeratin, and mucin negative; positive for vimentin and muscle-­specific actin 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Sessile Serrated Polyp  See Figures 6.92 and 6.93. • Also known as sessile serrated adenoma and sessile serrated lesion (probably the best term) • Typically right sided, large (>1 cm), sessile, and often poorly circumscribed • Likely is the specific precursor lesion of sporadic microsatellite instability–high (MSI-­H) colorectal carcinoma • Polyp type seen in serrated polyposis syndrome • May mimic enlarged mucosal fold; can show a tenacious mucus cap and peripheral debris endoscopically • Polyps containing four or more of the following characteristics should be classified as sessile serrated polyp and differentiated from hyperplastic polyp: • Basal crypt dilation • Crypt branching • Horizontal orientation of crypts • Inverted histology (glands malpositioned into muscularis mucosae or submucosa) • Prominent serration • Epithelial-­to-­stromal ratio exceeding 50% • No surface basement membrane thickening • Persistent nuclear enlargement, atypia, and nucleoli in the upper third of crypt • Mitosis figures in upper third of crypt • Abnormal patchy distribution of dystrophic goblet cells

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

379

•  Recommendation for postpolypectomy surveillance includes the following: • Small (95% glands; Grade 2: 50% to 95% glands; Grade 3: 1 cm • Often sausage-­like appendix • Mucin-­filled diverticula may be present • With coexisting carcinoma there can be a mass sometimes with abundant mucus and necrosis; may obliterate appendix, making exact site of origin difficult to determine 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

399

Histopathology Mucinous Cystic Neoplasms  •  Abundant mucus fills and dilates the appendiceal lumen • Can extend into diverticula with rupture • Atrophy of appendiceal wall, characterized by loss of muscularis mucosae, hyalinized fibrosis of muscularis propria, dystrophic calcifications, loss of lymphoid tissue • Intraluminal mucin may compress lining epithelium, complicating evaluation for dysplasia • May have villous or papillary architecture •  Circumferential proliferation of neoplastic columnar cells • LAMN •  Neoplastic cells with basally oriented nuclei and minimal cytologic atypia (Figure 6.132) • Dissecting mucin present with or without associated epithelial cells may be present in appendiceal wall or on serosal surface •  Neoplastic mucin on serosal surface may cause neovascularization • “Pushing” invasion: neoplastic cells growing along a fibrous stroma, but without a desmoplastic stromal response • HAMN • Architectural features of LAMN, but with more severe nuclear atypia, loss of nuclear polarity, and increased mitotic figures • Mucinous adenocarcinoma •  Neoplastic glands invade appendiceal wall with tumor desmoplasia (Figure 6.133) • May coexist with precursor mucinous lesion • Can be associated with pseudomyxoma peritonei • Nonmucinous adenocarcinoma • Identical to colorectal adenocarcinomas  Pseudomyxoma Peritonei  •  Peritoneal accumulation of gelatinous ascites caused by benign or malignant neoplasms of the vermiform appendix • Often composed of virtually acellular pools of mucus • Suggested classification depends on the extent of cellularity and degree of epithelial atypical within the mucus of the pseudomyxoma •  PSOGI suggests pseudomyxoma peritonei with low-­ grade histologic features, pseudomyxoma peritonei with high-­grade histologic features, and pseudomyxoma peritonei with signet ring cells (bad prognosis) • In women, pseudomyxoma peritonei can occur with concomitant ovarian mucinous tumors; the vermiform appendix is the primary site in all cases 

Special Stains and Immunohistochemistry • PAS, mucicarmine, and Alcian blue stains are all positive in mucinous tumors (generally unnecessary) • CK7, CK20, and CDX-­2 may be used to differentiate appendiceal/colonic primary versus ovarian mucinous neoplasia 

Other Techniques for Diagnosis • Noncontributory 

Figure 6.132  LAMN of the appendix showing a villous adenoma similar to that seen in the colon.

Figure 6.133  Invasive well-­differentiated adenocarcinoma arising in association with a mucinous cystic neoplasm of the appendix (mucinous cystadenocarcinoma). There is an infiltrating pattern to the neoplastic glands, which are surrounded by a tumor desmoplasia.

Differential Diagnosis Ruptured Acute Appendicitis  • May mimic LAMN • Characterized by acute inflammation, mural necrosis, and acute periappendicitis without dissecting mucus, neoplastic epithelium, or desmoplastic tissue reaction  Myxoglobulosis  • May present with mucocele • Term is applied to intraluminal tiny pearl-­like globules that are often calcified (Figure 6.134) • Histologically, eosinophilic laminations with external calcification are seen • Can coexist with appendiceal mucinous neoplasia •  Lining of appendix can undergo pseudosynovial metaplasia

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

400

Chapter 6  —  Gastrointestinal System

NEUROENDOCRINE TUMORS OF THE VERMIFORM APPENDIX Clinical Features Neuroendocrine Tumors  • Most common appendiceal neoplasm • Many are asymptomatic •  Can present with signs and symptoms of acute appendicitis  Goblet Cell Adenocarcinoma  • Previously called goblet cell carcinoid • Most common in Caucasians; median age 50 •  Can present with signs and symptoms of acute appendicitis • Prognosis depends on tumor stage and grade 

Gross and Endoscopic Pathology Figure 6.134  Myxoglobulosis of the vermiform appendix.  The resected dilated appendix contained these intraluminal pearl-­like globules along with a mucinous cystadenoma.

PEARLS • B  ecause many appendiceal neoplasms present with acute appendicitis, all appendectomy specimens should be carefully examined grossly to detect subtle mural lesions or tumors; routine histologic examination of the appendiceal margin of excision is highly recommended • For mucinous lesions, evaluation of the entire appendix may be necessary to exclude adenocarcinoma • Low-­grade mucinous neoplasia with acellular extra-­ appendiceal mucus limited to the periappendiceal area has a good prognosis • For adenocarcinoma—follow CAP protocols

Selected References Carr NJ, Cecil TD, Mohamed F, et al. A consensus for classification and pathologic reporting of pseudomyxoma peritonei and associated appendiceal neoplasia: the results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process. Am J Surg Pathol. 2016;40:14–26. Gonzalez JE, Hann SE, Trujillo YP. Myxoglobulosis of the appendix. Am J Surg Pathol. 1988;12:962–966. Nitecki SS, Wolff BG, Schlinkert R, et al. The natural history of surgically treated primary adenocarcinoma of the appendix. Ann Surg. 1994;219:51–57. Montgomery E, Yantiss K, Snover D, et al. Tumors of the Intestines. Atlas of Tumor Pathology, Fourth Series, Fascicle 26. Washington, DC: Armed Forces Institute of Pathology; 2017. Noffsinger AE. Neoplastic appendix. In: Noffsinger A, ed. Fenoglio-­ Preiser’s Gastrointestinal Pathology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2017:1069–1140. Pai RK, Beck AH, Norton JA, et al. Appendiceal mucinous neoplasms: clinicopathologic study of 116 cases with analysis of factors predicting recurrence. Am J Surg Pathol. 2009;33:1425–1439. Yantiss RK, Shia J, Klimstra DS, et al. Prognostic significance of localized extra-­appendiceal mucin deposition in appendiceal mucinous neoplasms. Am J Surg Pathol. 2009;33:248–255.

• Present as a nodule or thickening of appendiceal wall • Typically occur at the tip of the appendix 

Histopathology Neuroendocrine Tumors  • Insular (EC-­cell): typical midgut pattern of carcinoid tumor, well-­ demarcated variably sized islands composed of cells with uniform polygonal shape, little nuclear pleomorphism or mitotic activity with eosinophilic granular cytoplasm (Figure 6.135) •  Tubular (L-­ cell): dominant glandlike pattern sometimes with columns or ribbons and acinar arrangement of small neoplastic endocrine cells that lack pleomorphism, have little or no mitotic activity ­(Figure 6.136)  Goblet Cell Adenocarcinoma  • Graded based on proportion of low- and high-grade patterns •  Low-grade (classic) features: small, well-defined clusters and tubules of bland, mucus-secreting epithelial cells, extracellular mucin, few mitoses, and no stromal desmoplasia • High-grade features: single cell infiltration, complex architecture, increased nuclear atypia and mitotic figures, necrosis, and a desmoplastic stromal response 

Special Stains and Immunohistochemistry • Mucin stains can be done with goblet cell adenocarcinoma but are usually not necessary •  Chromogranin and synaptophysin immunohistochemistry is helpful in the differential diagnosis of tubular carcinoid versus carcinoma • Tubular carcinoids are frequently positive for immunoreactive glucagon 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis •  Fibrous obliteration of the lumen and appendiceal neuroma

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

Figure 6.135  Carcinoid tumor of the appendix, midgut pattern with insular groupings of carcinoid tumor cells showing cytoplasmic granules, round nuclei, and a coarsely granular chromatin pattern.

401

•  These spindle cell proliferations can contain scattered neuroendocrine cells that represent hyperplasia • A definite insular or tubular growth pattern, extension of the cells into the muscularis propria or beyond, or the presence of a gross nodule indicates neuroendocrine tumor •  Tubular carcinoid versus well-­ differentiated adeno­ carcinoma • Immunohistochemistry for chromogranin and synaptophysin helpful • Signet ring cell carcinoma versus goblet cell carcinoid • Signet ring cell carcinoma is more infiltrative, with increased pleomorphism and larger nuclei •  Neurofibroma, granular cell tumor, paraganglioma, ganglioneuroma, GI stromal tumor, sarcoma, and lymphoma have been described primarily within the vermiform appendix but are extremely rare PEARLS • C  omposite tumor with areas that look like conventional adenocarcinoma will act like conventional adenocarcinoma • Discovery of carcinoid and variant tumors is usually a surprise in an appendectomy specimen removed either incidentally or for acute appendicitis; therefore, routine examination of the resection margin is recommended • Indications for right hemicolectomy for appendiceal carcinoid tumor include size greater than 2 cm, invasion beyond muscularis propria, vascular invasion, incomplete excision (e.g., positive margin of resection), and coexisting adenocarcinoma • CAP protocol should be used in reporting

Selected References

Figure 6.136  Tubular carcinoid of the appendix composed of ribbons and small tubular structures.

Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128:1717–1751. Montgomery E, Yantiss K, Snover D, Tang L. Tumors of the Intestines. Atlas of Tumor Pathology, Fourth Series, Fascicle 26. Washington, DC: Armed Forces Institute of Pathology; 2017. Reid MD, Basturk O, Shaib WL, et al. Adenocarcinoma ex-­goblet cell carcinoid (appendiceal-­type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-­ abdominal dissemination: an analysis of 77 cases. Modern Pathol. 2016;29:1243–1253. Yozu M, Johncilla ME, Srivastava A, et al. Histologic and outcome study supports reclassifying appendiceal goblet cell carcinoids as goblet cell adenocarcinomas, and grading and staging similarly to colonic adenocarcinomas. Am J Surg Pathol. 2018;42:898–910.

SECONDARY MALIGNANCIES IN THE GASTROINTESTINAL TRACT GASTROINTESTINAL METASTATIC DISEASE Clinical Features

Figure 6.137  Appendiceal goblet cell carcinoid adenocarcinoma.  Note the insular growth pattern of neoplastic cells showing prominent signet resembling mature goblet cells.

Esophagus  • Primary tumors of the lungs, pharynx, thyroid, and stomach may invade the esophagus directly • Breast, kidney, testicular, prostate, and pancreatic neoplasms can metastasize to the esophagus • Breast cancer may produce strictures due to extensive lymphatic infiltration • Melanoma metastasizes to the GI tract in 43% of cases 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

402

Chapter 6  —  Gastrointestinal System

Stomach  • Stomach is a more common site of metastases than small or large bowel • Most common gastric metastases are melanomas and carcinomas of the lung and breast • Gastric metastases often have a targetoid endoscopic appearance due to extensive central necrosis (features particularly notable on radiologic examination)  Small Intestine  •  Because primary small bowel tumors are so uncommon, metastases (carcinomas and sarcomas) are the most common tumors of the small bowel • Larger tumors are often polypoid, causing obstruction, intussusception, or perforation •  Tumors near the ampulla may represent secondary involvement of the intestine by pancreaticobiliary adenocarcinoma; primary ampullary malignancies usually arise in a preexisting adenoma and have a better prognosis than pancreaticobiliary carcinoma • Malignant melanoma is the most common small bowel metastasis and often produces obstruction • About 5% of testicular tumors metastasize to the GI tract • Sarcomas only rarely metastasize to the small bowel • Bronchogenic squamous carcinoma has a propensity to metastasize to the proximal jejunum  Large Intestine  • Most common spread of metastases to the colon is by peritoneal seeding, particularly at the pouch of Douglas (anterior wall of rectum) • Prostatic carcinoma may directly invade the rectum, producing GI rather than urinary symptoms • Anal melanomas may extend into the rectum • Most common colonic metastases in males are from noncolonic GI tumors and lung carcinomas • Most common colonic metastases in females are from ovarian, breast, and lung carcinomas • Colonic metastases are often asymptomatic, but with large tumors, obstruction and bleeding may occur  Appendix  • Patients with mucinous tumors of the ovary may have a concurrent mucinous neoplasm in the appendix; all represent appendiceal primary tumors • Other metastatic tumors reported include breast, stomach, cervix, and lung 

Gross and Endoscopic Pathology Esophagus  • Nonspecific  Stomach  •  Often have multiple tumors that commonly show extensive central necrosis  Small Intestine  • Intramural masses form submucosal nodules and eventually produce bulging polypoid masses • Tumors may be circumferential • Black tumors in the small intestine suggest melanoma; however, melanoma is often amelanotic

Figure 6.138  Resection specimen of large cell lymphoma involving the small intestine showing a stricturing and ulcerating mass lesion with a homogeneous, fleshy cut surface.

• Fleshy cut sections are typical for lymphoma (Figure 6.138) •  Ovarian metastases are most likely to present with carcinomatosis • Ampullary tumors should be examined carefully to detect any residual adenoma (making the lesion more likely a primary small bowel neoplasm, rather than pancreatic)  Large Intestine  • Metastasis is suggested by a mural-­centered mass not involving the overlying mucosa 

Histopathology Esophagus  • Metastatic carcinoma including breast carcinoma preferentially involves the submucosal lymphatics and leaves overlying mucosa intact  Stomach  • Breast carcinoma may be diffusely infiltrative and difficult to distinguish from a primary poorly differentiated adenocarcinoma, diffuse type of Lauren  Small Intestine  • Ampullary tumors that are primary may have residual adenoma • Pancreatic primary tumors with secondary involvement of the duodenum grow as an infiltrating, well-­differentiated glandular proliferation or as highly anaplastic carcinoma with marked desmoplasia if high grade; often have non-­ neoplastic duodenal mucosa on the surface  Large Intestine  •  Primary colonic tumors may be distinguished from metastatic adenocarcinoma (such as lung) by the presence of extensive necrosis containing nuclear fragments (so-­called dirty necrosis) along with lack of a surface component and predominant mural location 

Special Stains and Immunohistochemistry • In all cases, immunohistochemical markers unique to a specific site outside the GI tract are helpful for diagnosing a metastasis (e.g., TTF-­1 for lung primary)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 6  —  Gastrointestinal System

• Combination of cytokeratin 20 and cytokeratin 7 are often helpful in distinguishing primary colonic carcinoma from metastases • Estrogen receptor (ER) and progesterone receptor (PR) testing can be performed on a metastatic breast carcinoma, but these immunostains are not specific for breast cancer • S-­100 protein, SOX-­10, and HMB-­45 are typically positive in metastatic malignant melanoma 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis • Clinical history is important • Regardless of the site, tumors in the GI tract that are not mucosal based or that predominantly involve the bowel wall and serosa should be considered potentially metastatic

403

PEARLS • A  ny small intestinal malignancy outside the ampullary region is more likely to be a metastatic tumor than a primary tumor • Metastases tend not to involve the surface epithelium; evaluation of the deeper lamina propria and submucosa is crucial, especially in biopsy specimens

Selected References Adair C, Ro JY, Sahin AA, et al. Malignant melanomas metastatic to gastrointestinal tract: a clinico-­pathologic study. Int J Surg Pathol. 1994;2:3. Berezauski K, Stastny J, Kornstein M, et al. Cytokeratin 7 and 20 and carcinoembryonic antigen in ovarian and colonic carcinoma. Mod Pathol. 1995;9:426. Telerman A, Gerard B, van den Hevle B, et al. Gastrointestinal metastases from extra-­abdominal tumors. Endoscopy. 1985;17:99–101.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7

Hepatobiliary System DUSTIN E. BOSCH  •  MATTHEW M. YEH  •  PAUL E. SWANSON

Chapter Outline Viral Hepatitis  405

Hepatoblastoma  427

Nonviral Infections  407

Bile Duct Hamartoma (Von Meyenburg Complex)  428

Drug-­Induced Liver Injury  408 Alcoholic Liver Disease and Alcoholic Steatohepatitis  409 Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis  411

Peribiliary Gland Hamartoma (Bile Duct Adenoma)  429 Mucinous Cystic Neoplasm  430 Intraductal Papillary Neoplasm of the Bile Duct  430

Acute Fatty Liver of Pregnancy  412

Cholangiocarcinoma: Intrahepatic, Extrahepatic, and Hilar (Klatskin Tumor)  432

Hemochromatosis  412 Wilson Disease  413 α1-­Antitrypsin Deficiency  414

Combined Hepatocellular-­Cholangiocarcinoma  433

Autoimmune Hepatitis  415

Gallbladder Carcinoma  434

Primary Biliary Cholangitis  416

Hepatic Metastases  436

Primary Sclerosing Cholangitis  417

Peliosis Hepatis  437

IgG4-­Related Sclerosing Cholangitis  418

Hemangioma  437

Liver Transplantation Pathology  419 Cirrhosis  420

Mesenchymal Hamartoma  440

Hepatocellular Adenoma  423

Embryonal (Undifferentiated) Sarcoma  441

Hepatocellular Carcinoma  424

VIRAL HEPATITIS CLINICAL FEATURES Hepatitis A Virus • Single-­stranded RNA (ssRNA) virus (picornavirus) • Transmission route: fecal-­oral • Incubation: 2 to 6 weeks • Self-­limited • Not associated with chronic carrier state, chronic hepatitis, or hepatocellular carcinoma (HCC) 

Hepatitis B Virus double-­ stranded

DNA

Epithelioid Hemangioendothelioma  439 Angiosarcoma  439

Focal Nodular Hyperplasia  422

•  Partially circular (hepadnavirus)

Infantile Hemangioendothelioma  438

virus

• Transmission route: perinatal, sexual, and parenteral • Incubation: 6 to 8 weeks • Chronic infection (10%): persistent serum hepatitis B surface antigen (HBsAg) more than 6 months after diagnosis • Associated with chronic hepatitis, fulminant hepatitis, cirrhosis, and HCC • Anti-­HBsAg confers long-­term immunity 

Hepatitis C Virus • ssRNA virus (flavivirus-like) • Transmission route: parenteral • Incubation: 6 to 12 weeks • Highest rate of chronic hepatitis (60% to 80%) and persistent infection

405

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

406

Chapter 7  —  Hepatobiliary System

B

A

Figure 7.1  A, Ground-­glass hepatocytes in hepatitis B. B, Chronic hepatitis C. Classic lymphoid aggregates with focal mild interface hepatitis.

• Associated with cirrhosis and HCC • Anti-­hepatitis C virus (HCV) does not confer immunity • Serum transaminases: fluctuating 

Hepatitis D (Delta Agent) Virus • Defective RNA virus requiring HBsAg (envelope protein) for infectivity • Transmission route: parenteral • Associated with more severe course of HBV infection, cirrhosis, and HCC 

Hepatitis E Virus • ssRNA virus • Water-­borne infection • Incubation: 6 weeks • Virion shed in stools • Usually self-­limited • High mortality rate among pregnant women 

Hepatitis G Virus • Nonpathogenic 

GROSS PATHOLOGY • Noncontributory 

HISTOPATHOLOGY Acute Viral Hepatitis Injury is predominantly hepatocellular in the acini (zone 3) • General features • Predominantly lymphocytic infiltrate, usually conspicuous in zone 3 •  Swollen hepatocytes with rarefied and granular cytoplasm •  Apoptotic hepatocytes showing pyknotic nuclear remnants, shrunken and dense cytoplasm

• Liver cell dropout with replacement by small groups of lymphocytes and macrophages • Specific features • Hepatitis A virus (HAV): perivenular cholestasis; hepatitis with periportal inflammation (interface hepatitis) and dense portal infiltrate, including abundant plasma cells • HBV: ground-­glass hepatocytes (indicating abundant HBsAg in the hepatocytes—evidence of viral infection) (Figure 7.1A) 

Chronic Viral Hepatitis • Persistent liver injury with positive viral serology and/ or nucleic acid test, and abnormally high serum aminotransferase of greater than 6 months’ duration •  Injury is accentuated in the portal and periportal regions • General features • Portal inflammatory infiltrate predominantly composed of lymphocytes with or without interface hepatitis of varying severity (see Figure 7.1B) • Spotty or confluent necrosis with or without bridging necrosis • Portal fibrous expansion, periportal fibrosis, bridging fibrosis to cirrhosis (stages 1 to 4) • Specific features • HBV: ground-­glass hepatocytes • HCV: lymphoid aggregates or follicles with or without germinal centers, focal mild macrovesicular steatosis, damaged interlobular bile ducts 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY •  Immunohistochemistry for hepatitis B core antigen (HBcAg), HBsAg, and hepatitis B e antigen (HBeAg) 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7  —  Hepatobiliary System

OTHER TECHNIQUES FOR DIAGNOSIS

407

• Electron microscopy: HBsAg in hepatocyte cytoplasm (22-­nm spheres and rods) 

• Periductal fibrosis and loss of interlobular bile duct • Association with ulcerative colitis is common • Characteristic beading on endoscopic retrograde cholangiopancreatography (ERCP) 

DIFFERENTIAL DIAGNOSIS

Drug-­Induced Liver Injury

• Serologic markers and virologic assays of viral infection are virtually essential to establish or exclude the diagnosis

PEARLS

Alcoholic Hepatitis • Clinical history is important • Fatty change is typical but not always present • Many ballooned hepatocytes and Mallory-­Denk bodies are usually seen • Megamitochondria may be seen • Lobular inflammatory foci (usually rich in neutrophils) •  Perivenular and pericellular fibrosis (chicken-­ wire pattern) 

Nonalcoholic Steatohepatitis •  Significant steatosis is present, predominantly macrovesicular • Zone 3 injury with lobular inflammatory foci pattern in adults • Zone 1 injury with portal inflammatory dominant pattern in children •  Ballooned hepatocytes and Mallory-­ Denk bodies are typical findings • Megamitochondria may be seen • Perivenular and pericellular fibrosis (chicken-­wire pattern) in adults • Fibrosis initiates in portal tracts in children 

Autoimmune Hepatitis • Serologic markers important (positive antinuclear antibody [ANA], anti–smooth muscle antibody [ASMA], or liver-­kidney microsomal antibody [LKM]) • Coexistent autoimmune diseases are common •  Prominent plasma cells in the portal and periportal region or deep within the parenchyma • Marked interface hepatitis and parenchymal activity • Bridging necrosis is common and may form hepatitis rosettes 

Epstein-­Barr Virus Hepatitis • Seen more often after transplantation •  Marked sinusoidal lymphoplasmacytic inflammatory infiltrate characteristically in single-­file arrangement • Marked hepatocellular regeneration • EBV encoded RNA in situ hybridization may be helpful 

Primary Biliary Cholangitis • Bile ductular reaction • Florid duct lesion with granuloma • Damage and loss of interlobular bile duct • Positive antimitochondrial antibody (AMA) • Cholestatic picture 

Primary Sclerosing Cirrhosis • Bile ductular reaction

• Clinical history is important (time course of drug use) • Negative serologic markers of viral infection

• S erologic markers (viral and autoimmune), virologic assays, as well as the pattern of hepatic enzyme elevations are most important in distinguishing the many causes of hepatitis.

Selected References Batts KP, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417. Gerber MA, Thung SN. The diagnostic value of immunohistochemical demonstration of hepatitis viral antigens in the liver. Hum Pathol. 1987;18:771–774. Goodman ZD, Ishak KG. Histopathology of hepatitis C infection. Semin Liver Dis. 1995;15:70–81. Ishak KG. Chronic hepatitis: morphology and nomenclature. Mod Pathol. 1994;7:690–713. Sciot R, Van Damme B, Desmet VJ. Cholestatic features in hepatitis A. J Hepatol. 1986;3:172–181.

NONVIRAL INFECTIONS CLINICAL FEATURES • High mortality rate •  Patients often have fever and right upper quadrant tenderness • Surgical drainage is often required • Bacterial abscesses are caused by portal spread of extrahepatic infection with Staphylococcus aureus, Salmonella typhi, and Treponema pallidum (syphilis) • Parasitic abscesses are caused by Entamoeba histolytica, Echinococcus species, malaria, Leishmania species, Ascaris lumbricoides, and liver flukes (e.g., Clonorchis sinensis, Fasciola hepatica, and Opisthorchis viverrini) 

GROSS PATHOLOGY •  Bacteremic spread through arterial or portal system: multiple, soft, grossly necrotic lesions • Bacteremic spread by direct extension or trauma: solitary, large, soft, grossly necrotic lesions

Syphilis • Single or multiple soft well-­circumscribed lesions (gummas) that eventually scar, resulting in hepar lobatum, which grossly resembles cirrhosis 

Entamebiasis •  Well-­ circumscribed lesion containing thick, dark material 

Echinococcal (Hydatid) Cyst • Space-­occupying cystic lesion with internal daughter cysts

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

408

Chapter 7  —  Hepatobiliary System

B

A

Figure 7.2  A, Bacterial abscess. Low-­power view shows liver parenchyma with marked necrosis. B, Amebic abscess. Liver tissue showing necrotic debris with trophozoites at the center of the photomicrograph.

•  Granular cyst contents (hydatid sand) composed of scolices and hooklets 

Ascariasis • Numerous foul-­smelling cavities 

Malaria and Leishmaniasis • Hepatomegaly (secondary Kupffer cell hyperplasia) 

HISTOPATHOLOGY Bacterial • Marked neutrophilic infiltrate with hepatocyte destruction (Figure 7.2A) 

Leishmaniasis • Kupffer cell hyperplasia and phagocytosis of organisms (Donovan bodies) 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Gram stain: helps highlight bacteria • Warthin-­Starry, Dieterle stain, or T. pallidum immunohistochemistry: syphilis • Giemsa stain to identify amastigotes: leishmaniasis •  Direct examination for Echinococcus species scolices and liver flukes 

Syphilis

OTHER TECHNIQUES FOR DIAGNOSIS

• Congenital: neonatal hepatitis •  Tertiary: gummas (granulomatous abscesses), which heal as dense scars 

• Culture or nucleic acid tests may help identify organism 

Entamebiasis • Necrotic debris with trophozoites at the periphery (see Figure 7.2B) 

Echinococcal Infection • Outer laminated nonnuclear layer, inner nucleated germinal layer with attached capsules containing numerous scolices that are released into the cyst cavity and give rise to daughter cysts • Secondary cholangitis results from obstruction of intrahepatic bile ducts 

Ascariasis • Necrotic debris with granulomatous and eosinophilic response to degenerated parasites 

DIFFERENTIAL DIAGNOSIS • See earlier discussion for specific infection characteristics PEARLS • A  mebic abscesses are more likely to spread into the thoracic cavity. • Echinococcal cysts should be removed intact, due to risk of severe allergic reactions with disruption.

Selected References Bissada AA, Bateman J. Pyogenic liver abscesses: a 7-­year experience in a large community hospital. Hepatogastroenterology. 1991;38:17–20. Koneman EW, Allen SD, Woods GL, et al., eds. Color Atlas and Textbook of Diagnostic Microbiology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1244–1326.

Liver Flukes

DRUG-­INDUCED LIVER INJURY

• Biliary epithelial hyperplasia, cholangitis, and periductal fibrosis 

CLINICAL FEATURES

Malaria • Kupffer cell hyperplasia and phagocytosis of ruptured erythrocytes 

•  Clinical history important (e.g., ingesting an agent known to cause liver disease) •  An appropriate time interval between exposure and onset of disease

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7  —  Hepatobiliary System

• A histologic lesion known to be associated with the suspect drug • Resolution of the lesion after withdrawal • Can be acute or chronic •  Correlation with laboratory testing (e.g., acetaminophen level) may be helpful • Drug-­specific clinical presentations and literature references are available from LiverTox (http://livertox. nlm.nih.gov/) 

HISTOPATHOLOGY • Different agents may result in different liver injury patterns, such as the following: • Zone 3 hepatocellular necrosis: acetaminophen •  Mimicking acute viral hepatitis: antituberculous drugs, anesthetics, herbal medicine, nonsteroidal antiinflammatory drugs • Cholestasis with duct damage and duct loss: amoxicillin and clavulanic acid (Augmentin) •  Vanishing bile duct: chlorpromazine, amoxicillin and flucloxacillin, haloperidol, temozolomide • Microvesicular steatosis: valproic acid, tetracycline, nucleoside analogues, salicylate (Reye syndrome) • Hypertrophic hepatic stellate cells and perivenular and pericellular fibrosis: hypervitaminosis A • Sinusoidal obstruction syndrome/veno-­occlusive disease: pyrrolizidine alkaloids or chemotherapeutic agents associated with bone marrow transpla­ntation • Steatohepatitis-­like: amiodarone, tamoxifen, methotrexate •  Hepatitis with features of autoimmune hepatitis: anti-­TNFα immunomodulators, immune checkpoint inhibitors • Drug toxicity should always enter the differential diagnosis when abundant eosinophils or epithelioid granulomas are present or when hepatitis and cholestasis are both present 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY

409

Biliary Obstruction • Imaging studies may help 

Primary Biliary Cholangitis • Positive AMA • Florid duct lesion PEARLS • C  areful correlation of past and present history is essential, including use of herbal remedies and over-­the-­counter medications. • Rule out other liver diseases.

Selected References Geller SA, Petrovic LM. Effects of drugs and toxins on the liver. In: Geller SA, Petrovic LM, eds. Biopsy Interpretation of the Liver. Philadelphia: Lippincott Williams & Wilkins; 2004:111–124. Kleiner DE. Drugs and toxins. In: Burt AD, Ferrell LD, Hubscher SG, eds. MacSween’s Pathology of the Liver. 7th ed. London: Churchill Livingstone; 2018:673–753. Kleiner DE. Recent advances in the histopathology of drug-­induced liver injury. Surg Pathol Clin. 2018;11(2):297–311. Zen Y, Yeh MM. Checkpoint inhibitor-­induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019;36:434–440. Zimmerman HJ. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.

ALCOHOLIC LIVER DISEASE AND ALCOHOLIC STEATOHEPATITIS CLINICAL FEATURES •  Nonspecific symptoms including malaise, anorexia, weight loss, and tender hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase • About 20% to 25% of heavy drinkers develop alcoholic steatohepatitis 

GROSS PATHOLOGY

• Noncontributory 

• Early: large, soft, greasy, yellow liver • Late: shrunken, mottled, red-­brown liver with bile staining • End-­stage: cirrhosis 

OTHER TECHNIQUES FOR DIAGNOSIS

HISTOPATHOLOGY

• Noncontributory 

• Steatosis • Zone 3 injury pattern • Ballooning degeneration (Figure 7.3A) •  Lobular inflammatory infiltrates, especially rich in neutrophils • Mallory-­Denk bodies and megamitochondria (see Figure 7.3B) • Perivenular and pericellular fibrosis (see Figure 7.3C) • Bile ductular reaction • Sclerosing hyaline necrosis 

DIFFERENTIAL DIAGNOSIS Viral Hepatitis • Positive serologic markers or viral nucleic acid tests • Immunohistochemistry may help to detect viral antigens (e.g., HBV, cytomegalovirus [CMV], herpes simplex virus [HSV], EBV) 

Autoimmune Hepatitis • Positive ANA, ASMA, and anti-­LKM • Prominent plasma cells • Responds to corticosteroids 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

410

Chapter 7  —  Hepatobiliary System

A

B

C Figure 7.3  Steatohepatitis.  A, Macrovesicular fat with ballooned hepatocyte and lobular inflammatory infiltrate. B, Mallory-­Denk bodies are present in the ballooned hepatocytes with associated inflammatory foci. C, Pericellular and perisinusoidal fibrosis (chicken-­wire pattern).

OTHER TECHNIQUES FOR DIAGNOSIS

Nonalcoholic Steatohepatitis

• Noncontributory 

• Clinical history is essential

• Steatosis is essential • Neutrophilic aggregates (satellitosis) are not common • Glycogenated nuclei are more common • Sclerosing hyaline necrosis or veno-­occlusive lesion are not present

Chronic Viral Hepatitis

PEARLS

DIFFERENTIAL DIAGNOSIS

•  Positive serologic and/or virologic markers of viral infection • Hepatocellular injury and initiation of fibrosis are more marked in the periportal areas, as opposed to alcoholic steatohepatitis (perivenular and pericellular fibrosis and hepatocellular injury predominantly in zone 3 region) • Mallory-­Denk bodies are more common in steatohepatitis 

Fatty Liver of Pregnancy

• M  ajor pathologic effects of alcohol are caused by interference with lipid metabolism, mitochondrial damage, and cytoskeletal injury. • Genetically determined susceptibility is thought to account for the fact that only 20% to 25% of heavy drinkers develop alcoholic steatohepatitis, whereas individuals with minimal to no alcohol intake may develop histologically identical nonalcoholic steatohepatitis.

• Typically occurs in third trimester of pregnancy • Steatosis is microvesicular 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7  —  Hepatobiliary System

Selected References Brunt EM. Alcoholic and nonalcoholic steatohepatitis. Clin Liver Dis. 2002;6:399–420. Geller SA, Petrovic LM. Alcoholic liver disease. In: Geller SA, Petrovic LM, eds. Biopsy Interpretation of the Liver. Philadelphia: Lippincott Williams & Wilkins; 2004:134–149. Scheuer PJ, Lefkowitch JH. Fatty liver and lesions in the alcoholic. In: Scheuer PJ, Lefkowitch JH, eds. Liver Biopsy Interpretation. London: WB Saunders; 2000:111–133.

NONALCOHOLIC FATTY LIVER DISEASE AND NONALCOHOLIC STEATOHEPATITIS CLINICAL FEATURES • A manifestation of the metabolic (insulin resistance) syndrome • Risk factors: central obesity, hyperglycemia, type II diabetes, arterial hypertension, and hypertriglyceridemia •  Nonalcoholic steatohepatitis (NASH) is the progressive lesion of nonalcoholic fatty liver disease (NAFLD), which may progress to cirrhosis and liver failure • Histologically, NASH is almost identical to alcoholic steatohepatitis but occurs in individuals who do not have significant alcohol history 

GROSS PATHOLOGY • Early: large, soft, greasy, yellow liver •  Late: shrunken, mottled, red-­ brown liver with bile staining • End-­stage: cirrhosis 

411

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY •  Immunohistochemical stains for ubiquitin and p62 have been developed to identify Mallory-­Denk bodies. • Rearrangement of the intermediate filament cytoskeleton in ballooned hepatocytes can be demonstrated by the loss of cytoplasmic keratin 8/18 immunostaining and may be evaluated as a marker for the more objective detection of hepatocellular ballooning in NASH. 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS • Clinical history is essential

Chronic Viral Hepatitis • Positive serologic/virologic markers of viral infection • Inflammation is more accentuated in the portal and periportal areas • Fibrosis initiates in portal regions •  Mallory-­ Denk bodies are more common in steatohepatitis 

Fatty Liver of Pregnancy • Typically occurs in third trimester of pregnancy • Steatosis is microvesicular 

HISTOPATHOLOGY

Biliary Obstruction (Especially PBC)

• Nonspecific steatosis in NAFLD • Predominantly macrovesicular fatty change • Typically starts in a zone 3 centrilobular pattern

• Mallory-­Denk bodies may be present and would most likely be seen in periportal as opposed to pericentral areas. 

Nonalcoholic Steatohepatitis

Wilson Disease

• In adults, begins as a zone 3 injury pattern consisting predominantly of macrovesicular steatosis, ballooned hepatocytes, and lobular inflammation •  In children, begins as a zone 1 injury pattern with steatosis and inflammation accentuated in periportal regions, and initiation of fibrosis in portal tracts • Pigmented macrophages and acidophile bodies can be seen •  Cytoplasmic Mallory-­ Denk bodies (fibrillary eosinophilic material composed of intermediate cytokeratin filaments associated with ubiquitin) • Zone 3 perivenular and pericellular fibrosis (chicken-­ wire pattern), which progresses to central-­ portal bridging • Cirrhosis (end-­stage disease) • A NAFLD activity scoring (NAS) system designed and validated by the NASH Clinical Research Network including assessment of steatosis, lobular inflammation, hepatocellular ballooning, and a separate staging scheme for fibrosis can be used after establishing the diagnosis of NASH for the evaluation of disease activity and stage before and after mitigation of NASH 

• Mallory-­Denk bodies may be present and would most likely be seen in periportal as opposed to pericentral areas • Marked copper overload 

Indian Childhood Cirrhosis • Occurs almost exclusively in India • Mallory-­Denk bodies are often present • Steatosis conspicuously absent • Marked copper overload PEARLS • P  resence of Mallory-­Denk bodies associated with lobular inflammatory infiltrates and steatosis (predominantly macrovesicular) in a zone 3 injury pattern suggests alcoholic or nonalcoholic steatohepatitis. • Mallory-­Denk bodies may be present in other pathologic processes, including chronic cholestatic disease, Wilson disease, Indian childhood cirrhosis, and even HCCs (about 10%).

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

412

Chapter 7  —  Hepatobiliary System

Selected References Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis. 2001;21:3–16. Brunt EM. Nonalcoholic steatohepatitis: pathologic features and differential diagnosis. Semin Diagn Pathol. 2005;22:330–338. Guy CD, Suzuki A, Burchette JL, Brunt EM, et al. Nonalcoholic steatohepatitis clinical research network. Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocytes injury in nonalcoholic fatty liver disease. Hum Pathol. 2012;43:790–800. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321. Yeh MM, Brunt EM. Pathologic features of fatty liver disease. Gastroenterology. 2014;147:754–764.

ACUTE FATTY LIVER OF PREGNANCY CLINICAL FEATURES •  Onset typically occurs during third trimester of pregnancy •  Bleeding, nausea and vomiting, jaundice, and occasionally coma • Usually resolves after delivery 

Figure 7.4  Acute fatty liver of pregnancy.  Marked microvesicular transformation of hepatocytes.

GROSS PATHOLOGY

Alcoholic Steatohepatitis

• Greasy, small, pale-­yellow liver 

• Mallory-­Denk bodies are typically prominent and often associated with a neutrophilic infiltrate

HISTOPATHOLOGY • Microvesicular steatosis (Figure 7.4) • Canalicular and intrahepatocytic cholestasis may occur • Portal tract inflammation may be prominent 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY •  Oil red O (on frozen-­ section slide) demonstrates microvesicular fat droplets. 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

PEARLS • O  nset during pregnancy, usually third trimester • Pathogenesis: defective intramitochondrial fatty acid oxidation

Selected References Kaplan MM. Acute fatty liver of pregnancy. N Engl J Med. 1985;313:367–370. Liu J, Ghaziani TT, Wolf JL. Acute fatty liver disease of pregnancy: updates in pathogenesis, diagnosis, and management. Am J Gastroenterol. 2017;112(6):838–846. Riely CA. Acute fatty liver of pregnancy. Semin Liver Dis. 1987;7:47–54. Rolfes DB, Ishak KG. Acute fatty liver of pregnancy: a clinicopathologic study of 35 cases. Hepatology. 1985;5:1149–1158.

HEMOCHROMATOSIS

DIFFERENTIAL DIAGNOSIS

CLINICAL FEATURES

• Clinical history is essential

•  Abnormal accumulation of iron in liver, pancreas, myocardium, and other organs • Hereditary: homozygous recessive, loss of function in the HFE gene •  Acquired: multiple transfusions, Bantu hemosiderosis (alcoholic beverages brewed in iron drums in sub-­ Saharan Africa) • Most often presents in men older than 40 years • Liver is the most severely affected organ • Classic triad: cirrhosis, skin pigmentation, and diabetes mellitus (not as common now owing to early diagnosis and treatment) • Patients may also have abdominal pain, cardiac dysfunction, and atypical arthritis • Laboratory studies show increased serum iron and ferritin • Increased risk for developing HCC 

Drug-­Induced Liver Injury • May show similar histologic features (e.g., tetracycline, valproic acid, nucleoside analogues), which are all associated with microvesicular fatty change • Clinical history is required for definitive distinction 

Reye Syndrome • Also shows microvesicular steatosis • History of aspirin use • Associated with encephalopathy 

Hepatitis C Virus • Typically shows macrovesicular steatosis • Shows lobular hepatitis and portal lymphoid aggregates 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7  —  Hepatobiliary System

A

413

B

Figure 7.5  Hemochromatosis.  A, Hepatocytes containing a large amount of iron. B, Prussian blue stain is strongly positive, highlighting the massive iron deposits.

GROSS PATHOLOGY

DIFFERENTIAL DIAGNOSIS

• Enlarged liver with dark-­brown pigmentation • Ultimately leads to cirrhosis with persistent dark-­brown pigmentation 

Hemosiderosis

HISTOPATHOLOGY

Cirrhosis of Nonbiliary Etiology

• Early: hemosiderin granules in cytoplasm of periportal hepatocytes • Middle: • Progressive iron deposition in lobules and eventually bile duct epithelium and Kupffer cells, resulting in hepatocyte necrosis, portal inflammation, and portal and bridging fibrosis (Figure 7.5A) • Lobular inflammation typically absent •  Late: fibrous septa develop over years with pro­ gression to cirrhosis with intense hemosiderin pigmentation 

•  Common to have iron overload in cirrhosis due to nonbiliary etiology (e.g., HCV, alcohol, NASH)

• Patients typically have a cause for secondary iron overload (e.g., multiple transfusions, porphyria cutanea tarda, or chronic dietary iron overload as in Bantu siderosis). 

PEARLS • Iron is directly hepatotoxic; no inflammatory mediators released. • Women are less commonly affected and present later as a result of physiologic blood loss during menstruation and pregnancy. • Treatment is reduction of iron overload by phlebotomy.

Selected References SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Prussian blue stain for iron highlights increased iron deposition (see Figure 7.5B) 

OTHER TECHNIQUES FOR DIAGNOSIS • Hepatic iron index (HII): biochemical quantitation of hepatic iron in fresh tissue or paraffin block calculated as micromoles of iron per gram dry weight divided by patient’s age •  Homozygotes: HII greater than 2 (may be greater than 40) • Heterozygotes: less than 2 • Normal individuals: less than 1 • Nucleic acid testing for germline loss-­of-­function variants in the HFE gene, most commonly C282Y and/or H63D 

Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-­mediated process. Hepatology. 1990;11:127–137. Brunt EM. Pathology of hepatic iron overload. Semin Liver Dis. 2005;25:392–401. Deugnier YM, Loreal O, Turlin B, et al. Liver pathology in genetic hemochromatosis: a review of 135 cases and their bioclinical correlations. Gastroenterology. 1992;104:228–234. Deugnier YM, Turlin B, Powell LW, et al. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histologic hepatic iron index: a study of 192 cases. Hepatology. 1993;17:30–34.

WILSON DISEASE CLINICAL FEATURES • Abnormal accumulation of copper in liver, brain, eyes, and other organs • Variable age of onset •  Autosomal recessive, mutations in the ATP7B gene encoding a copper transporter

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

414

Chapter 7  —  Hepatobiliary System

DIFFERENTIAL DIAGNOSIS Viral Hepatitis • Serologic/virologic markers are positive • No accumulation of copper 

Chronic Obstructive Cholestasis • Lesser degree of copper accumulation PEARLS

Figure 7.6  Wilson disease.  High-­power view shows liver cells containing cytoplasmic copper pigment.

•  Laboratory findings include decreased serum ceruloplasmin, increased hepatic copper, increased urinary excretion of copper • Serum copper levels not helpful • Most commonly presents with acute or chronic liver disease • Neuropsychiatric symptoms are also frequent at presentation secondary to involvement of basal ganglia •  Kayser-­ Fleischer rings are diagnostic (green-­ brown deposits of copper in Descemet membrane in limbus of cornea) 

GROSS PATHOLOGY • Liver eventually becomes cirrhotic 

HISTOPATHOLOGY • Excessive copper granules in hepatocytes can only be seen with special stain (Figure 7.6) • Mild to moderate fatty change • Focal hepatocyte necrosis • Glycogen vacuoles in hepatocyte nuclei • Mallory-­Denk bodies in periportal hepatocytes • Acute and chronic hepatitis • Cirrhosis following chronic hepatitis • Rarely, massive liver necrosis 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Rhodanine stain for copper positive • Orcein stain for copper-­associated protein positive 

OTHER TECHNIQUES FOR DIAGNOSIS • Quantitation of hepatic copper in fresh tissue or paraffin block (more than 250 μg copper/1 g dry liver), typically with mass spectrometry • Sequencing of ATP7B gene 

• N  ormally free copper is absorbed in the stomach and duodenum, weakly bound to albumin, transferred to hepatocytes, and incorporated into α2-­globulin to form ceruloplasmin, which is re-­secreted into plasma; senescent ceruloplasmin is taken up by hepatocytes, degraded by lysosomes, and copper excreted into bile. • Wilson disease gene is ATP7B on chromosome 13 and encodes a transmembrane copper-­transporting adenosine triphosphatase (ATPase) located on canalicular membrane of hepatocytes. • Treatment is copper chelation with D-­penicillamine.

Selected References Ludwig J, Moyer TP, Rakela J. The liver biopsy diagnosis of Wilson’s disease: methods in pathology. Am J Clin Pathol. 1994;102:443–446. Sternlieb I. Perspectives on Wilson’s disease. Hepatology. 1990;12: 1234–1239. Stremmel W, Meyerrose KW, Niederau C, et al. Wilson disease: clinical presentation, treatment and survival. Ann Intern Med. 1991;115:720–726. Stromeyer FW, Ishak KG. Histology of the liver in Wilson’s disease: a study of 34 cases. Am J Clin Pathol. 1980;73:12–24.

α1-­ANTITRYPSIN DEFICIENCY CLINICAL FEATURES • Variable age of onset • Autosomal recessive disease caused by mutations of the SERPINA1 gene on chromosome 14 • Absent or decreased α1-antitrypsin activity results in unchecked activity of neutrophilic elastase leading to pulmonary emphysema (destruction of elastic fibers supporting alveolar spaces) • The most common variant protein (E366K) associated with liver disease is abnormally folded, resulting in impaired transport to the Golgi and accumulation in the endoplasmic reticulum of hepatocytes • In some patients, there is liver disease without pulmonary emphysema owing to functional mutant forms that inhibit neutrophil elastase but that are not appropriately degraded in hepatocytes • Clinical hepatic presentations range from: • Neonatal hepatitis with cholestatic jaundice •  Young adults with recurrent attacks of hepatitis that either resolve or lead to chronic hepatitis and cirrhosis •  Middle-­ aged to older adults with cirrhosis after a clinically silent course •  Increased risk for HCC, especially in homozygous patients • Successful liver transplantation is curative

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7  —  Hepatobiliary System

415

•  Patients with PiMZ genotype have 50% normal α1-­ antitrypsin and 50% mutant form • Other mutant alleles include S (reduced levels of α1-­ antitrypsin but no clinical disease unless inherited in combination with another mutation) and null (no detectable protein) 

DIFFERENTIAL DIAGNOSIS • Other types of chronic hepatitis include viral, drug, and autoimmune hepatitis, but they do not demonstrate the PAS-­ positive and diastase-­ resistant globules that are characteristic of α1-­antitrypsin deficiency PEARLS Figure 7.7  α1-­Antitrypsin deficiency. Hepatocytes containing intracytoplasmic eosinophilic globules (periodic acid–Schiff stain with diastase).

• Augmentation therapy with intravenous α1-antitrypsin delays the natural course of lung disease, but does not impact liver disease 

GROSS PATHOLOGY • Noncontributory 

HISTOPATHOLOGY •  Round to oval, variably sized eosinophilic globules most concentrated in periportal hepatocytes • Otherwise variable histologic features • Neonatal hepatitis with or without cholestasis • Chronic hepatitic picture • Cirrhosis 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Eosinophilic globules are positive for periodic acid–Schiff (PAS) and resistant to diastase digestion (Figure 7.7) • Immunohistochemistry for α1-antitrypsin highlights eosinophilic globules 

OTHER TECHNIQUES FOR DIAGNOSIS • Serum α1-antitrypsin quantitation (50 per HPF in surgical specimens, >10 per high power field (HPF) in biopsies) (see Figure 7.11B) 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Primary Sclerosing Cholangitis • Highly associated with ulcerative colitis, and earlier age of onset (5 cm) at risk for rupture or hemorrhage; may present as abdominal emergency • Malignant transformation may occur, especially in β-­ catenin activated type •  Symptoms include epigastric and acute abdominal pain, the latter associated with rupture 

GROSS PATHOLOGY

PEARLS • M  ost characteristic features include central stellate scar, broad septa containing proliferating bile ducts, and the presence of all components of normal liver lobule • Maplike immunostaining pattern of glutamine synthetase in hepatocytes

Selected References Bioulac-­Sage P, Cubel G, Taouji S, et al. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes. Am J Surg Pathol. 2012;36:1691–1699. Bioulac-­Sage P, Laumonier H, Rullier A, et al. Over-­expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology. Liver Int. 2009;29:459–465. Ishak KG, Goodman ZD, Stocker JT. Benign hepatocellular tumors. In: Atlas of Tumor Pathology. 3rd series. Fascicle 31. Washington, DC: Armed Forces Institute of Pathology; 2001:9–48. Makhlouf HR, Abdul-­ Al HM, Goodman ZD. Diagnosis of focal nodular hyperplasia of the liver by needle biopsy. Hum Pathol. 2005;36:1210–1216. Nguyen BN, Flejou JF, Terris B, et al. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognitions of new histologic forms. Am J Surg Pathol. 1999;23:1441–1454.

• Any size; may measure up to 30 cm in diameter •  Usually solitary, well-­ defined, partially encapsulated, bulging mass • Often subcapsular • Multiple lesions may occur; greater than 10 adenomas indicates adenomatosis • Different color from surrounding liver (yellow to tan or brown) • Areas of necrosis or hemorrhage common 

HISTOPATHOLOGY • Tightly packed, well-­differentiated, glycogen-­rich hepatocytes with abundant eosinophilic cytoplasm (Figure 7.15) • No portal tracts • Unpaired arteries • Hepatocellular plates not thickened and pseudoglandular structures are rare • Intracellular and canalicular bile may be seen • Fatty change often conspicuous • Mitoses rare 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

424

Chapter 7  —  Hepatobiliary System

TABLE 7.1   CURRENT CLASSIFICATION OF HEPATOCELLULAR ADENOMAS LFABP IHC Glutamine synthetase IHC β-­catenin IHC (nuclear expression) SAA/CRP IHC Molecular findings

H-­HCA − (loss of staining) − − − HNF1A biallelic inactivation

b-­HCA and b-­IHCA + + (diffuse staining) +/− − CTNNB1 activation

I-­HCA + − −/+ + IL-­6/JAK/STAT pathway ­activation

b-­HCA, β-­catenin activated hepatocellular adenoma; CRP, C reactive protein; H-­HCA, HNF1α-­inactivated hepatocellular adenoma; I-­HCA, inflammatory hepatocellular adenoma; LFABP, liver fatty acid binding protein; SAA, serum amyloid A.

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY

Well-­Differentiated Hepatocellular Carcinoma

•  Hepatocyte antigen in paraffin (HepPar-­ 1) and Arginase-­1 positive • Glypican-­3 negative • Current classification of hepatocellular adenoma (HCA) based on immunohistochemistry and molecular findings (Table 7.1) • Glutamine synthetase • Perivenular or negative staining pattern in HNF1A-­inactivated (H-­ HCA) and inflammatory (I-­ HCA) subtypes • Diffusely overexpressed in β-­catenin activated (b-­HCA, b-­IHCA) subtypes, correlating to specific CTNNB1 gene mutations • β-­catenin • Membranous staining in H-­HCA and I-­HCA subtypes •  Nuclear staining may be present in b-­ HCA and b-­IHCA subtypes •  Occasional cases with “capillarization” of sinusoids (CD34 positivity similar to HCC) 

• Underlying liver diseases and cirrhosis common • Not female predominant

OTHER TECHNIQUES FOR DIAGNOSIS •  Genetic testing for variants in HNF1A, CTNNB1 (β-­ catenin), and the IL-­ 6/JAK/STAT pathway (not routinely used in practice) 

DIFFERENTIAL DIAGNOSIS

PEARLS • • • •

F ocal process with absence of normal portal elements Composed of normal-­appearing hepatocytes Difficult to separate from low-­grade HCC in a needle biopsy Never occurs in cirrhosis (by convention); similar lesions in cirrhosis classified as low-­grade dysplasia (macroregenerative nodule)

Selected References Bioulac-­Sage P, Cubel G, Taouji S, et al. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes. Am J Surg Pathol. 2012;36:1691–1699. Bioulac-­Sage P, Kakar S, Nault JC. Hepatocellular adenoma. In: WHO Classification of Tumours: Digestive System Tumours. 5th ed. Lyon: International Agency for Research on Cancer; 2019:224–228. DeCarlis L, Pirotta V, Rondinara GF, et al. Hepatic adenoma and focal nodular hyperplasia: diagnosis and criteria for treatment. Liver Transpl Surg. 1997;3:160–165. Goodman ZD, Mikel W, Lubbers PR, et al. Kupffer cells in hepatocellular adenomas. Am J Surg Pathol. 1987;11:191–196. Resnick MB, Kozakewich HP, Perez-­ Atayde AR. Hepatic adenoma in the pediatric age group: clinicopathological observations and assessment of cell proliferative activity. Am J Surg Pathol. 1995;19:1181–1190.

Focal Nodular Hyperplasia

HEPATOCELLULAR CARCINOMA

• Central stellate scar • Portal tracts and central veins present • Bile ducts in fibrous septa; bile ductular reaction pattern often prominent • Glutamine synthetase immunostain shows “maplike” pattern 

CLINICAL FEATURES

Nodular Regenerative Hyperplasia • Diffuse process • Portal tracts still present • No gender predilection •  Clinically associated with a wide variety of extrahepatic disorders or medication history 

•  Common carcinoma worldwide (ninth overall in women; fifth in men); strongly correlated with relative incidence of hepatitis B • Most common primary hepatic malignancy in adults • Most patients in Western countries are older than 50 years •  Fibrolamellar variant typically occurs in patients younger than 30 years • Male-­to-­female ratio about 4:1 • Patients often present with abdominal pain, ascites, or hepatomegaly; early disease typically asymptomatic

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 7  —  Hepatobiliary System

• Elevated serum α-­fetoprotein (AFP) in 60% to 80% of cases • Serum AFP more than 100 times the upper limit of normal is diagnostic if germ cell neoplasm is excluded •  Numerous associated risk factors, including cirrhosis, HBV (especially Hbx gene product) and HCV, fatty liver disease, alcohol, obesity, diabetes, hemochromatosis, progestational agents, anabolic steroids, aflatoxins, hepatocytic adenoma, ataxia-­ telangiectasia, α1-­antitrypsin deficiency, tyrosinemia, schistosomiasis • DNA ploidy abnormalities (especially 8p loss of heterozygosity [LOH]); microsatellite instability, altered β-­catenin expression, dysplasia, increases in transforming growth factor-­α (TGF-­α) and AFP expression, and increased proliferative activity often precede malignant transformation 

GROSS PATHOLOGY • Soft, yellow-­green or reddish nodules • Highly variable in size • Solitary, multinodular, and diffuse types •  Increasing numbers of small carcinomas (lesions 0.30 and/or >50 IgG4 expressing plasma cells in a single high power field). 

Selected References

Differential Diagnosis

1. Hruban RH, Pitman MB, Klimstra DS. Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series. Fascicle 6th ed. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2007. 2. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352–358. 3. Zamboni G, Capelli P, Scarpa A, et al. Nonneoplastic mimickers of pancreatic neoplasms. Arch Pathol Lab Med. 2009;133(3):439–453.

AUTOIMMUNE PANCREATITIS Clinical Features • Defined by irreversible loss of pancreatic parenchyma and function caused by the body’s own immune system targeting the pancreas. • Patients present with signs and symptoms of pancreatitis including recurrent attacks of abdominal and back pain and evidence of loss of pancreatic function

Other Techniques for Diagnosis • Not applicable 

Other Forms of Chronic Pancreatitis • Alcohol-­related • Obstructive  Infiltrating Ductal Adenocarcinoma • Haphazard arrangement of glands with loss of lobular architecture at low power • Glands immediately adjacent to muscular vessels • Perineural invasion • Vascular invasion • Variation in the area of nuclei in a single gland by more than 4 to 1 (“4 to 1 rule”) • Incomplete lumina • Luminal necrosis PEARLS • A  utoimmune pancreatitis is important to recognize ­because it may respond to treatment with steroids.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 8 — Pancreas

A

B

C

D

445

Figure 8.2  Autoimmune (lymphoplasmacytic sclerosing) pancreatitis. A, Characteristic mixed duct-centric inflammatory cell infiltrate. B, Immunolabeling for IgG4 highlighting an increased number of IgG4 expressing cells. C and D, Venulitis almost obliterating the vein. D is a Verhoeff van Gieson stain.

Selected References 1. Detlefsen S, Klöppel G. IgG4-­related disease with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis. Virchows Arch. 2018;472(4):545–556. 2. Shinagare S, Shinagare AB, Deshpande V. Autoimmune pancreatitis: a guide for the histopathologist. Semin Diagn Pathol. 2012;29(4):197–204. 3. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352–358.

PANCREATIC PSEUDOCYST Clinical Features • Account for 75% of cystic lesions of the pancreas •  The abnormal release of pancreatic enzymes causes the localized digestion of intrapancreatic and extrapancreatic tissues • A complication of acute pancreatitis, often in the setting of chronic alcoholic pancreatitis • May spontaneously resolve, may become infected, or may perforate adjacent organs

• Cyst fluid analysis typically demonstrates high amylase levels (>250 U/L) and low carcinoembryonic antigen (CEA) levels (55%  Solid-­Pseudopapillary Neoplasm • Predominantly in young women •  Discohesive cells form pseudopapillary structures around myxoid stroma • Eosinophilic globules •  Degenerative changes (foamy macrophages, cholesterol clefts) • Nuclear labeling for beta-­catenin  Ductal Adenocarcinoma • Paucicellular neoplasm with prominent desmoplastic stroma • Gland formation with mucin production

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 8 — Pancreas

• Nuclear pleomorphism • Express cytokeratin 7, negative for chromogranin, synaptophysin, and CD56  Acinar Cell Carcinoma • Acinar formations with basally placed nuclei and granular apical cytoplasm • Single prominent nucleoli • Express trypsin, chymotrypsin, and BCL10 • Acinar cell carcinoma can have a significant component with neuroendocrine differentiation (mixed acinar-­endocrine neoplasms), but the presence of histologic features of acinar cell carcinoma (acinar formation and large cells with prominent nucleoli) should distinguish these more aggressive neoplasms from the more indolent pure, neuroendocrine tumors  Pancreatoblastoma • Squamoid nests • Acinar formations with basally placed nuclei and granular apical cytoplasm • Single prominent nucleoli • Positive for trypsin, chymotrypsin, and BCL10 •  May also have a component with neuroendocrine differentiation  Islet Aggregation In Chronic Pancreatitis • Background of chronic pancreatitis • Small focal lesions • Polyclonal endocrine hormone production PEARLS • L arge neoplasms tend to be nonfunctioning as patients with functional neoplasms usually come to clinical ­attention early in their disease. • Behavior is difficult to predict, and all pancreatic e­ ndocrine neoplasms greater than 0.5 cm should be considered malignant. • Size, mitotic rate, lymph node metastases, invasion into another organ, and distant metastases are all ­prognosticators. • Although functioning gastrinomas causing Zollinger-­ Ellison syndrome do arise in the pancreas, they are most often duodenal. When a hormone is expressed, insulin is the most common among neuroendocrine neoplasms ­arising in the pancreas. • Multiple synchronous or metachronous neoplasms may be observed in patients with MEN1. • Well-­differentiated neuroendocrine tumors with a high ­mitotic index (G3) are biologically distinct from high-­grade neuroendocrine carcinomas (NECs) and have d ­ ifferent mutational profiles; importantly, they do not respond to chemotherapy regimens used for high-­grade NECs.

Selected References 1. Hruban RH, Pitman MB, Klimstra DS. Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series. Fascicle 6th ed. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2007. 2. Klöppel G, Hruban RH, Klimstra DS, et al. Non-­functioning neuroendocrine tumours. In: WHO Classification of Tumours Editorial Board, ed. World Health Organization Classification of Tumours.

457

5th ed. Digestive System Tumours. Lyon: IARC Press; 2019: 322–332. 3. Klöppel G, Klimstra DS, Hruban RH, et al. Pancreatic neuroendocrine tumors: update on the new World Health Organization classification. AJSP: Rev Rep. 2017;22:233–239. 4. Tang LH, Untch BR, Reidy DL, et al. Well-­differentiated neuroendocrine tumors with a morphologically apparent high grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res. 2016;22(4):1011–1017. 5. Tang LH, Basturk O, Sue JJ, Klimstra DS. A practical approach to the classification of WHO Grade 3 (G3) well-­ differentiated neuroendocrine tumor (WD-­ NET) and poorly differentiated neuroendocrine carcinoma (PD-­NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192–1202.

NEUROENDOCRINE CARCINOMA Clinical Features • Rare neoplasm primarily in adults (mean age ∼60 years) • Males more often than females •  May be associated with a paraneoplastic syndrome such as Cushing syndrome •  Need to rule out a lung primary metastatic to the pancreas • Extremely aggressive 

Gross Pathology • Solid white, poorly defined, often with necrosis 

Histopathology • Cellular neoplasm, often with geographic necrosis • Minimal cytoplasm, with high nuclear to cytoplasm ratio • Small cell variant has minimal cytoplasm with nuclear molding and inconspicuous nucleoli •  Large cell variant has more abundant, less granular cytoplasm, open chromatin with nucleoli, large nests with central necrosis, and peripheral palisading • Extremely high mitotic rate (Ki-­67 labeling index often >55%) • Often contain a minor component of adenocarcinoma 

Special Stains and Immunohistochemistry • Express cytokeratin, synaptophysin, and chromogranin • Very high labeling index with Ki-­67 (often >55%) 

Modern Techniques for Diagnosis • Abnormal p53, Rb (retinoblastoma), SMAD4 alterations 

Differential Diagnosis Pulmonary Small Cell Carcinoma Metastatic Pancreas • Clinical history, imaging of the lungs 

to the

Well-­Differentiated Pancreatic Neuroendocrine Tumor • Lower proliferative rate (Ki-­67 typically ≤55%) • The neoplastic cells “look like” those of normal islets of Langerhans with retention of organoid architecture • Uniform and more intense expression of synaptophysin and chromogranin  Lymphoma • Uniform, more dispersed sheets of round blue cells • Lack expression of neuroendocrine markers • Express lymphoid markers (e.g., CD45) 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

458

Chapter 8 — Pancreas

Primitive Neuroectodermal Tumors (PNET) and Other Round Blue Cell Tumors of Infancy and Childhood • Occur more commonly in pediatric patients • Specific immunohistochemical and cytogenetic findings. PNETs express CD99 and harbor the t(11:22)(q24;q12) translocation. Intraabdominal desmoplastic round cell tumors express cytokeratin, desmin, and WT-­1 and harbor the t(11;22)(p13;q12) translocation. Rhabdomyosarcomas express myoblast determination protein D (MyoD).

• Can express synaptophysin positive but are chromogranin negative • Diffuse nuclear labeling with antibodies to beta-­catenin •  Hyaline globules label with antibodies to alpha-­ 1 antitrypsin 

PEARLS

Well-­Differentiated Pancreatic Neuroendocrine ­Tumor • Cells are cohesive and nest and/or form trabeculae • “Salt and pepper” chromatin • Strongly express synaptophysin and chromogranin. • Membranous labeling with beta-­catenin • Hyaline globules can sometimes be seen • Degenerative changes (foam cells, cholesterol clefts) are less common 

• S  mall cell cancer of the lung must be excluded before establishing a pancreatic primary.

Selected References 1. Adsay NV, Perren A, Singhi A. Pancreatic neuroendocrine carcinoma. In: WHO Classification of Tumours Editorial Board, ed. World Health Organization Classification of Tumours. 5th ed. Digestive System Tumours. Lyon: IARC Press; 2019:322–332. 2. Basturk O, Yang Z, Tang LH, et al. The high grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well-­differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39(5):683–690. 3. Basturk O, Tang LH, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38(4):437–447.

NEOPLASMS WITH UNCERTAIN DIRECTIONS OF DIFFERENTIATION SOLID-­PSEUDOPAPILLARY Clinical Features • Most occur in young women in their twenties and thirties, with a female to male ratio of 10 to 1 and a mean age of 30 years • Present with nonspecific symptoms related to a large abdominal mass • Rarely rupture producing hemoperitoneum • Slow-­growing low-­grade malignancy 

Gross Pathology • May arise in the head, body, or tail of the gland •  Solitary, relatively large (mean size 10 cm), well-­ demarcated masses •  Soft white to yellow with areas of hemorrhage and ­cystic degeneration (Figure 8.14A) 

Histopathology • Uniform poorly cohesive cells that fall apart around myxoid stroma and delicate vessels creating pseudopapillae (see Figures 8.14B) • Nuclear grooves • Delicate branching blood vessels • Hyaline globules (see Figure 8.14C) • Foam cells • Cholesterol clefts 

Special Stains and Immunohistochemistry • Label with antibodies to CD10, CD99 (perinuclear dot-­ like labeling)

Other Techniques for Diagnosis • Beta-­catenin gene mutations (CTNNB1) result in the nuclear accumulation of the beta-­catenin protein 

Differential Diagnosis

Ductal Adenocarcinoma • Less cellular neoplasm with prominent desmoplastic stroma • Gland formation with mucin production • Nuclear pleomorphism • Express cytokeratin 7; negative for CD10 • Membranous labeling with beta-­catenin  Acinar Cell Carcinoma •  Cells are cohesive and form acinar structures with basally placed nuclei and granular apical cytoplasm • Single prominent nucleoli • Label with antibodies to trypsin, chymotrypsin, and BCL10 • Membranous labeling with beta-­catenin  Pancreatoblastoma • Squamoid nests •  Cells are cohesive and form acinar formations with basally placed nuclei and granular apical cytoplasm • Single prominent nucleoli • Positive for trypsin, chymotrypsin, and BCL10 •  May have focal, but usually not diffuse, abnormal nuclear labeling with antibodies to beta-­catenin, particularly in squamoid nests PEARLS • S hould be at the top of the differential for a pancreatic neoplasm in a woman in her twenties and thirties. • Touch preparations can highlight the delicate vasculature and poorly cohesive cells. • Hyaline globules are a clue to the diagnosis. • ALL are considered malignant.

Selected References 1. Hruban RH, Pitman MB, Klimstra DS. Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series. Fascicle 6th ed. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2007. 2. Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-­pseudopapillary tumors of the pancreas are genetically distinct from pancreatic

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 8 — Pancreas

A

459

B

Figure 8.14  A, Solid-­pseudopapillary neoplasm. Gross evaluation of the lesion demonstrates a predominantly solid lesion with areas of hemorrhage and cystic degeneration. B, Solid-­pseudopapillary neoplasm. Low-­power view showing uniform poorly cohesive cells surrounding delicate blood vessels. C, Solid-­pseudopapillary neoplasm. Hyaline globules are a feature of these tumors.

C

ductal adenocarcinomas and almost always harbor beta-­ catenin mutations. Am J Pathol. 2002;160(4):1361–1369. 3. Klimstra DS, Wenig BM, Heffess CS. Solid-­pseudopapillary tumor of the pancreas: a typically cystic carcinoma of low malignant potential. Semin Diagn Pathol. 2000;17(1):66–80.

METASTASES TO THE PANCREAS Clinical Features

Special Stains and Immunohistochemistry •  PAX8 and CAIX positive in metastatic renal cell carcinoma • Gross cystic disease fluid protein (GCDFP), estrogen, and PR receptor positive in metastatic mammary carcinoma • S-­100 protein, SOX10, HMB-­45, and Melan-­A positive in metastatic melanoma 

• History of a cancer in another organ • Lack of pancreatic ductal dilatation • May see multiple lesions 

Modern Techniques for Diagnosis

Gross Pathology

Differential Diagnosis

• Often multiple nodules 

Ductal Adenocarcinoma • Usually a single nodule • Prominent desmoplastic stroma • Adjacent pancreatic intraepithelial neoplasia (PanIN) or intraductal papillary mucinous neoplasm • Express cytokeratin 7 • 55% have loss of SMAD4

Histopathology • Clear cell neoplasm in metastatic renal cell carcinoma • Signet ring cell neoplasm in metastatic gastric carcinoma and lobular carcinoma of the breast • Melanin in metastatic melanoma 

• Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

460

Chapter 8 — Pancreas

PEARLS

Selected References

K •  nowledge of patient’s clinical history is crucial. • Patient’s imaging findings are critical to the correct diagnosis. • The most common metastasis to the pancreas is renal cell carcinoma. • Differentiation of pancreatic, biliary, and upper gastrointestinal tract neoplasms is difficult at best if one only relies on immunohistochemistry.

1. Adsay NV, Andea A, Basturk O, et al. Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature. Virchows Arch. 2004;444(6):527–535.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9

Adrenal Gland SYLVIA L. ASA  •  SANDRA E. FISCHER

Chapter Outline Adrenal Cortical Insufficiency (Addison Disease)  461 Congenital Adrenal Hyperplasia (Adrenogenital Syndrome)  462 Adrenal Cortical Hyperplasia  464 Adrenal Cortical Adenoma  465 Adrenal Cortical Carcinoma  469 Adrenal Medullary Hyperplasia  473

Ganglioneuroma  477 Ganglioneuroblastoma  478 Neuroblastoma  479 Primary Malignant Melanoma  481 Myelolipoma  482 Adrenal Cysts and Pseudocysts  483 Metastatic Tumors  485

Pheochromocytoma  474

ADRENAL CORTICAL INSUFFICIENCY (ADDISON DISEASE)

• Biochemistry: decreased cortisol and aldosterone as well as ACTH; renin and aldosterone levels are typically normal, 

CLINICAL FEATURES

GROSS PATHOLOGY

Primary Adrenal Cortical Insufficiency

• Idiopathic and secondary forms characterized by pale, shrunken adrenal gland, often weighing less than 2 to 3 g, with marked thinning of the cortical zone; severe atrophy in idiopathic disease may impair gross recognition of the adrenal glands • Other primary forms often associated with adrenal enlargement and infiltration by inflammation or tumor (Figure 9.1A) 

Etiology • Autoimmune etiology in 75% to 90% of cases, with circulating autoantibodies to endocrine antigens (21-­OH, P-­450scc, and 17-­OH) • Other causes include infectious diseases such as tuberculosis, hemorrhage (sepsis), metastatic tumors, amyloidosis, adrenoleukodystrophy, and drugs • Signs and symptoms: weakness, fatigue, salt craving, hypotension, anorexia and weight loss, hyperpigmentation (due to elevated adrenocorticotropic hormone [ACTH] and other pro-­opiomelanocortin fragments) • Biochemistry: decreased production of cortisol and aldosterone, elevated levels of ACTH and renin; hyponatremia and hyperkalemia may be seen as a result of decreased aldosterone • Therapy: corticosteroid and mineralocorticoid replacement; fatal if not treated 

Secondary Adrenal Cortical Insufficiency • Etiology: inadequate stimulation of the adrenal cortex as a result of low corticotropin-­releasing hormone (CRH) or ACTH •  Commonest cause is prolonged suppression of the hypothalamic-­ pituitary-­ adrenal axis by exogenous glucocorticoids • May be associated with destructive lesions of the hypothalamus or the pituitary gland • Signs and symptoms: weakness, fatigue, anorexia, weight loss, hypopigmentation; hyperpigmentation does not occur

HISTOPATHOLOGY • Secondary disease is characterized by small glands with prominent zona fasciculate (storage zone) and no zona reticularis (functional zone); zona glomerulosa is normal (see Figure 9.1B) • Idiopathic form exhibits marked atrophy of the adrenal cortex, with intact medulla surrounded by fibrous tissue containing few small islands of atrophic cortical cells; lymphoid infiltrate is often present (see Figure 9.1C and D) • Infiltrative forms due to inflammation or malignancy 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Special stains for microorganisms: may identify organisms in cases of infectious etiology 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

461

462

Chapter 9  —  Adrenal Gland

A

B

C

D

E

Figure 9.1  Adrenal cortical insufficiency (Addison disease).  A, Addison disease due to tuberculosis infection. Tissue destruction due to tuberculosis infection results in adrenal enlargement, but the gland is replaced by necrotic yellow material. No normal tissue is identified. The surrounding fat is unremarkable. B, Secondary adrenal cortical atrophy. The gland is small with an inactive cortex that is almost entirely composed of clear cells and lacks a zona reticularis. C, Addison disease due to tuberculosis infection. Caseating granuloma with giant cell reaction present in the adrenal cortex. D, Addison disease due to autoimmune inflammation. The adrenal is atrophic; the cortex is almost completely lost, and there is focal inflammation surrounding the residual medulla. E, Addison disease due to autoimmune inflammation. Inflammatory cells replace the cortex, and fibrosis is evident between the few residual cortical cells.

DIFFERENTIAL DIAGNOSIS • One must distinguish between primary and secondary adrenal insufficiency • If primary, one must attempt to determine etiology • Inflammatory; rule out infectious • Metastatic tumor • Amyloidosis (rare) PEARLS First described by Addison in 1855 • • Must have destruction of more than 90% of adrenal gland before symptoms develop • Immune form associated with autoimmune polyglandular syndrome (APS) type 1 and type 2 (Schmidt syndrome); APS type 1 is caused by mutations in the AIRE-­1 gene

Selected References Bancos I, Hahner S, Tomlinson J, Arit W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216–226.

Fujieda K, Tajima T. Molecular basis of adrenal insufficiency. Pediatr Res. 2005;57:62R–69R. Mitchell AL, Pearce SH. Autoimmune Addison disease: pathophysiology and genetic complexity. Nat Rev Endocrinol. 2012;8:306–316. Pazderska A, Pearce SH. Adrenal insufficiency—recognition and management. Clin Med (London). 2017;17(3):258–262. Shikama N, Nusspaumer G, Holländer GA. Clearing the AIRE: on the pathophysiological basis of the autoimmune polyendocrinopathy syndrome type-­1. Endocrinol Metab Clin North Am. 2009;38:273–288. Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007;119:e484–e494.

CONGENITAL ADRENAL HYPERPLASIA (ADRENOGENITAL SYNDROME) CLINICAL FEATURES • Etiology • Autosomal recessive disorder of cortisol biosynthesis resulting in impaired glucocorticoid feedback inhibition at the hypothalamic and pituitary levels, increased serum levels of CRH and ACTH, and adrenal hyperplasia

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

• Results from a defect in one of the five enzymatic steps involved in steroid synthesis; 90% to 95% of cases are caused by deficiency of 21-­ hydroxylase (mutation in CYP21A2), resulting in marked elevation of 17-­hydroxyprogesterone • Compound heterozygosity with different mutations that vary from mild missense to complete loss of function • Phenotype generally reflects residual enzyme activity of the milder mutation • Unusual causes: 20,22-­desmolase deficiency, 17α-­ hydroxylase deficiency, 3β-­hydroxysteroid dehydrogenase deficiency (mutation in HSD3B2), or 11 β-­hydroxylase deficiency (mutation in CYP11B1); rarely oxidoreductase deficiency (PORD), due to mutations in the cytochrome P450 oxidoreductase (POR) gene • Congenital lipoid adrenal hyperplasia • The most severe form of congenital adrenal hyperplasia (CAH), in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired • Lipoid CAH may be caused by a defect in either the steroidogenic acute regulatory (StAR) protein or P-­450scc • Epidemiology • Classic form occurs in 1 of 5000 to 15,000 live births • Nonclassic form occurs in 0.3% of the white population • Signs and symptoms • Clinical presentation correlates with severity of enzymatic deficiency • Virilization in females, precocious puberty in both sexes, varying degrees of adrenal cortical insufficiency and if severe, adrenal crisis, with vomiting, dehydration, hypoglycemia, hypotension, hyperkalemia, and hyponatremia • Most common cause of ambiguous genitalia in newborn females • Classic form • Can present as salt-­wasting form or simple virilizing type • Newborn females typically show virilization at birth as a result of increased circulating androgens (clitoral hypertrophy and pseudohermaphroditism) • Postpubertal females have oligomenorrhea, hirsutism, and acne • Newborn males usually present with salt-­losing crisis within days to weeks after delivery due to decreased synthesis of aldosterone (hypovolemia, hyperreninemia, and hyperkalemia can be life-­threatening) • Males later show enlargement of external genitalia and precocious puberty • Non-­classical form • Affected individuals are normal at birth and do not have cortisol and aldosterone deficiency • Develop signs of androgen excess (virilization) in late childhood or puberty • May present as adrenal insufficiency during pregnancy

463

• Therapy • Pharmacologic treatment involves glucocorticoid and mineralocorticoid replacement and the use of androgen and estrogen antagonists • Bilateral adrenalectomy performed in selected cases • Gene therapy studies under way 

GROSS PATHOLOGY • Bilateral adrenal gland enlargement with diffuse thickening of the cortex (Figure 9.2A) • Adrenal glands may weigh up to 10 to 15 times normal weight • Adrenals show a convoluted surface owing to numerous redundant folds 

HISTOPATHOLOGY • Thickened adrenal cortex with markedly thickened zona reticularis (active cells) and loss of zona fasciculate (storage); poorly defined zonation (see Figure 9.2B) • Most cortical cells have lipid-­depleted (compact) cytoplasm owing to sustained ACTH stimulation • In lipoid CAH, the gland enlargement results from the accumulation of cholesterol esters in large adrenal cortical cells with clear cytoplasm; further damage with cell rupture and foreign-­body granulomatous reaction to cholesterol clefts can be seen focally (see Figure 9.2C) 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Genetic testing for 21-­hydroxylase deficiency, or rarely 20,22-­ desmolase deficiency, 17α-­hydroxylase deficiency, 3β-­ hydroxysteroid dehydrogenase deficiency, or 11 β-­hydroxylase deficiency 

DIFFERENTIAL DIAGNOSIS Adrenal Cortical Hyperplasia • Primary hyperplasias are usually nodular unlike CAH; may be impossible to distinguish morphologically from ACTH-­dependent hyperplasia 

Adrenal Cortical Adenoma • Discrete adrenal cortical nodule rather than diffuse hypertrophy, and usually unilateral PEARLS • Defective adrenomedullary organogenesis owing to lack of glucocorticoids results in epinephrine deficiency and hypoglycemia • Several reported cases of cortical adenomas and cortical carcinomas developing in children with congenital adrenal hyperplasia; may be related to persistent ACTH stimulation • Adrenal cortical tumors may be seen developing in the testes/ovaries of patients with congenital cortical hyperplasia; believed to arise from ectopic adrenal cortical rests

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

464

Chapter 9  —  Adrenal Gland

A

C

B

Figure 9.2  Congenital adrenal hyperplasia (adrenogenital syndrome).  A, Congenital adrenal hyperplasia due to 21-­hydroxylase deficiency. The adrenal glands are diffusely enlarged with lipid-­depleted cortex. B, Congenital adrenal hyperplasia due to 21-­hydroxylase deficiency. Microscopic examination of the diffusely enlarged gland shows a prominent cortex with poor zonation and predominantly compact cells. C, Lipoid congenital adrenal hyperplasia. The adrenal cortex is thickened by large clear adrenal cortical cells containing increased amount of lipid with focal cholesterol clefts and multinucleated giant histiocytes. (A, Photo courtesy Dr. Glenn P. Taylor, Hospital for Sick Children, Toronto.)

Selected References El-­Manoush D, Arit W, Merke DP. Congenital adrenal hyperplasia. Lancet. 2017;390(10108):2194–2210. Lekarev O, New MI. Adrenal disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25:959–973. New MI, Abraham M, Yuen T, et al. An update on prenatal diagnosis and treatment of congenital adrenal hyperplasia. Semin Reprod Med. 2012;30:396–399. Ogilvie CM, Crouch NS, Rumsby G, et al. Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues. Clin Endocrinol. 2006;64:2–11.

ADRENAL CORTICAL HYPERPLASIA CLINICAL FEATURES • Two forms: primary (ACTH independent) which is usually nodular; and secondary (ACTH dependent), which is usually diffuse but may also form nodules • Etiology: depends on primary versus secondary and type of primary disease • Primary adrenal cortical hyperplasia, also known as ACTH-­independent: due to germline mutations • ACTH-­Independent Macronodular Adrenal Hyperplasia (AIMAH): due to activating mutations of ARMC5 or the ACTH receptor; multiple endocrine neoplasia type 1 (MEN 1) syndrome; familial adenomatous polyposis (FAP); amplification or aberrant expression of membrane receptors (GIP receptor, β-­adrenergic receptor, and LH receptor); activating mutations of GNAS 1 in McCune-­ Albright syndrome • Primary Pigmented Nodular Adrenal-­cortical Disease (PPNAD): due to inactivating germline mutations of the PRKAR1A and PDE11A genes, usually associated with Carney complex; rarely isolated



• Diffuse zona glomerulosa hyperplasia due to germline alterations in the KCNJ5 gene, rearrangements involving CYP11B1/CYP11B2 (type I familial hyperaldosteronism), chromosomal alterations at 7p22 (type II familial hyperaldosteronism) or the rare germline CACNA1HM1549V mutation. • Secondary (ACTH-­dependent) hyperplasia: due to ACTH excess from primary pituitary disease (corticotroph tumor or hyperplasia) or ectopic ACTH production by tumors at other sites • Signs and symptoms • Primary disorders may present with a variety of endocrine syndromes including Cushing syndrome, Conn syndrome, or virilization • Secondary disorder presents with severe Cushing syndrome, usually typical when pituitary dependent, and atypical (prominent wasting and pigmentation) when due to ectopic production by other malignancies • Biochemistry • Variable, depending on clinical manifestations (Cushing, Conn, and virilization syndromes); ACTH levels usually low (suppressed) with primary forms and high in secondary conditions • Therapy • Treatment of primary source of ACTH excess in secondary cases • Medical therapy to reduce glucocorticoid hypersecretion with ketoconazole, other drugs • Laparoscopic adrenalectomy for removal of adrenals followed by replacement therapies 

GROSS PATHOLOGY • Primary is usually nodular (Figure 9.3A)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

• Nodules vary from micronodules 1 cm (characteristic of AIMAH) • Pigmentation is characteristic of PPNAD • Secondary is usually diffuse hyperplasia of the adrenal cortex (see Figure 9.3B) • Degree of enlargement dependent on cause • Severe when due to ectopic ACTH, mild to moderate with pituitary-­dependent disease • Grossly undetectable when due to zona glomerulosa hyperplasia with Conn syndrome • Almost always bilateral • Combination of nodular and diffuse types may be seen 

HISTOPATHOLOGY • Adrenal cortex with diffuse hyperplasia or multinodular architecture, vague alveolar or trabecular pattern (see Figure 9.3C) • Cells are uniform in size with small, round nuclei • Cells have vacuolated (clear) or eosinophilic (compact) granular cytoplasm • Areas of lipomatous metaplasia may be seen • Zona glomerulosa hyperplasia limited to periphery of gland, characterized by continuous layer of nests of cells with scant cytoplasm averaging five nests in thickness (see Figure 9.3D) • Mixture of large clear cells and small compact cells in AIMAH • Pigmented nodules composed of enlarged, globular cortical cells with variable amounts of granular dark-­ brown pigment in PPNAD (see Figure 9.3E and F) • Cortical atrophy and disorganization of the normal zonation between nodules in PPNAD, as opposed to AIMAH, which shows characteristic interlobular hyperplasia 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • PPNAD nodules stain for synaptophysin and 17α-­ hydroxylase cytochrome P-­ 450; 3β-­hydroxysteroid dehydrogenase staining is dominant in AIMAH nodules 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Adrenal Cortical Adenoma • Presence of solitary, unilateral lesions with evidence of autonomous growth favors adenoma • Presence of small nodules adjacent to a larger nodule favors adrenal hyperplasia • Definitive distinction between nodular hyperplasia and adrenal cortical adenoma can often be difficult or even impossible

465

PEARLS • Hyperplasia of the adrenal cortex (micronodular and diffuse) has been reported in cases of familial hyperaldosteronism type I (glucocorticoid-­remediable aldosteronism), an autosomal dominant disorder caused by a hybrid gene formed by crossover between the ACTH-­responsive regulatory portion of the 11 β-­hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene; as a result, there is ACTH-­responsive ectopic secretion of aldosterone in the zona fasciculata

Selected References Assie G, Libe R, Espiard S, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med. 2013;369(22):2105–2114. Cazabat L, Ragazzon B, Groussin L, Bertherat J. PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary. 2006;9:211–219. Chui MH, Ozbey NC, Ezzat S, et al. Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancy-­ induced Cushing’s syndrome. Endocrine Pathol. 2009;20:256– 261. Duan K, Giordano TJ, Mete O. Adrenal cortex. In: Mete O, Asa SL, eds. Endocrine Pathology. Cambridge: Cambridge University Press; 2016:588–627. Lacroix A. ACTH-­independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009;23(2):245–259. Mete O, Duan K. The many faces of primary aldosteronism and Cushing syndrome: a reflection of adrenocortical tumor heterogeneity. Front Med (Lausanne). 2018;5:54.

ADRENAL CORTICAL ADENOMA CLINICAL FEATURES • Etiology • Most are sporadic with no known genetic basis • Association with familial disease (MEN 1, Carney complex, FAP, familial hyperaldosteronism, and congenital adrenal hyperplasia) can occur • May arise in patients with McCune-­Albright disease due to mosaic embryonic activating mutations of GNAS • Sporadic adenomas associated with Cushing syndrome may have mutations in PRKAR1A, PRKACA, GNAS, PDE11A, PDE8B, or rarely CTNNB1 that encodes beta-­catenin • Sporadic adenomas associated with Conn syndrome and hyperaldosteronism have mutations in the KCNJ5 potassium channel selectivity filter or in ATP1A1 and ATP2B3 encoding Na/K ATPases • Comparative genomic hybridization studies have demonstrated genetic alterations in 30% to 60% of adrenal adenomas; losses on chromosomes 2, 11q, and 17p, and gains on chromosomes 4 and 5 are the most common • TP53 and K-­ras mutations and loss of heterozygosity (LOH) of 11p15 and ACTH receptor are rare events in adenomas • Signs and symptoms • Most adrenal cortical adenomas are asymptomatic (nonfunctional) and found incidentally

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

466

Chapter 9  —  Adrenal Gland

A

B

C

D

E

F

Figure 9.3  Adrenal cortical hyperplasia.  A, Macronodular adrenal cortical hyperplasia. Gross photograph showing multiple adrenal cortical nodules. B, Diffuse adrenal cortical hyperplasia. Gross photograph showing a normal adrenal gland (top) and a diffusely enlarged gland with a lipid-­depleted cortex in a patient with ectopic adrenocorticotropic hormone syndrome (bottom). C, Macronodular adrenal cortical hyperplasia. Classic nodular adrenal cortical hyperplasia with multiple poorly defined cortical nodules composed of clear and compact cells. D, Zona glomerulosa hyperplasia. The adrenal gland is lined by a continuous layer of zona glomerulosa that is normally discontinuous. The cells are small and are on average five nests in thickness (inset). E, Primary Pigmented Nodular Adrenal-­cortical Disease (PPNAD) is characterized by nodules of enlarged eosinophilic cells with intervening normal-­appearing cortex. F, On higher magnification, the cells comprising the nodules in PPNAD are large with granular eosinophilic cytoplasm and accumulation of pigment.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

• Patients may present with Cushing syndrome or hyperaldosteronism (Conn syndrome); virilization is rarely associated with adenomas, and feminization in males is almost exclusively a sign of malignancy (see “Adrenal Cortical Carcinoma”) • Adenomas associated with Cushing syndrome and primary hyperaldosteronism are usually small and solitary; can rarely be multiple and bilateral • Biochemistry • Variable, depending on clinical manifestations (Cushing, Conn, and virilization syndromes); ACTH levels usually low (suppressed), except in Conn syndrome • Therapy • Laparoscopic tumor removal is the preferred treatment 

GROSS PATHOLOGY • Adenomas associated with Cushing syndrome or hyperaldosteronism are usually solitary and unilateral and weigh less than 50 g • Well-­defined tumors appear encapsulated • Adenomas associated with Cushing syndrome may be bright yellow or tan and are associated with atrophy of the adjacent nontumorous gland (Figure 9.4A) • Adenomas associated with Conn syndrome have a characteristic bright-­yellow or golden-­yellow color (see Figure 9.4B) • Adenomas may show focal hemorrhage or necrosis (typically in larger lesions) • Rarely, adenomas are diffusely pigmented black (pigmented adenoma) (see Figure 9.4C) • Oncocytic adrenal cortical adenomas have a dark-­tan to mahogany-­brown cut surface 

HISTOPATHOLOGY • See Figure 9.4D–I. • Circumscribed tumor with pushing borders, lacks true capsule (see Figure 9.4D and E) • Typically has trabecular or alveolar (nesting) architecture • Tumor cells are large and have round, regular nuclei with small, dotlike nucleoli; focal pleomorphism and large prominent nucleoli may be seen • Absent or rare mitotic activity; never atypical mitoses • Cytoplasm is abundant and “clear” or “compact” • In adenomas associated with Cushing syndrome, cytoplasm may be clear or eosinophilic (compact), and in most tumors, both types may be seen (see Figure 9.4F) • In adenomas associated with Conn syndrome, cytoplasm is clear, lipid rich, and vacuolated (see Figure 9.4G). • Pigmented adenomas have cells with eosinophilic cytoplasm containing prominent granular yellow-­ brown pigment (lipofuscin) (see Figure 9.4H). • Oncocytic adenomas have cells with abundant granular eosinophilic cytoplasm; focal marked nuclear

467

pleomorphism and nuclear pseudoinclusions may be seen • Histologic appearance of the tumor cannot reliably predict accompanying clinical presentation; examination of the adjacent nontumorous gland is more helpful • Atrophy of the normal cortex with loss of zona reticularis indicates Cushing syndrome with suppression of ACTH • In patients with Conn syndrome, there may occasionally be hyperplasia of the zona glomerulosa (paradoxical hyperplasia) • Spironolactone bodies (small eosinophilic laminated intracytoplasmic inclusions) may develop in the tumor and in cells of the zona glomerulosa if patient is treated with spironolactone; these are best seen with the Luxol fast blue (LFB) stain (see Figure 9.4I) 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • LFB for spironolactone bodies (see Figure 9.4I) • MIB1 or Ki-­67 labeling index usually below 2.5 • Immunostaining for HSD3B1/2 (3β-­hydroxysteroid dehydrogenase type 1 and type 2) and CYP11B1/2 (cytochrome P450 family 11 subfamily B member 1 and member 2) can distinguish tumors making aldosterone from those making cortisol; in particular, CYP11B2 (aldosterone synthase) is most useful to identify aldosterone-­producing tumors 

OTHER TECHNIQUES FOR DIAGNOSIS • Electron microscopy • Cells contain abundant lipid and prominent smooth endoplasmic reticulum; mitochondria are also numerous (see Figure 9.4J) • Mitochondrial morphology correlates with function: aldosterone-­producing cells (zona glomerulosa differentiation) have flat, platelike, “lamellar” cristae (see Figure 9.4K), whereas glucocorticoid and sex steroid-­producing cells (zona reticularis and fasciculata) have round or spherulated cristae (see Figure 9.4J) • Pigmented adenomas contain many electron-­ dense granules consistent with lipofuscin (see Figure 9.4L) • Spironolactone bodies are composed of concentric whorls of membranes 

DIFFERENTIAL DIAGNOSIS Adrenal Cortical Carcinoma • Usually large mass with gross evidence of hemorrhage and necrosis • Infiltrative borders typically invading into surrounding tissue • Tumor cells show marked pleomorphism and frequent mitotic activity 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

A

B

C

D

E

F

G

H

I

Figure 9.4  Adrenal cortical adenoma—gross appearance. A, Adrenal cortical adenoma associated with Cushing syndrome. Gross photograph shows that the nodule is well-­delineated and yellow with focal hemorrhage, and the adjacent gland shows marked atrophy. B, Adrenal cortical adenoma associated with Conn syndrome. Gross photograph shows that the tumor is well-­delineated and bright golden-­yellow. The adjacent adrenal is unremarkable. C, Adrenal cortical adenoma with pigmentation (“black adenoma”). Gross photograph shows that the nodule is well-­delineated and dark black owing to pigment deposition.  Part 2 Adrenal cortical adenoma—microscopy.  D, Adrenal cortical adenoma associated with Cushing syndrome. On microscopy, there is a large, well-­delineated but unencapsulated adenoma, and the adjacent gland exhibits marked atrophy with complete loss of the zona reticularis, indicating lack of adrenocorticotropic hormone stimulation. E, Adrenal cortical adenoma associated with Conn syndrome. On microscopy, there is a large, well-­delineated but unencapsulated clear cell adenoma, and the adjacent gland has zona glomerulosa hyperplasia (see Figure 9.3D). F, Adrenal cortical adenoma associated with Cushing syndrome. On microscopy, the adenoma has mixed clear and compact cell morphology with small round nuclei and abundant cytoplasm that varies from chromophobic to eosinophilic. G, Adrenal cortical adenoma associated with Conn syndrome. On microscopy, the tumor cells have abundant clear cytoplasm. H, Adrenal cortical adenoma, pigmented type. High-­power view showing proliferation of a monomorphic population of adrenal cortical cells with large amounts of eosinophilic cytoplasm containing yellow-­brown pigment. I, Adrenal cortical adenoma associated with Conn syndrome. The LFB stain highlights spironolactone bodies.   Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

J

K

469

L

Figure 9.4, cont’d  Part 3 Adrenal cortical adenoma—electron microscopy.  J, Adrenal cortical adenoma associated with Cushing syndrome. Electron microscopy shows that the tumor cells have abundant smooth endoplasmic reticulum, and the mitochondria have tubulovesicular cristae, consistent with differentiation as steroid-­producing cells. K, Adrenal cortical adenoma associated with Conn syndrome. Electron microscopy shows that the tumor cells have abundant smooth endoplasmic reticulum; the mitochondria have flat platelike cristae, consistent with zona glomerulosa differentiation and mineralocorticoid production; and there are lamellated spironolactone bodies. L, Adrenal cortical adenoma, pigmented type. Electron microscopy shows that the tumor cells have abundant smooth endoplasmic reticulum and numerous mitochondria, and there are large electron-­dense granules consistent with complex lysosomes containing lipofuscin.

Epithelioid Angiomyolipoma

Selected References

• An uncommon mesenchymal tumor with malignant potential, frequently associated with tuberous sclerosis complex • Composed of sheets or nests of large polygonal epithelioid cells with abundant eosinophilic or occasionally clear cytoplasm, often with prominent nucleoli; may include multinucleated and markedly pleomorphic forms • Exhibit immunoreactivity for both melanocytic and myoid markers • Ultrastructural evidence of melanosomes and premelanosomes

Beuschlein F, Boulkroun J, Osswald A, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-­producing adenomas and secondary hypertension. Nat Genet. 2013;45:440–444. Funder JW. The genetic basis of primary aldosteronism. Curr Hypertens Rep. 2012;14:120–124. Mete O, Asa SL. Morphologic distinction of cortisol-­ producing and aldosterone-­ producing adrenal cortical adenomas: not only possible but a critical clinical responsibility. Histopathology. 2012;60:1015–1016. Mete O, Asa SL, Giordano TJ, et al. Immunohistochemical biomarkers of adrenal cortical neoplasms. Endocr Pathol. 2018;29:137–149. Mete O, Duan K. The many faces of primary aldosteronism and Cushing syndrome: a reflection of adrenocortical tumor heterogeneity. Front Med (Lausanne). 2018;5:54. Mete O, van der Kwast TH. Epithelioid angiomyolipoma: a morphologically distinct variant that mimics a variety of intra-­abdominal neoplasms. Arch Pathol Lab Med. 2011;135:665–670. Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601–610.

PEARLS • Histologic appearance of adrenal cortical adenoma cannot be used to predict associated endocrine abnormality or syndrome, although the adjacent adrenal cortex may show atrophy (Cushing syndrome), or hyperplasia of the zona glomerulosa (Conn syndrome) • In tumors associated with Cushing syndrome, PRKACA-­ mutant adenomas usually occur in young patients, and are small tumors associated with pronounced hypercortisolism; PRKAR1A-­mutant adenomas may exhibit paradoxical increase in urinary cortisol in response to dexamethasone; tumors with CTNNB1 mutations are large with less severe hypercortisolism. • Treatment is typically resection of the adrenal gland containing the adenoma

ADRENAL CORTICAL CARCINOMA CLINICAL FEATURES • Etiology • Sporadic adrenal cortical carcinoma is most common; however, it also occurs in hereditary syndromes: Li-­Fraumeni, Beckwith-­Wiedemann, MEN1, Carney complex, FAP, and hereditary isolated glucocorticoid deficiency syndrome as well as Lynch syndrome • Sporadic carcinomas can harbor similar molecular defects, including germline and somatic mutations of TP53, beta-­catenin, and 17p13 LOH; rare menin mutations, but frequent 11q13 LOH; 17q22–24 LOH (PRKAR1A); 11p15 LOH and IGF-­II overexpression; 18p11 LOH (MC2-­R); mutations of APC, CTNNB1 encoding beta-­catenin and MUTYH

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

470

Chapter 9  —  Adrenal Gland

• Epidemiology • Rare tumor; occurs in about 1 per 1 million population • Typically presents in fourth and fifth decades of life; less common in pediatric population • Equal incidence in males and females • Signs and symptoms • Usually presents as incidental finding or associated with abdominal or flank pain; may present with a palpable abdominal mass or with evidence of distant metastasis • About 79% of carcinomas secrete hormones, and most functional tumors secrete cortisol with marked virilization owing to co-­secretion of 17-­ketosteroids and dehydroepiandrosterone (DHEA) • Less often, virilization in women and feminization in men can result from secretion of free testosterone and androstenedione, respectively • Mineralocorticoid excess is rare; however, combined secretion of cortisol and mineralocorticoid can occur • Therapy • Tumor removal is the preferred treatment • Residual unresectable tumor or metastases treated with mitotane 

GROSS PATHOLOGY • Usually large tumors weighing between 100 and 1000 g; may measure more than 20 cm (average, 14 to 15 cm) (Figure 9.5A) • Irregular, variegated, tan-­yellow mass with infiltrative borders • Extension into adjacent soft tissue or surrounding organs is common • Cut surface often shows extensive hemorrhage and necrosis 

• Cytokeratin may be negative or weakly positive • Synaptophysin may be positive (see Figure 9.5J) but chromogranin is negative • Reticulin staining is very helpful to distinguish adenoma from carcinoma (see Figure 9.5K and L) • Beta-­catenin nuclear translocation with loss of membrane staining • P53 positivity may be diffuse and strong or negative when mutated (see Figure 9.5M) • Cyclin E: positive staining correlates with advanced stage • Ki-­67 labeling index may be helpful to separate adenomas from carcinomas and has prognostic relevance, distinguishing low-­from high-­ grade carcinoma (see Figure 9.5N) 

OTHER TECHNIQUES FOR DIAGNOSIS • Electron microscopy: prominent rough and smooth endoplasmic reticulum; mitochondria with spherulated cristae; intracellular lipid droplets may be seen; these features are useful to characterize metastatic lesions as derived from adrenal cortex (see Figure 9.5F) • Cytogenetic studies: 17p13 LOH, 11p15 uniparental disomy (UPD), and IGF-­II overexpression are consistent findings 

DIFFERENTIAL DIAGNOSIS Metastasis • Separating adrenal cortical carcinoma from metastatic carcinomas from kidney and liver usually can be done using markers normally expressed in the adrenal cortex, including D11, SF-­1, inhibin-­α, and Melan-­A and markers of suspected primary site 

HISTOPATHOLOGY

Adrenal Cortical Adenoma

• Characteristic pattern is that of broad trabeculae with anastomosing architecture • Other common patterns include solid or alveolar architecture • Infiltrative growth pattern • Necrosis is common; often with calcification • Tumor cells may resemble normal adrenal cortical cells; however, there is marked nuclear atypia, atypical and frequent mitoses (more than 5/50 high-­power fields), vascular and extra-­adrenal invasion, and necrosis (see Figure 9.5B–D) and some tumors are highly pleomorphic (see Figure 9.5E) • Although uncommon, intracytoplasmic eosinophilic hyaline globules may be seen and are better visualized with periodic acid–Schiff (PAS) staining • Broad fibrous bands are a characteristic feature • Diagnostic features of malignancy include size (weight, >100 g), vascular invasion, and metastasis 

• Usually much smaller and lacks prominent hemorrhage or necrosis, pleomorphism, atypical mitotic figures, and vascular invasion • Multiple scoring systems have been proposed to distinguish low-­ grade carcinoma from adenoma (Weiss 1984, Modified Weiss 2002, Wieneke 2003 for pediatric tumors, Bisceglia-­Weiss for oncocytic tumors 2004, Reticulin algorithm 2009 and Helsinki 2015); all recognize necrosis (which can be due to previous biopsy), mitoses, and venous invasion, but all are subject to lack of reproducibility • The reticulin stain is very helpful as it shows intact acinar architecture in adenoma whereas carcinoma has either complete disruption or pericellular distribution of reticulin fibers • There is well documented progression from adenoma to carcinoma in some cases 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY

• Typically shows solid nesting architecture (zellballen) with cells containing indiscreet cell borders, abundant intracytoplasmic hyaline globules, strong synaptophysin and chromogranin positivity, and S-­ 100 protein highlighting sustentacular cells surrounding zellballen

• Vimentin, inhibin-­α, steroidogenic factor-­1 (SF-­1), and melan-­A positive (see Figure 9.5G–I)

Pheochromocytoma

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

A

B

C

D

E

F

471

Figure 9.5  Part 1. Adrenal cortical carcinoma. A, Gross photograph showing a large yellow tumor with areas of hemorrhage, necrosis, and cystic degeneration. B to D, On microscopy, the tumor is composed of a solid proliferation of neoplastic cells with moderately eosinophilic cytoplasm. There are areas of fibrosis (B), necrosis (C), and cytologic atypia (D). E, High-­grade adrenal cortical carcinoma can be composed of discohesive cells that are markedly pleomorphic and resemble other malignancies; immunohistochemistry is required to prove adrenal cortical differentiation. F, Electron microscopy characterizes the malignancy with prominent mitosis (top right) as derived from steroid-­secreting cells by the prominence of smooth endoplasmic reticulum and the numerous large mitochondria with spherulated cristae. Continued

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

472

Chapter 9  —  Adrenal Gland

G

H

I

J

K

L

M

N

Figure 9.5, cont’d  Part 2. Adrenal cortical car­cinoma—immunohistochemistry and reticulin.  G, Adrenal cortical carcinomas express nuclear SF1, and even in high-­grade tumors like this one, there is at least focal positivity. H, Adrenal cortical carcinomas express inhibin. I, Staining for Melan-­A is also seen in adrenal cortical carcinoma and must not be used to diagnose melanoma. J, Some adrenal cortical carcinomas express synaptophysin. K, The reticulin algorithm is useful to distinguish adrenal cortical carcinoma from adenoma; here there is complete breakdown of the reticulin pattern and L, there are areas of pericellular reticulin in carcinoma, unlike the normal regular acinar pattern of adenoma. M, Staining for p53 can be strong and diffuse in high-­grade adrenal cortical carcinoma. N, The Ki67 labeling index is prognostic and this tumor with a very high proliferation rate is a high-­grade adrenal cortical carcinoma with a poor prognosis.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

A

473

B

Figure 9.6  Adrenal medullary hyperplasia.  A, Low-­power view showing the adrenal gland with a diffusely hyperplastic medulla that extends all the way to the end of the wing. There is a suggestion of nodularity to the medulla. B, Low-­power view showing the adrenal gland with nodules of hyperplastic medulla.

PEARLS • Adrenal cortical carcinoma has a high mortality rate, with death typically occurring within 2 to 3 years • Large size, vascular invasion, and high mitotic rate and/or Ki67 labeling index are features of a more aggressive tumor • Vascular invasion requires strict definition as in other endocrine glands: intravascular tumor cells with associated thrombus, but not tumor cells underlying intact endothelium • Typical sites of metastasis include liver, lung, and lymph nodes

Selected References Assie G, Letouze E, Fassnacht M, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46:607–612. Beuschlein F, Weigel J, Saeger W, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015;100(3):841–849. Duregon E, Fassina A, Volante M, et al. The reticulin algorithm for adrenocortical tumor diagnosis: a multicentric validation study on 245 unpublished cases. Am J Surg Pathol. 2013;37(9):1433–1440. Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282–326. Mete O, Asa SL, Giordano TJ, et al. Immunohistochemical biomarkers of adrenal cortical neoplasms. Endocr Pathol. 2018;29:137–149. Mete O, Gucer H, Kefeli M, Asa SL. Diagnostic and prognostic biomarkers of adrenal cortical carcinoma. Am J Surg Pathol. 2018;42(2):201–213. Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-­ genomic characterization of adrenocortical carcinoma. Cancer Cell. 2016;29(5):723–736.

ADRENAL MEDULLARY HYPERPLASIA CLINICAL FEATURES • Etiology: usually associated with MEN IIA and MEN IIB syndromes • MEN IIA (Sipple syndrome) autosomal dominant syndrome includes medullary carcinoma of thyroid, pheochromocytoma, and parathyroid hyperplasia • MEN IIB autosomal dominant syndrome but usually de novo sporadic germline mutations; includes medullary carcinoma of thyroid,

pheochromocytoma, neuromas of the lip, mucous membranes, and gastrointestinal tract, and parathyroid hyperplasia • Occasionally associated with cystic fibrosis or Beckwith-­Wiedemann syndrome • Rarely reported in patients with SDHB, MAX, and TMEM127 germline mutations; not seen in other familial pheochromocytoma syndromes (von Hippel-­Lindau disease, neurofibromatosis) • Signs and symptoms • May resemble pheochromocytoma with paroxysmal hypertension, diaphoresis, and tachycardia • Biochemistry • Elevated urinary catecholamine and metanephrine levels • Therapy • Surgical resection of one or both adrenal glands is often indicated in both familial and sporadic forms 

GROSS PATHOLOGY • Usually bilateral, with increased adrenal gland weight • May be diffuse or have nodular architecture • Nodules must be less than 1 cm to be considered hyperplasia (nodules greater than 1 cm are considered pheochromocytoma) • Nodules are typically distinct and have a gray-­tan cut surface 

HISTOPATHOLOGY • Diffuse thickening of the medulla and expansion into the tail of the gland, with or without nodule formation, and with an increased medulla-­to-­cortex ratio (Figure 9.6) • Enlarged cells with or without pleomorphism and increased mitotic activity may be seen • Hyaline globules are commonly seen in patients with MEN II • No reliable morphologic criteria distinguish hyperplasia from pheochromocytoma apart from size, which is the best indicator for distinguishing these two entities 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

474

Chapter 9  —  Adrenal Gland

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Flow cytometry: tumor cells are usually diploid • Germline mutation of the ret proto-­oncogene can be detected by molecular studies in MEN II patients 

DIFFERENTIAL DIAGNOSIS • Distinction between nodular adrenal medullary hyperplasia and pheochromocytoma is currently based on the size of the lesion PEARLS • Armed Forces Institute of Pathology (AFIP) has designated adrenal medulla nodules less than 1 cm as medullary hyperplasia and nodules greater than 1 cm as pheochromocytoma • Medullary hyperplasia is believed to be the initial pathologic change in the adrenal gland, leading subsequently to the development of pheochromocytoma

Selected References Carney JA, Sizemore GW, Sheps SG. Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Pathol. 1976;66:279–290. Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005;29:254–274. DeLellis RA, Wolfe HJ, Gagel RF, et al. Adrenal medullary hyperplasia: a morphometric analysis in patients with familial medullary thyroid carcinoma. Am J Pathol. 1976;83:177–196. Mete O, Asa SL. Precursor lesions of endocrine system neoplasms. Pathology. 2013;5:316–330. Montgomery TB, Mandelstam P, Tachman ML, et al. Multiple endocrine neoplasia type IIb: a description of several patients and review of the literature. J Clin Hypertens. 1987;3:31–49. Qupty G, Ishay A, Peretz H, et al. Pheochromocytoma due to unilateral adrenal medullary hyperplasia. Clin Endocrinol (Oxford). 1997;47:613–617.

PHEOCHROMOCYTOMA CLINICAL FEATURES • Etiology • Although classic teaching indicated that only 10% of pheochromocytomas were hereditary, more recent studies show that almost half of pheochromocytomas are hereditary; a small percentage of these are bilateral or multifocal, involving extra-­adrenal paragangliomas • Germline mutations in VHL (3p26–25), resulting in von Hippel-­Lindau disease; RET (10q11.2), resulting in MEN II; NF1 (17q11.2), resulting in neurofibromatosis type 1 syndrome; or the succinate dehydrogenase genes SDHA, SDHB, SDHC, and SDHD (collectively “SDHx”), resulting in familial paraganglioma syndrome; other rare germline alterations implicated include mutations of TMEM127, FH, HIF2A, EPAS1, PHD1 and 2/EGLN2 and 1, MAX, SDHAF1, SDHAF2, BAP1, KIF1Bβ, KMT2D (MLL2), and DNMT3A

• Epidemiology • Sporadic tumors are usually diagnosed in patients aged 40 to 50 years, whereas hereditary forms are most often detected before age 40 years • Signs and symptoms • Clinical presentation is paroxysmal and results from the direct actions of secreted catecholamines, including hypertension, tachycardia, pallor, headache, and anxiety; up to 25% of pheochromocytomas are asymptomatic • Anesthesia and tumor manipulation most often elicit a catecholamine crisis, but several drugs and food can also induce paroxysms • Biochemistry • Diagnosis is made or confirmed based on measurements of urinary and plasma catecholamines, urinary metanephrines, and urinary vanillylmandelic acid (VMA) • Imaging techniques • Computed tomography or magnetic resonance imaging and localization with functional ligands such as 123I-­MIBG • Therapy • Laparoscopic tumor removal is the preferred treatment, after preoperative blocking of the effects of secreted catecholamines 

GROSS PATHOLOGY • Variable size and weight (from few grams to >2000 g) • Round to oval, sharply circumscribed mass that is often encapsulated • Cut surface shows a soft, variegated appearance with a dusky red-­brown color (Figure 9.7A) • Marked hemorrhage and necrosis may be seen; occasionally central cystic degeneration is seen • Compression of the adjacent adrenal gland is common; tumor may cause marked attenuation of the adrenal gland around the tumor 

HISTOPATHOLOGY • Tumor cells are arranged in well-­defined nests, zellballen appearance (see Figure 9.7B and C) • Distinct nests of tumor cells surrounded by thin strands of fibrovascular stroma that may (rarely) contain amyloid • Rim of sustentacular cells may be seen at periphery of cell nests • Tumor cells have varying size and shape with round nuclei, prominent nucleoli, and granular amphophilic to basophilic cytoplasm • Nuclei often show inclusion-­ like structures due to intranuclear cytoplasmic invaginations • Marked pleomorphism with bizarre tumor giant cells and numerous mitotic figures may be seen; these features are not diagnostic of metastatic behavior • Tumors of patients with von Hippel-­ Lindau disease have marked stromal edema, clear cell morphology (see Figure 9.7D), and may have lipid degeneration, resembling cortical tumors

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

475

• Tumors of patients with MEN II may be associated with adrenal medullary hyperplasia and may be multiple or bilateral • Composite pheochromocytoma is a pheochromocytoma with areas resembling neuroblastoma, ganglioneuroblastoma (GNB), or typical ganglioneuroma 

• Neurofilament and serotonin may show positivity • Ki-­67 is helpful to assess proliferative activity (see Figure 9.7I) • SDHB immunohistochemistry is a valuable screen for genetic predisposition since loss of SDHB is identified with any SDHx mutation (see Figure 9.7J) 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY

OTHER TECHNIQUES FOR DIAGNOSIS

• Chromogranin (see Figure 9.7E), synaptophysin, GATA3 (see Figure 9.7F), and tyrosine hydroxylase positive (see Figure 9.7G) • S-­100 protein: immunoreactivity of sustentacular cells surrounding zellballen; stain often decreases in malignant tumors (see Figure 9.7H)

• Electron microscopy: cells contain numerous neurosecretory granules • Cytogenetic studies: allelic losses on chromosomes 1p, 3p, 3q, 17p, and 22q are common in hereditary and nonhereditary pheochromocytomas 

A

B

C

D

Figure 9.7  Part 1. Pheochromocytoma gross and microscopy. A, The intra-­adrenal tumor has a characteristic dusky appearance due to the marked vascular congestion of this lesion. B, The adrenal cortex (right) is compressed by a tumor composed of nests of neoplastic cells surrounded by delicate strands of fibrovascular stroma. C, High-­power view showing solid nests, or zellballen, of polygonal neoplastic cells with poorly defined cell borders and abundant basophilic granular cytoplasm. D, High power of a pheochromocytoma from a patient with VHL disease shows clear cell morphology and stromal edema. Continued

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

476

Chapter 9  —  Adrenal Gland

E

F

G

H

I

J

Figure 9.7, cont’d  Part 2. Pheochromocytoma Immunohistochemistry.  E, Immunohistochemical staining for chromogranin confirms the diagnosis of a neuroendocrine neoplasm. F, Tumor cells have nuclear reactivity for GATA3. G, Positivity for tyrosine hydroxylase characterizes this as a pheochromocytoma or paraganglioma. H, Immunohistochemical localization of S-­100 protein highlights sustentacular cells that surround the nests of tumor cells and stain much more intensely than the tumor cells that are also positive. I, Like other neuroendocrine tumors, proliferation as determined by the Ki67 labeling index is prognostic. J, Immunohistochemistry for SDHB is negative in this pheochromocytoma from a patient with a known SDHD mutation; the endothelial and other stromal cells have intact staining, consistent with no loss of heterozygosity in normal tissue.

DIFFERENTIAL DIAGNOSIS

Neuroblastoma

Adrenal Cortical Adenoma

• Typically found in children younger than 4 years; composed of small round blue cells often with pseudorosette formation 

• Typically, adenomas appear golden-­ y ellow on gross examination; pheochromocytomas with lipid degeneration can have a similar gross appearance, but stains for chromogranin and synaptophysin are diagnostic 

Metastatic Neuroendocrine Tumor • These lesions are usually positive for keratins and negative for tyrosine hydroxylase

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

PEARLS • There is no classification of benign and malignant pheochromocytoma; metastatic behavior cannot be determined based on morphologic findings and only presence of distant metastases proves malignancy • SDHB mutations, more frequent in patients with extra-­ adrenal paraganglioma, are correlated with malignancy • Metastatic spread through lymphatic or hematogenous pathways most commonly involves lymph nodes, bones (particularly ribs and spine), lung, and liver • Pheochromocytoma is rare in children and is most often extra-­adrenal, multifocal, and associated with hereditary syndromes • Tyrosine hydroxylase and GATA3 immunoreactivity in pheochromocytomas is helpful to rule out metastatic neuroendocrine tumor; inhibin may be positive in hypoxic pathway disease and therefore does not confirm cortical differentiation; SF1 is a better biomarker of adrenal cortex

Selected References Assadipour Y, Sadowski SM, Alimchandani M, et al. SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery. 2017;161:230–239. Crona J, Taieb D, Pacak K. New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocr Rev. 2017;38:489–515. Fishbein L, Leshchiner I, Walter V, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31:181–193. Mete O, Tischler AS, De Krijger R, et al. Protocol for the examination of specimens from patients with pheochromocytomas and extra-­ adrenal paragangliomas. Arch Pathol Lab Med. 2014;138:182–188. Oudijk L, de Krijger RR, Pacak K, Tischler AS. Adrenal medulla and extra-­adrenal paraganglia. In: Mete O, Asa SL, eds. Endocrine Pathology. Cambridge: Cambridge University Press; 2016:628–676. Turchini J, Cheung VKY, Tischler AS, et al. Pathology and genetics of phaeochromocytoma and paraganglioma. Histopathology. 2018;72:97–105.

GANGLIONEUROMA

477

• May have elevated VMA and homovanillic acid (HVA) levels • Increased secretion of vasoactive intestinal peptide (VIP) or serotonin may cause diarrhea • Therapy • Tumor removal is the preferred treatment 

GROSS PATHOLOGY • Large, well circumscribed, although a true capsule is uncommon • Measure from 1 cm to more than 15 cm; average about 8 cm • Firm consistency with homogeneous, solid, tan-­yellow to gray-­white cut surface • Occasionally multifocal 

HISTOPATHOLOGY • Composed entirely of ganglion cells and stromal elements represented by Schwann cells and mature fibrous tissue (Figure 9.8) • Ganglion cells have compact eosinophilic cytoplasm with distinct cell borders and a single eccentric nucleus with a prominent nucleolus; may contain granular golden-­brown pigment (neuromelanin) • Variable numbers of ganglion cells may be present; few may be seen, making distinction from neurofibroma difficult • Mitotic activity and necrosis are absent • Mast cells may be present, although tumor does not contain neuroblasts or intermediate cells 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • S-­100 protein positive • Synaptophysin: ganglion cells positive • Ganglion cells also stain for neurofilament, Neu-­N 

CLINICAL FEATURES

OTHER TECHNIQUES FOR DIAGNOSIS

• Etiology • Ganglioneuromas can present as de novo tumors or may arise from neuroblastomas and GNBs that underwent spontaneous maturation or after treatment with chemotherapy • Epidemiology • Rare benign tumors found in older individuals; the median age at diagnosis ranges from 5.5 to 10 years; with a slight female predominance (1.5:1) • The most common locations are the posterior mediastinum (41%), retroperitoneum (37%), adrenal gland (21%), and neck (8%) • Most common tumor of sympathetic nervous system in adults • Signs and symptoms • Most often manifests as an asymptomatic mass • May present with symptoms of catecholamine excess, rarely with diarrhea • Biochemistry • Usually no abnormalities

• Electron microscopy: ganglion cells have an eccentric nucleus with a prominent nucleolus; cytoplasm shows peripheral rough endoplasmic reticulum, and neurosecretory granules 

DIFFERENTIAL DIAGNOSIS Neurofibroma • Lacks ganglion cell differentiation PEARLS • Ganglioneuroma is believed to be the fully differentiated counterpart of peripheral neuroblastic tumors • Considered a benign tumor; however, malignant transformation to malignant peripheral nerve sheath tumor (MPNST) has been reported • Thorough sampling needed to rule out less well-­ differentiated areas; all friable or hemorrhagic areas must be submitted for microscopic examination

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

478

Chapter 9  —  Adrenal Gland

A

B

Figure 9.8  Ganglioneuroma.  A, Ganglioneuroma. High-­power view showing characteristic proliferation of spindle cells with wavy nuclei. Several classic ganglion cells are present in the center of the field. B, Composite pheochromocytoma and ganglioneuroma. The lesion consists of two components: a typical pheochromocytoma (left) and spindle cell ganglioneuroma (right).

Selected References Khan AN, Solomon SS, Childress RD. Composite pheochromocytoma-­ ganglioneuroma: a rare experiment of nature. Endocr Pract. 2010;16:291–299. Lonergan GJ, Schwab CM, Suarez ES, Carlson CL. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: radiologic-­pathologic correlation. Radiographics. 2002;22:91–134. Mora J, Gerald WL. Origin of neuroblastic tumors: clues for future therapeutics. Exp Rev Mol Diagn. 2004;4:293–302. Tischler AS. Divergent differentiation in neuroendocrine tumors of the adrenal gland. Semin Diagn Pathol. 2000;17:120–126.

GANGLIONEUROBLASTOMA CLINICAL FEATURES • Epidemiology • Most often seen in patients 2 to 4 years old, and exceedingly rare after the age of 10 years; occurs with equal frequency in boys and girls • Signs and symptoms • Patients often present with an abdominal mass or with abdominal tenderness • Most common tumor site is the abdomen, followed by the mediastinum, neck, and lower extremity • Therapy • Prognosis and response to therapy is significantly more favorable than those of neuroblastoma 

GROSS PATHOLOGY • Well-­circumscribed mass with a variegated cut surface • Tumor appearance varies depending on the amount of mature to immature elements, ranging from predominantly solid to cystic • Firm tan-­white areas (better differentiated component) and hemorrhagic areas (poorly differentiated component) may be seen

• Granular calcifications are often present 

HISTOPATHOLOGY • Shows histologic features similar to those of neuroblastoma, except that ganglion cell differentiation is present • Variable amounts of neuroblastoma and ganglioneuroma are seen in the same tumor; typically the ganglioneuromatous component is in excess of 50% of the tumor • Subtypes (International Neuroblastoma Pathology Committee) • GNB: nodular classic (abrupt transition between the neuroblastomatous nodule and the surrounding ganglioneuromatous component) • GNB: nodular atypical (no nodules are seen on gross or microscopic examination; ganglioneuromatous component is present as a thin rim; metastasis shows neuroblastomatous features) • GNB: intermixed (tumor is composed predominantly of gangliomatous component with well-­ delineated microscopic foci of neuroblastomatous component) • These categories have prognostic significance: nodular has an unfavorable prognosis; intermixed has favorable prognosis 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Neuron-­specific enolase (NSE), chromogranin, synaptophysin positive • Neurofilament and Neu-­N positive • S-­ 100 protein positive in spindle cell population is prognostic; more abundant staining is associated with a better prognosis 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

OTHER TECHNIQUES FOR DIAGNOSIS • Electron microscopy: cells with abundant filiform cell processes; cytoplasm showing distinct neurosecretory granules and neurotubules 

DIFFERENTIAL DIAGNOSIS Neuroblastoma • Single population of small to medium-­sized blue cells with no ganglion cells or evidence of differentiation 

Ganglioneuroma • Spindle cell population in a loose, myxoid background with distinct ganglion cells and no component of neuroblastoma PEARLS • GNBs are transitional tumors of sympathetic cell origin that contain elements of both neuroblastoma and ganglioneuroma • It has been suggested that nodular GNB evolves as a result of clonal proliferation of more aggressive malignant tumor cells in a neuroblastomatous component of what originally was a GNB of intermixed type maturing ganglioneuroma • Nodules of nodular GNB may be identified by imaging studies and present with higher levels of urinary excretion of catecholamines compared with intermixed GNB and ganglioneuroma

Selected References Guo YK, Yang ZG, Li Y, et al. Uncommon adrenal masses: CT and MRI features with histopathologic correlation. Eur J Radiol. 2007;62:359–370. Koike K, Iihara M, Kanbe M, et al. Adult-­type ganglioneuroblastoma in the adrenal gland treated by a laparoscopic resection: report of a case. Surg Today. 2003;33:785–790. Peuchmaur M, d’Amore ES, Joshi VV, et al. Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer. 2003;98:2274–2281. Rha SE, Byun JY, Jung SE, et al. Neurogenic tumors in the abdomen: tumor types and imaging characteristics. Radiographics. 2003;23:29–43. Shimada H, Umehara S, Monobe Y, et al. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors. Cancer. 2001;92:2451–2461.

NEUROBLASTOMA

479

• Other biologic variables include deletions of 1p (25% to 35%), allelic loss of 11q (35% to 45%), and gain of 17q • Epidemiology • Incidence of about 8 per 1 × 106 population; most common extracranial solid tumor of childhood • Accounts for more than 7% of malignancies in patients younger than 15 years; more than 85% occur in children younger than 4 years • Can occur in a variety of locations, with adrenal gland being most common site (50% to 80%) • Other common sites include posterior mediastinum (about 15%) • Signs and symptoms • About 40% of patients present with localized disease ranging from an incidental adrenal mass discovered on prenatal ultrasound to large and invasive tumors • Classic signs of disseminated neuroblastoma include periorbital ecchymoses (raccoon eyes), proptosis, or both, due to metastasis to the bony orbit • Paraneoplastic syndromes include (1) intractable diarrhea and failure to thrive secondary to secretion of VIP and (2) opsoclonus-­myoclonus syndrome (2% to 4%) • Biochemistry • May produce catecholamines with increased levels of urinary VMA • Therapy • Surgery, chemotherapy, radiotherapy, and biotherapy, as well as observation alone in selected cases, are used according to risk group based on the presence or absence of unfavorable biologic features 

GROSS PATHOLOGY • Typically circumscribed, round to oval mass, often with a variegated, lobular cut surface; usually tan to gray-­white (Figure 9.9A) • May be variable in size ranging from less than 1 cm to greater than 10 cm • Usually solitary and unicentric, but bilateral cases have been reported • Typically solid but occasionally shows cystic degeneration • Often shows marked hemorrhage, necrosis, or calcification • Invasion into adjacent organs and soft tissue may be seen 

CLINICAL FEATURES

HISTOPATHOLOGY

• Etiology • Malignant tumor of sympathoadrenal lineage of the neural crest that can develop anywhere in the sympathetic nervous system • Genomic amplification of MYCN is common and consistently associated with poor outcome • ATRX mutations that result in an alternate lengthening of telomeres (ALT) phenotype increase with age and are associated with worse prognosis • ALK is overexpressed and/or mutated in some cases

• Cellular, small round blue cell tumor with vague lobular architecture (see Figure 9.9B and C) • Nodular aggregates of tumor cells separated by delicate fibrovascular septa • Prominent Homer-­ Wright pseudorosettes (round spaces surrounded by palisading peripheral nuclei and filled with a faintly eosinophilic fibrillary matrix) may be seen • Fibrillar matrix representing neuritic cell processes; resembles neuropil of the central nervous system

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

480

A

Chapter 9  —  Adrenal Gland

B

C

Figure 9.9  Neuroblastoma.  A, The adrenal gland is replaced by a circumscribed, round to oval mass with a variegated, lobular appearance, invading into the kidney. B, Low-­power view showing a monomorphic proliferation of small blue cells and adjacent residual adrenal cortex. C, High-­power view showing a monomorphic proliferation of small blue cells with fine granular chromatin and indistinct cytoplasmic borders. Notice the fibrillary background. (A, Photo courtesy Dr. Glenn P. Taylor, Hospital for Sick Children, Toronto.)

• Cells are medium sized and round to oval with high nuclear-­ to-­ cytoplasmic ratio and scant cytoplasm; hyperchromatic nuclei have stippled chromatin and inconspicuous nucleoli • Hemorrhage and microcalcifications are common findings • Variable mitotic activity • Microscopic grading criteria (International Neuroblastoma Pathology Committee [INPC]): the criteria divide tumors into subtypes • Neuroblastoma, undifferentiated: small, medium, or large round neuroblasts showing lack of differentiation or neuropil by routine light microscopy • Neuroblastoma, undifferentiated, pleomorphic subtype: neuroblasts are large, with pleomorphic nuclei, prominent nucleoli, and moderate to abundant cytoplasm (some cells may have rhabdoid features); no neuropil • Neuroblastoma, poorly differentiated: less than 5% neuroblasts show synchronous differentiation toward ganglion cells • Neuroblastoma, differentiating: more than 5% neuroblasts show synchronous differentiation toward ganglion cells • Mitosis karyorrhexis index (MKI) is based on percentage seen in 10 high-­power fields (total of 5000 cells): less than 2% (low), 2% to 4% (intermediate), and more than 4% (high) • Assessment of the MKI is crucial because it is used to determine prognostic categories (unfavorable versus favorable histology) in combination with the tumor differentiation and age of the patient (Table 9.1) 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • NSE, chromogranin, synaptophysin positive • Neurofilament and Neu-­N positive • S-­100 protein: spindle cell population positive • Cytokeratin positive

• Galectin-­ 3 expression may be associated with good prognosis • Negative for desmin, myoglobin, vimentin, leukocyte common antigen (LCA), and CD99 

OTHER TECHNIQUES FOR DIAGNOSIS • Electron microscopy: characteristically shows cytoplasmic filaments, dense-­core neurosecretory granules, and microtubules • Cytogenetic studies: MYCN and 1p deletion by fluorescent in situ hybridization technique • DNA index by flow cytometry 

DIFFERENTIAL DIAGNOSIS Ganglioneuroblastoma • Shows evidence of differentiation in the form of ganglion cells, which may appear normal or abnormal 

Rhabdomyosarcoma • A rare tumor, usually arising in or around the kidney, composed of large tumor cells with eccentric nuclei and prominent nucleoli; large eosinophilic cytoplasmic inclusions are often seen • Immunohistochemical stains: positive for desmin, myoglobin, myogenin, MyoD1, negative for NSE, chromogranin, and synaptophysin 

Malignant Lymphoma • Composed of diffuse sheets of atypical lymphoid cells without fibrovascular septa; lacks rosette formation and has no fibrillary matrix • CD45 (LCA) positive; negative for NSE, chromogranin, and synaptophysin 

Ewing Sarcoma • Typically found in long bones and occasionally in soft tissue

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 9  —  Adrenal Gland

481

TABLE 9.1   PROGNOSIS FOR NEUROBLASTOMA Age (Years)

Differentiation

Mitosis Karyorrhexis Index

Prognostic Category

1–21 1–21 >1–21 10 mitotic figures/hpf have a dismal prognosis (5 to 10 mitotic figures/hpf) but lacking significant cytologic atypia and necrosis should be classified as smooth muscle tumors of uncertain malignant potential (STUMP), or atypical leiomyomas • Myxoid leiomyosarcoma: mitotic count should be performed in more cellular areas

Selected References Giuntoli RL 2nd, Metzinger DS, DiMarco CS, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol. 2003;89:460–469. Hoang LN, Aneja A, Conlon N, et al. Novel high-­grade endometrial stromal sarcoma: a morphologic mimicker of myxoid leiomyosarcoma. Am J Surg Pathol. 2017;41(1):12. Ip PP, Cheung AN, Clement PB. Uterine smooth muscle tumors of uncertain malignant potential (STUMP): a clinicopathologic analysis of 16 cases. Am J Surg Pathol. 2009;33:992–1005. O’Neill CJ, McBride HA, Connolly LE, et al. Uterine leiomyosarcomas are characterized by high p16, p53 and M1B1 expression in comparison with usual leiomyomas, leiomyoma variants and smooth muscle tumors of uncertain malignant potential. Histopathology. 2007;50:851–858. Parra-­Herran C, Schoolmeester JK, Yuan L, et al. Myxoid leiomyosarcoma of the uterus. Am J Surg Pathol. 2016;40(3):285–301.

Clinical Features  • Rare, benign tumor • Occurs at any age but generally in older, postmenopausal women • Usually presents with abnormal bleeding • Uterus may be palpably enlarged 

Histopathology.  See Figure 12.39A • Small uniform oval to spindled cells resembling endometrial stromal cells • Minimal cytologic atypia and generally fewer than 10 mitotic figures/10 hpf •  Numerous thin-­ walled vessels evenly spaced among stromal cells and resembling spiral arterioles • Rare small foci of necrosis, cystic degeneration, foam cells, calcification, decidualization, and sex cord–like structures  Special Stains and Immunohistochemistry  • CD10 positive • Vimentin positive • Reticulin positive surrounding individual cells • Cytokeratin only focally positive, except in sex cord elements •  SMA, desmin mostly negative except for stromal myoma • Epithelial membrane antigen (EMA) negative  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Leiomyoma  • Unevenly spaced, thick-­walled vessels • Spindled cells and interlacing fascicles

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

668

Chapter 12  —  Female Reproductive System

•  Positive for SMA, desmin, smooth muscle myosin (SMMS), only focally positive for CD10  Low-­Grade Stromal Sarcoma  • Infiltrative margins • Prominent lymphovascular invasion  Hemangiopericytoma  • Extremely rare in the uterus • Large branching staghorn vessels • Definitively diagnosed by immunohistochemistry demonstrating neoplastic cells with pericytic differentiation PEARLS • B  enign without recurrence even if excised without hysterectomy • Usually expresses estrogen and progesterone receptors

Selected References Ali RH, Rouzbahman M. Endometrial stromal tumours revisited: an update based on the 2014 WHO classification. J Clin Pathol. 2015;68(5):325–332. Nucci MR. Practical issues related to uterine pathology: endometrial stromal tumors. Mod Pathol. 2015;29(S1):92–103.

Low-­Grade Endometrial Stromal Sarcoma Clinical Features  • Rare tumor that usually presents with abnormal vaginal bleeding • Occurs at any age but most common in older premenopausal or postmenopausal women • Uterus is often palpably enlarged  Gross Pathology  • Well-­circumscribed mass, diffusely infiltrative mass, or multiple confluent masses • Wormlike masses within myometrium (gross manifestation of lymphovascular invasion) • Foci of hemorrhage, necrosis, or cystic degeneration • Gross extrauterine extension in approximately 30% of cases at time of diagnosis  Histopathology  • Extensively infiltrative margins •  Plugs of tumor within lymphovascular spaces and myometrium (hence former name endolymphatic stromal myosis) • Variable numbers of mitotic figures, generally 10 to 20 mitotic figures/10 hpf •  Cells with minimal atypia resembling endometrial stromal cells (Figure 12.39B) • Foci of epithelioid differentiation appearing as glandular or sex cord–like elements • Foci of hemorrhage and necrosis are occasionally present • Calcification, decidualization, cystic degeneration, and foam cells may be identified  Special Stains and Immunohistochemistry  • CD10, vimentin positive • Cytokeratin occasionally focally positive • EMA negative • SMA, desmin: mostly negative (useful in distinguishing from smooth muscle tumors) 

Other Techniques for Diagnosis  • The most common rearrangement is t(7;17)(p21;q15) which results in JAZF1-­SUZ12 fusion gene. Rearrangements involving PHF1 are less common  Differential Diagnosis Stromal Nodule  • Lack of lymphovascular invasion • Noninfiltrating (pushing) margins  High-­Grade Stromal Sarcoma  • Marked cytologic atypia • Atypical mitotic figures and necrosis  Hemangiopericytoma  • Rare in uterus • Large, branching staghorn vessels  Intravenous Leiomyomatosis  • Purely smooth muscle with irregularly spaced, thick-­ walled vessels • Uncommon admixture of stromal cells or, rarely, epithelial components • More abundant cytoplasm •  Intracytoplasmic myofibrils demonstrated by trichrome or electron microscopy • Positive for SMA, MSA, desmin  Metaplastic Carcinoma versus Low-­Grade Endometrial Stromal Sarcoma with Prominent Epithelioid Elements  •  Metaplastic carcinoma has glands that are outright malignant • Generally does not show plugging of lymphovascular spaces  Adenosarcoma  • Papillary folds with slitlike or dilated glands composed of cells with nuclei that are epithelial, not stromal •  In general, demarcated from surrounding atypical stroma with some mitotic figures PEARLS • M  itotic activity is not predictive of aggressive behavior • Distinction from high-­grade stromal sarcoma is based on the absence of marked cytologic atypia, only minimal necrosis, and atypical mitotic figures • Treatment is usually total abdominal hysterectomy with bilateral salpingo-­oophorectomy with debulking of extrauterine tumor • Recurrence is common even after several years

Selected References Ali RH, Rouzbahman M. Endometrial stromal tumours revisited: an update based on the 2014 WHO classification. J Clin Pathol. 2015;68(5):325–332. Chang KL, Crabtree GS, Lim-­Tan SK, et al. Primary uterine endometrial stromal neoplasms: a clinicopathologic study of 117 cases. Am J Surg Pathol. 1990;14:415–438. Czernobilsky B. Uterine tumors resembling ovarian sex cord tumors: an update. Int J Gynecol Pathol. 2008;27:229–235. McCluggage WG, Sumathi VP, Maxwell P. CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. Histopathology. 2001;39:273–278. Nucci MR. Practical issues related to uterine pathology: endometrial stromal tumors. Mod Pathol. 2015;29(S1):92–107.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

669

A B

C Figure 12.39  A, Endometrial stromal nodule. The neoplastic cells are uniform in size and shape, and they have minimal cytologic atypia and no mitotic figures. B, Low-­grade endometrial stromal sarcoma. Round to spindled cells with bland nuclei, no mitotic figures, and small plexiform blood vessels. C, High-­grade endometrial stromal sarcoma (undifferentiated sarcoma). High mitotic activity and nuclear pleomorphism are ­evident.

High-­Grade Endometrial Stromal Sarcoma (Undifferentiated sarcoma) Clinical Features  • Rare tumor that generally occurs in postmenopausal women •  Usually presents with abnormal bleeding or pelvic pain • Aggressive tumor, with less than 50% 5-­year survival rate  Gross Pathology  • Grossly infiltrative masses, confluent mass, or diffuse infiltration of myometrium •  Endometrial involvement, hemorrhage, and necrosis are common • Wormlike infiltration of myometrium is usually absent  Histopathology  • Pronounced cytologic atypia; however, cells may still resemble endometrial stromal cells • Mitotic activity is generally more than 10 mitotic figures/10 hpf with atypical forms (Figure 12.39C) • Uneven distribution of thin-­walled vascular spaces • Coagulative necrosis

•  There may be areas composed of undifferentiated bizarre or giant sarcoma cells • Heterologous elements, including rhabdomyosarcoma or chondrosarcoma •  Epithelioid foci and wormlike plugs are generally absent • Frequent lymphovascular invasion • May be morphologically indistinguishable from other uterine sarcomas, leiomyosarcoma in particular  Special Stains and Immunohistochemistry  • Vimentin positive • Cytokeratin and CD10 focally positive • EMA negative • SMA generally negative (useful in distinguishing from leiomyosarcoma) • S-­100 protein positive if chondrosarcomatous component present  Other Techniques for Diagnosis  •  The most common rearrangement is t(10;17) with YWHAE-­FAM22 fusion. Also found in a subset of tumors are t(X;22)(p11;q13) with ZC3H7B-­ BCOR fusion and internal tandem duplications (ITDs) involving exon 15 of BCOR (BCOR ITD) 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

670

Chapter 12  —  Female Reproductive System

Differential Diagnosis Low-­Grade Stromal Sarcoma  • Minimal cytologic atypia • Evenly spaced vessels • Wormlike projections of tumor • May have epithelioid elements  Undifferentiated Endometrial Sarcoma  • Lacks endometrial stromal differentiation  Metaplastic Carcinoma  • Malignant epithelial and spindle cell components are present  Leiomyosarcoma  • Evidence of smooth muscle differentiation by hematoxylin and eosin (H&E) and immunohistochemistry • Whorling pattern of plump, atypical spindle cells as opposed to more random streaming distribution of cells in stromal sarcoma  Adenosarcoma  • Benign glandular epithelium  Other Sarcomas (e.g., Undifferentiated pleomorphic sarcoma, Rhabdomyosarcoma, Osteosarcoma)  • All of these are rare as primary tumors in the uterine corpus • These lack cell populations that resemble endometrial stromal cells  Poorly Differentiated Endometrial Carcinoma  • Positive for cytokeratin PEARLS • C  ytologic atypia has proved more accurate than mitotic count in distinguishing low-­grade from high-­grade stromal sarcomas as well as in predicting behavior • Necrosis is generally present, and epithelioid elements and wormlike endolymphatic stromal projections are generally absent • Treatment is usually total abdominal hysterectomy with bilateral salpingo-­oophorectomy and tumor debulking • Distinction from leiomyosarcoma has no clinical significance

• Present often in the pelvic peritoneum: covering the uterus, fallopian tubes, omentum, laparotomy scars, and so on; rarely in retroperitoneal lymph nodes • Affects women of reproductive age with a mean age of 30 years, rarely occurs in postmenopausal women • Generally an incidental finding • Originates in the secondary müllerian system • Associated with atypical proliferative serous tumors  Gross Pathology  •  Multiple small fluid filled cysts measuring less than 5 mm may be seen on the peritoneum covering the uterus, fallopian tubes, and ovaries  Histopathology  •  Glands of varying size and shapes and occasionally cystic lined by a single layer of benign tubal type epithelium • Loose or dense connective tissue stroma • Psammoma bodies in the gland lumina and stroma  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Extraovarian Serous Cystadenoma  • Solitary mass of significant size or fibromatous stroma • Implants of borderline serous tumors PEARLS • A  typical endosalpingiosis refers to cellular endosalpingiosis with cellular stratification and atypia and is to be considered in the differential diagnosis of peritoneal serous borderline tumors • May represent the precursor lesion of ovarian serous tumors

Selected References

Selected Reference

Chiang S, Lee CH, Stewart CJ, et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-­grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol. 2017;30(9):1251. Feng W, Malpica A, Robboy SJ, et al. Prognostic value of the diagnostic criteria distinguishing endometrial stromal sarcoma, low grade from undifferentiated endometrial sarcoma, 2 entities within the invasive endometrial stromal neoplasia family. Int J Gynecol Pathol. 2013;32(3):299–306. Lewis N, Soslow RA, Delair DF, et al. ZC3H7B-­BCOR high-­grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod Pathol. 2018;31(4):674. McCluggage WG, Lee CH. YWHAE-­ NUTM2A/B translocated high-­ grade endometrial stromal sarcoma commonly expresses CD56 and CD99. Int J Gynecol Pathol. 2019;38(6):528–532. Nucci MR, O’Connell JT, Huettner PC, et al. H-­caldesmon expression effectively distinguishes endometrial stromal tumors from uterine smooth muscle tumors. Am J Surg Pathol. 2001;24:455–463.

Zinser KR, Wheeler JE. Endosalpingiosis in the omentum: a study of autopsy and surgical material. Am J Surg Pathol. 1982;6:109–117.

Endosalpingiosis Clinical Features  •  Benign glands with fallopian tube–like epithelium, sometimes with calcifications

OVARY Inflammatory conditions of the ovary are uncommon and generally associated with PID or systemic infections such as tuberculosis. Immune oophoritis is a rare condition and most commonly a diagnosis of exclusion. Neoplasms of the ovary represent most of the pathology.

MISCELLANEOUS CONDITIONS Follicular Cyst and Corpus Luteum Cyst Clinical Features Follicular Cysts  • Common; they occur at any age but often in the reproductive years •  Occasionally associated with McCune-­ Albright syndrome

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

671

• Polyostotic fibrous dysplasia, irregular patches of pigmented skin, and endocrine dysfunction, especially precocious puberty in girls  Corpus Luteum Cysts  • Occur frequently during the reproductive years • Usually an incidental finding • May present as a palpable mass with endocrine manifestations like increased estrogen production and menstrual irregularities •  Rupture and bleeding into the peritoneum are relatively common 

• Theca interna cells •  Larger with abundant cytoplasm and mixed with vessels  Corpus Luteum Cyst  • Thin inner layer of connective tissue • Outer layer of luteinized, large vacuolated granulosa cells and smaller theca interna cells 

Gross Pathology  • Follicular cysts are typically unilocular with a thin wall and smooth inner surface, usually smaller than 10 cm in diameter, and filled with serous fluid (Figure 12.40A) •  Corpus luteum cysts are larger than 2 cm, have a smooth yellow lining, and have bloody fluid 

Other Techniques for Diagnosis  • Noncontributory 

Histopathology Follicular Cyst  • Inner layer of granulosa cells separated by the basement membrane from outer layer of theca interna cells; both are often luteinized (Figure 12.40B) • Granulosa cells • Small and round with scanty cytoplasm • Hyperchromatic nuclei with occasional grooves

Special Stains and Immunohistochemistry  •  Reticulin stain: highlights reticular network around theca interna cell layer in a follicular cyst 

Differential Diagnosis  • Serous cystadenoma versus follicular cyst • Presence of a theca interna layer points toward follicular cyst • May be diagnosed as a simple cyst if unclear • Corpus luteum versus corpus luteum cyst • Corpus luteum contains a cavity that is usually filled with blood (Figure 12.40C) • It displays luteinization effect of the cells •  Cyst is greater than 2 cm in diameter and has a smooth rather than a folded contour (Figure 12.40D) • Endometriosis versus hemorrhagic corpus luteum cyst

A

B

C

D

Figure 12.40  A, Follicular cyst. Cross section shows a thin-­walled unilocular cyst. B, Follicular cyst. The cyst wall is lined by an inner layer of granulosa cells and an outer layer of theca interna cells. C, Hemorrhagic corpus luteum. Multiple well-­demarcated cysts displaying a yellow rim and intraluminal blood. D, Corpus luteum. Low-­power view shows a classic convoluted cyst wall surrounded by hemorrhagic stroma. Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

672

Chapter 12  —  Female Reproductive System

• Peripheral theca interna cells are present, and organized blood clot is more typical of cysts •  Endometriosis must show endometrial glands, stroma, or hemosiderin pigment; the presence of two of the three is diagnostic PEARLS M •  ost regress spontaneously within 2 months • The large, solitary, luteinized follicular cyst of pregnancy and puerperium is usually an incidental finding during cesarean section or physical examination, with a median diameter of 25 cm; it consists of a lining of luteinized cells with hyperchromatic, pleomorphic nuclei

Selected References Dey P. Pathology of ovary: benign non neoplastic lesions. Color Atlas of Female Genital Tract Pathology. Springer. Singapore; 2019:277–290. Irving JA, Clement PB. Nonneoplastic lesions of the ovary. In: Kurman R, Ellenson LH, Ronnett BM, eds. Blaustein’s Pathology of the Female Genital Tract. 6th ed. New York: Springer; 2011:591–594. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:409–410.

Hyperreactio Luteinalis Clinical Features  • Associated with conditions in which high levels of human chorionic gonadotropin (HCG) are secreted, such as pregnancy and gestational trophoblastic disease (GTD) •  Associated with ovulation induction (ovarian hyperstimulation syndrome) • Usually asymptomatic, but may present as a palpable mass or abdominal pain related to hemorrhage, torsion, or rupture  Gross Pathology  • Large ovary with multiple bilateral, thin-­walled cysts filled with serous or bloody fluid resulting in massive ovarian enlargement 

A

Histopathology  • Numerous luteinized follicle cysts • Large cysts lined by enlarged, luteinized theca interna cells, and sometimes luteinized granulosa and stromal cells •  Ovarian stroma and the theca interna layer may be noticeably edematous  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Large, Solitary Luteinized Follicle Cyst of Pregnancy and Puerperium  •  Ovaries in hyperreactio luteinalis contain multiple cysts PEARLS • P  resent in approximately 10%–45% of women with GTD; the cysts regress after removal of the trophoblastic elements • Rarely coexists with a pregnancy luteoma

Selected References Irving JA, Clement PB. Nonneoplastic lesions of the ovary. In: Kurman R, Ellenson LH, Ronnett BM, eds. Blaustein’s Pathology of the Female Genital Tract. 6th ed. New York: Springer; 2011:594–596. Schenker JG. Clinical aspects of ovarian hyperstimulation syndrome. Eur J Obstet Gynecol Reprod Biol. 1999;5:13–20. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:424–426.

Polycystic Ovarian Syndrome See Figure 12.41A and B.

B

Figure 12.41  Polycystic ovary.  A, Cross section of both ovaries show cortical fibrosis and multiple cystic follicles. B, Expanded ovarian cortex exhibits focal nodular luteinization.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

Clinical Features  •  Characterized by numerous subcortical in particular follicular cysts, in both ovaries, anovulation, infertility, hirsutism, oligomenorrhea, and obesity • Also known as Stein-­Leventhal syndrome; affects 3.5% to 7% of females, usually in the third decade •  Most cases show an increased luteinizing hormone (LH): follicle-­stimulating hormone (FSH) ratio, whereas occasional cases show hyperprolactinemia  Gross Pathology  • Both ovaries are round and usually two to five times the normal size • Many small, superficial cysts visible under a smooth, thick, gray-­white outer cortex • Central homogeneous stroma lacking corpora lutea or albicantia  Histopathology  • Superficial cortex is thickened, hypocellular, and collagenous, frequently with thick-­walled blood vessels • Multiple follicular cysts lined by an inner nonluteinized granulosa and an outer hyperplastic luteinized theca interna (follicular hyperthecosis) • Corpora lutea are usually absent  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Pregnancy  • Luteinization of both granulosa and theca interna  Stromal Hyperthecosis  •  Polycystic ovaries show stromal hyperthecosis, but stromal hyperthecosis, as an entity, is idiopathic PEARLS P •  elvic ultrasound may help in diagnosis • Hyperandrogenemia, with increased conversion of androstenedione to estrone • Endometrium may show hyperplasia or adenocarcinoma in some cases • Virilism is rarely present • Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-­AN) syndrome may be associated and includes insulin resistance, acanthosis nigricans, and hyperandrogenism

673

Stromal Hyperplasia and Hyperthecosis

Clinical Features  • Patients with stromal hyperthecosis are usually in their sixth to ninth decades; occasional familial cases •  Stromal hyperthecosis in the premenopausal patient may present as virilization, obesity, hypertension, and glucose intolerance; less often it may resemble polycystic ovarian syndrome; some cases show endometrial hyperplasia or adenocarcinoma • Stromal hyperplasia typically presents in the sixth or seventh decade and may be associated with androgen hypersecretion, endometrial adenocarcinoma, obesity, hypertension, and decreased glucose tolerance  Gross Pathology  •  Bilateral involvement with or without ovarian enlargement • White or yellow tissue occupies a variable percentage of each ovary • Nodular hyperthecosis may appear as multiple yellow nodules  Histopathology  • Stromal hyperthecosis exhibits luteinization of stromal cells not attached to the follicles, arranged singly and in clusters; rarely as nodules, with a typical background of stromal hyperplasia (Figure 12.42) • Luteinized stromal cells are oval or round with eosinophilic or vacuolated cytoplasm and round, plump nuclei • Stromal hyperplasia displays minimal collagen production and a diffuse or vaguely nodular proliferation of small stromal cells; the nodules commonly coalesce • Stromal hyperplasia has no luteinized stromal cells  Special Stains and Immunohistochemistry  •  Oil red O stain: may highlight lipid in vacuolated luteinized cells in stromal hyperthecosis  Other Techniques for Diagnosis  • Noncontributory 

Selected References Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian syndrome (PCOS): long-­ term metabolic consequences. Metabolism. 2018;86:33–43. Anastasiou OE, Canbay A, Fuhrer D, Reger-­Tan S. Metabolic and androgen profile in underweight women with polycystic ovary syndrome. Arch Gynecol Obstet. 2017;296(2):363–371. Guzick D. Polycystic ovary syndrome: symptomatology, pathophysiology, and epidemiology. Am J Obstet Gynecol. 1998;179:S89–S93. Norman RJ, Dewailly D, Legro RS, et al. Polycystic ovary syndrome. Lancet. 2007;370:685–697.

Figure 12.42  Stromal hyperthecosis.  Foci of luteinized stromal cells are present within the ovarian stroma.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

674

Chapter 12  —  Female Reproductive System

Differential Diagnosis Luteinized Thecoma versus Stromal Hyperthecosis  • Most thecomas are unilateral and form a distinct nodule or tumor •  The pockets or collections of lutein cells in stromal hyperthecosis are surrounded by small hyperplastic stromal cells with minimal collagen production  Fibroma versus Stromal Hyperplasia  • Fibroma is composed of cells with larger nuclei and characteristic production of large amounts of collagen; typically measures greater than 3 cm in diameter  Low-­Grade Endometrial Stromal Sarcoma versus Stromal Hyperplasia  • Endometrial stromal sarcoma of the ovary, which is rare, shows significant ovarian enlargement, marked cellularity, mitotic activity, and regularly distributed arterioles

Fibromatosis  •  Proliferating spindle cells and collagen production enveloping occasional follicles • Clusters of lutein cells and foci of edema may be present 

PEARLS

PEARLS

• S  tromal hyperthecosis, with additional edema and fibrosis, may accompany the HAIR-­AN syndrome, which is characterized by HAIR-­AN

• C  ortical stromal hyperplasia and hyperthecosis are often associated

Selected References Dey P. Pathology of ovary: benign non neoplastic lesions. Color Atlas of Female Genital Tract Pathology. 2019:277–290. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:413–416.

Massive Edema and Fibromatosis Clinical Features  •  Enlargement of one or both ovaries with peak incidence in the second decade • Presents with abdominal pain •  Abnormal menstruation and androgenic manifestations may be present  Gross Pathology  • Usually unilateral, sometimes with torsion of the ovarian pedicle • Massive edema • Pearly white ovarian surface with seeping fluid • Cut section reveals watery or gelatinous tissue with numerous cystic follicles under the capsule • Averages 12 cm in diameter, often with hemorrhage • Fibromatosis • Smooth or lobulated ovarian surface, sometimes with cysts; averages approximately 11 cm in diameter  Histopathology Massive Edema  •  Pale, edematous, hypocellular stroma; spared outer cortex • Follicles widely separated with venous congestion and lymphatic dilation • Clusters of lutein cells and foci of fibromatosis may be present 

Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Edematous Fibroma versus Massive Edema  • Follicles and their derivatives are present in massive edema  Fibroma versus Fibromatosis  • Follicles and their derivatives are present in fibromatosis

Selected References Nielsen GP, Young RH. Fibromatosis of soft tissue type involving the female genital tract: a report of two cases. Int J Gynecol Pathol. 1997;16:383–386. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:416–420.

Pregnancy Luteoma Clinical Features  • Ovarian enlargement during pregnancy related to HCG stimulation •  Most patients are black and multiparous; peak incidence in third and fourth decades • May present with hirsutism or virilization; infants born to such mothers frequently show virilism  Gross Pathology  • Multiple in one-­half of cases, and bilateral in one-­third • Small to large nodules ranging from a few millimeters to 20 cm in diameter • Soft, well-­circumscribed, yellow-­brown, or gray on cut surface with areas of hemorrhage  Histopathology  •  Well-­ circumscribed nodules composed of solid proliferations of uniform polygonal cells with abundant eosinophilic, granular cytoplasm (Figure 12.43) • Nuclei are round and relatively large; may be hyperchromatic with moderate mitotic activity, in a sparse intercellular stroma divided by reticulin fibers into clusters  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

675

•  Endometriotic cysts frequently involve the ovaries, are often bilateral, and are usually less than 10 cm in diameter • Cyst lining is ragged and dark-­brown to yellow and contains thick chocolate-­ colored material (chocolate cyst) (Figure 12.44A) 

Figure 12.43  Pregnancy luteoma.  Solid proliferation of polygonal luteinized cells with abundant eosinophilic granular cytoplasm.

Differential Diagnosis Luteinized Thecoma  • Unilateral and unrelated to pregnancy in most cases •  Contains moderate to large amounts of lipid, as opposed to little or no lipid in pregnancy luteoma • Background of fibroma or typical thecoma with thin reticulin-­ positive fibers surrounding individual cells rather than clusters  Lipid-­Poor Steroid Cell Tumor  • Both may be virilizing • Rarely bilateral; if mitotic activity is brisk, more likely to show nuclear atypia PEARLS U •  sually an incidental finding • After delivery, the ovaries regress and return to normal size within a few weeks

Selected References Cronje HS, Niemand I, Bam RH, Woodruff JD. Review of the granulosa-­ theca cell tumors from the Emil Novak ovarian tumor registry. Am J Obstet Gynecol. 1999;180:323–327. Rodriguez M, Harrison TA, Nowacki MR, Saltzman AK. Luteoma of pregnancy presenting with massive ascites and markedly elevated CA 125. Obstet Gynecol. 1999;94:854. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:422–424.

Endometriosis Clinical Features  • Common in women of childbearing age • Defined as the presence of endometrial tissue outside the uterine corpus • Complications include rupture or hemorrhage • May occur in any organ system and mimic neoplasia  Gross Pathology  • Red, blue, or dark-­brown nodules or cysts with a raised or puckered appearance, often with fibrous adhesions on involved serosal surfaces • “Powder burns” refer to ecchymotic or brown areas

Histopathology  • Characterized by epithelium and stroma reminiscent of endometrium (Figure 12.44B) •  Hemosiderin-­ laden macrophages are also usually present • Appearance varies with hormonal fluctuations of the menstrual cycle • Menstruation may cause hemorrhage into the glands and stroma with a consequent inflammatory reaction consisting predominantly of histiocytes • Pseudoxanthoma cells are histiocytes that have transformed the red blood cells into glycolipid, hemofuscin, and hemosiderin pigment • Postmenopausal women show atrophic glands similar to the endometrium • Extensive fibrosis may be present  Special Stains and Immunohistochemistry  • CD10 highlights the endometrial stroma  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Endometrioid Cystadenoma  • Extremely rare and lined by stratified endometrial type epithelium • Does not contain endometrial-­like stroma or pseudo­ xanthoma cells  Hemorrhagic Corpus Luteum Cyst versus Endometriosis  • Presence of peripheral theca interna cells and organized blood clot are more typical of a corpus luteum cyst •  Endometriosis requires the presence of endometrial glands, stroma, or hemosiderin pigment (Figure 12.44C) PEARLS • H  yperplastic and atypically proliferating changes similar to those seen in the endometrium may be present (i.e., hyperplasia, metaplasia) • Approximately 0.5% of cases have a malignant neoplasm arising from the endometriotic lesion; associated with a hyperestrogenic state • Endometrioid and clear cell adenocarcinoma are the most frequent associations

Selected References Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007;14:241–260. Matias-­Guiu X, Stewart CJ. Endometriosis-­associated ovarian neoplasia. Pathology. 2018;50(2):190–204. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:430–434.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

676

Chapter 12  —  Female Reproductive System

BOX 12.1    Pathogenesis of Ovarian Cancer Type I Low grade with a precursor lesion in a stepwise fashion — Represented by cystadenomas and borderline tumors — Most often presents at stage 1; slow growing, indolent — Generally remains low grade but can progress to high grade — K-­ras/BRAF mutations in 65%, and TP53 mutation in 8% Includes — Low-­grade serous carcinoma — Mucinous, endometrioid, and clear cell carcinomas and transitional cell carcinoma (Brenner and non-­Brenner)  Type II High grade, arises de novo, and most often presents at a high stage Rapidly growing, aggressive Approximately 70% have p53 mutation, whereas K-­ras/BRAF mutation is rare (1%) 

A

Includes — High-­grade serous carcinoma — Malignant mixed müllerian tumor (carcinosarcoma)

SEROUS TUMORS Benign Serous Tumors See Figure 12.45A to C Clinical Features  • Common ovarian neoplasms with a peak incidence in the fifth decade • Makes up approximately 70% of all serous tumors • One of the two most common ovarian neoplasms seen in pregnancy 

B

Gross Pathology  • Bilateral in approximately 10% of cases • Cystadenomas: usually one (sometimes more) smooth, glistening, thin-­ walled cyst filled with clear, watery, serous (occasionally mucinous or hemorrhagic) fluid • Papillary cystadenomas: inner lining with small polypoid excrescences and an underlying cystic component • Surface papillomas: coarse papillary projections on the outer surface of the ovary without a cystic cavity •  Adenofibromas and cystadenofibromas are predominantly solid fibrous tumors with a variable number of fluid-­filled glands or cysts and firm papillary excrescences 

C Figure 12.44  Endometrioma.  A, Cystic ovary filled with blood and with a glistening external surface. B, Cyst lined by cuboidal epithelium associated with endometrial stroma and hemosiderin-­laden macrophages. Adjacent ovarian stroma can be seen. C, Endometriosis, presenting as an abdominal mass. Endometrial glands, stroma, and adjacent adipose tissue can be seen. Wells M. Recent advances in endometriosis with emphasis on pathogenesis, molecular pathology, and neoplastic transformation. Int Gynecol Pathol. 2004;23:316–320. 

SURFACE EPITHELIAL-­STROMAL TUMORS These are the most common tumors of the ovary. Box 12.1 shows the pathogenesis of ovarian cancer.

Histopathology  • In general, serous neoplasms mimic the epithelium of the fallopian tube • Cysts, papillae, and glands are lined mainly by a single layer of cuboidal to low-­columnar ciliated cells without significant nuclear atypia; they may also be lined by nonciliated cuboidal to columnar secretory cells •  Epithelium may be flattened by accumulated serous fluid in the lumen •  Stroma varies from dense and fibrous to distinctly edematous • Psammoma bodies may be rarely present •  Variants include cystadenoma and papillary cystadenoma, surface papilloma, and adenofibroma and cystadenofibroma

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

• Cystadenofibromas are characterized by broad fibrous papillary structures lined by epithelium, which is generally serous; other epithelia (i.e., mucinous, etc.) are less common  Special Stains and Immunohistochemistry  • Noncontributory  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Epithelial Inclusion Cyst versus Small Serous Cystadenoma  • Epithelial inclusion cyst is less than 1 cm in diameter  Follicle Cyst versus Serous Cystadenoma  • Both may have an atrophic lining, but the presence of a theca interna layer and inner granulosa cells points toward follicle cyst • May be diagnosed as simple cyst if the morphology of the lining is unclear  Struma Ovarii versus Serous Cystadenoma  • Struma ovarii always contains small colloid-­filled cysts • Histologically identical to thyroid tissue • Positive for thyroglobulin immunohistochemical stain  Rete Cystadenoma versus Serous Cystadenoma  • Rete cystadenomas are rare tumors arising in the rete ovarii (ovarian hilus) •  Lined by nonciliated epithelium, showing crevices along their inner surfaces • Smooth muscle and hilus cells commonly present in their walls PEARLS • Cystectomy or oophorectomy is curative

Selected Reference Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:51–79.

Atypical Proliferative Serous Tumor (Serous Borderline Tumor)

677

• No destructive stromal invasion • Cells generally have scant cytoplasm and bland nuclei but may have moderate to abundant eosinophilic cytoplasm with round hyperchromatic nuclei and obvious nucleoli • Psammoma bodies may be present •  Micropapillary pattern with no stromal invasion is considered a micropapillary variant of serous borderline tumor or noninvasive low-­grade serous carcinoma • Tumor is characterized by long, thin, nonhierarchical papillae without fibrovascular support arising from edematous large papillae without invasion of the stroma • Microinvasion is defined as small groups of cells showing similar morphology to the lining cells of borderline tumor, measuring less than 5 mm in greatest dimension. Microinvasion does not change the prognosis of borderline tumor • Noninvasive peritoneal implants: proliferating epithelium with complex glands with or without psammoma bodies resembling the ovarian tumor, which are not regarded as metastasis • Implants may also be identified in lymph nodes  Special Stains and Immunohistochemistry  • Weak or negative p53 essentially excludes high-­grade serous carcinoma • WT-­1 positive  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Endocervical-­Like Borderline Mucinous Tumor versus Mucin-­Secreting Borderline Serous Tumor  •  Borderline mucinous tumor cells are mucin filled, whereas serous tumors contain merely apical mucin  Retiform Sertoli-­Leydig Cell Tumor  • Peak incidence in first decade, sometimes presenting with androgenic manifestations •  Tubular and cystic structures lined by one or more layers of cells with round, regular nuclei and scanty cytoplasm

See Figure 12.45D.

PEARLS

Clinical Features  • Peak incidence between 30 and 60 years of age • Makes up 5% to 10% of all serous tumors 

• S urgical excision of tumors confined to the ovaries results in survival without recurrence in the majority (>95%) of patients • Postoperative recurrences can occur many years later

Gross Pathology  • Bilateral in 25% to 30% of cases • Gross is similar to that of benign tumors or with excrescences on the surface • Cysts lined by abundant, fine, somewhat firm papillary projections  Histopathology  • Complex, hierarchical branching papillae with small papillary projections on the surface lined by epithelium showing cellular buds and nuclear stratification

Selected References Burks RT, Kurman RJ, JDet al Seidman. Serous borderline tumours of the ovary. Histopathology. 2005;47:310–315. Gershenson DM, Silva EG, Tortolero-­Luna G, et al. Serous borderline tumors of the ovary with noninvasive peritoneal implants. Cancer. 1998;83:2157–2163. Hart WR. Borderline epithelial tumors of the ovary. Mod Pathol. 2005;18(suppl 2):S33–S50. Kurman RJ, Shih IM. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol. 2008;27:151–160.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

678

Chapter 12  —  Female Reproductive System

Seidman JD, Kurman RJ. Subclassification of serous borderline tumors of the ovary into benign and malignant types: a clinicopathologic study of 65 advanced stage cases. Am J Surg Pathol. 1996;20:1331–1345.  Yemelyanova A, Mao TL, Nakayama N, et al. Low-­grade serous carcinoma of the ovary displaying a macropapillary pattern of invasion. Am J Surg Pathol. 2008;32:1800–1806.

Low-­Grade Serous Carcinoma (Micropapillary, Cribriform, and Psammomatous) Clinical Features  • Mean age of patients is 45 for micropapillary; psammocarcinomas have a mean age of 54 • Asymptomatic pelvic mass in low stage • Abdominal pain, fullness, or distention are common in advanced stage • Well-­differentiated low-­grade tumor micropapillary is the most common pattern and cribriform is less frequent  Gross Pathology  • Bilaterality in 80% to 90%, and greater than 90% are advanced-­stage tumors • Tumors with an exophytic component are more often associated with advance-­stage cancer • Tumors are generally cystic with papillary, tan to yellow excrescences • Psammocarcinoma is most often of peritoneal origin  Histopathology  • Large, edematous bulbous papillae from which emanate smaller papillae with nonhierarchical branching of fine lacelike pattern with low-­grade nuclei infiltrating the ovarian stroma • Glands and tubules arranged in a cribriform fashion lined by mild to moderately atypical cuboidal cells •  Psammoma bodies are present in most well-­ differentiated papillary tumors • The tumor cells show low-­grade nuclei with only occasional mitotic figures •  Psammocarcinoma features numerous psammoma bodies with a scarce epithelial component • When invasive implants are present with serous borderline tumor, the tumor is better categorized as invasive low-­grade serous carcinoma 

High-­Grade Serous Carcinoma See Figures 12.45E to H. Clinical Features  •  Most common malignant ovarian neoplasm, with a peak incidence between 40 and 70 years of age and constituting approximately 20% to 25% of all serous tumors • Serum shows elevated level of CA-125 (cancer antigen 125) (not specific for serous tumors or malignancy) • The great majority originate in the fimbria of either fallopian tubes  Gross Pathology  • Bilateral in approximately 65% of cases

• Surface serous carcinomas include large hemorrhagic papillary excrescences on the surface of the ovary • Tumors may show solid areas of friable, necrotic, and hemorrhagic tissue with few recognizable papillae • Tumor adhesion to adjacent structures is common  Histopathology  • Cellular tumor with obvious invasion of the connective tissue stroma (desmoplasia) • May contain few papillae, which are generally thick, but the tumors are mostly composed of solid sheets of cells with pleomorphic nuclei • Hyperchromatic nuclei and atypical mitoses are characteristic of high-­grade tumors along with cellular budding and stratification •  Variants include cystadenocarcinoma, surface carcinoma, and carcinoma arising in adenofibroma • Considered fallopian tube primary when serous tubal intraepithelial carcinoma (STIC) is present in the fallopian tube  Special Stains and Immunohistochemistry  • Vimentin positive • CA 125 positive •  Low-­ grade serous carcinomas are negative for p53 mutation • P53 strongly positive or mutant null type in high-­grade serous carcinoma • Cytokeratin, WT-­1, and EMA positive  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Clear Cell Carcinoma  • Clear cell carcinoma displays plump hobnail cells with large nuclei, cells with clear cytoplasm, or oxyphilic cells •  Papillae are more regular and may have hyalinized cores  Endometrioid Carcinoma versus Poorly Differentiated Serous Carcinoma  •  Papillae and glands in endometrioid carcinoma are larger and more regular (villoglandular), without cellular budding •  Squamous differentiation is commonly associated with endometrioid carcinoma and rarely with serous carcinoma • Psammoma bodies are rare in endometrioid carcinomas  Adult Granulosa Cell Tumor versus Solid Serous Carcinoma  • Cell necrosis in serous carcinoma may be confused for Call-­Exner bodies • Serous carcinomas are positive for EMA and diffusely positive for keratin 8/18, whereas EMA is negative in adult granulosa cell tumor (AGCT), and keratin 8/18 shows focal positivity only • Inhibin is positive in AGCT and generally negative in serous carcinoma; likewise with calretinin 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

invasive low-­grade serous carcinoma: a study of 30 low-­grade serous tumors of the ovary in 18 patients with peritoneal carcinomatosis. Int J Gynecol Pathol. 2018. https://doi.org/10.1097/PGP.0000000000000566. Vang R, Hannibal CG, Junge J, et al. Long-­term behavior of serous borderline tumors subdivided into atypical proliferative tumors and non-­invasive low-­grade carcinomas: a population-­based clinicopathologic study of 942 cases. Am J Surg Pathol. 2017;41(6):725.

Retiform Sertoli-­Leydig Cell Tumor  • Rare tumor with a peak incidence in first decade, sometimes presenting with androgenic manifestations • Tubular and cystic structures; tubules lined by one or more layers of cells with round, regular nuclei and scanty cytoplasm; most retiform tumors are seen with other Sertoli-­Leydig cell tumor (SLCT) subtypes

MUCINOUS TUMORS

PEARLS

See Figure 12.46.

• M  ost high-­grade tumors show extensive intraperitoneal dissemination at diagnosis

Benign Mucinous Tumor Clinical Features  • Make up approximately 75% to 85% of all mucinous tumors • Peak incidence in fourth and fifth decades • Most common epithelial tumor in pregnancy • Signs and symptoms may be related to acute torsion 

Selected References Burks RT, Sherman ME, Kurman RJ. Micropapillary serous carcinoma of the ovary: a distinctive low-­grade carcinoma related to serous borderline tumors. Am J Surg Pathol. 1996;20:1319–1330. Kurman RJ, Shih IM. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol. 2008;27:151–160. Kurman RJ, Shih I-­M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34:433–443. Okoye E, Euscher ED, Malpica A. Ovarian low-­grade serous carcinoma. Am J Surg Pathol. 2016;40(5):627–635. Seidman JD, Savage J, Krishnan J, et al. Intratumoral heterogeneity accounts for apparent progression of noninvasive serous tumors to ­

A

C

679

Gross Pathology  • Bilateral in 2% to 4% of cases •  Large, mucin-­ filled, multiloculated tumor with a smooth inner lining • Stromal component of adenofibroma is firm and fibrous 

B

D

Figure 12.45  A, Benign serous tumor. The external surface of the cyst is smooth and glistening with a marked vascular pattern. B, Benign serous tumor. Papillary structures lined by a single layer of cuboidal epithelium. C, Serous cystadenofibroma. Papillary structures with a prominent stromal component. D, Serous borderline tumor. Complex branching papillae lined by stratified epithelial cells with formation of cellular buds. Continued Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

680

Chapter 12  —  Female Reproductive System

E

F

G

H

Figure 12.45—cont’d  E, Papillary serous carcinoma. Cut surface shows a solid tumor with focal cystic changes. F, Papillary serous carcinoma. Tumor is composed of crowded papillae lined by pleomorphic cells. G, High-­grade serous carcinoma. Poorly differentiated tumor cells are arranged in papillary architectures. H, Serous carcinoma of the ovary. WT-­1 stain is strongly positive, confirming the serous differentiation. Coexpression of p53 is also characteristic of high-­grade ovarian serous carcinoma.

Histopathology  • In general, mucinous tumors mimic endocervical and intestinal epithelium • Cysts, papillary structures, and cryptlike structures are lined by a single layer of columnar cells with clear, apical mucin and small basally located nuclei (picket fence–like) or intestinal-­ type epithelium with goblet cells (Figure 12.46B) • Fibrocollagenous walls and stroma • Mucinous tumors may have argyrophil and Paneth cells •  Variants include cystadenoma and adenofibroma or cystadenofibroma  Special Stains and Immunohistochemistry  • PAS highlights mucinous material • Cytokeratin 7 is generally positive  Other Techniques for Diagnosis  • Noncontributory 

Differential Diagnosis Serous Cystadenoma  • Mucinous cystadenomas may have a cuboidal epithelium similar to serous cystadenoma but with intracytoplasmic mucin and without ciliated cells  Heterologous Sertoli-­Leydig Cell Tumor  • Contains glands and cysts lined by mucinous epithelium that may be similar to the lining in benign mucinous tumors • Foci of SLCT of intermediate differentiation are characterized by cords of darkly staining Sertoli cells separated by a stroma containing Leydig cells with abundant eosinophilic cytoplasm • Areas of immature skeletal muscle, cartilage, or both may be seen  Mucinous Carcinoid Tumor versus Epithelial Mucinous Tumor  • Mucinous carcinoid tumors are mostly solid and only rarely predominantly cystic on gross examination

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

•  Argyrophil and argentaffin cells may be present in mucinous carcinoid tumors but are less abundant • Generally positive for chromogranin and synaptophysin immunostains PEARLS • M  ucinous tumors are associated with dermoid cysts in 3%–5% of cases, along with appendiceal mucoceles and pseudomyxoma peritonei • Mucinous cystadenomas are associated with benign transitional cell tumors (Brenner) • Pseudomyxoma peritonei: condition featuring extensive mucinous ascites, cystic and bland epithelial implants on the peritoneal surfaces, and adhesions most commonly in association with an appendiceal lesion (e.g., mucocele) or, less likely, mucinous ovarian tumor • Treatment consists of surgical excision of the tumor • Important to thoroughly sample tumor to exclude areas of borderline or malignancy

Selected References Hristov AC, Young RH, Vang R, et al. Ovarian metastases of appendiceal tumors with goblet cell carcinoidlike and signet ring cell patterns: a report of 30 cases. Am J Surg Pathol. 2007;31:1502–1511. Kurman RJ, Shih IM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186(4): 733–747. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:81–105. Seidman JD, Krishnan J. Ovarian epithelial inclusions with mucinous differentiation: a clinicopathologic study of 42 cases. Int J Gynecol Pathol. 2017;36(4). 372–326. Shiohara S, Shiozawa T, Shimizu M, et al. Histochemical analysis of estrogen and progesterone receptors and gastric-­type mucin in mucinous ovarian tumors with reference to their pathogenesis. Cancer. 1997;80:908–916. Yemelyanova AV, Vang R, Judson K, et al. Distinction of primary and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification. Am J Surg Pathol. 2008;32:128–138.

Atypical Proliferative Mucinous Tumor (Mucinous Borderline Tumor) Clinical Features  • Makes up approximately 10% to 15% of all mucinous tumors •  Peak incidence in third to fifth decades; intestinal-­ type tumors present later than endocervical-­ like tumors • Tumors consisting of mostly intestinal-­type cells are more common • Occasional cases show elevation in serum inhibin  Gross Pathology  • Bilateral in approximately 7% of intestinal-­type tumors and 40% of endocervical-­like tumors; both types are the largest ovarian epithelial tumors •  Bilaterality should prompt consideration of a metastatic carcinoma • Averages 15 to 20 cm in diameter • Similar to benign mucinous tumor in gross appearance, but the cyst lining shows bulging masses and papillary projections more often (Figure 12.46C)

681

•  Intestinal-­ type tumors are usually larger and more loculated  Histopathology  • Increased crowding of cysts, glands, and papillae, with areas of glandular budding, nuclear atypia, and stratification, but lacking destructive stromal invasion (Figure 12.46D) • Proliferative areas must comprise greater than 10% of the epithelial volume of the tumor to qualify as mucinous borderline tumor • Tumor cells are usually mucin filled and have irregular nuclei, large nucleoli, and increased mitotic activity • Most show mixed mucinous differentiation (intestinal and/or endocervical) • Tumors made up of predominantly endocervical-­like cells are less common and are often associated with infiltration by acute inflammatory cells •  Foreign body giant cells may be seen in association with mucin from ruptured cysts •  Microinvasion is defined as small foci of tumor cell nests in the stroma measuring less than 5 mm in greatest dimension  Special Stains and Immunohistochemistry  • CK7 and mucin positive  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Heterologous Sertoli-­Leydig Cell Tumor  • Contains glands and cysts lined by areas of mucinous epithelium, which may be similar to a borderline mucinous tumor • Foci of SLCT of intermediate differentiation also seen, with cords of darkly staining Sertoli cells separated by a stroma containing Leydig cells with abundant eosinophilic cytoplasm • Areas of immature skeletal muscle, cartilage, or both may be seen PEARLS • M  ore than 95% of mucinous carcinomas are of gastrointestinal origin, appendiceal in particular • Intestinal-­type tumors may be associated with pseudomyxoma peritonei but are less likely to have associated endometriosis than endocervical-­like tumors • Surgical excision of tumors confined to the ovaries may occasionally be associated with recurrence, spread, and rarely death • Important to thoroughly sample tumor to exclude areas of invasive malignant tumor

Selected References Bradley RF, Stewart JH, Russell GB, et al. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol. 2006;30:551–559. De Decker K, Speth S, ter Brugge HG, et al. Staging procedures in patients with mucinous borderline tumors of the ovary do not reveal peritoneal or omental disease. Gynecol Oncol. 2017;144(2): 285–289.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

A

C

E

B

D

F

G Figure 12.46  A, Mucinous cystadenoma. Cut surface shows a multiloculated cystic tumor. B, Mucinous cystadenoma. The cyst wall is lined by a single layer of tall columnar cells with basally arranged nuclei, reminiscent of cervical glandular epithelium. C, Borderline mucinous tumor. Cut surface shows a multiloculated tumor with focal solid areas. D, Borderline mucinous tumor. The neoplasm shows stratified mucinous epithelium, nuclear enlargement, and hyperchromasia. E, Malignant mucinous tumor. Cut surface shows a cystic tumor with a large solid component. F, Malignant mucinous tumor. High-­power view shows glandlike structures lined by stratified tall, columnar, and goblet cells. Stromal invasion is evident. G, Metastatic mucinous adenocarcinoma. Atypical glands with nuclear pleomorphism and associated mucin infiltrate the omentum. An ovarian primary is unlikely. Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System Hauptmann S, Friedrich K, Redline R, et al. Ovarian borderline tumors in the 2014 WHO classification: evolving concepts and diagnostic criteria. Virchows Archiv. 2017;470(2):125–142. Mackenzie R, Kommoss S, Winterhoff BJ, et al. Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-­ pathway activating mutations in borderline and cancerous neoplasms. BMC Cancer. 2015;15(1):415. Ronnett BM, Kurman RJ, Zahn CM, et al. Pseudomyxoma peritonei in women: a clinicopathologic study of 30 cases with emphasis on site of origin, prognosis and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol. 1995;56:509–524.

Mucinous Carcinoma (Malignant Mucinous Tumor) See Figure 12.46E to G. Clinical Features  • Makes up approximately less than 5% of all mucinous tumors • Peak incidence in fourth to seventh decades • Some patients show elevated levels of CEA, CA 19-­9, inhibin, and CA 125  Gross Pathology  • Bilateral in less than 20% of cases • Cystic spaces with papillae mixed with solid masses; sometimes the tumor is completely solid • Hemorrhage and necrosis have been reported  Histopathology  • Often a spectrum of architectural and cytologic atypia that can have benign, borderline, and malignant components • Cellular tumor containing crowded glands, cysts, papillae, or solid sheets of stratified mucinous cells, with stromal invasion by single or small groups of cells or glands, displaying a desmoplastic stromal response •  Cells with hyperchromatic nuclei, atypical mitoses with eosinophilic cytoplasm, and abundant mucin, sometimes with signet ring forms •  Large pools of extracellular mucin with associated histiocytes and less often a foreign body giant cell reaction • Variants include mucinous carcinoma arising in mucinous adenofibroma • Two types of invasive pattern: expansile and destructive stromal invasion  Special Stains and Immunohistochemistry  • Vimentin negative • Cytokeratin 7 and 20 positive • CEA: positive cytoplasmic staining  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Serous and Endometrioid Adenocarcinomas  •  May contain abundant luminal mucin but minimal intracytoplasmic mucin • WT-­1 positive in serous and negative in endometrioid and mucinous • CEA positive in mucinous and negative in serous and endometrioid 

683

Heterologous Sertoli-­Leydig Cell Tumor  • Contains glands and cysts lined by areas of mucinous epithelium, which may be similar to a malignant mucinous tumor •  Foci of SLCT of intermediate differentiation showing cords of darkly staining Sertoli cells separated by stroma containing Leydig cells with abundant eosinophilic cytoplasm • Areas of immature skeletal muscle, cartilage, or both may be seen  Krukenberg Tumor  • Metastatic mucin-­secreting adenocarcinoma with signet ring cells originating from an extragenital source • Breast and gastrointestinal tract are the most common primary sites • Contains goblet cells in the stroma and is usually bilateral PEARLS • T  reatment consists of surgery, sometimes with chemotherapy depending on the stage and grade of the tumor • Approximately 40% 5-­year survival rate, with recurrences often occurring in the lungs

Selected References Montiel DP, Angulo KA, Cantú-­de León D, et al. The value of SATB2 in the differential diagnosis of intestinal-­type mucinous tumors of the ovary: primary vs metastatic. Ann Diagn Pathol. 2015;19(4):249–252. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:81–105. Tabrizi AD, Kalloger SE, Kobel M. Primary ovarian mucinous carcinoma of intestinal type: significance of pattern of invasion and immunohistochemical expression profile in a series of 31 cases. Int J Gynecol Pathol. 2010;29:99–107. Taylor J, McCluggage WG. Ovarian seromucinous carcinoma. Am J Surg Pathol. 2015;39(7):983–992.

Endometrioid Tumors Clinical Features  • Most are malignant; benign and borderline variants are rare • Peak incidence in fifth decade; women with endometrioid carcinoma and endometriosis in the same ovary are 5 to 10 years younger on average • May be associated with ovarian or pelvic endometriosis and endometrial carcinoma; serum CA 125 is elevated in most cases  Gross Pathology  •  Most tumors are unilateral; approximately 30% of malignant tumors are bilateral • Similar in gross appearance to previously mentioned tumors but may contain obvious foci of endometriosis • Carcinomas measure up to 20 cm in diameter, are predominantly solid, but may contain papillae; some contain cysts filled with bloody or mucinous fluid  Histopathology  • In general, endometrioid tumors mimic the epithelium of the endometrium, containing cells with basophi­ lic cytoplasm, elongated nuclei, and obvious nucleoli (Figure 12.47)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

684

Chapter 12  —  Female Reproductive System

Malignant Mixed Müllerian Tumor versus Endometrioid Adenocarcinoma  •  Endometrioid adenocarcinoma may contain prominent foci of spindled epithelial cells, but they are less atypical than both the epithelial and spindle cell components of a malignant mixed müllerian tumor PEARLS • B  orderline tumors typically have a relatively benign course, if low stage • Endometrioid carcinomas are associated with the same risk factors as endometrial carcinomas • Endometrioid and clear cell carcinomas are the most common tumors arising adjacent to or within endometriosis

Selected References Figure 12.47  Endometrioid carcinoma of ovary.  Endometrial-­like glands and areas of squamous differentiation.

• Benign endometrioid tumor (rare) •  Usually have an adenofibromatous pattern with mature glands in a fibrous stroma Atypical Proliferative Endometrioid Tumor (Endometrioid Borderline Tumor)  •  Histology is similar to endometrial hyperplasia with atypia • No stromal invasion • Usually has an adenofibromatous pattern with fibrous stroma and squamous morulas  Malignant Endometrioid Tumor (Endometrioid Carcinoma)  • Characterized by stromal invasion and cribriforming of glands • Often displays squamous differentiation • Graded as other epithelial tumors  Special Stains and Immunohistochemistry  • Vimentin positive in endometrioid epithelium  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Poorly Differentiated Serous Carcinoma versus Endometrioid Carcinoma  •  Serous carcinoma contains irregular, slitlike glands, with smaller, complex papillae, cellular budding, and frequent psammoma bodies • Squamous differentiation points toward endometrioid carcinoma  Mucinous Carcinoma versus Endometrioid Carcinoma  •  Mucinous carcinoma contains abundant luminal mucin and goblet cells with mucin-­rich cytoplasm • Vimentin negative and CEA positive  Sertoli-­Leydig Cell Tumor versus Endometrioid Carcinoma  • SLCT has a well-­differentiated epithelium that is more abundant, has smaller tubules, and has only small amounts of intraluminal mucin • SLCT does not contain an adenofibromatous component or squamous differentiation 

Acs G, Pasha T, Zhang PJ. WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium. Int J Gynecol Pathol. 2004;23:110–118. Cho KR, Shih IM. Ovarian cancer. Annu Rev Pathol Mech Dis. 2009;4:287–313.  Meinhold-­Heerlein I, Fotopoulou C, Harter P, et al. The new WHO classification of ovarian, fallopian tube, and primary peritoneal cancer and its clinical implications. Arch Gynecol Obstet. 2016;293(4):695–700. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:107–128.

Clear Cell Tumors Clinical Features  • Most are malignant, with rare benign and borderline variants • Malignant tumors often occur in nulliparous women; peak incidence in fifth decade • Associated with endometriosis  Gross Pathology  • Most tumors are cystic with solid areas, but some are predominantly solid; often bilateral • Focal hemorrhage and necrosis may be present • Clear cell carcinomas average 15 cm in diameter, often have surface adhesions; typically consist of thick-­walled unilocular, sometimes multilocular, cysts with white or yellow-­tan solid papillary or nodular protrusions into the lumen  Histopathology Benign Clear Cell Tumor  • Usually have an adenofibromatous pattern with mature glands in a fibrous stroma  Atypical Proliferative Clear Cell Tumor (Clear Cell Borderline Tumor)  •  Usually an adenofibromatous pattern with atypical glands in a fibrous stroma  Clear Cell Carcinoma (Malignant Clear Cell Tumor)  • May show papillary, tubulocystic, solid, or mixed patterns with stromal invasion • Polyhedral, glycogen-­rich clear cells containing round or angular atypical nuclei with frequent abnormal mitoses

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 12  —  Female Reproductive System

685

PEARLS • C  lear cell and endometrioid carcinomas are associated with ovarian and pelvic endometriosis

Selected References

Figure 12.48  Clear cell carcinoma.  Low-­power view demonstrates a papillary pattern with hobnail-­shaped and pleomorphic clear cells.

• Clear cells line papillae (which usually have hyalinized cores), tubules, and cysts or may be arranged in nests • Nucleoli are generally not present, and hyaline globules are common • Hobnail cells have plump hyperchromatic nuclei and line papillae, tubules, and cysts (Figure 12.48) • Less often cells are cuboidal, flat, oxyphilic, or mucin-­ containing signet ring cells  Special Stains and Immunohistochemistry  • PAS highlights abundant glycogen in clear cells • Mucin negative • α-­Fetoprotein (AFP) rarely positive • Cytokeratin positive  Other Techniques for Diagnosis  • Noncontributory  Differential Diagnosis Dysgerminoma  • Peak incidence in second and third decades •  Dysgerminoma cell is large and round with smooth edges; it contains a central nucleus with one or more prominent nucleoli • Dysgerminoma has thin fibrous bands within an almost pure lymphocytic infiltrate  Yolk Sac Tumor  • Peak incidence in first and second decades • Yolk sac tumors (YSTs) and clear cell tumors may have a loose edematous pattern •  YST displays primitive nuclei and may demonstrate simple papillae arranged around a single central vessel (Schiller-­Duval bodies) typical of the endodermal sinus tumor (EST) • YST may show several other patterns or may be admixed with other forms of germ cell tumor (mixed germ cell tumor) • YSTs are AFP positive •  Clear cell carcinoma may be admixed with other types of carcinoma, often endometrioid, or with endometriosis

Cathro HP, Stoler MH. The utility of calretinin, inhibin, and WT1 immunohistochemical staining in the differential diagnosis of ovarian tumors. Hum Pathol. 2005;36:195–201. Chan JK, Teo D, Hu JM, et al. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol. 2008;109:370–376. Fadare O, Zhao C, Khabele D, et al. Comparative analysis of napsin A, alpha-­ methylacyl-­ coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours. Pathology. 2015;47(2):105–111. Scully RE, Young RH, Clement PB. Atlas of Tumor Pathology: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 3rd Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998:141–151. Shimizu M, Nikaido T, Toki T, et al. Clear cell carcinoma has an expression pattern of cell cycle regulatory molecules that is unique among ovarian adenocarcinomas. Cancer. 1999;85:669–677. Yamashita Y, Nagasaka T, Naiki-­Ito A, et al. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. Mod Pathol. 2015;28(1):111.

Transitional Cell Tumors (Brenner Tumors) See Figure 12.49A to C. Clinical Features  •  Most are benign transitional (Brenner) tumors; peak incidence in fifth decade •  Borderline tumors and transitional cell carcinomas usually occur in seventh decade • May be associated with estrogenic or, less often, androgenic manifestations  Gross Pathology  •  Most benign transitional cell tumors (Brenner) are small (75% of tumor) (Figure 13.24) • Pleomorphic cells with high nuclear grade and numerous mitoses • Must show a prominent lymphoplasmacytic response around tumor cells • No invasion into surrounding adipose tissue • Well-­defined margins with pushing borders • Glandular or ductal structures should not be seen 

DIFFERENTIAL DIAGNOSIS Infiltrating Ductal Carcinoma • Typically does not show extensive syncytial pattern • Less prominent lymphocytic infiltrate • Infiltrative borders PEARLS • R  elatively better prognosis than infiltrating ductal carcinoma • Patients have decreased likelihood of axillary lymph node metastases • Designation of atypical medullary carcinoma should be avoided because these lesions have been shown to behave similarly to infiltrating ductal carcinomas

Selected References Kostianets O, Antoniuk S, Filonenko V, et al. Immunohistochemical analysis of medullary breast carcinoma autoantigens in different histological types of breast carcinomas. Diagn Pathol. 2012;7:161. Kouhen F, Benhmidou N, Afif M, et al. Prognosis of medullary carcinoma of the breast: 10 years’ experience in a single institution. Breast J. 2017;23(1):112–114. Marginean F, Rakha EA, Ho BC, et al. Histological features of medullary carcinoma and prognosis in triple-­negative basal-­like carcinomas of the breast. Mod Pathol. 2010;23:1357–1363. Vincent-­Salomon A, Gruel N, Lucchesi C, et al. Identification of typical medullary breast carcinoma as a genomic sub-­group of basal-­like carcinomas, a heterogeneous new molecular entity. Breast Cancer Res. 2007;9:R24.

MUCINOUS (COLLOID) CARCINOMA CLINICAL FEATURES • Constitutes less than 2% of all breast carcinomas • Typically presents as a discrete mass • Older women are more commonly affected • Mammogram shows a well-­defined tumor 

GROSS PATHOLOGY • Well-­circumscribed, gelatinous mass 

HISTOPATHOLOGY • Clusters of infiltrating tumor cells surrounded by lakes of extracellular mucin (Figure 13.25) • Extracellular mucin must make up greater than 50% of the tumor

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

748

Chapter 13 — Breast

PEARLS • M  ucinous carcinoma is a variant of invasive ductal carcinoma • L ymph node metastases are found in fewer than 20% of patients • Mucinous carcinoma is associated with an excellent prognosis with increased survival compared with infiltrating ductal carcinoma

Selected References

Figure 13.25  Mucinous (colloid) carcinoma. Numerous clusters of neoplastic ductal cells surrounded by pools of extracellular mucin material.

Harrison BT, Dillon DA. An update of mucinous lesions of the breast. Surg Pathol Clin. 2018;11(1):61–90. Kryvenko ON, Chitale DA, Yoon J, et al. Precursor lesions of mucinous carcinoma of the breast: analysis of 130 cases. Am J Surg Pathol. 2013;37:1076–1084. Molavi D, Argani P. Distinguishing benign dissecting mucin (stromal mucin pools) from invasive mucinous carcinoma. Adv Anat Pathol. 2008;15:1–17. Tan PH, Tse GM, Bay BH. Mucinous breast lesions: diagnostic challenges. J Clin Pathol. 2008;61:11–19.

TUBULAR CARCINOMA • May have alveolar, cribriform, or papillary configuration or infiltrate as diffuse sheets of cells • Gland formation is not typically seen •  Classified as type A, which does not have neuroendocrine differentiation and is paucicellular, and type B, with neuroendocrine differentiation and increased cellularity • Intraductal carcinoma often involves peripheral ducts 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Cytokeratin 7 positive • Cytokeratin 20 typically negative • PAS highlights intracellular mucin • ER and PR: variable reactivity, usually positive • Her-­2 negative in most cases • Neuroendocrine markers positive in type B 

OTHER TECHNIQUES FOR DIAGNOSIS • Electron microscopy: demonstrates intracellular mucin (mucigen granules) • Flow cytometry: pure mucinous carcinomas are almost always diploid; mixed tumors with areas of invasive ductal carcinoma are more commonly aneuploid 

DIFFERENTIAL DIAGNOSIS Mucocele-­Like Tumor • Benign epithelial-­lined cysts containing mucin • No tumor cells floating in the extracellular mucin • Extracellular mucin dissecting through fibrous stroma 

Mixed Mucinous Carcinoma • Lesions with minimal mucin (90% in the reactive germinal centers and approximately 5% in the interfollicular areas • Plasma cells are polytypic with staining for kappa and lambda immunoglobulin light chains 

Other Techniques for Diagnosis • Flow cytometry shows evidence of polytypic B-cells and T-cells that express all the pan-­T-­cell antigens •  Immunoglobulin heavy chain gene (IgH) rearrangement analysis is typically negative • A subset of the patients with active autoimmune disease may have evidence of B-­ cell clonality by polymerase chain reaction (PCR), but this finding by itself does not indicate malignancy • Cytogenetic analysis shows a normal karyotype 

Differential Diagnosis Nonspecific Follicular Hyperplasia  • A patient without an established clinical diagnosis of autoimmune disease may show identical morphology and immunophenotype  Syphilis  • Usually presents with inguinal lymphadenopathy • Prominent perilymphadenitis with thickening of the capsule, marked plasmacytic infiltration, and vasculitis • Warthin-­Starry stain demonstrates evidence of spirochetes in endothelial cells, within blood vessels, and occasionally in germinal centers  Early Viral Infection  • HIV: frequent follicle lysis • Mononucleosis: expanded paracortex with numerous immunoblasts • Cytomegalovirus (CMV): monocytoid B-­cell hyperplasia and large intranuclear inclusions • Clinical history and serology confirm the diagnosis  Toxoplasma Lymphadenitis  •  Triad of follicular hyperplasia, monocytoid B-­ cell hyperplasia, and aggregates of epithelioid histiocytes in the lymphoid follicles • Clinical history and serology confirm the diagnosis  IgG4-­Related Lymphadenopathy  • Type II is characterized by follicular hyperplasia • Intrafollicular and paracortical plasmacytosis and scattered eosinophils • Immunohistochemical stains for IgG and IgG4 quantify the number of plasma cells • >100 IgG4-­positive plasma cells per high-­power field • IgG4/IgG ratio >40%  Follicular Lymphoma  • Usually in older patients with generalized lymphadeno­ pathy • Increased number of follicles, which appear monotonous in size and shape •  Neoplastic follicles present throughout the lymph node and may extend outside into the perinodal fat •  Lymph node capsule is thickened and frequently appears split due to the follicular proliferation • Mantle zone is attenuated or absent

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

• The cellular composition within the follicles is mono­ morphic • Tingible-­body macrophages are rare to absent • Lymphoid cells in the follicles coexpress Bcl-­2 • Proliferation rate within the follicles with Ki67 immunostain is 100 IgG4-­positive plasma cells per high power field in at least three high-­power fields • IgG4/IgG ratio >40% 

Other Techniques for Diagnosis •  Elevated serum level of IgG4 in approximately two-­ thirds of the patients • Imaging to rule out involvement of other organs 

Differential Diagnosis Castleman Disease  • Elevated IL-­6 and C-­reactive protein (normal levels in IgG4-­related disease) • No significant increase in IgG4-­positive plasma cells • May express HHV-­8 • May show light-­chain restriction in the plasma cells  Nonspecific Follicular Hyperplasia  • No significant increase in IgG4-­positive plasma cells • Diagnosis of exclusion  Progressive Transformation of Germinal Centers  • No significant increase in IgG4-­positive plasma cells  Inflammatory Pseudotumor  •  Spindle cell proliferation with a mixed infiltrate of small lymphocytes, immunoblasts, histiocytes, eosinophils, and many plasma cells

Figure 14.6  IgG4-­related lymphadenopathy.  A, Immunohistochemical stain for IgG4 highlights numerous positive plasma cells. B, Immunohistochemical stain for IgG from the same area.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

770

Chapter 14  —  Lymph Nodes

•  Infectious etiology can be proven in some of these cases (atypical mycobacteria, Treponema pallidum, EBV, and others) • Immunohistochemical staining to rule out increase in IgG4 plasma cells should be done in all cases of suspected inflammatory pseudotumor  Small B-­Cell Lymphoma with Plasmacytic Differentiation  • Immunohistochemical staining for kappa and lambda light chains shows light chain restriction in the plasma cells • Flow cytometry and PCR: evidence of a monoclonal B-­cell population •  Cytogenetics and FISH: evidence of cytogenetic abnormalities  Angioimmunoblastic T-­Cell Lymphoma  • Characteristic morphology with a polymorphous paracortical infiltrate composed of small to medium-­sized atypical lymphocytes with moderate pale cytoplasm admixed with numerous reactive small lymphocytes, immunoblasts, eosinophils, plasma cells, and histiocytes • Paracortical vascular proliferation •  T-cells have a follicular T-­ helper immunophenotype CD10+, BCL6+, PD-­1+, and CXCL13+ •  CD21 and CD23 highlight expanded follicular dendritic cell meshworks • No significant increase in IgG4-­positive plasma cells

Grimm KE, Barry TS, Chizhevsky V, et al. Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells. Mod Pathol. 2012;25:480–491. Rollins-­Raval MA, Felgar RE, Krasinskas AM, et al. Increased numbers of IgG4-­positive plasma cells may rarely be seen in lymph nodes of patients without IgG4-­related sclerosing disease. Int J Surg Pathol. 2012;20:47–53. Sato Y, Inoue D, Asano N, et al. Association between IgG4-­ related disease and progressively transformed germinal centers of lymph nodes. Mod Pathol. 2012;25:956–967. Stone JH, Zen Y, Deshpande V. IgG4-­related disease. N Engl J Med. 2012;366:539–551.

PROGRESSIVE TRANSFORMATION OF GERMINAL CENTERS Clinical Features • Typically an incidental finding of an isolated enlarged lymph node • Most common in children and young adults • Male predominance 

Histopathology • One to several well-­defined nodules (transformed germinal centers) with expanded mantle zone (Figure 14.7) • Residual germinal centers are fragmented or not evident •  No evidence of large atypical lymphoid cells in the nodules • Background of typical follicular hyperplasia 

Special Stains and Immunohistochemistry

PEARLS • T  here is growing evidence that the disease is CD4 positive cytotoxic and T-­follicular helper cell driven autoimmune process, and that the IgG4 antibodies are not pathogenic • The diagnosis cannot be rendered based on the increased number of IgG4-­positive plasma cells alone, because a large number of other entities can have such cells (carcinoma, lymphoma, etc.) • Capsular and septal-­based fibrosis with inflammatory pseudotumor-­like pattern is the most specific morphologic pattern for IgG4-­related disease • If the patient is not known to have systemic IgG4-­related disease, the suggested diagnosis is “reactive lymphoid hyperplasia with increased IgG4+ cells” • Clinician should be encouraged to rule out IgG4-­related disease clinically • IgG4-­related disease is clinically important because the patients have an excellent response to steroids • IgG4-­related lymphadenopathy differs from IgG4-­related involvement of other sites in that sclerosis is exceptionally rare

• Nodules are composed of CD20+, Pax-­5+ B lymphocytes with features of mantle cells (Bcl-­2+, IgD+) • No evidence of large atypical B lymphocytes inside or outside the nodules •  Increased number of CD57+ cells in the germinal centers 

Other Techniques for Diagnosis •  Flow cytometry may demonstrate a population of CD4+/CD8+ T lymphocytes • Cytogenetics and PCR: no evidence of B-­cell clonality 

Selected References Bledsoe JR, Della-­Torre E, Rovati L, et al. IgG4-­related disease: review of the histopathologic features, differential diagnosis, and therapeutic approach. APMIS. 2018;126(6):459–476. Cheuk W, Chan JK. Lymphadenopathy of IgG4-­ related disease: an underdiagnosed and overdiagnosed entity. Semin Diagn Pathol. 2012;29:226–234. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-­related disease. Mod Pathol. 2012;25:1181–1192.

Figure 14.7  Progressive transformation of germinal centers. A large well-­defined nodule with expanded mantle zone and a fragmented germinal center.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

Differential Diagnosis Nodular Lymphocyte-­Predominant Hodgkin Lymphoma  •  Generally the entire lymph node is involved by lymphoma • Characterized by presence of scattered large atypical lymphoid cells with a folded or multilobated nucleus and scant cytoplasm (“popcorn” cell or lymphocyte predominant (LP) cell) •  LP cells are ringed by CD3+, CD57+, PD-­ 1+ T lymphocytes • Rarely, may coexist with or have a history of PTGC  Follicular Lymphoma  •  Generally the entire lymph node is involved by lymphoma • The B-cells coexpress Bcl-­6, CD10, and Bcl-­2 • Flow cytometry: B lymphocytes show light chain restriction • Conventional karyotype and FISH: t(14;18); BCL2/IGH gene rearrangement  Mantle Cell Lymphoma  •  Generally the entire lymph node is involved by lymphoma • B lymphocytes coexpress CD5 and Cyclin D1 • Flow cytometry: B lymphocytes show light chain restriction •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement  IgG4-­Related Lymphadenopathy  • Increased number of plasma cells in the interfollicular area • >100 IgG4-­positive plasma cells per high power field • IgG4/IgG ratio >40% PEARLS • T  he differential diagnosis with nodular lymphocyte-­ predominant Hodgkin lymphoma (NLPHL) can be challenging and requires careful examination of morphology • Rarely, PTGC can precede, coexist with, or follow the diagnosis of NLPHL

Selected References Chang CC, Osipov V, Wheaton S, et al. Follicular hyperplasia, follicular lysis, and progressive transformation of germinal centers: a sequential spectrum of morphologic evolution in lymphoid hyperplasia. Am J Clin Pathol. 2003;120:322–326. Hicks J, Flaitz C. Progressive transformation of germinal centers: review of histopathologic and clinical features. Int J Pediatr Otorhinolaryngol. 2002;265:195–202. Nguyen PL, Ferry JA, Harris NL. Progressive transformation of germinal centers and nodular lymphocyte predominance Hodgkin’s disease: a comparative immunohistochemical study. Am J Surg Pathol. 1999;23:27–33. Rahemtullah A, Harris NL, Dorn ME, et al. Beyond the lymphocyte predominant cell: CD4 + CD8 + T cells in nodular lymphocyte predominant Hodgkin lymphoma. Leuk Lymphoma. 2008;49:1870–1878. Shaikh F, Ngan BY, Alexander S, et al. Progressive transformation of germinal centers in children and adolescents: an intriguing cause of lymphadenopathy. Pediatr Blood Cancer. 2013;60:26–30.

771

• Patients typically present with fever, pharyngitis, and cervical lymphadenopathy • Caused by EBV 

Histopathology • Lymph node architecture is distorted • Expanded paracortex with a polymorphous proliferation of small, medium-­sized, and numerous large lymphoid cells (immunoblasts) (Figure 14.8) • Immunoblasts may be morphologically atypical, sometimes resemble Reed-­Sternberg cells, and may form large aggregates • Increased mitotic activity • Necrosis may be present 

Special Stains and Immunohistochemistry •  Most immunoblasts are CD20+, Mum-­ 1+, CD10− B-cells •  Some immunoblasts express CD30, but are always CD15 negative • The majority of the small and medium-­sized lymphocytes are T-cells •  In situ hybridization for Epstein-Barr virus (EBV)encoded RNA (EBER) highlights numerous positive small and large lymphocytes 

Other Techniques for Diagnosis • Monospot (heterophile antibody) • Serology • EBV viral load 

Differential Diagnosis Diffuse Large B-­Cell Lymphoma  • Occurs in older individuals • The neoplastic B-­cell population is more homogeneous with sheets of large transformed lymphocytes • EBV-­encoded RNA (EBER) may be positive, but only in the large neoplastic cells  Peripheral T-­Cell Lymphoma  • There is evidence of T-­cell antigen loss or aberrant antigen expression • EBER may be positive, but in a much smaller number of cells and only in the large immunoblasts 

REACTIVE PARACORTICAL HYPERPLASIA INFECTIOUS MONONUCLEOSIS Clinical Features • Most patients are adolescents and young adults

Figure 14.8  Infectious mononucleosis.  Expanded paracortex with numerous large immunoblasts.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

772

Chapter 14  —  Lymph Nodes

Classical Hodgkin Lymphoma  • Even though immunoblasts in IM may appear atypical, most do not resemble Reed-­Sternberg cells • Reed-­Sternberg cells express CD30 and CD15 • EBER may be positive, but in a smaller number of cells and only in the large neoplastic cells  CMV Lymphadenitis  • Immunohistochemistry for CMV is positive • EBER is negative  HIV-­Associated Lymphadenopathy (Early Phase)  • Florid follicular hyperplasia without significant paracortical expansion • EBER may be positive, but only in rare scattered cells Figure 14.9  Herpes simplex virus lymphadenitis. Necrosis and cells with large viral inclusions. (Courtesy Dr. Dennis O’Malley, Clarient, Inc., Aliso Viejo, CA.)

PEARLS • L ymph node biopsy is not indicated in IM; thus, the diagnosis is not suspected clinically in the majority of the patients • The combination of immunoblastic proliferation and necrosis frequently raises the possibility of lymphoma • The possibility of IM has to be ruled out in every young patient with suspicion for aggressive high-­grade lymphoma or classical Hodgkin lymphoma (CHL) • IM is a frequent cause of misdiagnosis and second opinion send-­out

Selected References Kojima M, Nakamura S, Itoh H, et al. Acute viral lymphadenitis mimicking low-­grade peripheral T-­cell lymphoma: a clinicopathological study of nine cases. APMIS. 2001;109:419–427. Louissaint Jr A, Ferry JA, Soupir CP, et al. Infectious mononucleosis mimicking lymphoma: distinguishing morphological and immunophenotypic features. Mod Pathol. 2012;2:1149–1159. Pittaluga S. Viral-­ associated lymphoid proliferations. Semin Diagn Pathol. 2013;30:130–136.

HERPES SIMPLEX LYMPHADENITIS Clinical Features • Lymphadenopathy can be localized or generalized and is rarely biopsied •  Biopsy is usually performed on the inguinal lymph nodes, when there is a concurrent anogenital infection • Lymphadenopathy is usually painful • Many patients are immunosuppressed due to an associated malignancy or immunodeficiency 

Histopathology • Lymph node architecture is distorted but preserved •  Prominent paracortical hyperplasia with many immunoblasts • Multifocal necrosis with neutrophils, debris, and cells with viral inclusions (Figure 14.9) •  Cells with inclusions contain ground-­ glass nuclei or intranuclear eosinophilic inclusions with halos, chromatin margination, and multinucleation • Rare cases may present with nonspecific viral-­type morphologic pattern: florid follicular hyperplasia, monocytoid B-­cell hyperplasia, and paracortical hyperplasia without extensive necrosis 

Special Stains and Immunohistochemistry • Herpes simplex virus (HSV) immunostain is positive 

Other Techniques for Diagnosis • Viral culture • Serology 

Differential Diagnosis Histiocytic Necrotizing Lymphadenitis (Kikuchi Disease)  •  Numerous CD123+ plasmacytoid dendritic cells are present • There is extensive necrosis with admixed karyorrhectic debris but no neutrophils • Viral inclusions are absent  Cat Scratch Disease  •  Early lesions contain prominent monocytoid B-­ cell hyperplasia and neutrophils, but little necrosis • Late lesions show granulomas • Viral inclusions are absent • Warthin-­Starry stain shows numerous microorganisms  Diffuse Large B-­Cell Lymphoma  • The nodal architecture is effaced with sheets of large transformed lymphoid cells • Viral inclusions are absent PEARLS • N  ecrosis is not associated with granuloma formation, arguing against most other necrotizing infections • Rare cases of concomitant HSV and EBV infection in the same lymph node have been described in immunosuppressed patients • Rarely, initial diagnosis of genital HSV infection may be established by inguinal lymph node biopsy

Selected References Fleming SA, Strickler JG. Unusual initial presentation of herpes simplex virus as inguinal lymphadenopathy. Case Rep Pathol. 2015;2015:573230.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes Gattenlohner S, Etschmann B, Lippert BM, et al. Concomitant herpes simplex and Epstein-­Barr virus lymphadenitis with simultaneous lymph node metastases of an occult squamous cell carcinoma in a patient with chronic lymphocytic leukemia. Leuk Lymphoma. 2008;49:2390–2392. Higgins J, Warnke R. Herpes lymphadenitis in association with chronic lymphocytic leukemia. Cancer. 1999;86:1210–1215. Joseph L, Scott MA, Schichman SA, et al. Localized herpes simplex lymphadenitis mimicking large cell (Richter) transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2001;68:287–291. Witt M, Torno M, Sun M, et al. Herpes simplex virus lymphadenitis: case report and review of the literature. Clin Infect Dis. 2002;34:1–6.

DERMATOPATHIC LYMPHADENITIS Clinical Features • Found in patients with benign and malignant chronic skin conditions • Lymphadenitis occurs in the lymph nodes that drain the affected area • Axillary and inguinal lymph nodes are most commonly affected 

Histopathology • The lymph node architecture is preserved • Marked diffuse or nodular expansion of the paracortex • Proliferation of interdigitating dendritic cells, Langerhans cells, and histiocytes that contain melanin pigment (Figure 14.10) 

Special Stains and Immunohistochemistry • The lymphocytes are predominantly CD4+ T-cells • Langerhans cells express S-­100 and CD1a • Interdigitating cells express S-­100 and are negative for CD1a • Histiocytes are highlighted by CD68 and CD163 

Other Techniques for Diagnosis •  T-­ cell receptor gamma gene (TCR) rearrangement shows polyclonal T lymphocytes 

773

Differential Diagnosis Mycosis Fungoides  • Nodal architecture may be preserved or effaced depending on the degree of involvement • Atypical lymphocytes are present singly, in small clusters, or in large aggregates • Typical immunophenotype of neoplastic lymphocytes is CD3+, CD2+, CD5+, and CD4+, and negative for CD8 and CD7 • PCR: monoclonal TCR gene rearrangement • Conventional cytogenetics: many cases have a complex karyotype  Adult T-­Cell Leukemia/Lymphoma  • Lymphadenopathy is one of the most frequent manifestations of adult T-­cell leukemia/lymphoma (ATLL) • Diffuse architectural effacement with proliferation of medium-­sized or large pleomorphic cells is usually seen •  Atypical lymphoid cells have an abnormal T-cell phenotype • PCR: monoclonal TCR gene rearrangement  Langerhans Cell Histiocytosis  •  Numerous Langerhans cells, present singly or in aggregates •  Neoplastic proliferation occurs in the sinuses and is accompanied by eosinophils, neutrophils, plasma cells, and histiocytes  Nonspecific Paracortical Hyperplasia  • Dendritic cells and Langerhans cells are less numerous • No evidence of melanin-­containing macrophages PEARLS • E nlarged lymph nodes from patients with cutaneous T-­cell lymphoma, such as mycosis fungoides or ATLL frequently show dermatopathic changes • Cutaneous T-­cell lymphoma in lymph node can be subtle morphologically; thus, PCR for TCR gene rearrangement should be ordered in difficult cases • Melanin pigment particles are darker, smaller, and nonrefringent as opposed to hemosiderin

Selected References Chinen S, Miyagi T, Murakami Y, et al. Dermatopathic reaction of lymph nodes in HTLV-­1 carriers: a spectrum of reactive and neoplastic lesions. Histopathology. 2020;77:133–143. Garces S, Yin CC, Miranda RN, et al. Clinical, histopathologic, and immunoarchitectural features of dermatopathic lymphadenopathy: an update. Mod Pathol. 2020;33:1104–1121.

DRUG-­RELATED LYMPHADENOPATHY Clinical Features

Figure 14.10  Dermatopathic lymphadenitis. Nodular paracortical hyperplasia with numerous admixed dendritic cells and pigment-­ laden macrophages.

• Lymphadenopathy usually occurs 2 to 8 weeks after exposure to the drug • May be part of drug reaction with eosinophilia and systemic symptoms (DRESS) •  Most often associated with antiepileptic agents (carbamazepine, lamotrigine, phenytoin, phenobarbital), vancomycin and allopurinol

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

774

Chapter 14  —  Lymph Nodes

•  HHV-­ 6 reactivation is thought to contribute to the underlying pathogenesis and clinical manifestations of DRESS lymphadenitis • Cervical lymph nodes are usually involved, but lymphadenopathy may be systemic 

Histopathology • Paracortical hyperplasia with increased immunoblasts and eosinophilia (Figure 14.11) • Immunoblasts may form large aggregates 

Special Stains and Immunohistochemistry • Immunoblasts express CD30 and are negative for CD15 • HHV-­6 specific immunohistochemistry and in situ hybridization may highlight the large atypical T lymphocytes 

Other Techniques for Diagnosis

• C  ases with a prominent immunoblastic reaction have been called pseudolymphoma in the older literature • The relationship between drug-­related lymphadenopathy and HHV6-­associated lymphadenitis is for now unclear

Selected References Balakrishna JP, Bhavsar T, Nicolae A, et al. Human Herpes Virus 6 (HHV-­6)-­associated lymphadenitis: pitfalls in diagnosis in benign and malignant settings. Am J Surg Pathol. 2018;42(10):1402–1408. Brown JR, Skarin AT. Clinical mimics of lymphoma. Oncol. 2004;9:406– 416. Johnson S, Mathews S, Hudnall SD. Human herpesvirus 6 lymphadenitis in drug rash with eosinophilia and systemic symptoms syndrome: a lymphoma mimic. Histopathology. 2017;70(7):1166–1170. Mansur AT, Yaşar SP, Göktay F. Anticonvulsant hypersensitivity syndrome: clinical and laboratory features. Int J Dermatol. 2008;47:1184– 1189.

• Clinical history of exposure to high-­risk medication 

SINUS HISTIOCYTOSIS

Differential Diagnosis

ROSAI-­DORFMAN DISEASE

Diffuse Large B-­Cell Lymphoma  • The lymph node architecture is typically effaced • Tumor cells rarely express CD30 • Flow cytometry, cytogenetic analysis, and PCR show evidence of B-­cell clonality • Not related to recent exposure to a new medication 

Clinical Features

Human Herpesvirus 6–Associated Lymphadenitis  • If no history of drug exposure can be documented • Present with complete or partial effacement of architecture with marked paracortical hyperplasia • The large atypical lymphoid cells are T-cells with vesicular chromatin, and prominent eosinophilic intranuclear viral inclusions  Nonspecific Paracortical Hyperplasia  • If no history of drug exposure can be documented • Is a diagnosis of exclusion PEARLS • C  omplete and accurate clinical history is necessary to make the diagnosis

•  Also known as sinus histiocytosis with massive lymphadenopathy • Rare, usually self-­limited histiocytic disorder • Most common in children and young adults • Believed to be a reactive, polyclonal process • About 90% of patients present with bilateral cervical lymphadenopathy • Axillary, inguinal, and mediastinal lymph nodes also frequently involved • Patients also may have fever, weight loss, leukocytosis, anemia, elevated erythrocyte sedimentation rate (ESR) 

Histopathology • Lymph node architecture is preserved • The capsule is thickened • There is marked dilation of the sinuses and numerous intrasinusoidal histiocytes (Figure 14.12A) • Very large cells with abundant eosinophilic cytoplasm and round nuclei with a single central nucleolus • A variable number of the histiocytes contain well-­ preserved lymphocytes and, occasionally, plasma cells, neutrophils, and erythrocytes in their cytoplasm (emperipolesis) (see Figure 14.12B) •  The remaining intrasinusoidal infiltrate consists of small lymphocytes and abundant plasma cells 

Special Stains and Immunohistochemistry •  The histiocytes strongly express S-­ 100 protein and other macrophage-­ associated antigens (CD14, CD68, CD163) (see Figure 14.12C) • Lesional histiocytes frequently have strong and diffuse nuclear Cyclin D1 expression • The histiocytes are negative for CD1a and langerin • Some cases have an increased number of IgG4-­positive plasma cells 

Other Techniques for Diagnosis Figure 14.11  Drug-­related lymphadenopathy.  Paracortical hyperplasia with numerous immunoblasts.

• Sequencing studies demonstrate presence of recurrent KRAS, NF1, and MAP2K1 mutations in select cases • BRAF-­V600E mutation appears to be exceptionally rare or absent 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

A

775

B

Figure 14.12  Rosai-­Dorfman disease.  A, Dilated sinuses and numerous large histiocytes. B, Emperipolesis. C, S-­ 100 protein immunostain highlights the abnormal histiocytes.

C

Differential Diagnosis Nonspecific Sinus Histiocytosis  •  Lacks distinctive large histiocytes with round nuclei and prominent nucleoli • No evidence of emperipolesis • Histiocytes do not express S-­100  Lymph Nodes Draining Prosthetic Implants  • Histiocytes contain coarse refractile material • Lack distinctive large histiocytes with round nuclei and prominent nucleoli • No evidence of emperipolesis • Histiocytes do not express S-­100  Langerhans Cell Histiocytosis  • Langerhans cells are smaller and have irregular nuclei with grooves (coffee-­bean shape) • Langerhans cells express CD1a and langerin in addition to S-­100 protein •  Sequencing demonstrates presence of BRAF-­V600E mutation or MAP2K1 mutations in over 80% of cases  Metastatic Melanoma  • Large atypical cells with prominent macronucleoli and intracytoplasmic melanin pigment • Express S-­100, Melan-­A, HMB-­45, microphthalmia-­ associated transcription factor (MITF)  Metastatic Carcinoma  • Cohesive clusters of malignant epithelial cells • Express cytokeratins and epithelial membrane antigen (EMA) •  Adenocarcinoma cells may rarely be positive for S-­100

PEARLS • T  he abnormal histiocytic cells are distinctive and are diagnostic of the entity • Extranodal disease, specifically subcutaneous lesions, is more common than lymphadenopathy; the histologic features may be more subtle in these cases • Nodal and extranodal disease may also represent distinct disorders, as nodal disease is more frequently self-­limiting • Recent studies shed light on the pathogenesis of Rosai-Dorfman disease, demonstrating that at least a subset are neoplastic in nature, driven by recurrent mutations in MAPK-­related genes

Selected References Baraban E, Sadigh S, Rosenbaum J, et al. Cyclin D1 expression and novel mutational findings in Rosai-­Dorfman disease. Br J Haematol. 2019;186(6):837–844. Garces S, Medeiros LJ, Patel KP, et al. Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai‐Dorfman disease. Mod Pathol. 2017;30:1367–1377. Zhang X, Hyjek E, Vardiman J. A subset of Rosai-­Dorfman disease exhibits features of IgG4-­related disease. Am J Clin Pathol. 2013;139:622–632.

WHIPPLE DISEASE Clinical Features • Caused by Tropheryma whipplei, a gram-­positive bacillus related to Actinomycetes • Predilection for middle-­aged white males of European ancestry • Typically presents with migratory arthralgias, followed by diarrhea, weight loss, and abdominal pain • Uniform regional and frequent peripheral lymph node involvement 

Histopathology • Dilation of the sinuses (Figure 14.13A)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

776

Chapter 14  —  Lymph Nodes

Figure 14.13  Whipple disease.  A, The sinuses are distended with numerous histiocytes. B, Periodic acid–­Schiff special stain is positive in the histiocytes. (Courtesy Dr. Dennis O’Malley, Clarient, Inc., Aliso Viejo, CA.)

A

• Lipogranulomas • Abundant histiocytes with granular periodic acid–Schiff (PAS)–positive cytoplasm (see Figure 14.13B) • PAS may be negative in rare lymph nodes with low disease burden • Non-­necrotizing granulomas can be seen, especially in early or extraintestinal disease 

Special Stains and Immunohistochemistry • An immunostain for T. whipplei is available 

Other Techniques for Diagnosis • Electron microscopy • PCR on tissue or fluid (saliva, stool) • Small intestinal biopsy is the gold standard for diagnosis 

Differential Diagnosis Nonspecific Sinus Histiocytosis  • Sinus histiocytes should not stain with PAS  Atypical Mycobacterial Infection  •  The organisms are acid-­ fast bacilli (AFB) positive, whereas T. whipplei is AFB negative  Sarcoidosis  • PAS staining and electron microscopy are useful in this differential •  In early or atypical cases, the findings may be indistinguishable  Lymphadenopathy Due to Deposition of Exogenous Material  • Lymphangiography dye, silicone implants, prosthetic material • Extracellular spaces lined by histiocytes • Histiocytes contain small vacuoles, may be retractile or birefringent •  Lymph nodes draining prosthesis may contain PAS-­ positive granular material • Clinical information is important in this differential diagnosis  Lymphadenopathy Due to Deposition of Endogenous Lipid Material  • Typically in porta hepatis and celiac lymph nodes • Can be due to mineral oil, parenteral nutrition, cholesterol crystals, fat embolism, fat necrosis • Vacuolated sinus histiocytes, extracellular empty spaces, and giant cells

B • Histiocytes are PAS negative PEARLS • T  . whipplei is frequently identified in young children with gastroenteritis • T. whipplei DNA has also been detected in stool and saliva specimens from asymptomatic individuals • CNS involvement with varied symptoms is common in Whipple disease • Whipple disease can be fatal if not treated with antibiotics • It is important to consider Whipple disease in patients with characteristic clinical presentation and sarcoidosis-­ like histopathologic features • Small bowel biopsy should be recommended to confirm the distinction

Selected References Alkan S, Beals TF, Schnitzer B. Primary diagnosis of Whipple disease manifesting as lymphadenopathy: use of polymerase chain reaction for detection of Tropheryma whippelii. Am J Clin Pathol. 2001;116:898–904. Baisden BL, Lepidi H, Raoult D, et al. Diagnosis of Whipple disease by immunohistochemical analysis: a sensitive and specific method for the detection of Tropheryma whipplei (the Whipple bacillus) in paraffin-­embedded tissue. Am J Clin Pathol. 2002;118:742–748. Edouard S, Fenollar F, Raoult D. The rise of Tropheryma whipplei: a 12-­ year retrospective study of PCR diagnoses in our reference center. J Clin Microbiol. 2012;50:3917–3920. Finzi G, Franzi F, Sessa F, et al. Ultrastructural evidence of Tropheryma whipplei in PAS-­ negative granulomatous lymph nodes. Ultrastruct Pathol. 2007;3:169–172. Lagier JC, Lepidi H, Raoult D, et al. Systemic Tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine (Baltimore). 2010;89:337–345.

NECROTIZING LYMPHADENITIS KIKUCHI DISEASE Clinical Features • Rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy and fever •  Typically occurs in young adults with female predominance • More common in Asians • Patients may also have fatigue, joint pain, rash, leukopenia, and anemia • Disease is self-­limited in the majority of patients 

Histopathology See Figure 14.14A and B.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

A

777

B

Figure 14.14  Kikuchi disease.  A, Prominent paracortical hyperplasia with a large area of necrosis. B, Immunoblasts, histiocytes, and plasmacytoid dendritic cells surround the necrotic foci. No intact neutrophils are present. C, CD123 immunostain highlights numerous plasmacytoid dendritic cells around the area of necrosis.

C

• Proliferative phase has patchy nodal involvement • Prominent paracortical expansion by immunoblasts, small lymphocytes, plasmacytoid dendritic cells, and histiocytes • Single cell necrosis and eosinophilic granular debris • Necrotizing phase has extensive necrosis with karyorrhectic debris but no intact neutrophils • Immunoblasts and histiocytes surround the necrotic areas • Histiocytes often have crescentic nuclei and contain phagocytosed debris • Resolution phase has numerous foamy macrophages • The inflammatory infiltrate may extend into the perinodal fat 

Special Stains and Immunohistochemistry • CD8+ cytotoxic T lymphocytes are prominent in the necrotic phase • B lymphocytes are virtually absent outside reactive follicles •  Histiocytes express lysozyme, CD68, and myeloperoxidase • Plasmacytoid dendritic cells are positive for CD123 (see Figure 14.14C) 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Systemic Lupus Erythematosus  • Indistinguishable histologic features • Some cases contain abundant plasma cells •  Hematoxylin bodies (ill-­ defined purple structures in necrotic foci) are rarely present; these are not seen in Kikuchi disease

•  Azzopardi phenomenon (dark blue DNA material deposited on the basement membrane of blood vessels) is rarely present; it is also absent in Kikuchi disease • Prominent follicular hyperplasia may be seen  Herpes or CMV Lymphadenitis  • Patients are usually immunosuppressed • Necrotic areas contain neutrophils and are surrounded by granulation tissue with less pronounced histiocytic infiltration • Viral inclusions are present • Immunohistochemistry confirms the diagnosis  Kawasaki Disease  • Mainly affects children younger than 5 years •  Characteristic clinical presentation with conjunctivitis, rash, inflammation of the oral mucosa, and lymphadenopathy • Widespread necrosis with many neutrophils • Fibrin thrombi in small vessels and arteritis with fibrinoid necrosis are characteristic  Fungal Lymphadenitis  • Patients are usually immunosuppressed and have disseminated disease •  Well-­ formed granulomatous reaction is frequently present • Special stains reveal evidence of fungal forms  Tuberculous Lymphadenitis  • Well-­formed necrotizing granulomas with many multinucleated giant cells are seen • AFB stain reveals mycobacteria 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

778

Chapter 14  —  Lymph Nodes

Cat Scratch Disease  •  Early disease shows prominent follicular hyperplasia and monocytoid B-­cell hyperplasia with focal necrosis • Late disease has extensive necrosis with many neutrophils and granulomas • Warthin-­Starry and Steiner stains highlight the bacteria  Diffuse Large B-­Cell Lymphoma  • May resemble a proliferative phase of Kikuchi disease with numerous immunoblasts •  Extensive necrosis with karyorrhectic debris but no intact neutrophils is rare in diffuse large B-­cell lymphoma (DLBCL), but it is typical of Kikuchi disease • Immunohistochemical stains reveal numerous B lymphocytes, whereas B-cells are few in number in Kikuchi disease • Flow cytometry, cytogenetic analysis, and PCR demonstrate a monoclonal B-­cell population  Peripheral T-­Cell Lymphoma  •  Extensive necrosis with karyorrhectic debris but no intact neutrophils is rare in peripheral T-­cell lymphoma (PTCL) but is typical of Kikuchi disease •  Nodal T-­ cell lymphomas are usually CD4-­ positive, whereas the T lymphocytes in Kikuchi disease are CD8-­positive • Immunohistochemical stains usually show loss of pan– T-­cell antigens CD2, CD5, CD7, CD43, or Bcl-­2 •  Flow cytometry, cytogenetic analysis, and PCR may demonstrate a monoclonal T-­cell population  Classical Hodgkin Lymphoma  • Necrosis and a polymorphous inflammatory infiltrate are frequently noted • Prominent eosinophilia is common and is not a feature in Kikuchi disease • Presence of classic Reed-­Sternberg cells or lacunar cells is required for diagnosis; these cells are absent in Kikuchi disease • Reed-­Sternberg cells express CD30 and CD15  Metastatic Carcinoma  •  Signet-­ ring adenocarcinoma cells may be confused with crescentic histiocytes • Signet ring cells contain mucin, whereas the histiocytes contain phagocytized debris •  Usually presents in elderly patients with widespread metastatic disease • Immunohistochemical staining for cytokeratins establishes the diagnosis PEARLS • A  lthough it is commonly thought of as a disease of young Asian women, Kikuchi disease can occur in both sexes and in all age and ethnic groups • The relationship of Kikuchi disease and systemic lupus is controversial; some authors believe it is a forme fruste of lupus • A subset of patients subsequently develops lupus; thus, clinical workup for lupus in all cases is recommended

Selected References Cramer J, Schmiedel S, Alegre NG, et al. Necrotizing lymphadenitis: Kikuchi-­Fujimoto disease alias lupus lymphadenitis? Lupus. 2010;19:89–92. Kim SK, Kang MS, Yoon BY, et al. Histiocytic necrotizing lymphadenitis in the context of systemic lupus erythematosus (SLE): is histiocytic necrotizing lymphadenitis in SLE associated with skin lesions? Lupus. 2011;20:809–819. O’Malley DP, Grimm KE. Reactive lymphadenopathies that mimic lymphoma: entities of unknown etiology. Semin Diagn Pathol. 2013;30:137–145. Pileri SA, Facchetti F, Ascani S, et al. Myeloperoxidase expression by histiocytes in Kikuchi’s and Kikuchi-­like lymphadenopathy. Am J Pathol. 2011;159:915–924. Rosado FG, Tang YW, Hasserjian RP, et al. Kikuchi-­Fujimoto lymphadenitis: role of parvovirus B-­19, Epstein-­Barr virus, human herpesvirus 6, and human herpesvirus 8. Hum Pathol. 2013;44:255–259. Seong GM, Kim JH, Lim GC, et al. Clinicopathological review of immunohistochemically defined Kikuchi-­ Fujimoto disease-­ including some interesting cases. Clin Rheumatol. 2012;31:1463–1469. Sukswai N, Jung HR, Amr SS, et al. Immunopathology of Kikuchi-­ Fujimoto disease: a reappraisal using novel immunohistochemistry combinations. Histopathology. 2019;77.

SYSTEMIC LUPUS ERYTHEMATOSUS Clinical Features • Chronic inflammatory disease of unknown cause that can affect the skin, joints, kidneys, lungs, nervous system, serous membranes, and many other organs • Enlargement of lymph nodes occurs in approximately 50% of patients • Lymph nodes are soft, nontender, and discrete • Usually detected in the cervical, axillary, and inguinal areas • Lymphadenopathy is more frequently noted at the onset of disease or in association with an exacerbation • Numerous laboratory abnormalities include neutropenia, anemia, and positive tests for antinuclear antibodies (double-­stranded DNA and Smith antigen) 

Histopathology • Edema, hemorrhage, and areas of necrosis surrounded by histiocytes and immunoblasts • Some cases contain abundant plasma cells •  Hematoxylin bodies (ill-­ defined purple structures in necrotic foci) are typical of lupus •  Azzopardi phenomenon (dark blue DNA material deposited on the basement membrane of blood vessels) is typical of lupus • Prominent follicular hyperplasia and capsular inflammation may be present 

Special Stains and Immunohistochemistry • CD8+ cytotoxic T lymphocytes are prominent • B lymphocytes are virtually absent outside the reactive follicles • Histiocytes express lysozyme, CD68, and myeloperoxidase • Plasmacytoid dendritic cells are positive for CD123 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis •  See section on “Differential Diagnosis” for Kikuchi disease

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

779

PEARLS • D  iagnosis requires correlation with the clinical and laboratory findings • Lupus lymphadenitis may precede or follow cases of Kikuchi disease

Selected References Cramer J, Schmiedel S, Alegre NG, et al. Necrotizing lymphadenitis: Kikuchi-­Fujimoto disease alias lupus lymphadenitis? Lupus. 2010;19:89–92. Hu S, Kuo TT, Hong HS. Lupus lymphadenitis simulating Kikuchi’s lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature. Pathol Int. 2003;53:221–226. Kim SK, Kang MS, Yoon BY, et al. Histiocytic necrotizing lymphadenitis in the context of systemic lupus erythematosus (SLE): is histiocytic necrotizing lymphadenitis in SLE associated with skin lesions? Lupus. 2011;20:809–819. Zuo Y, Foshat M, Qian YW, et al. A rare case of Kikuchi Fujimoto’s disease with subsequent development of systemic lupus erythematosus. Case Rep Rheumatol. 2012;2012:325062.

Figure 14.15  Tuberculosis.  Large necrotizing granulomas are present.

Differential Diagnosis GRANULOMATOUS LYMPHADENITIS TUBERCULOSIS Clinical Features •  Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis • Cervical lymphadenitis is the most common site and is known as scrofula • Tuberculosis is responsible for up to 40% of peripheral lymphadenopathy in the developing world • In the United States, although the overall number of patients with tuberculosis has decreased, the proportion of tuberculous lymphadenitis has increased •  Isolated peripheral tuberculous lymphadenopathy is usually due to reactivation of disease • Abdominal tuberculous lymphadenopathy may occur via ingestion of sputum or milk infected with Mycobacterium tuberculosis or Mycobacterium bovis 

Histopathology See Figure 14.15. • Gross examination shows areas of white-­yellow, soft, crumbly cheeselike (“caseous”) material • Multiple well-­formed granulomas with epithelioid histiocytes and giant cells • Caseous necrosis with no discernible cell membranes in the center of the granulomas • AFB stain reveals the mycobacteria 

Special Stains (other than acid-­fast bacilli) and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Microbial culture • PCR 

Sarcoidosis  •  Granulomas are more uniform, better defined, and compact • Necrosis is rare, and when present it is focal • AFB stain is negative  Fungal Lymphadenitis  •  Fungal forms can be identified on the H&E-­ stained sections • AFB stain is negative •  Gomori methenamine silver (GMS) and PAS stains highlight the fungal forms  Foreign-­Body Type Granuloma  • Granulomas are non-­necrotizing • Giant cells have a different appearance (foreign-­body type) • Foreign material is usually easily identified in the cytoplasm of the giant cells • AFB stain is negative  Kikuchi Disease  •  No well-­ formed granulomas or multinucleated giant cells • Necrosis is coagulative and not caseous •  Numerous immunoblasts, crescentic histiocytes, and plasmacytoid dendritic cells around the areas of necrosis • AFB stain is negative  Aggressive B-­Cell Lymphoma  • May have extensive necrosis • Lymph node architecture is effaced •  No well-­ formed granulomas and no multinucleated giant cells • Sheets of medium-­sized or large atypical lymphoid cells surround areas of necrosis  Classical Hodgkin Lymphoma  • Frequently associated with granulomas and necrosis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

780

Chapter 14  —  Lymph Nodes

• Lymph node architecture is effaced •  Mixed inflammatory infiltrate with many small lymphocytes, plasma cells, eosinophils, and neutrophils • Presence of classic Reed-­Sternberg cells or lacunar cells is required for diagnosis  Peripheral T-­Cell Lymphoma  • Lennert lymphoma (lymphoepithelioid type) is characterized by clusters of epithelioid histiocytes •  No well-­ formed granulomas or multinucleated giant cells • Necrosis is very unusual  Metastatic Carcinoma  • Can be associated with granulomas • Nasopharyngeal carcinoma can cause marked necrotizing granulomatous inflammation • Granulomas can also be seen in lymph nodes that drain carcinoma •  Immunohistochemical staining for cytokeratin highlights the epithelial cells PEARLS • A  FB stain needs to be carefully examined under oil (100× magnification) because mycobacteria are usually few in number and are hard to find • Occasionally tuberculous lymphadenitis manifests with non-­necrotizing granulomas; thus, AFB stain should be performed on all such cases

Selected References Kato T, Kimura Y, Sawabe M, et al. Cervical tuberculous lymphadenitis in the elderly: comparative diagnostic findings. J Laryngol Otol. 2009;123:1343–1347. Linasmita P, Srisangkaew S, Wongsuk T, et al. Evaluation of real-­time polymerase chain reaction for detection of the 16S ribosomal RNA gene of Mycobacterium tuberculosis and the diagnosis of cervical tuberculous lymphadenitis in a country with a high tuberculosis incidence. Clin Infect Dis. 2012;55:313–321. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosis-­endemic area. Pediatr Infect Dis J. 2006;25:142–146. Peto HM, Pratt RH, Harrington TA, et al. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-­2006. Clin Infect Dis. 2009;49:1350–1357.

ATYPICAL MYCOBACTERIAL INFECTION AND LEPROSY Clinical Features •  Atypical mycobacterial infections are increasing in number and severity in developed countries • Atypical mycobacteria that cause lymphadenitis include Mycobacterium avium complex (MAC), M. kansasii, M. scrofulaceum, M. malmoense, and M. haemophilum • Found in the environment: water, soil, food products, and domestic and wild animals • Atypical mycobacterial lymphadenitis typically occurs in immunocompetent children (1 to 5 years old) •  Isolated cervicofacial nodes, particularly the submandibular nodes, are most frequently involved

• Presents as a unilateral, nontender node that slowly enlarges over several weeks • Atypical mycobacterial lymphadenitis may also occur in immunocompromised patients (HIV positive) • Associated with disseminated infection •  The incidence of leprosy appears to have markedly decreased since the 1990s • Countries with high numbers of cases include India, Brazil, Indonesia, Bangladesh, and Nigeria • Leprosy primarily involves skin and peripheral nerves; if left untreated it may spread to lymph nodes 

Histopathology • Enlarged, matted lymph nodes •  Immunocompetent patients with atypical mycobacterial lymphadenitis or tuberculoid leprosy have necrotizing and non-­ necrotizing granulomas with Langhans-­type giant cells •  Immunosuppressed patients with atypical mycobacterial lymphadenitis may fail to develop well-­formed granulomas • Small aggregates of histiocytes •  Rare cases of mycobacterial pseudotumors with a proliferation of foamy or spindle histiocytes, which contain numerous intracellular organisms (Figure 14.16A) • Immunosuppressed patients with lepromatous leprosy have abundant foamy macrophages that replace the paracortical area (see Figure 14.16B and C) • These macrophages contain numerous intracellular organisms 

Special Stains and Immunohistochemistry • AFB stain or Fite stain highlights the mycobacteria 

Other Techniques for Diagnosis • Microbial culture • PCR 

Differential Diagnosis Inflammatory Pseudotumor of the Lymph Node •  An umbrella term for an ill-­ defined entity that includes mycobacterial pseudotumor of HIV-­positive patients • Consists of a spindle cell proliferation with a mixed infiltrate of small lymphocytes, immunoblasts, histiocytes, eosinophils, and many plasma cells (see Figure 14.16A) • Infectious etiology can be proven in some of these cases (atypical mycobacteria, Treponema pallidum, EBV, and others) • Special stains for bacteria, mycobacteria, fungi, and immunohistochemical staining to rule out increase in IgG4 plasma cells should be done in all cases of suspected inflammatory pseudotumor • Please also see section on “Differential Diagnosis” for Tuberculosis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

A

781

B

Figure 14.16  Other mycobacterial infections.  A, Atypical mycobacterial lymphadenitis with sheets of spindle-­ shaped histiocytes. B, Lepromatous leprosy. Abundant foamy macrophages in the paracortical area. C, Lepromatous leprosy and foamy macrophages. (Courtesy Dr. Jose Jessurun, Weill Cornell Medical College, New York.)

C PEARLS • L ymph node excision is usually curative in children with atypical mycobacteria • Immunocompetent children have very few scattered mycobacteria, more readily identified at the edge of necrotic areas • On the contrary, immunosuppressed patients have numerous microorganisms that are readily identified by AFB or Fite stains

Selected References Cohen YH, Amir J, Ashkenazi S, et al. Mycobacterium haemophilum and lymphadenitis in immunocompetent children, Israel. Emerg Infect Dis. 2008;14:1437–1439. Cruz AT, Ong LT, Starke JR. Mycobacterial infections in Texas children: a 5-­year case series. Pediatr Infect Dis J. 2010;29:772–774. Gillis T, Vissa V, Matsuoka M, et al. Characterization of short tandem repeats for genotyping Mycobacterium leprae. Lepr Rev. 2009;80:250–260. Jarzembowski JA, Young MB. Nontuberculous mycobacterial infections. Arch Pathol Lab Med. 2008;132:1333–1341. Penn R, Steehler MK, Sokohl A, Harley EH. Nontuberculous mycobacterial cervicofacial lymphadenitis: a review and proposed classification system. Int J Pediatr Otorhinolaryngol. 2011;75:1599–1603. Pham-­Huy A, Robinson JL, Tapiéro B, et al. Current trends in nontuberculous mycobacteria infections in Canadian children: a pediatric investigators collaborative network on infections in Canada (PICNIC) study. Paediatr Child Health. 2010;15:276–282. Zhang FR, Huang W, Chen SM, et al. Genome wide association study of leprosy. N Engl J Med. 2009;361:2609–2618.

CAT SCRATCH DISEASE Clinical Features • One of the most common causes of benign lymphadenopathy in the United States •  Occurs in immunocompetent children and young adults

• Caused by Bartonella henselae and transmitted by flea bites or cat bites and scratches • Following inoculation of B. henselae into humans, the organism typically causes a local skin infection that manifests as regional lymphadenopathy • Nodes are tender and often have erythema of the overlying skin 

Histopathology • Early stage: follicular and monocytoid B-­cell hyperplasia • Small foci of necrosis develop within areas of monocytoid B-­cell hyperplasia • Microabscesses are also seen within germinal centers • Late stage: large stellate microabscesses and necrotizing granulomas with palisading histiocytes (Figure 14.17) • Areas of necrosis contain neutrophils and debris • Necrosis frequently extends outside of the capsule 

Special Stains and Immunohistochemistry • Warthin-­Starry and Steiner stains identify the bacilli • Very small, pleomorphic, slender organisms • Present singly, in clusters or chains • Most numerous in early cases •  Found within endothelial cells, macrophages, and areas of necrosis 

Other Techniques for Diagnosis • Serology (low sensitivity and specificity) • Blood or tissue culture (requires special conditions) • Tissue PCR (low sensitivity, but high specificity) 

Differential Diagnosis Acute Suppurative Lymphadenitis  • Caused by pyogenic cocci • Follicular hyperplasia may suggest cat scratch disease

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

782

Chapter 14  —  Lymph Nodes

Selected References Lamps LW, Scott MA. Cat-­scratch disease: historic, clinical, and pathologic perspectives. Am J Clin Pathol. 2004;121(suppl):S71–S80. Ridder GJ, Boedeker CC, Technau-­Ihling K, et al. Role of cat-­scratch disease in lymphadenopathy in the head and neck. Clin Infect Dis. 2002;35:643–649. Rolain JM, Lepidi H, Zanaret M, et al. Lymph node biopsy specimens and diagnosis of cat-­scratch disease. Emerg Infect Dis. 2006;12:1338– 1344. Weinspach S, Tenenbaum T, Schönberger S, et al. Cat scratch disease— heterogeneous in clinical presentation: five unusual cases of an infection caused by Bartonella henselae. Klin Pädiatr. 2010;222:273–278.

SARCOIDOSIS Clinical Features Figure 14.17  Cat-­ scratch disease, late stage.  Large necrotizing granulomas with palisading histiocytes.

• No evidence of palisading histiocytes • Tissue Gram stain highlights the cocci  Other Infectious Necrotizing Lymphadenitis  • Chlamydia trachomatis (lymphogranuloma venereum), Francisella tularensis (tularemia), Haemophilus ducreyi (chancroid), and Yersinia enterocolitica (mesenteric lymphadenitis) may have identical histologic features • Clinical presentation is distinct • Patients are systemically ill •  Gram stain, Giemsa stain, and Warthin-­ Starry stain help identify the respective organisms  Mycobacterial and Fungal Lymphadenitis  • Typically have more extensive necrosis • Fewer neutrophils • AFB stain and GMS stain identify the organisms 

•  Multisystem granulomatous disorder of unknown etiology • Typically affects young adults • More common and more severe in Blacks • Classic initial presentation with bilateral hilar adenopathy and pulmonary reticular opacities as well as skin, joint, or eye lesions • Peripheral lymphadenopathy is present in up to 40% of patients 

Histopathology •  Multiple compact well-­ defined granulomas (Figure 14.18) •  Granulomas are composed of epithelioid histiocytes and multinucleated giant cells • Necrosis is typically absent • Rare cases have small necrotic foci in the granulomas •  Granulomas may become confluent and hyalinized, and may replace the lymph node 

Special Stains and Immunohistochemistry

Kikuchi Disease  • Necrotic areas are surrounded by immunoblasts, crescentic histiocytes, and plasmacytoid dendritic cells • Neutrophils are absent • No evidence of organisms on special stains 

• Noncontributory 

Lymphoma  • Lymph node architecture is effaced • Sheets of large atypical lymphoid cells or classic Reed-­ Sternberg cells present

Differential Diagnosis

PEARLS L ymphadenitis typically resolves within 2 to 6 months • • A positive Warthin-­Starry stain does not provide a definitive diagnosis but strongly suggests it in patients with compatible clinical findings • Atypical cases may present with fever, hepatosplenomegaly, abdominal lymphadenopathy, night sweats, and weight loss • More likely to be biopsied • Immunocompromised patients tend to have widespread granulomatous inflammation, bacillary angiomatosis, or bacillary peliosis

Other Techniques for Diagnosis • Elevated CD4:CD8 ratio in the involved lymph node may be considered suggestive of sarcoidosis; however, the data are currently controversial  Tuberculous Lymphadenitis  • Extensive caseating necrosis • Granulomas are ill-­defined • Granulomas vary in size and shape • AFB stain helps highlight the organisms  Fungal Lymphadenitis  • Granulomatous inflammation with or without caseous necrosis •  The diagnosis is established with GMS stain and cultures  Cat Scratch Disease  • Granulomas are ill-­defined • Large microabscesses are not a feature of sarcoidosis • Warthin-­Starry stain helps highlight the organisms 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

783

Selected References Akao K, Minezawa T, Yamamoto N, et al. Flow cytometric analysis of lymphocyte profiles in mediastinal lymphadenopathy of sarcoidosis. PloS One. 2018;13(11):e0206972. Goswami T, Siddique S, Cohen P, et al. The sarcoid-­lymphoma syndrome. Clin Lymphoma Myeloma Leuk. 2010;10:241–247. Mehrotra R, Dhingra V. Cytological diagnosis of sarcoidosis revisited: a state of the art review. Diagn Cytopathol. 2011;39:541–548. Rosen Y. Pathology of sarcoidosis. Semin Respir Crit Care Med. 2007;28:36–52. Ruiz SJ, Zhang Y, Mukhopadhyay S. CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoidosis: analysis of flow cytometry data obtained by endobronchial ultrasound-­guided transbronchial needle aspiration. J Bronchology Interv Pulmonol. 2016;23(4):288–297.

CASTLEMAN DISEASE Figure 14.18  Sarcoidosis.  Numerous compact epithelioid granulomas with minimal necrosis.

Brucellosis  •  Transmitted to humans by contact with fluids from infected animals or derived from food products such as unpasteurized milk • Systemic infection with a broad clinical spectrum • Histologically may be indistinguishable from sarcoidosis or tuberculosis • The organisms are difficult to identify on histology • Diagnosed based on cultures and serology  Whipple Disease  • PAS staining and electron microscopy are useful in this differential •  In early or atypical cases, the findings may be indistinguishable  Syphilis  • Well-­formed granulomas frequently present • Prominent follicular hyperplasia • Marked interfollicular plasmacytosis • Capsular thickening and obliterative vasculitis are seen in secondary syphilis •  Warthin-­ Starry stain demonstrates the spirochetes within the blood vessel walls or inside the granulomas  Foreign-­Body Type Granulomas  • Foreign material noted within the histiocytes and the giant cells  Classical Hodgkin Lymphoma  • Frequently associated with granulomas • Lymphoid infiltrate outside of the granulomas should be carefully examined for the presence of Reed-­Sternberg cells •  Sarcoid-­ like granulomas may be present in uninvolved lymph nodes of patients with known Hodgkin lymphoma PEARLS • S arcoidosis is a diagnosis of exclusion and should be diagnosed histologically with great caution • Presence of fibrinoid necrosis does not exclude the diagnosis • We routinely perform special stains on all cases, to rule out an infectious etiology

CLINICAL FEATURES • Atypical lymphoproliferative disease divided into three subtypes: unicentric hyaline-­vascular type, unicentric plasma cell type, and multicentric • Unicentric hyaline-­vascular type is the most common subtype (80% to 90% of cases) • Isolated benign lymphoproliferative disorder of young adults • Usually is an incidental finding • Majority occurs in mediastinum • Unassociated with HHV-­8 infection • Curable with surgical resection • Unicentric plasma cell type (10% to 20% of cases) •  Similar presentation to unicentric hyaline-­ vascular type •  Approximately 50% of the patients have systemic findings: anemia, elevated sedimentation rate, hypergammaglobulinemia, and bone marrow plasmacytosis • Multicentric (very rare) • Middle-­aged and elderly adults • Systemic disease with generalized peripheral lymphadenopathy, hepatosplenomegaly, frequent fevers, and night sweats • Strongly associated with immunosuppression (e.g., HIV) and HHV-­8 infection •  However, many (30% to 50%) cases are HIV and HHV-­8 negative, and are defined as idiopathic multicentric Castleman disease (iMCD) • TAFRO syndrome is a clinically distinctive form of iMCD, defined as thrombocytopenia, anasarca, fever, reticulin fibrosis of the bone marrow, and organomegaly • May have an associated malignancy (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes [POEMS] syndrome, Kaposi sarcoma [KS], Hodgkin and non-­Hodgkin lymphoma) 

HISTOPATHOLOGY • Hyaline-­vascular type (Figure 14.19A) • Abnormal follicles with atrophic or “regressed” hyalinized germinal centers, which contain numerous follicular dendritic cells • The follicles are surrounded by broad mantle zones of small lymphocytes, present in an “onion skin” arrangement

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

784

Chapter 14  —  Lymph Nodes

Figure 14.19  Castleman disease.  A, Hyaline-­vascular type with an atrophic “lollipop” follicle, expanded mantle zone, and hyalinized, hypervascular interfollicular area. B, Plasma cell type with a regressed follicle and numerous interfollicular plasma cells. C, Plasmablastic type with large, atypical-­ appearing plasmablasts. D, Human herpesvirus-­ 8 immunostain highlights the plasmablasts.

A

B

C

D

• Two or more adjacent germinal centers may be surrounded by a single mantle zone •  The regressed germinal centers are often radially penetrated by a hyalinized blood vessel (“lollipop” follicle) • The interfollicular areas have increased vascularity • Sinuses are typically obliterated • Plasma cell type (see Figure 14.19B) •  A mixture of hyperplastic germinal centers and regressed follicles • The interfollicular region is hypervascular and contains sheets of plasma cells • Sinuses may be patent • The histologic features are similar in unicentric and multicentric disease • Occasional cases have mixed features of both hyaline-­ vascular and plasma cell types • Plasmablastic type •  Is part of multicentric disease and occurs in HIV-­ positive patients • Markedly atypical-­appearing large cells with plasmablastic morphology (previously called “microlymphoma”) (see Figure 14.19C) • Present inside germinal centers and in interfollicular areas 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY •  Regressed follicles contain an increased number of CD21-­positive, CD23-­positive follicular dendritic cell meshworks •  Plasma cell variant may contain monotypic plasma cells, usually of IgGλ or IgAλ isotype (up to half of the cases) •  Plasmablastic type contains IgMλ-­restricted atypical large cells • Interfollicular plasma cells are polytypic

• Up to 40% of patients with multicentric disease (and ∼100% of HIV patients) have expression of HHV-­8 (see Figure 14.19D) • Patients with unicentric disease rarely, if ever, have staining with HHV-­8 antibody 

OTHER TECHNIQUES FOR DIAGNOSIS • Elevated serum levels of IL-­6 • Tissue PCR for HHV-­8 • IgH gene rearrangement shows no evidence of B-­cell clonality

Differential Diagnosis HHV-­8–Positive DLBCL, Not Otherwise Specified (NOS) • Usually arises in association with HHV-­8–associated multicentric Castleman disease in patients with HIV infection • May represent progression of plasmablastic Castleman disease • The lymph node architecture is effaced due to large sheets of plasmablast-­ like cells that express IgM Lambda (IgMλ) light chain • IgH gene rearrangement studies reveal a monoclonal population Nonspecific Follicular Hyperplasia • Regressed follicles with “onion skin” mantle zones may be part of nonspecific reactive follicular hyperplasia • HHV-­8 is negative HIV-­Associated Lymphadenopathy • Late-­stage HIV is characterized by follicular regression • Follicles have attenuated mantle zones and do not show onion-­skin or lollipop appearance •  The interfollicular areas appear depleted with a decrease of CD4-­positive T-cells and an increase of plasma cells and histiocytes • No evidence of HHV-­8 expression

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

Low-­Grade B-­Cell Lymphoma • Expanded mantle zones may raise the possibility of mantle cell lymphoma (MCL) • Atrophic hyalinized follicles may be reminiscent of follicular lymphoma • Immunophenotyping and presence of typical cytogenetic abnormalities [t(11;14) and t(14;18), respectively] help in this differential diagnosis Angioimmunoblastic T-­cell Lymphoma (AITL) •  May resemble hyaline-­ vascular Castleman disease due to presence of regressed germinal centers, expanded follicular dendritic cell meshworks, lymphoid depletion, and marked proliferation of high endothelial venules • Morphologic evidence of atypical small to medium-­ sized lymphocytes with clear cytoplasm • Tumor cells are CD4-­positive T-cells that coexpress CD10, Bcl-­6, PD-­1, and CXCL13 Thymoma • Hyaline-­vascular follicles resemble Hassall corpuscles •  The epithelial cells in thymoma are easily highlighted by cytokeratin immunostains Autoimmune Lymphadenopathy • May have sheets of interfollicular plasma cells •  Clinical correlation is recommended to make this distinction IgG4-­Positive Lymphadenopathy •  Type I (multicentric Castleman disease–like) has hyperplastic and regressed follicles with interfollicular vascular proliferation •  In one study, sheetlike plasmacytosis was highly characteristic of idiopathic multicentric Castleman disease, while plasmacytic infiltration in IgG4-­related disease was always associated with intervening lymphocytes • The IgG4/IgG ratio in IgG4-­related disease is significantly higher than that in Castleman disease • Does not express HHV-­8 or have serum elevation of IL-­6 or C-­reactive protein • Both diseases may present high serum IgG4 Plasma Cell Neoplasm • Characterized by a marked interfollicular expansion due to a plasma cell proliferation • The lymphoid follicles do not have features of Castleman disease • Plasma cells are monoclonal, most commonly of IgG kappa (IgGκ) light chain isotype PEARLS • H  yaline-­vascular type is the most common form of disease and is almost invariably localized and HHV-8 negative • Plasma cell type may be localized or multicentric and is frequently associated with HIV and HHV-­8 infection • Whereas unicentric disease is indolent, multicentric disease may be rapidly progressive and even fatal • Recently, consensus criteria for the diagnosis of idiopathic multicentric Castleman disease have been proposed; they require both histopathologic and clinical laboratory abnormalities, with exclusion of infectious, malignant, and autoimmune mimickers • HHV-­8-­negative Castleman disease is a diagnosis of exclusion

785

Selected References Bower M, Newsom-­Davis T, Naresh K, et al. Clinical features and outcome in HIV-­associated multicentric Castleman’s disease. J Clin Oncol. 2011;29:2481–2486. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-­ based consensus diagnostic criteria for HHV-­ 8-­ negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12): 1646–1657. Iwaki N, Fajgenbaum DC, Nabel CS, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-­ 8-­negative multicentric Castleman disease. Am J Hematol. 2016;91 (2):220–226. Oksenhendler E, Boutboul D, Fajgenbaum D, et al. The full spectrum of Castleman disease: 273 patients studied over 20 years. Br J Haematol. 2018;180(2):206–216. Otani K, Inoue D, Fujikura K, et al. Idiopathic multicentric Castleman’s disease: a clinicopathologic study in comparison with IgG4-­related disease. Oncotarget. 2018;9(6):6691–6706. Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV-­8 in the increasing incidence of HIV-­associated multicentric Castleman’s disease. Ann Oncol. 2009;20:775–779. Yu L, Tu M, Cortes J, et al. Clinical and pathological characteristics of HIV-­and HHV-­ 8-­ negative Castleman disease. Blood. 2017;129(12):1658–1668.

SMALL B-­CELL NEOPLASMS SMALL LYMPHOCYTIC LYMPHOMA/ CHRONIC LYMPHOCYTIC LEUKEMIA Clinical Features • Most common adult leukemia in Western countries • Median age at diagnosis is 70 years • Most patients present with painless generalized lymphadenopathy with peripheral blood and bone marrow involvement • Monoclonal B-cell lymphocytosis invariantly precedes the onset of chronic lymphocytic leukemia (CLL) 

Histopathology • Lymph node architecture is effaced due to a diffuse proliferation of small lymphocytes (Figure 14.20A) • Lymphocytes have round nuclei with condensed chromatin, inconspicuous nucleoli, and scant cytoplasm • Proliferation centers are characteristic; these are pale nodular areas composed of a mixture of small, medium-­ sized (prolymphocytes), and large lymphoid cells (paraimmunoblasts) (see Figure 14.20B) • Rare cases have plasmacytic differentiation 

Special Stains and Immunohistochemistry •  Flow cytometry has characteristic features with dim CD20, CD5, CD23, bright CD200, absent FMC-­7, and dim monoclonal light chain expression • Immunohistochemistry: tumor cells aberrantly express CD5, CD23, and LEF1 •  Tumor cells do not express CD10, Bcl-­ 6, SOX11, or Cyclin D1 

Other Techniques for Diagnosis • PCR: monoclonal IGH gene rearrangement in the majority of cases • ∼80% of cases have cytogenetic abnormalities by FISH • Most common chromosomal abnormalities are deletion 13q14, trisomy 12, deletion 11q22, and deletion 17p13

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

786

Chapter 14  —  Lymph Nodes

Figure 14.20  Chronic lymphocytic leukemia (CLL).  A, Lymph node architecture is effaced with sheets of small lymphocytes and several pale-­ staining proliferation centers. B, Proliferation center is composed of a mixture of small lymphocytes, prolymphocytes, and paraimmunoblasts.

A

• Thirty-­three percent to 50% of patients have mutations by next generation sequencing •  The most common mutations are in NOTCH1, SF3B1, TP53, ATM, BIRC3, POT1, and MYD88 

Differential Diagnosis Follicular Lymphoma  •  Prominent follicular architecture with well-­ defined abnormal follicles • The neoplastic cells are a mixture of centrocytes and centroblasts • Tumor cells express germinal center markers CD10 and Bcl-­6 and are negative for CD5 • Flow cytometry: bright CD20 and light chain expression • Conventional karyotype and FISH: t(14;18); BCL2/IGH gene rearrangement  Mantle Cell Lymphoma  • May have a diffuse pattern similar to CLL • Small cells with irregular nuclei (centrocyte-­like) • No evidence of proliferation centers • Flow cytometry: tumor cells express bright CD5, CD20, FMC-­7, and light chain and are typically negative for CD23 and CD200 • Immunohistochemistry: Cyclin D1 and SOX11 are positive, LEF1 negative •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement  Marginal Zone Lymphoma  • Rare in lymph node •  Tumor cells usually surround reactive lymphoid follicles • Neoplastic cells are composed of monocytoid B-cells (marginal zone B-cells) with abundant pale cytoplasm, admixed with plasma cells and scattered immunoblasts • Prominent plasma cell differentiation may be seen •  Flow cytometry: bright CD20 and monoclonal light chain expression •  Immunohistochemistry: tumor cells are positive for MNDA, and negative for CD5, CD23, and LEF1 • Conventional karyotype and FISH: trisomy 3, 7, and 18 may be seen in a small subset of cases  Diffuse Large B-­Cell Lymphoma  • Occasional cases of CLL have an increased number of large cells or expanded proliferation centers

B • DLBCL contains sheets of large cells, whereas in CLL the large cells are always admixed with intermediate-­ sized and small lymphocytes • Five percent to 10% of patients with CLL progress to DLBCL (Richter syndrome) PEARLS • C  LL refers to peripheral blood and bone marrow involvement, and SLL represents nodal involvement by the same disease process • Expression of CD38, ZAP70, and p53 has prognostic significance and may influence treatment • CLL cells have slow growth; thus, FISH is more informative than conventional karyotype • Rare cases of CLL have dim expression of Cyclin D1 in the proliferation centers; these cases do not have t(11;14) translocation and should not be classified as MCL

Selected References Challagundla P, Medeiros LJ, Kanagal-­Shamanna R, et al. Differential expression of CD200 in B-­cell neoplasms by flow cytometry can assist in diagnosis, subclassification, and bone marrow staging. Am J Clin Pathol. 2014;142(6):837–844. Gradowski JF, Sargent RL, Craig FE, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma with cyclin D1 positive proliferation centers do not have CCND1 translocations or gains and lack SOX11 expression. Am J Clin Pathol. 2012;138:132–139. Landau DA, Tausch E, Taylor-­ Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526(7574):525–530. Landgren O, Albitar M, Ma W, et al. B-­cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360:659–667. Menter T, Dirnhofer S, Tzankov A. LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol. 2015;68(6):473–478. Menter T, Trivedi P, Ahmad R, et al. Diagnostic utility of lymphoid enhancer binding factor 1 immunohistochemistry in small B-­cell lymphomas. Am J Clin Pathol. 2017;147(3):292–300. Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121:1403–1412.

FOLLICULAR LYMPHOMA Clinical Features • One of the most common lymphomas in the United States and Europe • The median age is 60 years •  Most patients present with painless peripheral adenopathy in the cervical, axillary, inguinal, or femoral regions

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

• Liver, spleen, and bone marrow involvement is present in >50% of the patients •  Pediatric follicular lymphoma (FL) is very rare and tends to present with limited stage disease • Occasional patients have primary extranodal FL (duodenum, breast, skin, and other sites) • Variable clinical course: some patients have indolent stable disease for many years, whereas others progress rapidly and require treatment 

Histopathology • Closely packed follicles efface the lymph node architecture (Figure 14.21A) • Rarely, the infiltrate is follicular and diffuse or predominantly diffuse • Mantle zones are attenuated or absent • Follicles appear homogeneous and consist of a mixture of small cleaved lymphocytes (centrocytes) and large lymphoid cells with round nuclei and several small nucleoli (centroblasts) • Tingible-­body macrophages are absent •  The neoplastic infiltrate frequently splits the lymph node capsule and may extend into the perinodal soft tissue • FL is graded according to the number of centroblasts counted per high-­power (40×) field • Grade 1 (low-­grade): 0 to 5 centroblasts per high-­ power field (see Figure 14.21B) • Grade 2 (low-­grade): 6 to 15 centroblasts per high-­ power field (see Figure 14.21C) •  Grade 3 (high-­ grade): >15 centroblasts per high-­ power field (see Figure 14.21D) • Grade 3A contains a mixture of centrocytes and centroblasts • Grade 3B contains sheets of centroblasts • If there is a diffuse area composed predominantly of centroblasts, a separate diagnosis of DLBCL should be made 

Special Stains and Immunohistochemistry •  Flow cytometry: bright CD20+ B lymphocytes with CD10 expression and monotypic light chain restriction •  Immunohistochemistry: neoplastic lymphoid cells coexpress Bcl-­2, Bcl-­6, and CD10 • Bcl-­2 may be negative in ∼10% of low-­grade FL and up to 50% of high-­grade FL • Some (usually high-­grade) cases lack CD10; however, they retain Bcl-­6 • Mum-­1 is negative in low-­grade FL but may be expressed in grade 3 FL • CD21 and CD23 highlight the follicular dendritic cell meshworks •  Ki67 proliferative fraction typically correlates with grading (20% in high-­grade FL) 

Other Techniques for Diagnosis •  Conventional karyotype, FISH, and PCR: t(14;18); BCL2/IGH gene rearrangement in up to 90% of low-­ grade FL • BCL6 gene rearrangement in 5% to 15%, usually present in grade 3B FL

787

• PCR: monoclonal IGH gene rearrangement in ∼ 80% of cases •  Next generation sequencing: KMT2D, CREBBP, TNFRSF14, and EZH2 mutations appear most common 

Differential Diagnosis Reactive Follicular Hyperplasia  • Lymph node architecture is preserved: capsule is thin, sinuses are patent • Lymphoid follicles are heterogeneous in size and shape • Mantle zone is present and well defined • Cellular composition within the follicles is heterogeneous with tingible-­body macrophages • Well-­defined light and dark zones within germinal centers can be seen • Lymphoid cells in the follicles express Bcl-­6 and CD10, but not Bcl-­2 • Proliferation rate within the follicles with Ki67 immunostain is >90% • Flow cytometry reveals polytypic B lymphocytes • PCR for IgH gene rearrangement is polyclonal • Cytogenetic analysis shows a normal karyotype and no evidence of t(14;18) translocation  Mantle Cell Lymphoma  • May have a nodular pattern similar to FL • Small cells with irregular nuclei (centrocyte-­like); no evidence of centroblasts • Flow cytometry: tumor cells express CD5, CD20, and light chain and are negative for CD10 • Immunohistochemistry: CD10 and Bcl-­6 are negative; CD5, SOX11, and Cyclin D1 are positive •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement  Marginal Zone Lymphoma  • Rare in lymph nodes •  Tumor cells usually surround reactive lymphoid follicles • Neoplastic cells are composed of monocytoid B-cells (marginal zone B-cells) with abundant pale cytoplasm, admixed with plasma cells and scattered immunoblasts • Prominent plasma cell differentiation may be seen •  Flow cytometry: bright CD20 and monoclonal light chain expression •  Immunohistochemistry: tumor cells express MNDA and are negative for CD5, CD10, Bcl-­ 6, CD23, and Cyclin D1 • Conventional karyotype and FISH: trisomy 3, 7, and 18 may be seen in a small subset  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  • Proliferation centers may resemble neoplastic follicles • Tumor cells have round nuclei; prolymphocytes and paraimmunoblasts have large central nucleoli • Flow cytometry: B lymphocytes express CD5 and CD23 and have dim CD20 and dim monoclonal light chain expression •  Immunohistochemistry: tumor cells are negative for CD10 and Bcl-­ 6; no abnormal follicles highlighted with CD21 and CD23

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

788

Chapter 14  —  Lymph Nodes

Figure 14.21  Follicular lymphoma.  A, Lymph node architecture is effaced with numerous closely packed follicles. B, Follicular lymphoma grade 1. C, Follicular lymphoma grade 2. D, Follicular lymphoma grade 3.

A

B

C

D

• Conventional karyotype and FISH: deletion 13q14, trisomy 12, deletion 11q22, and deletion 17p13 are common abnormalities  Diffuse Large B-­Cell Lymphoma  • May coexist with FL in the same lymph node or represent disease progression in patients with known FL •  DLBCL contains diffuse sheets of large transformed lymphoid cells; there is no evidence of follicular architecture • CD21 and CD23 are negative in the areas involved by DLBCL PEARLS • W  hen grading, care should be taken to distinguish centroblasts from follicular dendritic cells (large cells with cleared-­out chromatin and small or absent nucleoli) • Small core biopsies may not have the recommended 10 neoplastic follicles; thus, grading is not required on small tissue samples • FL grade 1 and FL grade 2 have a similar clinical behavior and are grouped together as low-­grade, clinically indolent FL • FL grade 3A and FL grade 3B likely represent different entities, with 3B FL being more akin to DLBCL, although this is still controversial • Final diagnosis should mention the different components of lymphoma (i.e., grades 1 and 2 versus grade 3 versus DLBCL) and provide percentage of lymph node involvement by each pattern • Staining with CD21 and CD23 is essential to rule out DLBCL in cases of high-­grade FL • Approximately 10% of nodal FL do not harbor the translocation t(14;18) and do not express Bcl-­2 protein; these cases are enriched with postgerminal center signature genes by gene expression profiling, but they also show many similarities to conventional germinal center–derived FL

Selected References Horn H, Schmelter C, Leich E, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96:1327–1334. Hung SS, Meissner B, Chavez EA, et al. Assessment of capture and amplicon-­based approaches for the development of a targeted next-­ generation sequencing pipeline to personalize lymphoma management. J Mol Diagn. 2018;20(2):203–214. Karube K, Guo Y, Suzumiya J, et al. CD10-­MUM1 + follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features. Blood. 2007;109:3076–3079. Leich E, Salaverria I, Bea S, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009;114:826–834. Louissaint Jr A, Ackerman AM, Dias-­Santagata D, et al. Pediatric-­type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement. Blood. 2012;120:2395–2404. Misdraji J, Harris NL, Hasserjian RP, et al. Primary follicular lymphoma of the gastrointestinal tract. Am J Surg Pathol. 2011;35:1255–1263. Schmatz AI, Streubel B, Kretschmer-­Chott E, et al. Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol. 2011;29:1445–1451. Wahlin BE, Yri OE, Kimby E, et al. Clinical significance of the WHO grades of follicular lymphoma in a population-­based cohort of 505 patients with long follow-­up times. Br J Haematol. 2012;156:225–233.

MANTLE CELL LYMPHOMA Clinical Features • Occurs more commonly in Caucasian men • Median age at diagnosis is 68 years • Most patients present with advanced stage disease with lymphadenopathy, hepatosplenomegaly, peripheral blood, and bone marrow involvement •  May involve any region of the gastrointestinal tract (lymphomatous polyposis) • Generally incurable lymphoma with a median survival of 3 to 4 years • A subset of the patients have a leukemic non-­nodal presentation with peripheral blood, bone marrow, and

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

spleen involvement without lymphadenopathy; many have an indolent clinical course compared to the classic MCL variant 

Histopathology • Lymph node architecture is effaced with a vaguely nodular, diffuse, mantle zone or follicular lymphoid proliferation (Figure 14.22A) • Small to medium-­sized lymphoid cells with irregular nuclear shape (centrocyte-­like) • Hyalinized small vessels •  Scattered epithelioid histiocytes devoid of phagocytized nuclear debris (see Figure 14.22B) • Blastoid variant: tumor cells have finely dispersed chromatin with many mitoses (>20 to 30/10 high-­power fields); is associated with more aggressive behavior •  Pleomorphic variant: larger and pleomorphic cells including cells with prominent nucleoli • Mitotic rate of >10 to 40/15 high-­power fields is an adverse prognostic factor 

Special Stains and Immunohistochemistry • Flow cytometry: B lymphocytes express CD5, CD43, FMC-­7, and bright monotypic light chain restriction; tumor cells are negative for CD10, as well as negative or weakly positive with CD23 and CD200 •  Immunohistochemistry: neoplastic lymphoid cells express Cyclin D1 (>95% of cases) and SOX11 (>90% of cases, including the Cyclin D1 negative MCL) (see Figure 14.22C) • Leukemic non-­nodal variant MCL cells frequently have an atypical immunophenotype (SOX11 negative; can be CD5 negative and CD200 positive) • Ki67 proliferation rate of >40% to 60% is an adverse prognostic factor 

A

C

789

Other Techniques for Diagnosis •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement in >95% of cases • PCR: clonal IGH gene rearrangement in the majority of cases •  Next generation sequencing demonstrates frequent mutations in ATM, CCND1, KMT2D, TP53, and NOTCH1 genes 

Differential Diagnosis Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  • Proliferation centers may resemble neoplastic nodules of MCL • Tumor cells have round nuclei; prolymphocytes and paraimmunoblasts have large central nucleoli • Flow cytometry: B lymphocytes express CD5, CD23, and bright CD200, and have dim CD20 and dim monoclonal light chain expression; FMC-­7 is negative •  Immunohistochemistry: tumor cells are negative for Cyclin D1 and SOX11 • Conventional karyotype and FISH: deletion 13q14, trisomy 12, deletion 11q22, and deletion 17p13 are common abnormalities  Follicular Lymphoma  •  Prominent follicular architecture with well-­ defined abnormal follicles • The neoplastic cells are a mixture of centrocytes and centroblasts • Tumor cells express germinal center markers CD10 and Bcl-­6 and are negative for CD5 and Cyclin D1 • Flow cytometry: bright CD20, CD10, and bright light chain expression • Conventional karyotype and FISH: t(14;18); BCL2/IGH gene rearrangement 

B

Figure 14.22  Mantle cell lymphoma.  A, Vaguely nodular lymphoid proliferation. B, Small lymphocytes and scattered epithelioid histiocytes. C, Cyclin D1 immunostain is strongly positive in the neoplastic lymphocytes.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

790

Chapter 14  —  Lymph Nodes

Marginal Zone Lymphoma  • Rare in lymph nodes •  Tumor cells usually surround reactive lymphoid follicles • Neoplastic cells are composed of monocytoid B-cells (marginal zone B-cells) with abundant pale cytoplasm, admixed with plasma cells and scattered immunoblasts • Prominent plasma cell differentiation may be seen •  Flow cytometry: bright CD20 and monoclonal light chain expression •  Immunohistochemistry: tumor cells are positive for MNDA and negative for CD5, CD10, BCL-­6, CD23, and Cyclin D1 • Conventional karyotype and FISH: trisomy 3, 7, and 18 may be seen in a small subset  Lymphoblastic Lymphoma  • May resemble blastoid variant of MCL • Neoplastic cells express immature markers (CD34, TdT, CD10), are negative for Cyclin D1 and CD20, and do not express immunoglobulin light chains  Diffuse Large B-­Cell Lymphoma  • May resemble blastoid or pleomorphic variant of MCL • DLBCL contains sheets of large cells, whereas in MCL the neoplastic cells are intermediate-­ sized or small; pleomorphic variant of MCL may morphologically overlap with DLBCL • Do not express Cyclin D1 and SOX11 (with very rare exceptions; see References) •  Conventional karyotype and FISH: highly complex karyotype with no evidence of t(11;14); IGH/CCND1 gene rearrangement PEARLS M •  ore aggressive than other small B-­cell lymphomas • Rare cases may lack CD5 expression or may express CD23 or CD10; thus, Cyclin D1 should be performed on all cases of presumed low-­grade B-­cell lymphoma • Very rare cases may lack Cyclin D1 expression and t(11;14) translocation; these cases are positive for SOX11 and should be categorized as MCL • Virtually all Cyclin D1-­negative MCL carry CCND2/ CCND3 rearrangements • Cases of predominantly non-­nodal, splenomegalic leukemic MCL may correspond to a different molecular subtype of MCL with a long, indolent clinical course

Selected References Dictor M, Ek S, Sundberg M, et al. Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt’s lymphoma. Haematologica. 2009;94:1563–1568. Hsiao SC, Cortada IR, Colomo L, et al. SOX11 is useful in differentiating cyclin D1-­positive diffuse large B-­cell lymphoma from mantle cell lymphoma. Histopathology. 2012;61(4):685–693. Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-­negative subtype. Haematologica. 2009;94:1555–1562. Ondrejka SL, Lai R, Smith SD, et al. Indolent mantle cell leukemia: clinicopathologic variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011;96:1121–1127.

Royo C, Navarro A, Clot G, et al. Non-­nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia. 2012;26:1895–1898. Sakhdari A, Ok CY, Patel KP, et al. TP53 mutations are common in mantle cell lymphoma, including the indolent leukemic non-­nodal variant. Ann Diagn Pathol. 2019;41:38–42. Vela-­Chávez T, Adam P, Kremer M, et al. Cyclin D1 positive diffuse large B-­ cell lymphoma is a post-­ germinal center-­ type lymphoma without alterations in the CCND1 gene locus. Leuk Lymphoma. 2011;52:458–466. Zeng W, Fu K, Quintanilla-­Fend L, et al. Cyclin D1-­negative blastoid mantle cell lymphoma identified by SOX11 expression. Am J Surg Pathol. 2012;36:214–219. Zhang J, Jima D, Moffitt AB, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123(19):2988–2996.

NODAL MARGINAL ZONE LYMPHOMA Clinical Features • Primary nodal marginal zone lymphoma (MZL) is a rare lymphoma •  Most cases represent nodal involvement by extranodal mucosa associated lymphoid tissue (MALT) lymphoma • Similar proportion of men and women • Median age at diagnosis is 60 years • Most patients have asymptomatic lymphadenopathy and advanced stage disease at presentation 

Histopathology •  Tumor cells usually surround reactive lymphoid follicles (Figure 14.23A) • Follicular colonization is frequently seen • Neoplastic cells are composed of monocytoid B-cells (also called marginal zone B-cells) with abundant pale cytoplasm, admixed with plasma cells and scattered immunoblasts (see Figure 14.23B) •  Prominent plasma cell differentiation may be seen (although less common than in extranodal MALT-­type lymphomas) 

Special Stains and Immunohistochemistry •  Flow cytometry: bright CD20 and monoclonal light chain expression •  Immunohistochemistry: tumor cells are negative for CD5, CD10, Bcl-­6, CD23, and Cyclin D1 • Tumor cells express MNDA in 75%, CD43 in ∼50%, and BCL2 in most cases • CD21 and CD23 show expanded and colonized follicular dendritic cell meshworks • Plasma cells express monotypic immunoglobulin light chain in cases with plasmacytic differentiation 

Other Techniques for Diagnosis • Cytogenetics: trisomy 3, 7, and 18 may be seen in a small subset of cases • PCR: monoclonal IgH gene rearrangement •  Next generation sequencing: cases harbor frequent mutations in KMT2D, TET2, CREBBP, PTPRD, NOTCH2, TNFAIP3, and KLF2 genes •  A subset of cases has been found to have BRAF mutations; they occurred in cases with strong IgD expression 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

A

Figure 14.23  Nodal marginal zone lymphoma.  A, Neoplastic lymphocytes surround and colonize residual follicles. B, Small lymphocytes, plasma cells, and immunoblasts.

B

Differential Diagnosis Reactive Lymph Node with Monocytoid B-­Cell Hyperplasia  • Morphologic distinction can be difficult •  Immunohistochemistry: reactive monocytoid B-cells are negative for Bcl-­2, whereas neoplastic cells are usually positive • Plasma cells may be increased in number but are always polyclonal • PCR shows no evidence of IgH gene rearrangement  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  • Proliferation centers are not a feature of MZL • Prominent plasma cell differentiation is very unusual in CLL • Tumor cells have round nuclei; prolymphocytes and paraimmunoblasts have large central nucleoli • Flow cytometry: B lymphocytes express CD5 and CD23, and have dim CD20 and dim monoclonal light chain expression; FMC-­7 is negative •  Immunohistochemistry: tumor cells express CD5, CD23, and LEF1; no evidence of follicular dendritic cell meshworks •  Cytogenetics: deletion 13q14, trisomy 12, deletion 11q22, and deletion 17p13 are common abnormalities  Follicular Lymphoma  • Cases of MZL with prominent follicular colonization may appear virtually indistinguishable from FL • Cases of FL may also have marginal zone differentiation with numerous monocytoid B-cells surrounding the neoplastic follicles • In FL, the neoplastic cells are a mixture of centrocytes and centroblasts • Tumor cells express germinal center markers CD10 and Bcl-­6, whereas neoplastic cells in MZL do not express germinal center antigens •  Flow cytometry: neoplastic B-cells coexpress CD10 (CD10 is always negative in MZL) • Conventional karyotype and FISH: t(14;18); BCL2/IGH gene rearrangement  Mantle Cell Lymphoma  • May have a mantle zone growth around reactive follicles, similar to MZL • Does not show plasmacytic differentiation • Small cells with irregular nuclei (centrocyte-­like)

791

• Flow cytometry: tumor cells express CD5, CD20, and light chain •  Immunohistochemistry: CD5 and Cyclin D1 are positive •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement  Lymphoplasmacytic Lymphoma  • Distinction between these entities is very problematic • Lymphoplasmacytic lymphoma (LPL) generally arises in the bone marrow and has high levels of serum IgM with hyperviscosity, whereas MZL generally presents with lymphadenopathy and is rarely associated with hyperviscosity • LPL classically shows retention of the architecture with dilated sinuses, whereas MZL more typically has monocytoid cellular morphology, a marginal zone growth pattern, and follicular colonization • Mutations in the MYD88 gene have been found in virtually all nodal LPLs but are rare to absent in nodal MZLs  Diffuse Large B-­Cell Lymphoma  • May arise from a preexisting MZL • DLBCL contains large sheets of large cells, whereas in MZL the large neoplastic cells are admixed with small lymphocytes PEARLS • M  ZL is frequently a diagnosis of exclusion • Primary nodal MZL and nodal involvement by extranodal MALT lymphoma are morphologically similar • Monocytoid morphology and plasma cell differentiation are more typical of extranodal MALT lymphoma • Patients with Sjögren syndrome and Hashimoto thyroiditis are much more likely to have extranodal MALT lymphoma presenting in lymph node • Occasionally, exact diagnosis cannot be made after a careful examination and diagnosis of “small B-­cell lymphoma with plasmacytic differentiation” is warranted

Selected References Krijgsman O, Gonzalez P, Balague Ponz O, et al. Dissecting the grey zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features. Haematologica. 2013;98:1921–1929. Molina TJ, Lin P, Swerdlow SH, et al. Marginal zone lymphomas with plasmacytic differentiation and related disorders. Am J Clin Pathol. 2011;136:211–225.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

792

Chapter 14  —  Lymph Nodes

Naresh KN. Nodal marginal zone B-­cell lymphoma with prominent follicular colonization—difficulties in diagnosis: a study of 15 cases. Histopathology. 2008;52:331–339. Pillonel V, Juskevicius D, Ng CKY, et al. High-­throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations. Leukemia. 2018;32(11):2412–2426. Salama ME, Lossos IS, Warnke RA, et al. Immunoarchitectural patterns in nodal marginal zone B-­cell lymphoma: a study of 51 cases. Am J Clin Pathol. 2009;132:39–49. Spina V, Khiabanian H, Messina M, et al. The genetics of nodal marginal zone lymphoma. Blood. 2016;128(10):1362–1373.

LYMPHOPLASMACYTIC LYMPHOMA Clinical Features • Rare lymphoma that occurs in adults with a median age of 60 years • Majority of patients have a circulating monoclonal IgM that often leads to a hyperviscosity syndrome (Waldenström macroglobulinemia) • Most patients present with weakness and fatigue due to anemia • Some patients have neuropathy, autoimmune manifestations, or cryoglobulinemia • LPL is a bone marrow–based disease and lymphadenopathy is uncommon •  The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of small B-­ cell lymphoma with plasmacytic differentiation 

Histopathology • Lymph node architecture is frequently preserved • The neoplastic infiltrate is composed of small lymphocytes, plasma cells, and plasmacytoid cells (Figure 14.24) • Variable number of immunoblasts •  Sinuses are often open and may contain histiocytes containing PAS-­positive immunoglobulin • Other typical characteristics are Dutcher and Russell bodies, increased mast cells, and hemosiderin-­ laden macrophages • Less common/atypical morphologic features within the spectrum of LPL include complete architectural effacement, perinodal soft tissue involvement, a vaguely nodular growth pattern, and follicular colonization 

Special Stains and Immunohistochemistry • B lymphocytes are negative for CD5, CD10, and CD23 •  Plasma cells typically are of IgM isotype and are monotypic 

Other Techniques for Diagnosis • MYD88 L265P somatic mutation practically defines nodal LPL 

Differential Diagnosis Marginal Zone Lymphoma  • Distinction may be challenging •  LPL generally presents in the bone marrow with hyperviscosity, whereas MZL generally presents with lymphadenopathy •  LPL classically shows retention of the architecture with dilated sinuses, whereas MZL more typically has

Figure 14.24  Lymphoplasmacytic lymphoma (LPL). Lymphoplasmacytic lymphoma with a mixture of small lymphocytes, plasmacytoid  lymphoid cells, and plasma cells. (Courtesy Dr. Dennis O’Malley, Clarient, Inc., Aliso Viejo, CA.)

monocytoid cellular morphology, a marginal zone growth pattern, and follicular colonization • Mutations in the MYD88 gene are either absent or very unusual in nodal MZL  Plasmacytoma  • May be seen in patients with known myeloma or may be primary in the lymph node • There are sheets of plasma cells surrounding residual reactive follicles • B lymphocytes are benign and polyclonal • Plasma cells are monoclonal  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  • Proliferation centers are not a feature of LPL • Tumor cells have round nuclei; prolymphocytes and paraimmunoblasts have large central nucleoli • Flow cytometry: B lymphocytes express CD5 and CD23, and have dim CD20 and dim monoclonal light chain expression; FMC-­7 is negative •  Immunohistochemistry: tumor cells express CD5, CD23, and LEF1 •  Cytogenetics: deletion 13q14, trisomy 12, deletion 11q22, and deletion 17p13 are common abnormalities • Mutations in the MYD88 gene are very unusual in CLL  Mantle Cell Lymphoma  • Plasmacytic differentiation is very unusual; it occurs mainly in SOX11 negative cases • Small cells with irregular nuclei (centrocyte-­like) • Flow cytometry: tumor cells express CD5, CD20, and light chain and are negative for CD10 • Immunohistochemistry: CD10 and BCL6 are negative; CD5 and Cyclin D1 are positive •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement • No evidence of MYD88 L265P somatic mutation

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

PEARLS • W  aldenström macroglobulinemia is a clinical term that refers to the presence of IgM paraprotein • LPL is the most common lymphoma associated with Waldenström macroglobulinemia; however, MZL and CLL may also secrete IgM • Alternatively, not all LPLs express IgM and have symptoms related to Waldenström macroglobulinemia (some secrete IgG and rarely IgA) • Cases with atypical morphologic features may benefit the most from MYD88 L265P mutation analysis • Similarly, lack of MYD88 mutations in cases morphologically considered “typical” LPL suggests these cases are better classified as another type of B-­cell lymphoma

Selected References Hamadeh F, MacNamara SP, Aguilera NS, et al. MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma. Mod Pathol. 2015;28(4):564–574. Jiménez C, Sebastián E, Del Carmen Chillón M, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia. Leukemia. 2013;27:1722–1728. Swerdlow SH, Kuzu I, Dogan A, et al. The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing. Virchows Arch. 2016;468(3):259–275. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367:826–833. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom’s macroglobulinemia and related lymphoid neoplasms. Blood. 2013;121:2522–2528. Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-­cell lymphoproliferative disorders using conventional and quantitative allele-­ specific polymerase chain reaction. Blood. 2013;121:2051–2058.

DIFFUSE AGGRESSIVE B-­CELL LYMPHOMA DIFFUSE LARGE B-­CELL LYMPHOMA Clinical Features • The most common subtype of lymphoma •  Heterogeneous disease in terms of morphology, genetics, and biologic behavior • Median age at presentation is 64 years • Slightly more common in Caucasian males • About 60% of patients present with advanced stage disease •  Up to 40% of patients have extranodal disease at presentation

A

B

793

• Gastrointestinal tract is the most common location • M  ay also involve bone, testis, spleen, thyroid, salivary glands, tonsils, skin, uterine cervix, central nervous system, and virtually any other organ • Frequently represents transformation of a less aggressive lymphoma (i.e., CLL/SLL, MZL, FL) • Immunosuppression is an important risk factor • These lymphomas are typically EBV positive • DLBCL is the most common lymphoma in patients with HIV, history of transplant, or primary immunodeficiency •  EBV+ DLBCL, NOS (formerly designated EBV+ DLBCL of the elderly) usually occurs in patients >50 years old and is believed to be associated with senescence of the immune system •  DLBCL is aggressive but is also highly curable with intensive chemotherapy 

Histopathology • Lymph node architecture is effaced by sheets of large lymphoid cells •  Cell size is assessed by comparing a tumor cell to admixed histiocytes or endothelial cells • Tumor cell morphology is variable (Figure 14.25A and B): • Cells with round nuclei, several small nucleoli, and scant cytoplasm (centroblasts) • Cells with round nuclei, one large central nucleolus, and moderate basophilic cytoplasm (immunoblasts) • Cells with bizarre, multilobated nuclei • Medium-­sized cells • Numerous mitoses, apoptotic debris, and necrosis are common findings • T-­cell/histiocyte-­rich large B-­cell lymphoma (THRLBCL) has scattered large tumor cells admixed with numerous reactive small T lymphocytes or histiocytes •  EBV+ DLBCL, NOS overlaps with other EBV+ lymphoproliferative disorders and commonly contains a polymorphous infiltrate with variably sized tumor cells and many admixed reactive cells, associated with necrosis 

Special Stains and Immunohistochemistry •  Tumor cells express B-­ cell antigens CD20, Pax-­ 5, CD79a, Oct-­2, and Bob-­1 • CD30 may be positive but is typically weak and only expressed by a subset of tumor cells • Some cases have aberrant expression of CD5

Figure 14.25  Diffuse large B-­ cell lymphoma (DLBCL).  A, Numerous large cells with vesicular chromatin, irregular nuclei, and one to several nucleoli. B, Sheets of immunoblasts.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

794

Chapter 14  —  Lymph Nodes

• The neoplastic B-cells have variable expression of CD10, Bcl-­2, Bcl-­6, and Mum-­1 • Hans algorithm (CD10, Bcl-­6, Mum-­1) or Choi algorithm (CD10, Bcl-­6, Mum-­1, GCET, FoxP1) are used in most laboratories as a substitute for molecular classification of DLBCL • These methods are not standardized and at this point are only used in a research setting • Positive staining for Bcl-­2 (>50% of tumor cells) and MYC (>40% of tumor cells) defines the group of “double-­expressers” with inferior outcome • Proliferative fraction with Ki67 immunostain is high at >40% • EBV+ DLBCL, NOS: in situ hybridization for EBER stains the large neoplastic cells; these cells usually coexpress Mum-­1 and are negative for CD10 and Bcl-­6 • THRLBCL: B-­cell antigens highlight a small number of large atypical cells, whereas the small lymphocytes correspond to CD3+ T-cells •  Primary mediastinal large B-­ cell lymphoma (PMLBL) tumor cells express CD30 in >80% and CD23 and PD-­ L1/PD-­L2 in ∼70% of the cases 

Other Techniques for Diagnosis • Flow cytometry: may be insensitive to the presence of large tumor cells •  Cytogenetics: typically shows a highly complex karyotype •  Presence of c-­ MYC translocation is an important independent risk factor for poor outcome • Cases with c-­MYC translocation may have a concurrent IgH-­ BCL2 translocation or BCL6 break (double-­ hit lymphoma); these cases have a poor prognosis • PMLBL cases have gains and amplifications at chromosome 9p21.1 (JAK2/PDCL1 locus) in up to 75% of the cases • PCR: monoclonal IgH gene rearrangement •  Next generation sequencing demonstrates common mutations in KMT2D, PIM1, MYD88, B2M, TP53, TNFRSF14, and EZH2 genes • MYD88 mutation is extremely common in several extranodal types of DLBCL including primary testicular DLBCL, primary DLBCL of the central nervous system, primary cutaneous DLBCL leg type, and primary breast DLBCL • Constitutive activation of the JAK-­STAT and NF-­kB signaling pathways, including TNFAIP3, SOCS1, and PTNP1 mutations, are hallmarks of PMBL • Gene expression profiling classified DLBCL into two groups: germinal center type (superior outcome) and activated B-cell type (poor prognosis) •  Various panels of immunohistochemical markers have been proposed to substitute for DNA microarrays; none has been proven to be entirely concordant • There are several proposed genetic classification systems for DLBCL based on deep sequencing of DLBCL genomes • For now, there is no consensus regarding a preferred model nor clear evidence of advantages over current methods 

Differential Diagnosis Reactive Lymph Node with Immunoblastic Proliferation  • Benign immunoblasts are scattered and do not form confluent sheets • Immunoblasts express CD30 and are negative for CD15 • Other features of reactive lymph node are unfailingly present (preserved architecture, follicular hyperplasia, paracortical hyperplasia, etc.) • No evidence of B-­cell clonality with flow cytometry, cytogenetics, or PCR  Small B-­Cell Lymphoma  •  CLL may have large expanded proliferation centers, and distinction with DLBCL (Richter transformation) is occasionally difficult • FL has follicular architecture, highlighted by CD21 and CD23 immunostains •  MZL and LPL frequently contain scattered large transformed lymphoid cells; these do not form confluent sheets  Mantle Cell Lymphoma, Pleomorphic Variant  • Neoplastic cells express CD5, Cyclin D1, and SOX11 •  Conventional karyotype and FISH: t(11;14); IGH/ CCND1 gene rearrangement  Burkitt Lymphoma  • Tumor cells are medium sized, not large • Starry-­sky pattern due to very high mitotic rate • Ki67 proliferation rate is close to 100% • Characteristic immunophenotype: CD10+, Bcl-­6+, Bcl-­ 2−, and Mum1− •  Conventional karyotype and FISH: simple karyotype with evidence of c-­MYC translocation • “Gray-­zone” lymphomas exist (see section on “High-­ Grade B-­Cell Lymphoma”)  Lymphoblastic Lymphoma  • Tumor cells have finely dispersed chromatin and small nucleoli (DLBCL cells have vesicular chromatin) •  Immunophenotype is different from DLBCL with expression of immature markers CD34 and TdT • B-­lymphoblastic lymphoma cells express CD10, Pax-­5, and CD79a; they lack CD20 and light chain expression • T-­lymphoblastic lymphoma cells express CD1a and CD99; they variably are CD4+/CD8+, CD4−/CD8−, or rarely express only CD4 or CD8  Anaplastic Large Cell Lymphoma  • May morphologically mimic anaplastic DLBCL • Immunophenotype is different from DLBCL with lack of B-­cell antigen expression • DLBCL cells may rarely express CD30 or ALK1 • No evidence of a monoclonal B-­cell population by flow cytometry or PCR  Classical Hodgkin Lymphoma  • May morphologically mimic anaplastic DLBCL •  CHL contains Reed-­ Sternberg cells admixed with numerous reactive inflammatory cells • Reed-­Sternberg cells are usually scattered and do not form confluent sheets (exception: syncytial variant of nodular sclerosis [NS] CHL)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

• Immunophenotype is different from DLBCL, with expression of CD30, CD15, weak Pax-­5, and lack of CD20 • Reed-­Sternberg cells express either Oct-­2 or Bob-­1, but not both • “Gray-­zone” lymphomas with intermediate morphology and immunophenotype do, however, exist, especially in the mediastinum  Nodular Lymphocyte-­Predominant Hodgkin Lymphoma  • Typically present as a localized lymphadenopathy in a young male • May have a similar appearance to THRLBCL • THRLBCL may represent disease progression in patients with known NLPHL • CD21 and CD23 help highlight the expanded nodular architecture in NLPHL • Large neoplastic cells express CD20, Pax-­5, CD79a, and Bcl-­6 and are ringed by CD3+, CD57+, and PD-­1+ T lymphocytes • About 50% of cases have EMA expression • At present, an overlap between the two entities cannot be entirely excluded  Metastatic Neoplasm  • The patient usually has a history of a preexisting neoplasm (but not always) • Morphologic mimics include poorly differentiated carcinoma, melanoma, germ cell tumor, and sarcoma • An extensive panel of immunohistochemical stains is required for diagnosis •  CD45, CD20, Pax-­ 5, and CD3 are negative in the large tumor cells •  Neoplastic cells may express cytokeratins, S-­ 100, HMB-­45, MITF1, CD99, Fli1, PLAP, and Oct-­4  Myeloid Sarcoma  • The patient usually has a history of preexisting acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm (but not always) • May appear morphologically identical to DLBCL • Immunophenotype is very different from DLBCL, with lack of B-­cell antigen expression • Tumor cells express blast and myeloid cell markers: CD34, CD117, MPO, lysozyme, CD33, CD68, and CD43 • No evidence of a monoclonal B-­cell population by flow cytometry or PCR PEARLS • N  umerous immunohistochemical markers have been proposed for use as prognostic indicators; most are being studied in a research setting and are not used in routine clinical practice • Expression of CD30 in DLBCL may become clinically important with increasing use of anti-­CD30 antibody-­drug conjugate brentuximab vedotin • Rare cases have features intermediate between DLBCL and Burkitt lymphoma (BL); these are classified within the group of “high-­grade B-­cell lymphoma” in the 2008 World Health Organization (WHO) classification of hematopoietic tumors • While there has been a significant effort in genomic investigation and classification of DLBCL, none of these tests are currently part of routine practice

795

Selected References Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–690. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-­cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009;15:5494. Hong JY, Yoon DH, Suh C, et al. EBV-­positive diffuse large B-­cell lymphoma in young adults: is this a distinct disease entity? Ann Oncol. 2015;26(3):548–555. Hu S, Xu-­Monette ZY, Balasubramanyam A, et al. CD30 expression defines a novel subgroup of diffuse large B-­cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-­ CHOP consortium program study. Blood. 2013;121:2715–2724. Hu S, Xu-­Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-­ cell subtype of diffuse large B-­cell lymphoma and demonstrates high-­risk gene expression signatures: a report from the International DLBCL Rituximab-­CHOP consortium program. Blood. 2013;121(20):4021– 4031. Hung SS, Meissner B, Chavez EA, et al. Assessment of capture and amplicon-­based approaches for the development of a targeted next-­ generation sequencing pipeline to personalize lymphoma management. J Mol Diagn. 2018;20(2):203–214. Mottok A, Hung SS, Chavez EA, et al. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-­cell lymphoma. Blood. 2019;134(10):802–813. Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-­cell lymphoma in the RICOVER-­60 trial of the DSHNHL. Blood. 2010;116:4916–4925. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481–494. e15. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396– 1407.

LYMPHOBLASTIC LYMPHOMA Clinical Features • T-­lineage lymphoblastic lymphoma (T-­LBL) constitutes ∼90% of nodal cases; the remainder are B-­LBL • The majority of patients are children and young adults • Patients with T-­LBL present with cervical, supraclavicular, and axillary lymphadenopathy, or with a bulky anterior mediastinal mass associated with pleural effusions • Patients with B-­LBL present with involvement of lymph nodes and extranodal sites (bone, skin, gonads, central nervous system [CNS], other) • About 50% of patients develop a leukemic phase with bone marrow involvement • Children with T-­LBL have outcomes similar to those for children with B-­LBL • Among adults, T-­LBL has a more favorable outcome than B-­lineage LBL 

Histopathology • Lymph node architecture is effaced with a diffuse or, rarely, paracortical neoplastic infiltrate (Figure 14.26) • Tumor cells range from small to large and have finely dispersed chromatin with one to several small nucleoli • Numerous mitotic figures may be seen 

Special Stains and Immunohistochemistry • B-­LBL cells express CD34, TdT, Pax-­5, CD79a, and CD10; they usually lack CD20 and light chain expression •  Greater than 90% of T-­ LBL cases express TdT, CD2, CD3, CD5, and CD7

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

796

Chapter 14  —  Lymph Nodes

Thymoma  • Distinction from a T-­cell rich thymoma can be a challenge in a case of a small biopsy from an anterior mediastinal mass • Thymomas typically occur in middle-­aged adults •  Characteristic lobular appearance with separating fibrous bands • Immunohistochemistry for cytokeratin and EMA highlights the neoplastic thymic epithelial architecture • Spindle epithelial cells may express CD20 •  Lymphoid component consists of TdT-­ positive T lymphoblasts • Flow cytometry: thymoma has different populations of maturing T-cells, whereas LBL cases form tight clusters and may show loss of pan T-­cell antigens or aberrant antigen expression  Figure 14.26  Lymphoblastic lymphoma.  Sheets of large cells with fine chromatin and scant cytoplasm efface the lymph node architecture.



• Most cases also express CD1a, CD99, and CD43 • CD10 is seen in 40% of cases • CD34 is seen in ∼20% of cases •  Tumor cells are predominantly double positive for CD4 and CD8, whereas a minority of cases are double negative; rare cases express only CD4 or CD8 

Other Techniques for Diagnosis • Flow cytometry: immature B or T lymphocytes, which may have aberrant expression of myeloid antigens CD13, CD33, or CD117 • Cytogenetics: >50% of cases have various abnormalities •  PCR: monoclonal IgH gene (B-­ LBL) or TCR gamma gene rearrangement (T-­ LBL); many cases have both rearrangements •  Next generation sequencing: 50% to 60% of T-­ LBLs have activating mutations of NOTCH1 gene 

Metastatic Neoplasm  • The patient usually has a history of a preexisting neoplasm (but not always) •  Morphologic mimics include small round blue cell tumors (neuroblastoma, alveolar rhabdomyosarcoma, Ewing sarcoma) • A panel of immunohistochemical stains will reveal that the metastatic malignancy is of nonlymphoid origin and help pinpoint the precise etiology • CD45, CD34, TdT, and B-­and T-­cell markers are negative in the tumor cells •  Neoplastic cells may express CD99, Fli1, chromogranin, synaptophysin, neuron-­ specific enolase, MyoD1, myogenin, or desmin •  Conventional karyotype and FISH: characteristic translocations 

Diffuse Large B-­Cell Lymphoma  • Tumor cells are large and have vesicular chromatin • Immunophenotype is very different from LBL, with a lack of immature markers CD34 and TdT and strong expression of CD20 •  Flow cytometry: neoplastic B-cells show light chain restriction 

Myeloid Sarcoma  • The patient usually has a history of preexisting acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm (but not always) • The blasts usually have more abundant eosinophilic cytoplasm, compared to LBL •  Immunophenotype is very different from LBL, with expression of myeloid blast markers CD34, CD117, MPO, lysozyme, CD68, and lack of B-­or T-­cell antigens • Occasionally myeloid sarcoma (MS) cells may express TdT, CD4, CD7, CD43, Pax-­5, or CD79a • Cytogenetic analysis may show monosomy 7, trisomy 8, t(8;21) translocation, and other abnormalities common in myeloid disorders 

Burkitt Lymphoma  •  May be morphologically identical with very high mitotic rate • Lacks immature markers CD34 and TdT and has strong expression of CD20 • A large subset of cases expresses EBV •  Flow cytometry: neoplastic B-cells show light chain restriction •  Conventional karyotype and FISH: t(8;14); c-­ MYC translocation is characteristic 

Indolent T-­Lymphoblastic Proliferation  • Rare reports of chronic proliferation of polyclonal precursor T lymphoblasts requiring no therapy • Associated with other diseases (Castleman disease, follicular dendritic cell sarcoma, AITL, carcinoma) • Normal lymph node architecture is retained •  TdT-­ positive lymphoblasts are typically scattered or, rarely, form focal tumor-­like sheets •  PCR: no evidence of monoclonal TCR gamma gene rearrangement

Differential Diagnosis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

PEARLS • L BL and acute lymphoblastic leukemia are parts of a disease spectrum; therefore, the WHO classification of hematopoietic tissues advocated the unifying term “B (or T) lymphoblastic leukemia/lymphoma” • The term LBL may be used if the disease is confined to the lymph node with minimal involvement of peripheral blood and bone marrow • Many clinical protocols use the threshold of >25% bone marrow blasts, with or without a mass lesion for diagnosis of lymphoblastic leukemia • B-­LBL and BL may have a nearly identical morphology and immunophenotype; presence of immaturity and lack of light chain expression points toward B-­LBL

Selected References Li S, Juco J, Mann KP, Holden JT. Flow cytometry in the differential diagnosis of lymphocyte-­rich thymoma from precursor T-­cell acute lymphoblastic leukemia/lymphoblastic lymphoma. Am J Clin Pathol. 2004;121:268–274. Lin P, Jones D, Dorfman DM, et al. Precursor B-­cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement. Am J Surg Pathol. 2000;24:1480–1490. Loghavi S, Kutok JL, Jorgensen JL. B-­acute lymphoblastic leukemia/ lymphoblastic lymphoma. Am J Clin Pathol. 2015;144(3):393–410. Ohgami RS, Zhao S, Ohgami JK, et al. TdT + T-­lymphoblastic populations are increased in Castleman disease, in association with follicular dendritic cell tumors, and in angioimmunoblastic T-­cell lymphoma. Am J Surg Pathol. 2012;36:1619–1628. Patel JL, Smith LM, Anderson J, et al. The special stains and immunohistochemistry of T-­ lymphoblastic lymphoma in children and adolescents: a Children’s Oncology Group Report. Br J Haematol. 2012;159:454–461. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–271. You MJ, Medeiros LJ, Hsi ED. T-­lymphoblastic leukemia/lymphoma. Am J Clin Pathol. 2015;144(3):411–422.

797

• Sporadic BL: 30% of pediatric lymphomas in the United States and Europe • Median age of 11 years in children and 30 years in adults • Male predominance • Typically extranodal: involves distal ileum, stomach, kidney, testis, ovary, and the like • Lymphadenopathy is generally localized • Immunodeficiency-­associated variant is primarily seen in persons with HIV infection • Presents in patients with a relatively high CD4 count and no opportunistic infections • Rate of BL in the HIV-­positive population has not decreased with the advent of highly active antiviral therapy (HAART) •  More often involves lymph nodes, bone marrow, and CNS • BL is an extremely aggressive but a highly curable lymphoma; it requires intensive chemotherapy 

Histopathology • Lymph node architecture is effaced by a diffuse infiltrate of monotonous medium-­sized cells • Numerous mitoses and necrosis may be seen • Abundant apoptotic debris and scattered tingible-­body macrophages create a starry-­ sky appearance (Figure 14.27A) 

Special Stains and Immunohistochemistry

BURKITT LYMPHOMA

• Neoplastic lymphocytes express B-­cell antigens and are positive for CD10 and Bcl-­6 • MYC protein is strongly expressed in most cells • Tumor cells do not express Bcl-­2 or TdT •  Ki67 proliferation rate is close to 100% (see Figure 14.27B) • In situ hybridization for EBER is strongly diffusely positive in virtually all endemic cases and in a large subset of sporadic and immunodeficiency-­associated cases 

Clinical Features

Other Techniques for Diagnosis

• Three distinct clinical forms of BL are recognized: endemic (African), sporadic, and immunodeficiency associated • Endemic BL: 30% to 50% of all childhood cancer in equatorial Africa • Median age of 6 years • Typically presents as an abdominal mass or a jaw tumor

• Flow cytometry: mature B lymphocytes with light chain immunoglobulin restriction, expression of CD10, and no aberrant expression of myeloid antigens • Conventional karyotype and FISH (break-­apart probe): MYC gene rearrangement (chromosome 8q24) in >90% of cases •  A simple karyotype with few or no abnormalities besides MYC rearrangement

A

B

Figure 14.27  Burkitt lymphoma.  A, Lymph node architecture is effaced with a starry-­sky pattern. B, Ki67 immuno­ stain is positive in the majority of the tumor cells.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

798

Chapter 14  —  Lymph Nodes

• No evidence of BCL2 or BCL6 rearrangement • PCR: monoclonal IgH gene rearrangement •  Next generation sequencing: frequent mutations in the transcription factor 3 (TCF3) or ID3, its negative regulator 

Differential Diagnosis Diffuse Large B-­Cell Lymphoma  • Tumor cells are large and more pleomorphic with a heterogeneous appearance • Typically lacks the starry-­sky pattern • Immunophenotype may occasionally be similar to BL, but the Ki67 proliferation rate is not as high (80% of cases • Other common ALK abnormalities include t(1;2) and inv(2) •  Conventional cytogenetics and FISH in ALCL, ALK-­negative: •  t(6;7) (p25.3;q32.3) translocation involving the DUSP22 gene occurs in 30% of cases • TP63 rearrangement occurs in ∼8% of cases • PCR: monoclonal TCR gamma gene rearrangement 

Differential Diagnosis Classical Hodgkin Lymphoma  • Reed-­Sternberg cells express Pax-­5 and CD15 (negative in ALCL) in addition to CD30 • Many cases are EBV-­positive • Reed-­Sternberg cells do not express T-­cell antigens or EMA •  A polymorphous inflammatory background is not a feature of ALCL  Diffuse Large B-­Cell Lymphoma  •  Very rare cases of ALK-­ positive, EMA-­ positive DLBCL have been described; they express CD138 and cytoplasmic immunoglobulin and lack CD30 and T-­cell antigens • Some cases of anaplastic DLBCL have similar morphology to ALCL and are CD30-­positive; they express B-­cell antigens and lack T-­cell antigens • CD30 is partial and weak  Peripheral T-­Cell Lymphoma, Not Otherwise Specified  • Some cases have pleomorphic tumor cells with CD30 positivity • Loss of T-­cell antigens is more pronounced in ALCL • EMA is rarely expressed by PTCL, NOS • Studies have shown that ALCL, ALK– is most likely a separate entity from PTCL, NOS • They may be difficult to distinguish in some cases  Myeloid Sarcoma  • Patients with MS often have a history of preexisting acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm (but not always) • Lymph node architecture is effaced by sheets of blasts • Immunophenotypic expression of blast and myeloid markers CD34, CD117, MPO, lysozyme, and lack of EMA and T-­cell antigens •  MS cells express CD43 and may frequently have aberrant expression of CD4 or CD7 • The expression of CD30 is exceptional in MS and largely restricted to the rare megakaryocytic variant •  Cytogenetic analysis may show monosomy 7, trisomy 8, t(8;21) translocation, and other abnormalities common in myeloid disorders; ALK rearrangement is negative  Metastatic Neoplasm  • Metastatic carcinoma and melanoma may have similar morphologic features and a cohesive growth pattern with sinusoidal spread

• Immunohistochemical staining is required to make the diagnosis • Carcinomas express cytokeratins • Melanomas express S-­100 protein, HMB-­45, and Melan-­A • Mast cell sarcomas express mast cell tryptase • However, it is important to remember that CD30 can be positive in nonhematologic malignancies, including germ cell tumors and aggressive mast cell neoplasms PEARLS • C  D30 is a useful marker for workup of a poorly differentiated neoplasm in the lymph node, as ALCL may be negative for CD45 and CD3 • CD30 is an activation antigen and may be expressed by reactive immunoblasts • Immunohistochemistry for ALK is sensitive and specific; thus, genetic confirmation of ALK gene rearrangement is not necessary • Gene expression profiling studies have demonstrated different clustering patterns for ALCL, ALK+; ALCL, ALK–; and PTCL, NOS

Selected References Bovio IM, Allan RW. The expression of myeloid antigens CD13 and/ or CD33 is a marker of ALK + anaplastic large cell lymphomas. Am J Clin Pathol. 2008;130:628–634. King RL, Dao LN, McPhail ED, et al. Morphologic features of ALK-­ negative anaplastic large cell lymphomas with DUSP22 rearrangements. Am J Surg Pathol. 2016;40(1):36–43. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-­negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):1473–1480. Piva R, Agnelli L, Pellegrino E, et al. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-­ cell lymphoma within peripheral T-­ cell neoplasms. J Clin Oncol. 2010;28:1583–1590. Salaverria I, Beà S, Lopez-­Guillermo A, et al. Genomic profiling reveals different genetic aberrations in systemic ALK-­positive and ALK-­negative anaplastic large cell lymphomas. Br J Haematol. 2008;140:516–526. Savage KJ, Harris NL, Vose JM, et al. ALK-­anaplastic large-­cell lymphoma is clinically and immunophenotypically different from both ALK + ALCL and peripheral T-­ cell lymphoma, not otherwise specified: report from the international peripheral T-­cell lymphoma project. Blood. 2008;111:5496–5504.

PERIPHERAL T-­CELL LYMPHOMA, NOT OTHERWISE SPECIFIED Clinical Features • The most common subtype of T-­cell lymphoma • Occurs in the elderly with median age of 60 years and a male predominance (2:1) • Most patients present with advanced disease and have B symptoms; generalized lymphadenopathy; and bone marrow, liver, spleen, or extranodal involvement •  Highly aggressive lymphoma with poor response to therapy 

Histopathology • Tumor cell morphology is very heterogeneous •  Sheets of medium-­ sized or large, pleomorphic, monotonous-­appearing tumor cells •  Polymorphous infiltrate with small lymphocytes, eosinophils, plasma cells, and histiocytes (Figure 14.31)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

803

• Very rare cases of PTCL, NOS with true Reed-­Sternberg cells of B-­cell lineage have also been reported •  All of these cases had T-­ cell atypia and abnormal T-­cell immunophenotype, allowing for the correct diagnosis  Diffuse Large B-­Cell Lymphoma  • Immunophenotype is very different from PTCL with expression of B-­cell antigens and lack of T-­cell antigens • PCR: evidence of IgH gene rearrangement and lack of TCR gamma gene rearrangement 

Figure 14.31  Peripheral T-­cell lymphoma (PTCL), not otherwise specified (NOS).  Small and large atypical lymphoid cells are admixed with numerous epithelioid histiocytes.

• Clear cells and Reed-­Sternberg–like cells may be seen • Paracortical, follicular, or diffuse involvement of lymph node • High-­endothelial venules may be increased • One distinct variant is recognized •  Lymphoepithelioid (Lennert lymphoma) consists of small neoplastic cells, which may be obscured by numerous epithelioid histiocytes •  Follicular and T-­ zone PTCL have been previously grouped within PTCL, NOS but are now in the separate category of lymphoma of follicular T-­ helper phenotype 

Special Stains and Immunohistochemistry • CD45 positive tumor cells • Frequent loss of T-cell antigens CD5 and CD7 • Usually CD4+ and CD8− tumor cells •  Lymphoepithelioid lymphoma is characterized by CD8+ cells in the majority of cases • High Ki67 proliferation rate • Some cases have weak/focal expression of CD30 • The expression of TBX21 and GATA3 has been proposed as a basis for subclassification of PTCL, NOS • Reed-­Sternberg–like cells typically express EBV 

Other Techniques for Diagnosis • Conventional cytogenetics: complex karyotype • PCR: evidence of TCR gamma gene rearrangement • Gene expression profiling: studies identified 2 groups of PTCL, NOS characterized by different expression of TBX21/T-­BET or GATA3 transcription factors • PTCL-­GATA3 group has higher genomic complexity and inferior overall survival • PTCL-­TBX21 group has superior overall survival 

Differential Diagnosis Classical Hodgkin Lymphoma  • Reed-­Sternberg cells of CHL express Pax-­5 and CD15 in addition to CD30 • Reed-­Sternberg cells of CHL do not express CD45 or T-­cell antigens

Reactive Paracortical Hyperplasia  • Frequent differential diagnosis in T-­zone-­type PTCL • No morphologic atypia • T-cells do not show antigen loss • Similar number of CD4+ and CD8+ T lymphocytes • No evidence of T-­cell clonality by PCR  Angioimmunoblastic T-­Cell Lymphoma  • Characteristic morphology with a polymorphous paracortical infiltrate composed of small to medium-­sized atypical lymphocytes with moderate pale cytoplasm admixed with numerous reactive small lymphocytes, immunoblasts, eosinophils, plasma cells, and histiocytes • Paracortical vascular proliferation •  Presence of expanded follicular dendritic cell meshworks is not a feature of PTCL, NOS  Anaplastic T-­Cell Lymphoma  • PTCL, NOS may have pleomorphic tumor cells with CD30 positivity • Loss of T-­cell antigens is more pronounced in ALCL • EMA is rarely expressed by PTCL, NOS, and ALK1 is always negative • Studies have shown that ALCL, ALK– is most likely a separate entity from PTCL, NOS PEARLS • T  umors with T-follicular helper phenotype (defined as presence of ≥2 markers) are now excluded from this category • Similar to the DLBCL, gene expression profiling studies allowed for molecular classification of PTCL, NOS into two prognostic groups: GATA3+ and TBX21+ • Based on morphology, PTCL-­GATA3 positive group is more uniform, with sheets of monotonous tumor cells, minimal inflammatory background, CD4 expression, and lack of cytotoxic markers • Both immunohistochemical algorithms and morphologic evaluation may serve as surrogates for gene expression profiling analysis • PTCL, NOS is still a diagnosis of exclusion and should only be made if all other, better-­defined subtypes of T-­cell lymphoma have been excluded

Selected References Amador C, Greiner TC, Heavican TB, et al. Reproducing the molecular subclassification of peripheral T-­cell lymphoma-­NOS by immunohistochemistry. Blood. 2019;134(24):2159–2170.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

804

Chapter 14  —  Lymph Nodes

Heavican TB, Bouska A, Yu J, et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-­cell lymphoma. Blood. 2019;133(15):1664–1676. Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-­cell lymphoma Blood. 123(19):2915–2923. Nicolae A, Pittaluga S, Venkataraman G, et al. Peripheral T-­cell lymphomas of follicular T-­helper cell derivation with Hodgkin/ReedSternberg cells of B-­cell lineage: both EBV-­positive and EBV-­negative variants exist. Am J Surg Pathol. 2013;37:816–826. Piccaluga PP, Fuligni F, De Leo A, et al. Molecular profiling improves classification and prognostication of nodal peripheral T-­cell lymphomas: results of a phase III diagnostic accuracy study. J Clin Oncol. 2013;31:3019–3025. Wang T, Feldman AL, Wada DA, et al. GATA-­3 expression identifies a high-­risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014;123(19):3007–3015.

HODGKIN LYMPHOMA NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA Clinical Features • Constitutes ∼5% of all Hodgkin lymphoma cases •  Presents in young patients with a strong male predominance • Most patients have localized cervical, axillary, or inguinal lymphadenopathy 

Histopathology • Nodular proliferation of numerous small lymphocytes admixed with scattered large atypical-­appearing cells (Figure 14.32A) • Tumor cells have one large folded or multilobated nucleus with multiple nucleoli • Large cells are called LP (lymphocyte predominant) cells, L&H (lymphocytic and histiocytic) cells, or popcorn cells (see Figure 14.32B)

A

Figure 14.32  Nodular lymphocyte predominant Hodgkin lymphoma.  A, Lymph node architecture is effaced by a nodular proliferation of lymphocytes. B, LP or popcorn cells. C, PD-­1 immunostain shows T-­cell rosettes around the neoplastic large cells.

•  Some nodules may have a rim of epithelioid histiocytes • Eosinophils, neutrophils, fibrosis, or necrosis are not features of NLPHL •  Many cases have a peripheral rim of uninvolved lymph node tissue • Rare cases are predominantly diffuse and they can be confused with THRLBCL 

Special Stains and Immunohistochemistry • The nodules are composed predominantly of small B lymphocytes • The neoplastic large cells express CD45 and B-­cell antigens: CD20, Pax-­5, CD79a, Oct-­2, and Bob-­1 • Bcl-­6 and EMA are positive in the majority of cases • Large cells are negative for CD30, CD15, fascin, and EBV • Increased number of CD3+, CD4+, CD57+, and PD-­1+ T lymphocytes in the nodules; these cells may rosette around the LP cells (see Figure 14.32C) •  CD21 and CD23 highlight large expanded follicular dendritic cell meshworks in the nodules 

Other Techniques for Diagnosis • Flow cytometry is insensitive to the presence of LP cells but may detect a population of double-­positive CD4+/ CD8+ T lymphocytes • Conventional cytogenetics: may show various abnormalities in a subset of cases • PCR: no evidence of IgH gene rearrangement due to the scarcity of the tumor cells 

Differential Diagnosis Progressive Transformation of Germinal Centers  • PTGC is a focal finding in a lymph node with reactive follicular hyperplasia • PTGC does not contain LP cells

B

C

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

• T-cells may be increased within the nodules but are scattered, do not form aggregates, and do not rosette • EMA highlights the LP cells and is negative in PTGC • The relationship between the two entities is complex and incompletely understood, as they may coexist or precede each other  Classic Hodgkin Lymphoma, Lymphocyte-­Rich Type  • Both lymphomas have a nodular growth pattern • Reed-­Sternberg cells have a different immunophenotype from LP cells • CD45−, CD20−, Pax-­5 dim+, CD30+, and CD15+ • EBV is frequently expressed • Either Oct-­2 or Bob-­1 are positive, but not both  T-Cell/Histiocyte-­Rich Large B-­Cell  • THRLBCL is an aggressive lymphoma with generalized lymphadenopathy, usually present in elderly patients • The infiltrate is diffuse, not nodular, and completely effaces the lymph node architecture • CD21 and CD23 are negative • Small cells are almost exclusively CD3+ T lymphocytes • Immunophenotype of the large cells may be very similar to NLPHL • THRLBCL lacks PD-­1+ T-­cell rosettes around the large tumor cells • Flow cytometry and PCR are more likely to detect a monoclonal B-­cell population • THRLBCL may represent a variant or a form of disease progression in patients with known NLPHL PEARLS • E arly stage NLPHL may be curatively treated with excision of the involved lymph node • Frequent relapses and recurrences • Patients are predisposed to develop DLBCL, sometimes 10 to 20 years following the initial presentation

Selected References Al-­Mansour M, Connors JM, Gascoyne RD, et al. Transformation to aggressive lymphoma in nodular lymphocyte-­predominant Hodgkin’s lymphoma. J Clin Oncol. 2010;28:793–799. Biasoli I, Stamatoullas A, Meignin V, et al. Nodular lymphocyte-­predominant Hodgkin lymphoma: a long-­term study and analysis of transformation to diffuse large B-­cell lymphoma in a cohort of 164 patients from the Adult Lymphoma Study Group. Cancer. 2010;116:631–639. Boudova L, Torlakovic E, Delabie J, et al. Nodular lymphocyte predominant Hodgkin lymphoma with nodules resembling T-­ cell/ histiocyte-­ rich B-­ cell lymphoma: differential diagnosis between nodular lymphocyte-­predominant Hodgkin lymphoma and T-­cell/

A

B

805

histiocyte-­rich B-­cell lymphoma. Blood. 2003;102:3753–3758. Cotta CV, Coleman JF, Li S, Hsi ED. Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B-­cell lymphoma: a study of six cases concurrently involving the same site. Histopathology. 2011;59:1194–1203. Fan Z, Natkunam Y, Bair E, et al. Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol. 2003;27:1346–1356. Nam-­Cha SH, Roncador G, Sanchez-­Verde L, et al. PD-­1, a follicular T-­ cell marker useful for recognizing nodular lymphocyte-­predominant Hodgkin lymphoma. Am J Surg Pathol. 2008;32:1252–1257. Rahemtullah A, Reichard KK, Preffer FI, et al. A double-­positive CD4 + CD8 + T-­cell population is commonly found in nodular lymphocyte predominant Hodgkin lymphoma. Am J Clin Pathol. 2006;126:805– 814.

CLASSIC HODGKIN LYMPHOMA, NODULAR SCLEROSIS TYPE Clinical Features • Most common subtype of CHL in the United States and Europe (∼70% of cases) • Peak incidence is between 15 and 34 years of age • The majority of patients present with painless localized peripheral lymphadenopathy, typically involving the cervical region •  About 80% of the patients have mediastinal involvement • Highly curable lymphoma with an excellent prognosis 

Histopathology • Lymph node architecture is effaced •  Nodules composed of Hodgkin and Reed-­ Sternberg cells (HRS) admixed with numerous reactive small lymphocytes, eosinophils, histiocytes, plasma cells, and, occasionally, neutrophils (Figure 14.33A) • Diagnostic Reed-­Sternberg cells are large with abundant cytoplasm and at least two nuclear lobes with a prominent nuclear membrane, vesicular chromatin, and eosinophilic macronucleoli (see Figure 14.33B) • Hodgkin cells: mononuclear variants • Wreath cells: multinucleated variants • Mummified cells: variants with condensed cytoplasm and pyknotic hyperchromatic nuclei • Lacunar cells: formalin fixation-­related artifact that causes retraction of the cytoplasmic membrane, giving the appearance of a lacunar space around the nucleus and the cytoplasm • The nodules are separated by broad bands of collagen • Necrosis and granulomas may be seen 

Figure 14.33  Classical Hodgkin lymphoma, nodular sclerosis type.  A, Polymorphous proliferation of small lymphocytes, eosinophils, neutrophils, and numerous lacunar cells. B, Classic Reed-­Sternberg cell and lacunar cells.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

806

Chapter 14  —  Lymph Nodes

Special Stains and Immunohistochemistry •  The HRS cells express Pax-­ 5 (characteristically dim), CD30, and CD15 in the majority of cases (∼80%) and are negative for CD45 and CD20 • Weak CD20 in a subset of the tumor cells may be seen in 30% to 40% of cases • Mum-­1 is consistently positive • EMA is negative • Tumor cells express Oct-­2 or Bob-­1, but not both • In situ hybridization for EBER is positive in 10% to 40% of cases 

Other Techniques for Diagnosis •  Flow cytometry: normal B and T lymphocytes (noncontributory) • Conventional cytogenetics: may show various abnormalities in a subset of cases • PCR: no evidence of IgH gene rearrangement due to the scarcity of the tumor cells 

Differential Diagnosis Classical Hodgkin Lymphoma, Mixed Cellularity Type  • The differential diagnosis arises when the bands of sclerosis are not well developed or are not appreciated • CHL is typically not subtyped on small biopsies • EBV is expressed much more frequently  Nodular Lymphocyte Predominant Hodgkin Lymphoma  • Both lymphomas have a nodular growth pattern • LP cells have a different immunophenotype than HRS cells • CD45+, CD20+, Pax-­5 strong+, CD30+, and CD15− • EBV is consistently negative • Both Oct-­2 and Bob-­1 are positive  Diffuse Large B-­Cell Lymphoma (DLBCL)  • Syncytial variant of CHL has confluent aggregates of lacunar cells, which may morphologically mimic anaplastic DLBCL • Numerous reactive inflammatory cells are not a feature of DLBCL • Immunophenotype is usually very different from CHL, with expression of CD45, CD20, strong Pax-­5, absent or weak/partial CD30, and lack of CD15 • DLBCL cells express both Oct-­2 and Bob-­1 • “Gray-­zone” lymphomas with intermediate morphology and immunophenotype are well recognized, especially in the mediastinum  Anaplastic Large Cell Lymphoma  • No evidence of nodules or dense fibrosis •  A polymorphous inflammatory background is not a feature of ALCL • ALCL tumor cells express CD30 but are negative for Pax5 and CD15 • EBV is consistently negative • HRS cells do not express T-­cell antigens or EMA  Peripheral T-­Cell Lymphoma  • Some cases of PTCL consist of large Reed-Sternberg–like cells; these cells express T-­cell antigens and are negative for Pax-­5

• PTCL may also contain scattered Reed-­Sternberg–like B immunoblasts; these cells express CD45, CD20, strong Pax-­5, and CD30, and are negative for CD15 • Very rare cases of PTCL with true Reed-­Sternberg cells have also been reported • All PTCL cases have T-­cell atypia and abnormal T-­cell immunophenotype • PCR may be useful in difficult cases: monoclonal TCR gamma gene rearrangement  Infectious Mononucleosis  • Even though immunoblasts in IM may appear atypical, most do not resemble HRS cells • Most IM immunoblasts are CD45+, CD20+, strong Pax-­ 5+ B-cells •  Some immunoblasts express CD30; they are always CD15 negative • EBER highlights numerous small and large lymphocytes  Reactive Lymph Node  • A mistaken diagnosis of benign lymph node may occasionally be rendered on small biopsies, where HRS cells are few in number and may be missed • Marked fibrosis frequently causes crush artifact precluding optimal evaluation of HRS cells (most commonly seen in small mediastinoscopy biopsy specimens) •  These cases are usually submitted for frozen section evaluation, where additional tissue should be requested • If the lymph node appears reactive but the biopsy is small and clinical suspicion for CHL is high, rebiopsy should be recommended (especially relevant for fine-­ needle aspiration specimens) • Immunoblasts in reactive lymph node are large but do not have cytologic atypia • No diagnostic Reed-­Sternberg cells •  Immunoblasts express CD30 but are negative for CD15 PEARLS • C  areful morphologic evaluation is paramount to visualize the HRS cells • Avoid ordering CD30 and CD15 in reactive-­appearing lymph nodes without morphologic evidence of diagnostic Reed-­Sternberg cells • CD30 stains benign immunoblasts • CD15 stains neutrophils and histiocytes • The diagnosis of CHL requires a combination of diagnostic Reed-­Sternberg cells and the typical polymorphous inflammatory background • HRS cells are particularly numerous at the periphery of necrotic areas

Selected References Browne P, Petrosyan K, Hernandez A, Chan JA. The B-­cell transcription factors BSAP, Oct-­2, and BOB.1 and the pan-­B-­cell markers CD20, CD22, and CD79a are useful in the differential diagnosis of classic Hodgkin lymphoma. Am J Clin Pathol. 2003;120:767–777. Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin’s lymphoma. Cancer J. 2009;15:129–137. Eberle FC, Salaverria I, Steidl C, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol. 2011;24:1586–1597.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes Harris NL. Shades of gray between large B-­cell lymphomas and Hodgkin lymphomas: differential diagnosis and biological implications. Mod Pathol. 2013;26(suppl 1):S57–S70. Roemer MG, Advani RH, Ligon AH, et al. PD-­L1 and PD-­L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690–2697. Steidl C, Lee T, Shah SP, et al. Tumor-­associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875– 885. Stein H, Marafioti T, Foss HD, et al. Down-­regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood. 2001;97:496–501.

CLASSICAL HODGKIN LYMPHOMA, MIXED CELLULARITY TYPE Clinical Features • Comprises ∼25% of cases of CHL • More frequent in patients with HIV and in developing countries • Median age is 38 years • Marked male predominance (∼70%) • Most patients present with painless localized peripheral lymphadenopathy, typically involving the cervical region • Mediastinal involvement is uncommon • Highly curable lymphoma with an excellent prognosis 

Histopathology • Lymph node architecture is effaced • Diffuse proliferation of HRS cells admixed with numerous reactive small lymphocytes, eosinophils, histiocytes, plasma cells, and neutrophils (Figure 14.34) • No broad bands of collagen • Necrosis and granulomas may be seen 

Special Stains and Immunohistochemistry • HRS cells express Pax-­5 (characteristically dim), CD30, and CD15 in the majority of cases (∼80%), and are negative for CD45 and CD20 • Weak CD20 in a subset of the tumor cells may be seen in 30% to 40% of cases

807

• Mum-­1 is consistently positive • EMA is negative • Tumor cells express Oct-­2 or Bob-­1, but not both • In situ hybridization for EBER is positive in ∼75% of cases 

Other Techniques for Diagnosis •  Flow cytometry: normal B and T lymphocytes (noncontributory) • Conventional cytogenetics: may show various abnormalities in a subset of cases • PCR: no evidence of IgH gene rearrangement due to the scarcity of the tumor cells 

Differential Diagnosis Classical Hodgkin Lymphoma, Nodular Sclerosis Type  •  The differential diagnosis arises when there is focal interstitial fibrosis • No evidence of thick bands of sclerosis • EBV is expressed much less frequently  T-Cell/Histiocyte-­Rich Large B-­Cell Lymphoma  •  Contains rare scattered large neoplastic cells surrounded by numerous reactive small T lymphocytes and histiocytes • Eosinophils, neutrophils, and plasma cells are not features of THRLBCL • Immunophenotype is very different from CHL, with expression of CD45, CD20, strong Pax-­ 5, absent or weak/partial CD30, and lack of CD15 • DLBCL cells express both Oct-­2 and Bob-­1 PEARLS • S ee “Pearls” under “Classical Hodgkin Lymphoma, Nodular Sclerosis Type”

Selected References Browne P, Petrosyan K, Hernandez A, et al. The B-­cell transcription factors BSAP, Oct-­2, and BOB.1 and the pan-­B-­cell markers CD20, CD22, and CD79a are useful in the differential diagnosis of classic Hodgkin lymphoma. Am J Clin Pathol. 2003;120:767–777. Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin’s lymphoma. Cancer J. 2009;15:129–137. Steidl C, Lee T, Shah SP, et al. Tumor-­associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875–885. Stein H, Marafioti T, Foss HD, et al. Down-­regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood. 2001;97:496–501.

CLASSICAL HODGKIN LYMPHOMA, LYMPHOCYTE-­RICH TYPE Clinical Features

Figure 14.34  Classical Hodgkin lymphoma, mixed cellularity type. Small lymphocytes, eosinophils, histiocytes, and Reed-­ Sternberg cells and variants.

• Comprises ∼5% of cases of CHL • Median age is higher than in other subtypes of CHL • Marked male predominance (∼70%) • The majority of patients present with painless localized peripheral lymphadenopathy, typically involving the cervical region • Mediastinal involvement is uncommon • Highly curable lymphoma with an excellent prognosis 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

808

Chapter 14  —  Lymph Nodes

Histopathology See Figure 14.35. • Lymph node architecture is effaced by a nodular proliferation of small lymphocytes • Small regressed germinal centers usually present in the nodules • Scattered HRS cells are present in the nodules • Eosinophils and neutrophils are rare or absent 

Special Stains and Immunohistochemistry •  The HRS cells express Pax-­ 5 (characteristically dim), CD30, and CD15 in the majority of cases (∼80%), and are negative for CD45 and CD20 • Weak CD20 in a subset of the tumor cells may be seen in 30% to 40% of cases • Mum-­1 is consistently positive • EMA is negative • Tumor cells express Oct-­2 or Bob-­1, but not both • Small lymphocytes in the nodules consist of IgD+ mantle cell B-cells • CD21 and CD23 highlight small regressed residual germinal centers • In situ hybridization for EBER is positive in ∼50% of cases 

Other Techniques for Diagnosis •  Flow cytometry: normal B and T lymphocytes (noncontributory) • Conventional cytogenetics: may show various abnormalities in a subset of cases • PCR: no evidence of IgH gene rearrangement due to the scarcity of the tumor cells 

Differential Diagnosis Nodular Lymphocyte-­Predominant Hodgkin Lymphoma  • Both lymphomas have a nodular growth pattern • LP cells have a different immunophenotype from HRS cells • CD45+, CD20+, strong Pax-­5+, EMA+/−, CD30−, and CD15−

• EBV is consistently negative • Both Oct-­2 and Bob-­1 are expressed •  Follicular dendritic cell meshworks are large and expanded, whereas in CHL, lymphocyte-­rich (LR) they are small, round, and tight  Follicular Lymphoma  • Neoplastic cells are a mixture of centrocytes and centroblasts; no HRS cells are seen • Immunophenotype of small lymphocytes in the nodules represents their germinal center origin: CD10+, Bcl-­6+, Bcl-­2+, and IgD− • Flow cytometry always identifies a monoclonal B-­cell population, whereas flow cytometry in CHL shows polyclonal B lymphocytes PEARLS • C  HL, LR is unusual among CHL subtypes in that it does not show the typical polymorphous inflammatory background • Clinical behavior and prognosis appear more similar to NLPHL than to the other subtypes of CHL

Selected References Browne P, Petrosyan K, Hernandez A, et al. The B-­cell transcription factors BSAP, Oct-­2, and BOB.1 and the pan-­B-­cell markers CD20, CD22, and CD79a are useful in the differential diagnosis of classic Hodgkin lymphoma. Am J Clin Pathol. 2003;120:767–777. de Jong D, Bosq J, MacLennan KA, et al. Lymphocyte-­rich classical Hodgkin lymphoma (LRCHL): clinico-­ pathological characteristics and outcome of a rare entity. Ann Oncol. 2006;17:141–145. Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin’s lymphoma. Cancer J. 2009;15:129–137. Shimabukuro-­Vornhagen A, Haverkamp H, Engert A, et al. Lymphocyte-­ rich classical Hodgkin’s lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin’s Study Group Trials. J Clin Oncol. 2005;23:5739–5745. Steidl C, Lee T, Shah SP, et al. Tumor-­associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875– 885.

NONLYMPHOID DISORDERS OF LYMPH NODES LANGERHANS CELL HISTIOCYTOSIS Clinical Features • Wide age range with a peak incidence between 1 and 3 years of age • Localized, multifocal, or disseminated disease with a clonal expansion of Langerhans cells • Lymph node involvement may be the only site of disease or may be part of multisystem disease (usually with skin and bone involvement) • Asymptomatic swelling of cervical, inguinal, mediastinal, or retroperitoneal lymph nodes 

Histopathology

Figure 14.35  Classical Hodgkin lymphoma, lymphocyte-­ rich type.  Nodule with Reed-­Sternberg cells and variants amid numerous small lymphocytes.

• Lymph node architecture is usually preserved with a sinusoidal infiltration • The infiltrate consists of variable numbers of Langerhans cells, eosinophils, neutrophils, and small lymphocytes (Figure 14.36A)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

A

Figure 14.36  Langerhans cell histio­ cytosis.  A, Small lymphocytes, numerous eosinophils, and sheets of Langerhans cells. B, Langerhans cells have irregular folded nuclei with a “coffee bean” appearance.

B

•  Eosinophils may be numerous enough to form microabscesses • The Langerhans cells are large and contain abundant, ill-­defined acidophilic cytoplasm • The nuclei are irregular with an indented, folded, or creased appearance; nucleoli are inconspicuous • Many nuclei exhibit a longitudinal groove resulting in a “coffee-­bean” appearance (see Figure 14.36B) • Numerous multinucleated giant cells and epithelioid histiocytes containing “coffee bean” nuclei may also be present • Phagocytosis is not seen 

Special Stains and Immunohistochemistry • The Langerhans cells express S-­100 protein, langerin, CD45, CD1a, and perinuclear CD68 • S-­100 stains all the cells, whereas only a subset of the tumor cells expresses CD1a and langerin 

Other Techniques for Diagnosis • BRAF V600E mutation has been identified in about 50% of patients with Langerhans cell histiocytosis (LCH) and MAP2K1 mutation in about 25% • Electron microscopy: characteristic Birbeck granules • PCR: approximately 30% of cases have detectable IGH, IGK, or TCR gene rearrangements • Flow cytometry and cytogenetics are noncontributory 

Differential Diagnosis Rosai-­Dorfman Disease  • Abnormal histiocytic cells are larger and have round nuclei with prominent nucleoli • Langerhans cells do not exhibit emperipolesis • Abnormal histiocytic cells express S-­100 and are negative for CD1a and langerin  Sinus Histiocytosis  • Histiocytes do not have characteristic indented, folded, or creased “coffee-­bean” nuclei •  Eosinophils, neutrophils, and plasma cells are not conspicuous • Giant cells are absent •  Reactive histiocytes do not express S-­ 100, CD1a, or langerin  Dermatopathic Lymphadenitis  • May contain numerous Langerhans cells

809

• Paracortical involvement with preserved lymph node architecture; no sinus involvement • Langerhans cells are admixed with small lymphocytes and histiocytes; there is no evidence of eosinophils, neutrophils, or plasma cells PEARLS • L CH is a clonal myeloid malignancy, where the pathologic Langerhans cells are myeloid dendritic cells, and not dendritic cells of skin origin as thought previously • Electron microscopy is rarely used nowadays, and demonstration of Birbeck granules is not required for diagnosis

Selected References Badalian-­Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919–1923. Chakraborty R, Hampton OA, Shen X, et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood. 2014;124(19):3007–3015. Edelweiss M, Medeiros LJ, Suster S, et al. Lymph node involvement by Langerhans cell histiocytosis: a clinicopathologic and immunohistochemical study of 20 cases. Hum Pathol. 2007;38:1463–1469. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-­dendritic cell lineages. Blood. 2016;127(22):2672–2681. Lau SK, Chu PG, Weiss LM. Immunohistochemical expression of langerin in Langerhans cell histiocytosis and non-­Langerhans cell histiocytic disorders. Am J Surg Pathol. 2008;32:615–619. Milne P, Bigley V, Bacon CM, et al. Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-­Chester disease in adults. Blood. 2017;130(2):167–175. Sahm F, Capper D, Preusser M, et al. BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood. 2012;120:2700–2703.

KAPOSI SARCOMA Clinical Features •  Benign vascular neoplasm that most frequently involves the skin but also involves the oral cavity, lungs, gastrointestinal tract, and lymph nodes • AIDS-­epidemic KS: most common form in the United States • KS is an AIDS-­defining condition; it remains the most common neoplasm in this patient population • Lymph node involvement is common and may occur in the absence of mucocutaneous disease • Classic-­Mediterranean: rare in the United States and mostly affects elderly men • Only involves lymph nodes secondarily and generally late in the course of the disease 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

810

Chapter 14  —  Lymph Nodes

Histopathology

PEARLS

See Figure 14.37. • Early lesions are usually observed in or adjacent to the capsule, in the hilum, or, occasionally, in the perinodal adipose tissue • Vascular channels within the lymph node are prominent, are increased in number, and are associated with increased numbers of plasma cells • Over time, these areas may develop the classic histopathologic features of KS, including interwoven fascicles of spindle cells, vascular slits, and extravasated erythrocytes • In late stages of disease, the vascular proliferation may replace the entire lymph node 

Special Stains and Immunohistochemistry • Spindle cells and the vascular lining cells express endothelial cell–associated antigens: factor VIII–related antigen, CD34, CD31, and ERG •  HHV-­ 8 latency-­ associated nuclear antigen (LANA) is expressed in nearly all cases 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Angiosarcoma  • Metastatic angiosarcoma is much more common than primary angiosarcoma of the lymph node • Usually replaces the normal lymph node architecture • Consists primarily of interwoven fascicles of spindle cells displaying prominent cytologic atypia, numerous mitotic figures, and often striking pleomorphism • Always negative for HHV-­8 (LANA)  Vascular Transformation of Lymph Node  • Congestion of all subcapsular and medullary sinuses •  Anastomosing network of small vascular channels lined by reactive endothelial cells • Absence of capsular involvement (typical in KS) •  Absence of PAS–positive hyaline globules (typical of KS) • Always negative for HHV-­8 (LANA)

• A  IDS-­related KS may frequently coexist with other lymph node abnormalities (high-­grade lymphoma, Castleman disease, infection, HIV-­associated lymphadenopathy) • Positive immunohistochemical stain for HHV-­8 (LANA) is diagnostic of KS and is negative in all its mimickers

Selected References Cheuk W, Wong KO, Wong CS, et al. Immunostaining for human herpesvirus 8 latent nuclear antigen-­1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin Pathol. 2004;121:335–342. Hong YK, Foreman K, Shin JW, et al. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-­associated herpesvirus. Nat Genet. 2004;36:683–685. Patel RM, Goldblum JR, Hsi ED. Immunohistochemical detection of human herpes virus-­8 latent nuclear antigen-­1 is useful in the diagnosis of Kaposi sarcoma. Mod Pathol. 2004;17:456–460. Robin YM, Guillou L, Michels JJ, et al. Human herpesvirus 8 immunostaining a sensitive and specific method for diagnosing ­ Kaposi sarcoma in paraffin-­embedded sections. Am J Clin Pathol. 2004;121:330–334. Schwartz EJ, Dorfman RF, Kohler S. Human herpesvirus-­ 8 latent nuclear antigen-­ 1 expression in endemic Kaposi sarcoma: an immunohistochemical study of 16 cases. Am J Surg Pathol. 2003;27:1546–1550. Uldrick TS, Whitby D. Update on KSHV epidemiology, Kaposi sarcoma pathogenesis, and treatment of Kaposi sarcoma. Cancer Lett. 2011;305:150–162.

EXTRAMEDULLARY HEMATOPOIESIS Clinical Features • Typically an incidental finding • May be normal in small children but is always pathologic in adults • Most common etiologies include red blood cell disorders (sickle cell anemia, thalassemia, etc.) and myeloproliferative neoplasms •  Cases of extramedullary hematopoiesis (EMH) in patients treated with neoadjuvant chemotherapy have been reported 

Histopathology See Figure 14.38. • EMH may be seen in the sinuses or in the paracortex • Erythroid precursors are small cells with round hyperchromatic nuclei and scant cytoplasm; they have a typical intrasinusoidal location • Myeloid precursors are medium-­sized cells with round to irregular nuclear contours and moderate eosinophilic cytoplasm • Megakaryocytes are large cells with multilobated nuclei and abundant dense eosinophilic cytoplasm • One, two, or all three lineages may be present 

Special Stains and Immunohistochemistry

Figure 14.37  Kaposi sarcoma.  Lymph node capsule with a proliferation of small vascular channels.

• Erythroid precursors express glycophorin C and CD71 • Myeloid precursors stain with myeloperoxidase, lysozyme, and CD68 • Occasionally, monocytes are part of the EMH; these cells express CD14 • Megakaryocytes are positive for CD42b and CD61 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

A

811

Figure 14.38  Extramedullary hematopoiesis.  A, Interfollicular area is markedly expanded. B, High magnification of erythroid and myeloid precursors.

B

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Myeloid Sarcoma  • Sheets of myeloid blasts • No evidence of erythroid precursors or megakaryocytes • Myeloid blasts express CD34 and CD117 in addition to myeloperoxidase, lysozyme, and CD68  Metastatic Carcinoma  • EMH may be seen in axillary lymph nodes of patients with breast cancer •  Immunohistochemical staining with cytokeratin, myeloperoxidase, glycophorin C, and CD42b helps resolve the diagnostic difficulty  Classical Hodgkin Lymphoma  •  Megakaryocytes may occasionally be confused with Reed-­Sternberg cells, and maturing myeloid cells may be mistaken for eosinophils • Megakaryocytes are positive for CD42b and CD61 and do not express Pax-­5, CD30, or CD15 PEARLS • P  resence of an underlying myeloid malignancy or chronic anemia should be carefully investigated in an adult ­patient • Whereas a unilineage proliferation composed of erythroblasts is typical of a nonneoplastic condition, the presence of trilineage hematopoiesis is more suggestive of myeloproliferative neoplasms

Selected References Millar EK, Inder S, Lynch J. Extramedullary haematopoiesis in axillary lymph nodes following neoadjuvant chemotherapy for locally advanced breast cancer: a potential diagnostic pitfall. Histopathology. 2009;54:622–623. O’Malley DP. Benign extramedullary myeloid proliferations. Mod Pathol. 2007;20:405–415. Prieto-­Granada C, Setia N, Otis CN. Lymph node extramedullary hematopoiesis in breast cancer patients receiving neoadjuvant therapy: a potential diagnostic pitfall. Int J Surg Pathol. 2013;21:264–266.

MYELOID SARCOMA

Figure 14.39  Myeloid sarcoma.  Sheets of myeloblasts are present in the lower half of the image.

myelogenous leukemia or leukemic transformation in patients who have myelodysplastic disorders, as well as a forerunner of acute myeloid leukemia in nonleukemic patients • MSs most frequently involve soft tissues, lymph nodes, and skin or occur as isolated lytic bone lesions 

Histopathology • Most cases are composed of myeloblasts with or without features of promyelocytic or neutrophilic maturation (Figure 14.39) •  The blasts have round, ovoid, or reniform nuclei with finely stippled chromatin and one or two small nucleoli • Other cases are characterized by a diffuse monotonous proliferation of myelomonocytic or monoblastic cells 

Special Stains and Immunohistochemistry •  CD68/KP1 is the most commonly expressed marker (100%), followed by myeloperoxidase, CD117, CD99, lysozyme, CD34, TdT, and CD56 • About 90% of cases express CD45 • About 50% of MSs express CD43 • Rare cases positive for CD30 have been reported 

Clinical Features

Other Techniques for Diagnosis

•  MS occurs in patients who have acute myeloid leukemia, as a sign of impending blast crisis in chronic

• Cytogenetic analysis: ∼50% of cases have chromosomal abnormalities

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

812

Chapter 14  —  Lymph Nodes

• Monosomy 7, trisomy 8, MLL gene rearrangement, inv(16), t(8;21) translocation, and other abnormalities common in myeloid disorders 

Differential Diagnosis Diffuse Large B-­Cell Lymphoma  • Tumor cells are large and pleomorphic with vesicular nuclei • Immunophenotype is different from MS with expression of B-­cell antigens and lack of myeloid markers  Burkitt Lymphoma  • Tumor cells are medium sized and have a monotonous appearance • Starry-­sky pattern due to very high mitotic rate •  Immunophenotype is different from MS with expression of B-­ cell antigens and lack of myeloid markers  Peripheral T-­Cell Lymphoma, Not Otherwise Specified  •  Some tumors may have a monotonous appearance with effacement of lymph node architecture • Immunophenotype is different from MS with expression of T-­cell antigens and lack of myeloid markers  Anaplastic Large Cell Lymphoma  • Many cases of ALCL express myeloid markers CD13 and CD33 by flow cytometry • Immunophenotypic expression of EMA and T-­cell antigens and lack of myeloid blast markers • Many cases of ALCL express ALK1 • MS cells may have aberrant expression of T-­cell antigens CD43, CD4, or CD7  Lymphoblastic Lymphoma  • Tumor cells also have a blastoid appearance • Immunophenotype is different from MS with expression of B-­cell or T-­cell antigens and lack of myeloid markers  Metastatic Neoplasm  • Includes small round blue cell tumors in children and carcinoma and melanoma in adults • Immunophenotype is different from MS with lack of myeloid markers and blast markers

Figure 14.40  Mast cell disease in lymph node.  A, Aggregate of cells with clear cytoplasm. B, Giemsa stain highlights the metachromatic granules of the mast cells. (Courtesy Dr. Hans-­Peter Horny, Institut für Pathologie, Munich, Germany.)

A

PEARLS • Immunohistochemical stains to rule out MS should be performed in a high-­grade lymph node neoplasm that does not express CD20, CD3, and CD138 • CD43 is not a reliable marker for MS, as it also stains T- cells, plasma cells, and certain B-­cell lymphomas • CD34 is much less frequent in MS than in bone marrow– based acute myeloid leukemia • MS is considered an extramedullary equivalent of acute myeloid leukemia and is treated in the same fashion

Selected References Campidelli C, Agostinelli C, Stitson R, et al. Myeloid sarcoma: extramedullary manifestation of myeloid disorders. Am J Clin Pathol. 2008;132:426–437. Pileri SA, Ascani S, Cox MC, et al. Myeloid sarcoma: clinico-­pathologic, phenotypic and cytogenetic analysis of 92 adult patients. Leukemia. 2007;21:340–350.

MAST CELL DISEASE Clinical Features • May occur at any age • Mast cell proliferations most commonly involve the dermis, where they form small, localized tumors (mastocytomas) or disseminate (urticaria pigmentosa) • Other organs that are frequently involved include the spleen, liver, and gastrointestinal tract • Lymph nodes are involved in ∼25% of cases of systemic disease 

Histopathology • Complete effacement of the architecture is unusual • The mast cells preferentially infiltrate the paracortical area but may involve any compartment • Typically present as small clusters or sheets •  Most mast cells are round and have abundant clear cytoplasm with well-­ defined cytoplasmic borders ­(Figure 14.40A) •  Follicular hyperplasia, hypervascularity, increased eosinophils, plasmacytosis, and fibrosis are frequently seen • Some cases have eosinophilic abscesses and extreme eosinophilia obscuring other cell types

B

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 14  —  Lymph Nodes

•  Wright-­ Giemsa–stained touch preparations highlight the metachromatic granules of mast cells (see Figure 14.40B) 

Special Stains and Immunohistochemistry • Mast cells express CD117 and mast cell tryptase • Neoplastic mast cells have aberrant expression of CD2 or CD25 • CD30 may be positive in aggressive subtypes (e.g., mast cell leukemia) 

Other Techniques for Diagnosis • Elevated levels of serum tryptase • Activating point mutation of codon 816 of KIT gene 

Differential Diagnosis

813

•  Immunohistochemical staining reveals numerous B lymphocytes and shows no evidence of mast cell proliferation  Classical Hodgkin Lymphoma  • Polymorphous inflammatory background with eosinophilia and fibrosis may appear similar • Diagnostic Reed-­Sternberg cells are present  Sinus Histiocytosis  • Cases of mast cell leukemia may show striking involvement of the sinuses •  Immunohistochemical staining reveals presence of histiocytes and shows no evidence of mast cell proliferation PEARLS

Peripheral T-­Cell Lymphoma  • May have a component of clear cells, eosinophils, and hypervascularity • Immunohistochemical staining confirms that the clear cells are T lymphocytes 

• M  ast cells are virtually impossible to recognize on H&E-­ stained sections, as the granules are not visible • On the H&E-­stained sections, aggregates of mast cells may resemble fibrotic foci, histiocytes, or lymphoid aggregates

Langerhans Cell Histiocytosis  • Polymorphous inflammatory background with eosinophilia is similar •  Immunohistochemical staining highlights the Langerhans cells and shows no evidence of mast cell proliferation 

Selected References

Monocytoid B-Cells (in Reactive Hyperplasia or Marginal Zone Lymphoma)  • Usually associated with neutrophils, not eosinophils •  Immunohistochemical staining confirms their B-­ cell origin  Plasmacytoid Dendritic Cells  • More easily appreciated when present in aggregates • Plasmacytoid dendritic cells express CD123 and CD68 and are negative for CD117 and mast cell tryptase  Follicular Hyperplasia and Follicular Lymphoma  • Mast cell aggregates may resemble benign or neoplastic follicles

Escribano L, Díaz-­Agustín B, Bellas C, et al. Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res. 2001;25:563–570. Garcia-­Montero AC, Jara-­Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108:2366–2372. Tantravahi SK, Salama ME, Deininger MN. Aggressive systemic mastocytosis mimicking lymphoma: description of an unusual presentation and review of the literature on current management strategies. Leuk Lymphoma. 2014;55(12):2963–2966. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603– 625. Valent P, Sperr WR, Schwartz LB, et al. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-­mast cell hematopoietic neoplasms. J Allergy Clin Immunol. 2004;114:3–11.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15

Spleen SONAM PRAKASH  •  ATTILIO ORAZI

Chapter Outline Non-­Neoplastic Diseases Involving the Splenic White Pulp  816 Reactive Follicular Hyperplasia With Germinal Center Formation  816 Reactive Lymphoid Hyperplasia Without Germinal Center Formation  817

Chronic Myeloid Leukemia  839 Langerhans Cell Histiocytosis  840 Vascular Tumors  841 Splenic hemangioma  841 Littoral Cell Angioma  843

Castleman Disease  817

Splenic Angiosarcoma  844

Common Variable Immunodeficiency  818

Cysts and Pseudotumoral Lesions  845 Epidermoid Cyst (True Cysts)  845

Autoimmune Lymphoproliferative Syndrome  819 Neoplastic Diseases Involving the Splenic White Pulp  819 Splenic Marginal Zone Lymphoma  819 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  822 Prolymphocytic Leukemia  823 Mantle Cell Lymphoma  824 Follicular Lymphoma  824 Diffuse Large B-­Cell Lymphoma  825 Hodgkin Lymphoma  826 Non-­Neoplastic Diseases Involving the Splenic Red Pulp  827 Gaucher Disease and Other Storage Disorders 827 Hematologic diseases  829 Extramedullary hematopoiesis  829 Hereditary Spherocytosis  830 Sickle Cell Disease and Variants  831 Autoimmune Hemolytic Anemia  833 Idiopathic Thrombocytopenic Purpura (Autoimmune Thrombocytopenic Purpura)  833 Neoplastic Diseases Involving the Splenic Red Pulp  834 Splenic Diffuse Red Pulp Small B-­Cell Lymphoma  834 Hairy Cell Leukemia  835 Hairy Cell Leukemia-­Variant  836 Hepatosplenic T-­Cell Lymphoma  837 Systemic Mastocytosis  838

Pseudocyst  846 Parasitic (Echinococcal) Cyst  846 Splenic Hamartoma (Splenoma)  847 Sclerosing Angiomatoid Nodular Transformation of Spleen (Sant)  848 Inflammatory Pseudotumor of the Spleen  849 Inflammatory Pseudotumor-Like ­Follicular Dendritic Cell Tumor (IPT-­Like FDCT)  850 Circulatory Abnormalities  851 Congestive splenomegaly  851 Vasculitides  852 Polyarteritis Nodosa, Hypersensitivity Angiitis (Churg-­Strauss Disease), Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Thrombotic Thrombocytopenic Purpura  852 Viral and Other Nongranulomatous Infections  853 Infectious Mononucleosis  853 Cytomegalovirus Infection  854 Mycobacterium Avium-­Intracellulare  855 Malaria  855 Pyogenic Bacterial Infections (Abscess)  856 Granulomatous Diseases  857 Sarcoidosis, Miliary Tuberculosis, Histoplasmosis, Coccidioidomycosis, and Lipogranulomas  857 Other conditions  858 Amyloidosis  858 Hematoma and Traumatic Rupture  859

815

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

816

Chapter 15 — Spleen

Figure 15.1  Follicular white pulp hyperplasia, gross photograph.  The spleen is enlarged. Small, indistinct pale foci of hyperplastic white pulp are seen on the cut surface and under the capsule.

NON-­NEOPLASTIC DISEASES INVOLVING THE SPLENIC WHITE PULP REACTIVE FOLLICULAR HYPERPLASIA WITH GERMINAL CENTER FORMATION Clinical Features •  Occurs at any age; more common in children and younger adults • Caused by a variety of both acute and chronic immunologic stimuli (e.g., bacterial infections, autoimmune diseases including hemolytic processes) • May represent an incidental finding 

Gross Pathology • May present with splenomegaly, usually mild to moderate in degree (Figure 15.1) • Prominent white pulp nodularity may be grossly visible 

Histopathology •  Tripartite variably prominent germinal centers with well-­defined marginal and mantle zones •  Marginal zones may be expanded in chronic cases (Figure 15.2) • Polarized (dark and light zones) germinal centers with abundant mitoses and tingible body macrophages • Increased number of plasma cells and small plasma cell aggregates in red pulp 

Special Stains and Immunohistochemistry • Immunohistochemistry may be useful in differential diagnosis from lymphomatous infiltration •  Germinal centers are positive for CD20, CD10, and ­bcl-6, and negative for bcl-­2 • Mantle cells are positive for CD20 and bcl-­2 , may be positive for CD5 and negative for CD43 and cyclin D1 

Other Techniques for Diagnosis •  Evaluation of light-­ chain expression by flow cytometry may be complicated by high nonspecific binding;

Figure 15.2  Marginal zone hyperplasia.

nevertheless, polyclonal pattern is always seen supporting the diagnosis of reactive hyperplasia 

Differential Diagnosis Follicular, Mantle Cell, and Marginal Zone Lymphomas • Neoplastic follicles are less sharply defined, and may coalesce • Reactive follicles have well-­defined marginal and mantle zones with polarized germinal centers, tingible body macrophages, and mitotic figures •  Neoplastic lymphoid infiltrates are often present in red pulp as well as in periarteriolar lymphoid sheaths (PALS) of white pulp •  Immunophenotypic features are dependent on the lymphoma subtype PEARLS • H  istologic features of splenic lymphoid hyperplasia are largely similar to those of nodal reactive follicular hyperplasia • Well-­developed germinal centers are considered a normal finding in children and young adults; uncommon in elderly individuals; differential diagnosis includes follicular lymphoma or autoimmune disorders • Localized (nodular) reactive lymphoid hyperplasia is a rare nodular lesion that may grossly simulate lymphoma; histologically, it presents as an aggregation of hyperplastic follicles with typical reactive features • Prominent marginal zone expansion seen in chronic antigenic simulation may resemble marginal zone lymphoma; however, there is no infiltration of the germinal center or red pulp by marginal zone cells and mantle zones are preserved, a feature invariably missing in lymphoma cases • Common findings in patients with splenomegaly associated with systemic lupus erythematosus and rheumatoid arthritis (Felty syndrome) include follicular hyperplasia, plasmacytosis, and red pulp expansion that includes proliferation of CD3+ and CD57-­positive cytotoxic T cells, neutropenia, and leg ulcers

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

817

Special Stains and Immunohistochemistry • Immunohistochemistry can be useful in differential diagnosis from lymphomatous infiltration with immunoblastic proliferation (see Differential Diagnosis below) • Immunohistochemical stains and in situ hybridization studies to exclude viral infection (e.g., Epstein-­ Barr virus [EBV]) may be helpful 

Other Techniques for Diagnosis • Evaluation of light-­chain expression by flow cytometry shows polyclonal B-­cell population 

Differential Diagnosis

Figure 15.3  Primary (nonfollicular) white pulp hyperplasia. Heterogeneous lymphoid population including immunoblasts with open chromatin pattern.

Selected References Burke JS, Osborne BM. Localized reactive lymphoid hyperplasia of the spleen simulating malignant lymphoma: a report of seven cases. Am J Surg Pathol. 1983;7:373–380. Burks EJ, Loughran Jr TP. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev. 2006;20:245–266. Neiman RS, Orazi A. Reactive lymphoid hyperplasia. In: Neiman RS, Orazi A, editors. Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:67–84.

Diffuse Large B-­cell Lymphoma, Immunoblastic Variant •  Uniform expansive sheets of immunoblasts favor a diagnosis of diffuse large B-­cell lymphoma (DLBCL) • Correlation of histologic findings with clinical history and immunohistochemistry, flow cytometry, or molecular studies for clonality is of great value  Hodgkin Lymphoma • Immunoblastic proliferation in infectious mononucleosis may include Reed-­Sternberg–like cells •  Reactive immunoblasts are positive for B-­or T-­ cell markers and CD45, and they may be positive for CD30 antigen; however, in contrast to classical Hodgkin lymphoma, immunoblasts are negative for CD15 antigen PEARLS

REACTIVE LYMPHOID HYPERPLASIA WITHOUT GERMINAL CENTER FORMATION

• C  areful examination of the histologic sections with a high-­ power objective is mandatory; on low-­power examination, nonfollicular lymphoid hyperplasia may superficially resemble an unremarkable unstimulated spleen

Clinical Features

Selected References

• Occurs in any age group • Most common pattern encountered in viral infections (infectious mononucleosis, herpes simplex virus), transplant recipients, and immunosuppressed individuals (e.g., steroid-­ treated immune thrombocytopenic purpura, patients with rheumatoid arthritis on methotrexate) and in functional immunodeficiencies encountered in infants and elderly individuals 

Neiman RS, Orazi A. Reactive lymphoid hyperplasia. Neiman RS, Orazi A, editors. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:67–84. Smith EB, Custer RP. Rupture of the spleen in infectious mononucleosis: a clinicopathologic report of seven cases. Blood. 1994;61:317–333.

Gross Pathology • Modest splenomegaly • Cut surface may be grossly unremarkable 

Histopathology • White pulp shows a heterogeneous lymphoid population (Figure 15.3) • Numerous immunoblasts with open chromatin pattern and prominent nucleoli are seen • Tingible body macrophages may be prominent • Similar proliferation is seen in white pulp surrounding splenic arterioles (PALS) •  Transformed lymphocytes may infiltrate splenic trabeculae, predisposing to splenic rupture (e.g., in infectious mononucleosis) 

CASTLEMAN DISEASE Clinical Features • Splenic involvement occurs most frequently in multicentric Castleman disease, usually of plasma cell type • Patients with multicentric Castleman disease present with constitutional symptoms such as fever, night sweats, fatigue, and weight loss and frequently show a host of hematologic and immunologic abnormalities (anemia, thrombocytopenia, hypoalbuminemia, and hypergammaglobulinemia) • Multicentric Castleman disease in human immunodeficiency virus (HIV)-­positive patients is almost always human herpesvirus type 8 (HHV-­8) related. It is associated with HHV-­8 in about 40% of HIV-­negative cases • Splenic involvement by Castleman disease of hyaline-­ vascular type is exceptionally rare and poorly documented 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

818

Chapter 15 — Spleen

PEARLS • Interleukin-­6 (IL-­6) is important in the pathogenesis of multicentric type of Castleman disease (check serum IL-­6 level) • Multicentric Castleman disease (MCD) occurs relatively frequently in individuals with immune deficiencies such as HIV infection or elderly patients with Kaposi sarcoma • Scattered plasmablasts in HHV-­8-­positive MCD, although monotypic for lambda light chain are polyclonal by molecular studies • MCD with increased number of plasmablasts may progress to HHV-­8 positive DLBCL where the sheets of plasmablasts are often monoclonal

Selected References Figure 15.4  Castleman disease (mixed type).  Increased plasma cells and hyalinized germinal centers.

Gross Pathology • Modest to moderate splenomegaly 

Histopathology (Figure 15.4) • Hyaline-­vascular type (see Chapter 14) • Multicentric Castleman disease • Often plasma cell type • Hyperplastic or regressively transformed germinal centers often with hyalinization • Prominent mantle zones with increased numbers of large lymphoid cells with plasmablastic and immunoblastic features within the mantle zone cells and adjacent interfollicular regions • Significant red pulp plasmacytosis •  Plasmablasts may form small aggregates in the intrafollicular or perifollicular areas • With disease progression, aggregates of plasmablasts may coalesce to form sheets of lymphoma cells effacing the architecture with progression to DLBCL 

Special Stains and Immunohistochemistry • Plasma cells in the red pulp are cIG-­A positive, usually polyclonal and negative for HHV-­8 • Usually negative for EBV; only rare cases resembling germinotropic lymphoma are positive for both EBV and HHV-­8 • Plasmablasts are positive for immunoglobulin M (IgM), lambda light chain, HHV-­ 8, CD20+/−, CD79a−/+, CD138−, and PAX5–­and negative for Epstein-­ Barr virus–encoded RNA (EBER) 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Reactive Lymphoid Hyperplasia •  Hyalinization may be present; however, hyaline-­ vascular changes associated with follicles characteristic of hyaline-­vascular type Castleman disease are not seen  Rheumatoid Arthritis Versus Castleman Disease, Plasma Cell Type • Germinal centers in the white pulp may be hyperplastic • Polyclonal plasmacytosis of red pulp may be prominent • Clinical history and serologic tests are important

Cesarman E, Knowles DM. Kaposi’s sarcoma-­associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Semin Diagn Pathol. 1997;14:54–56. Dupin N, Diss TL, Kellam P, et al. HHV-­8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-­8-­positive plasmablastic lymphoma. Blood. 2000;95:1406–1412. Frizzera G. Castleman’s disease and related disorders. Semin Diagn Pathol. 1998;5:346–364. Menke DM, Tiemann M, Camariano JK, et al. Diagnosis of Castleman’s disease by identification of an immunophenotypically aberrant population of mantle zone B lymphocytes in paraffin-­embedded lymph node biopsies. Am J Clin Pathol. 1996;105:268–276. Weisenburger DD. Multicentric angiofollicular lymph node hyperplasia: pathology of the spleen. Am J Surg Pathol. 1988;12:176–181.

COMMON VARIABLE IMMUNODEFICIENCY Clinical Features • Presentation may occur from childhood to late adult life • Recurrent infections and autoimmunity • Splenomegaly in subset of patients • Clinical history necessary for adequate interpretation • Increased risk for lymphoma 

Gross Pathology • Spleen normal sized to enlarged • May be grossly unremarkable 

Histopathology • Variable histologic features dependent on the primary pathogenetic deficiency in lymphoid stimulatory molecules (inducible costimulator, transmembrane activator, and calcium modulating cyclophilin ligand [CAML] interactor or CD19 deficiencies) • Two broad groups: • White pulp hyperplasia (WPH) with reactive follicles, marginal zone hyperplasia, or periarteriolar T-­zone hyperplasia • Epithelioid granulomas with or without WPH; granulomas mostly in the marginal zones (rosary-­ bead distribution) or germinal centers • Immunoblastic proliferation and atypical cells resembling Hodgkin or Reed-­Sternberg cells may be present • There may be lymphoid hyperplasia in the red pulp 

Special Stains and Immunohistochemistry • Subset of cases may be positive for Epstein-­Barr virus– encoded latent membrane protein (EBV-­LMP) immunohistochemical stain or EBER in situ hybridization

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

819

• Reactive follicles are positive for CD20 and CD10 and negative for bcl2 •  Marginal zone hyperplasia is positive for CD20 and bcl2 • Periarteriolar lymphoid hyperplasia of mostly T-cells positive for CD3 and CD4 • Polyclonal B-­cell population by flow cytometry 

Other Techniques for Diagnosis • Polyclonal immunoglobulin gene rearrangement 

Differential Diagnosis Nonspecific Follicular Hyperplasia • Detailed clinical history of immunodeficiency; immunologic and genetic studies  Lymphoproliferative Disorders •  Careful clinical history of immunodeficiency must be obtained to avoid misinterpretation of significant immunoblastic proliferation or marginal zone hyperplasia associated with common variable immunodeficiency (CVID) as malignant lymphoma • Often necessary to establish clonality for a firm diagnosis of malignant lymphoma PEARLS H •  istologic features are variable and nonspecific • Include special stains for microorganisms in cases with granulomatous presentation

Selected References Cunningham-­Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48. Furudoï A, Gros A, Stanislas S, et al. Spleen histologic appearance in common variable immunodeficiency: analysis of 17 cases. Am J Surg Pathol. 2016;40:958–967. Salzer U, Grimbacher B. Common variable immunodeficiency: the power of co-­stimulation. Semin Immunol. 2006;18:337–346.

AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME Clinical Features •  Rare heritable lymphoproliferative syndrome due to mutations in Fas (CD95), Fas ligand, caspase 8, or caspase 10 genes • Presents in early childhood, usually in patients younger than 2 years •  Generalized lymphadenopathy, splenomegaly, and autoimmunity • Frequent association with immune cytopenias •  Increased risk for development of non-­ Hodgkin and Hodgkin lymphoma 

Figure 15.5  Autoimmune lymphoproliferative syndrome.  Mixed population of small T-cells, T-cell immunoblasts, and polyclonal plasma cells.

• Marked expansion of PALS and red pulp due to the infiltration by a mixed population of small T-cells, T-­cell immunoblasts, and polyclonal plasma cells (Figure 15.5) 

Special Stains and Immunohistochemistry • Double negative T-cells (T-­cell receptor [TCR]-­αβ positive, CD4 and CD8 negative) are the hallmark of the disease and can be predominantly found in the red pulp • Splenic T-cells are also negative for CD25 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Lymphoproliferative Disorder • Correlation with clinical history and the presence of splenomegaly in infancy is critical to avoid interpretation of an abnormal T-­cell population in the spleen as a T-­cell lymphoproliferative disorder PEARLS • F low cytometric immunophenotyping to look for double negative T-cells (CD4-­negative, CD8-­negative) in a child with lymphadenopathy and splenomegaly is very helpful to identify autoimmune lymphoproliferative syndrome (ALPS)

Selected References Lim MS, Straus SE, Dale JK, et al. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol. 1998;153:1541–1550. Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol. 2006;133:134–140.

Gross Pathology

NEOPLASTIC DISEASES INVOLVING THE SPLENIC WHITE PULP

• Massive splenomegaly 

SPLENIC MARGINAL ZONE LYMPHOMA

Histopathology

Clinical Features

• Prominent white pulp with follicular hyperplasia and expansion of marginal zones

• Most common in middle-­aged to elderly patients, without a distinct gender predominance

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

820

Chapter 15 — Spleen

• Presentation with left upper quadrant pain, anemia, and weight loss • Most common type of lymphoma to present with massive splenomegaly •  Some cases with autoimmune anemia or thrombocytopenia • Small monoclonal serum IgM/D paraprotein in one-­ third of cases • Splenic hilar lymph nodes, peripheral blood, bone marrow, and liver involvement are common at presentation • Lacks peripheral nodal involvement • Usually no lymphadenopathy •  Association with hepatitis C, cryoglobulinemia, and autoimmunity • Splenectomy may produce long-­term remission 

Gross Pathology • Prominent lymphoid follicle proliferation producing a miliary pattern of white pulp expansion 

Histopathology • Increase in size and number of white pulp follicles with a variable degree of PALS, and red pulp involvement is the rule • Malignant lymphoid cells may form expanded marginal zones or more often show colonization of germinal centers with attenuated mantle zones; combinations of the two patterns are frequently seen (Figure 15.6A) • A rare “indolent” variant, which closely simulates marginal zone hyperplasia, has been reported; its diagnosis usually requires demonstration of clonality • Red pulp involvement either as diffuse pattern or as lymphoid nodules • Rare cases may display a “red pulp predominant” proliferative pattern • Lymphoma cells are medium-­sized with round to oval nuclei and often abundant clear cytoplasm (see Figure 15.6B) • Larger lymphoid cells are usually seen at the periphery of neoplastic nodules • Bone marrow infiltration is the rule; may be intrasinusoidal, interstitial, or multinodular • Peripheral blood may show circulating small lymphocytes with abundant cytoplasm and short polar villi 

Special Stains and Immunohistochemistry •  Splenic marginal zone lymphoma (SMZL) expresses the B-­ cell markers CD20, PAX5, and CD79a; CD23, IgD and cytoplasmatic Ig are variable; CD5, cyclin D1, bcl-­6, annexin-­A1, and CD10 are absent; CD123 and CD103 are also usually negative • MIB-­1 shows an annular pattern with increased positivity in marginal zones and germinal centers • Due to the absence of specific markers, the diagnosis of SMZL is based on the absence of immunophenotypic features specific for other lymphoma subtypes 

Other Techniques for Diagnosis •  By flow cytometry, the expression of B-­ cell markers (CD19, CD20, and CD22) and clonal surface light chains is seen • Deletion of 7q32 is seen in about 45% of cases

Figure 15.6  Splenic marginal zone lymphoma.  A, Histologic section shows expanded marginal zone replaced by tumor cells. B, High-­ power view shows tumor cells with round nuclei and abundant clear cytoplasm and numerous plasma cells.

• Molecular studies for immunoglobulin gene rearrangements are clonal • No rearrangement of bcl-­1 and bcl-­2 genes 

Differential Diagnosis (also see Table 15.1) Splenic Diffuse Red Pulp Small B-­Cell Lymphoma • Diffuse involvement of red pulp with almost complete obliteration of white pulp • Cutaneous involvement may be present • Bone marrow involvement is often subtle with a predominant intrasinusoidal localization of the atypical lymphoid cells • Strong constant expression of DBA.44 and often of CD11c  Hairy Cell Leukemia • Red pulp involvement with prominent blood lakes • Cells with fine, hairlike cytoplasmic processes may be seen in peripheral blood • Diffuse pattern of bone marrow involvement (vs. nodular in SMZL)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

821

TABLE 15.1    MORPHOLOGIC AND IMMUNOPHENOTYPIC FEATURES OF B-­CELL NON-­HODGKIN LYMPHOMAS WITH PROMINENT SPLEEN INVOLVEMENT Morphologic and Immunophenotypic Features Type of Lymphomas

Architectural Features

Chronic lymphocytic leukemia/small lymphocytic lymphoma Mantle cell lymphoma

White and red pulp involvement; occasional growth centers White pulp involvement; nodular or mantle zone pattern

Follicular lymphoma

Splenic marginal zone lymphoma

Splenic diffuse red pulp small B-­cell lymphoma

Hairy cell leukemia

Cytologic Features

Small lymphoid cells with interspersed prolymphocytes and paraimmunoblasts, with or without growth centers Monotonous population of medium-­ sized lymphocytes with irregular nuclei; blastlike or pleomorphic cells in blastoid variant White pulp involvement; Medium-­sized lymphocytes with follicular pattern indented nuclei and variable admixture of large lymphoid cells Predominantly white pulp Medium-­sized lymphocytes with clear involvement; red pulp infilcytoplasm, indented nuclei, and trates with scattered cells and large lymphoid cells scattered at nodules of lymphoma cells the periphery of the nodules Red pulp involvement with Small to medium-­sized lymphoid cells (usually) obliteration of with pale or lightly eosinophilic cythe white pulp toplasm, round and regular nuclei with only occasional small distinct nucleoli; some cases may show plasmacytoid lymphoid cells Predominantly red pulp with Medium-­sized cells with abundant cytopseudosinuses plasm and cytoplasmic projections

•  Distinct immunophenotype: B-cells positive for tartrate-­ resistant acid phosphatase (TRAP), DBA.44, CD25, CD11c, and CD103 • BRAF V600E mutation by polymerase chain reaction (PCR) Hairy Cell Leukemia Variant  • Similar to classical hairy cell leukemia but with more pleomorphic cytologic features, including a variably prominent nucleolus and lack of CD25, annexin A1, and BRAF V600E mutation  T-­Cell Large Granular Lymphocytic Leukemia • Predominantly a red pulp infiltrate •  Distinct T-­ cell immunophenotype with varying degrees of loss or decreased density of CD7, CD2, and CD3; CD8 and CD57 positive in most cases; aberrant expression of natural killer receptors for class I major histocompatibility complex molecules (of killer cell immunoglobulin-­like receptor type, CD158 antigens, and C-­type lectin-like CD94 and NKG2 molecules); a minority of cases express CD56, CD16, or both  Hepatosplenic T-­Cell Lymphoma • More common in young men • May occur in the post-­transplantation setting and after anti-tumor necrosis factor (TNF) therapy • Typically presents with significant hepatomegaly and splenomegaly, abnormal liver function tests, and cytopenias •  Diffuse red pulp infiltration by slightly irregular medium-­sized lymphocytes • T-­cell immunophenotype with surface CD3 and associated γδ TCR, and absent CD5, CD4, and CD8 antigens; CD56 and CD16 are expressed in some cases

Immunophenotype Cytogenetics CD20, CD19, CD5, and CD23 positive

CD20, CD19, CD5, FMC7, and cyclin D1 positive; t(11;14)

CD20, CD19, CD10, BCL-­6, and BCL-­2 positive; t(14;18) CD20 and CD19 positive, CD43 positive or negative, positive for CD11c, negative for CD103 and CD123; variable positivity for CD25 and CD200 Positive for CD20, DBA.44, BCL2, and IgG, often positive for p53, variable positivity for CD11c, CD103, CD123 and IgD, and negative for CD25, CD10, CD23, BCL6, and annexin-­A1 CD20, CD19, CD103, CD25, CD123, CD200, annexin-­A1, and CD11c positive

PEARLS • T  horough examination of splenectomy specimens with clinical correlation and, if appropriate, with immunohistochemical, flow cytometric, and molecular analysis is mandatory because rare cases of minimal involvement by splenic marginal zone lymphomas have been reported, such as in cases of refractory idiopathic thrombocytopenic purpura (ITP) • Early cases of splenic marginal cell lymphoma may resemble marginal zone hyperplasia; however, in the latter, mantle zones are preserved, a feature invariably missing in lymphoma cases • Subtle lymphomatous infiltrate is also present in the red pulp • Bone marrow involvement is common, often subtle, and intrasinusoidal; sinusoidal infiltrate is best visualized by immunohistochemistry on the marrow core biopsy

Selected References Ngan BY, Warnke RA, Wilson M, et al. Monocytoid B cell lymphoma: a study of 36 cases. Hum Pathol. 1991;22:409–421. Piris MA, Onaindía A, Mollejo M. Splenic marginal zone lymphoma. Best Pract Res Clin Haematol. 2017;30:56–64. Rosso R, Neiman RS, Paulli M, et al. Splenic marginal zone cell lymphoma: report of an indolent variant without massive splenomegaly presumably representing an early phase of the disease. Hum Pathol. 1995;26:39–46. Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood. 2005;105:74–76. Traverse-­Glehen A, Verney A, Baseggio L, et al. Analysis of BCL-­ 6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-­cell lymphomas suggests a particular B-­cell origin. Leukemia. 2007;21:1821–1824.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

822

Chapter 15 — Spleen

• Two groups of CLL/SLL are recognized; this subclassification roughly corresponds to the expression of ZAP-­70 and CD38 molecules, which can be quantified by flow cytometry • One type corresponding to the pregerminal center phenotype (naive, showing no mutations in the variable region of immunoglobulin heavy-­chain [Vh] gene) • A second type derived from memory B-cells (postgerminal center, mutated Vh gene) 

Differential Diagnosis

Figure 15.7  Chronic lymphocytic leukemia/small lymphocytic lymphoma.  Histologic section shows a neoplasm composed of small uniform lymphoid cells with dense chromatin pattern and scant cytoplasm.

CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA Clinical Features • Occur predominantly in elderly individuals • Patients present with varying degrees of spleen, peripheral blood, and bone marrow involvement 

Gross Pathology •  Variable splenomegaly with prominent white pulp (miliary pattern) or more homogeneous diffuse involvement in advanced stages 

Histopathology • Diffuse infiltrate of both red and white pulp; no residual germinal centers are present • Neoplastic lymphoid cells are small with a coarse chromatin pattern, inconspicuous nucleoli, and scant cytoplasm (Figure 15.7) • Prolymphocytes and paraimmunoblasts can be intermingled with small lymphoid cells or form ill-­defined aggregates; proliferation centers (pseudofollicles) are much less common in the spleen than in lymph nodes or bone marrow 

Special Stains and Immunohistochemistry • Neoplastic cells express CD20, CD5, CD23, and CD43 

Other Techniques for Diagnosis • Neoplastic cells express CD19, CD5, CD23, and low-­ density clonal surface light chain, and are weakly positive for CD20 by flow cytometric immunophenotypic analysis • Clonal immunoglobulin gene rearrangement is present •  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are derived from recirculating CD5 and from IgM positive and IgD positive or negative B-cells normally present in the peripheral blood

Splenic Marginal Zone Lymphoma • Predominantly white pulp infiltrate, frequently with marginal zone pattern • Cells are strongly positive for CD20 and surface light chain (flow cytometry) and negative for CD5 and CD23  Follicular Lymphoma • Largely a white pulp distribution with only minimal red pulp involvement • Cytologically composed of a mixture of medium-­sized centrocytes and large centroblasts • Cells are positive for CD19, CD20, CD22, CD10, and bcl-­2 [t(14;18)] and negative for CD43, CD5, and CD23  Mantle Cell Lymphoma •  Predominantly white pulp involvement with expansion into the red pulp •  Uniform small to medium-­ sized cells with irregular nuclear outlines •  Neoplastic cells are positive for CD20, CD19, CD5, CD43, cyclin D1 [t(11;14)], and FMC7 (flow cytometry) and negative for CD23  Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) • The defining feature is the demonstration of monoclonal IgM protein in the serum, frequently with symptoms related to hyperviscosity •  Prominent plasmacytic component or a mixture of plasma cells and plasmacytoid lymphocytes •  B-cell–associated antigens, including CD19, CD20, and CD22, are consistently expressed; the surface IgM expression can be demonstrated in all cases, most cases show dim CD25; coexpression of CD5, CD23, and FMC7 have been reported; a minute monoclonal plasma cell component can be identified by flow cytometry in most cases • Molecular analysis for MYD88 L265P somatic mutation represents an additional useful diagnostic tool; the mutation that is present in greater than 90% of LPL cases is only rarely present in other types of small B-­cell lymphoma  Prolymphocytic Leukemia • In contrast to small lymphoid cells of CLL/SLL, prolymphocytes are medium-­sized atypical lymphoid cells with vesicular nuclei and prominent nucleoli • Patients typically present with high white blood cell counts

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

823

• Splenomegaly may be massive • CD20 and surface immunoglobulin density are stronger than in typical cases of CLL/SLL; CD5 expression is variable PEARLS • W  hite and red pulp infiltrate is composed of uniform small lymphoid cells • Modest splenic enlargement usually occurs; most patients whose disease is dominated by massive splenomegaly have mantle zone lymphoma or SMZL rather than SLL/ CLL • Richter transformation may present in the spleen; this appears as fleshy, cream-­colored tumor nodules similar to the involvement by DLBCL

Selected References Hollema H, Visser L, Poppema S. Small lymphocytic lymphomas with predominant splenomegaly: a comparison of immunophenotypes with cases of predominant lymphadenopathy. Mod Pathol. 1991;4:712–717. Pangalis GA, Nathwani BN, Rappaport H. Malignant lymphoma, well-­ differentiated lymphocytic lymphoma: its relationship with chronic lymphocytic leukemia and macroglobulinemias of Waldenström. Cancer. 1977;39:999–1010. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367:826–833. Van Krieken JH, Feller AC, te Velde J. The distribution of non-­Hodgkin’s lymphoma in the lymphoid compartments of the human spleen. Am J Surg Pathol. 1989;13:757–765.

PROLYMPHOCYTIC LEUKEMIA Clinical Features •  Presentation in elderly patients, with male predominance • Marked lymphocytosis (often >100 × 109/L) with more than 55% prolymphocytes • Massive splenomegaly with hypersplenism and resulting cytopenias and the absence of significant lymphadenopathy are common features 

Gross Pathology • Massive splenomegaly • Diffuse red pulp infiltration with variable prominence of white pulp 

Histopathology • Diffuse red pulp infiltration associated with involvement of the white pulp in most cases •  Heterogeneous population of lymphoid cells with a predominance of prolymphocytes characterized by medium size, abundant cytoplasm, and prominent nucleoli (Figure 15.8) 

Special Stains and Immunohistochemistry • Eighty percent of prolymphocytic leukemia cases are of B-­cell immunophenotype and are positive for CD20, with variable coexpression of CD5 and CD23 • Twenty percent of cases show T-­cell immunophenotype (T-­cell prolymphocytic leukemia) with a predominant expression of CD3, CD5, and CD4; loss of T-­cell antigens may be seen 

Figure 15.8  Prolymphocytic leukemia.  The infiltrate is composed of a heterogeneous population of lymphoid cells, many of which have large nuclei and prominent nucleoli.

Other Techniques for Diagnosis • By flow cytometry, strong expressions of CD20, CD19, FMC7, sIgM, and clonal surface immunoglobulin are seen in most cases 

Differential Diagnosis Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma • Massive splenomegaly is relatively uncommon • Homogeneous population of small lymphoid cells with scant cytoplasm; prolymphocytes are rare •  Weaker expression of surface immunoglobulins and CD20, positivity for CD5 and CD23, negativity for FMC7  Splenic Marginal Zone Lymphoma • Significant peripheral lymphocytosis is uncommon •  Neoplastic B-cells usually do not have prominent nucleoli PEARLS • P  rolymphocytic leukemia occurs predominantly in elderly males • Massive splenomegaly with significant lymphocytosis and absence of peripheral lymphadenopathy • Characterized by increased numbers of prolymphocytes (large to medium-­sized cells with prominent nucleoli) admixed with the small round lymphocytes • Usually B-­cell phenotype; variable expression of CD5 and CD23 (both positive in CLL/SLL)

Selected References Bearman RM, Pangalis GA, Rappaport H. Prolymphocytic leukemia: clinical, histopathological and cytochemical observations. Cancer. 1978;42:2360–2372. Lampert I, Catovsky D, Marsh GW, et al. The histopathology of prolymphocytic leukemia with particular reference to the spleen: a comparison with chronic lymphocytic leukemia. Histopathology. 1980;4:3–19.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

824

Chapter 15 — Spleen

MANTLE CELL LYMPHOMA Clinical Features •  Most patients present with widespread peripheral lymphadenopathy, hepatosplenomegaly, and bone marrow involvement •  A variant of mantle cell lymphoma with leukemic peripheral blood involvement, no appreciable lymphadenopathy, and sometimes splenic involvement, is now recognized: leukemic non-­nodal mantle cell lymphoma; this has a better prognosis than classic mantle cell lymphoma 

•  Neoplastic population composed of medium-­ sized lymphoid cells with rare admixed large cells • Neoplastic cells do not express CD5 or cyclin D1  Lymphoblastic Lymphoma •  Lymphoblasts are positive for TdT and negative for cyclin-­D1 PEARLS

Gross Pathology

• M  antle cell lymphoma can present with leukemic peripheral blood involvement and massive splenomegaly • Blastoid mantle cell lymphoma may mimic lymphoblast proliferation or DLBCL

• Prominent white pulp in an enlarged spleen • Massive splenomegaly may be seen (>1000 g) 

Selected References

Histopathology • Nodular expansion of white pulp with or without a mantle zone pattern (i.e., lymphoid proliferation surrounding residual germinal centers) • A pure mantle zone lymphomatous growth pattern is rarely seen • Homogeneous population of medium-­sized lymphoid cells with irregular nuclear outlines • Blastoid variant of mantle cell lymphoma is composed of blastlike lymphoid cells (lymphoblastoid variant) or of large pleomorphic cells resembling those of DLBCL 

Special Stains and Immunohistochemistry • Neoplastic cells are positive for CD20, CD5, cyclin D1 [t(11;14)], and SOX11 and negative for CD23 • The indolent leukemic non-­nodal mantle cell variant is negative for SOX11 • See Chapter 14 for more detailed information 

Other Techniques for Diagnosis • By flow cytometry, the neoplastic cells are positive for CD20 (bright expression), CD19, CD5, monotypic sIg light chain and FMC7, and negative for CD23 •  The defining feature of mantle cell lymphoma is the presence of t(11;14), the translocation of proto-­ oncogene cyclin D1 (bcl-­1; involved in the regulation of G1-­to S-­phase progression) to the immunoglobulin heavy-­chain gene locus 

Differential Diagnosis Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma • Diffuse red pulp infiltration is prominent • Small lymphocytes with some large cells (prolymphocytes and paraimmunoblasts) • Low-­density sIg and CD20 positivity; positive for both CD5 and CD23 • Lack of staining for cyclin D1  Splenic Marginal Zone Lymphoma • Present with massive splenomegaly without peripheral lymphadenopathy • Expanded, confluent marginal zones can be difficult to distinguish from expanded mantle zones

Angelopoulou MK, Siakantariz MP, Vassilakopoulous TP, et al. The splenic form of mantle cell lymphoma. Eur J Haematol. 2002;68:12–21. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma: a proposal for unification of morphologic, immunologic and molecular data. Am J Surg Pathol. 1992;16:637–640. Molina TJ, Delmer A, Cymbalista F, et al. Mantle cell lymphoma, in leukaemic phase with prominent splenomegaly: a report of eight cases with similar clinical presentation and aggressive outcome. Virchows Arch. 2000;437:591–598. Ondrejka SL, Lai R, Smith SD, et al. Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011;96:1121–1127.

FOLLICULAR LYMPHOMA Clinical Features • Patients typically present with multifocal lymphadenopathy and bone marrow involvement (stage IV) • About half of patients show splenic involvement, often detected only at the microscopic level • Most cases of follicular lymphoma in the spleen represent secondary involvement; very few cases of primary splenic follicular lymphoma have been reported 

Gross Pathology • Uniform expansion of the white pulp nodules (miliary pattern) 

Histopathology (Figure 15.9) •  Uniform multifocal involvement of the white pulp, frequently with small aggregates of lymphoma cells within red pulp •  In grades 1 and 2 follicular lymphoma, neoplastic follicles are composed predominantly of small to medium-­sized cleaved atypical lymphoid cells (centrocytes) with a variable admixture of large atypical lymphoid cells with vesicular nuclei and multiple nucleoli, mostly attached to the nuclear membrane (centroblasts) •  In grade 3 follicular lymphoma, large atypical lymphoid cells predominate 

Special Stains and Immunohistochemistry • The immunophenotype reflects the follicle center cell origin of follicular lymphoma

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

A

825

B

Figure 15.9  Follicular lymphoma.  A, Low-­power view shows multiple white pulp tumor nodules. B, The nodules are composed of predominantly centrocytes.

• B-­cell marker CD20 is positive, along with the coexpression of antigens characteristic for germinal center cells, such as CD10 and bcl-­6 • Antiapoptotic protein bcl-­2 is usually positive • See Chapter 14 for more detailed information 

Other Techniques for Diagnosis • By flow cytometry, pan B-­cell markers (CD19, CD20) and clonal surface immunoglobulin are present, along with the coexpression of CD10 antigen in most cases; the coexpression of CD10, similar in intensity to that seen in reactive follicular hyperplasia, in association with a relatively low-­intensity CD19, is a characteristic feature of follicular lymphoma •  Expression of bcl-­ 2 is due to the t(14;18)(q32;q21), which places the bcl-­2 gene under a promoter of the immunoglobulin heavy-­chain gene; rare cases of bcl-­2 protein negative or lacking t(14;18)(q32;q21) in follicular lymphoma, however, do exist (discussed later) 

Differential Diagnosis Reactive Follicular Hyperplasia • Well-­defined follicles with distinct marginal and mantle zones, polarization of germinal center into dark and light zones, tingible body macrophages, and mitotic figures • Germinal centers negative for bcl-­2  Castleman Disease • Expanded mantle zones • White pulp follicles are variably expanded or atrophic/ hyalinized • Red pulp is expanded with large numbers of polyclonal plasma cells  Mantle Cell Lymphoma • Uniform population of small to medium-­sized lymphocytes without centroblasts • Cells express CD5 and are generally CD10 negative • Overexpression of cyclin D1 •  Expression of bcl-­ 2 is not useful in the differential diagnosis  Splenic Marginal Zone Lymphoma • More prominent involvement of red pulp

•  The expression of markers associated with germinal center origin is not seen PEARLS • E xpression of bcl-­2 is seen in most types of indolent B-­cell lymphomas; however, when seen in nodular proliferation showing germinal center cell immunophenotype, bcl-­2 is diagnostic of follicular lymphoma • About 20% of follicular lymphomas are negative for bcl-­2 antigen; in a proportion of these cases, molecular studies (PCR or fluorescent in situ hybridization [FISH] based) may demonstrate the presence of t(14;18) or bcl-­6 rearrangement • Predominantly white pulp involvement, but discrete invasion of red pulp is common

Selected References Gauland P, D’Agay MF, Peuchmar M, et al. Expression of the bcl-­2 gene product in follicular lymphoma. Am J Pathol. 1992;140:1089–1095. Horsman DE, Okamoto I, Ludkovski O, et al. Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes. Br J Haematol. 2003;120:424–433. Howard MT, Dufresne S, Swerdlow SH, et al. Follicular lymphoma of the spleen: multiparameter analysis of 16 cases. Am J Clin Pathol. 2009;131:656–662. Shimono J, Miyoshi H, Kamimura T, et al. Clinicopathological features of primary splenic follicular lymphoma. Ann Hematol. 2017;96:2063–2070.

DIFFUSE LARGE B-­CELL LYMPHOMA Clinical Features • Rare, but accounts for about one-­third of lymphomas localized to the spleen at presentation • May arise de novo or represent transformation of low-­ grade lymphoma 

Gross Pathology •  Typically presents as large tumor nodules that may coalesce into larger masses randomly distributed in the splenic parenchyma • May show large areas of necrosis •  Usually involves hilar and retroperitoneal lymph nodes 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

826

Chapter 15 — Spleen

PEARLS • L arge tumor nodules, often with foci of necrosis • Tumor usually involves hilar and retroperitoneal lymph nodes, with or without peripheral lymphadenopathy

Selected References Falk S, Stutte HJ. Primary malignant lymphomas of the spleen: a morphologic and immunohistochemical analysis of 17 cases. Cancer. 1990;66:2612–2619. Kobrich U, Falk S, Middeke B, et al. Primary large cell lymphoma of the splenic sinuses: a variant of angiotropic B-­cell lymphoma (neoplastic angioendotheliomatosis)? Hum Pathol. 1992;23:1184–1187. Kraemer BB, Osborne BM, Butler JJ. Primary splenic presentation of malignant lymphoma and related disorders: a study of 49 cases. Cancer. 1984;54:1606–1619.

Figure 15.10  Diffuse large B-­cell lymphoma.  The tumor cells are large with irregular nuclei and high N:C ratio.

Histopathology • Focal large aggregates or sheets of large atypical lymphoid cells with variable cytologic features (centroblasts, immunoblasts) (Figure 15.10) • Involves both white and red pulp, effacing the normal splenic architecture 

Special Stains and Immunohistochemistry •  DLBCL expresses CD20 and CD79a; as in lymph nodes, it may express other antigens of germinal center derivation (bcl-­ 6 and CD10) or of nongerminal center derivation (MUM-­1); some cases may be positive for CD5 • See Chapter 14 for more detailed information 

HODGKIN LYMPHOMA Clinical Features • Although splenic involvement is not uncommon in cases of nodal-­based classical Hodgkin lymphoma, (CHL) true primary splenic Hodgkin lymphoma is exceedingly rare •  Nodular lymphocyte-­ predominant Hodgkin lymphoma rarely involves spleen 

Gross Pathology • Focal nodules scattered in spleen parenchyma, often with apparent fibrosis • Occasionally nodules are small, visible only on thin sectioning of the organ 

Histopathology (Figure 15.11)

• By flow cytometry, DLBCL expresses CD19, CD20, and CD22; most commonly, there is a clonal surface light-­ chain expression, although cases negative for surface light chains are not uncommon • Immunoglobulin gene rearrangement analysis can be useful (see Chapter 14 for more detailed information) 

• Early lesions are found in the T-­cell zones of white pulp (PALS) or marginal zones • Classical Hodgkin lymphoma: typical Hodgkin-­Reed-­ Sternberg cells within a polymorphous background of T-cells, histiocytes, and eosinophils •  Nodular lymphocyte-­ predominant Hodgkin lymphoma: “popcorn” cells characterized by large size and multilobate nucleus with delicate chromatin, within a cellular background of small lymphocytes • Accompanying fibrosis may be prominent • Epithelioid granulomas may be present 

Differential Diagnosis

Special Stains and Immunohistochemistry

Hodgkin Lymphoma • Patients almost always have nodal Hodgkin lymphoma •  Splenic involvement is often associated with liver involvement • Typical polymorphous cellular background composed of small lymphocytes, plasma cells, eosinophils, neutrophils, and macrophages with large pleomorphic Hodgkin-­Reed-­Sternberg cells and their variants • Neoplastic cells are typically negative for CD20, CD45, and CD3 but express PAX-­5 (weak) and CD30, with or without CD15 

•  Small lymphocytes are a mixture of CD3-­ positive T- cells (predominantly CD4-­positive helper T-­cell) and CD20-­positive B-cells; the former usually predominate • Reed-­Sternberg cells and their variants are positive for PAX-­5 (weak), CD30, and often CD15, and negative for CD45; CD3 and CD20 are usually negative; the latter, however, can be found expressed in a proportion of neoplastic cells with variable staining intensity •  Popcorn cells of nodular lymphocyte-­ predominant Hodgkin lymphoma are positive for CD20 and CD45 and can be surrounded by CD57-­and PD-­1-­positive T- cells (see Chapter 14 for more detailed information) 

Other Techniques for Diagnosis

Inflammatory Pseudotumor • Usually a single, well-­demarcated whitish mass • Histology shows a polymorphous collection of bland spindle cells and inflammatory cells

Other Techniques for Diagnosis • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

827

T-­ cell markers and anaplastic lymphoma kinase (ALK-­1) in a subset but are usually negative for CD15 and PAX-­5  Inflammatory Pseudotumor • Usually a solitary mass with whitish cut surface • Tumor localized to the spleen, no lymphadenopathy •  Mixture of bland spindle cells, lymphocytes, and plasma cells • Hodgkin-­Reed-­Sternberg cells are not identified  Splenic Hamartoma • Usually presents as solitary mass with reddish cut surface • Does not involve tissues other than the spleen • Typical red pulplike microscopic appearance  Metastatic Carcinoma or Melanoma • Almost always a previous history of primary tumor • Single or multiple randomly distributed tumor nodules •  Microscopy shows sheets of large nonhematopoietic cells (negative for lymphoid antigens) PEARLS • T  rue primary Hodgkin lymphoma of the spleen is rare (20 ng/mL) • Detection of activating KITD816V mutation 

CHRONIC MYELOID LEUKEMIA Clinical Features • Patients usually present with leukocytosis with significant neutrophilia, absolute basophilia, and a variable proportion of immature myeloid cells • Splenomegaly is common at presentation 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

840

Chapter 15 — Spleen

chronic myeloid leukemia from chronic myelomonocytic leukemia or other types of Ph′-­negative myeloid neoplasms Reactive Splenic Red Pulp Hyperplasia • Usually part of a nonspecific stress response process, which may be associated with a leukemoid reaction in the blood, or related to chronic congestive hypersplenism • Basophilia is uncommon • Elevated neutrophil alkaline phosphatase (NAP) • Normal cytogenetics 

Figure 15.24  Chronic myelogenous leukemia, blastic phase. Diffuse infiltration of the red pulp by leukemic blasts. Acute transformation may manifest itself in the spleen (extramedullary transformation).

Acute Leukemia •  Differential diagnosis is with blast crisis of chronic myelogenous leukemia • History of chronic phase disease or cytogenetic demonstration of t(9;22) is needed PEARLS

• White pulp is usually obliterated • Red pulp cords and sinuses show a polymorphic infiltration by myeloid cells at all stages of maturation with a predominance of mature granulocytes • Occasionally blastic transformation is first identified in the spleen (Figure 15.24) • Bone marrow is always involved 

• A  ssociated with the Philadelphia chromosome t(9;22) or BCR-­ABL1 gene translocation • Prominent splenomegaly with predominant involvement of red pulp • Patients may undergo a blastic transformation, which is associated with a poor outcome • In pediatric patients, chronic myelogenous leukemia, adult type, needs to be distinguished from juvenile myelomonocytic leukemia (JMML); in spleen sections, however, the two conditions largely overlap morphologically, although JMML displays monocytic differentiation, which can be identified by immunohistology with CD68R, CD14, or flow cytometry with histiocytic markers

Special Stains and Immunohistochemistry

Selected References

• Naphthol-­AS-­D chloroacetate esterase stain and antibodies such as myeloperoxidase or lysozyme can be used to facilitate the identification of myeloid cells •  A combination of markers, such as CD34 and TdT, can be used to confirm extramedullary (splenic) blastic transformation, and a panel of immunohistochemical stains (e.g., MPO, lysozyme, CD42b, CD79a, PAX5, CD3) is valuable in characterizing the lineage of blasts (e.g., myeloid transformation vs. lymphoid or megakaryocytic) 

Burke JS. Surgical pathology of the spleen: an approach to the differential diagnosis of splenic lymphomas and leukemias. Part II. Diseases of the red pulp. Am J Surg Pathol. 1981;5:681–694. Pinkus GS, Pinkus JL. Myeloperoxidase: a specific marker for myeloid cells in paraffin sections. Mod Pathol. 1991;4:733–741. Shepherd PC, Ganesan TS, Galton DA. Haematological classification of the chronic myeloid leukaemias. Baillieres Clin Haematol. 1987;1:877–906.

LANGERHANS CELL HISTIOCYTOSIS

Other Techniques for Diagnosis

Clinical Features

• Identification of Philadelphia chromosome translocation t(9;22) by karyotype analysis, PCR, or FISH for BCR-­ ABL1 in blood, marrow, or splenic tissue is necessary to confirm a diagnosis of chronic myeloid leukemia • In cases of blastic transformation, flow cytometry is useful to confirm the presence of blasts and evaluate their lineage 

•  Splenic involvement occurs in infants and young children with the disseminated form of the disease (Letterer-­Siwe disease) • Presenting symptoms include fever and skin lesions 

Differential Diagnosis

Histopathology

• The histologic features are classic, particularly in view of the peripheral blood findings •  In selected cases, cytochemistry for naphthyl butyrate esterase or reactivity with antibody to histiocytic markers may be helpful in separating extramedullary

• Langerhans cell infiltration of the red pulp may be diffuse or multinodular (loose aggregates are granuloma-­ like), only rarely shows large discrete tumor masses • Cells have typical pale, bean-­shaped nuclei and pale cytoplasm

Gross Pathology • Solid, red, homogeneous appearance • No lymphoid follicles visible 

Histopathology

Gross Pathology • Splenomegaly with diffuse red pulp enlargement 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

• Eosinophils and plasma cells are usually also present, although are much less numerous than in the localized form of the disease (eosinophilic granuloma) 

Special Stains and Immunohistochemistry • CD1a, S-­100 protein, and langerin positive • CD68R (PG-­M1) negative 

Other Techniques for Diagnosis • Electron microscopy to demonstrate Birbeck granules • Subset of cases show BRAF(V600E) mutation by molecular studies; they are positive for immunohistochemical stain for BRAF 

Differential Diagnosis Disseminated Juvenile Xanthogranuloma (JXG) • Nuclei not bean-­shaped • Characteristic presence of Touton giant cells; however, these cells may be either absent or present in reduced numbers in the various extracutaneous lesions when compared with JXG in the skin • Immunohistochemistry: the histiocytic cells are positive for CD68 and factor XIIIa and negative for S-­100 protein and CD1a  Gaucher Disease (and Other Lysosomal Storage Diseases) •  Infants present with neurologic deterioration and organomegaly; skin is not involved • Absence of eosinophils • Nuclei not bean-­shaped • Cells usually larger than Langerhans cells •  Cytoplasm abundant, with wrinkled-­ silk pattern in Gaucher disease • Cells periodic acid–Schiff (PAS) positive in most cases; S-­100 protein and CD1a negative  Hemophagocytic Syndromes • Patients are systemically ill with cytopenias (similar to Letterer-­Siwe disease) • Macrophages with red cells, leukocytes, and iron • CD68 positive; S-­100 protein and CD1a negative • Some cases are EBV-­related  Mycobacterium Avium-­Intracellulare • Rare in children • Patients usually have evidence of immune deficiency, often HIV •  Special stains for acid-­ fast bacilli, PAS, and Gomori methenamine silver (GMS) reveal organisms in the cells  Acute Myeloid Leukemia, Particularly Acute Monoblastic Leukemia • Presents with cytopenias and peripheral blood or bone-­ marrow involvement • Blasts have large nuclei with finely dispersed chromatin and scanty to variably abundant cytoplasm, depending on the acute myeloid leukemia subtype •  Mitoses more numerous than in Langerhans cell histiocytosis  Histiocytic Sarcoma (Malignant Histiocytosis) • Patients are seriously ill with profound cytopenias

841

• Bone marrow usually shows diffuse involvement • Rarely presents as isolated splenomegaly • Red pulp infiltration may be associated with prominent necrosis • Highly atypical cells with pleomorphic nuclei, which can be bean-­ shaped and eccentric with prominent nucleoli and irregularly clumped chromatin; giant cells may resemble Reed-­Sternberg cells • Mitoses much more numerous than in Langerhans cell histiocytosis • Erythrophagocytosis is seen in reactive macrophages and rarely in the tumor cells • May express S-­100 protein but always CD1a negative; expresses histiocytic markers (e.g., CD68, CD163) PEARLS • P  atients usually have skin, liver, and lymph node involvement • Diagnosis is more readily made from bone marrow biopsy • Splenic involvement is more likely to be seen at autopsy than in a surgical specimen

Selected References Herzog KM, Tubbs RR. Langerhans cell histiocytosis. Adv Anat Pathol. 1998;5:347–358. Pileri SA, Grogan TM, Harris NL, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002;41:1–29. Tran G, Huynh TN, Paller AS. Langerhans cell histiocytosis: a neoplastic disorder driven by Ras-­ERK pathway mutations. J Am Acad Dermatol. 2018;78:579–590. Vardiman JW, Byrne Jr GE, Rappaport H. Malignant histiocytosis with massive splenomegaly in asymptomatic patients: a possible chronic form of the disease. Cancer. 1975;36:419–427.

VASCULAR TUMORS SPLENIC HEMANGIOMA Clinical Features • Most frequent in young to middle-­aged adults with no sex predilection • Usually asymptomatic •  Symptoms and abnormalities reported include the following: • Abdominal discomfort • Hypersplenism with cytopenias • Consumptive coagulopathy (disseminated intravascular coagulation) 

Gross Pathology • Single, sometimes multiple masses • Spleen normal to moderately enlarged • Lesions are well circumscribed but not encapsulated • Reddish-­purple and spongy (Figure 15.25A) • Secondary changes may include infarct or fibrosis • Angiomatosis is diffuse replacement of the spleen by angiomatous tissue 

Histopathology (see Figure 15.25B) • Most are cavernous hemangiomas • Interconnected vascular channels of varying size

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

842

Chapter 15 — Spleen

Figure 15.25  Hemangioma.  A, Cut surface. In addition to the dilated vessels and cystic spaces, there are pale, spongy tumor nodules around dilated vessels. The intervening parenchyma looks normal. B, Photomicrograph. The dilated blood vessels of the tumor are surrounded by red pulp cordal macrophages.

• Channels may be thrombosed with focal infarction • Endothelium is usually flattened but may be plump, no endothelial tufting • Mitoses are usually absent (except in children) • No cellular pleomorphism or hyperchromasia 

Special Stains and Immunohistochemistry •  Endothelial lining cells are CD34, CD31, and factor VIII positive • CD8, CD68, CD21, D2-­40, and Ki-­67 are negative in the endothelial lining cells 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Cord Capillary Hemangioma • Another benign lesion termed cordal capillary hemangioma overlaps morphologically with capillary hemangiomas with sclerosis and may represent the same entity  Hematoma • Few or no blood vessels inside the mass  Peliosis • Often associated with hepatic peliosis • More often multifocal or diffuse • May be associated with spontaneous splenic rupture • Dilated sinuses with attenuated lining cells surrounded by splenic parenchyma; no perilesional fibrosis • Sinus-lining cells: CD8 and CD68 positive • Concentrated at the periphery of white pulp follicles (not a diffuse red pulp lesion)  Littoral Cell Angioma • More often multifocal or diffuse to almost involving the entire spleen • Endothelial cells are plump and cuboidal or tall, with papillary projections protruding into vascular spaces

• Endothelial cells are CD68 and CD163 positive and CD34 negative, CD21 and S-­100 may also be positive; in contrast with normal littoral cells, they are negative for CD8  Hemangioendothelioma • Greater cytologic atypia, for example, plump endothelial cells with hyperchromatic nuclei • Epithelioid and spindle cell variants • Low to absent mitotic activity and lack of necrosis and invasive growth  Angiosarcoma • Splenomegaly in elderly patients with fatigue, fever, weight loss, and abdominal pain • Poorly delineated, large, often necrotic tumor masses that may involve the entire organ • Papillary cell proliferation producing tufts and partially filling vascular spaces •  Anastomosing vascular channels may alternate with solid, poorly differentiated areas • Nuclear pleomorphism, hyperchromasia, and atypia • Frequent mitoses • Infiltrative growth pattern • CD31 is the best marker; expression of other endothelial antigens is variable  Splenic Hamartoma • Usually a single bulging and fleshy mass • Color similar to splenic red pulp •  Contains both cords and sinus structures (the latter CD8 positive) • Another lesion related to hamartoma is myoid angioendothelioma, a rare benign tumor of the spleen, which is morphologically characterized by a composite of vascular spaces and stromal cells with myoid features  Lymphangioma • Mostly occurs in children • Grossly indistinguishable • Gross cyst formation is common

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

843

Figure 15.26  Littoral cell angioma.  A, Rarely the whole spleen can be replaced by a spongy hemorrhagic, vaguely nodular proliferation. This may raise the possibility of an angiosarcoma. B, At this magnification, the larger size and more cuboidal to hobnail pattern of the cells lining the vascular spaces is apparent. These cells do not have the nuclear pleomorphism, atypia, or mitotic activity seen in more aggressive vascular tumors.

•  Spaces contain proteinaceous material, lymph, and cholesterol clefts (not blood) • Endothelial lining cells are D2-­40, CD31, and factor VIII positive; CD34 usually negative PEARLS • M  icroangiopathic hemolytic anemia, thrombocytopenia, and consumptive coagulopathy have been reported with large vascular lesions (Kasabach-­Merritt syndrome)

Special Stains and Immunohistochemistry • Reticulin: annular fibers around vascular spaces • Occasional PAS-­positive cytoplasmic globules • Distinctive phenotype of vascular lining cells: CD31, CD68, CD68R (both KP-­ 1 and PG-­ M1), CD21, and CD163 positive; negative for CD8 and CD34; may also express S-­100 protein 

Other Techniques for Diagnosis • Noncontributory 

Selected Reference

Differential Diagnosis

Arber DA, Strickler JG, Chen YY, Weiss LM. Splenic vascular tumors: a histologic, immunophenotypic, and virologic study. Am J Surg Pathol. 1997;21:827–835.

Hemangioma • No irregular anastomosing channels • More often single • Vascular spaces lined by flattened cells • Endothelial lining cells are CD68 negative 

LITTORAL CELL ANGIOMA Clinical Features

Splenic Hamartoma • Usually a single mass that is bulging and fleshy, color similar to splenic red pulp •  Contains both cords and sinus structures (the latter CD8 positive) Gross Pathology • Endothelia are of littoral cell derivation, positive for •  Single or multiple spongy, purplish-­ black, well-­ CD8 and CD68, and negative for CD34  circumscribed nodules • Rarely may replace the whole organ; can be only vaguely Hemangioendothelioma multinodular; in other cases, it may appear subdivided • Patients may have disease outside the spleen into lobules by bands of fibrosis (Figure 15.26A)  • Endothelial cells have hyperchromatic nuclei • Epithelioid or spindle-­shaped endothelia Histopathology • Endothelial cells are usually negative for CD68  •  Pleomorphic vascular spaces: from slitlike to dilated and cystic Angiosarcoma • Lined by cuboidal- to hobnail-shaped cells with large • Elderly patients vesicular nuclei (see Figure 15.26B) • Greater splenic enlargement •  Papillary projections protruding into the vascular • Infiltrative growth pattern and necrosis spaces • Anastomosing vascular channels lined by a papillary • Tumor cells can exfoliate into the lumen endothelial cell proliferation producing tufts and par • No significant cellular atypia, and mitotic activity is tially filling vascular spaces low •  More mitoses, nuclear pleomorphism, atypia, and • Always lacks solid areas and necrosis  hyperchromasia • Rare • Occurs at any age and in either sex • May cause splenomegaly and hypersplenism 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

844

Chapter 15 — Spleen

• Endothelial cells are more often negative for CD68 • Metastases are not uncommon PEARLS L ittoral cell angioma is benign despite its multifocality • • No counterpart exists outside the spleen • Extremely rare aggressive counterparts have been described (littoral cell angioendothelioma and littoral cell angiosarcoma)

Selected References Arber DA, Strickler JG, Chen YY, Weiss LM. Splenic vascular tumors: a histologic, immunophenotypic, and virologic study. Am J Surg Pathol. 1997;21:827–835. Falk S, Stutte HJ, Frizzera G. Littoral cell angioma: a novel splenic vascular lesion demonstrating histiocytic differentiation. Am J Surg Pathol. 1991;15:1023–1033. Peckova K, Michal M, Hadravsky L, et al. Littoral cell angioma of the spleen: a study of 25 cases with confirmation of frequent association with visceral malignancies. Histopathology. 2016;69:762–774. Rosso R, Paulli M, Gianelli U, et al. Littoral cell angiosarcoma of the spleen: case report with immunohistochemical and ultrastructural analysis. Am J Surg Pathol. 1995;19:1203–1208.

Special Stains and Immunohistochemistry • Expression of common endothelial cell antigens is variable but CD31 and Ulex lectin are usually positive • CD34 and factor VIII are usually detected in better differentiated areas only; CD163 is negative • Positivity for CD68 and CD8 suggests a littoral cell derivation (littoral cell angiosarcoma) • Expression of D2-­40, a marker of differentiation along the lymphatic endothelial lineage, has been reported in some cases; these cases could be classified as lymphangiosarcomas 

Other Techniques for Diagnosis • Electron microscopy: Weibel-­Palade bodies 

Differential Diagnosis Hemangioma • Lacks pleomorphism, mitoses, atypia • Vascular channels lined by a single layer of uniform cells • No necrosis or solid areas 

SPLENIC ANGIOSARCOMA Clinical Features • Although it can occur at any age, it is most common in elderly patients; no sex predominance • Often disseminated at presentation, it may be difficult to ascertain its primary site (splenic vs. extrasplenic origin) • Not associated with vinyl chloride or thorium dioxide (Thorotrast) exposure • Can cause splenic rupture • Fatigue, fever, weight loss, and abdominal pain; cytopenias have been reported •  Prognosis is poor: hematogenous metastases to liver and lung 

Gross Pathology • Splenomegaly, often marked (weight >1000 g common) •  Single or multiple hemorrhagic and necrotic masses or diffuse infiltration, blending with splenic red pulp (Figure 15.27A) 

Histopathology •  Cellular appearances, degree of differentiation, and proliferation vary within and among tumors •  Irregular anastomosing vascular channels or solid masses partially or largely occluding vascular spaces • Cells may be flattened, spindled, polygonal, epithelioid, or small and poorly differentiated; may form papillary projections that protrude into vascular spaces • Cytologic atypia varies from slightly prominent endothelial cells with slight hyperplasia, pleomorphism, and occasional mitoses to anaplastic cells with numerous mitoses, associated with areas of hemorrhage and necrosis (see Figure 15.27B) • EMH and erythrophagocytosis can both be found in some cases 

Figure 15.27  Splenic angiosarcoma.  A, In this case of splenic angiosarcoma, most of the organ is replaced by a neoplastic proliferation characterized by a mixture of spongy and solid areas with extensive necrosis and hemorrhages. B, Pleomorphic neoplastic endothelial cells with a high nuclear-­to-­cytoplasmic ratio and hyperchromatic nuclei lining the vascular spaces. Some of the cells appear to be floating free in the vascular spaces. Mitotic figures could be found easily. Outside the obvious vascular spaces are solid areas composed of cells similar to those lining the larger vascular spaces. Red cells are present in the vascular lumina.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

Hemangioendothelioma • Differentiation from angiosarcoma may be subtle • No necrosis • No solid areas • Less pleomorphism, less atypia, fewer mitoses, and less nuclear hyperchromasia  Hemangiopericytoma • Staghorn vascular channels • No necrosis • Usually few mitoses, little or no cellular pleomorphism • Endothelial cells lining the vascular spaces are a single layer of flattened cells with no atypia •  The proliferating spindle cells surround rather than form the vascular spaces; may be better demonstrated using silver stains • Tumor cells are positive for vimentin and show variable positivity for CD34 • It may correspond to myopericytoma (see “Pearls”)  Kaposi Sarcoma • Elderly men of Mediterranean ancestry or patients with acquired immunodeficiency syndrome (AIDS) • Usually forms small nodules • Composed of spindle cells without papillary formation or vascular channels (except for vessels at the periphery of the nodules) • No necrosis or hemorrhage • Slitlike vascular spaces with eosinophilic globules • Hemosiderin (can also be present in angiosarcoma) • Immunohistochemistry positive for D2-­40, CD34, and HHV-­8  Bacillary Angiomatosis • Typically younger individuals; increased incidence in AIDS patients • No anastomosing vascular channels • Few mitoses, little or no pleomorphism • Grayish interstitial material • Bacteria identified using Warthin-­Starry stain • HHV-­8 negative  Metastatic Melanoma • Patients usually have a history of melanoma elsewhere • Pigment may be melanin • No vascular channels • CD34, CD31, and factor VIII negative in tumor cells • S-­100 protein, HMB-­45, and Melan-­A positive in tumor cells • Electron microscopy can show melanosomes 

845

• M  yopericytoma represents a relatively recently delineated entity showing a hemangiopericytoma-­like vascular pattern; it is likely that at least a proportion of cases that have been previously termed splenic hemangiopericytoma may represent examples of myopericytoma • Most cases of myopericytoma behave in a benign fashion, but local recurrences and rarely metastases have been reported; more recently, a malignant variant has also been described

Selected References Das A, Arya SV, Soni N, et al. A rare presentation of hepatic and splenic cystic malignant fibrous histiocytoma: a case report and literature review. Int J Surg Case Rep. 2013;4:139–141. Falk S, Krishnan J, Meis JM. Primary angiosarcoma of the spleen: a clinicopathologic study of 40 cases. Am J Surg Pathol. 1993;17:959–970. Granter SR, Badizadegan K, Fletcher CD. Myofibromatosis in adults, glomangiopericytoma, and myopericytoma: a spectrum of tumors showing perivascular myoid differentiation. Am J Surg Pathol. 1998;22:513–525. He L, Zhang H, Li X, et al. Primary malignant fibrous histiocytoma of spleen with spontaneous rupture: a case report and literature review. Med Oncol. 2011;28:397–400.

CYSTS AND PSEUDOTUMORAL LESIONS EPIDERMOID CYST (TRUE CYSTS) Clinical Features •  Occurs in children to young adults; no gender predominance • Most likely of mesothelial derivation 

Gross Pathology • Single or, rarely, multiple lesions • Cyst has a trabeculated appearance covered by a shiny lining (resembling endocardium) (Figure 15.28) • Fluid clear to turbid and yellowish; can contain cholesterol crystals 

Histopathology • Thin, fibrous wall with epithelial lining • Epithelium may be attenuated or denuded • Epithelium can be squamous (more often), transitional, or columnar 

Malignant Fibrous Histiocytoma • Rarely primary in spleen • No anastomosing vascular channels • Multinucleated giant cells may be present • Vimentin, α1-­antichymotrypsin, α1-­antitrypsin, and CD68 positive; CD31 and factor VIII negative PEARLS • T  he existence of hemangiopericytoma as a separate entity has been questioned because a number of neoplasms of different lines of differentiation are characterized by a hemangiopericytoma-­like vascular growth pattern

Epidermoid cyst Figure 15.28  Epidermoid splenic cyst.  The wall is thicker, and its trabeculation may be reminiscent of the endocardial surface of the ventricular cavities. The cyst contained clear fluid.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

846

Chapter 15 — Spleen

Special Stains and Immunohistochemistry • Cytokeratin stains highlight the epithelium 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Pseudocyst • No epithelial lining  Parasitic (Echinococcal) Cyst • Adults are most commonly affected • Resident in areas of the world where the parasite is endemic (e.g., Greece); in the United States, the disease is rare, but it has been reported in several states (see also “Parasitic [Echinococcal] Cyst”) • Usually requires significant exposure to animal vectors • Cyst is often multilocular • Hepatic or peritoneal cysts commonly present • Granular wall with small granules in cyst contents • Scolices in wall or secondary cysts PEARLS

PEARLS • U  sually asymptomatic unless infected • Large cysts can rupture; resection is recommended • May be drained under radiologic guidance but are more likely to recur • Thought to be related to splenic trauma and organizing hematoma

PARASITIC (ECHINOCOCCAL) CYST Clinical Features • Occurs in residents of areas of the world where the parasite is endemic (e.g., Greece); in the United States, the disease is rare but has been reported in California, Arizona, New Mexico, and Utah • Adults are most commonly affected; patients usually have significant exposure to animal vectors; risk factors include exposure to cattle, sheep, pigs, or deer or exposure to the feces of dogs, wolves, or coyotes • Cysticercosis can produce grossly similar cysts, differing in the nature of the parasite 

Gross Pathology

T •  rue cysts are usually asymptomatic unless infected • Unclear whether these are congenital developmental abnormalities or the result of subtle abdominal trauma with mesothelial entrapment in the spleen

• Often multilocular • Hepatic or peritoneal cysts commonly present • Granular wall with small granules in cyst contents 

PSEUDOCYST

• Fibrous wall • Daughter cysts or brood capsules containing parasites with scolices • Inflammatory reaction is usually present 

Clinical Features • Four times more common than epithelial cyst • Clinical presentation identical to that of epithelial cyst • Believed to result from degradation of a splenic hematoma of posttraumatic origin or a consequence of cystic degeneration of a splenic infarct or infarcted hemangioma 

Histopathology

Special Stains and Immunohistochemistry • Smears of fluid or touch preparations of cyst wall reveal scolices • Scolices can be highlighted by stain for acid fast bacilli 

Gross Pathology

Other Techniques for Diagnosis

• Same as for epithelial cyst, but fluid is usually darker reddish brown 

• Noncontributory 

Histopathology

Epithelioid Cyst (see “Epidermoid Cyst [True Cysts]”) • No inflammation • No scolices • Epithelial lining 

• Smooth internal surface (rather than trabeculated) • Fibrous wall without epithelial lining • Calcification in wall • Cholesterol clefts can be present 

Differential Diagnosis

• Cytokeratin negative 

Pseudocyst • No inflammation • No scolices

Other Techniques for Diagnosis

PEARLS

Special Stains and Immunohistochemistry

• Noncontributory 

Differential Diagnosis Epithelioid Cyst • Epithelial lining present  Parasitic Cyst • See “Parasitic (Echinococcal) Cyst”

• Intraoperative rupture of the cyst with leakage of cyst contents can cause peritoneal dissemination of the disease and can be fatal

Selected References Garvin DF, King FM. Cysts and nonlymphomatous tumors of the spleen. Pathol Ann. 1981;16:61–80.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen Hirabayashi K, Kawanishi A, Morimachi M, et al. Histological and immunohistochemical analyses of splenic epidermoid cysts. Ann Diagn Pathol. 2019;41:51–56. Hulzebos CV, Leemans R, Halma C, de Vries TW. Splenic epithelial cysts and splenomegaly: diagnosis and management. Neth J Med. 1998;53:80–84.

SPLENIC HAMARTOMA (SPLENOMA) Clinical Features • Occurs at any age • Usually asymptomatic • Rarely causes abdominal pain or thrombocytopenia 

Gross Pathology • Usually single nodule (Figure 15.29A) • Size ranges from less than 1 cm to about 10 cm • Color usually resembles splenic red pulp • Bulging cut surface • Fleshy consistency • Well circumscribed but not encapsulated • Can have foci of infarction and fibrosis 

847

Histopathology (Figure 15.29B and C) • A tumor-­like lesion composed of structurally disorganized splenic red pulp tissue • Resembles normal red pulp with no “organized” white pulp within the lesion; may, however, contain scattered lymphocytes • Consists of both cordal and sinus-­like structures •  Compressed red pulp at the periphery, but no true capsule •  Can have foci of infarction and fibrosis, sometimes with hemosiderin deposition •  May contain immature hematopoietic cells and eosinophils • May show significant fibrosis • A histiocyte-­rich variant has also been described Special Stains and Immunohistochemistry • Endothelial lining cells are positive for CD8 and CD68 and negative for CD34 •  Reticulin stain shows a disorganized sinusoidal wall with partial loss of ring fibers 

Figure 15.29  A, Splenic hamartoma (splenoma), gross photograph. Hamartoma presents as a well-­demarcated, bulging lesion displaying a characteristic “red pulp only” appearance. B, Splenic hamartoma. Flattened endothelial cells line irregular vascular spaces, which are surrounded by disorganized red pulp tissue. Unlike a hemangioma, both the blood vessels and other red pulp spaces are disorganized. C, Splenic hamartoma (splenoma), cordal variant. A predominance of cordal macrophages is noted. Occasionally, this may resemble an inflammatory pseudotumor.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

848

Chapter 15 — Spleen

Other Techniques for Diagnosis • Noncontributory 

SCLEROSING ANGIOMATOID NODULAR TRANSFORMATION OF SPLEEN (SANT)

Differential Diagnosis

Clinical Features

Hemangioma • Hemorrhagic, not fleshy or bulging • Darker than red pulp • Vascular endothelial differentiation only, no sinus-like structures • Endothelial lining cells are CD34 positive; CD68 and CD8 negative 

• Occurs at any adult age with female predominance • Usually incidental finding on imaging, sometimes with abdominal pain •  May be associated with hematopoietic and non-­ hematopoietic neoplasms 

Littoral Cell Angioma • Usually multifocal dark, purplish black, spongy lesions • Irregular vascular spaces all of one type •  Mostly polygonal to tall lining cells with luminal shedding • Endothelial lining cells are CD68 and CD31 positive, CD34 negative  Inflammatory Pseudotumor • Usually paler than surrounding parenchyma • Lacks sinus structures • Numerous plasma cells and lymphocytes • Prominent spindle cell component • A proportion are EBV positive PEARLS • T  here is still controversy about whether this is a neoplasm or a “true” hamartoma • Always benign • Occurs only in spleen

Selected References Chiu A, Czader M, Cheng L, et al. Clonal X-­chromosome inactivation suggests that splenic cord capillary hemangioma is a true neoplasm and not a subtype of splenic hamartoma. Mod Pathol. 2011;24:108–116. Krishnan J, Frizzera G. Two splenic lesions in need of clarification: hamartoma and inflammatory pseudotumor. Semin Diagn Pathol. 2003;20:94–104.

A

Gross Pathology • Size ranges from 3 cm to 17 cm •  Well-circumscribed unencapsulated mass with multiple red-­brown nodules 

Histopathology • Well-circumscribed mass compressing adjacent spleen •  Multiple individual or confluent vascular/angiomatoid nodules surrounded by collagen fibers (Figure 15.30A) •  Variable fibrosclerotic stroma containing myofibroblasts, siderophages, plasma cells, and lymphocytes • Nodules composed of slitlike vascular spaces lined by plump endothelial cells (see Figure 15.30B) 

Immunohistochemistry • Mixture of different types of blood vessels • Sinusoids positive for CD31 and CD8, negative for CD34 • Capillaries positive for CD34 and CD31, negative for CD8 • Small veins positive for CD31, negative for CD34 and CD8 • Vascular lining cells are negative for D2-­40 and CD21 

Differential Diagnosis Littoral Cell Angioma • Distinct immunophenotype of lining cells: positive for CD31 and CD68, negative for CD34 and CD8  Hemangioma • Lacks typical trivascular pattern seen in SANT

B

Figure 15.30  Sclerosing angiomatoid nodular transformation (SANT).  A, Low power magnification demonstrating multiple nodules surrounded by dense fibrosis. B, Nodules are composed of slitlike vascular spaces lined by plump endothelial cells, and fibrosclerotic stroma.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

• Blood vessels positive for CD34 and CD31, negative for CD8, CD21, and CD68  Lymphangioma • Often cystic, filled with proteinaceous fluid • Lymphatic lining cells are positive for D2-­40, negative for CD21 and CD8  Splenic Hamartoma • Lacks typical trivascular pattern seen in SANT • Sinusoidal lining cells are positive for CD8 and CD68, negative for CD34 PEARLS N •  on-­neoplastic vascular lesion • N  odular transformation in response to an exaggerated non-­neoplastic stromal proliferation • Splenectomy has been curative in all cases reported

Selected References Awamleh AA, Perez-­Ordonez B. Sclerosing angiomatoid nodular transformation of the spleen. Arch Pathol Lab Med. 2007;131:974–978. Martel M, Cheuk W, Lombardi L, et al. Sclerosing angiomatoid nodular transformation (SANT): report of 25 cases of a distinctive benign splenic lesion. Am J Surg Pathol. 2004;28:1268–1279.

INFLAMMATORY PSEUDOTUMOR OF THE SPLEEN Clinical Features • Can occur at any adult age, often in older individuals •  Can be asymptomatic or present with fever, weight loss, or abdominal pain •  Rarely present in more than one organ in a given patient 

Gross Pathology • Size ranges from less than 1 cm up to 10 cm • Usually single but can be multiple; multiple lesions are usually small • Well circumscribed, pale to white, and bulging, often with central necrosis 

849

Histopathology (Figure 15.31) •  Irregularly oriented, bland spindle cells intermixed with variable numbers of lymphocytes, plasma cells, macrophages (which can be foamy), and neutrophils with usually, only rare eosinophils • No proliferative activity or cellular atypia •  Occasional features: sclerosis, hemorrhage, necrosis, calcification, and hemosiderin deposits 

Special Stains and Immunohistochemistry •  Spindle cells have smooth muscle differentiation: muscle-­specific actin, SMA, sometimes desmin positive •  In the “truly inflammatory pseudotumor (IPT),” the epithelioid and spindle cells are positive for vimentin and CD68 but lack expression of follicular dendritic cell markers and actin • A proportion of cases may show an increased IgG4/IgG ratio; in these cases the patient should be evaluated to exclude chronic pancreatitis or other evidence of “IgG4 related disease” • Lymphocytes are mostly T-cells • Plasma cells are polyclonal 

Differential Diagnosis Inflammatory Pseudotumor-­like Follicular Dendritic Cell Tumor (IPT-­like FDCT) • Shows marked female predilection • Spindle cells that are mostly bland admixed with lymphocytes and plasma cells • Spindle cells are strongly positive for EBER and follicular dendritic cell markers (CD21, CD23, or CD35). The FDC markers can be focal or weak. Presence of SMA positivity does not rule out the diagnosis  Splenic Hamartoma • Nodules are red and fleshy rather than pale • Contains sinus-­like structures, no solid areas except in foci of fibrosis • Less inflamed cellular background with fewer lymphocytes and plasma cells 

Figure 15.31  Inflammatory pseudotumor.  A, Macrophages and relatively rare myofibroblasts are found associated with numerous inflammatory cells, particularly plasma cells. B, The lesion has a predominance of spindle cells. Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

850

Chapter 15 — Spleen

Castleman Disease •  More often multifocal; patients usually have lymph node involvement • Distinct germinal centers (hyalinized or hyperplastic) in the lesion • Spindle cells not prominent • Sheets of plasma cells present in plasma cell and multicentric types  Hodgkin Lymphoma • Patients have Hodgkin lymphoma elsewhere • Eosinophils often numerous • Hodgkin-­Reed-­Sternberg cells present  Plasmacytoma • Occurs in older adults • Patients usually have known multiple myeloma •  Sclerosis is rare (exception: an osteosclerotic variant associated with hepatosplenomegaly known as POEMS syndrome [polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, and skin hyperpigmentation]) • Plasma cells are monoclonal  Follicular Dendritic Cell Sarcoma (versus IPT-­Like Follicular Dendritic Cell Tumor of the Spleen) • Sheets of plump spindle cells • Infiltrative growth pattern • Cells are CD21- and CD35-­positive and SMA-­negative • A small proportion of cases have been associated with Castleman disease of the hyaline-­ vascular type, and others with EBV infection  Mycobacterial Pseudotumor • Patients with AIDS • Most have mycobacteriosis elsewhere •  Few spindle cells (exception is the rare mycobacterial spindle cell pseudotumor, a lesion seen in immunocompromised patients, composed of proliferative spindle cells admixed with histiocytes and inflammatory cells associated with the presence of Mycobacterium avium-­intracellulare) • Sheets of large macrophages with abundant gray cytoplasm, not foamy cells • Acid-­fast stain positive • Culture for mycobacteria positive  Bacillary Angiomatosis • AIDS patients • Vascular proliferation • Gray interstitial material • Bacteria in interstitial material positive with Warthin-­ Starry stain • HHV-­8 negative PEARLS • Its precise characterization relies on a combination of morphology and immunohistochemistry • It should be distinguished from inflammatory myofibroblastic tumor, a clonal myofibroblastic proliferation which is ALK positive; this entity has not yet been reported to occur in the spleen

Selected References Kutok JL, Pinkus GS, Dorfman DM, et al. Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor. Hum Pathol. 2001;32:1382–1387. Neiman RS, Orazi A. Splenic cysts, nonhematopoietic tumors, and tumor like lesions. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:249–285.

INFLAMMATORY PSEUDOTUMOR-LIKE FOLLICULAR DENDRITIC CELL TUMOR (IPT-­LIKE FDCT) Clinical Features • Occurs in middle-­aged adults with a female predilection • Involves liver or spleen, sometimes simultaneously • Presentation is asymptomatic or with abdominal pain/ distension 

Gross Pathology • Solitary, well circumscribed, firm tan or yellow-­white lesion • Areas of necrosis or hemorrhage are common 

Histopathology •  Proliferation of spindle cells admixed with lymphocytes and plasma cells (Figure 15.32A) • Spindle cells are mostly bland with vesicular nuclei and small distinct nucleoli; a small subset of spindle cells with nuclear atypia are usually present • Histiocytic or granulomatous reaction may be present sometimes with prominent epithelioid granulomata • Necrosis and hemorrhage are common •  Admixed blood vessels with ectasia and fibrinoid deposits in walls are often present • Occasional cases may contain Reed-­Sternberg–like cells 

Special Stains and Immunohistochemistry • Spindle cells are usually positive for at least one follicular dendritic cell marker (CD21, CD23, or CD35); positivity may be focal or extensive • Spindle cells may be positive for smooth muscle actin (SMA) • Spindle cells are consistently positive for EBV (EBER); inflammatory cells are negative for EBER (Figure 15.32B) •  Spindle cells are negative for desmin, caldesmon, CD31, CD34, S100, ALK, and CD30 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis See “Differential Diagnosis” for “Inflammatory Pseudotumor of the Spleen” PEARLS Inflammatory pseudotumor-­like follicular dendritic cell tumor is positive for EBER in the spindle cells, which is a monoclonal episomal form. The clinical course is usually indolent; however, repeated recurrences can develop, particularly in cases also involving the liver.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

A

851

B

Figure 15.32  Inflammatory pseudotumor-­like follicular dendritic cell tumor.  A, Proliferation of spindle cells admixed with lymphocytes and fewer plasma cells. B, Spindle cells are positive for EBER; the inflammatory background is negative for EBER.

Figure 15.33  Fibrocongestive splenomegaly (chronic passive congestion).  A, High-­power magnification of red pulp. Both cords and sinuses are distended and are surrounded by an increased amount of stroma, which imparts a rigid appearance to the red pulp. B, Increased expression of smooth muscle actin due to a reactive hyperplasia of splenic myoid cells is a characteristic finding seen in spleen with chronic passive congestion.

Selected References Brittig F, Ajtay E, Jakso P, et al. Follicular dendritic reticulum cell tumor mimicking inflammatory pseudotumor of the spleen. Pathol Oncol Res. 2004;10:57–60. Horiguchi H, Matsui-­ Horiguchi M, Sakata H, et al. Inflammatory pseudotumor-­like follicular dendritic cell tumor of the spleen. Pathol Int. 2004;54:124–131. Lewis JT, Gaffney RL, Casey MB, et al. Inflammatory pseudotumor of the spleen associated with a clonal Epstein-­Barr virus genome: case report and review of the literature. Am J Clin Pathol. 2003;120:56–61. Van Baeten C, Van Dorpe J. Splenic Epstein-­ Barr virus-­ associated inflammatory pseudotumor. Arch Pathol Lab Med. 2017;141:722–727.

CIRCULATORY ABNORMALITIES CONGESTIVE SPLENOMEGALY Clinical Features • Occurs in patients with liver cirrhosis causing portal hypertension

• Occurs in patients with splenic vein thrombosis (e.g., in paroxysmal nocturnal hemoglobinuria or polycythemia vera) 

Gross Pathology • Moderate, diffuse splenic enlargement; weight usually less than 1 kg • White pulp inconspicuous • Red pulp dark, may be firm • Small infarcts common in larger spleens 

Histopathology • White pulp histology is variable • Diffuse expansion of the red pulp (Figure 15.33A) • In early stages, the red pulp is more cellular, becomes fibrotic and hypocellular in later stages • Increased number of hemosiderin-­laden macrophages • Longstanding cases

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

852

Chapter 15 — Spleen

• Fibrosis with excess reticulin deposition in longstanding cases • The sinuses may become dilated (pulled open by the fibrosis) • It may superficially resemble a capillary hemangioma with sclerosis or a hamartoma but is not circumscribed • Gamna-­Gandy bodies can occur (for definition of Gamna-­Gandy bodies, see “Sickle Cell Disease and Variants”) 

Special Stains and Immunohistochemistry • Reticulin stain shows increased fibrosis throughout the red pulp • A diffuse increased expression of SMA (splenic myoid cells) is typical (see Figure 15.33B) 

Other Techniques for Diagnosis • Noncontributory 

Figure 15.34  Vasculitis in a splenic vessel.  The section shows fibrinoid necrosis.

Differential Diagnosis Leukemic Infiltration • Red pulp is diffusely infiltrated by blasts, small lymphocytes, or hairy cells depending on the type of leukemia •  Immunohistochemistry to confirm the diagnosis of leukemia  Lymphoma •  Subtypes of lymphoid neoplasms involving the red pulp (e.g., HSTCL, intravascular large B-­cell lymphoma) • Intrasinusoidal lymphocytosis with cytologic atypia •  Immunohistochemistry to confirm the diagnosis of lymphoma  Myelofibrosis or Other Myeloproliferative Disorders • Lesions are more discrete • Prominent EMH, usually trilineage •  Atypical megakaryocytes often present in primary myelofibrosis or postpolycythemic myelofibrosis • Cellularity often increased  Peliosis • Lesions are more discrete • Dilated sinuses concentrated near white pulp follicles • Multifocal discrete lesions; sinuses appear dilated but there is no perivascular fibrosis PEARLS • C  ongestive splenomegaly can cause hypersplenism; splenectomy may be required • Consider additional causes if spleen weight is greater than 1 kg • Coagulation abnormalities in these patients are more commonly the result of liver disease

Selected References Neiman RS, Orazi A. Chronic passive congestion. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:238–239. O’Reilly RA. Splenomegaly in 2,505 patients at a large university medical center from 1913 to 1995. 1963 to 1995: 449 patients. West J Med. 1998;169:88–97. Sheth SG, Amarapurkar DN, Chopra KB, et al. Evaluation of splenomegaly in portal hypertension. J Clin Gastroenterol. 1996;22:28–30.

VASCULITIDES POLYARTERITIS NODOSA, HYPERSENSITIVITY ANGIITIS (CHURG-­ STRAUSS DISEASE), SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AND THROMBOTIC THROMBOCYTOPENIC PURPURA Clinical Features • Rarely limited to the spleen; more commonly part of a systemic vasculitis • Seen in patients with • Polyarteritis nodosa • Systemic lupus erythematosus • Rheumatoid arthritis • Thrombotic thrombocytopenic purpura • Hypersensitivity angiitis 

Gross Pathology • Multiple infarcts, which can be confluent • Splenic rupture has been reported 

Histopathology • Vasculitis similar to the manifestation of the basic disease in other organs • Infarcts can be present Polyarteritis Nodosa • Small arteries • Fibrinoid necrosis (Figure 15.34) • Neutrophils and eosinophils in vessel walls • Splenic rupture has been reported  Hypersensitivity Angiitis (Churg-­Strauss Disease) • Leukocytoclastic vasculitis in arterioles • Fibrinoid necrosis in small vessels • Eosinophils in infiltrate  Systemic Lupus Erythematosus • Patchy vascular involvement • Leukocytoclastic vasculitis in arterioles

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

853

Postmortem Clot • No lines of Zahn • No true vasculitis • No changes in splenic parenchyma  Amyloidosis • Patients usually have systemic amyloidosis • Eosinophilic deposits around small blood vessels • No vasculitis • Congo red or thioflavin T stains positive PEARLS

Figure 15.35  Systemic lupus erythematosus. Small artery with concentric collagen formation around a vessel. This is also termed onion-­skinning.

• Fibrinoid necrosis in small vessels • Onion-­skin appearance in arterioles owing to concentric perivascular fibrosis (Figure 15.35) • Plasmacytosis in red pulp  Rheumatoid Arthritis • Leukocytoclastic vasculitis in arterioles • Fibrinoid necrosis in small vessels • Splenomegaly in Felty syndrome • Follicular hyperplasia in white pulp • Lacks concentric perivascular fibrosis  Thrombotic Thrombocytopenic Purpura • Platelet-­fibrin thrombi in small vessels; no inflammatory infiltrate • Subendothelial PAS-­positive hyaline deposits • Onion-­skin periarteriolar fibrosis may occasionally be observed 

Special Stains and Immunohistochemistry • Elastic stains for vascular damage 

Other Techniques for Diagnosis •  Direct immunofluorescence for fibrinogen, immunoglobulin, and complement deposits • Serologic studies • Antinuclear antibody test and other anti-­DNA tests for lupus • Rheumatoid factor in rheumatoid arthritis 

Differential Diagnosis • The differential diagnosis in cases of vasculitis includes each of the entities listed previously; additional diseases to consider include the following: Thromboemboli • Patients usually have severe atherosclerotic cardiac disease, or left-­sided endocarditis • Thromboembolic or atheroembolic material in arterioles • True vasculitis only with septic emboli and endocarditis • Elastic stain may be useful 

• S plenic involvement in systemic vasculitis is rarely clinically significant • In lupus and other autoimmune disorders, the changes previously described may have been substantially modified by antecedent therapy (e.g., steroids) • Atypical lymphoid hyperplasia and rarely lymphoma may occur in patients treated with methotrexate for rheumatoid arthritis (methotrexate-­associated lymphoproliferative disorders) • Immunohistology for EBV may be helpful to confirm an immunosuppression-­associated etiology

Selected References Danning CL, Illei GG, Boumpas DT. Vasculitis associated with primary rheumatologic diseases. Curr Opin Rheumatol. 1998;10:58–65. D’Cruz D. Vasculitis in systemic lupus erythematosus. Lupus. 1998;7:270–274. Drenkard C, Villa AR, Reyes E, et al. Vasculitis in systemic lupus erythematosus. Lupus. 1997;6:235–242. Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis and Churg-­Strauss syndrome. Lupus. 1998;7:238–258.

VIRAL AND OTHER NONGRANULOMATOUS INFECTIONS INFECTIOUS MONONUCLEOSIS Clinical Features • Most commonly affecting adolescents and young adults • Patients have fever, malaise, and pharyngitis; rarely, splenic rupture •  May have generalized lymphadenopathy and hepatosplenomegaly • Caused by primary infection with EBV 

Gross Pathology •  Mild to moderate splenomegaly with red pulp congestion and hyperplastic white pulp; rarely, massive spleen enlargement • Splenectomy may have been performed for spontaneous rupture, which should be documented 

Histopathology • Borders between red and white pulp are blurred • Variable degree of follicular hyperplasia in white pulp • Red pulp is expanded by a polymorphic cellular population, which includes pleomorphic lymphocytes, immunoblasts, and plasma cells (Figure 15.36) • PALS may be infiltrated by lymphoid cells, including immunoblasts

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

854

Chapter 15 — Spleen

PEARLS • P  atients with acute infectious mononucleosis may have acute splenomegaly and are at risk for spontaneous splenic rupture • Infectious mononucleosis may be misinterpreted as malignant lymphoma or Hodgkin lymphoma owing to the massive immunoblastic proliferation, which may include Hodgkin-­Reed-­Sternberg–­like cells; the immunoblasts usually lack the typical eosinophilic nucleolus of classical Hodgkin-­Reed-­Sternberg cells • Detailed clinical history, EBV serology, and appropriate immunostains are helpful in the differential diagnosis

Selected References

Figure 15.36  Infectious mononucleosis.  High-­power magnification shows a heterogeneous lymphoid population with numerous immunoblasts.

• Splenic trabeculae, capsule, and vessels are often infiltrated by lymphoid cells 

Gowing NFC. Infectious mononucleosis: histopathologic aspects. Pathol Ann. 1975;1:1–20. Neiman RS, Orazi A. Reactive lymphoid hyperplasia. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:67–84. Reynolds DJ, Banks PM, Gulley ML. New characterization of infectious mononucleosis and a phenotypic comparison with Hodgkin’s disease. Am J Pathol. 1995;146:379–388.

CYTOMEGALOVIRUS INFECTION Clinical Features

• Immunohistochemical stains: large immunoblasts are positive for EBV, CD20, and often CD30 • Activated lymphoid population consists of mixed Bcells and T lymphocytes with a predominance of CD8-­ positive cytotoxic T-cells 

• Uncommon •  Occurs most commonly in immunocompromised patients •  Virus-­ associated hemophagocytic syndrome is a rare complication in early CMV infection; these patients present with general malaise, fever, chills, and leukopenia associated with thrombocytopenia 

Other Techniques for Diagnosis

Gross Pathology

• In situ hybridization for EBER is positive 

• Congested red pulp • White pulp usually inconspicuous • May have small, variably shaped red to pale foci of necrosis 

Special Stains and Immunohistochemistry

Differential Diagnosis Large Cell Lymphoma or T-­Cell/Histiocyte-­Rich Large B-­ Cell Lymphoma •  These lymphoid neoplasms generally form discrete masses in splenic parenchyma • Homogeneous population or B- or T-cells in large cell lymphomas; in T-­cell/histiocyte-­rich large B-­cell lymphoma, the neoplastic B-cells are scattered within a background of small T lymphocytes  Hodgkin Lymphoma • Usually forms discrete, grossly visible nodules rather than causing diffuse splenic enlargement • Classical Hodgkin-­Reed-­Sternberg cells are found scattered within lymphohistiocytic nodules; splenic follicles appear normal or reactive •  Eosinophils and plasma cells may be numerous in Hodgkin lymphoma and are rare in infectious mononucleosis  Reactive Lymphoid Hyperplasia Not Related to Epstein-­ Barr Virus Infection • May present similar histologic findings • Immunohistochemical stains to exclude the presence of other viruses (e.g., cytomegalovirus [CMV]) and correlation with viral serology are necessary for definitive diagnosis

Histopathology • Necrotic foci in cells with viral inclusions are typically found at the periphery of the lesions •  Scattered neutrophils may be present, but there are usually fewer than in bacterial infections 

Special Stains and Immunohistochemistry • Immunohistochemical stains for CMV 

Other Techniques for Diagnosis • In situ hybridization for CMV • Viral serology/cultures 

Differential Diagnosis Abscess • Often lacks viral inclusions, but degenerating cells at the periphery can resemble Cowdry (i.e., owl-­eye inclusion bodies) type A inclusions • Neutrophils more numerous • Bacteria or fungi may be present on appropriate stains or culture  Infarct • Peripheral location under capsule and wedge shape • No viral inclusions

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

855

• Diffuse tumor-­like infiltration is exceptional • Fite stain necessary to demonstrate organisms  Histoplasmosis • Most common in the Ohio River Valley and upper Mississippi River areas and adjacent Midwestern states • GMS and PAS stains demonstrate fungi in macrophages  Gaucher Disease (and Other Metabolic Storage Diseases) • Bone, liver, and joints involved (depending on disease type) • Gaucher cells have wrinkled-­silk appearance •  Stains for organisms negative, but storage products may be PAS positive or acid fast  Figure 15.37  Mycobacterium avium-­intracellulare.  Numerous intracellular organisms on periodic acid–Schiff stain.

PEARLS R •  arely seen in surgical pathology material • Occurs predominantly in immunocompromised patients

Selected Reference Neiman RS, Orazi A. Reactive lymphoid hyperplasia. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:67–84.

MYCOBACTERIUM AVIUM-­INTRACELLULARE Clinical Features • Occurs in patients with AIDS • Most patients present with generalized wasting, hepatosplenomegaly, and lymphadenopathy; anemia is the most common laboratory abnormality 

Gross Pathology • Variable degree of splenomegaly • White pulp variable, atrophic to hyperplastic • Diffuse, firm expansion of the red pulp 

Histopathology (Figure 15.37) • Diffuse expansion of red pulp by numerous large macrophages with abundant pale-­gray–staining cytoplasm • Erythrophagocytosis may be present 

Special Stains and Immunohistochemistry • AFB, Fite, and PAS stains are used to demonstrate the bacilli in the macrophages •  Wright-­or Papanicolaou-­ stained touch preparations may reveal negative images of the bacilli in macrophage cytoplasm 

Other Techniques for Diagnosis • Cultures 

Differential Diagnosis Lepromatous Leprosy •  Involvement is most intense in skin, nerves, and extremities; peripheral disease predominates clinically • History of residence in area where leprosy is endemic • Spleen usually contains clusters of macrophages filled with acid-­fast organisms (lepra cells)

Langerhans Cell Histiocytosis • Usually occurs in young children • Cells have pale pink cytoplasm and bean-­shaped nuclei • Eosinophils are usually prominent • Acid-­fast stain and microbiologic studies negative • Cells are S-­100 protein, langerin, and CD1a positive  Pneumocystis Carinii • Extracellular foamy exudate •  GMS or immunohistochemical stain highlight the organisms  Malaria • History of travel or residence in endemic area • Patients are anemic with intermittent fevers • Spleen is black with malarial pigment •  Macrophages contain red cells, malarial pigment, or both •  Stains for organisms may be difficult to interpret because of malarial pigment, but acid-­ fast stain is negative PEARLS • H  istory is important • Look for additional diseases in AIDS patients, including the following: • Other infections • Aggressive lymphoma • Kaposi sarcoma

Selected References Brettle RP. Mycobacterium avium intracellulare infection in patients with HIV or AIDS. J Antimicrob Chemother. 1997;40:156–160. Horsburgh Jr R. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS. J Infect Dis. 1999;179(suppl 3):S46 1-­S465.

MALARIA Clinical Features • Affects children and young adults living in endemic areas • History of travel or residence in an area where malaria is endemic •  Episodic recurrent fevers, hemolytic anemia, and hemoglobinuria • Most common cause of splenic rupture worldwide 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

856

Chapter 15 — Spleen

Gross Pathology •  Splenomegaly, most prominent in Plasmodium vivax infection • Acute phase: splenomegaly with dark-­red parenchyma due to congestion and deposition of malarial pigment (hemozoin); splenic rupture most frequent in acute phase •  Chronic phase: marked splenomegaly, gray discoloration with areas of fibrosis and scarring • White pulp normal to hyperplastic • Rarely, development of splenic pseudocyst due to cystic degeneration of hematoma or hemorrhagic infarct 

Histopathology Acute Phase • Venous sinuses engorged with parasitized red cells •  Proliferation of cordal macrophages and desquamation of sinus-lining cells containing phagocytosed erythrocytes • Increase in small lymphocytes (γδ T-cells) in red pulp • Macrophages lining the sinuses contain hemosiderin, red cell debris, and malarial pigment • Erythrocytes containing parasites can be seen in the sinuses in falciparum malaria • Sinus-lining cells may contain malarial organisms  Chronic Phase • Fibrosis and scarring •  Macrophages with malarial pigment concentrated around PALSs • Syndrome of hyperactive malarial splenomegaly • Common presentation of chronic infection in endemic areas • Sinusoidal and reticuloendothelial hyperplasia • Intense splenic sequestration and phagocytosis of erythrocytes 

Special Stains and Immunohistochemistry • Malarial pigment • Refractile, birefringent • Not melanin • Negative on iron stain (although macrophages will also contain hemosiderin) •  Thick film of peripheral blood stained to look for organisms 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Leishmaniasis • No malarial pigment in macrophages • Amastigotes of Leishmania species can be detected with Wright-­Giemsa staining • Splenic histology otherwise identical  Hemochromatosis •  Prolonged history of dark bronzed skin, arthralgias, and involvement of pancreas, liver, and heart • Symptoms associated with malaria, such as anemia and fevers, are not present • Abundant iron in tissues 

Formalin Pigment • Artifact of prolonged fixation in unbuffered formalin • Histologically similar to malarial pigment • Clinical manifestations of malaria are lacking PEARLS • D  iagnosis should be supported by clinical history and peripheral blood smear findings

Selected References Edington GM. Pathology of malaria in West Africa. Br Med J. 1967;1:715–718. Herwaldt BL. Leishmaniasis. Lancet. 1999;354:1191–1199. Neiman RS, Orazi A. Non-­neoplastic disorders of erythrocytes, granulocytes and platelets. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:67–84. Venizelos I, Tatsiou Z, Papathomas TG, et al. Visceral leishmaniasis in a rheumatoid arthritis patient treated with methotrexate. Int J Infect Dis. 2009;13:169–172.

PYOGENIC BACTERIAL INFECTIONS (ABSCESS) Clinical Features • Occurs in patients with acute systemic bacterial infections with hematogenous dissemination (e.g., patients with bacterial endocarditis) • Most often gram-­positive organisms, particularly Staphylococcus species 

Gross Pathology • Follicular hyperplasia with enlarged prominent white pulp follicles; not always present in immunocompromised or clinically septic patients • Abscesses are localized to white pulp and variably sized, soft to liquid, cream-­colored to greenish • May be surrounded by a thin rim of hyperemic tissue 

Histopathology • Septic emboli produce infarcts as well as abscesses •  Abscesses contain neutrophils and necrotic debris; older abscesses may be surrounded by granulation tissue or fibrous tissue 

Special Stains and Immunohistochemistry • Gram stain or fungal stains for organisms 

Other Techniques for Diagnosis • Microbiologic cultures for organisms 

Differential Diagnosis Splenic Infarct • Usually larger than abscess • Peripherally located and wedge shaped rather than round • Examine arteries carefully for thrombi or emboli • Infarcts are pale but firm, not liquid • Inflammation, if present, is most intense at the periphery of the infarct  Hodgkin Lymphoma •  Necrotic nodules of Hodgkin lymphoma; these are usually better circumscribed, firm to fibrotic, and

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

elevated above the cut surface of the spleen, but they may also form tumorous lumps under the splenic capsule • Nodules of Hodgkin lymphoma contain lymphocytes, Reed-­ Sternberg or Hodgkin cells, eosinophils, and plasma cells  Extramedullary Hematopoiesis • Rarely forms grossly evident nodules •  Clusters of erythroid precursors are usually evident on microscopic examination and are often the predominant cell type; also look for myeloid cells and megakaryocytes PEARLS • S plenic abscesses are seen more often on autopsy than in surgically resected spleens • When seen in a surgical specimen removed for other indications, consider the possibility of splenic embolization with infarcts

Selected Reference Neiman RS, Orazi A. Reactive lymphoid hyperplasia. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:67–84.

GRANULOMATOUS DISEASES SARCOIDOSIS, MILIARY TUBERCULOSIS, HISTOPLASMOSIS, COCCIDIOIDOMYCOSIS, AND LIPOGRANULOMAS Clinical Features Sarcoidosis • See Chapter 4 •  Patients usually have hilar adenopathy, pulmonary symptoms, or other sites of involvement •  Most common in African Americans; female predominance • Schaumann bodies and asteroid bodies may be present but are not diagnostic • Small foci of necrosis may be present • Stains and culture for infectious agents are negative 

857

Coccidioidomycosis • Occurs at any age • Splenic involvement is uncommon but can occur in elderly and immunocompromised patients • Occurs in California in the San Joaquin and Central Valleys (valley fever) and in the southwestern United States • Clinical spectrum ranging from asymptomatic infection to disseminated disease  Lipogranulomas • Lipogranulomatosis refers to the presence, in lymph nodes and spleen, of lipid material arising from endogenous sources, such as tumors, hematomas, cholesterol deposits, fat embolism, and fat necrosis • Common in the spleen (seen in 20% of splenectomy specimens and 62% of autopsy specimens; incidence increases with age) • Usually is an incidental finding without a clear etiology in spleens examined for other indications 

Gross Pathology Sarcoidosis • Often not seen grossly; white pulp inconspicuous •  Occasionally will show multiple small, round, well-­ circumscribed nodules  Miliary Tuberculosis • Modest splenomegaly • Small (1-­to 2-­mm diameter) whitish nodules resembling white pulp follicles; miliary pattern (Figure 15.38) • Larger confluent granulomas with dry, caseous to calcified material are uncommon  Histoplasmosis • May present with splenomegaly and hypersplenism • Spherical yellow to white calcified granules 1 to 2 mm in diameter • May present as a miliary pattern 

Miliary Tuberculosis • Occurs most often in elderly patients with history of tuberculosis and in immunocompromised patients  Histoplasmosis • Occurs at any age • Clinical spectrum ranging from asymptomatic infection to disseminated disease •  Splenic involvement more common in elderly and immunocompromised patients • Histoplasmosis is most common in the upper Midwest, upper Mississippi River, and the Ohio River regions • Organism found in soil • Pigeons are common vectors; exposure to pigeon droppings can lead to infection 

Figure 15.38  Miliary tuberculosis.  In this gross photograph, notice the multiple whitish granulomas with necrosis. In patients with miliary tuberculosis, especially immunocompromised patients, the granulomas are often less well formed and lack grossly visible necrosis.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

858

Chapter 15 — Spleen

Coccidioidomycosis •  Spherical yellow to white granules, 1 to 2 mm in diameter • May present as a miliary pattern  Lipogranulomas • Not seen on gross examination 

Histopathology Sarcoidosis • More commonly localizes to white pulp • Small epithelioid granulomas similar to those seen in lung and lymph nodes • Schaumann bodies and asteroid bodies may be present but are not diagnostic • Small foci of necrosis can be seen  Miliary Tuberculosis • Scattered randomly in the white and red pulp, may be more frequent in the latter • Granulomas with central caseous necrosis • Multinucleated Langhans giant cells are characteristic • Epithelioid cells and lymphocytes also are present • Lesions may calcify  Histoplasmosis • Scattered randomly in the white and red pulp, may be more frequent in the latter • In the acute phase, the infection often does not form distinct granulomas but manifests as small collections of histiocytes containing fungal forms, with an infiltrate of plasma cells and lymphocytes • Neutrophils are usually not seen • Old, inactive lesions are more common; these are partially calcified fibrous nodules with a few lymphocytes at the periphery • Histiocytes are generally not seen • Organisms can be detected with GMS stain  Coccidioidomycosis • Scattered randomly in the white and red pulp, may be more frequent in the latter •  Granulomas may have central necrosis, and fungal forms may be seen on H&E, GMS, and PAS stains  Lipogranulomas • Localized in the white pulp in the vicinity of arterioles, not seen within germinal centers • Small, ill-­defined aggregates of macrophages with single large or numerous small lipid vacuoles 

Special Stains and Immunohistochemistry • GMS, PAS, and acid-­fast stains to rule out infectious granulomas required in all cases • Additional techniques • Acid-­fast and fungal culture recommended; these organisms can survive snap-­freezing 

Other Techniques for Diagnosis • Noncontributory 

Figure 15.39  Amyloidosis. Masses of amorphous eosinophilic extracellular material (amyloid) replace normal splenic tissue. A few sinuses and blood vessels remain.

Differential Diagnosis • See all “Granulomatous Diseases” PEARLS • S pecial stains for microorganisms are essential when granulomas are present in the spleen sample • Correlation with results of culture or other microbiology studies from spleen or other source (e.g., blood) is helpful

Selected Reference Neiman RS, Orazi A. Granulomatous disorders. In: Disorders of the Spleen. 2nd ed. Philadelphia: WB Saunders; 1999:85–96.

OTHER CONDITIONS AMYLOIDOSIS Clinical Features • Most occur in older adults • Occur in patients with systemic amyloidosis • AL-­type amyloid in patients with plasma cell dyscrasia • AA-­type amyloid found in patients with tuberculosis, rheumatoid arthritis, or other chronic inflammatory processes 

Gross Pathology •  Three patterns; these do not correlate with amyloid protein type • Incidental: seen only on microscopic examination • Sago spleen: grayish-­white, small, multiple nodules resembling exaggerated white pulp • Lardaceous spleen: enlarged spleen with diffuse infiltration; dark, firm, rubbery 

Histopathology (Figure 15.39) •  Amyloid is a bright-­ pink (eosinophilic) amorphous hyaline-­like material • Incidental type: amyloid deposits around small vessels

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 15 — Spleen

• Sago spleen: deposits surround cells in the white pulp, eventually with replacement and atrophy of the white pulp • Lardaceous spleen: deposits in the red pulp adjacent to sinus walls and around small vessels; may become confluent and replace the red pulp 

Selected References

Special Stains and Immunohistochemistry

HEMATOMA AND TRAUMATIC RUPTURE

•  Congo red (apple-­ green birefringence with polarized light) or thioflavin T stain (fluorescent microscope) •  Immunohistochemistry for amyloid chain type and immunoglobulin light chains 

Other Techniques for Diagnosis • Electron microscopy: shows fibrils (generally not needed) • Mass spectrophotometry to determine type of amyloid-­ related protein 

Differential Diagnosis Castleman Disease, Hyaline-­Vascular Type • Rare in spleen •  Hyalinized follicular centers with penetrating arterioles, no perivascular hyaline deposits  Infarct • Grossly irregular, wedge-­shaped • Peripheral location, rarely diffuse • Microscopy shows coagulative necrosis  Granulomas •  Cores contain necrotic material or epithelioid giant cells (no amorphous uniform material); however, old granulomas can be extensively hyalinized  Hyalinosis •  A common, usually incidental microscopic finding occurring at any age after early childhood • Eosinophilic hyaline thickening of small arteries and arterioles in the spleen • Looks like early amyloid • Deposits are composed of plasma proteins • Congo red or thioflavin T stains negative PEARLS • C  lassification of amyloid is based on the protein type; 23 different fibril proteins are described in human amyloidosis and are associated with variable clinical features • AL amyloid is derived from immunoglobulin light chains, more often λ than κ, and is associated with plasma cell dyscrasias or B-­cell lymphoproliferative disorders • AA amyloid is derived from SAA protein, an acute-­phase reactant; accumulates in chronic inflammatory processes • Amyloid is also present in patients with familial Mediterranean fever (FMF), a febrile disease characterized by acute, spontaneously resolving episodes of fever and pain caused by serosal inflammation and associated with mutations in the FMF gene, MEFV (Mediterranean fever)

859

Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898–909. Westermark P. The pathogenesis of amyloidosis: understanding general principles. Am J Pathol. 1998;152:1125–1127.

Clinical Features •  Hematoma usually follows blunt trauma to the abdomen • Hematoma results from an internal tear without capsular rupture • Rupture may follow blunt abdominal trauma or penetrating injury •  Rupture can occur without abdominal trauma in patients with • Infections: malaria, infectious mononucleosis • Tumors: leukemia, lymphoma, angiosarcoma • Congestion • Rupture can occur “spontaneously” in a patient with a normal spleen (owing to cough, vomiting) 

Gross Pathology Hematoma • Spleen is expanded by an irregularly shaped soft, dark mass of blood • Capsule is intact • Parenchyma otherwise grossly normal  Rupture • Capsular tear with adherent blood clot •  Weigh spleen after removal of blood clot and gross examination to exclude spontaneous rupture from underlying splenic pathology 

Histopathology Hematoma • Mass of clotted blood • Older lesions may have granulation tissue at the periphery and progressive fibrosis • May be followed by a splenic pseudocyst  Rupture • Similar to hematoma but with capsular tear • Splenic parenchyma is usually normal 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Spontaneous Rupture • Spleen normal or enlarged • No history of abdominal trauma, or minimal abdominal trauma • Histologic features depend on cause 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

860

Chapter 15 — Spleen

PEARLS

Infarct • Lesion shows coagulative necrosis • Wedge-­shaped, peripheral focal lesions • Usually does not cause splenomegaly  Splenic Cyst •  Contents usually clear to turbid liquid hemorrhagic) • Fibrous wall • Epithelial lining may or may not be present  Hemangioma and Other Vascular Tumors • No granulation tissue at periphery • Proliferated blood vessels throughout the lesion

• S plenic hyalinosis has been reported to be more common in ruptured spleens; however, hyalinosis is present in most spleens, including those of children (not

Selected References Orloff MJ, Peskin GW. Spontaneous rupture of the normal spleen: a surgical enigma. Int Abstr Surg. 1958;106:1–11. Pratt DB, Andersen RC, Hitchcock CR. Splenic rupture: a review of 114 cases. Minn Med. 1971;54:177–184. Rawsthorne GB, Cole TP, Kyle J. Spontaneous rupture of the spleen in infectious mononucleosis. Br J Surg. 1970;57:396–398.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16

Bones and Joints ELIZAVETA BELYAEVA  •  JOHN J. SCHMIEG  •  BYRON CRAWFORD

Chapter Outline Osteoid Tumors  861 Osteoma  861

Osteofibrous Dysplasia (Ossifying Fibroma of Long Bones)  887

Osteoid Osteoma  862

Nonossifying Fibroma (Fibrous Cortical Defect, Metaphyseal Fibrous Defect)  887

Osteoblastoma  863 Conventional Intramedullary ­Osteosarcoma  865

Desmoplastic Fibroma  888 Fibrosarcoma  889

Telangiectatic Osteosarcoma  867

Malignant Fibrous Histiocytoma  890

Parosteal Osteosarcoma  868

Giant Cell Tumor  891

Periosteal Osteosarcoma  869

Giant Cell Granuloma (Giant Cell Reparative Granuloma)  893

High-­Grade Surface Osteosarcoma  870 Low-­Grade Central Osteosarcoma  870 Chondroid Tumors  871 Osteochondroma  871 Enchondroma  872 Periosteal Chondroma  874 Chondroblastoma  875 Chondromyxoid Fibroma  876 Intramedullary Chondrosarcoma (Conventional)  877

Adamantinoma  894 Small Cell Neoplasms  895 Ewing Sarcoma/Primitive Neuroectodermal Tumor  895 Lymphoma  896 Multiple Myeloma and Solitary ­Plasmacytoma of Bone  897 Miscellaneous Bone Lesions  899 Chordoma  899 Aneurysmal Bone Cyst  900

Dedifferentiated Chondrosarcoma  879

Unicameral Bone Cyst (Simple Cyst)  901

Mesenchymal Chondrosarcoma  880

Paget Disease of Bone  901

Clear Cell Chondrosarcoma  881

Metastatic Tumors  903

Vascular Tumors  882 Hemangioma  882

Joint and Synovial Diseases  904 Osteoarthritis  904

Epithelioid Hemangioendothelioma  883

Rheumatoid Arthritis  905

Solitary Fibrous Tumor (Formerly Hemangiopericytoma)  884

Gout  906

Angiosarcoma  885 Fibro-­Osseous, Histiocytic, and Giant Cell Lesions  885 Fibrous Dysplasia  885

OSTEOID TUMORS OSTEOMA Clinical Features • Male predominance (2:1 to 3:1) • Age ranges from second decade to elderly, with most cases occurring in fourth and fifth decades

Pseudogout (Chondrocalcinosis–­Calcium Pyrophosphate Deposition Disease)  906 Synovial Chondromatosis  907 Pigmented Villonodular Synovitis  908 •  Occurs most commonly in skull bones, including mandible, maxilla, frontal sinuses, ethmoid sinuses, paranasal sinuses, orbital bones, and calvarium; rarely involves the clavicles and long bones • May be asymptomatic or, if in sinuses, may present with signs of obstruction, including sinusitis and nasal discharges

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

861

862

Chapter 16  —  Bones and Joints

Selected References Larrea-­Oyarbide N, Valmaseda-­Castellon E, Berini-­Aytes L, et al. Osteomas of the craniofacial region: review of 106 cases. J Oral Pathol Med. 2008;37:38–42. Unni KK. Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. Philadelphia: Lippincott-­Raven; 1996:117–120.

OSTEOID OSTEOMA Clinical Features

Fig. 16.1  Osteoma.  Histologic section shows dense lamellar bone.

• Orbital tumors may produce diplopia, exophthalmos, and blindness 

Radiographic Findings • Radiodense, circumscribed surface, or intramedullary mass usually without destructive features 

Gross Pathology • Nodular or dome-­shaped, dense cortical bone 

Histopathology • Consists of dense lamellar bone with or without haversian canals and usually without a medullary component (Figure 16.1) • When a medullary component is present, it is represented by hematopoietic tissue or fibroadipose tissue; the process extends up to uninvolved bone and does not blend in with the adjacent normal bone 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Osteoblastoma • Lamellar bone with prominent osteoblastic rimming • Osteoma may have focal areas of reactive bone with similar features  Parosteal Osteosarcoma • Tumor osteoid is arranged in parallel arrays and separated by a hypocellular fibroblastic stroma PEARLS • A  symptomatic, nodular, radiodense tumor involving craniofacial bones and composed of mature osteoid is typically an osteoma • Gardner syndrome (colonic polyposis, fibromatoses, osteomas, and epidermal cysts of skin) should be considered in the presence of multiple osteomas or osteomas of long bones • If surgically removed, recurrences rarely develop; no reported cases of malignant transformation

• Male-­to-­female ratio of 3:1 • Usually occurs in second or third decade • Most commonly occurs in the leg, usually in the proximal femur • May involve tibia, vertebra (arch more so than body), and small bones of foot and hand • Typically intracortical tumors • Classic clinical presentation includes progressive pain that is greater at night and is relieved by aspirin • Depending on the site, other symptoms may develop • Vertebrae: peripheral nerve compression and painful scoliosis owing to muscle spasms (symptoms of intravertebral disk disease) • Upper and lower extremities: peritumoral muscular atrophy • Epiphyseal tumors: skeletal asymmetry, arthritis, and joint effusions 

Radiographic Findings • Routine radiographs reveal a small, round, central area of radiolucency (nidus) surrounded by sclerosis • Nidus is usually cortical in location and may exhibit central ossification • When plain radiographs fail to reveal the tumor (about 25%), tomograms, bone scans, computed tomography (CT), or magnetic resonance imaging (MRI) may be necessary 

Gross Pathology • Dense sclerotic bone surrounds a central nidus that is round, red, soft, and friable; nidus may be granular if ossified • Typically less than 1 cm 

Histopathology • Central nidus is composed of interlacing thin bone trabeculae or woven bone with variable degrees of mineralization (Figure 16.2) • Trabeculae may vary in thickness • Prominent benign osteoblastic rimming of the trabeculae and multinucleated osteoclast-­ like giant cells are present within intervening fibrovascular stroma • Outside the nidus is an abrupt zone of fibrovascular tissue surrounded by sclerotic compact lamellar bone • No cartilage in the tumor unless there has been a fracture at the tumor site • No hematopoietic tissue or adipose tissue within the tumor 

Special Stains and Immunohistochemistry •  In short decalcified biopsies, FosB proto-oncogene, AP-1 Transcription Factor Subunit (FOS) immunohis-

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

863

PEARLS

Fig. 16.2  Osteoid osteoma.  Histologic section shows a central nidus of thin bony trabeculae with prominent benign osteoblastic rimming.

tochemistry can be used to diagnose osteoid osteoma and osteoblastoma, as overexpression is seen in the majority, while being rare in their mimics 

Other Techniques for Diagnosis • Osteoid osteoma is shown to harbor FOS (87%) and FosB proto-oncogene, AP-1 Transcription Factor Subunit (FOSB) (3%) rearrangements • Preoperative tetracycline allows osteoblastic incorporation in the nidus, which is fluorescent under ultraviolet light • Preoperative intravenous technetium-­99 m with specimen autoradiography is another technique that may be used to identify a small nidus when curettage is used • May express c-­fos and c-­jun by immunohistochemical analysis; some cases have demonstrated partial deletion of the long arm of chromosome 22 (22q13.1) 

Differential Diagnosis Osteomyelitis and Bone Abscesses • Lack a central nidus • Prominent acute inflammatory cell infiltrate  Osteoblastoma • Pain is usually not as severe • Tumor size is usually much greater, and there is evidence of progressive growth • Lacks a peripheral rim of fibrovascular tissue •  Exhibits variable mineralization and thickness of woven osteoid trabeculae, whereas the nidus of an osteoid osteoma shows a pattern of central maturation toward a more calcified and thicker woven osteoid trabecula  Osteosarcoma •  Lacks the fibrovascular stroma and osteoblastic rimming of osteoid osteoma • May exhibit chondroid or fibrous differentiation  Stress Fracture • Zonal pattern with central, more mature, denser bone and peripheral woven bone • Cartilage with endochondral ossification may be present

• P  ain is related to the presence of unmyelinated nerve fibers in the fibrovascular stroma of the nidus, production of prostaglandin E2, and production of prostacyclin • Clinical pain may precede radiographic evidence of osteoid osteoma • When osteoid osteoma is present in the small bones of the hands and feet, patients are typically treated for an inflammatory process (osteomyelitis, arthritis) first • Intra-­articular tumors may produce chronic villous synovitis similar to rheumatoid arthritis • Prostaglandin receptors have been identified within bone, and it has been postulated that prostaglandins may also contribute to the formation of osteoid osteoma • Few reports of spontaneous regression of osteoid osteomas • Treatment is surgical removal

Selected References Baruffi MR, Volpon JB, Neto JB, et al. Osteoid osteomas with chromosome alterations involving 22q. Cancer Genet Cytogenet. 2001;124: 127–131. Franchi A, Calzolari A, Zampi G. Immunohistochemical detection of c-­fos and c-­jun expression in osseous and cartilaginous tumors of the skeleton. Virchows Arch [B]. 1998;432:515–519. Freiberger RH, Loitman BS, Helpern M, et al. Osteoid osteoma: a report on 80 cases. Am J Roentgenol. 1959;82:194–205. Lam SW, Cleven AHG, Kroon HM, et al. Utility of FOS as diagnostic marker for osteoid osteoma and osteoblastoma. Virchows Arch. 2020;476(3):455–463. Sim FH, Dahlin DC, Beabout JW. Osteoid-­osteoma: diagnostic problems. J Bone Joint Surg. 1975;57A:154–159. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:119–126.

OSTEOBLASTOMA Clinical Features • Male predominance, with a male-­to-­female ratio of 2:1 to 3:1 •  Occurs in first through fourth decades, with most occurring in second and third decades • Predilection for the vertebral column (arch) and sacrum followed by the mandible and craniofacial bones; the next most common sites are the extremities, where it follows a distribution similar to that of osteoid osteoma • Typically intramedullary • Localized pain may be present, but not with the intensity of an osteoid osteoma • Vertebral tumors may produce scoliosis, muscle atrophy, and neurologic deficits 

Radiographic Features •  Round, well-­ demarcated, expansile, radiolucent zone with a peripheral rim of sclerosis (sclerosis may not be as extensive as in osteoid osteoma) • Central radiolucent zone (nidus) is greater than 1.5 cm; central stippled calcifications may be present • Tumor may be surrounded by an area of new bone formation • About one fourth may exhibit cortical destruction with periosteal new bone formation, suggesting a malignant tumor (osteosarcoma)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

864

Chapter 16  —  Bones and Joints

Other Techniques for Diagnosis • Osteoid osteoma and osteoblastoma are shown to harbor FOS (87%) and FOSB (3%) rearrangements 

Differential Diagnosis Osteoid Osteoma • Usually smaller than 1 cm; clinically, the pain is of greater intensity • Periphery of tumor contains a fibrovascular rim • Nidus exhibits a more zonal pattern with central maturation and less variability in the thickness and degree of mineralization of the osteoid • No evidence of progressive growth  Fig. 16.3  Osteoblastoma.  Histologic section shows an irregular interlacing network of osteoid with prominent osteoblastic rimming.

• Secondary aneurysmal cyst formation may be present 

Gross Pathology •  Features similar to osteoid osteoma; however, these tumors are larger (>1.5 cm) • Central nidus is red, soft, and friable; if calcified, the nidus may be yellow and gritty • Cortical bone may be destroyed or thin, and there may be hemorrhagic cysts within the nidus, representing secondary aneurysmal cyst formation 

Histopathology •  Irregular interlacing network of osteoid with prominent osteoblastic rimming and features of woven bone (Figure 16.3) •  Osteoid may be fine and lacelike with variable mineralization • Osteoblasts have benign cytologic features • Osteoblasts may exhibit abundant mitotic activity but no atypical forms • Osteoid is separated by fibrovascular stroma containing multinucleated osteoclast-­like giant cells • Appears well circumscribed, with tumor osteoid merging with adjacent uninvolved bone • Large blood lakes representing secondary aneurysmal cystic changes may be seen • Cartilage is usually not present in the tumor, although rare cases have been reported • Osteoblasts may have epithelioid features represented by large cells with abundant eosinophilic cytoplasm and enlarged nuclei containing large nucleoli • When epithelioid cells exceed 75% of the osteoblast population, the diagnosis of aggressive osteoblastoma should be made, which denotes an increased risk for recurrence, although no cases of metastases are reported • Rare tumors may contain bizarre, cytologically atypical multinucleated giant cells without mitotic activity (these tumors may be designated bizarre osteoblastoma or pseudomalignant osteoblastoma) 

Special Stains and Immunohistochemistry • In short decalcified biopsies, FOS immunohistochemistry shows as overexpression in the majority 

Giant Cell Tumor • Usually involves the epiphyses of long bones • Rare in vertebrae, but when they occur in a vertebra, the body and not the arch is usually involved • Giant cells in giant cell tumors are larger and contain more nuclei • Often composed of sheets of giant cells • Giant cell tumors contain mononuclear stromal cells  Aneurysmal Bone Cyst •  Similar presentation and radiographic findings as osteoblastoma and also tend to involve the vertebra • Small foci of reactive osteoid may be present in aneurysmal bone cysts, which should not be confused with osteoblastoma  Osteoblastic Osteosarcoma • Radiographically, osteosarcoma is poorly circumscribed with cortical destruction and evidence of periosteal reactive bone • Permeative pattern of growth at the periphery • Stroma of osteosarcoma is sarcomatoid with cytologic atypia and atypical mitoses • Sheets or aggregates of atypical osteoblasts are present in osteosarcoma, in contrast to a single rim of osteoblasts around osteoid in osteoid osteoma • In short decalcified biopsies, FOS immunohistochemistry shows no overexpression PEARLS • A  bout one fourth of the cases of osteoblastoma exhibit radiographic evidence suggesting a malignant tumor (osteosarcoma); differentiation from an osteoblastic osteosarcoma can be difficult (see “Differential Diagnosis”) • In short decalcified biopsies, FOS immunohistochemistry can be used to diagnose osteoid osteoma and osteoblastoma, as overexpression is seen in the majority, while being rare in their mimics

Selected References De Oliveira CR, Mendonca BB, de Camargo OP, et al. Classical osteoblastoma, atypical osteoblastoma, and osteosarcoma: a comparative study based on clinical, histological, and biological parameters. Clinics (Sao Paulo). 2007;62:167–174. Jones AC, Prihoda TJ, Kacher JE, et al. Osteoblastoma of the maxilla and mandible: a report of 24 cases, review of the literature, and discussion of its relationship to osteoid osteoma of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:639–650.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

A

865

B

Fig. 16.4  Conventional osteosarcoma.  A, Gross photograph showing distal femur with destructive tumor mass with medullary and cortical involvement and extension into the surrounding soft tissue. B, Histologic section shows a neoplasm composed of sarcomatous stromal cells embedded in a background of osteoid.

Lam SW, Cleven AHG, Kroon HM, et al. Utility of FOS as diagnostic marker for osteoid osteoma and osteoblastoma. Virchows Arch. 2020;476(3):455–463. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:126–135. Vigorita VJ. Orthopaedic Pathology. Philadelphia: Lippincott Williams & Wilkins; 1999:322–325.

CONVENTIONAL INTRAMEDULLARY ­OSTEOSARCOMA Clinical Features • Slight male predominance, with a male-­to-­female ratio of 1.5:1 •  Bimodal age distribution, with most cases occurring in second decade; a second, smaller peak occurs in patients older than 50 years • Represents the fourth most common cause of malignancy in the pediatric age group • Patients with hereditary retinoblastoma are at increased risk for developing an osteosarcoma •  Other conditions that may be associated with the development of osteosarcoma: Li-­Fraumeni syndrome, Ollier disease, osteoblastoma, fibrous dysplasia, Paget disease of bone, hereditary multiple exostosis, previous radiation or chemotherapy, hypoplastic or aplasia of thumbs, Werner syndrome, and Rothmund-­Thomson syndrome • Occurs in parts of the skeleton with the highest growth rates • Predilection for the distal femur, proximal tibia, and proximal humerus • Approximately 50% of cases occur in the region of the knee •  Typically presents with a history of short-­ term (several weeks to several months), mild, intermittent pain • Affected area may be swollen and tender to palpation, and the overlying skin may exhibit telangiectasia and be warm • Serum alkaline phosphatase may be elevated 

Radiographic Features • Classically shows a large lytic, sclerotic, or mixed lytic-­ sclerotic mass arising in medullary bone of the metaphysis that extends through the cortex and creates a soft tissue mass •  Variable mineralization within the tumor, which causes cloudy opacities •  Outer cortical surface exhibits prominent periosteal reaction represented by Codman triangle, sunbursts, or onion-­skinning •  CT and MRI are used for staging (intramedullary involvement, presence of skip lesions in marrow, and soft tissue involvement) 

Gross Pathology • Resected specimens exhibit an intramedullary metaphyseal mass that has usually penetrated through the cortex and invades into soft tissue (Figure 16.4A) • Marrow extension of the tumor proximally is usually seen, and there may be skip lesions in which normal marrow separates islands of tumor • Gross characteristics of the tumor are heterogeneous and variable, depending on the stromal component • Highly ossified areas are yellow to white and hard • Chondroid areas are lobulated, translucent, and light gray to white •  Osteoblastic areas are firm, white to yellow, and sometimes gritty • Fibroblastic areas are soft and fleshy • Tumor may contain areas of necrosis, hemorrhage, and cystic changes 

Histopathology • Microscopic features may vary considerably in different areas of a tumor • Tumor is basically composed of sarcomatous, spindle-­ shaped cells exhibiting evidence of tumor osteoid production (see Figure 16.4B) •  Sarcomatous stroma is hypercellular and may exhibit osteoblastic, chondroblastic, fibroblastic, or malignant fibrous histiocytoma-­like differentiation

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

866

Chapter 16  —  Bones and Joints

• Cells usually have obvious cytologic malignant features, including brisk mitotic activity with atypical forms • Some cells may exhibit epithelioid features • Tumor osteoid is represented by eosinophilic, amorphous, fibrillary deposits between individual tumor cells or small aggregates of tumor cells •  Early tumor osteoid forms a lacelike pattern around tumor cells, whereas the more advanced type is mineralized and has the appearance of woven tumor bone •  As tumor cells become incorporated with tumor osteoid, they tend to become smaller; this feature is regarded as normalization • Some tumors exhibit prominent chondroblastic differentiation requiring careful search for tumor osteoid •  Fibroblastic areas may exhibit a herringbone pattern; diligent search for tumor osteoid is sometimes required • Some tumors may have large numbers of osteoclast-­ like giant cells and are designated as giant cell–rich osteosarcoma • Some tumors may contain foci rich in vascular structures with an hemangiopericytoma-­like pattern • Small cell variant •  May have features suggestive of Ewing sarcoma/­ primitive neuroectodermal tumor (PNET), mesen­chy­ mal chondrosarcoma, and lymphoma and require immunohistochemistry for differentiation • Presence of tumor osteoid • Rare cases of small cell variant share genetic features of Ewing sarcoma/PNET •  Preoperative chemotherapy may result in tumor necrosis represented by acellular tumor osteoid, acellular chondroid tissue, fibrosis, or hyalinized vascular stroma; preoperative chemotherapy is considered effective when greater than 90% of the tumor is ­ necrotic 

Special Stains and Immunohistochemistry •  SATB2: recently discovered osteoblast transcription factor (nuclear stain) critical for osteoblast lineage commitment •  SATB2 immunohistochemistry can be useful in the diagnosis of osteosarcoma when histologic features of matrix are equivocal (i.e., osteoid vs hyalinized collagen) and when biopsy only samples tumor with undifferentiated appearance 

Other Techniques for Diagnosis • DNA ploidy analysis usually shows prominent aneuploid clones •  Conversion from pretreatment aneuploidy to predominant diploidy after chemotherapy correlates with subtotal or total necrosis of the tumor •  One case of the small cell variant of osteosarcoma reportedly demonstrated chromosome translocation t(11;22)(q24;q12) typical of Ewing sarcoma/PNET; however, subsequent studies have not replicated this result •  Hereditary form shows a loss of function of the RB gene; in nonhereditary form, there may be mutation of the TP53 gene (about 20% of cases) 

Differential Diagnosis Fracture Callus • Callus woven bone or osteoid exhibits a parallel pattern with prominent osteoblastic rimming •  Absence of nuclear atypia and abnormal mitoses in callus • Cartilage with endochondral ossification is present in callus  Osteomyelitis • Radiographic findings may mimic osteosarcoma • Readily differentiated using histologic features  Osteoblastoma • Lacks atypical mitoses, infiltrative pattern, and destructive growth pattern  Giant Cell Tumor •  Giant cell tumors usually affect skeletally mature patients with closed epiphyses • Usually involve the epiphyses and extend toward the articular cartilage • Mononuclear stromal cells without atypia or abnormal mitotic activity • Radiographic findings can help in differentiating these two entities  Chondrosarcoma • Low-­grade chondrosarcoma with areas of ossification may mimic osteosarcoma, whereas chondroblastic osteosarcoma usually contains a high-­grade cartilaginous component •  Dedifferentiated chondrosarcoma contains an osteoblastic osteosarcoma component but retains low-­grade chondrosarcoma foci • Clear cell chondrosarcomas may produce bone, thus imitating osteosarcoma • Presence of clear cells and typical epiphyseal location of clear cell chondrosarcoma help differentiate these two entities  Malignant Fibrous Histiocytoma • Typically occurs in older patients • Lacks tumor osteoid formation  Fibrosarcoma • No production of tumor osteoid  Small Cell Tumors (Ewing Sarcoma/Primitive Neuroectodermal Tumor, Lymphoma, Mesenchymal Chondrosarcoma) •  Small cell variant of osteosarcoma will have tumor osteoid •  Immunohistochemistry may be helpful in differentiating these tumors (leukocyte common antigen [LCA] is positive in lymphoma, S-­100 protein is positive in mesenchymal chondrosarcoma, CD99 is positive in Ewing sarcoma/PNET, SATB2 is positive in osteosarcomas)  Metastatic Carcinoma • Prostate and mammary carcinomas can elicit a prominent osteoblastic reaction

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

867

•  Epithelial markers and specific tumor markers by immunohistochemistry can help differentiate metastatic carcinoma PEARLS • O  steosarcoma is the fourth most common malignant tumor found in adolescents; the three most common ones in descending order are leukemia, brain tumors, and lymphoma • If pain has been present for more than 1 year, the diagnosis of osteosarcoma is unlikely • About half of cases of primary osteosarcomas of bone occur in the knee region; osteosarcomas of the hands and feet are rare • Initial clinical presentation of osteosarcoma as a pathologic fracture is rare • Elevated serum alkaline phosphatase levels typically occur in tumors with prominent osteoblastic patterns but may also be elevated in other conditions such as osteoblastoma, osteomyelitis, and callus; a posttherapy increase in serum alkaline phosphatase suggests metastatic disease or recurrence • Most osteosarcomas exhibit diagnostic features on routine radiographs, whereas occasionally they may exhibit deceptively benign radiographic features • Rare cases of epiphyseal osteosarcoma may exhibit radiographic features of clear cell chondrosarcoma or chondroblastoma • A radiologically malignant metaphyseal tumor in 10-­to 30-­year-­olds is most likely osteosarcoma • Rare osteosarcomas contain cytologically benign-­ appearing stromal giant cells that hide the sarcomatous component; careful search is necessary to identify the sarcomatous component and tumor osteoid, which is usually found in a perivascular location • Osteosarcomas of craniofacial bones, ribs, and vertebrae are usually related to Paget disease or radiation and typically occur in older individuals

Selected References Benedict WF, Fung YK, Murphree AL. The gene responsible for retinoblastoma and osteosarcoma. Cancer. 1988;62:1691–1694. Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentiation in bone and soft tissue tumors. Histopathology. 2013;63:36–49. Dorfman HD, Czerniak B. Bone Tumors. St. Louis: Mosby; 1998:128–194. Glasser DB, Lane JM, Huvos AG, et al. Survival, prognosis, and therapeutic response in osteogenic sarcoma: the Memorial Hospital experience. Cancer. 1992;69:698–708. Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012;2012:627254. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:136–170.

TELANGIECTATIC OSTEOSARCOMA Clinical Features • Male-­to-­female ratio is 2:1 • Most occur in second decade • Accounts for about 4% of all osteosarcomas •  Similar distribution as conventional intramedullary osteosarcoma

Fig. 16.5  Telangiectatic osteosarcoma.  Histologic section shows cystlike spaces surrounded by atypical stromal cells and osteoid.

• Predominantly affects distal femur, proximal tibia, and proximal humerus •  Similar symptoms to conventional osteosarcoma, except it is more likely to present as a pathologic fracture (25% of cases) 

Radiographic Findings • Recognizable as a completely lytic lesion involving the metaphysis with infiltrating destructive margins • May cause cortical expansion of the bone • Periosteal new bone formation may be represented by onion-­skinning or Codman triangle • Some cases may exhibit benign features and mimic an aneurysmal bone cyst 

Gross Pathology • Hemorrhagic mass that may be multicystic and necrotic • No areas of fleshy, sarcoma-­like tissue or sclerotic areas 

Histopathology •  Multiple cystlike spaces resembling an aneurysmal bone cyst, except that the septa of the cysts contain stromal cells (mononuclear and multinucleated) with cytologically malignant features intermixed with benign osteoclast-­like giant cells (Figure 16.5) • Mitotic features are present, including atypical forms • Sometimes the malignant stromal cells are floating in the center of the hemorrhagic cysts; identification of the stromal cells may be difficult, requiring multiple sections • Tumor osteoid can be difficult to identify; it is usually focal and found in a delicate lacelike pattern 

Special Stains and Immunohistochemistry •  SATB2 immunohistochemistry can be useful in the diagnosis when histologic features of matrix are equivocal (i.e., osteoid vs. hyalinized collagen) and when biopsy only samples tumor with undifferentiated appearance 

Other Techniques for Diagnosis • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

868

Chapter 16  —  Bones and Joints

Differential Diagnosis Aneurysmal Bone Cyst •  Stroma may be cellular but typically lacks cytologic atypia and atypical mitoses; may contain reactive bone with atypical osteoblasts •  Definitive cytologic malignant features and atypical mitoses are absent  Conventional Osteosarcoma • Radiographically, these tumors are not purely lytic • Intramedullary osteosarcoma may contain focal telangiectatic areas, which should not be overinterpreted PEARLS • T  elangiectatic osteosarcoma is frequently the type of osteosarcoma associated with long-­term Paget disease • Better prognosis than conventional intramedullary osteosarcoma • When a diagnosis of aneurysmal bone cyst is being considered, all tissue should be evaluated histologically for evidence of malignant stroma to rule out telangiectatic osteosarcoma

Selected References Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentiation in bone and soft tissue tumors. Histopathology. 2013;63:36–49. McCarthy EF. Differential Diagnosis in Pathology: Bone and Joint Disorders. Vols 44–51. New York: Igaku-­Shoin; 1996:82–85. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:155–158. Weiss A, Khoury JD, Hoffer FA, et al. Telangiectatic osteosarcoma: the St. Jude Children’s Research Hospital’s experience. Cancer. 2007;109:1627–1637.

PAROSTEAL OSTEOSARCOMA Clinical Features • Also known as “juxtacortical osteosarcoma” •  Slight female predominance, with a male-­ to-­ female ratio of 1:1.5 • Occurs predominantly in third decade • Involves metaphyses of long bones with approximately three fourths of cases involving the distal posterior femur, with the proximal tibia as the second most common site • Clinically presents as a painless mass of long duration (slow growing); pain may occur late in the course but is not typical initially • May also present as an inability to flex the knee 

Radiographic Features •  Radiodense, bosselated, or mushroom-­ shaped mass arising on the surface of a bone (outside of periosteum); in long-­term lesions, tumor may encircle the bone • A separate lucent zone between the tumor and the cortex known as a string sign may be seen • No evidence of periosteal bone reaction • Peripheral lucent areas may represent a cartilaginous cap • Central lucent areas may represent high-­grade sarcoma or dedifferentiated tumors

Fig. 16.6  Parosteal osteosarcoma.  Histologic section shows parallel arrangement of tumor osteoid separated by fibroblastic stroma with only minimal atypia.

• CT or MRI may be necessary to visualize lucent areas 

Gross Pathology • Well-­ossified mass that appears attached to the cortical surface of the bone • Cartilaginous cap may be present and there may be soft foci, which should be sampled; these foci may represent high-­ grade sarcomatous regions or dedifferentiated tumor 

Histopathology • Tumor osteoid is arranged in parallel arrays and separated by a hypocellular fibroblastic stroma that exhibits minimal cytologic atypia and minimal mitotic activity without atypical forms (Figure 16.6) • Islands of cartilaginous tissue and a cartilaginous cap may be present • Chondrocytes are atypical and do not exhibit orderly arrangement •  Atypia is mild and reminiscent of chondrocytic atypia seen in enchondromas • No evidence of periosteal new bone formation • Areas of dedifferentiated high-­grade sarcoma may be seen (about 15% of cases) • No fatty or hematopoietic marrow is seen in association with the tumor 

Special Stains and Immunohistochemistry • SATB2 immunohistochemistry can be useful 

Other Techniques in Diagnosis • Cytogenetic studies: a ring chromosome may be seen 

Differential Diagnosis Osteochondroma •  Medullary spaces contain adipose tissue or marrow hematopoietic tissue  Myositis Ossificans • Maturation toward lamellar bone and marrow adipose tissue begins peripherally and extends centrally in this proliferative process, which is the reverse in parosteal osteosarcoma 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

High-­Grade Surface Osteosarcoma •  These are cytologically high-­ grade tumors that lack residual low-­grade areas  Periosteal Osteosarcoma • Abundant cartilage is present • Higher-­grade osseous component and evidence of periosteal reaction PEARLS S ymptoms may last up to 10 years • • Typically affects an older age group compared with intramedullary osteosarcoma • It is not uncommon for these patients to have a history of recurrence of a previously diagnosed osteochondroma • Radiologic and histologic evidence of periosteal new bone formation is absent • Central lucent areas identified on CT scan or MRI may represent high-­grade sarcomatous areas or regions of dedifferentiation • Children may exhibit radiographic lesions that mimic parosteal osteosarcoma of the distal femur; histologically, they have features of fibrous cortical defect

Selected References Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentiation in bone and soft tissue tumors. Histopathology. 2013;63:36–49. Han I, Oh JH, Na Y, et al. Clinical outcome of parosteal osteosarcoma. J Surg Oncol. 2008;97:146–149. Sinovic JK, Bridge JA, Neff JR. Ring chromosome in parosteal osteosarcoma: clinical and diagnostic significance. Cancer Genet Cytogenet. 1992;62:50–52. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:170–177.

PERIOSTEAL OSTEOSARCOMA Clinical Features • Slight male predominance, with a male-­to-­female ratio of 1.7:1 • Typically occurs in second to third decades (later than a conventional osteosarcoma appears and sooner than a parosteal osteosarcoma appears) • Most occur in the diaphysis and metaphysis of the tibia and femur • Patients present with pain, swelling, and tenderness; symptoms often present for less than 1 year • Rare (6 cm), and location (axial skeleton) 

Radiographic Findings • Radiographs reveal a pedunculated metaphyseal mass projecting from the surface of a bone (Figure 16.7A) •  Variable smooth or irregular surface and a variable base (narrow to wide); points toward the diaphysis and away from the nearest epiphysis • Has appearance of mature bone and is continuous with the cortex of the uninvolved adjacent bone • Surface cap represented by cartilage is not identified with routine radiographs unless calcified; MRI is necessary to evaluate the nonmineralized cartilaginous cap 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

872

Chapter 16  —  Bones and Joints

Gross Pathology

• Woven bone with deep basophilia may be present 

•  Pedunculated or broad-­ based mass containing a smooth, thin ( 6 cm) and radiographic features of malignancy (irregular thickened cartilaginous cap > 2 cm, radiolucent areas of the cartilaginous cap, extension through periosteum into soft tissue, and bone destruction) are more ominous and concerning for a secondary chondrosarcoma • High mitotic activity is indicative of malignancy 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Chromosome rearrangement of 8q24.1 (EXT1) is found in patients with Langer-­Giedion syndrome • Deletions of chromosomal bands 11p11-­12 (EXT2) is seen in patients with DEFECT-­11 syndrome • The EXT1 and EXT2 gene products add heparan sulfate to proteoglycans and may have tumor suppressor functions 

Differential Diagnosis Parosteal Osteochondromatous Proliferation (Nora Lesion) • Usually involves small bones of hands and feet • Occurs in third and fourth decades of life • Medullary component of lesion is not in continuity with host bone • Histologically, the cartilage is hypercellular with atypia and multinucleation • Chondroid nodules are separated by a spindle cell proliferation that exhibits mitotic activity (no atypical mitoses or nuclear atypia)

Chondrosarcoma Arising in an Osteochondroma • Clinical findings consist of pain and a rapidly enlarging mass •  Radiographic findings consist of thickened (>2 cm), irregular cartilaginous cap, radiolucent zones in cartilaginous cap, extension through periosteum into soft tissue, and evidence of bone destruction •  Histologic findings consist of increased cellularity, nuclear atypia represented by enlarged nuclei with open chromatin pattern, multinucleation, and mitotic activity • Fibroblastic stroma is present in the medullary spaces instead of fat and hematopoietic tissue • If a cartilaginous cap is present, it is composed of cytologically low-­ grade malignant chondrocytes without endochondral ossification • Presence of HEY1-­NCOA2 fusion gene  Parosteal Osteosarcoma • Continuity with the medullary component of the parent bone is not present •  Appears to be attached to the surface of the parent bone PEARLS • C  linical and radiographic findings are important in the evaluation of chondrocytic atypia • Radiographically, the long axis of the stalk points away from the nearest epiphysis • Malignant transformation is rare (1 year) • Primary bone lymphomas have a good prognosis even when they are the large cell type • Stage is the most important prognostic factor regardless of subtype 

Radiographic Features • Lytic lesion with a moth-­eaten appearance • May be sclerotic, suggesting Paget disease of bone • Usually no periosteal reaction •  Soft tissue mass may be present; MRI, CT, and isotope scans may be helpful in delineating the extent of disease 

Gross Pathology • Typically a soft, white, fleshy mass • Permeates the medullary cavity • Cyst formation, necrosis, and hemorrhagic foci may be present 

Histopathology • Diffuse large cell lymphomas are the most common type •  Composed of sheets of large cells that may or may not have cleaved nuclei; most are noncleaved (Figure 16.30) • Some tumors may contain multilobate nuclei or cells with immunoblastic features • May exhibit a prominent inflammatory infiltrate consisting of neutrophils and mature lymphocytes, which may suggest a diagnosis of osteomyelitis • Small cell lymphomas and mixed small cell–large cell lymphomas may also occur • Spindle cell patterns suggestive of sarcoma or clear cell patterns, signet ring cell variants, and clustering of epithelioid cells suggestive of metastatic carcinoma may occur •  Starry-­ sky pattern (Burkitt lymphoma) occurs in the maxilla and mandible 

Special Stains and Immunohistochemistry • Tumor cells express lymphoid markers and are usually of B-­cell type

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

• CD19, CD20, CD79a, CD45, and PAX-­5 positive • Large cell lymphomas may express bcl-­2 • Classical Hodgkin lymphoma expresses CD30 and usually CD15 • Anaplastic large cell lymphoma (a T-­cell lymphoma) expresses CD30 and may express ALK1 •  Reticulin stain highlights fine network of reticulin around individual tumor cells 

Other Techniques for Diagnosis • Phenotyping by flow cytometry and gene rearrangement studies may be helpful in ruling out benign processes that may mimic lymphoma • About 80% of non-­Hodgkin lymphomas have clonal chromosome abnormalities, some of which are disease specific 

Differential Diagnosis Neuroectodermal Tumor of Bone • Typically have prominent rosettes • Positive for NSE, chromogranin, synaptophysin, CD99 • Negative for LCA  Metastatic Neuroblastoma • Usually occurs in children younger than 5 years • May have elevated urinary catecholamine metabolites • Tends to metastasize to the skull • Characterized by Homer-­Wright rosettes with fibrillary background • Positive for NSE, chromogranin, and synaptophysin  Osteosarcoma, Small Cell Variant • Foci of tumor osteoid should be seen  Mesenchymal Chondrosarcoma • Foci of chondroid differentiation • Tumor cells express S-­100 protein; negative for LCA  Metastatic Small Cell Carcinoma • Positive for cytokeratin and neuroendocrine markers  Langerhans Cell Histiocytosis •  Composed of histiocytes with a prominent eosinophilic cellular infiltrate •  Histiocytes express S-­ 100 protein and CD1a and are negative for B-­and T-­cell markers and CD30  Sarcoma • Occasionally lymphomas will have a spindle cell component, mimicking sarcoma • Sarcomas do not express lymphoid markers  Chronic Osteomyelitis • Typically composed of a polymorphous inflammatory cell infiltrate with lymphocytes, eosinophils, and neutrophils; lacks large neoplastic lymphocytes • Immunophenotypically consists of a mixed population of B and T cells •  Absence of clonal population by flow cytometry or gene rearrangement

897

PEARLS • T  -­cell lymphomas of bone are extremely rare and are most common in Japan • Primary Hodgkin disease of bone is rare, with the most common types being nodular sclerosing and mixed cellularity; axial skeletal involvement is much more common than appendicular involvement • Primary lymphoma of bone is diagnosed only if there is no evidence of extraskeletal lymphoma 6 months after original diagnosis of the bone lesion and there is no prior history of extraskeletal lymphoma • Primary lymphoma of bone is more common in the appendicular skeleton, whereas secondary osseous lymphoma is more common in the axial skeleton • Low-­grade secondary osseous lymphomas do not necessarily have a worse prognosis, whereas secondary high-­ grade osseous lymphomas do have a worse prognosis

Selected References Lima FP, Bousquet M, Gomez-­Brouchet A, et al. Primary diffuse large B-­cell lymphoma of bone displays preferential rearrangements of the c-­MYC or BCL2 gene. Am J Clin Pathol. 2008;129:723–726. Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Vols 179–195. Lyon, France: International Agency for Research on Cancer; 2008: 214–366. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:231–240.

MULTIPLE MYELOMA AND SOLITARY ­PLASMACYTOMA OF BONE Clinical Features • Male-­to-­female ratio is about 2:1 • Most cases occur between ages 50 and 80 years •  Solitary plasmacytoma tends to occur at a slightly younger age • Vertebrae, ribs, skull, pelvis, and long bones are the most common sites •  Patients with multiple myeloma present with pain, usually of less than 6 months’ duration •  May cause weight loss, peripheral neuropathy, pathologic fracture, fever, anemia, bleeding, hypercalcemia, hypergammaglobulinemia, and renal dysfunction • Patients with solitary plasmacytoma of bone usually present with pain; about 10% of patients with solitary plasmacytoma are asymptomatic • Some cases may be associated with POEMS syndrome (polyneuropathy, organomegaly [hepatosplenomegaly and lymphadenopathy], endocrinopathy [amenorrhea, diabetes, gynecomastia, hirsutism, or impotence], M-­ protein, and skin changes [hyperpigmentation, hypertrichosis, or clubbing of digits]) 

Radiographic Features • In multiple myeloma, there are multiple punched-­out lytic lesions, typically without sclerosis or periosteal reaction (Figure 16.31A and B)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

898

Chapter 16  —  Bones and Joints

• Solitary plasmacytoma may exhibit a lytic lesion in vertebrae with cortical ridging (corduroy cloth) or a bubbly appearance in long bones; cortical expansion may be seen 

Gross Pathology • Soft, gray-­red tissue involving the marrow space 

Histopathology • Tumor is composed of sheets of small cells with plasmacytic features (see Figure 16.31C) •  Eccentric nuclei with stippled chromatin patterns (cartwheel or clock face) • Cytoplasm is eosinophilic with perinuclear clearing (perinuclear Golgi zone) •  Intracytoplasmic immunoglobulins may produce grapelike structures (Mott cells or morula) • Extracytoplasmic immunoglobulins may be found and are represented as Russell bodies (extracellular eosinophilic spherical bodies) • Plasma cells may be atypical, multinucleated, or immature (plasmablasts have large nuclei and prominent nucleoli) •  Generally, mitotic activity is not prominent unless atypical forms or plasmablasts are present •  Amyloid may be present accompanied by giant cell reaction 

A

Special Stains and Immunohistochemistry •  Predominance of either κ or λ light chains (clonal process) • CD38, CD138 positive • Positive for immunoglobulin (Ig) G or IgA, less commonly for either IgM or IgE •  Tumor cells may express EMA but are cytokeratin negative • Congo red stain with apple-­green birefringence is seen if amyloid is present • Aberrant loss of CD19 and CD45 is common • Aberrant gain of CD56, CD117, and CD20 can also be seen 

B

Other Techniques for Diagnosis •  Serum and urine protein electrophoresis is used to demonstrate the presence and quantity of a paraprotein (M spike) • M spike usually seen in the gamma region on serum protein electrophoresis (SPEP) but can be seen in the beta region in some IgA myelomas •  Serum and urine immunofixation electrophoresis (IFE) is used to demonstrate specific monoclonal light chains and heavy chains • Flow cytometry can be used to demonstrate light chain restriction and the aberrant loss or gain of markers • Gene rearrangements usually found in IgG heavy chain •  Clonal cytogenetic abnormalities are common and have prognostic significance 

Differential Diagnosis Chronic Osteomyelitis •  Typically composed of a polymorphous inflammatory cell infiltrate with lymphocytes, eosinophils, and neutrophils

C Fig. 16.31  Multiple myeloma involving the skull.  A, Multiple osteolytic, defined round lesions. B, Cross section of the scalp shows punched-­out lesions. C, Histologic section shows sheets of plasma cells.

• Prominent fibrosis • κ-­to-­λ light chain ratio is normal or slightly elevated (about 3:1)  Metastatic Carcinoma • Occasionally the plasma cell infiltrate will mimic an epithelial neoplasm • Epithelial cells are cytokeratin positive • EMA is not helpful because myeloma cells can be EMA positive

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

899

B-­Cell Immunoblastic Lymphoma • Positive for B-­cell markers PEARLS • In most patients, cases of solitary plasmacytoma of the bone progress to multiple myeloma • About 4% of cases of multiple myeloma are nonsecretory; paraprotein is made, but it is not secreted outside the cell (these patients tend to have a better prognosis than do those with the secretory form of myeloma) • Most common sites of solitary plasmacytoma of bone are thoracic and lumbar vertebrae • κ Light chains are the most common type of light chain produced in multiple myeloma • IgG and IgA are the most common monoclonal gammopathies seen in multiple myeloma (IgG more common than IgA) • About 75% of patients with solitary plasmacytoma do not have a serum paraprotein • A preponderance of immature plasmablastic cells is pathognomonic for myeloma in a subset of the literature • Multinucleated forms of plasma cells are not diagnostic of myeloma or solitary plasmacytoma; may be found in reactive and inflammatory processes • Multiple myeloma is the most common primary malignant bone tumor • Osteosclerotic myeloma is a rare form that presents in younger patients with sclerotic bone lesions

Selected References Bilsky MH, Azeem S. Multiple myeloma: primary bone tumor with systemic manifestations. Neurosurg Clin N Am. 2008;19:31–40. Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multiple myeloma. Bone. 2008;42:1007–1013. Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet. 2011;204:3–12. Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:196–213. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:222–231.

MISCELLANEOUS BONE LESIONS CHORDOMA Clinical Features • Malignant midline bone tumor arising from fetal notochord remnants • Male-­to-­female ratio is 2:1 • Most occur in fourth to seventh decades; occurrence in patients younger than 30 years is rare •  Spheno-­ occipital tumors tend to occur at a slightly younger age (10 years younger) than sacral tumors • Half of cases involve the sacrum, and one third occur in the spheno-­occipital region; remainder occur in cervical and lumbar regions of the spinal cord • Symptoms are dependent on site of tumor •  Sacral tumors present with pain, bladder dysfunction, and constipation • Spheno-­occipital tumors present with cranial nerve deficits, hypopituitarism, and diplopia

Fig. 16.32  Chordoma.  Histologic section shows nests and cords of large vacuolated cells within a myxoid mucoid matrix.

• Slow growing with frequent recurrences and late distant metastases to skin, bone, and ovary 

Radiographic Features • Midline lytic destructive tumor that may contain intralesional calcifications • In spheno-­occipital tumors, there may be erosion of the sella turcica, clivus, and sphenoid bones 

Gross Pathology •  Lobulated gelatinous gray tissue that may appear encapsulated 

Histopathology •  Lobulated mass containing vacuolated cells forming nests and cords or strands within a myxoid mucoid matrix (Figure 16.32) • Cellularity is variable, and some tumors may contain solid areas • Rare mitoses may be present • Classic physaliphorous cells are round to oval and have a central nucleus with a prominent nucleolus; cytoplasm is abundant and eosinophilic with circumferential perinuclear vacuoles imparting a bubbly appearance to the cell cytoplasm; typically found in a myxoid matrix and may form syncytia •  May exhibit foci of chondroid differentiation, especially in spheno-­occipital tumors; designated chondroid chordoma • Rare cases exhibit a malignant spindle cell component with features of malignant fibrous histiocytoma; designated dedifferentiated chordoma 

Special Stains and Immunohistochemistry •  Brachyury: recently identified marker that is highly sensitive and specific for chordoma • Brachyury shows nuclear positivity in chordomas but is negative in potential mimics including chondrosarcoma and metastatic carcinoma • Also positive for cytokeratin (CAM-­5.2), EMA, vimentin, and S-­100 protein 

Other Techniques for Diagnosis • Cytogenetics: tumors commonly aneuploid 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

900

Chapter 16  —  Bones and Joints

Differential Diagnosis Chondrosarcoma •  Tumor cells are negative for cytokeratin, EMA, and brachyury  Metastatic Adenocarcinoma • Does not have a physaliphorous pattern • Often exhibits glandular differentiation •  Metastatic adenocarcinoma will not be positive for brachyury  Liposarcoma •  Tumor cells are negative for cytokeratin, EMA, and brachyury PEARLS • C  hordoma is not an uncommon neoplasm; follows osteosarcoma, chondrosarcoma, and Ewing sarcoma/PNET in frequency of primary malignant bone tumors • Classic physaliphorous cells may be rare in some cases • In some studies, chondroid chordoma has a higher survival rate than traditional chordoma • Dedifferentiated chordomas typically occur after several recurrences of a classic chordoma; some of these patients have been irradiated, suggesting that these tumors are radiation induced

Selected References Jambhekar NA, Rekhi B, Thorat K, et al. Revisiting chordoma with brachyury, a “new age” marker: analysis of a validation study on 51 cases. Arch Pathol Lab Med. 2010;134:1181–1187. Oakley GJ, Fuhrer K, Seethala RR. Brachyury, SOX-­9, and podoplanin, new markers in the skull based chordoma vs chondrosarcoma differential: a tissue microarray-­based comparative analysis. Mod Pathol. 2008;21:1461–1469. Sangoi AR, Karamchandani J, Lane B, et al. Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases. Mod Pathol. 2011;24:425–429. Sell M, Sampaolo S, Di Lorio G, et al. Chordomas: a histological and immunohistochemical study of cases with and without recurrent tumors. Clin Neuropathol. 2004;23:277–285. Tirabosco R, Mangham DC, Rosenberg AE, et al. Brachyury expression in extra-­axial skeletal and soft tissue chordomas: a marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachondroma in soft tissue. Am J Surg Pathol. 2008;32:572–580.

ANEURYSMAL BONE CYST Clinical Features • Male-­to-­female ratio is about 1.3:1 • More than 75% of cases occur in first two decades • Three fourths occur in vertebrae (posterior aspect and spinous process), distal femur, and proximal tibia •  Small bones of the hands and feet and craniofacial bones are also relatively common sites • Pain of variable duration and swelling are presenting symptoms 

Radiographic Features • Eccentric metaphyseal or posterior vertebral cystic lytic lesion that initially exhibits a permeative growth pattern with cortical destruction • Periosteal bone formation may be seen

•  In older lesions, a thin outer bony shell (eggshell) develops, and the cyst becomes trabeculated 

Gross Pathology • Hemorrhagic, cystic, honeycomb mass (Figure 16.33A) • Fibrous septa separating the cavernous cystic spaces are gritty • Spaces are filled with blood or serosanguineous fluid • Solid, soft-­gray to white mass may be present, representing a precursor lesion in secondary aneurysmal bone cysts 

Histopathology •  Composed of numerous cavernous or cystic spaces filled with blood and lacking an endothelial lining • Spaces are separated by fibrous septa lacking smooth muscle and containing fibroblasts, capillaries, inflammatory cells, giant cells, benign osteoid (may resemble osteoblastoma), and benign chondroid tissue (see Figure 16.33B) • Chondroid areas may have myxoid features, which is characteristic of aneurysmal bone cysts • Mitotic activity may be brisk, but no atypical mitosis or stromal cell nuclear anaplasia is present •  Secondary aneurysmal bone cysts have solid areas exhibiting histologic features of the precursor lesion • Secondary aneurysmal bone cyst may occur in many tumors, including the following: osteosarcoma, malignant fibrous histiocytoma, metastatic carcinoma, osteoblastoma, chondroblastoma, chondromyxoid fibroma, giant cell tumor, nonossifying fibroma, fibrous histiocytoma, fibrous dysplasia, eosinophilic granuloma, hemangioma, giant cell reparative granuloma, and unicameral bone cyst 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis •  Ubiquitin specific protease 6 (USP6) gene rearrangement has been reported in approximately 70% to 75% of aneurysmal bone cysts • In one study, FISH detected abnormalities of chromosome 17p13.2 in 63% of primary aneurysmal bone cysts 

Differential Diagnosis Unicameral Bone Cyst • Fibrous septa are usually hypocellular, with foci containing occasional giant cells •  Fibrous septa lack inflammatory cells, osteoid, and chondroid tissue  Giant Cell Tumor • Located in the epiphyses in skeletally mature patients •  Stromal mononuclear cells and numerous evenly spaced multinucleated giant cells are present  Telangiectatic Osteosarcoma • Uncommon in vertebrae, craniofacial bones, and bones of hands and feet • Anaplastic tumor with production of tumor osteoid

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

• May show complex karyotypic abnormalities not found in aneurysmal bone cyst 

901

Histopathology

Secondary Aneurysmal Bone Cyst • Histologic evidence of a precursor lesion (see “Histopathology”) should be identified

•  Cyst wall is composed of thin, hypocellular fibrous tissue • Occasional giant cells may be seen in the fibrous septa • Inflammatory changes are absent or minimal • No osteoid or chondroid tissue 

PEARLS

Special Stains and Immunohistochemistry

• C  urettings and any solid areas of an excised tumor should be processed completely to evaluate for the presence of a precursor lesion • Clinicoradiographic correlation is necessary to determine whether the histology represents a secondary aneurysmal bone cyst • Precursor lesion is found in about half of aneurysmal bone cysts; most common preexisting lesions are giant cell tumor, chondroblastoma, fibrous dysplasia, and chondromyxoid fibroma • Radiographic features of an aneurysmal bone cyst may mimic a malignant process

• Noncontributory 

Selected References Althof PA, Ohmori K, Zhou M, et al. Cytogenetic and molecular cytogenetic findings in 43 aneurysmal bone cysts: aberrations of 17p mapped to 17p13.2 by fluorescence in situ hybridization. Mod Pathol. 2004;17:518–525. Basrir K, Piskin A, Guclü B, et al. Aneurysmal bone cyst recurrence in children: a review of 56 patients. J Pediatr Orthop. 2007;27:938–943. Li L, Bui MM, Zhang M, et al. Validation of fluorescence in situ hybridization testing of USP6 gene rearrangement for diagnosis of primary aneurysmal bone cyst. Ann Clin Lab Sci. 2019;49(5):590–597. Martinez V, Sissons HA. Aneurysmal bone cyst: a review of 123 cases including primary lesions and those secondary to other bone pathology. Cancer. 1988;61:2291–2304. Mendenhall WM, Zlotecki RA, Gibbs CP, et al. Aneurysmal bone cyst. Am J Clin Oncol. 2006;29:311–315. Saccomanni B. Aneurysmal bone cyst of spine: a review of literature. Arch Orthop Trauma Surg. 2007;128:1145–1147. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology:324–330.

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Aneurysmal Bone Cyst • Hemorrhagic cyst contents contain osteoid and chondroid tissue with fibromyxoid features, and giant cells  Giant Cell Tumor • Occurs in the epiphyses of bones in skeletally mature patients •  Composed of mononuclear stromal cells and many more giant cells than are normally seen in unicameral bone cyst PEARLS • F racture of unicameral bone cyst may complicate the histology because of the presence of reactive bone; may result in misinterpretation as aneurysmal bone cyst

Selected References Dorfman HD, Czerniak B. Bone Tumors. St. Louis: Mosby:879–891. McCarthy EF. Differential Diagnosis in Pathology: Bone and Joint Disorders. New York: Igaku-­Shoin; 1996:105–107. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:330. Vigorita VJ. Orthopaedic Pathology. Philadelphia: Lippincott Williams & Wilkins; 1999:256–261.

UNICAMERAL BONE CYST (SIMPLE CYST)

PAGET DISEASE OF BONE

Clinical Features

Clinical Features

• Male-­to-­female ratio is about 2:1 • Most cases occur in first two decades •  Most common sites are proximal humerus, midhumerus, and proximal femur • Most are asymptomatic, but some patients present with sudden onset of pain due to pathologic fracture 

• Also known as osteitis deformans • Male-­to-­female ratio is 2:1 •  Most cases occur in fifth and sixth decades; rarely found in patients younger than 40 years • Most common sites are pelvis, skull, femur, vertebrae, and tibia; rare in hands and feet • About 85% are polyostotic, 15% monostotic • Patients may be asymptomatic or present with pain • Other symptoms that may occur at presentation or develop later are largely due to hypercalcemia and include deafness and other cranial nerve deficits, high-­output heart failure, nephrolithiasis, hyperuricemia, arthritis, fractures, leonine facies, and femoral, tibial, or vertebral bowing •  Increased risk of developing a sarcoma (usually osteosarcoma) 

Radiographic Features • Elongated medullary expanding cystic lesion without cortical disruption • Bone fragment may be present in the dependent area of the cyst (fallen-­fragment sign) • Cyst may contain fluid that has the density of water 

Gross Pathology • Intramedullary cyst containing clear or straw-­colored, nonviscous, serous-­like fluid • May be multiloculated • Cyst is composed of thin, delicate fibrous tissue 

Radiographic Features • Bones show increased density with cotton-­wool appearance intermixed with lucent areas

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

902

Chapter 16  —  Bones and Joints

Other Techniques for Diagnosis • Genetic factors may play an important role, with mutations affecting different components of RANK-­NF-­κB signaling pathway •  Increased serum alkaline phosphatase and urinary hydroxyproline; normal or elevated serum calcium and serum phosphate 

Differential Diagnosis Osteoblastic Metastatic Carcinoma • Tumor cells positive for cytokeratin 

A

Chronic Osteomyelitis • Mixed inflammatory infiltrate consisting of intratrabecular plasma cells, lymphocytes, and occasional neutrophils  Fibrous Dysplasia • Osteoid islands do not exhibit osteoclastic or osteoblastic activity and do not contain abnormal cement lines  Osteoblastoma • Usually occurs in a younger age group • May involve the jaw bones but usually does not involve the calvarium • Radiographic evidence of calcification may be present within the tumor •  Histologically, osteoblastoma is sharply demarcated from uninvolved bone

B Fig. 16.33  Aneurysmal bone cyst.  A, Cross section shows complex, multiloculated cystic spaces filled with blood. B, Histologic section shows cystic spaces filled with red blood cells surrounded by giant cells, fibroblasts, and inflammatory cells.

• Flame-­shaped or V-­shaped lytic areas may be seen in long bones; known as a flame sign or blade of grass sign • Increased bone density or cortical thickening (window-­ frame appearance); round occipital and frontal bone radiolucencies (osteitis circumscripta) may be present 

Gross Pathology •  Pinkish discoloration of bone due to increased vascularity • Coarse, irregular, thickened cortex (Figure 16.34A) • Irregular, thickened medullary cancellous bone • Mosaic pattern of cement lines with rock-­hard, dense bone in late stages 

Histopathology • Initially prominent osteoclastic activity with clustering of osteoclasts (large multinucleate forms) • Bony trabeculae with Howship lacunae formation • Intratrabecular fibrosis with increased vascularization • Later, prominent osteoblastic activity and production of osteoid with abnormal collagen deposition are seen • In the final inactive stage, the bony trabeculae are irregularly thickened, and cement lines form a mosaic pattern (see Figure 16.34B) 

Special Stains and Immunohistochemistry • Noncontributory 

PEARLS • P  aget disease of bone is a manifestation of an imbalance in bone metabolism; dysregulated osteoclastic activity followed by osteoblastic activity • Symptoms may result from hypercalcemia when present • Measles virus has been found in osteoclast precursors in Paget disease of bone • Sarcoma occurs in about 1% of patients with Paget disease of bone; increases to about 20% in patients with polyostotic disease for more than 20 years • Most common sarcoma arising in Paget disease of bone is osteosarcoma; other tumors that may arise are malignant fibrous histiocytoma, fibrosarcoma, chondrosarcoma, and malignant giant cell tumor • Survival rate of patients with osteosarcoma arising in Paget disease of bone is much lower than that of classic osteosarcoma • An increase in the baseline serum alkaline phosphatase level in a patient with Paget disease of bone is suggestive of sarcomatous transformation

Selected References Deyrup AT, Montag AG, Inwards CY, et al. Sarcomas arising in Paget disease of bone: a clinicopathologic analysis of 70 cases. Arch Pathol Lab Med. 2007;131:942–946. Josse RG, Hanley DA, Kendler D, et al. Diagnosis and treatment of Paget’s disease of bone. Clin Invest Med. 2007;30:E210–E223. Layfield R. The molecular pathogenesis of Paget disease of bone. Expert Rev Mol Med. 2007;9:1–13. Sharma H, Mehdi SA, MacDuff E, et al. Paget sarcoma of the spine: Scottish Bone Tumor Registry experience. Spine. 2006;31:1344–1350.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

903

B

A

Fig. 16.34  Paget disease of bone.  A, Gross section of the calvarium shows marked overgrowth of the cortex. B, Histologic section shows irregularly thickened bony trabeculae with prominent cement lines.

Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology:368–370.

METASTATIC TUMORS Clinical Features • Most common sites are axial and proximal appendicular skeleton in adults and include pelvis, ribs, vertebrae, skull, and proximal femur and humerus • Pain, swelling, and tenderness are the most common symptoms; some patients present with a pathologic fracture • Most patients (about 80%) present with a history of a primary malignancy 

Radiographic Features • Consist of multiple, irregular, moth-­eaten destructive lesions that are usually lytic but can be blastic or mixed lytic-­blastic • Periosteal reaction may be present 

Gross Pathology • Usually poorly delineated with infiltrative margins • Variable in appearance, color, and consistency, depending on their primary tumor type • Prostatic metastases are osteoblastic and may be dense 

Histopathology (Figure 16.35) • Most metastatic lesions exhibit histologic features suggestive of some line of differentiation (squamous, glandular, mesenchymal, or melanocytic) • Clear cell patterns, glandular patterns with follicular features, and pigmented spindle cell tumors are indicative of renal cell carcinoma, follicular carcinoma of thyroid, and melanoma, respectively, and generally pose no problems in identifying the primary • Some tumors are undifferentiated and require immunohistochemistry for determination of the site of origin •  Spindle cell tumors require immunohistochemistry to differentiate true sarcomas from the spindle cell

Fig. 16.35  Metastatic adenocarcinoma.  Histologic section shows bone with metastatic adenocarcinoma in a patient with a lung primary.

variant of renal cell carcinoma and other spindle cell carcinomas 

Special Stains and Immunohistochemistry • Battery of immunohistochemical stains may be necessary to delineate primary tumor origin, depending on clinical history and morphology

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Osteosarcoma • Metastatic carcinoma may produce prominent osteoid, suggesting osteosarcoma • Negative for cytokeratin  Primary Bone Sarcomas • Differentiation of primary bone sarcomas (malignant fibrous histiocytoma and fibrosarcoma) can be difficult and requires clinical correlation 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

904

Chapter 16  —  Bones and Joints

Paget Disease • May mimic osteoblastic metastases • Osteoblasts lining trabecular bone may appear atypical but do not express cytokeratin PEARLS • M  etastatic tumor cells reach bone through arterial embolization or retrograde flow through venous plexuses (e.g., Batson plexus, which lacks valves) or through veins with defective valves • Metastases to bones distal to the elbows and knees are rare in adults • Metastatic acral bone tumors are usually due to metastatic lung carcinoma • Metastatic tumors to bone are more common in the appendiceal skeleton in children • The most common primary malignancies in adults to metastasize to bone are prostate, kidney, thyroid, lung, pancreas, and breast • In children, the most common are rhabdomyosarcoma, clear cell carcinoma of kidney, and neuroblastoma • Osteolytic lesions on radiographs are usually thyroid, kidney, lung, or gastrointestinal tract in origin • Osteoblastic lesions on radiographs are usually metastatic prostate, medulloblastoma, or carcinoid • Tumor cells of prostatic adenocarcinoma metastases to bone in patients previously treated may appear histiocytic and require immunohistochemistry (prostate-­specific antigen, prostatic acid phosphatase) to identify prostatic origin

Selected References Ricco AI, Wodajo FM, Malawer M. Metastatic carcinoma of the long bones. Am Fam Physician. 2007;76:1489–1494. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:321–324. Vigorita VJ. Orthopaedic Pathology. Philadelphia: Lippincott Williams & Wilkins; 1999:472–489.

pseudogout, Paget disease of bone, osteonecrosis, hemarthrosis, trauma, hemochromatosis, and Wilson disease 

Radiographic Features •  Diagnostic features include osteophyte formation, asymmetric joint space narrowing, subchondral osteosclerosis, and subchondral cyst formation 

Gross Pathology • Cartilaginous articular surface is thinned, irregular, or denuded, giving a polished ivory appearance to the outer subchondral bone (bony eburnation) • Subchondral bone is thickened and sclerotic • Peripheral osteophyte formation is common 

Histopathology • Articular cartilaginous surface is fibrillated, frayed, and thinned or denuded • Chondrocytic hyperplasia is represented by aggregates of chondrocytes surrounded by basophilic staining matrix •  Subchondral bone is represented by thickened trabeculae • Intratrabecular granulation tissue is present and may contain few lymphocytes and plasma cells • Intratrabecular granulation tissue may undergo myxoid changes, with coalescence producing subchondral cysts •  May be superficial foci of osteonecrosis, subcortical fibrocartilaginous production, and marginal cartilage proliferation, with endochondral ossification producing osteophytes •  Mild synovial cell hyperplasia with subsynovial lymphocytosis • Fragments of bone and cartilage may become embedded in synovium • Cartilage may ultimately form loose bodies or “joint mice” by proliferation of chondrocytes, with subsequent fragmentation into the joint space 

JOINT AND SYNOVIAL DISEASES OSTEOARTHRITIS Clinical Features • Also known as degenerative joint disease (DJD) • Male-­to-­female ratio is equal •  Greater than 80% occur in patients older than 55 years • Interphalangeal joints of the hands; metacarpophalangeal joint of the thumb, hips, and knees; cervical and lumbar vertebrae; and metatarsophalangeal joint of great toe may be affected •  Other joints may be affected in secondary osteoarthritis • Patients complain of arthralgia, limitation of motion, joint enlargement, and swelling • Vertebral involvement may produce paresthesias, muscle weakness, and hyperreflexia •  Secondary osteoarthritis may result from Legg-­ Calvé-­ Perthes disease, previous history of gouty arthritis, rheumatoid arthritis, infectious arthritis,

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Rheumatoid Arthritis •  Contains a subchondral intratrabecular infiltrate of plasma cells • Pannus formation  Osteoarthritis Secondary to Avascular Necrosis • Segmental osteonecrosis with bony trabeculae containing empty lacunae  Osteoarthritis Secondary to Chondrocalcinosis •  Contains clusters of calcium pyrophosphate crystals within chondroid matrix • Crystals are rhomboid and are weakly birefringent

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

905

Chapter 16  —  Bones and Joints

PEARLS • D  enervation of joints, most commonly associated with diabetes, may produce osteoarthritic changes and is called neuropathic joint • Spondylosis deformans is a form of osteoarthritis that involves the disks and vertebral bodies of the spine; disk cartilage herniates into the vertebral body (Schmorl node)

Selected References Benjamin M, McGonagle D. Histopathologic changes at “synovio-­ entheseal complexes” suggesting a novel mechanism for synovitis in osteoarthritis and spondylarthritis. Arthritis Rheum. 2007;56:3601–3609. Cushner FD, La Rosa DF, Vigorita VJ, et al. A quantitative histologic comparison: ACL degeneration in the osteoarthritic knee. J Arthroplasty. 2003;18:687–692. McCarthy EF, Frassica FJ. Pathology of Bone and Joint Disorders with Clinical and Radiographic Correlation. Philadelphia: WB Saunders; 1998:324–337.

RHEUMATOID ARTHRITIS Clinical Features • Male-­to-­female ratio is 1:3 • Can occur in all age groups, with most cases occurring in fourth and fifth decades • Most commonly affects joints of hands, feet, and knees but eventually may involve other joints, including hips, shoulders, ankles, and sternoclavicular joint • Patients present with arthralgia, stiffness, swelling, erythema, limitation of motion, and joint tenderness •  Extra-­ articular manifestations involving the heart, lung, pleura, skin/subcutaneous tissue, and hematolymphoid system can also be seen 

Radiographic Features •  Concentric joint space narrowing, osteopenia, and marginal bony erosions 

Gross Pathology •  Synovium is edematous with prominent villous architecture • Surfaces may have fibrinous deposits •  Articular cartilaginous surface is irregular and fibrillated and may be denuded, resulting in exposure of subchondral bone • Pannus is present in subchondral bone and extends to the surface of the articular cartilage • Rice bodies (detached inflamed fibrinous exudate) may be present 

Histopathology (Figure 16.36) • Subsynovial connective tissue contains plasma cell and lymphocytic infiltrate with lymphoid follicle formation • Perifollicular cuffing of plasma cells and multinucleated giant cells (Grimley-­Sokoloff synovial giant cells) may be present • Pannus is represented by inflamed granulation tissue that undermines and covers the articular cartilaginous surface •  Chondrolysis is represented by cartilage exhibiting decreased staining of chondroid matrix and loss of chondrocytic nuclei

Fig. 16.36  Rheumatoid arthritis.  Histologic section shows a pannus covering the degenerated articular surface.

•  Subchondral intratrabecular plasma cell infiltrates 

spaces

may

contain

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Serologic tests for serum autoantibodies: rheumatoid factor (RF) (low specificity); anti-­citrullinated protein antibodies (high specificity) • Class II major histocompatibility complex alleles DR4, DR1, or both 

Differential Diagnosis Osteoarthritis • Osteophytes are more prominent, and articular surface pannus is absent •  Subchondral granulation tissue may exhibit myxoid changes, and subchondral cysts may be present • Chondrolysis is not present • Serology studies are typically negative  Chronic Osteomyelitis • Presence of intratrabecular plasma cell infiltrates may mimic chronic osteomyelitis • Clinical and radiographic features are different • Serology studies are typically negative PEARLS • T  here are no pathognomonic histologic changes of rheumatoid arthritis • About 20% of patients with rheumatoid arthritis develop subcutaneous rheumatoid nodules • Clinical history and laboratory findings provide helpful clinicopathologic correlations

Selected References Gynther GW, Holmlund AB, Reinholt FP, et al. Temporomandibular joint involvement in generalized osteoarthritis and rheumatoid arthritis: a clinical, arthroscopic, histologic, and immunohistochemical study. Int J Oral Maxillofac Surg. 1997;26:10–16. McCarthy EF, Frassica FJ. Pathology of Bone and Joint Disorders with Clinical and Radiographic Correlation. Philadelphia: WB Saunders; 1998:337–345.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

906

Chapter 16  —  Bones and Joints

Other Techniques for Diagnosis • Polarized light and compensated polarized light have been used to identify crystals and categorize as uric acid (needle-­shaped crystals that are blue when perpendicular and yellow when parallel to compensated polarized light) 

Differential Diagnosis Pseudogout (Calcium Pyrophosphate Deposition Disease) • Crystals are rhomboid and birefringent • Crystals appear blue when parallel and yellow when perpendicular to compensated polarized light • Granulomatous inflammation is absent  Fig. 16.37  Gout.  Histologic section shows amorphous material surrounded by histiocytic and multinucleated giant cells. McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 22nd ed. Philadelphia: Elsevier/Saunders; 2011:980–983. Vigorita VJ. Orthopaedic Pathology. Philadelphia: Lippincott Williams & Wilkins; 1999:588–609.

GOUT Clinical Features • Male-­to-­female ratio is 2:1 • Peak incidence in fifth decade •  Usually monoarticular and involves large peripheral joints of the lower extremities • Great toe is the most common site • Acute gout presents with joint redness, swelling, and tenderness •  Chronic gout consists of painless tophi that may involve the ear helix, feet, hands, fingers, tibia, olecranon bursa, and Achilles tendon 

Radiographic Features • In acute phase, only subcutaneous swelling is seen •  In chronic phase, subcutaneous and periarticular masses adjacent to eroded bone are present • Bone erosions are most common in the hands and feet 

Gross Pathology •  Synovial pasty and chalk-­ white deposits in the soft tissue 

Histopathology • Specimens should be fixed in alcohol rather than formalin so as not to dissolve the crystals •  Polarizable needle-­ shaped uric acid crystals may be found within neutrophils and macrophages of synovial fluid • In acute gout, the synovium contains neutrophilic and lymphocytic infiltrates • In chronic gout, tophi are represented by pale-­staining amorphous material surrounded by histiocytes and multinucleated foreign body–like giant cells (Figure 16.37) 

Infectious Granulomatous Synovitis • Special stains (acid-­fast bacilli, Gomori methenamine silver, PAS) may be positive, but negative stains do not rule out infectious granulomatous synovitis • Cultures and clinicoradiographic correlation are necessary to rule out an infectious etiology PEARLS • If a surgeon is suspicious of gout, recommend submitting surgical tissue specimen in 100% ethanol to prevent uric acid crystals from dissolving (uric acid crystals are soluble in formalin and will dissolve)

Selected References Lam HY, Cheung KY, Law SW, et al. Crystal arthropathy of the lumbar spine: a report of 4 cases. J Orthop Surg. 2007;15:94–101. McCarthy EF, Frassica FJ. Pathology of Bone and Joint Disorders with Clinical and Radiographic Correlation. Philadelphia: WB Saunders; 1998:346–348. Vigorita VJ. Orthopaedic Pathology. Philadelphia: Lippincott Williams & Wilkins; 1999:533–537.

PSEUDOGOUT (CHONDROCALCINOSIS–­ CALCIUM PYROPHOSPHATE DEPOSITION DISEASE) Clinical Features • Male-­to-­female ratio is 1.4:1 • Mean age of 72 years • Rare before the age of 30 years • Typically affects the distal radioulnar joint, symphysis pubis, knee, and intervertebral disks • Many patients are asymptomatic • Patients may present with symptoms of acute arthritis, including pain, swelling, and redness of the affected joint •  Associated conditions include hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia, hypothyroidism, gout, neuropathic joints, amyloidosis, trauma, osteochondritis dissecans, and familial hypocalciuric hypercalcemia 

Radiographic Features •  Exhibits linear, punctate intra-­ articular calcifications within tendons, articular cartilage, and menisci 

Special Stains and Immunohistochemistry

Gross Pathology

• Noncontributory 

• Articular cartilage contains linear white deposits

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

907

•  Synovium exhibits white deposits of crystalline material 

Histopathology • Aggregates of crystals are present within cartilage and synovium •  Crystals are rhomboid and birefringent; the crystals appear blue when parallel and yellow when perpendicular to compensated polarized light • Inflammation is absent • If crystals are absent, the chondroid matrix may exhibit reduced basophilia and mucoid changes, which are considered diagnostic of pseudogout 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Polarized light and compensated polarized light have been used to identify crystals and categorize as calcium pyrophosphate, which appears yellow when parallel and blue when perpendicular to compensated polarized light 

Differential Diagnosis Gout • Crystals are needle shaped and not birefringent; they are yellow when parallel and blue when perpendicular to compensated polarized light • Granulomatous inflammation is present  Tumoral Calcinosis (Calcium Hydroxyapatite Deposition; Metastatic Calcification) • Radiographically, this process is represented by fused, round to oval soft tissue radiodensities •  Composed of nodular calcifications surrounded by macrophages and giant cells •  Intracytoplasmic giant cell calcifications, metaplastic bone, and psammoma bodies may be present • No polarizable crystals are present •  May be associated with a history of chronic renal dialysis

Fig. 16.38  Synovial chondromatosis.  Histologic section shows discrete nodules of mature hyaline cartilage.

SYNOVIAL CHONDROMATOSIS Clinical Features • Male-­to-­female ratio is 2:1 • Most cases occur in fourth and fifth decades • Most commonly affected joints are knees (70%), hips, and elbows • Most cases are monoarticular • Patients present with pain, swelling, and limitation of motion of variable duration (averaging 5 years) 

Radiographic Features • Well-­marginated ring-­shaped and stippled radiodensities in the joint or bursa • May be fusion of these densities, forming a mass • Bone erosion may be seen 

Gross Pathology • Synovium contains single or multiple well-­circum­scribed nodules of cartilaginous tissue • Detached free cartilaginous nodules may be in the joint space • Bosselated, larger nodules with outer granular surfaces representing fused smaller nodules may be identified • Tendons and bursa may be involved 

PEARLS

Histopathology

• B  y the age of 80 years, 20% of patients have joint deposits of calcium pyrophosphate • About 25% of patients who undergo knee replacement surgery have deposits of calcium pyrophosphate in the native joints

• Synovium contains multiple discrete nodules of hyaline cartilage, which may exhibit myxoid changes, calcification, or peripheral ossification (Figure 16.38) • Clusters of atypical chondrocytes showing nuclei with open chromatin; small multinucleated forms, and mitotic figures can also be seen •  Cartilaginous nodules may exhibit endochondral ossification • Chondrocytes with clear cell features and prominent eosinophilic cytoplasm may be seen 

Selected References Fenoy AJ, Menezes AH, Donovan KA, et al. Calcium pyrophosphate dihydrate crystal deposition in the craniovertebral junction. J Neurosurg Spine. 2008;8:22–29. McCarthy EF, Frassica FJ. Pathology of Bone and Joint Disorders with Clinical and Radiographic Correlation. Philadelphia: WB Saunders; 1998:348–350. Ryan LM, McCarty DJ. Arthritis associated with calcium containing crystals. In: Stein JH, ed. Internal Medicine. St. Louis: Mosby; 1998:1276–1279. Saffar P. Chondrocalcinosis of the wrist. J Hand Surg Br. 2004; 29:486–493.

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

908

Chapter 16  —  Bones and Joints

Differential Diagnosis Secondary Synovial Chondrometaplasia • Evidence of preexisting joint disease (history or radiographic features of chondral fracture, osteonecrosis, or osteoarthritis) •  Histologically, the cartilaginous nodule has a central nidus of detached hypocellular articular cartilage or detached, necrotic subchondral bone that is surrounded by concentric rings of metaplastic cartilage composed of benign-­appearing chondrocytes  Synovial Chondrosarcoma • May mimic synovial chondrometaplasia radiographically, but the radiodensities are poorly circumscribed or demarcated • Histologically, the cellularity is increased without clusters or cloning • Solid sheets of crowded chondrocytes exhibit more significant atypia and mitotic activity • Spindle-­shaped forms are located around the periphery of nodules, and necrosis may be present • Myxoid features may be more prominent  Secondary Joint Involved Chondrosarcoma •  Clinical and radiographic features suggest that the tumor is not arising in synovium but rather in bone with extension into the joint space PEARLS • C  hondrocytic atypia can be present in synovial chondrometaplasia to the degree that, in a different location (proximal or axial skeleton, not synovium), the diagnosis of chondrosarcoma might be made • Clinicoradiographic correlation is important for evaluating these lesions so that they are not overdiagnosed as chondrosarcomas • Malignant transformation has been reported

Selected References Galat DD, Ackerman DB, Spoon D, et al. Synovial chondromatosis of the foot and ankle. Foot Ankle Int. 2008;29:312–317. Murphey MD, Vidal JA, Fanburg-­Smith JC, et al. Imaging of synovial chondromatosis with radiologic pathologic correlation. Radiographics. 2007;27:1465–1488. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:386–389.

PIGMENTED VILLONODULAR SYNOVITIS Clinical Features • Male-­to-­female ratio is 1:2 • Majority occur in third and fourth decades • Knee is the most common joint involved (80%) • Hip, shoulder, and ankle are also commonly involved • Usually presents with a long history of pain, swelling, limitation of motion, and joint stiffness • Some patients present with hemarthroses 

Radiographic Features • Routine radiographs usually reveal soft tissue swelling

Fig. 16.39  Pigmented villonodular synovitis.  Histologic section shows subsynovial cellular infiltrate of mononuclear cells, multinucleated giant cells, foam cells, and scattered hemosiderin-­laden macrophages.

• May exhibit evidence of DJD, represented by subchondral cysts and erosions on both sides of the joint • Lucent bone lesions may be present • CT or MRI reveals pedunculated lesions in the joint 

Gross Pathology • Synovium is brown and thickened; contains papillary villous projections and nodular structures • Cut surface shows variable coloring, including yellow and red areas, depending on lipid and hemosiderin content • Pedunculated or polypoid masses may be seen 

Histopathology • Cellular infiltrates of mononuclear cells within the subsynovial connective tissue • Mononuclear cells have oval nuclei with vesicular or clumped chromatin and prominent cytoplasm • Mitotic activity may be brisk • Hemosiderin-­laden mononuclear cells, multinucleated giant cells, and foam cells are present (Figure 16.39) • In older lesions, areas of fibrosis are common 

Special Stains and Immunohistochemistry •  Mononuclear cells and multinucleated giant cells express CD68 and HAM-­56 

Other Techniques for Diagnosis • Cytogenetic studies: trisomy 7, trisomy 5, and aneuploid mononuclear cell lines may be seen • Structural rearrangements of 1p11–13 may be seen 

Differential Diagnosis Hemosiderotic Synovitis • Usually occurs in patients with hemophilia, on anticoagulant therapy, or having a past history of posttraumatic hemarthroses, or in the presence of synovial vascular tumors (hemangioma) •  Villous synovial projections are delicate and do not form nodules

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 16  —  Bones and Joints

• Mononuclear cells in pigmented villonodular synovitis (PVNS) are not present, and foam cells and multinucleated giant cells are not typical  Giant Cell Tumor • Does not exhibit radiolucent lesions on both sides of the joint • Giant cells are larger, have many more nuclei, and do not stain with histiocytic markers  Rheumatoid Synovitis • Synovial plasma cell and lymphocytic infiltrates with follicle formation • Hemosiderin is not prominent 

909

Selected References Carpintero P, Gascon E, Mesa M, et al. Clinical and radiologic features of pigmented villonodular synovitis of the foot: report of eight cases. J Am Podiatr Med Assoc. 2007;97:415–419. McCarthy EF, Frassica FJ. Pathology of Bone and Joint Disorders with Clinical and Radiographic Correlation. Philadelphia: WB Saunders; 1998:310–312. Somerhausen NS, Flecher CD. Diffuse-­type giant cell tumor: clinicopathologic and immunohistochemical analysis of 50 cases with extraarticular disease. Am J Surg Pathol. 2000;24:479–492. Unni KK, Inwards CY, Bridge J, et al. Tumors of the Bones and Joints, 4th Series, Fascicle 2. Washington, DC: Armed Forces Institute of Pathology; 2005:383–384.

Traumatic Synovitis •  Foam cells and multinucleated giant cells are not present  Detritic Synovitis • Foreign material is found associated with an inflammatory response PEARLS • E xtra-­articular nodular form of PVNS is called giant cell tumor of tendon sheath; occurs most often in older males and more commonly involves the fingers • Secondary bone invasion occurs in about one fourth to half of patients • Most cases are monoarticular • Polyarticular involvement may occur, but it is seen in younger patients, tends to be familial, and may be associated with multiple lentigines syndrome, pectus excavatum, or fibrous dysplasia • Malignant PVNS has been reported • Histologic features suggesting malignancy include cells with large, atypical nuclei containing large nucleoli and prominent eosinophilic cytoplasm; areas of necrosis and infiltrative borders are seen

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17

Soft Tissue IRA J. MILLER

Chapter Outline Nodular Fasciitis  912

Dedifferentiated Liposarcoma  940

Proliferative Fasciitis and Myositis  913

Rhabdomyoma  941

Myositis Ossificans  913

Rhabdomyosarcoma  942

Ischemic Fasciitis  914

Leiomyoma of Deep Soft Tissue  944

Elastofibroma  915

Leiomyosarcoma (Cutaneous and Deep Soft Tissue)  945

Superficial Fibromatoses  916 Fibrous Hamartoma of Infancy  917 Lipofibromatosis  917 Calcifying Aponeurotic Fibroma  918 Fibroma of Tendon Sheath  919 Collagenous Fibroma  920 Myofibroma/Myopericytoma and Myofibromatosis  920 Gardner Fibroma  921 Desmoid-­Type Fibromatosis  922 Calcifying Fibrous Tumor  923 Inflammatory Myofibroblastic Tumor  924 Solitary Fibrous Tumor  925 Hemosiderotic Fibrolipomatous Tumor and Myxoinflammatory Fibroblastic Sarcoma  926

Granular Cell Tumor  946 Schwannoma  947 Neurofibroma  948 Soft Tissue Perineurioma  950 Paraganglioma  950 Malignant Peripheral Nerve Sheath Tumor  951 Hemangioma  953 Glomus Tumor  954 Hemangioendotheliomas  955 Other Hemangioendotheliomas  956 Angiosarcoma  957 Lymphangioma  957 Myxoma  958

Low-­Grade Fibromyxoid Sarcoma  927

Ossifying Fibromyxoid Tumor  959

Low-­Grade Myofibroblastic Sarcoma  928

Angiomatoid Fibrous Histiocytoma  960

Infantile Fibrosarcoma  929

Synovial Sarcoma  961

Adult Fibrosarcoma  930

Epithelioid Sarcoma  962

Sclerosing Epithelioid Fibrosarcoma  930

Undifferentiated Round Cell Sarcomas, Including Extraskeletal Classic Ewing Sarcoma  964

Myxofibrosarcoma  931 Giant Cell Tumor of Tendon Sheath  932 Lipoma  933 Angiolipoma  934 Spindle Cell Lipoma and Pleomorphic Lipoma  935 Lipoblastoma and Lipoblastomatosis  936 Atypical Lipomatous Tumor/Well-­ Differentiated Liposarcoma  936 Myxoid and Round Cell Liposarcoma  938 Pleomorphic Liposarcoma  939

Desmoplastic Small Round Cell Tumor  965 Alveolar Soft Part Sarcoma  966 Clear Cell Sarcoma of Soft Tissue  967 Perivascular Epithelioid Cell Tumor  968 Extraskeletal Myxoid Chondrosarcoma  969 Myoepithelioma of Soft Tissue  970 Extranodal Rosai-Dorfman Disease  971 Pleomorphic Undifferentiated Sarcoma  972

911

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

912

Chapter 17  —  Soft Tissue

NODULAR FASCIITIS CLINICAL FEATURES •  Primarily affects young adults aged 20 to 40 years; occasionally seen in children • Presents as a rapidly growing solitary mass; may be painful •  Inconsistently associated with recognized previous trauma (10% to 15%) • Can involve any site; flexor aspect of forearm, chest, and back are common sites • Spontaneous regression is expected 

GROSS PATHOLOGY • Located in the deep dermis or subcutis; occasionally occurs intramuscularly • Round to oval, nodular, well-­circumscribed mass; usually smaller than 3 cm • Cut surface may be fibrous, myxoid, or cystic 

HISTOPATHOLOGY • Usually well circumscribed but occasionally infiltrative • “Tissue culture” appearance with long fascicles of spindled cells with a whorled growth pattern; extravasated red blood cells are a helpful feature (Figure 17.1) • Newer lesions have a loose, feathery collagenous stroma with myxoid or microcystic appearance, whereas older lesions are less cellular and more densely collagenized • Zonal pattern with cellular periphery and loose, feathery center that may be cystic •  Scattered inflammatory cells, typically lymphocytes and macrophages • Occasional mitotic figures; no abnormal mitotic figures • Variants • Intravascular fasciitis • Primarily affects children and adolescents • Involves arteries and veins • Cranial fasciitis • Affects infants younger than 1 year • Involves the scalp and skull • Ossifying fasciitis • Often shows osseous metaplasia • Periosteal location •  Similar to myositis ossificans but lacks triphasic zonal pattern 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Vimentin and smooth muscle actin (SMA) positive • Immunohistochemistry does not help to exclude other myofibroblastic or smooth muscle proliferations 

OTHER TECHNIQUES FOR DIAGNOSIS • Translocation t(17;22)(p13;q13.1), producing a MYH9-­ USP6 fusion demonstrable by molecular or in situ hybridization studies, typically cryptic by karyotype • Only seen in nodular fasciitis, not its variants 

Figure 17.1  Nodular fasciitis. Bland plump spindle cells with a “tissue culture” appearance are present in a myxoid to collagenous stroma with admixed inflammatory cells and extravasated RBCs.

DIFFERENTIAL DIAGNOSIS Kaposi Sarcoma • Ill-­defined margins • Prominent vasculature, extravasated red blood cells • Found in immunocompromised individuals; typically patients with acquired immunodeficiency syndrome (AIDS) • Immunoreactive for human herpesvirus type 8 (HHV-­ 8) latent nuclear antigen 1 (LANA-­1), and endothelial markers 

Myxoma • Characterized by a paucity of cells, myxoid matrix, and sparse vascularity 

Fibrous Histiocytoma (Dermatofibroma) • Spindle cell proliferation admixed with epithelioid and foamy histiocytes • Typically arranged in a storiform pattern •  Lacks prominent vasculature and extravasated red blood cells 

Fibromatosis (Desmoid Tumor) • Dense collagenous stroma usually lacking inflammatory component • Lacks thin-­walled vessels • Nuclear immunoreactivity for β-­catenin in most cases PEARLS • N  odular fasciitis is commonly misdiagnosed as a sarcoma • Confirmed as a neoplastic condition • Benign lesion with an excellent prognosis • May progress through myxoid, cellular, and fibrous phases • Conservative surgical resection is the treatment of choice, but close follow-­up is also acceptable

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

913

Selected References Amary MF, Ye H, Berisha F, Tirabosco R, et al. Detection of USP6 gene rearrangement in nodular fasciitis: an important diagnostic tool. Virchows Arch. 2013;463:97–98. Erickson-­Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-­USP6 gene fusion. Lab Invest. 2011;91:1427–1433. Montgomery EA, Meis JM. Nodular fasciitis: its morphologic spectrum and immunohistochemical profile. Am J Surg Pathol. 1991;15:942– 948. Price Jr EB, Sillaphant WM, Shuman R. Nodular fasciitis: a clinicopathologic analysis of 65 cases. Am J Clin Pathol. 1961;35:122–136. Sarangarajan R, Dehner LP. Cranial and extracranial fasciitis of childhood: a clinicopathologic and immunohistochemical study. Hum Pathol. 1999;30:87–92.

PROLIFERATIVE FASCIITIS AND MYOSITIS CLINICAL FEATURES • Typically occurs in adults (usually about 50 years of age) • Firm, palpable, rapidly growing subcutaneous or intramuscular nodule; may be painful • Proliferative fasciitis • Most common site is forearm, followed by leg and trunk • Often associated with a history of trauma • Proliferative myositis • Commonly located in the flat muscles of the trunk and shoulder girdle 

GROSS PATHOLOGY • Poorly circumscribed, gray-­white soft tissue mass • Typically measures 1 to 3 cm in diameter • Proliferative myositis is commonly a pale, gray, scarlike induration involving muscle and overlying fascia 

Figure 17.2  Proliferative fasciitis.  Numerous ganglion-­like cells are seen in a collagenous stroma.

DIFFERENTIAL DIAGNOSIS Rhabdomyosarcoma • Tumor of children, rarely seen in adults • Presence of rhabdomyoblasts rarely with cytoplasmic cross-­striations •  Immunoreactivity for desmin, muscle-­ specific actin (MSA), myogenin, and MyoD1 

Ganglioneuroblastoma • Intermixed neuroblasts and ganglion cells in a background of Schwannian spindle cell stroma • S100 protein is present in the Schwannian stroma • Tumor of young children; extremities an unusual location PEARLS

HISTOPATHOLOGY • Ill-­defined lesions characterized by large myofibroblasts that have large vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm (ganglion-­ like cells) admixed with immature spindle cells in a matrix composed of varying proportions of mucoid material and collagen •  Often numerous mitotic figures in spindled and ganglion-­like cells; they are not atypical (Figure 17.2) • Proliferative fasciitis •  Typically grows along fibrous septa between fat lobules • Proliferative myositis • Endomysial and epimysial growth separates bundles of atrophic skeletal muscle, creating a checkerboard pattern 

• P  athogenesis of proliferative fasciitis and myositis remains unexplained; fascial or muscular injury is thought to be a likely contributor • Benign, self-­limited, reactive process treated with conservative surgical excision • Proliferative fasciitis and proliferative myositis are similar reactive proliferations that are best distinguished by their locations

Selected References

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY

Chung EB, Enzinger FM. Proliferative fasciitis. Cancer. 1975;36:1450–1458. El-­Jabbour JN, Bennett MH, Burke MM, et al. Proliferative myositis: an immunohistochemical and ultrastructural study. Am J Surg Pathol. 1991;15:654–659. Enzinger FM, Dulcey F. Proliferative myositis: report of thirty-­three cases. Cancer. 1967;20:2213–2223. Meis JM, Enzinger FM. Proliferative fasciitis and myositis of childhood. Am J Surg Pathol. 1992;16:364–372. Wong NL. Fine needle aspiration cytology of pseudosarcomatous reactive proliferative lesions of soft tissue. Acta Cytol. 2002;46:1049– 1055.

• Ganglion-­like cells are often nonreactive toward muscle markers and react with vimentin only 

MYOSITIS OSSIFICANS

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

CLINICAL FEATURES •  Commonly affects young, athletic adults; usually involves the extremities

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

914

Chapter 17  —  Soft Tissue

• Uncommon in children •  Presents as a solitary, tender mass; often associated with a history of trauma (>50% of cases) • Radiographic findings show characteristic zonal ossification, with rapid mineralization evident on sequential studies 

GROSS PATHOLOGY •  Well-­ circumscribed, gray-­ yellow lesions with gritty areas •  Some cases have central blood-­ filled spaces and are regarded as a variant of aneurysmal bone cyst occurring outside of bone (Figure 17.3) 

HISTOPATHOLOGY •  Typically shows a triphasic pattern with distinct zonation • Central cellular region • Resembles nodular fasciitis • Cells have bland nuclear features and a variable mitotic rate • Occasional multinucleated giant cells • Intermediate region is composed of immature osteoid • Peripheral zone is composed of mature, “purposeful” lamellar bone • Cartilage may be present 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY

Figure 17.3  Myositis ossificans/aneurysmal bone cyst of soft tissue.  In this variant of myositis ossificans, a rim of bone is present around a central hemorrhagic cyst.

Selected References

• Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • USP6 translocation is detectible by fluorescence in situ hybridization (FISH) in some cases 

DIFFERENTIAL DIAGNOSIS Extraskeletal Osteosarcoma •  Characterized by disordered growth of hyperchromatic, pleomorphic cells with delicate lacelike osteoid formation, often with faint bluish calcification • Absence of zonation 

Ossifying Fibromyxoid Tumor • Chords and aggregates of plump spindle cells in a fibromyxoid matrix, with osteoblastic differentiation and bone formation generally around the outer rim of the tumor •  Lacks inflammatory cells and granulation tissue appearance PEARLS • M  yositis ossificans is a benign, self-­limited process with an excellent prognosis • Spontaneous regression can occur • A subset, likely those with USP6 translocation, have features of aneurysmal bone cyst

Ackerman LV. Extra-­osseous localized non-­neoplastic bone and cartilage formation (so-­called myositis ossificans): clinical and pathological confusion with malignant neoplasms. J Bone Joint Surg Am. 1958;40:279–298. Clapton WK, James CL, Morris LL, et al. Myositis ossificans in childhood. Pathology. 1992;24:311–314. Nuovo MA, Norman A, Chumas J, et al. Myositis ossificans with atypical clinical, radiographic, or pathologic findings: a review of 23 cases. Skeletal Radiol. 1992;21:87–101. Wilson JD, Montague CJ, Salcuni P, et al. Heterotopic mesenteric ossification (“intraabdominal myositis ossificans”): report of five cases. Am J Surg Pathol. 1999;23:1464–1470. Zhang L, Hwang S, Benayed R, et al. Myositis ossificans-­like soft tissue aneurysmal bone cyst: a clinical, radiological, and pathological study of seven cases with COL1A1-­ USP6 fusion and a novel ANGPTL2-­USP6 fusion. Mod Pathol. 2020;33:1492–1504.

ISCHEMIC FASCIITIS CLINICAL FEATURES • Also referred to as atypical decubital fibroplasia • Occurs over bony prominences or other pressure points in debilitated patients • Almost exclusively seen in late adulthood and rarely in younger patients • More commonly found in females 

GROSS PATHOLOGY • Poorly circumscribed, multinodular mass up to 10 cm in diameter • May have overlying ulceration 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

915

Selected References Ilaslan H, Joyce M, Bauer T, Sundaram M. Decubital ischemic fasciitis: clinical, pathologic, and MRI features of pseudosarcoma. Am J Roentgenol. 2006;187:1338–1341. Liegl B, Fletcher CD. Ischemic fasciitis: analysis of 44 cases indicating an inconsistent association with immobility or debilitation. Am J Surg Pathol. 2008;32:1546–1552. Perosio PM, Weiss SW. Ischemic fasciitis: a juxta-­skeletal fibroblastic proliferation with a predilection for elderly patients. Mod Pathol. 1993;6:69–72.

ELASTOFIBROMA CLINICAL FEATURES

Figure 17.4  Ischemic fasciitis.  A transition is seen between fibrin-­ rich necrosis and stellate myofibroblastic cells.

HISTOPATHOLOGY • Typical zonation pattern • Central necrotic region •  Liquefactive or coagulative necrosis with fibrin deposition (Figure 17.4) • Peripheral fibroblastic and vascular proliferation • Granulation tissue-­like with plump endothelial cells •  Atypical fibroblasts with abundant eosinophilic cytoplasm and ganglion-­like features • Vascular thrombosis and fibrinoid necrosis 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

• Usually presents as a deeply seated mass located in the lower subscapular area • Almost exclusively seen in late adulthood and rarely in younger patients • More commonly found in females 

GROSS PATHOLOGY • Firm, rubbery soft tissue mass with ill-­defined margins • Cut surface is gray-­white and glistening with entrapped foci of fat • Focal cystic degeneration often seen 

HISTOPATHOLOGY • Poorly defined lesion composed of thickened, coarse slightly basophilic elastic fibers and scant fibroblastic cells embedded in a heavily collagenized stroma (Figure 17.5A) • Entrapped mature adipose tissue is typically seen 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Atypical Lipomatous Tumor • Typical cases show scattered atypical cells present in adipose tissue with fibrous septa, which may resemble the reactive myofibroblasts in ischemic fasciitis • Myxoid change may be extensive, making adipocytic component difficult to find, especially in small samples • Fat necrosis is common, but not coagulative necrosis with fibrin 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY •  Verhoeff–van Gieson elastic stain: highlights elastic fibers (Figure 17.5B) 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS

Bursitis

Fibrolipoma

• May produce a mass with a central cavity, adjacent to a joint • Cavity lining is generally denuded with fibrin exudate, and surrounded by inflammatory cells

• Characterized by predominance of mature adipocytes with intervening fibrous connective tissue • Lacks elastic fibers 

PEARLS • Ischemic fasciitis is a benign, reactive process likely related to intermittent ischemia • Surgical excision is the treatment of choice; can recur owing to the persistence of the underlying cause

Spindle Cell Lipoma • Subcutaneous mass in neck and shoulder region • Ropy collagen present, but not prominent elastic fibers. May show extensive myxoid change and contain few to no adipocytes

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

916

Chapter 17  —  Soft Tissue

A Figure 17.6  Superficial fibromatosis.  Dupuytren contracture. Area of transition between cellular and collagenous zones.

SUPERFICIAL FIBROMATOSES CLINICAL FEATURES

B Figure 17.5  Elastofibroma.  A, Gross photo of cut section (with the surface inked black) showing a poorly marginated gray-­white mass. B, The tumor is paucicellular with bland fibroblasts and prominent elastic fibers in longitudinal and transverse cross section, evident on H&E (arrows), highlighted by elastic stain (inset).

• Presents as a small, slow-­growing, subcutaneous nodule or thickening • Palmar fibromatosis (Dupuytren contracture) • Palmar surface of the hand; may result in contractures • Almost exclusively in adults, males affected more than females • Often bilateral, especially in alcoholics • Plantar fibromatosis (Ledderhose disease) • Plantar, non-­weight-­bearing area of the foot • Occurs in both children and adults • Often multinodular • Penile fibromatosis (Peyronie disease) • Dorsal aspect of the shaft of the penis • Exclusively seen in adults 

GROSS PATHOLOGY • Single or multiple, gray-­white, firm nodules or scarlike tissue in the subcutis 

PEARLS • H  istology of elastofibroma is described as “spaghetti and meatballs” owing to long and globular elastic fibers • Increased incidence in manual laborers; related to repetitive motion injury • Can usually be diagnosed by radiology or fine-­needle aspiration

Selected References Lococo F, Cesario A, Mattei F, et al. Elastofibroma dorsi: clinicopathological analysis of 71 cases. Thorac Cardiovasc Surg. 2013;61:215– 222. Vincent J, Maleki Z. Elastofibroma: cytomorphologic, histologic, and radiologic findings in five cases. Diagn Cytopathol. 2012;40(suppl 2): E99–E103. Yamazaki K. An ultrastructural and immunohistochemical study of elastofibroma: CD 34, MEF-­2, prominin 2 (CD133), and factor XIIIa-­ positive proliferating fibroblastic stromal cells connected by Cx43-­ type gap junctions. Ultrastruct Pathol. 2007;31:209–219.

HISTOPATHOLOGY • Proliferative and involutional phases • Proliferative phase shows variably cellular fascicles of bland, spindled cells often arranged in a nodular pattern (Figure 17.6) • Occasionally prominent giant cells in plantar lesions • Mitotic figures may be seen •  Involutional or residual phase shows paucicellular, densely collagenized tissue 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

917

DIFFERENTIAL DIAGNOSIS Desmoid Type of Fibromatosis • Rare in hands and feet • Nuclear expression of beta-­catenin is not helpful to distinguish between these entities 

Fibroma of Tendon Sheath •  Well-­ circumscribed, sometimes multinodular mass firmly attached to tendon sheath • Hypocellular with bland spindle cells widely separated by hyalinized collagenous stroma 

Fibrosarcoma (Infantile and Adult Types) • Infantile fibrosarcoma usually affects children younger than 1 year • Adult fibrosarcoma is only rarely found in distal extremities • Highly cellular, infiltrative tumor composed of uniform fibroblasts with hyperchromatic nuclei and scant cytoplasm, arranged in a distinctive herringbone pattern • High mitotic rate is common; atypical mitotic figures may be seen • Areas of necrosis or hemorrhage may be seen

Figure 17.7  Fibrous hamartoma of infancy.  The triphasic population of collagen fascicles, primitive myoid bundles, and fat forms a stellate lesion.

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

PEARLS S uperficial fibromatosis may be multifocal • • Plantar or palmar fibromatosis may be highly cellular and mistaken for sarcoma • Associated conditions may include diabetes, cirrhosis, and epilepsy; some fibromatoses may have a hereditary component • Surgical excision is the treatment of choice

OTHER TECHNIQUES FOR DIAGNOSIS

Selected References

• Lacks a primitive mesenchymal component 

Allen PW. The fibromatoses: a clinicopathologic classification based on 140 cases. Am J Surg Pathol. 1977;1:255–270. Evans HL. Multinucleated giant cells in plantar fibromatosis. Am J Surg Pathol. 2002;26:244–248. Montgomery E, Lee JH, Abraham SC, et al. Superficial fibromatoses are genetically distinct from deep fibromatoses. Mod Pathol. 2001;14:695–701.

• Noncontributory 

DIFFERENTIAL DIAGNOSIS Lipofibromatosis Lipoblastoma • Lobulated mass with fat lobules separated by fibrous bands • Lacks a primitive mesenchymal component • Myxoid stroma and lipoblasts are present 

Embryonal Rhabdomyosarcoma

FIBROUS HAMARTOMA OF INFANCY

• Lacks fibrous and adipose tissue • Positive for desmin, myogenin, and MyoD1

CLINICAL FEATURES

PEARLS

• Rapidly growing, painless subcutaneous mass in young children, sometimes congenital • Common sites include trunk, shoulder, axilla, and groin • Most cases occur within the first 2 years of life 

GROSS PATHOLOGY • Poorly defined deep dermal or subcutaneous mass • Gray, firm cut surface with yellow flecks • Usually 2 to 5 cm but may be larger 

• F ibrous hamartoma of infancy is a benign lesion usually cured with local excision

Selected References Coffin CM, Dehner LP. Fibroblastic-­myofibroblastic tumors in children and adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991;11:569–588. Dickey GE, Sotelo-­Avila C. Fibrous hamartoma of infancy: current review. Pediatr Dev Pathol. 1999;2:236–243. Groisman G, Lichtig C. Fibrous hamartoma of infancy: an immunohistochemical and ultrastructural study. Hum Pathol. 1991;22:914–918.

HISTOPATHOLOGY •  Triphasic appearance comprising an admixture of fibrous tissue, adipose tissue, and bundles of immature mesenchymal cells (Figure 17.7) • Often has a stellate configuration and infiltrates surrounding fat 

LIPOFIBROMATOSIS CLINICAL FEATURES • Previously referred to as infantile fibromatosis, nondesmoid type

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

918

Chapter 17  —  Soft Tissue

Figure 17.8  Lipofibromatosis. Fascicles of bland spindle cells and collagen are admixed with mature adipose tissue.

• Occurs in childhood, between birth and second decade; males affected more than females •  Slowly growing, painless mass most commonly presenting in an extremity or on the trunk; rare cases in the head and neck • May cause isolated macrodactyly 

Figure 17.9  Calcifying aponeurotic fibroma.  Nodular calcifications are surrounded by chondrocyte-­like cells with intervening spindle cells in a hyalinized stroma.

PEARLS • L ipofibromatosis has a high rate of local recurrence but no metastatic potential • Wide local excision is the standard treatment

GROSS PATHOLOGY

Selected References

• Poorly defined subcutaneous mass with admixed adipose tissue • Usually 1 to 3 cm 

Deepti AN, Madhuri V, Walter NM, et al. Lipofibromatosis: report of a rare paediatric soft tissue tumour. Skeletal Radiol. 2008;37:555–558. Fetsch JF, Miettinen M, Laskin WB, et al. A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis. Am J Surg Pathol. 2000;24:1491–1500. Kenney B, Richkind KE, Friedlaender G, et al. Chromosomal rearrangements in lipofibromatosis. Cancer Genet Cytogenet. 2007;179:136– 139.

HISTOPATHOLOGY • Bands of bland spindled cells and collagen traversing through mature adipose tissue (Figure 17.8) • Infiltrative borders 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS

CALCIFYING APONEUROTIC FIBROMA CLINICAL FEATURES • Also known as juvenile aponeurotic fibroma or Keasbey tumor • Most commonly affects children but may also occur in adults • Presents as a slow-­growing, painless mass, usually on the palmar or plantar surfaces of the hands or feet, rarely in other locations 

Fibrous Hamartoma of Infancy

GROSS PATHOLOGY

• Contains a primitive mesenchymal component 

• Poorly circumscribed, firm, gray-­white, rubbery nodule usually smaller than 3 cm • Gritty cut surface 

Lipoblastoma • Lobulated mass with fat lobules separated by fibrous bands • Myxoid stroma and presence of lipoblasts 

Desmoid-­Type Fibromatosis • Contains moderately cellular areas of fibrous growth, which infiltrate into fat (or skeletal muscle); adipose tissue is not a primary component

HISTOPATHOLOGY • Bland oval plump fibroblasts in a heavily collagenized stroma •  Foci of stippled to confluent amorphous calcifications surrounded by rounded chondrocyte-­ like cells (Figure 17.9)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

919

• Infiltrative margins with extension into adipose tissue •  Osteoclast-­ like giant cells may be associated with calcification 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Fibromatosis (Palmar, Plantar) •  Characterized by fascicles of spindled uniform-­ appearing fibroblasts with varying amount of collagen • Growth along fascial planes and tendons • Absence of calcification or chondroid differentiation • Usually found in adults, but plantar fibromatosis occasionally seen in children 

Figure 17.10  Fibroma of tendon sheath. Slitlike pseudovascular spaces are present between hypocellular, collagenous nodules.

• Fibrous, often multinodular cut surface separated by clefts 

Chondroma of Soft Tissue

HISTOPATHOLOGY

• Typically occurs in hands of adults •  Characteristically a lobulated lesion composed of mature hyaline cartilage • “Chondroblastoma-­like” variant undergoes calcification in a diffuse pericellular rather than in a focal manner

• Spindled to stellate cells embedded in a collagenous stroma, sometimes myxoid •  Clefted, pseudovascular spaces separate the nodules (Figure 17.10) •  Degenerative cytologic atypia may be present; giant cells are rare 

PEARLS • C  alcifying aponeurotic fibroma is a locally aggressive lesion characterized by local recurrence (> 50% recur) • Younger lesions are less heavily calcified, and older lesions show more extensive calcification and chondroid differentiation • Surgical excision is the preferred treatment

Selected References Allen PW, Enzinger FM. Juvenile aponeurotic fibroma. Cancer. 1970;26:857–867. Coffin CM, Dehner LP. Fibroblastic-­myofibroblastic tumors in children and adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991;11:569–588. Fetsch JF, Miettinen M. Calcifying aponeurotic fibroma: a clinicopathologic study of 22 cases arising in uncommon sites. Hum Pathol. 1998;29:1504–1510.

FIBROMA OF TENDON SHEATH

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Giant Cell Tumor of Tendon Sheath • Numerous giant cells, plump mononuclear cells, and variable amounts of xanthoma cells 

Superficial Fibromatosis (Palmar, Plantar) • Growth along fascial planes and tendons with infiltrative borders

CLINICAL FEATURES

PEARLS

• Most commonly affects the hands of young to middle-­ aged adults; slight male predominance • Presents as a slow-­growing, painless mass, usually on the preaxial digits or wrist but may affect foot or knee joint 

• F ibroma of tendon sheath is benign and typically cured by surgical excision; recurrence is rare

GROSS PATHOLOGY •  Circumscribed, firm, gray-­ white, lobulated nodule attached to the tendon, usually smaller than 3 cm

Selected References Maluf HM, DeYoung BR, Swanson PE, et al. Fibroma and giant cell tumor of tendon sheath: a comparative histological and immunohistological study. Mod Pathol. 1995;8:155–159. Pulitzer DR, Martin PC, Reed RJ. Fibroma of tendon sheath: a clinicopathologic study of 32 cases. Am J Surg Pathol. 1989;13:472–479.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

920

Chapter 17  —  Soft Tissue

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Desmoid Fibromatosis

A

• Typically seen in younger patients • Fascicular growth pattern with infiltrative borders that entrap connective tissues •  Nuclear immunoreactivity for beta-­ catenin usually seen PEARLS • S urgical resection is the standard treatment, typically does not recur • May have a genetic link to fibroma of tendon sheath

Selected References

B Figure 17.11  Collagenous fibroma.  A, Gross photos showing lobulated, smooth surface with a thin fibrous pseudocapsule (left), and cut surface showing a white, fibrous, to edematous/myxoid areas. B, Bland to mildly activated fibroblasts with elongated or stellate morphology are sparsely distributed in stroma with a predominantly lightly collagenized appearance. Sciot R, Samson I, van den Berghe H, et al. Collagenous fibroma (desmoplastic fibroblastoma): genetic link with fibroma of tendon sheath? Mod Pathol. 1999;12:565–568.

Evans HL. Desmoplastic fibroblastoma: a report of seven cases. Am J Surg Pathol. 1995;19:1077–1081. Macchia G, Trombetta D, Moller E, et al. FOSL1 as a candidate target gene for 11q12 rearrangements in desmoplastic fibroblastoma. Lab Invest. 2012;92:735–743. Miettinen M, Fetsch JF. Collagenous fibroma (desmoplastic fibroblastoma): a clinicopathologic analysis of 63 cases of a distinctive soft tissue lesion with stellate-­shaped fibroblasts. Hum Pathol. 1998;29:676– 682. Nishio J, Akiho S, Iwasaki H, et al. Translocation t(2;11) is characteristic of collagenous fibroma (desmoplastic fibroblastoma). Cancer Genet. 2011;204:569–571.

MYOFIBROMA/MYOPERICYTOMA AND MYOFIBROMATOSIS

COLLAGENOUS FIBROMA

CLINICAL FEATURES

CLINICAL FEATURES

• Also known as infantile congenital myofibromatosis or congenital myofibromatosis in children • Most common fibrous tumor of infancy • About 90% occur within the first 2 years of life; however, adults may be affected •  Myofibroma refers to a solitary lesion (common), whereas myofibromatosis denotes multiple skin and soft tissue lesions with variable visceral involvement • Solitary subcutaneous nodules typically involve the head and neck but can occur anywhere •  Multicentric form may involve the lungs, heart, bones, and gastrointestinal (GI) tract 

• Also known as desmoplastic fibroblastoma • Most commonly presents as slow growing painless mass in subcutaneous or deep tissues of upper extremities • The majority occur in late adulthood but can occur in childhood 

GROSS PATHOLOGY • Well-circumscribed mass, usually less than 5 cm (Figure 17.11A) •  Cut surface gray-­ white with a lobulated or whorled appearance 

HISTOPATHOLOGY • Hypocellular spindle to stellate cell mass embedded in a loose collagenous stroma (Figure 17.11B) • Mitotic figures are typically not seen 

GROSS PATHOLOGY • Cut surface is rubbery gray-­white with a lobulated or whorled appearance • May have central necrosis or cyst formation • Margins may be well defined or focally infiltrative • Size from 0.5 cm up to 8 cm 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

921

PEARLS • P  atients with solitary and multiple lesions of myofibroma or myofibromatosis confined to soft tissues have an excellent prognosis; visceral involvement imparts a worse prognosis depending on the particular locations and extent of growth • Bilateral symmetric bone lesions are a radiographic clue to diagnosis in infants • Lesions may spontaneously regress • Surgical resection is the standard treatment

Selected References

Figure 17.12  Myofibroma.  Plump, bland ovoid cells are arranged around curved, slitlike vascular channels in the central zone of this tumor.

HISTOPATHOLOGY •  Typically shows a biphasic pattern or zonal phenomenon • Peripheral areas show fascicular or whorled growth of plump, spindled cells with eosinophilic cytoplasm (myofibroblasts) • Central areas of the lesion are more cellular with oval cells and a staghorn-­appearing, hemangiopericytoma-­ like vasculature (Figure 17.12) •  Variable mitotic activity but no atypical division figures •  Scattered lymphoplasmacytic infiltrate typically present • Polypoid protrusion into vascular spaces is typical at the edge of the lesion • Focal areas of hemorrhage, calcification, and necrosis may be seen centrally • May be well circumscribed or infiltrative 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • SMA and MSA positive • Desmin variable • Immunohistochemistry does not help to exclude other myofibroblastic or smooth muscle proliferations 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory aside from ruling out other selected lesions such as infantile fibrosarcoma 

DIFFERENTIAL DIAGNOSIS Angioleiomyoma • Occurs in skin and subcutis of adults •  Less cellular with more complete smooth muscle differentiation

Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer. 1981;48:1807–1818. Coffin CM, Dehner LP. Fibroblastic-­myofibroblastic tumors in children and adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991;11:569–588. Daimaru Y, Hashimoto H, Enjoji M. Myofibromatosis in adults (adult counterpart of infantile myofibromatosis). Am J Surg Pathol. 1989;13:859–865. Zand DJ, Huff D, Everman D, et al. Autosomal dominant inheritance of infantile myofibromatosis. Am J Med Genet. 2004;126:261–266.

GARDNER FIBROMA CLINICAL FEATURES • Benign lesion of childhood and early adulthood that has a strong association with desmoid-­type fibromatosis and familial adenomatous polyposis (Gardner syndrome) • Poorly defined, plaquelike soft tissue mass in superficial and deep tissues of back and paraspinal region, head and neck, extremities, and chest 

GROSS PATHOLOGY •  Ill-­ defined firm mass with a white-­ gray, rubbery cut surface • Ranges in size from 1 to 12 cm 

HISTOPATHOLOGY • Sheets of densely hyalinized bundles of collagen containing scant, small spindle cells (Figure 17.13) • Collagen fibers are separated by cracks or clefts • Infiltrative borders are seen with entrapped connective tissue 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • CD34 positive • β-­Catenin: most are positive with nuclear labeling 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Desmoid-­Type Fibromatosis • More cellular spindle cell proliferation with fascicular growth pattern 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

922

Chapter 17  —  Soft Tissue

Figure 17.13  Gardner fibroma. This tumor of low cellularity has small, bland fibroblasts and heavy collagenization with cracks between collagen bundles. Entrapped adipocytes are present.

Figure 17.14  Desmoid-­type fibromatosis. This area shows intermediate cellularity with bland fibroblasts and myofibroblasts in a collagenous to edematous stroma. Immunostain for β-­catenin (inset) shows nuclear and cytoplasmic reactivity in many of the cells.

Nuchal Fibroma • Bundles of hyalinized collagen with entrapped adnexal structures and connective tissues • Frequently has proliferation of small nerves similar to traumatic neuroma • Distinct clinical presentation, occurs in the posterior neck of middle-­aged adults (males affected more than females); associated with diabetes mellitus in about half of cases • CD34 and β-­catenin stains typically negative 

Elastofibroma • Densely eosinophilic elastic fibers intermixed with collagen as highlighted with the Verhoeff–van Gieson elastic stain •  Occurs in older patients, frequently in subscapular location • Not associated with familial adenomatous polyposis PEARLS • G  ardner fibroma may be the first presentation of familial adenomatous polyposis (Gardner syndrome) • About half of patients will develop desmoid-­type fibromatosis • Surgical resection is the standard treatment

Selected References Allen PW. Nuchal-­type fibroma appearance in a desmoid fibromatosis. Am J Surg Pathol. 2001;25:828–829. Coffin CM, Hornick JL, Zhou H, et al. Gardner fibroma: a clinicopathologic and immunohistochemical analysis of 45 patients with 57 fibromas. Am J Surg Pathol. 2007;31:410–416. Wehrli BM, Weiss SW, Yandow S, et al. Gardner-­associated fibromas (GAF) in young patients: a distinct fibrous lesion that identifies unsuspected Gardner syndrome and risk for fibromatosis. Am J Surg Pathol. 2001;25:645–651.

DESMOID-­TYPE FIBROMATOSIS CLINICAL FEATURES • Also referred to as aggressive or deep fibromatosis

• Relatively common neoplasm that typically occurs in adolescents and young adults, but age range is wide • Comprises a group of proliferative tumors that present as deep-­seated masses • Shoulder region, chest wall, thigh, and mesentery are favored sites • Musculoaponeurotic fibromatosis • Abdominal fibromatosis • Mesenteric fibromatosis •  Lesions are associated intimately with muscular aponeuroses • Rectus muscle is the favored location • Occurs almost exclusively in women who are pregnant or postpartum • Found in mesentery of the bowel or retroperitoneum • Often associated with previous history of abdominal surgery • May be associated with Gardner syndrome (familial adenomatous polyposis, mesenteric fibromatosis, osteomas, and multiple epidermal inclusion cysts) 

GROSS PATHOLOGY • May appear well defined but actually has infiltrative margins • Often grows along fascial planes • Firm tumor that often has a gritty cut surface •  Sectioning reveals a glistening, white, trabeculated surface 

HISTOPATHOLOGY • Composed of uniform-­appearing, spindle-­shaped fibroblasts and abundant collagen (Figure 17.14) • Infiltrative margins • Occasional mitotic figures are present in more cellular areas • Inconspicuous vasculature • Myxoid matrix may be seen, primarily in abdominal fibromatosis 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

923

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • β-­Catenin: positive nuclear immunoreactivity • SMA positive 

OTHER TECHNIQUES FOR DIAGNOSIS •  Recurrent chromosomal abnormalities include trisomies 8 and 20 and loss of 5q, not usually needed for diagnosis; CTNNB1 gene sequencing may identify mutations with prognostic relevance. 

DIFFERENTIAL DIAGNOSIS Low-­Grade Fibromyxoid Sarcoma • Alternating collagenized and myxoid zones with prominent curvilinear vessels • May contain hyaline collagen rosettes • Negative for nuclear β-­catenin; positive for MUC4 •  Presence of t(7;16)(q33;p11), producing an FUS-­ CREB3L2 fusion in molecular or cytogenetic analysis 

Fibrosarcoma (Infantile and Adult Types) • Most commonly affects children younger than 1 year; occasionally seen in adults • Highly cellular, infiltrative tumor composed of fibroblasts with hyperchromatic nuclei and scant cytoplasm arranged in a herringbone pattern • Mitoses are obvious, and atypical mitotic figures may be seen • Areas of necrosis or hemorrhage may be present • Infantile fibrosarcoma harbors t(12;15)(p13;q26), producing an ETV6-­NTRK fusion demonstrable by molecular or cytogenetic studies PEARLS • D  esmoid-­type fibromatosis has a high recurrence rate and may be locally aggressive but has no metastatic potential • Surgical removal is controversial for most cases due to high recurrence rate • Recurrence rate ranges between 25% and 80%

Selected References Bhattacharya B, Dilworth HP, Iacobuzio-­ Donahue C, et al. Nuclear beta-­catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol. 2005;29:653–659. Carlson JW, Fletcher CD. Immunohistochemistry for beta-­catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature. Histopathology. 2007;51:509–514. De Wever I, Dal Cin P, Fletcher CD, et al. Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology. Mod Pathol. 2000;13:1080–1085.

CALCIFYING FIBROUS TUMOR CLINICAL FEATURES •  Benign fibrous tumor that occurs predominantly in adolescents and young adults

Figure 17.15  Calcifying fibrous tumor. Paucicellular, sclerotic lesion contains lymphoplasmacytic infiltrate and psammomatous calcifications.

• Most common in subcutaneous and deep soft tissues of extremities, trunk, groin, and neck but has been described in many locations, including viscera 

GROSS PATHOLOGY • Typically a circumscribed solid mass, 3 to 5 cm, but may be larger • Cut surface is solid, firm, and gray-­white 

HISTOPATHOLOGY •  Hypocellular, sclerotic tissue with a sparse lymphoplasmacytic infiltrate and discrete calcifications (Figure 17.15) • Calcification may be psammomatous or dystrophic •  Germinal center formation may be seen at lesion periphery 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Noncontributory 

OTHER TECHNIQUES FOR DIAGNOSIS • Noncontributory 

DIFFERENTIAL DIAGNOSIS Desmoid-­Type Fibromatosis • Characterized by fascicles of spindle-­shaped fibroblasts with varying amounts of collagen and infiltrative borders • More cellular than calcifying fibrous tumor. Lacks significant calcification • Positive for β-­catenin nuclear reactivity in most cases 

Calcifying Aponeurotic Fibroma • Typically seen on hands and feet of young children

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

924

Chapter 17  —  Soft Tissue

•  Stippled calcification with surrounding chondroid differentiation • Infiltrative margins • Inflammation not typical PEARLS • C  alcifying fibrous tumor is a benign lesion with rare reports of recurrence • Treatment is complete surgical resection

Selected References Hill KA, Gonzalez-­Crussi F, Chou PM. Calcifying fibrous pseudotumor versus inflammatory myofibroblastic tumor: a histological and immunohistochemical comparison. Mod Pathol. 2001;14:784– 790. Kirby PA, Sato Y, Tannous R, et al. Calcifying fibrous pseudotumor of the myocardium. Pediatr Dev Pathol. 2006;9:384–387. Lau SK, Weiss LM. Calcifying fibrous tumor of the adrenal gland. Hum Pathol. 2007;38:656–659. Nascimento AF, Ruiz R, Hornick JL, et al. Calcifying fibrous “pseudotumor”: clinicopathologic study of 15 cases and analysis of its relationship to inflammatory myofibroblastic tumor. Int J Surg Pathol. 2002;10:189–196.

Figure 17.16  Inflammatory myofibroblastic tumor. Loose fascicles of plump myofibroblasts with admixed inflammatory cells are present. Immunostain for ALK1 (inset) shows membranous and cytoplasmic reactivity in this case.

OTHER TECHNIQUES FOR DIAGNOSIS INFLAMMATORY MYOFIBROBLASTIC TUMOR CLINICAL FEATURES • Previously known as inflammatory pseudotumor and plasma cell granuloma • Most often occurs in children and young adults but has a wide age range • Commonly seen in the lung; the most frequent extrapulmonary sites are mesentery and omentum, but it can involve any location • Systemic symptoms and signs may be present, including fever, weight loss, anemia, increased erythrocyte sedimentation rate, and elevated C-­ reactive protein levels 

GROSS PATHOLOGY •  Typically circumscribed, but nonencapsulated; often multinodular • Cut surface is solid, firm, and gray-­white 

HISTOPATHOLOGY • Variably cellular tumor comprised of spindle cells and mixed inflammatory cells in a myxoid or collagenized background (Figure 17.16) • Some lesions contain large histiocytoid ganglion-­like cells • May be hypocellular and resemble scars • Mitotic figures may be numerous 

SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY • Variably positive for smooth muscle markers • ALK-­1 protein present in about 40% of cases, more frequently in childhood tumors 

• Rearrangement of ALK locus at 2p23 by molecular or cytogenetic analysis 

DIFFERENTIAL DIAGNOSIS Leiomyosarcoma •  Characterized by fascicles of cytologically atypical spindle cells with hyperchromatic nuclei and variable but present mitotic activity • May have inflammatory infiltrate, usually patchy • Typically, middle-­aged and elderly adults are affected 

Desmoid-­Type Fibromatosis •  Fascicles of spindle-­ shaped fibroblasts with variable amounts of collagen and infiltrative borders • Positive for β-­catenin with nuclear labeling in most cases • Lacks inflammatory infiltrate 

Embryonal Rhabdomyosarcoma • Primitive spindle cells, usually in a myxoid background; focal strap cells may be present • Usually lacks inflammation • Positive for desmin, myogenin, and MyoD1 

Inflammatory Pleomorphic Undifferentiated Sarcoma • Usually occurs in older adults; retroperitoneum is the most common location • Cases with associated liposarcoma or MDM2 amplification are best classified as dedifferentiated liposarcoma • Atypical hyperchromatic cells with prominent mixed inflammation rich in xanthomatous cells • Negative for SMA and ALK-­1 

Metastatic Sarcomatoid Carcinoma • Usually supported by clinical history or imaging, with similar histology as primary

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 17  —  Soft Tissue

925

• May have areas of squamous differentiation • At least focally positive for keratin, EMA, MOC31, or p63 

Spindle Cell Melanoma • Variably cellular spindle cell lesion with variable cellular pleomorphism, prominent nucleoli, and nuclear pseudoinclusions • May show perineural invasion extending beyond the tumoral component • Positive for S100 protein, Sox10; rarely for tyrosinase, Melan-­A, or HMB-­45 PEARLS • Inflammatory myofibroblastic tumor is a neoplastic process • Treatment is based on surgical resection • May recur after excision

Figure 17.17  Solitary fibrous tumor.  Monotonous ovoid and spindle tumor cells arranged around a hyalinized vasculature.

Selected References Coffin CM, Dehner LP, Meis-­Kindblom JM. Inflammatory myofibroblastic tumor, inflammatory fibrosarcoma, and related lesions: an historical review with differential diagnostic considerations. Semin Diagn Pathol. 1998;15:102–110. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007;31:509–520. Cook JR, Dehner LP, Collins MH, et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol. 2001;25:1364–1371.

• “Hemangiopericytoma-­like” open, staghorn-­shaped, and hyalinized blood vessels • Epithelioid areas may be present • Low mitotic activity (50 IgG4+ plasma cells/high power field are highly suggestive of IgG4-­related aortitis 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1000

Chapter 18  —  Heart, Pericardium, and Blood Vessels

A B Figure 18.14  Giant cell aortitis.  A, Aorta shows a central area of inflammation disrupting the media, which in turn is acellular. The areas of absent smooth muscle cells correspond to laminar necrosis. In addition, there is fibrointimal hyperplasia, adventitial fibrosis, and mononuclear inflammation. B, Numerous multinucleated giant cells are admixed with the lymphohistiocytic infiltrates. C, Movat stain shows elastic lamellae within the eosinophilic areas of laminar medial necrosis.

Figure 18.15  Giant cell arteritis.  A, A temporal artery biopsy shows transmural granulomatous inflammation with giant cells in the media and adventitia of this muscular artery. B, Movat stain shows disruption of the internal elastic lamina in the areas with inflammation and marked intimal hyperplasia. Fibrinoid necrosis is occasionally observed.

C

A

Behçet Disease  •  Relapsing autoimmune disorder with recurrent oral and genital ulcers, eye and skin lesions, commonly in young adult males • Involves both large (aorta and pulmonary arteries) to small caliber arteries and veins • Arterial aneurysm with thrombosis and arterial occlusion similar to Takayasu arteritis may be seen • Intense mixed inflammatory infiltrates with giant cells are described in the active stage associated with medial destruction •  Cardiac manifestation includes right-­ sided mural thrombi and valvulitis • Superficial and deep venous occlusion due to thrombophlebitis; rarely portal and hepatic vein involvement results in Budd-­Chiari syndrome  Age-­Related Changes (Arteriosclerosis)  •  Concentric intimal thickening, fragmentation, and reduplication of the internal elastic lamina and foci of calcification may be seen in temporal arteries • Lacks inflammatory cell component

B PEARLS • G  iant cell arteritis and Takayasu arteritis cannot always be confidently differentiated based on histopathologic features only • Because of the frequent involvement of temporal arteries in giant cell arteritis, temporal arteritis has often been used interchangeably with giant cell arteritis in the literature; however, giant cell arteritis is the preferred term because not all patients with giant cell arteritis have temporal arteritis, and not all cases of temporal arteritis are caused by giant cell arteritis • Rate of positive temporal artery biopsies ranges between 10% and 20% of specimens; negative predictive value of temporal artery biopsy is about 90% • Lesions of giant cell arteritis are typically segmental • At least three hematoxylin-and-eosin-stained levels and one elastic stain of the temporal artery must be evaluated • Multiple sections of the aorta should be submitted • Takayasu arteritis • Frequently diagnosed by clinical criteria and vascular imaging

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 18  —  Heart, Pericardium, and Blood Vessels

• Stenotic lesions are found in up to 98% of patients and aneurysms in 27% • Abdominal aorta is affected in about 40% of patients • Most common sites requiring surgical intervention are aortic arch and branch vessels • Isolated aortitis • Most often discovered after surgical resection of ascending aortic aneurysms • Histopathologic features similar to those of giant cell arteritis, but patients lack evidence of systemic disease • Favorable outcome even without medical therapy

Selected References Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-­related disease. Mod Pathol. 2012;25:1181–1192. Genereau T, Lortholary O, Pottier MA, et al. Temporal artery biopsy: a diagnostic tool for systemic necrotizing vasculitis. French Vasculitis Study Group. Arthritis Rheum. 1999;42:2674–2681. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1–11. Stone JR, Bruneval P, Angelini A, et al. Consensus statement on surgical pathology of the aorta from the society for cardiovascular pathology and the association for European cardiovascular pathology: I. Inflammatory diseases. Cardiovasc Pathol. 2015;24:267–278.

MEDIUM-­VESSEL VASCULITIS Clinical Features Polyarteritis Nodosa  • Idiopathic systemic disease characterized by vasculitis involving medium-­sized and small muscular arteries • Most patients are in the fourth to sixth decades; male-­ to-­female ratio is 2:1 • Patients usually have nonspecific systemic symptoms of weight loss and fever with focal symptoms in the specific organ involved (peripheral neuropathy, testicular pain, livedo reticularis, myalgias, and gastrointestinal infarction) •  Associated with deposition of circulating immune complexes in hepatitis B infection • May become manifest in the course of hairy cell leukemia, rheumatoid arthritis, and Sjögren syndrome • Arteriography detects aneurysms or occlusions of visceral arteries; commonly involved vessels are renal, coronary, hepatic, and mesenteric arteries; lung involvement (bronchial arteries) in up to 30% of patients  Kawasaki Disease (Mucocutaneous Lymph Node Syndrome, Infantile Polyarteritis Nodosa)  • Acute self-­limited disease typically affects infants and children (range, 6 months to 15 years; peaks at 13 to 24 months) • Increased incidence in Japan and Korea • In the United States, children of American Asian and Pacific Island origin have higher incidence compared with African American and white children • Clinical criteria include fever for at least 5 days and at least four of the following clinical features: conjunctival injection, cervical lymphadenopathy, oral mucosal changes, polymorphous rash, and erythema and edema of the hands and feet

1001

• Typically affects coronary arteries, but any muscular artery may be involved; subclavian, axillary, iliac, femoral, renal, and superior mesenteric artery involvement has been observed 

Gross Pathology Polyarteritis Nodosa  • Tendency to occur at arterial branching sites • Aneurysms or stenosis of the arteries may be seen • Thrombosis is common  Kawasaki Disease  • Coronary ectasia or aneurysm can be seen in the acute stage; may be solitary or multiple • Regression of aneurysms is seen in half of the cases within 1 to 2 years • Progression of aneurysms to stenotic lesions occurs in about 10% 

Histopathology Polyarteritis Nodosa  • Lesions are usually in various stages of development • Acute injury is characterized by transmural inflammation with focal segmental destruction of the wall and deposition of amorphous eosinophilic material (fibrinoid necrosis) (Figure 18.16) • Inflammation is initially neutrophilic but later is composed predominantly of lymphocytes and macrophages • Healing lesions consist of granulation tissue within the vessel wall and may show luminal narrowing owing to thrombosis or fibrointimal proliferation • Aneurysms and pseudoaneurysms may develop owing to weakening of the vessel wall  Kawasaki Disease  • Inflammation consisting of lymphocytes, macrophages, and neutrophils is first seen in the intima and adventitia, then progresses into the media • Panarteritis is associated with neutrophilic infiltration, disruption of the internal elastic lamina, smooth muscle degeneration, and edema in the media • Fibrinoid necrosis is absent

Figure 18.16  Necrotizing arteritis. A testicular muscular-­type artery shows fibrinoid necrosis with focal transmural acute inflammation.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1002

Chapter 18  —  Heart, Pericardium, and Blood Vessels

• Chronic lesions show intimal myofibroblastic proliferation and chronic inflammation may persist for months to years • Aneurysms show thinning of the media, destruction of the internal elastic lamina, and fibrosis in the adventitia; may thrombose or become stenotic with intimal hyperplasia 

Special Stains and Immunohistochemistry • Elastic highlights destruction of the elastic lamina • Trichrome stains fibrin red • Movat highlights both elastin and collagen 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Isolated or Single-­Organ Vasculitis  •  Often an unexpected finding in surgical specimens resected for inflammatory processes or mass lesions • Isolated vasculitis has been reported from the gastrointestinal tract, gallbladder, appendix, breast, uterus, ovary, and testis • Necrotizing or granulomatous inflammation of the vessels can be present • Although the histologic features can be similar to those of polyarteritis nodosa (PAN), use of PAN in the diagnosis is discouraged because it can be misleading •  Cured with resection and does not require systemic therapy • May be the first manifestation of a systemic vasculitis; clues to systemic disease include the presence of systemic symptoms, acute-­phase reactants, and serologic autoimmune markers •  Long-­ term follow-­ up is necessary to confirm the absence of progression to systemic involvement  Small-­Vessel Vasculitis  •  If involvement of only small arteries is seen in a biopsy, differentiation between medium-­ vessel and small-­ vessel vasculitis cannot be made accurately because small arteries can be affected in both conditions  Vasculitis Associated With Connective Tissue Disorders  •  Most commonly arises in the setting of rheumatoid arthritis, SLE, or Sjögren syndrome and is correlated with disease activity • May involve vessels of any size; small-­vessel involvement predominates • Clinically manifest with cutaneous or visceral organ involvement (usually renal or gastrointestinal)  Cholesterol Atheroembolism  • Can present with multiorgan involvement including renal failure, tissue necrosis, or visceral organ infarction •  Cholesterol emboli derived from ulcerated plaques in the aorta often affect the kidneys, intestines, and extremities • Embolization can occur spontaneously but is often triggered by invasive procedures, cardiovascular surgery, anticoagulation, and thrombolytic therapy

• Occlusion of small arteries and arterioles by cholesterol emboli; cholesterol crystals induce foreign-­body giant cell reaction and variable infiltrates of neutrophils, eosinophils, and mononuclear cells  Segmental Mediolytic Arteriopathy  • Presence of visceral ischemia, intra-­abdominal hemorrhage, and multiple arterial aneurysms is usually mistaken for PAN • Abrupt gaps in the arterial wall due to loss of medial smooth muscle; gaps are bridged by fibrin deposits and hemorrhage • Vacuolar degeneration of smooth muscle cells results in intramural hemorrhage and dissection • Inflammation if present is minimal and limited to the adventitial fibrinous deposits PEARLS • PAN • Involvement of arterioles, venules, or capillaries (including pulmonary capillaritis and glomerulonephritis) is not consistent with a diagnosis of PAN as proposed in the Chapel Hill Consensus Conference • Classic PAN is not associated with antineutrophil cytoplasmic antibodies (ANCA) • Fibrinoid necrosis should not be equated with PAN • Most patients have a chronic relapsing course; high-­ dose corticosteroids and often cyclophosphamide are typically beneficial • Factors associated with a poor prognosis include age greater than 50 years and gastrointestinal, renal, or cardiac involvement • Five-­year survival rate approaches 80% in treated patients; often fatal if untreated • Kawasaki disease • Diagnosis is usually based on clinical criteria rather than tissue biopsy or angiography • Coronary artery aneurysm develops in 15% to 25% of untreated cases; male patients, infants younger than 6 months of age, children older than 8 years, patients who did not receive intravenous immunoglobulin treatment or who have persistent fever despite treatment are at highest risk for this complication • Giant aneurysms (diameter of coronary lumen >8 mm) are at risk for rupture in the acute phase and become stenotic with progressive intimal hyperplasia and thrombosis in the chronic phase

Selected References Colmegna I, Maldonado-­Cocco JA. Polyarteritis nodosa revisited. Curr Rheumatol Rep. 2005;7:288–296. Kato H, Sugimura T, Akagi T, et al. Long-­term consequences of Kawasaki disease: a 10-­to 21-­year follow-­up study of 594 patients. Circulation. 1996;94:1379–1385. Lightfoot Jr RW, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33:1088–1093. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-­term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–e999. Takahashi K, Oharaseki T, Naoe S, et al. Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int. 2005;47:305–310.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 18  —  Heart, Pericardium, and Blood Vessels

PAUCI-­IMMUNE SMALL-­VESSEL VASCULITIS Clinical Features Granulomatosis With Polyangiitis, Formerly Wegener Granulomatosis  • Syndrome characterized by a necrotizing granulomatous vasculitis involving the upper and lower respiratory tract and glomerulonephritis • Head and neck involvement includes the nose, middle ear, eyes, sinuses, and subglottis, with symptoms of sinusitis, rhinitis, proptosis, septal perforation, or airway stenosis • Pulmonary manifestations include cough, hemoptysis, cavitary nodular densities, and lung infiltrates • Renal disease characterized by hematuria and proteinuria; occasionally renal failure •  Typically affects individuals in their fifth and sixth decades, with equal male-­to-­female distribution • Strong association with ANCA • Autoantibodies directed against components of neutrophil granules and monocytes lysosomes • c-­ANCA (cytoplasmic) or PR3-­ANCA (proteinase-­3) present in up to 90% of cases •  p-­ ANCA (perinuclear) or MPO-­ ANCA (myeloperoxidase) is nonspecific and found in 5% to 10% of cases • Up to 20% of patients are negative for ANCA, especially those with the limited form of the disease confined to the respiratory tract or the eye  Eosinophilic Granulomatosis With Polyangiitis, Formerly Churg-­Strauss Syndrome  •  Systemic necrotizing vasculitis associated with severe asthma, peripheral blood and tissue eosinophilia, extravascular granulomas, and multiple organ involvement • Typically diagnosed in middle age, with slight male predominance •  Symptoms of allergic disease, eosinophilia, and systemic vasculitis usually do not occur simultaneously, and time interval between asthma and vasculitis is variable • Affects multiple organ systems •  Pulmonary infiltrates often noted on radiography; granulomatous pulmonary mass lesions and capillaritis causing alveolar hemorrhage more unusual in eosinophilic granulomatosis with polyangiitis (EGPA) than in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) • Mononeuritis multiplex, polyneuropathy, and central nervous system vasculitis • Nodules on extensor surfaces of joints; rash and palpable purpura on the lower extremities • Cardiac involvement is a significant cause of mortality; may be complicated by small coronary artery vasculitis and myocardial ischemia, mural thrombosis, endomyocardial fibrosis, cardiomyopathy, and acute or constrictive pericarditis •  Gastrointestinal symptoms are related to eosinophilic gastroenteritis and mesenteric artery vasculitis • Kidneys are affected in one fourth of patients • Associated with MPO-­ANCA in 40% to 60% of cases and less commonly with PR3-­ANCA (10%)

1003

•  ANCA-­ positive patients tend to have glomerulonephritis, pulmonary hemorrhage, and peripheral neuropathy; ANCA-­negative patients manifest with cardiac involvement  Microscopic Polyangiitis  •  Syndrome characterized by necrotizing small-­ vessel vasculitis with few or no immune deposits affecting arterioles, venules, and capillaries in the skin, kidneys, and lungs (glomeruli and pulmonary capillaries) •  Mean age of onset is 50 years, with slight male predominance •  Symptoms are nonspecific and include hemoptysis, hematuria, proteinuria, palpable purpura, neuropathy, myalgias, and arthralgias • Serum-­positive MPO-­ANCA is characteristic (70% of cases) • Glomerulonephritis is commonly present; pulmonary capillaritis often present • In contrast to GPA and EGPA, extravascular granulomatous inflammation is absent 

Gross Pathology • Noncontributory 

Histopathology Granulomatosis With Polyangiitis  • Geographic areas of parenchymal necrosis (coagulative or suppurative), often surrounded by epithelioid histiocytes, are frequently seen in nasal and oral cavities, paranasal sinuses, trachea, or lung parenchyma • Neutrophilic microabscesses with necrotic centers and nuclear debris • Granulomas are small and poorly formed with palisading histiocytes around microabscesses or necrotic foci •  Hyperchromatic multinucleated giant cells are randomly dispersed •  Lymphocytes and plasma cells are typically present; eosinophils may be seen but are not abundant •  Necrotizing vasculitis affects small to medium-­ sized arteries and veins and may be minimal or absent in biopsy tissue • Necrotizing vasculitis with partial or complete destruction of the vessel wall by granulomatous or nongranulomatous inflammation •  Other variants of pulmonary involvement include bronchocentric injury, intense stromal eosinophilia, bronchiolitis obliterans–organizing pneumonia-­ like, and pulmonary hemorrhage with capillaritis • Head and neck lesions show similar changes of tissue necrosis, granulomatous inflammation, and vasculitis, but these changes often are not found concurrently in biopsies, probably because of sampling limitations •  Kidney lesions include focal segmental necrotizing glomerulonephritis, crescentic glomerulonephritis, glomerular thrombosis, interstitial granulomatous inflammation, and papillary necrosis  Eosinophilic Granulomatosis With Polyangiitis  • Typically affects small and medium-­sized arteries and veins •  Vasculitis is characterized by fibrinoid necrosis with eosinophil-­ rich infiltrate; can be granulomatous or nongranulomatous

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1004

Chapter 18  —  Heart, Pericardium, and Blood Vessels

•  Inflammatory cells are an admixture of eosinophils, neutrophils, lymphocytes, plasma cells, histiocytes, and multinucleated giant cells • Pulmonary lesions consist of eosinophilic pneumonia, extravascular eosinophilic granuloma, and necrotizing vasculitis •  Skin biopsies reveal eosinophil-­ rich leukocytoclastic vasculitis, dermal eosinophilia, and extravascular necrotizing granuloma • Cardiac involvement is that of eosinophilic myocarditis • Glomerulonephritis can be focal, segmental, or crescentic glomerulonephritis  Microscopic Polyangiitis  • Destruction of the vessel wall by polymorphonuclear and mononuclear infiltrates, often with leukocytoclasia and segmental fibrinoid necrosis • Associated hemorrhage is common • Cutaneous lesions often involve upper and middle dermal venules with a histologic pattern of leukocytoclastic vasculitis •  Pulmonary lesions show inflammation and necrosis of interalveolar septa and capillaries with neutrophils, nuclear dusts, and intra-­alveolar hemorrhage • Renal lesions are those of necrotizing and crescentic glomerulonephritis • Lesions are typically of the same age • May affect small and medium-­sized arteries, but arterial involvement is not necessary for diagnosis • Occasional thrombosis present in arteritis results in tissue infarction and ulceration • Granulomatous inflammation is not seen 

Special Stains and Immunohistochemistry • Trichrome stains fibrin red • Movat highlights both elastin and collagen 

Other Techniques for Diagnosis •  Immunofluorescence microscopy: little or no staining with immunoglobulins (immunoglobulin G [IgG]) in the affected vessels (including glomeruli) for GPA, EGPA, and MPA; hence, these vasculitides are often referred to as pauci-­immune (ANCA-­associated) small-­ vessel vasculitis • Electron microscopy: no immune complex–type deposits are detected 

Differential Diagnosis • There are no histologic features that are specific for the different types of small-­vessel vasculitis; further classification is based on clinical criteria and serology in conjunction with biopsy of the relevant organ • Necrotizing and crescentic glomerulonephritis associated with ANCA vasculitis is histologically indistinguishable between MPA, GPA, and EGPA •  Although small arteries, arterioles, capillaries, and venules are predominantly affected, vasculitis may also involve medium-­sized arteries and veins Polyarteritis Nodosa  • Proposed distinguishing feature of PAN is the absence of involvement of small vessels (i.e., arterioles, venules, or capillaries)

• Vasculitis is characterized by lesions of varying ages, including focal and segmental fibrinoid necrosis and occasional multinucleated giant cells, but granulomatous inflammation is not seen •  Does not cause pulmonary capillaritis or glomer-­ ulonephritis • When small and medium-­sized arteries are involved, necrotizing arteritis as a component of MPA is histologically indistinguishable from that of PAN • Not associated with positive ANCA  Drug-­Induced Vasculitis  •  Associated with recent medication use, most commonly antibiotics and diuretics • Manifestations range from isolated skin involvement to multiorgan involvement; time interval from drug exposure to onset of clinical manifestations is highly variable •  Neutrophilic or lymphocytic vasculitis in superficial small vessels; if present, tissue eosinophilia is a clue to possible drug etiology • Usually no ANCA association •  Drug-­ related vasculitis with positive MPO-­ ANCA: hydralazine, pantoprazole, propylthiouracil, carbimazole, minocycline, and cimetidine  Infection-­Induced Vasculitis  • Commonly implicated infectious agents are hepatitis B, mycoplasma, meningococci, streptococci, S. aureus, Pseudomonas species, Yersinia species, Legionella species, Helicobacter pylori, herpesvirus, adenovirus, cytomegalovirus, parvovirus B19, Mycobacterium tuberculosis, Rickettsia species, and fungi • Histology shows neutrophilic small-­vessel vasculitis •  Septic vasculitis will show luminal thrombosis with neutrophils, hemorrhage, microabscesses, and necrosis •  Eccentric or segmental vessel wall necrosis is more characteristic of systemic vasculitides  Vasculitis Associated With Circulating Immune Complexes  • Immune complex deposition can occur in solid organ and hematologic malignancies, connective tissue disorders, chronic active hepatitis, and inflammatory bowel diseases  Sarcoidosis  •  Characterized by tight, compact granulomas usually without necrosis •  Granulomas typically distributed along interlobular septa and bronchovascular pathways • Non-­necrotizing granulomas within the media of vessels are frequently seen • Necrosis is not a prominent feature •  Commonly lung involvement; rarely kidney involvement • No association with PR3-­ANCA or MPO-­ANCA  Eosinophilic Pulmonary Infiltrates  •  EGPA needs to be differentiated from eosinophilic pneumonia, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis, parasitic infections, and Hodgkin disease 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 18  —  Heart, Pericardium, and Blood Vessels

Epstein-­Barr Virus–Associated Lymphoproliferative Disorders With Propensity for Angioinvasion  • Extranodal natural killer and T-­cell lymphoma, nasal type (angiocentric lymphoma) • Most commonly involves the nasal and nasopharyngeal areas • Atypical lymphoid cells are small to medium in size • Tumor necrosis often present; neutrophilic infiltration rare • Lymphomatoid granulomatosis • T-­cell–rich, B-­cell–proliferative disorder • Predilection for lung, but skin and central nervous system can also be affected • Destructive nodular infiltrates with central necrosis and prominent vascular and perivascular infiltration • Infiltrates consist of small lymphocytes, histiocytes, plasma cells, and atypical intermediate to large B-­cells • Absence of granulomatous inflammation PEARLS • V  asculitis involving arterioles, capillaries, and venules allows for the diagnosis of small-­vessel vasculitis • ANCA testing by indirect immunofluorescence microscopy confirmed by enzyme-­linked immunosorbent assay has about 99% sensitivity and 70% specificity; negative ANCA test does not rule out a diagnosis of pauci-­immune small-­ vessel vasculitis • Induction and remission therapy in pauci-­immune ANCA-­ positive small-­vessel vasculitis is similar for all subtypes and consists of systemic glucocorticoids and cyclophosphamide; rituximab is an alternative to cyclophosphamide • Granulomatosis with polyangiitis • Etiology is unknown; evidence suggests an immune-­ mediated mechanism with a synergistic effect of ANCA and proinflammatory stimuli most likely of infectious origin • Chronic carriage of S. aureus in the upper airways is associated with increased risk for relapses • Evolution of inflammatory vascular lesions and symptoms over time may cause a change in the diagnosis of patients from MPA to GPA if patients subsequently develop granulomatous lesions • Limited forms of GPA spare the kidney • PR3-­ANCA levels are often used to monitor disease activity • Eosinophilic granulomatosis with polyangiitis • Clinical manifestations may evolve over time or be suppressed by oral glucocorticoid therapy for asthma; sometimes, vasculitis precedes development of asthma • More frequent involvement of peripheral nerves, skin, and heart; less frequent involvement of kidneys; less frequently positive for ANCA than are GPA and MPA • Eosinophils may not be found or become less abundant in biopsies from patients treated with corticosteroids • Increased mortality rate is seen when two or more of the following are present at the time of diagnosis: elevated serum creatinine, proteinuria, and gastrointestinal, cardiac, and central nervous system involvement

1005

• Microscopic polyangiitis • Previously referred to as microscopic polyarteritis and microscopic periarteritis; however, arterial involvement is not a constant feature • Known clinical and histologic overlap with GPA

Selected References Guillevin L, Pagnoux C, Mouthon L. Churg-­Strauss syndrome. Semin Respir Crit Care Med. 2004;25:535–545. Jennette JC, Nachman PH. ANCA glomerulonephritis and vasculitis. Clin J Am Soc Nephrol. 2017;12:1680–1691. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum. 1990;33:1101–1107. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-­Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33:1094–1100. Sable-­Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-­Strauss syndrome. Ann Intern Med. 2005;143:632–638. Travis WD. Pathology of pulmonary vasculitis. Semin Respir Crit Care Med. 2004;25:475–482.

IMMUNE COMPLEX SMALL-­VESSEL VASCULITIS Clinical Features Anti-­Glomerular Basement Membrane Disease  •  Clinical presentation of pulmonary-­ renal syndrome of alveolar hemorrhage and rapidly progressive glomerulonephritis • Bimodal age distribution with peak in adolescence and young adults and another peak after the sixth decade • Associated with autoantibody directed to the noncollagenous domain of the α3 chain of type IV collagen present in the glomerular and alveolar capillary basement membrane  IgA Vasculitis, Formerly Henoch-­Schönlein Purpura  • Most common form of small-­vessel vasculitis in children (typically ages 3 to 15 years); males affected twice as commonly as females; rarely affects adults •  Commonly preceded by an upper respiratory tract infection •  Manifestations include nonthrombocytopenic palpable purpura, arthralgias, arthritis, colicky abdominal pain, and bloody diarrhea • Renal involvement with hematuria or mild proteinuria in up to 50% of cases; rarely a progressive renal disease • Serum IgA levels are increased in more than 50% of patients  Cryoglobulinemic Vasculitis  • Mixed cryoglobulins are composed of monoclonal IgM and polyclonal IgG in type II and polyclonal IgM and IgG in type III • Can be essential or secondary to connective tissue diseases, hematologic malignancies, and infections • Mixed cryoglobulins are found in 55% to 90% of patients with chronic HCV infection, but cryoglobulinemic vasculitis is present in fewer than 5% of these patients • Syndrome is characterized by purpura, arthralgias, and weakness, usually with peripheral nervous system and renal involvement

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1006

Chapter 18  —  Heart, Pericardium, and Blood Vessels

• Serologic tests show HCV viremia, anti-­HCV antibodies, mixed cryoglobulins, high titers of rheumatoid factor, and low complement levels •  Clonal B-­ lymphocyte expansion is responsible for autoantibody production with increased incidence of developing non-­Hodgkin lymphoma 

Gross Pathology • Noncontributory 

Histopathology Anti-­Glomerular Basement Membrane Disease  • Alveolar septal infiltration of neutrophils with pyknosis and karyorrhexis • Alveolar capillaries obscured by neutrophils or replaced by necrotic debris; fibrin thrombi occasionally found in capillaries • Alveolar wall destroyed with extravasation of erythrocytes and fibrin • Glomerulonephritis with crescent formation and focal segmental fibrinoid necrosis  IgA Vasculitis  • Small-­vessel vasculitis involving capillaries, postcapillary venules, and arterioles •  Characterized by neutrophilic infiltrate with fibrin deposits and nuclear debris in small, predominantly superficial dermal vessels • Renal lesions vary from focal to diffuse mesangial proliferation to crescentic glomerulonephritis  Cryoglobulinemic Vasculitis  • Skin biopsy shows leukocytoclastic vasculitis in superficial and deep dermal plexus • Some patients have lymphocytic vasculitis and involvement of medium-­sized arteries •  Membranoproliferative glomerulonephritis type I is the most common renal lesion; fibrinoid necrosis and crescents are absent to rare 

Special Stains and Immunohistochemistry • Noncontributory 

Other Techniques for Diagnosis Immunofluorescence Microscopy  •  Antiglomerular basement membrane disease: linear immunoglobulin deposition of IgG, often with C3, in glomerular and alveolar capillary basement membrane • IgA vasculitis (IgAV): glomerular (mesangial, capillary wall, arteriolar) and dermal vascular staining with IgA and C3 •  Cryoglobulinemic vasculitis: vascular staining with IgM, IgG, or C3  Electron Microscopy  • Antiglomerular basement membrane disease: absence of immune complex–­type electron-­dense deposits •  IgAV: with renal involvement, prominent electron-­ dense mesangial deposits are seen • Cryoglobulinemic vasculitis: mesangial and subendothelial deposits and intraluminal monocytes 

Differential Diagnosis Cutaneous Leukocytoclastic Vasculitis (Hypersensitivity Vasculitis)  • Localized, self-­limited cutaneous vasculitis often triggered by drugs or preceding infection • Similar histologic features of leukocytoclastic vasculitis in superficial vessels • Ulcers or subcutaneous nodules uncommon and suggest involvement of arteries in the dermal-­ subcutis interface in other systemic vasculitis •  Diagnosis of exclusion; no systemic vasculitis or glomerulonephritis  Hypocomplementemic Urticarial Vasculitis (Anti-­C1q Vasculitis)  •  Chronic or recurrent urticaria with leukocytoclastic vasculitis and deposition of immunoglobulins and complement around vessels • Hypocomplementemia observed in patients with systemic manifestations, including arthralgia or arthritis, uveitis or episcleritis, glomerulonephritis, recurrent abdominal pain, chronic obstructive pulmonary disease, and positive lupus band test on skin biopsy • Low serum C1q levels with anti-­C1q autoantibodies • Associated with SLE and Sjögren syndrome  Drug-­Induced Vasculitis  •  See “Differential Diagnosis” under “Pauci-Immune Small-­Vessel Vasculitis”  Infection-­Induced Vasculitis  •  See “Differential Diagnosis” under “Pauci-Immune Small-­Vessel Vasculitis”  Malignancy-­Associated (Paraneoplastic) Vasculitis  • Most common underlying malignancies are lymphomas and leukemias •  Histopathology shows leukocytoclastic vasculitis, rarely lymphocytic vasculitis  Connective Tissue Disease–Associated Vasculitis  • Frequently associated with SLE, rheumatoid arthritis, and Sjögren syndrome, and less commonly with dermatomyositis, scleroderma, and relapsing polychondritis • Affects small and medium-­sized vessels •  Can have neutrophilic, lymphocytic, or granulomatous infiltrates • Can be complicated by the presence of antiphospholipid antibodies that lead to vascular thrombosis • Can be positive for MPO-­ANCA and, less commonly, PR3-­ANCA  Pauci-­Immune Small-­Vessel Vasculitis  • Skin lesions can be part of the initial presentation in GPA, EGPA, and MPA • Absence or paucity of immunoglobulin or complement deposits in vascular lesions  IgA Nephropathy (Berger Disease)  • Renal lesions are histologically indistinguishable from IgAV

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 18  —  Heart, Pericardium, and Blood Vessels

•  Disease localized manifestations

to

the

kidney;

no

systemic

PEARLS Antiglomerular basement membrane disease • • Goodpasture syndrome refers to clinical presentation of both pulmonary and renal involvement; otherwise, patients may manifest with isolated renal or pulmonary disease • Up to 30% of patients with anti-­GBM disease can be ANCA positive; conversely, 5% of patients with ANCA-­ associated vasculitis have anti-­GBM antibodies • IgA vasculitis • Etiologic agent is currently unknown • Typically self-­limited; most cases spontaneously regress in 2 to 3 weeks without sequelae • Renal failure is the most common cause of morbidity and mortality; poor prognostic features include development of nephrotic syndrome and renal biopsy showing more than 50% of glomeruli with crescents • Treatment involves supportive therapy; corticosteroids only for severe systemic symptoms • Cryoglobulinemic vasculitis • There is no established classification or diagnostic criteria for cryoglobulinemic vasculitis • Diagnosis is established with serologic and histopathologic examination • Overlap of symptoms with Sjögren syndrome, autoimmune hepatitis, and B-­cell lymphoproliferative disorders is recognized

Selected References Carlson JA, Chen KR. Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes. Am J Dermatopathol. 2006;28: 486–506. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33:355–374. Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Henoch-­Schonlein purpura. Arthritis Rheum. 1990;33:1114–1121.

VARIABLE VESSEL VASCULITIS • Affects arteries and veins of all sizes (small, medium, and large)

1007

Cogan’s Syndrome  • Characterized by ocular inflammation and vestibulo-­ auditory symptoms that may lead to deafness • Affects young adults, equally by gender •  Cardiovascular involvement occurs in 10% of patients, manifesting as aortitis and aortic valvulitis or insufficiency 

Gross Pathology Behçet’s Disease  •  Large vessel involvement most commonly affects veins (superior and inferior vena cava and hepatic veins) • Pulmonary artery aneurysm is most common form of large arterial involvement in Behçet’s disease (BD) • Aorta and other peripheral arteries can also be involved and manifest as aneurysms • Intracardiac thrombosis predominantly involves right-­ sided chambers •  Valvular involvement results in insufficiency, most commonly of the aortic and mitral valves  Cogan’s Syndrome  • Most commonly affects the aorta and less frequently medium-­sized and small arteries •  Aortitis may lead to coronary ostial occlusion and extend to involve the aortic valve 

Histopathology Behçet’s Disease  • Neutrophilic vasculitis may be found in nodular skin lesions • Perivascular infiltrates in small vessels and vasa vasorum composed of lymphocytes, macrophages, and neu­ trophils often described rather than a true vasculitis • Vascular occlusion by thrombus  Cogan’s Syndrome  • Vasculitis may show mixed type of inflammatory infiltrates, occasional giant cells, and fibrinoid necrosis 

Special Stains and Immunohistochemistry •  Elastic confirms venous predilection for thrombosis in BD 

Other Techniques for Diagnosis

Clinical Features

• Noncontributory 

Behçet’s Disease  •  Characterized by recurrent oral and/or genital aphthous ulcers, papulopustular or nodular skin lesions, and uveitis; less commonly present with arthritis, gastrointestinal ulcers, vascular and central nervous system involvement •  Vascular disease subset manifest as lower extremity superficial and deep vein thrombosis, pulmonary artery aneurysms and thrombosis, intracardiac thrombosis, and Budd-­Chiari syndrome • Prevalence is high in the Middle East and Far East Asia • Usual onset is in the third decade, disease course more severe in men 

Differential Diagnosis Takayasu Arteritis  •  Pulmonary vascular involvement may be as high as 60% in asymptomatic patients • May be associated with pulmonary hypertension; stenosis more common than aneurysm • Affects more females than males • Pulmonary arteries show panarteritis with granulomatous inflammation, intimal hyperplasia, and marked adventitial fibrosis •  Histopathology alone may not always distinguish between Cogan’s syndrome and Takayasu arteritis

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1008

Chapter 18  —  Heart, Pericardium, and Blood Vessels

Other Techniques for Diagnosis

PEARLS Behçet’s disease • • The lack of specific laboratory findings or histopathologic features, multiple phenotypes, and geographical differences of disease expression make clinical diagnosis challenging • Morbidity and mortality related to large vessel and parenchymal central nervous disease • Hughes-­Stovin syndrome (pulmonary artery aneurysms and lower extremity venous thrombosis without other classical features of BD) is considered by some to represent vascular subtype of BD • Cogan’s syndrome • Mortality is related to complications of aortitis, aortic valvulitis, and systemic vasculitis

Selected References Emmi G, Bettiol A, Silvestri E, et al. Vascular Behçet’s syndrome: an update. Intern Emerg Med. 2019;14:645–652. Seyahi E. Phenotypes in Behçet’s syndrome. Intern Emerg Med. 2019;14:677–689. St Clair EW, McCallum RM. Cogan’s syndrome. Curr Opin Rheumatol. 1999;11:47–52.

BUERGER DISEASE (THROMBOANGIITIS OBLITERANS) Clinical Features • Inflammatory and occlusive vascular disorder affecting small and medium-­sized arteries and veins • Typically involves the vessels of the distal upper and lower extremities; rare involvement of mesenteric arteries and veins • Found most commonly in young men who are heavy smokers; male:female ratio of 3:1 • Onset usually before age of 40 years • Patients with advanced disease may present with claudication, ischemic ulcers, or gangrene 

Gross Pathology • Segmental involvement of arteries or veins with acute or organized thrombosis and luminal narrowing 

Histopathology • Involves both small and medium-­sized arteries and veins •  Acute lesions are diagnostic and consist of cellular inflammatory thrombus and mild acute transmural inflammation without fibrinoid necrosis • Microabscesses are noted within the thrombus, often with multinucleated giant cells • Older lesions show organizing thrombosis with chronic inflammation resulting in luminal occlusion; recanalization is often seen •  Internal elastic lamina remains intact in acute and chronic lesions • Superficial migratory thrombophlebitis with or without inflammatory thrombus is seen in fewer than half of the patients 

Special Stains and Immunohistochemistry • Elastic highlights the intact elastic lamina 

• Noncontributory 

Differential Diagnosis Organizing Thromboemboli  •  Giant cells and prominent inflammatory infiltrate within the organizing thrombus are not seen • Acute inflammation within the vessel wall is not seen  Necrotizing Arteritis  • Characterized by granulomatous or nongranulomatous inflammation with fibrinoid necrosis and destruction of the internal elastic lamina PEARLS • T  obacco use appears to be a universal factor associated with this condition • No laboratory or serologic tests are useful in establishing diagnosis • Cessation of smoking with or without steroid therapy usually renders a good prognosis

Selected References Ohta T, Ishioashi H, Hosaka M, Sugimoto I. Clinical and social consequences of Buerger disease. J Vasc Surg. 2004;39:176–180. Olin JW, Shih A. Thromboangiitis obliterans (Buerger’s disease). Curr Opin Rheumatol. 2006;18:18–24.

FIBROMUSCULAR DYSPLASIA Clinical Features •  Noninflammatory, nonatherosclerotic vascular diseases that affect medium and small muscular arteries • Can affect any artery, but the most commonly involved are the renal arteries (60% to 75%, bilateral in 35%) and extracranial carotid or vertebral arteries (25% to 30%) • About 28% of cases have multiple arteries involved • Most patients are asymptomatic; most common presentations are renovascular hypertension, cervical or epigastric systolic and diastolic bruit • Multisystem involvement mimics systemic necrotizing vasculitis with mesenteric ischemia, renal failure, syncope, stroke, end-­organ ischemia, or extremity ischemia • Typically affects young adults, more commonly women in the third and fourth decades •  Angiography shows the classic string-­ of-­ beads appearance 

Gross Pathology • Artery may show stenosis or segmental narrowing with or without dilations 

Histopathology Medial Fibromuscular Dysplasia  • Is divided into three subtypes • Medial fibroplasia is the most common histologic type and characterized by thick fibromuscular ridges alternating with areas of medial thinning

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 18  —  Heart, Pericardium, and Blood Vessels

• Smooth muscle cells are disorganized and separated by moderate accumulation of collagen and ground substance • External elastic lamina is frequently fragmented • Intima is normal •  Internal elastic lamina is disrupted in advanced lesions, with microaneurysm formation • Medial hyperplasia causes concentric luminal stenosis by proliferation of smooth muscle exhibiting minimal disorganization • Perimedial fibroplasia shows excessive accumulation of elastic tissue between the outer media and adventitia with effacement of the external elastic lamina  Intimal Fibroplasia  •  Segmental concentric or eccentric accumulation of loose fibrous tissue without lipids or inflammatory cells •  Internal elastic lamina is frequently fragmented or reduplicated • Media and adventitia are normal  Adventitial (Periarterial) Fibroplasia  •  Dense collagen replaces the adventitia and extends into the periadventitial soft tissue • Intima and media including external elastic lamina are intact 

Special Stains and Immunohistochemistry • Elastic stain highlights destruction of the elastic lamina 

Other Techniques for Diagnosis • Noncontributory 

Differential Diagnosis Atherosclerosis  • Occurs in older population with high atherosclerotic risk factors • Atherosclerotic disease tends to affect the renal artery ostia and proximal portion; in contrast, fibromuscular dysplasia affects the distal two-­thirds and branches of the artery • Fibroatheromatous plaques with focal disruption of the elastic lamina and medial atrophy  Healed Arteritis  • Medial destruction and focal loss of the elastic lamina may lead to aneurysm •  Often granulation tissue with neovascularization or fibrosis is seen in the media • Residual inflammatory cell infiltrate may be seen  Neurofibromatosis  • Aneurysms and stenotic arterial lesions often involve the renal arteries, aorta, carotid, vertebral, and mesenteric vessels •  Nodular intimal proliferation of spindle cells in a mucoid matrix, with disruption of the internal elastic lamina and attenuation of the media •  Characteristic skin and skeletal abnormalities and tumorous growths in neurofibromatosis allows for clinical differentiation

1009

PEARLS • D  issections, aneurysms, and arteriovenous fistulas are complications of fibromuscular dysplasia • Classic angiographic findings are suggestive of this condition • Percutaneous balloon angioplasty is performed for arterial stenosis; surgery is used to treat microaneurysms

Selected References Luscher TF, Lie JT, Stanson AW, et al. Arterial fibromuscular dysplasia. Mayo Clin Proc. 1987;62:931–952. Slovut DP, Olin JW. Fibromuscular dysplasia. N Engl J Med. 2004;350:1862–1871.

HERITABLE DISORDERS OF BLOOD VESSELS Clinical Features Marfan Syndrome  • Autosomal dominant trait with variable clinical manifestations, including bilateral ectopia lentis, tall stature, long and slender limbs, arachnodactyly, pectus excavatum or carinatum, and scoliosis • Aortic dissection follows a period of progressive aortic dilation • Patients with a second type of Marfan syndrome exhibit some of the cardiovascular and skeletal manifestations of Marfan syndrome but lack ocular abnormalities  Loeys-­Dietz Syndrome  • Autosomal dominant disorder characterized by a triad of arterial tortuosity and aneurysm, hypertelorism, and bifid uvula or cleft palate • Aneurysms in thoracic arterial branches are common, in addition to thoracic aortic aneurysm •  High incidence of pregnancy-­ related complications and aortic dissection or rupture in young patients  Ehlers-­Danlos Syndrome Type IV (Vascular Ehlers-­ Danlos Syndrome)  • Autosomal-­dominant group of heritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility • Only form of Ehlers-­Danlos syndrome associated with increased risk for premature death owing to arterial, intestinal, or uterine ruptures • A major event is the presenting feature in about 70% of patients  Familial Thoracic Aortic Aneurysms and Aortic Dissections  •  Aortic dilatation and aneurysm with positive family history and absence of clinical features of Marfan, Loeys-­Dietz, or Ehlers-­Danlos syndrome 

Gross Pathology • Aneurysmal aortic wall may be thin with a bluish tinge of the intima • Dissection may be evident with a hematoma between the split media • Chronic dissection shows a false lumen lined by white opalescent neointima

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1010

Chapter 18  —  Heart, Pericardium, and Blood Vessels

Figure 18.17  Cystic medial degeneration.  A, The hematoxylin and eosin stain shows areas of blue discoloration in the media. B, Movat stain shows corresponding mucopolysaccharide deposits with fragmentation and loss of elastic lamellae.

A

• Occasional intimal lacerations are not associated with intramural dissection and heal with neointima lining an ellipsoid intimal depression 

Histopathology • Medial degeneration is the suggested term referring to the sum of individual alterations described below • Mucoid extracellular matrix accumulation—accumulation of mucopolysaccharide material within lamellar units that may or may not be associated with alteration of the elastic lamellar architecture • Fragmentation and/or loss of elastic lamellae with or without significant proteoglycan deposition (Figure 18.17A) • As the severity of elastic fiber loss increases, disorganization of the smooth muscle cells and elastic fibers may be seen • Loss of smooth muscle nuclei in patches or in a band-­ like pattern • Laminar medial collapse is suggested to replace the older term laminar medial collapse characterized by loss of smooth muscle cells in the media with collapse of the elastic lamellae and fibrosis • Medial fibrosis can be confined to the intralamellar space with intact elastic lamellae or appear as fibrous scars with smooth muscle disorganization • Aortic dissection • Dissection typically occurs between the inner two-­ thirds and outer one-­third of the media • False lumen may be lined by blood, fibrin and thrombus, granulation tissue, or neointima, depending on the age of the lesion (Figure 18.18A and B) • Inner media usually shows medial necrosis • Acute inflammation is usually limited to fibrinous deposits and adventitia, extending minimally into the media

B

• Healed dissection is recognized by a linear vascularized collagenous scar tissue in the media 

Special Stains and Immunohistochemistry • Movat demonstrates structure of the elastic lamellae, presence of smooth muscle cells, and proteoglycan and collagen in the extracellular matrix (see Figure 18.17B) 

Other Techniques for Diagnosis Marfan Syndrome  • Classic Marfan syndrome patients have mutations in the fibrillin 1 gene, FBN1 •  Encoding transforming growth factor-­ β receptor 2 (TGFBR2) gene  Loeys-­Dietz Syndrome  •  Associated with mutations in TGFBR1, TGFBR2, SMAD2 (mothers against decapentaplegic homolog 2), SMAD3, TGFB2 (transforming growth factor beta-­2), or TGFB3  Ehlers-­Danlos Syndrome  •  Caused by mutations in type III procollagen gene, COL3A1  Familial Thoracic Aortic Aneurysms and Aortic Dissections  •  Associated mutations reported in TGFBR1, TGFBR2, ACTA2 (alpha-­actin), FOXE3 (Forkhead box E3), LTBP3 (latent TGF beta binding protein 3), LOX (lysil oxidase), MAT2A (methionine adenosyltransferase II, alpha), MFAP5 (microfibrillar-­ associated protein 5), MYH11 (myosin heavy chain), MYLK (myosin light chain kinase), PRKG1 (protein kinase, cGMP-­dependent, regulatory, type I), SMAD3, FBN1 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 18  —  Heart, Pericardium, and Blood Vessels

Figure 18.18  Aortic dissection.  A, An acute dissection shows a false lumen filled with recent thrombus in the media. B, The intimomedial flap of a chronic dissection is shown with a thick neointima lining the plane of dissection.

B

A

Differential Diagnosis • Medial changes are nonspecific, but quantitative differences are found between normal, aging aorta and diseased or dilated aorta •  Conditions associated with medial degeneration include the normal aging process, systemic hypertension, bicuspid aortic valve, and syndromic and non-­ syndromic isolated aortopathy Infectious Aortitis  • Etiologic agents include S. aureus, streptococci, Salmonella species, Escherichia coli, Mycobacteria, and Clostridium species • Results from hematogenous seeding of diseased intima/ atherosclerotic plaque, septic embolization from infective endocarditis, direct extension of infection from a contiguous site, or traumatic contamination • Abdominal aorta and femoral arteries are more commonly affected than thoracic aorta • Causes aortic rupture or produces mycotic aneurysms • Necrosis with marked acute inflammatory infiltrates in the media •  Inflammatory reaction in the adventitia common and includes neutrophilic infiltrates, microabscesses, edema, and granulation tissue

1011

• R  isk factors for aortic dissections include hypertension, bicuspid aortic valve, coarctation of the aorta, pregnancy, cocaine use, and strenuous exercise/weightlifting • Pathologic changes in the media vary considerably from one area to the next, necessitating multiple and extensive histologic sampling of the specimen

Selected References Halushka MK, Angelini A, Bartoloni G, et al. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases—nomenclature and diagnostic criteria. Cardiovasc Pathol. 2016;25:247–257. Homme JL, Aubry MC, Edwards WD, et al. Surgical pathology of the ascending aorta: a clinicopathologic study of 513 cases. Am J Surg Pathol. 2006;30:1159–1168. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [Updated 2018 Mar 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK1133/. Meester JAN, Verstraeten A, Schepers D, et al. Differences in manifestations of Marfan syndrome, Ehlers-­Danlos syndrome, and Loeys-­ Dietz syndrome. Ann Cardiothorac Surg. 2017;6:582–594.

PEARLS • A  scending aortic aneurysms are clinically distinct from descending thoracic and abdominal aortic aneurysms, which are usually associated with atherosclerosis • Most patients with ascending aortic aneurysm and dissection do not have known genetic mutations; approximately 20% of patients with no known heritable disorders have affected first-­degree relatives

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19

Central Nervous System ELIZABETH J. COCHRAN

Chapter Outline Diffuse Astrocytic Tumors  1014 Oligodendroglial Tumors  1017 Oligodendroglioma, IDH-­Mutant and 1p/19q-­Codeleted, Anaplastic Oligodendroglioma, IDH-Mutant and 1p/19q-­Codeleted (WHO Grades II To III) 1017 Other Astrocytic Tumors  1018 Pilocytic Astrocytoma (WHO Grade I) 1018 Pilomyxoid Astrocytoma (WHO Grade Not Assigned at Present)  1020 Pleomorphic Xanthoastrocytoma (WHO Grade II) and Anaplastic Pleomorphic Xanthoastrocytoma (WHO Grade III)  1020 Subependymal Giant Cell Astrocytoma (WHO Grade I)  1021 Ependymal Tumors  1023 Ependymoma (WHO Grade II), Anaplastic Ependymoma (WHO Grade III), Rela Fusion-­Positive Ependymoma (WHO Grade II or III)  1023 Myxopapillary Ependymoma (WHO Grade I)  1025 Subependymoma (WHO Grade I)  1026 Other Neuroepithelial Tumors  1026 Astroblastoma (No Assigned WHO Grade) 1026 Chordoid Glioma (WHO Grade II)  1027 Angiocentric Glioma (WHO Grade I)  1028 Neuronal and Glioneuronal Neoplasms  1029 Gangliocytoma (WHO Grade I), Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (No WHO Grade), Dysplastic Cerebellar Gangliocytoma (WHO Grade I), Desmoplastic Infantile Astrocytoma and Ganglioglioma (WHO Grade I), Ganglioglioma (WHO Grade I and II), and Anaplastic Ganglioglioma (WHO Grade III)  1029

Dysembryoplastic Neuroepithelialtumor (WHO Grade I)  1031 Central and Extraventricular Neurocytoma (WHO Grade II), Cerebellar Liponeurocytoma (WHO Grade II)  1032 Papillary Glioneuronal Tumor (WHO Grade I)  1033 Rosette-Forming Glioneuronal Tumor of The Fourth Ventricle (WHO Grade I)  1034 Diffuse Leptomeningeal Glioneuronal Tumor (No WHO Grade at Present) 1035 Paraganglioma of The Spinal Cord (WHO Grade I)  1036 Embryonal Tumors  1036 Medulloblastoma (WHO Grade IV)  1036 Other CNS Embryonal Tumors (Embryonal Tumor with Multilayered Rosettes, C19mc-­Altered and Nos, Medulloepithelioma, CNS Neuroblastoma, CNS Ganglioneuroblastoma, CNS Embryonal Tumor Nos) (WHO Grade IV) 1038 Atypical Teratoid/Rhabdoid Tumor (WHO Grade IV) 1040 Choroid Plexus Tumors  1041 Choroid Plexus Papilloma (WHO Grade I), Atypical Choroid Plexus Papilloma (WHO Grade II), and Choroid Plexus Carcinoma (WHO Grade III)  1041 Pineal Parenchymal Tumors  1042 Pineocytoma (WHO Grade I) and Pineal Parenchymal Tumor of Intermediate Differentiation (WHO Grades II and III) 1042 Pineoblastoma (WHO Grade IV) 1043 Papillary Tumor of the Pineal Region (WHO Grades II and III) 1044 Other Neoplasms and Related Entities  1045 Peripheral Nerve Sheath Tumors  1045 Meningioma (WHO Grades I), Atypical Meningioma (WHO Grade II), and Anaplastic Meningioma (WHO Grade III) 1047 Solitary Fibrous Tumor/ Hemangiopericytoma 1049

1013

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1014

Chapter 19  —  Central Nervous System

Hemangioblastoma (WHO Grade I)  1050 Malignant Lymphoma (Non-Hodgkin and Hodgkin)  1052 Germ Cell Tumors  1053 Neuraxial Cysts: Rathke Cleft Cyst, Colloid Cyst, and Enterogenous Cyst  1054 Pituitary Adenoma (Including ­Typical and Atypical Adenomas), ­Pituitary Carcinoma, and Pituitary Hyperplasia 1055 Pituicytoma (WHO Grade I), Spindle Cell Oncocytoma (WHO Grade I), and Granu­lar Cell Tumor of the Neurohypophysis (WHO Grade I)  1057 Craniopharyngioma (WHO Grade I)  1058

DIFFUSE ASTROCYTIC TUMORS DIFFUSE ASTROCYTOMAS OF EACH GRADE ARE NOW DIVIDED INTO ONE OF TWO DIAGNOSTIC CATEGORIES BASED UPON THE ISOCITRATE DEHYDROGENASE (IDH GENE MUTATION STATUS (IDH MUTANT OR IDH WILDTYPE). IF THE TESTING IS NOT AVAILABLE OR CANNOT BE PERFORMED THE DIAGNOSIS IS SPECIFIED AS DIFFUSE ASTROCYTOMA, ANAPLASTIC ASTROCYTOMA, OR GLIOBLASTOMA, NOS (NOT OTHERWISE SPECIFIED). THE IDH MUTATION MAY BE EITHER IN THE IDH1 OR IDH2 GENES. MOST LOW-­GRADE DIFFUSE ASTROCYTOMAS HAVE A MUTATION IN THE IDH1 GENE, MOST COMMONLY R132H Clinical Features Diffuse Astrocytomas, IDH Mutant, Wildtype,

and

Not Otherwise Specified  •  Commonly produce headaches, seizures, or focal neurologic deficits; symptoms related to the location of the tumor; they occur most frequently in cerebral hemisphere, most often in the frontal lobes. On MRI, low-­grade and anaplastic astrocytomas show an ill-­defined area of low signal on T1 with no contrast enhancement •  Astrocytomas, IDH mutant, WHO grade II, occur in adults at mean age of 30 to 40 years and at a slightly older age when anaplastic astrocytoma, IDH mutant WHO grade III (between 35 and 45 years) • Both diffuse astrocytomas and anaplastic astrocytomas, IDH mutant or wildtype (WT), have an inherent tendency to progress to higher grades eventually transforming into glioblastoma (WHO grade IV). Glioblastomas, IDH WT occur commonly between ages 55 and 85 years with a mean of 62 years; these individuals present with a mass lesion that already shows features of high grade on MRI (areas of necrosis and ring-­shaped enhancement) while glioblastomas IDH mutant occur at a mean of 45 years

Chordoma 1059 Secondary Tumors  1061 Non-­Neoplastic Conditions  1062 Vascular Malformations  1062 Cerebral Infarction and Intracerebral Hematomas 1064 Vasculitis 1066 Gross Pathology  1066 Brain Abscess  1067 Encephalitis and Meningoencephalitis 1068 Progressive Multifocal Leukoencephalopathy 1071 Demyelinating Diseases  1072 Dementia 1074

• Gliomatosis cerebri is a pattern of extensive involvement of the brain that may be evident on MRI. It shows diffuse enlargement of involved areas without a focal mass identifiable (T1 hypointensity, T2 hyperintensity); no enhancement  Diffuse Midline Glioma  •  Occurs mostly in children but can also occur in adults. • Predominates in midline, in brainstem, thalamus, spinal cord; less commonly cerebellum • MRI scans may show hemorrhage, necrosis, and contrast enhancement 

Gross Pathology • Diffuse astrocytoma, WHO grade II; and anaplastic astrocytoma, WHO grade III; IDH mutant or WT have variable appearances ranging from subtle, barely visible lesion to large, soft, gelatinous, gray-­white ill-­ defined infiltrative masses that blur the gray-­white border and expand the cortex or white matter •  Glioblastoma IDH mutant or WT: usually large, ill-­ defined, and centered in the white matter, often extending bilaterally and/or into the brainstem, with associated edema, hemorrhage, and necrosis •  Extension across the corpus callosum is common: “butterfly glioma” • Giant cell glioblastomas and gliosarcoma may each be sharply circumscribed and firm owing to presence of connective tissue components • Diffuse midline glioma (H3k27M mutant): diffuse infiltration of parenchyma is typical with areas of necrosis and hemorrhage 

Histopathology See Figure 19.1. Astrocytoma IDH Mutant (WHO Grade II)  • Hypercellular (relative to normal brain), infiltrative, ill-­ defined lesions typically centered in the white matter or less commonly the cerebral cortex • Neoplastic astrocytic nuclei vary from cigar shaped to oval with slight pleomorphism and hyperchromatism. They have fibrillary processes or scant not visible cytoplasmthat is not visible

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

A

B

C

D

Figure 19.1  A, Low-­grade astrocytoma. Cellular infiltrate of neoplastic astrocytes showing nuclear enlargement, nuclear membrane irregularity, and slight hyperchromasia. B, Anaplastic astrocytoma. Highly cellular tumor composed of neoplastic astrocytes with moderate nuclear pleomorphism, hyperchromatism, nuclear membrane irregularity, and mitoses. C, Glioblastoma (GBM). Notice the prominent area of necrosis with pseudopalisading. D, GBM. Neoplastic astrocytes surrounding endothelial proliferation (glial fibrillary acidic protein stain).

• Background microcysts may be present • Presence of a single mitosis should not prompt designation as an anaplastic astrocytoma • Sample size is important in this determination; a small sample with mitosis suggests an anaplastic designation, but a single mitosis in a large resection should not prompt a higher-­grade diagnosis  Gemistocytic Astrocytoma IDM (WHO Grade II)  • Neoplastic astrocytes have large cell bodies with abundant eosinophilic cytoplasm and short fibrillary processes and eccentric nuclei • Presence of at least 20% of gemistocytes is necessary for this designation • This subtype has a high tendency to progress to anaplastic astrocytoma • Mitotic figures are typically scant or absent  Anaplastic Astrocytomas IDH Mutant (WHO Grade III)  • Tumor shows higher cellularity, increased nuclear pleomorphism, and hyperchromasia • Mitotic figures are present (see the previous discussion of mitoses in astrocytoma) • MIB-­1 is elevated (5% to 10%) and glioblastomas (15% to 20%)  Glioblastoma IDH Mutant or Wildtype (WHO Grade IV)  • Infiltrative, highly cellular tumor with a wide range of abnormal cytology

• Cells with hyperchromatic, pleomorphic nuclei and ill-­ defined fibrillary cytoplasm are usually present •  The following may also be seen: multinucleated cells, lipidized cells, granular cells, and epithelioid change • Numerous mitotic figures are always present •  Rarely, metaplastic elements are present, including squamous or adenoid differentiation, bone, or cartilage (more common in gliosarcoma) • Required for diagnosis •  Endothelial cell proliferation or areas of necrosis with or without pseudopalisading  Variants of Glioblastoma  • Giant cell glioblastoma (WHO grade IV) •  Large, bizarre cells with markedly pleomorphic nuclei and multinucleation •  May have increased reticulin network and appear more circumscribed • Gliosarcoma (WHO grade IV) • Defined by the presence of a sarcomatous component in addition to a malignant astrocytic component in the neoplasm; molecular studies support a common origin of both cell types • Astrocytic component is high grade and may occasionally display adenoid or squamous metaplasia • Sarcomatous component most often shows histology suggesting fibrosarcoma • Epithelioid glioblastoma (WHO grade IV)

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1016

Chapter 19  —  Central Nervous System

•  Cells characterized by circumscribed cytoplasm (epithelioid cells); occasionally rhabdoid cells are present • Small cell astrocytoma (WHO grade III or IV) •  Monomorphous oval nuclei, mild nuclear hyperchromasia, occasional small nucleoli, scant cytoplasm, many mitoses • Endothelial proliferation or pseudopalisading necrosis may be present (if present, grade IV; if absent, grade III) • May exhibit architectural features causing confusion with oligodendroglioma, such as chicken-­wire vasculature, clear halos, perineuronal satellitosis, and calcifications • Glioblastoma with primitive neuroectodermal component (WHO grade IV) •  Presence of hypercellular nodules of cells with hyperchromatic carrot-­shaped nuclei, high nuclear-­ to-­cytoplasmic ratios, presence of abundant mitoses and karyorrhexis, and Homer Wright rosettes, within a glioblastoma; desmoplasia or large cell/anaplastic cytology may also be present  Diffuse Midline Glioma (H3 k27M Mutant)  •  A strocytic morphology most often with small monomorphic cells, but occasionally pleomorphic nuclei •  Most often with necrosis, endothelial proliferation, and mitoses 

Special Stains and Immunohistochemistry • Diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, and variants •  Glial fibrillary acidic protein (GFAP) positive in grades II and III; in glioblastoma less positive staining may be present •  MIB-­ 1 (Ki-­ 67): labeling index is low in low-­ grade astrocytomas (70%), which is not present in low-­grade diffuse astrocytomas and may be useful in distinguishing PAs from diffuse astrocytomas. This fusion is most frequently found in the cerebellar tumors but is seen in pilocytic tumors in all locations • Several other BRAF fusion have been identified in PAs. Additional molecular alterations (all affecting the MAPK pathway) found in PAs are: BRAF V600E, NF1, FGFR1 fusion, FGFR1 mutation, NTRK1 fusion, KRAS mutation, RAF1 fusion 

Differential Diagnosis Diffuse Astrocytoma  • Typically lack circumscription and contrast enhancement • Tissue infiltration and malignant behavior are much more common •  Usually lacks biphasic pattern, Rosenthal fibers, and eosinophilic granular bodies • IDH mutation  Pilomyxoid Astrocytoma  • May be difficult to exclude as focal areas of pilomyxoid morphology may be present in a PA • PMA typically do not have fibrillar areas, eosinophilic granular bodies, Rosenthal fibers, or calcifications; they do have a myxoid background, pseudorosette pattern, and monomorphic cells  Pleomorphic Xanthoastrocytoma  • Lacks biphasic pattern

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1020

Chapter 19  —  Central Nervous System

•  Typically more cellular and has increased nuclear pleomorphism • Xanthomatous cells are present that are not seen in PA 

Hemangioblastoma  • Also associated with cyst formation • Highly vascular with abundant reticulin formation • Contains foamy cells filled with lipid

• Angiocentric pattern of arrangement of cells suggestive of perivascular pseudorosettes is often evident • Limited peripheral parenchymal involvement • Rare nuclear pleomorphism • Usually lacks Rosenthal fibers and eosinophilic granular bodies • Mitotic figures may be present • Endothelial proliferation and necrosis reported in some cases • Tumors exhibiting features of both PMA and PA are reported and identified as intermediate lesions (see the section on PAs) 

PEARLS

Special Stains and Immunohistochemistry

Ganglion Cell Tumors  • Show clustered atypical neurons, which are immunohistochemically positive for neuronal markers 

• Important to distinguish pilocytic astrocytomas from fibrillary or diffuse astrocytomas because treatment and prognosis are different • Typically cured by complete resection; overall prognosis is excellent • Rare tumors have an aggressive clinical course, and transformation to glioblastoma has been reported

• GFAP: diffuse positivity • Synaptophysin: positivity has been reported • Neuronal markers: negative • MIB-­1 labeling index ranges from 2% to 20% 

Other Techniques for Diagnosis •  Cytogenetics: few studies that have been performed show KIAA1549-­BRAF fusion as seen in PA 

Selected References

Differential Diagnosis

Collins VP, Jones DTW, Giannini C. Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129:775–788. Collins VP, Tihan T, VandenBerg SR, et al. Pilocytic astrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:80–88. Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009;118:401–405. Reis GF, Tihan T. Practical molecular pathologic diagnosis of pilocytic astrocytomas. Surg Pathol Clin. 2015;8(1):63–71.

Pilocytic Astrocytoma  • Occurs also in the chiasm and hypothalamus • Rosenthal fibers and eosinophilic granular bodies present • Biphasic architecture PEARLS

PILOMYXOID ASTROCYTOMA (WHO GRADE NOT ASSIGNED AT PRESENT)

• R  eports suggest that pilomyxoid astrocytoma may be a variant of pilocytic astrocytoma • Pilomyxoid astrocytoma is locally aggressive with a tendency to recur (76%) and disseminate through the cerebrospinal fluid (14%); overall survival is 63 months

Clinical Features

Selected References

• Closely related to PA but may have a more aggressive clinical course • Occurs predominantly in infants and young children (mean age, 18 months) and involves the chiasm and hypothalamus most often; it occasionally occurs in adults and the elderly • Reported in temporal lobe, thalamus, posterior fossa, and spinal cord • Symptoms may be nonlocalizing: failure to thrive, developmental delay, vomiting and feeding difficulties, generalized weakness, and altered levels of consciousness • Focal neurologic symptoms also occur: visual disturbances and endocrine dysfunction • Tendency to disseminate through CSF and to recur •  MRI scans show hypointensity on T1-­ weighted and hyperintensity on T2-­weighted images with homogeneous contrast enhancement 

Gross Pathology • Myxoid ill-­defined mass 

Histopathology • Monomorphous, hypercellular, compact small bipolar cells set in a myxoid and fibrillary background

Collins VP, Tihan T, VandenBerg SR, et al. Pilomyxoid astrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:88–89. Johnson MW, Eberhart CG, Perry A, et al. Spectrum of pilomyxoid astrocytomas, intermediate pilomyxoid tumors. Am J Surg Pathol. 2010;34:1783–1791. Kulac I, Tihan T. Pilomyxoid astrocytomas: a short review. Brain Tumor Pathol. 2019;36:52–55. Tihan T, Fisher PG, Kepner JL, et al. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropath Exp Neurol. 1999;58:1061–1068.

PLEOMORPHIC XANTHOASTROCYTOMA (WHO GRADE II) AND ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (WHO GRADE III) Clinical Features • Rare astrocytic neoplasm usually found in children and young adults (66% are younger than 18 years) • Superficial location in the cerebral hemisphere (most frequently temporal lobe) often involving the meninges; rare involvement of the deep gray matter, cerebellum, spinal cord, sella, suprasellar region, and retina

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

• Patients present typically with a long history of seizures and occasional headaches; seldom with focal neurologic signs • CT and MRI show a well-­defined enhancing mass, adjacent to the meninges, that is solid or cystic with a mural nodule 

Gross Pathology •  Well-­ defined, cystic mass with a mural nodule or a solid mass •  Often attached to the meninges; may spread along brain surface

Histopathology  • Varied histologic pattern ranging from single or multinucleated giant cells to irregular spindle cells showing intracellular lipid accumulation (xanthomatous change) (Figure 19.3) • Reticulin network surrounding individual tumor cells; desmoplasia often present • Patchy lymphocytic infiltrates often seen • Variable degrees of vascular sclerosis •  Eosinophilic granular bodies or protein droplets prominent • Neuronal differentiation may be present • Usually absent or inconspicuous mitotic activity and necrosis in Grade II •  A diagnosis of anaplastic xanthoastrocytoma (WHO grade III) may be made when abundant mitoses are present. One study found that greater than equal to 5 or more mitoses/10 HPF was associated with poorer prognosis. Usually necrosis is also present. Endothelial proliferation is uncommon 

1021

Other Techniques for Diagnosis •  Electron microscopy: cells typically show abundant intermediate filaments, lysosomes, lipid droplets, basal lamina, and secondary lysosomes • Approximately 20% show ultrastructural features indicating neuronal differentiation: microtubules, dense core granules, and clear vesicles • Cytogenetic analyses: BRAF (V600E) mutations have been found in 50% to 78% of grade II pleomorphic xanthoastrocytomas and 47% of grade III anaplastic pleomorphic xanthoastrocytomas 

Differential Diagnosis Glioblastoma  •  Important distinction from pleomorphic xanthoastrocytoma because of poor prognosis associated with glioblastoma • Most lack reticulin investment and eosinophilic granular bodies • Usually not cystic with mural nodules; always a high mitotic index and endothelial proliferation or necrosis  Pilocytic Astrocytoma  • Biphasic pattern is characteristic • Rosenthal fibers are commonly found • Usually less cellular and without xanthomatous changes  Ganglion Cell Tumors  • Atypical neurons that are positive for neuronal markers (synaptophysin and neurofilament) are a defining feature • Usually lack xanthomatous changes

Special Stains and Immunohistochemistry

PEARLS

• GFAP, S-­100 protein, and CD34 positive •  Reticulin highlights fibrous network surrounding tumor cells • Synaptophysin and neurofilament variably positive • MIB-­1 labeling index: less than 1% (unless anaplastic) • BRAF V600E mutation may be identified by immunohistochemistry 

• S urgical resection is primary treatment with overall good prognosis, especially when gross total resection is possible in Grade II pleomorphic xanthoastrocytoma (PXA) • Hypothesized to arise from subpial astrocytes and often display neuronal differentiation

Selected References Giannini C, Paulus W, Louis DN, et al. Pleomorphic xanthoastrocytoma and anaplastic xanthoastrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:94–99. Ida CM, Rodriguez FJ, Burger PB, et al. Pleomorphic xanthoastrocytoma: natural history and long-­term follow-­up. Brain Pathol. 2015;25:575–586. Kepes JJ. Pleomorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol. 1993;3:269–274. Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma, and extra-­cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405.

SUBEPENDYMAL GIANT CELL ASTROCYTOMA (WHO GRADE I) Clinical Features Figure 19.3  Pleomorphic xanthoastrocytoma. Infiltrate of neoplastic astrocytic cells with marked nuclear pleomorphism and xanthomatous changes. Eosinophilic granular bodies are present.

• Most common neoplastic process involving the brain in patients with tuberous sclerosis (TS) • TS is an autosomal dominant disorder with markedly variable penetrance and an incidence between 1 per 9000 and 1 per 10,000 births

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1022

Chapter 19  —  Central Nervous System

• Central nervous system (CNS) abnormalities include cortical hamartomas (tubers), subcortical glioneuronal hamartomas, subependymal glial nodules, subependymal giant cell astrocytoma (SEGA); other organs affected are skin, lung, retina, kidney, and heart •  Neurologic symptoms in TS usually occur shortly after birth and include seizures and infantile spasms; cognitive disability and autism may become evident at older ages • Mutations in either of two genes, TSC1 (encoding hamartin) on chromosome 9 and TSC2 (encoding tuberin) on chromosome 16, are found in greater than 85% of patients with the TS complex • SEGA rarely occurs without association with TS • Occurs in 5% to 20% of persons with TS • Usually develops during childhood or adolescence • Clinical symptoms are usually secondary to obstructive hydrocephalus and occur when large SEGAs block CSF flow 

Gross Pathology • Typically an exophytic, solid, fleshy, well-­defined, tan mass arising in the wall of the lateral ventricle 

Histopathology • Variable cellular morphology, including the following • Polygonal cells with abundant eosinophilic cytoplasm suggestive of gemistocytic astrocytes (Figure 19.4) • Spindle-­shaped cells with fibrillary cytoplasm forming streams and bundles • Large pleomorphic cells with nuclei exhibiting prominent nucleoli, suggestive of neuronal differentiation (sometimes multinucleated) • Focal microcalcifications and scattered mast cells are common features • Ill-­defined pseudorosette formation may be seen • Variable mitotic activity • Vascular proliferation and necrosis are uncommon •  High-­ grade cytologic features do not appear to impose an adverse clinical course 

Special Stains and Immunohistochemistry •  GFAP, S-­ 100 protein, synaptophysin, and neurofilament positive • Class III β-­ tubulin and neuropeptides (somatostatin and met-­enkephalin) positive • MIB-­1 (Ki-­67): few positive cells (low proliferative index)

Other Techniques for Diagnosis  •  Cytogenetics: deletion mutations in TSC1 or TSC2 cause a constitutive up-­regulation of mTOR complex 1 tumor suppressor complex, resulting in abnormal cellular proliferation 

Differential Diagnosis Figure 19.4  Subependymal giant cell astrocytoma. Infiltrate of astrocytic-­appearing cells with abundant, frequently spindled eosinophilic cytoplasm. Prominent nucleoli are frequent.

A

Gemistocytic Astrocytoma  • May be considered because both lesions contain astrocytic cells with abundant pink glassy cytoplasm

B

Figure 19.5  A, Low-­grade oligodendroglioma. Moderately cellular tumor composed of cells with round hyperchromatic nuclei and clear cytoplasm, giving the characteristic fried-­egg appearance. B, Anaplastic oligodendroglioma. Notice the mitoses, high cellularity, nuclear enlargement, and hyperchromatism.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

•  Intraparenchymal tumor rather than an exophytic intraventricular mass • Typically shows an infiltrative architecture • No mast cell infiltrate and microcalcifications  Subependymal Glial Nodule  • Considered to be a precursor to SEGA • More frequently calcified than SEGA • Usually asymptomatic; shows no growth on serial brain scans • Histologically identical to SEGA PEARLS • Debate still exists as to whether SEGAs can occur outside the setting of TS • Believed to be an astrocytic neoplasm; however, studies have shown that many tumors show a more glioneuronal phenotype • Tumors occasionally recur, but unlike gemistocytic astrocytoma, no malignant transformation has been shown, although local invasion has been reported • Approximately 50% of TS patients have a positive family history, suggesting a high rate of spontaneous mutation • Current standard treatment is surgical resection; studies have shown reduction in tumor size with administration of everolimus, an inhibitor of the mTOR complex 1

Selected References Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol. 2004;63:1236–1242. Cotter JA. An update on the central nervous system manifestations of tuberous sclerosis complex. Acta Neuropathol. 2020;139:613–624. Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex. Neurology. 2004;63:1457–1461. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-­ cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–1811.

EPENDYMAL TUMORS EPENDYMOMA (WHO GRADE II), ANAPLASTIC EPENDYMOMA (WHO GRADE III), RELA FUSION-­POSITIVE EPENDYMOMA (WHO GRADE II OR III) Clinical Features • Occur most commonly in children and young adults •  Account for about 3% to 9% of all neuroepithelial tumors; most frequent neuroepithelial tumors of the spinal cord (50% to 60% of spinal gliomas) • Occur at any site along the ventricular system; most commonly in the posterior fossa, followed by the supratentorial compartment and then spinal cord • Most ependymomas in children occur in the brain and most that occur in adults are in the spinal cord • Newly defined ependymoma with C11orf 95-­RELA fusion is most common supratentorial ependymoma in children (approximately 70%). Patients most often present with symptoms of hydrocephalus, including nausea, vomiting, and headache; patients occasionally develop seizures • Posterior fossa tumors may cause visual disturbances or cerebellar ataxia 

1023

Gross Pathology • Soft gray-­pink tumors that may be solid or cystic • Areas of hemorrhage or necrosis may be present •  Typically protrude from the ventricular lining and fill the ventricular lumen; well demarcated, but may invade the adjacent brain parenchyma 

Histopathology See Figure 19.6. Ependymoma  • Cellular tumors composed of monomorphic cells with round to oval hyperchromatic nuclei and long fibrillary cell processes •  Perivascular pseudorosettes consisting of tumor cells radially arranged around blood vessels are prominent • True ependymal rosettes consisting of columnar cells radially arranged around a central lumen are less common than perivascular pseudorosettes • Calcification, as well as metaplastic cartilage or bone, may be seen • Areas of necrosis (with and without pseudopalisading) and endothelial proliferation may be seen in an otherwise low-­grade appearing ependymoma •  Histologic features distinguishing between grades II and III are unreliable (see below) • No RELA fusion-­ specific morphology described but will often have a branching vascular pattern or clear cell change  Ependymoma Variants  • Papillary ependymoma (WHO grade II) • Extensive papillary formations • Clear cell ependymoma (WHO grade II) • Cells exhibit round nuclei and perinuclear halos • Anaplastic histologic features are often present • Occurs more frequently in supratentorial compartment than in infratentorial compartment • Tanycytic ependymoma (WHO grade II) • Occurs more commonly in spinal cord • Composed of elongated spindled glial cells forming fascicles • Ependymal rosettes often not present; perivascular pseudorosettes may be ill-­defined  Anaplastic Ependymoma  •  Morphologic criteria that consistently correlate with prognosis are still debated and therapeutic decisions are not based on grading •  Features commonly present in tumors designated as anaplastic are: (1) hypercellularity with nuclear hyperchromasia and pleomorphism; (2) abundant mitotic activity; (3) endothelial proliferation and/or necrosis with pseudopalisading are often present, but may also be seen in low-­grade ependymomas • Perivascular pseudorosettes persist 

Special Stains and Immunohistochemistry •  GFAP: marked cytoplasmic immunoreactivity, especially prominent in the perivascular pseudorosettes •  Cytokeratin: AE1/AE3 immunoreactivity present in most ependymomas; focal and variably strong positivity with other keratin antibodies

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1024

Chapter 19  —  Central Nervous System

A

B

C Figure 19.6  Ependymoma.  A, Low-­power view shows a moderately cellular glial tumor with classic perivascular pseudorosettes. B, High-­power view shows classic ependymal rosettes. Notice glial cells radially arranged to form a canal (phosphotungstic acid–hematoxylin stain). C, Myxopapillary ependymoma. Glial cells exhibiting perivascular arrangement with abundant interposed mucin deposition.

• EMA: dotlike cytoplasmic immunoreactivity present in most neoplastic cells • CD99: diffuse and dotlike cytoplasmic immunoreactivity with accentuation at membrane surface •  MIB-­ 1 labeling index: more elevated in anaplastic ependymomas • L1CAM (CD171) immunoreactivity is associated with presence of RELA fusion gene (but is not specific) 

Other Techniques for Diagnosis • Electron microscopy: cells show polarity with well-­formed terminal bars; typically have surface microvilli, cilia, intercellular junctions (zonula adherens), and blepharoplasts • Cytogenetics: •  An association between neurofibromatosis type 2 (NF2) and sporadic mutations in NF2 and spinal ependymomas is established •  Gain of chromosome 1q is associated with poor prognosis in posterior fossa ependymomas •  Homozygous deletion of CDKN2A/B is associated with poor prognosis in supratentorial ependymomas • Distinct molecular subgroups of ependymomas have been identified in each neuroanatomic compartment (supratentorial, posterior fossa, spinal canal)





• In supratentorial compartment C11orf95-­RELA or YAP1 fusions are found • May be identified by various methods; fluorescent in situ hybridization (FISH) may be used • In the posterior fossa two groups identified: EPN-­A with few copy number alterations and EPN-­B with gains/losses of whole chromosomes and chromosome arms •  Spinal canal: ependymomas with gains/losses of whole chromosomes and chromosome arms identified 

Differential Diagnosis Metastatic Adenocarcinoma  • Morphology more consistently epithelial •  Cytokeratin positivity specific for site of origin; less likely positive in ependymoma  Fibrillary or Diffuse Astrocytoma  • Poorly defined infiltrative tumor • Lacks rosette formation • EMA typically negative • Lower grade tumors are IDH1/2 mutated 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

1025

MYXOPAPILLARY EPENDYMOMA (WHO GRADE I) Clinical Features

Figure 19.7  Choroid plexus papilloma.  Columnar epithelium overlying classic papillary architecture with central fibrovascular core.

Astroblastoma  • Rare tumor • Located away from the ventricle • Shows marked and diffuse vascular sclerosis • Tumor cells have short, broad processes • Lacks true rosette formation  Choroid Plexus Papilloma or Carcinoma  • Papillary architecture and no rosette formation (Figure 19.7) • Negative or only focally positive for GFAP •  Carcinomas have a loose papillary architecture and consist of sheets of pleomorphic cells with a high mitotic rate; extensive necrosis is common  Oligodendroglioma  • May be confused with clear cell ependymoma • Lacks fibrillary processes, perivascular pseudorosettes, and true rosettes • Has deletions of chromosomes 1p and 19q  Central Neurocytoma  • Round cells with areas of neuropil • Synaptophysin positive • GFAP negative PEARLS • Recent research indicates that histologic grading of ependymomas into WHO grades II and III does not predict biological behavior and that molecular subgrouping more strongly correlates with behavior.

Selected References Lester A, McDonald KL. Intracranial ependymomas: molecular insights and translation to treatment. Brain Pathol. 2020;30:3–12. Pajtler KW, Mack SC, Ramaswamy V, et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol. 2017;133:5–12. Pajtler KW, Witt H, Sill M, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Canc Cell. 2015;27:728–743. Wu J, Armstrong TS, Gilbert MR. Biology and management of ependymomas. Neuro Oncol. 2016;18(7):902–913.

• Represents about 10% to 13% of all ependymomas • Typically presents in young adults at an average age of 36 years • Occurs more frequently in males (2.5:1) •  Occurs almost exclusively in the conus-­ cauda-­ filum terminale region and rarely in the fourth or lateral ventricles or brain parenchyma •  Also reported in subcutaneous tissue overlying the sacrococcyx and in the presacral and postsacral regions • Signs and symptoms include low back pain, sciatica, and focal neurologic deficits referable to the tumor location 

Gross Pathology • Lobulated, circumscribed, soft gray tumors in the filum terminale or attached to nerve roots 

Histopathology • Composed of papillae lined by monotonous elongated or columnar cells surrounding a central vascular core • Occasionally fascicular architecture is present •  Abundant perivascular mucin pools and a fibrillary background 

Special Stains and Immunohistochemistry • GFAP, vimentin, and S-­100 protein positive • PAS and Alcian blue highlight perivascular mucin • Cytokeratin and EMA: each variably reported as positive and negative in literature • MIB-­1: low (5 mitoses/10 HPF) • Nuclear anaplasia •  Endothelial proliferation and necrosis with pseudopalisading 

Special Stains and Immunohistochemistry • GFAP, S-­100, and vimentin: strong immunoreactivity • EMA: focal membranous immunoreactivity • Cytokeratin (low molecular weight): variable • MIB-­1 index: low grade, 3%; high grade, greater than 10% 

Other Techniques for Diagnosis •  Electron microscopy: tumor cells contain abundant intermediate filaments and exhibit microvilli, poorly developed intercellular junctions, and rare cilia • Cytogenetics: No mutations in IDH1 or IDH2 genes. Recent molecular analyses have shown varied genetic abnormalities in tumors with astroblastoma morphology including BRAF V600E mutations, TP53 and TERT promoter mutations, CDKN2A/B homozygous deletions, and MN1 alterations 

Differential Diagnosis Ependymoma  • Most are infratentorial and within or close to a ventricle • Lacks vascular hyalinization • Shows formation of true rosettes • Cells have elongated fibrillary processes and fibrillary background  Angiocentric Glioma  • In contrast to astroblastoma, angiocentric gliomas are infiltrating lesions composed of piloid cells that exhibit

• D  iscovery of varied genetic make-­up of astroblastomas suggests that it may be a histologic pattern rather than a distinct brain entity. This may explain the difficulty in defining predictive histologic WHO grades

Selected References Boisseau W, Euskirchen P, Mokhtari K, et al. Molecular profiling reclassifies adult astroblastoma into known and clinically distinct tumor entities with frequent mitogen-­ activated protein kinase pathway alterations. Oncologist. 2019;24:1584–1592. Port JD, Brat DJ, Burger PC, et al. Astroblastoma: radiologic-­pathologic correlation and distinction from ependymoma. Am J Neuroradiol. 2002;23:243–247. Wood MD, Tihan T, Perry A, et al. Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain Pathol. 2018;28:192–202.

CHORDOID GLIOMA (WHO GRADE II) Clinical Features • Uncommon glioma arising in region of third ventricle • Mean age, 46 years; range, 12 to 70 years • Females affected more than males • Signs and symptoms usually secondary to obstructive hydrocephalus; reported symptoms include headache, weight loss, endocrine disturbances, autonomic disturbances, psychosis, and focal neurologic deficits • On MRI scan, well-­circumscribed, usually anterior third ventricle, T1-­ isointense, and show diffuse homogeneous contrast enhancement 

Gross Pathology • Well-­circumscribed, fusiform, ovoid shape containing cysts; may be attached to the hypothalamus 

Histopathology • Clusters of epithelioid cells and cords of spindle cells in a myxoid and mucinous background • Sparse to abundant lymphoplasmacytic infiltrates with Russell bodies •  Rare mitotic figures, no necrosis, and endothelial proliferation • Does not infiltrate into surrounding brain, but Rosenthal fibers are present in adjacent reactive brain tissue 

Special Stains and Immunohistochemistry •  Periodic Acid Schiff (PAS) and Alcian blue positive background; mucin negative • Reticulin surrounds clusters of epithelioid cells •  GFAP, CD34, and vimentin: strong diffuse immunoreactivity • TTF1 positive but variable in amount and intensity

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1028

Chapter 19  —  Central Nervous System

• EMA, cytokeratin, and s-100 variable positivity • MIB-­1 labeling index: generally less than 2% 

Other Techniques for Diagnosis • Electron microscopy: abundant intermediate filaments in cytoplasm, apical microvilli, abnormal cilia, focal basal lamina, and hemidesmosomes • Cytogenetics: No mutations in IDH1, IDH2, or BRAF genes have been found. A missense mutation in the PRKCA gene has recently been identified in approximately 30 cases 

Differential Diagnosis Chordoma  •  Limited cytokeratin immunoreactivity in chordoid glioma, compared with diffuse and strong reactivity in chordoma • Brachyury immunoreactive • Physaliferous cells characteristic  Chordoid Meningioma  •  Presence of whorls and psammoma bodies, nuclear pseudoinclusions •  No immunoreactivity for GFAP; usually positive for EMA and progesterone receptor • Both may have inflammatory infiltrates PEARLS • G  ross total resection is the optimal treatment, but adherence to hypothalamus may prevent complete resection and lead to significant morbidity and poor outcome • Cell of origin is hypothesized to be the tanycyte (glial progenitor cell with astrocytic and ependymal features) found in circumventricular organs (lamina terminalis in anterior third ventricular wall) • Metaplastic elements have been reported (chondroid)

•  MRI of tumor shows a homogeneous not well-­ demarcated lesion of the cortex and white matter with focal extension to the ventricular surface; a peripheral rim of hyperintensity on T1-­weighted images and hyperintensity on T2-­weighted and fluid-­attenuated inversion recovery images without enhancement are evident 

Gross Pathology • Not yet described 

Histopathology • Superficial cortical location with subpial accumulation • Infiltration of surrounding parenchyma • Monomorphous slender bipolar cells with angiocentricity •  Circumferential (more common) or radial arrangements around vessels of all sizes • Occasional fascicular architecture • Rare mitoses; no necrosis or endothelial proliferation • Palmini and colleagues’ type 1 cortical dysplasia has been described adjacent to the tumors 

Special Stains and Immunohistochemistry • GFAP: variable degrees of positivity, often around vessels • S-­100 and vimentin positive • EMA surface and paranuclear dotlike positivity • Neu-­N, chromogranin, and synaptophysin negative • MIB-­1 index: 1% to 5% 

Other Techniques for Diagnosis • Electron microscopy: perivascular cells contain cytoplasmic intermediate filaments and exhibit basement membrane; cell junctions, cilia, and microvilli are described, suggesting ependymal differentiation • Cytogenetics: IDH1 (R132H) mutation not present; recently MYB-­QKI gene fusions have been described in angiocentric gliomas 

Selected References

Differential Diagnosis

Bielle F, Villa C, Giry M, et al. Chordoid gliomas of the third ventricle share TTF-­1 expression with organum vasculosum of the lamina terminalis. Am J Surg Pathol. 2015;39(7):948–956. Goode B, Mondal G, Hyun M, et al. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun. 2018;9(1):810. Horbinski C, Dacic S, McLendon RE, et al. Chordoid glioma: a case report and molecular characterization of five cases. Brain Pathol. 2009;19:439–448. Rosenberg S, Simeonova I, Bielle F, et al. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat Commun. 2018;9(1):2371.

Astrocytoma  • Lacks monomorphic nuclear appearance of angiocentric glioma • No angiocentricity 

ANGIOCENTRIC GLIOMA (WHO GRADE I) Clinical Features • Slow-­growing glioma •  Reported in patients ranging in age from 2 to 70 years, but occurs most commonly in childhood and adolescence • Most present with seizures; longstanding history of seizures is common • Occurs most commonly in cerebral cortex

Pilocytic Astrocytoma  • Not infiltrative • EMA negative  Pilomyxoid Astrocytoma  • Mucinous and myxoid background • Usual location in hypothalamus • Contrast enhancing • Occurs in very young patients  Ependymoma  • Usually in or adjacent to a ventricle • Exhibits only radially arranged perivascular pseudorosettes and ependymal rosettes • Tumors containing patterns of angiocentric glioma and ependymoma have been reported so separation may be difficult 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

Astroblastoma  •  Radially arranged perivascular pseudorosettes with marked vessel sclerosis PEARLS • E xcellent prognosis; gross total resection is usually curative with termination of seizures • Hypothesized to be of ependymal or radial glial cell origin

Selected References Bandopadhayay P, Ramkissoon LA, Jain P, et al. MYB-­QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet. 2016;48(3):273–282. Burger PC, Jouvet A, Preusser M, et al. Angiocentric glioma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:110–120. Wang M, Tihan T, Fojiani AM, et al. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropath Exp Neurol. 2005;64:875–881.

NEURONAL AND GLIONEURONAL NEOPLASMS GANGLIOCYTOMA (WHO GRADE I), MULTINODULAR AND VACUOLATING NEURONAL TUMOR OF THE CEREBRUM (NO WHO GRADE), DYSPLASTIC CEREBELLAR GANGLIOCYTOMA (WHO GRADE I), DESMOPLASTIC INFANTILE ASTROCYTOMA AND GANGLIOGLIOMA (WHO GRADE I), GANGLIOGLIOMA (WHO GRADE I AND II), AND ANAPLASTIC GANGLIOGLIOMA (WHO GRADE III) Clinical Features • Gangliocytomas are WHO grade I; most gangliogliomas are WHO grade I; criteria for grade II gangliogliomas are not yet established and anaplastic gangliogliomas are uncommon (WHO grade III) • Low incidence (1.3% of all brain tumors), but the most common neoplasm in patients with chronic intractable focal epilepsy •  Typically, supratentorial and usually involves the temporal lobe , but occur throughout the CNS • Most present in the first three decades; may be found in all ages • Often associated with a history of treatment-resistant epilepsy • CT and MRI usually show a solid or cystic mass; often with calcification and variable contrast enhancement Multinodular Vacuolating Neuronal Tumor of the Cerebrum  • Occurs most frequently in adults, located in cerebrum (most often temporal lobe) • Presents with seizures • MRI scan shows hyperintense nonenhancing nodular mass • No WHO grade assigned yet 

1029

Dysplastic Cerebellar Gangliocytoma (Lhermitte-­ Duclos Disease), WHO Grade I  • Most often occurs in adults • Associated with Cowden syndrome • Not yet clear if it is neoplastic or hamartomatous • Clinical presentation is with cerebellar signs and symptoms, symptoms of obstructive hydrocephalus, or of mass effect • MRI scans demonstrate enlarged cerebellar folia  Desmoplastic Infantile Astrocytoma and Ganglioglioma (WHO Grade I)  • Most occur before 2 years of age •  Increasing head circumference, bulging fontanelles, lethargy 

Gross Pathology •  Gangliocytoma, ganglioglioma, and anaplastic ganglioglioma • Well-­circumscribed gray granular mass that is variably solid and cystic; mural nodule within the cystic component is often seen • May extend into the leptomeninges and subarachnoid space • Extensive calcification, hemorrhage, or necrosis may be seen •  Multinodular vacuolating neuronal tumor of the cerebrum •  Discrete gray firm nodules in lower cortex and at gray/white matter junction • Dysplastic cerebellar gangliocytoma (Lhermitte-­Duclos disease) • Single or multiple enlarged cerebellar folia • Desmoplastic infantile astrocytoma and ganglioglioma • Large cystic masses, superficially located, most often occurring in frontal and parietal lobes, may involve more than one lobe 

Histopathology Gangliocytoma  •  Composed entirely of neurons forming ill-­ defined groups, usually of low cellularity • Often exhibits cytologic atypia, including binucleation  Ganglioglioma and Anaplastic Ganglioglioma  • Tumor composed of atypical ganglion cells as well as a neoplastic glial component (Figure 19.8) •  Neoplastic neurons are characterized by haphazard clustering, lack of orderly distribution, and, often, an abnormal location (in white matter) • Abnormal neurons may be small or large; often they are binucleated and have large nuclei and prominent nucleoli •  Glial component is variably cellular and most commonly consists of a neoplastic astrocytic population; pilocytic morphology may be seen and oligodendro­ glial foci are rarely seen • Rosenthal fibers and eosinophilic granular bodies are often present • Atypical glial cells with large, bizarre, hyperchromatic nuclei with intranuclear cytoplasmic inclusions may be seen

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1030

Chapter 19  —  Central Nervous System

• CD 34: positive in neurons in surrounding cortex frequent • GFAP: astrocytic component is positive • MIB-­1: low index (2%) with or without the presence of endothelial proliferation, necrosis, and increased cytologic atypia 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

1033

Ependymoma (Especially Clear Cell Variant)  • Cells have long fibrillary processes • Characteristically shows true rosettes • Typically protrudes from ventricular lining • GFAP positive and synaptophysin negative  Neuroblastoma (Primitive Neuroectodermal Tumor)  • Hyperchromatic atypical cells with frequent mitoses • Lack of fine chromatin and neuropil islands • Intraparenchymal with tendency to seed neuraxis • Immunohistochemical profiles are the same PEARLS Figure 19.10  Central neurocytoma.  The neoplasm is composed of a monotonous population of small round cells with a fine chromatin pattern and occasional nuclei-­free islands suggesting neuropil.

Extraventricular Neurocytomas  • Cytologically similar to central neurocytomas • Architectural pattern is more varied, such as clusters, ribbons, or rosettes, in addition to sheets • Higher degree of ganglionic differentiation and possibly glial differentiation  Cerebellar Liponeurocytoma  • Composed of neurocytes, some showing lipidization 

Special Stains and Immunohistochemistry • Synaptophysin: diffusely positive • NSE and Neu-­N positive • Chromogranin and neurofilament usually negative •  GFAP negative in central neurocytomas; variable in extraventricular neurocytomas • MIB-­1 index: less than 2% in typical neurocytomas; more than 2% shortens recurrence-­free survival • Cerebellar liponeurocytoma: in addition to neuronal markers, focal GFAP positivity is often present 

Other Techniques for Diagnosis •  Electron microscopy: membrane bound dense core neurosecretory granules, cytoplasmic microtubular arrays •  Cytogenetic analyses: central neurocytomas have been shown to have trisomy 7, chromosome 17 deletion, and gains in 2p, 10q, 13q, and 18q; overexpression of IGF2, N-­Myc, PTEN, and PDGF have also been reported • Extraventricular neurocytoma has been reported to have deletions of 1p and/or 19q but no deletions of IDH1/2. 

Differential Diagnosis Oligodendroglioma  • Poorly circumscribed with an infiltrative border • Typically not located in the ventricle •  Lacks salt-­ and-­ pepper nuclei, neuropil islands, and ganglion cell differentiation • Synaptophysin negative 

• M  ost are slow-­growing tumors that are essentially cured by surgical resection; associated with an excellent prognosis • Recurrence and adverse outcomes are associated with subtotal resection and elevated MIB-­1 proliferation index and elevated mitotic count (>2/10 HPF)

Selected References Bonney PA, Boettcher LB, Krysiak RS, et al. Histology and molecular aspects of central neurocytoma. Neurosurg Clin N Am. 2015;26:21–29. Choudhari K, Kaliaperumal C, Jain A, et al. Central neurocytoma: a multi-­disciplinary review. Br J Neurosurg. 2009;23:585–595. Figarella-­Branger D, Soylemezoglu F, Burger P. Extraventricular neurocytoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:159–160. Kleihues P, Giangaspero F, Chimelli L, et al. Cerebellar liponeurocytoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:161–163. Lee SJ, Bui TT, Chen CHJ, et al. Central neurocytoma: a review of clinical management and histopathologic features. Brain Tumor Res Treat. 2016;4(2):49–57. Vasiljevic A, Francois P, Loundow A. Prognostic factors in central neurocytomas: a multicenter study of 71 cases. Am J Surg Pathol. 2012;36:220–227.

PAPILLARY GLIONEURONAL TUMOR (WHO GRADE I) Clinical Features • Usually low grade •  Rare neoplasm; wide age range, from 4 to 75 years (mean age, 23 years) •  Seizures, headaches, visual disturbances, language or gait disturbances, and mood changes have been reported as presenting symptoms •  Occurs in cerebral parenchyma, most commonly in frontal and temporal lobes • MRI shows a well-­circumscribed solid and cystic mass with contrast enhancement; may have a cyst with a mural nodule 

Gross Pathology • Well-­circumscribed solid and cystic mass, may have a mural nodule in a cyst 

Histopathology • Architecturally composed of pseudopapillae and solid areas • Pseudopapillae exhibit pseudostratified, small cuboidal cells without atypia around hyalinized vessels

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1034

Chapter 19  —  Central Nervous System

• Solid areas contain mixtures of neurocytes and ganglion cells and cells intermediate between the two within a fibrillar or basophilic mucoid matrix • Rosenthal fibers, calcification, and old hemorrhage are seen • Mitoses are rare or absent • No endothelial proliferation or necrosis 

Special Stains and Immunohistochemistry • GFAP, S100: cells of pseudopapillae positive • Synaptophysin, Neu-­N, and neurofilament: cells from solid areas (neurocytes and ganglion cells) positive • Chromogranin and CD34: negative • MIB-­1 index: range, 1% to 3%; reports of up to 26% •  Epidermal growth factor receptor (EGFR) and IDH1 (R132H) immunohistochemistry: negative • p53: most often negative 

Other Techniques for Diagnosis • Ultrastructural examination: pseudopapillae lining cells show astrocytic features with intermediate filaments; solid area cells show neuronal features such as microtubules, dense core, and clear vesicles and occasionally synaptic junctions • Cytogenetic analyses: fusion of SLC44A1-­PRKCA identified by FISH in most reported cases • No codeletions of 1p or 19q or reports of IDH1 gene mutations 

Differential Diagnosis Papillary Ependymoma  • Lacks solid component exhibiting neuronal elements  Papillary Meningioma  • EMA positive • GFAP negative • Synaptophysin and Neu-­N negative  Choroid Plexus Papilloma  • Papillary formation not consistently GFAP positive • Lacks solid areas composed of neuronal elements  Metastatic Papillary Adenocarcinoma  • Cytokeratin positive • GFAP, synaptophysin, and Neu-­N negative  Astroblastoma  • Lacks neuronal elements PEARLS G •  ood prognosis • C  ases with atypical features (mitoses, endothelial proliferation, necrosis), elevated MIB-­1 indices, and aggressive behavior have been reported

Selected References Bourekas EC, Bell SD, Ladwig NR, et al. Anaplastic papillary glioneuronal tumor with extraneural metastases. J Neuropathol Exp Neurol. 2014;73(5):474–475.

Komori T, Scheithauer BW, Anthony DC, et al. Papillary glioneuronal tumor: a new variant of mixed neuronal-­glial neoplasm. Am J Surg Pathol. 1998;22:1171–1183. Pages M, Lacrois L, Tauziede-­ Espariat A, et al. Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-­PRKCA fusion. Acta Neuropathol Commun. 2015;3:85.

ROSETTE-­FORMING GLIONEURONAL TUMOR OF THE FOURTH VENTRICLE (WHO GRADE I) Clinical Features •  Rare neoplasm occurring at mean age of 32 years (range, 12 to 70 years) • Women affected more than men • Signs and symptoms secondary to obstructive hydrocephalus, headaches, ataxia, visual disturbances, and vertigo • MRI scan T1-­weighted images show a heterogeneous (cystic or solid) isointense or hypointense lesion; it is hyperintense on T2-­ weighted images and usually shows focal contrast enhancement; calcifications may be seen on CT scan • Most often occur in the fourth ventricle, but they have been described in the spinal canal, pons, cerebellar vermis, and thalamus 

Gross Pathology • Soft, gelatinous, well demarcated 

Histopathology • Composed of neurocytic and glial cells •  Neurocytic component exhibits small round nuclei and scant cytoplasm and forms perivascular pseudorosettes and Homer Wright rosettes, often accompanied by a microcystic, myxoid background; rarely, ganglion cells may be seen •  Glial component exhibits piloid and spindle-­ shaped cells, may be more extensive than the neuronal component • Rosenthal fibers and eosinophilic granular bodies may be seen • Degenerative changes are often seen consisting of sclerotic vessels, collagen, calcifications, and hemosiderin-­ laden macrophages • Endothelial proliferation may be seen • Mitoses are rare • Well-­defined tumor-­parenchyma interface 

Special Stains and Immunohistochemistry •  Synaptophysin: positive granular staining of neurocytic component • NSE positive in neurocytic component • GFAP and S-­100 positive in glial component • MIB-­1 index: less than 3% 

Other Techniques for Diagnosis • Electron microscopy: glial component has bundles of intermediate filaments; neurocytic component exhibits cells with small round nuclei, ribosomes, and rough endoplasmic reticulum; Golgi apparatus, sparse dense core granules, and microtubules in the rosette formations; occasional presynaptic specializations are seen

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

1035

•  Cytogenetics: presence of PIK3CA and FGFR1 mutations and absence of KIAA1549-­BRAF fusions, BRAF (V600E) mutation, codeletions of 1p/19q, or pathogenic mutations of IDH1/2 

• MRI scans show diffuse leptomeningeal enhancement and thickening. Involvement of posterior fossa and cerebral leptomeninges also occurs • Most patients have multifocal cystic or nodular involvement of spinal cord parenchyma 

Differential Diagnosis

Gross Pathology

Pilocytic Astrocytoma  • Usually occurs in younger individuals • Lacks neurocytic component and Homer Wright rosettes • Presence of KIAA1549-­BRAF fusion 

• Diffuse spread in leptomeninges of spinal cord, posterior fossa, and cerebrum is typical with multifocal involvement of spinal cord parenchyma and extension along spinal roots 

Central Neurocytoma  • Does not have a biphasic appearance with the piloid astrocytic component alternating with the neurocytic component 

Histopathology

Papillary Glioneuronal Neoplasm  •  More often occurs in cerebrum rather than fourth ventricle • Does not display Homer Wright rosettes • Exhibits pseudopapillary architecture formed by astrocytic cells  Ependymoma  • Not biphasic (does not have the neurocytic component)  Medulloblastoma  • Not biphasic (typically does not have the glial component) and is composed of primitive-appearing cells PEARLS • Indolent growth; excellent prognosis with surgical resection • Multifocal tumor nodules have been reported

Selected References Ellezam B, Theeler BJ, Luthra R, et al. Recurrent PIK3CA mutations in rosette-­ forming glioneuronal tumor. Acta Neuropathol. 2012;123:285–287. Gessi M, Moneim YA, Hammes J, et al. FGFR1 mutations in rosette-­ forming glioneuronal tumors of the fourth ventricle. J Neuropathol Exp Neurol. 2014;73(6):580–584. Komori T, Scheithauer BW, Hirose T. A rosette-­forming glioneuronal tumor of the fourth ventricle: infratentorial form of dysembryoplastic neuroepithelial tumor? Am J Surg Pathol. 2002;26:582–591. Zhang J, Babu R, McLendon RE, et al. A comprehensive analysis of 41 patients with rosette-­ forming glioneuronal tumors of the fourth ventricle. J Clin Neurosci. 2013;20:335–341.

DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (NO WHO GRADE AT PRESENT) Clinical Features • Most occur in children (mean age 5 years), but range is from infancy to middle age • Males are affected more often than females •  Presenting signs and symptoms most often due to obstructive hydrocephalus (headache, nausea, vomiting) • Cranial nerve palsy, ataxia, signs of spinal cord involvement are also seen

•  Low to moderately cellular neoplasm composed of oligodendroglial-­like cells in desmoplastic and myxoid background • Ganglion cells are occasionally also present •  Most neoplasms are low grade, but a subset have anaplastic features (mitoses, microvascular proliferation) 

Special Stains and Immunohistochemistry • Olig2 and S100 strongly positive • GFAP positive in approximately 40% • Synaptophysin positive in approximately 2/3 of cases • MIB-­1 proliferative index is usually low • IDH R132H is negative 

Other Techniques for Diagnosis • Cytogenetics: KIAA1549-­BRAF fusion is most frequent abnormality found • Loss of 1p is consistently found but no loss of 19q has been reported and, in a small number of cases, codeletions of 1p/19q 

Differential Diagnosis Pilocytic Astrocytoma or Diffuse Astrocytoma with Leptomeningeal Dissemination  • Diffuse astrocytomas and PAs may have IDH1/2 mutations and BRAF V600E mutations, respectively, diffuse GFAP positivity and lack ganglionic cells  Leptomeningeal Carcinomatosis  • Will contain epithelial cells with cytokeratin positivity PEARLS • M  ost tumors were stable or showed slow growth; a subset behaved more aggressively

Selected References Deng MY, Sill M, Chiang J, et al. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol. 2018;136:239–253. Reifenberger G, Rodriguez F, Burger PC, et al. Diffuse leptomeningeal glioneuronal tumour. In: Louis DN, Ohgaki H, Wiestler OD, etal., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:152–155. Rodriguez FJ, Perry A, Rosenblum MK, et al. Disseminated oligodendroglial-­ like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol. 2012;124(5): 627–641.

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1036

Chapter 19  —  Central Nervous System

PARAGANGLIOMA OF THE SPINAL CORD (WHO GRADE I) Clinical Features •  Benign, encapsulated neoplasm arising from neural crest cells, occurring in cauda equina and filum terminale • Constitutes 3.5% of all neoplasms in this location • Mean age of occurrence is 48 years •  Patients most commonly present with back pain or sciatica and urinary or fecal incontinence; sensory or motor deficits are less common; symptoms secondary to hormonal manifestations are uncommon 

Gross Pathology • Most are intradural and encapsulated (80%) • Red-­brown soft tissue; may contain cysts • Usually attached to filum terminale 

Histopathology • Nests (Zellballen) of small uniform cells surrounded by sustentacular cells • Delicate vascular network (organoid pattern) • Cells are polygonal or columnar with round nuclei and fine chromatin and granular eosinophilic cytoplasm • Perivascular pseudorosette formation may occur • Mitoses and necrosis are infrequent • Ganglion cell differentiation present in up to 45% • Divergent differentiation is reported (homologous or heterologous components) •  Melanotic and oncocytic variants have been described 

Special Stains and Immunohistochemistry • Chromogranin, synaptophysin, and NSE positive • Neurofilament: variable staining • GFAP: sustentacular cells positive • Cytokeratin: positive and negative staining reported • S-­100: variably positive sustentacular cells; tumor cells often positive • MIB-­1 index: low 

Other Techniques for Diagnosis • Electron microscopy: cytoplasmic dense core secretory granules and intermediate filaments • Cytogenetics •  Associated with mutations in succinic dehydrogenase genes (part of mitochondrial complex II), tumor suppressor genes TMEM127 and MAX • Associated with the following autosomal dominant syndromes: von Hippel-­Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN2), and neurofibromatosis type 1 (NF1) 

Differential Diagnosis Schwannoma  • Characteristic Antoni A and B tissue without nesting pattern • Synaptophysin and chromogranin negative while diffusely S100 positive

Meningioma  • Usually whorls; no nesting pattern • EMA, progesterone receptor, and somatostatin receptor type IIA (SSTR2A) positive  Ependymoma  • GFAP positive • Fibrillary pattern with perivascular pseudorosettes and ependymal rosettes  Metastatic Carcinoma  • Cytologically anaplastic, lacking organoid pattern of uniform cells • Not encapsulated PEARLS • • • •

 ost are slow growing and curable with complete resection M Recurrence may occur with subtotal resection Subarachnoid space dissemination reported Morphologic criteria to distinguish between benign and aggressive tumors not described • Multiple paragangliomas or association with other neoplasms suggest a genetic syndrome

Selected References Brandner S, Soffer D, Stratakis CA, et al. Paraganglioma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:164–167. Gutenberg A, Wegner C, Pilgram-­Pastor SM, et al. Paraganglioma of the filum terminale: review and report of the first case analyzed by CGH. Clin Neuropathol. 2010;29. 227–232. Miliaras GC, Kyritsis AP, Polyzoidis KS. Cauda equina paraganglioma: a review. J Neuro Oncol. 2003;65:177–190.

EMBRYONAL TUMORS MEDULLOBLASTOMA (WHO GRADE IV) Clinical Features • Malignant neoplasm of cerebellum composed of progenitor neuroepithelial cells •  Symptoms include signs of cerebellar dysfunction (gait abnormalities, ataxia) or increased intracranial pressure • Molecular classification is essential to determine prognosis and appropriate treatment • Four major groups of medulloblastoma have been identified based upon molecular profiling (Table 19.1) • Overall survival rate is 70% after 5 years 

Gross Pathology • Overall, most occur in cerebellar parenchyma and may bulge into or fill the fourth ventricle • Classic medulloblastomas and medulloblastomas with extensive nodularity are more often in the vermis; desmoplastic/nodular medulloblastomas occur in either vermis or hemisphere, but most hemispheric medulloblastomas are desmoplastic/nodular •  Solid, variably demarcated (from well to poorly defined), homogeneous mass 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

1037

TABLE 19.1   CHARACTERISTICS OF THE MAJOR GROUPS OF MEDULLOBLASTOMA Genetic Profile of Medulloblastoma

Age at Presentation

WNT-­activated

Histology

Immunohistochemical Profile

Childhood (mean age 10 years) and young adults

Classic; rarely large cell/ anaplastic

SHH-­activated, TP53-­wildtype

Infancy, adulthood

SHH-­activated, TP53-­mutant

Childhood

All desmoplastic/nodular and extensive nodularity types and any other variant Any variant, often large cell/anaplastic

Group 3: non-­ WNT/non-­SHH

Infancy, childhood

Classic or large cell/ anaplastic

Group 4: non-­ WNT/non-­SHH

All ages

Classic or rarely large cell/anaplastic

GAB1-­negative; β-­catenin-­positive nuclear and cytoplasmic; filamin A-­positive cytoplasmic; YAP1-­positive nuclear and cytoplasmic GAB1-­positive cytoplasmic; β-­catenin-­ positive cytoplasmic; filamin A-­positive cytoplasmic; YAP1-­positive cytoplasmic and nuclear GAB1-­positive cytoplasmic; β-­catenin-­ positive cytoplasmic; filamin A-­positive cytoplasmic; YAP1-­positive cytoplasmic and nuclear GAB1-­negative; β-­catenin-­positive cytoplasmic; filamin A-­negative; YAP1-­ negative GAB1-­negative; β-­catenin-­positive cytoplasmic; filamin A-­negative; YAP1-­ negative

Common Genetic Abnormalities CTNNB1, DDX3X, SMARCA4, and TP53 mutations, monosomy 6 PTCH1 deletion or mutation, SMO or SUFU mutations, TERT promoter mutation, 10q loss TP53 mutation; MYCN, GLI2, or SHH amplification, 17p loss MYC amplification, isodicentric 17q, PVT1-­MYC, GFl1/ GFL1B structural variants MYCN amplification, isodicentric 17q, KDM6A, GFl1/GFL1B structural variants

Histopathology •  Four morphologic patterns are seen: classic, desmoplastic/nodular, extensive nodularity, and large cell/ anaplastic • See Table 19.1 for association of histologic subtypes with specific molecular categories • Classic medulloblastoma •  Highly cellular tumor composed of small round/ carrot-­shaped undifferentiated cells with mild/moderate nuclear pleomorphism, and minimal cytoplasm (Figure 19.11) • Homer Wright rosettes, single-­file streaming, or palisading of tumor cells may be seen • High mitotic rate, apoptotic bodies, and necrosis are common • Desmoplastic/nodular medulloblastoma • Pale nodular areas lacking reticulin are surrounded by hypercellular sheets containing abundant reticulin • Nodules contain cells with varying degrees of neuronal maturation, lower mitotic rate, often neuropil-­ like background • Surrounding cells are more primitive and have high mitotic rates • Medulloblastoma with extensive nodularity • Large pale areas composed of neurocytic cells, often with a streaming pattern, low mitotic rate, and reticulin-­free neuropil • Interlobular component is reticulin rich, hypercellular, and mitotically active • Large cell and anaplastic medulloblastoma •  Anaplastic changes are the presence of marked nuclear pleomorphism, cell wrapping and molding, high mitotic and MIB-­1 indexes, and abundant apoptosis •  Large cell changes are defined by cells with large round nuclei with prominent nucleoli, abundant mitoses, and apoptosis • Often, both large cells and anaplastic changes are found in the same neoplasm

Figure 19.11  Medulloblastoma. Highly cellular tumor, spreading in the subarachnoid space, composed of small cells with carrot-­shaped nuclei and indistinct cytoplasm forming Homer Wright rosettes.

• Rare morphologic variants of medulloblastoma: • Medulloblastoma with myogenic differentiation •  Spindle cells with rhabdomyoblastic differentiation are present • Medulloblastoma with melanotic differentiation • Contains cells with melanin pigment •  May also see ill-­ defined tubules or papillary formations 

Special Stains and Immunohistochemistry • Classic medulloblastoma: most are synaptophysin and Neu-­N positive, usually positive for other markers of neural differentiation (MAP2, NCAM, and NSE), and may show scattered GFAP positive cells •  Desmoplastic/nodular medulloblastoma and medulloblastoma with extensive nodularity: pale nodules contain cells positive for neuronal markers (synaptophysin, NeuN); pale islands positive for neurofilament;

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1038

Chapter 19  —  Central Nervous System

MIB-­1 immunoreactivity is higher in the internodular areas • Large cell/anaplastic medulloblastoma: neoplastic cells frequently positive for synaptophysin and less frequently for NeuN • Medulloblastoma with myogenic differentiation: positive for muscle markers (desmin, actin, myoglobin) • Medulloblastoma with melanotic differentiation: positive for melanocytic markers • Molecular subtype specific immunohistochemistry: see Table 19.1 

Lymphoma and Leukemia  • History of lymphoma and leukemia is often known • Lack nodular architecture and rosette formation • Neoplastic infiltrate is positive for LCA (CD45) and, if B-­cell type, CD20, and negative for markers of neuronal differentiation 

Other Techniques for Diagnosis

PEARLS

• Electron microscopy: undifferentiated neuroepithelial cells with scant cytoplasm and few organelles; may show prominent cytoplasmic processes; more differentiated neoplasms have microtubules, dense core vesicles, and synapses •  Four distinct molecular subtypes of medulloblastoma have been described with distinct clinical, prog­ nostic, and immunohistochemical characteristics. See Table 19.1 

Differential Diagnosis Embryonal Tumor with Multilayered Rosettes  • Multilayered true rosettes with slitlike lumens • LIN28a immunohistochemistry positive • Amplification or fusion of C19MC locus  Atypical Teratoid/Rhabdoid Tumor  • Usually in children younger than 2 years • Presence of rhabdoid cells •  Unique immunohistochemical profile positive for EMA, vimentin, smooth muscle actin (SMA), cytokeratin, and synaptophysin; negative INI1 protein antibody • hSNF5/INI1 deletion or mutation (found in 85%)  Peripheral Primitive Neuroectodermal Tumor and Extraosseous Ewing Sarcoma of the Craniospinal Vault  • Morphologically indistinguishable from medulloblastoma and supratentorial embryonal neoplasms • CD99: membranous staining • EWS-­FLI1 fusion gene detectable by FISH  Ependymoma  • Generally, less cellular, and cells have more cytoplasm (fibrillary); infrequent mitotic activity •  Form perivascular pseudorosettes and ependymal rosettes • GFAP positive • Synaptophysin negative  Pilocytic Astrocytoma  • Similar location and age range but different morphology • Less cellular tumor consisting of biphasic pattern with elongated astrocytic areas (piloid) and a microcystic architecture • GFAP diffusely positive • Synaptophysin negative • Duplication of 7q34 encompassing BRAF gene resulting in fusion between KIAA1549 and BRAF (>70%) 

Metastatic Neuroendocrine Carcinoma  • Typically found in older individuals • Lacks rosette formation • Positive for cytokeratin

• P  ropensity for leptomeningeal dissemination and spinal drop metastases • Surgical resection followed by craniospinal radiation and chemotherapy is the typical treatment

Selected References Ellison DW, Dalton J, Kocak M, et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-­SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121:381–396. Ellison DW, Eberhart CG, Pietsch T, et al. Medulloblastoma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:184–200. Giangaspero F, Wellek S, Masuoka J, et al. Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol. 2006;112:5–12. Juraschka K, Taylor MD. Medulloblastoma in the age of molecular subgroups: a review. J Neurosurg Pediatr. 2019;24:353–363. Kazmi SA, Perry A, Pressey JG, et al. Primary Ewing sarcoma of the brain: a case report and literature review. Diagn Mol Pathol. 2007;16:108–111. McLendon R, Adekunle A, Rajaram V, et al. Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study. Arch Pathol Lab Med. 2011;135:984–993. Min HS, Lee YJ, Park K, et al. Medulloblastoma: histopathologic and molecular markers of anaplasia and biologic behavior. Acta Neuropathol. 2006;112:13–20. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29:1408–1414. Pfister SM, Korshunov A, Kool M, et al. Molecular diagnostics of CNS embryonal tumors. Acta Neuropathol. 2010;120:553–566. Phillips J, Tihan T, Fuller G. Practical molecular pathology and histopathology of embryonal tumors. Surgical Pathol. 2015;8:73–88. Pickles JC, Hawkins C, Pietsch T, et al. CNS embryonal tumours: WHO 2016 and beyond. Neuropathol Appl Neurobiol. 2018;44:151–162.

OTHER CNS EMBRYONAL TUMORS (EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES, C19MC-­ALTERED AND NOS, MEDULLOEPITHELIOMA, CNS NEUROBLASTOMA, CNS GANGLIONEUROBLASTOMA, CNS EMBRYONAL TUMOR NOS) (WHO GRADE IV) • Recent molecular analysis of three types of embryonal tumors (embryonal tumor with abundant neuropil and true rosettes, ependymoblastoma, and medulloepithelioma) discovered the same genetic signatures in all three (C19MC amplification miRNA cluster at 19q13.42). Embryonal tumor with multilayered rosettes (ETMR) is the general name applied now to all three and to any embryonal neoplasm with C19MC amplification/fusion regardless of specific morphology. Rarely, both ETMR and medulloepithelioma

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

have been described without C19MC alterations and remain distinct entities with “not otherwise specified” (NOS) appended to ETMR neoplasms of this type. CNS neuroblastoma, CNS ganglioneuroblastoma, and CNS embryonal tumor NOS are a group of rare embryonal neoplasms for which specific morphologic features or genetic abnormalities have not been identified thus far and are described here

Clinical Features • ETMR, C19MC-­altered • Occur in cerebrum in 70% and cerebellum or brainstem in 30% • Occur in children less than 4 years of age; most often less than 2 years old • Presentation with signs and symptoms of increased intracranial pressure are common • Imaging shows large masses with cysts and/or calcifications and contrast enhancement •  Other embryonal tumors (medulloepithelioma, CNS neuroblastoma, ganglioneuroblastoma, and embryonal tumor, NOS) •  These occur most frequently in children (rarely adults) in the cerebral hemispheres and uncommonly in brainstem or spinal cord • Signs and symptoms are referable to the site of the mass lesion •  Imaging shows contrast-­ enhancing masses often containing calcification and cystic or necrotic areas 

Gross Pathology • ETMR: • Appear as a well-­circumscribed, tan-­gray, homogeneous mass, with hemorrhage and necrosis • Small cyst formation and calcification are common •  Leptomeningeal dissemination is common at late stage • Other embryonal tumors • Variable circumscription, solid or cystic, commonly with hemorrhage and necrosis 

Histopathology ETMR, C19MC-­altered •  Commonly found histologic feature is multilayered true rosettes • Rosettes are frequent, but not always present and may be inconspicuous • Characterized by round or slitlike lumen • Three histologic patterns: • Embryonal tumor with abundant neuropil and true rosettes: hypercellular areas (containing small cells with hyperchromatic round/oval nuclei and scant cytoplasm) alternating with hypocellular areas composed of a fibrillary matrix similar to neuropil; these areas may contain neurocytic cells, ganglion cells, or calcifications; mitoses are usually seen and necrosis may be present •  Ependymoblastoma: sheets of small cells with numerous multilayered rosettes; no fibrillary neuropil or ganglion cell components • Medulloepithelioma: sheets of small undifferentiated cells with multilayered rosettes and areas of papillary

1039

and tubular structures reminiscent of primitive neural tube Other embryonal tumors • Medulloepithelioma •  Neural tubelike structures composed of primitive cells and pseudostratified epithelium arranged in tubular, papillary, or trabecular architecture • Neuroblastoma •  Primitive embryonal cells alternating with foci of cells with neurocytic (larger nuclei and distinct cytoplasm) morphology, varying amounts of neuropil background, Homer Wright rosettes, and palisades • Ganglioneuroblastoma • Primitive embryonal cells and clusters of cells with neurocytic and ganglionic differentiation (large nuclei, nucleoli, abundant cytoplasm), Homer Wright rosettes, and palisades • Embryonal tumor, NOS •  Primitive embryonal cells, high nuclear/cytoplasmic ratios, Homer Wright rosettes, mitoses, necrosis, calcification 

Special Stains and Immunohistochemistry Embryonal Tumor with Multilayered Rosettes  • LIN28A immunohistochemistry positive • Nestin, vimentin, and INI1 positive • May show focal expression of cytokeratins, CD99, and EMA • Usually negative for neuronal and glial markers, but neuropil-­ like areas are synaptophysin and neurofilament positive • MIB-­1: high  Other Embryonal Tumors Ganglioneuroblastoma and Neuroblastoma  • Synaptophysin and S-­100 positive • NSE and neurofilament positive • GFAP and cytokeratin negative • MIB-­1 index: markedly variable, 0% to 85%  Medulloepithelioma  • Nestin and vimentin positive • GFAP, EMA, cytokeratin, and NF variably positive Embryonal Tumor, NOS • May show GFAP, synaptophysin, NeuN, or neurofilament positivity • MIB-­1 proliferative index is usually very high 

Other Techniques for Diagnosis • Cytogenetics • ETMR: FISH analysis of 19q13.42 locus: amplifications or fusions of C19MC locus • Medulloepithelioma, CNS neuroblastoma and ganglioneuroblastoma, and embryonal tumor, NOS by definition do not exhibit characteristic and consistent molecular alterations 

Differential Diagnosis Medulloblastoma  • Distinction from posterior fossa ETMR aided by lack of multilayered rosettes with lumens and lack of LIN28A immunoreactivity 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1040

Chapter 19  —  Central Nervous System

Anaplastic Ependymoma  • When supratentorial, C11orf95-­RELA fusion gene present • Perivascular pseudorosettes and GFAP positivity  Central Neurocytoma  • Located within the lateral or third ventricle • Lacks distinct rosette formation • Cells are uniform and have low mitotic activity  Peripheral PNET and Extraosseous Ewing Sarcoma of the Craniospinal Vault  • Morphologically indistinguishable from medulloblastoma and supratentorial PNET • CD99: membranous staining • EWS-­FLI1 fusion gene detectable by FISH  Metastatic Neuroendocrine Carcinoma  • Typically found in older individuals • Lacks rosette formation • Positive for cytokeratin  Desmoplastic Infantile Ganglioglioma  • Large cystic mass in infancy (usually younger than 18 months) • Typically involves frontal and parietal lobes •  Usually involves leptomeninges, prominent collagenous stroma • Divergent differentiation along astrocytic and neuronal lines •  Composed of GFAP-­ positive spindle cells and often inconspicuous ganglion cells  Glioblastoma with Primitive Neuroectodermal Tumor Foci  • Exhibits areas of malignant GFAP positive astrocytoma (variably sized nuclei with pleomorphism and hyperchromatism, often abundant eosinophilic cytoplasm), necrosis with or without pseudopalisading, and endothelial proliferation  Esthesioneuroblastoma (Olfactory Neuroblastoma)  • Occurs most often in the region of the cribriform plate in adults •  Composed of primitive neuroectodermal cells with scant ill-­defined cytoplasm, forming nests or lobules or sheetlike growth; well-­formed rosettes are rare •  Synaptophysin positive; S100 positive sustentacular cells are edges of nests PEARLS • E TMR are aggressive neoplasms and survival is usually approximately 12 months with treatment. Local tumor growth, dissemination, and systemic metastases may occur.

Selected References Eberhart CG, Brat DJ, Cohen KJ, et al. Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol. 2000;3:346–352. Gessi M, Giangaspero F, Lauriola L, et al. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol. 2009;33:211–217.

Korshunov A, McLendon R, Judkins AR, et al. Embryonal tumour with multilayered rosettes, C19MC-­ altered. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:201–208. Korshunov A, Sturm D, Ryzhova M, et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol. 2014;128:279–289. Spence T, Sin-­ Chan P, Picard D, et al. CNS-­ PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol. 2014;128:291–303.

ATYPICAL TERATOID/RHABDOID TUMOR (WHO GRADE IV) Clinical Features • Rare malignant neoplasm occurring most commonly in children younger than 3 years • About 50% of cases occur in the posterior fossa, with a predilection for the cerebellopontine angle; other reported sites include suprasellar region, pineal region, cerebrum, and spinal cord • May be intra-­axial or extra-­axial, with predilection for leptomeningeal dissemination • Symptoms may be nonlocalizing, consisting of lethargy, vomiting, and failure to thrive; in posterior fossa tumors, focal signs are usually cranial nerve palsies 

Gross Pathology • Gray-­white tissue with necrosis and hemorrhage 

Histopathology • Sheets or nests of large cells, each with a round nucleus, prominent nucleolus, plump cell body with homogeneous cytoplasm, or a dense round distinct cytoplasmic inclusion (rhabdoid cells) • Frequently co-­occurrence of foci or sheets of primitive neuroectodermal neoplastic cells, most often a minority component • Epithelial (adenomatous or papillary pattern) or mesenchymal (loosely packed spindle cells) neoplastic components may also be present (about 33%); epithelial component is least common • Abundant mitoses and necrosis • Leptomeningeal spread is common and may be evident on the surface of the cerebellum 

Special Stains and Immunohistochemistry • INI1 negative • EMA, vimentin, and SMA positive • GFAP, synaptophysin, and cytokeratin (high– and low– molecular-­weight cocktail) frequently positive •  Neurofilament, chromogranin, S-­ 100, desmin, and HMB-­45 may be positive • MIB-­1 index: more than 50% 

Other Techniques for Diagnosis • Cytogenetics: Mutation or loss of SMARCB1 locus at 22q11.2 • Rarely, the SMARCB1 locus is intact and SMARCA4 is mutated 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

Differential Diagnosis Cribriform Neuroepithelial Tumor  • Exhibit INI loss by immunohistochemistry and mutation or loss of SMARCB1 • No rhabdoid morphology; small undifferentiated cells with cribriform and papillary growth patterns  Medulloblastoma and Other Embryonal Tumors  • Rhabdoid cells not seen, EMA negative, INI1 positive  Choroid Plexus Carcinoma  •  Not usually in posterior fossa; cytokeratin positive, EMA negative, INI positive PEARLS M •  ean survival time is 10 to 15 months • Presence of rhabdoid cells is not diagnostic of atypical teratoid/rhabdoid tumor • Molecular genetic testing should be performed in all cases • Neoplasms with morphology of atypical teratoid rhabdoid tumor (ATRT but no inactivation of either SMARCB1 or SMARCB4 should be designated as CNS embryonal tumors with rhabdoid features.

Selected References Bambakidis NC, Robinson S, Cohen M, et al. Atypical teratoid/rhabdoid tumors of the central nervous system: clinical, radiographic and pathologic features. Pediatr Neurosurg. 2002;37:64–70. Judkins AR. Immunohistochemistry of INI1 expression: a new tool for old challenges in CNS and soft tissue pathology. Adv Anat Pathol. 2007;14:335–339. Judkins AR, Eberhart CG, Wesseling P, et al. Atypical teratoid/rhabdoid tumour. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016:209–212. Margol AS, Judkins AR. Pathology and diagnosis of SMARCB1-­deficient tumors. Cancer Genet. 2014;207:358–364. Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56–65.

CHOROID PLEXUS TUMORS CHOROID PLEXUS PAPILLOMA (WHO GRADE I), ATYPICAL CHOROID PLEXUS PAPILLOMA (WHO GRADE II), AND CHOROID PLEXUS CARCINOMA (WHO GRADE III) Clinical Features • Choroid plexus papilloma and atypical choroid plexus papilloma (WHO grades I and II) • Slow-­growing benign tumors account for less than 1% of brain tumors overall but constitute 13% of brain tumors occurring in the first year of life •  Characteristically found in the fourth ventricle (40%), lateral ventricle (50%), or third ventricle (5%) or at the cerebellopontine angle •  Commonly found in the first and second decades (50% found before age 20); more often occur in the lateral ventricles when in young individuals and in the fourth ventricle and cerebellopontine angle in adults

1041

• Choroid plexus papilloma grade II (atypical choroid plexus papilloma) is defined histologically (discussed later) • Choroid plexus carcinomas (WHO grade III) • Typically occur in patients younger than 10 years; rare in adults •  Most carcinomas affecting the choroid plexus in adults are metastatic carcinomas • Patients often present with signs and symptoms secondary to hydrocephalus owing to the overproduction of CSF or obstruction 

Gross Pathology • Well-­demarcated, pedunculated, or cauliflower-­like masses • Papillomas do not invade into the adjacent tissue • Carcinomas characteristically invade the surrounding tissue and are often necrotic and hemorrhagic 

Histopathology Choroid Plexus Papilloma (WHO Grade I)  • Papillary architecture is composed of a single orderly layer of columnar cells surrounding a distinct fibrovascular core • A mild degree of nuclear stratification, crowding of the nuclei, focal necrosis, and nuclear atypia may be seen • Stromal calcifications often present; may see metaplastic bone or cartilage • Mitotic activity is typically minimal • Small foci of ependymal differentiation may be seen  Atypical Choroid Plexus Papilloma (WHO Grade II)  • Defined by increase in mitoses (≥2 mitoses/10 hpf) • Hypercellularity, nuclear pleomorphism, solid growth pattern, and necrosis may also be present  Choroid Plexus Carcinoma  • Typically show a loose papillary architecture consisting of sheets of pleomorphic cells •  Extensive necrosis and high mitotic activity (>5 mitoses/hpf) • Brain invasion 

Special Stains and Immunohistochemistry • Cytokeratin 7 and 8 and 18, vimentin positive •  Transthyretin (prealbumin): approximately 80% are positive • KIR7.1 positive in choroid plexus papillomas and atypical choroid plexus papilloma but only approximately 50% of choroid plexus carcinomas • GFAP: papillomas may be focally positive; carcinomas typically negative • EMA variable to negative • Carcinoembryonic antigen (CEA) usually negative • INI1 protein positive •  Synaptophysin, S100, and cytokeratin 20 variable positivity • MIB-­1 index: range in papillomas is 2% to 5%; range in carcinomas is 14% to 18% 

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

1042

Chapter 19  —  Central Nervous System

Other Techniques for Diagnosis •  Electron microscopy: cells of both papillomas and carcinomas typically show cilia, microvilli, basement membrane, and desmosomes • Cytogenetics • Somatic TP53 mutations have been identified in 50% of choroid plexus carcinomas and 5% of choroid plexus papillomas 

Differential Diagnosis Normal Choroid Plexus  • Apical hobnail cuboidal cells instead of crowded, more columnar cells with some atypia are present in normal choroid plexus  Metastatic Carcinoma  • Usually found in older adults • Not usually associated with the ventricle • Typically positive for EMA and often also for CEA • Usually negative for S-­100 protein and GFAP  Ependymoma (Especially Papillary Subtype)  • Intraventricular location is common for both tumors •  Solid nonpapillary areas may be evident with both perivascular pseudorosette and true rosette formation • GFAP positive; usually more diffuse than in choroid plexus neoplasms  Atypical Teratoid and Rhabdoid Tumors  •  Important part of differential diagnosis in children with posterior fossa tumors • Epithelial areas form part, not all, of the neoplasm •  Rhabdoid cells and primitive neuroectodermal cell components are also present • INI1 protein negative  Papillary Endolymphatic Sac Tumor  • Occurs in inner ear and extends to cerebellopontine angle most often in middle age with symptoms of hearing loss and tinnitus • Histologically and immunohistochemically similar to choroid plexus papillomas occurring at cerebellopontine angle • Positive for pan-­cytokeratin, CK7, EMA, S-­100 and variably to GFAP; it is negative with transthyretin antibody and KIR7.1 antibody, which may help in distinction from choroid plexus papilloma PEARLS • G  FAP positivity demonstrates that choroid plexus tumors may show ependymal differentiation • Overall prognosis in surgically resected choroid plexus papilloma is good, but incompletely resected tumors occasionally recur • Leptomeningeal spread may occur in both papillomas and carcinomas but is rare in papillomas • Choroid plexus carcinoma has an overall poor prognosis • Brain invasion and cerebrospinal fluid spread is typically seen • Systemic metastases are rarely seen

Selected References Jeibmann A, Hasselblatt M, Gerss J, et al. Prognostic implications of atypical histologic features in choroid plexus papilloma. J Neuropathol Exp Neurol. 2006;65:1069–1073. Krishnan S, Brown PD, Scheithauer BW, et al. Choroid plexus papillomas: a single institutional experience. J Neuro Oncol. 2004;68:49–55. Paulus W, Janisch W. Clinicopathologic correlations in epithelial choroid plexus neoplasms: a study of 52 cases. Acta Neuropathol. 1990;80(6):635–641. Safaee M, Oh MC, Bloch O. Choroid plexus papillomas: advances in molecular biology and understanding of tumorigenesis. Neuro Oncol. 2013;15:255–267. Schittenhelm J, Roser F, Tatagiba M, et al. Diagnostic value of EAAT-­1 and Kir7.1 for distinguishing endolymphatic sac tumors from choroid plexus tumors. Am J Clin Pathol. 2012;138:85–89.

PINEAL PARENCHYMAL TUMORS PINEOCYTOMA (WHO GRADE I) AND PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION (WHO GRADES II AND III) Clinical Features • Pineocytoma and pineal parenchymal tumors of intermediate differentiation (PPTID) • Rare tumors accounting for less than 1% of all intracranial neoplasms •  Typically occur in adults with slight female predominance • Localized to the region of the pineal gland and surrounding structures; may extend into the third ventricle and compress the colliculi and cerebral aqueduct •  Variable clinical presentations: eye movement abnormalities, mental status changes, and symptoms related to increased intracranial pressure or endocrine abnormalities • In pineocytoma, MRI scan shows a well-­defined mass with homogeneous contrast enhancement, contrast-­ enhancing mass • In PPTID, MRI scan frequently shows local invasion and heterogeneous contrast enhancement 

Gross Pathology • Pineocytoma and PPTID • Well-­circumscribed tumor typically less than 3 cm in diameter • Gray-­tan homogeneous tumor often with small cyst formation • Small areas of hemorrhage may be present • Necrosis is not a typical finding 

Histopathology Pineocytoma  • Sheets of tumor cells without a distinct pattern or an irregular lobular arrangement with large aggregates of tumor cells separated by fibrous septa • Small and uniform cells with hyperchromatic nuclei, finely granular chromatin, inconspicuous nucleoli, and eosinophilic cytoplasmic processes

Downloaded for Anonymous User (n/a) at Egyptian Knowledge Bank from ClinicalKey.com by Elsevier on March 23, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Chapter 19  —  Central Nervous System

• Forms large (pineocytomatous) rosettes with abundant fibrillary cell processes in the center, sometimes with cytoplasmic club-­shaped terminal expansion; may or may not be centered around blood vessels • Calcification may be present • Ganglion cells, gangliocytic differentiation, and multinucleated giant cells are occasionally seen • Mitotic activity is minimal, and necrosis is not seen  Pineal Parenchymal Tumor of Intermediate Differentiation  •  Diffuse or lobulated tumors of moderate to high cellularity • Mild to moderate nuclear atypia, with less cytoplasm than typically seen in pineocytomas, sparse to moderately frequent mitoses •  Histologic criteria separating WHO grades II and III have not been defined 

Special Stains and Immunohistochemistry •  Synaptophysin, chromogranin, neurofilament, NSE, and S-­100 protein positive • Retinal S antigen and rhodopsin positive • GFAP highlights background residual reactive astrocytes • MIB-­1 labeling index • Pineocytoma: average is