Gnepp's Diagnostic Surgical Pathology of the Head and Neck [Third ed.] 9780323531146, 2020933828, 9780323547802, 9780323547819

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck Third Edition Douglas R. Gnepp, MD, MS Former Professor of Pathology Warren Alpert Medical School at Brown University Providence, Rhode Island United States

Justin A. Bishop, MD Professor and Director of Anatomic Pathology Jane B. and Edwin P. Jenevein M.D. Chair in Pathology UT Southwestern Medical Center Dallas, Texas United States

GNEPP’S DIAGNOSTIC SURGICAL PATHOLOGY OF THE HEAD AND NECK, THIRD EDITION    ISBN: 978-0-323-53114-6 © 2021, Elsevier Inc. All rights reserved. First edition 2001 Second edition 2009

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

Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Control Number: 2020933828

Content Strategist: Michael Houston Content Development Specialist: Kim Benson Publishing Services Manager: Shereen Jameel Project Manager: Umarani Natarajan Design: Amy Buxton Illustration Manager: Muthukumaran Thangaraj Marketing Manager: Claire McKenzie Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

CONTENTS

Preface vi

8 Bone Lesions  689 GILLIAN HALL AND JOHN WRIGHT

Acknowledgments vii List of Contributors  viii Abbreviations Used in Text  x

1 Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract  1

EDWARD ODELL, NINA GALE, SELVAM THAVARAJ, ALFONS NADAL, NINA ZIDAR, AND DOUGLAS R. GNEPP

2 Squamous Cell Carcinoma of the Upper Aerodigestive System  63 MARY S. RICHARDSON AND MARK WILLIAM LINGEN

3 Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx  126 ALESSANDRO FRANCHI AND JUSTIN A. BISHOP

4 Lesions of the Oral Cavity  188 LINDSAY MONTAGUE, ASHLEY CLARK, AND JERRY ELMER BOUQUOT

5 Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea  320 SILVANA DI PALMA, ANN SANDISON, NINA ZIDAR, AND DOUGLAS R. GNEPP

6 Salivary Glands  432 DOUGLAS R. GNEPP, ALENA SKALOVA, SILVANA DI PALMA, RODERICK H.W. SIMPSON, TOSHITAKA NAGAO, AND ELIZABETH ANN BILODEAU

7 Thyroid and Parathyroid Glands  606

9 Soft-Tissue Tumors of the Head and Neck  743 ANDREW L. FOLPE AND JUSTIN A. BISHOP

10 Odontogenic Cysts and Tumors  827 VICTORIA L. WOO, ANGELA C. CHI, AND BRAD W. NEVILLE

11 Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection  881

MITRA MEHRAD AND DOUGLAS R. GNEPP

12 Ear: External, Middle, and Temporal Bone  927 DIANA BELL

13 Benign and Malignant Hematopoietic Diseases of the Head and Neck  973 PEI LIN AND L. JEFFREY MEDEIROS

14 Cutaneous Tumors and Pseudotumors of the Head and Neck  1012 MARK ROBERT WICK

15 Pathology of the Conjunctiva, Orbit, Lacrimal Gland, and Intraocular Tumors  1098 NORA MARINA V. LAVER

APPENDIX: Guidelines for the Dissection of Head and Neck Specimens  1151 DOUGLAS R. GNEPP

Index 1161

REBECCA CHERNOCK AND MICHELLE D. WILLIAMS

v

PREFACE

The region of the head and neck is one of the most complex areas of the body from anatomic and pathologic perspectives, with a variety of different organ systems and tissue types within its domain. This new edition of Diagnostic Surgical Pathology of the Head and Neck includes the many recent advances in head and neck pathology, particularly in the molecular characterization of many of the lesions arising in this region. The general organization of the text has remained unchanged. To minimize redundancy throughout the various chapters, we have integrated the precancerous lesions from all mucosal sites in one chapter, the mucosal squamous carcinomas in another chapter, and the nonsquamous cancers and other lesions on a regional basis in individual chapters. In addition, there are separate chapters covering bone, soft tissue, hematopoietic diseases, and skin lesions that have a predilection for the head and neck. Instead of dedicating a chapter to molecular pathology, we have elected to incorporate the relevant molecular information within each chapter, under the appropriate topics. Also, the cytology chapter has been replaced by a chapter on major diseases of the conjunctiva, orbit, lacrimal gland, and intraocular

vi

tumors. Color pictures have again been integrated throughout this text; all photomicrographs are of hematoxylin-­eosin stained glass slides, except where otherwise indicated. The appendix illustrating grossing techniques from the last edition has been included as well. In addition, I have added Justin Bishop, one of the most distinguished head and neck pathologists of the next generation, to be a coeditor. This volume has greatly benefited from his added expertise. The purpose of this text is the same as the previous editions: to provide a comprehensive textbook that covers the full range of head and neck surgical pathology, again emphasizing differential diagnosis and more problematic areas. Our hope is that this text will help the surgical or oral pathologist when dealing with a difficult case, as well as to provide an in-­depth reference for the surgical pathologist, oral pathologist, head and neck or oral surgeon, the general otolaryngologist or dentist, or for anyone interested in reviewing head and neck pathology. It has always been an important goal, to share our experience and knowledge with other clinicians. I hope we have accomplished it.

ACKNOWLEDGMENTS

We would like to thank all the authors, including authors of previous editions, for their excellent contributions. I would like to thank my incredible family for their understanding and patience during the long hours spent preparing this edition, especially my wife, Diane, my children, Ethan, Ari, and Stella, and my two grandchildren, Max and Ian, who all supported me throughout this project. Lastly, I thank “my best friend,” our dog Gracie Anne, and dedicate this volume to her memory. Gracie kept me company throughout the process and encouraged me with her steadfast presence, wagging tail, and constant smile.

I thank my amazing wife Ashley and my wonderful children Riley, Avery, and Rory for allowing me to sacrifice the time needed to work on this book. Finally, I offer my sincerest appreciation and admiration to Doug Gnepp, one of the giants in the field of head and neck pathology. It is one of my proudest professional honors to be associated with the gold-standard head and neck pathology text that now bears your name. Justin A. Bishop, MD

Douglas R. Gnepp, MD, MS

vii

LIST OF CONTRIBUTORS

The editors would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors without whom this new edition would not have been possible.

Diana Bell, MD

Associate Professor Department of Pathology/Head and Neck Surgery University of Texas-MD Anderson Cancer Center Houston, TX, United States

Elizabeth Ann Bilodeau, DMD, MD, MSEd Associate Professor Department of Diagnostic Sciences University of Pittsburgh, School of Dental Medicine Pittsburgh, PA, United States

Justin A. Bishop, MD

Professor and Director of Anatomic Pathology Jane B. and Edwin P. Jenevein M.D. Chair in Pathology UT Southwestern Medical Center Dallas, TX, United States

Jerry Elmer Bouquot, DDS, MSD, DABOMP, DABOM (Hon), FICD, FACD Emeritus Professor & Past Chair Department of Diagnostic & Biomedical Sciences University of Texas School of Dentistry at Houston Houston, TX, United States Adjunct Professor & Past Chair Department of Diagnostic Sciences West Virginia University School of Dentistry Morgantown, WV, United States Director of Research Maxillofacial Center for Education & Research Morgantown, WV, United States

Rebecca Chernock, MD

Associate Professor Department of Pathology and Otolaryngology Washington University School of Medicine St. Louis, MO, United States

Angela C. Chi, DMD

Professor Department of Stomatology Medical University of South Carolina Charleston, SC, United States

Ashley Clark, DDS, DABOMP

Associate Professor Department of Diagnostic and Biomedical Sciences University of Texas at Houston Houston, TX, United States

viii

Silvana Di Palma, MD

Professor Division of Clinical Medicine University of Surrey Department of Histopathology Royal Surrey County Hospital Guildford, Surrey, United Kingdom

Andrew L. Folpe, MD

Professor of Laboratory Medicine and Pathology Department of Anatomic Pathology Mayo Clinic Rochester, MS, United States

Alessandro Franchi, MD

Professor Department of Translational Research University of Pisa Pisa, Italy

Nina Gale, MD, PhD Professor Emeritus Institute of Pathology Faculty of Medicine University of Ljubljana Ljubljana, Slovenia

Douglas R. Gnepp, MD, MS

Former Professor of Pathology Warren Alpert Medical School at Brown University Providence, RI, United States

Gillian Hall, BDS (Hons), FRCPath Consultant Head and Neck Pathologist Department of Head and Neck Pathology Guy’s and St Thomas’ NHS Trust London, United Kingdom

Nora Marina V. Laver, MD

Director, Ocular Pathology Laboratory Departments of Ophthalmology and Pathology and Laboratory Medicine Tufts Medical Center Boston, MA, United States

Pei Lin, MD

Professor Department of Hematopathology University of Texas-MD Anderson Cancer Center Houston, TX, United States

Mark William Lingen, DDS, PhD, FRCPath Professor Department of Pathology University of Chicago Chicago, IL, United States

List of Contributors

L. Jeffrey Medeiros, MD

Ann Sandison, MD

Mitra Mehrad, MD

Roderick H.W. Simpson

Lindsay Montague, DMD, DABOMP

Alena Skalova, MD, PhD

Adjunct Clinical Assistant Professor School of Dentistry University of Mississippi Medical Center Jackson, MS, United States

Selvam Thavaraj, BDS, PhD, FDSRCS, FRCPath

Professor and Chair Department of Hematopathology University of Texas-MD Anderson Cancer Center Houston, TX, United States Assistant Professor Department of Pathology, Microbiology and Immunology Vanderbilt University School of Medicine Nashville, TN, United States Adjunct Clinical Assistant Professor School of Dental Medicine Lake Erie College of Osteopathic Medicine Bradenton, FL, United States

Alfons Nadal, PhD, MD

Adjunct Medical Lecturer Department of Basic Clinical Practice University of Barcelona Barcelona, Spain

Toshitaka Nagao, MD, PhD

Professor and Chairman Department of Anatomic Pathology Tokyo Medical University Tokyo, Japan

Brad W. Neville, DDS

Distinguished University Professor Department of Stomatology Medical University of South Carolina Charleston, SC, United States

Edward Odell, BDS, FDS, MSc, PhD, FRCPath Professor of Oral Pathology and Medicine Department of Head and Neck/Oral Pathology King’s College London/Guy’s and St Thomas’ NHS Foundation Trust London, United Kingdom

Mary S. Richardson, MD, DDS Vice Chair for Clinical Affairs Director, Surgical Pathology Medical University of South Carolina Charleston, SC, United States Professor Department of Pathology Medical University of South Carolina Charleston, SC, United States

ix

Honorary Senior Lecturer Guy’s & St Thomas’ NHS Foundation Trust Kings College London, United Kingdom Professor of Pathology Department of Anatomical Pathology University of Calgary Calgary, AB, Canada Professor of Pathology Department of Pathology Charles University, Faculty of Medicine in Plzen Plzen, Czech Republic Senior Lecturer/Honorary Consultant Department of Head and Neck/Oral Pathology King’s College London/Guy’s and St Thomas’ NHS Foundation Trust London, United Kingdom

Mark Robert Wick, MD

Professor Department of Pathology University of Virginia Health System Charlottesville, VA, United States

Michelle D. Williams, MD

Professor Department of Pathology University of Texas-MD Anderson Cancer Center Houston, TX, United States

Victoria L. Woo, DDS

Professor Department of Biomedical Sciences University of Nevada Las Vegas, NV, United States

John Wright, DDS, MS

Regents Professor and Head Department of Diagnostic Sciences Texas A&M University College of Dentistry Houston, TX, United States

Nina Zidar, MD, PhD Professor Institute of Pathology Faculty of Medicine University of Ljubljana Ljubljana, Slovenia

ABBREVIATIONS USED IN TEXT

ABC  aneurysmal bone cyst AC  anaplastic carcinoma ACC  acinic cell carcinoma AciCC  acinic cell carcinoma AdCC  adenoid cystic carcinoma ADSC  adenosquamous carcinoma AFH  angiomatoid fibrous histiocytoma AFIP  Armed Forces Institute of Pathology AFX  atypical fibroxanthoma AgNOR  argyrophilic nucleolar organizer regions AIDS  acquired immunodeficiency syndrome AK  alveolar keratosis ALCL  anaplastic large cell lymphoma ALHE  angiolymphoid hyperplasia with eosinophilia ALT  atypical lipomatous tumor ANCAs  antineutrophilic cytoplasmic antibodies AOLP  adult-­onset laryngeal papillomatosis APMET  aggressive papillary middle ear tumor ARM  adult rhabdomyoma ARMS  alveolar rhabdomyosarcoma ARPC  AIDS-­related parotid cyst ASC  adenoid squamous carcinoma ASCC  adenoid squamous cell carcinoma ASPS  alveolar soft-­part sarcoma BCA  basal cell adenoma BCAC  basal cell adenocarcinoma BFH  benign fibrous histiocytoma BLEL  benign lymphoepithelial lesion BMT  benign mixed tumor BSC  basaloid squamous carcinoma BSCC  basaloid squamous cell carcinoma Ca-­ex-­PA  carcinoma ex pleomorphic adenoma CAT  cribriform adenocarcinoma of the tongue cBFH  cellular variant of benign fibrous histiocytoma CCC  clear cell carcinoma CEA  carcinoembryonic antigen CIS  carcinoma in situ CK cytokeratin CMV cytomegalovirus COF  cementoossifying fibroma CT  computed tomography DEC  ductal eccrine carcinoma DFS  desmoid-­type fibromatosis DFSP  dermatofibrosarcoma protuberans DL  dedifferentiated liposarcoma DLBCL  diffuse large B-­cell lymphoma DSCC  desmoplastic squamous cell carcinoma DTE  desmoplastic trichoepithelioma EAF  eosinophilic angiocentric fibrosis EBV  Epstein-­Barr virus ECS  ectopic hamartomatous thymoma ECT  ectomesenchymal chondromyxoid tumor of the anterior

tongue

EFT  Ewing family of tumors EGFR  epidermal growth factor receptor EH  epithelioid hemangioendothelioma EHT  ectopic hamartomatous thymoma

x

ELS  endolymphatic sac EMA  epithelial membrane antigen EMC  epithelial-­myoepithelial carcinoma EMP  extramedullary plasmacytoma ERMS  embryonal rhabdomyosarcoma ESMC  extraskeletal myxoid chondrosarcoma ES/PNET  Ewing’s sarcoma/primitive neuroectodermal tumor FCOD  florid cementoosseous dysplasia FD  fibrous dysplasia FNA  fine-­needle aspiration FRM  fetal rhabdomyoma FVPTC  follicular variant of papillary thyroid carcinoma GCF  giant cell fibroblastoma GCT  giant cell tumor GERD  gastrointestinal reflux disease GFAP  glial fibrillary acidic protein GMS  Gomori methenamine silver HCCC  hyalinizing clear cell carcinoma H&E  hematoxylin and eosin HHV  human herpesvirus HIV  human immunodeficiency virus HNSCC  head and neck squamous cell carcinoma HPC hemangiopericytoma HPV  human papillomavirus HSV  herpes simplex virus HT  Hashimoto’s thyroiditis HTA  hyalinizing trabecular adenoma Ig immunoglobulin IHC immunohistochemistry IM  infectious mononucleosis IMFT  inflammatory myofibroblastic tumor ITAC  intestinal-­type adenocarcinoma IVL  intravascular lymphomatosis JOLP  juvenile-­onset laryngeal papillomatosis kD kilodalton KFD  Kikuchi-­Fujimoto disease KHE  kaposiform hemiangioendothelioma KS  Kaposi’s sarcoma LCC  large cell carcinoma LCG  Langerhans cell granulomatosis LCH  Langerhans cell histiocytosis LCS  laryngeal chondrosarcoma LE  lupus erythematosus LEC  lymphoepithelial carcinoma LESA  lymphoepithelial sialadenitis LGSDC  low-­grade salivary duct carcinoma LMS leiomyosarcoma LOH  loss of heterozygosity LOS  laryngeal osteosarcoma MAC  microcystic adnexal carcinoma MALT  mucosa-­associated lymphoid tissue MC  mesenchymal chondrosarcoma MCs  medullary carcinoma MDNEC  moderately differentiated neuroendocrine

carcinoma

MEC  mucoepidermoid carcinoma MEN  multiple endocrine neoplasia

Abbreviations Used in Text

MESA  myoepithelial sialadenitis MF  mycosis fungoides MFH  malignant fibrous histiocytoma MGC  multinucleated giant cell MGCT  malignant cutaneous granular cell tumor MM  malignant melanoma MPNST  malignant peripheral nerve sheath tumor MS  myeloid sarcoma MSI  microsatellite instability MSS  monophasic synovial sarcoma MTB  Mycobacterium tuberculosis Nd:YAG  neodymium-­yttrium-­aluminum garnet NEC  neuroendocrine carcinoma NF neurofibromatosis NF-­1  neurofibromatosis type 1 NHL  non-­Hodgkin’s lymphoma NICO  neuralgia-­inducing cavitational osteonecrosis NK  natural killer NOS  not otherwise specified NPC  nasopharyngeal carcinoma NPDC  nasopalatine duct cyst NSM  necrotizing sialometaplasia OFMT  ossifying fibromyxoid tumor of soft parts ONB  olfactory neuroblastoma PA  pleomorphic adenoma PAS  periodic acid-­Schiff PBL  plasmablastic lymphoma PDNEC  poorly differentiated neuroendocrine carcinoma PDSS  poorly differentiated synovial sarcoma PEA  papillary endovascular angioendothelioma PEH  papillary endothelial hyperplasia PEN  palisaded encapsulated neuroma PFH  plexiform fibrous histiocytoma PL  pleomorphic lipoma PLGA  polymorphous low-­grade adenocarcinoma PMTMCT  phosphaturic mesenchymal tumor, mixed

­connective tissue type

PNCS  primary neuroendocrine carcinoma of the skin POF  peripheral ossifying fibroma PPAR  peroxisome proliferator–activated receptor PPT  proliferating pilar tumor PRM  pleomorphic rhabdomyosarcoma PsJOF  psammomatoid juvenile ossifying fibroma PSCC  papillary squamous cell carcinoma PT parathyroid PTC  papillary thyroid carcinoma

PTN  parathyroid hormone PVL  proliferative verrucous leukoplakia RA  rheumatoid arthritis RMS rhabdomyosarcoma RPC  relapsing polychondritis SANS  subacute necrotizing sialadenitis SC  sebaceous carcinoma SCC  squamous cell carcinoma SCCIS  squamous cell carcinoma in situ SCEC  small cell (neuro)endocrine carcinoma SCL  spindle cell lipoma SDC  salivary duct carcinoma SEC  superficial extending carcinoma SFT  solitary fibrous tumor SHML  sinus histiocytosis with massive lymphadenopathy SIN  squamous intraepithelial neoplasia SL  sebaceous lymphadenoma SLN  sentinel lymph node SmCC  small cell carcinoma SND  selective neck dissection SNEC  small cell neuroendocrine carcinoma SNUC  sinonasal undifferentiated carcinoma SpCC  spindle cell carcinoma SS  Sjögren’s syndrome T3 triiodothyronine T4 thyroxine TCO  tracheopathia chondroosteoplastica TCVPTC  tall cell variant of papillary thyroid carcinoma TDC  thyroglossal duct cyst TFL  tumefactive fibroinflammatory lesion TIA-­1  T-­cell intracellular antigen-­1 TL  tuberculoid leprosy TrJOF  trabecular juvenile ossifying fibroma TSG  tumor suppressor gene TSH  thyroid-­stimulating hormone TTF  thyroid transcription factor TUGSE  traumatic ulcerative granuloma with stromal

­eosinophilia

UADT  upper aerodigestive tract VC  verrucous carcinoma vHL  von Hippel-­Lindau disease WDL  well-­differentiated liposarcoma WDNEC  well-­differentiated neuroendocrine carcinoma WG  Wegener’s granulomatosis WHO  World Health Organization

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Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract EDWARD ODELL | NINA GALE | SELVAM THAVARAJ |  ALFONS NADAL  |  NINA ZIDAR  |  DOUGLAS R. GNEPP

General Introduction There is considerable literature on all aspects of precursor lesions for squamous cell carcinoma of the upper aerodigestive tract (UADT). Most data are specific to oral and laryngeal lesions. A common feature of all these precursor lesions, irrespective of their site of origin, is histological evidence of progressive and cumulative epithelial genetic and epigenetic alterations induced by exposure to carcinogens, particularly tobacco and alcohol, and in some cases human papillomavirus (HPV) or Epstein-­ Barr virus (EBV) infection, gastroesophageal reflux disease (GERD), and other detrimental agents.1–13 This chapter provides a brief history and reviews current understanding of precursor lesions in the head and neck, in two parts. The first section is devoted to intraepithelial changes of the oral cavity, oropharynx, and sinonasal tract, and the second the same lesions of the larynx and hypopharynx. Oral precursor lesions are more diverse and are clinically termed oral potentially malignant disorders, though there is also a risk of cancer development in clinically normal epithelium. Oral, laryngeal and hypopharyngeal lesions are classified histologically as dysplasia, which constitutes a spectrum of architectural and cytological epithelial changes, caused by an accumulation of genetic changes that can be associated with an increased likelihood of progression to squamous cell carcinoma (SCC). Although tobacco and alcohol use remain the most important etiological factors in head and neck carcinogenesis, high-­ risk HPV subtypes have also been implicated, usually for carcinomas of the palatine and lingual tonsils. Oral lesions’ clinical appearances correlate well with risk of transformation, as discussed later,14–16 but the macroscopic features of hypopharyngeal and laryngeal precursor lesions are not so well defined and their relative importance is not generally accepted.17,18 However, regardless of the macroscopic features of oral and laryngeal lesions, an accurate histological examination is always required after biopsy to classify lesions into grades with different risks of malignant transformation based on the epithelial architectural and cellular changes.18–21 Numerous and diverse classification systems have been proposed in the literature to characterize dysplasia in the UADT.17,22–46 This complicates microscopic definitions in published series, confuses the relationship between the morphologic changes and clinical behavior, and makes longitudinal trials difficult. All grading systems encompass a series of histologic changes that appear to form a continuum between normal mucosa at one end and high-­grade dysplasia/carcinoma in situ

(CIS) at the other, establishing a model of neoplastic progression.39 However, the simple progression model is not supported by longitudinal histological evidence and conflicts with current molecular understanding. A biopsy with representative tissue samples still serves as the main guidance for subsequent clinical management, as well as the most reliable prognostic factor of the biological behavior of the disease.18 The histopathologic diagnosis of preinvasive changes of the UADT continues to be a challenging area for surgical pathologists. There are several reasons for the difficulty. Squamous carcinoma may arise in epithelium that is histologically normal, or appears only hyperplastic, and even when dysplasia is evident it may regress or remain stable for many years. When the additional variation in normal tissue architecture and different etiological agents at different sites are taken into account, it is not surprising that pathologists have been unable to agree on a unified grading system or consensus list of morphological criteria for the whole UADT. This is reflected in the presentation of six histological systems for laryngeal lesions and two for oral lesions, with different terminologies, number of grades and morphological criteria, in the fourth edition of the World Health Organization (WHO) Classification of Head and Neck Tumors 2017. These various systems are not directly comparable to one another and none can be given significant precedence over the others. However, for laryngeal lesions, a unified two-­tier WHO 2017 grading system consisting of low-­and high-­grade dysplasia has been introduced; this system, based on the criteria of the amended Ljubljana classification, can also be transformed into a three-­tier classification for treatment purposes, by adding a distinction between high-­grade dysplasia and CIS.44,47 It has never proved possible to devise a system applicable to all sites, perhaps because of the fundamental differences in normal anatomy, etiology and microscopic features between sites, and differences in the treatment consequences at different sites. Inability to predict malignant transformation accurately has led to criticism of the methods. However, pathologists are not clairvoyant and the expectation that microscopic changes should predict malignant transformation reliably is inconsistent with our understanding of the disease process. It is up to pathologists to audit the predictive value associated with their diagnoses so that expectations are realistic, and patients receive appropriate treatment. Despite poor reproducibility, dysplasia grading remains the best predictor of malignant transformation.48–50 A major difficulty in understanding and describing UADT dysplasia has been the undue influence of concepts and terminology devised for uterine cervix. Historically, 1

2

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

this seemed logical, but current understanding of the role of HPV infection and paths to cancer in the cervix make it clear that any analogy is without foundation. Despite this, concepts of intraepithelial neoplasia and grading by thirds of epithelial thickness persist. Pathologists diagnosing UADT dysplasia must set aside the methods they use in the cervix. Similarly, models of colon cancer based on the adenoma-­ carcinoma sequence and the progressive accumulation of genetic changes do not necessarily apply to the UADT, where TABLE

1.1

causes are different and extensive genetic changes can be present from the outset. Despite an apparent histologic continuum between normal mucosa and severe dysplasia, there is no evidence to suggest that there is simple progression from stage to stage. In the future, increasing knowledge of molecular changes may well complement histological assessment to enable better prediction and tailored treatment.13 Lack of consistency in terminology is also confusing for the pathologist. The terms used throughout this chapter are defined in Table 1.1. 

Terminology for Premalignancy, Dysplasia, and Precursor Lesions

Term 

Definitions and Comments 

Atypia 

Atypia are the individual cytological features of dysplasia.

Hyperplasia 

An increase in the amount of tissue caused by increased cell number. Hyperplasia is a physiological growth response to a stimulus and reverses when the stimulus is removed. Hyperplasia is sometimes included as an early phase in a progression from normal to dysplasia and on to carcinoma. However, epithelium that appears hyperplastic microscopically may harbor morphologically undetectable genetic changes and it is technically incorrect, but frequently said, that basal cell hyperplasia is a feature of dysplasia. Unfortunately, distinguishing genuine hyperplasia from early dysplasia is difficult and hyperplasia is used in the terminology for low risk lesions, particularly in the larynx.

Squamous metaplasia

A reversible change in differentiation pattern. In the UADT, this usually is a pathological response to tobacco smoke and an alteration from respiratory to squamous epithelium or keratinizing squamous epithelium. Metaplasia in respiratory epithelium is considered an essential prerequisite to develop dysplasia.

Dysplasia

Dysplasia means no more than abnormal or disordered growth but in the context of epithelial dysplasia indicates a risk of malignant transformation. Epithelial dysplasia is identified by architectural and cytological changes. Dysplasia is the preferred term used to describe potentially malignant changes and is used similarly in colon and other sites. However, dysplasia in other contexts, such as hip dysplasia or specific diseases, such as fibrous dysplasia, has no connotation of potential malignancy.

Field change

The extensive background genetic changes detectable in any tissue that predispose to malignant change. Molecular analysis has revealed that patients may have widespread genetic changes well beyond the margins of any visible lesion and that apparently normal mucosa may therefore carry a risk of developing carcinoma. Often called field cancerization, though most of a field will never become malignant, it is a widespread dysplastic process.

Precancer and premalignancy

Both terms are often used to describe dysplastic processes but are considered poor terms by some, as they are felt to imply that progression to carcinoma will definitely occur, despite the fact that it rarely does. Though considered nonpreferred terms, they are in widespread use.

Oral potentially malignant disorder

Term proposed by a WHO-­sponsored workshop to replace oral premalignant lesions and premalignant conditions in 2005.37 Currently, the accepted umbrella term to include all diseases, lesions, and microscopic changes that carry a risk of transformation to squamous carcinoma in the mouth. This term is felt to be a better descriptor because it includes the large number of disorders that either never progress or even regress.

Premalignant lesion 

A term previously used to indicate a localized change in the oral mucosa, visible clinically, that carries a risk of malignant transformation at that site. Now obsolete because it is recognized that all apparently localized lesions are accompanied by surrounding invisible field change. Premalignant lesions are thus not biologically any different from premalignant conditions. See also premalignant, earlier.

Premalignant condition 

A term previously used to indicate a disease or change that carries a risk of malignant transformation at a site in the mouth or upper aerodigestive tract, away from the visibly affected area, such as lichen planus or submucous fibrosis. No longer felt to be worth distinguishing from premalignant lesions as all are associated with field change. See also premalignant, earlier.

Leukoplakia 

Leukoplakia means only white patch, but in common usage implies a risk of malignant transformation. A useful term to describe a well-­defined lesion of keratotic epithelium, but use should be confined to clinical description. There is no histological equivalent. Definitions of leukoplakia have changed over decades and are most important for epidemiological and clinical trials. The term is frequently misused. The current definition for oral patches is “a white patch of questionable risk, having excluded known diseases that carry no increased risk for cancer.” A biopsy is therefore required to exclude other conditions before the term can be correctly applied to a white patch. Once a histological diagnosis is available, that should be used to describe the lesion. At other sites the term is used much more loosely.

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

TABLE

1.1

3

Terminology for Premalignancy, Dysplasia, and Precursor Lesions—cont’d

Term 

Definitions and Comments 

Nodular and verrucous leukoplakia 

Leukoplakias with nodular, verrucous or otherwise irregular surfaces carry a higher risk of malignant transformation than flat and homogeneous leukoplakias and are therefore differentiated clinically.

Oral intraepithelial neoplasia 

An old term for dysplasia, adapted from terminology used for cervical carcinoma progression. However, it is clear that the dysplastic changes are not neoplastic. They may regress or remain stable and do not meet criteria for neoplasia.

Squamous intraepithelial lesion 

Alternative term for dysplasia, usually used for laryngeal dysplasia.

HPV-­associated dysplasia 

Terminology for mucosal infection by high-­risk types of HPV remains contentions. Currently HPV-­ associated dysplasia is proposed, but it remains unclear which mucosal high-­risk HPV infections should be considered dysplastic.

Koilocytic dysplasia

Term used to describe HPV mucosal infection, usually with high risk or genital subtypes. Term not currently used for HPV lesions because, as originally described, some cases appear to be simple infections in the immunosuppressed and only a few may have been truly dysplastic.

Verrucous hyperplasia 

A term originally introduced to describe changes seen at the margins of verrucous carcinomas, where neither invasion nor atypia were present. Not widely adopted. We consider that a properly developed verrucous morphology is an architectural feature of dysplasia and suggest these are better described as mild dysplasia because they are not truly hyperplastic, and the term fails to recognize their risk of transformation. Some may be a precursor to verrucous carcinoma without evident dysplasia or an early lesion of proliferative verrucous leukoplakia.

Carcinoma in situ 

In the context of laryngeal dysplasia, carcinoma in situ performs a useful function identifying changes that are felt to be just short of invasion and that invasion is inevitable. Using the term carcinoma may facilitate radiotherapy even though invasion cannot be confirmed. In oral and other head and neck sites, carcinoma in situ is considered synonymous with severe dysplasia as there are no defining criteria to differentiate these two states accurately.

Lichenoid dysplasia 

An attempt to prevent underscoring of oral dysplasia as a benign process when masked by a lichenoid host response by giving the combination of features a specific name. Not in widespread use. It is confusing to many whether lichenoid dysplasia is meant to be a specific condition and most prefer to designate such lesions simply as dysplasia.

Proliferative verrucous leukoplakia 

A clinical description for a specific presentation of oral multifocal white lesions with inexorable progression to carcinoma. Patients are often elderly females with no risk factors. See page 7.

HPV, Human papilloma virus; UADT, upper aerodigestive tract; WHO, World Health Organization.

Oral Cavity The most extensive data on precancer and potentially malignant disorders comes from study of the mouth and larynx. The larynx is dealt with separately, but many of the principles described in the oral cavity section apply to the pharynx. INTRODUCTION Squamous cell carcinoma (SCC) of the mouth is a major cancer burden, particularly where cigarette smoking and other forms of tobacco consumption or betel quid (paan) chewing are prevalent.51 Tobacco and alcohol are associated with dysplasia in the mouth and are assumed to be the cause.52–54 However, as tobacco use falls in Western countries, a higher proportion of patients with oral carcinoma and dysplasia have no apparent risk factors and much less is known of these apparently risk factor–free individuals and their precancerous changes. Patients with oral carcinomas present at late stage55 and early diagnosis is the main determinant of successful treatment. However, the assumption that treatment at a preinvasive stage will prevent carcinoma developing or improve outcome has not been borne out in research until relatively recently.56 Now that clinical benefit from treatment is accepted, the main function of identifying and grading oral dysplasia is clear: to identify patients at high risk so that they can be offered early ablative treatment or close

follow-­up. This aim cannot be achieved by histological assessment alone. Dysplasia and its grade, while important, must be combined with other clinical factors to determine any individual’s risk, and these factors are discussed in the section titled “Progression and Transformation of Oral Dysplastic Lesions.” The clinical context in which oral dysplasia is assessed differs from less accessible sites. The mouth is easily examined and readily sampled under local anesthetic. Repeated biopsy and long but close follow-­up are part of the management strategy, unlike for other UADT sites with difficult access, where biopsy may require general anesthetic. In sites such as larynx, clinicians are keen to identify the very highest risk patients with a likely short time to transformation. In the mouth, a lower predictive value is acceptable, mild dysplasia receives more intensive follow-­up and, for lower risk patients, a picture of the degree of risk may be built up over many years from multiple biopsy samples.  NORMAL ORAL ANATOMY The oral cavity stretches from the vermilion border junction with the labial mucosa to the anterior pillar of the fauces, including the anterior two-­thirds of the tongue. The oral cavity is lined by three types of mucosa: masticatory, lining, and specialized (Fig. 1.1). Transition zones between types of oral epithelium with different differentiation patterns are not prone to carcinoma or dysplasia.

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Fig. 1.1  Normal mucosa of the mouth. All sites shown at the same magnification. Top, dorsal tongue showing the alternating zones of thick nonkeratinized epithelium between short zones of thin keratinizing epithelium forming the filiform papillae, which are spikes of keratin. This complex rete pattern can produce the appearance of disorganized epithelium when cut obliquely. Middle row, lining mucosa, covered by nonkeratinizing epithelium, the buccal mucosa having the thickest epithelium (left). Bottom row, floor of mouth (left) with its very thin epithelium and hard palate (right). The gingiva looks like hard palate, but the epithelium is about half the thickness of the palatal epithelium shown here.

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

Lining mucosa covers the inner lips and cheeks, ventral tongue, and floor of mouth. It is elastic with relatively thick epithelium on the labial and buccal mucosa, and a thin epithelium on the ventral tongue and floor of mouth. Masticatory mucosa covers areas required to resist masticatory forces: the gingiva and hard palate. Here, the epithelium is relatively thin and parakeratinized or lightly orthokeratinized and tightly bound down. Minor degrees of keratinization can be seen as a physiological response to friction, typically forming the “linea alba” along the buccal mucosa level with the occlusal surfaces of the teeth, or on edentulous alveolar ridge. In normal mucosa, proliferation (and Ki67 expression) is limited to basal and immediately adjacent suprabasal layers. Mitoses are seen occasionally in normal mucosa, more frequently in lining mucosal epithelium, which has a higher turnover rate than keratinized epithelia. Specialized mucosa includes taste buds and other structures, including minor oral tonsils and the circumvallate, fungiform, filiform and foliate papillae. The dorsal tongue epithelium has a complex structure of alternating parakeratinized spikes (filiform papillae) with short stretches of nonkeratinized epithelium between. The thicker epithelium of the rete processes underlying the nonkeratinized epithelium and shorter rete processes of the keratinized epithelium produce a complex normal anatomy that can be misinterpreted by those unfamiliar with the appearance. Rete processes are usually absent in lining mucosa, where there is usually a flat basement membrane but dermal papillae extending up into the epithelium. Rete processes in keratinizing epithelia are short and rounded. Minor salivary glands underlie all lining mucosa, and the masticatory mucosa of the posterior hard palate. Dysplasia of the surface epithelium may extend down ducts and be misinterpreted as invasion. The degree of keratinization, thickness, presence of melanin, and degree of vascularization of the mucosa and its lamina propria all affect the color of the mucosa. These attributes are of relevance when correlating the clinical appearance of mucosal lesions with their microscopic composition. The appearances of dysplasia depend to some extent on the type of epithelium normally present at the site and the pathologist needs both accurate information on biopsy site and a good knowledge of the normal microanatomy57 to assess dysplasia correctly. In particular, dysplasia can only be assessed in the context of the thickness, rete process pattern and degree of keratinization normally found at the site.  ORAL POTENTIALLY MALIGNANT DISORDERS The pathologist needs to be aware of a range of oral conditions that carry a risk of transformation to squamous carcinoma (Table 1.2), collectively referred to as the oral potentially malignant disorders (OPMDs).37,58 This name is designed to replace older terms, such as precancer and premalignancy that were felt to overemphasize the risk of transformation (see terminology, Table 1.1). The evidence linking these disorders to carcinoma is of varying quality and not all disorders are associated with visible oral lesions before cancer develops. Some of these conditions will be covered elsewhere, and only elements relevant to dysplasia assessment are discussed here. OPMDs present in two main ways: as white patches caused by keratosis or red patches caused by epithelial atrophy, loss

TABLE

1.2

5

The Oral Potentially Malignant Disorders

Erythroplakia Leukoplakia Speckled leukoplakia (erythroleukoplakia) Proliferative verrucous leukoplakia Submucous fibrosis Lichen planus Discoid lupus erythematosus Human papilloma virus infection by high-­risk subtypes Dyskeratosis congenita Fanconi anemia Sideropenic dysphagia Tertiary syphilis Palatal lesions in reverse smokers Cheilitis glandularis Actinic cheilitis

of keratin, and subepithelial vascular dilation. Some disorders have specific presentations, but the highest risk is always associated with redness. Erythroplakia, Leukoplakia, and Speckled Leukoplakia Erythroplakia, leukoplakia, and speckled leukoplakia account for almost all lesions that transform and will be considered together first, as they share etiological and histological features, often coexist and have a shared evidence base. Erythroplakia (Erythroplasia). The term erythroplasia is adopted from the description of Queyrat in 1911 of an erythematous patch on the glans penis with a risk of malignant transformation. Erythroplakia is a red, hyperemic patch on the oral mucosa49,59 (Fig. 1.2). Some prefer the term erythroplasia to denote that these lesions are often diffuse poorly defined red areas with no distinct border, rather than a well-­defined plaque. The combination of erythroplakia and leukoplakia is referred to as speckled leukoplakia or erythroleukoplakia. Though a speckled appearance indicates a high risk, red and keratotic lesions may often be found side by side and the combination is always sinister, even when the classical speckled pattern is not seen. Erythroplakia is typically depressed below the level of the surrounding mucosa.49 Erythroplakia is a purely clinical term and has no histological use. It is defined it as a “fiery red patch that cannot be characterized clinically or pathologically as another definable lesion.”37 While the clinical identification of red mucosal changes in the oral cavity should raise the suspicion of dysplasia or carcinoma, some non-­neoplastic conditions can cause similar appearances, including lichen planus, Candida albicans infection, and histoplasmosis.60 Erythroplakia is much less common than leukoplakia, resulting in remarkably fewer publications defining the term and establishing its associated etiologic, clinical, and pathologic features. Most epidemiologic data concerning oral erythroplakia were collected in India and Southeast Asia, and indicate a prevalence of 0.02% to 0.83%,49,53 with the majority occurring in older individuals (sixth and seventh decades).61 In a study investigating the incidence of carcinoma in situ, which is the microscopic manifestation of many cases of oral erythroplakia, Bouquot and Ephros62 reported only six newly diagnosed cases per 1,000,000

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Fig. 1.2  Typical appearance of erythroplakia. Here presenting in the floor of mouth.

persons each year, translating to 1500 cases diagnosed annually in the United States. Erythroplakia is most commonly observed in thin mucosa and at high-­risk sites for squamous carcinoma; the ventral tongue, floor of the mouth, anterior pillars of fauces, and retromolar trigone.61,63 Shafer and Waldron reported the most common site to be the floor of the mouth.61 In women, the combined mandibular alveolar mucosa, mandibular gingiva, and mandibular sulcus were most commonly affected. In men, this combined site was the least common site of occurrence. Erythroplakia does not usually affect the tongue but is frequent on the lateral tongue as a component of erythroleukoplakia. Bouquot and Ephros62 indicated that 50% of lesions diagnosed as oral erythroplakia measured less than 1 cm in greatest dimension, with the majority being less than 1.5 cm in diameter. Erythroplakias carry the highest risk of malignant transformation of any OPMD. Most show severe dysplasia on biopsy and approximately half may harbor foci of squamous carcinoma on first biopsy.61,63 In several reports by Mashberg and colleagues,59,63,64 it was emphasized that “persistent asymptomatic erythroplakia rather than leukoplakia in high-­risk sites of the oral cavity is the earliest and primary sign of oral carcinoma.”59  Leukoplakia. The term leukoplakia, denoting white mucosal patches, was coined by Schwimmer,65 a Hungarian pathologist, in the second half of the 19th century. Currently, the WHO definition of leukoplakia is “a white plaque of questionable risk, having excluded (other) known diseases or disorders that carry no increased risk for cancer.” Over many years various definitions have been quoted, amended and often ignored. The history is reviewed in the current defining paper.37 However, those submitting biopsies may use the word either very loosely to mean any white patch, or to indicate that they consider a lesion to carry a risk of malignant transformation. Leukoplakia is not a histologic term, but the white appearance arises from increased keratinization,66,67 the thick keratin absorbing water and reflecting light (Fig. 1.3). The epidemiology of leukoplakia differs widely in different parts of the world and between studies, the latter partly caused by different criteria applied by examiners, their expertise, and the effort made to exclude insignificant keratosis. Most large

Fig. 1.3  A typical homogeneous leukoplakia on ventral tongue mucosa.

epidemiological studies have not been able to exclude alternative diagnoses by biopsy. The overlapping and variable terminology makes drawing conclusions from these studies difficult. However, leukoplakia is relatively common and more frequent in populations with high incidence of smoking, and smokeless tobacco and alcohol use. The vast majority of leukoplakia detected in epidemiological studies is either not potentially malignant at all, or carries a very low risk. Conversely, high transformation rates may be reported in studies performed in secondary care. Overall, the prevalence of oral leukoplakia varies between 0.6% and 10%, of which 0.2% to 1% has been reported to harbor dysplasia on histologic examination.14 The peak age of incidence is in the fifth to seventh decade.48 The peak age for dysplasia is the sixth decade, whereas that for carcinoma is a decade later, indirectly supporting the precursor role of dysplasia. Leukoplakia affects predominantly males, the reported percentages in males range from 54% (n = 3256)48 to 78% (n = 710).66 Leukoplakias are most frequent on the buccal mucosa and maxillary and mandibular sulci, followed by the palate and lips, alveolar ridge, and dorsal tongue.48,68 However, white patches in these locations may result from friction, candidal infection and other causes and are less frequently associated with dysplasia. Conversely, leukoplakia affecting the ventral tongue, fauces, floor of mouth, or retromolar trigone is more likely to harbor dysplasia.14,48,66,69,70  Speckled Leukoplakia (Erythroleukoplakia). Terms, such as erythroleukoplakia, leukoerythroplakia, erosive leukoplakia, speckled leukoplakia, and speckled erythroplakia have been used to describe combined red and white oral mucosal changes (Fig. 1.4). Current terminology considers these lesions to be a variant of leukoplakia37 rather than a specific entity, though, as noted earlier, it is the erythroplakic component that is the more significant, indicates the transformation risk and harbors the more severe dysplasia. The observation that many of the speckled leukoplakias may have previously been classified as leukoplakias may explain why some observers in the past found such a high frequency of malignant transformation in what was erroneously classified as “pure” or homogeneous leukoplakia.15 

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

Fig. 1.4  A rounded area of speckled leukoplakia. Approximately 8 mm in diameter at the posterior edge of an area of leukoplakia on the buccal mucosa. Note the associated erythroplakia just superiorly. Of the three areas, that with speckling is most likely to harbor carcinoma or severe dysplasia.

Etiology of Leukoplakia and Erythroplakia. Tobacco use, either smoking or as smokeless tobacco, and alcohol consumption, are the most significant risk factors for the development of oral erythroplakia and leukoplakia. The habit with the highest risk is use of betel quid or “paan” (comprising areca nut, spices, lime [calcium hydroxide], and often tobacco wrapped into a package in a betel vine leaf). Chewing the quid causes both the disease oral submucous fibrosis (see Chapter 4), as well as red and white oral lesions with and without dysplasia. Other carcinogenic habits include snuff dipping with dried tobacco snuff, chewing of qat (khat) in the Middle East and North Africa,71 and nass (chewing tobacco mixed with ash and cotton oil). All these habits have regional variation in composition and probably an ability to cause oral lesions and dysplasia. Though all were originally geographically restricted, they can now be found worldwide in emigrant communities. The pathologist must encourage clinicians to record all such habits accurately on pathology request forms, particularly when tobacco is used. As many lesions may show minimal dysplasia, awareness of such habits prevents the pathologist inadvertently dismissing a lesion as innocuous. Infection by C. albicans is common in leukoplakia,72 more frequent in dysplasia,73 but alone has not been proven to carry a risk of transformation despite reported associations.74,75 It is widely recognized that red or white lesions with dysplasia carry a higher risk when infected, and that infection alters the histological appearance to simulate a higher grade of dysplasia. The diagnosis of leukoplakia requires exclusion of conditions without risk and it is generally taken that red or white lesions that resolve completely on antifungal treatment are simple infections without risk. However, excess keratin is readily infected by Candida sp. and potentially more significant species are found in dysplastic lesions.76 Infection induces epithelial proliferation and potential carcinogenic mechanisms associated with candidal infection include disturbance of intracellular signaling and

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Fig. 1.5  A patient with late stage proliferative verrucous leukoplakia. Note the involvement of gingiva and tongue and the development of verrucous, nodular and red areas that had not been present in earlier years. These lesions have been present for over 25 years.

production of nitrosamines. A role for Candida as a cancer promoter is certainly possible, and is supported in animal models, but remains unproven in humans.  Proliferative Verrucous Leukoplakia Rather than a specific entity, proliferative verrucous leukoplakia (PVL) describes a clinico-­pathological presentation of particularly high transformation risk.77–80 The term is somewhat of a misnomer, as lesions do not show proliferation as a prominent feature histologically, rather they enlarge and become multifocal in the mouth. There are no absolute diagnostic features and the name has been used loosely in the literature, but it is important to restrict it to the correct patients, otherwise its significance is lost. Not all patients with multiple verrucous white lesions that develop carcinoma are cases of PVL.81 The key elements for diagnosis are an elderly patient, often female and with no conventional risk factors for carcinoma, with multiple leukoplakias that become more numerous and more widespread, more warty, verrucous, nodular or papillary, often over several decades (Fig. 1.5). Development of erythematous areas is a late feature and may not occur. Hansen and colleagues79 originally suggested 10 histologic stages in the continuum of PVL, which were reduced to 4 by Suarez and colleagues78: clinical flat leukoplakia, verrucous hyperplasia, verrucous carcinoma, and conventional SCC. However, this is by no means a required progression and different lesions in one patient may display any of these appearances, and combinations of them, during their clinical course. Separate lesions do not progress synchronously. The most common sites for the leukoplakias of PVL are the buccal mucosa (63%), gingiva (56%), and tongue (47%) in females, and the tongue (82%) and gingiva (45%) in males. The condition has been considered more prevalent in females (ratio of 4:1) by some,77,79 while others identify an equal gender distribution.80,82 Only 31% of patients have a history of tobacco use in some studies,77 while others prefer to exclude this diagnosis in smokers. The presence of HPV in PVL remains contentious, being mostly described using only polymerase chain reaction (PCR)-­based methods. More stringent

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methods of HPV detection in PVL do not show any association with biologically significant (transcriptionally active) viral infection.83,84 PVL often starts as a unifocal flat lesion, predominantly in mandibular or alveolar locations and buccal mucosa, which over many years develops a warty, somewhat papillary surface. Silverman and Gorsky77 studied 54 patients with PVL, 17 of whom were included in the original report by Hansen and colleagues.79 Seventy percent of patients developed carcinoma (mean, 7.7 years from initial diagnosis; range, 1–27 years); a second malignancy developed in another PVL site in 31.5% of the cases. In the final report by Hansen and colleagues,79 87% of their patients developed SCC in a follow-­up period that extended to 20 years in some patients. More than 40% of this cohort died of their carcinomas. If these data are combined with data from the Silverman and Gorsky series, the PVL-­associated death rate is 50%. It is often implied that malignant transformation is the defining characteristic and that PVL must be diagnosed retrospectively,79 but patients need to be identified earlier than the usual mean age of 62 years for aggressive treatment or close observation. Initial presentations of hyperkeratosis and homogeneous leukoplakia may not be recognized as PVL until the clinical course is recognized. Early lesions, and verrucous leukoplakias in general, often display minimal cytological atypia and may be mistakenly diagnosed as nondysplastic or mildly dysplastic, underestimating the risk. Many of the patients thought to have lichen planus with malignant transformation develop through a PVL-­type progression, particularly those with gingival leukoplakia, and are probably cases of PVL with a more prominent than usual host response to their lesions. Only in later disease does dysplasia become evident. PVL is considered to be resistant to treatment, and intervention remains contentious. The multifocality and a tendency to recur make all treatment options unreliable, including surgical excision, carbon dioxide (CO2) laser treatment, cryosurgery, chemotherapy, and photodynamic therapy and the morbidity from multiple excisions can be significant. Patients successfully treated for one carcinoma are at risk of further primary carcinomas,79,80 half developing a second and some patients several.85 In all cases, rigorous follow-­up is required for PVL patients and the repeated biopsy of both old and new lesions to detect early invasion, with selective excision, remains the mainstay of treatment.  Verrucous Hyperplasia Verrucous hyperplasia is a contentious diagnosis and one which we consider confusing and unhelpful. As noted in Table 1.1 and the section titled “Progression and Transformation of Oral Dysplastic Lesions,” the term hyperplasia has no place in the terminology of dysplasia or potential malignancy. Many verrucous leukoplakias display minimal cytological atypia, and so appear nondysplastic and histologically innocuous. However, the importance of architectural features of dysplasia is increasingly recognized and it is our preference to recognize a verrucous morphology in leukoplakia as an architectural feature of dysplasia and to automatically diagnose all such lesions as, at least, mildly dysplastic rather than hyperplastic. There is no site in the mouth, or UADT, that has a verrucous morphology physiologically and it never develops in response to physiological triggers, such as friction. Once a few lesions with a similar morphology are excluded, such as verruciform xanthoma, a verrucous architecture must be regarded with the utmost suspicion.

Fig. 1.6  Betel chewer’s mucosa. No dysplasia is present, but the architecture of the epithelium is distorted by the irritant effects of the betel quid, held in contact for prolonged periods.

The concept of verrucous hyperplasia has a long history, and a variety of now-­defunct diagnostic terms, including oral florid papillomatosis, have been considered equivalent in at least some cases.86 Verrucous hyperplasia was first described by Shear and Pindborg86 in 1980. It was said to involve the gingival and alveolar mucosa most frequently, followed, in decreasing order, by buccal mucosa, tongue, floor of the mouth, lip, and palate, similar to the distribution of PVL.78 However, in the initial report, 53% of patients had associated leukoplakia, 29% associated verrucous carcinoma, 66% epithelial dysplasia and in 10% a typical SCC.78,86 It seems obtuse to label such lesions as hyperplastic, when they appear to be transition zones at the margins of more dysplastic or neoplastic lesions. Verrucous hyperplasia has also been considered by some to be a phase in the development of PVL.79 Verrucous hyperplasia was said to be differentiated from verrucous carcinoma by the lack of the downward, pushing invasive growth exhibited by verrucous carcinoma. However, no criteria have been defined to distinguish verrucous hyperplasia from a verrucous leukoplakia with minimal cytological atypia and many now consider that verrucous hyperplasia is not a distinct entity. In addition to the oral cavity, similar histological appearances have been described in the sinuses associated with inverted papillomas and in the larynx, but whether it is any more deserving of recognition as a separate entity at these sites is equally doubtful.78  Oral Submucous Fibrosis and Changes in Betel Chewers The diffuse submucous fibrosis of this condition is discussed in Chapter 4. The current section covers only the mucosal changes seen both in submucous fibrosis and the mucosa of betel quid and areca users and their association with dysplasia. The cause is chewing of betel quid or areca nut, consumed in various formats and with different ingredients in different parts of the world.87 The risk of carcinoma and dysplasia rise when tobacco is included in the quid,88 with higher frequency of chewing and when patients sleep with quid in place.89 There are distinctive changes referred to as betel chewers’ mucosa that affect the site of habitual placement of the quid. Clinically, the mucosa is stained orange red, and this in  vivo staining by dyes from the nut is visible in hematoxylin and eosin (H&E) sections as an orange discoloration of surface keratin. The surface of the epithelium is rough, peeling, and shredded, and may contain particles of impacted and trapped quid (Fig. 1.6). These changes are considered a direct irritant reaction with superimposed trauma.90 These features alone do not constitute

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

dysplasia and carry no risk of carcinoma but may be superimposed on dysplastic lesions. Lichen planus-­like clinical appearances develop in about 1% of users, and this has been misdiagnosed as lichen planus itself, but the close association with betel quid use suggests this is a combination of keratosis and erythema, accompanied by a lichenoid host response histologically. Clinically, the features are not typical of lichen planus, the keratosis is more variable, patchy, streaky rather than in well-­defined striae and plaques, and the changes are most intense at the site of quid placement, often with atrophy or erythema and a radiating pattern of keratosis.91 As most patients have dark skin, melanin drop-­out and clinical pigmentation are prominent and usually darker peripherally. Histologically, there is a variable lichenoid host response with basal cell destruction and squamoid change, but often with an additional plasma cell element to the infiltrate. There is not usually a well-­defined band of infiltrate. The infiltrate density varies but when dense and prominent within the epithelium, may mask dysplasia. Any lichenoid histological pattern in a betel quid user must be viewed with suspicion. Users develop leukoplakia, erythroplakia and speckled leukoplakia that resemble those in nonusers, but the risk of carcinoma is extremely high, making this the most carcinogenic oral habit. Many studies on this topic are published. In one study from India where tobacco was included in the quid, the odds ratio for developing leukoplakia was 37.7 in females and 28 for those developing erythroplakia, rising to over 50 in long-­term users.53 Transformation rates for leukoplakia and erythroplakia derived from Indian populations usually include topical tobacco or betel users. The features of dysplasia in users appear no different from those in nonusers. A zone of subepithelial fibrosis can be found at the site of betel quid placement and need not indicate submucous fibrosis, but the more extensive fibrosis of this disease can accompany all the changes noted earlier.  Lichen Planus Despite decades of controversy, any premalignant potential of lichen planus remains contentious.92–95 There are good, fundamental reasons why a connection remains elusive. Firstly, lichen planus is not a specific entity but a terminal pathway of autoimmune destruction of keratinocytes that has multiple, and often unknown, causes and no individual specific diagnostic histological features.96 Secondly, if lichen planus does predispose to malignant transformation, the risk must be exceedingly small because lichen planus is so common. Certainly, it must be well below the 0.5% reported in hospital series.68,97,98 Third, the clinical diagnosis of lichen planus is also poorly defined, and overlaps with PVL and leukoplakia, especially when affecting the gingiva or in the plaque form. Finally, and probably most significant, dysplasia will often elicit a cell-­mediated host response that closely mimics lichen planus histologically99,100 (Fig. 1.7). A recent systematic review101 highlighted the difficulty in comparing data when diagnostic criteria are unclear or not stated and noted that lesions with mild degrees of dysplasia may well be diagnosed as lichen planus. The issue cannot be resolved on the basis of data published to date and, pending clarification, lichen planus remains classified by the WHO as an OPMD on the precautionary principle.37 Molecular analysis has not proved helpful to resolve the issue. Allelic imbalance102–104 and loss of heterozygosity105 can be detected in apparently typical lichen planus, however significant genetic instability seems unlikely from first principles.

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Fig. 1.7  Dysplasia with a lichenoid host response. Note that the basal cell layer is well preserved despite the epithelial infiltration by lymphocytes and few apoptoses are present. There is mild cytological irregularity in the basal cell layer and less change in keratin pattern than is usual in lichen planus.

Similarly, too high a proportion of lichen planus biopsies have been claimed to be aneuploid.106,107 Given the infrequency with which lichen planus becomes malignant, it would be expected to find genetic changes in only a minority of typical samples, if any.108 Whether or not genuine lichen planus is an OPMD, dysplastic lesions often closely resemble lichen planus clinically. Many cases of PVL seem to be diagnosed as lichen planus in biopsies from the early stages of disease. A degree of dysplasia is incompatible with the histological diagnosis of lichen planus, and the diagnosis of carcinoma arising in lichen planus is often retrospective, rather than supported by good evidence of preexisting typical disease. Most of our institution’s cases of apparent carcinoma in lichen planus did not stand careful scrutiny108 and Van der Meij and colleagues considered that transforming “lichen planus” was always abnormal clinically to some degree.109 The overlap in histological features between lichen planus and dysplasia with a host response makes confident diagnosis extremely difficult, indeed making this distinction may not even be possible in the early stages. Once dysplasia is present, making a diagnosis of lichen planus depends primarily on clinical features, detail of which is often not transmitted to the histopathologist. The destruction of basal cells in lichen planus induces a number of changes, including generalized early keratinization, large prickle cell nuclei with prominent eosinophilic nucleoli lying in the basal layer and, often, a proliferative response with reactive atypia in remaining basal cells (Fig. 1.8). Features normally considered as atypia may be frequently found in lichen planus.110 However, there are no different ways of scoring dysplasia in the presence of a host response or in lichen planus and conventional criteria discussed later are applied. In borderline cases, or for additional reassurance, a diploid result on deoxyribonucleic acid (DNA) ploidy analysis appears helpful in excluding risk.108 Lichenoid Dysplasia. In an attempt to clarify the difference between dysplasia with a host response, lichen planus, and lichenoid reactions, Krutchkoff and Eisenberg described the diagnosis of the subtle dysplastic features in borderline

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Fig. 1.8  Lichen planus with marked reactive atypia. Typical basal cells are lost, and prickle cells at the connective tissue interface show irregularity in size and early keratinization and many have enlarged nucleoli. Multinucleate keratinocytes are present, only seen when there is intense basal cell destruction.

lesions.99 Unfortunately, their term of “lichenoid dysplasia,” to describe the intermediate group, produced a further grey area rather than clarification and some pathologists and clinicians came to regard lichenoid dysplasia as a specific defined entity, while others were confused as to whether it was dysplasia with a host response or dysplastic lichen planus. Though this was a valuable attempt to differentiate the conditions, the terminology has not been widely adopted. The features considered helpful in identifying dysplasia in a lichenoid process were the absence of “liquefaction degeneration,” a mixed cellular lichenoid infiltrate, cellular pleomorphism, altered nuclear cytoplasmic ratio with hyperchromatism, altered stratification, abnormal keratinization, and loss of cohesion and abnormal mitotic figures; all are conventional features of dysplasia. The same authors,93 others,111 and the current authors consider carcinoma arising in lichen planus to be misdiagnosis of subtle dysplasia. Most consider a lichenoid host response to be a fairly frequent feature of dysplastic lesions, and it appears to carry no prognostic significance. There is no need to identify these lesions separately from other dysplastic lesions.  Discoid Lupus Erythematosus Oral discoid lupus erythematosus has a resemblance to lichen planus clinically and histologically. Though accepted as an OPMD, the evidence is sparse and suffers the same diagnostic limitations as that linking lichen planus to carcinoma. However, the concept is supported by the fact that skin lesions may also undergo malignant transformation.112 There is a consensus that lupus erythematosus involving the vermilion border carries particular risk.113–115 While the evidence for intraoral carcinomas is largely in the form of case reports, some are convincing and have multiple primary carcinomas,116 and the risk of transformation seems to be accompanied by dysplasia of conventional appearance.117  Human Papillomavirus and Oral Epithelial Dysplasia Human papillomavirus was initially implicated as a causative agent in the development and progression of oral cavity carcinogenesis in the early 1980s.118,119 Since then, numerous studies

have sought to detect the virus in precursor lesions of the oral cavity but have often used nonstandardized methods and investigated mixed series of lesions from diverse patient cohorts. Meta-­analyses suggest that the pooled prevalence of high-­risk HPV types in oral epithelial dysplasia is approximately 25%, and the odds ratio for detection of all genotypes is 3.9, using normal oral epithelium as the referent.120,121 However the overwhelming majority of these studies utilized PCR to detect HPV DNA, a technique known to have suboptimal specificity and overestimate viral prevalence. Furthermore, using PCR as a single modality test without longitudinal follow-­up does not elucidate the biological relevance of the virus; HPV may be present as a transient bystander infection lacking any viral oncoprotein driver functions. However, several groups have characterized a histomorphologically distinct group of lesions consistently harboring biologically active high-­risk HPV. These have been called virus-­ associated dysplasia, oral Bowen’s disease, oral Bowenoid papulosis, koilocytic dysplasia, HPV-­ associated oral intraepithelial neoplasia, and HPV-­associated oral epithelial dysplasia (HPV OED),12,122–126 the last being the preferred term. This entity is defined by specific histomorphologic criteria in conjunction with the demonstration of high-­risk HPV by in situ hybridization; the detection of viral DNA by PCR alone in oral dysplasia of conventional appearances is insufficient for diagnosis of HPV OED. Clinical Features. HPV OED presents as white to red/ white plaques or patches that occur more commonly on the floor of mouth and ventro-­lateral tongue but have also been reported to arise in the buccal mucosa, gingiva or hard palate. While in some reports and series, this entity appears to be more common in patients who are immunocompromised by human immunodeficiency virus (HIV) infection,12,122,123 others have found no association between this group of lesions and HIV.125 Nevertheless, the diagnosis of HPV OED should prompt the clinician to exclude the possibility of immunocompromise. The prevalence of HPV OED is currently unknown, since studies have been limited to small series with patient selection bias. In studies using retrospective case selection methods, reclassification of lesions as HPV OED is more common in those previously diagnosed as severe dysplasia or carcinoma in situ.12,126  Pathologic Features and Differential Diagnosis. In the majority of cases, low magnification views show aberrant maturation and attenuation of the prickle zone with loss of stratification often involving half to full thickness of epithelial depth together with variable retention of a parakeratin layer. Initial reports included full thickness epithelial changes as a defining criterion (hence the term oral Bowenoid papulosis),122,124 but more recent definitions allow these changes to be limited to the basal third. Interestingly, a single well-­ defined basal cell layer may be retained despite the presence of suprabasal atypia (Fig. 1.9), a useful diagnostic feature likely reflecting the virus life cycle. Features that distinguish these lesions from conventional oral dysplasia are karyorrhexis and bizarre nuclear fragmentation (Fig. 1.10) reminiscent of mitosoid bodies seen in multifocal epithelial hyperplasia (Heck’s disease), as well as isolated apoptotic or dyskeratotic cells, which may be present at any level but do not cluster (Fig. 1.11). The isolated individual karyorrhectic, dyskeratotic and apoptotic cells, randomly

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

distributed at any level of the epithelium, are characteristic and an indication for histological HPV testing, since these features are not usually seen in conventional oral epithelial dysplasia. Scattered pleomorphic or multinucleate cells may also be seen and, while not a consistent feature, koilocyte-­like cells may be present in the superficial prickle zone (Fig. 1.12). Though these features are highly characteristic, confirmation of biologically active HPV remains the absolute diagnostic criterion. Immunohistochemistry for p16 by itself cannot be used as a surrogate for HPV in dysplastic lesions, as discussed later. There are currently no agreed grading systems in HPV OED, primarily since this entity is still relatively underrecognized. In their series, Woo and colleagues followed up cases of

Fig. 1.9  Human papilloma virus–associated oral epithelial dysplasia. Dysplasia is characterized by loss of epithelial stratification, nuclear fragmentation in the prickle zone and isolated apoptotic keratinocytes. Note the relatively intact basal layer.

Fig. 1.10  Nuclear fragmentation in human papilloma virus–associated oral epithelial dysplasia. These cells can be present at any level within the epithelium. Apoptotic keratinocytes may occur in the vicinity as shown here, but adjacent cells may be devoid of obvious atypia.

11

HPV OED for a median period of 8.5 months in 12 patients. Malignant transformation occurred in a single patient with “high-­grade dysplasia” 25 months following initial biopsy.125 We have experience of a single case undergoing malignant transformation 9 years following an initial diagnosis of mild dysplasia. These reports are anecdotal and there is no large scale published data on the rate of malignant transformation in HPV OED. Until such knowledge becomes available, the clinical significance of individual and cumulative histological features of atypia remains unknown. HPV OED should therefore, at least for the present time, be graded and managed in the same way as conventional oral epithelial dysplasia. Therapeutic vaccination strategies remain untested in this disease. 

Fig. 1.11  Apoptosis in human papilloma virus (HPV)–associated oral epithelial dysplasia. Apoptotic keratinocytes without any associated intraepithelial inflammatory cell infiltrate and often occurring as isolated cells should alert the pathologist to the possibility of HPV infection.

Fig. 1.12  Koilocyte-­like cells in human papilloma virus–associated oral epithelial dysplasia (HPV OED). Cells reminiscent of koilocytes may be present within the cornified layer. However, this feature may be absent and should not be taken as a defining characteristic of HPV OED. Note also the apoptotic keratinocytes in the prickle zone.

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

Genetics. Little is known about the genetic changes in HPV OED, and mechanisms of HPV-­associated oropharyngeal or cervical carcinogenesis cannot be assumed to be replicated in this disease. Nevertheless, a consistent observation is overexpression of the cell cycle regulatory protein p16, which accumulates as a result of the inactivation of the retinoblastoma tumor suppressor protein through the action of high-­ risk HPV E7 oncoprotein. Strong nuclear and cytoplasmic p16 overexpression co-­localizes with morphological atypia, often with clear lateral demarcation from adjacent negatively stained epithelium (Fig. 1.13). The pattern of p16 overexpression mimics that seen in varying grades of cervical intraepithelial neoplasia (CIN) and is usually strongest basally, corresponding to zones where early viral genes E6 and E7 are most transcriptionally active in the HPV life cycle. Conversely, the chromogenic signal

of high-­risk HPV DNA in situ hybridization may not overlap with areas of strongest p16 overexpression and is usually most pronounced in the superficial epithelium where viral copy number is greatest during replicative HPV infection (Fig. 1.14). Some groups consider p16 overexpression as an appropriate surrogate marker for high-­risk virus types in HPV OED,127 but it should be noted that there are no established cut-­offs for p16 overexpression, since there are no agreed reference standards to test its accuracy. Furthermore, cyclin-­dependent kinase (CDK)N2A, the gene that encodes for p16, is frequently deregulated as an early event in oral carcinogenesis.128,129 Therefore the utility of p16 is limited to providing evidence that any HPV present is biologically active. A combination of p16 and either HPV DNA in situ hybridization or HPV E6/7 RNA in situ hybridization is required.  Dyskeratosis Congenita Dyskeratosis congenita is a rare disease characterized by nail dystrophy, reticular skin pigmentation, and oral leukoplakia that affects mainly males. It has numerous genetic forms and eponymous syndrome associations with slightly different clinical presentations and complications, but all are caused by defective telomerase activity. Almost all cases develop oral leukoplakia toward the end of the first decade, usually on the buccal mucosa, tongue, and oropharynx. The plaques are initially cytologically bland with keratosis, acanthosis and no dysplasia, but develop dysplasia of conventional patterns as they progress clinically to a scarred and fissured appearance.130–132 Verrucous, atrophic and red areas appear later, with verrucous lesions being particularly common. 

Fig. 1.13  p16 overexpression in human papilloma virus (HPV)–­ associated oral epithelial dysplasia. While strong diffuse nuclear and cytoplasmic staining for p16 immunohistochemistry (left) is associated with transcriptionally active high-­risk HPV infection, it should be noted that p16 is often overexpressed in oral dysplasia by HPV-­ independent mechanisms, and p16 alone does not indicate HPV OED. There is often an abrupt transition to negatively stained adjacent epithelium.

Fanconi Anemia The defects in DNA repair in Fanconi anemia are a well-­ recognized predisposition to oral carcinoma,133 but there are few descriptions of precursor lesions. Bone marrow transplant is associated with graft-­versus-­host disease, which can produce oral white lesions resembling lichen planus and confusing the picture. Approximately 12% of young Fanconi anemia patients are reported to have leukoplakia.134 However, loss of heterozygosity can be detected both in lesions and in a wider field of apparently normal mucosa from a young age.135 The few reports

Fig. 1.14  p16 immunohistochemistry and high-­risk human papilloma virus DNA in situ hybridization. The strongest expression of p16 (left) may not colocalize with the greatest viral DNA copy number (right); an observation that may reflect the virus life cycle.

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

suggest that erythroplakia and leukoplakia in Fanconi anemia patients show conventional patterns of dysplasia,136 but it seems clear that carcinoma in these patients is not necessarily associated with preexisting oral lesions.  Sideropenic Dysphagia Sideropenic dysphagia (Patterson-­Brown-­Kelly or Plummer-­ Vinson syndrome), a condition characterized by iron deficiency anemia with frequent associated autoimmune diseases, affects the UADT with atrophy of the oral and pharyngeal mucosa and a predisposition to the development of multiple carcinomas, predominantly in the posterior oropharynx, but also in the mouth.137 This was a feared condition 50 years ago, but has declined to the extent that the existence of the condition is now questioned.138 Symptoms are those of severe anemia with dysphagia, mucosal atrophy and, usually, oral candidiasis and angular cheilitis. The presence of any preexisting lesion apart from atrophy is very poorly documented and there is no good information on histology, with most describing just atrophic epithelium.  Syphilis Syphilis, previously in decline, is resurgent in both developed and developing countries, but the tertiary form associated with leukoplakia and oral carcinoma is now extremely rare. The combination of tertiary syphilis and leukoplakia carries a high risk of malignant transformation, well over 50%, regardless of treatment of the syphilis. The histological features of precursor lesions are rarely described but appear to show the features of conventional dysplasia.139  Palatal Changes in Reverse Smokers Reverse smoking, with the lighted end of a cigarette or cigar in the mouth, is practiced in many parts of the world for a variety of social, economic, and cultural reasons, often by women and children. Almost all reverse smokers use traditional coarse tobacco products rather than commercial cigarettes. The promoting effect of heat combined with tobacco carcinogens makes this a high-­risk habit for carcinoma development, usually affecting the palate or dorsal tongue.140,141 Dysplasia and carcinoma are otherwise very rare at these sites and mild histological signs of dysplasia might be dismissed if the habit is not known. Histological features of precursor lesions are subepithelial fibrosis, similar to submucous fibrosis, melanosis, and melanin drop-­out with patterns of dysplasia, as seen in other tobacco-­ associated lesions.141,142  Cheilitis Glandularis Cheilitisglandularis (CG) is a poorly characterized condition first described by von Volkman143 in 1870. The condition is supposed to present with lip thickening, inflammation and clinically evident dilation of the minor gland ducts, from which thick mucin can be expressed. The lower lip is typically affected, but lesions on the upper lip have been reported. Because of the relatively nonspecific features, multiple causes have been suggested including tobacco use, bacterial infection, actinic radiation, and poor oral hygiene.144 It has been claimed that the association with squamous cell carcinoma of the surface epithelium at the affected site is frequent,145,146 but a review of published cases reveals not only great heterogeneity in diagnosis but also that squamous carcinoma is relatively rare and associated with other recognized risk

TABLE

1.3

13

Clinical and Histopathological Risk Factors for Malignant Transformation of Oral Potentially Malignant Disorders

Presence of epithelial dysplasia Presence of erythroplakia or speckled leukoplakia Old age Long duration of lesion Large size of lesion Multifocality Location on the tongue Female gender Lack of tobacco use Presence of Candida albicans

factors.147 The condition is clearly clinically distinctive, but its status as an OPMD is in question and may be explained by particular sensitivity to solar radiation.145  Other Conditions The junctional and dystrophic forms of epidermolysis bullosa predispose to oral carcinoma in young patients and the risk is considered high148 but there are no good clinical or histological descriptions of precursor lesions. Some variants of palmoplantar keratoderma (tylosis) are associated with a high risk of esophageal and oral carcinoma. Oral leukoplakia is usually present and shows conventional dysplasia.149  PROGRESSION AND TRANSFORMATION OF ORAL DYSPLASTIC LESIONS Many of the OPMD described earlier have very high rates of transformation to carcinoma. Examples include proliferative verrucous leukoplakia and submucous fibrosis. This section relates to leukoplakia, erythroplakia and speckled leukoplakia and histological dysplasia. Transformation rates reported vary widely between different countries and populations, with smoking and other habits and period of follow-­up. Worldwide, a transformation rate of 1.36%/year has been estimated, though a mean figure is almost meaningless given the large geographical variation.150 Rates from hospital series grossly overestimate the risk significantly and the correct rate in Western populations cannot exceed 1%.151 One reason for the overestimates is that most papers calculate crude transformation rates without taking time to transformation into account. When a corrected annual transformation is calculated, even in a referral population, the rate is 2.6% in 9 years,152 probably also an overestimate. A meta-­analysis performed in 2009 identified 2837 outcome studies on patients with histological confirmation of diagnosis.56 Almost no series would meet current reporting guidelines for such studies and only 38 were eligible for review, none of which were randomized or case-­controlled studies. Despite this, outliers were few but the overall transformation rate of 12.3% is very high, reflecting referral bias of high-­risk patients. Notably, this rate is nearly twice the rate reported in a large population-­ based study in India, a very high-­risk population.140 Several clinical features indicate risk of transformation (Table 1.3). It appears that leukoplakia on the tongue153–155 and gingiva carry a higher risk of transformation than at other sites, though dysplasia grade is more predictive than site.50,156 One large UK study identified floor of mouth as the highest

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risk site,152 while others show no site correlation.151 Of all these findings, only a slightly higher risk for tongue dysplasia survives meta-­analysis.56 Despite the higher incidence of carcinoma in males, OPMD in females carry a higher risk of transformation. This has been reported in several studies; in the series of Banoczy66 the rate was 8.8% in females versus 5.1% in males. An even higher difference in incidence was found for tongue cancers, 86.6% of which occurred in females and a similar trend has been observed in other studies.152,153 Meta-­analysis suggests the difference is not large, the relative risk for male versus female being 0.77 (95% confidence interval [CI], 0.44–1.37), and though the higher risk in females is well evidenced in Western populations, it may not apply elsewhere.140,156 It seems likely that this difference may be accounted for by inclusion of patients with proliferative verrucous leukoplakia (who tend to be female and overrepresented in hospital referral series) and sex differences in smoking, which causes many nondysplastic keratotic lesions.157 This last factor is also reflected in the counterintuitive finding that leukoplakia occurring in nonsmokers has an excess risk of developing into SCC, compared with leukoplakia arising in smokers.153,158 It is frequently noted that patients with OPMD appear to be predisposed to develop second primary carcinomas, but it is difficult to prove that this is more frequent than in those without potentially malignant disorders as heavy smoking and radiotherapy for the first primary confound the issue. It was noted that for tongue carcinoma, the risk of a second primary was five times higher in those with preexisting leukoplakia than in those without,159 and in another study, seven of 20 patients with multiple primary carcinomas had preexisting OPMD.160 Much of this risk appears to relate to proliferative verrucous leukoplakia and lichen planus. Ten of 19 patients with PVL had a second primary carcinoma in one series85 and three of 20 with multiple primary oral squamous cell carcinomas had previously diagnosed PVL in another.160 It is striking that PVL patients may develop multiple oral carcinomas; we have seen five develop in one patient. Whether the carcinomas in such patients carry a better prognosis is contentious. Cancers associated with leukoplakia are smaller and less invasive, and their histologic grade is lower than those without it.161 In PVL, carcinomas often develop on gingiva, appear to be well differentiated and are often detected at low stage, all of which are favorable features. When follow-­up studies are published, it is conventional to exclude malignant transformation within 6 months of biopsy. This provides the best understanding of the natural history of the lesions, by excluding sampling error when carcinoma is already present. However, in clinical practice, the knowledge that severe dysplasia in a biopsy may indicate adjacent unsampled carcinoma is very useful. Ideally, both sets of data should be published and all cases should have histological confirmation of diagnosis.108 Studies reporting transformation rates of clinical leukoplakia, mixed OPMD, and different grades of dysplasia are summarized in Table 1.4.  Clinical Adjuncts to Diagnosis. Over the past two decades, there has been a dramatic increase in the development of potential oral cancer and precancer screening aids. These include brush biopsy sampling for cytology, systems based on reflectance or absorption of light at particular wavelengths, loss of fluorescence, and binding of toluidine blue dye. Despite

plausible possible mechanisms, none to date has provided definitive evidence to suggest that they improve the sensitivity or specificity of oral cancer screening beyond conventional oral examination. Furthermore, it is often unclear whether they are marketed as diagnostic or screening tests. In clinical series, each of these investigations can be shown to occasionally detect mucosal changes that are either missed or invisible on clinical examination, but the positive predictive value, when tested in primary care, is usually disappointing. Some may be useful for specific purposes, such as repeated sampling of patients at risk during follow-­up or as aids to select biopsy sites. However, few studies test these techniques against the variety of clinical conditions from which dysplasia, leukoplakia, and cancer must be differentiated clinically, and none reaches the excellent diagnostic accuracy required in the demanding area of cancer and dysplasia diagnosis.162–165 Pending further evidence, the histopathologist does best to disregard the results of any such investigations and assess dysplasia independently. Where such techniques are in use, it would aid clinicians to collect data to audit the techniques’ efficacy.  Pathological Features and Diagnosis. Assessing dysplasia and ascribing a specific degree of risk to any particular combination of features is difficult and cannot be reduced to simple algorithmic assessments of the histological appearances. Diagnosis often requires some thought and, in difficult lesions, is time consuming. Firstly, it is necessary to be able to understand the histological features as a reflection of structural and functional disturbances of the epithelium. Genetic changes are expressed as derangement of proliferation, maturation and stratification of the epithelium and as individual cytological atypia. Each dysplasia is different. Attempts to assess individual changes and identify clustering of features into identifiable patterns in dysplasia suggest the patterns and combinations overlap and are near random.40 Overall, dysplasias can be grouped into keratinizing types and nonkeratinizing types, the latter carrying the higher transformation risk and being associated with oral erythematous lesions. However, when assessing dysplasia, it is more useful to look at the tissue and try to assess which epithelial functions are deranged and how abnormal they are, rather than to try to assess individual features. Marked atypia with apoptosis probably indicates severe chromosomal instability and cell death and so would be of less significance than proliferation with mild atypia. As noted later, it appears that most oral carcinomas do not arise by progressive genetic clonal progression and expansion and few carcinomas appear to develop through increasing severity of grade of dysplasia. Despite this, more marked changes are usually assumed to carry a higher risk of carcinoma than mild, even though severely dysplastic cells may be incapable of transforming. Those that are severely genetically damaged may be incapable of undertaking the complex coordinated cell functions of invasion and metastasis. Only very few oral carcinomas arise in identified preexisting OPMDs, perhaps less than 5% to 7%, only half of which show dysplasia on biopsy.166 One large retrospective study of oral and oropharyngeal cancers showed that 7% of 201 invasive cancers had adjacent CIS, while an additional 2% had severe epithelial dysplasia.167 However, this association is difficult to study. Carcinoma may show Pagetoid spread at its margin,

1  Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

TABLE

1.4

15

Illustrative Studies on Malignant Transformation of Oral Leukoplakia, Oral Potentially Malignant Disorders, and Dysplasia

Study

Year

Country

No. Cases

Follow-­Up (Years)

% Malignant Transformation

Pindborg et  al.504 Silverman and Rozen68 Mehta et  al.54 Mincer et al.207 Silverman et  al.208 Bánóczy and Csiba69 Bánóczy66 Gupta et al.140 Silverman et  al.153 Lind505 Hogewind et al.169 Lumerman et al.198 Schepman et  al.151 Shiu et  al.506 Lee et al.50 Cowan et al.168 Saito et  al.507 Holmstrup et  al.170

1968 1968 1972 1972 1976 1976 1977 1980 1984 1987 1989 1995 1998 2000 2000 2001 2001 2006

Denmark United States Indiaa United States Indiaa Hungary Hungary Indiaa United States Norway Netherlands United States Netherlands Taiwan United States United Kingdom Japan Denmark

248 117 117 38b 4762 68b 670 90b 22b 157 46 44b 166 435 70 165b 142 254

Amagasa et al.155 Hsue et al.199 Arduino et al.206 Liu et al.154 Sperandio et al.108

2006 2007 2009 2011 2013

Japan Taiwan Italy China United Kingdom

444 1458 207b 138b 1401

0–9 1–11 10 1–8 2 6.3 mean 9.8 mean 7 mean 7.2 mean 6–16 2.5 mean 1.5 mean 2.5 median 1–10 7 median n/a 4 mean 7.5 mean 6.6 mean 1–29 3.5 mean 4.5 median 5.3 mean 5–15

Dost et al.204

2014

Australia

368b

4.4 6.0 0.9 11.1 0.13 13.2 6 6.7 36.3 8.9 3.6 16 2.9/yr 26 30 15 6.3 12 (surgically treated)  4 (not treated) 7.9 3.02 7.3 5. mean 1.95 excl. Tf 25/10 high-­power fields [HPFs]) (Fig. 3.21).139 If only areas of carcinoma in situ are detected in a SP, it is recommended to sample the entire lesion to exclude the presence of small areas of invasive carcinoma. Approximately 40% to 45% of patients affected by carcinoma arising in SP die with local or disseminated disease, an average of 2.6 years from the initial diagnosis of carcinoma.  Salivary Gland–Type Tumors Clinical Features.  Tumors of the salivary gland type reportedly constitute 4% to 8% of neoplasms of the sinonasal tract.157–160 These tumors arise from the seromucinous glands of the nasal cavity and paranasal sinuses and the overlying surface epithelium.158,161 The clinical features of sinonasal salivary gland–type tumors are nonspecific, and most patients with malignant tumors present with clinical stages T3 and T4.158,162,163  Pathologic Features.  The pathologic features of these lesions are essentially similar to those of major and minor salivary glands, with the notable exceptions of Warthin tumor and pure sebaceous lesions that have not been reported in this location.159 Benign salivary-­ type tumors include pleomorphic adenoma, oncocytoma,164,165 myoepithelioma,166,167 and basal cell adenoma.168 The most frequent sinonasal malignant salivary-type tumor is adenoid cystic carcinoma,157,163,169 (Fig. 3.22) followed by mucoepidermoid carcinoma170 and carcinoma expleomorphic adenoma.171,172 However, several other histotypes have been reported, including examples of myoepithelial carcinoma,173 acinic cell carcinoma,174 basal cell adenocarcinoma,175 polymorphous adenocarcinoma,176 epithelial-myoepithelial carcinoma,177,178 salivary duct carcinoma, and clear cell carcinoma.179 Dehner and colleagues described a peculiar lesion that they designated salivary gland anlage tumor or congenital pleomorphic adenoma.180 This lesion is characteristically located in the midline of the nasopharynx of newborns. Its congenital nature and histologic similarity to the normally developing salivary gland have led some authors to suggest that the salivary gland anlage tumor may be a hamartomatous lesion.181 The tumor is polypoid in appearance, and, although benign, it may cause respiratory and feeding problems, including acute airway obstruction because of its location. Imaging studies show a well-­ defined mass. Microscopically, the tumor is well circumscribed

143

Fig. 3.21  Squamous cell carcinoma (top) arising in association with an oncocytic sinonasal papilloma (bottom).

Fig. 3.22  Classic cribriform adenoid cystic carcinoma is the most common salivary-­type adenocarcinoma involving the sinonasal tract.

and is covered by an intact surface mucosa, which appears to be in direct continuity with branching ductlike structures and cystic or solid squamous cell nests, within the substance of the lesion (Fig. 3.23A). These epithelial structures compartmentalize multiple solid nodules of ovoid and spindle cells with bland cytologic features (Fig. 3.23B).182,183 Immunohistochemical and ultrastructural studies have demonstrated a variable degree of myoepithelial differentiation within these nodules.180,182 Simple surgical excision is curative.183,184  Differential Diagnosis.  The diagnosis of salivary gland tumors in the sinonasal tract rests in awareness of their occurrence in this location and recognition of their typical morphological features. The main differential diagnoses of malignant salivary gland tumors are well-­differentiated sinonasal adenocarcinoma and intestinal-­type adenocarcinoma. Adenoid cystic carcinoma needs to be distinguished from the newly described HPV-­related multiphenotypic sinonasal carcinoma, described in detail later.185 The latter presents areas of dysplasia/ carcinoma in situ of the surface epithelium and is associated

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

Fig. 3.23  Salivary gland anlage tumor. A, Cystic ductlike structures lined with benign squamous epithelium continuous with the surface epithelium, surrounded by myxoid stroma. B, The tumor is composed of cellular nodules with spindled myoepithelial cells and cystic ductlike structures with squamous epithelium.

A

with high-­risk HPV (especially type 33), which are not features of adenoid cystic carcinoma. Moreover, rearrangement of the MYB or MYBL1 genes can be detected in most cases of adenoid cystic carcinoma, but not in the HPV-­related multiphenotypic sinonasal carcinoma. In addition, pleomorphic adenomas in the sinonasal area may cause diagnostic confusion with an adenocarcinoma, because of their hypercellularity, infrequent cartilage formation, closely apposed ducts, and lack of a well-­developed capsule. Careful histologic sampling and identification of the myoepithelial component will help with this differential diagnosis.  Treatment and Prognosis.  The treatment of salivary gland–type neoplasms in the sinonasal tract is complete surgical resection. The surgical approach used, the extent of the surgery, and, ultimately, the prognosis depends on the location and structures involved by the tumor and its histologic type.162 The reported 5-­year survival rate for malignant salivary gland tumors in the sinonasal tract has varied from 40% to 63%,157,158,162,163 with adenoid cystic carcinoma being the most difficult to control, owing to its advanced clinical stage at diagnosis and frequent involvement of surgical resection margins. In sinonasal adenoid cystic carcinoma, the overall 5-­, 10-­, and 20-­year disease-­specific survival rates are 66.5%, 41.1%, and 17.6%, respectively.186 Factors that confer a survival benefit include absence of metastases and presentation primarily in the nasal cavity.186 Postoperative radiotherapy significantly improves local control.158,162,163  Adenocarcinoma By definition, these are non-salivary gland–type adenocarcinomas. According to the WHO classification of head and neck tumors, sinonasal adenocarcinomas are classified into intestinal and nonintestinal types.187,188 The latter are further divided into low-­grade and high-­grade tumors. Intestinal-­Type Adenocarcinoma Clinical Features. The intestinal-­ type adenocarcinoma (ITAC) is composed of cells mimicking normal, adenomatous,

B

or carcinomatous intestinal mucosa.187,189–191 Approximately 85% of patients affected are male; the age at presentation has ranged from 23 to 84 years, with a mean of 50 to 64 years. The ethmoid sinus is the most commonly involved site (40%), followed by the nasal cavity and the maxillary antrum. Advanced tumors may involve the skull base extensively. Symptoms at presentation include nasal obstruction, epistaxis, facial pain, and the presence of a growing mass. Intestinal-­ type sinonasal adenocarcinoma has a strong association with long-­term exposure to fine hardwood dusts in the woodworking industry.192 In such populations, the incidence approaches 1000 times that of the general public.193–195 Approximately 20% of ITAC cases occur in patients with industrial wood dust exposure. Smoking and exposure to leather dust and nickel have also been incriminated.190,196 Although the morphologic features are similar, there seem to be clinical and prognostic differences between those cases arising in woodworkers and nonoccupational cases. Barnes reported 17 cases of sporadic ITAC and compared them with published cases of ITAC arising in woodworkers and found that tumors related to industrial dust exposure occur predominantly in men (85%– 95%) and show a striking predilection for the ethmoid sinus.190 Sporadic tumors frequently affect women and often arise in the maxillary antrum (20%–50%).  Pathologic Features. ITACs recapitulate the entire range of appearances assumed by normal and neoplastic large and small intestinal mucosa. At the well-­differentiated end of the spectrum are tumors that resemble normal intestinal mucosa (Fig. 3.24A) replete with goblet, resorptive, Paneth, and argentaffin cells, along with well-­formed villi and a muscularis mucosae.197 Although it is tempting to label such proliferations benign heterotopias, they are in fact aggressive, invasive lesions. The papillary tumors consist of elongated fronds lined with stratified columnar goblet cells, suggestive of an intestinal villous or tubular adenoma (Fig. 3.24B). The most common form of sinonasal ITAC resembles conventional colonic adenocarcinoma (Fig. 3.25A). In this variant, the neoplastic glands are lined with pleomorphic columnar cells arranged in a back-­to-­back

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

A

145

B

Fig. 3.24  Well-­differentiated intestinal-­type adenocarcinoma of the sinonasal tract resembling: A, small intestinal mucosa and B, colonic adenoma.

A

B

Fig. 3.25  A, Sinonasal intestinal-­type adenocarcinoma usually resembles usual colonic adenocarcinoma. B, Mucinous subtype of sinonasal intestinal-­ type adenocarcinoma with malignant glands “floating” in pools of extracellular mucin.

pattern, vary in size, and widely invade the underlying stroma and bone. Intracellular mucin is present focally, but goblet cells are not prominent. In less-­differentiated tumors, solid sheets of tumor cells may be present with only focal glandular lumina formation. Completing the analogy to intestinal neoplasms are the less frequent mucinous tumors. The predominant pattern in this variant consists of large glands distended with mucin or pools of extracellular mucin (Fig. 3.25B), with small clusters of neoplastic cells floating in it. Signet-­ring cells form a minor component; rarely they are predominant. Barnes divided these tumors into five morphologic types: papillary, colonic, solid, mucinous, and mixed, the last displaying an admixture of the preceding morphologies.190 Kleinsasser and Schroeder divided ITACs into papillary-­tubular cylindrical cell type (grades I, II, and III corresponding to Barnes’s papillary, colonic, and solid), alveolar goblet cell type, signet-­ring cell type (both corresponding to Barnes’s mucinous), and transitional (mixed) type.189 The resemblance of ITAC to normal and neoplastic intestinal epithelium is not limited to the light microscopic appearance. Ultrastructural studies have confirmed the presence of resorptive, goblet, Paneth, and argentaffin cells identical to their intestinal counterparts, and these tumors are positive for CK20 (Fig. 3.26A), CDX2 (Fig. 3.26B), SATB2, and villin, with variable expression of CK7.191,198–202 Focal expression

of chromogranin and other neuroendocrine markers may be observed. In rare examples of sinonasal adenocarcinomas, neoplastic cells present clear cytoplasm and subnuclear vacuoles imitating an endometrioid carcinoma with a secretory pattern (Fig. 3.27).  Differential Diagnosis. The rare ITACs resembling normal intestinal mucosa and papillary carcinomas resembling villous adenoma can easily be recognized as primary nasal lesions because intestinal epithelium with this histology is not capable of metastasis. There are no morphological features or immunocytochemical markers to distinguish primary nasal ITAC from a metastatic colonic carcinoma. Sinonasal ITACs express CK20, CDX2, SATB2, and villin similar to colonic carcinoma and variably express CK7.200 Interestingly, in contrast to colonic carcinomas, molecular pathology studies show infrequent KRAS, BRAF, EGFR,203–205 and mismatch repair gene (hMLH1, hMSH2) mutations in sinonasal adenocarcinomas.206 Antigen-­presenting cell (APC) and β-­catenin gene mutations have not been documented.207 TP53 mutations and alteration of CDKN2A are the most frequent genetic alterations.208–210 In a review of 82 tumors metastatic to the nose and paranasal sinuses, five were primary in the gastrointestinal tract.211,212 However, only in rare instances is the sinonasal lesion the initial clinical manifestation of disease. Before making the diagnosis

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

A

B Fig. 3.26  Sinonasal intestinal-­type adenocarcinoma is positive for: A, CK20 and B, CDX2.

overall survival at 5 years is 60% to 70% and at 10 years is 40% to 50%.216,217 The factors influencing the survival rates are predominantly local recurrence, development of distant metastasis, and the local extension of the lesion, with sphenoid lateral or posterior wall invasion as well as dura and/or cerebral extension, significantly determining a worse prognosis.218 In addition, some studies suggest the prognostic implications of histologic subtyping. Well-­differentiated ITACs (papillary type) may have a more indolent course, while poorly differentiated (solid types) and mucinous adenocarcinomas seem to have poorer survival rates.189,190,198,219 

Fig. 3.27  Sinonasal intestinal-­type adenocarcinoma of the sinonasal tract with clear cytoplasm resembling secretory-­type endometrium.

of ITAC, it is appropriate to exclude the presence of a colorectal carcinoma through clinical investigations.  Treatment and Prognosis. The treatment of ITAC is surgical resection with or without radiation, depending on the extent of disease.193,213 Until recently, open craniofacial resection and maxillectomy were the mainstay surgical procedures for treatment of these tumors. However, endoscopic procedures have increasingly been used since the 1990s, either as pure endoscopic approaches or in combination with craniotomy. These procedures only rarely allow en-­bloc resections, while carcinomas are most often removed piecemeal. Thus, frozen section assessment of margins is essential to ensure complete resection of all microscopic disease. Endoscopic procedures, when properly planned and performed by experienced surgeons, while significantly reducing postoperative complications, still guarantee similar overall disease-­free and survival rates of open procedures.214,215 Intestinal-­ type sinonasal adenocarcinomas are aggressive neoplasms. Approximately, 40% to 50% of patients develop local recurrence, with a mean time interval between treatment of the primary tumor and development of local recurrence of 33 months.190,216,217 Lymph node metastases develop in 5% to 15% of patients and distant metastases in 10% to 20%.216,217 The

Nonintestinal-­Type Adenocarcinoma.  Sinonasal nonintestinal-­ type adenocarcinomas are heterogeneous and are divided into low-­grade and high-­grade groups. Clinical Features. Low-­ grade sinonasal nonintestinal adenocarcinomas are rare neoplasms with no sex predile­ ction.188,220 Most cases arise in middle-­ aged adults with a mean age of 50 years.221 They also occur in children and the elderly (age range, 9–75 years). The nasal cavity is the most frequently involved site, followed by the ethmoid and maxillary sinuses. There is no known association with carcinogens. At presentation, most patients complain of nasal obstruction and epistaxis. Pain is uncommon. High-­grade sinonasal nonintestinal adenocarcinomas arise more frequently in men over a wide age range, with a mean age in the sixth decade.222 They are aggressive tumors that in most cases present in advanced stage, with involvement of the nasal cavities and paranasal sinuses, as well as the orbit and cranial fossa.  Pathologic Features. Low-­ grade sinonasal nonintestinal adenocarcinomas are morphologically a heterogeneous group of tumors. In some, the architectural and cytologic uniformity frequently leads to a misdiagnosis of adenoma or papilloma. The majority of cases consist of small glands lined with a single layer of uniform cuboidal or columnar cells. The neoplastic glands have a back-­to-­back arrangement, without intervening stroma (Fig. 3.28A). Some glands are cystically dilated or slit-­like with epithelial tufts, and others contain well-­formed papillae (Fig. 3.28B). Nucleus size varies from case to case but tends to be uniform within a given lesion. Mitotic figures are generally rare. Origin from surface mucosa may be seen. A

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Fig. 3.28  A, Low-­grade sinonasal adenocarcinoma with back-­to-­back, fused glands. Nuclear atypia is minimal and mitotic figures are rare. B, Some forms have a tubulopapillary architecture.

A

B Fig. 3.29  Low-­grade sinonasal adenocarcinoma is often positive for A, S100 protein and B, SOX10.

subset of low-­grade adenocarcinomas presents squamoid or morular metaplasia, consisting of squamoid nests showing none to focal keratinization.221 Low-­grade sinonasal nonintestinal adenocarcinomas are typically positive for S100 protein (Fig. 3.29A) and a subset are positive for SOX10 (Fig. 3.29B) and/ or DOG1, suggesting that at least a subset of these tumors arise from the seromucinous glands, not the surface epithelium.221 A recent paper has also revealed that occasional cases of low-­grade sinonasal nonintestinal adenocarcinoma harbor ETV6-­NTRK3 fusions associated with salivary secretory carcinoma.223 These fusion-­positive adenocarcinomas were negative for mammaglobin and only focally S100 protein-­positive, distinguishing it from true secretory carcinoma.223 Rare cases of low-­grade sinonasal nonintestinal adenocarcinoma resemble metastatic renal carcinoma and such examples are designated as “sinonasal renal cell-­like adenocarcinoma.”224–226 They are composed of a uniform population of polygonal cells with abundant glycogen-­rich clear cytoplasm without mucin production (Fig. 3.30), which are strongly positive with CK7 and CAIX but negative with PAX-­8 and RCC.

Fig. 3.30  Renal-­cell like sinonasal adenocarcinoma is composed of glands lined by cuboidal cells with optically clear cytoplasm and dark, round nuclei.

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Fig. 3.31  High-­grade sinonasal adenocarcinoma with necrosis and an elevated mitotic rate. The growth pattern is predominantly solid, with focal gland formation.

High-­grade nonintestinal adenocarcinomas show a higher degree of histologic variability than their low-­grade counterparts, suggesting that this is a heterogeneous group. Common features among high-­ grade adenocarcinomas include solid growth, presence of necrosis, pleomorphism, marked cytologic atypia, and brisk mitotic activity (Fig. 3.31).188,222 Several patterns can be recognized, including the blastomatous with rosette-­like glands, the oncocytic/mucinous, the poorly differentiated/undifferentiated, with predominant solid growth and occasional cribriform and papillary areas, and others.222 Neoplastic cells contain mucin at least focally, that can be demonstrated by mucicarmine or periodic acid-­Schiff (PAS) staining.  Differential Diagnosis. Low-­grade sinonasal nonintestinal adenocarcinoma must be distinguished from ITAC because of the more aggressive clinical course of the latter. Distinction is usually straightforward, given the nuclear stratification and intestinal appearance of the latter neoplasms. In addition, intestinal-­ type tumors are cytologically more pleomorphic than low-­ grade adenocarcinomas, with the exception of rare nasal neoplasms resembling normal intestinal mucosa. Immunohistochemical staining for cytokeratin 20 and CDX2 are helpful with this distinction. OSP may also be confused with low-­grade nonintestinal adenocarcinoma. Heffner and colleagues listed the following differentiation features: (1) stratified epithelium in papillomas as opposed to single-­layered cells in adenocarcinoma, (2) true glandular lumina in adenocarcinoma, and (3) more abundant myxomatous stroma in papillomas.220 Low-­ g rade sinonasal nonintestinal adenocarcinoma may be very difficult to distinguish from SH and/or REAH. Indeed, lesions showing an association of REAH and low-­ grade adenocarcinoma have been reported by Jo et  al.103 The absence of a lobular pattern and the tendency of glands to crowd and show fusion are in favor of a diagnosis of low-­grade adenocarcinoma.103,104 Sinonasal “renal cell-­like” adenocarcinoma can be separated from metastatic renal cell carcinoma based on the absence of PAX-­8 and RCC expression. It is differentiated from salivary-­ type clear cell carcinoma by an absence of p40, p63, and CK5/6 immunostaining, and it lacks the EWSR1 fusions seen in most salivary clear cell carcinomas.227

The differential diagnosis of high-­ grade nonintestinal adenocarcinomas is broad and includes poorly differentiated squamous carcinoma variants, sinonasal undifferentiated carcinoma, high-­grade salivary-­type carcinomas and teratocarcinosarcoma. Metastases should also be ruled out on clinical, radiographic, and where appropriate, immunohistochemical grounds.  Treatment and Prognosis. Patients with low-­grade adenocarcinoma have a good prognosis. Most patients have localized disease at presentation and do not require radical surgical procedures for complete resection of their tumors. The value of radiotherapy is unknown. Recurrences develop in approximately 25% of cases but metastases and tumor-­ related deaths are exceptionally rare.103,220,228,229 In contrast, the prognosis of high-­grade adenocarcinomas is poor, with frequent recurrences, occasional regional or distant metastases, and the majority of patients dying within 5 years.188,220,230  Nasopharyngeal Papillary Adenocarcinoma.  Nasopharyngeal papillary adenocarcinoma is a rare, indolent, histologically low-­ grade neoplasm that is restricted to the nasopharynx.231 Clinical Features. Nasopharyngeal papillary adeno­carcino­ mas can occur in patients of any age, with a mean in the fourth decade.232 The tumor may arise in any part of the nasopharynx, and patients present with obstruction, epistaxis, rhinorrhea, or ear symptoms.231  Pathologic Features. Nasopharyngeal papillary adenocar­ cinoma s­hows papillary and glandular growth patterns. The papillae are complex, exhibiting arborization and hyalinized fibrovascular cores (Fig. 3.32A). The glands have a crowded appearance with a cribriform pattern. The epithelial cells lining these structures are columnar or pseudostratified. They possess eosinophilic cytoplasm and round to oval nuclei with optically clear chromatin. Moderate nuclear pleomorphism is present, but mitotic figures are uncommon. Psammoma bodies and focal necrosis are occasionally seen. By immunohistochemistry these adenocarcinomas are positive for epithelial membrane antigen (EMA) and CK5/6. Interestingly, many of these tumors also express TTF-­1 (thyroid transcription factor 1) immunoreactivity (Fig. 3.32B), but are negative for thyroglobulin.233,234  Differential Diagnosis. The complex papillary pattern, vesicular nuclei, focal psammoma bodies, and TTF-­1 positivity seen in some low-­ grade nasopharyngeal adenocarcinomas may mimic a metastatic papillary carcinoma of the thyroid gland. However, while nasopharyngeal adenocarcinomas have tumor nuclei that may be elongated with overlapping, well-­ developed grooves and pseudoinclusions are absent. Moreover, nasopharyngeal papillary adenocarcinomas are negative for thyroglobulin.  Treatment and Prognosis. Nasopharyngeal papillary adeno­ carcinoma is treated with excision alone. It is very indolent with essentially no metastatic potential.  High-­Grade Neuroendocrine Carcinoma Clinical Features.  Carcinomas with morphologic features indistinguishable from small cell carcinoma (SmCC) and large cell neuroendocrine carcinomas (LCNEC) of the lung occasionally arise in the nasal cavity and paranasal sinuses.235–239 These tumors presumably arise from the surface epithelium and are occasionally seen in association with squamous cell carcinoma; rare cases show an association with high-­ risk

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Fig. 3.32  Nasopharyngeal papillary adenocarcinoma. A, Complex proliferation of fused papillae with psammoma bodies. B, Thyroid transcription factor 1 is often positive, which can cause confusion with papillary thyroid carcinoma.

Fig. 3.33 Sinonasal small cell carcinoma. This lesion is destroying the anterior wall of the left maxilla, involving the nasal cavity and the maxillary and ethmoid sinuses.

HPV.156,239,240 The age at presentation has ranged from 26 to 77 years, with a mean age of approximately 51 years for SmCC and 49 to 65 years with for LCNEC. The most common symptom at presentation is epistaxis followed by exophthalmos and nasal obstruction. Some of these tumors may have elevated hormonal levels; Kameya and colleagues described increased levels of adrenocorticotropin and calcitonin in two of their patients.241 Almost invariably, patients present at an advanced clinical stage with involvement of multiple sinuses and invasion of the skull base (Fig. 3.33).241  Clinical Features.  SmCCs are composed of sheets (Fig. 3.34A) and nests of small-­to intermediate-­size cells with a high nucleus-­to-­cytoplasm ratio, hyperchromatic nuclei with absent

or inconspicuous nucleoli, and frequent mitotic figures (>10 mitoses per 10 HPFs) (Fig. 3.34B). Nuclear molding, geographic necrosis, and the DNA incrustation in vascular walls (Azzopardi phenomenon) are often seen. A peculiar glomeruloid vascular proliferation has also been described in neuroendocrine tumors of the sinonasal tract and other locations.242 In LCNEC, the tumor cells present moderate amounts of pale eosinophilic to amphophilic cytoplasm and the nuclei contain finely dispersed chromatin, usually with a single prominent nucleolus (Fig. 3.35B). LCNEC grows as organoid nests with peripheral palisading of tumor nuclei, rosettes, and trabeculae (Fig. 3.35A). Comedonecrosis and a high mitotic rate (>10 mitoses per 10 HPFs) are seen. Immunohistochemical studies show that they are invariably positive for keratins (Fig. 3.36A), often with a perinuclear dot-­ like staining, with expression of at least one neuroendocrine marker, such as synaptophysin (Fig. 3.36B), chromogranin (Fig. 3.36C), or CD56.235 TTF-­1 immunostaining is variable (Fig. 3.36D), and squamous markers (e.g., p40, CK5/6) are negative or, at most, focal. Rare examples of sinonasal neuroendocrine carcinoma combined with either squamous cell carcinoma (in situ or invasive) or adenocarcinoma have been described.237,243,244 These tumors consist of two separate tumor components (Fig. 3.37A) that differ also immunohistochemically (Fig. 3.37B). However, squamous cell carcinomas or adenocarcinomas that lack morphologic evidence of neuroendocrine differentiation, but show partial immunoreactivity for neuroendocrine markers, should not be regarded as sinonasal neuroendocrine carcinomas.  Differential Diagnosis.  The differential diagnosis of sinonasal neuroendocrine carcinoma in the sinonasal tract includes olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), poorly differentiated and nonkeratinizing squamous cell carcinomas, malignant lymphoma, Ewing sarcoma, and others. This distinction may be difficult in some cases, but the combination of clinical, morphologic, immunohistochemical, and ultrastructural studies should allow a definitive diagnosis in most instances (Table 3.1). Sinonasal neuroendocrine carcinomas should be

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Fig. 3.34  Sinonasal small cell carcinoma, with: A, sheets and ribbons of basophilic cells with necrosis. B, Tumor cells have minimal cytoplasm with dark nuclei, with indistinct nucleoli and nuclear molding. Mitotic figures are abundant.

A

B

Fig. 3.35  A, Large cell neuroendocrine carcinoma demonstrating an organoid growth pattern. B, Unlike small cell carcinoma, large cell neuroendocrine carcinoma has cells with abundant cytoplasm and nuclei with vesicular chromatin and prominent nucleoli. Necrosis is seen and the mitotic rate is high.

distinguished from ONB because the latter has a better prognosis. The cells of ONB are arranged in a lobular pattern, often within a fibrillary background, and exhibit moderate amounts of cytoplasm, round nuclei and a low nucleus-­to-­cytoplasm ratio. Necrosis is uncommon. In contrast, neuroendocrine carcinoma lacks neurofibrillary stroma. The cells of SNEC have scant cytoplasm, a high nucleus-­to-­cytoplasm ratio, round or oval dense hyperchromatic nuclei, and numerous mitotic figures and apoptotic cells accompanied by extensive areas of necrosis. Immunohistochemically, neuroendocrine carcinoma lacks the S100 protein positive cells seen at the periphery of the cell nests of ONB. The expression of keratin in ONB is uncommon and when present is patchy or limited to areas with gland-­like or olfactory differentiation, in contrast to the diffuse staining seen in neuroendocrine carcinomas (see Fig. 3.52C). Nonkeratinizing or basaloid forms of squamous cell carcinoma of the sinonasal tract can be difficult to differentiate from SmCC.245 Both neoplasms are composed of small pleomorphic cells with high nucleus-­ to-­ cytoplasm ratios, inconspicuous nucleoli, high mitotic activity, and extensive areas of necrosis. However, SmCC does not have the well-­defined tumor lobules

with peripheral nuclear palisading, smooth contours, and hyaline basal lamina seen in basaloid squamous cell carcinoma. All forms of squamous cell carcinoma are diffusely positive for p40 and CK5/6, but are negative for synaptophysin and chromogranin.246,247 Among sarcomas, alveolar rhabdomyosarcoma may express neuroendocrine markers (especially CD56) and cytokeratins, thus posing significant problems in the differential diagnosis. However, it is diffusely positive for desmin and myogenin, and harbors PAX3/7-­FOXO1A gene fusions. A subset of Ewing sarcomas, which may also occur in the sinonasal region, is characterized by an “adamantinoma-­like” morphology, cytokeratin expression, and focal positivity for neuroendocrine markers (Fig. 3.38).248 Such tumors may show a significant overlap with neuroendocrine (or squamous cell) carcinomas, and it is therefore recommended to test for EWSR gene rearrangements in such cases.  Treatment and Prognosis.  Neuroendocrine carcinomas of the sinonasal tract are aggressive, with frequent regional and/ or distant metastases and a 5-­year survival of about 50% to 65%.235 They are typically managed in a multimodal manner,

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Fig. 3.36  Sinonasal high-­grade neuroendocrine carcinomas are positive for: A, cytokeratin, often in a dot-­like pattern; B, synaptophysin; and C, chromogranin. D, Thyroid transcription factor 1 is variably positive.

A

B

Fig. 3.37  A, Combined squamous cell carcinoma and large cell neuroendocrine carcinoma. B, Only the squamous component is positive for p40.

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TABLE

3.1

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“Small Round Blue Cell” Tumors of the Sinonasal Tract CK

p40 or p63

SYN/CHR

S100

Other

Adamantinoma-­like Ewing sarcoma

+

++

+/–

–/+

CD99+; NKX2.2+; EWSR1-­FLI1 fusion

Adenoid cystic carcinoma, solid type

+ (biphasic pattern)

+/– (abluminal)

–

+/– (ductal or (abluminal)

Myoepithelial markers (actin, calponin, GFAP, etc.)+; c-­kit+ (ducts); MYB-­NFIB or MYBL1-­NFIB fusions

Alveolar rhabdomyosarcoma

–

–

–/focal+

–/+

CD56+; Desmin+; Myogenin+; PAX3/7-­FOXO1A fusions

B-­cell lymphoma

–

+/– (p63) – (p40)

–

–

CD20+; CD79a+

Ewing sarcoma (conventional)

–

–

+/–

–/+

CD99+; NKX2.2+; EWSR1-­FLI1 fusion

HPV-­related multiphenotypic sinonasal carcinoma

+

+ (abluminal)

–

+/– (ductal or (abluminal)

p16 and HPV+ (usually type 33); myoepithelial markers (actin, calponin, GFAP, etc.)+; c-­kit+ (ducts)

Melanoma

–

–

–

+

SOX10+; HMB45+, MelanA+

Nasopharyngeal carcinoma or sinonasal lymphoepithelial-­like carcinoma

+

++

–

–

EBER4+

Neuroendocrine carcinoma

+ (sometimes dot-­like)

–/focal+

+

–

TTF-­1 +/–

NK/T-­cell lymphoma

–

–/+ (p63) – (p40)

–

–

CD3 (cytoplasmic)+; CD56+; TIA+; granzyme+; perforin+; EBER+

Nonkeratinizing squamous cell carcinoma

+

++

–

–

HPV +/–

NUT carcinoma

+

++

–

–

NUT+; CD34+/–; NUTM1 fusions

Olfactory neuroblastoma

–/focal+

–

+

+ (sustentacular)

Calretinin+

Pituitary adenoma

+/–

–

+

–

Pituitary hormones +/–

Plasmacytoma

–

–

–

–

CD138+; CD38+; MUM1+; kappa or lambda chain restriction

Sinonasal undifferentiated carcinoma

+

–/focal+

–/focal+

–

IDH2 mutations +/–

SMARCB1-­deficient sinonasal carcinoma

+

+/–

–/+

–/+

SMARCB1–; SMARCB1 mutations

Teratocarcinosarcoma

+ (epithelial components)

++ (squamous component)

+ (neuro-­ ectodermal component)

–

Mesenchymal markers (e.g., desmin, myogenin) in spindled component

CHR, Chromogranin; CK, pan-­cytokeratin (AE1/AE3 or similar); EBER, Epstein-­Barr virus–encoded small ribonucleic acid; HPV, human papillomavirus; NK, natural killer, SYN, synaptophysin.

with combination surgery, chemotherapy, and/or radiation therapy. Although data is limited, LCNEC appears to have a better prognosis than SmCC.249–253  Neuroendocrine Carcinoma, Not Otherwise Specified.  Low-­ or intermediate-­ grade neuroendocrine carcinomas of the sinonasal tract are extremely uncommon, with only isolated case reports.254–256 The nature of these tumors, variably referred to as carcinoid tumors, “olfactory carcinomas,” or neuroendocrine carcinomas, not otherwise specified, is uncertain. Some of these reported tumors, particularly those involving the sphenoid sinus, likely represent ectopic pituitary adenomas.257,258 

Sinonasal Undifferentiated Carcinoma Clinical Features.  Sinonasal undifferentiated carcinoma (SNUC) is a highly aggressive, undifferentiated anaplastic carcinoma, without obvious squamous or glandular differentiation.259–261 This tumor is a distinct clinicopathologic entity and needs to be distinguished from other poorly differentiated carcinomas. The etiology of SNUC is uncertain. Although earlier reports suggested a role for Epstein-Barr virus (EBV) in the pathogenesis of SNUC,262 subsequent studies in morphologically well-­defined cases have not shown the EBV genome in SNUC.263,264 Only occasional cases have been reported to harbor high-­risk HPV.156,265,266

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Fig. 3.38  A, Adamantinoma-­like Ewing sarcoma consisting of lobules of primitive, basaloid cells. B, This variant is strongly positive for cytokeratin. C, Synaptophysin is variably positive, raising the possibility of neuroendocrine carcinoma. D, Like conventional Ewing sarcoma, the adamantinoma-­ like variant is positive for CD99 in a membranous pattern, and harbors EWSR1 translocations (inset).

The age range at presentation is broad, with both young adults and the elderly being affected. The median age is reported to be in the sixth decade. There is a male predominance (2–3:1), and an association with smoking has been reported.259,260,261 Symptoms are related to an extensively infiltrative and destructive sinonasal mass. Involvement of the nasal cavity, maxillary antrum, ethmoid sinus, sphenoid sinus, frontal sinus, nasopharynx, orbit, and cranial cavity is frequent (Fig. 3.39A).259–261  Pathologic Features.  SNUCs consist of nests, trabeculae, ribbons, and sheets of medium-­size polygonal cells, often with an organoid appearance (Fig. 3.39B). The nuclei are round to oval, slightly-­to-­moderately pleomorphic, and hyperchromatic. The chromatin varies from diffuse to coarsely granular, and the nucleoli are typically prominent (Fig. 3.39C). Most cells have small to moderate amounts of eosinophilic cytoplasm. Mitotic figures are numerous, and vascular invasion is extensive. Individual cell necrosis, and central comedo-­type necrosis of cell nests are common (see Fig. 3.39B). Squamous and glandular differentiation is absent, by definition; however, focal squamous differentiation has been reported in occasional cases.267 Occasional SNUCs may be associated with severe dysplasia or carcinoma in situ of the overlying surface

mucosa. Immunocytochemical stains for pan-­cytokeratin and simple keratins, including CK7, CK8, and CK19, are positive in all cases.268 SNUC is either negative or, at most, focally positive for the squamous markers CK5/6, p63, and p40. Focal immunoreactivity for synaptophysin and chromogranin may also be seen, but not to the extent of what is seen in neuroendocrine carcinomas.  Differential Diagnosis.  Differential diagnostic considerations for SNUC are extensive and include, among others, poorly differentiated squamous cell carcinoma, high-­ grade ONB (grades III–IV), lymphoepithelial-­like carcinoma (either primary to the sinonasal tract or secondary from the nasopharynx), large cell lymphoma, and malignant melanoma (see Table 3.1). SNUC is essentially a diagnosis of exclusion for a cytokeratin-­ positive, high-­grade malignant neoplasm that does not show specific differentiation at the histologic and immunophenotypic levels. Diffuse expression of the squamous markers p40 or CK5/6, for example, excludes the diagnosis of SNUC, as does positivity for EBV by Epstein-­Barr virus–encoded small RNAs (EBER). Recently, several tumor entities have been described that, in the past, likely would have been diagnosed as SNUC.

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C

Fig. 3.39  Sinonasal undifferentiated carcinoma. A, Imaging reveals a large, destructive tumor of the right maxillary sinus and nasal cavity (asterisk). B, The tumor grows in a nested pattern. C, Nests and ribbons of undifferentiated cells with a high mitotic rate are seen. No specific differentiation (i.e., squamous, glandular, or neuroendocrine) is apparent.

This group of “SNUC-­like” sinonasal tumors includes NUT carcinoma, SMARCB1-­ deficient sinonasal carcinoma, and adamantinoma-­like Ewing sarcoma.248,269,270 Emerging data has also shown that a subset of tumors diagnosed as SNUC harbor IDH2 mutations; it is not yet clear whether this group represents yet another distinct tumor type.271,272  Treatment and Prognosis.  The prognosis of SNUC is poor but has improved in recent years as a result of aggressive multimodality therapy. The median survival is approximately 22 months, with a 5-­year survival of 30% to 40%.261,273,274  NUT Carcinoma NUT carcinoma (formerly NUT midline carcinoma) is a recently recognized high-­grade malignancy that has a predilection for the mediastinum and head and neck, particularly the sinonasal tract. It is defined by the presence of gene fusions involving the NUT gene.269,275,276 Clinical Features.  NUT carcinoma can affect patients of any age but is seen most often in children and young adults (median, 22 years). Patients with nasal tumors present with a rapidly growing mass, obstruction, epistaxis, discharge, and eye-­related symptoms. About half of patients with NUT carcinoma present with metastatic disease.277 

Pathologic Features.  NUT carcinoma grows as nests and sheets of undifferentiated tumor cells with uniform round to oval nuclei and prominent nucleoli (Fig. 3.40A). An in situ carcinoma component is not identified. It is histologically high-­grade, with high mitotic rates, tumor necrosis, and frequent invasion of local structures (Fig. 3.40B). A histologic clue is the frequent presence of abrupt keratinization among the background of undifferentiated cells (Fig. 3.40C). An intratumoral infiltrate of neutrophils is also common. By immunohistochemistry, NUT carcinoma is positive for cytokeratins and usually positive for squamous markers like p40 and CK5/6. Occasionally, focal positivity for neuroendocrine markers may be seen. NUT carcinoma is defined by the presence of NUT gene fusion, usually with BRD4 but occasionally BRD3 or other genes. The introduction of a highly sensitive and specific immunostain for NUT has greatly simplified the diagnosis of NUT carcinoma, as diffuse (>50%) nuclear reactivity, usually with a speckled pattern, is considered diagnostic (Fig. 3.40D).275,278  Differential Diagnosis.  The histologic differential diagnosis of NUT carcinoma is extensive and includes essentially any of the sinonasal “small round blue cell” tumors (see Table 3.1). NUT carcinoma is most frequently confused for squamous cell carcinoma and SNUC.269 The presence of abrupt keratinization

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Fig. 3.40  NUT carcinoma. A, The tumor consists of nests and sheets of cells in the sinonasal submucosa. B, The tumor cells are highly undifferentiated, with high mitotic rates and necrosis. C, An “abrupt” pattern of keratinization is commonly seen. D, Diffuse NUT immunostaining confirms the diagnosis.

and nuclear uniformity in the face of other high-­ grade features are helpful clues to the diagnosis, but these features are not entirely reliable and are mimicked by the newly described adamantinoma-­like Ewing sarcoma.248 Ultimately when the diagnosis of NUT carcinoma is considered, NUT immunohistochemistry and/or molecular testing will resolve the diagnosis.  Treatment and Prognosis.  NUT carcinoma has a poor prog­ nosis, with a median survival of 9.8 months, with even aggressive multimodality therapy showing limited effectiveness.275 Recently, however, clinical trials for targeted agents (bromodomain inhibitors) have demonstrated encouraging results.279  SMARCB1-­Deficient Sinonasal Carcinoma SMARCB1 (INI-­1) is a tumor suppressor gene located on chromosome 22, and its gene product is expressed in nuclei of all normal tissues. Inactivation of SMARCB1 has been implicated in the pathogenesis of a group of malignant neoplasms with “rhabdoid” morphologic features, including atypical teratoid/ rhabdoid tumor of the brain, malignant rhabdoid tumors of the kidney and soft tissue, epithelioid sarcoma, renal medullary carcinoma, myoepithelial carcinoma of soft tissue, and others.280

Recently, several cases SMARCB1-­deficient sinonasal carcinoma have been described.270,281,282 While there is not yet a consensus on whether SMARCB1-­deficient sinonasal carcinoma is a distinct tumor entity, the evidence seems to suggest that it is. SMARCB1-­deficient sinonasal carcinomas defy classification as another recognized tumor type and they show no evidence of high-­grade transformation from a well-­differentiated carcinoma. Moreover, SMARBC1 loss is not encountered in other well-­defined types of sinonasal carcinomas, but rather seems to localize to a highly undifferentiated carcinoma with varying degrees of plasmacytoid/rhabdoid cells. Clinical Features.  More than 50 SMARCB1 (INI-­ 1)deficient sinonasal carcinomas have been described, arising in patients ranging from 19 to 89 years (mean, sixth decade) with a slight male predominance. Cases have been limited to the sinonasal tract, often with extension into the orbit. Patients present with nasal obstruction, pain, epistaxis, and occasionally with eye symptoms.  Pathologic Features.  SMARCB1-­deficient sinonasal carcinoma grows as nests of undifferentiated-­appearing cells in the sinonasal submucosa. Carcinoma-­in-­situ is not identified, although pagetoid epithelial spread of tumor cells is occasionally

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B

C

D

Fig. 3.41  SMARCB1-­deficient sinonasal carcinoma. A, Although carcinoma-­in-­situ has not been described, a pagetoid pattern of intraepithelial tumor spread is sometimes seen. B, A common, basaloid pattern resembles squamous cell carcinoma or sinonasal undifferentiated carcinoma at low pattern. C, Less often, the carcinoma is eosinophilic, made up of cells with a plasmacytoid or rhabdoid appearance. D, Even in the basaloid examples, scattered individual rhabdoid cells are usually present at least focally.

encountered (Fig. 3.41A). The carcinomas are highly infiltrative and high grade, with high mitotic rates and frequent necrosis (Fig. 3.41B). Nonspecific vacuoles are often seen within the invasive tumor nests. Approximately one-­third of cases are eosinophilic and composed of numerous tumor cells with a rhabdoid or plasmacytoid cytomorphology, similar to other SMARCB1-­deficient malignant neoplasms (Fig. 3.41C). The remaining two-­thirds of cases, however, have a more basaloid appearance, reminiscent of SNUC or nonkeratinizing squamous cell carcinoma at low power (see Fig. 3.41B). Even in these basaloid cases, however, occasional rhabdoid cells can be seen singly distributed in the tumor nests (Fig. 3.41D). A recent series expanded the spectrum of SMARCB1-­deficient sinonasal carcinomas to include rare examples with glandular or sarcomatoid features.282 By immunohistochemistry, SMARCB1-­deficient sinonasal carcinomas are consistently positive for cytokeratins and negative for SMARCB1 (Fig. 3.42). They are variably positive for p40, CK5, and CK7; occasional cases are focally positive for neuroendocrine markers synaptophysin, chromogranin, and CD56. All cases are negative for HPV, EBV, and NUT. Molecular analysis has shown that most, but not all, cases harbor either

homozygous or heterozygous deletions of SMARBC1 by fluorescent in situ hybridization (FISH).  Differential Diagnosis.  The differential diagnosis of SMARCB1-­deficient sinonasal carcinomas includes nonke­ ratinizing squamous cell carcinoma and SNUC for the basaloid variant (see Table 3.1), and myoepithelial carcinoma and epithelioid sarcoma for the rhabdoid/plasmacytoid variant. SMARCB1-­deficient sinonasal carcinoma does not show overt squamous differentiation, and the absence of SMARCB1 immunostaining excludes SNUC and squamous cell carcinoma. Separation from epithelioid sarcoma (which is usually SMARCB1-­deficient) and myoepithelial carcinoma (which occasionally lacks SMARCB1 expression) is more challenging. SMARCB1-­deficient sinonasal carcinoma lacks staining for myoepithelial markers, such as S100 protein, actin, calponin, and glial fibrillary acidic protein (GFAP). Epithelioid sarcoma has a pseudogranulomatous appearance and is often CD34-­positive, in contrast to SMARCB1-­deficient sinonasal carcinoma. Recent studies have shown that claudin-­4 immunoexpression is consistently seen in SMARCB1-­ deficient carcinomas and not in SMARCB1-­deficient sarcomas of various sites.283 

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Fig. 3.42  SMARCB1-­deficient sinonasal carcinoma demonstrates loss of expression of SMARCB1. Note the normal fibroblasts and vessels with retained staining.

Treatment and Prognosis.  There is no established therapy for SMARCB1-­ deficient sinonasal carcinoma. Patients have been treated with combined surgery, radiation, and/or chemotherapy. Affected patients tend to present at high-­stage, and 56% of patients have died of their disease, 15 months after diagnosis on average.282  HPV-­Related Multiphenotypic Sinonasal Carcinoma Recent studies using updated HPV detection techniques have consistently shown that 20% to 25% of sinonasal carcinomas harbor high-­risk HPV.156,266,284 While most cases of HPV-­ related sinonasal carcinoma have a nonkeratinizing squamous phenotype, there is one carcinoma that appears to be unique to the sinonasal tract: HPV-­related multiphenotypic sinonasal carcinoma (HMSC). HMSC, which was formerly known as HPV-­related carcinoma with adenoid cystic like features, is notable for its resemblance to salivary-­type carcinomas, especially adenoid cystic carcinoma.185,285 HMSC was included as a provisional entity in the newest WHO classification of head and neck tumors.286 Clinical Features.  Approximately 50 cases of HMSC have been published. They occur in adults ranging from 28 to 90 years (mean, 54 years), with a 3:2 female predominance. Patients present with obstruction, epistaxis, nasal discharge, and occasionally pain or eye symptoms.285  Pathologic Features.  HMSC consists of highly cellular proliferations of basophilic cells growing as solid nests (Fig. 3.43A), with minor components of tubular and/or cribriform structures (Fig. 3.43B). Necrosis is commonly seen, and mitotic rates are high. The tumors are biphasic, with a dominant population of cells that demonstrate myoepithelial phenotype, including cytoplasmic clearing, spindling, and/or hyaline matrix deposition (Fig. 3.43C). There is usually a minor population of ducts composed of cuboidal eosinophilic cells (see Fig. 3.43B); this ductal population is often subtle and unapparent at low power. While the biphasic population of ducts and myoepithelial cells is quite salivary-­like, HMSCs also exhibit features of squamous cell carcinoma. Most cases demonstrate surface tumor involvement in the form of severe squamous

157

epithelial atypia observed in the overlying surface epithelium (Fig. 3.43D). It is not yet clear whether this epithelial involvement represents true dysplasia; it often demonstrates a bizarre, degenerative appearance. On occasion, squamous differentiation is seen in the invasive tumor component as well. A recent paper has expanded the spectrum of HMSC to include rare cases with sarcomatoid features, including chondroosseous differentiation.285 Immunohistochemical studies highlight the biphasic nature of the HMSC. Myoepithelial markers p40 (Fig. 3.44B), calponin, S100 protein, and actin highlight the predominant myoepithelial cells, while c-­kit specifically labels ducts. Cytokeratin is strongly positive in the ducts and weakly positive in the myoepithelial cells (Fig. 3.44A).285 All cases are strongly positive for p16 by immunohistochemistry (Fig. 3.44C) and harbor high-­ risk HPV by in situ hybridization (Fig. 3.44D) or polymerase chain reaction (PCR). Interestingly, HPV type 33 is most commonly positive (in two-­thirds of cases), with only one published case positive for type 16.285  Differential Diagnosis.  The differential diagnosis of HMSC includes squamous cell carcinoma, particularly the basaloid variant, and a salivary-­type adenocarcinoma. The presence of two cell populations and myoepithelial differentiation excludes squamous cell carcinoma. While HMSC may closely resemble salivary type carcinomas, particularly adenoid cystic carcinoma, it is always HPV-­ positive, frequently demonstrates surface squamous carcinoma involvement, and consistently lacks MYB or MYBL1 fusions.285  Treatment and Prognosis.  HMSC has a high-­ grade histologic appearance and presents at high stage (T3 or T4) in nearly half of cases, yet appears to behave somewhat indolently. In the largest series by Bishop et  al., local recurrences were not uncommon (36%), only 5% of tumors metastasized, and no patients had died as a result of their carcinoma.285 HMSCs have been treated with surgery, radiation therapy, and/or chemotherapy either alone or in combination.  NEUROECTODERMAL/MELANOCYTIC TUMORS Paraganglioma Clinical Features.  Paragangliomas have been reported as primary tumors in the nasopharynx, nasal cavity, and paranasal sinuses,287–289 or as secondary lesions extending from a carotid body or jugulotympanic or vagal paraganglioma.287,290 Most reported cases have occurred in females with a wide age range. Paragangliomas are most commonly seen as polypoid or exophytic masses in the middle or inferior turbinate. They have also been described in the posterior ethmoidal area, lateral and posterior pharyngeal walls, and posterior choana.  Pathologic Features and Differential Diagnosis.  The recognition of paragangliomas in the sinonasal tract is mainly based on the awareness of their occurrence in this region. The microscopic characteristics are similar to those of paragangliomas in other head and neck locations. Paragangliomas may show significant nuclear pleomorphism; however, they are not mitotically active. The differential diagnosis primarily includes olfactory neuroblastoma (ONB) and pituitary adenoma. The cell nests of paraganglioma and ONB are surrounded by S100–positive sustentacular cells; however, the chief cells of paraganglioma have more abundant

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A

B

C

D

Fig. 3.43  Human papillomavirus–related multiphenotypic sinonasal carcinoma. A, The tumors grow as solid nests in the sinonasal submucosa. B, Cribriform structures are also often encountered. There are two cell types, the predominant myoepithelial cells and scattered eosinophilic ductal cells. C, Features of myoepithelial cell differentiation include clear cytoplasm and eosinophilic matrix production. D, Most cases demonstrate bizarre surface squamous epithelial atypia, which may represent a premalignant change.

cytoplasm and large vesicular nuclei that often exhibit prominent nucleoli and pseudonucleoli. Paragangliomas do not exhibit a neurofibrillary background or rosettes characteristic of ONBs. Pituitary adenomas may be distinguished from paragangliomas based on smaller tumor cell size and the immunohistochemical expression of cytokeratins and specific pituitary hormones. Up to 30% of head and neck paragangliomas are familial, and the most common genetic alteration in familial paragangliomas is a mutation in genes encoding various subunits of the succinate dehydrogenase (SDH) enzyme complex: SDH-­B, SDH-­C, and SDH-­D. Recent studies have shown that a lack of immunoexpression of SDH-­B protein strongly correlates with a germline mutation in one of the genes in the SDH complex. This may be useful prognostically (a lack of expression is associated with an increased risk of metastasis) and may also guide genetic screening.291  Treatment and Prognosis.  Sinonasal paragangliomas generally behave in a benign fashion, but rare cases of malignant paraganglioma of the nasal cavity have been described.288,289 The latter appear to be aggressive neoplasms characterized by the development of multiple local recurrences and brain metastases. The treatment of sinonasal paragangliomas is complete surgical

resection, if possible. In recurrent or malignant tumors, surgical debulking and radiotherapy may provide long-­term local control.  Malignant Melanoma Clinical Features.  Primary malignant melanoma of the sinonasal tract constitutes approximately 1% of all melanomas.292–295 The nasal cavity is more frequently affected than the paranasal sinuses. In the nasal cavity, involvement of the anterior septum, inferior turbinate, and middle turbinate is most common. The maxillary antrum, followed by the ethmoid sinuses, are the most frequently involved paranasal sinuses.296–298 Primary melanomas of the frontal and sphenoid sinuses and the nasopharynx are extremely rare. There is no sex or race predilection, and 80% of the patients are older than 50 years of age with median age in the seventh decade.295,298 Symptoms at presentation are nonspecific and are related to the location of the tumor; they include nasal obstruction, epistaxis, facial pain, and sometimes melanorrhea or black mucus discharge. Symptoms may be present for a few weeks, several months, or even several years.  Pathologic Features.  Sinonasal melanomas are frequently polypoid or sessile nodules of tan-­pink or brown-­black color, depending on the absence or presence of pigment (Fig. 3.45).

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

A

B

C

D

159

Fig. 3.44  Human papillomavirus–related multiphenotypic sinonasal carcinoma. A, Cytokeratin staining is biphasic, with strong staining in ducts and weak staining in myoepithelial cells. B, P40 demonstrates abluminal staining, sparing the tumor ducts. C, p16 is diffusely positive. D, High-­risk human papillomavirus is invariably present, as demonstrated by RNA in situ hybridization.

Fig. 3.45  Pigmented melanoma of the nasal cavity presenting as a sessile, dark tan nodule.

The polypoid masses are 2 to 3 cm in size; however, larger tumors involving several paranasal sinuses and extending into the skull base are not uncommon. Mucosal ulceration, hemorrhage, and necrosis are frequent. Histologically, melanomas have a varied cytologic appearance. Most are composed of large epithelioid

cells with abundant eosinophilic cytoplasm with round nuclei showing prominent eosinophilic nucleoli and/or spindle cells (Fig. 3.46A). Approximately 30% to 40% of the tumors are composed of undifferentiated small round blue cells resembling lymphoma or other small round blue cell tumors (see Fig. 3.46B). Tumors may show plasmacytoid, rhabdoid, or large, pleomorphic, multinucleated, bizarre giant cells and rarely clear or vacuolated cells. Frequently, an admixture of several morphologic tumor cell types is present. Tumor cells usually exhibit significant nuclear pleomorphism and numerous mitotic figures, including atypical forms. Approximately 80% of tumors have cytoplasmic pigment at least focally (Fig. 3.46C). The neoplastic cells are arranged in an array of architectural patterns: solid, organoid, trabecular, alveolar, or any combination of these patterns. Spindle cell tumors may resemble high-­grade sarcomas (Fig. 3.46D). Extensively necrotic tumors may show a pseudopapillary (peritheliomatous) architecture caused by the preservation of perivascular tumor cells (Fig. 3.47A).298,299 Vascular and neural invasion is frequent. Junctional activity or pagetoid changes and cellular nests or theques may be identified in the adjacent nonulcerated epithelium in more than 70% of tumors, if diligently searched (Fig. 3.47B). However, unlike the cutaneous and oral melanoma, sinonasal melanoma does not present as pure in situ preinvasive or intraepithelial tumors.299 All sinonasal melanomas are invasive, with 60%

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A

B

C

D

Fig. 3.46  Some of the variable patterns of sinonasal malignant melanoma. A, Nested; B, sheet-­like; C, pigmented; and D, spindled.

A

B

Fig. 3.47  A, Sinonasal malignant melanoma often exhibits a peritheliomatous pattern, with necrosis and viable tumor cells clinging to the vessels. B, Foci of melanoma-­in-­situ are often seen in cases of sinonasal melanoma.

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

incidence of infiltration into deep tissues (e.g., bone, cartilage, and/or skeletal muscle). Desmoplastic variants are exceedingly rare.300 Melanomas are usually positive for vimentin, S100 protein (95%) (Fig. 3.48A), HMB-­45 (98%) (Fig. 3.48B), and other melanocytic markers like MART1/A103 (Fig. 3.48C), SOX10 (Fig. 3.48D), MiTF, and tyrosinase. In amelanotic tumors, the use of these stains is very helpful in establishing a definitive diagnosis.301 However, there are some caveats in the use of immunohistochemical markers in the diagnosis of sinonasal melanoma that should be taken into account. These tumors may express neural markers such as neurofilament and synaptophysin,302,303 cytokeratins,304 and desmin.305 Unlike cutaneous melanoma, sinonasal melanoma presents higher rates of NRAS and KIT mutations, while BRAF is only rarely mutated.306  Differential Diagnosis.  The differential diagnosis of sinonasal malignant melanoma varies according to the cellular morphology and predominant architecture of the primary tumor. In lesions with epithelioid or spindle cell patterns, or both, the possibilities of a poorly differentiated carcinoma, sarcomatoid carcinoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor, and other sarcomas should be excluded. Tumors comprising small undifferentiated cells (small

161

round blue cells) need to be distinguished from lymphoma, rhabdomyosarcoma, Ewing sarcoma, ONB, and SmCC (see Table 3.1). The presence of melanin pigment and junctional activity accompanied by immunohistochemistry with an appropriate panel of antibodies is of great value in establishing a definitive diagnosis. Metastatic melanoma to the sinonasal area may rarely be seen in association with stage IV widely disseminated cutaneous melanoma. Clinical history and in situ melanoma in the respiratory mucosa may help distinguish primary from secondary sinonasal melanoma.  Treatment and Prognosis.  Clinical staging and histologic microstaging are independent predictors of survival.300,307,308 The most frequently used clinical staging is independent of tumor size and takes into account the presence of metastasis to the regional lymph nodes and distant sites. The vast majority (80%– 85%) of sinonasal melanomas are localized (N0M0) at presentation, and less than 10% have regional lymph node and distant metastasis.298,301,308 However, during the course of disease, 40% to 50% of the patients develop distant metastasis.301,308 Tumors with distant metastasis (stage III) or deep-­tissue invasion (level III) have a poor prognosis. The presence of undifferentiated tumor cells comprising more than 25% of the tumor or pseudopapillary or sarcomatoid architecture reduces survival significantly

A

B

C

D Fig. 3.48  Sinonasal malignant melanoma is positive for: A, S100 protein; B, HMB45; C, Melan-­A; and D, SOX10.

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compared with tumors without these features. In one study, vascular invasion was a significant predictor of disease progression (i.e., local recurrence, nodal metastasis, distant metastasis, and poor disease-­specific survival).308 Complete surgical resection is the treatment of choice. Radiotherapy and chemotherapy are of little value. Malignant melanoma of the sinonasal tract is an aggressive disease with a 60% to 80% local recurrence rate, median survival of 2 to 3 years, and 5-­year disease-­specific survival varying from 10% to 47%.294,295,297,298,308,309 Metastases to the lung, brain, and liver are common.296,297,310 Interestingly, long-­ term survival has been reported in a small number of patients. NRAS, KIT, and BRAF mutations represent possible targets for alternative treatments in patients with metastatic disease.311 The use of immunotherapy is currently under evaluation. Maxillary or ethmoid sinus disease has a worse prognosis than nasal cavity disease, and patients presenting with involvement of multiple sinuses show the worst prognosis.312  Olfactory Neuroblastoma Clinical Features.  ONB was first described by Berger and colleagues in 1924.313 Since then, it has been described and referred to by numerous terms: esthesioneuroblastoma, esthesioneuroepithelioma, esthesioneurocytoma, and olfactory placode tumor. ONB is an uncommon tumor and makes up approximately 10% of all nonsquamous malignancies in the nasal cavities and paranasal sinuses.314 These tumors arise almost exclusively in the area of the cribriform plate, in the superior portion of the nasal cavity. The putative cell of origin is a basal reserve cell, the olfactory stem cell that gives rise to both neuronal and epithelial (sustentacular) cells.315,316 There is no race or gender predilection. ONB is seen in a broad age range (11 to older than 90 years) with bimodal peaks at 15 and 50 years. However, most cases present in the third and fourth decades.315–317 The main presenting symptoms are nasal obstruction and epistaxis, while headache, visual disturbances and anosmia are uncommon. In rare cases, ONB may be associated with paraneoplastic syndromes caused by secretion of hormones and peptides by neoplastic cells.318 ONBs are slow-­ growing tumors, and symptoms may be present for a variable duration of time. Clinical and radiologic

A

examination usually demonstrates a polypoid mass high in the nasal cavity, often extending into the paranasal sinuses. The classic radiologic image is that of a dumbbell-­shaped mass in the superior nasal cavity with extension into the intracranial cavity across the cribriform plate.317 In 1976 Kadish and colleagues proposed a staging system for these neoplasms (Table 3.2).319 Most tumors are in stage B and C at presentation, with less than 10% having nodal and distant metastases.316,320 This system has been modified by Morita et al. by adding a stage D for the presence of loco-­regional and/or distant metastases.321  Pathologic Features.  Under low-­power magnification, most ONBs present a characteristic architecture, with distinct nests and lobules separated by fibrovascular stroma (Fig. 3.49A). The lobules may coalesce and interconnect, forming sheets of cells with a prominent capillary network. Approximately 60% to 70% of tumors have a variable amount of fibrillary stroma (Fig. 3.49B), although in some cases, this is focal. Homer Wright rosettes, also called pseudorosettes, are common in low-­grade examples (Fig. 3.49B). In contrast, Flexner-­ Wintersteiner rosettes are gland-­ like structures indicative of olfactory differentiation, seen in higher grade tumors (Fig. 3.50). The neoplastic cells are generally small or medium in size and have pale eosinophilic cytoplasm with indistinct borders. The nuclei are round, somewhat vesicular, with fine “salt-­ and-­ pepper” chromatin and absent or inconspicuous nucleoli. Most cases show no or only mild to moderate nuclear pleomorphism

TABLE

3.2

Kadish Staging of Olfactory Neuroblastoma

Stage

Features

Distribution

Survival

A

Tumor limited to nasal cavity

4%–20%

57%–88%

B

Tumor limited to sinonasal area

27%–53%

58%–60%

C

Tumor extending beyond sinonasal area

43%–61%

0%–50%

B

Fig. 3.49  Low-­grade olfactory neuroblastoma. A, A prominent nested growth pattern is noted. B, The tumor cells grow around fibrillary material forming a Homer Wright rosette. The tumor nuclei have minimal atypia and mitoses are absent.

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

(Fig. 3.49B) and a low mitotic rate. Necrosis is uncommon and is generally seen in high-­grade tumors with elevated mitotic counts (Fig. 3.50). Pagetoid extension of tumor cells in the adjacent respiratory epithelium and mucosal glands may sometimes be seen. Divergent differentiation (e.g., glandular differentiation [Fig. 3.51A]), squamous or myogenic differentiation (Fig. 3.51B),322,323 and melanin pigment have been described.324 Ganglion cells are rarely seen in ONB.325 Immunohistochemical studies have shown that the cells of ONBs express synaptophysin (Fig. 3.52A), chromogranin, and CD56. The periphery of the cell nests shows S100 protein–positive and GFAP-­positive (Fig. 3.52B) spindle or stellate cells (sustentacular cells), which may be sparse in poorly differentiated, high-­grade ONBs. ONBs are usually negative for CK; however, focal immunoreactivity may be found in approximately 20% to 25% of tumors (Fig. 3.52C). Calretinin has recently been reported as a useful marker for ONB, but it is not entirely specific (Fig. 3.52D).326 Hyams and colleagues introduced a four-­tier histologic grading system with the most well-­differentiated tumors at one end and the most anaplastic, poorly differentiated, highly

Fig. 3.50  High-­ grade olfactory neuroblastoma with a sheet-­ like growth pattern, scattered Flexner-­Wintersteiner rosettes, necrosis (bottom right), and an elevated mitotic rate.

A

163

mitotic and necrotic tumors at the other end of the system (Table 3.3).327 The low-­grade (grades I–II) tumors have a better 5-­year survival rate compared with high-­grade (grades III–IV) tumors. The majority of ONBs are low grade and well differentiated (52%–60%).316,328 However, all histologic grades can metastasize.  Differential Diagnosis.  The differential diagnosis of ONBs includes other neuroendocrine and small cell lesions of the sinonasal tract (see Table 3.1). Although ONB and sinonasal neuroendocrine carcinoma share certain morphologic features in addition to expression of neuroendocrine and epithelial markers, they should be differentiated because of significant prognostic differences. True sinonasal neuroendocrine carcinoma resembles neuroendocrine carcinoma (i.e., SmCC and LCNEC) of the lung. The degree of mitotic activity and the extensive areas of necrosis present in these neuroendocrine carcinomas are not seen in most ONBs. Neuroendocrine carcinomas do not exhibit cell nests surrounded by S100– positive cells. Cytokeratin and EMA expression in ONB is absent or limited, whereas neuroendocrine carcinoma is diffusely positive for both. ONBs should also be distinguished from alveolar rhabdomyosarcoma. Rhabdomyosarcoma is one of the most common sinonasal malignant tumors in children, but is also encountered in adults.329,330 In adults, the solid variant of alveolar rhabdomyosarcoma may pose a significant diagnostic problem (Fig. 3.53A). The nests of alveolar rhabdomyosarcoma may resemble the characteristic nests of ONB. The use of a panel of immunostains should be extremely helpful in establishing the correct diagnosis, though immunohistochemistry can also be misleading, since alveolar rhabdomyosarcoma is virtually always diffusely positive for CD56 (Fig. 3.53B) and may be focally positive for synaptophysin as well.331 Alveolar rhabdomyosarcoma diffusely expresses desmin, myogenin (Fig. 3.53C), myoD, muscle-­specific actin, and myoglobin, and is negative for synaptophysin. Therefore myogenic markers (desmin and myogenin) should be added to the immunohistochemical battery of stains for all small round blue cell tumors. ONBs are negative for myogenic markers, except for cases with divergent differentiation; in those exceedingly rare examples, expression of desmin and myogenin is focal (Fig. 3.51B).322 Finally, the characteristic gene fusion transcript PAX3/PAX7-­FOXO1 is a useful molecular tool

B

Fig. 3.51  Aberrant differentiation in olfactory neuroblastoma. A, Epithelial, with a ciliated gland-­like structure. B, Rhabdomyoblastic, with scattered myogenin-­positive cells (inset).

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for confirming the diagnosis of alveolar rhabdomyosarcoma. This differential diagnosis is critical, as the prognosis of rhabdomyosarcoma in adults is dismal, despite multimodal therapy. For a more detailed description of rhabdomyosarcoma, please refer to Chapter 9 (“Soft Tissue Tumors”) in this book. Malignant sinonasal melanoma, predominantly composed of small cells, may be confused with ONB. However, the degree of cytologic atypia and pleomorphism generally seen in melanoma is uncommon in ONB. Moreover, the immunophenotypes of these lesions are different, although in rare cases sinonasal

melanomas may be positive for neuroendocrine markers. However, ONB is negative for melanoma markers. The characteristic location of the S100 protein–positive cells in ONB should also be helpful in making this distinction. The small undifferentiated cells of teratocarcinosarcoma may resemble the cells of ONB;332,333 however, the lack of nesting coupled with the presence of other epithelial and mesenchymal elements should point to the correct diagnosis. Sinonasal pituitary adenomas should also be considered in the differential diagnosis of ONB, particularly in a tumor of

A

B

C

D

Fig. 3.52  Olfactory neuroblastoma is positive for: A, synaptophysin diffusely and B, S100 protein in a peripheral, sustentacular pattern. C, Cytokeratin is often focally positive. D, Calretinin positivity is another useful finding.

TABLE

3.3

Hyams Grading of Olfactory Neuroblastoma I

II

III

IV

Lobular architecture

Present

Present

Variable

Variable

Mitotic activity

Absent

Low

Prominent

High

Nuclear pleomorphism

Absent

Moderate

Prominent

Severe

Fibrillary matrix

Prominent

Present

Minimal

Absent

Rosettes

Homer Wright

Homer Wright

Flexner-­Wintersteiner

Flexner-­Wintersteiner

Necrosis

Absent

Absent

Variable

Common

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

A

165

characteristic, they may have overlapping expression of vimentin, S100 protein, cytokeratin, synaptophysin, CD56, and the new Ewing sarcoma marker NKX2.2.335 Confirmation of the diagnosis with an extensive immunohistochemical panel or molecular genetics is almost mandatory given the differences in management and prognosis of these neoplasms. Ewing sarcoma consistently demonstrates strong, membranous staining for CD99 and nuclear expression of FLI1. ONB is negative for CD99 and lacks the t(11;22) translocation seen in most Ewing sarcomas.336 Chapter 9 (“Soft Tissue Tumors”) describes the characteristics of Ewing sarcoma in greater detail.  Treatment and Prognosis.  Complete surgical resection, if feasible, and adjuvant radiotherapy is the treatment of choice for ONBs.316,317,325,337 Local recurrence is seen in 29% to 38%, and nodal and distant metastasis develop in 16% to 46%. Recurrence or metastases may develop as late as 21 years after initial diagnosis; therefore long-­term follow-­up is necessary. The prognosis of ONB depends to a certain extent on the clinical stage, although the clinical behavior is often unpredictable. Histologic grading into low grade (Hyams grades I–II) and high grade (Hyams grades III–IV), a proliferative index (poor prognosis if >10%), and the presence or absence of S100 protein– positive sustentacular cells (minimal or absent: poor prognosis) are additional prognostically relevant factors.320,325,338,339 

Soft-­Tissue Tumors

B

Soft-tissue tumors are rare in the sinonasal region. We describe here only those lesions that are restricted to, or seen with some frequency in, the nasal cavity and the paranasal sinuses. For a more detailed description of various soft tissue tumors, the reader is referred to Chapter 9 in this book, dedicated to soft tissue tumors. ANGIOFIBROMA

C Fig. 3.53  Alveolar rhabdomyosarcoma. A, A nested growth pattern with primitive appearing cells is classic. B, CD56 is almost always diffusely positive, which can cause confusion for neuroendocrine neoplasms like olfactory neuroblastoma. C, Myogenin is diffusely positive.

the sphenoid sinus. The lack of fibrillary background or S100 protein–positive sustentacular cells and the expression of keratin and specific pituitary hormones in pituitary adenomas indicate the correct diagnosis.334 The distinction of sinonasal Ewing sarcoma from ONB, particularly in small endoscopic biopsy specimens, can be difficult. Although the phenotypes of these two distinct neoplasms are

Clinical Features. Angiofibromas are uncommon and constitute less than 1% of all head and neck tumors.340 They occur exclusively in young males between 10 and 25 years of age. Well-­ documented examples have been described in younger children (juvenile nasopharyngeal angiofibroma) and middle-­ aged patients; however, the tumor’s existence in females is disputed. Hyams et al. described no female patients among 150 cases reviewed at the Armed Forces Institute of Pathology.341 Angiofibromas arise in a fibrovascular nidus in the posterolateral wall of the roof of the nasal cavity, where the sphenoidal process of the palatine bone meets the horizontal ala of the vomer and the pterygoid process, and present predominantly and initially as a nasopharynx mass. The most common presenting symptoms are unilateral nasal obstruction and epistaxis. Extensive infiltration of adjacent structures (e.g., nasal cavities and maxillary sinuses, skull base, orbit, pterygoid region, temporal and infratemporal fossa, and middle cranial cavity) may cause facial swelling, diplopia, proptosis, headache, anosmia, and pain. More than one-­half of the patients have had symptoms for more than 1 year before diagnosis. The diagnosis of angiofibroma should be considered in any male younger than 30 years of age who presents with a nasopharyngeal mass. Angiofibromas possess androgen, testosterone, and dihydrotestosterone receptors and basic fibroblast growth factor.342,343 This may explain their association with puberty

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Fig. 3.54  A, Angiography demonstrating the typical irregular vascularity of a nasopharyngeal angiofibroma. B, Surgical specimen of an angiofibroma showing its lobular and markedly fibrous appearance.

A

in young males. The stromal and endothelial cells express activating transforming growth factor β1, but only the stromal cells express β-­catenin and activating β-­catenin gene mutation, strongly suggesting that the stromal cells, not the vessels, are the neoplastic component of the tumor.344 Most cases are sporadic and harbor somatic mutations of the beta-­catenin gene (CTNNB1). An association with familial adenomatous polyposis has been only rarely reported.340,345 On plain radiographs, the growing mass causes bowing of the posterior wall of the maxillary antrum (known as the Holman-­Miller sign or antral sign).340 Selective carotid arteriogram demonstrates a typical and highly diagnostic vascular pattern (“blush”), which delineates the tumor and helps in presurgical embolization of the tumor (Fig. 3.54A). Using computed tomography scans and magnetic resonance imaging, the tumors are staged I to IV, depending on their extent: stage I is limited to the nasopharynx; stage II involves the nasal cavities and paranasal sinuses without bone destruction; stage III invades the pterygopalatine, infratemporal, orbital, or parasellar regions; and stage IV shows intracranial infiltration.346  Pathologic Features. Grossly, angiofibromas are well-­ circumscribed, lobulated, tan to purple-­ red masses, usually measuring up to 6 cm in size, but may occasionally be larger (Fig. 3.54B). The cut surface has a fibrous appearance. Often, blood vessels can be seen near the base of resection. Ulceration, necrosis, and cystic spaces are distinctly uncommon. Histologically, these tumors are characterized by the presence of a collagenized vascular stroma containing numerous, irregularly shaped (staghorn) blood vessels (Fig. 3.55A), lacking elastic fibers in their walls.347 The amount of collagen present in the stroma varies from fine to coarse strands embedded in a myxoid stroma to a dense, acellular collagenous tissue. The stroma contains spindle-­or stellate-­ shaped myofibroblasts with plump nuclei and numerous mast cells (Fig. 3.55B). Occasional multinucleated stromal cells and ganglion-­ like

B

cells similar to those seen in proliferative myositis can be encountered. Mitotic figures can also be seen, but they are uncommon. The shape and distribution of the blood vessels and stroma are variable within angiofibromas. The periphery of the lesion contains numerous small, capillary-­like vessels lined with a single layer of endothelial cells with little fibrous tissue, whereas larger vessels with thick muscular walls surrounded by dense collagenous tissue are found in the center of the tumor. They are immunoreactive for androgen receptor and β-­catenin (see Fig. 3.55 inset), with occasional expression of smooth muscle actin. CD31, CD34, desmin, and S100 protein are negative in the neoplastic cells.  Differential Diagnosis. The preoperative diagnosis of nasopharyngeal angiofibroma can be difficult. The diagnosis is based on clinical and radiologic findings. In fact, because of the characteristic radiologic appearance of angiofibroma, biopsy before definitive treatment is often unnecessary. These tumors should be distinguished from lobular capillary hemangioma, a distinction that can be extremely difficult in superficial biopsy material; however, the distinctive location of angiofibroma and its larger size and extension into adjacent structures make this differentiation possible. The differential diagnosis of nasopharyngeal angiofibroma also includes other highly vascular lesions, such as glomangiopericytoma, solitary fibrous tumor, and angiosarcoma, but the characteristic age, sex, and tumor location should strongly favor the diagnosis of angiofibroma. Furthermore, the thick blood vessels and the stellate stromal myofibroblasts seen in angiofibroma are not features of any of these neoplasms.  Treatment and Prognosis. Angiofibroma is a locally aggressive tumor and the prognosis depends on its local extent or stage. Surgical removal is the treatment of choice for resectable tumors. The recurrence rate is approximately 20% and is probably caused by incomplete resection in extensive, high-­stage tumors. Recurrences tend to occur within 1 to 2 years of surgery. Disease with intracranial extension has a

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Fig. 3.55  Nasopharyngeal angiofibroma with: A, dilated, staghorn-­like vessels. B, Bland stellate tumor cells are associated with abundant interstitial collagen. The tumor cells are positive for beta-­catenin by immunohistochemistry (inset).

higher frequency of recurrence. With recent advances in imaging and interventional neuroradiology, the recurrence rate has decreased considerably. Radiotherapy, hormone therapy, or chemotherapy may be used for unresectable or recurrent disease;348,349 however, sarcomatous transformation has been reported after radiotherapy.340 Preoperative embolization reduces the risk of intraoperative hemorrhage and incomplete tumor removal. Spontaneous regression, as well as rare metastasis, have been reported.350 The prognosis for a patient with angiofibroma is excellent; the mortality rate varies from 0% to 9% and is related to uncontrollable hemorrhage and intracranial extension.  GLOMANGIOPERICYTOMA Sinonasal glomangiopericytoma (synonym: sinonasal hemangio­ pericytoma-­like tumor) is defined as a tumor showing a perivascular myoid phenotype.351 Clinical Features. This unique, uncommon soft tissue neoplasm arises exclusively in the sinonasal tract. Most patients are middle-­aged or elderly adults, although tumors may be seen in a wide age range (5–86 years). There appears to be no race or sex predilection. The most common clinical symptoms are nasal obstruction and epistaxis. Physical and radiologic examinations reveal the presence of a polypoid mass high in the nasal cavity or a mass involving the paranasal sinuses, with secondary extension into the nasal cavity.351  Pathologic Features. Grossly, the tumors are polypoid, measuring from less than 1 to 8 cm (average, 3 cm). Histologically, at low-­power magnification these tumors are well circumscribed and unencapsulated and have a uniform cellular appearance. Blood vessels range from small capillaries to sinusoidal spaces with a staghorn shape, often showing hyalinized walls (Fig. 3.56A). Necrosis and hemorrhage are generally absent. The tumor cells are tightly packed with little intervening collagen and may show a solid, fascicular, whorled, or storiform architecture. They have a monotonous appearance with round to oval shape and indistinct cytoplasm. The nuclei are regular and bland, varying from small and dark to somewhat vesicular (Fig. 3.56B). Nucleoli are inconspicuous. Mitoses are generally absent or fewer

than three per 10 HPFs. Immunostains are helpful in excluding other lesions with a hemangiopericytoma-­like pattern. CD31 and CD34 highlight the endothelium but are negative in the tumor cells. Tumor cells consistently express vimentin and smooth muscle actin (Fig. 3.56C), muscle-­specific actin, fibroblastic growth factor-­2, vascular endothelial growth factor, and Factor XIIIa.351,352 Recently, somatic mutations in the beta-­catenin gene (CTNNB1) have been detected in these tumors,353,354 and this results in accumulation of β-­catenin in the nucleus, which can be detected immunohistochemically (Fig. 3.5D), and upregulation of Cyclin D1.  Differential Diagnosis. Solitary fibrous tumor is the most difficult lesion to distinguish from sinonasal glomangiopericytoma. Glomangiopericytomas have a homogeneously cellular architecture, in contrast to the more varied appearance of solitary fibrous tumor, which exhibits hypercellular and hypocellular areas with abundant collagen. CD34 and bcl-­2 are consistently expressed in solitary fibrous tumor but not in glomangiopericytoma. Importantly, glomangiopericytoma lacks the NAB2-­STAT6 gene fusion, which is a feature of solitary fibrous tumor, and therefore it is also negative for STAT6 at the immunohistochemical level.355,356 Finally, sinonasal glomangiopericytomas do not express desmin and cytokeratin, which may help to differentiate this smooth muscle tumor from synovial sarcoma.  Treatment and Prognosis. Most glomangiopericytomas behave in an indolent fashion and have an excellent prognosis after total surgical resection. However, recurrences are reported in 30% to 40% of cases, even after several years, and may be related to incomplete resection. Metastases are rare but well documented and are usually seen in the lung.357,358 Thus these tumors are considered of borderline or low malignant potential. Features of aggressive behavior appear to be large size, bone invasion, marked pleomorphism, necrosis, increased mitosis (more than four per 10 HPFs), and a proliferative index >10%.359  LOBULAR CAPILLARY HEMANGIOMA Clinical Features. Lobular capillary hemangioma (pyogenic granuloma) is a distinctive vascular lesion most commonly seen

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Fig. 3.56  Glomangiopericytoma. A, Sinonasal submucosa is filled with spindled cells arranged around variably hyalinized and dilated vessels. B, Tumor cells are ovoid to spindled with moderate eosinophilic cytoplasm and dark, bland nuclei. Extravasated red blood cells and eosinophils are noted. C, Smooth muscle actin is positive. D, Beta-­catenin is diffusely and strongly positive in a nuclear distribution.

in the fourth and fifth decades of life. It frequently affects pregnant females or males younger than 18 years of age.360–362 There is no sex difference after 40 years of age. Injury and hormonal factors seem to play a role in their etiology. The predominant sites of involvement are the anterior portion of the nasal septum (Little area) and the tip of the turbinates. The most common clinical symptoms are epistaxis and nasal obstruction. Lesions arising in pregnant females often undergo spontaneous regression after delivery.  Pathologic Features. Grossly, lobular capillary hemangiomas are red or blue nodules or polypoid masses with smooth contours measuring up to 2 cm in diameter (Fig. 3.57A). Microscopically, they are composed of small, uniform vascular channels with a lobular architecture, often surrounding a larger central vessel (feeder vessel) (Fig. 3.57B). The individual capillaries vary from solid nests of plump endothelial cells without lumina to large vessels lined with prominent endothelial cells showing mitotic activity. Intravascular papillary endothelial hyperplasia (tufting) may be seen. The endothelium is surrounded by pericytes and stromal cells. The stroma may be fibromyxoid; rare examples with extensive myxoid changes and/or stromal hyalinization may pose significant problems in the differential diagnosis.363 Second-

ary changes include mucosal ulceration with marked acute inflammation and a variable infiltrate of lymphocytes and plasma cells.361  Differential Diagnosis. Perhaps the most clinically important lesions that need to be distinguished from a lobular capillary hemangioma are granulation tissue, nasopharyngeal angiofibroma, glomangiopericytoma, and angiosarcoma. The capillaries in granulation tissue are frequently arranged perpendicular to the surface and lack the lobular architecture of a hemangioma. The thick abnormal blood vessels and spindle or stellate fibroblasts of angiofibroma are significantly different from the small capillary-­size vessels with a lobular pattern seen in hemangiomas. The nuclear atypia and infiltrative pattern that characterize angiosarcoma are also absent in a hemangioma. Glomangiopericytomas are larger and more cellular lesions than hemangiomas. They have an attenuated endothelial lining surrounded by a somewhat uniform population of plump to spindled cells, in contrast to the more prominent endothelial cells and the array of capillary-­sized blood vessels with the lobular architecture of a hemangioma.  Treatment and Prognosis. Lobular capillary hemangiomas are benign lesions, are treated by simple surgical resection, and only rarely recur. The pregnancy-­related ones may regress after the end of pregnancy. 

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Fig. 3.57  A, Lobular capillary hemangioma consists of a polypoid fragment of tissue with frequent surface ulceration. B, Tumor vessels have a specific arrangement: lobules of tightly coiled capillaries surrounding larger, feeder vessels.

Fig. 3.58  Schwannoma involving the left nasal cavity and maxillary ­sinus.

PERIPHERAL NERVE SHEATH TUMORS Schwannomas, neurofibromas, plexiform neurofibromas, and malignant peripheral nerve sheath tumors are encountered rarely in the nasal cavity and paranasal sinuses.362,364–368 Sinonasal peripheral nerve sheath tumors affect males and females equally. The age at presentation ranges from 16 to 75 years. Most cases have not been associated with neurofibromatosis, although some have been seen in this clinical setting. The symptoms at presentation are variable and depend on tumor location. Patients with lesions primarily located in the nasal cavity usually have nasal obstruction and epistaxis, whereas those with tumors arising in the sinuses present with headaches and facial swelling. Radiologic studies show fullness of the involved sinus (Fig. 3.58) and, not uncommonly, extensive

bone destruction with extension into the skull base. It is important to remember that these radiologic features are not necessarily an indication of malignancy.368 The histologic features of schwannomas and neurofibromas in this location do not, for the most part, differ histologically or immunohistochemically from lesions arising in other locations (Fig. 3.59B). One important exception is that schwannomas are typically unencapsulated in the sinonasal tract, a feature that can raise suspicion for malignancy, especially when combined with an aggressive-­appearing radiologic appearance (Fig. 3.59A).368 As in other locations, nuclear atypia may be present; it is not an indication of aggressive behavior. Most malignant peripheral nerve sheath tumors are poorly differentiated hypercellular lesions and are composed of spindle cells with hyperchromatic nuclei with frequent mitotic figures and necrosis.369,370 Some cases have shown rhabdomyoblastic differentiation and have been designated malignant triton tumors.371,372 It is likely that previously reported cases of “low-­ grade” malignant peripheral nerve sheath tumor of the sinonasal tract, in fact, represent biphenotypic sinonasal sarcomas (described later).372,373 Schwannomas and neurofibromas are benign lesions that only rarely develop local recurrences and have an excellent prognosis.362,367,368 The prognosis of malignant peripheral tumors in the sinonasal tract is more guarded and depends on the extent of disease, completeness of resection, use of adjuvant therapy, association with neurofibromatosis, and size of the tumor.369,372,374  BIPHENOTYPIC SINONASAL SARCOMA Biphenotypic sinonasal sarcoma (BSNS) (previously known as low-­g rade sinonasal sarcoma with neural and myogenic features) is a recently described low-­ g rade malignancy that, so far, has only been encountered in the sinonasal tract.375–377 Clinical Features. BSNS most often arises in the superior nasal cavity and ethmoid sinuses of women (female:male ratio of 3:1) ranging in age from 24 to 85 years (mean, 52 years). Patients present with nonspecific symptoms like nasal obstruction and facial pressure. 

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Fig. 3.59  A, Sinonasal schwannoma is characteristically unencapsulated, with tumor cells immediately beneath the surface epithelium. B, Verocay bodies classic for schwannoma.

Pathologic Features. Histologically, BSNS is a poorly circumscribed and infiltrative tumor (Fig. 3.60A) comprised of a uniformly hypercellular proliferation of intersecting fascicles, often exhibiting a “herringbone” growth pattern (Fig. 3.60C). Dilated slit-­like or “staghorn” (hemangiopericytoma-­like) vessels are common. The tumor nuclei are elongated, uniform, and hypochromatic. A peculiar histologic feature is the frequent presence of hyperplastic respiratory surface epithelium extending downward and entrapped by the BSNS (Fig. 3.60B). Necrosis is absent, and mitotic figures are rare. By immunohistochemistry, BSNS characteristically express­es S100 protein (Fig. 3.61A), smooth muscle actin (Fig. 3.61B), and calponin. Although the expression of S100 protein has been suggested to indicate neurogenic differentiation, SOX10 is consistently negative.378 BSNS is sometimes focally positive for desmin, EMA, cytokeratin, and TLE1. Most cases of BSNS exhibit focal nuclear immunoreactivity for beta-­catenin (Fig. 3.61C).378 BSNS harbors fusions involving PAX3, most frequently with MAML3. Alternate fusions PAX3-­FOXO1 and PAX3-­NCOA1 have been reported.379–381 Interestingly, PAX3-­NCOA1 cases may demonstrate focal rhabdomyoblastic differentiation, with strap cells and myogenin immunoreactivity.381  Differential Diagnosis. The S100 protein positivity consistently seen in BSNS often suggests cellular schwannoma or malignant peripheral nerve sheath tumor. Schwannomas of the sinonasal tract are unencapsulated and can be very hypercellular, but BSNS is not as diffusely immunoreactive for S100 protein as schwannoma, where essentially every cell is strongly positive. Moreover, unlike schwannoma, BSNS has been consistently negative for SOX10. Malignant peripheral nerve sheath tumor is generally much higher grade than BSNS, with necrosis and considerable nuclear hyperchromasia and pleomorphism. Given the occasional focal cytokeratin or TLE1 immunostaining, staghorn vasculature, and uniform nuclear features, a monophasic synovial sarcoma is another diagnostic consideration. However, all cases of BSNS are negative for synovial sarcoma fusion transcripts. Finally, staghorn vasculature raises the possibility of solitary fibrous tumor, but BSNS lacks the characteristic wiry

collagen and variable cellularity of solitary fibrous tumor, which is also CD34 and STAT6-­positive and S100 protein-­negative. Finally, the presence of the PAX3 rearrangement characteristic of BSNS is not encountered in any of the other diagnostic possibilities.  Treatment and Prognosis. Clinically, BSNS behaves relatively indolently. Almost half of patients with BSNS have experienced local recurrences, but none of the tumors have metastasized, and only rare patients have died of their disease.376–378,381 

Other Sinonasal Tumors MENINGIOMA Clinical Features. Meningiomas can extend into the sinonasal tract secondarily from the cranial cavity but can also rarely arise primary to the sinonasal tract, where they account for approximately 0.1% of all primary sinonasal neoplasms (Fig. 3.62). Sinonasal meningiomas affect men and women equally and have peak involvement in the fifth decade. They involve the nasal cavity more commonly than the paranasal sinuses.382–385  Pathologic Features. Most meningiomas in the sinonasal tract are of the meningothelial or transitional type and rarely the fibroblastic type. They consist of tumor cells with a syncytial appearance arranged in whorls, sheets, or broad bands with variable numbers of psammoma bodies. The cytoplasm is moderate to abundant with indistinct cell membranes (Fig. 3.63). The nuclei tend to be uniform with little pleomorphism and may exhibit nuclear pseudoinclusions. Bone invasion is frequent. Cases with mitotic activity and frankly malignant histologic features have been described.384 By immunohistochemistry, sinonasal meningiomas are positive for EMA, SSTR2a (Fig. 3.64A), and estrogen and progesterone receptors (Fig. 3.64B), but typically negative for cytokeratins, S100 protein, and GFAP.382  Differential Diagnosis. The differential diagnosis of meningioma in the sinonasal tract includes various carcinomas,

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Fig. 3.60  A, Biphenotypic sinonasal sarcoma is uniformly cellular and infiltrative, with scattered slit-­like vessels. B, Gland-­like invaginations of surface epithelium entrapped by tumor cells. C, Herringbone fascicular growth pattern with uniform cells with hypochromatic nuclei. Mitotic figures are rare.

­ alignant melanoma, and ONB. Identification of the typim cal cytologic features of meningioma, the absence of fibrillary stroma, the lack of significant cellular atypia and necrosis, and the lack of staining for keratins, S100 protein, HMB-­45, SOX-­ 10, and neuroendocrine markers, but expression of EMA, SS-

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Fig. 3.61  Biphenotypic sinonasal sarcoma is positive for: A, S100 protein; B, smooth muscle actin; and C, nuclear beta-­catenin.

TR2a, and progesterone receptor, are helpful in establishing a definitive diagnosis. Obviously, extension from an intracranial meningioma should be excluded on clinical grounds before accepting a diagnosis of primary sinonasal meningioma.  Treatment and Prognosis. Meningiomas are benign tumors, and complete local resection is curative. Nonetheless, they

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may exhibit recurrences and aggressive local behavior, and, occasionally, owing to their location, complete resection may be difficult to achieve.382,384  SINONASAL AMELOBLASTOMA

Fig. 3.62  Meningioma of the maxillary sinus. The tumor has a solid appearance and invades bone and the antrum.

Primary sinonasal ameloblastomas are rare.386 The largest series reported consists of 24 cases seen at the Armed Forces Institute of Pathology during a period of 30 years.387 Most patients are males, and the mean age at diagnosis is 59.7 years (15–25 years older than ameloblastoma of the gnathic bones). The most common symptoms are a nasal mass and obstruction. The histopathologic appearance of sinonasal ameloblastomas is similar to that of their gnathic counterparts, which are discussed in detail in Chapter 10 (“Odontogenic Cysts and Tumors”). By far the most common is the plexiform type characterized by a network of anastomosing cords of odontogenic epithelium surrounded by a loose, myxoid, reticulum-­like stroma (Fig. 3.65B). Primary sinonasal ameloblastomas are believed to arise from the surface epithelium (Fig. 3.65A). The main differential diagnoses of sinonasal ameloblastoma are nasal extension of a gnathic tumor and craniopharyngioma. Before establishing the diagnosis of a primary sinonasal ameloblastoma, the presence of a gnathic lesion should be excluded. Ameloblastomas lack the cyst formation, degenerative changes, calcifications, and cholesterol clefts typical of craniopharyngioma. The latter typically involves the nasopharynx or sinuses through downward extension from a suprasellar location. Other entities to be included in the differential diagnosis are basal cell adenoma, basaloid squamous cell carcinoma, basal cell adenocarcinoma, and biphasic synovial sarcoma. Reverse polarization of the nuclei typical of ameloblastoma is not observed in basal cell tumors. The prognosis is excellent after complete surgical resection; however, local recurrences are seen in approximately 20% of patients, and some may have multiple recurrences.387  ECTOPIC PITUITARY ADENOMA

Fig. 3.63  Sinonasal meningioma demonstrating nests and whorls of bland epithelioid cells.

A

Clinical Features. Pituitary adenomas may involve the sinonasal tract. Extension from a large intrasellar pituitary adenoma into the sinonasal tract is more common than truly ectopic

B Fig. 3.64  Sinonasal meningioma is positive for: A, Epithelial membrane antigen and B, progesterone receptor.

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Fig. 3.65  Sinonasal ameloblastoma. A, Continuity with surface epithelium is commonly seen. B, The tumor exhibits typical ameloblastic features, including peripheral palisading with reverse polarization and central stellate reticulum-­like cells.

pituitary adenomas. Ectopic pituitary adenomas are believed to arise in the remnants of embryonic adenohypophysis along the path of the developing Rathke cleft. These embryonic remnants (so-­called pharyngeal pituitary gland) are found in the body of the sphenoid bone in more than 90% of adults in autopsy studies. Not surprisingly, sphenoid sinus and bone are the most common locations of ectopic pituitary adenomas.334,388,389 Women are affected twice as often as males, and more than 58% of patients have evidence of hormone hyperactivity (e.g., Cushing disease, acromegaly, hyperthyroidism, or hyperparathyroidism). Patients with nonfunctional ectopic pituitary adenomas may present with nasal obstruction, headaches, and epistaxis.334,388,389  Pathologic Features. Most of these lesions display a histologic appearance similar to those located in the sella turcica. They are unencapsulated but well-­circumscribed and have an endocrine architecture with nests, ribbons, trabeculae, papillae, and rosettes, surrounded by a delicate vascular network (Fig. 3.66A). Most are of the chromophobe cell type. The nuclei are usually bland; however, some pleomorphism may be seen as is characteristic of all neuroendocrine tumors, and should not deter one from the diagnosis of adenoma. There are no mitoses and no necrosis except in infarcted tumors. By immunohistochemistry, the tumors usually express cytokeratin (Fig. 3.66B), as well as neuroendocrine markers (Fig. 3.66C). Specific pituitary hormones, most frequently prolactin or growth hormone, may be demonstrated (Fig. 3.66D).  Differential Diagnosis. Sinonasal ectopic pituitary adenomas should be distinguished from pituitary adenomas extending from the sella turcica, ONB, paraganglioma, carcinoid tumor, neuroendocrine carcinoma, and Ewing sarcoma. Awareness of the existence of pituitary adenoma in ectopic locations and clinicopathologic correlation, particularly endocrine function and radiologic studies, are essential in arriving at a correct diagnosis. The sphenoid sinus location, in particular, should alert pathologists to the possibility of a pituitary adenoma. One should also remember that very occasionally ectopic pituitary adenomas may arise primarily

in the maxillary sinus. Therefore this lesion needs to be considered in the differential diagnosis anytime one encounters a low-­grade epithelial neoplasm with abundant cytoplasm. Immunohistochemical stains including hormonal markers of pituitary adenomas are necessary to establish a diagnosis. Distinguishing it from ONB can be difficult, as both tumors are positive for neuroendocrine markers and often focal for cytokeratins. Although sustentacular cells are absent in pituitary adenoma, scattered S100 protein-­positive folliculodendritic cells are occasionally seen. The absence of fibrillary stroma and staining for pituitary hormones point toward pituitary adenoma. Although pituitary adenomas may show some degenerative-­type nuclear atypia, they do not have the degree of cellular pleomorphism, mitotic activity, and necrosis that characterize neuroendocrine carcinoma.  Treatment and Prognosis. Complete surgical removal is the treatment of choice; however, in large invasive lesions, this goal may not be achieved. For incompletely resected tumors, postoperative irradiation may be indicated. The prognosis is good, with occasional recurrences following incomplete excision.334  CRANIOPHARYNGIOMA Craniopharyngiomas are complex benign epithelial neoplasms most commonly seen in the sellar and third ventricle regions. Their proposed origin is the obliterated craniopharyngeal duct of Rathke pouch, although origin from misplaced odontogenic epithelium has also been proposed. Rarely, extracranial craniopharyngiomas arise in the nasopharynx or sinonasal tract.390–394 The microscopic appearance is similar to that of sellar adamantinomatous craniopharyngiomas, with their epithelial lobules, peripheral palisading, and internally loose epithelial cells reminiscent of stellate reticulum. Most lesions also have squamous metaplasia and cysts filled with keratin. These lesions are extremely uncommon in this location and should not be confused with a well-­differentiated squamous cell carcinoma. A high index of suspicion is necessary to make the diagnosis, if one is ever faced with this lesion. 

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Fig. 3.66  Ectopic sinonasal pituitary adenoma. A, Bland cells with round nuclei arranged in a vaguely lobular growth pattern with rosette formation. B, Cytokeratin is usually positive, often in a dot-­like pattern. C, Synaptophysin is positive, along with D, a pituitary hormone (in this case, prolactin).

TERATOCARCINOSARCOMA Clinical Features. This rare and unique neoplasm is characterized by a combination of histologic components showing features of teratoma and carcinosarcoma, without a malignant germ cell component.395 The histogenesis remains controversial, but it is currently considered a tumor deriving from a somatic pluripotent stem cell of the neuroepithelium of the olfactory membrane.396,397 It shows a male predominance and affects adults with an age range of 18 to 79 years and a mean age of 60 years.398–400 The symptoms at presentation include nasal obstruction, epistaxis, pain, and proptosis. Radiologic studies generally show a nasal mass with bone destruction and extension into the ethmoidal or maxillary sinus.  Pathologic Features. Grossly, the tumors may be polypoid, friable, and hemorrhagic. Histologically, they are characterized by a heterogeneous combination of epithelial and mesenchymal elements. The epithelial components are composed of a mixture of clear cell, nonkeratinizing epithelium (Fig. 3.67), squamous epithelium without clear cell elements, squamous cell carcinoma, and benign, atypical, or clearly malignant glandular elements (see Fig. 3.67). Immature neuro-

Fig. 3.67  Teratocarcinosarcoma with admixed tumor cell populations including “fetal”-appearing clear squamous cells (center right), glands (bottom), primitive neuroectodermal cells (center left), and spindled cells (top).

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epithelial tissue (see Fig. 3.67) resembling ONB with rosette formation, ganglion cells, and glial differentiation are also present. The mesenchymal tissues also have a variable appearance with areas of nonspecific myxomatous tissue, cellular areas of benign and malignant-­appearing fibroblasts, and smooth muscle cells. Rhabdomyoblastic and chondroblastic differentiation with areas of rhabdomyosarcoma, chondrosarcoma, or fetal cartilage may be seen. Primitive epithelial and mesenchymal elements resembling fetal lung have been reported. The epithelial component consists of poorly developed glands and squamous epithelium. The stroma is formed by a variable mixture of malignant myxoid, chondromyxoid, fibrous, and muscular tissues. Unlike gonadal or extragonadal germ cell tumors, there are no areas of seminoma, yolk sac tumor, or choriocarcinoma. The immunohistochemical findings are dependent on the areas studied.395,398 The primitive neuroepithelial tissue may be positive for CD99, NKX2.2, CD56, synaptophysin, and chromogranin. Keratin and rarely α-­fetoprotein may also be seen in the neuroepithelial component. S100 protein and GFAP are expressed by those areas with glial differentiation. EMA and keratin are seen in the epithelial elements. Desmin and myogenin are positive in areas with rhabdomyoblastic differentiation.  Differential Diagnosis. The differential diagnosis of teratocarcinosarcoma is broad and includes squamous cell carcinoma, sarcomatoid carcinoma, adenocarcinoma, ONB, craniopharyngioma, and other sarcomas. The histologic complexity of teratocarcinoma and the presence of mixed epithelial and mesenchymal elements should suggest the diagnosis. Clearly tissue sampling is critical; a definitive diagnosis may not be possible in small biopsy specimens.  Treatment and Prognosis. Most patients have been treated with a combination of surgery and radiation therapy. The survival rate ranges between 45% and 70% in different series.399–401  LYMPHOPLASMACYTIC TUMORS Chapter 13 (“Hematopoietic Lesions”) is entirely devoted to lymphomas and related entities. The following is only a very brief description of the most common hematolymphoid neoplasms of the sinonasal region. Non-­Hodgkin Lymphoma Primary sinonasal and nasopharyngeal non-­Hodgkin lymphomas (NHLs) are uncommon in North America, comprising approximately 1% of all NHLs.402,403 They are, however, the third most common malignancy of the sinonasal tract, following squamous cell carcinoma and adenocarcinoma.404,405 The majority of sinonasal lymphomas are the B-­cell type, the most common histologic type being diffuse large B-­cell lymphoma.402,403,406 In Asia and Latin America, the extranodal natural killer cell/T cell (NK/T cell) lymphoma of the nasal type is the most common lymphoma.402,407 Virtually any type of lymphoma, however, can be encountered in the sinonasal tract. The clinical symptoms at presentation are nonspecific and consist of nasal obstruction, epistaxis, rhinorrhea, and the presence of a mass.402,408–410 The mean age at presentation has ranged from 59 to 70 years, with the vast majority of patients in their sixth or seventh decade of life. Patients with diffuse large B-­cell lymphomas are generally a decade older than other

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patients. There is a slight male preponderance (1.2:1).402,407 Diffuse large B-­cell lymphoma most often involves the paranasal sinuses, while extranodal NK/T cell lymphoma, nasal type more frequently affects the nasal cavity.405 Most sinonasal lymphomas are locally advanced at presentation, with frequent bone destruction and extension into the adjacent sinuses, nasopharynx, or palate. The septal cartilage or palatal bone may be perforated, and proptosis may be seen in tumors invading the orbit. So-­called “B symptoms” (e.g., fever, night sweats) are encountered in 10% to 20% of cases.405 The diagnosis and classification of lymphomas in the sinonasal region are based on the same parameters used in nodal lymphomas. An adequate biopsy specimen with good cell preservation is of utmost importance. The differential diagnosis of NHL includes small round blue cell tumors (e.g., SNUC, SmCC, ONB, rhabdomyosarcoma, malignant melanoma, and nasopharyngeal carcinoma; see Table 3.1). Close attention to architectural and cytologic details and the use of an immunohistochemical panel that includes epithelial, lymphoid, myogenic, and melanocytic markers are necessary to establish a definitive diagnosis.  Extranodal NK/T Cell Lymphoma, Nasal Type Numerous terms have been used to describe the clinical and pathologic features of extranodal NK/T cell lymphomas involving the sinonasal tract (e.g., lethal midline granuloma, midline malignant reticulosis, polymorphic reticulosis, lymphomatoid granulomatosis, angiocentric peripheral T cell lymphoma, and angiocentric lymphoproliferative lesion). Extranodal NK/T cell lymphoma, nasal type is the current preferred terminology.411,412 Extranodal NK/T cell lymphoma, nasal type is most commonly seen in Asia, and an increased incidence has also been described in Latin American countries, such as Mexico, Guatemala, and Peru.407,413,414 The tumor has a strong association with EBV infection, with in situ hybridization for EBV–encoded small RNA (EBER) positive in virtually all cases. Clinical Features.  Extranodal NK/T cell lymphomas, nasal type are most frequently seen in males, with a male-­to-­female ratio of 2 to 3:1. The age at presentation ranges from 13 to 80 years, with a mean age of approximately 45 years in most series.414–418 Common symptoms are nasal obstruction, epistaxis, rhinorrhea, and the presence of an ulcerated nasal mass, frequently with extension to paranasal sinuses and palate. Bone destruction may also be present with perforation of the palate and nasal septum. Approximately 50% to 60% of patients have localized disease at presentation, and 25% may have involvement of cervical lymph nodes, skin, bone marrow, spleen, liver, or other extranodal sites.415,417,418  Pathologic Features.  Extranodal NK/T cell lymphomas, nasal type exhibit a broad morphologic spectrum, the hallmark being the presence of a polymorphic cellular infiltrate composed of atypical lymphoid cells admixed with a variable number of plasma cells, small lymphocytes, histiocytes, eosinophils, and neutrophils. The atypical cells vary in number, cell size, and cytologic atypia. In some cases, the neoplastic lymphoid cells are small to intermediate in size and possess dark, twisted hyperchromatic nuclei with irregular contours (Fig. 3.68A). In other cases, the cells are large with abundant pale to clear cytoplasm and exhibit large nuclei with prominent nucleoli (Fig. 3.68B). The distribution of the neoplastic cells in the tissue is irregular and may vary from field to field,

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A

B

Fig. 3.68  Extranodal natural killer/T cell lymphoma, nasal type. A, At times the malignant cells are obscured by a mixed population of smaller, benign lymphocytes. B, Other cases demonstrate a more obvious population of overtly malignant lymphocytes.

Fig. 3.69  Extranodal natural killer/T cell lymphoma, nasal type with prominent angiocentric growth.

and in some instances they may be obscured by the reactive inflammatory cells. Most cases show prominent angiocentricity with infiltration and destruction of the vessel wall (Fig. 3.69). As a result of this tumor angiocentricity, downstream necrosis is almost invariably present. Often, the necrosis has a zonal distribution and is accompanied by extensive mucosal ulceration and destruction of cartilage or bone. The presence of granulomas and multinucleated giant cells is not a feature of these tumors. The immunophenotype of extranodal NK/T cell lymphomas, nasal type is characteristic. The tumor cells are positive for the NK cell marker CD56 (Fig. 3.70A), the T-­cell markers CD2 and cytoplasmic CD3 (Fig. 3.70B), and the cytotoxic markers granzyme, TIA-­1 (Fig. 3.70C), and perforin. CD4, CD5, CD7, CD8, CD20 and CD57 are generally negative. Extranodal NK/T cell lymphomas, nasal type are essentially always positive for EBV by in situ hybridization for EBV encoded small RNA (EBER) (Fig. 3.70D). Extranodal NK/T cell lymphoma, nasal type has a complex genetic profile, with numerous reported alterations.412 

Differential Diagnosis.  The differential diagnosis of extra­ nodal NK/T cell lymphoma, nasal type includes nonspecific inflammation, sinonasal infections, especially fungal infections, granulomatosis with polyangiitis, and other NHLs. The diagnosis of these neoplasms requires a high index of suspicion and rests on a combination of clinicopathologic findings, microbiological cultures, characteristic immunophenotype, and, when necessary, molecular pathology analysis. The presence of a polymorphic lymphoid infiltrate with variable degrees of cytologic atypia, angioinvasion, and necrosis should strongly suggest a diagnosis of extranodal NK/T cell lymphoma, nasal type, especially in patients with no serum ANCAs and no evidence of pulmonary or renal abnormalities.  Treatment and Prognosis.  Extranodal NK/T cell lymphoma, nasal type is treated with combined chemoradiation. The prognosis of extranodal NK/T cell lymphoma, nasal type is stage dependent, with durable remissions of 70% to 80% for low-­stage (I–II) tumors and approximately 50% for high-­stage tumors.419,420 Levels of circulating EBV DNA appears to be a diagnostically useful biomarker.420–422  Extramedullary Plasmacytoma Extramedullary plasmacytoma is discussed in detail in Chapter 13. These tumors are uncommon, representing 5.7% of all plasmacytomas.423 By definition, they are localized neoplasms without an underlying plasma cell dyscrasia. Approximately 90% occur in the head and neck, the sinonasal tract being involved in approximately 75% of these cases.424 Sinonasal plasmacytomas most commonly affect males in their sixth and seventh decades of life.423–425 The symptoms at presentation are nonspecific and include unilateral nasal mass, obstruction, rhinorrhea, epistaxis, and facial pain. The finding of Bence-­Jones protein in urine is distinctly uncommon in the absence of disseminated disease. Extramedullary plasmacytomas are composed of plasma cells with a diffuse pattern of infiltration and variable degrees of differentiation (Fig. 3.71). In well-­differentiated tumors, the neoplastic cells closely resemble mature plasma cells, although occasional mitotic figures and bilnucleated forms can be seen. In moderately or poorly differentiated neoplasms, the cells are more pleomorphic and show a significant degree of atypia with frequent mitotic figures, large vesicular

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A

B

C

D

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Fig. 3.70  Extranodal natural killer/T cell lymphoma, nasal type is positive for: A, CD56; B, CD3 (cytoplasmic); C, TIA-­1; and D, Epstein-­Barr virus (EBV) as demonstrated by in situ hybridization for EBV encoded small RNA (EBER).

A

B

Fig. 3.71  A, Plasmacytoma with diffuse submucosal infiltration of plasma cells. B, The tumor cells exhibit mild atypia, including some binucleated forms.

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A

B Fig. 3.72  Metastatic renal cell carcinoma. A, Blood-­filled follicles lined by clear cells. B, PAX8 is positive.

nuclei with coarse chromatin, and often prominent nucleoli. By immunohistochemistry, plasmacytomas are positive for plasmacytic markers CD138, CD38, and MUM1. They will show light chain (kappa or lambda) restriction by immunohistochemistry or in situ hybridization. CD79a, CD56, and EMA are variably positive, while CD20, PAX5, and Cyclin D1 are typically negative. Low-­grade plasmacytomas can be difficult to distinguish from reactive plasma cell-­rich inflammatory conditions (which do not show light chain restriction) and low-­grade lymphomas like mucosa-­associated lymphoid tissue (MALT) lymphomas with extensive plasma cell differentiation. For B-­cell lymphomas with plasma cell differentiation, CD20 is usually diffusely positive and plasmacytic markers CD38, CD138, and MUM1 are variably positive, and usually in a patchy fashion. High-­grade plasmacytomas, on the other hand, can be difficult to separate from plasmablastic lymphoma, a high-­grade malignancy typically seen in immunosuppressed patients. CD56 positivity suggests plasmacytoma, and EBV positivity strongly points to plasmablastic lymphoma.411 Extramedullary plasmacytomas are radiosensitive. Large lesions may require surgical debulking. Most patients have localized disease and are cured by radiotherapy. Occasionally, the tumor may spread to regional or distant sites, and approximately 15% of cases will progress to plasma cell myeloma.425 

Metastatic Tumors Clinical Features. Metastatic involvement of the sinonasal tract by tumors of other sites is rare.211,426 The most common malignancies that secondarily involve the sinonasal tract are those of the kidney, lung, and breast.211,426–428 Other tumors that may occasionally metastasize to the nasal cavity and sinuses are malignant melanoma and carcinomas of the thyroid, pancreas, prostate, stomach, colon and rectum, testis, and adrenal gland. In most instances, metastases to the sinonasal tract are a manifestation of widespread, disseminated disease; however, sinonasal metastasis has been the initial presentation of carcinomas of the gastrointestinal tract, lung, liver, kidney, and thyroid.429–432 

Pathologic Features. Renal cell carcinoma in the sinonasal tract maintains its characteristic morphology of medium-­size or large clear cells arranged in nests or sheets surrounded by thin-­walled blood vessels (Fig. 3.72A). Unlike the clear cells of carcinomas of other sites, the cytoplasm in renal cell carcinoma does not have a vacuolated, granular, or pale eosinophilic appearance; instead, it is truly clear and often appears empty under light microscopy. The main differential diagnoses of renal cell carcinoma in the sinonasal tract are sinonasal renal cell-­ like adenocarcinoma, mucoepidermoid carcinoma and acinic cell carcinoma. The distinction between sinonasal renal cell-­like adenocarcinoma and metastatic renal clear cell carcinoma is mainly based on immunohistochemistry, since PAX8 is positive in metastatic renal carcinoma (Fig. 3.72B) whereas sinonasal renal cell-­like adenocarcinoma is negative.225 In most instances, adequate sampling will solve the differential diagnosis with mucoepidermoid carcinoma and acinic cell carcinoma, because these neoplasms are only rarely composed entirely of clear cells. Renal cell carcinoma does not contain the typical epidermoid or intermediate cells of mucoepidermoid carcinoma. The presence of mucous cells or intracytoplasmic mucin is also helpful in establishing the correct diagnosis. The presence of other cell types, particularly acinar cells with their characteristic PAS diastase–resistant granules, should exclude the diagnosis of metastatic renal cell carcinoma. Some myoepithelial tumors may show clear cells. However, the absence of the highly vascular pattern typical of renal cell carcinoma and expression of myoepithelial markers should point toward the myoepithelial origin of the tumor. The morphology and immunohistochemical profile of tumors of salivary gland origin are described in greater detail in Chapter 6 (“Salivary Glands”) in this book. There are no reliable morphologic features that allow distinction between metastatic colorectal carcinoma and moderately differentiated sinonasal intestinal-­type adenocarcinoma (ITAC). Immunohistochemistry is of no significant help, as both tumors have the immunophenotype of intestinal cells and express CK20, CDX2, SATB2, and villin.199,201,202 In this situation, correlation with medical history and clinical findings, including colonoscopy, is necessary to establish the correct diagnosis. Well-­differentiated ITAC and low-­grade papillary

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A

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B

Fig. 3.73  Metastatic lung carcinoma. A, The tumor has a spindled appearance that does not resemble any specific sinonasal carcinoma. B, Napsin-­A is positive.

adenocarcinoma are, in most cases, primary sinonasal tumors because these lesions resemble normal intestinal mucosa or villous adenomas, and intestinal lesions with this morphology do not have metastatic potential. Close attention to morphologic findings and correlation with clinical findings are necessary to exclude a metastatic neoplasm. The main differential diagnosis of other metastatic adenocarcinomas, such as those of the lung (Fig. 3.73A), breast, thyroid, pancreas, prostate, and stomach is mainly a poorly differentiated sinonasal adenocarcinoma, either intestinal or nonintestinal type. As a general rule, metastasis should be considered for any sinonasal malignancy that has an unusual, unconventional histologic appearance (Fig. 3.73A). In this setting, the use of antibodies against thyroglobulin and PAX8 (for thyroid gland) prostate-specific antigen and NKX3.1 (for prostate), TTF-­1

and Napsin-­A (for lung) (Fig. 3.73B) may be useful to exclude metastasis from those sites. Metastatic involvement of the sinonasal tract is, in most cases, evidence of advanced disease and is associated with a dismal prognosis. Given the bleak prognosis of these patients and the disseminated nature of their disease, radical treatment does not appear to be warranted. However, palliative treatment with radiotherapy with or without surgery may help to control local disease and pain. Radiotherapy with or without surgery has also been reported to prolong life in some cases. ACKNOWLEDGEMENTS The authors are grateful for the contributions of the previous authors of this chapter, Manju Prasad and Bayardo Perez-­Ordonez.

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el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 44–45. 352. Kuo, F.Y., Lin, H.C., Eng, H.L., et al., 2005. Sinonasal hemangiopericytoma-­like tumor with true pericytic myoid differentiation: a clinicopathologic and immunohistochemical study of five cases. Head Neck. 27, 124–129. 353. Lasota, J., Felisiak-­Golabek, A., Aly, F.Z., et al., 2015. Nuclear expression and gain-­of-­function beta-­ catenin mutation in glomangiopericytoma (sinonasal-­ type hemangiopericytoma): insight into pathogenesis and a diagnostic marker. Mod. Pathol. 28, 715–720. 354.  Haller, F., Bieg, M., Moskalev, E.A., et al., 2015. Recurrent mutations within the amino-­ terminal region of beta-­ catenin are probable key molecular driver events in sinonasal hemangiopericytoma. Am. J. Pathol. 185, 563–571. 355. Mohajeri, A., Tayebwa, J., Collin, A., et al., 2013. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer. 52, 873–886. 356. Doyle, L.A., Vivero, M., Fletcher, C.D., et al., 2014. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod. Pathol. 27, 390–395. 357. Billings, K.R., Fu, Y.S., Calcaterra, T.C., et al., 2000. Hemangiopericytoma of the head and neck. Am. J. Otolaryngol. 21, 238–243. 358.  Catalano, P.J., Brandwein, M., Shah, D.K., et al., 1996. Sinonasal hemangiopericytomas: a clinicopathologic and immunohistochemical study of seven cases. Head Neck. 18, 42–53. 359. Thompson, L.D., Miettinen, M., Wenig, B.M., 2003. Sinonasal-­ type hemangiopericytoma: a clinicopathologic and immunophenotypic analysis of 104 cases showing perivascular myoid differentiation. Am. J. Surg. Pathol. 27, 737–749. 360.  Heffner, D.K., 1983. Problems in pediatric otorhinolaryngic pathology. II. Vascular tumors and lesions of the sinonasal tract and nasopharynx. Int. J. Pediatr. Otorhinolaryngol. 5, 125–138. 361. Mills, S.E., Cooper, P.H., Fechner, R.E., 1980. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma. A study of 73 cases from the oral and nasal mucous membranes. Am. J. Surg. Pathol. 4, 470–479. 362. Thompson, L.D.R., Bullerdiek, J., Flucke, U., et al., 2017. Benign soft tissue tumors. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 47–50. 363. Guo, R,. Folpe, A.L., 2015. Extensively myxoid and hyalinized sinonasal capillary hemangiomas: a clinicopathologic study of 16 cases of a distinctive and potentially confusing hemangioma variant. Am. J. Surg. Pathol. 39, 1584– 1590. 364. Perzin, K.H., Panyu, H., Wechter, S., 1982. Nonepithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx. A clinicopathologic study. XII: Schwann cell tumors (neurilemoma, neurofibroma, malignant schwannoma). Cancer. 50, 2193–2202. 365. Hillstrom, R.P., Zarbo, R.J., Jacobs, J.R., 1990. Nerve sheath tumors of the paranasal sinuses:

electron microscopy and histopathologic diagnosis. Otolaryngol. Head Neck Surg. 102, 257–263. 366. Younis, R.T., Gross, C.W., Lazar, R.H., 1991. Schwannomas of the paranasal sinuses. Case report and clinicopathologic analysis. Arch. Otolaryngol. Head Neck Surg. 117, 677–680. 367. Azani, A.B., Bishop, J.A., Thompson, L.D., 2015. Sinonasal tract neurofibroma: a clinicopathologic series of 12 cases with a review of the literature. Head Neck Pathol. 9, 323–333. 368. Hasegawa, S.L., Mentzel, T., Fletcher, C.D., 1997. Schwannomas of the sinonasal tract and nasopharynx. Mod. Pathol. 10, 777–784. 369. Flucke, U., Franchi, A., Thompson, L.D.R., 2017. Malignant peripheral nerve sheath tumor. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 39–40. 370. Antonescu, C.R., Scheithauer, B.W., Woodruff, J.M., 2013. Malignant Tumors of Peripheral Nerves. AFIP Atlas of Tumor Pathology: Tumors of the Peripheral Nervous System. ARP Press, Silver Spring, MD, p. 381–474. 371. Victoria, L., McCulloch, T.M., Callaghan, E.J., et al., 1999. Malignant triton tumor of the head and neck: A case report and review of the literature. Head Neck. 21, 663–670. 372. Heffner, D.K., Gnepp, D.R., 1992. Sinonasal fibrosarcomas, malignant schwannomas, and “Triton” tumors. A clinicopathologic study of 67 cases. Cancer. 70, 1089–1101. 373. Shajrawi, I., Podoshin, L., Fradis, M., et al., 1989. Malignant triton tumor of the nose and para-­nasal sinuses -­a case-­study. Hum. Pathol. 20, 811–814. 374. Hellquist, H.B., Lundgren, J., 1991. Neurogenic sarcoma of the sinonasal tract. J. Laryngol. Otol. 105, 186–190. 375. Lewis, J.E., Oliveira, A.M., 2017. Biphenotypic sinonasal sarcoma. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 40–41. 376. Wang, X., Bledsoe, K.L., Graham, R.P., et al., 2014. Recurrent PAX3-­ MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet. 46, 666–668. 377. Lewis, J.T., Oliveira, A.M., Nascimento, A.G., et al., 2012. Low-­grade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases. Am. J. Surg. Pathol. 36, 517–525. 378. Rooper, L.M., Huang, S.C., Antonescu, C.R., et al., 2016. Biphenotypic sinonasal sarcoma: an expanded immunoprofile including consistent nuclear beta-­catenin positivity and absence of SOX10 expression. Hum. Pathol. 55, 44–50. 379. Fritchie, K.J., Jin, L., Wang, X., et al., 2016. Fusion gene profile of biphenotypic sinonasal sarcoma: an analysis of 44 cases. Histopathology. 69, 930–936. 380. Wong, W.J., Lauria, A., Hornick, J.L., et al., 2016. Alternate PAX3-­FOXO1 oncogenic fusion in biphenotypic sinonasal sarcoma. Genes Chromosomes Cancer. 55, 25–29. 381.  Huang, S.C., Ghossein, R.A., Bishop, J.A., et al., 2016. Novel PAX3-­NCOA1 fusions in biphenotypic sinonasal sarcoma with focal rhabdomyoblastic differentiation. Am. J. Surg. Pathol. 40, 51–59.

3  Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx 382. Ro, J.Y., Bell, D., Nicolai, P., et al., 2017. Meningioma. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 50–51. 383.  Perzin, K.H., Pushparaj, N., 1984. Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologic study. XIII: meningiomas. Cancer. 54, 1860– 1869. 384. Rushing, E.J., Bouffard, J.P., McCall, S., et al., 2009. Primary extracranial meningiomas: an analysis of 146 cases. Head Neck Pathol. 3, 116–130. 385. Thompson, L.D., Gyure, K.A., 2000. Extracranial sinonasal tract meningiomas: a clinicopathologic study of 30 cases with a review of the literature. Am. J. Surg. Pathol. 24, 640–650. 386. Wenig, B.M., 2017. Sinonasal ameloblastoma. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 51. 387. Schafer, D.R., Thompson, L.D., Smith, B.C., et al., 1998. Primary ameloblastoma of the sinonasal tract: a clinicopathologic study of 24 cases. Cancer. 82, 667–674. 388. Lloyd, R.V., Chandler, W.F., Kovacs, K., et al., 1986. Ectopic pituitary adenomas with normal anterior pituitary glands. Am. J. Surg. Pathol. 10, 546–552. 389. Luk, I.S., Chan, J.K., Chow, S.M., et al., 1996. Pituitary adenoma presenting as sinonasal tumor: pitfalls in diagnosis. Hum. Pathol. 27, 605–609. 390.  Katabi, N., Hunt, J.L., Thompson, L.D.R., et al., 2017. Benign and borderline lesions. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 72–73. 391. Byrne, M.N., Sessions, D.G., 1990. Nasopharyngeal craniopharyngioma. Case report and literature review. Ann. Otol. Rhinol. Laryngol. 99, 633–639. 392. Chiun, K.C., Tang, I.P., Vikneswaran, T., et al., 2012. Infrasellar craniopharyngioma of the posterior nasal septum: a rare entity. Med. J. Malaysia. 67, 131–132. 393.  Nourbakhsh, A., Brown, B., Vannemreddy, P., et al., 2010. Extracranial infrasellar ectopic craniopharyngioma: a case report and review of the literature. Skull Base. 20, 475–480. 394. Rakheja, D., Meehan, J.J., Gomez, A.M., 2005. Pathologic quiz case: sphenoid sinus mass in a 12-­year-­old girl. Infrasellar adamantinomatous craniopharyngioma. Arch. Pathol. Lab. Med. 129, e73–e74. 395. Franchi, A., Wenig, B.M., 2017. Teratocarcinosarcoma. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 26–27. 396. Pai, S.A., Naresh, K.N., Masih, K., et al., 1998. Teratocarcinosarcoma of the paranasal sinuses: a clinicopathologic and immunohistochemical study. Hum. Pathol. 29, 718–722. 397. Salem, F., Rosenblum, M.K., Jhanwar, S.C., et al., 2008. Teratocarcinosarcoma of the nasal cavity and paranasal sinuses: report of 3 cases with assessment for chromosome 12p status. Hum. Pathol. 39, 605–609. 398.  Fatima, S.S., Minhas, K., Din, N.U., et al., 2013. Sinonasal teratocarcinosarcoma: a clinicopathologic and immunohistochemical study of 6 cases. Ann. Diagn. Pathol. 17, 313–318.

399. Smith, S.L., Hessel, A.C., Luna, M.A., et al., 2008. Sinonasal teratocarcinosarcoma of the head and neck: a report of 10 patients treated at a single institution and comparison with reported series. Arch. Otolaryngol. Head Neck Surg. 134, 592–595. 400. Budrukkar, A., Agarwal, J.P., Kane, S., et al., 2010. Management and clinical outcome of sinonasal teratocarcinosarcoma: single institution experience. J. Laryngol. Otol. 124, 739–743. 401. Misra, P., Husain, Q., Svider, P.F., et al., 2014. Management of sinonasal teratocarcinosarcoma: a systematic review. Am. J. Otolaryngol. 35, 5–11. 402. Abbondanzo, S.L., Wenig, B.M., 1995. Non-­ Hodgkin’s lymphoma of the sinonasal tract. A clinicopathologic and immunophenotypic study of 120 cases. Cancer. 75, 1281–1291. 403. Fellbaum, C., Hansmann, M.L., Lennert, K., 1989. Malignant lymphomas of the nasal cavity and paranasal sinuses. Virchows Arch. A Pathol. Anat. Histopathol. 414, 399–405. 404. Cooper, J.S., Porter, K., Mallin, K., et al., 2009. National Cancer Database report on cancer of the head and neck: 10-­year update. Head Neck. 31, 748–758. 405. Chuang, S.S., Jaffe, E.S., 2017. Hematolymphoid tumors. In: el-­ Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 52–55. 406.  Proulx, G.M., Caudra-­ Garcia, I., Ferry, J., et al., 2003. Lymphoma of the nasal cavity and paranasal sinuses: treatment and outcome of early-­ stage disease. Am. J. Clin. Oncol. 26, 6–11. 407. Cheung, M.M., Chan, J.K., Lau, W.H., et al., 1998. Primary non-­Hodgkin’s lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J. Clin. Oncol. 16, 70–77. 408. Tran, L.M., Mark, R., Fu, Y.S., et al., 1992. Primary non-­Hodgkin’s lymphomas of the paranasal sinuses and nasal cavity. A report of 18 cases with stage IE disease. Am. J. Clin. Oncol. 15, 222–225. 409. Kapadia, S.B., Barnes, L., Deutsch, M., 1981. Non-­Hodgkin’s lymphoma of the nose and paranasal sinuses: a study of 17 cases. Head Neck Surg. 3, 490–499. 410. Frierson, H.F., Jr., Innes, D.J., Jr., Mills, S.E., et al., 1989. Immunophenotypic analysis of sinonasal non-­Hodgkin’s lymphomas. Hum. Pathol. 20, 636–642. 411. Crane, G.M., Duffield, A.S., 2016. Hematolymphoid lesions of the sinonasal tract. Semin. Diagn. Pathol. 33, 71–80. 412. Chuang, S.S., Gaulard, P., Jaffe, E.S., et al., 2017. Extranodal NK/T-­ cell lymphoma. In: el-­Naggar, A.K., Chan, J.K.C., Grandis, J.R., et al., eds. WHO Classification of Head and Neck Tumours. IARC Press, Lyon, France, p. 52–54. 413. Arber, D.A., Weiss, L.M., Albujar, P.F., et al., 1993. Nasal lymphomas in Peru. High incidence of T-­ cell immunophenotype and Epstein-­ Barr virus infection. Am. J. Surg. Pathol. 17, 392–399. 414. van de Rijn, M., Bhargava, V., Molina-­Kirsch, H., et al., 1997. Extranodal head and neck lymphomas in Guatemala: high frequency of Epstein-­Barr virus-­associated sinonasal lymphomas. Hum. Pathol. 28, 834–839.

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4

Lesions of the Oral Cavity LINDSAY MONTAGUE | ASHLEY CLARK | JERRY ELMER BOUQUOT

Fibrous, Fibrohistiocytic, and Fibrovascular Lesions The great majority of soft-tissue masses of the mouth are hyperplastic inflammatory responses to local, usually chronic, trauma or infection.1–18 Moreover, these reactive lesions are much more common in the mouth than in other parts of the body, presumably because of the close proximity of mucosa to hard, often sharp teeth and prosthetic appliances, as well as the inevitable low-­grade inflammation from gingival bacteria. These benign reactive lesions result from the proliferation of one or more components of the normal connective tissue stroma and are sometimes unique to the mouth because of their origin from periodontal or odontogenic tissues. Found in the mouths of 3% of adults, these lesions collectively represent more than 80% of biopsied oral masses.1–-1,9,13 Included in this first section are benign neoplastic lesions, with fibrous proliferation as the major characteristic. Look-­alike “fibrous” tumors of peripheral nerves and smooth muscle are discussed separately in this chapter, under the sections relating to benign nerve and muscle tumors. Altogether, neoplastic fibrous lesions are much less common than inflammatory hyperplasias, and they are more likely to represent a localized manifestation of a systemic process or syndrome.4–2,9,13 Many soft tissue nodules of the mouth are comprised predominantly of a moderately dense fibrous stroma but contain various nonfibrous components. These unique components are used to classify the masses as distinctly different entities, for example: (1) islands of benign and innocuous-­looking squamous epithelium, (2) islands of benign odontogenic or basaloid epithelium, (3) metaplastic or newly forming bone, (4) globular, acellular cementoid inclusions, (5) benign cartilage, (6) multinucleated giant cells, (7) entrapped minor salivary glands, or (8) adipose tissue. These types of nodules are explained later in this chapter and elsewhere in the text. IRRITATION FIBROMA AND LOCALIZED FIBROUS HYPERPLASIA Classic hyperplastic scar tissue or keloids of the skin are quite unusual in the mouth, but there is an oral counterpart comprised of avascular collagen: the irritation fibroma, also known as the traumatic fibroma. This entity is a very common submucosal response to trauma from teeth, dental prostheses, and gingival inflammation. First reported in 1846 as fibrous polyp and polypus, it is universally understood to be a reactive lesion rather than a neoplastic one, although it must be mentioned that rare neoplastic-­like fibromas do occur in the mouth.19–22 Found in 1.2% of adults (Table 4.1), this reactive hyperplasia is the most common oral mucosal mass submitted for biopsy 188

and is usually composed of types I and III collagen, with equivocal evidence, suggesting a pathophysiologic association with elevated transforming growth factor (TGF)-­α.1,2,9,21,22 Since it may be difficult to separate irritative hyperplasia from neoplasia in larger fibroma-­like masses, some authors have suggested Ki-­67 immunonegativity for confirmation of a nonneoplastic proliferation.22 Clinical Features. The irritation fibroma has a 66% female predilection and can occur at almost any age, but is usually biopsied in the fourth through sixth decades of life.2,21 It is, however, rare during the first decade. Since it is almost always seen as a single nodule, patients with multiple fibroma-­like masses may represent cases of familial fibromatosis, fibrotic papillary hyperplasia of the palate, symmetrical palatal fibromatosis (SPF), chronic lingual papulosis, tuberous sclerosis, Gardner syndrome, multiple hamartoma syndrome (Cowden syndrome), or multiple endocrine neoplasia syndrome 2B (MEN 2B, MEN 3). Those with a generalized fibrous overgrowth of gingival tissues are said to have fibrous gingival hyperplasia or gingival fibromatosis, discussed elsewhere in this chapter. Buccal mucosa, labial mucosa, and lateral tongue sites are those most likely to be traumatized and so it is not surprising to find that these sites account for 71% of all oral fibromas.2,9 The mass is typically pedunculated or sessile with a smooth surface. Usually reaching its maximum size within a few months (Fig. 4.1A), it seldom exceeds 1.5 cm in size, and once fully formed, it remains indefinitely without change. It is an asymptomatic, moderately firm, immovable mass with a surface ­coloration that is most often normal but may show pallor from decreased stromal vascularity, whiteness from thickened ­surface keratin, or brown discoloration from development in a pigmented portion of mucosa. Occasionally, surface ulceration arises from acute or recurring trauma. A fibroma beneath a denture has no room to expand uniformly in all directions and so develops as a flat, pancake-­ shaped mass with small surface irregularities along the outer edges. This leaf-­shaped fibroma is often associated with an underlying cupped-­out area of bony saucerization, with an associated convexity of palatal bone into the overlying sinus (Fig. 4. 1B).9,18 Another unique variant of denture-­related fibroma, epulis fissuratum (epulis means “mass on the gingiva”), is an irregular, linear, fibrous hyperplasia occurring in the mucosal vestibule or sulcus, adjacent to the alveolar ridge where the edge of a loose-­ fitting denture chronically traumatizes the tissue.23–25 The mass runs parallel to the edge of the denture (Fig. 4.1C). Eventually, three or more “waves” of fibrous redundant tissue may be seen, with deep grooves between them. The superior edges of these masses may have a line of papules or small secondary growths,

4  Lesions of the Oral Cavity

TABLE

4.1

Prevalence Rates for Selected Oral Mucosal Masses and Surface Alterations in US Adults

Diagnosis

Torus Irritation fibroma Fordyce granules Hemangioma Papilloma Epulis fissuratum Lingual varicosities Papillary hyperplasia Mucocele Enlarged lingual tonsil Lichen planus Buccal exostosis Median rhomboid glossitis Epidermoid cyst Oral melanotic macule Oral tonsils (except lingual) Lipoma Ranula Buccinator node, hyperplastic Pyogenic granuloma Nasoalveolar cyst Neurofibroma

NUMBER OF LESIONS PER 1000 POPULATIONa Males

Females

Total

22.8 13.0 17.7 8.4 5.3 3.4 3.5 1.7 1.9 2.4 1.2 0.9 0.8 0.7 0.5 0.5 0.2 0.2 0.1 0.0 0.0 0.0

30.0 11.4 5.2 4.1 4.2 4.4 3.4 3.8 2.6 1.2 1.1 0.9 0.5 0.4 0.3 0.3 0.1 0.1 0.07 0.07 0.07 0.07

27.1 12.0 9.7 5.5 4.6 4.1 3.5 3.0 2.5 1.6 1.1 0.9 0.6 0.5 0.4 0.4 0.2 0.2 0.08 0.04 0.04 0.04

aTotal

examined population = 23,616 adults; total number of masses = 1453. Data from Bouquot, J.E., 1986. Common oral lesions found in a large mass screening. J. Am. Dent. Assoc. 112, 50–57; Bouquot, J.E., Gundlach, K.K.H., 1986. Oral exophytic lesions in 23,616 white Americans over 35 years of age. Oral Surg. Oral Med. Oral Pathol. 62, 284–291; Bouquot, J.E., 1988. Epidemiology. In: Gnepp, D.R. (ed). Pathology of the Head and Neck. Churchill-­Livingstone, Philadelphia, p. 263–314.

perhaps explaining why the lesion was first reported in 1858 as mamillated epulis.23 The lesion accounts for about 3% of submitted oral biopsies and is usually found in persons 40 to 50 years of age.2,9 The most recent variant of the oral fibroma presents not as a single mass but as a cluster of small fibrous masses, often dozens, located on the dorsum of the tongue called chronic lingual papulosis.26 These patients present with clustered, sometimes generalized, collections of 2 to 4 mm individual masses that appear identical to the irritation fibroma and are usually slightly pedunculated (Fig. 4.1D). Occasionally, one mass will be much larger than the others but usually they are rather uniform in size and show no clinical erythema, edema, or ulceration. The masses probably represent fibrous hyperplasia of fusiform papillae, but there is no alteration in taste, and, in fact, there are no symptoms at all unless a secondary candidiasis develops between the masses. The lesion is typically of long duration, presumably lasting indefinitely once formed; it has been reported from childhood to early middle age. Some cases appear to be late-­onset developmental anomalies, while others seem to result from dry mouth or a mild, repeating physical irritation.  Pathologic Features and Differential Diagnosis. The irritation fibroma is composed of a dense, minimally cellular stroma of collagen fibers arranged randomly or organized into interlacing fascicles (Fig. 4.2A and B). The stromal cells are bipolar fibroblasts with plump nuclei and fibrocytes with thin,

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elongated nuclei and minimal cytoplasm. As with keloids of the skin, the mucosal fibroma may be remarkably avascular, but areas of degeneration or necrosis are not seen. Usually, a few scattered mature capillaries are found; perhaps with a few showing dilation. In cases resulting from the slow fibrosis of granulation tissue or pyogenic granuloma, focal areas of edema and neovascularity may be seen in the midportion or lower third of the mass. Occasional lesions may still contain residual granulation tissue, prompting some pathologists to prefer the term fibrotic pyogenic granuloma. Such lesions may be indistinguishable from the angiofibroma of tuberous sclerosis. Occasional fibroma-­like masses have surface lobulations and unusually large, stellate-­ shaped, sometimes multinucleated fibroblasts. These masses represent giant cell fibroma or other giant fibroblast-­containing lesions, described in following sections. Although usually nonencapsulated, some lesions show a pseudoencapsulation and may, therefore, be mistaken for neurofibroma or palisaded encapsulated neuroma. Scattered chronic inflammatory cells are seen in small numbers, typically beneath the epithelium or around blood vessels. Occasional fibromas demonstrate extreme elongation of rete processes and are called fibroepithelial polyps by some, presumably because of their similarity to the dermal lesion of that name. These polyps are seen especially on the tongue in patients with Gorlin syndrome (nevoid basal cell carcinoma syndrome). The surface epithelium is usually atrophic but may show signs of continued trauma, such as excess keratin, intracellular edema of the superficial layers, or small traumatic ulceration. The hyperkeratinized epithelium is not dysplastic or precancerous and is essentially a frictional keratosis. Rarely, melanin deposition is seen in the basal layer. The latter has no diagnostic significance, but its presence has led some to refer to such a lesion as pigmented fibromas. Epulis fissuratum is microscopically similar to routine irritation fibroma except that chronic inflammatory cells are more numerous, and the surface epithelium is much more likely to be ulcerated, especially in the base of the clefts between the redundant folds of tissue. The intact surface epithelium is often quite acanthotic, with occasional lesions showing enough elongation of rete processes to justify a secondary diagnosis of pseudoepitheliomatous hyperplasia (Fig. 4.2C). The pathologist must be very cautious about misinterpreting this epithelial hyperplasia as well-­differentiated squamous cell carcinoma or verrucous carcinoma, especially with samples showing elongated rete processes cut tangentially or at right angles, appearing as separate islands of epithelium deep in the stroma. It is important, in this regard, to understand that carcinoma in association with epulis fissuratum is extremely rare. Individual masses of chronic lingual papulosis are microscopically identical to the irritation fibroma, except that occasional taste buds may be found in the surface epithelium.  Treatment and Prognosis. Irritation fibroma and other localized fibrous hyperplasias are easily removed by conservative surgical excision, with no need to remove a large margin of surrounding normal mucosa. Recurrence is unlikely unless the inciting trauma/infection continues or is repeated. The bony concavity associated with some leaf-­shaped fibromas, under dentures, will recontour to normal after removal of the offending mass. For epulis fissuratum, the treatment includes both surgical removal and reline or remake of the offending

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Fig. 4.1  A, Pedunculated irritation fibroma of the left tongue. B, Leaf-­shaped fibroma of the hard palate has been forced by an overlying denture to enlarge laterally and remain flat. C, Epulis fissuratum of the left maxillary vestibule presents as a redundant, linear fold of tissue (arrow points to groove where denture usually seats). D, Chronic lingual papulosis with numerous papillae presenting as rounded, enlarged fibroma-­like masses.

denture. If the denture is not corrected, recurrence in much more likely. Chronic lingual papulosis requires no treatment and will remain indefinitely, once formed. If the affected lingual surface becomes tender or presents with a burning sensation, treatment for secondary candidiasis should be initiated.  GIANT CELL FIBROMA The giant cell fibroma is a fibrous mucosal mass with several unique features separating it from other oral fibrous hyperplasias. First reported in 1974, its etiology remains unknown, even though it now represents up to 5% of all oral fibrous proliferations submitted for biopsy. It does not appear to result from chronic irritation.6,27–25 The oral lesion is microscopically identical to its dermal counterpart, fibrous papule of the

face, although the tryptase-­positive mast cells and elastin of that entity are less frequently expressed in oral counterparts. The giant or stellate fibroblasts characteristic of both lesions can mimic large nevus cells but have been shown to be reactive to vimentin and prolyl 4-­hydroxylase, but not to Factor XIIIa or S-­100 protein.29,30 This indicates an origin from fibroblasts rather than melanocytic precursors, despite the presence in some lesions of stromal melanin. Several oral fibrous masses, all described in this section, have been classified as distinct or unique entities based on the presence of these unusual fibroblasts: • Giant cell fibroma • Retrocuspid papilla • Retromolar papule • Desmoplastic fibroblastoma (collagenous fibroma) • Symmetrical palatal fibromatosis

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A

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Fig. 4.2  A, The irritation fibroma is usually pedunculated, is covered by a somewhat hyperplastic epithelium, and is composed of dense collagenic tissue, sometimes with a few dilated veins. B, Thick collagen bundles are irregularly arranged, with few visible blood vessels. C, The epulis is more edematous and shows a more severe chronic inflammatory cell infiltration. This example also demonstrated extreme elongation of the surface epithelium (pseudoepitheliomatous hyperplasia); inset shows transected tips of rete processes, which appear as independent islands of “invading” epithelium.

Clinical Features. The giant cell fibroma is an asymptomatic fibrous nodule, which usually remains less than 1 cm in size (Fig. 4.3A). The base may be broad or pedunculated and the surface can be smooth but is typically lobulated or papillary, mimicking the squamous papilloma. Almost two-­ thirds of cases occur before age 30 years and there appears to be a slight female predilection.31 The most common site of occurrence in the mouth, representing approximately half of all cases, is the gingiva, with mandibular gingiva affected twice as often as the maxillary. The tongue and palate are also common sites of occurrence. An uncommon variant occurs on the retromolar pad of the posterior mandible, often bilaterally, and is sometimes called retromolar papule (Fig. 4.3B). This is not to be confused with the normal anatomic structure called the retromolar papilla (see later). A normal anatomic structure, the retrocuspid papilla, has similar histology to the giant cell fibroma but always occurs on the lingual gingiva of the anterior mandible and is typically less than 5 mm in greatest dimension. It is usually bilateral and is located behind the cuspids or lateral incisors. It is very common in the pediatric population and involutes as the patient ages; it is uncommon in adults. The retrocuspid papilla is usually identified clinically and is not biopsied. A similar

normal anatomic structure may be located on the retromolar pad of the posterior mandible and is referred to as the retromolar papilla.  Pathologic Features and Differential Diagnosis. The giant cell fibroma, and its look-­alike counterparts, the retrocuspid papillae and the retromolar papule, consists almost entirely of avascular, moderately dense fibrous connective tissue, often with regions of fibromyxomatous stroma (Fig. 4.3C). The surface epithelium typically has very elongated, thin, and often pointed rete processes, typically with surface papules or bosselations. The “giant” cells required for the diagnosis are not numerous and are mostly concentrated beneath the epithelium. This cell is a stellate fibroblast, which is several times larger than the typical spindle-­shaped fibroblast and often has a “smudged” appearance (Fig. 4.3D). Nuclei in these cells are enlarged but are not hyperchromatic; frequently a small number will have multiple nuclei. Some of these fibroblasts may contain melanin pigment, but they are not melanocytes.  Treatment and Prognosis. Giant cell fibroma remains small but can be treated by conservative surgical excision. It is unlikely to recur though recurrences have been reported. There is no malignant potential to the lesion.

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Fig. 4.3  A, The giant cell fibroma, here just inside the lip, is usually pedunculated and slightly lobulated. B, Finger-­shaped mass in retromolar pad area was bilateral. C, The lesion is composed primarily of avascular fibrous stroma, with long intertwining rete processes. D, The key diagnostic feature is a scattering of enlarged, stellate, sometimes multinucleated, pale-­staining fibroblasts, seen most frequently in the subepithelial stroma.

The retrocuspid papule also remains small and most will eventually disappear, therefore no treatment is usually necessary.  DESMOPLASTIC FIBROBLASTOMA The slow-­ growing fibrous mass, desmoplastic fibroblastoma (DF, collagenous fibroma), usually arises on the upper extremities but is occasionally found in submucosal, subcutaneous or intramuscular tissues of the maxillofacial region. First described in 1995 as a distinctly unique fibrous hyperplasia, it is now classified as a benign fibroblastic/myofibroblastic neoplasm with a reciprocal translocation, involving the long arms of chromosomes 2 and 11, that is, t(2;11), a defect shared with the fibroma of tendon sheath; occasionally, other chromosomal defects, such as trisomy 8, are found.32–35 The major issue involving the DF is misdiagnosis as a more aggressive, even malignant neoplasm of the fibrous tissues. In fact, the alternate name collagenous fibroma appears to have been deliberately applied to emphasize the lesion’s innocuous behavior.

Clinical Features. The DF occurs primarily in males (2.5:1 male:female ratio) aged 40 to 70 years (median age = 50 years), presenting as a slow-­growing, often bosselated mass, with individual lesions measuring 1 to 20 cm, at the time of diagnosis (average = 3.4 cm.).17,32 They have typically been present more than 6 months by the time of diagnosis. The masses may or may not be pedunculated and at least one has presented with pain.  Pathologic Features. DF is firm, well-­circumscribed, round or oval, and demonstrates a glistening gray-­to-­white, obvious fibrous, cut surface. Histologically, it is hypocellular, with few vessels, and consists of dense to moderately dense collagenous or myxocollagenous stroma with scattered larger-­ than-­ normal spindle- or stellate-­shaped, sometimes multinucleated, fibroblasts. These fibroblasts occasionally will contain melanin. Often, long, thick avascular bands of collagen are noted, and occasional lesions will contain areas of entrapped adipose tissue or smooth muscle. Chronic inflammatory cells or focal areas of extravasated erythrocytes may be noted, as may occasional mitotic activity near the lesional borders. The overlying surface epithelium

4  Lesions of the Oral Cavity

is normal, lacking the elongated, pointed rete processes of the giant cell fibroma and symmetrical palatal fibromatosis, and the border is well-­demarcated, sometimes appearing encapsulated, but a few examples have shown apparent infiltration into adjacent muscle. Lesional fibroblasts are diffusely, usually intensely, positive for vimentin and focally positive for smooth muscle actin (both muscle-­specific and alpha), and some lesions have been focally and sparsely positive for cytokeratin. Immunostains for desmin, S-­100 protein, and CD34 are typically negative. Ultrastructurally, the cells have characteristics of fibroblasts or myofibroblasts.  Treatment and Prognosis. Conservative surgical excision is the treatment of choice, with a small margin of normal surrounding tissue. DF can produce underlying saucerization overlying bone, but this will return to normal after lesion removal; there is no need to remove the periosteum. There is no malignant transformation potential, but some lesions have been misdiagnosed as sarcomas because of the unusual fibroblasts.  SYMMETRICAL PALATAL FIBROMATOSIS The SPF is an uncommon, site-­ specific fibrous hyperplasia clinically characterized by large bilateral masses of the posterior lateral hard palate and microscopically characterized by the presence of giant fibroblasts identical to the giant cell fibroma.36–39 Its etiology is unknown but it behaves like a developmental anomaly, with adult onset. Some have considered this to be a unique form of gingival fibrous hyperplasia, and subsequently termed the lesion symmetrical gingival fibromatosis. However, the anatomic origin is actually from the supraperiosteal stroma of the lateral hard palate, just where palatal bone meets alveolar bone. Since its first report in 1900, all reported lesions have been very large, and lesions from each side of the palate have been identical in size and shape, hence the use of the term symmetrical in the diagnostic name.40 Other giant fibroblast-­associated lesions, such as the giant cell fibroma, the retrocuspid papilla and the retromolar papule, are microscopically identical, and the retrocuspid and retromolar variants are often bilaterally symmetrical, but none have ever become as large as the typical SPF. Clinical Features. SPF is diagnosed in young adults and has an average duration of more than 7 years; no reported case has been initiated before age 15 years.40 There is no gender predilection. Each reported example has presented as bilateral and symmetrical, large and sessile, smooth-­ surfaced, slightly bosselated masses, usually moderately firm to palpation but occasionally soft, and always with normal surface coloration (Fig. 4.4A and B). The center of each mass is on the lateral walls of the hard palate in the region where alveolar bone meets palatal bone. Masses often push into and enlarge adjacent gingival tissues or the maxillary tuberosity, a feature which may lead to misdiagnosis as gingival fibromatosis. Underlying bone is unaffected, adjacent teeth are not resorbed or moved, and the lesion is asymptomatic.  Pathologic Features. Masses are comprised entirely of dense, avascular and rather acellular fibrous connective tissue with

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scattered thick bands of collagen (Fig. 4.4C) and occasional slight surface bosselation. Myxoid change may be prominent, so much so that some have been misdiagnosed as a cartilaginous hamartoma.40 Occasional lymphocytes may be seen, if so, they are typically toward the surface but may occasionally be found in deeper tissues. Significantly, the stroma contained scattered large, angular fibroblasts, these occasionally have multiple nuclei or a “smudged” appearance, identical to those found in giant cell fibromas (Fig. 4.4D). The surface stratified squamous epithelium may show occasional long, thin, sometimes pointed rete processes.  Treatment and Prognosis. SPF can enlarge to more than 5 cm in greatest diameter, but even large lesions do not interfere with speech patterns; however, food may become trapped above masses so large that they touch one another. Treatment is conservative surgical excision, with preservation of the underlying periosteum. No recurrence has been reported.  DESMOID-­TYPE FIBROMATOSIS (AGGRESSIVE FIBROMATOSIS) Soft-tissue fibromatosis of the oral region, though uncommon, is one of the most frequently diagnosed congenital or developmental masses of the oral soft tissues. Variously and confusingly called fibromatosis, juvenile aggressive fibromatosis, juvenile fibromatosis, infantile fibromatosis, extraabdominal fibromatosis, desmoplastic fibroma, extraabdominal desmoid tumor, and desmoid tumor, such proliferations typically behave in a benign manner but may be locally aggressive and may have an alarmingly infiltrative histopathologic appearance.41–44 The most recent World Health Organization (WHO) classification system places this entity in the intermediate (locally aggressive) category, while some consider it to be a low-­grade, nonmetastasizing fibrosarcoma.45 A more detailed discussion of this lesion and myofibromatosis can be found in Chapter 9. Occasionally, the term fibromatosis is applied to quite innocuous lesions with very bland histopathology, such as SPF; however, the latter contains characteristic “giant fibroblasts,” lacking in other fibromatoses. Rarely, multiple fibrous masses are associated with systemic disorders, such as palmar-­plantar fibromatosis. Generalized gingival fibromatosis or gingival fibrous hyperplasia is unique to the oral cavity and has a different biological behavior; it is discussed later in this chapter. Clinical Features. Fibromatosis occurs primarily in children and young adults but may first be seen in middle-­aged individuals as well.41,45,46 There is no gender predilection. This lesion presents as a broad-­b ased, firm, nonmoveable, sessile or slightly pedunculated, painless, slowly enlarging mass with normal surface coloration, perhaps with surface bosselations. (Fig. 4.5A). The speed of enlargement is variable and should not be used as a reliable predictor of aggressive future behavior; some lesions grow rapidly for a few months and then very slowly for years thereafter. Fibromatosis usually develops adjacent to the mandible, where underlying bone may be eroded or destroyed by infiltrating fibrosis (see Fig. 4.5A). Lesions average 3 to 4 cm

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Fig. 4.4  A, Symmetrical palatal fibromatosis with smooth surfaces, here large enough to touch each other in the midline. B, Small bilateral masses. C, The mass consists of rather avascular fibrous tissue with elongated rete processes of the surface epithelium. D, Large, angular, smudged fibroblasts are scattered throughout the stroma.

A

B

Fig. 4.5  A, Lobulated mass of the posterior right mandibular gingiva represents desmoid-type fibromatosis and has caused destruction of the underlying bone. B, Streaming fascicles of spindled cells are highly cellular, with lesional cells showing open nuclei, which are oval or elongated, often with pointed tips.

4  Lesions of the Oral Cavity

in size at diagnosis, but can be as large as 9 cm, and multiple lesions have been reported. Larger lesions may develop s econdary surface lobulation. This entity has also been ­ reported to arise from within the medullary spaces of the jawbones.  Pathologic Features. Fibromatosis is characterized by a proliferation of spindle-­shaped, somewhat primitive-­looking mesenchymal cells arranged in streaming fascicles (Fig. 4.5B). Reticulin stains and Masson trichrome stain will confirm the collagenic nature of the stroma. Immunohistochemistry is focally reactive to smooth muscle actin, shows nuclear positivity for beta-­catenin and is not reactive for desmin, h-­caldesmon, or CD34. Thin-­walled vascular spaces are invariably present but not in large numbers. The lesional periphery is poorly demarcated from surrounding tissues and often appears to be infiltrating those tissues. Erosion or pressure saucerization of underlying bone, or destruction of the cortex, may be seen. The degree of cellularity is variable, with some cases demonstrating moderate numbers of lesional cells in a background stroma of abundant mature collagen, while others showing minimal stroma with large numbers of active mesenchymal cells. In both types, cellularity is most pronounced at the periphery of the tumor. Hyperchromatic and pleomorphic nuclei are seldom seen, but occasional normal-­ appearing mitotic figures may be found. If present, the mitotic figures are never numerous. Regions near the periphery may show small numbers of chronic inflammatory cells. Immunostains are reactive to smooth muscle actin and nonreactive for desmin. Additional immunohistochemical features are described in Chapter 9. Occasional fibromatoses infiltrating striated muscle will induce atrophy, degeneration, and regeneration of muscle cells, resulting in the presence of osteoclast-­like multinucleated giant cells and imparting a giant cell lesion appearance. The presence of dysplastic mesenchymal cells should make the pathologist suspicious for fibrosarcoma, malignant fibrous histiocytoma, or fibroblastic osteosarcoma (if attached to bone). Additional differential diagnoses are described in Chapter 9.  Treatment and Prognosis. Though some lesions have spontaneously regressed, oral desmoid-­ type fibromatosis typically continues to enlarge slowly for months and years. It is usually treated by wide excision, including a thin margin of adjacent normal tissues. It has a locally aggressive, often infiltrative behavior. With surgical excision there is a recurrence rate of more than 20%, possibly because microscopically positive margins may be accepted to minimize local morbidity. Overall, this rate is similar to the rate for lesions of the sinonasal area but is far below the rate for lesions found in other extraabdominal locations (40%). Recurrences are treated by reexcision, although radiotherapy and chemotherapy are often used. Relative to the latter, noncytotoxic and cytotoxic agents have been tried for recurrence prevention, but the literature suggests that certain hormonal drugs, nonsteroidal antiinflammatory drugs (NSAIDs), biologic drugs, and cytotoxic chemotherapeutic drugs are more helpful.46,47 Severe, multicentric lesions with visceral involvement are much more serious and may lead to diarrhea or even respiratory distress. The oral lesions are usually of minimal consequence in such cases. 

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GINGIVAL FIBROMATOSIS AND DRUG-­INDUCED FIBROUS HYPERPLASIA The most common of the oral fibromatoses involves the gingiva, often affecting all gingival surfaces of both arches. First reported in 1856, under the rather descriptive term fungus excrescence of the gingiva, and later called gingivomatosis elephantiasis, this entity is now primarily referred to as gingival fibromatosis.9,48,49 The terms fibrous gingival hyperplasia or drug-­induced gingival hyperplasia (DIGH) may be used for cases induced by one of a variety of drugs, for example, immunosuppressants, anticonvulsants, and calcium channel blockers (Table 4.2).49–53 Most cases are either idiopathic or hereditary gingival fibromatosis, with the latter often being part of a more extensive syndrome (Table 4.3).53,54 Hereditary and idiopathic variants first present in childhood, perhaps as young as 2 years of age. DIGH first becomes noticeable 3 or more months after the onset of drug use, although cases can occur years after drug use is initiated. Drug-­induced examples are characterized by increased fibroblast numbers and collagen synthesis, and appear to be associated with connective tissue repair processes, especially those involving transforming growth factor (TGF), endothelin-­1 (ET-­1), angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), insulin-­like growth factor (IGF), and platelet-­derived growth factor (PDGF); the protease enzymes from mast cells also appear to play an important role.51,55 Inherited variants are typically autosomal dominant but can be autosomal recessive, and recent analyses have shown that lesional fibroblasts produce excess collagen 1 via synthesis of HSP47, TGF-­β1, CTGF, and TIMP-­1, among others.53,54 Genes affecting fibronectin, probably stimulated by the immune system, are also influential. As the fibrous hyperplasia is significantly enhanced by poor oral hygiene, gingivitis and periodontitis are invariably associated with the fibrosis. Occasional adults develop a large, smooth, fleshy hyperplasia of the soft tissues overlying the bone of the maxillary tuberosity. This symmetrical palatal fibromatosis can extend anteriorly and creep downwards into the palatal gingival tissues, making it appear to be a gingival fibromatosis. This latter entity is discussed earlier in this chapter. Clinical Features. Gingival fibromatosis/fibrous hyperplasia presents as a generalized, often irregular enlargement of the facial and lingual aspects of the attached

TABLE

4.2

Drugs Associated With Fibrous Gingival Hyperplasia

Amlodipine Bepridil Bleomycin Cyclosporine Diltiazem Felodipine Isradipine Nicardipine Nifedipine Nimodipine Nisoldipine Nitrendipine Oxidipine Phenytoin Sodium valproate Verapamil

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and marginal gingiva (Fig. 4.6A). It is often more severe in the anterior maxillary region, crossing the midline, but there can be involvement of one or all quadrants. Enlargement is painless, slowly progressive, and dependent to a great extent on the oral hygiene of the individual. It is not unusual for the fibromatosis to completely cover the teeth. Some syndrome-­ associated hyperplasias (noted in Table 4.3) may have papillary or nodular surface alterations. Although the hyperplastic tissues are usually firm to palpation, inflammation and edema may make some surface areas TABLE

4.3

Syndromes Associated With Gingival Fibromatosis

WITH GENERALIZED GINGIVAL FIBROMATOSIS Amelogenesis imperfecta-­nephrocalcinosis syndrome, enamel-­ renal syndrome (gingival fibromatosis, delayed tooth eruption, hypoplastic enamel, microdontia, intrapulpal calcifications, root dilaceration) Byars-­Jurkiewicz syndrome (gingival fibromatosis, hypertrichosis, giant fibroadenomas of the breast, and kyphosis) Cross syndrome (gingival fibromatosis, microphthalmia, mental retardation, athetosis, and hypopigmentation) Gingival fibromatosis and growth hormone deficiency Gingival fibromatosis, hypertrichosis, epilepsy, and mental retardation syndrome Gingival fibromatosis with craniofacial dysmorphism Jones-­Hartsfield syndrome (gingival fibromatosis and sensorineural hearing loss) Zimmermann-­Laband syndrome (gingival fibromatosis; ear, nose, bone, and nail defects; and hepatosplenomegaly) Murray syndrome (gingival fibromatosis with juvenile hyaline fibromatosis) Prune-­belly syndrome (hypoplastic abdominal muscle, cryptorchidism, obstructive nephropathy, and gingival fibromatosis) Ramon syndrome, oculodental syndrome–Rutherford type (gingival fibromatosis, hypertrichosis, cherubism, mental and somatic retardation, and epilepsy) Rutherford syndrome (gingival fibromatosis and corneal dystrophy) WITH PAPULAR GINGIVAL FIBROMATOSIS (PAPULOSIS) Acanthosis nigricans Cowden syndrome (multiple hamartoma syndrome) Tuberous sclerosis

A

spongy, erythematous, and hemorrhagic under palpation. When this change is limited to tissues overlying only one or two teeth, there is often a unique histopathologic presentation, referred to a spongiotic gingival hyperplasia; this is discussed in the next section.  Pathologic Features and Differential Diagnosis. Gingival fibromatosis is classically composed of dense or moderately dense, rather avascular, bland collagenic connective tissue, with scattered chronic inflammatory cells noted beneath the surface epithelium (Fig. 4.6B). The attached gingival epithelium may show elongation of rete processes; in some cases, this is extreme enough for a secondary diagnosis of pseudoepitheliomatous hyperplasia. The crevicular epithelium facing the tooth surfaces usually shows considerable degeneration, subepithelial edema, and extensive chronic inflammatory cell infiltration. Scattered neutrophils may be present; this is caused by the accompanying gingivitis or periodontitis. Among the drug-­induced examples, cyclosporine-­induced lesions exhibit much more chronic inflammation than fibrosis, while nifedipine-­and phenytoin-­ induced lesions are highly fibrotic. Such subtypes may also demonstrate a myxoid background. When evaluating the inflammatory cell infiltrate, the pathologist must be careful to differentiate the polyclonal, mixed infiltrate from a diffuse submucosal infiltration of atypical leukocytes like those seen in leukemia or diffuse extranodal lymphoma (mucosal-­associated lymphoid tissue [MALT] lymphoma). Both chronic and acute leukemia patients may develop a generalized gingival hyperplasia secondary to massive infiltration of neoplastic leukocytes, presumably because these cells retain a certain amount of normal chemotactic ability and are drawn to an area of inflammation, such as with gingivitis. The clinical presentation is often called leukemic gingivitis or leukemic gingival hyperplasia. The criteria used for the determination of leukemia or lymphoid malignancy are the same as those used for leukemic or diffuse extranodal (MALT) lymphoma infiltrations anywhere in the body. These are discussed further in Chapter 13.

B

Fig. 4.6  A, Generalized gingival fibrous hyperplasia involving the entire gingiva is the classic presentation of gingival fibromatosis. B, Dense and rather avascular collagen makes up almost all of the hyperplasia in this disease, usually with scattered subepithelial and perivascular lymphocytes, while the overlying epithelium is hyperplastic.

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Some cases of generalized gingival hyperplasia show focal collections of histiocytes intermixed with lymphocytes and foreign-­body type multinucleated giant cells. This granulomatous gingivitis may be a foreign body reaction to the pastes used in prophylactic dental cleanings, or to other dental products. However, it may also be indicative of a more systemic chronic granulomatous disease, such as sarcoidosis, Crohn disease, or Wegener granulomatosis (granulomatosis with polyangiitis).51,56 Other gingival hyperplasias have large numbers of plasma cells scattered throughout the subepithelial stroma. This plasma cell gingivitis is presumed to be an unusual allergic reaction.57 Juvenile hyaline fibromatosis, a hereditary condition that may involve the gingiva, can be distinguished from gingival fibromatosis by its prominent periodic acid-­Schiff (PAS)–positive background matrix of chondroitin sulfate. Finally, amyloid infiltration of the gingival tissues is not uncommon in primary or secondary amyloidosis. It can be readily identified via Congo red stain under polarized light, thioflavin T stain under fluorescent light, or immunoreactivity with antibodies for immunoglobulin light chains.  Treatment and Prognosis. Gingival fibromatosis is removed by gingivectomy, recurrences are treated in the same fashion or by more conservative removal of local areas of hyperplasia. Improved oral hygiene and topical antibiotics will greatly diminish the risk of recurrence. DIGH may also be treated by gingivectomy and plaque control. Discontinuation of drug use often results in cessation and even regression of the gingival enlargement. Recently, researchers have had some success with size reduction using antiinflammatory medications systemically.58 Granulomatous gingivitis and plasma cell gingivitis are treated by addressing the underlying etiologies, but this often will only keep the lesions from becoming more severe; they may last for many more months and, occasionally, for years.  LOCALIZED JUVENILE SPONGIOTIC GINGIVAL HYPERPLASIA The most recent variation of gingival hyperplasia, localized juvenile spongiotic gingival hyperplasia (LJSGH) or juvenile spongiotic gingivitis, is a localized lesion with a unique clinical and histopathologic appearance. Its etiology is unknown.59–61 It appears to be an inflammatory entity, however, removing all local causes of inflammation has little or no effect. Based on available evidence, the lesional surface keratinizing cells immunoreact more like junctional epithelial cells, representing an “exteriorization” of the junctional epithelium, which then exposes it to surface irritants from which it is normally protected.61–63 Clinical Features. LJSGH is typically seen in the first two decades of life, with an average patient age of 12 years. There appears to be equal gender predilection and almost all lesions are located on the anterior maxillary gingiva (80%–91% of cases).60 The lesion is typically an asymptomatic, well-­demarcated, erythematous, slightly elevated mass with a granular or papillary surface, sometimes with slight bosselations. It occurs on the marginal and attached gingiva and reaches its full size in a few months (Fig. 4.7A). Individual lesions often

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have a linear shape and remain less than 1.5 cm in greatest diameter. Multiple synchronous areas of gingival involvement may be present and there is no loss of underlying osseous structures.  Pathologic Features. This lesion exhibits a pronounced epithelial hyperplasia characterized by acanthosis, prominent spongiosis and neutrophilic exocytosis, often with considerable lengthening of rete processes (Fig. 4.7B and C). The mass itself is formed by focally edematous and congested fibrovascular stroma with neovascularity and variable numbers of chronic inflammatory cells, primarily, lymphocytes. Neutrophils are often found in the stroma, as well as an abundance of nuclear dust. Cytokeratin 19 (CK19) is strongly and diffusely positive throughout the thickness of the epithelium, similar to the staining pattern of junctional epithelium. In contrast, normal gingival epithelium exhibits CK19 staining limited to the basal cell layer.63 The normally dense, avascular fibrous hyperplasia of other forms of gingival hyperplasia is absent and the most likely mistaken diagnosis to be given is pyogenic granuloma (pyogenic granuloma type of hemangioma).  Treatment and Differential Diagnosis. Conservative surgical excision is the treatment of choice for this entity, with recurrences occurring up to 2 years after treatment. Multiple recurrences have been noted.  ORAL SUBMUCOUS FIBROSIS Southeastern Asia and the Indian subcontinent have long been known for the use of smokeless tobacco in various forms. This habit, usually involving the chewing of a betel quid composed of various mixtures of areca nut, betel leaf, tobacco, and slacked lime (calcium hydroxide), has led to the development of a unique generalized fibrosis in a large proportion of users. Called oral submucous fibrosis, it is found in 1 of every 250 adults in rural India; it is estimated that as many as 5 million young Indians are suffering with it as a result of the increased popularity of the habit of chewing pan masala.64–66 The condition is caused primarily by the areca nut, which is known to contain high levels of copper, a cause of lysyl oxidase-­ associated fibrosis.66 The disease also carries at least an 8% risk of oral carcinoma development, primarily from the tobacco in the quid.67–69 In fact, oral cancer is the most common cancer in males in India and is the third most common cancer amongst women.69 First reported in 1952, oral submucous fibrosis does not produce a distinct soft-tissue mass but, rather, a diffuse submucosal fibrosis in areas contacted by the quid or juices from the quid.64,66 It results in a marked rigidity with progressive inability to open the mouth. There is an unusual fibroelastic transformation of the juxtaepithelial connective tissues and minor salivary glands in the affected area may also show chronic inflammation, atrophy, and fibrosis. Clinical Features. Oral submucous fibrosis typically affects the buccal mucosa, lips, retromolar areas, and soft palate. Occasional involvement of the pharynx and esophagus is seen. Early lesions present as a blanching of the mucosa, imparting a mottled, marble-­like appearance (Fig. 4.8A). Later lesions demonstrate palpable fibrous bands running vertically in the buccal mucosa and in a circular

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A

B Fig. 4.8  A, Oral submucous fibrosis of the buccal mucosa shows patchy pallor and erythema with white surface keratosis (arrow). B, Affected epithelium shows hyperchromatic and somewhat pleomorphic basilar and parabasilar nuclei, with dense fibrosis of the underlying stroma.

B

C Fig. 4.7  A, Localized juvenile spongiotic gingival hyperplasia appears as an erythematous mass extending upward from the marginal gingiva, with a slightly papular surface. B and C, Epithelium shows acanthosis, prominent spongiosis and neutrophilic exocytosis, with elongated rete processes.

fashion around the labial mucosa. As the disease progresses, the mucosa becomes stiff, causing difficulty in eating and considerably restricting the patient’s ability to open the mouth (trismus). If the tongue is involved, it becomes stiff and diminishes in size. Mucosal petechiae are seen in more than 10% of cases. Most patients complain of a burning sensation, often aggravated by spicy foods. Salivary flow is diminished and blotchy melanotic mucosal pigmentation (reactive melanosis) is often seen. Patients can develop extrinsic staining of the oral mucosal tissues or, more commonly, of the teeth. More than one-­fourth of affected persons develop precancerous leukoplakia of one or more oral surfaces. Once present, oral submucous fibrosis does not regress, even after cessation of betel quid chewing.  Pathologic Features and Differential Diagnosis. Early cases of oral submucous fibrosis present as chronic inflammatory cell infiltration of subepithelial connective tissues (Fig. 4.8B). This otherwise nonspecific infiltrate usually contains a number of eosinophils, cells seldom found in routine oral inflammation. Older lesions demonstrate reduced vascularity, reduced numbers of inflammatory cells, and dense bundles and sheets of collagen immediately beneath the epithelium. The eventual thick band of hyalinized subepithelial collagen shows varying

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extension into submucosal tissues, typically replacing the fatty or fibrovascular tissues normal to the site. Minor salivary glands in the area of habitual quid placement often demonstrate a chronic inflammatory infiltrate and replacement of acinar structures by a hyalinized fibrosis. The hyalinized stroma can mimic amyloid deposits, but Congo red and/or thioflavin-­T staining can rule this out.66 The epithelium is atrophic, with or without excess surface keratin, and demonstrates intracellular edema. One-­fourth of the biopsied cases will demonstrate epithelial dysplasia at the time of biopsy. When squamous cell carcinoma is seen, it has the same features of carcinoma as those seen in persons without the betel quid chewing habit.  Treatment and Prognosis. There is no effective treatment for oral submucous fibrosis, and the condition is irreversible once formed. Plastic surgery may be required to allow for improved opening of the mouth. Surface leukoplakias are handled by close follow-­up and repeated biopsies of areas of severe involvement. All dysplasias and carcinomas are treated in the routine manner for those entities. Epidemiologic studies have shown that as many as 8% of oral submucous fibrosis patients develop an oral carcinoma.65–68 Since the tobacco is the component of the quid most associated with cancer development, cessation of the quid chewing habit or eliminating the tobacco from the quid will reduce the risk of oral cancer, even though the fibrosis is not altered.  FIBROSARCOMA Malignancies of fibroblasts and doppelgänger stromal cells are decidedly rare in the oral and oropharyngeal region, but fibrosarcoma was once considered to be the most common of them, representing more than half of all head and neck (H&N) sarcomas.70,71 With advances in genetic-­and immunotechnologies, however, it has been supplanted by a myriad of other diagnoses and now represents less than 2% of head and neck sarcomas.8,12 Radiotherapy to the local site is known to increase the risk of fibrosarcoma development but there are no other known etiologic factors.12,72 Clinical Features. Persons affected by oral/pharyngeal fibrosarcoma are usually 30 to 50 years of age, but there is a wide age range and many patients are less than 20 years of age. Fibrosarcoma has been diagnosed in the oral region of infants.8,73 There is no apparent gender predilection and any submucosal site may be involved, although the buccal mucosa and tongue account for three-­fourths of cases. Fibrosarcoma most often presents as a clinically innocuous, lobulated, sessile, usually painless, and nonhemorrhagic submucosal mass of normal coloration. It may, however, be a rapidly enlarging, hemorrhagic mass similar in clinical appearance to an ulcerated pyogenic granuloma, peripheral giant cell granuloma, or peripheral ossifying fibroma, if present on the gingiva or alveolar ridge. Even lesions that do not demonstrate surface ulceration or rapid growth may show destruction of underlying muscle and bone.  Pathologic Features and Differential Diagnosis. Fibrosarcoma is a lesion with a varied microscopic appearance and is a diagnosis of exclusion, used when all other spindle cell sarcomas are ruled out. Lesional cells are spindle-­shaped and uniform in size, with pale eosinophilic cytoplasm and spindled nuclei with tapered ends. Cells typically flow in interweaving fascicles or bundles and often produce focal areas with a

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herringbone pattern, a feature which helps greatly to separate this lesion from fibrous hyperplasias and fibromatoses. The lesion is typically quite cellular, but moderate amounts of mature collagen may be produced, perhaps with areas of hyalinization. Scattered, histologically normal mitotic figures are seen in small numbers, while cells and nuclei may be very pleomorphic. It is typically categorized into low-­grade, intermediate-­grade or high-­grade fibrosarcoma and aggressive clinical behavior must be taken into account when determining such grades. This chapter is not intended for microscopic detail and differential diagnosis of fibrosarcoma look-­alikes; these are presented, along with immunohistochemistry, in Chapter 9. The low-­grade or well-­differentiated variant is usually somewhat circumscribed and consists primarily of fascicles of uniformly shaped spindle cells that often form a “herringbone” pattern. However, most fibrosarcomas of the oral region are not low-­grade. High-­grade or poorly-­differentiated lesions show cellular and nuclear pleomorphism, more frequent mitotic figures and less collagen than do well-­differentiated tumors. Focal anaplasia and necrosis may be seen; these are missing from the low-­grade lesions. Immunohistochemical reactivity should be negative except for vimentin, a relatively nonspecific marker for mesenchymal intermediate filaments.74,75 Scattered or weak positivity for smooth muscle actin may be seen, suggesting myofibroblastic differentiation. Fibrosarcoma of infancy and early childhood demonstrates smaller, more numerous, and more primitive cells than the adult lesion. The pathologist must take special precautions to distinguish fibrosarcoma from spindle cell carcinoma, a task made more difficult by the existence of an epithelioid variant of fibrosarcoma, the sclerosing epithelioid fibrosarcoma.74,75 The latter has a low cellularity, a mildly pleomorphic, sclerotic hyaline matrix, and a deceptively benign initial behavior, although one-­third present with pain. It has recently been shown to have FUS-­CREB3L1/L2 fusion transcripts, using reverse transcription-­polymerase chain reaction, and so may actually be a low-­grade fibromyxoid sarcoma.74  Treatment and Prognosis. Well-­differentiated fibrosarcoma of the oral cavity is treated by wide local excision, whereas more poorly differentiated tumors require radical surgery, including removal of potentially invaded muscle and bone. Fibrosarcoma seldom metastasizes, except late in its clinical course, but when this does occur, the metastatic deposits are usually blood-­borne and carried to distant sites, especially the lungs, liver, and bones. Radiotherapy may be used as salvage for recurrences, which occur in almost half of all cases. The 5-­year survival rate ranges from 50% to 70%. The epitheliod variant has a somewhat better prognosis.  BENIGN FIBROUS HISTIOCYTOMA Benign fibrous histiocytoma (BFH), first reported by Kauffman and Stout in 1961, represents a diverse group of neoplasms that exhibit both fibroblastic and histiocytic differentiation.76–79 The cell of origin is believed to be the histiocyte, but the varied microscope appearances of the lesion has led to the use of numerous alternative diagnostic terms, including dermatofibroma, sclerosing hemangioma, xanthogranuloma, fibroxanthoma, and nodular subepidermal fibrosis. In addition, there have been several subtypes recently accepted, especially epithelioid, cellular, and angiomatoid (probably a border-­line malignancy rather than completely benign) variants.80–83

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BFH is rare in the oral cavity and when present is most likely to be a cellular variant. This and other variants are more thoroughly discussed as separate entities in Chapter 9. Also the malignant form of this neoplasm is discussed in the following section. Clinical Features. The most common location of BFH occurrence is the skin of the extremities, where it usually presents as a small, firm nodule. Oral and perioral lesions have a similar appearance and occur predominantly on the buccal and vestibular mucosa. The oral lesion is typically found in middle-­aged and older adults, where it presents as a painless submucosal nodule that can vary in size from a few millimeters to several centimeters.82 Deeper tumors tend to be larger and much less frequent. Most lesions cannot be easily moved about beneath the epithelium.81  Pathologic Features and Differential Diagnosis. Fibrous histiocytoma is characterized by a submucosal, cellular aggregation of spindle-­ shaped, fibroblast-­ like cells with relatively pale, oval nuclei; scattered rounded histiocytic cells are also present. Foamy histiocytes and Touton-­ type multinucleated giant cells may be seen to contain phagocytosed lipid or hemosiderin; these cells sometimes are so numerous that they form xanthomatous aggregates. A background stroma of variably dense collagenic tissue and vascularity is seen. The spindled cells may be arranged randomly, but usually there are large areas with tumor cells streaming in interlacing fascicles from a central nidus and intersecting with cells from adjacent aggregates, imparting a storiform or crisscross pattern on low-­power magnification. Polygonal epithelioid cells may be present in abundance. If they represent more than 50% of lesional cells, a diagnosis of epithelioid fibrous histiocytoma is preferred. The epitheliod cells have plentiful eosinophilic cytosol, vesicular chromatin and a prominent nucleolus. See ­Chapter 9 for a more detailed microscopic description, including immunohistochemistry, and differential diagnosis for the epithelioid variant. More cellular BFH lesions, that is, cellular fibrous histiocytomas, tend to present with a more extensive fascicular or storiform pattern. This variant typically is composed of spindled lesional cells with numerous mitotic figures, but none should be atypical. Unlike other forms of BFH, necrosis of central regions may be seen. Angiomatoid fibrous histiocytoma has a dense fibrous capsule surrounded by a lymphocytic infiltrate with germinal centers, and typically contains spaces filled with blood but not lined by endothelium.75 See Chapter 9 for a more detailed description of this entity.  Treatment and Prognosis. BFH is treated by wide surgical excision, with 5% to 10% of cases recurring locally.12,79 Deeper and larger lesions have a higher rate of recurrence. More aggressive examples may show microscopic features of malignancy, such as marked cellularity, mitotic activity, focal necrosis or atypical giant cells. It is sometimes very difficult to predict biologic behavior on the basis of cellular features, as illustrated by the occasional case that metastasizes, despite its bland histopathologic appearance. For this reason, extended follow-­up is recommended after surgical removal.  UNDIFFERENTIATED PLEOMORPHIC SARCOMA (MALIGNANT FIBROUS HISTIOCYTOMA) Undifferentiated pleomorphic sarcoma (UPS) is the preferred term for lesions previously diagnosed as malignant fibrous

histiocytoma. This entity, first described in 1964, under the name malignant fibrous xanthoma, has carried a variety of different names, now has several major variants and requires immunohistochemistry to rule out look-­alike liposarcoma, leiomyosarcoma, rhabdomyosarcoma, myxofibrosarcoma, even melanoma and anaplastic carcinoma.84–90 In other words, there can be no evidence for another cell of origin. Etiology is, as with most sarcomas, unknown, although several cases have developed in irradiated areas or areas near long-­standing osteomyelitis. It is the most commonly diagnosed of all sarcomas of adults and occurs primarily in the soft tissues of the extremities and retroperitoneum. Oral and maxillofacial sites are seldom involved; however, in these sites, either soft or hard tissues may be involved. A myxoid malignant fibrous histiocytoma variant is now considered to be a distinct entity called the myxofibrosarcoma, this is discussed in detail as such in Chapter 9. Clinical Features. The oral UPS occurs primarily in adults, especially those 50 to 70 years of age, but rare cases have been described in children. Regardless of the histopathologic subtype, men are affected almost twice as frequently as women.88 Within the maxillofacial region, the most common complaint is a moderately firm submucosal mass expanding slowly or moderately fast, with or without pain and surface ulceration. It is usually less than 4 cm in greatest diameter at the time of biopsy, with a bosselated or nodular surface. The lesion is typically attached to surrounding tissues and adjacent structures. The myxoid variant often has quite a soft consistency and the angiomatoid variant is often found in a location more superficial than that of the other variants.  Pathologic Features and Differential Diagnosis. Oral UPS has a wide spectrum of cellular and tissue alterations; the cellular differentiation and density vary markedly, even within the same tumor. The classic histopathologic features include an invasive, interlacing proliferation of spindled fibroblast-­like cells that tend to be arranged in short woven fascicles or bundles, with scattered areas showing a storiform pattern. Cellular and nuclear pleomorphism is common and there often appears to be an admixture of fibroblastic and histiocytic elements. Most lesional cells are spindle cells. They may be long and thin with minimal atypia, but there are usually areas with plump spindle cells containing enlarged, hyperchromatic, and irregular nuclei. Varying numbers of rounded, polygonal, and irregularly shaped histiocyte-­like cells may dominate some areas of the tumor, often with very pleomorphic, multinucleated giant cells interspersed. When the latter cells are numerous, some prefer to call the UPS a giant cell variant or malignant giant cell tumor of soft parts. The histiocytic cells have either abundant eosinophilic cytoplasm or pale foamy cytoplasm, and cell membranes are not easily visualized. Areas with histiocytic predominance usually have a haphazard structural appearance. When more of the lesion shows myxoid change, some prefer to call it myxoid UPS or myxofibrosarcoma. Fibroblasts within myxoid regions may have pleomorphic, hyperchromatic nuclei and can mimic lipoblasts. Myxoid lesions have been shown to have a better prognosis than other forms of UPS.87 Immunohistochemistry is required for this diagnosis. The spindle fibroblasts are vimentin-­immunopositive, often with bizarre nuclei with high Ki-­67 labeling scores. Chronic inflammatory cells are often scattered sparsely throughout the tumor, including foamy histiocytes, lymphocytes, and plasma cells.

4  Lesions of the Oral Cavity

Mitotic activity varies widely and is directly related to the degree of cellular pleomorphism.  Treatment and Prognosis. The prognosis of UPS of the mouth, or any other part of the body, depends very much on size, rate of enlargement and histologic grade, with larger, high-­ grade lesions showing a much worse prognosis. Overall, it is usually treated by radical surgical resection, with at least 40% recurring locally and a similar proportion metastasize within 2 years.89,90 The 5-­year survival rate is less than 30%, although it is somewhat better for the myxoid variant.  MYOFIBROMATOSIS (MYOFIBROBLASTOMA) Myofibromatosis and its often multicentric counterpart in infants, infantile myofibromatosis, is a rare, benign proliferation of lesional cells that seem to be an admixture of smooth muscle cells and stromal fibroblasts.91–95 It is usually less aggressive than pure fibromatosis of the oral region, but infantile variants may be part of a congenital generalized fibromatosis or generalized hamartomatosis.96–98 Multiple lesions tend to fall into two categories: (1) superficial myofibromatosis, with nodules confined to subcutaneous and submucosal stroma, with occasional involvement of skeletal muscle or bone; and (2) generalized myofibromatosis, with visceral lesions and a mortality rate approaching 80%.96,99 Some authorities refer to adult-­onset single nodules as solitary myofibroma.94 Clinical Features. Myofibroma in the mouth is usually diagnosed within the first four decades of life but can present at any age. The average age of 22 years is older than extraoral lesions.92 There is a slight female predominance in oral cases, in contrast to myofibromas in other parts of the body. Myofibroma is most often found within the mandible; in the oral soft tissues, it typically is seen on the gingivae or tongue, followed by the buccal mucosae. The soft-tissue lesion presents as a painless, slowly enlarging, moderately firm mucosal mass. Three-­fourths of oral myofibromatosis cases are present at birth.98 Other cases may arise in patients up to 2 years of age; rarely, cases develop in young adulthood. The tongue is, by far, the most common site of origin.100 Virtually all patients with

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oral involvement will present with myofibromas of other parts of the body, ranging from a few to a hundred lesions.  Pathologic Features. Myofibromatosis or myofibroma presents with a microscopic appearance similar to that of fibromatosis, but the peripheral cells demonstrate eosinophilic cytoplasm reminiscent of smooth muscle. There is usually a biphasic pattern of lightly staining fibrous areas, separated by regions of pericyte-­like vascular cell or smooth muscle-­like spindle cell proliferations (Fig. 4.9A and B). It is most vascular centrally, where it may mimic a hemangiopericytoma or glomus tumor, with lesional cells proliferating around blood vessels. Collagen is present but seldom abundant and regions of chondroid-­like stroma may be seen. The more fibrotic lesions must be differentiated from fibromatosis, irritation fibroma, neurofibroma, angiofibroma, and fibrotic pyogenic granuloma. Lesional cells show features of both myofibroblastic and fibroblastic cells, with fuchsinophilic and phosphotungstic acid hematoxylin (PTAH)-­positive intracellular fibrils.99 These cells are immunoreactive for vimentin and smooth muscle actin, but not for desmin or S100 protein. Regions with more primitive appearance may show minimal or missing actin reactivity. These stains help demonstrate the smooth muscle nature of the lesion and separate myofibromatosis from neurofibroma and fibrous histiocytoma, although they are less helpful for nodular fasciitis, which also contains myofibroblasts. More detailed immunohistochemistry, genetic and differential diagnosis information may be found in Chapter 9.  Treatment and Prognosis. Myofibromatosis is much more innocuous than fibromatosis and spontaneous regression may occur. The typical treatment for oral lesions is surgical removal, with occasional recurrence expected. Multifocal involvement may produce serious, even fatal, extragnathic complications for the patient, especially when visceral lesions are present at birth.  NODULAR FASCIITIS Nodular (pseudosarcomatous) fasciitis is a presumably reactive vascular and fibroproliferative response to injury. An etiology is unknown, although some have suggested trauma

B

Fig. 4.9  A, Alternating areas of cellular myofibroblastic proliferation with more fibrotic zones, creating a biphasic pattern. B, The stroma often has a chondroid or myxoid appearance, with variable amounts of collagen.

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or infection.101–104 The lesion is benign but has a rapid rate of growth and a histopathologic appearance that can be mistaken for sarcoma, as illustrated by the name given, the first reported lesion in 1955 was subcutaneous pseudosarcomatous fibromatosis. Proliferative fasciitis and proliferative myositis are related lesions, which are discussed in detail in Chapter 9. Approximately 17% of all cases occur in the head and neck region, usually the fascia of the neck and face. The rare oral lesions seen arise from the submucosal stroma.105 Clinical Features. While occurring at all ages, oral nodular fasciitis is most often diagnosed in persons 30 to 40 years of age, with no gender predilection.106 It is a discrete, adherent, slightly tender, submucosal nodule with occasional surface ulceration. The lesion is typically more superficially located than fibromatosis of the oral region. Unlike true fibromatoses, it rapidly enlarges, taking only 3 to 6 weeks to reach its full-­size potential, though occasional cases may be slow growing. Rarely does this lesion becomes greater than 2 cm in diameter.  Pathologic Features and Differential Diagnosis. Nodular fasciitis presents as haphazardly arranged, well-­circumscribed, unencapsulated bundles of fibroblasts in a myxoid or mucoid background. The growth pattern is often described as feathery or “tissue culture-­like” because of the tears and pools of mucin seen in the stroma. The fascia origin may not be obvious in oral examples. Lesional fibroblasts are typically large and plump, similar to those seen in granulation tissue, but are more crowded or hypercellular. Pleomorphic fibroblasts may be present and numerous, normal mitotic figures may be quite common. A variable amount of collagen and acid mucopolysaccharide are noted in the intercellular matrix, although the latter may not be readily visible without special staining with Alcian blue or colloidal iron.104 An important diagnostic feature is a fine capillary network arranged in a radial pattern around a larger central vessel or vessels. Scattered chronic inflammatory cells are typically present in small to moderate numbers, and long-­standing lesions may demonstrate foamy histiocytes and osteoclast-­like multinucleated giant cells. When striated muscle is involved (intramuscular fasciitis), it is completely replaced by the fibrovascular proliferation, unlike proliferative myositis, which infiltrates between muscle fibers. Proliferative fasciitis is a variant of nodular fasciitis with large, ganglion-­like cells with abundant amphophilic or basophilic cytoplasm. Nodular fasciitis has a characteristic immunohistochemical profile, which includes reactivity for vimentin, smooth muscle actin and muscle-­specific actin, indicating its myofibroblastic character.104,105 It is nonreactive for keratin, S100 protein and desmin. Additional microscopic and immunohistochemical detail of this lesion can be found in Chapter 9, as can its histopathological differential diagnosis.  Treatment and Prognosis. Despite its often, aggressive microscopic appearance, nodular fasciitis is a self-­ limiting lesion that is readily treated by simple local excision. Deeper lesions tend to be somewhat larger and less well demarcated; they require a wider local excision. Recurrence rates vary from 1% to 6%; some lesions have been reported to regress and disappear without treatment or incisional biopsy.107 The major prognostic factor here is an accurate diagnosis; recurrences should be evaluated carefully. Earlier studies have shown that as many as one-­fourth of all cases were erroneously interpreted as malignant and, conversely, numerous cases of

well-­ differentiated fibrosarcoma have been misdiagnosed as nodular fasciitis.  PROLIFERATIVE MYOSITIS Another reactive pseudosarcomatous lesion is proliferative myositis, a reactive fibroproliferative lesion of injured striated muscle, comprised of fibroblastic and myofibroblastic cells.108 Some authorities consider it to be an early stage of heterotopic ossification or myositis ossificans, whereas others consider it to be a separate clinical and histopathologic entity. An identical lesion in a subcutaneous or fascial location is referred to as nodular fasciitis or proliferative fasciitis.109 This reactive lesion is usually seen in the flat muscles of the shoulder girdle, but occasionally presents in the head and neck region, particularly in the sternocleidomastoid muscle. It was first described by Kern in 1960 and is quite rare in the mouth.110–112 As with nodular fasciitis, accurate microscopic diagnosis is extremely important. In some investigations, more than 40% of proliferative myositis cases have been erroneously diagnosed as sarcoma, especially rhabdomyosarcoma.108,109 Clinical Features. Proliferative myositis of the oral region is a rapidly enlarging, immovable, perhaps tender submucosal mass. Children are rarely affected, and the typical patient is 45 to 65 years of age at tumor onset. There is a slight female predilection. The lesion is usually 1.5 to 5.0 cm in greatest dimension at the time of diagnosis and involves the muscle in a diffuse, infiltrative fashion.  Pathologic Features. Proliferative myositis appears almost scar-­like on gross examination, with a poorly circumscribed periphery and a grayish-­white cut surface. Microscopically, plump fibroblast-­like cells are the predominant cell type, though giant ganglion-­like cells, with deeply staining basophilic cytoplasm and prominent nucleoli, are the hallmark of proliferative myositis. These cells are also myofibroblasts but are often so bizarre, they impart a strong similarity to rhabdomyosarcoma or other sarcoma. Likewise, atrophic or degenerated muscle cells may contribute to the overall impression of striated muscle malignancy. Fibrosis is seen to involve the endomysium, perimysium, and epimysium. Lesional cells are immunoreactive for vimentin, actin, smooth m ­ uscle actin, Factor XIIIa, and fibronectin and are usually not reactive for desmin or myosin. However, they may occasionally react for desmin and myosin. Ultrastructurally, they appear to be myofibroblasts. Focal ossification or dystrophic calcification may be observed in some cases, but never is it as pronounced as in heterotopic ossification.  Treatment and Prognosis. Treatment of this self-­limiting lesion is conservative surgical excision, and recurrence should not be expected. Spontaneous regression and disappearance have been rarely reported. The major prognostic difficulty is arriving at a correct diagnostic interpretation of the tissue; therefore recurrent lesions should be carefully evaluated for an alternative diagnosis.  ORAL FOCAL MUCINOSIS Oral focal mucinosis is the microscopic counterpart of the cutaneous focal mucinosis or cutaneous myxoid cyst. It is not common, and its cause is uncertain, but the lesion appears to represent a degenerative change, resulting in overproduction

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B

Fig. 4.10  A, Focal mucinosis is characterized by a loose myxoid stroma admixed with scattered bipolar and stellate fibroblasts, here with stroma extending to the surface epithelium. B, Lesional cells may be hyperchromatic but mitotic figures are not seen.

of hyaluronic acid by local fibroblasts during collagen synthesis.113–116 Clinical Features. This lesion has a strong female predilection (2:1) and occurs primarily in young adults.114,115 Most maxillofacial cases are seen on bone-­bound, heavily keratinized mucosa. Three-­fourths of all cases occur on the gingiva, with most of the remainder occurring on the hard palate, including a bilateral palatal case in a 2-­ year-­ old child.116,117 The lesion presents as a sessile or pedunculated, soft, painless nodule with normal surface coloration. Some cases are lobulated, even verruciform, and the mucosal surface may show ulceration.116,118 Lesions enlarge slowly and typically remain less than 2 cm in greatest dimension.  Pathologic Features and Differential Diagnosis. Oral focal mucinosis consists of a submucosal, well-­ localized but nonencapsulated nidus of very loose, myxomatous, or “mucinous” connective tissue (Fig. 4.10A and B). More superficial lesions may produce atrophy and loss of rete ridges of the overlying squamous epithelium. Fibroblasts are seen in minimal to moderate numbers within the mucinous area, often demonstrating delicate, fibrillar processes. The mucinous zone is much less vascular than surrounding connective tissues, and inflammatory cells are not associated with the lesion, except as a perivascular infiltrate of lymphocytic Tcells at the periphery. The hyaluronic acid of the lesion will stain positive with Alcian-­blue (pH 2.5) in frozen sections, but this is not always the case with paraffin-­embedded sections.115 There are microscopic similarities between oral focal mucinosis and cutaneous mucinosis of infancy, which may represent a localized form of papular mucinosis or lichen myxedematous. Differentiation from another look-­alike lesion, the oral mucocele, is usually not difficult. The mucocele is more strongly demarcated from surrounding fibrovascular tissues by a peripheral “encapsulation” of granulation tissue, and it has bloated inflammatory cells floating within the extravasated mucus. Mucicarmine staining will demonstrate mucus in the mucocele and one may find a traumatized salivary duct in the area of the extravasated mucus. A slight similarity is also seen between mucinosis and the nerve sheath myxoma (neurothekeoma, bizarre neurofibroma, Pacinian neurofibroma), a variant of neurofibroma that rarely affects mucosa of the upper aerodigestive tract. The nerve sheath myxoma, however, is more circumscribed, has fibrous

septa between multiple myxoid nodules, and has more plump stromal cells.  Treatment and Prognosis. Oral focal mucinosis is treated by conservative surgical removal. It does not recur with this treatment.  INFLAMMATORY PAPILLARY HYPERPLASIA Inflammatory papillary hyperplasia (IPH), also known as papillary hyperplasia of the palate and erroneously as palatal papillomatosis, is almost always restricted to the mucosa, under a denture base.119,120 First reported by Berry in 1851, it results from selective but severe edema and eventual inflammatory fibrosis of the connective tissue papillae between the rete processes of the palatal epithelium.121 The great majority of cases are seen beneath ill-­fitting dentures of long use; this lesion is found in 20% of persons who do not take their dentures out overnight.9 The lesion seems to result from a combination of chronic, mild trauma and low-­ grade infection by bacteria or Candida. IPH is occasionally seen in patients without dentures but with high palatal vaults, with the habit of breathing through the mouth or with human immunodeficiency virus (HIV)-­induced oral candidiasis. It was once thought to be a precancerous condition because of misdiagnosed squamous cell carcinoma of lesional epithelium.120,122 For many decades now, however, these cases have been recognized as pseudoepitheliomatous hyperplasias and this entity is not considered to have an elevated risk of cancer. Clinical Features. IPH is seen in middle-­aged and older persons and there is a strong female predilection (2:1).119 The disease occurs on the bone-­bound oral mucosa of the hard palate and alveolar ridges. It presents as a cluster of individual papules or nodules that may be erythematous, somewhat translucent, or normal in surface coloration, depending on their duration; they tend to become fibrotic over time (Fig. 4.11A). Often the entire vault of the hard palate is involved, with alveolar mucosa being largely spared. White cottage cheese–like colonies of Candida may be seen in clefts between papules. There is seldom pain, but a burning sensation may be produced by a secondary yeast infection.  Pathologic Features and Differential Diagnosis. Connective tissue papillae are greatly enlarged by edematous connective tissue, granulation tissue, densely fibrotic tissue, or a combination thereof,

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is surprisingly rare, and deeper tissues show few alterations beyond a mild chronic inflammatory cell infiltration. Although individual nodules may appear identical to pyogenic granuloma and irritation fibroma, the palatal location and the multinodularity of this process makes the diagnosis of papillary hyperplasia an easy one. In addition to fungal colonies being found in the clefts between nodules, a silver or PAS stain will frequently identify Candida spores and hyphae in the superficial portions of the epithelium, especially in cases with severe acanthosis or pseudoepitheliomatous hyperplasia.  Treatment and Prognosis. The old concern that papillary hyperplasia of the palate held increased risk for cancer is no longer accepted. Even extensive lesions will continue indefinitely, waxing and waning in the early years, but remaining more constant as nodules become more and more fibrotic. Occasional proliferations are so exuberant that clefts between nodules may be more than a centimeter deep. Early lesions may completely disappear with cessation of denture use for 2 to 4 weeks, perhaps aided by topical antibiotic or antifungal therapies. Persistent lesions must be surgically removed or laser ablated and the patient must be fitted for a properly-­fitting denture.123,124  PERICORONITIS

B

C Fig. 4.11  A, Papillary hyperplasia under a maxillary denture shows scattered, sometimes clustered nodules on the mucosal surface. B and C, Older lesions, that is, those usually biopsied, show surface nodules composed of dense fibrous tissue, with occasional lymphocytes and elongation of the rete processes.

depending on the duration of the lesion (Fig. 4.11B and C). Small to moderate numbers of chronic inflammatory cells are present, perhaps admixed with occasional polymorphonuclear leukocytes. Each enlarged papilla produces a surface nodule that may be pedunculated or sessile, with deep clefts between nodules. Covering epithelium is often atrophic but may be acanthotic, especially near the base of the internodal troughs. Occasional lesions demonstrate extensive pseudoepitheliomatous hyperplasia. And may show p53 immunoreactivity.122 Basal cell hyperchromatism and basal layer hyperplasia often impart a false appearance of mild epithelial dysplasia. Surface ulceration

The mandibular retromolar pad or operculum is often hyperplastic, pushing against or even overlapping the last molar in the arch. Food debris and bacteria may become entrapped between this pad and the tooth, resulting in acute infection and extreme pain, especially when the adjacent molar is tilted posteriorly.125,126 This pericoronitis was first reported by Gunnel in 1844 as “painful affection.”127 Clinical Features. Pericoronitis typically occurs in teenagers and young adults, presenting shortly after the eruption of the second or third mandibular molars.128 It presents as an erythematous, tender or painful, sessile swelling of the retromolar pad. The surface may be ulcerated by continuous trauma from the opposing maxillary molars (Fig. 4.12A). Pus may be expressed from the tissue-­tooth interface, and a foul taste may be present. Pain is usually intense and may radiate to the external neck, the throat, the ear or the oral floor. The patient often cannot close the jaw because of tenderness; conversely the extreme pain may result in the inability to open the jaws more than a few millimeters (trismus or “lock jaw”). Cervical lymphadenopathy, fever, leukocytosis, and malaise are common signs and symptoms, and the malady may be associated with an ipsilateral tonsillitis or upper respiratory infection.129,130  Pathologic Features. Pericoronitis is usually surgically removed after a course of antibiotic therapy to prevent future painful episodes, so active pus production is seldom seen in biopsy samples. The retromolar mass is composed of an admixture of moderately dense collagenic tissue and edematous granulation tissue, with moderate to large numbers of mixed chronic inflammatory cells throughout (Fig. 4.12B). The superior mucosa may be ulcerated, with an ulcer bed of fibrinoid necrotic debris. The epithelium, immediately adjacent to the offending tooth, typically presents with a combination of rete process hyperplasia, degeneration, and necrosis, perhaps with associated neutrophils. Bacterial colonies, dental plaque, and necrotic food debris may be attached to the epithelium. The pathologist should distinguish this lesion from pyogenic

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B Fig. 4.12  A, Pericoronitis is noted here as an enlarged retromolar pad posterior to the last molar of the right mandible; it partially overlaps the crown of the tooth. B, The mass is comprised of edematous granulation tissue with scattered chronic inflammatory cells.

granuloma and routine gingivitis, which often requires correlation with clinical features.  Treatment and Prognosis. Acute pericoronitis is treated by local antiseptic lavage and gentle curettage under the flap, with or without systemic antibiotics. Once the acute phase is controlled, the offending molar may be extracted or a wedge of the hyperplastic pad tissue is removed surgically. Recurrence is unlikely with either of these treatments. With or without treatment, patients with pericoronitis are at increased risk of future gingivitis and periodontitis.131,132  PYOGENIC GRANULOMA Pyogenic granuloma of the oral and oropharyngeal region is similar to its counterparts in other parts of the body, although it may occur under rather unique circumstances. During pregnancy, for example, hormonal excesses combine with poor oral hygiene to produce a generalized inflammatory enlargement of the gingiva, occasionally with one or more interdental papillae,

205

increasing to more than 2.0 cm in size. This pregnancy tumor (granuloma or epulis gravidarum) usually regresses after the birth of the child, possibly to reappear with the next pregnancy.135–137 Hullihen, the Father of Oral & Maxillofacial Surgery, first described this in 1844; his report was most likely the first pyogenic granuloma reported.138 Another special pyogenic granuloma is the epulis granulomatosum (epulis haemangiomatosum), a hemorrhagic gingival mass of granulation tissue protruding from the poorly healing bony socket of a recently extracted tooth. The term pyogenic granuloma is not well chosen, as there is seldom pus production and there is never granuloma formation. It has, nevertheless, become entrenched in our vocabulary and is widely used today. Although considered common, the lesion has a prevalence rate of only 1/10,000 adults.2 Vascular adhesion molecules intercellular adhesion molecule (ICAM)-­1 and vascular cell adhesion molecule (VCAM)-­1, vascular endothelial growth factor (VEGF), and the angiogenesis marker CD34 are at high levels in areas of microvascular density in pyogenic granulomas, suggesting a pathoetiologic mechanism.137–139 Clinical Features. In addition to these special events, pyogenic granuloma can occur at any mucosal location of acute or chronic trauma or infection. In the mouth, the vast majority of these lesions occur on the gingiva (Fig. 4.13A), where they may develop as soft masses, usually on facial gingival surfaces.140 Dumb-­bell shaped lesions may occur, with a facial mass extending as a thin isthmus between teeth to create a similar mass on the lingual gingival surface. Other sites of common involvement include the tongue, the lip mucosa and vermilion, and the buccal mucosa. It tends not to push adjacent teeth away, in contrast to other reactive masses of the gingiva, such as the peripheral ossifying fibroma and peripheral giant cell granuloma, discussed elsewhere in this chapter. All ages and both genders are susceptible to this exuberant inflammatory response. The lesion is usually a pedunculated, bright red mass with or without white areas of surface ulceration; older lesions tend to have a more normal coloration. Rarely does pyogenic granuloma exceed 2.5 cm in size and it usually reaches its full size within weeks or months, remaining indefinitely thereafter. Occasional lesions have presented as conical or horn-­like masses, with granulation tissue proliferating around a central vertical vessel. Rare examples have been reported of multiple oral pyogenic granulomas arising acutely and simultaneously.141 A rather unique form of a look-­alike granulation tissue proliferation is the traumatic ulcerative granuloma with stromal eosinophilia (TUGSE). This trauma-­related lesion of young adults and middle-­aged individuals has a more aggressive biological behavior; it is discussed in more detail in the “Ulcerative and Blistering Mucosal Lesions” section.  Pathologic Features and Differential Diagnosis. The pyogenic granuloma is characterized by a rich profusion of neovascularity, with anastomosing vascular channels, lined by endothelial cells with plump nuclei, extending into the lumen (Fig. 4.13B and C). The background stroma is typically edematous, but fibroplasia is often active and older lesions may have undergone considerable fibrosis (fibrotic pyogenic granuloma, Fig. 4.13D). The fibroblasts are typically plumb and mitotic activity may be noted in the stromal cells. Older lesions demonstrate fewer and more mature cells, that is, fibrocytes. Bacteria are virtually never found within lesional tissue, even

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A B

C

D

Fig. 4.13  A, The pyogenic granuloma is usually pedunculated and lobulated, with an ulcerated surface. B, Active vessels are admixed with inflammatory cells in an edematous background stroma. C, Higher power of the granulation tissue. D, Over time fibrous stroma replaces most of the granulation tissue (fibrotic pyogenic granuloma).

with a Gram stain, but they may occasionally be seen coating ulcerated surface areas. The blood vessels may show a clustered or medullary pattern with grouped vessels separated by less vascular fibrotic septa. This has led to a recent acceptance of the pyogenic granuloma as a polypoid form of capillary hemangioma, specifically called lobular capillary hemangioma, although some prefer the term granulation tissue-­type hemangioma. A mixed chronic and acute inflammatory cell infiltrate is scattered throughout the stroma, with early lesions containing more neutrophils than older lesions. Occasional lesions demonstrate an extreme predominance of plasma cells, prompting some pathologists to call them plasma cell granuloma, a term that is best avoided because of the potential confusion with mucosal solitary plasmacytoma or multiple myeloma. Rare examples of intravenous pyogenic granuloma have been reported. Occasionally, classical pyogenic granulomas may also exhibit regions identical to intravascular papillary endothelial hyperplasia, with thin-­wall dilated vessels and papillary projections of endothelial cells producing vascular channels, which are associated with areas of an organizing thrombus.142 The overlying stratified squamous epithelium may be atrophic or hyperplastic and it is usually degenerated or ulcerated in large areas. If the epithelium is very spongiotic, a diagnosis

of localized juvenile spongiotic gingival hyperplasia (discussed earlier in this section) should be considered. When ulcerated, the ulcer bed is composed of fibrinoid necrotic debris, and regenerating epithelium at the ulcer edge may have a primitive or dysplastic appearance. The histopathologic differentiation of pyogenic granuloma from hyperplastic gingival inflammation is sometimes impossible; the pathologist must depend on the surgeon’s description of a distinct clinical mass to make the pyogenic granuloma diagnosis. Usually, however, routine gingivitis has edema confined to the subepithelial regions of crevicular mucosa (facing the teeth) with more exposed epithelium, demonstrating a normal or hyperplastic appearance without ulceration. Quite often, the differentiation of pyogenic granuloma from inflamed capillary hemangioma is also impossible. Kaposi sarcoma, bacillary angiomatosis, and epithelioid hemangioma must also be distinguished from pyogenic granuloma. Kaposi sarcoma of acquired immunodeficiency syndrome (AIDS) shows proliferation of dysplastic spindle cells, vascular clefts, extravasated erythrocytes, and intracellular hyaline globules, none of which are features of pyogenic granuloma. Bacillary angiomatosis, also AIDS-­related, shows dense, extracellular deposits of pale hematoxyphilic granular material representing masses of bacilli that stain positive

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TABLE

4.4

207

Disorders Presenting With Oral Granulomas

Diagnosis

Distinguishing Diagnostic Features

Anderson-­Fabry disease Cheilitis granulomatosa of Miescher Cholesterol granuloma Crohn disease Eosinophilic granuloma Foreign body reaction Granulomatosis with polyangiitis

X-­linked defect of glycosphingolipid metabolism Same as in Melkersson-­Rosenthal syndrome but with only lip involvement of lips Identification of associated submucosal inclusion cyst and cholesterol clefts Gastrointestinal involvement, no microorganisms identified Combination of eosinophils, multinucleated giant cells, histiocytes Identification of associated foreign material Wegener granulomatosis (granulomatosis with polyangiitis); may show strawberry gingiva and osteonecrosis Gingival location only In addition to multinucleated and histiocytic cells, dysplastic lymphocytes are seen No etiologic factor can be identified Occurs after 2 years in 26% of childhood patients, perhaps related to tacrolimus Rx. Swollen lips, eyelids, facial paralysis, benign migratory glossitis Fungus identified by silver stains Bacteria identified by Gram stain No microorganisms identified Spirochetes demonstrated by immunostain for Treponema pallidum Bacillus demonstrated by acid-­fast stain; areas of caseous necrosis

Granulomatous gingivitis Hairy cell leukemia Idiopathic orofacial granulomatosis Liver transplantation Melkersson-­Rosenthal syndrome Mycotic granulomatous infection Salmonella infection Sarcoidosis Tertiary syphilis (gumma) Tuberculosis

with the Warthin-­Starry stain. Epithelioid hemangioma has a plumper, histiocytoid, endothelial cell proliferation without an acute inflammatory cell infiltrate. These entities are discussed in more detail in Chapter 9.  Treatment and Prognosis. Pyogenic granuloma is treated by conservative surgical or laser excision with removal of potential traumatic or infective etiologic factors. Recurrence occurs in approximately 15% of cases with gingival cases showing a higher recurrence rate than lesions from other oral mucosal sites.143 Therefore pyogenic granuloma of the gingiva should not only be excised, but the surgical wound bed should be curetted, and adjacent teeth should be scaled and root-­planed. If possible, removal in a pregnant woman should be postponed until after the birth. Lesional shrinkage at that time may make surgery unnecessary; also, pregnant patients show a higher rate of recurrence. 

Granuloma-­Like Mucosal Lesions With Giant Cells The oral soft tissues are associated with a variety of lesions containing multinucleated giant cells. With a few of these, as discussed in this section, the giant cells become the most significant part of the diagnosis. See Table 4.4 for a brief review of pertinent lesions with multinucleated giant cells. PERIPHERAL GIANT CELL GRANULOMA The reactive lesion, peripheral giant cell granuloma (PGCG) is, for all practical purposes, a site-­specific variant of pyogenic granuloma embedded with foreign-­body type multinucleated giant cells and arising exclusively from the periodontal ligament enclosing the root of a tooth.144–146 This unique origin, of course, means that such a lesion can only be found within or upon the gingiva or alveolar ridge; no other site is acceptable. The giant cells of this lesion are immunohistochemically closely akin to osteoclasts and are thought to arise from syncytial fusion of mononuclear preosteoclasts and/or macrophages of the stroma.147–150 Called variously giant cell reparative granuloma, osteoclastoma, giant cell epulis, and myeloid epulis, this lesion was first reported as fungus flesh in 1848. An intraosseous

variant, the central giant cell granuloma (CGCG) is discussed in Chapter 8. Almost half of all cases have lesional cells containing surface receptors for estrogen and this has led to speculation that some peripheral giant cell granulomas are responsive to hormonal influences.151 Immunohistochemical and computer-­ assisted histomorphologic analysis have shown that both peripheral and CGCGs are similar, but each is quite different from the microscopically identical giant cell tumor of bone. Mononucleated cells in the CGCG demonstrate overexpression of osteopontin, and integrin α, suggested an explanation for the more aggressive (still benign) behavior of these lesions and the unusual proliferation of new bone at the lesional periphery, compared to other oral inflammatory hyperplasias.147–150 Clinical Features. The usual age at diagnosis is the fourth through sixth decades, but there is no specific age predilection. More than 60% of cases occur in females, and this female predilection is more pronounced in the older age groups. Individual lesions are nodular and pedunculated, frequently with an ulcerated surface, and often have a red, brown, or bluish hue (Fig. 4.14A and B). In general, larger than the pyogenic granuloma, the lesion may exceed 5 cm in size, but typically remains less than 2 cm in diameter. Any gingival region may be affected, with radiographs showing either a saucerization of underlying bone, periodontitis of underlying tissues, or an isthmus of soft tissue connecting to an intraosseous central giant cell granuloma.  Pathologic Features and Differential Diagnosis. The PGCG is composed of an unencapsulated aggregation of rather primitive but uniform mesenchymal cells with oval, pale nuclei and with a moderate amount of eosinophilic cytoplasm. Mitotic activity is not unusual and may even be pronounced in lesions developing in children and adolescents. Mitotic activity within the giant cells is, however, not seen and, if present, should be considered to be a sign of sarcomatous change. Stromal cells may be spindled, with a background of collagenic fibers, or may be rounded with a less fibrotic background. There may be occasional chronic inflammatory cells admixed with the mesenchymal cells or within surrounding fibrovascular tissues. A thin band of routine fibrovascular tissue separates the lesion from the overlying epithelium, often with dilated veins

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cytoplasm, which electron microscopy has shown to contain large numbers of mitochondria. Blood vessels within the lesional stroma are not obvious but, when seen, show plump endothelial cell nuclei. Scattered extravasation of erythrocytes is almost universally seen and is a strong diagnostic feature. Hemosiderin deposition may be found in areas of old hemorrhage. Metaplastic or osteoblastic new bone formation may be seen if the lesion has affected underlying bone. Dystrophic calcification may be present higher in the mass, but this is not common. Occasional lesions show an admixture of tissue types compatible with PGCG, peripheral ossifying fibroma, and pyogenic granuloma, presumably because of the common pathoetiology of these lesions. Such lesions are traditionally diagnosed according to the dominant tissue type. PGCG can be differentiated from osteoblastic osteosarcoma by the uniformity of the stromal cells and by the lack of dysplasia in these cells. In young persons, however, numerous mitotic figures and active proliferation of stromal cells may make this distinction difficult. PGCG may be indistinguishable from the rare extraosseous brown tumor of hyperparathyroidism.152  Treatment and Prognosis. PGCG is treated by conservative surgical excision, followed by curettage of any underlying bony defect and careful scaling and root-­ planning of associated teeth. A recurrence rate of 10% to 18% has been reported, so reexcision may be necessary.145 Very large or recurring lesions may represent brown tumors of hyperparathyroidism and will require treatment of the underlying endocrine dysfunction prior to surgical removal. 

B

OROFACIAL GRANULOMATOSIS AND GRANULOMATOUS MUCOSITIS

C

Granulomatous inflammation of the oral and oropharyngeal submucosal tissues is not common, but when found, it presents a definite diagnostic dilemma because of the wide variety of possible etiologic diseases and the rather generic appearance of the individual lesions. The matter is made more confusing by the common use of the term “granuloma” to describe maxillofacial diseases with little or no resemblance to true granulomas, such as pyogenic granuloma, periapical granuloma, PCGC, pulse granuloma, TUGSE and epulis granulomatosa. The group of true granulomatous diseases is collectively called orofacial granulomatoses.153–156 Until the latter two-­thirds of the 20th century, the most common of the oral granulomatous lesions were those produced by tuberculosis and tertiary syphilis. Today, they are more likely to represent oral manifestations of delayed hypersensitivity reactions and/or autoimmune disorders, such as Crohn disease, sarcoidosis, localized allergic reactions or deep fungal infections, and even a potential response to antitransplant rejection medications.157–162 The name of the associated systemic disease is traditionally applied to oral lesions whenever possible, but a certain number of cases remain idiopathic and are diagnosed simply as granulomatous mucositis, granulomatous gingivitis, or orofacial granulomatosis. Before such generic terminology can be applied, however, the pathologist must make every effort to rule out histologically distinctive granulomatous diseases and specific granulomatous infectious processes (see Table 4.4). Cases associated with systemic disease may present with or without involvement of extraoral regions at the time of diagnosis.

Fig. 4.14 A, The peripheral giant cell granuloma must be located on alveolar bone and often shows surface ulceration, as in this example, which is “growing” out of a recent extraction socket. B, The gross specimen shows aggregated brown areas of extravasated erythrocytes. C, Osteoclast-­like cells are scattered throughout a primitive mesenchymal stroma with few visible blood vessels.

and capillaries. When surface ulceration is present, the ulcer bed consists of routine fibrinoid necrotic debris over granulation tissue. Admixed throughout the stroma are numerous osteoclast-­ like multinucleated giant cells containing varying numbers of pale vesicular nuclei, similar to those within the surrounding stromal cells (Fig. 4.14C). These cells have eosinophilic

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209

A Fig. 4.15  Syphilitic gumma of the lateral tongue was initially proliferative but has now started to ulcerate.

Clinical Features. Granulomatous lesions of the oral and oropharyngeal mucosa usually present as sessile lobulated, moderately firm and relatively nontender nodules and papules with normal coloration and with little or no surrounding inflammatory mucosal erythema. With time, some of the granulomas may ulcerate centrally and present as a deep, painless ulcer with a nonerythematous rolled border, reminiscent of squamous cell carcinoma (Fig. 4.15). The granulomas of tertiary syphilis, tuberculosis, and deep mycotic infections may reach a size of more than 3 cm, but those related to autoimmune phenomena, especially sarcoidosis (Fig. 4.16B), cheilitis granulomatosa, and Crohn disease, typically remain smaller and often present as multiple nodules and papules, sometimes clustered together to impart a cobblestone appearance to the mucosa.163–168 Several granulomatous diseases have unique clinical features. The granulomas of deep fungal infections, Langerhans cell disease (eosinophilic granuloma), sarcoidosis, and Wegener granulomatosis (granulomatosis with polyangiitis) may destroy underlying bone when located on gingival or alveolar mucosa (Fig. 4.16A).167,168 This is also true for palatal lesions of tertiary syphilis and tuberculosis, which have a special affinity for perforating the hard palate. Granulomatous gingivitis is the only granulomatous lesion typically associated with pain and, of course, by definition must occur on gingival mucosa. Extensive involvement of submucosal areas may produce a generalized enlargement of the affected site, especially noticeable on the lips and tongue, as in cheilitis granulomatosa, Melkersson-­ Rosenthal syndrome, and syphilitic glossitis.164–166  Pathologic Features and Differential Diagnosis. Most granulomatous lesions of the oral region present as small, noncaseating granulomas with peripheral lymphocytes, central epithelioid histiocytes, and usually, multinucleated giant cells (see Fig. 4.16B). Foreign bodies within the giant cells and histiocytes may polarize and microorganisms may be identified by appropriate acid-­fast bacterial and fungal stains (see Table 4.4). Wegener granulomatosis (granulomatosis with polyangiitis) may have no granulomas visible but will show a pattern of mixed inflammatory infiltrates around blood vessels, with focal areas of necrosis and areas with heavy neutrophilic infiltration and nuclear dust (Fig. 4.16C). The oral epithelium in this disease may demonstrate severe acanthosis or pseudoepitheliomatous hyperplasia, as may granulomatous

B

C Fig. 4.16  A, Massive, painless destruction of soft tissues and bone has exposed the right maxillary sinus in Wegener granulomatosis. B, Multiple submucosal, nonnecrotizing epithelioid granulomas with scattered microcalcifications surrounded by chronic inflammation and fibrosis in sarcoidosis. C, Mixed inflammatory infiltrate with multinucleated giant cells is seen in gingival tissue of Wegener granulomatosis, with necrosis, nuclear dust, and edema.

infection by blastomycosis, and it is the granulomatous disease most likely to be associated with extravasated erythrocytes. Many of the granulomatous diseases listed in Table 4.4 require physical examination and laboratory evaluation for an appropriate diagnosis. These are beyond the scope of the

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present chapter, but many such entities are discussed in other chapters.  Treatment and Prognosis. The treatment of orofacial granulomatosis and the various forms of granulomatous mucositis will be subject to the underlying or systemic cause, and the prognosis of oral lesions will depend on the patient’s response to therapies for the systemic disease. Many lesions eventually resolve spontaneously with or without therapy, especially those associated with sarcoidosis, but others continue to progress despite rather aggressive therapy. Localized lesions without a systemic connection can be treated by conservative surgical removal and plastic surgical reconstruction. Prior to surgery, a host of medications may be used with variable results: intralesional and systemic corticosteroids, low-­dose radiotherapy, methotrexate, dapsone, salazosulfapyridine (sulfasalazine), and hydroxychloroquine sulfate, among others. No therapy has proven to be universally effective in such cases.169,170 

Soft-Tissue Lesions With Bone or Cartilage The oral soft-tissue are the site of a variety of developmental and reactive proliferations composed of tissue types not normal to the site, such as bone or cartilage, or of an admixture of multiple tissue types in an unusual fashion, such as teratoma. These are often small and innocuous malformations that are not biopsied or formally diagnosed. Some examples, in particular the reactive masses, have a nonspecific clinical appearance or are located in sites that interfere with proper function or proper oral hygiene, and hence, are biopsied for microscopic interpretation. Others are excised to rule out neoplastic growth, and yet others, such as the various cortical exostoses, behave like developmental anomalies but are not seen until young adulthood, and are so obvious clinically that they are seldom excised. The reader is reminded, furthermore, that focal deposits of bone and cartilage may be present in a variety of other benign and malignant lesions discussed in other sections of this chapter: peripheral giant cell granuloma, malignant peripheral nerve sheath tumor, liposarcoma, and undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma). TORUS AND BONY EXOSTOSIS While not technically soft tissue masses, the torus palatinus, torus mandibularis, and buccal exostosis are all lesions that present as cortical surface masses that mimic benign oral masses, hence, are included here. They are common but quite unique bony lesions and the jawbones experience, by far, more such bony masses and more types of surface masses, than any other bones in the human skeleton, probably more than all other bones, combined. The first mention of a torus, the torus palatinus, was in an 1857 review of palatal tumors by Parmentier.171 They collectively can be found in at least 3% of adults (see Table 4.1), with some surveys finding them in over half of those examined.2,172–174 Jawbone tori are considered to be both a developmental anomaly and a reactive lesion.175,176 There is an obvious hereditary aspect (autosomal dominant) to some cases and certain embryologic features suggest developmental stimuli, perhaps

explaining the occasional infantile cases.177,178 However, tori and exostoses typically do not present until the teenage or adult years and often will continue to grow slowly throughout life. They are found most often in persons with occlusal grinding and clenching habits, and they grow at sites of maximum torque (torus mandibularis), or low, constant pressure, such as that from the nasal septum pressing on the hard palate midline (torus palatinus), or lateral pressures from tooth roots (buccal exostosis). The most similar bony growth outside the jaws is the bunion of the lateral foot. Osteochondroma (chondroid exostosis) of the metaphyseal region of long bones may be a similar phenomenon but has cartilage, a feature not found in jawbone exostoses and tori. Since torus means simply sessile mass, the term is used for occasional normal anatomy, such as the torus tubarius of the deep auditory canal and, for reasons unexplained for certain angled torus, or buckle, fractures of long bones in children. Clinical Features. These entities are all very site specific. The palatal torus is found only in the midline of the hard palate (Fig. 4.17A). The mandibular torus is found only on the lingual surface of the mandible, near the bicuspid and first molar teeth (Fig. 4.17B). The buccal exostosis is found only on the facial surface of alveolar bone, directly overlying a tooth under occlusal stress. When a similar reactive cortical prominence develops beneath a fixed prosthesis (dental bridge), it is referred to as subpontic cortical hyperplasia.130,179 Bony surface proliferations found in any other jawbone site are typically given the generic diagnosis of reactive exostosis or osteoma; they are considered to be trauma-­induced inflammatory periosteal reactions or true benign neoplasms, respectively. Unless such a bony prominence is specifically located or is associated with an osteoma-­producing syndrome, such as Gardner syndrome, there may be no means by which to differentiate an exostosis from an osteoma, especially under the microscope. As previously stated, these lesions are not present until the late teen and early adult years, and many, if not most, continue to slowly enlarge over time. Fewer than 3% occur in children, but taken as a group, these lesions can be found in up to 50% of adults and, while the torus palatinus is more common in females than in males, the others show no gender bias.172–174 The palatal and mandibular tori may be bosselated or multilobulated and the mandibular masses are usually bilateral and always located on the lingual side of the mandible. Lesions may become 3 to 4 cm in greatest diameter but are usually less than 1.5 cm at biopsy. A definite hereditary basis, usually autosomal dominant, has been established for some cases of tori, and Asians, especially Koreans, have a much higher prevalence rate than do other ethnic groups.176 Exostoses are typically single and may be pedunculated, but buccal exostoses may be numerous and may be on both jaws. A recently reported pathologic change in tori has been identified in patients taking bisphosphonates for osteoporosis, Paget disease of bone or metastatic neoplasms in bone. A number of such individuals have presented with chronically exposed alveolar bone after oral surgical procedures or bone trauma. Approximately 10% of cases of this medication-­related osteonecrosis of the jaws (MRONJ) occur within tori, typically after traumatic ulceration of the surface mucosa.180,182 This entity is more completely discussed later in the present chapter. 

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A

C

211

B

D

Fig. 4.17  A, Torus palatinus is always in the midline of the hard palate and is often multilobulated. B, Torus mandibularis is always on the lingual aspect of the mandibular alveolus and is frequently bilateral (inset: surgical specimen). C, The mass is comprised of dense, lamellated cortical bone. D, There are few marrow spaces in the bone of the typical torus and many lesions show considerable loss of osteocytes, indicative of ischemic damage.

Pathologic Features. On cut surface, the torus and exostosis usually show dense bone with a laminated pattern (Fig. 4.17C). They are usually composed of dense, mature, lamellar bone with scattered osteocytes and small marrow spaces filled with fatty marrow or a loose fibrovascular stroma. Conversely, some lesions are osteoporotic, having a thin rim of cortical bone overlying inactive cancellous bone with considerable fatty or hematopoietic marrow present. Typically, there is minimal osteoblastic activity, but occasional lesions will show reactive bone beneath the periosteum. Large areas of bone may show enlarged lacunae with missing or pyknotic osteocytes (Fig. 4.17D), indicative of ischemic damage to the bone. Ischemic changes, such as marrow fibrosis and dilated marrow capillaries and veins (medullary congestion), may also be found in the marrow, with rare examples showing microinfarctions in the fatty marrow.  Treatment and Prognosis. Neither the torus nor the bony exostosis requires treatment unless it becomes so large that it interferes with function, denture placement, or suffers from recurring traumatic surface ulceration (usually from sharp foods or factitial trauma). With or without bisphosphonate use, the medullary bone beneath an ulcerated torus might be necrotic. When treatment is elected, the lesions may be chiseled off of the cortex or removed via bone burr, cutting through the base of the lesion.182 It has been suggested that bone chips from

an excised bony mass can be used as an autogenous bone graft material for periodontal or other surgical defects.183 Slowly enlarging, recurrent lesions are occasionally seen, but there is no malignant transformation potential. The young patient should be evaluated for Gardner syndrome, especially if multiple bony growths are found outside of the classic torus or buccal exostosis locations. Intestinal polyposis and cutaneous cysts or fibromas are other common features of this autosomal dominant syndrome.  PERIPHERAL OSSIFYING FIBROMA In addition to the peripheral giant cell granuloma, mesenchymal cells of the periodontal ligament are capable of producing another unique inflammatory hyperplasia, the peripheral ossifying fibroma (POF), also referred to as the peripheral cementifying fibroma or the peripheral cementoossifying fibroma, depending on whether or not bone or cementum or both are seen microscopically.184–190 The pluripotential cells of the ligament have the apparent ability to transform or metaplastically alter into osteoblasts, cementoblasts, or fibroblasts. The reader is reminded that this is a reactive lesion, not the peripheral counterpart of the intraosseous neoplasm called central ossifying fibroma. Odontogenic lesions of the gingiva, moreover, may produce various calcified materials and are discussed in more detail in Chapter 8.

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A B

C

D

Fig. 4.18  A, Peripheral ossifying fibroma must be located on the alveolar mucosa or gingiva and is often ulcerated and lobulated on the surface. B, The mass has pushed teeth apart but the underlying bone loss is from periodontitis, not the tumor itself. C, Metaplastic bone often shows irregular osteoblastic rimming in some areas. D, Some lesions have rounded globular cementoid structures (lower right) rather than bone. (A, Photos courtesy of Dr. Mark Wong, University of Texas School of Dentistry at Houston.)

By definition, the POF must be associated with gingival tissues, and the diagnosis cannot be used for lesions of other oral sites. The presence of teeth is not, however, required for the diagnosis, as periodontal ligament fibers remain within and above alveolar bone, long after their associated teeth have been extracted. Shepherd first reported this entity as alveolar exostosis in 1844.191 Clinical Features. POF presents as a painless, hemorrhagic, and often lobulated mass of the gingiva or alveolar mucosa (Fig. 4.18A and B), perhaps with large areas of surface ulceration. Early lesions are quite irregular and red, but older lesions can have a smooth salmon-­pink surface and may be indistinguishable clinically from the much more common irritation fibroma. Most POFs are 1 to 2 cm in size, but some may slowly enlarge to more than 5 cm.192 Early growth is often alarmingly rapid, and occasional examples of multiple synchronous lesions have been documented. A lesion may vary somewhat in size over time, depending on the amount of superficial inflammation and edema involved. Although this tumor is typically diagnosed in teenagers and young adults, it may occur at any age, especially in individuals with poor oral hygiene, and multiple lesions in a single patient have been reported.193,194 Radiographs occasionally show

irregular, scattered radiopacities in a POF, but this change is usually not present.185  Pathologic Features and Differential Diagnosis. An aggregated submucosal proliferation of primitive oval and bipolar mesenchymal cells is the hallmark of peripheral ossifying fibroma. The POF can be very cellular or may be somewhat fibrotic but scattered throughout are islands and trabeculae of woven or lamellar bone, usually with abundant osteoblastic rimming (Fig. 4.18C). Metaplastic bone may also be seen. The calcified tissues can have the dark-­staining, acellular, rounded appearance of cementum, in which case the term peripheral cementifying fibroma has traditionally been used (Fig. 4.18D). Many examples show an admixture of bone and cementum, that is, peripheral cementoossifying fibroma, and early lesions may contain only small ovoid areas of dystrophic calcification. Although the lesional stroma may be similar to that of POF, the erythrocyte extravasation of the latter lesion is not a feature of POF and osteoclast-­like cells are quite rare in the POF. Osteopontin expression is universal to all POFs.189,190 Surrounding tissues are often edematous, with neovascularity and variable numbers of chronic and acute inflammatory cells. By way of differential diagnosis, the exuberant callus, so common to the long bones, is almost never found

4  Lesions of the Oral Cavity

at the surface of jawbones and so is not a serious diagnostic distinction from peripheral ossifying fibroma. Some gingival masses, however, contain large areas of classic pyogenic granuloma, irritation fibroma, or peripheral giant cell granuloma, as well as POF. In such cases, the pathologist usually chooses for the appropriate diagnosis the lesional type that predominates. Also individual cells must be carefully examined for dysplastic changes to rule out osteoblastic or juxtacortical osteosarcoma, but frequent mitotic figures of normal configuration are acceptable for the benign diagnosis, especially in POF in the first decade of life.194  Treatment and Prognosis. Conservative surgical excision must be followed by diligent curettage of the wound and root-­ planing of adjacent teeth, if recurrence is to be avoided. With simple removal, the recurrence rate is 10% to 20% and may be higher.189 Malignant transformation has not been reported for this lesion.190 

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HETEROTOPIC OSSIFICATION Heterotopic ossification, once widely known as myositis ossificans, is a reactive bone-­producing soft-tissue proliferation of muscle or other connective tissues.195–200 When occurring in subcutaneous or submucosal fat, it is often referred to as panniculitis ossificans or fasciitis ossificans. A more serious and extensive form, myositis ossificans progressiva or fibrodysplasia ossificans progressiva, involves skeletal muscle, tendons, fascia, aponeuroses, and ligaments.201,202 The progressive form is also associated with assorted congenital anomalies, especially of the toes and thumbs, with ankylosis of the digits and a history of joint pain and swelling. Multiple and sometimes massive heterotopic ossification and calcification may develop, especially in Albright’s hereditary osteodystrophy.203,204 Several other conditions, such as fibroosseous pseudotumor, florid reactive periostitis and bizarre parosteal osteochondromatous proliferation, are probably variations of heterotopic ossification. Hypercalcemia, hypoparathyroidism, and pseudohypoparathyroidism may produce multiple focal soft-tissue calcifications as well. Heterotopic ossification may occur after acute or chronic trauma to a muscle. The musculature of the head and neck region is an uncommon site for this phenomenon, but occasional cases have occurred in the masseter and other facial muscles, and around the temporomandibular joint.205 Most authorities presume this lesion to originate from an intramuscular hematoma with metaplastic transformation of pluripotential stromal cells, but traumatic implantation of periosteum is another logical explanation for selected cases; chronic ischemia seems to be a common phenomenon or pathophysiologic mechanism. Clinical Features. Heterotopic ossification of the head and neck region typically occurs in the masseter muscle of a young person after a single severe injury. There is no gender predilection. Shortly after the injury, a painful mass begins enlarging to 2 to 4 cm in greatest dimension. The tumor usually reaches its maximum size within 1 to 2 weeks. It is minimally movable beneath the skin or mucous membrane and may be rather firm to palpation. Radiographs of early lesions will reveal feathery opacities caused by ossifications along muscle fibers. Older lesions show more solid opaque masses that may coalesce to appear as one large, irregularly opaque mass, often with a central or acentric zone of radiolucency (Fig. 4.19A). The mass is not attached to adjacent bone.

B

C Fig. 4.19  A, Heterotopic ossification typically presents as a rounded, rather well-­demarcated radiopacity, as seen here posterior to the last maxillary molar. B, The most intense and active new bone formation is seen at the periphery. C, Higher-power view of newly forming bone shows very active osteoblasts. (A, Courtesy of Dr. Nadarajan Vigneswaran, University of Texas at School of Dentistry at Houston.)

Computed tomograms show the lesion to be well circumscribed, usually with a shell of ossification surrounding a less mineralized core. Conversely, the lesion may appear to be poorly defined and infiltrative on magnetic resonance images. Myositis ossificans progressiva is rare, slowly progressive, inherited, and associated with a microdactyly or adactyly of the thumbs and great toes, and with the eventual onset of fibroblastic proliferations and calcification during the first decade of

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life.201,202 Sporadic examples have been reported and there is no gender predilection. Diffuse or multinodular, doughy, soft-­tissue involvement is seen most commonly on the back, shoulders, and upper arms. Facial and lip involvement have been reported, with masseter muscle involvement sometimes severe enough to interfere with jaw opening. Muscles become progressively stiffened and contraction deformities may occur. Joint ankylosis is a frequent problem, as are exostoses and osteoporosis.  Pathologic Features and Differential Diagnosis. Active, poorly organized fibroblastic proliferation is seen throughout the lesion. The stromal cells are plump and bipolar and may demonstrate considerable mitotic activity, but they never demonstrate cytologic atypia or true dysplasia. The background consists of loosely arranged collagen and reticulin fibers with neovascularity becoming more pronounced toward the lesional periphery. The fibroblasts also form into fascicles toward the periphery, with an admixture of osteoblasts and reactive new bone (Fig. 4.19B and C). The bone is woven or immature in early lesions, but in older lesions it is mature lamellar bone, perhaps with fatty or hematopoietic marrow. Large amounts of cartilage may also be seen, tempting the pathologist to call the tumor soft-tissue chondroma or soft-tissue chondrosarcoma. Those ossifications with very active stromal cells might, likewise, tempt the pathologist to consider a soft-tissue osteosarcoma. Some lesions contain cystic spaces centrally, where the tissues can take on the appearance of aneurysmal bone cyst, a bone lesion with rare examples in soft tissues.  Treatment and Prognosis. Treatment is usually not necessary, as most tumors of heterotopic ossification regress spontaneously. The lesion for which treatment is elected, however, can be removed by conservative surgical excision. Occasional recurrences do occur, often with rapid onset after surgery and with rapid growth after onset. There have been a few reported cases of malignant transformation of heterotopic ossification into extraskeletal osteosarcoma, but there is some concern that these may actually have been misdiagnosed at the outset.206 Patients with myositis ossificans progressiva or fibrodysplasia ossificans progressiva will, of course, have more serious, perhaps life-­threatening sequelae, such as anorexia from difficult mouth opening and pneumonia or respiratory failure in early life.  SOFT-TISSUE OSSEOUS/CARTILAGINOUS CHORISTOMA Extraskeletal proliferation of bone and cartilage, in oral and maxillofacial soft tissues, probably reflects the multipotential nature of primitive mesenchymal cells throughout the region. Usually developmental in origin, some of these proliferations seem to occur as a result of local trauma. Several terms are used for them. Choristoma (aberrant rest, heterotopic tissue) is defined as a histologically normal tissue proliferation or nodule of a tissue type not normally found in the anatomic site of proliferation. Hamartoma is defined as a benign tumor-­like nodule composed of an overgrowth of mature cells and tissues that are normally found in the affected part, but with disorganization and often with one element predominating. The occurrence of multiple hamartomas in the same patient is called hamartomatosis. It is possible that some or many examples of osseous choristoma are

nothing more than old cases of heterotopic ossification, but the two lesions have traditionally been classified as separate and distinct entities. Likewise, the presence of ectopic tissue elements from more than one germ cell layer has traditionally been called teratoma (see the “Noncalcified Soft Tissue Tumors With Mixed or Ectopic Tissues” section later in this chapter), and it is not unusual for an oral or cervicofacial teratoma to contain bone or cartilage. Clinical Features. Osseous/cartilaginous choristoma is characteristically diagnosed as a painless, firm nodule in children or young adults, especially in females, and has most frequently been reported on the tongue, although no submucosal site is immune.207–214 It seldom reaches a size greater than 1.5 cm, although even small lesions may produce local dysfunction, if located on the lateral border of the tongue. A similar lesion, osteoma cutis, is found beneath the skin of the face and other areas, but is usually considered to be a different entity. A unique cartilage-­producing form of this tissue-­level disorder is found on the edentulous alveolar ridge of a denture wearer, especially in the anterior maxilla. Presumably trauma-­ induced, this self-­limiting Cutright tumor (chondroid choristoma, traumatic osseous and chondromatous metaplasia) may produce pressure atrophy of underlying bone, may become tender, and may contain bone in addition to cartilage.215 When multiple primary cutaneous ossifications are encountered, it may be part of Albright’s hereditary osteodystrophy, which is associated with congenital or early subcutaneous ossifications of the extremities, trunk, and scalp. Oral mucosal involvement is very rare. The bony spicules in this disease may produce surface ulceration or may extrude from the surface. Pseudohypoparathyroidism and pseudopseudohypoparathyroidism are frequently observed in this condition, which is inherited as an X-­linked or autosomal dominant trait.  Pathologic Features and Differential Diagnosis. The osseous/cartilaginous choristoma is composed of a submucosal proliferation of benign and normal (perhaps immature) bone or cartilage. These “abnormal” tissues are embedded within a background stroma of fibrovascular connective tissue, usually without true encapsulation, but often with a pseudoencapsulation. Cartilage may be active and mimic synovial chondromatosis (joint mice) or soft-tissue chondroma (Fig. 4.20A and B). Bone maturation often results in lamellar bone, perhaps with hematopoietic or fatty marrow. Choristomas and hamartomas given other specific diagnostic names, such as Fordyce granules (ectopic sebaceous glands) and oral tonsils (benign lymphoid aggregates), are discussed under those names in this text. Osseous choristoma may be confused with heterotopic ossification (myositis ossificans), but the latter is typically located in muscle and has more osteoblastic activity than the choristoma. Differentiation of osseous choristoma from peripheral ossifying fibroma is not usually difficult because the latter has a unique cellular stroma of oval, primitive mesenchymal cells and is found exclusively on alveolar bone surfaces. Neither cartilage nor marrow is produced by the peripheral ossifying fibroma and, by tradition, a cartilaginous choristoma of the crest of the alveolar ridge in a denture wearer is called a Cutright tumor. Osseous choristoma should not be confused with the dystrophic calcification so frequently found in old thrombi, hematomas and keratin-­ filled soft-tissue cysts. This darkly

4  Lesions of the Oral Cavity

A

215

B

Fig. 4.20  A, The Cutright tumor is a cartilaginous choristoma with very mature and localized submucosal cartilage in a background stroma of dense fibrous tissue. B, Cartilage globules can appear quite mature and obvious in their origin, as seen here, but not all cases are this obvious.

staining aggregation of precipitated salts does not have a bone-­ like organization.  Treatment and Prognosis. The choristoma is best treated by conservative surgical excision. Surgery for congenital lesions is often delayed for 6 to 12 months. No recurrences have been reported with this therapy.  ECTOMESENCHYMAL CHONDROMYXOID TUMOR Ectomesenchymal chondromyxoid tumor (ECT) of the anterior tongue was first described in 1995 by Smith et al.216 Currently, fewer than 100 cases have been described in the literature.217–222 Other chondromyxoid lesions have been described in the oral cavity, including focal mucinosis, myxoma, ossifying fibromyxoid tumor, chondroid choristoma, pleomorphic adenoma, and myoepithelioma. However, the clinical findings, pathologic features and immunostaining profile of ECT are distinct enough from these other entities to warrant its own classification. Lesional cells are strongly reactive for vimentin, S100, and glial fibrillary acidic protein (GFAP), but negative for cytokeratin and epithelial membrane antigen. In primary cultures, the cells derived from the ECT are morphologically similar to neuronal cells.220,222 To date, it appears that this lesion is derived from relatively primitive neuroectodermal cells. Recent molecular studies have found a RREB1-­MKL2 fusion product in 90% of tumors and EWSR1 gene rearrangement in some.222 The RREB1-­MKL2 fusion gene regulates smooth muscle and striated muscle differentiation, as well as multiple neuronal and dendritic processes associated with neuronal development.222 Clinical Features. Nearly all reported cases of ECT have occurred on the anterior dorsal tongue. A recent case report and literature review found 74 lingual tumors (56/63 tumors [89%], where location was specified, were located in the anterior tongue and four on the posterior tongue, three were located on tongue dorsum, not otherwise specified [NOS]); only three extralingual tumors were found, two arose in the palate (the diagnosis in one of these has been called into question) and one in the tonsillar bed.221,222 No sex predilection was found and a wide age range was noted (7–78 years; mean: 39 years). The tumor size clinically ranges from 0.3 to 5.0 cm. The duration of the lesion varies, with one patient reporting up to a 20-­year

history, while other patients describe a slow growing mass of only a few months duration. Most patients are asymptomatic. Clinical examination shows a firm, nonmobile, dome-­shaped submucosal mass with normal overlying epithelium.  Pathologic Features and Differential Diagnosis. Gross examination reveals a rubbery nodule that on cut surface demonstrates a well-­circumscribed mass, which may show foci of hemorrhage or which may have a gelatinous consistency. Microscopic examination shows a multilobulated, well-­ delineated, but not encapsulated tumor in the submucosa (Fig. 4.21A). The overlying epithelium is uninvolved although the epithelial rete ridges may be flattened by tumor extension. Along the periphery of the tumor, vessels and small nerves may be compressed, while entrapped muscle fibers, small nerves and blood vessels can be seen within the tumor. The tumor is composed of spindle- to round-­shaped cells with small uniform nuclei (Fig. 4.21B and C). The faintly basophilic cytoplasm can be sparse to moderate. Occasional binucleation, nuclear pleomorphism, hypercellularity, focal necrosis, and hyperchromatism can be seen, but mitotic figures are rare and atypical mitoses are not seen. The background stroma is predominantly myxoid and can have areas of hyalinization or chondroid matrix. The stroma is positive for Alcian blue stains at pH 0.4 and 2.5, and mucicarmine stains are faintly positive in the extracellular matrix.219,220 ECT shows strong and diffuse immunoreactivity with both monoclonal and polyclonal GFAP. Variable immunoreactivity has been reported with S100, smooth muscle actin, cytokeratins, CD57, p63, Sox 10, desmin, myogenin, and vimentin (Fig. 4.21D). Differential diagnosis of ECT includes other tumors that have a chondroid or myxoid stroma. Oral focal mucinosis, the oral counterpart of cutaneous focal mucinous, generally occurs on the gingivae or the hard palate, but there have been reported cases in the tongue. However, the histochemical and immunohistochemical features are different from ECT. Oral soft-tissue myxomas are uncommon oral lesions that can be distinguished from ECT by the hypocellular stroma and ill-­defined margins. Myxomas show positive immunostaining only with vimentin, unlike ECT. Another look-­ alike lesion, ossifying fibromyxoid tumor (OFT) of soft parts, is a fairly well-­defined and lobulated tumor

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A

B

C

D

Fig. 4.21  A, Ectomesenchymal chondromyxoid tumor of the tongue is composed of multiple well-­demarcated lobules of chondromyxoid material surrounded in part by compressed fibrous stroma and admixed with small spindled or rounded cells with little cytosol. B and C, The amount of cellularity and myxoid change varies from one part of the tumor to another. D, Lesional cells exhibiting immunoreactivity to desmin.

composed of small round cells arranged in nests or in a trabecular pattern. Bone formation is present along the periphery of the tumor, which is not a feature of ECT. Approximately two-­thirds of OFT exhibit positive immunoreactivity with S100 protein, but electron microscopy favors a Schwann cell origin for this tumor. This is in contrast to the ECT, which likely derives from undifferentiated ectomesenchymal progenitor cells of neural crest origin. Finally, OFT has not been described in the tongue. Nerve sheath myxoma (myxoid neurothekeoma) can occur on the tongue and microscopically can appear as a well-­ circumscribed myxoid lesion demonstrating S100 protein immunopositivity, but it is generally negative for cytokeratins and GFAP. Neurothekeoma, unlike ECT, is hyaluronidase sensitive with Alcian blue staining. Lastly, there is significant overlap in the microscopic findings and immunohistochemical profile with myoepitheliomas. Neoplastic myoepithelial cells of salivary gland origin are positive for S100 protein, GFAP, and cytokeratins; they show variable positivity with smooth muscle actin. The dorsal anterior tongue where ECT occurs is devoid of salivary glands; however, myoepithelioma of soft-tissue origin is thought by some authors to be synonymous with ECT. soft-tissue myoepitheliomas have been reported in the upper and lower limbs, scalp, face, and trunk. 

Treatment and Prognosis. Complete surgical excision is the treatment of choice. Of the several dozen cases reported, follow-­up information is available for fewer than 25. Simple excision is usually curative; three patients had recurrences, one at 3 months, one at 19 months and the other at 41 months.221,222 Recurrences are treated with reexcision. Malignant behavior has not been reported.  PAROSTEAL (JUXTACORTICAL) AND PERIOSTEAL OSTEOSARCOMA Two variants of juxtacortical osteosarcoma arise on the surface of bone rather than within the medullary spaces. They represent up to 6% of all osteosarcomas.225 Occurring most frequently on the surfaces of long bones, several dozen examples have involved the jaws. The parosteal osteosarcoma arises from the cortex itself, while the periosteal osteosarcoma arises from the periosteum above the cortex. They initially grow outward but will, over time, perforate through the underlying cortex and proliferate within cancellous bone. They are included because they may mimic the peripheral ossifying fibroma, which is completely benign but may show high mitotic activity and somewhat alarming stromal cells.

4  Lesions of the Oral Cavity

The parosteal version was reported first by Geschickter and Copeland in 1951, as a benign parosteal osteoma, but is today considered to be a low-­grade malignancy.223–230 Either of these lesions are different from extraskeletal osteosarcoma (soft-tissue osteosarcoma), which arises completely within connective tissues above the periosteum, some distance from the cortex and is not physically associated with a bone. Extraskeletal osteosarcoma is not further discussed in this chapter. Clinical Features. Parosteal osteosarcoma and periosteal osteosarcoma present in a similar fashion: an irregular, lobulated or fungating, nonmoveable submucosal mass of the attached gingiva or alveolar mucosa, covering the mandible or maxilla.225,228,229 It is seldom painful, but may present with a dull ache. The malignancy occurs more frequently on the surface of the mandible than the maxilla, and there seems to be a strong predilection for males. The typical patient is 35 years of age at diagnosis, and lesions have been present for 1 to 5 years before diagnosis; the age range, however, is quite broad: 17 to 63 years. Irregular radiopacities are seen on up to 90% of routine radiographs of the lesions.228 A unique jawbone feature is widening of the periodontal ligament space around the teeth. This occurs as lesional cells infiltrate down into the space. Also teeth are pushed aside by the tumor.  Pathologic Features and Differential Diagnosis. Parosteal osteosarcoma is characterized by a high degree of tissue differentiation, and the bland histology may lead the pathologist to a benign diagnosis, such as osteoblastoma, peripheral ossifying fibroma, or heterotopic ossification. The criteria, however, for intramedullary malignancy are also used for the peripheral lesions, namely, dysplasia or anaplasia of the mesenchymal stroma and the production of bone by that neoplastic stroma. Periosteal osteosarcoma is more poorly differentiated and often has a prominent chondroid component. The classic parosteal osteosarcoma demonstrates scattered trabeculae of immature or woven bone, which may run parallel one to the other (Fig. 4.22). The bone shows only mild osteoblastic rimming; only occasional lesional cells become incorporated into the new bone. Occasionally, very primitive reticular osteoid is produced. Small foci of chondroid metaplasia may also be seen. The fibrous stroma is usually hypocellular and the cellular dysplasia required for a malignant diagnosis may be

217

rather sparse in the parosteal osteosarcoma, but periosteal version typically has numerous lesional cells that are moderately or poorly differentiated. The latter shows at least some regions where normal or proliferative periosteum can be seen beneath the tumor and the underlying cortex. It may, additionally, have so much cartilage production that there is a strong similarity to the intramedullary chondroblastic osteosarcoma. The differentiation of juxtacortical osteosarcoma from peripheral ossifying fibroma, reactive cortical exostosis, heterotopic ossification, osseous choristoma, and peripheral giant cell granuloma, with reactive bone, is based predominantly on the identification of pleomorphic or otherwise dysplastic stromal cells producing bone in the osteosarcoma. The other lesions, all of which are discussed elsewhere in this chapter, may show many plump, active stromal cells with moderate mitotic activity, but true dysplasia is lacking. Moreover, heterotopic ossification has its most active stromal proliferation centrally located, while the juxtacortical osteosarcoma has the most active regions toward its periphery. Finally, although some lesions may mimic osteochondroma, that benign lesion has not yet been reported to arise from the surface of the jawbones, except near the mandibular condyle. Once malignancy has been established, radiographic and clinical information may be required to ensure that the lesion is not an intramedullary osteosarcoma that has perforated through to the periosteal surface. This task is sometimes made impossible by the converse invasion of a juxtacortical lesion into cancellous bone.  Treatment and Prognosis. Lesions are treated by extensive surgical removal. Well-­differentiated lesions may be handled more conservatively than poorly differentiated ones, but it is important to remember that different sites within the same tumor may show different tissue grades. Juxtacortical osteosarcoma has a considerably better prognosis than its intraosseous counterpart, although the few jawbone cases reported do not allow for specific commentary to be made for that anatomic site. Well-­differentiated lesions of long bones have an approximate 80% 5-­year survival rate, whereas the survival rate of those with poorly differentiated lesions is less than half that.225,229 However, only a few deaths have been reported from the juxtacortical osteosarcomas of the jaws. 

Noncalcified Soft-Tissue Tumors With Mixed or Ectopic Tissues GLIAL CHORISTOMA

Fig. 4.22  Primitive osteoid in parosteal osteosarcoma is formed from a relatively nondysplastic fibrous stroma.

The glial choristoma consists of microscopically normal but ectopic CNS glial cells.231–235 It presents as a rare, soft, painless, submucosal, or deep nodule that is 1 to 2 cm in diameter and is only slightly movable. It has been reported in teenagers and young adults and may be an example of teratoma with glial predominance rather than true heterotopic brain tissue.234 The tumor is not associated with CNS pathosis or syndromes; in the head and neck region, the most common sites of presentation are the cribriform area of the nasal sinus (nasal glioma) and the bridge of the nose (extranasal glioma).233–235 Pathologic Features. Glial choristoma is composed of an unencapsulated but fairly well-­ demarcated submucosal aggregation of loose glial fibers, intermixed with a variable number of mononuclear and multinucleated oval and stellate

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astrocytes, with moderate eosinophilic cytoplasm. Ganglion cells may be numerous. Bands of fibrous tissue may be intermingled with the lesional cells or may surround clusters of cells. There is no evidence of cellular dysplasia or tissue necrosis. Glial tissues with astrocytic differentiation are immunoreactive for GFAP, S100 protein, and sometimes for vimentin. In general, the number of GFAP-­positive cells is proportional to the degree of differentiation, and with glial choristoma, there is enough cellular maturity to provide strong and diffuse ­reactivity.232,234 This diffuse reactivity will help to differentiate the lesion from neurilemoma, which lacks glial filaments, and from lingual metastasis of an anaplastic brain neoplasm. This entity is described in more detail in Chapter 3.  Treatment and Prognosis. Glial choristoma is removed by conservative surgical excision. No recurrence has been reported, nor has malignant transformation been reported.  TERATOMA A teratoma (pleural, teratomata) is a germ cell tumor derived from pluripotential cells and made up of elements of different types of tissue from all three germ cell layers.236–241 Most often found in the ovary or testis, the rare teratoma of the head and neck region arises primarily from Rathke’s pouch remnants of the sphenoid bone region, from the lateral neck, and from the tongue. Incidence of such lesions is 1:35,000 to 1:200,000 live births per annum, and they represent less than 2% of all teratomas.241 Rathke’s pouch teratomas may extend into the mouth through a cleft palate. Such an oropharyngeal lesion is often referred to as an epignathus. Although typically congenital, the teratoma is a true neoplasm of multiple tissue types foreign to the site from which it arises. Tissues derived from different embryonic germ layers are the rule rather than the exception. This tumor varies considerably in the differentiation and maturation of its involved tissues, with some lesions containing fingers, teeth, jawbone, or diminutive skeletons, whereas others demonstrate no more than an admixture of various tissue types, with no attempt at maturation or structural development. Most paraoral cases are cystic and relatively undifferentiated. Oral lesions have, however, been known to contain tissues from all parts of the body, including brain, bone, cartilage, skin, lung, and the gastrointestinal tract. Clinical Features. The oral presentation of epignathus is that of a large, focally soft, polypoid, lobulated mass, extending through a cleft palate into the mouth, often partially or completely filling the mouth.238,239 Lobules may extend into the oropharynx as well. The lesions are not painful but may interfere severely with breathing, swallowing, or feeding. The teratoma typically remains less than 4 cm in greatest diameter, but huge examples have been reported.240 Large lesions extend out of the mouth and may be the size of the newborn’s head. The mass is attached to a defect in the skull base via a stalk and magnetic resonance imaging (MRI) may show a considerably larger mass in the pituitary region of the brain.  Pathologic Features. The various tissue types found in a teratoma are, for the most part, mature, although full differentiation is often lacking. The tissues are randomly admixed one with another, showing little or no correlation with their normal anatomic relationships. The lesion is typically encapsulated and well demarcated from the surrounding normal tissues. There may or may not be a fibrovascular background stroma separating the different tissue types.

The keratin-­filled dermoid cyst of the oral floor midline has abortive sebaceous glands, perhaps even hair follicles, in its walls. Many authorities consider this to be a teratoma, going so far as to call such a lesion a teratoid cyst and equating it with the ovarian dermoid cyst. It is best, however, to refer to such a lesion as a dermoid cyst, since it contains elements from only two germ cell layers. Malignant teratomas do occur, usually with only a single component demonstrating dysplastic changes.242,243 When a rhabdomyoblastic component is seen, a variety of heterologous or mixed tumors must be ruled out, and when multiple components appear malignant, terms, such as malignant mesenchymoma, malignant ectomesenchymoma, and teratocarcinosarcoma, may be applied.  Treatment and Prognosis. Treatment of a teratoma consists of conservative surgical removal, a procedure that often requires finesse and delicacy because of the close proximity to important anatomic structures of the head and neck region.244,245 With conservative removal, occasional recurrence is to be expected, especially when portions of the teratoma must be left in place to preserve normal anatomic structures. Careful and long-­ term follow-­up is recommended. Malignant teratoma is treated according to its most prominent malignant component, usually by radical surgery, with or without radiotherapy. Rarely, a benign teratoma has been reported to transform into malignancy, especially carcinoma.  FORDYCE GRANULES Sebaceous glands are normal adnexal structures of the dermis but are also common within the mouth, where they are referred to as Fordyce granules or ectopic sebaceous glands. This variation of normal anatomy is seen in the majority of adults, perhaps as much as 90% of them, but seldom are granules found in large numbers.246–249 When seen as a streak of individual glands along the interface between the skin of the lip and the vermilion border, the terms Fox-­Fordyce disease and Fordyce’s condition have been used. Fordyce first described this condition in 1896.250 Clinical Features. Fordyce granules appear as rice-­like, white or yellow-­white, asymptomatic papules of 1 to 3 mm in greatest dimension (Fig. 4.23A). There is no surrounding mucosal change and the granules remain constant throughout life. The most common sites of occurrence are the buccal mucosa (often bilateral), the upper lip vermilion, and the mandibular retromolar pad and tonsillar areas, but any oral surface may be involved. Some patients will have hundreds of granules, while most have only one or two. There is a rarely reported systemic association with the hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome), especially the variant called Muir-­Torre syndrome.251–253 In addition, at least one investigation found the lesions to be more numerous or more pronounced in persons with hyperlipidemia.254 A Fordyce granule has been reported on gingival tissues, with pressure saucerization, producing a small underlying radiolucency. Occasionally, several adjacent glands will coalesce into a larger cauliflower-­like cluster similar to sebaceous hyperplasia of the skin. In such an instance, it may be difficult to determine whether to diagnose the lesion as sebaceous hyperplasia or sebaceous adenoma. The distinction may be moot because both entities have the same treatment, although the adenoma has a

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a local elevation of the epithelium. Individual sebaceous cells are large, with central dark nuclei and abundant foamy cytoplasm (Fig. 4.23C). The surrounding stroma may contain occasional chronic inflammatory cells because of trauma with adjacent teeth. Large numbers of lobules coalescing into a definitely elevated mass may be called benign sebaceous hyperplasia, and occasional small keratin-­filled pseudocysts may be seen and must be differentiated from epidermoid cyst or dermoid cyst with sebaceous adnexa. The pathologist must be careful to differentiate such lesions from salivary neoplasms with sebaceous cells, such as sebaceous lymphadenoma and sebaceous adenoma, and their malignant counterparts sebaceous lymphadenocarcinoma and sebaceous carcinoma (see Chapter 6).  Treatment and Prognosis. No treatment is required for Fordyce granules, except for cosmetic removal of labial lesions. Inflamed glands can be treated topically with clindamycin. When removal is elected, conservative surgical or laser excision is the treatment of choice, with no recurrence expected. Neoplastic transformation is very rare but has been reported.255  JUXTAORAL ORGAN OF CHIEVITZ

B

C Fig. 4.23  A, Fordyce granules appear as multiple small cauliflower-­ like whitish yellow papules. B, The granules are submucosal sebaceous glands with rudimentary excretory ducts or no visible ducts. C, Higher-power view of sebaceous cells.

greater growth potential. It should be mentioned that sebaceous carcinoma of the oral cavity has been reported, presumably arising from Fordyce granules or hyperplastic foci of sebaceous glands.255,256  Pathologic Features and Differential Diagnosis. Fordyce granules are usually not biopsied because they are readily diagnosed clinically, but they are often seen as incidental findings of mucosal biopsies of the buccal, labial, and retromolar mucosa. The granules are similar to normal sebaceous glands of the skin but lack hair follicles and almost always lack a ductal communication with the surface (Fig. 4.23B). The glands are located just beneath the overlying epithelium and often produce

The juxtaoral organ was first described by Chievitz in 1885 and is considered to be a vestigial organ, perhaps of the developing parotid gland, or to be epithelium entrapped during the embryonic development of the interface between the maxillary and mandibular processes.257–262 A neuroendocrine receptor function has been suggested. It is present in almost all individuals and is located bilaterally in the buccotemporal fascia on the medial surface of the mandible, near the angle. Clinical Features. Until recently, it was thought that the organ produces no visible or palpable mass; it was an occasional incidental finding in biopsied tissue samples from the region. A few proliferative masses of the lingual aspect of the posterior mandible have, however, now been reported as examples of tumors of the juxtaoral organ.259 A similar structure has been found within the anterior maxillary bone, but no embryonic explanation has been offered for its presence in that location.  Pathologic Features and Differential Diagnosis. The juxtaoral organ is a multilobulated nest or aggregation of two to 10 discrete islands of moderately large, oval, or angular cells, with a distinct squamoid appearance but with no keratin formation and with few, if any, intercellular bridges (Fig. 4.24A and B). Most islands also have smaller, darkly staining basaloid cells, usually aligned at the periphery, and a few show central epithelioid cells with clear cytoplasm. There is a definite glandular or organoid pattern. The background stroma is moderately dense fibrous tissue with no inflammatory infiltrate, no obvious encapsulation, and perhaps with extracellular melanin deposits. Characteristically, there is a prominent PAS-­positive basement membrane around the epithelial islands, and there are numerous small, myelinated, often degenerated nerves admixed with the epithelial islands.262 Occasional epithelial islands will demonstrate focal areas of dystrophic calcification. A word of caution is warranted. Because the organ of Chievitz is located so deep in the soft tissues, it may be mistakenly interpreted by the pathologist as well-­differentiated squamous cell carcinoma, mucoepidermoid carcinoma, or metastatic deposits from a visceral organ.261 Neuroepithelial structures similar to the organ have been reported in the posterior tongues of several individuals, in close association with the subepithelial nerve plexus of taste buds.260 Location should easily rule out an organ

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Fig. 4.24  A, The juxtaoral organ of Chievitz consists of multilobulated nests of squamoid cells with mild polarization of peripheral basaloid cells. B, Higher-power view of squamoid nests.

of Chievitz in such cases, but immunohistochemistry has been used as well.  Treatment and Prognosis. Although the function of this structure is completely unknown, it is a very innocuous variation of normal anatomy and requires no treatment. The few reported cases of tumorous growth of the organ had no recurrence 8 months after conservative surgical removal.  BENIGN LYMPHOID AGGREGATE (ORAL TONSIL TAG) Nodules of tonsillar tissue, usually called benign lymphoid aggregates, lingual tonsils (posterior lateral tongue), oral tonsils, or oral tonsil tags, are found in several oral and pharyngeal regions, besides the tonsillar beds of the lateral pharynx.263,264 This tissue, which corresponds to the adenoidal tissue of the nasopharynx, responds to infection and antigenic challenges, undergoing proliferation and appearing to become more numerous as very small, clinically invisible aggregates enlarge to a visible size. Lymphoid hyperplasia is the state in which many of these variants of normal anatomy are biopsied. The prevalence of hyperplastic oral tonsils is one to two per 1000 adults.1,264 It should be mentioned that one in 10 individuals have a small buccinator lymph node of the anterior buccal region below the occlusal plane. Some of these are located immediately beneath the mucosal epithelium and may enlarge to a size of 1 to 2 cm as a result of local trauma, dental infection, or upper respiratory infection. Histopathologic inflammatory changes are consistent with those found in cervical and other lymph nodes. Clinical Features. Intraoral and pharyngeal lymphoid aggregates are more prominent in younger individuals, reaching their peak size during the adolescent and teenage years. Although they may become especially large in young people, the hyperplastic state may be seen in persons of any age.263 Sites of occurrence, in decreasing order of frequency, are the posterior pharyngeal wall, the lateral posterior tongue, the soft palate, and the oral floor. During and for several days after an upper respiratory or other acute infection, benign lymphoid aggregates become enlarged, erythematous or yellowish, and perhaps somewhat tender, but they do not reach a size greater than 1 cm except on the posterior lateral tongue, where reported

cases have been 1.5 cm or greater in diameter. Without hyperplasia, the aggregates are 0.1 to 0.4 cm in size and have a pale yellow, semitransparent appearance (Fig. 4.25A). They are often mistaken for mucosal cysts because of their apparent transparency. There is no surrounding erythematous or inflammatory halo.  Pathologic Features. The benign lymphoid aggregate is composed predominantly of well-­differentiated lymphocytes collected into a single aggregation, usually with one or more germinal centers containing reactive lymphoblasts, predominantly B-­ cell types (Fig. 4.25B and C). Mitotic figures are seen in the germinal centers, as are macrophages containing phagocytized “tingible bodies” of nuclear debris from the surrounding proliferating lymphocytes. Linear streaking, or single filing, of lymphocytes may be seen at the periphery of the aggregate, and scattered lymphocytes are occasionally present in the surrounding fibrovascular stroma. There is no nodal encapsulation and vascular channels are minimally present, perhaps invisible without special staining. The surface epithelium is often atrophic, but occasional nodules of lymphoid aggregation show deep “tonsillar” clefts from the surface, which may be filled with sloughed keratin. These clefts can crimp off at the surface, resulting in a keratin-­filled lymphoepithelial cyst, or they may be considerably widened by the keratin build-­up. In the latter case, the keratin may mushroom above the surface and become clinically visible as a tonsillar keratin plug. The lymphoid cells of a lymphoid aggregate must be carefully evaluated to differentiate it from extranodal lymphoma and to determine whether the aggregate is hyperplastic. Microscopic criteria for hyperplasia and lymphoma are the same as those used for other lymphoid tissues of the body. Differentiation from a simple chronic inflammatory cell infiltrate is usually not difficult because the inflammatory infiltrate is much less abruptly demarcated from surrounding stroma, has many more lymphocytes in the surrounding stroma, has a greater admixture of inflammatory cell types, lacks germinal centers and is not monoclonal with histochemical analysis. It should be mentioned that certain very chronic inflammatory or immune-­related conditions, such as lichen planus or lupus erythematosus, may demonstrate small lymphoid aggregates deep in the submucosal tissues. These never produce

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A Fig. 4.26  The lingual thyroid presents as a midline mass of the posterior tongue (arrow: biopsied tissue shows routine features of the thyroid gland).

to provide an appropriate diagnosis and to rule out cystic lesions and lymphoid or other malignancy.  LINGUAL THYROID

B

C Fig. 4.25  A, “Oral tonsils” or benign lymphoid aggregates are often multiple and present as slightly yellowish, almost translucent nodules, as here on the oral floor. B, Each individual nodule is comprised of one or more well-­demarcated aggregates of lymphocytes, with occasional germinal centers (a small lymphoepithelial cyst is seen on lower left). C, The deep margin of one nodule shows tightly aggregated, mature lymphoid cells with one germinal center.

surface nodules. Also a large, generalized infiltration of the hard palatal soft tissues, referred to as benign lymphoid hyperplasia of the palate and often found microscopically to be a B-­cell lymphoma (see Chapter 13), is clinically so different from these small nodules of lymphoid aggregation that they cannot be clinically confused.265–270  Treatment and Prognosis. The benign lymphoid aggregate requires no treatment but may have to be excisionally biopsied

Late in the first month of life, the anlage of the thyroid gland descends from the posterior dorsal midline of the tongue (actually the floor of the pharyngeal gut) to its final position in the lower neck. The initial site of descent eventually becomes the foramen cecum, located in the midline at the junction of the anterior (oral) tongue and the tongue base. If the embryonic gland does not descend normally, ectopic or residual thyroid tissue (technically either a choristoma or hamartoma) may be found between the foramen caecum and the epiglottis. Occasionally when this happens, an unexplained cystic lesion may develop in empty thyroid bed in the lower neck. Of all ectopic thyroids, 90% are found on the lingual dorsum, where they are called lingual thyroid or ectopic lingual thyroid.271–275 Rarely, parathyroid glands are associated with the ectopic thyroid tissue. Other sites of ectopic thyroid deposition include the cervical lymph nodes, submandibular glands, and the trachea. Approximately two-­thirds of patients with lingual thyroid lack thyroid tissue in the neck and occasional patients will have thyroid tissue in the tongue, as well as the inferior midline of the neck, or any location along the normal descent of the gland. The prevalence of lingual thyroid is rare.1,264,275 Clinical Features. The lingual thyroid is four times more common in females than in males.273,275 It presents as an asymptomatic nodular mass of the posterior lingual midline, usually less than a centimeter in size but sometimes reaching more than 4 cm (Fig. 4.26). Larger lesions can interfere with swallowing and breathing, but most patients are unaware of the mass at the time of diagnosis, which is usually in the teenage or young adult years. Up to 70% of patients with lingual thyroid have hypothyroidism and 10% suffer from cretinism.272  Pathologic Features. The lingual thyroid consists of a nonencapsulated collection of embryonic or mature thyroid follicles, which may extend between muscle bundles, raising suspicions of malignant invasion. The follicular cells, however, are normal or atrophic in appearance. All diseases capable of affecting the normal thyroid gland can, of course, affect the glandular tissue entrapped in the tongue. Thyroid adenoma,

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goiter, hyperplasia, inflammation, and carcinoma occur in lingual thyroids, and must therefore be evaluated in the same fashion as would any biopsied thyroid gland. Parathyroid tissue may be seen but has not been neoplastic in reported cases.  Treatment and Prognosis. Surgical excision or radioiodine therapy are effective treatments for lingual thyroid, but no treatment should be attempted until an iodine-­ 131 radioisotope scan has determined that there is adequate thyroid tissue in the neck.276,277 In those patients lacking thyroid tissue in the neck, the lingual thyroid can be excised and autotransplanted to the muscles of the neck. Most cases require no treatment and biopsy should be considered with caution because of the potential for hemorrhage, infection, or release of large amounts of hormone into the vascular system (thyroid storm). Occasional patients with parathyroid tissue associated with their lingual thyroid have developed tetany after the inadvertent removal of this tissue. Rare examples of thyroid carcinoma arising in the mass have been reported, almost always in males, but an enlarged lingual thyroid is more likely to reflect a normal compensatory response to thyroid hypofunction.278–280 Endocrine evaluation for hypothyroidism should therefore be done in such cases. In this light, it is important to know that three of every four patients with infantile hypothyroidism have ectopic thyroid tissue. 

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CONGENITAL (GRANULAR CELL) EPULIS First described by Neumann in 1971, the congenital epulis (congenital granular cell myoblastoma, granular cell epulis of infancy, granular cell fibroblastoma) is a unique and rare congenital tumor of the alveolar mucosa of the jaws.281–284 The exact nature of this entity is not clear. Once thought to be a form of odontogenic dysgenesis, it is now believed to originate from primitive mesenchymal cells of neural crest origin; although the evidence for this is less than conclusive, an origin from true neural tissue has been excluded with immunohistochemistry.284,285 Clinical Features. The congenital epulis is almost exclusively found on the anterior alveolar ridges of newborns, although a few cases have reportedly developed shortly after birth. The earliest reported case was identified by ultrasonography in a 31-­week fetus.286 Approximately 90% of cases occur in girls, and 10% present with multiple lesions.284 This mass presents as a 0.5 to 2.0 cm soft, pedunculated, and perhaps lobulated nodule of the alveolar mucosa, especially the mucosa of the maxilla (Fig. 4.27A). A few lesions have been as large as 9 cm in size at birth and several cases have had involvement of both jaws. Large lesions obviously interfere with feeding. There is no tenderness or surface change and the lesion does not increase in size after birth. In fact, many of the smaller examples spontaneously regress after birth.  Pathologic Features and Differential Diagnosis. The mucosal mass is composed almost entirely of large, rounded and polyhedral, histiocyte-­like cells with small, dark, oval nuclei and abundant eosinophilic granular cytoplasm (Fig. 4.27B and C). Lesional cells may be somewhat spindled. There are vascular channels between granular cells, but fibrous stroma is minimally present and often appears to be completely lacking. The tumor cells extend to the overlying epithelium, which is atrophic and

B

C Fig. 4.27  A, The congenital epulis typically presents as a soft mass of the anterior maxilla. B and C, The lesion is composed almost entirely of histiocyte-­like granular cells; the overlying epithelium is always atrophic, with a general loss of rete ridges. (Courtesy of Dr. Robert Gorlin, University of Minnesota.)

never demonstrates the pseudoepitheliomatous hyperplasia so commonly seen in the granular cell tumor of adults. Lesion cells do not immunoreact for laminin or S100 protein, as do the granular cells of the granular cell tumor. They are also negative for Leu7, neuron-­specific enolase, and other neural markers and reactive only to vimentin. These cells are also strongly positive for acid phosphatase.283–285 There is no other congenital alveolar mucosal lesion that is similar to the congenital epulis, but oral involvement by

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Langerhans cell disease might have enough tissue histiocytes to somewhat mimic the epulis. Occasional odontogenic tumors contain abundant granular cells, but these are almost never congenital and seldom located outside the bone. Conversely, 30% to 50% of cases show odontogenic epithelial rests among the granular cells.285,287 The granular cell tumor has cells that are histopathologically identical to those of the granular cell epulis, but the early onset, unique location, and pedunculated appearance make the epulis easily differentiated from the tumor.286–288 The tumor, moreover, is not encapsulated, is S100 positive and infiltrates into underlying tissues, and many of the lesional cells have a spindled appearance, especially at the deep margin of the tumor. Similar granular cells are found in the connective tissue papillae of verruciform xanthoma, but the association of this lesion with overlying papillomatosis and the older age at onset make it easily distinguished from granular cell epulis.  Treatment and Prognosis. Before birth, the congenital epulis enlarges at a rate similar to that of the growing fetus, but after birth the mass tends to spontaneously regress and disappear over the first 8 to 12 months of life. Residual remnants do not interfere with tooth eruption. There is therefore no need to

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treat a small congenital lesion. Larger lesions interfering with feeding require conservative excision as soon as the child is large enough to safely undergo surgery. There is no tendency for recurrence and malignant transformation has not been reported.  MEDIAN RHOMBOID GLOSSITIS The embryonic tongue is formed by two lateral processes (lingual tubercles) meeting in the midline and fusing above a central structure from the first and second branchial arches, the tuberculum impar. The posterior dorsal point of fusion is occasionally defective, leaving a rhomboid-­ shaped, smooth erythematous mucosa lacking in papillae or taste buds. This median rhomboid glossitis (central papillary atrophy, posterior lingual papillary atrophy) is a focal area of susceptibility to recurring or chronic atrophic candidiasis, prompting some to prefer the diagnostic term posterior midline atrophic candidiasis.289–292 Since all cases are not associated with Candida, this seems rather inappropriate. The erythematous clinical appearance, moreover, is caused primarily by the absence of filiform papillae, rather than by local inflammatory changes, as first suggested in 1914 by Brocq and Pautrier.293

B

A

C

Fig. 4.28 A, Median rhomboid glossitis presents as an erythematous region of depapillated mucosa at the posterior midline of the tongue (posterior arrow; anterior arrow points to a granular cell tumor). B, Elongated rete processes with neutrophils embedded and with lymphocytes in underlying stroma. C, The elongated rete processes, which may be severe enough to mimic squamous cell carcinoma, that is, may produce pseudoepitheliomatous hyperplasia.

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The lesion is found in one of every 100 to 2000 adults, depending on the rigor of the clinical examinations.294,295 The prevalence rate in diabetic patients, with their known susceptibility to mucosal candidiasis, may be as high as 65%.296 Clinical Features. Median rhomboid glossitis presents in the posterior midline of the dorsum of the tongue, just anterior to the V-­shaped grouping of the circumvallate papillae (Fig. 4.28A). The long axis of the rhomboid, diamond-­shaped or oval area of red depapillation is in the anterior-­posterior direction. Most cases are not diagnosed until the middle age of the affected patient, but the entity is, of course, present in childhood. There appears to be a 3:1 male predilection.294 Those lesions with atrophic candidiasis are usually more erythematous but some respond with excess keratin production, and therefore show a white surface change. Infected cases may also demonstrate midline soft-palate erythema in the area of routine contact with the underlying tongue movement; this is euphemistically referred to as a kissing lesion. Lesions are typically less than 2 cm in greatest dimension, and most demonstrate a smooth, flat surface, although it is not unusual for the surface to be lobulated, sometimes dramatically so. Occasional lesions have surface mamillations raised more than 5 mm above the tongue surface, and rare lesions are located somewhat anterior to the usual location. None have been reported posterior to the circumvallate papillae. Prior to biopsy, if elected, the clinician should be certain that a lobulated midline lesion does not represent a lingual thyroid, as it may be the only thyroid tissue present in the patient’s body. Additional clinical look-­alike lesions include the gumma of tertiary syphilis, the granuloma of tuberculosis, deep fungal infections, and granular cell tumor.  Pathologic Features. Median rhomboid glossitis shows a smooth or nodular surface covered by atrophic stratified squamous epithelium overlying a moderately fibrosed stroma with somewhat dilated capillaries. Fungiform and filiform papillae are not seen, although surface nodules may mimic or perhaps represent anlage of these structures. A mild to moderately intense chronic inflammatory cell infiltrate may be seen within subepithelial and deeper fibrovascular tissues. Chronic Candida infection may result in excess surface keratin or extreme elongation of rete processes and premature keratin production within individual cells or as epithelial pearls (dyskeratosis) deep in the processes (Fig. 4.28B and C). Silver or PAS staining for fungus will reveal Candida hyphae and spores in the superficial layers of the epithelium of such cases.290,296 This pseudoepitheliomatous hyperplasia may be quite pronounced, and the tangential cutting of such a specimen may result in the artifactual appearance of cut rete processes as unconnected islands of squamous epithelium, leading to a mistaken diagnosis of well-­differentiated squamous cell carcinoma. Because of this difficulty, it is recommended that the patient be treated with topical antifungals before biopsy of a suspected median rhomboid glossitis. It should also be mentioned that the posterior midline region of the oral tongue is a very, very unlikely sight for carcinoma development.  Treatment and Prognosis. No treatment is necessary for median rhomboid glossitis, but nodular cases are often removed or incised for microscopic evaluation. Recurrence after removal is not expected, although those cases with pseudoepitheliomatous hyperplasia should be followed closely for at least a year after biopsy to be certain of the benign diagnosis. Antifungal therapy (topical troches or systemic medication) will reduce clinical erythema and inflammation caused by Candida infection. This therapy, as stated earlier, should ideally

be given prior to the biopsy, to reduce the Candida-­induced pseudoepitheliomatous hyperplastic features. Some lesions will disappear entirely with antifungal therapy.  SOFT-TISSUE CYSTS Epithelium-­lined cystic spaces are occasionally found beneath the oral and pharyngeal mucosa. These may have their origins in the embryonic development of teeth (odontogenic cysts), in epithelial remnants left over from maxillofacial embryogenesis and development (nonodontogenic cysts, fissural cysts, ductal cysts), or in viable epithelial fragments traumatically embedded beneath the oral mucosa (inclusion cysts, entrapment cysts). Such cysts usually have a very limited growth potential, with slow enlargement, presumably generated by the slightly elevated hydrostatic pressures within the cystic lumina. Taken as a group, oral softtissue cysts are found in at least one of every 2000 adults.1 Several soft-tissue cysts are discussed elsewhere in this text. The salivary retention cyst, for example, is an epithelium-­lined cyst arising from back-­up pressures secondary to a plugged salivary gland duct; it is discussed in Chapter 6. The eruption cyst, discussed in Chapter 10 with odontogenic lesions, occurs on the crest of the alveolar process and is actually a dentigerous cyst associated with an underlying erupting tooth. In this instance, the cortical bone separating the dentigerous cyst from the surface mucosa has been resorbed and only a thin layer of fibrovascular stroma separates the cyst epithelium from the surface epithelium. Also a small proportion of nasopalatine duct cysts arise at the oral orifice of the incisive canal, presenting as softtissue cysts. When this occurs, the cyst is traditionally referred to as a cyst of the incisive papilla. There are also pseudocysts of the oral and pharyngeal soft tissues. By traditional definition, these lack an epithelial lining. The mucocele is one such lesion, consisting of a submucosal pool of extravasated mucus from a ruptured minor salivary gland. This entity is much more common than true soft-tissue cysts of the mouth and throat, with one case diagnosed in every 200 to 300 adults.1 The mucocele and its much larger submandibular gland counterpart, the ranula, are discussed with other salivary diseases in Chapter 6. A second type of pseudocyst is an artifact, produced by tangential cutting of a deep surface indentation during laboratory processing. It is mentioned throughout the text when appropriate.  EPIDERMOID AND DERMOID CYST The epidermoid (epidermal) cyst, often mistakenly called a wen (sebaceous cyst), is a very common skin lesion that arises from traumatic entrapment of surface epithelium (epidermal inclusion cyst) or, more often, from aberrant healing of the infundibular epithelium, during an episode of follicular inflammation or folliculitis. The oral epidermoid cyst occurs much less frequently and may remain undetected by the patient because it remains so small.297–303 Syndromes associated with multiple cutaneous epidermoid cysts, such as Gardner syndrome, Gorlin syndrome, and pachyonychia congenita, do not demonstrate cysts of the oral mucosa, but facial cysts may occur. The epidermoid cyst of the oral floor midline has a much greater growth potential than epidermoid cysts occurring at other oral sites.302 The large cyst is, moreover, often labeled erroneously as dermoid cyst by some who believe it to be a forme fruste of benign cystic teratoma. Since its first description in 1852 as a sublingual cyst or wen, the distinction between the oral floor epidermoid and dermoid cyst has been rather confused.304

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As it is likely that most examples represent cystic degeneration of embryonically entrapped epidermis, and as the microscopic features of this cyst are almost always identical to those of the epidermoid cyst of the skin or other oral locations, we suggest that the use of the term dermoid cyst be reserved only for those cysts with epidermal adnexa beneath the lining epithelium. Congenital teratoid cysts contain elements derived from all three germ layers, ectoderm, mesoderm, and entoderm. A special type of epidermoid cyst, the gingival cyst of adult, is a superficial lesion located exclusively on the attached gingiva, almost always on the facial surface, and remains indefinitely thereafter.305,306 This arises from one of the many odontogenic/ dental lamina embryonic rests remaining into adulthood within the subepithelial stroma. It is discussed in more detail as an odontogenic lesion in Chapter 10, as is a similar superficial cyst of alveolar mucosae of newborns, called the gingival cyst of newborns. Clinical Features. The oral epidermoid cyst occurs primarily on the lateral and ventral tongue, the oral floor and the lateral soft palate, especially above the pharyngeal tonsils. Some refer to soft palate cysts as velar cysts. Most cases are diagnosed during the teen or young adult years.298 The cyst typically remains less than 1 cm in diameter and may be somewhat movable beneath the surface, except on bone-­bound mucosa. The cyst is almost always superficial, producing a sessile nodule with a white or yellow-­white; the occasional deeper lesions may show a normal color (Fig. 4.29A). The larger cyst is usually found in the oral floor midline above the mylohyoid muscle. Occasionally, such a lesion is dumbbell-­ shaped because it has penetrated through a hiatus in the muscle to extend into the submental area, possibly imparting a double chin appearance.301 In this location, the cyst may reach 6 to 7 cm in greatest diameter, may become infected, and may interfere with swallowing or the proper function of the tongue.302 The clinically similar gingival cyst of adult is, by definition, found on the attached alveolar or gingival mucosa and appears as a pink or clear, translucent nodule less than 6 mm in diameter. Larger cysts may eventually impart a downward pressure on the underlying bone, producing a well-­demarcated saucerized area of thin cortex, which often is radiolucent on a dental radiograph.  Pathologic Features. The epidermoid cyst is lined by a thin stratified squamous epithelium with few rete processes (Fig. 4.29B and C). Quite often, there is no granular cell layer and keratin from the surface of the epithelium can be seen to be sloughing into the cystic lumen, which is usually filled with degenerated and necrotic keratinaceous detritus. Areas of epithelial degeneration or ulceration may be seen, usually associated with a mild to moderately intense chronic inflammatory cell reaction. Inflammation may extend deeply into subepithelial fibrovascular stroma. Occasional cysts have contained fungi, bacteria, or necrotic food debris in their lumina, and darkly hematoxyphilic precipitated salts (dystrophic calcification) may be seen within the necrosed keratin. When keratin degenerates within an ulcer bed of the cyst wall, cholesterol crystals form elongated, sharp-­ended clefts (cholesterol clefts), which are clear spaces in stained tissue sections because of the dissolution of the associated fats by laboratory processing. Foreign-­body multinucleated giant cells are frequently seen adjacent to or surrounding such clefts. This cholesterol granuloma will occasionally proliferate into the lumen of the cyst from an area of ulceration, but they are usually seen within the ulcer bed itself. The dermoid cyst differs from epidermoid cyst only in the presence within its walls of normal or dysmorphic adnexal appendages, usually sebaceous glands or abortive hair follicles.

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B

C Fig. 4.29  A, The epidermoid cyst presents as a sessile and moveable yellowish-­white submucosal mass. B, The cyst lining is atrophic stratified squamous epithelium. C, Higher power of (B).

If the cyst wall contains other elements, such as muscle (other than pilar arrector smooth muscle) or bone, the term teratoid cyst is preferred. The gingival cyst is lined by thin squamous epithelium, occasionally with focal nodular thickenings, and shows a lumen filled with a clear fluid. Occasionally, chronic inflammatory cells are seen in the surrounding stroma or the cystic lumen.  Treatment and Prognosis. Treatment consists of conservative surgical removal, trying not to rupture the cyst, as the luminal contents may act as irritants to fibrovascular tissues, producing postoperative inflammation. The presence

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or absence of a cholesterol granuloma has no bearing on the prognosis. Recurrence is unlikely after treatment. Malignant transformation of oral cysts has not been reported, although it has occurred in cysts of the skin. Large oral floor cysts are problematic surgically because a portion is found beneath the floor muscles. The increased difficulty means that recurrence is more likely, so follow-­up examination for a year or two is important. The gingival cyst of adult almost never requires more than surgical excision. If the underlying cortex is saucerized, it will return to normal spontaneously, over the following months.  PALATAL AND GINGIVAL CYSTS OF THE NEWBORN A special form of odontogenic cyst is found in as many as 80% of newborn infants.307 Although this gingival cyst of the newborn (gingival cyst of infants, dental lamina cyst) has the microscopic appearance of an epidermoid cyst, it arises from epithelial remnants of the deeply budding dental lamina during tooth development, after the fourth month in utero, and is therefore discussed with the odontogenic lesions in this text (see Chapter 10). A similar palatal cyst of the newborn is commonly found in the posterior midline of the hard palate, where it arises from epithelial remnants remaining in the stroma after fusion of the palatal processes, which meet medially to form the palate. As originally described in the 1880s, the cysts along the median raphe of the palate were called Epstein’s pearls and the term Bohn’s nodules was used for cysts that originated from palatal gland structures and were scattered more widely over the hard and soft palates.308–312 Today, these two terms are frequently used interchangeably for both palatal and gingival cysts of newborns. Clinical Features. Gingival cysts of the newborn typically present as multiple (usually less than six) 1 to 4 mm milia-­ like yellow-­ white, sessile mucosal papules of the alveolar processes. Palatal cysts have a similar appearance but are less numerous and are found on the midline of the posterior hard palate, and occasionally of the anterior soft palate. Occasional palatal cysts are located some distance from the midline. The cysts are usually somewhat larger and less numerous than the gingival cysts of the alveolar processes in newborns, but the two entities are otherwise clinically identical. Both types of cyst are so superficial that several may be ruptured at the time of examination.  Pathologic Features. Both gingival and palatal cysts of the newborn show a thin stratified squamous epithelium cyst lining with a routine fibrovascular connective tissue stroma, usually without an inflammatory cell infiltrate. The cystic lumen is filled with degenerated keratin, usually formed into concentric layers or “onion rings,” and the epithelium lacks rete processes. Occasional cysts will demonstrate a communication with the surface.  Treatment and Prognosis. No treatment is required for gingival or palatal cysts of the newborn. The cysts are very superficial and within weeks will rupture to harmlessly spill their contents into the oral or pharyngeal environment. The cyst lining then fuses with the overlying mucosa and becomes part of it. Occasionally, a larger cyst or a cyst situated more deeply in the submucosal stroma will remain for 6 to 8 months before

rupturing. These cysts do not interfere with tooth eruption, should they last that long.  NASOLABIAL CYST The nasolabial cyst (nasoalveolar cyst, Klestadt’s cyst) is now considered to originate from remnants of the embryonic nasolacrimal duct or the lower anterior portion of the mature duct, although a popular past theory presumed it to arise from epithelial rests remaining from the “fusion” of the globular process with the lateral nasal process and the maxillary process.313–318 Zuckerkandl may have been the first to describe this cyst, and several hundred examples have thus far been reported, including one family with a father and daughter having similar involvement.319 This entity represents just over 2% of all cysts in some oral pathology biopsy services.317 Clinical Features. The nasolabial cyst has a strong female predilection (75% occur in women) and appears to occur more frequently in blacks than in whites.316,318 It is found near the base of the nostril, just above the periosteum, or in the superior aspect of the upper lip (Fig. 4.30A), it is bilateral in approximately 10% of all cases.318 The cyst usually obliterates the nasolabial fold and may elevate the ala of the nose on the affected side. It also obliterates the maxillary vestibule and frequently extends into the floor of the nasal vestibule, occasionally causing nasal obstruction or pressure erosion of the bone of the nasal floor. When located in the lip, there almost always is a fibrous or epithelial attachment to the nasal mucosa. Most examples are less than 1.5 cm in greatest diameter, but some have reached much larger sizes. Injection of a radiopaque dye into the lumen will help define the cyst outline, as will ultrasound.320 It may be somewhat irregular, even bilobed, and it is not unusual to be secondarily inflamed and somewhat tender to palpation. Occasional cysts rupture or drain into the oral cavity or nose.  Pathologic Features and Differential Diagnosis. The nasolabial cyst is lined by respiratory epithelium, stratified squamous epithelium, pseudostratified columnar epithelium, or a combination of these (Fig. 4.30B). Mucus-­filled goblet cells may be scattered within the epithelium and apocrine change has been reported.321 Chronic inflammatory cells may be seen in the surrounding fibrovascular stroma. The nasolabial cyst might be confused with epidermoid cyst or eruption cyst. The epidermoid cyst, however, is more superficial, being located immediately beneath the mucosal epithelium, does not extend into nasal sinus region, and lacks the respiratory epithelial features of the nasolabial cyst. The eruption cyst can be radiographically identified by its association with an underlying erupting tooth.  Treatment and Prognosis. This cyst is treated by conservative surgical excision, usually using access from the anterior maxillary vestibule.322,323 The surgical procedure may have to be extended deeply into the nasal sinus, and it is sometimes necessary to remove part of the nasal mucosa to remove the entire cyst. Marsupialization from the nasal sinus floor has been successful in numerous cases.  CYST OF THE INCISIVE PAPILLA The cyst of the incisive papilla (CIP) is the soft-tissue counterpart of the intraosseous nasopalatine duct cyst (NPDC), also known as the incisive canal cyst, since humans after birth seldom have an actual open duct in the canal.324–329 The CIP develops at the

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A

227

B

Fig. 4.30  A, The nasolabial cyst is always located in the upper lip or nasal floor. B, The cyst lining in this example is pseudostratified columnar epithelium. (Courtesy of Dr. Ben Crawford, University of Texas School of Dentistry at Houston.)

incisive foramen, of the canal, in the midline of the anterior palate, posterior to the central incisors. The NPDC and CIP both originate from the same epithelium, or remnants thereof, of the nasopalatine duct. During embryologic development, the duct traverses the incisive canals connecting the nasal cavity to the oral cavity. Near the superior or nasal end, this epithelium is respiratory, then becomes transitional or cuboidal and finally, becomes squamous, as it approaches the oral mucosa. Branches of the descending palatine and sphenopalatine arteries, the nasopalatine arteries and nerve, and mucous glands are found in the canal; all may be found in the stroma surrounding a developing cyst. Clinical Features. The CIP has a male predilection and occurs over a wide age range, but most affected patients are in the fourth to sixth decade by the time of diagnosis.325 The cyst presents as an immoveable sessile, normally colored mass of the anterior hard palate midline (Fig. 4.31A). When the cyst is very superficial, a blue discoloration may be seen. Symptoms are variable and usually correlate to cyst size. Small cysts are usually asymptomatic but may be painful because of trauma or inflammation of the nerves projecting from the incisive canal. Larger cysts are more likely to be painful, produce swelling or drainage with fistula formation. Bone resorption can also be noted radiographically. Teeth adjacent to the lesion test vital, a significant feature since routine dental radiographs taken at an angle may show the CIP superimposed over the apex of an incisor, mimicking a periapical infection.327,328  Pathologic Features and Differential Diagnosis. The CIP is lined by squamous epithelium, although occasional examples exhibit respiratory or cuboidal epithelial types. The cyst lumen may contain sloughed or desquamated epithelial cells, inflammatory cells and mucin, but it is usually clear. The cyst may be secondarily infected, showing a chronic or acute inflammatory cell infiltrate in the stroma, perhaps associated with hemorrhage. An important diagnostic feature is the presence in the cyst wall of the normal contents of the incisive canal, including large nerves, arteries, and mucous glands; adipocytes are sometimes present (Fig. 4.31B). No other oral cysts are characterized by such stromal structures. Other cystic entities to consider in the differential diagnosis include periapical (radicular) cyst, odontogenic keratocyst (OKC), primordial cyst, lateral periodontal cyst, and NPDC.

A

B Fig. 4.31 A, The cyst of the incisive papilla is typically a sessile, fluctuant mass of the midline, posterior to the maxillary central incisors. B, The cyst lining may be respiratory or squamous in nature, or a combination of the two.

The periapical cyst is invariably inflamed but typically remains within the bone near the apex of the maxillary incisors. Those which project toward the palate and perforate the cortical bone can be distinguished from CIP by their association with a nonvital (nonviable) tooth and by their location close to the apex of the affected tooth, as determined by triangulated radiographs or computed tomography (CT) scans.327,328

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The OKC and lateral periodontal cyst also remain centrally within the alveolar bone and do not show as soft-tissue masses; they each have unique squamous epithelial linings (see bone and odontogenic pathology Chapters 8 and 10 for more detail). The primordial cyst is also central within the alveolar bone and has an epithelium that may mimic the CIP but without the vascular and neural stromal structures. A small, inferiorly located NPDC may be indistinguishable from CIP but, by definition, must be located completely within maxillary bone. Radiographic confirmation can be made via cone beam CT imaging but sometimes cannot be made, except at the time of surgical removal of the cyst.327 A final note on the differential diagnosis. A few bronchogenic cysts have been reported in the mouth, but only from the soft palate and tongue. These, of course, have respiratory epithelium and may show stromal mucus glands, but no large vessels or nerves.330 In addition, CIP can clinically look like a mucocele. This should have no epithelial lining at all and should not occur at this site because there are no mucus glands on the anterior hard palate. They must occasionally occur there, however, since a mucocele in an infant has been reported from the anterior palate.  Treatment and Prognosis. Surgical enucleation is the treatment of choice, and there is a low recurrence rate. Because the branches of the sphenopalatine nerve are removed during enucleation, chronic paresthesia of the anterior palate can occur, although this is reported to occur less than 10% of the time. Complete bone regeneration is generally reported. Although extremely rare, cases of squamous cell carcinoma arising in the epithelial lining of a NPDC have been reported; this has not been reported for CIP.  LYMPHOEPITHELIAL CYST The oral lymphoepithelial cyst develops within tonsillar mucosal tissues. In the mouth, this usually signifies a benign lymphoid aggregate or accessory tonsil.331–334 The surface of such aggregates may be indented with tonsillar crypts, as are the much larger pharyngeal tonsils of the lateral pharyngeal walls. The crypts may become obstructed by keratin or other debris, or the surface opening may become constricted during episodes of inflammatory hyperplastic responses. Certain cases develop a complete disunion of the crypt epithelium from the surface epithelium, resulting in a subepithelial cyst, lined by the old crypt epithelium. This cyst was first reported by Parmentier in 1857 as hydatid cyst.335 Outside of the head and neck region, lymphoepithelial cyst is found most frequently in the pancreas and testis.336 A similar but much larger cervical lymphoepithelial cyst (branchial cleft cyst) most probably develops from entrapped salivary duct epithelium in the lymph nodes of the lateral neck, rather than from the branchial cleft.337,338 These are discussed separately in Chapter 11. Another similar cyst, the parotid cyst or submandibular cyst, is found in major salivary glands, especially in AIDS patients, although it often lacks a surrounding lymphoid aggregate.339–341 This cyst is also discussed in Chapter 6. Clinical Features. Oral lymphoepithelial cyst presents as a movable, painless submucosal nodule with a yellow or yellow-­white discoloration (Fig. 4.32A). Occasional cysts are transparent. Almost all cases are less than 0.6 cm in diameter at the time of diagnosis, which is usually during the teen years

or the third decade of life.334 Approximately half of all intraoral examples are found on the oral floor, but the lateral and ventral tongue are also common sites of occurrence. Occasional cysts are found on the soft palate or the mucosa above the pharyngeal tonsil or, rarely, in the hypopharynx.342 Of course, this cyst may also occur within the pharyngeal tonsils themselves. Occasional superficial cysts of the pharyngeal tonsil rupture to release a foul-­tasting, cheesy, keratinaceous material. This cyst has a clinical appearance similar to that of an epidermoid cyst or a dermoid cyst of the oral and pharyngeal mucosa, but its growth potential is much less than that of the other cysts. The lymphoepithelial cyst never occurs on the alveolar mucosa, so it can easily be distinguished from a gingival cyst of adults or from an unruptured parulis or “pus pocket” at the terminus of a fistula (extending from the apical or lateral region of an abscessed tooth). Occasionally, bilateral cysts are seen.333  Pathologic Features and Differential Diagnosis. The lymphoepithelial cyst is lined by atrophic and often degenerated stratified squamous epithelium, usually lacking in rete processes and usually demonstrating a minimal granular cell layer (Fig. 4.32B–D). Orthokeratin is seen to be sloughing from the epithelial surface into the cystic lumen, often completely filling the lumen and sometimes showing dystrophic calcification. Rarely, mucus-­filled goblet cells or sebaceous cells may be seen within the superficial layers of the epithelium, and occasional cysts will demonstrate an epithelium-­ lined communication with the overlying mucosal surface.339 The cyst is entrapped within a well-­ demarcated aggregate of mature lymphocytes (see Fig. 4.32C and D). The aggregate or “tonsil” will have a variable number of germinal centers, sometimes none at all. The lymphoid aggregate may be hyperplastic. This combination of epithelium-­lined cyst with lymphoid aggregates is unique enough to make the diagnosis an easy one, but the pathologist must differentiate this lesion from the Warthin tumor (papillary cystadenoma lymphomatosum). The latter lesion is lined not by squamous epithelium but by a bilayered cuboidal, columnar, or oncocytic ductal epithelium. It is almost always found in the parotid gland, but rare oral examples have been reported. Occasional cysts have very small lumina, with degenerated epithelial linings, and may mimic metastatic deposits of well-­ differentiated squamous cell carcinoma. Deeper sections will reveal the true nature of the benign lesion.  Treatment and Prognosis. No treatment is necessary for the oral lymphoepithelial cyst unless its location is such that it is constantly being traumatized. Most lesions are, however, removed by conservative surgical excision to arrive at a definitive diagnosis. There is no malignant potential to this lesion but the lymphoid stroma, as with all lymphoid tissues, can become involved with an extranodal lymphoma.  THYROGLOSSAL DUCT CYST The anlage of the median lobe of the thyroid gland arises in the foramen caecum area of the posterior dorsal tongue, at the junction between the anterior one-­third and the posterior two-­ thirds of the tongue. During its descent to the lower neck, it retains an attachment with its point of origin, the thyroglossal duct or tract. Normally this duct is obliterated by the sixth week of life, but remnants can remain and undergo cystic degeneration to form a thyroglossal duct cyst or thyroglossal duct fistula

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C

A

B

D

Fig. 4.32  A, The oral lymphoepithelial cyst usually presents as a small, sessile, yellow-­white, submucosal mass of the posterior lateral tongue (arrow). B, The submucosal cyst is filled with sloughed keratin, has a thin epithelial lining of squamous cells, and is adjacent to or surrounded by a benign lymphoid aggregate. C, Another example wherein the cyst is not centrally located in the tonsil tag. D, Higher power of (C).

later in life.343–347 Autosomal dominant inheritance has been reported in some cases.348 Clinical Features. The thyroglossal duct cyst may occur anywhere along the thyroglossal duct itself, with 70% arising in the anterior midline of the neck, below the level of the hyoid bone.344,347 Oral examples are usually found deep in the muscle of the tongue. There is no gender predilection. Normally diagnosed during the first two decades of life, more than a third of cases are not diagnosed until middle age. The typical case is less than 3 cm in diameter at diagnosis, but examples 10 cm in size have been recorded. When the cyst maintains an attachment to the hyoid bone or tongue, it will move vertically during swallowing or protrusion of the tongue.345 The intraoral thyroglossal duct cyst is a sessile, movable, often tender nodule of the posterior dorsum of the tongue. It is usually in a midline location, but 20% are found at a somewhat lateral location. Other possible masses occurring at this site include median rhomboid glossitis, lingual thyroid,

granulomatous infection, and granular cell tumor. It is important to remember that the lingual dorsum is an extremely rare site of carcinoma development outside of specific systemic diseases, such as tertiary syphilis (syphilitic glossitis) and chronic, severe iron deficiency anemia (Plummer-­Vinson syndrome). Deep cysts have normal color, but more superficial ones appear semi-­translucent, filled with a watery or serous fluid. Dorsal surface lesions may produce dysphagia, hoarseness, difficulty in phonation, or mild choking attacks.345 Those that occur in the posterior oral floor or deep tongue tissues may elevate the tongue to the point of causing protrusion of the tongue or difficulty with swallowing. As many as a third of these cysts have a fistulous connection to the oral or dermal surface, allowing repeated infections, and occasional cysts have developed a parathyroid adenoma from parathyroid tissue within their stroma.345–347  Pathologic Features. The thyroglossal duct cyst is lined by stratified squamous epithelium, ciliated columnar epithelium, nonciliated columnar epithelium, an intermediate epithelium,

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A

B

Fig. 4.33  A, The thyroglossal duct cyst may become quite large, with multiple fluid-­filled cystic, interconnected spaces; B, The cyst lining is often ciliated and nests of degenerative thyroid glandular tissue are frequently found in the stroma.

or a combination thereof (Fig. 4.33A and B). There may be an epithelium-­lined fistula to the surface. Mucous glands may be seen in the subepithelial fibrovascular stroma and mucus may be seen in the lumen of the cyst. Aberrant thyroid tissue may also be seen in the stroma, and these must be carefully evaluated for thyroid carcinoma, especially papillary carcinoma, which occasionally occurs in these cysts.349,350 Chronic inflammatory cells are typically scattered throughout the cyst stroma.  Treatment and Prognosis. Thyroglossal duct cyst is treated by wide surgical excision to remove all aberrant thyroid tissue. This may necessitate a rather major surgical procedure (the Sistrunk procedure), in which the lesion is approached through the hyoid bone or the anterior neck.345,351 In this procedure, the entire thyroglossal tract is removed from the neck to the base of the tongue. This requires removal of the midportion of the hyoid bone. Without such a procedure, the recurrence rate is above 50%, with it the rate falls to approximately 5%. Rare cases of thyroid carcinoma have been reported to arise from untreated thyroglossal duct cysts.349,350,355-357   HETEROTOPIC ORAL GASTROINTESTINAL CYST Ectopic or heterotopic gastric mucosa has been found all up and down the gastrointestinal tract, including the esophagus, small intestines, pancreas, gallbladder and Meckel’s diverticulum. The mouth has not been spared, there have been numerous reported cases of heterotopic gastric cyst or heterotopic intestinal cyst of the tongue or oral floor; some prefer to call them foregut duplication cyst.355–359 These cystic choristomas are either embedded deeply in the tongue or present as superficial, movable nodules of the lingual dorsum or oral floor. Some have been found within salivary glands and some have had a communication with the surface. Rarely, such a cyst becomes so large that it causes respiratory distress and eating difficulties.359 Congenital cases have been reported but usually the patient is a young adult by the time the cyst becomes large enough to be noticed.360–362 Pathologic Features. The cyst wall is usually composed of routine gastric mucosa of the type seen in the body and fundus of the stomach. Ciliated columnar epithelium and stratified squamous epithelium may be admixed with the gastric mucosa,

and a muscularis mucosae may be present. Both parietal and chief cells may be found, and pancreatic tissue was noted in one cyst. Occasionally, other tissue types, such as glial tissue or epidermoid cyst, have been seen.363–365  Treatment and Prognosis. The heterotopic gastrointestinal cyst of the mouth is treated by conservative excision. Recurrence has not been reported, nor has malignant transformation. This cyst is not associated with any known syndrome. 

Vascular Lesions Vascular lesions of the oral and pharyngeal soft-tissue constitute a group of lesions that often have poorly understood pathoetiologies, frustrating treatment options, and unpredictable biologic behaviors. For the pathologists, nomenclature is an additional problem. It is not unusual, furthermore, for vasoformative abnormalities to be multiple or diffuse, or to be simply one component of a syndrome with serious manifestations outside the head and neck region (Table 4.5) Some of the vascular lesions are, moreover, clinically obvious but do not present as elevated or submucosal masses. These may not be very demonstrable in a biopsy sample and are better diagnosed using clinical criteria. Lingual varicosities and telangiectasias are examples that are seldom biopsied because experience has taught us that the clinical diagnosis is much more reliable than the histologic identification of collapsed venous channels beneath the oral mucosa. Some vascular lesions may be the result of a more generalized or systemic phenomenon. Spider nevi or submucosal telangiectasias may, for example, result from liver cirrhosis, from pregnancy, or from association with a syndrome (see Table 4.5). VENOUS ANEURYSM The venous aneurysm (traumatic angiomatous lesion, solitary varix, venous pool, venous lake) is a small focal area of superficial venous dilation, similar to a telangiectasia but somewhat larger.366–368 It occurs after trauma and remains indefinitely thereafter. As used in the mouth, this is distinct from a varicosity or veracious vein with its dilation of a linear section of vein,

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TABLE

4.5

Abbreviated Listing of Vascular Oral Lesions Associated With Syndromes or Systemic Disorders

HEMANGIOMAS Beckwith-­Wiedemann syndrome Branchio-­oculo-­facial syndrome Cowden syndrome Epidermal nevus syndrome Fetal alcohol syndrome Hemangiomatosis Hemifacial hyperplasia Klippel-­Trenaunay syndrome Maffucci syndrome Neurofibromatosis Opitz trigonocephaly syndrome Proteus syndrome Roberts syndrome (Roberts-­SC phocomelia) Sturge-­Weber syndrome Thalidomide embryopathy Tuberous sclerosis TELANGIECTASIAS Acrolabial telangiectasias Ataxia-­telangiectasia Bloom syndrome CREST syndrome Dyskeratosis congenita Fabre syndrome Goltz-­Gorlin syndrome Hemifacial hyperplasia Hereditary hemorrhagic telangiectasia I-­cell disease Klippel-­Trenaunay syndrome Rothmund-­Thomson syndrome Turner syndrome Van Lohuizen syndrome Xeroderma pigmentosum VARICES Klinefelter syndrome Klippel-­Trenaunay syndrome Lingual varicosities Maffucci syndrome Traumatic angiomatous lesion (venous pool, venous lake) PETECHIAE Agranulocytosis Fellatio trauma (soft palate) Hemophilia Hypercoagulation state (microinfarction) Infectious mononucleosis (soft palate, gingiva) Lupus erythematosus Measles (soft palate) Upper respiratory infection (soft palate)

but even that entity has occasional focal dilations (clinically called caviar spots). Clinical Features. The varix presents as a single bluish, sessile, soft, discrete, painless nodule that is somewhat movable beneath the epithelium (Fig. 4.34A). It is usually seen after 40 years of age, with no gender predilection, and almost all head and neck cases are located on the lower lip mucosa or vermilion, or on the buccal mucosa. Pressure on the feeder vessel will produce blanching, and the lesion is almost never larger than 6 mm in greatest diameter. If it is tender, there is probably a recently formed thrombus causing local ischemia; if this occurs, the nodule may be quite firm.367 There does not seem to be a risk of thrombotic embolization.

231

The venous aneurysm also differs from varicose veins in location (varicosities are usually on the ventral tongue), in its lack of multiple vessel involvement, and in its nodular rather than serpiginous appearance. It differs from the telangiectasias of hereditary hemorrhagic telangiectasia and similar developmental disorders by the pattern and increased numbers of vascular lesions associated with the latter.369  Pathologic Features. The venous aneurysm is seen as focal area of dilated vein located superficially beneath the surface epithelium, above the striated muscle. The endothelial nuclei are quite inactive and flattened and the vessel lumen is filled with erythrocytes. There may be a slight encirclement by fibrous tissues and there often is an organizing thrombus in the lumina of biopsy samples (Fig. 4.34B). Lesions that are continuously traumatized by the teeth will have chronic inflammatory cells in the background stroma. Occasionally, papillary endothelial hyperplasia has been noted.370  Treatment and Prognosis. No treatment is necessary for this entity because it remains small indefinitely. Occasional lesions may be conservatively excised, however, for esthetic reasons or for reasons of tenderness from recurring trauma or thrombus formation.371  CALIBER-­PERSISTENT ARTERY Miko et al. first described a developmental anomaly referred to by them as persistent caliber artery of the lower lip.372 Also called retained caliber artery and caliber-­persistent artery, the lesion is exactly what the name implies. The inferior alveolar artery retains its large size and thickened walls even after it leaves the bone, through the mental foramen, and travels through the orbicularis oris muscle to supply the mucosal aspects of the lower lip.372–376 The artery becomes superficial toward the midline of the lower lip, and the persistent size makes it palpable, usually a few millimeters inferior to the vermilion border. This is also a phenomenon elsewhere in the body, in particular in the gastric and jejunal mucosa, where it has produced lethal hemorrhage.377 Clinical Features. Of the reported examples of oral persistent caliber artery, more than 80% have been on the lower lip and a few have been on the upper lip and hard palate.375,376 Patients have been 40 to 88 years of age at diagnosis, but lesions are present for months and years prior to diagnosis. The artery typically presents as a sessile, elongated nodule, perhaps serpiginous, that may be pulsatile and is well-­visualized with Doppler ultrasound.378 It can be tender or ulcerated as a result of recurrent trauma or irritation from the anterior teeth, and this has led some to confuse the lesions clinically with ulcerative lip carcinoma.379 Multiple lesions have also been reported. A similar phenomenon, the persistent hypoglossal artery, occurs deep in the ventral tongue, with the vessel not losing diameter or muscle thickness from its branching off of the external carotid artery to the tip of the tongue.380 It is most likely to be visualized via magnetic resonance (MR) angiography. A persistent caliber artery has also been reported from the buccal mucosa.  Pathologic Features and Differential Diagnosis. A large artery with thick smooth muscle walls (Fig. 4.35) is separated from the overlying stratified squamous epithelium by a variable amount of routine fibrovascular connective tissue in this lesion. The “retained caliber” of this artery is obvious and the vessel is typically somewhat parallel to the surface. Sometimes it

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A

B

Fig. 4.34  A, The traumatic angiomatous lesion (venous aneurysm) presents as a blanching sessile bluish bleb, usually of the lip. B, There is focal dilation of a vein with a partially organized thrombus.

a lesion may lead to malignant transformation has not been substantiated by others.379  HEMANGIOMA AND VASCULAR MALFORMATION

Fig. 4.35  The retained caliber artery is normal in every way, except that it is far too large for a vessel close to the midline.

presents as a more focal, rounded dilation rather than a linear one, and sometimes it can be quite tortuous in shape. Excess keratin on the surface and scattered chronic inflammatory cells in the stroma are evidence of chronic trauma. This lesion is easily distinguished from its venous counterpart, the venous aneurysm (traumatic angiomatous lesion, solitary varix, venous pool, venous lake) by the thickness of its muscled walls. It may, at times, be difficult to differentiate caliber-­ persistent artery from arteriovenous malformation (A-­V shunt), but typically the latter entity involves multiple intertwining arterioles rather than a single large artery. The A-­V shunt also has a greater admixture of arteriole and venous vessels. There is no encapsulation of either lesion.  Treatment and Prognosis. No treatment is necessary for caliber-­ persistent labial artery unless it becomes tender or excessively enlarged from recurring trauma. Simple surgical removal of the offending vessel will provide cure, although excessive hemorrhage may be a surgical problem. It has recently been reported that triamcinolone (40 mg/mL), injected twice at low pressure into the lesion, causes deposits of colloidal particles within the lesion, occluding and eliminating it.381 The suggestion by Miko et  al. that chronic ulceration of such

Vasoformative tumors represent 14% to 28% of oral masses submitted for biopsy from the oral region and have prevalence rates of 4/1000 adults and 5/1000 children.2,382,383 First reported in 1842 as bluish excrescence and erectile tissue, such lesions were usually termed hemangioma until the 1990s when differences in pathogenesis, genetics, clinical features, and treatment outcomes led them to be classified into two major subtypes, hemangioma and vascular malformation.384–386 While this section will discuss the features of oral lesions, it should be remembered that such vascular masses may be associated with other anomalies or syndromes (see Table 4.5). The term hemangioma is now reserved for true, benign neoplasms arising from endothelial cell proliferation (Table 4.6); they are most commonly seen in infants and children and are divided into two basic types: infantile hemangioma and congenital hemangioma. 387–391 The infantile type is the most common and is not present at birth but appears within the first few weeks of life.392–395 It exhibits rapid growth, and usually, gradual involution. The congenital type is less common and, by definition, is present and fully developed at birth.389 It may rapidly regress, partially involute or remain stable through life. Vascular malformations (previously cavernous hemangioma) are developmental abnormalities of the blood vessels with normal endothelial cell turnover, that is, no cell proliferation.385–391 They appear at birth, but depending on location, may not be noticeable until later ages. They grow proportionally with the patient and persist throughout life and can be classified by the type of vessels present into: simple (capillary, venous, lymphatic, arteriovenous) or combined (mixture of vessels present).391,392 Many maxillofacial entities of a nonvascular nature have vascular subtypes, such as angioleiomyoma and angiolipoma; these are typically neoplastic rather than vascular malformations. Also the pyogenic granuloma (see earlier in this chapter), which is neither a hemangioma nor developmental anomaly, is

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TABLE

4.6

International Society for the Study of Vascular Anomalies (ISSVA) Classification for Vascular Anomalies, Revised 2018

BENIGN VASCULAR TUMORS Infantile hemangioma/hemangioma of infancy Congenital hemangioma (rapidly involuting, noninvoluting, partially involuting) Tufted angiomaa Epithelioid hemangioma Pyogenic granuloma (lobular capillary hemangioma)b Other and related lesions (at least 12 entities) LOCALLY AGGRESSIVE OR BORDERLINE AGGRESSIVE Kaposiform hemangioendotheliomaa Retiform hemangioendothelioma Papillary intralymphatic angioendothelioma, Dabska tumor Composite hemangioendothelioma Pseudomyogenic hemangioendothelioma Polymorphous hemangioendothelioma Hemangioendothelioma, not otherwise specified Kaposi sarcoma Others MALIGNANT VASCULAR TUMORS Angiosarcoma (postradiation) Epithelioid hemangioendothelioma Others aSome

experts believe that tufted angioma and kaposiform hemangioendothelioma are part of a spectrum rather than distinct entities bReactive proliferative vascular lesions are listed with benign tumors

often referred to as lobulated capillary hemangioma or pyogenic granuloma-­like hemangioma. Occasionally, a paraoral hemangioma is associated with an overlying reactive hyperkeratosis and papillomatosis and is labeled as a verrucous hemangioma.396 The cherry angioma (senile angioma, De Morgan’s spots) so common to the skin of older adults is not seen on the mucosa of the mouth and throat. Clinical Features. The infantile hemangioma is present shortly after birth and undergoes rapid proliferation within the first year, followed by slow involution over the next 5 to 10 years.390–392 It shows a distinct female predilection. Intraoral lesions are relatively uncommon and have been reported from a variety of locations, most often the lips, tongue and buccal mucosa, and have been noted within major salivary glands.390,395 The lesion is usually less than 2 cm in greatest dimension, but may be so extensive as to encompass much of the oral and pharyngeal tissues. Regardless of subtype, the mucosal hemangioma is typically a soft, moderately well circumscribed, painless mass that is red or blue in coloration (Fig. 4.36A). The more superficial ones are often lobulated and will blanch under finger pressure. Deeper lesions tend to be raised or dome-­shaped with normal or blue surface coloration; they seldom blanch. The vascular malformation persists from birth throughout life and varies in clinical appearance depending on the predominant vessel type involved. Similar to the hemangioma, it is most frequently reported in the lips, tongue and buccal mucosa but may occur at a variety of sites.396 Capillary malformations, also called port wine stains, appear as red or purple macules that may darken in color or become nodular over time. Venous malformations present as bluish macules or masses, which are easily compressible (Fig. 4.36B). They may enlarge with increased venous pressure or secondary to thrombosis or phlebolith

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formation. Arteriovenous malformations have direct flow of blood from the arterial to the venous system, bypassing the capillary beds. They present as red or blue macules or masses, often with a thrill or bruit or an obviously warmer surface.  Pathologic Features388. The infantile (capillary) hemangioma is characterized by an unencapsulated proliferation of capillaries in a focal area of submucosal or deeper connective tissues. While lacking a capsule, it is often well circumscribed and there is typically a central feeder vessel with radiating, lobular extensions, or vascular proliferations. Lobular vascular architecture is used to confirm the benign nature of such lesions and may also be seen in epithelioid hemangioma and some pyogenic granulomas (lobular capillary hemangioma). During the proliferative phase, the endothelial cells and pericytes appear plump, may demonstrate mitotic activity and form small and poorly defined lumina. This distinctive appearance has led some to prefer to call this type juvenile or cellular hemangioma. During the involution phase, the dense cellularity is diminished, the endothelial cells appear flatter and the lumina open as the lesion ages (Fig. 4.36C). As involution progresses, the basement membrane around the capillaries thickens and the vessels are slowly replaced by fibrous or fibrofatty tissue. Increased numbers of mast cells are also observed around the remaining capillaries.388 Endothelial proliferation that takes place completely or almost completely within a venous lumen, typically with tufts and papillary projections, may also be seen and is termed papillary endothelial hyperplasia. During all stages of infantile hemangioma, the endothelial cells will stain positive for GLUT-­1, helping to differentiate it from other vascular lesions.387,388 Capillary malformations (port wine stain) consist of dilated capillaries and/or venules with round luminal spaces lined by thin, elongated endothelial cells and peripheral pericytes. In contrast to the infantile hemangioma, the endothelial cells and pericytes do not show evidence of proliferation and mitotic activity. Over time, the vessel walls become thickened and fibrous.388 Venous malformations exhibit superficial or deep aggregates of dilated veins lined by flat, inactive endothelial cells (Fig. 4.36D). Blood flows less swiftly through these structures and the dilated vessels are often filled with erythrocytes. Venous stasis may lead to formation of fresh thrombi, organizing thrombi or calcified thrombi (phleboliths), within the lumina, and recanalizing thrombi may show papillary endothelial hyperplasia. Thrombi and foci of papillary endothelial hyperplasia help to differentiate venous malformation from arteriovenous malformation, which are high flow and high pressure.388 Arteriovenous (AV) malformations exhibit a mixture of small vessels and larger diameter arteries and veins within a fibrous stroma. Clinical and radiographic correlation, as well as negative GLUT-­1 staining, help to differentiate the various vascular malformation from infantile hemangioma.388,393 Additional and more detailed discussion of hemangioma of the head and neck region can be found in Chapter 9 and 11.  Treatment and Prognosis. Infantile hemangioma typically involutes over time and treatment via “watchful waiting” is suggested for innocuous lesions.389–392 For patients with lesions of the face, lips, or airway that can potentially cause disfigurement or impair normal function, and those that show ulceration and hemorrhage, treatment is recommended during the proliferative phase.391 Therapy with the beta blocker propranolol has become the first line of treatment

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Fig. 4.36  Examples of infantile hemangiomas still present in adulthood. A, Capillary hemangioma is often pedunculated and red. B, Cavernous hemangioma is typically sessile, lobulated and bluish. C, Capillary hemangioma is comprised of an unencapsulated aggregation of small capillaries with activated endothelial nuclei. D, Cavernous hemangioma is comprised of large spaces filled with erythrocytes and lined by relatively inactive endothelial cells; inset higher-power view. (Courtesy of Dr. Richard Hart, West Virginia University School of Dentistry.)

for complicated infantile hemangiomas that are potentially life threatening, disfiguring, ulcerative, or those that do not respond to other treatments. Systemic corticosteroids, other systemic therapies, or surgery may be considered if propranolol is contraindicated or ineffective.391,395 Capillary malformations of the skin may be managed with pulsed dye laser therapy.389–390,395 Management of venous malformations depends on size and location. Treatment options include conservative surgical excision, sclerotherapy and laser ablation. Arteriovenous malformations are managed with embolization or preoperative embolization followed by surgery.395 The lack of encapsulation and the infiltrating nature of the lesion often force the surgeon to perform a simple debulking procedure, with remnants of tumor deliberately left behind to preserve the maximum amount of surrounding normal tissues. Recurrence is not unusual unless the tumor is completely excised and may require additional embolization or surgical procedures.  HEMANGIOENDOTHELIOMA A varied group of proliferative and neoplastic vascular lesions, called collectively hemangioendothelioma, seems to have a biologic behavior that falls somewhere between the benign hemangioma and the malignant angiosarcoma.397 Of the six or more variants, most are considered to be of intermediate biologic

behavior, while the most common oral tumor, the epithelioid hemangioendothelioma, is considered a low-­grade malignant neoplasm.398–401 The Kaposiform hemangioendothelioma, also reported as an oral lesion, is characterized by an histopathologic similarity to Kaposi sarcoma, but without expression of herpes virus type 8.402,403 Along with the tufted angioma, it is the only vascular neoplasm sometimes associated with the Kasabach-­ Merritt phenomenon (KMP), a coagulopathy with thrombocytopenia, hypofibrinogenemia and anemia.404 Of the remaining subtypes, only the composite hemangioendothelioma and the pseudomyogenic hemangioendothelioma have been reported as oral lesions.405,406 Clinical Features. Most oral cases of hemangioendothelioma present as soft to moderately soft, asymptomatic, red or blue nodules that may be multiple and are usually quite superficial.398,403 Any oral mucosal site may be involved, and diagnosis is typically made during the second and third decades of life; there is no gender predilection. Approximately 10% of cases are associated with other developmental anomalies or syndromes, including early-­onset varicose veins, lymphedema, Klippel-­Trenaunay-­Weber syndrome, Kasabach-­Merritt syndrome, and Maffucci syndrome.397  Pathologic Features and Differential Diagnosis. The hemangioendothelioma is a poorly circumscribed, usually biphasic proliferation of venous or capillary vessels. There are dilated

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and congested veins with inactive endothelial cell nuclei and with occasional thrombi or phleboliths. These vessels are intermixed with solid sheets of epithelioid (epithelioid hemangioendothelioma) or spindle-­shaped (spindle cell hemangioendothelioma) mesenchymal cells with minimal dysplasia, few mitotic figures, and minimal differentiation toward a vascular lumen or channel. In the Kaposiform variant, slit-­like vascular channels, similar to those of Kaposi sarcoma, are seen, perhaps with mild extravasation of erythrocytes and hemosiderin deposition within or outside of macrophages.402,403 It also exhibits a histopathologic admixture of tissues similar to both capillary hemangioma and Kaposi sarcoma, as well as glomeruloid nests of tumor cells and a variable lymphatic component. More detailed discussion of this entity can be found in Chapter 9.  Treatment and Prognosis. Hemangioendothelioma is treated with wide surgical excision, with more than half of all cases recurring at the operative site or several centimeters distant.397,400 Those tumors with significant cellular atypia and mitotic activity are associated with more aggressive clinical behavior, but not all tumors that metastasize have these changes at initial biopsy. Almost a third of epithelioid hemangioendotheliomas develop metastases in regional lymph nodes (at least 50% or more of all metastatic cases) or in the lungs, liver, or bones.400,401 Patients who develop metastases have a 50% 5-­year survival rate. The spindle cell hemangioendothelioma is rarely associated with metastasis but has a higher rate of local recurrence than does the epithelioid variant of this tumor (60% vs. 13%, respectively).397 

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demonstrate positive immunoreactivity for nuclear STAT6; this is highly specific for SFT.412,413 Clinical Features. The oral SFT is typically a rapidly enlarging red or bluish mass that arises in all age groups but is rare before the second decade or after the seventh decade. There is no gender predilection. It is soft or rubbery, is usually painless, and is relatively well demarcated from the surrounding mucosa. The lesion may be sessile or somewhat pedunculated, and may demonstrate a surface lobularity or telangiectasis. Intraosseous examples have been reported. In addition, the oral/pharyngeal mucosa is, as previously mentioned, one of the most common locations for this rarely reported infantile hemangiopericytoma.414 This lesion is usually multiple and congenital and often demonstrates an alarmingly rapid rate of enlargement after birth. Although this entity tends to recur after surgical excision, there is no potential for metastasis.  Pathologic Features and Differential Diagnosis. SFT has a variable histopathology, with different features seen in different parts of the tumor. The more fibrous form is characterized by tightly packed spindled cells immediately surrounding hyalinized, thick-­ walled vessels with opened lumina (Fig. 4.37A and B) and strong CD34 reactivity; bcl-­

SOLITARY FIBROUS TUMOR (HEMANGIOPERICYTOMA) Originally described in the pleura by Wagner in 1870, this neoplasm was thought to arise from pleural mesenchymal cells, but in 1942, Stout and Murray suggested that lesional cells were actually pericytes, and they proposed calling it hemangiopericytoma, stating that it was a distinctly different vascular neoplasm.407 Long known under this terminology, the 2013 WHO Classification of Bone and Soft Tissue Tumors, suggested that the pericytic designation was far too limiting, considering this lesion to be of fibroblastic/myofibroblastic origin.408 Today, most such soft-tissue lesions are called solitary fibrous tumor (SFT) and the hemangiopericytoma diagnosis is reserved for a small subcategory of certain central neural lesions (meningeal hemangiopericytoma), a sinonasal mass called sinonasal-­type hemangiopericytoma (glomangiopericytoma, myopericytoma), a very rare oral lesion, infantile hemangiopericytoma, currently considered a perivascular myoid neoplasm, perhaps a myopericytoma, and capable of a remarkable rate of enlargement.408,409 A pericyte origin is more solidly founded in these entities. The SFT is a neoplasm that usually behaves benignly but has a definite malignant counterpart, representing 11% to 20% of the total, capable of eventual metastasis.409–411 Head and neck lesions represent 16% to 25% of all reported cases, and SFT represents 2% to 3% of all soft-tissue sarcomas in humans.410–412 Some examples of SFTs have been identified in persons with hypoglycemia, although the significance of this remains unclear. Also chromosomal translocations t(12;19) and t(13;22) have been observed in lesional cells.411,412 These aid in forming the NGFI-­A binding protein 2 (NAB2)/STAT6 fusion gene and it has been shown that SFT lesional cells almost universally

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B Fig. 4.37  A, Solitary fibrous tumor has a variable histopathology, but is characterized by tightly packed spindled cells, immediately surrounding hyalinized, thick-­walled vessels with opened lumina. B, The fibrous variant has far fewer perivascular cells and hyalinization.

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2 is also reactive in almost all cases.409–411 The other end of the spectrum is a very cellular form (more similar to the old hemangiopericytoma) with branching, thin-­ walled vessels and only focal or absent CD34 reactivity. The latter still shows a medullary tissue pattern, sometimes with palisading of cells, reminiscent of a neural tumor. The cells are haphazardly arranged and demonstrate round to ovoid nuclei and indistinct cytoplasmic borders. The blood vessels often show irregular branching, which results in a characteristic “staghorn” and “antlerlike” appearance. Older, less aggressive lesions tend to have less cellularity and may have a largely mucoid interstitial appearance, which can be mistaken for myxoid lipoma or myxoid liposarcoma; this issue is made more confusing by the rare occurrence at SFT variant called lipomatous hemangiopericytoma, which has lipid-­containing cells admixed with fibrous and vascular entities.415 Focal cartilage production may rarely be seen, and such lesions must be differentiated from mesenchymal chondrosarcoma. Criteria for malignancy in SFT include more than four mitotic figures per 10 high-power fields, dysplastic lesional stromal cells with hyperplasia, both cellular and nuclear pleomorphism, and nuclear hyperchromatism. Focal necrosis, large tumor size, and a very high degree of cellularity are also considered to be signs of a more aggressive lesion. These features have been stratified into a risk assessment scheme for metastasis; see Chapter 9 for more details.  Treatment and Prognosis. The treatment of SFT is dependent on the amount of cellular dysplasia and mitotic activity. The more bland lesions with minimal mitotic activity are treated by wide local excision, but the more active and dysplastic lesions are treated by radical surgical excision, with or without adjunctive radiotherapy.410 Surgical removal is usually preceded by ligation of the feeder vessels or by embolization to reduce the size of the tumor and the risk of operative hemorrhage. A multiinstitutional study of H&N tumors in this location have a higher risk of local recurrence (36%) compared to SFT of other anatomic sites. Large tumor size (>5 cm) and high mitotic index (>4/10 high-power fields) are risk factors for recurrence.409 The rate of metastasis for this tumor during the first 5-­year postoperative period varies from 17% to 56%, and metastasis occasionally occurs up to 10 years after surgery.411 Metastases are usually to the lungs and bones; lymph node metastasis is uncommon. Most recurrent tumors will eventually demonstrate metastasis. The overall 5-­year ­survival rate for the microscopically high-­grade SFT is somewhat less than 50%.  ANGIOSARCOMA The term angiosarcoma, previously hemangiosarcoma or lymphangiosarcoma, is still used to designate the vascular neoplasm with a definitively aggressive, malignant clinical course and a histopathologic appearance that is more atypical than the lower-­ grade lesion called hemangioendothelioma. It is a decidedly rare entity, representing less than 1% of all sarcomas in humans, and there is often little or no microscopic evidence for the vessels of origin, that is, blood or lymphatic vessels.416–422 More than half of all cases are found in the head and neck region, and in this area, the scalp and facial skin are the most commonly affected sites; about 8% of head and neck lesions arise from oral cavity sites.419,421 Trauma, long-­ standing

lymphedema, and irradiation of benign vascular lesions appear to be contributory factors in the onset of some cases, but most cases present with no obvious etiology. Clinical Features. Angiosarcoma of the oral region is a disease of older individuals, averaging more than 65 years of age. There is no gender predilection, and the tumor is typically a solitary or multifocal submucosal nodule that may be bosselated, may be ulcerated, and may bleed spontaneously. The clinical appearance may be vascular enough so as to be clinically indistinguishable from pyogenic granuloma. The lesion is rather painless, firm and fixed to surrounding soft tissues, and adjacent bony structures; margins are difficult to define. Those attached to or adjacent to bone typically cause destruction of the cortex and underlying cancellous bone. Some tumors grow rapidly, whereas others take many months to reach a size of 4 to 5 cm. Occasional lesions will be deceptively small at clinical examination, only to reveal deep and widespread submucosal extension at surgery.  Pathologic Features and Differential Diagnosis. The histopathologic appearance of this neoplasm varies greatly, depending on the degree of cellular differentiation. The well-­ differentiated lesions may be quite similar to SFT, with distinct, endothelium-­lined vascular channels, with relatively flattened endothelial nuclei and surrounding densely packed spindled or polygonal stromal cells. There is, however, a tendency for the channels in angiosarcoma to anastomose with one another and to produce dilated sinusoids. Moreover, endothelial cells are typically hyperplastic and hyperchromatic, and background hemorrhage may be remarkable. The sarcoma has a strongly infiltrative, dissecting pattern at its interface with the normal surrounding tissues. Tumor cells typically show reactivity to vascular endothelial markers, such a CD31, CD34, and factor VIII-­related antigen.418,421,423 This can help to differentiate it from the occasional case of acantholytic squamous cell carcinoma, called by some pseudovascular adenoid squamous carcinoma, with a very strong associated vascularity and concurrent aggressiveness.424,425 A more detailed description of this entity can be found in Chapter 2.  Treatment and Prognosis. Angiosarcoma of the oral region is treated by wide local excision, although radiotherapy is sometimes used for large or multifocal lesions. It is not unusual for tumor cells to be found more than a centimeter beyond the grossly evident lesional periphery. Positive necks are treated by radical neck dissection. The prognosis is very much dependent on two features: the degree of cellular differentiation and the clinical size of the tumor. The overall survival is poor, approximately 10% to 15% after 5 years, with most recurrences and metastases occurring within 2 years of treatment.426 In some series, no patients survived who had lesions with diameters greater than 5 cm.421  KAPOSI’S SARCOMA Kaposi’s sarcoma (KS) is a multicentric proliferation of vascular and spindle cell components, which was first described in 1872.427 Now considered to be a human herpesvirus (HHV) 8 viral-­induced or viral-­associated tumor, it is unclear whether the lesion is a true neoplasm or a simple hyperplasia.428–430 Today, it is strongly affiliated with AIDS and its course is greatly influenced by the immune status of the affected individual. Although

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found predominantly in persons infected with HIV, the virus does not seem to be the direct cause of the tumorous proliferation and HIV amino acid sequences have not been identified within lesional cells.431 KS represents about 20% of all head and neck sarcomas.432 These cells produce several cytokines capable of stimulating their own growth, and HIV-­infected lymphocytes are also capable of producing their own set of similar cytokines. This may influence secondary Candida and other infections, and therefore alter the clinical and microscopic picture of KS. Langerhans cells are also protective in this regard: their numbers are considerably diminished in lesions with a superimposed candidiasis.433 Clinical Features. Kaposi sarcoma has four major clinical presentations: classic (chronic) KS, endemic (lymphadenopathic; African) KS, immunosuppression-­associated (transplant) KS, and AIDS-­related KS.428,431 The classic variant affects older males of Italian, Slavic, or Jewish ancestry and is rare in the United States. It is often associated with altered immune states, as well as lymphoreticular and other malignancies, where it has no association with HIV infection. Cutaneous multifocal blue-­red nodules develop on the lower extremities and slowly increase in size and numbers, with some lesions regressing, while new ones are forming on adjacent or distant skin. Oral involvement in this form of the disease is quite unusual, but when it occurs, it does so as soft, bluish nodules of the palatal mucosa or gingiva.430,434 Lymphadenopathic KS is endemic to young African children and presents as a localized or generalized enlargement of lymph node chains, including the cervical nodes.431 The disease follows a fulminating course, with visceral involvement and minimal skin or mucous membrane involvement. In the head and neck region, salivary glands may be affected. This variant does not appear to be HIV related. Transplantation-­associated KS is seen in 1% to 4% of renal transplant patients, usually becoming manifest 1 to 2 years after transplantation and apparently related to the immunosuppressants used for this procedure.434 The extent and progression of the disease correlate directly with the loss of cellular immunity of the host. Sarcomatous involvement occurs on the skin, as well as internal organs, but oral mucosal lesions are decidedly rare. Since KS is sometimes associated with immunosuppression for autoimmune disorders, such as pemphigus vulgaris, some prefer to call this type iatrogenic KS.435 In the United States, AIDS-­related KS is found primarily in male homosexuals, but in Africa, heterosexual transmission and needle-­stick contamination seem to be much more strongly associated. Prior to the advent of effective therapies, approximately 40% of homosexual AIDS patients would develop KS, often as an early sign of the disease.434 Affected patients in the United States are usually young adults or early middle-­aged males, with the average age at sarcomatous diagnosis being 39 years. Individual lesions occur in many cutaneous locations, especially along lines of cleavage and on the tip of the nose. Oral lesions are seen in half of AIDS patients at the time of diagnosis.434 They can also occur on any mucosal surface but have a strong predilection for palatal, gingival, and lingual mucosa. KS is the initial sign of HIV disease in up to one-­fourth of all diagnosed AIDS patients, but is becomes decided uncommon

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once current therapies are instituted.436 Early oral mucosal KS is flat and slightly blue, red, or purple. With time, the lesion becomes more deeply discolored and surface papules and soft nodules develop, usually remaining less than 2 cm in size (Fig. 4.38A). If the lesion overlies bone, it may invade and/or necrose the bone, and occasional lesion are so hemorrhagic or so painful that local treatment becomes a necessity. Individual lesions may coalesce and occasional patients never develop the nodular variant. Cervical lymph nodes and salivary gland enlargement may also be seen. The patient may have oral candidiasis and AIDS-­related gingivitis as well.  Pathologic Features and Differential Diagnosis. KS progressively evolves from patch to plaque to nodular stages, but there is a similar histopathologic appearance in all of these clinical subtypes.434,437 The early lesion (patch stage) presents as a macule and is characterized by a proliferation of small veins and capillaries around one or more dilated vessels. A pronounced mononuclear inflammatory cell infiltrate, including mast cells, is often noted, as are scattered erythrocytes and hemosiderin deposits. There may be an inconspicuous perivascular proliferation of spindle cells, but cellular atypia is minimal. In more established plaque lesions, the vascular proliferation involves the submucosa almost completely with a bland spindle cell proliferation limited to areas around proliferating vessels, resulting in a slightly elevated skin lesion. More advanced lesions are nodular and show increased numbers of small capillaries or dilated vascular channels, interspersed with proliferating sheets of sarcomatous or atypical spindle cells, often with large numbers of extravasated erythrocytes and abundant hemosiderin deposition (Fig. 4.38B–D). Slit-­like vascular channels without a visible endothelial lining are typically interspersed with the spindle cells. Lesional cells have enlarged, hyperchromatic nuclei with mild to moderate pleomorphism. Mitotic activity is quite variable but is usually minimal. Infiltration by chronic inflammatory cells is also variable. Occasional lesions show such exuberance of the spindled component that the vascular features become minimally visible. Rarely, the vascular component dominates with anastomosing channels lined by anaplastic endothelial cells, similar in appearance to angiosarcoma. The tumor cells of KS will stain with vascular endothelial cell markers, but positive reactivity to HHV-­8 (LNA-­1) is the most helpful in differentiating KS from other vascular lesions.438 Prox-­1, a nuclear transcription factor playing a major role in lymphangiogenesis, is considered a specific and sensitive lymphatic endothelial cell marker.439,440 Virtually all KS lesions are positive for this, while all other vascular proliferations are negative, hence this can be used to distinguish KS from other similar lesions. Additional information relative to the histopathology of this entity is provided in more detail in Chapter 9.  Treatment and Prognosis. Various treatments have been used with oral KS with variable success. Small or localized lesions can be surgically excised with a small surrounding margin of clinically normal tissue, but more recent therapies have concentrated on low-­dose irradiation and intralesional chemotherapy and sclerosing solutions.432,441,442 For larger and multifocal lesions, systemic chemotherapy is often effective. KS responds to vinblastine, vincristine, etoposide, bleomycin, Adriamycin, actinomycin D, doxorubicin, and alpha-­interferon.442 

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Fig. 4.38  A, Oral Kaposi sarcoma often presents as somewhat flattened, reddish-­purple nodules, sometimes ulcerated, as seen here. B, Vascular channels are lined by atypical endothelial cells and the background stroma shows erythrocyte extravasation with pleomorphic spindled and rounded lesional cells. C and D, Higher-power views of (B). (A, Courtesy of Dr. Peter Reich, West Virginia University School of Medicine.)

LYMPHANGIOMA (LYMPHATIC MALFORMATION) Virchow first described the lymphangioma (lymphatic malformation) in 1854 as a benign hamartomatous hyperplasia of lymphatic vessels, although the first oral lesion, referred to as chronic clustered vesicles, was probably reported in 1850, without microscopic description.443,444 Three-­fourths of all cases occur in the head and neck region.441–446 The International Society for the Study of Vascular Anomalies (ISSVA) classification categorizes this entity according to its associated vessels: (1) capillary lymphatic malformation, (2) lymphatic venous malformation, (3) capillary lymphatic arteriovenous malformation, and (4) capillary lymphatic venous malformation.386 Although occasional adult-­onset cases occur, more than 90% are diagnosed within the first 2 years of life and so this tumor is thought to be a developmental malformation of vessels that have poor communication with the normal lymph system.445–449 Very large cystic spaces may be seen in lesions proliferating in loose connective tissues and fascial spaces. Diagnosed cases are typically superficial but may extend deeply into underlying connective tissues. Rarely, multiple lesions are seen in infancy and childhood in lymphangiomatosis, the lymphatic counterpart to angiomatosis of blood vessels and a potentially life-­threatening disease when visceral involvement occurs.450

Clinical Features. Oral mucosal lymphatic malformations almost always become apparent before the second year of life; half of all cases are congenital.447 There is no gender predilection. Oral lesions are most frequently found on the tongue, where they may produce considerable macroglossia and dysfunction. Any oral or pharyngeal site may, however, be affected and the most common head and neck location is the lateral neck, where this lesion typically contains large cystic spaces and is commonly called cystic lymphangioma or cystic hygroma, discussed in more detail in Chapter 11.446 The cervical lymphangioma occurs most frequently in the posterior triangle, but lesions of the anterior triangle tend to be more problematic, interfering with the patient’s ability to breathe or swallow and extending upward into the oral cavity, or downward into the mediastinum. Torticollis or wry neck may develop from cervical involvement and cervical lesions tend to be much larger than oral or pharyngeal lesions, sometimes larger than the patient’s head at birth. Superficial oral mucosal lymphangioma often demonstrates a pebbled or botryoid appearance, once referred to as chronic “clustered blisters” because of the translucent appearance of the lymphatic channels, which may have only sparse fibrovascular tissue separating their endothelial walls from the surface epithelium (Fig. 4.39A). Secondary hemorrhage into the lymphatic vessels may cause some of the surface “vesicles” to appear red or

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Fig. 4.39  A, The lymphangioma often presents as a cluster of “bubbles.” B, Each surface bleb is comprised of one or more dilated lymphatic vessels with few, if any, erythrocytes in the lumen. C, Deeper involvement shows a mix of dilated and less dilated lesional vessels. D, Endothelial walls are inactive.

blue. Satellite lesions, several millimeters from the main lesional mass, may be seen. Occasional lesions show only widely scattered clear “vesicles” interspersed with blood-­ filled papules or blebs. These capillary lymphatic venous malformations, previously referred to as hemangiolymphangioma, may be associated with occasional hemorrhagic episodes from trauma.451 A unique congenital alveolar lymphangioma is seen on the alveolar mucosa of African-­American neonates.447 This lesion is seldom greater than a centimeter in size and is often bilateral on the alveolar ridge. The mandible is more often affected than the maxilla and the lesion typically disappears during the months after birth. Deeper lymphangiomas present with an irregular surface nodularity and are quite soft and painless. They may feel like a “ball of worms” on palpation, but are usually rather nonspecific and ill-­defined.  Pathologic Features and Differential Diagnosis. The lymphangioma consists of multiple, intertwining lymph vessels in a loose fibrovascular stroma, sometimes with scattered aggregates of lymphoid tissue. The lymphatic vessels are lined by a single layer of endothelial cells with flattened, occasionally plump nuclei (Fig. 4.39B–D), and delicate valves extending into the lumen. The vessels may have the diameter of capillaries, with a much-­attenuated lumen, or may be so dilated that the cystic areas can be visualized at surgery. Oral examples are more likely to contain the dilated vessels. When other types of

arterial and venous vessels are interspersed, the more specific diagnoses of capillary lymphatic malformation, lymphatic venous malformation, capillary lymphatic arteriovenous malformation, and capillary lymphatic venous malformation are used.  Treatment and Prognosis. Because of the nonencapsulated and “infiltrating” nature of the oral lymphangioma, complete removal is often inadvisable and may be impossible without excessive removal of surrounding normal structures. Surgical debulking of the tumor is therefore the typical treatment provided, with the understanding that additional debulking procedures will most likely be required as the affected child grows.447 Most patients will need two to four procedures before full growth and development have been achieved.388,391 Recurrence is possible but unlikely for those lesions able to be removed completely via excisional surgery. Recently, radiofrequency and laser ablation have shown promise.451–453 Radiotherapy and chemical cauteries are much less effective with the lymphangioma than they are with the hemangioma. 

Tumors of Fatty Tissue Tumors of fatty tissue are seldom encountered in biopsied oral and pharyngeal soft tissues. When this does occur, the lesion is almost always benign and will represent a traumatic herniation of submucosal adipose tissue, a developmental anomaly, or

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Fig. 4.40  A, Herniated buccal fat pad shows exposed fatty tissue shortly after acute trauma of the buccal mucosa. B, The fat pad is typically surrounded by dense fibrous stroma but it is not encapsulated. C, Higher power of (B). D, Occasionally, the fat pads are comprised of multiple lobules of fatty cells.

a true neoplasm. The frequency of these lesions in the adult or childhood populations is unknown. HERNIATED BUCCAL FAT PAD Many adults have a rather thick, diffuse layer of fatty tissue, the buccal fat pad (buccal sucking pad), between the submucosal fibrovascular stroma and the underlying masseter muscle of the buccal region, or between the masseter and buccinator muscles. This bilateral condition is common in infants and is occasionally seen in adults, especially in obese persons and persons with rounded faces. Acute trauma from biting the buccal tissues may rupture this fatty tissue, allowing a portion of it to herniate as a sessile or pedunculated submucosal mass that may be several centimeters across (Fig. 4.40A).454–458 Once this occurs, the herniated buccal fat pad does not further increase in size but seems not to revert to normal. It usually must be surgically excised to prevent further injury of the resultant exophytic mass. The histopathology is that of normal, mature adipose tissue interspersed with a variable number of fibrous bands or trabeculae (Fig. 4.40B–D), although focal areas of trauma-­induced necrosis may be seen.459 

LIPOMA The lipoma is a very common benign tumor of adipose tissue, but its presence in the oral and oropharyngeal region is relatively uncommon. The first description of an oral lesion, referred to as a yellow epulis, was provided in 1848 by Roux in a review of alveolar masses.460 Although most lesions are developmental anomalies, those that occur in the maxillofacial region usually arise late in life and are presumed to be neoplasms of adipocytes, occasionally associated with a traumatic etiology.459–463 Multiple head and neck lipomas have been observed in neurofibromatosis, Gardner syndrome, orofacial digital syndrome, encephalocraniocutaneous lipomatosis, multiple familial lipomatosis, and Proteus syndrome. Generalized lipomatosis has been reported to contribute to unilateral facial enlargement in hemifacial hypertrophy.464 Clinical Features. The oral lipoma is a slowly enlarging, soft, smooth-­surfaced mass of the submucosal tissues (Fig. 4.41A).459–463 When superficial, there is a yellow surface discoloration. When well-­ encapsulated tumors are freely movable beneath the mucosa, but less well-­demarcated lesions

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B

A

C Fig. 4.41  A, The lipoma presents as a smooth-­surfaced, soft, sessile mass with yellow/white discoloration (inset: cut surface). B, Mature adipocytes are admixed with fibrous streaks and surrounded by a pseudocapsule of compressed fibrous stroma. C, Higher-power views of adipocytes showing empty spaces, surrounded by adipocyte cell walls because the fat is removed during laboratory processing.

are not movable. The lesion may be pedunculated or sessile and occasional cases show surface bosselation. The tumor has a less dense and more uniform appearance than surrounding fibrovascular tissues when it is transilluminated. MRI scans are very useful in the clinical diagnosis; CT scans and ultrasonography are less reliable. Few oral or pharyngeal lesions occur before the third decade of life and there is no gender predilection.461 Once present, a mucosal oral lipoma may increase to 5 to 6 cm over a period of years, but most cases are less than 3 cm in greatest dimension at diagnosis. Rarely, a lipoma will occur within maxillary bones or sinuses, but usually this entity is found in the buccal, lingual, or oral floor regions.  Pathologic Features and Differential Diagnosis. As with all fatty tissue, a lipoma will float on the surface of formalin rather than sink to the bottom of a biopsy specimen jar. The lipoma is composed predominantly of mature adipocytes, possibly admixed with collagenic streaks, and is often well demarcated from the surrounding connective tissues (Fig. 4.41B and C). A thin fibrous capsule may be seen, and a distinct lobular pattern can be present. Quite often, however, lesional fat cells are seen to “infiltrate” into surrounding tissues, producing long, thin extensions of fatty tissue radiating from the central tumor mass. Occasional lipomas contain glandular structures (adenolipoma), cartilage, or bone.465–467 When located within

striated muscle, the infiltrating variant of lipoma is called intramuscular lipoma (infiltrating lipoma), but extensive involvement of a wide area of fibrovascular or stromal tissues might best be termed lipomatosis.468 On occasion, lipoma of the buccal mucosa cannot be distinguished from a herniated buccal fat pad, except by the lack of a history of sudden onset after trauma. In addition, atypical fat cells suggest alternative diagnoses, such as lipoblastoma, hibernoma, or liposarcoma. Otherwise, lipoma of the oral and pharyngeal region is not difficult to differentiate from other lesions. More detailed discussion of this entity can be found in Chapter 9.  Treatment and Prognosis. Conservative surgical removal is the treatment of choice for oral lipoma, with occasional recurrences expected. An infiltrating lipoma often must be simply debulked, a portion of the infiltrating fat being deliberately allowed to remain to preserve as much normal tissue as possible.  LIPOSARCOMA Liposarcoma, first described by Virchow in 1857, is the second most common of all sarcomas, represent 17% to 30% of them, although only 3% occur in the head and neck region.469–474 Oral involvement is decidedly rare and, when present, it is usually the intermediate-­grade subtype called atypical lipomatous

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tumor/well-­ differentiated liposarcoma (ALT/WDL).475 This rather awkward name emphasizes its history as a single lesion once thought to be two distinctly separate tumors, each with a different diagnostic name. Such tumors tend not to metastasize unless dedifferentiation occurs in some of its component cells. No well-­established causative factor has been identified, although trauma has been implicated. Development from a preexisting benign lipoma is very rare and most cases arise de novo. Clinical Features. Oral liposarcoma can develop at any age but most cases occur in middle-­aged individuals, with an average age of 57 years.472 The tumor has a slight male predilection, but the number of reported cases is small and this may reflect a case-­selection bias. The typical example is a slowly enlarging, painless, deep, moderately soft mass, without surface ulceration or hemorrhage. Occasional cases grow with alarming rapidity, however, and these tend to metastasize very early as well. Any oral site may be affected, but the most commonly involved sites are the tongue and buccal mucosa.475 Transillumination may show an area of decreased density, but magnetic resonance imaging is the best imaging method for identifying and outlining the lesion. The fatty tissue of liposarcoma gives a bright signal on T1-­weighted MRI scans, with progressively decreasing signal on T2-­weighted images.473 Fat-­ suppression images show signal dropout within the neoplastic mass.  Pathologic Features and Differential Diagnosis. The liposarcoma demonstrates considerable microscopic variability, resulting in a variety of diagnostic names: (1) ALT/WDL, (2) myxoid/small cell liposarcoma, (3) pleomorphic liposarcoma, and (4) dedifferentiated liposarcoma.471,472 The ALT/WDL is often so mature in appearance and so innocuous in its clinical behavior that the previous use of the term atypical lipoma seems justified.475 The oral lesion, like lesions found elsewhere, is composed of broad sheets and streaks of adipocytes admixed with occasional lipoblasts, separated by fibrous septa, containing spindle cells with hyperchromatic and mildly pleomorphic nuclei. Signet-­ring cells are usually present and are important to the diagnosis; multivacuolar lipoblasts may be seen as well. Focal necrosis and occasional mitotic activity may also be observed. Rare lesions are extremely primitive in appearance or may show sarcomatous change of other cell types; these are often referred to as dedifferentiated liposarcoma.472,476,477 The myxoid/small cell liposarcoma is comprised of abundant lipoblasts within a myxoid stroma which, in turn, has a rich capillary network.471,478 The lesional cells are typically small and rounded, with enlarged, pleomorphic nuclei, leading to an initial impression of a nonfatty sarcoma. These cells form lobules with increased cellularity at the periphery. The round cell liposarcoma is a more aggressive form of myxoid liposarcoma with less differentiated, rounded cells. This terminology is losing popularity in favor of high-­grade myxoid liposarcoma. Pleomorphic liposarcomas exhibit extreme cellular pleomorphism and bizarre giant cells. Dedifferentiated liposarcomas are characterized by an intermixing of well-­differentiated liposarcoma with poorly differentiated, nonlipogenic sarcomatous changes. These features may coexist in the same neoplasm, or the dedifferentiated changes may develop in a recurrent tumor or metastasis. More detailed discussion of the histopathology of this entity can be found in Chapter 9. 

Treatment and Prognosis. Liposarcoma of the oral region is typically treated by wide local excision. Radiotherapy may be used to control local recurrence and lessen the risk of metastasis. Five-­year survival rates are similar to those of other anatomic sites and are very much dependent on lesional size and the histopathologic grade and subtype. Patients with well-­differentiated lesions have an 85% to 100% 5-­year survival, whereas those with myxoid liposarcoma have a somewhat lesser survival rate (75%), and those with round cell (high-­grade) and pleomorphic liposarcoma have a survival rate of only 20%.472,473 Individuals with dedifferentiated liposarcoma have a 30% 5-­year survival rate.477 

Neural Tumors A variety of reactive proliferations and benign neoplasms of peripheral nerves may be seen within oral soft tissues, although they represent less than one of every 500 biopsy samples submitted to oral pathology biopsy services. Except for the traumatic neuroma, these neural tumors are paradoxically painless and nontender and seldom present serious clinical problems. Many of the head and neck examples, however, are associated with syndromes having very serious consequences, such as neurofibromatosis and multiple mucosal neuroma (multiple endocrine neoplasia 2B) syndrome. Two associated lesions, the glial choristoma and juxtaoral organ of Chievitz, are discussed separately in this chapter’s section on developmental anomalies. TRAUMATIC NEUROMA The traumatic neuroma (amputation neuroma), representing almost half of all neural masses presenting to oral pathology biopsy services, is a reactive proliferation of nerve fibers that occurs as a result of poor healing after damage to a peripheral nerve.479–481 The proximal portion of a severed nerve regenerates and attempts to reestablish its normal distribution by sending axons toward the distal, degenerating segment. When granulation or scar tissue interferes with this process, the regenerating fibers turn back on themselves and proliferate randomly to produce a mass, somewhat akin to a “ball of worms.” A similar phenomenon in an area of simple myelin destruction may produce a very small nerve tuft along the side of an axon. Tumor necrosis factor-α (TNF-α), interleukin (IL)-­1β and IL-­6 levels are significantly elevated in such lesions and possibly play a role in their creation.482–484 Conversely, IL-­10 may inhibit neuroma formation. Because many of the new nerve fibers lack myelin sheathing, abnormal pain signals may be generated when mild physical pressure on the neuroma forces several adjacent nerve fibers into contact (cross-­ talk).485 Other abnormal sensations can be produced, such that a patient may feel the presence of an amputated limb (phantom limb) or spontaneous pain (phantom pain). Within the bone, a traumatic neuroma may produce a toothache-­like pain (phantom toothache), even when no teeth are present. Clinical Features. The traumatic neuroma of mucosal surfaces tends to be a smooth-­surfaced submucosal nodule (Fig. 4.42A), usually in the mental foramen area but occasionally on the lateral tongue or lower lip.479,480 It typically remains less than 6 mm in diameter but occasional diffuse lesions may be several centimeters across.486 The lesion can occur at any age

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Fig. 4.42  A, The traumatic neuroma is typically a well-­circumscribed submucosal nodule. B, Occasionally the feeder nerve is seen in the deeper portions of the biopsy. C, The lesion is a relatively disorganized aggregate of normal appearing (perhaps degenerated) small nerves, entrapped within dense fibrous tissue. D, Individual nerve fibers often lack an identifiable myelin sheath.

but is most common in middle-­aged adults and is slightly more common in females than in males. It can occur within the jawbones after tooth extraction or other surgery, presenting as a well-­demarcated radiolucency if radiographically visible at all. At least two-­thirds of traumatic neuromas of the mouth are nonpainful, but when pain is present, it may occur as a mild tenderness, a constant or intermittent aching, a burning sensation, or a severe radiating pain. The neuroma of the mental foramen area in an edentulous individual may be chronically painful because of constant irritation from overlying dentures.  Pathologic Features. The traumatic neuroma consists of a moderately loose fibrovascular stroma admixed with numerous intertwining or haphazardly arranged nerve fibers (Fig. 4.42B–D). The nerves themselves are normal, except for their tortuous and exuberant proliferation and the frequent appearance of immaturity or “regeneration.” Luxol fast blue stain will show some fibers to be myelinated, while others are not. Occasional lesions have contained normal glial cells and others have shown neural proliferation, extending into the overlying squamous epithelium. Chronic inflammatory cells may be seen in small to moderate numbers in the stroma.487,488 There is seldom an attempt toward encapsulation of this tumor, and tumor growth is rather asymmetrical. With maturation, perineuria form around the proliferated axons and the background stroma may become quite densely fibrotic. Early lesions may demonstrate Wallerian degeneration of

recently severed nerve stumps incorporated into the proliferative mass.  Treatment and Prognosis. Traumatic neuroma is best treated by conservative surgical removal, but lesions associated with larger nerves may require selective microsurgical removal of the irregular neural mass, with preservation of the nerve itself. The lesion occasionally recurs.  MUCOSAL NEUROMA The mucosal neuroma is found almost exclusively in the MEN 2B (MEN 3) syndrome.489–492 Since all persons with the syndrome have these oral nodules, another name for the disorder is multiple mucosal neuroma syndrome, initially described by Wagenmann in 1922.493 Like all multiple mucosal neoplasia syndromes, this one, MEN 2B, is characterized by tumors of neuroendocrine origin, especially adrenal pheochromocytoma, medullary carcinoma of the thyroid and diffuse intestinal ganglioneuromatosis. Occasional patients will demonstrate only the oral neuromas, with no apparent syndromic association; this entity has been called multiple idiopathic mucosal neuromas.494 The disease is caused by germline mutations in the RET protooncogene and is transmitted as an autosomal dominant trait, with many cases appearing as spontaneous mutations.495–497 A small number of persons with such spontaneous mutations present with the typical features of MEN

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A

B

C Fig. 4.43  A, Mucosal neuromas are typically multiple, small, yellow-­white nodules of the anterior tongue. B, Tortuous nerves are often aggregated and separated from a dense fibrous stroma by a loose zone of myxoid change. C, Lesional nerves may be embedded within a myxoid background. (A, Courtesy of Dr. Carl Witkop, University of Minnesota.)

2B but without associated endocrinopathies; some consider this to represent a distinct condition termed pure mucosal neuroma syndrome.492 Clinical Features. The affected individual has a tall, lanky, marfanoid body type, with a narrow face and with possible muscle wasting. The adrenal and thyroid tumors typically do not present until after puberty, whereas the oral mucosal neuromas usually develop during the first decade of life.489–492 The oral mucosal neuroma presents as a 2 to 7 mm yellowish-­ white, sessile, painless nodule of the lips, anterior tongue, and buccal commissures (Fig. 4.43A). Usually there are two to eight (or more) neuromas, with deeper lesions exhibiting normal mucosal coloration. There may be enough neuromas in the body of the lips to produce macrocheilia or enlarged, “blubbery lip” appearance. Similar nodules may be seen on the eyelids, sometimes producing eversion of the lid, and on the sclera. Facial skin, especially around the nose, may also be involved. Abnormal laboratory values are part of this syndrome. When a medullary thyroid carcinoma is present, serum and urinary calcitonin levels are elevated.491,494 When a pheochromocytoma is present, there is often an increase in the serum levels of vanillylmandelic acid and altered epinephrine/norepinephrine ratios.494  Pathologic Features and Differential Diagnosis. The mucosal neuroma is composed of a partially encapsulated

aggregation or proliferation of small nerves, often with thickened perineurium, intertwined with one another in a plexiform pattern (Fig. 4.43B and C). This tortuous pattern of nerves is seen within a background of loose endoneurium-­like fibrous stroma. Individual nerves flow in fascicles of two to three fibers and are histologically normal except for occasional hyperplasias and bulbous expansions. Luxol fast blue staining will identify myelin sheathing of some fibers, and lesional cells react immunohistochemically for S100 protein, collagen type IV, vimentin, neuron-­specific enolase, and neural filaments.492 More mature lesions will react also for EMA, indicating a certain amount of perineurial differentiation. Early lesions have a stroma rich in acid mucopolysaccharides, and will thus stain positively with Alcian blue. Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues. There may be close microscopic similarity with traumatic neuroma, but the streaming fascicles of mucosal neuroma are usually more uniform and the intertwining nerves of the traumatic neuroma lack the thick perineurium of the mucosal neuroma.  Treatment and Prognosis. The neuromas of this syndrome are asymptomatic and self-­limiting, and present no problem requiring treatment. They may, however, be surgically removed for esthetic purposes or if they are being constantly traumatized.

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It is very important that affected patients be followed by an internist, endocrinologist, or other appropriate clinician relative to his or her potential thyroid and adrenal malignancy. Because of the serious nature of the latter conditions, it is strongly suggested that other family members be evaluated for MEN 2B/3. Genetic analysis is especially important. Over 70 RET mutations are known to cause MEN 2A and MEN 2B/3, and effective management appears to be associated with the exact mutation in any individual patient.496,497  PALISADED ENCAPSULATED NEUROMA A benign neural neoplasm, the palisaded encapsulated neuroma (PEN, solitary circumscribed neuroma) was first reported as a distinct entity in 1972.498–501 It is now recognized as one of the more common of the superficial nerve tumors of the head and neck region, although neural tumors in general are rather rare events in that anatomic site.502 The etiology of this lesion is unknown, but trauma is considered by some to induce or trigger its development. Nine of every 10 examples of PEN have been reported as facial lesions, usually from the region of the nose and midface.500 Oral lesions are often misdiagnosed as neurofibroma or schwannoma. The lesion is not associated with MEN syndromes. Clinical Features. Oral examples of PEN are seen most frequently on the hard palate, although any oral or pharyngeal mucosal surface may be affected.500 It presents as a soft, perhaps rubbery, sessile nodule with normal mucosal coloration and no symptoms (Fig. 4.44A). The diagnosis is typically made during the fifth through seventh decades of life, but many lesions have

been present for years prior to biopsy and formal diagnosis. There is no gender predilection. The oral lesion is almost always less than 1 cm in greatest diameter and occasionally multiple nodules are clustered together.  Pathologic Features. The PEN has an histological appearance between that of neurofibroma and schwannoma, consisting of a well-­demarcated nodule of interlacing bundles or fascicles of spindle cells (Schwann cells) with thin, wavy, pointed nuclei and with no dysplasia or mitotic activity (Fig. 4.44B).499,500 The cellular fascicles are typically four to six cells thick and are arranged in parallel streams in some areas (Fig. 4.44C and D), and nuclear palisading is seldom pronounced, as it is in schwannoma. Since so many PEN lesions lack this palisading feature, there is a preference among some for solitary circumscribed neuroma as the more appropriate diagnostic name.502 This is discussed in more detail in Chapter 9. Nuclear pleomorphism and mitotic activity are not seen. Silver stains for axons and luxol fast blue stain for myelin will confirm the presence of neural tissue within the tumor, and the fascicles are immunoreactive for neural filaments. The neural tissue of this lesion is well circumscribed and usually encapsulated, but large areas of the periphery may lack a capsule, especially along the superficial aspects. Pseudoepitheliomatous hyperplasia of the overlying epithelium has been reported. Occasional lesions demonstrate areas reminiscent of the palisading Verocay bodies of Antoni A tissue in schwannomas, but true Verocay bodies are not seen. This lesion should be differentiated from schwannoma and neurofibroma, as described subsequently.503 

A

C

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B

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Fig. 4.44  A, Gross appearance of well-­demarcated palisaded encapsulated neuroma within a pedunculated mucosal mass. B, Low-­power view shows a well-­demarcated cellular mass. C, Wavy fascicles of spindle cells are densely cellular. D, Lesional cells show spindled, sometimes wavy nuclei.

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Treatment and Prognosis. The treatment for this self-­ limiting lesion is conservative excision, with few recurrences reported.491 Unlike neurofibroma and schwannoma, the PEN is not a feature of neurofibromatosis 1 (NF-­1, von Recklinghausen disease) or of MEN 2B/3.  SCHWANNOMA (NEURILEMOMA) The schwannoma (neurilemoma) is a benign neoplasm of the Schwann cells of the neural sheath. At least a fourth, perhaps as much as half of all cases of schwannoma and neurofibroma occur in the head and neck region.504–507 A small percentage (6 μm).

B

Leishmania and Trypanosoma are within the same size range as Histoplasma but lack the prominent clear halo of the latter. Leishmania and Trypanosoma can be seen with hematoxylin and eosin and reticulin stains. Histoplasma is a round to oval organism; Leishmania and T. cruzi have a “diaper pin” shape. Histoplasma will stain with Gomori methenamine silver and PAS stains, but Trypanosoma and Leishmania will not. Both Trypanosoma and Leishmania have intracellular kinetoplasts that are not visualized on hematoxylin and eosin–stained sections, but may be seen on Giemsa-­stained touch preparations. Poorly encapsulated Cryptococcus usually retains some mucinophilia and so may be distinguished from Histoplasma. B. dermatitidis may be distinguished from Histoplasma by its broad-­based pattern of budding.  Treatment. The distinction between Histoplasma and Leishmania is particularly important in cases of disseminated infection because the treatments are very different (antifungal agents vs. antiprotozoal agents). Histoplasmosis can be treated with itraconazole, ketoconazole, or amphotericin B. Laryngeal

histoplasmosis requires a prolonged course of therapy; it is generally many months before the hoarseness completely resolves. Prophylaxis with itraconazole (200 mg/day) in patients with HIV and CD4 counts less than 150 cells/mm3 is highly effective and should be considered if the case rate of histoplasmosis exceeds 10 cases per 100 patient-­years.  Laryngeal Rhinosporidiosis. R. seeberi has a worldwide distribution, but is endemic to India, Sri Lanka, Malaysia, Brazil, and Argentina. In the United States, cases have been reported from the rural South and West.113 Mucosal trauma is considered necessary in establishing infection. Stagnant pools of water and men and animals bathing together in the river (e.g., Durg district, Madya Pradesh, India) have been associated with many cases. Clinical Features. Rhinosporidium most commonly infects the nasal cavity, causing friable, lobulated red or pink polyps that may become massive and extend posteriorly to fill and obstruct the nasopharynx, oropharynx, and hypopharynx. Extranasal

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B

Fig. 5.15  Rhinosporidiosis. A, Papillary hyperplasia seen at low power may mimic other entities, such as papillomas or adenocarcinomas. Note large cysts within the lamina propria. B, A submucosal mature cyst (spherule), approximately 240 μm in diameter, with a thick wall of approximately 4 to 7 μm; numerous variably sized spores are noted within the cyst.

manifestations are relatively uncommon. Conjunctival infection may also occur, usually after local injury. Laryngeal involvement by Rhinosporidium is extremely rare and always secondary to nasopharyngeal involvement.114,115,117,118 The nature of the etiologic agent of rhinosporidiosis has long been elusive.116 Originally, it was considered a fungus and more recently has been classified as a blue-­green algae. However, recent molecular biological investigations have led to the classification of Rhinosporidium as a Mesomycetozoea, a novel clade that is phylogenetically at the animal-­fungus divergence in the evolutionary tree.119,120  Pathologic Features. In hematoxylin-eosin–stained tissue, an intense acute and lymphoplasmacytic infiltrate is present. Cysts (also referred to as spherules or sporangia) are numerous, round, large (100–350 μm), and thick walled (Fig. 5.15). The thick cyst wall stains with hematoxylin and eosin, Gomori methenamine silver, digested PAS, and mucicarmine; it is also birefringent. The largest, most mature cysts are closest to the mucosal surface.121 Hundreds to thousands of small (2-­to 9-­ μm) spores are seen within mature cysts. The spores are initially uninuclear and range in size from 10 to 100 μm in diameter, but on maturation are multinucleated, forming clusters of 12 to 16 “naked” nuclei. Mitotic figures within these spores are infrequently observed. On maturation, the cysts extrude the spore morulas into the surrounding tissue from a pore. In cases of disseminated rhinosporidiosis, it is possible to find single spores in body fluids, such as urine.  Differential Diagnosis. The differential diagnosis of Rhinosporidium is mainly with mucosal Coccidioides immitis. In fact, Seeber initially believed that Rhinosporidium was related to C. immitis; but its spherules are not as large (60 μm); its walls are not as thick, birefringent, or mucinophilic; and its endospores are not as numerous. If one sees only the extruded mature spores, which range from 2 to 9 μm in diameter, one might consider all other yeast forms within that range. Oncocytic schneiderian papilloma (cylindrical cell papilloma) may also be confused histologically with rhinosporidiosis; however, the cysts of the former are intramucosal and contain mucin and polymorphonuclear cells versus the spore-­ filled submucosal cysts of the latter. 

Treatment. Surgical debridement is indicated for these polypoid lesions. Response to dapsone therapy has been demonstrated.122,123  Viral Infections Laryngeal Cytomegalovirus Infection. Cytomegalovirus (CMV) is a double-­stranded DNA virus and member of the Herpesviridea family, causing common infection in humans, usually presenting as a mild, self-­limited mononucleosis-­like syndrome. It is trophic for endothelial cells, B and T lymphocytes, and mononuclear and epithelial cells. After primary infection, the virus becomes latent and can be reactivated, particularly in a situation of immunosuppression. In immunocompetent host, both primary infection and reactivation are either asymptomatic or result in a self-­limited disease. In immunosuppressed populations, CMV may result in severe multiorgan disease, involving the lung, kidney, gastrointestinal tract, and retina, with a high mortality rate. Populations at risk are newborns, patients with HIV infection, patients with transplanted organs, patients treated with chemotherapy or corticosteroids, and critically ill patients.124 Clinical Features. The larynx and trachea may be sites for ulcerative CMV infections, even in the absence of CMV pneumonitis.125–129 The clinical differential diagnosis of ulcerative laryngeal lesions in HIV patients would also include candidal and herpetic infection and may be resolved by tissue biopsy, touch preparation, or smear plus cultures. Vocal cord paralyses (without mucosal ulceration) are seen because of laryngeal neuritis: CMV inclusions have been demonstrated at autopsy within the recurrent laryngeal nerve.128 This mechanism may explain the case of pharyngeal CMV infection causing vocal cord immobility.130 Concomitant supraglottic diffuse large cell lymphoma and CMV epiglottitis have been reported.131  Pathologic Features. CMV inclusions are most frequently seen in the endothelial cells adjacent to areas of ulceration. The classic CMV-­infected cell has a large pink intranuclear inclusion, surrounded by a clear halo and, less commonly, amphophilic smaller cytoplasmic inclusions (Fig. 5.16 C and D). The combination of intranuclear and intracytoplasmic inclu-

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Fig. 5.16  Infection with cytomegalovirus and herpes simplex virus type 1 in the hypopharyngeal and oropharyngeal mucosa, diagnosed at autopsy. A, Erosion (upper right), with giant cells containing intranuclear inclusions in the surrounding epithelium (upper left). B, Positive immunohistochemistry for herpes simplex virus type 1 in the infected epithelial cells. C, Enlarged endothelial cells with intranuclear inclusions in a small blood vessel deep in the stroma (center). D, Positive immunohistochemical reaction for cytomegalovirus in endothelial cells.

sions is seen only after the viral infection undergoes a replication phase, which occurs in a minority of infected cells.  Special Studies. Before replication, infected cells produce great quantities of immediate early antigen and early antigen, which may be detected immunohistochemically as intranuclear inclusions. This accentuates the importance of special studies in the absence of classic CMV inclusions. This also explains the enhanced sensitivity to immunohistochemistry for early antigen compared with in situ hybridization for the CMV genome in early infections lacking classic histology.  Differential Diagnosis. The characteristic appearance of productively infected cytomegalic cells, with their intranuclear and intracytoplasmic inclusions, leaves little room for other possibilities. However, in early infections, enlarged “funny-­looking” cells are seen, which may raise the possibility of other infections, such as herpes simplex virus (HSV) infection. Slowly resolving mucocutaneous herpetic ulcers and disseminated infection can occur in AIDS patients and possibly extend to the hypopharynx and larynx. However, primary laryngotracheal HSV infection is an extremely rare occurrence.132 HSV laryngitis is more likely to be seen in the

context of HSV pneumonitis, usually in transplant recipients, burn victims, and the immunocompromised. It can manifest as vesicular or ulcerative lesions or vocal cord paralysis. HSV-­infected cell nuclei become enlarged and reveal peripheral chromatin beading and homogeneous ground-­glass inclusions that may be basophilic or “cleared out.” Multinucleated HSV syncytial cells also contain intranuclear inclusions and cytoplasmic inclusions. The nuclei of these multinucleated cells may mold with each other rather than overlap. Immunohistochemistry on formalin-­fixed, paraffin-­embedded biopsy specimens for HSV-­1 and HSV-­2 and CMV antigens can be helpful in making the distinction between HSV and CMV infections. Rarely, in immunocompromised patients, one may see both infections in one patient (see Fig. 5.16).  Treatment. Ganciclovir or Foscarnet may be used to treat CMV laryngitis.  Protozoan Infections Trichinella. Trichinella, a nematode commonly found in temperate zones, is transmitted by ingestion of smoked, ­

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

­ reserved, or inadequately cooked or frozen infected meat. p Heating meat to at least 60°C for 30 minutes per pound or deep-­ freezing it for at least 3 weeks at −15°C will kill the parasites. Because of current meat regulations in the United States, most current cases of trichinosis can be traced to noncommercial, home-­ slaughtered meats. Cases are usually caused by pork ingestion, but other meats such as bear, horse, wallaby, and kangaroo have caused trichinosis.133,134 Clinical Features. Most cases of trichinosis are self-­limited; the severity generally depends on inoculum size. The acute stage of trichinosis can start 10 days to 2 weeks after ingestion and last approximately 2 months. Trichinosis initially presents with fever, nausea, vomiting, myalgias, headache, fatigue, and diarrhea. After migration from the host small intestine, the initial site of infestation, Trichinella becomes encysted in skeletal muscle; it especially favors muscles with a rich blood supply, such as the extraocular muscles, intrinsic laryngeal muscles, the diaphragm, and the deltoid and gastrocnemius muscles. After the first week, the symptoms correspond to peripheral migration of the larvae into muscle; they include periorbital or facial edema, myositis, blurry vision, and peripheral eosinophilia. Eye movement and swallowing may be painful, and there is profound diffuse muscle weakness. Parasite invasion into the lungs, heart, and central nervous systems is infrequent, and fatalities are rare. In late-­stage infection, acute symptoms may disappear, but myalgia and fatigue can persist. The parasite alters the myocyte intracellular environment so that both can remain viable for years. Accordingly, Trichinella may be an incidental finding, many years after infection, in the sternocleidomastoid muscle of radical neck dissections or within the intrinsic laryngeal muscles in laryngectomy specimens (Fig. 5.17).135,136  Pathologic Features. Trichinella (genus Trichina, Greek, “hair”) was first histologically identified at autopsy by James Paget as a medical student. The larvae appear as a tightly coiled worm within an intramuscular double-­walled capsule. If the larvae are missed on muscle biopsy because of sampling error, nonspecific myositis may be seen. Calcified cysts denote remote infection.  Treatment. If Trichinella is an incidental finding in a laryngectomy specimen, no treatment is indicated. Treatment consists of steroids and anthelminthics (e.g., mebendazole,

Fig. 5.17  Trichinella spiralis in a neck muscle. An incidental finding in a neck dissection specimen from a patient with laryngeal carcinoma.

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albendazole), which must be administered before the end of the acute phase for relief of the acute migratory symptoms.  Schistosoma. Schistosoma is a parasitic blood fluke. Schistosoma mansoni is endemic to Africa, South America, the West Indies, and Puerto Rico; Schistosoma japonicum is endemic to China, Japan, and the Philippines; Schistosoma haematobium is endemic to the Nile Valley and India; Schistosoma mekongi is endemic to the Mekong River basin in Cambodia; and Schistosoma intercalatum is endemic to Western and Central Africa. Schistosoma derives its name (“split body”) from the fact that the male parasite body curves in ventrally to form an enclosed gynecophoral canal, in which the female fluke “reposes.” Schistosoma enters the host in the aqueous larval stage (cercaria) by penetrating the skin, which causes intense pruritus. The parasites migrate to the vasculature and are carried to the nutritious hepatic portal system, where they mature and produce eggs. The eggs, as well as dead flukes, evoke severe chronic granulomatous inflammation and fibrosis in the liver and intestines (S. mansoni, S. japonicum) and rectum, bladder, and pelvis (S. haematobium). Occasional cases of laryngeal involvement by Schistosoma have been reported.137–139 Pathologic Features. The ova of Schistosoma may be calcified and are usually in a granulomatous reaction or in receding inflammation. S. mansoni and S. haematobium ova are elongated and oval. S. mansoni has a prominent, pointed lateral spine, and S. haematobium has a prominent terminal spine. S. japonicum ova are rounder and plumper than S. mansoni and S. haematobium ova, with a small lateral spine.  Leishmania. Leishmania is a protozoan infection transmitted to humans and animals through the bites of female Phlebotomus sandflies. In tropical and subtropical areas, the animal population maintains the disease reservoir. Leishmaniasis is endemic to Central and Eastern Asia, the Middle East, India, Central Africa, Central and South America, Italy, Sicily, Greece, and Turkey. In endemic regions, children are particularly vulnerable; malnutrition also increases vulnerability to infection. There are three clinical forms of leishmaniasis: cutaneous, mucocutaneous, and visceral. Temperature is an important factor that helps determine the localization of leishmanial disease. Species causing visceral leishmaniasis (Leishmania donovani, Leishmania infantum, Leishmania chagasi) are able to grow at core body temperatures, whereas those causing mucocutaneous leishmaniasis (Leishmania braziliensis, L. infantum, Leishmania tropica mexicana) grow better at lower temperatures. Although the Leishmania species differ clinically and biologically, each of the three clinical disease forms can be produced by multiple overlapping species. Clinical Features. Cutaneous leishmaniasis is marked by skin papules that progress and ulcerate. Satellite nodules and regional lymphadenopathy are seen. Cutaneous leishmaniasis may progress to mucocutaneous disease. Mucocutaneous leishmaniasis is characterized by multiple mucosal ulcerations that develop after hematogenous spread; buccal mucosa, lips, palate, tongue, tonsils, and the larynx can be affected.140,141 These mucosal ulcerations can clinically mimic neoplasia. Visceral leishmaniasis (kala azar: Hindi, black fever) may have an incubation period from weeks to months affecting the liver, spleen, bone marrow, lymph nodes, heart, and kidneys, causing weight loss, hepatosplenomegaly, anemia, and thrombocytopenia. Immunosuppression associated with infection with human immunodeficiency virus and systemic autoimmune diseases is known to increase the incidence of visceral leishmaniasis in nonendemic areas.142 Laryngeal

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leishmaniasis has also been reported in association with inhaled corticosteroids.143 Laryngeal leishmaniasis can occur as part of mucocutaneous leishmaniasis, or visceral leishmaniasis, as an isolated disease,144 or in human immunodeficiency virus– associated visceral leishmaniasis.145,146  Pathologic Features. Isolated ulcerating lesions may develop in the oropharyngeal nasal and laryngeal mucosa, as well as in the anogenital mucosa. Mucocutaneous leishmaniasis is characterized by surface ulceration, granulomatous reaction, dense lymphoplasmacytic infiltrate with necrosis, and granulation tissue. The leishmanial amastigotes are seen in histiocytes, under oil immersion or in hematoxylin-eosin– or Giemsa-­stained sections. The number of amastigotes varies with host immunity status: tissue from patients with isolated lesions and adequate immunity will reveal epithelioid histiocytes and sparse organisms, whereas those from anergic patients with diffuse involvement will reveal foamy macrophages with abundant amastigotes. The diagnosis can be confirmed by culture, enzymatic analysis of the isolates and polymerase chain reaction (PCR).142,146 Treatment consists of antimonial compounds, usually meglumine antimonate.  VOCAL CORD NODULES, POLYPS, AND REINKE’S EDEMA Vocal cord nodules (also called laryngeal nodules or singer’s, preacher’s, or screamer’s nodes), polyps, and Reinke’s edema are stromal reactions occurring in Reinke’s space (Figs. 5.18 and 5.19). Reinke’s space is a gelatin-­like potential space in the vocal fold subepithelium, containing loose fibers and extracellular matrix. It is devoid of vessels and lymphatics, thus making this area susceptible to accumulation of fluids and proteins (Fig. 5.18B). They are etiologically related to smoking, voice overuse (excessive quantity of voice use), voice abuse (yelling), voice misuse (vocal hyperfunction with excessive muscular tension), obesity, reflux, and hormonal disturbances.147–152 Clinical Features. Vocal nodules are usually bilateral and symmetric (Fig 5.19A); there is a female predisposition. Nodules form after repetitive tissue trauma from vocal misuse or excess vocal abuse151; smoking may also play some role. The female gender predominance of nodules may relate to abnormalities in glottic closure in the female larynx.153 Vocal

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nodules occur on the vibratory surface of the true vocal cord, usually the junction of the anterior and middle thirds, which is the point of maximum vibratory impact. The presenting symptom is hoarseness. Vocal polyps usually occur on the anterior third of the vocal fold (see Fig. 5.19B and C). Occasionally, polyps may originate from the ventricular fold or rarely, from the aryepiglottic fold.154 They are usually unilateral and have a male predisposition. The most frequent symptoms are hoarseness and voice change. Large polyps may present with respiratory symptoms, such as asthma and respiratory obstruction.155 They may appear gray or white, translucent, sessile, or pedunculated and usually measure a few millimeters in diameter. Vocal cord polypoid degeneration or Reinke’s edema causes unilateral or bilateral diffuse vocal cord swelling in the middle-­ aged to elderly population (see Fig. 5.18); it is unrelated to vocal abuse, but it is associated with smoking.156 The incidence of Reinke’s edema in men and women is believed to be the same, but women are more likely to seek medical help because their voice becomes deeper and more masculine. Symptoms usually begin in the fourth and fifth decades and the process rarely affects children.  Pathologic Features. Accurate classification of the exudative lesions arising in Reinke’s space is difficult. There is overlap in the histological features, and the correct diagnosis can only be made if clinical information is available. Biopsy, however is needed to exclude neoplasia, infection, or concomitant injury.157 Vocal cord nodules and vocal polyps can be histologically indistinguishable. Only the size of the biopsy specimen may support the particular process.158 A lesion smaller than 3 mm suggests a vocal nodule, whereas a lesion greater than 3 mm supports a polyp. Collectively, polyps and nodules are characterized by the finding of stromal changes: stroma is either myxoid or edematous, fibrous, vascular, or fibrinous, underlying the stratified squamous epithelium (Fig. 5.20). Dilated vascular spaces or foci of sparse hemorrhage may be present. Amyloid-­like stromal change (hyalinized fibrin material; see Fig. 5.20B) can be seen. Inflammatory cell infiltrates are infrequent, and glandular elements are absent. The squamous epithelium may be normal, atrophic, or hyperkeratotic and, at times, dysplastic.159 Ulceration of vocal polyps is infrequent;

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Fig. 5.18  Reinke’s edema. A, Endoscopic view, showing diffuse swelling of the vocal cords. B, Microscopically, there is abundant edematous stroma.

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C Fig. 5.19  Nodule and polyp of the vocal cord. A, Bilateral vocal nodules at the mid-­true cord. Clinically, a biopsy is rarely performed on typical symmetrical nodules like these; rather, a biopsy may be performed on unilateral vocal nodules. B, Large translucent vocal polyps at the anterior commissure. C, Endoscopic view of a vocal polyp, arising in the middle third of the left true vocal cord. (A, Courtesy of Greta Fries.)

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Fig. 5.20  True vocal cord polyp. A, Microscopically, this polyp consists of abundant edematous stroma with dilated blood vessels and fibrin deposition; it is covered by nonkeratinizing squamous epithelium. B, Higher-power detail.

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however, it may be seen in vocal nodules. The presence of atypical stromal cells has been observed in vocal cord polyps. On a limited superficial biopsy sample, the finding of a thickened and somewhat blurry basement membrane may be the only hint that one is looking at a vocal cord polyp. Gray and colleagues159 found two patterns of injury in these laryngeal lesions. One pattern showed prominent fibronectin deposition in the superficial lamina propria with thick collagen type IV bands, indicating basement membrane injury. The other pattern showed minimal injury to the basement membrane zone and little fibronectin deposition.  Differential Diagnosis. When prominent, the myxoid stromal change may be mistaken for a myxoma and the hyaline variant for laryngeal amyloid. Myxomas are extremely rare in the larynx. Myxomas form expansile tumors that are relatively hypovascular. Vascularity, hemorrhage, and fibrin deposition distinguish myxomatous change in a laryngeal polyp from an actual myxoma (Fig. 5.21). Amyloid deposits tend to be more nodular and may even be associated with the presence of a granulomatous reaction with multinucleated giant cells. The usual stains for amyloid, namely, Congo red, crystal violet, and thioflavine T, are negative in vocal cord nodules and polyps; therefore the possibility of amyloid can be easily excluded when suspected. Systemic diseases, such as hypothyroidism and mucopolysaccharidosis, may cause diffuse, edematous laryngeal thickening with deposition in the lamina propria.160  Treatment and Prognosis. These lesions have a benign clinical course but may persist if the etiologic factors remain. Treatment options include surgical excision, intralesional steroid injection, and voice therapy.161,162 Phonomicrosurgery usually represents the preferred treatment for removing these lesions. Voice therapy has been mainly indicated for treating functional dysphonia when there is no abnormality of the vocal fold. However, recent studies suggest that voice therapy may shrink vocal cord polyps and may play a complementary role, both before and after surgery.162,163 

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CYSTS Laryngeal cysts can be divided into four categories: (1) laryngoceles, which are air-­filled pulsion diverticula of the saccule; (2) saccular cysts, resulting from the obstruction of the saccule; (3) ductal cysts (squamous, oncocytic, or tonsillar cysts), which are mucin filled, arising from minor salivary ducts; and (4) miscellaneous cysts. There are several classification systems for laryngeal cysts but none is entirely satisfactory.164,165 A recent review of all publications on the PubMed/MEDLINE database, related to laryngeal cysts by clinicians from the Mayo Clinic,165 stressed the importance of histology in the definitive diagnosis of laryngeal cysts and proposed a new classification of supraglottic cysts based on anatomic location and incorporating the type of epithelial cyst lining to improve management of the lesions. Oncocytic cysts appeared to be associated with multiplicity and recurrence. These authors also found that laryngeal cysts are more common in men but increasingly symptomatic in women. Computerized tomography is the imaging modality of choice and magnetic resonance imaging (MRI) is essential for the assessment of complex lesions. It may be possible to treat all types of cysts by transoral resection, including saccular cysts that traverse the thyrohyoid membrane. Congenital laryngeal cysts are uncommonly encountered. They present dramatically with neonatal stridor and respiratory distress. Congenital laryngeal cysts are most often subglottic and of the saccular type, but rarely can be classified as laryngeal duplication cysts (see later discussion). According to Saha et al., laryngeal duplication cysts are histologically similar to bronchogenic cysts, and from the pathologist point of view they can all be called “bronchogenic cysts.”166 Subglottic cysts (SGCs) tend to occur in previously intubated infants, but in a study of nine children with SGCs treated between 2003 and 2010, only three-­ninths had a history of intubation, suggesting that other factors, such as prematurity, gestational age, and low birth weight play a role for the development

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Fig. 5.21  Supraglottic myxoma. A, Cut surface reveals a lobulated pale myxoid tumor. The differential diagnosis of this tumor grossly may include a lipomatous tumor, with myxoid change, and pleomorphic adenoma, with prominent myxoid change. B, Histologically, small bland spindle cells in a loose myxoid stroma are seen. The uniform pattern and relatively low vascularity aid in establishing the diagnosis.

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

of SGCs.167 The majority of SGCs are of saccular/bronchogenic type, with only three reported cases of an ectopic thymic cyst presenting as a subglottic mass.168 Laryngeal bronchogenic cysts, lined predominantly by respiratory epithelium with focal squamous epithelium, and surrounded by fibromuscular bundles containing seromucinous glands, are, however, rare.169 Laryngocele The laryngeal ventricle (sinus of Morgagni) is the space or pocket between the vocal fold (true cord) and the ventricular fold (false cord). The bilateral upward extension or cul-­de-­sac of the ventricle is the laryngeal saccule. A laryngocele is the symptomatic dilation of the laryngeal saccule by entrapped air, that is, a pulsion diverticulum, which still communicates with the laryngeal lumen. A laryngocele may remain confined to the endolarynx (internal laryngocele) as a supraglottic submucosal bulge. It may also undermine the paraglottic space superiorly, protrude over the superior rim of the thyroid lamina, and herniate through the thyrohyoid membrane, via the foramen of the superior laryngeal neurovascular bundle. This type of laryngocele (mixed external/internal or foramina cyst) presents as an anterior neck mass (Fig. 5.22). It stands to reason that external laryngoceles must have some internal component and for that reason may be termed mixed laryngoceles. Patients with internal and mixed laryngoceles report hoarseness, dyspnea, and chronic cough. Newborn infants with laryngoceles present with a feeble cry, difficulty in feeding, cough, and a neck mass. Histologically, they are lined with respiratory mucosa. Lymphoid tissue, as the inferior extension of Waldeyer’s ring, may also be present. No other neck cyst would present as an air-­filled cyst. The air-­filled nature of laryngoceles is easily confirmed on radiographic examination. Sometimes laryngoceles undergo intermittent obstruction, and secretions will result in a mucus-­ filled sac. Coughing may clear the obstruction, dispelling the secretions. If communication exists between the sac and the laryngeal lumen, this can still be classified as a laryngocele. A laryngopyocele is an obstructed laryngocele or a saccular cyst, which has become secondarily infected. Laryngoceles are usually unilateral, but rare cases of bilateral involvement are reported170 and may be seen over a wide age range, from neonates171 to the middle aged and elderly.172 In very rare cases, laryngocele complicated by infection (laryngopyocele) can cause almost 100% obstruction of the airway, requiring emergency tracheotomy.173 Even rarer is sudden death associated with laryngopyocele. The recent cases reported by Töro et  al. and Byard and Gilbert are the third and fourth patients who succumbed because of laryngo(pyo)cele.174,175 The other two lethal cases were reported in the 1950s and are not listed here. For pathologists performing a postmortem examination, only careful dissection of the larynx may demonstrate the ­characteristics of the underlying lesion and the possible mechanism of death.175 For more information, the reader is encouraged to see the systematic review of laryngopyoceles by Al-­Yahya et al.176 Only a small subset of patients with laryngoceles are involved with activities involving increased intralaryngeal pressure (e.g., glass blowers, trumpet players), ingestion of a fish bone,177 or change in altitude during air flight.178 It is thought that enlarged saccules may be prevalent in the general

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population and render these persons more vulnerable to laryngocele formation. These enlarged saccules may be a phyllogenous laryngeal remnant akin to primate lateral laryngeal air sacs.179 MacFie radiographically demonstrated a high incidence of asymptomatic laryngoceles (56%) occurring in 93 musicians (wind instrumentalists).179 These laryngoceles could be demonstrated on forceful expiration with an open glottis (see Fig. 5.22; a maneuver similar to playing a wind instrument), yet could not be demonstrated on forced exhalation with a closed glottis (Valsalva maneuver). Treatment. Simple conservative excision is the treatment of choice. Patients with internal laryngocele are treated with endoscopic CO2 laser resection, while those with a combined laryngocele are better treated with resection via a V-­shaped lateral thyrotomy approach.172  Saccular Cyst A saccular cyst (SC) is a mucin-­filled dilatation of the laryngeal saccule, secondary to obstruction, either acquired or congenital in origin, analogous to a sinonasal mucocele. It may extend either medially or laterally. Medial SCs obscure the anterior vocal fold but are limited in size and extension by the anterior commissure. Lateral SCs point superolaterally and like external laryngoceles may herniate through the thyrohyoid membrane and reach massive proportions if neglected (Fig. 5.23).180 Reviewing 28 cases of congenital SC, Xiao et al. found that 5/28 were anterior SC and 23/28 were lateral. These authors found that the congenital SC can recur if excision is not complete.181 SCs are lined with saccular mucosa, usually the respiratory type, but occasionally squamous or oncocytic mucosa, and filled with mucinous material. This latter feature distinguishes SC from laryngoceles. SCs may be indistinguishable from thyroglossal duct cysts because remnant thyroid tissue may be absent from the latter. The majority of thyroglossal duct cysts are present in the anterior midline, inferior to the hyoid bone. However, rare thyroglossal duct cysts may push on the thyrohyoid membrane to encroach on the preepiglottic space.182 In this case, one relies on thorough histologic sampling of the cyst and the anatomic location to make the distinction between the two: the stalk or tract of a thyroglossal duct cyst is midline and should lead to the hyoid bone, whereas the stalk of a large SC is lateral and herniates through the thyrohyoid membrane. The differential diagnosis of SC may also include a branchial cleft cyst. The anatomic location of the duct or tract will also aid in this distinction. The tract of a branchial cleft cyst will not lead through the thyrohyoid membrane but will continue superiorly along the anterior border of the sternocleidomastoid muscle and may end at the angle of the mandible or in the tonsillar bed. Squamous cell carcinomas have been known to obstruct the saccule, resulting in a secondary mucocele or laryngocele.183 Treatment. SC and symptomatic mixed laryngoceles may be cured by surgical excision.  Ductal Cysts (Squamous, Tonsillar, and Oncocytic) Laryngeal cysts can be the result of blockage of a minor salivary gland duct and are the most commonly encountered type of laryngeal cyst.184 They are clinically relevant, as they can cause acute airway obstruction.185 The cyst lining is the dilated

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Fig. 5.22  Laryngoceles. A and B, Bilateral upper neck masses are seen on forceful expiration with an opened glottis. C and D, Plain radiographs demonstrate the internal (i) and external (e) air-­filled components of these bilateral laryngoceles. Arrow in C demonstrates the connection between the internal and external laryngocele. E, This air-­filled cyst is confined to the endolarynx (asterisk) and therefore may be classified as an internal laryngocele. F and G, Delivery of two laryngoceles from an external cervical approach. (Courtesy of Dr. Hugh Biller.)

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C ductal epithelium (Fig. 5.24); it may be squamous, oncocytic (see subsequent discussion of salivary lesions), or squamous with surrounding lymphoid stroma; the third cyst is referred to as a tonsillar cyst. Squamous and oncocytic cysts have a predisposition for the ventricular bands, ventricle, aryepiglottic folds, and epiglottis. Tonsillar cysts have a predisposition for the vallecula, an area with tonsillar remnants, but rarely it can

Fig. 5.23  Saccular cyst. A and B, A bulky cyst of the anterior neck. C, Computed tomography reveals a mucus-­filled cyst of the anterior neck. The distinction between a saccular cyst and a thyroglossal duct cyst is made at the time of surgery by the location of the tract: the thyroglossal duct cyst tracks back to the hyoid bone, whereas the saccular cyst herniates through the thyrohyoid membrane.

occur in the false vocal cord.186 Simple conservative excision is curative.  Other Laryngeal Cysts and Sinuses Epidermal inclusion cysts (epidermoid cysts),187 dermoid cysts,188 and branchial cleft cysts189 may occur in the endolarynx. An epidermoid cyst, a keratin-­ filled cyst lined with

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stratified squamous mucosa, may be the result of a traumatic mucosal inclusion or a congenital rest. Rarer still are dermoid cysts, which contain skin adnexal structures and are purely mature benign growths of presumed congenital rests. Congenital laryngeal duplication cysts contain both endodermal and mesodermal (cartilaginous) elements.190 Branchial cleft anomalies primarily involving the supraglottis are extremely rare. The supraglottis is derived, embryologically, from branchial arches 3 and 4, whereas the glottic compartment is derived from arches 5 and 6. Fourth branchial pouch sinuses manifest as sinus tracts leading from the pyriform sinus to skin or may follow the course of the left recurrent laryngeal nerve into the mediastinum and back to the cricothyroid joint, ending in the pyriform sinus. Retrograde excision, beginning at the pyriform apex, ensures complete removal of the tract.191 The differential diagnosis between branchial cleft cysts, which can be lined with columnar epithelium, stratified squamous mucosa, or a combination of both and mixed laryngocele, can be very difficult.189 Foamy histiocytes, cholesterol crystals, and inflammatory cells may be present within the cyst; a prominent lymphoid stroma usually accompanies the cyst lining.  LARYNGEAL AMYLOIDOSIS

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C Fig. 5.24  Ductal cyst. A, Endoscopic view of cyst of right anterior vocal fold. B, Congenital epiglottic cyst. Congenital laryngeal cysts are most often of the saccular type and less commonly the duplication type. This cyst is the ductal type. C, Cystically dilated duct lined by oncocytic columnar epithelium. (A, Courtesy of Dr. Richard V. Smith.)

Amyloidosis is a diverse group of disorders that share the feature of deposition of amorphous, extracellular deposits of abnormal fibrillary protein at various sites.192,193 It may be hereditary or acquired, localized or systemic in distribution. It is extremely rare, developing in about eight of every 1 million people, with a male predisposition. More than 20 different types of amyloid protein have been recognized, which are indistinguishable from one another histochemically and ultrastructurally. They share a common beta-­ pleated sheet structural configuration that is responsible for the unique staining properties of amyloid, that is, Congo red staining and birefringence under polarized microscopy. The peptide subunits of the protein fibrils vary among the different proteins. Amyloid diseases are defined by the biochemical nature of the protein in the fibrils and classified according to distribution (systemic, localized), and their clinical patterns. The nomenclature is “AX,” where “A” indicates amyloidosis, and “X” indicates the protein in the fibrils. The most common types of amyloids are AL (amyloid light chain) amyloid and AA (amyloid-­ associated) amyloid. AL amyloid is composed of immunoglobulin light chains and is most commonly related to primary systemic amyloidosis. It is the result of a clonal B cell disorder and may be associated with overt myeloma or lymphoma. AL amyloidosis can also present as a localized disease, most commonly in the upper aerodigestive tract. AA amyloid is composed SAA (serum amyloid-­associated) protein, which is an acute-­phase reactant serum protein and is associated with chronic inflammation caused by immune-­mediated diseases or infection. It has been termed reactive systemic amyloidosis; previously it was referred to as secondary amyloidosis. Amyloidosis of the upper aerodigestive tract is rare and most commonly affects the larynx or the tongue.192–197 Amyloidosis of the tongue is invariably part of a primary systemic amyloidosis, while amyloidosis of the larynx is most often localized or is part of hereditary apoA1 amyloidosis. Clinical Features. Localized laryngeal amyloidosis presents as either a nodule or a diffuse infiltrating laryngeal process.

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Hoarseness is the most common symptom, in some patients accompanied by cough, dysphagia, dyspnea, stridor, and rarely, hemoptysis. The false cord is the single most common site of laryngeal amyloid, followed by the true vocal cord and ventricle. However, primary amyloid deposits can occur at any location within the larynx, and multiple sites of involvement are not unusual.198 A recent study by Rudy et al. suggests that additional organ involvement may be found in 18% of patients with laryngeal amyloidosis.199 The diagnosis of laryngeal amyloidosis is established by biopsy. Lewis and colleagues194 found that the mean age of 22 patients with laryngeal amyloid was 56 years. The common sites were the false vocal cords (12 cases), ventricle (8 cases), subglottis (8 cases), true vocal cords (6 cases), arytenoids and aryepiglottic folds (5 cases), and anterior commissure (3 cases). In six cases, there was concomitant involvement of the trachea, usually when the subglottis was involved.  Pathologic Features. Laryngeal amyloidosis usually presents as a firm polypoid lesion covered by an intact mucosa. On cut surface, it is firm, pale, waxy, and tan yellow to gray. Microscopically, amyloid is seen as a discrete nodular mass or a diffuse subepithelial deposit of amorphous eosinophilic material in the stroma, blood vessel walls, or basement membranes of mucoserous glands and results in atrophy (Fig. 5.25A). Dense amyloid cracks in tissue sections, leaving cleft-­like spaces. Amyloid may also form hyaline rings around adipose tissue cells and may be associated with a granulomatous reaction surrounding nodular deposits. An associated infiltrate of plasma cells, lymphocytes, or histiocytes may be present. Histochemically, amyloid of any type can be confirmed by demonstrating the typical apple-­green birefringence on polarized microscopy, after staining with Congo red (Fig. 5.25B). Metachromasia on staining with crystal violet or thioflavine T immunofluorescence may also be used. Ultrastructurally, amyloid is composed of linear, nonbranching fibers 10 to 15 nm in width.  Special Studies. Immunohistochemistry for immunoglobulin light chains (AL amyloid) and other proteins (amyloid A protein, prealbumin, transthyretin, and beta2-­microglobulin) is used to characterize the type of amyloid deposits. In a study of 20 cases, laryngeal amyloid was confirmed as monoclonal light chain deposition (AL amyloid) in 12 (60%) cases.194 

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Differential Diagnosis. Laryngeal amyloid may be confused on routine sections for vocal cord nodules with hyalinized stroma; however, the diagnosis is easily made on a Congo red stain because vocal cord nodules lack the apple-­ green birefringence. It is important to determine whether laryngeal amyloidosis is localized or part of systemic amyloidosis.200 A work-­up to rule out systemic disease is therefore needed, including serum studies (hemoglobin, creatinine, total protein, albumin, bilirubin, free light chains), urine studies (protein, kappa or lambda light chains, creatinine clearance), cardiac studies (electrocardiography and echocardiography), and fine-­needle aspiration of abdominal fat, a simple and safe technique.  Treatment and Prognosis. Most patients with localized laryngeal amyloidosis can be successfully treated by simple excision via direct laryngoscopy.200,201 Recurrence or persistence of the laryngeal amyloid can occur in 60% of patients, usually within 5 years after initial therapy, although some had multiple recurrences more than 10 years later. Recurrence is related to difficulty in removal of extensive, multifocal submucosal disease.202 In these cases, death may result from progressive tracheobronchial involvement.  ENDOTRACHEAL INTUBATION Clinical Features. Prolonged endotracheal intubation results in endolaryngeal pressure necrosis and ulceration. Vocal cord ulceration is a common complication of prolonged intubation observed in 76% of patients intubated for 3 to 58 days (mean, 9 days); it usually resolves after 4 weeks.203 Granulation tissue and scar formation may follow, impairing cord mobility. This directly correlates with the duration of intubation and the use of a larger endotracheal tube.204 Other possible intubation sequelae include arytenoid dislocation, synechiae (dense scar), and transient unilateral or bilateral vocal cord paralysis (the latter resulting in postextubation airway obstruction), as a result of pressure neurapraxia.205,206 Focal subglottic mucinosis has also been described as a postintubation sequela.207 Granuloma formation as a result of endotracheal intubation was first described in 1932. Subsequent studies showed predisposing factors were prolonged

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Fig. 5.25  Laryngeal amyloidosis. A, Abundant deposition of amorphous eosinophilic material in the subepithelial stroma. B, Positive reaction with Congo red staining. The congophilic areas stained appropriately with polarized light (not shown).

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traumatic intubation, the use of a large diameter endotracheal tube, high pressure in endotracheal tube balloons, and inadequate sedation. The latter results in involuntary swallowing and phonatory movements that push the vocal fold against the tube and damages the epithelium of the vocal apophyses. Intubation granulomas are more common in females, who have a smaller larynx than in males. In one study of 66 patients with laryngeal granulomas, 15 occurred after intubation; 6 were in males and * in females. Intubation granulomas are usually associated with prolonged intubation and occur in adults. However, they have been described in the infant larynx and after short intubation periods (< 2.5 hours).208,209  Pathologic Features. Donnelly210 described the sequelae of intubation in a series of 99 autopsy cases. Most damage is in the posterior larynx and the subglottic region. The earliest changes, seen after 1 to 3 hours, were deepithelialization of the posterior cricoid and vocal processes. Loss of basement membrane was seen after 4 to 6 hours. Between 12 and 48 hours, mucosal ulceration could be seen in the vocal processes and the subglottis, with inflammation of the perichondrium. After 96 hours of intubation, the perichondrium of the vocal process and cricoid lamina was invariably exposed with cartilaginous excavation. These changes can all be attributed to the constant pressure and abrasion of the tube, which moves with each respiration, against the relatively stationary larynx. Further, the endotracheal cuff, which is inflated against the trachea to prevent backflow of expressed air from the ventilator, will result in subglottic erosion. Gastroesophageal reflux will add to ongoing damage. Subglottic stenosis and collapse are possible sequelae of this damage. Persistent postextubation hoarseness requires laryngoscopy. A detailed histology and electron microscopic study of biopsies from 10 patients showed mild epithelial hyperplasia, associated with edema and intense stromal inflammation and vascular proliferation. Ultrastructurally, collagen was not present and intracytoplasmic changes in fibroblasts suggested cell dysfunction and damage.212 A characteristic biopsy sample revealed hyperplastic mucosa, acute and chronic inflammation, and exuberant granulation tissue. A giant cell reaction or storiform fibroblastic proliferation may be seen. Dilated vessels may have a ramifying and staghorn appearance. Wenig and ­Heffner211 noted that these biopsies may often lead to diagnostic confusion with neoplastic processes. Submitted diagnoses by pathologists contributing vocal cord granulomas included hemangioma, hemangiopericytoma (HPC), angiosarcoma, inflammatory pseudotumor, squamous cell carcinoma, and verrucous carcinoma. Focal mucinosis may be noted but is rare and probably related to previous trauma. It appears as a relatively avascular basophilic myxoid matrix within the lamina propria, with small spindled or stellate cells. Focal mucinosis lacks infiltrating borders and extensive reticulin and collagen fiber network, all features present in myxomas.  Differential Diagnosis. Biopsies from vocal cord ulcerations and changes caused by vocal abuse or chronic gastroesophageal reflux may have similar histological features. Distinguishing granulomas from benign or malignant vascular tumors should not be difficult in light of a clinical history of recent intubation. A proliferative squamous component with pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and verrucous carcinoma. A pronounced inflammatory and granulation tissue component, as well as

pertinent clinical history, should lead one to reconsider a malignant diagnosis in this situation.  CONTACT ULCERS Larynx contact ulcers (sometimes called contact granulomas or pyogenic granulomas) are distinguished from vocal cord nodules/polyps in that they occur most commonly on the posterior vocal fold, on the vocal process of the arytenoids, as a result of forceful apposition during vocalization. They are associated with vocal abuse, intubation, as described earlier, and gastroesophageal acid reflux disease (GERD).213 They may be unilateral or bilateral (Fig. 5.26). There is a male predominance, characteristically arising in lawyers, salesmen, managers, and preachers (preacher’s nodules), who must affect a deep, low-­ frequency, forceful voice. Females are more likely to develop contact ulcer postintubation (see earlier). Patients present with hoarseness or throat pain and may develop habitual throat clearing or cough.213 Pathologic Features. Grossly, these lesions appear tan, yellow, or red and polypoid with or without an ulcerated surface. The histologic findings are nonspecific. One can see polypoid granulation tissue with or without surface fibrin and secondary overgrowth of bacteria and fungi. Over time, chronic reactive reepithelialization may result in hyperplastic surface squamous epithelium but there should be no dysplasia. The radial arrangement of capillaries in contact ulcers can distinguish them from capillary hemangioma/pyogenic granulomas, which characteristically show a lobular arrangement, and since granulomas are not seen the name contact granuloma is technically also a misnomer.  Treatment. Treatment is directed at the underlying cause; voice counseling for voice overuse/abuse, therapy for acid reflux, and endoscopic laser resection may be warranted for unresponsive and/or advanced lesions. 

Fig. 5.26  Contact ulcer. Polypoid lesion with saucer-­ like traumatic ulceration, projecting from the arytenoid process as a result of vocal abuse. (Courtesy of Dr. Peak Woo.)

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

FOREIGN BODY GRANULOMAS In the early 1960s, the technique of injecting foreign material into the vocal fold for the treatment of vocal cord paralysis was introduced. Material, such as Teflon, was injected into the lateral thyroarytenoid muscle tissue of the paralyzed vocal fold to bring it toward the midline. Medializing a paralyzed vocal fold results in a more complete glottic closure on cord adduction and may fortify a breathy voice and improve vocal quality. However, misplaced injections or overinjections can cause symptomatic foreign-­body granulomas. The clinician may recognize these masses as being secondary to Teflon (or other injected material) or may assume the presence of malignancy. Teflon migration

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into the neck may also simulate malignancy. A case report describes a lesion resembling vocal fold granuloma that developed after injection of polyacrylamide gel, which at operation proved to be a superficial accumulation of the material itself.214 Pathologic Features. The biopsy interpretation is usually straightforward. One sees a foreign-­body giant cell reaction with typical multinucleated giant cells. “Asteroid”-­type bodies may be seen.215 Intracellular and extracellular Teflon is abundant, colorless, glassy, refractile, and amorphous material that is most clearly demonstrated when viewed under polarized light (Fig. 5.27). Dense fibroconnective tissue accumulates over time, apparently peaking and remaining unchanged after 6

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Fig. 5.27  Teflon granuloma as viewed by polarized microscopy (A–C) and conventional light microscopy (D). Note prominent polarization of Teflon with numerous histiocytes and chronic inflammatory cells.

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months.216 Teflon may also migrate from the endolarynx and be detected in cervical lymph nodes. The nature of this material can be confirmed by dispersive radiographic analysis or infrared absorption spectrophotometry. The differential diagnosis includes other foreign materials that may historically have been injected for symptomatic relief of unilateral vocal cord paralysis. This may include paraffin, cartilage, bone, silicon, Gelfoam, glycerin, tantalum oxide, and tantalum powder.216–218 However, injection of most of these materials has been abandoned. The three main agents currently used for intracordal injection for the treatment of vocal cord paralysis are hyaluronic acid, calcium hydroxyapatite, and autologous fat.219 Interestingly, vocal cord augmentation by autologous fat injection has been shown to enhance remission of vocal process granuloma in a small series of patients.220  Treatment. Conservative excision of the foreign body– induced granulation tissue is indicated for symptomatic relief of upper airway symptoms. To date, no case of foreign body– induced malignancy after Teflon injection has been reported.  SARCOIDOSIS Clinical Features. Sarcoidosis is a chronic granulomatous disease, most often diagnosed between the second and fourth decades of life; it is more common in women. The highest incidences are seen in Sweden, Norway, the Netherlands, and England. In the United States, it is 10 times more common among African-Americans than whites and is most prevalent in the southeast. Migration from the southeast does not decrease the rate of sarcoidosis in these individuals. In general, there is an inverse relationship between susceptibility to mycobacterium tuberculosis (MTB) and sarcoid; sarcoid is virtually nonexistent among populations with a high susceptibility to MTB, that is, Eskimos, Indians, and Chinese.221,222 Patients may present with lymphadenopathy, hepatosplenomegaly, pulmonary, arthritic and ocular symptoms, or nonspecific symptomatology, such as fever, malaise, weight loss, and erythema nodosum. Yet others are totally asymptomatic, and the diagnosis will be picked up on an incidental chest radiograph that reveals enlarged hilar lymph nodes and a diffuse pulmonary reticular pattern. Among those clinically symptomatic individuals, the majority of patients follow a self-­limiting course, the disease burns out, usually within 2 years. Fewer individuals will progress to severe pulmonary fibrosis and renal involvement. The anterior or posterior cervical lymph nodes are most commonly involved in the head and neck. Extranodal head and neck involvement can be seen in 38% of sarcoid patients, usually ophthalmic manifestations. Less commonly, the parotid and lacrimal glands and upper respiratory tract submucosa may be involved. Otolaryngologic effects are rare. Laryngeal involvement is reported to occur between 1% and 5% of patients with sarcoidosis. In a review of 2319 patients, only 6% had isolated laryngeal involvement.223 Pediatric laryngeal sarcoidosis is particularly rare. Strychowsky et al. reported a case in a 12-­year-­old child and identified seven previously published cases. In 4/7 (57%) patients, the disease was confined to the larynx, while in 3/7 (43%), it was part of systemic sarcoidosis.224 The variable symptoms and clinical features may cause laryngeal abnormalities to be overlooked until the symptoms are severe. The disease results in upper airway symptoms, such as progressive dyspnea and upper airway obstruction.225 The most common presenting symptoms are hoarseness,

dyspnea, dysphagia, chronic cough, and obstructive sleep apnea.223 The lamina propria of the supraglottis appears preferentially involved. The mucosa may be edematous and “boggy” or reveal granular coalescent fleshy nodules in the epiglottis, arytenoids, or aryepiglottic folds.224,226,227 The pale pink swelling associated with supraglottic sarcoidosis has been described as turban like.223 Reviewing the literature, de Moraes et al. found the most common laryngoscopy findings were edematous, elevated, and pale mucosa, involving in descending order: epiglottis, arytenoid, aryepiglottic folds, and vestibular folds. More rarely, it can involve subglottis and in 24% of the cases, vocal folds, also causing their immobility, either caused by sarcoid infiltration of crycoarytenoid joint or impairment of the vagus nerve.228 One case report has described bilateral vocal fold involvement229 and there is one report of transglottic involvement.223At later stages, the mucosa appears fibrotic. There is no tendency toward ulceration. The apparent sparing of the vocal folds may relate to the relative paucity of lymphatics in the vocal cords. Vocal cord paralysis occurs usually in the setting of polyneuritis, although recurrent laryngeal nerve compression by mediastinal adenopathy is another possible mechanism. The exact etiologic agent of sarcoidosis is uncertain, most likely it is a multifactorial disease. Although many infectious agents have been suspected, to date, none have been unequivocally identified by case-­control studies.230,231  Pathologic Features. Sarcoid granulomas are characteristically small, nonconfluent, nonnecrotic, and densely hyalinized. Rarely, however, they may be associated with necrosis. The pathologist must then rule out tuberculosis or fungal infection through multiple cultures and histologic studies. Pathognomonic features of sarcoid include asteroid bodies, Schaumann’s bodies, and Hamazaki-­Wesenberg inclusions. Asteroid bodies are star-­like crystalline inclusions seen within multinucleated giant cells. Schaumann and Hallberg232 described calcified laminated concretions within multinucleated giant cells of patients with sarcoid. Akin to Michaelis-­Gutmann bodies, Schaumann’s bodies may be the result of degenerating organisms. Hamazaki-­ Wesenberg inclusions are seen within histiocytes, unrelated to granulomas, and are round (coccoid), oval, or rod-­shaped golden brown inclusions 3 to 15 μm in greatest dimension that autofluoresce with ultraviolet light and may also stain with Ziehl-­ Neelsen and the intensified Kinyoun carbol fuchsin stains.  Differential Diagnosis. Noncaseating sarcoid-­type granulomas are not entirely specific; in addition to tuberculosis and fungal infections, they may be observed with rheumatoid arthritis (RA)233 and can also be seen in lymph nodes adjacent to a malignancy. Despite the described characteristic appearance, the diagnosis of sarcoidosis should remain one of exclusion, only to be rendered after ancillary studies rule out infection.  Treatment and Prognosis. Asymptomatic or mildly symptomatic patients do not require therapy and undergo spontaneous remission. A tracheotomy may be necessary to relieve acute airway obstruction in patients with severe disease.223 Various treatment regimens exist, all intended to remove the disease or slow progression. Parenteral steroid therapy is indicated for airway compromise. Intralaryngeal steroid injection may be attempted for localized lesions. Many patients require long-­ term, low-­ dose oral steroid therapy to maintain remission. Steroid-sparing therapies to avoid side effects have included external beam radiotherapy, cytotoxic agents such as azathioprine, and immune modulators such as cyclosporine and hydroxychloroquine.223,232

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

Clofazimine has been successfully used in one patient with symptomatic laryngeal sarcoidosis refractory to steroids.233 A number of surgical techniques to excise or debulk laryngeal sarcoid lesions have been described. Open techniques, such as laryngofissure and laryngectomy, carry significant morbidity and disability. More recently, minimally invasive endoscopic surgery, with and without intralesional corticosteroid injection, has been shown to be effective.232  GOUT Gout is a metabolic disorder resulting from hyperuricemia. The prevalence of the condition has been increasing in populations throughout the world. In a study between 2006 and 2008, the prevalence in North America was 3.9%, which translates into 8.3 million US adults. In the United Kingdom, the prevalence in 2012 was 2.49%, in Sweden between 0.5% and 1.8%, and in France and Italy, it was 0.9%. In Taiwan, one in 16 people have gout and Pacific Islanders, including New Zealand Maoris, are prone to developing gout because of a genetic predisposition.242 Uric acid is the end product of the metabolism of purines, part of the nucleic acid backbone. Primary gout may be caused by increased uric acid production (e.g., increased dietary uric acid from purine-­rich food, such as meat, sweetbreads, and anchovies, in the face of an inherent biochemical defect). It is well recognized that gout is associated with renal impairment, and data from a study of German patients with chronic renal disease generated a prevalence of 24.3%.242 Secondary gout may be caused by decreased urinary uric acid excretion (lead poisoning,236 lead nephropathy [saturnine gout], thiazide diuretics), or purine overproduction because of increased cell turnover (myeloproliferative diseases). There is a pronounced male predisposition. Clinical Features. Acute arthritic gout is episodic, monoarticular, and self-­limiting. Acute episodes may be provoked by stress, trauma, weight reduction, hyperalimentation, starvation, alcohol ingestion, or medication (e.g., diuretics, insulin, and penicillin). Urates (the ionic form of uric acid) are present in plasma, extracellular fluid, and synovial fluid.237 Sodium urate crystal deposition in a synovial space results in an acutely inflamed and exquisitely tender joint. The large toe is most commonly involved (podagra); other joints (fingers, wrists, and elbows) may

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be ­involved. Symptomatic urate crystal deposition leads to acute or chronic arthritis. Chronic gout results from the long-­term deposition of sodium urate crystals, usually in distal, cooler sites, resulting in pathognomonic tophi. Imaging has not been useful in the diagnosis of gout, until degenerative changes develop in affected joints or well-­formed tophi appear in soft tissue. However, recent advances in ultrasound and dual-­energy computed tomography (CT) scanning have made possible the detection of urate crystal deposition even in asymptomatic patients with hyperuricemia.237 In the head and neck, gouty tophi present as asymptomatic deposits on the outer helix of the pinna. Laryngeal involvement by gout is infrequently reported,238–241, 243 but probably many cases are unreported and more are unrecognized. Diagnosis is made on biopsy as the clinical presentation and appearance on microlaryngoscopy is not specific. The cricoarytenoid joint, vocal folds, ventricles, and subglottis may be involved sites. Involvement of the cricoarytenoid joint may result in hoarseness, pain, dysphagia, and cord fixation. Clinically, gouty deposits may cause discrete lesions of the vocal fold mucosa or result in exophytic papillary lesions.  Pathologic Features. On gross examination, gouty tophi are filled with “cheesy” curd-­like material. Microscopically, tophi appear as large deposits of amorphous, amphophilic material with surrounding foreign-­ body reaction, foamy histiocytes, and lymphoplasmacytic infiltrates (Fig. 5.28). The urate crystals may be seen as closely packed birefringent needle-­like structures. They are best preserved and observed in ethanol-­ fixed tissue; urate crystals dissolve in aqueous fixatives, such as formalin. A Degalanta stain will stain black for uric acid crystals even after formalin fixation. Massive urate deposition in the cricoarytenoid joint results in destruction of the articular cartilage and fibroinflammatory joint fixation.  Differential Diagnosis. Other deposits, such as amyloid or Teflon, may be considered in the differential diagnosis. Amyloid is more eosinophilic than amphophilic, with areas of varying density. Although a scattering of lymphoplasmacytic cells might be present, the intense histiocytic and foreign-­body giant cell infiltrate of a tophus is not seen. Injected foreign material (e.g., Teflon, paraffin) will not stain and appears as refractile noncrystalline material or as empty space in the tissue. 

B

Fig. 5.28  Gouty tophus. A, Low-­power view of large deposits of amorphous material with intense foreign-­body reaction. B, High-­power view. The inflammatory reaction is greater in gouty tophus than in amyloid.

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Treatment. Acute episodes of gout may be treated with colchicine and nonsteroidal antiinflammatory drugs. Blood levels of uric acid should be kept below 6 mg/dL, if possible.242 Chronic hyperuricemia is managed by encouraging weight loss and avoidance of provocative agents, such as alcohol, fruit juices and drinks with high concentration of fructose,242 purine-­ rich foods, aspirin, and diuretics. Allopurinol, a xanthine oxidase inhibitor, or uricosuric agents, such as probenecid and benzbromarone, can be used to manage and prevent the sequelae of chronic hyperuricemia. Gouty tophi presenting in the larynx and other head and neck sites may require surgery.237  AUTOIMMUNE DISEASES AND DISEASES OF UNCERTAIN MECHANISMS The larynx is not an uncommon site for involvement in systemic autoimmune diseases, such as rheumatoid arthritis (RA), lupus erythematosus (LE), Hashimoto’s thyroiditis, and Sjögren’s syndrome.242 Laryngeal involvement in autoimmune diseases is often underdiagnosed, because of nonspecific symptoms.245 Common features of laryngeal autoimmune diseases include mucosal edema, inflammation, subglottic stenosis, rheumatoid nodules, cricoarytenoid arthritis, and vocal fold “bamboo nodes.”245–247 Vocal fold bamboo nodes are the most important feature suggesting an autoimmune nature of a laryngeal disease. They appear as whitish transverse bands on the cephalic surface in the middle third of vocal folds, where larger mucosal wave and vibration amplitude are found, suggesting phonotrauma as the pathogenetic mechanism. Histologically, they resemble rheumatoid nodules, but are distinguished by their transverse orientation and regular pattern of occurrence, along the probable contact points, during vibratory cycle.247 They have been described in association with a variety of autoimmune diseases.247–249 Their presence strongly suggests an autoimmune condition and can appear before clinically overt autoimmune systemic disease.250 Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune-­mediated disease, characterized by a symmetric polyarthritis, often resulting in joint damage and physical disability.251 It is a systemic disease, with a variety of extraarticular manifestations. The majority of patients with RA have rheumatoid factor in the serum, which represents autoantibodies against the Fc fragment of immunoglobulin (Ig)G (antiidiotype antibodies). Rheumatoid factor is not specific for RA because it may also be elevated in other autoimmune illnesses, such as LE, pernicious anemia, and Hashimoto’s thyroiditis, as well as nonautoimmune chronic illnesses. The synovium is the primary target of RA; it becomes hyperplastic, papillary, and villiform (pannus) in the face of a chronic lymphoplasmacytic infiltrate. The pannus acts to erode the articular surfaces of the joint space. Patients with RA may also have rheumatoid nodules. Rheumatoid nodules are necrotizing inflammatory nodules that may form in soft tissues adjacent to joints, skin and tendons, extensor surfaces, bony prominences, and within visceral organs, such as the heart, lungs, and gastrointestinal tract. Like rheumatoid factor, rheumatoid nodules may be seen in other autoimmune diseases. Clinical Features. Laryngeal involvement in RA includes arthritis of the cricoarytenoid joints, rheumatoid nodules in the

soft tissues of the larynx, and vocal cord bamboo nodes. Laryngeal symptoms have been noted in up to 26% of patients,252 and endoscopic abnormalities in up to 72% of patients with generalized RA.253A female predominance is seen. The larynx can be affected also in children with idiopathic juvenile arthritis.254,255 Cricoarytenoid involvement can cause joint fixation resulting in hoarseness, exertional dyspnea, and stridor. Patients may report a sensation of a foreign body in their throat. There may be a history of intermittent aphonia. Speaking, coughing, or swallowing may elicit pain, as does anterior pressure on the larynx. On examination, the arytenoid mound is erythematous and edematous. The cords may be fixed and immobile to manipulation (Fig. 5.29). Arytenoid fixation and edema may cause acute upper airway obstruction.256  Pathologic Features. Uniarticular or bilateral joint involvement may be seen. The cricoarytenoid joint may reveal swelling and thickening of the synovia, which is heavily infiltrated by mononuclear inflammatory cells, resulting in villous hypertrophy, with increased vascularity and proliferation of granulation tissue. This results in the formation of a pannus that grows over the articular cartilage and causes erosion, progressing to destruction of the cartilage. The articular surface may be destroyed and reveal an irregular, widened joint space filled with fibrous adhesions, occasionally leading to bony ankylosis.255 Rheumatoid nodules may be present in the soft tissue adjacent to the joint or in the vocal fold. They are characterized by an area of fibrinoid necrosis, rimmed by palisading macrophages and other chronic inflammatory cells (Fig. 5.30). The presence of fibrin can be confirmed on trichrome stain (red) and phosphotungstic acid hematoxylin stain (blue).  Differential Diagnosis. Cricoarytenoid fixation, mucosal swelling, bamboo nodes, and rheumatoid nodules are not specific findings for RA; they may be seen in other autoimmune illnesses, such as systemic LE. Discovering a rheumatoid nodule or bamboo nodes will at least categorize the disease process as autoimmune. If necrosis was seen in the vocal cord biopsy, it would still be wise to rule out acid-­fast bacilli and fungal organisms. 

Fig. 5.29  Rheumatoid arthritis. Endoscopic view of limited abduction because of cricoarytenoid joint involvement. (Courtesy of Dr. Richard V. Smith.)

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Fig. 5.30  Laryngeal rheumatoid nodule as a presenting finding in lupus erythematosus. A, Zones of fibrinoid necrosis. B, Fibrinoid necrosis (left) with rimming of histiocytes (arrows) and leukocytoclastic vasculitis (curved arrow).

Treatment. There is a stepwise progression for the therapy of RA, based on disease severity. Salicylates and nonsteroidal antiinflammatory drugs can be used as a first-­line regimen to reduce joint symptoms. Hydroxychloroquine has been moderately effective for early RA. Unrelenting disease can be treated with gold injections, penicillamine, and immunosuppressive drugs, such as methotrexate and azathioprine, all of which have significant toxicities. Corticosteroids may be used, episodically, in conjunction with these drugs. RA of the cricoarytenoid joint may be treated with laser arytenoidectomy or fixation of the arytenoid in abduction using a wire, thereby increasing the glottic airway space and improving symptoms.  Lupus Erythematosus Lupus erythematosus (LE) is an autoimmune disease characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), directed against double-­stranded DNA, nuclear histones, nucleolar antigens, and nonhistone proteins bound to RNA. Tissue injury is mainly caused by deposition of immune complexes and binding of antibodies to various cells and tissues. LE primarily affects the skin, joints, kidneys, nervous system, and mucosal membranes, particularly in the oral cavity. It tends to affect younger individuals, in the third and fourth decades of life, with a pronounced female predominance. Patients report polyarthralgia, malar rash, photosensitivity, fever, and malaise. Pulmonary involvement may take the form of pleural effusions, pleuritis, capillaritis, vasculitis, and pulmonary hypertension. Pericarditis, myocarditis, coronary vasculitis, and valvular dysfunction may occur. Glomerulonephritis may progress to renal insufficiency. The neurologic manifestations of LE include seizure disorder, transverse myelitis, and emotional disturbances.257 LE is also associated with an increased risk of overall cancer, including carcinoma of the larynx, oropharynx, and thyroid gland, as well as Hodgkin’s and non-­Hodgkin’s lymphomas, leukemia, and others.258 Clinical Features. Laryngeal involvement in LE is thought to be underappreciated, but may occur in as many as one-­third of patients.259–261 It follows a highly variable course, ranging from no symptoms, to areas of mild ulceration, vocal cord paralysis, or a life-­threatening, severely compromised upper

airway.260 Recent data suggest that most LE patients present with dysphonic symptoms. de Macedo et al. measured objective vocal parameters and perceived vocal quality with the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale in LE patients and compared them to matched healthy controls. LE patients had significantly lower vocal intensity and harmonicsto-noise ratio, as well as increased jitter and shimmer. All subjective parameters of the GRBAS scale were significantly abnormal in LE patients. In addition, the vast majority of LE patients reported at least one perceived vocal deficit, with the most prevalent deficits being vocal fatigue and hoarseness.262 The laryngeal involvement in LE may be similar to that of RA: hoarseness, decreased cricoarytenoid mobility, bamboo nodes, and rheumatoid nodules. Hypopharyngeal and laryngotracheal edema, ulceration, and an inflammatory mass obstructing the upper airway may be present. Mucosal edema, which occurs in 28% of patients, especially of the epiglottis, may necessitate intubation. Rarely, acute cricoarytenoiditis can be the initial presentation of LE.263 Hougardy et al. reported a 20-­year-­old Caucasian man with no prior medical history who was admitted to the emergency department for hoarseness, stridor, and pyrexia. Multiple investigations revealed LE and his vocal cord dysfunction was attributed to laryngeal involvement because of LE.264 Sequelae include laryngitis sicca, laryngeal scarring, vocal cord paralysis, and subglottic stenosis. Superimposed infectious laryngitis, unresponsive solely to corticosteroids, may also occur in LE; therefore bacterial and fungal cultures are important at the time of laryngoscopy. Although laryngeal symptoms usually occur during active, generalized LE, occasionally vocal cord rheumatoid nodules, bamboo nodes, or subglottic stenosis may be the initial presentation of LE (Fig. 5.30).265,266 Vocal cord paralysis in LE occurred in 11% of patients in one literature review.260 This may be caused by cricoarytenoid arthritis, joint fixation, or neurogenic causes. The clinician will be able to make the distinction between neurogenic origin versus joint fixation, at the time of laryngoscopy. If the arytenoid is freely mobile on spatula palpation, then the joint obviously is not fixed, and the vocal cord paralysis has a neurogenic etiology. This paralysis may be caused by compression of the left recurrent laryngeal nerve, as a result of dilated pulmonary arteries secondary to LE-­associated pulmonary hypertension. The left recurrent laryngeal nerve may be compressed between the

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Fig. 5.31  Lupus erythematosus cells. Mononuclear cells with engulfed hematoxylin bodies. Note the homogenized remains of nuclei exposed to antinuclear antibodies, which appear as large amphophilic cytoplasmic inclusions.

engorged left pulmonary artery and the aortic arch, as it wraps around it to return to the neck.267 Recurrent laryngeal nerve palsy in LE may also be the result of other mechanisms, such as vasculitis, and may be bilateral.268 Serologically, patients may have positive rheumatoid factor; ANAs such as antidouble-­stranded DNA and anti-­Smith antibodies are specific for LE. Drug-­induced LE may occur secondary to a number of drugs (e.g., procainamide, hydralazine, isoniazid, methyldopa, quinidine, chlorpromazine), usually in patients who are slow drug acetylators, have received large daily doses of the drug, or, in the case of hydralazine-­induced LE, have the human leucocyte antigen (HLA)-­DR4 genotype. Laryngeal LE, secondary to drug-­ induced LE (hydralazine hoarseness), has been described.269  Pathologic Features. The rheumatoid nodules seen in LE are identical to those seen in RA. Hematoxylin bodies and LE cells, when present, are fairly specific for LE (see Fig. 5.31). Hematoxylin bodies (LE bodies) are nuclei of damaged cells, which react with ANAs, lose their chromatin pattern and become enlarged and homogeneous. Phagocytes (neutrophils or macrophages) that engulf LE bodies, are referred to as LE cells and have large, amphophilic, cytoplasmic inclusions. Both hematoxylin bodies and LE cells stain strongly with Feulgen stain. Vasculitis is another histologic hallmark of LE, although a rare finding in laryngeal LE. Vasculitis affects small and medium arteries and may be present in any tissue. It is characterized by fibrinoid necrosis of the vessel wall, with acute and chronic inflammatory cell infiltration. In its chronic stage, fibrous thickening with luminal narrowing may occur.  Differential Diagnosis. In the absence of hematoxylin bodies and LE cells, the histology may be indistinguishable from RA. Vasculitis is not specific for LE and may also be seen in relapsing polychondritis, granulomatosis with polyangiitis (this was previously referred to as Wegener’s granulomatosis; GPA), polyarteritis nodosum, and RA. Superimposed infectious laryngitis may also be present and should be considered when evaluating biopsies. Nocardia laryngitis270 has been reported in LE patients. Nocardia are filamentous bacteria that do not stain well with hematoxylin and eosin stain but are best seen with a modified Ziehl-­Neelsen stain. Chronic mucosal inflammation may be suggestive of the early stages of scleroma.

Cricoarytenoid fixation may be seen in RA, gout, Reiter syndrome, costochondritis (Tietze’s syndrome), traumatic arytenoid subluxation, and infections such as gonorrhea, syphilis, and mumps. Subglottic stenosis may also be a sequelae of relapsing polychondritis, GPA, previous trauma, prolonged endotracheal intubation, tracheopathia chondroosteoplastica, perichondritis of syphilis, and severe pulmonary/tracheal infections, such as tuberculosis, scleroma, and histoplasmosis.  Treatment and Prognosis. Corticosteroids are the mainstay of controlling active disease. Most cases of lupus laryngitis will resolve with corticosteroid immunosuppression. Epinephrine inhalation may also be necessary for acute laryngeal edema, and patients may require emergency tracheostomy for airway management. Superimposed infection should be considered for cases nonresponsive to immunosuppression. Laryngotracheal stenosis may be corrected with surgical reconstruction during quiescent disease periods.  Granulomatosis With Polyangiitis (Wegener’s Granulomatosis) Granulomatosis with polyangiitis (GPA), previously referred to as Wegener’s granulomatosis, is a systemic disease characterized by necrotizing vasculitis of small and medium sized blood vessels, formation of granulomas in the upper and lower upper respiratory tract, and glomerulonephritis.271,272 In addition to the classic triad of the upper and lower respiratory tracts and the kidney, any other organ can be involved, such as the skin, eyes, heart, and central nervous system. Although the etiology currently remains unknown, circulating antineutrophil cytoplasmic antibodies (ANCA) are present in the majority of patients during active disease; they may play a role in the pathogenesis of GPA and can be helpful in establishing the diagnosis. Clinical Features. Males and females are affected equally; the disease can affect patients at any age, even children.273 Eighty-­ five percent of affected patients are older than the age of 19 years, and the mean age is ∼40 years. The majority of affected patients are white. It is believed that GPA starts in the upper respiratory and digestive tracts, and later spreads to involve the lower respiratory tract and the kidney, and other organs.274 The disease incidence has been slowly increasing.275

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

Upper respiratory and digestive tracts are involved in the vast majority of patients (up to 95%).274,276 The sinonasal tract is most commonly affected, followed by the ear, larynx, pharynx, and oral cavity; rarely, the parotid gland may be involved.275 The most frequent symptoms include severe chronic sinusitis. Nasal septal collapse leads to a saddle nose deformity. Otologic manifestations include serous otitis media, otitis externa, and sensorineural loss. Oropharyngeal ulcerative inflammation and hyperplastic gingivitis may occur. Laryngotracheal disease, usually subglottic, may be seen in as many as one-­fourth of patients with GPA and rarely may be a presenting symptom. Endoscopically, the subglottis appears erythematous and indurated. Laryngotracheal involvement can lead to intractable subglottic stenosis requiring tracheostomy for airway maintenance.277 Patients with juvenile-­onset GPA were found to be five times more likely to develop subglottic stenosis than adult-­onset GPA patients.278 Pulmonary involvement commonly leads to cavitating necrotic lesions that radiographically may mimic carcinoma. Other pulmonary manifestations include interstitial fibrosis, alveolar hemorrhage, bronchopneumonia, and bronchiolitis.279 Renal involvement occurs in about 70% of patients, resulting in a crescentic glomerulonephritis, with rapidly progressive renal failure, without appropriate treatment. Patients may also suffer from migratory arthritis, and ocular, genitourinary, and gastrointestinal symptoms, related to ischemia because of vasculitis. Cranial nerve deficits and posterior pituitary intracranial manifestations (diabetes insipidus) may also be seen.279 The diagnosis of GPA is based on clinical features, biopsy and the presence of ANCA with a cytoplasmic pattern (c-­ANCA) (Fig. 5.32C). Biopsy of the head and neck mucosa with inflammation, granulomas, and vasculitis is extremely helpful in establishing the diagnosis of GPA, both in early and advanced stages of the disease. A positive biopsy has few or no false positive results. However, frequently only nonspecific features are seen and vasculitis is rarely found (see later). Patients with active GPA usually have elevated titers of ANCA in a cytoplasmic pattern, directed against enzyme proteinase­3. However, 10% to 50% of patients with GPA may be ANCA negative. ANCAs may persist after symptoms abate and hence should not be the basis for treatment. Conversely, a patient in quiescence, who converts from negative to positive c-­ANCA, is at risk of a disease flare-­up. ANCAs in a cytoplasmic pattern are positive in more than 90% of patients with active disease and 65% of those with active limited disease. ANCAs staining the cytoplasm may have two patterns: coarse/diffuse cytoplasmic staining and perinuclear cytoplasmic staining. It is the former pattern that is highly specific for GPA; however, this pattern may also, occasionally, be seen in patients with polyarteritis nodosa and Churg-­Strauss vasculitis. Cocaine abusers have sinonasal and palatal destruction that may mimic GPA and also may have elevated c-­ANCAs.280 Perinuclear cytoplasmic staining of ANCAs is a nonspecific pattern that may also be found in other diseases, such as polyarteritis nodosa, Churg-­Strauss vasculitis, lupus erythematosus (LE), Goodpasture’s syndrome, Crohn’s disease, and Sjögren’s syndrome.  Pathologic Features. Microscopic features of GPA include necrosis with inflammation, granulomas, and vasculitis (see Fig. 5.32). Necrosis has a patchy, “geographic” distribution; it is usually basophilic, with a fine granular appearance.

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Granulomas can be intravascular and/or extravascular and consist of necrosis, palisading histiocytes, and scattered giant cells. They tend to be loose and are not as closely packed as in sarcoidosis or as may be seen in tuberculosis. Vasculitis typically affects small to medium-­sized arteries and veins. It is characterized by fibrinoid necrosis, fragmentation of the elastic lamina, infiltration with acute and chronic inflammatory cells, and granulomas (see Fig. 5.32B). These lesions may undergo healing, organization, and scar formation, which may lead to subglottic stenosis. In the study by Devaney and colleagues of head and neck GPA,281 two of the three histologic findings necessary for diagnosis (vasculitis, necrosis, and granulomatous inflammation), suggestive for GPA, were found in 44% of patients. The classic triad was found in only 16%. In a more recent study, Masiak and coworkers reviewed the usefulness of nonrenal biopsies in establishing a diagnosis of GPA.275 These authors confirmed that tissue biopsy is the “gold standard” of diagnosing GPA. The usefulness of tissue biopsy is even more critical in patients with a negative ANCA, in localized disease or in patients with unusual clinical presentations. These authors found that nasal mucosa and paranasal sinuses had the highest yields, 32% and 50%, respectively, for all three histologic findings typical of GPA (see earlier), while the larynx had a much lower yield (7%). These authors additionally noted that, especially in the acute lesions of GPA, the predominant pattern of inflammation is purulent, not granulomatous. Therefore biopsy specimens, taken early in disease evolution, may have the appearance of an abscess rather than a granuloma. Also, it is important for the clinician to properly sample the abnormal areas, focusing more on the viable and abnormal tissues adjacent to areas of necrosis, rather than the totally necrotic regions. Frequently, biopsies in the upper respiratory tract need to be repeated, trying to obtain a more definitive diagnosis.  Differential Diagnosis. The differential diagnosis of laryngotracheal granulomatous inflammation with necrosis includes tuberculosis, syphilis, histoplasmosis, cryptococcosis, blastomycosis, paracoccidioidomycosis, coccidioidomycosis, and candidiasis. Subglottic stenosis may also be a sequelae of relapsing polychondritis, LE, and previous trauma, including prolonged endotracheal intubation; it may also be of idiopathic origin. Vasculitis, when present, must be differentiated from other vasculitides and autoimmune diseases, such as LE, eosinophilic granulomatosis with polyangiitis (Churg-­ Straus syndrome), and microscopic polyarteritis.  Treatment and Prognosis. The combination of immuno­ suppressant drugs and corticosteroids has converted this previously fatal illness, typically occurring within months in patients with renal disease, into one in which 80% of patients achieve remission and improvement is achieved in 90% of patients.272 Immunosuppressive treatment usually consists of cyclophosphamide and prednisone. Prednisone can be tapered after improvement of symptoms, over 6 to 9 months. Cyclophosphamide therapy should be limited to 3 to 6 months. Remission can be maintained with methotrexate or azathioprine. Trimethoprim/sulfamethoxazole therapy can be initiated for patients with disease limited to the paranasal sinuses and upper and lower airways, without systemic vasculitis and renal involvement.282 Tracheostomy may be necessary for airway control and surgical laryngeal reconstruction may be needed; this is usually done during the quiescent stage. However, despite considerable therapeutic progress over the

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C Fig. 5.32  Granulomatosis with polyangiitis (Wegener’s granulomatosis). A, Geographic zones of necrosis with loose granulomas and giant cells. B, Vasculitis with segmental fibrinoid necrosis of the vessel wall (left middle) and giant cells (right middle). C, Antineutrophil cytoplasmic antibodies with cytoplasmic pattern in the serum.

last decades, relapses remain frequent (50% at 5 years), and maintenance treatment is now the main therapeutic challenge.272 Early diagnosis is essential to avoid morbidity and mortality associated with extended disease. As early disease is usually limited to the upper respiratory tract, the head and neck pathologist, by recognizing microscopic features suggestive of GPA, can play a crucial role in making the correct diagnosis. 

MUCOSAL BULLOUS DISEASES Benign Mucosal Pemphigoid and Pemphigus Vulgaris Though bullae (blister) formation on the skin and mucous membranes can develop in many diseases, there is a group of disorders in which blister formation is the primary and most distinctive feature. They are the result of the damage to desmosomes and

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

hemidesmosomes, caused by acquired or inherited defects in proteins, which are constituents of desmosomes or hemidesmosomes or bind to these structures. The target is the skin and/ or mucous membranes, particularly of the oral cavity and less frequently, of the pharynx, nose, esophagus, and larynx. They are classified based on the level of epithelial separation. Biopsy is needed to make the correct diagnosis, together with direct immunofluorescence, using skin or mucosal biopsy to detect in  vivo bound antibodies, and indirect immunofluorescence, using the patient’s serum and a substrate to detect circulating autoantibodies.283 Pemphigus and pemphigoid are the most important bullous diseases that may affect the larynx.  Pemphigoid Cicatricial pemphigoid (benign mucosal pemphigoid, bullous pemphigoid) is a chronic, progressive autoimmune subepithelial blistering disease with a female-­to-­male ratio of 2:1. Bullous pemphigoid is a more intense variant of cicatricial pemphigoid, with a predilection for the skin rather than mucous membranes. The incidence of cicatricial pemphigoid increases with advancing age. In a series of 142 patients (93 women and 49 men) with benign mucosal pemphigoid from the Mayo Clinic, 94% of patients were older than 50 years, and the peak age at onset was in the eighth decade of life.284 The mucous membranes are primarily affected, usually oral (88%) and ocular (60%); additionally, 18% of patients have mild skin lesions, usually of the limb flexor surfaces. The larynx and the oropharynx/hypopharynx are involved in 10% and 8% of patients, respectively, usually in the setting of disseminated disease.285–287 Clinical Features. Laryngeal involvement is an unusual primary manifestation of mucosal pemphigoid. Patients report hoarseness, odynophagia, or increasing dyspnea. Laryngeal erosive bullae tend to form on the epiglottis and/or aryepiglottic folds. The lesions of benign mucosal pemphigoid are erythematous and usually noncrusting. Nikolsky’s sign is indicative of the general mucosal fragility: a small amount of pressure applied to the normal mucosa (finger, pencil erasure, air blast) will result in mucosal shearing and ulceration. This test is nonspecific and can be positive in other mucocutaneous diseases, such as pemphigus vulgaris, erythema multiforme, and bullous lichen planus.

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Pemphigoid lesions heal by intense scarring; hence the appellation cicatricial. Mucosal scarring can lead to laryngeal stenosis and airway compromise. Ocular involvement and scarring lead to conjunctival symblepharon, corneal ulceration, and opacification.  Pathologic Features. Pemphigoid is the result of autoantibodies formed against hemidesmosomal proteins in the basement membrane zone: bullous pemphigoid antigen 180, bullous pemphigoid 230, α6 integrin, and β4 integrin.288 Rarely, autoantibodies to laminin 5 (epiligrin) are produced; this is referred to as antiepiligrin cicatricial pemphigoid.289 Separation or clefting of the mucosa from the lamina propria, at the level of the basement membrane, is diagnostic (Fig. 5.33). The lamina propria has a chronic inflammatory infiltrate and increased vascularity. Intramucosal acantholysis (Tzanck cells, tombstone cells) is not present; this histologic feature distinguishes pemphigus from pemphigoid.  Special Studies. Direct immunofluorescence reveals a linear deposition of IgG and/or IgM and complement directed against the basement membrane (see Fig. 5.33B). Indirect immunofluorescence, using patient serum against control skin, reveals the same pattern of deposition of IgG and complement against basement membrane. Immunoelectrophoresis studies of patient serum incubated against normal human epidermal extract can further identify the nature of the autoantibodies, that is, distinguishing IgG type IV collagen complexes from IgG laminin 5 complexes.  Differential Diagnosis. The differential diagnosis includes artifactual submucosal clefting, pemphigus vulgaris, erosive lichen planus, herpetic vesicles, and epidermolysis bullosa acquisita. Artifactual clefting may be difficult to distinguish from pemphigoid by light microscopy, especially if the lamina propria is inflamed. Clinical history and immunofluorescence can distinguish between pemphigoid and artifact. On light microscopy, the distinction between pemphigus and pemphigoid is made on the location of the mucosal clefting (intraepithelial with acantholysis for pemphigus vulgaris, subepithelial for pemphigoid). Reepithelialization of the floor of the blister in pemphigoid may be confused with the intramucosal clefting of pemphigus.  Treatment.  See treatment for pemphigus. 

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Fig. 5.33  Pemphigoid. A, Subepidermal separation with formation of a subepithelial vesicle. B, Immunofluorescence examination shows linear deposition of immunoglobulin G antibodies along the basement membrane, with a characteristic linear pattern.

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Pemphigus Pemphigus is a progressive mucocutaneous autoimmune intramucosal vesiculobullous disease. It occurs most commonly in the fourth and fifth decades of life, and there appears to be a predisposition for Jewish and Mediterranean individuals. Pemphigus may be subclassified as pemphigus foliaceous, pemphigus erythematosus, pemphigus vegetans, and pemphigus vulgaris. Pemphigus foliaceous is characterized by an extensive dermal exfoliative component, with little or no mucosal involvement. Pemphigus erythematosus (Senear-­ Usher syndrome) mimics lupus erythematosus in its malar distribution of the erythematous scaling crusting lesions; there is also little or no mucosal involvement. The lesions of pemphigus vegetans and pemphigus vulgaris initially appear on the mucous membranes, with subsequent dermal involvement. The actual oral vesicles are often not clinically observed because the acantholysis is suprabasal (intraepithelial), resulting in early rupture of the flaccid vesicles. Such ulcers are usually not serosanguineous, and they crust readily. Oral pemphigus involves the oral mucosa more diffusely than pemphigoid. The eroded bullae of pemphigus vegetans develop hypertrophic granulation tissue, producing hyperplastic lesions in the skin and vermilion border of the lips. Upper airway involvement by pemphigus vulgaris occurs in approximately 10% of patients and results in supraglottic laryngeal edema, which can lead to airway obstruction. Laryngotracheal (16%) and pharyngeal (49%) involvement occurs usually in the setting of clinically disseminated disease (oral and skin involvement).287 Laryngeal/ pharyngeal bullae can present as initial indicators of disease. Patients report sore throat, a burning sensation, and hoarseness. The hypopharynx, epiglottis, and aryepiglottic folds may reveal edema, ulceration, and inflamed mucosa.287 Patients with pemphigus have circulating IgG autoantibodies against desmosomal glycoprotein desmogliens. Pemphigus may also be drug induced, usually by thiol-­containing drugs, such as penicillin, and laryngeal involvement has been reported in drug-­induced pemphigus. It also can occur as a paraneoplastic syndrome associated with a hematologic malignancy. An increased risk for laryngeal and esophageal cancer has been

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observed in patients with pemphigus compared with control patients.290 Pathologic Features. Epithelial cell separation (acantholysis) and intraepithelial clefting are diagnostic for pemphigus, reflecting the loss of intercellular bridges caused by desmosomal antibodies (Fig. 5.34). The basal layer remains intact, attached to the lamina propria. The cells below the intramucosal cleft have a “tombstone”-­like effect, irregular with decreased cytoplasm and almost naked, rounded nuclei that protrude into the clefts, resembling tombstones on a hill. Individual spherical acantholytic cells, Tzanck cells, are seen floating within the intraepithelial clefts; they are rounded and enlarged and have large hyperchromatic nuclei.  Special Studies. Immunofluorescence reveals intercellular deposition of IgG and complement throughout the mucosal thickness, especially concentrated in the “prickle layer,” ­corresponding to deposition of autoantibodies against desmosomal tonofilament complexes (see Fig. 5.34B).  Treatment. Conventional therapy for mucocutaneous vesicular bullous disease consists of systemic corticosteroids and immunosuppressant agents, such as methotrexate, azathioprine, and cyclophosphamide.291 Tracheostomy may be necessary for airway management in acute disease. Disease remission can also be induced with intravenous immunoglobulin therapy, immunoadsorption, combination tetracycline, and niacinamide, and Rituximab.292–295  CROHN’S DISEASE Crohn’s disease (CD) or regional enteritis is one of the two major types of inflammatory bowel diseases. It may affect any part of the gastrointestinal tract, from mouth to anus. It is believed to develop as a result of interaction between genetic and environmental factors, which promote an excessive response of the gut-­associated immune system against the gut microbiota. The resulting chronic inflammation is mediated by cytokines, which play a crucial role in intestinal inflammation and the associated clinical symptoms, but may also regulate extraintestinal disease manifestations and

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Fig. 5.34  Pemphigus. A, Slit-­like intraepithelial vesicle with a few acantholytic cells. The cells below the intramucosal cleft have a “tombstone-­like” arrangement. B, Immunofluorescence examination shows deposition of immunoglobulin G antibodies in the intercellular region of the epithelium.

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

systemic effects. Extraintestinal manifestations of CD include inflammation of the joints, eyes, liver, and skin.296 The intestinal tract is primarily involved, most commonly the terminal ileum, cecum, and/or colon. It is characterized by transmural inflammation with ulcers, fistula formation, and in some patients, fibrosis of the bowel wall, leading to bowel stenosis and obstruction. The morphologic hallmark of CD are noncaseating granulomas, which are present in approximately 35% of patients.296 Clinical Features. Patients usually present with diarrhea, abdominal pain, weight loss, and fever. Upper aerodigestive tract involvement by CD is extremely rare, the most common site being the oral cavity. Oral inflammatory symptoms may precede the onset of intestinal symptoms in as many as 60% of patients.297 Laryngeal CD can occur anytime during the course of the disease, even in patients with a quiescent intestinal tract CD.298 Oropharyngeal and laryngeal manifestations can develop after ileocolectomy. Gianoli and Miller299 identified five cases of laryngeal involvement, plus one case of their own: a 44-­year-­old woman with ulcerations of the palate, nasal cavity, and vocal cords, as well as genital ulcers and evidence of small intestinal disease. Recently, Fawaz et al. included another case of laryngeal involvement by CD, making a total of less than 10 cases reported in the literature.298 In general, a female predominance is noted, with a peak incidence in the third decade of life. Many patients had generalized systemic involvement at the time of laryngeal symptoms. Upper airway involvement may be diffuse, with ulceration involving the entire oral and laryngotracheobronchial tract.300 Edema of the supraglottis and cricoarytenoid area and ulcerations are the most common laryngeal manifestations of CD.301 Pervez et al. reported on a child with CD, with severe involvement of the arytenoids and supraglottis, resulting in obstructive sleep apnea.302 Limited cricoarytenoid motility may occur, possibly as a result of joint arthritis.  Pathologic Features. In the small intestine, transmural chronic inflammation with interposed “skip areas” of relatively uninflamed mucosa are characteristic of CD. Involvement of the upper airway in CD is usually histologically nonspecific, revealing edema, ulceration, and/or nongranulomatous chronic inflammation.301 Occasionally, noncaseating granulomas may be seen in laryngeal or oral biopsies.302 Granulomas in CD are typically without necrosis, composed of macrophages and giant cells.  Differential Diagnosis. In the absence of granulomas, the histology of the upper airway mucosa is entirely nonspecific and correlation with the clinical picture is necessary to establish an association. If granulomas are seen, mycobacterial and fungal infections or sarcoidosis is included in the differential diagnosis.  Treatment. Acute upper airway ulcerative lesions can be managed with corticosteroid therapy. Infliximab, a chimeric antitumor necrosis factor α antibody, administered intravenously, is a promising therapeutic agent for patients with symptomatic Crohn’s enteritis, refractory to conventional therapy.297  NECROTIZING SIALOMETAPLASIA Clinical Features. Necrotizing sialometaplasia (NSM) is a benign, self-­healing, necrotizing, ulcerative, and inflammatory

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condition that arises in the salivary or seromucinous glands. The oral cavity, typically the palate, is the most common site; less commonly, the major salivary glands, trachea, and larynx may be involved.303–305 Abrams and colleagues303 initially described the clinicopathologic entity in 1973 as a benign lesion that may clinically and pathologically mimic mucoepidermoid carcinoma (MEC) or epidermoid carcinoma. We have reviewed the literature for primary cases of NSM of the larynx and found only occasional cases, involving the subglottis and false vocal cord306; one of them was associated with an adenosquamous carcinoma.307 In the larynx, NSM rarely produces a visible lesion. It is commonly encountered as an incidental postbiopsy finding within seromucinous glands. In this setting, NSM may cause diagnostic difficulty during evaluation of laryngectomy surgical margins, particularly during intraoperative frozen-­section evaluation.  Pathologic Features and Differential Diagnosis. Histologically, necrotizing sialometaplasia (NSM) in the larynx is similar to that described in minor salivary glands of the palate, characterized by lobular necrosis and sialadenitis, intermixed with squamous metaplasia of excretory ducts and acini. Laryngeal NSM can be distinguished from tumor extension into excretory ducts by recognizing smooth contours of the squamous nests, arranged in a lobular fashion with residual ductal lumina. Occasionally, however, severe regenerative atypia may accompany NSM, making it difficult to distinguish it with complete certainty from cancerization of seromucinous glands. Deeper histologic sections will usually clarify this dilemma by demonstrating extension of the atypical epithelial population from the overlying mucosa in the latter s­ ituation. Occasionally, invasive carcinoma may have invasive nests with smooth contours. Myoepithelial stains, in difficult cases, should help clarify this differential diagnosis by demonstrating an intact peripheral myoepithelial layer, supporting a ­noninvasive process.  Treatment and Prognosis. No treatment is necessary for NSM. It will heal spontaneously without intervention.  IMPACT OF GASTROINTESTINAL REFLUX DISEASE ON THE LARYNX Clinical Features. In addition to the symptoms of epigastric pain and reflux associated with gastrointestinal reflux disease (GERD), patients may also report hoarseness or change in vocal quality, dry scratchy throat, or pain radiating to the ear. It is estimated that up to 15% of all visits to otolaryngologists are because of manifestations of laryngopharyngeal reflux.308 In a recent study, Johnson reported that one in 10 new patient referrals to otolaryngologists, receives a diagnosis of GERD, suggesting the disease is increasingly diagnosed.309 GERD is known to affect the posterior glottis (interarytenoid region), causing contact ulcerations or granulomas (see later discussion). Laryngoscopy and symptomatic relief with proton-­pump inhibitors can indirectly establish the diagnosis of GERD-­related laryngitis.  Pathologic Features. Clinically, the endoscopic findings are localized to the posterior larynx (interarytenoid area). They range from mild edema and erythema to pronounced ulceration.308 Biopsy of a chronic, nonresolving laryngitis is recommended to rule out infections (e.g., tuberculosis) or neoplasia. The histopathology of reflux laryngitis is nonspecific and may overlap with contact granulomas (contact ulcer).

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The clinical history of GERD is helpful in establishing the diagnosis.  Differential Diagnosis. As the histology of GERD-­related laryngeal pathology is nonspecific, the differential diagnosis can be broad. Significant inflammation is not a common finding in laryngeal biopsies, and discussion with the clinician is recommended for laryngeal inflammatory lesions.  Treatment. Nocturnal antireflux precautions (avoid solid or liquid intake 2 to 3 hours before sleep, sleep with elevated head and shoulders) may relieve symptoms in half of affected patients. H2 blockers may be necessary in 25% of affected patients, in addition to nocturnal precautions. The remaining 25% of patients usually have more severe reflux laryngitis and require prolonged treatment with proton-­pump inhibitors, in addition to nocturnal precautions or Nissan fundoplication. In addition, new compounds, such as Marial (containing E-­Gastryal and magnesium alginate), are being tested to treat GERD that may also prove beneficial treating laryngopharyngeal reflux disease.310  CHONDROMETAPLASIA Clinical Features. Laryngeal chondrometaplasia refers to an expansile formation of benign, metaplastic cartilaginous tissue of limited growth potential.311–314 These lesions have also been referred to as chondromas. They are invariably small (1 cm or less) polypoid tumors on the middle or posterior vocal fold or arytenoid and usually asymptomatic. They have been incidental findings in less than 2% of autopsy larynges and are thought to be a degenerative consequence of vocal nodule formation. They can also occur after laryngeal trauma.314,315 Hyams and Rabuzzi311 identified nine cases of the vocal fold, with some additional cases reported in the last few decades.312–317 The lesions varied in size from 0.3 to 1 cm in maximum dimension, and patients typically presented with hoarseness. Few case reports describe imaging of chondrometaplasia, and there appears to be no specific features to distinguish the lesions from other laryngeal tumors; however, MRI may be useful to determine the extent of disease.318 

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Pathologic Features. Chondrometaplasia is composed of bland fibrohyaline cartilage with no direct attachment to underlying cartilaginous structures (Fig. 5.35). Hyams and Rabuzzi311 do point out that some “cordal lesions...seemed to infiltrate along seromucinous glands.” Elastic staining will reveal a high content of elastic fibers within the chondrometaplasia. There may be a peripheral rim of fibroblastic tissue merging with more mature chondrocytes toward the center.314  Differential Diagnosis. Overlying polypoid laryngeal mucosa and submucosa may mask the chondrometaplastic nature of the lesion. One might mistakenly assume that the cartilage present is part of normal anatomy rather a pathologic process. Correlation with the clinical impression of a mass lesion and confirmation of site of biopsy will be helpful in establishing the diagnosis. Conversely, one may question whether the cartilage is metaplastic or neoplastic. Neoplastic cartilage has a lobular growth pattern with tumor islands being sharply demarcated from the surrounding tissue, whereas chondrometaplasia blends into the surrounding soft tissue. Clinicopathological correlation is important. Cartilaginous neoplasms of the larynx most commonly occur in the posterior lamina of the cricoid cartilage and are rarely described in the glottis. A history of laryngeal trauma would favor a metaplastic process.  Treatment and Prognosis. Conservative endoscopic excision is usually curative. Hyams and Rabuzzi311 reported no recurrence of vocal cord chondrometaplasia. Anecdotally, we have seen one case of polypoid chondrometaplasia of the vocal cord, distinct from the arytenoid, which recurred after 6 years.  RELAPSING POLYCHONDRITIS Clinical Features. Relapsing polychondritis (RPC) is the term coined by Pearson and colleagues319 for an extremely rare, multisystem disease targeting connective tissues and cartilage. The cause of RPC is still unknown. It is considered an immune-­mediated disease and there is clinical overlap between well-­documented RPC, with other rheumatic and autoimmune diseases.326 The rarity of the condition means that epidemiological data is scarce. Studies in the United States have estimated an

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Fig. 5.35  A, Chondrometaplasia of the vocal fold; central ossification can be seen. The periphery reveals a mature chondroid matrix that blends into the surrounding fibroconnective tissue. B, Normal cartilaginous structures (e.g., cuneiform and corniculate cartilages) will also blend into the surrounding fibroconnective tissues. The distinction between chondrometaplasia and a normal cartilaginous structure is made by clinical correlation with the intraoperative origin of the biopsy.

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

incidence of 3.5/million people and a prevalence of 4.5/million, and in the United Kingdom, a study reported an incidence of 0.71/million per year and a prevalence of 9/million.320 RPC can occur over a wide age range, with a peak onset in the fifth decade of life and a slight male preponderance. The majority of affected sites are in the head and neck.321–323 A Japanese study showed a prevalence of organ involvement as follows: auricular cartilage 78.2%, inner ear 27.2%, nasal cartilage 39.3%, airway 50%, eye 46%, joints 38.9%, and cardiac 7.1%.320 The external ears are commonly involved and one-­third of cases present with chondritis of the pinna, resulting in a soft and “flabby” ear. Chondritis of the pinna may be present in up to 90% of cases during the course of the disease. The inflammation affects one or both ears and may be acute, subacute, or chronic. The affected ear is painful and looks red.320 The noncartilaginous auricular lobule is spared. Conductive hearing loss can occur as a result of external auditory meatal and eustachian tube involvement. The symptoms last for a few days or weeks and often spontaneously resolve. Recurrent episodes of pinna chondritis result in a scarred deformed ear (cauliflower ear). Seventy-­five percent of patients develop nasal involvement, commencing with a painful erythematous nose and progressing to septal collapse and saddle nose deformity. One series reported saddle nose deformity affecting 29% of patients. Nasal disease is less symptomatic and the saddle deformity may develop painlessly.320 At least half of patients develop upper airway symptoms, most commonly chronic progressive bronchitis and stridor caused by laryngotracheal chondritis. There may be cough and dyspnea. The thyroid cartilage is tender to palpation. Laryngotracheal edema may lead to early upper airway obstruction. Stenosis may be subglottic and localized or diffuse. Late complications include chronic obstructive pneumonia and fatal tracheal stenosis. It is important to identify airway involvement early and to treat inflammation aggressively, as it is an important cause of mortality.320 Patients report arthralgias as a result of involvement of articular cartilages (78%). Other manifestations include costochondritis (47%), episcleritis (60%), iritis (27%), and cataracts (33%). Temporal bone manifestations include cranial nerve VIII deafness, tinnitus, vertigo, otitis media, and mastoiditis. Cardiovascular involvement may lead to aortic ring insufficiency and aortic aneurysm. Cardiac disease is more common in elderly male patients and is the second most common cause of death in patients relapsing polychondritis.320 The audiovestibular symptoms and cardiovascular complications may be the result of a vasculitic component that can be present in RPC. Association with other autoimmune disease is common and seen in one-­ fourth to one-­third of patients with RPC, most often autoimmune vasculitis (e.g., granulomatosis with polyangiitis [GPA] [previously known as Wegener’s granulomatosis], Churg-­Strauss syndrome). The kidneys are rarely affected but renal disease carries a poor prognosis. Skin manifestations are present in about a third of patients and are more commonly seen in association with concomitant myelodysplastic syndrome.320 A recent Japanese study suggested airway chondritis was associated with nasal cartilage involvement and not with external ear chondritis,324 but other studies have not supported this observation.325 Diagnosis is based on characteristic clinical manifestations and currently, the criteria to be met are proven inflammation in at least two of three of the auricular, nasal, or laryngotracheal cartilages or proven inflammation in one of these cartilages plus two other signs, including eye involvement, vestibular dysfunction, seronegative inflammatory arthritis, or hearing loss.326

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The pathogenesis of RPC involves autoantibodies to type II collagen in cartilage, which are elevated in serum during the acute disease phase. The diagnosis is made based on clinical findings; the erythrocyte sedimentation rate is usually elevated during disease flare-­up. Serum anti–type II collagen antibodies are not diagnostically helpful because this test is prone to false-­ positive results. During active disease, the chondrolysis results in elevated urinary acid mucopolysaccharides. Calcific deposits can be appreciated radiographically in the pinna, nasal cartilages, and trachea. It would be uncommon for pathologists to receive biopsy specimens for diagnostic purposes; rather, the pathologist may see involved tissue after reconstructive surgery during disease quiescence. During acute periods, acute and chronic inflammatory cells infiltrate cartilage, and chondrocyte “dropout” is present. The cartilaginous matrix lacks the normal basophilic hue and becomes fragmented, leached out, and disintegrated (chondrolysis). The laryngotracheal mucosa is edematous and inflamed. Eventually, granulation tissue and fibrosis replace the cartilaginous structures, and metaplastic ossification may be seen. A vasculitic component may also be present in RPC.  Differential Diagnosis. Clinically, the erythema and painful nodules of the helix may mimic chondrodermatitis nodularis chronica helicis. The entire pinna is not swollen and erythematous in chondrodermatitis nodularis chronica helicis, and the remaining aerodigestive tract and audiovestibular system are unaffected. Saddle nose deformity may be seen in other entities, such as GPA, tertiary or congenital syphilis, and cocaine abuse. Disease affecting the larynx, trachea, and bronchi may cause symptoms that mimic chronic asthma. The otic symptoms may also be seen in GPA, polyarteritis nodosa, and Cogan’s (oculovestibuloauditory) syndrome. The latter is characterized by abrupt onset of tinnitus and vertigo, with progression to sensorineural deafness often occurring in conjunction with other autoimmune diseases. Frostbite may also cause calcifications of the pinna and nose.  Treatment and Prognosis. No standard treatment protocols have been developed for RPC; the condition is rare and no randomized controlled clinical trials have been reported. Treatment is aimed at controlling symptoms, maintaining a patent, stable airway, and preventing disease progression. Nonsteroidal antiinflammatory drugs, corticosteroid suppression b and/or dapsone are indicated for active disease. Steroid sparing immunosuppressive therapy includes treatment with cytotoxic drugs, such as methotrexate, colchicine, cyclosporine, and chlorambucil. Modern approaches to treatment include the use of biologic substances, such as anti-­ tumor necrosis factor (TNF)α agents. Stem cell transplantation and myeloablation therapy has been used in patients with severe disease who are at risk of organ failure. Plastic surgery and endoscopic surgical procedures can help manage disease and improve quality of life. Procedures, such as balloon dilatation and stenting of the airway, endobronchial laser and laryngotracheal reconstruction are usually reserved for those patients in whom medical treatments have failed, or who require airway support during therapy, or who have developed airway stenosis or obstruction.327 Many patients will require tracheostomy for airway management. Most fatalities are the result of airway collapse or chronic pneumonia and sepsis caused by immunosuppression. Recently, a long-­term study using uncovered self-­expanding metal stents to treat central airway involvement of RPC was completed.

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Long-­term clinical benefits, including improvement of lung function, exercise tolerance and dyspnea were found.328 In a French study of 142 patients, the authors observed they could separate their cohort of patients into three prognostic categories or clusters: a “hematologic” group, wherein the RP was associated with hematological malignancy, usually myelodysplastic syndrome, and which carried a very poor prognosis resulting in death; a “respiratory” subgroup that was associated with infection and intensive care unit admission; and a “mild” subgroup, associated with few clinical symptoms and spontaneous remission. The poorest prognosis was associated with male sex, cardiac involvement, and associated hematological malignancy.325  TRACHEOPATHIA CHONDRO-OSTEOPLASTICA Clinical Features. Tracheopathia chondro-osteoplastica (TCO), sometimes called tracheobronchopathia osteochondroplastica, is a disease of unknown etiology, almost always limited to the trachea, which causes progressive ossification and increasing tracheal rigidity. The disease is known to occur rarely in cricoid cartilage, and recently a case report described the condition affecting thyroid cartilage in the larynx.329 The incidence is reported as one in every 2000 to 5000 patients.330 In a large cohort of 41,600 patients who underwent bronchoscopy in Shanghai China, TCO was diagnosed in 22 (0.05%) people.331 Another Chinese series reported an incidence of two cases in approximately 2000 (0.1%) patients undergoing bronchoscopy in Sichuan Province.332 A review of the English literature for indexed cases of tracheopathia chondro-osteoplastica resulted only in 72 scientific publications confirming the rarity of the disease.333 Symptoms appear in the third and fourth decades of life but have occurred as early as 12 years of age.334 Patients usually have a long history of chronic cough and asthma, which may progress to hemoptysis, inspiratory stridor, and laryngotracheobronchitis. Associated atrophic rhinitis is common. The degree of tracheal involvement varies widely; accordingly, the exact incidence of TCO is unknown. Rare familial involvement has been reported.335 An association between TCO and amyloidosis has been described, and it has been suggested that TCO represents an end stage of primary localized tracheal amyloidosis or a variant of primary pulmonary amyloidosis336; however, an autopsy series failed to confirm an association.337 Other authors claim that tracheal amyloidosis is readily distinguishable from TCO on bronchoscopy because amyloid typically affects the posterior aspect and appears as grey mucosal nodules that bleed on contact.330 Chronic infection has been cited as another possible etiologic factor. TCO has been reported in association with K. ozaenae infection and with tuberculosis. Case reports have described TCO in association with other conditions, including pneumoconiosis, lung cancer, myeloma, and non-­Hodgkin lymphoma.338–340 Some theories implicate pluripotential stem cells present in the tracheal mucosa in the abnormal formation of bone and cartilage associated with this condition.339 Virchow, in 1863, suggested that TCO might be a localized form of enchondroses, a theory still in vogue.341 It has been suggested that only 51% of patients affected with TCO are diagnosed in their lifetime. The symptoms are nonspecific and the time interval between presentation for specialist treatment and diagnosis may be as long as 2 to 5 years.342 Diagnosis may involve pulmonary function tests (PFTs), CT imaging,

and endoscopy. Imaging is more effective than PFTs in detecting patients with mild disease and calcified nodules are easily seen on bronchial or tracheal CT, usually measuring between 1 and 6 mm.338 Laryngoscopy and bronchoscopy reveal gritty small submucosal nodules, 0.5 cm or smaller, causing a beaded or “rock garden” appearance. The projections arise from the lateral and anterior tracheal walls; the membranous posterior trachea is usually spared. Serum calcium and phosphorus are generally normal. The trachea may be severely narrowed, as the tracheal walls become more rigid and thickened. The vocal cords are only occasionally involved. Rarely, TCO exclusively affects the larynx.343,344  Pathologic Features. It has to be said that TCO is usually diagnosed clinically, and biopsy is considered unnecessary by most experts.338 In the largest cohort of patients reported to date (41 patients) by a French group, biopsy was diagnostic in 70%.345 Heterotopic calcification and ossification, with mature bone formation resembling osteomas, are seen in the lamina propria.346 Marrow spaces develop new bone growth. Some of the ossifications are unconnected to the tracheal rings, whereas others are contiguous with the tracheal rings. Osseous metaplasia of the tracheal rings may also be seen. Areas of atypical disorganized cartilaginous tissue resembling enchondroses may be seen (Fig. 5.36). Young and colleagues346 maintain that serial sectioning always reveals a connection between the ossified projection and the internal perichondrium of the tracheal rings, favoring Virchow’s enchondroses theory. Amyloid deposits can be seen in some cases.347 The French study reported 2 of 16 biopsies tested for amyloid were positive.345 Coincidental bronchial mucoepidermoid carcinoma (MEC) and TCO have been reported.348 

Fig. 5.36  Tracheopathia chondro-osteoplastica. Note areas of atypical disorganized cartilaginous tissue that is connected with underlying tracheal cartilage. (From Muckleston, H.S., 1909. On so-­called “multiple osteomata” of the tracheal mucous membrane. Laryngoscope. 19, 881–893.)

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Differential Diagnosis. If disorganized cartilaginous tissue is present on a tracheal biopsy sample, the differential diagnosis includes a low-­ grade cricoid chondrosarcoma. Clinical and radiographic correlation can aid in this distinction. One needs to distinguish normal tracheal metaplastic ossification seen as part of the aging process from pathologic ossification; ossification seen in the tracheal lamina propria, separate from the tracheal ring, is pathologic. Heterotopic bone formation (myositis ossificans) is rare in the larynx.349 It is included in the differential diagnosis of TCO, which rarely affects the larynx exclusively. Histologically, TCO involves ossification of metaplastic cartilage, whereas myositis ossificans typically has a zonation effect of a central immature, proliferative, fibroblastic component with osteoid formation, and an outer shell of varying thickness composed of maturing bone. Importantly, endochondral ossification is not a usual component of myositis ossificans as it is of TCO. The clinical distinction between localized TCO and laryngeal myositis ossificans is not important because laryngeal function may be restored in both by conservative excision.  Treatment and Prognosis. There are no specific treatment recommendations for TCO and the aims are to alleviate symptoms and minimize complications. Severely symptomatic patients may be treated with laser bronchoscopy, in an attempt to increase the tracheal lumen size. Hemoptysis may require treatment, such as argon plasma ablation or electrocautery.338 Occasional mortalities have been attributed to complications of TCO, whereas other cases are incidental autopsy findings.  POSTRADIATION TREATMENT CHANGES During the last two decades, primary treatment of laryngeal cancer has trended toward organ-­preserving strategies. Radiation therapy is now considered the treatment option not only for patients with early-­stage laryngeal carcinoma, with excellent local control and survival rates, but also for high-­stage laryngeal carcinoma, usually in combination with chemotherapy or targeted therapy.350 The larynx can also be included incidentally in the irradiation field when radiotherapy is administered for head and neck cancer at other sites. Radiation effect unfortunately is not restricted to tumor cells; normal tissue is also injured during radiotherapy. The degree of damage is dependent on the treatment regimen-­related factors, including type of radiation, total dose administered, and field size/fractionation. Radiotherapy toxicity is generally separated into acute toxicity occurring during or shortly after the radiotherapy, and long-­term toxicity, which can manifest itself months to years after the completion of the treatment. The acute effects of radiation toxicity are attributed to cell death and subsequent inflammation. The late effects, which are progressive and irreversible, are likely caused by blood vessel injury resulting in ischemia, depletion of slowly proliferating stem cells and fibroblast dysfunction, with excessive collagen deposition leading to fibrosis.351 Experimental studies suggest that irradiated fibroblasts exhibit an accelerated extracellular matrix synthesis with a predilection for deposition of early immature (randomly organized) collagen type III fibrils, as opposed to mature type I collagen.352 Proliferative cells, such as epithelial cells, salivary glands, stromal fibroblasts, and endothelial cells are most vulnerable to radiation-­induced injury. Cartilage has few blood vessels and rare proliferating cells, making it intrinsically resistant to

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the direct effects of ionizing radiation. In contrast, the perichondrium, from which the cartilage receives its blood supply, is sensitive to radiation injury. Chondronecrosis thus follows perichondritis and/or breakdown of the overlying mucosa. As laryngeal cartilages ossify with age, they develop their own blood supply and become susceptible to radiation damage.353,354 Clinical Features. Radiation-­induced injury of the larynx can present clinically with hoarseness, dyspnea, pain, dysphagia, weight loss, hemoptysis, edema, and upper airway obstruction that may require a tracheostomy. The severity of radiation injury to various organs, including the larynx, can be assessed using toxicity grading systems, which are useful in choosing the most optimal treatment.355 The signs and symptoms of radiation-­ induced injury are also similar to recurrent carcinoma. Therefore recurrent carcinoma is always part of the differential diagnosis.  Pathologic Features. The most frequent features of radiation-­ induced laryngeal injury include mucosal edema, ulceration, necrosis, and fibrosis. Severe fibrosis may develop resulting in glottic stenosis. Salivary glands are also highly vulnerable to radiation, resulting in destruction and severe gland atrophy, contributing further to mucosal damage. Perichondritis, chondronecrosis, and osteonecrosis are rare complications, which may require salvage laryngectomy. They occur more often in patients with cancer infiltrating the cartilage and ongoing smoking and alcohol abuse after radiation.354 The arytenoid cartilages commonly ossify in adults and are a common site of chondroosteonecrosis.353,354 Osteonecrosis of the hyoid bone has also been described.356 Secondary infection, particularly with fungi, may play an important role in the development of extensive postirradiation necrosis of the larynx.357 Radiation-­induced injury generally increases cell size, nuclei are especially large, and cells may be multinucleated. Nucleoli may be prominent. However, in pure radiation change, the chromatin appears washed out, smudged, blurry, and homogeneous, not coarse. The nucleus-­to-­cytoplasm ratio is preserved, not increased. Nucleus and cytoplasm vacuolization is present; the latter results in pseudoglandular spaces seen in postradiation SCC. Additional changes that bespeak previous irradiation include acinar atrophy of minor salivary glands, squamous metaplasia of ducts, perivascular hyalinization, vascular intimal hyperplasia, stromal atypia, and dense fibrosis (Fig. 5.37). Dysplasia may be superimposed on radiation changes; the result is that the degree of dysplasia may be overestimated or the dysplasia may mimic invasion. These cases should be handled prudently, with the awareness of the histologic pall cast by radiation. Tangentially sectioned epithelial hyperplasia, from either surface mucosa or salivary ducts, is especially prone to overdiagnosis. Although distorted, recognizing the basic structure of a duct, such as smooth contours, basement membrane, and ductal lumina, may be helpful. Step sections can confirm the presence of a ductal lumen. Detection of recurrent carcinoma in patients, with severe postirradiation damage, is demanding, both clinically and pathologically. Pathologists should be reluctant to diagnose infiltrating squamous cell carcinoma in the setting of generalized pseudoepitheliomatous hyperplasia. Invasive carcinoma usually has jaggedly contoured tumor nests. Not surprisingly, recurrent carcinoma in radiation failure often consists of smaller and more widely dispersed tumor islands, which may be entirely subepithelial, thus accounting for the difficulties in clinically evaluating the larynx after radiation therapy.

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Fig. 5.37  Radiation changes. A, Epithelial hyperplasia in the setting of previous irradiation for carcinoma. The elongated rete pegs tempt the diagnosis of infiltrating squamous cell carcinoma, which need not be accompanied by surface carcinoma in situ. The smooth contours speak for benignity. B, Intimal hyperplasia and perivascular fibrosis. C, Severe atrophy of the laryngeal seromucinous glands; only dilated ducts are preserved. D, Fibrosis of the lamina propria, with scattered plump to elongated atypical fibroblasts.

The surgical pathologist should be familiar with the appearance of radiation effects and not misdiagnose postirradiation changes as recurrent carcinoma. This is especially critical if the patient has received chemoradiation. The cytologic atypia of mucosa treated with this latter combination often is severely atypical, frequently much more atypical than with radiation therapy alone, and therefore it is important for the pathologist to remember this or else there may be a tendency toward overdiagnosis of malignancy, rather than severely atypical, reactive changes. Also, the atypia from radiation treatment may be

present for long periods after completing radiation therapy, frequently for the rest of the patient’s life.  HAMARTOMA A hamartoma is a benign tumor-­like growth composed of mature tissue indigenous to the region. Laryngeal hamartomas are rare. Rinaldo and colleagues reviewed 11 reported cases with published histology.358 Laryngeal hamartomas have been reported in children and in adults. In the newborn, a hamartoma can cause

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

airway obstruction at birth.359 In pediatric patients, the clinical presentation includes recurrent pneumonia and persistent stridor,360 as well as respiratory distress and changes in voice and eating.361 Some pediatric laryngeal hamartomas are associated with cleft larynges362,363; adult hamartomas have not been associated with laryngeal defects.364 Hamartomas present as exophytic/polypoid masses ranging up to more than 8 cm in greatest dimension.365 Upper airway symptoms are common to all patients. Pathologic Features. Hamartomas may be classified as either epithelial, mesenchymal, or mixed types. The term mesenchymoma has also been applied to tumors of benign indigenous mesenchymal histology; however, the designation hamartoma conveys unquestionable benignity. The hamartoma may form a septum-­like mass, originating from the posterior larynx that is covered with epithelium. Histologically, it is composed of mature but disorganized skeletal muscle, mature cartilage, minor salivary tissue, and adipose tissue. Other laryngeal hamartomas appear as polypoid tumors histologically composed of either mesenchymal elements (fat, vessels, muscle, fibrous tissue) and/ or epithelial elements (salivary-type tissue; Fig. 5.38). The cartilaginous component has been noted to blend or merge into the surrounding stroma. A case containing ectopic thymus has also been reported.366  Differential Diagnosis. The diagnosis of pediatric lesions should be straightforward, especially in the presence of laryngeal malformation. In adults, the differential diagnosis may include chondrometaplasia, pleomorphic adenoma, low-­grade cartilaginous neoplasms, teratoma, adult rhabdomyoma, and low-­ grade liposarcoma. Chondrometaplasia is an expansile formation of benign, metaplastic cartilaginous tissue of limited growth potential, usually of the vocal fold. It appears as bland cartilage that typically blends into the surrounding soft tissue, rather than pushing against it. The cartilaginous tissue of the polyp has no direct attachment to underlying cartilaginous structures and is not associated with other tissue types (e.g., muscle, glands). Pleomorphic adenoma can be distinguished from the other lesions by the presence of myoepithelial cells

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within the chondroid stroma and surrounding glandular/ductular tumor cells. The overall tissue maturity and lack of nonindigenous tissue types will distinguish a hamartoma from a cervical teratoma, which is usually a mixture of immature and maturing tissue of ectodermal, mesodermal, and endodermal origin. A hamartoma may be distinguished from an adult-­type rhabdomyoma by the presence of other endogenous elements, such as adipose and fibroblastic tissues. A low-­grade liposarcoma may have a prominent fibroblastic component and mimic a mesenchymal hamartoma, but additional elements (e.g., thick-­ walled vessels, smooth or skeletal muscle) should also be seen in the latter.  Treatment and Prognosis. The lesions require excision to improve the airway and voice. Direct laryngoscopy and (multiple) debulking procedures may be necessary. However, overall oncologic aggression has not been reported.   LARYNGOMALACIA Laryngomalacia is a structural anomaly of supraglottic cartilage, causing inward collapse of the supraglottic airway on inspiration. It comprises 60% of congenital laryngeal abnormalities, and it is the commonest cause of pediatric upper a­ irway obstruction (45%–75% of cases), presenting as inspiratory stridor commencing at 2 weeks of age.367 Other causes include bilateral vocal cord paralysis, subglottic stenosis, subglottic hemangioma, saccular cyst, laryngeal web, and, finally, laryngeal atresia.368 In affected children, the epiglottis is long and tubular with an abnormal, “ohm symbol” shape (Ώ) and the cuneiform and corniculate cartilages prolapse over the laryngeal inlet. In severe cases of laryngomalacia, the vocal cords cannot be visualized, and pectus excavatum may be present. Symptoms of laryngomalacia usually resolve spontaneously by the time the child is 12­to 18 months old, but surgery is required for persistent disease and in about 10% of cases at presentation.

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Fig. 5.38  A, Endotracheal polypoid hamartoma. This tumor contained disorganized maturing cartilage, fibroadipose, and vascular tissue. The arrow indicates tracheal cartilage (inset). B, Another laryngeal hamartoma that arose within the ventricle and contained cartilaginous (c) and neural tissue (n). (Courtesy of Dr. J. Hille.)

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Laryngomalacia is a very rare cause of airway obstruction in the adult, with about 30 cases reported in the literature, including 20 males and 10 females. It occurs in patients with no history of congenital disease who present with supraglottic airway collapse on inspiration. The age range is 21 to 73 years, and the mean age at presentation was 44.5 years for males and 46.4 years for females. Exercise induced laryngomalacia is a disease affecting mostly female athletes in adolescence. In adults, the epiglottis appears anatomically and histologically normal, but there is abnormal movement on inspiration.369 Laryngomalacia is diagnosed and staged most accurately by fiberoptic endoscopy alone in the majority of cases.370,371 Recently, a small study from Israel showed that laryngeal ultrasound could be used reliably to diagnose infantile laryngomalacia in the majority of cases, in a series of 24 patients with stridor. The results from ultrasound scan was in accordance with the diagnosis made on flexible laryngobronchoscopy in 21/24 cases (88%). There were three false negative diagnoses using ultrasound scanning and these patients were diagnosed with mild disease on flexible laryngobronchoscopy.372 Symptoms other than airway obstruction include obstructive sleep apnea, gastroesophageal reflux (13%–60% patients), as well as genetic and neurologic conditions. Up to 80% patients have reported apneic events prior to surgery with the incidence increasing with disease severity. The incidence of neurological conditions also appears to increase with increasing severity of the laryngomalacia. The reported incidence of associated neurological abnormality is 8% of patients with mild laryngomalacia, 11% of patients with moderate disease and 34% of patients with severe disease.367 Cor pulmonale is seen in association with severe laryngomalacia that develops as a result of pulmonary hypertension and polycythemia.367 There is no universally accepted classification of disease severity. A simple classification of laryngomalacia describes three types that correlate with the type of surgery required to relieve the obstruction. Type 1 laryngomalacia patients have anterior prolapse of bulky arytenoid tissue; in type 2, there is medial collapse of short aryepiglottic folds; and in type 3, there is posterior collapse of the epiglottis. Most patients present with a mixture of one or more of these subtypes.367 In a series of 103 term and preterm infants, anterior and posterior collapse was the most common finding in 31%, posterior collapse alone was seen in 25%, anterior alone in 14%, lateral alone in 10%, lateral and posterior in 5%, anterior and lateral in 3%, and 12% of patients had collapse in all three anatomic locations. In 41% of patients, there was a secondary airway lesion, with tracheomalacia being the most common.370,373 In adult patients the commonest abnormality was posterior prolapse of the epiglottis on inspiration.369 Early studies suggested that the mechanisms causing laryngomalacia could be related to anatomical or cartilage abnormalities; however no ultrastructural or histologic abnormality of cartilage has been demonstrated and an underlying neurological abnormality is now favored; although such a mechanism was first suggested as long ago as 1900.367 Recently, research into the etiology of laryngomalacia has focused on neuromuscular pathways, and possible immaturity of peripheral nerves or brain integration pathways associated with swallowing and airway maintenance. Such theories have been supported by abnormal nerve conduction studies in patients and the histological observation of a difference in size of the branches of the laryngeal nerve in patients and age-matched controls. Also,

the spontaneous resolution of symptoms could be explained by maturation of peripheral and nervous system pathways. The finding of hypertrophic nerves in resected supraglottic tissue also seems to support this theory.367 The condition in adults is divided into two main groups, idiopathic and acquired. The acquired group may be further subdivided into neurological, iatrogenic, and traumatic etiology.369 Since symptoms resolve spontaneously in the majority of cases, treatment for mild to moderate disease is conservative, using observation and positional therapy. Antireflux therapy is also indicated, as gastroesophageal reflux is a common aggravating cofactor in laryngomalacia. The suggested mechanism for the effect of gastroesophageal reflux disease (GERD) is that the reflux causes inflammation and edema that, in turn, causes laryngeal mucosal prolapse. The edema may also exacerbate preexisting poor or reduced tissue tone and sensation.367 However, although there is an increased incidence of GERD in patients with laryngomalacia and subglottic stenosis, there is no firm evidence of a causal relationship and several studies have shown weak and inconsistent evidence of improvement in symptoms after antireflux therapy.374 The small group of children in whom symptoms persist may require surgical intervention, possibly a combination of a partial epiglottectomy, division of the aryepiglottic folds and removal of redundant mucosa. Although arysupraglottoplasty is the treatment of choice in children requiring surgery, there is still marked variation and lack of consensus in treatment practice.370 Surgical rates between 12% and 31% (most are between 12%–15%) are reported, and the average age of the patents undergoing surgery is between 3.8 and 5.5 months. In a series of children with congenital stridor reported from India, 80% had laryngomalacia, nine patients (22.5%) required surgery, and six patients (15%) were treated with tracheostomy to relieve airway obstruction.371 Reported success rates for surgical treatment range between 50% and 95%.375,376 Poorer outcomes appear to be related to the severity of disease, presence of synchronous airway lesions and/or comorbidities and to prematurity.377 Adult patients with laryngomalacia have been treated by supraglottectomy and epiglottectomy, using laser, preferably CO2 laser. The outcomes have been good with only one procedure being required.369 Comparison of surgical techniques and management are impaired by the lack of good data, including the types of surgery used. An accepted classification of the type and severity of laryngomalacia is required to guide the decision for surgical management and to allow comparison of outcomes.370 

Benign and Malignant Laryngeal Neoplasia LARYNGEAL PAPILLOMATOSIS: JUVENILE-­ ONSET AND ADULT-­ONSET PAPILLOMAS AND AGGRESSIVE PAPILLOMATOSIS Laryngeal squamous cell papillomas are benign exophytic epithelial tumors, consisting of a central fibrovascular core, lined by squamous epithelium. Ullman,378 in 1928, suspected an infectious etiology for laryngeal papillomas; he successfully produced papilloma-­like growths on his arm and on the arm of his assistant after injection of cell-­free tissue extracts derived from a laryngeal papilloma from a child. The association of papillomas with human papilloma virus (HPV) infection is now proven; they are caused mostly by infection with HPV types 6 and 11, but occasionally coinfection with HPV-18 has been reported.379

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As they usually exhibit multiplicity, recurrences, and propensity to spread to adjacent areas, a new term, recurrent respiratory papillomatosis, has been proposed for laryngeal papillomatosis. They occur in children and in adults. Because of this bimodal age distribution, they are divided into juvenile-­onset and adult-­ onset papillomas. Clinical Features. Juvenile-­onset laryngeal papillomatosis (JOLP) is usually characterized by an aggressive course, distinct from adult-­onset laryngeal papilloma (AOLP). JOLP presents often before the age of 5 years, without gender predominance. The papillomas are multiple and may carpet the endolarynx

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and subglottis, resulting in extreme hoarseness and airway obstruction (Fig. 5.39). The clinical course of JOLP is marked by innumerable recurrences, potential airway obstruction, and need for multiple laser CO2 microdebrider excisions to maintain airway patency.380 Most cases resolve by puberty, but some patients with JOLP may have disease that persists into adulthood. By contrast, AOLP occurs after the second decade of life, with a strong male predominance. These lesions are usually single and amenable to endoscopic excision. Occasionally, AOLP may present with multiple lesions that recur after

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Fig. 5.39  Laryngeal papillomatosis. A, Endoscopic view of laryngeal papillomatosis. B, Macroscopic view after excision. C, Microscopically, papillomas consist of mature nonkeratinizing squamous epithelium and a fibrovascular core. D, In situ hybridization for human papilloma virus 6/11 is positive in many epithelial cell nuclei.

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excision and develop dysplasia and malignant transformation. In a 10-year retrospective study, Karatayli-­Ozgursoy et al. collected 159 patients: 96 were AOLP, and 63 JOLP; 139 patients (87%) had only benign papilloma as a histopathologic diagnosis. In the AOLP cohort, 10 patients (10%) were diagnosed with dysplasia or carcinoma in situ in addition to papilloma, and 5 patients (5%) had malignant transformation to invasive carcinoma-­ex-­papilloma. Of the 63 JOLP patients, there were no cases of dysplasia, but 3(5%) patients were diagnosed as having invasive carcinoma-­ex-­papilloma, all involving pulmonary disease.381 The association of HPV with JOLP and AOLP has been clearly established; HPV-­6 and HPV-­11 are most commonly detected.382,383 Latent HPV infection, defined as HPV detected in histologically normal mucosa, is the source of reactivation and clinical recurrences. HPV is detected in approximately 50% of laryngeal and tracheal nonpapilloma samples from patients with recurrent laryngeal papillomatosis.384 The upper airway may be first exposed to HPV during vaginal delivery.385 A history of maternal condyloma is common among patients with laryngeal papillomas. The exposure rate for neonates of HPV-­positive mothers is significant: HPV DNA was isolated from the nasopharyngeal secretions of 47% of vaginally delivered neonates whose mothers had been demonstrated to have HPV-­positive cervical cells. The infection rate appears to be low, in keeping with the relative rarity of laryngeal papillomas, despite the high incidence of genitourinary condylomas. Transplacental hematogenous transmission is also possible.386 The transmission of AOLP is presumably via sexual contact. Patients with AOLP have greater numbers of lifetime sexual partners than control patients without AOLP.387  Pathologic Features. Histologically, laryngeal papillomas are composed of branching thin projections of stratified squamous epithelium over fibrovascular cores (see Fig. 5.39). The squamous mucosa is usually immature, without significant keratinization. Basal cell hyperplasia with an increased mitotic rate is often present. Clusters of koilocytes can be seen in the upper layers of the epithelium. They are the only visible cytopathic effect of HPV infection and are recognized by dark, wrinkled, or angulated nuclei, surrounded by a clear cytoplasm.388 Dense keratinization, intramucosal keratinization, diffuse dysplasia of any degree, or full-­thickness dysplasia should raise the possibility of a squamous cell carcinoma-­ex-­papilloma or a papillary squamous cell carcinoma. Dysplasia in a papilloma predicts the likelihood of a clinical recurrence.  Differential Diagnosis. Among benign lesions, the main distinction is with verruca. Laryngeal verruca vulgaris is uncommon and has been associated, as with papillomas, with HPV-­6 and HPV-­11.389 Verruca vulgaris lacks the more complex branching fibrovascular cores seen in papillomas and has a thick coating of hyperkeratosis and parakeratosis, usually with prominent keratohyaline granules. The rete pegs of verruca vulgaris are a thin, nonclubbed shape and do not push into underlying deep tissues. Also the fibrovascular cores of verruca vulgaris frequently radiate from a central focus. The main malignant differential diagnoses, especially in adults, are papillary squamous cell carcinoma (SCC), in situ or invasive types, and exophytic SCC. Squamous papillomas have a defined stalk and smoothly lined papillae, whereas papillary SCC are usually broad-­based or sessile with fronds, demonstrating complicated, irregular silhouettes. Papillary SCC may be noninfiltrating or have an infiltrating component. Papillary

carcinoma in situ produces finger-­like growths with fibrovascular cores covered by a dysplastic epithelial lining; the dysplasia frequently extends into seromucinous ducts. Exophytic SCC has a cauliflower-­like appearance and is composed of ribbons of stratified squamous cells, aligned atop a basement membrane, thus bearing superficial resemblance to papilloma. This tumor has a more complicated, crowded exophytic papillary arrangement than does squamous papilloma. The presence of dysplasia and greater degree of keratinization, especially intraepithelial keratin pearls and foci of microinvasion help distinguish it from papillomas. Intraepithelial keratin pearls are not routinely seen in papillomas and should raise suspicion of malignant progression, papillary SCC, or exophytic SCC.  Treatment and Prognosis. Patients with JOLP may require innumerable endoscopic procedures to maintain airway patency. A tissue microdebrider or a CO2 laser is used to remove the papillomas. If surgical procedures are needed more frequently than four times in 12 months, adjuvant therapy with antiviral drugs must be considered. Adjuvant therapy with antiviral drugs, for example, with cidofovir, acyclovir, valacyclovir may increase the interval between relapses.390–392 Promising results are expected from vaccination with a quadrivalent vaccine against HPV strains 6, 11, 16, and 18.392 It may prolong the time to recurrence in the recurrent respiratory papillomatosis (RRP) population. Furthermore, it is expected that wide-spread HPV vaccination could reduce RRP incidence indirectly, by preventing vertical HPV transmission to newborns. Preliminary data indicate that adjuvant use of quadrivalent vaccine has significant benefit on patients with laryngeal papillomatosis.393–395 Some studies, on the contrary, indicate that vaccination has no impact on the disease course.396 Large clinical trials have been recommended to decide if vaccination should become the standard of therapy.395 AOLP may be treated by conservative endoscopic excision. Patients with dysplastic papillomas require close clinical follow-­up. In up to 25% of patients with either JOLP or AOLP, florid aggressive papillomatosis or aggressive papillomatosis may occur. It refers to diffuse laryngotracheal papillomatosis, which carpets the endolarynx and may extend into the tracheobronchial tree and the pulmonary parenchyma. These patients require tracheostomy for airway control and may require laryngectomy for disease control.397 Malignant transformation is a feared consequence of laryngeal papillomatosis. This may occur in concert with known external promoters (e.g., irradiation, cigarette smoking) or may rarely develop de novo; the reported rate of transformation for all laryngeal papillomas has been variable, between 2% and 17%.398–402 Malignant transformation is usually related to long disease duration and may occur in localized and diffuse cases, in both JOLP and AOLP. The transformation rate of JOLP is much lower than that of AOLP, which is approximately 10%.381 Cofactors promoting carcinogenesis include irradiation, smoking, and bleomycin. Bronchopulmonary extension of papillomatosis and failure to respond to interferon-­alfa therapy can predict malignant transformation.402 Clinical findings that suggest malignant transformation include decreased vocal fold mobility, the presence of enlarged cervical lymph nodes, exuberant and rapid growth requiring very frequent excisions, and laryngeal edema. Histologically, malignant transformation may be preceded by progression of dysplasia; however, some well-­differentiated carcinomas may develop in the absence of dysplasia.403 Interestingly, HPV-­11, and occasionally HPV-­6,

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

can be associated with malignant transformation.402–404 An associated carcinoma was found to contain episomal HPV-­6a genomes, with duplications of the upstream regulatory region, the late region, and a portion of the early region. These duplications were absent from the associated benign laryngeal papilloma, suggesting that viral mutation may be necessary for induction of carcinogenesis in low-­risk HPV types.404  GRANULAR CELL TUMOR Clinical Features. Granular cell tumors are benign, slow-­ growing tumors of schwannian or preschwannian origin, and occur with a female preponderance and in a greater than expected proportion of African-Americans. A wide age range is seen, with a peak incidence in the third to fifth decades of life. Although these tumors can occur throughout the body, the head and neck are the most common sites for granular cell tumors, usually the anterior tongue and subcutaneous tissues of the head and neck.405 The larynx and trachea are less commonly involved, representing 1.6% to 3.7% of involved sites.406,407 In a recent review of nonepithelial tumors of the larynx, from a single institution, over a 10-­year period, Karatayli-­Ozgursoy et  al. found 3/24 (12.5%) cases were granular cell tumors.408 Equally, Jobrack et al. found only 1/13 (7.7%) cases in the larynx, in an extensive review over 20 years.409 Multiple synchronous or metachronous tumors at various sites occur in approximately 5% of patients. Laryngeal granular cell tumors are smooth, white, polypoid tumors arising from the posterior true vocal folds or, less often, from the anterior commissure, false cords, subglottis, arytenoid,308,410 and trachea. Pediatric laryngeal granular cell tumors, unlike the adult laryngeal counterparts, have a predisposition for the anterior subglottis,411 but transglottic cases are reported in both children412 and adults.413 Patients with laryngeal granular cell tumors usually report hoarseness; those with tracheal tumors invariably have a long history of intractable asthma. In children, they can be mistaken for papillomas or even laryngeal malignancy.414 The white tumor surface is caused by squamous mucosal hyperplasia that accompanies approximately half of these cases.  Pathologic Features. Granular cell tumors typically appear as a submucosal nodule at laryngoscopy.415 Histologically, they have an infiltrative growth pattern and a histiocytoid-­ type cytologic appearance. The tumor cells grow in small nests and cords; their nuclei are generally small and eccentric and their cytoplasm is abundant, granular, or stippled (Fig. 5.40). They have indistinct cytoplasmic boundaries, and cytoplasmic granules, which are PAS positive and resistant to digestion. Nuclear pleomorphism and mitotic figures are not usually seen in granular cell tumors. Pseudoepitheliomatous hyperplasia of the overlying mucosa may be present in as many as 50% of cases; on occasion, it may even mimic infiltrating squamous cell carcinoma. Rare cases can have a moderate degree of epithelial atypia. The pseudoepitheliomatous hyperplasia can be a clue, on superficial biopsy specimens, that one may be dealing with a granular cell tumor. It should lead the pathologist to look for granular cells in the subepithelial layer, which are highlighted immunohistochemically by S100 protein. Marked desmoplasia may be seen in older or larger tumors. True malignant granular cell tumors can be either cytologically benign, yet large (usually >9 cm) or metastasizing, or they may be histologically malignant, showing nuclear

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pleomorphism, spindled tumor cells, increased mitoses, and necrosis.416 Rare cases are particularly disturbing in that they appear perfectly benign histologically, yet metastasize (see Fig. 5.40E).  Special Studies. Ultrastructural examination of a granular cell tumor confirms a relationship to Schwann cells. The cytoplasmic granules are actually lysosomal structures that contain infoldings of cell membranes similar to schwannian extensions.417 Typically, both granular cell tumors and Schwann cells express S100 protein strongly, and both may also express markers of histiocytic differentiation (e.g., KP-­1, CD68).  Differential Diagnosis. The overall benign appearance of a granular cell tumor limits the differential diagnosis to rhabdomyoma, paraganglioma, and histiocytic infiltrates. The cells of a rhabdomyoma are much larger than granular cells and contain cross-­striations. Paraganglioma characteristically has a nesting pattern and will stain with neuroendocrine markers. Granular cells can be distinguished from histiocytes by the lack of inflammatory cells. Histiocytes assembled as a reaction to a foreign body or infection will appear in diffuse sheets or clumps, without the infiltrating, nesting, and ribboning pattern seen in granular cell tumors.  Treatment and Prognosis. Conservative endoscopic removal will be curative for most cases. Granular cell tumors have a very low rate (8%) of recurrence, even after incomplete excision. Recurrent tumors or frankly malignant tumors require resection with free margins. Twelve of 20 (60%) patients reported in the literature, with metastatic malignant granular cell tumor, ultimately died of the disease.416 We have seen a large (4.7 cm) hypopharyngeal granular cell tumor in a 29-­year-­old woman that was ultimately fatal after locoregional metastasis (see Fig. 5.40D). We have also seen a recurrent, nonmetastasizing laryngeal granular cell tumor, with atypical features (nuclear pleomorphism, spindling of cells, pagetoid spread into overlying mucosa) that we classified as an atypical granular cell tumor (see Fig. 5.40F).418 Chiang and colleagues419 reported a patient with malignant laryngeal granular cell tumor and lung metastases.  NEUROENDOCRINE TUMORS Neuroendocrine Carcinomas Neuroendocrine tumors (NETs) of the larynx are divided into two broad categories based on their tissue of origin: epithelial and paraganglionic. These epithelium-­derived tumors are uncommon and account for less than 0.1% of laryngeal malignancies.420–422 The most recent World Health Organization (WHO) classification of neuroendocrine tumors of the larynx divides neuroendocrine carcinoma (NEC) into three subtypes: well-­ differentiated neuroendocrine carcinoma (WDNEC), also previously known as carcinoid tumor; moderately differentiated neuroendocrine carcinoma (MDNEC), also previously known as atypical carcinoid tumor; and poorly differentiated neuroendocrine carcinoma (PDNEC). PDNEC is further subdivided into small cell and large cell types.423 This latter tumor category is a major change from the previous WHO edition (2005), where the large cell carcinomas were included in the moderately differentiated NEC group. This is important to remember, as the large cell NECs have a worse prognosis than the MDNECs. A fourth category (combined NEC) has been added to include hybrid carcinomas (squamous cell

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A

B

C

D

E

F

Fig. 5.40  Laryngeal granular cell tumor. A and B, Marked pseudoepitheliomatous hyperplasia is present. C, Syncytia of cells with abundant light pink granular cytoplasm and small eccentric nuclei typical for granular cell tumor. D, Malignant granular cell tumor presenting as a large (4.7 cm) hypopharyngeal/laryngeal tumor in a 29-­year-­old woman with locoregional metastasis. Only a mild degree of nuclear pleomorphism is seen with prominent nucleoli. E, Metastatic malignant granular cell tumor to the lymph node. This case is an example of a large, histologically benign, yet clinically malignant, granular cell tumor. F, Atypical granular cell tumor presenting as a recurrent, nonmetastasizing tumor. Pleomorphic granular cells are seen at the mucosal basement membrane; elsewhere they could be seen coursing through the mucosa. Spindling and pleomorphism were also present.

carcinoma or adenocarcinoma) mixed with a NEC. Patients with WDNEC survive longer with less morbidity than those with PDNEC, while MDNEC has a biological behavior intermediate between the other two.424–437 There is no universal agreement on which terminology should be used for the NETs, and the classification systems used may vary depending on which organ system one is considering. The authors of

this text use the current Head and Neck WHO classification (2017), which has similar criteria to that used in the lung.423 For additional information, the reader is referred to a recent review discussing the evolution of terminology for NET of the larynx, with a comparison to terminology used in other organ systems and potential additional areas of study to develop a more precise classification.438–440 By following strict criteria

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

and separating these tumors into four separate NEC categories, better clinical pathologic correlations will be possible. Clinical Features. To date, more than 750 laryngeal NECs have been described in the literature.429,437,441–445 MDNEC and the small cell variant of PDNEC are the most frequently encountered types of NEC, while the WDNEC and the large cell variants of PDNEC are the least common subtypes; both are extremely rare in the larynx.438,443,447,448 Since the recognition and acceptance of large cell neuroendocrine (LCNEC) as a separate entity, more cases have been reported. In a recently reported series of 10 cases of LCNEC in head and neck sites, three cases affected the larynx. The authors of this case series cited 38 other cases of LCNEC reported in the literature, and of these, 22 occurred in larynx.425 A review of the US National Cancer database428 reported 347,252 carcinomas of head and neck, of which 1042 (0.3%) were small cell carcinomas. The larynx was the most commonly affected site (35% of cases). A review from the Armed Forces Institute of Pathology indicated a ratio of 54:14:2 for MDNEC, PDNEC, and WDNEC, respectively, of 8469 malignant laryngeal neoplasms.432 A series of carcinoid tumors and their variant endocrinomas, from the Niigata Registry, found 42 WDNECs, 199 MDNECs, and 44 PDNECs arising in the larynx.437 If one combines this series with the more than 500 cases in the literature up to 1998, 60% of cases are MDNEC, 25% PDNEC small cell type, 8% paragangliomas, 6% WDNEC, and 1% PDNEC large cell type.432, 437 A recent meta-­analysis of all reported cases of laryngeal NEC, by a group from the Netherlands, described 436 cases from 182 studies. The tumors were classified according to most recent WHO guidelines and showed 23 (5.2%) cases were WDNEC, 163 (37.3%) MDNEC, 183 (41%) small cell poorly differentiated NEC and 29 (6.6%) large cell poorly differentiated NEC, with 38 cases designated NEC unspecified type because of conflicting or inadequate histological data.443 Data contrasting the clinical and pathologic aspects of these tumors are summarized in Table 5.1. Patients with NECs most often present in the sixth to eighth decades of life. There is a strong male predisposition, with the most frequent presenting symptom being hoarseness; laryngeal pain/discomfort and dysphagia were also frequent findings. In addition, patients with PDNECs often present with a neck mass. An analysis of small cell carcinoma of head and neck, using the American National Cancer database, showed larynx small cell carcinoma had the highest incidence of cervical adenopathy and 34% were stage IVa at presentation.428 There is a strong association of MDNEC and PDNEC with a history of smoking; a significant number of WDNECs are also associated with a history of smoking. Tumors most commonly arise in the supraglottis, and only occasionally from other laryngeal areas. Paraneoplastic syndromes have exceptionally been described in association with laryngeal NECs. The exact incidence is unknown. They appear to be slightly more frequent with the PDNEC small cell variant. A recent review of all patients reported in the literature found 10 cases of paraneoplastic syndromes associated with laryngeal NEC, *neuroendocrine (including carcinoid syndrome, syndrome of inappropriate antidiuretic hormone secretion [SIADH] and ectopic adrenocorticotropic hormone [ACTH]), and one neurologic (Eaton-­Lambert myasthenic syndrome). Five tumors were PDNEC small cell type, four were MDNEC, and one was WDNEC.448 Paraneoplastic syndromes have not

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been described in association with laryngeal paraganglioma or large cell NEC.  Pathologic Features. Patients present with supraglottic submucosal or polypoid masses, usually ranging from a few millimeters to more than 5 cm in greatest dimension (Fig. 5.41). Mucosal ulceration may be associated with higher-grade tumors.447 Fewer than 15 well-­documented examples of WDNECs are found in the literature.431,449 These tumors are characterized by nests, sheets, glands, and/or trabeculae ­composed of bland, uniform, round to spindled cells, separated by a fibrovascular or hyalinized connective tissue stroma (Fig. 5.42A and B). Nuclei are round to oval, with stippled or vesicular chromatin, inconspicuous or absent nucleoli, and eosinophilic cytoplasm. Occasionally, oncocytic d ­ ifferentiation may be found, and rosettes may be present. Cellular pleomorphism and necrosis are not seen in WDNEC; mitoses are usually a­ bsent but occasionally may be seen (10/10 hpfs

Prominent Oval/spindle ± eccentric

Vesicular with coarse ­chromatin

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

TABLE

Nucleoli

Occasional

Absent

Variable

Absent to ­inconspicuous

May be p ­ rominent

Cytoplasm

Eosinophilic to clear

Eosinophilic, ­oncocytic

Variable

Minimal to moderate

Abundant ­eosinophilic

N/C ratio

Variable

Low

Variable

High

Low

Epithelial mucin

Absent

Common

Argyrophilia

+++

Variable ++

Rarely positive

Absent

Argentaffinity

90–230 nm ­abundant

Rarely present

Neurosecretory ­granules

100–250 nm

Junctional complexes

Infrequent

Present

70–420 nm common

Scanty

Lumina

Absent

Present

Usually absent

Expression of ­epithelial markers (cytokeratin, EMA, CEA)

Absent

Present

Present

Expression of neuroendocrine polypeptides (calcitonin, bombesin)

Absent

Expression of p16

Absent

Not described

Not described

Molecular evidence of HRHPV Expression of SDHA or SDHB ­immunostain

Absent

Not described

Rare

Negative staining strongly ­correlates with germline mutations in SDHx genea

Present Present in ∼70% Not described

20%–30%

SDH mutations are known to be associated with nonparaganglionic NETs – presence or incidence in laryngeal NEC unknownb

2018493 2015492 ††Modified from references: Van der Laan, T.P., 2015; Ferlito, 2016 (for paraneoplastic syndromes); Uccell, S., 2017; Hunt, J.L., 2019; Williams, M.D., 2017. ACTH, Adrenocorticotropic hormone; CEA, carcinoembryonic antigen; DSS, disease-specific survival; EMA, epithelial membrane antigen; hpfs, high-power fields; HRHPV, high-risk human papilloma virus; MDNEC, moderately differentiated neuroendocrine carcinoma; NSE, neuron-specific enolase; NETs, neuroendocrine tumors; PDNEC, poorly differentiated neuroendocrine carcinoma; SDH, succinate dehydrogenase; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; WDNEC, well-­differentiated neuroendocrine carcinoma. bNiemeijer,

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

Expression of ­neuroendocrine markers (NSE, ­Chromogranin, S100, INSM1)

aUdager,

50–200 nm rare

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A

B Fig. 5.41  A and B, Polypoid supraglottic neuroendocrine carcinomas.

clinical evaluation is necessary to exclude a metastasis from a distant primary tumor (collision tumor) before considering a diagnosis of a combined carcinoma. The large cell variant of PDNEC is one of the rarest NECs of the larynx and has only recently been accepted as a separate entity in this location, as discussed earlier. This tumor is defined in a fashion similar to pulmonary large cell NECs. It usually has areas of typical neuroendocrine morphology with organoid nesting, trabeculae, rosettes, or palisading, and may have sheet-­like growth (see Fig. 5.42G–J). Necrosis is prominent, often with large zones of necrosis. The mitotic rate is brisk (11 mitoses or more per 10 high-­power fields). The cells are larger than the small cell variant, with a low nucleus-­to-­cytoplasm ratio, vesicular, with coarse to fine nuclear chromatin, often with frequent nucleoli. Positive staining for one or more of the neuroendocrine markers (preferably at least two, other than neuron-­specific enolase) or the demonstration of neuroendocrine granules on ultrastructural studies is necessary.438 Ultrastructural studies demonstrate neurosecretory granules in all types in varying numbers and sizes (see Table 5.1); desmosomes and tonofilaments are frequent in WDNEC and MDNEC, but are less common in the small-cell variant of PDNEC, whereas lumina (true and intracellular) are frequent in WDNEC and MDNEC and are usually absent in PDNEC. Argyrophil silver stains are frequently positive in WDNEC and MDNEC and are usually negative or focally positive in PDNEC. Classic neuroendocrine markers (e.g., chromogranin, neuron-­ specific enolase, synaptophysin, CD56, insulinoma-­associated protein 1), as well as epithelial markers (e.g., cytokeratin, epithelial membrane antigen, and carcinoembryonic antigen) will usually be positive in all NECs. Neuron-­specific enolase staining, by itself, is insufficient to establish neuroendocrine differentiation. Calcitonin is also positive in all three types of NEC. PDNECs of both types are consistently negative for CK5/6 and they are negative or only weakly positive for p63.423 Immunostaining for

p16 may be positive in about 70% of high-­grade neuroendocrine carcinomas, however this may not be associated with the presence of HPV infection. Alos et  al. reported a series of 19 PDNECs, 7 of which were in the larynx. Fourteen cases were intensely positive for p16, but all tested negative for HPV and polyoma virus.424 In a series of 10 cases of large cell PDNEC, 6 tumors were p16 positive and 3 were also positive for HPV DNA with in situ hybridization studies.425 It has been suggested that the high expression of p16 in PDNEC may be related to dysregulation of the p16/rb/cyclin D1 oncogenesis pathway rather than to HPV.424  Differential Diagnosis. Differentiating WDNEC from MDNEC and paraganglioma are the two most important differential diagnoses for WDNEC. Using the absence of necrosis and mitotic counts as described earlier will allow separation from MDNEC, while the absence of epithelial markers and the presence of S100-positive sustentacular cells, characteristic of paraganglioma, will allow separation from a WDNEC. In addition, GATA3, which is negative in NEC, appears to be a reliable marker for paraganglioma.440 Differential diagnoses of the higher-grade carcinomas frequently include melanoma, paraganglioma, medullary thyroid carcinoma, and poorly differentiated SCC. S100 protein, a common marker for melanoma, may be positive in laryngeal NEC; therefore Melan-­A, HMB-­45, and other melanin-­specific antibodies should be added to the immunohistochemical profile. Ultrastructural studies may be helpful to evaluate for melanosomes or premelanosomes. Calcitonin positivity and positive staining with an epithelial marker (e.g., cytokeratin, epithelial membrane antigen, carcinoembryonic antigen) or ultrastructural evidence of glandular lumina with microvilli can distinguish NEC from paraganglioma. Medullary thyroid carcinoma shares many histologic and immunohistochemical features of MDNEC. Both contain intracellular calcitonin and may contain extracellular amyloid.454,455 Clinicopathologic correlation should establish

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

the proper diagnosis. Also, thyroid transcription factor-­1 is helpful with this differential diagnosis because medullary carcinoma frequently demonstrates diffuse, intense positive staining for this marker, whereas MDNEC is usually negative and, when positive, stains only focally and in a weak fashion.440,456 In addition, although both may secrete calcitonin, an elevated serum calcitonin is much more frequently associated with medullary thyroid

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carcinoma; however, there have been three examples of serum calcitonin elevations in patients with a primary laryngeal NEC.456 Poorly differentiated SCC may occasionally have ribbons or cords of tumor cells and can grow in sheets somewhat similar to MDNEC or PDNEC; however, immunohistochemical and ultrastructural studies for neuroendocrine markers (neuron-­specific enolase ubiquity notwithstanding) are negative in the SCCs.

A

B

C

D

E

F

Fig. 5.42  A and B, Well-­differentiated neuroendocrine carcinoma with an organoid pattern. B, The tumor is composed of round, relatively nonpleomorphic nuclei, with stippled chromatin and prominent intranuclear holes. C and D, Moderately differentiated neuroendocrine carcinoma with an infiltrating glandular pattern. D, Note the increased nuclear pleomorphism. The finely stippled chromatin is still present. E and F, Poorly differentiated neuroendocrine carcinoma, small-­cell type. Note diffuse submucosal infiltrates with several submucosal vessels filled with tumor. The tumor is composed of plump to elongated nuclei with fine chromatin and inconspicuous nucleoli, with minimal cytoplasm (F).

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G

H

I

J

K

Fig. 5.42, cont’d  G–K, Poorly differentiated large-­cell neuroendocrine carcinoma. G and H, Variably sized nests of mild to moderately pleomorphic tumor cells with a prominent focus of necrosis. I, Detail of closely packed tumor cells with mild pleomorphism, fine chromatin, prominent nucleoli, and abundant cytoplasm. J, An area with tumor rosettes. K, Synaptophysin immunohistochemical stain.

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

Adenoid cystic carcinoma (AdCC) and basaloid SCC might be considered in the differential diagnosis with PDNEC, small cell type. These can be separated by the negative staining with neuroendocrine markers of the former and by the positive staining of the latter. In addition, basaloid SCC typically stains for highmolecular-weight keratin (34βE12), whereas the small cell variant of NEC is usually negative.457 In the series of 19 cases of PDNEC of the head and neck reported by Alos et al, immunostaining for p16 was found in 74% of tumors, while p63 was expressed in only 3 cases, one of which was a composite tumor SCC/PDNEC. All were negative for HPV and polyoma virus. Therefore p16 positive staining together with a negative p63 stain, which should be positive in a poorly differentiated SCC, may be a useful adjunct to distinguish between poorly differentiated nonkeratinizing squamous cell carcinoma and PDNEC.424  Treatment and Prognosis. Laryngeal NEC often presents as an aggressive tumor with an advanced stage of disease; treatment is based on the histological grade of the tumor.458 Surgery is the primary therapy for WDNEC and MDNEC, and a lymph node dissection is indicated for MDNEC because of the high rate of cervical nodal metastases. Data in the literature on primary or adjuvant radiation therapy are inconclusive.459 A comparative study has shown improved survival in NEC of the sinonasal tract treated by surgery, whereas patients with NEC of the larynx did better when treated with radiotherapy, suggesting surgery is best reserved for laryngeal NEC presenting at an early stage.460 PDNEC should be treated with a combination of radiation and chemotherapy, similar to the protocols used for pulmonary PDNEC, small cell (oat cell) type because of early hematogenous spread.428,432–435 Unlike pulmonary small cell PDNEC, there does not appear to be a role for prophylactic cranial irradiation in patients with tumors occurring in the larynx.461 WDNEC is associated with the best prognosis of the laryngeal NECs. In a review of 12 well-­documented cases, 7 of 12 patients were disease free 1.5 to 8 years after treatment. No patient presented with cervical lymph node metastases. Two patients died of unrelated causes at 12 and 27 months, one patient was alive with disease at 8 years after one recurrence, and one patient was alive with metastatic disease and the carcinoid syndrome at 4 years.429,431 Four patients developed distant metastasis (including the liver, lymph nodes, soft tissue, and bone); only one patient with systemic metastases died of disease 5 years after surgical treatment. One patient had a concomitant SCC, and a second had an adenocarcinoma of the soft palate. Soga and colleagues437 reviewed 278 laryngeal neuroendocrine tumors in the Niigata Registry for Gut-­Pancreatic Endocrinomas in 2002 and found 39 typical carcinoid tumors. These data were collected from published reports in approximately 50 countries. They found a metastatic rate of 33% for typical carcinoids with a 5-­year survival rate of 53.8%. The 5-­year survival results are different from the previous literature review indicated. The placement of tumors into their respective categories, in this latter study, was based on histologic descriptions and photomicrographs. If the reports did not have histologic descriptions or photomicrographs, cases were still categorized as typical carcinoids. In all likelihood, some atypical carcinoid tumors were included in their typical carcinoid group, which would have adversely affected the 5-­year survival rates. Therefore including only cases with good histologic documentation, as in the first review, should give a more accurate reflection of the behavior of this tumor, which had a 92% 5-­year survival rate.431,434

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The MDNECs are more aggressive, with 5-­and 10-­year cumulative survival rates of 48% and 30%, respectively.430 They frequently have a predilection to develop cutaneous and subcutaneous metastasis.459,462 Tumors larger than 1 cm appear to be more aggressive, and patients in whom skin or subcutaneous involvement develops have a worse prognosis.430 In a review of 119 MDNECs, with follow-­up information, 74% of the 66 patients treated with neck dissections during their disease course had metastatic disease.459 The most aggressive type of laryngeal NEC is PDNEC. In the series of small cell carcinoma of larynx, from the US National Cancer database, the median survival was 17.9 months and the overall 2-­year survival was 40.9%. A report from the Mayo clinic on the largest series of treated patients, with PDNEC treated at a single institution, included eight patients, and the median overall survival was 44 months. Median recurrence-free survival was 23 months. Five patients had large cell NEC and two died of disease at 3 and 11 months after presentation.444 In the largest published series, 73% of patients with PDNEC died, with an average survival of only 9.8 months (range, 1–26 months).429 Two-­and 5-­year survival rates were 16% and 5%, respectively. However, a study, using the National Cancer Institutes’ Surveillance Epidemiology and End Results (SEER) database, found 5-­year survival rates of 15% and 24.1%, respectively, for glottic and supraglottic tumors. This difference may be because of more modern treatment protocols or, possibly, nonstringent inclusion criteria.463 In addition, these tumors may be associated with paraneoplastic syndromes, including Cushing’s, Eaton-­ Lambert, and Schwartz-­Bartter syndromes.431,449,464 All patients with paraneoplastic syndromes usually die of the disease. In a series of 10 cases of laryngeal NEC (5 PDNEC; 4 MDNEC [at least 1 of which, in retrospect, should likely be reclassified as a large cell NEC using current definitions]; and one WDNEC) associated with paraneoplastic syndromes, reported by Ferlito et al., 9 have died and 1 is alive with liver metastases; 3 patients were recorded as having died of disease within 1 year.448  LARYNGEAL PARAGANGLIOMA Clinical Features. Nonepithelial, endocrine tumors or paragangliomas (PGL) are of neural crest origin and usually occur in the adrenal gland.465 When extraadrenal PGL involve the head and neck area, they are called according to the paraganglia site of origin: carotid body, jugulotympanic, vagal and laryngeal PGL, which are normally present along parasympathetic nerves at the common carotid bifurcation, middle ear, glossopharyngeal, and vagus nerves, and along the three superior and one inferior laryngeal nerves (see Chapter 9). Extraadrenal PGL of the head and neck usually are of parasympathetic type and typically do not produce neuroendocrine hormones contrary to sympathetic tumors of abdomen and thorax, but there are very rare exceptions of sympathetic PGL arising from the superior sympathetic cervical ganglia.466 Rarely, PGL can be multicentric and be in combination with laryngeal and carotid body PGL.467–469 Laryngeal PGLs are typically found in the supraglottic region. They are polypoid, submucosal tumors usually confined to the larynx.470,471,473–475 Transglottic and transventricular laryngeal paraganglioma are difficult to diagnose for their rarity and unusual location.476,477 Inferior laryngeal paragangliomas are usually dumbbell shaped, with intralaryngeal and also extralaryngeal extension (Fig. 5.43A and B), with occasional cases clinically confused with thyroid tumors.478

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Fig. 5.43  Inferior laryngeal paraganglioma. A, The radiograph demonstrates the intratracheal component. B, Intraoperative view. The cricoid has been cut and retracted. The intratracheal tumor component is seen as a vascular polypoid tumor. C, The resection specimen revealed a dumbbell-­ shaped subcricoid mass, protruding between the inferior cricoid and the first tracheal ring. D, Low-­power view demonstrates a highly vascular tumor. E, The tumor contains nests of cells with finely stippled nuclear chromatin and abundant cytoplasm. F, A reticulin stain highlights the zellballen effect.

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

SLP

ILP

ILP

ILP

Thyroid

G Fig. 5.43, cont’d  G, The right side of the larynx in this diagram demonstrates sites where the superior laryngeal paraganglia (SLP) and inferior laryngeal paraganglia (ILP) are located. The left side demonstrates the configuration of reported inferior laryngeal paragangliomas.

Supraglottic PGLs produce symptoms of hoarseness, dyspnea, and hemoptysis.470–­475 Rarely, they can be confused with hemangioma preoperatively.479 Infraglottic tumors may also produce dyspnea, and hoarseness is caused by nerve palsy of the recurrent laryngeal nerve. Barnes480 noted PGL to have a female-­to-­male ratio of 3:1 and a right-­sided laryngeal predisposition, with a right-­to-­left ratio of 2.3:1. Until 2004, PGLs were considered mostly sporadic tumors, except for a few cases (∼10%) associated with familial/genetic syndromes.481 Moreover, head and neck PGLs in particular have been found to have a high association with germline mutations of at least three succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, and SDHD).482 More recently, germline mutations, in more than 19 hereditary susceptibility genes,483 have revealed >10 genes that are associated with head and neck PGLs,484 making PGL the highest hereditary predisposition of any tumor (∼40% of cases), even more than medullary thyroid carcinoma.485 The last decade has also seen the recognition of the novel paraganglioma-­pheochromocytoma (PCC) syndrome, which has revealed the importance of genetic counselling to diagnose patients with hereditary PGL/PCC syndromes.486,487 The disease is characterized by autosomal dominant inheritance for SDHD mutations caused by germline mutations, in genes encoding subunits of the succinate dehydrogenase (SDH) enzyme, which creates a link between mitochondrial tumor

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suppressor genes and neural crest-­derived cancers. Germline mutations in SDH genes are responsible for more than 80% of paraganglioma and pheochromocytoma with familial associations: 38% of malignant tumors, 29% of pediatric cases, 6% of sporadic PGL, and 9% of pheochromocytomas with variable clinical manifestations, depending on the mutated gene.488 The rare laryngeal PGL tested was no exception and showed a mutation in the SDHD C gene.489 Since the discovery of first mutations in the SDHD gene, further genetic studies have revealed a major role for mutations in subunits of mitochondrial complex II SDH-­SDHB and SDHD, in the predisposition to both familial and nonfamilial pheochromocytoma-­paraganglioma syndromes481 and expression of hypoxia induced genes, giving a molecular explanation of increased risk of developing PGL, in conditions of chronic hypoxia.490 Finally, in the 2017 edition of the World Health Organization Classification of Tumors Pathology & Genetics for both Head and Neck Tumors and Tumors of Endocrine Organs, there is a unification of concepts in PGL and an emphasis on the familial/ syndromic PGLs, which represent ∼40% of all head and neck PGLs.491 An extensive explanation of this topic can be found in the excellent review by Williams and Tischler in 2017.491  Pathologic Features. Tumor hypervascularity imparts a red to blue hue, and profuse bleeding may occur during biopsy; it behooves the wise surgeon to establish the diagnosis by preoperative imaging. PGL are vascular, epithelioid neoplasms and the center of the tumor preferentially exhibits a ball of cells (zellballen) pattern. These cells are compactly arranged in ball-­like nests, separated by fibrovascular tissue (organoid pattern), which is highlighted by reticulin stain (Fig. 5.43D–F). Two types of cells are seen: chief cells and sustentacular cells. The chief cells are polygonal, with abundant granular cytoplasm and round nuclei, with “salt and pepper” stippling of chromatin. Cellular pleomorphism can be present in PGL and occasionally may be marked, but the zellballen pattern is maintained at least focally. Mitotic figures are not usually seen. Cellular pleomorphism may be found and has no independent prognostic value. The sustentacular cells are spindled cells scattered at the periphery of the cell balls.  Special Studies. Ancillary tests confirm that PGL are positive for neuroendocrine markers, such as synaptophysin, chromogranin, or insulinoma-­ associated protein-­ 1. Kimura et  al. have demonstrated positive staining for somatostatin receptor 2A in familial PGL.494 Mib-­1 is usually very low, both in primary tumors and lymph node metastases.494 Immunostaining for S100 and glial fi ­ brillary acidic protein (GFAP) highlights the peripheral Schwann-­like sustentacular cells that gives the zellballen appearance. PGL are usually negative for epithelial markers, such as cytokeratin, ­carcinoembryonic antigen, and epithelial membrane ­antigen. More recently, pathologists have developed a pivotal role for the diagnosis and management of PGL491 by performing immunohistochemistry for SDH protein, which correlates with ­mutation in the SDH-­associated genes. Specifically, it is the loss of i­mmunohistochemical protein expression of SDH in the tumor cells that reflects underlying germline mutation.495 This abnormal finding is seen in the majority of PGLs, arising from patients with SDHx germline mutations, but it requires strict guidelines for assessment.496  Differential Diagnosis. The main differential diagnosis is with neuroendocrine carcinomas (NEC), which may also have

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Fig. 5.44  Oncocytic cystadenoma. This multicystic and papillocystic lesion is composed of cuboidal and columnar oncocytes lining cystic irregularly shaped spaces. The cytoplasm is abundant, granular, and intensely eosinophilic without atypia (inset).

finely stippled chromatin and focally have a zellballen pattern. NEC has a higher nucleus-­to-­cytoplasm ratio than PGL and shows evidence of infiltration, necrosis, and mitotic figures. NEC will also stain with epithelial markers, unlike PGLs. The clinical information of catecholamine production favors NEC and not PGL, which are nonfunctional. For additional differential diagnosis information the reader is referred to Table 5.1.  Treatment and Prognosis. Laryngeal paragangliomas are treated with conservative surgery. The prognosis is difficult to establish. In both the Head and Neck and the Endocrine WHO “Blue Books” PGLs are not classified as benign or malignant, but are considered to represent a spectrum of tumors with metastatic potential. Given the rarity of laryngeal PGL, the metastatic potential is difficult to establish; however, it is estimated at 2%.497  SALIVARY TUMORS Salivary gland–type neoplasms are rare tumors in the larynx, accounting for 1% of all laryngeal neoplasms.498 The majority are benign tumors. Oncocytic cystadenomas are the most common benign tumors and pleomorphic adenomas are a distant second, unlike their frequent occurrence in the salivary glands at other sites. When confronted with a malignant tumor of larynx, the initial impression may be in favor of the more common squamous cell carcinoma, but the index of suspicion for a tumor of salivary gland type should be high when a submucosal mass is present.499 Laryngeal malignant salivary gland tumors have a male versus female ratio of 2:1, the most common location is the supraglottic region (52%), and the most predominant histological subtypes are adenoid cystic carcinoma (46%), mucoepidermoid carcinoma (35%), and adenocarcinoma, not otherwise specified (12%).500 Other rare laryngeal salivary tumors include benign and malignant myoepithelioma,501,502 polymorphous low-­ grade adenocarcinoma,503 acinic cell carcinoma,511 epithelial myoepithelial carcinoma504,505 clear cell carcinoma,506 and salivary duct carcinoma.507,508 Laryngeal adenocarcinoma in the form of salivary duct carcinoma is not well recognized and the incidence may be higher. Laryngeal carcinoma-­ex-­pleomorphic adenoma

and true malignant mixed tumor (carcinosarcoma) has rarely been reported.499,509,510 Oncocytic Cysts and Cystadenomas Laryngeal oncocytic cysts and oncocytic cystadenomas have been found in 0.1% to 1% of laryngeal biopsy specimens.512,513 They are clinically relevant, as they can be confused with laryngocele or cause acute stridor.514,515 They often occur in the supraglottis, where seromucinous glands are most dense. Most patients are in their seventh and eighth decades of life. Bilateral, multifocal, and diffuse distribution has been noted, which accounts for the symptomatic recurrence after biopsy.516,517 The cyst size in the majority of cases is less than 1 cm in greatest dimension, but some have been reported to be extensive, bulky tumors.515 They may produce the usual supraglottic symptomatology. The retrograde ductal obstruction that can occur may result in impressive cyst formation progressing to upper airway obstruction. Pathologic Features. Oncocytic cystadenomas range from predominantly simple cystic lesions (oncocytic cysts) to more complex multicystic and papillocystic lesions (oncocytic cystadenoma). Lymphocytic infiltrates may be prominent and reminiscent of Warthin tumors. Simple cysts without papillations should be termed oncocytic cysts, whereas more complex multicystic lesions with a papillary component should be classified as cystadenomas (Fig. 5.44). The lesion is composed of cuboidal and columnar oncocytes, lining cysts and papillary structures, with a variable amount of intraductal/intracystic hyperplasia. The surrounding minor seromucinous gland tissues frequently reveals oncocytic metaplasia. Atypia is usually absent.  Differential Diagnosis. Cystic papillary oncocytic cystadenomas are histologically benign and should pose no diagnostic problem for the pathologist. We have seen a case of papillary oncocytic cystadenoma diagnosed as low-­grade papillary adenocarcinoma. Reversal of this diagnosis obviously saved the patient unnecessary surgery (see later discussion). Careful attention to cytology should allow recognition of cuboidal oncocytes. Small nests of oncocytes may be closely packed together, but the ductal/cystic nature of oncocytic cystadenomas should

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B

Fig. 5.45  A, Pleomorphic adenoma. Epithelial and myoepithelial cells forming ductal structures within a myxoid background. Epiglottic benign pleomorphic adenoma (curved arrow; inset). B, The abundant spindled myoepithelial cells blur the boundary between the epithelial and mesenchymal components. This is a common feature of pleomorphic adenoma. (A, inset, Courtesy of Dr. Hugh Biller.)

be obvious. Predominantly solid, diffuse, noncystic true oncocytic tumors of the larynx are exceptionally known to occur in humans,518 but it is more common to see tumors showing oncocytic differentiation. Thus a laryngeal biopsy of a predominantly noncystic, diffuse, seemingly oncocytic-­like tumor should raise suspicion of another diagnoses. For instance, neuroendocrine carcinoma, mucoepidermoid carcinoma, and squamous cell carcinoma of the larynx may be extremely eosinophilic and can be confused with an oncocytic tumor. Nuclear pleomorphism can be seen in all these tumors and would not be seen in oncocytic cystadenoma.  Treatment and Prognosis. Simple conservative endoscopic excision is curative for most cases. Occasionally, laryngeal oncocytic cystadenomas may recur, more likely as a manifestation of diffuse or multifocal oncocytic metaplasia rather than oncologic aggressiveness.  Pleomorphic Adenoma Clinical Features. Salivary benign pleomorphic adenomas (PA) are the most common of all salivary neoplasia and present in the third to sixth decades of life; rarely, they may arise in the pediatric age range. Laryngeal PA are extremely uncommon (Fig. 5.45). Two literature reviews in 1997519,520 revealed approximately 20 cases. A more recent review showed 23 cases.521 When non-­English literature case reports are included,522,523 the total number still does not reach 30 cases. The majority of tumors involve the supraglottis, usually the epiglottis, and may be as large as 4 cm in greatest dimension. The laryngeal ventricle is an uncommon site of occurrence.521  Pathologic Features and Differential Diagnosis. Histologi­ cally, a laryngeal PA is similar to those at other sites (see Fig. 5.45). For a detailed histologic description, refer to Chapter 6. Proliferation of small ductules, surrounded by myoepithelial cells, with foci of cartilaginous differentiation., is the hallmark of a PA. Because of its rarity, a diagnosis of laryngeal PA should be made cautiously; one needs to exclude more likely possibilities, such as mucoepidermoid carcinoma (MEC), mucinous adenocarcinoma, adenoid cystic carcinoma (AdCC), and chondrosarcoma. If chondromyxoid stroma is seen, MEC,

AdCC, and mucinous adenocarcinoma can be excluded. AdCC does not exhibit the varied growth patterns typical of PA and is infiltrative. A PA can be distinguished from chondrosarcoma by the presence of both epithelial and myoepithelial components.  Treatment and Prognosis. Complete surgical excision is the treatment of choice; PAs are benign and should be cured if completely removed. Rarely however, a carcinoma can arise in association with a PA.509  Adenoid Cystic Carcinoma Clinical Features. Adenoid cystic carcinoma (AdCC) of the larynx comprises less than 1% (0.07%–0.25%) of laryngeal carcinomas.524 It is uncommon with slightly more than 120 cases reported.525 Laryngeal AdCC is seen over a broad age range, with a slightly increased incidence in the fourth to sixth d ­ ecades of life,526–528 and has been reported in childhood and adolescence.529,530 AdCC is slightly more common in females.525 Approximately 60% involve the subglottis, 33% the supraglottis, and 6% the vocal fold.524 Hoarseness, pain radiating to the ear, dysphagia, and dyspnea are the most common presenting symptoms for supraglottic tumors; subglottic tumors may be associated with asthma, pain, hoarseness, or dyspnea on exertion. Extralaryngeal invasion may result in initial presentation as a thyroid mass.  Pathologic Features. Most AdCCs invade the submucosa and adjacent soft tissues in a diffuse, surreptitious scar-like fashion, without protruding into the laryngeal lumen. AdCCs of the larynx are morphologically similar to those arising in the salivary glands and are composed of a somewhat uniform population of basaloid tumor cells growing in solid, cribriform, and/or tubular patterns (Fig. 5.46). For a detailed histologic description, refer to Chapter 6. They are widely infiltrative, hampering preoperative estimations of clinical extent. Therefore intraoperative frozen-­section examination is extremely useful to map out disease extent and the type of resection required.  Differential Diagnosis. It is important to rule out basaloid squamous cell carcinoma (SCC) and neuroendocrine carcinoma (NEC). Basaloid SCC is much more likely to be encountered. Basement membrane deposition by basaloid SCC can impart a cribriform-­like pattern (see Fig. 5.46C). AdCC

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Fig. 5.46  A, Adenoid cystic carcinoma. A predominant solid pattern is seen here with necrosis and a cribriform pattern. B, Detail of the tumor from a cribriform area demonstrating hyperchromatic nuclei with minimal cytoplasm and scattered true lumena (D). C, Basaloid squamous cell carcinoma can grow in a nesting pattern and deposit hyaline material, mimicking adenoid cystic carcinoma. D, Basaloid squamous cell carcinoma with a solid growth pattern and focal necrosis (lower right). The findings of either squamous carcinoma in situ or keratinization, within the invasive tumor, can aid in distinguishing basaloid squamous carcinoma from adenoid cystic carcinoma. Rarely, however, adenoid cystic carcinoma can also produce areas of keratinization, especially after fine-­needle aspiration biopsy.

lacks the malignant squamous component, typical of basaloid SCC, and there is much less cytologic atypia, mitotic activity, and necrosis in AdCC than is found in basaloid SCC. NEC does not exhibit a cribriform growth pattern; AdCC does not form trabecular, rosette-­like, or organoid patterns. However, with small biopsies, this differential diagnosis may be problematic and immunohistochemistry can be helpful. NEC, AdCC, and basaloid SCC may all express low-­molecular-­weight cytokeratin, S100 protein, and neuron-­specific enolase, to varying degrees. Strong synaptophysin, chromogranin, and insulinoma-­ associated protein 1 expression is consistent with NEC, whereas expression of high-­ molecular-­ weight cytokeratin, P63, and CK5, would favor basaloid SCC.  Treatment and Prognosis. The treatment of choice is complete surgical excision, partial or complete laryngectomy, plus adjuvant radiotherapy. However, a recent series showed that radiation therapy may also be used primarily to avoid a total laryngectomy or after laryngeal preservation surgery, with excellent local control rates and preservation of laryngeal function and voice.531 Cervical lymph node dissection is not usually recommended, unless there is palpable lymphadenopathy. AdCC has a slow, relentless course marked by high local recurrence rates and late distant metastases. In a

recent cases series, distant metastasis occurred in 33.7% (2/6) of the patients, with one lung metastasis, 5 years after operation, and one liver metastasis, 4 years after operation.528 Recurrence rates are in the range of 50%. Isolated pulmonary metastasis should be treated aggressively and not alter treatment of the primary tumor. Tumors with perineural invasion appear to have a higher risk of local recurrence. Some patients may have rapid disease progression or acceleration to a more rapid clinical course. Unfortunately, similar to AdCC of other upper aerodigestive sites, most patients will eventually die of their tumor. An AdCC metastatic to the larynx from another salivary gland primary site, although extremely rare, needs to be ruled out before any treatment begins.532  Mucoepidermoid Carcinoma Clinical Features. Laryngeal MEC has an incidence similar to that of AdCC.533–538 These tumors usually occur between the ages of 45 and 75 years; they rarely may arise in children and adolescents.539 These tumors most frequently develop in the supraglottic area, but rarely can occur in the subglottis.540 Presenting symptoms are similar to those of SCC patients, frequently reporting hoarseness, and rarely they may present with a neck mass. 

5  Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

Pathologic Features. Tumors usually originate in the submucosa and may be as large as 5 cm in greatest dimension. They have an appearance similar to that of their salivary gland counterpart, are composed of clear, mucin-­ secreting, intermediate, and squamous-­like cells, in varying proportions arranged in solid or cystic nests (for a detailed histologic description, refer to Chapter 6). Occasional tumors may arise from surface mucosa; a clear cell variant has also been reported.537  Differential Diagnosis. The differential diagnosis includes a hamartomatous proliferation of mucinous glands, necrotizing sialometaplasia (NSM), and adenosquamous carcinoma (ADSC). Benign hamartomatous mucinous gland proliferations will occasionally arise in the larynx and may have dilated ductal structures similar to those of MEC. The mucinous glands are usually better formed than those in MEC, and squamous and intermediate cells are lacking in the hamartomas. NSM retains a lobular pattern and is noninvasive. The most problematic differential diagnosis is between high-­grade MEC and ADSC; the latter is more frequent than MEC. ADSC always involves the surface mucosa, with two distinct components. The most superficial portion of the tumor is usually a SCC, with easily recognizable intracellular junctions and keratin production; deeper portions of the tumor frequently demonstrate a poorly differentiated adenocarcinoma. The presence of an in-­ situ component or keratinizing SCC strongly supports the diagnosis of ADSC. In addition, ADSC does not usually contain goblet cells as does MEC and, unlike MEC, frequently contains distinct separate areas of SCC and adenocarcinoma.  Treatment and Prognosis. Organ conservation is the preferred approach using laser treatment,540 but partial or total laryngectomy may be indicated.541 A neck dissection should be performed for palpable lymphadenopathy; however, the decision to perform an elective neck dissection relates to histologic grade on the preoperative biopsy. Elective neck dissection and/ or cervical radiation therapy is indicated for high-­grade MEC. If the preoperative diagnosis is intermediate-­grade MEC, the need for elective neck dissection is unclear. One would not expect a low-­ grade MEC to metastasize. MECs should be graded after thorough sampling (see Chapter 6 for more specific information on grading). The prognosis is dependent on the histological features. Low-­grade tumors have a good prognosis. In high-­grade tumors, recurrence is more common and radical surgery with radiotherapy is recommended (for more specific information about survival, see Chapter 6).  MELANOMA AND LARYNGEAL MELANOSIS Clinical Features. Mucosal melanoma comprises less than 2% of all Western melanomas542 and represents 4% of malignancies arising from nasal cavity and paranasal sinus.543 A large study in Japan of cutaneous, mucosal, ocular, and unknown primary melanomas has shown that cutaneous melanoma is less frequent (80.5% of melanomas), whereas mucosal melanoma has a higher incidence (15% of melanomas) than in Western countries.544 Laryngeal and hypopharyngeal melanomas are very rare. In a recent update, the most frequently affected regions were supraglottis (60%) and glottis (40%).545 The majority of these tumors arise in elderly white males. Clinically, mucosal melanomas appear as brown, tan, or bluish polypoid tumors, but in some patients, melanoma can present with dark discoloration of the supraglottic larynx and incomplete mobility of the vocal fold.546 When occurring in

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the glottis, mucosal melanoma can manifest with hoarseness of voice, leading to early diagnosis.547 Other symptoms include hemoptysis, sore throat, neck pain, and foreign-­body sensation.  Pathologic Features. Macroscopically, mucosa/laryngeal melanoma presents as a nodular neoplasm arising from the mucosa. The detection of in situ components is more difficult in upper aerodigestive tract mucosa because of the thinness of the surface epithelium and frequent ulceration. Histologically, melanoma has earned the reputation as the great masquerader: sarcoma-­like, epithelioid, or pleomorphic patterns may be seen (Fig. 5.47). Melanoma can have a plasmacytoid, spindle cell, or epithelioid cytology. Plasmacytoid melanomas have nuclei that are eccentric and cytoplasm that is bright pink to dirty brown and granular. Intranuclear vacuoles or holes or pink nucleoli are helpful giveaways to the true diagnosis. Spindle cell melanomas can mimic a sarcoma, and the nuclei often have a variable morphology. Melanin deposition may still be observable in the cytoplasm. Epithelioid melanoma forms sheets of large plump cells that have a nesting tendency. Intranuclear vacuolations are seen, and, again, melanin pigment may be seen in the cytoplasm. However, one should remember that the majority of mucosal melanomas are amelanotic. Junctional activity can be observed in primary mucosal melanomas,548 but not in metastatic tumors, but its absence does not preclude the diagnosis of primary mucosal melanoma. Intramucosal spread of melanocytes, in the adjacent epithelium, histologically favors a primary tumor. The question may arise as to whether a laryngeal or pharyngeal melanoma represents primary or metastatic tumor. Certainly, this is a significant question, as metastatic cutaneous melanoma is one of the most common secondary malignancies (along with renal cell carcinoma) to occur in the larynx. It is unlikely, in the absence of a history of cutaneous melanoma, that a screening examination will uncover an occult primary. If the patient has a history of a skin melanoma, the laryngeal/pharyngeal tumor should be considered a metastasis and probably a harbinger of disseminated disease.549,550 The immunohistochemical profile of positive staining with anti-­S100, HMB-­45, Melan-­A/Mart-­1, and other melanocytic

Fig. 5.47  Melanoma, the great masquerader. Epithelioid cells with prominent amphophilic nucleoli are shown.

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markers, such as tyrosinase and MITF551 is diagnostic, keeping in mind that melanocytic markers may be lost in melanoma with spindle cell morphology.552 Currently, there is limited use of SOX10 as a mucosal melanoma marker. Mucosal/laryngeal melanoma can be staged according to the American Joint Committee on Cancer (AJCC) recent recommendations.553 Because even superficial tumors exhibit aggressive behavior with significant recurrence and death, the T1 and T2 categories are not used. Therefore mucosal melanomas limited to the mucosa and underlying soft tissues are classified as T3 tumors, while moderately advanced melanomas are classified as T4a and very advanced tumors as T4b. In situ melanomas are rare and are not staged. Prasad et al.554 proposed a microstaging system for mucosal melanoma. Their staging system was based on invasion of tissue compartments within the mucosa: level I (in situ disease); level II (superficially invasive: melanoma invading up to the lamina propria); and level III melanomas (deeply invasive: muscle, bone, or cartilage). Prasad’s staging system shows statistically significant differences in the survival rates for levels I, II, and III (5-­year disease-­specific survival [DSS] rates of 75%, 52%, and 23%, respectively).554 However, to date there is no standardized staging system used by all clinicians.  Differential Diagnosis. The differential diagnosis varies with its particular appearance and with the fact that most mucosal/ laryngeal melanomas are amelanotic. As a small, blue, round cell tumor, one should also consider poorly differentiated neuroendocrine carcinoma, lymphoma, and plasmacytoma. As a pleomorphic tumor, undifferentiated carcinoma and rhabdomyosarcoma (RMS) should also be ruled out. As a spindle cell tumor, the differential diagnosis includes spindle cell carcinoma and sarcomas, such as leiomyosarcoma and malignant fibrous histiocytoma. The immunohistochemical profile of staining with anti-­ S100, HMB-­ 45, Melan-­ A, antivimentin, and SOX10 is diagnostic. Melanocytic markers may be lost in melanoma with spindle cell morphology (cytokeratin and epithelial membrane antigen are occasionally expressed in melanomas).555 Please refer to Chapter 14 for more information on differential diagnosis. The molecular landscape of mucosal melanomas is described in the chapter discussing nasal/paranasal tumors, where the biological differences between mucosal and cutaneous melanoma are highlighted. In essence, mucosal melanoma shows increased frequency of c-­KIT (CD117) mutations,556 followed by RAS somatic mutations and overexpression seen in 20% and over 90%, respectively, in mucosal melanoma.557 Interestingly, BRAF mutation, which is present in 50% to 70% of cutaneous melanomas, arising in sun-exposed areas,558 is seen extremely rarely (25% cases, 56 of 220) and 12q14-­15 (13.2% cases, 29 of 220), characteristic of PAs. The translocations/rearrangements result in gene fusions

6  Salivary Glands

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Fig. 6.14  Carcinoma ex pleomorphic adenoma, invasive type. A, Note the benign component with numerous small irregular ducts in a hyalinized stroma (upper left) and a focus of adenocarcinoma with associated necrosis (lower right). B, Detail of adenocarcinoma with back-­to-­back gland formation and necrosis. C–E, Invasive carcinoma ex pleomorphic adenoma. The typical pleomorphic adenoma portions are seen in the upper left area (C). The mucoepidermoid carcinoma portion is seen in the right half of C and in D. It is composed of multiple nests of a mildly pleomorphic population of cells that have replaced the normal ductal elements. E, A mucicarmine stain demonstrates scattered cells with intracellular mucin. F, Earliest change in a noninvasive carcinoma ex pleomorphic adenoma. Scattered ducts have their inner layer partially replaced by large cells, with prominent nucleoli and abundant cytoplasm. Other foci in the tumor had areas with back-­to-­back glands, confirming the diagnosis of a noninvasive carcinoma ex pleomorphic adenoma.

involving the transcription factor–encoding genes pleomorphic adenoma gene 1(PLAG1) and high-­mobility group AT-­hook 2 (HMGA2). PLAG1 encodes a DNA-­binding zinc finger protein, controls PLAG1 target genes and insulin-­like growth factor 2 signaling pathways. HMGA2 is an architectural transcription factor; its target genes include cell cycle regulators cyclin A1 and cyclin B2. Overexpression of PLAG1 is caused by promoter

swapping with at least one of four other genes (catenin β1, leukemia inhibitory factor receptor, coiled-­ coil-­ helix-­ coiled-­ coil-­helix domain–containing 7, transcription elongation factor A1).423 Rearrangements of HMGA2 are caused by fusion of 3′ parts of HMGA2 with 3′ parts of nuclear factor 1/B (NF1B), WNT inhibitory factor 1 gene, or fragile histidine triad genes. It has been noted that the PLAG1 and HMGA2 fusions are present

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only in PA and Ca-­exPA and have not been encountered in any other types of salivary gland neoplasms.423 Compared to PA, subsets of Ca-­ex-­PA also show amplification of human homolog of mouse double minute 2 gene, mutations of tumor protein p53 gene (TP53), and amplification of human epidermal growth factor receptor 2 gene (HER2/neu), as molecular markers of malignant transformation.434 Abnormalities in chromosome 8 are the most commonly encountered in PA and Ca-­ ex-­ PA, indicative of an early event in the genesis of these tumors. Rearrangements of 8q12 are the most frequent finding, and alterations at 12q13-­ 15 with amplifications of HMGIC and MDM2 genes have been described.484 These findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign PA.485–­486 Microsatellite analysis of CA-­ex-­PA has revealed that loss of heterozygosity (LOH) is common on chromosome 8q and 12q in both benign PA and Ca-­ex-­PA, suggesting the presence of tumor suppressor genes at these locations.486–­487 LOH at chromosome 17p was also reported, but only in CA-­ex-­PA. In addition, chromosome 17p alterations correlated with an increased proliferative rate and a high disease stage.486 Based on these findings, it has been proposed that changes in 8q and/or 12q are an early event in the progression of PA to Ca-­ ex-­PA and that LOH at 12q might identify a subset of PAs that are more likely to undergo metastasis.486 LOH at 17q may be a separate event preceding frank malignant transformation and progression. These late events may relate to loss or mutation of p53, which resides on 17p. Interestingly, p53 overexpression has been reported in dysplastic foci in PA.488 Homozygous deletion of p16 on chromosome 9q21 has also been reported in the malignant, but not the benign, component of one of four cases of Ca-­ex-­PA.489 Microsatellite instability was also found in the malignant elements of two cases and in a single case, it was detected in the benign component, suggesting premalignant genetic instability.  Treatment and Prognosis. In general, the recommended treatment for Ca-­ex-­PA is wide local excision. Contiguous lymph node dissection and adjuvant radiation therapy is recommended for widely invasive tumors. A recent study demonstrated significantly improved 5-­year local control from 49% to 75% with postoperative therapy.479 Lewis and colleagues470 similarly demonstrated that postoperative radiation significantly improved local control. If the carcinomatous component is noninvasive or minimally invasive and if the tumor is adequately excised, then adjuvant radiation therapy may not be necessary. However, all patients with intracapsular and minimally invasive carcinoma should have careful long-­term follow-­up. Patients with noninvasive or minimally invasive Ca-­ ex-­PA frequently have a prognosis similar to that of benign PA.470 However, there are several reports of noninvasive and minimally Ca-­ex-­PAs, with ductal or myoepithelial carcinomas, which presented with or developed cervical nodal or distant metastases.490–­494 Therefore until a better understanding of how to separate this latter group of tumors from the former group, a comment should be included in the surgical pathology report, reflecting that infrequently these tumors may behave more aggressively and recommend close clinical follow-­up. Widely invasive Ca-­ex-­PAs, however, are extremely aggressive malignancies, and approximately 40% to 50% of patients

experience one or more recurrences.461,469,470 The metastasis rate varies with each series; local or distant metastasis develops in as many as 70% of patients. Metastatic sites, in order of frequency, are the lung, bone (especially spine), abdomen, and central nervous system.495 Patients with noninvasive or minimally invasive Ca-­ ex-­PA have a much better prognosis, almost as good as patients with a typical benign pleomorphic adenoma (see previous discussion). Ca-­ex-­PA, with capsular penetration of more than 6 mm, is associated with a more aggressive clinical course; survival rates at 5, 10, 15, and 20 years range from 25% to 65%, 18% to 50%, 10% to 35%, and 0% to 38%, respectively.469–­471 Therefore it is important to designate those Ca-­ex-­PAs that are confined within the capsule and those invading through the capsule as noninvasive or minimally invasive, but also specify the degree of extension outside the capsule of the PA.474–­477 The influence of tumor size on survival has been variable. Some have reported a poorer prognosis in larger tumors,462,470 whereas others have found no significant correlation between size and survival.469,471 Lewis and colleagues470 found no correlation with tumor subtype, unlike Tortoledo and colleagues,471 who reported a correlation between 5-­year survival rates and the subtype of the carcinomatous component. In this latter study, there was a 30% survival rate for undifferentiated carcinomas, 50% for myoepithelial carcinomas, 62% for adenocarcinomas (NOS), and 96% for polymorphous low-­grade adenocarcinoma. Other factors reported to be of prognostic significance include pathologic stage, grade, proliferation index, perineural invasion, lymph node involvement, extent of tumor invasion, and the proportion of carcinoma.470,496 A recent study479 indicated that patients with pathologically positive cervical lymph nodes had a worse prognosis than patients with pathologically negative or unknown nodal status (5-­year survival rates of 16% vs. 67%). In addition, this study indicated that survival with pathologic involvement of the facial nerve was worse (5-­year survival rates of 37% vs. 53%). Chen and coauthors reported, after a careful review of the Surveillance, Epidemiology and End Results database (SEER), that the presence of two or more cervical lymph node metastases correlated with a poor prognosis, 42.7% versus 85.9% 5-­year disease-­specific survival, when compared to patients with one or no positive lymph nodes.497 In addition, a recent paper indicated that the presence of both positive HER2 and EGFR CISH can separate out the most clinically aggressive subgroup of the ductal type carcinomas.498 Another report supported the correlation between decreased numbers of tumor myoepithelial cells with invasion and metastatic spread493 and Sedassari et al. recently demonstrated that increased expression of SOX2 (>50% positive tumor cells) was associated with an adverse outcome.499  CARCINOSARCOMA Clinical Features. The term carcinosarcoma was used in the 2005 WHO classification of salivary gland tumors and retained in the 2017 WHO edition. It is defined as a biphasic tumor composed of a mixture of carcinomatous and sarcomatous elements. Most cases appear to arise de novo; however, rare cases may be associated with a benign pleomorphic adenoma.480,500 Unlike Ca-­ex-­PA, in which only the carcinomatous elements may metastasize, both carcinomatous and sarcomatous elements of carcinosarcoma may metastasize. Parenthetically, a pure chondrosarcoma apocryphally arising in a benign PA has been reported.501 The real incidence of carcinosarcoma is difficult to

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A

Fig. 6.15  Carcinosarcoma. A, The tumor is composed predominantly of a high-­ grade sarcoma with small foci of high-­grade carcinoma (top). Detail of the carcinoma component demonstrates nests of pleomorphic carcinoma cells (inset). B, Higher-­ power detail from midportion of tumor demonstrating chondrosarcomatous differentiation (right), as well as focal osteosarcoma (upper left).

B

establish as most reports are usually single cases. It is, however, very rare, with 7 per 10 high-­ power fields) and an MIB-­1 proliferative index greater than 10%.557,558

471

Other differential diagnoses of benign MYO depend on the predominant cell type. Thus tumors composed of spindle cells resemble various benign mesenchymal neoplasms and tumor-­ like lesions, such as nodular fasciitis, solitary fibrous tumor, fibrous histiocytoma, leiomyoma, schwannoma, and Kaposi sarcoma. The clear cell variant must be distinguished from other clear cell salivary gland tumors, including metastatic renal cell carcinoma559 (Table 6.10). Immunohistochemistry is valuable in identifying a myoepithelial phenotype in a problem tumor. In particular, none of the benign salivary gland soft-­tissue tumors express cytokeratins, and renal cell carcinoma is S100 protein negative. If mucin containing signet ring cells are seen, a battery of multiple myoepithelial markers should be done to confirm the myoepithelial nature of the tumor. One should also remember that plasmacytoid myoepithelial cells frequently do not stain with myoepithelial markers; therefore a bland noninvasive/encapsulated tumor, containing many mucin, containing plasmacytoid cells, is likely a mucinous variant of MYO and not a signet ring carcinoma.547,552  Treatment and Prognosis. Because benign MYOs are considered to represent one extreme of the histologic spectrum of PAs, the treatment and prognosis are essentially the same as those for benign pleomorphic adenoma. Patients with these neoplasms should be treated by a complete excision that ensures a tumor-­free margin (e.g., superficial parotidectomy); in minor gland sites, this will usually involve surgical excision with a rim of normal surrounding tissue. Neither growth pattern nor cell type appears to carry prognostic significance. Recurrence rate is similar to or slightly less than typical pleomorphic adenoma. Malignant change to myoepithelial carcinoma in a benign lesion has been described,560 but too little information is available to know how often this occurs. However, it is not unreasonable to postulate that it is probably similar to that of a myoepithelial carcinoma arising in a PA.  Myoepithelial Carcinoma The terms myoepithelial carcinoma and malignant myoepithelioma are interchangeable. The former is preferred in the 2017 WHO classification and is used here. It is defined as a neoplasm, composed almost exclusively of tumor cells, with myoepithelial differentiation.561 It is characterized by infiltrative growth and potential for metastasis. Clinical Features. The average age of patients at presentation is approximately 55 years (range, 0–86 years), and the sex incidence is approximately equal in most studies.542 Approximately two-­thirds of cases are found in the parotid gland, approximately 10% in the submandibular gland, and the remaining one-­fourth in minor salivary glands, usually the palate, but they occasionally may arise in the sinonasal tract, larynx, breast, or lung; rarely myoepithelial carcinoma may arise in soft-­tissue sites.209,557,558,562–­567 They may arise de novo, but at least 50% develop in a preexisting PA or benign MYO.560,563,566 Most patients present with a painless mass of duration, lasting from a few weeks to several years. Weight loss is seen in a minority, and a large series of 573 tumors found a 14.4% rate of nodal disease at initial presentation.567  Pathologic Features. Macroscopically, myoepithelial carcinomas are uncircumscribed masses usually 2 to 5 cm in diameter; a tumor with a maximum dimension of 25 cm has been seen by one of the authors (RHWS.). The microscopic architecture is often multinodular, with infiltration into adjacent tissues (Fig. 6.18). Perineural invasion is seen in 44%

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A

B

C

D

E

F

G

Fig. 6.18  Myoepithelial carcinoma. A, There is a poorly circumscribed tumor infiltrating adjacent salivary tissue. B, It is composed of a sheet of pleomorphic plump to spindled tumor cells with minimal cytoplasm. This tumor stained for cytokeratin and muscle-­specific actin, confirming its myoepithelial nature (not illustrated). C–G Mucinous variant of malignant myoepithelioma, with several cells containing abundant intracellular mucin material (D and inset); an Alcian blue stain with hyaluronidase confirms the presence of areas with abundant intracellular mucin material (E), while a PAS-­diastase stain demonstrates scattered cells with intracellular PAS-­positive material (F). A calponin immunohistochemical stain is diffusely positive (G). Cytokeratin, CK7, GFAP, and S-­100 protein immunohistochemical stains were also positive (not illustrated).

of patients and vascular involvement in 16%.563,568 The nodules comprise solid and sheet-­like growths of tumor cells, often with plentiful myxoid or hyaline material, and sometimes displaying central necrosis. The range of cell types reflects that seen in benign myoepitheliomas and includes epithelioid cells (the

most frequent), often arranged in trabecular or pseudoacinar structures, with cleft-­like spaces. Cells with clear cytoplasm or vacuolation (resembling lipoblasts) and cells with hyaline (plasmacytoid) and spindle to stellate forms are also seen.569,570 A recently described mucinous variant is comprised of cells

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with eosinophilic to foamy gray-­blue cytoplasm with varying amounts of intracellular mucin (Fig. 6.18C–G).547,552 In most myoepithelial carcinomas, one cell type predominates, but there is usually a minor component of other cell types.571 The nuclei vary from relatively uniform, small with finely distributed chromatin, lacking obvious nucleoli, to markedly enlarged and pleomorphic, showing chromatin clumping and large nucleoli. Multinucleate,570 rhabdoid,572 and bizarre tumor giant cells may occasionally be seen. Mitotic figures may be plentiful (range, 3–51 per 10 high-­power fields) and include atypical forms. In one series, 40% of tumors were categorized as high-­grade and 60% as low-­grade, using the degree of cytologic atypia, based on nuclear parameters including size, pleomorphism, membrane abnormalities, size of nucleoli, and chromatin density, and aberrations.563 The tumor-­related matrix is generally prominent and is hyalinized or myxoid. Metaplastic changes are frequent and include areas showing squamous differentiation, often with keratinization.209 No true glands or lumina are seen in pure myoepithelial carcinomas, but a few authors believe that, as with their benign counterparts, occasional small ducts in a neoplasm, with otherwise typical features of myoepithelial carcinoma, should not preclude the diagnosis.573 Special stains in tumors without any ductal differentiation usually show no mucicarmine-­positive mucus, but glycogen is found in clear cells and the myxoid matrix is positive with Alcian blue. One of the authors (DRG) recently described a mucinous variant of myoepithelial carcinoma (with positive staining for myoepithelial markers and cytokeratin) that contains scattered cells with intracellular mucin vacuoles.547,552 To date, there have been 17 reported cases of mucinous (secretory) MYO (four benign and 13 malignant), with the majority presenting in the minor salivary glands (76%).547,552,574 All myoepithelial carcinomas display general or patchy positivity for S100 protein, vimentin, and broad-­ spectrum cytokeratins (e.g., AE1/AE3, MNF116). The cytokeratin antisera Cam 5.2 and 34βE12 show some reactivity in most tumors, and CK14 is positive in approximately half of cases. Of the more specific myoepithelial markers, approximately 75% of tumors, including those composed of plasmacytoid cells, express calponin; approximately 50% and 60% react with alpha-­smooth muscle actin and p63, respectively; p40 also is frequently positive.555,556 Among other markers, GFAP is positive in 31% and epithelial membrane antigen (EMA) in 20%, in addition to highlighting any true small ducts, but carcinoembryonic antigen (CEA) and androgen receptor are usually negative. CD117 (c-­ kit) was positive in the few cases studied.575 The mean MIB-­1 (Ki-­ 67) index in one series was 35% (range, 15%–65%), with any count greater than 10% said to be diagnostic of malignancy in a myoepithelial neoplasm.558 Electron microscopy shows that some tumor cells demonstrate evidence of myoepithelial differentiation, that is, intracytoplasmic intermediate filaments with dense bodies, extracellular basement membrane material, and junctional complexes, but actin filaments may be few.563  Differential Diagnosis. The variable appearance of myoepithelial carcinoma leads to a wide differential diagnosis, including other salivary carcinomas. Nodules with central necrosis mimic the comedocarcinoma structures in salivary duct carcinoma, but there is usually more stromal material in the myoepithelial neoplasms, and, in addition, S100 protein and/or myoepithelial markers are usually positive.570 The spindle cell type can mimic various soft-­tissue sarcomas, and the

473

plasmacytoid cell type must be distinguished from melanoma and plasmacytoma. The clear cell variant resembles the many other benign and malignant, primary and secondary salivary neoplasms composed of clear cells (see Table 6.10), including primary clear cell carcinoma, NOS, and metastatic renal cell carcinoma. In almost every case, immunohistochemistry is helpful in excluding these other neoplasms,559 as myoepithelial carcinoma almost always expresses both epithelial and myoepithelial markers. Notably, metastatic renal cell carcinoma is positive for both vimentin and CD10, but not S100 protein. Epithelial myoepithelial carcinoma, with a biphasic pattern of ducts lined with inner and outer layers of epithelial and myoepithelial cells, may contain prominent foci of clear myoepithelial cells without the inner ductal layer. It is our preference to include any malignant clear cell carcinoma with myoepithelial differentiation in the epithelial-­myoepithelial carcinoma tumor category, if it contains any areas with biphasic differentiation. Extensive squamous metaplasia might suggest squamous or mucoepidermoid carcinoma, and both demonstrate cytokeratin and p63 expression; however, the former is usually obviously monomorphic, and the latter also includes intermediate and mucus-­ producing cells and is negative for myoepithelial immunohistochemical markers. The mucinous variant of myoepithelial carcinoma will include other mucin producing tumors in the differential diagnosis, including those with signet ring cells, such as metastatic adenocarcinomas, colloid carcinoma, mucoepidermoid carcinoma, intraductal carcinoma, and salivary duct carcinoma. Negativity for myoepithelial immunohistochemical markers with adequate sampling will allow proper diagnosis. Myoepithelial carcinomas arising in a PA most commonly exhibit PLAG1 and HMGA2 rearrangements, thus fluorescent in situ hybridization for PLAG1 and HMiGA2 may aid in determining a de novo carcinoma from a myoepithelial carcinoma ex PA.566  Treatment and Prognosis. The prognosis of myoepithelial carcinoma is variable, but approximately one-­third of patients die of the disease, another one-­third have residual tumor or recurrences (often multiple), and the remaining one-­ third are disease free.558,562,563,566 When metastases occur, they can be found in neck lymph nodes and at distant sites, most commonly the lungs, kidney, brain, and bones. Treatment consists of wide surgical excision, combined with radiation, but any role for chemotherapy is not yet established. Whether low-­grade and low-­stage tumors can be treated with wide surgical excision only needs to be further studied. Various potential prognostic factors have been considered in attempts to predict the behavior of any particular myoepithelial carcinoma, but with only limited success. In a series of 473 myoepithelial carcinomas, a 78% 2-­year survival and 64% 5-­year survival were reported.567 In a series of 48 cases, myoepithelial carcinomas, arising from pleomorphic adenoma, as well the presence of necrosis, were two independent predictors of worse disease-­free survival; however, in this series, no correlation was seen between disease-­free survival and nuclear atypia, and thus the authors suggest using necrosis as a criteria for high-­ grade myoepithelial carcinoma.566 These findings contradict a previous, smaller series that concluded tumors arising in ordinary PAs behave in the same way as those that arise de novo,563 but it has been suggested that neoplasms developing in recurrent mixed tumors may pursue a prolonged course.557 A further suggestion is that myoepithelial carcinomas composed mainly

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of plasmacytoid cells may be more aggressive.576,577 However, Savera and colleagues,563 in their series of 25 cases, found only a weak statistical correlation of outcome with cytologic atypia (high-­grade), but other parameters (tumor size, site, cell type, mitotic rate, presence of a benign tumor, necrosis, perineural, and vascular invasion) were not helpful at all.563 In the future, molecular analysis may aid in prognostication in myoepithelial carcinomas. EWSR1 rearrangement has been reported in clear cell myoepithelioma and clear cell myoepithelial carcinoma, but this rearrangement may also be seen in the epithelioid, spindle, plasmacytoid, and rhabdoid cell types.572,578,579 EWSR1 rearranged clear cell myoepithelial carcinomas appear to have a poorer outcome, with necrosis present in 88% of the 21 EWSR1 positive cases, with adequate follow-­up; lymph node metastases were present in 24% of patients and 33% developed distant metastases. Outcomes included 14% of patients alive with recurrent and metastatic disease and 38% dead of disseminated carcinoma.578  WARTHIN TUMOR (PAPILLARY CYSTADENOMA LYMPHOMATOSUM) Warthin tumor (WT) is the second most frequent tumor arising in the parotid gland after pleomorphic adenoma and is generally the easiest to diagnose by microscopy.580 It is defined in the 2017 WHO classification as “a benign salivary gland tumor composed of oncocytic epithelial cells lining ductal, papillary, and cystic structures in a lymphoid stroma.”581 Synonyms include papillary cystadenoma lymphomatosum, adenolymphoma, and cystadenolymphoma,460 but WT is preferred to avoid any possible mistaken impression of a lymphoid malignancy. Clinical Features. The average annual incidence rate for WT in the United States (Jefferson County, AL) is 1.43 per 100,000 persons.360 In the Armed Forces Institute of Pathology, it comprised approximately 3.5% of all primary epithelial tumors (5.3% in the parotid gland),212 but other parotid series found 14.4% in the United Kingdom,355 27% in Denmark,581 and 30% in Pennsylvania.582 In Africa, it is rare.583 It is common in whites and Asians,584 but less so in Hispanic and African Americans209,585,586 (perhaps now increasing586) and black Africans.587 The mean age at diagnosis is 62 years (range, 12–92 years),209,585 and it is rare before the age of 40 years. The relative sex incidence has changed during the past half century: in 1953, the male-­to-­female ratio was 10:1,585 whereas now, it is almost equal.209,582,586 Only very occasional cases have been reported in the same families,588,589 and there is one report of a familial occurrence in monozygotic twins.590 Patients typically present with a painless mass, but rarely WT may be associated with facial nerve palsy.591,592 WT is almost entirely restricted to the parotid glands and periparotid lymph nodes. Most cases involve the lower pole; as many as 10% may arise in the deep lobe, however, one recent study found less than 1% of WTs in the deep lobe.593 Occasional tumors (2.7% in one series) arise within adjacent lymph nodes,594 mimicking lymph node metastases.595,596 Very rare examples have been reported at other sites, but some tumors thought initially to be within the submandibular gland have usually arisen from the anterior tail of the parotid gland or from lymph nodes.209 Nevertheless, rare tumors with a similar histologic appearance have been reported in the oral cavity,597 larynx,598,598 lacrimal gland,599 and nasopharynx.600

WT is clinically multicentric in 12% to 20% of patients (either synchronous or metachronous) and is bilateral in 5% to 17%.398,601,602 In addition, serial sectioning reveals additional subclinical lesions in 50% of patients.603 There is a strong link between WT and cigarette smoking.583,587,604–­608 The duration of smoking is also a strong risk factor; however, this appears to decrease, similar to lung cancer, following smoking cessation.607 WT is eight times more common in smokers than nonsmokers.609 And a more recent review indicated that the odds ratio for ever having smoked cigarettes was 15.3.610 There also appears to be a strong positive correlation with the amount of nicotine intake and bilateral tumors.602 In addition, the increased incidence in women since 1950 parallels the larger number of female smokers during this period.586,604 However, one review suggests that WTs may be more common in nonsmoking women.610 The mechanisms are not clear, but it has been speculated that irritants in tobacco smoke cause metaplasia in the parotid gland.606 Nevertheless, WT develops in only a small proportion of smokers (including black Africans and African Americans), and therefore smoking is likely to be a promoting factor rather than the main etiologic agent.606 Other possible significant factors include radiation exposure, as an increase in WTs among atomic bomb survivors was documented.611,612 Also, autoimmune disorders appear to be more frequent in patients with WT than in those with pleomorphic adenomas or healthy subjects.613 A recent series demonstrated a 16 times increased incidence of autoimmune thyroiditis in patients with WT.614 Patients with WTs may also have an increased risk of developing lung carcinoma.615 In some cases, especially where there are multiple tumors, the EBV genome has been isolated from the cytoplasm of luminal cells.616 This has not been confirmed in other studies.617 Human papilloma virus, types 16 and 18 have been demonstrated in four WTs; however, the authors of this latter paper could not confirm any etiologic association of this virus618 and in one study, human herpesvirus (HHV)-­8 DNA was found in 43% (19 of 43 tumors) of WTs.619 A recent study looked for prevalence of 62 viruses in 28 WTs, using fresh frozen tissues and sensitive detection methods.620 These authors found a high prevalence of EBV1 viral DNA (46% of tumors) as compared to controls (14%); in addition, they found beta-­papilloma virus DNA in 29% of WTs, alpha-­papilloma virus DNA in 11% of WTs, and 57% of WTs contained DNA from at least one species of herpes virus. What role these viruses have in development of WTs has yet to be elucidated. WTs may rarely become secondarily involved with infectious processes, including mycobacterium tuberculosis,621 an atypical mycobacterium,622 a fungal abscess,623 or a bacterial infection.624 The metaplastic (infarcted) variant can follow trauma, particularly from FNA biopsy.397,580,625,626 Possible mechanisms include trauma by the needle626 and an increased sensitivity of oncocytic cells to hypoxia.627 Most patients present with a painless mass over the angle of the mandible, on average, 2 to 4 cm in diameter, although occasional cases have reached 12 cm.628 The mean duration of symptoms is 21 months, but in 41% of patients, it is less than 6 months.629 Many patients notice fluctuation in the size of the tumor, especially when eating.630 Pain has been reported in 9%,631 particularly those with the metaplastic variant.580,606 Facial paralysis is very rare591 and is usually the result of secondary inflammation and fibrosis and likewise can be seen in the metaplastic variant.580,631 Imaging studies have shown that

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B

C Fig. 6.19  A, Warthin tumor is typically tannish brown, often with cystic spaces. In addition, this tumor demonstrates areas of degeneration and necrosis (yellowish foci). B and C, Warthin tumor is composed of papillary fronds (not shown) and ducts lined with two layers of oncocytic epithelium surrounded by lymphoid stroma (B). Occasionally, foci of prominent squamous metaplasia (left inset) and mucinous metaplasia (right inset) may be seen within this tumor (C).

WT is able to concentrate technetium 99, appearing as a “hot” lesion.  Pathologic Features. WTs, on gross examination, present as round to oval, well-­circumscribed masses that are typically encapsulated. Their cut surfaces may be brown to tan-­white, depending on the relative proportions of epithelium and lymphoid stroma (Fig. 6.19A). They contain a variable number of cysts, ranging from small slits to spaces up to several centimeters, which contain clear, yellowish, mucoid, creamy white, or brown fluid, and rarely, semisolid caseous material.585 The metaplastic variant is often firm and fibrous, frequently with a necrotic center. In all cases of WT, the parotidectomy specimen should be examined for second lesions. The proportions of the epithelial and lymphoid components vary between different tumors and even within a single lesion. WTs have been subclassified into typical (both components approximately equal), stroma poor (epithelial component >70%), and stroma rich (epithelial component of 98%) was composed of sheets of clear cells with slightly pleomorphic, eccentrically located nuclei and abundant clear cytoplasm. B, Periodic acid–Schiff (PAS) stain. Note the detail of clear cells (left). Very focally within the sheets of clear cells and at the periphery of a few of the sheets are cells with abundant, slightly purplish granular cytoplasm that stained positive with a diastase-­treated PAS stain, confirming the diagnosis of acinic cell carcinoma.

A

B

C

D

Fig. 6.32  High-­grade transformation in acinic cell carcinoma. A and B, The majority of this tumor was composed of sheets of poorly differentiated carcinoma with clear cell features. C and D, Very focally (95% of tumor cells) that we believe it is appropriate to designate these tumors as the clear cell variant of AciCC (Fig. 6.31).1046 Other described variants of AciCC include AciCC with high-­grade transformation, also referred to as dedifferentiated (Fig. 6.32), oncocytic (Fig. 6.33), hybrid tumors, and the recently separated well-­differentiated AciCC with lymphoid stroma. The well-­differentiated AciCC with lymphoid stroma is an AciCC with a better prognosis than the conventional AciCC. It is defined as a well-­circumscribed to encapsulated tumor, with a solid or microcystic pattern, in which the tumor cells are all surrounded by and intermingled with a prominent lymphoid response (see Fig. 6.30A).1047 AciCC with high-­ grade transformation1036,1039,1040,1042,1048 exhibits foci of low-­grade AciCC, frequently, the microcystic variant, and areas of high-­ grade adenocarcinoma, poorly differentiated carcinoma, small cell carcinoma, or undifferentiated carcinoma within the same tumor (see Fig. 6.32). The high-­grade component lacks acinic cell differentiation and may be very focal or can occupy >95% of the mass. Occasional cases have also included an undifferentiated spindle cell neoplasm1049 and a multiply recurrent tumor showing myoepithelial differentiation.1050 Perineural and vascular/ lymphatic space invasion and regional lymph node metastases are common. Oncocytic change in AciCC may obfuscate the diagnosis (see Fig. 6.33).1044,1051 We have seen several tumors with extensive oncocytic change in which a diagnosis of oncocytoma was entertained. In one, a heavy lymphoid infiltrate

501

raised the suspicion of AciCC. PAS-­diastase–resistant granules with ultrastructural confirmation was useful in establishing the presence of secretory or zymogen granules in such tumors.1052 Multiple examples of unusual hybrid tumors, combining AciCC with various other tumor types, have been described, including terminal duct carcinoma (polymorphous low-­ grade adenocarcinoma; polymorphous adenocarcinoma, low-­ grade variant) with acinous cell differentiation,1053 AciCC ex pleomorphic adenoma,461 AciCC combined with salivary duct carcinoma,1054,1055 AciCC combined with mucoepidermoid carcinoma,1056 and an AciCC with neuroendocrine differentiation.1057 By electron microscopy examination, AciCCs display multidirectional differentiation toward acinar, ductal, and myoepithelial elements.998,999 Zymogen granules appear as membrane-­limited, round bodies, containing flocculent material of low electron density.1046 Granule density is fixation dependent.1058 Ultrastructurally, both dense zymogen-­ like granules and light mucus-­type granules have been shown in AciCC.998 Immunohistochemistry has been of little practical aid in diagnosis, in part because of differing antigen expression between the same and differing histologic types of AciCC.1000,1059 Cells exhibiting acinar differentiation may stain positively for carbonic anhydrase VI (CA6),1060 amylase,1059 lactoferrin,997 and vasoactive intestinal polypeptide1000 and negatively for keratin997,999; however, keratin, EMA, and CEA1000,1061 positivity is present in the luminal lining cells of the ductal elements in the cystic/follicular foci.997 Absence of CK7 staining in AciCC has been proposed as a potential feature discriminating it from adenocarcinoma NOS,1062 although others described CK7 positivity in AciCC.1063 Two more recent studies clarified these differences. CK7 does not usually stain AciCC with the solid pattern (it may rarely stain minimally), but will stain those tumors that have intercalated duct-­ type differentiation in a strong, diffuse pattern.1064,1065 Normal serous acini are frequently immunoreactive for amylase; however, amylase is found in only occasional AciCCs and is therefore not useful in establishing this diagnosis.1059 Recently, a new promising marker, DOG1 has been used in AciCC,1066 allowing immunohistochemistry to differentiate AciCC from mammary analogue secretory carcinoma, as the latter is typically mammaglobin positive and DOG-­1 negative, and S100 protein and vimentin positive, whereas AciCC usually shows the reverse immunoprofile.338,1066–­1072 Also, lysozyme has been shown to be helpful with this differential diagnosis, as it stains almost 87% of MASCs and not AciCC.1073 Recently, NR4A3 immunostaining was described as a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-­ grade transformation and in “zymogen granule”-­ poor examples within the differential diagnostic spectrum of AciCC and MASC.1074 Molecular Findings. There is only minimal information in the literature on molecular changes in AciCC. The EGFR(– Akt)–mTOR-­ dependent pathway is activated in AciCC1075 and AciCC expresses markers of activated mTOR signaling. Therefore this pathway may prove to be a useful target for the mTOR inhibitors.1076,1077 P13K pathway changes have also been reported; however, the significance of these changes is unknown.1078 A recent report identified a rearrangement of the MSANTD3 gene and the HTN3-­MASNTD3 fusion gene in a small subset of AciCCs (∼3%).1079 The tumors with this latter fusion were serous AciCa and did not experience recurrence during follow-­up, suggesting that patients with this gene may have a more indolent course. Additional studies are necessary to

502

TABLE

6.14

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

Clinicopathologic Differences Between Mammary Analogue Secretory Carcinoma (MASC) and Acinic Cell Carcinomaa Acinic Cell Carcinoma

Secretory Carcinoma (MASC)

Site

Major salivary, 95% present in parotid, minor salivary very rare

Major and minor salivary common

Sex distribution

Female predominance

Slight male predominance

Growth pattern

Solid, follicular, and microcystic common, macrocystic and papillary cystic rare

Tubular and microcystic/solid predominant, Follicular and papillary cystic common

Cell morphology

Acinar basophilic with granular PAS positive-­diastase resistant cytoplasm, intercalated ductal, clear, oncocytic, vacuolated less common

Eosinophilic, clear, vacuolated or foamy appearance Serous acinar differentiation is absent

Cytoplasm

Zymogen granules present; are necessary for diagnosis

Pale pink, granular or vacuolated cytoplasm; zymogen granules absent

Nuclei

Monomorphic

Low-­grade vesicular nuclei with finely granular chromatin and distinctive centrally located nucleoli

Immunoprofile

S-­100 protein weak to negative, p63 and mammaglobin negative, DOG1 strong membranous and apical staining

S-­100 protein, mammaglobin, GATA 3 positive, DOG 1 weak and focal to negative, p63 negative

Molecular alteration

Rare tumors (∼3%) contain a HTN3-­MSANTD3 gene fusionc

t(12;15) ETV6-­NTRK3 t(12;XX) ETV6-­RETb ETV6-­MET

aModified

according to Skalova, et al., 2017. Am. J. Surg. Pathol. 41, e33–e47. A., Vanecek, T., Martinek, P., et al., 2018. Molecular profiling of mammary analog secretory carcinoma revealed a subset of tumors harboring a novel ETV6-­RET translocation: report of 10 cases. Am. J. Surg. Pathol. 42(2), 234–246. cRooper, L.M, Karantanos T, Ning Y, et al. 2018. Salivary secretory carcinoma with a novel ETV6-­MET fusion: expanding the molecular spectrum of a recently described entity. Am J Surg Pathol. 42(8):1121–1126 bSkalova,

confirm this initial impression. However, the one patient with a MSANTD3 gain metastasized to cervical lymph nodes and lungs.  Differential Diagnosis. The most important differential diagnostic consideration for the papillary cystic and follicular variants of AciCC is mammary analogue secretory carcinoma (MASC).1067 MASC, also known as secretory carcinoma, is a distinctive low-­grade malignant salivary cancer that harbors a characteristic chromosomal translocation t(12;15) (p13;q25), resulting in an ETV6–NTRK3 fusion.1080 MASC has been recently recognized as an entity different from AciCC on the basis of three major findings.1067 First, MASC showed no basophilic granularity in the cytoplasm in any of the constituent cells, this being the hallmark of the serous acinar cells of AciCC that are indicative of the presence of cytoplasmic zymogen granules. Second, MASC has a completely different immunohistochemical profile than AciCC, almost always strongly expressing S100 protein and mammaglobin, and lacking DOG1 expression.1066 Finally, unlike AciCC, most cases of MASC were found to harbor an ETV6–NTRK3 fusion gene because of a t(12;15) (p13,q25).1067 Major differential diagnostic features of MASC and AciCC are summarized in Table 6.14. Chiosea et al. reviewed 81 neoplasms originally diagnosed as AciCC, and reclassified most intercalated duct cell–predominant AciCC as MASC, based on demonstrating the ETV6 translocation.1081,1082 A further study by Bishop et al. of apparent AciCC from minor and submandibular glands showed that most harbored the ETV6-­NTRK3 translocation and should therefore be reclassified as examples of MASC.1006 The authors concluded that AciCC outside the parotid gland is rare and that the diagnosis of AciCC should be reserved for tumors with obvious zymogen granules.1008 The differential diagnosis of the solid variant of AciCC is limited; however, these tumors may so closely recapitulate normal salivary gland, both architecturally and cytologically, that a diagnosis of sialadenitis and/or sialadenosis is considered,

especially on frozen-­section examination. The lack of intercalated, striated, and excretory ducts and normal lobular architecture,346 however, aids in recognizing the neoplastic nature. Attention should also be paid to the distribution of lymphocytes because a symmetric and approximately equal distribution of lymphocytes, and tumor cells in a well-­ circumscribed tumor warrant a diagnosis of the well-­differentiated variant, which has a better prognosis. Microcystic AciCC is often mistaken for MEC. The absence of goblet cells and a squamous element distinguishes AciCC from MEC. Also p63 expression can be used in this differential diagnosis, as it is positive in MEC and negative in AciCC.1083 Furthermore, mucicarminophilic material is frequently extracellular and nuclei tend to be more bland, uniform, and peripherally located in AciCC. The papillary-­ cystic variant of AciCC must be distinguished from papillary cystadenocarcinoma. The presence of recognizable AciCC and/or zymogen granules, by PAS staining or ultrastructural examination, may be essential in making this distinction, which may be quite difficult. The follicular variant is a potential mimic of follicular carcinoma of the thyroid.1084 Thyroglobulin staining is of potential aid in this situation; however this is an extremely rare occurrence. Clear cell oncocytoma and primary or metastatic clear cell carcinoma may be diagnostic considerations in the face of extensive clear cell change, although in our experience, rare single cells with PAS-­positive, diastase-­resistant granules can still be identified in the clear cell variant of AciCC (see Fig. 6.31). In clear cell oncocytoma, nuclei are usually more central and uniform, whereas clear cell AciCC has more peripherally located and slightly more pleomorphic nuclei. Thorough histologic sampling will usually allow proper classification.  Treatment and Prognosis. Surgical excision with clear margins is the goal of treatment. For the majority of parotid tumors, superficial lobectomy1024,1034,1044 is adequate, although some have advocated total parotidectomy.1018,1021,1033 However,

6  Salivary Glands

for neoplasms involving the deep lobe, total parotidectomy is warranted. Elective neck dissection is not indicated. 1019,1033,1034,1044 Recurrences tend to be multiple and require rigorous surgical reexcision.1043,1044 Most studies suggest that radiation therapy is of little use in the treatment of AciCC. 1019,1035,1044 AciCC is capable of a notoriously protracted clinical course, and tumors may recur even 30 years after initial treatment. Disease-­free and determinate survival curves do not level off until after a decade.1035 Five-­year determinate survival rates range from 76% to 91%. Survival decreases to between 44% and 67% after 15 years.1004,1005,1020,1035,1044 Expected rates of recurrence, metastasis, and mortality, with modern surgical therapy, approximate 30%, 13%, and 13%, respectively.1035 Regional lymph node metastases occur in 10% of patients, increase with increasing T stage, and may be occult.1085 Patients may die of progressive locoregional or metastatic disease. The latter may be by either lymphatic and/ or hematogenous spread.1020 The lung and bone are the most common sites of hematogenous spread. Long-­term survival is possible after documentation of metastatic disease. Twenty-­ year disease-­free survival in patients with distant metastases is almost 22%.1023 Efforts to histologically identify those tumors that will ultimately behave aggressively have generally been disappointing.346,1034,1043 Some have noted a trend toward aggressive behavior in tumors with increased mitotic activity, cellular atypia,1002,1020,1021,1035,1044 and desmoplasia.1035 Lewis and colleagues,1035 in particular, found a strong positive correlation between increased mitotic activity and aggressive behavior that is corroborated by recent MIB-­1 studies.1034,1086,1087 Others,999,1001,1045 moreover, have described some success in prognostically grading AciCC. These efforts aside, the relative rarity of AciCC, the biological progression of histologically bland tumors, and the lack of standardized criteria make clinically relevant grading of these tumors difficult at best. Michal and colleagues1035 have reported a well-­differentiated variant that is surrounded completely by lymphoid stroma, which has a better prognosis than conventional tumors. These tumors had a low mitotic index, and all 12 patients in their series remained well without evidence of disease with follow-­up periods averaging just less than 7 years (range, 19 months to 14 years). Whether this trend will continue will require additional cases with longer follow-­up. Conflicting results have been reported using ploidy in predicting outcome in AciCC. El-­Naggar and colleagues1088 noted an association between aneuploidy and poor outcome. Others, however, have found the majority of AciCCs to be diploid, 1002,1089 concluding that ploidy is of little utility. Moreover, Timon and colleagues1090 found that neither S-­phase values nor mean AgNOR (argyrophilic nucleolar organizer regions) counts allow separation of AciCC for prognostic purposes. In our experience, and as reported by others, 1004,1005,1023,1034, 1044,1085 clinical stage at presentation gives the most prognostic information. Accordingly, metastases,1004,1005,1023,1044,1091 large size (>3 cm),1004,1034,1044,1091 deep lobe parotid involvement, 1004,1044 multinodularity,1034 age older than 45 years,1091 and being male,1091 have all been associated with poor clinical outcome. Finally, dedifferentiated AciCC carries a poor prognosis and warrants treatment afforded for high-­grade carcinomas.1040 Eighty-­six percent of tumors recurred in the largest published series, with a median survival of 2.2 years (mean 3.3 years), despite receiving aggressive therapy.1036 

503

MAMMARY ANALOGUE SECRETORY CARCINOMA (SECRETORY CARCINOMA) Mammary analogue secretory carcinoma (MASC), also known as secretory carcinoma, is a distinctive low-­grade malignant salivary cancer that harbors a characteristic chromosomal translocation, t(12;15) (p13;q25), resulting in an ETV6–NTRK3 fusion.339,1068,1069,1092–­1094 MASC was recognized as an entity different from AciCC on the basis of three major findings.1092 First, MASC showed no basophilic granularity in the cytoplasm in any of the constituent cells, this being the hallmark of the serous acinar cells of AciCC that are indicative of the presence of cytoplasmic zymogen granules. Second, MASC has a completely different immunohistochemical profile than AciCC, almost always strongly expressing S100 protein and mammaglobin, and lacking DOG1 expression.1066 Finally, unlike AciCC, most cases of MASC were found to harbor an ETV6–NTRK3 fusion gene because of a t(12;15) (p13,q25), a finding identical to secretory carcinoma of the breast,1095 and absent from AciCC of the breast1096 and salivary glands.1092 Based on the morphological similarity and sharing of the identical fusion transcript ETV6– NTRK3, one chapter author (AS) proposed the term mammary analogue secretory carcinoma of salivary gland.1092 The most recent version of the World Health Organization (WHO) Classification of Head and Neck Tumours uses the terminology of secretory carcinoma for consistency and because secretory carcinomas (mammary analogue secretory carcinomas) have been recently described at other sites, such as thyroid gland and skin.1080 Many MASCs were historically diagnosed as AciCC or adenocarcinoma not otherwise specified.1022,1081,1097 Clinical Features. MASC is usually encountered in adults (mean, 47 years; range, 14–78 years), with a slight male predominance.1068,1069,1092,1094,1097 Most published cases involved the parotid gland, followed by the oral cavity (23%), submandibular gland (8%), with two cases in the accessory parotid gland (2%). Although parotid is still the most common site, in contrast to AciCC, minor salivary sites are frequently involved.1008,1098 Since its description, >400 cases of MASC have been reported. Initially thought to be a rare type of salivary gland carcinoma, a reappraisal of low-­ grade salivary gland neoplasms, formerly designated as mucoepidermoid carcinoma, adenocarcinoma not otherwise specified, and especially AciCC, has found that a significant subset of these tumors actually represent MASCs.1022,1093,1069,1098 MASC typically presents in adults with an equal sex distribution or slight male preponderance, in contrast to the female predominance in AciCC, and usually, but not always, behaves in an indolent manner.1008,1068,1069,1082,1092–­1094,1098,1099  Pathologic Features . Grossly, MASC is usually a firm rubbery mass, with a white-­tan to gray cut surface. Occasionally, on cut surface, cystic spaces may be seen, containing yellow-­whitish fluid. The borders of the tumors are usually circumscribed but not encapsulated and broad-­front invasion within the salivary gland is often present. Perineural invasion and extension to extraglandular tissues often occurs as well, but lymphovascular invasion and necrosis are uncommon. Microscopically, most cases of MASC consist of a circumscribed mass divided by thin fibrous septa into lobules composed of microcystic, tubular, and solid structures (Fig. 6.34A). Abundant bubbly secretions are present within microcystic and tubular spaces (Fig. 6.34B). This secretory material stains positively with mucicarmine, PAS before and after diastase digestion, and with Alcian blue (Fig. 6.34C). Less commonly, a prominent fibrosclerotic stroma, with isolated tumor cells

504

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

A

B

C

D

E

F

Fig. 6.34  A, Mammary analogue secretory carcinoma (MASC) consists of a circumscribed mass divided by thin fibrous septa into lobules composed of microcystic, tubular, and solid structures. B, Abundant bubbly secretions are present within microcystic and tubular spaces. C, The intraluminal secretory material stains positively with mucicarmine (not illustrated), and for Periodic acid–Schiff before and after diastase digestion. D, Prominent fibrosclerotic stroma with isolated tumor cells in small islands or trabeculae are seen in some cases of MASC. E, MASC can be dominated by a single or several large cysts with a multilayered apocrine or hobnail epithelial lining. F, The tumor cells have low-­grade vesicular round to-­oval nuclei, with finely granular chromatin and a distinctive centrally located prominent nucleolus.

6  Salivary Glands

in small islands or trabeculae, is are seen mostly in the central part of the tumor (Fig. 6.34D). Occasionally, MASC can be dominated by several large cysts or a single large cyst with a multilayered apocrine-­like or hobnail epithelial lining, with only a minor part of the tumor displaying the characteristic tubular, follicular, macro-­and microcystic or papillary architecture, and typical secretions (Fig. 6.34E). The tumor cells have low-­grade vesicular round-­to-­oval nuclei, with finely granular chromatin and a distinctive centrally located prominent, but small, nucleolus (Fig. 6.34F). The cytoplasm may be pale eosinophilic to clear, with a granular, vacuolated, or foamy appearance. Cellular atypia is generally mild, and mitotic figures mostly rare. Thus MASC may histologically resemble zymogen granule-­ poor AciCC, low-­grade cribriform cystadenocarcinoma, and adenocarcinoma NOS. In contrast to AciCC, serous acinar differentiation with zymogen cytoplasmic granules is always absent. MASC with high-­ grade transformation (HG MASC) is characterized by focal proliferation of a distinct population of anaplastic cells arranged in solid and trabecular patterns, with frequent perineural invasion and comedo-­like necrosis (Fig. 6.35A).1100 In contrast to low-­grade MASC, the tumor cells of the high-­grade component display nuclear polymorphism, distinctive nucleoli, atypical mitotic figures, and they fail to reveal any secretory activity. Perineural and perivascular invasion is commonly observed in HG MASC (Fig. 6.35B). MASC may rarely be associated with other tumors. Petersson and coworkers reported an unusual MASC, with an associated low-­grade, mucin containing adenocarcinoma and low-­grade intraductal (in situ) carcinoma. All three components had a break in their ETV6 gene, supporting similar histogenesis of the three components.1101 Mossinelli et al. reported a patient with a synchronous left parotid superficial lobe MASC and a deep lobe AciCC.1102  Immunohistochemical Findings. MASC is consistently positive for pan-­ cytokeratin (AE1-­ AE3 and CAM5.2), CK7, CK8, CK18, CK19, epithelial membrane antigen (EMA), S100 protein, and mammaglobin (Fig. 6.36A–C), typically in a strong and diffuse pattern.944,1008,1068,1069,1070,1092,1100 The tumor cells of MASC in most cases also express gross cystic disease fluid protein 15 (GCDFP-­15) (which also particularly stains the secretory material), SOX10, and GATA-­ 3. Basal cell/myoepithelial cell markers, such as p63, calponin, CK14, smooth muscle actin, and CK5/6 are virtually negative, as described in the original report.1092 Since then, we have observed that although p63 protein is typically absent in the cells of MASC, it may occasionally reveal areas of peripheral staining.1069,1093,1094 Another important finding is that the DOG1 staining profile in MASC is different from AciCC. This chloride channel (anoctamin-­1) is selectively expressed in the luminal plasmalemma of serous acinar and intercalated ductal cells. Most cases of MASC are DOG1 negative, whereas most AciCCs demonstrate intense apical membranous staining around lumina and variable cytoplasmic positivity.1066 Some have postulated that morphology, together with S100 protein and mammaglobin immunoreactivity, is sufficient to diagnose MASC and molecular confirmation of ETV6 gene rearrangement is not required.1103 This may be true for typical cases, but FISH still remains the gold standard for confirming the diagnosis of MASC in carcinomas with unusual morphology, particularly MASC with high-­grade

505

transformation,1100,1103–­1105 and/or cases with morphology departing from usual appearances.1068,1069,1106,1107  Molecular Findings. MASC of salivary glands, just as with secretory carcinoma of the breast, harbors a recurrent balanced chromosomal translocation t(12;15) (p13;q25), which leads to a fusion gene between the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15.1092 The biological consequence of the translocation is the fusion of the transcriptional regulator (ETV6) with membrane receptor kinase (NTRK3) that activates kinase through ligand independent dimerization and thus promotes cell proliferation and survival. The presence of the ETV6–NTRK3 fusion gene has not been demonstrated in any other salivary gland tumor so far, but the same translocation can be seen not only in secretory carcinoma of breast1095 but also in infantile fibrosarcoma,1108,1109 congenital mesoblastic nephroma,1110,1111 some hematopoietic malignancies,1112 ALK-­negative inflammatory myofibroblastic tumors,1113 and in radiation-­ induced papillary thyroid carcinoma.1114 Other molecular changes that have recently been described in MASC include ETV6-­RET gene fusion1115,1116 or ETV6-­MET (high-­grade variant).1117 A small subset of MASCs show ETV6 rearrangements with as-­yet unknown partner(s). Recent studies have indicated that a few MASCs may also display atypical exon junctions ETV6-­NTRK3.1107 These atypical molecular features may be associated with more infiltrative histological characteristics of MASC, and less favorable clinical outcomes in patients.1106,1107 In addition, MASCs with ETV6–X gene fusion and other atypical fusion transcripts often demonstrate abundant fibrosclerotic stroma and particularly prominent, thick hyalinized fibrous septa. The neoplastic cells may be embedded in a completely hyalinized central part of the tumor (see Fig. 6.34D). ETV6-­ rearranged carcinomas with secretory features have also been reported in the skin,1118–­1121 and sinonasal mucosa.1122 Moreover, MASCs of thyroid gland have been recently reported in patients with no history of radiation exposure.1123–­1125 Interestingly, two of these thyroid MASCs showed a minor component of well-­ differentiatd thyroid papillary carcinoma.1123 FISH was performed, revealing ETV6 rearrangement in both components, hence supporting common follicular cell differentiation of primary thyroid MASCs.  Differential Diagnosis. The most important differential diagnostic consideration for MASC is acinic cell carcinoma (AciCC).1022 The major differential diagnostic features of MASC and AciCC are summarized in Table 6.14. Chiosea et al. reviewed 81 neoplasms originally diagnosed as AciCC, and reclassified most intercalated duct cell predominant AciCC as MASC, based on demonstrating the ETV6 translocation.1081,1082 A further study of apparent AciCC from minor and submandibular glands showed that most harbored the ETV6-­ NTRK3 translocation and should therefore be reclassified as examples of MASC. The authors concluded that AciCC, outside the parotid gland, is rare and that the diagnosis of AciCC should be reserved for tumors with obvious zymogen granules.1008 Immunohistochemistry can help differentiate the two, as MASC is typically mammaglobin positive and DOG-­1 negative, and S100 protein and vimentin positive, whereas AciCC usually shows the reverse immunoprofile.1068,1069,1070,1071,1092–­1094 Another less common, but still important differential diagnostic consideration for MASC, is intraductal carcinoma. This rare tumor is characterized by a prominent cystic tumor

506

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

A

B

Fig. 6.35  A, Mammary analogue secretory carcinoma (MASC) with high-­grade transformation is characterized by focal proliferation of a distinct population of anaplastic cells arranged in solid and trabecular patterns. B, Perineural invasion is commonly observed in high-­grade MASC.

A

B

C Fig. 6.36  A–C, MASC is consistently positive for cytokeratin CK7 (A), SOX10 (B), and S­100 protein (C).

component associated with proliferation of bland eosinophilic ductal cells, frequent intraluminal secretions, and S100 protein and mammaglobin immunoexpression, features that overlap with MASC.1126 In contrast to MASC, however, the epithelial structures of intraductal carcinoma are characteristically surrounded by an intact layer of p63-­positive myoepithelial

cells. Rarely, this pattern may be mimicked by MASC displaying a focal intraductal (in situ) component, but with only a very limited number of abluminal p63-­positive cells.1069,1093 Low-­grade mucoepidermoid carcinoma is another potential consideration in the differential diagnosis of MASC because both tumors can have a prominent cystic component with

6  Salivary Glands

cytologically bland cells that can be eosinophilic, clear, or vacuolated. Focal mucicarmine staining in MASC can cause confusion. In contrast to MASC, mucoepidermoid carcinoma is consistently positive for p63 in the epidermoid foci and is usually negative for S100 protein and mammaglobin. Finally, most cases of low-­grade mucoepidermoid carcinoma harbor a different chromosomal translocation, t(11;19), resulting in a CRTC1-­MAML2 fusion.1070,1127 Other diagnostic considerations could include occasional cases of polymorphous low-­ grade adenocarcinoma (PLGA), low-­ grade adenocarcinoma NOS or cystadenocarcinoma, and cystadenoma. PLGA could be a consideration primarily because of its bland cytologic features, constant S100 protein, and sometimes mammaglobin immunoexpression.1070 The latter stain is usually very patchy, compared to the diffuse staining of MASC, and the architectural tumor growth patterns are more varied than is noted in MASC. Treatment and Prognosis. MASC usually behaves indolently, but like other low-­ grade salivary gland carcinomas, there is considerable capacity for aggressive behavior, including locoregional recurrence and distant metastasis. Particularly important, is the rare occurrence of high-­grade transformation that may result in tumor-­related death.1100,1104,1105 The treatment of MASC has been variable, ranging from simple excision to radical resections, neck dissections, adjuvant radiotherapy, and/or adjuvant systemic chemotherapy. The treatment of choice for low-­grade MASC is complete surgical resection, in line with the standard of care for low-­grade salivary carcinomas in general. Few such cases recur after surgical resection.1092,1094,1128 Locoregional radiation therapy can be considered for larger tumors or those with positive margins or perineural invasion. Systemic chemotherapy may be implemented for distant metastases, however, little is known about clinical outcomes and optimal treatments for HG MASC.1100,1104,1105 Therefore recognizing MASC and testing for ETV6 rearrangement may be of potential value in patient treatment. The translocation results in the generation of a constitutively active tyrosine kinase, which leads to downstream promotion of cell signaling pathways and cellular proliferation. Response to tyrosine kinase inhibitors has been reported in clinical cases of leukemia with ETV6 translocation.1129,1130 Use of and response to tyrosine kinase inhibitors in MASC is limited to date.1131  ADENOID CYSTIC CARCINOMA Adenoid cystic carcinoma (AdCC) is a common salivary gland carcinoma of both minor and major glands and the sinonasal mucosa. AdCC is characterized by its slow but relentless clinical progression. It is a morphologically bland but highly infiltrative and aggressive biphasic basaloid tumor, composed of abluminal myoepithelial and luminal ductal cells arranged in tubular, cribriform, and solid growth patterns. AdCC is encountered from the first to the ninth decades of life, although most cases are diagnosed from the fourth to seventh decades.1132–­1134 The female-­ to-­ male ratio is approximately 3:2.562 The literature suggests considerable geographic variation in the incidence of AdCC. In England and Western Europe and in the older literature, it is the most common malignant intraoral salivary gland tumor. However, in the contemporary United States, mucoepidermoid carcinoma, polymorphous low-­ grade adenocarcinoma (polymorphous adenocarcinoma, low-­grade variant), and other tumors are more frequently encountered. 355,562,780

TABLE

6.15

507

Distribution of Sites for Adenoid Cystic Carcinoma of the Upper Aerodigestive Tract

Site

No. of Cases (%)

Parotid gland

336 (21.0)

Palate

271 (17.0)

Other site, not stated

242 (15.0)

Submandibular gland

210 (13.0)

Sinonasal, nasopharynx

184 (11.0)

Tongue, floor of mouth

129 (8.0)

Tonsil, pharynx

69 (4.3)

Lip

53 (3.3)

Buccal

44 (2.7)

Sublingual gland

30 (1.8)

Retromolar trigone

21 (1.3)

Gingiva

10 (0.6)

Larynx/trachea

10 (0.6)

Lacrimal gland

5 (0.3)

Total

1614 Huvos,1142

Data from Spiro and Conley and Casler,1143 Garden et al.,1144 Kim et al.,1147 and Auclair et al.819

Clinical Features. Typically, AdCC is a slow-­growing, widely infiltrative tumor with a tendency for perineural spread. Patients generally present with pain and a mass; the latter may have evolved over years. Mucosal ulceration, especially of the palate, is common. Occasional tumors present with intracranial involvement and can mimic a meningioma clinically and radiographically. Uncommonly, a tumor may have an occult presentation.355,780,1135,1136 Table 6.15 represents a compilation of tumor sites for AdCC derived from more than 1600 cases.819,1132–­1134 The parotid gland, palate, submandibular gland, and sinonasal tract are the most commonly affected upper aerodigestive tract sites, although, importantly, the minor salivary gland and seromucinous gland sites are more frequently involved than the major salivary glands combined (see Table 6.15). After squamous cell carcinoma, AdCC is the second most frequent malignant tumor of the trachea. The male-­to-­female ratio is almost equal, and the average age at presentation is between 45 and 60 years (range, 15–80 years).1137 Histologically, similar tumors can also be found at other sites, including the external ear, lacrimal glands, esophagus, breast, prostate, cervix, ovary, Bartholin’s gland, lung, and skin.1138–­1143  Pathologic Features. Grossly, these tumors are firm and gray-­white and often locally invasive, although they can appear as subtle scar-­like lesions. Smaller tumors may be circumscribed or, rarely, encapsulated. They have a tendency to extend along nerves, and skip lesions may be encountered considerable distances away from the main tumor mass. Rarely, tumors will present in an occult fashion, involving interlobar septa, without a definitive primary mass.1136 The rare finding of necrosis or/ hemorrhage may indicate high-­grade transformation.1144 The WHO classification schema divides AdCC into three microscopic patterns: tubular, cribriform (glandular), and solid (Fig. 6.37).352 The cribriform is the most frequent, and the solid is the least frequent pattern observed. AdCCs are composed

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of cells of two types: ductal cells and abluminal myoepithelial cells. Cytologically, AdCC is composed of a somewhat uniform, bland population of cells, with oval basophilic nuclei with homogeneous chromatin distribution, and usually with little cytoplasm, reminiscent of basal cell carcinoma of the skin. The nuclei are frequently angulated and may rarely have coarse chromatin and prominent nucleoli. These latter two features are more likely in the solid, high-­grade tumors, although high-­ grade cytology may occasionally be seen with intermediate-­ grade tumors. A mixture of patterns is common in AdCC; classification is made according to the predominant pattern. However, if a tumor has more than 30% of the solid pattern, it is classified as the solid variant, given its more aggressive behavior. The tubular pattern (well differentiated or grade I) is characterized by slender tubules, solid cords, and glandular structures infiltrating a well-­hyalinized background (see Fig. 6.37B). Central lumina are lined with small cuboidal, less commonly columnar, epithelial cells surrounded by abluminal myoepithelial cells. The cribriform pattern (moderately differentiated or grade II) is characterized by invasive tumor islands with multiple holes (pseudocysts or pseudolumina), punched out in a “Swiss cheese” or sievelike pattern (see Fig. 6.37A). The pseudolumina are sharply demarcated from the surrounding cells and may contain a rind of dense pink basement membrane material and central blue mucopolysaccharides, or they may be entirely filled with the basement membrane material.1145 They are not true glandular lumina, lacking microvilli and apical junctional

complexes,1146 but attest to the productivity of AdCC tumor cells, which make type IV collagen, laminin, chondroitin sulfate, and fibronectin. True lumina are surrounded by myoepithelial cells and are scattered between the pseudocysts. These lumina are much smaller than the pseudocystic spaces and are lined with cuboidal cells similar to those seen in normal salivary gland intercalated ducts. The solid pattern (poorly differentiated or grade III) consists of large islands of carcinoma, composed predominantly of myoepithelial cells, with infrequent true lumina, lined with cuboidal epithelial cells, with only occasional punctuation by pseudocysts (see Fig. 6.37C). A temporal progression in tumor grade may be observed,1147 with recurrent disease acquiring a solid pattern. Perineural spread is a feature common to all patterns (see Fig. 6.37D). Mitotic figures and apoptotic cells are occasionally present in intermediate-­grade tumors and are common to high-­grade or solid pattern AdCC. Necrosis is seen, usually only in the solid pattern, and, when present, it is often centrally located within cell nests, imparting a comedo appearance. Typical AdCC may commingle with a dedifferentiated high-­ grade component (AdCC with high-­ grade transformation), similar to that rarely encountered in acinic cell carcinoma.1148–­1150 This may occur in primary or recurrent tumors. A recent review of cases published since 1999 found 44 cases in the literature; 11 arose in the submandibular gland, 9 in the paranasal sinuses, 9 in the oral cavity, 5 in the parotid, 3 each in the nasal cavity and lacrimal gland, and 4 were in other sites.1149 The transformed component may be poorly differentiated adenocarcinoma or

A

B

C

D

Fig. 6.37  Adenoid cystic carcinoma. A, Cribriform pattern. B, Tubular pattern (polyclonal carcinoembryonic antigen stain). C, Solid pattern. D, Cribriform pattern with prominent perineural invasion.

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undifferentiated carcinoma; uncommonly, a myoepithelial carcinoma may be found.1150 Proliferation indices are elevated in dedifferentiated foci.1148,1150 A p53 gene mutation was implicated in dedifferentiation in one case.1151 The clinical course of such tumors is rapid progression, with frequent recurrence and metastasis. Occasionally, the high-­grade component may be very small. Therefore very generous histologic sampling (the entire tumor if possible) of all AdCCs is important to evaluate for this possibility.1149  Molecular Findings. The most significant advance in the understanding of the molecular pathology of AdCC is the discovery and characterization of the t(6;9)(q22-­ 23;p23-­ 24) translocation.1152–­1154 The translocation results in a MYB-­ NFIB gene fusion, which is the main genomic hallmark of AdCC.1155–­1157 The fusion is an oncogenic driver, which activates several critical downstream targets with transforming potential.1156 Activation of the MYB oncogene by gene fusion or other mechanisms (e.g., enhancer hijacking) has been shown by break-­ apart or fusion FISH or fusion transcript reverse transcriptase (RT)-­ PCR, in up to 80% of AdCCs.1158–­1160 Recently, a small subset of MYB-­NFIB negative cases were shown to have t(8;9) translocations, resulting in closely related MYBL1-­NFIB fusions 1218.1161–­1162 So far, MYB-­status has not been shown consistently to correlate with prognosis or other clinicopathologic features,1158,1159 but the use of MYB-­testing has been proposed as a useful ancillary test in the routine clinical diagnosis of salivary gland tumors, in which AdCC enters the differential diagnosis. Other genomic alterations in AdCC are variable with solid tumors, showing a higher number of copy number alterations, including chromosomal losses involving 1p and 6q.1163 There is good evidence to suggest that 1p36 deletion correlates with poor prognosis.1163,1164 Studies of the mutational landscape of more than 100 AdCCs have revealed a low exonic mutation rate and a wide mutational spectrum.1157,1165,1166 Although the frequency of mutations in individual genes seems to be very low, the mutations preferentially cluster in certain pathways, including those involved in chromatin regulation, DNA-­ damage/checkpoint signaling, FGF-­IGF-­PI3K-­and NOTCH-­ signaling, and axonal guidance. Interestingly, several of these are actionable mutations, calling for genetic testing of patients with AdCC to individualize and optimize the treatment.1158 Molecular genetic studies have shown that a progression in tumor grade is associated with the accumulated loss of tumor suppressor genes. p53 mutations appear to be a late event in the histogenesis of AdCC and are more involved with tumor progression and recurrence. LOH analyses derived from microdissections of varying grades of AdCC, within the same tumor, reveal that the number of mutations at either the p53 or Rb gene is greater in higher-­grade foci than in lower-­grade foci.1167  Differential Diagnosis. Low-­ or intermediate-­g rade (tubular and cribriform pattern) tumors must be distinguished from basal cell adenoma (BCA) and polymorphous low-­ grade adenocarcinoma (polymorphous adenocarcinoma, low grade; PLGA). Typically, these tumors are misdiagnosed as AdCC rather than the converse. Tumor infiltration and the presence of perineural invasion are the most important features to distinguish AdCCs from BCAs because the latter are circumscribed or encapsulated tumors lacking perineural invasion. Rarely, however, AdCCs may be totally encapsulated. With limited biopsy material, it may be literally impossible to differentiate between these tumors, as the bland

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cytology, myoepithelial-­ epithelial relationship, and tubular and cribriforming patterns can be features of both tumors. In addition, the presence of blue “goo” (basophilic-­staining mucopolysaccharides) within cystic spaces is common in AdCC and rarely, if ever, seen in BCA. AdCC-­like foci can also be seen in benign pleomorphic adenoma and may present diagnostic difficulty with limited biopsy material or with the rare encapsulated AdCC. In addition, we have seen one typical case of AdCC that had a small focus of cartilaginous metaplasia. Typical plasmacytoid myoepithelial cells are common in pleomorphic adenomas and are not seen in AdCC, and most pleomorphic adenomas have a more varied growth pattern than is found in AdCC. Squamous metaplasia can be seen in BCA and pleomorphic adenoma; it is an extremely rare and focal finding in AdCC and so may serve as a hint that one is not looking at AdCC. The distinction between PLGA, cribriform adenocarcinoma (CAC; cribriform adenocarcinoma of the tongue and of the [minor] salivary glands) and AdCC is more challenging. All three tumors are basaloid neoplasms and have similar growth patterns (cribriform, solid, and tubular) and a tendency for local infiltration and perineural spread. PLGA, however, has a varied, polymorphous architecture but is composed of a monomorphic cell population. AdCC has a more limited range of histologic patterns (solid, tubular, and cribriform growth) and is a biphasic tumor composed of both epithelial and myoepithelial cells; tumor nuclei in many tumors are focally angulated and hyperchromatic, as compared to the bland nuclei of PLGA. CAC has nuclei that are similar to papillary carcinoma of the thyroid with sightly more pleomorphism and, most importantly, nuclear clearing, that are not found in significant numbers in the other two tumors. In our experience and in the experience of others,545,1168 many of the myoepithelial markers may be found in PLGA (HHF35, S100 protein, smooth muscle actin, GFAP, p63), but are not as frequently positive and are much more patchy with less intense staining; however, Prasad and colleagues,568 using three smooth muscle markers (smooth muscle actin, smooth muscle myosin heavy chain, and calponin), stained the myoepithelial cells in all AdCCs, whereas all the PLGAs examined were negative. In addition, foci of papillary growth and areas of single-­file cell infiltration are characteristic of PLGA but not of AdCC. Basophilic pools of glycosaminoglycans are frequent in AdCC and are not typical of PLGA. By contrast, at low power, PLGA will reveal a steel gray type of stromal background.1168 PLGAs may form solid areas, but they lack the overall high-­grade “feel” (coarse chromatin, increased mitotic figures, apoptosis, and necrosis) associated with solid AdCC. Several observers have recommended using C-­kit in the differential diagnosis of AdCC and PLGA, but there are conflicting results in the literature; therefore we do not find this antibody to be useful in this differential diagnosis.1169–­1173 The one antibody combination that appears to be helpful is p63 and p40 immunohistochemical staining. PLGA has consistent p63 positivity with a negative p40 stain in almost 90% of tumors (sensitivity 100%; specificity 93% for identifying PLGA), while AdCC is positive for both markers in almost 90% of tumors.1173 The one PLGA that did not stain with p63 or p40 was one with high-­grade features; one AdCC did demonstrate rare p63 positive cells. If mitotic figures are easily found, then PLGA becomes an unlikely possibility, although occasional mitoses may be noted. Commensurate with this, the MIB-­1 proliferative index, which

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reflects expression of the cell cycle–associated antigen Ki-­67, may be helpful. Skalova and colleagues1174 studied 21 PLGA and 20 AdCC cases and found that PLGA had a mean proliferative index of 2.4%, whereas AdCC had a mean value of 21.4%; no overlap in MIB-­1 index values was seen between both groups (for more information on proliferative rates, please refer to the “Polymorphous Low-­Grade Adenocarcinoma, Differential Diagnosis” section). However, one author (DRG) has seen an encapsulated AdCC, with a proliferative rate of less than 1% that metastasized. The true nature of this tumor became obvious when the patient developed a cervical lymph node metastasis, with typical tubular and cribriform morphology, several months after diagnosing the original tumor as a pleomorphic adenoma, with adenoid cystic-­like metaplastic changes. Recently, several publications confirmed that many PLGAs are characterized by a protein kinase D1 hotspot mutation E710D. When present, this mutation is highly specific for PLGA and can be used in the differential diagnosis with AdCC and pleomorphic adenoma.1156,1175 Basaloid squamous carcinoma (BSC) also enters into the differential diagnosis of solid AdCC, in minor salivary or seromucinous gland sites, and particularly at sites of predilection for BSC, such as the base of the tongue.1176 Both tumors may produce basement membrane–like material and have cribriform and solid areas. The basement membrane material secreted by BSC tends to dissect between tumor cells rather than to form crisp cribriform spaces, as seen in AdCC. Necrosis and basaloid cells (ovoid with high nucleus-­ to-­ cytoplasm ratio), with prominent nucleoli and coarse chromatin, can be seen in both tumors, although single-­cell necrosis, a brisk mitotic rate, and a greater degree of nuclear atypia are much more frequent in BSC. One can distinguish BSC from solid AdCC by identifying focal keratinization, attachment to the rete pegs, the presence of a surface squamous dysplasia/carcinoma in situ component or a superficially located invasive squamous cell carcinoma. In addition, true lumina are found in AdCC, whereas they are not seen in BSC. Gnepp and Heffner1177 found areas of surface mucosal origin, some of which were associated with surface mucosal in situ changes, in 58% of sinonasal AdCC. The mucosal carcinoma-­in-­situ changes were not squamous in origin, as is seen in BSC, but were similar to the deeper tumor epithelium. Recently, staining patterns for p63 have been proffered as an aid to distinguish between AdCC and BSC.1178 Although the former tends to show compartmentalization of staining (preferential staining of myoepithelial cells), the latter exhibits diffuse tumor cell staining. Both BSC and AdCC can express cytokeratin and S100 protein, but solid AdCC may express vimentin diffusely and retain some myoepithelial smooth muscle antigenicity, such as GFAP and smooth muscle actin. BSC may also express vimentin, and, when it does, it has a dot-­ like cytoplasmic distribution. Basal cell adenocarcinoma (BCAC) may also enter the differential diagnosis of intermediate-­or high-­grade AdCC, especially for parotid tumors. An infiltrating cribriform pattern, palisading basaloid cells, and hyaline deposition are features that may be common to both BCAC and AdCC. BCAC is usually composed of a blander population of tumor cells than AdCC. In addition, BCAC may have a jigsaw puzzle– type pattern of discrete interlocking tumor islands. The cells in the center of these islands can be discohesive and loosely aggregated, reminiscent of the stellate reticulum pattern seen in some ameloblastomas. Squamous differentiation and this

latter pattern are not seen in AdCC and, when present, help distinguish BCAC from AdCC. One should be reluctant to diagnose AdCC on limited biopsy material, especially in the absence of definite tumor infiltration. The cribriform pattern, so typical of AdCC, may also rarely be seen in basal cell adenomas (BCAs), pleomorphic adenomas and PLGAs, as discussed previously. The diagnosis of minor salivary gland tumors on limited biopsy material is especially challenging because benign minor salivary tumors are rarely encapsulated but are frequently well circumscribed. Treatment and Prognosis. Wide surgical resection, with negative margins, is the standard primary therapy. Adjuvant radiation therapy is usually indicated for most tumors, although one study suggests that the benefit of radiotherapy is greatest in patients with advanced T-­ stage (T4) tumors.1179 Well-­ resected T1 AdCC may not require adjuvant radiation therapy. Primary conventional radiotherapy has never been shown to provide sufficient local disease control. However, there are emerging data suggesting that neutron therapy, which involves larger particles of greater energy, can achieve reasonable local control as a primary therapeutic modality.1180–­1182 Adoptive immunotherapy, in combination with chemoradiotherapy, has shown promising results.1183 Larger series with more patients are necessary to confirm these preliminary data. Early data are conflicting regarding the efficacy of imatinib mesylate in the treatment of highly expressing, kit-­positive AdCC,1184,1185 although the dramatic tumor regression, as seen with gastrointestinal stromal tumors is not typical. Also patients with major salivary gland AdCCs have an increased risk of developing a second primary in the oral cavity and nasopharynx.1032,1186 AdCC has been noted to have a greater local recurrence rate compared with other malignant salivary tumors (P = 0.0059).1187 This propensity for local recurrence (as many as 62%) is highest within the first 5 years, but a local recurrence will develop in a significant number of patients after 10, 15, and 20 years.1134,1174 Actuarial local control rates at 5, 10, and 15 years of 95%, 86%, and 79%, respectively, have been reported.1134 Distant metastases are much more frequent than local lymph node metastases. The rate of distant metastasis development is 40% to 50% for all AdCCs,1132,1134,1188,1189 and these may occur from 10 to 108 months (median, 96 months), after initial diagnosis. Approximately 3% to 8% of patients have metastases at initial presentation.1190 These tumors most frequently metastasize to the lung and less frequently to bone and soft tissues. We have seen solid-­pattern AdCC metastasize to the spine within 6 months of primary diagnosis in the parotid gland. An AdCC of the maxillary sinuses may rarely metastasize to cervical nodes before the primary tumor is detected.1190 Also AdCC may rarely metastasize to unusual sites, such as the breast and hypophysis.1191 Distant metastasis usually occurs in conjunction with local recurrence, but may develop in the absence of locoregional disease.1134,1192 It was the most common type of treatment failure in one report.1192 Spiro1188 reported disease-­ free intervals, after adequate primary therapy, from 1 month to 19 years (median, 36 months) and disease-­free intervals of longer than 10 years, in nine of 113 patients (8%). Survival with distant metastases was less than 3 years in 54%, but more than 10 years (with a maximum of 16 years) in 10% of patients. Kokemueller and colleagues1189 reported a mean recurrence-­free survival of 9.1 years in a study of 74 patients, in which complete resection was achieved in 45 patients. Mean survival was 4.7 years after recognition of tumor progression. A series from the M.D. Anderson Cancer Center

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of 160 patients, using consistent surgical and radiation therapy in 87.5% of patients, yielded disease-­specific survival rates at 5, 10, and 15 years of 89%, 67.4%, and 39.6%, respectively.1192 Treatment failure was documented in 37% of patients, ranging from 2 months to 19 years. Eight percent failed locoregionally only, 22% only failed distantly, and 7% had both locoregional and distant failures. Major nerve (large nerves with a specific name) invasion, positive margins, and solid histologic features predicted treatment failures, whereas node metastases, major nerve involvement, solid histologic features, and four or more symptoms present at diagnosis were associated with increased disease mortality. Surgical prognosticators in other series include tumor grade, stage, site, nerve involvement, and resection margins. A number of studies confirm that the grading system, based on the pattern of differentiation and tumor stage, correlates with survival for AdCC.1193–­1198 Regarding grade as a prognosticator, the cumulative survival rates at 5, 10, and 15 years, respectively, are 92%, 65%, and 14% for grade I tumors; 76%, 26%, and 5% for grade II tumors; and 39%, 26%, and 5% for grade III tumors.1194 Tumor site is another important prognosticator: generally, major salivary gland sites have a more favorable outcome than minor salivary gland sites.1132,1133 AdCCs of the trachea have a better prognosis than their counterparts in the upper respiratory tract, with 5-­year survival rates ranging between 66% and 100% and 10-­year survival rates ranging between 50% and 75%. These data are summarized in a review by Azar and colleagues.1137 Sites such as the sinonasal tract are inherently less resectable and have the worst prognosis.1133 Spiro and Huvos1132 showed that tumor stage is a better prognostic discriminator than tumor grade. This fact has been underappreciated because AdCCs are not commonly encountered as stage I tumors. Patients with stage I tumors had a lower rate of local recurrence (23%) than that for patients with tumors of stages II through IV (60%). Their cumulative 10-­year survival rates per stage were 75% (stage I), 43% (stage II), and 15% (stage III/IV). Histologic grade did have a survival impact early in the disease course: one-­third of recurrences were evident within 1 year for intermediate-­or high-­grade tumors, whereas only 14% of low-­grade tumors recurred in 1 year. The presence of cervical lymph node metastasis, in major salivary gland AdCC, is associated with a worse prognosis, and advanced T stage (T3 and T4) is associated with an increased risk of cervical nodal metastases. Two recent reviews of large population based studies of 720 patients and 483 patients indicated a rate of 17% and 18.6%, respectively, of cervical lymph node metastasis. The metastases usually were located in levels II and III. Therefore any patient with a T3 or T4 primary tumor, as well as tumors with other histologic risk factors, should have elective neck treatment.1186,1199 Garden and colleagues1134 reported on 83 patients (42%) with microscopic-­ positive margins and 55 patients (28%), with close margins (defined as less than 5 mm) or uncertain margins. Perineural spread was seen in 69% of cases, and invasion of a major (named) nerve occurred in 28% of patients. Local recurrences developed in 18% of patients with positive margins, compared with 9% of patients with close or uncertain margins, and 5% of patients with negative margins (P = 0.02). Patients with major (named) nerve involvement had a crude failure rate of 18% (10 of 55), compared with 9% (13 of 143) of patients without major nerve involvement (P = 0.02). A more recent review of 507 patients indicated that positive margins on multivariate analysis had a hazard ratio of 2.68 and 2.63 for

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overall survival and disease-­specific survival, respectively, while close margins (17% of tumor cells touching stroma in cystic areas), rather than pools of mucin between the stroma and tumor cells. MEC may occasionally be associated with prominent pools of acellular

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mucin. Careful histologic sampling will reveal more typical areas with squamous, intermediate, and mucin-­ secreting elements. Mucin-­rich SDC, with careful histologic sampling, will usually have areas with the histologic appearance of a typical SDC, allowing separation from CC. Metastasis can be ruled out by careful clinical history and evaluation. Mucin extravasation phenomenon contains pools of interstitial mucin, often with inflammatory changes and areas of fibrosis. Unlike CC, neoplastic epithelium is not found within the mucin pools.  Treatment and Prognosis. All reported cases were treated with surgical resection; four patients also received postoperative and one preoperative radiation therapy. Two of 13 patients presented with cervical lymph node metastasis. Clinical follow-­up was available for all patients, ranging from 6 months to 24 years. Five patients were alive and well, ranging from 6 months to 56 months (mean 22.4 months). Four patients were alive with disease (two with recurrent cervical

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lymph node metastases at 42 and 72 months, one with tumor recurrence and pulmonary metastasis at 24 months, and one with local recurrence at 24 years.) Three patients died of other causes without evidence of disease at 6, 29, 36 months. One patient died with cervical tumor recurrence and lung metastasis at 29 months. From the preceding, one can conclude that primary CC of the salivary glands is a low-­to intermediate-­grade carcinoma with a risk of local recurrence (15%), cervical lymph node metastasis (15%; both of which recurred in the neck), and pulmonary metastasis (15%). Wide surgical excision with free margins and a cervical lymphadenectomy for clinically positive lymph nodes would seem to be the most prudent therapy. However, because of the rarity of these tumors and small numbers in the literature, additional studies evaluating and possibly modifying the earlier diagnostic criteria are necessary to more firmly establish the biologic behavior of this tumor. 

A

B Fig. 6.53  A and B, Colloid carcinoma composed of multiple pools of mucin in a delicate fibrous stroma that surrounds atypical pleomorphic carcinoma cells. Detail of carcinoma nests demonstrating prominent nucleoli and moderate amounts of eosinophilic cytoplasm (B, inset).

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C

D

E Fig. 6.53, cont’d  C–E, Mucinous cystadenocarcinoma composed of mucin-­filled cystic spaces simulating a colloid carcinoma. The cystic spaces are almost all lined, at least partially, with atypical pseudostratified column epithelium that separates the mucin from the adjacent stroma. This differential diagnostic feature will allow differentiation from a colloid carcinoma. Tumors with malignant epithelium lining portions of more than 17% of the cystic spaces are best classified as mucinous cystadenocarcinomas. Detail of carcinoma cells (E, inset).

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ADENOCARCINOMA NOT OTHERWISE SPECIFIED Clinical Features. Adenocarcinoma not otherwise specified (AdCaNOS) is a group of salivary gland carcinomas, with ductal or glandular differentiation, that fail to meet the diagnostic criteria for any other specific tumor type. These tumors are uncommon, but not rare, and typically affect older white males with high clinical stage and high-­grade carcinomas.1691,1692 At the Armed Forces Institute of Pathology (AFIP), this group accounted for 9% of salivary gland tumors and 16.8% of all salivary gland malignancies from 1985 to 1996.562 The relative frequency of these tumors is quite variable in the literature, ranging from 1.9% to 12.2% of salivary gland tumors, but they usually rank as one of the three most common types of malignant salivary gland tumors.1693,1694 In a series of parotid tumors reclassified, using the 2005 WHO classification, AdCaNOS represented 2.7% of all epithelial tumors and 17.8% of malignant epithelial tumors1635 and in a more recent epidemiologic review of primary parotid gland carcinomas, AdCaNOS accounted for 14% of malignancies.1085 This percentage is likely to decrease because of recent identification of new tumor types (mammary analogue secretory carcinoma, cribriform adenocarcinoma of minor salivary gland and microsecretory adenocarinoma1695) and new variants and better diagnostic criteria of known carcinomas, such as salivary duct carcinoma (SDC), which have been removed from the pool of AdCaNOS. This latter fact was confirmed in a large series of malignant salivary gland tumors, reviewed at the National Cancer Institute in Milan, where most SDCs were initially classified as AdCaNOS.1696 Approximately 60% occur in the major salivary glands, with 90% of these arising in the parotid gland, and 10% in the submandibular gland.562 Occasional cases have been reported in the sublingual gland.1693 AdCaNOS represented only 2.1% of intraoral minor salivary gland tumors in a study of 380 cases from northern California.779 In order of decreasing frequency, these arose in the palate (usually the hard palate), buccal mucosa, and upper and lower lips. At the AFIP, these tumors were slightly more common in women than in men, with an average age at presentation of 58 years (range, 10–93 years). In a recent review of parotid tumors, the median age was 67 years with a peak incidence between 60 and 80 years. Increasing age was correlated with increasing tumor grade. AdCaNOS is rare in the pediatric population. Other series, including the largest epidemiologic review published to date, have shown a slight male predominance.1691,1692,1697 Patients present clinically with asymptomatic or painful masses; fixation to adjacent or deeper tissues is frequent.562  Pathologic Features. Tumors frequently range in size to as large as 10 cm in greatest dimension and may have circumscribed or infiltrating borders.1693 Grossly, they are firm with cut surfaces, ranging from white to whitish yellow; areas of necrosis may be seen.562 A myriad of cell types (including cuboidal, columnar, polygonal, oncocytoid, clear, mucinous, and plasmacytoid, among others) may be encountered1622 that are arranged in an endless variety of growth patterns, with areas of glandular or ductal differentiation. As stated previously, these tumors lack the requisite criteria for placement into one of the known (named) types of salivary gland carcinoma. As such, one should thoroughly search for focal areas of classifiable tumor. On several occasions, we have found areas, often quite limited, of pleomorphic adenoma, acinic cell carcinoma (AciCC), and adenoid cystic carcinoma, in a tumor

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initially thought to represent AdCaNOS. We interpret this phenomenon as biological progression or dedifferentiation of a lower grade tumor, an occurrence that may be more common than appreciated. Furthermore, classifiable carcinomas may exhibit areas that share histologic overlap with AdCaNOS. As Ihrler and colleagues1062 aptly noted, this is particularly true with AciCC. These authors reported the utility of CK7 in aiding in the distinction between these tumors. Although CK7 immunohistochemistry is diffusely positive in most AdCaNOS, it is negative or only focally positive (usually in intercalated duct-­like areas) in AciCC. They also found that CK18 expression was helpful, as AciCC was characterized by strong membranous staining, with only minimal cytoplasmic staining, whereas AdCaNOS had a moderate to strong diffuse cytoplasmic staining pattern. Tumors are classified as low, intermediate, or high grade using criteria similar to those used for adenocarcinomas in other anatomic areas. Metastatic tumor merits exclusion in all cases of AdCaNOS. The most recently described possible new tumor entity that is currently listed under the AdCaNOS category is the microsecretory adenocarcinoma recently described by Bishop et al.1695 This tumor has a novel MEF2C-­SS18 gene fusion and is characterized by intercalated duct-­like cells with eosinophilic to clear cytoplasm, small, oval uniform nuclei, infiltrative cords and microcysts, abundant intraluminal secretions, and cellular fibromyxoid stroma with a low mitotic rate and absent necrosis.  Treatment and Prognosis. Treatment is wide local excision for low-­grade and low-­stage tumors, whereas intermediate-­or high-­grade tumors, with positive or close margins, or advanced-­ stage tumors, should be treated more aggressively with wide surgical excision and adjuvant radiation therapy. In addition, for high-­grade tumors, the appropriate neck area should be treated with radiation or neck dissection, as there is a greater incidence of occult lymph node metastases in patients with high-­grade disease (3.8% for low grade vs. 31.6% for high grade).1692 Referral for neutron beam therapy is a therapeutic option for inoperable cases. Information on the biological behavior of AdCaNOS is sparse. Data from two older series,1691,1697 published before the 2005 WHO classification of salivary gland tumors, is likely somewhat sullied because some of their tumors would certainly be reclassified as newly recognized variants of salivary gland carcinoma. In addition to the major and minor salivary glands, cases from upper respiratory sites were also included. Despite these limitations, the data remain of interest.562 Matsuba and colleagues1697 recorded a median survival for the 54 patients in their series of 4 years. They found that survival depended on tumor location, with oral cavity tumors having a more favorable prognosis (approximately 76% at 10 years) than those of the parotid (26% at 10 years) or submandibular glands. In addition, patients with low-­ grade tumors had lower rates of distant and cervical lymph node metastasis and greater disease-­free intervals. Cervical lymph node metastases developed in 23% of patients, with 73% dying within 3 years; distant metastases developed in 37% of patients, with 93% dying within 3 years. These authors concluded that tumor grade did not significantly affect overall patient survival, which was similar for well, moderately, and poorly differentiated tumors (approximately 25% at 10 years). Spiro and colleagues1691 found that grade, and especially tumor stage, were important prognostic indicators in their

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series of 204 patients. Recurrence was more frequent in patients with high-­grade tumors, and there was good correlation with survival: grade 1, 2, and 3 tumors had 69%, 46%, and 8% 5-­year and 54%, 31%, and 3% 15-­year survival rates, respectively. The most accurate predictor of outcome appeared to be clinical stage, with stage I, II, and III tumors having 15-­year cure rates of 67%, 35%, and 8%, respectively. Patients with tumors of the oral cavity had better survival rates (56% at 5 years) than those seen in patients with tumors of the parotid gland (45% at 5 years), who, in turn, had better survival rates than those in patients with tumors arising in the submandibular gland (13% at 5 years). Twenty-­six percent of patients developed distant metastases, which were more frequent in previously treated patients or in those with high-­grade tumors. After culling the National Swedish Cancer Registry, Wahlberg and colleagues1698 reported a 55% 10-­year survival rate for parotid gland AdCaNOS. Only undifferentiated carcinoma carried a worse prognosis, with a 10-­year survival of 44%. The largest study, an epidemiologic review of 3155 primary parotid carcinomas, from the US National Cancer Data Base (1998–2017) found a 47% 5-­year overall survival rate; advanced stages (3 and 4) had a worse prognosis (68% vs. 28%, 5-­year survival for early disease vs. advanced disease). Lymph node metastases are common in patients with parotid gland AdCaNOS (45.2% of patients).1085 Patients with distant metastasis had a poor survival rate compared to those without distant metastases (9% vs. 50% 5-­year survival, respectively), and regional lymph node metastases equated to decreased survival, when compared to patients without metastases (26% vs. 60% 5-­year survival, respectively). Five-­year overall survival with positive margins was also lower than in patients with negative margins (43% vs. 61%, respectively).1085  PEDIATRIC AND CONGENITAL TUMORS, INCLUDING SIALOBLASTOMA The most frequent neonatal or congenital major salivary gland tumor is a hemangioma. Other neoplasms are uncommon in this population and include teratoma, hamartoma, sialoblastoma, and adult-­type salivary gland tumors.704,1699 In a recent review of pediatric salivary gland tumors and tumor-­like conditions, Agaimy and coauthors1700 found angiomatous lesions (juvenile capillary hemangioma, lymphangioma, and vascular malformations) and pleomorphic adenomas to represent the most common benign pediatric mesenchymal and benign epithelial tumors, respectively. Other benign tumors that may be seen in this population include teratoma and hamartoma and, rarely, adult-­ type neoplasms, such as sebaceous adenoma. The vast majority of salivary gland carcinomas in children and adolescents are low-­grade mucoepidermoid carcinomas, followed by acinic cell and adenoid cystic carcinomas (AdCC). Together, they account for >80% of carcinomas; rarely, other adult-­type salivary gland tumors may be found, including poorly differentiated carcinoma, epithelial myoepithelial carcinoma, and adenocarcinoma, NOS. Other uncommon malignant neoplasms included (rhabdomyo-­) sarcomas, malignant lymphomas, and sialoblastoma. Sialoblastoma was first reported in 1966 by Vawter and Tefft,1701 who used the term embryoma. Since that time, there have been multiple terms applied to describe this group of tumors, including congenital basal cell adenoma (BCA), basaloid adenoma, monomorphic adenoma, basaloid adenocarcinoma, congenital hybrid BCA-­AdCC, low-­grade basaloid carcinoma, AdCC, and sialoblastoma.704,1702,1703 In a case report, Taylor1704

drew an analogy between this tumor and others with a blastomatous appearance, suggesting the term sialoblastoma. The authors of this chapter prefer to use the guidelines originally proposed by Batsakis and colleagues,1705 with slight modification, for congenital and neonatal tumors: (1) neoplasms fulfilling criteria for a specific salivary gland tumor (e.g., pleomorphic adenoma [PA], mucoepidermoid carcinoma, hamartoma, etc.) should be classified as such; (2) neoplasms not classifiable according to the criteria used for adult tumors that meet the criteria described in the following sections should be called sialoblastoma and graded as low, intermediate, or high grade; (3) criteria for defining histologic grade are similar to those for adult tumors and include vascular or neural invasion and the presence of cytologic atypia beyond that expected for embryonic epithelium. However, Batsakis and colleagues1705 have stated that invasive growth, without the later findings, is a less reliable criterion because invasion is intrinsic to embryonic epithelium. There is one case report, however, in which the invasive pattern correlated with multiple recurrences, increasing cytologic atypia and tumor progression.1702 Some observers prefer to separately classify these congenital tumors into BCA and hybrid basal cell-­ adenoid cystic carcinoma, in addition to a separate category of sialoblastoma; however, these authors concede that sialoblastoma and BCA are similar and have overlapping histologic features.704 Because of these overlapping and varied histologic features, the rarity of these neoplasms, and the lack of in-­depth experience at any single institution, it is our preference to combine all congenital basaloid tumors into one group termed sialoblastoma. In the 2005 WHO tumor classification, sialoblastoma was moved into the malignant group of tumors, reflecting its potential for aggressive behavior.349 The most recent 2017 WHO classification has also retained sialoblastoma in the category of malignant tumors; however, it was placed into an “uncertain malignant potential” subgrouping, as it may behave in a benign or malignant fashion.1706 As more experience is accrued, suggestions have been made to subdivide this group into meaningful subcategories that are associated with different biological behavior. One classification scheme includes: (1) well differentiated (grade 1), including the basal cell subtype, as well as tumors without cytologic atypia or invasive growth; (2) moderately differentiated (grade 2), including cases with invasive growth, greater cytologic atypia, and necrosis, but without definitive evidence of neural or vascular invasion or metastatic spread; and (3) poorly differentiated (grade 3), tumors that have evidence of neural or vascular invasion and prominent cytologic atypia. Proliferative rate has also been suggested as a way to separate benign from clinically aggressive tumors.1707 Clinical Features. Since the recognition of sialoblastoma as a distinct diagnostic category in the last decade, there has been a continuum of reviews and case reports.1708–­1710 To date, there are 64 cases reported in the English literature.1710 The age at initial presentation ranged from before birth to 15 years.1709,1710 The parotid gland was the most common location (approximately 75% of cases), 20% arose in the submandibular gland, two cases in minor salivary glands of the cheek, and one from an ectopic salivary gland.1710–­1712 Two tumors have been associated with hamartomatous lesions of the skin, an organoid nevus1713 and a sebaceous nevus,1702 one with a congenital nevus1714 and four with hepatoblastoma.1717 Sialoblastomas are more common in males than in females (2:1). They arise most frequently in the

6  Salivary Glands

perinatal period, with occasional tumors (17%) presenting after 2 years of age.1710 In addition, Daley and Dardick1715 reported a somewhat similar-­appearing neoplasm in an adult.  Pathologic Features. Grossly, these tumors range up to 15 cm in greatest dimension1710 and are usually encapsulated or at least well circumscribed, but they frequently are locally infiltrative, occasionally extending into adjacent soft tissue, muscle, skin, and bone. Microscopically, these tumors recapitulate embryonic development of the major salivary glands, with their histologic patterns reflecting the various stages of phenotypic expression and differentiation.1705 Sialoblastomas frequently have variable histologic patterns within the same tumor and in different tumors. This consists of solid, multinodular nests and sheet-­like collections of primitive-­ appearing epithelial cells, with a basaloid morphology. Focally, these cells form ducts and duct-­like structures, which may have peripheral palisading (Fig. 6.54). The primitive nested pattern is frequently destructive and aids in separating this tumor from AdCC and BCA or adenocarcinoma NOS. Basal cell adenoma does not exhibit destructive growth, whereas adenoid cystic or basal cell adenocarcinoma usually grows in a less destructive pattern. Cribriform areas similar to those in AdCC may be found and areas of spindling, sebaceous cell clusters, nests of myoepithelial cells, and foci with squamous differentiation have been described.704 Occasional acinar differentiation may also be seen. This latter feature, together with more embryonic-­ type histology, will help separate sialoblastoma from hamartoma, which usually has much more prominent acinar differentiation and mature elements. The nuclei in sialoblastoma are round to oval, usually with minimal to moderate amounts of cytoplasm. Nuclear pleomorphism is variable, as is the presence of nucleoli. Necrosis may be present and is more frequent in intermediate-­ and high-­grade tumors. Surrounding the nests and collections of epithelium, there is a loose mesenchyme, which often has an embryonic appearance.1699 Mitoses are frequently noted and may be plentiful; atypical mitoses are not usually seen. Neural and occasionally vascular invasion may be found. Tumor cells are reactive to low-­molecular-­weight keratins, p63, SOX10, and S100 protein.1709,1716 EMA antibodies stain the ductal elements and occasional cells in the solid islands, while actin stains many of the abluminal cells.1702–­1704 Proliferative rates are quite variable and may be useful in grading tumors. One tumor with favorable morphology had a proliferative rate (Ki-­67) of 3%, whereas three tumors with unfavorable histology had proliferative rates of 40%, 50%, and 80%.1707,1713 Proliferative rates and cytologic atypia may also increase with tumor recurrence.1702 Cytogenics have been done on two cases. One demonstrated a normal 46X,Y phenotype, with a diploid chromosome complement,1717 and one had premature centromere division. This latter case was also associated with increased alpha-­ fetoprotein serum levels that returned to normal within 6 months of surgical excision. Two other patients had alpha-­ fetoprotein expression in their tumors.1707 Treatment and Prognosis. Complete surgical excision with negative margins is the treatment of choice.1702,1703,1709,1710 Adjuvant chemotherapy was used in 17 patients; 15 had a good response.1709 Adjuvant radiotherapy has been tried, but the limited number of cases makes this modality difficult to access. Nine of 62 patients treated surgically developed metastatic disease to the

553

A

B

C Fig. 6.54  A–C, Sialoblastoma. This tumor is composed of variably sized nests and solid sheets of basaloid cells with focal ductal differentiation and cystic and microcystic change. Tumor cells are fairly uniform, with minimal cytoplasm and only slight pleomorphism. Detail of a solid nest with several mitotic figures (C, inset).

lung, lymph nodes, or bone. All six patients with lung metastases responded well to chemotherapy; their lung metastasis did not seem to have a significant effect on their prognosis.1710 Almost a third of patients had recurrence; over two-­thirds of patients were tumor-­free for at least 1 year following their last treatment.1709 Only four patients have died from disease.1710 Low-­grade tumors appear to be less aggressive than higher-­grade tumors, with only one recurrence in eight tumors in one review.704 High mitotic rates, increased proliferative rates, and tumor necrosis are associated with a poor prognosis. 

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

METASTASIS TO MAJOR SALIVARY GLANDS Clinical Features. Metastatic involvement of the major salivary glands or of the adjacent lymph nodes is frequent, accounting for one-­third of all metastases to head and neck sites, in one epidemiologic survey.1718 The parotid glands contain 3 to 32 (average, 20) intraglandular lymph nodes that are interconnected by a plexus of lymph vessels that drain the skin from the side of the head above the parotid gland, the orbital region, and the nose, upper lip, external auditory canal, eustachian tube, and tympanic membrane.11,1719 Secondary involvement of the parotid gland appears to be increasing over the last four decades.1720 In a recent study of metastases to parotid nodes, the primary tumor was found in the ocular adnexa, facial skin, upper aerodigestive tract and in one case only, in thyroid gland, confirming the close connection between parotid lymph nodes and tumors of the head and neck area.1721 Parotid metastases of cutaneous squamous cell carcinoma, especially from the head and neck, is the most common subtype.11,1720 Metastatic tumors involving parotid gland but arising from nonhead and neck areas are very rare and are frequently from the kidney, which is known for its propensity to give metastases to unusual locations.1323 Metastases of the major gland parenchyma and the intraparotid lymph nodes constitute between 1% and 4% of salivary gland neoplasms, in different published surveys,11 and approximately 16% (range, 3%–72%) of all salivary carcinomas,11 the exact figure varying from series to series, depending on factors, such as different incidences of particular cancers in the population studied. For example, studies from Australia reported that metastases, mainly squamous cell carcinoma and melanoma, constituted 75% of all parotid malignancies, reflecting the high incidence of skin cancer.1722,1723 O’Brien and coworkers recommended that a cutaneous squamous cell carcinoma staging system should separate parotid nodal disease stage (based on tumor size) from cervical lymph node involvement, as the prognosis for involvement of the parotid gland was an independent prognostic factor on survival.1724,1725 Approximately 71% to 90% of metastases involve the parotid region, with the remainder involving the

Fig. 6.55  Metastatic renal cell carcinoma composed of variably sized nests of clear cells with slight nuclear pleomorphism and a prominent vascular background.

submandibular gland.1726 In an AFIP series and literature review up to 1991, of 785 cases of parotid metastases,11 squamous cell carcinoma and malignant melanoma were the most common, accounting for 60% and 14.5% of cases, respectively.11 Eighty-­three percent to 88% of tumors with known primary sites metastasizing to the parotid area originated in the head and neck region, with 83% to 89% of those arising from the skin.11,1720,1726,1727 The other 11% to 17% of the parotid metastases had primary locations in nonhead and neck sites, most commonly the lung, kidney (Fig. 6.55), and breast. 11,1726–­1729 Other sites of primaries include, in decreasing order of incidence, the large intestine, prostate gland, distant skin, stomach, uterus, pancreas, liver, and esophagus1720,1730 (Table 6.17). Of these 785 AFIP cases, only four were from the prostate, but this is likely underrecognized.11 This possibility should always be considered in older men.1731 In contrast, neither the submandibular nor sublingual glands contain any intraparenchymal lymph nodes; the submandibular glands are more likely to be affected by carcinomas from infraclavicular sites (85%), the most common of which were also the breast, kidney, and lung.11,1732 Metastases to the sublingual gland have not been reported, but involvement of the oral cavity by melanoma,1733 rectal and colonic adenocarcinoma,1734,1735 nonsmall cell carcinoma of the lung,1736,1737 and lobular carcinoma of the breast1233 have been noted. Patients with salivary gland metastases can be any age, but most (85%) are older than 50 years, and there is an approximate 2:1 male-­to-­female ratio.1738 They usually present with a unilateral mass, but can develop facial nerve palsy.1739 In most cases, a history of a primary malignancy is known, but occasionally the metastasis is the initial presentation of disease, and, rarely, bilateral involvement may be seen.  Differential Diagnosis. Microscopically, metastases in the salivary glands can resemble almost any primary tumor, so that, for example, mammary duct and lobular carcinomas are morphologically similar to (but immunohistochemically different from) salivary duct carcinoma (SDC) and polymorphous low-­ grade adenocarcinoma (PLGA), respectively. Likewise, renal cell carcinoma is part of the differential diagnosis of any clear cell tumor of the salivary glands,1740 but unlike most primary malignant salivary neoplasms, it is usually negative

6  Salivary Glands

TABLE

6.17

Metastases to the Parotid Gland

Location of Primary

No. of Tumors

Skin of head and neck

422 (53.8%)

Upper aerodigestive tract (mouth, nose, sinuses, pharynx)

63

Eye (conjunctiva, lacrimal gland)

6

Thyroid

5

Head NOS

4

Central nervous system

4

Submandibular salivary gland

1

DISTANT SITES Lung

28

Kidney

23

Breast

19

Colorectal

7

Prostate

4

Skin, distant

3

Stomach

2

Uterus

1

Pancreas

1

Total, distant sites

88 (11.2 %)

Skin NOS

108

Unknown primary site

84

Total, all sites

785

NOS, Not otherwise specified. Adapted from Gnepp, D.R., 1991. Metastatic disease to the major salivary glands. In: Ellis, G.L., Auclair, P.L., Gnepp, D.R., (eds). Surgical Pathology of the Salivary Glands. WB Saunders, Philadelphia, p. 560–569.

with CK7 and frequently has a prominent vascular background (see Fig. 6.55); in contrast, CD10 stains most renal carcinomas, but may be positive in salivary tumors with myoepithelial differentiation; myoepithelial-­specific markers (smooth muscle actin, muscle-­specific actin, p63, calponin, etc.) are usually negative in clear cell renal cell carcinomas. Other markers, such as PAX-­2, PAX-­8, and CA-­IX, will help to establish the diagnosis of clear cell renal cell carcinoma.1741,1742 However, the possibility of a metastasis is still best excluded by imaging the kidneys. Examples of metastatic prostate carcinoma have been mistaken for primary carcinoma, usually acinic cell carcinoma (AciCC)1731; prostate-­specific antigen and prostate-­specific acid phosphatase are almost always positive in prostate carcinoma, but SDC occasionally expresses these markers also,1421 as well as CK7, unlike in prostatic carcinoma. Melanoma can mimic carcinoma or spindle cell neoplasms, particularly if amelanotic.1743 Most cases express S100 protein, but so do salivary myoepithelial tumors, and a wider panel of markers, including Melan-­ A/MART-­ 1, microphthalmia transcription factor protein, SOX-­10, and HMB-­45, should be used. The follicular variant of AciCC and mammary analogue secretory carcinoma may be histologically similar to follicular-­forming

555

thyroid carcinomas, but do not express thyroglobulin or thyroid transcription factor 1. Treatment and Prognosis. Treatment should consist of complete surgical excision, with a modified cervical lymph node dissection, for patients with palpable disease or imaging evidence of lymph node involvement.1744 The use of adjuvant radiation therapy is controversial with variable recommendations, depending on the primary tumor, operative tumor spillage, or residual microscopic disease,1744 whereas others recommend combination surgery and radiotherapy for all patients with metastatic carcinoma of the skin.1745 A recent series recommended more extensive surgery, including lateral temporal bone resection for head and neck skin primaries, to improve local control rates in advanced disease.1746 These authors found that immunosuppression and no adjuvant radiotherapy were associated with a significant reduction in disease-­specific survival. It is impossible to generalize about prognosis because of the different tumor types and primary sites. For most malignancies, metastatic disease implies a poorer prognosis for a given primary tumor. If the salivary gland lesion derives from an infraclavicular primary and is only one of many widespread deposits, the prognosis is particularly poor, but a single metastasis could be amenable to local control of it and the primary tumor.1738 Involvement of the parotid parenchyma, in patients with head and neck skin primaries, indicates a worse prognosis than metastases confined to the intraparotid lymph nodes (79% vs. 8% local recurrence rates).1747 The rate of disease control in the parotid area, in a series of 77 patients with carcinoma of the skin and parotid metastases, was 82% at 5 years, with an overall 5-­year survival rate of 54%.1745 Patients with head and neck mucosal primaries have a very poor prognosis, with only 10% of patients disease free at 5 years.1727 In patients with malignant melanoma involving the parotid gland, oddly those in whom no primary site is found have a better prognosis1748; in a series of 19 patients, 6 had no known primary, and only 1 died of tumor (at 17 months), the other 5 being disease free (mean, 4.2 years; range, 1.2–7.5 years). Extraparotid primary melanomas were found in the other 13 cases (10 cutaneous and 3 mucosal); nine patients died of tumor (range, 10 months–5 years); 3 had residual metastatic disease (range, 3–6 years); and only 1 patient was disease free at 2 years. Parotid melanomas should be treated with a total parotidectomy; 12 of 95 patients (13%) treated with a superficial parotidectomy alone developed parotid bed recurrences, while none of the 34 patients treated with total parotidectomy developed recurrence.1749  CENTRAL SALIVARY GLAND TUMORS OF THE MAXILLA AND MANDIBLE Rarely, salivary gland tumors arise primarily within the jaws. To accept a tumor as primary and central in origin, there must be no evidence of a primary lesion within the salivary glands or at any other site. Radiographic evidence of bone destruction, integrity of cortical bone, and a definitive histologic diagnosis of a salivary gland neoplasm are also necessary to confirm a central origin.1750 These tumors may arise from ectopic salivary gland tissue enclaved during embryogenesis, seromucinous glands displaced from the maxillary sinus, or neoplastic transformation of the lining of an odontogenic cyst or odontogenic tissue remnants.38,562

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Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

Clinical Features. Central tumors account for nearly 3% of minor salivary gland neoplasms.1750 Approximately 75% of these tumors develop in the mandible,1751 particularly the posterior body and angle, whereas 25% involve the maxilla,1752 at least 30% are associated with a dental cyst or an impacted tooth. A unique case of bilateral intramandibular adenoid cystic carcinoma (AdCC) was reported.1753 Tumors may involve the periapical area of a tooth and simulate an endodontic lesion.1754–­1756 The mean age at presentation was 48 years (range, 1–85 years), with a very slight female predilection. Many tumors are asymptomatic and are discovered fortuitously during routine radiography. Jaw swelling is the most frequent presenting symptom, but, in decreasing order of frequency, there may also be pain, trismus, paresthesia, mobile teeth, and drainage or hemorrhage.  Pathologic Features. The most common intraosseous salivary gland tumor of the jaws in the largest review of 224 tumors38 is mucoepidermoid carcinoma (MEC), accounting for approximately 77% of tumors; the second most common tumor is AdCC1757 (∼11%); other tumors in this series were carcinoma ex pleomorphic adenoma (∼3%), adenocarcinoma NOS (∼3%), pleomorphic adenoma (∼3%), acinic cell carcinoma (∼2%), monomorphic adenoma (∼1%), and hyalinizing clear cell carcinoma1349 (∼1%). Other authors have reported several myoepithelial carcinomas,496,1758,1759 several adenoid cystic carcinomas,1751,1760 a pleomorphic adenoma,1761 an acinic cell carcinoma,1762 a carcinoma ex pleomorphic adenoma,1763 an epithelial myoepithelial carcinoma,1764 a polymorphous low-­grade adenocarcinoma (polymorphous adenocarcinoma, low-­ grade or typical type),1756 and a hyalinizing clear cell carcinoma.1765  Differential Diagnosis. The differential diagnosis for MEC in this location consists of glandular odontogenic cyst, also known as sialoodontogenic or mucoepidermoid cyst, clear cell odontogenic carcinoma, metastatic renal cell carcinoma, and calcifying epithelial odontogenic tumor. There is some overlap in the histologic features of the glandular odontogenic cyst and MEC. These can be separated by paying attention to the lining of a glandular odontogenic cyst, which is thinner and does not demonstrate areas of thickening or microcystic change, as MEC does. In addition, the differential expression of CK18

Fig. 6.56  Infantile hemangioma. The normal parenchyma has been totally replaced by a cellular hemangioma composed of proliferating immature, closely packed capillaries. Scattered residual salivary ducts are still visible. Detail of closely packed blood vessels (inset).

and CK19, in these two entities, may facilitate their distinction because all MECs expressed CK18 and 50% CK19, whereas only 30% of glandular odontogenic cysts expressed CK18, and 100% CK19.1766 Clear cell odontogenic carcinoma and metastatic renal cell carcinoma both lack intracellular mucin and a squamous component, whereas calcifying epithelial odontogenic tumor will typically have foci with amyloid-­like stromal material, with or without the presence of calcospherites. Treatment and Prognosis. Complete surgical excision is the treatment of choice, with radical excision offering a better chance for cure than more conservative procedures, such as marginal resection, enucleation, or curettage. For MEC, the recurrence rates with conservative and radical therapy were 40% and 13%, respectively; 9% of patients died of their disease.1750 Within each histologic tumor type, there appears to be no correlation between tumor grade and prognosis. However, the histologic type of carcinoma is significant, with 50% of patients with AdCC having metastatic disease, whereas in the MEC group, the metastasis rate was 9%.  MESENCHYMAL NEOPLASMS Nonepithelial tumors, excluding lymphoid neoplasms, account for 1.9% to 4.7% of salivary gland tumors,3,906,1767 with benign lesions being more common than sarcomas. The ratio of benign to malignant mesenchymal neoplasms varies from series to series, ranging from 18:1 to 2.4:1.3,609 Greater than 85% of soft-­ tissue neoplasms involve the parotid gland, more than 10% arise in the submandibular gland, and only a rare tumor involves the sublingual gland. Vascular tumors are the most common benign mesenchymal neoplasm, representing almost 40% of the benign tumors.3,609 Vascular neoplasms are hemangiomas 75% to 80% of the time, with the greatest incidence occurring in the first decade of life. Most of these are of the juvenile subtype and occur in the first year of life, frequently arising in the parotid gland1768 (Fig. 6.56), but case reports in the adult population can be found in old and more recent literature.1769,1770 The majority of the other vascular tumors are lymphangiomas, which can reach the size of 15 cm,1771 with an occasional hemangiopericytoma (solitary fibrous tumor) being reported. Other types of

6  Salivary Glands

benign soft-­tissue neoplasms arising in the major salivary glands include neural tumors, most frequently schwannoma, including the uncommon, more cellular, plexiform subtype, and neurofibroma, with a rare meningioma609,1768,1772,1773 and fibrous tumors, most frequently nodular fasciitis, fibrous histiocytoma and fibromatosis with an occasional myxoma, myofibromatosis, fibroma, solitary fibrous tumor,1774–­1776 or inflammatory pseudotumor.1777,1778 Agamy reviewed a series of salivary gland fat-­ containing tumors showing that the histological spectrum is wide, ranging from lipoma, including the pleomorphic variety,1779,1780 to oncocytic lipoadenoma, nononcocytic sialolipoma, and pleomorphic adenoma/myoepithelioma, with extensive lipometaplasia.1781 Miscellaneous other soft-­ tissue tumors may arise in these areas, including granular cell tumor,1782 with only a dozen cases reported in the parotid gland, some of which were associated with multiple granular cell tumors of the tongue,1854 angiomyoma, glomangioma, giant cell tumor, osteochondroma, lipoblastoma,1783 and giant cell angiofibroma.1784 These tumors may occasionally present as a parapharyngeal mass.1785 The several reports of lipomas with entrapped benign salivary gland ductal and acinar elements, often with metaplastic epithelial changes, are now reclassified as sialolipoma or lipoadenoma (Fig. 6.57).1781 One case in their series, in addition, had sebaceous differentiation.1626 To date, the reported cases have occurred, ranging in age from 7 weeks to 75 years.1624,1626,1781,1786–­1788 These accounted for 0.3% of salivary gland tumors in one series; ordinary lipomas accounted for 0.5% of tumors.1782 Thirteen (77%) have arisen in the parotid gland, two cases were reported in the palate, one in the floor of the mouth, and one in the submandibular gland. Salivary gland sarcomas arise in an older population than that of their benign soft-­tissue counterparts. They are rare tumors, accounting for only 0.3% of salivary gland tumors.67 In a series of 16 molecularly assessed round cell sarcomas of the head and neck area, only two cases were located in the submandibular area.1789 Virtually any type of sarcoma may arise primarily in the salivary gland (Table 6.18), 609,1084,1790,1791 including the recently recognized sclerosing

Fig. 6.57  Sialolipoma. The tumor is encapsulated and composed of mature adipose tissue surrounding a few normal serous acini and ducts.

557

rhabdomyosarcoma (WHO), which can mimic myoepithelial carcinoma of salivary glands.1792 The most common types include rhabdomyosarcoma, solitary fibrous tumor, and malignant peripheral nerve sheath tumors (see Table 6.18). Angiosarcomas are less common and can present in an intraparotid lymph node.1793 Two series reviewed oral and salivary gland angiosarcomas and liposarcomas,1794,1795 and a recent report reviewed the literature on primary parotid gland liposarcomas.1796 Major salivary gland sarcomas are aggressive neoplasms, with frequent distant metastases and local recurrence; 40% to 64% of patients experience recurrences and metastases develop in 24% to 64% (usually hematogenous) of patients.1084,1790,1791 The mortality rate at 5 and 10 years is 46% and 18%, respectively, in the most recent review, with death occurring usually within 3 years of diagnosis.1084,1790,1791Poor prognostic indicators for sarcomas arising in adults include tumor diameter greater than 5 cm, positive surgical margins, local extension to the bone, skin, or major neurovascular structures, and high histologic grade.1791 The most successful treatment is wide surgical excision or surgery, combined with radiation. However, the treatment of choice will usually be dictated by the sarcoma histologic type. Chemotherapy-­ sensitive sarcomas, such as rhabdomyosarcoma, would also benefit from the addition of chemotherapy. For more specific information, the reader should refer to Chapter 9 and a recent text on soft-­tissue tumors.  HYBRID TUMORS Neoplasms, with more than one growth pattern, fall into one of three categories: hybrid, collision, or biphasic. A hybrid tumor is defined as a single lesion arising at a single site, but composed of two (or more) distinct entities, each of which conforms to a defined neoplastic category. A collision tumor occurs when two malignant neoplasms arise at independent topographic sites and invade each other. A biphasic tumor is characterized by a mixture of two cell types, and this combination is so regular and repetitive that it defines the entity (i.e., spindle cell/sarcomatoid salivary duct carcinoma).1054 These definitions do not include the

558

TABLE

6.18

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

Salivary Gland Sarcomasa NUMBER OF CASES

Tumor Type

Armed Forces Institute of Pathology Registry1856

M.D. Anderson Cancer Center Registry1790,1791 with literature review (1990–1997/2010)

Rhabdomyosarcoma

7

34

2

Hemangiopericytoma (Solitary fibrous tumor)

14

18

—

Malignant peripheral nerve sheath tumor

13

16

2

Fibrosarcoma

12

7

—

Malignant fibrous histiocytoma

9

18

4

Angiosarcoma

5

14

—

Synovial sarcoma

4

10

—

Kaposi sarcoma

3

10†

—

Leiomyosarcoma

3

8

—

Liposarcoma

2

14

—

Langerhans cell histiocytosis

__

5

__

Endodermal sinus tumor

—

4

—

Interdigitating dendritic cell sarcoma

__

3

__

Alveolar soft part sarcoma

2

1

—

Epithelioid sarcoma

1

1

—

Myelosarcoma

—

3

—

Osteosarcoma

—

6

—

Chondrosarcoma

—

2

—

Atypical lipomatous tumor

—

3

—

Sarcoma ex pleomorphic adenoma

__

3

__

Malignant hemangioendothelioma

__

__

1

Desmoplastic small round cell tumor

__

3

__

Dermatofibrosarcoma protuberans

__

2

__

Epithelioid hemangioendothelioma

—

2

—

Ewing sarcoma

—

2

—

Granulocytic sarcoma

—

2

—

Sarcoma, poorly differentiated, undifferentiated or unclassified

9

2

__

Miscellaneous (only one case each type)

__

8

__

Total

85

201

9

University of Hamburg Registry3

aExcluding †Some

lymphomas. arose in intraparotid lymph nodes.

development of malignancy in a benign tumor, for example, carcinoma ex pleomorphic adenoma. Hybrid tumors of the salivary glands are found only rarely. 551,859,933,934,983,1054,1056,1111,1149,1797–­1801 Seifert and Donath1054 found only five examples among the 6600 tumors in the Hamburg Salivary Gland Register (40%) by immunohistochemistry supports an IgG4-­related disease association. Differential diagnosis includes the fibrosing variant of Hashimoto thyroiditis, discussed previously, and the fibrous atrophy variant of Hashimoto thyroiditis. In contrast to the latter condition, the gland in Riedel thyroiditis is typically enlarged. Because occasional cases of PTC may be accompanied by extensive fibrosis, a tumor should be ruled out by extensive sampling in suspected cases of Riedel thyroiditis. The paucicellular variant of anaplastic (undifferentiated) thyroid carcinoma may also mimic Riedel thyroiditis. This variant of anaplastic thyroid carcinoma appears hypocellular with atypia of the spindle cells that is not present in Riedel thyroiditis.98 Further, necrosis should not be observed in Riedel thyroiditis and warrants close scrutiny to exclude anaplastic thyroid carcinoma. Immunoreactivity for cytokeratins or PAX8 can be useful to support a diagnosis of paucicellular variant of anaplastic thyroid carcinoma.  Treatment and Prognosis. Surgical treatment alone is often insufficient to alleviate the symptoms of compression. Standardized treatments are lacking given the rarity of disease. However, studies by Few and colleagues99 suggest that tamoxifen is effective for treatment of this disorder. The mechanisms of action of this drug may be related to the stimulation and release of transforming growth factor β, which may have a role in the inhibition of fibroblastic proliferation. Corticosteroids are also effective and most patients are treated with either or both corticosteroids and tamoxifen.100 

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Fig. 7.18  Amyloid goiter. The parenchyma is almost completely replaced by amyloid deposits and groups of adipocytes.

AMYLOIDOSIS Amyloid goiter is a rare condition characterized by massive enlargement of the thyroid as a result of the deposition of amyloid fibrils in the interstitium and blood vessels of the gland in patients with primary or secondary amyloidosis.101 The disease may be unilateral or bilateral, and the gland is typically firm, waxy, and yellow-­tan on cross section. The amyloid deposits exhibit congophilia and green birefringence in polarized light. The follicular cells are typically atrophic, but may be elongated and compressed by the amorphous, lightly eosinophilic amyloid deposits; occasional nuclear enlargement may be evident (Fig. 7.18). Diffuse infiltration of the thyroid gland by mature adipose tissue is often present and, in some cases, a foreign-­ body giant cell reaction may be evident. Amyloid typing by mass spectroscopy may be useful to identify the underlying cause. As discussed in a subsequent section, occasional cases of medullary thyroid carcinoma may be almost completely replaced by amyloid deposits and may, therefore, simulate an amyloid goiter. However, the amyloid deposition in medullary thyroid carcinoma is not as evenly distributed as it is in amyloid goiter. Extensive sampling of such cases, together with immunostaining for calcitonin, is usually sufficient to identify foci of tumor. Treatment. For patients who have massive amyloid goiters, thyroidectomy may be required to relieve compressive symptoms.  HYPERPLASIA OF THE THYROID Hyperplastic diseases of the thyroid are common entities that are manifested by diffuse or nodular enlargement of the gland. Clinically, enlargement of the thyroid gland by any cause is referred to as goiter. Hyperplasia of the thyroid gland may be associated with hyperfunction (Graves disease), hypofunction (endemic goiter, dyshormonogenetic goiter), or normal function (multinodular goiter). Graves Disease (Diffuse Hyperplasia) Graves disease (diffuse toxic goiter) is the most frequent cause of thyrotoxicosis. The term thyrotoxicosis refers to a spectrum of changes that result from exposure of the body to excess

quantities of thyroid hormone.15 Hyperthyroidism refers to syndromes associated with overproduction of thyroid hormones by the thyroid gland. The causes of hyperthyroidism in the order of frequency include Graves disease, toxic multinodular goiter, and toxic adenoma. It has been estimated that Graves disease occurs in approximately 0.4% of the population in the United States. Clinical Features and Pathogenesis. Most patients with Graves disease present in the third or fourth decade, with a four-­to five-­ fold predominance in women.15 Clinically, Graves disease is characterized by diffuse goiter, thyrotoxicosis, infiltrative ophthalmopathy, and infiltrative dermopathy (pretibial myxedema). The disease has an autoimmune origin and is initiated by the presence in the serum of antibodies against the TSH receptor (thyroid-­stimulating immunoglobulin). The binding of antibodies to the TSH receptor results in activation of adenyl cyclase, leading to stimulation of growth and function of the thyroid gland. A genetically determined organ-­specific defect in suppressor T lymphocytes may be responsible for initiating immunoglobulin production by B lymphocytes.  Pathologic Features and Differential Diagnosis. Typically, the thyroid gland in patients with Graves disease is diffusely and symmetrically enlarged, with weights ranging from 50 to 150 g (Fig. 7.19). On cross section, the gland lacks the glistening appearance of normal thyroid but rather appears beefy and red. Microscopically, there is preservation of the normal lobular architecture; however, the follicles appear irregularly shaped. This is due to the presence of numerous papillary epithelial infoldings with basally placed nuclei (diffuse hyperplasia) (Fig. 7.20).102 Follicular cells are tall and column shaped, with more abundant, focally vacuolated cytoplasm and basally placed, mildly enlarged nuclei. Colloid is scanty and typically exhibits a very pale eosinophilic appearance with peripheral scalloping. Increased abundance of colloid is often present at the time of thyroidectomy following medical treatment to slow the release of thyroid hormones from the follicles. The stroma may appear slightly fibrotic, and occasional lymphoid follicles with active germinal centers may be evident. The papillary areas in Graves disease may, on occasion, be confused with those seen in PTC. An important feature to differentiate these entities is the preservation of the lobular architecture in cases of Graves disease and the diffuse nature

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Fig. 7.19  Graves disease. Both lobes of the thyroid are diffusely enlarged.

Fig. 7.20  Graves disease. Diffuse papillary hyperplasia is present with fibrous septa. Minimal pale colloid is present.

of the papillary hyperplasia. Moreover, the papillae in Graves disease tend to be simple and nonbranching, whereas those in PTC more often exhibit a more complex branching architecture. Although the colloid in Graves disease tends to be pale and watery, the colloid in cases of PTC is often darker and densely stained. In contrast to the basal localization of nuclei in areas of papillary hyperplasia, the nuclei in PTCs have no polarity; moreover, the nuclei in PTC are typically overlapped with finely dispersed chromatin, contain grooves, and also may exhibit characteristic inclusions, as discussed in subsequent sections. Some immunostains may aid the diagnosis. HBME-­1 immunoreactivity is common in PTCs but not in Graves disease.103 The pathology of the gland is affected by specific types of treatment.104,105 In patients treated with potassium iodide, the follicles become filled with colloid and the follicular cells assume a more cuboidal shape. Following treatment with propylthiouracil, the appearance of the gland is unchanged, presumably owing to the continued stimulation of the gland by TSH. Treatment with radioactive iodine results in the involution of the

follicular cells, which become cuboidal rather than columnar, and in the accumulation of colloid. The late changes include fibrosis with follicular atrophy and scattered follicular cells with enlarged hyperchromatic nuclei.  Treatment and Prognosis. The treatment of patients with Graves disease is controversial. The major agents employed in the chemotherapeutic management of affected patients include drugs of the thioamide class, which inhibit the oxidation and organic binding of iodide.16 Cessation of treatment, however, leads to a relatively frequent recurrence of thyrotoxicosis. Subtotal thyroidectomy, conversely, is associated with recurrent disease in only 10% of cases, but the risk of complications, including permanent hypothyroidism, vocal cord paralysis, and hypoparathyroidism, is relatively high. Radioiodine administration produces the ablative effects of surgery without the immediate operative and postoperative complications of subtotal thyroidectomy. The major disadvantage of radioactive iodine administration, however, is the late development of hypothyroidism. Selection of specific forms of therapy should be tailored to the needs of individual patients.16  Goitrous Hypothyroidism and Endemic Goiter Goitrous hypothyroidism is characterized by an impaired ability to synthesize T3 and T4 because of inadequate dietary iodine (endemic goiter), ingestion of drugs that interfere with thyroid hormone synthesis, or enzymatic defects in the biosynthesis of thyroid hormones.106 As a result of inadequate thyroid hormone production, there is hypersecretion of TSH, which leads to increased thyroid growth and stimulation of thyroid hormone biosynthesis. The term endemic goiter is used when this condition occurs in more than 10% of the population in a defined geographic area. The most important endemic goiter regions include the northern and southern slopes of the Himalayas, the Andean region of South America, the European Alps, mountainous regions of China, central regions of Africa, and, to a lesser extent, the coastal areas of Europe. Low levels of dietary iodine are the major cause of endemic goiter; however, ingestion of natural goitrogens (vegetables of the Brassica family, including cabbage and turnips, which contain high concentrations of thioglucosides) may be responsible for the development of goiter. Cyanoglucosides represent another important group of goitrogens and are found in high concentrations in cassava, maize, bamboo shoots, and sweet potatoes.107 Flavonoids, which are found in high concentrations in millet, are also goitrogenic. In general, the severity of goiter formation is related to the extent of iodine deficiency. Initially, goiter formation is diffuse, but with repeated episodes of hyperplasia and involution, multiple nodules supervene to produce a diffuse and nodular goiter, similar to that observed in patients with nontoxic nodular goiter. Endemic goiter can be prevented by the addition of iodine to the diet and by the elimination of goitrogens in the diet. In adults with large goiters, suppression of TSH by the administration of T4 can lead to diminished thyroid size. Surgical treatment is reserved for individuals with very large goiters that fail to involute after TSH suppression or those patients in whom malignancy is suspected.107  Dyshormonogenetic Goiter Clinical Features and Pathogenesis. Defects in hormone biosynthesis are rare causes of goitrous hypothyroidism

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A

621

B

Fig. 7.21  Dyshormonogenetic goiter. A, A thyroid nodule with a microfollicular pattern (right) appears circumscribed. The adjacent thyroid parenchyma has a solid appearance. B, The thyroid parenchyma has a solid appearance without colloid. Occasional nuclei appear hyperchromatic.

(dyshormonogenetic goiter).108 Although goiter may be present at birth, it more commonly develops at 1 to 2 years of age. Most of the enzymatic defects are inherited as autosomal recessive traits. The various defects include those involved in iodide transport, organification, iodotyrosine coupling, iodotyrosine dehalogenase activity, and iodoprotein secretion. Goiters in affected individuals tend to be very large and multinodular.109,110  Pathologic Features and Differential Diagnosis. Typically, the thyroid gland is markedly enlarged and multinodular. On cross section, individual nodules vary from those that are beefy red to those that are firm and white to gray-­tan. Individual nodules may be surrounded by broad bands of fibrous connective tissue. Histologically, the nodules vary from those with papillary or follicular architectural patterns to those that are predominantly solid (Fig. 7.21). Generally, the papillae are nonbranching and lack the nuclear features that are typical of PTCs. The luminal spaces contain little or no colloid. In those nodules with follicular patterns of growth, there may be considerable variation in nuclear size and shape (see Fig. 7.21B). Other nodules may exhibit more solid growth patterns with pronounced nuclear hyperchromasia and mitotic activity. Because of the atypical cytologic features, the solid appearance of many of the nodules, and the presence of partial fibrous encapsulation, the possibility of malignancy is often entertained, particularly when the clinical history is unavailable. Rare examples of follicular and papillary thyroid carcinoma developing in patients with dyshormonogenetic goiter have been reported.111,112 The diagnosis of malignancy in this setting should be rendered with particular caution and should be made only when there are overt papillary cytologic features or evidence of invasion of adjacent normal tissues, metastases, or unequivocal vascular invasion.  Treatment and Prognosis. Treatment of patients with dyshormonogenetic goiter includes the administration of T4 until the serum TSH becomes normalized. Even with thyroid replacement goiters may develop. Surgery is indicated in those patients with very large goiters causing physical disfigurement or compressive symptoms. The prognosis is generally excellent for patients with mild enzymatic defects. In patients with severe forms of the disease, both growth retardation and mental

retardation occur unless thyroid hormone is replaced very early in the course of the disease.  Nontoxic Nodular Goiter Clinical Features and Pathogenesis. The term nontoxic goiter, also known as multinodular, simple, or colloid goiter, refers to nodular enlargement of the thyroid gland in the absence of hyperthyroidism or hypothyroidism, inflammatory processes, or neoplasms.21 Nontoxic nodular goiter is the most common form of goiter in the United States. With large goiters, displacement or compression of the esophagus and trachea may give rise to dysphagia or dyspnea. Pain may be associated with hemorrhage into one of the nodules. Clinically, the incidence of nontoxic nodular goiter is 3% to 5%.113 At autopsy, the prevalence of this disorder is substantially higher and is in the range of 30% to 50%. The development of goiter most likely results from a variety of mechanisms that lead to impairment of T3 and T4 production.16 This leads to increased production of TSH and subsequent stimulation of the thyroid gland. One hypothesis is that the inability to form sufficient T3 and T4 represents an inborn error of metabolism that is related to, but not as severe as, that present in patients with dyshormonogenetic goiter. The levels of TSH are not substantially increased in individuals with nodular goiter, however. This suggests that levels of TSH may be only minimally or sporadically increased in affected patients. An alternative possibility is that subsets of thyroid follicular cells may be more susceptible to the stimulatory actions of normal levels of TSH. It has also been suggested that there may be a class of thyroid growth–stimulating immunoglobulins that stimulate growth but do not stimulate adenylase activity in patients with nontoxic nodular goiter. A recent association with germline mutations in DICER1 and multinodular hyperplasia has been identified in young adults particularly women.114,115 DICER1 is a ribonuclease that processes miRNA involved in regulating thyroid function.  Pathologic Features and Differential Diagnosis. The initial phase of the development of this type of goiter is characterized by diffuse glandular enlargement. There is nodular hyperplasia of follicular cells with the formation of papillary infoldings of the epithelium and scant amounts of colloid. In the phase of

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involution, the follicles become filled with colloid. Rupture of follicles may lead to inflammation with histiocytes, lymphocytes, and multinucleate giant cells. The disease process is, therefore, characterized by alternating phases of hyperplasia and involution. Nodular thyroids are typically enlarged, with weights of up to 500 g (Fig. 7.22). Usually, the gland is markedly distorted by multiple nodules that measure from less than 1 cm to many centimeters in diameter. In some instances, the growth may extend beneath the sternum (substernal goiter). Individual nodules have a remarkable array of histologic appearances. Some may be composed of markedly enlarged follicles that are distended with colloid (Fig. 7.23), whereas others may have a microfollicular appearance. Other nodules may appear hyperplastic, with papillary formations extending into the follicular spaces (Fig. 7.24). Nodules composed of oncocytes may also occur. Individual nodules may be partially demarcated from the adjacent thyroid parenchyma by an incomplete fibrous capsule. In contrast to adenomas, which typically have a uniform follicular architecture, hyperplastic nodules are characterized by variation in follicular size. The adjacent thyroid parenchyma is not usually compressed adjacent to hyperplastic nodules, in contrast to the compressive effects of adenomas. Degenerative changes including hemorrhage, calcification, and ossification are frequent. Some follicular nodules may undergo complete cystic degeneration. In some cases, a single nodule may be present, with the remainder of the gland showing either normal or mild hyperplastic change. The nodules may be partially encapsulated and have a relatively uniform microfollicular growth pattern. In such cases, the distinction between a hyperplastic nodule and a follicular adenoma is particularly difficult. The term adenomatoid nodule or adenomatous change is sometimes used for those nodules, acknowledging a similarity of their appearance to follicular adenomas. Studies employing molecular techniques have revealed that, although most of the nodules in multinodular goiters are

Fig. 7.23  Multinodular (nontoxic) goiter. There is considerable variation in follicular size. One follicle is markedly enlarged.

Fig. 7.22  Multinodular (nontoxic) goiter. This thyroid lobe is completely replaced by multiple nodules, some of which are partially encapsulated.

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Fig. 7.24  Multinodular (nontoxic) goiter. This nodule exhibits a prominent degree of papillary hyperplasia.

polyclonal and therefore non-­neoplastic, some of them may represent clonal proliferations.116 In some series, as many as 70% of hyperplastic nodules in multinodular goiter were monoclonal, whereas the adjacent thyroid parenchyma was polyclonal.117 Moreover, there were no morphologic differences with respect to cellularity or encapsulation in nodules that were monoclonal or polyclonal.  Treatment and Prognosis. Patients with large multinodular goiters with evidence of compressive symptoms are generally treated by thyroidectomy. In patients with normal or elevated levels of TSH, administration of thyroid hormone may lead to a decrease in the size of the goiter. Radioactive iodine has also been used in some instances.  THYROID NODULES AND THYROID CANCER: GENERAL CONSIDERATIONS The prevalence of thyroid nodules depends on numerous factors, including the age of the population, geographic locale, and the sensitivity of the detection system. In the Framingham study, thyroid nodules were identified clinically in 6.4% of women and 1.5% of men, with a nodule accrual rate of 0.09% per year.118 The prevalence of thyroid nodules is 5 to 10 times higher in glands studied by ultrasonography and in thyroid glands examined directly at autopsy.113 Of those nodules that have been surgically removed, 42% to 77% prove to be hyperplastic nodules, 15% to 25% are adenomas, and 8% to 17% are carcinomas, depending on the series.113,119 The prevalence of thyroid nodules of all types, including carcinomas, however, is substantially higher in individuals previously exposed to ionizing irradiation. Thyroid cancer accounts for 3.4% of all malignant tumors diagnosed in the United States.120 More than 57,000 new cases are diagnosed in the United States and 220,000 worldwide.121 The incidence of thyroid cancer has increased 3.4% per year over the past 10 years. The death rate for thyroid cancer of all types is approximately five cases per million, with an increase of 0.7% per same time frame. Thyroid cancer is three times more common in women than in men. Genetic and environmental factors have been implicated in the development of thyroid cancer.122,123 Radiation exposure is a well-­known risk factor, and doses in the range of 200 to 500 cGy are associated with the development of thyroid cancer at a rate

of 0.5% per year.124 Radiation exposure in childhood produces a higher risk of the development of thyroid cancer than does radiation exposure in adulthood.125 In the series of thyroid cancer cases after the Chernobyl nuclear accident, the highest number of patients in whom cancer subsequently developed was in the group of children who were younger than 1 year of age at the time of exposure, and this number decreased progressively through age 12 years.86 Iodine supplementation of the diet is associated with a decreasing risk of follicular carcinoma but a corresponding increasing risk of PTC.122 The vast majority of benign and malignant thyroid neoplasms are of follicular cell origin. In general, PTCs and minimally invasive follicular carcinomas are low-­grade malignancies with an excellent prognosis, whereas anaplastic (undifferentiated) thyroid carcinomas are high-­grade malignancies with a very poor prognosis. Widely invasive follicular carcinomas and poorly differentiated thyroid carcinomas have a prognosis that is intermediate between these two groups. Tumors of C-­cell origin account for approximately 2% to 3% of all thyroid neoplasms, whereas malignant lymphomas account for a smaller proportion of the cases. The treatment of thyroid cancer is covered in several recent reviews.121–126 Diagnostic Approaches The current paradigm for thyroid nodule evaluation includes ultrasound evaluation to risk stratify nodules requiring further evaluation by fine-­needle aspiration (FNA) biopsy. Both the ATA 2015 nodules assessment guideline (recommendation 8) and Thyroid Imaging, Reporting and Data System (TIRADS) define ultrasound characteristics that are more commonly associated with increased risk of carcinoma.127–129 Additionally, per the guidelines, a size of >1 cm is the lower threshold to consider FNA if associated with high-­suspicion sonographic features. FNA biopsy is the most sensitive, specific, and cost-­effective approach for the diagnosis of thyroid nodules. The introduction of this technique has resulted in a decreased rate of thyroid surgery and an increased rate of identifying cancer when surgery is performed. In general, the true false-­negative rate varies between 1% and 2%,130 whereas the false-­positive rate is approximately 1%. False-­positive results are usually caused by interpretative errors. The most common sources of error include nodular goiter with papillary hyperplasia,131 Hashimoto

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thyroiditis with papillary hyperplasia, and follicular adenomas with artefactual nuclear clearing and nuclear atypia. Each of these conditions may be misinterpreted as PTC.132 The overinterpretation of oncocytic cells in Hashimoto thyroiditis, goiters, or adenomas also represents a common source of error.18 The two most significant limitations of FNA technique are nondiagnostic aspirates and indeterminate results.133 To augment FNA cytologic determination for triaging patients to observation versus surgery, multiple ancillary molecular/ expression-­based testing has matured to the CLIA environment.134 The two main categories of adjuvant tests include those that have a high negative predictive value for malignancy that “rule out” malignancy in indeterminate FNAs versus testing by looking for alterations associated with malignancy “rule­in” testing. Rule-­in testing continues to expand across known mutations, translocations, copy number alterations, and miRNA panels to enhance the positive-­predictive values in these adjuvant tests.134–136 ATA guidelines (recommendation 13) note that if molecular testing is being considered, a patient should be counseled as to the potential benefits and limitations of such testing.127 Currently, FNA has an accuracy that is at least comparable to that of frozen sections.137,138 For PTC, the accuracy of FNA biopsies, in fact, is superior to that of frozen section.139 Frozen sections, however, may be useful for intraoperative diagnoses and decision making in patients with unsatisfactory or suspicious FNA biopsy diagnoses.138,140 However, for follicular lesions, although frozen sections can demonstrate capsular or vascular invasion, complete sampling of the lesion at the time of frozen section is impractical. Additionally, nuclear changes for noninvasive follicular thyroid neoplasm with papillary-­like nuclei (NIFTP) and/or follicular variants of papillary thyroid carcinoma can be difficult to discern, even on touch preparations. Therefore frozen section is often only reported as follicular neoplasm and final classification is deferred to permanent review.  THYROID CYSTS Cystic lesions of the thyroid gland are common, representing 6% to 35% of all surgically removed solitary thyroid nodules. They are usually the result of degeneration, hemorrhage, or necrosis of an adenomatous nodule. Similar changes may occur in benign or malignant neoplasms, particularly PTC. True primary cysts of the thyroid are exceedingly rare, although cystic degeneration of solid cell nests has been reported. Cystic change occurs more commonly in lesions larger than 4 cm. FNA biopsy is a useful technique, first, in identifying thyroid lesions as cysts, and, second, in detecting malignant cells. Aspirates of many thyroid cysts are often technically insufficient because of poor cellularity. It is therefore essential to assess the adequacy of the specimen to avoid a false-­negative diagnosis. Any cyst that recurs or any palpable nodule identified after evacuation of a cyst must be reaspirated to rule out malignancy. However, only 1% of all aspirated cysts prove to be malignant.141  BENIGN TUMORS Follicular Adenoma Clinical Features and Pathogenesis. Follicular adenomas are benign, encapsulated tumors with evidence of follicular

Fig. 7.25  Follicular adenoma with extensive recent hemorrhage.

cell differentiation. Molecular studies have established that most adenomas have a clonal origin.113,142 Adenomas occur predominantly in women and usually present as single, painless nodules that are cold on iodine scan. Hyperfunctioning (toxic) adenomas, in contrast, will appear “hot” on radioactive iodine uptake thyroid scan. Rarely, patients may present with pain and rapid enlargement of the adenoma due to hemorrhage, which may occur spontaneously or as a consequence of FNA biopsy (Fig. 7.25). Numerous adenomas (25%), adenomatoid nodules (75%), and follicular (45%) or papillary carcinomas (60%) may occur in Cowden syndrome and are often accompanied by C-­cell hyperplasia in the background gland.143, 144  Pathologic Features and Differential Diagnosis. Typically, adenomas are expansile, round to ovoid lesions that are separated from the adjacent normal thyroid parenchyma by a thin but complete fibrous capsule (Fig. 7.26), with compression of the adjacent normal thyroid parenchyma. In contrast to follicular carcinomas, follicular adenomas lack evidence of capsular or vascular invasion. Most resected adenomas measure from 1 to 3 cm in diameter, although occasional very large adenomas may occur. They vary from pink-­white and red to tan-­brown. Foci of hemorrhage, cyst formation, fibrosis, and calcification may be evident. Usually, the pattern of follicular growth is uniform within the adenoma, in contrast to hyperplastic nodules, which commonly exhibit variations in the sizes and shapes of individual follicles. Adenomas are subclassified according to the predominant pattern of follicular growth. The embryonal (trabecular or solid) adenoma is composed of nests of follicular cells with few or no follicles. Microfollicular (fetal) adenomas are composed of small follicles containing scanty luminal colloid. Simple (normofollicular) adenomas are composed of follicles of approximately the same size as those in the adjacent normal thyroid, whereas macrofollicular adenomas are composed of follicles that are substantially larger than those of the adjacent normal follicles. The nuclear features in follicular adenomas are typically round and hyperchromatic. Follicular adenomas contain both low-­ molecular-­ weight cytokeratins (CKs) and vimentin. In addition, the cells are positive for thyroglobulin, TTF-­1, PAX8, and CK7 but are negative for CK20.145,146 CK19 is usually absent, except in areas of degenerative change. Foci of clear cell change may be present throughout the tumor or may be restricted to small groups of follicles. Factors

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Fig. 7.26  Follicular adenoma. The tumor (upper right) is separated from the adjacent thyroid by a complete fibrous capsule.

Fig. 7.27  Follicular adenoma. A healing needle tract site extends through the capsule into the periphery of the adenoma.

responsible for clear cell change in follicular adenomas include the presence of cytoplasmic vesicles, which may originate from degenerated and cystically dilated mitochondria, or from dilatation of the endoplasmic reticulum or Golgi vesicles. In some instances, clear cell change has been traced to the intracellular accumulation of glycogen, lipid, or thyroglobulin. Occasional adenomas may contain cells with a signet ring appearance. The cytoplasmic vacuoles are typically positive for thyroglobulin and may also contain mucin. Such tumors have been referred to as signet ring adenomas.147 The differential diagnosis includes adenomatous (hyperplastic) nodules, follicular carcinoma, noninvasive follicular thyroid neoplasm with papillary-­like nuclei (NIFTP), the follicular variant of PTC, and the follicular (tubular) variant of medullary carcinoma. Generally, adenomatous nodules are multiple and exhibit considerable variation in the size of the component follicles, whereas the follicular structure of adenomas tends to be more uniform. Moreover, the capsule surrounding adenomas is complete, whereas it is often incomplete around adenomatous nodules. The distinction of follicular adenoma from carcinoma depends on the demonstration of capsular or vascular invasion,

or both, in the latter. A thickened capsule should prompt complete capsular interface evaluation for diagnostic features of carcinoma. Distinguishing between true capsular invasion and the changes associated with FNA biopsy may, at times, be exceedingly difficult. These changes have been referred to as WHAFFT (worrisome histologic alterations following fine-­needle aspiration of the thyroid).148 Acute changes (occurring 30%, mitosis >3 per 10 high-­power fields, or necrosis should preclude this diagnosis (Table 7.2).171–178 Evaluation for invasion requires full capsular evaluation. While mushrooming invasion may be seen when a capsule is present, the findings of similar clusters of thyroid cells as seen in

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A

B

Fig. 7.33  Noninvasive follicular thyroid neoplasm with papillary thyroid-­like nuclei. A, This entity should be well circumscribed without evidence of invasion; a demarcated fibrous capsule is present in this case. B, A follicular growth pattern is present with notable nuclear enlargement, irregularity, and clearing consistent with papillary thyroid-­like changes

the nodule but located within the adjacent thyroid parenchyma would also constitute invasion and exclude a diagnosis of NIFTP. Psammoma bodies are an exclusion criterion, as they represent dead mummified papillae and are therefore typically associated with conventional papillary thyroid carcinomas. The other exclusion criteria of mitoses, solid growth, and/or necrosis are those features defining poorly differentiated thyroid carcinomas and are further discussed in that section. Interpathologist variability regarding the determination of the presence and/or extent of “papillary-­like” nuclear changes was approached in the sentinel paper on this subject.171 A nuclear assessment guide (see supplement for reference) used three parameters to quantitate the degree of papillary-­like nuclear changes: (1) nuclear size and shape (enlargement, elongation and overlap); (2) nuclear membrane irregularity (grooves, folds, irregular contours); and (3) chromatin characteristics (nuclear clearing/chromatin margination, powdery, glass, or delicate). Slight changes in these three parameters are insufficient for classification; however, the presence of two or all three categories would be within the definition of papillary-­like nuclei for this classification. The nuclear characteristics in the nodule are compared to the background thyroid parenchyma present in each case. Typically, the nuclear features are “less developed” than those seen in a conventional papillary thyroid carcinoma and full-­blown papillary-like nuclei should lead to careful scrutiny for other exclusionary features. Nuclear changes may be focal or patchy within the nodule, and their presence in more than 30% of the nodule has been proposed as sufficient to be considered within the spectrum of NIFTP.179 The introduction of this entity into thyroid nomenclature has led to reevaluation of fine-­needle aspiration (FNA) biopsies to determine the impact of NIFTP on the Bethesda classification system for thyroid nodules. Faquin et al. found that in 173 NIFTP cases, 31% were diagnosed as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 26% as follicular neoplasm (FN), and 24% as suspicious for malignancy, with few cases diagnosed as malignant by cytology.180 This in turn lowers the associated risk of malignancy in each Bethesda category by 5% to 13.6%.  Molecular Genetics. In the original study, 22% of the initial cohort harbored molecular alterations in RAS and PPAX8-­

PPARg fusions, with further studies confirming clonality in up to 80% of NIFTPs with additional mutations in EIF1AX, BRAF K601E, and THADA fusion.171, 179 The authors note that BRAF V600E and RET/PTC fusions are not a component of this entity and are found in conventional papillary thyroid carcinomas, for which a high rate of recurrence is known.171,179  Treatment and Prognosis. As this entity cannot be diagnosed by FNA, a lobectomy is both diagnostic and therapeutic. Retrospective papers evaluating large (>4 cm) and smaller nodules ( H > rare K), which retained higher levels of thyroid differentiation expression by mRNA.227 Point mutations of the BRAF gene coding for serine/threonine kinase are the most common genetic alteration in sporadic PTCs.223,228 Virtually all mutations involve nucleotide 1799 and result in a valine-­to-­glutamate substitution at residue 600 (V600E). Among thyroid tumors, the V600E BRAF mutation is restricted to PTCs, poorly differentiated, and anaplastic thyroid carcinomas arising from PTC.229 Therefore, the identification of this mutation in cells obtained by fine-­needle aspiration of the thyroid gland or in surgical material is virtually diagnostic of PTC.230–232 BRAF mutations are associated with older patient age, classic papillary histopathology, or the tall cell variant.

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A

B

C

D

Fig. 7.40  Papillary thyroid carcinoma, follicular variant. A, The tumor is encapsulated and consists predominantly of microfollicles. B, The nuclei of tumor cells are focally crowded and show chromatin clearing, irregularity of contours, and nuclear grooves. C, Galectin-­3 immunostain reveals strong cytoplasmic and nuclear reactivity in the tumor cells. D, HBME-­1 immunostain shows strong membranous staining of the tumor cells.

TABLE

7.1

Diagnostic Criteria for Other Encapsulated Follicular-­Patterned Thyroid Tumors CAPSULAR OR VASCULAR INVASION

Papillary­like nuclei

Present (sufficient) Questionable Absent

Present

Equivocal

Absent

Invasive encapsulated FV-­PTC WD carcinoma, NOS Follicular carcinoma

WD tumor of UMP

NIFTP

Follicular tumor of UMP

Follicular adenoma

Modified from WHO 4th ed. FV-­PTC, Follicular variant of papillary thyroid carcinoma; NIFTP, noninvasive follicular thyroid neoplasm with papillary-­like nuclear features; NOS, not otherwise specified; UMP, uncertain malignant potential; WD: well differentiated.

BRAF alterations, including gene fusions (BRAF/AGK, BRAF/ FAM114A2, MKRN1/BRAF), also occur in a low percentage of PTCs.227 The most common gene rearrangement in PTCs is RET/ PTC that results in fusion of the 3’ portion of the RET receptor tyrosine kinase gene to the 5’ portion of various genes.233 The two most common rearrangement types, RET/PTC1 and RET/PTC3, are paracentric inversions because both RET and its respective fusion partner, H4 or ELE1 (NCOA4), reside on the long arm of chromosome 10.233–236 RET/PTC2 occurs as a result of interchromosomal translocation t(10;17)(q11.2;q23) that

leads to fusion with the gene encoding the regulatory subunit of c-­AMP-­dependent protein kinase A. Several additional variants of the RET/PTC oncogene have also been reported in single cases of PTCs, mostly in tumors associated with radiation exposure.237,238 The prevalence of RET/PTC in PTCs has significant geographic variation and is higher in tumors from patients with a history of radiation exposure and in pediatric populations.237 In tumors arising after radiation exposure, RET/PTC1 was found to be associated with classic papillary histology, whereas the RET/PTC3 type was more common in the solid variant of PTCs.239 Overall, tumors with RET/PTC rearrangements

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usually present at a younger age, have classic papillary histology, frequent psammoma bodies, and a high rate of lymph node metastases.226 Although several studies reported the detection of RET/PTC in thyroid adenomas and other benign thyroid lesions, it is generally accepted that abundant RET/PTC expression is restricted to PTCs. Point mutations, which involve several specific sites (codons 12, 13, and 61) of N-­RAS, H-­RAS, or K-­RAS genes are found in 10% to 15% of PTCs.240–242 The most common mutation is in codon 61 of the N-­RAS gene. Tumors with RAS mutations are almost all the follicular variants of PTCs, which are also found in NIFTPs. This mutation also correlates with significantly less prominent nuclear features, more frequent encapsulation, and a low rate of lymph node metastases.226 Mutations of the RAS gene are not restricted to PTC and are also found in other benign and malignant thyroid tumors, as well as in neoplasms from other tissues. The spectrum of gene fusions found in PTCs continues to expand and was also delineated in the TCGA papillary thyroid carcinoma cohort. Beyond the RET rearrangements noted earlier, ALK translocations occur with multiple partner genes (STRN, EML4, TFG, GTF2IRD1) (Chr 2p22.2 and 2p23).243 The overall incidence of ALK translocations in thyroid cancer is 30% of tumor cells (Fig. 7.52A and 7.52B).289 Moderate to severe nuclear pleomorphism is also notable. A comment should be made if focal areas are identified meeting these criteria, as the tumor may still behave aggressively. The significance of the hobnail variant is the high rate of distant metastasis (44%) (bone, lung, brain) and poor disease-­ specific survival rate of 46% to 66% compared with conventional PTC (97%). Vascular invasion (71%) is also commonly present. Hobnail may be present concomitantly with other variants of PTC, including tall cell, columnar, and solid types. Moreover, an association of the hobnail variant with transformation to either poorly differentiated or anaplastic carcinomas has also been described.289–291

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Fig. 7.52  Hobnail variant of papillary thyroid carcinoma. A, Papillary growth pattern with tufting and rounding of cells apically. B, At higher power the nuclei show variable hyperchromasia and papillary nuclear features.

Molecular evaluation of the hobnail variant highlights frequent BRAF V00E mutations (58%–72%), as well as TERT promoter mutations (12%–44%), PIK3CA (28%), and/or TP53 mutations (17%–56%).292,293 The hobnail variant should be differentiated from the diffuse sclerosing variant PTC, which often occurs in younger patients and often shows prominent psammoma bodies and squamous metaplasia. The tall cell variant, in comparison, shows elongated cells two to three times taller than wide that retain the classic papillary thyroid carcinoma features and polarity of the nuclei.  Cribriform Morular Variant. Although some authors consider cribriform morular carcinoma a distinct histopathologic entity, most consider it a variant of PTC.294 Up to 40% of tumors occur in patients with familial adenomatous polyposis or Gardner syndrome, but they may also occur sporadically.295 In patients with familial adenomatous polyposis, the tumors are usually multifocal and characterized by focal papillary architecture, cribriform features, solid and spindle areas, and squamous morules (Fig. 7.53A–C).296 Colloid is not present. Although some nuclei appear clear, others are hyperchromatic. Nuclear grooves are inconstant, and nuclear pseudoinclusions are rare. Approximately 5% of patients have evidence of nodal metastases.297  Treatment and Prognosis. The treatment paradigm of PTC is increasingly controversial. Although some authors recommend lobectomy and isthmusectomy (followed by suppression of TSH), others recommend total thyroidectomy, as this allows for possible postoperative radioactive iodine treatment (I131) and allows for more accurate monitoring of serum thyroglobulin levels for recurrent disease. Central lymph node dissection is also controversial. In the absence of metastatic disease or in small-­volume primary tumors, lymph node dissection is often dependent on a surgeon’s training. More recently, clinical trials for active surveillance with ultrasound to monitor for tumor growth have been initiated in the United States based on studies in Japan and South Korea.298,299 This concept is based on the finding that screening tests, which are often imaging studies, lead to identification and overdiagnosis of thyroid nodules that would not become clinically relevant or lead to altered overall survival. The prognosis of PTC is dependent on numerous variables184,300,301 and, generally, patients can be stratified into low-­ risk and high-­risk subsets. Several scoring systems have been

developed for risk assessment. The AGES scoring system incorporates age, tumor grade, tumor extent, and tumor size.300 The AMES system, developed by Cady and colleagues,302,303 uses age, distant metastases, extrathyroidal invasion and metastases, and primary tumor size. The European Organization for Research and Treatment of Cancer developed a scoring system that includes age, sex, principal cell type, extrathyroidal invasion, and distant metastases.304 A tumor, node, and metastasis (TNM) staging system, which was introduced by the International Union Against Cancer, has also been used extensively for prognostic assessment.304–306 The American Thyroid Association (ATA) has also stratified risk of recurrence by histologic and molecular features when known.273 Based on an ATA taskforce report, patients can be stratified for risk of recurrence based on a number of factors related to lymph node findings: clinically N0 neck with pN1a disease classified by the American Joint Commission on Cancer (AJCC) show a 2% risk of recurrence versus 20% recurrence with cN1a disease at presentation; the number of positive lymph nodes (< or >5) increases the rate or recurrence, as does the presence of extranodal extension. Size of lymph node metastasis (0.2 cm) is also used in stratifying patients for risk of local recurrence.307 Some have advocated that the lymph node ratio (number of metastatic nodes over the total number of nodes harvested) as well as the total number of lymph nodes removed are prognostic.308 However, this lost significance without a lateral lymph node dissection that is not performed unless there is clinically evident disease. Studies show that prophylactic neck dissection for cN0 often has microscopic pN1a levels of 40% to 50% in the central neck.309 AJCC staging also continues to refine prognostic groups for thyroid carcinoma in the 8th edition. Modifications from the 7th edition decrease the stage for patients between 45 and 55 years, whereby all patients under the age of 55 years are now stage I when local and/or regional disease is present, and stage II if distant metastases are detected. Histologic variants associated with a worse prognosis than conventional PTCs include the columnar, tall cell, and hobnail variants. Tumors with foci of poorly differentiated or anaplastic carcinoma are associated with a poor prognosis and are discussed further later. 

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C Fig. 7.53  Cribriform morular variant. A, At low power a cribriform growth pattern is present with absence of colloid. B, At higher power, condensed, cellular areas form morulas with variable spindled to squamoid features. C, Beta-­ catenin immunohistochemical stain showing nuclear expression in the tumor cells.

Follicular Carcinoma Clinical Features and Pathogenesis. Follicular carcinomas are malignant epithelial tumors that show evidence of follicular cell differentiation but lack the diagnostic nuclear features of PTC.121,310 They account for approximately 15% of malignant thyroid tumors. The relative incidence of follicular carcinoma

is higher in iodine-­deficient areas. The frequency of this tumor type has decreased in recent years, owing primarily to the recognition of the follicular variant of PTC.311 Similar to PTCs, previous radiation exposure also increases the risk of follicular carcinoma, although to a lesser extent. Patients with follicular carcinoma are, on average, 10 years older than those with PTC. Similar to PTCs, follicular carcinomas are considerably more common in females than in males.312 Most patients present with a palpable thyroid nodule, which is usually “cold” on scan. Occasionally, patients may present with distant metastasis involving bone or the lung. Follicular carcinomas are subdivided into encapsulated and widely invasive types.  Pathologic Features and Differential Diagnosis. The gross features of encapsulated follicular carcinomas do not differ significantly from those of follicular adenomas. However, the capsules of carcinomas are often thicker than those of adenomas.313 Microscopically, carcinomas may exhibit normofollicular, microfollicular, or macrofollicular features; however, they tend to exhibit a greater tendency for microfollicular, solid, or trabecular growth patterns.314 Foci of clear cell change may be evident (Fig. 7.54). The diagnosis of malignancy rests on the demonstration of capsular or vascular invasion. Accordingly, it is essential to examine multiple sections that include the capsule. If the lesion is sufficiently small, the entire capsular region should be examined. For larger lesions, at least five blocks should be examined. In the presence of areas suspicious for invasion or in cellular and mitotically active lesions, at least five additional blocks should be examined.268 To qualify as capsular invasion, most pathologists require penetration of the entire thickness of the capsule (Fig. 7.55A). Often, this takes the form of a mushroom-­like pattern of extension of the tumor through the capsule. In cases in which the tumor is present within the capsule but does not extend into the adjacent normal parenchyma, additional levels should be prepared. If additional levels do not reveal full capsular penetration, a diagnosis of follicular carcinoma should not be made. In some cases, a separate nodule may be present, external to the capsule. Serial sections are required to determine whether there is a connection with the main tumor mass. The demonstration of a connection between the two nodules is indicative of a carcinoma, but the absence of a connection does not completely rule out this possibility. Tangential cuts of the edge of a follicular neoplasm may also simulate capsular invasion, and additional sections may be required to demonstrate that the lesion is, in fact, invested by an intact capsule. Franssila detailed vascular invasion in follicular carcinoma requiring tumor cells should be present in vessels within or beyond the capsule (see Fig. 7.55B). The tumor cells should project into the lumen of the vessel and should conform to the overall shape of the vessel. The intravascular tumor should also be covered at least in part by endothelial cells.172,314 Asa and colleagues note that rigid criteria should be utilized for vascular invasion that includes both tumor cells invading through a vessel wall and endothelium with associated fibrin adherent to intravascular tumor.172 The presence of follicles simply bulging beneath the endothelium of a thin-­walled vessel is insufficient evidence of vascular invasion, particularly when deeper sections fail to reveal unequivocal evidence of vascular invasion. It has been suggested that when it is not possible to demonstrate unequivocal invasion, the term follicular tumor of uncertain malignant potential should be used.264

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Fig. 7.54  Follicular carcinoma. This tumor exhibits focal areas of clear cell change.

Artefactual dislodgement of tumor cells into vessels may occur during specimen preparation and sectioning. Typically, the tumor cell clusters in such instances have irregular outlines, are not attached to vascular walls, and are not associated with fibrin.172 The diagnosis and nomenclature of encapsulated follicular carcinomas are controversial. Currently, encapsulated follicular carcinomas are subdivided into minimally invasive carcinomas with capsular invasion only and angioinvasive carcinomas that show vascular invasion. Based on the observation that tumors showing only capsular invasion rarely behave as true carcinomas, some have even suggested that tumors with capsular invasion only should be classified as follicular neoplasms of low malignant potential.315 Widely invasive follicular carcinomas feature extensive invasion of the adjacent thyroid parenchyma with multiple foci of capsular and vascular invasion (see Fig. 7.55C and D). These tumors are more likely to exhibit mitotic activity and areas of pleomorphism. Common sites of metastasis include the lung, bone, and liver. In contrast to the excellent prognosis of the encapsulated tumors, the prognosis of widely invasive follicular carcinomas is poor.312  Immunohistochemistry. Follicular carcinoma cells are positive for thyroglobulin, TTF-­ 1, PAX8, and low-­ molecular-­ weight cytokeratins. The CK7+/CK20-­ pattern of immunoreactivity in these tumors is similar to that seen in PTCs and non-­neoplastic thyroid cells.213,216,220 The expression of the PPARγ protein, which can be detected by immunohistochemistry and correlates well with the presence of PAX8-­PPARγ rearrangement, may be of diagnostic value; this is discussed in detail in the next section. Follicular carcinomas are usually positive for Bcl-­2 and p27, have low expression of cyclin D1, and are negative for p53.121  Molecular Genetics. Most common genetic alterations in follicular thyroid carcinomas include point mutations of the RAS genes and PAX8-­PPARγ rearrangement. RAS mutations, most commonly affecting N-­RAS codon 61 or H-­RAS codon 61, are found in 40% to 50% of follicular carcinomas,316–318 and in some studies were found to correlate with tumor dedifferentiation and a less favorable prognosis.319,320 PAX8-­PPARγ fusion results from the translocation t(2;3)(q13;p25).321 It occurs in 25% to 40% of follicular carcinomas and in approximately 7% of follicular adenomas.322–324 It has been suggested that follicular adenomas

positive for this rearrangement may be preinvasive follicular neoplasms or tumors in which invasion was overlooked.325 Tumors with PAX8-­PPARγ tend to present at a younger age, are smaller, and more frequently have vascular invasion than those with mutant RAS.322,324 Another rearrangement leading to the fusion of PPARγ to the FTCF gene located on chromosome 7 was also described.121 More recently, an association of TERT promoter mutations with follicular carcinomas present in 17% to 30% of tumors has also suggested correlation with a more aggressive clinical course and poorer overall survival.221,325 RAS mutations cannot be used as a diagnostic marker of follicular carcinoma because they also occur with significant prevalence in follicular adenomas and the follicular variant of PTC. However, detection of PAX8-­PPARγ rearrangement may be of diagnostic value because it occurs almost exclusively in follicular carcinomas. The rearrangement results in overexpression of PPARγ protein, which can be detected by immunohistochemistry.321 However, only strong diffuse nuclear staining correlates with the presence of rearrangement (Fig. 7.56B).326 The development of this immunostaining method may be challenging because not all commercially available PPARγ antibodies give a reliable result. The presence of strong diffuse PPARγ staining in the tumor nodule, especially if confirmed by reverse-­ transcriptase polymerase chain reaction or fluorescence in situ hybridization, should justify the submission of additional sections of the capsule and the obtaining of deeper levels of all suspicious areas in a search for capsular or vascular invasion. However, in the absence of invasion, the diagnosis of carcinoma cannot be established. Follicular carcinomas are characterized by a considerable rate of loss of heterozygosity (LOH) and frequent losses of multiple chromosomal regions. The average rate of LOH per chromosome arm is approximately 20% in follicular carcinomas, compared with 6% in follicular adenomas and only 3% in PTCs.327 The most commonly deleted regions in follicular carcinomas are on chromosomes 2p, 3p, 9q, 10q, 11p, 15q, and 17p.327–332 Some studies observed that 3p and 17q deletions were significantly more common in follicular carcinomas than in adenomas.328,333 Oncocytic follicular carcinomas show a comparable or even higher rate of LOH than conventional follicular tumors.329–331 In Hürthle cell carcinomas, the most frequently lost regions were on chromosomes 3q and 18q in one study329

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Fig. 7.55  Follicular carcinoma. A, Minimally invasive follicular carcinoma. The tumor transgresses the connective tissue capsule. B, Encapsulated angioinvasive follicular carcinoma. Tumor is present within a capsular vein and is attached to the venous wall. C, Widely invasive follicular carcinoma. This tumor has a predominant microfollicular growth pattern. D, Widely invasive follicular carcinoma. Multiple areas of vascular invasion are present.

and on chromosomes 1q, 2p, 8q, and 14q in another observation.331 In the latter report, two markers (1q and 2p) showed a significantly higher rate of LOH in Hürthle cell carcinomas than in adenomas, with 100% sensitivity and 65% specificity in the detection of malignant tumors.  Treatment and Prognosis. The prognosis for patients with encapsulated follicular carcinoma is excellent and is generally similar to that of patients with PTCs of the usual type.334 Ten-­ year survival rates approach 100%. Factors that have a negative impact on prognosis include stage at presentation, age older than 50 years, the extent of angioinvasion, and absence of radioactive iodine uptake by metastasis. Thus, young patients with encapsulated tumors will have an excellent prognosis. In contrast, 10-­year survival rates in patients with widely invasive tumors are in the 40% to 80% range.312,335 The treatment of follicular carcinomas, particularly those of the encapsulated type, is controversial. Some surgeons favor lobectomy with isthmusectomy and suppression of TSH with

thyroxine.336 Other surgeons favor total thyroidectomy with ablation of any remaining thyroid tissue with 131I. The latter approach also permits the use of serum thyroglobulin measurements to monitor the development of metastases. For patients with angioinvasive tumors, most authors favor total thyroidectomy followed by 131I treatment.  Hürthle Cell Carcinoma Clinical Features and Pathogenesis. Hürthle cell carcinomas are malignant neoplasms composed of cells of follicular derivation that are characterized by relatively abundant, finely granular eosinophilic cytoplasm due to the presence of numerous mitochondria. This may be a consequence of somatic mutations and sequence variants in mitochondrial DNA.154 Other names have included follicular carcinoma, oncocytic variant, and oncocytic carcinoma. To qualify as a Hürthle cell carcinoma, the tumor should be composed almost exclusively (>75%) of cells with oncocytic features.121

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Fig. 7.56  Follicular carcinoma. A, The tumor has a thick capsule and shows vascular invasion. B, Peroxisome proliferator–activated receptor γ ­immunostain demonstrates strong diffuse nuclear immunoreactivity. This case was confirmed for PAX8-­PPARγ rearrangement by reverse-­transcriptase polymerase chain reaction.

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B Fig. 7.57  Hürthle cell carcinoma. This tumor has a mixed solid and trabecular growth pattern.

Although Thompson and colleagues337 suggested in 1974 that all oncocytic tumors of the thyroid were malignant or potentially malignant, more recent studies reject this claim.156 It is now recognized that Hürthle cell adenomas exist and that they can be distinguished from Hürthle cell carcinomas using criteria similar to those used to distinguish follicular adenomas from carcinomas. Thus, Hürthle cell carcinomas should be defined based on capsular or vascular invasion, as discussed in the ­section on follicular carcinoma. Of note though, Hürthle cell carcinomas are less likely to develop a thick worrisome capsule, and thus growth pattern with invasion into adjacent thyroid follicles should be evaluated in all cases, regardless of whether capsule formation is present. Hürthle cell carcinomas account for approximately 3% to 4% of all thyroid malignancies and occur more commonly in women, with a female-­to-­male ratio of 2:1. On average, patients with Hürthle cell carcinomas are approximately a decade older than those with Hürthle cell/oncocytic adenomas. The clinical presentation does not differ from that of patients with follicular carcinomas of the non-­oncocytic type.  Pathologic Features and Differential Diagnosis. Hürthle cell carcinomas are generally larger than oncocytic adenomas, but

the size range is considerable. In the series reported by Carcangiu and colleagues,156 most of the carcinomas measured more than 5 cm in diameter. Minimally invasive tumors are generally surrounded by a fibrous connective tissue capsule, which makes their distinction from oncocytic adenomas impossible grossly. Widely invasive carcinomas exhibit extensive capsular invasion or may lack a capsule altogether. Multiple nodules of tumor may be present in the adjacent thyroid parenchyma next to the main tumor mass. A subset of tumors may have equivocal features of malignancy (minimal or questionable capsular invasion, a predominantly solid growth pattern, marked nuclear atypia, or extensive necrosis), but these tumors are likely to behave in a benign fashion.156 Compared with adenomas, Hürthle cell carcinomas are more likely to have a solid or trabecular pattern (Fig. 7.57). In one series, only 14% of the carcinomas had a follicular pattern.156 Additionally, the tumor cells in carcinomas are more likely to have a higher nucleus-­to-­cytoplasm ratio than adenomas, and occasional mitotic figures may also be evident. Foci of clear cell change may be present.160 The tumors are generally positive for thyroglobulin, TTF-­1, PAX8, and cytokeratin, although the intensity of staining is generally less than that of non-­oncocytic

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Fig. 7.58  Poorly differentiated thyroid carcinoma. A, This tumor has a nesting/insular growth pattern. B, Some of the tumor nests have central necrosis.

follicular tumors. A diagnosis of Hürthle cell carcinoma should be made only when there is evidence of capsular or vascular invasion, and the criteria for these features are the same as those described for conventional follicular neoplasms. Hürthle cell carcinomas have a greater propensity for invasion into the surrounding soft tissues than do conventional follicular carcinomas. Additionally, soft-tissue deposits from lymphovascular spread may occur outside of the thyroid in addition to lymph node metastases.338 Known molecular alterations in Hürthle cell carcinomas include TP53 and PTEN.339 In an aggressive cohort of 12 Hürthle cell carcinomas, 42% showed TP53 mutations, with three cases of concomitant PTEN alterations.  Treatment and Prognosis. Generally, both minimally and widely invasive Hürthle cell carcinomas are treated by near-­ total or total thyroidectomy. Radioactive iodine and external irradiation are of questionable value in the postoperative management of patients with these tumors. As noted previously, Hürthle cell carcinomas are more likely to invade the soft tissues of the neck than follicular carcinomas. The most common sites of metastasis are the lung and bone.340 Lymph node metastases are more common than in follicular carcinomas, and less common than in PTCs. Overall, the prognosis for Hürthle cell carcinomas is less favorable than the prognosis for follicular carcinomas. Five-­year survival rates are in the range of 50% to 60%, with most of the mortality due to widely invasive tumors. The prognosis for minimally invasive Hürthle cell carcinomas is, in general, as good as for minimally invasive follicular carcinomas of conventional type.  Poorly Differentiated Thyroid Carcinomas Clinical Features and Pathogenesis. Poorly differentiated thyroid carcinomas include a heterogeneous group of neoplasms whose behavioral and histologic features are intermediate between well-­differentiated and anaplastic thyroid carcinomas.341–343 Synonyms include insular carcinoma. The frequency of this tumor type appears to differ in different geographic regions. In central Italy, the tumors account for approximately 4% of all thyroid carcinomas. It is much less common in the United States and most other countries. There is a slight female predominance, and the median age at diagnosis is 55 years. Most patients present with a thyroid mass

of variable duration. Analysis of several series of cases revealed regional metastases in 36% and distant metastases in 26% at presentation.283  Pathologic Features and Differential Diagnosis. Grossly, the tumors appear solid and gray-­white, with foci of necrosis and infiltrative margins.342 Insular, solid, and trabecular growth patterns can be seen (Fig. 7.58A). Scattered microfollicles containing small deposits of colloid are not uncommon. The tumor cells are usually small and uniform, with round nuclei and a high nucleus-­ to-­ cytoplasm ratio. The tumor exhibits variable numbers of mitoses and foci of necrosis (Fig. 7.58B). Both vascular and lymphatic metastases are common. The Turin conference established consensus for characterizing poorly differentiated thyroid carcinomas, which has been adopted by the fourth edition of the WHO endocrine tumors.344,345 Criteria defining a poorly differentiated thyroid carcinoma include a solid or trabecular pattern or growth, lack of papillary-­like nuclei, and the presence of three or more mitoses per 10 high-­ power fields or the presence of necrosis.344 Critical for exclusion are solid papillary thyroid carcinomas and some adenomas, and/ or follicular carcinomas with insular growth that lack mitoses as noted and necrosis. Criteria for poorly differentiated Hürthle cell carcinomas may also be similar; however, these were not defined in this consensus conference secondary to insufficient case numbers. A more recent study by Bai et  al. supports the application of Turin criteria to Hürthle cell carcinomas.346 Papillary thyroid carcinomas may also show high-­ grade features or act like a poorly differentiated thyroid carcinoma; however, there is lack of a consensus for utilizing these additive terms in papillary thyroid carcinoma specifically. The pathology group at Memorial Sloan Kettering Cancer Center proposed a definition for poorly differentiated thyroid carcinoma that includes any follicular cell-­derived tumors, including papillary morphology as tumors with >5 mitoses/10 HPF and/or tumor necrosis.347 The tumor cells are typically focally positive for thyroglobulin, have substantial TTF-­1 and PAX8 immunoreactivity, and are strongly positive for cytokeratin.146 Molecular alterations in poorly differentiated thyroid carcinomas are variable based on the associated underlying tumor and bridge the frequencies between well-­differentiated thyroid carcinomas and anaplastic thyroid carcinoma. In a large cohort

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Fig. 7.59  Anaplastic thyroid carcinoma. This tumor is composed of large pleomorphic cells with areas of spindle cell growth.

by Landa et al., of 84 poorly differentiated thyroid carcinomas meeting the Turin or Memorial Sloan Kettering definitions, the frequencies were BRAF (33%) and RAS (N-­RAS 21%, H-­RAS 5%, K-­RAS 2%).348 While a subset of poorly differentiated (insular) thyroid carcinomas appear de novo, no genetic mutations unique for poorly differentiated thyroid carcinoma have been identified to date. This suggests that poorly differentiated thyroid carcinoma, as a group, more likely represents a distinct step in the evolution from well-­differentiated to anaplastic thyroid carcinoma, rather than an entirely separate type of thyroid malignancy. The differential diagnosis includes anaplastic thyroid carcinoma, solid variant of PTC, and medullary carcinoma. Anaplastic thyroid carcinomas generally feature nuclear pleomorphism with frequent mitoses, which is not a characteristic of poorly differentiated thyroid carcinoma, usually a cytologically monotonous tumor. Additionally, anaplastic thyroid carcinomas grow in sheets, often with prominent necrosis and an inflammatory infiltrate. Thyroglobulin and TTF-­1 may be present or reduced, although seldom lost in poorly differentiated thyroid carcinomas compared to anaplastic (undifferentiated) thyroid carcinomas.349 The solid variant of PTC is characterized by the presence of diagnostic nuclear features in the tumor cells, low mitotic activity, and lack of tumor necrosis.276 Medullary thyroid carcinomas can be distinguished from poorly differentiated thyroid carcinomas based on positive reactions for calcitonin and chromogranin.  Treatment and Prognosis. Treatment modalities for poorly differentiated thyroid carcinomas are not fully established, as conventional chemotherapy fails to significantly modify the overall outcome for median survival (3.2 years). Metastases are common, with the most frequent sites of metastatic disease being regional lymph nodes, the liver, and bone. Targeted therapies to molecular alterations are currently in clinical trials in advanced thyroid carcinoma patients.350 The prognosis for insular carcinoma is poor. In a recent review, 25% of patients had died of their disease, 29% were alive with evidence of disease, 41% had no evidence of disease, and 5% had died with disease.283 The prognosis of well-­differentiated thyroid carcinomas with focal areas of poorly differentiated thyroid carcinoma depends on the extent of the poorly differentiated component. 

Anaplastic (Undifferentiated) Thyroid Carcinoma Clinical Features and Pathogenesis. Anaplastic thyroid carcinomas are highly malignant tumors that appear wholly or partially undifferentiated by light microscopy but often show retained evidence of epithelial differentiation by immunohistochemistry (presence of cytokeratins). Anaplastic thyroid carcinomas are uncommon tumors that account for less than 2% of all thyroid malignancies.351 The tumors occur principally in older adults, with a mean age of 65 years and a female predominance. In some instances, a preexisting thyroid mass may have been present for many years, and in approximately 30% of cases, residual papillary or follicular carcinomas can be identified (see Fig. 7.50). The tumors are more frequent in areas of endemic goiter. Anaplastic thyroid carcinomas present most commonly as rapidly enlarging masses with evidence of hoarseness, dyspnea, or dysphagia. Occasional patients may have evidence of distant metastases at presentation. A subset of anaplastic thyroid carcinoma patients will show leukocytosis in the blood.  Pathologic Features and Differential Diagnosis. Anaplastic thyroid carcinomas are typically very large tumors with evidence of extensive infiltration of the adjacent soft tissues of the neck. On cross section, they have a fleshy appearance with foci of necrosis and hemorrhage. The histologic features are highly variable, but three basic patterns have been recognized (Figs. 7.59–7.61). Tumors composed of round to polygonal cells and resembling nonkeratinizing squamous cell carcinomas have been designated squamoid type.352 Occasional foci of keratinization may also be evident in some cases. The spindle cell or sarcomatoid variant is composed of bundles of spindle-­shaped cells resembling fibrosarcoma, or pleomorphic sarcoma (see Fig. 7.61A). The giant cell variant is composed of very large tumor cells with single or multiple hyperchromatic nuclei, some of which may resemble Reed-­ Sternberg cells. Rare variants containing multiple giant cells with osteoclast-­like features also occur (see Fig. 7.61B).353 The paucicellular variant of anaplastic thyroid carcinoma is characterized by the presence of acellular fibrous tissue or infarcted tissue with central dystrophic calcification and hypocellular foci with mildly atypical spindle cells admixed with collagen and lymphocytes (see Fig. 7.60).354 Most cases

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Fig. 7.60  Anaplastic thyroid carcinoma. A, This tumor is paucicellular, with extensive areas of fibrosis and few atypical cells with large hyperchromatic nuclei. B, A cytokeratin stain shows positivity in the atypical cells.

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Fig. 7.61  Anaplastic thyroid carcinoma. A, This tumor focally exhibits a hemangioendotheliomatous appearance. B, This tumor contains osteoclast-­ like giant cells.

that were previously classified as anaplastic carcinomas of the “small cell type” have now been shown to represent malignant lymphomas. Virtually all types of anaplastic thyroid carcinoma reveal evidence of intense mitotic activity, areas of necrosis, and vascular invasion. Some tumors may contain prominent populations of acute inflammatory cells. Most anaplastic carcinomas will show positive reactions for both cytokeratins and vimentin355,356; however, keratin immunoreactivity may be both weak and focal. Most studies revealed absent staining for thyroglobulin and TTF-­1 except in foci of preexisting, well-­differentiated

carcinomas that may be present within the tumors. PAX8 is a nuclear marker that is retained in 50% to 75% of anaplastic thyroid carcinomas, and has become a useful marker in this clinical setting to aid in supporting thyroid origin.357 As noted by Rosai,358 a diagnosis of anaplastic thyroid carcinoma should be favored when any pleomorphic or highly necrotic tumor appears to arise within the thyroid, particularly if the patient is elderly and particularly if there is evidence of a residual better-­ differentiated thyroid tumor within the gland. In those instances, the most appropriate interpretation would be undifferentiated malignant tumor, consistent with anaplastic thyroid carcinoma.

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Anaplastic thyroid carcinomas typically have a highly unstable, complex karyotype with numerous gains and losses of whole chromosomes and smaller chromosomal regions.359 Next-­generation sequencing has expanded the number of genes evaluated in these tumors.348,360 TERT promoter mutations and p53 mutations were identified in 73% of tumors; BRAF V600E in 45% and RAS in 24%. Other frequent recurring mutations and translocations involved PIK3CA (18% and 39%, respectively). Tumor suppressor mutations including PTEN (15%) and ATM, RB1, NF1 (all at 9%) and other genes at lower frequency were also identified.348 Mutations in exon 3 of the β-­catenin (CTNNB1) gene have been reported in 66% of anaplastic thyroid carcinomas.361 The differential diagnosis includes malignant lymphoma, sarcoma, medullary thyroid carcinoma, and metastatic carcinoma. Malignant lymphomas are typically positive for leukocyte common antigen (CD45RO) and other markers of lymphoid differentiation. Additionally, malignant lymphoma cells may be seen percolating into adjacent follicles within the colloid in contrast to anaplastic thyroid carcinoma, which surrounds or overruns the follicles. True primary sarcomas of the thyroid gland are very rare and the older literature is misleading, as it was published prior to the understanding of dedifferentiation and sarcomatoid carcinoma transformation from epithelial malignancies in the thyroid. More likely a sarcoma of the neck soft tissues may secondarily involve the thyroid gland. Only when mitoses are rare/ki67 is low might a sarcoma be a diagnosis of exclusion. Anaplastic carcinomas may express sarcoma markers and show heterologous elements in a rare subset of these tumors. Metastatic carcinomas are discussed in a subsequent section. Medullary carcinomas of the spindle and giant cell types may resemble anaplastic thyroid carcinomas; however, medullary carcinomas are typically positive for chromogranin and calcitonin.  Treatment and Prognosis. The algorithm for the treatment of anaplastic thyroid carcinomas is changing.362,363 While the combination of external irradiation and chemotherapy is still widely used, targeted therapeutic options have received recent FDA approval. Specifically, in anaplastic thyroid carcinomas harboring BRAF V600E mutations, the combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, may be used. The extent of disease at presentation often precludes surgical resection as a primary treatment option. 131I treatment is ineffective. The prognosis for anaplastic thyroid carcinoma is poor, with a mean survival of 6 months.352 Most patients die as a direct result of extensive local tumor growth. The tumors also frequently metastasize to regional lymph nodes, and hematogenous metastases are common both at presentation or during the course of the disease.  Squamous Cell Carcinoma Clinical Features and Pathogenesis. Pure squamous cell carcinomas of the thyroid, as defined by obvious squamous differentiation and cytologic atypia, are rare.364 These tumors occur most often in elderly patients who may have a history of goiter. The tumors typically grow rapidly and are associated with extensive local invasion. Occasional patients may present with fever, leukocytosis, and hypercalcemia, which may be mediated by the secretion of interleukin 1.365,366  Pathologic Features and Differential Diagnosis. Squamous cell carcinomas are typically large tumors that replace the thyroid gland extensively. The tumors may show a spectrum of appearances

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ranging from well differentiated to poorly differentiated. In many cases, the squamous components merge with areas of anaplastic thyroid carcinoma; accordingly, some authors placed these tumors in the undifferentiated category. Similar to anaplastic thyroid carcinomas, small foci of well-­differentiated PTC or follicular carcinoma may be found within squamous carcinomas. This finding supports the view that some squamous cell carcinomas may arise from metaplastic foci of differentiated thyroid carcinomas, particularly of the papillary type. Primary squamous cell carcinomas of the thyroid must be distinguished from metastases of squamous cell carcinomas to the thyroid gland and from direct extension of primary squamous cell carcinomas originating from the larynx or trachea.  Treatment and Prognosis. Treatment is essentially identical to that of anaplastic thyroid carcinomas. The prognosis is very poor, with most patients dying as a consequence of the effect of local tumor invasion.  Medullary Carcinoma Clinical Features and Pathogenesis. Medullary carcinoma is a malignant thyroid tumor composed of neuroendocrine cells showing evidence of C-­cell differentiation. This tumor type was first described as a distinctive morphologic entity by Horn367 in 1951. Hazard and colleagues368 subsequently defined its major histologic features, including the presence of stromal amyloid, and suggested the name medullary carcinoma to describe it. Based on similarities to certain solid thyroid tumors in animals and to normal parafollicular C cells, Williams369 suggested that medullary carcinomas were derived from C cells. With the demonstration of the C-­cell origin of calcitonin, subsequent studies demonstrated calcitonin in tumor extracts and in the serum of affected patients.370 These tumors account for around 5% of all thyroid malignancies.371 They may occur sporadically or as a component of type 2 multiple endocrine neoplasia (MEN) syndromes, which are inherited as autosomal dominant traits.372 In most large series, sporadic tumors account for approximately 75% of all cases. MEN 2A is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid chief cell hyperplasia or adenoma. A second genetically distinct syndrome (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytoma, ocular and gastrointestinal ganglioneuromatosis, and skeletal abnormalities. Sporadic medullary carcinomas are principally tumors of middle-­aged adults (mean age, 50 years) with a slight female predominance.373 Generally, patients present with unilateral gland involvement with or without associated nodal metastasis. Patients with MEN 2A–associated medullary carcinomas have a mean age of approximately 20 years, whereas patients with MEN 2B may develop thyroid tumors in childhood. With the use of biochemical and molecular screening methods, the average age of patients with familial tumors has decreased progressively. In contrast to sporadic tumors, which are usually unilateral, familial medullary carcinomas may be bilateral at presentation. Despite these differences, there is significant clinical overlap between sporadic and hereditary tumors, and thus genetic testing to exclude hereditary disease is recommended in all patients. As discussed in the next section, familial tumors are associated with germline mutations in the RET proto-­oncogene, whereas somatic mutations of RET are present in a subset of sporadic tumors.372 Sporadic tumors occur with equal frequency in

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Fig. 7.62  Medullary thyroid carcinoma. This tumor from a patient with type 2A multiple endocrine neoplasia has a solid appearance.

different parts of the world. There are no data to support a link between the development of these tumors and previous irradiation to the head and neck.  Pathologic Features and Differential Diagnosis. The tumors may vary considerably in size, and are occasionally well circumscribed (Fig. 7.62). Tumors measuring less than 1 cm in diameter have been referred to as medullary microcarcinomas.374 On cross section, the tumors are tan to pink, and their consistency can vary from soft to firm. Some tumors may appear grossly fibrotic with small foci of yellow discoloration. The smaller tumors typically occur at the junctions of the upper and middle thirds of the lateral lobes, corresponding to the areas in which C cells normally predominate. When the tumors become very large, they may replace the entire lobe. Sporadic tumors are generally unilateral, but familial tumors may be bilateral, multicentric, and associated with C-­cell hyperplasia (see “Familial Medullary Thyroid Carcinoma and C-­Cell Hyperplasia” section). Most sporadic and familial tumors exhibit a solid growth pattern; however, organoid, lobular, trabecular, and insular patterns are also common (Fig. 7.63).375 Some tumors may also contain follicular structures containing material resembling colloid. Although most tumors appear grossly circumscribed, microscopic evaluation usually demonstrates an infiltrative margin. Individual tumor cells may be round, polygonal, or spindle shaped, with frequent admixtures of these cell types. Nuclei are round/ovoid to spindled with speckled chromatin and often eccentric. Binucleate cells may be present, as well as variable numbers of giant cells. Nuclear pseudoinclusions may be prominent and occasionally accompanied by nuclear grooves, mimicking PTC. The cytoplasm varies from amphiphilic to pale

eosinophilic, and, in well-­fixed preparations, it may be granular. Occasional tumors may have clear cytoplasm. Mucin-­positive vacuoles may be present in the cytoplasm of some tumor cells. Foci of necrosis, mitotic activity, and hemorrhage are more commonly present in larger tumors. Stromal amyloid deposits are present in approximately 80% of cases (Fig. 7.64). Occasionally, the amyloid deposits may elicit a foreign-­body giant cell reaction. Additionally, the stroma may appear quite fibrotic with foci of calcification. Rare psammoma bodies may be present. Numerous variants of medullary thyroid carcinoma have been described, including follicular (tubular; Fig. 7.65),376 papillary and pseudopapillary,377 angiomatous,378 small cell (Fig. 7.66A),379 giant cell (Fig. 7.67B),380 clear cell,381 melanotic (Fig. 7.66B),382 oncocytic,383 squamous,383 amphicrine (see Fig. 7.67A; composite calcitonin and mucin producing),384 and paraganglioma-­like.385 An encapsulated adenoma-­like variant was also described.386 Medullary carcinomas of all types are usually positive for low-­molecular-­weight cytokeratins, whereas high-­molecular-­ weight keratins are rarely expressed.211 TTF-­1 is almost universally positive in MTC, while PAX8 is variable in staining, pattern, and intensity, which may depend on the antibody clone. The tumors are typically positive for markers of neuroendocrine differentiation, including chromogranin and synaptophysin.387 In addition, medullary carcinomas are typically positive for carcinoembryonic antigen (CEA). Calcitonin is a sensitive marker, present in approximately 95% of medullary carcinomas. Those cases that are negative for the peptide may give positive signals with in situ hybridization methods for calcitonin mRNA.388 Calcitonin can be expressed in neuroendocrine tumors from other organ systems (including the larynx and lung), so it is a sensitive marker for medullary thyroid carcinoma; however, it is only specific in the context of a known thyroid neoplasm.389 In addition to calcitonin, medullary carcinomas may contain somatostatin, adrenocorticotropin and pro-­opiomelanocortin derivatives, neurotensin, serotonin, and other amines.11 Ultrastructurally, medullary carcinomas are characterized by the presence of membrane-­bound secretory granules, which represent the sites of storage of calcitonin and other peptide products. The larger granules have an average diameter of 280 nm with moderately electron-­dense, finely granular contents that are closely applied to the limiting membranes of the granules.390 Smaller granules have an average diameter of 130 nm with more electron-­dense contents that are separated from the limiting membranes by a narrow electron lucent space. As mentioned earlier, medullary thyroid carcinomas may mimic virtually the entire spectrum of benign and malignant thyroid neoplasms. Occasional tumors may have a papillary or pseudopapillary appearance with nuclear pseudoinclusions, grooves, and/or psammoma bodies. The absence of colloid, in conjunction with amphiphilic cytoplasm and more hyperchromatic nuclei, should raise the concern of a neoplasm mimicking PTC. Medullary carcinomas may contain neoplastic follicular structures and must, therefore, be distinguished from follicular carcinomas. Entrapped residual normal thyroid follicles are found frequently in medullary carcinomas and should not be mistaken for evidence of follicular differentiation in the tumor. The oncocytic variant is particularly treacherous, as they are histologically similar to oncocytic neoplasms of follicular cell origin, which often lack significant amounts of colloid. Given the morphologic variability of medullary thyroid carcinoma

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Fig. 7.63  Medullary thyroid carcinoma. A, This tumor is composed of large nests of cells with relatively abundant granular cytoplasm. B, Immunoperoxidase stain for calcitonin demonstrates intense positivity in the tumor cells. C, This tumor has a spindle cell growth pattern. D, This tumor is composed predominantly of clear cells.

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Fig. 7.64  Medullary thyroid carcinoma. A, This tumor contains abundant stromal amyloid deposits. B, Congo red stain photographed in polarized light. The amyloid deposits exhibit green birefringence.

Fig. 7.65  Medullary thyroid carcinoma. This tumor has a follicular (tubular) architecture.

and its ability to mimic other thyroid neoplasms, liberal use of immunohistochemistry in nodules that are solid or have cytologic features suggestive of neuroendocrine differentiation is suggested. Calcitonin, CEA, and neuroendocrine marker positivity distinguishes medullary from other thyroid carcinomas. Medullary carcinomas must also be distinguished from poorly differentiated (insular) thyroid carcinomas. The latter tumors are characterized by the presence of solid sheets, nests, and trabeculae

of tumor cells. They are typically positive for thyroglobulin, and their stroma is negative for amyloid. Medullary carcinomas of spindle and giant cell types must also be distinguished from anaplastic thyroid carcinomas. The latter tumors are negative for calcitonin and chromogranin. Medullary carcinomas must also be distinguished from malignant lymphomas, which are typically positive for leukocyte common antigen and other lymphoid differentiation markers. Medullary carcinomas may have

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Fig. 7.66  Medullary thyroid carcinoma. A, This tumor is composed predominantly of small cells. B, This tumor contains melanin-­rich cells.

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Fig. 7.67  Medullary thyroid carcinoma. A, This tumor is composed of mucin-­rich cells that were also positive for calcitonin (amphicrine type). B, This tumor is composed of giant cells.

a plasmacytoid appearance and must be distinguished from plasmacytomas. The latter tumors may also contain amyloid deposits, but the component cells are usually positive for immunoglobulins. Eusebi and colleagues391 described two cases of small cell thyroid carcinoma that were positive for chromogranin but negative for calcitonin by immunohistochemistry. Both tumors were negative for calcitonin mRNA when studied by in situ hybridization. These tumors may represent primary small cell carcinomas of the thyroid and should be separated from the small cell variant of medullary carcinoma based on the lack of immunoreactivity for calcitonin, somatostatin, and CEA. The hyalinizing trabecular tumor is typically encapsulated, as are some variants of medullary carcinoma. A

trabecular growth pattern may be present in both tumors, and both may exhibit areas of hyalinization. However, the stroma of medullary carcinoma is typically positive for amyloid, whereas that of hyalinizing trabecular adenoma is not. Moreover, hyalinizing trabecular adenomas are negative for calcitonin. Paragangliomas are negative for cytokeratins and typically positive for chromogranin in the chief cells, whereas the sustentacular cells are positive for S100 protein. Occasional intrathyroidal parathyroid adenomas may be mistaken for medullary carcinomas. Parathyroid tumors can be identified based on their positivity for parathyroid hormone and GATA3, and absence of calcitonin, TTF-­1, or CEA expression. 

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Fig. 7.68  A, C-­cell hyperplasia in a patient with multiple endocrine neoplasia type 2A (MEN 2A; immunoperoxidase stain for calcitonin). There is a diffuse increase in the number of C cells. B, Nodular C-­cell hyperplasia in a patient with MEN 2A (immunoperoxidase stain for calcitonin). The central follicle is filled with C cells.

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Fig. 7.69  A, C-­cell hyperplasia in a patient with multiple endocrine neoplasia type 2A (MEN 2A). C cells form small follicles around the central colloid-­filled follicle. B, Immunoperoxidase stain for calcitonin.

Familial Medullary Thyroid Carcinoma and C-­Cell Hyperplasia Familial and possibly some sporadic tumors are preceded by phases of C-­cell hyperplasia that have been identified on the basis of enhanced calcitonin secretory responses to calcium and pentagastrin stimulation tests.392 C-­cell hyperplasia is characterized by increased numbers of C cells within follicular spaces. With further progression, C cells fill and expand follicles to produce nodular C-­cell hyperplasia373,390 (Figs. 7.68 and 7.69). Transition of this phase of C-­cell growth to medullary thyroid carcinoma (Fig. 7.70) is characterized ultrastructurally by extension of C cells through the follicular basement membrane into the interstitium of the thyroid gland. McDermott and colleagues393 confirmed these findings using an immunoperoxidase technique for the demonstration of type IV collagen. The distinction of normal C-­cell distribution from the earliest phases of C-­cell hyperplasia is difficult.394 It is generally accepted that the diagnosis should be made when there are at least 50 C cells per low-­power field.395 C-­cell hyperplasia associated with MEN 2 syndromes is usually both diffuse and

nodular, and can often be diagnosed based on examination of hematoxylin-­eosin–stained sections. C-­cell hyperplasia has also been reported in association with hypercalcemic states, in patients with Hashimoto thyroiditis, and adjacent to papillary and follicular carcinomas. This type of C-­cell hyperplasia has been referred to as secondary or physiologic C-­cell hyperplasia. Perry and colleagues396 propose that the C-­cell hyperplasia seen in association with MEN 2 syndromes and physiologic C-­cell hyperplasia represent distinct histologic and biological entities. According to these authors, physiologic C-­cell hyperplasia is characterized by increased numbers of normal C cells, which can be distinguished from adjacent follicular cells only based on positive immunostains for calcitonin. However, in our experience it is not uncommon to encounter histologically visible, nodular C-­cell hyperplasia as an incidental finding in thyroid glands removed for other indications. These foci are indistinguishable from C-­cell hyperplasia in patients with MEN 2 syndrome. The only way to exclude MEN 2 in such cases is with genetic testing.397 C-­cell hyperplasia may also occur in patients with Cowden syndrome.144

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Fig. 7.70  A, Early medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2A (MEN 2A). Neoplastic C cells have begun to infiltrate the thyroid stroma. B, Medullary thyroid microcarcinoma in a patient with MEN 2A. This tumor focus measured 0.3 cm and was composed of spindle-­shaped cells.

Molecular Genetics. The RET proto-­oncogene has been identified as the key molecule associated with the development of most medullary carcinomas, including both familial and sporadic forms of the disease. In medullary carcinomas, RET is activated by point mutation, in contrast to its activation via chromosomal rearrangement in PTCs. Germline mutations in specific functional regions of the gene are found in almost all patients with familial forms of medullary carcinoma. In MEN 2A, mutations are located in the extracellular domain, within the cysteine-­rich region, and less commonly within the intracellular tyrosine kinase domains.376,399 Codon 634 mutations are the most common and associated with the earliest onset of medullary carcinoma.400,401 In MEN 2B, 95% of the mutations involve codon 918 in the intracellular tyrosine kinase domain.402,403 These germline mutations lead to constitutive activation of the RET receptor. The tumorigenic role of mutant RET was confirmed in transgenic mice expressing RET mutated at codon 634.404 Almost all animals developed bilateral C-­cell hyperplasia at as early as 3 weeks of age and subsequently presented with multicentric medullary carcinomas. In sporadic medullary carcinomas, somatic mutations of RET are found in up to half of cases.405 The majority of those affect codon 918, although they have also been identified in other regions and the number of novel mutation spots continues to grow.406,407 Codon 918 mutations are associated with a more aggressive disease phenotype.405 A more recent discovery is the presence of activating RAS mutations in the majority of RET mutation-­negative tumors.408 RAS and RET mutations are, with rare exception, mutually exclusive. A new prognostic marker in medullary carcinomas correlating with poor overall survival and distant disease is CDKN2C copy number loss, which may be detected by FISH or other methods.409 Further, CDKN2C loss coexisting with a RET codon 918 mutation was associated with a worse outcome than either genetic alteration alone.409  Treatment and Prognosis. Both familial and sporadic forms of medullary carcinoma are treated by total thyroidectomy with dissection of the central lymph nodes from the region of the hyoid bone to the innominate vein. Generally, a modified lateral node dissection is reserved for patients with jugular nodal metastases. The probability of nodal metastases increases

with the size of the primary tumor, ranging from 20% in tumors smaller than 0.7 cm in diameter to 82% in tumors larger than 1.5 cm.410 In addition to metastases involving the central and lateral cervical nodes, medullary carcinomas may metastasize to distant sites such as the lung, bones, and liver. The adrenal glands are also common sites of metastasis, and in patients with MEN 2A and 2B, metastases to pheochromocytomas may be evident. The 5-­year survival rate for patients with these tumors is 60% to 70% and the 10-­year survival rate is in the range of 40% to 50%. Patients with small MEN 2A–associated tumors (95%.426 

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Plasmacytoma Plasma cell neoplasms may arise directly within the thyroid gland or may involve the gland secondarily as a manifestation of multiple myeloma. Primary plasmacytomas typically occur in older individuals, and most commonly arise in a background of chronic lymphocytic thyroiditis.427,428 The tumors are composed of mature and immature plasma cells with round nuclei, coarsely clumped chromatin, and generally small nucleoli. Immunophenotypic studies reveal monoclonality of these cells. Amyloid deposits may be present. The differential diagnosis includes MALT lymphoma, plasma cell granuloma, and medullary thyroid carcinoma. MALT lymphomas may contain a high proportion of plasma cells in addition to small lymphocytes, some of which may appear atypical. In plasma cell granulomas, the plasma cells are typically polyclonal, as discussed subsequently. The nuclei of medullary thyroid carcinoma cells may resemble those of plasma cells, and the stroma of these tumors often contains amyloid. However, the carcinoma cells are typically positive for chromogranin and calcitonin.  Hodgkin Lymphoma Hodgkin lymphoma, usually of the nodular sclerosing type, may rarely arise within the thyroid gland.429 Secondary involvement of the gland may also occur by direct extension of cervical node disease.430 The features of Hodgkin disease in the thyroid are similar to those seen in other sites.  Other Lymphoproliferative and Hematologic Disorders Langerhans cell histiocytosis (eosinophilic granuloma) may involve the thyroid gland as a primary disorder or may be a manifestation of systemic disease.431–433 This disorder is characterized by the presence of cells with grooved vesicular nuclei and faintly eosinophilic cytoplasm. Variable numbers of eosinophils are present. The diagnosis can be confirmed by positive immunostains for S100 protein, lysozyme, CD1a, and CD68, and the presence of Birbeck granules at the ultrastructural level. In patients with disease confined to the thyroid, the prognosis is excellent. Patients with disseminated disease, conversely, have a poor prognosis. Sinus histiocytosis with massive lymphadenopathy (Rosai-­ Dorfman disease) may rarely occur as a primary thyroid lesion or may involve the thyroid secondarily from involved parathyroidal lymph nodes. On occasion, sinus histiocytosis with massive lymphadenopathy may simulate subacute thyroiditis clinically.434 The histiocytic cells are characterized by round to ovoid vesicular nuclei with abundant eosinophilic cytoplasm and evidence of phagocytosed lymphocytes (emperipolesis), erythrocytes, or neutrophils. The cells exhibit positivity for S100 protein, α1-­antichymotrypsin, CD68, and lysozyme. Plasma cell granuloma is characterized by the presence of nodular lesions composed of polyclonal plasma cells together with other inflammatory elements. The lesions may infiltrate adjacent tissues, and may, therefore, simulate plasmacytomas. Moreover, plasma cell granulomas may be associated with polyclonal gammopathy.435 Rare examples of extramedullary hematopoiesis have also been reported in the thyroid gland.436  Mesenchymal Tumors Clinical Features and Pathogenesis. Both benign and malignant mesenchymal tumors may occur in the thyroid

gland. Benign tumors include those of vascular (hemangioma, lymphangioma), muscle (leiomyoma), neural (neurilemmoma), and adipocyte (lipoma) origins. Sarcomas are malignant tumors of presumed mesenchymal origin.437 Virtually all types of sarcomas have been reported as primary thyroid malignancies, including angiosarcoma and peripheral nerve sheath tumors.438 Much of the historic literature represents misclassified anaplastic thyroid carcinoma, with true mesenchymal tumors constituting only a small proportion of primary thyroid malignancies.439 They tend to occur in older individuals, are rapidly growing, and are usually fatal owing to extensive local invasion. In this regard, they are similar to anaplastic carcinomas. Angiosarcoma is the most common of this group of tumors and occurs primarily in the endemic goiter regions of Europe.440 The mean age of affected patients is 60 years, and there is a slight male predominance. The debate continues as to whether some of these are in fact merely a variant of anaplastic carcinoma.  Pathologic Features and Differential Diagnosis. Grossly, sarcomas are large tumors that may replace part or all of the thyroid gland. The tumors often have a fleshy appearance, with frequent areas of necrosis and hemorrhage. Direct invasion of the soft tissues of the neck is common. Angiosarcomas are commonly hemorrhagic, with multiple blood-­filled cystic spaces. Histologically, angiosarcomas vary from those that are solid to those with irregular vascular slits or anastomosing channels lined with large atypical endothelial cells. The tumor cells are usually positive for vimentin, Ulex europaeus, and the factor VIII–related antigen. CD31 and CD34 may also be positive. Tumors with epithelioid features may exhibit cytokeratin positivity.441,442 Ultrastructurally, Weibel-­Palade bodies are present in well-­differentiated angiosarcomas. The histologic features of other sarcomas are similar to those described in other sites.438 The major differential diagnosis of thyroid sarcomas is anaplastic carcinoma. Generally, however, anaplastic carcinomas exhibit evidence of epithelial differentiation, as determined by ultrastructural analysis and immunohistochemistry. In some instances, this distinction may be impossible, particularly because some sarcomas may exhibit focal immunoreactivity for cytokeratins.  Treatment and Prognosis. Treatment usually includes a combination of surgery, radiotherapy, and chemotherapy. Even with these combined approaches, prognosis is very poor and is generally comparable to that of anaplastic carcinomas.  Unusual Thyroid Tumors Thymic and related branchial pouch tumors may occur as primary thyroid neoplasms.443 Thymomas occur most commonly in middle-­aged women and probably arise from intrathyroidal thymic remnants. The tumors are generally surrounded by a fibrous capsule with extensions of fibrous tissue into the substance of the neoplasm. They are composed of variable numbers of polygonal to spindle-­shaped epithelial cells and lymphocytes. The differential diagnosis includes anaplastic carcinoma and malignant lymphoma. Anaplastic carcinomas lack the lobular pattern that is typical of thymomas and almost always feature cells with pronounced nuclear atypia and prominent mitotic activity. Lymphomas can be excluded by the absence of cytokeratin positivity. The vast majority of intrathyroidal thymomas behave as benign neoplasms. A separate tumor type is the SETTLE (spindle epithelial tumor with thymus-­like differentiation) tumor (Fig. 7.74).443,444

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Fig. 7.74  Spindle epithelial tumor with thymus-­like differentiation (SETTLE). A, This tumor is composed primarily of spindle-­shaped cells. B, This tumor has a few areas of gland formation.

This tumor occurs primarily in late adolescence. Histologically, the tumor is biphasic, composed of bundles of spindle-­shaped cells that merge into epithelium-­type cells and form cords, tubules, or papillae. Glandular structures lined with mucinous or respiratory-­type epithelium may also be present. The tumor cells, including the spindle cell elements, are positive for cytokeratins. The main entity in the differential diagnosis is synovial sarcoma. Absence of SYT rearrangements distinguish SETTLE from synovial sarcoma.445 The behavior of SETTLE tumors is unpredictable, and delayed metastases may occur many years after excision of the primary tumors. Intrathyroidal thymic carcinomas, previously termed CASTLE (carcinomas showing thymus-­like differentiation) tumors, have also been described, which represents ectopic thymic carcinomas. The mean age at onset is approximately 50 years.443 These tumors most commonly involve the lower poles of the thyroid and extend frequently into the adjacent soft tissues of the neck. Typically, tumors present as firm, lobulated, gray-­ white masses. Tumor cells are of intermediate to large size with vesicular nuclei, coarsely clumped chromatin, and prominent nucleoli. Foci of squamous differentiation may be apparent (Fig. 7.75). Lobules and cords of tumor cells are usually separated by fibrous septa containing lymphocytes and plasma cells. These features distinguish thymic carcinoma from anaplastic thyroid carcinomas. In addition, positive immunostaining for CD5 would support thymic derivation. Nodal metastases occur in approximately 50% of patients and most patients have relatively long survival periods. Teratomas of the thyroid are rare tumors that usually arise in the neck and involve the thyroid gland by direct extension. They have been reported both in neonates and in adults.446 As in other sites, teratomas are composed of derivatives of ectoderm, endoderm, and mesoderm. In neonates and infants, the tumors may attain enormous proportions and typically contain both solid and cystic areas. Although some of the tumors in neonates and infants contain immature elements, the majority pursue a benign clinical course. Teratomas in adults occur somewhat more commonly in females than in males. In contrast to their typically benign behavior in infants, teratomas in adults are most often aggressive neoplasms that pursue a malignant course.447–449 Rosai and colleagues437 suggest that thyroid

teratomas in adults are not germ cell neoplasms, but rather represent malignant neuroepithelial tumors. Paragangliomas of the thyroid gland are exceptionally rare. These tumors most likely arise from paraganglia that may be present within the capsule of the thyroid.27,450 Grossly, they present as encapsulated neoplasms that vary in size from those that are barely visible grossly to those that measure as large as 3 cm in diameter. Typically, they are composed of nests of cells separated by a fibrovascular stroma. Paragangliomas contain chief cells and sustentacular cells; however, the sustentacular cells are difficult to visualize in hematoxylin-eosin–stained sections (Fig. 7.76). Typically, the sustentacular cells are positive for S100 protein, whereas the chief cells are positive for chromogranin A. Ultrastructurally, the chief cells contain typical membrane-­ bound neurosecretory granules. The differential diagnosis includes hyalinizing trabecular tumor, the solid variant of PTC, and medullary thyroid carcinoma. The first two tumors are typically positive for cytokeratins and thyroglobulin, and medullary carcinomas are positive for cytokeratins and calcitonin. Paragangliomas, conversely, are negative for thyroglobulin, calcitonin, and cytokeratins, but contain S100–positive cells surrounding the nests of chief cells. Mucoepidermoid carcinomas rarely may arise in the thyroid gland.451–453 These tumors have been reported to occur over a wide age range, although most occur in the fifth to seventh decades. They tend to be circumscribed but not encapsulated, and are characterized by an admixture of squamous and mucous cells in a solid or cystic pattern. Cribriform areas and foci of necrosis may be evident, and the stroma is typically fibrotic. Mucoepidermoid carcinomas of the thyroid are indolent tumors that tend to metastasize to cervical lymph nodes, a pattern of spread similar to that of PTC. This finding, together with the presence of psammoma bodies, suggests a histogenetic link to PTC. Miranda and colleagues454 reported a follicular variant of PTC that contains foci of mucoepidermoid carcinoma. Both components were also identified in foci of extracapsular invasion and in nodal metastases. Sclerosing mucoepidermoid carcinoma with eosinophilia typically occurs on a background of Hashimoto thyroiditis.455 The tumor is characterized by nests and cords of neoplastic cells embedded in a fibrous stroma containing abundant eosinophils.

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Fig. 7.75  Carcinoma showing thymus-­like differentiation (CASTLE). A, The tumor cells have a plump spindle shape. B, Foci of keratinization are present in this field.

Fig. 7.76  Paraganglioma. The tumor is composed of cell nests in a zellballen pattern. Sustentacular cells cannot be clearly distinguished in this preparation.

Recently, another salivary type carcinoma, secretory carcinoma (previously termed mammary analogue secretory carcinoma or MASC), has been described in the thyroid gland.248,257,456 Thyroid MASCs are morphologically similar to their salivary counterparts and may show solid, cribriform, microcyst, tubular, and focally papillary growth. Histologic features may closely resemble PTC. However, these tumors are

positive for mammaglobin and S100 but negative for thyroid markers (TTF-­1 and thyroglobulin). Even though expression of thyroid markers is lacking, coexisting PTC is observed in some cases and suggests a thyroid follicular cell origin.248 ETV6 rearrangements are present in thyroid secretory carcinoma but are not diagnostic in isolation, as a minority of PTCs are also positive for this translocation.457 Examples with an aggressive

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Fig. 7.77  A, Metastatic poorly differentiated lung adenocarcinoma. B, Metastatic small cell lung carcinoma. The tumor is composed of small cells with hyperchromatic nuclei. C, Metastatic renal cell carcinoma in an adenomatous nodule. D, Metastatic renal cell carcinoma. Collections of red blood cells are present in the centers of the tumor cell nests.

clinical course have been reported.456 Interestingly, a targeted therapy against the NTRK family of genes is now FDA approved for advanced cancers.249 Adenosquamous carcinomas of the thyroid are exceptionally rare neoplasms that are probably unrelated to the aforementioned mucoepidermoid carcinomas.458 Histologically, they are composed of malignant squamous cells with foci of mucin production. Their behavior is identical to that of anaplastic thyroid carcinomas.  Secondary Tumors Secondary involvement of the thyroid by tumor may occur as a result of direct extension from contiguous structures, such as the larynx, or as a result of hematogenous spread. Autopsy studies have revealed thyroid metastases in as many as 20% of patients with disseminated carcinomatosis, with breast, lung, and skin (melanoma) being the most common primary sites (Fig. 7.77).459 In a clinical series, nearly half of metastases are from renal cell carcinomas. Colorectal, lung, breast, and sarcomas metastases are also common.460 In many cases, the metastasis occurs after a long interval following the primary diagnosis. This suggests that the appearance of a new thyroid mass in a patient with a known history of cancer should be considered as a potential metastatic site.

Metastases from clear cell kidney carcinomas may be extremely difficult to differentiate from primary clear cell tumors of the thyroid (see Fig. 7.77C and D).459,461 The latter tend to be single, whereas metastases are more commonly multiple; moreover, metastases tend to have prominent degrees of vascularity. Immunohistochemical staining for thyroglobulin and TTF-­1 is typically negative in metastatic tumors; however, residual normal follicular cells that can be entrapped within the tumor may be positive. PAX8 is not a useful marker as it is positive in both renal cell carcinoma and primary thyroid carcinomas. 

Parathyroid Glands EMBRYOLOGY The parathyroid glands are first recognizable at 5 to 6 weeks of development (8–9 mm embryonic stage) as thickenings of the anterodorsal branchial pouch epithelium.2,462 The superior pair of glands, termed parathyroid IV, develop from the fourth brachial pouch together with the ultimobrachial body. Typically, parathyroid IV are fairly constant in their final position close to the point at which the inferior thyroid artery crosses the recurrent laryngeal nerve at the cricothyroid junction. In contrast, the

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Fig. 7.78  Normal adult parathyroid gland. Chief cells have relatively small hyperchromatic nuclei with focally vacuolated cytoplasm. Oncocytes have abundant eosinophilic cytoplasm. A small amount of stromal fat is present in the field.

inferior parathyroids (termed parathyroid III), together with the thymus, are derived from the third pouch. Both the thymus and parathyroid III have a complex pattern of migration before they assume their final position caudad to the derivation of the fourth pouch. Failure of separation of parathyroid III from the thymus results in its appearance in the lower neck within the thymic tongue, anterior mediastinum, or, rarely, in the posterior mediastinum. Early separation of parathyroid III from the thymus, conversely, may result in its final position cephalad to parathyroid IV. Because of these features, parathyroid III may be found from the angle of the jaw to the pericardium.  ANATOMY AND PHYSIOLOGY Most adults have four parathyroid glands; approximately 13% have more than four and 3% have only three glands.463 Normal parathyroid glands most often appear as flattened, ovoid, or bean-­shaped structures ranging from 4 to 6 mm in length, 2 to 4 mm in width, and 1 to 2 mm in thickness. The average combined weight of the glands is 120 ± 3.5 mg for males and 142 ± 5.2 mg for females, with no single gland over 60 mg.464 The superior parathyroid glands (IV) are most commonly found within a circumscribed area 1 cm from the intersection of the recurrent laryngeal nerve and the inferior thyroid artery.465 Sometimes glands may be found tucked in along the thyroid parenchyma and, rarely, entirely within the thyroid gland. The superior parathyroids also may occasionally be present within the carotid sheath, in the retroesophageal or retropharyngeal space. The inferior parathyroids (III) exhibit considerably more variation in their anatomy than the superior parathyroids. Sixty-­ one percent of the inferior glands are inferior, posterior, or lateral to the lower pole of the thyroid, whereas 17% are located higher on the anterior aspect of the thyroid. Other sites for the inferior glands include the thyrothymic ligament, cervical or lower thymus, and lower mediastinum. The arterial supply of the parathyroid glands is derived from branches of the superior thyroid artery (parathyroid IV) and inferior thyroid artery (parathyroid III). Venous drainage of the upper glands occurs via the superior or lateral thyroid vein, whereas drainage of the lower glands occurs via the lateral

or inferior thyroid vein. Lymphatic drainage originates from a subcapsular plexus into the superior deep cervical, pretracheal, paratracheal, retropharyngeal, and inferior deep cervical nodes. The parathyroid parenchymal cells include chief cells, varying numbers of oncocytes, and transitional oncocytes (Fig. 7.78).464 The chief cells are often polyhedral (6–8 μm in diameter). The nuclei are round and centrally located, with coarse chromatin and sharp nuclear membranes. The cytoplasm is faintly eosinophilic and may appear clear or vacuolated. Ultrastructurally, resting chief cells have relatively straight plasma membranes; increased functional activity is associated with greater tortuosity of the membranes. Chief cells contain moderate numbers of mitochondria as well as secretory granules. Prosecretory granules have a diameter of 0.2 μm and are located adjacent to the Golgi regions. Mature secretory granules are larger at 0.3 μm. Resting chief cells contain frequent, fine lipid droplets and relatively abundant glycogen.466 Oncocytes are larger at 12 μm in diameter and have a densely eosinophilic granular cytoplasm (Fig. 7.79). The nuclei tend to be larger and more vesicular than those found in chief cells. Ultrastructurally, oncocytes contain numerous mitochondria with relatively few secretory granules. Transitional oncocytes are smaller and less eosinophilic than oncocytes and contain fewer mitochondria between chief cells and oncocytes. The oncocytes appear first at puberty and increase in number with advancing age. Oncocytic nodules may be particularly prominent in the parathyroid glands of elderly individuals. When parathyroid cells produce excess glycogen, the cytoplasm becomes clear with well-­defined borders described as the water clear cell. This histologic finding is quite uncommon. Chief cells and oncocytes contain cytokeratins as the major intermediate filament, whereas vimentin is restricted to stromal cells.467 Parathyroid hormone may be identified by immunohistochemistry in all secretory cell types.468 The chief cells also contain parathyroid hormone secretory protein, which can be demonstrated with antibodies to chromogranin A.470 GATA binding protein 3 is also expressed in the nucleus of parathyroid cells.469,471 The stroma within the gland includes mature adipocytes, blood vessels, and connective tissue, which tends to increase with the age of the individual. Until adolescence, the amount of stromal adipose is minimal, although it tends to appear in

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Fig. 7.79  Normal adult parathyroid. The oncocytes have abundant granular eosinophilic cytoplasm.

TABLE

7.2

Diagnostic Criteria for Noninvasive Follicular Thyroid Neoplasm With Papillary-­Like Nuclear Features

FEATURES PRESENT IN NIFTP Follicular patterned (30% Necrosis Mitosis >3 per 10 high-­power fields NIFTP, Neoplasm with papillary-­like nuclear features.

higher amounts in obese children. The number of adipocytes increases until the age of 25 to 30 years. In older individuals, the amount of adipose tissue is determined largely by constitutional factors and may represent up to 80% of the cellular mass.472 Stromal fat is often irregularly distributed throughout the gland, and polar regions tend to be richer in fat than more central regions. Biopsies in the polar regions, therefore, may give spuriously high stromal fat-­to-­parenchymal ratios. Parathyroid hormone is an 84 amino acid peptide with a molecular weight of 9500.473 It is encoded by a gene on the short arm of chromosome 11. The hormone is synthesized as a 115 amino acid–containing precursor, pre-­ /proparathyroid hormone. This precursor enters the endoplasmic reticulum where the 25 amino acid–containing N-­terminal portion of the molecule is cleaved. The resultant intermediary protein, proparathyroid hormone, is subsequently transported to the Golgi region where cleavage of the hexapeptide-­containing N-­terminal segment of the molecule occurs. As a result, proparathyroid hormone is converted to parathyroid hormone. The levels of calcium and phosphorus are controlled by the actions of parathyroid hormone, calcitriol, and calcitonin.473 The normal adult serum concentration of calcium ranges from 8.9 to 10.1mg/dL. The normal serum calcium range in children

and teens is slightly higher based on age. In the extracellular fluid, 46% of the calcium is bound to protein, 48% is present as ionized calcium, and the remainder is associated with diffusible ion complexes. The most important regulator of the synthesis and secretion of parathyroid hormone is ionized calcium. Increased levels of ionized calcium inhibit the synthesis of parathyroid hormone, whereas decreased levels of calcium stimulate its synthesis. Parathyroid hormone maintains serum calcium levels by promoting calcium entry into the blood from bone, kidney, and the gastrointestinal tract. In bone, it stimulates bone resorption and inhibits bone formation. By stimulating renal synthesis of calcitriol, parathyroid hormone favors gastrointestinal absorption of calcium. In the kidney, parathyroid hormone stimulates resorption of calcium, enhances clearance of phosphate, and promotes an increase in the enzyme that is important in the production of active vitamin D.  HYPERPARATHYROIDISM Hyperparathyroidism is a metabolic derangement characterized by increased production of parathyroid hormone.474 Serum calcium may be decreased, increased, or normal depending on renal function and other factors. In primary hyperparathyroidism, excess parathyroid hormone is produced by the parathyroid gland, which may pathologically be an adenoma (∼85%), hyperplasia (10–15%), or carcinoma (H>>K)

TERT Promoter

ALK Fusions

NTRK Fusions

All PTC histologies

30%–90%

5%–35%

0%–35%

5%–25%

0%–5%

0%–5%

Conventional

45%–80%

5%–25%

0%–15%

5%–15%

n/a

n/a

Follicular variant

5%–25%

5%–25%

15%–35%

5%–15%

n/a

n/a

Tall cell

60%–95%

50% drop at 5 or 15 minutes post removal of the parathyroid supports autonomous adenoma function. In some series, intraoperative parathyroid hormone assays have been as much as 96% effective in predicting successful removal of the abnormal gland.521 Rates of recurrent disease in patients with adenomas are very low; however, recurrent hyperparathyroidism can occur because of incomplete removal of the adenoma or spillage of tumor tissue at the time of primary surgery. The traditional four-­ gland exploration is typically reserved for nonlocalized glands by imaging, redo surgeries for persistent hyperparathyroidism, and in cases where hyperplasia is suspected (such as in young patients with possible MEN 1).  PARATHYROID CARCINOMA Clinical Features and Pathogenesis. Parathyroid carcinoma is a rare neoplasm that accounts for 0.5% to 2% of all cases of hyperparathyroidism. Most cases occur in the fifth or sixth decade, although rare cases have been reported in adolescence.522 This tumor has a high probability of local recurrence and the potential to metastasize late in its course to regional nodes and distant sites. The sex ratio of patients with parathyroid carcinoma is approximately equal in contrast to adenomas, which predominate in women. Most affected patients have serum calcium levels in excess of 14mg/dL, although occasional tumors may be nonfunctional.523 Severe metabolic complications tend to be more common in patients with carcinomas than in those with adenomas. Although the etiology remains unclear in the majority

B

Fig. 7.89  Parathyroid lipoadenoma. A, The stromal component of this tumor is composed of fat and fibromyxoid tissue. B, The chief cells are arranged in thin branching cords.

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of patients, hereditary factors are now known to be present in a subset of patients carrying germline alterations in the CDC73 gene. Rarely, parathyroid carcinomas have followed irradiation to the head and neck,524 and a few cases were reported in patients with secondary hyperparathyroidism.525 Comparative genomic hybridization studies have demonstrated losses of 1p and 13q in more than 40% of parathyroid carcinomas.526 Based on their studies, Kytola and colleagues526 suggest a model of progression characterized by early gains of Xq and 1q followed by loss of 13q, 9p, and 1p and by gain of 19p. Losses of 1p, 4q, and 13q and gains in 1q, 9q, 16p, 19p, and Xq were significantly more common in carcinomas than in adenomas. Loss of 11q13, the most common abnormality found in adenomas, was undetectable in carcinomas. This finding suggests that adenomas developing along the MEN 1 pathway have a slight potential for progressing to carcinomas.526 Several groups demonstrated LOH on chromosome 13q, a region that includes the RB and BRCA1 genes. In the series reported by Cryns and colleagues,527 11 of 11 carcinomas and 1 of 19 adenomas lacked an RB allele. The BRCA gene has also been suggested as a candidate tumor suppressor gene that may have a role in the development of parathyroid carcinomas. However, the contribution of these genes to the development of carcinomas has been controversial.528 Genetic susceptibility for parathyroid carcinoma has the strongest ties with the tumor suppressor gene CDC73 germline and/or sporadic mutations. Parathyroid carcinoma occurs in 10% to 15% of affected germline carriers. The role of the CDC73 gene (formerly termed HRPT2) in the development of parathyroid carcinomas was first demonstrated by Howell and colleagues529 in 2003. In the same year, Shattuck and colleagues530 demonstrated CDC73 mutations in parathyroid carcinomas in 10 of 15 patients. The mutations predicted inactivation of its coding protein parafibromin. Subsequent studies show a 50% sensitivity for parafibromin loss, defined as 4:1, prominent irregular nuclear membranes, hyperchromasia, and prominent nucleoli.510 Staging systems previously precluded parathyroid carcinomas secondary to the limited number of cases and lack of sufficient evidence for correlation with outcomes.550,551 The eighth edition of the AJCC now includes a chapter on parathyroid neoplasm, which includes atypical parathyroid neoplasm of uncertain malignant behavior as Tis.510 T classification is based on tumor extent, with soft-tissue extension being separated from thyroid gland and nerve invasion (as well as other adjacent structures). Metastasis appears to be the predominant factor contribution to poor overall survival.552  Treatment and Prognosis. Clinical (markedly elevated parathyroid hormone and severe hypercalcemia) and/or intraoperative suspicion of parathyroid carcinoma should prompt resection without disruption of the capsular region and may require resection of the thyroid lobe.550,551 Regional lymph node dissection is generally reserved for those patients with documented metastases. Recurrences are usually apparent within 3 to 5 years of primary surgery. Metastatic disease develops in approximately one-­third of patients, with common sites of involvement including the lung, cervical lymph nodes, and liver. Most of the patients with metastases eventually die of the effects associated with excessive parathyroid hormone production. The 5-­year survival rate is 85% and the 10-­year survival rate is 50%.553  PRIMARY CHIEF CELL HYPERPLASIA

C Fig. 7.91  Parathyroid carcinoma. A, This tumor directly invaded the soft tissue of the neck. B, This tumor invaded a large vascular channel. C, This tumor directly invaded the thyroid gland.

Immunohistochemical evaluation for galectin 3 and PGP9.5 have also been highly expressed in some parathyroid carcinomas,544–547 whereas weak or negative staining for APC, CDKN1B, and Rb have also been described.547,548

Clinical Features and Pathogenesis. The term primary chief cell hyperplasia refers to an absolute increase in parenchymal cell mass resulting from a proliferation of chief cells, with variable numbers of oncocytes and transitional oncocytes in multiple parathyroid glands in the absence of a known stimulus for parathyroid hormone hypersecretion.475 This disease was first recognized as a cause of primary hyperparathyroidism in 1958.554 Primary chief cell hyperplasia accounts for approximately 15% of all cases of primary hyperparathyroidism and is more common in women than men (3:1 ratio). Approximately 75% of patients with this disorder have apparent sporadic disease, and the remainder have isolated familial hyperparathyroidism or one of the MEN syndromes (see Table 7.4). At least 90% of patients with dominantly inherited MEN 1 will have evidence of primary hyperparathyroidism. In addition to parathyroid disease, patients with MEN 1 also have gastroenteropancreatic and pituitary tumors. Other tumors occurring in these patients include carcinoids of the lung, stomach, and thymus, and adrenal cortical tumors, lipomas, and facial angiomas and collagenomas. Thirty percent to 40% of patients with MEN 2A also have evidence of chief cell hyperplasia. Parathyroid proliferative disease does not occur in patients with MEN 2B or familial medullary thyroid carcinoma.

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673

Fig. 7.92  Nodular chief cell hyperplasia in a patient with multiple endocrine neoplasia type 1. The gland contains multiple nodules of chief cells.

Identification of patients with these syndromes can be accomplished by the use of molecular diagnostic procedures. As discussed in the section on familial medullary thyroid carcinoma, dominant activating germline mutations have been identified in the RET proto-­oncogene (10q11.2) in patients with MEN 2A and MEN 2B and familial medullary thyroid carcinoma.372 The gene for MEN 1, conversely, was localized to chromosome 11q13. This gene contains 10 exons and encodes a ubiquitously expressed 2.8kb transcript.555 The predicted 610 amino acid protein product, termed menin, exhibits no similarities to any previously known protein. The gene belongs to the tumor suppressor gene family, and a variety of loss-­of-­function mutations have been identified in affected individuals.555 In patients with MEN 1, an inherited mutation leads to inactivation of one copy of the gene followed by deletion or mutation of the second copy of the gene. Sporadic tumors of the types occurring in MEN 1, by comparison, result from two sequential mutations of the gene in a single somatic cell.556 Approximately 50% to 60% of parathyroid lesions in MEN 1 harbor clonal allelic losses of chromosome 11q13 similar to those in pancreatic tumors from patients with MEN 1.557 Allelic losses tend to occur in parathyroid lesions that are larger than those without such losses. These findings suggest that the development of parathyroid lesions in MEN 1 may be preceded by phases of polyclonal hyperplasia without allelic losses and that hyperplasia in these instances might occur as a result of diminished function of the inherited mutant allele. Hyperplasia could result from an abnormal response of parathyroid tissue to physiologic stimuli or to the presence of an abnormal circulating factor. In this regard, Brandi558 described a circulating mitogen for parathyroid endothelial cells in the sera of MEN 1 patients.  Pathologic Features and Differential Diagnosis. Symmetric enlargement of all glands occurs in approximately one-­half of patients with primary chief cell hyperplasia, whereas the remainder have evidence of asymmetric glandular enlargement.559,560 The former pattern of hyperplasia has been

termed classic hyperplasia, and the latter has been referred to as pseudoadenomatous hyperplasia. Occult hyperplasia refers to minimal enlargement of all glands. Total gland weight varies considerably in cases of hyperplasia, with 54% weighing less than 1 g, 28% weighing 1 to 5 g, and 18% weighing 5 to 10 g. The predominant cell in this form of primary hyperplasia is the chief cell, although variable numbers of oncocytes and transitional oncocytes are also evident. Stromal fat cells are usually markedly reduced. However, because of the regional variations in stromal fat cells, small biopsy samples of hyperplastic glands may show a relatively high ratio of stromal fat cells to chief cells. The proliferation of chief cells may occur either in a diffuse or nodular pattern (Figs. 7.92 and 7.93). The nodular pattern is more common and may be particularly evident in the early phase of the disease. Hyperplastic chief cells may be arranged in solid sheets, cords, or follicles. Occasional cases of chief cell hyperplasia have abundant stromal fat cells, and biopsies of such glands may lead to an erroneous diagnosis of a normocellular gland if the pathologist is not aware of the gland size. Strauss and colleagues561 introduced the term lipohyperplasia to describe hyperplastic glands with abundant stromal fat. Multifocal aggregates of hyperplastic chief cells may be evident in the soft tissues of the neck or mediastinum in patients with primary hyperparathyroidism or occur after primary resection with disruption of the parathyroid during surgery.562 These lesions, which are referred to as parathyromatosis, may be responsible for persistent or recurrent hyperparathyroidism in patients treated by subtotal parathyroidectomy for primary chief cell hyperplasia. Chronic parathyroiditis is rarely found in association with primary chief cell hyperplasia.563 Although the origin of the lymphocytic infiltration is unknown, it was suggested that this disorder may have an autoimmune origin. Cystic changes in primary chief cell hyperplasia are uncommon and, when they occur, they usually involve markedly enlarged hyperplastic glands.564,565 An unusual familial variant of primary cystic chief cell hyperplasia was also reported.566

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Fig. 7.93  Nodular chief cell hyperplasia (same case as Fig. 7.92). The stroma in the diffusely hyperplastic area contains a few fat cells. The nodular focus is devoid of fat cells.

Fig. 7.94  Clear cell hyperplasia. The cells have extensively vacuolated cytoplasm.

The major differential diagnosis is parathyroid adenoma. As discussed in a previous section, parathyroid adenomas most commonly involve a single gland, whereas chief cell hyperplasia involves multiple glands.  Treatment and Prognosis. The treatment of primary chief cell hyperplasia is subtotal parathyroidectomy or total parathyroidectomy with grafting of approximately 100 mg of parathyroid tissue into the forearm.567 The rate of recurrent hyperparathyroidism in patients treated by subtotal parathyroidectomy is approximately 15%. Cases of recurrent disease may be due to failure to recognize and remove supernumerary or ectopic glands, the presence of parathyromatosis, or inadvertent implantation of hyperplastic parathyroid tissue into the soft tissues of the neck. In cases of recurrent disease, proliferation of autografted parathyroid tissue may be extreme enough to simulate malignancy.568  PRIMARY CLEAR CELL HYPERPLASIA Clinical Features and Pathogenesis. Primary clear cell hyperplasia is a rare disorder characterized by an absolute increase in parathyroid parenchymal cell mass resulting from

a proliferation of vacuolated water clear (wasserhelle) cells in multiple parathyroid glands in the absence of a known stimulus for parathyroid hormone hypersecretion.476,569 There is no apparent familial incidence of the disease, and no known association with any of the MEN syndromes. The degree of hypercalcemia tends to be greater in patients with clear cell hyperplasia than in those with chief cell hyperplasia.  Pathologic Features and Differential Diagnosis. Most patients with primary clear cell hyperplasia have enlargement of all four parathyroid glands. The glands are typically red-­brown to brown with foci of cystic change, hemorrhage, and fibrosis.476 The latter changes tend to involve the largest glands. Upper glands tend to be larger than lower glands. Clear cell hyperplasia typically involves the glands in a diffuse fashion. Individual cells have multiple, small cytoplasmic vacuoles that are thought to be derived from the Golgi vesicles (Fig. 7.94). The extensive cytoplasmic vacuolization is responsible for the clear cytoplasmic appearance.570 Nuclei are round to ovoid and moderately hyperchromatic, with an eccentrically placed nucleolus. The differential diagnosis includes parathyroid adenoma, clear cell thyroid tumors, and metastases of clear cell carcinoma, particularly of renal origin. The absence of thyroglobulin and

7  Thyroid and Parathyroid Glands

A

675

B

Fig. 7.95  Secondary hyperparathyroidism. A, The gland exhibits both diffuse and nodular hyperplasia. B, Some of the nodules are composed of oncocytes exclusively.

calcitonin, which are typically found in follicular and C-­cell tumors, respectively, and of parathyroid hormone or chromogranin A, which are typically found in parathyroid lesions, should raise the possibility of metastatic disease.  Treatment and Prognosis. The treatment of choice for patients with clear cell hyperplasia is subtotal parathyroidectomy. The rate of recurrence and long-­ term prognosis are not well established because of the rarity of the disease.  SECONDARY HYPERPARATHYROIDISM Clinical Features and Pathogenesis. Secondary hyperparathyroidism refers to an adaptive increase in parathyroid parenchymal mass resulting from a proliferation of chief cells, oncocytes, and transitional oncocytes in multiple parathyroid glands in the presence of a known stimulus of parathyroid hormone secretion, most commonly low levels of ionized calcium in the blood.473 The most common cause of secondary hyperparathyroidism is chronic renal failure. Other causes include dietary deficiency of vitamin D, other abnormalities of vitamin D metabolism, and pseudohypoparathyroidism. Once the process of parathyroid hyperplasia begins, the set point for the control of parathyroid hormone secretion by ionic calcium increases, and this leads to further parathyroid hyperplasia and hypersecretion of parathyroid hormone.571 The major clinical manifestations include bone pain and skeletal deformities (renal osteodystrophy), muscle weakness, growth retardation, and extraskeletal calcification. Although the parathyroid changes that occur in patients with secondary hyperparathyroidism are classified as hyperplasias, molecular studies indicate that some of the proliferations are monoclonal.572,573 It is possible that clonal lesions in the setting of secondary hyperplasia may have greater autonomy than polyclonal lesions, but the exact significance of clonal proliferations remains to be determined.  Pathologic Features and Differential Diagnosis. The gross appearance of the glands is generally similar to that seen in patients with primary chief cell hyperplasia.574,575 Generally, however, there is a greater uniformity of gland size than in

patients with primary hyperplasia, particularly in the early stages of the disease. With prolongation of the stimulus for parathyroid hormone hypersecretion, there is a tendency for a greater degree of variation in gland size. In a large series of cases reported by Roth and Marshall,575 the weight of the glands varied from 120 mg to 6 g. The earliest change in the glands is a decreased number of fat cells and their replacement by widened cords and nests of chief cells. Typically, the proliferating chief cells are present in diffuse sheets, but other areas may show cordlike, acinar, or trabecular growth patterns. Prominent mitotic activity may be evident. Advanced stages of secondary hyperplasia are characterized by nodular proliferations of chief cells and oncocytes (Fig. 7.95). The proliferation of oncocytic cells may be particularly striking. In some instances, the foci of nodular proliferation may be surrounded by a fibrous capsule. Areas of hemorrhage, calcification, chronic inflammation, and cyst formation may be evident, particularly in large glands. Parathyromatosis may be responsible for the recurrence of hyperparathyroidism after parathyroidectomy in patients with chronic renal failure.576 The etiology of postsurgical parathyromatosis is the seeding of parathyroid tissue in the soft tissue of the neck after surgical manipulation. Parathyromatosis may also occur as a result of developmental dispersion of parathyroid tissue in the neck or mediastinum (ontogenous parathyromatosis). The differential diagnosis includes primary chief cell hyperplasia, parathyroid adenoma, and parathyroid carcinoma. Primary and secondary hyperplasia cannot be distinguished based on gross or microscopic examination. The clinical history is essential to make this distinction. As noted in previous sections, parathyroid adenoma typically involves a single gland, whereas secondary hyperplasia involves multiple glands. Glands from patients with long-­standing secondary hyperplasia may, on occasion, be difficult to distinguish from those with parathyroid carcinoma. The glands from both conditions may exhibit extensive fibrosis, hemorrhage, and mitotic activity. Hyperplastic glands, however, lack the infiltrative properties of parathyroid carcinomas.  Treatment and Prognosis. Surgical treatment is indicated in cases of secondary hyperplasia when medical management fails to control progressive skeletal symptoms, pruritus, and

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Fig. 7.96  Parathyroid cyst. The cyst is lined with glycogen-­rich chief cells with a clear appearance.

extraskeletal calcification.576 Subtotal parathyroidectomy is the treatment of choice. Approximately 50 mg of parathyroid tissue is left in situ in the neck or is autotransplanted into the forearm. Recurrent hyperparathyroidism is generally treated by excision of the parathyroid remnant or the engrafted tissue. In some instances, the proliferation of autografted tissue may be extreme enough to simulate malignancy.568  TERTIARY HYPERPARATHYROIDISM The term tertiary hyperparathyroidism refers to the development of autonomous parathyroid hyperfunction in patients with previously documented secondary hyperparathyroidism.578 The mechanisms for the development of tertiary hyperparathyroidism are unknown, although several studies suggested that it may result from a calcium set point error. According to this hypothesis, the cellular response function is shifted away from normal toward higher calcium concentrations. Parathyroid chief cells, which have higher set points of suppression, increase their biosynthetic and secretory activities and are stimulated to divide even at normal calcium concentrations. This sequence of events leads to an increased parenchymal cell mass. In the series of cases studied by Krause and Hedinger,579 only 5% of the patients had adenomas. The hyperplasia was predominantly diffuse in 44%, and the remaining patients had nodular hyperplasia. Glands with nodular hyperplasia were larger than those with diffuse hyperplasia. Patients with tertiary hyperparathyroidism are generally treated by subtotal parathyroidectomy.577  SECONDARY TUMORS Secondary involvement of the parathyroid gland by tumor may occur by direct extension from adjacent structures such as the thyroid or larynx or lymphatic and hematogenous spread. Historically metastases to the parathyroid glands were found in 6% to 12% of autopsy studies.580,581 The most common sites of origin were the breast, skin (melanoma), and lung. Hypoparathyroidism resulting from tumorous involvement of these parathyroids is rare. 

PARATHYROID CYSTS Cystic lesions of the parathyroid glands may develop as a result of degeneration of adenomas or hyperplastic glands. Some cysts of the parathyroid have a developmental origin. Cysts containing thymus and parathyroid are sometimes referred to as third pharyngeal pouch cysts.582 Parathyroid cysts are loosely attached to the thyroid, and their walls are typically gray-­white and translucent.583,584 The cyst fluid is usually thin, watery, and straw colored. One hypothesis for their development suggests that they may represent persistent Kürsteiner canals, which are found in association with the developing parathyroid. The wall is composed of fibrous connective tissue, and the cysts are usually lined with cuboidal cells of chief cell origin (Fig. 7.96).  HYPOPARATHYROIDISM AND PSEUDOHYPOPARATHYROIDISM Deficiency of parathyroid hormone results in hypocalcemia, hypocalciuria, and hypophosphatemia. Clinically, hypoparathyroidism is characterized by increased neuromuscular excitability, mental changes, calcifications in the basal ganglia, and lens and cardiac conduction abnormalities. The most common cause of hypoparathyroidism is inadvertent excision or devascularization of the glands during thyroid or parathyroid surgery. Congenital abnormalities involving maldevelopment of the third and fourth pharyngeal pouches (DiGeorge syndrome) may also be associated with neonatal hypoparathyroidism.585 Autoimmune processes may involve the parathyroid gland and may result in hypoparathyroidism. In patients with type I polyglandular autoimmune disease, there is evidence of hypoparathyroidism, Addison disease, and mucocutaneous candidiasis.586 Affected individuals may also have evidence of insulin-­dependent diabetes mellitus, primary hypogonadism, autoimmune thyroid disease, or pernicious anemia. Histologically, autoimmune parathyroid disease is characterized by glandular atrophy and lymphocytic infiltration. Infiltrative processes such as amyloidosis may also involve the parathyroid glands and may give rise to hypoparathyroidism.

7  Thyroid and Parathyroid Glands

Genetic disorders that may be inherited as dominant, recessive, or X-­linked traits have also been implicated in the development of some forms of hypoparathyroidism. Some of these disorders have been traced to mutations in the gene encoding parathyroid hormone. The term pseudohypoparathyroidism is used to describe patients with hypocalcemia, hyperphosphatemia, increased plasma levels of parathyroid hormone, and unresponsiveness of target tissues to the effects of parathyroid hormone.587

677

Affected patients typically have mental retardation, short stature, multiple defects in bone development, and soft-tissue calcifications (Albright hereditary osteodystrophy). Affected patients also demonstrate resistance to other hormones (type Ia). The term pseudo-­ pseudohypoparathyroidism refers to patients with the phenotype of Albright hereditary osteodystrophy but with normal biochemical parameters. Parathyroid glands in pseudohypoparathyroidism disorder are hyperplastic.588

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Bone Lesions GILLIAN HALL  |  JOHN WRIGHT

Benign Bone Tumors OSTEOMA Osteoma occurs almost exclusively in the head and neck region, only rarely developing elsewhere. Its reported incidence varies considerably, depending on the population studied, ranging from 0.002% in patients attending an otolaryngologic clinic to 3% among patients with sinonasal inflammatory disease.1 The true incidence is unknown, however, because only approximately 10% of osteomas are symptomatic.2 Clinical Features. Osteomas are most frequently diagnosed in the second to fourth decades of life, being uncommon in the first decade. The average patient age has varied from 25 to 35 years.2,3 Paranasal sinus osteomas are more common in male patients.2–4 Osteoma is frequently an incidental finding in radiologic evaluations for other problems of the head and neck.1,3,5 Symptoms may be quite diverse depending on the lesion’s location and include chronic sinusitis, local pain, headache, nasal obstruction, a painful or painless mass, exophthalmos, focal facial asymmetry, difficulty opening the mouth, meningitis, and hearing loss or a sensation of ear plugging.1,6 Surface lesions that protrude from the bone are more likely to cause symptoms than those confined within the central medullary cavity. The most common site of origin is the paranasal sinuses,1–2,5,6 with the frontal sinus (Fig. 8.1A) the most frequent location1–3 and the ethmoid, maxillary, and sphenoid sinuses involved in descending order of frequency.3,6 Osteomas also arise from either the inner or outer tables of the cranial bones,7–9 including the mastoid, and middle ear, and the jaw bones (Fig. 8.1B), especially the mandible.7,9–6 Extraskeletal osteomas occur in the buccal mucosa, tongue,12 and nasal cavity.6 However, these are not true neoplasms and are termed choristomas.13 Radiologically, an osteoma typically appears as a dense, opaque, sharply defined mass that is usually broad based1,3,6 and ranges from less than 1 to 8.5 cm in maximum size.1,6 An important clinical feature of head and neck osteomas is their association with Gardner syndrome and familial adenomatous polyposis.5,9–7 In this association, the osteomas tend to be multiple and most frequently arise in the mandible, especially at the mandibular angle,9–11 and in the maxilla. Osteomas may be the first manifestation of these syndromes and occur as early as 10 years before the discovery of the intestinal polyps.5,10  Pathologic Features. Histologically, most osteomas are composed of hard, dense, compact lamellar bone, similar to cortical bone, in which Haversian systems are present (Fig. 8.2). Cement lines may be prominent, with densely stained parallel accretion lines at the peripheral margin. These so-­called

ivory or compact osteomas have little stroma, and that which is present consists of bland fibrous tissue. Osteomas may also be composed predominantly of mature lamellar trabecular bone between which fat and marrow elements are found.1,6,14,15 Osteomas on the surfaces of the bones forming the paranasal sinuses bulge into the sinus cavity covered by sinus mucosa.  Treatment and Prognosis. Osteomas found incidentally in asymptomatic patients need not be removed because follow-­up studies frequently have shown no increase in size over several years’ duration.2 For symptomatic lesions, local excision is curative in almost all cases,2,5,6 although rare recurrences after several years are reported.2,5,6  OSTEOID OSTEOMA Clinical Features. Most patients with osteoid osteoma are in the second decade of life, with approximately 75% between the ages of 5 and 30 years; mean and median ages range from 12 to 17 years.7,8,16–13 Male patients outnumber female patients in a ratio of 2:1 to 3:17,8,16,17; in spinal osteoid osteomas, this ratio is 6:1.18 In the head and neck, the cervical spine is the most common site,18,19 with other locations, including the mandible,8,20 maxilla,20,21 and various skull bones.22–24 Overall, however, osteoid osteoma is uncommon in the head and neck. Among 861 cases in four series, only 18 (2.1%) were so situated.7,8,14,16 In the spine, the tumor usually arises from the posterior elements, with the base of the transverse process, the lamina, and the pedicle being the most common sites; the vertebral body is only rarely involved.18,19 Pain is virtually a universal symptom in patients with osteoid osteoma, with only rare cases being painless.19 The pain is usually most severe at night and is frequently dramatically relieved by aspirin. Patients with cervical spine involvement may have limitation of neck movement or a scoliosis associated with torticollis. Neurologic symptoms and signs with reflex changes and muscle atrophy also occur.18,19 First-­bite syndrome, excruciating pain felt at the first bite of each meal, has been described in temporal bone lesions.25 In the absence of abnormal radiologic studies, the duration of symptoms before diagnosis may be quite long, with some patients having symptoms for several years.18,19 Patients have been referred for psychiatric evaluation because of their persistent complaint of unexplained pain.19,23 Osteoid osteoma should be considered in any young patient who has persistent neck pain or painful scoliosis, and appropriate radiologic studies should be instituted. Conventional radiographs of osteoid osteoma in its active proliferative phase show a lucent, round to oval area, the nidus, surrounded by a zone of dense bone (Fig. 8.3). The size of the lesion is determined by the size of the nidus, not including the 689

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Fig. 8.1  A, Radiograph of the skull shows a well-­circumscribed, diffusely dense, ovoid ivory osteoma in the right frontal sinus. B, Radiographic view of the mandible shows a homogeneously dense, slightly lobulated mass adherent to the cortex, consistent with a surface-­based osteoma.

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Fig. 8.2  A, Osteoma of frontal sinus. Compact and trabecular bone is present beneath intact mucosa at the left of the field. B, Compact cortical-­ type bone of the osteoma shown in (A) contains Haversian systems.

surrounding sclerotic bone. Although most osteoid osteomas are 1 cm or less in maximum size, some authors have accepted lesions as large as 1.5 to 2 cm as osteoid osteoma.26,27 This radiographic pattern, combined with the clinical presentation, is virtually diagnostic of osteoid osteoma. However, routine radiographic studies may either fail to show the lesion or show a lesion without the typical pattern.18,19,26,28 Bone scans are the most sensitive method for discovering the lesion, with increased radionuclide uptake found in all cases19,26,28; computed tomography (CT) scans are also more sensitive and accurate than routine radiographs for locating the lesion and showing its extent.28 Over time, the nidus becomes increasingly calcified and ossified and eventually may become completely opaque. The nidus may be located within the cancellous bone or cortex or beneath the periosteum.7,27,29,30 An intracortical location is most frequent, and here the nidus expands to reach the periosteum, where it induces the production of extensive, and highly

dense, new bone that surrounds and extends for a considerable distance on either side of the nidus.27 Osteoid osteomas confined to the spongiosa may have little or no reactive bone about them, a situation often found in vertebra-­based lesions.26  Pathologic Features. In its active growth phase, in which there is considerable vascularity, osteoid osteoma grossly appears as a discrete, round to oval lesion marked by a cherry-­ red or reddish-­brown color.31 In this phase, it is quite granular and friable and easily displaced from the adjacent bone.31 In its mature phase, in which there are more calcification and bone production, the lesion is hard and gritty and blends with the bone around it. Histologically, the nidus consists of active new bone, in various stages of maturity, within a loose fibrous stroma that contains numerous dilated thin-­walled blood vessels (Fig. 8.4).8,15,27,31 Seams of osteoid are present that are lined with plump osteoblasts, lacking pleomorphism or atypia (see Fig. 8.4B). Occasionally,

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osteoblasts are found that have large hyperchromatic nuclei in association with brisk, but normal, mitotic activity.15 The osteoid gradually undergoes calcification and conversion to woven and mature bone. Active osteoclastic activity is also present, so that one may find simultaneous new bone production and bone resorption, which eventually results in bone that has a mosaic, pagetoid appearance.8,27 In some lesions, the nidus consists entirely of osteoid arranged in broad sheets with focal calcification; other lesions contain calcium and woven bone. The center is usually the most highly mineralized portion of the lesion. The periphery of the nidus may have mature bone trabeculae that form an anastomotic or interlacing network that fuses with either the normal cortical bone or, if present, adjacent sclerotic compact bone. In intramedullary osteoid osteomas that

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lack adjacent compact bone, the nidus is separated from the adjacent cancellous bone by a zone of vascular connective tissue.  Differential Diagnosis. The distinction between osteoid osteoma and osteoblastoma cannot be made based on histology alone because both tumors are morphologically similar. Osteoblastoma is larger than osteoid osteoma, usually greater than 2 cm in maximum size and, unlike osteoid osteoma, which has a limited growth potential and rarely exceeds 1 cm, is a progressive and expansive lesion. Clinically, the pain associated with osteoblastoma is also less often relieved by aspirin. Osteoid osteoma is distinguished from osteosarcoma by its radiologic pattern, strict histologic circumscription, and lack of significant cytologic atypia, abnormal mitotic figures, or malignant cartilage.  Treatment and Prognosis. Almost all osteoid osteomas are cured by complete en-­bloc excision of the nidus.22 Although some patients are cured even when no nidus is histologically found, recurrences may develop in such individuals. Recent innovations have involved the destruction of the nidus by percutaneous drilling or the use of radiofrequency techniques.32  OSTEOBLASTOMA

Fig. 8.3  Osteoid osteoma of the vertebra. Computed tomography scan shows a relatively large, lucent area (nidus) containing a small central zone of calcification in the pedicle. The adjacent bone shows markedly increased density.

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Osteoblastoma accounts for approximately 1% of primary bone tumors.33 It is typically a slow-­growing, benign bone tumor. Among osteoblastomas, the reported incidence in the head and neck has varied from 13% to 26%.7,8,16 Clinical Features. Approximately 75% to 90% of osteoblastomas occur in patients younger than 30 years of age, with only occasional cases in older patients.7,17,34–37 It most frequently arises in the vertebral column.33 Across all body sites, there is a male to female ratio of 2:138 However, a female predominance is reported in those lesions located in the jaws33 and temporal bone.25 In the head and neck, the cervical spine is the most common location.7,17,34–37 Other sites include the facial and skull bones,17,34,35 including the temporal bone; occipital bone; and ethmoid, frontal and sphenoid bones; the orbit supraorbital region; mandible; and maxilla. There are approximately 67

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Fig. 8.4  A, Nidus of osteoid osteoma abuts thickened mature bone. B, Osteoid trabeculae, some partially calcified, within the nidus of an osteoid osteoma. The trabeculae are rimmed with plump osteoblasts with occasional osteoclasts. The stroma is hemorrhagic.

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Fig. 8.5  A, Osteoblastoma involving posterior elements of a vertebra. Computed tomography scan shows an expansive lesion, with an intact shell of bone (arrow), similar to that seen in an aneurysmal bone cyst. B, Another view of the lesion shown in (A) (arrows) shows its aggressive appearance with destruction of bone and growth into the spinal canal.

reported cases involving the mandible and maxilla.33 The mandible is more commonly affected than the maxilla, with a ratio ranging from 2 to 3.8:1.33,39,40 The incidence of skull involvement among all cases of osteoblastoma has varied from 2% to 20%.41 In the vertebrae, osteoblastoma arises mainly from the posterior elements14; an origin in the vertebral body is uncommon. Patients with osteoblastoma are frequently symptomatic, with pain present in as many as approximately 90% of cases.34,35,37 In the jawbones, osteoblastoma may present as a swelling that may be painless; 50% of patients in a recent series were pain free.33 Osteoblastomas of the spine and base of the skull frequently produce neurologic symptoms because of their extension into the spinal canal.34,37 Those in the cervical vertebrae may, similar to osteoid osteoma, be associated with scoliosis and torticollis. Symptoms may be present for as short a time as 1 to 2 months35 or for several years before diagnosis, especially in patients with spinal lesions in whom plain radiographs often fail to demonstrate the lesion. However, even osteoblastomas of the jaw have been present for long periods before diagnosis.17,34 Radiologically, osteoblastoma is usually a lucent, well-­ circumscribed, expansive defect (Fig. 8.5) that may contain focal calcification and radiopaque areas.35,37 Cortical destruction may occur and be associated with periostitis and expansion into the soft tissue (see Fig. 8.5B), such that the radiologic pattern suggests an aggressive process.34,35 Plain radiographs may not demonstrate the lesion, especially in vertebral cases, but bone scans are invariably positive and are a sensitive and accurate means of finding the lesion. CT scans are also of great value in determining the precise location and extent of the lesion.37 Osteoblastoma may have a periosteal, cortical, or medullary location, with the last most frequent; however, a periosteal location is more common for osteoblastomas in the facial and cranial bones, especially the maxilla. Intracortical osteoblastoma is associated with surrounding sclerotic bone, which is absent in medullary lesions. The nidus of osteoblastoma is greater than 2 cm, with most ranging from 4 to 7 cm in maximum size.8,15,42 Unlike osteoblastoma of the long bones, which seldom extends into the soft

tissue, vertebral osteoblastoma frequently spreads into the epidural space and the paraspinal tissues and may extend to involve adjacent vertebrae.  Pathologic Features. On gross examination, osteoblastoma appears fairly well delimited within either the cortex or cancellous bone. The tumor is hemorrhagic and is purple to reddish-­brown and has a gritty or granular consistency, with occasional cystic regions.8,14,15,43 Within the head and neck, osteoblastoma may reach a surprisingly large size (>5 cm),35 with vertebral lesions as large as 15 cm reported.34 The basic histologic pattern of osteoblastoma is similar to that of osteoid osteoma (Fig. 8.6), consisting of a well-­vascularized connective tissue stroma containing widely dilated capillaries in which there is active production of osteoid and primitive woven bone.8,14,42,43 However, there is considerable variation in this pattern from tumor to tumor. In the less mature lesion, there is an abundance of connective tissue stroma in which osteoclast-­ type giant cells and small foci of osteoid are present, some in a lacelike pattern. With maturation, there is progressive mineralization of the osteoid with conversion to trabeculae of coarse woven bone, rimmed by plump osteoblasts. The trabeculae may fuse to form an anastomosing, netlike pattern. The osteoblasts usually lack any significant atypia, having round to oval regular nuclei, often with prominent nucleoli. Mitotic activity is infrequent. The most mature portion of osteoblastoma is located at its periphery, where lamellar bone is found. Here, the interface between the tumor and the adjacent normal bone is usually sharp, with little or no evidence of infiltration into the normal bone. Osteoclasts are present and frequently found to be actively resorbing (remodeling) the newly formed bone trabeculae. The combination of bone production and resorption leads to the formation of pagetoid-­appearing bone with prominent cement lines.7,14 Some osteoblastomas contain large sheets of osteoid with little or no stroma and few osteoblasts. The intertrabecular stroma in osteoblastoma is loosely arranged with its content of thin-­walled blood vessels and lacks the crowding and sheetlike grouping of atypical cells that occurs in osteosarcoma. Rare osteoblastomas contain an abundant number of large cells, with bizarre, atypical, hyperchromatic nuclei and

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Fig. 8.6  A, Nidus of osteoblastoma shows active production of osteoid trabeculae, some in the early stage of bone formation. The trabeculae are lined with enlarged osteoblasts with occasional osteoclasts. Numerous dilated capillaries are present in the stroma. B, Large epithelioid osteoblasts, in osteoblastoma, have abundant cytoplasm and large nuclei containing prominent nucleoli. Formation of lacelike osteoid is seen.

large nucleoli, in combination with osteoid and bone production. Such lesions, which have been described as “malignant” osteoblastoma44 and aggressive osteoblastoma,42 may easily be histologically confused with conventional osteosarcoma.15,43,45 Common to these tumors is the presence of numerous large, epithelioid-­like osteoblasts that rim the bone trabeculae or are focally arranged in large sheets (see Fig. 8.6B). Numerous osteoclast-­ type giant cells are also present. Highly calcified tumor bone, intensely stained with hematoxylin and termed spiculated tumor bone, was found in the cases.44 Aggressive osteoblastoma may focally contain areas that cannot be distinguished histologically from osteosarcoma, but an important feature is their lack of atypical mitotic figures, necrosis, malignant cartilage, or peripheral permeation at the interface between the lesion and the adjacent normal cancellous bone.46 Complicating this issue, Bertoni and colleagues47,48 reported examples of osteosarcoma that histologically resembled osteoblastoma and suggested that these were similar to the lesions described as malignant and aggressive osteoblastoma. Although both aggressive and malignant osteoblastomas were reported to have a greater tendency than conventional osteoblastomas for local recurrence, none had metastasized. Other investigators, however, found no difference between these tumors and classic osteoblastoma in their clinical behavior.34,35 A few genetic aberrations, including hypoploidy, hyperploidy, and deletions, have been reported in osteoblastoma.49–51 However, none of these changes is a consistent finding.  Differential Diagnosis. The histologic distinction between osteoblastoma and osteosarcoma is one of the most difficult diagnostic problems in orthopedic tumor pathology. The problem is compounded by the fact that osteoblastoma may, on occasion, have an aggressive-­appearing radiologic pattern,34,35 and osteosarcoma may contain foci that are histologically indistinguishable from osteoblastoma.47,52,53 With an adequate amount of tissue, the most critical histologic feature that allows separation of osteoblastoma from an osteoblastoma-­ like osteosarcoma is the sharp, noninfiltrative margin found in osteoblastoma, in contrast to the characteristically peripheral infiltrative pattern of osteosarcoma. However, when only small biopsy specimens are available, the peripheral margin may not be represented, and it may not be possible to distinguish

between these two tumors.34,35,47,53 Conventional osteoblastic osteosarcoma is distinguished from osteoblastoma by its atypical pleomorphic stromal cells and osteoblasts with their sheetlike intertrabecular grouping, atypical mitotic figures, necrosis, and malignant cartilaginous areas. Although osteoblastoma lacks cartilage in most cases, foci of mature or immature chondroid may occur, but, unlike the cartilage in osteosarcoma, this chondroid lacks cytologic atypia.48 The distinction between osteoid osteoma and osteoblastoma is not possible histologically, and the diagnosis rests on the size of the lesion and the clinical setting. Osteoid osteoma is rarely larger than 1.5 cm and, unlike osteoblastoma, is rarely progressive.44 Although the pain associated with osteoblastoma may, as in osteoid osteoma, be more prevalent at night, it is rarely as sharply intense as in osteoid osteoma and not as frequently relieved by aspirin.7,14,15 Osteoblastoma is far more frequent in the vertebrae, jawbones, and skull than is osteoid osteoma.40 Some advocate use only of the term osteoblastoma for benign jaw lesions that are composed of osteoblasts that form osteoid and bony trabeculae. This is largely on the basis that the smaller lesions, which by size criteria would be classified as osteoid osteoma, are only infrequently associated with the pathognomonic sign of nocturnal pain relieved by aspirin.33 As a highly imaged part of the skeleton, it seems likely that jaw osteoblastomas could be picked up more readily at a smaller size. In the jaw bones, it may be difficult, on histologic grounds alone, to distinguish osteoblastoma from cementoblastoma. The latter is an odontogenic tumor that is intimately associated with the cementum of the tooth root.13,54  Treatment and Prognosis. Complete en-­bloc resection of osteoblastoma is usually curative34; depending on its location, however, this procedure is not always possible and marginal resection or curettage procedures must be used. In such cases, local recurrence rates of 10% to 20% are reported.34,35 Death caused by local extension of the tumor may occur,34 as well as from surgical complications of its treatment.35 Malignant transformation of osteoblastoma is reported as usually, but not always, occurring only after local recurrence.34,53 However, some of these cases may represent an underdiagnosed osteoblastoma-­ like osteosarcoma.47,48 

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Osteosarcoma GENERAL CONSIDERATIONS Osteosarcoma is the most common primary malignant neoplasm of bone and is characterized by direct formation of bone or osteoid by the tumor cells. Osteosarcoma constitutes a diverse group of bone-­producing neoplasms with varied histologic features and clinical behavior. Some subcategories are based on distinctive histologic differences, but without biologic relevance, while others alter biologic aggressiveness and affect prognosis. As many as 80% of osteosarcomas present as a conventional intramedullary type or, less frequently, as rare variants, including periosteal, parosteal, telangiectatic, small cell, epitheloid, giant cell, osteoblastoma-­ like, chondroblastoma-­ like, and low-­grade central types. Approximately 80% to 85% of osteosarcomas arise in the long bones; they are relatively infrequent in the head and neck area. Among 5155 cases of osteosarcoma in seven large series, only 336 (6.5%) involved the skull, mandible or maxilla, facial bones, or cervical vertebrae.7,8,14,16,55–57 Osteosarcoma generally arises de novo but may arise secondarily to some underlying condition, the most frequent of which include Paget disease, usually in the polyostotic form58,59; fibrous dysplasia (FD), also most frequently occurs in the polyostotic form60,61; chronic osteomyelitis or bone infarct62; and irradiated bone.63 The craniofacial region is the most common site for osteosarcoma arising on the basis of preexisting FD.60,61 Very rarely, extraosseous variants are documented. 

Conventional Osteosarcoma DEFINITION Conventional osteosarcoma is a primary intramedullary malignant bone tumor in which the neoplastic cells produce osteoid, but in highly variable amounts. Clinical Features. Osteosarcoma occurs in patients of all ages; however, 70% to 95% of patients are in the first two decades of life, with a peak incidence in the second decade.7,8,14,16 At Memorial Sloan–Kettering Hospital in New York, 10% of all osteosarcomas occurred in patients older than 60 years of age, more than one-­half of whom had some underlying condition, such as Paget disease.64 Older patients (older than 50 years of age) have a higher incidence of craniofacial involvement than younger patients, with this site accounting for 13% to 33% of osteosarcomas in this age group.64,65 In general, osteosarcoma is more common in male patients, with male-­to-­female ratios of 1.3:1 to 2:1.7,8,14,16 Radiologically, osteosarcoma has an aggressive appearance with extensive cancellous and cortical bone destruction with tumor extension into the soft tissues. Depending on the proportion of bone produced by the tumor, it will appear either totally lytic or densely sclerotic or, in the majority of cases, have a mixed lytic-­sclerotic pattern.8,15,41  Pathologic Features. On gross examination, there is good correlation with the radiologic pattern with extensive bone destruction being present and, in more than 90% of cases, an associated soft-­ tissue mass.15 The tumor’s appearance and consistency vary considerably depending on the proportion of cartilage, soft tissue, and bone present. It may be pink to gray-­white, with a “fish flesh” appearance or gray to blue-­gray associated with firm, white fibrous nodular masses. In tumors

with abundant bone production, the tumor may be quite hard and require a saw to section. Yellow to yellow-­white calcific foci are usually found throughout the lesion, as well as areas of hemorrhage, necrosis, and cystic change. In most osteosarcomas, even those with abundant bone formation, the peripheral soft-­ tissue margins usually contain highly cellular regions that are soft enough to section with a scalpel blade, and it is from such regions that tissue should be obtained whenever frozen-­section biopsy material is needed. It is important to emphasize that the finding of unequivocal osteoid or tumor bone formed by malignant-­appearing stromal cells establishes the diagnosis of osteosarcoma, regardless of the quantity of matrix present. The pattern and amount of tumor osteoid or bone vary considerably, not only from tumor to tumor but also from area to area within the tumor. Osteoid may be found as thin, eosinophilic strands of hyaline-­like material interspersed between the malignant stromal cells, producing a lacelike pattern (Fig. 8.7A). These strands may fuse to form larger, irregular seams or trabeculae. The osteoid may also occur in broad sheet-­like masses in which the malignant stromal cells become “choked off ” and eventually disappear. Of diagnostic importance, the osteoid trabeculae are not rimmed by an orderly layering of osteoblasts as in benign reactive bone. Also, unlike reactive new bone formation, in which the stroma between the bone trabeculae contains dilated capillaries and loosely arranged bland stromal cells, in osteosarcoma this space is usually packed with malignant stromal cells (Fig. 8.7C). Under polarized light, osteoid has a woven or mat-­like appearance, unlike the more orderly longitudinal fiber array found in collagen.15 However, at times, the light microscopic distinction between collagen and osteoid may be problematic, with the diagnosis depending on the experience of the pathologist. To convert to bone, osteoid must undergo calcification, such that the presence of fine granules of calcification within the eosinophilic strands or trabeculae is a helpful clue to identify the osteoid. A further histologic problem is distinguishing osteoid from chondroid. Contrary to common belief, chondroid, like osteoid, stains pink with conventional hematoxylin-­eosin stains and not blue like hyaline cartilage. Chondroid usually occurs as well-­ defined islands, usually sharply set off from the surrounding cellular stroma, and has a less fibrillar appearance than does osteoid.15 Immunohistochemical stains for the noncollagenous bone proteins, osteocalcin and osteonectin, have been used in an attempt to distinguish osteosarcoma from other malignant bone tumors. Although osteonectin is found in osteosarcoma, its presence in a variety of other tumors makes it unreliable as a diagnostic marker.66,67 Reactivity for osteocalcin has been used by some authors for distinguishing osteosarcoma from pleomorphic undifferentiated sarcoma (MFH) and fibrosarcoma, but it has been found to occur in chondroblasts as well.68 As the osteoid in osteosarcoma becomes calcified to form tumor bone, it may be deposited on residual normal trabeculae. This tumor bone has an irregular appearance, is strongly hematoxylinophilic, and, by polarized light, has a woven or basket-­ weave pattern, unlike the uniform lamellar pattern of normal bone. Within this tumor bone, the now-­incorporated stromal cells (malignant osteoblasts) lie within lacunar spaces. These “osteocytes” have small hyperchromatic and irregularly shaped nuclei. 

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C

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Fig. 8.7  A, Osteosarcoma. Lacelike streamers of pink osteoid produced by malignant stromal cells (osteoblasts). B, Area in a conventional osteosarcoma shows a combination of osteoid, malignant cartilage, and spindle cell fibrous zones. C, Conventional osteosarcoma shows trabeculae of irregular tumor bone. Malignant osteoblasts fill the space between the trabeculae. Compare with the osteoblastoma shown in Fig. 8.6A. D, murine double-­minute type 2 (MDM2) immunohistochemistry reactivity in a low-­grade gnathic osteosarcoma.

Histologic Subtypes Although the majority of osteosarcomas produce an abundance of osteoid and tumor bone and are thus classified as osteoblastic, others contain a predominance of malignant cartilage (chondroblastic type) or fibrous spindle cell areas (fibroblastic/fibrohistiocytic type) where osteoid or tumor bone may be scarce and require examination of many sections. Additional other histologic subtypes of osteosarcoma have been reported, including telangiectatic,7 chondroblastoma-­like,69 chondromyxoid fibroma–like,15 osteoblastoma-­like,48 clear cell,70 epithelioid,71 and malignant fibrous histiocytoma-­like58,63,64; however, with the exception of the last subtype, all the others are exceptionally rare. The abundant tumor bone produced by osteoblastic osteosarcoma may be so extensive that it obscures much of the intervening stroma, such that it may be difficult to find stromal cells directly producing osteoid or bone. Despite this, the general permeative growth pattern and the quality and abundance of the irregular tumor bone serve to establish the diagnosis of osteosarcoma.15 Chondroblastic osteosarcomas contain an abundance of malignant-­appearing cartilage arranged in lobules or islands with cells within lacunar spaces.72 The periphery of the lobules tends to be more cellular, and the cells frequently assume spindle shapes. Calcification with enchondral ossification may be present. It is important to note that enchondral

ossification can also be found is chondrosarcomas; the distinction being that the malignant cells in osteosarcoma must also directly produce osteoid. Fibroblastic osteosarcoma contains large areas composed of spindle cells that may assume a herringbone pattern indistinguishable from fibrosarcoma. Fibrohistiocytic osteosarcomas have abundant large pleomorphic tumor cells with bizarre enlarged nuclei and abnormal spindle-­ shaped cells. Multinucleated tumor giant cells with an abundant glassy eosinophilic cytoplasm are frequent, as are smaller histiocyte-­like cells having a fine granular cytoplasm. A storiform pattern may be found in the spindle cell areas, the overall pattern appearing identical to that of soft-­tissue pleomorphic undifferentiated sarcoma (MFH). Small biopsies may not contain obvious osteoid or tumor bone, and the diagnosis of osteosarcoma must be presumptive, pending further sectioning or examination of a resection specimen. Most conventional intramedullary osteosarcomas express a wide spectrum of histologic patterns8,15 and contain a mixture of elements, from areas showing osteoid or tumor bone to those with cartilaginous, fibrosarcomatous, or fibrohistiocytic foci (see Fig. 8.7B). All forms of osteosarcoma are characterized by a permeative growth pattern with tumor invading between and entrapping existing normal bone trabeculae. More than one-­fourth of osteosarcomas contain scattered benign osteoclast-­type giant

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cells15,73 that at times may be so numerous as to simulate a giant cell tumor (GCT). Such cells may be frequent in osteosarcomas arising in Paget disease.59,73 Distinguishing a GCT with bone formation from an osteoclast-­rich osteosarcoma may be difficult, especially on biopsy tissue.15,73 However, with adequate tissue, the bone in true GCT is frequently at the periphery of the lesion, rather than scattered haphazardly throughout the tumor as in osteosarcoma, and it is rimmed by an orderly array of plump osteoblasts as in reactive bone as opposed to the unlined bone of conventional osteosarcoma. Malignant cartilage is absent in GCT, and osteoclast-­rich osteosarcoma will invariably have foci diagnostic of conventional osteosarcoma elsewhere. Osteosarcomas that arise in association with Paget disease or radiated bone are most frequently of the fibrosarcomatous or fibrohistiocytic type,58,61,74 as are those osteosarcomas that occur in patients older than the age of 60 years.64 Mitotic activity is easily found in all forms of conventional osteosarcoma, with frequent abnormal forms. The absence of mitotic activity should give one pause in making a diagnosis of osteosarcoma and suggests the possibility of a pseudosarcomatous tumor.15 Hemorrhage and necrosis are also frequent. Such spontaneous necrosis may involve 40% to 70% of the total tumor.75,76 The degree of tumor necrosis induced by chemotherapy has been correlated with prognosis,76 with patients classified as good responders when the necrosis involves 90% or more of the tumor and poor responders when there is a lesser degree of necrosis; patients with a good therapeutic response have significantly better 5-­year survival rates.76 However, these data are based almost entirely on the results obtained for appendicular osteosarcomas. Although some experienced bone tumor pathologists attempt to grade conventional intramedullary osteosarcomas,77 the extensive variability from area to area that exists in the majority of these tumors makes such grading suspect, as well as the fact that, with the exception of the well-­differentiated intraosseous form of osteosarcoma, grading of head and neck tumors appears to have little prognostic value.78  OSTEOSARCOMA OF THE HEAD AND NECK Osteosarcoma of the head and neck represents a small percentage of osteosarcomas in all sites, with occurrences between 0.5% and 13% and an average between 6% and 7%.79–81 Among the 336 cases of osteosarcoma of the head and neck reported in seven large series, the jaw bones were involved in 255 cases (75%) with 40% in the maxilla and 35% in the mandible. The skull bones were affected in 72 cases (21%). The cervical vertebrae were the least common site, accounting for only nine cases (2%).7,14,16,56,57,82,83 The National US Cancer Data Base reported 496 cases of head and neck (HN) osteosarcoma from 1985 to 1996. Approximately 56% affected the skull/facial bone, 39% the mandible and 5% other, although the International Classification of Disease coding system used precluded separating maxilla, which was grouped with the skull/facial bones.78  OSTEOSARCOMA OF THE SKULL Clinical Features. In as many as one-­ half of cranial osteosarcomas, the tumor arises secondary to some underlying condition, most commonly Paget disease, FD, or in irradiated bone.63,84 Although the age range is considerably wider, most

patients are in the fourth and fifth decades of life, an older age than for those with osteosarcoma of the appendicular skeleton.63,84,85 This reflects the component of patients with cranial osteosarcoma who have Paget disease or radiation sarcoma, conditions that most often occur in older patients. Such secondary osteosarcomas occur in patients approximately 20 to 30 years older than those with primary cranial osteosarcoma.63,86 Unlike the male predominance in osteosarcoma of the long bones, the male-­to-­female ratio in osteosarcoma of the skull is roughly equal.63,84,85 Any of the skull bones may be involved, with reported cases in the calvarium and skull base; the occipital, parietal, frontal, and temporal bones; the orbit; the ethmoid, sphenoid, and maxillary sinuses; the nasal fossa; the zygoma; and the sella area. In some cases, the tumor may be so large that its exact site of origin cannot be established. Clinically, the dominant symptom is that of a painless mass, although cranial nerve symptoms, epistaxis, and eye displacement may occur, reflecting the location of the tumor.63,84 Most cases are diagnosed within 6 months of the onset of symptoms.63,84  Pathologic Features. Osteoblastic osteosarcoma is the most common type encountered in the skull,6,63,84,87 but chondroblastic,6,63 fibroblastic,6,84,85,88 fibrohistiocytic,63,85 small cell, telangiectatic, and well-­differentiated subtypes also occur.89  Treatment and Prognosis. In a review of 201 patients with craniofacial osteosarcoma, 61 of whom had cranial lesions, the best overall and disease-­free survival rates were associated with complete surgical removal of the tumor and the use of chemotherapy, the latter improving survival even in those patients with incomplete resections.90 The prognosis for osteosarcoma of the skull and facial bones is generally poor, with the reported results influenced by the number of secondary osteosarcomas in the series. The 5-­year survival rate is approximately 10%,6,85,87 with only a few long-­ term survivors63,84; metastases develop in approximately 45% of cases.6,84,87 By contrast, of the 276 patients with skull/facial bone osteosarcomas reported by the National Cancer Data Base in the United States, 57% survived 5 years and only 10.5% experienced distant metastasis, but lesions affecting the maxilla were included in the skull/facial bone group.78 Patients with osteosarcoma secondary to Paget disease have a very poor prognosis, with almost all dying of the tumor.63,84  OSTEOSARCOMA OF THE JAW BONES Clinical Features. The jaws constitute 5% to 13% of all cases of osteosarcoma.91,92 The ratio of mandibular to maxillary cases varies in the literature, with the mandible accounting for 44% to 73% of cases and the maxilla for 27% to 56%. Within the mandible, the body is the most common location, accounting for 55% to 75% of cases followed in order of frequency by the angle, the ramus, and the symphysis. In the maxilla, the alveolar ridge is the most common site. Although cases occur in children,88,93–90 this is uncommon; most patients are in the third to fourth decades of life, generally one decade older than patients with osteosarcoma of the long bones and the gender distribution is roughly equal or slightly favoring males.91,92 Clinically, the majority of patients report a swelling or mass that is often, but not always, painless91; pain alone may also occur.93,94 Numbness or paresthesia of the lip or chin reflects

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tumor involvement of the inferior alveolar nerve and is an important clue to the diagnosis of an aggressive lesion.93,96 Loosening of the teeth may be the first or even dominant manifestation of the disease,94 such that the dentist may be the one the patient first sees for medical attention. Other symptoms include nasal obstruction, epistaxis, or visual disturbances secondary to antral involvement. Although a history of symptoms for as long as 30 years is recorded,96 most patients seek medical attention within 6 months of the onset of symptoms.93 Osteosarcoma of the jaw bones may develop as a consequence of predisposing conditions, the most common of which is previous radiation therapy to the region; in approximately 10% of cases,92–94 tumors also develop secondary to Paget disease, FD, and chronic osteomyelitis.94,97,98 Radiologically, osteosarcoma of the jaw has a purely lytic and destructive pattern (Fig. 8.8A) in 35% to 45% of cases, a sclerotic pattern in 5% to 65% of cases, and a mixed pattern of lysis and sclerosis in 22% to 50% of cases.88,93,94 A sunburst pattern, with radiating spicules of bone (Fig. 8.8B) is considered a characteristic feature of osteosarcoma of the jaw, especially in mandibular lesions94,99; however, it is not frequent, occurring in 7% to 27% of cases.94,99 Extraosseous soft-­tissue extension is radiologically evident in 30% to 100% of cases.88,93,94 An important radiologic feature of osteosarcoma of the jaws is symmetric widening of the periodontal membrane space that may also be associated with loss of the lamina dura (see Fig. 8.8B). Although not specific for osteosarcoma, its occurrence is suggestive of an aggressive process.96,99 

Fig. 8.8  A, Osteosarcoma of the mandible. Large, predominantly osteolytic, aggressive-­appearing lesion involves the left hemimandible. The tumor has destroyed the cortex superiorly, with marked displacement and distortion of the teeth. B, Specimen radiograph of a mandibular osteosarcoma shows the canine tooth (left) and first and second premolars. There is widening of the periodontal membrane space (large arrow) associated with loss of the lamina dura. Spiculated, extraosseous tumor expansion is present (small arrows).

Pathologic Features. Osteosarcomas of the jaw bone have ranged from 2 to 10 cm in maximum size.91,93,94 The histologic type has varied in different series, with some reporting a predominance of osteoblastic tumors93,96 and others reporting a chondroblastic88,91,94 or fibroblastic29 predominance. In addition to parosteal and periosteal osteosarcomas (see subsequent discussion), examples of telangiectatic,100,101 small cell,102 well-­ differentiated,103 and high-­grade surface88 osteosarcoma are reported.  Treatment and Prognosis. Marginal excision of osteosarcoma of the jaw leads to local recurrence in 36% to 100% of cases.93,94,96,100,104 Such recurrences carry a poor prognosis93,94 because most patients die of local recurrence. The rate of local recurrence in maxillary osteosarcoma has varied from 29% to 60% and in mandibular lesions from 43% to 66%.94,96 Distant metastases occur, although there is considerable variation in the literature as to its incidence, with reported rates of 6% to 52%.94,96,99 Metastases from mandibular osteosarcoma are more frequent than maxillary lesions, with mandibular lesions ranging from 33% to 71% and of maxillary lesions from 13% to 20%.96 Gnathic osteosarcomas metastasize at a considerably lower rate than those in long bone. Historically, the overall 5-­year survival rates range from 23% to 47%, with most series reporting rates of 35% to 45%.93,94,96,99 Radical excision yields the best prognosis,94 with 5-­year survival rates for maxillary lesions of 25% to 63% and for mandibular lesions of 24% to 71%,96,99,104 but overall 5-­year survival rates

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of 70% are currently being reported.105 Some authors express the view that mandibular lesions have a better prognosis than maxillary tumors.99 The role of neoadjuvant chemotherapy in the outcomes in patients with osteosarcoma of the head and neck needs further study. The authors of one study showed an obvious improvement in the 5-­year local control, distant metastasis, and overall survival compared with historical cohorts.106 However, no outcome advantage was reported for chemotherapy in the largest series of gnathic osteosarcomas reported to date and the 496 cases reported from the US National Cancer Data Base of Head and Neck lesions also disclosed no outcome advantage for chemotherapy.78,107 

Pathologic Features. Most cases of vertebral osteosarcoma are osteoblastic, although cases of chondroblastic, fibroblastic, and fibrohistiocytic subtypes occur.108,109,111 Distinguishing osteoblastoma from osteosarcoma is a major problem because cases of vertebral osteosarcoma have been misdiagnosed as osteoblastoma on biopsy tissue.109,111 Perhaps contributing to this problem is the knowledge that the spine is a common site for osteoblastoma, but an uncommon location for osteosarcoma. As mentioned earlier, the most helpful histologic feature that separates osteoblastoma from osteosarcoma is the peripheral permeative pattern in osteosarcoma, in contrast to the sharp interface of the nidus of osteoblastoma with the host bone at its periphery. Rare cases will be found where the distinction between these tumors may be histologically impossible, and only the course of the disease unmasks the true nature of the lesion.  Treatment and Prognosis. The prognosis in vertebral osteosarcoma is dismal, with almost all patients dying of the tumor, usually within 1 year of diagnosis.108–110 This no doubt reflects the difficulty in adequately resecting tumors in this region. In none of the 10 patients with vertebral osteosarcoma treated at Memorial Hospital could the tumor be completely resected.109 Of 27 patients with vertebral osteosarcoma reported from the Mayo Clinic, there was only one survivor (3.7%); all those with cervical vertebral lesions died.108 The poor prognosis in vertebral osteosarcoma may also be a reflection of the number of older patients with Paget disease or radiation-­induced tumors. However, the prognosis in the 45 patients with primary vertebral osteosarcoma, reported by Kebudi and colleagues,110 was also poor, with 36 (80%) dying of the tumor, two (4.4%) alive with tumor, and only seven (15%) alive without tumor, only two of whom were long-­term survivors. 

VERTEBRAL OSTEOSARCOMA

Genetics of Osteosarcoma

Fig. 8.9  Osteosarcoma arising from C7 shows sclerotic and spiculated tumor bone associated with destruction of the left half of the vertebra.

Clinical Features. Most vertebral osteosarcomas arise secondary to some other condition, most notably Paget disease or after radiation therapy to the region, with de novo cases being uncommon.108,109 In 1994 Kebudi and colleagues110 found only 45 cases of vertebral osteosarcoma in the absence of Paget disease or radiation therapy in the American and European medical literature since 1904. Despite the high incidence of spinal involvement in Paget disease, the actual occurrence of vertebral osteosarcoma in such patients is quite uncommon. Patients with vertebral osteosarcoma have ranged from 3 to 70 years of age108,109 and are older, on average, than those with appendicular osteosarcoma,108,109 reflecting the inclusion of older adults with Paget disease and radiation-­induced tumors. Virtually all patients with vertebral osteosarcoma present because of pain that is frequently associated with neurologic symptoms, sensory, as well as motor.108,109 Those with osteosarcoma of the cervical vertebrae may have pain that radiates to the upper extremity.110,111 The presence of a palpable mass is uncommon.108,110 Radiologically, vertebral osteosarcoma is a destructive, usually nonexpansive lesion with soft-­tissue extension found in the majority of cases (Fig. 8.9).108,109,111 Within the vertebra, the body is involved in almost all cases,108–111 although the tumor frequently extends to involve the posterior elements as well; primary origin in the posterior elements is uncommon.108,109 

Several hereditary syndromes are associated with an increased risk of osteosarcoma development, most notably hereditary retinoblastoma, Li-­ Fraumeni and Rothmund-­ Thomson syndromes. Familial retinoblastoma is caused by germline mutation in the RB1 tumor suppressor gene and is frequently associated with second site primary tumors, including osteosarcoma. These tumors are likely to show loss of heterozygosity at 13q and alteration in the RB1 gene. Mutation in the RB1 gene also has been reported in 30% to 40% of sporadic osteosarcoma cases.112–114 The prognosis in these cases is poorer than in cases without RB1 mutations.114 Li-­Fraumeni syndrome patients with a p53 germline mutation have an increased risk of developing a variety of tumors, including osteosarcoma. Loss of heterozygosity at 17p, as well as p53 mutations, are seen in approximately 35% of sporadic osteosarcoma cases115–117; tumor-­free survival has been reported to be lower in osteosarcoma patients with TP53 mutations.118 Sporadic osteosarcoma, in contrast to some other sarcomas, is not associated with specifically recurrent translocations or any other chromosomal rearrangement.119 Cytogenetic studies reveal that the majority (70%) of osteosarcomas are characterized by complex numerical and structural chromosomal abnormalities. Multiple clones with different degrees of ploidy are not uncommon.120–122 Numerous genetic changes that cause the inactivation of tumor suppressor genes and activation of

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oncogenes have been demonstrated.119 One of the chromosomal regions most commonly involved in these changes is 17p11.2–p12122; amplification of this region has been found in 13.32% of conventional osteosarcomas.122,123 Low grade osteosarcomas (LGO) of the jaws can be confused with other benign fibroosseous lesions. LGO tend to have ring or giant marker chromosomes with amplification of 12q13-­15.124–129 This region includes murine double-­minute type 2 (MDM2) and cyclin dependent kinase 4 (CDK4), which have been overexpressed in LOS in 29% to 79% of cases (see Fig 8.7D).130,131 Expression of MDM2 and CDK4 by immunohistochemistry (IHC) has been useful to distinguish LGO from its benign mimics, and Tabareau-­Delalande et  al., in 2015, showed no overexpression (but variable amplification) of MDM2 in 30 cases of ossifying fibroma and 17 cases of fibrous dysplasia compared to overexpression and amplification in 100% (15/15) of LGO by quantitative polymerase chain reaction (qPCR).132,133 Others, however, have questioned the utility of MDM2 to distinguish benign from malignant bone tumors.134 While MDM2 and CDK4 overexpression are seen in most LGOs, they have been reported in conventional gnathic osteosarcoma as well.135 MDM2 and CDK4 are useful for some diagnostic purposes; they also offer opportunities for targeted therapeutic intervention by inhibiting the suppressor effect on p53 proapoptotic function.136 

Osteosarcoma Variants Osteosarcomas can occur on the surface of a bone and are generally referred to as juxtacortical osteosarcomas, although historically juxtacortical has been used synonymously with parosteal. These are divided into parosteal (low grade), periosteal (intermediate grade) and high-­grade surface (high grade). PAROSTEAL OSTEOSARCOMA Parosteal osteosarcoma affects the long bones in approximately 95% of cases, with the femur involved in the majority of cases. Among 226 cases of parosteal osteosarcoma at the Mayo Clinic, only one, a mandibular lesion, was located in the head and neck region.137 In the head and neck region, the mandible and maxilla have been the most common sites of involvement,138–140 in addition to the cranial bones.141 Clinical Features. Patients with parosteal osteosarcoma are generally older than those with conventional osteosarcoma, with 80% older than 20 years of age; most patients are in the third and fourth decades of life.17,82,137 In the head and neck, a painless swelling is the most common symptom, although the lesion may be tender.138,140,141 The tumor typically grows slowly, and although in some patients the tumor is detected within a few days to several months of symptom onset,141 other patients have had a mass for as long as 10 years before diagnosis.138,141 Parosteal osteosarcoma arises on the surface of the bone and forms a coarsely lobulated or bosselated, usually broad-­based mass that rests on and bulges from the cortical surface.142 Radiologically, the underlying cortex is frequently thickened, and a radiolucent cleavage plane may be seen between the tumor and the underlying cortex. The base of the lesion is usually more densely ossified than the periphery. Radiolucent zones may be found within the tumor that represent entrapped normal soft

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tissue, low-­grade cartilage, fibrous tissue, or areas of dedifferentiated tumor.137 Occasionally, invasion into the underlying bone is seen.141 The central portion of parosteal osteosarcoma is not in direct continuity with the medullary cavity of the underlying bone. Even in the confined space of the head and neck, some parosteal osteosarcomas have been as large as 16 cm, although most are between 3 and 5 cm.138,141  Pathologic Features. Grossly, parosteal osteosarcoma app­ ears well delimited and typically grows to envelop the external aspect of the bone.142 Medullary involvement is infrequent, and its development appears correlated with the length of time that the tumor has been present, with long-­standing tumors eventually invading the underlying cortex which varies from 1.3% to 59%.55,137,143 A fibrous capsule or a cartilaginous cap may be found at the tumor’s peripheral margin.144 Despite this seemingly gross circumscription, microscopically, the tumor may invade and incorporate the adjacent skeletal muscle and fat.82 The consistency of the tumor varies depending on the proportion of fibrous, osseous, and cartilaginous tissue present. The periphery may be soft and fleshy and easily cut with a scalpel, but the basal portion is usually hard, requiring a saw to section. Here, the cut surface shows white to yellow-­white chalklike areas of calcification and ossification.8 In long-­standing tumors, the entire lesion may be rock hard because of extensive bone formation. Histologically, parosteal osteosarcoma may be difficult to diagnose, especially on small biopsy specimens, if careful attention is not given to the clinical and radiologic features. The stromal and osseous elements in parosteal osteosarcoma usually lack clear evidence of cytologic malignancy or that which is present may be so scarce, as to require many sections to discover. The tumor is composed of a fibrous stroma in which reside irregular spicules and trabeculae of bone (Fig. 8.10A). The stroma varies in its cellularity; some cases are relatively hypocellular with the stroma containing abundant collagen separating bland-­appearing spindle cells (Fig. 8.10B); in others, the stroma is more cellular, containing plumper and more atypical cells, creating a fibrosarcoma-­ like pattern. Mitotic figures may be scarce. The bone trabeculae are irregular, being of a woven or lamellar type, and frequently arranged in parallel arrays (see Fig. 8.10A). Unlike conventional osteosarcoma, a layer of plump but benign-­appearing osteoblasts may rim the trabeculae.15,82 In other areas, the bone arises directly by metaplastic transformation of the fibrous stroma as in FD.15,144 It is at the peripheral margin of the tumor that one finds more cellular zones composed of primitive-­appearing cells that have enlarged and irregular nuclei and that form osteoid.8 Here, direct invasion of skeletal muscle and fat is found. The base of the lesion consists of densely compact woven or lamellar bone in contrast to its more fibrous, spindle cell peripheral component. Cartilaginous foci, of variable size, occur in 50% to 80% of cases.137,144 These foci may have cytologic features of low-­grade chondrosarcoma, with increased cellularity and atypia and show enchondral ossification. The amount of cartilage varies from tumor to tumor, but it is never the dominant element as it is in periosteal osteosarcoma. Foci of dedifferentiation in which areas of high-­grade sarcoma, usually pleomorphic undifferentiated sarcoma (MFH), fibrosarcoma, or conventional osteosarcoma are found, may occur in an otherwise typical parosteal osteosarcoma. Such

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Fig. 8.10  A, Trabeculae of parosteal osteosarcoma have prominent cement lines, creating a pagetoid appearance. The tumor lacks the abundant stromal cells filling the spaces between trabeculae, as found in conventional osteosarcoma. B, Fibrous stroma of parosteal osteosarcoma contains cells with ill-­defined cytoplasmic limits and oval to round nuclei with mild atypia. A few mitotic figures are present. The cells are separated by strands of collagen.

dedifferentiated areas usually develop only after several local recurrences, but may be found at the time of initial presentation.137,139,144 The incidence of dedifferentiation varies from 16% to 43%. Dedifferentiated lesions have occurred in the head and neck region.140 In the literature, some osteosarcomas listed as parosteal type have been histologically graded numerically from I to III, a grade III lesion being an overtly malignant tumor with features of conventional osteosarcoma.14,55,145 However, such a tumor is best classified as a high-­grade surface osteosarcoma146 rather than a parosteal osteosarcoma because it has a considerably worse prognosis than does true parosteal osteosarcoma.  Differential Diagnosis. The differential diagnosis of par­ osteal osteosarcoma includes sessile osteochondroma, myositis ossificans, and periosteal osteosarcoma. Unlike parosteal osteosarcoma, the radiologic pattern of osteochondroma shows continuity between the lesion and the underlying parent bone. Histologically, osteochondroma has a cartilage cap composed of benign rather than malignant cartilage; the cancellous bone is of the lamellar type, and the central portion of the lesion contains marrow fat or hematopoietic elements and lacks the fibrous stroma of parosteal osteosarcoma. Periosteal osteosarcoma has more abundant and more atypical cartilage than parosteal osteosarcoma, and its spindle cell elements are larger and more atypical than the spindle cells of parosteal osteosarcoma. Essentially, periosteal osteosarcoma is an intermediate-­grade surface chondroblastic osteosarcoma, in contrast to the low-­grade fibroosseous character of parosteal osteosarcoma. Myositis ossificans is the lesion most likely to be histologically confused with parosteal osteosarcoma. The clinical and radiographic features may enable one to easily separate the two conditions, provided there is a history of recent trauma to the involved site, followed by the rapid appearance of a soft-­ tissue mass that gradually ossifies over time. However, such a history may be lacking, the patient reporting only a slowly enlarging mass. Radiologically, myositis ossificans usually appears separate from the underlying bone, although in some long-­standing cases, it may continue to grow and ultimately

attach itself to the bone and thus radiologically simulate parosteal osteosarcoma. The classic histologic feature of myositis ossificans is its zonal pattern, in which the periphery of the growing lesion shows the most mature degree of bone differentiation, with the more central and basal aspects composed of a stroma of immature, and sometimes atypical, cells in which there is primitive (woven) bone production. This contrasts with parosteal osteosarcoma, in which the periphery of the lesion shows the least mature elements and the basal or central regions contain more mature bone. In the fully developed form of myositis, the lesion may become totally ossified, being composed of mature compact lamellar bone so as to resemble an osteoma; such a degree of organization is never found in parosteal osteosarcoma. Unlike conventional osteosarcoma, parosteal osteosarcoma is characterized by one or more supernumerary ring chromosomes, often as the sole alteration.4,147,148 Mutations in RB1 have not been found to be present in parosteal osteosarcoma.114,149 Parosteal osteosarcoma shows similar MDM2 and CDK4 overexpression as LGO.132,150  Treatment and Prognosis. In general, parosteal osteosar­ coma has an excellent prognosis after complete surgical excision, with a 5-­ year survival rate of approximately 80%. However, 10-­year survival rates are somewhat lower, owing to the appearance of late metastases in some patients.137 The course of parosteal osteosarcoma in the head and neck region is not well established because of its rarity, with only a few reports containing long-­term follow-­up information.140,141 At the time of these reports, however, almost all the patients were alive and well. Dedifferentiated parosteal osteosarcoma has a poor prognosis, with metastases in approximately 50% of patients at 5 years.137,151 Whenever possible, a wide local complete excision should be done for parosteal osteosarcoma to prevent local recurrence and the possibility of dedifferentiation.137  PERIOSTEAL OSTEOSARCOMA Periosteal osteosarcoma is a subperiosteal surface-­based tumor that occurs in the long bones in more than 95% of cases. Location in the head and neck is rare. In a series of 17 cases from

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the Netherlands, only one, a mandibular lesion, was in the head and neck region16; in 26 cases at the Mayo Clinic, none arose in the head and neck.8 There are only individual case reports of mandibular and maxillary periosteal osteosarcoma.152–155 and a single case in the cranium.156 Clinical Features. The age range for periosteal osteosarcoma is quite broad, with approximately 60% to 75% of patients in the second decade of life; it is uncommon in the first decade. In the few head and neck cases, patients have ranged from 20 to 65 years of age.16,41,152–154 Periosteal osteosarcomas of the mandible and maxilla are usually small, ranging from 2.7 to 3.5 cm.152–156 Although the radiologic appearance of periosteal osteosarcoma in the long bones usually shows a radiating pattern of osseous spicules that extend outward from the cortex, the few cases reported in the jaws have not, with an occasional exception,153 demonstrated this pattern.  Pathologic Features. On gross examination, periosteal osteosarcoma rests on a thickened cortex, which may be minimally invaded by the tumor,157 and appears well delimited by the periosteum. On section, the periphery of the tumor is soft and well-­rounded and has a distinct chondroid appearance with glistening gray to gray-­white lobules that contain white to yellow streaks of calcification or ossification.152,154 Microscopically, periosteal osteosarcoma consists of lobules of high-­grade malignant cartilage that are separated by spindle-­shaped mesenchymal cells, in which eosinophilic lacelike ribbons of osteoid are found. However, these osteoid areas may be quite sparse and difficult to find and are best seen at the peripherally growing margin of the lesion.157 In some cases, fibroblastic or even osteoblastic foci may be found and even predominate, such that the tumor may be difficult to distinguish from a conventional high-­grade surface osteosarcoma.158 Complex karyotypic patterns were identified in three cases of periosteal osteosarcoma, and in one case, trisomy 17 was the only change.149,159  Differential Diagnosis. Unlike parosteal osteosarcoma, large seams of parallel-­oriented osteoid or tumor bone do not occur in periosteal osteosarcoma, nor does it have the abundant fibroblastic stroma of parosteal osteosarcoma. The scarcity of osteoid in some cases of periosteal osteosarcoma has led to diagnostic confusion with juxtacortical chondrosarcoma, a problem further compounded by the fact that the eosinophilic ribbons that occur in periosteal osteosarcoma are considered by some as representing collagen and not osteoid.157,160 In contrast to periosteal osteosarcoma, however, juxtacortical chondrosarcoma is composed of low-­grade hyaline cartilage and lacks atypical spindle cell elements. Conventional high-­grade OSs can occur on the surface of a bone and have been designated as surface high-­grade osteosarcomas. They behave as conventional OSs.  Treatment and Prognosis. In the long bones, periosteal osteosarcoma has a prognosis that is intermediate between that of parosteal osteosarcoma and conventional osteosarcoma, with a lower incidence of metastases than conventional osteosarcoma.154,158 The few patients with periosteal osteosarcoma of the jaw were all alive and well at the time of the reports.152–154  EXTRASKELETAL OSTEOSARCOMA Clinical Features. Extraskeletal osteosarcoma accounts for only 2% to 5% of all osteosarcomas.161,162 It occurs in older patients. The mean and median ages are in the sixth decade of

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life, only 5% to 10% of patients are younger than 30 years of age.163–165 The majority of extraskeletal osteosarcomas occur in the lower extremity, with the head and neck region involved in less than 5% of cases. Here, extraskeletal osteosarcoma has occurred in the soft tissues of the face,163 neck,164 floor of the orbit,166 larynx,167 and tongue.168 Extraskeletal osteosarcoma has developed secondary to previous radiation therapy,169 including cases in the head and neck.166  Pathologic Features and Differential Diagnosis. With only rare exceptions, extraskeletal osteosarcomas are high-­ grade lesions whose varied morphologic pattern mirrors that of conventional intraosseous osteosarcoma.161,163 However, other malignant epithelial and mesenchymal tumors may contain focal bone formation and pose diagnostic problems.169 Surface osteosarcomas of bone may invade soft tissue. Before a diagnosis of extraskeletal osteosarcoma is made, therefore other soft-­tissue tumors with bone formation must be excluded and radiologic studies done to exclude an origin in adjacent bone. Important in the differential diagnosis is the distinction of extraskeletal osteosarcoma from myositis ossificans. In its fully developed and mature form, myositis ossificans is composed of compact lamellar bone residing within a fibrous stroma, resembling an osteoma. However, in its evolving early stages, the central portion of myositis ossificans contains immature stromal fibroblasts and myofibroblasts, which may show nuclear atypia, frequent mitotic figures, and florid new bone and osteoid formation, such that it may be impossible to distinguish it from extraskeletal osteosarcoma when only a small amount of biopsy tissue is available. The well-­delimited mature, new bone formation at the peripheral margin of a more mature myositis ossificans is in contrast to the invasive, anaplastic, spindle cell periphery of extraskeletal osteosarcoma that lacks bone maturation. It is imperative that when there is a strong clinical likelihood that the lesion represents a developing myositis ossificans, the pathologist be made aware of such information.  Treatment and Prognosis. Extraskeletal osteosarcoma is highly aggressive, with a high incidence of local recurrence after surgical excision and distant metastases,161,163,165 with most patients dying of the tumor within 2 to 3 years of diagnosis.162,165 

Benign Cartilaginous Tumors CHONDROMA (ENCHONDROMA) Chondromas are rare in the head and neck region. In more than 10,000 bone lesions at the Mayo Clinic, there were no cases of enchondroma in the jaw or facial bones.9 Among 1243 chondromas in four large series, only four (0.32%) were in the head and neck region.7,8,14,16 Clinical Features. Most patients with chondromas are in the second to fourth decades of life7,8; those with head and neck lesions have ranged in age from the first to the eighth decades of life. Chondromas of the head and neck are reported in patients in Ollier disease and Maffucci syndrome.170–172 Chondromas may develop within bone or the soft tissues. Those in the cranial bones usually originate in the base of the skull, with the origin in the sella, clivus, parasellar area, and posterior fossa. Other sites include the nasal cartilage, cervical

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Fig. 8.11  A, Enchondroma shows small, uniform chondrocytes whose nuclei are densely hyperchromatic (ink dot) without a visible chromatin pattern. Cells are well separated from each other. B, An island of hyaline cartilage in an enchondroma is separated from the adjacent bone trabeculae by a zone of normal marrow tissue. This pattern of growth contrasts with that of chondrosarcoma shown in Fig. 8.17.

vertebrae, soft palate, paranasal sinuses, nasopharynx, region of the foramen magnum, eustachian tube, tongue, gingiva, cheek and buccal mucosa, and larynx. Soft-­ tissue chondromas of the oral cavity are believed to be choristomas rather than true neoplasms.13 Chondromas of the cervical spine frequently cause cord or nerve compression with neurologic impairment, including Horner syndrome; respiratory difficulty may be produced by direct pressure on airway passages. Intracranial chondromas produce a variety of signs and symptoms caused by compression of cranial nerves, with resulting nerve palsies, or increased intracranial pressure, with headache, diplopia, visual loss, tinnitus, hearing loss, and facial numbness among the most frequent symptoms, as well as pituitary dysfunction and optic nerve atrophy. Laryngeal chondromas are most frequently associated with hoarseness or dyspnea.173 Owing to the slow growth of chondromas, it is not uncommon for patients either to know of the presence of a mass or to have symptoms for several years before diagnosis.  Pathologic Features. Grossly, enchondromas consist of blue-­white to blue-­gray cartilage with white to yellow foci of calcification. The surface is translucent and has a distinct lobular configuration. Histologically, most chondromas consist of lobules of hyaline cartilage with chondrocytes within well-­formed lacunae.8,174 The chondrocytes are small, with indistinct cytoplasmic borders; nuclei are typically small, round, and densely hyperchromatic (Fig. 8.11A). Occasional binucleate cells may be found but are not numerous. Calcified foci are frequently present. In these areas, the lacunar spaces and the chondrocytes are enlarged, with irregular plump nuclei. Such calcified areas with their enlarged and atypical cells in chondromas should be taken into consideration in evaluating a cartilaginous lesion for the possibility of chondrosarcoma. The cartilage lobules are found in nests between the cancellous bone trabeculae and separated from them by a clear zone (Fig. 8.11B). The periphery of the individual islands of cartilage may show encasement by woven or lamellar bone,175 a sign of slow growth, usually indicating a benign process. In contrast to chondrosarcoma, there is no infiltration of the intertrabecular

marrow spaces with entrapment of the bone trabeculae or cortical Haversian system invasion. The degree of cellularity varies considerably, and those in children and adolescents may be quite hypercellular and contain plump and irregular chondrocytes, so as to resemble low-­grade chondrosarcoma. In adults, occasional chondromas may have chondrocytes that have large, open-­faced nuclei with a visible chromatin pattern and binucleate cells that are easily found to such a degree that chondrosarcoma is suggested. In such cases, a radiologic pattern that shows an absence of cortical destruction or soft-­tissue extension is an important point that favors a benign diagnosis. Those chondromas in Ollier disease and Maffucci syndrome may be more cellular than conventional chondromas, contain atypical nuclei and binucleated chondrocytes, and have a more myxoid stroma, all features that suggest low-­grade chondrosarcoma.176 Again, the radiologic appearance is of critical importance in distinguishing such lesions from chondrosarcoma. Mitoses are extremely rare to nonexistent in chondroma, and the finding of more than a rare mitotic figure indicates a high probability that the tumor is malignant.174 The occurrence of malignant transformation of chondroma is much debated, with some authors claiming that all chondrosarcomas arise from preexisting chondromas,174 whereas others claim to find no evidence of a preexisting chondroma in their chondrosarcoma cases.176 However, it is well accepted that patients with Ollier disease and Maffucci syndrome have a high risk of malignant change in their enchondromas, with a reported incidence that varies from 12% to 50%.8,177,178 The histologic distinction between chondroma and high-­ grade chondrosarcoma presents no difficulty, although its distinction from well-­differentiated chondrosarcoma is among the most difficult problems in orthopedic pathology. Indeed, in the head and neck region, some cartilaginous tumors are found where this separation is not possible. Individual chondrocyte necrosis, numerous binucleated cells, occasional mitotic figures, and enlarged plump chondrocytes, with visible nuclear chromatin are all features that favor a diagnosis of chondrosarcoma, as is invasion of intertrabecular marrow

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spaces and cortical bone.178 However, biopsy tissue specimens may not show these features, and the diagnosis will depend on the experience of the examining pathologist. In the head and neck, we believe that all symptomatic cartilage lesions should be considered and treated as chondrosarcoma. Conventional cytogenetic analysis of chondromas shows simple structural abnormalities, particularly involving chromosomes 6 and 12.179 High-mobility group AT-hook 2 (12q15) has been expressed by reverse transcriptase (RT-­PCR) in 8/14 chondromas and 13/14 chondrosarcomas.180  OSTEOCHONDROMA Osteochondromas tend to occur as isolated solitary lesions, but an autosomal dominant form results in multiple exostoses. Less than 1% of all osteochondromas occur within the head and neck region; among 2381 cases in four series,7,8,14,16 only 14 were in the head and neck. Clinical Features. A solitary osteochondroma occurs in patients in the second decade of life, the majority younger than 20 years of age.7,8,16 In the head and neck, however, spinal and mandibular osteochondromas occur later in life, with patients usually being 40 years of age or older, with some in the sixth or seventh decade of life.181–184 Osteochondromas have developed after external radiation therapy, especially in children.185 In the head and neck region, the cervical spine is the most common location7,8,16; almost one-­half of patients with cervical spine involvement have osteochondromas in other bones.186 Other reported sites include the mandible, maxilla, and, rarely, the cranial bones, especially from the skull base.14 However, some of the tumors reported, as examples of osteochondroma of the skull base, may represent chondromas or well-­differentiated chondrosarcomas. In the spine, osteochondroma is usually situated in the posterior elements (Fig. 8.12) with only rare examples arising anteriorly from the vertebral body.181 In the mandible, the coronoid area and condyle are the most frequent sites. Symptoms caused by osteochondroma depend on its location. Vertebral osteochondromas may cause a variety of neurologic deficits associated with spinal cord compression.187 Pressure from spinal osteochondromas may cause dysphagia and vocal cord paralysis, as well as carotid, subclavian, and vertebral artery compression. Mandibular lesions may produce facial asymmetry, malocclusion, or difficulty in opening the mouth. Lesions of the mandibular condyle typically cause deviation of the mandible to the contralateral side on opening. If superficially located, a painful or painless mass may be found on physical examination. Because of the anatomic complexity of the head and neck region, routine radiographs may not demonstrate the osteochondroma, especially those involving the vertebrae, such that symptoms may be present for relatively long periods before the diagnosis is established.17  Pathologic Features. Osteochondroma may be a pedunculated or sessile mass protruding from the parent bone; its cortex is in direct continuity with the cortex of the affected bone, being enveloped by its periosteum. Externally, it is covered by a cartilaginous cap that is either smooth and uniform or irregular and bosselated with a cauliflower-­like appearance.8 The cartilage caps in adults are generally either only a few millimeters in thickness or completely absent, the latter the result of loss from

Fig. 8.12  Osteochondroma. Lateral radiograph of the spine shows a lobulated, calcified mass rising from the spinous process of C6, without bone destruction or a soft-­tissue mass.

wear and tear abrasion; in children and adolescents, the cap may be several centimeters thick.8,14 In an adult, the development of secondary chondrosarcoma arising in an osteochondroma results in cartilage that is several centimeters thick, usually greater than 2 cm, and such a finding is strongly indicative of malignancy.7,14,188 In the confined space of the head and neck, osteochondromas are usually small. In the spine, they are generally 2 to 3 cm in maximum size, but even here, tumors as large as 7 cm are reported. Mandibular lesions range from 2 to 6 cm. Although osteochondroma is predominantly composed of cancellous bone, its growth is by enchondral ossification of its cartilaginous cap, similar to that which occurs at the epiphyseal growth plate. As such, the growth of an osteochondroma parallels that of the remainder of the skeletal system. When the parent bone in which the osteochondroma occurs ceases its growth, so does the osteochondroma. An increase in the size of a known osteochondroma in a skeletally mature individual is highly suspicious of secondary malignant change. Histologically, the cartilage cap of osteochondroma is composed of hyaline cartilage, the chondrocytes of which usually have a single, small, dark nucleus, and rests within individual lacunae (Fig. 8.13). Binucleate chondrocytes are numerous in young patients and are not an indication of chondrosarcoma, as would be suggested in adult lesions. In actively growing osteochondromas, the chondrocytes align themselves in closely opposed parallel columns with increasing size of the lacunar spaces, as they approach the interface with the underlying cancellous bone. If bone growth has ceased, however, the

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Fig. 8.13  A, Peripheral portion of osteochondroma shows a cartilage cap covered by a layer of periosteum (perichondrium). Active enchondral ossification is present, with widely dilated capillaries present at the base of the cartilage. The marrow is filled with fat. B, Bone within osteochondroma shows persistence of partially ossified hyaline cartilage within the centers of the trabeculae.

chondrocytes are noncolumnated and are widely spaced from each other. The junction of the cartilage with the cancellous bone resembles that of a normal epiphyseal growth plate; the cartilage becomes calcified, is invaded by small blood vessels, and undergoes enchondral ossification with the formation of mature bone trabeculae (see Fig. 8.13A). However, bone trabeculae containing persistent central cores of nonossified or partially ossified cartilage may be found within the deeper portions of the lesion (see Fig. 8.13B). Fatty marrow, with or without hematopoietic elements, is also present within the cancellous portion of the osteochondroma, an important distinction from parosteal osteosarcoma in which marrow elements are not present. If bone growth has ceased, the cartilage-­bone interface appears quiescent without evidence of vascular invasion or enchondral ossification. It has long been debated whether osteochondroma is a developmental disorder or a true neoplasm. Cytogenetic aberrations involving the EXT1 gene located at 8q22-­24.1, in both sporadic and hereditary osteochondromas, favor the latter.189  Treatment and Prognosis. Local excision is curative in almost all cases, provided the entire lesion, with its periosteal membrane, is removed. Although malignant tumors, und­ ifferentiated pleomorphic sarcoma (MFH) and osteosarcoma, are reported to arise in a solitary osteochondroma,190 the most frequent secondary malignant tumor is chondrosarcoma.188 In adults, a thick cartilage cap, increased cellularity, frequent binucleated chondrocytes, enlarged chondrocyte nuclei with a visible chromatin pattern, and occasional mitotic figures are all features of secondary chondrosarcoma. The incidence of malignant change in a solitary osteochondroma ranges in the literature from 1% to 4%.188 However, the true incidence is unknown because many osteochondromas are asymptomatic and never come to medical attention. The incidence of malignant change in multiple osteochondromatosis is higher than in the solitary form, with incidence rates varying from 2% to 25%.8,188 Death secondary to spinal cord compression by osteochondroma has occurred.191 

CHONDROBLASTOMA Chondroblastoma has a strong predilection for the epiphyses of long bones and accordingly, most report an incidence of less than 1% in the head and neck.7,16,192 In the Mayo Clinic series of 495 cases, however, 6.9% were located in the skull or facial bones.193 Clinical Features. Approximately 60% to 75% of chondroblastomas occur in the second decade of life, with mean and median ages ranging from 17 to 22 years.7,8,194,195 Patients with chondroblastoma of the skull or facial bones are older, however,196,197 with mean and median ages in the fourth decade. In the Mayo Clinic series, 83% of the cases in the head and neck region were in patients older than 30 years of age.193,198 Within the head and neck, chondroblastoma has occurred in the mandible, maxilla, cervical vertebra, parietal bone, and occipital bone, but the most frequently involved site is the temporal bone. In a review of 44 cases of chondroblastoma of the cranial bones, 33 were in the neurocranium, with the temporal bone involved in 32 of these cases.199 In general, 80% to 95% of patients with chondroblastoma of any site present because of pain,192,194 which may be associated with local swelling. Patients with temporal bone involvement frequently have associated ear symptoms, including hearing loss, sensation of ear plugging, tinnitus, otalgia, and dizziness or vertigo; seizures also may occur. Patients with vertebral chondroblastoma may have neck stiffness and neurologic symptoms. Many patients seek medical attention within a few weeks to months of the onset of their symptoms, but others have symptoms for several years before diagnosis. Radiologically, chondroblastoma has ranged from 1 to 19 cm but most commonly is approximately 4 cm in maximum size. It is usually a round or oval lytic lesion, which is sharply delimited from the adjacent normal bone and may be bordered by a sclerotic rim. In the head and neck region, however, it is often not as well delimited and may have an aggressive appearance

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Fig. 8.14  A, Chondroblastoma. Axial computed tomography image shows a tumor (arrow) arising from the temporal bone. The matrix of the tumor appears calcific, and there is partial destruction of the cortical bone. B, Coronal magnetic resonance image shows the tumor (arrowhead) arising from the floor of the temporal bone with extension into the middle cranial fossa. Calcium deposits (black) are scattered throughout the tumor.

(Fig. 8.14) with destruction of cortical bone. Focal calcification (see Fig. 8.14B) is apparent in 35% to 50% of cases.194,195  Pathologic Features. Curettage specimens of chondroblastoma consist of friable, reddish-­brown to gray fragments that may contain flecks of calcium; hemorrhagic cystic regions may be present. Histologically, chondroblastoma is characterized by broad areas of round, oval, or polyhedral chondroblasts that have well-­defined cytoplasmic borders; the cytoplasm usually is densely eosinophilic (Fig. 8.15A). Nuclei are round, oval, or reniform and frequently are indented or cleaved (Fig. 8.15B); one or two small nucleoli may be present. Cells with enlarged hyperchromatic nuclei may occur and are more frequently found in chondroblastomas of the head and neck than in other sites.193,194 Mitotic activity is seen in approximately 75% of cases but is usually not abundant, with only one to two mitotic figures per 10 high-­power fields.193–195 Multinucleated osteoclast-­type giant cells occur in 15% to 73% of cases (see Fig. 8.15A).193,195,198 Characteristic foci of individual cell necrosis occur and are associated with dystrophic calcification (Fig. 8.15C) that may form a lacelike arrangement about the individual necrotic cells, creating a chicken-­wire pattern. Such dystrophic calcification occurs in approximately 30% to 67% of cases.193–195,198 Islands of pink chondroid (see Fig. 8.15C) are present in 90% to 97% of cases,193–195 and its presence is taken by some as essential for the diagnosis.197 In chondroblastomas of the head and neck, however, chondroid material is found less frequently than in the long bones and in some cases may be quite scarce.193,198 Epithelioid-­like cells are found in 10% to 15% of cases193,194 and are most prominent in chondroblastomas of the head and

neck.193 There are hemosiderin-­laden tumor cells and macrophages (pigmented cells) in 80% to 90% of head and neck cases. Cystic, hemorrhagic foci that simulate aneurysmal bone cyst (ABC) are seen in 15% to 40% of cases192–195; such lesions have been called cystic chondroblastomas. Hyaline cartilage with enchondral ossification may be found, as well as foci of osteoid and mature bone.14,193,197 Most chondroblastomas are diploid with a low proliferative fraction, as revealed by flow cytometric studies.200,201 They generally express SOX9, FGFR 1 and 3, bcl2, p21, PTHrP, PTHR1, but not RUNX2 or osterix.202,203 Like chondrosarcomas, chondroblastomas show loss of heterozygosity (LOH) on 5q, 9p, 11p,13q and 19q.204 Recurrent structural abnormality involving chromosomes 5 and 8 has been observed, suggesting a preferential involvement of these chromosomes in chondroblastoma.205 Mutations in the H3F3B genes have been reported in a significant percentage of chondroblastomas.206,207 Distinct H3F3A and H3F3B driver mutations define giant cell tumor of bone and chondroblastoma.208  Differential Diagnosis. Although the diagnosis of chondroblastoma does not typically require immunohistochemical stains, the chondroblasts are positive for S-­100 protein and lack reactivity for macrophage markers. Aberrant cytokeratin reactivity has been found in the cells of chondroblastoma.195 SOX-­9 and DOG-­1 may also provide some utility in diagnosis.209 Because of the presence of osteoclast-­type giant cells, a diagnosis of GCT may be considered, but chondroid tissue and hyaline cartilage are not found in true GCT, and driver genes are different, H3F3A for GCT and H3F3B for chondroblastoma.208 Because of the rare occurrence of bone formation in chondroblastoma, osteoblastoma may enter the

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Fig. 8.15  A, Chondroblastoma. Tumor contains compact mononuclear cells with densely eosinophilic cytoplasm and well-­defined borders. Osteoclast-­type giant cells are also present. B, Convoluted and grooved nuclei are present in some cells of this chondroblastoma. Such cells may resemble those of eosinophilic granuloma. C, Focus of dystrophic calcification in chondroblastoma. At the periphery of the focus, islands of pink chondroid are present.

differential diagnosis, but osteoblastoma has a more florid production of osteoid and bone and only rarely contains cartilage. The stroma of osteoblastoma is also more vascular, containing thin-­walled, dilated capillaries, and the stromal cells lack the dense eosinophilic cytoplasm and cleaved nuclei of the chondroblasts in chondroblastoma. The histiocytes in eosinophilic granuloma, with their eosinophilic cytoplasm and cleaved nuclei, may appear similar to the chondroblasts of chondroblastoma and also contain S-­100 protein. However, the cells of eosinophilic granuloma are reactive for CD1a and lack the chondroid and dystrophic calcification found in chondroblastoma. Clear cell chondrosarcoma,210 a tumor that mainly involves the long bones but has also been reported in the maxilla and skull,96,211 may pose a problem in histologic diagnosis. This sarcoma contains chondroblast-­like cells, scattered osteoclast-­ type giant cells, and chicken-­wire–type calcification. However, the cells of clear cell chondrosarcoma have abundant

clear cytoplasm, with distinct cytoplasmic borders, unlike the densely eosinophilic cytoplasm of the cells of chondroblastoma. In addition, small areas of ossification are scattered throughout clear cell chondrosarcoma, and in approximately 50% of the cases, areas of conventional chondrosarcoma are present.210  Treatment and Prognosis. Therapy for chondroblastoma consists primarily of surgical curettage. Local recurrence after such therapy occurs in approximately 15% of cases,192,194,195 with time to recurrence ranging from 5 months to 8 years.192,194 Recurrences are cured by further conservative surgical procedures in almost all cases. Locally aggressive behavior and even metastases and death have been reported in rare cases of chondroblastoma,193,194 including a patient with cervical spine chondroblastoma who died because of direct invasion of the mediastinum.212 Malignant change secondary to radiation therapy is reported in chondroblastoma, as well as spontaneous malignant transformation.213,214 

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Fig. 8.16  A, Chondrosarcoma of vertebrae. Axial computed tomography image shows destruction of the right posterior elements of the vertebral body with extensive calcification. B, Low-­grade chondrosarcoma of the left maxilla. Note the well-­defined expansive, relatively benign-­appearing lesion, with spotty calcification (arrow).

CHONDROSARCOMA Among a total of 2235 cases of chondrosarcoma in four series, 127 (5.7%) were in the head and neck region, with the incidence among the individual series varying from 4.2% to 6.7%7,8,14,16 and 4.9% in the most recent Mayo Clinic series.215 It represents 0.1% of all head and neck neoplasms.216 Clinical Features. In contrast to osteosarcoma, chond­ rosarcoma is uncommon in the first two decades of life,217 with most patients in the fourth to sixth decades.7,8,16,215 There is a slight male predilection.218 In head and neck cases, the peak age of presentation is in the fourth decade219 with mean and median patient ages ranging from 35 to 45 years.86,220–217 Patients younger than 20 years of age are reported.218 This age of onset variation between those tumors arising in the head and neck and other body sites is in the opposite direction to those age differences observed in osteosarcoma. Secondary chondrosarcomas arising in benign precursors, such as osteochondroma or enchondroma are rare.223 There is a 25% to 30% risk of chondrosarcoma developing in patients with Maffucci syndrome and Ollier disease178,224; these patients are generally younger than those with primary chondrosarcoma, with just over half presenting in the third and fourth decades of life.215 In a review of over 300 cases of radiation-­induced sarcomas of the head and neck, just 2.1% have been designated as chondrosarcoma.225 Chondrosarcoma has occurred in virtually every site within the head and neck region, with the most common locations being the maxilla,86,217,226–233 mandible,26,218,226,230 base of the skull,230–227,234 cervical vertebrae,7,8,14,16,221,226,227,230,233 and nasal cavity and nasal septum.8,86,218,226,235 Less common sites include the paranasal sinuses,86,218,226,230 orbit and retrobulbar region,217,226,230 bones of the cranium,16,217,220,222,226,236 hyoid bone,8,230 and nasopharynx.230,237 Chondrosarcoma

of the larynx is discussed separately. Chondrosarcomas in the head and neck region that occur in children are prone to involve the nasal cavity, paranasal sinuses, and facial bones.86,217 In the head and neck, patient symptoms are nonspecific and vary from the presence of a painful or painless mass to headache, hearing loss, and neurologic problems, depending on tumor location. The duration of symptoms has ranged from a few months to 35 years before diagnosis.86,233 Chondrosarcomas of the head and neck have occurred in patients with Ollier disease and Maffucci syndrome.86 Radiologically, chondrosarcoma has the features of an aggressive destructive lesion in almost all cases (Fig. 8.16), with evident calcification in 45% to 80% of cases.41,86,221,222,231,238 Those chondrosarcomas with an extensive myxoid component frequently lack calcification.222 Base of the skull chondrosarcomas cannot be radiologically distinguished from chordoma.234,238 Chondrosarcomas often attain a large size before diagnosis, even in the limited anatomic space of the head and neck. They may be relatively large, with those greater than 10 cm reported.86,233,237  Pathologic Features. On gross examination, erosion of the cortex with soft-­tissue extension is usually present, an important feature distinguishing chondrosarcoma from enchondroma. On sectioning, chondrosarcoma has a lobular, blue-­gray to gray-­white, translucent, glistening surface.7,8 Although firm, they are usually easily cut with a scalpel, except for those areas that appear as yellow to yellow-­white flecks or spicules of dense calcification or ossification.7 Soft, gelatinous, myxoid foci may exist and even predominate in some cases.7,8 Necrosis within the center of the lobules is common.41 Histologically, chondrosarcoma usually contains an abundant amount of hyaline-­type cartilage, with lacunae containing round to oval cells that have enlarged nuclei possessing a clearly

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visible chromatin pattern (Fig. 8.17A). The cells may occur in clusters or be haphazardly arranged in broad sheets. In general, chondrosarcomas are hypercellular, with increasing cellularity in the more poorly differentiated tumors (Fig. 8.17B). Numerous binucleated cells and tumor cells with large, single or multiple nuclei may be found. The occurrence of binucleated cells should not, of itself, be taken as evidence of malignancy, as even the most histologically bland-­appearing chondroma may contain occasional binucleated cells. In chondrosarcoma, however, such cells are much more frequent, being most numerous in the more poorly differentiated tumors. High-­ grade chondrosarcomas have increased numbers of pleomorphic cells with large atypical bizarre nuclei, and foci containing atypical spindle-­shaped cells may also be present (see Fig. 8.17B).7,8,15 Although the finding of mitotic activity in a cartilaginous tumor is an excellent indication of malignancy, even high-­grade chondrosarcomas may

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lack this feature. The lobules of chondrosarcoma usually lack the peripheral encasement by woven or lamellar bone that frequently occurs in chondromas,174,239 although in long-­standing, well-­differentiated chondrosarcoma one may find some bone formation at the peripheral margin of occasional lobules. Both benign and malignant cartilage tumors contain areas of calcification. Within and adjacent to such areas, the chondrocytes are enlarged and may have hyperchromatic irregular nuclei. It is important not to evaluate such areas when trying to determine whether the lesion is cytologically benign or malignant. However, the finding of individual cell necrosis, within areas not marred by calcification or degeneration, is an important clue to the diagnosis of chondrosarcoma.15 Calcified cartilage, whether benign or malignant, may undergo ossification. This bone forms directly on the cartilage and may histologically appear quite normal, even when the preexisting cartilage

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C Fig. 8.17  A, Low-­grade chondrosarcoma. The tumor cells are larger than normal chondrocytes, with larger, open-­faced nuclei that have a uniform, fine chromatin pattern. Several mitotic figures are present, an uncommon finding in most chondrosarcomas. B, High-­grade chondrosarcoma. Hypercellular tumor contains pleomorphic cells, some with large, bizarre nuclei. A few cells are spindle shaped. C, Growth pattern of chondrosarcoma shows infiltration between existing normal bone, resulting in trabeculae that are closely abutted and surrounded by tumor.

8  Bone Lesions

has high-­grade malignant features. Myxoid degeneration of the stroma, with a vacuolated to bubbly appearance, is a common feature in chondrosarcoma. This may be quite extensive, with the cells widely separated within the myxoid matrix and arranged in loose strands or cords. Here the tumor cells may have a vacuolated cytoplasm. Chondrosarcoma infiltrates between existing normal bone trabeculae and directly abuts and surrounds them (Fig. 8.17C), unlike the pattern in enchondroma, in which the islands of cartilage remain apart from the trabecular bone, separated from it by a clear zone of loose fibrous tissue. Chondrosarcoma causes endosteal erosion and invades the cortex, filling the Haversian canals, and extends into the soft tissue, features not found in enchondroma.174,240 The cartilage associated with Ollier disease and Maffucci syndrome may be hypercellular, with a haphazard distribution of cells that frequently reside in a myxoid stroma and demonstrate nuclear atypia, such that care must be exercised to avoid an overdiagnosis of chondrosarcoma. Recourse to the clinical situation and the absence of an aggressive radiologic appearance in such lesions are helpful in avoiding this error. A variety of systems have been used for the grading of chondrosarcoma,8,240,241 with emphasis on such items as nuclear morphology, mitotic activity, and degree of cellularity, usually dividing the tumors into three or four grades (I–IV). Recently, the term atypical cartilaginous tumor has been introduced as a synonym for grade I chondrosarcoma. As in other areas of bone and soft tissue pathology, this is to acknowledge that whilst locally aggressive behavior is possible, regional or distant metastasis is exceptional.242 Most chondrosarcomas are well to moderately differentiated (grades I and II) tumors that contain an abundance of hyaline-­like cartilage, although myxoid or mucinous foci of degeneration may be present.241,243 Most chondrosarcomas in the head and neck region are well-­differentiated (grade I) tumors,86,221,226,234 although here too, myxoid change may be found,86,222 especially in temporal bone lesions.222 Poorly differentiated (grade III) chondrosarcomas are uncommon, regardless of anatomic location. Interobserver variation in grading exists as it does in many areas of pathology, but grading is important, since there are huge variations in metastatic potential; almost negligible in Grade I tumors and in excess of 50% for grade III lesions.216,244  Differential Diagnosis. Despite the foregoing histologic description, the diagnosis of chondrosarcoma may be among the most difficult problems in orthopedic tumor pathology. The diagnosis of high-­grade, poorly differentiated chondrosarcoma usually poses no difficulty, but a low-­grade, well-­differentiated chondrosarcoma may often be impossible, based on histology alone, to distinguish from a benign enchondroma. The occurrence of chondrocytes with enlarged atypical nuclei having a distinct chromatin pattern and individual cell necrosis, although good indicators of malignancy, may be absent in small biopsy specimens, the cartilage resembling that of enchondroma. The interface of tumor and adjacent normal tissue may not be included in the sample, precluding assessment of a permeative growth pattern. Mitoses are usually absent in low-­grade chondrosarcomas, and lack of these cannot be used as an exclusion of malignancy. In addition, enchondromas may contain some cells with enlarged, open-­faced nuclei, as in chondrosarcoma. It is important, in cases in which the histologic pattern is not clear-­cut to assess other parameters,

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including the clinical presentation, location, and radiologic appearance, to determine whether the lesion is malignant. It should be noted that enchondroma of the jaw and facial bones is extremely rare; at the Mayo Clinic, no enchondroma of these sites was found in more than 10,000 tumor cases, so that any clinically symptomatic cartilage lesion in this area is probably best considered malignant.86,215 The histologic distinction between a chondroblastic osteosarcoma, with its abundant malignant cartilaginous component, and chondrosarcoma may also be quite difficult when one is dealing with only small biopsy samples. Although bone formation occurs in chondrosarcoma, it does so on the framework of a preexisting cartilage matrix and not, as in osteosarcoma, directly by malignant stromal cells. However, biopsy may miss the latter areas, obtaining samples of only malignant cartilage. In such cases, the correct diagnosis may be made only after examination of the entire resection specimen. Rare cases of clear cell chondrosarcoma210 have been reported in the head and neck region.211,245 This form of chondrosarcoma is characterized by the presence of large cells, with a clear to granular cytoplasm and well-­defined cell borders, interspersed with osteoclast-­type giant cells and small spicules of bone or osteoid. These clear cell tumors may frequently contain small foci of conventional chondrosarcoma.210 Osteoclast-­type giant cells are not a feature of conventional chondrosarcoma. Only 10 cases in head and neck sites exist in the literature, all arising at sites that are described for conventional chondrosarcoma.246,247 Dedifferentiated chondrosarcoma248 may develop after the local recurrence of a previous low-­grade chondrosarcoma or arise de novo. It occurs predominantly in the long bones and is characterized by the occurrence of lobules or islands of low-­ grade malignant cartilage or normal-­appearing hyaline cartilage that are juxtaposed to sarcomatous spindle cell foci that most often have the features of a high-­grade undifferentiated sarcoma, but at times may show osteosarcomatous, rhabdomyosarcomatous, or angiosarcomatous differentiation.249–252 Because spindle cell areas also occur in high-­grade chondrosarcomas, it is important that the diagnosis of dedifferentiated chondrosarcoma, which has an exceedingly poor prognosis, not be made in the presence of high-­grade malignant cartilage. Dedifferentiated chondrosarcoma has been reported in the supraorbital region230 and larynx.253 Because chondrosarcoma may exhibit a myxoid stroma, in which the tumor cells are widely separated and may contain cytoplasmic vacuoles, the distinction between it and chordoma becomes important, especially in those chondrosarcomas arising in the base of the skull, which are frequently myxoid. The problem is further compounded by the not infrequent occurrence of cartilaginous foci in chordomas of the base of the skull. Such chondroid chordomas may be impossible to distinguish from true chondrosarcoma by routine light microscopy, requiring immunohistochemistry or electron microscopy studies for their distinction (see “Chordoma” section). Immunohistochemistry adds little value in diagnosis of chondroid lesions outside of this setting at present. Differential expression of various immunohistochemical markers, including osteonectin, various metalloproteinases, ezrin, and galectin-­3, have been suggested as aids to diagnostic separation of chondrosarcoma from chondroblastic osteosarcoma.216,219  Genetics. IDH-­1 and IDH-­2 mutations have been described in a high proportion of central chondrosarcomas, but not in all,

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range 38%–70%.242,254 These are thought to occur at an early stage of tumorigenesis and are also encountered in enchondromas of Ollier disease and Maffucci syndrome, hence of no use in the differentiation of benign from low-­ grade malignant lesions. A two hit tumorigenesis model is proposed, whereby early stage mutations of IDH genes (or others) lead to formation of a low-­grade lesion, with acquisition of further mutations that are common to many cancers (p53, pRB, bcl-­2, MAPK/AP1), resulting in tumors that morphologically are of higher grade (II and III).254,255 IDH mutations are also seen in around 50% of dedifferentiated chondrosarcoma, these in addition showing significantly more structural and numerical chromosomal abnormalities.242  Treatment and Prognosis. Prognosis in chondrosarcoma depends primarily on the ability to adequately excise the tumor and surgery is the preferred treatment, but this is often a problem in the restricted confines of the head and neck. Positive surgical margins result in an increased incidence of local recurrence226 and evolution of the lesion to a higher grade. Well-­differentiated chondrosarcomas have a low incidence of metastatic disease and a relatively good prognosis.221,226,252 The 5-­year survival rate for chondrosarcoma of the head and neck has varied from 43% to 95%.86,217,226,256,257 Although considered to be a radioresistant tumor, with some exceptions noted,258 proton beam therapy has been successfully used in the treatment of head and neck chondrosarcoma.256,257,259 The benefit of conventional chemotherapy is negligible,216 particularly in low-­grade tumors but may have a role in high-­grade tumors and those with distant metastases. Chondrosarcoma of the head and neck region usually grows slowly and may cause death by uncontrolled local spread.86,222,226,231 Metastases are not common, with some series having no patients in whom metastatic disease developed,86,222 whereas others report a metastasis rate of 8% to 18%.226 Future targeted treatment modalities show promise for those chondrosarcomas that harbor IDH mutations. IDH-­1 and IDH-­ 2 mutations are encountered in around 20% of acute myeloid leukemias. First-generation inhibitors of mutant IDH have entered clinical trials and are showing promising results in this setting.260–262 

reported to have had symptoms for as long as 18 years,263 most are diagnosed within 1 year of symptom onset.173,265,266 Laryngeal chondrosarcomas vary considerably in size, with lesions as large as 4 to 13 cm reported. Most often they appear as smooth, rounded, soft to hard submucosal masses. The tumor is usually discovered before the occurrence of any invasion beyond the confines of the larynx, although in some series such extension was frequent. Radiologic analysis of the larynx (Fig. 8.18) demonstrates the presence of tumor that, in almost all cases, will characteristically show coarse or stippled calcifications.173,267 CT scanning (see Fig. 8.18B) accurately reflects the site and extent of the lesion.  Pathologic Features. Histologically, the majority, 67%263 of laryngeal chondrosarcomas are conventional, well-­ differentiated (low-­ grade) hyaline tumors173,267,272; however, examples of dedifferentiated,253,267,273–276 myxoid,270,277 and high-­ grade chondrosarcomas are reported,266,278 as are rare radiation-­induced chondrosarcomas.279

A

CHONDROSARCOMA OF THE LARYNX Clinical Features. Chondrosarcoma is the third most common malignancy affecting the larynx, but accounts for only 0.2% of malignant tumors at this site.263 Patients with laryngeal chondrosarcoma are usually between 40 and 70 years of age, mean 62.5 years.263 Only rarely does the tumor occur in people younger than 30 years of age.16,173,264–271 There is a male to female ratio of 3:1.263 Chondrosarcoma has been reported in almost every site in the laryngeal region, including the supraglottic and subglottic regions, the arytenoid, the vocal cord, the epiglottis, the hyoid bone, and the corniculate. However, 70% to 90% of cases arise from the cricoid cartilage, especially the posterior or lateral cricoid,264,265–267 with the thyroid cartilage accounting for an additional 10% to 25% of cases.264,265–267 Symptoms reflect the presence of a mass lesion that obstructs the airway, compresses or involves the vocal cord, or compresses the adjacent esophagus, with hoarseness, dysphagia, and dyspnea being the most frequent presenting symptoms. A cervical mass may be found on palpation. Although some patients are

B Fig. 8.18  A, Laryngeal chondrosarcoma. Lateral xeroradiograph shows a large calcified mass anterior to the C4 to C6 vertebral bodies. The pattern and shape of the calcification are abnormal and not those of normal laryngeal cartilage. B, Computed tomography scan of the larynx shows scattered disorganized calcification posteriorly, with an associated soft-­tissue mass. The anterior component impinges on and narrows the laryngeal airway.

8  Bone Lesions

The diagnosis of laryngeal chondrosarcoma may pose significant problems because the tumor is frequently submucosal; therefore obtaining representative biopsy tissue by endoscopy may be difficult. Also, the well-­differentiated hyaline pattern makes the distinction from benign chondroma frequently impossible.280–282 Indeed, it is not uncommon for the biopsy tissue to be interpreted as a benign chondroma267,281 that is excised, only to have it recur years later as a histologically overt chondrosarcoma.264,280,281 The occurrence of a true chondroma of the larynx is quite rare, however, because more than 90% of all laryngeal cartilaginous tumors are chondrosarcomas.264,265 Any symptomatic cartilage lesion of the larynx is best diagnosed and treated as a chondrosarcoma despite the presence of a bland histologic appearance.  Treatment and Prognosis. Although total laryngectomy for laryngeal chondrosarcoma may be curative, the usual slow growth of this tumor has led to the use of conservative resection for its management.265,280,283 with the aim of organ preservation and maintenance of a functional larynx.216 The most recent data obtained from a systematic review of 592 cases,263 almost all treated by a variety of surgical techniques, revealed recurrences in 24.2% of the group and with 4.8% of patients dying of their disease. Disease specific survival figures were 91.4% at 5 years, 81.8% at 10 years and 68% at 20 years. The patients who died of disease had a higher proportion of more advanced histologically graded tumors (grade II and above). 

Chondrosarcoma Variants MESENCHYMAL CHONDROSARCOMA Clinical Features. Mesenchymal chondrosarcoma (MC) accounts for 3% to 5% of all chondrosarcomas.7,8,14,15,215,284 The tumor may arise either within bone or from the soft tissues. One-­third to one-­half of MCs are extraosseous in origin.285–287 In contrast to conventional chondrosarcoma, the head and neck region is a relatively common location for MC, accounting for 16% to 30% of cases.219,286–284 Although congenital examples of MC are reported,290,291 as well as cases in patients older than 80 years of age,8,287,288,292–289 most patients are in the second to third decades of life,7,8,286–284,292,294 with mean and median ages of 20 to 30 years.7,16,285,286,288,292,294–291 In the head and neck, the mandible287,288,293,294 and maxilla285–283,294,297 are the most frequent sites, with the maxilla less commonly involved than the mandible. Other sites include the orbit,287,291,295 nasopharynx,287,292 ethmoid sinus,292,298 maxillary sinus,292 parapharyngeal-­tonsillar area,299 soft tissue of the face and neck,16,285,296 cerebellum,293 bones of the skull,286,287,293 and cervical vertebrae.287,296 Symptoms are nonspecific, with pain, swelling, or an evident mass. The duration of symptoms is quite variable, with patients having symptoms for as long as 10 years or for only a few days or weeks. Radiologically, intraosseous MC appears similar to conventional chondrosarcoma, being lytic with or without matrix calcification.287,292,294 Those of soft-­tissue origin appear as masses that frequently contain calcification.287  Pathologic Features. Grossly, MC has a gray, gray-­white, or pink surface and is soft, firm, or even hard. Nodules of blue-­

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gray cartilage may be visible, and almost all cases contain white to yellow-­white areas of calcification or ossification.7,8,286,300 In the head and neck, MC varies from 3 to 7 cm in maximum size.288,292,299 Histologically (Fig. 8.19), soft-­tissue and skeletal MCs are identical, showing a biphasic pattern of undifferentiated-­ appearing stromal cells that exist in combination with islands of cartilage. The stromal cells, usually arranged in broad expanses, are small with little cytoplasm and have hyperchromatic, round to spindle-­shaped nuclei. The cells are fairly uniform without significant pleomorphism and resemble the cells of Ewing sarcoma. Mitoses may be either frequent or difficult to find. An abundant, thin-­walled, vascular network is diffusely present among the stromal cells, which protrude into the vascular lumens, creating a pattern of staghorn-­shaped spaces similar to those in hemangiopericytoma (see Fig. 8.19A). An abundant reticulin fiber network is found about the stromal cells. The cartilage in MC may be so abundant that it is easily found in random sections of the tumor or so scarce that numerous sections are required for its discovery. The islands of cartilage tend to be small and cytologically resemble either normal hyaline cartilage or low-­grade chondrosarcoma (see Fig. 8.19B). The interface between the stromal cells and the cartilage is usually quite sharp, although there are cases in which this transition is gradual. The cartilage may show calcification and foci of enchondral ossification. By electron microscopy, the stromal cells of MC have a primitive mesenchymal appearance with a transition to cells that show cartilaginous differentiation; cytoplasmic glycogen is either absent or scant.301 Immunohistochemically, the stromal cells are reactive for vimentin296 but lack S-­100 protein, which, however, is found in the cells of the cartilage islands.302 Reactivity of the tumor cells for CD99 (p30/32MIC2), using antibody O13 with antigen retrieval techniques, is found in the stromal cells with absent or focal weak reactivity in the cells of the cartilaginous foci.303  Differential Diagnosis. The histologic differential diagnosis of MC includes Ewing sarcoma, solitary fibrous tumor, sinonasal glomangiopericytoma, small cell osteosarcoma, and dedifferentiated chondrosarcoma. When adequate tissue is present, the distinction between Ewing sarcoma and MC poses no great difficulty because Ewing sarcoma lacks the reticulin meshwork and vascular pattern of MC, usually has a moderate to abundant amount of cytoplasmic glycogen, and, most importantly, lacks cartilaginous foci. However, small biopsy specimens may only contain the undifferentiated small cell component that is morphologically similar in both tumors, and the cells of both tumors may be positive for CD99. In such cases, the distinction between these two tumors may be impossible by light microscopy and require molecular testing (HEY-­NCOA2 in MC and EWSR1-­FLI1 in Ewing sarcoma) or full examination of a resection specimen. Unlike the relatively high incidence of MC in the head and neck, less than 5% of Ewing sarcomas occur in this region.7,8,41,304 Small cell osteosarcoma is distinguished from MC by the presence of lacelike osteoid strands or tumor bone produced by its cells. Although bone may be found in MC, it arises from enchondral ossification of the cartilage islands and is not formed directly by the stromal cells. Dedifferentiated chondrosarcoma may simulate MC with lobules of normal or low-­grade chondrosarcoma, juxtaposed with spindle-­shaped stromal cells;

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Fig. 8.19  A, Low-­ power view of a hemangio­ pericytoma-­like area in a mesenchymal chondrosarcoma. Tightly compacted small blue cells surround and bulge into gaping vascular spaces. B, Islands of chondroid surrounded by small tumor cells in mesenchymal chondrosarcoma. Nuclei of the chondrocytes within lacunar spaces resemble the nuclei of the stromal tumor cells.

B

however, these spindle cells are large and pleomorphic with highly atypical nuclei, in contrast to the uniform nuclei of the small cells of MC. The stromal areas in dedifferentiated chondrosarcoma may have the pattern of fibrosarcoma, malignant fibrous histiocytoma, or even osteosarcoma, as opposed to the uniformly undifferentiated appearance of the cells of MC. A history of removal of a low-­grade chondrosarcoma also helps separate these two tumors. Glomangiopericytoma, most likely encountered in the sinonasal tract, shows immunohistochemical positivity for smooth muscle actin and nuclear staining of β-­catenin. While solitary fibrous tumor has a similar pattern of staghorn vessels, it is generally a spindle cell neoplasm that is unlikely to be confused with MC. It is positive for CD34 and STAT6. Immunohistochemical positivity for SOX-­9, a regulator of chondrogenesis, can also aid in the differentiation from other small round blue cell tumors.219  Genetics. IDH-­1 and IDH-­2 mutations have not been identified in mesenchymal chondrosarcoma.216,242 A fusion

between two genes that are present in relatively close proximity on chromosome 8 is well described and disease specific.242 It is suggested that a small interstitial deletion of genomic material between the HEY1 and NCOA2 genes results in the fusion, with identification of this genetic aberration allowing for molecular confirmation of the diagnosis on relatively small samples that may not include lesional cartilage.242 At present, whilst thought to be a sensitive marker for mesenchymal chondrosarcoma, there is known but infrequent genetic heterogeneity meaning that in small numbers of cases, false negative results will be obtained.219  Treatment and Prognosis. The clinical course of MC is quite variable, with some patients experiencing early metastases and death, and others having a protracted clinical course with long-­ term survival. In one European series, 15% had metastasis at presentation, this found to influence survival.289 Metastases or local recurrence have occurred more than 10 years after treatment, and in some cases, as long as 20 years after it.287,288,292 Metastases, most commonly to the

8  Bone Lesions

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Fig. 8.20  A, Lobular pattern of myxoid chondrosarcoma. Tumor cells are more closely arranged at the periphery of the lobules. B, Radial, cordlike arrangement of tumor cells in myxoid chondrosarcoma. Cells are embedded in grayish myxoid stroma.

lungs but also to regional or distant lymph nodes and bones, may develop after several local recurrences or in the absence of local recurrence.287 The rate of metastases of MC of all sites varies from 45% to 75%,285,287,288,292,293 with overall 5-­year survival rates in older series ranging from 40% to 55%286– 283,292,305 but more recently reported as high as 70%289; 10-­year survival rates are lower secondary to the development of late metastases.289 In the head and neck, death from tumor has occurred in 35% to 80% of cases.285,286,288,292,293,296 Surgery is the mainstay of treatment,289 with chemotherapy and/ or radiotherapy used in instances of unresectable disease or when metastasis has occurred.  EXTRASKELETAL MYXOID CHONDROSARCOMA Extraskeletal myxoid chondrosarcoma (ESMC) is a malignant mesenchymal tumor of uncertain differentiation and in the most recent World Health Organization (WHO) classification resides within the soft tissue tumor group rather than amongst those arising in bone, or other chondrosarcoma variants. It accounts for 50% polygonal epithelioid cells, with abundant eosinophilic cytoplasm and nuclei with vesicular chromatin and a prominent nucleolus (B). The tumor is positive for Factor XIIIa (C) and ALK1 (D).

basophilia rather than eosinophilia, and absent immunoreactivity for desmin, MyoD1, and myogenin should readily allow for this distinction. Nodular fasciitis not uncommonly affects the parotid gland, where it is often confused with a myoepithelioma; however, keratin expression is lacking.50  EPITHELIOID FIBROUS HISTIOCYTOMA Clinical Features. Epithelioid fibrous histiocytoma (EFH; epithelioid cell histiocytoma) was previously believed to be simply a variant of cutaneous benign fibrous histiocytoma but recently has become recognized as a distinct entity. EFH typically occurs in young to middle-aged adults (mean age approximately 40 years) and presents as a small, flesh-­colored papule on the skin of the extremities.51–55 Head and neck involvement is rare. EFH is a benign neoplasm that only rarely recurs following excision.  Pathologic Features. EFH is a well-­circumscribed dermal-­ based exophytic nodule surrounded by a collar of epidermis at the lesional base (Fig. 9.7A). EFH is defined by having >50% polygonal epithelioid cells, with abundant eosinophilic cytoplasm, and nuclei with vesicular chromatin and a prominent nucleolus (Fig. 9.7B). EFH may have areas of more conventional-­ appearing benign fibrous histiocytoma, though an inflammatory component, giant cells, and collagen trapping is less commonly encountered in EFH. The stroma

is typically highly vascular. Rarely, EFH shows an unusual pattern of pericellular calcification, reminiscent of that seen in chondroblastoma of bone. By IHC, EFH may show limited expression of Factor XIII (Fig. 9.7C) and epithelial membrane antigen (EMA), and is occasionally CD34 and smooth muscle actin positive as well. Desmin, keratin, and S100 protein are negative. Recent studies have shown that EFH consistently harbors ALK rearrangements with associated expression of ALK1 protein (Fig. 9.7D), a finding that solidifies EFH as a distinct entity.56,57  Differential Diagnosis. Other epithelioid cutaneous tumors in the morphologic differential diagnosis of EFH include cutaneous syncytial myoepithelioma and epithelioid sarcoma, tumors that also present in young patients and express EMA. Cutaneous syncytial myoepithelioma, however, is also typically positive for S100 protein and negative for ALK1. Epithelioid sarcomas exhibit more cytologic atypia and a much more infiltrative growth pattern than does EFH, are negative for ALK1, and characteristically demonstrate loss of SMARCB1 expression.  CELLULAR BENIGN FIBROUS HISTIOCYTOMA Clinical Features. Benign fibrous histiocytomas (BFH) are extremely common lesions in the legs, arms, and trunk. However, conventional BFH are extremely unusual in the head and neck, with less than 1% of cases occurring in this

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location.58 For unknown reasons, however, up to 30% of the cellular variant of benign fibrous histiocytoma (CFH) may involve the head and neck.59 CFH present as asymptomatic nodules ranging in size from 50% myxoid areas is significantly better than that of those with less myxoid change, and the diagnosis of “myxoid UPS” or “myxofibrosarcoma” should be restricted to such tumors. Myxofibrosarcomas typically display a multinodular growth pattern, often with diffuse infiltration along preexisting fibrous septae and extension for some distance beyond their grossly apparent borders (Fig. 9.18C and D). Within the myxoid areas, characteristic arcuate or curvilinear, thick-­walled vessels are seen, with the neoplastic cells often appearing to radiate from these blood vessels in a “Christmas tree” pattern. The cells within the myxoid areas are spindled and stellate and have atypical hyperchromatic nuclei. “Pseudolipoblasts,” representing fibroblastic cells with distended endoplasmic reticulum containing myxoid substance are frequently are present, and

B

Fig. 9.17  A, Infantile fibrosarcoma, diffusely infiltrating skeletal muscle. B, The neoplastic cells of infantile fibrosarcoma are usually smaller than those of adult fibrosarcoma, with a high nuclear to cytoplasmic ration, and are associated with numerous small lymphocytes.

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E Fig. 9.18  A, Undifferentiated pleomorphic sarcoma, consisting of highly pleomorphic spindled cells in a variably collagenous background. B, Marked cytologic pleomorphism in undifferentiated pleomorphic sarcoma. C, Myxofibrosarcoma typically grows as a multinodular mass, with juxtaposed myxoid and solid nodules. D, High-­grade myxofibrosarcoma, with strikingly pleomorphic tumor cells radiating from a thick-­walled blood vessel. E, Low-­ grade myxofibrosarcoma containing relatively bland spindled cells and numerous tumor cells distended with myxoid substance (pseudolipoblasts).

should be distinguished from true lipoblasts, which contain optically clear, lipid-­filled vacuoles (Fig. 9.18E).  Differential Diagnosis. UPS is a diagnosis of exclusion. Careful histologic evaluation, looking for evidence of specific differentiation (e.g., smooth muscle, rhabdomyoblasts, osteoid,

cartilage, preexisting areas of well-­differentiated liposarcoma (WDL) or pleomorphic lipoblasts) is the key to distinguishing other pleomorphic sarcomas from UPS. Similarly, evidence of a preexisting in situ or invasive epithelial or melanocytic lesion should point strongly toward the diagnoses of sarcomatoid

9  Soft-Tissue Tumors of the Head and Neck

carcinoma or melanoma, respectively. This is particularly true in the head and neck, where sarcomatoid carcinomas and melanomas far outnumber true sarcomas. IHC for epithelial, melanocytic, myoid, and hematolymphoid markers also plays a critical role in the distinction of UPS from its various mimics. UPS may show limited smooth muscle actin expression, indicating myofibroblastic differentiation (so-­ called pleomorphic myofibrosarcoma), which does not appear to be of clinical significance. Low-­ grade myxofibrosarcoma must be distinguished from myxomas and nodular fasciitis, which lack hyperchromatic cells, pseudolipoblasts and a well-­ developed, thick-­ walled, arborizing vasculature. Myxoid liposarcomas do not show the degree of pleomorphism shown by myxofibrosarcoma, and has a characteristic “chicken-­wire” vascular pattern, different from the thick-­walled vasculature of myxofibrosarcoma. Focal myxoid change may also be seen in essentially any pleomorphic sarcoma. Osteoclast-­like giant cells may be seen in carcinomas and melanomas, as well as essentially any other sarcoma, and these must be excluded before diagnosing “giant cell” UPS.  ATYPICAL FIBROXANTHOMA Clinical Features. The term atypical fibroxanthoma (AFX) should be reserved for small (80% and a roughly similar percentage of SCSRMS and PRMS, as compared to only a smaller percentage of ARMS (19%).414  Genetic Findings. At the cytogenetic level, ERMS are characterized by complex structural and numerical abnormalities, including trisomies of chromosomes 2, 8, and 13.415,416 Molecular analyses commonly show allelic loss at chromosome 11p15, a site containing a number of putative tumor suppressor genes, including IGF2, H19, and CDKN1C.417 By comparative genomic hybridization (CGH), EMRS frequently show whole chromosome copy number alterations, in particular gains of chromosome 8 and high-­level expression of genes from this chromosome.397 A specific translocation has not been associated with ERMS, unlike ARMS. ARMS are characterized in nearly all cases by one of two specific translocations, t(2;13)(q35;q14), found in approximately 80% of cases, or t(1;13) (p36;q14), found in approximately 20% of cases.418 The t(2;13) results in fusion of the PAX3 gene on chromosome 2 to the FOXO1 gene on chromosome 13, whereas the t(1;13) results in fusion of the PAX3 gene of chromosome 1 to the FOXO1 gene.418 Both fusion genes function as potent transcriptional regulators and produce high levels of their respective fusion proteins.419 These gene fusions may be demonstrated by traditional cytogenetics, reverse transcriptase (RT)-­PCR or FISH, and are specific for ARMS, allowing its distinction from other round cell sarcomas.420,421 A subset of ARMS have been described as “fusion negative”; recent molecular genetic and clinical data suggests that such lesions are essentially indistinguishable from ERMS, and the precise classification of these rare tumors remains to be fully elucidated.397 Although SCSRMS were originally thought to be related to ERMS, recent genetic evidence has shown them to represent a distinct entity. SCSRMS, in particular tumors showing sclerosing morphology, typically show mutations involving exon L112R of the MYOD1 gene.378,380,422,423 A subset of cases also show mutations of the PIKC3A gene.378,380 There is also a very rare congenital form of spindle cell RMS that frequently shows rearrangements involving the NCOA2 and/or VGLL2 genes.380 A specific genetic event has not been identified in PRMS. As with other high-­ grade pleomorphic sarcomas, it most often shows complex structural and numerical chromosomal abnormalities.424  Differential Diagnosis. Conventional ERMS may show a spectrum of differentiation, and may therefore be confused with both other primitive round cell tumors, when poorly differentiated, or with rhabdomyomas and leiomyomas, when

9  Soft-Tissue Tumors of the Head and Neck

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Fig. 9.59  A, Spindle cell rhabdomyosarcoma may closely mimic a smooth muscle or fibroblastic tumor. B, Leiomyosarcoma-­like spindle cell rhabdomyosarcoma. Identification of such tumors as rhabdomyosarcoma requires the use of ancillary immunohistochemistry for myogenin and MyoD1. C, Sclerosing rhabdomyosarcoma, consisting of highly malignant round cells in an abundant, vaguely chondroosseous-appearing matrix. D, Microalveolar pattern and primitive round cells in sclerosing rhabdomyosarcoma. E, Desmin expression may be limited in extent in spindle cell/sclerosing rhabdomyosarcoma. F, MyoD1 expression is typically widespread in spindle cell/sclerosing rhabdomyosarcoma, reflecting the MYOD1 mutations that underlie many of these tumors.

well ­differentiated. IHC for desmin, myogenin, and MyoD1 are critical in the distinction of ERMS from other round cell tumors and should be performed on any such tumor in a child. In general, RMS displays greater pleomorphism than do the other common round cell malignancies in the head and neck of children, specifically Ewing sarcoma and lymphoblastic

lymphoma. MPNST with rhabdomyoblastic differentiation (so-­ called malignant Triton tumor) may closely simulate ERMS histologically and immunohistochemically. In general, MPNST with rhabdomyoblastic differentiation occur in much older patients with a long history of NF1, and may arise from a preexisting neurofibroma. Infantile fibrosarcoma occurs in

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Fig. 9.60  A, Sheet-­like growth of large, eosinophilic tumor cells in pleomorphic rhabdomyosarcoma. B, Higher-power view of bizarre-­appearing rhabdomyoblasts in pleomorphic rhabdomyosarcoma.

slightly younger patients than does ERMS, lacks expression on myogenic markers, and harbors a diagnostic translocation, t(12;15) (ETV6-­NTRK3). Extremely well-­differentiated ERMS may be distinguished from rhabdomyomas by the presence of infiltrative growth, mitotic activity, and greater cytologic atypia. ARMS differ from ERMS by virtue of its occurrence in older patients, distinctive pseudoalveolar pattern, usual absence of strap cells, and strong myogenin, rather than MyoD1, expression. Identification of a PAX3 or PAX7-­FOXO1 fusion gene may be necessary for the confident distinction of ARMS from the most primitive forms of ERMS. IHC for myogenic markers is critical in the distinction of ARMS from other small round cell tumors, such as Ewing sarcoma, lymphoblastic lymphoma, small cell carcinoma, and melanoma. Desmoplastic round cell tumor may display a nested pattern reminiscent of ARMS and frequently expresses desmin, but lacks expression of myogenin or MyoD1, and contains a diagnostic t(11;22) (EWSR1-­WT1) gene fusion. Alveolar soft part sarcomas are composed of large, eosinophilic cells, rather than small, round cells. The differential diagnosis of SCSRMS depends to a degree on the relative proportion of spindled and sclerotic areas. Predominantly spindled tumors may resemble a variety of other low- and high-­grade spindle cell sarcomas. In general, a panel of immunohistochemical markers, including desmin and MyoD1 should allow for confident diagnosis of spindle cell RMS. Sclerosing RMS may mimic osteosarcoma or chondrosarcoma, however identification of small foci of rhabdomyoblastic differentiation and appropriate immunostains for myogenic markers should establish the correct diagnosis. The microalveolar pattern of SCSRM may also simulate ARMS, however the absence of strong myogenin expression and negative molecular testing for PAX3/7-­FOXO1 should point toward SCSRMS. The differential diagnosis of PRMS includes a variety of pleomorphic sarcomas, including undifferentiated pleomorphic sarcoma, pleomorphic liposarcoma, and pleomorphic leiomyosarcoma. In general, the cells of PRMS show much more striking cytoplasmic eosinophilia than do these other tumors. Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion. The presence of pleomorphic lipoblasts is definitional of pleomorphic liposarcoma. Pleomorphic LMSs do not express

MyoD1 and myogenin. In children, ERMS may rarely show striking cytologic atypia (so-­called ERMS with anaplasia), and as such cases are currently treated under ERMS protocols; it is important not to diagnose these as PRMS.425  Outcome. The prognosis for pediatric patients with the most common forms of RMS, ERMS and ARMS depends on a combination of histologic type, site, extent of invasion, tumor size, and node status.426–428 Patients with RMS are assigned to risk groups, with the “low-­risk” group consisting of patients with ERMS at favorable anatomical locations and at unfavorable locations if totally resected; long-­ term event free survival for this group is 85% to 95%.429–431 The “intermediate-­risk” category includes all ARMS and ERMS of stage 2–3, group III, with ERMS in this category having a roughly 73% event-­free survival, and ARMS having a slightly worse event-­free survival of 65%. The event-­free survival for “high-­risk” (metastatic) ARMS and ERMS is 35% and 15%, respectively.429–431 The prognosis of patients with advanced disease having PAX7-­ rearranged ARMS may be favorable as compared to those with PAX3 rearrangement, although data is limited.432 There is comparatively little data on the outcome of patients with SCSRMS. Many previously reported cases have behaved in an aggressive fashion, with metastatic disease and death from disease.378–380,386,389,399,423 A recent study of head and neck RMS has shown the behavior of SCSRMS in this location to be similar to that of ARMS, with a 5-­year overall survival of roughly 50%.381 The prognosis of PRMS is dismal, with over 70% of patients dead of disease in less than 5 years.390 

Miscellaneous Tumors BIPHENOTYPIC SINONASAL SARCOMA Clinical Features. Biphenotypic sinonasal sarcoma (BSNS) (previously known as low-­grade sinonasal sarcoma with neural and myogenic features) is a recently described low-­ grade malignancy seen only in the sinonasal tract. BSNS typically arises in the superior aspects of the nasal cavity and ethmoid sinuses of women (male:female ratio is 1:3), ranging in age from 24 to 85 years (mean, 52 years). Patients present with nonspecific

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Fig. 9.61  Biphenotypic sinonasal sarcoma is unencapsulated, entrapping invaginations of surface epithelium (A). It grows as fascicles of monotonous spindled cells with bland, hypochromatic nuclei (B). The tumor is consistently positive for both S100 protein (C) and smooth muscle actin (D).

symptoms, like nasal congestion and facial pressure. Clinically, BSNS behaves relatively indolently. Almost half of patients with BSNS have experienced local recurrences, but none of the tumors have metastasized, and only rare patients have died of their disease.433–436  Pathologic Features. Histologically, BSNS is a poorly circumscribed and unencapsulated tumor, comprised of a uniformly hypercellular proliferation of intersecting fascicles, often exhibiting a “herringbone” fascicular growth pattern (Fig. 9.61A and B). Slit-­like or “staghorn” (hemangiopericytoma-­ like) vessels are also common. The tumor cell nuclei are elongated, uniform, and hypochromatic. A useful histologic feature is the frequent presence of hyperplastic respiratory surface epithelium extending downward and entrapped by the spindle cell tumor (see Fig. 9.61A). BSNS lacks more than occasional mitotic figures or necrosis. By IHC, BSNS characteristically expresses smooth muscle actin, calponin, and S100 protein (Fig. 9.61C–D). Although the expression of S100 protein has been suggested to indicate neurogenic differentiation, SOX10 is consistently negative.433 BSNS is sometimes also focally positive for desmin, EMA, cytokeratin, and transducin-­like enhancer of split 1 (TLE1). Most cases of BSNS exhibit focal nuclear immunoreactivity for β-­catenin.433 Almost all examples of BSNS harbor rearrangements of PAX3,

and the most frequent translocation partner is MAML3. Alternate fusions PAX3-­FOXO1 and PAX3-­NCOA1 have been reported.434,437,438 Interestingly, PAX3-­NCOA1 BSNS often show focal rhabdomyoblastic differentiation, with rare strap cells and myogenin immunoreactivity.434  Differential Diagnosis. The S100 protein positivity may suggest a nerve sheath tumor-­like schwannoma or MPNST. Although schwannomas of the sinonasal tract are often unencapsulated and somewhat hypercellular, they typically display uniform, intense immunoreactivity for S100 protein and SOX10, whereas BSNS tends to show weaker S100 protein expression and is SOX10 negative. MPNST may, like BSNS, show aberrant muscle (i.e., malignant Triton tumor) or epithelial differentiation. However, MPNST is generally much more obviously malignant-­ appearing than is BSNS, with necrosis and considerable nuclear hyperchromasia and atypia. It is likely that examples in the literature, diagnosed as nasal “low-­grade” malignant Triton tumor are, in fact, BSNS. Given the sometimes focal keratin or TLE1 immunostaining, staghorn vasculature, and uniform nuclear features, a MSS is another diagnostic consideration. However, BSNS is negative for synovial sarcoma fusion transcripts by molecular methods. Finally, although the “staghorn” vasculature of BSNS raises the question of SFT, BSNS lacks the abundant interstitial

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collagen and the “patternless” fibroblastic proliferation that characterizes SFT, and lacks expression of CD34 and STAT6. Ultimately, however, demonstration of PAX3 rearrangement is the single most useful ancillary test for the definitive diagnosis of BSNS.  SUPERFICIAL ANGIOMYXOMA AND CUTANEOUS MYXOMA Clinical Features. Superficial angiomyxoma presents as a small, slow-­growing dermal or subcutaneous nodule, usually in the head and neck of adults.439,440 Identical lesions may be associated with the Carney complex, an autosomal dominant disorder with multiple manifestations, including cardiac myxomas, cutaneous myxomas, myxoid fibroadenomas of the breast, spotty cutaneous pigmentation, primary pigmented nodular adrenocortical disease, large cell calcifying Sertoli cell tumor of the testes, pituitary adenomas, and psammomatous melanotic schwannomas.441–443 Angiomyxomas of the external ear are particularly suggestive of Carney complex. Although most angiomyxomas are not associated with Carney syndrome, one should always raise this possibility when confronted with this lesion. All angiomyxomas, whether sporadic or Carney complex–associated, are benign tumors with some capacity for local recurrences.  Pathologic Features. Angiomyxomas are typically poorly circumscribed, typically multinodular, and often entrap dermal adnexal structures, with secondary epithelial proliferation, often in the form of cysts.439,440 Embedded within an abundant myxoid matrix are numerous, arborizing capillary-sized vessels, around which are arrayed bland spindled to stellate cells, lymphocytes and neutrophils (Fig. 9.62A and B). The presence of neutrophils is particularly characteristic of angiomyxoma and assists in its distinction from other low-­ grade myxoid tumors. We have seen examples of angiomyxoma showing loss of the Carney syndrome–associated gene product PRKAR1A, suggesting that this marker may have some value in the diagnosis of angiomyxoma, although formal study is necessary.  Differential Diagnosis. Angiomyxoma is typically confused with other low-­ grade myxoid tumors, including myxofi­ brosarcoma and myxoid liposarcoma. Both myxofibrosarcoma and myxoid liposarcoma are rare in the head and neck, and typically present as much larger, more deeply situated tumors. Angiomyxomas lack the hyperchromatic spindled cells and the arborizing thick-­ walled vessels seen in myxofibrosarcomas, and may contain neutrophils, which are not typically a feature of myxofibrosarcomas. Myxoid liposarcomas usually show a much more fully developed, arborizing capillary network, show accentuated peripheral cellularity, and contain uni-­and multivacuolated lipoblasts, often found in association with capillaries. 

firm, single or multiple nodules that mimic nonspecific ulcers or “infected warts.” Most are less than 3 cm at initial diagnosis. ESs recur in over 70% of cases, often as multiple subcutaneous nodules in the more proximal extremity.444–446 For this reason, even in this era of conservative, micrographic, and limb salvage surgery, aggressive local therapy (i.e., wide excision or ray amputation) may be indicated at the time of initial diagnosis. Nearly 50% of ESs will eventually metastasize distantly, most often to lymph nodes and the lungs, but also to skin and softtissue sites.444–446 Almost all patients with metastatic disease will die of disease. ESs are not graded under the FNCLCC grading system.260 Adverse prognostic features include male sex, proximal location, size >5 cm, deep location, high mitotic rate, necrosis, and vascular invasion.  Pathologic Features. ESs typically grow as distinctly nodular, vaguely circumscribed, but invariably infiltrative masses, which typically undergo central necrosis. Fusion of individual tumor nodules and extension along tendons may create a garland-­ like or scalloped appearance. This pattern of necrosis and the relatively bland nuclear features of the neoplastic cells may closely mimic a granulomatous process, such as a necrobiotic granuloma.444–446 This mimicry is further enhanced by the chronic inflammatory cell infiltrate seen around many tumors. The neoplastic cells range from small epithelioid

A

EPITHELIOID SARCOMA Clinical Features. ESs most commonly occur in the hands, fingers, and lower arm of adolescents and young adults but may occur in essentially any location and any age group.444–446 Less than 1% of ESs involve the head and neck; lesions in this location seem to be more common in the scalp, nose, and ears, and in young children.447–450 Many occur in association with a tendon or aponeurosis, however they may involve skin away from such structures. Clinically, these lesions typically present as ulcerated,

B Fig. 9.62  A, Superficial angiomyxoma (cutaneous myxoma), a myxoid dermal tumor containing numerous small blood vessels. B, Arborizing small blood vessels, bland fibroblastic cells, and stromal neutrophils in superficial angiomyxoma.

9  Soft-Tissue Tumors of the Head and Neck

cells, to larger rhabdoid cells, to elongated and distinctly spindled forms (Fig. 9.63A–C). The cells usually have distinctly eosinophilic cytoplasm and relatively uniform appearing, but hyperchromatic nuclei. ESs may be deceptively bland, although careful inspection will invariably reveal hyperchromatic cells. Some ESs consist almost entirely of spindled cells, mimicking both benign and malignant spindle cell tumors, such as benign fibrous histiocytoma or fibrosarcoma.307,451 ESs occasionally blend in with the overly­ ing epidermis, closely simulating squamous cell carcinoma, may display poor cellular cohesion, hemorrhage and pseudovascular space formation, mimicking angiosarcoma, and may contain calcifications and/or bone, suggesting synovial sarcoma or calcifying aponeurotic fibroma. By IHC, ESs coexpress both keratins and vimentin, and express CD34 in roughly 50% of cases. ESs express a wide variety of different keratins, including both high-­and low-­ molecular-­ weight keratins.307,445,452–454 In general, they do not express keratins 5/6, a finding that may help to distinguish them from squamous cell carcinomas.455 A small number of epithelioid sarcomas are cytokeratin ­negative. Epithelioid sarcomas do not show CD31, FLI-­1 or vWF expression, distinguishing them from epithelioid angiosarcomas.351 They may, however, show variable expression of erythroblast transformation-­specific (ETS)-related gene (ERG) protein, depending on which ERG antibody is used.456 Roughly 90% of ESs demonstrate loss of SMARCB1

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(Fig. 9.63D), a finding particularly helpful in their distinction from carcinomas and keratin-­positive endothelial tumors, which show retained (normal) expression.457,458 Loss of SMARCB1 expression in ESs is typically the result of gene deletions, unlike the SMARCB1 mutations that typify rhabdoid tumors.459  Differential Diagnosis. Granulomatous inflammation is the best known and potentially the most serious pitfall in the diagnosis of ES. Careful attention to the typical admixture of epithelioid and spindled cells and the distinct hyperchromatism of the neoplastic cells in ES, in conjunction with cytokeratin immunostains, should allow this distinction in most cases. ESs with hemorrhage and poor cellular cohesion may closely mimic angiosarcoma. Although both ES and angiosarcomas may express low-­ molecular-­weight keratins, vimentin and CD34, ESs may be distinguished from angiosarcoma by positive staining for high-­ molecular-­ weight keratins and negative staining for SMARCB1, CD31, FLI-­ 1 protein, and vWF. ES-­ like/ pseudomyogenic hemangioendotheliomas may closely resemble ESs and show keratin expression but are CD34 negative and SMARCB1 retained. ESs may appear to blend into the overlying epidermis, simulating and invasive and in situ squamous cell carcinoma. Unlike most squamous cell carcinomas, ESs do not show squamous pearl formation and often appear to blend into the surrounding collagen.

A

B

C

D

Fig. 9.63  A, Malignant-­appearing epithelioid cells with central necrosis in epithelioid sarcoma. B, A characteristic feature of epithelioid sarcoma is this admixture of epithelioid and spindled cells, with imperceptible transition between the two forms. Highly spindled epithelioid sarcomas may be easily mistaken for cellular fibrous histiocytomas. C, Despite their aggressive behavior, epithelioid sarcomas are usually composed of deceptively bland cells. D, Loss of expression of SMARCB1 protein is seen in approximately 90% of epithelioid sarcomas.

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Immunohistochemistry for CD34 (positive in 50% of ESs and negative in carcinomas), p63, or p40 (markers of squamous stem cells positive in squamous cell carcinoma, but usually not in ESs), cytokeratin 5/6 (positive in squamous cell carcinoma but usually not in ESs), and SMARCB1 (retained in squamous cell carcinoma, lost in most ESs) may be very helpful. Exclusively or largely spindled epithelioid sarcomas are deceptively bland appearing and often contain hyalinized collagen, and may very closely simulate BFH. This is of particular concern in unusual locations, such as the head and neck, where clinical suspicion for epithelioid sarcoma may be extremely low. ESs do not contain the secondary elements seen in BFH, such as foamy macrophages and siderophages, and show a greater degree of nuclear hyperchromatism (although this may be very subtle). Keratin immunostains are often critical in making this crucial distinction, and one should have a very low threshold for performing such immunostains on any suspicious lesion, particularly in a child. ESs may be Factor XIIIa p ­ ositive, and this marker is not helpful in this differential diagnosis.  ALVEOLAR SOFT PART SARCOMA Clinical Features. Although most cases of alveolar soft part sarcoma (ASPS) occur in the deep soft tissues of the extremities, a substantial percentage occur in the head and neck, in particular, the orbit and tongue. The head and neck appears to be a particularly common location for ASPS in children. ASPS is extremely rare, accounting for less than 1% of soft-tissue tumors overall. Approximately 60% of ASPS occur in women.460 ASPS usually present as painless masses, which may be highly vascular on imaging studies. ASPS of the orbit and tongue are often quite small at the time of initial diagnosis. ASPS are relatively indolent, but relentless sarcomas, characterized by late metastases and an extended clinical course. The largest series to date has reported survival rates of 77% at 2 years, 60% at 5 years, 38% at 10 years, and only 15% at 20 years.460 Lingual and orbital tumors appear to have very high survival rates, likely reflecting a combination of small size at time of diagnosis and younger patient age.461,462 ASPS most frequently metastasize to lungs, brain, and bone. Systemic therapy does not appear to be effective in the treatment of ASPS.460,463  Pathologic Features. ASPS is characterized by uniform, organoid nests of polygonal tumor cells, separated by

A

fibrovascular septa and delicate capillary-­ sized vascular channels.464,465 Within these nests, there is prominent cellular discohesion, imparting the characteristic pseudoalveolar pattern (Fig. 9.64A and B). Some tumors may be composed of sheets of epithelioid cells. Tumors occurring in younger patients and in confined locations, such as the tongue, often show very small nests of cells, closely mimicking paragangliomas.462 Intravascular tumor extension is present in most cases. The cells of ASPS have distinct cell borders and abundant eosinophilic to clear, somewhat granular cytoplasm. A characteristic finding is the presence of PAS-­positive, diastase-­resistant crystalline structures, which may be rhomboid, rod-­like, or spiked, in individual, sheaf-­like or stacked configurations.466 The cells of ASPS typically have round, regular, eccentrically placed nuclei with vesicular chromatin and a prominent central nucleolus; multinucleation may be present in a minority of cells. Mitotic activity is usually low and necrosis is infrequent. IHC plays a very limited role in the diagnosis of ASPS. ASPS are negative for keratins, EMA, chromogranin A, synaptophysin, HMB45, and Melan A. Nonspecific markers such as neuron-­ specific enolase and vimentin may be present in roughly 30% to 50% of cases. Antibodies to pan-­muscle actins, smooth muscle actins, and skeletal muscle actins, have been reported to be positive in nearly 50% of ASPS. Desmin expression may be seen in close to 50% of ASPS, typically only in a small number of cells. Despite this occasional expression of actins and desmin, there is no convincing evidence that ASPS show myogenous differentiation, inasmuch as they are consistently negative for specific markers of skeletal muscle differentiation, such as myogenin and MyoD1. ASPS are characterized by a tumor specific der(17) t(X;17) (p11;q25) that fuses the TFE3 gene at Xp11 to the ASPSCR1 (ASPL) gene at 17q25, creating an ASPSCR-­TFE3 fusion protein.467 Demonstration of TFE3 rearrangement by FISH is diagnostic, in the appropriate clinical and morphological context. Unfortunately, IHC for TFE3 is much less specific, with TFE3 immunoreactivity frequently being found in potential morphological mimics, such as granular cell tumor.183,468 The characteristic crystals of ASPS consist of aggregates of the monocarboxylate transporter protein MCT1 and its cellular chaperone, CD147.469  Genetic Features. At the genetic level, ASPS is characterized by an unbalanced translocation: der(17)t(X:17)(p11;p25), resulting in the fusion of a gene of unknown function, ASPSCR, on chromosome 17 to the TFE3 transcription factor gene on the X chromosome.467 It has been suggested that the female

B

Fig. 9.64  A, Alveolar soft part sarcoma with extension into a vein. Intravascular extension is almost always present. B, Nests of dishesive eosinophilic cells, with prominent nucleoli typify alveolar soft part sarcoma.

9  Soft-Tissue Tumors of the Head and Neck

predominance seen in patients with ASPS is caused by the presence of two X chromosomes in these patients, increasing their chances of a translocation involving this chromosome.467  Differential Diagnosis. The differential diagnosis of ASPS includes neoplasms that may show nested/organoid patterns of growth and cells with abundant eosinophilic cytoplasm, including metastatic carcinoma (renal, adrenal, hepatocellular), paraganglioma, melanoma, and granular cell tumor. Positive TFE3 FISH and negative immunostaining for keratins, melanocytic markers (e.g., HMB45), and chromogranin/synaptophysin should allow the ready discrimination of ASPS from carcinomas, melanomas, and paragangliomas, respectively. Granular cell tumors lack the striking cytologic atypia seen in ASPS, in most instances, and show strong S100 protein expression. TFE3, again, is often expressed by granular cell tumors.470 TFE3 rearrangement is also seen in a rare group of renal cell carcinomas, often occurring children, which are characterized by nested architecture and voluminous cytoplasm and may closely mimic ASPS.471,472 Similar tumors have not, however, been reported to occur in the head and neck.  OSSIFYING FIBROMYXOID TUMOR OF SOFT PARTS Clinical Features. Ossifying fibromyxoid tumor of soft parts (OFMT) is an extremely rare mesenchymal tumor that may occur

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in essentially any soft-tissue location. However, approximately 10% to 15% of OFMT involve the head and neck.473–477 OFMT occur almost always in adults, where they present as relatively small, painless masses, often with a radiographically apparent shell of bone. OFMT of the sinuses and orbit may erode bone and appear clinically and radiographically aggressive. Although OFMT were initially felt to be benign tumors, they are now classified by the WHO as mesenchymal tumors of intermediate (borderline) malignancy, as even histologically benign OFMT may produce distant metastases in up to 6% of cases.8,473,477 Histologically, malignant OFMT behave as high-­ grade sarcomas, with distant metastases and adverse patient outcomes in nearly 60% of reported cases.  Pathologic Features. Typical OFMT are characterized by a peripheral shell of bone in 70% of cases, lobulated growth, and small, bland cells arranged in cords and nests within a fibromyxoid stroma. The stroma of OFMT varies from highly myxoid to fibrous, and may be on occasion hyalinized and calcify. OFMT vary little from case to case, and are typically composed of small, round to oval cells with scant eosinophilic cytoplasm, and round, regular nuclei with fine chromatin and indistinct nucleoli (Fig. 9.65A and B).473,475,477–479 A very characteristic feature of OFMT is its even and regular cell-­cell spacing. Mitotic activity is usually very low. Blood vessels are

B

A

C Fig. 9.65  A, Approximately 70% of ossifying fibromyxoid tumors of soft parts have a peripheral shell of metaplastic bone. B, Typical ossifying fibromyxoid tumor, with fibromyxoid-­appearing matrix and small, bland round cells arranged in vague rosette-­like structures, with uniform cell-­cell spacing. C, Malignant ossifying fibromyxoid tumor, showing high cellularity and nuclear grade.

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typical abundant and may be hyalinized. Malignant OFMT maintain the overall cytoarchitectural features of benign OFMT but show greatly increased cellularity with nuclear overlapping, coarse chromatin and prominent nucleoli, and mitotic activity of >2/50 HPF (Fig. 9.65C).473,478–480 The neoplastic cells may take on a more spindled appearance and grow in short fascicles, reminiscent of malignant peripheral nerve sheath tumor, or may be embedded in a markedly hyalinized matrix, simulating sclerosing epithelioid fibrosarcoma. There is often marked accentuation of the normal lobular growth pattern. Bone production may either be absent or may be increased, sometimes within the center of the lesion. Necrosis and vascular invasion are often present. S100 protein is expressed by over 70% of typical OFMT and by a smaller percentage of atypical and/or malignant OFMT (∼50%). It should be emphasized that S100 protein expression is typically limited in extent in OFMT, and may be entirely absent. Between 5% to 15% of OFMT will show focal, “anomalous” expression of keratin, smooth muscle actin or desmin.473,479 Some OFMT may also express other markers of putative nerve sheath differentiation, such as CD56, neurofilament, CD57, “neuron-­ specific” enolase, and glial fibrillary acidic protein.473,474,479,481 OFMT characteristically demonstrates a “mosaic” pattern of SMARCB1 expression loss, with SMARCB1 deletion by FISH.479 Recent studies have shown that 50% to 80% of OFMTs harbor PHF1 rearrangements, with rare cases showing variant fusions, involving BCORL1 and WWTR1.478,480,482,483 Similar rearrangements are seen in morphologically typical, atypical and malignant OFMT, further confirming the clinical and histological spectrum of these rare tumors.479 480,483  Differential Diagnosis. OFMT may be confused with epithelioid nerve sheath tumors, such as epithelioid schwan­ noma, mixed tumor/myoepitheliomas, extraskeletal myxoid chondrosarcomas, and osteosarcomas. Epithelioid schwanno­ mas lack the bone shell and extremely uniform cell-­cell spacing seen in OFMT, and often arise adjacent to a nerve, a feature lacking in OFMT. Epithelioid MPNST show much greater cytologic atypia than do OFMT, often resembling melanoma. Mixed tumors/myoepitheliomas do not produce a bone shell, usually show clear-­ cut epithelial differentiation, and express epithelial markers, such as keratins, much more often than do OFMT. EWSR1 rearrangements, but not PHF1 rearrangements are often seen in soft-tissue myoepithelial tumors. Extraskeletal myxoid chondrosarcomas are extremely rare in the head and neck, and contain distinctly eosinophilic cells that grow in nests, cords and chains, often with abundant associated hemorrhage and hemosiderin staining. Osteosarcomas lack a lobular growth pattern, show much greater cytologic atypia and pleomorphism than do even malignant OFMT, and often produce abundant lace-­ like osteoid, as well as malignant-­ appearing chondroid matrix.  EWING SARCOMA Clinical Features. Ewing sarcomas (ES) are rare sarcomas of bone and soft tissue, which uncommonly involve the head and neck, in both bone and soft-tissue locations.484,485Although ES and primitive neuroectodermal tumor were originally regarded as totally separate entities, they are now regarded as ends along the histologic spectrum of a single neoplasm, sharing in over 90% of cases, a balanced translocation (11;22) (q24;q12).486 The term primitive neuroectodermal tumor (PNET) has fallen out of favor.

ES may arise in patients of any age, but most commonly involve patients less than 30 years of age. Essentially, any location in the head and neck can be involved. ES are high-­grade sarcomas, with a just over 60% 10-­year survival rate reported in pediatric ES of the head and neck treated with multimodality therapy.487 This is roughly similar to the survival of patients with ES at other locations, also treated with modern multimodality therapy.488  Pathologic Features. In its classic form, ES shows a sheet-­like to vaguely lobular growth pattern, a well-­developed capillary vasculature, and uniform cell population of round cells with small amounts of clear to lightly eosinophilic cytoplasm, regular nuclear contours, finely dispersed chromatin, and inapparent or small nucleoli (Fig. 9.66A and B). Geographic necrosis and individual degenerating cells are frequently present.489 Features suggesting more complete neuroectodermal differentiation include pseudorosette formation and a mild to moderate degree of spindling.489 There are also rare and unusual histologic variants of ES, in particular large cell (“atypical”), and “adamantinoma-­like” ES.489–491 The adamantinoma-­like variant has been increasingly reported in the head and neck (especially sinonasal tract, parotid, thyroid) and shows features of classic ES, but also evidence of squamous epithelial differentiation, including peripheral nuclear palisading and diffuse expression of keratins, including high-­ molecular-­ weight keratins (Fig. 9.66C and D).492 Identification of these variants usually requires cytogenetic and/or molecular genetic confirmation, either by FISH or RT-­PCR, looking for evidence of the t(11;22) (EWSR1-­FLI1) or one of the variant translocations. It is likely that cases previously regarded as representing ES with spindled morphology in the head and neck represent instead EWSR1-­ rearranged soft-tissue myoepithelial neoplasms.489,493,494 There is also an emerging family of “Ewing-­like” sarcomas, characterized by rearrangements involving the CIC and BCOR genes.495–500 These will be discussed in greater detail in the following section of this chapter. By IHC, the overwhelming majority of ES/PNET show intense membranous expression of CD99 (p30/32, MIC2), and one should be extremely reluctant to make this diagnosis in the absence of this finding. IHC for FLI1 protein, identifying the EWSR-­FLI1 fusion protein, is positive in close to 90% of histologically typical ES, and may at times be useful in confirming this diagnosis.489 ERG protein expression is seen in ES harboring EWSR1-­ERG fusions.501 NKX2.2 and PAX7 are also highly sensitive and specific for ES, especially when used in combination with CD99.414,502 Approximately 25% of ES may show anomalous expression of keratins.489,503 Keratin expression is usually confined to only scattered cells, but may be extensive at times, particularly in the extremely rare “adamantinoma-­ like” variant of ES.489,490,492,504,505 Adamantinoma-­ like ES also expresses p63, p40, and high-­ molecular-­ weight keratins in keeping with squamous differentiation.492,504,505 With the exception of this very rare variant, ES express only low-­ molecular-­ weight keratins. Anomalous desmin expression may be seen in a very small minority of cases (55 years, and having >4 mitoses/10 HPF having a high risk of metastasis and death.580 Histologically, benign SFT should be treated with complete excision and careful follow-­up; malignant SFT may require adjuvant therapy.  Pathologic Features. Classic SFT show a uniformly distributed, prominent vasculature, composed of branching and often hyalinized thick and thin-­walled blood vessels (“staghorn” pattern). The neoplastic cells are generally normochromatic, small to medium sized, ovoid, and undifferentiated ­ appearing, and are somewhat randomly distributed around the blood vessels (Fig. 9.72A and B).577 The intervening stroma is usually partially hyalinized but generally does not show the abundant collagen seen in classic cases of SFT. Myxoid change may be seen. A subset of SFT shows a variable percentage of mature fat (“lipomatous SFT”), which may on occasion closely mimic a WDL.581–583 The cells of SFT are often arranged in short fascicles or occasionally storiform arrays (Fig. 9.72C and D). Areas within the tumor may show an entirely haphazard arrangement of neoplastic cells (“patternless pattern”). Broad areas of hyalinization and collagenization are frequently present, with associated cracking artifact.578,579,584 Occasional cases contain mature fat or multinucleated giant cells (so-­ called giant cell angiofibroma) (Fig. 9.72E).585,586 Benign SFT within the nose may show an infiltrative growth pattern, which does not connote malignancy. Mitotic activity is low and nuclear pleomorphism is usually absent. Malignant change in SFT is often in the form of “dedifferentiation”, with an abrupt transition to a pleomorphic, undifferentiated-­ appearing sarcoma. By immunohistochemistry, most SFT are intensely CD34 ­positve, although occasional cases may show only patchy, weak, or even absent staining.578,579,584 Myoid markers and S100 protein are negative. CD99 and bcl-­2 are frequently positive, and nuclear β-­catenin expression may be seen.587–590 Cytokeratin and EMA expression may be seen on occasion

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A

B

C

D

E Fig. 9.71  A, Phosphaturic mesenchymal tumor, mixed connective tissue type, showing small, innocuous-­appearing spindled cells, abundant myxoid matrix, small capillaries, and “grungy” calcification. B, Bland spindled cells embedded in a calcifying matrix, in phosphaturic mesenchymal tumor, mixed connective tissue type. C, For unknown reasons, phosphaturic mesenchymal tumors of the sinonasal region lack calcified matrix and consist instead of glomoid-­appearing cells admixed with mature fat, often with scattered osteoclast-­like giant cells. D, Osteoclast-­like giant cells, hemorrhage and bland spindled cells in sinonasal phosphaturic mesenchymal tumor. E, Chromogenic in situ hybridization for FGF23 messenger ribonucleic acid (mRNA) may be very helpful in confirming the diagnosis of phosphaturic mesenchymal tumor.

in otherwise typical SFT, but seems to be more common in malignant SFT. Recently, it has been shown that SFT harbor a NAB2 -­STAT6 fusion, which appears to be entirely specific.591 This fusion leads to the nuclear expression of STAT6 protein, and STAT6 IHC is highly sensitive and specific for

SFT (Fig. 9.72F).592,593 Expression of STAT6 may, however, be limited in extent.  Differential Diagnosis. Essentially any mesenchymal tumor, in particular synovial sarcoma, LMS, and MPNST may show a prominent HPC-­like vascular pattern. Application of

9  Soft-Tissue Tumors of the Head and Neck

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B

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D

E

F

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Fig. 9.72  A, Branching, “staghorn” blood vessels in solitary fibrous tumor. B, The neoplastic cells of solitary fibrous tumor are oval to spindled and usually arranged in a somewhat “random” fashion around the blood vessels. C, Like sinonasal schwannomas, otherwise-­typical sinonasal solitary fibrous tumors may grow in an infiltrative fashion. D, Branching blood vessels, abundant collagen and a “patternless” growth pattern in solitary fibrous tumor. E, Solitary fibrous tumors with multinucleated syncytial tumor cells, as shown here, have been referred to as giant cell angiofibromas. These are relatively frequent in the orbit. F, STAT6 expression in solitary fibrous tumor.

a panel of immunostains including CD34, STAT6, keratins, S100 protein, actin, and desmin will assist in the identification of these potential mimics. SFT share some features with MSS, such as wiry collagen and HPC-­like vessels, but lack the clearly

malignant spindled cells and alternating zones of hypo-­and hypercellularity seen in the latter tumor. Lipomatous SFT lack the enlarged, hyperchromatic cells present within fibrous septae and blood vessel walls seen in atypical lipomatous tumors.

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566. van Nederveen, F.H., Gaal, J., Favier, J., Korpershoek, E., Oldenburg, R.A., de Bruyn, E.M., et al., 2009. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 10(8), 764–771. 567. Williams, M.D., Rich, T.A., 2014. Paragangliomas arising in the head and neck: a morphologic review and genetic update. Surg. Pathol. Clin. 7(4), 543–557. 568.  Folpe, A.L., Fanburg-­ Smith, J.C., Billings, S.D., Bisceglia, M., Bertoni, F., Cho, J.Y., et al., 2004. Most osteomalacia-­ associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am. J. Surg. Pathol. 28(1), 1–30. 569. Weidner, N., Santa Cruz, D., 1987. Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer. 59(8), 1442–1454. 570. Kumar, R., 2002. New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-­ related protein-­ 4 are phosphaturic factors derived from tumors associated with osteomalacia. Curr. Opin. Nephrol. Hypertens. 11(5), 547–553. 571. Lee, J.C., Su, S.Y., Changou, C.A., Yang, R.S., Tsai, K.S., Collins, M.T., et al., 2016. Characterization of FN1-­FGFR1 and novel FN1-­ FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod. Pathol. 29(11), 1335–1346. 572. Lee, J.C., Jeng, Y.M., Su, S.Y., Wu, C.T., Tsai, K.S., Lee, C.H., et al., 2015. Identification of a novel FN1-­FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J. Pathol. 235(4), 539–545. 573. Agaimy, A., Michal, M., Chiosea, S., Petersson, F., Hadravsky, L., Kristiansen, G., et al., 2017. Phosphaturic mesenchymal tumors: clinicopathologic, immunohistochemical and molecular analysis of 22 cases expanding their morphologic and immunophenotypic spectrum. Am. J. Surg. Pathol. 41(10), 1371–1380. 574.  Florenzano, P., Gafni, R.I., Collins, M.T., 2017. Tumor-­ induced osteomalacia. Bone Rep. 7, 90–97. 575. Singh, D., Chopra, A., Ravina, M., Kongara, S., Bhatia, E., Kumar, N., et al., 2017. Oncogenic osteomalacia: role of Ga-­68 DOTANOC PET/ CT scan in identifying the culprit lesion and its management. Br. J. Radiol. 90(1072), 20160811. 576. Carter, J.M., Caron, B.L., Dogan, A., Folpe, A.L., 2015. A novel chromogenic in situ hybridization assay for FGF23 mRNA in phosphaturic mesenchymal tumors. Am. J. Surg. Pathol. 39(1), 75–83. 577. Enzinger, F.M., Smith, B.H., 1976. Hemangiopericytoma. An analysis of 106 cases. Hum. Pathol. 7(1), 61–82. 578. Vallat-­Decouvelaere, A.V., Dry, S.M., Fletcher, C.D., 1998. Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-­thoracic tumors. Am. J. Surg. Pathol. 22(12), 1501–1511. 579. Gold, J.S., Antonescu, C.R., Hajdu, C., Ferrone, C.R., Hussain, M., Lewis, J.J., et al., 2002. Clinicopathologic correlates of solitary fibrous tumors. Cancer. 94(4), 1057–1068.

580. Demicco, E.G., Park, M.S., Araujo, D.M., Fox, P.S., Bassett, R.L., Pollock, R.E., et al., 2012. Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod. Pathol. 25(9), 1298–1306. 581. Guillou, L., Gebhard, S., Coindre, J.M., 2000. Lipomatous hemangiopericytoma: a fat-­ containing variant of solitary fibrous tumor? Clinicopathologic, immunohistochemical, and ultrastructural analysis of a series in favor of a unifying concept. Hum. Pathol. 31(9), 1108–1115. 582. Folpe, A.L., Devaney, K., Weiss, S.W., 1999. Lipomatous hemangiopericytoma: a rare variant of hemangiopericytoma that may be confused with liposarcoma. Am. J. Surg. Pathol. 23(10), 1201–1207. 583. Nielsen, G.P., Dickersin, G.R., Provenzal, J.M., Rosenberg, A.E., 1995. Lipomatous hemangiopericytoma. A histologic, ultrastructural and immunohistochemical study of a unique variant of hemangiopericytoma. Am. J. Surg. Pathol. 19(7), 748–756. 584. Suster, S., Nascimento, A.G., Miettinen, M., Sickel, J.Z., Moran, C.A., 1995. Solitary fibrous tumors of soft tissue. A clinicopathologic and immunohistochemical study of 12 cases. Am. J. Surg. Pathol. 19(11), 1257–1266. 585. Guillou, L., Gebhard, S., Coindre, J.M., 2000. Orbital and extraorbital giant cell angiofibroma: a giant cell-­rich variant of solitary fibrous tumor? Clinicopathologic and immunohistochemical analysis of a series in favor of a unifying concept. Am. J. Surg. Pathol. 24(7), 971–979. 586. Dei Tos, A.P., Seregard, S., Calonje, E., Chan, J.K., Fletcher, C.D., 1995. Giant cell angiofibroma. A distinctive orbital tumor in adults. Am. J. Surg. Pathol. 19(11), 1286–1293. 587. Renshaw, A.A., 1995. O13 (CD99) in spindle cell tumors. Reactivity with hemangiopericytoma, solitary fibrous tumor, synovial sarcoma, and meningioma but rarely with sarcomatoid mesothelioma. Appl. Immunohistochem. 3(4), 250–256. 588.  Rakheja, D., Molberg, K.H., Roberts, C.A., Jaiswal, V.R., 2005. Immunohistochemical expression of beta-­catenin in solitary fibrous tumors. Arch. Pathol. Lab. Med. 129(6), 776–779. 589. Hasegawa, T., Matsuno, Y., Shimoda, T., Hirohashi, S., Hirose, T., Sano, T., 1998. Frequent expression of bcl-­2 protein in solitary fibrous tumors. Jpn. J. Clin. Oncol. 28(2), 86–91. 590. Chilosi, M., Facchettti, F., Dei Tos, A.P., Lestani, M., Morassi, M.L., Martignoni, G., et al., 1997. bcl-­2 expression in pleural and extrapleural solitary fibrous tumours. J. Pathol. 181(4), 362–367. 591.  Robinson, D.R., Wu, Y.M., Kalyana-­ Sundaram, S., Cao, X., Lonigro, R.J., Sung, Y.S., et al., 2013. Identification of recurrent NAB2-­STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat. Genet. 45(2), 180–185. 592.  Doyle, L.A., Vivero, M., Fletcher, C.D., Mertens, F., Hornick, J.L., 2014. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod. Pathol. 27(3), 390–395. 593. Yoshida, A., Tsuta, K., Ohno, M., Yoshida, M., Narita, Y., Kawai, A., et al., 2014. STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am. J. Surg. Pathol. 38(4), 552–559.

10

Odontogenic Cysts and Tumors VICTORIA L. WOO  |  ANGELA C. CHI  |  BRAD W. NEVILLE

Introduction Odontogenic cysts and tumors represent a surprisingly diverse group of pathologic lesions of the jaws and overlying soft tissues. Basic familiarity with the histology and embryology of tooth formation can help in understanding the development and histopathology of these lesions. Tooth formation is a complex process that involves both epithelial and connective tissues.1,2 There are three major tissue components involved in odontogenesis: the enamel organ, the dental papilla, and the dental follicle. The enamel organ is an epithelial structure that is derived from oral ectoderm. The dental papilla and dental follicle are connective tissue structures that are considered ectomesenchymal in nature because they are derived from the neural crest. For each tooth, odontogenesis begins with a downward proliferation of the oral surface epithelium known as the dental lamina. This epithelium gives rise to the enamel organ, a cap-­ shaped structure that subsequently evolves into a bell shape, corresponding to the future shape of the tooth crown (Fig. 10.1A). After the formation of the enamel organ, the cord of dental lamina epithelium from the surface mucosa normally fragments and degenerates. However, small islands of this epithelium (rests of the dental lamina) may remain after tooth formation and may be found within the gingival soft tissues and superficial alveolar bone. These primitive dental lamina remnants are believed to be capable of giving rise to several types of developmental odontogenic cysts and tumors.3 The enamel organ has four layers of epithelium. The innermost lining layer (on the inside of the “bell”) is known as the inner enamel epithelium and will become the ameloblastic layer that forms the tooth enamel (Fig. 10.1B). Adjacent to this is a flattened row of epithelial cells known as the stratum intermedium. Next is a broad layer of loosely arranged cells known as the stellate reticulum. The outermost layer of the enamel organ is called the outer enamel epithelium. Surrounding the enamel organ is loose connective tissue known as the dental follicle. Filling the inside of the bell-­shaped enamel organ is immature connective tissue known as the dental papilla. Contact with the enamel organ epithelium induces the differentiation of a peripheral layer of specialized cells in the dental papilla, which are known as odontoblasts. The odontoblasts are the dentin-­forming cells and are located adjacent and parallel to the ameloblasts. As the odontoblasts begin to form the dentin of the tooth, they in turn induce the ameloblasts to begin enamel formation. After crown formation has begun, a thin layer of enamel organ epithelium (Hertwig epithelial root sheath) proliferates downward and stimulates odontoblastic differentiation in the root area of the tooth. This epithelial extension later becomes fragmented but leaves behind small epithelial nests (rests of

Malassez) in the periodontal ligament. The rests of Malassez are believed to be the source of epithelium for most periapical cysts, but generally are not believed to give rise to odontogenic neoplasms, except possibly for the rare squamous odontogenic tumor. For the purposes of this chapter, we use a modified version of the classification scheme for odontogenic cysts and tumors published by the World Health Organization (WHO).4 The odontogenic cysts are listed in Table 10.1, and the classification of odontogenic tumors is given in Table 10.2. 

Odontogenic Cysts DENTIGEROUS CYST (FOLLICULAR CYST) Tooth enamel is an ectodermally derived structure that is formed by specialized epithelium known as the enamel organ. After enamel formation is completed, the enamel organ epithelium atrophies to form a thin, flattened layer of cells that covers the enamel of the unerupted tooth. This layer of epithelium is then known as the reduced enamel epithelium (Fig. 10.2). In the normal sequence of events, this reduced enamel epithelium later merges with the surface epithelium and forms the initial gingival crevicular epithelium of the newly erupted tooth. Before tooth eruption, if fluid accumulates between the reduced enamel epithelium and the crown of the tooth, a dentigerous (or follicular) cyst will form. The dentigerous cyst is the most common developmental odontogenic cyst, making up approximately 20% of all epithelium-­lined cysts of the jaws.5–10 Clinical Features. By definition, a dentigerous cyst occurs in association with an unerupted tooth. As logic would dictate, such cysts are most common around impacted teeth, especially mandibular third molars.5–11 Maxillary third molars and maxillary cuspids are also frequent sites. However, dentigerous cysts may occur in association with virtually any tooth, including supernumerary teeth and odontomas.12 Dentigerous cysts arising around unerupted deciduous teeth are distinctly rare.13,14 Although they may occur at any age, dentigerous cysts are most commonly diagnosed in teenagers and young adults.5,8,9 There is a male predilection, and their prevalence appears to be higher in white patients than black patients. Most dentigerous cysts are small, asymptomatic lesions that are discovered on routine radiographs. Some dentigerous cysts may grow to considerable size and produce bony expansion that is usually painless, unless secondarily infected. However, any particularly large dentigerous radiolucency should raise clinical suspicion of a more aggressive odontogenic lesion, such as an odontogenic keratocyst or ameloblastoma. 827

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dl

sr si eo e d

dp a df Fig. 10.1  Low-­power (A) and high-­power (B) views of the bell stage of odontogenesis. a, Ameloblasts; d, early dentin formation; df, dental follicle; dl, dental lamina; dp, dental papilla; e, early enamel matrix formation; eo, enamel organ; o, odontoblasts; si, stratum intermedium; sr, stellate reticulum. (A, Courtesy of Dr. Rudy Melfi; B, courtesy of Dr. William Ries.)

TABLE

10.1

a

o

dp A

Odontogenic Cysts

DEVELOPMENTAL Dentigerous cyst Eruption cyst Odontogenic keratocyst Orthokeratinized odontogenic cyst Gingival cyst of the newborn Gingival cyst of the adult Lateral periodontal cyst Glandular odontogenic cyst Calcifying odontogenic cyst INFLAMMATORY Periapical cyst Residual periapical cyst CARCINOMA ARISING IN ODONTOGENIC CYSTS

Radiographically, the dentigerous cyst presents as a well-­ defined unilocular radiolucency, often with a sclerotic border (Fig. 10.3).5,15 Because the epithelial lining is derived from the reduced enamel epithelium, this radiolucency typically surrounds just the crown of the tooth, with the crown projecting into the cyst lumen (central variety; Fig. 10.4). In the lateral variety, the cyst develops laterally along the tooth root and partially surrounds the crown. This variety is most commonly associated with mesioangular impacted mandibular third molars. In the circumferential variety, the cyst surrounds the crown but also extends down along the root surface, as if the tooth were erupting through the center of the cyst. Some dentigerous cysts may result in considerable displacement of the involved tooth. In addition, larger cysts can cause resorption of adjacent erupted teeth. The radiographic distinction between an enlarged dental follicle and a small dentigerous cyst can be difficult and rather arbitrary.16,17 In general, any pericoronal radiolucency that is larger than 3 to 4 mm in diameter is suggestive of cyst

B

TABLE

10.2

Odontogenic Tumors

BENIGN EPITHELIAL ODONTOGENIC TUMORS Ameloblastoma Calcifying epithelial odontogenic tumor Squamous odontogenic tumor Adenomatoid odontogenic tumor BENIGN MIXED EPITHELIAL AND MESENCHYMAL ODONTOGENIC TUMORS Ameloblastic fibroma Ameloblastic fibroodontoma Odontoma Primordial odontogenic tumor Odontoameloblastoma Dentinogenic ghost cell tumor BENIGN MESENCHYMAL ODONTOGENIC TUMORS Central odontogenic fibroma Peripheral odontogenic fibroma Granular cell odontogenic tumor Odontogenic myxoma MALIGNANT ODONTOGENIC TUMORS Metastasizing ameloblastoma Ameloblastic carcinoma Primary intraosseous squamous cell carcinoma Clear cell odontogenic carcinoma Ghost cell odontogenic carcinoma Intraosseous mucoepidermoid carcinoma Ameloblastic fibrosarcoma Odontogenic carcinosarcoma

formation. However, the radiographic appearance alone cannot be considered diagnostic for a dentigerous cyst because odontogenic keratocysts, ameloblastomas, and other odonto­ genic tumors can have an identical appearance. For this reason, biopsy is mandated for all significant pericoronal radiolucencies to confirm the diagnosis.  Pathologic Features. The microscopic appearance of the dentigerous cyst is variable, and clinical correlation is necessary to

10  Odontogenic Cysts and Tumors

establish the diagnosis. If the cyst is not inflamed, it is usually lined with a thin, flattened layer of nonkeratinizing epithelium, without rete ridge formation (Fig. 10.5A).5,15 Because the wall of the cyst is derived from the dental follicle, it is characteristically composed

se

lp

r e d

Fig. 10.2  Medium-­power view showing the reduced enamel epithelium covering a tooth just before eruption. d, Dentin; e, enamel space (enamel is lost during decalcification); lp, lamina propria; r, reduced enamel epithelium; se, surface epithelium. (Courtesy of Dr. William Ries.)

A

829

of loose fibrous connective tissue that often contains scattered odontogenic epithelial rests. Sometimes these rests undergo dystrophic calcification. If a dentigerous cyst becomes secondarily inflamed, the epithelial lining may become thicker and form rete ridges (Fig. 10.5B). The wall of an inflamed dentigerous cyst is often more densely collagenized. Focal mucin-­producing cells are often found in the epithelial lining (Fig. 10.6).18,19 Although such mucous cells are usually an incidental finding, it has been hypothesized that they could be a source for the rare intraosseous mucoepidermoid carcinoma of the jaws.20 Rarely, ciliated epithelial cells will be found.19 Such findings are indicative of the multipotentiality of odontogenic epithelium.  Differential Diagnosis. The two most significant lesions to distinguish from a dentigerous cyst are the cystic ameloblastoma and the odontogenic keratocyst. In the cystic ameloblastoma, the basilar cells become columnar and demonstrate prominent nuclear hyperchromatism. The nuclei may demonstrate polarization away from the basement membrane (reverse polarization), and the superficial epithelial layers may become loosely arranged and resemble the stellate reticulum of the enamel organ. In the odontogenic keratocyst, the epithelium is uniform in nature, usually four to eight cells thick. The basilar layer consists of a palisaded row of cuboidal to columnar cells that may demonstrate hyperchromatism. Characteristically, a corrugated or wavy layer of parakeratin is produced on the epithelial surface and desquamated keratin may be found in the cyst lumen. Some lesions submitted as dentigerous cysts are partially lined with a thin, fragmented layer of eosinophilic columnar cells that represents the postfunctional ameloblastic layer. It is probable that most of these lesions do not technically represent true cysts but just hyperplastic dental follicles.16 Although the lining cells in these cases may be columnar, they do not exhibit nuclear hyperchromatism or other features suggestive of ameloblastomatous transformation. In other instances, one may see follicle-­like connective tissue that is only focally or partially lined with a thin, fragmented layer of squamoid epithelium. The pathologist is at a disadvantage in such cases because it is impossible to determine microscopically whether this epithelium-­ lined connective tissue was a true fluid-­filled sac around the tooth or a normal or hyperplastic follicle. Clinical correlation

B

Fig. 10.3  Dentigerous cyst. A, Well-­circumscribed radiolucency associated with the crown of an impacted mandibular third molar. B, Large dentigerous cyst associated with an impacted mandibular second premolar. (A, Courtesy of Dr. Brent Klinger; B, courtesy of Dr. Cornelious Slaton.)

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Fig. 10.4  Dentigerous cyst. Gross photograph of a dentigerous cyst being held open by two sticks. The tooth crown projects into the cyst lumen.

A

in such cases is important; if the surgeon clinically describes a cystic lesion, then the diagnosis of dentigerous cyst can be supported.21–23 However, importantly in such cases, the pathologist can rule out the possibility of a more aggressive lesion, such as an ameloblastoma or odontogenic keratocyst.  Treatment and Prognosis. Most dentigerous cysts are treated by enucleation along with removal of the associated tooth. In situations where removal of an entire mandibular third molar might risk damage to the inferior alveolar nerve or bone fracture, coronectomy can be performed without removing the tooth roots.24 If it is important to save the tooth, it may be possible to remove only a portion of the cyst and then aid tooth eruption via orthodontic measures or marsupialization.25,26 Similarly, if the associated tooth has been displaced by the cyst and extraction may be difficult, orthodontic movement of the tooth to a more advantageous location for extraction may be accomplished.27 Particularly large dentigerous cysts can sometimes be treated by marsupialization (with a biopsy to confirm the diagnosis), which can allow shrinkage of the lesion before total removal. The prognosis for dentigerous cysts is excellent, and the lesion almost never recurs. A rare complication is the development of an ameloblastoma from the cyst lining or

B

Fig. 10.5  A, Dentigerous cyst lined with a thin layer of nonkeratinizing stratified squamous epithelium. B, A secondarily inflamed dentigerous cyst showing irregular proliferation of rete ridges. A mostly chronic inflammatory infiltrate is present in the cyst wall.

Fig. 10.6  Dentigerous cyst. Scattered mucin-­producing cells along the surface layer of the epithelium.

10  Odontogenic Cysts and Tumors

Fig. 10.7  Eruption cyst. Seven-­year-­old boy with a bluish swelling of the posterior right mandibular ridge overlying the erupting mandibular first permanent molar.

from odontogenic epithelial rests within the cyst wall.28 Also, a squamous cell carcinoma may rarely arise from a dentigerous cyst lining.29–31 Many investigators believe that some intraosseous mucoepidermoid carcinomas arise from mucous cells in a dentigerous cyst.20,32 For these reasons, careful microscopic examination of all dentigerous cysts is necessary.  ERUPTION CYST (ERUPTION HEMATOMA) The eruption cyst is a soft-­tissue variant of the dentigerous cyst.33–35 It arises from accumulation of cystic fluid or hemorrhage, or both, between the crown of an erupting tooth and the surrounding dental follicle. Clinical Features. The eruption cyst presents as a dome-­ shaped swelling of the alveolar mucosa overlying an erupting tooth. It characteristically is translucent with a bluish hue because of the collection of cystic fluid and hemorrhage within the follicular sac (Fig. 10.7). Most cases occur in children younger than the age of 10 years. Although such lesions can develop over any erupting tooth, they are most often associated with primary incisors and first permanent molars. Multiple eruption cysts occasionally may occur.35,36  Pathologic Features. Eruption cysts are rarely submitted for microscopic examination. Most such specimens consist of the excised roof of the lesion, which has been removed to allow tooth eruption. The surface of the specimen is covered by normal alveolar mucosa. The deep margin is lined with a thin layer of nonkeratinizing stratified squamous epithelium, which represents the roof of the cyst. A variable amount of inflammation may be present.  Treatment and Prognosis. Most eruption cysts do not require treatment because they usually rupture and allow the tooth to come into place. If tooth eruption appears to be impeded by the lesion, the cyst can be unroofed, which usually allows the tooth to erupt.  ODONTOGENIC KERATOCYST (KERATOCYSTIC ODONTOGENIC TUMOR) The odontogenic keratocyst is a distinctive type of developmental odontogenic cyst that was first described by Philipsen37

831

in 1956. It is believed to arise from remnants of dental lamina epithelium. Recognition of this cyst is important for three reasons: (1) the odontogenic keratocyst tends to behave more aggressively than other odontogenic cysts, (2) the odontogenic keratocyst has a higher recurrence rate than other odontogenic cysts, and (3) the odontogenic keratocyst sometimes may be associated with the nevoid basal cell carcinoma syndrome. The odontogenic keratocyst is estimated to make up 8% to 12% of all odontogenic cysts.38–42 Controversy exists regarding whether the odontogenic keratocyst should be classified as an odontogenic cyst or an odontogenic tumor.43–49 In the 2005 WHO Classification of Head and Neck Tumors the odontogenic keratocyst was renamed as the “keratocystic odontogenic tumor.”50 Arguments favoring classification as a tumor include its potential for aggressive behavior, high recurrence rate, and rare examples of “solid” odontogenic keratocyst. In addition, approximately 30% of sporadic odontogenic keratocysts, and up to 85% of keratocysts associated with the nevoid basal cell carcinoma syndrome, show patched 1 (PTCH1) gene mutations. Genetic analysis also has revealed loss of heterozygosity for various other tumor suppressor genes. However, in the latest WHO classification released in 2017, this lesion was returned to its previous designation as odontogenic keratocyst.51 Proponents of classification as a cyst point out that most nonsyndromic odontogenic keratocysts do not show PTCH1 mutations, and loss of heterozygosity has been reported in other odontogenic cysts. Also, the question has been raised over whether odontogenic keratocysts truly demonstrate autonomous growth because they can undergo regression after decompression/marsupialization procedures. Ultimately, regardless of the philosophy one prefers for the classification of this lesion, it should be recognized that both terms currently are in common use. Clinical Features. The odontogenic keratocyst can occur anywhere within the jaws, and examples within the gingival soft tissues have even been reported.52–54 Approximately 65% to 75% of cases are seen in the mandible, with a predilection for the molar/ ramus area.39–41,55–58 Frequently, the cyst occurs in association with an impacted tooth, thus clinically mimicking a dentigerous cyst. Odontogenic keratocysts may also clinically mimic other cysts of the jaws, such as the lateral periodontal cyst,59 periapical cyst,60,61 and nasopalatine duct cyst.62,63 Some examples of the so-­called globulomaxillary cyst (which is no longer considered a true entity) will turn out to be odontogenic keratocysts when examined microscopically.64,65 Odontogenic keratocyst can occur at any age, but approximately 60% of all cases are diagnosed between the ages of 10 and 40 years. In his series of 312 cysts, Brannon41 found a mean age of 37 years, 9 months. The peak prevalence was in the second and third decades of life, with only 15% of cases occurring past the age of 60 years. Woolgar and colleagues66 reviewed 682 odontogenic keratocysts from 522 patients and found a mean age of 40.4 years for patients with a single, nonrecurrent cyst and 26.2 years for patients with multiple cysts or the nevoid basal cell carcinoma syndrome. Although odontogenic keratocysts of the anterior midline maxillary region are uncommon, they usually occur in much older individuals, with a mean age of nearly 70 years.63 The reason for the surprising age difference in this particular subset of odontogenic keratocysts is unknown. Smaller lesions are usually asymptomatic and often discovered only during routine radiographic examination. Larger cysts may result in clinical expansion and palpable thinning of

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A

B

Fig. 10.8  Odontogenic keratocyst. A, Unilocular radiolucency of the right mandible. B, Large multilocular radiolucency of the left mandibular ramus. (A, Courtesy of Dr. A. Paul King; B, courtesy of Dr. Samuel McKenna.)

Fig. 10.9  Odontogenic keratocyst. Small unilocular radiolucency distal to the left mandibular second molar. Because the third molar never developed in this area, this lesion fulfills the clinical criteria for a primordial cyst. However, microscopic examination revealed an odontogenic keratocyst.

the overlying cortical bone. Occasional odontogenic keratocysts cause pain or drainage, but even extremely large cysts may not exhibit any symptoms. On radiographic examination, a small odontogenic keratocyst usually presents as a well-­circumscribed unilocular radiolucency that often demonstrates a corticated border (Fig. 10.8A). Larger cysts may appear multilocular, especially when arising in the mandibular molar/ramus region (Fig. 10.8B). In the older literature, the term primordial cyst was used to describe a cyst that occurred in the place where a tooth should have developed (Fig. 10.9).67 Presumably, the occurrence of such cysts was caused by degeneration of the enamel organ before the formation of any mineralized tooth structure. However, microscopic examination of such clinical lesions almost always reveals features of an odontogenic keratocyst. For a while, these two terms sometimes were used synonymously because odontogenic keratocysts are believed to arise from the dental lamina or dental primordium. However, the term odontogenic keratocyst

is today the preferred designation for such lesions if they show the characteristic microscopic features described in the next section. It is uncertain whether there are any true examples of a clinical primordial cyst (i.e., a cyst occurring in the place of a tooth) that is not an odontogenic keratocyst; however, if such lesions do exist, they must be exceedingly rare.68  Pathologic Features. On gross examination, the odontogenic keratocyst often demonstrates a thin, friable wall. The cyst lumen may be filled with clear fluid or a creamy to cheesy keratinaceous material. However, this keratinaceous material is not specific for the odontogenic keratocyst because other odontogenic cysts may be filled with similar semisolid keratin-­ like products. The odontogenic keratocyst is lined with a uniform layer of stratified squamous epithelium that ranges from four to eight cells in thickness (Fig. 10.10A).38,50,51,69,70 This epithelium is usually devoid of rete ridges and sometimes may separate from the fibrous connective tissue wall. The basal layer consists of a palisaded row of cuboidal to columnar cells that are often hyperchromatic (Fig. 10.10B). Characteristically, a corrugated or wavy layer of parakeratin is produced on the luminal surface, and abundant desquamated keratin may be found in the cyst lumen. On occasion, focal areas of orthokeratinization may be seen in addition to the more typical parakeratinization. The wall of the cyst often contains odontogenic epithelial rests and may demonstrate the formation of smaller satellite or “daughter” cysts. In rare instances, cartilage has been reported in the wall of odontogenic keratocysts.71–73 Although the odontogenic keratocyst is developmental in origin, it may become secondarily inflamed.55,70,74 If this occurs, the inflamed portion of the lining epithelium will lose its characteristic features and may become irregular and proliferative with the formation of rete ridges (Fig. 10.11). In such cases, the diagnosis depends on a thorough examination of the entire cyst with the identification of characteristic features in uninflamed and unaltered areas of the lining. In a diffusely inflamed, otherwise unremarkable, intrabony jaw cyst, even a very small segment of uninflamed cyst lining that displays a uniform thin epithelium with luminal parakeratin production and a palisaded basal cell layer is enough to render a diagnosis of odontogenic keratocyst. 

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Fig. 10.10  Odontogenic keratocyst. A, Low-­power photomicrograph showing a cyst lined with stratified squamous epithelium of uniform thickness. Desquamated keratin can be seen within the cyst lumen. B, High-­power view of the epithelial lining showing a palisaded cuboidal to columnar basal cell layer and a corrugated parakeratinized surface.

Fig. 10.11  Odontogenic keratocyst. Classic odontogenic keratocyst lining is seen on the left side of this photomicrograph, but inflammation has altered the epithelium on the right side, resulting in a nonspecific histopathologic appearance.

Differential Diagnosis. Although the production of keratin gives the lesion its name, keratinization should not be considered the sine qua non of the odontogenic keratocyst. Some keratocysts may produce only a thin layer of parakeratin on the epithelial surface without any significant accumulation in the lumen. Such cases are easily misdiagnosed as a dentigerous cyst, periapical cyst, or other jaw cyst depending on the clinical history. Findings of a palisaded cuboidal/columnar basal cell layer and a wavy, corrugated epithelial surface are more consistent and reliable microscopic features in making the diagnosis of odontogenic keratocyst. In addition, not every cyst of the jaws that keratinizes is an odontogenic keratocyst. The orthokeratinized odontogenic cyst also exhibits keratin production, but orthokeratin is seen rather than parakeratin. Also, orthokeratinized odontogenic cysts do not demonstrate a palisaded basal cell layer or a corrugated epithelial surface. 

Treatment and Prognosis. Because the diagnosis may not be known or suspected before initial surgery, many odontogenic keratocysts are first treated with enucleation and curettage in a manner similar to treatment of other cysts of the jaws. However, the odontogenic keratocyst has a high recurrence rate that has been estimated in the range of 25% to 30%.38,51,75 For this reason, peripheral ostectomy with a bone bur is often recommended if the diagnosis is known or suspected preoperatively.76 If the cyst has broken through the cortical plate and is adherent to the overlying mucosa, excision of this mucosa may be indicated.77 On occasion, a particularly large and aggressive keratocyst may finally require resection and bone grafting.75,78–80 Although too few cases of peripheral odontogenic keratocyst have been described to make a firm conclusion regarding its biological behavior, at least two examples of recurrence have been reported.53 Some clinicians prefer to use chemical cautery of the bony cavity or intraluminal injection of Carnoy solution to free the cyst from the bony wall and allow easier removal with a lower recurrence rate.51,76,81,82 However, Carnoy solution is not available or is no longer allowed at many treatment centers. Cryotherapy with liquid nitrogen has been used with some success to reduce the recurrence rate, although not all hospitals have access to such equipment.83 Others have advocated insertion of a polyethylene drainage tube into large keratocysts after cystotomy and incisional biopsy to allow decompression and subsequent reduction in lesion size.84,85 Such decompression treatment results in thickening of the cyst lining, allowing easier removal with an apparently lower recurrence rate.51,75,76 Except for its high recurrence rate and potential for significant bone destruction, the prognosis for the odontogenic keratocyst is generally good. Although most recurrences are seen within several years of the initial surgery, recurrences may not become manifest until 10 or more years after the initial diagnosis. Therefore long-­term follow-­up is mandated. Malignant transformation has been reported but is quite rare.86–88 Although most odontogenic keratocysts occur as isolated lesions, they sometimes are a component of the nevoid basal cell carcinoma syndrome, or Gorlin syndrome.66,68,89,90 Multiple keratocysts frequently develop in affected patients (Fig. 10.12). Gorlin syndrome is an autosomal-dominant inherited disorder

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Fig. 10.12  Nevoid basal cell carcinoma syndrome. Multiple odontogenic keratocysts involving the right posterior mandible, left posterior mandible, and right maxilla. Right mandibular and maxillary lesions are associated with impacted teeth. (Courtesy of Dr. Richard DeChamplain.)

Fig. 10.13  Odontogenic keratocyst. Extensive daughter cyst formation in the wall of an odontogenic keratocyst from a patient with the nevoid basal cell carcinoma syndrome.

with a variety of clinical manifestations. Affected individuals may demonstrate frontal and temporoparietal bossing, hypertelorism, and mandibular prognathism. Other frequent skeletal anomalies include bifid ribs and lamellar calcification of the falx cerebri. The most significant clinical feature is the tendency for multiple basal cell carcinomas, which may affect both exposed and non–sunexposed areas of the skin. Pitting defects on the palms and soles can be found in nearly two-­thirds of affected patients. Odontogenic keratocysts are a common finding in patients with Gorlin syndrome, and these cysts are usually the first manifestation that leads to the diagnosis. For this reason, any patient with an odontogenic keratocyst should be evaluated for this condition. Although the cysts in patients with Gorlin syndrome cannot definitely be distinguished microscopically from those not associated with the syndrome, they often demonstrate more epithelial proliferation and daughter cyst formation in the cyst wall (Fig. 10.13).91 Foci of calcification also appear to be more common in syndrome cysts.69,91  ORTHOKERATINIZED ODONTOGENIC CYST In addition to the odontogenic keratocyst that produces parakeratin, other odontogenic cysts may produce orthokeratin.92

In the past, these lesions were referred to as variants of odontogenic keratocyst.93 However, because these lesions are clinically and microscopically different from the more common odontogenic keratocyst, they currently are designated as orthokeratinized odontogenic cysts.94–96 These orthokeratinized odontogenic cysts represent 10% to 13% of keratinizing odontogenic cysts.93,95,96 Clinical Features. Orthokeratinized odontogenic cysts predominantly occur in teenagers and young adults, with one study finding 86% of patients between the second and fifth decades of life.93 There is a male predilection, with 61% to 76% of reported cases in men.93,96,97 The lesion occurs much more often in the mandible (70% to 90% of cases) than in the maxilla, with a tendency to involve the posterior areas of the jaws.96,97 Approximately 50% to 75% of all cases are associated with an impacted tooth, thereby clinically mimicking a dentigerous cyst.93,96,97 The orthokeratinized odontogenic cyst usually presents radiographically as a unilocular radiolucency, but some examples are multilocular.96,98 The size can vary from less than 1 cm in diameter to 15 cm or more.96 The lesion is frequently asymptomatic and discovered only on routine radiographic examination; however, some cases are associated with pain or

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Fig. 10.14  Orthokeratinized odontogenic cyst. A, The cyst is lined with a uniform layer of stratified squamous epithelium that exhibits a prominent granular cell layer and abundant orthokeratin production. B, On rare occasions, focal sebaceous glands may be seen along the basal cell layer.

swelling. Multiple orthokeratinized odontogenic cysts have been reported.99  Pathologic Features. Orthokeratinized odontogenic cysts are lined with a thin, uniform layer of stratified squamous epithelium that is typically four to eight cells thick (Fig. 10.14A).92,94 The basal layer usually consists of a row of flattened to cuboidal cells with infrequent rete ridge formation. Orthokeratin is produced on the epithelial surface and associated with a subjacent granular cell layer. Abundant desquamated keratin may be found in the cyst lumen. Some cysts may show focal parakeratin production, but other features of odontogenic keratocyst are not observed. On rare occasions, focal sebaceous glands may be found in orthokeratinized odontogenic cysts (Fig. 10.14B).100,101  Differential Diagnosis. The most important lesion to distinguish from the orthokeratinized odontogenic cyst is the true odontogenic keratocyst. However, the odontogenic keratocyst exhibits a palisaded basal layer of cuboidal to columnar cells that is often hyperchromatic. A corrugated or wavy layer of parakeratin is produced on the epithelial surface, and no granular cell layer should be present.  Treatment and Prognosis. Orthokeratinized odontogenic cysts are usually treated by enucleation and curettage. Unlike odontogenic keratocyst, recurrence is rare, having been reported in approximately 2% of cases.93,94 In addition, the orthokeratinized odontogenic cyst is not associated with the nevoid basal cell carcinoma syndrome. This further underscores the importance of distinguishing this lesion from the odontogenic keratocyst.  GINGIVAL (ALVEOLAR) CYST OF THE NEWBORN (DENTAL LAMINA CYST) Gingival cysts of the newborn are small, keratin-­filled cysts on the alveolar mucosa of neonates. They arise from remnants of the dental lamina epithelium.102,103 Their true frequency is

Fig. 10.15  Gingival cysts of the newborn. Multiple small, pearl-­like papules on the alveolar ridge of a newborn infant. (From Neville, B.W., Damm, D.D., Allen, C.M., Bouquot, J.E. (eds), 2009. Odontogenic cysts and tumors. In: Oral and Maxillofacial Pathology, 3rd ed. WB Saunders, Philadelphia, p. 692.)

difficult to determine because of inconsistencies in terminology; however, gingival cysts of the newborn appear to be quite common, with some studies reporting their presence in as many as 44% to 97% of newborns.103–105 Clinical Features. Gingival cysts of the newborn typically present as multiple small (1 to 3 mm in diameter), white, pearl-­like papules on the alveolar mucosa (Fig. 10.15).102,103 The lesions are more common on the maxillary arch than the mandibular arch, with maxillary cysts favoring the buccal aspect and mandibular cysts favoring the lingual aspect.104,105  Pathologic Features. Although rarely examined microscopically, the gingival cyst of the newborn is lined by stratified squamous epithelium. The cyst lumen is filled with desquamated parakeratin (Fig. 10.16). 

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Fig. 10.16  Gingival cysts of the newborn. A small keratin-­ filled cyst is seen within the lamina propria. Adjacent odontogenic epithelial rests (rests of the dental lamina) are evident.

Treatment and Prognosis. No treatment is required for these asymptomatic lesions because they will disappear on their own within the first few months of life. In most instances, it is believed that the cyst ruptures and spills its keratin contents, which allows healing to occur.103  GINGIVAL CYST OF THE ADULT The gingival cyst of the adult is an uncommon developmental odontogenic cyst that occurs on the gingiva or alveolar mucosa. It accounts for only 0.6% of jaw cysts and represents the peripheral counterpart of the lateral periodontal cyst.106 The lesion is believed to arise from rests of the dental lamina epithelium.107–109 Although the gingival cyst of the newborn also arises from these same cell rests, the gingival cyst of the adult is considered a separate, distinct entity. Clinical Features. The gingival cyst of the adult most commonly occurs in middle-­ aged and older adults, with a mean age of approximately 48 to 51 years.107,110–112 About 80% of cases arise in the mandibular mucosa, with a marked predilection for the canine and premolar region.110 Maxillary examples also are seen, most frequently around the canines and premolars, as well as the lateral incisor area. The facial aspect of the gingiva is affected more often than the lingual side. Most lesions are solitary, although bilateral or multifocal involvement also has been reported.111,113–115 The gingival cyst of the adult typically appears as a painless, dome-­shaped swelling measuring 0.5 cm or less in maximum diameter, but occasional lesions may be greater than 1 cm (Fig. 10.17).110 The overlying mucosa often appears normal in color, although some lesions appear blue or translucent because of the fluid contents. In some instances, the cyst may cause “cupping-­ out” resorption of the underlying alveolar bone, which may or may not be evident on radiographic examination. Sometimes such a lesion may appear to be partially within soft tissue and partially within bone, raising the question as to whether it would be better classified as a lateral periodontal cyst. However, because the lateral periodontal cyst and the gingival cyst of the adult are essentially the same lesion, this question is only academic. 

Fig. 10.17  Gingival cyst of the adult. Dome-­shaped bluish swelling on the gingival mucosa between the right mandibular canine and first premolar.

Pathologic Features. The gingival cyst of the adult is lined with a thin, flattened layer of epithelium that often appears to be only one to two cells thick (Fig. 10.18A).107,108 Sometimes this lining is so thin that the lesion is easily missed or is mistaken for the endothelial lining of a dilated blood vessel. Often one can see focal thickened plaques within the epithelial lining. These thickenings usually contain glycogen-­rich cells with clear cytoplasm (Fig. 10.18B).  Differential Diagnosis. On occasion, peripheral examples of odontogenic keratocyst occur within the gingival soft tissues. However, these cysts are lined with a thicker, uniform layer of epithelium that is four to eight cells thick with a palisaded basal layer of cuboidal to columnar cells. In addition, a corrugated or wavy layer of parakeratin is produced on the epithelial surface, and desquamated keratin is often found in the cyst lumen.  Treatment and Prognosis. The gingival cyst of the adult is treated by excisional biopsy. The prognosis is excellent and the lesions typically do not recur.110 

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Fig. 10.18  Gingival cyst of the adult. A, Low-­power view showing a cyst with a thin epithelial lining. B, High-­power view showing the thin epithelial lining on the right and a thickened plaque with glycogen-­rich clear cells on the left.

LATERAL PERIODONTAL CYST (BOTRYOID ODONTOGENIC CYST) The lateral periodontal cyst is a developmental odontogenic cyst that typically occurs along the lateral root surface of a tooth. It is believed to arise from remnants of the dental lamina epithelium within the alveolar bone.108,116 The lateral periodontal cyst represents the intrabony counterpart of the gingival cyst of the adult and accounts for less than 2% of all epithelium-­lined jaw cysts.117 In the past, the term lateral periodontal cyst has been used to describe a variety of cysts that may be found in a lateral periodontal location, especially laterally positioned radicular cysts and odontogenic keratocysts.59 However, the lateral periodontal cyst should be distinguished from these other lesions because of its distinctive clinical and histopathologic features. Clinical Features. Most lateral periodontal cysts are diagnosed in patients in the fifth through seventh decades of life, with a mean age of approximately 51 years (range, 14–85 years).118–120 The lesion is usually asymptomatic and often is discovered during routine radiographic examination. Although most cases measure less than 1 cm in maximum diameter, larger examples may produce painless expansion. Like the gingival cyst of the adult, the lateral periodontal cyst shows a striking predilection for the mandibular canine/premolar region. Maxillary examples also favor the canine/premolar area. Radiographically, the lesion typically presents as a solitary, well-­circumscribed, and unilocular radiolucency lateral to the roots of vital teeth (Fig. 10.19). Multifocal, bilateral, or periapical involvement has been reportedly only rarely.120–122 Occasionally, the lesion may be polycystic and exhibit a multilocular appearance grossly and/or radiographically. Because this polycystic variant resembles a cluster of grapes, it is often called a botryoid odontogenic cyst.123–125  Pathologic Features. The cyst is lined with a thin layer of cuboidal or nonkeratinizing squamous epithelium that is only about one to three cells thick in most areas.117,126,127 In addition, there are often focal nodular epithelial thickenings

Fig. 10.19  Lateral periodontal cyst. Well-­circumscribed radiolucency located between the roots of the left mandibular canine and first premolar. (Courtesy of Dr. James Tankersley.)

(Fig. 10.20), which may exhibit a “swirling” appearance and frequently contain numerous glycogen-­rich cells with clear cytoplasm. Islands of similar-­appearing clear cells may be found in the cyst wall and are believed to be rests of the dental lamina. Botryoid odontogenic cysts show multiple, separate cystic spaces (Fig. 10.21).123–125  Differential Diagnosis. The lateral periodontal cyst and the gingival cyst of the adult are essentially the same lesion; clinicoradiographic correlation is needed to determine whether the cyst originated within bone (as in a lateral periodontal cyst) or soft tissue (as in a gingival cyst of the adult). The glandular odontogenic cyst may show features resembling a lateral periodontal cyst, including an epithelial lining with variable thickness, swirling spherical aggregates, and clear glycogen-­ containing cells;

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Fig. 10.20  Lateral periodontal cyst. The cyst is lined with a thin layer of epithelium with a focal nodular thickening.

Fig. 10.21  Lateral periodontal cyst. A botryoid odontogenic cyst showing multiple cystic spaces lined with thin epithelium with nodular thickenings.

­ oreover, multiple cystic compartments may be evident in both m the glandular odontogenic cyst and the botryoid odontogenic cyst. However, the glandular odontogenic cyst also shows luminal eosinophilic cuboidal/columnar cells, microcysts (duct-­like spaces), and mucin production. In addition, the glandular odontogenic cyst generally exhibits greater growth potential compared to the lateral periodontal cyst.  Treatment and Prognosis. The lateral periodontal cyst is treated by conservative surgical enucleation, and recurrence is unusual. Because of its polycystic nature, the botryoid variant may have an increased recurrence potential.124,125,128  GLANDULAR ODONTOGENIC CYST (SIALO-ODONTOGENIC CYST) The glandular odontogenic cyst is a rare developmental odontogenic cyst. Although an odontogenic origin generally is accepted, the lesion also demonstrates glandular features (such as cuboidal/

columnar cells, mucin production, and/or cilia), which presumably reflect the pluripotentiality of odontogenic epithelium. Clinical Features. The glandular odontogenic cyst has been reported over a broad age range (second through ninth decades), with a mean age of approximately 45 to 51 years.129–132 It shows a striking predilection for the anterior mandible, with many cases crossing the midline (Fig. 10.22). Maxillary examples are less common, but also usually occur in the anterior region. The size of the cyst can vary from less than 1 cm in diameter to large, destructive lesions that involve most of the jaw. The most common clinical symptom is swelling; infrequent findings include pain, secondary infection, and paresthesia. Small asymptomatic lesions may be discovered only incidentally on radiographic examination. Radiographically, the lesion presents as either a unilocular or multilocular radiolucency, usually with well-­defined borders and buccolingual expansion.131,133 Most lesions occur adjacent to tooth roots, although a minority of cases develop around the crowns of unerupted teeth. Other

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Fig. 10.22  Glandular odontogenic cyst. Large multilocular radiolucency of the anterior midline mandible. (Courtesy of Dr. Joseph Carlisle.)

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Fig. 10.23  Glandular odontogenic cyst. A, Stratified squamous epithelial lining that exhibits ciliated columnar cells on the surface. B, The epithelium contains prominent glandlike spaces that are also lined with columnar cells.

possible radiographic findings include scalloped borders, tooth displacement, root resorption, and cortical perforation.131,132  Pathologic Features. The cyst is lined with stratified squamous epithelium that is variable in thickness and often forms multiple compartments.132 However, the superficial layer characteristically consists of eosinophilic cuboidal/columnar (or “hobnail”) cells; these cells may demonstrate apocrine snouting (simulating decapitation secretion) or cilia (Fig. 10.23). The surface layer is often irregular and somewhat papillary. Mucous cells also may be present. In addition, the lining typically contains microcysts (duct-­ like spaces) surrounded by a single layer of cuboidal, columnar, or goblet cells. The microcysts may contain pools of mucicarmine-­positive material or may appear empty. In the basal or parabasal layers, there may be clear or vacuolated cells with intracytoplasmic glycogen. In some areas, the squamous epithelial cells may form swirling spherical aggregates reminiscent of those seen in the lateral periodontal cyst (Fig. 10.24). This latter finding supports the belief that these cysts are of odontogenic origin. In addition, immunohistochemical studies of glandular odontogenic cysts showing expression of cytokeratins 14 and 19 suggest an odontogenic origin.134,135 Some investigators have proposed specific diagnostic criteria for the glandular odontogenic cyst. For example, Kaplan et al.136,137 suggested the following major criteria must be at least focally present: (1) squamous epithelial lining, with a flat connective tissue interface and no basal palisading; (2) an epithelial lining with

Fig. 10.24  Glandular odontogenic cyst. This area of the cyst shown in Fig. 10.23A shows a thin lining with a nodular thickening suggestive of a lateral periodontal cyst.

variable thickness, with or without “spheres”/ “whorls” or focal luminal proliferation; (3) cuboidal eosinophilic or “hobnail” cells; (4) mucous (goblet) cells with intraepithelial mucous pools, with or without crypts lined by mucous cells; and (5) intraepithelial glandular/microcystic/duct-­like structures. In addition, these authors posited that the following minor criteria may be present but are not necessary for diagnosis: (1) papillary proliferation of the lining epithelium, (2) cilia, (3) multicystic or multiluminal architecture, and

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(4) clear or vacuolated cells. Nevertheless, Fowler et al.132 noted that glandular odontogenic cysts do not always exhibit the aforementioned proposed major criteria. Instead, these authors found that the presence of 7 out of the following 10 microscopic parameters is highly predictive of glandular odontogenic cysts: eosinophilic cuboidal cells, microcysts, apocrine snouting, clear (vacuolated) cells, variable thickness, tufting (papillary projections), mucous cells, cilia, clear (vacuolated) cells, epithelial spheres, and multiple compartments. In particular, the latter three features were most helpful in their study for distinguishing the glandular odontogenic cyst from its mimics.  Differential Diagnosis. The differential diagnosis may include various other types of jaw cysts, including the dentigerous cyst, lateral periodontal cyst, and botryoid odontogenic cyst. Both glandular odontogenic cysts and metaplastic dentigerous cysts can exhibit luminal eosinophilic cuboidal cells, cilia, and mucous cells. However, these findings tend to be more focal within dentigerous cysts compared to glandular odontogenic cysts, and only a minority of glandular odontogenic cysts develop in a dentigerous (pericoronal) relationship to unerupted teeth. In addition, some dentigerous cysts may demonstrate intraepithelial pseudomicrocysts. These pseudomicrocysts are lined by flattened cells, whereas the true microcysts within the glandular odontogenic cyst are lined by cuboidal, columnar, or mucous cells. Moreover, Fowler et al.132 reported that the presence of microcysts, clear cells, and epithelial spheres may be helpful in distinguishing pericoronal glandular odontogenic cysts from metaplastic dentigerous cysts. Epithelial spheres are also a prominent feature of the lateral periodontal cyst and its multilocular variant known as the botryoid odontogenic cyst. However, the lateral periodontal cyst does not exhibit luminal eosinophilic cuboidal cells and mucin pools. In addition, compared to the glandular odontogenic cyst, the lateral periodontal cyst tends to have more limited growth potential, with most lesions measuring less than 1 cm in maximum diameter. Low-­ grade central mucoepidermoid carcinoma also can mimic the glandular odontogenic cyst. Both lesions exhibit cystic growth with a mixture of squamous epithelial and mucous cells. Rarely, glandular odontogenic cysts even may exhibit small islands resembling mucoepidermoid carcinoma within their walls.132,138 However, glandular odontogenic cysts tend to have a thinner and less proliferative lining compared to central mucoepidermoid carcinomas. In addition, the epithelial spheres that are characteristic of the glandular odontogenic cyst are not usually found in mucoepidermoid carcinoma. Moreover, Bishop et  al.139 detected MAML2 rearrangement in 5 of 5 central mucoepidermoid carcinomas versus 0 of 21 glandular odontogenic cysts; these findings do not support conjecture that the glandular odontogenic cyst represents a precursor to, or low-­grade form of, central mucoepidermoid carcinoma. Also, in one small-­scale immunohistochemical study, Vered et al.140 reported that extensive maspin expression in the cytoplasm and nuclei of epithelial-­mucous cells may favor a diagnosis of low-­grade central mucoepidermoid carcinoma over glandular odontogenic cyst.  Treatment and Prognosis. Most glandular odontogenic cysts have been treated by enucleation or curettage. However, a high recurrence rate of approximately 30% to 55% has been reported.131,132,136,141 Some investigators have noted a tendency for recurrence among large multilocular lesions with cortical

perforation.142 For such lesions, some authors have suggested en bloc resection.136,141,143  CALCIFYING ODONTOGENIC CYST (CALCIFYING CYSTIC ODONTOGENIC TUMOR) The calcifying odontogenic cyst initially was described by Gorlin and colleagues144 in 1962 as a possible oral analogue to Malherbe’s calcifying epithelioma (pilomatricoma) of the skin, owing to the presence of ghost cell keratinization in both lesions. Although predominantly cystic (>85% of cases), a significant percentage of these lesions demonstrates a solid, neoplastic growth pattern and have been referred to as dentinogenic ghost cell tumor. Moreover, malignant transformation of both the cystic and solid variants has been described (ghost cell odontogenic carcinoma, among other terms). Several excellent papers have reviewed the debate pertaining to classification of ghost cell lesions.145,146 We herein describe the following three main subtypes: • Calcifying odontogenic cyst (also known as calcifying cystic odontogenic tumor) • Dentinogenic ghost cell tumor (also known as ghost cell odontogenic tumor, epithelial odontogenic ghost cell tumor, and odontogenic ghost cell tumor) • Ghost cell odontogenic carcinoma The etiopathogenesis of calcifying odontogenic cyst remains somewhat elusive. Sekine et  al.147 demonstrated beta-­catenin mutations in nine of 10 calcifying odontogenic cysts analyzed in their study. Bose et al.148 found multiple genetic aberrations in a single case of ghost cell odontogenic carcinoma, including alterations in the sonic hedgehog pathway, a deleted exon in the ubiquitin protein ligase E3 component N-­ recognin 5 (UBR5) gene, and a novel adenomatosis polyposis coli (APC) mutation. Clinical Features. The calcifying odontogenic cyst can be encountered at any age, with a peak in the second and third decades (mean age, 33 years) and no significant gender predilection. There is an equal distribution between the maxilla and mandible, with the majority of lesions involving the incisor/ canine region.149,150 Radiographic examination typically shows a well-­defined, unilocular radiolucency, although 10% to 25% of cases are multilocular (Fig. 10.25A). Scattered radiopacities may be present in 30% to 50% of cases (Fig. 10.25B).151 Approximately one-­third of calcifying odontogenic cysts are associated with an impacted tooth, and resorption or divergence of adjacent tooth roots is frequently noted. Lesions seldom exceed 4 cm in greatest diameter; however, large lesions measuring over 10 cm have been described.152 Approximately 15% to 21% of these lesions have been reported within the gingival soft tissues (peripheral or extraosseous calcifying odontogenic cyst) and present as nonspecific sessile or pedunculated masses that mimic fibromas or other reactive gingival proliferations.150,153 Compared to its intraosseous counterpart, the peripheral calcifying odontogenic cyst develops in an older patient population, with a peak in the sixth and seventh decades.153 The dentinogenic ghost cell tumor comprises less than 3% of all ghost cell lesions and has a mean age at diagnosis of approximately 30 to 40 years.42,152 These tumors favor the posterior jaws and present clinically as slowly ­growing swellings that may or may not be painful. Radiographic examination reveals a unilocular or multilocular lesion that ranges from completely radiolucent

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Fig. 10.25  Calcifying odontogenic cyst. A, Well-­demarcated radiolucency of the anterior mandible. B, Well-­demarcated, corticated radiolucency with central radiopaque areas of the anterior maxilla.

Fig. 10.26  Calcifying odontogenic cyst. Medium-­power photomicrograph showing odontogenic epithelium surrounding a cystic lumen. Note the palisaded cuboidal basal cells associated with stellate-­ reticulum-­ like tissue and non-nucleated, eosinophilic cells (ghost cells). High-­power photomicrograph showing aggregates of ghost cells undergoing focal calcification (inset).

to mixed radiolucent-­radiopaque. The margins can vary from well-­to ill-­defined, and root resorption can be seen.154 Ghost cell odontogenic carcinoma can arise de novo or from malignant degeneration of a preexisting calcifying odontogenic cyst or dentinogenic ghost cell tumor.152,155 Ghost cell odontogenic carcinoma demonstrates a similar age predilection as dentinogenic ghost cell tumor and is found more frequently in the maxilla than the mandible.156 The clinical presentation can include a slowly or rapidly progressive swelling that may be accompanied by pain, tooth mobility, paresthesia, and invasion of the contiguous soft tissues. Radiographic examination typically reveals an ill-­defined radiolucent or mixed radiolucent-­radiopaque lesion with resorption or displacement of the adjacent tooth roots.  Pathologic Features. Various classification schemes have been proposed for ghost cell lesions.145,146,157 Regardless, it is important to recognize the histopathologic diversity displayed by

this group of lesions. Overall, a predominantly cystic architecture is seen in 85% of cases, whereas a solid, neoplastic growth pattern is evident in 15% of cases.145 In most instances, the calcifying odontogenic cyst is encompassed by a fibrous capsule that is lined with odontogenic epithelium. The epithelial lining shows a peripheral basal cell layer of cuboidal or columnar cells that support loosely arranged, stellate reticulum-­like cells reminiscent of an ameloblastoma. The presence of suprabasilar epithelial cells that undergo a process called ghost cell change is the most distinctive feature of this lesion (Fig. 10.26). These cells are characterized by pale, eosinophilic cytoplasm and loss of nuclei, with only a faint nuclear membrane outline (see Fig. 10.26, inset). The mechanism of this cellular alteration is unclear and has been attributed to aberrant keratinization or coagulation necrosis.145,158 The ghost cell component frequently undergoes dystrophic calcification (Fig. 10.27) that

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Fig. 10.27  Calcifying odontogenic cyst. High-­power photomicrograph showing ghost cell change with areas of dystrophic calcification.

may range from fine granules to larger conglomerates of calcification. On occasion, a calcified matrix that likely represents dysplastic dentin is identified. The cyst lumen may be filled with ghost cells and dystrophic calcifications or, in rare instances, projections of epithelium that mimic an ameloblastoma. Satellite cysts that elicit a foreign body reaction may be observed within the cyst wall. The calcifying odontogenic cyst can be associated with other odontogenic tumors, such as odontoma (most commonly),159,160 adenomatoid odontogenic tumor, ameloblastic fibroma, and ameloblastoma.145,152 Dentinogenic ghost cell tumors appear as more solid proliferations of odontogenic epithelium that infiltrate the surrounding connective tissues. The epithelium exhibits ameloblastic features, including columnar peripheral cells that demonstrate nuclear palisading and surround stellate reticulum-­ like tissue. Typically, ghost cells are readily identifiable, and varying amounts of juxtaepithelial dentinoid are present. Ghost cell odontogenic carcinoma displays features similar to those of the dentinogenic ghost cell tumor but with cytologic features of malignancy, including cellular atypia and pleomorphism, conspicuous mitotic activity, necrosis, and infiltration of the adjacent tissues. Transition from a calcifying odontogenic cyst or dentinogenic ghost cell tumor may be seen. Although immunohistochemical studies are limited, at least one group has demonstrated consistent positivity in the epithelial cells of calcifying odontogenic cysts for cytokeratins 7, 8, 14, and 19.161 Another study reported nuclear and cytoplasmic expression of beta-­catenin.147 Two-­thirds of ghost cell odontogenic carcinomas are p53 positive.155,162  Differential Diagnosis. The epithelium in ameloblastoma closely resembles that of calcifying odontogenic cyst. However, ghost cells and dentinoid would not be expected in ameloblastoma. Similarly, these features aid in distinguishing ghost cell odontogenic carcinoma from ameloblastic carcinoma. Ghost cells also have been described in ameloblastic fibroodontomas and odontomas, although they do not tend to be a prominent component of these tumors. Interestingly, marked similarities exist between calcifying odontogenic cyst and pituitary craniopharyngioma.163 However, discriminating between these two lesions usually is not challenging because craniopharyngioma is found intracranially or in a suprasellar location. 

Treatment and Prognosis. Enucleation and curettage are the treatments of choice for the calcifying odontogenic cyst, and the prognosis is good. Even with conservative therapy, fewer than 5% of cases recur.149 For peripheral lesions, conservative excision is typically curative. The behavior of dentinogenic ghost cell tumors and ghost cell odontogenic carcinomas is difficult to predict because of their rarity. En bloc resection generally is advocated, as is long-­ term clinicoradiographic surveillance. Recurrences have been described, especially after conservative therapy. For ghost cell odontogenic carcinomas, the 5-­year survival rate is 73%, with deaths attributed to uncontrolled local disease or metastases.162  PERIAPICAL CYST (RADICULAR CYST, APICAL PERIODONTAL CYST) The periapical cyst is the most common type of jaw cyst and accounts for more than half of all odontogenic cysts.164,165 It is an inflammatory cyst that develops in association with a nonvital tooth. When the pulp of a tooth undergoes necrosis because of caries or trauma, a granulation tissue response (known as a periapical granuloma) may develop around the root apex as a defensive reaction to bacteria and toxic products from the root canal. If this inflammation persists, it may stimulate proliferation of epithelium around the root to form a cyst. In most instances, the source of this epithelium is believed to be the rests of Malassez, which are remnants of odontogenic epithelium found within the periodontal ligament along the tooth root. In other instances, the cystic epithelium may originate from the gingival crevicular epithelium, sinus mucosa, or lining of a fistulous tract.166 Clinical Features. Periapical cysts occur in patients over a wide age range, with a peak in the third and fourth decades of life.165 It is rare for such cysts to develop in association with deciduous teeth.167–170 Periapical cysts are most common in the anterior maxillary region.165 However, cysts associated with deciduous teeth occur more often in the mandible.167 Clinical findings may include tenderness, pain, swelling, and drainage. However, many periapical cysts are asymptomatic and discovered incidentally during routine radiographic examination.165,166 The radiograph shows a radiolucency at the root apex with loss of the lamina dura (the thin layer of radiopaque bone that normally surrounds the tooth root) (Fig. 10.28A).

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Fig. 10.28 A, Periapical cyst. Well-­ circumscribed radiolucency located at the apex of the maxillary left lateral incisor. Associated root resorption is evident. B, Lateral radicular cyst. Well-­circumscribed radiolucency located lateral to the root of the right maxillary lateral incisor, which has already undergone root canal therapy. (A, Courtesy of Dr. Richard SoJourner; B, courtesy of Dr. Larry Durand.)

Fig. 10.29  Periapical cyst. Low-­power view showing a cyst lined with an irregular and proliferative layer of stratified squamous epithelium. High-­power view showing arcading of the rete ridges and scattered inflammatory cells within the epithelium and cyst wall (inset).

The radiolucency may appear either well defined or poorly circumscribed, and adjacent root resorption is possible. Most periapical cysts are 2 cm or less in maximum diameter, although occasional lesions may demonstrate dramatic enlargement with destruction of a significant portion of the jaw. A lateral radicular cyst represents a periapical cyst variant that occurs along the lateral aspect of a tooth root rather than at the apex; it presumably results from pulpal necrosis that spreads through a lateral or accessory canal (Fig. 10.28B).166 Some cases also may develop from communication with a deep periodontal pocket. Although such cysts may appear radiographically similar to the developmental lateral periodontal cyst, they should be distinguished as being inflammatory in etiology. When a nonvital tooth is extracted, periapical inflammatory tissue that is not curetted from the socket may give rise to another variant, known as a residual periapical cyst (or residual cyst). Such a lesion usually presents as a well-­circumscribed radiolucency in the extraction site. Older residual periapical

cysts sometimes develop dystrophic calcification, resulting in a central area of radiopacity.171  Pathologic Features. Because many periapical cysts are friable or incompletely formed when they are curetted, they frequently are submitted in multiple fragments, which belie their cystic nature.165 However, gross examination of an intact periapical cyst typically exhibits a thick wall surrounding a central lumen. At times, the wall may exhibit bright yellow zones that microscopically correspond to collections of lipid-­ laden foamy macrophages. The lumen may contain brownish fluid or shimmering cholesterol crystals. Microscopically, most lesions are lined by nonkeratinizing stratified squamous epithelium, although ciliated pseudostratified columnar or simple cuboidal epithelium also may be noted in some cases. The squamous epithelial lining often exhibits neutrophilic exocytosis, spongiosis, and hyperplasia with “arcading” rete (Fig. 10.29); however, long-­standing lesions may exhibit flattened squamous epithelium without rete.165,172

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Fig. 10.30  Periapical cyst. Rushton bodies in the epithelial lining of a periapical cyst.

Because of extensive ulceration, some periapical cysts may show only focal remnants of an epithelial lining. Mucous cells have been identified in approximately 7% to 40% of periapical cysts; these cells usually are found along the surface layer, either individually or in a continuous row.173,174 Occasionally, the cyst lining also may exhibit apoptotic bodies and Rushton bodies.172 The latter appear as glassy, eosinophilic, linear, and curved to straight bodies, sometimes with hairpin or polycyclic morphology (Fig. 10.30).175 The pathogenesis of Rushton bodies remains uncertain; many investigators believe that they represent some type of secretory product of odontogenic epithelium, although some authors also have proposed a hematogenous or vascular origin.165,176 The wall of a periapical cyst is comprised of fibrous connective tissue with a variable inflammatory cell infiltrate that may include lymphocytes, plasma cells, neutrophils, histiocytes, and occasional eosinophils. In addition, many periapical cysts contain cholesterol clefts that are associated with a giant cell reaction. Hemorrhage, hemosiderin, foreign matter (i.e., root canal filling material), dystrophic calcification, odontogenic epithelial rests, and giant cell hyaline angiopathy (pulse granulomas) may be evident as well.  Differential Diagnosis. Although the degree of inflammation within the lesion may suggest a diagnosis of periapical cyst, the histopathologic findings are not specific. Other developmental odontogenic cysts (e.g., dentigerous cysts, odontogenic keratocysts) can have a similar microscopic pattern if secondary inflammation is present. Therefore clinical correlation and careful microscopic examination of the entire cystic lining are necessary to ensure the correct diagnosis.  Treatment and Prognosis. The treatment of periapical cysts usually involves either root canal therapy or extraction of the associated tooth. If the tooth is extracted, the cyst should be curetted and submitted for histopathologic examination to confirm the diagnosis. If root canal therapy is performed in an effort to save the tooth, it is important for the clinician to follow the lesion radiographically for subsequent bone regeneration. If the lesion does not resolve after root canal therapy, then

Fig. 10.31  Squamous cell carcinoma arising in a dentigerous cyst. There is a large destructive radiolucency of the right mandibular ramus that is associated with an impacted third molar. (Courtesy of Dr. Ramesh Narang.)

periapical surgery (including apicoectomy with retrofill) and biopsy may be indicated.  CARCINOMA ARISING IN ODONTOGENIC CYSTS Carcinomatous transformation of the epithelial lining of an odontogenic cyst is rare. Such malignancies may represent less than 2% of all carcinomas seen in some oral and maxillofacial pathology services.177 Clinical Features. Although carcinomas arising within odontogenic cysts occur over a wide age range, they are seen most frequently in older adults.178–180 A male predominance and predilection for the mandible have been noted. Most examples have been reported in association with residual periapical cysts and dentigerous cysts (Fig. 10.31). In addition, there have been several documented cases of carcinomas arising in odontogenic

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Fig. 10.32  Squamous cell carcinoma arising in a dentigerous cyst. A, The cystic lining demonstrates severe epithelial dysplasia. B, Islands of invasive squamous cell carcinoma can be seen infiltrating into the cyst wall.

keratocysts.88,181,182 In very rare instances, malignant transformation of other odontogenic cyst types (e.g., orthokeratinized odontogenic cyst, lateral periodontal cyst) may occur as well, and many investigators have provided no specific odontogenic cyst classification.179,183–186 The most common symptoms are pain and swelling, although some lesions are asymptomatic.179 Other possible findings include tooth mobility, infection, sinus tract formation, lymphadenopathy, paresthesia, trismus, and pathologic jaw fracture.178–180 The radiographic features may mimic any benign odontogenic cyst, although the area of bone destruction is often more irregular and ragged in nature. Compared to plain radiography, computed tomography may be superior for demonstrating border irregularity and tumor extent.187  Pathologic Features. Carcinomas arising from odontogenic cysts are most often well-­differentiated squamous cell carcinomas, although mucoepidermoid carcinomas, spindle cell carcinomas, and other types also have been described.178 Dysplasia may be found within the cystic epithelial lining along with islands of invasive carcinoma in the cyst wall (Fig. 10.32). Occasionally, one may be able to find a transition from normal cystic epithelium to carcinoma. In some cysts, the lining epithelium is markedly hyperkeratotic, with features of verrucous carcinoma (i.e., warty surface architecture with downward growth of broad, bulbous rete and mild cytologic epithelial atypia) or verrucous dysplasia188,189; thorough examination of such lesions is needed to rule out an invasive squamous cell carcinoma component.  Differential Diagnosis. Squamous cell carcinomas arising in odontogenic cysts represent a subset of primary intraosseous squamous cell carcinoma (discussed later). Strictly speaking, a diagnosis of primary intraosseous squamous cell carcinoma requires correlation of microscopic, clinical, and radiographic findings to exclude the following: (1) a metastatic lesion, (2) a malignant odontogenic tumor of specific type (e.g., ameloblastic carcinoma, sclerosing odontogenic carcinoma, clear cell odontogenic carcinoma, ghost cell odontogenic carcinoma), (3) a sinonasal carcinoma, and (4) an intraosseous salivary gland neoplasm (e.g., mucoepidermoid carcinoma).190 

Treatment and Prognosis. The treatment and prognosis for a carcinoma arising from an odontogenic cyst are similar to those for other oral carcinomas and depend on tumor size and extent. Management typically includes en bloc excision or radical resection, often with adjunctive radiation therapy. The prognosis is difficult to ascertain because of disease rarity and limited patient follow-­up data; however, 2-­year survival rates of approximately 60% and 5-­year survival of approximately 40% have been noted by some large case series or literature reviews.179,180 Metastases to regional lymph nodes have been reported but appear uncommon.178 

Odontogenic Tumors BENIGN EPITHELIAL ODONTOGENIC TUMORS Ameloblastoma The ameloblastoma is a benign but locally aggressive odontogenic epithelial neoplasm. If one excludes odontomas (which are considered hamartomas), it is the most common odontogenic tumor.191,192 Ameloblastomas may arise from various odontogenic epithelial sources, including the rests of dental lamina, epithelial lining of odontogenic cysts, and basal cells of the oral mucosa. The cells in this tumor closely mimic the ameloblasts and stellate reticulum of the developing tooth organ. With respect to etiopathogenesis, previous studies have suggested that expression of parathyroid hormone-­related protein and matrix metalloproteinase may contribute to the aggressiveness of this neoplasm.193,194 More recently, a variety of molecular aberrations have been implicated in tumorigenesis. Most involve the mitogen-­ activated protein kinase (MAPK) and sonic hedgehog (SHH) pathways. In particular, investigators have demonstrated BRAF-­V600E mutations in approximately 63% of ameloblastomas and smoothened (SMO) gene mutations in 16% to 39% of cases.195–198 Less common mutations involve the fibroblast growth factor receptor 2 (FGFR2); RAS (KRAS, NRAS, HRAS); phosphatidylinositol-­4,5-­bisphosphate 3-­kinase catalytic subunit alpha (PIK3CA); catenin beta 1 (CTNNB1); and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) genes.195–197

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Fig. 10.33  Conventional ameloblastoma. A, Well-­defined unilocular radiolucency of the posterior mandible associated with adjacent root resorption of the permanent first molar. Biopsy specimen revealed conventional follicular ameloblastoma. B, Well-­defined multilocular radiolucency of the posterior mandible on the right side. Biopsy specimen revealed conventional follicular ameloblastoma.

The mutations are mutually exclusive in the majority of lesions, with the exception of SMO-­mutated tumors, which often occur concomitantly with FGFR2 or RAS mutations.195,197 The following three main subtypes of ameloblastoma are discussed subsequently: 1. Conventional solid or multicystic ameloblastoma 2. Unicystic ameloblastoma 3. Peripheral ameloblastoma 

CONVENTIONAL SOLID OR MULTICYSTIC AMELOBLASTOMA Clinical Features. Conventional solid or multicystic ameloblastoma is the most common subtype, accounting for approximately 92% of ameloblastomas.199 It arises most often in the third to seventh decades of life, and less than 2% are discovered before 10 years of age. No significant gender or ethnic predilection has been observed. Approximately 80% of ameloblastomas develop in the mandible, with the majority occurring in the molar/ramus area. Other subsites in order of decreasing frequency include the anterior mandible, posterior maxilla, and anterior maxilla.191,192,200 The most common presentation is a painless jaw swelling, which may be accompanied by tooth mobility, trismus, paresthesia, and soft-tissue invasion. Large tumors can cause pain, marked facial deformity, and, uncommonly, airway compromise.201 In contrast, small lesions often remain completely asymptomatic and are discovered incidentally.202 Radiographic examination shows a multilocular or unilocular radiolucency with well-­defined borders (Fig. 10.33A). The loculations may be large or small, imparting a soap-­bubble or honeycomb appearance, respectively (Fig. 10.33B). The tumor is associated with an impacted tooth in 15% to 40% of cases, and more than half of unilocular lesions present in a pericoronal relationship. Tooth resorption or displacement and cortical expansion are relatively common, especially in larger examples. The unusual desmoplastic variant of conventional ameloblastoma favors the anterior and premolar regions of the jaws and occurs with equal frequency in the maxilla and mandible.203,204

The typical radiographic presentation is a mixed radiolucent-­ radiopaque lesion with well-­to ill-­defined borders.205 Interestingly, ameloblastomas with BRAF mutations demonstrate a striking predilection for the mandible, whereas the majority of those with SMO mutations involve the maxilla.197 Also, BRAF-­mutated tumors occur in younger patients (mean age, 34 years) compared to those without BRAF mutations (mean age, 54 years).195  Pathologic Features. Conventional ameloblastomas are solid infiltrating tumors with a tendency to undergo cystic change. The cysts may be small and grossly undetectable or large and prominent. There are six main histopathologic subtypes: follicular, plexiform, acanthomatous, granular cell, basal cell, and desmoplastic. The follicular and plexiform subtypes constitute the majority of cases, although two or more patterns can be observed in any individual tumor. Regardless, the histopathologic subtype does not impact prognosis. Follicular ameloblastoma is characterized by discrete islands of odontogenic epithelium interspersed within a mature collagenous connective tissue stroma (Fig. 10.34).206 The peripheral epithelial cells are cuboidal or columnar and exhibit nuclear palisading, reverse nuclear polarization (i.e., nuclei oriented away from the basement membrane), and vacuolated basal cytoplasm (see Fig. 10.34, inset).206 The central portion of the islands contains loosely arranged, stellate or angular epithelial cells that resemble the stellate reticulum of the developing enamel organ. Edema and microcyst formation are common findings. In plexiform ameloblastoma, the odontogenic epithelium is arranged in anastomosing strands and cords that often appear to encompass central areas of collagenous or loose, vascular stroma (Fig. 10.35A). Ameloblastic features, such as reverse nuclear polarization of the peripheral cells, are still present but tend to be less prominent than in the follicular variant. Stellate reticulum-­like tissue and cyst formation are seen less frequently in the plexiform variant than in the follicular variant. In the acanthomatous type, the typical features of follicular ameloblastoma are seen, but the central portions of the epithelial islands show squamous metaplasia (Fig. 10.35B). On rare occasions, extensive keratin pearl formation is noted and has been designated keratoameloblastoma.207,208 In the granular

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Fig. 10.34  Conventional ameloblastoma, follicular type. Islands of odontogenic epithelium interspersed within mature collagenous connective tissue. Increased magnification showing peripheral columnar differentiation and reverse nuclear polarization of the islands (inset).

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Fig. 10.35  A, Conventional ameloblastoma, plexiform type. Long interconnecting strands and cords of odontogenic epithelium that appear to surround central areas of supporting stroma. B, Conventional ameloblastoma, acanthomatous type. Island of ameloblastic epithelium the central portion demonstrates squamous differentiation. C, Conventional ameloblastoma, granular cell type. Island of ameloblastic epithelium containing cells that demonstrate abundant eosinophilic and granular cytoplasm. D, Conventional ameloblastoma, basal cell type. Interconnecting strands and cords of ameloblastic epithelium that exhibit basophilic nuclei and little cytoplasm.

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cell pattern, the tumor cells exhibit abundant eosinophilic, cytoplasmic granules (Fig. 10.35C).209 The extremely rare basal cell variant is characterized by islands of basaloid cells with scant cytoplasm, similar to the tumor cells that comprise basal cell carcinoma (Fig. 10.35D). The classic ameloblastic features are generally inconspicuous in this histologic subtype, which may confound the diagnosis. Lastly, the desmoplastic variant is composed of dense, collagenized stroma surrounding widely scattered, compressed islands and cords of hyperchromatic epithelial cells (Fig. 10.36).210–212 The periphery of the small islands is typically lined by cuboidal or flattened cells; peripheral columnar cells with reverse nuclear polarization are difficult to appreciate but usually can be identified with a meticulous search. Histochemical evaluation suggests that the dense stroma is not scar tissue but rather represents de novo synthesis of extracellular matrix proteins, possibly attributed to upregulated expression of transforming growth factor beta (TGF-­β).213 Desmoplastic ameloblastoma also can exhibit osseous metaplasia of the stroma. This feature in combination with the stromal density may contribute to a mixed radiolucent-­radiopaque appearance that can be confused with a fibroosseous lesion. Immunohistochemical studies of ameloblastoma have shown that the tumor cells may be positive for CK14, CK19, and CD56; expression of calretinin has been reported but tends to be localized to the stellate reticulum-­like areas.214–217 Although ancillary studies typically are not necessary for the diagnosis of ameloblastoma, overexpression of BRAF or SMO plus other molecular findings may be of increasing relevance with regard to treatment and prognosis. These mutations can be identified by molecular methods or, in the case of BRAF, via immunohistochemistry using the BRAF-V600E mutation-specific antibody as described by Kurppa et al.196 and Brown et al.195  Differential Diagnosis. The differential diagnosis of ameloblastoma is broad and may include any odontogenic cyst or tumor that features epithelium with ameloblastic differentiation (i.e., peripheral columnar cells with reverse nuclear polarization and central loosely arranged, stellate cells). The calcifying odontogenic cyst and its variants are cystic or solid lesions characterized by cuboidal or columnar abluminal cells, with reverse nuclear polarization. The presence of numerous eosinophilic ghost cells and focal calcifications

Fig. 10.36  Conventional ameloblastoma, desmoplastic variant. Numerous small, compressed islands of hyperchromatic odontogenic epithelium within hypocellular collagenous stroma.

helps to differentiate these lesions from ameloblastoma. Columnar cell differentiation also may be observed in adenomatoid odontogenic tumor, although in this tumor, the columnar cells form duct-­like structures and contain nuclei oriented towards the basal cytoplasm. Ameloblastic fibroma and ameloblastic fibroodontoma demonstrate islands of odontogenic epithelium with ameloblastic features; however, the characteristic dental papilla-­ like stroma in both these tumors and the formation of dental hard tissue in the latter aid in distinction from ameloblastoma. Rests of dental lamina can be seen within a dental follicle or wall of a dentigerous cyst. On occasion, these rests may demonstrate peripheral columnar cells with reverse nuclear polarization. These isolated foci do not represent neoplasia and should not be overdiagnosed as ameloblastoma.218 The presence of squamous metaplasia in the acanthomatous variant may raise the possibility of other intraosseous lesions with squamous differentiation. Acanthomatous ameloblastomas with only focal peripheral columnar differentiation and reverse nuclear polarization can closely resemble a squamous odontogenic tumor. In these instances, a thorough search for definitive ameloblastic differentiation is necessary to avoid misdiagnosis. Primary intraosseous squamous cell carcinoma may also be considered in the differential diagnosis but should display some degree of cytologic atypia and no columnar cells with reverse nuclear polarization. An epithelium-­rich central odontogenic fibroma demonstrates a significant number of odontogenic epithelial islands within a background of fibrous connective tissue and may be confused with a desmoplastic ameloblastoma. Although the ameloblastic features may be subtle in the desmoplastic variant, identification of such would confirm this diagnosis.  Treatment and Prognosis. There is much debate regarding optimal treatment of conventional ameloblastoma – especially pertaining to conservative therapy, resection margins, and maxillary lesions.219 Because these tumors have a propensity to infiltrate the surrounding bone and extend beyond their apparent clinical and radiographic boundaries, marginal or en bloc resection, 1 to 2 cm beyond the radiographic perimeter of the tumor, is the most widely used form of therapy.220,221 One group performed presurgical marsupialization to reduce the extent of surgical resection,222 while others have advocated conservative

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tumor removal and peripheral ostectomy for select cases.223,224 Maxillary lesions often require more aggressive therapy compared to mandibular lesions, because of anatomic restrictions, tumor infiltration of the thin bony architecture, and proximity to vital structures.219,225,226 Furthermore, early recurrence of maxillary ameloblastoma may be difficult to detect radiographically in this anatomically complex area. The recurrence rates reported in various reviews range from 20% to 90%, depending on the treatment modality.222,227,228 A large review of 3677 cases reported an overall recurrence rate of 23%, with 35% recurrence for lesions treated by enucleation and curettage and 17% for those managed with radical resection.199 Similarly, a systematic review and meta-­analysis by Antonoglou and Sandor229 reported 38% recurrence with conservative therapy versus 8% with radical treatment, although the authors noted a very low quality of evidence and very high risk of bias among the studies included in their analysis.229 Other studies have shown recurrence rates ranging from 50% to 90% following curettage.191,223,227 Recurrence is primarily determined by the adequacy of surgical margins, which is particularly problematic for maxillary lesions that have extended to adjacent vital structures. Other factors that may influence recurrence include tumor size and location, patient age and medical comorbidities, and multilocularity. Importantly, nearly half of all recurrences become clinically evident 2 to 5 years after the initial surgical procedure, although recurrence intervals of up to 45 years have been documented.223,230 Hence, lifelong follow-­up is recommended. Death typically is related to uncontrolled disease or malignant transformation (discussed later). Adjunctive radiation therapy has a limited role in the management of ameloblastoma, given variable response rates and the potential for osteoradionecrosis and postradiation malignancy. 230–233 Such treatment may be considered for large or recurrent tumors, especially those involving the maxilla. 234 An exciting prospect is the development of biological therapies for ameloblastoma. Pharmacologic inhibitors are available for most of the mutations identified thus far, including BRAF,

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SMO, NRAS, and FGFR2. Although clinical trials are needed, in vitro studies and case reports have reported promising findings with the BRAF inhibitors (e.g., vemurafenib, dabrafenib); trametinib, an inhibitor that acts downstream from Ras in the MAPK pathway; and sonic hedgehog signaling inhibitors.195,197,235 Such agents may reduce morbidity in the surgical treatment of conventional ameloblastoma. Furthermore, they may also be useful for the treatment of metastasizing ameloblastoma (discussed later).236 Prognostically, Brown and colleagues195 found that ameloblastomas harboring the BRAF-­V600E mutation recurred later than wild-­t ype lesions. Hence, there is great interest in further defining the molecular profile of these tumors, as it is likely to impact diagnosis, treatment, and prognostication.  UNICYSTIC AMELOBLASTOMA Clinical Features. Unicystic ameloblastoma is the second most common subtype of ameloblastoma and comprises 5% to 22% of all ameloblastomas.199,237 These tumors exhibit a predilection for young individuals, with nearly half detected during the second decade of life.238 Lesions associated with an impacted tooth tend to develop in younger patients (mean age, 22 years) compared with those that are not.237 There is no significant gender predilection.239 The most commonly affected sites are the angle and posterior body of the mandible in the third molar region, followed by the mandibular ramus and coronoid process.239 Maxillary lesions are distinctly rare and, likewise, favor the posterior region. Most patients present with a slowly growing, painless swelling in the affected bone, although intermittent pain has been reported rarely.239,240 Some cases are asymptomatic and discovered incidentally or following radiographic examination for failed tooth eruption. Radiographically, the unicystic ameloblastoma appears as a welldefined, unilocular radiolucency, similar to a dentigerous cyst. However, a pericoronal relationship with an impacted tooth is not always present (Fig. 10.37). Purported multilocular examples have been reported, but the existence of

Fig. 10.37  Unicystic ameloblastoma. Well-­defined pericoronal radiolucency associated with an impacted mandibular permanent second molar in a 14-­year-­old girl. (Courtesy of Dr. Robert Coles.)

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Fig. 10.38  A, Unicystic ameloblastoma, luminal variant. Cystic lining that demonstrates columnar differentiation and reverse nuclear polarization of the basal cell layer. Note the loose stratum spinosum that resembles stellate reticulum. B, Plexiform unicystic ameloblastoma. Interconnecting cords of odontogenic epithelium supported by a delicate and vascular connective tissue stroma. This plexiform epithelial proliferation often is seen projecting into the lumen of the cyst.

a true multilocular unicystic ameloblastoma has been questioned by some.241 Root resorption and cortical perforation are common in larger lesions.  Pathologic Features. Two major histopathologic variants of unicystic ameloblastoma are recognized: (1) luminal and (2) intraluminal. The luminal variant is lined with epithelium exhibiting classic ameloblastic features, including columnar or cuboidal basal cells with nuclear hyperchromasia, reverse nuclear polarization, and cytoplasmic vacuolization (Fig. 10.38A). The luminal aspect of the lining is composed of discohesive eosinophilic cells that bear resemblance to stellate reticulum. The connective tissue adjacent to the lining epithelium often exhibits a uniform band of hyalinization. No intraluminal proliferation or intramural extension should be found. The intraluminal type is characterized by one or more nodules of ameloblastoma projecting into the lumen of the cyst, with no tumor extension into the surrounding connective tissue wall. On occasion, the proliferation in the lumen will assume a plexiform pattern composed of interconnecting epithelial cords supported by delicate, vascular connective tissue (Fig. 10.38B). These lesions have been designated as plexiform unicystic ameloblastoma. Typical ameloblastic features may be difficult to discern in this variant. In many cases, invasion of the cyst wall by ameloblastic epithelium is seen.237,242 These lesions have been termed mural or intramural unicystic ameloblastoma and may exhibit more aggressive behavior.243,244 This diagnosis can be used for cases with focal or minimal infiltration of the cyst wall. However, careful and extensive sampling is necessary to rule out more significant mural invasion, which would warrant a diagnosis of conventional ameloblastoma.  Differential Diagnosis. A number of odontogenic cysts may be confused with unicystic ameloblastoma. Dentigerous cysts frequently exhibit a similar clinicoradiographic presentation but lack columnar basal cells with nuclear hyperchromasia and reverse polarization histopathologically. The hyperplastic epithelium of periapical cysts may resemble plexiform unicystic

ameloblastomas. However, periapical cysts are localized to the apices of nonvital teeth and microscopically show significant inflammation without a polypoid intraluminal growth pattern. Odontogenic keratocysts also exhibit an epithelial lining with a hyperchromatic and palisaded basal cell layer but lack reverse nuclear polarization, cytoplasmic vacuoles, and stellate reticulum-­like luminal cells. Some investigators have suggested that calretinin may be a useful immunohistochemical marker for ameloblastoma. One study found positive expression of calretinin in 93.5% of conventional ameloblastomas and 81.5% of unicystic ameloblastomas versus no expression in odontogenic keratocysts, residual periapical cysts, and dentigerous cysts.245 Calcifying odontogenic cyst and adenomatoid odontogenic tumor may also have areas that mimic ameloblastic change. However, the former exhibits ghost cells and focal calcifications, and the latter has duct-­like structures without reverse nuclear polarization. A diagnosis of unicystic ameloblastoma requires clinical and radiographic correlation plus careful microscopic examination of the entire surgical specimen to rule out significant mural invasion. Conversely, large cysts within a conventional ameloblastoma may be be misdiagnosed as a luminal unicystic ameloblastoma.  Treatment and Prognosis. The optimal treatment of unicystic ameloblastomas is controversial, particularly because these tumors primarily affect children with incomplete facial growth and dental development.239 Previously reported treatment methods include enucleation and curettage, with or without adjunctive measures, such as peripheral ostectomy, cryotherapy, thermal cautery, or chemical cautery (e.g., Carnoy solution); decompression or marsupialization followed by enucleation; and resection.239 Although the most common treatment is enucleation and curettage, recent systematic reviews and meta-­ analyses have found inadequate evidence to support any one treatment modality and have called for improved studies.229,239 Until then, therapy should be individually tailored to each case and take into account factors, such as patient age, tumor

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location, extent of mural invasion and history of recurrence. More aggressive therapy may be indicated for maxillary lesions, tumors with significant mural invasion (warranting a diagnosis of conventional ameloblastoma), and patients unlikely to comply with recommended follow-­up protocols.239 In the largest study to date of 3677 ameloblastomas, a recurrence rate of 13.7% for unicystic ameloblastoma was reported.199 A subsequent systematic review and meta-­analysis showed a recurrence rate of 4% for unicystic ameloblastomas treated with radical resection compared to 17% for those managed conservatively.229 The interval for recurrence generally ranges from 1 to 11 years, with a mean of 4.4 years; more than half of recurrences occur within 5 years of initial treatment199,239 and are likely attributable to incomplete surgical removal. Long-term follow-up is recommended.  PERIPHERAL AMELOBLASTOMA Peripheral (or extraosseous) ameloblastoma accounts for approximately 1% to 10% of all ameloblastomas.246,247 These lesions most likely arise from remnants of dental lamina, and the vast majority of cases affect the gingiva and alveolar mucosa. Occurrence in other oral sites is rare and suggests a possible origin from the pluripotent basal cells of the surface epithelium.248,249 Clinical Features. The average age at diagnosis is 51 years, which is approximately 15 years older than for intraosseous ameloblastoma. There is a slight male predominance.192 The most common locations are the mandibular retromolar area and maxillary tuberosity; involvement of the anterior gingiva is also possible.199 Clinical examination usually reveals a normal-­colored to erythematous, smooth-­surfaced, and sessile mass that does not exceed 1.5 cm in greatest dimension. Such lesions can mimic the more common reactive gingival epulides (i.e., fibroma, pyogenic granuloma, peripheral ossifying fibroma, peripheral giant cell granuloma). Some peripheral ameloblastomas may display a granular, warty, or papillary surface.247 No radiographic alterations are evident, except for occasional saucerization or pressure erosion of the underlying cortical bone. If more significant involvement of the underlying bone is evident, an intraosseous ameloblastoma that has perforated through the cortical plate and extended into the soft tissue should be considered. The majority of lesions are solitary, although multicentric involvement has been reported rarely.250,251  Pathologic Features. Peripheral ameloblastomas demonstrate the histopathologic diversity of conventional ameloblastomas.199 Often times, the ameloblastic proliferation will be confluent with the overlying surface epithelium (Fig. 10.39), which may also exhibit papillary hyperplasia.  Differential Diagnosis. The differential diagnosis includes various peripheral odontogenic lesions (e.g., the peripheral variants of calcifying odontogenic cyst, adenomatoid odontogenic tumor, ameloblastic fibroma, ameloblastic fibroodontoma, squamous odontogenic tumor, and odontogenic fibroma). Squamous cell carcinoma is another diagnostic consideration (see preceding discussion). Also, basal cell carcinomas of the gingiva have been described, although there is debate regarding whether these actually represent peripheral ameloblastomas.247,252–254  Treatment and Prognosis. Most peripheral ameloblastomas are treated with conservative excision. The recurrence rate

Fig. 10.39  Peripheral ameloblastoma. Low-­power photomicrograph showing islands of ameloblastic epithelium that merge with the surface epithelium.

is approximately 16% to 20%, and recurrent lesions are generally amenable to local reexcision.255 Long-term followup is necessary, as recurrence has been reported as late as 8 years after initial excision.256 Rare cases of carcinomatous transformation have been documented.257–260  CALCIFYING EPITHELIAL ODONTOGENIC TUMOR (PINDBORG TUMOR) The calcifying epithelial odontogenic tumor (or Pindborg tumor) is a rare benign odontogenic epithelial neoplasm that accounts for less than 1% of all odontogenic tumors.261–263 Its histogenesis remains uncertain, with proposed origins from the stratum intermedium, remnants of dental lamina, or reduced enamel epithelium.264,265 Peripheral (extraosseous) lesions involving the gingiva likely arise from rests of dental lamina.264 Clinical Features. The calcifying epithelial odontogenic tumor has been documented over a broad age range that spans from the first to tenth decades, with a peak in the fifth decade.264,266 There is no significant gender predilection. The majority of cases are intraosseous, but approximately 6% arise peripherally.264 There is a 3:1 mandible-­to-­maxilla ratio, and lesions most commonly involve the premolar/molar region.264 In contrast, rare peripheral examples favor the anterior gingiva.

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Fig. 10.40  Calcifying epithelial odontogenic tumor. Well-­ defined pericoronal radiolucency associated with an impacted first permanent mandibular molar on the right side. (Courtesy of Dr. Samuel McKenna.)

Fig. 10.41  Calcifying epithelial odontogenic tumor. Sheet of large eosinophilic polyhedral epithelial cells that exhibit mild cellular and nuclear pleomorphism. Note pools of acellular eosinophilic amyloid.

A

Clinically, calcifying epithelial odontogenic tumors present as slowly enlarging and painless swellings. On occasion, patients may report pain, nasal stuffiness, epistaxis, or headaches. Radiographic examination in most cases reveals a unilocular radiolucency, with or without intermixed radiopacities. The radiographic borders can vary from well-­to ill-­defined. With enlargement, there is a tendency for the lesion to assume a honeycomb-­like, multilocular configuration. The calcifications may range from faint to prominent, with some lesions exhibiting “driven-­snow” opacities around the crown of an impacted tooth.267 More than half of cases are associated with an impacted tooth or odontoma (Fig. 10.40).266 Peripheral (extraosseous) tumors have a relatively nonspecific clinical appearance and most often present as a well-­ circumscribed, sessile gingival mass. Associated radiographic changes are uncommon, although pressure erosion of the underlying bone can be observed in some examples.  Pathologic Features. Calcifying epithelial odontogenic tumors are characterized by sheets, islands, nests, or cords of epithelial cells surrounded by a mature fibrous connective stroma. The epithelial cells are eosinophilic and polyhedral with sharply defined borders and distinct intercellular bridging. Striking cellular and nuclear pleomorphism can be seen (Fig. 10.41). Such features are considered ­a cceptable within the histomorphologic spectrum of these tumors and do not indicate malignant transformation (see later). Intermixed with the epithelial cells and/or stroma are globules of amorphous, eosinophilic, amyloid-­like material that demonstrate apple-­green birefringence with Congo red staining when viewed under polarized light (Fig. 10.42A). The amount and distribution of this material can vary widely between lesions. On occasion, extensive intraepithelial accumulation imparts a cribriform pattern to the neoplastic islands (Fig. 10.42B). This material may also undergo Liesegang calcification, which is characterized by concentric, basophilic rings. Amino acid sequencing and mass spectrometry have shown that the material consists of a unique protein, designated as odontogenic ameloblast-­associated protein.268–270 This protein

B

Fig. 10.42  Calcifying epithelial odontogenic tumor. A, Pools of homogeneous and eosinophilic amyloid-­like material intermixed with small islands and cords of odontogenic epithelium. B, Intraepithelial accumulation of amyloid-­like material creating a cribriform appearance of the involved neoplastic island.

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may also be produced by other odontogenic tumors and dental follicles.268 A number of histopathologic variants of calcifying epithelial odontogenic tumor have been described, including a clear cell variant, cystic variant, and noncalcifying variant with Langerhans cells.271,272 Careful examination of these variants will reveal more diagnostic areas. Immunohistochemical analysis of a limited number of tumors has shown expression of p63, CK5/6, epidermal growth factor receptor (EGFR), and bcl-­2.273–275 One group demonstrated immunoreactivity to PTCH and two sonic hedgehog (SHH)-­related transcription factors, Gli1 and Gli2.276 They proposed that the SHH pathway may play a role in the pathogenesis of this tumor. Malignant transformation of a calcifying epithelial odontogenic tumor is extremely rare.277 Most cases have arisen in the mandible from a primary or recurrent tumor,278 and both regional and distant metastasis have been described.279,280 Microscopically, these lesions demonstrate features of malignancy, including increased mitotic activity atypical mitotic figures, perineural invasion, and intravascular spread.281 Loss of p53 expression in the carcinomatous component has been reported.278  Differential Diagnosis. The pleomorphic, eosinophilic epithelial cells in calcifying epithelial odontogenic tumor may be confused with malignancies exhibiting squamous differentiation, such as primary intraosseous squamous cell carcinoma, central mucoepidermoid carcinoma, and metastatic squamous cell carcinoma to the jaws. However, the presence of amyloid-­ like material and Liesegang calcifications is pathognomonic for calcifying epithelial odontogenic tumor. Also, mitotic activity is more likely in the aforementioned malignancies. An epithelium-­rich central odontogenic fibroma with small amounts of amyloid-­like material may closely resemble a calcifying epithelial odontogenic tumor, although the epithelial cells in odontogenic fibroma do not demonstrate the characteristic eosinophilia, sharp cell borders, and intercellular bridging seen in the latter. Amyloid-­like deposits can also be found in some adenomatoid odontogenic tumors but will be accompanied by spindled epithelial cells with duct-­like spaces and rosettes. Lastly, calcifying epithelial odontogenic tumor-­ like areas have been identified in dental follicles but tend be focal findings in the setting of otherwise normal follicular tissue.282 Central mucoepidermoid carcinoma, metastatic renal cell carcinoma, and clear cell odontogenic carcinoma may be considered in the differential diagnosis of the clear cell variant of calcifying epithelial odontogenic tumor. However, none of these lesions produce amyloid-­like material. Additional distinguishing features include the presence of mucous cells in mucoepidermoid carcinoma and glycogenrich, lipid-positive clear cells in renal cell carcinoma. Furthermore, metastatic renal cell carcinoma is consistently immunoreactive for PAX8, whereas detection of the EWSR1ATF1 fusion would support a diagnosis of clear cell odontogenic carcinoma.  Treatment and Prognosis. Although calcifying epithelial odontogenic tumor is a benign neoplasm, it has an overall recurrence rate of approximately 15%.273 In the mandible, aggressive curettage or conservative local resection with a rim

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of normal tissue is the current therapy of choice. In the maxilla, more aggressive treatment should be considered because of the potential for extensive tumor growth within the relatively thin bone in this region.264,283 Peripheral examples respond well to conservative excision, and no recurrences have been reported to date. Although some authors have suggested that the clear cell variant of calcifying epithelial odontogenic tumor may exhibit more aggressive behavior (such as perineural invasion and frequent cortical perforation), recurrence rates for the clear cell variant and conventional type are similar.284,285 Regardless of histologic subtype, long-­ term follow-­ up is recommended.  SQUAMOUS ODONTOGENIC TUMOR The squamous odontogenic tumor is a very rare benign epithelial odontogenic tumor with postulated derivation from the dental lamina, rests of Malassez, or basal epithelium of the oral mucosa.286–290 Although many examples exhibit indolent behavior akin to a hamartoma, others exhibit clinical activity that supports classification as a neoplasm. The etiopathogenesis of squamous odontogenic tumor remains somewhat enigmatic. However, various molecular events have been implicated, including mutation of the ameloblastin (AMBN) gene and expression of Notch receptors and metallotheionein.291 Clinical Features. The squamous odontogenic tumor occurs over a wide age range (second to eighth decades), with a peak in the third to fourth decades and a mean age of 38 years.290,292 There is a slight male predilection.293 Tumors develop with equal frequency in the maxilla and mandible, with maxillary lesions favoring the anterior region and mandibular lesions favoring the premolar/molar region. Rare peripheral examples have been documented.290 The most common clinical presentation is a gingival swelling with mobility of the adjacent teeth. However, a significant proportion of cases are asymptomatic and discovered incidentally during routine radiographic examination. Confusion with localized periodontal disease is possible in some cases due to the shared presence of pain, gingival inflammation, deep probing depths, and radiographic evidence of vertical bone loss.294 Radiographically, squamous odontogenic tumor presents as a well-­or ill-­defined, semicircular or triangular radiolucency in the crestal portion of the alveolar ridge between the roots of the adjacent teeth (Fig. 10.43). For lesions with a triangular configuration, the apex usually is oriented toward the alveolar crest; this contrasts with periodontitis-­related vertical bone loss, in which the apex of the triangle is typically located toward the tooth root apices. Root resorption and divergence can be seen. Large tumors may appear multilocular, extending into the mandibular body or involving the maxillary sinus. Rare examples have been described in association with an impacted tooth and in edentulous regions of the jaws.292 Two or more sites of involvement by squamous odontogenic tumor have been reported in slightly less than one-­third of affected patients.292,295,296 Multifocal involvement can occur within the maxilla, mandible, or both jaws. One report documented multicentric occurrence in three siblings, supporting a

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familial pattern.296 The potential for multiple lesions mandates the need for a thorough clinical and radiographic examination of all tooth-­bearing areas in a patient with squamous odontogenic tumor.  Pathologic Features. Squamous odontogenic tumor is characterized by variably sized islands of well-­differentiated squamous epithelium that lack cytologic atypia and mitotic activity (Fig. 10.44). The peripheral cells range from flat to cuboidal and do not demonstrate columnar differentiation, nuclear palisading, and reverse nuclear polarization. The islands usually exhibit smooth, rounded borders and are embedded in a mature collagenous stroma. Internally, the squamous islands are often characterized by vacuolization, keratinization, and microcyst formation (see Fig. 10.44A). Intraepithelial, eosinophilic, globular structures, histochemically consistent with prekeratin rather than amyloid, have been reported as well.287 Laminated calcifications may also be seen within the epithelial islands or the surrounding connective

tissue. Isolated mucous metaplasia and sebaceous differentiation are rare findings.291  Differential Diagnosis. The bland appearance of the epithelial cells allows for squamous odontogenic tumor to be readily distinguished from squamous cell carcinoma. Squamous odontogenic tumor can be differentiated from acanthomatous ameloblastoma by the lack of hyperchromatic peripheral columnar cells that demonstrate reverse nuclear polarization. Desmoplastic ameloblastoma may be challenging to distinguish from squamous odontogenic tumor because obvious ameloblastic features may not be evident. However, close microscopic examination reveals at least focal areas with more typical ameloblastic differentiation in the former. Several authors have documented squamous odontogenic tumor-­ like proliferations within the walls of odontogenic cysts.297 These foci do not develop into solid tumor and the associated cysts behave no differently than their conventional counterparts. Ultimately, clinical, radiographic, and histopathologic correlation should aid in differentiating these epithelial proliferations from a true squamous odontogenic tumor.  Treatment and Prognosis. Local excision with extraction of any involved teeth is the therapy of choice, and recurrence is rare. Some believe that maxillary lesions behave more aggressively than mandibular lesions, although this may be related to the porous quality of the bone rather than the inherent biology of maxillary squamous odontogenic tumors.298 For unusually large lesions, en bloc resection may be necessary. Of note, one case of bilateral maxillary squamous odontogenic tumors has been reported in association with a primary intraosseous squamous cell carcinoma of the mandible.299 In addition, a mandibular squamous odontogenic tumor with focal dedifferentiation into squamous cell carcinoma has been documented.300  ADENOMATOID ODONTOGENIC TUMOR

Fig. 10.43  Squamous odontogenic tumor. Semicircular radiolucency of the left maxilla. (Courtesy of Dr. Ed McGaha.)

A

Adenomatoid odontogenic tumor is an uncommon benign odontogenic epithelial neoplasm that represents less than 5% of all odontogenic tumors.301,302 The neoplastic nature of these

B

Fig. 10.44  Squamous odontogenic tumor. A, Medium-­power photomicrograph showing multiple islands of squamous epithelium. Note vacuolization of some of the islands and lack of ameloblastic features. B, High-­power photomicrograph depicting well-­differentiated and bland squamous cells that comprise the tumor islands.

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lesions has been debated, with some authors suggesting that they behave more like hamartomas.303 Adenomatoid odontogenic tumors can be subdivided into three clinicoradiographic variants: (1) follicular or pericoronal, (2) extrafollicular or extracoronal, and (3) peripheral or extraosseous. Clinical Features. Adenomatoid odontogenic tumors predominantly affect young patients, with approximately 87% of cases occurring in the second and third decades.304–306 Occurrence after the age of 35 years is rare.306 The lesion is often referred to as the two-­thirds tumor because approximately two-­thirds of cases affect females, arise in the maxilla, and occur pericoronal to an impacted tooth (i.e., follicular variant); moreover, about two-­thirds of pericoronal lesions are associated with an impacted canine.306 Interestingly, lesions in patients older than 30 years exhibit a predilection for males and the mandible.302,307 Most adenomatoid odontogenic tumors are less than 3 cm in diameter

Fig. 10.45  Adenomatoid odontogenic tumor. Well-­demarcated unilocular radiolucency with fine radiopaque flecks associated with the crown of an impacted right mandibular first premolar. (Courtesy of Dr. Tony Traynham.)

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and asymptomatic, although larger lesions have been reported. Radiographic examination reveals a well-­circumscribed, unilocular radiolucency that may contain radiopaque flecks (Fig. 10.45).307 Divergence of the adjacent tooth roots or displacement of teeth frequently occurs, but root resorption is distinctly rare. When associated with an impacted tooth, the lesion often surrounds the crown and encompasses a portion of the root.304 Extrafollicular examples most often present as unilocular radiolucencies between the roots of erupted teeth. Peripheral (extraosseous) lesions represent less than 3% of reported cases and typically appear as small, sessile gingival masses that are indistinguishable from the more common reactive gingival epulides.306  Pathologic Features. Gross examination shows an encapsulated mass that, on sectioning, may exhibit solid to focally cystic areas. Microscopically, adenomatoid odontogenic tumors are characterized by a proliferation of odontogenic epithelial cells surrounded by a thick, fibrous capsule. The epithelial component is mainly comprised of spindle-­shaped cells that form sheets, nests, whorled masses, or interlacing cords (Fig. 10.46 and Fig. 10.47). Columnar to cuboidal epithelial cells arranged in characteristic duct-­like structures often are seen. Close examination of these duct-­like structures shows that the nuclei are located toward the base of the cell (see Fig. 10.47, inset), contrasting with the reverse nuclear polarization of true ameloblastic proliferations. Within the lumina of these structures, there may be globules of eosinophilic material believed to represent odontogenic ameloblast-­ associated protein.308 Scattered rosette-­like structures and focal basophilic, dystrophic calcifications may be present. On occasion, larger areas of calcified material resembling dentinoid or cementum are identified. Some adenomatoid odontogenic tumors show areas of calcifying epithelial odontogenic tumor, calcifying odontogenic cyst, or odontoma. Even cases comprised predominantly of calcifying epithelial odontogenic tumor-like regions demonstrate an age distribution and clinical behavior most consistent with adenomatoid odontogenic tumor. As such, the presence of these elements in an otherwise classic adenomatoid odontogenic tumor is

Fig. 10.46  Adenomatoid odontogenic tumor. Medium-­ power photomicrograph showing an encapsulated proliferation of odontogenic epithelium present in solid, swirling zones. Numerous ductlike structures are seen.

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Fig. 10.47  Adenomatoid odontogenic tumor. Medium-­ power photomicrograph showing solid areas composed of spindle-­shaped cells associated with a duct-like (adenomatoid) structure and focus of calcification. High-­power photomicrograph showing a ductlike structure composed of cuboidal to columnar epithelial cells (inset).

considered within the accepted spectrum of this entity.203 Lastly, rare cases of adenomatoid odontogenic tumor associated with a peripheral fibroosseous reaction have been reported.309,310  Differential Diagnosis. The microscopic features of this lesion are rather distinctive and diagnosis is rarely challenging. The duct-­like structures may raise the remote possibility of a salivary gland lesion. However, intraosseous salivary gland neoplasms are exceedingly rare, and the majority represent intraosseous mucoepidermoid carcinomas, which bear little histopathologic resemblance to adenomatoid odontogenic tumor. A conventional ameloblastoma might be considered because of the presence of columnar cells, although in ameloblastoma these cells will be found at the periphery of the epithelial islands and demonstrate reverse nuclear polarization. Grossly, the infiltrative margins of conventional ameloblastoma differ from the well-­defined and encapsulated borders of adenomatoid odontogenic tumor.  Treatment and Prognosis Enucleation with curettage is the treatment of choice, and the prognosis is excellent. Recurrence is very rare.311 

Benign Mixed Epithelial and Mesenchymal Odontogenic Tumors AMELOBLASTIC FIBROMA Ameloblastic fibroma is a benign neoplasm that constitutes approximately 0.6% to 3.1% of odontogenic tumors.312 Both the epithelial and mesenchymal components of this tumor are neoplastic. There continues to be debate regarding whether ameloblastic fibromas and ameloblastic fibroodontomas are true neoplasms or hamartomas (i.e., different stages in the development of odontomas).313 Although some of these lesions exhibit behavior more akin to a hamartoma, others (especially those occurring after 22 years of age) become large and can cause significant expansion and bone destruction.312 Clinical Features. The ameloblastic fibroma usually affects younger individuals, with a mean age of approximately 15 years; about 80% are diagnosed before 22 years of age.312,314 Approximately 70% to 80% of cases are found in the posterior

Fig. 10.48  Ameloblastic fibroma. Large radiolucency involving the right posterior mandible. (Courtesy of Dr. Robert Owens.)

mandible, and a slight male predilection has been reported.312,314 Small lesions are typically asymptomatic, whereas larger tumors may produce a painless or painful swelling. Radiographic examination shows a unilocular radiolucency that may gradually enlarge and become multilocular (Fig. 10.48). The radiographic margins are usually sharply demarcated and corticated. Approximately 80% of lesions are associated with one or more impacted teeth.312,315,316 Aggressive features, such as root resorption and cortical perforation, are seldom seen. Peripheral tumors have been described but are exceptionally rare.317  Pathologic Features. Ameloblastic fibroma is composed of a mixture of odontogenic epithelial and mesenchymal elements. The mesenchymal component resembles the dental papilla of the developing tooth organ and is characterized by uniformly spaced fibroblastic cells within a background of delicate collagen fibers and myxoid ground substance. Embedded in this fibromyxoid matrix are thin cords of bilayered odontogenic epithelium, which

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Fig. 10.49  Ameloblastic fibroma. Medium-­power photomicrograph showing delicate strands of odontogenic epithelium set in a myxoid background that resembles dental papilla. Medium-­power photomicrograph showing bilayered cords of odontogenic epithelium; focal nuclear palisading is evident (inset).

resemble embryonic dental lamina (Fig. 10.49). Occasionally, there may be larger epithelial islands with peripheral columnar cells and central stellate reticulum-­like tissue, reminiscent of follicular ameloblastoma. The stroma may display varying degrees of hyalinization, which often occurs around the epithelial elements; however, there is no formation of dental hard tissues.  Differential Diagnosis. Failure to recognize the characteristic mesenchyme of ameloblastic fibroma may lead to a misdiagnosis of ameloblastoma. Unlike ameloblastic fibroma, ameloblastoma exhibits densely collagenized stroma and large epithelial islands with a tendency to undergo microcystic change. In addition, ameloblastic fibroodontoma closely mimics ameloblastic fibroma but can be differentiated by production of dental hard tissues. Lastly, ameloblastic fibrosarcoma should be considered when a tumor resembling ameloblastic fibroma displays increased cellularity, mitotic activity, and atypia of the mesenchymal component.  Treatment and Prognosis. The recommended treatment can range from aggressive curettage for a relatively small, unilocular lesion to wide local excision for a large, multilocular tumor. Conservative therapy is generally adequate for a significant percentage of lesions, with a recurrence rate of 16% to 33% in most large series.312,318 The majority of recurrences have been observed in younger patients, possibly related to more conservative initial treatment, to reduce morbidity and to minimize disturbances in facial growth and tooth development. Recurrences in this age group are usually detected earlier (median, 1.5 years) compared to recurrences in older individuals (median, 7 years).312 Malignant transformation into an ameloblastic fibrosarcoma has been reported in 6% to 11% of cases.312, 315,318 The potential for ameloblastic fibromas to recur and undergo malignant degeneration has led some authors to advocate a more aggressive treatment approach, such as wide local excision and long-­term follow-­up.319  AMELOBLASTIC FIBROODONTOMA Ameloblastic fibroodontoma is an uncommon odontogenic tumor that has histopathologic features of an ameloblastic fibroma but demonstrates formation of dental hard tissues.320,321 Since it was first described in the mid-­1960s,322 there continues to be a lack of consensus regarding whether the ameloblastic

Fig. 10.50  Ameloblastic fibroodontoma. Well-­ demarcated radiolucency with prominent central radiopacity. This represents a late-­stage lesion that consists mostly of complex odontoma with an area of ameloblastic fibroma in the superior portion. Note the impacted molar tooth. (Courtesy of Dr. Bruce Wetmore.)

fibroodontoma is a separate entity or merely an early stage in the development of an odontoma.312 However, a number of ameloblastic fibroodontomas have demonstrated significant growth, suggesting that at least a subset of these tumors merit classification as a true, distinct neoplasm. Clinical Features. Ameloblastic fibroodontomas occur most often in the first two decades of life and are rarely seen in adults. Males are affected slightly more often than females.323 They most commonly involve the mandible, with a predilection for the posterior regions of the jaws. Unless a particularly large lesion causes clinical swelling, the tumor usually remains asymptomatic and is detected incidentally on routine radiographs. The radiographic presentation consists of a wellcircumscribed unilocular or, rarely, multilocular radiolucency with central opacities that vary in density with the quantity and maturity of the mineralized component (Fig. 10.50). The lesion

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often surrounds the crown of an impacted tooth. Infrequent findings include cortical perforation, root resorption, and tooth displacement. Peripheral lesions are rare and exhibit a predilection for the anterior gingiva.323  Pathologic Features. The ameloblastic fibroodontoma is composed of both odontogenic soft and hard tissue components. The soft tissues are indistinguishable microscopically from ameloblastic fibroma, whereas the hard tissues resemble an odontoma (Fig. 10.51). These two components may be present in varying proportions. Occasionally, the calcified portion is comprised exclusively of dentin and dentinoid;

A

such lesions have been termed ameloblastic fibrodentinoma, although it is debatable whether separate designation is warranted.  Differential Diagnosis. The lack of distinctive mesenchyme will aid in differentiating ameloblastoma from ameloblastic fibroodontoma. In addition, the presence of dental hard tissues argues against the diagnosis of ameloblastoma.  Treatment and Prognosis. The recommended treatment is curettage, and the prognosis is excellent. Recurrence after conservative therapy is uncommon. Malignant transformation to an ameloblastic fibrosarcoma (“ameloblastic fibroodontosar-

B

Fig. 10.51  Ameloblastic fibroodontoma. A, Medium-­power photomicrograph showing tissue resembling ameloblastic fibroma in conjunction with dental hard tissues. B, High-­power photomicrograph showing dentin (left) and enamel matrix (right) admixed with ameloblastic fibroma-­like tissue.

A

B

Fig. 10.52  A, Compound odontoma. Well-­demarcated unilocular radiolucency that contains several radiopaque structures resembling small malformed teeth. B, Complex odontoma. Well-­demarcated unilocular radiolucency with central radiopacity involving the posterior mandible. Note impacted molar tooth at the inferior aspect of the lesion. (A, Courtesy of Dr. Brent Bernard; B, courtesy of Dr. D.C. Wetmore.)

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coma,” “ameloblastic fibrodentinosarcoma”) is reported but ­exceedingly rare.324,325  ODONTOMA The odontoma is the most common odontogenic tumor, with a prevalence exceeding that of all other odontogenic tumors combined. This lesion is generally considered to be a hamartoma rather than a true neoplasm. Odontomas usually develop within the jawbones in one of two recognized forms: (1) compound (composed of multiple small, tooth-­like structures), or (2) complex (consisting of irregular masses of dentin and enamel with no anatomic resemblance to a tooth). Overall, compound odontomas are slightly more common than complex odontomas. Rare peripheral involvement is seen.326,327

Fig. 10.53  Compound odontoma. Gross examination reveals numerous small, malformed toothlike structures.

A

859

Clinical Features. Most odontomas are detected during the first two decades of life and show an equal distribution among males and females.328 Lesions occur slightly more often in the maxilla than the mandible, with the compound type favoring the anterior maxilla and the complex type favoring the posterior mandible.328,329 Odontomas are usually asymptomatic and associated with an unerupted tooth. In many instances, failure of tooth eruption prompts radiographic evaluation that leads to discovery of the lesion. The majority of odontomas are small, although rare examples have grown to approximately 6 cm.330 Radiographically, the compound odontoma presents as a collection of small, tooth-­like radiopacities that are surrounded by a narrow radiolucent border (Fig. 10.52A). In contrast, the radiopaque component in the complex odontoma appears more amorphous. The degree of internal calcification can vary from minimal in developing odontomas to densely radiopaque in well-­developed tumors (Fig. 10.52B).  Pathologic Features. The compound odontoma is comprised of multiple small, malformed teeth (Fig. 10.53), which exhibit the normal anatomic relationships of enamel, dentin, cementum, and pulp tissue on histopathological examination. In contrast, the complex odontoma shows a disorganized admixture of dentin, enamel matrix, cementum, odontogenic epithelium, and dental papilla (Fig. 10.54). Foci of ghost cells may be found in some cases. The dental hard tissues in both forms are surrounded by fibromyxoid connective tissue resembling a dental follicle with variable amounts of odontogenic epithelium.328 In some cases, there is an associated dentigerous cyst.  Differential Diagnosis. An odontoma can be mistaken for odontoameloblastoma because of the shared presence dental hard tissues. However, infiltrative islands of ameloblastomatous epithelium should aid in recognition of odontoameloblastoma.  Treatment and Prognosis. Treatment consists of conservative enucleation, and the prognosis is excellent. For large complex odontomas of the posterior mandible, thinning of the buccal or lingual plates may render the mandible susceptible

B

Fig. 10.54  Complex odontoma. A, Medium-­power photomicrograph showing dentin with clefts of enamel matrix. B. The dentin and enamel matrix are associated with odontogenic epithelium that resembles reduced enamel epithelium.

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to fracture, which mandates modifications in surgical planning.331  PRIMORDIAL ODONTOGENIC TUMOR Primordial odontogenic tumor is a recently described benign odontogenic neoplasm.332 To date, seven cases have been reported in the literature.333,334 Clinical Features. Most primordial odontogenic tumors have developed in children and adolescents (mean age, 12.5 years), with no apparent gender predilection.333,334 The lesion often presents in the posterior mandible as a large, well-­defined unilocular radiolucency associated with the crown of an impacted tooth.333,334 Root resorption and tooth displacement may be evident as well. 

Pathologic Features. Microscopically, the primordial odontogenic tumor is characterized by a proliferation of variably cellular, primitive mesenchymal tissue resembling the dental papilla of the developing tooth organ (Fig. 10.55). This fibromyxoid tissue is rimmed by a layer of cuboidal or columnar epithelium that often mimics the inner enamel epithelium (Fig. 10.56).334 Epithelial nests or islands may appear in central areas of the lesion because of tangential sectioning of the marginal epithelium (Fig. 10.56B). Odontoblastic differentiation and dentin production have not been documented.  Differential Diagnosis. The fibromyxomatous appearance of the primordial odontogenic tumor may resemble other mesenchyme-­r ich odontogenic tumors, such as odontogenic myxoma, ameloblastic fibroma, or central odontogenic

Fig. 10.55  Primordial odontogenic tumor. Low-­power photomicrograph showing a hypercellular mesenchymal proliferation that is reminiscent of the dental papilla. A thin layer of epithelium lines the periphery of the lesion. (Courtesy of Dr. Douglas Damm.)

A

B

Fig. 10.56  Primordial odontogenic tumor. A, High-­power photomicrograph demonstrating a peripheral thin band of odontogenic epithelium composed of cuboidal basal cells with focal evidence of nuclear palisading. B, A solitary epithelial nest within the mesenchyme resulting from tangential sectioning of the peripheral epithelium. (A and B, Courtesy of Dr. Douglas Damm.)

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fibroma. However, these entities are not characterized by a peripheral rim of odontogenic epithelium that encompasses dental-papilla like tissue. Furthermore, a more florid proliferation of odontogenic epithelium would be expected in ameloblastic fibroma and epithelium-­r ich central odontogenic fibroma. A hyperplastic dental follicle and dental papilla may also cause diagnostic confusion. Close clinical and radiographic correlation is required, as these entities generally do not exhibit the growth potential of a primordial odontogenic tumor.  Treatment and Prognosis. Local excision is the treatment of choice. No recurrences have been reported to date.335  ODONTOAMELOBLASTOMA Odontoameloblastoma is a very rare benign odontogenic tumor that is believed to represent an ameloblastoma arising in conjunction with an odontoma.336 Also referred to as ameloblastic odontoma,337,338 it is no longer classified as a stand-­alone tumor in the 2017 WHO Classification.49 However, we believe that brief mention is warranted, because it may be mistaken for histologically similar but clinically distinct lesions, such as ameloblastic fibroodontoma and odontoma. The pathogenesis remains debated; investigators have proposed that these lesions may represent synchronous development of an ameloblastoma and odontoma (i.e., a collision tumor) or an ameloblastoma that has induced hamartomatous proliferation of dental hard tissues.339 Clinical Features. The few cases described have occurred in young patients, with an average age of approximately 12 years.340 There is a slight male predilection, and the lesions most often involve the posterior regions of the mandible and maxilla.340 Clinical signs and symptoms include bony expansion that may be accompanied by pain, tooth displacement, and delayed tooth eruption. Radiographs reveal a unilocular or multilocular radiolucency with variable amounts of radiopaque material.340 Root resorption and divergence can be seen.  Pathologic Features. Odontoameloblastomas are characterized by an ameloblastic proliferation (typically with a follicular or plexiform pattern) that is intimately associated with dental hard tissues resembling a compound or complex odontoma.  Differential Diagnosis. Odontoameloblastoma may be confused with ameloblastic fibroodontoma and odontoma. However, odontoameloblastoma lacks the cellular, primitive ectomesenchyme characteristic of ameloblastic fibroodontoma and demonstrates a more proliferative and invasive epithelial component compared with odontoma. Distinction between these entities is important to avoid inappropriate treatment. The rare finding of focal ghost cells may raise the possibility of a calcifying odontogenic cyst or its variants; however, more abundant ghost cells would be expected in a true ghost cell lesion.  Treatment and Prognosis. The rarity of these tumors precludes definitive recommendations regarding management and prognosis. In a review of 14 odontoameloblastomas, Mosqueda-­Taylor et  al.340 found that 3 (22%) recurred. These authors suggest that these lesions be treated like ameloblastomas (i.e., wide excision and periodic follow-­ up for at least 5 years).340 Overall, the prognosis appears similar to that of ameloblastoma.339,340 

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Benign Mesenchymal Odontogenic Tumors CENTRAL ODONTOGENIC FIBROMA Central odontogenic fibroma is a rare, benign neoplasm of odontogenic ectomesenchyme. The nomenclature for this lesion has been debated for several decades. Gardner341 initially proposed two subtypes, the so-­called simple type and the WHO type. In 1991, Handlers et al.342 suggested that one name, central odontogenic fibroma, be used because the two subtypes behaved similarly and histopathologic distinction was often ambiguous. The 2017 WHO classification defines odontogenic fibroma as a neoplasm of mature fibrous connective tissue with variable amounts of odontogenic epithelium, and delineates two clinical variants: intraosseous (central) and extraosseous (peripheral; discussed later).343 Clinical Features. The central odontogenic fibroma usually presents in adults, with most series reporting a mean age of approximately 38 years (range, 4–80 years).344 There is a slight female predilection.343 The maxilla and mandible are affected equally, with maxillary lesions favoring the anterior segments and mandibular lesions favoring the posterior segments.344–346 Smaller lesions are typically asymptomatic, whereas larger examples present as localized swellings. In certain maxillary cases, depression of the palatal mucosa may be noted. Tooth mobility and displacement are possible features. Radiographically, early lesions present as well-­ defined unilocular radiolucencies (Fig. 10.57), which may become multilocular with enlargement. Radiopaque flecks are noted in approximately 12% of cases.347 The lesions commonly arise between the tooth roots, causing root divergence and resorption in some instances. Nearly one-­ third of reported cases involve the crown of an impacted tooth. 

Fig. 10.57  Central odontogenic fibroma. Radiolucency of the anterior maxilla showing significant root resorption of the lateral incisor and canine teeth. (Courtesy of Dr. Mark Bowden.)

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Fig. 10.58  Central odontogenic fibroma. Low-­power photomicrograph showing a mildly cellular fibroblastic proliferation associated with scattered strands of odontogenic epithelium. High-­ power photomicrograph showing a strand of odontogenic epithelium that does not exhibit evidence of columnar peripheral cells and reverse nuclear polarization (inset).

Fig. 10.59  Central odontogenic fibroma. Medium-­ power photomicrograph showing a mildly cellular proliferation of fibroblasts with abundant background collagen and strands of odontogenic epithelium.

Pathologic Features. Most central odontogenic fibromas are characterized by moderately cellular fibrous connective tissue with variable amounts of odontogenic epithelial nests, strands, or islands. (Figs. 10.58 and 10.59). Areas of myxoid change and hyalinization may be seen. The epithelial component can range from completely absent to highly conspicuous343 and lacks palisading, reverse nuclear polarization, and stellate reticulum–like areas (see Fig. 10.58, inset). Rarely, foci of dystrophic calcification, cementum-­like material, or dentinoid material are present; amyloid-­ like deposits, most likely representing odontogenic ameloblast-­associated protein, may also be evident. Infrequently, a giant cell granuloma–like component can accompany these tumors.346,348–350 It is unclear if these so-­called combined or hybrid lesions represent a synchronous association of both entities or if one process induces the other. 

Differential Diagnosis. A central odontogenic fibroma with relatively sparse odontogenic epithelium may be mistaken for a desmoplastic fibroma, a central fibromatosis that usually shows denser collagen with a more fascicular and infiltrative growth pattern. The possibility of odontogenic myxoma may be entertained if prominent myxoid change is seen; however, the myxoid areas tend to be more sporadic in central odontogenic fibromas than odontogenic myxomas. Tumors that contain a prominent epithelial component may be mistaken for ameloblastoma, particularly desmoplastic ameloblastoma. However, careful examination should reveal at least focal peripheral columnar cells with reverse nuclear polarization in ameloblastoma. An ameloblastic fibroma can be ruled out based on its distinctive ectomesenchyme and ameloblastic, ribbon-­like epithe-

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Fig. 10.60  Peripheral odontogenic fibroma. A, Ulcerated nodule of the left anterior mandibular facial gingiva. B, Lobulated mass with focal erythema and ulceration of the left anterior maxillary facial gingiva. (A, Courtesy of Dr. Ken Rasenberger.)

Fig. 10.61  Peripheral odontogenic fibroma. Medium-­power photomicrograph depicting dense fibrous connective tissue associated with strands of odontogenic epithelium. Note the myxoid stroma surrounding the epithelium. Scattered chronic inflammatory cells are also seen.

lium. A recently described entity, sclerosing odontogenic carcinoma, may also enter the differential diagnosis due to the presence of thin epithelial cords and nests within a markedly sclerotic stroma. However, sclerosing odontogenic carcinoma often demonstrates aggressive clinical and radiographic characteristics, including perineural and softtissue invasion.351,352  Treatment and Prognosis. Curettage is generally the treatment of choice, and the overall prognosis is good.342 Removal of involved teeth may be necessary. A recurrence rate of approximately 4% has been reported.353  PERIPHERAL ODONTOGENIC FIBROMA This uncommon lesion of the gingival soft tissues represents the extraosseous counterpart of central odontogenic fibroma. Previous reports of odontogenic gingival epithelial hamartoma and

peripheral fibroameloblastic dentinoma may represent examples of peripheral odontogenic fibroma. Clinical Features. The peripheral odontogenic fibroma occurs over a wide age range, with a peak prevalence in the second to fourth decades.345,346,354 There is no significant predilection for the mandible or maxilla. The lesion presents clinically as a firm, slow-­growing, sessile gingival mass, which is often associated with the incisors or cuspids (Fig. 10.60).354 The majority of cases are less than 2 cm in diameter at the time of treatment. No radiographic changes are observed, except for occasional pressure resorption or “cupping” of the underlying bone.354 Fine internal radiopacities are detected in some cases.  Pathologic Features. Histopathologic examination reveals a benign proliferation of cellular fibrous connective tissue that may be interspersed with regions of myxoid change. Islands or strands of odontogenic epithelium are scattered throughout the connective tissue, particularly in the myxoid areas (Fig. 10.61). However, the amount of epithelium varies considerably from one lesion to the next. Dysplastic dentin, ovoid cementum–like calcifications, osteoid, or dystrophic calcifications are occasionally seen.354  Differential Diagnosis. The peripheral ossifying fibroma can demonstrate clinical and microscopic overlap with the peripheral odontogenic fibroma, although the former is characterized by more abundant mineralization and less conspicuous epithelial elements in most cases. The absence of peripheral columnar cells with reverse nuclear polarization in peripheral odontogenic fibroma aids in distinction from peripheral ameloblastoma.  Treatment and Prognosis. Treatment typically consists of conservative excision, although some investigators have reported recurrence rates as high as 50%.354,355  GRANULAR CELL ODONTOGENIC TUMOR The granular cell odontogenic tumor (also known as granular cell odontogenic fibroma or granular cell ameloblastic fibroma) is an exceptionally rare benign odontogenic mesenchymal neoplasm, with approximately 38 examples described in the literature.356 The WHO currently classifies this tumor as a variant of central odontogenic fibroma.343

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Clinical Features. At the time of diagnosis, most patients are middle-­aged or older adults, with a reported mean age of approximately 45 years.356 There is a female predilection, and the mandibular premolar/molar region is commonly involved. Lesions are typically asymptomatic, but painless expansion has been noted in some instances. Locally aggressive behavior, such as cortical perforation, tooth displacement, mucosal ulceration, and maxillary sinus involvement, has been reported.357,358 Radiographic examination shows a well-­demarcated, unilocular or multilocular radiolucency (Fig. 10.62). Small intralesional calcifications are described in some cases.356–358 In rare instances, the lesion may develop peripherally in the gingival soft tissues.359,360  Pathologic Features. Histopathologic examination reveals sheets of large cells with abundant, faintly eosinophilic, granular

cytoplasm (Fig. 10.63). Interspersed among these granular cells are cords and islands of bland odontogenic epithelium, which may show peripheral cell nuclear palisading and reverse polarization encompassing central stellate reticulum-­like areas. Calcified structures resembling cementum or foci of dystrophic calcification are occasionally evident. Immunohistochemical studies show that the granular cells in this tumor are positive for vimentin, CD68, and lysozyme but negative for epithelial markers and S100 protein.361,362 This immunoprofile, along with the ultrastructural finding of lysosome-­like structures, suggest that the granular cells are histiocytic in origin.359,362  Differential Diagnosis. The differential diagnosis for granular cell odontogenic tumor includes the granular cell variant of ameloblastoma, although the location of the granular cells differs in these tumors (i.e., within the epithelial islands in ameloblastoma vs. surrounding the epithelial islands in granular cell odontogenic tumor).  Treatment and Prognosis. Curettage is curative in most cases, and the prognosis is excellent. Recurrence is not anticipated, even with conservative therapy.  ODONTOGENIC MYXOMA

Fig. 10.62  Granular cell odontogenic tumor. Well-­circumscribed radiolucency interdigitating between the roots of the left maxillary second premolar and first molar. (Courtesy of Dr. Steve Ferry.)

A

The odontogenic myxoma is a benign mesenchymal neoplasm and the third most common odontogenic tumor after odontoma and ameloblastoma.192,363,364 The lesion appears to arise exclusively within the jawbones, although there is some controversy regarding whether an extragnathic counterpart exists. Interestingly, odontogenic myxomas have been reported in isolated patients with tuberous sclerosis and nevoid basal cell carcinoma syndrome, but not in patients with conditions that predispose to soft-tissue myxomas, such as Carney complex.365–367 Clinical Features. Odontogenic myxoma can occur over a wide age range, and most cases are detected in the second to fourth decades of life.368 The mandible is involved more often than the maxilla, and there is no gender predi-

B

Fig. 10.63  Granular cell odontogenic tumor. A, Medium-­power photomicrograph showing sheets of mesenchymal cells with eosinophilic granular cytoplasm associated with strands of odontogenic epithelium. B, High-­power photomicrograph depicting the lesional granular cells surrounding islands of bland odontogenic epithelium.

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lection. Slow, painless expansion is noted in most instances, although unusual cases with rapid growth have been reported.369 Radiographically, early lesions appear as unilocular radiolucencies that may be detected incidentally. With enlargement, lesions can become multilocular and assume a soap-­bubble or cobweb configuration (Fig. 10.64). Other potential findings include cortical perforation, tooth displacement, resorption of adjacent tooth roots, and maxillary sinus obliteration. Importantly, the radiographic margins often appear deceptively well-­defined on plain radiographs. Hence, computed tomography (CT) or magnetic resonance imaging (MRI) is recommended for accurate evaluation of the tumor borders.370  Pathologic Features. Gross examination of odontogenic myxoma shows a loose, gelatinous mass that tends to infiltrate the adjacent bone. Histopathologically, these lesions bear a resemblance to the dental papilla and follicle of the developing tooth. They are composed of a proliferation of

Fig. 10.64  Odontogenic myxoma. Multilocular expansile radiolucency of the posterior mandible. (Courtesy of Dr. T.R. Kerley.)

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spindle-­shaped to stellate fibroblasts in a myxoid background of delicate collagen fibers and abundant ground substance (Fig. 10.65).371,372 Odontogenic epithelial rests are seen occasionally but tend not to be a prominent feature. The proportion of collagen can vary between tumors, and examples with an increased proportion of collagen may be termed odontogenic fibromyxomas or odontogenic myxofibromas. Immunohistochemical studies have shown that the lesional cells react with antibodies to vimentin and muscle-­specific actin.88,373 There are conflicting reports regarding S100 protein expression.368,373  Differential Diagnosis. Within the jaws, myxoid change can be seen in normal structures, as well as odontogenic and nonodontogenic processes. The dental papilla and dental follicle are both characterized by myxoid tissue and may be mistaken for an odontogenic myxoma.16,374 However, radiographic correlation and microscopic identification of a peripheral rim of cuboidal to columnar epithelial cells should aid in recognizing a dental papilla. Likewise, a dental follicle is lined, at least partially, by reduced enamel epithelium. The cellular, primitive mesenchyme of primordial odontogenic tumor may also resemble an odontogenic myxoma but can be differentiated by its peripheral rim of cuboidal or columnar cells with reverse nuclear polarization. Central myxoid neurofibroma is another diagnostic consideration but can be distinguished from odontogenic myxoma by a more prominent fascicular growth pattern, a conspicuous mast cell population, and immunohistochemical expression of S100 protein. Finally, chondromyxoid fibroma and myxoid chondrosarcoma may exhibit microscopic similarities to odontogenic myxoma. However, both these lesions should show at least focal evidence of chondroid differentiation, and cellular atypia in the case of myxoid chondrosarcoma.  Treatment and Prognosis. Aggressive curettage may be adequate for small lesions, whereas large lesions may require en bloc or segmental resection.375 Recurrence can be anticipated in as many as one-­fourth of odontogenic myxomas treated with conservative therapy and is likely attributable

Fig. 10.65  Odontogenic myxoma. Low-­power photomicrograph showing a hypocellular proliferation of mesenchymal cells within a myxoid matrix. High-­ power photomicrograph showing bland spindle-­shaped to stellate fibroblasts in a background of delicate collagen fibers (inset).

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to incomplete excision.371 Follow-­up for at least 5 years is recommended. Malignant transformation to myxosarcoma is rare.376,377 These malignancies tend to pursue an aggressive course, marked by diffuse infiltration of the surrounding bone and invasion of adjacent structures. Death can result from extension to vital structures, although there is no apparent propensity for distant metastasis. 

Malignant Odontogenic Tumors MALIGNANT VARIANTS OF AMELOBLASTOMA Ameloblastomas with evidence of malignancy are separated into two categories: (1) metastasizing ameloblastoma and (2) ameloblastic carcinoma.378 The former refers to an ameloblastoma that is microscopically identical to its benign counterpart in both the primary and metastatic sites but is malignant by virtue of metastasis.257–260,378–381 This lesion is sometimes referred to as malignant ameloblastoma.382 In contrast, ameloblastic carcinoma demonstrates cytopathologic features of malignancy in the primary tumor, recurrence, and metastatic foci.383–386 Both tumors are exceedingly rare, with an annual incidence of 1.79 cases per 10 million people.387,388 Factors that may contribute to malignant degeneration in ameloblastoma include extensive local disease and incomplete surgical removal.379,380,389,390  METASTASIZING (MALIGNANT) AMELOBLASTOMA Clinical Features. Metastasizing ameloblastomas can occur over a broad age range, with most primary tumors detected between the third and fifth decades of life (average age, 30 years) and approximately one-­third discovered in patients younger than 20 years.380,382,391 Among reported cases, there has been an average of four recurrences before development of metastasis.391 The interval between initial diagnosis and discovery of metastasis ranges from 3 months to 31 years, with a mean of 18 years.390,391 Studies have reported a slight male predilection or no significant gender predilection.379,389,391 The majority (81%) of primary tumors occur in the mandible, with a clinicoradiographic presentation similar to conventional solid or multicystic ameloblastoma.391 Pulmonary metastases are seen in approximately 70% to 80% of cases, followed in frequency by regional metastasis to the cervical lymph nodes.379,385,389–392 Other documented sites include bone, liver, brain, diaphragm, kidney, small bowel, and skin. Both the primary and metastatic tumors exhibit indolent yet persistent growth.379,391  Pathologic Features. In metastasizing ameloblastoma, the histopathologic features of both the primary and metastatic lesions do not differ significantly from those of conventional ameloblastoma. The majority of lesions exhibit a plexiform pattern, although follicular, granular cell, and acanthomatous patterns have been observed.  Differential Diagnosis. All the diagnostic considerations discussed previously for conventional solid or multicystic ameloblastoma would be appropriate for the primary oral tumor of metastasizing ameloblastoma. In extragnathic sites, deposits of metastasizing ameloblastoma might be mistaken for oth-

er primary or metastatic basaloid neoplasms. However, these lesions usually lack ameloblastic differentiation. Adamantinomas of the tibia and craniopharyngiomas of the sella turcica may demonstrate “ameloblastic” microscopic features but can be differentiated based on location, absence of a primary intraoral tumor, and, in the latter, the presence of ghost cells and wet keratin.  Treatment and Prognosis. Following treatment for the primary tumor, therapeutic options for the metastatic deposits include close observation, surgical resection, and, in select cases, radiation therapy and/or chemotherapy.391 Positive responses to chemotherapy have been documented, although there are no consistently effective regimens to date.393,394 Recent reviews of metastasizing ameloblastoma reported an average overall survival of approximately 18 years after discovery of the initial tumor and 6.7 to 10 years after development of metastatic disease.387,389,391 The 5-­year survival rate is 37% for patients with pulmonary metastasis and 67% for patients with cervical lymph node metastasis.389 Accurate prediction of prognosis is limited by the paucity of cases.  AMELOBLASTIC CARCINOMA Clinical Features. Ameloblastic carcinomas can be subclassified as primary (arising de novo) or secondary (malignant transformation of a preexisting or recurrent ameloblastoma).219 In their review of 104 cases, Yoon and colleagues214 found that the majority of tumors developed de novo and only five cases demonstrated convincing evidence of malignant transformation of a preexisting lesion. Ameloblastic carcinomas tend to occur in a slightly older age group than metastasizing ameloblastomas and are usually diagnosed in the sixth decade of life, with an average age of approximately 50 years.214 Males are affected twice as often as females. There is a mandibular predilection and the posterior regions of the jaws are affected most frequently.395 Clinically and radiographically, these tumors behave more aggressively than ­conventional ameloblastomas. The most common presentation is an asymptomatic swelling, although pain, rapid growth, ­trismus, and dysphonia are possible.396 Radiographically, the lesions are typically ill-­defined and may cause cortical perforation with extension into surrounding soft tissue (Fig. 10.66A). Rare peripheral examples of ameloblastic carcinoma have been documented.257–259  Pathologic Features. Ameloblastic carcinoma is characterized by ameloblastic epithelium (i.e., peripheral columnar cells with reverse nuclear polarization surrounding stellate reticulum-­like tissue) that displays malignant features, such as cellular pleomorphism, hypercellularity, increased nuclear-­to-­ cytoplasmic ratio, atypical mitotic figures, increased mitotic index, tumor necrosis, perineural invasion, and vascular invasion (Fig. 10.66B). Overt ameloblastic differentiation can be lost in some tumors, making diagnosis challenging. In cases arising from a preexisting lesion, fortuitous sections may show a transition from benign-­appearing ameloblastoma to its cytologically malignant component.  Differential Diagnosis. Ameloblastic carcinoma can demonstrate significant microscopic overlap with conventional ameloblastoma, although cytologic atypia is lacking in the latter. Moreover, increased sex determining region Y-­box 2 (SOX2) expression and higher Ki-­67 proliferation index may aid in distinguishing

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Fig. 10.66  Ameloblastic carcinoma. A, Large, irregular radiolucency of the mandible that caused perforation of the cortical plate and displacement of the adjacent dentition. B, The tumor cells demonstrate considerable pleomorphism and mitotic activity, but peripheral palisading can still be seen. (A, From Neville, B.W., Damm, D.D., White, D.K., Waldron, C.A., 1991. Color Atlas of Clinical Oral Pathology. Lea & Febiger, Philadelphia.)

ameloblastic carcinoma from ameloblastoma.397 Primary intraosseous squamous cell carcinoma, squamous cell carcinoma arising in an odontogenic cyst, metastatic carcinoma to the jaws, and carcinoma of the overlying soft tissues that has invaded bone may be considered in the differential diagnosis but will lack peripheral columnar cells with reverse nuclear polarization. The peripheral palisading, central lobular necrosis, and microcysts that characterize basaloid squamous cell carcinoma can also mimic ameloblastic carcinoma. However, periodic acid-­Schiff (PAS) staining highlights the microcystic spaces in basaloid squamous cell carcinoma but rarely reacts within the tumor nests in ameloblastic carcinoma.214,398  Treatment and Prognosis. Ameloblastic carcinomas are aggressive tumors with a marked propensity to perforate the adjacent cortices and extend into the surrounding soft tissues. On diagnosis, a thorough physical evaluation for evidence of nodal or distant metastasis is required. Owing to the small number of cases and insufficient follow-­ up, the therapy of choice for ameloblastic carcinoma remains unclear at present. Complete surgical resection with 2-­to 3-­cm bony margins, with or without neck dissection, is generally advocated.399,400 Response to radiotherapy or chemotherapy is not well documented, although these modalities have been used in select cases, such as locally advanced lesions and tumors not amenable to surgical resection.401 In their comprehensive review of 104 ameloblastic carcinomas (including 59 with follow-­ up information), Yoon et al.214 found recurrence rates ranging from 28% to 92%, depending on treatment approach (i.e., resection vs. conservative therapy). Local recurrences have been detected from 5 to 151 months after initial therapy, emphasizing the need for long-­term follow-­up.214 A metastatic rate of 22% to 30% is documented in several large studies of ameloblastic carcinoma, and both distant and regional lymph node metastasis have been described.214,395 The most common site of distant metastasis is the lung, followed by the brain, bone, and liver. As with metastasizing ameloblastoma, the time between initial surgery and detection of metastatic disease is often protracted. In a review of 80 cases for which follow-­ up was available, metastasis occurred as early as 4 months and as late as 47 months postoperatively.395 The 5-­year survival rate is approximately 73% for ameloblastic carcinomas and 21% for patients with

demonstrated metastasis.214 Death following metastasis typically occurs within one year.  PRIMARY INTRAOSSEOUS SQUAMOUS CELL CARCINOMA Primary intraosseous squamous cell carcinoma (also referred to as primary intraosseous carcinoma not otherwise specified [NOS], primary intraosseous de novo squamous cell carcinoma, or primary odontogenic carcinoma) is a rare malignancy that arises within the jaws and exhibits no initial connection with the oral surface mucosa. The histogenesis remains speculative, although the tumor appears to develop from entrapped odontogenic epithelium, most likely rests of dental lamina or Malassez. The diagnosis is made only after excluding origin from the oral mucosa, overlying skin, antral mucosa, nasal mucosa, or a distant primary carcinoma. The World Health Organization uses the term primary intraosseous carcinoma to designate both primary intraosseous squamous cell carcinoma and carcinoma arising in odontogenic cysts.190 We have elected to describe carcinomas arising in odontogenic cysts separately within this chapter. The discussion that follows pertains to primary intraosseous squamous cell carcinoma that develops de novo, without a known cystic precursor. Clinical Features. Most cases arise within the fifth to seventh decades of life, with a range of 4 to 81 years and a mean of 52.5 years.402–405 The male-­to-­female ratio is approximately 2.6:1.406 Approximately 90% of reported cases involve the mandible, with a striking predilection for the posterior regions.402 Although maxillary lesions primarily occur in the anterior segments of the jaw, it has been postulated that the lack of reported cases in the maxillary posterior segment is likely caused by difficulty in differentiating this tumor from antral carcinoma. Patients typically present with swelling, sometimes associated with pain or paresthesia.405 Symptoms that mimic a toothache (e.g., tooth mobility, pain) are common and may lead to diagnostic delays ranging from several weeks to 18 months (average, 6.9 months).406,407 Radiographic examination shows a radiolucent area of bone destruction. Slowly growing tumors often demonstrate well-­defined borders, whereas rapidly expanding lesions exhibit poorly defined, ragged borders.

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B

Fig. 10.67  Primary intraosseous squamous cell carcinoma. A, Medium-­power photomicrograph showing islands of atypical squamous cells without evidence of ameloblastic differentiation. B, High-­power photomicrograph showing well-­differentiated squamous cells characterized by abundant, glassy cytoplasm and spinous processes.

Aggressive lesions may be associated with root resorption and cortical perforation.  Pathologic Features. The microscopic appearance can vary from a well-­differentiated carcinoma with significant keratinization (Fig. 10.67) to a poorly differentiated tumor without appreciable squamous differentiation. A spindle-cell pattern can predominate in rare cases. Importantly, no definitive ameloblastic differentiation (such as peripheral columnar cells demonstrating reverse nuclear polarization) is evident.  Differential Diagnosis. The differential diagnosis includes various entities that exhibit squamous differentiation, such as squamous odontogenic tumor, acanthomatous ameloblastoma, intraosseous mucoepidermoid carcinoma, carcinoma of the maxillary antrum or nasal mucosa, squamous cell carcinoma of the oral surface mucosa, and metastatic carcinoma. Squamous odontogenic tumor can be distinguished from primary intraosseous squamous cell carcinoma by the lack of cytologic atypia. Acanthomatous ameloblastoma can be differentiated by the presence of ameloblastic differentiation (i.e., peripheral columnar cells with reverse nuclear polarization). The squamous component of intraosseous mucoepidermoid carcinoma may also mimic primary intraosseous squamous cell carcinoma, although the former exhibits mucous cells that stain with mucicarmine. Perhaps the most difficult entity to discriminate from primary intraosseous squamous cell carcinoma is squamous cell carcinoma arising from contiguous sites. Definitive exclusion from these sites may not be feasible in advanced cases but is possible in early cases that have not yet merged with the overlying oral mucosa and that show no surface ulceration. In fact, some authorities contend that ulceration, except perhaps from antecedent trauma, precludes the diagnosis of primary intraosseous squamous cell carcinoma.190 Distinction from metastatic carcinoma poses another diagnostic challenge. The most common primary carcinomas to metastasize to the jaws are the lung, breast, and kidney; less common sites include the thyroid, colon and rectum, prostate, and stomach.407 The majority of metastatic squamous cell carcinomas to the jaws arise from the lungs. Hence, patients

diagnosed with primary intraosseous squamous cell carcinoma of the jaws should undergo a thorough physical evaluation and CT-­positron emission tomography (PET) imaging to rule out an occult primary tumor of distant origin.  Treatment and Prognosis. Currently, wide surgical resection is the therapy of choice. Regional lymph node dissection is recommended if there is clinical or radiographic evidence of nodal involvement. About 20% of cases recur locally, and 30% demonstrate regional or distant metastasis.402 Interestingly, there appears to be no relationship between nodal involvement and survival time.403 Radiation therapy and chemotherapy occasionally are administered after recurrence, but further studies are needed to evaluate their effectiveness. The overall prognosis for primary intraosseous squamous cell carcinoma is poor. In a pooled analysis of the world literature, the 1, 2, and 3-­ year survival rates were 75.7%, 62.1%, and 37.8%, respectively.405  CLEAR CELL ODONTOGENIC CARCINOMA Initially described in 1985, clear cell odontogenic carcinoma is an odontogenic malignancy of uncertain histogenesis.408–410 Derivation from clear cell rests of the primitive dental lamina is currently favored. To date, there have been more than 90 well-­ documented cases in the literature.411,412 A recent investigation by Bilodeau et  al.413 detected EWSR1-­ATF1 translocation in more than 80% of clear cell odontogenic carcinomas. Clinical Features. The mean age at presentation is 52 years, with the majority distributed evenly over the fifth to eighth decades and rare occurrence before 30 years of age.409,411 There is a mandibular (75%) and female (62%) predominance.411 The most common clinical finding is jaw swelling, which may be accompanied by mild pain, mucosal ulceration, and tooth mobility.411 Infrequent features include paresthesia and softtissue invasion. Small lesions that remain confined to bone may be asymptomatic and are most often detected incidentally on routine radiographs. Radiographic examination shows an ill-­to well-­defined radiolucency (Fig. 10.68).  Pathologic Features. Clear cell odontogenic carcinoma consists of clear to lightly eosinophilic epithelial cells arranged in

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Fig. 10.68  Clear cell odontogenic carcinoma. Ill-­defined radiolucency of the right mandible. (Courtesy of Dr. Samuel McKenna.)

islands, sheets, cords, or nests. There are three histopathologic patterns: biphasic, monophasic, and ameloblastomatous.414 The biphasic pattern is the most common and consists of the following two cell types in variable proportions: (1) clear or lightly eosinophilic cells with well-­demarcated membranes and irregular, hyperchromatic nuclei, and (2) small basaloid cells with scant eosinophilic cytoplasm (Fig. 10.69). The rare monophasic pattern is composed entirely of clear cells. The ameloblastomatous pattern exhibits islands or nests of clear cells with a tendency toward peripheral columnar differentiation and reverse nuclear polarization. In all three patterns, the tumor cells are embedded within a mature fibrous or hyalinized stroma. Peripheral infiltration is typical and frequently leads to permeation of the adjacent medullary bone. Close examination of the tumor cells will reveal some degree of cytologic atypia, including cellular pleomorphism, nuclear hyperchromatism or pyknosis, and a slight increase in mitotic figures.411 Necrosis and neurovascular invasion are uncommon findings.411 In most cases, the tumor cells are periodic acid-­Schiff (PAS) positive and diastase-­labile, although PAS positivity is not remarkable in some examples. Mucicarmine stains are usually negative. Ultrastructural examination suggests that the clear cytoplasm is a result of sparse organelles rather than enriched glycogen granules or mucin. By immunohistochemistry, the tumor cells generally express CK14, CK19, AE1/AE3, CK5/6, epithelial membrane antigen (EMA), filaggrin, and p63.415–420 There is typically no or mild reactivity for CK7, CK8, CK18, vimentin, S100 protein, smooth muscle actin (SMA), desmin, calponin, glial fibrillary acid protein (GFAP), HMB-­45, CD10, CD31, and CD45.411,421,422 Moderate to strong cytoplasmic and nuclear positivity has been noted for p16 and p53.411  Differential Diagnosis. The clear cell variant of calcifying epithelial odontogenic tumor may contain areas that resemble clear cell odontogenic carcinoma. However, careful evaluation of the former should reveal foci of more conventional eosinophilic polyhedral cells intermixed with amyloid-­ like material and concentric calcifications. Intraosseous mucoepidermoid carcinoma may also demonstrate clear cells, but they are not present in significant numbers. In addition, mucous cells and squamous differentiation are pathognomonic for this entity.

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Fig. 10.69  Clear cell odontogenic carcinoma. Infiltrating islands of odontogenic epithelium comprised of clear cells and small basaloid cells with scant eosinophilic cytoplasm.

Differentiating clear cell odontogenic carcinoma from hyalinizing clear cell carcinoma of the salivary glands can pose a considerable challenge given their overlapping histomorphologies and genetic profiles. Confirmation of an origin from the salivary glands and microscopic observation of true ducts and glands favors a primary salivary gland tumor. In contrast, identification of peripheral palisading supports a diagnosis of clear cell odontogenic carcinoma, although this feature is absent in approximately 50% of cases.421 Some clear cell odontogenic carcinomas show peripheral columnar cells reminiscent of an ameloblastoma. A greater number of clear cells in the center of the tumor islands would favor a clear cell odontogenic carcinoma. Metastatic clear cell tumors to the jaws are unusual but also enter the differential diagnosis. Definitive diagnosis requires clinical, radiographic, and pathologic correlation. Renal cell carcinoma is a major consideration, in addition to other metastatic carcinomas (e.g., prostate, thyroid, lung, breast) with clear cell components and clear cell melanoma. A broad immunohistochemical panel (e.g., PAX 8, CD10, S100 protein, SOX10, Melan-­ A, PSA, PSAP, TTF-­ 1, CK7, CK20, high-­and low-­ molecular weight cytokeratins, ER, PR) may aid in elucidating potential sites of origin.412  Treatment and Prognosis. Clear cell odontogenic carcinoma usually pursues an aggressive clinical course, characterized by bone erosion and soft-tissue extension. Regional and distant metastases have been documented in approximately 19% and 12% of cases, respectively.411 Distant metastases most frequently involve the lungs. Wide local resection with clear margins is the current treatment of choice. If clinical or radiographic evidence of nodal involvement is noted, lymph node dissection should be considered. The response to radiotherapy and chemotherapy has not been evaluated adequately to warrant strong recommendation, although adjuvant therapy may be considered in cases that show soft-tissue invasion, aggressive growth, or positive surgical margins.422 Median survival is 14 years, and several patients have died of the disease (mortality rate, 14.3%).411,422 Long-term follow-­up is recommended. 

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Fig. 10.70  Intraosseous mucoepidermoid carcinoma. Multilocular radiolucency of the mandible immediately posterior to the permanent second molar. (Courtesy of Dr. Joseph Finelli.)

INTRAOSSEOUS MUCOEPIDERMOID CARCINOMA Approximately 2% to 3% of mucoepidermoid carcinomas arise within the jaws, and many authorities classify these lesions as odontogenic tumors rather than salivary gland neoplasms.135,194,423–428 Intraosseous (or central) mucoepidermoid carcinoma most likely arises from odontogenic epithelium, such as the lining of odontogenic cysts or the primitive rests of dental lamina. Interestingly, mucous cell prosoplasia is a common finding in odontogenic cysts. One review found mucous cells in 42% of dentigerous cysts, 40% of apical periodontal cysts, 20% of lateral periodontal cysts, and 4% of odontogenic keratocysts.173 No significant difference in mucous cell prevalence is seen in maxillary and mandibular cysts, suggesting that anatomic proximity to the antrum or nasal cavity does not contribute to the development of these cells. Less likely origins of intraosseous mucoepidermoid carcinoma include salivary tissue entrapped during embryonic development, salivary gland tissue entrapped iatrogenically, and maxillary sinus epithelium.429,430 Small-­scale studies have found 56% to 100% of intraosseous mucoepidermoid carcinomas exhibit t(11;19) translocations, resulting in CRTC1-­MAML2 fusion.139,431,432 In addition, MAML2 may demonstrate other fusion partners, such as TORC1.433 Further studies are needed to determine if MAML2 rearrangements in intraosseous mucoepidermoid carcinomas correlate with microscopic features, histologic grade, and tumor behavior.432,434,435 Clinical Features. Intraosseous mucoepidermoid carcinoma has a 2:1 female predominance and occurs over a broad age range (1–78 years), with a peak in the fourth and fifth decades.426,431 The tumor is two to three times more common in the mandible than the maxilla. Most patients present with swelling of the retromolar trigone, which can be accompanied by pain.436 Radiographic examination shows a well-­defined radiolucency, which may be multilocular in approximately half of cases (Fig. 10.70). Association with an impacted tooth is observed in 30% to 50% of cases.423,427 A staging system for intraosseous mucoepidermoid carcinoma has been proposed and is primarily predicated on the

Fig. 10.71  Intraosseous mucoepidermoid carcinoma. Sheet of neoplastic epithelium that exhibits a mixture of squamoid cells and mucous cells.

integrity of the adjacent bone. Using this system, stage 1 designates lesions that are surrounded by intact cortical plates with no evidence of expansion; stage 2 includes lesions that are surrounded by intact bone but demonstrate some degree of expansion; and stage 3 denotes lesions that have caused cortical perforation, periosteal destruction, and/or nodal metastasis.427  Pathologic Features. The microscopic presentation of intraosseous mucoepidermoid carcinoma is similar to its salivary gland counterpart and may be predominantly cystic or solid. Most tumors are low-­grade, being composed of a conspicuous admixture of mucous cells and well-­differentiated squamous cells without significant atypia (Fig. 10.71). Cyst formation usually is prominent, and basaloid intermediate cells may be seen. Cystic lesions often display intraluminal projections. High-­ grade lesions are encountered less frequently and are characterized by a solid proliferation of squamous and intermediate cells that may exhibit significant pleomorphism and mitotic activity. Scattered mucous cells are present, although they may be scarce. As with mucoepidermoid carcinoma of the soft tissues, clear cell differentiation can occur.  Differential Diagnosis. Adherence to strict diagnostic criteria for intraosseous muco­epidermoid carcinoma helps to avoid confusion with soft-tissue mucoepidermoid carcinoma. These criteria are as follows: (1) intact cortical plates, (2) radiographic evidence of bone destruction, (3) exclusion of another primary tumor (i.e., salivary gland or odontogenic origin), (4) histopathologic confirmation of mucoepidermoid carcinoma, and (5) intracellular mucin detection.32,437 Maxillary lesions should be completely encased within the alveolar bone without evidence of antral communication. Because cortical bone may be destroyed by these tumors, the requirement of an intact cortical plate sometimes is waived if there is no overlying tumefaction that would indicate primary soft tissue origin. Like intraosseous mucoepidermoid carcinoma, the glandular odontogenic cyst is comprised of an admixture of squamous and mucous cells. However, the lack of an invasive, solid component or significant intraluminal proliferation should permit distinction, even from low-­grade, cystic mucoepidermoid carcinoma. Also, presence of the MAML2 gene rearrangement would support a diagnosis of intraosseous mucoepidermoid carcinoma over glandular odontogenic cyst.139

10  Odontogenic Cysts and Tumors

871

Fig. 10.72  Ameloblastic fibrosarcoma. Medium-­power photomicrograph showing a hypercellular proliferation of spindle-­ shaped cells surrounding an island of bland odontogenic epithelium. High-­power photomicrograph showing hyperchromatic and pleomorphic fibroblastic cells (inset).

Squamous odontogenic tumor and squamous cell carcinoma may mimic the squamous component of mucoepidermoid carcinoma, although these tumors do not exhibit mucous cell differentiation. Likewise, significant numbers of mucous cells help to distinguish clear cell-­predominant intraosseous mucoepidermoid carcinoma from other clear cell tumors, such as clear cell odontogenic carcinoma, the clear cell variant of calcifying epithelial odontogenic tumor, and metastatic clear cell malignancies.  Treatment and Prognosis. The treatment of choice is en bloc resection, with segmental mandibulectomy reserved for extensive tumors.427 Neck dissection is indicated in cases with evidence of nodal metastasis, and adjuvant radiation may be advised for high-­grade tumors or those with close surgical margins.426 The overall recurrence rate is approximately 25%, ranging from 40% with conservative therapy to 4% with radical surgery (with or without adjuvant therapy).438 Spread to regional lymph nodes occurs in approximately 10% of patients, and metastasis to the clavicle, lungs, and brain has been described.439 Rare tumor-­related deaths have been attributed to uncontrolled local recurrence or extension into the base of the brain.22,440 Overall, the prognosis is considered good when appropriate treatment is rendered.431 Targeted therapy for translocation-­positive intraosseous mucoepidermoid carcinomas requires further study.  AMELOBLASTIC FIBROSARCOMA The ameloblastic fibrosarcoma is a distinctly uncommon odontogenic malignancy that may arise de novo, from a recurrent ameloblastic fibroma, or, seldomly, from a recurrent ameloblastic fibroodontoma (sometimes designated ameloblastic fibroodontosarcoma or ameloblastic fibrodentinosarcoma). As the name implies, the mesenchymal component is malignant, whereas the epithelium retains its benign features. Molecular studies of a limited number of cases have shown a higher mean fraction of allelic loss in ameloblastic fibrosarcoma compared to ameloblastic fibroma and ameloblastic fibroodon­ toma.441 In all three tumor types, the most frequently lost genetic

loci were p53 (17p13) and CHRNB1(17p13). Overexpression of p53 in the stromal component of ameloblastic fibrosarcomas also has been confirmed in immunohistochemical studies.442 Clinical Features. Ameloblastic fibrosarcoma exhibits a slight male predilection and develops in an older age group (mean age, approximately 28 years) than ameloblastic fibroma.319,443 Lesions that arise de novo tend to occur in a younger patient population (mean age, 23 years) than those that arise from a recurrent ameloblastic fibroma.319,444 Approximately 74% to 80% involve the mandible, with a predilection for the posterior region.442,444 The most common clinical findings are slowly to rapidly progressive swelling associated with pain and sensory deficits. Radiographic examination typically reveals a destructive radiolucency with ragged margins. Internal opacities are present on occasion.  Pathologic Features. Microscopically, the epithelial component appears benign, while the mesenchymal component exhibits hypercellularity, cellular pleomorphism, nuclear hyperchromatism, increased mitotic activity, and other features of malignancy (Fig. 10.72). With successive recurrences, the epithelial component may diminish, yielding a tumor that closely resembles a fibrosarcoma.319 A rare example of a very aggressive lesion displaying malignant features in both the epithelial and mesenchymal components has been described, suggesting a diagnosis of odontogenic carcinosarcoma.445  Differential Diagnosis. The differential diagnosis includes fibrosarcoma, although this tumor lacks the ameloblastic epithelium that characterizes ameloblastic fibrosarcoma. In addition, failure to recognize the malignant mesenchymal component may lead to a misdiagnosis of ameloblastic fibroma or ameloblastoma.  Treatment and Prognosis. Treatment consists of radical surgical excision with negative margins.442 Adjuvant radiation therapy and chemotherapy have been used in a limited number of cases.442,446 Local recurrence is documented in approximately 54% of cases, and regional and distant metastases occurs in less than 10% of patients.442 An overall mortality rate of 20% has been reported.442

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436.  Grubka, J.M., Wesley, R.K., Monaco, F., 1983. Primary intraosseous mucoepidermoid carcinoma of the anterior part of the mandible. J. Oral Maxillofac. Surg. 41, 389–394. 437.  Alexander, R.W., Dupuis, R.H., Holton, H., 1974. Central mucoepidermoid tumor (carcinoma) of the mandible. J. Oral Surg. 32, 541–547. 438. Tucci, R., Matizonkas-­Antonio, L.F., de Carvalhosa, A.A., et al., 2009. Central mucoepidermoid carcinoma: report of a case with 11 years’ evolution and peculiar macroscopical and clinical characteristics. Med. Oral Patol. Oral Cir. Bucal. 14, E283–E286. 439.  Lebsack, J.P., Marrogi, A.J., Martin, S.A., 1990. Central mucoepidermoid carcinoma of the jaw with distant metastasis: a case report and review of the literature. J. Oral Maxillofac. Surg. 48, 518–522. 440. Fredrickson, C., Cherrick, H.M., 1978. Central mucoepidermoid carcinoma of the jaws. J. Oral Med. 33, 80–85. Ameloblastic Fibrosarcoma 441.  Galvão, C.F., Gomes, C.C., Diniz, M.G., et al., 2012. Loss of heterozygosity (LOH) in tumour suppressor genes in benign and malignant mixed odontogenic tumours. J. Oral Pathol. Med. 41, 389–393. 442.  Servato, J.P.S., Faria, P.R., Ribeiro, C.V., et al., 2017. Ameloblastic fibrosarcoma: a case report and literature review. Braz. Dent. J. 28, 262–272. 443. Gilani, S.M., Raza, A., Al-­Khafaji, B.M., 2014. Ameloblastic fibrosarcoma: a rare malignant odontogenic tumor. Eur. Ann. Otorhinolaryngol. Head Neck Dis. 131, 53–56. 444.  Bregni, R.C., Taylor, A.M., Garcia, A.M., 2001. Ameloblastic fibrosarcoma of the mandible: report of two cases and review of the literature. J. Oral Pathol. Med. 30, 316–320. 445.  Kunkel, M., Ghalibafian, M., Radner, H., et al., 2004. Ameloblastic fibrosarcoma or odontogenic carcinosarcoma: a matter of classification? Oral Oncol. 40, 444–449. 446. Lai, J., Blanas, N., Higgins, K., et al., 2012. Ameloblastic fibrosarcoma: report of a case, study of immunophenotype, and comprehensive review of the literature. J. Oral Maxillofac. Surg. 70, 2007–2012.

11

Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection MITRA MEHRAD  |  DOUGLAS R. GNEPP

The occurrence of a cervical mass is a rather common event in a wide variety of conditions, including congenital, inflammatory, and neoplastic diseases. The disease process may be located within lymph nodes or in the soft tissues of the head and neck, and it may appear as a cystic or solid tumor. Because of this diversity, a broad spectrum of possibilities must be considered in the differential diagnosis of patients who present with a cervical mass. Although information obtained by routine history, physical examination, and radiologic studies allows considerable narrowing of the diagnostic possibilities, a definitive diagnosis depends on histologic evaluation of the surgical specimen. Preoperative fine-needle aspiration biopsy studies are also very useful. These usually allow the surgeon to have a better idea of what the process is in the neck and possibly modify their surgical approach.

Anatomy Most descriptions of the neck divide the anatomy, for discussion purposes, into triangles. These triangles are simply an organizational device that parcels the volume of anatomic detail in the neck into reasonable study units.1,2 The triangles of the neck aid in localization of superficial mass lesions and define lymph node drainage patterns. TRIANGLES OF THE HEAD AND NECK Classically, the neck is divided into two major triangles, the anterior and the posterior triangles (Fig. 11.1). The anterior triangle is defined laterally by the sternocleidomastoid muscle, superiorly by the mandible, and anteriorly by the midline. The hyoid bone divides the anterior triangle into the suprahyoid region, containing the floor of the mouth, sublingual gland, submandibular gland, and lymph nodes, and the infrahyoid region, containing the larynx, hypopharynx, cervical trachea, esophagus, thyroid gland, and parathyroid glands. The anterior triangle is subdivided by the superior belly of the omohyoid muscle into four smaller triangles: the submental, submandibular, carotid, and muscular triangles. The single submental triangle is bounded laterally by the anterior belly of the digastric muscles, superiorly by the mandible, and inferiorly by the hyoid bone. The submandibular triangle, also known as the digastric triangle, is bounded anteriorly by the anterior belly of the digastric muscle, posteriorly by the posterior belly of the digastric muscle, superiorly by the mandible, and inferiorly by the mylohyoid and hypoglossus muscles. The carotid triangle is bounded by the superior belly of the omohyoid muscle, the posterior belly of the digastric muscle,

and the sternocleidomastoid muscle and inferiorly by the inferior pharyngeal constrictor and thyrohyoid muscles. The muscular triangle, or inferior carotid triangle, is bounded anteriorly by the midline of the neck, posteriorly and superiorly by the superior belly of the omohyoid muscle, and posteriorly and inferiorly by the sternocleidomastoid muscle. The posterior triangle of the neck is bounded by the clavicle and the sternocleidomastoid and trapezius muscles. This triangle is divided by the inferior belly of the omohyoid muscle into the supraclavicular triangle inferiorly and the occipital triangle superiorly. The occipital triangle is bounded by the sternocleidomastoid muscle, the inferior belly of the omohyoid muscle, and the trapezius muscle. The supraclavicular triangle is bounded by the inferior belly of the omohyoid muscle, the sternocleidomastoid muscle, and the clavicle; the floor of the triangle is formed by the scalene muscles. The components of each triangle are listed in Table 11.1.  LYMPHATIC REGIONS OF THE NECK According to the anatomic studies of Rouviere3 and the radiologic studies of Fisch4 and Som and colleagues,5 the cervical lymphatic system is organized into three functional units: (1) Waldeyer’s tonsillar ring, (2) the transitional lymph nodes located between the head and neck, and (3) the cervical lymph nodes, in their proper sense. Waldeyer’s tonsillar ring consists of the palatine tonsils, lingual tonsil, adenoids, and adjacent submucosal lymphatics. The transitional nodes are arranged in a circular manner at the transition of the head and neck regions and include: (1) submental lymph nodes, (2) submandibular lymph nodes, (3) parotid lymph nodes, (4) retroauricular lymph nodes, (5) occipital lymph nodes, (6) retropharyngeal nodes, and (7) sublingual lymph nodes. The cervical lymph nodes comprise superficial and deep nodes, and each of these groups includes lateral and medial nodes. The deep lateral cervical lymph nodes are arranged in three chains: (1) the internal jugular vein chain, (2) the spinal accessory nerve chain, and (3) the supraclavicular lymph node chain. The internal jugular nodes and the spinal accessory lymph nodes are divided into upper, middle, and lower groups. The deep medial cervical group consists of the prelaryngeal, prethyroidal, pretracheal, and paratracheal lymph nodes. The superficial cervical lymph nodes include a lateral group and a medial group. The superficial medial lymph nodes of the neck are distributed around the anterior jugular vein. The superficial lateral cervical nodes are located along the external jugular vein. 881

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TRIANGLES

MUSCLES

Submental

Submandibular

Mylohyoid

Digastric

Superior carotid

Right

Sternohyoid Omohyoid

Muscular Occipital

IB

IIB

IA

IIA Trapezius Subclavian

VA III

Fig. 11.1  Muscles and triangles of the neck. TABLE

11.1

VI

Sternocleidomastoid

VB SC

Contents of Triangles of the Neck

Triangle

Contents

Submental

Submental lymph nodes Branches of facial artery and vein

Submandibular

Submandibular lymph nodes Submandibular gland and duct Hypoglossal and lingual nerves

Carotid

Superior and middle cervical lymph nodes Internal jugular vein, common carotid artery and its bifurcation, external carotid artery and superior thyroid, lingual, and occipital branches Hypoglossal and vagus nerves

Supraclavicular

Inferior cervical lymph nodes. Thoracic duct on left side, subclavian vein and artery Phrenic nerve

Occipital

Posterior superficial cervical lymph nodes Parts of supraclavicular, transverse cervical, greater auricular, lesser occipital, and spinal accessory nerves

Muscular

Infrahyoid strap muscles, aerodigestive tract, and thyroid gland complex

Data from Bielamowicz, S.A., Storper, I.S., Jabour, B.A., et al., 1994. Spaces and triangles of head and neck. Head Neck. 164, 383–388.

Fig. 11.2 shows the system for describing the location of lymph nodes in the neck using the levels and sublevels recommended by the Committee for Head and Neck Surgery and Oncology of the American Academy for Otolaryngology-­Head and Neck Surgery, updated in 20025,7 and included in the most recent American Joint Committee on Cancer (AJCC) Cancer Staging Manual (eighth edition).8 

Cysts of the Neck Cervical cysts are common. They are often congenital, resulting from aberrations in the normal progression of development of the head and neck. In other cases, they represent benign or malignant neoplastic diseases. In adults, an asymptomatic a malignancy until proven otherwise.9 With the exception of

IV

Fig. 11.2  Level and sublevel system for location of cervical lymph nodes. IA, Submental group; IB, submandibular group; II, upper jugular group; IIA, jugulodigastric group; IIB, supraspinal accessory group; III, middle jugular group; IV, lower jugular group; V, posterior triangle group; VA, spinal accessory group; VB, transverse cervical group; VI, anterior compartment; SC, supraclavicular nodes.

thyroid nodules and salivary gland tumors, neck masses in adults follow these general rules: 80% of the masses are neoplastic, 80% of the neoplastic masses are malignant, 80% of these malignancies are metastatic, and in 80% of these metastatic tumors, the primary tumor is located above the level of the clavicle.9 In contrast, 90% of neck cysts in children represent benign conditions. In a review by Torsiglier and colleagues10 of 445 children with neck masses, 55% of the masses were congenivtal cysts, 27% were inflammatory, 11% were malignant, and 7% were miscellaneous conditions. Table 11.2 lists the causes of neck masses in the order of frequency with which they occur, according to the age of the patient. Table 11.3 lists the anatomic site, histopathologic characteristics, and differential diagnoses of the most common benign cystic tumors in the neck.9–14 DEVELOPMENTAL CYSTS Branchial Cleft Cysts, Sinuses, and Fistulas Branchial apparatus anomalies are lateral cervical lesions that result from congenital developmental defects arising from the primitive branchial arches, clefts, and pouches. Embryogenesis. Structural malformations, including lateral cysts, sinuses, and fistulas, are related to the abnormal persistence of pharyngeal grooves and/or pharyngeal pouches.15 The postnatal location of these structures indicates the location of their embryonic precursors. External fistula openings are usually noted in the neck anterior to the sternocleidomastoid muscle. Fistulas arising from remnants of pharyngeal grooves II or III are

11  Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection

thought to result from incomplete closure of the cervical sinus by tissue from the hyoid arch. Cervical cysts, although present from birth, are often clinically inapparent until after puberty, when they expand because of increased epithelial secretions from the inner cyst surface caused by maturational changes. Preauricular sinuses or fistulas, which are usually found in a triangular shaped preauricular region, are also common. These structures are thought to represent persistent clefts between preauricular hillocks on the first and second arches.

TABLE

11.2

Order of Frequency of Cystic Tumors of Neck According to Age

Infants and Children

Adolescents

Adults

Thyroglossal duct cyst

Thyroglossal duct cyst

Metastatic cystic carcinoma

Branchial cleft cyst

Branchial cleft cyst

Thyroglossal duct cyst

Lymphangioma

Cervical bronchial cyst

Cervical ranula

Hemangiomas

Cervical thymic cyst

Branchial cleft cyst

Teratoma and dermoid

Teratoma and dermoid

Laryngocele

Cervical bronchial cyst

Metastatic thyroid carcinoma

Parathyroid cyst

Cervical thymic cyst

Cervical thymic cyst

Laryngocele Metastatic thyroid carcinoma Data from references 9 to 14.

TABLE

11.3

883

Cervicoaural fistulas represent persisting ventral portions of the first pharyngeal groove, which extend from a pharyngeal opening to somewhere along the auditory tube or the external auditory meatus.15 The branchial apparatus undergoes this complex development and differentiation during the third through seventh embryonic weeks. Many anatomic structures develop completely or in part within the branchial apparatus (Table 11.4).14 A number of theories have been proposed to explain the genesis of branchial cleft anomalies.16–19 The most widely accepted theory is that the remnants result from incomplete obliteration of the branchial clefts, arches, and pouches. Lesions may take the form of cysts, sinuses (internal or external), or fistulas. Cystic lesions presumably develop as the result of buried epithelial cell rests. Sinus anomalies have, by definition, a communication with either the external skin surface or the pharyngeal mucosa, and they end as a blind tubular or saccular anomaly within mesenchymal tissue. These anomalies likely arise from incomplete obliteration of part of a branchial groove. Fistulas suggest complete communication from the ectodermal surface to the endodermal surface and presumably relate to an incompletely closed or ruptured branchial plate. Despite this seemingly simple embryogenic concept, agreement has not been reached on a wholly acceptable hypothesis of the origin of branchial anomalies. Most theories center on the idea that they originate in pharyngeal-­tonsillar epithelium, salivary gland inclusions in lymph nodes, or the branchial apparatus.16–18 However, most authorities still favor the branchial duct theory.  Clinical Features. Branchial cleft cysts, fistulas, and sinuses occur with equal frequency in males and females. The precise location and course of these anomalies depend on the particular branchial pouch or cleft from which they are derived. They are bilateral in 2% to 10% of patients, and some may be familial, the

Benign Cystic Neck Lesions

Lesion

Usual Location

Pathology

Main Differentials

Thyroglossal duct cyst

Midline, two-­thirds below hyoid bone, one-­fourth off midline, anteromedial to CA and IJV

Lined with respiratory and/or squamous epithelium, 40% contain thyroid tissue; salivary gland tissue or skin structures may be present

Dermoid, ranula if suprahyoid, cystic neuroma

First branchial cleft cyst

Medial inferior or posterior to concha and pinna

Type I lined by keratinized stratified squamous epithelium without adnexal structures; lymphoid tissue in majority; type II ectodermal and mesodermal elements

Parotid cyst, dermoid

Second branchial cleft cyst

Lateral neck, unrelated to hyoid, anterior to SCM and lateral to CA and IJV; most present near angle of mandible

Lined by stratified squamous epithelium (90%), respiratory epithelium (8%), or both (2%); lymphoid tissue nodular or diffuse (90%)

Metastatic cystic squamous carcinoma, lateral thyroglossal duct cyst, cystic neuroma

Third branchial cleft cyst

Region of laryngeal ventricle or deep to internal carotid, intimately associated with vagus nerve

Lined with stratified squamous epithelium

Laryngocele, saccular cyst

Cervical thymic cyst

Off midline, lower neck anterior to CA and IJV

Lined with cuboidal, columnar, or stratified squamous epithelium, thymic tissue in wall

Parathyroid cysts, cervical thymoma

Parathyroid cyst

95% near inferior thyroid border, off midline, anterior to CA and IJV

Lined with cuboidal epithelium; parathyroid tissue in wall

Cystic parathyroid adenoma, thyroid cyst, thyroglossal duct cyst

Subcutaneous bronchial cyst

Subcutaneous tissue or skin, suprasternal notch, manubrium sterni, skin of lower neck (rarely)

Lined with ciliated, pseudostratified columnar epithelium; smooth muscle and mucous serous glands in wall; rarely, cartilage present

Dermoid, teratoma, branchial cyst, thyroglossal cyst

Dermoid cyst

Near midline, usually in upper neck

Lined with stratified squamous epithelium, numerous ectodermal derivatives

Thyroglossal duct cyst; ranula if suprahyoid

Cervical ranula

Off midline and suprahyoid in submental or submandibular triangles

Pseudocyst without epithelial lining; extravasated mucin, histiocytes, and mucocytes

Dermoid cyst; thyroglossal duct cyst

CA, Carotid artery; IJV, internal jugular vein; SCM, sternocleidomastoid muscle.

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mode of inheritance being an autosomal dominant gene, with reduced penetrance and variable expressivity.18 They generally exist as an isolated phenomenon, but in rare instances may be associated with other defects, such as patent ductus arteriosus, tear duct atresia, hearing abnormalities, preauricular pits, or malformed auricles.20,21 A recent report suggested a link between increased estrogen in pregnancy and growth of branchial cleft cysts.22 Salivary duct fistulas can mimic branchial cleft fistula, clinically.23 A malignancy may develop rarely in ectopic salivary tissue associated with these pharyngocervical tracts. Differential diagnosis of a branchial cleft cyst arising in an adult always includes a cystic metastasis of a squamous cell carcinoma, especially if cytologic atypia is noted. P16 immunohistochemistry may be helpful if this differential diagnosis arises; however, a significant number of benign branchial cleft cysts may also show diffuse p16 positive staining.26 In these latter cases, additional human papilloma virus (HPV) molecular testing (in situ hybridization, polymerase chain reaction [PCR], etc.) should be done to confirm the presence of HPV and the diagnosis of metastatic squamous cell carcinoma.25 Also there is a recent description of three well-­differentiated squamous cell carcinomas having areas of columnar epithelium, with surface cilia presenting

TABLE

11.4

Structures Derived from the Branchial Apparatus

Branchial Apparatus

Structures Derived

First

Incus, malleus, sphenomandibular ligament, mandible, anterior 2/3 of tongue, sublingual and submandibular glands, eustachian tube, tympanic cavity and membrane, mastoid air cells, and external auditory canal, and contributes to the pinna

Second

Stapes, styloid process, stylohyoid ligament, part of hyoid bones, stapedius muscle, muscles of expression, part of the base of tongue, and a portion of the auricle, and contributes to the tonsils

Third

Hyoid bone, tongue, inferior parathyroid glands, and thymus

Fourth

Thyroid cartilage, epiglottis, muscles of the pharynx, and superior parathyroid glands

Data from references 15, 32, 33, 58.

Fig. 11.3  Type I first branchial cleft abnormality. Stratified squamous epithelium is lining the cavity. Note the absence of adnexal structures.

as cystic neck masses.26 One of these was originally diagnosed as a branchial cleft cyst. Some observers have previously interpreted the presence of cilia as equating with a benign process; however, as these cases indicate, the presence of cilia in a cystic lesion, by itself, is insufficient to rule out a metastatic carcinoma. One needs to consider the possibility of any cystic neck mass, involving a lymph node, with a high index of suspicion for metastatic carcinoma, for all patients over the age of 30 years. Evaluation of HPV status is useful in this situation, as branchial cleft cysts have not been found to harbor biologically active high-­risk HPV.26  First Branchial Cleft Anomalies. One of the most comprehensive review of these anomalies was by Olson and colleagues. They reviewed 460 branchial cleft anomalies at the Mayo Clinic; 38 (8%) were of first branchial cleft origin. Of these, 68% were cysts, 16% were sinuses, and 16% were fistulas. These anomalies occurred predominantly in females and were found in persons of every age from newborn to elderly. Clinically, they may masquerade as parotid tumors, otitis with ear drainage or as ear canal cholesteatoma.27,28,30,31,49 First branchial cleft disorders are classified into two types.32 Type I defects are those that embryologically duplicate the membranous external auditory canal and contain only ectodermal elements. They often are confused on histologic examination with ordinary epidermoid cysts because they are lined only with keratinized stratified squamous epithelium unassociated with adnexal structures (hair follicles, sweat glands, sebaceous glands) or cartilage (Fig. 11.3). Characteristically, they are located medially, inferiorly, or posteriorly to the concha and pinna. Drainage from the cyst or fistula may occur in any of these sites. The fistula (or sinus tract) often parallels the auditory canal and ends in a blind cul-­de-­sac at the level of the mesotympanum. In some instances, parotid tissue may be associated with the tract. The external auditory canal, both membranous and bony, is intact, and hearing is normal. Type II deformities are composed of both ectodermal and mesodermal elements and therefore contain, in addition to skin, cutaneous appendages and cartilage (Fig. 11.4). This type of defect is thought to represent an embryologic duplication of both the auditory canal and the pinna.32 Patients with a type II defect usually present with an abscess or fistula at a point just below the angle of the mandible. The tract extends upward over the angle of the mandible through the parotid gland, toward the external auditory canal. The tract may end short of or drain into

11  Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection

885

Fig. 11.4  Type II first branchial cleft abnormality. Note the presence of skin adnexal structures and cartilage.

the auditory canal, usually along the anteroinferior border near the cartilaginous-­bony junction.32 Communication of the tract with the middle ear is distinctly uncommon. Type II defects are therefore more intimately associated with the parotid gland thcytoplasmic stainingn are type I defects; however, both may mimic a parotid tumor.24,30 In some instances, because of the histology and/or location, a distinction between type I and II lesions cannot be made. Olson and colleagues therefore suggested that first cleft abnormalities be classified only as to whether the lesion is a cyst, sinus, or fistula. First branchial cleft abnormalities must be differentiated pathologically from epidermoid cysts (especially type I), dermoids (especially type II), and cystic sebaceous lymphadenomas.27,28 Rarely a “hybrid” first and second branchial cleft cyst may occur.29  Second Branchial Cleft Anomalies. These are by far the most common branchial cleft anomalies, accounting for as many as 90% of such anomalies in some series.33 The external opening, when present, is usually located along the anterior border of the sternocleidomastoid muscle at the junction of its middle and lower thirds. The tract, if there is one, follows the carotid sheath; it crosses over the hypoglossal nerve, courses between the internal and external carotid arteries, and ends at the tonsillar fossa.34,35 Cysts of the second cleft are three times more common than fistulas.34,35 There is no sex predominance. Most patients (75%) are 20 to 40 years old at the time of diagnosis. Because less than 3% of cysts are found in patients older than 50 years of age, pathologists must be careful in making such a diagnosis in this age group; a metastatic squamous cell carcinoma in a cervical lymph node, with cystic degeneration, may masquerade as a branchial cleft cyst.36 Looking for atypical squamous epithelium will help separate these two entities and confirm the latter diagnosis (see “Clinical Features” earlier). The cysts are usually 2 to 6 cm in diameter and are lined with stratified squamous epithelium (90%), respiratory epithelium (8%), or both (2%).18 Repeated infections cause the wall to become fibrotic, and the epithelium may then be partially replaced by granulation or fibrous tissue. Lymphoid tissue, either nodular or diffuse, occurs in the wall of 97% of the cysts and often contains germinal centers and subcapsular or medullary sinuses, or both (Fig. 11.5).17,18 Ectopic salivary gland tissue has been identified in the cyst wall.37 The contents of the cysts

Fig. 11.5  Second branchial cleft cyst showing lymphoid tissue in the wall. The cyst is lined with stratified respiratory epithelium (inset).

may be cheesy, mucoid, serous, or, if infected, purulent. Rarely a “hybrid” first and second branchial cleft cyst may occur.29  Third Branchial Cleft Anomalies. Disorders of this cleft are rare. Cysts, when they occur, present in the region of the laryngeal ventricle and are lined with stratified squamous epithelium.33 Fistulas open externally along the anterior margin of the lower third of the sternocleidomastoid muscle. If complete, the tract should ascend in relation to the carotid sheath, pass superior to the hypoglossal nerve and inferior to the glossopharyngeal nerve, course behind the internal carotid artery, penetrate the thyrohyoid membrane, and open into the pyriform sinus.33,34,38 Cysts lying deep to the internal carotid artery and intimately associated with the vagus nerve are probably remnants of the third cleft or pouch.38 The third branchial anomalies, similar to the fourth, are usually found on the left side of the neck but may also arise on the right side. Patients have various clinical presentations, including acute suppurative thyroiditis, a neck abscess, a fistulous opening in the lower neck, or a retropharyngeal abscess or fistula. In addition, a third branchial cleft fistula passes over both the

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superior and recurrent laryngeal nerves, but a fourth branchial cleft fistula passes under the superior laryngeal nerve and over the recurrent laryngeal nerve.41 This anatomic difference may be useful in establishing whether one is dealing with a third or fourth branchial cleft anomaly.  Fourth Branchial Cleft Anomalies. These anomalies are extremely uncommon, with slightly fewer than 50 cases reported between 1972 and 2003.39 These anomalies might have external openings along the anterior border of the sternocleidomastoid muscle in the lower neck, and the tracts would typically descend along the carotid sheath into the chest, passing under either the arch of the aorta on the left or the subclavian artery on the right (both vessels are derived from the fourth branchial arch). They would then ascend in the neck, and their internal openings would be in the esophagus, a fourth bronchial pouch derivative.38,40 Anomalies in this area of the body might be confused with thymic cysts. In addition, a third branchial cleft fistula passes over both the superior and recurrent laryngeal nerves, but a fourth branchial cleft fistula passes under the superior laryngeal nerve and over the recurrent laryngeal nerve.41 This anatomic difference may be useful in establishing whether one is dealing with a third or fourth branchial cleft anomaly. Salivary fistulas arising from ectopic salivary gland tissue may also clinically mimic a branchial cleft fistula. The fourth branchial anomalies, similar to the third, are usually found on the left side of the neck but may also involve the right side. Their clinical presentation varies from no symptoms to acute suppurative thyroiditis, a neck abscess, a cutaneous fistula and rarely a neck mass which may have suddenly enlarged. One case has also been associated with ipsilateral thyroid agenesis.42 Neonatal cases account for only 8.7% of the fourth branchial anomalies.41  Treatment. Complete surgical excision is the only satisfactory method of treatment for branchial cleft anomalies. The lesions are prone to recurrent infection and scarring, rendering dissection tedious and difficult. Any infection should be treated with antibiotics and the area drained before surgical excision is attempted. Aspiration of an uninfected cyst is not indicated because this may predispose the patient to infection and make dissection more hazardous and increase recurrence rates. The wall of the cyst and the tract may be extremely adherent to adjacent nerves and vessels. The surgical principles are similar, regardless of whether one is dealing with a first, second, third or fourth cleft remnant, although the approaches are different.33–35,38,40 Confirming the extent of the tract is mandatory preoperatively, as these lesions are closely associated to some of the most vital structures of the neck. Injection of dye intraoperatively to delineate the course of the embryonal tract, as much as possible, and careful microscopic dissection and removal of the tract, along with surrounding tissue, is very important in preventing recurrences. All first branchial cleft abnormalities appear to be associated with external ear canal abnormalities (all 41 patients with type I had an abnormality in the posterior wall of the external ear canal, and 96.6% of 29 patients with type II had an abnormality in the inferior wall).62 Therefore the abnormal skin and cartilage of the external ear canal should be excised together with the other branchial cleft abnormalities to avoid recurrence. Recurrence rates with careful dissection should be less than 3%.74 If patients are ineligible for surgery or refuse surgery, ethanol ablation treatment appears to be a safe alternative.43 

Congenital Midline Cervical Cleft Congenital midline cervical cleft (CMCC) is a rare anomaly of the anterior aspect of the neck that may be present at any level between the mandible and manubrium. Although varying presentation has generated controversy as to whether a CMCC should be considered a distinct entity, most authors consider it within the spectrum of branchial arch developmental abnormalities.47,48 In 1985, Gargan and colleagues47 reported 12 cases of CMCC as part of their series of 612 thyroglossal and other branchial cleft sinuses, representing an incidence of 1.7%. Other series have reported an incidence ranging from 99%) presented with a mobile, midline mass with very occasional patients presenting with a lateral neck mass. Seventy-­six percent of patients had an infrahyoid presentation and 24% were suprahyoid. Five patients had a fixed mass, of which three were associated with thyroid carcinomas and 23% had pain or tenderness.57 The exact incidence of a TGDC is unknown, but is estimated to be 2.23/100,000 population.57 Rarely, TGDCs are familial.61 Cysts may fluctuate in size. Often there are no symptoms except the presence of the mass, unless the cyst becomes infected.62,63 Rare TGDCs (1.6%) developed within the thyroid gland.57 Intralingual cysts may cause choking spells, dysphagia, and cough. Fistulas may occur spontaneously or may be secondary to trauma, infection, drainage, or inadequate surgery. These occur in 10% to 34% of patients.62,57 Thyroid radiographic studies should probably be obtained on all patients undergoing surgical excision of a thyroglossal duct cyst. Despite the fact that a small amount of functioning thyroid tissue is associated with the tract in 30% of cases, it rarely, if ever, represents the only functioning thyroid tissue, as is often true with lingual thyroid cyst.64  Pathologic Features. TGDCs have a mean diameter of 2.6 cm,57 but cysts up to 10 cm in diameter have been reported.65,66 They are lined with respiratory (38%) or squamous epithelium

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Fig. 11.6  Thyroglossal duct cyst lined with ciliated columnar epithelium. Note dilated mucous glands in the wall.

(10%) or both (51%) or, if infection has occurred, with granulation tissue or scar tissue (Fig. 11.6).57 Fistulas are almost invariably secondary to infection. The incidence of finding ectopic thyroid tissue in association with TGDC varies in different series and likely varies according to the diligence with which it is sought. It ranges from 31% to 83% of specimens (measuring 0.01-5 cm in greatest dimension) and may be located in the cyst wall, adjacent skeletal muscle and/or adjacent fat.57,72 Seromucous glands (possibly ectopic salivary gland tissue) were identified in 60% of cases studied by Sade and Rosen66 and in 15% of patients in Thompson and Heffner series.57 Skin adnexal structures, cartilage and gastric mucosa have also been noted in the wall of the cysts.57,63,67 A thyroid carcinoma, all papillary carcinomas, was identified in 22 cysts from this latter series (3.2%), ranging in size from 0.1 to 3.8 cm in greatest dimension (see next section).  Treatment and Prognosis. The treatment of thyroglossal duct remnants, whether cyst, sinus, or fistula, is complete surgical excision using the Sistrunk operation.68 This consists of an en bloc excision of the entire thyroglossal tract to the foramen cecum, as well as removal of the central 1 to 2 cm of the hyoid bone. If this procedure is used, the rate of disease recurrence is approximately 3%. If the central hyoid bone is not removed, a recurrence rate as high as 45% may be expected.57 Rare reports of malignancy in thyroglossal duct remnants are found in the literature. Eighty percent to 92% of such neoplasms are papillary thyroid carcinomas with the remaining neoplasms being predominantly follicular carcinomas or squamous cell carcinomas with a rare adenosquamous or anaplastic carcinoma.69–72 Medullary carcinoma does not appear to arise from TCDCs as there are no parafollicular C cells in TGDCs.72 Criteria for diagnosis include demonstration of a thyroglossal remnant and a normal thyroid gland. Because of the paucity of cases and the fact that the malignancy is not recognized until after complete pathologic examination of the remnant, it is difficult to delineate treatment and prognosis. If there is a history of sudden increase in size or clinical presentation of a fixed, hard mass, then the possibility of a malignancy arising in a TGDC needs to be considered. Most researchers agree, however, that: (1) total thyroidectomy is not routinely indicated, as long as there are no palpable abnormalities in the gland, the carcinoma is not high ­grade or aggressive and no significant radiographic findings are found; and (2) that the Sistrunk operation offers a

reasonable chance of cure.69–71 In a recent literature review of 164 patients with thyroglossal duct cyst carcinoma, there was a 4.3% recurrence rate with a mean time to recurrence of 42.1 months from initial treatment. Only one patient died of TGDC carcinoma, while all other patients were disease free at the time of last follow-­up (mean follow-­up was 46.1 months).71  Cervical Thymic Cyst Cervical thymic cysts are morphologically identical to their mediastinal counterparts.73 They are found in the anterior triangle of the neck along the normal path of descent of the thymus, with or without parathyroid glands, and they may have a fibrous band or a solid thymic cord connection to the pharynx or mediastinum. Cervical thymic cysts represent less than 1% of cystic lateral neck masses; approximately 50% have thoracic extension.79 Embryogenesis. Originating in third pharyngeal pouch, the paired endodermal thymic primordia begin to migrate during the sixth week.15 Early in migration, they separate from the parathyroid primordia and migrate through a substrate of mesenchymal cells, until reaching the region of the future mediastinum behind the sternum. By the end of their migration, the two closely apposed thymic lobes are still epithelial structures but are surrounded with a capsule of neural crest–derived connective tissue, which also forms septa among the endodermal epithelial cords and contributes to the thymic vasculature. Lymphocyte precursors first invade the thymic primordia during migration before they have become vascularized. This is followed by a refractory period, which persists until the thymic primordia have completed their migration and have become vascularized. By 14 to 15 weeks of gestation, blood vessels grow into the thymus, and a week later, epithelial cells aggregate into Hassall’s corpuscles.15 It is believed that most cervical thymic cysts arise from the persistence of tissue rests (ectopic thymus) along the pathway of migration of the thymic primordia.15  Clinical Features. Cervical thymic cysts are virtually never recognized as such, clinically; most are confused with a branchial cleft cyst or, less often, a TGDC or laryngocele. The most common presenting symptom is a slowly enlarging mass that may or may not be painful; rarely a patient may present with increasing swelling, while phonating.83 The cysts occur more often on the left side; they rarely are familial, and males are affected twice as often as females.73,75 Sixty-­seven percent

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Fig. 11.7  Cervical thymic cyst lined with cuboidal epithelium. Note thymic tissue in wall.

Fig. 11.8  High-­power view of a Hassall’s corpuscle in the wall of a cervical thymic cyst.

occur in the first decade of life. The remainder occur in the second and third decades of life.73,76–78 Cervical thymic cysts characteristically occur adjacent to or within the carotid sheath and therefore present in or near the anterior cervical triangle. They can be found anywhere from the angle of the mandible to the sternum, paralleling the sternocleidomastoid muscle and the normal embryologic pathway of the thymus.78 Cysts containing both thymus and parathyroid may be referred to as third pharyngeal pouch cysts.78 Rarely thymic cysts can present intrathyroidal84 or as a subglottic mass.81  Pathologic Features. The cysts are round to tubular, are unilocular or multilocular, and can measure more than 9 cm in greatest dimension.80,83 The epithelial lining may be composed of columnar, cuboidal, or stratified squamous cells (Fig. 11.7). In some areas, it may be replaced by granulation or fibrous tissue, and occasionally cholesterol clefts are present.74 Thymic tissue found in the cyst wall qualifies the cyst as a thymic cyst. Numerous sections may be required, however, to identify the thymic tissue (Fig. 11.8). In addition, the cyst may have a fibrous cord tracking inferiorly to the superior mediastinum.79 Parathyroid tissue may or may not be present. Moran and colleagues78 reported three patients with carcinoma arising in a multilocular cervical thymic cyst. 

Treatment. Complete surgical excision is the treatment of choice. To date, no cases with postoperative recurrence have been reported.82  Cervical Bronchial Cyst Bronchial cysts are uncommon congenital lesions found predominantly in the thoracic cavity, within the lung, or in the mediastinum. In some instances, they may present clinically in the neck.85 Embryogenesis. Bronchial cysts are derived from small buds of diverticula that separate from the foregut during formation of the tracheobronchial tree. When they occur outside the thoracic cavity, the cysts presumably arise from erratic migration of sequestered primordial cells.89  Clinical Features. Most cervical bronchial cysts are present in the skin and the subcutaneous tissue of the suprasternal notch. Rarely, they are found in the lower anterior neck, chin, shoulder, intraorally, posterior pharyngeal wall, thyroid gland, and cervical spinal canal.85–87,89,90 Cervical bronchial cysts may also extend into the mediastinum. They are more common in males than in females (ratio, 3:1).89 The cysts usually become clinically apparent at or soon after birth and appear as asymptomatic nodules that slowly increase in size. They are less common in

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Fig. 11.9  Cervical bronchial cyst. Respiratory epithelium lines the cyst.

adults. Draining sinuses that exude mucoid material are present in approximately one-­ third of cases.85 The cyst frequently becomes more conspicuous when the patient performs the Valsalva maneuver.  Pathologic Features. Noninfected cysts are grossly tubular rather than of an ovoid configuration and are filled with either clear serous or thick mucoid material. The cyst wall is thin, and the inner surface is smooth or trabeculated. The bronchial cyst is lined with ciliated, pseudostratified, or columnar epithelium (Fig. 11.9). Squamous stratified epithelium often makes up the lining of the sinus, but this epithelium rarely lines the cyst, unless the cyst is infected. The cyst wall contains smooth muscle, elastic fibers, and mucoserous glands.85,89 Cartilage is seldom present in cervical cysts, although it is common in their intrathoracic counterparts. Lymphoid tissue, when present, is scanty and focal, never diffuse or excessive.  Differential Diagnosis. A bronchial cyst can be distinguished from a teratoma by the complete absence of tissues, other than those that can be explained based on a malformation of the respiratory tract. A dermoid cyst can be excluded by the lack of hair and skin appendages and the absence of squamous epithelium. The presence of smooth muscle, mucoserous glands, and cartilage (should it be found), and paucity of lymphoid tissue, eliminates the possibility of a branchial cleft cyst. A TGDC can be differentiated from a bronchogenic cyst by the presence of thyroid follicles. Furthermore, a TGDC does not contain smooth muscle and almost never cartilage.89 A lack of ciliated epithelium distinguishes lateral cervical cysts containing gastric mucosa from cervical bronchogenic cysts.91  Treatment. Complete surgical excision of the cyst along with its sinus tract is usually curative.85,89 Malignancies arising in cervical bronchial cysts are exceedingly rare but they do occur.88  Parathyroid Cysts Parathyroid cysts are rare lesions that have a surgical incidence rate of 0.001% to 3% and that constitute 0.6% of all thyroid and parathyroid lesions.94 Well over 300 cases have been reported in the literature.92 The anterior cervical triangle is the site of most parathyroid cysts that present as neck masses.94–96 The cysts may be functional, but the majority are nonfunctional.94 Embryogenesis. The parathyroid/thymus primordium develops early from the third pouch endoderm; by 5 weeks of gestation, cells identifiable as parathyroid tissue can be

recognized in the endoderm. The primordia of the thymus and the parathyroid glands lose their connection with the third pharyngeal pouch and they migrate caudally. Although the parathyroid III primordia initially migrates with the thymic primordia, they separate and the parathyroid primordia ultimately continue to migrate toward the midline, where they join with the thyroid gland and pass the parathyroid primordia of the fourth pouch to form the inferior parathyroid glands. As with their counterparts from the third pouch, the parathyroid IV primordia lose their connection with the fourth pouch and migrate toward the thyroid gland as superior parathyroid glands.15 The cause of parathyroid cysts is not clear, and a variety of theories have been proposed. The suggestion that the cysts are embryologic remnants of the third or fourth branchial cleft or result from coalescence of multiple microscopic cysts, degeneration of a parathyroid adenoma, and retention of glandular secretions has been put forth. No single theory adequately explains all cases. It may be that those cysts with clear, colorless fluid are developmental in origin, whereas the cysts with bloody or straw-­colored fluid may result from infarction or cystic degeneration of a parathyroid adenoma.94 These latter lesions tend to be functioning cysts.94  Clinical Features. Most patients with parathyroid cysts present with an asymptomatic low anterior neck mass. Tracheal and esophageal compression, hoarseness secondary to recurrent laryngeal nerve compression, and pain secondary to hemorrhage into the cyst have been reported.94–96 Approximately 95% of the cysts occur below the inferior thyroid border, and 65% are associated with the inferior parathyroid glands.94 Cysts have been identified everywhere from the angle of the mandible to the mediastinum; however, they can occur in the thyroid lobe or posterior to it.94 They are more common on the left side and may be multiple.93 Nonfunctioning cysts make up the majority of cases and are approximately two to three times more common in women than in men. The mean age of patients with this cyst is 43.3 years. Nonfunctioning cysts occur almost exclusively in the inferior parathyroid glands.95 Functioning cysts account for 11.5% to 30% of the cases, are more common in men (ratio, 1.6:1), and tend to occur in sites other than the inferior parathyroid glands, from the angle of the mandible to the mediastinum.97 The mean age of these patients is 51.9 years. Most patients with

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891

Fig. 11.10  Parathyroid cyst. Cuboidal epithelium lines the cyst. Note parathyroid tissue in the wall.

a functioning cyst have signs and symptoms of hyperparathyroidism, but the disease can be clinically occult and may be discovered incidentally by abnormal serum calcium and phosphorus levels or an elevated serum parathyroid hormone level.94 Multiple parathyroid cysts have been reported in patients with hyperparathyroidism, and rarely a multiloculated cyst occurs.97 Fine-­needle aspiration is the principal diagnostic tool. Aspiration of clear fluid with an elevated parathyroid hormone level is a definite indication of a parathyroid cyst. The C-­terminal/ midmolecule of the parathyroid hormone should be assayed because the N-­terminal–specific assay is frequently associated with false-­negative results.96  Pathologic Features. Parathyroid cysts vary from 0.06 was significantly lower (hazard ratio: 2.11).395 These authors recommended more intensive adjuvant therapy with radiotherapy and short interval follow-­up for patients in this latter group. Gil and coauthors, using a LNR cutoff of 0.06, found that LNR was the only independent predictor of overall survival in patients with oral cancer.398 LNR was also found to be the only significant outcome predictor in patients receiving adjuvant radiotherapy and, within individual subgroups of pN1 or pN2 patients, the LNR reliably stratified patients according to their failure risk. Bharath and coauthors evaluated the LNR in carcinomas of the tongue.401 The 2-­year overall survival and disease-­ free survival was 37.5% and 46.3%, respectively, for patients with LNR >0.10 and 88.2% and 83.6%, respectively, for patients with a LNR 0.10 also was a prognostic parameter in HPV-­related oropharyngeal squamous

cell carcinoma.399 Based on the aforementioned, LNR appears to be another useful tool to stratifying risk in patients with head and neck cancer. 

The Number of Positive Lymph Nodes The prognostic value of the number of positive nodes (pN), a term used to describe the number of pathologically positive lymph nodes identified after neck dissection, has also been suggested to be of prognostic importance.396 Roberts and coauthors demonstrated that both the number of positive lymph nodes and a lymph node ratio (LNR) >0.125 predict survival better than the AJCC lymph node staging system in their overall study sample and the site-­specific analyses (oral cavity, oropharynx, hypopharynx and larynx).396 These authors also concluded that the number of positive lymph nodes demonstrated superior prognostic value prediction when compared with the LNR and American Joint Committee on Cancer lymph node staging; patients with more than five positive nodes in all subsites showed markedly decreased survival. Further research is necessary, however, to establish the clinical usefulness of this parameter.

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11  Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection 353.  Cachin, Y., 1983. Management of cervical nodes in head and neck cancer. In: Evans, P.H.R., Robin, P.E., Fielding, J.W.L., Ed. Head and Neck Cancer. Alan R, New York: Liss, p. 168–177. 354. Olsen, K.D., Caruso, M., Foote, L., 1994. Primary head and neck cancer. Histologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch. Otolaryngol. Head Neck Surg. 120, 1370– 1374. Inapparent Metastasis 355. Ferlito, A., Shaha, A.R., Rinlado, A., 2002. The incidence of lymph node micrometastases in patients pathologically staged NO in cancer of oral cavity and oropharynx. Oral Oncol. 38, 3–5. 356. Barrera, J.E., Miller, M.E., Said, S., et al., 2003. Detection of occult micrometastases in patients with head and neck squamous cell carcinoma. Laryngoscope. 113, 892–893. 357. Becker, M.T., Shores, C.G., Yu, K.K., et al., 2004. Molecular assay to detect metastatic head and neck squamous cell carcinoma. Arch. Otolaryngol. Head Neck Surg. 130, 21–27. 358. Byers, R., Weber, R.S., Andrews, T., et al., 1997. Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue. Head Neck. 19, 14–19. 359. Rhee, D., Wenig, B.M., Smith, R.V., 2002. The significance of immunohistochemically demonstrated nodal micrometastases in patients with squamous cell carcinoma of head and neck. Laryngoscope. 112, 1970–1974. Sentinel Lymph Node 360. Stoeckli, S.J., Steiner, H., Pfaltz, M., et al., 2001. Sentinel lymph node evaluation in squamous cell carcinoma of the head and neck. Otolaryngol. Head Neck Surg. 125, 221–225. 361. Stoeckli, S.J., Pfaltz, M., Steiner, H., et al., 2002. Histopathologic features of occult metastasis detected by sentinel lymph node biopsy in oral and oropharyngeal carcinoma. Laryngoscope. 112, 111–115. 362. Alex, J.C., 2004. The application of sentinel node radiolocalization to solid tumors of head and neck: a 10-­year experience. Laryngoscope. 114, 2–19. 363. Hard, R.D., Nasser, J.G., Trites, J.R., et al., 2005. Sentinel lymph node biopsy in NO squamous cell carcinoma of the oral cavity and oropharynx. Arch. Otolaryngol. Head Neck Surg. 131, 34–38. 364. Nieuwenhuis, E.J.C., Leeman, C.R., 2005. Histopathologic validation of the sentinel node concept in oral and oropharyngeal squamous cell carcinoma. Head Neck. 27, 150–158. 365. Stoeckli, S.J., Pfaltz, M., Ross, G.L., et al., 2005. The Second International Conference on sentinel node biopsy in mucosal head and neck cancer. Ann. Surg. Oncol. 12, 919–924. 366. Paleri, V., Rees, G., Arullendran, P., et al., 2005. Sentinel node biopsy in squamous cell cancer of the oral cavity and oral pharynx: a diagnostic meta-­analysis. Head Neck. 27, 739– 747. 367. Chernock, R.D., Lewis, J.S., 2015. Approach to metastatic carcinoma of unknown primary in the head and neck: squamous cell carcinoma and beyond. Head Neck Pathol. 9(1), 6–15. 368. Strojan, P., Ferlito, A., Medina, J.E., et al., 2013. Contemporary management of lymph

node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck. 35(1), 123–132. 369. Cianchetti, M., Mancuso, A.A., Amdur, R.J., et al., 2009. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 119(12), 2348–2354. 370. Radkay-­Gonzalez, L., Faquin, W., McHugh, J.B., Lewis, J.S., Tuluc, M., Seethala, R.R., 2016. Ciliated adenosquamous carcinoma: expanding the phenotypic diversity of human papillomavirus-­associated tumors. Head Neck Pathol. 10(2), 167–175. 371.  Lewis, J.S., 2012. p16 Immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 6(S1), S75–82. 372. Chernock, R.D., Wang, X., Gao, G., et al., 2013. Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx. Mod. Pathol. 26(2), 223–231. 373.  Beadle, B.M., William, W.N., McLemore, M.S., Sturgis, E.M., Williams, M.D., 2013. p16 Expression in cutaneous squamous carcinomas with neck metastases: a potential pitfall in identifying unknown primaries of the head and neck. Head Neck. 35(11), 1527–1533. 374. Jensen, D.H., Hedback, N., Specht, L., et al., 2014. Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival. PLoS One. 9(11), e110456. 375.  Lydiatt, W.M., Patel, S.G., O’Sullivan, B., et al., 2017. Head and Neck cancers-­major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J. Clin. 67(2), 122–137. 376. Kim, C.M., St John, M.A., 2019. Should the contralateral tonsil be removed in cases of HPV-­positive squamous cell carcinoma of the tonsil? Laryngoscope. 129(6), 1257–1258. 377. Ren, J., Yang, W., Su, J., et al., 2019. Human papillomavirus and p16 immunostaining, prevalence and prognosis of squamous carcinoma of unknown primary in the head and neck region. Int. J. Cancer. [Epub ahead of print]. 378. Golusinski, P., Di Maio, P., Pehlivan, B., et al., 2019. Evidence for the approach to the diagnostic evaluation of squamous cell carcinoma occult primary tumors of the head and neck. Oral Oncol. 88, 145–152. 379. Holmes, B.J., Maleki, Z., Westra, W.H., 2015. The fidelity of p16 staining as a surrogate marker of human papillomavirus status in fine-­needleaspirates and core biopsies of neck node metastases: implications for HPV testing protocols. Acta Cytol. 59(1), 97–103. 380. McDowell, L.J., Young, R.J., Johnston, M.L., et al., 2016. p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary. Cancer. 122(8), 1201–1208. 381. Piazza, C., Incandela, F., Giannini, L., 2019. Unknown primary of the head and neck: a new entry in the TNM staging system with old dilemmas for everyday practice. Curr. Opin. Otlaryngol. Head Neck Surg. [Epub ahead of print].

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382. Ohi, Y., Umekita, Y., Sagara, Y., et al., 2012. Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer. Br. J. Cancer. 107, 1239–1243. 383. Ferris, R.L., Xi, L., Raja, S., et al., 2005. Molecular staging of cervical lymph nodes in squamous cell carcinoma of the head and neck. Cancer Res. 65(6), 2147–2156. 384.  Becker, M.T., Shores, C.G., Yu, K.K., Yarbrough, W.G., 2004. Molecular assay to detect metastatic head and neck squamous cell carcinoma. Arch. Otolaryngol. Head Neck Surg. 130(1), 21–27. 385.  de Carvalho, A.C., Scapulatempo-­ Neto, C., Maia, D.C., et al., 2015. Accuracy of microRNAs as markers for the detection of neck lymph node metastases in patients with head and neck squamous cell carcinoma. BMC Med. 13, 155. 386. Schilling, C., Shaw, R., Schache, A., et al., 2017. Sentinel lymph node biopsy for oral squamous cell carcinoma. Where are we now? Br. J. Oral Maxillofac. Surg. 55(8), 757–762. 387. Cho, W.K., Roh, J.L., Cho, K.J., Choi, S.H., Nam, S.Y., 2019. Lymph node ratio predictive of recurrence, distant metastasis, and survival in submandibular gland carcinoma patients. J. Cancer Res. Clin. Oncol. [Epub ahead of print]. 388. Aro, K., Ho, A.S., Luu, M., et al., 2018. Development of a novel salivary gland cancer lymph node staging system. Cancer. 124(15), 3171– 3180. 389. Ho, A.S., Kim, S., Tighiouart, M., et al., 2018. Association of quantitative metastatic lymph node burden with survival in hypopharyngeal and laryngeal cancer. JAMA Oncol. 4(7), 985– 989. Lymph Node Ratio 390. Kassouf, W., Agarwal, P.K., Herr, H.W., et al., 2008. Lymph node density is superior to TNM nodal status in predicting disease-­specific survival after radical cystectomy for bladder cancer: analysis of pooled data from MDACC and MSKCC. J. Clin. Oncol. 26(1), 121–126. 391. Ooki, A., Yamashita, K., Kobayashi, N., et al., 2007. Lymph node metastasis density and growth pattern as independent prognostic factors in advanced esophageal squamous cell carcinoma. World J. Surg. 31(11), 2184–21891 392. Zhang, H., Liang, H., Gao, Y., et al., 2016. Metastatic lymph node ratio demonstrates better prognostic stratification than pN staging in patients with esophageal squamous cell carcinoma after esophagectomy. Sci. Rep. 6, 38804. 393. Fleming, N.D., Frumovitz, M., Schmeler, K.M., et al., 2015. Significance of lymph node ratio in defining risk category in node-­positive early stage cervical cancer. Gynecol. Oncol. 136(1), 48–53. 394.  Chen, C.C., Lin, J.C., Chen, K-­ W., 2015. Lymph node ratio as a prognostic factor in head and neck cancer patients. Radiat. Oncol. 10, 181. 395. Samani, R.E., Shirkhoda, M., Hadji, M., et al., 2018. The prognostic value of lymph node ratio in survival of head-­and-­neck squamous cell carcinoma. J. Res. Med. Sci. 23, 35. 396. Roberts, T.J., Colevas, A.D., Hara, W., Holsinger, F.C., Oakley-­Girvan, I., Divi, V., 2016. Number of positive nodes is superior to the lymph node ratio and American Joint Committee on Cancer N staging for the prognosis of surgically treated head and neck squamous cell. Cancer. 122(9), 1388–1397.

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12

Ear: External, Middle, and Temporal Bone DIANA BELL

Introduction Lesions of the ear reflect the composition and environmental exposures of the ear’s constituent parts: the skin, subcutaneous tissues, and cartilage of the external ear; the mucosa, ossicles and bone, nerves, muscles, and blood vessels of the middle ear and mastoid; and the specialized epithelium and nerves of the inner ear, which, encased within the temporal bone, transmute sound and position sensation to electrical impulses and produce and regulate the flow of endolymph. Embryologically, the ear is formed by the intersection of three developmental embryonic layers “not causally connected in development but linked together only through the medium of their definitive functioning” (Yntema cited by Van De Water and Rubin1). The external ear, including the pinna or auricle, external auditory meatus, and canal to the squamous epithelial layer of the tympanum (eardrum), is formed by the ectoderm and mesoderm of the first branchial groove and adjacent first (mandibular) and second (hyoid) branchial arches. The middle ear epithelium, lining the auditory (eustachian) tube, middle ear, and mastoid cavities, is an endodermal derivative of the first pharyngeal pouch, with mesodermal contributions lining the mastoid and epitympanic and hypotympanic cavities. The tympanic membrane is derived from both external and middle ear; the external squamous surface is contiguous with that of the external auditory canal, and an endodermally derived simple cuboidal, columnar, or flat epithelium lines the middle ear. A portion of the tympanum, the pars flaccida, lacks an intermediate mesenchyme. The middle ear ossicles and supporting tissues are first and second branchial arch mesenchyme derivatives. The inner ear develops, by mesodermal and neural induction, from the ectodermal otic placode rather than from the branchial apparatus. An appreciation of the embryologic origins of the ear is useful in interpreting the origins of tumors, the potential of cells for metaplastic change, and discussions of choristoma and the origin of cholesteatoma. Ross and Sasaki2 review the surgical anatomy of the ear in their discussion of radical temporal bone surgery for malignant tumors. Michaels’s3 presentation of the histology of the ear is comprehensive and well illustrated, as is the ear, nose, and throat pathology text by Michaels and Hellquist.4 The majority of ear lesions submitted for pathologic examination (biopsy) are: (1) from the skin5,6 of the external ear (pinna, meatus, or canal); (2) inflammatory (8:1 ratio of inflammatory to neoplastic lesions7); and (3) due to traumatic or actinic insults. Analysis of tumors of the ear from major referral centers and community and university hospitals7,8 shows similar

frequencies of tumor types and location (Table 12.1). In the Barnes Hospital, St. Louis, MO, series,7 the most common tumors, in order of frequency, were squamous cell and basal cell carcinomas, predominantly of the external ear (45%); paragangliomas of the middle ear (14%); middle ear adenomas (10%); osteomas of the external canal (7%); carcinomas not otherwise specified (6%); nerve sheath tumors (3%); and nevi or melanomas of the external ear (3%). Remaining were miscellaneous benign and malignant mesenchymal tumors, including rhabdomyosarcoma (RMS; 1%) in children. Lesions of the internal auditory canal are underrepresented in these series. The relative numbers of lesions of the external ear and nevi or melanoma and acoustic neuroma vary depending on the nature of the referring services, that is, otology, dermatology, or neurosurgery. Neoplasms of the ear9–11 are rare relative to inflammatory lesions. However, because they occur in the same age groups and have similar clinical presentations, biopsy sample differentiation between inflammation and neoplasia (benign or malignant) is necessary and often difficult. Lesions of the external ear are predominantly lumps and bumps of skin and cartilage origin in elderly individuals. Tumors of the external canal are often not visible and are manifested early by fullness and later by a mass, fluid drainage, or bloody discharge. Hearing loss and pain are symptoms of increasing size and invasion, and are clinical manifestations of malignancy. Ulceration and superimposed inflammation can lead to an erroneous diagnosis of inflammation, but, except for otitis in diabetic patients, necrotic inflammatory masses are usually necrotic tumors. Evaluation of the site, size, and spread of neoplastic lesions with sophisticated imaging techniques is mandatory. Middle ear lesions present with hearing loss, and, with an otoscope, a mass can be seen behind the normal or bulging eardrum. Chronic otitis media is a sequel of acute otitis media in children, but in adults, chronic otitis media is a sign of a systemic disease or neoplasm. Hearing loss occurs early in the course of middle ear disease owing to encroachment on the conductive chain of ossicles. An enlarging lesion can cause the drum to bulge into the external canal or destroy the drum. Both neoplasms and infection spread from the middle ear posteriorly into the mastoid, medially into the jugular fossa, and superiorly through the tegmen into the cranial cavity and laterally through the drum. Lesions of the inner ear, located within the temporal bone, had been relatively inaccessible to biopsy, but with current imaging techniques, fine-­needle aspiration biopsy, endoscopes, and recently developed base of the skull 927

928 TABLE

12.1

Gnepp’s Diagnostic Surgical Pathology of the Head and Neck

Frequency (%) of Ear Neoplasms at Four Institutions

Neoplasm

BHa

AFIP†

YNH†

BPT†

Squamous Benign cysts, papilloma, etc. Squamous cell carcinoma Basal cell carcinoma Neuroepithelial/neural Nevi Melanoma Nerve sheath Schwannoma Neurofibroma Granular cell Paraganglioma Merkel cell carcinoma Meningioma Heterotopic brain Neuroblastoma Glandular Adenoma Auricle External canal Middle ear Adenocarcinoma Carcinoma not otherwise specified Benign not otherwise specified Metastases Malignant not otherwise specified Mesenchymal lesions Fibrohistiocytic Benign Malignant Keloid Leiomyoma Leiomyosarcoma Rhabdomyosarcoma Sarcoma not otherwise specified Vascular Kaposi sarcoma Lymphangioma Hemangioma Bone/cartilage Benign Malignant Langerhans cell histiocytosis Lymphoproliferative Congenital Dermoid Hamartoma Choristoma Tragus Total

48 3 35 10 21 2 1 3 12