AFIP ATLAS OF TUMOR PATHOLOGY 4 Series Tumors of the Cervix, and Vulva Vagina, MD Robert Kurman, J. MD Brigitte M. Ronnett, MD Mark Sherman, E. MD Edward Wilkinson, J. AFIP ARP ForfreeInternetaccesstothisfascicle,goto: www.afip.org/publications/myfascicles Valid fororiginal purchase only Serial #4F13-407559734 ARP PRESS ARP PRESS Silver Spring Maryland , Editorial Director: Mirlinda Q. Caton Production Editor: Dian S. Thomas Editorial Assistant: Magdalena C. Silva Editorial Assistant: Alana N. Black Copyeditor: Audrey Kahn Available from the American Registry of Pathology Armed Forces Institute of Pathology Washington, DC 20306-6000 www.afip.org ISBN 1-933477-11-3 978-1-933477-11-4 Copyright © 201 0 The American Registry of Pathology All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means: electronic, mechanical, photocopy, recording, or any other information storage and retrieval system without the written permission of the publisher. AFIP ATLAS OF TUMOR PATHOLOGY Fourth Series Fascicle 13 TUMORS OF THE AND CERVIX, VAGINA, VULVA by MD Robert Kurman, J. Johns Hopkins University School ofMedicine Departments ofGynecology-Obstetrics and Pathology Professor and Director, Gynecologic Pathology Baltimore, Maryland MD Brigitte M. Ronnett, Johns Hopkins Univesity School ofMedicine Department of Pathology Professor, Gynecologic Pathology Baltimore, Maryland MD Mark E. Sherman, National Cancer Institute Hormone and Reproductive Epidemiology Branch Rockville, Maryland MD Edward Wilkinson, J. Univesity ofFlorida Medical Center NATIONALINSTITUTES OFHEALTH Department of Pathology NIH LIBRARY Gainesville, Florida JAN 1.5 2019 BLDG 10, 10CENTERDR Published by the bethesda, md. 20892-hso American Registry ofPathology Washington, DC in collaboration with the Armed Forces Institute ofPathology Washington, DC 2010 AFIP ATLAS OF TUMOR PATHOLOGY EDITOR MD Steven G. Silverberg, Department of Pathology University ofMaryland School ofMedicine Baltimore, Maryland ASSOCIATE EDITOR ASSOCIATE EDITOR MD MD William A. Gardner, Leslie H. Sobin, American Registry of Pathology Armed Forces Institute of Pathology Washington, DC Washington, DC EDITORIAL ADVISORY BOARD MD Jorge Albores-Saavedra, Instituto Nacional de Ciencias Medicas Mexico City, Mexico Ronald A. DeLellis, MD Lifespan Academic Medical Center Providence, Rhode Island William Frable, MD Virginia Commonwealth University J. Richmond, Virginia Kim R. Geisinger, MD Wake Forest University School of Medicine Winston-Salem, North Carolina MD Donald West King, National Library of Medicine Bethesda, Maryland MD Leonard B. Kahn, Long Island Jewish Medical Center New Hyde Park, New York MD James Linder, Cytyc Corporation Marlborough, Massachusetts MD Virginia A. LiVolsi, University of Pennsylvania Medical Center Philadelphia, Pennsylvania Elizabeth Montgomery, MD Johns Hopkins University School of Medicine Baltimore, Maryland MD Juan Rosai, Istituto Nazionale Tumori Milano, Italy Mark H. Stoler, MD University ofVirginia Health Sciences Center Charlottesville, Virginia MD William D. Travis, Memorial Sloan-Kettering Cancer Center New York, New York MD Noel Weidner, University of California San Diego Medical Center San Diego, California Mark R. Wick, MD University ofVirginia Medical Center Charlottesville, Virginia ManuscriptReviewedby: Thomas A. Bonfiglio, MD Mark H. Stoler, MD EDITORS' NOTE The Atlas of Tumor Pathology has a long and distinguished history. It was first conceived at a cancer research meeting held in St. Louis in September 1947 as an attempt to standardize the nomenclature of neoplastic diseases. The first series was sponsored by the National Academy of Sciences-National Research Council. The or- ganization ofthis Sisyphean effort was entrusted to the Subcommittee on Oncology of the Committee on Pathology, and Dr. Arthur Purdy Stout was the first editor-in- chief. Many ofthe illustrations were provided by the Medical Illustration Service of the Armed Forces Institute of Pathology (AFIP), the type was set by the Government Printing Office, and the final printing was done at the Armed Forces Institute of Pa- thology (hence the colloquial appellation "AFIP Fascicles"). The American Registry of Pathology (ARP) purchased the Fascicles from the Government Printing Office and sold them virtually at cost. Over a period of 20 years, approximately 15,000 copies each of nearly 40 Fascicles were produced. The worldwide impact of these publications over the years has largely surpassed the original goal. They quickly became among the most influential publications on tumor pathology, primarily because of their overall high quality, but also because their low cost made them easily accessible the world over to pathologists and other students of oncology. Upon completion of the first series, the National Academy of Sciences-National Research Council handed further pursuit of the project over to the newly created Universities Associated for Research and Education in Pathology (UAREP). A second series was started, generously supported by grants from the AFIP, the National Can- cer Institute, and the American Cancer Society. Dr. Harlan I. Firminger became the editor-in-chief and was succeeded by Dr. William H. Hartmann. The second series' Fascicles were produced as bound volumes instead of loose leaflets. They featured a more comprehensive coverage of the subjects, to the extent that the Fascicles could no longer be regarded as "atlases" but rather as monographs describing and illustrating in detail the tumors and tumor-like conditions of the various organs and systems. Once the second series was completed, with a success that matched that of the first, ARP, UAREP, and AFIP decided to embark on a third series. Dr. Juan Rosai was appointed as editor-in-chief, and Dr. Leslie H. Sobin became associate editor. A distinguished Editorial Advisory Board was also convened, and these outstanding pathologists and educators played a major role in the success of this series, the first publication of which appeared in 1991 and the last (number 32) in 2003. The same organizational framework applies to the current fourth series, but with UAREP no longer in existence, ARP plays the major role. New features include a hardbound cover, illustrations almost exclusively in color, and an accompanying electronic version of each Fascicle. There is also an increased emphasis (wherever appropriate) on the cytopathologic (intraoperative, exfoliative, and/or fine needle aspiration) and molecular features that are important in diagnosis and prognosis. What does not change from the three previous series, however, is the goal ofprovid- ing the practicing pathologist with thorough, concise, and up-to-date information on the nomenclature and classification; epidemiologic, clinical, and pathogenetic features; and, most importantly, guidance in the diagnosis of the tumors and tu- morlike lesions of all major organ systems and body sites. As in the third series, a continuous attempt is made to correlate, whenever pos- sible, the nomenclature used in the Fascicles with that proposedbythe World Health Organization's Classification of Tumors, as well as to ensure a consistency of style throughout. Close cooperation between the various authors and their respective liaisons from the Editorial Board will continue to be emphasized in order to mini- mize unnecessary repetition and discrepancies in the text and illustrations. Particular thanks are due to the members of the Editorial Advisory Board, the re- — viewers (at least two for each Fascicle), the editorial and production staff, and first — and foremost the individual Fascicle authors for their ongoing efforts to ensure that this series is a worthy successor to the previous three. MD Steven G. Silverberg, MD William A. Gardner, MD Leslie H. Sobin, PREFACE AND ACKNOWLEDGEMENTS The advances in the field ofcervical, vaginal, andvulvarpathology since thepublica- tion ofthe last edition ofthis Fascicle in 1992 have been remarkable, and the progress that two ofthe authors (Robert Kurman and Edward Wilkinson) have witnessed since they were first introduced to the field in the1970s has been stunning. At that time, the consensus was that herpesvirus type 2 caused cervical cancer and the nomencla- ture for cervical cancer precursors was cervical dysplasia and carcinoma in situ (CIS), with the emphasis placed on distinguishing severe dysplasia from CIS. Since then, we have learned that high-risk human papillomaviruses (HPVs) represent the etiologic agents that cause essentially all cervical and vaginal cancers, their precursors, and a substantial fraction of vulvar neoplastic lesions. The convincing efficacy of the recently developed prophylactic vaccines in preventing HPV infections and cervical cancerprecursors based on cytologic and morphologic diagnosis provides undeniable evidence of the early causal role of the virus in the pathogenesis of cervical neopla- sia. Examination of the trajectory of this extraordinary achievement highlights the significant contributions made by a number of disciplines, including molecular biol- ogy, epidemiology, and pathology. Undoubtedly, molecular biology has played the preeminent role with the identification by Professor Harald zur Hausen in 1977 of HPV 16 DNA in cervical cancer specimens. The award of the Nobel Prize in Medicine to Professor zur Hausen capped this remarkable and significant achievement. Pathology's contributions to the diagnosis ofcervical, vaginal, andvulvar cancers and theirprecursorshavealsoplayedanextremelyimportantrole, asthepathologicdiagnosis provides the endpoint, and hence, proof of efficacy for the large clinical trials such as theASC-US/LSILTriage study (ALTS), whichlaidthe foundation forthe management of cervical precursors, and forthevaccine trials. Other developments that occurred during this time were the introduction ofhigh-risk HPV DNA testing as a supplement to cytol- ogy for screening in concert with the development ofThe Bethesda System Classifica- tion (TBS), first for cervical cytology and subsequently for histopathology. The use of molecular biologic methods in conjunction with a histopathologic classification based on the natural history of the disease ushers in a new approach for surgical pathology, which undoubtedly will continue to evolve in the future. Thus, the publication of this Fascicle marks the transition in diagnosis of lower genital tract lesions from a largely morphologic activity to one based upon in- tegrated assessment using microscopy and molecular biology. Furthermore, the ability to integrate these diagnostic approaches with clinical data for patient man- agement has been heightened. The introduction of vaccination in the community also thrusts pathology into a new unprecedented public health role with regard to disease monitoring, which will likely expand over time. Finally, the realization that cervical cancer is becoming increasingly preventable, carries with it both a sense of accomplishment and the recognition that this must now be translated into an achievable goal of cancer prevention in underdeveloped nations. There are a number of significant changes in this edition of the Fascicle that are worthy of mention. Although the text has remained concise in order to maintain the primary function of the Fascicle as an atlas rather than a comprehensive text- book, it has been substantially updated to reflect the changes in the field as noted above. In this regard, the number of illustrations, all of which are in color, has almost doubled. Both the text and the photomicrographs emphasize the impor- tance of immunohistochemistry and molecular in situ hybridization as adjuncts to morphology in routine clinical diagnosis. Although HPV infection was a separate chapter in the previous edition, it has been greatly expanded and updated in the present edition. Abinary (low-grade and high-grade squamous intraepithelial lesion) classification for histology, analogous to TBS for cytology, replaces the four-tiered dysplasia/CIS system and the three-tiered CIN system. The binary classification has been controversial. This approach was advocated in the last edition and our experi- ence since then has convinced us of its utility based on our (RJK, BMR, and MES) and our colleagues' (Mark Stoler, Alex Ferenczy, and Dorothy Rosenthal) collective experience reviewing over 100,000 cervical, vaginal, and vulvar biopsies as part of the pathology panels for the ALTS and Merck vaccine trials. The publication of this Fascicle has depended on the assistance of many indi- whom We viduals to the authors are greatly indebted. are especially grateful to Drs. Mark Stoler and Tom Bonfiglio for their thoughtful review and comments on the entire text. At Johns Hopkins, Ms. Evelyn Hinton, our Administrative Assistant, provided excellent secretarial assistance, and Mr. Norman Barker, Associate Profes- sor and Director of Pathology, Digital Imaging and Computer Graphics reviewed and edited all of the photomicrographs, many of which required his considerable expertise since the images were scanned from Kodachrome slides. At the University of Florida, our program assistant, Ms Karen Hyde, provided valuable secretarial as- sistance. Drs. and Professors John Reith and Vladimir Vincek provided thoughtful review of the vulvar soft tissue and melanoma sections. Mr. Robin Foss, Associate Director of Surgical Pathology Services, provided expertise with the gross specimen photographs and digital imaging of the vulvar chapter. Finally, there are many individuals, including those from other disciplines who, through our collaboration with them, have enhanced our understanding of the pathobiology of neoplasms of the lower female reproductive organs. They are far too numerous to specifically mention, but their influence on us has been considerable. To all these people we wish to express our thanks. MD Robert Kurman, J. MD Brigitte M. Ronnett, MD Mark Sherman, E. MD Edward Wilkinson, J.