Gynecologic and Obstetric Pathology, Volume 2 [1st ed.] 978-981-13-3018-6;978-981-13-3019-3

Table of contents :
Front Matter ....Pages i-xix
Uterine Mesenchymal Lesions (Brooke E. Howitt, Marisa R. Nucci)....Pages 1-52
Fallopian Tube (David L. Kolin, Brooke E. Howitt)....Pages 53-77
Benign Diseases of the Ovary (David Suster, Martina Z. Liu, Douglas I. Lin)....Pages 79-120
Ovarian Epithelial Carcinogenesis (Jing Zhang, Elvio G. Silva, Anil K. Sood, Jinsong Liu)....Pages 121-139
Serous Neoplasms of the Ovary (Preetha Ramalingam)....Pages 141-171
Ovarian Endometrioid and Clear-Cell Tumors (Jennifer Katzenberg, Andres A. Roma)....Pages 173-201
Ovarian Mucinous, Brenner Tumors, and Other Epithelial Tumors (Cathleen Matrai, Taylor M. Jenkins, Esther Baranov, Lauren E. Schwartz)....Pages 203-230
Germ Cell Tumors and Mixed Germ Cell-Sex Cord-Stromal Tumors of the Ovary (Hao Chen, Charles Matthew Quick, Oluwole Fadare, Wenxin Zheng)....Pages 231-271
Sex Cord-Stromal Tumors of the Ovary (Mohamed Mokhtar Desouki)....Pages 273-322
Secondary Tumors of the Ovary (Kelley Carrick, Wenxin Zheng)....Pages 323-366
Peritoneum and Broad Ligament (M. Ruhul Quddus, Sharon Liang, Wenxin Zheng, C. James Sung)....Pages 367-403
Endometriosis and Endometriosis-Associated Tumors (Rosalia C. M. Simmen, Charles Matthew Quick, Angela S. Kelley, Wenxin Zheng)....Pages 405-426
Complications of Early Pregnancy and Gestational Trophoblastic Diseases (Philip P. C. Ip, Yan Wang, Annie N. Y. Cheung)....Pages 427-457
Overview of Placenta Pathology (John Paul B. Govindavari, Anna R. Laury)....Pages 459-492
Placenta and Pregnancy-Related Diseases (Erica Schollenberg, Anna F. Lee, Jefferson Terry, Mary Kinloch)....Pages 493-539
Principles and Practical Guidelines of Intraoperative Consultation (Hannah Goyne, Emily Paull Acheson, Charles Matthew Quick)....Pages 541-570
Gynecologic Cytology (Uma Krishnamurti, Marina Mosunjac, Georgios Deftereos, Krisztina Z. Hanley)....Pages 571-630
Back Matter ....Pages 631-639

Citation preview

Wenxin Zheng Oluwole Fadare Charles Matthew Quick Danhua Shen Donghui Guo Editors

Gynecologic and Obstetric Pathology, Volume 2

123

Gynecologic and Obstetric Pathology, Volume 2

Wenxin Zheng  Oluwole Fadare Charles Matthew Quick Danhua Shen  Donghui Guo Editors

Gynecologic and Obstetric Pathology, Volume 2

Editors Wenxin Zheng Department of Pathology Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center Dallas, TX USA Charles Matthew Quick Department of Pathology, College of Medicine University of Arkansas for Medical Sciences Little Rock, AR USA

Oluwole Fadare Department of Pathology University of California San Diego San Diego, CA USA Danhua Shen Department of Pathology Peking University People’s Hospital Beijing China

Donghui Guo Department of Obstetrics and Gynecology Tianjin Gynecologic and Obstetrics Central Hospital Tianjin China

ISBN 978-981-13-3018-6    ISBN 978-981-13-3019-3 (eBook) https://doi.org/10.1007/978-981-13-3019-3 © Science Press & Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are reserved by the Publishers, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publishers, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publishers nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publishers remain neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Foreword

The field of gynecologic and obstetric pathology is at a cross-roads. In the past decade we have begun to witness the departure of venerated contributors to this discipline and now we are being inundated with new information about pathogenesis that informs diagnostic expectations and patient outcome. The old model in which the next generation sits at the knee of the learned and patiently awaits their turn at the helm is rapidly fading. Succession is now not simply achieved by learning the old language but by speaking a new one. The textbook Gynecologic and Obstetrics Pathology, edited by Drs. Zheng, Fadare, and Quick is emblematic of the sea change. We’ve all heard the joke about resorting to one’s grandchild to solve a computer conundrum. How many of us turn to our younger colleagues to interpret emerging genomic information in the management of gynecologic cancer? An appreciation of such talent is crucial to our evolution as well as that of our discipline. The senior editor in this project, Dr. Wenxin Zheng, has a long track record of innovation. With this has come a facility to recognize the most talented young clinician-investigators and to recruit them into this new textbook. Drs. Fadare and Quick as well as the younger chapter authors are well on their way, having already put us on notice that by their dedication, creativity and their role in discovery. Their input is what will keep this and subsequent editions at the forefront of pathology texts dedicated to women’s health. Energy and intellect drive discovery but experience is essential to provide a needed perspective when this information is transmitted to the practicing pathologist. The editors wisely balance the list of talented newcomers with recognized experts in the field. Together they provide the finer details of diagnosis and differential diagnosis while eliciting the nuances relevant to clinical management. In the current world, where discoveries and their impact on practice can become global almost instantaneously, one does not need to travel far to realize that expertise in obstetric and gynecologic pathology is intercontinental. In recognizing this, Zheng et al. will also provide an edition written in Chinese, bringing this message to pathologists (and their patients) in countries where the language is read and spoken. To my knowledge, this book will be the first of its kind to accomplish this, creating a truly international presence that will place this first edition among the leading texts in the field. The editors and authors are to be commended for their contribution and I look forward to their success in opening a new chapter (and book!) in the history of the pathology of the female reproductive tract. Christopher P. Crum Division of Women’s and Perinatal Pathology Harvard Medical School, Brigham and Women’s Hospital Boston, MA, USA

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Preface

Pathology of the female genital tract is complex, and encompasses a wide spectrum of neoplastic and non-neoplastic diseases of the gonads, reproductive ducts, secondary müllerian system, and external genitalia. Clinical practitioners in this discipline must therefore familiarize themselves with a broad spectrum of pathology, including skin-like diseases of the vulva, a myriad of peritoneal diseases, as well as conventional diseases of other female genital tract organs. This field progresses in a vibrant and dynamic academic environment in which diagnostic concepts continually evolve as our understanding of various disease processes improves over time. The contemporary gynecologic pathologist is in a unique position to recognize and define morphologic correlates to newly defined genomic profiles and individual gene mutations, assess whether they are likely to have diagnostic or prognostic significance for a given patient and/or her family, and broadly participate in the push towards increasingly personalized cancer care. These exciting trends notwithstanding, it remains true that definitive pathologic classification of gynecologic disease is still primarily based on the traditional pillars of surgical pathology, including gross pathology, morphologic assessment buttressed by immunophenotypic analysis where needed, and careful clinicopathologic correlation. This book is envisioned as a “bridge” that acknowledges both of the aforementioned realities. It is designed to provide a broad coverage of diagnostic gynecologic and obstetric pathology, inclusive of both neoplastic and non-neoplastic diseases. The book is neither a dense and comprehensive treatise on every disease process nor is it a dry listing of relevant “facts” about each entity. Rather, it is best conceptualized as a large scale aggregation of the most up to date information in gynecologic pathology, all presented in a concise and narrative manner that is designed to be easily accessible to the general practitioner, specialist and student alike. An overt effort has been made to discuss each topic in a way that is maximally relevant to the diagnostic surgical pathologist, such that by reading any section should substantially increase the reader’s confidence that the most germane clinicopathologic information on that entity has been reviewed before a diagnostic decision is made. The material is organized into 36 chapters, representing the full spectrum of diagnostic gynecologic pathology. In addition to chapters on traditional topics in gynecologic pathology, there are individual chapters on site-specific carcinogenesis, gynecologic cytology, intra-­ operative consultation, endometriosis and development/maldevelopment of the female reproductive system, among others. Additionally, in a departure from most current texts, there are stand-alone chapters to provide intensive coverage of some traditionally under-covered topics, including melanocytic lesions of the female genital tract, non-neoplastic diseases of the endometrium, and vulvovaginal soft tissue lesions. Entities with a significant diagnostic component are presented, where feasible, divided into the following subsections: Clinical features, Gross findings, Microscopic findings, Differential diagnosis, Biomarkers, and Genetic features. As expected, not all entities or chapters lend themselves to this specific format, but most chapters are broadly structured based on these general themes. Microscopic findings are lavishly illustrated, and numerous tables help summarize pertinent points for easy reference. The overall objective of each chapter is to integrate traditional pathologic features, clinical features, where applicable, and current paradigms in disease classification into a format that can be readily applied in routine practice. These chapters are authored by over 50 physicians, most of whom vii

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Preface

are experienced subspecialty practitioners of clinical gynecologic pathology from around the world, and without whose expertise, dedication, and diligence this work would not have been possible. It is the sincere hope of the editors that all of those who are interested in gynecologic pathology—diagnostic pathologists, students, residents and investigators—will find this book tremendously useful. The understanding of gynecologic disease involves pathologists and researchers from across oceans and all over the world, and to that end an exciting feature of this book is that it is written with a direct linkage to the second edition of the book “Gynecologic and Obstetric Pathology”. The latter book is in Chinese, and is published by Science Press, Beijing, China. The current text is published in both English and Chinese, representing a collaborative effort by both publishers: Springer and Science Press. Although the titles and the number of chapters are identical in the two books, the authors of the chapters are different. Additionally, while the chapter outlines and some of the contents overlap, the two books do not represent a direct translation from one to the other. Rather, they are best considered complementary “sister” books. This results from Dr. Wenxin Zheng serving as the first editor-in-chief for both books. Considering this special and close relationship, the co-editors for the Chinese book, Drs. Danhua Shen and Donghui Guo, are listed as co-editors of the English version of this book, while Drs. Fadare and Quick are also listed as co-editors on the second edition of the Chinese book. Dallas, TX San Diego, CA  Little Rock, AR 

Wenxin Zheng Oluwole Fadare Charles Matthew Quick

Acknowledgments

To my dear wife Wenda and my beloved family (Yuxin, Genfu, and Deshun) for their constant love and endless support! In memory of my parents Maoguan Zheng and Jinxian Wang as well as my ultimate mentor Dr. Stuart C. Lauchlan. Wenxin Zheng To my wife Abby for her love, encouragement, and inspiration, and to our beloved children Nathaniel, Darrell and Olivia for (mostly) putting up with the occasional absences that were required to do this. Oluwole Fadare To my everything, Shelly, and my wonderful children Dexter, Bernice, and Alice. Charles Matthew Quick To my beloved family members for their continuous support and care, and to all my colleagues who participated in editing this outstanding book. I am honored to be an editor for this prestigious book. Danhua Shen To my beloved family members for their constant support and care, and to Drs. Zhaoai Kong and Song Lin whose past instruction and training have been and continues to be invaluable. Donghui Guo The Editors would like to sincerely thank Dr. Christopher P. Crum, M.D. for serving as a senior consulting adviser for this book. Dr. Crum has made significant contributions to the field of gynecologic pathology and has trained innumerable residents and fellows, including many who have served as an author for this book. The quality of this work is in part attributable to his years of dedicated teaching and research in the field of gynecologic pathology.

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Contents

1 Uterine Mesenchymal Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Brooke E. Howitt and Marisa R. Nucci 2 Fallopian Tube. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 David L. Kolin and Brooke E. Howitt 3 Benign Diseases of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 David Suster, Martina Z. Liu, and Douglas I. Lin 4 Ovarian Epithelial Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Jing Zhang, Elvio G. Silva, Anil K. Sood, and Jinsong Liu 5 Serous Neoplasms of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Preetha Ramalingam 6 Ovarian Endometrioid and Clear-Cell Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Jennifer Katzenberg and Andres A. Roma 7 Ovarian Mucinous, Brenner Tumors, and Other Epithelial Tumors. . . . . . . . . . 203 Cathleen Matrai, Taylor M. Jenkins, Esther Baranov, and Lauren E. Schwartz 8 Germ Cell Tumors and Mixed Germ Cell-­Sex Cord-Stromal Tumors of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Hao Chen, Charles Matthew Quick, Oluwole Fadare, and Wenxin Zheng 9 Sex Cord-Stromal Tumors of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Mohamed Mokhtar Desouki 10 Secondary Tumors of the Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Kelley Carrick and Wenxin Zheng 11 Peritoneum and Broad Ligament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 M. Ruhul Quddus, Sharon Liang, Wenxin Zheng, and C. James Sung 12 Endometriosis and Endometriosis-­Associated Tumors. . . . . . . . . . . . . . . . . . . . . 405 Rosalia C. M. Simmen, Charles Matthew Quick, Angela S. Kelley, and Wenxin Zheng 13 Complications of Early Pregnancy and Gestational Trophoblastic Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Philip P. C. Ip, Yan Wang, and Annie N. Y. Cheung 14 Overview of Placenta Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 John Paul B. Govindavari and Anna R. Laury 15 Placenta and Pregnancy-Related Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 Erica Schollenberg, Anna F. Lee, Jefferson Terry, and Mary Kinloch

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16 Principles and Practical Guidelines of Intraoperative Consultation. . . . . . . . . . 541 Hannah Goyne, Emily Paull Acheson, and Charles Matthew Quick 17 Gynecologic Cytology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Uma Krishnamurti, Marina Mosunjac, Georgios Deftereos, and Krisztina Z. Hanley Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

Contents

About the Editors

Oluwole  Fadare  Dr. Oluwole Fadare is a Professor of Pathology at the University of California San Diego School of Medicine (UCSD, San Diego, CA, USA), where he also serves as the Chief of Anatomic Pathology for the UCSD Health System and Director of the Gynecologic/Breast Pathology fellowship. Dr. Fadare completed a fellowship in breast and gynecologic pathology at the Yale University School of Medicine (New Haven, CT, USA) in 2005, and has spent his subsequent academic career focused on the pathologic aspects of women’s health. Dr. Fadare has been the recipient of numerous prestigious awards, including most recently the 2018 Arthur Purdy Stout Prize from the Arthur Purdy Stout Society of Surgical Pathologists in recognition of “significant career achievements in Surgical Pathology by a Surgical Pathologist (less than 45 years old) whose publications have had a major impact on diagnostic pathology”, a 2018 Stowell-Orbison Certificate of Merit from the United States and Canadian Academy of Pathologists (USCAP), and a 2017 Excellence in Mentoring Award from UCSD Health Sciences International “in recognition of a sustained commitment to helping create a cadre of global leaders in innovative academic medicine”. Dr. Fadare has published more than 200 peer-reviewed articles in high impact scientific journals, predominantly centered on gynecologic pathology. Previous books edited or co-written include Diagnosis of Neoplasia in Endometrial Biopsies: A PatternBased and Algorithmic Approach (Cambridge University Press, 2014) and Precancerous Lesions of the Gynecologic Tract: Diagnostic and Molecular Genetic Pathology (Springer 2015). Dr. Fadare has served in various editorial capacities for over 80 journals, and is currently an editorial board member for the International Journal of Gynecological Pathology, Human Pathology, Advances in Anatomic Pathology, Archives of Pathology and Laboratory Medicine, Archives of Medical Research, and Diagnostic Pathology, among others. He is also active in various professional societies, and currently serves on the education committee for the International Society of Gynecologic Pathologists and on the membership committee for USCAP. Dr. Fadare’s research has been clinical based, and has focused on integrating morphological, immunohistochemical and molecular aspects of gynecologic tract neoplasms to optimize diagnostic, prognostic and predictive patient care.

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About the Editors

Donghui  Guo  Dr. Guo graduated from the Fourth Military Medical University of China in 1974, and is one of the top gynecologic pathologists in China. Mentored by Professor Song Lin in the early part of her career, Dr. Guo has practiced gynecologic pathology for more than 30 years. Dr. Guo served as Chairman in the Department of Pathology, Tianjin Central Hospital of Obstetrics and Gynecology for 10 years. She has mentored many graduate students, residents, and fellows with an interest in gynecologic pathology. Dr. Guo has served as a committee member as well as a well-recognized expert in gynecologic pathology for many professional societies in China. Dr. Guo has completed 4 major scientific achievements (please provide the details here) with multiple awards in Tianjin, China. Dr. Guo has authored and co-edited 5 pathology books and has published more than 30 peer-reviewed articles. Charles Matthew Quick  Dr. Charles “Matt”hew Quick is an associate professor and clinical educator in the Department of Pathology at UAMS in Little Rock, Arkansas. He completed fellowships in surgical pathology at UAMS and Women’s & Perinatal pathology at Harvard Medical School, Brigham & Women’s Hospital. Dr. Quick serves as the Director of Anatomic Pathology Sub-Specialty Practice, Gynecologic Pathology, and the Surgical Pathology Fellowship. He has published numerous research publications and review articles, and has authored and co-edited multiple textbooks, including “High-Yield Pathology: Gynecologic and Obstetric Pathology.” He loves all things teaching and gynecologic pathology related and has won numerous teaching awards for his medical student and resident education efforts, including UAMS’s campus-wide “Chancellor’s Award for Teaching Excellence.” Dr. Quick is dedicated to expanding pathology education in medical school and has started numerous programs at UAMS to effect this change including the UAMS pathology interest group: SCOPE, a summer pathology preceptorship, and the integration of autopsy pathology into the first year gross anatomy course, earning him an Education Innovation award in 2015. His efforts have led to a dramatic increase in medical students choosing pathology as a career in the state of Arkansas. Dr. Quick serves as an Ambassador for the United States and Canadian Academy of Pathology, and has taught numerous interactive microscopy courses for the USCAP at both annual meetings and the new teaching complex located in Palm Springs, California. He serves as the Gynecologic Pathology Course Director for the USCAP Interactive Microscopy Center. Dr. Quick’s research interests include the study of endometrial precancers, vulvar squamous carcinogenesis and the impact of epithelial-mesenchymal transition on tumor behavior.

About the Editors

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Danhua  Shen  Dr. Danhua Shen, Associate Professor of Pathology, is the Chairman of the Department of Pathology, People’s Hospital of Peking University, China. Dr. Shen is one of the top gynecologic pathologists in China. In addition to her dedication to pathology diagnosis, Dr. Shen has participated in many research projects of National Natural Science Foundation of China. She is the head of the Female Reproductive Diseases Group of the Pathology Branch of the Chinese Medical Association, and serves as an executive committee member for many prestigious professional societies including the Chinese Gynecologic Oncology Group, Chinese Society of Obstetrics and Gynecology, and Chinese Society of Colposcopy and Cervical Pathology, etc. Dr. Shen is also an editorial board member for the Journal of Chinese Pathology and the Chinese Journal of Obstetrics and Gynecology, and the Journal of Diagnostic Pathology. Dr. Shen has published more than 100 peer reviewed articles, and has been involved in seven clinical and pathological related monographs/books or book chapters either as an editor-­in-­chief or deputy editor-in-chief. Dr. Shen has also participated in many book translations in the field of Pathology and Obstetrics and Gynecology. Wenxin  Zheng  Dr. Zheng is a tenured Professor in the Department of Pathology and the Department of Obstetrics and Gynecology at the University of Texas Southwestern Medical Center (UTSW). An internationally recognized gynecologic pathologist as well as active physician scientist, he specializes in all aspects of gynecologic pathology and holds the Mark and Jane Gibson Distinguished Professorship in Cancer Research. Dr. Zheng also serves as the Director of Gynecologic Pathology service and the Director of Gynecologic Pathology Fellowship at the UTSW Medical Center. Dr. Zheng earned his medical degree at Shanghai Medical College Fudan University. He completed a residency in obstetrics and gynecology at the Hospital of Obstetrics and Gynecology in Shanghai and, later, a residency in anatomic and clinical pathology at New York Hospital-Cornell Medical Center. He received advanced training through a gynecologic pathology fellowship at Women & Infants Hospital of Rhode Island and a research fellowship in molecular reproductive medicine at Columbia University College of Physicians and Surgeons (New York). Dr. Zheng runs an active consultation practice that receives material world wide. Dr. Zheng has published more than 180 peer-reviewed articles in high impact scientific journals, mostly in the field of gynecologic pathology. He has served in various editorial capacities for over 50 journals, and is currently an editorial board member for multiple journals in the biomedical sciences. His main research contributions include endometrial serous carcinogenesis and precancerous lesion endometrial glandular dysplasia, cell origin of low-grade

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About the Editors

ovarian serous carcinoma, molecular mechanism of progestin resistance in endometrial cancer and its precancers, hormonal etiology of ovarian epithelial cancers, and tubal contribution of ovarian endometriosis and its associated ovarian cancers. In addition, Dr. Zheng has created a novel approach called onestop cervical care (OSCC) to diagnose and treat cervical precancers. Dr. Zheng Loves teaching gynecologic pathology to residents and fellows and have taught numerous gynecologic pathology courses nationally and internationally.

Contributors

Emily Paull Acheson  Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA Esther Baranov  Penn Medicine, University of Pennsylvania Heath System, Philadelphia, PA, USA Kelley Carrick  Departments of Pathology, Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA Hao Chen  Department of Pathology, UTSouthwestern Medical Center, Dallas, TX, USA Annie N. Y. Cheung  Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, China Department of Pathology, HKU-Shenzhen Hospital, Shenzhen, China Georgios Deftereos  University of Utah School of Medicine, Salt Lake City, UT, USA Mohamed  Mokhtar  Desouki Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA Oluwole Fadare  Department of Pathology, University of California San Diego, San Diego, CA, USA John Paul B. Govindavari  Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Hannah Goyne  Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA Krisztina Z. Hanley  Emory University Hospital, Atlanta, GA, USA Brooke E. Howitt  Department of Pathology, Stanford University Medical Center, Stanford, CA, USA Philip P. C. Ip  Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, China C. James Sung  The Warren Alpert Medical School of Brown University, Women & Infants Hospital, Providence, RI, USA Taylor M. Jenkins  Penn Medicine, University of Pennsylvania Heath System, Philadelphia, PA, USA Jennifer  Katzenberg Department of Pathology, University of California San Diego, San Diego, CA, USA Angela S. Kelley  Department of Obstetrics and Gynecology, University of Michigan Health Systems, Ann Arbor, MI, USA

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Mary Kinloch  Saskatoon City Hospital, Saskatoon, SK, Canada University of Saskatchewan, Saskatoon, SK, Canada David  L.  Kolin Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA Uma Krishnamurti  Emory University Hospital, Atlanta, GA, USA Anna R. Laury  Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Anna  F.  Lee  Children’s and Women’s Health Centre of British Columbia, Vancouver, BC, Canada University of British Columbia, Vancouver, BC, Canada Sharon Liang  Department of Pathology and Laboratory Medicine, Allegheny Health Network West Penn Hospital, Drexel University College of Medicine, and Temple University School of Medicine, Pittsburgh, PA, USA Douglas I. Lin  Foundation Medicine, Inc., Cambridge, MA, USA Martina Z. Liu  Brigham and Women’s Hospital, Boston, MA, USA Jinsong Liu  Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Cathleen  Matrai Weill Cornell Medical College, Cornell University and New  York-­ Presbyterian Hospital, New York, NY, USA Marina Mosunjac  Emory University Hospital, Atlanta, GA, USA Marisa R. Nucci  Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA Charles  Matthew  Quick Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA Preetha  Ramalingam  Department of Pathology and Laboratory Medicine, MD Anderson Cancer Center, University of Texas, Houston, TX, USA Andres A. Roma  Department of Pathology, University of California San Diego, San Diego, CA, USA M.  Ruhul  Quddus The Warren Alpert Medical School of Brown University, Women & Infants Hospital, Providence, RI, USA Erica Schollenberg  IWK Health Centre, Halifax, NS, Canada Dalhousie University, Halifax, NS, Canada Lauren E. Schwartz  Penn Medicine, University of Pennsylvania Heath System, Philadelphia, PA, USA Elvio  G.  Silva Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Rosalia C. M. Simmen  Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA Anil K. Sood  Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA David Suster  Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA

Contributors

Contributors

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Jefferson Terry  Children’s and Women’s Health Centre of British Columbia, Vancouver, BC, Canada University of British Columbia, Vancouver, BC, Canada Yan Wang  Department of Pathology, HKU-Shenzhen Hospital, Shenzhen, China Jing  Zhang Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, People’s Republic of China Wenxin Zheng  Departments of Pathology, Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

1

Uterine Mesenchymal Lesions Brooke E. Howitt and Marisa R. Nucci

Abstract

This chapter will cover the pathology of uterine mesenchymal tumors, including endometrial stromal neoplasms, undifferentiated uterine sarcomas, uterine tumors resembling ovarian sex cord-stromal tumors (UTROSCT), smooth muscle tumors, perivascular epithelioid cell tumor (PEComa), Mullerian adenosarcoma, and inflammatory myofibroblastic tumor, as well as some less common mesenchymal tumors that may be encountered in the uterus. The salient histopathologic, immunophenotypic, as well as molecular findings that help separate these different tumor types will be discussed. Keywords

Leiomyoma · Leiomyosarcoma · Endometrial stromal tumor · Endometrial stromal sarcoma · PEComa · Inflammatory myofibroblastic tumor · Adenosarcoma · Uterine tumor resembling ovarian sex cord-stromal tumor

1.1

Introduction

This chapter will cover the pathology of uterine mesenchymal tumors, including endometrial stromal neoplasms, undifferentiated uterine sarcomas, uterine tumors resembling ovarian sex cord-stromal tumors (UTROSCT), smooth muscle tumors, perivascular epithelioid cell tumor (PEComa), Mullerian adenosarcoma, and inflammatory myofibroblastic tumor, as well as some less common

B. E. Howitt Department of Pathology, Stanford University Medical Center, Stanford, CA, USA e-mail: [email protected] M. R. Nucci (*) Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA e-mail: [email protected]

­ esenchymal tumors that may be encountered in the uterus. m The salient histopathologic, immunophenotypic, as well as molecular findings that help separate these different tumor types will be discussed.

1.2

Endometrial Stromal Tumors (ESTs)

Currently, the World Health Organization (WHO) recognizes four main categories of endometrial stromal tumors: (1) endometrial stromal nodule, (2) low-grade endometrial stromal sarcoma, (3) high-grade endometrial stromal sarcoma, and (4) undifferentiated uterine sarcoma. High-grade endometrial stromal sarcoma is now recognized as a distinct entity largely due to its unique histology, clinical behavior, and underlying molecular alterations [1, 2]. Additional molecularly defined “high-grade uterine sarcomas” with alterations in the gene BCOR have more recently been described and thus have not been formally adopted into the WHO categorization of endometrial stromal tumors and therefore will be discussed separately.

1.2.1 Endometrial Stromal Nodule 1.2.1.1 Definition Endometrial stromal nodule (ESN) is defined as an endometrial stromal neoplasm with no or minimal myometrial invasion and no vascular invasion. 1.2.1.2 Clinical Features Endometrial stromal nodules (ESN) are benign neoplasms that occur across a very wide age range but are most frequently encountered in women in their fifth to sixth decades [3–6]. 1.2.1.3 Gross Findings ESN may be located at the submucosal layer of the uterine wall, project into the endometrial cavity as an exophytic

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_1

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Fig. 1.1  Endometrial stromal nodule. Endometrial stromal nodules are well circumscribed, and typically soft in consistency and yellow to tan in coloration. This example also shows some cystic change

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Fig. 1.2  Endometrial stromal nodule. This is an example of an endometrial stromal nodule, composed of cells with bland fusiform nuclei, often forming whorls around small arteriole-like vessels. These high-­ power cytologic features are indistinguishable from a low-grade endometrial stromal sarcoma

mass, or occur deep within the myometrium with no apparent connection to the endometrium. On gross examination, they are well circumscribed and may be mistaken for a leiomyoma; however, ESNs are usually softer in consistency and less rubbery without a bulging cut surface. Additionally, ESNs tend to be more yellow in coloration (Fig.  1.1). Hemorrhage and cystic degeneration may be seen. Endometrial stromal nodules can vary in size but are usually > stage I) [68]. 1.2.3.3 Gross Findings HGESS grossly may appear very similar to LGESS, with either an intracavitary or intramural fleshy tan to yellow mass (Fig.  1.12); however, necrosis and/or hemorrhage is more common.

Fig. 1.12  High-grade endometrial stromal sarcoma, gross appearance. High-grade endometrial stromal sarcoma may appear very similar to low-grade stromal sarcoma on macroscopic examination, with a soft, fleshy consistency, yellow to tan color, and “wormlike” infiltration of the myometrium

1.2.3.4 Microscopic Findings and Histologic Grading HGESS have high-grade, but uniform, cytologic atypia and tend to lack the typical morphology of LGESS in that they do not closely resemble nonneoplastic endometrium. In some cases HGESS may be associated with more typical appearing areas of LGESS [69, 70] and, in very rare cases, may be composed of low-grade morphology entirely [68, 71]. HGESS typically has a nodular permeative growth within the myometrium; however, destructive myometrial infiltration may also be seen (Fig.  1.13a). Moreover, the background vascular pattern is different; HGESS has numerous delicate and arborizing vessels as opposed to the spiral arteriolar-like vascular network of LGESS (Fig. 1.13b). In the high-grade areas, the tumor cells are epithelioid with moderate to scant amount of variably eosinophilic cytoplasm and rounded nuclei with conspicuous nucleoli. Mitotic activity is frequently brisk, >10 per 10 HPFs and tumor necrosis is not uncommon. The low-grade components, when present, may have typical LGESS morphology but is also highly enriched for the fibromyxoid variant. 1.2.3.5 Biomarkers HGESS has a distinctly different immunohistochemical profile from that seen in LGESS, typically with a CD10−/cyclin D1+ (>70% of tumor nuclei)/ER−/PR− pattern in the morphologically high-grade areas [70]. In cases with both histologic low- and high-grade components, different patterns of staining may be seen in the morphologically low-grade versus high-grade component, with the low-grade component showing positivity for CD10, ER, and PR and only patchy positivity (usually weak and focal) for cyclin D1 [70]. In

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Fig. 1.13  High-grade endometrial stromal sarcoma, microscopic features. (a) Though permeative fingerlike infiltration is often seen, destructive myometrial invasion (pictured here) may also be identified in high-grade stromal sarcoma. (b) In contrast to low-grade endometrial

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stromal neoplasms, the vasculature in high-grade endometrial stromal sarcoma is characterized by thin-walled, delicate arborizing vessels. Additionally the tumor cells are epithelioid with vesicular nuclei

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Fig. 1.14  High-grade endometrial sarcoma (YWHAE-rearranged) is strongly and diffusely positive for cyclin D1 (a) and BCOR (b)

contrast, the high-grade component is typically negative for CD10, ER, and PR and shows strong and diffuse positivity (>70% tumor cell nuclei) for cyclin D1 (Fig. 1.14a), which may be used as a marker for YWHAE rearrangement [32, 70, 72], although this is not entirely sensitive or specific [73, 74]. Additionally, CD117 (c-kit) and BCOR (Fig. 1.14b) may be positive in HGESS [75, 76].

worth noting that other biologically related genomic alterations have been recently discovered in high-grade uterine sarcomas (see BCOR-altered sarcomas below). Although most HGESS are positive for CD117 (c-kit), they lack hot spot mutations in CKIT [75].

1.2.3.7 Differential Diagnosis Given that HGESS has an epithelioid appearance, it may be 1.2.3.6 Genetic Profile confused with an undifferentiated carcinoma, particularly in HGESS has the characteristic karyotypic abnormality limited sampling such as a biopsy or curettage. One pitfall to t(10;17)(q22;p13) associated with a YWHAE-NUTM2A/B keep in mind is that endometrial undifferentiated carcinoma fusion [67, 68]. YWHAE rearrangements have not been found can also show strong and diffuse positivity for cyclin D1; in other gynecologic tumors, and FISH or RT-PCR studies however, they will usually show focal positivity for EMA, a may serve as a useful adjunct to the histologic diagnosis [72, broad-spectrum cytokeratin. Undifferentiated carcinomas 77]. FISH analysis on FFPE tissue for the YWHAE-­ may also be positive for CD10 [73]. Identification of a well-­ NUTM2A/B rearrangement is becoming more widely avail- differentiated adenocarcinoma component is helpful in able and is feasible to use in routine clinical practice. It is establishing a diagnosis of undifferentiated carcinoma

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(“dedifferentiated carcinoma”) rather than HGESS. In cases lacking a well-differentiated adenocarcinoma component or significant EMA/cytokeratin expression, molecular studies may be necessary (YWHAE FISH). HGESS must also be distinguished from LGESS, which in cases where the dominant morphology is low-grade may be difficult. Adequate sampling and attention to identifying the high-grade areas is key to distinguishing HGESS from LGESS. Features that should raise suspicion for a HGESS include high disease stage at presentation, destructive myometrial invasion, and a large epithelioid cell population arranged in nests or cords among an arborizing delicate vascular network. The correct block must be selected to stain immunohistochemically, as the morphologically low-grade areas in HGESS can stain identically to LGESS. However, molecular studies such as FISH may be performed on any tumor block as even the low-grade areas will harbor the YWHAE translocation. HGESS may also be confused with undifferentiated uterine sarcoma (UUS), particularly in a limited biopsy. UUS can be positive for cyclin D1, but the finding of co-­expression of strong and diffuse CD10 is helpful in excluding HGESS.  Conversely, identification of a low-grade component is helpful to support a diagnosis of HGESS rather than UUS.  In many cases molecular studies will be required to make a definitive diagnosis. A diagnosis of leiomyosarcoma (LMS) may also be considered in the differential of HGESS, particularly when the dominant LMS morphology is epithelioid. In contrast to HGESS which typically has a very uniform morphology and may include areas of low-grade ESS morphology, LMS often has more prominent pleomorphism and lacks the prominent vasculature resulting in the characteristic nested growth pattern of HGESS.  Immunohistochemistry will generally be very helpful in this regard; SMA, desmin, and/ or caldesmon will be positive in LMS while generally negative in HGESS, and conversely cyclin D1 diffuse positivity is seen in HGESS but only focal staining, if any, is present in LMS.

1.2.3.8 Management and Outcomes Patients with HGESS frequently have recurrences, usually within a few years of initial diagnosis [68]. The 5-year survival is ~33%, much worse than that seen in LGESS [62]. Treatment is primarily surgical, with hysterectomy and bilateral salpingo-oophorectomy and tumor debulking. Although experience is limited, both adjuvant chemotherapy and radiation therapy appear to have some benefit in HGESS [62], particularly anthracycline-based chemotherapy [78]. Hormonal therapy is likely ineffective as HGESS is typically negative for estrogen and progesterone receptor.

B. E. Howitt and M. R. Nucci

1.2.4 U  terine Stromal Sarcoma with BCOR Alterations Recently, new genomic subtypes of uterine sarcomas have been described, which appear to be high grade in morphology and clinical behavior and are associated with distinct genetic alterations in the gene BCOR. The first involves the gene fusion ZC3H7B-BCOR (or the reverse fusion BCOR-­ ZC3H7B) and the second, internal tandem duplications (ITD) of BCOR [74, 79–81].

1.2.4.1 Clinical Features Patient with ZC3H7B-BCOR uterine sarcomas have a mean age of presentation of 54 years (range 28–71) [79]. In tumors with BCOR ITD, patients appear to be younger (mean age 24 years) [74]. 1.2.4.2 Gross Findings The gross findings are not well-known for this new group of tumors but appear to be similar to other uterine sarcomas (Fig. 1.15a). 1.2.4.3 Microscopic Findings and Histologic Grading In tumors with ZC3H7B-BCOR fusions, the tumors predominantly involved the endometrium with tonguelike myometrial invasion similar to that seen in LGESS (Fig.  1.15b). Histologically, the tumor cells are spindled with mild to moderate nuclear atypia and set in a prominent myxoid stroma in the majority of cases (Fig. 1.15c). Collagen plaques may also be seen. Mitoses are conspicuous. No cases described to date have associated conventional LGESS morphology [79, 80]. In uterine sarcomas with BCOR ITD, tumors have a similar morphologic appearance to those harboring BCOR gene fusions, with uniform spindle and round cells with abundant mitotic figures, frequently in a myxoid stroma with a prominent vascular network [74]. Lymphovascular invasion is common. 1.2.4.4 Biomarkers All tumors with ZC3H7B-BCOR fusions express CD10 (Fig.  1.16a) while displaying negative or limited reactivity with smooth muscle markers (SMA, desmin, and h-­caldesmon) [79]. ER/PR positivity may be seen in a ­minority of cases, but not diffuse strong positivity. Cyclin D1 is positive in the majority of cases (Fig. 1.16b) [79]. BCOR IHC is positive in half of cases, suggesting that IHC is not a sensitive marker for this tumor [79]. Uterine sarcomas with BCOR ITD have diffuse cyclin D1 and BCOR immunohistochemical expression and only focal or negative CD10 expression and were negative for muscle markers [74].

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Fig. 1.15  BCOR-altered sarcoma. (a) The gross appearance of a BCORfusion sarcoma is similar to other uterine sarcomas with a fleshy, heterogeneous cut surface and foci of hemorrhage and necrosis. (b) These sarcomas

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Fig. 1.16  BCOR-altered sarcoma, immunohistochemistry. (a) CD10 is strongly and diffusely positive in BCOR-fusion sarcomas as pictured here; however, those with internal tandem duplications of BCOR tend to

frequently demonstrate a permeative, fingerlike pattern of myometrial invasion. (c) Histologically, a myxoid stroma is typically prominent in sarcomas with BCOR ITD, with hyperchromatic spindled tumor cells

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be negative or only weakly focally positive for CD10. (b) Cyclin D1 is strongly and diffusely positive in BCOR-altered sarcomas

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1.2.4.5 Differential Diagnosis The primary diagnostic considerations for BCOR-altered uterine sarcomas include undifferentiated uterine sarcoma with uniform morphology, high-grade endometrial stromal sarcoma (YWHAE-altered), and myxoid leiomyosarcoma. The distinction of BCOR-altered sarcomas from HGESS and UUS may be difficult on morphologic and immunohistochemical grounds as there can be significant overlap; however, the high-grade component of BCOR-fusion sarcomas are typically CD10 positive which is in contrast to YWHAE-­ related HGESS.  Myxoid leiomyosarcoma typically has hyperchromatic spindled nuclei and shows positivity for smooth muscle markers. In difficult cases, molecular testing may be needed.

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1.2.5.3 Gross Findings UUS typically presents as a large tan-yellow to gray, fleshy intracavitary polypoid mass or masses. Hemorrhage and necrosis are common.

1.2.5.4 Microscopic Findings and Histologic Grading UUS is a sarcoma composed of cells that, unlike LGESS, do not resemble proliferative-phase endometrial stroma and, in contrast to LGESS, usually shows destructive infiltration of the myometrium. Histologically, there are two subgroups of UUS, the pleomorphic type (Fig.  1.17), in which the neoplastic cells show variable but frequently marked cytologic pleomorphism and numerous mitoses, including atypical forms, without evidence of differentiation toward any tissue 1.2.4.6 Genetic Profile type both cytologically and architecturally by pattern of ZC3H7B-BCOR gene fusions or BCOR ITD identified by growth within the myometrium. [83]. In contrast, UUS with either targeted sequencing or FISH are the hallmark feature uniform morphology is characterized by atypical but fairly of these tumors [74, 79, 80]. Of note, one ESS had previ- monomorphic epithelioid tumor cells which overlap morously been reported to have this genomic alteration, but a phologically with tumors we now classify as HGESS with detailed histopathologic review was not performed in this YWHAE translocations or high-grade uterine sarcomas with case [82]. BCOR alterations as described previously. In practice, the diagnosis of UUS should only be made after extensive sampling of tumor, to exclude a recognizable line of differentia1.2.4.7 Management and Outcomes Limited clinical data suggest that patients with ZC3H7B-­ tion within the tumor, and after HGESS with YWHAE BCOR sarcomas present at higher stage and have worse translocation or BCOR alterations have been excluded, prognosis compared with LGESS and may include lung, which might require molecular studies. bone, and skin metastases and progressive peritoneal disease after chemotherapy [79, 80]. 1.2.5.5 Biomarkers Long-term follow-up in two of three patients with BCOR UUS has no well-defined immunohistochemical marker but ITD revealed one patient to be alive without evidence of dis- often demonstrates positivity for both CD10 and cyclin D1. ease 22 years after diagnosis and the other to be dead of dis- Additionally, UUS (particularly the pleomorphic type) ease 8  years after diagnosis, suggesting that the clinical course of uterine sarcomas with BCOR ITD is more indolent than those with BCOR gene fusion [74].

1.2.5 Undifferentiated Uterine Sarcoma 1.2.5.1 Definition Undifferentiated uterine sarcoma (UUS) is a heterogeneous group of tumors and likely represents dedifferentiated forms of specific uterine sarcomas (adenosarcoma, endometrial stromal sarcoma, carcinosarcoma, leiomyosarcoma, etc.). Some consider this entity as “undifferentiated endometrial sarcoma”; however, we prefer the term UUS, as some of these tumors are likely not of endometrial stromal derivation. 1.2.5.2 Clinical Features UUS are rare tumors encountered in postmenopausal women who present with postmenopausal bleeding, symptoms related to the uterine mass, or symptoms related to metastatic disease.

Fig. 1.17  Undifferentiated uterine sarcoma, pleomorphic type. These tumors demonstrate marked pleomorphism and abundant mitoses including abnormal forms and have no specific line of differentiation by either morphology or immunohistochemistry

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f­ requently have abnormal overexpression of p53 in contrast to HGESS [84].

1.2.5.6 Differential Diagnosis The diagnosis of UUS is essentially a diagnosis of exclusion and should only be considered after excluding an undifferentiated carcinoma, carcinosarcoma, leiomyosarcoma, and high-grade endometrial sarcoma; all of which may have areas of morphologic overlap. A diagnosis of UUS should only be made on a complete excision specimen, as biopsies may lack the diagnostic features of other uterine sarcomas/ carcinomas. Extensive tumor sampling, immunohistochemical staining, and in some cases molecular testing are required to confidently diagnose UUS. UUS can be distinguished from undifferentiated carcinoma and carcinosarcoma by identifying areas diagnostic of an epithelial component, either morphologically or immunohistochemically (EMA and/or cytokeratin positivity). Similarly, leiomyosarcoma (LMS) may demonstrate a variety of patterns and identifying a better differentiated area of the tumor is key  – LMS should contain, at least focally, strong positivity for one or more smooth muscle markers (SMA, desmin, caldesmon). The distinction of UUS from HGESS was discussed previously in the HGESS section. In all of these cases, adequate sampling and careful evaluation of all tumor morphologies is necessary in making a diagnosis of UUS.  As molecular studies are more widely available, these should be considered to exclude known translocation-­ associated entities including YWHAE, JAZF1, and BCOR FISH as well as examining for BCOR internal tandem duplications. 1.2.5.7 Genetic Profile UUS tend to be cytogenetically complex, particularly when histologically pleomorphic [85]. As mentioned above, previously termed “UUS with uniform morphology” likely represent various forms of HGESS and rarely may harbor JAZF1 translocation [83]. TP53 mutations are not uncommon in UUS, in contrast to endometrial stromal neoplasms [83], suggesting that those UUS with TP53 mutation may have no relationship with ESS or that they have acquired a secondary TP53 mutation. One study interrogated for KIT, EGFR, and PDGFR hot spot mutations as well as amplification of EGFR in UUS; none of the tumors included in their study had any molecular aberration in these genes [86]. In an array CGH study on endometrial sarcomas, a large number of copy number alterations in UUS are described, including gain of 7p in a subset [85]. 1.2.5.8 Management and Outcomes UUS is an aggressive tumor with a dismal prognosis. The mean overall survival is less than 2 years [87]. In one study, one third of patients did survive >5 years, suggesting there

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are subgroups of UUS with varying prognoses [88]. Treatment options include complete debulking surgery as well as consideration of radiation therapy for local control and chemotherapy for systemic control.

1.2.6 Diagnostic Considerations from Curettage Specimens A suspected endometrial stromal neoplasm identified in a curettage or biopsy specimen must be distinguished from potential mimics, including nonneoplastic aglandular functionalis, endometrial basalis, as well as benign neoplasms such as endometrial polyp and malignant neoplasms most notably adenosarcoma. Multiple fragments of aglandular cellular endometrial-type stroma containing spiral arteriolelike vessels are suggestive of a stromal neoplasm (Fig. 1.18); in one study, curettage of a stromal neoplasm typically produces fragments of aglandular stroma measuring ≥5  mm [89]. Distinction of endometrial stromal neoplasms from fragments of basalis is made by virtue of the presence of an orderly component of glands in the latter. Strips of aglandular functionalis, usually associated with submucosal leiomyomata (Fig. 1.19) or occasionally progestin therapy, tend to be less cellular and show features of compression or reactive surface changes when related to submucosal leiomyoma. Fragments of cellular endometrial polyps usually exhibit other features of polyp, including large thick-walled vessels and abnormal glandular architecture. Adenosarcoma also may exhibit a cellular stroma that is CD10 positive but typically has an epithelial component with glandular cuffing, albeit sometimes subtle. Appreciation of a more spindled atypical stroma without the characteristic vascular network facilitates this distinction.

Fig. 1.18  Recognizing endometrial stromal neoplasia in an endometrial curettage. Multiple large fragments or thick strips of pure endometrial stromal tissue without any glands is concerning for an endometrial stromal neoplasm. The finding of sex cord elements, as demonstrated here, is additionally supportive of a neoplasm

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while type 2 represents what we currently consider to be “UTROSCT” [61].

1.2.7.2 Clinical Features UTROSCT occurs across a wide age range in reproductiveand postmenopausal-aged women, with a mean age of 52 years at diagnosis [93]. Patients most often present with abnormal uterine or postmenopausal bleeding [92, 93]. 1.2.7.3 Gross Findings Upon gross examination, UTROSCT is generally a well-­ circumscribed, firm to fleshy, tan, yellow, or gray mass that may be found anywhere within the endomyometrium and rarely in the cervix. Tumor size is generally small (mean ~6 cm) but may be >20 cm [61, 91–93]. Areas of hemorrhage may be appreciated but necrosis is typically absent. Fig. 1.19  Aglandular functionalis may raise concern for an endometrial stromal neoplasm; however, the strips are usually thin and lined by endometrial surface epithelium and may show reactive surface changes

If an endometrial stromal neoplasm is suspected upon histologic evaluation, the next step in interpretation is to determine whether it is benign or malignant. Unfortunately, this distinction is based on whether or not there is myometrial infiltration or lymphovascular invasion, two criteria that generally cannot be assessed on biopsy or curettage material. Performing immunohistochemistry can aid in confirming endometrial stromal differentiation, and if a JAZF1 translocation is identified, the proliferation can be classified as an endometrial stromal neoplasm, but these ancillary studies cannot aid in determining benign versus malignant. One could raise the possibility of sarcoma if some fragments of tissue contain myometrium infiltrated by stromal tumor or definite lymphovascular invasion is identified; however, as this is highly uncommon to see in a biopsy specimen, prudent clinical and radiologic correlation is critical. In general, diagnosis of an endometrial stromal neoplasm with a comment explaining the inability to reliably distinguish between a stromal nodule and LGESS in a biopsy or curettage specimen is appropriate.

1.2.7 U  terine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) 1.2.7.1 Definition UTROSCT is a rare tumor in the uterus that morphologically resembles various forms of sex cord-stromal differentiation typically seen in the ovary [61, 90–92], including Sertoli cell, granulosa cell, and Leydig cell differentiation. In the original description, “UTROSCT” included type 1 and type 2; however, it is now generally accepted that type 1 refers to endometrial stromal tumors with sex cord-like elements,

1.2.7.4 Microscopic Findings Though typically recognized as a well-circumscribed mass grossly, UTROSCT may demonstrate infiltration of the myometrium upon histologic examination. Morphologically, it is purely or predominantly composed of epithelial-like cells arranged in one or more architectural patterns consistent with ovarian sex cord-stromal tumors, most commonly granulosa cell tumor (adult type) or Sertoli cell tumors, including the retiform pattern (Fig. 1.20a). Leydig cells are generally not encountered in UTROSCT. The variety of architectural patterns includes solid, nested, trabeculae, cords, glandular, and retiform though nests, trabeculae, and cords are the most common growth patterns. Cytologically, atypia is minimal and mitoses are generally low (20 cm) and solitary or numerous. The usual leiomyoma is grossly well circumscribed and has a firm, rubbery texture (Fig. 1.22). Leiomyoma typically bulges out upon sectioning because of increased intratumoral pressure. The cut surfaces are white or slightly pink and the bands of neoplastic smooth muscle are often whorled, giving the impression that the smooth muscle bundles are wrapped around a central core. Lastly, there should be minimal variation in the appearance of the cut surface. Minute foci of hemorrhage may be seen,

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varying degrees, particularly in the luteal phase of reproductive women [112, 113]. Atypical mitotic figures, however, are worrisome and should prompt further examination and exclusion of malignancy. Within leiomyoma, one may see varying numbers of mast cells and occasionally even prominent infiltrates of other chronic inflammatory cells [114, 115]. Occasionally, dense lymphocytic infiltrates rarely may simulate lymphoma [116, 117]. There is a wide variation in the amount of collagenous extracellular matrix within leiomyoma. Similar to their gross appearance, usual leiomyoma is well circumscribed microscopically.

Fig. 1.22  Gross appearance of typical uterine leiomyoma. Leiomyomas are characterized by being well-circumscribed, white to tan with a bulging rubbery cut surface

Fig. 1.23  Histologic features of leiomyoma (typical). Leiomyomas contain fascicular bundles of spindle cells with abundant pink cytoplasm and blunt-ended nuclei which have a relatively uniform shape and size

1.3.1.5 Secondary and Iatrogenic Changes in Leiomyoma Degenerative changes in leiomyomata, including myxoid/ gelatinous change, hyalinization, and calcification, are common but usually easily appreciated as such. When hemorrhage or necrosis is present as a form of degenerative change (Fig.  1.24), it tends to have a grossly uniform appearance, resulting in an even pink or red cut surface. Histologically, the interface between the viable and nonviable tissue has a uniform arc with a transition zone composed of fibroblasts, viable and nonviable smooth muscle cells, and scattered inflammatory cells typical of ischemic infarction, in contrast to the abrupt, sharply defined necrosis seen in tumor cell (coagulative) necrosis. From time to time, thrombosis may be seen in tumor vessels, suggesting that ischemia is the principal cause of benign degeneration. Other clinical situations in which rapid degeneration may be noted include pregnancy and other iatrogenic hormonal stimuli (i.e., oral contraceptives or clomiphene), as well as torsion of a pedunculated subserosal or submucosal tumor. Over time, hyalinization, mummification, or even dystrophic calcification may become prominent.

but large hemorrhagic areas are not characteristic. Similarly, necrosis is not identified grossly, although areas of myxoid degeneration may be appreciated as having a more gelatinous appearance. Any significant variation or deviation from this appearance should warrant additional sampling and consideration by the pathologist.

1.3.1.4 Microscopic Findings Histologic examination of a typical leiomyoma shows fascicles of bland spindled smooth muscle cells, which are virtually indistinguishable from their normal counterparts. Specifically, the cells are long and tapered, have abundant pink cytoplasm, and contain spindle-shaped nuclei with blunt ends which have a relatively uniform shape and size (Fig. 1.23). The chromatin is pale, finely textured, and uniformly dispersed. Nucleoli may be noted but if present are small and inconspicuous. Mitotic figures may be present to

Fig. 1.24  Leiomyoma with degeneration and hemorrhage. Hemorrhage and myxoid degeneration may be seen in leiomyoma and may be related to an iatrogenic process

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Fig. 1.25  Histologic features of leiomyoma with hydropic change. (a) Prominent edema is present in hydropic leiomyoma, which may mimic myxoid stroma, and make the recognition of a smooth muscle neoplasm

more difficult. (b) From low-power magnification, alternating hyperand hypocellular regions may be apparent

Hydropic foci may be microscopic and patchy (Fig. 1.25a). Microscopic foci of hydropic degeneration may be worrisome at lower magnifications because they often have more irregular contours and may have sharp borders (Fig. 1.25b). Careful attention at higher magnification often resolves this by noting the fluid-filled intercellular spaces and the absence of truly necrotic cells. When more extensive, the wet, slippery cut surface of hydropic degeneration may often be described as “myxoid.” Such tumors should be histologically examined to exclude a myxoid leiomyosarcoma by recognizing their edematous nature and lack of other malignant features. In contrast to myxoid leiomyosarcoma, hydropic leiomyomata do not infiltrate into the fascicles of adjacent myometrium. In addition to the naturally occurring patterns of degeneration, we now frequently encounter iatrogenic necrosis and other changes related to attempted conservative (nonsurgical) management of uterine fibroids. A number of new therapeutic strategies to noninvasively ablate uterine leiomyomata have been devised. The most widespread of these new procedures is uterine artery embolization [118]. In this technique, a catheter is threaded into the uterine artery and spheres of synthetic polymer are injected. Because the blood supply to leiomyomata is larger than to the surrounding myometrium, the tumors tend to be more vulnerable to ischemia. Of note, embolization material can frequently be seen distending and occluding vessels within and near the tumor. Another noninvasive therapy for uterine leiomyomata is MRI-guided thermal ablation by focused application of ultrasound energy. Of interest to pathologists, the gross appearance of a leiomyoma early after this type of treatment has some features grossly concerning for malignancy. Specifically, the borders of sonicated and nonsonicated tissues may be geographic and well-­ defined, and sonicated tissues may be variegated in color and show extensive hemorrhage. In distinction to geographic tumor necrosis, thermal effect resulting from focused ultra-

sound energy transfer results in microscopically bland coagulative necrosis lacking atypical ghost cells.

1.3.1.6 Genetic Features of Leiomyoma Leiomyoma is characterized by recurrent point mutations and small deletions as well as characteristic chromosomal translocations. The karyotype of leiomyoma is either normal (60%) or noncomplex with one or more chromosomal translocations (40%) [119–124]. The gene most commonly mutated in leiomyoma is MED12, with heterozygous MED12 mutations found in up to 70–80% of uterine leiomyomas [125–130]. The vast majority of these are located in exon 2 at the codon 44 position. There is no evidence to date that germline MED12 mutations play a role in the development of leiomyoma. HMGA1 or HMGA2 overexpression is common in leiomyoma, reflecting chromosomal translocations involving 6p21 (HMGA1) and 12q14 (HMGA2). HMGA2 overexpression is found in 10–25% of uterine leiomyomas and tends to be mutually exclusive with MED12 mutations [127]. When considering uterine leiomyomas lacking MED12 mutation, HMGA2 overexpression is found in ~40% of tumors. Other recurrent molecular aberrations in leiomyoma include COL4A5/6 deletions, which are mutually exclusive with MED12, HMGA2, and FH alterations [131]. Leiomyomas lack TP53 mutations [128, 131]. Recurrent chromosomal aberrations in leiomyoma include (in addition to HMGA2/HMGA1 as described above) 13q, 1p36, 10q22, 7q deletion, trisomy 12, 1p deletion, and monosomy 22 [122, 132–137]. Interestingly, 7q deletions have been identified in both MED12-mutated and HMGA2-­ altered leiomyoma, suggesting that loss of 7q may be important for progression rather than initiation of tumorigenesis. 1.3.1.7 Clinical Management and Outcome Leiomyomata are the most common indication for hysterectomy [108, 138]. However, leiomyomata may be managed

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expectantly if associated with no or minimal symptoms. Myomectomy (resection with uterine conservation) is the most widely employed hysterectomy alternative for women who wish to preserve fertility [139]. Tumor size and location play an important role in determining which technique is most appropriate. When compared with hysterectomy, the alternatives are associated with several unique risks, namely, the risks of tumor “recurrence” and uterine rupture during pregnancy following myomectomy [108]. The risk of symptomatic recurrence is more likely due to the growth of a second crop of leiomyomata and requires a second operation in a subset of cases [108]. Morcellation with powered devices may result in peritoneal dissemination of benign and malignant smooth muscle tumors [140, 141]. In fact, studies have shown that the rate of unexpected sarcoma after a laparoscopic morcellation procedure may be far higher than once thought and that dissemination of leiomyosarcoma by morcellation occurs in nearly two thirds of cases, some resulting in mortality [141]. Uterine artery embolization as described previously results in symptomatic improvement for most patients, but this technique has been associated with adverse outcomes ranging from postprocedure fevers to amenorrhea, uterine rupture, endomyometritis, and fatal sepsis [142–144]. Uterine artery embolization also has been implicated as a factor delaying the diagnosis of uterine sarcomas [145]. Medical therapy, in the form of androgenic steroids, gonadotropin-­releasing hormone (GnRH) agonists, or selective estrogen receptor modulators, may also be attempted in the clinical management of symptomatic fibroids, with variable success rates [146, 147].

1.3.2 Variants of Leiomyoma According to the 2014 WHO classification, there are a number of distinct morphologic variants of leiomyoma, including cellular leiomyoma, leiomyoma with bizarre nuclei, mitotically active leiomyoma, hydropic leiomyoma, apoplectic leiomyoma, epithelioid leiomyoma, myxoid leiomyoma, and dissecting (cotyledonoid) leiomyoma, some with specific genetic alterations. Additionally, there are leiomyomas with other cellular elements such as lipoleiomyoma and angioleiomyoma (or “vascular leiomyoma”). Each of these will be discussed below with relevant clinicopathologic and genetic information included with each variant.

1.3.2.1 Mitotically Active Leiomyoma Both nonneoplastic myometrium and leiomyoma demonstrate variation in mitotic rate depending on the phase of menstrual cycle [113]. Some investigators have noted that exogenous progesterone increases the mitotic rate in leiomyomata [148]. Occasionally, leiomyomas may be histologically unremarkable but demonstrate mitotic activity up to 15

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mitoses per 10 high-power fields; such tumors are classified as “leiomyomata with increased mitotic activity” [2, 149– 152]. This diagnostic term is useful in denoting the special nature of these tumors, as well as communicating the absence of other worrisome features. Ki-67 is a proliferation marker that may be helpful in the diagnosis of leiomyoma with increased mitotic activity. One way in which Ki-67 immunohistochemistry might be useful is in excluding pyknotic nuclei as a mimic of mitoses. It should be noted that proliferative “hot spots” may be seen beneath eroded and attenuated mucosal surfaces of submucosal leiomyoma or adjacent to ischemic changes. Mitotically active leiomyoma is not known to have any clinical significance with regard to recurrence or progression to malignancy. Similarly, there are no known molecular or cytogenetic alterations specific to mitotically active leiomyoma. Atypical mitotic figures reflect genomic instability and as such should be considered a worrisome finding. Detection of atypical mitoses in a smooth muscle tumor that would otherwise be classified as a leiomyoma with increased mitotic activity should raise suspicion for a more ominous diagnosis as these are rarely if ever encountered in benign leiomyomata. Mitotically active leiomyomas appear to have similar molecular features as conventional leiomyoma, with frequent MED12 mutations, but infrequent abnormal expression of HMGA2 or FH [128, 153].

1.3.2.2 Cellular Leiomyoma Leiomyomata are often more cellular than their surrounding myometrium. The term cellular leiomyoma is reserved for notably cellular tumors. Although hypercellularity is necessary to classify a tumor as this benign variant, it is quite ­subjective and difficult to quantitate just how cellular a tumor must be to make a diagnosis of cellular leiomyoma. On inspection of tissue sections without the microscope, the heavy hematoxylin staining of a cellular leiomyoma often will stand out, reflecting the increased number of nuclei as well as the relative lack of extracellular matrix deposition. One practical approach is to classify only those tumors with an extreme or eye-catching degree of cellularity as cellular leiomyoma. Another approach is to reserve the term “cellular leiomyoma” for cases in which an endometrial stromal neoplasm was at least considered in the microscopic differential diagnosis. Few studies have examined the molecular alterations specifically in cellular leiomyoma. From the published data available for review, they lack TP53 mutations [128], only 6% have PTEN deletions, and only 9–14% have MED12 mutations [128, 154], suggesting the pathogenesis of cellular leiomyoma may differ from conventional leiomyoma. 1p deletion was present in 23% of cellular leiomyomas in one study [155] and a subset have been reported to have 10q22 rearrangements, which have also been described in conventional leiomyoma [156].

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1.3.2.3 Highly Cellular Leiomyoma Highly cellular leiomyoma is a markedly cellular variant of leiomyoma that frequently has an irregular border, which in combination with its marked cellularity may mimic a low-­ grade endometrial stromal sarcoma. Highly cellular leiomyoma can be recognized based on its characteristic histologic features which include the presence of fascicular areas at least focally, large thick-walled blood vessels within the tumor, and cleft-like spaces [8]. In problematic cases, immunohistochemistry may be useful. Highly cellular leiomyomata are often positive with markers of smooth muscle differentiation (SMA, desmin, and caldesmon), though notably some cases show decreased staining with caldesmon. It is important to note that highly cellular leiomyoma may be diffusely positive for CD10; therefore, this marker alone is often not useful in distinction from endometrial stromal tumors [20]. 1.3.2.4 Epithelioid Leiomyoma One of the most frequent alternative patterns of differentiation has an epithelioid appearance, which is also referred to as being “plexiform.” However, epithelioid and plexiform leiomyomas likely represent distinct leiomyoma variants as molecular studies have shown that the gene expression profiles of plexiform leiomyomas are distinct from leiomyomata with “true” epithelioid morphology [157]. In plexiform leiomyoma, there is abundant extracellular matrix that results in small ribbons or islands of rounded smooth muscle cells (Fig.  1.26a, b), giving it a pseudo-epithelioid appearance, which is not an uncommon finding in otherwise conventional leiomyoma. They may sometimes have an infiltrative pattern and consequently mimic endometrial stromal sarcoma [158, 159]. In contrast, “true” epithelioid leiomyomas are uncommon and composed of rounded cells with abundant eosinophilic cytoplasm. The clinical features of women with epithelioid leiomyomata are similar to those with leiomyomata showing conventional spindle cell morphology. Specifically, these tumors present in the latter reproductive years but can occur at any age beginning in the third decade [160]. Epithelioid leiomyomata may have an unusual macroscopic appearance, including a yellow to tan color and softer consistency, which is not specific but should prompt additional sampling. The prognosis of epithelioid leiomyoma is somewhat uncertain. This unpredictability has led some to regard all epithelioid smooth muscle neoplasms as tumors of uncertain malignant potential [161]. In one of the largest series (n = 18) studied to date, Prayson et  al. retrospectively correlated pathologic features with clinical outcome [160]. Similar to non-epithelioid smooth muscle tumors, no one histologic feature was predictive of metastatic potential. In general, benign epithelioid smooth muscle tumors were smaller (100) of leiomyomata which are confined to the uterus [173]. Typically, on gross examination, there are innumerable masses which enlarge and distort the uterus and often appear confluent on cut section. Microscopically, the tumors tend to be more cellular than conventional leiomyoma and show indistinct borders with merging of the adjacent tumor masses. Nuclear atypia, necrosis, and vascular involvement are absent. This is a clinically benign entity of uncertain etiology although molecular studies have shown the tumorous masses to be polyclonal suggesting that patients with this disease are prone to leiomyoma development [174].

1.3.2.7 Leiomyoma with Other Cellular Components: Lipoleiomyoma Lipoleiomyoma is a leiomyoma variant in which adipocytic differentiation is present [167]. The number of adipocytes varies, although usually it is a minor component, and the amount correlates with the gross appearance. As the fat content increases, the tumor can have a yellow cut surface. In dramatic examples in which the fat content predominates, the tumor can grossly mimic a lipoma. Although some have speculated that adipocytic differentiation is degenerative,

1.3.2.10 Intravenous Leiomyomatosis Intravenous leiomyomatosis (IVL) is a condition in which a smooth muscle tumor is morphologically indistinguishable from conventional leiomyoma yet invades vascular spaces and in dramatic cases may track along the vena cava and extend into the right heart [52–54, 175, 176]. It affects primarily women in their late reproductive ages but has been reported as early as 21  years of age [177]. The presenting symptoms often depend on the extent of growth. If IVL is associated with a large leiomyoma of the uterus, pelvic pain

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or bleeding typically predominates. If extension into the vena cava is significant, symptoms such as syncope and dyspnea may be prominent. Upon gross examination, wormlike tumor projections may be seen in the parametria of hysterectomy specimens (Fig. 1.27a). This pattern of intravascular growth also may be seen in endometrial stromal sarcoma as well as uterine leiomyosarcoma [55]; however, the appearance of IVL is otherwise identical to that of typical leiomyoma, with a firm, white to tan rubbery cut surface. Similarly, the microscopic appearance in most cases of IVL is that of a typical uterine leiomyoma but uncommonly may exhibit the same spectrum of benign variant morphologies as seen in leiomyoma [52] (Fig. 1.27b). Atypical histology and adhesion to the vessel wall may be associated with a more aggressive clinical course [178]. Intravenous extension might be considered an

a

b

Fig. 1.27  Intravenous leiomyomatosis (IVL). (a) The gross appearance of IVL may mimic an endometrial stromal sarcoma, with extensive “wormlike” tumor projections within the myometrium and parametrium. (b) IVL are usually histologically indistinguishable from leiomyoma and often demonstrate plexiform-like morphology. Intravascular foci may be seen adjacent to a larger leiomyoma, as shown here

B. E. Howitt and M. R. Nucci

aggressive biologic property. Despite this malignant characteristic, the intravascular growth is usually indolent. In most cases, surgical intervention is sufficient treatment. Gonadotropin-releasing hormone agonist (e.g., leuprolide) may be used as short-term therapy. Molecularly, IVL appears to have similar cytogenetic alterations commonly seen in conventional leiomyoma such as t(12;14). Regional losses on chromosomes 22q and 1p and gains on chromosomes 12q were the most common alterations in one study [179]. MED12 mutations have not been documented in IVL [179]. Karyotypes of two cases of IVL have shown the presence of a derivative chromosome, der(14)t(12;14)(q15;q24), which is also frequently found in typical uterine leiomyomata [180]. Presumably, the ability of IVL to grow within venous spaces reflects some additional unknown genetic alterations.

1.3.2.11 Benign Metastasizing Leiomyoma Benign metastasizing leiomyoma (BML) is a somewhat controversial entity characterized by bland-appearing smooth muscle tumors in the lung or lymph nodes and is thought to represent “metastasis” from a histologically unremarkable uterine leiomyoma, a theory that has molecular support of common origin [181–183]. The typical clinical scenario is the presentation of one or several small masses in the lung or abdominopelvic lymph nodes in women with a history of hysterectomy in which one or more typical leiomyomata were present in the hysterectomy specimen. The histologic appearance of the extrauterine tumors consists of bland smooth muscle cells, indistinguishable from that seen in conventional benign leiomyoma. As its name suggests, the clinical course is benign. BML are characterized by 19q and 22q terminal deletions as well as loss of 3q and 11q in one study [181, 184], which are alterations not commonly found in typical leiomyomata, suggesting that benign metastasizing and typical uterine leiomyomata do not share a common origin. While BML is thought to be unrelated to conventional benign leiomyoma, some have proposed a relationship between BML and IVL based on histopathologic and molecular genetic studies [185, 186]. 1.3.2.12 Disseminated Peritoneal Leiomyomatosis Disseminated peritoneal leiomyomatosis (DPL) is a disorder in which smooth muscle tumorlets are scattered across peritoneal and omental surfaces [187–189]. It is rare and occurs generally in women of reproductive age but occasionally in postmenopausal women. The tumorlets can range from microscopic to 25 mm in size and number from less than five to several hundred. The striking peritoneal involvement may initially clinically mimic an aggressive ovarian neoplasm; however, the correct diagnosis is made by recognizing that each tumorlet is a small leiomyoma. The cut surfaces of the larger lesions have the white to tan, bulging whorled

1  Uterine Mesenchymal Lesions

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a­ppearance of typical uterine leiomyoma. Similarly, the microscopic appearances of the tumorlets also are identical to typical uterine leiomyomata. Occasionally, they may be associated with foci of endometriosis imparting an adenomyoma-­like appearance. DPL generally has a benign clinical course. The leiomyomatous nodules may even persist or recur over many years [187]. Clonality analysis of these tumorlets, however, demonstrates that each nodule is clonal [187]. Moreover, these studies found that all the tumorlets have an identical pattern of X chromosome inactivation, strongly suggesting that all the nodules arose from a common clonal origin via a single transformation event. Thus, these disseminated tumor nodules are truly “metastatic.” In some cases, the mechanism of dissemination appears to be iatrogenic, as this disorder has been reported to follow morcellation procedures, and it is unclear if the biology of iatrogenic BML is different from that of non-­ iatrogenic BML [141, 190, 191]. Regardless, the molecular Fig. 1.28  Leiomyosarcoma, gross appearance. Leiomyosarcoma is mechanisms that permit intraperitoneal dissemination and/or typically a large, heterogeneous appearing mass with irregular borders. Abundant necrosis and hemorrhage is evident in this example growth of otherwise benign-appearing smooth muscle tumors on peritoneal surfaces have yet to be elucidated.

1.3.3 Leiomyosarcoma 1.3.3.1 Definition (Conventional Leiomyosarcoma) Malignant tumors of smooth muscle origin with predominantly spindle cell, fascicular growth patterns are considered to represent typical or conventional leiomyosarcoma. 1.3.3.2 Clinical Features Leiomyosarcoma (LMS) is the most common malignant uterine mesenchymal tumor, comprising over one half of malignant uterine mesenchymal tumors and 1–2% of all uterine malignancies, and generally occurs in late reproductive-­aged or postmenopausal women [14]. The typical clinical presentation is abnormal uterine bleeding/postmenopausal bleeding followed by palpation of a mass or pelvic pain [192]. In some cases, leiomyosarcoma develops after pelvic radiation. Although LMS are generally considered to arise de novo, there is limited molecular evidence for LMS arising from a pre-existing leiomyoma in a minority of cases [193, 194]. Approximately one third of women with LMS present with extrauterine disease [192]. 1.3.3.3 Gross Findings LMS is generally encountered as a large, often solitary myometrial mass (mean diameter 10 cm) [2]. In contrast to leiomyoma, the cut surface of LMS is gray, yellow, or tan and soft, frequently with visibly necrotic and/or hemorrhagic foci, and demonstrates irregular infiltration of the surrounding myometrium (Fig. 1.28).

Fig. 1.29  Conventional leiomyosarcoma, microscopic appearance. Histologically, leiomyosarcoma is composed of fascicles of spindled cells with abundant eosinophilic cytoplasm and moderate to severe nuclear atypia. In this case there are conspicuous mitotic figures

1.3.3.4 Microscopic Findings Conventional leiomyosarcomas are characterized histologically by hypercellular bundles of hyperchromatic atypical spindled tumor cells growing in fascicles, with appreciable eosinophilic cytoplasm (Fig.  1.29). The interface of LMS with the surrounding myometrium is frequently destructively infiltrative (Fig. 1.30) although some tumors appear grossly and microscopically well-circumscribed. The tumor nuclei, similar to benign smooth muscle cells, are often described as “cigar-shaped” due to the blunted or rounded ends of the nucleus. A minor component of variant morphology such as epithelioid cells may be present. The degree of nuclear atypia may vary throughout the tumor though most cases

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Fig. 1.30  Conventional leiomyosarcoma, microscopic appearance. Leiomyosarcoma typically shows destructive infiltrative invasion into surrounding nonneoplastic myometrium

B. E. Howitt and M. R. Nucci

Fig. 1.32  Leiomyosarcoma, tumor cell necrosis. Tumor cell necrosis has a very sharp border between viable and nonviable tumor tissue, without areas of fibrosis, hyalinization, or significant inflammation

that do not meet these diagnostic thresholds may be categorized as smooth muscle tumors of uncertain malignant potential or atypical leiomyoma (see pertinent sections below). Histologic grading of leiomyosarcoma is somewhat controversial and is not currently accepted as a prognostic indicator in uterine LMS [196]. However, there may be value in assigning a “morphologic” grade, particularly for review of and correlation with future tumor recurrences or metastasis.

Fig. 1.31  Conventional leiomyosarcoma, microscopic appearance. Leiomyosarcoma often has at least focally marked pleomorphism and multinucleated tumor giant cells

d­emonstrate diffuse cytologic atypia that is moderate to severe. Multinucleated tumor cells are present in over half of cases (Fig. 1.31). Tumor cell necrosis is defined as an abrupt transition between viable tumor and necrotic areas, without an intervening area of hyalinization/inflammation or other ischemia-­ related histopathology (Fig.  1.32). Tumor cell necrosis and abundant mitotic activity is usually, but not always, present. If tumor cell necrosis is present in a smooth muscle neoplasm with at least diffusely moderate nuclear atypia, then the mitotic index is not critical for the diagnosis of leiomyosarcoma. If, however, tumor cell necrosis is absent, then both significant diffuse moderate to severe nuclear atypia as well as mitoses numbering at least 10 per 10 HPFs is required for the diagnosis of LMS [195]. Tumors

1.3.3.5 Biomarkers Immunohistochemically, LMS are usually positive for smooth muscle markers including smooth muscle actin (SMA), desmin, and caldesmon; however, it is not unusual to lose expression for one or more of these, particularly in morphologically high-grade or poorly differentiated tumors. Of note, LMS may demonstrate keratin and/or EMA positivity [20, 197, 198]. Once the line of smooth muscle differentiation is established, additional stains have been proposed to aid in classification of the smooth muscle tumor, including p16, p53, ER, PR, ki67, stathmin, fascin, and IMP-3. p16 and p53 are overexpressed in most LMS, and proliferation as indicated by ki67 index is also significantly higher in LMS [199–205]. Complete absence of p16 staining may also be seen in LMS [206]. Stathmin is not a specific marker for LMS, but the presence of only weak stathmin staining in a smooth muscle tumor should prompt special consideration for a benign variant as all LMS were diffusely strongly positive for stathmin in one study [207]. Fascin and IMP-3 are two additional markers showing increased expression in LMS and STUMP compared to leiomyoma [208, 209]. Approximately one third of LMS express ER/PR, which may have prognostic and/or therapeutic implications (see “Management and Outcomes” section below).

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1.3.3.6 Genetic Profile LMS have markedly complex karyotypes, which makes it difficult to identify alterations specific to LMS. Some of the recurring chromosomal arm-level alterations described in LMS include gains of 1q, 17p, and Xp, and loss of heterozygosity for 10q (including in the PTEN gene locus) and 13q (containing the gene RB1) is present in >50% of LMS [134, 210–213]. TP53 mutations are common in LMS, reported in up to 65% of cases [128, 212, 214–217]. MED12 mutations are found in ~10% of LMS [127, 128, 218] although reports range from 2 to 20% [129, 130, 218–222]; however, most of the MED12 mutations present in LMS are not the typical hot spot mutations seen in leiomyoma and rather represent complex or truncating mutations [128]. HMGA2 overexpression is seen in ~35% of LMS and appears to be mutually exclusive with MED12 mutation [127], similar to leiomyoma. HMGA1 rearrangements have been described in only two LMS [223]. α-Thalassemia/mental retardation syndrome X-linked (ATRX) and death domain-associated (DAXX) are two genes frequently mutated in LMS and are associated with the alterative lengthening of telomere (ALT) phenotype contributing to the pathogenesis of uterine leiomyosarcoma in up to 78% of cases [213, 215, 217, 219, 224, 225]. More recent molecular studies on LMS have identified additional genes that are upregulated or downregulated with correlation with clinical outcome and response to therapeutic treatment. Briefly, one study analyzed three independent cohorts of sequenced LMS data to identify key genes upregulated in LMS including CCNE1, MMP9, APOE, and SDC1 [226]. Another study also found upregulation of CCNE1 frequently in LMS and, in addition to finding frequent PTEN deletions, also described a possible novel tumor suppressor gene, VIPR2, which is a negative regulator of smooth muscle proliferation, as the most frequent gene altered in LMS in their study [212]. Deletion of VIPR2 was also associated with poorer clinical outcome. Another study divided LMS into two molecular subgroups based on differing gene expression profiles and found that one type had an expression profile more closely resembling nonneoplastic smooth muscle and the other type had upregulation of genes known to be involved in common tumorigenesis pathways [227]. This group also showed that response to chemotherapy differed between the two molecular subtypes; however, the histologic features were also likely different between these two groups as the type I tumors were characterized as “low-grade,” while the type II tumors were high grade with invasive and anaplastic morphology. Thus it is unclear if the molecular features are superior to histologic features in determining prognosis and chemotherapeutic response in LMS. 1.3.3.7 Differential Diagnosis One of the most challenging diagnostic considerations is the distinction of LMS from other uterine smooth muscle tumors

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including STUMP and atypical leiomyoma (“leiomyoma with bizarre nuclei”). This is based on mitotic counts, assessment of nuclear atypia, and presence of coagulative tumor cell necrosis. There are significant interobserver differences in the interpretation of tumor cell necrosis [228] as well as subjectivity in determining what constitutes “at least moderate” cytologic atypia. Additionally, assessment of mitotic index may be difficult as pyknotic and apoptotic nuclei may mimic mitoses but should not be included in the mitotic count. Moreover, mitotic rates may vary throughout the tumor; thus examination of mitotic index on multiple different sections of tumor is required. Immunohistochemistry has proven to be variably useful in this distinction, with panels including p16, p53, ER, PR, and ki-67/mib-1 [201, 205, 229]. However, no immunohistochemical stain or panel of stains is definitive for distinction of LMS from other smooth muscle tumors, and these should only be considered in the context of tumor morphology. PEComa may also be considered in the differential diagnosis with LMS; however, this is more commonly encountered in the epithelioid variant of LMS.  Given that conventional LMS can have epithelioid areas and PEComa may have a significant spindled component, there may be morphologic overlap. Immunohistochemistry is helpful in this distinction; while PEComa may be positive for both SMA and desmin, it is generally negative for caldesmon. Conversely, LMS may have limited HMB-45 positivity (but again this is more frequent in the epithelioid variant) but should not be MelanA positive. Endometrial stromal sarcoma may be considered, particularly when the pattern of invasion is not destructive, and the tumor is highly cellular imparting a “blue” appearance from low power. The tumor cytomorphology and morphology of intratumoral vasculature will aid in the diagnosis (as previously discussed in the endometrial stromal tumors section). Additionally, endometrial stromal tumors with smooth muscle differentiation do not typically have the severe cytologic atypia present in most LMS.  Confirmatory immunohistochemistry including a panel of SMA, desmin, caldesmon, and CD10 may also prove useful. Carcinosarcoma with a predominance of the sarcomatous component may be confused with LMS, particularly in limited sampling. Recognizing an epithelial component is key to diagnosing carcinosarcoma; and extensive leiomyosarcomatous differentiation is not typical of carcinosarcoma. Poorly differentiated and dedifferentiated LMS should be distinguished from undifferentiated uterine sarcoma. Indeed, some cases of UUS may in fact represent dedifferentiated LMS without any residual morphologic or immunophenotypic evidence of smooth muscle differentiation. The presence of fascicular growth should prompt consideration of LMS.  Additionally, extensive sampling of large tumors is needed before a diagnosis of UUS should be made.

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Immunohistochemistry should be performed selectively on the blocks of tumor containing fascicular growth as staining more poorly differentiated/undifferentiated tumor foci will be of little use. Inflammatory myofibroblastic tumor (IMT) may be considered in the differential diagnosis of LMS, though more commonly in myxoid variants and LMS with less severe cytologic atypia as well as smooth muscle tumors of uncertain malignant potential (STUMP; discussed later). The presence of a prominent lymphoplasmacytic inflammatory cell component and myxoid stroma should prompt consideration of IMT.  Positive Alk immunohistochemistry and/or breakapart FISH can confirm the diagnosis [230]. Gastrointestinal stromal tumor/sarcoma may rarely be encountered in the uterus and as there may be significant morphologic overlap with smooth muscle tumors including LMS, a panel of desmin, CD34, c-kit (CD117), and DOG-1 will aid in classification. Of note, both DOG-1 and c-kit may be expressed strongly in LMS, but without associated KIT mutation [231–233]. Rhabdomyosarcoma, particularly those with predominantly spindled morphology, may be confused with LMS, although the latter is overwhelmingly more common in the uterus [234]. Morphologic features to raise concern for rhabdomyosarcoma include densely eosinophilic cytoplasm and presence of cross-striations. Immunohistochemistry for caldesmon and myogenin or other skeletal muscle-specific marker will distinguish between smooth muscle and skeletal muscle differentiation.

B. E. Howitt and M. R. Nucci

[245–247]. Ovarian preservation has been considered in premenopausal patients with early-stage leiomyosarcoma but appears to yield little benefit [192, 241]. Intraperitoneal morcellation of an unsuspected LMS results in increased risk of recurrence and shorter time to recurrence [248]. Most studies have found that adjuvant chemotherapy or radiotherapy has minimal, if any, effect on survival [192, 237, 240] though some recent studies have shown benefit of chemotherapy in metastatic LMS [192, 247]. Aromatase inhibitors may prolong progression-free survival for some patients with ER-positive leiomyosarcoma [249–251]. mTOR inhibition has been proposed in uterine LMS as activated AKT/mTOR pathway proteins are highly expressed [252–254]. With the advent of widely available next-generation sequencing and other molecular testing on tumor specimens, it is likely that a personalized approach to the treatment of LMS may prove more beneficial than standard chemotherapy. One recent example of this is palbociclib, a CDK4/6 inhibitor, which has been shown to be effective for LMS harboring CDKN2A alterations, which is encountered in LMS in up to 20% of cases [255].

1.3.3.9 Variants of Leiomyosarcoma: Diagnostic Considerations and Molecular Features Epithelioid Leiomyosarcoma Epithelioid leiomyosarcoma (Fig.  1.33) shows epithelioid differentiation in the form of round to polygonal cells with ample eosinophilic cytoplasm (Fig. 1.34); conventional spindled areas may be seen, and in these cases, a leiomyosarcoma, mixed epithelioid and spindle types, can be considered. Similar to conventional spindled leiomyosarcoma, features indicative of malignancy include large tumor size, nuclear

1.3.3.8 Management and Outcomes LMS is an aggressive tumor, with high rates of both local recurrence and distant metastasis. The 5-year survival rate for LMS is 25–50%, albeit a bit higher in stage I disease [235–237]. No study has shown a definite prognostic importance of the morphologic grade once the diagnostic threshold for leiomyosarcoma is met. Factors that affect outcome include patient age and stage at presentation, and within the early-stage cohort, vascular invasion, mitotic count, and tumor circumscription have also been shown to have prognostic significance in some studies [238–241]. Progesterone receptor (PR) expression appears to be a favorable prognostic indicator in low-stage LMS [242]. Similarly, androgen receptor (AR) expression may also be a positive prognostic indicator, particularly when co-expressed with ER and/or PR [243]. High levels of IMP-3 expression in LMS may be associated with worse disease-specific survival [244]. The treatment of choice for leiomyosarcoma is total abdominal hysterectomy and bilateral salpingo-­ oophorectomy. The likelihood of nodal disease is quite low in the absence of more obvious disease, suggesting that Fig. 1.33  Epithelioid leiomyosarcoma, gross appearance. Similar to upfront lymph node dissection has little prognostic or other uterine sarcomas, epithelioid leiomyosarcoma has a fleshy, multitherapeutic role in the management of leiomyosarcoma nodular appearance with hemorrhage and necrosis ­

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Fig. 1.34 Epithelioid leiomyosarcoma, microscopic appearance. Epithelioid leiomyosarcoma is composed of small nests and cords of atypical polygonal cells, with eosinophilic cytoplasm and mitoses

Fig. 1.35  Epithelioid leiomyosarcoma, immunohistochemistry. Smooth muscle actin (SMA) (shown here) is positive in epithelioid leiomyosarcoma, as is desmin and caldesmon; however, the extent and intensity of positivity can be variable

atypia, necrosis, mitotic rate, and vascular invasion. Tumors with significant cytologic atypia and a mitotic rate ≥5 per 10 high-power fields are classified as malignant [160]. Epithelioid leiomyosarcomas are typically positive for smooth muscle markers, including smooth muscle actin, desmin, and h-caldesmon, although the expression can be variable (Fig.  1.35). Of note, some may show focal HMB-45 expression, and in these instances, the possibility of a PEComa should be considered [256]; other characteristic areas of PEComatous differentiation should be identified and co-expression of other melanocytic markers such as melanA and cathepsin K (which should be diffuse in PEComa) should be evaluated [257]. No studies have specifically evaluated the molecular features of epithelioid LMS. The differential

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diagnosis of epithelioid LMS is broad and includes other tumors with epithelioid cytomorphology. Epithelioid leiomyoma can be rendered if the tumor is well circumscribed and lacks cytologic atypia and the mitotic rate is 50% shows a prominent myxoid matrix is considered sufficient in diagnosing a leiomyosarcoma as of the myxoid rather than the conventional subtype [258]. The differential diagnosis also includes myxoid leiomyoma, hydropic leiomyoma, inflammatory myofibroblastic tumor, and BCOR-altered high-grade sarcoma. Myxoid leiomyoma is a very uncommon tumor and should only be diagnosed when a myxoid smooth muscle tumor is well circumscribed, lacks cytologic atypia, and shows no or only rare mitoses. Hydropic leiomyoma typically has a watery rather than gelatinous cut surface which corresponds microscopically to edema fluid which appears “pink” rather than “bluish”; in addition, it is well circumscribed, lacks atypia, and usually shows minimal to no mitoses. The distinction from inflammatory myofibroblastic tumor is more challenging as both can be myxoid and have infiltrative margins, and indeed these tumors have been misclassified as myxoid LMS in the past [258], most likely because they can have leiomyoma-like areas as well as these only being relatively recently recognized as occurring in the gynecologic tract. They tend to have a “fasciitis-like” appearance being composed of cells with enlarged nuclei, vesicular chromatin, and prominent nucleoli. This appearance in combination with the finding a lymphoplasmacytic infiltrate sprinkled throughout and aggregating at the periphery of the mass are clues to the diagnosis. Inflammatory myofibroblastic tumors can be positive for desmin and SMA but also are positive in most cases for ALK, which corresponds to rearrangements of the ALK gene. In addition, they

Smooth muscle tumors of uncertain malignant potential (STUMP) are not well defined secondary to poor reproducibility agreement on histomorphologic classification, but with this caveat in mind, one study found that 11% of STUMPs harbor MED12 mutations, similar to the frequency in LMS [128]. Likewise, approximately one third of STUMPs have PTEN deletions [128]. STUMPs with any degree of myxoid features should be stained immunohistochemically for Alk or examined with FISH analysis for ALK rearrangement, given that a recent study found that a significant minority of STUMPs were reclassified as inflammatory myofibroblastic tumor (IMT) after Alk ­ immunohistochemical staining [260]. Our practical approach to the consideration of whether a tumor should be considered of uncertain malignant potential (or of uncertain biologic behavior) is the following. Tumors with significant cytologic atypia and a mitotic rate that is near the threshold (i.e., 8 or 9 mitoses per 10 high-power fields) should be considered of uncertain malignant potential as it seems unlikely there is significant biologic difference in tumors with such close mitotic rates; as a practical point, in any situation in which the mitotic rate is close to the threshold, extensive sampling and exhaustive mitotic counts should be performed (every block of tissue; at least 100 high-power fields counted). In some cases, a proliferation marker can be used to identify “hot spots.” A stand-­alone diagnosis of “STUMP” should not be used in a biopsy/curettage as the fragments may not be large enough to provide a formal mitotic count; in this scenario, “atypical smooth muscle tumor representing at least STUMP” can be rendered. STUMP can also be considered in epithelioid or myxoid tumors in which the mitotic rate is also near the threshold. Recently, additional histologic parameters for the diagnosis of STUMP have been proposed which include atypical mitoses, infiltrative margins, and vascular involvement [261]. In this study, the risk of adverse outcome was higher (36.4%) than in previously published reports (range 7–26.7%) suggesting that use of more stringent criteria can exclude some patients from further follow-up.

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1.3.5 A  typical Leiomyoma (“Leiomyoma with Bizarre Nuclei”) Atypical leiomyoma is characterized by significant cytologic atypia (readily seen from 4× objective) (Fig. 1.37a) but lacks both tumor cell necrosis and significant mitotic activity [195]. Nuclear atypia in atypical leiomyoma ­comprises some combination of nuclear enlargement, multinucleation, hyperchromasia, coarse chromatin, or prominent nucleoli (Fig.  1.37b). The atypia may be focal or diffuse. Though in the past these tumors have variably been named atypical leiomyoma, symplastic leiomyoma, and pleomorphic leiomyoma, it has been proposed that these be termed “leiomyoma with bizarre nuclei,” in the most recent WHO [2]; however, many of the molecular alterations present in these tumors overlap with those found in LMS.  Specifically, 12% have TP53 mutations, 10% have MED12 mutations, and 24% have PTEN deletion [128]. Additionally, the miRNA profile of atypical leiomyoma was more similar to LMS/STUMP than to conventional leiomyoma or cellular leiomyoma [128]. Histologically, the distinction of atypical leiomyoma from LMS is the absolute absence of tumor cell necrosis and a mitotic index no higher than ordinary leiomyomata. Bell et  al. have suggested that atypical leiomyoma have no more than 10 mitotic figures per 10 HPFs [195]. While one study has shown no evidence of recurrence [262], another has shown that atypical leiomyomas have a low risk (50% of myxoid and conventional LMS had abnormal p53 or p16 [206]. The STUMP category of uterine fusions not involving ALK, similar to extrauterine IMT, most smooth muscle tumors has also been shown to include misnotably the ETV6-NTRK3 fusion [342, 344, 345]. ROS1-­ diagnosed (i.e., underdiagnosed) cases of IMT, in up to 14% rearranged IMT have been described in other viscera/soft tis- of cases [260, 348]. sue but have yet to be documented in the uterus [346, 347]. Similar to IMT, the myxoid variant of endometrial stromal tumors [28, 50] also may present as a polypoid endome1.5.2.7 Differential Diagnosis trial mass; however, LGESS has a characteristic multinodular There can be significant morphologic overlap for IMT with or tonguelike pattern of myometrial infiltration, and at least myxoid LMS and other smooth muscle neoplasms. Thus, focally there is an appearance of typical endometrial stromal the differential diagnosis includes myxoid leiomyosarcoma, neoplasia with its characteristic growth pattern and promimyxoid leiomyoma, and the myxoid variant of endometrial nent (arteriolar) vascular component. Immunohistochemistry stromal sarcoma. When evaluating myxoid uterine tumors, for CD10 is unlikely to be helpful as many IMTs demonthe diagnosis of IMT should be considered, particularly as strate CD10 positivity; however, LGESS is negative for ALK IMTs with larger size, higher proportions of myxoid stroma, immunohistochemistry. and higher mitotic activity may have a higher propensity for more aggressive behavior [230, 340]. Similar to the conven- 1.5.2.8 Management and Outcomes tional spindle cell type of uterine leiomyosarcoma, myxoid Uterine IMT only rarely recurs, and histologic parameters leiomyosarcoma also typically affects women in their sixth that may be associated with more aggressive behavior decade who may present with abnormal vaginal bleeding, include tumor cell necrosis, large tumor size (≥8 cm), high pelvic pain, or a pelvic mass. However, in contrast, myxoid mitotic activity (≥7 per 10 HPFs), a predominantly myxoid leiomyosarcoma usually will have a more gelatinous gross pattern, lymphovascular invasion, and infiltrative borders appearance with a glistening cut surface, although this may [230, 340]. However no definitive criteria for “malignancy” vary in extent depending on the amount of extracellular exist in uterine IMT as the total number of cases reported is myxoid matrix deposition. The tumor cells may be spindled small and many with limited clinical and follow-up data. The or stellate and the degree of (Alcian blue positive) extracel- epithelioid variant, which is associated with a distinctive lular matrix deposition may obscure the tumors fascicular nuclear membrane or perinuclear pattern of Alk staining and architecture. Although the majority of IMTs may have a an aggressive clinical course, has not been described in the bland cytomorphologic appearance, tumor cells typically uterus to date [349]. Although surgery is the mainstay of exhibit at least focal moderate atypia. IMT can be distin- therapeutic management of IMT, tyrosine kinase inhibitor guished from myxoid leiomyosarcoma by its typically (but therapy may be considered in patients with recurrence or not always) pushing border without vascular invasion, the with metastatic disease. The presence of ALK rearrangement presence of a prominent lymphoplasmacytic infiltrate, and makes IMTs amenable to tyrosine kinase inhibition similar immunohistochemical expression of ALK. Because uterine to other ALK-rearranged tumors [350], with promising preIMTs typically have a rounded, pushing border and may liminary results in small studies [351].

1  Uterine Mesenchymal Lesions

1.5.3 Adenomatoid Tumor Adenomatoid tumors are tumors of mesothelial origin that typically involve the serosal surfaces of uterus or (more commonly) the fallopian tube. In addition to their characteristic anatomic location, the gross appearance of adenomatoid tumors are firm, rubbery tumors with white or gray cut surfaces. The border with the adjacent myometrium may not bulge out or be as defined as typical leiomyomata. Microscopically, the mesothelial proliferation forms gland-­like spaces nestled between smooth muscle fascicles (Fig. 1.50), but the mesothelial cells are not infrequently inconspicuous. Consequently, the gland-like spaces may look more like venules or even adipose or signet ring cells. The mesothelial origin of these cells can be confirmed by their expression of cytokeratins, WT-1 [352], D2-40, and calretinin, but not of CD-31 or CD-34 [353]. It is presumed that the mesothelial cells are neoplastic and the smooth muscle cells are hyperplastic. As adenomatoid tumors are usually benign, under 2 cm in size, and an incidental finding in women in the years before menopause, they have no clinical impact apart from their mimicry of leiomyomata and other benign tumors. Distinction from malignant mesothelioma is not a common diagnostic dilemma as mesothelioma demonstrates a highly infiltrative growth pattern.

1.5.4 Rhabdomyosarcoma Rhabdomyosarcomas are malignant tumors showing skeletal muscle differentiation by morphology and immunohistochemical expression; of note, rhabdomyosarcomatous differentiation can be seen as a component of other tumor types (as a heterolo-

Fig. 1.50  Adenomatoid tumor. Adenomatoid tumor is characterized by attenuated flattened to cuboidal mesothelial cells forming cyst-like spaces within myometrium. In this example, the mesothelial component is conspicuous

41

gous component) most commonly Mullerian adenosarcoma and carsinosarcoma and are not included in this discussion. In general, rhabdomyosarcoma is separated into three histologic types  – embryonal, alveolar, and pleomorphic. In the female genital tract, embryonal rhabdomyosarcoma (ERMS) is uncommon and most frequently occurs in the uterine cervix but has also been reported in the uterine corpus [234, 354–359]. When primary in the cervix, it typically occurs in children or young women and often presents as a polypoid, grape-like mass; in this scenario it is referred to as “botryoid rhabdomyosarcoma” which just refers to the subset of ERMS that occur at a mucosal site and grow in this distinctive fashion. ERMS of the uterine corpus occurs over a wide age range, but patients are typically older than those presenting with cervical primaries. Patients typically present with vaginal bleeding or abdominal distension or pain. On gross examination, the tumor also typically projects into endometrial cavity with a “grape-like” appearance and has a graywhite fleshy to glistening cut surface (“botryoid subtype”) but can also be an intramural mass. Necrosis and hemorrhage may be seen. Histologically, uterine ERMS has similar features to that of soft tissue and other sites; namely, a tumor composed of small, round to spindle-shaped “undifferentiated” blue cells intermingled with variable numbers of rhabdomyoblasts with brightly eosinophilic cytoplasmic processes that may contain cross-striations (also termed “tadpole” or strap cells). The botryoid subtype typically shows alternating hypocellular and hypercellular primitive-­appearing spindled cells (Fig.  1.51a) that frequently condense underneath surface epithelium to form a “cambium” layer (Fig. 1.51b, c). Tumor cells may also demonstrate striation (“strap” cells) and islands of cartilaginous differentiation may be present (Fig. 1.50d). Immunohistochemistry shows positivity for skeletal muscle markers, although it may be patchy. This tumor may be ­difficult to recognize, particularly in older women, and there can be morphologic overlap with adenosarcoma as well as a poorly sampled carcinosarcoma, both of which may commonly have rhabdomyosarcomatous differentiation. The only well-characterized molecular alteration in ERMS is DICER1 mutation, which may occur as either germline or somatic inactivation [359–364]. DICER1 is involved in miRNA processing and its inactivation is likely a key step in the pathogenesis of ERMS.  No studies to date have evaluated for the presence of DICER1 mutations in other tumors demonstrating rhabdomyosarcomatous differentiation aside from the aforementioned adenosarcoma [275]. ERMS in adults, even if of the botryoid subtype, appears behave more aggressively with a worse overall survival [355]. Alveolar and pleomorphic rhabdomyosarcoma are rare in the uterus [355, 365–369]. The former is characterized by rounded undifferentiated cells growing in a nested/alveolar pattern surrounded by fibrous septa and admixed with variable numbers of wreath-like multinucleate cells and rhabdomyoblasts. Most alveolar rhabdomyosarcomas express PAX3-FKHR or PAX7-FKHR gene fusions with the latter

42

B. E. Howitt and M. R. Nucci

a

b

c

d

Fig. 1.51  Rhabdomyosarcoma, embryonal type. (a) Embryonal rhabdomyosarcoma with alternating hypocellular and hypercellular areas, with hyperchromatic, primitive-appearing spindled cells in the hypercellular foci. (b) The classic histologic feature of embryonal rhabdomyosarcoma is the “cambium” layer in which the tumor cells condense

underneath nonneoplastic surface epithelium. (c) In some cases, the cambium layer can be very subtle, particularly in areas of hemorrhage. (d) Cartilaginous differentiation, as shown here, may be seen in embryonal rhabdomyosarcoma

possibly associated with a more favorable prognosis [370]. Pleomorphic rhabdomyosarcoma is a high-grade sarcoma composed of pleomorphic cells which may show features of ERMS or alveolar subtype elsewhere and may best be considered “anaplastic” rhabdomyosarcoma in this context.

present at a wide age range (34–81 years). Tumors range in size from 3.5 to 12.5  cm and grossly appear as a well-­ circumscribed firm yellow-tan nodule. Histologic appearance is similar to SFT described elsewhere with bland spindle cells arranged in a “patternless pattern” and alternating hypo- and hypercellular areas, as well as the characteristic staghorn or hemangiopericytoma-like thin-walled branching vasculature. An adipocytic component or myxoid change may be present in a minority. Also similar to SFTs reported elsewhere, histologic features are not entirely helpful in determining malignant potential; indeed at least one case in the largest series that metastasized to the lung demonstrated low mitotic activity, nuclear atypia, or necrosis, although the tumor size was 10 cm [371, 372]. Immunohistochemically, SFT are positive for CD34 and STAT6 but negative for the smooth muscle markers SMA, desmin, and caldesmon.

1.5.5 Solitary Fibrous Tumor (SFT) Solitary fibrous tumor rarely occurs in the uterus, but is worth mentioning as the clinical and imaging impression is often that of leiomyoma, and thus pathologic recognition of this entity is essential as SFT are considered tumors of uncertain malignant potential, even when no worrisome histologic features are present. Within the female genital tract, the uterine corpus is the most common location [371] and patients

1  Uterine Mesenchymal Lesions

1.5.6 Angiosarcoma Angiosarcoma of the uterus is exceedingly rare as a pure, primary tumor as the largest case series to date comprises four cases [373]; however, within the female genital tract, it is the second most common site after the ovary. Clinically patients present in the perimenopausal or postmenopausal years. These are aggressive tumors similar to angiosarcoma of soft tissue, with most patients dying of disease, often within a year of diagnosis [373, 374]. Likewise, immunohistochemistry for uterine angiosarcoma reveals CD31 and CD34 positivity; presumably ERG would also be positive in these tumors. When one encounters a tumor that morphologically appears to have angiosarcomatous features, the tumor should be carefully examined for other components (carcinosarcoma, adenosarcoma) and immunohistochemistry applied to confirm the diagnosis. Additionally, metastasis should be excluded clinically and radiologically.

1.5.7 Lymphoma Lymphoma/leukemia involving the uterine corpus is rare, with few series reported in the literature. Within the female genital tract, involvement of the cervix or ovaries is more common than the uterine corpus. Histologic types described include diffuse large B cell, nodular lymphoma, Burkitt’s lymphoma, and granulocytic sarcoma among others [375]. Treatment and prognosis are dependent upon the specific type of lymphoma present.

1.5.8 Adenomyosis/Adenomyoma Including Intravascular Adenomyomatosis Adenomyosis is defined as the presence of endometrial glands and/or stroma within the myometrium. Adenomyosis is a common, nonneoplastic abnormality seen in 20–25% of women who may complain of a variety of symptoms or may be asymptomatic, most typically in the reproductive years. Histologically, adenomyosis is defined as the presence of endometrial-type glands and/or stroma within the myometrium, located (arbitrarily) at least one 100× field (~2.5 mm) from the endomyometrial junction. Similarly, adenomyoma is a grossly apparent mass composed of endometrial tissue surrounded by a well-developed smooth muscle component resembling leiomyoma. Both adenomyosis and adenomyoma do not usually present diagnostic difficulties; however, when the adenomyosis is “gland poor,” concern for a low-­grade endometrial stromal sarcoma may arise [34]. Gland-­poor adenomyosis most commonly occurs in postmenopausal women and is an incidental finding. Similarly, adenomyosis/adenomyoma may also involve vascular spaces similar to leiomyoma (“intravascular adenomyomatosis”) again raising concern for a low-grade endometrial stromal sarcoma [376, 377].

43

Features that are helpful in distinguishing between an ­adenomyosis-related process and an endometrial stromal sarcoma include the presence of obvious adenomyosis elsewhere, a thickening or hypertrophy of the surrounding myometrium, and lack of a grossly evident mass. The presence of variant morphologic features (such as sex cord ­differentiation, hyaline bands or plaques, and foamy histiocytes) should raise high suspicion for LGESS and warrants molecular investigation for JAZF1 rearrangement.

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1  Uterine Mesenchymal Lesions 318. Rao Q, et  al. PSF/SFPQ is a very common gene fusion partner in TFE3 rearrangement-associated perivascular epithelioid cell tumors (PEComas) and melanotic Xp11 translocation renal cancers: clinicopathologic, immunohistochemical, and molecular characteristics suggesting classification as a distinct entity. Am J Surg Pathol. 2015;39(9):1181–96. 319. Tanaka M, et al. Perivascular epithelioid cell tumor with SFPQ/ PSF-TFE3 gene fusion in a patient with advanced neuroblastoma. Am J Surg Pathol. 2009;33(9):1416–20. 320. Pan CC, et al. Comparative genomic hybridization study of perivascular epithelioid cell tumor: molecular genetic evidence of perivascular epithelioid cell tumor as a distinctive neoplasm. Hum Pathol. 2006;37(5):606–12. 321. Silva EG, et al. A uterine leiomyosarcoma that became positive for HMB45 in the metastasis. Ann Diagn Pathol. 2005;9(1):43–5. 322. Silva EG, et al. Uterine leiomyosarcoma with clear cell areas. Int J Gynecol Pathol. 1995;14(2):174–8. 323. Simpson KW, Albores-Saavedra J.  HMB-45 reactivity in conventional uterine leiomyosarcomas. Am J Surg Pathol. 2007;31(1):95–8. 324. Ruco LP, et  al. Epithelioid lymphangioleiomyomatosis-like tumour of the uterus in a patient without tuberous sclerosis: a lesion mimicking epithelioid leiomyosarcoma. Histopathology. 1998;33(1):91–3. 325. Michal M, Zamecnik M.  Hyalinized uterine mesenchymal neoplasms with HMB-45-positive epithelioid cells: epithelioid leiomyomas or angiomyolipomas? Report of four cases. Int J Surg Pathol. 2000;8(4):323–8. 326. Kwon BS, et al. Two cases of perivascular epithelioid cell tumor of the uterus: clinical, radiological and pathological diagnostic challenge. Eur J Med Res. 2017;22(1):7. 327. Mills AM, Longacre TA.  Smooth muscle tumors of the female genital tract. Surg Pathol Clin. 2009;2(4):625–77. 328. Fadare O. Uterine perivascular epithelioid cell tumors (PEComas) and epithelioid smooth muscle neoplasms. Arch Pathol Lab Med. 2008;132(11):1714. 329. Fadare O.  Perivascular epithelioid cell tumors (PEComas) and smooth muscle tumors of the uterus. Am J Surg Pathol. 2007;31(9):1454–5. author reply 1455–6 330. Schoolmeester JK, et al. Alveolar soft part sarcoma of the female genital tract: a morphologic, immunohistochemical, and molecular cytogenetic study of 10 cases with emphasis on its distinction from morphologic mimics. Am J Surg Pathol. 2017;41(5):622–32. 331. Folpe AL, et  al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol. 2005;29(12):1558–75. 332. Wagner AJ, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1  in tumors. J Clin Oncol. 2010;28(5):835–40. 333. Starbuck KD, et  al. Treatment of advanced malignant uterine perivascular epithelioid cell tumor with mTOR inhibitors: single-­ institution experience and review of the literature. Anticancer Res. 2016;36(11):6161–4. 334. Gao F, et al. Combination targeted therapy of VEGFR inhibitor, sorafenib, with an mTOR inhibitor, sirolimus induced a remarkable response of rapid progressive uterine PEComa. Cancer Biol Ther. 2016;17(6):595–8. 335. Dickson MA, et al. Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: clinical and molecular correlates. Int J Cancer. 2013;132(7):1711–7. 336. Ghosh I, et  al. Metastatic perivascular epithelioid cell tumor responding to mammalian target of rapamycin inhibition. Indian J Med Paediatr Oncol. 2014;35(1):99–102.

51 337. Benson C, et  al. A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: the Royal Marsden Hospital experience. Anticancer Res. 2014;34(7):3663–8. 338. Coffin CM, et  al. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19(8):859–72. 339. Rabban JT, et  al. Inflammatory myofibroblastic tumor of the uterus: a clinicopathologic study of 6 cases emphasizing distinction from aggressive mesenchymal tumors. Am J Surg Pathol. 2005;29(10):1348–55. 340. Bennett JA, et  al. Inflammatory myofibroblastic tumor of the uterus: a clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum. Mod Pathol. 2017;30(10):1489–503. 341. Fuehrer NE, et  al. ALK-1 protein expression and ALK gene rearrangements aid in the diagnosis of inflammatory myofibroblastic tumors of the female genital tract. Arch Pathol Lab Med. 2012;136(6):623–6. 342. Yamamoto H, et  al. ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology. 2016;69(1):72–83. 343. Cessna MH, et al. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases. Mod Pathol. 2002;15(9):931–8. 344. Takahashi A, et al. Anaplastic lymphoma kinase-negative uterine inflammatory myofibroblastic tumor containing the ETV6-NTRK3 fusion gene: a case report. J Int Med Res. 2018;46:3498–503. 345. Alassiri AH, et al. ETV6-NTRK3 is expressed in a subset of ALK-­ negative inflammatory myofibroblastic tumors. Am J Surg Pathol. 2016;40(8):1051–61. 346. Antonescu CR, et  al. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. 2015;39(7):957–67. 347. Hornick JL, et al. Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors. Mod Pathol. 2015;28(5):732–9. 348. Subbiah V, et al. STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion. J Hematol Oncol. 2015;8:66. 349. Marino-Enriquez A, et al. Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol. 2011;35(1):135–44. 350. Butrynski JE, et  al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18):1727–33. 351. Mosse YP, et  al. Targeting ALK with Crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a children’s Oncology Group study. J Clin Oncol. 2017;35(28):3215–21. 352. Schwartz EJ, Longacre TA.  Adenomatoid tumors of the female and male genital tracts express WT1. Int J Gynecol Pathol. 2004;23(2):123–8. 353. Sangoi AR, et  al. Adenomatoid tumors of the female and male genital tracts: a clinicopathological and immunohistochemical study of 44 cases. Mod Pathol. 2009;22(9):1228–35. 354. Ditto A, et al. Embryonal rhabdomyosarcoma of the uterine cervix in adults: a case report and literature review. J Low Genit Tract Dis. 2013;17(4):e12–7. 355. Ferguson SE, et  al. Clinicopathologic features of rhabdomyosarcoma of gynecologic origin in adults. Am J Surg Pathol. 2007;31(3):382–9.

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2

Fallopian Tube David L. Kolin and Brooke E. Howitt

Abstract

Keywords

The fallopian tube contains a muscular wall and plicae lined by ciliated, tubal-type epithelium. While primary tumors of the fallopian tube are unusual, benign, borderline, and malignant tumors occur, many of which have similar counterparts in the endometrium and ovary. Over the past two decades, there has been a realization that the fimbriae are the source of many (and some believe all) cases of “ovarian” high-grade serous carcinoma. The spectrum of serous tubal neoplasia includes p53 signatures, serous tubal intraepithelial carcinoma, and high-­ grade serous carcinoma. These entities have unique morphologic, immunophenotypic, and genetic features, with varied clinical significance. The fallopian tube is a frequent site of metastatic disease from not only the ovary and uterus but may also contain metastases from distant sites (most often the gastrointestinal tract and breast). Metastases may be located within the serosa, mucosa, muscular wall, or intravascular spaces. The fallopian tube can manifest several metaplasias, such as mucinous and transitional, as well as reactive phenomena, including pseudocarcinomatous hyperplasia. Sexually transmitted diseases are the most common causes of infectious salpingitis, which may result in pelvic inflammatory disease and ectopic pregnancy. Because the fimbriae are a site of serous carcinogenesis, the SEE-FIM grossing protocol was developed to extensively sample the fimbria in risk-­reducing salpingectomies and is now applied in many specimens containing salpingectomies, including those from low-risk women. At a minimum, entirely submitting and examining the distal fallopian tube are generally advised.

Fallopian tube · Serous carcinoma · Serous tubal ­intraepithelial carcinoma · Ectopic pregnancy · Pelvic inflammatory disease

D. L. Kolin Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA B. E. Howitt (*) Department of Pathology, Stanford University Medical Center, Stanford, CA, USA e-mail: [email protected]

2.1

Introduction

The fallopian tube has garnered increased attention over the past 15 years as it has become implicated as the site of origin of many pelvic high-grade serous carcinomas. High-grade serous carcinoma of the fallopian tube was likely underappreciated in the past, as a result of under-sampling of the fallopian tube and lack of recognition of in situ lesions. Now that serous tubal intraepithelial carcinoma (STIC) is recognized as the precursor of many, if not all, high-grade serous carcinomas, more tumors are being classified as fallopian tube primaries. With the introduction of the Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol for grossing fallopian tubes, the ability to detect small intramucosal lesions in the fimbria has increased significantly. Since the fallopian tube is now accepted to be the site of origin of many BRCA1- and BRCA2-related “ovarian” malignancies, the frequency of prophylactic salpingectomies has increased significantly in recent years. It therefore behooves the pathologist to familiarize themselves with the spectrum of intraepithelial lesions which are commonly encountered in routine salpingectomy specimens. This chapter begins with a review of fallopian tube anatomy and histology. Tubal neoplasias are described, with an emphasis on both benign and malignant tumors which are unique to the fallopian tube. Nonneoplastic disorders are then addressed, including inflammatory conditions and various metaplasias which may be observed and are important to recognize as they may mimic neoplastic processes. Special attention is given to tubal ectopic pregnancies. Finally, suggested grossing protocols are given for the most commonly encountered tubal specimens.

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_2

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2.2

D. L. Kolin and B. E. Howitt

Fallopian Tube Anatomy and Histology

The fallopian tubes traverse from the uterus to the ovary through the broad ligament and have a length of 7–12 cm [1]. Anatomically, the fallopian tube is comprised of four regions: the infundibulum and its fimbriated end, closest to the ovary; the ampulla, the longest portion of the tube; the isthmus, a narrow portion of the tube nearest the uterus; and a short intramural (or interstitial) portion of the tube which is within the uterine corpus. The infundibulum is funnel-shaped and has attached to its end approximately 25 finger-like folds comprising the fimbriae, which are immediately adjacent to the ovary and help to capture the egg during ovulation [2]. A band of smooth muscle, the fimbria ovarica, attaches the fimbriated end of the fallopian tube to the ovary. The fallopian tube mesentery, the mesosalpinx, is the region of the broad ligament between the ovary and the fallopian tube. Blood supplies the fallopian tube via the tubal branches of the ovarian and uterine arteries [1]. Lymphatic drainage of the fallopian tube either follows the ovarian vessels to para-­ aortic lymph nodes or the uterine vessels to internal iliac nodes [3]. Histologically, a cross section of the tube shows the outer serosal layer, middle muscular layer (myosalpinx), and an inner mucosal layer (endosalpinx). The myosalpinx is composed of an inner circular and outer longitudinal layer. Invaginations of the tubal mucosa, termed plicae, become increasingly complex from the interstitium to the fimbria. The plicae are lined by three different cell types: secretory, ciliated, and intercalated (peg) cells (Fig. 2.1). The ciliated cells are crucial for enabling tubal transport of ova.

Fig. 2.2  Pigmented macrophages in the tubal lamina propria are termed melanosis tubae or pseudoxanthomatous salpingiosis and are associated with endometriosis

The cells lining the plicae vary as a function of the menstrual cycle. At ovulation, the fraction of ciliated cells and cell height are highest [4]. During the luteal stage, when serum progesterone levels are high, the percent of ciliated cells and the height of fimbrial cells both decrease [4, 5]. These changes are exaggerated further during pregnancy, when progesterone levels are higher [5]. There are variations of normal histology which may be encountered routinely in fallopian tubes. Plical fibrosis is present in 35% of salpingectomy specimens, and its severity increases with patient age [6]. Intramuscular edema of the wall may be seen and is associated with recent pregnancy [6]. Pigmented macrophages containing hemosiderin and/or lipofuscin are occasionally seen in the lamina propria of the fallopian tube (Fig. 2.2) [7]. This phenomenon occurs in 5% of salpingectomies and is called melanosis tubae, pseudoxanthomatous salpingiosis, or pigmentosis tubae and is associated with endometriosis, infertility, and hydrosalpinx [6–8].

2.3

 elationship with Pelvic Serous R Tumors

2.3.1 Overview

Fig. 2.1  Normal fallopian tube plicae are lined by secretory (blue), ciliated (red), and peg cells (black), which are variants of secretory cells

Interest in the fallopian tube as a possible source of “ovarian” carcinoma started after reports in 2001 showed an increase in tubal dysplasia and early carcinoma in women with BRCA1 mutations [9–13]. Since then, a spectrum of tubal serous neoplasia has been described, including p53 signatures and serous tubal intraepithelial carcinoma (STIC, Table 2.1). Clinical, pathologic, and molecular evidence now shows that most so-called ovarian high-grade serous

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2  Fallopian Tube Table 2.1  Terminology for serous tubal intraepithelial proliferations Lesion p53 signature

Benign serous tubal epithelial proliferation/lesion Serous tubal epithelial proliferation/lesion of uncertain significance

Serous tubal intraepithelial carcinoma (STIC)

Diagnostic criteria • Secretory cell outgrowth • Abnormal p53 staining by IHC • Abnormal p53 staining by IHC • Mild nuclear enlargement • Abnormal p53 staining by IHC • Nuclear enlargement • Increased N:C ratio • Preserved polarity • Increased Ki-67 proliferative index • Abnormal p53 staining by IHC • Nuclear enlargement • Increased N:C ratio • Lost polarity • Increased Ki-67 proliferative index

Significance No increased risk of serous carcinoma No increased risk of serous carcinoma Unknown risk of future HGSC, but probably very low Perform deeper levels to rule out STIC Risk of later developing HGSC: 4–11% Consider germline testing for BRCA1/2 mutations

Adapted from ref. [15]

c­arcinoma (HGSC) originates from tubal epithelium. The introduction of a protocol to extensively examine the tubal fimbria (SEE-FIM, described in detail later) has facilitated detection of precursor lesions [14]. As risk-reducing (prophylactic) salpingo-oophorectomies become more common, pathologists will encounter these tubal lesions with increasing frequency.

2.3.2 Terminology of Tubal Serous Neoplasia 2.3.2.1 Secretory Cell Expansion and Outgrowths Tubal secretory cell expansion (SCE) and outgrowths (SCOUTs) are benign proliferations of either serous/ciliated (type I) or endometrioid (type II) cytomorphology. A SCE is defined as more than 10 secretory cells in a row, while a SCOUT contains more than 30 secretory cells in a row [15, 16]. The main differential diagnoses include a p53 signature and serous tubal intraepithelial carcinoma (STIC). Both SCE and SCOUTs have minimal cytologic atypia, wild-type p53 staining, and a low Ki-67 proliferation index. For clinical purposes, these terms are considered “benign tubal epithelial proliferations” and do not need to be mentioned in a pathology report. 2.3.2.2 p53 Signature p53 signatures are non-obligate precursors of serous carcinoma. They occur most frequently in the fimbria and are characterized by a segment of at least 12 consecutive secretory cells with abnormal p53 immunohistochemistry and a

Fig. 2.3  p53 signatures are characterized by a secretory cell outgrowth and abnormal p53 staining pattern (diffuse overexpression or null)

low Ki-67 proliferation index (Fig.  2.3) [17, 18]. They are thought to be early precursors of serous carcinoma because they are often found adjacent to a STIC, and they share both identical TP53 mutations with concomitant STICs and risk factors with ovarian carcinoma, such as lower parity and older age at first childbirth [17, 18]. In diagnosing serous carcinoma precursors of the fallopian tube, p53 immunohistochemistry is often used as a surrogate for TP53 mutations [10]. Lesions with wild-type TP53 show a wild-type or patchy pattern of p53 staining, while tumors with TP53 mutations display an abnormal pattern of p53 expression characterized by either diffuse overexpression (>75%) or a null pattern (complete absence) of staining. Li-Fraumeni syndrome, in which patients have germline mutations in one allele of TP53, serves as an interesting model for the carcinogenesis of the distal tube. Patients with Li-Fraumeni have abundant p53 signatures (up to 20 in each section of fimbria), indicating frequent biallelic inactivation of TP53 [19]. The high frequency of loss of heterozygosity in these patients demonstrates that the fimbria is prone to TP53 mutations. The fimbrial mucosa has been postulated to be especially vulnerable to mutations because of its ­proximity to inflammatory mediators and oxidative stress secondary to ovulation [20]. However, there is no increased risk of ovarian carcinoma in Li-Fraumeni syndrome [19]. This suggests that mutations in TP53 are necessary, but not sufficient, for the development of high-grade serous carcinoma and that additional mutations (e.g., in BRCA1/2) are required for carcinogenesis. Conversely, p53 signatures are not more common in BRCA1/2 carriers than in controls, despite the fact that BRCA1/2 carriers are at high risk for serous ­carcinoma [18].

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2.3.2.3 Serous Tubal Intraepithelial Carcinoma ­proliferation index (Fig. 2.4b, c) [11]. There is no accepted (STIC) or validated Ki-67 cutoff for STIC lesions, although most Serous tubal intraepithelial carcinoma (STIC) is a precursor STICs show greater than 75% staining [11]. Positive staining lesion of high-grade serous carcinoma found in the fallopian with stathmin 1 and p16 (strong and diffuse) is also supporttube. Approximately 90% of STICs are located within the ive of STIC (Fig. 2.4d). fimbria and with the remainder in the more proximal tube STIC is by definition intraepithelial and thus “noninva[11, 21]. STICs are seen in 5–8% of risk-reducing salpingo-­ sive”; however, similar to serous endometrial intraepithelial oophorectomy specimens [10, 22]. They are also identified carcinoma, it may disseminate in the peritoneum or less in the setting of a tubal or ovarian HGSC: 61% of ovarian, commonly metastasize to lymph nodes before progressing to 67% of tubal, and 22–50% of so-called primary peritoneal an invasive tubal carcinoma [26]. Given this metastatic HGSC are associated with a STIC [21, 23]. It is uncommon potential, STIC is usually staged as Tla (AJCC) or IA to detect a STIC incidentally (i.e., in non-BRCA1/2 carriers (FIGO), even in the absence of invasion [27]. without HGSC) in a salpingectomy specimen (0.1–0.8%) One may encounter serous tubal intraepithelial prolifera[24, 25]. tions that do not fully satisfy criteria for a STIC. Occasionally, STICs are characterized by increased nuclear-to-­ one is seen adjacent to a high-grade serous carcinoma withcytoplasmic ratio, loss of polarity, mitotic activity, and epi- out an identified STIC [28]. This suggests that invasion may thelial stratification (Fig.  2.4a). Immunohistochemically, have occurred directly from the intraepithelial proliferation they show abnormal p53 staining and increased Ki-67 or that the carcinoma overgrew a pre-existing STIC.

a

b

c

d

Fig. 2.4  Serous tubal intraepithelial carcinoma (STIC) is characterized by increased nuclear-to-cytoplasmic ratio, mitotic activity, loss of polarity, and prominent nucleoli (a). Compared to the adjacent benign

tubal epithelium STIC shows increased Ki-67 proliferative activity (b), abnormal p53 staining pattern (c), and diffuse positivity for p16 (d)

2  Fallopian Tube

There is little evidence to guide treatment of patients diagnosed with a STIC in the absence of an invasive malignancy. A small but significant fraction of these patients (4–11%) will go on to develop so-called “primary peritoneal” serous carcinoma at a later time [22, 29, 30]. Peritoneal washings may be positive in up to 15% of patients with an incidentally detected STIC [31], but the prognostic significance of positive washings is unclear. Given the potential for extratubal metastases, patients are usually observed with serial serum CA-125 and pelvic ultrasounds, with consideration of BRCA1/2 germline testing if not already performed [30, 32]. Some have advocated for staging, including lymphadenectomy, following a STIC diagnosis [26, 30]. The role for prophylactic chemotherapy, if any, is unclear [29].

2.3.3 T  ubal Fimbria as the Main Source of Pelvic Serous Carcinoma Historically, the ovarian surface epithelium or cortical inclusion cysts were thought to be the site of origin of ovarian high-grade serous carcinoma. A new paradigm emerged when examination of risk-reducing salpingo-oophorectomy specimens in BRCA1 and BRCA2 mutation carriers identified early tubal carcinomas, and it was postulated that the fallopian tube may be the source of ovarian serous carcinoma [9–13]. Incidentally discovered STICs in patients without disease in the ovary added additional evidence that HGSC arises in the tube [33–35]. Next-generation sequencing of synchronous STICs and ovarian HGSC have found identical mutations in TP53, further bolstering the evidence for STICs as HGSC precursors [36]. There has been some debate about whether all pelvic (i.e., tubal, ovarian, and peritoneal) HGSC arises from the fallopian tube or if there may be a second, fallopian tube-­ independent, pathway. For example, STIC is seen less frequently in BRCA1/2 carriers with HGSC than those without germline mutations, raising the possibility of two different mechanisms for oncogenesis in these populations [37]. Integrated genomic analyses of cases of HGSC both with and without identified STICs have shown similar copy number alterations and mRNA expression profiles between the two groups, providing evidence that both share a common origin (putatively the fallopian tube) [38]. Details of the cell of origin of ovarian serous carcinomas are described in Chap. 4 of this book. Given the high lifetime risk of ovarian carcinoma, prophylactic bilateral salpingo-oophorectomies are recommended for BRCA1/2 carriers. Since the fimbria is now recognized as the site of origin for the majority of “ovarian” carcinoma, prophylactic salpingectomies are sometimes performed first, with delayed oophorectomies [39]. This gives some of the benefits of risk reduction for ovarian

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carcinoma, while delaying premature menopause. It has been speculated that cells from a STIC may exfoliate or detach from the fallopian tube and later result in advanced pelvic carcinoma (“precursor escape”) [28]. This mechanism has been postulated to explain some cases of pelvic high-grade serous carcinoma that arise following prophylactic salpingo-oophorectomies.

2.3.4 D  efinition of Primary Organ Site of Cancers Involving Tube, Ovary, and Peritoneum There is some controversy regarding how to assign a primary site to high-grade serous carcinomas that involve the tube, ovary, and/or peritoneum. Traditional clinicopathologic parameters which have been used to differentiate primary ovarian carcinoma from metastatic disease, such as bilaterality and surface involvement, are less useful in determining the site of origin of serous carcinoma [21]. Features which favor a tubal primary include unilateral tubal disease, a ­spectrum of neoplasia in the tube including STIC, and the absence of advanced (e.g., omental) disease spread [28]. Recent consensus guidelines have suggested an algorithm for assigning the primary site of serous carcinoma (Table 2.2). They state that when the tube is involved by carcinoma (by STIC and/or invasive carcinoma), the primary organ site should be specified as the fallopian tube, even if there is a greater burden of disease present in one of the ovaries [27, 40]. Furthermore, high-grade serous carcinoma should only Table 2.2  Guidelines for assigning a primary site for carcinomas involving the tube, ovary, and peritoneum Primary site Criteria Fallopian STIC present, with or without ovarian or peritoneal tube disease OR Invasive mucosal carcinoma in tube, with or without ovarian or peritoneal disease OR Fallopian tube incorporated in tubo-ovarian mass Ovary Ovarian carcinoma (even microscopic), in the absence of a STIC or tubal mucosal carcinoma AND Tubes must be fully evaluated with SEE-FIM to exclude a tubal primary Primary No STIC or invasive carcinoma in tubes or ovaries, peritoneal after examining with SEE-FIM and submitting ovaries in toto N.B. Do not diagnose “primary peritoneal” in the setting of neo-adjuvant chemotherapy; these cases should be assigned a site of origin of “tubo-ovarian,” even if there is no residual disease at these sites Tubo-­ HGSC diagnosed on cytology or omental biopsy OR ovarian Tumors treated with neo-adjuvant chemotherapy in which there is peritoneal disease, but no remaining tumor in the tubes or ovaries Adapted from ref. [27]

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be assigned a primary site of the ovary if both tubes have been examined using the SEE-FIM protocol and tubal neoplasia has been excluded. Primary peritoneal serous carcinoma should only be diagnosed when the tubes and ovaries have been examined microscopically and are disease-free. Neoadjuvant therapy for HGSC is common and can greatly reduce tumor burden and may obscure the site of origin. Consequently, in the setting of treated disease, a tubo-­ovarian primary should be assumed even if no residual disease remains in the tubes or ovaries. The stage-adjusted outcomes of tubal, ovarian, and primary peritoneal high-grade serous carcinoma are similar, suggesting that these diagnoses could be grouped together as “tubo-ovarian” or “pelvic” high-grade serous carcinoma [41]. Others argue that because the ovaries are frequently involved by disease, the terminology “HGSC of ovary” should be retained [42]. The incidence of fallopian tube carcinoma will likely increase as cases that may have previously been classified as primary ovarian carcinoma are now recognized to have likely originated from the f­ allopian tube.

2.4

Tumors of the Fallopian Tube

2.4.1 Overview The tube is a site of a wide variety of neoplasia, including benign and malignant epithelial and mesenchymal tumors. Historically, the fallopian tube was viewed as an unusual site for neoplasia in the female genital tract. However, with the recognition that many so-called ovarian carcinomas arise from the fimbria, the relative incidence in tubal carcinoma has increased. In this chapter, attention will be given to those lesions which are common or unique to the tube. The WHO classification of fallopian tube tumors is presented in Table 2.3. Many tumors that occur in the fallopian tube have more common, histologically identical, counterparts in the ovary and endometrium; those lesions are discussed in the relevant chapters.

Table 2.3  WHO classification of fallopian tube tumors Epithelial tumors and cysts Hydatid cyst Benign epithelial tumors    Papilloma    Serous adenofibroma Epithelial precursor lesion: serous tubal intraepithelial carcinoma Epithelial borderline lesion: serous borderline tumor Malignant epithelial tumors    Low-grade serous carcinoma    High-grade serous carcinoma    Endometrioid carcinoma    Undifferentiated carcinoma    Mucinous carcinoma    Transitional carcinoma    Clear cell carcinoma Tumor-like lesions    Tubal hyperplasia    Tubo-ovarian abscess    Salpingitis isthmica nodosa    Metaplastic papillary tumor    Placental site nodule    Mucinous metaplasia    Endometriosis    Endosalpingiosis Mixed epithelial-mesenchymal tumors    Adenosarcoma    Carcinosarcoma Mesenchymal tumors    Leiomyoma    Leiomyosarcoma Mesothelial tumors    Adenomatoid tumor Germ cell tumors    Mature teratoma    Immature teratoma Lymphoid and myeloid tumors Modified slightly from ref. [40]

2.4.2.1 Benign Tumors

2.4.2.2 Borderline Tumors Serous borderline tumors of the fallopian tube are rare and have a morphologic appearance similar to those of the ovary [45, 46]. They usually present with abdominal pain and can range in size from 2 to 23 cm [45]. Most are treated conservatively, with excellent outcomes [45, 46]. Both endometrioid and mucinous borderline tumors of the fallopian tube have also been reported [47, 48].

Papillomas Papillomas of the fallopian tube are rare neoplasms composed of branching papillary cores lined by bland, non-­ciliated, non-metaplastic, epithelium [43]. Papillomas may represent a variation of papillary tubal hyperplasia; a localized, massforming process favors a papilloma, while hyperplasia often affects the entire tube. Papillomas may cause tubal obstruction, resulting in hydrosalpinx or infertility [43, 44].

2.4.2.3 Malignant Tumors The vast majority of malignant tumors of the fallopian tube are high-grade serous carcinomas. It is not entirely clear why we do not encounter low-grade serous carcinoma of the fallopian tube. It may be that the cell of origin for low-grade serous neoplasia is not of fallopian tube origin, but no studies to our knowledge have evaluated this directly. The lack of frequent precursor lesions in the fallopian tubes in cases of

2.4.2 Epithelial Tumors

2  Fallopian Tube

ovarian low-grade serous carcinoma, in stark contrast to high-grade serous carcinoma, lends indirect support to this possibility. FIGO staging of fallopian tube carcinomas is incorporated into the staging system for ovarian and peritoneal carcinoma [49]. Given the pathogenic link between fallopian tube and high-grade ovarian carcinoma described earlier, it is not surprising that some of the risk factors, such as nulliparity, are shared for tubal and ovarian carcinoma [50]. Combined estrogen-progestin postmenopausal hormone replacement also appears to increase the risk of tubal carcinoma [51]. Clinically, fallopian tube carcinomas classically present with the Latzko triad of pelvic mass, abdominal pain, and vaginal discharge caused by a sudden release of fluid from a hydrosalpinx (“hydrops tubae profluens”). However, these symptoms are only found in 15% of patients with tubal carcinoma [36]. The average age of fallopian tube carcinomas is 55 years [52]. They often present at a high stage when disease has disseminated elsewhere in the abdomen. High-Grade Serous Carcinoma The histology and immunophenotype of tubal high-grade serous carcinoma are the same as in the ovary, which is described in Chap. 5. Grossly, the lumen may be distended, and the tumor often involves the fimbria (Fig.  2.5). Architecturally, HGSC may be papillary, pseudoglandular, or composed of sheets of tumor cells with slit-like spaces (Fig.  2.6a). Cytologically, the nuclei are pleomorphic with prominent nucleoli. Mitotic activity is usually abundant (>12/10 HPFs). Immunohistochemically, they are positive for CK7, PAX-8, WT-1, and p16, with an aberrant pattern of p53 staining (Fig.  2.6b–d). One interesting biomarker is estrogen receptor, which is expressed in >50% of tumor cells in about 60% of HGSCs [53]. The differential diagnosis of high-grade serous carcinoma includes low-grade serous carcinoma, high-grade endometrioid carcinoma, and a metastasis from an endometrial serous carcinoma or a non-gynecologic site. The two-tiered grading of serous carcinoma in the ovary, using nuclear atypia and mitotic activity, can also be applied to tubal serous carcinoma [54]. In cases with ambiguous histomorphology, WT-1 is an excellent marker of serous lineage in the tube, and abnormal p53 staining is helpful when the differential diagnosis is between high- and low-grade serous carcinoma. The presence of squamous differentiation, endometriosis, or an adenofibromatous component would favor an endometrioid tumor. Metastatic serous carcinoma from the endometrium is usually negative for WT-1 [55]. A previous history of a malignancy elsewhere is most helpful to suggest a metastasis from a non-gynecologic site. In cases where the tumor morphology does not seem compatible with a Müllerian primary, an appropriate immunohistochemical panel, often including PAX-8, can be used to work up possible metastatic disease.

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a

b

Fig. 2.5  Tubal high-grade serous carcinoma may protrude from the ostium (a) and distend the lumen (b)

Tubal HGSC may spread to the ovaries, uterine serosa, and peritoneum. Lymphatic spread, while less common, most frequently results in metastases to the para-aortic and pelvic lymph nodes. The surgical management and ­chemotherapeutic regimens for primary fallopian tube carcinoma are the same as in the ovary. Carcinosarcoma Carcinosarcomas, also called malignant mixed Müllerian tumors, are biphasic tumors composed of both malignant stroma (sarcoma) and epithelium (carcinoma) (Fig.  2.7). They have a poor prognosis [56]. Their histology is the same as those which arise elsewhere in female genital tract, although they occur much less frequently in the fallopian tube than in the endometrium and ovary. The histotype of the epithelial component may be difficult to subclassify as a single Müllerian histotype, and it is not necessary to do so. Heterologous differentiation (e.g., rhabdomyosarcomatous or chondrosarcomatous differentiation) is associated with a

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a

b

c

d

Fig. 2.6 (a) High-grade serous carcinoma is composed of nests of pleomorphic, hyperchromatic cells. Mitotic activity is abundant, and calcifications may be present. (b) The tumor shows diffuse overexpres-

a

sion of p16 (b), and abnormal p53 staining pattern (c). In contrast to endometrial serous carcinoma, which is usually WT-1 negative, tubo-­ ovarian serous carcinoma is positive for WT-1 (d)

b

Fig. 2.7  Carcinosarcoma is a biphasic malignant tumor. (a) A malignant epithelial proliferation involves the tubal fimbria. (b) Elsewhere, there is a malignant stromal component (chondrosarcoma, in this case)

2  Fallopian Tube

worse prognosis and should be reported if present. There is no minimum amount of sarcomatous differentiation required to qualify as a carcinosarcoma, and the combination of any amount of sarcoma with a carcinoma should be diagnosed as a carcinosarcoma. Other Tumors Primary fallopian tube mucinous, endometrioid, and clear cell carcinomas have been reported but are extremely rare [57–59]. Gestational trophoblastic disease (partial mole, complete mole, and gestational choriocarcinoma), identical to intrauterine disease, rarely arises in ectopic pregnancies [60].

2.4.3 M  ixed Epithelial and Mesenchymal Tumors 2.4.3.1 Serous Adenofibroma Serous adenofibromas of the tube are benign biphasic tumors composed tubal epithelium overlying a fibromatous stromal nodule (Fig.  2.8). They are small and often incidentally found during examination of salpingectomies for other indications. They are seen in 10% of women with either BRCA1/2 mutations or a strong family history of breast/ovarian carcinoma but only in 2.5% of non-high-risk women [25]. 2.4.3.2 Adenosarcoma Adenosarcomas are malignant neoplasms composed of benign epithelium and sarcomatous stroma. Primary fallopian tube adenosarcomas are extremely rare and share the same morphology with leaf-like architecture and periglandular stromal condensation as those in the endometrium or cervix [61].

a

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2.4.4 Other Tubal Tumors 2.4.4.1 Benign Mesenchymal Tumors Leiomyomas are uncommon in the fallopian tube, but are the most common mesenchymal tumor of this site. They are identical histologically to those that arise in the myometrium. Rare cases of cavernous and capillary hemangiomas of the fallopian tube have been described [62, 63]. 2.4.4.2 Malignant Mesenchymal Tumors Primary sarcomas of the fallopian tube are extremely rare [64]. Leiomyosarcomas of the tube have a morphology and immunophenotype which mimics those of uterine ­leiomyosarcomas. Criteria for malignancy are the same as in the uterus. Their prognosis is generally poor [65, 66]. There are single case reports describing biphasic synovial sarcoma [67], well-differentiated liposarcoma [68], and chondrosarcoma [69] of the fallopian tube. Embryonal, alveolar, and pleomorphic rhabdomyosarcomas of the fallopian tube, not arising in an adenosarcoma or carcinosarcoma, have also been reported [70–72]. 2.4.4.3 Adenomatoid Tumor Adenomatoid tumors are the most common benign tumor of the fallopian tube. They are mesothelial-derived proliferations that may occur in the uterus, tube, and ovary. Grossly, they are solid tan-white nodules, usually smaller than 2 cm. In the fallopian tube, they are well-circumscribed and usually lack the infiltrative border seen in other organs [73]. Histologically, they may show a variety of architectures including angiomatoid, tubular, or solid (Fig.  2.9). A lipoblast-­like or signet-ring cell morphology is frequently identified [73]. Cytologic atypia in the form of bizarre or symplastic-type atypia (i.e., enlarged, hyperchromatic nuclei

b

Fig. 2.8 (a) Serous adenofibromas may form small nodules on the fallopian tube, typically on the fimbria. (b) They are benign biphasic tumors composed of a fibromatous stromal component and serous epithelial component

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b

Fig. 2.9 (a, b) Adenomatoid tumors of the tube form well-circumscribed nodules and are often composed of small tubules

with smudgy chromatin) may be seen in adenomatoid tumors and does not affect the excellent prognosis. They display a mesothelial immunophenotype and are positive for pankeratin, calretinin, WT-1, and D2-40 [73, 74]. They are more likely to occur in immunosuppressed patients post-renal transplant, but the mechanism for this phenomenon is unclear [75]. The differential diagnosis includes mesothelioma, salpingitis isthmica nodosa, and metastatic adenocarcinoma. Mesothelioma is larger, is often symptomatic, and, by definition, has infiltrative growth with invasion into adipose tissue or adjacent organs. Salpingitis isthmica nodosa is lined by tubal epithelium and is negative for mesothelial-specific markers such as D2-40 and calretinin.

2.4.4.4 Metastatic Tumors The fallopian tube is an uncommon site of metastatic disease. In one series of 287 fallopian tubes from 145 patients removed for various reasons, metastatic carcinoma was identified in 1.4% of tubes [6]. Metastatic tumors in the tube may be present in lymphovascular spaces or in intraluminal, mucosal, submucosal, muscular, or serosal compartments of the tube (Fig. 2.10) [76–78]. By far the most common type of metastatic malignancy is adenocarcinoma (87%), although lymphoma, neuroendocrine tumors, and mesothelioma may also metastasize to the tube [77]. Excluding the uterus and ovary, the most common primary sites of metastatic carcinoma are the appendix, colon, stomach, biliary system, and breast [76, 77]. Metastatic mucosal disease may histologically mimic a STIC, so care should be taken when diagnosing these lesions in patients with a synchronous primary or history of a previous malignancy [36, 77]. Of note, tubal mucosal metastases from both endometrioid and serous endometrial carcinoma can histologically mimic STICs [36, 79]. Immunohistochemistry for p53, p16, and WT-1 may be helpful, depending on the context. Caution should be used with p53 and p16, since metastases to the

tube often show an aberrant expression, which can mimic the staining pattern of a STIC [77]. Recent phylogenetic analysis of cases of synchronous STICs and ovarian highgrade serous carcinoma have shown that the STIC, usually presumed to be the precursor lesion, in some cases actually represents an intramucosal metastases from the ovarian tumor [80].

2.5

Nonneoplastic Disorders of the Fallopian Tube

2.5.1 T  ubal Epithelial Metaplasia and Hyperplasia 2.5.1.1 Mucinous Metaplasia Mucinous metaplasia is found in approximately 3% of fallopian tubes [25]. Although rare, it is significant because it may accompany mucinous lesions elsewhere in the female genital tract and be associated with Peutz-Jeghers syndrome. Mucinous metaplasia of the tube is associated with mucinous cystadenomas, mucinous ovarian tumors of low malignant potential, and lobular endocervical glandular hyperplasia [81, 82]. In patients with Peutz-Jeghers syndrome, the mucinous epithelium is positive for MUC6 by immunohistochemistry, suggesting pyloric gland differentiation [81]. Metastases to the tubal epithelium may occasionally show mucinous differentiation with bland cytology, so care should be taken when diagnosing mucinous metaplasia in a patient with a history of adenocarcinoma elsewhere [77]. 2.5.1.2 Transitional Metaplasia and Walthard Cell Rest Walthard cell rests are small, solid, or cystic nests of transitional epithelium (Fig. 2.11). They are seen in 5% of salpingectomy specimens and are of no significance [6].

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a

b

c

d

Fig. 2.10 (a, b) Metastatic breast carcinoma NOS to the fallopian tube forms a mural nodule composted of epithelioid cells. (c) In this metastatic gastric carcinoma to the fallopian tube, tumor is present predomi-

a

nantly in lymphovascular spaces. (d) Metastatic lobular carcinoma of the breast is composed of inconspicuous signet-ring cells

b

Fig. 2.11  Walthard cell rests may be solid or cystic (a) and are composed of benign transitional epithelium (b)

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2.5.1.3 Metaplastic Papillary Tumor Metaplastic papillary tumor is a rare lesion of the fallopian tube. Twelve cases have been reported to date, and it is almost always found during pregnancy or in the immediate postpartum period [83, 84]. It is usually not grossly visible. Microscopically, the tumor shows papillary architecture with edematous papillary cores with sparse lymphocytic inflammation. Cytologically, the cells are columnar and non-­ ciliated, with enlarged nuclei and occasional prominent nucleoli. Epithelial budding and pseudostratification can be seen. Very infrequent mitotic activity is permitted [83, 84]. It is uncertain if the tumor represents a metaplasia or is a true neoplasm. The differential diagnoses include other papillary lesions of the tube, including a papilloma, papillary hyperplasia, and a borderline tumor. 2.5.1.4 Other Metaplasias Oncocytic (eosinophilic) metaplasia is incidental and seen in 4% of fallopian tubes [6]. Clear intraepithelial vacuoles, which are PAS and mucicarmine negative, are thought to represent a degenerative change seen in older patients [6]. 2.5.1.5 Tubal Mucosal (Epithelial) Hyperplasia Inflammatory conditions of the tube can induce a florid hyperplasia of the tubal epithelium, with complex architecture which may mimic a neoplasm. Hyperplasia can be differentiated from neoplasia based on the lack of significant atypia and mitotic activity and the presence of an inflammatory infiltrate. 2.5.1.6 Papillary Tubal Hyperplasia Papillary tubal hyperplasia refers to a specific form of epithelial hyperplasia, in which the epithelium forms papillary tufts with detached papillae within the lumen (Fig. 2.12). It is often, but not always, associated with psammoma bodies or chronic salpingitis. It has been suggested that epithelial a

D. L. Kolin and B. E. Howitt

clusters from papillary tubal hyperplasia may shed from the tube and seed the ovarian or peritoneal surface, where they become cortical inclusion cysts or endosalpingiosis [61]. These deposits may then acquire KRAS or BRAF mutations and develop into borderline serous tumors. Others have not found an association between papillary hyperplasia and borderline tumors [85]. The lack of diagnostic criteria and inter-­ observer variability complicate this diagnosis.

2.5.1.7 Pseudocarcinomatous Hyperplasia Definition Pseudocarcinomatous hyperplasia is an exuberant proliferation of the tubal epithelium which may be mistaken pathologically for carcinoma. It usually occurs between the ages of 17–40 (mean 29 years), much younger than most serous carcinomas. It may either present as an adnexal mass or be discovered incidentally [86]. Half of cases are seen in association with pelvic inflammatory disease [86]. Pathological Findings Grossly, the tube may be enlarged with a thickened wall. Pyosalpinx, a tubo-ovarian abscess, or hydrosalpinx may also be present. Microscopically, plical fusion results in the epithelium forming cribriform and pseudoglandular structures (Fig.  2.13). Invagination of the epithelium into the stroma may induce a stromal response which resembles desmoplasia [86]. Cytologically, the cells may show moderate nuclear atypia, including prominent nucleoli and focal loss of polarity [86]. However, there is usually only infrequent mitotic activity, with no atypical forms, and cells often maintain a normal nuclear-to-cytoplasmic ratio. Marked chronic inflammation, occasionally associated with an acute infiltrate, is always present. Psammoma bodies are often seen, as is overlying mesothelial hyperplasia. Papillary structures may even be present in tubal lymphatics [86]. b

Fig. 2.12 (a, b) Papillary tubal hyperplasia is characterized by abundant detached papillae within the tubal lumen

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a

b

Fig. 2.14  In salpingitis isthmica nodosa, tubal diverticula protrude into the wall of the tube and are surrounded by fibrosis or smooth muscle hypertrophy, without inflammation

Grossly, salpingitis isthmica nodosa forms nodules ranging from millimeters to 2  cm in size [88]. Histologically, bland tubal epithelium forms diverticula into the wall. There is often smooth muscle hypertrophy surrounding the epithelium (Fig. 2.14).

Fig. 2.13 (a, b) Pseudocarcinomatous hyperplasia may show complex cribriforming and pseudoglandular architecture

Differential Diagnosis The most important differential diagnosis is malignancy, most likely high-grade serous carcinoma. Given the associated inflammatory infiltrate, infections should also be considered. Mitotic activity may be the most helpful feature to differentiate pseudocarcinomatous hyperplasia from malignancy, as the former can show both architectural and cytologic features suggestive of carcinoma [86]. A wild-type pattern of p53 immunohistochemistry would also be reassuring. Areas of solid growth and atypical mitoses should not be observed in pseudoepitheliomatous hyperplasia, but are common in high-grade serous carcinoma.

2.6

Inflammatory Disorders

2.6.1 Salpingitis Isthmica Nodosa Salpingitis isthmica nodosa is seen in 3–5% of fallopian tubes and is strongly associated with ectopic pregnancy, where is it present in 25–50% of cases [25, 87]. It has also been associated with infertility [88].

2.6.2 Tubo-ovarian Abscess Tubo-ovarian abscesses are most frequently sequelae of salpingitis from an ascending sexually transmitted disease. Risk factors include infection with a sexually transmitted disease, multiple sexual partners, HIV infection, and age between 15 and 25 [89]. Tubo-ovarian abscesses are most commonly caused by Chlamydia trachomatis or Neisseria gonorrhoeae. Rarer causes include tuberculosis, actinomyces, and leprosy. Abscesses may also form secondary to ruptured appendicitis or inflammatory bowel disease.

2.6.2.1 Pathological Changes Salpingitis leads to blockage of the tube with subsequent abscess formation and necrosis. As it resolves, tubo-ovarian adhesions may form. 2.6.2.2 Granulomatous Salpingitis Rarer causes of salpingitis include mycobacteria, actinomyces, and leprosy, all of which manifest as granulomatous inflammation (Fig.  2.15). Mycobacterial infection can be confirmed with a Ziehl-Neelsen stain or PCR which can be performed on formalin-fixed paraffin-embedded tissue. Actinomyces israelii salpingitis is associated with IUDs and also presents with granulomatous inflammation [90]. Tubal schistosomiasis is a cause of ectopic pregnancies in the

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developing world but is rarely seen in North America [57]. It can induce an extensive inflammatory infiltrate with fibrosis, granulomatous reaction, and destruction of normal tubal architecture (Fig. 2.16). Noninfectious causes of granulomatous salpingitis include Crohn disease, sarcoidosis, and foreign body reactions (Fig. 2.17). It may be difficult to determine a specific etiology without adequate history.

Pelvic Inflammatory Disease Xanthogranulomatous salpingitis may occur after longstanding PID and is characterized by foamy macrophages in the wall of the tube (Fig.  2.18). Pelvic tuberculosis may clinically present as pelvic inflammatory disease and should be considered in immunocompromised patients [85]. Rare cases of salpingitis can also be caused by Enterobius vermicularis and pelvic coccidioidomycosis [91, 92].

2.6.2.3 Evolution and Outcomes Even with prompt treatment, resolving pelvic inflammatory disease and tubo-ovarian abscesses may result in tubo-­ ovarian adhesions and fibrosis. These can result in long-term sequelae of infertility, ectopic pregnancy, pelvic pain, and recurrent episodes of PID [89].

Pyosalpinx

Fig. 2.15  Tuberculosis infection of the tube shows non-necrotizing granulomatous inflammation

Fig. 2.16  Fibrous tissue surrounds calcified Schistosoma eggs in the fallopian tube

a

In acute salpingitis, an inflammatory infiltrate composed predominantly of neutrophils may involve the tubal lumen and lamina propria (Fig. 2.19). In severe cases, the tubal lumen may become distended with an acute inflammatory infiltrate with necrotic debris, grossly visible as pus, and is termed

b

Fig. 2.17 (a) Foreign bodies may elicit a giant cell reaction. (b) The foreign material can often be visualized with polarization

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a

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b

Fig. 2.18 (a, b) Xanthogranulomatous salpingitis is associated with PID and is characterized by a mixed inflammatory infiltrate, including foamy macrophages

Fig. 2.19  Neutrophils fill the tubal lumen and infiltrate the lamina propria in acute salpingitis

Fig. 2.20  Acute salpingitis may eventually result in plical fusion, termed follicular salpingitis

pyosalpinx. As the acute salpingitis resolves, the plicae may become fused and lamina propria fibrotic, called follicular salpingitis (Fig. 2.20).

2.6.3 Tubal Ectopic Pregnancy

Hydrosalpinx

As salpingitis resolves, the fimbria may fuse. The tube secondarily becomes distended with clear serous fluid, a condition termed hydrosalpinx. It commonly mimics a serous cystadenoma both clinically and grossly. Microscopically, however, smooth muscle bundles are present in the cystic wall in a hydrosalpinx, which differentiate it from a cystadenoma (Fig. 2.21). The tubal-type epithelial lining is the same in both a hydrosalpinx and serous cystadenoma.

Ectopic pregnancies are those in which the embryo implants outside the endometrium. The vast majority (~95%) occur in the fallopian tube and less frequently in the cervix, ovary, and abdominal cavity [93]. It occurs in 1% of natural pregnancies and 2–3% of pregnancies which are a result of assistive reproductive technologies [94]. Most tubal ectopics are in the ampulla (80%), and less commonly in the isthmus (12%), infundibulum, fimbria, or cornua [93].

2.6.3.1 Etiology Tubal ectopic pregnancies are caused by pathologic processes which obstruct the tubal lumen and interfere with the transport

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b

Fig. 2.21 (a) A hydrosalpinx cystically distends the fallopian tube lumen. (b) The hydrosalpinx is lined by tubal-type epithelium, with a muscular wall

of the ovum or embryo. Three-quarters of cases have an identified risk factor [94]. The factors most strongly associated with ectopic pregnancies are previous ectopic, previous tubal surgery, and salpingitis isthmica nodosa [87, 95]. Historically, in utero diethylstilbestrol exposure was also strongly linked to ectopic pregnancy [95]. However, it was banned for use in pregnancy by the Food and Drug Administration in 1971, so a history of exposure is now rarely found in women of childbearing age. Other risk factors less strongly associated with ectopic pregnancy are previous infection with gonorrhea or chlamydia, pelvic inflammatory disease, infertility, more than one lifetime sexual partner, history of pelvic or abdominal surgery, smoking, and age of first intercourse less than 18 [95]. In salpingitis secondary to gonorrhea or chlamydia, the tubal lumen can be distended with suppurative inflammation, and cilia can be lost, both of which impede transport of the fertilized egg and increase the likelihood of an ectopic pregnancy. Although pregnancy is much less common when a progestinsecreting intrauterine device or oral contraceptive pill is used, when a pregnancy does occur in these settings, it is much more likely to result in an ectopic pregnancy [96], presumably because progestins inhibit ciliary activity and increase the probability of tubal implantation.

2.6.3.2 Development and Outcome The most common presenting symptoms are abdominal pain and vaginal bleeding [94]. Rupture of the tube can cause tachycardia, syncope, shock, and ultimately death if treatment is delayed. Diagnosis is usually based on physical examination, serum β-HCG, and ultrasound findings, such as absence of a gestation in the uterus. In cases with equivocal findings, a diagnostic laparoscopy may be performed. An endometrial biopsy may also be performed; an absence of villi in the setting of a persistently elevated β-HCG is highly

Fig. 2.22  A tubal ectopic pregnancy causes distension of the tube with serosal congestion

suggestive of an ectopic pregnancy. Management can be medical (with methotrexate), surgical, or expectant. In terms of surgical options, salpingotomy is usually preferred as it maintains the possibility of fertility on the ipsilateral side. However, salpingectomy may be performed if the tube has extensive damage and is not salvageable.

2.6.3.3 Pathological Findings Grossly, the fallopian tube may be distended with blood (Fig.  2.22). Villi or an embryo may be visible within the lumen (Fig. 2.23). The wall of the tube is perforated in some cases. Adhesions on the fallopian tube may reflect previous infection or abdominal surgery. Histologically, an ectopic pregnancy can be documented by the presence of villi in the fallopian tube, often accompanied by significant hemorrhage (Fig. 2.24). Implantation site and embryo may also be visualized. It may resemble a partial hydatidiform mole, because of the trophoblastic proliferation and hydropic villi, which

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can be caused by methotrexate. Chronic salpingitis and salpingitis isthmica nodosa are also frequently seen (in 88% and 43% of cases, respectively) [97].

2.6.3.4 Secondary Disorders Associated with Tubal Ectopic Pregnancy Previous ectopic pregnancy is the strongest risk factor for a future ectopic pregnancy. In cases treated with salpingotomy, persistent trophoblast in the fallopian tube occurs in 8% of cases and is treated with methotrexate [94]. Rarely intermediate trophoblast lesions, such as placental site nodules and placental site trophoblastic tumors, may occur in the tube following an ectopic gestation [98]. Fig. 2.23 An embryo and chorionic villi from a tubal ectopic pregnancy

a

2.6.4 Tubal Sterilization Tubal sterilization is often performed during a caesarian section, and the tubes may show pregnancy-related changes such as deciduosis (see below). Interestingly, a large study involving 4489 patients with endometrial cancer showed that previous tubal ligation was associated with fewer cases of stage III and IV disease, and decreased mortality [99]. This suggests that tubal ligation prevents peritoneal disease by eliminating transtubal spread as a possible mechanism of dissemination.

2.6.5 Pregnancy-Related Changes Ectopic decidua (deciduosis) is identified in about 10% of the postpartum tubal ligation specimens, although the mechanism is unclear. It may be present in either the plicae or subserosal tissue in specimens from pregnant or postpartum patients (Fig.  2.25) [6]. Deciduosis can also be seen in

b

Fig. 2.24 (a) At low power, the tube is distended with hemorrhage. (b) Higher power shows chorionic villi with trophoblast adherent to the tube

Fig. 2.25  Cells with abundant eosinophilic cytoplasm in tubal deciduosis resemble the stromal cells in gestational endometrium

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patients taking high-dose progestins. The high levels of progesterone during pregnancy also cause physiologic shifts in the histology of the tubal epithelium, as described earlier.

2.6.6 Endometriosis There is tubal involvement in 6% of patients with endometriosis [100]. Clinically, it may cause infertility if the endometriosis is mass-forming and occludes the tubal ­ lumen. Histologically, the diagnosis is made if two of the following three features are noted: Müllerian glands (usually endometrioid), endometrial-type stroma, and hemosiderin-laden macrophages (Fig.  2.26). If only glands are present, endosalpingiosis should be considered. In a pregnant patient, deciduosis manifests as only decidualized endometrial stroma without glands. Salpingitis is present in 66% of patients with endometriosis and may be seen even if the fallopian tube itself is not involved with endometriosis [101]. Pseudoxanthomatous salpingiosis is frequently seen with tubal endometriosis (Fig.  2.2). In so-called polypoid endometriosis, the endometriosis forms a mass and may be clinically mistaken for a neoplasm. Occasionally the proximal fallopian tube mucosa is colonized by endometrial glands and stroma, a process termed endometrialization [102]. This process is associated with tubal ligation.

D. L. Kolin and B. E. Howitt

such as paratubal cysts or hydrosalpinx [103]. Grossly, the tube appears congested, with possible ischemic necrosis. Microscopically, tubal blood vessels may be dilated and associated with hemorrhage and necrosis. Treatment options include laparoscopic reduction of the torsion or salpingectomy. In resected specimens, the tubes may show congestion and ischemic changes. Untreated cases may progress to peritonitis.

2.6.7 Other Nonneoplastic Disorders

2.6.7.2 Tubal Prolapse Prolapse of the fallopian tube through the vaginal vault may occur after either vaginal or abdominal hysterectomies. Most cases present symptomatically with vaginal discharge, pelvic pain, or postcoital bleeding [104]. Predisposing factors are those which impede healing of the vault, such as infection or vaginal cuff hematoma [104]. It is more common in premenopausal women and can occur at any time post-­hysterectomy (reports range from the immediate postoperative period to 32 years after surgery) [104]. Instead of involving the vaginal vault, the tube may rarely prolapse through an abdominal caesarian section wound [105]. Histologically, prolapsed tube shows distortions from its usual appearance, with a polypoid shape, tubal epithelium, and an increase in stroma (Fig.  2.27). Clinically, the prolapsed tube resembles granulation tissue under colposcopy and may be misdiagnosed as “adenocarcinoma” pathologically as well if tubal epithelium is not appreciated [106]. On cervical cytology, prolapsed fallopian tube shows columnar cells which may be mistaken for malignancy if with significant reactive atypia [107].

2.6.7.1 Torsion of the Tube Torsion of the fallopian tube is an uncommon cause of pelvic pain in adolescent and middle-aged women. It is often associated with other pathology which distorts the tubal anatomy,

2.6.7.3 Paratubal Cyst Paratubal cysts are common, benign simple cysts found adjacent to the tube and lined by tubal-type epithelium. They are also known as hydatid cysts of Morgagni, despite being

a

Fig. 2.26 (a, b) Endometriosis involving the tubal serosa

b

2  Fallopian Tube

n­ oninfectious in origin. They are often small lesions incidentally noted in resection specimens, but they may also present as a mass. Similar to hydrosalpinx, paratubal cysts commonly contain smooth muscle fibers in the cystic wall.

2.6.7.4 Tubal Submucosal Hilus Cells Heterotopic hilus cells, or Leydig cell hyperplasia, are seen in less than 1% of fallopian tubes and may involve the endosalpinx or mesosalpinx [108]. Clinically, they may be associated with androgenic manifestations. Microscopically, they are composed of epithelioid cells with abundant, eosinophilic cytoplasm and prominent nucleoli and are ­

Fig. 2.27  Prolapsed fallopian tube may show fimbria lined by tubal-­ type epithelium, as well as areas resembling granulation tissue. Photomicrograph courtesy of Dr. C.  Crum (Brigham and Women’s Hospital, Boston, MA)

a

71

identical to those found in the ovary and testis (Fig. 2.28) [109, 110]. Hilus cell heterotopia in the tube can be associated with ipsilateral hilus cell hyperplasia [110]. They occasionally show brown lipofuscin pigment or Reinke crystals [109]. Most cases form discrete, circumscribed nodules; however, others may display an infiltrative, singlefile morphology which mimics metastatic lobular breast carcinoma [110].

2.6.7.5 Salpingoliths Salpingoliths are calcifications of the fallopian tube that may be intraluminal, epithelial, or in the lamina propria, with an associated overlying epithelial proliferation (Fig.  2.29) [101]. Salpingoliths occur in about a third of tubes with acute or chronic salpingitis or in cases with ovarian serous neoplasia, but in only 5% of cases without tumors or salpingitis

Fig. 2.28  Hilus cell hyperplasia in the tube is composed of cells identical to ovarian hilus cells, with large, epithelioid cells with abundant eosinophilic cytoplasm

b

Fig. 2.29  Salpingoliths are calcifications in the tube and may be intraluminal (a) or within the tubal stroma (b)

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D. L. Kolin and B. E. Howitt

[101]. There is conflicting evidence on a possible association between salpingoliths and serous borderline tumors of the ovary [101, 111].

2.7

 rossing Methods for Tubal G Specimens

2.7.1 Tubal Segments from Tubal Ligation The length and diameter of the tubal segment should be measured. The presence (or absence) of fimbria should be documented because it may have relevance to the planning and success of a future reversal procedure. The tubal serosal surface is examined for exudates, adhesions, and paratubal cysts. A probe can be used to assess for patency. Representative cross sections of the tubal segment are submitted and embedded so that an entire cross section can be visualized microscopically to ensure sterilization has taken place.

2.7.2 Uterus with Attached Bilateral Tubes The length and diameter of the fallopian tubes should be measured. The presence and state of fimbria should be noted, and the surface examined for exudates, adhesions, and paratubal cysts. A probe can be used to assess for patency. For hysterectomies performed for benign conditions (e.g., leiomyomata, prolapse), the fimbria should be amputated and submitted in toto. The remained of the tube is cross-sectioned at 5 mm intervals. Any luminal contents such as hemorrhage or purulent exudate should be noted. Representative sections of the midportion and cornual portion of the tube are submitted. The recommendation for complete sampling of the fimbria in all cases arises because an incidental STIC is found in approximately 1% of salpingectomies performed for benign indications [34]. For hysterectomies performed for malignancies, including ovarian and endometrial carcinoma, the fallopian tubes including fimbriated ends should be submitted in toto according to the SEE-FIM protocol (see next section). Increased sampling is warranted because of the potential for microscopic metastatic deposits which may upstage a patient. In one series, metastatic deposits were found in 1.6% of cases endometrial carcinoma with grossly normal tubes [112]. SEE-FIM should also be used in cases in which the patient has a personal history of breast cancer, or a family history of breast and/or ovarian cancer.

2.7.3 T  ubal Specimens from High-Risk Patients Patients with known germline mutations in BRCA1/2, a personal history of breast cancer, or a family history suspicious for BRCA1/2, have an increased risk of tubal neoplasia. Salpingectomies performed for prophylaxis in these patients should be sectioned following the Sectioning and Extensively Examining the FIMbria (SEE-FIM) protocol, which maximizes the amount of fimbria examined microscopically (Fig.  2.30) [11, 14]. In SEE-FIM, the fimbriae are amputated, longitudinally sectioned at 2–3 mm intervals, and submitted in toto. The remainder of the tube is also sectioned and submitted in toto. There is mixed evidence regarding the utility of routine deeper levels to increase the STIC detection rate [113, 114]. This protocol for high-risk patients should be considered for all patients with a history of prior malignancy, as thorough sampling can increase the detection rate of occult metastases [78].

2.7.4 T  ubal Specimens Containing “Essure” Devices The Essure system, developed by Bayer, is an alternative to tubal ligation for permanent sterilization. It involves the placement of a metal coil in each fallopian tube, which induces tubal fibrosis and prevents pregnancy. Since it was introduced in 2002, there have been reports of pelvic pain, tubal perforations, and pregnancies [115]. Essure devices may be received either in salpingectomy specimens or as part of a hysterectomy. Given their potential medicolegal significance, they should be given special care in the grossing room. Specimens containing Essure coils are weighed, measured, and photographed. Radiographs should also be obtained (Fig. 2.31a). The tubal serosal surface is examined for areas of possible disruption or perforation. The tube should be pinned and fixed prior to opening. The tubes can be opened longitudinally. Photographs and radiographs are repeated before removing the coils (Fig. 2.31b). The size of the coil and its position in the tube is documented. After the coil is removed, the region of the fallopian tube in contact with the coil is submitted in toto. The fimbria should also be submitted in toto, as well as representative sections of the remaining tube. (This Essure protocol was adapted from a version created by Dr. Bradley Quade, Dr. Carolyn Glass, and Delia Liepins, Department of Pathology, Brigham and Women’s Hospital.)

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Fig. 2.30  In the SEE-FIM protocol, the fimbriae are amputated and longitudinally sectioned to maximize the surface area of the fimbrial mucosa examined microscopically. The remainder of the tube is cross-sectioned and submitted in toto. Adapted from ref. [14]

a

b

Fig. 2.31 (a) Radiograph of fallopian tube containing metal contraceptive coil (“Essure”). (b) Fallopian tube containing coil after opening longitudinally

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76 73. Sangoi AR, McKenney JK, Schwartz EJ, et  al. Adenomatoid tumors of the female and male genital tracts: a clinicopathological and immunohistochemical study of 44 cases. Mod Pathol. 2009;22:1228–35. https://doi.org/10.1038/ modpathol.2009.90. 74. Terada T. An immunohistochemical study of adenomatoid tumors of the uterus and fallopian tube. Appl Immunohistochem Mol Morphol. 2012;20:173–6. 75. Mizutani T, Yamamuro O, Kato N, et  al. Renal transplantation-­ related risk factors for the development of uterine adenomatoid tumors. Gynecol Oncol Rep. 2016;17:96–8. https://doi. org/10.1016/j.gore.2016.05.003. 76. Stewart CJR, Leung YC, Whitehouse A.  Fallopian tube metastases of non-gynaecological origin: a series of 20 cases emphasizing patterns of involvement including intra-­ epithelial spread. Histopathology. 2012;60:E106–14. https://doi. org/10.1111/j.1365-2559.2012.04194.x. 77. Rabban JT, Vohra P, Zaloudek CJ. Nongynecologic metastases to fallopian tube mucosa. Am J Surg Pathol. 2015;39:35–51. https:// doi.org/10.1097/PAS.0000000000000293. 78. Na K, Kim H-S.  Clinicopathological characteristics of fallopian tube metastases from primary endometrial, cervical, and nongynecological malignancies: a single institutional experience. Virchows Arch. 2017;471:363–73. https://doi.org/10.1007/ s00428-017-2186-z. 79. Kommoss F, Faruqi A, Gilks CB, et al. Uterine serous carcinomas frequently metastasize to the fallopian tube and can mimic serous tubal intraepithelial carcinoma. Am J Surg Pathol. 2017;41:161– 70. https://doi.org/10.1097/PAS.0000000000000757. 80. Eckert MA, Pan S, Hernandez KM, et  al. Genomics of ovarian cancer progression reveals diverse metastatic trajectories including intraepithelial metastasis to the fallopian tube. Cancer Discov. 2016;6:1342–51. https://doi.org/10.1158/2159-8290. CD-16-0607. 81. Kato N, Sugawara M, Maeda K, et al. Pyloric gland metaplasia/ differentiation in multiple organ systems in a patient with Peutz-­ Jegher’s syndrome. Pathol Int. 2011;61:369–72. https://doi. org/10.1111/j.1440-1827.2011.02670.x. 82. Seidman JD. Mucinous lesions of the fallopian tube. A report of seven cases. Am J Surg Pathol. 1994;18:1205–12. 83. Jang MI, Sung J-Y, Kim J-Y, Kim H-S. Clinicopathological characteristics of metaplastic papillary tumor of the fallopian tube. Anticancer Res. 2017;37:3693–701. 84. Saffos RO, Rhatigan RM, Scully RE. Metaplastic papillary tumor of the fallopian tube—a distinctive lesion of pregnancy. Am J Clin Pathol. 1980;74:232–6. 85. Wolsky RJ, Price MA, Zaloudek CJ, Rabban JT.  Mucosal proliferations in completely examined fallopian tubes accompanying ovarian low-grade serous tumors: Neoplastic precursor lesions or normal variants of benign mucosa? Int J Gynecol Pathol. 2018;37:262–74. https://doi.org/10.1097/ PGP.0000000000000410. 86. Cheung AN, Young RH, Scully RE. Pseudocarcinomatous hyperplasia of the fallopian tube associated with salpingitis. A report of 14 cases. Am J Surg Pathol. 1994;18:1125–30. 87. Majmudar B, Henderson PH, Semple E.  Salpingitis isthmica nodosa: a high-risk factor for tubal pregnancy. Obstet Gynecol. 1983;62:73–8. 88. Jenkins CS, Williams SR, Schmidt GE.  Salpingitis isthmica nodosa: a review of the literature, discussion of clinical significance, and consideration of patient management. Fertil ­ Steril. 1993;60:599–607. 89. Chappell CA, Wiesenfeld HC. Pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and tuboovarian abscess. Clin Obstet Gynecol. 2012;55:893–903. https://doi. org/10.1097/GRF.0b013e3182714681.

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3

Benign Diseases of the Ovary David Suster, Martina Z. Liu, and Douglas I. Lin

Abstract

In surgical pathology, an understanding of the normal ovarian anatomy and the range of nonneoplastic lesions of the ovary is essential during the examination of gynecological specimens. Pathologists routinely evaluate nonneoplastic adult ovaries as components of (1) hysterectomy procedures for uterine leiomyomata, uterine prolapse, vaginal bleeding, or gynecological cancer and (2) risk-­reducing prophylactic salpingo-oophorectomy, with the primary goals of excluding ovarian malignancy and/or determining whether the ovary is the source of hormone production driving uterine cancer. In these scenarios, with the exception of endometriosis, ovarian infection, or a hormone-producing lesion, any incidental nonneoplastic lesion encountered in the ovary is likely not of clinical significance. However, another frequently encountered scenario is examination of the ovary via biopsy, cystectomy, or excision for a specific purpose, including ovarian enlargement, cyst formation, masses, torsion, infection, infertility, or ectopic pregnancy, in which the ovary is submitted for evaluation for a clinical or radiological reason. Each of these settings requires the pathologist to have knowledge of the normal ovarian anatomy, the histology, and the range of nonneoplastic lesions of the ovary in order to guide the obstetrician-gynecologist or gynecologic oncologist to the appropriate treatment and follow-up. Keywords

Ovary · Benign · Nonneoplastic · Anatomy · Histology

D. Suster Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA M. Z. Liu Brigham and Women’s Hospital, Boston, MA, USA D. I. Lin (*) Foundation Medicine, Inc., Cambridge, MA, USA e-mail: [email protected]

3.1

 natomy, Histology, and Function A of the Ovary

3.1.1 Cortex, Medulla, and Hilus 3.1.1.1 Gross Ovarian Anatomy The ovaries are paired pelvic reproductive organs that are grossly located posterior to both the broad ligament and the ipsilateral fallopian tube, which is helpful in determining the laterality of a specimen. Grossly, the ovaries are ovoid in shape, but size and surface appearance vary according to age. In general, ovaries from reproductive-age women are larger (up to 5 cm) with smoother outer surface, compared to postmenopausal ovaries, which can typically shrink in size and acquire more convoluted, cerebriform surface (Fig.  3.1). Three ill-defined ovarian components can be grossly identified the outer cortex, the inner medulla, and the hilus [1]. 3.1.1.2 Histology of Cortex, Medulla, and Hilus Microscopically, the ovarian surface is lined by the ovarian surface epithelium (OSE), which is composed of a single layer of modified peritoneal mesothelial cells. The morphology of OSE ranges from flat to cuboidal to columnar with a low nuclear-to-cytoplasmic ratio and inconspicuous nuclei. OSE is separated from the underlying cortex by a basement membrane (Fig.  3.2). OSE is thought to be derived from embryonic coelomic epithelium, which becomes the mesothelium lining the serous body cavities and the surface epithelium covering the ovary [2]. For this reason, by immunohistochemistry, OSE cells are positive for cytokeratin, WT1, calretinin, estrogen and progesterone receptor, and Ber-EP4. In addition, several studies have shown that OSE is typically negative for both Pax2 and Pax8, reflecting the specific Müllerian lineage-determinant nature of these latter transcription factors. The presence of occasional PAX2-­positive and PAX8-positive Müllerian-like epithelial cells on the ovarian surface may represent the transfer of fallopian tubal epithelial cells to the ovary because of their anatomic proximity, physiological contact, or adhesion [2].

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_3

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Fig. 3.1  Gross ovary

Fig. 3.2  Ovarian surface epithelium and cortical stroma

Alternatively, a metaplasia or differentiation process from OSE to Müllerian-type or fallopian tube-like epithelium has also been proposed to account for areas of PAX2-positive and PAX8-positive OSE [3]. The ovarian cortex is composed of ovarian stromal cells, which are spindle-shaped with scant cytoplasm, and is arranged in a storiform growth pattern with variable amount of collagen (Fig. 3.2). The border between the cortex and medulla is subtle and ill-defined as cortical and medullary stromal cells have similar morphology. Ovarian stromal cells can respond to pituitary and pregnancy hormones, and they are capable of producing steroid hormones, including androstenedione, testosterone, estradiol, and estrone [4, 5]. By immunohistochemistry, ovarian stromal cells stain for smooth muscle actin, desmin, estrogen receptor, and progesterone receptor. The medulla is more easily identifiable during menopause or postmenopause, when the cortex

D. Suster et al.

a­ trophies and corpora albicantia and large vessels remain in the medulla. The proximal medulla merges with the hilus, which contains large blood vessels derived from ovarian artery and vein, large lymphatic trunks and plexuses, fibroconnective tissue, and nerve fibers (Fig. 3.3). The ovarian hilus attaches to the broad ligament, and unique cell subtypes may be identified in the hilar region. The first cell type is the ovarian hilus cells, which are characterized by eosinophilic cytoplasm, round nuclei, and prominent nucleoli and are morphologically similar to testicular Leydig cells (Fig. 3.4) [6]. Reinke crystals, lipid vacuoles, and golden-brown pigment may be present, and they are positive for inhibin and calretinin by immunohistochemistry. The hilus cell population secretes steroid hormones and may undergo expansion [7], which is described later in the hilus cell (Leydig) hyperplasia section.

Fig. 3.3  Ovarian hilus

Fig. 3.4  Hilus cells

3  Benign Diseases of the Ovary

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Fig. 3.5  Rete ovarii

Fig. 3.7  Walthard’s nest

Fig. 3.6  Wolffian remnants (epoophoron)

Fig. 3.8  Multiple primordial follicles in neonatal ovary

A second cell population that can be identified in the hilus is the epithelial lining constituting the rete ovarii, which resembles the male rete testis counterpart. Morphologically, this cell population ranges from cuboidal to columnar and is arranged in a network of clefts, tubules, and small papilla (Fig.  3.5). The rete ovarii stains positively for EMA, cytokeratin, and Pax8 and is negative for Pax2 and Gata3 [8, 9]. The rete ovarii may be in close proximity to mesonephric tubule remnants (i.e., epoophoron) (Fig. 3.6) and Walthard’s nests (i.e., transitional cell metaplasia) (Fig. 3.7).

become atretic if not selected for ovulation. At birth, thousands of primordial follicles are present in the neonatal ovary (Fig. 3.8); and, throughout life, their numbers steadily decrease through folliculogenesis and atresia. In the reproductive age ovary, primordial, primary, and secondary follicles are found in the superficial ovarian cortex (Fig. 3.9). Primordial follicles are characterized by a primary oocyte surrounded by a single layer of flattened, mitotically inactive, granulosa cells (Fig.  3.10). In the first stage of maturation from primordial to primary follicle, the flattened, mitotically inert granulosa layer assumes a cuboidal to columnar shape, becomes mitotically active, and increases in size (Fig. 3.11). Proliferation of the granulosa cells results in their stratification with up to five concentric layers of granulosa cells around the oocyte and progression to a secondary or pre-antral ­follicle (Fig. 3.12).

3.1.2 Follicular Development and Atresia Follicular development (folliculogenesis) is a continuous process wherein primordial follicles are either selected and undergo maturation in preparation for ovulation or

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Fig. 3.9  Primordial, primary, and secondary follicles in the cortex

Fig. 3.12  Secondary (pre-antral) follicle

Fig. 3.10  Primordial follicles in reproductive age ovary

Fig. 3.13  Mature (Graafian) follicle. From left to right: antrum, granulosa cell layer, theca cell layers, and ovarian cortical stroma

Fig. 3.11  Primary follicle

Secondary (pre-antral) follicles subsequently mature into Graafian (mature) follicles as they increase in size and migrate deeper into the ovarian cortex. At this point, the ­surrounding stroma differentiates into layers of theca interna and theca external cells (Fig. 3.13). Simultaneously, a large cavity or antrum is formed within the Graafian or mature ­follicle that is filled with interstitial fluid and is lined by granulosa cells (Fig.  3.13). At the same time, the oocyte migrates to an eccentric position at one pole of the follicle within the cumulus oophorus, which projects into the antrum (Fig. 3.14). During each ovulatory cycle, typically only one mature Graafian follicle will progress to a preovulatory follicle, in which the oocyte and a surrounding layer of granulosa cells (corona radiate) float freely in antrum fluid (Fig. 3.15). Physiologically, preovulatory follicles may reach up to 2–3 cm in diameter. Following ovulation, the ovulatory

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follicle devoid of the oocyte develops into a corpus luteum (Fig.  3.16a, b). In the absence of fertilization, the corpus luteum degenerates (Fig. 3.17a–c), and the regressed corpus luteum is converted to a scar, the corpus albicans (Fig. 3.18). Developing follicles that do not progress to ovulation undergo atresia, which is a continuous process from birth to the end of reproductive life. Molecular mechanisms that induce follicular atresia are not completely known [10, 11]; however a morphologic spectrum of atretic follicles may be seen during the routine histological examination of the ovary (Fig. 3.19a–c).

3.1.3 H  ormones and Peptides Secreted by the Ovary Fig. 3.14  Mature (Graafian) follicle

Fig. 3.15  Preovulatory follicle. Oocyte with surrounding zona pellucida and layer of granulosa cells floating in antrum fluid

a

Fig. 3.16  Corpus luteum low (a) and high (b) power

The ovary produces a variety of hormones and peptides that are secreted into the blood in both physiologic and pathological conditions. We will focus on hormones and peptides that are produced by the benign ovary and that are physiologically and clinically useful. Factors that are associated with neoplasia, such as elevated CA125 and germ cell tumor markers, are discussed elsewhere in the book. Briefly, regarding CA125, in addition to a variety of cancers, a number of benign ovarian or gynecological conditions may be associated with CA125 elevation, such as endometriosis, fibroids, pelvic inflammatory disease, menses, pregnancy, and peritonitis [12]. The ovary is a site of steroid hormone production in both physiological and pathological conditions. Numerous studies have demonstrated the extra-adrenal steroidogenic potential and gonadotropin responsiveness of ovarian sex cord stromal cells. During ovulatory cycles, there is an intimate physiologic interrelationship between the hypothalamo-­ pituitary-­ovarian-endometrial axis. The interplay of rising b

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Fig. 3.17  Morphological changes of degenerating corpus luteum (a–c)

Fig. 3.18  Corpus albicans

pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels regulates late stages of follicular maturation, ovulation, and cyclic steroid hormone production by follicular granulosa and theca cells. The ovarian estrogens

and progesterone, produced by the follicular granulosa theca cells and by the corpus luteum, respectively, induce cyclic endometrial alterations to provide an appropriate environment for implanting the fertilized embryo [13]. Progesterone production by corpus luteum is controlled by placental human chorionic gonadotropin (HCG) and is also required for maintenance of early pregnancy until the placenta takes over this function. In addition to estrogen production, the ovary is also a source of small amounts of extra-adrenal androgen production, such as testosterone and androstenedione. This androgenic, steroidogenic activity by ovarian stromal cells is accentuated during menopause with complete follicular atresia and depletion of follicles. Both androgenic and estrogenic activity may also be seen with benign or neoplastic proliferations of sex cord stromal cells, including stromal ­ hyperplasia, hyperthecosis, or sex cord stromal tumors. This excess hormone production in turn may play a role in the development of virilization symptoms and endometrial neoplasia.

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Fig. 3.19  Morphologic spectrum of atretic follicles (a–c)

The ovarian sex cord stromal cells also produce nonsteroidal hormones, such as glycoproteins, inhibin A and B, which are secreted into the bloodstream and negatively regulate FSH synthesis by the pituitary [14]. The main cellular sources of inhibin B are the growing follicle granulosa cells and granulosa cell tumors, while inhibin A is mainly produced by the corpus luteum and the placenta [15]. For this reason, in infertile women who are undergoing assisted reproduction therapies, inhibin B may be a useful marker of ovarian reserve, a term that describes the remaining pool of oocytes or a woman’s reproductive potential [16], since low inhibin B levels have been shown to predict a poor ovulatory response [15]. In addition, serum inhibin B levels are helpful in the diagnosis and management of granulosa cells tumors. Both adult and juvenile types of granulosa cells tumors may present with elevation of serum inhibin B in either a primary or a recurrent tumor setting. Besides inhibin B, another marker of ovarian reserve is the anti-Müllerian hormone (AMH). AMH levels, as well as chronologic age, early follicular phase FSH levels, and

early follicular phase inhibin B levels, are all correlated with ovarian reserve and are predictive of reproductive potential [17]. AMH is produced by the granulosa cells of small growing follicles. During follicular maturation, AMH physiologically inhibits initial follicle recruitment and subsequent FSH-­dependent selection and growth of pre-antral and small antral follicles. As follicles mature, AMH remains highly expressed in cumulus cells [18]. For these reasons, AMH levels reflect the number of antral and pre-antral follicles present in the ovaries, and the levels of circulating AMH in blood have been used in various clinical scenarios and applications. For instance, circulating AMH levels have been suggested to predict the ovarian response to hyperstimulation of the ovaries for in  vitro fertilization (IVF) and egg/oocyte retrieval and the timing of menopause. Low AMH levels have also been proposed to indicate iatrogenic damage to the ovarian oocyte reserve, and AMH has also been used as a surrogate marker for antral follicle count in the diagnosis of polycystic ovary syndrome (PCOS) [19].

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Finally, a number of other ovarian growth factors involved in cell cycle or apoptosis, together with gonadotropins and estrogens, have been proposed to regulate follicular development and follicular atresia. During follicle development, local ovarian growth factors, such as IGF-I, EGF/TGF-alpha, basic FGF, and cytokines, including interleukin-1 beta, activate different intracellular cell cycles and anti-apoptotic pathways to prevent follicles from undergoing atresia and apoptotic demise [10]. IGF-I and estrogen induce the proliferation of granulosa cells via activation of the mitotic cell cycle and promote granulosa cell survival via anti-apoptotic signals. The main cell cycle and antiapoptotic molecular pathway induced by IGF-I and estrogen appear to be via activation of phosphatidylinositol 3-kinase and its downstream target, protein kinase B/Akt [11]. In contrast, other signaling factors have been implicated in promoting follicle atresia, such as androgens, TNF-alpha, and Fas ligand, the latter two presumably by acting through receptors with a death domain. These diverse hormonal, growth, and signaling factors may then converge on selective intracellular pathways to regulate follicle cell growth, proliferation, survival and apoptosis during follicular development, and atresia [10].

3.2

Fig. 3.20 Corpus luteum of pregnancy, low power, undulating architecture

Pregnancy-Associated Findings

3.2.1 Corpus Luteum of Pregnancy 3.2.1.1 Clinical Features Secretion of progesterone by corpus luteum is critical to secretory differentiation of the endometrium in preparation for embryo implantation and for the maintenance of pregnancy in the first 8 weeks of gestation. As the placenta develops, the corpus luteum gradually regresses during pregnancy. However, the corpus luteum may persist in later gestation, and it can present as a benign ovarian lesion during pregnancy [20]. 3.2.1.2 Pathology Grossly, the corpus luteum of pregnancy is a single, yellow, cerebriform nodule, often with hemorrhagic center. Microscopically, wedge-shaped invaginations imparting a cerebriform, undulating architecture are seen at low power magnification (Figs. 3.20 and 3.21). The surrounding ovarian stroma may undergo deciduosis or ectopic decidua (Fig. 3.21, top). On high power, the lesion is composed of luteinized granulosa cells with eosinophilic cytoplasm and central nuclei with prominent nucleoli (Fig. 3.22). In contrast to the nonpregnant corpus luteum, pink hyaline globules and calcifications are features specific of the corpus luteum of pregnancy (Fig. 3.22). The main differential diagnosis includes pregnancy luteoma [21]. Features favoring corpus luteum of

Fig. 3.21  Corpus luteum of pregnancy, medium power, invaginations

Fig. 3.22  Corpus luteum of pregnancy, high power hyaline globules

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pregnancy over pregnancy luteoma include occurrence in early pregnancy, yellow gross color, cerebriform architecture, and presence of hyaline globules and calcifications.

3.2.2 P  regnancy Luteoma (Theca-Lutein Hyperplasia of Pregnancy) 3.2.2.1 Clinical Features Pregnancy luteoma (also known as theca-lutein hyperplasia of pregnancy) is a rare, tumor-like lesion that may be incidentally discovered during pregnancy. It more frequently occurs in multiparous African-American women, and these lesions are thought to arise from theca-lutein cells (­ luteinized theca interna cells of the follicle) or from stroma-lutein cells (luteinized stromal cells) [22]. Therefore, pregnancy luteoma may secrete androgens, including testosterone, which may cause hirsutism or virilization of mothers and their female infants [23]. Luteoma of pregnancy can simulate a tumor and present as an adnexal mass. By imaging, they can appear solid but may have a cystic component [24]. These lesions are benign and are likely under the influence of human chorionic gonadotropin, as they undergo spontaneous regression and serum androgen levels normalize after delivery [25]. Due to their benign nature, conservative management is recommended with preservation of the ovary unless the lesion persists in the postpartum period. 3.2.2.2 Pathology Grossly, pregnancy luteomas are discrete or multinodular brown or red/hemorrhagic solid nodules ranging from 1.0 cm up to 20 cm that replace the ovarian parenchyma (Fig. 3.23). They may be bilateral in up to a third of cases [22, 23]. Microscopically, the nodules are typically composed of a

Fig. 3.24  Luteoma of pregnancy, low power: diffuse, solid, sheet-like architecture

Fig. 3.25  Luteoma of pregnancy, high power: solid growth of eosinophilic cells with round nuclei, prominent nucleoli, and delicate blood vessels

solid proliferation of luteinized stromal cells with eosinophilic cytoplasm (Fig. 3.24) and central nuclei with small to prominent nucleoli (Fig. 3.25). Mitotic activity may be brisk, up to 7/10 per high power fields. Necrosis, cystic changes, or follicle-like spaces containing eosinophilic (colloid-like) secretion may be seen (Fig.  3.26) [21]. In the postpartum period, degenerative changes, frothy/pale rather than eosinophilic cytoplasm, and fibrosis can be present. By immunohistochemistry, lesional cells are positive for inhibin, calretinin, and Melan A and are negative for keratins and other melanoma markers.

Fig. 3.23  Luteoma of pregnancy gross: Tan brown and red solid nodule with foci of hemorrhage

3.2.2.3 Differential Diagnosis The main differential diagnosis includes other sex cord stromal tumors such as steroid cell tumor, luteinized thecoma or

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anomalies and preeclampsia with its sequelae [27]. Virilization of the pregnant woman due to elevated androgens is observed in less than half of cases but only rarely observed in female fetuses. As this is a benign condition which regresses after delivery, management should be conservative to preserve future fertility. Surgical intervention is warranted only in the setting of ovarian torsion or rupture.

Fig. 3.26  Luteoma of pregnancy, high power: typical follicle-like spaces containing colloid-like secretory secretion

3.2.3.2 Pathology Hyperreactio luteinalis is characterized by bilateral ovarian enlargement up to 15 cm or more in greatest dimension. The ovarian surface is lobulated, and sectioning reveals numerous cysts ranging from 1 to 3 cm in size (Fig. 3.27) that are remarkable for a smooth, yellow lining. The cyst content is clear watery to hemorrhagic. Morphologically, the cysts are lined by luteinized granulosa and theca interna cells often with edema or features of torsion of the cyst wall and ovarian stroma (Fig. 3.28).

luteinized granulosa cell tumor, Leydig cell tumor, and metastatic carcinoma or melanoma.

3.2.3 Hyperreactio Luteinalis 3.2.3.1 Clinical Features Hyperreactio luteinalis is a rare condition characterized by bilateral massive, cystic enlargement of the ovaries during pregnancy. It occurs more commonly in primiparous women and is most frequently associated with singleton pregnancies [26]. Hyperreactio luteinalis is characterized by the formation of numerous, large theca-lutein cysts; this occurs in response to abnormally high levels of human chorionic gonadotropin (HCG) or, in rare cases, to increased sensitivity of the ovarian stroma to HCG.  Elevated HCG during gestation has been observed secondary to conditions resulting in a large placenta, such as multiple gestation, diabetes mellitus, and Rh sensitization; however, most cases of hyperreactio luteinalis are observed in normal singleton gestations. Additionally, similar effects on the ovaries are seen in molar pregnancies, trophoblastic disease, and choriocarcinoma [26]. Presenting signs and symptoms are related to maternal virilization secondary to increased circulating androgens produced by the ovaries or abdominal pain due to ovarian enlargement, torsion, or rupture. A significant proportion of cases are discovered incidentally on routine imaging or occasionally at the time of cesarean section. Ultrasound typically shows bilateral enlarged ovaries with numerous cystic structures, and these findings should not be mistaken for malignancy [26]. Although hyperreactio luteinalis is a benign process, it has been associated with adverse effects on the pregnancy secondary to elevated hCG, including the slightly increased risk of fetal

Fig. 3.27  Hyperreactio luteinalis, low power, associated with torsion

Fig. 3.28  Hyperreactio luteinalis cyst lining, high power, associated with torsion

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3.2.3.3 Differential Diagnosis The histological differential diagnosis includes luteinized follicular cyst, luteoma of pregnancy, and cystic granulosa cell tumor. The gross examination and clinical history, in particular with regard to bilateral ovarian enlargement due to numerous luteinized follicular cysts, are essential in differentiating these entities.

3.2.4 L  arge Solitary Luteinized Follicular Cyst of Pregnancy 3.2.4.1 Clinical Features Large solitary luteinized follicle cyst is a rare, unilateral tumor-like ovarian lesion with less than 15 cases having been reported in the literature as of 2017. It is typically discovered during mid- to late pregnancy or puerperium, and although its pathogenesis is unknown, a role of abnormal response to hCG has been postulated [28, 29]. Due to its enormous size, patients typically present with signs and symptoms of a large ovarian or adnexal mass with or without torsion or rupture [30]. Endocrine manifestations are typically absent [28]. Following excision, no recurrences have been reported highlighting a benign biological behavior. 3.2.4.2 Pathology The gross appearance is of a large unilocular cyst, up to 55 cm in size (average diameter of 25 cm), filled with either serous or mucoid fluid [28]. The cyst wall is typically thin, measuring less than 0.5 cm [31], which, upon histological examination, is composed of up to ten layers of luteinized cells with eosinophilic to vacuolated cytoplasm lining the cyst wall. Distinct granulosa and theca layers are typically not seen. Instead, the luteinized cells lining the cyst wall are uniform with small, round nuclei, smooth nuclear contours, and small nucleoli (Fig.  3.29). However, foci of scattered cells may show marked nuclear enlargement, hyperchromasia, and bizarre and pleomorphic nuclei (Fig. 3.30) [28]. Importantly, hyaline bodies or calcified foci that are frequently seen in corpus luteum of pregnancy are not present. Mitosis, apoptosis, and necrosis are typically absent. Nests of luteinized cells, similar in appearance to those lining the cyst, can be identified within the stroma of the cyst wall, which should not be mistaken for invasion. A reticulin stain can highlight scattered fibrils surrounding the nests of luteinized cells [29]. 3.2.4.3 Differential Diagnosis The major malignant differential diagnoses that should be excluded include unilocular cystic granulosa cell tumors of either adult or juvenile types. Other benign differential diagnoses include corpus luteum of pregnancy, pregnancy luteoma, and hyperreactio luteinalis, which can be distinguished based on the gross and histological features.

Fig. 3.29  Large solitary luteinized follicle cyst of pregnancy: lining composed of luteinized cells with clear and eosinophilic cytoplasm and small uniform round nuclei

Fig. 3.30  Large solitary luteinized follicle cyst of pregnancy with focal nuclear atypia

3.2.5 Ectopic Decidua (Deciduosis) 3.2.5.1 Clinical Features The development of ectopic decidua is considered a physiologic phenomenon of pregnancy and has been reported in almost all ovaries at term [32]. During pregnancy, ectopic decidua may also be encountered in diverse locations such as endocervical stroma, uterine serosa, fallopian tubes, omentum, appendix, small and large intestine, and urinary bladder [33]. Involvement of the appendix may give rise to signs and symptoms of acute appendicitis during pregnancy [34]. Ectopic decidua may also occur in early gestation, as well as in nonpregnant women with progestin treatment, with trophoblastic disease, and with a hormone-producing ovarian or extra-ovarian lesion [33]. Deciduosis is a benign

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process that regresses in the postpartum period without any major complications.

3.2.5.2 Pathology Gross lesions are often not seen but, if present, may mimic a neoplasm as gray to white nodules, polyps, or sheets on the ovarian surface or extra-ovarian sites [32]. Microscopically, ectopic decidua typically involves the ovarian cortex or areas of periovarian adhesions (Fig. 3.31). Morphologically, deciduosis resembles the decidualized endometrial stroma counterpart of the gestational endometrium, and it is characterized by epithelioid cells with abundant clear to pink c­ytoplasm and bland, round nuclei (Fig.  3.32). Mitotic activity is absent, but focal nuclear pleomorphism, hyperchromasia, prominent nucleoli, and necrosis may be seen [35].

Fig. 3.31  Ectopic decidua involving the ovarian cortex

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3.2.5.3 Differential Diagnosis The differential diagnosis includes a luteinized sex cord stromal tumor or a metastatic neoplasm (melanoma, deciduoid mesothelioma, carcinoma), especially when encountered in non-gynecological sites such as the omentum [36].

3.2.6 Pregnancy-Associated Granulosa Cell Proliferation 3.2.6.1 Clinical Features Pregnancy-associated granulosa cell proliferations are benign, incidental findings in ovaries removed during pregnancy. They are thought to occur due to the FSH-like activity of HCG and the hormonal milieu of pregnancy. Follow-up data on these lesions is scant, with only ten reported cases in the literature; however they are considered benign nonneoplastic lesions of the ovary [37, 38]. 3.2.6.2 Pathology Because they are incidental findings, gross appearance has not been described. Microscopically, they are characterized by multifocal, microscopic foci of solid, non-cystic, intrafollicular granulosa cell proliferation, typically measuring 10–12) by ultrasound. In addition, most patients with PCOS will have a variety of laboratory abnormalities. High levels of LH are commonly encountered and are likely the driving force behind theca cell growth. Patients tend to have normal or slightly higher levels of FSH and will usually present with a LH:FSH ratio of greater than 2 [60–62]. Levels of anti-­ Müllerian hormone and prolactin tend to be increased as well [18]. Most patients have increased androgen production with raised levels of total testosterone (as well as circulating free testosterone due to low levels of sex hormone-binding protein), androstenedione, DHEA, and DHEA-s. Clinically, patients present with symptoms of hyperandrogenism (hirsutism, menstrual irregularities, etc.), infertility (secondary to anovulation), abdominal pain, hepatic steatosis, abnormal uterine bleeding, and polycystic ovaries, among others. Pharmacologic therapy with oral contraceptives for managing hyperandrogenism and menstrual dysfunction, combined with weight-loss strategies, is the first-line therapy for PCOS [60]. Metformin may also play a role in restoring normal metabolic functions and ovulation; however, for women desiring pregnancy, clomiphene is now a treatment of choice [64]. Surgery is no longer commonly used in the treatment of PCOS; however, it may still be useful for specific patients [65–67]. The clinical differential diagnosis for PCOS is broad and includes congenital adrenal hyperplasia, thyroid disease, and hyperprolactinemia as well as other causes of androgen excess including ovarian tumors, adrenal tumors, and ovarian hyperthecosis. In these other entities, there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, and the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the underlying cause [68].

3.3.4.2 Pathology Grossly, the ovaries in PCOS are symmetrically enlarged and usually have a thick capsule. On cut sections, there is an

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Fig. 3.42  PCOS, low power, multiple cystic follicles

Fig. 3.43  PCOS, high power, luteinized stromal cells (hyperthecosis)

outer cortical linear array of multiple small cysts. Microscopically, multiple cystic follicles of a relatively uniform size are seen (Fig.  3.42). Due to anovulation, corpus luteum and corpus albicans are usually not present. Theca cell hyperplasia occurs in follicles and may also be identified as islands or isolated theca cells in the cortical stroma (stromal hyperthecosis) (Fig. 3.43). Atretic and involuted follicles may be present combined with some increased stromal fibrosis.

3.3.4.3 Differential Diagnosis The microscopic differential diagnosis includes hyperreactio luteinalis and ovarian hyperstimulation syndrome. Similar microscopic findings mimicking PCOS may also be seen in oophorectomy specimens of transgender patients following androgen treatment and sex-reassignment female-to-male surgical procedure.

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3.3.5 Ovarian Endometriosis Ovarian endometriosis is a leading cause of infertility in reproductive age women with a prevalence of 0.5–5% in fertile and 25–40% in infertile women [69]. In contrast, there appears to be no significant link between endosalpingiosis and infertility, suggesting endometriosis and endosalpingiosis are two different clinical disease processes with different presentations [70]. The clinicopathological characteristics of ovarian endometriosis and endosalpingiosis are described in full elsewhere in the book (see Chap. 12 and endosalpingiosis section below in this chapter, respectively).

3.4

 varian Findings in Perimenopausal O and Postmenopausal Women

Fig. 3.45  Atrophy, low power

3.4.1 Ovarian Atrophy 3.4.1.1 Clinical Features Typically, the ovaries gradually decrease in volume with each decade of life from age 30 to age 70, and the mean volume in premenopausal women is significantly greater than in postmenopausal women [71]. Atrophy is the extreme reduction of ovarian volume and function in postmenopausal women. 3.4.1.2 Pathology Grossly, ovaries are small and shrunken in size, typically 1 cm grossly or radiologically visible, well-circumscribed mass in patients with a fibroma.

3.8.2 Mesothelial Proliferation Similar to other mesothelial-lined surfaces, the ovarian surface and/or periovarian adhesions may exhibit a reactive mesothelial hyperplasia, in some cases florid, which may mimic neoplasia. These benign mesothelial proliferations are characterized by small nests, cords, and gland-like, sheet-­like, or nest-like arrangements of mesothelial cells

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Fig. 3.102  Benign mesothelial proliferation within ovarian surface adhesions and hemosiderin deposition

Fig. 3.103 Benign architecture

mesothelial

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(Fig.  3.102), similar to the spectrum of florid mesothelial proliferations of the testicular tunica vaginalis [121]. In addition, another common pattern of mesothelial proliferation is composed of surface micropapillary projections comprised of stromal or fibrotic cores and lined by mesothelial-like ovarian surface epithelium (Fig.  3.103). Factors that may predispose to mesothelial hyperplasia include pelvic inflammation, a large primary ovarian mass, torsion or infarction, ascites, and endometriosis [122]. The differential diagnosis of a benign mesothelial proliferation includes invasive or metastatic ovarian tumor and cystic or papillary mesothelioma.

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3.8.3 Artifacts of Granulosa Cells

3.9

Benign granulosa cells may cause diagnostic confusion and mimic malignancy in two scenarios: (1) artifactual displacement of granulosa cells in ovarian lymphovascular channels and/or fallopian tubes and (2) tangentially sectioning of a developing and maturing cystic follicle. In the first scenario, artifactual vascular displacement of granulosa cells within the ovary is thought to be secondarily related to surgical procedure, to specimen manipulation in the pathology laboratory, or to ovulation. In this situation, cohesive groups of benign inhibin- or calretininpositive, mitotically active granulosa cells can be identified in either ovarian lymphovascular spaces or within fallopian tube lumen and stroma [123–125]. The displaced granulosa cells may mimic an adult granulosa cell tumor, a high-grade carcinoma such as small cell carcinoma or an immature teratoma. Premenopausal age, the presence of an associated follicle with similar cells, and absence of mass lesion to suggest a tumor are helpful in confirming the artifactual lymphovascular displacement of benign granulosa cells. In the second scenario, tangential sectioning of a developing follicle in the ovary may mimic a small adult granulosa cell tumor, either during intraoperative frozen section consultation or on permanent sections. In this situation, a solid or cystic population of granulosa cells with bland nuclear features may be seen in the ovarian stroma (Fig. 3.104). The presence of a surrounding theca cell population and obtaining additional tissue levels may be helpful in confirming the diagnosis of a developing cystic follicle instead of an adult granulosa cell tumor.

3.9.1 R  esidual Ovarian Syndrome (Ovarian Remnant Syndrome)

Fig. 3.104  Tangentially sectioned follicle

Other Rare Disorders

3.9.1.1 Clinical Features Residual ovarian syndrome, also known as ovarian remnant syndrome, refers to a condition occurring in women who have persistent ovarian tissue that was unintentionally left behind in the patient after a bilateral oophorectomy. As a result of this residual ovarian tissue, patients most frequently present with pelvic pain and/or a pelvic mass, possibly many years after bilateral oophorectomy [126]. Risk factors for residual ovarian syndrome include a history of endometriosis, pelvic inflammatory disease, multiple previous surgeries, and pelvic adhesive disease, all of which may be associated with incomplete removal of an ovary during initial oophorectomy [127]. The recommended treatment for residual ovarian syndrome is surgical excision of residual ovarian tissue and/or pelvic mass. 3.9.1.2 Pathology Definitive criteria for diagnosis of residual ovarian syndrome include a history of bilateral oophorectomy with histological documentation of ovarian tissue obtained during subsequent surgical excision. Pathological examination may reveal ovarian-­type stroma, follicles, corpus luteum, or an ovarian-­ type tumor (Figs. 3.105 and 3.106), with or without associated endometriosis or fibrous adhesions. If a pelvic mass is present, care should be taken to exclude possible malignant transformation of residual ovarian tissue and/or associated endometriosis.

Fig. 3.105  Ovarian remnant syndrome. Ovarian-type fibroma presenting as a pelvic mass in a patient 12 years after a total hysterectomy and bilateral salpingo-oophorectomy

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Fig. 3.106  Ovarian remnant syndrome. Cortical-type stroma identified within pelvic mass of same patient Fig. 3.107  Uterus-like adnexal mass, low power

3.9.2 Uterus-Like Adnexal Mass 3.9.2.1 Clinical Features Uterus-like adnexal mass is a rare condition that typically presents as an ovarian or adnexal mass that is discovered incidentally or in the setting of abdominal pain. Rarely, it has been associated with elevated CA-125, raising clinical suspicion for ovarian malignancy; however, increased CA-125 may occur in the setting of similar benign processes such as endometriosis [128]. Imaging typically shows a well-defined, thick-walled, cystic mass associated with the ovary or adjacent adnexal structures. The cyst may be multiloculated or have a solid component [129]. The origin of uterus-like adnexal mass is controversial with two coexisting theories. The first is that uterus-like adnexal mass represents a congenital anomaly of the Müllerian tract, as it has been described in association with genitourinary anomalies and malformation of the uterus [130, 131]. The second is that uterus-like adnexal mass is derived from metaplasia of the ovarian surface in association with foci of endometriosis. This theory is supported by the presence of myofibroblasts within the ovarian stroma, which have been shown to undergo smooth muscle metaplasia [132]. In addition, the majority of cases have been diagnosed in the absence of associated congenital anomalies of the Müllerian and genitourinary tract. Proponents of this model prefer the term “endomyometriois” rather than uterus-like adnexal mass to describe this entity. 3.9.2.2 Pathology Uterus-like adnexal mass has been reported to range in size from 4 to 13 cm in greatest dimension. By gross e­ xamination,

Fig. 3.108  Uterus-like adnexal mass, medium power

the mass should be well circumscribed with a thick muscular wall surrounding cystic spaces lined by rough, hemorrhagic tissue like that lining the endometrial cavity. The cyst may be complex with septations or solid portions. Cyst content is thick and brown as is seen in an endometriotic cyst. Residual ovarian stroma may be present. Histologically, the cyst wall is composed of bundles of smooth muscle with associated fibroconnective tissue and large muscular blood vessels as seen in native myometrium. The cyst cavity is lined by endometrial tissue including endometrial stroma and glands associated with a prominent smooth muscle component (Figs.  3.107, 3.108, and 3.109). The smooth muscle component is positive for smooth muscle actin, desmin, and vimentin. The endometrial glands are positive for cytokeratin and epithelial membrane antigen,

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Fig. 3.109  Uterus-like adnexal mass, high power

and the endometrial-type stroma is positive for CD10. Both the smooth muscle and endometrial lining are positive for estrogen and progesterone receptors.

Fig. 3.110  Ovary with non-necrotizing granuloma. A giant cell with asteroid body suggestive of sarcoidosis is present on the right side

3.9.2.3 Differential Diagnosis The differential diagnosis includes extrauterine adenomyoma and smooth muscle metaplasia of ovarian endometriosis. Extrauterine adenomyoma is mass forming with a prominent smooth muscle component, but it does not show uterus-like organization that is seen in uterus-like adnexal mass. Smooth muscle metaplasia is a relatively common finding in ovarian endometriosis (up to 17% of endometriosis cases in one study), but this process is typically focal and not mass forming [132].

3.9.3 S  econdary Ovarian Involvement by Systemic Disorders Rarely, the ovary is a site of secondary involvement by systemic disorders, and ovarian involvement is usually an incidental finding in women with systemic disease. For instance, systemic inflammatory disorders such as sarcoidosis, Crohn’s disease, or vasculitis have been reported in the literature to secondarily involve the ovary [133–137]. In addition, systemic amyloidosis and systemic storage disorders involving the ovary have also been reported [138, 139]. Patients may present with a tumor-like ovarian mass, uterine bleeding, and constitutional symptoms such as fever. Microscopically, features in the ovary are similar to morphological changes seen in other organ systems. This is illustrated by the presence of non-necrotizing granulomas in the ovary in cases of secondary involvement by either (1) systemic sarcoidosis or Crohn’s disease; (2) vasculitis involving ovarian hilar or adnexal vessels in cases of systemic giant cell arteritis, polyarteritis nodosa, and ­

Fig. 3.111  Ovary with non-necrotizing granuloma due to polarizable foreign material. The patient had a history of abdominal myomectomy years prior to oophorectomy

scleroderma; or (3) amyloid deposition in the ovaries with systemic amyloidosis [137, 139, 140]. Clinical history and pathological correlation are helpful in identifying secondary involvement by these disorders. The main differential diagnosis of non-necrotizing granulomas in the ovary is a foreign body reaction to exogenous material (Figs.  3.110 and 3.111), often suture material introduced from a previous operative procedure, to keratin from a teratoma or to refractile crystalline material of uncertain origin [140]. In the differential of ovarian necrotizing granulomas due to systemic disease, an infectious oophoritis process with abscess formation and necrotic pseudoxanthomatous nodular inflammation due to endometriosis must also be excluded [141].

3  Benign Diseases of the Ovary

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4

Ovarian Epithelial Carcinogenesis Jing Zhang, Elvio G. Silva, Anil K. Sood, and Jinsong Liu

Abstract

The mortality rate of epithelial ovarian carcinoma (EOC) ranks the highest in all gynecological malignancies, although it is the third common cancer in the female reproductive system. In spite of the progress in reductive surgery and the extensive applications of platinum and paclitaxel and the other first-line chemotherapeutic drugs, the 5-year survival rate of EOC patient is improved merely from 36% in 1975 to 46% in 2011 [1]. The reason is that the definitions and carcinogenetic mechanisms closely related to EOC remain poorly understood. For over a decade, the rapid development of molecular genetics provides a new foundation for our understanding of ovarian epithelial carcinogenesis. In the current chapter, we will focus on the cell origin, pathogenesis, molecular genetics, and clinical applications of different EOC histological subtypes to improve our understanding of this deadly disease. Keywords

Brenner tumors · cancer stem cell · carcinogenesis · clear cell carcinoma · endoreplication · endocycle · endometrioid carcinoma · endometriosis · endomitosis · epithelial ovarian carcinoma · epithelial-mesenchymal transition (EMT) · fere ex nihilo model · high-grade serous carcinoma · immune checkpoint · intraepithelial carcinoma · low-grade serous carcinoma · malignant mixed Müllerian tumors (MMMT) · mesenchymal-epithelial transition (MET) · mucinous carcinoma · ovarian epithelial inclusion J. Zhang Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, People’s Republic of China E. G. Silva · J. Liu (*) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] A. K. Sood Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

· ovarian inclusion cyst · p53 signature · polyploid giant cancer cells (PGCCs) · secretory cell expansion · seromucinous carcinoma · serous tubal intraepithelial carcinoma · somatic blastomere · the dualistic model of ovarian carcinogenesis · the secondary Müllerian system · the somatic blastomere model · TP53 mutation · tumor progression · undifferentiated carcinoma · Walthard cell nests

The mortality rate of epithelial ovarian carcinoma (EOC) ranks the highest in all gynecological malignancies, although it is the third common cancer in the female reproductive system. In spite of the progress in reductive surgery and the extensive applications of platinum and paclitaxel and the other first-line chemotherapeutic drugs, the 5-year survival rate of EOC patient is improved merely from 36% in 1975 to 46% in 2011 [1]. The reason is that the definitions and carcinogenetic mechanisms closely related to EOC remain poorly understood. For over a decade, the rapid development of molecular genetics provides a new foundation for our understanding of ovarian epithelial carcinogenesis. In the current chapter, we will focus on the cell origin, pathogenesis, molecular genetics, and clinical applications of different EOC histological subtypes to improve our understanding of this deadly disease.

4.1

 he Models of Ovarian T Carcinogenesis

Several theories have been proffered on the origins of ovarian cancer. Most intriguing are the theories on ovarian surface epithelial metaplasia, the secondary Müllerian system, the dualistic model of ovarian carcinogenesis, the fere ex nihilo model, and the recently described role of polyploid cells in tumor initiation and progression. Ovarian epithelial metaplasia is a classic theory of EOC, but it is difficult to find the transformation between ovarian surface epithelium (OSE) and carcinoma. Analogously, although the second Müllerian system theory is well-known, the progression process of EOC also cannot be confirmed.

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_4

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Therefore, these two theories have become less popular in recent years. On the other hand, the dualistic model of ovarian carcinogenesis is among most discussed model in past decade. However, ovarian cancer can be potentially have multiple cell origins, and the malignant transformation may be achieved via formation of tetraploidy or polyploidy as an intermediate stage and followed by amitosis rather mitosis to generate genetically aberrant stem cells for cancer initiation. In order to better understand the overall landscape of ovarian carcinogenesis, we will discuss each of cell origins and mechanisms involved in tumor progression in light of the most recent research progress.

4.1.1 The Ovarian Surface Epithelial Cells This theory is based on the speculation that all ovarian epithelial tumors originate from OSE. The OSE represents mesothelial-like cells and is configured as a single layer of stable epithelium without prominent differentiated characteristics in the general state. They possess two potentials that differentiate into mesenchymal cells or epithelial cells, called epithelialmesenchymal transition (EMT) or reversal of this process named mesenchymal-epithelial transition (MET). As one of the normal physiological functions, EMT/MET plays a vital role in regulating the OSE repair process after ovarian ovulation [2]. The imbalance of EMT/MET is suggested to be a possible mechanism in the initiation of EOC. In this hypothesis, ovarian epithelial inclusion (OEI)/inclusion cyst (OIC) is formed via OSE invagination. These OEIs may transform into Müllerian epithelial cells via metaplasia and give rise to different histological types (e.g., serous, endometrioid, clear cell, mucinous and transitional cells) under the influence of local factors (such as steroid hormones). Their morphologies are parallel to the mucosa of fallopian tube, endometrium, gastrointestinal tract or endocervix, and bladder, respectively. These OEIs with Müllerian phenotype further gain the ability for malignant transformation and to progress to corresponding EOCs (serous carcinoma, endometrioid carcinoma, mucinous carcinoma, or other subtype) with lineage infidelity via an abnormal regulation of homeobox (HOX) gene [3]. In this process of tumor transformation, both OEIs and cancer cells show the changes that cells gradually lose the characteristics of mesenchymal cells and obtain different Müllerian epithelial differentiated features, including the expression of specific epithelial marker (E-cadherin) in the differentiated stage [4]. However, the theory has been challenged in the several aspects: 1. Different cells of origin: OSE belongs to the coelothelium (mesothelial cells), rather than Müllerian epithelium. The histotypes of EOCs primarily show differentiation toward Müllerian, rather than mesothelial cells. 2. Discrepancy in immunophenotype: OSE does not express common EOC markers (such as PAX-8), but highly express calretinin and the other mesothelial markers.

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3. The unknown origin of OEI: Some epithelial cells in OEI exhibit the differentiation toward fallopian tube epithelium, rather than OSE. 4. Different histomorphology: There are no obvious histological transitions between mesothelial cells and Müllerian epithelium. In addition, the histological observations on the ovaries from the carriers with hereditary BRCA mutation or contralateral normal ovary of sporadic EOC reveal that the morphological changes (hyperplastic papillae on the ovarian surface, the increase and dilatation of cortical inclusion cysts, and mild cell atypia) are not sufficient to achieve the diagnostic criteria for precancerous lesions. For all of the abovementioned reasons, this theory has become less popular in the past two decades.

4.1.2 The Secondary Müllerian System At the early stage of embryogenesis, the somatic epithelium and its subepithelial mesenchyme are derived from the Müllerian ducts. During the embryonic development, the distal parts of the two Müllerian ducts (also known as the primary Müllerian system) fuse to form the uterus, cervix, and proximal one third of the vagina, while the proximal Müllerian ducts remain separated to become the two fallopian tubes [5]. The mucosal epithelium lining on those sites is called the Müllerian epithelium. Indeed, the ovaries do not belong to the Müllerian system because the gonads and reproductive tract are developed separately in embryonic stage. In view of the similarity between ovarian epithelial tumors and Müllerian epithelium, Lauchlan [6] put forward the second Müllerian system theory in 1972, which is that the coelothelium has an ability to transform into the Müllerian epithelium. Taking this ability into consideration, he further suggested that OSE, OEI, and all extraovarian Müllerian-­ type epithelial tissues adjacent to fallopian tube and pelvic cavity are part of the second Müllerian system. The second Müllerian system includes endometriosis, endosalpingiosis, and endocervicosis, which are collectively referred to as Müllerianosis. With his comprehensive understanding of the morphologic features of these lesions, Dr. Lauchlan thought that these three lesions can change into each other through metaplasia and thus that all epithelial tumors in the ovary and pelvic cavity can be potentially derived from the second Müllerian system. Similar to OSE metaplasia theory described above, the secondary Müllerian system theory cannot entirely account for other observations on ovarian carcinogenesis and accordingly has become less popular in recent years. However, it remains a potential cell of origin for extraovarian or pelvic Müllerian epithelial tumors, especially low-grade lesions (type I) as described below.

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4.1.3 The Dualistic Model

Table 4.1  The comparison between type I and type II epithelial ovarian carcinomas [9]

In recent years, data have accumulated on the histological observation and molecular genetic levels demonstrated that EOCs are heterogeneous diseases with several histological subtypes with different cells of origin, pathogenesis, and clinical biological features. Kurman and colleagues proposed the “dualistic model” of ovarian carcinogenesis, i.e., EOC could be classified as type I and type II tumors based on their distinct set of clinicopathologic features [7–9]. Type I EOCs include low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, seromucinous carcinoma, mucinous carcinoma, and malignant Brenner tumors. In the genesis, these carcinomas often follow a sequential pattern of evolution from benign to borderline to malignant tumors. Clinically, these tumors grow slowly and most of them have an indolent biological behavior; most are confined to one ovary at presentation. All histological subtypes of type I EOCs are low-grade tumors, and the prognosis is relatively good, with the exception of clear cell carcinoma. The mortality rate accounts for only 10% of all EOCs. The tumor genomes are relatively stable at the molecular genetic level, although there are different genotypes in different histological types (see Table 4.1) [9]. Type II EOCs include high-grade serous carcinoma, undifferentiated carcinoma, and malignant mixed Müllerian tumors (MMMT, also called carcinosarcoma). Clinically, these tumors are highly aggressive and rapidly progressive. All histological subtypes of type II EOCs belong to high-­ grade tumors. More than 75% of cases are diagnosed at advanced stage (FIGO III and IV) with extensive dissemination. The prognosis is poor and the mortality rate accounts for 90% of all EOCs. In the molecular genetics, these tumors have highly unstable genomes and prone to have the amplification or deletion of DNA copy numbers. Among them, TP53 gene mutation is most common (>95% of high-grade serous carcinoma) (Table 4.1) [9].

4.1.4 The Fere Ex Nihilo Model The dualistic model of ovarian carcinogenesis helps in our understanding of EOCs and may even provide a frame work to guide clinical decision-making. However, this model may be too simplified for such a highly heterogeneous group of diseases. For example, even among high-grade serous carcinomas, the tumors have different clinical biological behaviors [10]. In particular, Silva raised several questions that argue against fallopian tube theory for pelvic serous carcinoma (see Sect. 4.2.1.2). Toward this end, Silva put forward the fere ex nihilo model (or out of nothing) from unremarkable primitive or early epithelial or mesenchymal stem cells: this model hypothesizes that uncommitted or stem cells from the mesenchyme could be a potential source of transformation for both benign and malignant tumors. During this process, stromal fibroblasts, via MET,

Type I epithelial ovarian Type II epithelial carcinomas ovarian carcinomas Histologic features Histological Low-grade serous types carcinoma, endometrioid carcinoma, clear cell carcinoma, seromucinous carcinoma, mucinous carcinoma, malignant Brenner tumors Tumor grade Low-grade (except clear cell carcinoma) Proliferation Usually low activity Clinical features FIGO stage Usually early stage (FIGO I)

High-grade serous carcinoma, undifferentiated carcinoma, malignant mixed Müllerian tumors

High-grade Usually high

Clinical process Response to chemotherapy Progress course

Slow and indolent General

Early screening Prognosis Genetic features Chromosomal instability Common gene mutation

Feasible Relatively good

Usually advanced stage (FIGO III and FIGO IV) Rapid and aggressive Good (but late recurrence) Mostly from serous tubal intraepithelial carcinoma Difficult Relatively poor

Low

High

KRAS, BRAF, PTEN, ARID1A, PIK3CA, CTNNB1, ERBB2, PPP2R1A Rare

TP53, BRCA1/2

Deficiency of homologous recombination repair proteins

Benign to borderline to malignant tumors

Common

could be the origin of high-grade serous carcinoma, and both stromal-epithelial interaction and steroid hormones play critical roles in tumorigenesis and progression [11]. The stem cells are defined as a subgroup of cells with differentiation potential and the ability for self-renewal. Under certain conditions, these cells can differentiate into a variety of functional cells. It has been reported that both OSE and ovarian cancer cell are capable of expressing stem cell markers such as SOX2 [12], CD133 [13], and NANOG [14]. The small populations of stem cells, which possess the features of stem cell or mimic stem cells, are predominantly located in hilar OSE in mouse model. The hilum OSE are cycling slowly and express stem cell markers ALDH1, LGR5, LEF1, CD133, and CK6B [15]. Therefore, those OSE cells or other stromal cell types that express stem cell markers can potentially be the cell of origin of benign and malignant ovarian tumors [16, 17]. Evidence supporting this view includes the development of benign epithelial neoplasms of the ovaries from guinea

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pigs following treatment of testosterone and estrogenic hormones [18, 19]. Inflammation is a well-known risk factor for ovarian cancer, as may occur in ovulation, which causes the rupture of OSE and a repair process, resulting in pelvic foci of inflammatory microenvironment. Using SV40 T/t antigen to disable to ovarian surface epithelial cells together with oncogene RAS, Liu’s laboratory has successfully been able to transform the normal ovarian epithelial cells into high-­grade Müllerian carcinoma, which is associated with massive upregulation of inflammatory cytokine (e.g., interleukin-1β, interleukin-6, and interleukin-8) [20]. Through the chemokines and cytokines secreted by cancer cells, for example, Gro-1 can induce stromal fibroblast senescence [21]. CXCR2 and interleukin-1β promote tumor cell proliferation [22, 23]. The close interaction among tumor cells, stromal cells, and inflammatory tumor microenvironment provides a favorable condition for tumor cell recruitment, adhesion, migration, survival, and colonization [24, 25]. The fact that OSE can be transformed into high-­grade Müllerian carcinoma provides further support that the OSEs can be also the potential cells of origin for high-grade carcinoma.

4.1.5 Somatic Blastomere Model The above theories described the cell of origin for ovarian cancer. However, it remains unknown how the cells are transformed into carcinoma. The most accepted paradigm in carcinogenesis is an accumulation of genetic mutations or aneuploidy [26, 27]. However, these theories at the individual gene or individual chromosomal levels cannot entirely account for enormous genomic and epigenetic changes detected by The Cancer Genome Atlas (TCGA) projects in high-grade carcinomas [28]; it has been argued that somatic mutation theory may be wrong for most cancer [29]. In addition, all of the four models described above fail to consider the level of differentiation as reflected in the level of malignancy in different histotypes. Recently, we have proposed a unified somatic blastomere model to explain the origin of all cancers and disease relapse [30]. This model is based on long-term and puzzling observation that early blastomere stage embryo is highly chaotic [31] with high frequency of polyploidy [32, 33]. The endoreplication and cell fusion are required for development from blastomere to compaction/ morula stage embryo, which is required for the first differentiation event to become trophoblasts and inner cell mass following fertilization [34]. Unlike the mitotic cell cycle, which involves several distinct phases including DNA synthesis (S) and distribution of replicated DNAs to two identical daughter cells via mitosis (M) with the intervening gap phase (G), endoreplication represents a specific process in which nuclear membrane does not break down while the genome is replicated twice or multiple times without cell division and subsequently separated into daughter cells without formation

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of mitotic spindle. There are two kinds of endoreplication. The first form is called the endocycle, which consists of alternating DNA synthesis (S) phases and gap (G) phases without chromosome segregation during a mitotic (M) phase or cell division (cytokinesis). The developmentally controlled endocycle results in cells with a single polyploid nucleus and no feature of mitosis to support specific need of development [35–39]. Another form of endoreplication is known as endomitosis, in which cells execute an abortive mitosis that does not result in fully separate sister chromatids or cell division, followed by subsequent re-entering of S phase to generate multinucleated cells [36–39]. Endocycle and endomitosis can be mixed, and the distinction between the two forms may be context development depending on specific type of development. Polyploid giant cancer cells (PGCCs), characterized by a single, giant nucleus or multinucleated cells, are commonly found in tumor tissues with high-grade carcinoma or after treatment (such as chemotherapy, radiotherapy, or targeted therapy) [40–42]. PGCCs have a distinct advantage over regular cancer cells in dealing with stresses (e.g., hypoxia, starvation, temperature, pH, and diet conditions in physiologic stresses; drugs and radiation in pathologic stresses) and reproduction [35–39]. Increasing DNA content by endoreplication is a widely utilized effective mechanism to sustain the mass production of proteins and high metabolic activity necessary for tumor growth. Following endoreplication, cancer cells may thus arrest the mitotic cell cycle and allow the cell to survive during mitotic catastrophe or genotoxic stresses and enter endoreplication cell cycle to form PGCCs [30, 43–45]. Accumulating evidence suggests that PGCCs may have played a fundamental role in tumor initiation. They may have hijacked normal embryonic developmental program to facilitate the generation of new diploid cancer initiating cells in response to oncogenic and therapeutic stress [30, 45]. Our laboratory has provided the first experimental evidence that normal ovarian or fallopian tubal epithelial cells and cancer cells can undergo endoreplication [42, 46]. This process can lead to genomic instability and dedifferentiation into more primitive state, to facilitate the reprogramming and emergence of new cancer initiating cells. We have shown that this multistep reprogramming process includes four distinct but overlapping process including initiation, self-renewal, termination, and stability and facilitating normal or cancer cells to be reprogrammed to cancer cells or resistant cancer cells [45]. The mitotic apparatus for well-known mitotic division is shut down with activation of senescence program in the giant cell cycle; emergence of new tumor initiating cells is largely from amitotic separation from giant mother cells including budding, splitting, and branching, the more primitive mode of cell division used in fungi [42, 45]. Unexpectedly, endoreplication of ovarian cancer cells recapitulates the division and growth pattern of blastomere stage embryo to form compaction and morulae-like embryonic cell types, which is

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associated with massive mitotic and cytokinesis failure and genomic instability [30]. Moreover, the endoreplicating cells recapitulate the morphology and spatial and time-dependent activation of embryonic reprogramming factor OCT4/ NANOG/SOX2, capable of differentiation into three germ layers and develop into malignant  germ cell tumors [30]. Formation of tetraploidy or polyploidy is a common feature at the border of normal epithelial cells and mesenchymal and high grade carcinoma, which is associated with activation of senescence and dedifferentiation program and stem cell activation, supporting the generality of our model to other types of cancer [47]. Further, formation of polyploidy appears to be a major mechanism in response to starvation or mitotic insult in Drosophila [48]. Subsequent generation of intestinal stem cells from polyploidy cells is associated amitosis, a primitive form of cell division without using mitotic spindle [48]. Taken together, the above data together provide a previously appreciated mechanism via formation of polyploid cells for generating genetically altered daughter stem cells in response to acute or chronic insults using primitive mode of cell division for cancer initiation [47]. Our model also explains the level of differentiation observed in the ovarian cancer. Depending on the level of stem cell arrested at the specific developmental hierarchy during organ development, the tumors could behave in benign or low-grade type of malignancy such as cystadenoma or borderline tumor or high-grade carcinoma (type II a

b1

Initiation (mitosis/ cytokinesis failure)

b2

Self-renewal (Enreplication/ Endocycle)

Fig. 4.1 A schematic diagram of somatic blastomere-like model for how normal fallopian tubal and ovarian epithelial cells are transformed into high-grade serous carcinoma. Normal fallopian tubal cells (or ovarian epithelial cells or stromal fibroblasts) (a) the nucleus starts endoreplication due to mitotic/cytokinesis failure; (b) endoreplicating cells grow autonomously (self-renewal, b1 and b2) and lead to genomic chaos and

tumor). The closer toward the embryonic stage, the higher developmental potential to allow the tumor to behave in malignant manner [30]. Thus, it is possible that high-grade serous carcinoma or the other EOCs, particularly those cancers with marked nuclear atypia, may be achieved via the giant cell cycle-mediated reprogramming following the re-­ differentiation and followed by developmental arrest [30, 42, 45]. This model also offers a sensible explanation why high-­ grade serous carcinoma is usually detected in late stage with wide dissemination in the peritoneal cavity. The schematic diagram on how epithelial or mesenchymal cell is transformed into cancer cells via the giant cell cycle is shown in Fig. 4.1. The details on the role of the PGCCs and the giant cell cycle in tumor initiation and disease relapse can be found in recent review by Liu [47].

4.2

 he Cell Origin and Molecular Genetic T Profiles

During the past decade, it has become clear that some high-­ grade serous carcinomas arise from the mucosal epithelium of fallopian tube fimbria [49–51]. In addition, significant progress has also been made in the cell origin of the other subtypes of EOCs. These progresses will help out our understanding on the origin of EOC and offer a new potential strategy for treatment and early screening. c

Termination (Endomitosis)

d

Stability

facilitate the genomic reorganization and reprogramming. With the termination of the giant cell cycle  via endomitosis to form early tumor papillae (c), multiple tumor papilla with different genetic and epigenetic changes together generated via amitotic endoreplication division. In this process, the clone(s) with advantageous p53 mutations achieve the stable tumor expansion and develop into high-grade serous carcinoma (d)

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4.2.1 Ovarian Serous Carcinoma

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directly detach and adhere to the ovarian surface, it is possible that the tubal OEIs may be formed via the shedding and Serous carcinoma is the most common histological subtype invagination of tubal mucosal epithelium into the ovarian corof ovarian epithelial tumors. It represents a heterogeneous tex. Interestingly, the different proportional distribution of group of tumors at both morphology and molecular genetics mixed ciliated and secretory cells has been found in the tubal and exhibits a typical dualistic model of ovarian carcinogen- OSEs, tube OEIs, serous cystadenomas, and borderline esis. In 2004, based on the systematic analysis of histology tumors, with a remarkably increasing secretory/ciliated cell and clinical behavior with more than 10-year follow-up, ratio in the low-grade serous carcinoma, suggesting that tubal Malpica et  al. [40] at MD Anderson Cancer Center first epithelial cells could be the potential origin of these tumors. ­proposed a two-tier system for grading ovarian serous carciIn the 2014 WHO classification, ovarian borderline serous noma. Namely, ovarian serous carcinoma is classified as tumors are further divided into two types, namely, serous low-grade and high-grade. This grading system is currently borderline tumor/atypical proliferative serous tumor and widely used and is accepted by the WHO classification of borderline serous tumor-micropapillary variant/noninvasive gynecological tumors [52, 53]. Although they are in the same low-grade serous carcinoma. Both of them have the same category of serous carcinoma, low-grade serous carcinoma is KRAS mutation rate (about 50% of cases); however, there is significantly different from high-grade serous carcinoma in a more analogous genetic profile between borderline serous morphology, genotyping, and biological behavior. tumor-micropapillary variants and low-grade serous carcinoma in comparison with serous borderline tumor, which 4.2.1.1 Low-Grade Serous Carcinoma suggests that borderline serous tumor-micropapillary variant Low-grade serous carcinoma has typical features of type I may be an intermediate lesion in the development of borderEOCs. The progression from benign to borderline to malig- line serous tumor to low-grade serous carcinoma [52]. On nant process can be observed histologically. The epithelial the other hand, development of low-grade serous carcinoma cells lining on the serous cystadenoma have the same histo- from serous borderline tumor, regardless conventional type logical and immunophenotype as OEI cells. The areas of or micropapillary variants, is time-dependent [56]. With benign serous components present in almost all borderline increasing follow-up time, conventional serous borderline tumors. Likewise, the transition from borderline to malig- tumor will also develop into low-grade serous carcinoma. It nant components also exists in the majority of low-grade remains to be determined whether such further subclassificaserous carcinoma. As the precursor lesion represents an tion is clinically meaningful or potentially misleading as the important clue for tumor origin, the abovementioned patho- term of atypical proliferative tumor neglects the low maliglogical findings suggest that the ovarian serous cystadenoma, nant potential of conventional serous borderline tumor. borderline tumor, or low-grade carcinoma may develop via a Genetic and genomic profiles: The most common molecular sequential progression process from OEIs. genetic alterations in low-grade serous carcinoma are KRAS, Cells of origin: While it is well-known that the fallopian BRAF, or ERBB2 mutations. These three gene mutations can tube can serve as a precursor lesion for high-grade serous promote the transduction of growth signals into the nucleus, carcinoma, recent evidence suggests that these epithelial resulting in uncontrollable cell proliferation and malignant cells can be also potential source of low-grade lesions includ- transformation via sustained activation of the downstream ing cystadenoma, serous borderline tumor, and low-grade MAPK kinase signaling pathway [57, 58]. Accumulating eviserous carcinoma. Due to close anatomic relationship dence points toward that there are mutually exclusive relationbetween the fallopian tubal fimbria and ovaries, ovarian rup- ships among KRAS, BRAF, or ERBB2 mutations with only one ture caused by periodic ovulation may provide an opportu- gene mutation exists at an individual tumor in most cases. The nity for implantation of the epithelial cells of fallopian tube mutation rate accounts for about 2/3 of the borderline tumors on the ovary. Through morphological and immunohisto- and low-grade serous carcinoma, of which 33.3% of the borchemical comparisons among OSEs, OEIs, tubal epithelium, derline tumors and low-­grade serous carcinomas have KRAS serous cystadenomas, serous borderline tumors, and low-­ mutations at codon 12 and 13, 33.3% of serous borderline grade serous carcinomas, Zheng and Kong et al. [23, 54, 55] tumors and a small number of low-grade serous carcinomas found two types of OEIs including mesothelial type (cal- show BRAF mutation at codon 600, whereas ERBB2 mutation retinin+/PAX8−/tubulin–) and tubal type (calretinin–/ is less than 5% of entire tumors. KRAS or BRAF mutation is PAX8+/tubulin+). The tubal OEIs account to 78% of all OEIs considered to be an early event in low-grade serous carcinomas and have a significantly higher proliferative index, which may because they also exist in serous cystadenomas adjacent to borfurther proliferate and progress to ovarian serous cystade- derline serous tumors [59]. Compared with BRAF mutation, noma or borderline tumors. Conversely, mesothelial OEIs serous borderline tumors with KRAS mutation have a greater may not develop to tumor because of its low proliferative rate. potential to progress to low-grade serous carcinoma. In fact, As the mucosal epithelium of fallopian  tubal fimbria can BRAF mutation in advanced low-grade serous carcinoma is

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127 KRAS / BRAF / ERBB2 mutation

Tubal mucosal epithelium

a

b

c

d

f

?

e

1p, 5q, 8p, 18q, 22q and Xp allelic imbalance

Fig. 4.2  The illustration of progression of ovarian low-grade serous carcinoma and associated changes in molecular genetics. The mucosal epithelial cells (a) of fallopian tubal fimbria may shed and adhere to the ovarian surface and then form the tubal OEIs (b, yellow arrow). The progression process is from serous cystadenoma (c) to borderline serous tumor/atypical proliferative serous tumor (d) and eventually to low-­

grade serous carcinoma (f), with/without the stage of borderline serous tumor-micropapillary variants/noninvasive low-grade serous carcinoma (e). During the period of tumorigenesis and progression, the KRAS/ BRAF/ERBB2 mutation rate gradually increases. And the multiple chromosomal allelic imbalances also promote the formation of low-grade serous carcinoma simultaneously

very rare [60]. In addition, the low-grade serous carcinomas are more likely to have an allele imbalance of 1p, 5q, 8p, 18q, 22q, and Xp chromosomes than borderline tumors [61]. The heterozygosity deletion of ch1p36 and the heterozygosity/homozygous deletion of ch9p21 often are found in low-grade serous carcinoma. Given that there are tumor suppressor genes (such as miR-34a) in ch1p36 region and CDKN2A/B (encoding tumor suppressor protein p14, p16, and p15) in ch9p21 region, these deletions may lead to the uncontrollable cell growth in borderline tumors and eventually progress to low-grade serous carcinomas [62] (Fig. 4.2).

ing evidence accumulated in the literatures that provide the support for the origin of high-grade serous carcinoma. (1) In the specimens of prophylactic bilateral salpingectomy from the patients with hereditary BRCA1/2 mutation carriers, there are the occult precancerous lesions that are p53 signature and STICs, but no malignant ovarian tumors. The p53 signature is arbitrarily defined as more than 12 successive secretory cells with benign morphological features exhibiting strongly positive expression of p53 immunohistochemical staining and less than 10% of Ki-67 cell proliferation index [65]. As for STIC, its cytological features are enlarged, polymorphic, and hyperchromatic nuclei with nucleoli and mitotic figures, high ratio of nucleus to cytoplasm, multi-­ layered cells, or the lack of cellular polarity. The immunohistochemical staining of p53 exhibits strongly positive or totally negative expression, and Ki-67 cell proliferation index is more than 10% [51]. (2) There are tubal p53 signature and/or STICs in 50–60% of cases with the sporadic ovarian and/or peritoneal high-grade serous carcinoma [62]. (3) Similar to ovarian high-grade serous carcinomas, there are the overexpression of p53 protein and the mutation of TP53 gene both in p53 signature and STICs. The TP53 mutation rate gradually increases with the process of tumor progression from p53 signature to STICs to high-grade serous carcinoma. (4) The evidence that there is the same TP53 mutation site in concurrent p53 signature, STICs, and ovarian high-grade serous carcinoma supports the notion that high-grade serous carcinoma arises from the clonal proliferation of p53 signature cells [66, 67]. (5) The genetic profile of high-grade serous carcinoma is close to tubal epithelial

4.2.1.2 High-Grade Serous Carcinoma High-grade serous carcinoma is the most common EOC. Its incidence is about 60–80% of all EOCs. More than 75% of tumors are in advance stage with extensive abdominopelvic dissemination at the diagnosis [63]. However, there are usually no morphologically recognizable precursor lesions in ovarian tissues. Recent studies showed that some ovarian high-grade serous carcinomas may not originate in ovarian tissues but in the seeding from serous epithelial tumor cells in the mucosal epithelium of fallopian tubal fimbria as secondary tumors. The spectrum of tumorigenesis and progression is from tubal secretory cell expansion [64] or secretory cell outgrowths to tubal p53 signature, to tubal serous tubal intraepithelial carcinoma (STIC)/noninvasive high-grade serous carcinoma, to shedding and implantation on the ovary, and eventually to ovarian high-grade serous carcinoma. Evidence supporting the fallopian tubal epithelial origin as the main source of pelvic serous carcinoma: The follow-

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cells [68]. (6) STICs have shorter telomeres compare with concurrent ovarian high-grade serous carcinoma, while telomere shortening is known to be an early molecular event of tumorigenesis [69]. (7) In the models of genetically modified mice, the secretory cells in the mucous of fallopian tube can transform to malignant lesion due to Tp53, Pten, and Brca mutations, resulting in STIC and ovarian high-grade serous carcinoma [70, 71]. (8) A recent study confirmed that the salpingectomy is an effective method to reduce EOC risk in the general population based on the analysis of large clinical database between 1973 and 2009 [72]. Based on above data, the secretory cells in the mucosa of fallopian tube have been proposed to be the cell origin of high-grade serous carcinoma via the following process [73]: the secretory cells have DNA damages that cannot be normally repaired due to the stimulation of a variety of DNA toxicity factors, resulting in the accumulation of DNA damages. Because of the pressure of survival, there are a series of molecular genetic alterations in the damaged cells, such as adaptive TP53 mutations, which lead to uncontrollable cell growth, over-proliferation, secretory cell outgrowths, and then p53 signature. Some cells with p53 signature can develop to STIC directly or through tubal dysplasia to form STIC [65, 74]. Due to the close contact between the fallopian tubal fimbria and the ovarian surface, and the loose adhesion between STIC cells, it is possible the tumor cells shed and implant on the ovarian surface and ultimately form “ovarian” high-grade serous carcinoma, a possibility that is more plausible than ovarian metastasis via lymphovascular invasion. Recent studies that there are tumor cells in the intraperitoneal washings in some patients with STIC also provide a direct evidence for this disseminated implantation [51]. Evidence against fallopian tubal epithelial cells as main source of pelvic serous carcinoma: Despite of prevalent view of fimbria of fallopian tube as a major source of high-grade serous carcinoma discussed above, there are several important clinical and pathological observations of pelvic serous carcinoma that cannot be clearly explained by fallopian tube origin [11]: 1. Most of high-grade serous carcinomas are at stages III and IV, while 70% the fallopian tubal carcinoma are stage I or II. 2. There is no direct evidence that the cells from small tubal intraepithelial carcinoma can travel all the way against gravity to the abdomen rather to the pelvis, which is against the law of gravity. 3. Most STICs are noninvasive, while most high-grade serous carcinomas are highly invasive; it is difficult to rationalize that the noninvasive precursor carcinomas give rise to 70% invasive carcinoma in peritoneal cavity. 4. Many high-grade serous carcinomas are located intraovarian stromal, not on the surface.

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5. No STICs in the fallopian tube are identified in 50% serous carcinoma; it will be very difficult to unify a theory while no precursor lesions are identified in 50% of cases of the same cancer. 6. The main molecular evidence of clonality of the same TP53 mutation should be treated with caution as it has been shown to be an unreliable indicator of metastasis in many other tumors. Ovarian serous carcinoma as multicellular cells of origin: As mentioned above, there are approximately half of the cases of ovarian high-grade serous carcinoma without concurrent STIC, suggesting that these tumors may be derived from other cell origins [75, 76]. One possible source of cell origin is the OEIs within ovarian cortex; some OEIs may be formed by direct shedding and implantation of normal fallopian tubal epithelial cells into the ovarian cortex [55, 77], which undergo a series of molecular genetics and morphological change including TP53 mutations, and eventually develop into high-grade serous carcinomas [78]. In addition, it is documented that a small number of low-grade ovarian serous carcinoma can progress into high-grade serous carcinoma or that borderline serous tumors can progress to high-­ grade serous carcinoma after tumor recurrence. The incidence by this pathway is likely to be low, since less than 3% of high-grade serous carcinomas show concurrent serous borderline tumor, low-grade carcinoma, and high-grade components in same tumor. These low-grade serous carcinomas may progress to high-grade carcinoma possibly via TP53 mutations [79]. In addition, some high-grade serous carcinoma has been observed to arise from adenofibroma; and the fibroma components cannot be explained by tubal implantation theory. Based on the clinical and pathologic observation and arguable evidence for fallopian tube theory, in his alternative view article, Silva proposed that the fere ex nihilo model including the multicentric cell origin under the influence of environmental factors (such as hormones) may be the responsible for development of various ovarian carcinomas (see Sect. 1.1.4). However, regardless of the cells of origin, the transformation process can be achieved via the giant cell cycle described above (Fig. 4.1). Subclassification of high-grade serous carcinoma. Through the morphological analysis of high-grade serous carcinoma-associated BRCA1/2 mutation, Soslow et al. [80] found that these tumors usually present with solid pattern, endometrioid carcinoma- and transitional cell carcinoma-­ like feature, which is characterized by “SET” (solid, pseudo endometrioid, transitional cell carcinoma-like). BRCA1-­ associated cancer is associated with highly cellular proliferative activity, tumor-infiltrating lymphocytes, and geographic or comedo necrosis. Compared with the classic high-grade serous carcinoma whose histological patterns are papillary, glandular, cribriform, and solid area with slit-like space, the

4  Ovarian Epithelial Carcinogenesis

SET subtype is more common in younger women, and the tumor cells are more sensitive to chemotherapy due to deficiencies of homologous recombination. Moreover, the patients have better prognosis [80, 81]. In view of the abovementioned different clinicopathological characteristics, it is suggested that high-grade serous carcinoma should be divided into classic subtype and SET subtype [9]. Based on the results of TCGA genome analysis, in 2013 Verhaak et al. [82] presented a molecular subtype of high-­ grade serous carcinoma associated with the prognosis of patients. That is classification of ovarian cancer (CLOVAR). The tumors were classified into differentiated, proliferative, immunoreactive, and mesenchymal type. Among these subtypes, the prognosis of patients with immunoreactive type is the best, and the prognosis is the worst in patients with mesenchymal type. In 2016 Murakami et al. [83] further associated the molecular typing with tumor morphology: the mesenchymal type often presents a significant desmoplastic reaction; the immunoreactive type usually manifests as plenty of lymphocyte infiltration in the tumor tissues; the proliferative type frequently has the solid growth pattern; and the differentiation type generally exhibits the papillary pattern. However, this molecular subtype needs be further confirmed by more studies before used clinically. Common genetic and genomic alterations: The most prominent genetic features of high-grade serous carcinoma are genomic instability (the abnormalities of many DNA copy number and structure) and TP53 mutations. According to genomic TCGA project, TP53 mutation is found in almost all tumors tissues (96%) through a sequenced genomic analysis on 489 cases of high-grade serous carcinoma [28]. The TP53 mutation rate is as high as 57% even in precancerous lesions, p53 signature [84]. TP53 mutation is not only an initial event of high-grade serous carcinogenesis but also involved in tumor progression. In addition, nearly half of the high-grade serous carcinomas display BRCA1 (17q21.31) and BRCA2 (13q13.1) inactivating mutations (including germline mutation, somatic mutation, or promoter methylation). Further, common amplification of CCNE1, NOTCH3, PIKCA3, and AKT, and the inactivation of RB and NF1 has also been observed in some tumors [28, 85]. Alterations in DNA copy number have been observed in early lesions like STICs [86]. High-grade serous carcinoma with BRCA1/2 mutation is characterized by numerous alterations in DNA copy number but without CCNE1 amplification, a very common event in primary and refractory tumors [81]. The minority of high-grade serous carcinomas with inherited mutations also has germline deletion mutations in BARD1, BRIP1, MRE11, NBN, RAD51C, RAD51, and PALB2 genes involved in the signaling pathway of Fanconi anemia [87]. Although TP53 mutation is a common event in high-­grade serous carcinoma, the mutation alone in TP53 is not sufficient to induce malignant transformation, suggesting other molec-

129

ular genetic alterations also participate in the transformation process. Norquist et al. [88] found that the loss of BRCA1/2 allele exists in STICs, but not in p53 signature, suggesting that both TP53 mutation and BRCA1/2 deletion are the key events in early carcinogenesis. Kim et al. [71] reported that ovarian/fallopian tubal high-grade serous carcinoma cannot be directly induced by Tp53 mutation alone but by both Tp53 and Pten mutation. Drapkin and Dinulescu et  al. [70] also confirmed that the combination of Brca1/2, Tp53, and Pten mutations in tubal epithelial cells leads to STIC and highgrade serous carcinoma, whereas only Tp53 mutation cannot induce tumor formation. The simultaneous loss of functions leads to a decrease in cell genome stability, a series of oncogene activation and/or tumor suppressor gene inactivation, and leads to multiple chromosomal breaks and deletions and the formation of aneuploidy or polyploidy, which is conducive to avoiding immune surveillance, over-proliferation, and the progression to high-grade serous carcinoma from STIC. The prevalent view of carcinogenesis of high-grade serous carcinoma and its main molecular genetic alterations is shown in Fig. 4.3. Because of conflicting evidence and different views that is for or against the tubal theory, we ask readers of this chapter to take the views from different authors with great caution and make your own observation during the daily practice and decide which theory will best fit with what you observe, rather than blindly believe what are described by a particular author, journal, or academic group. We want to point out that health discussion and expression of different opinions should greatly help us to clarify controversial points and move field to next level. As Einstein puts it, “blind belief in authority is the greatest enemy of truth.”

4.2.2 T  he Other Ovarian Epithelial Carcinomas 4.2.2.1 Endometrioid Carcinoma, Clear Cell Carcinoma, and Seromucinous Carcinoma Ovarian endometrioid and clear cell carcinoma account for about 25% of all EOCs, which are the most common tumors after serous carcinoma. Seromucinous carcinoma (also known as endocervical-type mucinous or mixed epithelial carcinomas of Müllerian type) is very rare. It is composed predominately of serous and endocervical-type mucinous epithelium, foci of clear cells, and uncommon area of endometrioid and squamous differentiation. All of three tumors belong to type I EOCs and are believed that at least 1/3 of the cases originate in endometriosis [89, 90]. These tumors usually have endometriosis, endometrial benign, and/or borderline tumors in the background lesions. Most endometrial carcinomas are low-grade (FIGO grade 1), whose clinical manifestations are consistent with the features of type I EOCs. Only a few endometrial carcinomas

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a

66 Skin, hair, sebaceous glands, white fat, brain tissue (children) 33–66 Sweat glands, brain tissue (adult), smooth muscle, peripheral neural tissue, cartilage, bone, respiratory epithelia 5–33 Teeth, gastrointestinal epithelia, thyroid, ependymal tissue, melanocytes 90% 5-year survival rate. The most prognostic factor is the size of the tumor (G mutation can be identified in the circulating tumor DNA of patients with adult-type granulosa cell tumor. J Mol Diagn. 2017;19(1):126–36. 79. Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27(2):159–66. 80. Roth LM, Liban E, Czernobilsky B. Ovarian endometrioid tumors mimicking Sertoli and Sertoli-Leydig cell tumors: Sertoliform variant of endometrioid carcinoma. Cancer. 1982;50(7):1322–31.

322 81. Tacha D, Qi W, Zhou D, Bremer R, Cheng L.  PAX8 mouse monoclonal antibody [BC12] recognizes a restricted epitope and is highly sensitive in renal cell and ovarian cancers but does not cross-react with b cells and tumors of pancreatic origin. Appl Immunohistochem Mol Morphol. 2013;21(1):59–63. 82. Kato N, Fukase M, Ono I, Matsumoto K, Okazaki E, Motoyama T.  Sertoli-stromal cell tumor of the ovary: immunohistochemical, ultrastructural, and genetic studies. Hum Pathol. 2001;32(8):796–802. 83. Szyfelbein WM, Young RH, Scully RE. Struma ovarii simulating ovarian tumors of other types. A report of 30 cases. Am J Surg Pathol. 1995;19(1):21–9. 84. Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol. 1994;18(11):1102–16. 85. Cannistra SA.  Cancer of the ovary. N Engl J Med. 1993;329(21):1550–9. 86. Mancari R, Portuesi R, Colombo N. Adult granulosa cell tumours of the ovary. Curr Opin Oncol. 2014;26(5):536–41. 87. Jarboe EA, Hirschowitz SL, Geiersbach KB, Wallander ML, Tripp SR, Layfield LJ. Juvenile granulosa cell tumors: immunoreactivity for CD99 and Fli-1 and EWSR1 translocation status: a study of 11 cases. Int J Gynecol Pathol. 2014;33(1):11–5. 88. Kalfa N, Ecochard A, Patte C, et  al. Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab. 2006;91(5):1842–7. 89. Bessiere L, Todeschini AL, Auguste A, et  al. A hot-spot of in-­ frame duplications activates the oncoprotein AKT1  in juvenile granulosa cell tumors. EBioMedicine. 2015;2(5):421–31. 90. Heravi-Moussavi A, Anglesio MS, Cheng SW, et  al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med. 2012;366(3):234–42. 91. Witkowski L, Mattina J, Schonberger S, et  al. DICER1 hotspot mutations in non-epithelial gonadal tumours. Br J Cancer. 2013;109(10):2744–50. 92. Young RH, Lawrence WD, Scully RE.  Juvenile granulosa cell tumor–another neoplasm associated with abnormal chromosomes and ambiguous genitalia. A report of three cases. Am J Surg Pathol. 1985;9(10):737–43. 93. Young RH. New and unusual aspects of ovarian germ cell tumors. Am J Surg Pathol. 1993;17(12):1210–24. 94. Witkowski L, Carrot-Zhang J, Albrecht S, et  al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014;46(5):438–43. 95. Erdreich-Epstein A, Monforte HL, Lavey RS, Joshi S, Phillips JD, Villablanca JG. Successful multimodality therapy of recurrent multifocal juvenile granulosa cell tumor of the ovary. J Pediatr Hematol Oncol. 2002;24(3):229–33. 96. Frausto SD, Geisler JP, Fletcher MS, Sood AK. Late recurrence of juvenile granulosa cell tumor of the ovary. Am J Obstet Gynecol. 2004;191(1):366–7. 97. Oliva E, Alvarez T, Young RH. Sertoli cell tumors of the ovary: a clinicopathologic and immunohistochemical study of 54 cases. Am J Surg Pathol. 2005;29(2):143–56. 98. Young RH, Scully RE. Ovarian Sertoli cell tumors: a report of 10 cases. Int J Gynecol Pathol. 1984;2(4):349–63. 99. Ferry JA, Young RH, Engel G, Scully RE. Oxyphilic Sertoli cell tumor of the ovary: a report of three cases, two in patients with the Peutz-Jeghers syndrome. Int J Gynecol Pathol. 1994;13(3):259–66.

M. M. Desouki 100. Conlon N, Schultheis AM, Piscuoglio S, et  al. A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-­ stromal tumors. Mod Pathol. 2015;28(12):1603–12. 101. Prat J, Young RH, Scully RE.  Ovarian Sertoli-Leydig cell tumors with heterologous elements. II.  Cartilage and skeletal muscle: a clinicopathologic analysis of twelve cases. Cancer. 1982;50(11):2465–75. 102. Robboy SJ, Scully RE, Norris HJ. Primary trabecular carcinoid of the ovary. Obstet Gynecol. 1977;49(2):202–7. Epub 1977/02/01 103. Young RH, Scully RE.  Ovarian tumors of probable wolffian origin. A report of 11 cases. Am J Surg Pathol. 1983;7(2):125–35. 104. Tiltman AJ, Allard U.  Female adnexal tumours of probable Wolffian origin: an immunohistochemical study comparing tumours, mesonephric remnants and paramesonephric derivatives. Histopathology. 2001;38(3):237–42. 105. Scully RE.  Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer. 1970;25(5):1107–21. 106. Young RH, Welch WR, Dickersin GR, Scully RE.  Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer. 1982;50(7):1384–402. 107. Gloor E.  Ovarian sex cord tumor with annular tubules. Clinicopathologic report of two benign and one malignant cases with long follow-ups. Virchows Arch A Pathol Anat Histol. 1979;384(2):185–93. 108. Han Y, Li S, Wu L, Zhang X, Cao D.  Non-Peutz-Jeghers syndrome-­ associated ovarian sex cord tumor with annular tubules: report of a malignant case. J Obstet Gynaecol Res. 2016;42(2):224–7. 109. Young RH, Scully RE.  Ovarian Sertoli-Leydig cell tumors. A clinicopathological analysis of 207 cases. Am J Surg Pathol. 1985;9(8):543–69. 110. Young RH, Scully RE. Well-differentiated ovarian Sertoli-Leydig cell tumors: a clinicopathological analysis of 23 cases. Int J Gynecol Pathol. 1984;3(3):277–90. 111. Young RH, Perez-Atayde AR, Scully RE. Ovarian Sertoli-Leydig cell tumor with retiform and heterologous components. Report of a case with hepatocytic differentiation and elevated serum alpha-­ fetoprotein. Am J Surg Pathol. 1984;8(9):709–18. 112. McClean GE, Kurian S, Walter N, Kekre A, McCluggage WG. Cervical embryonal rhabdomyosarcoma and ovarian Sertoli-­ Leydig cell tumour: a more than coincidental association of two rare neoplasms? J Clin Pathol. 2007;60(3):326–8. 113. Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol. 2005;18(Suppl 2):S81–98. 114. Foulkes WD, Priest JR, Duchaine TF. DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer. 2014;14(10):662–72. 115. Schultz KA, Pacheco MC, Yang J, et al. Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol. 2011;122(2):246–50. 116. Slade I, Bacchelli C, Davies H, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet. 2011;48(4):273–8. 117. Seidman JD.  Unclassified ovarian gonadal stromal tumors. A clinicopathologic study of 32 cases. Am J Surg Pathol. 1996;20(6):699–706.

Secondary Tumors of the Ovary

10

Kelley Carrick and Wenxin Zheng

Abstract

Secondary tumors of the ovary (STO) are tumors from extraovarian sites. Determining the primary versus secondary nature of an ovarian neoplasm is an exercise that may range from simple to essentially impossible due to similarities in gross, microscopic, and clinical features of some primary and secondary ovarian tumors. Adding to the difficulty is the fact that, in some cases, the pathologist (and clinician) may be unaware of a synchronous or historical extraovarian primary neoplasm. As misdiagnosis impacts prognosis and treatment, it is important that the pathologist have an appropriate index of suspicion of metastasis, and a grasp of the possible gross, microscopic, clinical, and immunohistochemical staining features of secondary ovarian tumors. Tumors metastatic to the ovary may originate from almost any primary site, especially in young females, in whom the rich vascularization of the ovaries may render them more susceptible to metastasis. As ovarian metastasis has been documented to appear many years after diagnosis, it is emphasized that a history of neoplasia of any type, even if remote, may be significant in the evaluation of an ovarian tumor with morphologic features unusual for a primary ovarian neoplasm.

present the pathologist with little differential diagnostic dilemma in some cases, while in other cases there may be significant diagnostic challenge due to similarities in the gross, microscopic, and clinical features of some primary and secondary ovarian tumors. Adding to the diagnostic difficulty presented by the frequent overlap in morphologic and clinical features is the fact that, in some cases, the pathologist (and clinician) may be unaware of a synchronous or historical extraovarian primary neoplasm. As misdiagnosis impacts the expected prognosis of the tumor and may have an adverse effect on treatment, it is important that the pathologist have an appropriate index of suspicion regarding the possibility of metastasis, and a grasp of the possible gross, microscopic, clinical, and immunohistochemical staining features of secondary ovarian tumors. Tumor metastatic to the ovary may originate from almost any primary site, especially in young females, in whom the rich vascularization of the ovaries may render them more susceptible to metastasis. As ovarian metastasis has been documented to appear many years after diagnosis of primary tumor originating from various extraovarian sites, it is emphasized that a history of neoplasia of any type, even if that history is remote, may be significant in the evaluation of an ovarian tumor with morphologic features unusual for an ovarian primary neoplasm.

Keywords

Krukenberg tumor · Metastasis · Ovarian malignancies · Secondary tumors of the ovary

10.1 Overview Secondary tumors of the ovary (STO) are those neoplasms that spread to the ovary from extraovarian sites. Determining the primary versus secondary nature of an ovarian neoplasm may K. Carrick (*) · W. Zheng Departments of Pathology, Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected]

10.2 Epidemiology Available data regarding the frequency of STOs varies across different studies, a finding which may be explained by several factors including the geographic region under study, study methodology (inclusion of autopsy versus surgical cases, inclusion of only those tumors presenting clinically as an abdominopelvic mass versus asymptomatic/incidentally discovered tumors, etc.), thoroughness of pathologic examination of the ovaries, and pathologist experience [1, 2]. Given the caveat that available data are somewhat uneven, the proportion of tumors metastatic to the ovaries is estimated to vary from approximately 3–17% in Western nations

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_10

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[3–5] to approximately 21–30% in Eastern nations [6, 7]. The proportion of STOs and the relative frequency of primary sites of origin vary across different geographic regions due to geographic differences in the prevalence of various extraovarian primary neoplasms and their relative tendency to metastasize to the ovaries [1]. While gastric cancer, which has a relatively high rate of ovarian spread, accounts for 23.4% and 30.4% of tumors metastatic to the ovary in Japan and Korea, respectively, it is found in a reported 4.5% of STOs in the Netherlands, which reflects its incidence in those countries [7–9]. In several series examining secondary ovarian malignancies in Europe and the USA, tumors of colorectal, breast, endometrial, and appendiceal origin have been demonstrated to be the most common [4, 5, 9]. Patient age at diagnosis of a STO appears to be associated with the origin and typical age distribution of the primary tumor [1]. For some of the most common types of metastatic tumors (intestinal, gastric, and breast), the average age of patients presenting with ovarian involvement is lower than the average age of those without ovarian spread, which suggests that the increased vascularization of ovaries in young women renders them more receptive to metastasis [2].

10.3 Clinical Presentations Clinically, ovarian metastasis may be symptomatic or asymptomatic, and may present synchronously or metachronously with the extraovarian primary tumor. Ovarian metastatic tumor tends to remain asymptomatic until it reaches a certain size. Presenting symptoms, found in a reported 70% of patients, are nonspecific and do not clearly differ from those related to primary ovarian neoplasia [10]. Symptoms related to an ovarian mass and to an advanced stage of disease can include abdominal pain, weight loss, and increasing abdominal girth [4]. As STOs, like primary tumors of the ovary, can induce ovarian stromal luteinization with consequent hormone production (“functioning stroma”), the patient may also experience consequences of increased estrogen, progesterone, or androgens including abnormal uterine bleeding, virilization, and hirsutism [11]. Importantly, the ovarian metastasis may be the presenting sign of disease from a small, clinically occult non-ovarian primary tumor (for example, a small gastric carcinoma). In some cases, the primary tumor may not be discovered until years after discovery of the ovarian metastasis or until autopsy. The primary tumor may remain unknown in up to 15–20% of cases [4, 9].

10.4 R  outes of Tumor Metastasis to the Ovary Tumor may secondarily involve the ovary via any of several routes of spread, which accounts for some of the more typical gross and microscopic features of STO.  Tumor may

K. Carrick and W. Zheng

metastasize to the ovary via blood vessels or lymphatics, as evidenced by the notable intravascular tumor identified in many cases of STO. Direct spread is a frequent pathway for carcinomas of the fallopian tube and uterus to involve the ovary, for some colorectal and appendiceal carcinomas, and for the rare mesothelioma [2, 12]. Tumor may also reach the ovary through the fallopian tube lumen, a route deemed to account for spread of some carcinomas from the uterine corpus and cervix [13, 14]. Transperitoneal spread, another route of ovarian involvement, is typically accompanied by ovarian surface implantation, involvement of the superficial ovarian cortex, and general peritoneal spread. A good example of this kind of spread is from high-grade serous carcinoma of the fallopian tube.

10.5 G  eneral Pathologic Findings and Clinical Correlation STOs may have considerable morphologic overlap with ovarian primary neoplasms, presenting diagnostic challenge in many cases. The most challenging issues in differential diagnosis typically involve mucinous tumors, endometrioid, and endometrioid-like tumors. Over the years, several gross and microscopic features have been proposed in the literature to aid in the distinction of primary versus secondary ovarian tumors, the most important of these being laterality and size of the ovarian tumor. Several studies have shown that an algorithm using tumor size and laterality can accurately distinguish a substantial majority of primary and metastatic tumors (bilateral tumors of any size, or unilateral tumor less than 10 cm more likely to be metastatic; unilateral tumor greater than or equal to 10  cm more likely an ovarian primary neoplasm) [15, 16]. A 2008 study examining 194 primary and metastatic ovarian tumors demonstrated that adjusting the size criterion of the algorithm to 13 cm rather than 10 cm optimized performance of the algorithm, correctly classifying 87% of tumors overall, including 98% of primary tumors and 82% of metastatic tumors [17]. Tumor size and laterality are helpful guidelines, especially in the operative setting. Exceptions are common, however, particularly among cases of colorectal and endocervical adenocarcinomas [15, 17]; thus, laterality and tumor size alone are not sufficient for determination of primary site. In fact, there is a growing body of evidence to indicate that a significant proportion of STOs are unilateral and relatively large [18]. A recent study from the Netherlands including 2312 cases of tumor metastatic to the ovary from various primary sites demonstrated that STOs from all sites taken together were bilateral in the majority (46.3%) of cases, with 63.9% of breast, 62.9% of gastric, and 58.9% of appendiceal primaries generating bilateral metastases. In contrast, a minority (40.2%) of colorectal cancers had bilateral metastases in this study [9]. Another study including 19 tumors metastatic from the lower and upper gastrointestinal

10  Secondary Tumors of the Ovary

tract demonstrated that over 80% of these tumors were greater than 10 cm [19]. Based on the above understanding and our own experience, we summarize general gross features which are suggestive of metastasis to the ovary as follows:

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7. Tubules and follicle-like spaces can be seen in metastases from various sites and can mimic ovarian primary tumors, particularly sex cord-stromal tumors [12]. 8. Ovarian stromal luteinization and resulting hormonal manifestations (“functioning stroma”) are nonspecific and can appear in association with primary or metastatic 1. Bilateral ovarian involvement (notable exception: tubo-­ tumors. ovarian serous carcinoma, which is often bilateral). As metastatic tumor may be small and not enlarge the ovary, As noted above, STOs and primary ovarian neoplasms adequate sampling is needed to rule out metastasis. may have overlapping morphologic and clinical features that 2. Tumor size less than 10–12 cm. confound diagnosis. Thus, in addition to careful gross and 3. A multinodular growth pattern. microscopic examination of the tumor, consideration of met 4. Presence of tumor on the ovarian surface and/or in the astatic disease and clinical correlation are necessary when superficial cortex. the diagnosis is not clear. This assessment may require intraoperative and/or postoperative evaluation for an extraovarian As with gross features, microscopic features of STOs may primary neoplasm if pathologic examination suggests the bear similarity to microscopic features of primary ovarian possibility of a metastasis, or if the pattern of tumor spread is tumors, particularly in mucinous and endometrioid/ unusual for an ovarian primary neoplasm. A directed panel endometrioid-­ like tumors. Microscopic features favoring of immunohistochemical stains is useful in many cases and metastasis include the following [2, 12, 20]: should be undertaken in any case in which the primary versus secondary nature of the ovarian tumor is uncertain. As 1. Presence of signet ring cells primary and secondary ovarian tumors often have overlap 2. Infiltrative growth pattern with stromal desmoplasia ping immunohistochemical staining patterns (particularly in 3. Notable variation in growth pattern from one area to another the case of mucinous ovarian tumors arising in association 4. Histomorphology unusual for an ovarian primary with a teratoma, which have an intestinal immunophenotype 5. Multinodular growth pattern indistinguishable from metastatic tumor of gastrointestinal 6. Involvement of the ovarian surface and superficial cortex origin), a panel of immunostains should be employed and 7. Hilar and/or extraovarian lymphovascular space correlated with gross, microscopic, and clinical findings. It is involvement also important to note that metastatic tumors may have an immunohistochemical staining pattern that deviates from the Other pearls that can be useful in determining the primary usual, expected pattern. For typical immunohistochemical versus secondary nature of an ovarian tumor include the staining features of primary and secondary ovarian tumors following: with mucinous and endometrioid/endometrioid-like morphology, see Table  10.1. Additional information regarding 1. A history of an extraovarian primary tumor should raise the use of immunohistochemical stains is provided in subsesuspicion of metastasis, even if this history is remote. quent sections. 2. Metastatic tumors may be unusually large with thin-­ walled cysts mimicking a primary ovarian neoplasm, even if cysts are not a feature of the extraovarian primary 10.6 Secondary Ovarian Tumors tumor [2, 12]. from the Gastrointestinal Tract 3. If tumor is bilateral and morphology is mucinous or endometrioid/endometrioid-like, the probability of metastasis 10.6.1 Krukenberg Tumor increases, as bilateral mucinous and endometrioid ovarian primaries are relatively rare. Definition: The term “Krukenberg tumor” has not been con4. A carcinoma with mucinous morphology and either sistently defined over the years but has historically referred advanced stage or association with pseudomyxoma peri- to tumors metastatic to the ovary that have a significant comtonei is likely to be metastatic. ponent of mucin-containing signet ring cells. A recent source 5. For endometrioid/endometrioid-like tumors, an adenofi- defines “Krukenberg tumor” as a metastatic adenocarcinoma bromatous background or presence of endometriosis in which signet ring cells comprise at least 10% of the neofavors a primary ovarian origin. plasm [2]. The stomach, most often the pylorus, is the most 6. The presence of foci of histologically benign-appearing common source for these tumors, representing the primary and low-grade proliferative mucinous epithelium (border- site in greater than 60% of cases [11]. Other possible primary line/atypical proliferative features) that might suggest an sites include colon, rectum, breast, gallbladder, bile ducts, ovarian origin is nonspecific and does appear in meta- appendix, and less commonly the small intestine, pancreas, static tumors. urinary bladder, renal pelvis, and cervix [11 24]. Rare

Positive

Endocervical

Negative

Negative/ positivei

Positive (CK20>CK7) Positive/negative

Positive (CK20>CK7)

CK20 Endometrioid: Negative Mucinous: Variable positive to negativea,b

Positive/ negativek

Negative

Negative

Negative

Negative

PAX8 Endometrioid: Positive Mucinous: positive/ negativec

Negativek

Negative

Negatived

Negative

Negative

ER Endometrioid: Usually positive Mucinous: usually negatived

Negativek

Negative

Negatived

Negative

Negative

PR Endometrioid: Usually positive Mucinous: usually negatived

Negativek

Negative

Negative or positive

Positive

Positive

SATB2 Endometrioid: Negative Mucinous: Negativea,e

Negative/ positivek

Signet ring type: variable staining Intestinal type: positive Negative/ positivej

Positive

Positive

CDX2 Endometrioid: Negativef Mucinous: often positivef

Negative (approx. 50% of pancreatic carcinomas negative) Positive

Positive

Positive

Positive (approx. 90% of cases)

DPC4/SMAD4 Endometrioid: Positive Mucinous: Positive

Strong diffuse positivel

Negative to focal positive

Negative to focal positive Negative/positive

P16 Endometrioid: Negative to patchy positive Mucinous: Negative to patchy positive Negative to patchy positive

a

Primary ovarian epithelial tumors are typically CK7+/CK20−; thus a CK7−/CK20+ immunophenotype suggests a metastasis. Notable exception: The subset of ovarian mucinous tumors of intestinal phenotype arising in association with a teratoma has an immunohistochemical staining profile indistinguishable from that of metastatic tumors of intestinal origin (CK7−/CK20+/SATB2+/ CDX2+/ER−/PR−/PAX8−) b Ovarian primary mucinous tumors of intestinal type are typically positive for CK7, often with diffuse strong positivity for this marker; they are often positive for CK20 as well, although with patchy variable staining. As noted above, the subset of ovarian mucinous tumors of intestinal phenotype arising in association with teratomas have an immunohistochemical staining profile indistinguishable from that of metastatic tumors of intestinal origin (CK7−/CK20+). Ovarian seromucinous tumors, separated from ovarian mucinous tumors in the 2014 WHO Classification of Tumors of Female Reproductive Organs, typically have a CK7+/CK20−/PAX8+/CDX2− immunophenotype c PAX8 staining is variable in ovarian tumors of mucinous type unassociated with a teratoma, negative in ovarian mucinous tumors arising in association with a teratoma, and typically positive in ovarian seromucinous tumors d ER and PR are typically negative in ovarian mucinous tumors (those with and without an associated teratoma) and positive in ovarian seromucinous tumors. Weak ER or PR staining does not rule out stomach as a primary site e SATB2 is typically negative in ovarian mucinous tumors unassociated with a teratoma, positive in ovarian mucinous tumors associated with a teratoma, negative in ovarian seromucinous tumors, and positive in metastatic tumors of colorectal or appendiceal origin f Ovarian mucinous tumors unassociated with teratoma show variable staining for CDX2. CDX2 is typically positive in ovarian mucinous tumors arising in association with a teratoma, and negative in ovarian seromucinous tumors. Endometrioid adenocarcinoma may have focal positivity for CDX2 in morules and in foci of squamous differentiation g Adenocarcinomas of rectal origin may be positive for CK7 h Approximately one-third of appendiceal mucinous neoplasms are positive for CK7; in contrast, appendiceal adenocarcinomas of usual intestinal type typically have negative to focal positivity for CK7, like colonic adenocarcinomas i Approximately one-third of pancreatic ductal adenocarcinomas are positive for CK20, with focal positivity most common j Approximately 30% of pancreatic ductal adenocarcinomas are positive for CDX2 k PAX8 is positive in the majority of endocervical adenocarcinomas. ER and PR are negative in the majority of endocervical adenocarcinomas. Endocervical adenocarcinomas may infrequently be positive for SATB2. CDX2 is expressed in endocervical adenocarcinoma of intestinal type and in some nonintestinal types of endocervical adenocarcinoma l Endocervical adenocarcinoma expresses strong diffuse positivity for p16 in the vast majority of cases related to HPV; HPV-unrelated subtypes are negative for p16

Positive

Negative (75–90% of cases negative)g Negative (70% of cases)h Positive/negative

CK7 Endometrioid: Positive Mucinous: Positivea,b

Pancreatobiliary

Gastric

Appendiceal

Colorectal

Primary site of origin Ovarian

Table 10.1  Typical immunohistochemical staining features of primary and secondary tumors with mucinous and endometrioid/endometrioid-like morphology [19, 21–23]

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Krukenberg-type tumors have been deemed to be of primary ovarian origin [11]. Clinical Features: Patients with Krukenberg tumors are younger than the average patient with tumor metastatic to the ovary, with an average age of 45 years and an age range of 13 to 84  years in one large series. A significant proportion of patients (35–45%) in this series were younger than 40 years of age [11]. This young age can be ascribed to the relatively high percentage of gastric adenocarcinomas of signet ring type giving rise to Krukenberg tumors, and the relatively high frequency of this tumor type in younger females [25]. Patients may be asymptomatic or may present with nonspecific symptoms of abdominal pain or increased abdominal girth due to the ovarian mass(es) or ascites. Patients may also present with abnormal uterine bleeding, hirsutism, or virilization related to ovarian stromal luteinization and resultant hormone production (“functioning stroma”) within those metastatic tumors. Symptoms related to involvement of the primary site or due to extraovarian spread (lung metastasis, bone metastasis) may also be encountered. The primary tumor is most often identified preoperatively, intraoperatively, or within a few months of discovery of the Krukenberg tumor, although the primary site may not be discovered for several years or until autopsy. Significantly, primary gastric and breast cancers may be small and difficult to detect clinically [12]. Pathologic Findings: Gross: Krukenberg tumors are bilateral in the majority of cases (63% of cases in one large series) [11]. Krukenberg tumors have been found in ovaries ranging from the normal size up to 34 cm, with an average size of 10.4 cm [11, 24]. As Krukenberg tumors can involve ovaries of normal size, the above-noted percentage of bilaterality in Krukenberg tumors is likely artificially low, as tumor may not be detected if a normal-sized ovary is not removed or adequately sampled. The involved ovary is generally smooth surfaced and bosselated. The cut surface is typically white to tan to pale yellow and may have foci of red, brown, or purple discoloration due to hemorrhage (Fig. 10.1). The cut surface may be solid and multinodular, or solid and cystic with cysts ranging from small to large enough to suggest an ovarian primary neoplasm. Cysts may contain mucoid, serous, or hemorrhagic fluid. The cut surface may be firm and similar to that of a fibroma, or may be relatively soft and edematous, fleshy, or gelatinous. The central portion of the tumor may be softer and of a different color and consistency than the periphery of the tumor [11]. Microscopic: As Krukenberg tumor is defined as a metastatic adenocarcinoma with a significant component (at least 10%) of mucin-containing signet ring cells, a significant component of signet ring cells is required for diagnosis; however, a variety of cell types and architectural patterns are often present in the tumor, and the stromal component may

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Fig. 10.1  Krukenberg tumor of gastric origin. The tumor is smooth surfaced and bosselated, as is typical of Krukenberg tumors. The cut surface is solid and tan with red discoloration due to hemorrhage

Fig. 10.2  Krukenberg tumor of gastric origin. The low-power appearance is one of variably defined nodularity, a feature common to secondary tumors of the ovary

vary as well. The low-power appearance is often one of ill-­ defined nodularity, typical of tumors metastatic to the ovary (Fig.  10.2). Tumor nodules may coalesce or may be separated by less cellular areas with edematous or mucoid stroma. A second low-power appearance commonly seen in Krukenberg tumors is that of a more cellular periphery, with edema and lesser cellularity centrally [11]. Surface involvement is seen less commonly than with other metastases of gastrointestinal origin, possibly due to an increased frequency of lymphovascular, rather than transcoelomic, spread of the tumor [24]. Foci of hemorrhage and necrosis may be present. High-power examination often demonstrates variability in both the epithelial and stromal components of the tumor with different cell types and architectural patterns,

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Fig. 10.3  Krukenberg tumor of gastric origin. Classic signet ring cells

Fig. 10.5  Krukenberg tumor of gastric origin. Signet ring cells in an active stroma

Fig. 10.4  Krukenberg tumor of gastric origin. Signet ring cells line tubules

Fig. 10.6  Krukenberg tumor of gastric origin. The tumor must have a significant component of signet ring cells (10%) to be classified as a Krukenberg tumor, but cell types and architectural patterns may vary, as in this case. Moderately well-formed small glands are present in a background of conspicuous edema, a feature of many Krukenberg tumors

sometimes with an abrupt transition from one architectural pattern to another. Tumor cells may be abundant and obvious, or inconspicuous and sparsely scattered within a fibrous stroma. The proportion of signet ring cells often varies markedly in different areas of the tumor, being inconspicuous or absent in some areas. Signet ring cells have a variable amount of eosinophilic or basophilic intracytoplasmic mucin and may be disposed singly or in cords, clusters, sheets, or lining part or all of a tubule (Figs. 10.3, 10.4, and 10.5). Signet ring cells are often accompanied by variably well-formed tumor glands of various sizes, including both small and large glands and cysts (Figs. 10.6 and 10.7). Hollow and solid sertoliform tubules may be present. Extracellular mucin may be abundant [11]. Stroma may be fibrous with a fibroma-like appearance, rendering diagnosis more challenging when tumor cells are few, especially in the intraoperative setting. Stroma

may be cellular, may have a storiform architecture, and may be prominently edematous or mucoid. Stromal reactivity/ desmoplasia may be present or absent. Stromal luteinization is often present and may be prominent [11]. Lymphovascular invasion is commonly seen, most often in the ovarian hilum and at the tumor periphery. Biomarkers: Periodic acid-Schiff (PAS), Alcian blue, or mucicarmine stains may be used to highlight intracytoplasmic mucin. A directed panel of immunohistochemical stains may be employed to aid in the determination of the primary site. Typical immunohistochemical staining profiles of the more common primary sites generating Krukenberg tumors are as follows [22, 26, 27]:

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Fig. 10.7  Krukenberg tumor of gastric origin. This tumor shows a notable variation in growth pattern from one area to another with an abrupt transition between different architectural patterns, a feature common to secondary tumors of the ovary

–– Stomach: Variable staining with CK7 and CK20; CDX2 is variably expressed, with positivity ranging from 20 to 90% of cases; SATB2 may be negative or positive, more often negative; weak ER and PR expression may be seen; typically positive for CA 19-9; may be positive for HepPar1. –– Colon/rectum: Predominantly CK7− (exception: adenocarcinomas of rectal origin may be CK7 positive)/CK 20+/CDX2+/SATB2+. –– Breast: Predominantly CK7+/CK20−/GATA3+/ER+/ PR+. Differential Diagnosis: The differential diagnosis of Krukenberg tumors includes a relatively long list of potential primary sites that may give rise to metastatic tumors with signet ring morphology, including the stomach (most frequent primary site), colon, rectum, breast, gallbladder and bile ducts, appendix, and less commonly the small intestine, pancreas, urinary bladder, renal pelvis, and cervix. Several primary ovarian neoplasms may also present a differential diagnosis with Krukenberg tumor, including primary ovarian mucinous carcinoma (although this does not typically have signet ring cells), clear-cell carcinoma, mucinous carcinoid tumor with signet ring cells, sclerosing stromal tumor, signet ring stromal tumor, small-cell carcinoma of hypercalcemic type, Sertoli-Leydig cell tumor (if sertoliform tubules are present in the Krukenberg tumor; of note, signet ring cells may be seen in Sertoli-Leydig cell tumors of heterologous type with small nests of mucinous carcinoid), and fibroma (if tumor cells are few and stroma has a fibromatous quality). Tumor-like lesions such as mucicarminophilic histiocytosis may also present a differential diagnosis [12, 24]. Clues to the diagnosis of Krukenberg tumor include features typical of tumors metastatic to the ovary, such as fre-

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quent bilaterality of the neoplasm, prominent lymphovascular space invasion, and frequent multinodular growth. The presence of signet ring cells and architectural patterns not typical of primary ovarian neoplasia are other helpful clues. For determination of primary site when metastasis is suspected, clinical correlation and a directed panel of immunohistochemical stains should be employed to aid in diagnosis. Management and Outcome: There are no uniform guidelines in the treatment of Krukenberg tumors of the ovary, as these are a heterogeneous group with variable biologic characteristics. Tumors must be treated according to the site of origin and stage. Treatment remains challenging. Patients with tumors of gastrointestinal origin may benefit from metastasectomy, chemotherapy which may include adjuvant chemotherapy and HIPEC (hyperthermic intraperitoneal chemotherapy), and targeted therapy such as monoclonal antibodies against EGFR for colorectal cancer and Her2neu for gastric cancer [1, 28, 29].

10.6.2 Gastric Adenocarcinoma, Non-­Krukenberg Type Definition: An adenocarcinoma of gastric origin with an intestinal phenotype, thought to arise from metaplastic epithelium. As Krukenberg tumors arising from the stomach may have foci of glandular differentiation, intestinal type tumors of gastric origin may also have signet ring cells, although signet ring cells may not exceed 10% of the tumor to qualify for the diagnosis of adenocarcinoma of non-­ Krukenberg type. Clinical Features: These tumors are uncommon relative to metastatic gastric tumors of diffuse type/signet ring cell type, and thus data is limited. A 2006 series of four cases [30] and a 1982 series of three cases [31] noted a somewhat older age of patients with metastatic gastric intestinal type carcinoma relative to patients with metastatic signet ring cell carcinoma (patients with metastatic gastric intestinal type carcinoma are in the sixth decade on average). Tumors are either bilateral or unilateral. In the majority of patients, ovarian metastases are identified after the gastric primary is discovered, although one reported patient presented initially with a presumed ovarian primary carcinoma. The limited data suggest that metastatic adenocarcinoma of gastric origin, intestinal type, typically occurs in the setting of widespread metastatic disease throughout the abdomen and pelvis [30]. Pathologic Findings: Gross: Ovarian masses in the few cases reported have ranged from 4 to 19 cm with an average diameter of 11.5 cm. The cut surface is typically solid and cystic with a multinodular appearance to the solid areas. Necrosis is common. Tumors may contain mucinous or hemorrhagic fluid [30, 32].

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Microscopic: The microscopic appearance of these tumors is similar to that of metastatic tumors of intestinal origin. The tumors are formed of medium-sized to large tubular glands with a pseudoendometrioid appearance, characterized by columnar epithelium with only focal intracytoplasmic mucin. Other microscopic features, commonly shared by metastatic tumors of intestinal origin, include segmental necrosis of epithelium lining the neoplastic glands, high-grade nuclear features, variable to brisk mitotic activity, and frequent intraluminal “dirty” necrosis. In addition to the moderate to well-­formed glands typical of tumors of intestinal type, these tumors may show papillary, cribriform, trabecular, and nested patterns. Some tumors have abundant intracytoplasmic mucin with cells ranging from goblet type to foveolar type, raising the differential diagnosis of a primary ovarian mucinous carcinoma, but have the varied histologic patterns and desmoplasia typical of mucinous neoplasms metastatic to the ovary. Microscopic features common to metastatic tumors in general include areas of bland, benign-appearing mucinous epithelium and cysts lined by flattened epithelium, prominent stromal edema in areas, and notable morphologic variability within a small zone of tumor [30–32]. Signet ring cells, if present, by definition do not comprise more than 10% of the tumor. Biomarkers: Gastric adenocarcinoma of intestinal type shows variable positivity for CK7 and CK20, like gastric adenocarcinoma of diffuse type. Unlike gastric adenocarcinoma of diffuse type, CDX2 is typically strongly, diffusely expressed. SATB2 may be positive or negative (limited data exists on SATB2 staining in gastric adenocarcinomas). There may be weak staining for ER and/or PR. Tumor may be positive for CA 19-9 and/or HepPar1 [21, 22]. Differential Diagnosis: The differential diagnosis includes primary ovarian mucinous and endometrioid adenocarcinomas, and metastatic adenocarcinomas that may have a mucinous, endometrioid, or pseudoendometrioid morphology (primarily tumors of intestinal or appendiceal origin, less commonly tumors of gallbladder or biliary tract origin). Management and Outcomes: Limited data is available on this infrequently reported ovarian metastasis. Of the four patients reported in the 2006 series noted above, the three patients with follow-up information were deceased within 1 year of discovery of the ovarian metastasis [30].

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Clinical Features: In one 2006 series of 86 cases of colorectal adenocarcinoma metastatic to the ovary, patients ranged in age from 19 to 85 years with a median age of 51; 24% of patients were younger than 40 [18]. A single case in a 12-year-old patient has been documented [32]. The majority of patients have known intestinal carcinoma prior to diagnosis of the ovarian tumor, while a minority (less than 10%) present with an ovarian mass and postoperative workup discloses the intestinal primary. Some patients present with symptoms related to their colorectal mass (rectal bleeding, change in bowel habits, etc.), while others present with symptoms related to either the ovarian mass or the stromal luteinization generated by the tumor (abnormal uterine bleeding, breast tenderness, etc.). Some patients present with nonspecific symptoms such as abdominal or pelvic pain [18 32]. Importantly, patients with ovarian metastasis from primary colorectal adenocarcinoma may have no symptoms related to the primary tumor and may have a unilateral ovarian mass greater than 10 cm [33]. Pathologic Findings: Gross: Metastasis may be unilateral or bilateral. Several series have documented a higher percentage of unilateral than of bilateral metastasis [9, 33, 34], although this has not been demonstrated in all series. Tumor size ranges from 2 to 24 cm and may be greater than 10 cm [18, 33]. Tumors tend to have a smooth capsule without gross evidence of surface involvement by tumor, and lack the bosselation typical of Krukenberg tumors. A minority are ruptured [33]. The cut surface may be solid or solid and cystic, and may show large thin-walled cysts suggesting an ovarian primary neoplasm. Tissue is soft, friable, yellow, red, or gray, and may contain mucinous or clear fluid, recent or remote hemorrhage, and necrosis (Fig. 10.8) [2, 32].

10.6.3 Colorectal Adenocarcinoma Definition: Adenocarcinoma originating in the colon or rectum. Colorectal adenocarcinoma is one of the most common sources of metastatic ovarian tumor. One recent series of STOs including 713 adenocarcinomas of colorectal origin found that 50% of tumors originated from the rectosigmoid colon, 37% from the ascending colon and cecum, 8% from the descending colon, and 5% from the transverse colon [9].

Fig. 10.8  Metastatic colonic adenocarcinoma. The external surface is relatively smooth and uninvolved by tumor. The cut surface in this case is solid, soft, yellow-tan, and necrotic appearing

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Microscopic: Microscopically, tumors often have a pseudoendometrioid, mucinous, or mixed pseudoendometrioid and mucinous character [34]. The pseudoendometrioid appearance is most typical of metastatic colorectal adenocarcinoma and overall resembles typical primary colorectal adenocarcinoma; this pattern features columnar cells with only focal intracytoplasmic mucin (scattered goblet cells may be present) and marked nuclear atypia with nuclear stratification and brisk mitotic activity (Figs. 10.9 and 10.10). A mucinous-type epithelium, with more extensive well-­ differentiated mucin-rich cells, is a less commonly encountered cell type. In tumors characterized by the more common

pseudoendometrioid morphology, tumor glands are typically of moderate size but may range from small and tubular to large and cystic (Figs.  10.11 and 10.12). Broad areas of necrosis may be present (Fig.  10.13). Frequently encountered architectural patterns include a cribriform pattern and a “garland” pattern (neoplastic epithelium draped at the periphery of necrotic material). Intraluminal “dirty” necrosis and segmental necrosis of glandular epithelium are common features (Figs. 10.14 and 10.15). A papillary pattern, characterized by well-formed papillae or micropapillae, is occasionally seen [17, 18, 32, 34]. Rarely, a classic pattern of colloid carcinoma with clusters of neoplastic cells floating in

Fig. 10.9  Metastatic colonic adenocarcinoma. Like the majority of secondary ovarian tumors of colorectal origin, this tumor has pseudoendometrioid cytologic features, characterized by columnar cells with only focal intracytoplasmic mucin. This area has a cribriform pattern

Fig. 10.11  Metastatic colonic adenocarcinoma. Tumor glands are most often of moderate size but may range from small and tubular to large and cystic, as in this case. Large cystic glands may mimic a primary ovarian mucinous neoplasm

Fig. 10.10  Metastatic colonic adenocarcinoma. Brisk mitotic activity and marked nuclear atypia, in excess of that typically seen in endometrioid adenocarcinoma with a comparable degree of glandular differentiation, typify these tumors

Fig. 10.12  Metastatic colonic adenocarcinoma. Malignant epithelium in the top portion of the photomicrograph lines a large cystic tumor gland and is cytologically bland (“maturation phenomenon”), potentially mimicking the benign or borderline areas of a primary ovarian mucinous neoplasm

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pools of mucin may be encountered [32]. Occasionally, ­metastatic tumors of small bowel or large bowel origin have cells with clear cytoplasm, which may mimic an ovarian primary clear-cell carcinoma or secretory variant of endometrioid adenocarcinoma (Fig.  10.16). Signet ring cells may be present in small numbers. No squamous differentiation is present. Stroma may be desmoplastic, edematous, or mucoid, and often contains luteinized stromal cells [2]. Lymphovascular space invasion is common [12]. Biomarkers: Typical immunohistochemical staining profiles for metastatic colorectal adenocarcinoma and its more challenging differential diagnostic considerations are as follows [19, 21–23]:

Fig. 10.13  Metastatic colonic adenocarcinoma. Broad areas of necrosis, as seen in this tumor, are more common in metastatic tumors than in primary ovarian tumors

–– Colorectal adenocarcinoma: Negative for CK7 in approximately 75–90% of cases, although adenocarcinomas of rectal origin may be positive for CK7; typically strongly

Fig. 10.14  Metastatic colonic adenocarcinoma. Intraluminal “dirty” necrosis is a common feature

Fig. 10.15  Metastatic colonic adenocarcinoma. Segmental necrosis of glandular epithelium and a “garland pattern” in which the neoplastic epithelium is draped at the periphery of necrotic material are often seen

Fig. 10.16  Metastatic colonic adenocarcinoma with unusual morphologic patterns. Left: A papillary pattern, with large well-formed papillae. A micropapillary pattern may also be seen. Center: Adenocarcinoma of small or large bowel origin may have clear cytoplasm, mimicking

mullerian clear-cell adenocarcinoma. Right: Tumor may occasionally have a colloid appearance, with groups of tumor cells floating in abundant dissecting mucin

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Fig. 10.17  Metastatic colonic adenocarcinoma. In contrast to endometrioid adenocarcinoma, tumor is typically immunoreactive for CK 20 (left), CDX2 (center), and SATB2 (right)

––

––

–– ––

positive for CK20 (80–100% of cases), but may infrequently show no or only focal positivity for CK20 (decreased CK20 staining is associated with microsatellite unstable carcinomas); typically positive for SATB2 (96%), CDX2 (72–100%), and DPC4/SMAD4; negative for PAX8, ER, and PR (Fig. 10.17). Mucinous tumors of intestinal phenotype, ovarian origin (excluding the subset of ovarian mucinous carcinomas arising in association with a teratoma): Typically positive for CK7, although infrequently may be negative; CK20 expression variable, sometimes negative but more often patchy positive; variable expression of CDX2 and PAX8; typically positive for DPC4/SMAD4; typically negative for SATB2, ER, and PR. Mucinous tumors of intestinal phenotype, ovarian origin, arising in association with a teratoma: Immunohistochemical staining profile is indistinguishable from that of metastatic tumors of intestinal origin (CK7−/CK20+/SATB2+/CDX2+/PAX8−/ER−/PR−). Seromucinous tumors of ovarian origin: Typically CK7+/ PAX8+/ER+/PR+/CK20-/CDX2−. Endometrioid tumors of ovarian or endometrial origin: CK7+/ER+/PR+/PAX8+/DPC4/SMAD4+/CK20−; may focally express CDX2.

Immunohistochemical staining may be used in the workup of mucinous and endometrioid/pseudoendometrioid tumors involving the ovary, although there is overlap in staining patterns between ovarian primary and metastatic neoplasms; thus, circumspect interpretation and correlation with clinical findings are required. Note that CDX2 is not specific for intestinal carcinoma and may be demonstrated in tumors of endometrial, pancreatobiliary, gastric, lung, bladder, and ovarian origin. For additional information regarding immunohistochemical staining features of tumors in this differential, please see Table 10.1. Differential Diagnosis: The differential diagnosis includes primary ovarian tumors of mucinous and endometrioid types, and metastatic tumors with similar morphology that may arise from the appendix, small bowel, stomach,

gallbladder, bile ducts, pancreas, uterine cervix, endometrium, or urachus. Adenocarcinoma of breast and lung origin may also occasionally mimic endometrioid adenocarcinoma [32]. Of these, mucinous and endometrioid adenocarcinomas of ovarian origin are the most difficult to exclude when considering metastasis from a colorectal primary. Features helpful in discriminating between the top differential diagnostic considerations are as follows: Features favoring metastatic colon cancer: • A known colorectal primary. • Gross findings of bilaterality, multinodularity of tumor, and ovarian surface involvement. • Prominent “dirty” necrosis, segmental necrosis of tumor epithelium, higher nuclear grade and more mitotic activity than is typical of endometrioid adenocarcinoma with a similar degree of glandular differentiation, and lymphovascular space invasion. Features favoring primary ovarian endometrioid adenocarcinoma: • Squamous differentiation, an adenofibromatous component, and/or a background of endometriosis. • Gross findings of unilaterality of tumor, an often cystic cut surface, and presence of chocolatey material related to remote hemorrhage and endometriosis. • Primary endometrioid adenocarcinoma usually has less prominent necrosis than does metastatic colorectal adenocarcinoma; however, it may show the “dirty” and/or segmental epithelial necrosis more characteristic of colorectal adenocarcinoma [2]. Features favoring adenocarcinoma:

primary

ovarian

mucinous

• Presence of a teratoma. • Large unilateral tumor (although metastatic colorectal carcinoma may also be unilateral and large) [9, 18, 33, 34].

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• Like primary ovarian endometrioid adenocarcinoma, primary ovarian mucinous adenocarcinoma has a lower incidence of multinodularity and ovarian surface involvement than does metastatic colorectal adenocarcinoma. • Microscopically, small areas of invasive carcinoma with extensive benign-appearing mucinous tumor favor an ovarian primary mucinous tumor, although metastatic colorectal cancers may also have deceptively bland epithelium and large cysts that mimic a benign or borderline primary ovarian tumor (Figs. 10.11, 10.12). • Primary ovarian mucinous carcinoma does not typically show the “dirty” necrosis or lymphovascular space invasion more characteristic of metastatic colorectal cancer. • Ovarian primary mucinous carcinomas have goblet cells more frequently than do metastatic colonic adenocarcinomas, although metastatic colonic adenocarcinomas may have goblet cells as well [2, 12]. Metastatic colorectal cancer is the most common primary site generating metastatic tumor to the ovary in many series in Western nations, and has a greater tendency to be unilateral and greater than 10 cm relative to other primary sites. This evidence is contradictory to the conventional concept of metastatic cancer, in which metastatic tumor is more frequently bilateral and less than 10 cm in size. Therefore, we recommend that the threshold should be relatively low for considering the possibility of metastatic colon cancer for tumors with microscopic features suggesting that diagnosis. A directed panel of immunohistochemical stains should be employed when the primary site is not clear, although overlap in immunohistochemical staining patterns mandates that caution in interpretation is warranted, and that clinical findings must be taken into consideration. Management and Outcomes: Colorectal adenocarcinoma metastatic to the ovary qualifies as stage IV disease and has had a poor outcome relative to the primary ovarian neoplasms in the differential diagnosis. The treatment strategy is not currently well defined. A few studies have supported a higher median overall survival in patients undergoing metastasectomy [36, 37].

10.6.4 Metastasis from Small Intestine Definition: Adenocarcinoma of small bowel origin metastatic to the ovary. Clinical Features: Most intestinal tumors metastatic to the ovary are from the large bowel, although occasional tumors originate from the small intestine. Risk factors for adenocarcinoma of the small intestine include Crohn’s disease, celiac disease, Peutz-Jeghers syndrome, familial adenomatous polyposis (FAP), and hereditary nonpolyposis colorectal cancer syndrome [38]. In accordance with its low incidence, small-

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bowel adenocarcinoma accounted for only 1.7% of ovarian metastases in one large series [9]. A 2017 case report and review of the literature detailing 72 cases of adenocarcinoma of small bowel origin metastatic to the ovary noted a mean patient age of 46.7  years in the 12 cases well documented enough to report, with solitary metastasis to the ovary in the majority of these cases and peritoneal dissemination in a substantial minority of cases [39]. Although the duodenum is the area of the small bowel most frequently involved by adenocarcinoma (with most of the tumors arising around the ampulla of Vater), the jejunum was the most frequently involved section of small bowel generating ovarian metastasis in this 2017 series, giving rise to 69% of the 12 well-documented cases. Pathologic Findings: Gross: Literature regarding gross findings in metastatic tumors of small bowel origin is limited. Metastatic tumor may be bilateral or unilateral, and may be cystic or solid and cystic. In the 2017 series noted above, 51% of the tumors were bilateral and 49% unilateral. The largest documented tumor was 26 cm [39]. Microscopic: Literature regarding microscopic findings in metastatic tumors of small bowel origin is likewise limited. Microscopically, the tumors most often appear as conventional intestinal type adenocarcinoma as would be seen in metastasis from the large bowel, and thus may have a pseudoendometrioid or mucinous character. Tumor differentiation varies from well differentiated to moderately to poorly differentiated [39]. Adenocarcinoma of small bowel origin may occasionally have an unusual, strikingly clear cytoplasm, which may mimic ovarian clear-cell carcinoma or the secretory variant of endometrioid adenocarcinoma. Tumor with this unusual morphology is characterized by glands and cysts lined by cells with abundant clear cytoplasm, including some areas with subnuclear or supranuclear vacuoles. These cases do typically show the “dirty” necrosis characteristic of intestinal type adenocarcinomas. Tumors demonstrating both conventional intestinal type adenocarcinoma morphology and the more unusual clearcell morphology noted above have been described [35]. Biomarkers: –– Non-ampullary small intestinal adenocarcinomas tend to have a CK7+/CK20+ immunophenotype (66%). CK7 expression may be focal or diffuse. Approximately 33% have a CK7+/CK20− immunophenotype. Both of these staining patterns contrast with that of colorectal adenocarcinoma (usually CK7−/CK20+) [22]. –– Approximately 60–70% of small intestinal adenocarcinomas stain positively for CDX2 [22]. –– A subset (46%) of small intestinal adenocarcinomas stain positively for SATB2, although staining tends to be less strong and diffuse than that seen in colorectal adenocarcinomas [40]. –– Tumors are negative for PAX8, ER, and PR.

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Differential Diagnosis: Small-bowel adenocarcinoma with conventional intestinal type differentiation: For small-bowel adenocarcinoma with conventional intestinal type differentiation, the differential diagnosis includes primary ovarian mucinous and endometrioid tumors, and metastatic tumors with a similar morphology that may arise from the large bowel, appendix, stomach, gallbladder, bile ducts, pancreas, uterine cervix, endometrium, or urachus [2]. Adenocarcinoma of breast or lung origin may also be included in the differential diagnosis due to their occasional resemblance to endometrioid adenocarcinoma [32]. Of these, primary ovarian mucinous and endometrioid adenocarcinomas are the most challenging to exclude. Clinical and morphologic features that may aid in this differential diagnosis are as described above in the section on differential diagnosis of metastatic tumors of colorectal origin. Clear cell variant of small-bowel adenocarcinoma: For the clear cell variant of small-bowel adenocarcinoma, the differential diagnosis includes primary ovarian clear-cell carcinoma and endometrioid adenocarcinoma, secretory variant. Importantly, the clear cell variant of small-bowel adenocarcinoma does not have the classic morphologic features diagnostic of mullerian clear-cell adenocarcinoma (tubulocystic architectural pattern, papillae with hyalinized fibrovascular cores, hobnailing of cells, etc.); however, papillae and micropapillae may be seen in metastatic carcinomas of intestinal origin [32]. Secretory endometrioid adenocarcinoma is rare and, when seen, may have squamous differentiation, an association with endometriosis, or a component of endometrioid adenofibroma, like conventional endometrioid adenocarcinoma. Areas with other morphologies typical of mullerian primaries may also be seen and provide a clue to the diagnosis. Clinical identification of small-bowel primary tumors can be challenging, as they are not revealed on colonoscopy or upper endoscopy; thus, if an ovarian tumor with an intestinal phenotype is identified and metastasis is suspected, it is reasonable to consider the small bowel as a source, even when endoscopy is negative [38]. Management and Outcomes: Small-bowel adenocarcinoma is typically resected when possible. Tumors are most often diagnosed at an advanced stage. A median survival of 39.7 months was demonstrated in one large study of surgically resected cases [41], whereas median survival has been demonstrated to be markedly lower (8 months) in patients with unresectable tumors [42]. Chemotherapy using fluoropyrimidine plus a platinum salt appears to be the most effective treatment regimen in nonrandomized prospective trials for advanced small-bowel adenocarcinoma at this time. Targeted therapy against EGFR is not yet established but is under investigation. Phase I and phase II studies to evaluate the safety and efficacy of targeted therapies in small-bowel adenocarcinoma treatment are currently underway [43].

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10.6.5 Metastasis from Appendix Definition: Metastasis to the ovary from a primary appendiceal neoplasm. Diagnostic entities in the appendix with capacity to metastasize include low-grade appendiceal mucinous neoplasm (LAMN), high-grade appendiceal mucinous neoplasm (HAMN, rare), and adenocarcinoma. Adenocarcinomas may be of mucinous type, conventional intestinal type, or signet ring cell type. Clinical Features: Ovarian metastasis of appendiceal origin is less common than metastatic colorectal or breast cancer in most series [3, 6, 9]. Ovarian spread from a primary appendiceal neoplasm is most common in cases of LAMN of the appendix, although ovarian spread may also be seen in cases of adenocarcinoma of the conventional intestinal and mucinous types, carcinomas with neuroendocrine differentiation and focal goblet cell carcinoid patterns, colloid and signet ring cell carcinomas, and rarely typical carcinoid tumors [2, 44, 45]. LAMN: LAMNs usually present in the sixth decade, and may present as an abdominal mass or as an ovarian metastasis [46, 47]. Other presentations include abdominal pain or distention, which is often due to pseudomyxoma peritonei (see below). Approximately 15–20% of LAMNs are incidental findings in patients undergoing surgery for unrelated conditions [46]. With LAMN, the appendix is usually dilated and often has adherent mucin; an obvious associated solid mass is often not detected. Appendiceal Adenocarcinoma: Appendiceal adenocarcinomas are uncommon, with an incidence of 0.082% out of 50,000 appendectomy specimens. Patients are usually in the fifth to seventh decades, and usually present with symptoms of acute appendicitis [46]. Less common presentations include a palpable mass, intestinal obstruction, gastrointestinal bleeding, or symptoms related to metastasis. Patients may also be asymptomatic. One 2007 study including 48 patients with primary appendiceal malignant neoplasms of various histologic types metastatic to the ovary determined that the most common symptoms were abdominal pain and bloating [48]. Pseudomyxoma Peritonei: “Pseudomyxoma peritonei” refers to a clinicopathologic syndrome in which the peritoneal cavity contains more or less abundant mucinous material, associated with variable amounts of viable epithelial glandular cells derived from a mucinous neoplasm. Historically, it was stated that the primary lesion could be a borderline or malignant mucinous neoplasm of appendiceal, pancreatic, or ovarian origin. More recently, however, studies have led to the conclusion that the appendix is the site of origin in almost all cases, and that any ovarian involvement is metastatic [49, 50]. Most cases of pseudomyxoma peritonei arise from low-grade appendiceal mucinous tumors, either LAMN or low-grade adenocarcinoma. Rarely, a primary ovarian mucinous neoplasm of gastrointestinal ­

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Fig. 10.18  Pseudomyxoma peritonei involving the omentum. The external surface shows the characteristic gelatinous appearance

Fig. 10.19  Metastatic LAMN. Abundant mucin and neoplastic epithelium involve the ovarian surface

p­ henotype associated with a teratoma may spread to the peritoneum and cause pseudomyxoma peritonei [51]. Pathologic Findings: Gross: LAMN: Secondary ovarian tumors originating from LAMNs are bilateral in the majority of cases [52], with a mean diameter of 15–16 cm. There is often generalized pseudomyxoma peritonei (Fig.  10.18), and mucinous material may conspicuously coat the surface of one or both ovaries. Tumors are usually multilocular/multicystic and mucoid on cut surface, although in some cases the tumor may have a firmer, more solid character due to organization of mucin with fibrosis [49]. Appendiceal Adenocarcinoma: Secondary ovarian tumors originating from appendiceal adenocarcinoma are also bilateral in the majority of cases, and have a mean diameter of 11 cm. The cut surface is usually solid and firm, but a cystic component may be present, particularly in low-grade adenocarcinomas [52]. Ovarian involvement by appendiceal adenocarcinoma of conventional intestinal type has a gross appearance similar to that of metastatic intestinal ­adenocarcinoma, while ovarian involvement by appendiceal adenocarcinoma of signet ring type has a gross appearance similar to that of Krukenberg tumor. Moderate- to high-grade mucinous adenocarcinomas may have nonspecific gross features or may have a gelatinous consistency [12]. Microscopic: LAMN: Secondary ovarian tumors originating from LAMNs usually have mucin on the ovarian surface, which may or may not be associated with neoplastic epithelium, and dissecting extracellular mucin within the ovary (pseudomyxoma ovarii) (Figs.  10.19 and 10.20). The neoplastic glands and cysts are lined by tall, well-differentiated, mucin-­ rich (hypermucinous) epithelium, from which mucin often

Fig. 10.20  Metastatic LAMN. Large neoplastic glands, some incomplete, haphazardly involve the ovarian stroma and are associated with dissecting extracellular mucin (pseudomyxoma ovarii)

appears to extrude (Fig.  10.21). The glands and cysts are haphazardly distributed in the ovarian stroma, are often incomplete, may have a scalloped contour, and often exhibit retraction from the adjacent stroma resulting in cleft-like spaces around the neoplastic glands (Fig. 10.22). This retraction from the adjacent stroma is a characteristic feature of metastatic LAMN [12, 50, 52]. Overall, there is a remarkably bland appearance to the tumor cells throughout most of the neoplasm in the majority of cases, although there may be some mild-to-moderate nuclear atypia [2]. Appendiceal Adenocarcinoma: Secondary ovarian tumors originating from appendiceal adenocarcinomas may be of conventional intestinal type, intermediate- to h­ igh-­grade mucinous type, or signet ring type. Tumors of conventional

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Fig. 10.21  Metastatic LAMN. Neoplastic epithelium is tall columnar and bland with mucin-rich cytoplasm

Fig. 10.22  Metastatic LAMN. Neoplastic epithelium has a scalloped contour and shows retraction from the adjacent stroma, unique features seen in many cases of metastatic LAMN

intestinal type and mucinous type resemble those of similar type arising from elsewhere in the GI tract. These tumors have no unique morphologic characteristics, except for the presence of operative findings suggesting the appendix as the likely primary site [2]. A diversity of morphology is present in some cases, such that the adenocarcinoma may show both gland formation and signet ring cells (Fig. 10.23) [32, 44]. Adenocarcinoma with Neuroendocrine Differentiation: The appendix may also give rise to adenocarcinomas with neuroendocrine differentiation, which have historically been termed “goblet cell carcinoid” (Fig. 10.24). There is limited literature on ovarian spread of these tumors. A 2007 series of 30 cases of ovarian metastases from tumors of this type noted that the overall clinical features and morphologic findings support classification of most of these tumors as metastatic

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Fig. 10.23  Adenocarcinoma of appendiceal origin metastatic to the ovary. Tumor in this field has nonspecific medium-sized gland morphology and destructive stromal invasion. The tumor showed a diversity of morphology in other sections, with both gland formation and signet ring cells

Fig. 10.24  Tumor classified as “goblet cell carcinoid,” metastatic to the ovary. In this area the tumor shows the characteristic neoplastic goblet cells, arranged in small tight clusters. In other areas there was a classic pattern of gland-forming adenocarcinoma with frankly infiltrative growth

adenocarcinomas with neuroendocrine differentiation rather than goblet cell “carcinoids” [53]. In this series, the appendiceal and ovarian tumors showed a variety of architectural patterns including signet ring cell, glandular, nested, and corded patterns with goblet cells. Interestingly, signet ring cells are often a conspicuous feature of this tumor, and metastasis from this tumor constitutes one form of Krukenberg tumor [2, 32]. The metastatic tumors may have focal areas with features diagnostic of what has historically been termed “goblet cell carcinoid,” but the presence of frank destructive, infiltrative growth merits classification of the

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tumor as an adenocarcinoma with neuroendocrine differentiation [53, 54]. Of note, the involved appendix may be firm and thickened but may not have a grossly identifiable discrete mass; thus, the appendiceal primary tumor may be overlooked at operation [53]. Even when an appendiceal primary tumor is not identified, a goblet cell carcinoid-like pattern within an ovarian tumor should suggest an appendiceal primary tumor. Appendiceal tumors meeting the criteria for “goblet cell carcinoid,” as strictly defined, rarely metastasize to the ovary. Likewise, typical carcinoids of appendiceal origin rarely metastasize to the ovary [32]. Biomarkers: –– LAMNs and mucinous adenocarcinomas of appendiceal origin typically express CK20, CDX2, DPC4/SMAD4, and SATB2. Approximately one-third express CK7, with approximately 25–75% of cells staining. –– Appendiceal adenocarcinomas of conventional intestinal type are immunophenotypically similar to colorectal adenocarcinomas. –– Appendiceal “goblet cell carcinoids” have a mixed immunophenotype that shows both neuroendocrine and glandular differentiation; most are positive for CK20, up to 70% are positive for CK7, and staining with neuroendocrine markers synaptophysin and chromogranin A is focal rather than diffuse [22]. Differential Diagnosis: LAMN: The differential diagnosis of secondary ovarian involvement with LAMN is with primary ovarian mucinous cystadenoma, mucinous borderline tumor, and mucinous carcinoma. Metastatic LAMN is favored by the presence of an appendiceal neoplasm, bilateral ovarian involvement, pseudomyxoma peritonei and/or ovarii, scalloped neoplastic glands, and subepithelial clefting. The presence of a teratoma or PAX-8 positivity favors an ovarian primary. Importantly, a lack of grossly identifiable appendiceal rupture does not rule out that the tumor originated in the appendix, as the rupture site may be small and difficult to identify, or healed over by fibrosis [55]. Appendiceal adenocarcinoma: The differential diagnosis of metastatic appendiceal adenocarcinoma is with primary ovarian mucinous and endometrioid adenocarcinomas, and with metastatic adenocarcinomas of mucinous and endometrioid/pseudoendometrioid types originating elsewhere. The distinction of a primary ovarian neoplasm from metastatic tumor of appendiceal or other origin depends to a great degree on adequate sampling of the ovarian neoplasm and clinical correlation. General features favoring metastatic carcinoma include a known extraovarian primary tumor, bilaterality, multinodular growth pattern, involvement of the ovarian surface, high stage of disease, and histologic features unusual for a primary ovarian neoplasm.

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As primary and metastatic tumors to the ovary may have overlapping immunohistochemical staining patterns, immunostaining may be of limited value in certain cases; however, a panel of immunostains should be employed when the source of tumor is uncertain. Positive staining for PAX8, CK7, ER, or PR favors a primary ovarian tumor, although negative staining for these markers does not exclude an ovarian primary. Rare mucinous primary ovarian tumors with an intestinal phenotype associated with a teratoma may generate pseudomyxoma peritonei, a finding almost always ascribable to an appendiceal primary neoplasm [51]; these tumors have an immunophenotype indistinguishable from metastatic tumors of intestinal origin (CK7−/CK20+/ CDX2+/SATB2+/PAX8−). Management and Outcomes: Overall, low-grade appendiceal mucinous neoplasms (LAMNs) involving the ovary exhibit more indolent behavior and have a better prognosis than appendiceal adenocarcinomas [56]. The prognosis and treatment of LAMN are dependent on tumor stage. LAMN pursues a progressive clinical course when it is widely disseminated in the peritoneum [46]. Currently, complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the most commonly employed treatment for pseudomyxoma peritonei (PMP). Regarding appendiceal adenocarcinomas, the reported 5-year survival rates range from 18.7 to 55%. Patients with mucinous carcinoma have a better prognosis than those with non-mucinous carcinoma. Patients with peritoneal carcinomatosis have a poor prognosis. As with LAMN, treatment depends on disease stage [46].

10.7 M  etastasis from the Pancreas, Biliary Tract, and Liver 10.7.1 Pancreas Definition: Metastatic adenocarcinoma originating from the pancreas, most often adenocarcinoma of ductal type. Ovarian metastases of pancreatic mucinous cystadenocarcinoma, acinar cell carcinoma, neuroendocrine tumors, and solid pseudopapillary tumor have also been infrequently to rarely reported. Clinical Features: The frequency of pancreatic adenocarcinoma metastatic to the ovary has varied in recent Western series, although the pancreas typically represents the source of fewer than 10% of nongenital tract primary tumors generating a clinically apparent ovarian metastasis [4]. Ovarian spread is often part of disseminated disease but has been the dominant clinical finding or presenting clinical finding in some cases [57]. Patients are usually in their mid to late years of life, with reported mean ages ranging from 56 to 63 years.

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Pathologic Findings: Gross: Ovarian metastases originating from pancreatic ductal adenocarcinoma and mucinous cystadenocarcinoma are typically bilateral and often form solid nodules like other tumors metastatic to ovary; however, the tumors may be large, unilateral, cystic, or multiloculated, mimicking a primary ovarian mucinous carcinoma [57]. Microscopic: Metastatic pancreatic ductal adenocarcinoma and mucinous cystadenocarcinoma may form solid nodules and/or cysts. In tumors with solid nodules, a pattern of small neoplastic glands haphazardly infiltrating a desmoplastic stroma is the typical appearance. Single tumor cells and signet ring cells may be present. In tumors with cyst formation, foci resembling mucinous cystadenoma, mucinous borderline tumor, and primary ovarian moderately differentiated to well-differentiated mucinous adenocarcinoma may be present (Fig.  10.25); interestingly, this variation from high-grade invasive malignancy to low-grade cystic neoplasia (“maturation phenomenon”) is a distinctive feature of the tumor which may provide a clue to the diagnosis. Foci of frank malignancy are often present but may be focal. Surface tumor implants and lymphovascular invasion may be seen. Rarely, the gross and microscopic appearance is typical of Krukenberg tumor [2, 57]. Only a few cases of pancreatic acinar cell carcinoma metastatic to the ovary have been reported [58]. Microscopically, tumors are characterized by cells with round nuclei, stippled chromatin, prominent nucleoli, and abundant pale to eosinophilic finely granular cytoplasm, similar to their primary counterpart in the pancreas. Architectural patterns include solid nests and acinar structures of varying sizes ranging up to small cysts, with little intervening stroma. The mitotic rate is typically brisk, and lymphovascular space invasion is common.

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Biomarkers: –– Pancreatic ductal adenocarcinoma: Typically CK7 positive. Staining with CK20 is variable, with most tumors being either negative or focally positive. Loss of reactivity for DPC4/SMAD4 specifically suggests a pancreatic primary, as approximately 50% of these tumors show loss of DPC4/SMAD4; however, positivity for DPC4/SMAD4 does not rule out a pancreatic primary or suggest any other primary neoplasm specifically. –– Pancreatic acinar cell carcinoma: Positive for chymotrypsin and trypsin, and negative for neuroendocrine markers [59]. Differential Diagnosis: The differential diagnosis of pancreatic adenocarcinoma of ductal or mucinous type includes primary ovarian mucinous neoplasms and similar-appearing metastases from other sites. General features favoring metastasis include bilaterality, a multinodular growth pattern, tumor implants on the ovarian surface and in the superficial cortex, variable histologic patterns, lymphovascular space invasion, and intra-abdominal spread of tumor [2, 12]. The differential diagnosis for the rare pancreatic acinar cell carcinoma metastatic to the ovary can include carcinoid tumor and other neuroendocrine tumors due to the acinar architecture, although the distinctive eosinophilic granular ­cytoplasm and nuclear characteristics of acinar cell carcinoma contrast with those of usual endocrine neoplasms [2]. Management and Outcomes: Pancreatic adenocarcinoma typically has a poor prognosis due to the early development of systemic metastatic disease. Currently available chemotherapeutic agents show a modest but statistically significant improvement in survival [60].

10.7.2 Tumors of Gallbladder, Extrahepatic and Intrahepatic Bile Ducts

Fig. 10.25  Pancreatic adenocarcinoma metastatic to the ovary. This particular example features well-differentiated glands of varying sizes

Definition: Adenocarcinoma of gallbladder or biliary ductal (extrahepatic or intrahepatic) origin. Clinical Features: The incidence of biliary tract cancer metastatic to the ovary varies significantly with geographic area, reflecting the variable regional incidence of biliary tract adenocarcinoma. In the United States, few examples have been reported over the years [61, 62]. Thailand has the highest incidence of cholangiocarcinoma worldwide due to infestation with Opisthorchis viverrini, endemic in northern regions of the country; thus, metastatic biliary neoplasms are more common there than elsewhere [32]. In a 2006 study of 170 tumors of gynecologic and nongynecologic origin metastatic to the ovary in Northern Thailand, cancer involving intrahepatic bile ducts accounted for 10% of ovarian metastases, while cancer involving extrahepatic biliary ducts and

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gallbladder accounted for 7% of ovarian metastases [6]. Patients range in age from the third to the ninth decades, with a mean age of 59 years. Tumors may present with symptoms related to the primary tumor (jaundice, pruritis, cholangitis, etc.), or may present initially as an ovarian mass [62–64]. Pathologic Findings: Gross: Regarding carcinoma of the gallbladder and extrahepatic bile ducts metastatic to the ovary, most tumors are bilateral, with a mean size of 9.4 cm. The cut surfaces are variable, most often solid and cystic but sometimes solid or multicystic [63]. Regarding carcinoma of the intrahepatic bile ducts metastatic to the ovary, about two-thirds of cases are bilateral, with a mean size of 12 cm. Again, the majority of reported tumors are solid and cystic, but many are cystic or uniformly solid [2, 64]. Microscopic: Carcinoma metastatic to the ovary from the gallbladder and extrahepatic or intrahepatic bile ducts often shows the multinodular growth (obvious or vague), ovarian surface involvement, and varied histologic patterns typical of metastatic tumor, but may closely mimic a primary ovarian mucinous neoplasm [61, 62]. Cytologic and architectural patterns vary and overall are similar to primary ovarian mucinous tumors and mucinous adenocarcinomas metastatic from other sites, including colon and, most notably, pancreas. Tumors are typically gland forming and may show a mucinous morphology with or without abundant extracellular mucin, a pseudoendometrioid morphology, or the nonspecific small- to medium-sized gland morphology typical of biliary tract adenocarcinomas (Figs. 10.26, 10.27, 10.28, and 10.29). Some tumors have shown substantial signet ring morphology, qualifying for a diagnosis of Krukenberg tumor [32, 61, 63, 64]. Tumors may have striking cytologic atypia

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Fig. 10.27  Metastatic adenocarcinoma of gallbladder origin. The tumor has a mucinous morphology overall, although intracytoplasmic mucin is not prominent

Fig. 10.28  Metastatic adenocarcinoma of gallbladder origin. Signet ring cells are interspersed among columnar cells and line papillae. Exceptionally, tumors of biliary tract origin may have substantial signet ring morphology

Fig. 10.26  Metastatic adenocarcinoma of gallbladder origin. Tumor may show a mucinous, pseudoendometrioid, or nonspecific small- to medium-sized gland morphology typical of biliary tract neoplasms. This example forms large glands, mimicking a primary ovarian neoplasm

discordant with the degree of glandular differentiation. Additionally, like metastatic tumors of pancreatic origin, tumors may show remarkably bland, benign-appearing areas mimicking a mucinous cystadenoma or mucinous borderline tumor (“maturation” phenomenon), although most tumors are clearly malignant [32, 62]. Biomarkers: Carcinomas of the extrahepatic bile ducts and gallbladder almost always express CK7 and may also express CK20. In contrast, intrahepatic cholangiocarcinomas are positive for CK7 but tend to be negative for CK20. The tumors typically express CA 19.9 and CK19. ER may be detected in a small percentage of cases [59]. Differential Diagnosis: Adenocarcinomas of gallbladder and intrahepatic or extrahepatic bile duct origin metastatic to

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the ovary have no strikingly unique morphologic or immunohistochemical staining features and may resemble mucinous and endometrioid or pseudoendometrioid adenocarcinomas originating from the ovary and other sites. Immunohistochemistry is of limited value in determining primary site in this instance. If gross and microscopic features suggest metastasis but the primary site is not clear, correlation with clinical findings, and a directed battery of immunohistochemical stains, is recommended. Management and Outcomes: Metastatic biliary tract cancer overall has a poor prognosis. Currently available systemic therapies for advanced/metastatic biliary tract cancers are of limited therapeutic efficacy [65]. Candidate agents for targeted, “personalized” therapy are emerging [66].

Microscopic findings overall are characteristics of hepatocellular carcinoma, although in rare cases cysts may be prominent. Neoplastic cells show the moderate to abundant eosinophilic cytoplasm and polygonal cell shape typical of hepatocellular carcinoma [2, 67, 68]. Biomarkers: Hepatocellular carcinomas are negative for CK20 and CKAE1/AE3, and are often negative for CK7 (approximately 30% may be positive). They are often positive for CK8, CK18, and CAM5.2. They are usually positive for HepPar 1 (80–100% of cases) and may be positive for glypican-3 (50–90% of cases) and AFP (17–70% of cases) [59]. Differential Diagnosis: Given the relatively distinctive cytomorphologic features of hepatocellular carcinoma, the differential diagnosis includes primary ovarian hepatoid yolk sac tumor and hepatoid adenocarcinomas of primary ovarian and extraovarian origin. Hepatoid yolk sac tumor typically occurs at a younger age than hepatocellular carcinoma and hepatoid adenocarcinomas, and should show other morphologic features characteristic of yolk sac tumor and/or other germ cell elements. Hepatoid adenocarcinomas are rare, and may originate from the ovary and from various extraovarian sites including the stomach, gallbladder, colon, lung, and urinary bladder, among other sites [69]. Hepatoid ­adenocarcinomas are often more pleomorphic than hepatocellular carcinoma and occur in an older age group [12]. Hepatoid adenocarcinomas may also show foci of more typical adenocarcinoma, providing a clue to the diagnosis. Hepatoid adenocarcinomas often express the hepatocellular markers HepPar1, glypican-3, and AFP, limiting their usefulness in the differential diagnosis. Management and Outcomes: For patients with metastatic hepatocellular carcinoma, significant challenges exist in achieving favorable treatment outcomes with currently available systemic therapies. Patients with advanced-stage disease have an overall poor prognosis [70].

10.7.3 Metastasis from Liver

10.8 Metastatic Neuroendocrine Tumors

Definition: Tumor of hepatocellular origin metastatic to the ovary. Clinical Features: Hepatocellular carcinoma metastasizes to the ovary less commonly than pancreatobiliary adenocarcinoma, and only a few such cases have been reported [67, 68]. All patients have been adults. Ovarian metastases have been discovered prior to discovery of the liver tumor, synchronously, and after detection of the liver tumor. Pathologic Findings: Gross: Ovarian tumors in the two reported series range from 4 to 11  cm. Most tumors have a solid cut surface. A green hue may provide a clue to the diagnosis [2, 67, 68]. Microscopic: Features typical of metastatic disease, such as ovarian surface involvement, are seen in some cases.

Neuroendocrine tumors arise in various organs including the gastrointestinal tract, pancreas, thyroid, lung, and skin. The most common type of neuroendocrine tumor giving rise to ovarian metastasis is the well-differentiated type of neuroendocrine tumor historically referred to as “carcinoid tumor.” They are most often of small bowel origin, although occasionally of appendiceal, colonic, gastric, pancreatic, or lung origin (of note, the term “carcinoid tumor” is no longer commonly used in reference to neuroendocrine tumors of the gastrointestinal tract, and has been replaced by the term “well-differentiated neuroendocrine tumor” (NET)). The following discussion focuses on well-differentiated neuroendocrine tumors/carcinoid tumor. High-grade neuroendocrine carcinoma, a more clinically aggressive and poorly differentiated tumor type

Fig. 10.29  Metastatic adenocarcinoma of gallbladder origin. Like metastatic tumors from the pancreas and other gastrointestinal sites, metastatic adenocarcinoma of biliary tract origin may have areas with bland cells mimicking the benign or borderline areas of a primary ovarian mucinous neoplasm

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exemplified by, but not restricted to, small-­cell carcinoma of the lung, metastasizes to the ovary from various organs less often than well-differentiated neuroendocrine tumors, and is discussed briefly in relevant sections below. Definition: Tumor arising from cells that release hormones into the bloodstream in response to a signal from the nervous system. Clinical Features: Evaluation of literature related to well-differentiated neuroendocrine tumor/carcinoid tumor metastatic to the ovary is complicated by the varied criteria that have been employed over the years for diagnosis of such tumors. If strict diagnostic criteria are applied, tumors meeting the diagnostic criteria for well-differentiated endocrine tumor/carcinoid tumor from any source rarely metastasize to the ovary [32]. Two relatively large series of carcinoid tumors metastatic to the ovary have been reported [71, 72]. Rare cases of pancreatic neuroendocrine neoplasms metastatic to the ovary have also been reported outside of these series [73–75]. Carcinoid tumors account for approximately 2% of metastases that form detectable ovarian masses [2]. Most metastatic carcinoid tumors are of ileal origin, although less frequently the primary site is the jejunum, appendix, colon, stomach, pancreas, or lung [71–79]. In the largest series (35 cases) of carcinoid tumors metastatic to the ovary to date, patients ranged from 21 to 82 years of age, with a median age of 57 years. Patients may present with manifestations of the carcinoid syndrome (flushing and diarrhea), may have symptoms related to an intestinal or ovarian mass, or may be asymptomatic. A majority of patients with ovarian metastasis have extraovarian metastasis as well, which contrasts with the rarity of extraovarian spread of primary ovarian carcinoid tumor. Outside of the two large series of carcinoid tumors metastatic to the ovary noted above, rare pancreatic neuroendocrine neoplasms metastatic to the ovary have been reported including a VIPoma [73], a glucagonoma [74], and an ACTH-secreting tumor [75]. Ovarian metastasis was discovered years after diagnosis of the pancreatic primary tumor in the patients with VIPoma and glucagonoma. In the patient with metastatic ACTH-secreting pancreatic endocrine tumor, however, the initial presentation was due to bilateral ovarian masses, hirsutism, and Cushing’s syndrome; subsequent workup disclosed the pancreatic neuroendocrine tumor. Pathologic Findings: Gross: Carcinoid tumor metastatic to the ovary is usually bilateral, in contrast with primary ovarian carcinoid tumor, which is almost always unilateral. These tumors are typically of relatively modest size, ranging from microscopic foci up to 9.5 cm, and have a smooth or bosselated external surface. The cut surface is typically solid, but may be solid and cystic or predominantly cystic, with cysts containing clear, watery fluid. Tumors typically show the discrete to confluent nodular architecture often seen in metastatic lesions. The tumor is

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white to yellow and may resemble an ovarian fibroma or thecoma grossly [2, 32, 71, 72]. Microscopic: Metastatic carcinoid tumor in the ovary shows microscopic features similar to primary carcinoid tumor in the ovary and other organs. Tumor cells are characteristically uniform with round to ovoid nuclei, finely granular chromatin, inconspicuous nucleoli, and moderate-to-abundant eosinophilic cytoplasm (Fig.  10.30). Mitoses are infrequent, but occasional pleomorphic cells or cells with nucleolar prominence may be seen. These classic cytologic features are the most frequently encountered, but cells may occasionally have clear or oncocytic cytoplasm, or a spindled morphology. Cells are typically disposed in one or more architectural patterns common to neuroendocrine neoplasms in general including insular, trabecular, ribbonlike, acinar, or solid tubular patterns (Fig.  10.31). When the acinar pattern is encountered, acini often contain eosinophilic secretions, which may calcify in a psammomatous or nonpsammomatous fashion [2, 32, 71, 72]. In addition to the above-noted common architectural patterns, larger cysts and follicle-like spaces are sometimes seen (Fig.  10.32) [12]. Metastatic carcinoid tumor often has a prominent paucicellular fibrous stroma, which may be extensively hyalinized (Fig. 10.33). Vascular invasion may be seen occasionally [12]. Biomarkers: –– Well-differentiated neuroendocrine tumors/carcinoid tumors from any primary site typically express selected cytokeratins and a variety of neuroendocrine markers, although the immunostaining profile varies somewhat depending on the site of origin. –– Well-differentiated neuroendocrine tumors/carcinoid tumors express LMWCKs (CAM5.2) in nearly 100% of cases, and HMWCKs (AE1/AE3) a bit less frequently.

Fig. 10.30  Metastatic well-differentiated neuroendocrine tumor of ileal origin. Tumor cells are uniform with round to ovoid nuclei, inconspicuous nucleoli, and subtly granular eosinophilic cytoplasm

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Fig. 10.31  Metastatic well-differentiated neuroendocrine tumor of ileal origin, insular architectural pattern

Fig. 10.32  Metastatic well-differentiated neuroendocrine tumor of ileal origin, insular pattern, and follicle-like space with eosinophilic intraluminal secretion

Fig. 10.33  Metastatic well-differentiated neuroendocrine tumor of ileal origin. This neuroendocrine tumor shows the insular pattern and prominent fibrous stroma often seen in these neoplasms

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–– Well-differentiated neuroendocrine tumors/carcinoid tumors of small bowel, appendiceal, colonic, and rectal origin express synaptophysin. Chromogranin expression is frequent but not as consistent, and is more often negative in tumors of rectal origin [22]. –– CDX2 expression in well-differentiated neuroendocrine tumors/carcinoid tumors likewise varies with the site of origin. Srivastava and colleagues demonstrated CDX2 positivity in nearly 100% of ileal and appendiceal carcinoid tumors, but none in gastroduodenal and rectal primaries [80]. –– Pancreatic neuroendocrine tumors: Express CAM5.2  in greater than 90% of cases and CKAE1/AE3 in approximately 50% of cases. –– Pancreatic neuroendocrine tumors almost always express at least one marker of neuroendocrine differentiation; NSE and synaptophysin are expressed in greater than 90% of these neoplasms, while chromogranin A, which is more specific, is detected in 85–90%. –– Pancreatic endocrine tumors are often multihormonal, and multiple specific neuroendocrine markers (insulin, glucagon, ACTH, gastrin, VIP, etc.) may be expressed [59]. Differential Diagnosis: ccs that may have an insular, tubular/acinar, or tubular and cystic architectural pattern reminiscent of carcinoid tumor, including granulosa cell tumor of adult type, Sertoli or Sertoli-­Leydig cell tumor, Brenner tumor, and adenocarcinoma of various types, most notably endometrioid and breast carcinoma. Careful consideration of gross and microscopic features, and immunohistochemical staining when the diagnosis is uncertain, should resolve the differential diagnosis in most cases. Gross and microscopic features helpful in the differential diagnosis are as follows: Primary ovarian carcinoid tumor: Primary ovarian carcinoid tumor is almost always unilateral, does not typically show extraovarian spread, and is not typically multinodular or associated with lymphovascular space invasion like metastatic carcinoid tumors. Primary ovarian carcinoid tumor is often associated with a teratoma, mucinous tumor, or struma ovarii; thus, the presence of any of these features strongly suggests a primary ovarian carcinoid tumor and essentially excludes metastatic carcinoid tumor, except for the rare possibility of a collision tumor. When bilateral ovarian carcinoid tumors or extraovarian spread of tumor is found, an extraovarian primary tumor is likely [2]. It has been noted that cystic or follicle-like spaces are more commonly encountered in metastatic than in primary ovarian carcinoid tumors (Fig. 10.32). Immunohistochemical staining for CDX2 does not distinguish between tumors of intestinal origin and primary ovarian carcinoid, as primary ovarian carcinoid tumors may express CDX2 [81], and carcinoid tumors of intestinal origin may fail to express CDX2. Of note, a carcinoid tumor in the small intestine may be small and difficult to locate clinically [2].

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Granulosa cell tumor: The Call-Exner bodies of granulosa cell tumor may resemble the acinar structures of carcinoid tumor, although the cytologic features of these tumors are distinct. Granulosa cell tumor has round, ovoid, or angulated, grooved nuclei and scant indistinct cytoplasm. The cells are rather haphazardly oriented relative to each other and to the lumen of the Call-Exner body. In contrast, carcinoid tumors typically have round to ovoid nuclei with finely granular chromatin, no nuclear grooving, more distinct and abundant cytoplasm, and a more orderly polarity around the acinar spaces. Granulosa cell tumors of adult type typically express inhibin, calretinin, CD99, and WT-1, but are negative for neuroendocrine markers [23]. Sertoli/Sertoli-Leydig cell tumor: The hollow and solid tubules of Sertoli/Sertoli-Leydig cell tumor may mimic the acinar and ribbonlike structures of carcinoid tumor, although carcinoid tumor usually has longer, thicker ribbons with a more orderly architecture. Of note, Sertoli/Sertoli-Leydig cell tumor may have a component of carcinoid tumor, typically minor in extent and associated with heterologous elements. Sertoli/Sertoli-Leydig cell tumors stain for inhibin, MART-1, and calretinin, which are typically negative in carcinoid tumors [2, 23, 32]. Brenner tumor: Brenner tumor, with its fibromatous stroma and nests of bland epithelium, may mimic primary or metastatic insular carcinoid tumor. In Brenner tumor, epithelial nests are of transitional type with ovoid, grooved nuclei. Immunohistochemical stains for neuroendocrine markers are negative. Endometrioid adenocarcinoma: These tumors may also have small tubules that resemble the acinar structures of carcinoid tumor. Consideration of nuclear and architectural features and immunohistochemical staining should resolve the differential diagnosis. Squamous elements or morular metaplasia excludes carcinoid tumor. Endometrioid adenocarcinoma is typically positive for PAX-8, ER, and PR, which are typically negative in carcinoid tumor. Endometrioid adenocarcinoma and other carcinomas may contain neuroendocrine cells that stain focally for neuroendocrine markers, though staining is less diffuse than in carcinoid tumor. Of note, both endometrioid adenocarcinoma and ovarian carcinoid tumor may express CDX2 [23, 81]. Management and Outcomes: Among the 17 patients with carcinoid tumor metastatic to the ovary in the 2007 series by Strosberg and colleagues [72], two deaths occurred in the follow-up interval (range of follow-up 8–146 months), yielding a projected 5-year survival rate of 94%. All patients underwent surgical resection of the ovarian masses, and most underwent surgical resection of the primary tumor, with or without more extensive debulking. Fifteen patients received long-term depot-octreotide therapy, and two received streptozocin-based chemotherapy. It is postulated that cytoreductive surgery and treatment with octreotide substantially

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improved the course of disease in these patients. Surgical resection is recommended when possible. Nonsurgical treatment options for patients with well-­differentiated gastroentero-pancreatic neuroendocrine tumors include somatostatin analogues, multi-kinase inhibitors, targeted therapy, chemotherapy, and radiolabeled somatostatin analogues [82].

10.9 Metastatic Cervical Carcinoma Definition: Tumor metastatic to the ovary from the uterine cervix. Ovarian metastases from cervical carcinomas of various histologic types, including adenocarcinoma, squamous carcinoma, high-grade neuroendocrine carcinoma/small-cell carcinoma, mixed high-grade neuroendocrine carcinoma/ small-cell carcinoma and adenocarcinoma, adenosquamous carcinoma, glassy cell carcinoma, transitional cell carcinoma, and undifferentiated carcinoma, have been reported [83, 84]. Of these, cervical adenocarcinoma is the most frequent histologic type to develop ovarian metastasis [2, 32, 85]. Clinical Features: Ovarian spread of cervical carcinomas of all types has been considered infrequent. A 2006 study of 3471 patients with stage Ib to IIb cervical cancer who underwent radical hysterectomy and bilateral salpingo-­ oophorectomy demonstrated ovarian metastasis in 5.31% of those with endocervical adenocarcinoma and only 0.79% of those with cervical squamous cell carcinoma [85]. Patients have ranged in age from approximately 29 to 73 years, with a mean age of 49.9 years in one large study [85, 86]. Ovarian metastasis may present synchronously or metachronously in reference to the cervical primary tumor. In some cases, ovarian metastasis becomes apparent several years after diagnosis of the primary tumor, while in other cases the ovarian metastasis is the presenting sign of a clinically unsuspected cervical tumor [13, 83, 87]. Cervical tumors giving rise to ovarian metastasis are clearly invasive in most cases, and some are of advanced stage, with extrauterine involvement or a bulky primary tumor [83, 86]. In a substantial minority of cases, however, the cervical tumor is not clinically evident prior to discovery of the ovarian metastasis, and may demonstrate only small foci of superficial invasion or no unequivocal stromal invasion. Extension of cervical tumor into the lower uterine segment or uterine corpus has been identified as a possible risk factor for ovarian metastasis, postulated mechanisms including transtubal spread of tumor [13, 86]. Pathologic Findings: Gross: Metastatic endocervical adenocarcinoma: For endocervical adenocarcinoma metastatic to the ovary, metastasis may be bilateral or unilateral. Some tumors are unilateral and large (reported tumors have ranged up to 30 cm), mimicking a primary ovarian mucinous neoplasm. Tumors have a

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Fig. 10.34  Large ovarian metastasis from an endocervical adenocarcinoma, with a smooth bosselated external surface

smooth or nodular external surface (Fig. 10.34). The cut surface may be predominantly solid or multicystic, sometimes with solid or papillary areas [13, 86]. Metastatic cervical squamous carcinoma: Squamous cell carcinoma metastatic to the ovary may be unilateral or bilateral. Reported tumors have ranged up to 17 cm. Tumors show a smooth or nodular external surface, and a solid, solid and cystic, or predominantly cystic cut surface [83, 86, 87]. Microscopic: Metastatic endocervical adenocarcinoma: Among the various subtypes of endocervical adenocarcinoma, the usual (HPV related) type is the most common to exhibit ovarian metastasis. In the ovary, these tumors show microscopic features similar to their primary endocervical counterparts. The majority of these tumors have a pseudoendometrioid appearance with hybrid endometrioid and mucinous features, characterized by an endometrioid appearance at low magnification but with varying amounts of apical mucin evident at higher magnification. Nuclei are typically hyperchromatic and elongated, with numerous apical mitoses and frequent apoptosis (Figs.  10.35 and 10.36). In the ovary, the growth pattern(s) may be borderline-like, confluent glandular, cribriform, papillary, or villoglandular, and may not be readily recognized as invasive, thus simulating a primary ovarian mucinous borderline tumor or well-differentiated primary ovarian mucinous carcinoma with a confluent invasive pattern [13]. Of note, a “carpeting” pattern of tumor spread, in which endocervical adenocarcinoma spreads superficially in the endometrium without obvious myometrial invasion or lymphovascular invasion, may be seen in endocervical adenocarcinomas with adnexal involvement [86]. Endocervical adenocarcinoma of the rarer gastric type (HPV unassociated) has also been reported to metastasize to the ovary, although less commonly. These tumors typically

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Fig. 10.35  Metastatic endocervical adenocarcinoma of usual type. The tumor has the hybrid endometrioid-mucinous features typical of endocervical adenocarcinomas of usual type. The cells are columnar with varied glandular, papillary, and cribriform architecture

Fig. 10.36  Metastatic endocervical adenocarcinoma of usual type. Tumor cells are columnar and stratified with apoptosis and apical mitosis. Apical mucin varies in these tumors and is scant in this case, simulating the appearance of an endometrioid adenocarcinoma primary or metastatic to the ovary

have distinctive clear and/or pale eosinophilic, abundant cytoplasm with distinct cell borders. They may show single-­ cell infiltration and foci of signet ring and intestinal type differentiation with goblet cells or Paneth-like neuroendocrine cells [88]. Metastatic cervical squamous cell carcinoma: With involvement by cervical squamous cell carcinoma, the ovaries show nodules of metastatic tumor replacing normal ovarian parenchyma (Figs 10.37 and 10.38) [86]. Microscopic features are typical, except that some tumors show striking cyst formation within the squamous nests [83, 87]. Similar to the “carpeting” pattern of tumor spread noted in some cases

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of endocervical adenocarcinoma, cervical squamous cell carcinoma in situ has been documented to extend to involve the endometrium, fallopian tubes, ovarian surface, and ovarian epithelial inclusion glands, with secondary ovarian stromal involvement [14]. Biomarkers:

Fig 10.37  Cervical primary squamous cell carcinoma with early stromal invasion (stage T1a2), generating ovarian metastasis

Fig 10.38  Squamous cell carcinoma metastatic to the ovary. The tumor shows cytomorphologic features that are the usual for squamous cell carcinoma. Tumor is disposed in variably sized nests

Fig 10.39 Metastatic endocervical adenocarcinoma of usual type. This HPV-­ related neoplasm shows strong, diffuse positivity for p16 (left) and HR-HPV infection by in situ hybridization (right)

–– Endocervical adenocarcinoma of usual (HPV-associated) type shows HR-HPV infection by in situ hybridization and PCR, and expresses p16 in a diffuse, strong nuclear and cytoplasmic pattern (Fig.  10.39). Importantly, p16 can serve as a useful surrogate marker for HPV infection when direct HPV detection methods are unavailable; however, direct detection of HPV is more specific than is immunostaining for p16 due to the occasional strong, diffuse p16 positivity seen in some HPV-unrelated adenocarcinomas that may present a differential diagnosis. Endocervical adenocarcinoma of usual type generally does not express vimentin, ER, or PR, or does so only focally. –– Endocervical adenocarcinoma of gastric type is usually HPV unassociated and thus does not demonstrate HR-­ HPV infection by PCR or in situ hybridization, and is negative or shows focal to patchy positivity for p16. p53 is often expressed in endocervical adenocarcinoma of gastric type, as p53 mutations are often found in these tumors [23]. –– Squamous carcinomas are almost always associated with HPV infection and thus show HR-HPV infection by in situ hybridization and PCR, and express p16 in a diffuse, strong nuclear and cytoplasmic pattern like HPV-related endocervical adenocarcinomas. Differential Diagnosis: Although exceptions arise, gross and microscopic features common to ovarian metastasis are often seen in cases of cervical carcinoma metastatic to the ovary and provide a clue to the diagnosis. Bilateral tumor, a multinodular architecture, surface nodularity, foci of destruc-

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tive stromal invasion, microscopic features uncommon for a primary ovarian neoplasm, prominent lymphovascular invasion, and a known cervical primary tumor all suggest metastasis. Strong, diffuse staining with p16 is likewise strongly suggestive of a metastatic HPV-related tumor. Identification of HPV infection by in situ hybridization or molecular methods confirms the diagnosis. Other points helpful in the differential diagnosis are as follows: Metastatic endocervical adenocarcinoma: The differential diagnosis of metastatic endocervical adenocarcinoma includes ovarian mucinous borderline tumor, primary ovarian mucinous adenocarcinoma with a confluent invasive pattern, and other primary and metastatic carcinomas of mucinous and endometrioid/pseudoendometrioid types (most notably primary and metastatic endometrioid adenocarcinoma, and adenocarcinomas of intestinal, appendiceal, gastric, and pancreatic origin). The most challenging differential is with primary ovarian mucinous neoplasia, which metastatic endocervical adenocarcinoma may mimic grossly and microscopically; thus, an appropriate index of suspicion for possible metastasis is warranted. Clinical correlation and immunohistochemical staining should be employed when the diagnosis is uncertain. Clues to an ovarian primary endometrioid adenocarcinoma include squamous morules, endometriosis, or an endometrioid adenofibroma. Primary and metastatic endometrioid adenocarcinomas typically express vimentin, ER, and PR; show only patchy positivity for p16; and are negative for CEA; in contrast, endocervical adenocarcinomas are typically CEA positive, p16 block positive (when HPV related), vimentin negative, and negative to focally positive for ER and PR. Please see Table 10.1 for typical immunohistochemical staining features of other tumors with mucinous and endometrioid/endometrioid-like morphology. Metastatic cervical squamous cell carcinoma: A squamous tumor in the ovary may be metastatic or rather a primary ovarian tumor associated with a teratoma, endometriotic cyst, or massive squamous overgrowth in an endometrioid adenocarcinoma [32]. Adequate gross evaluation and sampling are essential to evaluate for associated features. Primary ovarian squamous carcinoma is rare and, before an ovarian primary squamous carcinoma is diagnosed, the possibility of metastasis from an occult squamous carcinoma in the cervix or elsewhere should be entertained [32]. Ovarian transitional cell carcinoma should also be excluded prior to making the diagnosis of metastatic squamous cell carcinoma, although this tumor is rare. Management and Outcomes: A 2006 study including 52 patients with stage Ib to IIb cervical cancer and ovarian metastasis who underwent radical hysterectomy, pelvic lymphadenectomy, and bilateral salpingo-oophorectomy demonstrated a poor outcome for these patients, unrelated to FIGO stage or histologic type. Five-year survival rates for patients with ovarian metastasis were 46.6% for stage Ib,

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37.5% for stage IIa, and 18.0% for stage IIb, despite administration of adjuvant therapy (radiotherapy and/or chemotherapy) to 92.3% of patients [85].

10.10 Metastatic Endometrial Carcinoma Definition: Metastasis to the ovary originating from an endometrial adenocarcinoma. The most common histologic type of endometrial adenocarcinoma to secondarily involve the ovary is endometrioid adenocarcinoma. Metastases of endometrial serous carcinoma, uterine carcinosarcoma, and other types of endometrial adenocarcinoma are less common. Clinical Features: Synchronous endometrial and ovarian carcinoma is found in approximately 10–15% of patients with ovarian cancer and 5% of patients with endometrial cancer [89–91]. When encountered, this finding raises the important question of whether the two lesions represent independent primary tumors or whether one lesion is a metastasis from the other. When histology is dissimilar the distinction is relatively easy, but when similar the distinction may be challenging. Making this distinction is essential for prognostication and treatment planning. Patients with synchronous primary endometrial and ovarian carcinomas tend to be younger, present with early-stage disease, and have a more favorable overall prognosis than do patients who present with only an endometrial or ovarian carcinoma at the same clinical stage [89, 91–94]. Likewise, patients with synchronous, independent primary cancers have a better prognosis than do patients with endometrial cancer with ovarian metastasis [95]. Pathologic Findings: Gross: Endometrial tumors secondarily involving the ovary are usually smaller than 5  cm and bilateral. These tumors may be solid or solid and cystic on the cut surface. General gross features favoring metastatic tumor include bilaterality, a multinodular growth pattern, and tumor on the ovarian surface (with the caveat that tumor may develop in the ovary in the context of surface endometriosis; thus, a careful search for endometriosis can be helpful). Microscopic: Endometrial tumors secondarily involving the ovary have microscopic features similar to their endometrial counterparts (Figs. 10.40, 10.41, and 10.42). Microscopic features favoring metastasis include a multinodular growth pattern, involvement of the ovarian surface (again with the caveat that tumor may develop in the ovary in the context of surface endometriosis), and hilar or extraovarian lymphovascular space invasion. An unusual finding occurring occasionally in the setting of an endometrial endometrioid adenocarcinoma with squamous differentiation is that of keratin deposits or degenerated mature squamous cells with an associated foreign-body giant cell reaction on the surface

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Fig. 10.40  Metastatic endometrioid adenocarcinoma of uterine corpus origin. These tumors show morphology similar to their uterine counterparts. Papillary, glandular, and cystic patterns may be seen

Fig. 10.41  Metastatic endometrioid adenocarcinoma of uterine corpus origin. Tumor typically has less cytologic atypia and mitotic activity than the usual metastatic tumor of gastrointestinal origin, which often displays a pseudoendometrioid morphology

of one or both ovaries [96]. If no viable tumor is present, this finding does not appear to worsen the patient’s prognosis, even if keratin granulomas are identified elsewhere in the peritoneum. Biomarkers: Endometrioid adenocarcinoma is the most common histologic type of endometrial tumor to metastasize to the ovary, with endometrial serous carcinoma being less common and other tumor types rare. Typical immunohistochemical staining features of endometrioid adenocarcinoma and endometrial serous carcinoma are as follows: –– Endometrioid adenocarcinomas typically express CK7, CA125, ER, PR, and vimentin, and are usually negative for CK20. Staining for p53 is usually wild type (patchy

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Fig. 10.42  Metastatic endometrioid adenocarcinoma of uterine corpus origin. Squamous differentiation may be seen in endometrioid adenocarcinomas primary to the ovary or metastatic from the uterine corpus. Squamous differentiation is not seen in adenocarcinomas of intestinal, gastric, or appendiceal origin

and weak to moderate in intensity); however, a mutation pattern of p53 expression (that is, either intense expression of p53 in greater than 75% of tumor cell nuclei or nearcomplete negativity for p53 consistent with the null phenotype) may be noted in a minority of FIGO grade 2 and 3 endometrioid adenocarcinomas. Expression of p16 is typically patchy, although occasional high-grade endometrioid adenocarcinomas express p16  in a strong, diffuse pattern. Nuclear B-catenin expression, loss of PTEN, and loss of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) may be seen. Unexpected expression of mammaglobin, CDX2, TTF-1, and GATA3 may also be encountered. Of note, immunohistochemical staining is not helpful in the distinction between endometrial and ovarian primary endometrioid adenocarcinoma [23]. –– Endometrial serous carcinomas express CK7, CA125, and sometimes vimentin, while they are usually negative for CK20. In contrast to endometrioid adenocarcinomas, endometrial serous carcinomas express p16  in a strong, diffuse fashion and show a mutation pattern of p53 staining (approximately 90% of endometrial serous carcinomas express p53  in a strong, diffuse fashion, while approximately 10% show near-complete negativity for p53 consistent with the “null” phenotype). Most have low levels of ER expression and low-to-absent PR expression. In contrast to serous carcinomas of ovarian, tubal, or peritoneal origin, which express WT-1 in about 90% of cases, endometrial serous carcinomas express WT-1  in only 20–30% of cases [23]. Differential Diagnosis: Differential diagnosis for metastatic endometrioid adenocarcinoma includes primary

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o­varian endometrioid adenocarcinoma, and other primary and metastatic tumors with an endometrioid-like architectural pattern. Differential diagnosis includes some highgrade serous and clear-cell carcinomas, Sertoli/Sertoli-Leydig cell tumor, endometrioid yolk sac tumor, and metastatic tumors of endocervical, gastrointestinal, and appendiceal origin [12]. Helpful features that can be used to resolve the differential diagnosis are as follows: Metastatic endometrioid adenocarcinoma versus primary ovarian endometrioid adenocarcinoma: Literature over the last 20 years or so has focused on the view that synchronous tumors of the endometrium and ovary more often represent independent primary tumors. The idea of synchronous endometrial and ovarian carcinomas representing two separate primary tumors in the majority of cases has been supported by the fact that most synchronous tumors have a favorable overall prognosis, which would be unexpected if either tumor were metastatic. Most tumors with synchronous involvement of the endometrium and ovary are of endometrioid type. When tumors are of the serous type or any other histologic type, there is a greater statistical likelihood that the ovarian tumor is metastatic [32]. Over the years, various studies have delineated histologic and genetic criteria to aid in the determination of whether synchronous endometrial and ovarian tumors with similar histology represent independent primary tumors or metastatic disease [97]. Historic criteria favoring synchronous independent endometrioid primary tumors are presented in Table  10.2, while features favoring metastasis to the ovary are listed in Table  10.3 [97]. Beyond the features listed in Table 10.3, another feature suggesting ovarian metastasis is the presence of tumor within the fallopian tube lumen. This feature, and some of those listed in Tables 10.2 and 10.3, can Table 10.2  Endometrioid tumors of ovary and endometrium, features favoring independent primary tumors 1. Histologic dissimilarity of the tumors 2. No or only superficial myometrial invasion of the endometrial tumor 3. No vascular space invasion of the endometrial tumor 4. Atypical endometrial hyperplasia/endometrial intraepithelial neoplasia (EIN) present 5. Absence of other evidence of spread of endometrial tumor 6. Ovarian tumor unilateral (80–90%) of cases 7. Ovarian tumor located in parenchyma 8. No vascular space invasion, surface implants,a or predominant hilar location in ovary 9. Absence of other evidence of spread of ovarian tumor 10. Ovarian endometriosis presentb 11. Dissimilar molecular genetic or karyotypic abnormalities in the tumor Infrequently, primary ovarian endometrioid adenocarcinoma may arise from endometriosis involving the ovarian surface b In addition to ovarian endometriosis, the presence of an endometrioid adenofibroma in the ovary suggests an ovarian primary tumor a

Table 10.3  Endometrioid tumors of ovary and endometrium, features favoring ovarian metastasis from endometrial primary 1. Histologic similarity of the tumors 2. Large endometrial tumor, small ovarian tumor(s) 3. Atypical endometrial hyperplasia/endometrial intraepithelial neoplasia (EIN) present 4. Deep myometrial invasion with direct extension into adnexa and/ or vascular space invasion in myometrium 5. Spread elsewhere in typical pattern of endometrial carcinoma 6. Ovarian tumors bilateral and/or multinodular 7. Hilar location, vascular space invasion, surface implants,a or combination in ovary 8. Ovarian endometriosis absentb 9. Similar molecular genetic or karyotypic abnormalities in both tumors Infrequently, primary ovarian endometrioid adenocarcinoma may arise from endometriosis involving the ovarian surface b In addition to ovarian endometriosis, the presence of an endometrioid adenofibroma in the ovary suggests an ovarian primary tumor a

also be used for tumor types other than endometrioid. In many cases there is strong evidence regarding whether an ovarian tumor represents a metastasis or an independent primary tumor, but in some cases this distinction is difficult or impossible. Recently, studies from different research groups using different molecular techniques have suggested that tumors that would be categorized as independent synchronous primary tumors by historic morphologic criteria are often clonally related and may thus represent dissemination/metastasis from one site to another [98–100]. They furthermore suggest that the relatively good prognosis of most of these patients might be explained by isolated ovarian spread of an indolent endometrial tumor, possibly through the fallopian tube lumen, without invasion of vascular structures or easy access to the peritoneal cavity [100]. This evolving concept has not gained widespread acceptance at this time, and further work is required. An alternate explanation that has been proffered for the similar molecular alterations identified in some synchronous endometrial and ovarian endometrioid adenocarcinomas is that a common carcinogenic agent acting on endometrium and ectopic endometrial tissue within the ovary could induce similar genetic events in the two locations, simulating metastasis from one site to another. It is furthermore noted that a metastatic lesion may exhibit a different molecular profile from the primary tumor due to tumor heterogeneity and progression. Currently, ovarian endometrioid adenocarcinomas are evaluated for their likely primary or secondary nature according to the morphologic criteria presented in Tables 10.2 and 10.3. Endometrioid adenocarcinoma versus serous carcinoma: Lower nuclear grade, a more orderly glandular and villous pattern with smooth luminal borders, squamous differentiation, and a lack of associated serous tubal intraepithe­ lial carcinoma (STIC) favor endometrioid adenocarcinoma.

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Immunohistochemical staining may be helpful in cases with ambiguous morphologic features. Serous carcinomas show a mutation pattern of p53 staining, strong diffuse staining with p16, and diffuse staining with IMP3. Serous carcinomas of tubo-ovarian or peritoneal origin also stain for WT-1 in the majority of cases. Endometrioid adenocarcinomas, in contrast, tend to show a wild-type pattern of p53 staining, patchy positivity for p16, focal staining for IMP3, and minimal staining with WT-1. Endometrioid adenocarcinoma versus clear-cell carcinoma: Endometrioid adenocarcinoma may have areas of cytoplasmic clearing, raising the possibility of clear-cell adenocarcinoma. Features favoring a diagnosis of endometrioid adenocarcinoma with cytoplasmic clearing over clear-­ cell adenocarcinoma include a lack of the classic cytologic and architectural features diagnostic of clear-cell carcinoma (“hobnail” cells, cells with polyhedral as opposed to columnar cytology, a tubulocystic architectural pattern, or a papillary pattern with hyalinized vascular cores), and an ER+/ PR+ immunoprofile. Mullerian clear-cell carcinoma typically shows absent or markedly diminished staining with ER and PR, which can be quite helpful in this differential diagnosis. Mullerian clear-cell carcinoma also expresses racemase (p504s) and Napsin A with greater frequency than other histologic subtypes of mullerian adenocarcinoma, although the practical utility of these stains is limited by their sensitivity and specificity [101, 102]. Endometrial or ovarian endometrioid adenocarcinoma versus endocervical adenocarcinoma: Endocervical adenocarcinoma of usual type often has focal cytoplasmic mucin and a vaguely endometrioid appearance. Positivity for HPV, strong diffuse staining for p16, and focal to negative staining with ER and PR are seen in endocervical adenocarcinoma of usual type. Endometrioid adenocarcinoma versus Sertoli/Sertoli-­ Leydig cell tumor: Endometrioid adenocarcinoma may have a sertoliform architectural pattern (hollow or solid tubules, cords) in areas that mimics primary Sertoli or Sertoli-Leydig cell tumor. Features favoring endometrioid adenocarcinoma include areas with a more classic endometrioid architectural pattern, squamous differentiation (rules out a sex cord-stromal tumor), and an immunoprofile consistent with endometrioid adenocarcinoma (CK7+/EMA+/ inhibin−/calretinin−/WT1−/FOXL2−). Of note, endometrioid adenocarcinomas can occasionally show inhibin positivity. Endometrioid adenocarcinoma versus endometrioid yolk sac tumor: Yolk sac tumor may have an endometrioid architectural pattern, suggesting primary or metastatic endometrioid adenocarcinoma. Features favoring endometrioid adenocarcinoma in this differential include older patient age, squamous differentiation, lack of any of the architectural patterns more typical of yolk sac tumor, and a SALL-4−/glypi-

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can-­3−/CK7+/EMA+/ER+/PR+ immunostaining profile. Of note, most yolk sac tumors show staining for AFP, although the AFP staining may be focal and weak [23]. Endometrioid adenocarcinoma versus metastatic tumor of intestinal, appendiceal, or gastric origin: Metastatic tumors of intestinal, appendiceal, or gastric origin may have a pseudoendometrioid morphology. These tumors typically show increased nuclear atypia and mitotic activity, intraluminal “dirty” necrosis, segmental necrosis of glandular epithelium, and disposition of glandular epithelium at the periphery of necrotic areas. Squamous differentiation is virtually never seen. A CK7+/CK20−/ER+/PR+/PAX8+ immunoprofile is consistent with endometrioid adenocarcinoma, whereas a CK7 variable/CK20+/ER−/PR−/PAX8− immunoprofile is consistent with metastatic carcinoma of gastrointestinal origin. Management and Outcomes: Patients with endometrial adenocarcinoma metastatic to the ovary, as diagnosed by historic morphologic criteria, have a worse prognosis than those patients with independent, synchronous endometrial and ovarian primary tumors. In a 2016 retrospective review of 72 patients with simultaneous carcinomas of the endometrium and ovary with the same histopathologic subtype, 10-year survival rate for patients with endometrial tumor metastatic to the ovary was 36.6%, as opposed to 61.3% for patients with independent synchronous primary tumors [95].

10.11 Other Metastatic Tumors from Uterus Definition: Non-carcinomatous tumors of uterine origin secondarily involving the ovary, most commonly low-grade endometrial stromal sarcoma (ESS), and less commonly leiomyosarcoma (LMS). Rare cases of mullerian adenosarcoma [103], uterine choriocarcinoma [104], and placental site trophoblastic tumor [105] metastatic to the ovary have also been reported. Discussion will focus on ESS and LMS, as these are the most common. Clinical Features: Of the non-carcinomatous uterine tumors that have been documented to metastasize to the ovary, ESS metastasizes to the ovary more frequently than any other and can present diagnostic challenge [32]. Patients are usually perimenopausal or postmenopausal, but occasional patients are younger. In a series of 21 uterine and extragenital sarcomas metastatic to the ovary reported by Young and Scully in 1990, eight ESS patients ranged in age from 33 to 79 years, with an average age of 50 [106]. Some patients with ESS metastatic to the ovary have a documented history of ESS, greatly facilitating diagnosis, while in some cases there is no or incorrect reporting of the uterine primary tumor (i.e., history of a “fibroid”) [32, 106, 107]. Ovarian metastasis accounts for the clinical presentation in occasional patients, and symptoms are those attributable to an

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ovarian mass. In other patients, the ovarian metastasis is diagnosed synchronously with the uterine primary tumor, or years after diagnosis of the uterine primary [32, 106]. In one reported case, ovarian and extraovarian metastases were reported 17  years after diagnosis of a uterine low-grade endometrial stromal sarcoma [108]. LMS metastasizes to the ovary less frequently than does ESS but is probably more common than the rare reports in the literature suggest, particularly in patients with widespread disease [2, 109]. In the aforementioned 1990 study by Young and Scully, three LMS metastatic to the ovary occurred in patients 35, 44, and 49 years of age. In the first patient, a large ovarian metastasis became symptomatic 14  months after hysterectomy. In the second patient, the ovarian metastasis occurred in the setting of widespread disease, while in the third, ovarian involvement was microscopic [106]. Pathologic Findings: Gross: Low-grade ESS: Low-grade ESS metastatic to the ovary is more often bilateral, and may vary in size from microscopic to greater than 15  cm. Tumors are predominantly solid or solid and cystic, rarely multicystic, and may have discernible nodularity. The cut surface is white to gray white, with or without foci of yellow coloration, hemorrhage, and necrosis [106]. A wormlike pattern of vascular plugging may rarely be seen on the cut surface [32]. Uterine LMS: Uterine LMS metastatic to the ovary may be bilateral or unilateral and ranges in size from microscopic up to 15 cm. Available gross descriptions detail cut surfaces with multiple firm tumor nodules or the lobulated, white-tan, fleshy appearance typical of LMS [106]. Microscopic: Low-grade ESS: Low-grade ESS metastatic to the ovary can show all the varied morphologic patterns that may be seen in primary ESS, such as fibrous or myxoid change, smooth muscle differentiation, endometrioid gland formation, and epithelioid cells [32, 108]. The diagnostic difficulty presented in some cases is due to a lack of the classic architectural patterns of ESS. Metastatic tumor typically shows the small round to ovoid nuclei characteristic of ESS, although the “tonguelike” pattern of uterine invasion, and the characteristic vascular pattern of prominent interspersed small arterioles, may be focal or absent. A diffuse pattern is the most common architectural pattern [32]. Tumor may also have a nested, nodular, clustered, corded, tubular, or singlecell pattern. Diagnostic challenge may arise secondary to finding fibrous bands or large pauci- to acellular fibromatous areas suggestive of fibroma, or hyaline plaques suggesting a diagnosis of thecoma [32, 106]. Uterine LMS: Uterine leiomyosarcoma metastatic to the ovary is most often seen in the setting of more widespread disease and typically does not present a significant diagnos-

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tic challenge [12]. The few reported cases of uterine leiomyosarcoma metastatic to the ovary with microscopic description available have had the spindled myoid cells with variable nuclear atypia and increased mitotic activity characteristic of LMS.  One tumor showed prominent myxoid change [106]. Biomarkers: –– ESS typically expresses CD10, ER, PR, and WT-1, with varied extent and intensity. Many also express SMA, cytokeratin, or AR in a patchy fashion. Expression of desmin and CD34 is rare. Of note, this immunohistochemical staining profile is characteristic of the portion of tumor resembling proliferative-type endometrium; any metaplastic elements, such as endometrioid glands, sex cord elements, or smooth muscle, tend to acquire the immunophenotype of the corresponding metaplastic element [23]. –– Leiomyosarcomas typically express the smooth muscle markers SMA, desmin, and h-caldesmon, although desmin may be negative. Leiomyosarcomas may also express CD10, ER, and PR. Cytokeratin is frequently expressed in a patchy fashion. Differential Diagnosis: The differential diagnosis of ESS metastatic to the ovary includes primary ovarian ESS and primary ovarian sex cord-stromal tumors with similar histology such as fibroma, thecoma, granulosa cell tumor, and Sertoli/Sertoli-Leydig cell tumor. Features helpful in the differential diagnosis are as follows: Metastatic ESS versus primary ovarian ESS: Primary ovarian ESS is rare but does occur [107, 110]. Given the rarity of primary ovarian ESS, when ESS is encountered in the ovary, metastasis must be considered. A clinical history of a primary uterine ESS is of course strongly suggestive of metastatic tumor. Bilaterality of tumor favors metastasis, although bilateral ovarian primary ESS has also been documented [110]. Associated ovarian endometriosis favors an ovarian primary neoplasm [32, 106, 107]. Metastatic ESS versus sex cord-stromal tumors: As the distinctive vascular pattern and “tonguelike” or “wormlike” infiltration pattern typical of primary uterine ESS may be seen only focally in an ovarian metastasis, and as metastatic ESS may show morphologic features overlapping with some primary ovarian sex cord-stromal tumors, a primary ovarian sex cord-stromal tumor may present a plausible differential diagnosis. A diffuse growth pattern in the metastatic ESS may suggest a granulosa cell tumor. The presence of paucicellular or acellular fibromatous areas may resemble fibroma. Areas with hyaline plaques may raise a differential diagnosis with thecoma. Areas of a cord-like or sex cord-like growth may suggest a granulosa cell tumor or a Sertoli/Sertoli-­ Leydig cell tumor. Careful microscopic examination should demonstrate absence of the nuclear features characteristic of

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granulosa cell tumor. The pattern of small arterioles characteristic of ESS is often seen at least focally in the ovary and is a significant clue to the diagnosis. Additionally, the “tonguelike,” often intravascular pattern of tumor infiltration typical of ESS is not usually seen in the ovary, but is often seen in extraovarian foci of tumor, facilitating diagnosis. Bilaterality and extraovarian spread of tumor are typical of metastatic ESS but rare with the sex cord-stromal tumors in the differential [32, 106]. More thorough sampling to uncover areas of more revealing histology, and a directed battery of immunohistochemical stains, may be performed in cases in which there is diagnostic uncertainty. LMS and other non-carcinomatous uterine tumors: Outside of ESS, other non-carcinomatous uterine tumors metastatic to the ovary are relatively rare. Uterine LMS metastatic to the ovary tends to occur in the setting of more widespread disease, and does not typically present much diagnostic difficulty when encountered. As with primary ovarian ESS, LMS occurring primarily in the ovary or periovarian tissue is rare; thus, LMS encountered in the ovary is more likely representative of metastasis. Ovarian metastasis of uterine choriocarcinoma is rare and must be distinguished from primary ovarian choriocarcinoma of gestational or germ cell origin [12, 104, 111]. If choriocarcinoma is identified in the ovary and is not clearly metastatic from a uterine or tubal gestational choriocarcinoma, the ovarian tumor must be adequately sampled to rule out teratomatous or other germ cell elements. If no teratoma or other germ cell elements are found, it may be impossible to differentiate between a primary ovarian choriocarcinoma of either gestational or germ cell origin and metastasis from a uterine choriocarcinoma that has regressed [2]. Ovarian metastasis of uterine adenosarcoma has also been documented [103]. Of note, ovarian/adnexal adenosarcoma may represent a primary tumor, particularly if it is associated with endometriosis. Management and Outcomes: Adnexal spread of low-­ grade ESS occurs in approximately 15% of cases [12]. The tumor may behave indolently and patients may have prolonged survival, with recurrence developing more than a decade after initial diagnosis [112]. Stage is the most important prognostic factor for this tumor. At this time, the optimal treatment of recurrent or metastatic low-grade endometrial stromal sarcoma remains to be determined. Surgical resection is the primary treatment and is recommended when possible. The tumors are relatively chemo- and radioresistant. Hormonal treatment with progestin therapy or aromatase inhibitors may be effective in achieving disease control in some cases due to the frequent presence of ER and PR, although further study is required [112, 113]. Targeted therapies are also under investigation [114]. Uterine LMS is an aggressive neoplasm with a poor outcome regardless of clinical stage. Surgical resection is the cornerstone of treatment for early-stage tumor. Advanced-­ stage, recurrent, or metastatic LMS is treated with cytotoxic chemotherapy, although currently available regimens are of

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limited benefit. There is some evidence that secondary cytoreductive surgery may improve outcome. Targeted therapies are under investigation [115]. 

10.12 Metastatic Tumors from the Tubal Fimbriated End Definition: Tumors originating in the fallopian tube fimbria with secondary involvement of the ovary. Historically, carcinomas with predominant ovarian involvement were thought to be derived from the ovarian surface epithelium. Mounting evidence from a number of related studies [116–119], however, suggests that a majority of high-grade serous ovarian carcinomas actually arise in the fimbriae rather than the ovarian surface epithelium. Studies have demonstrated that the long-sought-for precursor of ovarian high-grade serous carcinoma appears to develop from an occult intraepithelial carcinoma in the fimbria designated “serous tubal intraepithelial carcinoma” (STIC), which may involve the ipsilateral and contralateral ovarian surfaces and/or peritoneal surfaces secondarily. Another possible mechanism of spread is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs, causing the development of cortical inclusion cysts, which may develop neoplastic changes over time [120]. Invasive tumor involving the distal fallopian tube may also extend directly into the ovarian parenchyma, sometimes aided by the presence of tubo-ovarian adhesions [2]. Clinical Features: The clinical presentation of ovarian carcinoma developing secondarily from the tubal fimbriae is similar to that of tumors which would historically have been classified as primary ovarian neoplasia. Patients with symptomatic tumors are typically postmenopausal, with a mean age ranging from 56 to 63 years [121–123]. In symptomatic patients, the most common symptoms include an abdominal/ pelvic mass, and abdominal pain and distention due to bulky tumor or ascites. Abnormal uterine bleeding/discharge is also a relatively common symptom [124]. Some patients will have tumor identified in an endometrial biopsy/curettage, endocervical curettage, or Pap smear. The majority of patients are white, non-Hispanic [121]. Patients with BRCA1 or BRCA2 germline mutations are at increased risk for the development of serous tubal intraepithelial carcinoma (STIC), with or without tubal invasion and ovarian spread. Among symptomatic patients with fallopian tube carcinoma, women with BRCA-associated tumors present at a slightly younger age than those with sporadic tumors, although available literature suggests that both patient groups have similar clinicopathologic features [125, 126]. Pathologic Findings: The majority of malignant neoplasms developing in the fallopian tube fimbriae are high-­ grade serous carcinomas (Figs.  10.43, 10.44, 10.45, 10.46, and 10.47), and a smaller percentage are endometrioid

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Fig. 10.43  Serous carcinoma, high grade, of tubal fimbrial origin involving both ovaries

c­ arcinomas. Other types of carcinoma developing in the fallopian tube fimbriae are rare; few examples of undifferentiated carcinoma and mucinous carcinoma have been documented [122, 127]. Secondary ovarian involvement from a fallopian tube primary carcinoma may vary from minimal, with only involvement of the ovarian surface epithelium, to massive, such that determination of primary site is difficult or impossible. Biomarkers: Immunohistochemistry may be employed as an adjunctive aid in the determination of tumor type (serous, endometrioid, mucinous, clear cell, etc.). Biomarkers are not useful, however, in distinguishing between an ovarian primary neoplasm and a tumor of tubal origin secondarily involving the ovary. Differential Diagnosis: The most common differential diagnosis for ovarian involvement by a tubal primary is an ovarian primary tumor with secondary tubal involvement. As

Fig. 10.44  Serous tubal intraepithelial carcinoma (STIC) involving tubal fimbria. Note malignant epithelium of serous type with a high nuclear grade and nuclear disarray, contrasting with that of normal ciliated benign tubal type epithelium (left). Serous tubal intraepithelial

carcinoma (STIC) shows a mutation pattern of staining with p53 (strong, diffuse staining in this case) (right). Caution is warranted in the interpretation of tubal intraepithelial carcinoma, as adenocarcinoma metastatic to the fallopian tube may closely mimic STIC

Fig. 10.45  Serous tubal intraepithelial carcinoma involving tubal fimbria, with underlying mucosal invasion (left). Both the STIC and the invasive carcinoma show a mutation pattern of p53 staining, as is typical of high-grade serous carcinoma. In this case the mutation is evi-

denced by strong, diffuse nuclear staining in >75% of the tumor cells. In approximately 10% of cases, a p53 mutation is indicated by virtually no p53 staining (“null pattern”)

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Fig. 10.46  Serous carcinoma, high grade, of tubal fimbrial origin secondarily involving the ovary. High-grade serous carcinoma may have a glandular, papillary, or solid architectural pattern. Psammoma bodies are a frequent finding but are not pathognomonic for serous carcinoma

Fig. 10.47  Serous carcinoma, high grade. High-grade serous carcinoma is characterized by a high nuclear grade and frequent mitotic activity. In contrast to endometrioid adenocarcinoma, serous carcinoma more often has crack-like, rather than smooth, glandular luminal borders, and more prominent nuclear disarray

noted previously, the vast majority of fallopian tube primary carcinomas are of high-grade serous type, with a smaller percentage of endometrioid adenocarcinomas. Given the great rarity of primary fallopian tube clear-cell and mucinous carcinomas, tubo-ovarian involvement by a tumor of either of these two types would usually be considered primary to the ovary [2]. If there is both tubal and ovarian involvement by serous, endometrioid, or undifferentiated carcinoma, a tubal primary is of greater likelihood and should be considered. Current (2018) College of American Pathologists ­guidelines for assignment of primary site in tubo-ovarian

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high-­grade serous carcinoma advocate that if serous tubal intraepithelial carcinoma (STIC) or mucosal invasive carcinoma is identified in the fallopian tube, the fallopian tube should be designated the primary tumor site, regardless of the presence or size of ovarian or peritoneal disease; likewise, if the fallopian tube is partially or completely incorporated into a tubo-ovarian mass, the fallopian tube should be designated the primary site, regardless of the presence or size of ovarian or peritoneal disease [128]. For patients with high-grade serous carcinoma, it is recommended that the tubal fimbriae be carefully examined and entirely submitted. It should be noted that metastasis to the fallopian tube may colonize the epithelium and closely mimic serous tubal intraepithelial carcinoma (STIC); thus, circumspection is warranted in the interpretation of tubal intraepithelial carcinoma. Of note, although designation of the primary site for a carcinoma involving both the fallopian tube and ovary has implications for cancer epidemiology, registration, and entry into clinical trials, there is limited therapeutic and prognostic significance associated with this designation [129]. Management and Outcomes: High-grade serous carcinoma, the most common type of fallopian tube primary carcinoma to secondarily involve the ovary, has a similar prognosis and treatment whether the primary site is considered to be fallopian tube or ovary. The most important prognostic factor for high-grade serous carcinoma is stage; by the time patients become symptomatic, they have advanced-­ stage disease in approximately 75–80% of cases, and less than 25% of patients will be cured by current therapies. The current mainstay of treatment for almost all patients with high-grade serous carcinoma is cytotoxic chemotherapy. Tumors arising in association with BRCA1 and BRCA2 germline mutations have been demonstrated to have a more favorable prognosis than do sporadic tumors [130]. A series of new therapeutic drugs that target poly(ADP-ribose) polymerase (PARP) is under investigation for treatment of BRCA mutation-positive ovarian cancer [131].

10.13 Metastatic Breast Carcinoma Definition: Carcinoma of breast origin metastatic to the ovary. Clinical Features: Breast carcinoma metastatic to the ovary is uncommonly identified in surgical specimens but is relatively common at autopsy [4, 6]. Ovarian metastasis is found at autopsy in approximately 10–15% of women with breast cancer, and in about 1% of risk-reducing salpingo-­ oophorectomy specimens from BRCA patients [2, 12]. Mean age at diagnosis of ovarian metastasis was 52 in one series [132]. Ovarian metastasis was discovered at a median of 5 years after the diagnosis of breast cancer in two large series [132, 133]; rarely, ovarian metastasis is detected before the

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breast cancer [134]. Most patients are asymptomatic from their ovarian metastasis, but a minority of patients are symptomatic (ascites, pelvic pain) and/or present with a relatively large mass mimicking an ovarian primary neoplasm. A majority of patients with ovarian metastasis have extraovarian metastasis as well [132, 133]. Patients with breast cancer are at increased risk of developing ovarian cancer and vice versa, especially patients with BRCA1 or BRCA2 mutations [135]. Of note, breast cancer patients ­presenting with a new adnexal or pelvic mass have been found to be more likely to have an independent ovarian or tubal primary malignancy than metastatic breast cancer by a ratio of 3:1 [136]. Pathologic Findings: Gross: Ovarian metastases are bilateral approximately two-thirds of the time [134]. Metastases from breast carcinoma are generally small compared with other metastatic tumors, usually less than 5 cm and as small as 1 mm or less [12, 134]. Infrequently, the metastases may be larger than 5 cm and grossly indistinguishable from a variety of primary and metastatic ovarian tumors [134, 137]. The cut surface is typically solid and white with discrete to confluent nodules, but may rarely be solid and cystic or show prominent cyst formation [12, 134]. Microscopic: Breast carcinoma metastatic to the ovary has the same range of cell types and histologic patterns characteristic of primary breast cancer [2]. Lobular breast cancer metastasizes to the ovary more often than does ductal cancer [12, 132, 138] although, due to the greater frequency of ductal carcinoma, a majority of ovarian metastases from breast cancer are of the ductal type [12]. Ductal carcinomas can show tubular, cribriform, solid, papillary, insular, sheetlike, corded, and signet ring patterns, as well as mixtures of these patterns (Fig. 10.48). Lobular car-

Fig. 10.48  Mammary carcinoma of ductal type metastatic to the ovary. Tumors with a glandular or cribriform architecture like this one raise a differential diagnosis of endometrioid adenocarcinoma, primary or metastatic

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Fig. 10.49  Mammary carcinoma of lobular type metastatic to the ovary. Metastatic mammary carcinoma with a single file pattern such as this one may raise a differential diagnosis of leukemia, lymphoma, or granulosa cell tumor

cinomas may have corded, insular, diffuse, or dispersed patterns, and tumor cells may be sparse and thus easily missed on H&E (Fig. 10.49). Signet ring cells are usually not a prominent feature but can infrequently be abundant and generate a tumor meeting the criteria for Krukenberg tumor [139]. Tumor cells may involve the theca interna of the Graafian follicle, the granulosa or theca layer of the corpus luteum, or a corpus albicans [12]. The stroma often has no distinctive features and is rarely luteinized, in contrast to that of gastrointestinal tumors metastatic to the ovary. Lymphovascular invasion may be inapparent or multifocal [32, 134]. If a patient has received chemotherapy, tumor cells may be altered with foamy cytoplasm and minimal cytologic atypia, and reduced to absent mitoses, rendering diagnosis more challenging. Ovarian surface involvement may be seen but is generally not as conspicuous as in tumors metastatic from the gastrointestinal tract and other intra-abdominal sites [2]. Biomarkers: –– In general, breast carcinoma is positive for CK7, GATA3, GCDFP-15, mammaglobin, and ER (Figs.  10.50 and 10.51). It is typically negative for CK20, PAX8, and WT-1. –– Up to 30% of breast carcinomas may be negative for GCDFP-15 and mammaglobin [26]. –– Of note, mammaglobin diffusely stains some endometrioid adenocarcinomas, and occasional serous and clear-­ cell carcinomas [140]. –– GATA3 stains approximately 90% of mammary ductal carcinomas and up to 100% of lobular carcinomas but is not specific for breast carcinoma and marks a variety of other neoplasms including urothelial carcinoma,

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Fig. 10.50 Mammary carcinoma of ductal type metastatic to the ovary. Mammary carcinomas often express GATA3 (left) and ER (right). Of note, endometrioid adenocarcinomas also infrequently express GATA3. Expression of PAX-8 and/or CA125 strongly favors endometrioid adenocarcinoma

Fig. 10.51  Mammary carcinoma of ductal type metastatic to the ovary. This tumor has a small tubular architecture (left). Expression of mammaglobin (right) is often demonstrated in mammary carcinomas, although mammaglobin is not specific and may diffusely mark some endometrioid adenocarcinomas

s­ quamous cell carcinoma, mesothelioma, and rare endometrial adenocarcinomas [141]. –– Use of a directed panel of immunostains is recommended when ancillary testing is needed, as no single marker is adequately informative. Differential Diagnosis: The differential diagnosis includes primary ovarian surface epithelial carcinomas (endometrioid, serous, or undifferentiated carcinoma), other metastatic carcinomas, granulosa cell tumor, carcinoid tumor, desmoplastic small round cell tumor, and hematopoietic neoplasms [12]. Metastatic breast tumors with a predominantly glandular architecture may resemble endometrioid adenocarcinoma, and tumors with an insular pattern may mimic carcinoid tumor. A tumor with a diffuse/dispersed or single file pattern may suggest leukemia or lymphoma. Metastatic breast carcinoma may also mimic granulosa cell tumor [2]. Careful attention to gross and microscopic features will provide a clue to the diagnosis in many cases, but immunostaining and clinical correlation will be required for some cases. Features helpful in the differential diagnosis are as follows: Endometrioid adenocarcinoma: Shares the CK7+/ CK20−/ER+ immunoprofile typical of breast carcinoma and may also mark with mammaglobin and GATA3 less frequently, although positivity for PAX8 and/or CA125 strongly favors endometrioid adenocarcinoma. Endometrioid adenocarcinoma tends to be unilateral and may arise in the setting of endometriosis or an endometrioid adenofibroma.

Serous carcinoma: Is positive for CK7 and negative for CK20, and may show positivity for ER and mammaglobin, although mutation-type staining for p53 and positivity for PAX8, CA125, and/or WT1 strongly favor serous carcinoma. Carcinoid tumor: Is positive for synaptophysin in virtually 100% of cases, and with other neuroendocrine markers (NSE, PGP9.5, and chromogranin) in many cases. Granulosa cell tumor: Is typically unilateral and shows ovoid or angulated small nuclei with scant indistinct cytoplasm and characteristic nuclear grooves in at least some cells. These tumors are usually EMA negative but may show patchy or punctate marking for LMWCKs, whereas carcinomas tend to have strong diffuse marking for EMA and various cytokeratins. An inhibin+/calretinin+/WT1+/CD99+/ FOXL2+/GATA3−/mammaglobin−/GCDFP− immunophenotype is consistent with granulosa cell tumor [23]. Desmoplastic small round cell tumor: Is characterized by small round uniform cells with hyperchromatic nuclei and scant cytoplasm, and may have tubular or glandular formations or signet ring cells that suggest the possibility of a metastatic breast carcinoma. Although these tumors may occur in the elderly, most tumors develop in adolescents or young adults. They show a distinctive immunohistochemical staining pattern with positivity for epithelial (keratin, EMA), muscular (desmin), and neural (NSE) markers, which contrasts with that of metastatic breast carcinoma [12, 142]. Hematolymphoid neoplasms: If the metastatic breast carcinoma has a dispersed, diffuse, or cord-like pattern, the

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findings could suggest a hematolymphoid neoplasm. Use of immunohistochemical stains for keratins and hematolymphoid antigens is confirmatory of the diagnosis. Management and Outcomes: A 2016 study of 28 patients with ovarian metastasis from previously treated breast cancer demonstrated a mean survival of 49.5 months (approximately 4 years) after discovery of the ovarian metastasis. Survival was 120.8  months for patients with an ovarian metastasis alone versus 106.9 months for patients with multiple secondary sites, a difference of nearly 14 months, implying that multifocal metastasis is a poor prognostic feature [132]. A 2010 study of 29 women with ovarian involvement with metastatic breast cancer compared outcomes between patients who underwent macroscopic resection of metastases versus patients who did not; data indicated that survival improved significantly when optimal debulking surgery was performed, even when patients had advanced pelvic disease [133].

10.14 Metastatic Malignant Melanoma Autopsy studies have demonstrated ovarian involvement by metastatic melanoma in approximately 20% of patients who died of melanoma, although clinical detection of ovarian metastasis is rare [2, 12]. Data from occasional case reports and three large series of melanoma metastatic to the ovary indicate that patients may be symptomatic from the ovarian metastasis, with abdominal swelling or pain [143–147]. A majority of patients with ovarian metastasis also have synchronous extraovarian metastasis. Most of the reported cases have had an antecedent cutaneous melanoma, prior removal of a pigmented skin lesion, or rarely an ocular melanoma [144, 148]. The interval may be long (up to 22 years in one reported case), and in some patients no prior history of antecedent melanoma is described. In these instances, the primary melanoma may be unknown to the clinician, or may have regressed [149]. Pathologists know that melanoma may show different cytologic features and different architectural patterns, and may appear in unexpected locations; thus, the diagnosis may be challenging. In the ovaries, metastatic melanoma may be bilateral or unilateral, and may be solid, solid and cystic, or even predominantly cystic. No specific gross features have been described except for brown or black coloration, which may be focal, in some tumors. Tumors average approximately 10 cm but may be as large as 20 cm [145–147]. Microscopically, the most common cell type is a variably pleomorphic, large epithelioid cell with abundant eosinophilic cytoplasm. Small cells with scant cytoplasm are also common. Fewer tumors have a spindled cytomorphology. Admixed cell types may be seen. Prominent nucleoli, characteristic of melanoma, are seen in approximately 80% of cases, nuclear pseudoinclusions in approximately 25% of

cases, and melanin pigment in approximately 50% of cases. Unexpected findings include clear cells, rhabdoid cells, and myxoid stroma. Architecturally, the tumor tends to have a solid growth pattern. A distinctive architectural feature found in many metastatic melanomas is a pattern of discrete rounded aggregates with a nevoid appearance. Other possible patterns include follicle-like spaces and a pseudopapillary appearance [32, 145–147]. Melanoma metastatic to the ovary may grossly and microscopically mimic an ovarian primary neoplasm but, like other tumors metastatic to the ovary, metastatic melanoma tends to have a multinodular gross and microscopic appearance. The differential diagnosis for metastatic melanoma includes primary ovarian melanoma and, depending on the cytoarchitectural features of the case, may include granulosa cell tumor of juvenile or adult type, small-cell carcinoma of hypercalcemic type, undifferentiated carcinoma, lipid-poor steroid cell tumor, pregnancy luteoma, and sarcoma [32]. A panel of immunohistochemical stains is very helpful in establishing the diagnosis of melanoma, especially in cases where melanin pigment is not identified. S-100 marks at least 98% of melanomas, regardless of histologic type, although S-100 is not a specific marker, and thus is most helpful as a screen for melanoma. HMB-45 and melan-A are both relatively specific for melanocytic type cells and have a sensitivity of 60–80%. SOX-10 positivity has also been found in the majority of melanomas. Of note, S-100 and melan-A are positive in some ovarian sex cord-stromal tumors [23, 150]. Once a diagnosis of melanoma has been established, it must be determined whether the melanoma is primary or metastatic. Primary ovarian malignant melanoma is rare but may occur in the setting of teratoma, including monodermal teratoma (struma ovarii) [151, 152]; thus, a background of teratoma is an important clue to the possible primary nature of the neoplasm. In these rare cases, junctional activity at the base of squamous epithelium may be seen. Bilaterality and multinodular growth suggest metastatic tumor, even in the absence of an identifiable primary tumor. In some cases it may not be possible to determine whether the melanoma is primary or metastatic [32].

10.15 M  etastasis from Kidney and Lower Urinary Tract Metastasis from kidney: Renal cell carcinoma rarely metastasizes to the ovaries. Most reported cases of renal cell carcinoma metastatic to the ovaries have been of the clear cell type [153–155], although other types (chromophobe, collecting duct, and unclassified types) have been infrequently reported [153, 156]. In some cases, the ovarian tumor is discovered prior to diagnosis of the renal primary. In other

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cases, the ovarian tumor is discovered after diagnosis of the clear-cell carcinoma and lipid-rich ovarian steroid cell renal primary, with one reported ovarian metastasis present- tumors are as follows: ing 14 years after discovery of the renal primary. The differential diagnosis of metastatic clear-cell renal –– Clear-cell renal cell carcinoma: The most useful panel cell carcinoma involving the ovary includes mullerian clear-­ of antibodies for distinguishing clear-cell renal cell carcicell carcinoma and lipid-rich ovarian steroid cell tumor. noma from mullerian clear-cell carcinoma is CK7, CD10, Although some morphologic overlap exists between these and RCC, as clear-cell renal cell carcinoma typically entities (most notably, clear cytoplasm), certain distinctive expresses CD10 and RCC but not CK7, while mullerian morphologic features and variations in the immunostaining clear-cell carcinoma typically expresses CK7 but not patterns facilitate diagnosis. Morphologic features helpful in CD10 or RCC. Clear-cell renal cell carcinoma also typithe differential diagnosis are as follows: cally expresses CA-IX and vimentin, while mullerian clear-cell carcinoma often expresses Napsin-A and p504s. • Metastatic clear-cell renal cell carcinoma: Tends to Of note, both tumors usually express PAX8, and fewer maintain the expected morphologic pattern. Grossly, than 10% of mullerian clear-cell carcinomas express ER tumors are solid or solid and cystic, and uniformly or and PR [23, 157]. focally yellow to orange [153–155]. Classic morphologic –– Steroid cell tumors: Are typically inhibin+/calretinin+/ features of clear-cell renal cell carcinoma include a premelan-A+/EMA−. Approximately 40–50% stain for dominance of cells with clear cytoplasm disposed in sheets cytokeratin [23]. or in tubules containing intraluminal blood or eosinophilic material. The prominent vascular pattern of renal cell carMetastasis from lower urinary tract: Urothelial carcicinoma is also usually present. In contrast to the relatively noma metastatic to the ovary from the urinary bladder, ureuniform clear-cell cytology typically shown by metastatic ter, or renal pelvis is rare (Figs. 10.52 and 10.53). This may clear-cell renal cell carcinoma, mullerian clear-cell carci- mimic a primary tubo-ovarian transitional cell carcinoma, noma typically has greater cytologic and architectural malignant Brenner tumor, or undifferentiated carcinoma variation, with a mix of clear, eosinophilic, cuboidal, hob- [32]. A single case of urothelial carcinoma of renal pelvis nail, and flat cells. The cells may be disposed in various origin and three cases of urothelial carcinoma of bladder oriarchitectural patterns including sheets, papillae, and lining gin with glandular differentiation and signet ring morpholcystic spaces, usually with at least focal presence of the ogy are reported to have metastasized to the ovary and round tubulocystic glands characteristic of mullerian generated Krukenberg tumors [158, 159]. Thorough samclear-cell carcinoma. Luminal mucin, eosinophilic hyaline pling of the ovarian tumor may disclose benign or borderline globules, and papillae with stromal hyalinization also Brenner elements, or the presence of benign mucinous elefavor mullerian clear-cell carcinoma [32, 155]. ments, which provide clues to the diagnosis of a primary • Ovarian steroid cell tumors of lipid-rich type: Do not malignant Brenner tumor. Most primary ovarian transitional show the tubular growth pattern with intraluminal blood cell carcinomas are thought to be high-grade serous carcior eosinophilic material typical of clear-cell renal cell car- noma with transitional like morphology; these tumors may cinoma. Careful morphologic examination should pro- have areas of more classic serous-type morphology, or less vide a clue to the diagnosis. commonly endometrioid morphology, which establish the primary nature of the tumor. Undifferentiated ovarian carciTypical immunohistochemical staining patterns helpful in noma tends to have high-grade cytologic features and may distinguishing clear-cell renal cell carcinoma from mullerian have pseudopapillae due to necrosis, but lacks the true Fig. 10.52  Urothelial carcinoma metastatic to the ovary. This example is characterized by nests of malignant urothelium with central necrosis, involving a desmoplastic stroma. The tumor closely mimics primary ovarian malignant Brenner tumor, and may closely resemble primary ovarian transitional cell carcinoma

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Fig. 10.53  Urothelial carcinoma metastatic to the ovary. A different area from the same tumor depicted in Fig. 10.52 shows a second pattern typical of urothelial carcinoma, well-formed papillae lined by malignant urothelium

p­ apillae with smooth luminal borders characteristic of urothelial carcinoma and some primary ovarian “transitional cell” carcinomas [12]. Immunohistochemical staining features useful in the differential diagnosis between urothelial carcinoma and its chief mimics are as follows: –– Urothelial carcinoma typically expresses both CK7 and CK20, p63, thrombomodulin, GATA3, and uroplakin III [157]. –– Primary tubo-ovarian “transitional” carcinomas typically have an immunohistochemical staining pattern similar to that of ovarian high-grade serous carcinoma and express CK7, WT1, PAX8, p16, and often ER. A mutation-type pattern with p53 staining (diffuse or null pattern) is seen in most cases. These tumors are usually negative for CK20, p63, uroplakin, and thrombomodulin, although GATA3 may be expressed [23]. –– Limited data exists regarding the immunohistochemical staining patterns of malignant Brenner tumors. Benign Brenner tumors show an immunophenotype similar to urothelium, suggesting true urothelial differentiation in these tumors, although borderline and malignant Brenner tumors exhibit urothelial markers less often than their benign counterparts [23].

10.16 Metastasis from the Lung and Mediastinum Metastasis from the lung: The clinical presentation of ovarian metastasis from a primary lung carcinoma is relatively rare. Approximately 5% of women with lung cancer are

found to have ovarian metastasis at autopsy, although ovarian metastasis discovered during life is less common. Challenges in the differential diagnosis may arise, especially if the pulmonary primary is unknown, or if the metastasis involves an ovary harboring a primary ovarian neoplasm [79, 160]. Ovarian spread of primary pulmonary neoplasms has received limited attention in the literature, the largest published series being a 2005 report of 32 cases [79]. Among these cases, it was noted that 53% of patients had a known history of lung cancer, 31% had synchronously discovered pulmonary and ovarian tumors, and 16% presented first with an ovarian mass and no known history of lung cancer. Histologic types in this series included small-cell carcinoma (44%), adenocarcinoma (34%), large-cell carcinoma (16%), squamous cell carcinoma (3%), and atypical carcinoid (3%). Two cases of pulmonary adenocarcinoma of the fetal type metastatic to the ovary have also been reported [161, 162]. In the aforementioned 32 case series, the mean ovarian size was 9.7  cm, and a minority (one-third) of the metastases were bilateral. Features common to metastatic tumors in general (such as multinodular growth, prominent necrosis, and extensive lymphovascular invasion) were noted in many of the tumors. Notation of these features, of any histologic features uncommon to ovarian primary neoplasms in general, and of any clinical history available will aid in making the correct diagnosis in most cases. Immunohistochemical staining for TTF-1 may be of adjunctive aid in the diagnosis, as many pulmonary adenocarcinomas, small-cell carcinomas, and atypical carcinoid tumors express TTF-1. It should be noted that TTF-1 expression may be seen in endometrioid tumors arising from the uterus or ovary. Metastasis from the mediastinum: Ovarian metastasis of mediastinal tumors is less commonly reported than ovarian metastasis of lung tumors. There are rare reported cases of thymoma metastatic to the ovary [163]. A case of a child with a posterior mediastinal neuroblastoma metastatic to the ovary has also been reported [164].

10.17 L  ymphoma and Leukemia Involving the Ovary Lymphoma involving the ovary: While as many as 25% of disseminated lymphomas were found to involve one or both ovaries at autopsy in a 1972 study [165], lymphoma presenting clinically as an ovarian mass is rare. Lymphoma presenting as an incidental finding in the ovary is also rare. An exception to the above is ovarian involvement in countries where Burkitt lymphoma is endemic; in these nations, the ovary is a frequent site of involvement, and the patients are typically children [166]. Any type of lymphoma may involve the ovary, and affected patients span all age groups. In most cases in which ovarian lymphoma is discovered there is more

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disseminated disease with associated abdominal or pelvic lymph node involvement. In a minority of cases, however, there is exclusive involvement of a single ovary, suggesting that the ovary is the primary site [167]. Ovarian involvement by lymphoma may be a small incidental finding or a large mass (masses ranging up to 25 cm have been reported). The external surface is typically smooth or bosselated and intact. The cut surface is usually white to tan, fleshy to firm or rubbery, and solid, with occasional areas of cystic degeneration, hemorrhage, or necrosis [168– 171]. Most lymphomas involving the ovary are of B-cell type, the most common subtypes including diffuse large B-cell type, Burkitt lymphoma, and follicular lymphomas. Rare tumors are of T-cell type, reported cases including T-cell anaplastic large-cell lymphoma and precursor T-lymphoblastic lymphoma [167–169]. Primary plasmacytoma of the ovary and secondary ovarian involvement by multiple myeloma have also been rarely reported [172–174]. Cytologically, lymphomas in the ovary are similar to their counterparts in lymph nodes and extranodal sites, although sclerosis may be more prominent in the ovary, and may induce unusual patterns including single file, trabecular, insular, and storiform arrangements. Lymphomas may also diffusely involve the ovary, and spare or obliterate physiologic structures [12, 175]. Possibly due to the propensity of these tumors to have associated sclerosis, lymphoma cells in the ovary may appear more epithelioid or spindled than in extraovarian sites, causing diagnostic difficulty. The differential diagnosis includes other tumors characterized by relatively small cells that may be singly disposed, including granulosa cell tumor, dysgerminoma, small-cell carcinoma of hypercalcemic type, granulocytic sarcoma, undifferentiated carcinoma, melanoma, and breast carcinoma. The differential diagnostic considerations can be excluded with a directed panel of immunohistochemical stains [12, 175]. Leukemia involving the ovary: The most substantial data regarding leukemic involvement of the ovaries consists of autopsy studies and case series reported before 2000, which would be expected to reflect treatment efficacy at the time [168, 170, 176–178]. More recent information consists of one series of 124 leukemic ovarian tumors which focused on survival data [179], and infrequent case reports [180, 181]. Leukemic involvement of the ovary appears to be less common than lymphomatous involvement of the ovary; in studies that have included both leukemias and lymphomas, there were only three cases of ovarian leukemia among a total of 61 cases. In a 1987 autopsy study of 1206 cases of acute and chronic leukemias gathered between 1958 and 1982, the ovary was involved by leukemia in 11% of the cases of acute myelogenous leukemia, 9% of cases of chronic myelogenous leukemia, 21% of cases of acute lymphoblastic

K. Carrick and W. Zheng

leukemia, and 22% of cases of chronic lymphocytic leukemia [177]. The percentage of cases involving the ovary was noted to decrease over the time period of the study, likely reflecting increasing efficacy of treatment. Leukemic involvement of the ovary infrequently produces a symptomatic ovarian mass. In a 1997 study focusing on 11 cases of granulocytic sarcoma of the female genital tract, 7 cases had ovarian involvement and produced masses ranging from 5 to 14 cm. Three of the tumors had a green cut surface. Myeloid differentiation was readily recognizable in three of the cases, whereas the other cases presented more of a diagnostic challenge due to primitive cytologic features without the classic eosinophilic myelocytes. Sclerosis was present in the majority of tumors, and prominent in one tumor [176]. Microscopic features of leukemia in the ovary are similar to those of lymphoma, although nuclei have paler, finer chromatin than do most lymphomas, and the cytoplasm is more abundant, pale pink, or deeply eosinophilic. Once leukemia enters the differential diagnosis, the diagnosis can be confirmed by staining for chloroacetate esterase or a directed battery of immunohistochemical stains. The differential diagnosis includes lymphoma and, as noted above with lymphoma, other tumors consisting of singly disposed cells such as granulosa cell tumor, dysgerminoma, undifferentiated carcinoma, melanoma, and metastatic carcinomas including breast carcinoma.

10.18 Other Rare Metastatic Tumors Virtually any tumor can metastasize to the ovary, and the list of such tumors is not limited to those reported above. Thus, it is critical that when one encounters an ovarian tumor with cytologic or architectural features uncommon to primary ovarian neoplasia, metastasis is considered. Head and neck tumors of thyroid, salivary gland, esophageal, and sinonasal origin: Head and neck tumors have infrequently been the source of ovarian metastasis. The thyroid is a rare source of ovarian metastasis, even in autopsy series [2]. Few cases of thyroid follicular carcinoma and papillary thyroid carcinoma have been reported to metastasize to the ovary, up to 12 years after the initial presentation in the thyroid [182–184]. In a recent study, anaplastic thyroid carcinoma was found to involve the ovary in 2% of 45 cases examined at autopsy [185]. As thyroid tissue may develop in the ovary as a component of a teratoma or as a monodermal teratoma, malignant thyroid tissue in the ovary raises the differential diagnosis of malignant struma ovarii. If other teratomatous elements are not found on thorough sampling, a diagnosis of malignant struma ovarii should be made only when the possibility of spread from a thyroid neoplasm has been explored and excluded [182].

10  Secondary Tumors of the Ovary

Rare salivary gland tumors have been documented to involve the ovary and present during life. A patient with adenoid cystic carcinoma of the submandibular gland developed abdominal pain 10 years after the initial presentation and was found to have a 10 cm left ovarian mass and a single metastatic tumor nodule involving the right ovary [186]. A second anecdotal account of adenoid cystic carcinoma metastasizing to the ovary and forming a symptomatic mass 11 years after initial presentation is available [2]. In addition to head and neck tumors of thyroid and salivary gland origin, a single case of esophageal carcinoma [187] and a single case of undifferentiated carcinoma of the ethmoid sinus [2] have been reported to metastasize to the ovary. Several of the above-noted cases are remarkable for the relatively long duration between initial diagnosis and presentation of the ovarian metastasis, underlining the importance of consideration of any history of neoplasia when an unusual ovarian tumor is encountered. Other rare tumor types: There are few accounts of other tumor types metastatic to the ovary. Skin tumors other than melanoma rarely metastasize to the ovary; Merkel cell carcinoma has rarely been documented to form a clinically significant ovarian mass [188, 189]. Regarding tumors originating in the neuraxis, single cases of meningioma, medulloblastoma, and chordoma metastatic to the ovary have been described [164, 190]. A case of an ovarian smallcell carcinoma of pulmonary type arising in a mature cystic teratoma, with metastasis to the contralateral ovary, has also been reported [191]. Ovarian metastasis in the pediatric population: Tumors reported metastatic to the ovary in the pediatric age group are different from what is encountered in the adult population, reflecting the unique spectrum of primary tumors affecting children and young adults. In addition to certain types of lymphoma and leukemia, which affect children and young adults more often, several other tumor types have been reported to metastasize to the ovary in children. A 1993 study of 14 cases of metastatic ovarian tumors in children found eight neuroblastomas (seven primary to the adrenal gland and one primary in the mediastinum), three ­rhabdomyosarcomas (primary to the ethmoid sinus, right occipital region, and left thigh), and single examples of Ewing’s sarcoma, rhabdoid tumor, and a carcinoid tumor (primary to the fibula, kidney, and lung, respectively). Of these, two patients presented symptomatically, and three had clinical manifestations suggesting an ovarian primary neoplasm. This 1993 study included a literature review and suggested that the most common childhood tumor to spread to the ovary is neuroblastoma, and that rhabdomyosarcoma is the most common childhood sarcoma that spreads to the ovary [164].

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Peritoneum and Broad Ligament

11

M. Ruhul Quddus, Sharon Liang, Wenxin Zheng, and C. James Sung

Abstract

The peritoneum is a site for diverse nonneoplastic and neoplastic disease processes including those encountered in many other organ systems in the body. Once proposed as part of the secondary Müllerian system, its role in the pathogenesis of primary serous carcinomas has recently been questioned. It has been postulated that primary Müllerian peritoneal/omental serous carcinoma is a metastasis from the similar tumor of the fallopian tubes. This theory, however, applies to serous carcinomas only, not tumors of any other Müllerian cell types. Far from being a mere receptacle for metastasis from other organ sites, the notion that the peritoneum and its derivatives serve as important source of primary peritoneal carcinomas remains a valid concept. Keywords

Müllerian system · Primary peritoneal carcinoma Implants · Mesothelioma

The peritoneum is a site for diverse neoplastic and nonneoplastic disease processes including inflammation, reactive changes, and neoplasms, including benign, borderline, and malignant tumors. It has unique potential to give rise to M. Ruhul Quddus · C. James Sung (*) The Warren Alpert Medical School of Brown University, Women & Infants Hospital, Providence, RI, USA e-mail: [email protected]; [email protected] S. Liang Department of Pathology and Laboratory Medicine, Allegheny Health Network West Penn Hospital, Drexel University College of Medicine, and Temple University School of Medicine, Pittsburgh, PA, USA e-mail: [email protected] W. Zheng Departments of Pathology, Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected]

tumors identical to those of the Müllerian system commonly seen within the pelvis and thus extending the territory of Müllerian tumors beyond the pelvic brim up to the level of the diaphragm. Peritoneal diseases in females include lesions arising from native components of the peritoneum as well as tumors related to the secondary Müllerian system. Therefore, discussion of peritoneal diseases should include all lesions of the female genital system. Accordingly, this chapter first addresses the general diseases followed by diseases of the secondary Müllerian system.

11.1 S  ection 1: General Diseases of the Peritoneum 11.1.1 Anatomy and Histology Similar to the pleura, the peritoneum also has parietal and visceral layers. The parietal peritoneum covers the posterior abdominal wall, diaphragm, retroperitoneal cavity, and surfaces of the pelvis. The visceral peritoneum covers the alimentary track and the surfaces of intra-abdominal organs. The parietal and visceral peritoneum combines at the vascular mesentery which is rich in blood vessels, lymphatics, lymph nodes, and nerves. Unlike the closed peritoneal cavity in males, the female peritoneal covering is discontinued at the fimbriated end of fallopian tube creating a natural thoroughfare along the tube, uterine cavity, vagina, and eventually to the exterior. This exposes the female peritoneum to external (environmental) stimuli [1]. The interrupted peritoneal covering thus forms a unique uterotubal–peritoneal structure. This unique anatomic characteristic fulfills physiological functions of reproduction, but serendipitously allows ascending movement for physiologic and pathologic agents, such as menstrual blood, chemical substances, and possibly pathogens, resulting in ailments. The peritoneum is derived from the mesoderm but expresses both mesenchymal and epithelial cell ­intermediate

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_11

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filaments. It is covered by a single layer of flat or low cuboidal mesothelial cells with central nuclei (Fig.  11.1), sparse or abundant cytoplasm, and distinct cell borders. The nucleolus is typically inconspicuous. Ultrastructurally, mesothelial cells have tight junctions, intercellular bridges, long microvilli, and tonofilaments. The long microvilli on the cell surface, being most characteristic (Fig. 11.2), help distinguish it from metastatic adenocarcinoma. By immunohistochemistry, mesothelial cells express different kinds of cytokeratins as well as other proteins, including cytokeratin 5/6, EMA, CEA, and Leu-M1 (CD15). Mesothelial cells also express special markers including calretinin (Fig. 11.3), thrombomodulin, and basal laminin. They are negative for Ber-EP4 and B72.3. These characteristics aid in differentiating mesothelial lesions from metastatic ­epithelial lesions.

M. Ruhul Quddus et al.

Fig. 11.3  Mesothelial cells stain strongly with calretinin, both nuclear and cytoplasmic staining (IHC, 400×)

Fig. 11.4  Acute peritonitis with numerous inflammatory cells infiltrating omentum (H&E, 200×) Fig. 11.1  Histology of mesothelial cells (H&E, 400×)

11.1.2 Inflammatory Diseases 11.1.2.1  Acute Peritonitis Diffuse acute peritonitis may result from infection or irritation by chemical agents, a common occurrence after rupture of acute appendicitis or diverticulitis. The disease is characterized by massive infiltration of acute inflammatory cells and exudates (Fig.  11.4). Fat necrosis may be present. Children, immunocompromised patients, and adults with cirrhosis may develop spontaneous bacterial peritonitis. Recurrent acute peritonitis is characteristic of Mediterranean fever, a recessive hereditary disease, more frequently seen in Sephardic Jews, Armenians, Turkish, and certain Middle Eastern populations [2, 3]. Localized acute peritonitis is typically associated with inflammation of pelvic organs.

Fig. 11.2  Ultrastructural image of mesothelial cells showing long slender microvilli on the surface of the cells. This gives the typical “window” effect around the mesothelial cells under light microscope

11.1.2.2  Granulomatous Peritonitis Many infectious and noninfectious agents may inflict a granulomatous response in peritoneum. Presence of diffuse

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Fig. 11.5  Granulomatous peritonitis with a classic necrotizing granuloma (tubercle), caseation necrosis, and Langhans-type multinucleated giant cells (H&E, 200×)

g­ ranulomata in the peritoneum may be misinterpreted as disseminated carcinomatosis. Histological examination is required to confirm the diagnosis. Mycobacterial infection is the most common infection in the peritoneum (Fig. 11.5), showing an increase in incidence in recent years, especially in immunocompromised patients [4]. The mode of transmission could be via systemic dissemination or direct spread of intraperitoneal infection. Caseating necrosis, epithelioid cells, and Langhans-type giant cells are characteristics of this lesion. Acid-fast stain or immunofluorescence stains may detect mycobacterium; however, they may also be negative. Molecular testing for mycobacterium, typically via polymerase chain reaction (PCR), can help to resolve difficult cases. Rare cases of granulomatous peritonitis may also be caused by fungal infection. Noninfectious granulomata are caused by non-pathogens such as surgical glove talcum powders, suture materials, contrast medium, and other iatrogenic agents (Fig. 11.6). Fecal contamination, pancreatic enzymes, digestive secretions, and bile resulting from intestinal perforation or ruptured neoplasm, such as dermoid cyst or ovarian tumors, may induce noninfectious granulomas. Keratin-induced foreign body granulomas may be seen in endometrial or ovarian carcinomas with squamous differentiation, as well as teratomas with keratin formation. It has been reported that the presence of keratin granulomata without viable tumor cells does not affect prognosis in patients with endometrioid carcinoma [4, 5]. Sarcoidosis and Crohn’s disease may rarely cause granulomatous peritonitis.

11.1.2.3  Non-granulomatous Histiocytic Lesions Endometriosis can trigger histiocytic response in the peritoneum and omentum. Decidualization, endosalpingiosis, and endocervicosis (endocervical mucinous-type epithelia) may

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Fig. 11.6  Foreign-body granuloma composed of inflammatory cells, multinucleated foreign body-type giant cells, and empty spaces with talc powder (H&E, 200×)

also be encountered. Sometimes histiocytic proliferation may occur around necrotic nodules, known as necrotic pseudo-xanthomatous tubercles, with or without pigmentation. Pigmented histiocytic proliferation is rarely seen, and typically is secondary to deposition of melanin pigments, a condition known as peritoneal melanosis, usually associated with ruptured mature cystic teratoma [6]. These pigment-­ laden histiocytes lack organelles, a differentiating point from malignant melanoma.

11.1.2.4  Peritoneal Fibrosis and Adhesions Peritoneal fibrous adhesions and reactive fibrosis often occur after inflammation and abdominal surgery. Severe adhesions may result in intestinal obstruction. Patients with cirrhosis, pulmonary tuberculosis, or asbestos exposure may develop localized transparent plaques on the surface of the liver or spleen. Diffuse fibrosis in the abdomen is known as sclerotic or fibrotic peritonitis (Fig. 11.7). This condition is typically idiopathic, although occasionally asbestos has been implicated. Sarcoidosis, abdominal peritoneal dialysis, and use of beta-anti-adrenergic agents may also be contributory [7]. Sclerosing peritonitis is a rare, often fatal condition of peritoneal inflammation secondary to peritoneal dialysis. It may follow renal or liver transplantation. The patients are typically young females of reproductive age, presenting with abdominal pain, abdominal distention, ascites, intestinal obstruction, and a pelvic tumor. The condition may also be associated with anticonvulsant treatment [8, 9]. Sclerotic peritonitis is thought to be a reactive process and it may be confused with desmoplastic type mesothelioma of the peritoneum. 11.1.2.5  Rare Subtypes of Peritonitis Other rare types of peritonitis include eosinophilic peritonitis and peritonitis secondary to collagen vascular diseases, including systemic lupus erythematosus.

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11.1.3 Tumorlike Diseases

Fig. 11.7  Sclerotic peritonitis. Lower power view showing submesothelial fibrosis and inflammatory infiltrates (H&E, 100×)

a

11.1.3.1  Mesothelial Hyperplasia Mesothelial hyperplasia is usually an incidental finding, often caused by irritation due to intra-abdominal hemorrhage, ascites, and/or inflammation. It is a reactive process characterized by proliferation of mesothelial cells. Mesothelial hyperplasia is usually localized and mild, with solitary small nodules. Microscopically mesothelial hyperplasia may appear as solid sheets, trabeculae, tubules, papillae, or tubulo-papillary growths (Fig.  11.8a–c). When mesothelial hyperplasia presents with papillary or tubulo-­papillary lesions, it may mimic serous borderline tumor or metastatic adenocarcinoma. Mesothelial hyperplasia may occasionally involve underlying mesenchymal tissue, making it even harder to differentiate from other neoplasms (Fig. 11.9a, b).

b

c

Fig. 11.8  Mesothelial hyperplasia, various morphologic types. (a) Mesothelial cells proliferate to become stratified or papillary. (b). Small tubular growth. (H&E 400) (c) Marked papillary growth (H&E, 100×)

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a

371

b

Fig. 11.9  Reactive mesothelial cells may appear sheetlike (a) but the cells appear monotonous or pleomorphic with abundant cytoplasm (H&E, 200×) and (b) without nuclear atypia (H&E, 400×)

The morphologic appearance of reactive mesothelial cells varies depending upon the degree of proliferation and complexity of architectural patterns. In mild hyperplasia, the nuclei are small, regular, round, or oval, with centrally placed nucleoli. The cytoplasm may be eosinophilic and vacuolated. In more severe cases, mesothelial cells may be multinucleated with enlarged nuclei, abundant cytoplasm, and prominent nucleoli, mimicking adenocarcinoma; however, cells of mesothelial hyperplasia are typically uniform in size with abundant cytoplasm. Conversely, adenocarcinoma cells usually have pleomorphism, much larger nuclei, increased N/C ratios, and frequent mitotic figures. Florid mesothelial hyperplasia must be differentiated from diffuse malignant mesothelioma (DMM). The differences between the two scenarios are summarized in Table 11.1. The presence of grossly visible nodules, necrosis, vacuolated cytoplasm, nuclear pleomorphism, and deep tissue infiltration supports the diagnosis of diffuse malignant mesothelioma (DMM). Positive immunostaining with p53 and EMA also supports the diagnosis of diffuse malignant mesothelioma (DMM) [10, 11]. Mesothelial hyperplasia must also be differentiated from serous borderline tumor of the peritoneum or ovary. The differences of ovarian or peritoneal tumors are usually quite apparent. The presence of columnar-type tumor cells, absent microvilli (the so-called window around mesothelial cells), crack artifacts around tumor cell nests, seromucinous proteinaceous materials, and abundant psammoma bodies may support a diagnosis of serous tumor. Characteristics of serous tumor will be discussed later in this chapter and in other chapters.

Table 11.1  Differences between marked mesothelial hyperplasia versus diffuse malignant mesothelioma

Clinical presentations

Marked mesothelial hyperplasia No previous history of asbestos exposure

Gross findings

Not grossly visible

Cytologic morphology

Monotonous population of small or enlarged, distinct cell border Abundant eosinophilic cytoplasm, with occasional vacuoles None or superficial pseudoinvasion CK +, vimentin +, desmin +

Cytoplasm

Tissue infiltration Immunohistochemical staining

Diffuse malignant mesothelioma Previous history of asbestos exposure Grossly visible, necrotic Pleomorphic

Prominent vacuolation Deeply infiltrative p53 +, EMA +

11.1.3.2  Peritoneal Inclusion Cyst Peritoneal inclusion cysts may have a variety of clinical presentations. It is usually seen in females of reproductive age, often with a prior history of abdominopelvic surgery, inflammation, or endometriosis, which may indicate that inflammation is causal in this entity [12]. In most cases, peritoneal inclusion cysts are incidental findings during intra-­abdominal surgery. Some patients may present with lower abdominal pain or a pelvic mass. Some evidence suggests that hormonal changes may affect the disease process. Therapeutic options include observation or surgical resection. Most cases are benign although recurrences may occur in 50% of the cases. Surgery is generally curative.

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b

Fig. 11.10  Multicystic peritoneal inclusion cyst is composed of multiple cysts separated by fibrous septae lined by (a) flat mesothelial cells (H&E, 100×), with (b) may show occasional squamous metaplasia (H&E, 200×)

Multicystic peritoneal inclusion cysts (MPIC) have also been described as benign cystic mesothelioma, cystic peritonitis, or postsurgical peritoneal inclusions. Use of the term “mesothelioma” often creates unnecessary anxiety among the clinicians and patients, so many have elected to avoid this term in clinical practice. The lesion is composed of multiple thin-walled cysts forming grapelike clusters attached to peritoneal surfaces. The cysts may range from several millimeters up to 20  cm, containing clear serous fluid. ­ Microscopically the cysts are separated by fibrous stroma lined by single- or multilayered flat or cuboidal mesothelial cells with benign-­appearing nuclei or slight nuclear pleomorphism (Fig.  11.10a, b). Focal mesothelial hyperplasia, adenomatous changes, or squamous differentiation may be encountered. The differential diagnoses of multicystic peritoneal inclusion cysts include malignant mesothelioma, cystic mesothelioma, cystic lymphangioma, and adenomatoid tumor. Malignant mesothelioma presents as papillary or tubulo-­ papillary neoplasm, containing tumor cells with nuclear pleomorphism and marked proliferative activity. Multicystic lymphangioma, another differential diagnosis of mesothelioma, is a congenital condition often seen in children, which typically occurs in the small intestinal mesentery, omentum, mesentery of the sigmoid colon, and retroperitoneum. The cysts are characterized by spongiform spaces lined by endothelial cells. Smooth muscle cells and lymphocytes are often present in the cyst wall of cystic lymphangioma, but not in MPIC. Adenomatoid tumors typically are seen in the fallopian tubes or uterine serosa with a classic gross and microscopic appearance and generally lack marked inflammatory infiltrate. The differential diagnosis of multicystic peritoneal inclusion cysts from cystic mesothelioma is discussed later in the chapter.

11.1.3.3  Calcifying Fibrous Pseudotumor This rare benign soft-tissue lesion is defined as a paucicellular collagenous reaction associated with inflammation and dystrophic calcifications. It possibly represents a reactive process and often presents as an incidental finding in the visceral peritoneum of the small intestine and the stomach, typically in younger patients below 20 years of age. Grossly the lesion presents as a well-defined solid tumor up to 20  cm. The cut surfaces are gritty (or sandy). Microscopically dense collagen fibers are arranged in a concentric pattern and admixed with benign-appearing fibroblasts, lymphocytes, and plasma cells. Focal psammoma bodies or dystrophic calcifications are present. It can undergo torsion and present as acute peritonitis [13]. It has been suggested that the lesion may be associated with inflammatory myofibroblastic tumor [14, 15] or sclerotic phase of inflammatory myofibroblastic tumor [16, 17] which are discussed later in the chapter. 11.1.3.4  Splenosis In splenosis, multiple nodules of ectopic splenic tissue are present in the abdominal cavity. The condition typically occurs as a result of autoimplantation of splenic tissue after traumatic rupture of the spleen and is typically asymptomatic. Splenosis is generally an incidental finding many months or even years after splenectomy during subsequent intra-abdominal surgery or autopsy. Some female patients may present with abdominal pain, having symptoms similar to those of endometriosis, adnexal tumor, or diffuse peritoneal carcinomatosis [18–20]. The number of the nodules may vary from case to case with some cases demonstrating over 100. The nodules vary in size from several millimeters to centimeters. The nodules are typically composed of red pulp surrounded by a dense collagenous pseudocapsule devoid of smooth muscle or elastic fibers. Larger splenic

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nodules may contain all the components of a normal spleen. The condition may cause intra-abdominal adhesions, resulting in intestinal obstruction. It is easy to distinguish splenosis from accessory spleen. The latter is a congenital phenomenon, typically found in the splenic hilum, near the tail of pancreas or anywhere along the splenic vessel to the left side of abdomen and measuring from a few millimeters to 2–3 cm. Accessory spleens ­typically have a true capsule and a small splenic hilum, and no history of adhesions or traumatic injury. It is relevant to recapitulate that splenic parenchymal involvement by a malignant epithelial tumor of gynecologic origin is considered stage IV disease.

11.1.3.5  Trophoblastic Implants Extratubal secondary trophoblastic implants in the abdomen are a rare complication of laparoscopic procedures for tubal ectopic pregnancy or in  vitro fertilization (IVF) [21, 22], with an estimated incidence of 3.6% [23–25]. It is more commonly seen in intra-abdominal laparoscopic surgery as opposed to open laparotomy, as well as oviduct reanastomosis as opposed to salpingectomy. The clinical presentations include a rebound of serum or urine hCG levels after surgical removal of an ectopic pregnancy, abdominal pain, and/or abdominal hemorrhage. Trophoblastic cells in decidualized stroma can be seen by microscopic examination (Fig. 11.11). It may be prevented by a thorough examination of surgical field after removal of ectopic pregnancy. 11.1.3.6  Peritoneal Keratin Granulomas Peritoneal keratin granulomata are formed due to local reaction to keratin debris derived from other intraabdominal sources. The condition is often seen in cases of endometrial adenocarcinoma or ovarian carcinoma with squamous ­differentiation or ruptured ovarian mature cystic teratoma (dermoid cyst). Keratin may reach the abdomen through the

Fig. 11.12  Peritoneal keratin granuloma. Remnants of keratin and squamous cells are surrounded by multinucleated giant cells and inflammatory cells (H&E, 400×)

endometrial–tubal–pelvic routes. Occasionally peritoneal keratin granulomas may be associated with carcinoma of the uterine cervix or atypical polypoid adenomyoma of the uterus [4, 26, 27]. The center of the granulomata contains keratinous material or remnants of squamous cells, surrounded by chronic inflammation, foreign-body giant cells, and dense fibrosis (Fig.  11.12). Residual anucleated keratin material may also be seen after radiation therapy of a malignant tumor. The granulomata are typically present on the serosal surfaces of the adnexa, uterus, colon, and appendix and may be misinterpreted as metastatic tumor. A few studies with small sample size showed that peritoneal keratin granulomata without viable tumor cells do not affect patient’s prognosis. Pathological examination is mandated to rule out viable tumor in these foci [26].

11.1.3.7  Infarcted Appendix Epiploica Appendix epiploicae are polypoid adipose tissue on the serosal surfaces of large intestine, especially of the transverse colon and sigmoid colon. They may undergo torsion, infarction, and calcification. If detached, they float freely in the abdominal cavity. Microscopically these nodules are composed of central fat necrosis and calcification surrounded by pseudo-­capsule of dense fibrous tissue (Fig. 11.13).

11.1.4 Mesothelioma 11.1.4.1  Benign Mesothelioma

Fig. 11.11  Focal decidual stromal reaction with rare trophoblastic cells in peritoneum (patient had a recent history of ectopic pregnancy) (H&E, 100×)

Adenomatoid Tumor Adenomatoid tumor is a benign mesothelial derived tumor often seen near the oviducts in females and epididymis in males, uterine serosa, broad ligament, and occasionally near the ovarian hilum and ovary.

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By  definition, this tumor is noninvasive. It may present as a diffuse or multifocal entity on peritoneal surfaces within the abdominal cavity. Approximately 80% of cases have been reported in females of reproductive age and follow-up of most of these demonstrates a benign course [31–33]. Often the tumor is an incidental finding during intra-abdominal surgery, although some patients may present with abdominal pain or ascites. According to the literature, most patients have not been exposed to asbestos [31].

Fig. 11.13  Infarcted and pseudo-capsulated appendix epiploica of the intestine (H&E 40×)

Fig. 11.14  Adenomatoid tumor composed of gland-like spaces lined by cuboidal mesothelial cells (H&E, 100×)

1. Gross examination: This tumor often demonstrates a gray-yellow tubercle-like growth pattern, and is typically solitary. Occasional tumors may present with multiple nodules of variable sizes ranging from several millimeters to multiple centimeters. 2. Microscopic examination: Typically, this tumor forms irregular, reticular slit-like spaces lined by a single layer of flat or low cuboidal, epithelial-like cells (Fig.  11.14) with mild nuclear pleomorphism and rare mitoses. Several rare atypical histological subtypes such as solid, angiomatous, and cystic variants have been reported [28].

11.1.4.2  Malignant Mesothelioma Well-Differentiated Papillary Mesothelioma Well-differentiated papillary mesothelioma of the peritoneum is rare and has an indolent clinical course [29, 30].

1. Gross examination: Well-differentiated papillary mesothelioma may present as a solitarily lesion or multiple gray or white firm nodules. Occasionally the tumor may appear papillary, and is typically smaller than 2 cm. The tumor often involves the omentum and the pelvic peritoneum; however, involvement of the stomach, intestine, and mesentery has also been reported [31]. 2. Microscopic examination: Well-differentiated papillary mesotheliomas of the peritoneum are composed of broad fibrovascular cores lined by a single layer of cuboidal to flat mesothelial cells (Fig. 11.15a). Occasional basal vacuoles may be seen. Some fibrovascular cores may show mucinous change, with prominent fibrosis or hyalinization. The tumor cells are uniform in size and shape, lacking mitosis, nucleoli, or tissue necrosis (Fig.  11.15b). Other rare histological subtypes include tubulo-papillary, adenomatoid, branching, and solid patterns. Rare cases may present with multinucleated giant cells and psammoma bodies. Histochemical, immunohistochemical, and ultrastructural characteristics of this tumor support mesothelial origin of this tumor. 3. Differential diagnoses: It is important to differentiate well-differentiated papillary mesothelioma from malignant mesothelioma because they have a vastly different prognosis. Even though the gross appearance of well-­ differentiated papillary mesothelioma is quite different from that of invasive malignant mesothelioma, some features resembling well-differentiated papillary mesothelioma may also be present focally in malignant mesothelioma [32]. Therefore the diagnosis of well-­ differentiated papillary mesothelioma must adhere to strict criteria including both the lack of nuclear pleomorphism and tissue infiltration. Tumors showing any evidence of invasion must be noted and may represent focally malignant mesothelioma as opposed to well-­ differentiated papillary mesothelioma. Also to remember that well-differentiated mesothelioma with invasive foci in the papillae is prone to multifocality and recurrence. However, they rarely are fatal [33]. The histologic difference between well-differentiated papillary mesothelioma and serous borderline tumor is rather striking as the latter shows irregular feather-like cell clusters. The nuclei of serous borderline tumors usu-

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ally demonstrate more nuclear pleomorphism when compared to those of a well-differentiated papillary mesothelioma; however they may be difficult to distinguish in some cases. Scattered ciliated cells in the lining epithelium can help to identify a serous tumor if present. Immunohistochemical characteristics of serous borderline tumor are discussed later in the chapter. 4. Treatment and prognosis: The treatment of choice for well-differentiated papillary mesothelioma is surgery; however, this may not be curative. This tumor typically presents with an indolent clinical course, with many patients surviving several years or even several decades. Low-Grade Cystic Mesothelioma Most cystic mesothelial lesions appear as a reactive process, e.g., peritoneal inclusion cysts, but rare cases may represent a true neoplastic process such as low-grade cystic mesothelioma (Fig. 11.16a) [34]. Unlike peritoneal inclusion cysts, cystic mesothelioma may be lined by atypical mesothelial cells. Focally the tumor may show a classic pattern similar to that seen in malignant mesothelioma. Under low power, this tumor may be confused with an adenomatoid tumor (Fig.  11.16b). Cystic mesothelioma typically behaves in an indolent fashion, but may infrequently recur after resection. Diffuse Malignant Mesothelioma (DMM) Fewer cases of peritoneal diffuse malignant mesothelioma (DMM) are encountered compared to those occurring in the pleura. DMM in peritoneum composes 10–20% of all cases of malignant mesothelioma and predominantly affects middle-­aged or elderly males [35, 36]. The causal relationship between diffuse malignant mesothelioma and asbestos

a

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exposure remains controversial. One recent study reported that 29% of 96 male patients had occupational asbestos exposure while none of the 113 female patients had any history of asbestos exposure [37]. Some authors also noted that mesothelioma in female patients may be related to radiation, chronic inflammation, organic chemicals, or nonasbestos fibers. Approximately 40% of female patients survived more than 4  years, much more than their male counterparts [38]. 1. Clinical characteristics: The clinical presentation of diffuse malignant mesothelioma is similar to that of ovarian or other peritoneal malignancies. Patients typically report abdominal discomfort, abdominal distention, indigestion, and weight loss. Many patients present with ascites. Occasional cases may present with retroperitoneal, intestinal, or pelvic tumors; intussusception; deep umbilical subcutaneous nodules; or even cervical or inguinal lymphadenopathy. The tumor may be confused with a disseminated ovarian tumor when both ovaries are involved. Diagnosis requires a thorough histologic examination, although some cases are diagnosed by cytologic examination of the ascites fluid [39]. 2. Gross examination: Both the visceral and parietal peritoneum will show diffuse thickening with extensive tumor nodules and plaques. The tumor may encase or infiltrate visceral organs. In contrast to the behavior of malignant epithelial tumors, these tumors less frequently show local invasion and metastasis. 3. Microscopic examination: Diffuse malignant mesothelioma of the abdominal and pleural cavities has identical histological features. The tumor may show tubular or papillary or tubulo-papillary morphologic features (Fig.  11.17a, b). Some may present as solid sheets

b

Fig. 11.15  Well-differentiated papillary mesothelioma. (a) Low-­power view shows broad fibrovascular core lined by flat to cuboidal mesothelial cells (H&E, 200×). (b) Higher power view shows that the mesothelial cells are rather uniform with no mitosis or prominent nucleoli (H&E, 400×)

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b

Fig. 11.16  Low-grade cystic mesothelioma. (a) Gross examination reveals numerous thin-walled cysts. (b) Low-power view may be similar to adenomatoid tumor (H&E, 100×)

(Fig. 11.17c) and others may appear granulomatous. The tumor may occasionally show invasion of sub-peritoneal tissue such as the omentum. Intra-abdominal lymph nodal involvement may also be identified in some instances. The cytology of the tumor cells may vary, but vague apical cytoplasmic protrusions are commonly seen as well as moderate-to-severe nuclear pleomorphism. Although there is more nuclear pleomorphism and mitotic activity than in benign mesothelial tumors, the nuclear pleomorphism and frequency of mitotic figures are much less pronounced than those seen in low-grade serous adenocarcinoma (Fig. 11.18). Compared to pleural malignant mesothelioma, abdominal malignant mesothelioma may have the following unusual morphological characteristics: (a) Decidualization (Fig.  11.19) characterized by solid sheets of polygonal eosinophilic tumor cells with abundant cytoplasm, well-demarcated cell borders, and prominent nucleoli [40]. Two-thirds of this subtype occurs in females, even as early as in adolescence. This rare subtype is associated with a high mortality rate. (b) Biphasic differentiation, which is uncommon. (c) Rare tumors may be associated with marked inflammatory infiltrate (Fig.  11.20), often with lymphoid follicles. Others may be entirely replaced by fibrous tissue, resulting in diagnostic challenge. (d) Localized malignant mesothelioma: These tumors should be distinguished from diffuse malignant mesothelioma because of their localized presentation and better prognosis. These are localized circumscribed lesions of the serosal membranes having similar microscopic appearance to that of diffuse variant. The median age is 63 with male preponderance (male/female 2:1).

Most patients were alive and free of disease on followup between 18 months and 11 years [38]. 4. Immunohistochemical characteristics: Immuno­ histochemistry is critical to the accurate diagnosis of mesothelioma. Mesotheliomas are frequently positive for specific tumor markers, e.g., calretinin, WT-1, CK 5/6, and mesothelin (Table 11.2). Rarely, rather less specific markers, e.g., D2-40 and h-caldesmon, are positive. Similar to serous tumors, malignant mesothelial cells are often positive for pancytokeratins, EMA, CK7, and CA125. In contrast to serous tumors, malignant mesothelial cells do not express CEA, LeuM1, B72.3, Ber-EP4, ER, and PR. However, some ovarian or peritoneal serous tumors may not express CEA and LeuM1. Therefore staining with B72.3, Ber-EP4, and other more specific markers may be a better panel to be used in distinguishing these two entities [41, 42]. 5. Ultrastructure: Mesothelial cells are characterized by long slender microvilli whereas in adenocarcinoma the tumor cells demonstrate short, stout microvilli. Malignant mesothelial cells may contain cytoplasmic glycogen but not mucin. Intermediate filaments may be present near the nuclei. 6. Differential diagnosis: Differentiating diffuse malignant mesothelioma from atypical mesothelial hyperplasia, diffuse fibroblastic malignant mesothelioma, and reactive fibrosis is already briefly discussed previously in this chapter. Differentiating diffuse malignant mesothelioma from pelvic high-grade serous adenocarcinoma is the most important, yet most difficult, distinction to be made. The characteristics of these two tumors are summarized in Table 11.2. Features supporting a diagnosis of mesothelioma include prominent tubulo-papillary structures, follicular tumor cells, moderate amount of eosinophilic cytoplasm,

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a

377

b

c

Fig. 11.17  Diffuse malignant mesothelioma. (a–b) Papillary and tubular structures may be present (H&E, 200×). (c) Diffuse solid sheet pattern (H&E, 200×)

Fig. 11.18  Diffuse malignant mesothelioma. The tumor cells may show moderate nuclear atypia with relatively constant nuclear cytoplasmic ratio (H&E, 400×)

mild-to-moderate nuclear atypia, fewer mitosis, and presence of acidic mucin (Alcian Blue positive). The most specific immunohistochemical markers for adenocarcinoma are B72.3, Ber-Ep4, and MOC-31, while calretinin (Fig.  11.21) and h-caldesmon are relatively specific for mesothelial lesions. The deciduoid pattern of abdominal malignant mesothelioma must be differentiated from an abdominal ectopic decidual reaction. Malignant mesothelioma typically forms masses and displays significant cytologic atypia. The tumor cells are positive for cytokeratin, whereas decidual cells are negative (Fig. 11.19). 7. Treatment and prognosis: No effective treatment for diffuse malignant mesothelioma is available to date. Primary surgical resection with adjuvant chemotherapy is still being studied. The mortality rate is nearly 100%. Most patients survive less than a year from diagnosis.

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M. Ruhul Quddus et al. Table 11.2  Diffuse malignant mesothelioma versus high-grade serous adenocarcinoma Characteristics Clinical  History of asbestos exposure  Diffuse abdominal tumor

Fig. 11.19  Diffuse malignant mesothelioma. Tumor cells show conspicuous deciduoid change (HE, 600×)

 Response to chemotherapy Histology  Biphasic differentiation  Columnar cells  Psammoma bodies  Nuclei  Mucin secretion

Ultrastructure  Tonofilaments  Cilia  Intracytoplasmic lumens  Apical snouts  Immunohistochemistry

Fig. 11.20  Diffuse malignant mesothelioma. Tumor may be associated with significant fibrosis and inflammatory infiltrates (H&E, 200×)

11.1.5 Miscellaneous Primary Neoplasms 11.1.5.1  I ntra-abdominal Desmoplastic Small Round Cell Tumor (DSRCT) Intra-abdominal desmoplastic small round cell tumor (DSRCT) is an infrequently encountered undifferentiated tumor seen in adolescents and young people. The origin of the tumor, whether or not from primitive mesothelium, remains unclear. Most tumors arise in the abdomen, although some pleura-based cases have also been reported [43]. DSRCT is more commonly seen in males (male-to-female ratio of 4:1). The average age is 25  years. Typical clinical symptoms include abdominal distention, pain, and palpable mass. Some patients may present with ascites. In females, the disease may be confused with primary ovarian tumors when limited to the pelvis.

Diffuse malignant mesothelioma

High-grade serous adenocarcinoma

Often

None

Yes

Predominantly ovarian and pelvic involvement Partial response

No response. Typically lethal Present Rare Rare Rounded Acidic cytoplasmic mucin

Absent Prominent Often Oval or elongated Apical neutral mucin

Abundant Rare Often seen

Rare Abundant Rarely seen

Rare Ber-Ep4 (−), CA 19-9 (−), Leu M1 (−), MOC-31 (−), calretinin (+), h-caldesmon (+), WT-1 (+)

Often seen Ber-EP4 (+), CA 19-9 (+), Leu M1 (+), MOC-31 (+), calretinin (−), h-caldesmon (−), WT-1 (+)

1. Microscopic examination: The tumor is composed of small epithelioid cells forming round or irregular islands tucked in dense fibrous stroma, hence the name (Fig. 11.22a). Rosettes, glands, and basal palisading pattern may be seen. Under low power, central necrosis and focal calcifications are frequently present. On high power, the tumor cells appear morphologically similar, with scant cytoplasm and indistinct cell borders (Fig. 11.22b). Sometimes the tumor cells may appear as striated muscle cells with abundant eosinophilic cytoplasm and eccentric nuclei. Abundant mitoses, single-cell necrosis, and lymphovascular space invasion are frequently seen. 2. Immunohistochemical phenotypes: Immunohistochemical staining confirms that DSRCT displays a variety of differentiation [44–46]. Almost all tumors express epithelial markers CAM5.2 and AE1/AE3 but they do not express CK20. About 4/5 of the tumors express EMA, NSE, desmin (with perinuclear punctated distribution), and vimentin. 2/5 to 2/3 of the tumors express Ber-EP4, CD57 (Leu-7), CD15 (Leu-M1), and CA125. Another 90% of cases are positive for WT1. WT1 is not helpful in differentiating small-cell carcinoma from juvenile granulosa cell tumors. It has been reported that intra-

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abdominal desmoplastic round cell tumors react to WT1 (C-­terminal) in contrast to serous carcinomas of the ovaries/fallopian tubes and mesotheliomas which typically react to N-­terminal of WT1 [47]. The combined immunohistochemical characteristics are helpful in differentiating this tumor from other diagnostic considerations. 3. Genetics: This tumor frequently contains a translocation of t(11;22)(p13;q12) resulting in fusion of EWS1 gene on chromosome 22 with Wilms tumor-suppressor gene (WT1) on chromosome 11 [48, 49]. This fused EWS/WT1 may be detected using RT-PCR.  This translocation is unique to this tumor and therefore its detection confirms the diagnosis [50].

Fig. 11.21  Diffuse malignant mesothelioma. Tumor cells are diffusely positive for calretinin (IHC, 200×)

a

379

4. Differential diagnoses: DSRCT should be differentiated from several other small round blue cell neoplasms such as neuroblastoma, extra-skeletal Ewing sarcoma, primitive neuroectodermal tumor, immature teratoma, lymphoma, rhabdomyosarcoma, rhabdoid tumor, poorly differentiated stromal tumors, adult-type or juvenile granulosa cell tumor, and small-cell carcinoma associated with hypercalcemia. In general, the age of the patient, lack of extra-abdominal primary tumor, tumor distribution, and characteristic microscopic and immunohistochemical staining patterns help support a diagnosis of DSRCT. DSRCT reacts to C-terminal of the WT1 which is helpful to differentiate from some of the tumors discussed here as the others react with the N-terminal of WT1. The EWS/WT1 gene fusion can be detected by RT-­ PCR and the presence supports the diagnosis of DSRCT. The presence of unusual features such as tubular, glandular, cystic, papillary, anastomosing trabecular, and single-cell cord-like patterns may contribute to diagnostic difficulty. Chromosome analysis usually clinches the diagnosis. 5. Treatment of prognosis: Patients with DSRCT require chemotherapy and radiation therapy after surgical resection. Neoadjuvant chemotherapy has also been adopted. Some patients may benefit from bone marrow transplantation. Unfortunately more than 90% of patients die of the disease despite aggressive therapy.

11.1.5.2  Inflammatory Myofibroblastic Tumor Inflammatory myofibroblastic tumor has had many synonyms in the past, e.g., inflammatory pseudotumor, plasma cell granuloma, fibrous xanthoma, pseudo-sarcoma, lymphoid hamartoma, myxoid hamartoma, inflammatory myo-

b

Fig. 11.22  Intra-abdominal desmoplastic small round cell tumor (DSRCT). (a) Low-power view shows cluster of small round blue cells separated by abundant fibrous stroma (H&E, 200×). (b) High-power view shows rather uniform neoplastic cells with scant cytoplasm and inconspicuous cell border (H&E, 400×)

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Fig. 11.23  Inflammatory myofibroblastic tumor appears as scar-like tissue with dark-staining nuclei of myofibroblastic cells (H&E, 200×)

fibrohistiocytic proliferation, and benign myofibroblastoma. The etiology of this entity is unknown. It may originate in diverse anatomic sites including the lung, mesentery, omentum, and retroperitoneum [51, 52]. Histologically the tumor is composed of spindle-shaped myofibroblastic cells accompanied by a varying amount of collagen fibers and inflammatory infiltrate. Inflammatory myofibroblastic tumor is typically found in females less than 20 years old. Patients may present with fever, general malaise, weight loss, chronic anemia, thrombocythemia, polyclonal hypo-­ gammaglobulinemia, splenomegaly, and a mass in the mesentery. There are three histologic patterns: nodular fasciitis-like, fibrohistiocytic-like, and fibroma (or cicatrix)like (Fig. 11.23). The pathogenesis of the disease remains unknown; however, 50–60% of the cases show a point mutation at 2p23, involving the ALK gene [53, 54], which may play an important role in the pathogenesis of this tumor. Some authors currently believe that this entity may in reality represent a group of diseases with diverse etiology and pathogenesis, ranging from reactive changes to a lowgrade neoplasm with potential for local recurrence or even metastasis. Solitary Fibrous Tumor Solitary fibrous tumor, a primary mesenchymal tumor possibly composed of sub-mesothelial fibroblasts, was ­ previously known as fibrous mesothelioma. This benign tumor is typically discrete and well demarcated [55–57]. The tumor is often seen in the pleura. The clinical presentations and immunohistochemical characteristics of peritoneal and ­ pleural solitary fibrous tumor are similar. Although rarely infiltrative, most patients are cured after surgical resection [58], although recurrence has been reported in some cases [59].

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1. Gross examination: The size of tumor varies from 1 to 20  cm. It is usually solitary and surrounded by fibrous tissue. 2. Microscopic examination: Solitary fibrous tumor has been classified into three distinct histological subtypes. (a) Nonspecific type: This tumor is formed by coarse sclerotic collagen fibers associated with elongated slits. The tumor cells are elongated and inconspicuous (Fig. 11.24a). (b) Vascular tumorlike with branching staghorn blood vessels. (c) Cellular type: This type is characterized by benign spindle cells with varying cellularity organized in a sheetlike pattern (Fig. 11.24b). (d) Mixed type: Showing features of both nonspecific and cellular type. 3. Immunohistochemical phenotypes: The tumor cells may express vimentin, CD34 (Fig.  11.24c), and BCL–2, but are negative for cytokeratin, actin, S100, CD31, and desmin. These immunohistochemical characteristics help differentiate this tumor from mesothelioma. Solitary fibrous tumor should also be differentiated from gastrointestinal stromal tumor (GIST) with the latter expressing c-kit (CD117).

11.1.5.3  O  mental Mesenteric Myxoid Hamartoma This rare tumor was first reported in three infants in 1983 [60]. In these cases, multiple tumor nodules were found in the omentum and mesentery, which were characterized ­histologically by plump mesenchymal cells in a myxoid, well-­vascularized stroma. They were initially diagnosed as sarcomas, including liposarcoma, primitive sarcoma, or ­leiomyosarcoma; however, long-term follow-up showed no evidence of recurrence after surgical removal of the tumor. This tumor is now classified as a hamartoma or a variant of myofibroblastic tumor [60].

11.1.6 Secondary Neoplasms The peritoneum may serve as a generous receptacle for secondary neoplasms either by direct spread or by metastasis from intraabdominal or pelvic organs sites, e.g., fallopian tubes, ovaries, breasts, colon, appendix, stomach, and pancreas. Metastatic tumors to the peritoneum can be divided into two major categories: mucinous or serous, with the ­former originating from the gastrointestinal tract and latter generally thought to be from the gynecologic tract. A better understanding of mucinous tumors secondarily involving the peritoneum has been achieved lately; however, the pathogenesis of high-grade serous carcinoma involving peritoneum is still evolving (see the segment on Müllerian tumors below).

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Fig. 11.24  Solitary fibrous tumor. (a) Nonspecific solitary fibrous tumor is composed of coarse collagen fibers accompanied by elongated slit-like spaces. The tumor cells are elongated and inconspicuous (H&E, 200×). (b) Cellular type solitary fibrous tumor is composed of highly cellular benign spindle cells (H&E, 400×). (c) CD34 immunostain positivity of solitary fibrous tumor (IHC, 100×)

11.1.6.1  Pseudomyxoma Peritonei (PMP) Secondary mucinous involvement of the peritoneum is known as pseudomyxoma peritonei (PMP), but the terminology is not specific as the term is used to describe several clinical scenarios where the patient presents with mucinous ascites [61–63]. In the past most authors considered pseudomyxoma peritonei to originate from the ovary. This was because more frequently than not, both ovaries were also involved, and demonstrated histological features of mucinous borderline tumor. In recent years it has being shown that the majority of pseudomyxoma peritonei originate from the gastrointestinal tract, most commonly from the vermiform appendix, while some originate from the colorectum, or rarely from the pancreas and biliary tract [64, 65]. A few cases of pseudomyxoma peritonei have been found to be associated with ovarian mucinous borderline tumors associated with ovarian mature cystic teratomas [66– 68]. Genetic studies have revealed that most pseudomyxoma peritonei express the MUC2 protein, which is only expressed

in goblet cells of gastrointestinal tract and not by ovarian mucinous tumors. Some scholars have suggested that pseudomyxoma peritonei does not arise from ruptured ovarian tumors; on the contrary, the associated ovarian borderline tumors are in fact secondary or metastatic lesions [69]. 1. Clinical characteristics: The clinical symptoms of pseudomyxoma peritonei are vague and nonspecific. They typically occur in patients ranging from 33 to 82  years (mean 47  years) of age. Patients may present initially with abdominal distention, pain, or fullness depending on the severity of disease. With disease progression, more mucin accumulates, increasing abdominal distention, which can be accompanied by a mechanical or functional ileus. On rare occasions patients may incidentally be diagnosed during surgical procedures or hernia repair. 2. Pathologic findings: A low-grade mucinous neoplasm of the vermiform appendix is the leading source of second-

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Fig. 11.26  Abundant acellular mucin pool dissecting peritoneum partially surrounded by reactive mesothelial cells (H&E, 200×)

Fig. 11.25  Appendiceal mucinous neoplasm. Low-power view showing muscular wall of the appendix infiltrated by the mucinous tumor (H&E, 100×)

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Fig. 11.27  Low-grade mucinous neoplasm resulting in pseudomyxoma peritonei. (a) A few neoplastic cells are floating in the mucin pool (H&E, 400×); (b) occasionally intestinal type mucinous epithelium is recognizable (H&E, 400×)

ary peritoneal mucinous tumors (Fig. 11.25). The primary appendiceal mucinous lesions may range from mucinous adenomas to low-grade appendiceal mucinous neoplasms to frankly invasive adenocarcinoma [70]. Other sources of secondary peritoneal mucinous tumor are usually associated with high-grade colorectal adenocarcinoma with destructive invasion. Morphology of the epithelial component of PMP differs and such morphologic differences determine the clinical course and prognosis. Low-grade tumors usually demonstrate acellular mucin or scant, bland, mucin-­ containing epithelial cells floating in mucinous fluid (Fig. 11.26). The epithelial cells, when present, may be

similar to those of a hyperplastic polyp or low-grade mucinous neoplasm. Some authors prefer the term “acellular mucin” or mucinous epithelium consistent with pseudomyxoma peritonei. The peritoneal lesion may be accompanied by conspicuous fibroblastic reaction and reactive mesothelial cells. The ovaries may also show abundant acellular mucin with or without free-floating tumor cells dissecting the ovarian parenchyma (Fig. 11.27a). Intestinal type epithelium is usually evident (Fig. 11.27b). Various designations have been used in the literature describing this phenomenon, e.g., well-­ differentiated mucinous adenocarcinoma, disseminated peritoneal mucinous adenosis, and secondary low-grade

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Fig. 11.28  High-grade mucinous neoplasm of the gastrointestinal tract secondarily involving the peritoneum. (a) Mucin and neoplastic cells (mucicarmine, 200×). (b) Higher power view showing prominent nucleoli of the tumor cells (mucicarmine, 400×)

peritoneal mucinous neoplasm. The current authors favor 4. Immunohistochemical characteristics: Immunohis­ the designation of low-grade peritoneal mucinous tochemical staining characteristics of most peritoneal sec­neoplasm [70]. ondary mucinous neoplasms are similar to those of the High-grade mucinous neoplasms usually show more appendix, expressing a CK7−/CK20+ phenotype, as epithelial cells and moderate to marked nuclear pleomoropposed to the CK7+/CK20− phenotype seen in primary phism and prominent nucleoli (Fig.  11.28a, b). Signet-­ ovarian tumors. This supports the recent evidence that most ring cells, when present, should alert the pathologists to secondary peritoneal mucinous tumors originate from the search for gastric carcinoma or invasive lobular carciappendix. It is important to recognize that ­occasional appennoma of the breast. dicular tumors may be positive for both CK7 and CK20 in It is noteworthy that peritoneal secondary mucinous varying amounts. The positive staining should be diffuse tumors often involve bilateral ovaries, and can have strikand strong if to be supportive in differentiating one site from ing similarities to primary ovarian mucinous cystadenothe other; in some cases staining will be equivocal. mas, intestinal type mucinous borderline tumors, or 5. Pathology report: Pseudomyxoma peritonei is a clinical primary ovarian mucinous adenocarcinoma [71]. Cross term and therefore should not be used as a diagnosis in a sections of the tumor may reveal numerous cysts of varying pathology report. The pathology report should consider sizes containing abundant mucus. The ovarian capsule may (a) the nature of the appendiceal or ovarian tumor (benign, be involved, and therefore must be differentiated from borderline, or malignant), and whether the primary lesion mechanical involvement of acellular mucin associated with was ruptured; (b) the nature of the intra-abdominal disa ruptured ovarian primary mucinous tumor. It is important ease, classified as acellular mucinous ascites, cellular to note that some mucinous tumors metastatic to the ovamucin, organizing mucin, or septated (lobulated) mucin; ries may undergo “reverse maturation” causing their epiand (c) the grade of the epithelium if present in the mucin thelium to appear similar to that seen in a mucinous (benign, borderline, or malignant). Pathology reports that cystadenoma; therefore, the determination of primary verexplicitly characterize these components help clinicians sus secondary ovarian mucinous lesions should not be plan appropriate management of these cases. based on the identification of “precursor” epithelium. 6. Treatment and prognosis: The clinical course of a peri 3. Sampling: Proper and adequate sampling of peritoneal toneal secondary mucinous tumor is determined by the secondary mucinous neoplasms is paramount. All lesions presence or absence of neoplastic cells within the should be extensively sampled, including grossly normal mucin, their grade, and the mucin volume [72]. Intravermiform appendix. The vermiform appendix should be abdominal ascites with acellular mucin is associated entirely submitted for microscopic examination to deterwith better prognosis. The clinical course may be indomine the nature of any epithelial lesion, and to establish lent if the mucinous epithelial cells appear benign or primary source of the tumor. Immunohistochemistry and mildly atypical. Patients whose mucinous ascites is molecular characterization may be needed to determine associated with mucinous adenocarcinoma may be the origin of the tumor. associated with lymph node or visceral metastasis.

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These patients have a worse prognosis. The goals of surgical treatment include debulking with an intention to resolve or prevent mechanical obstruction and to preserve natural function as much as possible. For patients with an obviously malignant neoplasm, treatment usually consists of tumor debulking accompanied by intraperitoneal chemotherapy [73].

11.1.6.2  Gliomatosis Peritonei Gliomatosis peritonei is a rare disease, often associated with mature or less commonly immature teratomas of the ovaries. It presents as mature glial tissue on the surface of the peritoneum. In some cases the glial tissue may be the result of implantation of neuroglial tissue after the rupture of the ovarian teratoma. However, a recent molecular study showed that the glial tissue may also originate from the pluripotential peritoneal stem cells [74]. 1. Microscopy: The implants are typically composed entirely of glial tissue with no other component of the teratoma (Fig. 11.29a–c). Further classification of peritoneal gliomatosis is discussed in Chap. 8. 2. Treatment and prognosis: Most gliomatosis peritonei are either grade 0 or grade 1 (Fig. 11.30). These patients have good prognosis and do not require further treatment. Recurrence or malignant transformation may appear in patients with grade 2 or grade 3 diseases. These patients may require additional chemotherapy to control disease progression.

11.1.6.3  I mplanted Leiomyoma Following Morcellation Minimally invasive laparoscopic surgical procedures have recently been popularized in the USA because of shorter postoperative hospital stays and faster patient recovery. Laparoscopic hysterectomy with morcellation is one such procedure where bulky uteri with leiomyomata can be cut into smaller fragments inside the abdomen with the help of a morcellator and removed from the body through a smaller opening created in the anterior abdominal wall. The procedure was deemed to be fairly safe; however, unintended consequences have been encountered just a few years of the introduction of the procedure [75]. A number of incidental malignancies were reported in these morcellated specimens causing management challenges. Parasitic leiomyoma of the peritoneum is one of the less consequential events that have been encountered (Fig. 11.31a). These leiomyomas are often detected incidentally, even after many years of the initial intra-abdominal morcellation procedure. Patients with torsion of the peritoneal leiomyoma may present as acute abdomen, a medical emergency (Fig. 11.31b).

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11.2 S  ection 2: Diseases of the Müllerian System The concept of secondary Müllerian system was proposed in the late 1960s and widely accepted until the end of 1990s. The concept aimed to explain the pathogenesis of Müllerian lesions within and above the pelvic brim. Based on common embryogenesis from the coelomic membrane, it was theorized that Müllerian tissue be organized into primary and secondary Müllerian systems. The primary Müllerian system is composed of epithelial and stromal cells lining the unfused and fused segments of Müllerian ducts resulting in the fallopian tubes, uterus, uterine cervix, and upper third of the vagina, whereas similar tissue formed from metaplasia on the ovarian coverings, visceral serosa, free peritoneum, and omentum makes up the secondary Müllerian system [76]. Ovarian-peritoneal Müllerian diseases such as endometriosis, endosalpingiosis, ectopic deciduosis, disseminated peritoneal leiomyomatosis, and ovarian epithelial neoplasms were thought to arise from the secondary Müllerian system. The concept of a secondary Müllerian origin of these d­ iseases, proposed by Lauchlan, was based on indirect and circumstantial evidence [76, 77]. The following observations were made in favor of secondary Müllerian system: the majority of primary peritoneal carcinomas are of serous type, although tumors of other cell types have also been identified. The relative frequency of malignant serous tumors involving omentum is much higher than that of endometrioid carcinoma (15:1), so is the ratio of their benign counterparts of endosalpingiosis versus endometriosis (10:1). The inference drawn from this observation is that serous and endometrioid neoplasms may arise primarily in the omentum as well as anywhere in the gynecologic tract [78]. The presence of epithelial implants, with and without epithelial proliferation in the omentum, has been reported to be associated with a higher risk of recurrence in serous borderline tumor of the ovary even after bilateral salpingo-­ oophorectomy [79]. The overall proliferative activity of Müllerian epithelia may be the underlying risk factor for these neoplasms. This offers additional support that serous neoplastic proliferations in the peritoneum likely represent a field effect rather than a focal disease with widespread metastasis. Thorough examination of the epithelia of all Müllerian-derived reproductive organs in a series of ovarian carcinomas revealed presence of endometrial intraepithelial carcinoma (EIC), serous tubal intraepithelial carcinoma (STIC), and/or endometrial hyperplasia in more than half of the cases [80]. Coexistence of these preinvasive lesions was common and thought to represent field effect, although implantation of migrating tumor cells has also been postulated.

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Fig. 11.29  Gliomatosis peritonei. (a) Numerous small gray-white tubercles of various sizes and shapes in the omentum (gross photograph). (b) The small tubercles represent typical neurofibrillary tissue

Fig. 11.30  Gliomatosis peritonei. Grade 0 gliomatosis with uniform glial cells (H&E. 400×)

(H&E, 40×). Inset: Higher power view on the right (H&E, 100×, 200×). (C) positive staining for GFAP (IHC, 40×)

Recently a theory proposed that many lesions of the secondary Müllerian system probably are not primary tumors arising from malignant transformation of metaplastic epithelia in the peritoneum but rather are metastases from the fimbria of the fallopian tubes (see the chapter on fallopian tubes). This theory has gained traction such that bilateral salpingectomies are now widely performed whereas the ovaries are preserved, reversing a decades-old practice. Klymenko et  al., postulated that the epithelial ovarian tumors metastasize via transcoelomic route. The cells from the fallopian tube tumor detach from the primary site, either as a single cell or as a small group of cells, anchor themselves with the submesothelial matrix, and grow. This is possibly an example of a highly permissive microenvironment which allows epithelial-mesenchymal transition and vice versa [81]. This primary fallopian tube theory, although not totally free of challenge, began with an observation in early 2001

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Fig. 11.31 (a) Implanted leiomyoma following laparoscopic hysterectomy with morcellation (H&E, 20×). (b) Infarcted leiomyoma. Had morcellation 9  years ago, Now pregnant, and presented with acute

abdomen mimicking ruptured ectopic pregnancy. Gross and microscopy (H&E, 20×). Positive smooth muscle actin (SMA) immunostain (IHC, 20×)

when Peik et al. reported dysplastic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian carcinoma [82]. Crum et al. called attention to the distal fallopian tube and proposed that migrating tumor cells from the fallopian tube are an important source of serous carcinoma in the omentum, rather than arising in the peritoneum [83]. As a result of this theory, it has now been proposed that primary peritoneal serous carcinoma should only be diagnosed when ovarian parenchymal involvement is less than 5  ×  5  mm, involvement of extra-­ovarian sites are

larger than the involvement of the surface of either ovary, and total submission and examination of both fallopian tubes do not reveal any in situ or invasive carcinoma [84]. Investigators have recently used advanced molecular techniques to characterize the relationship between serous tubal intraepithelial carcinoma (STIC) and high-grade serous carcinoma (HGSC) in detail. They have found similarities between STIC and HGSC which may support the fallopian tube origin theory. Perhaps more interestingly it was also discovered that not all morphologically bona fide STICs are of

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tubal origin [85]. The fallopian tube mucosa can also be a receptacle for metastatic carcinomas arising elsewhere, and the authors cautioned pathologists to be extremely careful in diagnosing STIC without first considering the possibility of metastasis. Routinely used immunohistochemical stains can be used to determine if a STIC-like lesion is tubal or non-­ gynecologic in origin. PAX 8, WT1, CK7, ER-negative lesions mimicking STIC may represent metastatic tumors of non-gynecologic origin. CDX2 positivity will point towards a metastatic intestinal lesion. A word of caution here is that positive p53 immunoreactivity should not be considered diagnostic of STIC as metastatic breast and colon cancers may be p53 positive [86]. In the context of uterine and non-­ uterine HGSC, it may be argued that STIC may represent a metastasis rather than the site of origin, particularly when widespread disease is present. Although assigning a primary site of tumor has limited prognostic and therapeutic relevance in the case of a serous carcinoma with widespread pelvic and omental/peritoneal involvement, a recent attempt has been made to achieve that goal based on a survey of pathologists and clinicians [87]. It appears, at least as of now, that the origin of peritoneal serous carcinoma is still evolving. The validity of the secondary Müllerian system theory cannot be disregarded completely. The secondary Müllerian system, in theory, offers explanation for the pathogenesis of all types of Müllerian epithelia, e.g., serous, endometrioid, mucinous, and transitional, whereas the proposed fallopian tube origin theory can only explain the origin of serous-type epithelium in peritoneum. As late Stuart C.  Lauchlan once stated “Far from being a mere receptacle for metastasis from other sites, the omentum is an important source of primary peritoneal (secondary Müllerian system) carcinoma” [79]. As a result of the above discussion, it has been proposed that serous Müllerian tumors be designated as “pelvic serous carcinoma,” rather than arbitrarily assigned to a specific pelvic organ such as ovary, fallopian tube, or peritoneum.

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like lesion (Fig. 11.32b). The clinical and pathological characteristics as well as the pathogenesis of endometriosis are discussed in detail in Chap. 12.

11.2.2 Serous (Tubal Type Epithelium) Lesions Tubal type, or serous, epithelial lesions of the peritoneum include endosalpingiosis and serous neoplasms. Many controversies abound regarding the pathogenesis, interaction, and even definition of these lesions among the gynecologic pathology community. Primary serous adenocarcinoma of the peritoneum is defined as a serous adenocarcinoma involving primarily the peritoneum, with relatively uninvolved or only superficially involved normal ovaries. A set of criteria have recently been proposed as described earlier in this chapter [84]; however, using the size and distribution of tumor as absolute criteria to determine the origin of the disease was

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11.2.1 Endometriosis Endometriosis is defined as the presence of endometrial glands and/or stroma outside of the endometrium and myometrium; it is more commonly encountered in the pelvis than the peritoneum [79]. Endometriosis is typically seen in females of reproductive age as well as asymptomatic postmenopausal women. The most common locations involved are the ovaries, uterosacral ligament, round ligament, broad ligament, cul-de-sac, rectovaginal septum, serosal surfaces of the uterus, fallopian tube, rectosigmoid colon, ureters, and urinary bladder. Histologic diagnosis is relatively easy in the presence of both the epithelium and stroma (Fig.  11.32a). Marked decidual stromal reaction may give rise to a tumor-

Fig. 11.32  Endometriosis. (a) Endometrioid epithelium is surrounded by endometrial stromal cells (H&E, 200×). (b) Marked decidual stromal reaction may lead to a “mass-like” lesion; inset: higher magnification (left H&E, 20×; right H&E, 400×)

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disputed by some workers as they have suggested that most high-grade serous adenocarcinomas may derive from early serous lesions of the fimbria and become widely disseminated in the peritoneum. Low-grade serous adenocarcinoma is felt to arise possibly from implants of papillary carcinoma of the ovaries (serous borderline tumors of the ovaries, or even micropapillary serous borderline tumors). Primary serous adenocarcinoma of the peritoneum may be rare, but is certainly not nonexistent.

11.2.2.1  Endosalpingiosis Endosalpingiosis is the presence of benign tubal type epithelium in the peritoneum, sub-peritoneal tissue, or retroperitoneal lymph nodes; it is more frequently encountered in the peritoneum compared to the pelvis [79]. The pathogenesis of endosalpingiosis remains unknown. It was thought to arise from implanted desquamated tubal epithelium from ­chronically inflamed fallopian tubes, similar to the implants arising from serous borderline tumor. An alternate explanation was that endosalpingiosis is a metaplastic process of the secondary Müllerian system. Given the recently proposed theory on the role of early tubal lesions of the fimbria in the pathogenesis of serous tumors, the metaplastic theory of secondary Müllerian system has been revisited. To avoid confusion, some investigators suggested using the term “serous change” instead of endosalpingiosis. Endosalpingiosis is reported to be ten times more frequent than endometriosis in the peritoneum, whereas in the pelvis the ratio is reversed [79]. 1. Gross examination: The lesion is most commonly seen on the serosa of the uterus, fallopian tubes, ovaries, and uteroa

Fig. 11.33  Endosalpingiosis. (a) The glandular epithelial cells show characteristic tubal “serous”-type epithelium with readily visible cilia. Note the absence of endometrial stroma (H&E, 400×). (b) Virilization

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rectal pelvic peritoneum. It is typically grossly invisible, although some may appear as multiple small (1–2  mm) white or yellow spots. Alternatively, the lesion may appear opaque or as semitranslucent cysts or granules. 2. Microscopic examination: Endosalpingiosis may appear as rounded, oval, or cystically dilated glands with no stroma. The outline of the focus may be somewhat irregular with slightly crowded glandular epithelium, occasionally with intraluminal papillary protrusions. The glands are lined by a single layer of tubal type epithelium (Fig. 11.33a), composed of all three epithelial cells of the normal fallopian tube: pale ciliated cells, secretory cells, and slightly darker peg cells, typically with no cytologic atypia or mitosis. The glands are surrounded by dense connective tissue but not endometrial stroma. Occasional mononuclear inflammatory cells may be present. Psammoma bodies may be present within the lumen or nearby stroma. Epithelial tufting, or more complex epithelial growth, may be seen and some authors have designated these lesions “proliferative endosalpingiosis” [79, 80]. Rarely endosalpingiosis may display cytologic atypia described as “atypical endosalpingiosis.” The lining epithelium appears stratified with varying degrees of cytologic atypia but lacks the characteristics of a typical serous borderline tumor. Atypical endosalpingiosis may coexist with peritoneal serous borderline tumor. 3. Differential diagnosis: There is much controversy in differentiating atypical endosalpingiosis from peritoneal serous borderline tumors (see below). The differences between endosalpingiosis and serous borderline tumor are shown in Table 11.3. b

of Müllerian duct remnant in a transgender receiving exogenous androgen therapy (H&E, 600×)

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Table 11.3  Endosalpingiosis versus serous borderline tumor

Location Structure

Endosalpingiosis Surface or under the peritoneum Single round or oval glands

Cytology

No pleomorphism

Interstitial reaction

Absent

Serous borderline tumor (primary and implants) Surface or under the peritoneum Single glands, often associated with papillary cell clusters, isolated cell clusters, and psammoma bodies Mild-to-moderate pleomorphism, stratified epithelium May or may not show desmoplasia

Another differential diagnosis consideration is mesonephric duct remnants. Mesonephric duct remnants typically occur next to the fallopian tubes or within the broad ligaments. Mesonephric remnants are typically lined by a single layer of cuboidal or low-columnar epithelium without cilia and are surrounded by layers of smooth muscle. Virilization of the mesonephric remnants has recently been described in female-to-male transgender patients receiving testosterone therapy (Fig. 11.33b) [88].

11.2.2.2  Peritoneal Serous Borderline Tumor Peritoneal serous borderline tumors are morphologically identical to ovarian serous borderline tumors. Currently many unresolved issues exist pertaining to its definition, etiology, and related pathology. It is usually associated with infertility or chronic lower abdominal pain, typically in women under 35  years. The tumor presents in the peritoneum, outside of the ovaries, with localized or disseminated, miliary or granular lesions accompanied by pelvic peritoneal and omental fibrous adhesions. Peritoneal serous borderline tumors may arise from peritoneal endosalpingiosis or proliferative endosalpingiosis. 1. Microscopic examination: Peritoneal serous borderline tumors may present with papillary structures with cellular stratification, small clusters of epithelial hyperplasia, and interspersed loose cell clusters. Nuclear pleomorphism and mitosis may be present but there is no true invasion (Fig. 11.34). Morphologically it may be similar to noninvasive, desmoplastic implants of ovarian serous borderline tumor. Up to 85% of cases are associated with endosalpingiosis. The survival rate is reported to be 95%, which is similar to that of noninvasive peritoneal implants of ovarian serous borderline tumors [89]. 2. Implants: Most peritoneal implants associated with serous tumors arise from ovarian serous borderline tumor. They can be subclassified as noninvasive and

Fig. 11.34  Serous borderline tumor of the peritoneum. Morphologically identical to ovarian serous borderline tumor (H&E, 200×)

invasive implants. Noninvasive implants can further be subclassified as desmoplastic or non-desmoplastic (epithelial) implants. It may be difficult to differentiate desmoplastic noninvasive implants from invasive implants. The following features may be helpful: Noninvasive implants are characterized by localized nondestructive fibroblastic growth. Clinically they appear as fibrous plaques the surgeon can easily strip from the underlying tissue. The relative ratio of epithelial cells to desmoplastic tissue is low, especially when compared to invasive implants. Conversely, invasive implants are characterized by epithelium-rich, disseminated, irregular, destructive growth equivalent to low-grade serous carcinoma. The typical lobular architecture of the omental fat is disturbed. Clinically it is important to differentiate noninvasive implants from invasive implants because the treatments and prognosis are entirely different. Invasive implants have now been considered as low-grade serous carcinoma. Pathological characteristics of these two lesions are summarized in Table 11.4. It is worth mentioned that these two lesions may be present concurrently in the same patient (Figs. 11.35, 11.36, and 11.37). Occasionally the epithelial lining of noninvasive implants may present with atypical features such as papillary, solid, cribriform, sievelike, or clustering patterns [90–92]. These growth patterns are generally considered features of malignancy, but most experts agree that if these abnormal features are localized and confined, their clinical significance may be similar to that of microinvasion of ovarian serous borderline tumor, with no significant adverse effects on prognosis [93, 94] (see Chap. 5 for additional morphological characteristics and further discussion).

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Table 11.4  Noninvasive implants versus invasive implants Histology

Noninvasive implants Well demarcated and distinct from the underlying tissue Involve interstitial spaces of omentum with intact omental lobules, well demarcated Nonsolid or cribriform structures with small nests or isolated tumor cells surrounded by small clefts

Cytology

None to moderate nuclear pleomorphism, rare mitoses

Ancillary tests Surgical stripping

Diploid Easy to strip off

Invasive implants Irregularly infiltrate visceral peritoneum or omental adipose tissue with destructive growth pattern Involve interstitial spaces of omentum resulting in destruction of normal adipose lobules; reactive fibrosis surrounds adipose cells Solid sheets or non-­ cribriform tumor growth extending beyond desmoplastic fibrosis; prominent clefts around tumor cells and abundant isolated tumor cells Prominent nuclear pleomorphism, abundant mitoses, and atypical mitoses Diploid or aneuploid Difficult, may result in bleeding or perforation

Sometimes it may be difficult to determine if an implant is associated with invasion or not. Biopsy tissue may be too small and overtly calcified, or may have processing artifacts. In these instances, it may be essential to designate this lesion as “implant, invasion indeterminate.” 3. Differential diagnosis: Compared with ovarian serous borderline tumors, there are both similarities and differences. Some diagnostic dilemmas exist: (A) How to differentiate primary peritoneal serous borderline tumor from peritoneal implants associated with ovarian serous borderline tumor, and more importantly whether there is any clinical significance? (B) Is the biological behavior of peritoneal serous borderline tumor different from ovarian serous borderline tumor with peritoneal implants? (C) What is the definition of atypical endosalpingiosis? Does it exist? And if so, does it give rise to peritoneal serous borderline tumor? (D) When accompanied by desmoplasia, how to differentiate desmoplastic implants of ovarian serous borderline tumor from primary peritoneal serous carcinoma? (E) How to differentiate invasive implants from noninvasive implants especially when the lesions elicit conspicuous fibrous stromal reaction. 4. Prognosis: The prognosis of peritoneal serous borderline tumor is largely determined by FIGO staging, the presence or absence of invasive implants, and the quantity of postoperative residual disease. Recent studies have shown that 16% of patients with extra-ovarian disease suffered recurrence or died of disease [95]. Another study demon-

strated that the presence of noninvasive implants has negative impact on long-term prognosis [96] with recurrence in 44%. Survival in this study ranged among 10% less than 5 years, 19% between 5 and 10 years, 10% between 10 and 15 years, and 5% for more than 15 years. The presence of invasive implants (i.e., low-grade serous carcinoma) and grossly visible residual disease are major adverse prognostic indicators. Studies have shown that the average time to recurrence may be as early as 2 years, and after recurrence many patients progress to low-grade serous adenocarcinoma [97]. Only a minor fraction of patients respond to chemotherapy.

11.2.2.3  Malignant Neoplasms Low-Grade Peritoneal Serous Carcinoma (LGSC) The morphology of low-grade peritoneal serous carcinoma (LGSC), including psammocarcinoma, is similar to that of invasive implants of serous borderline tumors, characterized by the presence of papillary growth pattern (Fig. 11.38) [98]; as a result invasive implants are now being considered as low-grade serous carcinoma. The cells in LGSC are generally of low nuclear grade, lack frequent mitosis, have absent to rare atypical mitosis, and lack lymphovascular space invasion. Solid growth may be observed. The average age is between 50 and 60  years. Atypical clinical presentations include abdominal pain or mass-forming lesions. More than 40% of patients are diagnosed incidentally. The primary differences between low-grade peritoneal serous carcinoma and peritoneal serous borderline tumor are the presence of stromal invasion and confluent growth that may be seen in the former. On rare occasions progression of a low-grade peritoneal serous carcinoma to a high-grade serous carcinoma may occur [99]. Psammocarcinoma is a subtype of low-grade peritoneal serous carcinoma characterized by having psammoma bodies in more than 75% of the papillary growths or cell nests (Fig.  11.39) along with the presence of stromal invasion. There may be slight nuclear atypia. Typically, the tumor cell nests are composed of less than 15 cells. The patients are typically around 40  years old, presenting with abdominal pain or masses. Careful sampling of the excised specimen is required to rule out the presence of concomitant high-grade serous adenocarcinoma. The prognosis of low-grade peritoneal serous carcinoma and peritoneal psammocarcinoma is fairly good. No patient deaths due to psammocarcinoma are recorded in the literature [100, 101]. The long-term prognosis remains unclear due to limited case reports available. High-Grade Peritoneal Serous Carcinoma (HGSC) In the past, the incidence of primary peritoneal serous adenocarcinoma was one-tenth that of ovarian serous adeno-

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a

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Fig. 11.35  Noninvasive implant. (a) Solitary implant is seen on the surface of the peritoneum (H&E, 40×). (b) Typical features of serous borderline tumor seen in higher power view (H&E, 200×). (c) Desmoplastic noninvasive implant (H&E, 40×). (d) Immunostaining with pancytokeratin shows preponderance of stroma over actual

e­ pithelia (IHC, 40×). (e) Higher magnification shows prominent fibrous tissue surrounding small clusters of tumor cells or single tumor cells without tissue invasion (H&E, 200×) (a, c, d, and e: courtesy of W. Dwayne Lawrence, MD)

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Fig. 11.36  Comparing noninvasive implant and invasive implant. (a) Noninvasive implant with papillary proliferations between fat lobules in the omentum. No invasion into surrounding adipose tissue (H&E,

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b

100×). (b) Invasive implants with abundant tumor growths destroying fat lobules of the omentum (H&E, 40×) (B: courtesy of W.  Dwayne Lawrence, MD)

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Fig. 11.37  Invasive implant. (a) Invasive implant in the intestinal wall (H&E, 20×). (b and c) Invasive implants diffusely present in the omental adipose tissue (H&E, 20×). (d) Higher magnification view shows

tumor cells resembling low-grade serous carcinomatous cells surrounded by clefts (H&E, 400×)

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Fig. 11.38  Gross (left) and microscopy of low-grade peritoneal serous adenocarcinoma with small papillary clusters of tumor cells surrounded by fibrovascular stroma (H&E, upper right 40×, lower right 200)

Fig. 11.39 Psammocarcinoma, a low-grade peritoneal serous adenocarcinoma with more psammoma bodies than neoplastic cells. Gross picture is on the left, low-power view of the microscopic picture is on the upper right, while magnified view is on the low right (gross photo: courtesy of W. Dwayne Lawrence, MD)

carcinoma [102]. The traditional criteria for diagnosis of peritoneal serous adenocarcinoma included (a) size of bilateral ovaries being normal or near normal; (b) the tumor being present mostly in the peritoneum, with only limited tumor involvement on the surface of bilateral ovaries; (c)

microscopically absent tumor in the ovary, or tumor limited to the surface of bilateral ovaries without parenchymal invasion; (d) tumor present on the surface as well as parenchyma of the ovary, but tumor size less than 5  mm2; (e) ovarian parenchymal involvement, with tumor size less

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than 5 mm2; and (f) the histology of the tumor being similar to that of ovarian serous adenocarcinoma of any grade. The above criteria were based mainly on the size and distribution of the tumor, which was rather arbitrarily defined. In recent years, it has been proposed that most ovarian and peritoneal serous adenocarcinomas arise from the fimbria of the fallopian tube. This new school of thought challenged the traditional concepts, terminology, and diagnostic criteria of pelvic serous adenocarcinoma [103]. As a result, many previously diagnosed primary peritoneal serous adenocarcinomas would now be considered to arise from the fallopian tube. Female patients with BRCA gene mutations are at a higher risk for developing these tumors (see chapter on fallopian tube) [104, 105]; however, this theory has only gained acceptance in cases of serous neoplasia. Tumors of other histologic subtypes cannot be explained by this proposed theory. Recent proposed guidelines in the diagnosis of primary peritoneal HGSC are discussed earlier in this chapter. Immunohistochemical staining is of little value in differentiating these tumors. Unlike endometrial serous adenocarcinoma which lacks WT-1 expression, peritoneal, ovarian, and fallopian tube serous adenocarcinomas all express WT-1. Peritoneal serous adenocarcinoma should also be differentiated from diffuse malignant mesothelioma, especially the papillary variant. Malignant mesothelioma expresses calretinin, h-caldesmon, and CK 5/6, whereas peritoneal serous adenocarcinoma expresses Ber-EP4 and B72.3 (see previous section). The clinical presentation of patients with peritoneal serous adenocarcinoma is similar to that of ovarian serous adenocarcinoma. The patients are typically between 50 and 60  years old. The clinical symptoms are nonspecific, with many presenting with abdominal distention, gastrointestinal discomfort, increased abdominal girth, and constipation. Physical examination may reveal abdominal or pelvic masses, with or without ascites. Serum CA 125 may be elevated. The lifetime risk of ovarian carcinoma in BRCA1 gene-mutated patients is estimated to be 20–50% [106, 107], whereas the lifetime risk of ovarian carcinoma in a BRCA2 gene-mutated patient is 15–30% [106, 107]. Peritoneal serous adenocarcinoma typically presents as an omental cake. The peritoneal surfaces are covered by disseminated tumor nodules or solid masses. Most nodules are located on peritoneal surfaces with invasion into the subepithelial mesenchyme, especially omental adipose tissue. Theoretically, the ovarian tissue should remain normal, and only have surface involvement, or minimal involvement as described above (Fig. 11.40). Certain subtypes of peritoneal serous carcinoma may grow on the surface of the peritoneum without tissue invasion, and therefore may be confused with malignant mesothelioma or peritoneal adenocarcinoma of an unknown primary.

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Fig. 11.40 High-grade peritoneal serous adenocarcinoma. Tumor cells may form solid sheet or papillary structures with highly atypical nuclei (H&E, 400×)

The prognosis and management of high-grade peritoneal serous adenocarcinoma are similar to those of ovarian high-­ grade serous adenocarcinoma. The most important prognostic indicators are the stage of the tumor, whether optimal tumor debulking is achieved, and tumor response to chemotherapeutic agents. The average 5-year survival rate is approximately 40%.

11.2.3 Mucinous Diseases 11.2.3.1  Endocervicosis Peritoneal endocervicosis is defined by the presence of benign endocervical type mucinous epithelium in the peritoneum. This condition is exceedingly rare and may involve the serosa of the uterus, urethrorectal cul-de-sac, vaginal apex, paracervical soft tissue, and urinary bladder according to isolated case reports [108, 109]. When the urinary bladder is involved, it typically occurs in the posterior wall and dome. Microscopic examination shows benign endocervical type glands present between smooth muscle layers of the lamina propria (Fig. 11.41). A few case reports described the presence of infiltrative growth pattern, slight epithelial atypia, and a periglandular stromal reaction [109]. These features may falsely lead to the impression of well-­differentiated adenocarcinoma. The pathogenesis of endocervicosis remains controversial. Proposed theories include peritoneal metaplasia from the secondary Müllerian system or a lesion arising from the urachal remnant. 11.2.3.2  Mucinous Neoplasms Primarily peritoneal endocervical type mucinous neoplasm is a tumor that occurs in extra-ovarian sites, primarily in the retroperitoneum, in the absence of a primary ovarian muci-

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Fig. 11.41  Endocervicosis. The glandular epithelium shows obvious endocervical type mucinous differentiation (H&E, 200×)

nous neoplasm. The neoplasm is usually a large cystic tumor with morphologic similarity to its counterparts in the ovary, e.g., mucinous cystadenoma, borderline mucinous tumor, or mucinous adenocarcinoma [110–112]. Ovarian type stroma may be seen within this tumor, suggesting that the tumor may arise from ectopic ovarian tissue, which is extremely rare. Most believe that this tumor arises directly from the peritoneum, but the pathogenesis remains elusive.

11.2.4 Other Epithelial Diseases Other rare peritoneal epithelial lesions include transitional cell metaplasia, squamous metaplasia, and clear cell change. The last two entities are extremely rare. The Walthard rest is a benign transitional type epithelial proliferation, frequently encountered in the female pelvic peritoneum, especially on the serosal surfaces of the fallopian tubes, mesosalpinx, and mesovarium.

11.2.5 Submesothelial Interstitial Diseases 11.2.5.1  Peritoneal Decidual Reaction Peritoneal decidual reaction is defined as decidualization of submesothelial stromal cells in the peritoneum, usually an incidental microscopic finding. It is most commonly seen on the serosa of fallopian tube, uterus, uterine ligaments, vermiform appendix, and omentum. Most cases of peritoneal decidual reaction occur during pregnancy. Occasional cases occur in patients receiving exogenous progestin therapy. Peritoneal decidual reaction may present as multiple nodules or macules, and are grossly visible during cesar-

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Fig. 11.42  Peritoneal decidual reaction (mucicarmine, 400×)

ean section or tubal ligation. Microscopically the decidual cells appear benign with abundant cytoplasm and no mitosis (Fig. 11.42). Occasionally, decidual cells in the omentum may contain abundant basophilic mucin and slightly eccentric nuclei. These cells may be confused with metastatic signet-­ring cell carcinoma, but signet-ring cell carcinomas are usually positive for PAS-positive neutral mucin and cytokeratin. Peritoneal decidual reaction may also be confused with the deciduoid variant of peritoneal malignant mesothelioma. Malignant mesothelioma with decidual differentiation typically shows significant nuclear pleomorphism and abundant mitotic figures (see section: Diffuse Malignant Mesothelioma).

11.2.5.2  Disseminated Peritoneal Leiomyomatosis 1. Clinical characteristics: Disseminated peritoneal leiomyomatosis is a rare condition where the peritoneum is seeded by numerous benign smooth muscle tumors of varying sizes and shapes [113, 114]. This condition is most common in women of reproductive age, with up to 70% being pregnant, postpartum, or on oral contraceptive pills. Most cases are incidentally discovered during cesarean section or tubal ligation. Occasional cases may present with symptoms of pressure or compression similar to that of uterine leiomyoma. 2. Histologic features: The lesions typically form nodules consisting of smooth muscle with no apparent nuclear pleomorphism or mitosis (Fig.  11.43). Decidualization may be seen in pregnant women. In 10% of cases, these nodules coexist with endometriosis and endosalpingiosis. 3. Pathogenesis: Disseminated peritoneal leiomyomatosis may occur as a result of smooth muscle metaplasia of submesothelial stromal cells. The changes may be associated with pregnancy, use of exogenous hormones, post-

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Fig. 11.43  Disseminated peritoneal leiomyomatosis. The lesions are composed of nodules of smooth muscle cells (H&E, 40×)

Fig. 11.44  Endosalpingiosis involving lymph node in the peritoneal cavity (H&E, 40×)

partum state, or surgical castration. The lesional cells often express progesterone receptor [115]. 4. Treatment and prognosis: Even if not completely excised, disseminated peritoneal leiomyomatosis is self-limiting. Rare cases have been reported to recur or undergo malignant transformation, resulting in death [114, 116]. Some cases of disseminated peritoneal leiomyomatosis may be treated with gonadotropin-releasing hormone.

nodes in pelvic malignancies. The glands are typically located in the capsule of the lymph node or between subcortical lymphoid follicles. Histologically endosalpingiosis of the lymph node is similar to endosalpingiosis in other locations (Fig. 11.44). Endosalpingiosis in the lymph node must be differentiated from metastatic low-grade serous neoplasia from the ovary. Borderline and malignant serous neoplasms have been reported to originate in pelvic lymph nodes [117].

11.2.5.3  Implanted Leiomyoma Implanted leiomyoma in the peritoneum is a recently reported entity that occurs as a result of inadvertent seeding secondary to laparoscopic hysterectomy or myomectomy. These patients invariably have a previous history of a morcellation procedure, or other procedure, and may present many years after the antecedent operation [75]. These tumors may grow during pregnancy and may undergo torsion leading to an acute abdomen or may mimic a ruptured ectopic pregnancy (Fig. 11.31a, b). These lesions are discussed earlier in this chapter in section 11.1.6.3.

11.2.6.2  Intranodal Decidua Intranodal decidual change unrelated to endometriosis is very rare. It is usually an incidental finding during extensive sampling of periaortic and pelvic lymph nodes in radical hysterectomy specimen for uterine cervical carcinoma. Subepithelial decidual reaction may also be seen in the pelvis in these cases (Fig. 11.45).

11.2.6 Lesions of the Lymph Nodes 11.2.6.1  Endosalpingiosis Tubal type glandular inclusions of coelomic origin are not uncommonly seen in pelvic and para-aortic lymph nodes [117]. Depending on the number of lymph nodes sampled or the method of histological sampling for microscopic examination, the incidence of nodal endosalpingiosis has been reported to range from 2 to 41% [118, 119]. Almost all cases of lymph nodal endosalpingiosis are discovered in pelvic or para-aortic nodes removed during surgery for pelvic malignancies. Its presence often presents a significant challenge for the pathologists during intraoperative evaluation of lymph

11.2.6.3  Leiomyomatosis Benign smooth muscle nodules in pelvic and aortic lymph nodes have been reported (Fig.  11.46) [120, 121], usually associated with typical uterine leiomyoma. In rare cases, patients may present with disseminated peritoneal leiomyomatosis or pulmonary leiomyomatosis. Possible mechanisms of the disease may include: 1. Metaplasia of subcoelomic mesenchymal cells or fibromyoblastic metaplasia of intranodal decidua cells. 2. Lymphatic metastasis of leiomyoma (benign metastasizing leiomyoma). 3. Leiomyoma originating within the lymphatics: These patients may also present with multiple sclerosis and pulmonary leiomyomatosis. 4. Metastasis of low-grade uterine leiomyosarcoma. Intranodal leiomyomatosis is extremely rare. Clini­ copathological correlation is required in each case.

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Fig. 11.45  Intranodal decidual reaction. The presence of a central gland suggests that this focus possibly represents endometriosis (H&E, 100×)

Fig. 11.47  Ectopic adrenal rest (H&E, 200×)

zona fasciculata (Fig. 11.47). In rare instances, ectopic adrenocortical cells may become hyperplastic and secrete glucocorticoids as a result of stimulation by the presence of a pituitary tumor.

Fig. 11.46  Intranodal leiomyomatosis. The lymph node is almost completely replaced by smooth muscle cells with small foci of residual lymphoid tissue (H&E, 200×)

11.3 S  ection 3: Diseases of the Broad Ligament 11.3.1 Tumorlike Lesions 11.3.1.1  Embryonal Remnants The most commonly seen embryonal remnants in the broad ligament are the mesonephric duct remnants, which are composed of small tubules lined by cuboidal epithelium without cilia but with a distinct basal membrane. These tubules are frequently surrounded by circular smooth muscle tissue. Extensive sampling of the peritoneum may reveal ectopic adrenocortical tissue near the ovarian vein in over 20% of females. This ectopic adrenal cortical tissue is arranged in trabecular or cord-like structures, similar to those seen in

11.3.1.2  Cyst Cysts of varying size, ranging from microscopic to up to 20 cm or larger, may be seen in the broad ligament. The epithelial lining of some of the largest cysts is typically nonspecific and cannot be further characterized. Some of these cysts may derive from the Müllerian duct or mesothelium. A few cases may derive from the mesonephric duct. The presence of ciliated cells may help to differentiate Müllerian duct-­ derived cyst from cysts of the mesothelium or mesonephric duct. Complications of these cysts include torsion, infarction, or infection. 11.3.1.3  Endometriosis Endometriosis may involve the broad ligament. It is frequently associated with endometriosis of the pelvis and other pelvic organs. Detailed clinical presentations, pathological characteristics, and pathogenesis of endometriosis are discussed in detail in Chap. 12.

11.3.2 Neoplasms The incidence of neoplasia arising in the broad ligament is low, only 20% of that of ovarian tumors. Only about 2% of broad ligament tumors are borderline or malignant, while 25% of ovarian tumors are borderline or malignant [122– 124]. The clinical presentation of broad ligament tumors is similar to that of ovarian tumors.

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11.3.2.1  Müllerian Tumors Serous cystadenoma is the most common Müllerian-type tumor of the broad ligament. Compared with nonneoplastic simple cysts, serous cystadenoma has thicker cyst wall with abundant fibrous tissue or ovarian cortex-like stroma. The cyst wall is devoid of germ cells or follicles allowing differentiation from primary ovarian tumors. Serous borderline tumor is the second most common tumor of the broad ligament. The clinical and pathological characteristics of serous borderline tumor of the broad ligament are similar to those of primary ovarian serous borderline tumor. Unlike ovarian serous borderline tumors, almost all broad-ligament serous borderline tumors have a benign course. Adenocarcinoma involving the broad ligament may be endometrioid, clear cell, or serous types. The clinical and pathological characteristics of these tumors are similar to those of primary ovarian adenocarcinoma. Endometrioid or clear-cell adenocarcinoma of the broad ligament usually arises in endometriosis. 11.3.2.2  P  apillary Cystadenoma with Von Hippel-Lindau Disease Papillary cystadenoma associated with von Hippel-Lindau disease in the broad ligament is a benign lesion. Rare reports are available in the literature [125]. The tumor may be cystic or solid with a typical diameter smaller than 5 cm. The cyst usually contains papillary structures lined by cuboidal epithelial cells without cilia. The nuclei of these cuboidal cells are not atypical. There is a distinct basal membrane, similar to that of the Wolffian duct. Female Adnexal Tumor of Probable Wolffian Origin (FATWO) 1. Clinical characteristics: Originally described in 1973, female adnexal tumor of probable Wolffian origin (FATWO) typically occurs along the mesonephric duct remnants in the broad ligament, paratubal soft tissue, and ovarian hilum [126]. Recent ultrastructural studies and immunohistochemical expression of cytokeratin and inhibin support a mesonephric origin of this tumor. This tumor is very rare, with less than 100 cases reported in the literature so far. Patients’ age ranges from 15 to 81 years. Clinical presentations include abdominal pain, and mass lesions, but this tumor is more frequently an incidental finding. 2. Gross examination: The tumor is typically unilateral with a well-demarcated border with or without a capsule. It is usually located in the broad ligament or found hanging from the fallopian tube by a pedicle. Tumor size may range from 1.3 to 20 cm with a mean tumor size of 8 cm. The cut surface of the tumor is tan to yellow, solid, firm, or rubbery with occasional small

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Fig. 11.48 Female adnexal tumor of probably Wolffian origin (FATWO), gross photograph. The cut surface appears solid and firm

cysts or calcifications (Fig.  11.48). Hemorrhage and necrosis are rare. 3. Microscopic examination: Classically FATWO has three histological patterns: (a) sievelike structures with trabeculae and tubules of varying shapes and diameters, sometimes with cystic dilatation similar to adenomatoid tumor (Fig.  11.49a); (b) compact tubular structures mimicking a solid appearance; and (c) diffuse type with solid tumor cell nests with a vague spindled appearance (Fig. 11.49b). All three histological subtypes may occur in the same tumor. Some tumors may have a prominently hyalinized stroma or fibrous bands rendering a lobular appearance. Upon high-power examination the tumor cells have minimal eosinophilic cytoplasm with occasional spindle cells. The nuclei are pale, rather uniform, and with rare or no mitosis. Rare tumors may display nuclear atypia and increased mitoses, which may be associated with malignant behavior of the tumor (Fig. 11.50). 4. Immunohistochemical characteristics: The tumor cells typically express calretinin, inhibin, CD10, and vimentin and are nonreactive to EMA, Tag72, CEA, ER, and PR. The immunohistochemical phenotype may help differentiate this tumor from other Müllerian neoplasms. 5. Ultrastructural characteristics: The tumor cells have a thick peritubular basal lamina but lack cilia. The presence of a Golgi apparatus, secretory granules, and glycogen favors a Wolffian duct origin of this tumor. 6. Differential diagnosis: The main differential diagnostic consideration is endometrioid adenocarcinoma of the fallopian tube, especially when the endometrioid adenocarcinoma is associated with spindle cells and ­ microacini [127]. Genuine endometrioid adenocarcinoma contains true glands and is frequently associated with squamous metaplasia and intraluminal mucin. Unlike

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Fig. 11.49 (a) Female adnexal tumor of probably Wolffian origin (FATWO). Often shows lobular growth pattern with areas that may appear as solid sheets (H&E, 100×). (b) This tumor displays predomi-

nantly sievelike structure with cystic dilatations of variable shapes and sizes (H&E, 100×)

Fig. 11.50  FATWO showing small lumens surrounded by tumor cells with little nuclear pleomorphism (H&E, left 100× and right 400×)

FATWO, it is also frequently present inside the lumen of the fallopian tube. Other differential diagnoses include Sertoli-Leydig cell tumor and other ovarian surface epithelial tumors. It is noteworthy that inhibin cannot reliably differentiate FATWO from Sertoli-Leydig cell tumor as both tumors are positive [128].

7. Treatment and prognosis: Most FATWO has a benign clinical course with rare instances of malignant behavior [129]. There is no reliable morphological predictor of malignant potential and recurrent tumors are usually morphologically similar to the primary tumor. Treatment of choice is surgical resection. Chemotherapy is reserved for

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malignant tumors. Because FATWO possesses a low potential for malignancy, these patients should be followed long term.

11.3.2.3  Ependymoma Ependymoma of the broad ligament is extremely rare [130]. The average age of presentation is 38 years (range 13–48). Typical clinical presentations include a mass, acute abdominal pain, or even intraperitoneal bleeding requiring urgent surgery [131]. 1. Gross examination: The tumor is usually solid, cystic, or nodular. The cut surface is soft with patchy hemorrhage or necrosis. 2. Microscopic examination: The morphology of ependymoma of the broad ligament is similar to that occurring in the central nervous system. The tumor may be composed of papillary structures, tightly packed tubules, or solid areas. The papillary or tubular structures are lined by flat or columnar ciliated cells. The nuclei may be centrally placed or apical, rounded, or elongated. Perivascular rosettes, psammoma bodies, and small foci of mature cartilage may be present. 3. Differential diagnosis: The main differential diagnosis includes papillary serous adenocarcinoma as both tumors may contain papillary structures and psammoma bodies. The presence of perivascular rosettes and positivity for GFAP favor a diagnosis of ependymoma. 4. Treatment and prognosis: There is limited experience regarding treatment options and prognosis because of the rarity of this tumor. Some tumors may present with metastases, and some may recur after several decades.

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Endometriosis and Endometriosis-­ Associated Tumors

12

Rosalia C. M. Simmen, Charles Matthew Quick, Angela S. Kelley, and Wenxin Zheng

Abstract

Endometriosis is a chronic gynecologic disorder that affects ~10% of adolescent girls and premenopausal women. The condition, classically defined as the presence of endometrial glands and stroma outside of the uterine cavity, is multifactorial and highly recurrent, and causes considerable morbidities that can significantly diminish the quality of life of affected women. The disease is linked to immune dysfunctions, infertility, and increased risk for ovarian and other cancers. The histological diagnosis of endometriosis, while typically uncomplicated, may be compromised by the heterogeneity of the endometriotic foci which can manifest a spectrum of lesions with distinct and atypical features of stromal and glandular components. Moreover, signs and symptoms of endometriosis remain nonspecific and there is a current lack of predictive noninvasive markers. This chapter aims to provide current understanding of the etiology, pathogenesis, and clinicopathologic features of endometriosis and to highlight the remaining challenges clinicians and pathologists face in the diagnosis, management of symptoms, and provision of care in women with this condition. Keywords

Endometriosis · Pathological features · Endometriosisassociated tumors R. C. M. Simmen (*) Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA e-mail: [email protected] C. M. Quick Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA A. S. Kelley Department of Obstetrics and Gynecology, University of Michigan Health Systems, Ann Arbor, MI, USA W. Zheng Departments of Pathology, Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

12.1 General Characteristics Endometriosis is a benign, but chronic, gynecologic condition of adolescent girls and reproductive-age women. The disease is defined as the presence of viable endometrial glands and stroma in extrauterine sites and its development is  widely recognized as an estrogen-dependent, pro-­ inflammatory process [1, 2]. Clinical sequelae of endometriosis include painful menstrual periods, pelvic pain, ovarian cysts, and/or infertility [1]. While the prevalence of endometriosis is difficult to quantify, it is estimated that 25–50% of infertile women, and 30–80% of women with pelvic pain, have a diagnosis of endometriosis [3]. Endometriosis may be a disabling condition for many women (estimated at >200  million worldwide) during the prime years of their lives, and endometriosis-related healthcare expenditures are significant [4, 5] . Treatment of endometriosis may include medical management and/or surgery [6, 7]. However, as a chronic condition without a known cure, endometriosis remains a challenge for affected women and their healthcare providers. Endometriosis affects women of all races and ethnicities, with a strong familial association [8]. Susceptibility to endometriosis also depends on a variety of environmental, immunologic, and endocrine factors [9]. Risk factors for the development of endometriosis include early onset of menarche, longer menstrual bleeding, and short menstrual cycles, while parity and paradoxically obesity and smoking are considered protective [6]. Women with endometriosis also exhibit higher rates of concurrent pain, mood, or autoimmune conditions [10, 11]. Women with endometriosis may be asymptomatic, or may report a wide range of symptoms including dysmenorrhea, dyspareunia, chronic pelvic pain, infertility, abnormal bleeding, or ovarian cysts [2]. There are currently no well-­ validated screening tests for endometriosis, and definitive diagnosis can only be made by surgical biopsy and histopathologic confirmation of ectopic endometrium in extrauterine locations [12]. In clinical practice, many women with

© Science Press & Springer Nature Singapore Pte Ltd. 2019 W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_12

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suspected endometriosis receive empiric medical therapy, with hormonal suppression and/or pain control, to avoid the inherent risks of diagnostic surgery. To assist with conception in infertile women, assisted reproductive technologies such as in vitro fertilization may be employed [13]. As a chronic condition, endometriosis-related symptoms may progress, regress, or remain stable until menopause, when endometriosis generally becomes quiescent. There is increasing evidence, however, that endometriosis may persist even in the postmenopausal state [14]. Women with endometriosis have a two- to threefold increased risk for ovarian cancers and other malignancies such as endometrial and breast ­cancers [15]. The definitive diagnosis of endometriosis can only be made surgically, with histopathologic visualization of both endometrial glands and stroma within a surgical biopsy. Endometriosis lesions may vary in appearance at the time of laparoscopy; the classic description is that of a blue or black “powder burn lesion,” but implants may also be hemorrhagic or nonpigmented [16, 17]. However, even with experienced laparoscopic surgeons, there may be inconsistencies between suspected endometriosis (by visual appearance) and confirmed endometriosis by histopathology [16, 18, 19], highlighting the importance of histologic evaluation.

12.2 Clinical Relevance The American Society for Reproductive Medicine (ASRM) has developed the most commonly accepted classification system for endometriosis [20]. This guideline accounts for lesion size, appearance, anatomic location, and depth of invasion of endometriotic lesions visualized during diagnostic surgery (Table 12.1). Based on these parameters, patients Table 12.1  American Society for Reproductive Medicine Classification for Endometriosisa Stage I. Minimal II. Mild

III. Moderate

IV. Severe

Reference [20]

a

Location (size) Peritoneum (1–3 cm) Ovary (3 cm) Ovary (3 cm) Ovary (1–3 cm) Ovary Ovary-filmy adhesions Fallopian tubes(3 cm) Ovary (1–3 cm) Ovary Fallopian tube (>2 cm) Cul de sac

Depth of endometrial explants Superficial Superficial Deep endometriosis Superficial Superficial Deep endometriosis Deep endometriosis Dense adhesions Superficial Dense adhesions Deep endometriosis Deep endometriosis Dense adhesions Dense adhesions Complete obliteration

are stratified into four stages: stage 1 (minimal), 2 (mild), 3 (moderate), and 4 (severe). Stage 1 endometriosis is characterized by small, isolated, superficial endometriosis implants on the peritoneum or within the ovaries. On the other hand, stage 4 endometriosis is characterized by numerous endometriosis lesions, which may be superficial or deeply infiltrating, in addition to dense peritoneal or pelvic adhesions, and possibly a large ovarian endometriosis cyst. The majority of women with endometriosis are assigned to stages 1–2; however, there is little correlation between stage of endometriosis and severity of pain symptoms [21]. A recent consensus statement by the World Endometriosis Society has incorporated additional endpoints that are highly relevant to women with endometriosis [22]. At present, there are no good serum markers with sufficient accuracy currently to assess the severity of endometriosis. Serum Cancer Antigen-125 (CA-125) levels have been reported to significantly differ in patients with pelvic versus extra-pelvic (i.e., pelvic > extra-pelvic) lesions [23]. Another study failed to confirm this finding and instead observed that extra-pelvic endometriosis was associated with higher patient serum CA-125 levels and lesions displaying increased expression of the epithelial-mesenchymal transcription factor ZEB1 than pelvic endometriosis [24]. The use of magnetic resonance imaging (MRI) to distinguish endometriotic tissue from adhesions and fibrosis has been recently reported and may be suitable for the diagnosis of endometriosis at unusual anatomic sites in symptomatic patients [25]. Given the nonspecific nature of endometriosis symptoms, the diagnosis of the condition is often delayed. Indeed, while the mean age at diagnosis is ~25–29  years, most patients manifest symptoms of pelvic pain and dysmenorrhea at the start of menarche. Symptoms of endometriosis do not differ between women surgically diagnosed during adolescence compared with those diagnosed as adults [26]. A summary of the differential diagnosis of endometriosis depending on the symptom was provided in Mounsy et al. [27]. Dysmenorrhea in endometriosis may be primary or secondary. Generalized pelvic pain, while characteristic of endometriosis, may also arise from malignant or benign neoplasms, pelvic adhesions, pelvic inflammatory disease, obstructive genital anomalies, or non-gynecologic causes. Women with dyspareunia may have endometriosis but the differential diagnosis also includes pelvic infection and bowel or urinary pathology. The diagnosis becomes more challenging if the lesions are located in distal sites. Thus, direct visualization (via laparoscopy) and histological confirmation of biopsied lesions must be strongly considered for cases of suspected endometriosis to facilitate timely initiation of appropriate therapy. Clinically useful serum biomarkers for diagnosis and staging of endometriosis and/or to differentiate endometriosis subtypes are currently lacking. Cancer Antigen (CA) 125, CA 19-9, and the cytokine interleukin-6 have been suggested

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as possible noninvasive markers; however, an extensive meta-analysis raised questions on their diagnostic specificity and accuracy [28]. One study reported that a four-marker panel of CA-125, macrophage chemotactic protein-1, leptin, and macrophage migration inhibitory factor could diagnose 48% of subjects with 93% accuracy [29], but this procedure has yet to be incorporated clinically. Tumor necrosis factor levels in the peritoneal fluids were found to be higher in women with than in those without endometriosis [30]; however, the test may have limited application since it relies upon an invasive procedure. Recent studies using mouse models of endometriosis [31] and women with the condition [32] have tested the feasibility of using circulating microRNAs (miRNAs) as biomarkers for endometriosis. While the results appear promising, the accuracy and specificity of these identified miRNAs have yet to be rigorously vetted in clinical settings.

12.3 Pathogenesis of Endometriosis Several theories have been proposed to explain the pathogenesis of endometriosis. Below, we discuss four theories which may account for the development and persistence of endometriosis in affected women. It is important to recognize that no individual theory has been accepted to fully explain this complex, multifactorial disorder [33, 34].

12.3.1 Histogenesis 12.3.1.1 Retrograde Menstruation The concept of retrograde menstruation is the most cited explanation for the pathogenesis of endometriosis. This theory involves the retrograde flow of endometrial glands and stromal cells, sloughed during menses, through the fallopian tubes and into the peritoneal cavity [2, 35]. Implantation and proliferation of these endometrial cells then occur within ectopic sites, where they are resistant to apoptosis [9]. Support for the theory of retrograde menstruation has been demonstrated in animal models [36, 37]. In addition, the prevalence of endometriosis is increased in women with obstructive outflow tract anomalies, such as cervical stenosis, where the likelihood of retrograde menstruation is higher [1, 38]. The risk of endometriosis also increases with shorter menstrual cycles, increased menstrual frequency, and heavier menstrual flow, lending support to the role of menstruation in the pathogenesis of endometriosis [2]. Though not explained by retrograde menstruation, endometriosis lesions which develop in perineal scars following an obstetric laceration, or in abdominal incisions after cesarean delivery, are likewise

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best explained by the migration or transplantation of endometrial cells into ectopic, extrauterine locations. Nevertheless, retrograde menstruation occurs frequently in women with patent fallopian tubes who do not develop endometriosis [39, 40]. In addition, endometriosis has been noted in previously hysterectomized women, and even in men undergoing treatment for prostate cancer [41]. Such findings suggest that menstruation is not definitively required for the development of endometriosis and highlight the multifactorial nature of the condition.

12.3.1.2 Metaplasia An alternative theory is that of coelomic metaplasia. Coelomic epithelial cells are found within the peritoneal cavity, such as on the surface of the ovary, in addition to the pleural space. It is proposed that coelomic epithelial cells may undergo metaplastic transformation into endometrial cells, leading to ectopic endometrial lesions which ultimately develop into endometriosis [2, 42]. Metaplasia may be induced by exposure to chemical insults (such as menstrual fluid) or high levels of estrogen [43]. Support for this theory includes observations that endometriosis may be found in distant sites such as the pleural cavity, where coelomic epithelium exists, and that endometriosis can occur in prepubertal girls prior to the onset of menarche [33, 44]. Furthermore, case reports have demonstrated surgical evidence of endometriosis in women with Mayer-Rokitansky-Kuster-Hauser syndrome (defined as congenital agenesis of the uterus, cervix, and vagina due to failure of the Mullerian duct to develop), indicating that a functional uterus is expendable for the development of endometriosis [44–46]. 12.3.1.3 Stem Cell Theory In normal menstrual cycles, the human endometrium is continually regenerated by both local adult progenitor cells and bone marrow-derived multipotent stem cells [41]. Stem cells are undifferentiated cells which are characterized by their ability to self-renew and to later develop into a variety of mature cell types [39]. Support for the role of endometrial stem cells in the pathogenesis of endometriosis and their potential involvement in ectopic endometrial proliferation and differentiation have largely come from experimental mouse and nonhuman primate models [41]. In women with endometriosis, refluxed stem cells (via retrograde menstruation) deposited into the peritoneal ­cavity can subsequently undergo differentiation into endometrial glands and stroma [35, 41]. The migration of extrauterine stem cells through lymphatic or vascular channels may contribute to the development of distant endometriosis lesions [39]. Understanding the phenomenon of “stem cell trafficking” is a growing field of endometriosis research [47].

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12.3.1.4 Tubal Origin of Ovarian Endometriosis The fallopian tube has been recently proposed as a cellular contributor to the development of endometriosis [48]. About a decade ago, it was noticed that there are very early morphologic changes in cases of ovarian endometriosis, defined as “initial endometriosis” [49]. Subsequently, a study of the cellular origin of ovarian low-grade serous carcinoma found that ovarian epithelial inclusions (also called as endosalpingiosis) are most commonly derived from the fallopian tube [50]. Considering that initial endometriosis (Fig. 12.1) morphologically overlaps with ovarian epithelial inclusions, it was proposed that ovarian endometriosis, which develops from ovarian “initial endometriosis,” may also arise from the fallopian tube. In a study to evaluate this hypothesis, microarray analysis was used to compare gene expression between the fallopian tube and the endometrium of patients with ovarian endometriosis and corresponding lesions. There were

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significant gene expression similarities between the fallopian tube and ovarian endometriosis, compared to expression profiles between the endometria and ovarian endometriosis. It was concluded that a substantial portion of ovarian endometriosis may originate from the fallopian tube [51]. The above findings are relevant in light of growing evidence that ovarian epithelial cancers, and possibly endometrioid cancers, may originate in the fallopian tubes [52–54]. Additionally, epidemiologic evidence suggests that bilateral salpingectomy (defined as the surgical removal of the bilateral fallopian tubes) may decrease lifetime risk of ovarian cancer in high-risk (e.g., women with BRCA1/2 gene mutations) as well as in low-risk populations [55–57]. If future investigations confirm the contribution of the fallopian tubes to the pathogenesis of endometriosis, the findings may have significant therapeutic and preventative implications for reproductive-age women who have completed childbearing.

a

b

c

d

Fig. 12.1  Initial endometriosis. Shown here are ovarian epithelial-like inclusions in the ovarian cortex. Stromal changes including microcapillary vessels are present surrounding the epithelial inclusions (a). Stromal and vascular changes are evident in a magnified view (b). Another inclusion-like structure shows fresh bleeding adjacent to the glandular structure (c, left and mid-right), while typical ovarian stroma

is present on the top right (c). The dramatic differences noted in the stroma surrounding the ovarian epithelial inclusions are presented at a higher magnification (d). The non-spindle stroma enriched with microcapillary vessels represents the earliest morphologic change of endometriosis

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12.3.2 Etiology 12.3.2.1 Genetics Genomic (and proteomic) studies comparing ectopic lesions and eutopic endometria from women with endometriosis with endometria from women without the disease have demonstrated altered expression of a large number of molecules, but their individual contribution as a mechanistic cause of lesion incidence and establishment remains largely undefined [58–61]. Table  12.2 provides a partial list of novel, recently identified genes that have been strongly implicated in disease establishment, based on clinical (afflicted women) and experimental (mouse models of endometriosis) observations [62–72]. The list does not include steroid hormone receptors and pro-inflammatory molecules, which are discussed in more detail in subsequent sections (below). The broad functional spectrum of the listed genes underscores the multifactorial and heterogeneous nature of the disease. Different mechanisms such as aberrant (hyper- or hypo-) methylation, somatic mutations, or posttranslational modifications involving microRNAs may explain the loss or gain of functions of these genes, leading to abnormal regulation of endometrial proliferation and apoptosis that characterize endometriosis [73–75]. Genome-wide association studies (GWAS) have been increasingly utilized to evaluate genetic contributions to endometriosis [76]. Genetic variants in loci, predominantly Table 12.2  Genes potentially involved in endometriosis Gene name HOXA10 P450 Arom SRC1 (variant) COUP-TFII Cx43 KLF9 REA PTEN KRAS

Model Women Mice Women Mice Women Mice Women Women Mice Women Mice Women Mice Women Mice Women

Expression Decrease, stromal EC Increase, stromal EC Increase, pain Increase, stromal EC Increase, stromal EC Decrease, stromal EC Decrease, stromal EC Decrease, stromal EU Decrease, stromal EC Decrease, stromal EC Decrease, stromal EC Decrease, stromal EC Decrease, stromal EC Decrease, stromal EC Increase, EU Increase, EU

References [47] [48] [50] [51] [52] [53] [54] [55] [56] [57]

HOXA10, HomeoboxA10; P450 Arom, P450 aromatase;SRC1 (variant), steroid receptor co-activator 1 (70  kDa variant); COUP-TFII, chicken ovalbumin upstream promoter-transcription factor II; Cx43, connexin 43; KLF9, Krüppel-like factor-9; REA, repressor of estrogen receptor activity; PTEN, phosphatase and tensin homolog deleted in chromosome 10; KRAS, Kirsten-ras sarcoma virus oncogene b Expression change is relative to endometrium of women without endometriosis; EU eutopic endometrium of women with endometriosis, EC ectopic lesions a

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located in intergenic or intronic regions and in different chromosomes, have identified WNT4 (wingless-type MMTV integration site family member 4), GREB1 (growth regulation by estrogen in breast cancer 1), FN1 (fibronectin1), ID4 (inhibitor of DNA binding 4), VEZT (verzatin), and MAP3K4 (mitogen-activated protein kinase kinase kinase 4) as candidate genes. Nevertheless, a major challenge in the understanding of disease pathogenesis and causes of disease heterogeneity is the identification of which of these genes represent “drivers” as opposed to “passengers.”

12.3.2.2 Sex Steroid Hormones and Receptors Dysregulation of steroid hormone signaling is a major feature of endometriosis, given the estrogen dependence of the disease. Estrogen-modulated events including cell proliferation, angiogenesis, and cyst formation are exacerbated in endometriosis due in part to alterations in the ratio of estrogen receptor (ER) isoforms ER-α and ER-β; increased local estrogen biosynthesis (due to higher aromatase enzyme activity in ectopic lesions); and decreased progesterone receptor expression leading to unopposed estrogen action [77]. The pathological overexpression of ER-β (100 times higher in endometriosis than in normal endometrial tissue) relative to ER-α is caused by deficient methylation of the ER-β promoter and has been experimentally demonstrated using a mouse model of endometriosis, to result in enhanced inflammation and reduced apoptosis in lesions leading to disease progression [78, 79]. Progesterone resistance is also a characteristic feature of endometriosis. The loss of progesterone sensitivity is due to reductions in progesterone receptor expression and transcriptional activity, promoted in part by the increased inflammatory status of endometriotic lesions [59, 80, 81]. Current drugs for the management of endometriosis are aimed at decreasing systemic and local estrogen synthesis, reducing estrogen activity, and increasing progesterone sensitivity [82]. Due to side effects from long-term use of these medications, ongoing studies continue to explore new therapies to increase efficacy with minimal discomfort [83, 84]. 12.3.2.3 I mmune Response and Inflammatory Factors Recent studies have provided support to the link between endometriosis and many immune diseases. Immune dysfunctions associated with endometriosis include systemic lupus erythematosus, rheumatoid arthritis, allergies, and asthma [11, 85, 86]. Endometriosis patients (and corresponding ectopic lesions) demonstrate elevated levels of pro-­ inflammatory cytokines, including interleukins (IL)-1, 6, 17A, and 33 as well as macrophage-stimulating factors (e.g., granulocyte-monocyte colony-stimulating factor) than women without the disease [87]. While it is not clear whether endometriosis is a cause or a consequence of immune dysfunctions, removal of ectopic lesions was shown to ­

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s­ignificantly reduce the systemic inflammatory profiles in these women, suggesting lesions as major drivers of systemic inflammation [88]. The enhanced inflammatory status of women with endometriosis is likely caused by the highly estrogenic dependence of the disease, given the demonstrated cross talk between pro-inflammatory molecules (e.g., IL-6) and estradiol during early disease progression [89] and the role of estrogens in the recruitment of pro-inflammatory molecules within ectopic lesions [90]. Thus, recently identified estrogen receptor antagonists that can concurrently suppress estrogenic and inflammatory activities [91] may show promise as preventative and treatment strategies for endometriosis. As mentioned earlier, the role of progesterone resistance in the progression of endometriosis may be linked to the enhanced inflammatory status of women with the disease. Gene expression analyses have shown that loss of progesterone receptor expression in lesions is associated with their higher expression of inflammatory cytokines [58, 59]. Mechanistically, it has been demonstrated that inflammatory molecules such as IL-1 and tumor necrosis factor (TNF)-α can significantly reduce progesterone receptor expression [81]. Conversely, progestin treatment of endometriotic stromal cells can suppress TNF-α-induced inflammation [92]. The significant contribution of pro-inflammatory molecules to endometriosis raises the interesting potential for nonsteroidal anti-inflammatory drugs such as prostaglandin synthesis inhibitors (e.g., cyclooxygenase-2 inhibitors) and diets rich in anti-inflammatory components (e.g., resveratrol in grapes) in the management of endometriosis. While there is sufficient support to these possibilities in animal models [93, 94] and in studies using endometriotic stromal cells [95], their potential has yet to be achieved in a clinical setting [96].

12.4 Pathologic Features of Endometriosis Endometriosis, pathologically, is defined by the presence of ectopic functional endometrial tissue, which may be accompanied by cyclic bleeding induced by hormonal changes and associated with adjacent tissue response and accompanying adhesion or scar formation.

12.4.1 Clinicopathologic Types Endometriosis lesions are most commonly located in the pelvic surface of peritoneum and ovary (peritoneal endometriosis), in the ovary as cysts lined by endometrioid mucosa (ovarian endometriomas), and in pelvic structures between the rectum and vagina as a solid mass comprised of endometriotic tissue with local adipose and fibromuscular tissue (deep-infiltrating endometriosis). Rectovaginal endometrio-

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sis accounts for 5–10% of women with disease. Endometriosis may also be established at distant locations such as the pleural space, diaphragm, or breast [16]. The implantation and proliferation of endometrial cells in ectopic sites result in inflammation, fibrosis, and distortion of normal anatomy. The ovary and peritoneum are the most frequent locations of pelvic endometriosis. Other pelvic sites include the bowel [97] or bladder. Extra-pelvic lesions are less common, likely deeply infiltrating, and found in such anatomic locations as hepatobiliary and urinary systems, upper abdomen (lung, thorax), abdominal wall, and adrenal glands. Diagnosis of pelvic and extra-pelvic lesions can be challenging. Endometriosis of the uterine cervix is generally asymptomatic and can be mistaken for cervical neoplasia due to the presence of a cervical mass [98, 99]. Intestinal endometriosis may present with abdominal pain or gastrointestinal bleeding [100], and the differential diagnoses may include diverticulitis, appendicitis, Crohn disease, irritable bowel syndrome, carcinoma, and lymphoma. Patients subsequently diagnosed with thoracic endometriosis may initially present with shoulder pain, catamenial pneumothorax, and/ or hemoptysis [101]. In patients with bowel endometriosis, lesions display a characteristic “comet” appearance and have been associated with obliteration of the cul-de-sac and pelvic pain [102]. Abdominal wall endometriosis occurs when endometrial cells attach to the fascia or dermis at the time of obstetrical or gynecological surgery. Approximately 1% of women who have had a caesarean delivery subsequently presented with focal pain and/or palpable mass near the surgical scar which was diagnosed as endometriosis [103].

12.4.1.1 Peritoneal Endometriosis Peritoneal endometriosis, also termed superficial endometriosis, is typically present on the surface of the peritoneum or the serosa of the peritoneal organs. Lesions of endometriosis can be single or in clusters. Grossly, they may present as raised, cystic, polypoid, or nodular. Peritoneal endometriosis may show different colors under gross or laparoscopic examination, based on the “age” of the disease. Early lesions are typically colorless and 2–3 mm in size (Fig. 12.2).The lesions then may become red (fresh or recent bleeding) (Fig.  12.3), blue or black (old or remote bleeding) (Figs. 12.4 and 12.5), and white (inflammation and fibrosis) (Fig. 12.2), representing different stages of growth. It takes years for an early cystic colorless lesion to develop into a whitish scar-like lesion. Peritoneal lesions may be multifocal (i.e., other lesions are located within a 2 cm area) or multicentric (i.e., lesions are located beyond 2 cm from the main lesion); as many as 50 lesions may involve the peritoneum. Presence of endometroid epithelia as well as endometrial stromal cells varies depending on the disease status. Typically, both can be found in more than 95% of red lesions,

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Fig. 12.2  Peritoneal endometriosis. A laparoscopic view of the peritoneal cavity reveals several transparent cystic structures, ranging from 2 to 4 mm in size, which represent foci of endometriosis prior to bleeding. Also shown are several white raised nodules (2–3 mm in size) probably representing endometriosis with fibrotic changes

Fig. 12.4 Peritoneal endometriosis. Shown here are one black, “powder-­burn” spot in the center and another purple spot in the lower area. Both represent relatively old hemorrhage in endometriotic lesions. Based on the color, the purple lesion is more likely less established than the black lesion

Fig. 12.3  Peritoneal endometriosis. This laparoscopic view of the peritoneum shows several red-tan, irregular-shaped, slightly raised lesions, which represent foci of endometriosis with fresh bleeding

Fig. 12.5  Peritoneal endometriosis. Multiple blue and black lesions representing old hemorrhage within foci of endometriosis are shown

and in only 50–60% of bluish or black lesions. The clinicopathologic appearance of peritoneal endometriosis is summarized in Table 12.3.

finding (Figs.  12.6, 12.7, 12.8, and 12.9). Large cysts can form around the ovary and may acutely rupture, causing release and adherence of their contents to the abdominal cavity.

12.4.1.2 Ovarian Endometriosis Endometriosis in the ovary typically presents as a cystic lesion with either a single cyst or multilocular cysts. Ovarian endometriotic cysts are termed endometriomas. The cystic wall is typically thickened because of fibrotic reaction. Blood clot or condensed blood containing chocolate-like material (aptly named “chocolate cyst”) is a common gross

12.4.1.3 Deep-Infiltrating Endometriosis Deep-infiltrating endometriosis (also called adenomyosis externa) is the most severe clinical form of endometriosis and in >95% of cases is associated with severe pain. It typically presents as solid, multifocal nodules larger than 0.5 cm in diameter which can grow up to 5–6 cm in size [104, 105].

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Table 12.3  Clinicopathologic appearance of peritoneal endometriosis Gross color Disease status Appearance Colorless Prior to Grey small bleeding cysts Focally raised Red Early Granular and bleeding polypoid Red or yellowish Blue or Active Burned black growth appearance Irregular folding White Healing stage Focal adhesion Scar

Microscopic finding of endometrial tissue (%)

Close to 100

Up to 95

50–60

70%)

Positive High (>70%)

Positive Low (70%) Diandric diploidy (46XX, 46XY)

d­ iploid (46, XX or 46 XY) with a paternal only genome [24, 44, 45] (Fig. 13.10).

13.5.1.2 Clinical Features Patients usually present with second-trimester vaginal bleeding, and a large-for-dates uterus, accompanied by markedly elevated serum hCG levels [46]. There may be hyperemesis gravidarum and other symptoms related to preeclampsia, hyperthyroidism, and hyperreactio luteinalis [47, 48]. Rarely, there is vaginal passage of molar vesicles or manifestations related to metastases. In those presenting in the first trimester, there is usually an abnormal ultrasound scan with absence of fetal heartbeat [49]. The typical “snowstorm” pattern may not be well developed in such early cases and the clinical diagnosis is commonly a missed abortion [50, 51]. 13.5.1.3 Pathological Findings The classical appearance of grossly evident vesicles may not be readily appreciable especially if presentation is in the first trimester. When present, the vesicles are grapelike, semi-

Variable

transparent, and of various sizes (Fig.  13.11). Some may reach 1  cm or more in diameter. The vesicles are often admixed with blood clot and decidua while normal placental or fetal tissues are not found, except in cases in which there is a concurrent twin pregnancy [52]. Histologically, the chorionic villi are irregular in shape and sizes. Some may be strikingly edematous (Fig. 13.12) while some may show club-shaped stromal projections (Fig.  13.13) [53, 54]. They may appear avascular, and enlarged with cistern formation. Numerous small blood vessels are usually present but they are more conspicuous with CD31 immunohistochemistry [55, 56]. Karyorrhectic debris is prominent and especially in early moles (Fig. 13.14) [46, 53, 55]. In first-trimester complete hydatidiform moles, the central cisterns may be small or absent. The villous stroma is pale to bluish in hematoxylin and eosin-stained sections (Fig. 13.15), and fibrosis is usually not a conspicuous finding. Intravillous trophoblastic inclusions are not common but may be seen. There is circumferential hyperplasia of the

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a

435

b

Normal Fertilization

Ovum, 23X

Monospermic Complete Hydatidiform Mole Empty Ovum 46XX

46XX

Sperm, 23X

c

Sperm, 23X

Dispermic Complete Hydatidiform mole Empty Ovum

d

Partial Hydatidiform Mole

Ovum, 23X 69 XXX/ 69 XXX/ 69 XYY

46XX/ 46XY

Both Sperm, 23X or 23Y

Fig. 13.10  Chromosome compositions in normal conceptus and hydatidiform moles. Normal fertilization involves fusion of one haploid chromosome from both the father and mother (a). Diploid chromosome composition is also seen in most complete moles. In monospermic complete mole (b), one sperm enters an empty ovum with no maternal

Both Sperm, 23X or 23Y

chromosome and duplicates. In dispermic complete mole (c), two sperms enter an empty ovum and unite. In contrast, two haploid sets of paternal chromosomes fuse with an ovum with intact maternal haplotype to produce triploid genome in a partial mole (d) [47]

Fig. 13.12  Photomicrograph of a complete mole with prominent cistern formation and circumferential trophoblast hyperplasia

Fig. 13.11  Obvious vesicles are found in a case of complete hydatidiform mole

cytotrophoblasts, villous intermediate trophoblasts, and syncytiotrophoblasts. Syncytiotrophoblasts may contain cytoplasmic vacuoles and form lacelike projections from the surface. There is also marked proliferation of extravillous

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Fig. 13.13  Photomicrograph of a complete mole with club-shaped villi with florid trophoblastic proliferation

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Fig. 13.16  The nuclei of the cytotrophoblasts (CT) and stromal cells (S) of this complete mole are negative for p57 immunoreactivity while the villous intermediate trophoblast (VIT) can be strongly positive

trophoblasts. The hyperplastic trophoblasts usually exhibit severe nuclear atypia and hyperchromasia, which is often apparent under low magnification. The degree of nuclear pleomorphism may be indistinguishable from that is seen in choriocarcinomas.

Fig. 13.14  Photomicrograph of a complete mole with cistern formation and apoptosis of stromal cells

Fig. 13.15  Photomicrograph of an early complete mole with club-­shaped villi and myxomatous stroma. Cistern formation is inconspicuous

13.5.1.4 Biomarkers The p57 immunohistochemistry is useful in confirming diagnosis (Fig.  13.16) [57, 58]. It has been shown to correlate with genotyping and can serve as a reliable marker for diagnosis of complete hydatidiform moles, as well as identifying mosaic conceptions [59]. The p57 is the protein product of the cyclin-dependent kinase inhibitor 1C (CDKI1C) gene (p57, Kip2) on chromosome 11p15.5, which is a paternally imprinted, maternally expressed gene. Lack of maternal chromosomes in complete mole renders the loss of expression in the villous trophoblasts and stromal cells. P57 immunoreactivity is usually retained in the villous intermediate trophoblast and implantation-site extravillous intermediate trophoblasts among decidua and may serve as an internal positive control. Almost all complete hydatidiform moles are p57 negative. It is also important to be aware of aberrant p57 expression in some special scenarios. Rare cases of complete moles may show aberrant expression due to the retention of maternal copy of chromosome 11 such as in trisomies. In androgenetic/biparental mosaic/chimeric conceptuses (which may show either typical complete mole morphologies or absence of trophoblastic hyperplasia), there is discordant p57 expression with different expression profile in the villous cytotrophoblasts and stromal cells in same villi, i.e., positive immunoreactivity in cytotrophoblast but negative in villous stromal cells, or vice versa [59, 60]. Divergent

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expression may also be seen in twin gestations, in which the p57 is absent in the villi of the complete hydatidiform mole but retained in those from the non-molar conceptus [61]. Familial biparental diploid products of gestation or complete moles related to NLRP7 mutations may show variable levels of p57 expression and evidence of fetal development and mild trophoblastic proliferation resembling triploid partial mole. Such differential diagnosis should be kept in mind particularly in cases with a history of recurrent molar pregnancies. Stromal apoptotic index has been shown to be higher in complete hydatidiform mole than in partial mole of normal placenta [56]. Overexpression of mRNA and protein of the transcription factor Nanog has also been shown to increase the risk of persistent gestational trophoblastic disease [62, 63].

13.5.1.5 Genetic Profile Complete hydatidiform mole has a diploid androgenic only genome (two sets of paternal chromosomes) arising from Fig. 13.17 Microsatellite polymorphisms of the decidua (upper panel) and villi (lower panel) of a case of complete hydatidiform mole. The patient is heterozygous for the marker generating alleles of 136–153 bp. The hydatidiform mole is homozygous giving rise to allele 145 bp

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fertilization of an empty ovum by one (monospermic) or two (dispermic) sperms (Fig. 13.10). In 80–90%, it is a result of fertilization of an empty ovum by one sperm (homozygous) and in 10–20% of an ovum by two sperms (heterozygous) with absence or subsequent loss of maternal chromosomes. Such absence of maternal alleles facilitates the diagnosis of complete moles using microsatellite analysis (Fig.  13.17). Mitochondria DNA of maternal origin, however, exists [64]. Rarely, they are tetraploid (containing four paternal haploid chromosomes, with a 92 XXXX karyotype) [44, 65–67]. Biparental Complete Moles Rare cases of recurrent complete moles are biparental diploidy (as opposed to androgenetic diploidy) and are thought to be familial in origin. They have been shown to be related to maternal mutations in NLRP7 or KHDC3L (C6orf221) genes [16, 17, 68–70]. The mutations cause multiple epigenetic defects which result in the failure to establish maternal identity at imprinted loci and with abnormal expression of

120 122 124 126 128 130 132 134 136 138 140 142 144 146 148 150 152 154 156 158 560 490 420 350 280 210 140 70 0 PATIENT

136

153

800

600

400

200

0 HM

145

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imprinted genes. It is estimated in a recent study that recessive NLRP7 and KHDC3L mutations were found in 55% and 5% of patients with recurrent moles, respectively [69]. Genotyping of available molar tissues from these patients confirmed the diploid biparental contribution to all molar tissues from patients with recessive mutations in the known genes. Such genetic predisposition can be identified by appropriate genetic tests. Suitable genetic counselling and assisted reproduction may be provided in experienced centers. Live births (7–15% of pregnancies) have been reported

among patients with recessive mutations and ovum donation was found to be helpful [71]. Indeed, in a study on products of gestations from patients with two defective NLRP7 alleles, all the conceptuses were found to be biparental diploid (Figs.  13.18 and 13.19). Variable p57 (KIP2) expression was found [70]. Positive p57 expression was found in cases with missense NLRP7 mutations and was strongly associated with the presence of embryonic tissues of inner cell mass origin and mild trophoblastic proliferation, features often considered supporting

Fig. 13.18  Multiplex short tandem repeat genotyping results for a diploid biparental complete hydatidiform mole from a patient with biallelic mutations in NLRP7. Genotypes at three informative markers are shown and demonstrate at each of the three markers the presence of one allele inherited from the mother and another inherited from the father.

For example, at marker D16S539, the complete mole received a 278 bp allele from the father and a 286 bp allele from the mother [contributed by Dr. Rima Slim, McGill University Health Center Research Institute Glen Site]

13  Complications of Early Pregnancy and Gestational Trophoblastic Diseases

Fig. 13.19  Photomicrograph of a HM from a patient with diploid biparental biallelic NLRP7 mutations [contributed by Dr. Rima Slim, McGill University Health Center Research Institute Glen site]

diagnosis of triploid partial moles. In contrast, cases with protein-truncating NLRP7 mutations were negative for p57 (KIP2) expression and displayed florid trophoblastic proliferation with absence of embryonic tissues and excessive trophoblastic proliferation [70].

13.5.1.6 Differential Diagnosis The differential diagnoses include early complete hydatidiform mole, and conditions in which there is abnormal villous morphology but have retained maternal genetic component. They include hydropic abortions, partial hydatidiform moles, trisomy 11, and placental mesenchymal dysplasia [25]. In early hydatidiform mole, central cisterns are not well developed. The hydropic villi usually have club-shaped stromal bulbous projections and the stroma is usually more hypercellular with many stellate cells, accompanied by striking stromal karyorrhexis [56]. There is a prominent labyrinthine network of villous stromal canaliculi. Trophoblastic hyperplasia is typically focal when compared with a second-­trimester complete mole, and the process involves both villous surface and chorionic plate. Cytologic atypia is apparent even at this early stage [53]. The loss of p57 i­mmunoreactivity in the villous trophoblasts and stromal cells confirms the diagnosis of a complete hydatidiform mole. Hydropic abortus and partial hydatidiform moles may have hydropic villi but they both lack the club-shaped stromal projections and stromal karyorrhexis of complete hydatidiform mole [53–55, 72, 73]. Although early abortus may show some degree of circumferential trophoblastic proliferation, they generally lack the nuclear atypia of a complete hydatidiform mole. The retained p57 immunoreactivity in

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both villous trophoblasts and stromal cells facilitates their diagnoses [58]. In trisomy 11, the histologic appearance may resemble a typical complete mole. However, the triplicated chromosome 11 (the same chromosome on which the CDKI1C gene is located) can result in retained expression of p57 [58, 74]. Placental mesenchymal dysplasia may be confused with hydatidiform moles since there are usually a population of hydropic villi with central cisterns. Unlike hydatidiform moles, the hydropic change in placental mesenchymal dysplasia usually involves the stem rather than terminal villi. The villous blood vessels are also thickened with fibromuscular hyperplasia. The p57 immunostain shows a discordant pattern and is expressed in the villous trophoblasts but not in the stromal cells. The fetus may be normal or shows features of Beckwith-Wiedemann syndrome [75, 76].

13.5.1.7 Prognosis and Outcome Persistent gestational trophoblastic disease occurs in 15–20% of patients with complete hydatidiform moles in which the serum hCG failed to normalize after the initial uterine curettage [26, 31, 77]. It is noteworthy that hCG assays for monitoring of GTN should be able to detect all forms of hCG and may be different from those for routine pregnancy test [26]. In fact, negative pregnancy test has occasionally been reported in patients with GTD [78]. Residual molar villi are usually found in repeated curettages. The risk of persistent disease is higher in those with a maternal age of >40  years, previous molar pregnancy, pre-evacuation hCG levels of >100,000 mIU/ml, a markedly enlarged uterus, and the presence of hyperreactio luteinalis, preeclampsia, hyperthyroidism, or trophoblastic emboli [61]. Those having a heterozygous genotype may also have a higher risk [79]. Uterine curettage performed in the first trimester does not appear to help reducing the frequency of persistent disease, although metastatic disease and choriocarcinoma are less frequent. Complete cure is usually seen either in patients who do not have metastasis, or only if the metastases are confined to the lungs or vagina, or when the serum hCG is 40,000  mIU/mL, cure may be achieved in >80% of cases. The risk of subsequent choriocarcinoma was reported to be 2–3% although risk is as high as 13% in Asian populations (see under subsequent section on choriocarcinoma) [31, 80]. Rarely, minimally invasive and quiescent GTD has been described (defined as patients with elevated hCG who show a falling trend on follow-up). False-positive hCG assay needs to be excluded and the need of chemotherapy is controversial [81, 82]. Recurrent complete mole is defined by discovering a new gestational trophoblastic disease after a post-chemotherapy remission. Recurrent complete mole has been reported to

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occur in 1–1.8% who has had a previous complete mole, and 10–18% who has had two complete moles [83, 84].

13.5.2 Partial Hydatidiform Moles 13.5.2.1 Definition Partial hydatidiform mole shows diandric triploidy (one maternal and two paternal sets of chromosomes). They contain a mixture of normal-sized and enlarged hydropic chorionic villi with localized and mild degree of trophoblastic hyperplasia [75, 85, 86]. 13.5.2.2 Clinical Features Patients usually present with vaginal bleeding or missed abortion in the late first or early second trimester. The serum hCG is usually low or normal for gestational age [46, 51]. Preeclampsia may occur later than for a complete hydatidiform mole [87]. Ultrasound scan of the uterus may show small or normal for dates uterus, presence of a fetus, and focally cystic placenta [88].

Fig. 13.21  Photomicrograph of a partial mole. Relatively normal-­ sized sclerosed villi and hydropic villi with cistern are both present

13.5.2.3 Pathological Findings Gross appearance is dependent on the age of gestation. First-­ trimester partial moles may be indistinguishable from normal pregnancies. In a well-developed case, there is usually a mixture of markedly hydropic vesicles and normal placental tissue (Fig.  13.20). The fetus and an intact gestational sac may be seen [75]. Histologically, there are two populations of hydropic and normal-sized chorionic villi (Fig. 13.21). The hydropic villi are at least two to three times larger than the normal ones Fig. 13.22  Photomicrograph of a partial mole. Trophoblastic proliferation is mild

Fig. 13.20  Vesicles can be found in part of a placenta in this case of partial hydatidiform mole

[75]. They show central cisterns but the frequency is less than that in complete hydatidiform mole. The villi are often irregular in shape, with scalloped borders and trophoblastic inclusions (invaginations of trophoblasts into the villous stroma). Trophoblastic hyperplasia is focal and mild compared with a complete mole (Fig. 13.22), and characterized by sprouts or knuckles of cells projecting from the villous surface. Circumferential hyperplasia is less common. The majority of hyperplastic cells are syncytiotrophoblasts and they quite often contain prominent cytoplasmic vacuoles and appear lacelike when the cells are arranged in sheets. In the villous stroma, there are fetal vessels containing nucleated red blood cells. Some of the blood vessels may appear ectatic. The normal-sized chorionic villi often have a fibrous stroma [54, 75]. The morphologic features of a classical partial mole may not always be present and may vary consider-

13  Complications of Early Pregnancy and Gestational Trophoblastic Diseases

Fig. 13.23  The cytotrophoblasts and stromal cells of this partial mole are positive for p57 immunoreactivity

ably from case to case, and the appearance is dependent on the gestational age. For example, in early partial mole there may only be very few hydropic villi and the trophoblastic hyperplasia may be absent. Fetal tissue, chorionic and amnion membranes, and umbilical cord tissue may be present [72, 73].

13.5.2.4 Biomarkers Although there is no specific immunohistochemical marker for diagnosis of partial hydatidiform mole, p57 is useful in the distinction from complete hydatidiform mole. In partial mole, the villous trophoblasts and stromal cells are immunoreactive for this marker (Fig. 13.23) [72]. The p57 immunoexpression is also retained in hydropic abortus and therefore this marker cannot be used to distinguish it from a partial mole [57, 58, 61, 85]. 13.5.2.5 Genetic Profile Almost all partial hydatidiform moles have a triploid karyotype [72, 73, 86] (Fig. 13.10). Most are 69XXY (70%), followed by 69XXX (27%), and the least common are 69XYY (3%) [86, 89]. Rarely, they are tetraploid in which there are three sets of paternal and one set of maternal chromosomes [90]. It should be noted that, while almost all partial moles are triploid, not all triploid conceptuses are partial moles (see under differential diagnosis below) [91]. 13.5.2.6 Differential Diagnosis The main differential diagnoses include entities in which abnormal chorionic villi are found. These are hydropic with or without other abnormal villous morphologies [25]. They include complete hydatidiform mole, hydropic abortions, gestations with chromosomal abnormalities, placental mesenchymal dysplasia, twin gestations, as well as familial bipa-

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rental diploid POG/complete moles with missense NLRP7 mutations. Early complete hydatidiform mole may show immature hydropic chorionic villi without well-developed central cisterns (see under complete hydatidiform mole). Presence of fetal vessels and nucleated red blood cells, and retained p57 staining, will support a diagnosis of partial mole or hydropic abortion [72]. It has also been suggested that the MIB1 proliferative index (ki-67) in molar specimens is increased to >70%, in contrast to hydropic abortus which usually has an index of 100,000  mIU/mL, presence of liver, or brain metastases at diagnosis were among poor prognostic factors [31, 130, 131]. Nevertheless, with modern chemotherapy regimens, the prognosis has been drastically improved with cure achieved in >90% of patients [97, 108, 109].

13.8 Placental Site Trophoblastic Tumor 13.8.1 Definition Placental site trophoblastic tumor is a malignant trophoblastic tumor of intermediate trophoblasts. The cell of origin is believed to be extravillous implantation-site trophoblasts [132].

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13.8.2 Clinical Features The affected women are usually in the reproductive age group (with a mean age of 30) and commonest presentation is abnormal vaginal bleeding but some may have amenorrhea or abdominal distention, simulating a normal pregnancy. Rarely, the presentation is that of a postmenopausal woman. An antecedent full-term pregnancy is found in more than two-thirds of women, with a median latent period of 18 months. The remainder follows a non-molar abortion or miscarriage [132–136]. Glomerular diseases including lupus nephritis are occasionally found in patients with PSTT [137, 138].

13.8.3 Pathological Findings

Fig. 13.35  Confluence mass of PSTT found next to pieces of endometrium in a uterine curetting

The tumor involves both endometrium and myometrium and presents as infiltrative masses ranging from 1 to 10 cm and cervical involvement is found in 10% [10, 120, 139].

13.8.5 Genetic Profile There is usually a paternal X chromosome. There are occasional cases which show genetic imbalances [124, 140–143].

13.8.6 Differential Diagnoses The differential diagnoses include choriocarcinoma, epithelioid leiomyosarcoma, poorly differentiated carcinomas, melanomas, and exaggerated placental site reaction [25] (Tables 13.4 and 13.6). Unlike placental site trophoblastic tumor, choriocarcinoma usually has a combination of features including very high serum hCG, a hemorrhagic mass, and a plexiform growth but lacking the angiocentric and angioinvasive pattern of placental site trophoblastic tumor (see under differential diagnosis of choriocarcinoma). Poorly differentiated placental site trophoblastic tumor may be indistinguishable from some choriocarcinomas and may rarely coexist.

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13  Complications of Early Pregnancy and Gestational Trophoblastic Diseases Table 13.6  Differentiated diagnosis of PSTT

Serum hCG level Histological feature

PSTT Mildly elevated Angiocentric-­ angioinvasive pattern

CCA Markedly elevated Hemorrhagic mass with plexiform growth

Tumor cell origin Fibrinous deposition hCG immunostain Pan-cytokeratin Muscle marker

IT + + + −

CT, ST, villous IT − +++ + −

Epithelioid leiomyosarcoma Normal Arranged in sheets, nests, cords that may form a plexiform pattern Smooth muscle cell − − − +

Poorly differentiated carcinomas Normal Arranged in sheets, nests, cords Epithelial cell − − + −

PSTT placental site trophoblastic tumor, CCA choriocarcinoma, IT intermediate trophoblasts, CT cytotrophoblasts, ST syncytiotrophoblasts

Fig. 13.41  Spindle-shaped PSTT cells with eosinophilc degeneration resemble keratinizing squamous cell carcinoma of cervix

Fig. 13.42  Spindle-shaped PSTT cells resembling leiomyosarcoma

Distinction from epithelioid leiomyosarcoma, poorly differentiated carcinomas, and melanomas in the uterine corpus or cervix may be difficult particularly during interpretation of frozen section or small biopsies (Figs.  13.41 and 13.42). Identification of more typical histopathological features and immunohistochemical profiling are helpful in the differential diagnoses. PSTT usually shows permeation of blood vessel wall, splitting apart of well-preserved myometrial cells, and conspicuous fibrinoid deposit. Epithelioid leiomyosarcomas may be confirmed by absence of the distinctive vascular pattern of placental site trophoblastic tumor; immunoreactivity for h-caldesmon, desmin, and actin; and negative for hPL and inhibin. Poorly differentiated carcinomas usually show some histologic evidence of a better differentiated component (squamous or glandular) and an immunoprofile of hPL/hCG/inhibin nonreactivity.

other pelvic sites, and metastases to lymph nodes, lungs, and liver. Half of these patients may die from tumor. Metastases and recurrent tumors respond poorly to chemotherapy and often result in fatality. Pathologic features associated with poor outcome include extensive necrosis, cells with clear cytoplasm, deep myometrial invasion, and >5 mitotic figures per 10 high-power fields. In multivariate analysis, FIGO stage III/IV, a latency of ≥2  years since last pregnancy, and presence of clear cells are independently associated with a poor prognosis [133, 144–147].

13.8.7 Prognosis and Outcome The majority of patients present at FIGO stage I [132]. Approximately 30% are high stage with involvement of

13.9 Epithelioid Trophoblastic Tumor 13.9.1 Definition Epithelioid trophoblastic tumor is a malignant trophoblastic tumor of intermediate trophoblasts. The cell of origin is believed to be chorionic-type trophoblasts [148].

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13.9.2 Clinical Features The affected women are usually in the similar age group as placental site trophoblastic tumors (with a mean age of 36 years) and commonest presentation is abnormal vaginal bleeding and a mildly elevated serum hCG. In addition to the corpus, 50% of tumor commonly arises in the lower uterine segment and cervix and often have a long interval from an antecedent pregnancy (with a mean of 6 years), which may be a term pregnancy, abortion, or hydatidiform mole [148–152]. Fig. 13.44  The ETT cells are positive for p63

13.9.3 Pathological Findings Grossly, the tumor may be nodular infiltrative masses but often with involvement of mucosa associated with ulceration [148, 153]. The cut surface may show necrosis and hemorrhage. Microscopically, the tumor cells are arranged in expansile nodules, nests, or cords separated by abundant extracellular eosinophilic hyaline-like material (Fig. 13.43) [148, 151, 154]. Geographic necrosis and perivascular viable tumor cells are often striking. In some cases, decidualized stromal cells may be found at the periphery. The tumor cells are mononuclear, well-defined cell membrane, uniform in size with eosinophilic or clear cytoplasm. There is moderate nuclear atypia and a low mitotic count (range between 0 and 10 mitotic figures per 10 high-power fields, with a mean of 2) [139].

13.9.4 Biomarkers There is immunoreactivity for H3D3B1, CD10, and cyclin E but also cytokeratins, EMA, and p63 (Fig. 13.44). Staining for other trophoblastic markers, such as hPL, hCG, inhibin, Mel-CAM, and HLA-G, may be focal. The MIB1 prolifera-

Fig. 13.43  A metastatic ETT presented as lung nodule. Cellular nodules and nests are separated by abundant extracellular eosinophilic material

tive index (ki-67) ranges from 10% to 25% [10, 12, 120, 155, 156].

13.9.5 Genetic Profile The majority lack Y chromosome complement [124]. Rare comparative genomic hybridization studies showed an undisturbed genome [140, 157]. There are some suggestions of malignant transformation from a preexisting placental site nodule [158].

13.9.6 Differential Diagnosis These include squamous cell carcinoma, epithelioid leiomyosarcoma, and other gestational trophoblastic tumors [25] (Table  13.4). In small biopsies, distinction from placental site nodule may be difficult. Some of the gross (cervical mucosal involvement) and microscopic features (epithelial involvement resembling high-grade squamous intraepithelial lesion, eosinophilic hyaline material) and immunoprofile (positive staining for cytokeratins, EMA, and p63) of epithelioid trophoblastic tumors mimic those of squamous cell carcinomas. Overt squamous differentiation, absence of staining with trophoblastic markers, and a normal serum hCG level support squamous cell carcinoma [151, 159, 160]. Epithelioid leiomyosarcoma usually contains a component of more typical smooth muscle tumor differentiation and is immunoreactive for smooth muscle markers. Compared with epithelioid trophoblastic tumor, placental site trophoblastic tumor has a more infiltrative dissecting growth, has a typical angiocentric and angioinvasive pattern, and shows more extensive staining with hPL and Mel-CAM and negative for p63. Epithelioid trophoblastic tumors may coexist with other gestational trophoblastic tumors as mixed tumors. Some choriocarcinomas which have been treated with chemotherapy may show degenerative features which

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are difficult to distinguish from some epithelioid trophoblastic tumors [161]. Placental site nodules are hypocellular and diffusely hyalinized, and the cells are mitotically inactive, negative for cyclin E. The MIB1 proliferative index is 6 per 10 high-power fields. Patients without metastases have excellent prognosis. In 25% of patients, there is blood-borne metastasis and half of these usually died of tumor [151, 162].

13.10 Exaggerated Placental Site

Fig. 13.45  Photomicrograph of exaggerated placental site reaction found with complete mole

13.10.1 Definition

13.10.4 Differential Diagnosis

Exaggerated placental site is the unusual prominence of implantation-site intermediate trophoblasts found at the implantation site of a placenta (synonym: exaggerated placental site reaction) [139, 163].

Placental site trophoblastic tumor is favored in the presence of a mass (clinically or radiologically), high serum hCG levels, destructive myoinvasion, typical angioinvasive pattern, tumor necrosis, and a MIB1 proliferative index >10%. A low MIB1 index and presence of decidua and villi are in favor of exaggerated placental site.

13.10.2 Pathological Findings Exaggerated placental site may be seen in first-trimester induced or spontaneous abortions and has been suggested to be more common in association with an underlying hydatidiform mole (Fig.  13.45) [163]. There is usually no gross lesion. The distinction between what constitutes a normal or exaggerated placental site is unclear and subjective. In a definitive case of exaggerated placental site, there is a striking increase in the number of intermediate trophoblasts in the endometrium and myometrium, either in small nests, sheets, or individually, and without destructive invasion of the myometrium such that the myometrial anatomy is ­preserved. These cells are recognized under low-power magnification due to the nuclear atypia, hyperchromasia, and multinucleation [164]. They are usually mitotically inactive [13, 139].

13.10.5 Prognosis and Outcome

13.10.3 Biomarkers

13.11.2 Pathological Findings

The intermediate trophoblasts are immunoreactive for cytokeratins, hPL, inhibin, Mel-CAM (CD146), and MIB1 proliferative index (ki-67)