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Diagnosis of Endometrial Biopsies and Curettings A Practical Approach Tricia A. Murdock Emanuela F. T. Veras Robert J. Kurman Michael T. Mazur Third Edition 123 Diagnosis of Endometrial Biopsies and Curettings Tricia A. Murdock • Emanuela F. T. Veras Robert J. Kurman • Michael T. Mazur Diagnosis of Endometrial Biopsies and Curettings A Practical Approach Third Edition Tricia A. Murdock Emanuela F. T. Veras Department of Pathology Department of Pathology The Johns Hopkins Hospital The Johns Hopkins Hospital Baltimore, MD Baltimore, MD USA USA Robert J. Kurman Michael T. Mazur Department of Pathology Department of Pathology and The Johns Hopkins Hospital Laboratory Medicine, State University Baltimore, MD of New York Upstate Medical University USA Syracuse, NY USA ISBN 978-3-319-98607-4 ISBN 978-3-319-98608-1 (eBook) https://doi.org/10.1007/978-3-319-98608-1 Library of Congress Control Number: 2018960871 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, 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 publisher, 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 publisher 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 publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface The third edition of Diagnosis of Endometrial Biopsies and Curettings: A Practical Approach developed from positive comments received from the second edition and recognition that several topics have advanced since the last publication. The emphasis of this book is to provide a foundation for a daily, pragmatic approach for common entities found in endometrial samples. Our understanding of endometrial pathology has evolved, and clinical termi- nology accompanying these specimens also has changed. Therefore, the entire text has been updated; all illustrations are now in color. As with the first two editions, the focus of this book is to assist the patholo- gist in the routine evaluation of endometrial tissue specimens. The book is not intended to be an all-encompassing text of endometrial pathology but to guide the pathologist through the more common diagnoses such as artifacts, benign entities, precursor lesions, and neoplasia. We recognize that for cer- tain areas, such as precursors of endometrial cancer, there is ongoing debate and study regarding the terminology for these lesions. Different investigators and practitioners prefer different terminologies (hyperplasia/atypical hyper- plasia versus hyperplasia/endometrial intraepithelial neoplasia [EIN]), and we therefore attempt to provide a balanced discussion of both so readers can decide which they prefer. For the majority of the text, the terminology and classification schemes mirror the most recent edition (2014) of the WHO Classification of Tumors of Female Reproductive Organs in an effort to pro- mote uniform and comprehensive communication with our clinical col- leagues as ultimately this is the most important role of the diagnostic surgical pathologist. In the second edition, immunohistochemistry (IHC) was largely discussed in the final chapter on methodology, but as its use in diagnosis has greatly expanded, the current edition incorporates IHC into each of the individual chapters. Furthermore, IHC now has an important role as a surrogate marker of genetic aberrations, knowledge of which is becoming increasingly impor- tant for diagnostic and therapeutic purposes. For example, the use of fumarate hydratase staining to detect fumarate hydratase-deficient leiomyomas can lead to the recognition of the hereditary leiomyomatosis and renal cell carci- noma syndrome. Although molecular diagnostics currently are infrequently used in routine evaluation of endometrial specimens, pathologists need to be familiar with the advances in molecular genetics as this is transforming our understanding of many of the pathologic conditions that can be found in endometrial v vi Preface samples. For example, the classification of endometrial stromal tumors has been modified based on fluorescence in situ hybridization and targeted RNA sequencing that have demonstrated different types of high-grade endometrial stromal sarcomas depending on their molecular genetic features. Another example is that through molecular genotyping, we are now able to defini- tively diagnose partial hydatidiform moles, whereas in the past morphologi- cal, immunohistochemical, and cytogenetic studies were insufficiently reliable to make a definitive diagnosis. In summary, we hope that this new edition continues to be a foundation for the diagnosis of endometrial specimens with a strong emphasis on the impor- tant morphologic features and that this will be useful to pathologists and gynecologists. Baltimore, MD, USA Tricia A. Murdock Baltimore, MD, USA Emanuela F. T. Veras Baltimore, MD, USA Robert J. Kurman Syracuse, NY, USA Michael T. Mazur Acknowledgments We are grateful to Norman Barker, a friend and colleague, who provided his expertise in the field of medical illustration and tirelessly assisted us with the images depicted in this edition. We are also grateful to Dr. Lora Ellenson, another good friend and esteemed colleague, for generously supplying updated information that helped enrich the contents of this book. vii Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Indications for Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Clinical History and Biopsy Interpretation . . . . . . . . . . . . . . . . . . . 2 Abnormal Uterine Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Infertility Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Products of Conception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Clinical Queries and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2 The Normal Endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 General Considerations in Histologic Evaluation . . . . . . . . . . . . . . 10 Histologic Features of Normal Cycling Endometrium . . . . . . . . . . 13 Proliferative Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Secretory Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Menstrual Endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Pitfalls in The Histologic Assessment of The Normal Endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Sample Adequacy and Standardized Reporting . . . . . . . . . . . . . . . 24 Artifacts and Contaminants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Irregular Secretory Endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Clinical Queries and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 3 Pregnancy, Abortion, and Ectopic Pregnancy . . . . . . . . . . . . . . . 39 Endometrial Glands and Stroma in Pregnancy . . . . . . . . . . . . . . . . 40 Early Gestational Endometrium (1–3 Weeks Postfertilization) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Endometrium in Later Pregnancy (4 or More Weeks Postfertilization) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Arias-Stella Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Other Glandular Changes in Pregnancy . . . . . . . . . . . . . . . . . . . . . 47 Trophoblast and Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Trophoblastic Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Immunohistochemistry of Trophoblastic Cells . . . . . . . . . . . . . . 51 Placental Implantation Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Chorionic Villi and Villous Trophoblast in the First Trimester . . . . 57 ix x Contents Hydropic Change and Other Pathologic Changes in Abortions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Chorionic Villi and Villous Trophoblast After the First Trimester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Placental Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Placenta Accreta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Endometrium Associated with Ectopic Pregnancy . . . . . . . . . . . . . 64 Clinical Queries and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 4 Gestational Trophoblastic Disease . . . . . . . . . . . . . . . . . . . . . . . . . 75 Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 General Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Complete Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Partial Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Cytogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Abnormal (Non-molar) Villous Lesions . . . . . . . . . . . . . . . . . . . 90 Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Persistent Postmolar Gestational Trophoblastic Disease and Invasive Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . . 91 Clinical Queries and Reporting of Hydatidiform Mole . . . . . . . 93 Gestational Trophoblastic Neoplasms. . . . . . . . . . . . . . . . . . . . . . . 94 Choriocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Placental Site Trophoblastic Tumor . . . . . . . . . . . . . . . . . . . . . . 100 Epithelioid Trophoblastic Tumor . . . . . . . . . . . . . . . . . . . . . . . . 107 Nonneoplastic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Exaggerated Placental Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Placental Site Nodule and Plaque . . . . . . . . . . . . . . . . . . . . . . . . 111 Clinical Queries and Reporting of Trophoblastic Neoplasms . . . . . 112 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 5 Abnormal Uterine Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Morphologic Features of Glandular and Stromal Breakdown in Menstrual and Abnormal Bleeding . . . . . . . . . . . . . . . . . . . . . . . 122 Abnormal Uterine Bleeding: Nonstructural Causes . . . . . . . . . . . . 126 Estrogen-Related Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Proliferative Endometrium with Glandular and Stromal Breakdown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Disordered Proliferative Endometrium and Persistent Proliferative Phase . . . . . . . . . . . . . . . . . . . . . . . . 132 Atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Progesterone-Related Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Irregular Secretory Endometrium . . . . . . . . . . . . . . . . . . . . . . . . 136 Irregular Shedding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Abnormal Secretory Endometrium with Breakdown of Unknown Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Clinical Queries and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Contents xi 6 Effects of Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Estrogenic Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 Progestins, Oral Contraceptives, and Selective Progesterone Receptor Modulators . . . . . . . . . . . . . . . . . . . . . . . . . 146 Patterns of Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Decidual Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Secretory Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Inactive Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Other Stromal Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Combined Estrogen and Progestin as Replacement Therapy for Menopausal Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Progestin-Like Effects with No Hormone Use . . . . . . . . . . . . . . 154 Effects of Other Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Selective Progesterone Receptor Modulators . . . . . . . . . . . . . . . 155 Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Raloxifene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Clomiphene Citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Danazol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Human Menopausal Gonadotropins/Human Chorionic Gonadotropin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Gonadotropin-Releasing Hormone Agonists . . . . . . . . . . . . . . . 162 Antiprogestin RU486 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Clinical Queries and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Postmenopausal Hormone Replacement . . . . . . . . . . . . . . . . . . . 163 Abnormal Uterine Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Treatment of Hyperplasia and Endometrioid Carcinoma . . . . . . 164 Infertility Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 7 Endometritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Nonspecific Endometritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Inflammatory Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Stromal Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Abnormal Glandular Development . . . . . . . . . . . . . . . . . . . . . . . 178 Epithelial Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Glandular and Stromal Breakdown . . . . . . . . . . . . . . . . . . . . . . . 179 Specific Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Granulomatous Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Actinomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Cytomegalovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Herpesvirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Mycoplasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Clinical Queries and Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 8 Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Classification and Histologic Features . . . . . . . . . . . . . . . . . . . . . . 200 Common Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

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The 3rd edition of this text entails a comprehensive review of endometrial pathophysiology, including the recognition of physiologic conditions (i.e. normal phases and pregnancy), as well as the accurate interpretation of pathologic entities (i.e. polyps, endometritis, gestational trophoblastic dise
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