Cytopathology of the Glandular Lesions of the Female Genital Tract

Cytopathology of theGlandular Lesions of theFemale Genital TractMatías Jiménez-Ayala MadridBeatriz Jiménez-Ayala Portillo MadridIncluding contributions byFrancesc Alameda BarcelonaCarmen Alvarez-Santín MontevideoBelén Lloveras BarcelonaDina R. Mody Houston, Tex.Ritu Nayar Chicago, Ill.Manuel Nevado Santos MadridLara Pijuán BarcelonaFernando Pinedo Moraleda MadridMaria Carmen Rodríguez Alvarez MontevideoVolker Schneider FreiburgAdela Sica MontevideoMichael Thrall Houston, Tex.170 figures, 168 in color, and 26 tables, 2011Basel · Freiburg · Paris · London · New York · Bangalore ·Bangkok · Shanghai · Singapore · Tokyo · Sydney

Monographs in Clinical CytologyDr. Matías Jiménez-AyalaInstituto Jiménez-AyalaHermosilla 126E-28028 Madrid (Spain)E-Mail matiasjimenezayala@hotmail.comDr. Beatriz Jiménez-Ayala PortilloInstituto Jiménez-AyalaHermosilla 126E-28028 Madrid (Spain)E-Mail beatriz@institutojimenezayala.comLibrary of Congress Cataloging-in-Publication DataThis publication was sponsered byJiménez-Ayala, Matías.Cytopathology of the glandular lesions of the female genital tract /Matías Jimenéz-Ayala, Beatriz Jimenéz-Ayala Portillo ; includingcontributions by Frances Alameda Barcelona ... [et al.].p. ; cm. -- (Monographs in clinical cytology, ISSN 0077-0809 ; v.20)Includes bibliographical references and index.ISBN 978-3-8055-9464-6 (hard cover : alk. paper) -- ISBN 978-3-8055-9465-3(e-ISBN)1. Generative organs, Female--Cytopathology. I. Jiménez-Ayala Portillo,Beatriz. II. Title. III. Series: Monographs in clinical cytology ; v. 20.0077-0809[DNLM: 1. Genital Neoplasms, Female--diagnosis. 2. Genital Neoplasms,Female--pathology. 3. Cytodiagnosis--methods. 4. Neoplasms, Glandular andEpithelial--diagnosis. 5. Neoplasms, Glandular and Epithelial--pathology.W1 MO567KF v. 20 2011 / WP 145]RG107. 5. C95. J56 2011618.1--dc222010041126Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents®.Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s).The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. Thepublisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content oradvertisements.Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendationsand practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapyand drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This isparticularly important when the recommended agent is a new and/or infrequently employed drug.All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, includingphotocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.© Copyright 2011 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)www.karger.comPrinted in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, BaselISSN 0077–0809ISBN 978–3–8055–9464–6e-ISBN 978–3–8055–9465–3

To Sara, for her family ‘sacrifices’ during her first 2 years of life andin the hope she will be the third step in our cytopathology saga.

ContentsXIIIXIVXVXVIPrefaceForewordList of AbbreviationsList of AuthorsChapter 1Cytopathological Techniques for the Diagnosis of Glandular Lesions of the Genital Tract1 1.1. Introduction1 1.2. Fixation2 1.3. Staining3 1.4. Special Techniques4 ReferencesChapter 22001 Bethesda System Classification of Glandular Lesions on Cervical Cytology5 2.1. Introduction6 2.2. Glandular Epithelial Cell Abnormalities6 2.2.1. Atypical Glandular Cells6 2.2.2. Atypical Endocervical Cells7 2.2.3. Atypical Endometrial Cells8 2.3. Endocervical Adenocarcinoma in situ9 2.4. Adenocarcinoma12 2.5. Other12 2.5.1. Endometrial Cells in Women ≥40 Years of Age13 2.6. Impact of the 2001 Bethesda System13 2.7. Management14 ReferencesChapter 3Cytopathology of the Benign Glandular Lesions of the Cervix and Glandular Cytopathology of the Vagina15 3.1. Cytopathology of Benign Glandular Lesions of the Cervix15 3.1.1. Benign tumorsVII

15 3.1.1.1. Endocervical Polyp15 3.1.1.2. Müllerian Papilloma16 3.1.2. Other Non-Tumoral Lesions16 3.1.2.1. Tubal Metaplasia17 3.1.2.2. Microglandular Hyperplasia18 3.1.2.3. Cells of the Lower Uterine Segment19 3.1.2.4. Endometriosis19 3.1.2.5. Arias-Stella Reaction20 3.2. Glandular Cytopathology of the Vagina20 3.2.1. Tumoral Lesions20 3.2.1.1. Benign Tumoral Lesions: Adenomas20 3.2.1.2. Malignant Tumoral Lesions: Adenocarcinomas20 3.2.1.2.1. Clear Cell Adenocarcinoma21 3.2.1.2.2. Endometrioid Adenocarcinoma22 3.2.1.2.3. Mucinous Adenocarcinoma22 3.2.1.2.4. Mesonephric Adenocarcinoma22 3.2.2. Non-Tumoral Lesions22 3.2.2.1. Adenosis23 3.2.2.2. Fistulous Tracts23 3.2.2.3. Tubal Prolapse24 3.2.2.4. Post-Hysterectomy Glandular Cells24 ReferencesChapter 4Cytopathology of Adenocarcinoma in situ of the Endocervix and Its Differential Diagnosis26 4.1. Introduction26 4.2. Normal Endocervical Mucosa27 4.3. Benign and Reactive Changes27 4.4. Adenocarcinoma in situ30 4.5. Clinical Management of AIS31 4.6. Microinvasive Adenocarcinoma31 4.7. CIN 3 Mimics AIS31 4.8. Pregnancy Changes31 4.9. The Vaginal Cuff32 ReferencesChapter 5Cytopathology of the Malignant Invasive Lesions of the Endocervix34 5.1. Introduction34 5.2. Types of Malignant Invasive Lesions of the Endocervix34 5.3. Invasive Endocervical Adenocarcinoma34 5.3.1. Early Invasive Adenocarcinoma35 5.3.2. Mucinous Adenocarcinoma36 5.3.2.1. Endocervical Type Adenocarcinoma of the Endocervix38 5.3.2.2. Intestinal Variant38 5.3.2.3. Signet-Ring Cell Variant38 5.3.2.4. Minimal Deviation Variant39 5.3.3. Villoglandular Adenocarcinoma40 5.3.4. Endometrioid Adenocarcinoma of the Cervix40 5.3.5. Clear-Cell Adenocarcinoma41 5.3.6. Serous AdenocarcinomaVIIIContents

41 5.4. Uncommon Carcinomas of the Cervix41 5.4.1. Adenosquamous Carcinoma of the Cervix41 5.4.2. Glassy Cell Carcinoma Variant42 5.4.3. Adenoid Cystic Carcinoma of the Cervix43 5.4.4. Adenoid Basal Carcinoma of the Cervix43 5.4.5. Neuroendocrine Tumors43 5.5. Tumors Metastatic to the Cervix44 ReferencesChapter 6Endometrial Hyperplasias45 6.1. Introduction45 6.2. Clinical Features45 6.3. Pathophysiology46 6.4. Histopathology: WHO Classification47 6.5. Multicentric European Study on Endometrial Hyperplasia47 6.6. Diagnosis of Endometrial Hyperplasia47 6.7. Differential Diagnosis of Endometrial Hyperplasias48 6.8. Endometrial Intraepithelial Neoplasia48 6.8.1. Concept48 6.8.2. Clinical Features48 6.8.3. Diagnosis48 6.8.4. Management of EIN48 6.9. Current Status of Cytopathology of Endometrial Hyperplasias49 6.10. Practical Considerations49 6.11. Cytopathology of Endometrial Hyperplasias: The Jiménez-Ayala Classification49 6.11.1. Endometrial Hyperplasia50 6.11.2. Endometrioid Neoplasia51 ReferencesChapter 7Endometrial Adenocarcinoma: Current Status and Future of Prevention andEarly Diagnosis52 7.1. Introduction52 7.2. Current Status of the Prevention and Early Diagnosis of Endometrial Adenocarcinoma52 7.2.1. Increasing Incidence52 7.2.2. Pathogenesis53 7.2.3. High-Risk Population53 7.2.4. High-Risk Factors53 7.2.5. Diagnostic Methods for Endometrial Screening Program54 7.2.5.1. Techniques of Endometrial Cytology54 7.2.5.2. Histological Techniques55 7.2.5.3. New Gynecological Methods55 7.2.6. Histopathology of EmA: Grading55 7.2.7. Cytopathological Grading of EmA56 7.2.7.1. Low-Grade Adenocarcinoma (Well Differentiated)56 7.2.7.2. High-Grade Adenocarcinoma (Poorly Differentiated)57 7.2.8. Liquid-Based Preparation57 7.3. Future of Prevention and Early Diagnosis57 7.3.1. Challenges in Detection of Endometrial Malignant Lesions57 7.3.1.1. Assessment of High-Risk PopulationContentsIX

86 9.7. Final Remarks86 ReferencesChapter 10Glandular Lesions of the Fallopian Tube87 10.1. Histology of the Fallopian Tube87 10.2. Benign Fallopian Tube Lesions87 10.3. Tumors of the Fallopian Tube88 10.3.1. Benign Epithelial Tumors88 10.3.2. Malignant Epithelial Tumors89 10.3.3. Borderline Epithelial Tumors89 10.3.4. Carcinoma in situ89 10.4. Diagnosis of Tubal Carcinoma90 10.4.1. Cytology90 10.4.2. Cytological Features91 10.5. Differential Diagnosis91 ReferencesChapter 11Metastatic Glandular Lesions92 11.1. Introduction92 11.2. Metastases to the Genital Tract92 11.2.1. Metastases to the Vulva93 11.2.2. Metastases to the Vagina94 11.2.3. Metastases to the Cervix95 11.2.4. Metastases to the Endometrium95 11.2.5. Metastases to the Ovary96 11.3. Origin of Metastases96 11.3.1. Intragenital Metastases96 11.3.1.1. Metastases of Ovarian Origin97 11.3.1.2. Metastases of Endometrial Origin97 11.3.2. Extragenital Metastases97 11.3.2.1. Breast carcinoma97 11.3.2.2. Gastrointestinal Tract98 11.4. Clues for the Diagnosis of Metastatic Carcinomas in Cervicovaginal Smear99 ReferencesChapter 12Ancillary Techniques for the Diagnosis of Glandular Lesions of the Female Genital Tract101 12.1. Introduction102 12.2. HPV Probe102 12.2.1. Hybrid Capture II102 12.2.2. PCR103 12.3. Immunohistochemical Techniques for p16105 12.4. Other Techniques106 12.5. Conclusion106 References107 IndexContentsXI

PrefaceFollowing our first publication in the Karger seriesMonographs in Clinical Cytology (vol. 17), which wasdevoted to endometrial adenocarcinoma, we have spent thelast 2 years to preparing this second volume, GlandularLesions of the Female Genital Tract. We have been supportedin this by series editor Dr. Svante Orell and KargerPublishers. The subject is an area in which we have wideexperience and, on this occasion, we have been honored towelcome contributions from 12 international experts in thecytopathology of glandular lesions. Their writings cover thewide spectrum of this challenging subject.Genital glandular lesions, both benign and malignant,are an attractive area of cytopathology. Malignant lesions ofthe endocervix and endometrium are becoming more commonall the world, compared to squamous cell carcinoma.In this volume we present discussions of in situ and invasiveendocervical adenocarcinoma, endometrial adenocarcinomaand endometrial hyperplasias.Ovarian lesions focusing data obtained from intraoperativestudies are considered. Other areas of the genital tract,such as the vulva and the fallopian tube, which are less commonand thus have seen fewer publications, are also presented.The impact of the Bethesda System and basic andancillary techniques in the study of glandular lesions completeour monograph.We hope that this monograph will be useful tocytopathologists, pathologists, cytotechnologists and to studentsof these specialities, as it deals with the most commonareas of their daily work.AcknowledgementsOur gratitude goes to Dr. Svante Orell and to Mr. Thomas Noldfor their stimulating discussions and help in the preparation ofthis book. Thanks also to the contributors and to the staff of theInstituto Jiménez-Ayala, with special mention to PalomaFernandez Rueda for her dedicated and efficient secretarial work,and to senior cytotechnologist Concha Chinchilla.Matías Jiménez-Ayala, FIAC. Instituto Jiménez-Ayala andFormer Chair, Department of Cytology, HospitalUniversitario Gregorio Marañón, Madrid, SpainBeatriz Jiménez-Ayala Portillo, MIAC. Director, InstitutoJiménez-Ayala, Madrid,XIII

List of AuthorsFrancesc Alameda, MIAC. Department of Pathology,Hospital del Mar, Barcelona, Spain. Officer, SpanishSociety of Cytology (Chapter 12).Carmen Alvarez-Santín, MIAC. Former Professor ofPathology, University of Montevideo, Uruguay.Secretary General, Latin American Society of Cytology(Chapter 8).Matías Jiménez-Ayala, FIAC. Instituto Jiménez-Ayala,Madrid. Former Chair, Department of Cytology,Hospital Universitario Gregorio Marañón, Madrid,Spain. Former President of the International Academyof Cytology (Chapters 5, 6, 7, 9, 10, 11).Beatriz Jiménez-Ayala Portillo, MIAC. Director, InstitutoJiménez-Ayala, Madrid, Spain (Chapters 3, 5, 10, 11).Belén Lloveras, Department of Pathology, Hospital delMar, Barcelona, Spain (Chapter 12).Dina R. Mody, MD. Professor of Pathology and LaboratoryMedicine, Weill Medical College of Cornell University.Director of Cytology Laboratory and FellowshipProgram, The Methodist Hospital, Houston, Tex., USA(Chapter 2).Ritu Nayar, MIAC. Professor of Pathology and Director ofCytopathology, Northwestern University, FeinbergSchool of Medicine, Chicago, Ill., USA (Chapter 2).Manuel Nevado Santos, MIAC. Chair, Department ofPathology, Hospital Infanta Cristina, Parla, Madrid,Spain (Chapter 1).Lara Pijuán, Department of Pathology, Hospital del Mar,Barcelona, Spain (Chapter 12).Fernando Pinedo Moraleda, Chair, Department ofPathology, Hospital Universitario Fundación Alcorcón,Madrid, Spain (Chapters 1, 9, 10).Maria Carmen Rodríguez Alvarez. Chair,Dermatopathology Area, Department of Pathology,Centro Hospitalario Pereira Rosell, Montevideo,Uruguay (Chapter 9).Volker Schneider, FIAC. Head, Pathology Laboratory,Freiburg, Germany. Former Secretary General,International Academy of Cytology (Chapter 4).Adela Sica. Department of Pathology, University ofMontevideo, Montevideo, Uruguay (Chapter 8).Michael Thrall, Assistant Professor, Department ofPathology and Laboratory Medicine, Weill MedicalCollege of Cornell University, The Methodist Hospital,Houston, Tex., USA (Chapter 2).XVI