ESGO 2016.indb - Pathology Outlines

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TEXTBOOK OF GYNAECOLOGICAL ONCOLOGY Editors

Ali Ayhan Nicholas Reed Murat Gultekin Polat Dursun Associate Editors

Irem Kucukyildiz Mujdegul Karaca

Turkish Society of Gynecologic Oncology

GÜNEŞ PUBLISHING

TEXTBOOK OF GYNAECOLOGICAL ONCOLOGY Copyright ©2016 by the Güneş Publishing ISBN: 978-975-277-645-6 Name: Textbook of Gynaecological Oncology Publisher: Güneş Publishing Editors: Ali Ayhan, Nicholas Reed, Murat Gultekin, Polat Dursun All rights reserved. Printed in Turkey. Exclusive rights by Güneş Publishing and editors for manufacture and export. Due to the Turkish legislations of 5846 and 2936, except as permitted, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. All the copying and distribution rights belong to Güneş Publishing and the editors of this book.

Director of the Publisher Company: Murat Yılmaz Deputy Director of Publisher Company: Polat Yılmaz Publishing Consultant and Medical Coordinator: Ufuk Akçıl Foreign Language Editor: Nicholas Reed Designer: İhsan Ağın Published in: Ayrıntı Basımevi - İvedik Organize Sanayi Bölgesi 28. Cad. 770 Sok. No: 105-A Ostim/ANKARA/TURKEY Telefon: (0312) 394 55 90-91-92 • Faks: (0312) 394 55 94 Sertifika No: 13987

WARNING Medical information is continuously renewed day by day. During reading this book, it should be kept in mind that some changes may be necessary in the treatment and drug administration protocols in the light of the evidence coming from the current literature. Always, safety standards should be applied on management of patients. It is advised for the readers to check once more the information of the drugs related to the product info, dosage and administration forms and contraindications before administering the drug to the patients. Publishers and the editors are not responsible for any medical damage to the patients or the equipments. THIS BOOK IS ENDORSED by EUROPEAN SOCIETY of GYNACOOGICAL ONCOLOGY (ESGO) The scientific contents can not be accepted as official ESGO recommendations. All scientific information and recommendations only concern the corresponding authors.

GÜNEŞ PUBLISHING

www.guneskitabevi.com

ESGO Members Quotes on the 1st Edition of Textbook of Gynaecological Oncology, 2009 “An innovative presentation of great topics! It is the “must have” for everyone interested in Gynaecologic Oncology! It covers all fields of Gynaecological Oncology - from basic articles to controversial discussions on cutting-edge subjects. Includes famous Gynaecologic Oncologists writing about their field of speciality – an absolute must read!” Dr. Michaela Bossart, Germany “The textbook is an easy to read and very complete guide on Gynecologic Oncology. The quality of authors is awesome and the contents concise and practical. It´s a great introduction and good general view of all aspects of the subspecialty; this without a doubt should be the reference for young trainees. Congratulations on a great job. “ Dr. Ignacio Zapardiel, Spain “The 1st edition of the Textbook contains comprehensive coverage of the huge field of Gynaecological Oncology. On the one hand it provides a basic knowledge on topics of interest for trainees, on the other hand, specialists can find up to date information on surgery, radiotherapy, chemotherapy and imaging specialties. Every single topic provides insightful information and areas for discussion. It gives a wonderful overview of the pros and cons and provides a platform for discussion in the most discussion provoking areas of our subject.” Dr. Rene Laky, Austria “This edition covers the most interesting topics of Gynecologic Oncology and will be incredibly useful for trainees and young doctors. The book includes topics of gynaecancer and pregnancy that is also very important and useful for the clinical practice of each OBGYN doctor. It is great to have a book that introduces all new technologies and management in Gynaecological Oncology.” Dr. Suzanna Babloyan, Armenia “A thoroughly enjoyable read! It is a great first edition, extremely comprehensive covering several complex topics and areas of interest for trainees. It helped me personally to improve my understanding in a number of interesting areas and it is a good reference book. I congratulate the editors, the authors and ESGO on this massive effort!” Dr. Ranjit Manchanda, UK “Excellent! Covered several different topics and answered many pending questions. The combination of the enthusiasm of ENYGO’s authors along with the experience of the senior authors makes the book unique. Can be read by the young residents of gynecology as well as by the senior gyn oncologists - both will find topics of their interest. Simply mesmerizing! ” Dr. Dimitrios Haidopoulos, Greece “The first edition is a very interesting book on gynecologic oncology, extremely clear on different topics and easy to consult also for trainees. Each chapter has been written by the experts in gynecologic oncology, very useful in clinical practice. Great references. Congratulate the editors and authors for their efforts.” Dr. Michele Peiretti, Italy “Exceptional work which is due to its rapidness of the writing and up-to-date editing as an journal article whilst maintaining the comprehensiveness of a textbook. The author list presents all the most famous current onco gynaecologists which makes the texts scientifically outstanding.” Dr. Michael Halaska, Czech Republic “In itself the Idea of creating this book is an ambitious, timely and grandiose one. Many thanks to the Editors and ESGO/ENYGO for the ability to realize this idea. Authorship of the main chapters belongs to the most competent and qualified specialists in this area. The book is very useful not only for beginners, but experienced doctors. It is very convenient to have such a Clear Guide with the final recommendations in diagnostics and treatment of the reproductive tract malignances.” Dr. Elena Ulrikh,Russia “The textbook is easy-to-read and understand It should be on the shelf of every gynecologic oncologist’s office. Makes a difference on an every day basis The authors’ tremendous amount of knowledge of the area is quite evident A must for all gynecologic oncologist’s....” Dr. Karina Dahl Steffensen, Denmark “The textbook has been written in easy and smart style. All-round contents of contemporary gynecologic oncology (including even history!) and breast cancer enables any interested doctor or tutor to find useful information easily. It makes this textbook a table-book for oncology trainees, young specialists and experienced doctors. Of course, for me too!” Looking forward to receiving the second edition! Dr. Gauhar Dunenova, Kazakhstan “This is a very good book which aggregates most of the techniques, knowledge and expertise in Gynaecologic Oncology in a very accurate and interesting way. Both trainees and specialist benefit from reading it.” Dr. Filipe Martins, Portugal

Preface to the Third Edition

The European Society of Gynaecological Oncology is proud to present to you the third edition of its textbook. This textbook is one of our most ambitious and successful educational projects. It is built on the unique ESGO network of experts, who have voluntarily compiled topics in which they are the key opinion leaders. Each edition reflected recent developments in gynaecologic oncology but gradually it has expanded into other specialities and that makes the book truly multidisciplinary. The textbook does not represent for ESGO an isolated initiative; it is part of a logical and mutually complementary mosaic, together with many other educational projects such as web portal e-Academy, traditional bi-annual congresses, a new format of State-of-the-Art meetings in the odd years when the congress is not held, dozens of ESGO-endorsed sessions, videos of surgical procedures, teaching DVDs, etc. On behalf of the ESGO Council, I would like to extend my gratitude for and appreciation of all the contributing authors and their co-workers. A special credit goes to two men behind the textbook, Dr. Murat Gultekin, who initiated and run the project, and Dr. Nicholas Reed, who carefully revised and refined the majority of the chapters. I can proudly encourage you to commence your reading! David Cibula ESGO President

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Preface

Dear All Gynaecologic Oncology, our lovely profession, take more and more acceptance since its first establishment. It requires a multidisciplinary team to provide the diagnosis, treatment and postoperative care of the cancer patients. Therefore, a didactic training program is necessary for the management of patients with gynaecologic cancers. Unfortunately, despite the fact that most of the gynaecologic cancers seen in undeveloped or developing countries, official gynecologic oncology training programmes are approved in only a few number of well developed countries. Our main intend to edit such a book was to be contribute to the gynaecologic oncologic training; especially in countries where such an official training is not available. Our goal was to provide a comprehensive and practical book to guide gynaecologic oncology workers. With this purpose, “Textbook of Gynaecologic Oncology” was written to provide a concise update of current clinical gynaecologic oncology. As editors, we tried to include all the subjects of gynaeocologic cancersfrom preinvasive diseases to metastatic diseases. Surgical and medical treatments of all gynaecologic oncologic disases are summarized by the authors. We also tried to include the new surgical and medical developments in gynaecologic oncology. There are discussions about the most debate areas of gynaecologic oncology and review of multinational trials. Also, future aspects of gynaecologic oncology and recent advances are reviewed. I would like to thank to ESGO council and Prof.David Cibula, President of ESGO, for their endless support for the preparation of this book. Such a comprehensive textbook is not possible without the help of our colleagues. The authors of this book are chosen all around the world and are very famous in their topics. As you will see from the list of authors, this book almost include all the living pioneers and famous gynaecologic oncologists. Many thanks are due to all the authors who have contributed to this book and also editorial staff of Güneş Publishing. We would like to also specially thank to our co-editors. Without their tireless efforts, this book has never come to reality. The knowledge and love increase with sharing May wisdom and love reign in the light of intelligence Ali Ayhan - Murat Gultekin - Polat Dursun

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Preface to the Third Edition

It is a remarkable achievement that within 7 years this book has run to a third edition and the editorial team working with ESGO, ENYGO and the Turkish Society of Gynaecologic Oncology must be congratulated for producing such a remarkable volume. So many of the world’s leading experts have voluntarily contributed state-of-the-art chapters in a remarkable turnaround time. As one of the editors I have read just about every chapter and can vouch for the clinical excellence and up-to-date status. Although hard work at times and demanding when a batch of 10 chapters was sent in, it has been a pleasure to read and review these. It is a credit to all the societies involved and is fantastic asset for trainees in all disciplines of gynaecological oncology. I think it will also be a wonderful asset for established specialists who will find its state-of-the-art references an invaluable resource. If the reader feels that there are areas of overlap with some of the chapters, this is because we had tried to get as many viewpoints as possible. Medicine is not black and white and in many situations there are varying shades of grey and opinions. We also try to reflect international practice with expert contributors from the Americas, Central Europe, the Middle East, South Asia, the Far East and Australasia. Of course the world is shrinking place with modern travel and we are a far more integrated Society, but there are cultural and ethnic diversities which are reflected in medical practice. We also recognise that resources vary internationally and that not every Centre has access to robotic surgery, PET/CT scanning all the latest targeted chemotherapy agents even though they may aspire to them. However what they do have is enthusiastic and dedicated surgeons, oncologists, pathologists, radiologists and nurses. In this modern age where so much information and learning is gained digitally through the Web, it is remarkable to have a physical resource which is so up-to-date and supportive. Once again I must congratulate Murat Gultekin and Polat Dursun for the never-ending enthusiasm support and professionalism in persuading busy gynaecological Cancer specialists all around the world to either update their chapters or write new chapters. I would also like to pay tribute to Professor Ali Ayhan without whose original stimulus, this project would never have got off the ground. It has been a great honour and pleasure to be associated with this third addition and we look forward to future additions although whether these are conventional book forms ordered DVD discs. Finally I would like to acknowledge a wonderful work of the production team, especially Irem Kucukyildiz and Mujdegul Karaca without whose enthusiasm and support this would never have been produced. Nicholas Reed, Glasgow UK

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Authors

Nadeem R. Abu-Rustum, MD

Banu Arun, MD

Sunil J. Advani, MD

Macit Arvas, MD

Memorial Sloan Kettering Cancer Center, New York, USA University of California, San Diego, USA

Ali Akdemir, MD

Ege Üniversity School of Medicine, Izmir, Turkey

Levent Akman, MD

Ege University Medical School, Izmir, Turkey

Bahriye Aktas, MD

University of Duisburg-Essen, Germany

Sercan Aksoy, MD

Univeristy of Texas, M.D. Anderson Cancer Center, Texas, USA Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey

Banu Atalar, MD

Acibadem University, School of Medicine, Istanbul, Turkey

Elisabeth Åvall-Lundqvist, MD, PhD

Linköping University, Linköping, Sweden

Ali Ayhan, MD

Hacettepe University Faculty of Medicine, Ankara, Turkey

Baskent University Faculty of Medicine, Ankara, Turkey

Senem Alanyali, MD

Ayse Ayhan, MD, PhD

Ege University, School of Medicine, Izmir, Turkey

Giovanni D. Aletti, MD

European Institute of Oncology, Milano, Italy

Fiori Alite, MD

Seirei Mikatahara Hospital, Japan John Hopkins University School of Medicine, Baltimore, MD, USA Hamamatsu and Hiroshima University School of Medicine, Japan

Enrica Bentivegna, MD

Institut Gustave Roussy, Villejuif, France

Jonathan S. Berek, MD

Stanford Women’s Cancer Center, Stanford University School of Medicine, Stanford, USA

Christine Bergeron, MD, PhD Laboratoire Cerba, France

Kjell Bergfeldt, MD, PhD

Regional Cancer Center Stockholm/Gotland Karolinska Institutet, Dept MEB, Sweden

Johannes Berkhof, PhD

Klinikum der Stadt Wolfsburg, Germany

Adriana Bermudez, MD, PhD

Buenos Aires University Hospital, Buenos Aires, Argentina

Penny Blomfield, MD

Royal Hospital for Women University of Tasmania, Tasmania, Australia

Andreas du Bois, MD, PhD

Stritch School of Medicine Loyola University Chicago Cardinal Bernardin Cancer Center, USA

Evandro de Azambuja, MD, PhD

Institut Jules Bordet and Université Libre de Bruxelles, Brussels, Belgium

Kliniken Essen Mitte (KEM) Evang, Huyssens-Stift ung/Knappschaft GmbH Henricistr, Essen, Germany

Maribel Almonte, PhD

Claire Bailey, MRCOG

Pierre-Adrien Bolze, MD

International Agency for Cancer Research, Lyon, France

Sonsoles Alonso, MD

MD Anderson Cancer Center, Madrid, Spain

Aytekin Altintas, MD

Sandwell and West Birmingham NHS Trust, UK

Jamie N. Bakkum-Gamez, MD Mayo Clinic, Minnesota, USA

Lyon Sud University Hospital

Lorenzo Bono, MD, Bsc University of Turin, Italy

Dustin L. Boothe, MD

Cukurova University, Faculty of Medicine, Adana, Turkey

Marie Bannier, MD

Institut Paoli Calmettes, Marseille, France

Huntsman Cancer Hospital, University of Utah, USA

Mustafa Kadri Altundag, MD

Marc Barahona, MD

Mostafa A. Borahay, MD

Hacettepe University Faculty of Medicine, Ankara, Turkey

Ozden Altundag, MD

Baskent University Faculty of Medicine, Ankara, Turkey

Giulia Amadio, MD

Gynecologic Oncology Unit, Catholic University, Rome, Italy

Frederic Amant, MD, PhD

University Hospitals Leuven, Leuven, Belgium

Antonios Anagnostopoulos MD

Liverpool Women’s Hospital, Liverpool, UK

Stefano Angioni, MD, PhD University of Cagliari, Italy

Marc Arbyn, MD, MSc, DrTMH Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium

Deborah K. Armstrong, MD

John Hopkins Kimmel Cancer Center, Baltimore, MD, USA

University Hospital of Bellvitge IDIDELL Barcelona, Spain

Tara D. Barwick, MBChB, MSc, MRCP, FRCR

Imperial College Healthcare NHS Trust, London, UK Honorary Clinical Senior Lecturer, Faculty of Medicine, Imperial College London, UK

Anne-Sophie Bats, MD, PhD

Georges Pompidou European Hospital, APHP, Paris, France René Descartes, Paris V University, Paris, France

Uziel Beller, MD

Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel

Chérazade Bensaïd, MD

Hôpitaux de Paris, Hôpital Européen GeorgesPompidou, Chirurgie Cancérologique Gynécologique et du Sein, Paris, France

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University of Texas Medical Branch, Texas, USA

F. Xavier Bosch, MD

Institut Català d’Oncologia, IDIBELL, Cancer Epidemiology Research Programme (CERP), Spain

Tjalling Bosse, MD, PhD

Leiden University Medical Centre, The Netherlands

Peter Bösze, MD

Editors in Chief of EJGO and Chairman of EAGC, Budapest, Hungary

Revaz Botchorishvili, MD

CHU - Hospital Estaing, France

Loic Boulanger, MD

Centre Oscar Lambret, Lille, France

Nicolas Bourdel, MD

CHU - Hospital Estaing, France

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Authors

Robert E. Bristow, MD, MBA University of California, USA

Jubilee Brown, MD

University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Sjoerd H. van der Burg, PhD

Leiden University Medical Center, Leiden, Netherlands

Isabelle Cadron, MD

Universitaire Ziekenhuizen Leuven, Leuven, Belgium

Kristel Van Calsteren, MD, PhD

Lieve Coenegrachts, MD

University Hospitals Leuven, Leuven, Belgium

Robert L. Coleman, MD

The University of Texas, M.D. Anderson Cancer Center, Houston, USA

Nicoletta Colombo, MD

European Institute of Oncology, Milan, Italy

An Coosemans, MD, PhD

University Hospitals Leuven, Leuven, Belgium

Nandita deSouza, M. MD, FRCR

The Institute of Cancer Research and Honorary Consultant at The Royal Marsden Hospital NHS Foundation Trust, UK

Mireia Diaz, PhD

Institut Català d’Oncologia, IDIBELL Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme (CERP), Spain

Violante Di Donato, MD, PhD

Umberto I, ‘‘Sapienza’’ University, Rome, Italy

Valentina Corda, MD

Cristina Donfrancesco, MD

University of Cagliari, Italy

Umberto I, ‘‘Sapienza’’ University, Rome, Italy

Allan Covens, MD

Oliver Dorigo, MD

Carien L. Creutzberg, MD PhD

Jean Doyen, MD

Michel Canis, MD, PhD

Leiden University Medical Center Leiden, The Netherlands

Evelyn Cantillo, MD, MPH

Antonella Cromi, MD, PhD

Women and Infants’ Hospital, USA

University of Insubria, Varese, Italy

Polat Dursun, MD

Silvia Cardinale, MD

Emma J. Crosbie, MRCOG, PhD

Joseph W. Carlson, MD, PhD

Sandra Curiner, MD

CHU - Hospital Estaing, France

UT MD Anderson Cancer Center, Houston, USA

Jack Cuzick, PhD

Jens Einenkel, MD

Queen Mary University of London Charterhouse Square, London, UK

Centre for Women’s and Children’s Health Leipzig University, Germany

Centre for Cancer Prevention

Scott M. Eisenkop, MD

Wolfson Institute of Preventive Medicine Queen Mary University of London

Women’s Cancer Center of Southern California, CA, USA

Emanuela D’Angelo, MD

Ram Eitan, MD

University Hospitals Leuven, Leuven, Belgium

Sandrine Campagne, MD

CHU - Hospital Estaing, France

Adriana Bittencourt Campaner, MD, PhD Santa Casa de Sao Paulo Hospital,Brazil CHU - Hospital Estaing, France

University of Insubria, Varese, Italy Karolinska University Hospital, Stockholm, Sweden

Antonio Casado, MD, PhD

Hospital Universitario Clínico San Carlos, Madrid, Spain

Jvan Casarin, MD

University of Insubria, Varese

Assunta Casorelli, MD

Umberto I, ‘‘Sapienza’’ University, Rome, Italy

Husnu Celik, MD

Baskent University Faculty of Medicine, Adana, Turkey

Cyrus Chargari, MD, PhD

Institut Gustave Roussy, France

Cariad Chester, MD

Sunnybrook Health Sciences Center, Toronto, Canada

University of Manchester, Manchester, UK

Stanford Women’s Cancer Center, Stanford University School of Medicine, Stanford, USA CHU de Liège, University of Liège, Liège, Belgium Baskent University Faculty of Medicine, Ankara, Turkey

Patricia Eifel J., MD

Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain

Obstetrics and Gynecology, Rabin Medical Center, Israel

Pernilla Dahm-Kähler, MD, PhD

Palliative Care Service University of California San Francisco, USA

Sahlgrenska University Hospital, Gothenburg, Sweden

Giovanni Elia, MD

Karim S. ElSahwi, MD, FACOG

Stanford University School of Medicine, Stanford, California, USA

Nagindra Das, MRCOG

Royal Cornwall Hospital, Truro, UK

Meridian Health Rutgers-RWJMS, Neptune, USA

Dennis S. Chi, MD

Marjolein DeCuypere, MD

Ingeborg B. Engelsen, MD, PhD

Luis M. Chiva, MD, PhD

Murat Dede, MD

Ane Gerda Zahl Eriksson, MD

Gulhane Military University Hospital, Ankara, Turkey

Memorial Sloan Kettering Cancer Center, New York, USA

Hackensack University Medical Center, Hackensack, NJ & Englewood Hospital, Englewood, NJ

Suha Deen, FRCPath

Pedro F. Escobar, MD

Nottingham Univestiry Hospitals, Nottingham, UK

Cleveland Clinic Foundation, Cleveland, OH, US

Youn Jin Choi, MD

Katty Delbecque, MD

Amanda N. Fader, MD

CHU de Liège, University of Liège, Liège, Belgium

Cleveland Clinic Foundation, Cleveland, OH, US

David Cibula, MD, PhD

Fuat Demirkiran, MD

Giovanni Favero, MD

Memorial Sloan Kettering Cancer Center, New York, USA MD Anderson International Spain, Madrid, Spain

Jennifer E. Cho, MD, FACOG

Seoul St. Mary’s Hospital, School of Medicine, The Catholic University of Korea General University Hospital, First Medical School, Charles University, Prague, Czech Republic

William A. Cliby, MD

Mayo Clinic Arizona, USA

CHU de Liège, University of Liège, Liège, Belgium

Istanbul University Cerrahpasa School of Medicine Istanbul, Turkey

Lynette Denny, MD, PhD

University of Cape Town, Cape Down, South Africa

Haukeland University Hospital, Bergen, Norway

Asklepios Hospital Hamburg, Germany

Jacques Ferlay, ME

Informatics Officer, Section of Cancer Surveillance International Agency for Research on Cancer, Lyon, France

Authors

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Andreia Fernandes, RN, MSc

Khadra Galaal, FRCOG

Sébastien Gouy, MD, PhD

Gustavo Leme Fernandes, MD

Alberto Gallardo, MD

Jacek P. Grabowski, MD, PhD

Royal Marsden Hospital, UK

Santa Casa de Sao Paulo Hospital, Brazil

Royal Cornwall Hospital, Truro, UK

Luz M. Fernandez, MD

University of Louisville, USA

Hospital de la Santa Creui Sant Pau, Autonomous University of Barcelona, Spain and “La Sapienza” University Faculty of Medicine, Rome, Italy

Gabriella Ferrandina, MD

Carmen Gan, MRCOG

Catholic University, Rome, Italy

Annamaria Ferrero, MD, PhD

Mauriziano Hospital, University of Torino, Torino, Italy

Frank D. Ferris, MD, FAAHPM, FAACE Palliative Medicine, Research & Education OhioHealth, Columbus, Ohio, USA

Gwenael Ferron, MD, PhD

Institut Claudius Regaud, University of Toulouse, France

Anna Festi, MD

AOUI - University Hospital of Verona, Italy

Ulas Fidan, MD

Gulhane Military University Hospital, Ankara, Turkey

Daniela Fischerova, MD, PhD

First Faculty of Medicine and General University Hospital, Charles University in Prague, Czech Republic

Rosalie Fisher, MBChB, FRACP University of Auckland, Auckland, New Zealand

Paul A. Foster, MD, PhD

Institute of Metabolism & Systems Research, University of Birmingham, Birmingham, UK

Stelios Fotiou, MD, PhD

University of Athens, Aretaieion Hospital, Athens, Greece

Christina Fotopoulou, MD, PhD

Imperial College London Department of Gynaecology, London, UK

Gianluca Franceschini, PhD

Catholic University of Rome, Italy

Michael Friedlander, MD, PhD

Australia and New Zealand Gynecologic Oncology Group ANZGOG Camperdown, Sydney, Australia

Fieke EM Froeling, MD

Imperial College London, London, UK

Shingo Fujii, MD

The Tazuke Kofukai Medical Research Institute, Osaka, Japan

Keiichi Fujiwara, MD, PhD

Saitama Medical University International Medical Center, Saitama, Japan

Institut Gustave Roussy, Villejuif, France European Competence Center for Ovarian Cancer, Charite-University Medicine of Berlin, Germany

Heidi J. Gray, MD

Royal London Hospital, London, UK

University of Washington, Cancer Care Alliance Seattle Washington, USA

Amparo Garcia-Tejedor, MD

Stefano Greggi, MD, PhD

University Hospital of Bellvitge IDIDELL Barcelona, Spain

Ginger J. Gardner, MD

Memorial Sloan Kettering Cancer Center, New York, USA

Hugo Gaspar, MD

Hospital Dr Nélio Mendonça University, Madeira, Portugal

Fabio Ghezzi, MD

University of Insubria, Varese, Italy

Lilian T. Gien, MD, MSc, FRCSC

National Cancer Institute “G. Pascale”, Naples, Italy

Anne Sophie Grémeau, MD

CHU - Hospital Estaing, France

John A. Green, MD, FRCP

Institute of Translational Medicine University of Liverpool Clatterbridge Centre for Oncology, Bebington, UK

Alexandru Calin Grigorescu, MD, PhD, RDI

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Canada

ESMO Palliative and Supportive Care Working Group, Institute of Oncology Bucharest, Romania

Isabelle Gingras, MD

Perry W. Grigsby, MD

Hopital du Sacré-Coeur de Montréal, Montreal, Québec, Canada

Rosalind Glasspool, MBBS, PhD, FRCP West of Scotland Cancer Centre and University of Glasgow, Road, Glasgow

Barbara A Goff. MD

University of Washington, Cancer Care Alliance SeattleWashington, USA

Washington University School of Medicine, USA

Liidia Gristsenko, MD

The North Estonian Medical Center, Woman’s Disease Department, Estonia

Maria Elena Guerrieri, MD University of Pisa, Italy

Frédéric Goffin, MD, PhD

Umran Kucukgoz Gulec, MD,

Hopital De La Citadelle, Belgium, Liège, Belgium

Cukurova University, Faculty of Medicine, Adana, Turkey

Gary L. Goldberg, MD

Murat Gultekin, MD

Albert Einstein College of Medicine, Montefiore Medical Center Bronx, NY, USA

François Golfier, MD

Lyon Sud University Hospital, Lyon, France

Eva Gómez-García, MD

Turkish Ministry of Health, Cancer Control Department, Ankara, Turkey Hacettepe University Faculty of Medicine, Ankara, Turkey

Haldun Guner, MD

Oncology Center ISSEMYM, Toluca, México

Gazi University Faculty of Medicine, Ankara, Turkey

Preethi Gopinath, MRCS, FRCPath

Mete Gungor, MD

The Princess Alexandra Hospital NHS Trust, Harlow, UK

Martin E. Gore, PhD, FRCP The Royal Marsden Hospital London, UK

Toon Van Gorp, MD

School for Oncology and Developmental Biology, AZ Maastricht, The Netherlands

Walter H. Gotlieb, MD, PhD

Acibadem University Faculty of Medicine, Istanbul, Turkey

Tayfun Gungor, MD

Hitit University Faculty of Medicine, Corum, Turkey

Frédéric Guyon, MD

Institut Bergonie Comprehensive Cancer Center, Bordeaux, France

Angiolo Gadducci, MD

Ahmet Baris Guzel, MD

University of Pisa, Italy.

McGill University Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada

David K. Gaffney, MD, PhD

Charlie Gourley, MD, PhD

Ali Haberal, MD

University of Utah, Huntsman Cancer Hospital, Utah, USA

University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, UK

Cukurova University, Faculty of Medicine, Adana, Turkey Baskent University Faculty of Medicine, Ankara, Turkey

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Authors

Neville F. Hacker, MD

Royal Hospital for Women, University, Sydney, Australia

Warner K. Huh, MD

University of Alabama at Birmingham, USA

Pervin Hurmuz, MD

Sami G. Kilic, MD

University of Texas Medical Branch, Texas, USA

Hacettepe University Medical School, Ankara, Turkey

Rainer Kimmig, MD

Institut Gustave Roussy, France

Michael J. Halaska, MD, PhD

Alexia Iasonos, PhD

Henry C. Kitchener, MD, FRCS, FRCOG

Memorial Sloan Kettering Cancer Center, New York, NY, USA

University of Manchester, Manchester, UK

Sileny N. Han, MD, PhD

Okechukwu A. Ibeanu, MD, MPH

Baskent University Faculty of Medicine, Ankara, Turkey

Matthew M. Harkenrider, MD

Ermina Iljazović, MD, PhD

Christine Haie-Meder, MD

2nd Medical Faculty, Charles University, Prague, Czech Republic University Hospitals Leuven, Leuven, Belgium Loyola University Chicago Cardinal Bernardin Cancer Center, USA

Diane M. Harper, MD, MPH, MS University of Louisville, USA

Philipp Harter, MD

Kliniken Essen-Mitte; Huyssen-Stiftung/ Knappschaft GmbH, Essen, Germany

Kosei Hasegawa, MD, PhD

Saitama Medical University International Medical Center, Saitama, Japan

Annette Hasenburg, MD

Leiterin Gynäkologische Onkologie Leitende Oberärztin, Freiburg, Germany

A. Peter M. Heintz, MD, PhD

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA University Clinical Center Tula, Bosnia and Herzegovina

Sara Isani, MD

Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, UK

Martee Hensley, MD

Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, USA

María de la Luz Hernández, PhD

International Agency for Cancer Research, Lyon, France

Danijela Jelovac, MD

Frédéric Kridelka, MD

Memorial Sloan Kettering Cancer Center, New York, USA Memorial Sloan Kettering Cancer Center, New York, USA

Loyola University Medical Center

Matias Jurado, MD, PhD

Clinica Universidad de Navarra, Pamplona, Spain

Ilker Kahramanoglu, MD

Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey

Soon-Beom Kang, MD, PhD

CHU de Liège, Liège, Belgium

Venkatesh Krishnan, MD

Stanford University School of Medicine, Stanford, California, USA

Cor de Kroon, MD, PhD

Leiden University Medical Center, Leiden, The Neterlands

Irem Kucukyildiz, MD

Turkish Ministry of Health, Cancer Control Department, Ankara, Turkey Etlik Zubeyde Hanim Women’s Health, Teaching and Research Hospital, Ankara, Turkey

Elisabetta Kuhn, MD

Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy University of Ferrara, Ferrara, Italy

Mujdegul Karaca, MD, PhD

The North Estonian Medical Foundation, Estonia

Martin Heubner, MD

West-German Tumor Center, University of Duisburg-Essen, Germany

Zeynep Kamil Women Health Research and Training Hospital, Istanbul, Turkey

Michael Höckel, MD

John Kavanagh, MD

Institut Paoli Calmettes, Marseille, France

University Hospital Krems, Austria

Konkuk University College of Mediceine, Seoul, Korea

Ates Karateke, MD

Gilles Houvenaeghel, MD

Acibadem University Atakent Hospital, Istanbul, Turkey

Elizabeth Jewell, MD, MHSc

University of Cincinnati, University of Cincinnati Cancer Institute, Cincinnati, USA

Regional Cancer Center Stockholm/Gotland Karolinska Institutet, Sweden

University Clinical Center Tula, Bosnia and Herzegovina

Gudrun Kreye, MD

Thomas J. Herzog, MD

Johanna Hök, MSc Pharm, PhD

Stanford University School of Medicine, Stanford, California, USA

The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Turkish Ministry of Health, Cancer Control Department, Ankara, Turkey Zekai Tahir Burak Women’s Health Research and Training Hospital, Ankara, Turkey

University of Lipzig, Lipzig, Germany

Holbrook Kohrt, MD

Faruk M. Kose, MD

Beth Israel Deaconess Medical Center, Israel

William Small Jr, MD, FACRO FACR, FASTRO

C. William Helm, MB.BChir, FRCS

Asklepios Hospital Hamburg, Germany

Joanne Jang, MD

Florian Heitz, MD

Oslo University Hospital, Oslo, Norway

Christhardt Köhler, MD

Maja Konrad-Čustović, MD

Mario M. Leitao Jr, MD

Taran P. Hellebust, PhD

Eda Kocaman, MD

Albert Einstein College of Medicine, Montefiore Medical Center Bronx, New York, USA

University of Utrecht and The Dutch School of Gynecologic Oncology and Pelvic Surgery, Utrecht, The Netherlands Kliniken Essen-Mitte; Huyssen-Stiftung/ Knappschaft GmbH, Essen, Germany

University Hospital, Essen, Germany

Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Vesna Kesić, MD, PhD

Faculty of Medicine, University of Belgrade, Serbia; Oncology Unit, Department of Obstetrics and Gynecology, Clinical Center of Serbia, Belgrade, Serbia

Kersti Kukk, MD

Pardeep Kumar, MB, FRCS, PhD Royal Marsden Hospital, UK

Charles A. Kunos, MD, PhD

Northeast Ohio Medical University, Ohio, USA

Akira Kurosaki, MD, PhD

Saitama Medical University International Medical Center, Saitama, Japan

Esra Kuscu, MD

Baskent University Faculty of Medicine, Ankara, Turkey

Christina L. Kushnir, MD

Women’s Cancer Center of Southern California, CA, USA

Authors

xi

A. Scott LaJoie, MSPH, PhD

Teresa C. Longoria, MD

Eva –Katharina Masel, MD

Erik Lajtman, MD, PhD

Alberto de Barros Lopes, FRCOG

Riccardo Masetti, MD

Royal Cornwall Hospital, Truro, UK Retired

Multidisciplinary Breast Center, Catholic University of Rome, Italy

Domenica Lorusso, MD

Jérôme Massardier, MD

University of Louisville School of Public Health and Information Sciences, USA Faculty Hospital Nitra, Slovakia

Rene Laky, MD

Medical University Graz, Austria

University of California, Irvine Medical Center, USA

Department for Internal Medicine, Medical University, Vienna, Austria

Fabio Landoni, MD

Lyon University Hospital, Lyon, France

European Institute of Oncology, Milan, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Maria Clelia Larussa, MD

David Luesley, MA, MD, FRCOG

Norfolk and Norwich University Hospital, Colney Lane, Norwich

Sandwell and West Birmingham NHS Trust, UK

Radboud University Medical Centre, The Netherlands

Eric Pujade Lauraine, MD, PhD

Helle Lund, MD

Hotel Dieu, Paris & Hopital Européen, France

Eric Leblanc, MD

Centre Oscar Lambret, Lille, France

Fabrice Lécuru, MD, PhD

Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Chirurgie Cancérologique Gynécologique et du Sein, Paris, France INSERM UMR-S 1124, Université Paris Descartes, Paris, France

Aalborg University Hospital and Department of Clinical Medicine, Aalborg University, Denmark

Chiara Macchi, MD

University of Turin, Italy

Javier F. Magrina, MD

Mayo Clinic Arizona, USA

Bhagirath Majmudar, MD

Grady Memorial Hospital Emory University, Atlanta, GA, USA

Ranjit Manchanda, MD, MRCOG, PhD

Leon Massuger, MD

Patrice Mathevet, MD, PhD

University of Lausanne, Lausanne, Switzerland

Amandine Maulard, MD

Institut Gustave Roussy, Villejuif, France

Marie-Hélène Mayrand, MD, PhD

Université de Montréal, Montreal, Canada)

Renaud Mazeron, MD, PhD

Institut Gustave Roussy, France

Chris J.L.M. Meijer, MD, PhD

Klinikum der Stadt Wolfsburg, Germany

Gulden Menderes, MD

Yale University School of Medicine, Yale, USA

Usha Menon, MD, FRCOG

Cancer Research UK and UCL Cancer Trials Centre, Cancer Institute, University College London, London, UK

Barts Cancer Institute, Queen Mary University of London Royal London Hospital Whitechapel Road, London, UK

Ahwon Lee, MD, PhD

Aránzazu Manzano, MD

Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel

Sung Jong Lee, MD, PhD

Maria Marchetti, MD

Jonathan A. Ledermann, BSc, MD, FRCP

School of Medicine, The Catholic University of Korea St. Vincent Hospital Korea

Taek-Sang Lee, MD, PhD

SMG-SNU Boramae Medical Center, Seoul, Korea

Alba Di Leone, MD

Multidisciplinary Breast Center, Catholic University of Rome, Italy

Karin Leunen, MD

University Hospitals Leuven, Leuven, Belgium

Werner Lichtenegger, MD, PhD

Charite Universitaetsmedizin Berlin Universitäts Frauenklinik, Berlin, Germany

Kristina Lindemann, MD, PhD

The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway NHMRC Clinical Trials Center, University of Sydney, Camperdown, NSW, Australia Crown Princess Mary Cancer Center; Westmead Hospital, Westmead, NSW, Australia

Megan Llewelyn, MBBS

Royal Marsden Hospital, UK

Sanjay Logani, MD Incyte Diagnostics, WA, USA

Hospital Universitario Clínico San Carlos, Madrid, Spain

Institute for Women’s Health University College, London, UK

Rachel Michaelson-Cohen, MD

Rowan Miller, MA, PhD, MRCP

Universtiy of Pauda, Pauda, Italy

University College London Hospitals, London, UK

Nicola Marconi, MD

Lucas Minig, MD

University of Insubria, Varese, Italy

Andrea Mariani, MD

Mayo Clinic, Minnesota, USA

Maurie Markman, MD

Cancer Treatment Centers of America, Philadelphia, PA Drexel University College of Medicine, Philadelphia, USA

Janina Markowska, MD, PhD

Poznan University of Medical Sciences, Poznan, Poland

Simone Marnitz, MD

University of Cologne, Germany

Valencian Institute of Oncology, Valencia, Spain

Mansoor R. Mirza, MD

Copenhagen University Hospital, Denmark

Selim Misirlioglu, MD

VKF Koc University School of Medicine, Istanbul, Turkey

Marco Mitidieri, MD University of Turin, Italy

Milos Mlyncek, MD, PhD

Faculty Hospital Nitra, Slovakia

Miziana Mokbel, MD

Christian Marth, MD, PhD

Innsbruck Medical University, Austria

Hôpitaux de Paris, Hôpital Européen GeorgesPompidou, Chirurgie Cancérologique Gynécologique et du Sein, Paris, France

Lola Martí, MD

Bradley, J. Monk, MD, FACOG, FACS

University Hospital of Bellvitge IDIDELL Barcelona, Spain

Alejandra Martinez, MD

Chirurgie Institut Universitaire Toulouse, France

Creighton University School of Medicine at St. Joseph Hospital, Phoenix, Arizona, USA

Mitsuru Mori, MD

Sapporo Medical University School of Medicine, Sapporo, Japan

xii

Authors

Philippe Morice, MD, PhD

Institut Gustave Roussy, Villejuif, France

John W. Moroney, MD

The University, Chicago, USA

Penelope Moyle, MD, MBChB, FRCR Cambridge University Hospital, UK

Anna Mozos, MD

Hospital de la Santa Creui Sant Pau, Autonomous University of Barcelona, Barcelona, Spain

Asima Mukhopadhyay, MD, MRCOG, PhD, MSc Tata Medical Center, Kolkata, India

Ann Muls, RN, Msc

Royal Marsden Hospital, UK

Francesco Multinu, MD

Research Fellow, Division of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota

George L. Mutter, MD

Brigham and Women’s Hospital, Harvard Medical School Boston, USA

Fabrice Narducci, MD

Centre Oscar Lambret, Lille, France

Patrick Neven, MD, PhD

University Hospitals Leuven, Leuven, Belgium

Farr Nezhat, MD, FACOG, FACS

Cornell University, New York, USA Stony Brook University, New York,USA Winthrop Univerity Hospital, New York

Charlotte Ngo, MD, PhD

Hôpitaux de Paris, Hôpital Européen GeorgesPompidou, Chirurgie Cancérologique Gynécologique et du Sein, Paris, France

Isa Niemann, MD

Aarhus University Hospital, Denmark

Claude Nos, MD

Hôpitaux de Paris, Hôpital Européen GeorgesPompidou, Chirurgie Cancérologique Gynécologique et du Sein, Paris, France

Remi A. Nout, MD PhD

Leiden University Medical Center Leiden, The Netherlands

Andreas Obermair, MD

Royal Brisbane & Women’s Hospital, Qld, Austria

Aikou Okamoto, MD

The Jikei University School of Medicine, Tokyo, Japan

Esther Oliva, MD

Massachusetts General Hospital, Boston, USA

Anil Onan, MD

Gazi University Faculty of Medicine, Ankara, Turkey

Antonio Onnis, MD

Founder of EJGO an ESGO, Always Among Us With His Great Achievements In Gynaecologic Oncology

Firat Ortac, MD

Ankara University Faculty of Medicine, Ankara, Turkey

Andrew W. Orton, MD

University of Utah, Huntsman Cancer Hospital, Utah, USA

Murat Oz, MD

Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey

Jacobus Pfisterer, MD, PhD

Gynecologic Oncology Center, Germany

Martine Piccart-Gebhart, MD, PhD

Institut Jules Bordet and Université Libre de Bruxelles (U.L.B), Brussels, Belgium

Jurgen M.J. Piek, MD, PhD Catharina Cancer Institute, Eindhoven, The Netherlands

Emre Ozgu, MD

Elisa Piovano, MD

Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey

Departement Surgical Sciences University of Turin, Italy

Nejat Ozgul, MD

M. Jesús Pla, MD, PhD

Ahmet Aydin Ozsaran, MD

Karl C. Podratz, MD, PhD

Hacettepe University Faculty of Medicine, Ankara, Turkey Ege University Medical School, Izmir, Turkey

Zeynep Ozsaran, MD

University Hospital of Bellvitge IDIDELL Barcelona, Spain Division of Gynecologic Oncology, Mayo Clinic, Minnesota, USA

Ege University, School of Medicine Izmir, Turkey

Alexandra de Pokomandy, MDCM, MSc

Enis Ozyar, MD

Cinzia Baima Poma, MD

Acibadem University, School of Medicine, Istanbul, Turkey

Nesrin Bozdogan Ozyilkan, MD

Baskent University Faculty of Medicine, Adana, Turkey

Niraj H. Pahlajani, MD

Baylor Scott and White Health-Memorial Hospital Texas A&M College of Medicine, Texas, USA

McGill University, Montreal, Canada Departement Surgical Sciences University of Turin, Italy

Christophe Pomel, MD, PhD

Jean Perrin Comprehensive Cancer Center, Clermond Ferrand, France

Jordi Ponce, MD, PhD

University Hospital of Bellvitge IDIDELL Barcelona, Spain

László Pálfalvi, MD, PhD

Richard Pötter, MD

Pierluigi Benedetti Panici, MD

Jaime Prat, MD, FRCPath

Saint Stephen Hospital Budapest Umberto I, ‘‘Sapienza’’ University, Rome, Italy

Ioanna Papadopoulou, FRCR

Radiology Registrar, Imperial College Healthcare NHS Trust, London

Jong Sup Park, MD, PhD

Seoul St. Mary’s Hospital, School of Medicine, The Catholic University of Korea

Medical University of Vienna, Vienna, Austria Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain

Eleonora P. Preti, MD

Preventive Gynaecologic Unit – European Institute of Oncology, Milan, Italy

Katinka Prince, MD, PhD

Patricia Pautier, MD

Gustave Roussy Villejuif, France

VU University Medical Center, Amsterdam, The Netherands

Michele Peiretti, MD, PhD

Denis Querleu, MD

University of Cagliari, Italy

Valeria A. Peñalver, MD

Institut Bergonie Comprehensive Cancer Center, Bordeaux, France

Hospital Universitario Clínico San Carlos, Madrid, Spain

Benoît Rabischong, MD

M. Eli Pendleton, MD

Pedro T. Ramirez, MD

University of Louisville School of Medicine, USA

Ivy A. Petersen, MD

Mayo Clinic, 200 1st St. SW, Rochester, Minnesota, USA

Karl-Ulrich Petry, MD, PhD

Klinikum der Stadt Wolfsburg, Germany

Krista S. Pfaendler, MD

Clinical Instructor, University of California, USA

CHU - Hospital Estaing, France The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Thomas Randall, MD

Global Oncology Initiative, DanaFarber Harvard Cancer Center, Boston, Massachusetts, USA

Paula Ravasco, Nutricionist, MSc, MD, PhD Laboratory of Nutrition of the Faculty of Medicine of the University of Lisbon and University Hospital of Santa Maria, Portugal

Authors

Isabelle Ray-Coquard, MD

Azra Sadiković, MD

Nicholas Reed, MD

Hanifi Sahin, MD

Centre Léon Bérard, & University Claude Bernard Lyon, France Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, Scotland, UK

University Clinical Center Tula, Bosnia and Herzegovina Baskent University Faculty of Medicine, Ankara, Turkey

xiii

Michael Scott, MD, FRCPath

University Hospital of South Manchester, UK

Michael J. Seckl, MD

Imperial College London, London, UK

Jalid Sehouli, MD, PhD

Satoru Sagae, MD

Sapporo West Kojinkai Clinic, Sapporo, Japan

Charite University, Campus VirchowKlinikum, Berlin, Germany

Helga Salvesen, MD, PhD

Kentaro Sekiyama, MD

Always Among Us With Her Great Achievements In Gynaecologic Oncology

The Tazuke Kofukai Medical Research Institute, Osaka, Japan

Senior Research Associate, EGA Institute for Women’s Health, University College London, London, UK

Vanessa Samouelian, MD

Mehmet Ali Nahit Sendur, MD

Anthony Richards, MD

Alejandro Martin Sanchez, MD

Nick Reed, MD

Consultant Clinical Oncologist Beatson Oncology Centre Gartnavel General Hospital, Scotland, UK

Dan Reisel, MBBS, PhD

Centre Oscar Lambret, Lille, France

Gynaecology Oncology; St. Lukes hospital, Potts Point, NSW, Australia

Catholic University of Rome, Italy

Dominique Berton Rigaud, MD

Complejo Hospitalario Universitario InsularMaterno Infantil, Las Palmas de Gran Canaria, Canary Islands, Spain.

ICO Centre René Gauducheau, Saint HERBLAIN, France

Dorien C. Rijkaart, PhD

Klinikum der Stadt Wolfsburg, Germany

Lukas Rob, MD, PhD

2nd Medical Faculty, Faculty Hospital Motol, Prague, Czech Republic

Claudia Robles, PhD

Institut Català d’Oncologia, IDIBELL Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme (CERP), Spain

Helena Robova, MD, PhD

3rd Medical Faculty, Charles University, Prague, Czech Republic

Andrea G. Rockall, BSc, MBBS, MRCP, FRCR

Octavio Arencibia Sanchez, MD, PhD

Silvia de Sanjosé, MD

Institut Català d’Oncologia, IDIBELL, Cancer Epidemiology Research Programme (CERP), Spain

Rengaswamy Sankaranarayanan, MD

Special Advisor (CCO) and Head Screening Group Section of Early Detection and Prevention International Agency for Research on Cancer, Lyon, France

Alessandro D. Santin, MD

Yale University School of Medicine, New Haven,USA

Sezin Yuce Sari, MD

Ataturk Chest Disease and Chest Surgery Training and Research Hospital, Ankara, Turkey

Hacettepe University Faculty of Medicine, Ankara, Turkey

Taylan Senol, MD

Zeynep Kamil Women Health Research and Training Hospital, Istanbul, Turkey

Lucy Side, MD, MRCP

EGA Institute for Women’s Health, University College London, London, UK

Naveena Singh, MD, FRCPath

Barts Health NHS Trust, London, UK

Vasileios D. Sioulas, MD, PhD

Memorial Sloan Kettering Cancer Center, New York, USA

Brentley Smith, MD

University of Alabama at Birmingham, USA

Robert A. Smith, PhD

American Cancer Society, Atlanta GA, USA

Peter J.F. Snijders, PhD

Klinikum der Stadt Wolfsburg, Germany

Lavinia Spain, MBBS, FRACP

The Royal Marsden NHS Foundation Trust Visiting Professor of Radiology, Imperial College London, UK

Toyomi Satoh, MD, PhD

University of Tsukuba, Tsukuba-City, Japan

The Royal Marsden Hospital London, UK

Alexandros Rodolakis, MD, PhD

Ugur Saygili, MD

9 Eylul University Medical School, Izmir, Turkey

Nick M. Spirtos, MD

University of Athens, “Alexandra” Hospital, Athens, Greece

Ignacio Romero, MD

Valencian Institute of Oncology, Valencia, Spain

Peter G. Rose, MD

Cleveland Clinic Foundation, Cleveland, Ohio, USA

Adam N. Rosenthal, PhD, FRCOG

EGA Institute for Women’s Health, University College London Hospital, London, UK

José Roberto Rossari, MD, MSc

Hospital Moinhos de Vento, Porto Alegre, Brazil

Gordon J.S. Rustin, MD, Msc, FRCP

Cono Scaffa, MD, PhD

National Cancer Institute “G. Pascale”, Naples, Italy

Giovanni Scambia, MD

Catholic University, Rome, Italy

Daniel J. Scanderbeg, PhD

Moores Cancer Center University of California, San Diego, USA

Maximilian Schmid, MD

Medical University of Vienna, Vienna, Austria

Achim Schneider, MD, MPH

Institute for Cytology and Dysplasia, Fürstenberg-Karree, Berlin, Germany

University of Nevada School of Medicine and Th e Women’s Cancer Center of Nevada, USA

Ashley Stuckey, MD, FACOG, FACS Women & Infants Hospital, USA

Alina Sturdza, MD, FRCPC

Medical University of Vienna, General Hospital of Vienna, Vienna, Austria

Paul H. Sugarbaker, MD, FACS, FRCS

Program in Peritoneal Surface Malignancy Washington Cancer Institute Washington, USA

Lone Sunde, MD

Aarhus University Hospital, Denmark

Gita Suneja, MD, MSHP

Mount Vernon Cancer Centre, Northwood, UK

Sophie Schur, MD

Medical University, Vienna, Austria

University of Utah, Huntsman Cancer Hospital, Utah, USA

Daniele De Ruvo, MD

Peter E. Schwartz, MD

Nobuyuki Susumu, MD

University of Turin, Italy

Yale University School of Medicine, Yale, USA

Keio University, Tokyo, Japan

xiv

Authors

Nicole B. Swarte, MD, PhD

University of Utrecht, Utrecht, The Netherlands

Laszlo Tabar, MD

University of Uppsala, Sweden

Amy Tang, MD

Queensland Centre for Gynaecological Cancer, Australia

Siriwan Tangjitgamol, MD

Taner A. Turan, MD

Etlik Zubeyde Hanim Women’s Health, Teaching and Research Hospital, Ankara, Turkey

Ilknur Cetinaslan Turkmen, MD

Istanbul Medipol University, Faculty of Medicine, Istanbul Turkey

Sandra Tuyaerts, PhD

University Hospitals Leuven, Leuven, Belgium

Lori E. Weinberg, MD

Illinois Masonic Medical Center, Chicago, USA

Joachim Weis, MD

University Clinic Centre Freiburg, Germany

Theresa L. Werner, MD

University of Utah, Huntsman Cancer Hospital, Utah, USA

Pauline Wimberger, MD, PhD

University of Bangkok Metropolis, Bangkok, Thailand

Stefano Uccella, MD, PhD

Cagatay Taskiran, MD

László Ungár, MD, PhD, MHCOG Szeged University, Hungary

Women’s and Children’s Health Leipzig University, Germany

Alexandra Taylor, MBBS, MD

Alp Usubutun, MD

R. Brent Wright, MD, MMM

Hofstra-Northwell School of Medicine, Northwell Cancer Institute, Lake Success, New York, USA

Giovanni Di Vagno, MD

Catheryn M. Yashar, MD, FACRO

Mustafa Cosan Terek, MD

Zvi Vaknin, MD

Mufit C. Yenen, MD

School of Health Professions Education, Maastricht, The Netherlands

Ingrid Vandenput, MD

Ferah Yildiz, MD

Krishnansu S. Tewari, MD, FACOG, FACS

Anke Vanderstraeten, MD

Nikolaos Thomakos, MD, PhD

Mehmet Ali Vardar, MD

VKF Koc University, Istanbul, Turkey Royal Marsden Hospital, UK

Eleonora Teplinsky, MD

Ege University Medical School, Izmir, Turkey

Pim Teunissen, MD, PhD

Irvine Medical Center, California, USA

University of Athens, “Alexandra” Hospital, Athens, Greec

Eric D. Thomas, MD

University of Alabama at Birmingham, USA

Elisa Tripodi, MD

University of Torino, Torino, Italy

Nienke van Trommel, MD

Center for Gynecologic Oncology Amsterdam, location Academic Medical Center Amsterdam, The Netherlands

University of Insubria, Varese, Italy

Hacettepe University Medical School, Ankara, Turkey Umberto I Hospital - ASL Bari, Corato (BA), Italy Assaf Harofe Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel University Hospitals Leuven, Leuven, Belgium University Hospitals Leuven, Leuven, Belgium Cukurova University, Faculty of Medicine, Adana, Turkey

Roberto J. Vargas, MD

Benjamin Wolf, MD

University of Louisville, Department of Family and Geriatric Medicine, USA Moores Cancer Center University of California, San Diego, USA Gulhane Military University Hospital, Ankara, Turkey Hacettepe University Medical School, Ankara, Turkey

Kunter Yuce, MD

Hacettepe University Faculty of Medicine, Ankara, Turkey

Ignacio Zapardiel, MD, PhD

La Paz University Hospital, Madrid, Spain

Cleveland Clinic Foundation, Cleveland, Ohio, USA

Alain G. Zeimet, MD, PhD

Ignace Vergote, MD, PhD

Michal Zikan, MD

Universitaire Ziekenhuizen Leuven, Leuven, Belgium

Ailyn Vidal, MD

European Institute of Oncology, Milan, Italy

Jone Trovik, MD, PhD

Cecilia Escayola Vilanova, MD

Haukeland University Hospital, Bergen, Norway

International Advanced Surgery, Barcelona, Spain

Jeremie de Troyer, MD

Akila N. Viswanathan, MD, MPH

Institut Paoli Calmettes, Marseille, France

Johns Hopkins Medicine, Baltimore, USA

Jill H. Tseng, MD

Ivan Richter Vogelius, PhD

Memorial Sloan Kettering Cancer Center, New York, USA

Copenhagen University Hospital, Denmark

Gokhan Tulunay, MD

Metaxa Memorial Cancer Hospital, Greece

Etlik Zubeyde Hanim Women’s Health, Teaching and Research Hospital, Ankara, Turkey

University Dresden, TU Dresden, Germany

George Vorgias, MD, PhD Boris Vraneš, MD

Clinical Center of Serbia, University of Belgrade Medical School, Serbia

Innsbruck Medical University, Austria Gynecological Oncology Center Charles University in Prague - First Faculty of Medicine and General University Hospital Prague, Czech Republic

Oliver Zivanovic, MD, PhD

Memorial Sloan Kettering Cancer Center, New York, USA

Paolo Zola, MD, PhD

University of Turin, Italy

Contents

SECTION I: BASICS OF GYNAECOLOGICAL CANCERS 1.

17. Diagnostic Immunohistochemistry in Gyne-Oncologic Pathology: A Βrief Appraisal of Common Applications . . . . . 163 Elisabetta Kuhn, MD, Ayse Ayhan, MD, PhD

History of Gynaecologic Oncology . . . . . . . . . . . . . . . 3 Krishnansu S. Tewari, MD, FACOG, FACS Antonio Onnis, MD, Maria Marchetti, MD, Peter Bösze, MD Polat Dursun, MD, Murat Gultekin, MD, Ali Ayhan, MD

2.

18. Pathology for Gynaecologic Oncologists . . . . . . . 171 Suha Deen, FRCPath

19. How to Report Pathology Specimens in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . . 176

Molecular Basis of Gynaecologic Cancers: What Should we Know? . . . . . . . . . . . . . . . . . . . . . . . . 27

Ayse Ayhan, MD, PhD

Zvi Vaknin, MD, Walter H. Gotlieb, MD, PhD

3.

Genetics in Gynaecologic Oncology . . . . . . . . . . . . . 38

4.

Hereditary Women’s Cancer . . . . . . . . . . . . . . . . . . . . 42

5.

The Future of Cancer Stem Cells in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . . . 53

20. Role of Frozen Section in Gynaecological Oncology . . . . . . . . . . . . . . . . . . . . . 185 Emanuela D’Angelo, MD, Anna Mozos, MD Alberto Gallardo, MD, Jaime Prat, MD, FRCPath

Rachel Michaelson-Cohen, MD, Uziel Beller, MD

21. Statistics for the Beginners in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . . 189

Dan Reisel, MBBS, PhD, Lucy Side, MD, MRCP Adam N. Rosenthal, PhD, FRCOG

Alexia Iasonos, PhD

SECTION II: CERVICAL DISEASES AND HPV

Karim S. ElSahwi, MD, FACOG, Alessandro D. Santin, MD

6.

Global Burden of Gynaecological Cancer . . . . . . . . 62

7.

Prevention of Gynaecologic Cancers . . . . . . . . . . . . 75

8.

9.

Rengaswamy Sankaranarayanan, MD, Jacques Ferlay, ME

22. HPV Infection Epidemiology and Prevention . . . 195 Alexandra de Pokomandy, MDCM, MSc Marie-Hélène Mayrand, MD, PhD

Satoru Sagae, MD, Nobuyuki Susumu, MD Aikou Okamoto, MD, Mitsuru Mori, MD

23. HPV and Cervical Carcinogenesis . . . . . . . . . . . . . . 201 Antonios Anagnostopoulos, MD, John A. Green, MD, FRCP

Prognostic Factors for Gynaecologic Cancers . . . . 78 Krista S. Pfaendler, MD, Okechukwu A. Ibeanu, MD, MPH Robert E. Bristow, MD, MBA

24. Human Papillomavirus Associated Cancers Other Than Cervical Cancer . . . . . . . . . . . 207 Lynette Denny, MD, PhD

Screening in Gynaecological Cancers . . . . . . . . . . . 85 Carmen Gan, MRCOG, Usha Menon, MD, FRCOG Ranjit Manchanda, MD, MRCOG, PhD

25. The Spectrum and Clinical Sequelae of Human Papillomavirus Infection . . . . . . . . . . . . . . 214

10. Circulating Tumor Markers in Gynaecological Oncology . . . . . . . . . . . . . . . . . . . . . 100

Krishnansu S. Tewari, MD, FACOG, FACS Bradley, J. Monk, MD, FACOG, FACS

Kunter Yuce, MD, Husnu Celik, MD

26. Condylomas & Evidence-Based Review of Medical and Surgical Treatments of Genital Warts . . . . . . . . . . . . . . . . . . 223

11. Proteomics in Gynaecologic Oncology . . . . . . . . . 109 Toon Van Gorp, MD, Isabelle Cadron, MD Ignace Vergote, MD, PhD

Eleonora P. Preti, MD, Ailyn Vidal, MD, Fabio Landoni, MD

12. Ultrasonography in Gynaecological Cancers . . . 113

27. HPV-Based Cervical Cancer Screening . . . . . . . . . 229

Daniela Fischerova, MD, PhD

Karl-Ulrich Petry, MD, PhD, Chris J.L.M. Meijer, MD, PhD Dorien C. Rijkaart, PhD, Johannes Berkhof, PhD, Peter J.F. Snijders, PhD, Marc Arbyn, MD, MSc, DrTMH

13. Conventional CT and MRI in Gynaecological Malignancy . . . . . . . . . . . . . . . . . . . 130

28. New Technologies for Cervical Cancer Screening . . . . . . . . . . . . . . . . . . . . . 236

Nandita M. deSouza MD, FRCR

14. PET CT in Gynaecologic Oncology . . . . . . . . . . . . . 140

Maribel Almonte, PhD, María de la Luz Hernández, PhD Jack Cuzick, PhD

Perry W. Grigsby, MD

29. Bivalent HPV Vaccine Approved for Cervical Cancer Prevention in Females . . . . . . . . . 247

15. Functional Imaging for Measuring The Response to Treatment . . . . . . . . . . . . . . . . . . . 143

Luz M. Fernandez, MD, M. Eli Pendleton MD R. Brent Wright, MD, MMM, Diane M. Harper, MD, MPH, MS

Ioanna Papadopoulou, FRCR Andrea G. Rockall, BSc, MBBS, MRCP, FRCR Alexandra Taylor, MBBS, MD Tara D. Barwick, MBChB, MSc, MRCP, FRCR

30. Quadrivalent and Nonavalent HPV Vaccine Approved for Males and Females for HPV Associated Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 279

16. Imaging-Guided Interventions in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . . 157

A. Scott LaJoie, MSPH, PhD, Luz M. Fernandez, MD M. Eli Pendleton, MD, Diane M. Harper, MD, MPH, MS

Michal Zikan, MD, PhD

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Contents

31. Cost-Eff ectiveness of HPV Vaccination . . . . . . . . . 309 Mireia Diaz, PhD, Claudia Robles, PhD Silvia de Sanjosé, MD and F. Xavier Bosch, MD

32. Immune Therapies for Human Papillomavirus-Induced Diseases . . . . . . . . . . . . . . 321 Sjoerd H. van der Burg, PhD

33. Cervical Pre-Invasive Disease . . . . . . . . . . . . . . . . . . 329 Vesna Kesić, MD, PhD

34. Cervicovaginal Cytology: Normal and Abnormal Cells and Adequacy of Specimens . . . 336 Christine Bergeron, MD, PhD

35. The Basic Principles of Colposcopy . . . . . . . . . . . . 343 Claire Bailey, MRCOG, David Luesley, MA, MD, FRCOG

36. Picture Gallery for Abnormal Cytology and Colposcopic Findings . . . . . . . . . . . . . . . . . . . . . 348 Ermina Iljazović, MD, PhD, Azra Sadiković, MD Maja Konrad-Čustović, MD

37. How to Manage Pre-Invasive Cervical Diseases? An Overview . . . . . . . . . . . . . . . 357 Mufit C. Yenen, MD, Ulas Fidan MD, Firat Ortac, MD Murat Dede, MD, Mete Gungor MD.

50. Compartment Resection in Gynaecologic Oncology: TMMR and LEER . . . . . . 450 Michael Höckel, MD, Rainer Kimmig, MD

51. Nerve-Sparing Surgery in Cervical Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Shingo Fujii, MD, Kentaro Sekiyama, MD

52. Neoadjuvant Chemotherapy in Cervical Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 463 Roberto J. Vargas, MD, Peter G. Rose, MD

53. Concomitant Chemotherapy in Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Giovanni Scambia MD, Giulia Amadio MD Gabriella Ferrandina MD

54. Systemic Therapy for Recurrent and Metastatic Cervical Cancer 1st Line Anti-Angiogenesis Therapy and Translational Rationale for Emerging 2nd Line Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476 Krishnansu S. Tewari, MD, FACOG, FACS Bradley, J. Monk, MD, FACOG, FACS

38. Destructive Techniques for Cervical Preinvasive Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

55. Radiotherapy for Cervical Cancer . . . . . . . . . . . . . . 487

39. Excisional Techniques for Cervical Preinvasive Lesions . . . . . . . . . . . . . . . . . . 366

56. Local Management of Relapse in Cervical Cancer With Radiotherapy . . . . . . . . . . . . 495

40. Management of Positive Resection Margin After Treatment for Cervical Precancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372

SECTION III: DISEASES OF UTERINE CORPUS

Liidia Gristsenko, MD, Kersti Kukk, MD

Gokhan Tulunay, MD, Nejat Ozgul, MD

Fuat Demirkiran, MD

41. The Pathology of Cervical Cancer . . . . . . . . . . . . . . 376 Michael Scott, MD, FRCPath

42. Management of Small Volume Cervical Cancers . . . . . . . . . . . . . . . . . . . . . . 381 Akira Kurosaki, MD, PhD, Kosei Hasegawa, MD, PhD Keiichi Fujiwara, MD, PhD

43. Radical Vaginal Trachelectomy . . . . . . . . . . . . . . . . 387 Christhardt Köhler, MD, Giovanni Favero, MD Achim Schneider, MD, MPH

44. Chemo-Conization for Early Staged Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 Anna Festi, MD, Fabio Landoni, MD

45. Surgery in Bulky Cervical Cancer . . . . . . . . . . . . . . 406 Christhardt Köhler, MD, Giovanni Favero, MD Achim Schneider, MD, MPH, Simone Marnitz, MD

46. Management of Locally Advanced Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422 Christine Haie-Meder, MD, Cyrus Chargari, MD, PhD Renaud Mazeron, MD, PhD, Philippe Morice, MD, PhD

47. The Role of Lymph Node Dissection in Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 Cecilia Escayola Vilanova, MD, Denis Querleu, MD

48. Management of Incompletely Operated Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 Gustavo Leme Fernandes, MD Adriana Bittencourt Campaner, MD, PhD

49. Sentinel Lymph Node in Cervical Cancer . . . . . . . 440 Cagatay Taskiran, MD, Selim Misirlioglu, MD, Anil Onan, MD Haldun Guner, MD, Ali Ayhan, MD

Mansoor R. Mirza, MD, Ivan Richter Vogelius, PhD Taran P. Hellebust, PhD

Megan Llewelyn, MBBS, Alexandra Taylor, MBBS, MD

57. Endometrial Hyperplasia Without Atypia and Endometrioid Intraepithelial Neoplasia (EIN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 George L. Mutter, MD

58. Treatment of Endometrial Hyperplasia . . . . . . . . 516 George Vorgias, MD, PhD, Stelios Fotiou, MD, PhD

59. Hysteroscopy in Endometrial Cancer . . . . . . . . . . . 522 Milos Mlyncek, MD, PhD, Erik Lajtman, MD, PhD

60. Endometrial Cancer: Epidemiology and Treatment . . . . . . . . . . . . . . . . . 529 Stefano Uccella, MD, PhD, Fabio Ghezzi, MD Jvan Casarin, MD, Francesco Multinu, MD Jamie N. Bakkum-Gamez, MD, Andrea Mariani, MD

61. Histopathology of Endometrioid Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 539 Tjalling Bosse, MD, PhD

62. Uterine Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 Esther Oliva, MD

63. Treatment of Advanced and Recurrent Endometrial Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . 550 Ingrid Vandenput, MD, Lieve Coenegrachts, MD Frederic Amant, MD, PhD

64. Compartment Resection in Endometrial Cancer: Peritoneal Mesometrial Resection (PMMR) and Therapeutic Lymphadenectomy . . . . . . . . . . . . . . . 558 Rainer Kimmig, MD, Bahriye Aktas, MD Martin Heubner, MD

Contents

65. Uterine Serous Carcinomas . . . . . . . . . . . . . . . . . . . 565 Peter E. Schwartz, MD, Gulden Menderes, MD Alessandro D. Santin, MD

66. Uterine Clear Cell Carcinomas . . . . . . . . . . . . . . . . . 579 Christina Fotopoulou, MD, PhD Werner Lichtenegger, MD, PhD

67. Conservative Treatment of Early Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 586 Boris Vraneš MD, Vesna Kesić MD, PhD,

68. Management of Incompletely Operated Endometrial Cancer . . . . . . . . . . . . . . . . . 594 Heidi J. Gray MD, Barbara A. Goff MD

69. The Management of Uterine Sarcomas . . . . . . . . . 600 Nicholas Reed, MD

70. Chemotherapy, Hormonal Therapy and Targeted Therapies for Endometrial Cancer . . . . 608 Ozden Altundag, MD, Husnu Celik, MD Esra Kuscu, MD

71. Other Therapies for Endometrial Cancer . . . . . . . 618 Lucas Minig, MD, Ignacio Romero, MD

72. Immunotherapy in Uterine Cancers . . . . . . . . . . . . 628 An Coosemans, MD, PhD, Sandra Tuyaerts, PhD Anke Vanderstraeten, MD Frederic Amant, MD, PhD

73. Radiation Therapy in Early Endometrial Cancers; Pro . . . . . . . . . . . . . . . . 638 Remi A. Nout, MD PhD, Carien L. Creutzberg, MD PhD

74. Radiation Therapy in Early Staged Endometrial Cancers: Con . . . . . . . . . . . . . 644 Jamie N. Bakkum-Gamez, MD, Ivy A. Petersen, MD Stefano Uccella, MD, PhD Andrea Mariani, MD Karl C. Podratz, MD, PhD

75. Use of Preoperative Biomarkers to Identify High Risk Endometrial Carcinoma Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 653 Helga Salvesen, MD, PhD, Ingeborg B. Engelsen, MD, PhD Jone Trovik, MD, PhD

76. Lymphadenectomy for Endometrial Cancer: Pro . . . . . . . . . . . . . . . . . . . . . . 660 Elizabeth Jewell, MD, MHSc

77. Lymph Node Resection in Endometrial Cancer: Con . . . . . . . . . . . . . . . . . . . . . . 665 Emma J. Crosbie, MRCOG, PhD Henry C. Kitchener, MD, FRCS, FRCOG

SECTION IV: OVARIAN AND TUBAL DISEASES 78. Adnexal Mass: Evaluation and Treatment . . . . . . 671 Jennifer E. Cho MD, FACOG Farr Nezhat, MD, FACOG, FACS

79. The Non-Ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679 Elisabetta Kuhn, MD, Ayse Ayhan, MD, PhD

80. Pathology of Malignant and Borderline Ovarian Tumours . . . . . . . . . . . . . . . . . . 689 Naveena Singh, MD, FRCPath Preethi Gopinath, MRCS, FRCPath

xvii

81. Borderline Tumors of The Ovary . . . . . . . . . . . . . . . 698 Janina Markowska, MD, PhD, Jacek P. Grabowski, MD, PhD Ignacio Zapardiel, MD, PhD

82. Early Stage Epithelial Ovarian Cancer . . . . . . . . . . 703 Nicoletta Colombo, MD, Lucas Minig, MD

83. Surgical Management of Advanced Stage Epithelial Ovarian Cancer . . . . . . . . . . . . . . . 708 Ali Ayhan, MD, Macit Arvas, MD, Eda Kocaman, MD, Irem Kucukyildiz, MD, Hanifi Sahin, MD

84. Metastatic Ovarian Cancers . . . . . . . . . . . . . . . . . . . 731 Sung Jong Lee, MD, PhD, Youn Jin Choi, MD Ahwon Lee MD, PhD, Jong Sup Park, MD, PhD

85. Malignant Ovarian Germ Cell Tumours . . . . . . . . . 737 Michael J Seckl, BSc, MD, PhD FRCP Gordon J.S. Rustin, MD, Msc, FRCP

86. Ovarian Carcinosarcomas . . . . . . . . . . . . . . . . . . . . . 747 Nicholas Reed, MD

87. Sex Cord-Stromal Tumors of The Ovary . . . . . . . . 754 Michele Peiretti, MD, PhD, Stefano Angioni, MD, PhD Valentina Corda, MD, Nicoletta Colombo, MD

88. Role of Lymphadenectomy in Ovarian Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760 Pierluigi Benedetti Panici, MD, Cristina Donfrancesco, MD Assunta Casorelli, MD, Violante Di Donato, MD, PhD

89. Management of Incompletely Operated Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . 766 Emre Ozgu, MD, Murat Oz, MD, Tayfun Gungor, MD

90. Krukenberg Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 771 Soon-Beom Kang, MD, PhD, Taek-Sang Lee, MD, PhD

91. Pseudomyxoma Peritonei . . . . . . . . . . . . . . . . . . . . . 774 Ahmet Aydin Ozsaran, MD, Levent Akman, MD Ugur Saygili, MD, Mustafa Cosan Terek, MD

92. Primary Peritoneal Carcinomas . . . . . . . . . . . . . . . . 777 Giovanni Di Vagno, MD, Stefano Greggi, MD, PhD Cono Scaffa, MD, PhD

93. Primary Cytoreduction: Factors Impacting Operability and The Extent of Surgery . . . . . . . . . 782 Giovanni D. Aletti, MD, William A. Cliby, MD

94. Debulking Surgery in Advanced Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791 Jalid Sehouli, MD, PhD, Christina Fotopoulou, MD, PhD Jacobus Pfisterer, MD, PhD, Philipp Harter, MD Andreas du Bois, MD, PhD

95. Upper Abdominal Cytoreduction for Advanced Ovarian Cancers . . . . . . . . . . . . . . . . . . . . 795 Scott M. Eisenkop, MD, Christina L. Kushnir, MD Nick M. Spirtos, MD

96. Technique of Liver Resection in Cytoreductive Surgery for Advanced Ovarian Cancer . . . . . . . . . 801 Teresa C. Longoria, MD, Robert E. Bristow, MD, MBA

97. Techniques of Diaphragmatic Surgery . . . . . . . . . 809 Benjamin Wolf, MD, Jens Einenkel, MD

98. Splenectomy and Distal Pancreatectomy . . . . . . . 821 Faruk M. Kose, MD, Taner A. Turan, MD, Ali Haberal, MD

99. Video-Assisted Thoracic Surgery . . . . . . . . . . . . . . 825 Ram Eitan, MD, Dennis S. Chi, MD

100. Metastatic Gynaecologic Cancers . . . . . . . . . . . . . . 828 Joseph W. Carlson, MD, PhD, Pernilla Dahm-Kähler, MD, PhD Elisabeth Åvall-Lundqvist, MD, PhD

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Contents

101. Neuro-Endocrine Tumours of Gynaecological Tract . . . . . . . . . . . . . . . . . . . . . . . . . 834 Nicholas Reed, MD

102. Secondary Cytoreduction in Recurrent Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840 Philipp Harter, MD, Florian Heitz, MD Christina Fotopoulou, MD, PhD, Jalid Sehouli, MD, PhD

103. Tertiary Cytoreduction . . . . . . . . . . . . . . . . . . . . . . . . 845 Jill H. Tseng, MD, Mario M. Leitao, Jr., MD

104. Fallopian Tube Neoplasm . . . . . . . . . . . . . . . . . . . . . 854 Helena Robova, MD, PhD

105. Choosing Treatments for Recurrent Ovarian Cancer: The Platinum-Free Interval . . . . . . . . . . . . . . . . . . . . 859 Evelyn Cantillo, MD, MPH, Ashley Stuckey, MD, FACOG, FACS

106. Debulking Surgery in Advanced Ovarian Cancer – Pro Primary Surgery . . . . . . . . . 867 Jacobus Pfisterer, MD, PhD, Philipp Harter, MD Jalid Sehouli, MD, PhD, Andreas du Bois, MD, PhD

107. Neoadjuvant Chemotherapy or Primary Debulking Surgery in Advanced Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . 872 Ignace Vergote, MD, PhD, Leen Verleye, MD Toon Van Gorp, MD, Karin Leunen, MD Patrick Neven, MD, PhD, Frederic Amant, MD, PhD

108. The Role of Interval Debulking Surgery in The Management of Advanced Stage Ovarian Cancer . . . . . . . . . . . . . . . 875 Philippe Morice, MD, PhD, Enrica Bentivegna, MD Amandine Maulard, MD, Sébastien Gouy, MD, PhD

109. Systemic Chemotherapy in Epithelial Ovarian Cancer: Pro . . . . . . . . . . . . . . . . . . . . . . . . . . 879 Angiolo Gadducci, MD, Maria Elena Guerrieri, MD

110. Intraperitoneal Chemotherapy in Epithelial Ovarian Cancer: Pros and Cons . . . . . . 885 Danijela Jelovac, MD, Deborah K. Armstrong, MD

111. Secondary Cytoreduction in the Treatment of Recurrent Ovarian Cancer . . . . . . . . 890 Ram Eitan, MD, Dennis S. Chi, MD

117. Other Diseases of Vulva (Paget’s, Melanoma and Sarcoma) . . . . . . . . . . . . . 931 Violante Di Donato, MD, PhD, Cristina Donfrancesco, MD Assunta Casorelli, MD, Pierluigi Benedetti Panici, MD

118. Chemotherapy for Carcinoma of The Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940 Nicholas Reed, MD

119. Radiotherapy for Vulvar Cancers . . . . . . . . . . . . . . 944 David K. Gaffney, MD, PhD, Theresa L. Werner, MD Dustin L. Boothe, MD

SECTION VI: DISEASES OF VAGINA 120. Pre Invasive Diseases of The Vagina . . . . . . . . . . . 955 Jean Doyen, MD, Katty Delbecque, MD Frédéric Goffin, MD, PhD, Frédéric Kridelka, MD

121. Pathology of Vaginal Cancers . . . . . . . . . . . . . . . . . 964 Ilknur Cetinaslan Turkmen, MD, Alp Usubutun, MD

122. Vaginal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970 Neville F. Hacker, MD

123. Rare Vaginal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 975 Eric D. Thomas, MD, Brentley Smith, MD, Warner K. Huh, MD

124. Cancers of The Vagina: The Role of Chemotherapy . . . . . . . . . . . . . . . . . . . . 983 Nicholas Reed, MD

125. Radiotherapy for Vaginal Cancer . . . . . . . . . . . . . . 985 Andrew W. Orton, MD, Gita Suneja, MD, MSHP David K. Gaffney, MD, PhD

SECTION VII: GESTATIONAL TROPHOBLASTIC DISEASES 126. Epidemiology, Genetics, and Pathology of GTD/GTN . . . . . . . . . . . . . . . . . . . 995 Isa Niemann, MD, Lone Sunde, MD, Helle Lund, MD

127. Hydatidiform Mole . . . . . . . . . . . . . . . . . . . . . . . . . . 1003 Nienke van Trommel, MD, Leon Massuger, MD

128. Treatment of Gestational Trophoblastic Neoplasia . . . . . . . . . . . . . . . . . . . . . 1010 François Golfier, MD, Frédéric Goffin, MD, PhD Jérôme Massardier, MD, Pierre-Adrien Bolze, MD

SECTION V: DISEASES OF VULVA

129. Ultra High Risk Gestational Trophoblastic Neoplasia (GTN) . . . . . . . . . . . . . . . 1016

112. Pre - Invasive Diseases of Vulva . . . . . . . . . . . . . . . 897

130. Rationale for Centralization and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021

Marjolein DeCuypere, MD, Frédéric Kridelka, MD Katty Delbecque, MD, Frédéric Goffin, MD, PhD

Fieke EM Froeling, MD, Michael J. Seckl, MD

Frédéric Goffin, MD, PhD, Leon Massuger, MD Frédéric Kridelka, MD, François Golfier, MD

113. Pathology of Vulvar Cancers . . . . . . . . . . . . . . . . . . 905 Sanjay Logani, MD, Bhagirath Majmudar, MD

114. Vulval Cancers; Epidemiology and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911 Khadra Galaal, FRCOG, Nagindra Das, MRCOG Alberto de Barros Lopes, FRCOG

115. Surgical Techniques for Vulvar Cancer . . . . . . . . . 917 Neville F. Hacker, MD, Penny Blomfield, MD

116. Flap Reconstruction Following Gynaecologic Tumor Resection . . . . . . . . . . . . . . . . 924 Sara Isani, MD, Gary L. Goldberg, MD

SECTION VIII: SURGERY IN GYNAECOLOGIC ONCOLOGY 131. Surgical Anatomy in Pelvic Gynaecologic Oncology . . . . . . . . . . . . . . . . 1031 Hugo Gaspar MD, Octavio Arencibia Sanchez, MD PhD Jordi Ponce, MD PhD

132. Perioperative Patient Care in Gynaeoncological Surgery . . . . . . . . . . . . . . . . . . . 1043 Ates Karateke, MD, Taylan Senol, MD Ilker Kahramanoglu, MD

Contents

133. Fertility Preservation for Gynaecologic Cancer Patients . . . . . . . . . . . . . . . . 1051 Alexandros Rodolakis, MD, PhD, Nikolaos Thomakos, MD, PhD

134. Sentinel Lymph Node Biopsy in Cervical Cancer: An Update Review Article . . . . 1063 Anne-Sophie Bats, MD, PhD, Miziana Mokbel, MD Charlotte Ngo, MD, PhD, Chérazade Bensaïd, MD Claude Nos, MD, Patrice Mathevet, MD, PhD Fabrice Lécuru, MD, PhD

135. Minimally Invasive Surgery in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1073 Stefano Uccella, MD, PhD, Nicola Marconi, MD Antonella Cromi, MD, PhD, Silvia Cardinale, MD Andrea Mariani, MD, Fabio Ghezzi, MD, ”

xix

148. Type D Radical Hysterectomy: The Laterally Extended Parametrectomy (LEP) . . . . . . . . . . . . . . . . . . . . . . . 1179 László Pálfalvi, MD, PhD, László Ungár, MD, PhD, MHCOG

149. Pelvic Exenteration . . . . . . . . . . . . . . . . . . . . . . . . . . 1183 László Pálfalvi, MD, PhD, László Ungár, MD, PhD, MHCOG

150. Technique of Laparoscopic Exenteration . . . . . . 1188 Alejandra Martinez, MD, PhD, Gwenael Ferron, MD, PhD Christophe Pomel, MD, PhD

151. Colorectal Surgery in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1191 Luis M. Chiva, MD, PhD, Matias Jurado, MD, PhD

136. Principles of Laparoscopic Surgery . . . . . . . . . . . 1107

152. The Role of Neobladder Reconstruction in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1197

137. Laparoscopic Surgery in Gynaecological Oncology . . . . . . . . . . . . . . . . . . . . 1114

153. Types of Urinary Diversions . . . . . . . . . . . . . . . . . . 1205

Lilian T. Gien, MD, MSc, FRCSC, Allan Covens, MD

Eric Leblanc, MD, Denis Querleu, MD Fabrice Narducci, MD, Vanessa Samouelian, MD Loic Boulanger, MD, Gwenael Ferron, MD, PhD

138. Single-Port Surgery for Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1125 Lori E. Weinberg, MD, Amanda N. Fader, MD Pedro F. Escobar, MD

139. Laparoscopic Hysterectomy A Standardized Technique . . . . . . . . . . . . . . . . . . . 1131 Michel Canis, MD, PhD, Revaz Botchorishvili, MD Benoît Rabischong, MD, Anne Sophie Grémeau, MD Sandra Curiner, MD, Sandrine Campagne, MD Nicolas Bourdel, MD

140. Classification System of Radical Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . 1137 David Cibula, MD, PhD

Sonsoles Alonso, MD, Matías Jurado, MD, PhD Luis M. Chiva, MD, PhD Jeremie de Troyer, MD, Marie Bannier, MD Gilles Houvenaeghel, MD

154. Classification of Complications in Gynaecological Malignancies Treatments . . . . . 1209 Paolo Zola, MD, PhD, Elisa Piovano, MD Annamaria Ferrero, MD, PhD, Lorenzo Bono MD, Bsc Marco Mitidieri MD, Chiara Macchi MD Daniele De Ruvo MD, Cinzia Baima Poma MD

SECTION IX: CANCER AND HUMAN REPRODUCTION 155. Pregnancy and Cancer . . . . . . . . . . . . . . . . . . . . . . . 1219 Michael J. Halaska, MD, PhD, Vesna Kesić, MD, PhD Lukas Rob, MD, PhD

156. Management of CIN in Pregnancy . . . . . . . . . . . . 1226 Vesna Kesić, MD, PhD

141. Technique for Abdominal Radical Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . 1141

157. Cervical Cancer in Pregnancy . . . . . . . . . . . . . . . . . 1231

142. Introduction of a Robotic Surgery Program . . . 1147

158. Fertility-Sparing Radical Abdominal Trachelectomy for Cervical Carcinoma . . . . . . . . 1239

Alejandra Martinez, MD, PhD, Gwénaël Ferron, MD, PhD Denis Querleu, MD, Pedro T. Ramirez, MD Ali Akdemir, MD, Mostafa A. Borahay, MD Sami G. Kilic, MD

143. Step by Step Robotic Lymphadenectomy . . . . . 1154 Jordi Ponce, MD, PhD Marc Barahona, MD Amparo Garcia-Tejedor, MD, PhD M. Jesús Pla, MD, PhD Lola Martí, MD, PhD

144. Robotic Radical Hysterectomy: Surgical Technique . . . . . . . . . . . . . . . . . . . . . . . . . . 1160 Javier F. Magrina, MD

145. Technique on Laparoscopic Radical Hysterectomy and Comparison of Three Techniques: Laparotomy, Laparoscopy and Robotics . . . . . . 1165 Amy Tang, MD, Andreas Obermair, MD

146. Laparoscopic Extraperitoneal Aortic Dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168 Denis Querleu, MD, Alejandra Martinez, MD Frédéric Guyon, MD, Eric Leblanc, MD

147. Indocyanine Green Fluorescence Guided Compartmental Surgery in Uterine Cancer by Robotic Surgery . . . . . . . . . . . 1172 Rainer Kimmig, MD, Bahriye Aktas, MD, Martin Heubner, MD

Michael J. Halaska, MD, PhD, Helena Robova, MD, PhD Lukas Rob, MD, PhD

Nadeem R. Abu-Rustum, MD

159. Ovarian Malignancies in Pregnancy . . . . . . . . . . . 1243 Alain G. Zeimet, MD, PhD, Christian Marth, MD, PhD

SECTION X: MEDICAL ONCOLOGY 160. Basic Principles of Chemotherapy and Drugs Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1251 Lavinia Spain, MBBS, FRACP, Rosalie Fisher, MBChB, FRACP Martin E. Gore, PhD, FRCP

161. Surgical Oncological Care of Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1258 Pauline Wimberger, MD, PhD, Annamaria Ferrero, MD, PhD Elisa Tripodi, MD

162. Medical Oncological Care of Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264 Annamaria Ferrero, MD, PhD, Pauline Wimberger, MD, PhD Elisa Tripodi, MD

163. The Role of Chemotherapy in Gynaecologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1271 Aránzazu Manzano, MD, Valeria A. Peñalver, MD Antonio Casado, MD, PhD

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Contents

164. Targeted Therapy in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1281 Maurie Markman, MD

165. Cytoreductive Surgery and Perioperative Hyperthermic Chemotherapy for Peritoneal Metastases . . . . . 1286 Paul H. Sugarbaker, MD, FACS, FRCS

166. Technique of Intraperitoneal Chemotherapy: Normothermic and Hyperthermic . . . . . . . . . . . . 1293 Asima Mukhopadhyay, MD, MRCOG, PhD, MSc C. William Helm, MB.BChir, FRCS

167. Cytotoxic Trials by the Gynaecologic Oncology Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1308 Siriwan Tangjitgamol, MD, John Kavanagh, MD

168. Novel Biologic Therapies in The Treatment of Epithelial Ovarian Cancer . . . . . . . 1323 John W. Moroney, MD Robert L. Coleman, MD

169. PARP Inhibitors and Homologous Recombination Deficiency . . . . . . . . . . . . . . . . . . . 1335 Rowan Miller, MA, PhD, MRCP Jonathan Ledermann, BSc, MD, FRCP

170. Current Immunotherapeutic Approaches to Ovarian Cancer Treatment . . . . . . . . . . . . . . . . . . . 1343 Venkatesh Krishnan, MD, Cariad Chester, MD Holbrook Kohrt, MD, Jonathan S. Berek, MD Oliver Dorigo, MD

171. Management of Chemotherapy-Induced Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354 Eleonora Teplinsky, MD, Thomas J. Herzog, MD

172. Management of Chemotherapy Complications in Gynaecological Malignancy Treatments . . . . . . . . . . . . . . . . . . . . . . 1366 Alexandru Calin Grigorescu, MD, PhD, RDI

SECTION XI: RADIATION ONCOLOGY 173. Principles of Radiation Therapy in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1375 Catheryn M. Yashar, MD, FACRO, Daniel J. Scanderbeg, PhD Sunil J. Advani, MD

174. Current Radiotherapy Protocols in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1383 Joanne Jang, MD, Akila N. Viswanathan, MD, MPH

175. Cyberknife Stereotactic Body Radiosurgery in Gynaecologic Carcinomas . . . . 1389 Charles A. Kunos, MD, PhD

176. Image Guided vs. Conventional Radiation Therapy in Gynaecologic Cancers . . . . . . . . . . . . . 1396 Alina Sturdza, MD, FRCPC, Maximilian Schmid, MD Richard Pötter, MD

177. Chemoradiotherapy: Neoadjuvant, Concomitant, Sequential, or Monomodality Treatment? . . . . . . . . . . . . . . . . . . . 1405 Patricia J. Eifel, MD

178. Gynaecological Brachytherapy . . . . . . . . . . . . . . . 1413 Niraj H. Pahlajani, MD, Matthew M. Harkenrider, MD Fiori Alite, MD, William Small Jr., MD, FACRO FACR, FASTRO

179. Pelvic Irradiation: Acute and Late Toxicity . . . . . 1425 Alexandra Taylor, MBBS, MD, Andreia Fernandes, RN, MSc Pardeep Kumar, MB, FRCS, PhD, Ann Muls, RN, Msc

180. Management of Radiotherapy Complications in Gynaecological Malignancies Treatments . . . . . . . . . . . . . . . . . . . . 1437 Banu Atalar, MD, Senem Alanyali, MD Zeynep Ozsaran, MD, Enis Ozyar, MD

SECTION XII: PALLIATIVE CARE IN GYNAECOLOGIC ONCOLOGY 181. Challenges and Opportunities in Palliative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449 Giovanni Elia, MD, Frank D. Ferris, MD, FAAHPM, FAACE

182. Management of Chemotherapy Induced Nausea and Vomiting (CINV) . . . . . . . . . 1459 Gudrun Kreye, MD, Eva –Katharina Masel, MD Sophie Schur, MD

183. Pain Palliation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1470 Nesrin Bozdogan Ozyilkan, MD

184. Nutrition: The Relevance in Gynaecological Cancer . . . . . . . . . . . . . . . . . . . . . . . 1482 Paula Ravasco, Nutricionist, MSc, MD, PhD

185. Complementary, Alternative and Integrative Medicine Use Among Patients With Gynaecological Cancers . . . . . . . . 1489 Kjell Bergfeldt, MD, PhD, Johanna Hök, MSc Pharm, PhD

186. Psychological Support . . . . . . . . . . . . . . . . . . . . . . . 1495 Joachim Weis, MD, Annette Hasenburg, MD

187. Euthanasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1500 A. Peter M. Heintz, MD, PhD, Nicole B. Swarte, MD, PhD

188. Quality of Life (QoL) in Oncologic Patients . . . . 1505 Adriana Bermudez, MD, PhD

189. Lymphocele, Lymphorrhea After Lymphadenectomy . . . . . . . . . . . . . . . . . . . . . . . . . . 1507 Ahmet Baris Guzel, MD, Umran Kucukgoz Gulec, MD, Mehmet Ali Vardar, MD, Aytekin Altintas, MD

SECTION XIII: RARE GYNAECOLOGICAL CANCERS 190. Rare Gynaecological Cancers: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515 Nicholas Reed, MD

191. GCIG Rare Tumor Consensus Review & Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . 1520 Isabelle Ray-Coquard, MD, PhD, Jonathan A. Ledermann, MD Philipp Harter, MD, Michael Friedlander, MD, PhD Frederic Amant, MD, PhD Aikou Okamoto, MD, PhD Eva Gómez-García, MD, Charlie Gourley, MD, PhD Martee Hensley, MD, Patricia Pautier, MD Keiichi Fujiwara, MD, PhD Domenica Lorusso, MD, Satoru Sagae, MD Akila N. Viswanathan, MD, MPH, Mario M. Leitao Jr, MD Toyomi Satoh, MD, PhD, Nick Reed, MD, Jubilee Brown, MD, Dominique Berton Rigaud, MD Rosalind Glasspool, MBBS, PhD, FRCP Eric Pujade Lauraine, MD, PhD

Contents

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SECTION XIV: BREAST CANCER

SECTION XV: TRAINING IN GYNAECOLOGIC ONCOLOGY

192. How Eff ective Are Breast Cancer Screening Programmes? . . . . . . . . . . . . . . . . . . . . . 1531

201. Gynaecologic Training in Europe . . . . . . . . . . . . . 1607

Laszlo Tabar, MD, Robert A. Smith, PhD

193. Investigation of Suspected Breast Cancer . . . . . 1540 Penelope Moyle, MD, MBChB, FRCR

194. Hereditary Breast Cancer Risk and Genetic Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . 1547 Banu Arun, MD

195. Surgical Treatment of Breast Cancer . . . . . . . . . . 1554 Riccardo Masetti, MD, Alba Di Leone, MD Alejandro Martin Sanchez, MD, Gianluca Franceschini, PhD

196. Medical Treatments in Breast Cancer . . . . . . . . . 1563 Isabelle Gingras, MD, José Roberto Rossari, MD, MSc Evandro de Azambuja, MD, PhD Martine Piccart-Gebhart, MD, PhD

197. New Approaches to Radiotherapy in Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577

Michael J. Halaska, MD, PhD

202. Gynaecologic Oncology Fellowship Training in the USA . . . . . . . . . . . . . . . . . . . . . . . . . . 1615 Vasileios D. Sioulas, MD, PhD, Ane Gerda Zahl Eriksson, MD Ginger J. Gardner, MD, Oliver Zivanovic, MD, PhD

203. Fellowship Training in Australia and New Zealand . . . . . . . . . . . . . . . . . . . 1617 Kristina Lindemann, MD, PhD, Anthony Richards, MD

204. ESGO Training Opportunities . . . . . . . . . . . . . . . . 1621 Rene Laky, MD, Maria Clelia Larussa, MD

205. Teaching and Learning Skills in the 21st Century: From Authority Based to Evidence Based Learning and Teaching Techniques . . . . . . . . . . . . . . . . . . . . . . . . 1626 Katinka Prince, MD, PhD, Cor de Kroon, MD, PhD Pim Teunissen, MD, PhD, Jurgen M.J. Piek, MD, PhD

Sezin Yuce Sari MD, Pervin Hurmuz, MD, Ferah Yildiz, MD

198 A Review of New Therapeutic Modalities in Breast Cancer . . . . . . . . . . . . . . . . . . 1587 Mehmet Ali Nahit Sendur, MD, Sercan Aksoy, MD Paul A. Foster, MD, PhD, Mustafa Kadri Altundag, MD

199. Unanswered Questions in Gynaecologic Oncology . . . . . . . . . . . . . . . . . . . . . . 1596 Lucas Minig, MD, Thomas Randall, MD

200. Pregnancy Associated Breast Cancer . . . . . . . . . . 1600 Sileny N. Han, MD, PhD, Kristel Van Calsteren, MD, PhD Frederic Amant, MD, PhD

Index 1633

THE NONOVARIAN ORIGIN AND PATHOGENESIS OF OVARIAN CARCINOMAS: UPDATE ON THE PATHOLOGICAL AND MOLECULAR CLUES

79

Elisabetta Kuhn, MD Ayse Ayhan, MD, PhD

Introduction Ovarian cancer remains the most lethal gynaecological malignancy, despite the significant advances over last decades in imaging technologies, surgical techniques, chemotherapeutic regimens and delivery strategies. Classically, ovarian cancer has been classified based on histological types and treated as a “single” uniform disease. On one hand, the heterogeneity of primary ovarian tumors has been well accepted, and includes substantially epithelial, sex-cord stromal, and germ cell tumors that parallel the distinctive cellular compartments of such a unique organ. On the other hand, both sex-cord stromal and germ cell tumors undoubtedly originate from the ovary itself, analogously to the testis (the male gonad), whereas the origin of epithelial tumors still remains by and large shrouded in darkness. The more we learn about the earliest histopathological features, molecular alterations and natural history of ovarian cancers, the more we have been questioning the historical terminology and classification. The genuine purpose of any tumor classification is to make the terminology consistent and to standardize the criteria used in scientific investigations and by doctors, in order to generate most advantageous descriptors for the patients, to compare studies, and finally to better guide management, even when the therapeutic options are few. Tumors should therefore be sorted out with such a discerning formula to create a firm framework into which individual neoplasms that share specific factors, such as derivation (cell or organ of origin), histology, clinical behavior and management, fit in, forming the basis for integrity between clinicians, pathologists, and researchers. Determining the appropriate management based on the experience of well-characterized prior group of patients allows universal comparison thus transmission of evidence-based scientific know-how without ambiguity. The most commonly used staging system for malignant tumors is the TNM, elaborated and maintained by the collaboration of the AJCC (American Joint Committee on Cancer) and the UICC (Union for International Cancer Control). The TNM staging system describes the spread

of tumor for each primary location based on the size and extent of the primary tumor (T), regional lymph nodes involvement (N) and presence of distant metastases (M) and is traditionally solely anatomic, but in recent years it is supplemented by designated non-anatomic prognostic factors. Notably, ovarian, fallopian tube and peritoneal tumors are described by the same staging system, since the ovarian and tubal tumors usually associate with a diffuse peritoneal dissemination. Apart from the intratumoral heterogeneity, which occurs in any malignant neoplasm, the heterogeneity between different epithelial ovarian malignancies renders them a “group of diseases”, each of which should be clustered differently due to relevant differences in both morphology and clinical behavior, even if the origin were the same. On the basis of recent findings, the new understanding of ovarian epithelial carcinogenesis, laying the foundations on the cell of origin, the putative precursor lesions and molecular genetic alterations, compels us to reevaluate all the previous theories and to reconsider even the name. Therefore, in this chapter, we will trace the controversies in ovarian cancer field necessitating a prompt reevaluation and the misleading, even distorting facts that led the scientists unsighted for many years. Later we will touch upon the improved and updated model of epithelial carcinogenesis that divides ovarian cancer into two broad categories based on clinicopathological and molecular genetic features. In our review we will focus on epithelial ovarian tumors (EOTs) and present the most recent experimental findings, the latest pathogenetic theories and our personal interpretations. First of all, what needs to be acknowledged is the heterogeneity and the difference of origin among the so-called “ovarian epithelial” tumors.

The Multiformity Of Epithelial Ovarian Tumors Over forty years ago the World Health Organization (WHO) proposed the first classification of ovarian tumors, distinguishing EOTs in different histotypes, 679

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The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

which are categorized based on cell features and architecture patterns and named based on morphological resemblance of the tumor to normal tissues (1). With the advent of new technology, the molecular features of tumors have been revealed with a previously unconceivable precision. This new knowledge supports molecularly the histological classification of epithelial ovarian cancer (EOC), redefines novel overlooked entities and unveils targetable biomarkers. Last WHO classification of Tumours of the Female Reproductive Organs, released in 2014, differs minimally from the previous, and EOTs are categorized into five main histological subtypes and generally subdivided in benign, borderline and malignant tumors (i.e. carcinomas) (2). The vast majority of EOCs are so called “serous” for their resemblance to the normal fallopian tube epithelium, and account for over 80% of EOC. Endometrioid carcinoma, the second EOC in frequency (approximately 15%), mimics morphologically normal endometrium. Clear cell carcinoma resembles endometrium of pregnancy and accounts for about 5% of EOC. Mucinous carcinoma, whose cells are similar to gastrointestinal epithelium, represents about 2-3% of all EOCs. Finally, the most recent classification introduces a new diagnostic entity so called “seromucinous” tumors that recall the endocervical epithelium, which previously were included into the mucinous tumors as endocervical-type. The remaining EOCs include Brenner tumors, characterized by transitional-like appearance (also called urothelial), and undifferentiated carcinomas, constituted by a discohesive and monotonous cell population, which show no

morphologic differentiation. Accordingly, serous, endometrioid, clear cell and seromucinous tumors share a Müllerian phenotype, while undifferentiated carcinoma, mucinous, and Brenner tumors do not. The main histotypes of EOC are further subclassified based on the degree of differentiation. The FIGO grading system has been recommended for both ovarian endometrioid and seromucinous carcinomas in the International Collaboration on Cancer Reporting data. For serous carcinoma, lately, it has advocated a twodegree system, replacing a three-degree system, that favours low-grade and high-grade not only for simplicity and reproducibility but also grounded on distinct molecular pathogenesis. Therefore, serous carcinoma has been dichotomized into low-grade and high-grade by the 2014 WHO classification. Though based on current terminology they appear as two morphological spectra of the same tumor, it should be stressed that they represent two different tumor types (3-5). Notably, both the histological subtypes and degree of differentiation correlate with clinical behavior of EOC.

The Ovarian Surface Epithelium Origin: The Unifying Traditional Theory The female pelvic tumors manifest usually as a primary ovarian mass with various involvement of the peritoneum, as a consequence, it has been assumed that they primarily originate from the ovary, though EOCs show indubitable morphological resemblance to specific tissues not normally present in the ovary. In fact, the ovary is composed mainly of germ and stromal cells and virtually

Figure 1. Schematic representation of the ovarian surface epithelium hypothesis for the origin of epithelial ovarian cancers. Abbreviations: OSE, ovarian surface epithelium; CIC, cortical inclusion cysts; SC, serous cyst; MC, mucinous cyst; EC, endometriotic cyst; EOC, epithelial ovarian cancer; HGSC, high-grade serous carcinoma; LGSC, low-grade serous carcinoma; SMC, seromucinous carcinoma; EMC, endometrioid carcinoma; CCC, clear cell carcinoma.

The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

no real epithelial cells, so that EOCs traditionally are thought to originate from the so called ovarian surface epithelium (OSE) or its invaginations into the ovarian cortex, named cortical inclusion cysts (CICs) (6, 7). The OSE is an innocent monolayered modified mesothelium that lines the ovary, with an uncommitted morphology and differentiation. Therefore, to reconcile the unspecialized morphology of OSE with the morphological heterogeneity of EOTs, the OSE was believed to carry the potential of differentiating in different epithelial directions, as previously mentioned, recapitulating the divergent specialization similar to those shown by the Müllerian duct epithelium during normal embryonal development (Figure 1). Coherently, CICs show variable morphological characteristics and immunophenotypes (8). Ultimately, a common histogenesis from a single cell type was a convenient and readily understood concept to group the majority of epithelial neoplasms occurring within the ovary. In this conventional view of ovarian carcinogenesis the “incessant ovulation” theory proposed by Fathalla indicates the cyclic ovulation and the repeated trauma and repair processes as the cause of DNA damage and consequent neoplastic transformation of the OSE (9).

The Controversies: Through A Renewed Manifold Theory This theory has endured for over fifty decades in spite of numerous inconsistencies. First, as mentioned above, the common morphological features of EOTs do not mimic in anyway the normal appearance of OSE. In addition, Müllerian metaplasia derived from OSE should show, at least temporarily, intermediate hybrid phenotypes with contemporary expression of Müllerian and OSE markers, but this event is extremely rare. Second, OSE being phenotypically and ultrastructurally indistinguishable from mesothelium, its neoplastic transformation should theoretically look like mesothelioma and this is not true for EOCs. Third, the testis, the male gonad, similarly to the ovary is recovered by a modified mesothelium called the tunica albuginea, but only exceptionally develops epithelial tumors. Forth, only few reports have described putative precursor lesions, such as significant epithelial atypia, dysplasia or carcinoma in situ, involving the OSE or CICs (6, 10, 11). Fifth, the few molecular studies that have investigated OSE at a molecular level failed to identify differences in the expression of genes commonly deregulated in EOC. To our knowledge, few molecular alterations characteristic of EOC are documented in OSEs-CICs, such as the overexpression of p53 and TP53 mutations but just in few reports (12-15). Moreover, a recent molecular genetic analysis showed aneuploidy in CICs but not in the OSE (13) supporting the proposal that EOC indeed begins in these CICs rather than the OSE itself.

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These inconsistencies have led investigators to propose the alternative origin from the “secondary Müllerian system” (16), which they defined as such “Müllerian epithelium-bounded structures found outside fallopian tubes, uterus, and cervix” (i.e. paraovarian/ paratubal cysts, endometriosis, endosalpingiosis, endomucinosis and rete ovarii) to account for the Müllerian phenotype expressed by most EOC. Also this occurrence is rather unlikely since Müllerian-type carcinomas developing outside the ovary, where the secondary Müllerian system is frequently found, are extremely uncommon.

The Tubal Origin of Serous Tumors Serous carcinoma is the most frequent EOC. Currently, it is subclassified based upon its degree of differentiation in two main subtypes, high-grade serous carcinoma (HGSC) that alone accounts for more than 70% of the EOC, and low-grade serous carcinoma (LGSC) that represents around 5% of EOC. Based on biological, molecular and clinical-pathological evidences, they are two distinct entities, and the supposed progression between LGSC to HGSC appears more semantic than real in the majority of cases. However, there are growing evidences that both HGSC and LGSC may indeed derive from fallopian tube epithelium rather than OSE (Figure 2).

Serous Tubal Intraepithelial Carcinoma: The Watershed for High-Grade Serous Carcinoma The OSE paradigm has started being revaluated, with regard to HGSC, since 2001 when Piek and al. described dysplastic lesions and occult HGSC in the fallopian tubal epithelium, but not in the ovary, in patients who had undergone prophylactic ovariosalpingectomy for germline mutations in BRCA1 and BRCA2 genes, that genetically predispose to HGSC. Subsequent studies have confirmed the presence of the tubal lesions, later called “serous tubal intraepithelial carcinoma” (STIC). Additional studies in which fallopian tubes were carefully examined by SEEFIM protocol (i.e. sectioning and extensively examining the fimbriated end) have revealed that STICs and early invasive tubal carcinomas occur not only in women with a HGSC genetic predisposition, but also in 50-60% of women with sporadic HGSC (without either HGSC family history or known BRCA1-2 mutations) (17-25). Further evidence supporting STICs as the precursors of HGSC has emerged by molecular studies, firstly the identification of identical TP53 mutations in STICs and concomitant ovarian HGSCs, indicating a clonal relationship between them (24, 26, 27). Further support of the link between STICs and HGSC was the demonstration that STICs and concomitant ovarian HGSCs, besides expressing alike p53, also co-express p16, FAS, Rsf-1, and cyclin E1 (28). We have also found

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The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

Figure 2. Schematic representation of the fallopian tube hypothesis for the origin of serous carcinomas. Abbreviations: FTE, fallopian tube epithelium; PTH, papillary tubal hyperplasia; SC, serous cyst; STIC, serous tubal intraepithelial carcinoma; SBT, serous borderline tumor; HGSC, high-grade serous carcinoma; LGSC, low-grade serous carcinoma.

shortened telomeres, as occur in other precursor lesions, in the majority of STICs (29). Finally, we recently have reported concordant copy number of CCNE1, one of the most frequently amplified genes in HGSC, in STICs and concurrent HGSC and a more prevalent centrosome amplification in HGSC as compared to STIC; these findings further support latter as the HGSC precursor (30). Importantly, these lesions are generally detected in the fimbria. Therefore, it has been subsequently proposed that the implantation of malignant cells from the STIC to the ovary develops into a tumor mass that gives the impression that the tumor originated in the ovary (Figure 2) (31). In theory some STIC cell clusters detach from tubal mucosa, due to cell discohesiveness, and adhere to

the disrupted OSE after ovulation (32), or onto the OSE and induce OSE displacement from the area underneath through a mechanism similar to that described for other peritoneal surfaces (33). In hindsight, the logical assumption that the precursors of ovarian carcinoma would be found in the ovary delayed the identification of STIC, since the tubes were not carefully examined by pathologists (6, 7, 17). However, this STIC theory does not completely explain the origin of all HGSCs, so that incongruences still need to be pointed out. In fact, even the accurate SEE-FIM protocol does not allow to identify STIC lesion in a relevant percentage of HGSCs, at least 30%. In particular, HGSCs with a solid, pseudoendometrioid,

The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

and transitional growth pattern (SET morphology) have a reduced prevalence of concurrent STICs, that implies the possibility of missing alternative HGSC precursors (34). One possible explanation is that small STICs can be missed despite complete sampling of the tubes. Another explanation is that indeed not all ovarian HGSCs arise from STICs, but some develop from the peritoneum, socalled “primary peritoneal carcinoma” or from the ovary. Yet possibility is that a minority of HGSCs develops from peritoneal endosalpingiosis or ovarian CICs. Although, endosalpingiosis and ovarian CICs instead to derive from metaplastic transformation of the peritoneal or ovarian mesothelium, could be derived from the fallopian tube epithelium, particularly of the fimbria, that implants onto the peritoneum or on the disrupted ovarian surface following ovulation (35). In fact, both endosalpingiosis and CICs frequently show morphological features and immunophenotype identical to fallopian tubal epithelium (36-39). Parenthetically, ovulation itself with the physiological mesothelial clearance may favor the adhesion of tubal fimbriae to the ovary, particularly in view of the close anatomical location. Moreover, the released follicular fluid during the ovulation has been shown to contain reactive oxygen species (free radicals) and high levels of sex hormones, which possibly induce changes in both the epithelial cells of fimbria and the local microenvironment, and so play a role in early ovarian carcinogenesis (40). This brings back and reconciles to Fathalla’s theory and is consistent with epidemiologic evidence linking decreased ovulations (either as a result of oral contraceptives usage or multiple pregnancies) with a decreased risk of ovarian cancer (41, 42). Therefore, some HGSCs may indeed develop from peritoneal endosalpingiosis or ovarian CICs (13) but these could very well be derived, at least some, from implanted fimbrial tubal epithelium (35). Parenthetically, gene expression studies show that HGSC resembles tubal epithelium rather than OSE, therefore gene expression profile associated with ovarian HGSC is consistent with a Müllerian (i.e. tubal) embryonic origin and not with mesothelial/urogenital/ovarian origin. Coherently, differently from OSE, immunohistochemically HGSC expresses Müllerian markers, as PAX8, but not mesothelial markers such as calretinin (35).

Putative Precursors of Low-Grade Serous Carcinoma Into The Fallopian Tube LGSC is commonly associated with serous borderline tumors, and molecular evidences suggest that LGSC derives in a stepwise progression from a serous cystadenoma or serous adenofibroma through a serous borderline tumor to a noninvasive LGSC (i.e. micropapillary variant of serous borderline tumor) that finally becomes an invasive LGSC. Lately, some investigators have proposed

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that serous borderline tumors derive from fallopian tube epithelium, analogously to HGSC (37, 43, 44). In fact, a careful examination of fallopian tubes in women with serous borderline tumors has disclosed tubal proliferations in the form of PAX2-null secretory cell outgrowths or of the so-called “papillary tubal hyperplasia” (44, 45). This later lesion is characterized by small papillary formations of bland appearing tubal epithelium (with both secretory and ciliated cells) budding from the tubal epithelium, located in the tubal lumen, and often containing psammoma bodies. The authors have proposed that these detached papillae of tubal epithelium implant either on the ovary where they can develop into serous borderline tumor or on the pelvic or abdominal peritoneum to produce endosalpingiosis and implants (also in absence of borderline tumors). Furthermore, similarly to HGSCs, borderline tumors can originate from ovarian CICs, indeed deriving from tubal epithelium (Figure 2, right). As a matter of fact, CICs sometimes show papillary formations and they possibly may transform in borderline tumors (46). Both FTE and CICs are composed of a dual cell component, represented by secretory and ciliated cells, that is conserved in serous cystadenoma (37, 47). Furthermore, secretory cells increases progressively in serous borderline tumors, whereas LGSCs contain almost exclusively secretory cells, so that Li et al. proposed that LGSC pathogenetic pathway is due to a progressive clonal expansion of secretory cells and impaired maturation program (37).

The Endometrial Origin of Ovarian Endometrioid, Clear Cell and Seromucinous Tumors Endometrioid and clear cell carcinomas are the most frequent types of EOC after serous carcinoma, accounting for approximately 15-20% of EOC in Western countries. Back in 1925 Sampson hypothesized that EOC arise from malignant transformation of endometriosis. Since that time, epidemiologic morphological and molecular studies have indicated endometriosis as the precursor of ovarian endometrioid, clear cell and, more recently, seromucinous tumors. Coherently, patients with endometriosis have about 3 to 10 times increased risk of developing ovarian endometrioid and clear cell carcinoma and, approximately 40% of ovarian endometrioid and 50-90% of clear cell carcinoma are associated with endometriosis (48-50). On the other hand, shared molecular genetic alterations revealing a clonal relationship between endometriosis and endometrioid and clear cell carcinoma, are supportive for the above hypothesis and will be described later in this chapter. Endometriosis is a quite common chronic disorder affecting females in reproductive age, characterized by the growth of endometrial-type gland and stromal tissues outside of the uterine cavity. Its origin is still

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The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

debated - either from retrograde menstruation-stem cell, coelomic metaplasia or Müllerian remnants. Although latter hypotheses are difficult to prove with experimental methods, there are accumulated evidences supporting the former; including but not limited to the following factors. First, endometriosis occurs exclusively in humans and primates, species that menstruate (51) and its increased risk is associated with increased menstrual exposure. Second, tubal ligation reduces the incidence of ovarian endometrioid and clear cell carcinoma (52). Molecularly, eutopic endometrium exhibits intrinsic molecular abnormalities similar to endometriosis in women with endometriosis, such as activation of the oncogenic Ras and Wnt pathways (53). Presumably, these changes favor endometrial tissue to survive, implant, and invade ovarian and peritoneal tissues. Notably, even if endometriosis involves multifocally the pelvic cavity, the ovary represents, by far, the main site of cancer onset associated with endometriosis. As a consequence

mainly endometrioma, i.e. ovarian endometriosis, represents the precursor of endometriosis-associated ovarian cancer (Figure 3). Coherently, both ovarian endometrioid and clear cell carcinomas associate specifically to endometrioma rather than endometriosis elsewhere. It is conceivable that, even if the endometriosis cyst fluid and microenvironment are characterized by inflammation and iron overload, that have been demonstrated to induce DNA damage and mutagenesis, driving malignant transformation, the latter may be accelerated and potentiated by ovarian microenvironment. Therefore, endometrioma–related EOTs would derive from endometrium through a long pathogenetic process. The endometrium cells settled into the ovary first would form an endometrioma or rarely an adenofibroma. The endometrioma epithelium exposed to high concentration of ferric iron, inflammation factors and sex hormones would progressively transform to become an atypical endometriosis, then a borderline tumor and

Figure 3. Schematic representation of the endometrioma hypothesis for the origin of endometriosis-related epithelial ovarian cancers. Abbreviations: EMAF, endometrioid adenofibroma; CCAF, clear cell adenofibroma; Atypical, atypical endometrioma; EMBT, endometrioid borderline tumor; CCBT, clear cell borderline tumor; EMC, endometrioid carcinoma; CCC, clear cell carcinoma.

The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

finally an invasive carcinoma, specifically an endometrioid or clear cell carcinoma (Figure 3). Endometrioid carcinomas of the ovary, as well as their uterine counterparts, harbor CTNNB1 mutations, mutations affecting the MAP kinase pathway, including BRAF and KRAS, and the PI3K/Akt pathway, including PIK3CA and PTEN, and microsatellite instability. In mice, endometriosis-like lesions carrying concurrent kras and pten mutations transform to invasive endometrioid carcinomas, suggesting that they represent early carcinogenic events. ARID1A somatic mutations occur in a large proportion of endometrium-related neoplasms, including 30 to 60% of ovarian endometrioid carcinomas, also in endometrioma, but not in eutopic endometrium (54). Moreover, ARID1A loss in both endometrioma and associated ovarian endometrioid carcinoma in most cases, indicate that ARID1A mutation is an early molecular event in the development of ovarian endometrioid carcinomas, that occurs before malignant transformation (55). Ovarian clear cell carcinomas harbor ARID1A mutations in up to 75% of cases and PIK3CA activating mutations in 20-40% of cases (56). Interestingly, same ARID1A and PIK3CA mutations are identified consistently in concurrent endometriosis when present in clear cell carcinoma (55, 57). Moreover, similar c-MET copy number appears in atypical endometriosis and adjacent clear cell carcinoma (50, 58, 59). Therefore, these data suggest that these molecular genetic aberrations likely represent early events during neoplastic transformation. Eventually, the molecular similarities of ovarian endometrioid and clear cell carcinoma are strong supportive evidences for their close relationship and origin from endometrioma. A short paragraph is necessary to summarize seromucinous carcinomas. In fact, there are convincing evidences that these tumors are derived from endometriosis and must be included in the group of “endometrioma-related neoplasms”. Approximately one third of seromucinous tumors are associated with endometriosis, similarly to endometrioid and clear cell carcinomas, and show an immunoprofile resembling endometrioid and clear cell tumors (except that some are WT1 positive). In addition, mutant ARID1A in conjunction with loss of ARID1A expression is detected in over one third of seromucinous tumors (60).

The Origin of Non-Müllerian Epithelial Ovarian Tumors A minority of EOTs does not manifest a Müllerian phenotype and these include mucinous tumor (previously called mucinous tumors, intestinal-type), Brenner tumors and undifferentiated carcinomas. Their cell of origin is still debated. In addition to the possibility of deriving from OSE through mucinous or transitional metaplasia, there have been emerging few novel hypotheses.

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The common association of mucinous tumors with either teratoma or Brenner tumor suggests that they may take origin from both of these tumors. Interestingly, we recently proposed that, similarly to serous tumors, Brenner tumors originate from fallopian tubal epithelium at the tubal-mesothelial junction, where it is common to find transitional metaplasia (47). Based on our observations, these metaplastic foci, derived from the tubal epithelium at the tubo-mesothelial junction, would implant onto the ovary as Walthard nests and, under hormonal stimulation, would grow as a benign Brenner tumor. Successively, the progressive accumulation of molecular genetic aberrations would transform the benign Brenner tumor first to a borderline Brenner tumor, then rarely in a malignant Brenner tumor (61). In addition, Brenner tumors or their metaplastic precursors also may give rise to mucinous tumors (62). Then again, mucinous tumors may derive from endometrioma with mucinous metaplastic epithelium, through the mechanism described previously (i.e. endometrioma hypothesis, Figure 3). Finally, the ovarian epithelial tumors may take the form of an undifferentiated carcinoma, this tumor does not show any Müllerian differentiation and based on the common association with low-grade endometrioid carcinoma and common molecular characteristics, at least a dual derivation can be inferred, through extreme dedifferentiation of either an endometrioid carcinoma or HGSC (63).

Dualistic Pathogenetic Model of Epithelial Ovarian Tumors The heterogeneous nature of EOC has been united in a pathogenetic dualistic model that distinguishes two groups of EOC (type I and type II), based on different clinicopathologic and molecular genetic features (64). Type I tumors include low-grade serous, low-grade endometrioid, clear cell, seromucinous and mucinous carcinoma. They present as large masses, usually confined to one ovary (stage I), and have a rather good prognosis. They typically display a variety of somatic mutations that involve ARID1A, BRAF, CTNNB1, KRAS, PIK3CA, PPP2R1A, PTEN, RNF43 and hTERT, while only rarely TP53, and are usually genetically stable (58, 64-66). They are thought to develop in a stepwise fashion from benign lesions such as adenomas and endometriosis through borderline tumors. Constitutive activation of the PI3K/ Akt and MAPK signaling pathways, due to somatic mutation of genes BRAF, ERBB2, KRAS, PIK3CA, and PTEN, seems to play a preeminent role in the carcinogenic process of type I tumors. On the other hand, type II tumors include HGSC, high-grade endometrioid carcinoma, carcinosarcomas (i.e. malignant mixed Müllerian tumors) and undifferentiated carcinomas,

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The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues

which typically present in advanced stage (stages II-IV) and are highly aggressive. HGSC, the prototypical type II tumor, harbors TP53 mutations in more that 95% of cases, and BRCA suppression, either by mutation or via promoter methylation, in up to 40-50%, so that are genetically highly unstable (67). They only rarely display the mutations found in the type I tumors. Based on the fallopian tube hypothesis, type II tumors are established carcinomas from the beginning arising in the fimbria and capable of implanting on the ovary and other sites in the pelvic and abdominal cavities. The difference in the nature of the precursor lesions may explain why type I tumors remain confined to the ovary for a long periods and have an indolent course whereas type II tumors spread rapidly and are highly aggressive at their onset. The updated model, based on recent molecular studies, underscores the heterogeneity of EOC, and emphasizes that type I and type II tumors are clinically two different groups of disease. It is important to point out to the reader that type I and type II tumor model refers to different “tumorigenic pathways” and that it has limited relation with diagnostic terminology, and to be honest, it is not perfect yet. As a matter of fact, recently we found that CCNE1 copy number gain characterizes clear cell carcinomas and high-grade serous carcinomas with poor prognosis and is absent in the other type I neoplasms, joining molecularly aggressive type 1 and type 2 tumors (Ayhan, Kuhn et al. in press). This model is rather a meaningful etiopathogenetic representation, that groups different histological types into two broad categories combined for clinical utility, therapeutic and prognostic relevance. An appreciation of the vastly different biology of these tumors should lead to a more informed approach to diagnosis and treatment, thereby reducing the burden of this devastating disease.

Conclusion Recent clinical-pathological, immunohistochemical and molecular genetic studies suggest that most EOCs most probably develop from non-ovarian epithelial cells that implant or home on the ovary. In particular, HGSC may derive from fallopian tubal epithelium either antecedently transformed (STIC cells) or not, LGSC directly from borderline tumors, that in turn seem to take origin from tubal precursors. Finally, endometrioid, clear cell and seromucinous carcinomas potentially arise from endometrium implanted on the ovary, climbing up through the fallopian tube, either in a mature or stemcell form. As a consequence, recognizing the cell of origin of EOC in the fallopian tube and endometrium instead of the ovary not only redirects the attention outside the ovary as a source of precursor lesions, but also as a site of prophylactic intervention to reduce the burden of this disease. Nevertheless, it designates the fallopian tube as the secret hero or gambler on the ominous game of

ovarian cancer by either playing the leading or conveyer role. Since HGSCs are usually detected in advanced stages, because current screening methods with CA125 and transvaginal ultrasound do not allow to predate the diagnosis of HGSC, they have inauspicious course (68). This new knowledge may allow discovery of novel biomarkers for early detection of ovarian carcinoma. Moreover, the current approach to prophylaxis for ovarian cancer should be reevaluated in the light of the evolving new paradigm of ovarian carcinogenesis. The current prophylactic intervention for women with a family history of ovarian carcinoma and/or BRCA1-2 mutations is hysterectomy and bilateral salpingo-oophorectomy. The unequivocal demonstration that the HGSC rises up from the fallopian tube would indicate salpingectomy alone as the best prophylactic intervention to prevent the risk of ovarian cancer while avoiding the adverse effect of ovary ablation (iatrogenic menopause), a practice which has started to become common in Canada (i.e. opportunistic bilateral salpingectomy) (69). Finally, in the light of this novel view, scientists and clinicians should focus on defining the biological mechanisms that lead the Müllerian epithelia to sit into the ovary and give rise to EOC, including the tubal and ovarian microenvironment factors, that favor fullfledged cancer development. This effort will allow developing reliable biomarkers for early detection of ovarian carcinoma, and identifying the best prophylactic strategies, thereby reducing the burden of this devastating disease.

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