Sweden. Antonio Casado, MD, PhD. Hospital Universitario ClÃnico San .... Christina Fotopoulou, MD, PhD ..... Barts Cancer Institute, Queen Mary University.
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
iv
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
v
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
vi
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
vii
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
viii
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
ix
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
x
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
xv
xvi
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
xviii
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
xx
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
xxi
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 NONOVARIAN 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
680
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.
681
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
682
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
683
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
684
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.
685
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,
686
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.
References 1. Serov SF SR, Sobin LH. Histological Typing of Ovarian Tumours. 1973 ed. 2. Kurman RJ CM, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. Lyon: International Agency for Research on Cancer; 2014. 3. Ayhan A, Kurman RJ, Yemelyanova A, Vang R, Logani S, Seidman JD, et al. Defining the cut point between low-grade and high-grade ovarian serous carcinomas: a clinicopathologic and molecular genetic analysis. Am J Surg Pathol 2009;33(8):1220-4. 4. Singh N, Ayhan A, Menon U, Chin Aleong JA, Faruqi AZ, Gayther SA, et al. Grading of serous ovarian carcinoma: further evidence of a lack of agreement between conventional grading systems. Histopathology 2008;52(3):393-5. 5. Vang R, Shih Ie M, Salani R, Sugar E, Ayhan A, Kurman RJ. Subdividing ovarian and peritoneal serous carcinoma into moderately differentiated and poorly differentiated does not have biologic validity based on molecular genetic and in vitro drug resistance data. Am J Surg Pathol 2008;32(11):1667-74. 6. Bell DA, Scully RE. Early de novo ovarian carcinoma. A study of fourteen cases. Cancer 1994;73(7):1859-64.
The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues
7. Deligdisch L, Gil J, Kerner H, Wu HS, Beck D, GershoniBaruch R. Ovarian dysplasia in prophylactic oophorectomy specimens: cytogenetic and morphometric correlations. Cancer 1999;86(8):1544-50. 8. Banet N, Kurman RJ. Two types of ovarian cortical inclusion cysts: proposed origin and possible role in ovarian serous carcinogenesis. Int J Gynecol Pathol 2015;34(1):3-8. 9. Fathalla MF. Incessant ovulation--a factor in ovarian neoplasia? Lancet 1971;2(7716):163. 10. Gusberg SB, Deligdisch L. Ovarian dysplasia. A study of identical twins. Cancer 1984;54(1):1-4. 11. Graham JB, Graham RM, Schueller EF. Preclinical Detection of Ovarian Cancer. Cancer 1964;17:1414-32. 12. Balkwill F, Bast RC, Berek J, Chenevix-Trench G, Gore M, Hamilton T, et al. Current research and treatment for epithelial ovarian cancer. A Position Paper from the Helene Harris Memorial Trust. Eur J Cancer 2003;39(13):1818-27. 13. Pothuri B, Leitao MM, Levine DA, Viale A, Olshen AB, Arroyo C, et al. Genetic analysis of the early natural history of epithelial ovarian carcinoma. PLoS One 2010;5(4):e10358. 14. Nnene IO, Nieto JJ, Crow JC, Sundaresan M, MacLean AB, Perrett CW, et al. Cell cycle and apoptotic proteins in relation to ovarian epithelial morphology. Gynecol Oncol 2004;92(1):247-51. 15. Hutson R, Ramsdale J, Wells M. p53 protein expression in putative precursor lesions of epithelial ovarian cancer. Histopathology 1995;27(4):367-71. 16. Dubeau L. The cell of origin of ovarian epithelial tumors and the ovarian surface epithelium dogma: does the emperor have no clothes? Gynecol Oncol 1999;72(3):43742. 17. Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 2007;25(25):3985-90. 18. Carcangiu ML, Radice P, Manoukian S, Spatti G, Gobbo M, Pensotti V, et al. Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers. Int J Gynecol Pathol 2004;23(1):35-40. 19. Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol 2001;25(10):1283-9. 20. Finch A, Shaw P, Rosen B, Murphy J, Narod SA, Colgan TJ. Clinical and pathologic findings of prophylactic salpingooophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol 2006;100(1):58-64. 21. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006;30(2):230-6. 22. Paley PJ, Swisher EM, Garcia RL, Agoff SN, Greer BE, Peters KL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 2001;80(2):176-80. 23. Shaw PA, Rouzbahman M, Pizer ES, Pintilie M, Begley H. Candidate serous cancer precursors in fallopian tube
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36. 37.
38.
687
epithelium of BRCA1/2 mutation carriers. Mod Pathol 2009;22(9):1133-8. Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 2007;31(2):161-9. Przybycin CG, Kurman RJ, Ronnett BM, Shih Ie M, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol 2010;34(10):1407-16.. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007;211(1):26-35. Kuhn E, Kurman RJ, Vang R, Sehdev AS, Han G, Soslow R, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions. J Pathol 2012;226(3):421-6. Sehdev AS, Kurman RJ, Kuhn E, Shih Ie M. Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP), cyclin E and fatty acid synthase. Mod Pathol 2010;23(6):844-55. Kuhn E, Meeker A, Wang TL, Sehdev AS, Kurman RJ, Shih Ie M. Shortened telomeres in serous tubal intraepithelial carcinoma: an early event in ovarian high-grade serous carcinogenesis. Am J Surg Pathol 2010;34(6):829-36. Kuhn E, Wang TL, Doberstein K, Bahadirli-Talbott A, Ayhan A, Sehdev AS, et al. CCNE1 amplification and centrosome number abnormality in serous tubal intraepithelial carcinoma: further evidence supporting its role as a precursor of ovarian high-grade serous carcinoma. Mod Pathol 2016;Jul 22. doi: 10.1038/modpathol.2016.101. Epub ahead of print Piek JM, van Diest PJ, Zweemer RP, Jansen JW, PoortKeesom RJ, Menko FH, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001;195(4):451-6. Yang-Hartwich Y, Gurrea-Soteras M, Sumi N, Joo WD, Holmberg JC, Craveiro V, et al. Ovulation and extra-ovarian origin of ovarian cancer. Sci Rep 2014;4:6116. Davidowitz RA, Selfors LM, Iwanicki MP, Elias KM, Karst A, Piao H, et al. Mesenchymal gene program-expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance. J Clin Invest 2014;124(6):2611-25. Howitt BE, Hanamornroongruang S, Lin DI, Conner JE, Schulte S, Horowitz N, et al. Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma. Am J Surg Pathol 2015;39(3):287-93. Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010;34(3):433-43. Auersperg N. The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol 2011;30(1):12-21. Li J, Abushahin N, Pang S, Xiang L, Chambers SK, Fadare O, et al. Tubal origin of ‘ovarian’ low-grade serous carcinoma. Mod Pathol 2011;24(11):1488-99. Tong GX, Chiriboga L, Hamele-Bena D, Borczuk AC. Expression of PAX2 in papillary serous carcinoma of
688
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53. 54.
The Non-ovarian Origin and Pathogenesis of Ovarian Carcinomas: Update on the Pathological and Molecular Clues
the ovary: immunohistochemical evidence of fallopian tube or secondary Mullerian system origin? Mod Pathol 2007;20(8):856-63. Ardighieri L, Lonardi S, Moratto D, Facchetti F, Shih Ie M, Vermi W, et al. Characterization of the immune cell repertoire in the normal fallopian tube. Int J Gynecol Pathol 2014;33(6):581-91. Emori MM, Drapkin R. The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis. Reprod Biol Endocrinol 2014;12:60. Risch HA, Weiss NS, Lyon JL, Daling JR, Liff JM. Events of reproductive life and the incidence of epithelial ovarian cancer. Am J Epidemiol 1983;117(2):128-39. Beral V, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007;369(9574):1703-10. Chen C, Li J, Yao G, Chambers SK, Zheng W. Tubal origin of ovarian low-grade serous carcinoma. Am J Clin Exp Obstet Gynecol 2013;1(1):13-36. Laury AR, Ning G, Quick CM, Bijron J, Parast MM, Betensky RA, et al. Fallopian tube correlates of ovarian serous borderline tumors. Am J Surg Pathol 2011;35(12):1759-65. Kurman RJ, Vang R, Junge J, Hannibal CG, Kjaer SK, Shih Ie M. Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 2011;35(11):1605-14. Resta L, Russo S, Colucci GA, Prat J. Morphologic precursors of ovarian epithelial tumors. Obstet Gynecol 1993;82(2):181-6. Kuhn E, Ayhan A, Shih Ie M, Seidman JD, Kurman RJ. Ovarian Brenner tumour: a morphologic and immunohistochemical analysis suggesting an origin from fallopian tube epithelium. Eur J Cancer 2013;49(18):383949. Fukunaga M, Nomura K, Ishikawa E, Ushigome S. Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 1997;30(3):249-55. Russell P. The pathological assessment of ovarian neoplasms. I: Introduction to the common ‘epithelial’ tumours and analysis of benign ‘epithelial’ tumours. Pathology 1979;11(1):5-26. Veras E, Mao TL, Ayhan A, Ueda S, Lai H, Hayran M, et al. Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Surg Pathol 2009;33(6):844-53. D’Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update 2002;8(1):84-8. Rosenblatt KA, Thomas DB. Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Cancer Epidemiol Biomarkers Prev 1996;5(11):933-5. Bulun SE. Endometriosis. N Engl J Med 2009;360(3):26879. Samartzis EP, Samartzis N, Noske A, Fedier A, Caduff R, Dedes KJ, et al. Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic
transformation? Mod Pathol 2012;25(6):885-92. 55. Ayhan A, Mao TL, Seckin T, Wu CH, Guan B, Ogawa H, et al. Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma. Int J Gynecol Cancer 2012;22(8):1310-5. 56. Kuo KT, Mao TL, Jones S, Veras E, Ayhan A, Wang TL, et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol 2009;174(5):1597-601. 57. Anglesio MS, Bashashati A, Wang YK, Senz J, Ha G, Yang W, et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J Pathol 2015;236(2):201-9. 58. Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010;363(16):1532-43. 59. Yamamoto S, Tsuda H, Miyai K, Takano M, Tamai S, Matsubara O. Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas. Mod Pathol 2012;25(1):122-30. 60. Wu CH, Mao TL, Vang R, Ayhan A, Wang TL, Kurman RJ, et al. Endocervical-type mucinous borderline tumors are related to endometrioid tumors based on mutation and loss of expression of ARID1A. Int J Gynecol Pathol 2012;31(4):297-303. 61. Kuhn E, Ayhan A, Shih Ie M, Seidman JD, Kurman RJ. The pathogenesis of atypical proliferative Brenner tumor: an immunohistochemical and molecular genetic analysis. Mod Pathol 2014;27(2):231-7. 62. Wang Y, Wu RC, Shwartz LE, Haley L, Lin MT, Shih Ie M, et al. Clonality analysis of combined Brenner and mucinous tumours of the ovary reveals their monoclonal origin. J Pathol 2015;237(2):146-51. 63. Kuhn E, Ayhan A, Bahadirli-Talbott A, Zhao C, Shih Ie M. Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma. Am J Surg Pathol 2014;38(5):660-5. 64. Shih Ie M, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 2004;164(5):1511-8. 65. Jones S, Wang TL, Shih Ie M, Mao TL, Nakayama K, Roden R, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010;330(6001):228-31. 66. Wu RC, Ayhan A, Maeda D, Kim KR, Clarke BA, Shaw P, et al. Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J Pathol 2014;232(4):473-81. 67. Weroha SJ, Becker MA, Enderica-Gonzalez S, Harrington SC, Oberg AL, Maurer MJ, et al. Tumorgrafts as in vivo surrogates for women with ovarian cancer. Clin Cancer Res 2014;20(5):1288-97. 68. Parker WH, Broder MS, Chang E, Feskanich D, Farquhar C, Liu Z, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study. Obstet Gynecol 2009;113(5):1027-37. 69. Foulkes WD. Preventing ovarian cancer by salpingectomy. Curr Oncol 2013;20(3):139-42.