Disaia and Creasman Clinical Gynecologic Oncology

ISBN: 978-0-323-77684-4

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2018, 2012, 2007, 2002, 1997, 1993, 1989, 1984, and 1981.

Content Strategist: Nancy Anastasi Duffy Content Development Manager: Meghan Andress Content Development Specialist: Kevin Travers Publishing Services Manager: Deepthi Unni Project Manager: Radjan Lourde Selvanadin Design Direction: Margaret Reid Printed in India Last digit is the print number: 9 8 7 6 5 4 3 2 1

CONTRIBUTORS Floor J. Backes, MD Professor Obstetrics and Gynecology; Division of Gynecologic Oncology The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus Ohio United States Lindsey B. Beffa, MD Cleveland Clinic Division of Gynecologic Oncology, Cleveland Ohio United States Caroline C. Billingsley, MD Associate Professor Obstetrics and Gynecology Univerisity of Cincinnati, Cincinnati Ohio United States Michael J. Birrer, MD, PhD Director Winthrop P. Rockefeller Cancer Institute UAMS, Little Rock Arkansas United States Kristin Bixel, MD Assistant Professor Obstetrics & Gynecology, Division of Gynecologic Oncology The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus Ohio United States Teresa K.L. Boitano, MD Division of Gynecologic Oncology Department of Obstetrics and Gynecology University of Alabama at Birmingham, Birmingham Alabama United States

Wendy R. Brewster, MD, PhD Professor Obstetrics and Gynecology University of North Carolina, Chapel Hill, Chapel Hill North Carolina United States Director, Center for Women’s Health Research University of North Carolina, Chapel Hill North Carolina United States Dana M. Chase, MD Associate Professor Creighton University School of Medicine Phoenix, Arizona United States Shaina Bruce, MD Gynecologic Oncology Fellow Obstetrics and Gynecology Washington University School of Medicine, St Louis Missouri United States Angelena Crown, MD Breast Surgery, True Family Women’s Cancer Center, Swedish Cancer Institute, Seattle Washington United States Christina S. Chu, MD Professor Division of Gynecologic Oncology Fox Chase Cancer Center, Philadelphia Pennsylvania United States Daniel L. Clarke-Pearson, MD Robert A. Ross Distinguished Professor and Chair (Emeritus) Department of Obstetrics and Gynecology University of North Carolina, Chapel Hill North Carolina United States

Brian Crosland, MD University of California, Irvine, Orange California United States Joshua G. Cohen, MD Division of Gynecologic Oncology University of California Los Angeles Medical Center, Los Angeles California United States Robert L. Coleman, MD, FACOG, FACS Professor & Deputy Chair Department of Gynecologic Oncology & Reproductive Medicine Chief Scientific Officer, US Oncology Research and Texas Oncology, The Woodlands, United States Paul A. DiSilvestro, MD Director Program in Women’s Oncology Women and Infants Hospital, Department of Pathology & Laboratory Medicine Providence, Rhode Island United States Oliver Dorigo, MD, PhD Director and Associate Professor Obstetrics and Gynecology, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology Stanford University, Palo Alto United States Linda R. Duska, MD, MPH Professor Department of Obstetrics and Gynecology UVA, Charlottesville Virginia United States

iii

Contributors

Ramez Nassef Eskander, MD Associate Professor Obstetrics and Gynecology, Reproductive Sciences UC San Diego, La Jolla California United States

Lindsay Kuroki, MD, MSCI Assistant Professor Obstetrics and Gynecology Washington University School of Medicine, St. Louis Missouri United States

Mary L. Gemignani, MD, MPH Breast Service Department of Surgery Memorial Sloan Kettering Cancer Center, New York New York United States

Katherine Kurnit, MD, MPH Assistant Professor Department of Obstetrics & Gynecology Section of Gynecologic Oncology University of Chicago Medicine

Camille Catherine Gunderson, MD University of Oklahoma, Mercy Hospital Section of Gynecologic Oncology Oklahoma City Oklahoma United States Andrea R. Hagemann, MD, MSCI Associate Professor Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, Saint Louis Missouri United States Thomas J. Herzog, MD Professor Paul & Carolyn Flory Professor of Obstetrics & Gynecology Deputy Director, University of Cincinnati Cancer Center Univerisity of Cincinnati, Cincinnati, Ohio United States Travis R. Korenaga, MD University of California, Irvine, Orange California United States Warner K. Huh, MD Division of Gynecologic Oncology Department of Obstetrics and Gynecology University of Alabama at Birmingham, Birmingham Alabama United States

Robert S. Mannel, MD Director, University of Oklahoma Stephenson Cancer Center Obstetrics and Gynecology University of Oklahoma Health Sciences Center, Oklahoma City Oklahoma United States L. Stewart Massad Jr., MD Departement of Obstetrics and Gynecology Washington University St. Louis, St. Louis Missouri United States Cara A. Mathews, MD Associate Professor Obstetrics and Gynecology, Division of Gynecologic Oncology Alpert Medical School of Brown University, Providence Rhode Island United States David S. Miller, MD, FACOG, FACS Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology, UT Southwestern, Dallas, Texas United States Bradley J. Monk, MD Professor Division of Gynecologic Oncology University of Arizona College of Medicine Creighton University School of Medicine Phoenix United States

Director, Principal Investigator Community Research Development, HonorHealth Research Institute David G. Mutch, MD Judith and Ira Gall Professor Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Washington University School of Medicine, St Louis Missouri United States Rachita Nikam, CGC Washington University in St. Louis School of Medicine, Department of Pediatrics, Division of Genetics & Genomic Medicine United States JoAnn V. Pinkerton, MD, NCMP Professor Department of Obstetrics and Gynecology University of Virginia Health Sciences, Charlottesville Virginia United States Matthew Powell, MD Department of Obstetrics and Gynecology Washington University School of Medicine, St Louis Missouri United States Dominique L. Rash, MD Department of Radiation Medicine and Applied Sciences Radiation Medicine and Applied Sciences University of California San Diego Health, La Jolla California United States Lisa M. Landrum, MD, PhD Indiana University Department of Obstetrics and Gynecology Indianapolis, IN Kari L. Ring, MD Assistant Professor Obstetrics and Gynecology University of Virginia, Charlottesville Virginia United States

Contributors Malte Renz, MD, PhD Gynecologic Oncology Division, Department of Obstetrics & Gynecology, Stanford University, Palo Alto United States Brandon Roane, MD Gynecologic Oncologist, Texas Oncology–Methodist Charlton Cancer Center and Methodist Dallas Cancer Center Gynecologic Oncology Texas United States Stephen C. Rubin, MD Professor of Gynecologic Oncology, Grotzinger-Raab Chair in Surgical Oncology Division of Gynecologic Oncology Fox Chase Cancer Center, Philadelphia Pennsylvania United States Ritu Salani, MD, MBA Professor Obstetrics & Gynecology Division of Gynecologic Oncology University of California Los Angeles, Los Angeles California United States Jane Satero, PharmD, BCOP Pharmacy Manager at Ironwood Cancer and Research Centers Scottsdale Arizona United States Anil K. Sood, MD, FACOG Professor and Vice Chair Department of Gynecologic Oncology & Reproductive Medicine M.D. Anderson Cancer Center, Houston Texas United States John T. Soper, MD Distinguished Professor of Gynecologic Oncology Obstetrics and Gynecology University of North Carolina, Chapel Hill North Carolina United States

Elizabeth Christina Stock, MD Gynecologic Oncology Fellow Obstetrics and Gynecology Washington University School of Medicine, St Louis Missouri United States

Jaclyn A. Wall, MD Division of Gynecologic Oncology Obstetrics and Gynecology University of Alabama at Birmingham, Birmingham Alabama United States

C. James Sung, MD Women & Infants Hospital Department of Pathology & Laboratory Medicine, Providence Rhode Island United States

Christina Washington, MD Gynecologic Oncology Fellow Department of Obstetrics and Gynecology University of Oklahoma Health Science Center, Oklahoma City Oklahoma United States

Krishnansu Sujata Tewari, MD Professor & Director of Research Obstetrics & Gynecology; Division of Gynecologic Oncology University of California, Irvine Medical Center, Orange California United States Director of Gynecologic Oncology The Center for Cancer Prevention and Treatment St. Joseph’s Medical Center, Orange California United States Michael D. Toboni, MD, MPH Obstetrics and Gynecology Washington University, St. Louis Missouri United States Katherine Tucker, MD Assistant Professor Division of Gynecologic Oncology, Department of Obstetrics and Gynecology` University of North Carolina School of Medicine, Chapel Hill North Carolina United States Joan L. Walker, MD Professor Obstetrics and Gynecology Stephenson Cancer Center, OUHSC, Oklahoma City Oklahoma United States

Lari B. Wenzel, PhD Professor University of California, Irvine California United States Shannon N. Westin, MD, FACOG Associate Professor Department of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer Center, Houston Texas United States Catheryn M. Yashar, MD, FACR, FABS, FASTRO Professor Department of Radiation Medicine and Applied Sciences University of California San Diego, La Jolla California United States William T. Creasman, MD Medical University of South Carolina, Charleston South Carolina United States Rosemary E. Zuna, MD The Univeristy of Oklahoma Department of Pathology, Oklahoma City Oklahoma United States

DiSaia and Creasman

TENTH EDITION

CLINICAL GYNECOLOGIC ONCOLOGY William T. Creasman, MD

Medical University of South Carolina, Charleston, SC, USA

David G. Mutch︎, MD

Judith and Ira Gall Professor Obstetrics and Gynecology Washington University School of Medicine St Louis MO, USA

Robert S. Mannel︎, MD

Director, University of Oklahoma Stephenson Cancer Center Obstetrics and Gynecology University of Oklahoma Health Sciences Center Oklahoma City OK, USA

Krishnansu Sujata Tewari︎, MD Professor & Director of Research Obstetrics & Gynecology; Division of Gynecologic Oncology University of California, Irvine Medical Center Orange CA, USA Director of Gynecologic Oncology The Center for Cancer Prevention and Treatment St Joseph’s Medical Center Orange CA, USA

P R E FAC E Over 40 years ago, Phil DiSaia was stimulated by a recognized need for a readable textbook on Gynecologic Oncology and related subjects. Our paths crossed while we were both at the MD Anderson Hospital, and we developed a close relationship both collegially and personally. After leaving Anderson and although being on opposite coasts, we were jointly involved with several clinical research endeavors and, when he asked me if I would be interested in joining his project, I was delighted to accept his kind offer. He identified a publisher and sketched out a table of contents. He was adamant that this would address primarily community physicians, residents, and other students involved with these patients. The clinical presentation and management of these problems were to be heavily employed. In areas where more than one approach to management was present, he felt that the author should inject their own bias. It should be easily readable, in which one could comfortably read a chapter in one sitting. It would not be a reference book, but most major topics would be created in depth and supplemented with ample references to current literature. It would provide a comprehensive resource for study by the resident, fellow, or student of Gynecologic Oncology and serve as a source for review material. A noble project! It was intense, but enjoyable. We would do a chapter and send it via mail (no internet) to each other to critique for corrections and/or additions. This was continued in this manner for the first six or seven editions at which time we invited three associate editors to join us in a successful project. The subsequent editions have expanded as new information in therapy have been developed, including topics not previously introduced, and expanded areas as new information became available. Not only have we added three associate editors, but also several new authors, taking advantage of their expertise. The first edition contained 16 chapters and was 478 pages including the bibliography and 3 appendices. The

ninth edition contained 16 chapters and was 631 pages long, including 5 appendices with the bibliography being online. The physician must be prepared to treat the malignancy in light of today’s knowledge and to deal with the patient and her family in a compassionate and honest manner. Patients with gynecological cancer need to feel their physicians are confident and goal oriented. Although, unfortunately, gynecological cancers will cause the demise of some individuals, it is hoped that the information collected in this book will help increase the survival rate of these patients by bringing current practical knowledge to the attention of the primary care and specialized physician. We were all looking forward to what we consider to be a landmark 10th edition. Before this could be accomplished, unfortunately, our friend and colleague Phil DiSaia, became ill and passed away. It is with renewed energy and endeavor that those of us remaining wanted to make sure this would be not only an excellent edition but truly a fitting attribute to Phil and his multiple contributions to our specialty. The 10th edition is dedicated to everything he has accomplished during his lifetime. “Our ideas are only intellectual instruments which we use to break into phenomena; we must change them when they have served their purpose, as we change a blunt lancet that we have used long enough” —Claude Bernard (1813–1878) “Some patients, though conscious that their condition is perilous, recover their health simply through their contentment with the goodness of the physician” —Hippocrates (440–370 bc) William T. Creasman, MD David G. Mutch, MD Robert S. Mannel, MD Krishnansu Sujata Tewari, MD

CONTENTS 1. Preinvasive Disease of the Cervix, 1 Jaclyn A. Wall, Teresa K.L. Boitano, L. Stewart Massad Jr. and Warner K. Huh

2. Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders, 20 Cara A. Mathews and Joan L. Walker

3. Invasive Cervical Cancer, 40 Krishnansu Sujata Tewari and Bradley J. Monk

4. Endometrial Hyperplasia, Estrogen Therapy, and the Prevention of Endometrial Cancer, 104 Kari L. Ring, JoAnn V. Pinkerton, Lisa M. Landrum, Rosemary E. Zuna and Linda R. Duska

5. Adenocarcinoma of the Uterine Corpus and Sarcomas of the Uterus, 125 William T. Creasman, David S. Miller, Ramez Nassef Eskander and Matthew Powell

6. Invasive Cancer of the Vulva, 175 Thomas J. Herzog and Caroline C. Billingsley

7. Gestational Trophoblastic Disease, 204 John T. Soper

8. Adnexal Masses, 229 Christina Washington, Camille Catherine Gunderson and Robert S. Mannel

9. Epithelial Ovarian Cancer, 250 Katherine Kurnit, Shannon N. Westin and Ritu Salani

10. Germ Cell, Stromal, and Other Ovarian Tumors, 282 Lindsey B. Beffa, C. James Sung and Paul A. DiSilvestro

11. Breast Diseases, 311 Angelena Crown and Mary L. Gemignani

12. Cancer in Pregnancy, 345 Travis R. Korenaga, Brian Crosland and Krishnansu Sujata Tewari

13. Complications of Disease and Therapy, 415

15. Targeted Therapy and Molecular Genetics, 464 Shannon N. Westin, Anil K. Sood and Robert L. Coleman

16. Molecular Hallmarks of Cancer, 489 Michael J. Birrer and Brandon Roane

17. Immunotherapy in Gynecologic Malignancies, 506 Malte Renz and Oliver Dorigo

18. Genes and Cancer: Genetic Counselling and Clinical Management, 521 Andrea R. Hagemann, Rachita Nikam and David G. Mutch

19. Palliative Care and Quality of Life, 560 Dana M. Chase, Jane Satero, Lari B. Wenzel and Bradley J. Monk

20. Role of Minimally Invasive Surgery in Gynecologic Malignancies, 594 Joshua G. Cohen, Kristin Bixel and Floor J. Backes

21. Epidemiology of Commonly Used Statistical Terms, and Analysis of Clinical Studies, 615 Wendy R. Brewster

22. Basic Principles in Gynecologic Radiotherapy, 624 Dominique L. Rash and Catheryn M. Yashar

Appendix A Staging, 646 Michael D. Toboni, David Mutch

Appendix B Modified from Common Terminology Criteria for Adverse Events (CTCAE), 648 Shaina Bruce, David Mutch

Appendix C Blood Component Therapy, 649 Lindsay Kuroki, David Mutch

Appendix D Suggested Recommendations for Routine Cancer Screening, 653 Elizabeth Christina Stock, David Mutch

Appendix E Normal Nutrition, 655 Elizabeth Christina Stock, David Mutch

Index, 660

Katherine Tucker and Daniel L. Clarke-Pearson

14. Basic Principles of Chemotherapy and Other Systemic Therapies, 443 Christina S. Chu and Stephen C. Rubin

vii

1 Preinvasive Disease of the Cervix Jaclyn A. Wall, MD, Teresa K.L. Boitano, MD, L. Stewart Massad Jr., MD, Warner K. Huh, MD

OUTLINE Introduction, 1 Human Papillomavirus Natural History, 1 Epidemiology, 3 Human Papillomavirus Vaccination, 4 Screening, 5

Management of Abnormal Screening Results, 8 Management of Post-Colposcopic Results, 13 Management of Abnormal Screening Results in Pregnancy, 17 Future Directions, 18

KEY POINTS 1. Persistent expression of human papillomavirus (HPV) is required for progression to cancer. 2. HPV vaccination has the potential to eradicate cervical cancer. 3. Screening guidelines have changed dramatically with the use of contesting and increased intervals between screenings.

4. The main screening objective is to allow for modified evaluation and treatment based on an individual woman’s risk. 5. Self-collection HPV testing may increase screening by reaching those in traditionally under-screening areas or with other barriers to clinic-based screening.

INTRODUCTION

over 50% of cervical cancers. HPV-18 is found in approximately 10% of cervical cancers, and is more frequently found in adenocarcinoma, which is commonly missed by Papanicolaou (Pap) testing. The other types are less oncogenic but have been reported in large typing studies of cervical cancers. HPV-18 and related HPV-45 are linked to cancers found in younger women. Interactions of the HPV E6 and E7 gene products with p53 and pRb are critical for HPV-induced carcinogenesis. By inactivating or activating degradation of their targets, E6 and E7 eliminate genetic surveillance and allow unchecked cell cycling, leading to the accumulation of mutations and the potential for invasive cancer. HPV-16 E6 and E7 bind their targets with greater affinity than gene products of other HPV types which may partly explain its greater oncogenicity. The progression from persistent HPV infection to cancer requires several key steps. First, infection of basal epithelial cells leads to establishment of a ring chromosome from which carcinogenic proteins are amplified while virion production occurs in maturing epithelium. Subsequently, disruption of the ring, often at the HPV E2 regulatory region, allows integration of E6 and E7 sequence into the host genome. The accumulation of mutations leads to nuclear changes visible cytologically as high-grade squamous intraepithelial lesions (HSILs) and histologically as highgrade cervical intraepithelial neoplasia (CIN) (Fig. 1.2). Selection for invasiveness and metastasis through additional mutations and gene methylation ultimately results in the development of cancer. Notably, preexisting HPV infections do not appear to predispose to or protect from infection by unrelated types.

Worldwide, cervical cancer is a leading cause of cancer-related death and morbidity in women. In the United States, it is the third most common and lethal gynecologic malignancy. Despite the implementation of cytologic screening (Papanicolaou [Pap] testing) in the United States, it is estimated that in 2021 there will be over 14,000 new cases of cervical cancer, and almost 4000 cervical-cancer related deaths. The majority of cervical cancers are caused by persistent infection of the human papillomavirus (HPV). Women’s health providers must understand and comply with primary screening recommendations and management of abnormal screening results, particularly in ways that balance benefits and harms of screening and are cost-conscious.

HUMAN PAPILLOMAVIRUS NATURAL HISTORY Over 99% of cervical cancers arise from persistent infection with HPV (Fig. 1.1). HPV is an approximately 8000 base pair DNA virus, encoding eight major proteins. Approximately 200 strains of HPV have been identified, with 12 classified as carcinogenic (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, and -59). Other types have been described as possibly carcinogenic (HPV-26, -53, -66, -67, -68, -70, -73, and -82). New genotypes are based on DNA sequencing and must share less than 90% DNA homology in the L1, E6, and E7 coding domains compared with existing HPV types. HPV-16 is the most oncogenic, and perhaps the most clinically significant, genotype, and historically has accounted for

CHAPTER 1

Preinvasive Disease of the Cervix

B Figure 1.1 A, Koilocytotic cells with intranuclear virions (36900). B, Human papillomavirus particles. Note the intranuclear crystalline array (“honeycomb”) arrangement of virions (320,500). See the insert (380,000). (Courtesy of Alex Ferenczy, MD, Montreal, Canada.)

Figure 1.2 A cervical intraepithelial neoplasia lesion with multiple mitotic figures.

While lifetime abstinence protects against genital HPV infection, nonpenetrative sexual behaviors may still transmit the virus, and additional male exposures increase female risk. For example, spouses of men who engaged in sex with prostitutes were at higher risk for cervical cancer than those of men who did not, and cervical cancer risk is higher among women whose husbands had more sexual partners. Women who report recent sex only with women are also at risk, though their risk may be lower than that of heterosexual women. Condom use is not fully protective against HPV infection because condoms fail to cover wide areas of genital skin, though it speeds clearance of HPV infections. Male circumcision also reduces but does not eliminate HPV and cancer risks. For these reasons, all women with prior sexual experience, including those who have not been sexually active for years, remain at risk for cervical cancer and require screening until they meet criteria for screening exit as discussed later. While the percentage of women who at some point develop HPV infection is high, most women infected with carcinogenic HPV do not develop cervical cancer. The majority of infections are cleared immunologically, and women who clear the virus are at low risk for progression to cancer or reappearance of CIN21. HPV is an intraepithelial virus, and clearance appears to require recognition of infection by cell-mediated immune cells. Roughly half of new infections are cleared within 6 months, with half of the remainder cleared by the end of the first year after infection. Clearance is associated with greater density of CD81 cells and lower density of T-regulatory cells in underlying stroma. Cervical treatment speeds clearance and reduces risk for posttreatment acquisition of new HPV infections. The type distribution of HPV infection after hysterectomy shows that HPV-16 and HPV-18 have a greater predilection for cervical rather than vaginal epithelium, with HPV types of lesser oncogenicity dominating in the post-hysterectomy vagina. Women infected at an increased age do not typically develop preinvasive disease or cancer of the vagina; however, increased age may result in immune senescence which suggests that some HPV infections in older women derive from reactivation of previously acquired latent infections. Although determinants of HPV persistence and progression of HPV infection to invasive cancer are poorly understood, several risk factors are known. HPV infection of a cervix undergoing active metaplasia increases risk, as reflected by the epidemiologic observations that early onset of first intercourse is associated with cancer. Smoking is linked to both CIN and cervical cancer. Benzopyrenes have been identified in cervical mucus, and the interaction of tobacco carcinogens with carcinogenic HPV increases risk substantially. Smoking also reduces immune-mediated HPV clearance. Cervical adenocarcinoma and adenocarcinoma in situ (AIS) have been linked to oral contraceptive use. Variants of common HPV types that segregate by ethnicity and polymorphisms in genes related to HPV immune recognition or HPV protein products also modulate HPV persistence and carcinogenic progression. Perhaps most important, lack of screening is a high-risk factor for progression of HPV infection to precancer and cancer. Appropriately screened and managed women with multiple risk factors are at relatively low risk, and women with few risk factors who are not screened are at higher risk.

CHAPTER 1

Immune factors play a clear role in the clearance or persistence of HPV-related cervical lesions, but the nature of immune defects is poorly understood. Immunosuppression related to coinfection with the human immunodeficiency virus (HIV-1) illustrates the importance of immunity in the typical control of HPV. Women with HIV have much higher rates of HPV infection, including multitype infections. HPV clearance rates are lower, although most women do clear their HPV infections if observed long enough, especially if immune reserve as measured by CD4 lymphocyte count remains above 200 cells/mm3. Although most HPV infections in HIV-seropositive women are cleared to such low levels of viral expression that they become nondetectable even with sensitive assays, reactivation appears to occur. This is apparent in cohort studies as the reappearance of previously cleared infections in women who deny sexual activity, often because of illness. Risks in other immunosuppressed states appear to be similar. HPV infection predicts risk for subsequent CIN21, even among cytologically normal women. In most cases, persistent HPV infections result first in cytologically detectable abnormalities and then in colposcopically visible lesions that grow before developing into invasive cancers. The 10-year risk of CIN21 after a single detected HPV infection exceeds 10%. As developed by Richart through observational studies of the cervix using cytology and colpomicroscopy, a diagnosis of CIN was based on progressively severe nuclear aneuploidy, abnormal mitotic figures, and loss of epithelial maturation. Initially considered a progressive lesion, CIN was thought to begin as a small lesion with atypia near the basement membrane of the cervical transformation zone, gradually increasing in size and becoming less differentiated with an increasing proportion of the epithelium taken up by atypical cells until a full-thickness carcinoma in situ developed and then became invasive. Given this concept of progression from low-grade to CIN21 disease to cancer, lesions of all grades were treated. When progression does occur, however, it appears to require years. HPV acquisition commonly follows sexual debut, the median age being approximately 17 in the United States, but the peak age of cervical cancer diagnosis lags by some 3 decades. This long transition time allows for even moderately sensitive screening tests to identify persistent lesions for treatment before invasive cancer develops. Gradually, the regressive nature of most low- and midgrade lesions becomes apparent. Low-grade lesions, which include genital warts and CIN1, are histologic expressions of HPV infection and are thus not considered to be premalignant. Greenberg and associates found that of 163 women with CIN1 after low-grade cytology followed for a median of 36 months, 49% regressed, 43% persisted, and only 8% progressed to CIN3. In the Atypical Squamous Cells of Undetermined Significance/Low Grade Squamous Intraepithelial Lesion Triage Study (ALTS), a large randomized trial of management options for women with borderline cytology results conducted under the auspices of the US National Cancer Institute (NCI), 2-year risk for CIN3 was 10% among women with CIN1. As reported by Castle et al., after controlling for HPV genotype, with HPV-16–associated CIN1 progressing to CIN3 in 19% of cases, biopsy-proven CIN1 was not a risk factor for progression. However, these risk estimates may be substantially higher for women with prior CIN21 cytology.

Preinvasive Disease of the Cervix

CIN2 lesions or greater (CIN21) appear to represent clonal lesions arising from single-type HPV infections. Although women may harbor multiple HPV types in the genital tract, most multitype infections are associated with multifocal lesions. Moscicki et al. showed that 63% of adolescents and young women with CIN2 lesions had resolution without treatment within 2 years; subsequent clearance was minimal, rising only to 68% after an additional year. McAllum et al. showed a similar 62% regression after only 8 months of observation for women with CIN2 younger than 25 years of age. No patients in either study progressed to cancer during observation. In both studies, CIN2 likely represented recent HPV infections, not true premalignant lesions. Regression rates are lower in older women, at least in part because lesions detected later may have been persistent for years, and lesions that have evolved mechanisms to evade host immune-mediated clearance are likely to continue to persist. Castle et al. compared CIN2 rates in the immediate colposcopy and cytology surveillance arms of the ALTS. They found that over 2 years, approximately 40% of CIN2 regressed. Trimble and colleagues showed that HPV-16– associated lesions are less likely to resolve. Their finding of associations with human leukocyte antigen (HLA) alleles and regression support a role for HLA-restricted HPV-specific immune responses in determining clearance. Untreated, CIN3 poses considerable risk of progression to invasive cancer. An observational study of women in New Zealand with CIN3 diagnosed between 1955 and 1976 were observed; among 143 women reported by McCredie et al. managed only by punch or wedge biopsy, 31 progressed to cancer of the cervix or vagina after 30 years. Risk rose to 59% in 92 women with persistent disease after 2 years of observation. These findings show both that treatment of CIN3 should be strongly considered regardless of age or other factors, but also that not all CIN3 lesions will inevitably progress to cancer. Even treated CIN3 continues to pose a risk of progression to cancer. Women in the New Zealand study whose treatment appeared adequate by current standards faced only 0.7% cancer risk after 30 years. Studies from Scandinavian countries with integrated health systems can link databases on procedures and subsequent cancers and provide accurate long-term results with minimal loss to follow-up. Strander et al. showed that risk for cervical cancer rose significantly in previously treated women after age 50 years, with standardized incidence ratios compared with untreated women ranging from 3 to 5. Vaginal cancer risks were elevated across all ages, although the absolute risk of vaginal cancer was low. In Finland, Kalliala et al. confirmed this long-term increased risk and also found an elevated risk for nongenital smoking-related cancers. Jakobsson et al. found that in addition to cervical cancer, women treated for CIN faced higher mortality rates from cardiovascular disease, alcoholrelated, and traumatic death, consistent with the demographic and behavioral factors linked to CIN.

EPIDEMIOLOGY Approximately 20 million Americans and 630 million persons worldwide are infected with HPV. In the United States, about

CHAPTER 1

Preinvasive Disease of the Cervix

6.2 million people will acquire a new infection annually. More than 80% of sexually active individuals acquire genital HPV infections. Prevalence rates are highest among women in their late teens and early 20s. Risk factors for HPV acquisition include smoking, oral contraceptive use, and new male partners. Among high-risk HPV types, HPV-53 is most common, detected in 5.8% of US women ages 14 to 59 years screened in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2006. This was followed by HPV-16 (4.7%), HPV-51 (4.1%), HPV-52 (3.6%), and HPV-66 (3.4%). HPV-18 was present in only 1.8% of screened women. In this study, demographic risk factors for prevalent HPV infection included younger age (peaking at ages 20 to 24 years), non-Hispanic black ethnicity, non-married status, non-college educated, and living below the poverty line. Behavioral risk factors included reporting ever having sex, age of first intercourse before 16 years, increased number of lifetime partners, and number of partners in the past year. HPV infection determines subsequent risk for precancer. Among women enrolled in a Portland health maintenance organization who had HPV-16, the 10-year risk for CIN3, AIS, or cancer was more than 15% after HPV-16 infection, almost 15% after HPV-18 infection, less than 3% after other oncogenic HPV infections, and less than 1% after a negative HPV test result. A Danish study of over 8000 women found that infection with, and especially persistence of, HPV-16/18/31/33, was associated with high absolute risks of development of CIN31. Additionally, in a study by Elfgren et al., the authors demonstrated persistence of HPV infection at 1- and 3-year intervals following initial screening was predictive of CIN21. It is estimated that there were approximately 14,000 new cases of cervical cancer in the United States in 2020. However, the annual incidence of CIN21 is approximately 6 to 10 times higher than cervical cancer incidence. Preinvasive lesions begin to appear on average 2 years after infection. Cancer risk is quite low soon after infection; despite a high prevalence of HPV among sexually active teens, cervical cancer incidence is only about 1 in 1,000,000 before 20 years of age. Among women who develop CIN21, only 30% to 50% will develop cancer over years of observation. Clear risks for CIN and cervical cancer have been identified. The international Collaboration of Epidemiological Studies of Cervical Cancer reviewed evidence for various risk factors for cervical cancer and carcinoma in situ (though their studies were not linked to HPV data). They found that oral contraceptive use raised the risk for cervical disease by 1.9-fold for every 5 years of use. First intercourse before 15 years of age was associated with twice the risk of cervical cancer found in women with first intercourse after 23 years of age, and having more than five lifetime sexual partners carried more than double the cervical cancer risk of lifetime monogamy. Lesser but still significant increases in risk were associated with number of pregnancies and earlier age at first term pregnancy. Both squamous cancers and adenocarcinomas share epidemiologic risk factors, except that smoking is linked only to squamous cancers. The most notable risk factor for the development of invasive cervical cancer, however, is infection with and persistence of HPV, particularly HPV-16, which is found in nearly 50% of cases.

The role of family history in determining cervical cancer risk is complex. Dissociating genetic components of familial risk from cultural ones is difficult, as sexual attitudes and behaviors, reproductive patterns, and smoking are often linked to family. Zelmanowicz et al. assessed the role of family history in cohorts of women prospectively studied in Costa Rica and the United States. A family history of cervical cancer in a first-degree relative tripled the risk for CIN3 or squamous cervical cancer. The effect persisted after controlling for HPV exposure. No effect of family history on adenocarcinoma risk was seen. Although several genome-wide association studies (GWASs) have identified a range of genetic variants in candidate pathways that might contribute to cervical oncogenesis, Chen et al. in a large Chinese GWAS found that only HLA and major histocompatibility class I polypeptide-related sequence A genes were identified as candidate risk genes across several populations. Lower socioeconomic status (SES) and minority ethnicity are also linked to CIN and cervical cancer risk in the United States, although distinguishing cultural contributions to cervical cancer risk, such as a sense of fatalism, distrust of the medical care system providing screening services, and lack of health education about the benefits of screening, are difficult to distinguish from biologic risks related to ethnicity and SES, such as genetic predisposition, toxin exposure, and micronutrient deficiencies.

HUMAN PAPILLOMAVIRUS VACCINATION HPV vaccination has the potential to eliminate cervical cancer, given HPV causes the vast majority of cases. Intramuscular delivery of synthetic HPV L1 capsid antigens results in humor immunity; current vaccines are created in protein synthesis using cell culture systems. No actual live or killed virions are used, and therefore HPV vaccines cannot cause HPV-related cancer. Despite early concerns that humoral immunity would be insufficient to prevent infection, vaccine efficacy in preventing type-specific HPV persistence approaches 100%. Currently available vaccines are largely prophylactic. However, a recent meta-analysis demonstrated that patients who underwent surgical excision followed by HPV vaccination were less likely to develop recurrent CIN. Three HPV vaccines have been used in the United States. The quadrivalent HPV vaccine (available 2006–17) protected against HPV-16 and -18, which together account for almost 70% of all cervical cancers, as well as HPV-6 and -11, which are the most common causes of genital warts. The benefit of cervical cancer prevention, which might take decades to become manifest, is augmented by its ability to prevent genital warts, a concern for many young women. The bivalent HPV vaccine protects against only HPV-16 and -18. It is no longer available for use in the United States and may have superior antigenicity and may have some cross-protection against HPV types related to HPV-16 and -18. The nonavalent vaccine (available since 2017) is effective against the same types as the quadrivalent vaccine and also includes coverage against HPV types 31, 33, 45, 52, and 58; enhanced coverage should prevent 90% of all cervical cancers and many other HPV-related cancers at other sites.

CHAPTER 1

Ideally, because HPV vaccines are prophylactic, populationbased vaccination should begin before the initiation of sexual activity. Because 5% of US 13-year-old girls are sexually active, the target age for HPV vaccination is the ages of 11 to 12 years. However, vaccination can be initiated at 9 years of age. The vaccination schedule is dependent on patient age. For patients younger than 15, two doses of the vaccine should be administered, with the second administration between 6 and 12 months following the initial. Because teen sexual activity is unpredictable, delaying vaccination until girls are more mature risks missing the vaccination window for many. Nevertheless, many sexually active young women show no evidence of infection by target HPV types, and “catch-up” vaccination up to 26 years of age should be considered. Vaccination through age 45 years has been approved but appears cost-ineffective with minimal population-level cancer prevention impact. Testing of cervicovaginal secretions and serum antibody testing are both insensitive for detecting prior HPV vaccination and are not recommended before a decision about HPV vaccination. After age 15, three doses of the vaccine should be administered (at 0, 1 to 2, and 6 months). These vaccination strategies are endorsed by the CDC. Several countries have instituted organized vaccination programs, either mandatory or using a school-based opt-in mechanism with high uptake. Countries that used quadrivalent vaccine have documented a dramatic decrease in genital warts among teens but not older women, and abnormal cytology rates have also fallen in the youngest women. In the United States, vaccination rates are suboptimal. Data in 2019 demonstrated that in adolescents aged 13 to 17, 71.5% had started the vaccine series and nearly 54.2% had completed it. However, this is still well below the Healthy People 2030 goal of 80%. Regrettably, despite the potential for vaccination to eliminate the disparately high risk of cervical cancer among women of minority ethnicity and lower SES, uptake has been lowest in these groups, potentially widening cancer disparities in future years. Work by the CDC’s HPV-IMPACT group has demonstrated vaccine effectiveness of 1, 2, and 3 doses of the HPV vaccine and falling rates of CIN21 lesions positive for HPV-16 and -18, particularly in the youngest women receiving the vaccine. Risks of vaccination are low and the most commonly cited adverse effects are tolerable. These include fever, rash, injection site pain, nausea, headache, and dizziness. Anaphylactic and vagal reactions may be fatal, so vaccination should only be administered in sites with ability to manage anaphylaxis and fainting. Despite initial concerns, HPV vaccination status does not enter into young women’s decisions to initiate sexual activity. Vaccination is contraindicated for pregnant women, although no congenital anomalies or adverse pregnancy outcomes have been linked to HPV vaccination, and the series may begin after delivery. Interruption of vaccination does not appear to require re-initiation of the three-shot series. The duration of vaccine effectiveness is unclear, but antibody levels remain elevated for several years after vaccination. Presently, history of HPV vaccination does not alter screening recommendations for US women, but this is expected to change in the future. This is because many women of screening

Preinvasive Disease of the Cervix

age were not vaccinated before initiating intercourse, so vaccine effectiveness is unclear. There is no central US vaccine registry, and identifying vaccinated women by self-report may be inaccurate. No HPV vaccine covers all carcinogenic HPV types, so women vaccinated before first intercourse remain at risk for infection and cancer due to strains not covered by the vaccine. In October of 2018, the Food and Drug Administration (FDA) extended the approval of the nonavalent HPV vaccine to previously unvaccinated individuals up to age 45 for men and women for the prevention of all HPV-related cervical, vaginal, vulvar, anal, oropharyngeal, and other head and neck cancers. Previous approval extended only through age 26. However, modeled studies have shown that reductions in cases of CIN21 and cervical cancer by extending vaccine approval are extremely modest while significantly increasing costs.

SCREENING The goal of any cancer prevention program is the reduction of morbidity and mortality through intervention prior to the onset of symptoms. For cervical cancer, the current mechanism to achieve this goal is the identification and destruction of CIN21 lesions that are presumed precancers. Classically, screening has relied on Papanicolaou cytology testing followed by colposcopic assessment of women with Pap abnormalities, directed biopsies, and treatment of biopsy proven CIN21 lesions. However, Papanicolaou testing is relatively insensitive, and a single Pap test may be negative in almost half of women with CIN21. Simultaneously, progression from HPV infection to cancer usually requires several years, allowing for multiple rounds of screening, with greater sensitivity than single tests. Cytologic interpretation includes all mutations, methylations, and other genetic modifications that alter the nuclear and cytoplasmic appearance of cells. To be clinically useful, these changes must be categorized in a manner that reflect a common natural history. Papanicolaou developed a five-class grading system, from normal to invasive cancer, with atypia, dysplasia, and carcinoma in situ between. To unify terminology, the NCI convened a consensus meeting that developed the 1988 terminology known as the Bethesda System for cervicovaginal cytologic diagnosis. The Bethesda System has been revised multiple times, most recently in 2014. It identifies cytology as satisfactory or unsatisfactory, includes nonneoplastic changes, and divides epithelial cell abnormalities into squamous and glandular changes of varying degrees of severity (Table 1.1). Distinguishing squamous from glandular abnormalities is critical because glandular abnormalities carry much higher risk for CIN21, including squamous abnormalities, as well as endometrial cancer and cervical adenocarcinoma and AIS. Squamous changes related to HPV are termed “squamous intraepithelial lesions (SILs)” because some lesser changes do not reflect dysplasia or neoplasia, only cytomorphologic changes of HPV infection. Indeterminate lesions are termed “atypical squamous cells (ASCs),” and these are subdivided into ASC “of undetermined significance (ASC-US),” which carries a low risk of associated CIN21, or “cannot exclude high-grade SIL (ASC-H),”

CHAPTER 1

Preinvasive Disease of the Cervix

TABLE 1.1 Bethesda 2001 Classification . Negative for intraepithelial lesion or malignancy 1 a. Organisms may be identified b. Other nonneoplastic findings may be noted (1) Inflammation (2) Radiation changes (3) Atrophy c. Glandular cells status after hysterectomy d. Atrophy 2. Epithelial cell abnormalities a. Squamous cells (1) Atypical squamous cells (ASCs) (2) Of undetermined significance (ASC-US) (3) Cannot exclude high-grade squamous intraepithelial lesion (ASC-H) (4) Low-grade squamous intraepithelial lesions (LSILs) (5) Human papillomavirus (HPV), cervical intraepithelial neoplasia (CIN) 1 (6) HSIL (CIN2, CIN3) (7) Squamous cell carcinoma b. Glandular cell (1) Atypical glandular cells (AGC)—specify origin (2) Atypical glandular cells favor neoplastic—specify origin (3) Endocervical adenocarcinoma in situ (AIS) (4) Adenocarcinoma

which is a more worrisome finding that requires immediate colposcopy. An online atlas allows pathologists to standardize findings and interpretations against national norms (https:// screening.iarc.fr/atlascyto.php). Most cytologic tests in the United States are conducted using liquid-based assays. In these tests, cells are collected and suspended in preservative solution and then transferred to a slide. Liquid-based cytology was marketed as more sensitive than conventional Pap tests. However, a meta-analysis by Arbyn et al. showed that, although liquid-based cytology yields more abnormalities, including CIN21, it is not superior to conventional smears in cancer prevention. Nevertheless, it remains preferred in the United States primarily because it allows for molecular triage of equivocal results using HPV and other assays. Interpretation is still done visually, although some centers use automated imaging and pattern recognition software to eliminate the least abnormal slides. Cytotechnologists perform initial assessment, with slides containing abnormal findings and a proportion of normal slides read by cytopathologists. The effectiveness of screening has not been demonstrated in randomized trials, but population studies have shown clear benefits. An NCI study by Erickson et al. assessed cytology screening by vaginal aspiration for 108,000 women in Shelby County, Tennessee. They showed a high yield of unsuspected CIN21 and early cancer at the first screen, with a substantial reduction in invasive lesions in the second screen. Gustafsson et al. reviewed data from 17 cancer registries and showed marked effects, especially in Scandinavian countries. Eddy assessed the impact of screening on cervical cancer incidence and death. Without screening, a 20-year-old average-risk woman faces a 2.5% risk of cancer and a 1.2% risk of cancer death. Triennial screening between ages 20 and 75 years reduces risk to less than

0.4% and 0.1%. Annual screening does improve effectiveness, but by less than 5% and with a notable increase in cost. Initially, screening was opportunistic, and women underwent screening when they presented for care, which was generally at annual visits. This screening strategy remains the norm in the United States, although recommended screening intervals have lengthened; some electronic medical records prompt clinicians when screening is due; and some health care organizations have developed standards, rewards, and reminders. Several countries with centralized medical care systems have developed organized screening, with coordinated identification, invitation, and management of women due for screening (though this is not the case in the United States). Serraino et al. showed that the move from opportunistic to organized screening in Italy resulted in a decline in cervical cancer incidence and a downstaging of incident cervical cancers after an increase in precursor detection. Additionally, Quinn et al. found that a national call/recall system with incentive payments to general practitioners in Britain instituted in 1988 increased screening coverage to 85% of the target population, increased detection of CIN21, and reduced mortality in women younger than 55. Despite its overall benefit, cytology-based screening has several weaknesses. Most fundamentally, the process of screening, triage, and treatment is cumbersome, and noncompliance, which can be a significant problem, at any point renders it ineffective. Cytology results are reported in ways that can be confusing, and efficient, effective management may require integration of current results with prior abnormalities. Costs of combined HPV testing with cytology are increased compared to cytologic testing alone. Multiple studies have shown that most women who develop cervical cancer in developed countries, especially those presenting at advanced stages, are inadequately screened. Sung et al. studied incident cancers in a US prepaid health plan and found that 53% were nonadherent to screening, 28% had false-negative Pap tests, 4% had inadequate follow-up after an abnormal Pap test result, and the rest either developed cancer despite appropriate investigations or were unclassified. Kinney et al. in the same US health maintenance organization found that 60% of cervical cancer patients were inadequately screened. Deeper exploration of the records of long-standing plan members with inadequate screening showed that 70% had missed opportunities for screening in primary care clinics. In addition, cytology-based screening performs poorly in younger women. Sasieni et al. showed that cervical screening in women ages 20 to 24 years had little impact on actual cancer risk until those women reached 30 years of age, but screening older women results in an immediate benefit. Because younger women have low rates of cervical cancer incidence and death but high rates of HPV infection, abnormal cytology, and CIN destined to regress, the benefits of early initiation of screening may be difficult to balance against potential harms. Cytology preferentially detects squamous cell carcinomas, and the impact of cytology screening on adenocarcinoma incidence has been muted. Over 99% of all cervical cancer is caused by HPV. The incorporation of HPV testing into screening has allowed for the

CHAPTER 1

implementation of longer screening intervals. As HPV assays have been developed, protocols have utilized HPV testing as a primary screening test as well as in combination with cytology (co-testing) and as a triage test for women with borderline cytology results. Only high-risk HPV types have a role in screening; because low-risk types essentially play no role in identification of HPV infection in the absence of visible genital warts, testing for low-risk types is contraindicated. HPV genotyping assays for types 16 and 18 identifies women at higher risk. The disadvantage of HPV testing is its lower specificity, with up to 30% of young women testing positive in some studies. Because all commercially available HPV tests have a detection threshold designed to balance sensitivity and specificity, a negative test result does not exclude low-level HPV infection, and prior cytologic or histologic abnormalities may mandate close followup or even treatment despite absence of detectable HPV. HPV tests should not be collected in media whose effects of test performance have not been evaluated by the FDA. Screening does have potential harms. Identification of HPV infection, abnormal cytology, and cervical cancer precursors is not without consequences, including anxiety, relationship disruption after diagnosis of a sexually transmitted infection, the inconvenience and cost of accelerated follow-up visits, and the pain of repeated examinations. Treatment of precursor lesions also carries risks, including bleeding, infection, and injury to adjacent organs. Some studies have suggested that destructive cervical treatments increase the risk for preterm delivery and pregnancy loss. US studies have failed to replicate these results in women after cervical loop electrosurgical excision procedure (LEEP). Women with CIN21 are at higher risk for pregnancy loss than those who do not, perhaps because of common risk factors, including smoking, nutritional deficiencies, and lower SES, and these confounding factors may account for differences. However, there may be a threshold effect for treatment, and women with deep or repeated excisional procedures may be at higher risk for pregnancy loss. Harms of excessive screening are limited, and include stigmatization, unfounded fear of cancer, and the potential of undergoing interventions without cancer prevention benefit. Sharp et al. showed that depression, distress, and anxiety occurred in 15% to 30% of women in the months after reporting of marginal cytology abnormalities. After the utility of screening is accepted, societies, women at risk, and clinicians must decide when to initiate screening, which screening tests to use, how often to screen, and when toward the end of life the identification of asymptomatic disease ceases to be beneficial. With all choices, sensitivity and specificity must be balanced. Earlier screening starts with more sensitive tests at shorter intervals until later in life will decrease cancer incidence and mortality, but costs and harms from diagnosing lesions that would never have progressed to cancer will increase. In developed societies, guidelines for screening have been developed by experts assessing evidence for benefit and harm and deciding how these can best be balanced. In 2012, guidelines were released by the US Preventive Services Task Force (USPSTF) and a consensus conference sponsored by the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American

Preinvasive Disease of the Cervix

TABLE 1.2 Comparison of Current US Cervical Cancer Screening Guidelines USPSTF

ACS/ASCCP/ASCP

When to start?

Age 21 years

Age 21 yearsa

How often?

Pap tests every 3 years Co-tests every 5 years at ages 30–64

Pap tests every 3 years at ages 21–29 years Co-tests every 5 years at ages 30–64 years preferred Pap tests every 3 years remain an option

When to stop?

Age 65 years if adequate prior screens

Age 65 years if the patient has had three negative Pap tests or two negative co-tests After hysterectomy for benign disease

In the most recent update from the ACS, primary recommendation is initiation of screening at age 25 with primary HPV testing; if unavailable, co-testing every 5 years or cytology alone every 3 years are acceptable alternatives ACS, American Cancer Society; ASCCP, American Society for Colposcopy and Cervical Pathology; ASCP, American Society for Clinical Pathology; HPV, human papillomavirus; USPSTF, US Preventive Services Task Force. a

Society for Clinical Pathology (ASCP) (Table 1.2). Guidelines for screening recommended by the USPSTF were updated in 2018 and those by the ACS were updated in 2020. The USPSTF recommends the initiation of screening at age 21 with cytology every 3 years until the age of 30; beginning at age 30, patients may continue with cytology every 3 years or have co-testing or HPV testing alone every 5 years. In women with continued normal screening results and no history of CIN21, screening should continue until age 65 or time of hysterectomy, after which no further screening is indicated. The most recent screening guidelines from the ACS recommend commencement of screening at age 25 with primary HPV testing every 5 years. If primary HPV testing is not available, cotesting every 5 years or cytology alone every 3 years are acceptable. Similar to the recommendations put forth by the USPSTF, screening should be discontinued at age 65 or at the time of hysterectomy, provided certain criteria are met regarding their prior screening history. Again, HPV infections are common in sexually active young women. The rationale for initiating screening at 21 years of age is founded on the low risk of cervical cancer in teens: with only one to two cases per 1,000,000 women, few cancers will be missed by a later screening start, and there will be fewer unnecessary interventions for lesions that will spontaneously regress. Although CIN21 is more common, most HPV infections, abnormal cytology test results, and CIN1 and CIN2 in young women will regress with time. As girls who were vaccinated before their first intercourse reach the age of screening initiation, the population risks for cancer and precancer have declined. Screening options include cytology alone, primary HPV testing, or co-testing. The frequency of screening depends both on the method used as well as patient age. In general, the screening interval with cytology alone is every 3 years; primary

CHAPTER 1

Preinvasive Disease of the Cervix

Figure 1.3 Strategies for incorporating primary human papillomavirus screening into practice. ASC-US, Atypical squamous cells undetermined significance; hrHPV, high risk human papillomavirus; NILM, negative for intraepithelial lesion or malignancy.

HPV testing every 5 years; and co-testing every 5 years. These intervals assume no prior abnormal screening history and normal results upon screening. Surveillance describes the followup and management of women with abnormal screening results or treatment history and differs based on the specific abnormality and management strategy. Other factors, such as age and fertility desires, may also play a role. Notably, screening intervals should be based on documented results; Boyce et al. have shown that women’s ability to recall prior screening is flawed. In 2014, the FDA approved HPV testing as a primary screening test for cervical cancer. Approval was granted only for the cobas HPV test (Roche). At an initial consensus meeting sponsored by the Society of Gynecologic Oncologists and ASCCP, Huh and fellow consensus meeting delegates developed interim guidelines to inform clinicians and women at risk on strategies to incorporate primary screening into practice. When used according to an algorithm (Fig. 1.3) that appears to optimize disease detection while minimizing colposcopy, HPV testing is more sensitive than Pap testing when initiated at 25 years of age. Screening intervals for primary HPV testing are controversial. Ultimately, the authors recommended that screening be no more often than every 3 years, language that reflected disagreement about 3-year versus 5-year testing intervals. The pivotal trial for the cobas HPV test did not extend beyond 3 years, so performance data are unknown. However, other HPV tests with similar sensitivity and specificity have been tested, and a 5-year interval seems to provide sensitivity superior to 3-year cytology screening while allowing more time for transient lesions to regress. Performance characteristics of HPV-based screening among women ages 25 to 29 years should improve as HPV risk declines as vaccinated girls age into that range. The risk for cervical cancer in adequately screened women after 65 years of age becomes negligible. Prior HPV infection that has been cleared without development of CIN21 does not appear to increase risk substantially. New HPV infections may be acquired after 65 years of age despite prior negative screening, but in the absence of active metaplasia, these are unlikely to progress to cancer for years and so are unlikely to result in morbidity or mortality, but evaluation and treatment of atrophic

postmenopausal women is technically difficult and painful. Vaginal cancer risks are low after hysterectomy for benign disease and does not justify continued screening in women with no abnormal screening history. Women with CIN21 remain at risk for cervical and vaginal cancer despite treatment, including hysterectomy, and evaluation until comorbidity suggests a short residual lifespan remains indicated. Women at low risk for disease during their remaining lifespans should not be screened. This is most apparent for women with illnesses that will be fatal in the medium term, as the discomfort and risks of screening and treatment of identified precursors are not justified when the woman is unlikely to survive long enough to develop symptomatic cervical cancer. Similarly, cervical and vaginal cancer risk in the absence of a cervix approaches zero. After hysterectomy for CIN, screening appears justified based on risk for coexistent vaginal intraepithelial neoplasia and vaginal cancer, and posttreatment surveillance for recurrent cervical cancer treated with hysterectomy is recommended. Women who reach 65 years of age after multiple negative cytology results, including three in the previous decade and two in the previous 5 years, are at low risk for cervical cancer, as are women with two negative HPV–cytology co-test results, including one in the previous 5 years. These women can stop undergoing screening. Women without adequate prior screening should continue undergoing screening until they meet these criteria. Although older women can acquire new HPV infections, they are not undergoing active metaplasia, and transition time to cancer appears to be decades long, as in younger women, so few are likely to survive to develop cancer. For this reason, acquisition of new sexual partners by women who have otherwise met criteria for stopping should not be a consideration for continuing screening. There are few predictors of CIN21 identified that would allow clinicians to focus more intensive screening efforts on high-risk groups. Boardman and colleagues found that smokers faced a higher risk of CIN21 than nonsmokers, but the odds ratio of 1.6 did not provide sufficient discrimination to allow observation of nonsmokers. Fundamentally, cytology and HPV testing are powerful tools for identifying risk, and the low positive predictive value of borderline cytology grades can be refined by triage using HPV testing or genotyping. Women with abnormal cytology or high-risk HPV infections merit further assessment regardless of demographic or behavioral risks.

MANAGEMENT OF ABNORMAL SCREENING RESULTS In 2007, Castle et al. proposed that management of abnormal cervical cancer screening tests should be based on the associated risk for significant disease. Cancer mortality would be the ideal risk outcome for comparison across tests, but it is too uncommon in screened populations and its frequency is determined by downstream interventions after most tests. Katki and associates proposed instead that risk after various test results and combinations should be benchmarked to CIN3 or worse (CIN31, including CIN3, AIS, and cancer). Because some lesions are present but inapparent initially because women fail to

CHAPTER 1

present for assessment or lesions are clinically too small for detection, the optimal benchmark endorsed by a 2012 consensus conference is 5-year risk for CIN31. Using this benchmark, clinicians can use similar management strategies for women with similar levels of risk, without regard to how risk was determined. Conventionally, risk was defined by cytology and colposcopy findings. More recently, HPV testing allowed recalibration of risk, especially for women with borderline findings such as ASC-US. HPV genotyping for types 16 and 18 further defines risk categories. On the horizon are other molecular tests whose results will modify risk stratification and management, such as spectroscopic analysis and molecular testing for p16ink4a, the Ki-67 proliferation marker, methylation status, and others. Determining optimal management for each test or combination can be arduous and confusing. In an ideal world, comparative trials would define which triage tests were optimal. Unfortunately, few comparative trials have been undertaken. National health budgets across the developed world are increasingly constrained. Industry lacks incentive to fund trials that might find their products inferior. With the proliferation of screening tests, management options become increasingly complex because algorithms must incorporate all options clinicians might select. Previously management guidelines have been criticized as too complex for even experts to master. Fortunately, the adoption of risk-based management introduced with the new 2019 guidelines has eliminated the need for clinicians to memorize cervical cancer prevention strategies. Electronic medical record platforms can be programmed to generate reminders when women come due for screening. Smartphone apps allow entry of patient information and lead clinicians to relevant algorithms. Previously, Katki et al. analyzed data from more than 1 million women screened by the Kaiser Permanente of Northern California health care system to define 5-year CIN31 risk after various tests and test combinations. At the base of management options is the 5-year follow-up for women who test negative in Pap/HPV co-testing; these women have a 5-year CIN31 risk of less than 0.01%. Women screened with cytology alone are followed at 3-year intervals when their test results are negative, with a 5-year CIN31 risk of less than 0.1%. One-year retesting is standard for women with a positive test result for HPV but negative cytology, with a risk less than 5%. The consensus threshold for colposcopy in the United States is a low-grade SIL result, with 5-year CIN31 risk of just above 5%; lesser results are triaged by serial testing or triage tests. The threshold for treatment is CIN2, although not all women with CIN2 require treatment, and few studies have assessed use of other test results except CIN21 cytology as a treatment indication. More recently, data was expanded and analyzed to include approximately 1.5 million individuals between 2003 and 2017 to estimate immediate and 5-year rates of CIN31 using various combinations of screening history and current testing results; these data were critical to the updated risk-based (rather than test-based) guidelines developed in 2019. Traditionally, colposcopy was used as the triage modality to identify women with CIN21 for treatment. Colposcopy is the magnified stereoscopic visualization of the cervix under intense

Preinvasive Disease of the Cervix

TABLE 1.3 Abnormal Colposcopic Findings Atypical transformation zone Keratosis Acetowhite epithelium Punctation Mosaicism Atypical vessels Suspect frank invasive carcinoma Unsatisfactory colposcopic findings

B Figure 1.4 A, Squamocolumnar junction (transformation zone). B, Large transformation zone.

illumination. Magnification ranges from 33 to 303. A green filter over the light source accentuates vascular patterns and lesion margins. Although colposcopy without staining has been advocated to maximize visualization of cancer, most colposcopic assessments are augmented by the application of vital stains such as 3% to 5% acetic acid and Lugol’s iodine solution.

Colposcopy In colposcopy, the cervical transformation zone is assessed. The transformation zone is that area of the cervix and vagina initially covered by columnar epithelium that has undergone metaplasia to squamous epithelium. A range of terms are used to describe colposcopic findings (Table 1.3 and Figs. 1.4–1.7). The procedure for colposcopy is inspection of the cervix without stains and then cleansing of the cervix with an application of 3% to 5% acetic acid for at least 90 seconds. This removes

CHAPTER 1

Preinvasive Disease of the Cervix

Figure 1.5 White epithelium at the cervical os (a colposcopic view).

Figure 1.6 A punctation pattern is seen clearly above a mosaic structure (a colposcopic view).

mucus and debris and accentuates vascular and epithelial patterns. Most cervical lesions stain white with acetic acid (acetowhitening). In 2017, the ASCCP discussed risk-based colposcopy standards with four main working groups. These included: (1) role

Figure 1.7 A large anterior lip lesion with white epithelium punctation and mosaic patterns.

of colposcopy, benefits and harms of terminology, (2) risk-based colposcopy and biopsy, (3) colposcopy procedures and adjuncts, and (4) quality control. One of the main goals of the second working group was to define risk-based colposcopy and to evaluate how results prior to colposcopy and colposcopy results could be combined in order to improve outcomes. Previous studies had shown that only taking a single biopsy may miss up to 40% of precancers and that there was an increase in CIN21 detection when at least two targeted biopsies were taken. The recommendation was made for “adapting colposcopy practice to previous risk and colposcopy impression.” In other words, based on the risk level, colposcopy practice can be modified. For most women, colposcopy with 2 to 4 biopsies is required for optimal sensitivity. However, in low-risk women with no acetowhitening, no HPV-16/18, and cytology less than HSIL, colposcopy can be deferred and women followed with co-testing. In women where the risk of precancer is very high, immediate excisional treatment can be performed in order to decrease costs and repeat visits. In patients who are of intermediate risk, multiple targeted biopsies leads to increased detection of precancerous changes. HPV vaccination promises to reduce cervical cancer risk in coming decades but more immediately will reduce the prevalence of CIN21 lesions. This in turn will reduce the specificity of screening tests and lower the sensitivity of colposcopy. Opportunities for further changes to screening and management strategies will follow, especially longer screening intervals, more HPV-based assessment, more intermediate triage tests before colposcopy, and a move toward immediate treatment without colposcopy for women at highest risk.

CHAPTER 1

Screening and Treatment in Immunocompromised Women The screening for immunocompromised women differs from immunocompetent women and management guidelines are directed by recommendations from the CDC. Immunocompromised patients include (but are not limited to) those with HIV, solid organ transplant, allogenic hematopoietic stem cell transplant (HSCT), systemic lupus erythematous (SLE), or patients requiring immunosuppressive treatments. Women with HIV are screened according to the guidelines for the prevention and treatment of opportunistic infections in HIV-infected adolescents and adults from the CDC. Patients with HIV are more likely to have persistent HPV infections and should start screening within 1 year of onset of sexual activity (if prior to 21 years old) but no later than 21 years of age. One group demonstrated that up to 1 in 4 women do not get annually tested despite regular visits to their primary care physician. These women should be screened twice in their first year following their diagnosis, followed by yearly screening as long as initial results are normal. If the results of three consecutive tests are normal, the screening interval can change to every 3 years. Screening should continue indefinitely and not cease at age 65 as in noninfected women. Immunocompromised women without HIV infection includes those women with solid organ transplant, HSCT, and autoimmune diseases (i.e., SLE, rheumatoid arthritis [RA], and inflammatory bowel disease [IBS]). The evidence is limited, but expert recommendations were published in 2019. For patients with solid organ transplant less than 30 years old, screen with cytology annually for 3 years and if normal, patients can transition to every 3 years. For patients aged 30 and older, the recommendation is for co-testing every 3 years if normal. If the transplant occurs before the age of 21, then screening should begin within 1 year of sexual debut. Screening should continue throughout the patient’s lifetime (do not stop at 65 years old). Recommendations are similar for patients with HSCT, IBS on immunosuppressant treatments, and SLE and RA on immunosuppressant treatments. For patients less than 30 years old, screen with cytology annually for 3 years and if normal normal, patients can transition to every 3 years. For patients aged 30 and older, the recommendation is for cotesting every 3 years if normal. If a patient is started on an immunosuppressant treatment prior to the age of 21 or undergoes HSCT, they should start cervical cancer screening within 1 year of sexual debut. All screening should be continued throughout the patient’s lifetime. Patients with IBS, SLE, or RA not on immunosuppressant treatments can follow the general population screening guidelines. Patients exposed to diethylstilbestrol (DES) in utero are recommended to undergo yearly surveillance by both ACOG and the NCI including a Pap test that obtains cells from the cervix and vaginal walls. Similar to immunocompromised women, there is no age cut-off for when Pap tests should stop in DES-exposed women. Vaginal cytology should continue to be performed in DES-exposed women who have undergone a hysterectomy.

Preinvasive Disease of the Cervix

Management of Abnormal Screening Results Since 2001, the ASCCP has led four consensus development conferences (2001, 2006, 2012, 2019) to define standard guidelines for management of US women with abnormal cervical cancer screening test results and CIN or AIS. Risk-based guidelines were initially introduced in 2012. The most recent guidelines, released in 2019, more closely align management recommendations with the growing understanding of the natural history of HPV and cervical carcinogenesis. Healthcare providers can use these guidelines via the http://asccp.org website, the ASCCP phone application, or the tables in Egemen et al. A patient’s risk is assessed through age, current screening results, past screening/biopsy results, and if they have immunosuppression. These guidelines also included adjustments for women with an unknown history of screening. All of these factors are used to decide on surveillance, colposcopy, and treatment for patients. If a patient’s risk is 4% or greater for CIN 31, then immediate management with colposcopy or treatment is recommended. In those with less than 4% risk, the 5-year risk of CIN 31 is evaluated and triages the patients into a 1-, 3-, or 5-year return. The overarching goal of current ASCCP risk-based guidelines is to allow modified evaluation and treatment in alignment with a woman’s risk. Subsequent management recommendations are based on risks, not merely results, and promulgate the concept of “equal management for equal risk.” Additionally, these guidelines importantly factor in that time matters, and that the longer an HPV infection has been present, the higher the risk for precancer and cancer (CIN3 and higher); this serves as the framework and foundation of the updated guidelines. The four guiding principles of this update are: (1) HPV-based testing is the basis of risk estimation; (2) personalized risk-based management is possible with knowledge of current results and past history; (3) guidelines must allow updates to incorporate new test methods as they are validated and to adjust for decreasing CIN31 risks as more patients who received HPV vaccination reach screening age; and (4) colposcopy practice must follow guidance detailed in the ASCCP Colposcopy Standards. Using combined clinical data from patients’ prior and current screening results, recommendations for management are made based on predefined clinical action thresholds. These correspond to a patient’s particular risk strata that is calculated within the electronic app based on validated large-cohort perspective data, all based on the immediate risk of CIN31 (Fig. 1.8). As introduced previously, these clinical action thresholds are for 5-, 3-, or 1-year return to clinic follow-up, immediate colposcopy, expedited treatment or colposcopy acceptable, or immediate treatment preferred. The primary driver of risk stratification into a particular clinical action threshold is the persistence or absence of highrisk HPV. For example, consecutive negative HPV screening is highly predictive that CIN31 will not develop. A 2018 study demonstrated that the 5-year risk of invasive cancer following a negative HPV result decreased from 0.0092% for the first negative result to 0.0015% for a negative result on a third test preceded by two negative screening tests. On the opposite end of the spectrum, long-term persistent HPV is particularly high-risk

CHAPTER 1

Preinvasive Disease of the Cervix

Expedited treatment preferred 60%–100% (Immediate CIN3+risk)

Look at immediate CIN3+ risk and find the correct

Expedited treatment or colposcopy acceptable 25%–59% (Immediate CIN3+risk)

Yes

Colposcopy recommended 4%–24%

Is immediate CIN3+ risk greater than or equal to 4%?

(Immediate CIN3+risk)

Return in 1 year 0.55%

(5–year CIN3+risk)

Look at 5–year CIN3+ risk and find the surveillance interval.

Return in 3 years 0.15%–0.54% (5–year CIN3+risk)

Return in 5 years 0.15% (5–year CIN3+risk)

Figure 1.8 Determination of patient risk based on current screening results and screening history.

(with persistent HPV-16 conferring the highest risk); a study of over 8500 women followed for 12 years for the development of CIN31 showed that two consecutive tests positive for HPV-16 conferred a 47% risk of CIN31 over the follow-up period. In the following sections, we will detail the specific management of select scenarios of abnormal screening. However, given the improved and more dynamic nature of individualizing screening follow-up and management put forth by the new guidelines outlined earlier, we will not fully outline all results and management strategies as previously put forth. The reader is encouraged to utilize the ASCCP app and web-based program for the most individualized results as they pertain to a specific patient and clinical scenario.

testing should not be ordered, and if obtained, results should not modify management. Additionally, because of concerns about impact on subsequent pregnancies, women with biopsies read as CIN2, CIN21, or HSIL can be observed, provided colposcopy is satisfactory. There is no specific age range for observational management of these lesions, and a decision to treat or follow these lesions depends on a discussion between the woman and her clinician, balancing the potential risk to future pregnancies against the risk of progression to cancer during observation; both risks appear to be low. Treatment is recommended for women in this age group for which CIN3 is specified as CIN3 is considered an immediate precursor to cancer.

Managing Abnormal Results in Young Women

Managing Unsatisfactory Cytology

Cervical cancer risk is low among women 21 to 24 years of age, but high-risk HPV infections can be found in more than 20%. Most CIN1 and many CIN2 lesions in this age group will regress without intervention, and CIN3 is unlikely to progress to cancer if missed prior to subsequent screening. Treatment of intermediate-risk lesions may impact future pregnancies. For these reasons, women in this age group are managed less aggressively than older women. For women in this age group, most abnormal cytology results reflect HPV infection; HPV

When cytology is unsatisfactory for evaluation and HPV status is either unknown, not tested for, or negative, it must be repeated. The ideal timeframe is within 2 to 4 months. For women of age greater than 25 with unsatisfactory cytology and an HPV-positive result, repeat cytology with concurrent colposcopy in 2 to 4 months is acceptable. For women with atrophy, a short course of vaginal estrogen may improve sample cellularity. Women with obscuring inflammation should be assessed for specific infections and treated for any that might be

CHAPTER 1

identified; empiric vaginal antibiotic therapy does not appear beneficial. Samples that are unsatisfactory because of obscuring blood raise concern for cancer. When repeated samples are unsatisfactory, colposcopy should be considered.

Cytology-Negative, Human Papillomavirus-Positive Women

Preinvasive Disease of the Cervix

will regress. HPV results modulate risk, but even women with HPV-HSIL face up to a 30% 5-year risk for CIN31. For this reason, colposcopy is required regardless of HPV result, and triage of HSIL cytology using HPV testing is unacceptable, as is observation with repeat cytology.

Atypical Glandular Cells

Identification of a carcinogenic HPV type carries substantial risk for CIN31, but the 5-year risk does not reach the 5% threshold for colposcopy. A positive HPV result is most often encountered in HPV–cytology co-testing for women ages 30 to 65 years. Specific management differs based on if HPV genotyping was performed. If not initially performed and not available, women should have repeat co-testing in 1 year, in which time HPV infection may regress. If at 1 year either result is abnormal, colposcopy should be performed. If HPV-genotyping was performed and is either HPV-16 or HPV-18 positive, colposcopy should be performed as the risk exceeds the 5% threshold. Management of ASCUS, low-grade squamous intraepithelial lesions (LSILs), and atypical squamous cells, cannot exclude HSIL (ASC-H). For specific management guidance, we recommend the reader reference the new interactive guidelines via the app or through tables available at asccp.org. General notes only are provided. ASC-US results are common. Triage using HPV testing on the liquid-based cytology sample appears to be cost effective and minimizes delay and loss to follow-up. If HPV testing is positive, then colposcopy is indicated; immediate risk of CIN31 is approximately 4.4%. A negative HPV result in the context of ASC-US indicates a low risk of CIN31 (less than 1%), though the risk is higher than among women with negative co-testing, and 3-year co-testing is recommended. HPV genotyping distinguishes between higher-risk women with HPV-16/-18 and lower-risk women negative for HPV-16/18, but for all HPV-positive women, 5-year CIN31 risk approximates or exceeds the threshold for colposcopy. Because management is not changed by results, HPV genotyping is not recommended for triage of ASC-US cytology. LSIL previously set a paradigmatic threshold for colposcopy in the United States. Most women triage into colposcopy, though variables such as age and HPV status/history will more accurately triage patients into either follow-up or colposcopy. Immediate treatment is unacceptable.

Despite its name, atypical glandular cells (AGCs) cytology is more often associated with squamous than glandular lesions. The risk of CIN3, AIS, or cancer (CIN31) after a Pap test read as AGC is almost 10%, and risk for cancer is 3%. AIS has been on the rise in the last 20 years, especially in younger women between the ages of 30 to 40. Squamous and glandular lesions can coexist, and identification of CIN does not rule out adenocarcinoma. Many associated cancers are of endometrial origin and would be HPV negative; endometrial lesions are more common in older women and in women with such risk factors as obesity, unexplained bleeding, and anovulation. Thorough evaluation is needed regardless of HPV test results. Women with AGC cytology need colposcopy with endocervical sampling and biopsies of any acetowhite cervical lesion. Endometrial sampling is needed if the patient is older than 35 years of age or if endometrial cancer risk factors are present. For women with AGC subcategorized as “atypical endometrial cells,” evaluation can be truncated: initial endometrial biopsy and endocervical curettage are needed, with colposcopy only if no endometrial pathology is found. In contrast to ASC-US, triage of AGC results with HPV testing is not appropriate, nor is cytologic testing. Management of AGC in women 21 to 24 years of age is identical to that of older women. Pregnant women with AGC cytology results need colposcopy, but endocervical curettage and endometrial sampling are contraindicated until following pregnancy.

Management of High-Grade Squamous Intraepithelial Lesion

MANAGEMENT OF POST-COLPOSCOPIC RESULTS

CIN21 is found in some 60% of women with HSIL cytology, and approximately 2% will have cancer at time of colposcopy. Given such a substantial risk, aggressive management is justified. In many settings, especially for women in clinics with high rates of loss to follow-up and for women who have completed childbearing, immediate loop excision is an efficient approach to management. Immediate excision is unacceptable for women up to 24 years of age because of their low near-term risk for cancer and the likelihood that CIN1 and CIN2, but not CIN3,

Management of Women With No Lesion or CIN1 at Colposcopy

Management of Endometrial Cells in Older Women Among postmenopausal women, a finding of benign endometrial cells on cytology is associated with a 5% risk of clinically important pathology, including cancer. However, endometrial cells, endometrial stromal cells, or histiocytes in premenopausal women are not associated with disease; as such, no further work-up is necessary. For postmenopausal women with endometrial cells on cytology, endometrial assessment is indicated using either endometrial sampling or imaging of endometrial thickness.

A colposcopic biopsy result of no lesion or CIN1 does not exclude the presence of a higher-grade lesion in an unsampled area of the cervix. The risk for subsequent CIN31 depends on patient age as well as the prior abnormality. Risk is lower for women with what ASCCP terms “lesser abnormalities” than for women with ASC-H, HSIL, or AGC. Lesser abnormalities

CHAPTER 1

Preinvasive Disease of the Cervix

include negative cytology with either HPV-16 or repeated HPV positivity, ASC-US, or LSIL. As mentioned previously, for women with lesser abnormalities and no lesion or only CIN1 on colposcopy, observation with serial co-testing is indicated. If a first co-test result is negative, repeat testing is indicated 3 years later. If all test results are negative, then routine screening is appropriate. If any test result is abnormal, repeat colposcopy is required. This can become burdensome. Treatment of CIN1 is acceptable once disease has persisted for 2 years, although continuing observation is also acceptable if fertility is a concern. Treatment of persistent HPVpositive tests or persistent ASC-US/LSIL cytology in the absence of a cervical lesion is not indicated because many of these women will have vaginal lesions. This includes topical therapies such as trichloroacetic acid. Hysterectomy is never indicated for CIN1 or abnormal cytology. For women 21 to 24 years of age with no lesion or CIN1 after ASC-US or LSIL, observation with repeat cytology annually is indicated. Repeat colposcopy is only needed if cytology progresses to ASC-H, HSIL, or AGC, or if cytology remains borderline abnormal for 2 years. After a negative result, routine screening at 3 years is indicated. HPV testing and co-testing are not indicated in this age group. For pregnant women with no lesion or CIN1 after lesser abnormalities during pregnancy, colposcopy should be deferred until postpartum. Management differs if colposcopy reveals no lesion or CIN1 after ASC-H or HSIL cytology, as the risk for CIN31 is much higher (Fig. 1.9). Histology and colposcopic biopsy results can be reviewed by experts to confirm diagnosis. Observation at Initial cytology is AGC – NOS or AEC-NOS*

1 and 2 years is also appropriate granted colposcopy was adequate. A diagnostic excisional procedure is recommended if HSIL/ASC-H persists at 1 year in women older than 25 or for 2 years in women younger than 25. For pregnant women with no lesion or only CIN1 after ASC-H or HSIL, colposcopy should be repeated postpartum: the short-term cancer risk is low, and no other intervention is needed during pregnancy. When no lesion or CIN1 is found after AGC cytology, annual co-testing at 1 and 2 years is indicated, with colposcopy for any abnormality; after two negative co-test results, risk declines, and resumption of three regular co-testing intervals is appropriate (Fig. 1.10). Colposcopy is needed if any result is abnormal. Hysterectomy is unacceptable as primary therapy for any grade of CIN, although after prior excision, hysterectomy may be indicated if lesions recur or persist and repeat diagnostic excision is not feasible.

Management of Women With CIN21 A colposcopic biopsy of CIN21 is the threshold for treatment. CIN2 is an intermediate lesion: many represent transient but exuberant HPV infection, and half or more resolve without therapy. However, some will progress to CIN3 and cancer. For women younger than 25 and CIN2 is specified, observation is acceptable; observation is also acceptable in women older than 25 with concerns regarding future fertility (Fig. 1.11). Again, specific situations can be managed to tailor each patient’s individual circumstance utilizing the updated ASCCP guidelines and app. All lesions read as CIN3 should be treated regardless of the patient’s age or desire for future childbearing, because there is Initial cytology is AGC (favor neoplasia), or AIS

No CIN2+, AIS, or cancer

CIN2+ but no glandular neoplasia

No AIS or cancer by colposcopy/biopsy

Cotest at 1 and 2 years

Manage per 2019 ASCCP guidelines

Diagnostic excisional procedure**

Both negative Cotest 3 years later

Any abnormality Colposcopy *Atypical endocervical cells **Should provide an intact specimen with interpretable margins. Concurrent endocervical sampling above excision bed preferred @ Copyright, 2020, ASCCP. All rights reserved.

Figure 1.9 Management of histologic low-grade squamous intraepithelial lesions (CIN1) or less preceded by ASC-H cytology. AEC, Atypical endocervical cells; AGC, atypical glandular cells; AIS, adenocarcinoma in situ; ASC-H, cannot exclude high-grade squamous intraepithelial lesions; ASCCP, American Society for Colposcopy and Cervical Pathology; NOS, not otherwise specified.

CHAPTER 1 Observation: Cytology 25 years HPV-based testing 25years at 1 and 2 years*

Negative cytology or HPV-based testing at 1 year and 2 years

HPV-based testing in 3 years

Abnormal test results

Manage per 2019 ASCCP guidelines

Preinvasive Disease of the Cervix Review of cytologic, histologic, and colposcopic findings

Age 25years: cytology HSIL at 1 or 2 years or ASC-H at 2 years

Diagnostic excisional procedure^

Manage per 2019 ASCCP guideline for revised diagnosis

Age 25 yrs: cytology HSIL or ASC-H at 2 years *Only if colposcopy visualizes the entire squamocolumnar junction and upper limit of lesion(s), and endocervical sampling negative ^Except in pregnant women @ Copyright, 2020, ASCCP. All rights reserved.

Figure 1.10 Subsequent management of atypical glandular cells (AGC). ASC-H, Cannot exclude high-grade SIL; ASCCP, American Society for Colposcopy and Cervical Pathology; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesions.

CIN2 specified Observation preferred 25 years Acceptable 25 years if concerns about treatment effects on future pregnancy outweigh concerns about cancer.

HSIL, unspecified Observation acceptable 25 years. Treatment preferred 25 years.

Observation: Colposcopy & cytology 25 years Colposcopy & HPV-based testing 25 years at 6 and 12 months

2 consecutive evaluations both ASC-H cytology and CIN2 histology

Colposcopy remains CIN2 or cytology ASC-H2 AGC or HSIL with biopsy CIN2

HPV-based testing (25 years) or cytology (25 years) in 1 year Any test abnormal Test results negative

CIN3 specified; any histologic HSIL with SCJ or upper limit of lesion(s) not visualized; or ECC with CIN 2+ or ungraded

Diagnostic excisional procedure

CIN3 develops at any point or CIN2 histology or ASC-H, HSIL, or AGC cytology persists for 2 years

Continue observation: Colposcopy & cytology 25 years Colposcopy & HPV-based testing 25 years at 6-month intervals up to a total of 2 years since first CIN2 diagnosis

Figure 1.11 Management of CIN21 in patients whose concerns about the effects of treatment on a future pregnancy outweigh their concerns about cancer. AGC, Atypical glandular cells; ASC-H, cannot exclude highgrade SIL; ECC, endocervical curettage; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesions; SCJ, squamocolumnar junction.

CHAPTER 1

Preinvasive Disease of the Cervix

no margin for progression, and some will harbor undiagnosed cancer; ongoing pregnancy is the main exception to this standard. Additionally, treatment is preferred if histologic HSIL cannot be specified (reported as histologic HSIL or HSIL [CIN2,3] (CIN3)). Observation is an acceptable option for women who, after counseling, consider risk to future pregnancies from treatment to outweigh cancer risk from observation. There is no specific age threshold: a 21-year-old woman who has had a tubal ligation should be treated, but a 43-year-old woman undergoing infertility treatment after a diagnosis of incompetent cervix might prefer to be observed. Observation is only acceptable when the entire lesion and squamocolumnar junction is observed colposcopically. Observation consists of colposcopy and cytology at 6-month intervals until the lesion resolves, as evidenced by regression of colposcopic abnormalities and normalization of cytology (i.e., results are , ASC-H cytology and/or CIN21 histology). After that occurs, women should be followed with a co-test 1 year later and then 3 additional years later before returning to routine screening. If histology remains CIN2 or cytology is ASC-H, HSIL or AGC with histology , CIN2, continued observation at 6-month intervals for up to a total of 2 years since the initial CIN2 diagnosis.

In 2020, Teoh et al. published recommendations regarding the diagnosis and management of cervical AIS. In women with AIS, an excisional procedure is needed to rule out invasive adenocarcinoma before definitive treatment is performed (Fig. 1.12). An intact specimen with a length of 10 mm and negative margins is recommended. If a provider is unable to consistently perform this, a referral to a gynecologic oncologist should be considered. When a patient has completed childbearing, a hysterectomy is preferred given that even in women with negative margins there is 20% risk of persistent AIS and lesser risk of invasive cancer. In patients who desire future fertility, conservative management with close follow-up is acceptable in the setting of negative margins. These patients should undergo co-testing with endocervical sample every 6 months for 3 years and then annually for at least 2 years. Patients who have had negative co-testing results for 5 years may then undergo testing every 3 years. Hysterectomy is still recommended once childbearing is complete.

Treatment of Cervical Disease Cure rates for CIN21 requires excisional or destructive procedures. In the United States, ablative therapies include cryotherapy and laser ablation. Excision can be accomplished with

Diagnostic excision procedure to rule out invasive cancer

Margins involved or ECC positive

Re-excision to achieve negative margins preferred Even if hysterectomy is planned**

Margins negative

Hysterectomy Preferred

Conservative management Acceptable only if future fertility desired

HPV-based testing annually x 3 total years, then test at 3 year intervals for at least 25 years

Re-evaluation* every 6 months for 3 years then annually x 2 years acceptable

Abnormal test All testing negative Continued HPV-based screening every 3 years until hysterectomy or for at least 25 years

*Those desiring fertility-sparing management cotesting with endocervical sampling **For patients with AIS and persistent positive margins for whom additional excisional procedures are not feasible, either simple or modified radical hysterectomy is acceptable

Manage per 2019 guidelines

Hysterectomy following childbearing

Figure 1.12 Management of adenocarcinoma in situ (AIS). ECC, Endocervical curettage; HPV, human papillomavirus.

CHAPTER 1

an electrosurgical wire loop or needle or with a scalpel. In the United States, excisional procedures are performed more commonly than ablative procedures. Cervical ablation results in the elimination of lesions without rendering a specimen for pathologic analysis and while an option, is not the preferred option for management. For this reason, many gynecologists consider outpatient loop excision a preferred approach. However, randomized trials showed similar failure rates for excision and ablation. This suggests that as long as invasive cancer is microinvasive, with little risk for metastasis, the method of destruction is irrelevant. Nevertheless, using ablative therapies for cervical disease requires careful attention to well-defined exclusion criteria. The 2019 ASCCP guidelines have specific criteria for ablation though stress that excision is the preferred treatment. Ablation cannot be undertaken unless the entire squamocolumnar junction, including all tissue with lesions, is visible colposcopically. Ablation of such an unsatisfactory transformation zone risks missing invasive cancer within the endocervix that then progresses undetected. Furthermore, if disease extends into the endocervical canal and lesion covers more than 75% of the surface area of the ectocervix, ablation is inappropriate. The entire squamocolumnar junction must be visualized to perform an ablative procedure. Additional criteria that must be met include: an endocervical curettage (ECC) should not contain CIN21, there should be no history of CIN21 that has been treated, all obtained biopsies/ cytologics should have been adequate to ensure diagnosis, and obviously, invasive cancer should not be highly suspected. Cryotherapy is performed using nitrous oxide, a delivery gun, and various sizes of metal probes designed to cover the transformation zone of the cervix. Figge and Creasman described use of a freeze–thaw–freeze technique with good success rates, but regardless of the use of double- or single-freeze approaches, identifying the development of at least a 5-mm “ice ball” or zone of freezing lateral to the cryotherapy probe is essential to achieving deep thermal destruction. Advantages of cryotherapy include relatively low cost and low risk for injury. Disadvantages include a copious discharge from cervical tissues suffering from sublethal thermal injury and lack of a surgical specimen. Cervical laser ablation involves the use of carbon dioxide laser energy to destroy abnormal cervical tissue. When optimally used, the laser energy is delivered at a power density of 750 to 1250 W/cm2. This results in flash boiling of impacted cells, and energy is dissipated from the operating field through the smoke plume without causing deeper tissue injury. Lower power density may create the illusion of greater control of tissue destruction, but it requires longer beam application, with greater hidden, delayed coagulation injury to underlying stroma. As with all therapies, laser should be used to ablate the entire at-risk transformation zone. CIN can involve the metaplastic epithelium of cervical glands, which extend some 5 mm into the cervical stroma; for this reason, ablation should be carried to a depth of about 7 mm and should encompass all lesions. If the lesion extends onto the vagina, ablation is carried only to 1 to 2 mm in depth. As described by Stanhope and associates, laser therapy can result in persistent CIN risk of less

Preinvasive Disease of the Cervix

than 90%. Advantages include precision in application, allowing extension of therapy to lesions that involve the vagina, and rapid recovery from injury. Disadvantages include the need for an expensive laser generator that requires frequent maintenance. Unskilled use of laser energy can result in both immediate and delayed injury. Most gynecologists in the United States treat cervical precancers by excision with electrosurgical loops, termed LEEP. The entire transformation zone is excised using loops with diameters of 1.5 to 2.5 cm. Excision should extend to the deepest glands, or 7 to 8 mm. For women with disease extending into the endocervical canal and those with inadequate colposcopy, either use deeper loops or a second endocervical pass, colloquially termed a “top-hat” excision for the appearance of the stacked specimen that results; this endocervical excision must encompass the lateral extent of endocervical glands, so 6 to 8 mm from the endocervical surface. For most women, LEEP can be done in an office setting under local anesthesia. Epinephrine is injected with the local anesthetic to minimize blood loss. The injection should be subepithelial rather than stromal, and a paracervical block does not provide the same hemostatic benefit of intracervical injection. Colposcopic visualization allows optimal tailoring of the excision. Hemostasis is achieved with a combination of fulguration using ball electrodes and application of Monsel’s solution. Delayed bleeding should occur in fewer than 5% of cases but is a known complication of the procedure and women should be counseled as such. Obese women and those with anatomic variations or anxiety that prevents optimal cervical visualization in the office may require general anesthesia. Advantages to LEEP include the availability of a surgical specimen with minimal thermal artifact at margins and the ability to adapt excision to the extent of lesions and metaplasia. Disadvantages include risk of surgical injury. Lesions such as AIS and microinvasive cancers require intact diagnostic specimens to exclude invasive cancer and assess margins. Traditionally, these lesions have been treated with knife conization (Figs. 1.13 and 1.14) which results in an optimal diagnostic specimen while treating in situ and microinvasive lesions for women who wish to retain fertility. As LEEP has become pervasive in training programs, knife conization skills may be disappearing in general gynecologists. Needle or straight-wire electrosurgical conization has been developed as an alternative, allowing similar adaptation of excision while minimizing blood loss and tissue injury.

MANAGEMENT OF ABNORMAL SCREENING RESULTS IN PREGNANCY The risk is remote for cancer developing during pregnancy in women who have CIN, including CIN3. ASC-US and LSIL cytology results do not require colposcopy until postpartum, even if associated with HPV infection, although colposcopy is acceptable. Wetta et al. found no cancers and few CIN21 lesions among 625 pregnant women with these borderline cytology results. For women with ASC-H, HSIL, or AGC cytology results, colposcopy is indicated. Because of the vascularity of the pregnant cervix, often only one biopsy can be obtained; mini-Tischler forceps

CHAPTER 1

Preinvasive Disease of the Cervix worsens. Conization is indicated only when cancer is suspected by examination, cytology is read as showing malignant cells, or colposcopy or biopsy shows possible invasion. When performed, complete excision of the transformation zone is not needed because the goal is to determine if a deeply invasive cancer is present, not to definitively treat the cervix. Limited excision using an electrosurgical loop with blended current in a controlled operating room setting that allows for cervical suturing may be considered; Israeli studies have demonstrated the safety of LEEP when performed in the first 15 weeks of pregnancy. Endocervical curettage, endometrial biopsy, and definitive treatment without histologic biopsy are unacceptable in pregnant patients.

FUTURE DIRECTIONS

Figure 1.13 Cone biopsy for endocervical disease. Limits of the lesion were not seen colposcopically.

Figure 1.14 Cone biopsy for cervical intraepithelial neoplasia of the exocervix. Limits of the lesion were identified colposcopically.

should be used and immediate direct pressure applied to the biopsy site. Clinicians without experience with colposcopy during pregnancy should consider referral to a center with expertise because pregnancy will cause colposcopic abnormalities. Biopsy should be done only for lesions that appear high grade because limiting biopsy to malignant-appearing lesions results in missed cancers. Women with CIN21 may be followed with postpartum colposcopy and repeat biopsy or with serial colposcopy during pregnancy, with repeat biopsy only if the colposcopic impression

Among patients diagnosed with cervical cancer, over half have not been screened appropriately. Further, approximately half of patients diagnosed with cervical cancer have never had a screening Pap test; another 10% have not been screened in at least 5 years. This strongly demonstrates the vast importance of screening and calls for action of widespread screening and vaccination programs so cervical cancer can reach its potential as a true preventable disease. Perhaps most important to decline in cervical cancer is the widespread adoption of HPV vaccination. A Swedish study published in the New England Journal of Medicine demonstrated that women aged 10 to 30 years old who were vaccinated with the quadrivalent HPV vaccination had a substantially reduced risk of invasive cervical cancer at the population level. As HPV-16 and -18 prevalence fall among at-risk women as vaccinated girls age, the prevalence of CIN31 women will decline. This will result in a lower incidence of abnormal Pap test results and more abnormalities that occur will reflect transient HPV infections or benign cytologic changes. As the disease prevalence falls, the positive predictive value of an abnormality should also decline; this should drive a shift away from cytology as a primary screening test, and primary HPV testing should eventually replace cytology as screening. Although cytology may be retained as a triage test for women with HPV types other than 16 or 18, other tests may prove superior, either because of greater predictive accuracy or because they can be automated. Management recommendations will also likely continue to shift as women who were vaccinated as children/ adolescents before HPV exposure enter the screening pool. Another promising method to increase cervical cancer screening is the use of self-collection HPV testing. This method bypasses some barriers including living in an underscreened area, financial difficulties, work commitments, lack of access, history of sexual trauma, or various cultural beliefs. With self-collection, a woman takes the sampling device, inserts it into her own vagina, and then returns it to the healthcare center. The sample is then processed to detect HPV. HPV-based testing relies on detecting viral nucleic acid rather than morphological cell changes. Viral nucleic acid is shed from the cervix into the vaginal canal, so a woman only needs to be able to swab the inside of the vagina in order to get a sample. It allows for screening in rural and low-resource settings, in women who

CHAPTER 1

are unable to attend a routine office visit, or in other various situations. While this is not currently an approved screening method, significant effort and research is being placed to move in that direction. As more widespread vaccination continues and these women age, guidelines regarding screening and management will continue to require adjustment. The goal of cancer prevention remains unaltered, and the objective of preventing cancer while minimizing unnecessary testing and procedures

Preinvasive Disease of the Cervix

will require dynamic modifications as results of current management strategies become available. Primary care providers, general gynecologists, and subspecialists in gynecologic oncology all have critical roles to play in ensuring that the appropriate screening and management strategies are employed and in understanding the impact of the current guidelines on clinical practice. For the bibliography list, log onto www.expertconsult.com.

BIBLIOGRAPHY American Cancer Society: Key Statistics for Cervical Cancer, 2021. https://www.cancer.org/cancer/cervical-cancer/about/key-statistics.html. Updated January 12, 2021. Boardman LA, Adams AE, Peipert JF: Clinical predictors of cervical intraepithelial neoplasia 2 or greater in women with mildly abnormal Pap smears, J Reprod Med 47(11):891–896, 2002. Boyce JG, Fruchter RG, Romanzi L, et al: The fallacy of the screening interval for cervical smears, Obstet Gynecol 76(4):627–632, 1990. Castellsague X, Bosch FX, Munoz N, et al: Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners, N Engl J Med 346(15):1105–1112, 2002. Castle PE, Kinney WK, Xue X, et al: Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study, Ann Intern Med 168(1):20–29, 2018. Castle PE, Kreimer AR, Wacholder S, et al: Influence of loop electrosurgical excision procedure on subsequent acquisition of new human papillomavirus infections, J Infect Dis 199(11):1612–1620, 2009. Castle PE, Sideri M, Jeronimo J, et al: Risk assessment to guide the prevention of cervical cancer, Am J Obstet Gynecol 197(4):356.e1–e6, 2007. Cutler SJ, Erickson CC, Everett BE Jr, et al: Population screening for uterine cancer by vaginal cytology; preliminary summary of results of first examination of 108,000 women and second testing of 33,000 women, J Am Med Assoc 162(3):167–173, 1956. de Sanjose S, Quint WG, Alemany L, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective crosssectional worldwide study, Lancet Oncol 11(11):1048–1056, 2010. Eddy DM: Screening for cervical cancer, Ann Intern Med 113(3): 214–226, 1990. Egemen D, Cheung LC, Chen X, et al: Risk estimates supporting the 2019 ASCCP risk-based management consensus guidelines, J Low Genit Tract Dis 24(2):132–143, 2020. Figge DC, Creasman WT: Cryotherapy in the treatment of cervical intraepithelial neoplasia, Obstet Gynecol 62(3):353–358, 1983. Greenberg MD, Reid R, Schiffman M, et al: A prospective study of biopsy-confirmed cervical intraepithelial neoplasia grade 1: colposcopic, cytological, and virological risk factors for progression, J Low Genit Tract Dis 3(2):104–110, 1999. Gustafsson L, Ponten J, Zack M, et al: International incidence rates of invasive cervical cancer after introduction of cytological screening, Cancer Causes Control 8(5):755–763, 1997. Hachisuga T, Fukuda K, Kawarabayashi T: Local immune response in squamous cell carcinoma of the uterine cervix, Gynecol Obstet Invest 52(1):3–8, 2001. Halec G, Alemany L, Lloveras B, et al: Pathogenic role of the eight probably/possibly carcinogenic HPV types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer, J Pathol 234(4):441–451, 2014. Hawkes D, Keung MHT, Huang Y, et al: Self-collection for cervical screening programs: from research to reality, Cancers (Basel) 12(4):1053, 2020. Hogewoning CJ, Bleeker MC, van den Brule AJ, et al: Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial, Int J Cancer 107(5):811–816, 2003. National Cancer Institute: Diethylstilbestrol (DES) and Cancer. Online: National Institute of Health, 2011. https://www.cancer.gov/aboutcancer/causes-prevention/risk/hormones/des-fact-sheet. Jentschke M, Kampers J, Becker J, et al: Prophylactic HPV vaccination after conization: a systematic review and meta-analysis, Vaccine 38(41):6402–6649, 2020.

Johnson Jones ML, Gargano JW, Powell M, et al: Effectiveness of 1, 2, and 3 doses of human papillomavirus vaccine against high-grade cervical lesions positive for human papillomavirus 16 or 18, Am J Epidemiol 189(4):265–276, 2020. Katki HA, Schiffman M, Castle PE, et al: Benchmarking CIN 31 risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines, J Low Genit Tract Dis 17(5 Suppl 1):S28–S35, 2013. Kim JJ, Simms KT, Killen J, et al: Human papillomavirus vaccination for adults aged 30 to 45 years in the United States: a cost-effectiveness analysis, PLoS Med 18(3):e1003534, 2021. Kinney W, Sung HY, Kearney KA, et al: Missed opportunities for cervical cancer screening of HMO members developing invasive cervical cancer (ICC), Gynecol Oncol 71(3):428–430, 1998. Kjaer SK, Frederiksen K, Munk C, et al: Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence, J Natl Cancer Inst 102(19):1478–1488, 2010. Laprise JF, Chesson HW, Markowitz LE, et al: Effectiveness and costeffectiveness of human papillomavirus vaccination through age 45 years in the United States, Ann Intern Med 172(1):22–29, 2020. Lei J, Ploner A, Elfstrom KM, et al: HPV vaccination and the risk of invasive cervical cancer, N Engl J Med 383(14):1340–1348, 2020. Moscicki AB, Flowers L, Huchko MJ, et al: Guidelines for cervical cancer screening in immunosuppressed women without HIV infection, J Low Genit Tract Dis 23(2):87–101, 2019. Moscicki AB, Ma Y, Wibbelsman C, et al: Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women, Obstet Gynecol 116(6):1373–1380, 2010. Nayar R, Wilbur DC. The Pap test and Bethesda 2014, Cancer Cytopathol 123(5):271–281, 2015. NCI. SEER 18 Registries. Oster AM, Sullivan PS, Blair JM: Prevalence of cervical cancer screening of HIV-infected women in the United States, J Acquir Immune Defic Syndr 51(4):430–436, 2009. Perkins RB, Guido RS, Castle PE, et al: 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors, J Low Genit Tract Dis 24(2):102–131, 2020. Pretorius RG, Belinson JL, Burchette RJ, et al: Regardless of skill, performing more biopsies increases the sensitivity of colposcopy, J Low Genit Tract Dis 15(3):180–188, 2011. Promotion ODPHP: Healthy People 2030. Online: US Department of Health and Human Services, 2021. https://health.gov/healthypeople/ objectives-and-data/browse-objectives/cancer/increase-proportionfemales-who-get-screened-cervical-cancer-c-09. Quinn M, Babb P, Jones J, et al: Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics, BMJ 318(7188):904–908, 1999. Rosenblum HG, Lewis RM, Gargano JW, et al: Declines in prevalence of human papillomavirus vaccine-type infection among females after introduction of vaccine—United States, 2003–2018, MMWR Morb Mortal Wkly Rep 70(12):415–420, 2021. Sahlgren H, Elfstrom KM, Lamin H, et al: Colposcopic and histopathologic evaluation of women with HPV persistence exiting an organized screening program, Am J Obstet Gynecol 222(3):253.e1–e8, 2020. Salani R, Puri I, Bristow RE. Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients evaluating the predictive value of conization margin status, Am J Obstet Gynecol 200(2):182.e1–e5, 2009. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data, BMJ 339:b2968, 2009.

e2 Serraino D, Gini A, Taborelli M, et al: Changes in cervical cancer incidence following the introduction of organized screening in Italy, Prev Med 75:56–63, 2015. Sharp L, Cotton S, Little J, et al: Psychosocial impact of alternative management policies for low-grade cervical abnormalities: results from the TOMBOLA randomised controlled trial, PLoS One 8(12):e80092, 2013. Siegler E, Lavie O, Amit A, et al: Should the risk of invasive cancer in pregnancy and the safety of loop electrosurgical excision procedure during the first 15 weeks change our practice? J Low Genit Tract Dis 21(4):299–303, 2017. Teoh D, Musa F, Salani R, et al: Diagnosis and management of adenocarcinoma in situ: a society of gynecologic oncology evidence-based review and recommendations, Obstet Gynecol 135(4):869–878, 2020. Trimble CL, Piantadosi S, Gravitt P, et al: Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype, Clin Cancer Res 11(13):4717–4723, 2005.

Walker TY, Elam-Evans LD, Yankey D, et al: National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years—United States, 2018, MMWR Morb Mortal Wkly Rep 68(33):718–723, 2019. Wentzensen N, Schiffman M, Silver MI, et al: ASCCP colposcopy standards: risk-based colposcopy practice, J Low Genit Tract Dis 21(4):230–234, 2017. Wentzensen N, Walker JL, Gold MA, et al: Multiple biopsies and detection of cervical cancer precursors at colposcopy, J Clin Oncol 33(1):83–89, 2015. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors: erratum, J Low Genit Tract Dis 24(4):427, 2020.

2 Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders Cara A. Mathews, MD, Joan L. Walker, MD

OUTLINE Embryology and Diethylstilbestrol Exposure, 20 Treatment of Women Exposed to Diethylstilbestrol, 21 Nonneoplastic Epithelial Disorders of the Vulva and Vagina, 22

Vulvar Intraepithelial Neoplasia, 28 High-Grade Squamous Intraepithelial Lesion of the Vagina, 36

KEY POINTS 1. Vaccination for human papilloma virus (HPV) should decrease the incidence of high-grade squamous intraepithelial lesions (HSILs) of the vulva and vagina. 2. Lichen sclerosus is associated with vulvar cancer.

3. If there is any concern for malignancy, wide local excision is the treatment of choice for vulvar HSIL. 4. Topical treatments such as imiquimod and cidofovir offer non-surgical management options for HSIL.

EMBRYOLOGY AND DIETHYLSTILBESTROL EXPOSURE

18 weeks as adenosis is more common in patients whose mothers began DES treatment early in pregnancy and is not observed if DES administration began after that point. At least 20% of women exposed to DES show an anatomic deformity of the upper vagina and cervix; transverse vaginal and cervical ridges, cervical collars, vaginal hoods, and cockscomb cervices have all been described. The transverse ridges and anatomic deformities found in one-fifth of women exposed to DES make it difficult to ascertain the boundaries of the vagina and cervix. The cervical eversion causes the cervix grossly to have a red appearance. This coloration is caused by the numerous normal-appearing blood vessels in the submucosa. With a colposcope and application of acetic acid solution, numerous papillae (“grapes”) of columnar epithelium are observed, similar to those seen in the native columnar epithelium of the endocervix. The hood (Fig. 2.2) is a fold of mucous membrane surrounding the portio of the cervix; it often disappears if the portio is pulled down with a tenaculum or is displaced by the speculum. The cockscomb is an atypical, peaked appearance of the anterior lip of the cervix, and vaginal ridges are protruding circumferential bands in the upper vagina that may hide the cervix. A pseudopolyp formation (see Fig. 2.2) has been described that occurs when the portio of the cervix is small and protrudes through a wide cervical hood. The occurrence of vaginal adenosis among young women without in utero DES exposure implies that an event in embryonic development is responsible. The development of the müllerian system depends on and follows formation of the wolffian, or mesonephric, system. The emergence of the müllerian system as the dominant structure appears unaffected by intrauterine exposure to DES when studied in most animal systems. However, it is apparent that steroidal and nonsteroidal estrogens,

At approximately 12 to 14 weeks of gestation, the simple columnar epithelium that lines the vaginal portion of the uterovaginal canal begins to undergo transformation into stratified müllerian epithelium. This transformation proceeds cranially until it reaches the columnar epithelium of the future endocervical canal. The vagina, which is lined initially by simple columnar epithelium of müllerian origin, acquires stratified müllerian epithelium. The vaginal plate advances in a caudocranial direction, obliterating the existing vaginal lumen. By caudal cavitation of the vaginal plate, a new lumen is formed, and the stratified müllerian epithelium is replaced by a stratified squamous epithelium, probably from a urogenital sinus origin. Local proliferation of the vaginal plate in the region of the cervicovaginal junction produces the circumferential enlargement of the vagina known as the vaginal fornices, which surround the vaginal part of the cervix. The administration of diethylstilbestrol (DES) through the 18th week of gestation can apparently result in the disruption of the transformation of columnar epithelium of müllerian origin to the stratified squamous successor (Fig. 2.1). This retention of müllerian epithelium gives rise to adenosis. Adenosis may exist in many forms: glandular cells in place of the normal squamous lining of the vagina, glandular cells hidden beneath an intact squamous lining, or mixed squamous metaplasia when new squamous cells attempt to replace glandular cells. Vaginal adenosis is rarely observed in patients without a history of DES exposure and is usually clinically insignificant. The critical time of DES exposure in utero appears to be prior to 20

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Müllerianderived epithelium

Wolffian ducts

Adenosis

Müllerian ducts

Squamous epithelium

Urogenital sinus

Figure 2.1 A–C, Schematic representations of the embryologic development of the vagina in unexposed (A) and diethylstilbestrol-exposed (B and C) women. (From Stillman RJ: In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance in male and female offspring, Am J Obstet Gynecol 142[7]:905, 1982.)

of persistent, untransformed müllerian columnar epithelia in the vagina as the explanation of adenosis.

TREATMENT OF WOMEN EXPOSED TO DIETHYLSTILBESTROL

Figure 2.2 Hood surrounding the small diethylstilbestrol-exposed cervix, which is completely covered by columnar epithelium (pseudopolyp).

when administered during the proper stage of vaginal embryogenesis in mice, can permanently prevent the transformation of müllerian epithelium into the adult type of vaginal epithelium, thus creating a situation like adenosis. The colposcopic and histologic features of vaginal adenosis strongly support the concept

Essentially no DES has been prescribed to pregnant women since 1971, when the US Food and Drug Administration issued an alert regarding the risk of vaginal clear cell adenocarcinoma for females exposed in utero. The youngest women with in utero exposure were born in 1972, and many previously important clinical topics, such as teenage cancers, diagnosis of congenital anomalies in young women, and associated infertility and pregnancy risks, have become less relevant in everyday practice. However, an understanding of the disease process through the lifespan remains essential in order to care for this cohort of women as they age. Additionally, the evolution and understanding of DES is of great historical importance with many implications and lessons for today’s practice. Approximately 60% of women with in utero DES exposure have vaginal adenosis, cervical-like epithelium in the vagina, which appears red and granular. This is a benign condition that does not require treatment unless symptomatic, and it will generally resolve on its own over time. The premenopausal risk of clear cell adenocarcinoma is approximately 40 times higher among women with in utero DES exposure compared with those without the exposure. The 20-year overall survival with vaginal clear cell carcinoma is approximately 70%. In unexposed women, clear cell adenocarcinoma occurs almost exclusively in menopause, while in a registry of women with in utero DES exposure, the median age of diagnosis was 22 and 80% of cases were diagnosed between the age of 15 and 30. The oldest reported patient with DES-associated clear cell adenocarcinoma was diagnosed at 51 years. Overall, the absolute number of women diagnosed and incidence of clear cell adenocarcinoma is low in women with in utero exposure (≈1.5 cases/1000 women), but the risk is significantly higher than

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

among unexposed women. The etiology of clear cell adenocarcinoma is unclear, and evolution of adenosis to cancer has never been directly proven, only suspected. Because of the increased risk of clear cell adenocarcinoma of the cervix and vagina and an increased risk of cervical high-grade squamous intraepithelial lesion (HSIL), annual examinations with cytology testing are recommended for the entire lifetime of women with in utero DES exposure. No increased association has been observed with squamous cell cervical cancer; however, the risk of cervical intraepithelial neoplasia (CIN) II or greater was approximately doubled and the overall incidence approximately 5% in a large cohort study of women (n 5 4120) with in utero DES exposure. Similarly, the same study found the risk of breast cancer after age 40 was also nearly doubled for women with DES exposure. More recently, DES exposure has been associated with coronary artery disease and myocardial infarction (but not stroke), independent of traditional cardiovascular risk factors. Future research is also incorporating the study of third-generation “DES granddaughters,” as these women may have an increased risk of amenorrhea, irregular menstrual cycles, and preterm delivery. All DES-exposed females should have an annual gynecologic examination with cytology screening of the cervix and vagina. If suspicious lesions are present, colposcopy and directed biopsies should be performed regardless of the cytology results. If delineations of the vagina, cervix, and endocervix are difficult, Lugol’s solution may be helpful in detecting abnormal areas. Colposcopic examination of these patients is hindered by the abnormal patterns seen with squamous metaplasia (Fig. 2.3), which can be confused with neoplastic lesions. Histologic confirmation is essential before any treatment is undertaken. Marked mosaic (Fig. 2.4), and punctation patterns that normally herald intraepithelial neoplasia are commonly seen in the vagina of DES-exposed women as a result of widespread metaplasia. The purpose of regular examination is to permit detection of adenocarcinoma and squamous neoplasia during the earliest stages of development. Although many therapies have been attempted, no recommended treatment plan for vaginal adenosis exists. In most cases, the area of adenosis is physiologically transformed into squamous epithelium during varying periods of observation, and no therapy is necessary.

B Figure 2.3 A, Area of white epithelium of squamous metaplasia. B, Histologic section of the area in A showing metaplasia to the left partially covering the adenosis (columnar epithelium) to the right.

NONNEOPLASTIC EPITHELIAL DISORDERS OF THE VULVA AND VAGINA Nonneoplastic epithelial disorders of the vulvar skin and mucosa are frequently seen in clinical practice. Diagnosis is difficult without a biopsy to provide a histologic result, and multiple changes in terminology over the past 25 years add confusion to clinical management. The current classification guideline published in 2007 by the International Society for the Study of Vulvovaginal Disease (ISSVD) (Table 2.1) was updated in 2011 to expand upon the clinical characteristics of the diagnoses. The lichenoid pattern subset includes two chronic diseases, lichen sclerosus and lichen planus, which are relevant to this review because of the association of those two diseases with vulvar cancer. Lichen simplex chronicus is not included in the lichenoid subset; it is classified in the acanthotic pattern subset. This is appropriate from an

Figure 2.4 Heavy mosaic pattern (histologically proven metaplasia) in a hood surrounding the cervix of an offspring exposed to diethylstilbestrol.

oncology viewpoint because lichen simplex chronicus is not associated with invasive cancer. With similar presenting symptoms and a hyperkeratotic appearance, however, lichen simplex chronicus can be difficult to discriminate from lichen sclerosus and lichen planus on examination (Table 2.2).

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Lichen Simplex Chronicus Lichen simplex chronicus presents in girls and women of all ages, but it is more common in the reproductive and postmenopausal years. Lichen simplex chronicus is a chronic eczematous condition, and most women with this condition also have a history of atopic dermatitis. Pruritus is the most common symptom, and over time, scratching leads to epithelial thickening and hyperkeratosis. The status of the skin usually relates to the amount of scratching. Exacerbating agents may include heat, moisture, sanitary or incontinence pads, and topical agents. Lichen simplex chronicus may be seen in conjunction with other processes such as Candida infections or lichen sclerosus; these primary diseases must be treated in order to treat the pruritus leading to scratching and hyperkeratosis.

TABLE 2.1 2006 World Congress International Society for the Study of Vulvovaginal Disease (Classification of Vulvar Dermatoses) Pathologic Subset

Clinical Correlate

Spongiotic pattern

Atopic dermatitis Allergic contact dermatitis Irritant contact dermatitis

Acanthotic pattern

Psoriasis Lichen simplex chronicus Primary (idiopathic)

Lichen sclerosus represents a specific disease found in genital and nongenital sites. The vulva is the most common lesion site in women. The age distribution of the disease is bimodal with peaks during the premenarchal and postmenopausal years, but the highest incidence is among postmenopausal women. Although the overall incidence and prevalence are unknown, Leibovitz and colleagues reported the prevalence among elderly women in a nursing home setting as 1 in 30. The mean age in this population was 82 years, 88% were wheelchair users, and 86% were incontinent. Over time, pruritus occurs with essentially all lesions, leading to scratching, which can develop into ecchymosis and ulceration (Fig. 2.5). Symptoms evolve to include burning, tearing, and dyspareunia. Studies have suggested that the epithelium in lichen sclerosus is metabolically active and non-atrophic. A chronic inflammatory, lymphocyte-mediated dermatosis is present. The etiology of the disease is poorly understood, but

Lichen sclerosus Lichen planus

Dermal homogenization/sclerosis pattern

Lichen sclerosus

Vesiculobullous pattern

Pemphigoid, cicatricial type Linear IgA disease

Acantholytic pattern

Hailey-Hailey disease Darier disease Papular genitocrural acantholysis

Granulomatous pattern

Crohn disease Melkersson-Rosenthal syndrome

Vasculopathic pattern

The locations most often involved on the vulva include the labia majora, interlabial folds, outer aspects of the labia minor, and clitoris. It is particularly common among women with chronic incontinence to find involvement of the labia majora at point of contact with incontinence pads and sparing of the medial labia and mucosa centrally where the pad is not in contact with the epithelium. Changes can also extend to the lateral surfaces of the labia majora or beyond. Areas of lichen simplex chronicus are often localized, elevated, and well-delineated, but they may be extensive and poorly defined. The appearance of lesions may vary greatly even in the same patient. The vulva often appears dusky red when the degree of hyperkeratosis is slight and may appear thickened and leathery when hyperkeratosis persists. At other times, well-defined white patches may be seen, or a combination of red and white areas may be observed in different locations. Thickening, fissures, and excoriations require careful evaluation because carcinoma may be exhibited by these same features. For this reason, biopsy is essential if there is any ambiguity in order to ascertain the correct diagnosis. Biopsy reveals a variable increase in the thickness of the horny layer (hyperkeratosis) and irregular thickening of the malpighian layer (acanthosis). This latter process produces a thickened epithelium and lengthening and distortion of the rete pegs. Parakeratosis may also be present. The granular layer of the epithelium is usually prominent. An inflammatory reaction is often present within the dermis with varying numbers of lymphocytes and plasma cells.

Lichen Sclerosus

Secondary (superimposed on other vulvar disease) Lichenoid pattern

Aphthous ulcers Behçet disease Plasma cell vulvitis

TABLE 2.2 Other Dermatoses Disorder

Lesion

Genital

Other Locations

Seborrheic dermatitis

Erythema with mild scale oval plaques

Mild scaling; also “inverse type”

Central face, neck, scalp, chest, back

Psoriasis

Annular scaly plaques that bleed easily

Red plaques with gray-white scale

Scalp, elbows, knees, sacrum

Tinea

Annular plaques with central clearing

Common

Skinfolds or single “ringworm” lesion

Lichen simplex chronicus

Lichenified plaques, some dermatitic

Scrotum or labia majora

Nape of the neck, ankle, forearm, antecubital and popliteal fossae

Lichen planus

Flat-topped lilac papules and plaques

White network, erosive vaginitis

Volar wrists, shins, buccal mucosa

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Figure 2.5 Lichen sclerosus with stenosis of the introitus, fissuring in the posterior fourchette, and perianal involvement producing the “keyhole appearance.” (Courtesy of Dr. Lori Boardman, MD, ScM, University of Central Florida College of Medicine.)

autoimmune mechanisms appear to be involved. Among women with lichen sclerosus as compared to those without the disease, there is an increased likelihood of thyroid dysfunction. The microscopic features of lichen sclerosus include hyperkeratosis, epithelial thickening with flattening of the rete pegs, cytoplasmic vacuolization of the basal layer of cells, and follicular plugging. Beneath the epidermis is a zone of homogenized, pink-staining, collagenous-appearing tissue that is relatively acellular. Edema is occasionally seen in this area. Elastic fibers are absent. Immediately below this zone lies a band of inflammatory cells that is consistent with lymphocytes and some plasma cells. Lichen sclerosus is often associated with foci of both hyperplastic epithelium and thin epithelium. Lichen simplex chronicus has been found in 27% to 35% of women with lichen sclerosus after microscopic study of vulvar specimens, likely secondary to pruritus and scratching. In a well-developed classic lesion, the skin of the vulva is crinkled (“cigarette paper”) and thinned, or appears parchmentlike. The process often extends around the anal region in a figureof-8 or keyhole configuration, and 30% of women have perianal lesions. At other times, the changes are localized, especially in the periclitoral area or the perineum. Clitoral involvement is usually associated with edema of the foreskin, which may obscure the glans clitoris. Phimosis of the clitoris is often seen late in the course of the disease. As the disease progresses, there is loss of architecture of the normal external genitalia (Fig. 2.6). The labia minora may completely disappear as a result of atrophy. Synechiae often develop between the edges of the skin in these

B Figure 2.6 Progression from early (A) to late (B) lichen sclerosus, with characteristic loss of labial architecture. (Courtesy Dr. Lori Boardman, MD, ScM, University of Central Florida College of Medicine.)

locations, causing pain and limited physical activity. Fissures also develop in the natural folds of the skin and especially in the posterior fourchette. The introitus may become so strictured or stenosed that intercourse is impossible. The urethra may also become obstructed (Fig. 2.7). The vaginal mucosa is generally spared in this disease, which is helpful in discriminating between lichen sclerosus and lichen planus. In a study by Dalziel, 44 women with lichen sclerosus were evaluated for sexual dysfunction. Apareunia was experienced by 19 of the women at some point. Dyspareunia and decreased frequency of intercourse were noted by 80%, and orgasm was altered and relationships were affected in 50%. Local steroids improved sexual function in twothirds of these patients. In a recent publication by Kohn and colleagues, approximately 40% of women receiving care in gynecology, vulvar, and dermatology clinics for lichen sclerosus were not sexually active because of lichen and approximately 40% of those women became sexually active again after using topical steroids.

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Figure 2.7 Urethral obstruction secondary to lichen sclerosus (A) was diagnosed in the clinic and under anesthesia, the labia were separated with gentle traction (B and C) to reveal the urethra and (spared) vagina (D).

Lichen sclerosus is a risk factor for invasive vulvar cancer, likely as a result of chronic inflammation and sclerosis. Wallace followed 290 women with lichen sclerosus for an average of 12.5 years and found that 4% (n 5 12) developed vulvar cancer. Carlson et al. reported that 4.5% of patients with lichen sclerosus developed vulvar cancer over a mean of 10 years. In treated populations, however, the risk may be lower. Cooper and associates treated 233 women in a vulvar teaching clinic over a 10-year period; 89% of the cohort received superpotent steroid treatment. Invasive vulvar cancer developed in 3% (n 5 7), and vaginal intraepithelial neoplasia (VAIN) developed in 2% (n 5 4). Jones and colleagues reported one case of cancer from a vulvar clinic treating 213 girls and women older than age 8 years. Renaud-Vilmer et al. reported

results from an urban dermatology clinic caring for 83 girls and women with no prior treatment of vulvar lichen sclerosus. Invasive cancer was present at the time of presentation in 7% (n 5 6) and developed in 2% (n 5 2); in those who developed cancer, one did not return for follow-up, and one did not use the prescribed treatment. In a cohort followed prospectively with repeat vulvar examinations at the University of Florence by Carli and associates, two cases of invasive cancer and one case of vulvar intraepithelial neoplasia (VIN) developed among 211 women with treated lichen sclerosus. All three cases occurred after more than 3 years of follow-up in the cohort. The absolute incidence of vulvar cancer is low in women with lichen sclerosus, but 50% to 70% of squamous cell vulvar

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

cancers occur in a background of lichen sclerosus. Currently, there is no diagnostic tool to differentiate between lichen sclerosus that will remain benign versus lichen sclerosus that will evolve into squamous cell carcinoma (SCC). Two biomarkers, p53 and monoclonal antibody MIB1, have shown promise in retrospective tissues studies, but further testing is necessary. The standard of care for cancer screening in this population remains serial examination with directed biopsies for new, evolving, or suspicious lesions, teaching self-examination with a mirror, and self-reporting to a physician when lesions change visibly and to palpation.

Lichen Planus Lichen planus is a distinct dermatologic disease that may affect the oral mucosa, esophageal mucosa, skin, scalp, nails, and eyes in addition to the vulva. The three subtypes of lichen planus that appear to have similar clinical characteristics, but different pathologic appearances, are classic, erosive, and hypertrophic. Approximately 1% of the population likely develops lichen planus; 25% to 50% of women with lichen planus are believed to have vulvar symptoms. Both vulvovaginal-gingival syndrome and penile-gingival syndrome have been described. The disease appears to be a cell-mediated immune disorder causing chronic inflammation. Similar to lichen sclerosus, symptoms are most common in postmenopausal women in their 50s and 60s; usually include pruritus; and can evolve as the disease progresses to include burning, pain, and dyspareunia. Labial agglutination and loss of architecture of the labia and clitoris may occur. The vaginal mucosa is frequently involved, as opposed to lichen sclerosus, which rarely involves the vagina (Fig. 2.8).

The relationship between lichen planus and vulvar cancer is not as well-established as the association between lichen sclerosus and cancer. Small studies have suggested an increased risk of vulvar cancer, and subjects with oral lichen planus may also have an increased risk of oral cancer. In the early 1990s, case reports by Franck and Young, Lewis and Harrington, and Dwyer and colleagues reported incidences of vulvar SCC in subjects with lichen planus and within erosive lichen planus lesions. In a review of 113 patients with erosive vulvar lichen planus followed by Kennedy and colleagues over an 8-year period, one woman developed vulvar cancer. Of interest, two women in this cohort with oral lichen planus were subsequently diagnosed with oral or esophageal cancer, and two additional women were diagnosed with cervical adenocarcinoma in situ (AIS) and rectal adenocarcinoma. Similar findings were reported by Cooper and associates. Of 114 women with erosive vulvar lichen planus, 7 developed VIN, 1 developed oral SCC, 2 developed anogenital SCCs of the labium minora and perianal area. Because lichen planus can also be a challenging pathologic diagnosis, some of these studies may have mistakenly included women with differentiated VIN (dVIN) rather than lichen planus. Day et al. performed a histopathologic review of a cohort of non–human papilloma virus (non-HPV) associated vulvar cancer and identified lichen sclerosus in 95% of the specimens and dVIN in 88%, with no cases of lichen planus identified. Among those cases with dVIN, 24% resembled erosive lichen planus and 16% resembled hypertrophic lichen planus, highlighting the importance of accurate diagnosis between dVIN and lichen planus. Overall, this study also highlights the overall low contribution of lichen planus to non-HPV vulvar cancer cases.

Pigmented Lesions Pigmented lesions of the vulva are usually intraepithelial, with the exception of melanoma. Pigmented lesions account for approximately 10% of all vulvar disease. The most common pigmented lesion is a lentigo, which is a concentration of melanocytes in the basal layer of cells. It can have the clinical appearance of a freckle, although it is more commonly confused with a nevus. The borders are fuzzy, but it is not a raised lesion. A lentigo is benign, and the diagnosis is usually made by inspection with magnification. If there is any doubt, a biopsy should always be performed as intraepithelial neoplasia of the vulva may appear as a pigmented lesion. Additionally, characteristic raised, hyperkeratotic pigmented lesions are suggestive of carcinoma in situ (CIS) and precursor lesions and should be biopsied. The management of nevi, however, can be conservative once diagnosed. A nevus can often be detected only microscopically. Unfortunately, a simple nevus and an early melanoma cannot be differentiated on clinical evaluation. Excisional biopsy of these raised, smooth, pigmented areas can be done easily in the physician’s office. If the nevus changes in color, size, and shape, it should be removed for diagnostic purposes. After a nevus is removed, no further therapy is needed regardless of whether it is a compound, intradermal, or junctional type.

Diagnosis and Treatment Figure 2.8 Erosive lichen planus. (Courtesy of Dr. Lori Boardman, MD, ScM, University of Central Florida College of Medicine.)

Biopsies are critical to appropriate management; before any treatment is given on a long-term basis, biopsies should be

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

TABLE 2.3 Vulvar Nonneoplastic Epithelial

Disorders Disorder

Treatment

Lichen sclerosus

Topical high-potency steroid ointment

Lichen planus

Topical high-potency steroid ointment

Lichen simplex chronicus

Topical corticosteroid after evaluation and removal of offending environmental agents and treatment of concurrent vaginitis, lichen sclerosus, or lichen planus

performed from representative areas to ensure the correct diagnosis. (The exception for biopsy is the pediatric population, which will not be discussed here.) Site selection should be focused on sites of fissuring, ulceration, induration, and thick plaques. Patient education regarding hygienic measures for keeping the vulva clean and dry is important; any soaps, perfumes, deodorizers, or other contact irritants should be avoided. A thorough history should be taken to evaluate possible causes of vulvar pruritus. After lesions with malignant potential have been ruled out, local measures for control of symptoms, primarily pruritus, can be instituted (Table 2.3). Additionally, infectious vaginitis should be ruled out with a saline wet preparation, potassium hydroxide (KOH) wet preparation, and yeast culture to evaluate for atypical yeast that may be missed on plain microscopy. The psychosocial effect should also be considered as many women will feel isolated and have significant detrimental effects in self-perception and intimate relationships.

Lichen Simplex Chronicus Therapy for lichen simplex chronicus is treatment of the underlying cause of irritation and pruritus. All offending environmental agents should be avoided, including wipes, lubricants, sanitary and incontinence pads, detergents, perfumes, and soaps. A thorough history is often necessary to identify possible sources of irritation. Any underlying vaginitis also requires treatment. For isolated lichen simplex chronicus, a topical steroid ointment such as triamcinolone 0.1% or hydrocortisone 2.5% can be applied daily (after bathing to help seal in moisture) until symptoms are improved, generally in 3 to 4 weeks. If symptoms are particularly severe or a course of low-dose steroids is insufficient, a trial of higher-dose steroid ointment is acceptable. Pruritus is often most severe at night, and shortterm use of a pharmacologic sleep aid may be necessary. Lichen simplex chronicus should resolve with removal of the offending agent and treatment; if symptoms persist or recur, repeat biopsies and reconsider the diagnosis. Lichen Sclerosus Lichen sclerosus is a chronic condition with no curative treatment; the goal is symptom control. The standard treatment for lichen sclerosus is a topical corticosteroid. Typical regimens begin with a superpotent steroid ointment (i.e., clobetasol propionate ointment 0.05%) used nightly until resolution of symptoms (usually 8 to 12 weeks). Because of the chronicity of lichen sclerosus, maintenance therapy is typically necessary after initial treatment; application one to three times per week is usually

sufficient. Many women stop treatment when their symptoms improve and then represent months later with recurrent symptoms. Therapy can be reinitiated at treatment levels for 6 to 12 weeks, and emphasis given to maintenance therapy. Theoretically, long-term use of topical steroids may result in striae and thinning of the dermis, but this is infrequently observed in patients with lichen sclerosus. Topical testosterone is no longer the treatment of choice for lichen sclerosus. A prospective randomized study by Bracco and associates evaluated 79 patients with lichen sclerosus using four different treatment regimens: a 3-month course of testosterone (2%), progesterone (2%), clobetasol propionate (0.05%), and a cream base preparation. Patients experienced greater relief of symptoms with clobetasol (75%) than with testosterone (20%) or other preparations (10%). Clobetasol therapy was the only treatment in which the gross and histologic evaluation of patients improved after treatment. Recurrences after stopping the steroid occurred, but symptoms were relieved when therapy was resumed. Clobetasol was also more effective than testosterone in the randomized trial performed by Bornstein and colleagues, with a significant improvement in long-term relief experience by clobetasol users. Lorenz and colleagues reported 77% had complete remission of symptoms with clobetasol therapy but again noted that maintenance therapy was needed after baseline treatment. In the cohort followed by Cooper and associates discussed previously, 65% were symptom free, 31% had a partial response, and 5% had a poor response after steroid use. Improvement was also seen on physical examination; 23% had total resolution, 69% had partial resolution (improvement in purpura, hyperkeratosis, fissures, and erosions but no change in color and texture), 6% had minor resolution, and 2% had no improvement. Occasionally, vulvar pruritus is so persistent that it cannot be relieved by topical measures. Topical treatment may also fail if significant hyperkeratosis is present. In such cases, intradermal and lesional injection of steroids has been reported to be effective. If lesions persist and symptoms do not improve after a course of superpotent topical steroids, biopsies should be repeated to confirm the initial diagnosis. It is again critical to rule out cancer and VIN to ensure appropriate treatment. Other regimens have been reported for lichen sclerosus recalcitrant to corticosteroids. Calcineurin inhibitors, such as tacrolimus and pimecrolimus, show some benefit through immunomodulation but are considered second-line therapy. Laser and photodynamic therapy may have some efficacy, but further trials are necessary as initial data has been inconclusive regarding the benefit of these treatments. As further investigation clarifies the complex pathophysiology and etiology of lichen sclerosus, additional targets for treatment will also be elucidated. Specifically, the understanding of the autoimmune nature of the disease with increase in inflammatory cytokines and activation of the T helper response is promising for further development of treatment options.

Lichen Planus Lichen planus is similarly treated with complete evaluation, patient education, and topical steroids. Additionally, the physical

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

examination should include evaluation for the presence of lichen planus on the skin, scalp, nail beds, and oral mucosa. If systemic disease is present, consultation with a dermatologist is useful. Treatment of vulvar lesions should begin with an ultrapotent steroid ointment (i.e., clobetasol propionate ointment 0.05%) applied nightly for 6 to 8 weeks. If symptoms improve, the frequency of application can be reduced to two to three times weekly for 4 to 8 additional weeks. Cooper and associates reported that in a cohort of 114 women followed and treated for lichen planus, 71% of those treated with ultrapotent topical corticosteroids experienced relief of symptoms with treatment. On examination, 50% experienced healing of erosions, but no patients had resolution of scarring. When lichen planus symptoms are in a prolonged remission, the lowest effective dose is used for maintenance therapy, which may involve less frequent administration and a lower-potency steroid. Similar to lichen sclerosus, symptoms will return if maintenance therapy is not used. Lichen planus does appear more resistant to therapy than lichen sclerosus. In a small series of women with vulvar lichen planus that was nonresponsive to other treatments, Byrd and colleagues at the Mayo Clinic reported that 15 of 16 subjects experienced symptomatic relief after a course of topical tacrolimus. The mean response time was 4 weeks, and six subjects experienced mild irritation, burning, or tingling that resolved with persistent use. Tacrolimus therapy was less successful in the subjects followed by Cooper and associates, who were nonresponsive to topical steroid treatment. Of seven patients treated, two had complete symptomatic relief, three had some relief, and two had no improvement in symptoms.

VULVAR INTRAEPITHELIAL NEOPLASIA Terminology Vulvar pathologic terminology has evolved over the past two decades and clear communication of results and definitions is important for appropriate clinical care. For this reason, many pathology reports include historic terminology in addition to current terminology. Furthermore, current pathology diagnoses are not reflected in the ICD10 system which further inhibits analysis of data, clinical communication, and understanding. Because of the rapid changes, it is also important for today’s clinicians to understand the recent historical terminology in order to interpret medical evidence. In 2004, the ISSVD clarified the VIN classification system (Table 2.4) and created two distinct VIN categories: VIN usual TABLE 2.4 2015 International Society for the Study of Vulvovaginal Disease (Classification of Vulvar Squamous Intraepithelial Lesions) A. Low-grade SIL B. High-grade SIL C. Differentiated-type VIN SIL, Squamous intraepithelial lesions; VIN, vulvar intraepithelial neoplasia.

(uVIN) and VIN differentiated (dVIN), eliminating VIN 1 from the traditional VIN 1, 2, and 3 system as there was no evidence that VIN 1 was a precancerous lesion. The two distinct subtypes of VIN, uVIN and dVIN, were recognized for their differences in epidemiology, morphology, and association with vulvar cancer (Table 2.5). Differentiated type VIN tends to: occur in older women, be unifocal and unicentric, be found at the edge of vulvar SCC and in the setting of lichen sclerosus or planus, and be less frequently associated with HPV. On the other hand, uVIN was identified as being more likely to be found in younger women, have a strong association with cigarette smoking, be multifocal, be less frequently found in conjunction with squamous cell cancer, and usually associated with HPV. Biomarkers also help differentiate uVIN and dVIN, with p16 positivity noted with most uVIN and p53 mutation noted in dVIN. Subsequently, a separate consensus group, cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP), in 2012 created a classification system (Lower Anogenital Squamous Terminology [LAST]) among HPV-associated lesions of the lower genital tract, including the cervix, vagina, vulva, and anus, to unify the terminology related to HPV-associated intraepithelial neoplasia of the lower genital tract. but this classification system did not include HPV negative VIN. The recommended terminology for all cervical, vaginal, vulvar, and anal lesions is “low-grade” or “highgrade” squamous intraepithelial lesion (SIL) based on a combination of cell morphology and p16 immunostaining. The ISSVD modified their classification in 2015 to share terminology with LAST regarding HPV-associated VIN. The usual type, associated with HPV, was reclassified as HSIL, similar to the LAST criteria, while low-grade squamous intraepithelial lesion (LSIL) was added to ISSVD to encompass the category previously defined as HPV effect or condyloma (and many of the historic VIN 1 lesions.) This resulted in three separate ISSVD classifications of VIN: LSIL, HSIL, and dVIN. As clinical practice continues to trail the new guidelines, it is important to understand all of the terminology used recently and to talk to the pathologist before making meaningful clinical decisions if there is any doubt about terminology being used.

Progression to Cancer According to a Surveillance, Epidemiology, and End Results (SEER) data analysis by Judson and colleagues, whereas the incidence of vulvar CIS increased 411% between 1973 and 2000, the rates of invasive vulvar cancer rose only 20%. Several hypotheses regarding the changing incidence of VIN exist: increased physician awareness and evaluation of vulvar disease, increased prevalence of smoking among women, and increased HPV prevalence. Women with a history of preinvasive cervical disease or cervical cancer are at increased risk of preinvasive vulvar dysplasia. HPV is a risk factor for vulvar disease, but the progression from HPV infection to precancer to invasive cancer is poorly understood. In contrast to cervical cancer, which has a peak age in dysplasia incidence followed by a peak age in invasive cancer (after a lag period), there is no similar time course established in vulvar cancer. In fact, the peak incidence of VIN

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

TABLE 2.5 Vulvar Squamous Intraepithelial Lesion Subtypes and Associations

Age

Low Grade Squamous Intraepithelial Lesion (vulvar LSIL, previously VIN 1, flat condyloma, or HPV effect) Premenopausal women (30s–40s)

High Grade Squamous Intraepithelial Lesion (vulvar HSIL, previously VIN Usual Type, VIN2 or VIN 3) Premenopausal women (30s–40s)

Overall % of high grade SILs

N/A

≈95

≈5

HPV associated

Yes

HPV type

6, 11

N/A

Risk factors

Smoking, immunosuppression

None identified

Distribution

Multifocal

Unifocal, unicentric

Background histology Progression to

Differentiated VIN (dVIN) Postmenopausal women (65 years)

Lichen Sclerosus Condyloma

Warty, basaloid squamous cell cancer

Keratinizing squamous cell cancer

HPV, Human papilloma virus; NA, not applicable; SILs, squamous intraepithelial lesions; VIN, vulvar intraepithelial neoplasia.

occurs during the mid-40s followed by a declining incidence, but the incidence of invasive vulvar cancer continues to increase and never stabilizes, reaching approximately 13 in 100,000 women by the age of 80 years. The difference in demographics may represent the association of HPV-negative dVIN with women in later decades of life versus HPV-positive HSIL in younger women. Case reports definitively document the development of invasive squamous cell cancers in patients with HSIL VIN lesions followed prospectively. In a review of more than 3300 patients with VIN III, van Seters identified occult invasive cancer in 3.2% of subjects at the time of excision, and an additional 3.3% developed cancer during follow-up. Chafe and associates noted that 19% of women who were thoroughly evaluated and thought to have VIN actually had invasive cancer on the vulvectomy specimen. Kagie and associates reported on 66 women with invasive vulvar SCC; 39 (62%) had synchronous VIN. In other cases, it appears that invasive lesions may arise de novo rather than from precursor VIN lesions, but this may be from a misdiagnosis of differentiated VIN previously diagnosed as lichen sclerosus. In a population of 405 women followed for VIN II and III in New Zealand between 1962 and 2003, 2% of cases recurred in the same location as an invasive cancer at a median time of 2.4 years, and 1.8% of cases recurred as invasive cancer in new fields at a median time of 13.5 years. Additionally, 11.6% of biopsy-proven VIN regressed before treatment (mean age, 24.6 years). If observation is considered in young women with small lesions and usual type histology, frequent examinations with directed biopsies are necessary. Barbero and colleagues noted 3 of 55 patients treated with VIN whose conditions progressed to carcinoma in 14 months to 15 years. These three patients ranged in age from 58 to 74 years. In the New Zealand cohort, there were 10 cancers diagnosed in untreated patients; Jones and McLean have previously reported on five of the cases diagnosed between 1970 and 1974, and an additional five cases were diagnosed between 1983 and 1992. The median interval between VIN and invasive cancer was 3.9 years (range, 1.1 to 7.3 years).

A recent analysis of the Dutch Pathology Registry (PALGA) evaluated women with HSIL and dVIN from 1991 to 2011. Among women with a diagnosis of HSIL and dVIN, the risk of invasive vulvar squamous cell cancer in the 10 years following their VIN diagnosis was 10% and 50% respectively. In the Dutch cohort, age and presence of lichen sclerosis were independent risk factors in addition to HSIL/dVIN and only 3% of all VIN was designated as dVIN versus HSIL. Bowenoid papulosis is a variant of a pigmented lesion noted by dermatologists for some time and continues to be reported in the dermatologic literature. These are small, pigmented papules that develop and spread rapidly. According to dermatologists, these papules often regress spontaneously. Histologically, at least on the vulva, these are SCCs in situ. These lesions have been reported to have an aneuploid DNA pattern. Many authorities have not found bowenoid papulosis of the vulva to spontaneously regress. Regardless of the clinical characteristics, if VIN is present histologically, the physician should treat the patient accordingly.

Human Papilloma Virus and Vaccination HPV is strongly associated with HSIL (uVIN), but it is less commonly associated with dVIN. There is a wide variation in the reported presence of HPV in VIN because of population differences, the changing terminology and classification of VIN, and the improved sensitivity of recent HPV testing. In more recently published literature, HPV is present in 61% to 100% of VIN. HPV-16 is consistently the most common HPV type identified, accounting for as high as 91% of infection in some series. The prevalence of HPV infection in vulvar cancer decreases with age, probably reflecting a change in the underlying histology type and association with HPV. The efficacy of HPV vaccines in preventing vulvar dysplasia and cancer will be determined not only by the vaccine properties but also by the prevalence of HPV-related vulvar disease in the population. For example, the HPV VVAP (Vulvar, Vaginal, and Penile) study group published an analysis of HPV contribution to VIN and

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

invasive cancers worldwide. In their sample, whereas approximately 87% of VIN was associated with HPV positivity, 27% of invasive cancer was HPV positive, and HPV-16 was the most common type, accounting for 72.5%. HPV was present more commonly in invasive cancers of younger women than older women. Their conclusion was that the overall contribution of HPV to vulvar cancer may have been overestimated. In initial publications from the vaccine studies, there does appear to be efficacy against VIN. Joura and colleagues report on the vaccine efficacy in reducing specifically HPV-16– or HPV-18–related VIN with a mean duration of follow-up of 36 months. Among subjects who remained HPV negative while receiving the vaccination series, the vaccine was 100% efficacious; zero cases were diagnosed in 7811 vaccinated women, and eight cases were diagnosed in 7785 women who received placebo. Among subjects who were HPV negative at the time of the first injection but did not necessarily remain HPV negative for the duration of the vaccination series, the vaccine was 95% efficacious; one case was diagnosed in 8757 vaccinated women, and 20 cases were diagnosed in 8774 women who received placebo. An analysis was also performed on the incidence of VIN, regardless of HPV association, among all subjects, HPV naïve and HPV exposed at the time of vaccination, and the rate of VIN II/III was reduced by half in the vaccinated group, but there did not appear to be any benefit for those who were HPV exposed at the time of vaccination. Updated studies with longer-term follow-up and inclusive of the nine-valent HPV vaccine are consistent with initial findings. Giulano et al. compared the nine-valent vaccine to historic placebo controls in three vaccine trials and found that women who were HPV negative, specifically 16 and 18, at the time of vaccination had a markedly reduced risk of HSIL compared to placebo. However, there was substantially less clinical effect among subjects who had already been exposed to one of the nine included HPV types, particularly those who were PCR positive to types 6, 11, 16, or 18 at time of vaccination. This gives further credence to vaccination of young women prior to HPV exposure. Additionally, HPV vaccinations as treatment are now being studied. Kenter and colleagues tested a synthetic long-peptide vaccine as treatment for VIN in women with HPV-16–positive VIN using a series of three or four vaccinations. Among 19 patients examined on 12-month follow-up, 9 had a complete clinical response, and this was maintained at 24 months. This suggests a potential treatment role for vaccines in addition to prevention.

Diagnosis The disease is asymptomatic in more than 50% of cases. In the remainder of cases, the predominant symptom is pruritus. The presence of a distinct mass, bleeding, or discharge strongly suggests invasive cancer. The most productive diagnostic technique is careful inspection of the vulva in bright light during a routine pelvic examination followed by biopsies of suspicious lesions. A handheld lens or colposcope can be very helpful, especially after application of 5% acetic acid to the skin and introitus. Careful inspection of the vulva during routine gynecologic examinations is essential; this remains the most likely diagnostic

Figure 2.9 Multiple white lesions (arrows) of the vulva caused by vulvar intraepithelial neoplasia.

Figure 2.10 Histologic section of carcinoma in situ of the vulva.

technique. Early VIN first appears clinically as pale areas that vary in density. More severe forms are seen as papules or macules, coalescent or discrete, or single or multiple. Lesions on the cutaneous surface of the vulva usually appear as lichenified or hyperkeratotic plaques or white epithelium (Figs. 2.9 and 2.10). By contrast, lesions of mucous membranes are usually macular and pink or red. Vulvar lesions are hyperpigmented in 10% to 15% of patients (Fig. 2.11). These lesions range from mahogany to dark brown, and they stand out sharply when observed solely with the naked eye. The entire vulva, perineum, and perianal area must be evaluated for multifocal lesions. It is not uncommon to find intraepithelial lesions on hemorrhoid tags or more superiorly in the gluteal cleft. The use of acetic acid is helpful in identifying subtle lesions or in clarifying margins (Fig. 2.12). In contrast to the mucous membrane of the cervix, the keratinized epithelium of the vulva requires application of acetic acid for 5 minutes or longer before many lesions become apparent. Placement of soaked cotton balls or sponges on the vulva for several minutes before examination is effective. Colposcopy can be a useful adjunct and a handheld magnifying glass can also be used, which allows greater viewing area at one time compared with

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Figure 2.11 Hyperpigmented lesions of vulvar carcinoma in situ.

the colposcope. In general, whereas multifocal lesions are more common in premenopausal patients, postmenopausal patients have a higher rate of unifocal disease. Some investigators prefer to use toluidine blue to identify vulvar lesions, but this is less common in current clinical practice. A 1% aqueous solution of the dye is applied to the external genital area. After drying for 2 to 3 minutes, the region is then washed with 1% to 2% acetic acid solution. Suspicious foci of increased nuclear activity become deeply stained (royal blue); normal skin accepts little or none of the dye. Hyperkeratotic lesions, even though neoplastic, are only lightly stained, but benign excoriations are often brilliant, an observation that accounts for the high false-positive and false-negative rates. The diagnosis of VIN can be subtle. To avoid delay, the physician must exercise a high degree of suspicion. Vulvar biopsy should be performed on any suspicious lesion. It is best accomplished under local anesthesia (lidocaine or bupivacaine) with a Keyes dermatologic punch. This instrument allows removal of an adequate tissue sample and orientation for future sectioning. The biopsy site can be made hemostatic with silver nitrate, Monsel’s, a stitch, or a piece of absorbable gelatin powder cut with the Keyes punch; this is positioned in the skin defect and kept in place with a small dressing for at least 24 hours. Adequate biopsy specimens can also be obtained with a sharp alligator-jaw instrument if one has proper traction on the skin. The problem with ordinary knife “shave” biopsies is that only superficial epithelium can be reached and invasive cancers may be misdiagnosed as CIS because depth of the cellular changes cannot be identified. If this technique is used, one must be careful to get full-thickness skin to adipose tissue for adequate sampling of deeper layers.

Management

B Figure 2.12 Vulvar high-grade squamous intraepithelial lesions prior to (A) and following (B) dilute acetic acid placement.

Surgical excision is the mainstay of therapy for VIN, but ablative techniques including laser are frequently used, especially for multifocal lesions, and medical management with immune modulators has become more common. An important advantage of surgical excision is that complete histologic assessment is performed; lesions with early invasion can thus be found. Most localized lesions are managed effectively by wide local excision with end-to-end approximation of the defect. The vulvar skin and mucous membrane are usually very elastic, and cosmetic results are satisfactory after uncomplicated healing.

Excision Wide local excision is the most commonly performed treatment of VIN and should be performed whenever there is suspicion for invasive disease. Margin status and histology results are available on final pathology results, which is a benefit of the excisional procedure. The goal of surgery is to obtain a 5-mm disease-free margin. Modesitt and associates reported that recurrences were three times higher (46% vs. 17%) when margins were positive for residual VIN II and III. In the New Zealand study discussed previously, 50% of those with positive margins versus 15% of those with negative margins required further treatment. Hillemanns and colleagues showed an overall recurrence rate of 43% in subjects retrospectively analyzed who had

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

been heterogeneously treated with laser, photodynamic therapy, excision, or vulvectomy. No patients recurred in the vulvectomy group (n 5 8). In the natural history review by van Seters and colleagues, 1921 patients were surgically treated. Recurrences were significantly lower after free surgical margins (17%) than after positive surgical margins (47%). Progression to invasive disease occurred in 58 patients, 52% of the time after vulvectomy, and 48% of the time after local excision. In this retrospective review, the surgical approach was likely selected based on individual patient characteristics so that patients considered at higher risk for invasive cancer may have more frequently received vulvectomy. Vulvectomy is significantly more morbid than local excision and wide local excision is the accepted excisional procedure for VIN. In the series by Modesitt and colleagues, 17 of 73 subjects were diagnosed with invasive cancer at the time of treatment for VIN III. Similarly, 16 of 78 patients undergoing surgical excision for VIN III had invasive cancer in the report by Husseinzadeh and Recinto. To avoid returning to the operating room for deeper reexcision and lymph node dissection, biopsies must be liberally performed preoperatively. Multiple biopsies may be required. Adequate postoperative follow-up with repeat biopsy for any suspicious lesions is also essential as the risk of recurrence or progression to cancer is high. Rarely, a skinning vulvectomy is indicated if closure of the excision cannot be completed after resection of extensive disease. With multicentric lesions (Fig. 2.13), the involved skin can be excised and substituted with a split-thickness skin graft taken from the buttocks or inner aspect of the thigh. This skinning vulvectomy and skin graft procedure was introduced by Rutledge and Sinclair in 1968 (Fig. 2.14). Its purpose was to replace the skin at risk in the vulvar site with ectopic epidermis

70%

26%

20%

48%

38%

64% 38%

58% 42% 92%

32%

28%

Figure 2.13 Plot of lesion locations in 36 patients treated for multifocal carcinoma in situ of the vulva.

from a donor site. In more than 100 patients treated, the authors reported no complaints of dyspareunia or diminished sexual responsiveness. The benefits of the skinning vulvectomy and skin graft procedure are preservation of the subcutaneous tissue of the vulva and a better cosmetic and functional result (Fig. 2.15). In previous editions of this text, Creasman reported a modification of the procedure with preservation of the clitoris, in which any lesions on the glans are scraped off with a scalpel blade, and the epithelium of the glans regenerates without loss of sensation. Postoperatively, a skin graft operation requires prolonged bedrest (6 to 7 days) to allow the split-thickness graft to adhere to the graft bed. Thus, the potential for morbidity is increased. This procedure may also be performed with a multidisciplinary team including gynecology and plastic surgery. A staged procedure may be necessary if the affected areas involve the entire vulva and anus.

Laser Ablative therapy is an alternative to excision. The disadvantage of ablative therapy is that a necrotic ulcer on the vulva may result, and wound healing may be slow. Complete healing may take up to 3 months. The treated area is often very painful for much of that time. Many consider laser therapy the treatment of choice in the management of multifocal VIN. Additionally, laser therapy may be particularly effective around areas where excision can lead to external sphincter weakening. Townsend and colleagues treated 33 patients with laser therapy and reported success in 31 (94%), but 14 patients required two or more treatments, and 2 patients required five laser treatments. The results published by Baggish and Dorsey were similar; 32 of 35 patients were believed to have been cured from their disease, 26 of 35 patients required three or more treatments, and two women had six treatments. Only a small portion of the vulva can be treated without anesthesia. Patients require surgery in the operating room if large areas of the vulva are treated at one time. Pain, which is severe in some patients, is the main complication with laser therapy. Bleeding and infection have also been reported. The cosmetic results are generally satisfactory to patients. It appears that laser therapy can be an acceptable treatment modality, but patients must be carefully evaluated before treatment to rule out invasive carcinoma (Table 2.6). Greater expertise with the laser is required for this therapy than is needed for cervical vaporization. The depth of destruction must be controlled. Too deep a wound can result in long-term ulcers, which may take some time to heal and cause considerable discomfort. Benedet and colleagues evaluated 165 women with VIN. Of the 122 patients with VIN III, the mean thickness of the epithelium was 0.52 mm (range, 0.1 to 1.9 mm). In patients with hair follicles involved with VIN, the mean depth of involvement was 1.9 mm (range, 1 to 3.4 mm). Only 19 patients had appendiceal involvement. Age did not seem to affect the thickness of involved epithelium. Multifocal lesions were present in 64% of all patients. The most common sites were the labia minora, posterior fourchette, and perineum. Based on this study, the authors believe that 1-mm destruction of non–hair-bearing epithelium is adequate treatment. If

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Island lesions

Confluent lesions

Line of incision

Figure 2.14 Skinning vulvectomy and skin graft. A, Excise all areas of involvement en bloc. B, Lesions may be isolated or confluent. C, Preserve all subcutaneous tissue as the graft bed. D, Suture the skin graft to the graft bed.

skin appendages are involved, 2.5 to 3 mm is required (Fig. 2.16). When performing excision, the burn level does not need to be carried to the level of the subcutaneous fat. Also, the carbon from the surgical site can be wiped during the procedure to be certain that the shiny white lower dermis is preserved. Reid has defined surgical planes in the vulva as a guide to laser therapy. The first plane is the surface epithelium only, which includes the basement membrane. Opalescent cell debris is noted through the heat char. Healing is rapid, with good cosmetic results. The second plane involves the dermal papillae, with necrosis extending to the deep papillary area. The appearance is a homogeneous yellow color that resembles a chamois cloth. Again, healing is rapid with good cosmesis.

The third plane affects the upper and midreticular area, where the pilosebaceous ducts are located. Some hypertrophy may appear in this area during the healing process. The fourth plane affects the deep reticular area, and “sand grains” can be visualized. Healing is slow and usually occurs by granulation from the sides. Skin grafting may be required. Destruction to the third plane is adequate for hair-bearing tissue; plane one to two is the depth needed for non–hair-bearing skin. After laser therapy, the vulva is covered with Silvadene. Sitz baths, topical lidocaine, and rinsing of the vulva with water after urination and defecation are important. A hair dryer on cool setting can also aid in drying the area. A local anesthetic can be applied for mild to moderate pain control. Oral pain medication,

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders postoperative pain and less scarring. Other adverse events, including infection, dysuria, adhesions, and discharge, were similar between both groups. Argon beam coagulation (ABC) is also employed for multifocal HSIL. Kushnir reports an approximately 48% recurrence rate at a mean time of 23 months in a retrospective review of 29 patients treated with ABC. Patients overall tolerated the treatment well, however, with 2 patients requiring narcotics for moderate pain during the first 2 weeks.

Figure 2.15 Healing after superficial vulvectomy and skin graft for vulvar intraepithelial neoplasia.

TABLE 2.6 CO2 Laser Vaporization of the

Vulva

Instrument

CO2 laser, colposcopic, micromanipulator

Power density

600–1000 W/cm2

Depth of destruction

Nonhairy areas ,1 mm

Hairy areas

.3 mm

Lateral margins

“Brush”

Anesthesia

General, local

Analgesia

Significant postlaser pain: narcotics

including narcotics, may be necessary. The most severe pain is usually evident 3 to 4 days after the laser therapy. Preoperative counseling to set expectations regarding postoperative pain is an important component of this procedure.

Alternative Ablative Techniques A cavitational ultrasonic surgical aspirator (CUSA) is a less frequently used ablative option. In a randomized prospective trial, von Gruenigen and associates compared outcomes from laser ablation versus CUSA. Recurrence was similar in both arms (25% overall), but subjects treated with CUSA had less

Non-surgical Treatment Medical treatment is an alternative to surgical excision in patients with HSIL (uVIN) in whom there is no suspicion for malignancy. Patients should be counseled regarding potential side effects of therapy including pain, erythema, and itching, the necessity for repeat biopsies with close follow up, and the possibility of surgical excision if medical treatment is not effective. Imiquimod. Imiquimod 5% cream is an immune response modifier with indirect antiviral and antitumor properties. It activates macrophages and dendritic cells to release interferona and other cytokines that provoke an antigen-specific immune response. Imiquimod cream was first shown to be effective and safe in the treatment of HPV-associated genital warts and was subsequently evaluated in the treatment of HSIL. In a phase II trial completed by Le and colleagues, 33 patients with VIN 2/3 were treated for 16 weeks with 5% imiquimod application; six additional subjects were unable to complete the study. At 20 weeks, 21 of 33 subjects had complete response (complete disappearance of the visible lesion and histologic regression), 9 of 33 had a partial response (50% decrease from baseline measurement), and three had stable lesions. In a randomized, double-blinded controlled trial, Mathieson and associates treated 21 subjects with 5% imiquimod and 10 with placebo. There was a complete response in 17 of 21 subjects in the treatment group (complete histologic regression) and in none of the 10 subjects in the placebo group. Because of side effects, the dose was reduced in 14 of 21 women in the treatment group. Van Seters and colleagues report similar results but also include 12-month follow-up from their randomized controlled trial (RCT). In 26 subjects treated with imiquimod, histologic and virologic regression was seen in 15 and 14 subjects, respectively. In the 26 subjects who received placebo, histologic and virologic regression was seen in one and two subjects, respectively. Progression to invasive disease occurred in one subject in the treatment arm (who initially had a weak, partial response with imiquimod) and two subjects in the placebo arm. Treatment was reduced to once-weekly application in five women receiving imiquimod because of severe inflammation. Investigatorreported side effects, including erythema, erosion, vesiculation, and edema, were significantly worse in the treatment group than in the placebo group. At 20 weeks and 12 months, however, self-reported pruritus and pain were significantly better in the treatment group than in the placebo group. In a study of women randomized to surgical excision alone versus surgical excision followed by imiquimod, there was no difference in recurrence between groups (45% and 48%, respectively), but recurrence was more common in women with multifocal disease.

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Epidermis First plane Papillary dermis Second plane Sweat glands Pilosebaceous duct

Reticular dermis

Third plane Hair follicle Fat

Figure 2.16 “Planes” for therapy for vulvar intraepithelial neoplasia using a laser.

A Cochrane Review of patients diagnosed with highgrade VIN (VIN 2 and VIN 3) enrolled in RCTs (including the previously-mentioned Mathieson and van Seters trials) concluded that approximately half of women had a complete response to imiquimod and that the responses were generally maintained at 12 months. Complete response may be associated with smaller lesions and data is lacking regarding the continuation of response after 1 year. Cidofovir. Cidofovir, an antiviral agent with activity against HPV, has also been reported as treatment for HSIL. In an RCT (n 5 180) comparing imiquimod and cidofovir applied three times per week for 24 weeks in women with VIN 3, 46% of patients in each treatment group achieved a complete clinical response at the 6-week posttreatment visit. However, grade 3 or higher toxicities were more significant in the imiquimod group (46%) compared with the cidofovir group (37%), with grade 3 vulvar pain reported in 2% of cidofovir users and 1% of imiquimod users. These patients were followed for 24 months following completion of therapy, and a subsequent publication reported continued complete response. Among those treated with cidofovir, 94% remained VIN-free versus 72% in the imiquimod at a median follow up of 18 months. Further translational work in this cohort of patients indicated that 136 of the 167 cases with biopsy specimen available for testing were HPV-16 positive. Although final specimen numbers and cases were small, methylation of HPV E2 was potentially associated with response with higher methylation status in those who responded to cidofovir and lower methylation in those who responded to imiquimod. Further validation is necessary to draw conclusive evidence, but this study’s findings highlight

the potential for personalized treatment based on biology of disease. Photodynamic therapy. Multiple variations of photodynamic therapy have been trialed for the treatment of VIN, but clinical utility has been limited by patient discomfort and inconvenience. A combination of a photosensitizing agent with a light energy source causes reactive oxygen species that increases immune response and directly destroys abnormal cells. Cosmetic outcomes are generally favorable to patients and this strategy is employed for many non-melanoma skin malignancies, but efficacy remains unclear for VIN. One of the obvious benefits of medical therapy is avoidance of disfiguring surgery. Randomized trials show promise in a variety of non-surgical treatments as primary therapy for VIN, and topical medical treatments have been relatively well tolerated, but dose reductions have been necessary in all trials for a considerable number of subjects. The trials previously mentioned varied in application frequency from once per week to three times per week when tolerated. Because some of the main benefits are quality-of-life related, it will be important to evaluate the side effects and complications of medical treatments versus excisional procedures. Even in women who did not receive a complete response, a partial response was observed in many. Reduction in lesion size may be another potential application of the therapy, particularly if disease is present in a multifocal, clitoral, or sphincter distribution. Because the ISSVD classification has now changed, future trials should specifically evaluate efficacy in HSIL. Additionally, further information is necessary in the efficacy of these treatments in immunosuppressed patients as data is lacking.

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

Surveillance After initial diagnosis and treatment, American College of Obstetrics and Gynecology guidelines recommend repeat visualization of the vulva at 6 and 12 months and annually thereafter. Frequency of examinations is based on expert opinion, however, and a recent survey of ISSVD members identified 26 different strategies for follow-up. If there is increased concern in a specific clinical setting, more frequent examination is also appropriate. An increased risk of recurrence has previously been associated with increasing lesion size, dVIN, positive margins, smoking history, and multifocal disease. Patient education is an important component of the surveillance strategy. In women diagnosed with vulvar HSIL, consideration should also be given to cervical/vaginal screening with cytology, even if women have undergone hysterectomy or do not meet cervical screening guidelines based on age. Buchanan and colleagues found an 8% risk of HSIL of the cervix or vagina among women previously treated for vulvar cancer or HSIL. This correlates with HPV as an infection of the anogenital tract, rather than of a specific organ. The anus should also be considered for screening in this population as abnormal anal cytology has been diagnosed in 20% of women with vulvar HSIL when studied in dysplasia cohorts, although guidelines are not yet established regarding anal screening in this population. In summary, it is important to remember that these vulvar lesions often develop in young women who remain asymptomatic. Women should be taught vulvar self-examination to identify early lesions. Physical examination of the vulva performed by a physician will likely become inadvertently less frequent as Pap screening guidelines continue to evolve, and self-examination may become more important in the future. Postmenopausal women should be instructed in the importance of annual vulvar examinations, even if Pap screening is not required. The goal of earlier diagnosis and intervention is more successful therapy that is also less radical. Early diagnosis depends on careful vulvar examination under a bright light at regular intervals. Biopsy must be done on any suspicious lesions, and if the histologic report confirms HSIL, an examination for multicentric foci should follow. The therapy of choice depends on the extent of disease, the location of the lesions, and the personal desires of the patient.

HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION OF THE VAGINA Clinical Profile The incidence of vaginal HSIL is not well described. The first report was by Graham and Meigs in 1952. They reported three patients with carcinoma of the vagina, two intraepithelial and one invasive, that were discovered 6, 7, and 10 years, respectively, after total hysterectomy for CIS of the cervix. CIS is a historical diagnosis, equivalent to the modern diagnosis of HSIL. The most recent analysis of the incidence of vaginal HSIL in the United States, published in 1977, reported 0.2 to 0.3 cases per 100,000 women. Data published by Joura and colleagues from a select population within a large vaccine trial give a more recent estimate: the incidence of HSIL of the vagina in the placebo

group—women from 24 countries between 16 and 26 years of age who were followed for a mean of 36 months—was 21 cases in 9087 subjects. There may be multiple reasons for the higher incidence observed in the vaccine trial such as a true rise in incidence since 1977 similar to the increase seen for vulvar HSIL, a higher rate of diagnosis because the women were being followed with serial examinations, or a different population from a more heterogeneous international setting. Cervical and vaginal HSIL have similar risk factors, including smoking, earlier age at first intercourse, increased number of sexual partners, and HPV infection. HSIL of the vagina is much less common than that of the cervix or vulva. Because of the low prevalence of the disease, routine screening for VAIN and vaginal cancer is not recommended. After hysterectomy for benign disease, the incidence of VAIN is extraordinarily low, and guidelines from the American College of Obstetricians and Gynecology (ACOG) and the ASCCP do not support Pap testing in this population. These guidelines were written in part based on past evidence from Pearce, Noller, and Stokes-Lampard showing that a huge number of women would undergo unnecessary cytology screening and colposcopy in order to diagnose a single rare outcome. Utilizing modern HPV screening has shown similar results; Cao performed an analysis of over 8500 women, including approximately 10% with a history of cervical HSIL, who underwent hysterectomy, postoperative cytology with HPV screening, and referral for colposcopy as indicated. The incidence of vaginal HSIL among those with versus without a history of cervical dysplasia was 5% vs 0.1% with a mean follow-up of 34 months. On the other hand, women who have a history of in utero DES exposure, immunosuppression, or have a history of cervical or vulvar dysplasia should continue to undergo screening. This recommendation should be reviewed with patients who advocate for hysterectomy as treatment for HSIL of the cervix because many women believe hysterectomy will be definitive management and excuse them from future screening or further HPV-mediated disease. The ASCCP updated guidelines in 2019 for vaginal screening among women with a history of cervical HSIL (CIN II/CIN III) or cervical AIS to recommend annual HPV-based testing for 3 years following hysterectomy and then enter 25 years of long-term surveillance with screening performed every 3 years. Additionally, lesser cytology abnormalities of ASCUS and LSIL of the vagina can undergo repeat screening in 1 year, while cytology results of HSIL, atypical glandular cells (AGC), or atypical squamous cells (ASC-H) should be referred for immediate vaginal colposcopy. Many women dutifully attended annual Pap testing and may require counseling and patient education to accept these guidelines. Rare, unfortunate cases of VAIN or invasive cancer will occasionally be diagnosed in women who have undergone hysterectomy for benign disease, but these exceptional cases cannot drive screening guidelines. Furthermore, because VAIN and vaginal cancer are strongly associated with HPV infection, the HPV vaccination should drive a decrease in the number of these cases in the future. Patients with vaginal HSIL have a high risk of either an antecedent or coexistent neoplasia in the lower genital tract. HPV

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

mapping has shown identical DNA integration loci between primary lesions of cervical dysplasia and later dysplastic lesions of the vagina and vulva, indicating that later disease may result from monoclonal lesions from the primary cervical dysplasia. In patients who have been treated for disease in the cervix or vulva, VAIN can appear many years later, necessitating longterm follow-up. First van der Linde, then Gusberg and Marshall, and later Parker indicated that 2%, 1.9%, and 0.9% of patients, respectively, had vaginal recurrences after hysterectomy for a similar lesion in the cervix. More recently, Schockaert and associates were able to follow 94 women who had hysterectomies with a diagnosis of CIN II, CIN III, or FIGO stage Ia1 cervical cancer. In a median interval of 35 months, 7.4% developed VAIN21 (vaginal intraepithelial neoplasia 2 or greater), including two vaginal cancers. Ferguson and Maclure reported positive cytologic findings in 151 (20.3%) of 633 previously treated patients. This large group included invasive and in situ cancers of the cervix, which were treated by irradiation or hysterectomy. The long-term recurrence rate for HSIL of the vagina is uncertain, but it is sufficient to merit continued careful follow-up. Vaginal HSIL and invasive cancer are both associated with HPV. HPV positivity rates reported in the literature range from 82% to 94% for VAIN and 60% to 75% for vaginal cancer, with HPV-16 and -18 accounting for the majority of HPV positivity. In early reports, vaccination appears to be effective at preventing HPV-16– and HPV-18–associated vaginal lesions in women who receive the vaccination before HPV exposure. At a population level, there has been a demonstrated decline in vaginal HSIL incidence among Danish women who were vaccine eligible based on age after vaccine introduction in 2006, but no significant decline among older women over the same period, suggesting vaccine efficacy. Vaginal dysplasia appears to mimic cervical dysplasia with a high prevalence of HPV infection, as opposed to vulvar dysplasia, which displays inconsistent associations. Isolated lesions can usually be recognized colposcopically (Fig. 2.17). The most frequent finding is acetowhite epithelium; mosaicism and punctuation can also be present, and some authors have described a “pink blush” appearance or a slightly granular texture. The diagnosis is confirmed by biopsy. The extent of the lesion can be evaluated with the colposcope or with Lugol’s solution. Most lesions are asymptomatic and diagnosis is made after abnormal screening, although a patient will occasionally have discharge or postcoital staining. In almost all series, the upper third of the vagina is most frequently involved.

Diagnosis Patients with an abnormal screening cytology or HPV result who do not have a cervix or patients with an abnormal test result and no cervical abnormality visualized should undergo a careful examination of the vaginal epithelium. As the frequency of colposcopy declines with HPV vaccination and decreased indication, experienced colposcopists should perform this evaluation. Colposcopic examination of the vagina can be difficult to perform. The largest possible speculum should be used and repositioned frequently to allow inspection of all surfaces.

Figure 2.17 Carcinoma in situ of the vagina (colposcopic view).

Colposcopic findings are similar to those described for the cervix. Each of the four walls should be examined from the apex to the introitus as separate and sequential steps. Small biopsy specimens are taken with a Tischler or Kevorkian–Younge alligator-jaw forceps. Sometimes a sterilized skin-hook for traction at the biopsy site may be helpful. Most patients can tolerate these biopsies without local anesthesia, but the anticipated pain from the biopsies versus pain from a local anesthetic injection should be considered. Because of the importance of long-term follow-up and attendance for screening tests and colposcopy, attention and consideration of the patient’s anxiety and pain level is extremely important and anxiolytics or intravenous sedation should be considered when necessary. Lugol’s solution is often helpful in delineating lesions of the vagina. Normal vaginal epithelium stains brown, but dysplastic lesions with abnormal glycogen levels remain pale. In postmenopausal patients, local use of estrogen creams for several weeks helps to highlight the abnormal areas for identification by colposcopy. The majority of VAIN is multifocal; even if a lesion is identified, one must search the entire vagina for coexisting, multiple lesions. Lesions are more common in the upper third of the vagina, but disease-free skip areas may be encountered with additional HSIL in the lower vagina.

Management Local excision of the involved area has been the mainstay of therapy. In many cases, a single isolated lesion can be removed

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

easily in the office with biopsy forceps. If larger areas are involved, an upper colpectomy or vaginal wide local excision may be necessary to surgically remove the lesion. A dilute pitressin solution or lidocaine with epinephrine can be injected submucosally at the beginning of the procedure and will greatly facilitate the vaginectomy. Chai reports in an observational study of 111 women with HSIL of the vagina treated with an excisional procedure that following excision, 19% had residual disease, 7% recurred, and 4% had complications related to surgery. With a median follow-up time of 76 months in this study, 6% of women subsequently developed vaginal cancer from 19 to 86 months following initial excision, highlighting the importance of long-term surveillance for these patients. If there is any concern for malignancy, extensive biopsies or excision should be performed rather than alternative treatments. Cryosurgery has largely fallen out of favor in the treatment of VAIN, and laser therapy is preferred as an ablative technique. To give guidance about the depth of vaginal destruction required by the laser, Benedet and associates evaluated 56 patients who ranged from 22 to 84 years of age. Measurement of the epithelium was performed on involved and uninvolved tissue. The involved epithelium had a mean thickness of 0.46 mm (range, 0.1 to 1.4 mm). Uninvolved tissue was thinner and had a mean thickness of 0.28 mm. No statistical difference was seen in the thickness of the involved epithelium in the premenopausal and postmenopausal patients; however, the uninvolved epithelium was thinner in the postmenopausal patients compared with the premenopausal patients (0.25 vs. 0.37 mm). Based on this study, the authors believed that destruction of 1 to 1.5 mm would only destroy the epithelium without damaging underlying structures. Over a 6-year period, Townsend and associates treated 36 patients from two large referral hospitals with a CO2 laser. In 92% of the patients, the lesions were completely removed by the laser without significant side effects. Almost one-fourth of the patients, however, required more than one treatment session. Krebs treated 22 patients with topical 5-fluorouracil (5-FU) and 37 patients with laser therapy. The success rate was similar for the two treatments. Pain and bleeding are the main complications, but appear to be minimal. Healing is excellent and impaired sexual function was not a problem. The optimal technique of laser therapy for vaginal lesions has yet to be determined, even as the incidence of HSIL of the vagina increases. A thorough diagnostic investigation of the vagina to rule out invasive cancer can be difficult, but it is obviously mandatory prior to treatment as evidence from vaginectomy series shows that invasive cancer may be present concurrently with vaginal HSIL. In the 105 patients with VAIN II or VAIN III treated with vaginectomy by Indermaur and colleagues, 12% had invasive cancer on final pathology, and 22% had negative findings. In the previously cited Chai study, 2.6% had invasive cancer at time of diagnosis and in a similar Italian cohort, 5.5% of those undergoing excision had occult invasive vaginal cancer. Multifocal lesions, particularly after hysterectomy, with deep vaginal angles may be difficult to treat with the laser. Small skin hooks and dental mirrors can be used as adjuncts to successful laser therapy. As with HSIL of the cervix and vulva, modalities of therapy alternative to surgery have been investigated for vaginal treatment.

Many patients have been treated historically with 5-FU, but toxicity generally makes this a less desirable option, particularly in women who are sexually active. However, studies by Petrilli, Caglar, and Fiascone indicate that this modality can be effective. One of the problems with 5-FU is the selection of the best mode of application, dosage, and length of treatment. Several techniques have been suggested with equivalent results. One-quarter applicator of 5% 5-FU cream is inserted high in the vagina each night after the patient is in bed. The patient can be instructed to coat the vulva and introitus with white petroleum because the cream leaks out during sleep. A small tampon or cotton ball at the introitus is also helpful to prevent leakage. Because of irritation to the vagina and perineum, the cream should be removed by douching with warm water the next morning. This is done every night for 5 to 8 days followed by a 10- to 14-day rest period, and then the application cycle is repeated. This usually allows an adequate treatment time without having the patient experience the tremendous local reaction that can occur with prolonged use. Treatment can be repeated if it is not successful after the first cycle. Weekly insertions of 5-FU cream, approximately 1.5 g (one-third of an applicator), deep into the vagina once per week at bedtime for 10 consecutive weeks has also been shown to be efficacious. Again, placement of cotton balls at the introitus and application of a petroleum barrier on the perineum and vaginal introitus help prevent 5-FU contamination of the perineum with resultant skin irritation. Douching the next morning, which is advocated by some, is unnecessary with the weekly instillation. Patient compliance is likely higher and toxicity less with the second approach. Dungar and Wilkinson noted an interesting finding in the vagina after 5-FU therapy, and it has been confirmed by others. After treatment, a red area suggestive of a lack of squamous epithelium may be present. They found that this represented columnar epithelium consistent with a metaplastic process in which squamous epithelium is replaced with columnar epithelium. They called this finding “acquired vaginal adenosis.” These changes are usually found in the upper third of the vagina but may extend into the middle third. The columnar epithelium was of a low cuboidal or mucus-secreting endocervical type. In some cases, squamous epithelium was noted overlying the glandular elements. Marked superficial chronic inflammation was also present. This has also been noted in the vagina after laser therapy. More recently, experience with 5% imiquimod cream in the management of VAIN has been reported. Inayama et al. performed a meta-analysis of five studies (with 28 total patients) using imiquimod for vaginal HSIL and incorporated data from nine of their own patients (n 5 9), to evaluate complete response, defined as complete regression or normalization of histology and cytologic screening. A variety of 5% imiquimod regimens were used including both vaginal creams and suppositories, single versus multiple dosing weekly, and total time of treatment of 3 to 16 weeks. At the authors’ own institution, 5% imiquimod cream was utilized three times per week for 3 to 16 weeks duration. The complete response rate was 76% overall and appeared higher in women who had undergone previous hysterectomy versus those who had not. The side effects were similar between studies that reported adverse events and

CHAPTER 2

Preinvasive Disease and Dystrophies of the Vagina and Vulva and Related Disorders

included fever, diarrhea, abdominal pain, flu-like symptoms, and local irritation. Ultrasonic surgical aspiration has been successfully used by Robinson, von Gruenigen and colleagues, and Matsuo and colleagues, but the technique is not widely practiced. Some have advocated surface irradiation using an intravaginal applicator, but adverse effects may be severe and include vaginal stenosis, urinary symptoms, and vaginal ulceration. Additionally, vaginal stenosis can make follow-up extremely difficult. Total vaginectomy, with vaginal reconstruction using a split-thickness skin graft, should be reserved for the patient who has failed more conservative therapy because there appears to be no recurrence benefit from the more invasive procedure. Treated VAIN often recurs, regardless of the treatment method, and there is no clear standard of treatment. In a retrospective series of 121 women treated for VAIN between 1989 and 2000 by Dodge and colleagues, 33% of subjects experienced recurrence of VAIN, and 2% progressed to invasive cancer; multifocal lesions were more likely to recur. When stratified by treatment type, VAIN recurred in 0% (n 5 0 of 13) of those treated with partial vaginectomy, 38% (n 5 16 of 42) of those treated with laser, and 59% (n 5 13 of 22) of those treated with 5-FU. However, Indermaur and colleagues noted a higher rate of recurrence in their cohort of patients treated with vaginectomy. Of 52 patients available for follow-up who received vaginectomy as treatment for VAIN II or VAIN III, 6 patients recurred at a mean of

24 months, and one was diagnosed with invasive cancer. Sillman and associates reported on 94 patients with VAIN who were treated by various methods. The remission rate was high, but 5% of the cases progressed to invasive disease despite close follow-up. Incomplete excision of sufficient vaginal cuff with hysterectomy for CIS of the cervix with involvement of the fornices may explain an early recurrence. The finding of CIS in the vaginal cuff area in less than 1 year after hysterectomy makes this explanation likely. Therefore, it is important to perform a preoperative evaluation of the upper vagina by Schiller tests or colposcopy at the time of hysterectomy for CIS of the cervix. This allows the surgeon to determine accurately how much of the upper vagina has to be removed. It is also apparent that both CIS and dysplasia may develop in the vagina as primary lesions without an association with a similar process on the cervix or vulva. Still other preinvasive lesions of the vagina may appear after irradiation therapy for invasive carcinoma of the cervix. Data from MD Anderson suggest that these post-radiation lesions are premalignant and can progress to invasive cancer if they are not treated. Without therapy, approximately 25% of the patients in this series progressed to the invasive state over varying periods of follow-up. Local therapy must be executed with care because of the previous irradiation. For the bibliography list, log onto www.expertconsult.com

BIBLIOGRAPHY Embryology and Diethylstilbestrol Fowler WC Jr, Schmidt G, Edelman DA, et al: Risks of cervical intraepithelial neoplasia among DES-exposed women, Obstet Gynecol 38:720, 1981. Hoover RN, Hyer M, Pfeiffer RM, et al: Adverse health outcomes in women exposed in utero to diethylstilbestrol, N Engl J Med 365:1304, 2011. Huo D, Anderson D, Herbst AL: Follow-up of patients with clear-cell adenocarcinoma of the vagina and cervix, N Engl J Med 378:1746, 2018. National Cancer Institute: Diethylstilbestrol (DES) and Cancer. Accessed March 21, 2021. https://www.cance r.gov/about-cancer/ causes-prevention/risk/hormones/des-fact-sheet. r.gov/about-cancer/causes-prevention/risk/hormones/des-fact-sheet . Ng ABP, Reagan JW, Nadji M, et al: Natural history of vaginal adenosis in women exposed to diethylstilbestrol in utero, J Reprod Med 18:1, 1977. O’Brien PC, Noller K, Robboy SJ, et al: Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, Obstet Gynecol 53:300, 1979. Robboy SJ, Noller KL, O’Brien P, et al: Increased incidence of cervical and vaginal dysplasia in 3980 diethylstilbestrol-exposed young women, JAMA 252:2979, 1984. Stillman RJ: In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance and male and female offspring, Am J Obstet Gynecol 142:905, 1982. Titus L, Hatch EE, Drake KM, et al: Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): a report from the US National Cancer Institute DES Third Generation Study, Reprod Toxicol 84:32, 2019. Troisi R, Titus L, Hatch EE, et al: A prospective cohort study of prenatal diethylstilbestrol exposure and cardiovascular disease risk, J Clin Endocrinol Metab 103:206, 2018. Ulfelder H, Robboy SJ: The embryologic development of the human vagina, Am J Obstet Gynecol 126:769, 1976. Waggoner SE, Mittendorf R, Biney N, et al: Influence of in utero diethylstilbestrol exposure on the prognosis and biologic behavior of vaginal clear-cell adenocarcinoma, Gynecol Oncol 55:238, 1994.

Nonneoplastic Epithelial Disorders of the Vulva American College of Obstetrics and Gynecology, Practice Bulletin No. 224: Diagnosis and management of vulvar skin disorders, Obstet Gynecol 136:e1, 2020. Bornstein J, Heifetz S, Kellner Y, et al: Clobetasol dipropionate 0.05% versus testosterone propionate 2% topical application for severe vulvar lichen sclerosus, Am J Obstet Gynecol 178:80, 1998. Bracco GL, Carli P, Sonni L, et al: Clinical and histopathologic effects of topical treatment of vulval lichen sclerosus, J Reprod Med 38:37, 1993. Byrd JA, Davis MDP, Rogers RS: Recalcitrant symptomatic vulvar lichen planus, Arch Dermatol 140:715, 2004. Carli P, Cattaneo A, De Magnis A, et al: Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study, Eur J Cancer Prev 4:491, 1995. Carlson AJ, Ambros R, Malfetano J, et al: Vulvar lichen sclerosus and squamous cell carcinoma, Hum Pathol 29:932, 1998. Chi CC, Baldo M, Kirtschig G, et al: Topical interventions for genital lichen sclerosus, Cochrane Database Syst Rev (1):CD008240, 2010. Cooper SM, Gao XH, Powell JJ, et al: Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol 140:702, 2004. Cooper SM, Wojnarowka F: Influence of treatment of erosive lichen planus of the vulva on its prognosis, Arch Dermatol 142:289, 2006. Dalziel KL: Effect of lichen sclerosus on sexual function and parturition, J Reprod Med 40:35l, 1995.

Day T, Otton G, Jaaback K, et al: Is vulvovaginal lichen planus associated with squamous cell carcinoma? J Low Genit Tract Dis 22(2):159, 2018. Derrick EK, Ridley CM, Kobza-Black A, et al: A clinical study of 23 cases of female anogenital carcinoma, Br J Dermatol 143:1217, 2000. Dwyer CM, Kerr RE, Millan DW: Squamous carcinoma following lichen planus of the vulva, Clin Exp Dermatol 20:171, 1995. Franck JM, Young AW: Squamous cell carcinoma in situ arising within lichen planus of the vulva, Dermatol Surg 21:890, 1995. Harrington CI, Dunsmore JR: An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus et atrophicus, Br J Dermatol 104:563, 1981. Hart WR, Norris HJ, Helwig EB: Relation of lichen sclerosus et atrophicus of vulva to the development of carcinoma, Obstet Gynecol 45:369, 1975. Jones RW, Scurry J, Neill S, et al: Guidelines for the follow-up of women with vulvar lichen sclerosus in specialist clinics, Am J Obstet Gynecol 198:496.e1, 2008. Kennedy CM, Peterson LP, Galask RP: Erosive vulvar lichen planus: a cohort at risk for cancer? J Reprod Med 53:781, 2008. Kohn JR, Connors TM, Chan W, et al: Clinical outcomes and adherence to topical corticosteroid therapy in women with vulvar lichen sclerosus: a retrospective cohort study. J Am Acad Dermatol 83(4):1104, 2020. Leibovitz A, Kaplun V, Saposhnicov N, et al: Vulvovaginal examinations in elderly nursing home women residents, Arch Gerontol Geriatr 31: 1, 2000. Leibowitch M, Neill S, Pelisse M, Moyal-Baracco M: The epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histological and viral findings in 78 women, Br J Obstet Gynaecol 97(12):1135-1139, 1990. doi: 10.1111/j.14710528.1990.tb02502.x. PMID: 2177649. Lewis FM, Harrington CI: Squamous cell carcinoma arising in vulval lichen planus, Br J Dermatol 131:703, 1994. Lorenz B, Kaufman RH, Kutzner SK: Lichen sclerosus, therapy with clobetasol propionate, J Reprod Med 43:790, 1998. Lynch PJ, Moyal-Barrocco M, Bogliatto F, et al: 2006 ISSVD classification of vulvar dermatoses, J Reprod Med 52:3, 2007. Lynch PJ, Moyal-Barracco M, Scurry J, et al: 2011 ISSVD Terminology and classification of vulvar dermatological disorders: an approach to clinical diagnosis, J Low Genit Tract Dis 16:339, 2012. Lewis FM, Tatnall FM, Velangi SS, et al: British Association of Dermatologists guidelines for the management of lichen sclerosus, 2018, Br J Dermatol 178:839, 2018. Raspollini MR, Asirelli G, Moncini D, et al: A comparative analysis of lichen sclerosus of the vulva and lichen sclerosus that evolves to vulvar squamous cell carcinoma, Am J Obstet Gynecol 197:592.e1, 2007. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, et al: Vulvar lichen sclerosus, Arch Dermatol 140:709, 2004. Sadownik LA, Koert E, Maher C, et al: A qualitative exploration of women’s experiences of living with chronic vulvar dermatoses, J Sex Med 17:1740, 2020. Tran DA, Tan X, Macri CJ, et al: Lichen sclerosus: an autoimmunopathogenic and genomic enigma with emerging genetic and immune targets, Int J Biol Sci 15:1429, 2019. Wallace HJ: Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soc 57(1):9-30, 1971. Zaki I, Dalziel KL, Solomonsz F, et al: The under-reporting of skin disease in association with squamous cell carcinoma of the vulva, Clin Exp Dermatol 21:334, 1997.

Intraepithelial Neoplasia of the Vulva American College of Obstetricians and Gynecologists, Committee Opinion No. 675: Management of vulvar intraepithelial neoplasia, Obstet Gynecol 128:e178, 2016.

e2 Baggish MS, Dorsey HJ: CO2 laser for treatment of vulvar carcinoma in situ, Obstet Gynecol 57:371, 1981. Barbero M, Micheletti L, Preti M, et al: Biologic behavior of vulvar intraepithelial neoplasia, J Reprod Med 38:108, 1993. Benedet JL, Wilson PS, Matisic J: Epidermal thickness and skin appendage involvement in VIN, J Reprod Med 36:608, 1991. Bonvicini F, Venturoli S, Ambretti S, et al: Presence and type of oncogenic human papillomavirus in classic and in differentiated vulvar intraepithelial neoplasia and keratinizing vulvar squamous cell carcinoma, J Med Vir 77:102, 2005. Bornstein J, Bogliatto F, Haefner HK, et al: The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) terminology of vulvar squamous intraepithelial lesions, J Low Genit Tract Dis 20:11, 2016. Bowen JT: Precancerous dermatoses, J Cutan Dis 30:241, 1912. Buchanan TR, Zamorano AS, Massad LS, et al: Risk of cervical and vaginal dysplasia after surgery for vulvar intraepithelial neoplasia or cancer: a 6 year follow-up study, Gynecol Oncol 155(1):88, 2019. Centers for Disease Control and Prevention: Quadrivalent human papillomavirus vaccine, MMWR 56(RR02):1, 2007. Chafe W, Richards A, Morgan L, et al: Unrecognized invasive carcinoma in VIN, Gynecol Oncol 31:154, 1988. Chovanec J, Mouková L, Feranec R: Preinvasive lesions in gynecology – vulva, Klin Onkol 26(Suppl):S44–S46, 2013. Review. Czech. Darragh TM, Colgan TJ, Cox JT, et al: The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology, Arch Pathol Lab Med 136(10):1266–1297, 2012. de Witte CJ, van de Sande AJ, van Beekhuizen HJ, et al: Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review, Gynecol Oncol 139(2):377–384, 2015. Edey KA, Allan E, Murdoch JB, et al: Interventions for the treatment of Paget’s disease of the vulva, Cochrane Database Syst Rev (10):CD009245, 2013. doi:10.1002/14651858.CD009245.pub2. Review. doi:10.1002/14651858.CD009245.pub2. Friedrich EG Jr: Reversible vulvar atypia, Obstet Gynecol 39:173, 1972. Giuliano AR, Joura EA, Garland SM, et al: Nine-valent HPV vaccine efficacy against related diseases and definitive therapy: comparison with historic placebo population, Gynecol Oncol 154:110, 2019. Green N, Adepipe T, Dmytryshyn J, et al: Management of vulvar cancer precursors: a survey of the International Society for the Study of Vulvovaginal Disease, J Low Genit Tract Dis 24:387, 2020. Guerra R, Misra S: Management of extramammary Paget’s disease: a case report and review of the literature, Case Rep Dermatol Med 2013:436390, 2013. doi:10.1155/2013/436390. [Epub 2013 Nov 14]. doi:10.1155/2013/436390. Hampl M, Sarajuuri H, Wentzensen N, et al: Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer, Obstet Gynecol 108:1361, 2006. Higgins RV, Van Nagell JR, Donaldson ES, et al: The efficacy of laser therapy in the treatment of cervical intraepithelial neoplasia, Gynecol Oncol 36:79, 1990. Hillemanns P, Wang X, Staehle S, et al: Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN), Gynecol Oncol 100:271, 2006. Hurt CN, Jones SEF, Madden TA, et al: Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN), BJOG 125:1171, 2018. Italian Study Group in Vulvar Disease: Clinicopathologic analysis of 370 cases of vulvar intraepithelial neoplasia, J Reprod Med 41:665, 1996.

Jones SEF, Hibbitts S, Hurt CN, et al: Human papillomavirus DNA methylation predicts response to treatment using cidofovir and imiquimod in vulval intraepithelial neoplasia 3, Clin Cancer Res 23:5460, 2017. Jones RW, McLean MR: CIS of vulva: a review of 31 treated and 5 untreated cases, Obstet Gynecol 68:499, 1986. Jones RW, Park JS, McLean MR, et al: Human papilloma virus in women with VIN III, J Reprod Med 35:1124, 1990. Joura EA, Leodolter S, Hernzandez-Avila M, et al: Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, AND 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions, Lancet 369:1693, 2007. Judson PL, Habermann EB, Baxter NN, et al: Trends in the incidence of invasive and in situ vulvar carcinoma, Obstet Gynecol 107:1018, 2006. Kagie MJ, Kenter GG, Hermans J, et al: The relevance of various vulvar epithelial changes in the early detection of squamous cell carcinoma of the vulva, Int J Gynecol Cancer 7:50, 1997. Kaushik S, Pepas L, Nordin A, et al: Surgical interventions for high grade vulval intraepithelial neoplasia, Cochrane Database Syst Rev (3):CD007928, 2009. doi:10.1002/14651858. doi:10.1002/14651858. Kenter GG, Welters MJP, Vanlentijn RPM, et al: Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia, NEJM 361:1838, 2009. Kolářová D, Havránková A, Líbalová P, et al: Extramammary Paget’s disease of the vulva—a case report, Ceska Gynekol 79(5):394–398, 2014. Czech. Kushnir CL, Fleury AC, Hill MC, et al: The use of argon beam coagulation in treating vulvar intraepithelial neoplasia III: a retrospective review, Gynecol Oncol 131:386, 2013. Lawrie TA, Nordin A, Chakrabarti M, et al: Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia, Cochrane Database Syst Rev (1):CD011837, 2016. Le T, Menard C, Hicks-Boucher W, et al: Final results of a phase 2 study using continuous 5% imiquimod cream application in the primary treatment of high-grade vulva intraepithelial neoplasia, Gynecol Oncol 106:579, 2007. Luyten A, Sörgel P, Clad A, et al: Treatment of extramammary Paget disease of the vulva with imiquimod: a retrospective, multicenter study by the German Colposcopy Network, J Am Acad Dermatol 70(4):644–650, 2014. doi:10.1016/j.jaad.2013.12.008. [Epub 2014 Jan 14]. doi:10.1016/j.jaad.2013.12.008. Marchitelli C, Peremateu MS, Sluga MC, et al: Treatment of primary vulvar Paget disease with 5% imiquimod cream, J Low Genit Tract Dis 18(4):347–350, 2014. Marchitelli C, Secco G, Perrotta M, et al: Treatment of bowenoid and basaloid VIN 2/3 with imiquimod 5% cream, J Reprod Med 49: 876, 2004. Mathieson O, Buus SK, Cramers M: Topical imiquimod can reverse vulvar intraepithelial neoplasia, Gynecol Oncol 107:219, 2007. McNally OM, Mulvany NJ, Pagano R, et al: VIN 3: a clinicopathologic review, Int J Gynecol Can 12:490, 2002. Miller BE: VIN treated with cavitational ultrasonic surgical aspiration, Gynecol Oncol 85:114, 2002. Modesitt SC, Waters AB, Walton L, et al: Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence, Obstet Gynecol 92:962, 1998. Park IU, Ogilvie JW Jr, Anderson KE, et al: Anal human papillomavirus infection and abnormal anal cytology in women with genital neoplasia, Gynecol Oncol 114:399, 2009. Reid R: Superficial laser vulvectomy, Am J Obstet Gynecol 152:504, 1985.

e3 Rodolakis A, Diakomanolis E, Vlachos G, et al: VIN-diagnostic and therapeutic challenges, Eur J Gynaecol Oncol 24:317, 2003. Roma AA, Hart WR: Progression of simplex (differentiated) vulvar intraepithelial neoplasia to invasive squamous cell carcinoma, Int J Gynecol Pathol 26:248, 2007. Rutledge F, Sinclair M: Treatment of intraepithelial carcinoma of the vulva by skin excision and graft, Am J Obstet Gynecol 102:806, 1968. Sanjose S, Aleman L, Ordi J, et al: Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva, Eur J Cancer 45:3450, 2013. Srodon M, Stoler MH, Baber GB, et al: The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VAIN), Am J Surg Pathol 30:1513, 2006. Sykes P, Smith N, McCormick P, et al: High grade VIN. A retrospective analysis of patient characteristics, management, outcome, and relationship to squamous cell carcinoma of the vulva 1989–1999, Aust N Z J Obstet Gynaecol 42:69, 2002. Smith JS, Backes DM, Hoots BE, et al: Human papillomavirus typedistribution in vulvar and vaginal cancers and their associated precursors, Obstet Gynecol 113:917, 2009. Thuijs NB, van Beurden M, Bruggink AH, et al: Vulvar intraepithelial neoplasia: incidence and long-term risk of vulvar squamous cell carcinoma, Int J Cancer 148:90, 2021. Todd RW, Etherington IJ, Lineseley DM: The effects of 5% imiquimod cream on high grade VIN, Gynecol Oncol 85:67, 2002. Tosti G, Iacobone AD, Preti EP, et al: The role of photodynamic therapy in the treatment of vulvar intraepithelial neoplasia, Biomedicines 6:13, 2018. Townsend DE, Levine RU, Richart RM, et al: Management of vulvar intraepithelial neoplasia by carbon dioxide laser, Obstet Gynecol 60:49, 1982. Tristram A, Fiander A: Clinical responses to cidofovir applied topically to women with high grade vulval intraepithelial neoplasia, Gynecol Oncol 99:652, 2005. Tristram A, Hurt CN, Madden T, et al: Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia, Lancet Oncol 15:1361, 2014. van de Nieuwenhof HP, Bulten J, Hollema H, et al: Differential vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma, Mod Pathol 24:297, 2011. van der Linden M, Meeuwis KA, Bulten J, et al: Paget disease of the vulva, Crit Rev Oncol Hematol 101:60–74, 2016. Van Seters M, van Beurden M, deCraen AJM: Is the assumed natural history of VIN IV based on enough evidence? A systematic review of 3322 published patients, Gynecol Oncol 97:645, 2005. Van Seters M, van Beurden M, ten Kate FJ, et al: Treatment of vulvar intraepithelial neoplasia with topical imiquimod, N Engl J Med 358:1465, 2008. von Gruenigen VE, Gibbons HE, Gibbins K, et al: Surgical treatments for vulvar and vaginal dysplasia, Obstet Gynecol 109:942, 2007. Wallibilich JJ, Rhodes HE, Milbourne AM, et al: Vulvar intraepithelial neoplasia (VIN 2/3): comparing clinical outcomes and evaluating risk factors for recurrence, Gynecol Oncol 127:312, 2012.

Intraepithelial Neoplasia of the Vagina Benedet JL, Wilson PS, Matisic JP: Epidermal thickness measurements in VAIN, J Reprod Med 37:809, 1992. Bertoli HK, Baandrup L, Aalborg GL, et al: Time trends in the incidence and survival of vaginal squamous cell carcinoma and highgrade vaginal intraepithelial neoplasia in Denmark—a nationwide population-based study, Gynecol Oncol 158:734, 2020. Caglar H, Hurtzog RW, Hreshchyshyn MM: Topical 5-FU treatment of vaginal intraepithelial neoplasia, Obstet Gynecol 58:580, 1981.

Carter ER, Salvaggio AT, Jarkowski TL: Squamous cell carcinoma of the vagina following vaginal hysterectomy of intraepithelial carcinoma of the cervix, Am J Obstet Gynecol 82:401, 1961. Chai YK, Cheung SYC, Chan KKL: Outcome of vaginal stripping for vaginal intraepithelial neoplasia: a 20-year observational study, J Obstet Gynaecol Res 46:2511–2517, 2020. Daling JR, Madeleine MM, Schwartz SM, et al: A population-based study of squamous cell vaginal cancer, Gynecol Oncol 84:263, 2002. Diakomanolis E, Haidopoulos D, Stefanidis K: Treatment of high grade VAIN with imiquimod cream, N Engl J Med 347:374, 2002. Dodge JA, Eltabbakh GH, Mount SL, et al: Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia, Gynecol Oncol 83:363, 2001. Dungar CF, Wilkinson EJ: Vaginal columnar cell metaplasia: an acquired adenosis associated with topical 5-FU therapy, J Reprod Med 40:361, 1995. Ferguson JH, Maclure JG: Intraepithelial carcinoma, dysplasia, and exfoliation of cancer cells in the vaginal mucosa, Am J Obstet Gynecol 87:326, 1963. Fiascone S, Vitonis AF, Feldman S: Topical 5-fluorouracil for women with high-grade vaginal intraepithelial neoplasia, Obstet Gynecol 130:1237, 2017. Graham JB, Meigs JV: Recurrence of tumor after total hysterectomy for carcinoma in situ, Am J Obstet Gynecol 64:1159, 1952. Graham K, Wright K, Cadwallader B, et al: 20-year retrospective review of medium dose rate intracavitary brachytherapy in VAIN 3, Gynecol Oncol 106:105, 2007. Gusberg SB, Marshall D: Intraepithelial carcinoma of the cervix: a clinical reappraisal, Obstet Gynecol 19:713, 1962. Hampl M, Sarajuuri H, Wentzensen N, et al: Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer, Obstet Gynecol 108:1361, 2006. Henson D, Tarone R: An epidemiologic study of cancer of the cervix, vagina, and vulva based on the Third National Cancer Survey in the United States, Am J Obstet Gynecol 129:525, 1977. Inayama Y, Yamanishi Y, Nakatani E, et al: Imiquimod for vaginal intraepithelial neoplasia 2–3: a systematic review and meta-analysis, Gynecol Oncol 160:140, 2021. Indermaur MD, Martino MA, Fiorica JV, et al: Upper vaginectomy for the treatment of vaginal intraepithelial neoplasia, Am J Obstet Gynecol 193:577, 2005. Insinga RP, Liaw KL, Johnson LG, et al: A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States, Cancer Epidemiol Biomarkers Prev 17:1611, 2008. Joura EA, Leodolter S, Hernzandez-Avila M, et al: Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions, Lancet 369:1693, 2007. Koss LG, Melamed MR, Daniel WW: In situ epidermoid carcinoma of the cervix and vagina following radiotherapy for cervical cancer, Cancer 14:353, 1961. Krebs HB: Treatment of vaginal intraepithelial neoplasia with laser and topical 5FU, Obstet Gynecol 73:657, 1989. Matsuo K, Chi DS, Walker LD, et al: Ultrasonic surgical aspiration for vaginal intraepithelial neoplasia, Int J Gynaecol Obstet 105:71, 2009. Munoz N, Kjaer SK, Sigurdsson K, et al: Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women, J Natl Cancer Inst 102:325, 2010. Noller KL: Screening for vaginal cancer (Editorial), N Engl J Med 335: 1599, 1996.

e4 Parker RT: Clinical problems of early cervical neoplasia, Obstet Gynecol Surv 24:684, 1969. Pearce KF, Haefner HK, Sarwar SF, et al: Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease, N Engl J Med 335:1559, 1996. Perkins R, Guido R, Castle P, et al: 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors, J Low Genit Tract Dis 24:102, 2020. Petrilli ES, Townsend DE, Morrow CP, et al: Vaginal intraepithelial neoplasias: biologic aspects and treatment with topical 5-fluorouracil and the carbon dioxide laser, Am J Obstet Gynecol 138:321, 1980. Robinson JB, Sun CC, Bodurka-Bevers D, et al: Cavitational ultrasonic surgical aspiration for the treatment of vaginal intraepithelial neoplasia, Gynecol Oncol 78:235, 2000. Schockaert S, Poppe W, Arbyn M, et al: Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia, Am J Obstet Gynecol 199:113.e1, 2008. Sherman JF, Mount SL, Evans MF, et al: Smoking increases the risk of high-grade vaginal intraepithelial neoplasia in women with oncogenic human papillomavirus, Gynecol Oncol 110:396, 2008.

Sillman FH, Fruchter RG, Chen YS, et al: Vaginal intraepithelial neoplasia: risk factors for persistence, recurrence, and invasion and its management, Am J Obstet Gynecol 176:93, 1997. Smith JS, Backes DM, Hoots BE, et al: Human papillomavirus typedistribution in vulvar and vaginal cancers and their associated precursors, Obstet Gynecol 113:917, 2009. Sopracordevole F, Clemente N, Di Giuseppe J, et al: Clinical characteristics and long-term follow-up of patients treated for highgrade vaginal intraepithelial neoplasia: results from a 20-year survey in Italy, J Low Genit Tract Dis 24:381, 2020. Srodon M, Stoler MH, Baber GB, et al: The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VAIN), Am J Surg Pathol 30:1513, 2006. Stokes-Lampard H, Wilson S, Waddell C, et al: Vaginal vault smears after hysterectomy for reasons other than malignancy, BJOG 113:1354, 2006. Townsend DE, Levine RU, Crum CP, et al: Treatment of vaginal carcinoma in situ with carbon dioxide laser, Am J Obstet Gynecol 143:565, 1982. Vinokurova S, Wentzensen N, Einenkel J, et al: Clonal history of papillomavirus-induced dysplasia in the female lower genital tract, J Natl Cancer Inst 97:1816, 2005.

3 Invasive Cervical Cancer Krishnansu Sujata Tewari, MD, Bradley J. Monk, MD

OUTLINE General Observations, 40 Clinical Profile of Invasive Cancer, 42 Glandular Tumors of the Cervix, 47 Staging, 48 Treatment of Early-Stage Disease, 53 Superficial Carcinoma of the Cervix, 54 Adenocarcinoma, 58 Treatment of Locally Advanced Disease, 73

Neuroendocrine and Other Uncommon Tumors of the Cervix, 84 Glassy Cell Carcinoma, Carcinosarcoma, Lymphoma, and Melanoma, 85 Survival Results and Prognostic Factors for Early-Stage and Locally Advanced Disease, 86 Recurrent and Advanced Carcinoma of the Cervix, 87

KEY POINTS 1. Conservative management of early-stage cervical cancer in young women should be considered if childbearing is important to that patient. 2. In many developing countries, cervical cancer is the leading cause of cancer death in young women. 3. Adenocarcinoma of the cervix is increasing in frequency.

4. Positron emission tomography is a very sensitive method for detecting the extent of cervical cancer. 5. Adjuvant chemotherapy using cisplatin and concomitant radiation therapy is the standard of care for locally advanced cervical cancer.

GENERAL OBSERVATIONS

connective tissue with stratified muscle fibers and elastic tissue. The elastic tissue is found primarily around the walls of the larger blood vessels. The stratified squamous epithelium of the portio vaginalis is composed of several layers that are conventionally described as basal, parabasal, intermediate, and superficial. The basal layer consists of a single row of cells and rests on a thin basement membrane. This is the layer in which active mitosis occurs. The parabasal and intermediate layers together constitute the prickle-cell layer, which is analogous to the same layer in the epidermis. The superficial layer varies in thickness, depending on the degree of estrogen stimulation. It consists primarily of flattened cells that show an increasing degree of cytoplasmic acidophilia toward the surface. The thickness and the glycogen content of the epithelium increase after estrogen stimulation and account for the therapeutic effect of estrogens in atrophic vaginitis. The staining of glycogen in the normal epithelium of the portio vaginalis is the basis of the Schiller test.

Anatomy The cervix (Latin for “neck”) is a narrow, cylindrical segment of the uterus; it enters the vagina through the anterior vaginal wall and lies, in most cases, at a right angle to it. In the average patient, the cervix measures 2 to 4 cm in length and is contiguous with the inferior aspect of the uterine corpus. The point of juncture of the uterus and the cervix is known as the isthmus; this area is marked by slight constriction of the lumen. Anteriorly, the cervix is separated from the bladder by fatty tissue and is connected laterally to the broad ligament and parametrium (through which it obtains its blood supply). The lower intravaginal portion of the cervix, a free segment that projects into the vault of the vagina, is covered with mucous membrane. The cervix opens into the vaginal cavity through the external os. The cervical canal extends from the anatomic external os to the internal os, where it joins the uterine cavity. The histologic internal os is where there is a transition from endocervical to endometrial glands. The intravaginal portion of the cervix (portio vaginalis, exocervix) is covered with stratified squamous epithelium that is essentially identical to the epithelium of the vagina. The endocervical mucosa is arranged in branching folds (plicae palmatae) and is lined by cylindrical, columnar epithelium. The stroma of the cervix consists of 40

Epidemiologic Studies Clinical Profile In the United States, the mortality from cervical cancer in 1945 was 15 of 100,000 women. This had declined to approximately 4.6 of 100,000 by 1986 and 3.4 of 100,000 by 1991. It is unclear

CHAPTER 3

TABLE 3.1 Proposed Schedule for Interval

Evaluation of Cervical Cancer after Radiotherapy or Surgery (Asymptomatic Patienta) Year

Frequency

Examination

3 months

Pelvic examination, Pap smear

6 months

Chest radiography, CBC, BUN, creatinine

1 year

IVP or CT scan with contrast

4 months

Pelvic examination, Pap smear

1 year

Chest radiography, CBC, BUN, creatinine, IVP or CT scan with contrast

6 months

Pelvic examination, Pap smear

3 to 5

Symptomatic patients should have appropriate examination where indicated. BUN, Blood urea nitrogen; CBC, complete blood count; CT, computed tomography; IVP, intravenous pyelogram; Pap, Papanicolaou. a

whether the mortality rate from cervical cancer is falling as a result of cervical cytologic screening and intervention at the in situ stage or whether cervical screening has caused an increase in the proportion of early-stage cancer at diagnosis and registration. After therapy for invasive disease, adequate follow-up is the key to early detection of a recurrence (Table 3.1). The yield of examinations such as intravenous pyelography (IVP), computed tomography (CT) scan, and chest radiograph in patients with initial early disease (stages I to IIa) is so low that many have discontinued their routine use. West studied the age of registration and the age of death of women with cervical cancer in South Wales. He found that the observed age at death was very close to 59 years regardless of stage and age at diagnosis. Although the 5-year survival rate of women with localized (early-stage) cervical cancer was much

Invasive Cervical Cancer

higher than that of women with nonlocalized (late-stage) cancer, the women with localized cancer tended to be younger than those with advanced cancer. Calculations of expected age at death of the whole population suggest that more than half the advantage in survival rate shown by women with early-stage cancers is a result of the diagnosis of the former in younger women. Christopherson and colleagues reported that the percentage of patients diagnosed as having stage I disease increased by 78% in the population studied from 1953 to 1965. The increase was most remarkable in younger women. The authors concluded that the major problem in cervical cancer control was the screening of older women. Older women had higher incidence rates; the percentage with stage I disease also decreased with each decade, reaching a low of 15% for those 70 years of age and older. These older women with cervical cancer are rarely screened and contribute heavily to the death rate. The initial advanced stage contributes to the patient population with advanced recurrent cervical cancer. These patients, therefore, deserve very close posttreatment observation in an effort to detect a recurrence in its earliest possible form. In 2022, there will be approximately 14,100 new cases of invasive cervical cancer and 4280 deaths from this disease in the United States. In fact, for the past decade, the annual incidence and mortality rates due to cervical cancer have been approximately 12,000 and 4000, respectively. It is particularly distressing that more than one-third of women diagnosed will die from a disease that is largely preventable by vaccination and screening. There is no other human malignancy for which we have identified the causative agent, have successfully implemented excellent screening programs, and now have efficacious and tolerable prophylactic vaccination available (Fig. 3.1). Oncogenic subtypes of the human papillomavirus (HPV) have been identified as the etiologic cause of cervical

Figure 3.1 Human papillomavirus prophylactic vaccine. (From www.cancer.gov.)

CHAPTER 3

Invasive Cervical Cancer Disruption of cell growth cycle p53 Telomerase

Regulation of virus gene expression and virus replication

pRb E6

URR

ori 7904/1 L1 7000 Capsid proteins

6000

1000

HPV-16

5000

E1 2000

3000 4000

DNA replication

E4 E2

E5 Membrane signaling protein

Assembly and release

Gene expression

Figure 3.2 Human papillomavirus genome. (From microbiologybytes.com.)

neoplasia (Fig. 3.2). The power, consistency, and specificity of the association between subclinical HPV infection and cervical neoplasia raise the strong possibility that this relationship is causal. The biologic plausibility of this is supported by evidence that this sexually transmitted oncogenic virus often produces persistent asymptomatic infection of metaplastic epithelium in the cervical transformation zone. Epidemiologic surveillance studies performed in the United States during the past 2 decades have documented decreased incidence rates for invasive cervical cancer. Ethnic and racial disparities, however, still exist. In a Surveillance, Epidemiology and End Results (SEER) analysis of 13 US cancer registries containing cases from 1992 to 2003, Hispanic whites had the highest incidence rate of cervical cancer overall (24 per 100,000), squamous cell carcinoma (SCC) (18 per 100,000), and adenocarcinoma (5 per 10,000). Non-Hispanic whites had the lowest rates of cervical cancer overall (11 per 100,000) and SCC (7 per 100,000), and African Americans had the lowest rate of adenocarcinoma (2 per 100,000). In a recent study using data obtained from the Cancer in North America (CINA) deluxe 1995 to 2004 database created by the North American Association of Central Cancer Registries (NAACCR), African American and Hispanic US populations continue to have the highest rates of invasive cervical cancer compared with non-Hispanic whites. Variations in screening utilization and socioeconomic status are thought to account for the majority of the racial/ethnic disparities.

In November 2014, the nine-valent HPV9 (providing protection against HPV-6, -11, -16, -18, -31, -33, -45, -52, and -58) was approved by the US Food and Drug Administration (FDA) for the same indications as HPV-4 (i.e., GARDASIL). The current HPV Vaccination Guidelines issued by the Centers for Disease Control recommend a 2-dose schedule for 9- to 14-year-olds, with the second dose given 6 to 12 months after the first dose. The standard 3-dose schedule is recommended for individuals who receive the first dose on or after their 15th birthday.

CLINICAL PROFILE OF INVASIVE CANCER A substantial and well-publicized screening program is needed to make the public and the profession more aware of cervical cancer as the possible cause of even minimal gynecologic symptoms. All public education should emphasize the prevention and cure of cancer, and a more optimistic attitude would help motivate patients and physicians to seek appropriate action. The need for early diagnosis rests on the incontrovertible fact that definite cure, in actuarial terms, is readily achieved when cervical cancer is minimal—but almost impossible if the tumor is given time to grow and spread to the pelvic wall or into adjacent structures such as the bladder and rectum. The gradient of percentage curability from early invasive cancer to late, grossly invasive disease is such a steep one that even a moderate reduction in tumor

CHAPTER 3

Figure 3.3 Multinucleated “tadpole” cell–early invasive squamous cell carcinoma.

size could not fail to create a substantial improvement in curability. It is true, of course, as with other cancers, that some carcinomas of the cervix grow more rapidly than others. The basis for this difference in growth rate is still beyond our knowledge, but it is not beyond our capability to prevent unnecessary growing time. Even the relatively slow-growing malignancy, if given enough time, will become incurable, and the most rapidgrowing tumor, if diagnosed while of still moderate dimension, is definitely curable. The earlier that most tumors are detected and treated, the better will be the chance of cure. A Pap smear from a patient with early invasive SCC illustrates a typical multinucleated “tadpole” cell (Fig. 3.3). Cytology and colposcopy are valuable tools in the eradication of cervical cancer. Every opportunity should be taken to disseminate modern concepts of cancer control to schools of nursing and other paramedical organizations because there is still a need for a more coordinated effort in these fields. The burden should not be left with physicians alone. The frequency with which invasive cervical cancer

Invasive incidence Mortality In situ incidence

5 3 1945

1950

1955

1960

occurs in the United States is unknown, but the best incidence data indicate a rate of approximately 8 to 10 per 100,000/year (Fig. 3.4). The incidence and mortality rates in the United States have been slowly declining (Fig. 3.5). The occurrence of cervical cancer is apparently less frequent in Norway and Sweden than in the United States. However, in the underdeveloped areas of the world, the frequency of cervical cancer is more noteworthy, relative to the overall cancer problem, especially compared with that in the United States (Table 3.2) and Western Europe. In many South American, Asian, and African countries, cervical cancer accounts for the largest percentage of cancer deaths in women. One wonders whether nutritional deficiencies in these underdeveloped nations play a role in the etiology of cervical cancer. Orr and colleagues reported that abnormal vitamin levels were more commonly present in patients with cervical cancer. When compared with control values, levels of plasma folate, beta-carotene, and vitamin C were significantly lower in patients with cervical cancer. The World Health Organization has approved visual inspection with acetic acid with immediate cryotherapy triage for cervical cancer screening in India and many sub-Saharan African nations. Personal cigarette smoking and exposure to passive smoke as risk factors for cervical carcinoma have been examined in casecontrol studies. Personal cigarette smoking increases the risk of cervical cancer after adjustment for age, educational level, church attendance, and sexual activity. The adjusted risk estimate associated with being a current smoker was 3.42; for having smoked for 5 or more pack-years, it was 2.81; and for having smoked at least 100 lifetime cigarettes, it was 2.21. The adjusted risk estimate associated with passive smoke exposure for 3 hours or more per day was 2.96. This study, reported by Slattery and colleagues in 1989, has been reinforced by others, confirming a strong association of smoking and increased risk of SCC of the cervix. Some studies suggest that cancer of the cervix is more frequent among oral contraceptive users; however, these studies may be influenced by confounding factors such as early onset of sexual

Incidence of preinvasive and invasive cervical lesions

Rate per 100,000 women

Invasive Cervical Cancer

1965

1970

1975

1980

1985

1990

Year Figure 3.4 American Cancer Society data for 1991. Cervical cancer incidence and mortality.

CHAPTER 3

Invasive Cervical Cancer 14,000 12,000 10,000 8,000 6,000 4,000 2,000 0 New cases Deaths

2003 12,200 4,100

2004 10,520 3,900

2005 10,370 3,710

2006 9,170 3,700

Figure 3.5 Cervical cancer in the United States: 2003 to 2006. (From Jermal A, Siegel R, Ward E, et al: Cancer statistics, 2006, CA Cancer J Clin 56:106–130, 2006.)

TABLE 3.3 Stage Ia1

TABLE 3.2 Stage 1a Cancer of the Cervix Stage

Description

Cancer invasion identified only microscopically. All gross lesions, even with superficial invasion, are stage Ib cancers. Measured stromal invasion with maximum depth of 5 mm and no wider than 7 mm

IaI

Measured invasion of stroma up to 3 mm

Ia2

Measured invasion of stroma of 3–5 mm and no wider than 7 mm

activity after puberty, multiple sexual partners, and previous history of sexually transmitted diseases. Ursin and colleagues reported a twofold greater risk of adenocarcinoma of the cervix, especially among those who used oral contraceptives for 12 years or more. Because of the cervix’s sensitivity to hormonal influences, it may be considered biologically plausible that oral contraceptives could induce or promote cervical carcinoma. Piver reviewed a large number of early investigations of this issue and failed to show a consistent association. Moreover, these data are based on exposure to oral contraceptive preparations that contained high doses of estrogen and progestin and are no longer available. In most large series, approximately 75% to 80% of malignant lesions of the cervix are squamous cell, but other lesions are possible (Table 3.3). Most information regarding etiology and epidemiology is pertinent only to the more common squamous cell lesions. The greatest risk for cervical cancer is not ever having a Pap test or obtaining one infrequently. Low socioeconomic status often tracks with never/sporadic screening and therefore, is also considered an important risk factor. Others include a history of cervical intraepithelial neoplasia or carcinoma in situ, a history of abnormal Papanicolaou testing, history of sexually transmitted

LVSI

Positive Nodes/PLN

Recurrence

Rob et al.

3/3

Pluta et al.

3/3

0/3

0/3 10/387

Elliott et al.

47/387

1 /121

Lee et al.

7/174

3c/116

2/174

Takeshima et al.

5/297

1b/82

0/297

Yoneda et al.

10/10

0/10

—

Bisseling et al.

3/515

3 /261

6/515

Nam et al.

5/149

0/100

1/149

Reade et al.

9/282

2/209

3/336

—

99/1994 (4.9%)

13/1033 (0.13%)

24/2035 (0.1%)

12% Glandular tumors. Adenocarcinoma, LVSI negative; c 2/3 LVSI negative. LVSI, Lymph vascular invasion; PLN, pelvic lymph node. Modified from Buchanan. Overtreating stage Ia cervical carcinoma. Am J Obstet Gynecol 2017. a

diseases and anogenital warts, immunosuppression by virtue of HIV infection/AIDS or organ transplantation, tobacco use, early sexual debut, multiple sexual partners/promiscuous partner(s), and finally a history of in utero diethylstilbesteros exposure. Everywhere in the world where the incidence of cervical cancer and its death rates have decreased, an active screening program is present. The older patients have a higher incidence of cervical cancer, at least in the United States, and these women have the most infrequent Pap smear screening.

Symptoms A typical patient with clinically obvious cervical cancer is a multiparous woman between 45 and 55 years who married and

CHAPTER 3

delivered her first child at an early age, usually before 20 years of age. Probably the first symptom of early cancer of the cervix is a thin, watery, blood-tinged vaginal discharge that frequently goes unrecognized by the patient. The classic symptom is intermittent, painless metrorrhagia or spotting only postcoitally or after douching, although this is not the most common symptom. As the malignancy enlarges, the bleeding episodes become heavier and more frequent, and they last longer. The patient may also describe what seems to her to be an increase in the amount and duration of her regular menstrual flow; ultimately, the bleeding becomes continuous. In postmenopausal women, the bleeding is more likely to prompt early medical attention. Late symptoms or indicators of more advanced disease include the development of pain referred to the flank or leg, which is usually secondary to the involvement of the ureters, pelvic wall, or sciatic nerve routes. Many patients complain of dysuria, hematuria, rectal bleeding, or obstipation resulting from bladder or rectal invasion. Distant metastasis and persistent edema of one or both lower extremities as a result of lymphatic and venous blockage by extensive pelvic wall disease are late manifestations of primary disease and frequent manifestations of recurrent disease. Massive hemorrhage and development of uremia with profound inanition may also occur and occasionally be the initial presenting symptom.

Gross Appearance The gross clinical appearance of carcinoma of the cervix varies considerably and depends on the regional mode of involvement and the nature of the particular lesion’s growth pattern. Three categories of gross lesions have traditionally been described. The most common is the exophytic lesion, which usually arises on the ectocervix and often grows to form a large, friable, polypoid mass that can bleed profusely. These exophytic lesions sometimes arise within the endocervical canal and distend the cervix and the endocervical canal, creating the so-called barrelshaped lesion. A second type of cervical carcinoma is created by an infiltrating tumor that tends to show little visible ulceration or exophytic mass but is initially seen as a stone-hard cervix that regresses slowly with radiation therapy. A third category of lesion is the ulcerative tumor (Fig. 3.6), which usually erodes a portion of the cervix, often replacing the cervix and a portion of the upper vaginal vault with a large crater associated with local infection and seropurulent discharge.

Routes of Spread The main routes of spread of carcinoma of the cervix are as follows: 1. Into the vaginal mucosa, extending microscopically down beyond visible or palpable disease 2. Into the myometrium of the lower uterine segment and corpus, particularly with lesions originating in the endocervix 3. Into the paracervical lymphatics and from there to the most commonly involved lymph nodes (i.e., the obturator, hypogastric, and external iliac nodes) 4. Direct extension into adjacent structures or parametria, which may reach to the obturator fascia and the wall of the true pelvis. Extension of the disease to involve the bladder or

Invasive Cervical Cancer

Figure 3.6 Ulcerative squamous cell carcinoma of the cervix.

rectum can result, with or without the occurrence of a vesicovaginal or rectovaginal fistula. The prevalence of lymph node disease correlated well with the stage of the malignancy in several anatomic studies. Lymph node involvement in stage I is between 15% and 20%; in stage II, it is between 25% and 40%; and in stage III, it is assumed that at least 50% have positive nodes. Variations are sometimes seen with different material. The best study of lymph node involvement in cervical cancer was done by Henriksen (Fig. 3.7). The nodal groups described by Henriksen follow.

Primary Group 1. The parametrial nodes, which are the small lymph nodes traversing the parametria 2. The paracervical or ureteral nodes, located above the uterine artery where it crosses the ureter 3. The obturator or hypogastric nodes surrounding the obturator vessels and nerves 4. The hypogastric nodes, which course along the hypogastric vein near its junction with the external iliac vein 5. The external iliac nodes, which are a group of six to eight nodes that tend to be uniformly larger than the nodes of the other iliac groups 6. The sacral nodes, which were originally included in the secondary group Secondary Group 1. The common iliac nodes 2. The inguinal nodes, which consist of the deep and superficial femoral lymph nodes 3. The periaortic nodes In his autopsy studies, Henriksen plotted the percentage of nodal involvement for treated and untreated patients (Figs. 3.8 and 3.9). Distribution is, as one would expect, with a greater

CHAPTER 3

Invasive Cervical Cancer

Common iliac Sacral Direct extension

Hypogastric External iliac

Ureteral Obturator Paracervical

Inguinal

Figure 3.7 Lymph node chains draining the cervix. (From Henriksen E: The lymphatic spread of carcinoma of the cervix and of the body of the uterus; a study of 420 necropsies, Am J Obstet Gynecol 58:924–942, 1949.)

Distant metastases: 53% Aortic: 33%

Sacral: 27%

Distant metastases: 27% Aortic: 27%

Common iliac: 47%

Common iliac: 31% Sacral: 23%

Hypogastric: 60% Paracervical: 47% Obturator: 47%

Hypogastric: 31% Paracervical: 31%

External iliac: 67% Parametrium: 33% Inguinal: 7%

Figure 3.8 Percentage involvement of draining lymph nodes in treated patients with cervical cancer. (From Henriksen E: The lymphatic spread of carcinoma of the cervix and of the body of the uterus; a study of 420 necropsies, Am J Obstet Gynecol 58:924–942, 1949.)

Obturator: 27%

External iliac: 27% Parametrium: 77% Inguinal: 8%

Figure 3.9 Percentage involvement of draining lymph nodes in untreated patients with cervical cancer. (From Henriksen E: The lymphatic spread of carcinoma of the cervix and of the body of the uterus; a study of 420 necropsies, Am J Obstet Gynecol 58:924–942, 1949.)

CHAPTER 3

number of involved nodes found in the region of the cervix than in distant metastases. Although the series was an autopsy study, Henriksen found that only 27% had metastasis above the aortic chain. Cervical cancer kills by local extension, with ureteral obstruction in a high percentage of patients. In 1980, the Gynecologic Oncology Group (GOG) reported the results of a series of 545 patients with cancer of the cervix who were surgically staged within their institutions. This study was prompted because traditional ports of radiation therapy were destined to treatment failure when the disease extended to the periaortic nodes (Fig. 3.10). They found periaortic node involvement in 18.2% of patients with stage IIa disease and up to 33.3% in patients with stage IVa disease. Piver correlated the size of the cervical lesion with the incidence of lymph node metastasis (LNM) in stage I disease (Table 3.4). When clinical staging was compared with surgical staging, inaccuracies were found of the magnitude of a 22.9% misstaged occurrence in stage IIb disease and a 64.4% misstaged occurrence in stage IIIb disease. These data raise the question of whether knowing that disease has spread to the periaortic area enables the clinician to institute therapeutic modalities that can result in increased salvage. In other words, does the treatment of patients with spread of disease beyond the pelvis result in more cures? Berman and colleagues, reporting the GOG experience with staging laparotomy, indicated that 20% of 436 patients (stages IIb to IVa) were found to have metastatic disease to periaortic nodes. He also reported that 25% of these patients, or 5% of those surgically staged, demonstrated a 3-year, disease-free survival. Most of the patients with known periaortic node involvement received extended postoperative field irradiation. Cumulative results from many studies utilizing lymphadenectomy in the surgical staging of cervix cancer have shown increased frequency of positive pelvic nodes, as shown in Table 3.5.

GLANDULAR TUMORS OF THE CERVIX Approximately 75% to 80% of cervical cancers are SCCs, and most of the remaining cases are adenocarcinomas. There appears to be an increase in the frequency of cervical adenocarcinomas,

Figure 3.10 A computed tomography scan of the abdomen illustrating very enlarged periaortic nodes that have eroded a portion of the vertebral bone on the right.

Invasive Cervical Cancer

TABLE 3.4 Stage Ia2 LVSI

Positive Nodes/PLN

Recurrence

Rob et al.

4/10

0/10

Raju et al.

0/7

Smrkolj et al.

12.89

0/46

1/89

Lee et al.

4/28

1/27

0/28

Elliott et al.

47/89

2/59

2/89

Takeshima et al.

7/33

1/29

1/33

Rogers and Luesley

—

1/156

6/205

Yoneda et al.

5/40

2/40

0/40

Bisseling et al.

7/506

2/261

5/506

Reade et al.

15/99

0/90

1/117

Creasman et al.

12/51

0/51

Pluta et al.

4/11

1/11

0/11

—

117/963 (12.1%)

10/787 (1.3%)

16/1186 (0.13%)

LVSI, Lymph vascular invasion; PLN, pelvic lymph node. Modified from Buchanan. Overtreating stage Ia cervical carcinoma. Am J Obstet Gynecol, 2017.

TABLE 3.5 Percentage Increase of Pelvic and Periaortic Node Metastasis by Clinical Stage Clinical Stage

Positive Pelvic Nodes

Positive Periaortic Nodes

15.4

6.3

28.6

16.5

III

47.0

8.6

but this may be a result of the decrease in the incidence of invasive squamous cell lesions. With respect to histopathology, a SEER population study conducted on cases registered from 1973 to 2002 noted increasing numbers of adenocarcinomas despite a general decline, suggesting the inefficiency of conventional screening for these tumors. Adenocarcinoma arises from the endocervical mucous-producing gland cells, and because of its origin within the cervix, it may be present for a considerable time before it becomes clinically evident. These lesions are characteristically bulky neoplasms that expand the cervical canal and create the so-called barrel-shaped lesions of the cervix. The spread pattern of these lesions is similar to that of SCC, with direct extension accompanied by metastases to regional pelvic nodes as the primary routes of dissemination. Local recurrence is more common in these lesions, and this has resulted in the commonly held belief that they are more radioresistant than are their squamous counterpart. It seems more likely, however, that the bulky, expansive nature of these endocervical lesions, rather than a differential in radiosensitivity, accounts for the local recurrence. Two controversial issues continue with regard to management of adenocarcinoma of the cervix. First, does this cell type carry a worse prognosis than squamous or adenosquamous cell types?

CHAPTER 3

Invasive Cervical Cancer

Second, for early-stage disease, which therapy (radical surgery, radiation, or combined treatment) is superior? Most studies suggest no difference in survival when adenocarcinomas are compared with SCCs after correction for stage. The 1998 Federation for International Gynecologists and Obstetricians (FIGO) Annual Report, which reported more than 10,000 SCCs and 1138 adenocarcinomas using multivariant analysis, noted no difference in survival in stage I cancers. In a study by Chen and associates of 302 adenocarcinomas, it was noted that in early stages, multivariant analysis noted better survival in patients treated with radical surgery compared with those treated with radiation therapy. Kjorstad and Bond investigated the metastatic potential and patterns of dissemination in 150 patients with stage Ib adenocarcinoma of the cervix treated from 1956 to 1977. All patients were treated with a combination of intracavitary radium followed by radical hysterectomy (RH) with pelvic lymph node dissection. The incidence of pelvic metastases and distant recurrences and the survival rates were the same as those given in previously published reports for SCC treated in the same manner. In one respect, the adenocarcinomas showed a significant difference from the squamous cell cancers. The incidence of residual tumor in the hysterectomy specimens after intracavitary treatment was much higher (30% vs. 11%). Kjorstad and Bond considered this a strong argument for surgical treatment of patients with early stages of adenocarcinoma of the cervix. Moberg and colleagues reported on 251 patients at Radiumhemmet in Stockholm with adenocarcinoma of the uterine cervix. The 5-year survival rate was compared with that in the total of cervical epithelial malignancies, and the rate was lower in the adenocarcinoma cases, with respective crude 5-year survival rates of 84%, 50%, and 9% in stages I, II, and III, respectively. Combined treatment consisting of two intracavitary radium treatments with an interval of 3 weeks followed by a RH with pelvic lymphadenectomy (PL) done within 3 months gave improved 5-year survival in a nonrandomized series. Prempree and colleagues also suggested combined therapy for stage II lesions or for those larger than 4 cm. A large series of 367 cases of adenocarcinoma of the cervix was reported by Eifel and associates. Their conclusions were that the central control of adenocarcinomas with radiation therapy is comparable to that achieved for SCCs of comparable bulk. They found no evidence that combined treatment (radiation therapy plus hysterectomy) improved local regional control or survival. In their study, radiation therapy alone was as effective a treatment for most patients with stage I disease. They noted, as others have, that patients with bulky stage I (.6 cm), stage II, or stage III disease, particularly with poorly differentiated lesions or evidence of nodal spread, had a very high rate of extrapelvic disease spread. Eifel reported the results of 160 patients with adenocarcinoma of the cervix. Of these patients, 84 were treated with radiation therapy alone, 20 were treated with external and intracavitary radiation followed by hysterectomy, and 56 were treated with RH. Survival was strongly correlated with tumor size and grade. There was a 90% survival rate for lesions smaller than 3 cm. After 5 years, 45% of the patients treated with RH had a recurrence.

These recurrences were strongly correlated with lymph or vascular space invasion, poorly differentiated lesions, and larger tumor size. Chen and associates from Taiwan reviewed 3678 cases of cervical cancer treated between 1977 and 1994, of which 302 (8.5%) were adenocarcinoma. A higher proportion of cases with adenocarcinoma were of the lower stages and in the younger patient even within a given stage. Survival was better in all stages in patients with squamous compared with adenocarcinoma (81% vs. 76% in stage I, P 5 .0039). When surgery was primary therapy, there was no difference in survival in stage I (83% vs. 80.3% survival of squamous and adenocarcinoma, respectively). Survival with radiation therapy noted 71% versus 49%, respectively (P 5 .0039), in stage I. Survival decreased as age increased within a given stage. The MD Anderson Hospital group compared 1538 patients with SCC with 229 patients with adenocarcinoma, all stage Ib and treated with radiation. In patients with tumors larger than 4 cm, multivariate analysis confirmed that patients with adenocarcinoma had a significantly poorer survival than did those with SCC (59% vs. 73%). In a study by the GOG, 813 stages Ia2 and Ib cancers were evaluated. All were treated with RH. There were 645 squamous, 104 adenocarcinoma, and 64 adenosquamous cancers. Radiation was given postoperatively to 16% squamous, 13% adenocarcinomas, and 20% of adenosquamous patients. After adjusting for multiple risk factors, survival was worst for adenosquamous cancer compared with squamous and adenocarcinoma (71.8%, 82.1%, and 88%, respectively). A similar finding was noted in a study from Taiwan in which 134 stages Ib or II cervical adenocarcinomas or adenosquamous cancers were compared with 757 similarly staged squamous carcinomas treated with RH. The overall survival (OS) rate was 72.2% for the former compared with 81.2% for the SCCs. The histology was an independent prognostic factor for recurrencefree survival and OS.

STAGING The staging of cancer of the cervix is a clinical appraisal, preferably confirmed with the patient under anesthesia; it cannot be changed later if findings at operation or subsequent treatment reveal further advancement of the disease.

International Federation of Gynecology and Obstetrics International classification of cancer of the cervix according to FIGO was recently revised in 2018 (Fig. 3.11): Stage

Description

The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded) Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion ,5 mma Measured stromal invasion ,3 mm in depth Measured stromal invasion $3 and ,5 mm in depth

IA1 IA2

Continued

CHAPTER 3

Stage

Description

Invasive carcinoma with measured deepest invasion $5 mm (greater than stage IA), lesion limited to the cervix uterib Invasive carcinoma $5 mm depth of stromal invasion, and ,2 cm in greatest dimension Invasive carcinoma $2 and ,4 cm in greatest dimension Invasive carcinoma $4 cm in greatest dimension The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall Involvement limited to the upper two-thirds of the vagina without parametrial involvement Invasive carcinoma ,4 cm in greatest dimension Invasive carcinoma $4 cm in greatest dimension With parametrial involvement but not to the pelvic wall The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodesc The carcinoma involves the lower third of the vagina, with no extension to the pelvic wall Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause) Involvement of pelvic and/or para-aortic lymph nodes, irrespective of tumor size and extent (with r and p notations)c Pelvic lymph node metastasis (LNM) only Para-aortic LNM The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. (A bullous edema, as such, does not permit a case to be allotted to stage IV) Spread to adjacent pelvic organs Spread to distant organs

IB1 IB2 IB3 II

IIA IIA1 IIA2 IIB III

IIIA IIIB

IIIC1

IIIC1 IIIC2 IV

IVA IVB

Two important changes appear in the 2018 FIGO staging for cervical cancer. FIGO stage IB has been separated into three substages (IB1, IB2, IB3) based on the size of the primary lesion. FIGO stage IIIC has been added to reflect pelvic LNM alone (i.e., FIGO stage IIIC1) or para-aortic LNM (i.e., FIGO stage IIIC2). Designation of LNM by radiographic images (r) or by pathologic evaluation (p) is included in the stage assignment. This is the first time that FIGO has addressed lymph node metastases in cervical cancer staging as the committee finally acknowledged that lymph node involvement is clearly associated with treatment failure, recurrence, and death among women diagnosed with FIGO stages I to III carcinoma. The clinical evaluation of patients with cervical cancer is outlined in Table 3.6. The following diagnostic aids are acceptable for determining a staging classification: physical examination, routine radiographs, colposcopy, cystoscopy, proctosigmoidoscopy, IVP, and barium studies of the lower colon and rectum. Other examinations, such as lymphography, CT scans, magnetic resonance imaging (MRI) examinations, arteriography, venography, laparoscopy, and hysteroscopy, are not

Invasive Cervical Cancer

recommended for staging because they are not uniformly available from institution to institution. It is important to emphasize that staging is a method of communicating between one institution and another. Probably more important, however, is that staging is a means of evaluating the treatment plans used within one institution. For these reasons, the method of staging should remain fairly constant. Staging does not define the treatment plan, and therapy can be tailored to the architecture of the malignancy in each patient.

Positron Emission Tomography In 2005, the Centers for Medicare & Medicaid Services implemented coverage for 18-fluorodeoxyglucose positron emission tomography (FDG-PET) for patients with newly diagnosed and locally advanced cervical cancer undergoing pretreatment staging who have no extrapelvic metastases on conventional imaging studies (Fig. 3.12). It should be noted that all imaging modalities are more specific than sensitive in detecting nodal metastases. The pooled sensitivity of PET in detecting pelvic nodal metastases in patients with untreated cervical cancer approaches 80% compared with MRI (≈70%) or CT (≈48%). It is important to recognize that the available studies are limited by low numbers of patients and wide confidence intervals (CIs). Grosu and colleagues from Munich analyzed the results of clinical studies on the integration of PET in target volume definition for lung, head and neck, genitourinary (GU), and brain tumors. FDG-PET had a significant impact on gross tumor volume (GTV) and planning target volume delineation in lung cancer and was able to detect lymph node involvement and differentiate malignant tissue from atelectasis. In high-grade gliomas and meningiomas, methionine PET helped to differentiate tumor from normal tissue. Furthermore, the investigators suggest that FDG-PET seems to be particularly valuable in lymph node status definition in cervical cancer. With limited experience, several commentators have noted that FDG-PET may be superior to CT and MRI not only in the detection of lymph node metastases but also in the detection of unknown primary cancer and in the differentiation of viable tumor tissue after treatment. The accurate delineation of GTV suggests the potential for sparing of normal tissue. The imaging of hypoxia, cell proliferation, angiogenesis, apoptosis, and gene expression by new PET tracers such as choline and acetate may lead to the identification of different areas of a biologically heterogeneous tumor mass that can be individually targeted using intensity-modulated radiotherapy (IMRT). In addition, a biologic dose distribution can be generated permitting dose painting. A 2007 meta-analysis of 41 studies was undertaken to compare the diagnostic performances of CT, MRI, and PET or PET/CT in patients for detection of metastatic lymph nodes in patients with cervical cancer. Whereas PET or PET/CT showed the highest pooled sensitivity (82%) and specificity (95%), CT showed 50% and 92% and MRI showed 56% and 91%, respectively (Table 3.7). In a recent investigation of 83 women with FIGO stages IB1 to IIIB cervical cancer, F-18 fluorodeoxyglucose-avid pelvic lymph nodes (SUVPLN) was found to be a prognostic biomarker, predicting treatment response, pelvic recurrence risk, and disease-specific survival. Finally, a

CHAPTER 3

Invasive Cervical Cancer

4m m 3m m 2m m 1m m

m 3m m 2m m 1m

Stage Ia1

Stage Ia2

3 cm

Squamocolumnar junctions

Stage Ia

Stage Ib1

Stage IIa

5 cm

Stage Ib2

Figure 3.11 A–J, Federation of International Gynecologists and Obstetricians staging and classification of cancer of the cervix. See staging in Appendix A.

CHAPTER 3

Stage IIb

Invasive Cervical Cancer

Stage IIIa

Ureter Ureteral obstruction by tumor

Stage IIIb

Stage IIIb (urinary)

Omentum

Periaortic nodes

Inguinal nodes Stage IVa

J Figure 3.11, cont’d

Stage IVb

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.6 Clinical Evaluation of Patients With Newly Diagnosed Cervical Cancer History

Review of Systems

General Physical Examination

Risk factors (STDs, smoking, OCPs, HIV), prior abnormal Pap tests, previous dysplasia and treatment

Abnormal vaginal bleeding or discharge; pelvic pain, flank pain, sciatica, hematuria, rectal bleeding, anorexia, weight loss, bone pain

Peripheral lymphadenopathy

Evaluation

Common procedures (FIGO)

Alternative procedures

Invasive cancer

Cervical biopsy

Histologic diagnosis required

Endocervical curettage

—

Cervical conization

—

Tumor size; involvement of the vagina, bladder, rectum and parametria

Pelvic examination under anesthesia

MRI pelvis preferred over CT

Anemia

Complete blood count

—

Renal failure

Serum chemistries

—

Hematuria

Urinalysis

—

Bladder involvement

Cystoscopy with biopsy and urine cytology

CT, MRI pelvis

Rectal infiltration

Proctoscopy with biopsy

CT, MRI pelvis; barium enema

Hydronephrosis

IVP

Renal ultrasonography; CT abdomen

Pulmonary metastases

Chest radiography

CT chest; PET scan

Retroperitoneal lymphadenopathy

—

Lymphangiogram, CT, MRI, PET scan

CT, Computed tomography; FIGO, Federation of International Gynecologists and Obstetricians; HIV, human immunodeficiency virus; IVP, intravenous pyelography; MRI, magnetic resonance imaging; OCP, oral contraceptive pill; PET, positron emission tomography; STD, sexually transmitted disease.

disease-specific survival than those with PET-negative lymph nodes (P , .001). The hazard ratios (HRs) for disease recurrence increased incrementally based on the most distant level of nodal disease: pelvic, 2.4 (95% CI, 1.63, 3.52); paraaortic, 5.88 (95% CI 3.8, 9.90); and supraclavicular, 30.27 (95% CI, 16.56, 55.34). The GOG together with the ACRIN cooperative group studied treatment planning with PET in the ACRIN-6671/GOG0233 clinical trial. The important observation from this study was that a diagnostic CT should be considered with each PET scan as there was a trend for greater sensitivity of detecting abdominal nodal metastases with combined PET-diagnostic CT (sensitivity 0.5; 95% CI, 0.44 to 0.56) versus CT alone (sensitivity 0.42; 95% CI, 0.36 to 0.48) (P 5 .052).

Surgical Staging

Figure 3.12 Positron emission tomography. (From http://www.radassociates.com.)

prospective validation study conducted between 2000 and 2009 enrolled 560 women who underwent pretreatment FDG-PET lymph node staging. Overall, 47% of patients had lymph node involvement by FDG-PET at diagnosis and within a stage, patients with PET-positive lymph nodes had significantly worse

Findings uncovered by fusion PET-CT or conventional MR and CT examinations can be used in the planning of therapy but should not influence the initial clinical staging of the lesion. Unfortunately, clinical staging is only of rough value in prognosis because disease distribution and extent are often included under one stage subheading. Clinical staging is enhanced with the liberal use of rectovaginal examinations (Fig. 3.13) in that this type of pelvic examination allows more complete palpation of the parametria and cul-de-sac. The role of surgical assessment of lymph nodes with extraperitoneal, laparoscopic, or robotic lymphadenectomy is expanding. The ability to perform pelvic and paraaortic lymphadenectomy provides prognostic information, improves direction of radiation therapy (i.e., extended-field radiation with positive paraaortic nodes), and may offer a therapeutic effect particularly in grossly involved lymph nodes. To date, no prospective data on surgical

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.7 Sensitivity of FDG-PET for Lymph Node Staging in Locally Advanced Disease n

FIGO Stages

Imaging Modality

Lymph Nodes

Sensitivity

Sugawara et al.

IB-IVA

PET vs. CT

Overall

0.86 (PET) 0.57 (CT)

Rose et al.

IIB-IVA

PET

PALN

0.75

PELN

1.00

Yildirim et al.

IIB-IVA

PET

PALN

0.5

Grigsby et al.

152

IB-IV

PET

Overall

0.67

Narayan et al.

IB-IVB

PET

PELN

0.80

Yeh et al.

IB-IVA

PET

PALN

0.83

Lin et al.

IB-IVA

PET

PALN

0.86

Yen et al.

135

IB2-IVB 1 recurrence

PET

PELN

0.88

PALN

0.95

Choi et al.

IB-IVA

PET-CT

PELN

0.77

Amit et al.

I-IV

PET-CT

PELN

0.60

Loft et al.

119

IB1-IVA

PET-CT

PELN

0.96

PALN

1.00

CT, Computed tomography; FDG, 18-fluorodeoxyglucose; PALN, paraaortic lymph nodes; PELN, pelvic lymph nodes; PET, positron emission tomography. Adapted from Magne N, Chargari C, Vicenzi L, et al: New trends in the evaluation and treatment of cervix cancer: the role of FDG-PET, Cancer Treat Rev 34:67–68, 2008.

to reduce morbidity from the procedure. More advanced lesions have been investigated with a retroperitoneal lymphadenectomy to determine the extent of disease before planning radiotherapy fields (Fig. 3.14). Fig. 3.15 illustrates one such approach. With the increased use of PET, it is expected that the indications for surgical staging in cervical cancer will decrease.

TREATMENT OF EARLY-STAGE DISEASE

Figure 3.13 Technique of rectovaginal examination.

staging of cancers of the cervix exist to indicate a survival advantage to this approach. Some gynecologic oncologists believe that limited staging procedures are warranted on patients with advanced-stage cervical cancer to place patients on institutional or national group protocols. The status of paraaortic nodes should be known before treatment is initiated in such cases to plan appropriate modalities, such as the extent of the radiation field or concomitant chemotherapy. An extraperitoneal approach for removal of the periaortic nodes is preferred by many clinicians in an effort

After the diagnosis of invasive cervical cancer is established, the question is how to best treat the patient. Proposed management algorithms for early-stage disease, locally advanced malignancy, and disseminated tumors appear in Fig. 3.16. Specific therapeutic measures are usually governed by the age and general health of the patient, by the extent of the cancer, and by the presence and nature of any complicating abnormalities. It is thus essential to carry out a complete and careful investigation of the patient (see Table 3.6), and then a joint decision regarding treatment should be made by the radiotherapist and gynecologic oncologist. The choice of treatment demands clinical judgment, but apart from the occasional patient for whom only symptomatic treatment may be best, this choice lies between surgery and radiotherapy (almost always given with cisplatin chemotherapy). In most institutions, the initial method of treatment for locally advanced disease is chemoradiation, both intracavitary and external radiographic therapy. The controversy between surgery and radiotherapy has existed for decades and essentially surrounds the treatment of stages I and IIa cervical cancer (see Fig. 3.17). For the most part, most patients with stages more advanced than stages I and IIa are treated with combination cisplatin and radiotherapy (see Fig. 3.17). The 5-year survival figures from two large series, one treated with radiotherapy alone and the other with

CHAPTER 3

Invasive Cervical Cancer

Figure 3.14 Pelvic diagram. The dashed line indicates the radiation field and the position of the uterus and cervix within the field. The bold line indicates the J incision path relative to the field and to the major vessels.

surgery, are included here. Currie reported the results of 552 radical operations for cancer of the cervix: Stage

Patients

Preinvasive carcinoma in situ Stage I Stage IIa Stage IIb Other stages

555 cases (99.9%) 189 cases (86.3%) 103 cases (75%) 78 cases (58.9%) 41 cases (34.1%)

Some of these patients with positive nodes received postoperative radiotherapy. In 1981, Zander and colleagues reported results of a 20year cooperative study from Germany of 1092 patients with stages Ib and II cancer of the cervix treated with RH of the Meigs type and bilateral pelvic lymphadenopathy. Of the 1092 patients, 50.6% had surgery only, with a 5-year survival rate of 84.5% in stage Ib and 71.1% in stage II (most were stage IIa). This correlates well with the figures reported by Currie and Falk. The rest of the patients reported by Zander received postoperative whole-pelvis irradiation therapy. No significant difference could be observed in the survival rates of patients undergoing only surgery compared with those of patients undergoing adjuvant postoperative radiation. In fact, in 199 patients with lymph node involvement, the difference in survival rates of those undergoing only surgery and those undergoing additional postoperative radiation therapy was statistically insignificant. Landoni and colleagues from the University of Milan conducted a prospective randomized trial in 243 patients comparing class II versus class III RH in stages IB to IIA cervical cancer. Although mean blood loss and transfusions were similar for both arms, mean operative time and late urologic morbidity

were significantly lower in patients who underwent class II RH. The use of adjuvant radiotherapy was similar in both arms (54%, 55%). The recurrence rate (24%, 26%) and overall disease-free survival (75%, 73%) was not significantly different between the arms. Multivariate analysis confirmed that survival did not depend on the type of operation, even when stratifying lesions by size # or .4 cm. This rare phase III surgical trial in early-stage cervical cancer has served as the platform from which our (non-phase III) experience in less radical surgery (LRS) for early-stage disease is based (e.g., radical trachelectomy and cervical conization for fertility preservation in the setting of invasive disease). In general, in the early stages, comparable survival rates result from both treatment techniques. The advantage of radiotherapy is that it is applicable to almost all patients, but radical surgery of necessity excludes certain patients who are medically inoperable. The possible occurrence of immediate serious morbidity must be kept in mind when this treatment plan is selected. In many institutions, surgery for stages I and IIa disease is reserved for young patients in whom preservation of ovarian function is desired and improved vaginal preservation is expected. The modern operative mortality rate and the postoperative ureterovaginal fistula rate both have been reported to be less than 1%, making an objective decision for therapy even more difficult. Other reasons given for the selection of radical surgery over radiation include cervical cancer in pregnancy, concomitant inflammatory disease of the bowel, previous irradiation therapy for other disease, presence of pelvic inflammatory disease or an adnexal neoplasm along with the malignancy, and patient preference. Among the disadvantages of radiation therapy, one must consider the permanent injury to the tissues of the normal organ bed of the neoplasm and the possibility of second malignancies developing in this bed.

SUPERFICIAL CARCINOMA OF THE CERVIX The evolution concerning the diagnosis and management of superficially invasive carcinoma of the cervix has occurred since Mestwerdt in 1947 observed that invasive carcinoma of the cervix diagnosed only microscopically could be cured by non-radical surgery. During the last five decades, definitions and treatment plans have changed dramatically. Much of the confusion can be related to the fact that FIGO has changed the criteria for earlystage invasive carcinoma of the cervix several times since 1960. These changes were made as additional information in regard to disease process became available. Over the years, as many as 20 different definitions have been proposed and as many as 27 terms have been applied to this entity. The recommended therapy has also changed going from radical surgery with any invasion to more conservative with various depths of invasion. In 1971, FIGO designated stage IA carcinoma of the cervix as cases of preclinical carcinoma. In 1973, the Society of Gynecologic Oncologists (SGO) accepted the following statement concerning the definition of “microinvasive carcinoma” of the cervix: 1. Cases of intraepithelial carcinoma with questionable invasion should be regarded as intraepithelial carcinoma. 2. A microinvasive lesion should be defined as one in which a neoplastic epithelium invaded the stroma in one or more

CHAPTER 3

Invasive Cervical Cancer

Figure 3.15 A, Path of incision. First measurement of 2 to 3 cm (two finger widths) above the pubic symphysis; second measurement 2 to 3 cm medial to the anterior superior iliac spine. A diagonal line connects these points. A vertical line is drawn superiorly to 3 to 4 cm above the level of the umbilicus. The incision begins at the lateral margin of the rectus muscle. B, Division of the external sheath of the rectus and a cross-section. After the initial incision through the skin, the lateral margin of the sheath is divided with a Bovie along the length of the muscle. On cross-section, an arrow points to the ideal point of separation. C, Division of the internal sheath of the rectus and a cross-section. The rectus muscle is mobilized medially. The internal sheath is divided carefully to preserve the underlying exposed peritoneum. D, Blunt dissection with a hand following the plane of the peritoneum and separating it from the transversalis fascia. E, Blunt dissection: perspective cross-section. Dissection along the peritoneum until contact is made with the left ureter. The ureter is preserved with the peritoneum and is mobilized medially as dissection continues. The psoas muscle and the common iliac vessels are exposed. F, A cross-section. Proper pathway of dissection along the peritoneum over the psoas.

CHAPTER 3

Invasive Cervical Cancer

I H

J Figure 3.15, cont’d G, Cross-section of deep dissection. Exposure of the left and right common iliac vessels underneath the peritoneum at about the level of L5 to S1. Avoid damage to the inferior mesenteric artery. H, Lymphadenectomy begins along the left common iliac vessels. After medial and superior retraction of the mesentery and beginning about the bifurcation of internal and external iliac vessels, lymph nodes are removed along the length of the left common iliac to the junction with the aorta. I, Obturator nodes. Lateral mobilization of the external iliac vessels with a vein retractor. The obturator nerve is identified, and nodes are removed. J, The right common iliac. The right common and paraaortic lymph nodes are clipped and removed. The diagram shows deep access to the right common iliac nodes.

CHAPTER 3

Invasive Cervical Cancer

Figure 3.16 Algorithm for primary therapy.

places to the depth of less than 3 mm below the basement membrane and in which lymphatic or vascular involvement is not demonstrated (Fig 3.17). In 1985, for the first time FIGO attempted to quantify the histological definition of stage IA carcinoma of the cervix. Stage IA was defined as the earliest forms of invasion in which minute foci of invasion are visible only microscopically. This definition has been criticized for several reasons. Although the upper limits of the invasion for depth and width were stated, upper limits for measurement of stage IA1 were not defined. It was therefore difficult to quantify patients in the two subsets. Other areas of criticism were aimed at the fact that the FIGO definition could not be used as a guide for treatment and the definition covered patients with vascular lymphatic space involvement. These variations illustrated problems with specific definitions. In 1994, FIGO, in an attempt to better quantify early invasive disease, adopted the following definition (see Table 3.2). Stage IA1 cancers are those with stromal invasion up to 3 mm in depth and no greater than 7 mm. Lymphatic vascular space involvement does not exclude a patient from this definition. It should be emphasized that the diagnosis of a stage IA cancer can be made only with the adequate pathological material (conization) and only when a clinical lesion is not present. If a clinical lesion is present, irrespective of the depth of stromal invasion, the diagnosis is stage IB.

Stage IA1 Therapy for any cancer is predicated on risk factors for metastatic disease. Tumor volume is the most important risk factor for any cancer. In early cervical cancer this is well defined. In patients with IA1, 0 to 3 mm depth invasion and 0 to 7 mm width are well established parameters (FIGO 1994 staging). LNM is the most common metastatic site. That incidence to a large extent determines definitive therapy. The status of cervical conization margins should always be tumor free. Unfortunately, multiple studies have reported series which include patients categorized as IA1 or IA2 when positive cone margins are present in the hysterectomy specimen. By definition those patients cannot be classified as IA1 or IA2 as definition cannot be satisfied. The inclusion of these patients into the true IA1 or IA2 classification could change the incidence of nodal metastasis and recurrence. Ostor, a gynecologic pathologist reviewed the literature in 1995 using the 1994 FIGO definition of stage I cancers. In the IA1 cancers only 666 of 5007 reported cases had pelvic lymphadenectomies and 1.2% had metastasis (Table 3.8). Assuming that in those without lymphadenectomies the overwhelming

C Figure 3.17 A, Microinvasion (stage Ia1) of squamous cell carcinoma of the cervix. Invasion of less than 1 mm, no confluency or vascular space involvement; true microinvasion. B, Microcarcinoma with less than 3 mm of invasion but with vascular space involvement. C, Microcarcinoma “spray” type with less than 1 mm of invasion.

majority did not have nodal metastasis, then the incidence was close to 0.16%. As the overall disease-free survival was 991%, that would tend to be a realistic assumption. More recent reports (see Table 3.3) would support Oster’s observations as LNM was 0.13% and recurrence 1%. In comparison

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.8 Literature Review Stage IA1

Cervical Cancer

IA1

IA2

N 5 5007

N 5 624

1 VSIa

182 (3.6%)

124 (18.4%)

1 Nodes

8/666 (1.2%)

14/221 (6.3%)

8/5007 (0.16%)

14/634 (2.0%)

Recurrence

35 (0.7%)

25 (4.0%)

Dead of Cancer

10 (0.2%)

13 (2.0)

VSI, Vascular space involvement.

Ostor, Ann Path, 1995.

between those treated conservative or radically, the recurrence rate and OS is similar. Based on these data conservative therapy is indicated—either simple hysterectomy or conization if fertility is desired, provided surgical margins are free of cancer. Lymph vascular space involvement (LVSI) was excluded from the SGO’s definition for microinvasive disease (0 to 3 mm invasion, 1973). Rationale for exclusion was not stated but probably based on “opinion.” As a result, when LVSI was present the recommendation was to perform a lymphadenectomy. FIGO in their 1994 staging guidelines did not exclude LVSI from their staging. This was for several reasons. Pathologists disagree with regard to the reproducibility of this entity and to a large extent it is subjective. In several studies the number of slides prepared from the cervix determined the incidence of LVSI. Shrinkage artifacts can lead to an over-diagnosis and verification has been suggested with special staining to verify true capillary-like space involvement. In one study in which myeloperoxidase staining with Ulex Europaeus agglutinin 1 lectin (UEA I) was used, 10 of 32 cases of LVSI were excluded in which involvement was initially thought to exist. In another study LVSI was compared to H&E with immunostaining with pancytokeratin and CD31 endothelial cell marker antibodies in 97 patients with early-stage cervical cancer. LVSI was present in 29 immunohistochemistry and 18 H&E. There was a significant association between LVSI and H&E positivity for nodal metastasis and tumor recurrence. In contrast LVSI by immunohistochemistry was not associated with any pathologic factors, recurrence or survival. The review article by Buchanan details studies noted in Tables 3.3 and 3.4 which evaluated LVSI, LNM, and survival. The current data (post FIGO 1994) do not support LVSI to be a poor prognostic factor and therefore should not be used to imply a lymphadenectomy is indicated.

Stage IA2 Traditionally stage IA2 has been mainly treated radically including, in many instances, PL. This recommendation was suggested before the FIGO 1994 staging was published. The histologic criteria were not standardized before then and was based on really no data but opinion. It should be remembered that not too long ago radical surgery was recommended for stromal invasion of less than 1 mm. With increasing experience this mandate for radical therapy has been questioned. Ostor reviewed the literature and identified 674 patients with 3 to 5 mm of invasion of which 221 had lymphadenectomy and 14 (6.3%) LNM (see

Table 3.8). With 4% recurrence and 2% deaths, the number of LNM in the 453 not having lymphadenectomies must be considerably less than the 6.3% in those receiving lymphadenectomies. In reviews of recent studies LNM was 1.3% and recurrence was 0.13% (see Table 3.4). An evaluation of the SEER database identified women younger than 45 years who had a diagnosis of stage IA2. The main purpose of the study was to evaluate radical treatment, modified medical or radical hysterectomy (MRS), compared to LRS. Of the 1343 women identified, 873 (65%) underwent LRS including conization, trachelectomy, or simple hysterectomy. At 110 months median follow-up, disease-free survival was 98.3% versus 98.2% (LRS vs. MRS). A recent study utilizing the National Cancer Data Base reviewed women with stage IA2 to determine the outcome of simple hysterectomy compared to RH. There were 1530 patients. Rates of simple hysterectomy increased from 37.8% to 52.7% from 2004 to 2014. The 5-year survival for RH was 95.1% compared to 97.6% for simple hysterectomy. LVSI was said to be similar in the two treatment groups (15.6% vs. 15.8%). Of those undergoing lymphadenectomies 2.9% had LNM. The importance of following strict FIGO guidelines and evaluating risk factors was exhibited in the GOG study that evaluated patients who had 3 to 5 mm invasion with negative surgical margins on conization specimens. Per protocol all had external path review and underwent a RH and PL. No residual disease was noted in the hysterectomy specimen. LVSI was noted in 23.5% of cases. No LNM were noted and there were no recurrences. To recommend radical surgery including lymphadenectomy does not appear appropriate in view of the current data. Simple hysterectomy or conization with negative surgical margins if fertility is desired is as effective as more radical surgery.

ADENOCARCINOMA Historically many considered adenocarcinoma to carry a worse prognosis and therefore RH was considered treatment of choice for these lesions. Contemporary data notes numerous studies in which survival for women with adenocarcinoma and less than 5 mm of invasion is excellent. Bisseling reviewed the literature and identified 515 cases with 0 to 3 mm invasion of which 3/261 (1.1%) undergoing PLND had LNM. LVSI was evaluated in 214 and 7 had PLND and none had metastasis whereas 2/202 (1.0%) without LVSI had LNM. Of the 506 patients with 3 to 5 mm invasion, 264 (52%) underwent PLND and only 2 (0.7%) had metastasis. There were no LNM in the 10 LVSI identified compared to 0/66 in the LVSI negative patients. Recurrence was 6/383 (1.6%) with 0 to 3 mm invasion and 5/536 (1.5%) with 3 to 5 mm invasion. No recurrences were noted in the 59 stage IA patients treated with conization alone. Data from the SEER database identified 3997 women with stages IA1 and IA2 cancers; 988 (24.8%) with adenocarcinoma compared to 2999 with squamous carcinoma. In stage IA1, only 19% of squamous lesions had PLND and 3.8% had LNM. For adenocarcinoma 49% had PLND with 0.7% LNM. In stage IA2, 39% of squamous lesions had PLND and 3% had LNM. In those with adenocarcinoma 60% had PLND and only 0.8% had LNM. In multivariate analysis, women with stage IA1 adenocarcinoma or stage IA1 squamous cell carcinoma had similar disease-free survival; the 5-year survival for those treated with

CHAPTER 3

cone was 95.1% as compared with 95.6% for those treated with hysterectomy. In those with squamous compared with adenocarcinoma, survival was 98.8% and 96.9%, respectively. For stage IA2 survival for squamous lesions treated with conization was 90.2% compared to 96.3% treated with hysterectomy. For adenocarcinoma survival was 97.8% and 98.2%, respectively.

Based on Current Data Radical Treatment is Not Justified in Patients With Adenocarcinoma Stage IA RH and PL has been a mainstay of therapy for early-stage carcinoma of the cervix for over a century. Initially morbidity and mortality were significant. Wertheim reported his experience in 1912 and noted a 31% morbidity and 18% mortality. Fortunately, morbidity and mortality have both improved considerably but radical surgery still carries risks. Intraoperatively blood loss can be greater than 1500 mL with its inherent potential morbidity. Covens described a large series of 864 patients treated with RH1PL with an intraoperative complication of 6%, significantly higher than the 1% to 2% seen with a simple hysterectomy. Postop complications are a more significant source of morbidity. Deep venous thrombosis (DVT) and even pulmonary embolus have been noted after radical surgery. Urinary dysfunction is common after RH with reports of up to 70% having some form of urinary deficit. A study compared a simple hysterectomy to a RH with respect to quality of life (QoL). Urinary incontinence was almost twice as frequent in RH. Late complications after RH which may occur after initial recovery include sexual dysfunction, lymphocysts, and significant lymphedema. Current data indicate long-term survival for stage IA managed with simple hysterectomy or conization with negative surgical margins if fertility is desired is equivalent to RH1PL. With morbidity of RH1PL being considerably higher compared to simple surgery, there appears to be no rational argument for RH1PL for this early disease.

Invasive Cervical Cancer

This data and recommendations are based on the 1994 FIGO definition of stage IA cancers. Recently FIGO decided to eliminate the horizontal definition based on the fact it was difficult to determine. No data was furnished. Data does note an increased LNM and recurrence with disease greater than 7 mm horizontal spread. The above data and treatment recommendation is extensive using the 1994 FIGO guidelines and is a valid guide for management.

Radical Abdominal Hysterectomy with Lymphadenectomy The use of RH in the United States was initiated first by John Goodrich Clark in 1892 at Johns Hopkins University, and later by Joe V. Meigs at Harvard University in 1944, and shortly thereafter, the RH with pelvic lymphadenopathy was adopted by many clinics in the United States because of dissatisfaction with the limitations of radiotherapy. Some had found that many lesions were not radiosensitive, and some patients had metastatic disease in regional lymph nodes that were alleged to be radioresistant. Radiation injuries had been reported, and one of the overriding points in favor of surgery was that gynecologists were surgeons rather than radiotherapists and thus felt more comfortable with this treatment. At the time of the popularization of this procedure, modern techniques of surgery, anesthesia, antibiotics, and electrolyte balance had emerged, reducing the enormous morbidity that once attended major operative procedures in the abdomen. RH is a procedure that must be performed by a skilled technician with sufficient experience to make the morbidity acceptable (1% to 5%). The procedure involves removal of the uterus, the upper 25% of the vagina, the entire uterosacral and uterovesical ligaments (Fig. 3.18), and all of the parametrium on each side, along with pelvic node dissection encompassing the four major pelvic lymph node chains: ureteral, obturator, Pubovesical ligament

Prevesical space Bladder

Vesical fascia

Vesicovaginal space

Vesicouterine ligament

Cervix

Paravesical space

Cervical fascia Retrovaginal space Uterosacral ligament l cta re ra ce Pa spa

Cardinal ligament Rectum

Retrorectal space Sacrum Posterior sheath of rectal septum

Rectal fascia

Figure 3.18 Cross-section of the pelvis at the level of the cervix.

CHAPTER 3

Invasive Cervical Cancer Right renal vein

Left renal vein

Kidney

Left ovarian vein

Right ovarian vein

Left ovarian artery

Vena cava Right ovarian artery Common iliac artery

Abdominal aorta

Right ureter

Left ureter

Psoas muscle

Internal iliac artery External iliac artery

Uterus

Bladder Fallopian tube Ovary

Figure 3.19 The retroperitoneal anatomy of the pelvis and lower abdomen illustrating the course of the ureters.

hypogastric, and iliac. Metastatic lesions to the ovaries are rare, and preservation of these structures is acceptable, especially in young women with small lesions. The procedure is complex because the tissues removed are in close proximity to many vital structures such as the bowel, bladder, ureters (Figs. 3.19 and 3.20), and great vessels of the pelvis. The object of the dissection is to preserve the bladder, rectum, and ureters without injury

but to remove as much of the remaining tissue of the pelvis as is feasible. There is no doubt that in stage I and in the more restricted stage II cases, surgical removal of the disease is feasible. The addition of PL to the operative procedure caused considerable controversy in the early part of the century. Wertheim removed nodes only if they were enlarged and then not systematically. He

CHAPTER 3

Superior vesical artery

Invasive Cervical Cancer

Uterus Bladder

3rd part of ureter 2nd part of ureter

Ovary

Uterine artery

1st part of ureter

Broad ligament

Rectum

Uterosacral ligament

Ureter

Infundibulopelvic ligament Hypogastric artery

Figure 3.20 Relationship of the ureter to the uterosacral ligaments, uterine artery, infundibulopelvic ligament, and uterus.

believed that when accessible regional nodes were involved, the inaccessible distant nodes were also involved, and removal of suspicious nodes was more for prognostic than therapeutic value. He thought that node involvement was a measure of the lethal quality of the tumor and not merely a mechanical extension of the disease. The operative procedure popularized by Meigs included meticulous PL. Meigs demonstrated a 42% 5-year survival rate in another series of patients with positive nodes. Lymphadenectomy is now an established part of the operative procedure for any patient with disease greater than stage Ia1. There has been some interest in combining a radical vaginal operation with a retroperitoneal lymphadenectomy, and the results reported by Mitra, Navratil and Kastner, and McCall are surprisingly good. The survival rate in patients with negative nodes is usually in the range of 90% or more. Piver, Rutledge, and Smith devised a system of rating radicality of hysterectomy (Table 3.9) used in treating women with cervical cancer at the MD Anderson Hospital. He suggested that the term “RH” is not adequate to record and communicate the different amounts of therapy attempted and the subsequent risk of complications when different surgeons report their results. These authors believed that describing the technical features of five operations enabled them to evaluate more accurately their results and provided a better understanding of the need to tailor each patient’s treatment by using an operation that was adequate but not excessive. The goal of the class I hysterectomy was to ensure removal of all cervical tissue. Reflection and retraction of the ureters laterally without actual dissection from the ureteral bed allows one to clamp the adjacent paracervical tissue without cutting into the side of the cervical tissue itself. Class I operations are advocated primarily for in situ and true microinvasive carcinomas of the

TABLE 3.9 Rutledge’s Classification of Extended Hysterectomy Class

Description

Indication

Extrafascial hysterectomy; pubocervical ligament is incised, allowing lateral deflection of the ureter

CIN, early stromal invasion

Removal of the medial half of the cardinal and uterosacral ligaments; upper third of the vagina removed

Microcarcinoma postirradiation

III

Removal of the entire cardinal and uterosacral ligaments; upper third of the vagina removed

Stages Ib and IIa lesions

Removal of all periureteral tissue, superior vesical artery, and three fourths of the vagina when preservation of the bladder is still possible

Anteriorly occurring central recurrences

Removal of portions of the distal ureter and bladder

Central recurrent cancer involving portions of the distal ureter or bladder

CIN, Cervical intraepithelial neoplasia. From Piver MS, Rutledge FN, Smith PJ: Five classes of extended hysterectomy for women with cervical cancer, Obstet Gynecol 44: 265–272, 1974. Reprinted with permission from The American College of Obstetricians and Gynecologists.

cervix. A class I procedure is also performed after preoperative radiation in adenocarcinoma of the cervix or after preoperative radiation in the so-called barrel-shaped endocervical SCC. The operation described is essentially the extrafascial hysterectomy used routinely at the MD Anderson Hospital.

CHAPTER 3

Invasive Cervical Cancer

Figure 3.22 Broken lines identify the point of transection of the uterosacral ligaments in class II and class III radical hysterectomy. (Courtesy of Gregorio Delgado, MD.)

Figure 3.21 Broken lines identify the point of transection of the cardinal ligaments in class II and class III radical hysterectomy. (Courtesy of Gregorio Delgado, MD.)

Class II extended hysterectomy is described as a modified RH. The purpose of the class II hysterectomy is to remove more paracervical tissue (Fig. 3.21) while still preserving most of the blood supply to the distal ureters and bladder. The ureters are freed from their paracervical position but are not dissected out of the pubovesical ligament. The uterine artery is ligated just medial to the ureter as it lies in “the tunnel,” ensuring preservation of the distal ureteral supply. The uterosacral ligaments are transected midway between the uterus and their sacral attachments (Fig. 3.22). The medial halves of both cardinal ligaments are removed, as is the upper 25% of the vagina. A PL is usually performed with a class II hysterectomy. A class II operation is reported to be suitable for the following conditions: 1. Microinvasive carcinomas in which the depth of invasion is considered greater than early stromal invasion 2. Small postirradiation recurrences limited to the cervix. The class III procedure is a wide radical excision of the parametrial and paravaginal tissues in addition to the removal of the pelvic lymphatic tissue. The uterine artery is ligated at its origin on the internal iliac artery. In the dissection of the ureter from the pubovesical ligament (between the lower end of the ureter and the superior vesical artery), care is taken to preserve the ligament, maintaining some additional blood supply to the

Figure 3.23 Broken lines illustrate the level of vaginal removal of class II and class III radical hysterectomy. (Courtesy of Gregorio Delgado, MD.)

distal ureter. The hazard of fistula formation is decreased by preservation of the superior vesical artery along with a portion of the associated pubovesical ligament. The uterosacral ligaments are resected at the pelvic sidewall. The upper 25% of the vagina is removed (Fig. 3.23), and a PL is routinely performed. This operation is primarily for patients with stage I or IIa carcinoma of the cervix with or without preservation of ovarian function.

CHAPTER 3

The aim of the class IV RH is complete removal of all periureteral tissue; a more extensive excision of the paravaginal tissues; and, when indicated, excision of the internal iliac vessels along an involved portion of the medial pelvic wall tissue. This differs from the class III operation in three respects: 1. The ureter is completely dissected from the pubovesical ligament 2. The superior vesical artery is sacrificed 3. Fifty percent of the vagina is removed. This procedure is used primarily for more extensive anteriorly occurring central recurrences when preservation of the bladder is seemingly still possible. Extension of the dissection laterally is needed when the disease has focally involved the medial parametrium. Sacrificing blood vessels to the bladder is unfavorable because the risk of fistula formation increases significantly. In most cases, these patients are more appropriately treated with an anterior exenteration. The purpose of the class V hysterectomy is to remove a central recurrent cancer involving portions of the distal ureter or bladder. It differs from a class IV operation because the disease involves a portion of the distal ureter, bladder, or both, which is removed with the disease. A reimplantation of the ureter into the bladder, often as a ureteroneocystostomy, is then performed. This procedure has a rare application to a small, specifically located recurrence when exenteration is considered unnecessary or has been refused by the patient. The modified Rutledge classification of extended hysterectomies has considerable practical value. It again underlines the necessity for the surgeon to tailor the operative procedure to the disease extent. A stage Ia2 lesion does not need an operative procedure that is as radical as the procedure for a large IIa lesion. This is particularly pertinent in the decision between a class II and class III RH. In many countries, the class II RH (called a modified RH) is combined with a bilateral PL as standard therapy for early-stage cervical cancer. Indeed, the class III type of RH is a phenomenon of particular prevalence in the Western hemisphere and Asia because of the dual influences of Meigs and Okabayashi. The class III, or Meigs–Okabayashi procedure, is a derivative of the Halstedian principle that a lesion should be removed en bloc with its draining lymphatics; thus, the class III RH calls for removal of all the parametria at the pelvic sidewall and transection of the uterosacral ligaments at the sacrum. Advocates of the modified RH or class II procedure with PL for stages I and IIa lesions suggest that the intervening lymphatics are not at risk in an early cancer of the cervix. Indeed, spread from the primary lesion to the draining pelvic wall nodes probably occurs as an embolic phenomenon. One virtually never finds a tumor in lymphatics except surrounding the primary lesions. However, it is prudent for the pathologist to take several sections of the most distal portion of the parametria following a class III RH for stage I or IIa cervical cancer in an effort to determine the presence or absence of malignant cells in lymphatics distant from the primary lesion. In the presence of a bulky central lesion, the need for an adequate surgical margin of resection often mandates a more extensive procedure than the typical class II RH. However, preservation of any portion of the lateral parametria appears to be associated with a greatly diminished incidence of bladder atony. Forney reported on 22 women extensively studied after

Invasive Cervical Cancer

undergoing RH; in 11 women, the cardinal ligaments had been divided completely, and in the other 11, the inferior 1 to 2 cm of these ligaments had been spared. Satisfactory voiding occurred significantly earlier (20 vs. 51 days) in women who had undergone an incomplete transection. In a similar manner, preservation of a portion of the uterosacral ligaments appears to be associated with fewer complaints of postoperative obstipation. Undoubtedly, the preserved tissue contains intact nerve tracts, which avoid the extensive denervation associated with the typical class III type or RH.

Complications Acute complications of RH include pelvic hemorrhage, urinary tract injury, injury to the genitofemoral or obturator nerves, DVT, and pulmonary embolism. Although hemorrhage requiring transfusion of blood products is a risk of any RH, this complication may occur more frequently when this procedure is performed in obese patients. Soisson and colleagues reported on 43 women undergoing RH for early-stage cervical cancer. All patients had a body weight at least 25% greater than their ideal weight. Survival was not compromised, and the incidence of serious complications was not increased in obese patients compared with a control group. The operative technique is more difficult; the procedure lasts longer, and surgery is associated with greater blood loss. Pulmonary embolism is the one complication most likely to cause death in the period surrounding the operative therapy of cervical cancer. This must be kept in mind at all times, and particular care must be exercised during and after surgery to avoid this devastating complication. The operative period is the most dangerous period for the formation of a thrombus in the leg or pelvic veins. Care should be taken to ensure that a constriction of veins in the leg does not occur during the operative procedure, and careful dissection of the pelvic veins should lead to minimal thrombus formation in those structures. Because of the risk of pulmonary embolism and DVT, prophylactic heparin or pneumatic compression boots (or both) are strongly recommended. Chronic complications after RH include urinary dysfunction, lymphocyst formation, lymphedema, extensive abdominal scarring, fistula formation (vesicovaginal and rectovaginal), compromised sexual function, and loss of fertility. All of these complications are preventable, and the incidence is decreasing steadily (Table 3.10). With highly successful surgical treatment

TABLE 3.10 Complications of Radical

Hysterectomy With Approximate Incidences Complication

Patients (%)

Vesicovaginal fistula

Ureterovaginal fistula

Severe bladder atony

Bowel obstruction (requiring surgery)

Lymphocyst (requiring drainage)

Thrombophlebitis

Pulmonary embolus

CHAPTER 3

Invasive Cervical Cancer

programs in place for early-stage disease, QoL among survivors becomes important. The major complication after radical surgery for invasive cancer of the cervix is postoperative bladder dysfunction. Reports in the literature by Seski and Carenza and Nobili and Giacobini suggest that bladder dysfunction is a direct result of injury to the sensory and motor nerve supply to the detrusor muscle of the bladder. The more radical the surgery, the greater will be the extent of damage and the more likely postoperative bladder dysfunction will result. This dysfunction is usually manifested in the patient by a loss of the sense of urgency to void and an inability to empty the bladder completely without the Credé maneuver. Although most patients learn to compensate for the sensory and motor loss and return to near-normal function, patients occasionally need to be taught intermittent self-catheterization, or long periods of constant bladder drainage may be necessary postoperatively. Sophisticated urodynamic studies have shown that a residual hypertonicity in the bladder detrusor muscle and urethral sphincter mechanism sometimes produces dysuria and stress incontinence. Treatment is symptomatic, with near-total recovery in most patients. Limitation of the extent and radicality of surgery, especially in patients with early lesions, can minimize this morbidity. Bandy and colleagues reported on the long-term effects on bladder function after RH (class III) with and without postoperative radiation. In his study, the necessity for bladder drainage of 30 or more days after surgery in 30% of patients was associated with significantly worse long-term residual and other bladder dysfunction. Adjunctive pelvic radiation was associated with significantly more contracted and unstable bladder. In a study reported from Greece of stage Ib cancers, 68 had a Rutledge type III, and 50 had a type II RH. Age, grade, bulky tumor, and LNM were similar in the two groups. Postoperative radiation was given to 31% of type III and 64% of type II hysterectomies. Major complications, mainly voiding problems, were significantly more common in those treated with type III hysterectomy; however, the disease-free survival was better in the class III hysterectomy (86.5% vs. 76.5%, P , .05). This study would suggest type III surgery is better than type II plus radiation. Ureteral fistulas are now infrequent (0% to 3%), primarily as a result of the improvement in techniques, such as avoiding excessive damage to the structure itself and preserving alternate routes of blood supply. With respect to lymphocyst formation, two studies testing the hypothesis that avoiding reperitonealization of the pelvic peritoneum obviates the need for such drainage have been reported; both studies suggest that drainage is not necessary if the peritoneum is left open over the surgical site. Ligation of the lymphatics entering the obturator fossa under the external iliac vein helps reduce the flow of lymph into this area, where lymphocyst formation is prevalent. Lymphocysts, if present, rarely cause injury and are usually reabsorbed if given enough time. Choo and colleagues reported that cysts smaller than 4 to 5 cm usually resolve within 2 months and that only observation is necessary. Surgical intervention is necessary when there is some evidence of a significant ureteral obstruction. During laparotomy, the surgeon should unroof the lymphocyst and

Figure 3.24 Diagram illustrating the location of transposed adnexae to a nonpelvic site where they can be spared from postoperative pelvic irradiation. (From DiSaia PJ: Surgical aspects of cervical carcinoma, Cancer 48:548, 1981. Copyright 1981 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley.)

prevent re-formation by suturing a tongue of omentum into the cavity (internal marsupialization). Percutaneous aspiration of the cyst, which is often associated with subsequent infection, should be used cautiously. Preservation of ovarian function is often desirable for patients who must undergo a surgical procedure for invasive cancer of the cervix. Often, after a careful histologic examination of the operative specimen, including the pelvic lymph nodes, a postoperative recommendation for pelvic radiation is indicated. Standard pelvic placement of preserved ovaries will result in postirradiation ovarian failure; therefore, a procedure for transposition of the ovaries to an extrapelvic site (Fig. 3.24) has been devised. Shielding during postoperative pelvic irradiation is possible with the ovaries so placed. The ovaries receive some radiation but not usually enough to prevent continued steroid production. A word of caution has been interjected by Mann and others regarding the rare occurrence of occult metastases to the ovary in patients with adenocarcinoma of the cervix. The two largest studies suggest that the incidence is between 0.6% and 1.3%. Most patients with metastatic disease in the ovary are postmenopausal or have had gross adnexal pathology or positive pelvic lymph nodes. These guidelines can be helpful in identifying patients for whom preservation of ovarian tissue is unwise. The incidence of occult metastasis to the ovary from SCC of the cervix (stages I and IIa) is so rare that preservation of ovarian tissue does not carry the same concerns. Lateral ovarian transposition will be discussed further in the following section on fertility preservation.

Indications for Postoperative Adjuvant Therapy Table 3.11 contains data sets from two randomized studies that have established the role for adjuvant therapy after radical surgery based on intermediate and high-risk surgicopathologic factors. In

CHAPTER 3

TABLE 3.11 When to Use Adjuvant

Therapy After Radical Hysterectomy

Randomized Trial of Adjuvant Pelvic Radiotherapy for FIGO Stage IB Recurrence (%) RRb GOG 92a n Adjuvant pelvic RT

137

n 5 21 (15)

No further therapy

140

n 5 39 (28)

0.53, P 5 .008

Randomized Trial of Synchronous Adjuvant Radiation Therapy and Chemotherapy for FIGO Stage IA2–IIA Projected PFS Projected OS (%) GOG 109/SWOG n (%) 8797/RTOG 91-12c Adjuvant pelvic RT 1 CT

127

80 HR 2.01, P 5 .003

81 HR 1.96, P 5 .007

Adjuvant pelvic RT alone

116

All patients underwent radical hysterectomy and lymphadenectomy, followed by randomization based on intermediate surgicopathologic risk factors (i.e., depth of stromal invasion, tumor size, presence of angiolymphatic space involvement). b Reduction in the relative risk of recurrence. c All patients underwent radical hysterectomy and lymphadenectomy followed by randomization based on high surgicopathologic risk factors (i.e., metastatic tumor to the lymph nodes, parametria, or vaginal margin). CT, Chemotherapy; FIGO, Federation of International Gynecologists and Obstetricians; GOG, Gynecologic Oncology Group; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RR, relative risk; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group; SWOG, Southwestern Oncology Group. GOG-92 data from Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study, Gynecol Oncol 73:177–183, 1999; GOG 109/SWOG 8797/RTOG 91-12 data from Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix, J Clin Oncol 18:1606–1613, 2000. a

a GOG study (protocol 92) of 277 patients with intermediate risk factors, stage Ib cancers were randomized to RH with or without postoperative irradiation. Of these patients, 137 were randomly assigned to radiation therapy, and 140 were not given further treatment. Based on a previous GOG study, intermediate risk was defined as greater than one-third of stromal invasion, lymph space involvement, and large clinical tumor diameter. (Note that the term lymph space involvement is used interchangeably with vascular space involvement.) All patients had negative lymph nodes. Four combinations of the risk factors were developed. Tumor size varied to greater than 4 cm. Although the two arms were equal with regard to the four combinations, in which group(s) the recurrences occurred is not stated. Using a one-tail test, there is a greater recurrence-free survival for the combined group (84.6% compared with 72.1%). OS was not significant; 11% died of cancer compared with 18% of the RH-only group. There was a 10% noncompliance rate in the radiation group. These authors are able to apply this information to clinical practice because more than 90% of patients would be treated without benefit with regard to survival. Data were presented with an intent-to-treat evaluation

Invasive Cervical Cancer

(see Table 3.11). A phase 3 randomized follow-up trial to determine the impact on survival for women with intermediate high-risk factors treated with adjuvant radiation with or without radiosensitizing chemotherapy following RH is ongoing by the NRG Oncology cooperative group (NCT01101451). Patients with positive pelvic nodes usually receive postoperative whole-pelvis irradiation and chemotherapy (see Table 3.11). Peters and colleagues randomized 268 patients with FIGO stages Ia2, Ib, and IIa carcinoma of the cervix, initially treated with RH and PL and found to have positive pelvic lymph nodes or positive margins or microscopic involvement of the parametrium, to receive either pelvic radiation therapy alone or concurrent chemoirradiation. Among the 243 patients who were accessible, progression-free survival (PFS) and OS were significantly improved in the patients receiving chemotherapy. The projected PFS at 4 years was 63% with pelvic radiation therapy alone and 80% with concurrent chemoirradiation (HR, 2.01; P 5 .003). The projected OS rate at 4 years was 71% with pelvic radiation therapy alone and 81% with concurrent chemoirradiation (HR, 1.96; P 5 .007). The combined therapy arm had more frequent grade III and IV hematologic and gastrointestinal (GI) toxicity. This landmark intergroup study of the GOG (protocol 109), the Southwest Oncology Group (protocol 8797), and the Radiation Therapy Oncology Group (RTOG) (protocol 91 to 12) was one of five randomized trials to be published between 1999 and 2000 attesting to the value of radiosensitizing chemotherapy in the management of cervical cancer (discussed further later). NRG Oncology is running a follow-up phase 3 randomized trial in this population to determine the impact of survival of adjuvant chemoradiation with and without additional chemotherapy among patients having undergone RH and found to have one or more high-risk factors according to the GOG 109 study (NCT00980954). Prognostic factors have been evaluated by several authors in patients with early-stage disease who have been treated surgically. In a study by Francke and associates, 105 patients with stage Ib were treated with RH and had negative lymph nodes. Only LSI showed significant correlation with local failure. There were 32 patients with SCC and positive LSI, 17 received postoperative radiation with 0 of 17 recurrences, and 4 of 15 (27%) treated with surgery only developed recurrence. The OS rate at 5 years was 96% in those treated with radiation and 93.3% in those with LSI not treated with radiation. Stockler and colleagues evaluated 194 patients with stage Ib and IIa who were treated with RH and had negative nodes. Nuclear grade 2 or 3 (P 5 .02) and small cell squamous histology (P 5 .001) were each associated with a fourfold increase in risk of recurrence, but LSI (P 5 .02), age younger than 36 years (P 5 .03), and either tumor size greater than 28 mm (P 5 .03) or surgical clearance less than 5 mm (P 5 .02) was associated with a 2.5-fold increase in risk of recurrence. Survival data were not given. Delgado, in reporting a GOG study of 645 women with stage Ib squamous carcinoma, including 100 patients with positive nodes, found depth of invasion, tumor size, and lymph space involvement to be important risk factors for recurrence in multivariate analysis. The group from Boston evaluated 171 patients with lymph

CHAPTER 3

Invasive Cervical Cancer

node–negative stage Ib and IIa cervical cancer treated primarily with surgery. A total of 116 (68%) patients were treated with surgery only, and 55 (32%) received radiation. Overall, 28 patients (16%) developed recurrent disease with no difference in the two treatment groups. After correction for other factors, patients with LSI who received radiation were less likely to develop recurrence than similar patients treated with surgery only (P 5 .04); however, OS was similar in the two groups. In a study from Gateshead, United Kingdom, 527 patients with stage Ib to IIb cervical cancer treated with RH were evaluated. There were 102 (19.3%) with LNM. In those with LNM, histologic differentiation (P 5 .009) and metastatic extent (P 5 .045) were the only independent prognostic factors for risk of cervical cancer deaths. Shibata and colleagues evaluated adjuvant chemoradiation in 37 patients who had undergone RH with PL. In addition to accepted high-risk surgicopathologic criteria (e.g., positive pelvic lymph nodes or positive surgical margins), the investigators also included the presence of lymphovascular space involvement (LVSI) as part of their inclusion criteria for protocol eligibility. Adjuvant chemotherapy consisted of cisplatin (70 mg/m2 on day 1) and 5-fluoracil (5-FU) (700 mg/m2/day on days 1 to 4) every 4 weeks for a total of three cycles. Pelvic radiotherapy was started concurrently with the first cycle of chemotherapy and administered to a dose of 45 gray (Gy) in 25 fractions. The incidence of grade III/IV toxicities included neutropenia (24.3%), nausea and vomiting (8.1%), and diarrhea (18.9%). The 5-year PFS was 89.2%. Both the GOG and the Korean GOG have emphasized the importance of further improvement of outcomes of women found to have high-intermediate surgicopathologic risk factors (e.g., large tumor diameter, deep stromal invasion, LVSI) after radical surgery for early-stage disease. A prospective, randomized trial involving adjuvant pelvic radiotherapy versus adjuvant single agent weekly cisplatin-based chemoradiation has recently been designed through collaboration of both cooperative groups. The optimal adjuvant therapy for patients found to have high-risk surgicopathologic factors has not yet been determined. Specifically, the role of adjuvant chemotherapy in place of or in addition to adjuvant chemoradiation has been the subject of much debate. Takeshima and colleagues treated 65 consecutive patients with FIGO stage IB to IIA cervical carcinoma with adjuvant chemotherapy after RH and PL. Patients with intermediate-risk factors (stromal invasion .50%; n 5 30) and those with high-risk factors (positive surgical margin, parametrial invasion, or lymph node involvement; n 5 35) were treated with bleomycin, vincristine, mitomycin, and cisplatin (three cycles for intermediate-risk cases and five cycles for high-risk cases). Chemotherapy was well tolerated with no significant adverse effects and no cases of severe bleomycin-related pulmonary toxicity. The 5-year disease-free survival was 93.3% for the intermediate-risk group and 85.7% for the high-risk group. All patients with SCCs in the intermediate-risk group and 89.3% of high-risk patients with SCC remained disease free. Despite the absence of adjuvant pelvic radiotherapy, local-regional recurrence occurred in 3.3% of the intermediate-risk group and in 8.6% of the high-risk group. A randomized trial comparing adjuvant chemoradiation with and without continued systemic

“consolidation” platinum-based and taxane-based chemotherapy is being considered by the GOG for patients found to have high-risk surgicopathologic factors after radical surgery. To summarize, the recommendation for postoperative adjuvant therapy (pelvic radiotherapy with or without radiosensitizing chemotherapy) after RH is based on highintermediate-risk surgicopathologic factors (i.e., tumor diameter, depth of stromal invasion, and presence of LVSI) and high-risk surgicopathologic factors (i.e., presence of tumor at the vaginal margin, in the parametria, or in the lymph nodes). The major research questions center around limiting the toxicity of chemoradiation, continued intravenous systemic therapy, and the triage of patients with locally advanced resectable lesions (i.e., IB2-IIA) to primary chemoradiation versus potentially trimodality therapy (i.e., radical surgery followed by adjuvant chemoradiation).

Sexual Function The subject of sexual function after therapy for cervical cancer is often ignored. Many patients never regain pretreatment sexual function. Patients treated with full pelvic irradiation therapy (i.e., external-beam and vaginal brachytherapy) experience decreased sexual function resulting from vaginal stricture formation with obliteration and premature ovarian failure (see forthcoming discussion). Andersen studied the sexual behavior, the level of sexual responsiveness, and the presence of sexual dysfunction of 41 women with uterine cancer compared with a matched group of healthy women. The two groups were similar until the onset of signs of disease, which sometimes occurred long before diagnosis, at which time the patients with cancer began experiencing significant sexual dysfunction. Sexual morbidity therefore begins actually in the prediagnosis period for many patients. Seibel reported on 46 patients who were interviewed more than 1 year after treatment for carcinoma of the cervix to establish the effects of radiation therapy and of surgical therapy on sexual feelings and performance. The patients who were irradiated experienced statistically significant decreases in sexual enjoyment, opportunity, and sexual dreams. The surgically treated group had no significant change in sexual function after treatment. Both groups experienced a change in self-image but did not believe that their partners or families viewed them differently. Myths about cancer and the actual effects of pelvic irradiation were found to have disrupted the sexual marital relationships of many women. Therapeutic programs with counseling and vaginal rehabilitation with the use of estrogen vaginal creams and possibly the use of dilators may be beneficial. Although RH offers an enhanced functional outcome, the procedure does not always leave sexual function undisturbed, with orgasmic problems and dyspareunia resulting from reduced vaginal size having been reported.

Nerve-Sparing Radical Hysterectomy Lin and colleagues evaluated urodynamic function in 20 women with cervical cancer who underwent RH. Urodynamic parameters measured preoperatively and postoperatively included bladder voiding and bladder storage functions, both of which

CHAPTER 3

were found to be significantly impaired in all 20 cases after surgery. Surgical damage to the pelvic autonomic nerves is likely to be responsible for not only subsequent impaired bladder function but also in defecation problems and sexual dysfunction. The development of a nerve-sparing procedure that does not compromise the radicality of the operation is highly desirable. Trimbos and colleagues introduced elements of the Japanese nerve-sparing technique in their Dutch population, citing that in various Japanese oncology centers, it had been recognized that the anatomy of the pelvic autonomic nerve plexus permits a systematic surgical approach to preserve these structures. The investigators first identified and preserved the hypogastric nerve in a loose tissue sheath underneath the ureter and lateral to the uterosacral ligament; next, the inferior hypogastric plexus in the parametrium is lateralized and avoided during parametrial transection; finally, the most distal part of the inferior hypogastric plexus is preserved during the dissection of the posterior part of the vesicouterine ligament. Trimbos and colleagues concluded that the procedure is feasible and safe and deserves further consideration. An updated series was presented by Maas and colleagues, who observed that the incidence of urinary dysfunction appears to be very low after nerve sparing. These findings have been supported by an Italian series of 23 patients reported by Raspagliesi and colleagues and by two recent Japanese papers for which urodynamic data were recorded for 27 patients. In the study by Sakuragi and colleagues, none of 22 patients for whom the nerve-sparing procedure was performed had urinary dysfunction, compared with 3 of the 5 patients for whom the procedure could not be performed. Nerve-sparing RH is an attractive approach because of improved urogenital, anorectal, and sexual functions. The sympathetic fibers that innervate the uterus, vagina, urinary bladder, and rectum come from T11 to L2 and form the superior hypogastric plexus. The parasympathetic fibers come from S2 to S4 at the pelvic wall as the pelvic splanchnic nerve. These fibers merge and form the inferior hypogastric plexus and branch to innervate the uterus and the urinary bladder. Professor Fujii from the Kyoto University Gynecology Group has gone to great lengths to provide a step-by-step anatomic identification of the nerve-sparing RH (Table 3.12). The first step in the nervesparing procedure involves isolation and separation of the deep uterine vein from the pelvic splanchnic nerve (Fig. 3.25). This is then followed by isolation and separation of the hypogastric nerve. Ultimately, the bladder branch from the inferior hypogastric plexus is identified running parallel to the blood vessels in the paracolpium, and the uterine branch from the inferior hypogastric plexus is separated and divided (Fig. 3.26). This procedure can be accomplished only through meticulous division of the posterior leaf of the vesicouterine ligament. Through separation of the inferior vesical vein in this ligament, the bladder branch from the inferior hypogastric plexus can be identified and preserved. van den Tillaart and colleagues evaluated the feasibility, safety, and local recurrence rate in 122 patients with FIGO stage IA to IIA lesions and compared them with 124 patients who

Invasive Cervical Cancer

TABLE 3.12 Comparison of Nerve-Sparing

Radical Hysterectomy With Traditional Radical Hysterectomy

FIGO stage IB1

Nerve-Sparing Radical Hysterectomy

Traditional Radical Hysterectomy

PValue

FIGO stage IB2

FIGO stage IIA

Mean operative time (min)

197

155.5

.05

Median lymph nodes removed (n)

17.8

15.7

Hospital stay (days)

7.6

8.4

Postvoid residual urine volume . 50 mL (days)

3.5

9.1

.00078

Mean decrease in hgb concentration (g%)

1.7

2.5

Complications

1 (blood transfusion)

FIGO, Federation of International Gynecologists and Obstetricians; hgb, hemoglobin; NS, not specified. Modified from Skret-Magierlo J, Naróg M, Kruczek A, et al: Radical hysterectomy during the transition period from traditional to nervesparing technique, Gynecol Oncol 116:502–505, 2010.

underwent non–nerve-sparing surgery. Unilateral or bilateral sparing of nerves was possible in 80% of cases in the nervesparing group. Operative time and blood loss were less in the nerve-sparing group, but the postoperative courses were similar. The local recurrence rates were not significantly different at 2 years of follow-up. Nerve-sparing surgery was not a significant prognostic factor for local recurrence in univariate and multivariate regression analyses. Neuronavigation systems and robotic-assisted nerve-sparing techniques continue to be under investigation along with the incorporation of the nerve-sparing procedure to radical trachelectomy for fertility preservation. From 2003 to 2005, Roh et al. randomly assigned 92 women with FIGO stage IA2 to IIA disease to conventional RH or nerve-sparing surgery. The patients were well-balanced in clinicopathologic characteristics, and among 86 patients included in final analysis, the frequency of long-term urinary symptoms was higher in the conventional surgery group, with significant deterioration of volume of residual urine and bladder compliance at 12 months. There were no significant differences observed in the 10-year disease-free survival between groups. In 2009, Querleu and Morrow proposed a new classification system for RH that continues to gain acceptance, particularly in Europe. In this new scheme, four main categories are described according to the extent of removal of the paracervix, using only the ureter, internal iliac vessels, and pelvic wall as reliable landmarks. The new system also incorporates nerve-preservation techniques and paracervical lymphadenectomy in subcategory assignments. In class A, the cervix is removed completely with minimal removal of the paracervix;

CHAPTER 3

Invasive Cervical Cancer

Paravesical space

Bladder

Cut end of uterine artery Obturator artery Cut end of deep uterine vein Obturator nerve

Pelvic splanchnic nerve

Obturator vein

Hypogastric nerve Rectum

External iliac artery

Pararectal space

External iliac vein Ureter

Common iliac artery and vein Internal iliac artery

Internal iliac vein

Figure 3.25 Nerve sparing. (From Fujii S: An atomic identification of nerve-sparing radical hysterectomy: a step-by-step procedure, Gynecol Oncol 111[2 suppl]:S33–S41, 2008.)

Cutting line of the nerve-sparing hysterectomy

Cut end of deep uterine vein

Vagina

Cervix

Cutting line of the original Okabayashi’s radical hysterectomy Urinary bladder

Ureter Cut end of middle vesical vein

Uterine branch from the hypogastric plexus

Inferior vesical vein Rectum

Pelvic splanchnic nerve

Hypogastric nerve

Cut end of deep uterine vein Rectovaginal ligament

Figure 3.26 Nerve sparing. (From Fujii S: An atomic identification of nerve-sparing radical hysterectomy: a step-by-step procedure, Gynecol Oncol 111[2 suppl]:S33–S41, 2008.)

in class B, the paracervix is removed to the level of the ureter. In class C, the entire paracervix is removed at the pelvic sidewall, and class D describes various exenterative procedures. Class C1 allows for preservation of the autonomic nerves, class D1 includes removal of the vascular parietal system, and class D2 requires removal of muscle and fascia at the lateral pelvic wall. Cibula et al. have approached the new classification scheme by Querleu and Morrow by developing it further into a threedimensional (3D) model using the standard anatomic landmarks for definition of resection margins in longitudinal and transverse dimensions. In their 2011 manuscript, figures

included photographs of the resulting 3D anatomic template that presents the parametrial resection in three dimensions along with the nerve-sparing procedure. The investigators intent is to increase adoption of the new classification scheme within the oncologic community and to enhance harmonization of clinical practice as it pertains to RH.

Sentinel Lymph Node Identification Although the risk of nodal metastases is low in women with small, early cancers (i.e., FIGO Ia2 and Ib1 lesions), the need for bilateral pelvic lymphadenectomies must still be emphasized. Controversy has centered on the existence and ability to identify

CHAPTER 3

sentinel lymph nodes (SLNs) in cervical cancer. The rationale for identifying an SLN in cervical cancer is to avoid full pelvic lymphadenectomies, which can result in lymphocyst formation and lower-extremity lymphedema, especially when adjuvant pelvic radiotherapy is given. Two techniques for sentinel node identification are available. An injection is performed around the tumor using either a blue dye or an isotopic colloid. Ideally, the two techniques are used concomitantly in patients with early-stage lesions (Fig. 3.27). Dargent and Enria reported the results on 70 consecutive patients. Failure in identification of the SLN occurred in 14 of the 139 attempted dissections. One SLN was detected in 121 dissections, and 2 SLNs were detected in 4 dissections. The investigators carried out a systematic PL after removal of the SLN. A metastatic

Invasive Cervical Cancer

involvement of the SLN was put in evidence in 19 of the 129 retrieved SLNs. The other regional lymph nodes were involved in 13 cases and not involved in six cases. In the 110 cases in which the SLN was not involved, all of the other regional nodes were free from metastasis. Table 3.13 contains studies on SLN detection in cervical cancer from 2007 to 2010. Most studies were performed with a combination of blue dye and a radioactive tracer with detection rates ranging from 87.3% to 100%. False-negative rates have ranged from 0% to 22.6%. Darlin and colleagues noted that the technique appears to be an accurate method for identifying lymph node metastases in cervical cancer patients with tumors that are 2 cm or smaller. The investigators recommend that in the case of a unilateral SLN only, a complete

Figure 3.27 Sentinel node. A, Lymphoscintigraphy. B, Blue dye. (A, From Niikura H, Okamura C, Akahira J, et al: Sentinel lymph node detection in early cervical cancer with combination 99mTc phytate and patent blue, Gynecol Oncol 94[2]:528–532, 2004. B, From Gil-Moreno A, Díaz-Feijoo B, Roca I, et al: Total laparoscopic radical hysterectomy with intraoperative sentinel node identification in patients with early invasive cervical cancer, Gynecol Oncol 96[1]:187–193, 2005.)

TABLE 3.13 Studies on Sentinel Node Detection in Cervical Cancer Reference

Patients (n)

Technique

Detection Rate (%)

Metastases Sentinel Node (%)

False-Negative (%)

Frumovitz et al.

831

R/B

89.8

20.5

8.2

Bats et al.

R/B

87.3

25.8

Altgassen et al.

590

R/B

88.6

15.7

22.6

Diaz-Feijoo et al.

R/B

100

Unknown

Kara et al.

R/B

100

28.1

Fader et al.

R/B

92.1

15.7

16.7

Van de Lande et al.

R/B

96.6

21.4

Pluta et al.

R/B

100

8.3

B, Blue dye; R, radioactive tracer. Modified from Oonk MHM, van de Nieuwenhof HP, de Hullu JA, et al: The role of sentinel node biopsy in gynecological cancer: a review, Curr Opin Oncol 21:425–432, 2009.

CHAPTER 3

Invasive Cervical Cancer

lymphadenectomy should be performed on the radionegative side. Although a randomized clinical trial to assess the equivalency of SLN mapping will not be feasible because a sample size of more than 1800 patients will be required to evaluate a decrease in recurrence rate from 15% to 10%, the GOG is prospectively studying the utility of lymphatic mapping and SLN identification in patients with early-stage cervical cancer (GOG protocol 206). In addition, the SENTICOL III trial (NCT03386734) will ultimately randomize 950 women to SLN mapping with or without PL at the time of hysterectomy/trachelectomy.

Minimally Invasive Radical Hysterectomy With Lymphadenectomy During preceding editions of this textbook, reports on the efficacy of laparoscopic RH and robotic-assisted laparoscopic RH to treat women with early-stage cervical carcinoma had been included as experience with these innovative surgical techniques accumulated. However, in 2018 the results of the phase III, international Laparoscopic Approach to Cervical Cancer (LACC) trial (NCT00614211) were presented. The trial activated during 2008 and enrolled patients with FIGO 2014 stage IA1 (with lymphovascular space invasion [LVSI]), IA2, and IB1 SCC, adenocarcinoma, and adenosquamous carcinoma. Participants were randomized to MIS RH (laparoscopic or robotic per surgeon preference) or open RH. The planned sample size of 740 patients was estimated to provide 87% power to declare MIS noninferior to open surgery with 4.5 years of follow-up and a noninferiority margin of -7.2 percentage points. DFS at 5 years from surgery was the primary endpoint. OS, patterns of recurrence, feasibility of sentinel lymphatic mapping, perioperative morbidity, QoL, and costs were secondary endpoints. The study closed prematurely in June 2017 due to an imbalance in deaths, at which time 85% of the trial had been enrolled (MIS, n 5 319; open, n 5 312), with both arms balanced for preoperative clinicopathologic characteristics and rates of postoperative adjuvant therapy (chemotherapy or radiotherapy). On March 26, 2018 at the 49th Annual Meeting of the Society of Gynecologic Oncology (SGO) in New Orleans, Ramirez et al. reported that at a median follow-up of 2.5 years (0.0 to 6.33 years) the MIS DFS in the intention-to-treat population was 86.0% compared to 96.5% for open surgery (difference, -10.5 percentage points, 95% CI, -16.4 to -4.7; P 5 .87 for noninferiority). At the time of analysis, 34 patients had experienced recurrence, with MIS relapse (n 5 27) almost four times higher than open surgery (n 5 7); greater than 40% of recurrences in both arms occurred in the vaginal vault or pelvis, with all non-vaginal vault pelvic recurrences reported in the MIS arm. The per-protocol analysis corroborated these results with DFS at 4.5 years of 87.1% for MIS versus 97.6% for open (difference, -10.5 percentage points; 95% CI, -16.0 to -5.0; P 5 .88 for noninferiority). The 3-year DFS was lower with MIS (91.2%) versus open (97.1%) (HR for disease recurrence or death due to cervical cancer, 3.874; 95% CI, 1.63 to 8.58). The difference persisted after adjustment for age, body-mass index, stage of disease, LVSI, lymph node involvement, and ECOG performance status score.

With 22 deaths reported, 3-year OS was also found to be inferior in the MIS group (93.8%, n 5 19 deaths) where patients were six times as likely to die during the follow-up period compared with the open group (99.0%, n 5 3 deaths) (HR 6.56; 95% CI, 1.48 to 29.00). Interpretation of data from the LACC trial has been controversial. Because previous randomized controlled trials (RCTs) comparing minimally invasive surgery to open surgery in clinical early-stage endometrial cancer, nonmetastatic colon cancer, and distal gastric cancer had reported equivalent survival rates and reduced surgical morbidity, the results of the LACC trial were met with some skepticism. Inferior mortality rates associated with MIS RH were also reported by Melamed et al. using the National Cancer Database (2010–2012) and the Surveillance, Epidemiology, and End Results (SEER) Database (2006 onwards), and in other retrospective studies following presentation of LACC. It is possible that the use of a uterine manipulator which may fragment the tumor, the steep Trendelenburg position required, and the high-pressure CO2 insufflation system with vaginal colpotomy may all be linked with tumor spread, higher rate of relapse, and ultimately death. It should be noted that most patients treated on the LACC trial underwent laparoscopic RH which most surgeons would argue is technically more challenging than the robotic approach. In addition, the surgical approach to small visible lesions (e.g., 2 cm or less) and/or microinvasive disease has not been adequately addressed by the LACC study. Our recommendation is to avoid minimally invasive surgery for any woman with cervical cancer found to have a visible lesion on the cervix. On November 13, 2018, the SGO issued a statement to its members summarizing the LACC trial findings and encouraged gynecologic oncologists to consider all available data when counseling patients. On February 28, 2019, the United States FDA posted a safety communication urging the oncology community to exercise caution when using roboticallyassisted surgical devices in women’s health including mastectomy and other cancer-related surgeries. Although the FDA warning was not restricted to cervical cancer, it is interesting that the only publication cited was that of the LACC trial.

Fertility-Preserving Surgery for Early-Stage Tumors For patients with microinvasive cervical carcinoma, management depends on the depth of invasion, and select patients may undergo conservative treatment with either cervical conization (FIGO Ia1) or radical trachelectomy with lymphadenectomy (FIGO Ia1 with LVSI, FIGO Ia2, and FIGO Ia adenocarcinoma) (see Fig. 3.17). In addition, patients with FIGO stage Ib lesions smaller than 2 cm with limited endocervical involvement and no pathologic evidence of lymph node metastases may be candidates for radical trachelectomy. In patients who are selected for conservative therapy, there should be no clinical evidence of impaired fertility and a strong desire for future childbearing. In addition, close surveillance should be instituted with scheduled Pap testing, colposcopic evaluation, and endocervical curettage.

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.14 Conization for Microinvasive Adenocarcinoma of the Cervix Depth #3.0 mm

Recurrences

Depth 3.1–5.0 mm

Recurrences

Schorge et al.

Author

—

McHale et al.

—

Webb

Not specified

Smith

Ceballos et al.

—

Poynor et al.

Bisseling et al.

Total

Modified from Bisseling KC, Bekkers RL, Rome RM, Quinn MA: Treatment of microinvasive adenocarcinoma of the uterine cervix: a retrospective study and review of the literature, Gynecol Oncol 107:424–430, 2007.

Cervical Conization for Adenocarcinoma In Situ and Microinvasive Carcinoma There has been a movement during the past decade to seriously explore fertility-sparing surgery for patients with adenocarcinoma in situ (AIS) and microinvasive carcinomas. For many patients with AIS, local excision appears to be sufficient treatment provided ectocervical and endocervical margins are clear and patient compliance with follow-up is demonstrable. It would appear that cold knife, CO2 laser, and large loop excision of the transformation zone (LLETZ) conization procedures produce acceptable results; however, these approaches should be reserved for highly selected patients (Table 3.14). Patients with margin involvement should be considered for repeat excisional biopsy. A 2009 meta-analysis composed of 33 studies indicated a recurrence rate for AIS of 2.6% for negative margins and 19.4% for positive margins (odds ratio [OR], 2.48; 95% CI 1.05, 1.622; P , .001). Invasive adenocarcinoma was more commonly associated with positive margins (5.2%) compared with negative margins (0.1%). In a study of 85 patients with FIGO stage IA1 SCC treated by electrosurgical conization and cold conization to preserve fertility, there was one recurrence (1.2%) at a median follow-up of 81 months. In a second report containing 75 patients with FIGO stage IA1 SCC, there were no recurrences among the 53 women who underwent conization followed by hysterectomy nor in the 22 who underwent conization alone. As in the case with AIS and microinvasive SCC, conservative fertility-preserving therapy may be considered for select cases of microinvasive adenocarcinoma, although this remains controversial. It would seem that for FIGO stage IA1 adenocarcinomas, conization is safe. When LVSI is present, laparoscopic PL seems advisable. In summary, for highly selected patients with early-stage disease seen in consultation with a gynecologic oncologist, cold knife cervical conization is a reasonable alternative to preserve fertility provided compliance with follow-up is not problematic and pathology review has excluded highly aggressive histologic subtypes (e.g., neuroendocrine tumors).

Vaginal Radical Trachelectomy With Laparoscopic Lymphadenectomy Radical trachelectomy involves removing all or most of the cervix along with the bilateral parametria and upper vagina. This procedure allows for preservation of the uterus for childbearing

and although it can be performed vaginally, abdominally, or through a minimally invasive approach (i.e., straight-stick laparoscopy or robotic-assisted laparoscopy), we strongly recommend avoiding laparoscopy and/or robotic-assisted approaches for patients known to have invasive carcinoma with visible lesions. Of note, patients with stage Ia2 disease have a 6.3% risk of nodal metastases, so treatment must include a formal PL. In 1987, Dargent designed a fertility-preserving operation for stage Ia2 and some Ib1 lesions. A variant of the classical Schauta operation of vaginal RH, the vaginal radical trachelectomy (VRT) is performed in conjunction with bilateral laparoscopic lymphadenectomies. The VRT is performed with division of the uterus underneath the isthmus, and at the completion of the procedure, the uterus is sutured to the vagina. Oncologically, the technique is satisfying because a wide margin around the lesion is obtained containing the parametria and the upper vagina but leaving the body of the uterus in situ. Plante and colleagues collected more than 600 reports of the vaginal technique from the past decade’s literature, including 115 of her own. Oncologic outcomes have been satisfactory with an overall recurrence rate of 4.5% and death rate from disease of 2.5% (Table 3.15). Risk factors for recurrence include TABLE 3.15 Oncologic Outcomes After

Vaginal Radical Trachelectomy Author

Patients (n)

Median Follow-Up (mo)

Recurrence Rate (%)

Death (%)

Marchiole

118

7 (6)

5 (4)

Plante

115

4 (3)

2 (2)

Shepherd

112

3 (3)

2 (2)

Hertel

100

3 (3)

2 (2)

Covens et al.

7 (7.5)

4 (4)

Sonoda

1 (3)

Burnett et al.

2 (10.5)

Schlearth

Total

603

—

27 (4.5)

15 (2.5)

From Plante M: Vaginal radical trachelectomy: an update, Gynecol Oncol 111:S105–S110, 2008.

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.16 Obstetrical Outcomes After Vaginal Radical Trachelectomy

Author

Pregnancies

TAB, Ectopic (%)

FirstTrimester Loss (%)

SecondTrimester Loss (%)

ThirdTrimester Deliveries (%)

Deliveries ,32 Weeks (%)

Deliveries 33–36.6 Weeks (%)

Deliveries .37 Weeks (%)

Currently Pregnant

Plante

4 (5)

17 (20)

3 (4)

58 (66)

3 (5)

8 (14)

47 (81)

5 (5)

Mathevet

5 (9)

9 (16)

8 (14)

34 (61)

2 (6)

3 (9)

29 (85)

Shepherd

3 (5)

14 (25)

7 (13)

28 (51)

8 (29)

12 (43)

8 (29)

3 (5)

Bernardini et al.

3 (14)

1 (4)

18 (82)

3 (17)

12 (67)

Hertel

2 (11)

1 (5)

12 (67)

—

3 (16)

Sonoda

3 (27)

4 (36)

4 (100)

4 (36)

Burnett et al.

Schlearth

Total

256

14 (5)

47 (18)

22 (8.6)

158 (62)

18 (12)

26 (16)

102 (65)

15 (6)

From Plante M: Vaginal radical trachelectomy: an update, Gynecol Oncol 111:S105–S110, 2008.

lesions 2 cm or larger (29% vs. 1%) and the presence of LVSI (12% vs. 2%). Adenocarcinomas and adenosquamous carcinomas are not clearly associated with an increased risk of recurrence. Patients with neuroendocrine tumors should probably not be offered fertility-sparing surgery. Approximately 10% to 12% of patients selected for VRT are found to have more extensive endocervical disease at the time of surgery or positive nodes on frozen section, leading to abandoning the procedure in favor of adjuvant therapy or completion RH. Plante and colleagues also tabulated obstetric outcomes for 256 patients (Table 3.16). Approximately 62% of pregnancies after VRT will reach the third trimester, of which 65% will reach term. The preterm delivery rate is in the range of 28%, but only 12% will end with significant prematurity (,32 weeks) in which most neonatal morbidity occurs. Overall, 40% of all pregnancies can be expected to culminate with the birth of a healthy newborn at term. Abdominal approaches to radical trachelectomy may include nerve-sparing, laparoscopic, or robotic-assisted techniques. Potential benefits of the abdominal approach for radical trachelectomy include wider parametrial resection, possible lower intraoperative complication rates, and techniques familiar to most gynecologic oncologists (Fig. 3.28). Cibula and colleagues reviewed the more than 100 reported cases of abdominal radical trachelectomy (ART) in 2008 and then updated their own experience with the abdominal approach in 2009. Specific indications for the abdominal approach have included clear cell carcinoma of the upper vagina, clear cell cervical carcinoma in pediatric patients, cervical cancer in patients with distorted vaginal anatomy, cancer in the cervical stump after subtotal hysterectomy, bulky exophytic cervical cancer, extent and location of cervical cancer that requires increased radicality of parametrial resection (type III), and cervical cancer in the first half of pregnancy. In total, nine live births have been reported, of which at least two were premature deliveries. Einstein and colleagues compared surgical and pathologic outcomes for 43 adult patients with FIGO stage IB1 lesions who

Figure 3.28 Vaginal radical trachelectomy. (From Einstein MH, Park KJ, Sonoda Y, et al: Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes, Gynecol Oncol 112:73–77, 2009.)

underwent VRT (n 5 28) or ART (n 5 15) (Table 3.17). The median measured parametrial length in the VRT group was 1.45 cm compared with 3.97 cm in the ART group (P , .0001). Parametrial nodes were only detected in the ART specimens (n 5 8, 57.3%). There was no difference in histologic subtypes, LVSI, or median total regional lymph nodes removed in the two groups. Median blood loss was greater but not clinically significant in the ART group, and the median operating time was less in the ART group. The two groups did not differ significantly in the overall complication rate. The investigators concluded that the abdominal approach allows for wider parametrial resection, including contiguous parametrial nodes. By allowing for the preservation of the body of the uterus and thereby the potential for reproductive function, the

CHAPTER 3

TABLE 3.17 Pathologic Results of the

Unfixed Trachelectomy Specimens With Bilateral Parametrial Measurements by the Pathologist VRT (n 5 28)

ART (n 5 15)

P Value

Median gross length (cm)

1.45 (0.73–1.63)

3.97 (2.7–5.36)

.01

Median histologic length (cm)

1.07 (0.89–1.25)

1.51 (1.36–1.77)

#.0001

Patients with parametrial lymph nodes detected

0 (0%)

8 (57.3%)

rates. There are no clear consensus guidelines regarding the safety of ART for such patients. One option is to administer neoadjuvant chemotherapy to reduce tumor size. In a recent literature review by Pareja et al., different approaches to radical trachelectomy were analyzed, and the outcome measures appear in the table below:

.0002

ART, Abdominal radical trachelectomy; VRT, vaginal radical trachelectomy. From Einstein MH, Park KJ, Sonoda Y, et al: Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes, Gynecol Oncol 112:73–77, 2009.

Invasive Cervical Cancer

Pregnancy Recurrence

ART > 2 cm (%)

NACT ART All Followed VRT Sizes by Surgery VRT > 2 cm (%) (%) (%) (%)

— 6

16.2 3.8

30.7 7.6

24 4.2

— 17

ART, Abdominal radical trachelectomy; NACT, neoadjuvant chemotherapy; VRT, vaginal radical trachelectomy.

Lateral Ovarian Transposition

Figure 3.29 Abdominal radical trachelectomy. (From Einstein MH, Park KJ, Sonoda Y, et al: Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes, Gynecol Oncol 112:73–77, 2009.)

radical trachelectomy emerges as a true breakthrough in the management of young women with early-stage cervical cancer (Fig. 3.29). It is currently the fertility-sparing procedure with the most available data supporting its use. Although these results are encouraging, there is lack of level I evidence (i.e., RCTs) comparing safety and survival rates between conservative and radical methods. Therefore, these techniques should be used by fully trained operators. In our opinion, the vaginal approach can be considered in conjunction with laparoscopic transperitoneal lymphadenectomy in patients who strongly desire future fertility and harbor a stage Ia1 lesion with LVSI, an Ia2 lesion, or an Ib1 tumor less than 2 cm in diameter. In a recent series, Smith et al. reviewed the oncologic outcomes and obstetrics outcomes among patients who underwent radical trachelectomy. Over 1491 patients underwent VRT, 955 underwent ART, and 120 underwent laparoscopic radical trachelectomy. The 5-year OS ranged from 97.4% to 98.6% for the vaginal and abdominal approaches, respectively, while the 5-year survival for patients treated laparoscopically has not been reached. As stated earlier, we do not recommend minimally invasive radical trachelectomy in the setting of a visible carcinoma. There were a total of 225 post-trachelectomy pregnancies in this series of 2566 patients total, with the preterm delivery rate ranging from 40% to 57%, and an overall upper limit live birth rate of approximately 75%. For patients with FIGO stage IB tumors larger than 2 cm, VRT is not recommended because of unacceptable recurrence

As described previously, young patients with FIGO stage I to IIa cervical carcinoma who are considered to be at high risk for requiring adjuvant pelvic irradiation (with or without radiosensitizing chemotherapy) should have the ovaries transposed to the paracolic gutters at the time of radical abdominal hysterectomy. The infundibulopelvic ligament is mobilized, and two large metallic clips should be placed in an “X” formation across the mesosalpinges to assist in radiographic localization during radiation treatment planning. Patients with locally advanced carcinomas (i.e., FIGO stages Ib2 to IVa) who will receive primary chemoirradiation can undergo lateral ovarian transposition via laparoscopy in anticipation of therapy. The incidence of ovarian failure following transposition ranges from 28% to 50% when pelvic irradiation is used. There is a tendency to become postmenopausal if the scatter radiation dose at the transposed ovaries is greater than 300 centigray (cGy). This scatter radiation dose does not appear to depend on the distance the ovaries are placed from the linea innominata. The risk of premature ovarian failure when adjuvant radiation therapy is not required is approximately 5% in patients who have undergone lateral ovarian transposition. The risk of developing symptomatic ovarian cysts appears to be approximately 5%. Husseinzadeh and colleagues performed lateral ovarian transposition in 22 patients with invasive cervical cancer, 15 of whom received whole pelvic external radiation therapy. Nine patients also received one or two intracavitary insertions. Ovarian function was measured by the serum gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Five patients developed postmenopausal symptoms. Ovarian function was preserved in seven patients, all of whom received an average dose of 250 cGy to the ovaries via external radiation and intracavitary insertion(s). FSH values ranged from 3.3 to 38.8 mIU mL21 (mean, 17.7 mIU mL21).

TREATMENT OF LOCALLY ADVANCED DISEASE Radiotherapy Over the past century, radiotherapy has emerged as a notable alternative to radical surgery, primarily because of improvements in technique. The number of radiation-resistant lesions

CHAPTER 3

Invasive Cervical Cancer

was discovered to be small, and skilled radiologists limit radiation injury, especially with the moderate dosages used for early disease. Much evidence has been presented that proves that radiotherapy can destroy disease in lymph nodes and in the primary lesion. Over the past 2 decades, RH has been reserved in many institutions for patients who are relatively young, lean, and in otherwise good health. In other areas of the United States, radiotherapy or surgery is used alone when the alternative modality is not available. The relative safety of both treatment modalities and the high curability for stages I and IIa lesions give physicians and patients a true option for therapy. Radiotherapy for cancer of the cervix was begun in 1903 in New York by Margaret Cleaves. In 1913, Abbe was able to report an 8-year cure. The Stockholm method was established in 1914, the Paris method in 1919, and the Manchester method in 1938. Radium was the first element used; it has always been the most important element in radiotherapy of this lesion. External irradiation was used to treat the lymphatic drainage areas in the pelvis lateral to the cervix and the paracervical tissues. Successful radiation therapy depends on the following: 1. Greater sensitivity of the cancer cell, compared with the cells of the normal tissue bed, to ionizing radiation 2. Greater ability of normal tissue to recuperate after irradiation 3. A patient in reasonably good physical condition. The maximal effect of ionizing radiation on cancer is obtained in the presence of a good and intact circulation and adequate cellular oxygenation. Preparation of the patient for a radical course of irradiation therapy should be as careful as the preparation for radical surgery. The patient’s general condition should be as well maintained as possible with a diet high in proteins, vitamins, and calories. Excessive blood loss should be controlled, and hemoglobin should be maintained well above 10 g. Some consideration must be given to the tolerance of normal tissues of the pelvis, which are likely to receive relatively high doses during the course of treatment of cervical malignancy. The vaginal mucosa in the area of the vault tolerates between 20,000 and 25,000 cGy. The rectovaginal septum is said to tolerate approximately 6000 cGy over 4 to 6 weeks without

difficulty. The bladder mucosa can accept a maximal dose of 7000 cGy. The colon and rectum will tolerate approximately 5000 to 6000 cGy, but small bowel loops are less tolerant and are said to accept a maximal dose of between 4000 and 4200 cGy. This pertains to small bowel loops within the pelvis; the tolerance of the small bowel when the entire abdomen is irradiated is limited to 2500 cGy. One of the basic principles of radiotherapy is implied here: the normal tissue tolerance of any organ is inversely related to the volume of the organ receiving irradiation. External irradiation and intracavitary radium therapy must be used in various combinations (Table 3.18). Treatment plans must be tailored to each patient and her particular lesion. The size and distribution of the cancer, not the stage, should be treated. Success in curing cancer of the cervix depends on the ability of the therapy team to evaluate the lesion (and the geometry of the pelvis) during treatment and then make indicated changes in therapy as necessary. Intracavitary radium therapy is ideally suited to the treatment of early tumors because of the accessibility of the portio of the cervix and the cervical canal. It is possible to place radium or cesium in close proximity to the lesion and thus deliver surface doses that approximate 15,000 to 20,000 cGy. In addition, normal cervical and vaginal tissue has a particularly high tolerance to irradiation. One therefore has an ideal situation for the treatment of cancer because there are accessible lesions that lie in a bed of normal tissue (cervix and vagina) that is highly radioresistant.

Intensity-Modulated Whole Pelvic Radiotherapy Traditional external-beam radiotherapy is based on field limits determined by bony landmarks, resulting in generous amounts of healthy tissue being encompassed by large treatment volumes. However, the margins of oncologic security are large, so target motion and the GTV have a negligible impact. With increasing adoption of conformal treatment and attendant steep dose gradients, both the GTV and clinical target volume (CTV) must be precisely defined. Using variable intensity across the face of the radiation beam to shape isodoses, IMRT delivers a high tumor dose

TABLE 3.18 Suggested Therapy for Cervical Cancer WHOLE PELVIS Stage

Radiation Dose (cGy)

Brachytherapy (mg/h)

Surgery

Ial true microinvasive

—

Extrafascial hysterectomy

Ia2

2000 (2000 parametrial)

8000 (two applications)

Radical hysterectomy with bilateral pelvic lymphadenectomy as an option

4000

6000 (two applications)

IIb

4000–5000a

5000–6000 (two applications)

IIIa

5000–6000a

2000–3000 or interstitial implant

—

IIIb

5000–6000a

4000 (one application), 5000 (two applications)b

—

IVa

6000

4000 (one application), 5000 (two applications)b

—

IVb

500–1000 pulse two to four times 1 week apart

Palliative

—

Consider pelvic exenteration for tumor persistence

Patients with larger lesions or poor vaginal geometry merit the higher dose of external radiation. Two applications are suggested after whole-pelvis radiation with larger lesions or when the first application has less than optimum dosimetry.

a b

CHAPTER 3

with minimization of radiation exposure to healthy tissue. Dosimetric advantages can be exploited using a combination of 3D planning and variable radiation intensity in each field. Reductions of both acute and chronic GI and GU toxicity have been trumpeted among the dosimetric advantages of IMRT and some evidence suggesting that IMRT can spare bone marrow. Uncertainty exists when considering IMRT for the management of locally advanced cervical cancer, including delineation of the required margins and what the acceptable degree of homogeneity is for the target. Importantly, given the large volume of hematopoietically active marrow in the pelvis and lower lumbar spine, in their review, Fernandez-Otz and Crook propose specific planning constraints be required, including use of a contouring atlas for pelvic volumes as currently used in RTOG protocols (now part of NRG Oncology). RTOG protocol 0418 established the current role of IMRT in gynecologic cancers to be relegated to the postoperative (i.e., adjuvant) setting. The unacceptable toxicity of dose escalation to the pelvis and paraaortic regions using conventional radiotherapy has been prohibitive. However, with IMRT, simultaneous boosts to the target or affected lymph nodes results in an improvement of the therapeutic ratio and the added advantage of shortening the treatment time. Because of cervical-utero movement, the use of IMRT in the setting of the intact cervix requires continued investigation. RTOG protocols require a full bladder and empty rectum to minimize movement, but cervical tumor regression during treatment is also an issue, with a median volume reduction of 46% being reported in the literature. For this reason, Fernandez-Otz and Crook suggest that IMRT should be replanned during the final third of treatment to take advantage of the shrinking GTV. Ly et al. developed dose-volume histograms of the target volume in a comparison of conventional radiotherapy, 3D conformal radiotherapy, and IMRT for cervical cancer. They reported that the planning target volume dose of the IMRT was significantly higher than the other two modalities and that when more than 30 Gy was administered in IMRT, organs at risk including the small intestine, rectum, bladder, and bone marrow received reduced volumes of radiations. To date,

Manchester technique

Invasive Cervical Cancer

however, there are no head-to-head randomized phase III trials comparing IMRT with conventional radiotherapy in the primary treatment of locally advanced cervical cancer.

Radium and Cesium Therapy Radium is the isotope that has been used traditionally in the treatment of cancer of the cervix. Its greatest value is that its half-life is approximately 1620 years; therefore, it provides a very stable, durable element for therapy. In recent years, both cesium and cobalt have been used for intracavitary therapy. Cesium has a half-life of 30 years; with the current technology, cesium provides an adequate substitute for radium. Four major technologies for the application of radium in the treatment of cervical cancer continue to be favored among gynecologists. Of these technologies, three are intracavitary techniques using specially designed applicators, and the fourth technique involves the application of radium in the form of needles directly into the tumor. The variations among the three techniques of intracavitary brachytherapy are found in the Stockholm, Paris, and Manchester schools of treatment (Fig. 3.30). The differences are mainly found in the number and length of time of applications, the size and placement of the vaginal colpostats, and radium loading. In the United States, the tendency has been to use fixed radium applicators with the intrauterine tandem and vaginal colpostats originally attached to each other. Over the past 3 decades, a flexible afterloading system, Fletcher-Suit, has gained increasing popularity because it provides flexibility and the safety of afterloading techniques. The Paris method originally used a daily insertion of 66.66 mg of radium divided equally between the uterus and the vagina. The radium remained in place for 12 to 14 hours, and the period of treatment varied from 5 to 7 days. An essential feature of the Paris method, and a part of the modification of this technique, is the vaginal colpostat, which consists of two hollow corks that serve as radium containers joined together by a steel spring that separates them into the lateral vaginal wall. The Stockholm technique uses a tandem in the uterine cavity surrounded by a square radium plaque applied to the vaginal wall and portio vaginalis of the cervix. No radium is placed in the lower cervical canal, and vaginal sources are used to cover

Paris technique

Stockholm technique

Figure 3.30 Three techniques of intracavitary brachytherapy.

CHAPTER 3

Invasive Cervical Cancer

the cervical lesion. The uterine tandem and vaginal plaque are immobilized by packing and left in place for 12 to 36 hours. Two or three identical applications are made at weekly intervals. The Manchester system is designed to yield constant isodose patterns regardless of the size of the uterus and vagina. The source placed in the neighborhood of the cervical canal is considered the unit strength. The remaining sources in the corpus and vagina are applied as multiples of this unit and are selected and arranged to produce equivalent isodose curves in each case and an optimal dose at preselected points in the pelvis. The applicator is shaped to allow an isodose curve that delivers radiation to the cervix in a uniform amount. The Fletcher-Suit system (Fig. 3.31) previously mentioned is a variation of the Manchester technique. An effort is made in the two radium insertions to administer approximately 7000 cGy to the paracervical tissues as the total of the dose from both external and intracavitary irradiation. The isodose distribution around a Manchester system is pear shaped (Fig. 3.32). The maximal total dose delivered by the two radium insertions is a function of the total dose to the bladder and rectum. The total dose received by the rectal mucosa from both radium applications usually ranges between 4000 and 6000 cGy. The nearest bladder mucosa may receive between 5000 and 7000 cGy. When whole-pelvis irradiation is used, the radium dose must be reduced to keep the total dose to the bladder and rectum within acceptable limits. In conjunction with the development of a system of radium distribution, British workers have defined two anatomic areas of the parametria (see Fig. 3.34) where dose designation can be correlated with clinical effect. These are situated in the proximal parametria adjacent to the cervix at the level of the internal os

and in the distal parametria in the area of the iliac lymph nodes and are designated point A and point B. The description states that point A is located 2 cm from the midline of the cervical canal and 2 m superior to the lateral vaginal fornix. The dose at point A is representative of the dose to the paracervical triangle, which correlates well with the incidence of sequelae and with the 5-year control rate in many studies. Point B is 3 cm lateral to point A. This point, together with the tissue superior to it, is significant when considering the dose to the nodebearing tissue. It is clear from what has been said relative to points A and B that they can represent important points on a curve describing the dose gradient from the radium sources to the lateral pelvic wall. This gradient is different for the various techniques. In a comparison of the physical characteristics of radio techniques, the ratio of the dose at point A to the dose at point B should help define physical differences. In addition, determining the dose at point A relative to the calculated dose at points identified as bladder trigone and rectal mucosa provides a means of assessing the relative safety of one application over another. The concepts of points A and B have been questioned by many authors, including Fletcher and Rutledge. They remain as imaginary points but seem to provide a framework in which therapy is planned. Again, the distribution of the disease must be the primary guide in planning therapy, and the total dose to either point A or point B is relative only to their position with regard to the disease distribution. Whole-pelvis irradiation is usually administered in conjunction with brachytherapy (e.g., intracavitary radium or cesium) in a dose range of 4000 to 5000 cGy. Megavoltage machines such as cobalt, linear accelerators, and the betatron have the distinct advantage of giving greater homogeneity of dose to

Figure 3.31 Fletcher-Suit radium applicators: ovoids and tandem with inserts.

CHAPTER 3 3500 cGy

Invasive Cervical Cancer

5 cm 2 cm

3 cm

2 cm

Figure 3.32 Pear-shaped distribution of radiation delivered to tissues surrounding a typical radium application with the Manchester type of applicators. Points A and B are noted as reference points.

the pelvis. In addition, the hard, short rays of megavoltage pass through the skin without much absorption and cause very little injury, allowing almost unlimited amounts of radiation to be delivered to pelvic depths with little if any skin irritation. Orthovoltage, because of its relatively long wavelength and low energy, has the disadvantage that doses to the skin are particularly high and, in delivering the required amount of radiation to the pelvis, may cause temporary and permanent skin changes. Thus, for pelvis irradiation, high-energy megavoltage equipment has definite advantages over orthovoltage and even lowenergy megavoltage equipment.

Interstitial Therapy In advanced carcinoma of the cervix, the associated obliteration of the fornices or contracture of the vagina may interfere with accurate placement of conventional intracavitary applicators. Poorly placed applicators fail to irradiate the lesion and the pelvis homogeneously. Syed and Feder have revived a solution to this problem by advocating transvaginal and transperineal implants. The technique uses a template to guide the insertion of a group of 18-gauge hollow steel needles into the parametria transperineally (Fig. 3.33). These hollow needles are subsequently “afterloaded” with iridium wires when the patient returns to her hospital room. Theoretically, this technique locates a pair of paravaginal interstitial colpostats in both parametria. This approach appears promising, but longterm studies illustrating an improved survival rate and reasonable morbidity are not available. Also, there is no report reflecting, prospectively, the effectiveness, in comparable groups of patients, of the interstitial technique versus the standard intracavitary approach.

Figure 3.33 Diagram of the technique of interstitial therapy for advanced cervical cancer using a Syed-Noblett template.

Interstitial therapy may have particular value in the treatment of carcinoma of the cervical stump. Although carcinoma of the cervical stump has become a relatively rare disease, accounting for fewer than 1% of all gynecologic malignancies, it does create difficult problems in terms of optimal geometry for delivery of effective irradiation therapy. In some series of cervical cancer, the incidence of carcinoma of the cervical stump is approximately 10%. Prempree, Patanaphan, and Scott reported excellent results with absolute survival rates of 83.3% for stage I, 75% for stage IIa, and 62.5% for stage IIb using radiation therapy with an emphasis on parametrial interstitial implants in the more advanced diseases. Similar results have been obtained by Puthawala and associates.

Extended-Field Irradiation Therapy Over the past 2 decades, attempts have been made to improve survival for more patients with advanced cervical cancer by identifying the presence of paraaortic lymph node metastases and applying extended-field irradiation to the area (Fig. 3.34). The en bloc pelvic and periaortic portals extend superiorly as far as the level of the dome of the diaphragm and inferiorly to the obturator foramen. The width of the periaortic portion of the field is usually 8 to 10 cm, and the usual dose delivered is between 4000 and 5000 cGy in 4 to 6 weeks. A booster dose of 1000 cGy is often given to the pelvic field alone. Identification of paraaortic lymph node involvement was initially attempted by use of lymphangiography, but this technique did not find general acceptance because of varied accuracy from institution

CHAPTER 3

Invasive Cervical Cancer

Figure 3.34 Abdominal radiograph showing portals for extended-field irradiation in cervical cancer.

TABLE 3.19 Late Complications of Radiation

Therapy With Approximate Incidence Complication

Patients (%)

Sigmoiditis

Rectovaginal fistula

Rectal stricture

Small bowel obstruction

(with extended field)

Vesicovaginal fistula

Ureteral stricture

to institution and from radiologist to radiologist. Surgical localization of periaortic involvement has been more satisfactory. Several reports have discussed survival and complications in patients with carcinoma of the cervix and periaortic metastases who received extended-field irradiation (Table 3.19). Piver and Barlow of Roswell Park Memorial Institute, Buffalo, reported on 20 women with previously untreated cervical cancer who received radical irradiation to the periaortic lymph nodes and

pelvis after the diagnosis of periaortic lymph node metastases had been established by surgical staging. They noted that 90% of these patients received 6000 cGy to the periaortic nodes and pelvis in 8 weeks using a split-course technique. A later report shows that 30% died of complications of this therapy, and 45% died of recurrent disease. Only 25% of patients survived disease free for 16, 18, 24, and 36 months. The criticism may be that the dose is too high, yet a lesser dose might be ineffective, and four patients did survive. It is obvious that a safe yet effective dosage level for extended-field irradiation therapy has not yet been established. Wharton and colleagues of the MD Anderson Hospital reported on 120 women treated with preirradiation celiotomy. Of these patients, 32 had severe bowel complications, and 20 (16.6%) eventually died as a result of the surgery or of the surgery and irradiation. Four of these patients died immediately as a result of the surgical procedure. Of 64 patients with positive nodes who were irradiated, 17% lived for 13 to 38 months after treatment. No patient had survived for 5 years. Wharton and associates further reported that in 36 women with positive nodes, it was possible to accurately determine the failure sites after completion of the full course of irradiation therapy. In 25 of these patients, distant metastases were the first evidence of treatment failure, 11 had disease or developed recurrence within the treatment fields, and disease of the pelvic wall was found in only two patients. The role of surgical staging in removal of paraaortic or pelvic nodes in cervical cancer remains controversial. The results of the aforementioned experience would question significant benefit in view of the complications and survival. Retroperitoneal lymphadenectomy, compared with the intraperitoneal approach, has decreased complications mainly as a result of adhesions and possible bowel complications. More recently, patients with advanced disease have had the paraaortic nodes reevaluated so that extended fields could be added if necessary. The laparoscopic approach is currently being evaluated. Less invasive approaches such as lymphangiogram, CT, and MRI studies have also been evaluated. The sensitivity is less, and falsenegative results may be as high as 24% in patients with stage IIIB disease. Many gynecologic oncologists will obtain a CT scan and, if the result is positive, do a fine-needle aspiration. If the result is negative, then surgical removal may be done. An alternative is to radiate the paraaortic areas prophylactically. This has been done with little or no survival benefit. All of the studies note that the severe complication rate essentially doubles (5% to 10%) when radiation was given to the paraaortic area. Experience has shown that doses of about 4500 cGy, particularly when administered in daily fractions of 150 to 180 cGy, are safely tolerated by the organs in the periaortic treatment volume, and a complication rate of 5% should be expected. Extraperitoneal surgery appears to be associated with less postradiation morbidity, probably because of reduced bowel adhesions. The issues of the utility of periaortic radiation and surgical staging in the management of cervical carcinoma are closely intertwined. Although many hypotheses have been raised to support or reject the use of surgical staging, it is clear that some patients with biopsy-proven periaortic node metastases

CHAPTER 3

can be cured with radiotherapy using extended fields. Approximately 20% of patients who receive extended-field radiotherapy survive cervical cancer metastatic to the periaortic lymph nodes. Rubin and colleagues had a 50% survival rate in a group of patients with stage Ib disease with documented periaortic lymph node involvement. In many reports, the true value of extendedfield radiation is clouded because patients with periaortic node involvement often have advanced disease in which any node or regional therapy may have little effect on long-term survival. The incidence of pelvic recurrence after irradiation alone for stages Ib, IIa, and IIb carcinomas of the cervix increases with the diameter of the tumor. Data from the MD Anderson Hospital showed an improved pelvic control rate, and a small increase in survival, when patients with the bulky, so-called barrel-shaped lesions were treated with preoperative irradiation followed by extrafascial hysterectomy. The subject continues to be controversial, with conflicting studies in the literature. Gallion and colleagues reported on 75 patients with “bulky, barrel-shaped” stage Ib cervical cancer; 32 patients received radiation alone, and 43 patients were treated with radiation followed by extrafascial hysterectomy. The incidence of pelvic recurrence was reduced from 19% to 2%, and extrapelvic recurrence was reduced from 16% to 7% in patients treated by combination therapy, which produced no increase in treatment-related complications. However, Weems and colleagues described 123 such patients treated from two different eras at his institution. Examination of pelvic control rates, and disease-free survival, showed no significant advantage in pelvic control, disease-free survival, or absolute survival for either treatment group when compared by stage and tumor size. Unfortunately, no large prospective randomized study has been done that could clarify this issue.

Radiation and Chemotherapy Radiation therapy alone fails to control the progression of cervical cancer in 35% to 90% of women with locally advanced disease. Concurrent chemoirradiation has been used in the treatment of many cancers in an attempt to improve local control and eradicate distant metastases and has been successfully integrated into the therapeutic program of not only cervical carcinomas but also those of the head and neck and anal canal. The rationale for chemoradiation is based on the finding that tumor radiosensitivity can be enhanced through the formation of DNA-platinum adducts. There is a correlation of radiosensitivity with platinum sensitivity. Specifically, the therapeutic index may be improved by loading the tumor with platinum salts containing fast atomic ions. Mechanisms of drug–radiation interaction leading to enhanced radiation kill may include modification of the slope of the dose-response curve, inhibition of sublethal damage repair, inhibition of recovery from potentially lethal damage, alterations in cellular kinetics, decrements in tumor volume leading to improved blood supply and tissue oxygenation, and increased radiosensitivity. Five phase III trials of concurrent chemoirradiation performed by the GOG, the RTOG, and the Southwestern Oncology Group (SWOG) have demonstrated a reduction in the risk of recurrence by up to 50% in patients with locally confined bulky or advanced-stage cervical cancer, regional

Invasive Cervical Cancer

spread, or high-risk features after hysterectomy (Table 3.20). Three studies compared radiotherapy alone with radiotherapy plus cisplatin-based chemotherapy, one of which addressed the prescription of adjuvant therapy following radical surgery for early-stage tumors (Intergroup Trial, discussed previously). Excluding patients with nodal involvement by CT scan, GOG protocol 123 evaluated the benefit of preoperative chemoirradiation therapy (weekly cisplatin 40 mg/m2; maximal weekly dose of 70 mg) compared with radiation therapy alone in patients with locally advanced disease confined to the cervix (i.e., stage IB2). All patients underwent adjuvant hysterectomy. In this landmark study, the rates of both PFS (P , .001) and OS (P 5 .008) were significantly higher in the combined therapy group at 4 years. Patients receiving radiosensitizing chemotherapy experienced higher frequencies of grade III and grade IV adverse hematologic effects and adverse GI effects. An update of GOG 123 was provided by Stehman and colleagues in which chemoradiation was found to significantly improve longterm PFS and OS without significantly increasing serious late effects. Morris and colleagues reported the results from RTOG protocol 90-01. In this study, the effects of pelvic radiation plus concurrent cisplatin and 5-FU were compared with pelvic radiation plus extended-field radiation therapy. This was the only trial to include chemotherapy during low-dose-rate brachytherapy. Eligibility requirements for this study differed from the previous GOG studies with the inclusion of patients with FIGO stage IB2 to IIA tumors. The estimated 5-year survival rates were 73% versus 58%, respectively, for patients treated with chemoirradiation therapy versus radiation therapy alone. A significant difference in disease-free survival was also seen in favor of the chemotherapy arm. The addition of chemotherapy to radiation therapy was effective in reducing both the frequency of local recurrences and distant metastases, with the latter observation refuting those detractors who claim that the benefit conferred by radiosensitizing chemotherapy is strictly a function of increasing the relative dose intensity of the radiation that can be delivered to the pelvis. These results have been sustained in an update of RTOG protocol 90-01 with 8 years of follow-up provided by Eifel and colleagues. Two additional phase III trials have confirmed the superiority of cisplatin-based chemoirradiation for the treatment of locally advanced cervical cancer. Whitney and colleagues published the results of concurrent cisplatin plus 5-FU and pelvic radiation therapy versus hydroxyurea plus pelvic radiation therapy in women with FIGO stage IIB to IVA disease who had undergone surgical staging and were found to have negative common iliac and aortocaval lymph nodes (GOG protocol 85). Among 368 eligible patients, the median follow-up time among survivors was 8.7 years. Disease progression occurred in 43% of patients randomly assigned to cisplatin plus 5-FU versus 53% of patients randomized to hydroxyurea. PFS was significantly better among patients treated with the combined chemotherapy regimen (P 5 .033), with 3-year survival rates of 67% (cisplatin–5-FU arm) versus 57% (hydroxyurea). Rose and colleagues reported the results from the threearm GOG trial of pelvic radiation therapy plus concurrent

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.20 Five Pivotal Trials of Chemoradiation in Locally Advanced Cervical Cancer Trial GOG 85

GOG 109b

Author Whitney et al.

Peters et al.

Year 1999

2000

Eligibility IIB-IVAa

IA2-IIA

Patients (n) 177

Complete Response 60% P 5 .033

Median Survival 65% P 5 .018

Pelvic RT 1 hydroxyurea 3 g/m2 (23/week)

191

48%

50%

PFS at 4 years

OS at 4 years

Adjuvant pelvic RT 1 cisplatin 70 mg/m2 1 5-FU adjuvant pelvic RT

127

80%

81%

116

63%

Arms Pelvic RT 1 cisplatin 50 mg/m2 1 5-FU 4 g/ m2/96 h (2 cycles)

P 5 .003

71%

PFS at 4 years GOG 120

GOG 123

RTOG 90-01

Rose et al.

Keys et al.

Morris et al.

1999

IIB-IVA

IB2d

IB –IIA tumor $5 cm IIB-IVA or positive pelvic nodes e

Pelvic RT 1 cisplatin 40 mg/m / week Pelvic RT 1 cisplatin 50 mg/m2 1 5-FU 4 g/ m2/96 h 1 hydroxyurea 2 g/m pelvic RT 1 hydroxyurea 3 g/m2 (23/week) 2

60%

173

60%

58%

177

45%

34%

183

Preoperative pelvic RT

186

Pelvic RT 1 cisplatin 75 mg/ m2 1 5-FU 4 g/m2/96 h (3 cycles Pelvic RT 1 extended-field RT

P 5 ,.001

OS at 4 years

176

Preoperative pelvic RT 1 cisplatin 40 mg/m2/week

P 5 .007

60%

P 5 .002–.004c

PFS at 4 year

OS at 4 year

80%

86%

P , .001

P 5 .008

64%

72%

DFS at 5 years

OS at 5 years

193

67%

73%

193

40%

P , .01

P 5 .004

58%

Negative paraaortic nodes. Intergroup: Gynecologic Oncology Group (GOG) 109/Southwestern Oncology Group (SWOG) 8797/Radiation Therapy Oncology Group (RTOG) 91-12; no randomization. c Platinum-based regimens compared with hydroxyurea. d Negative nodes. e State IB lesions included bulky tumors and those with positive pelvic lymph nodes. 5-FU, 5-Fluroracil; DFS, disease-free survival; PFS, progression-free survival; OS, overall survival; RT, radiation therapy. a

single-agent cisplatin versus cisplatin plus 5-FU plus hydroxyurea versus hydroxyurea alone (protocol 120). All patients had FIGO stage IIB to IVA cervical cancer with surgically confirmed negative common iliac and aortocaval lymph nodes. The median duration of follow-up was 35 months for 526 women included in the final analysis. Significant improvements in PFS and OS were observed in patients randomly assigned to either cisplatin-containing arm. Effectively, the results from GOG protocol 85 and GOG protocol 120 were critical in supplanting hydroxyurea as the radiosensitizer of choice. In 2007, Rose and colleagues provided their own update of GOG 120 in which again it was found that the improvement in PFS and OS observed with cisplatin-based chemoradiation was sustained without significant increases in late toxicity (Table 3.21).

Because the combination of cisplatin plus 5-FU results in added toxicity, weekly single-agent cisplatin dosed at 40 mg/m2 has emerged as the standard radiosensitizer in locally advanced cervical cancer. At present, radiosensitizing chemotherapy is recommended during that part of the treatment program when external-beam pelvic radiotherapy is administered. These pivotal phase III trials not only identified a significant survival advantage associated with the addition of concurrent chemotherapy but also were noteworthy in that the degree of benefit achieved with chemotherapy was remarkably similar for each of the four trials that studied chemoirradiation for primary therapy (Fig. 3.35). The results changed the standard of care for the treatment of locally advanced cervical cancer and formed the basis for the 1999 National Cancer Institute (NCI)

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.21 Updates and Ad Hoc Analysis of Pivotal Chemoradiation Trials in Cervical Cancer Study

Description

Update

Intergroup trial

Adjuvant RT

Absolute 5YS benefit for CRT: tumors .2 cm, $2 positive nodes

Adjuvant CRT GOG 123

RT plus adjuvant hysterectomy CRT plus adjuvant hysterectomy

CRT significantly improves long-term PFS and OS; serious late effects not increased significantly

RTOG 9001

RT plus EFRTCRT

CRT: superior OS and DFS (IB–IIB); superior DFS (III–IVA); serious late effects not increased significantly

GOG 120

CDDP–RTCDDP/HU/5-FU–CDDP–HU

CDDP-based CRT improves long-term PFS and OS; no significant increase in late toxicity

CDDP, Cisplatin; CRT, chemoradiation; DFS, disease-free survival; EFRTCRT, extended field radiation therapy plus chemoradiation; GOG, Gynecologic Oncology Group; HU, hydroxyurea; OS, overall survival; PFS, progression-free survival; RT, radiation therapy; RTCDDP, radiation therapy plus cisplatin; RTOG, Radiation Therapy Oncology Group.

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 GOG #85 Stage IIbIVa

GOG #120 Stage IIbIVa

GOG #123 Stage Ib

SWOG #8797 (GOG 109) Stage Ib or IIa

RTOG #9001 Stage Ib-IVa

Relative risk—with 90% Cl Figure 3.35 Relative risk estimate of survival from five phase-III, randomized controlled clinical trials of chemoradiation in women with cervical cancer. GOG, Gynecologic Oncology Group; RTOG, Radiation Therapy Oncology Group; SWOG, Southwestern Oncology Group.

Clinical Announcement (Practice Alert) in cervical cancer. At that time, NCI Director Richard D. Klausner, MD, stated the following: “The findings of these five trials are remarkably consistent. They are likely to change the standard of care for invasive cervical cancer.” A meta-analysis of 19 RCTs of chemoradiation versus radiation therapy alone containing a sample of 4580 patients treated from 1981 to 2000 was published in 2001 by Green and colleagues. In their report, the HRs for both PFS and OS favored chemoradiation (HR 0.61; P , .0001 and HR 0.71; P , .0001, respectively). The Cochrane review from 2005 analyzed 24 RCTs of 4921 patients. Chemoradiation was associated with a 10% absolute benefit in OS, a 13% absolute benefit in PFS, and a significant benefit was noted for local control. Acute hematologic and GI toxicity were reported more frequently with chemoradiation, but treatment-related deaths attributable to multimodality therapy were rare. Late effects were not able to be adequately determined in the Cochrane review. Most recently, a meta-analysis of 18 randomized trials containing

3517 patients again reported superiority of chemoradiation to radiation therapy alone in terms of relative risk (RR), 3-year survival, and 5-year survival. In this third meta-analysis, although GI toxicity, myelosuppression, and leukopenia occurred more frequently with the use of chemoradiation, there were no significant differences noted between the two modalities in terms of proctitis, cystitis, and nausea or vomiting. A phase III experience from the Ion Chiricuta Cancer Institute in Romania involved 566 patients with FIGO IIB-IIIB lesions who were randomly assigned to pelvic radiation therapy (46 Gy) plus high-dose rate brachytherapy (10 Gy) with or without cisplatin (20 mg/m2 3 5 days). The 5-year survival rate was significantly improved with the use of chemoradiation (74% vs. 64%; P , .05), as was the local control rate (78% vs. 67%; P 5 .01). In a 2007 study of practice patterns within the Gynecologic Cancer Intergroup, a global consortium of 14 cooperative groups, the mean external-beam radiation therapy dose was 47 Gy (3.5 Gy SD [standard dose]). The mean total dose to point A was 79.1 Gy (7.9 Gy SD), and the upper border for extended-field radiation therapy among 63% of respondents was T12 to L1. Approximately 85% used high-dose rate systems for vaginal brachytherapy. Of note, all groups reported using concurrent chemotherapy, with weekly cisplatin being the agent of choice for 83%. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology were updated in 2010 for cervical cancer. For patients with selected bulky tumors, those with FIGO stages IB2 and IIA lesions (.4 cm), and those with FIGO stage IIB to IVA disease, category 1 treatment constitutes pelvic radiotherapy plus concurrent cisplatincontaining chemotherapy plus brachytherapy. The latest phase III trial to study chemoradiation in the locally advanced cervical cancer population was conducted in Mexico by Duenas-Gonzalez et al. In their open-label, randomized phase III trial, the authors studied cisplatin-based chemoradiation followed by brachytherapy with and without concurrent gemcitabine (125 mg/m2 weekly) and by adjuvant cisplatin (50 mg/m2 day 1) plus gemcitabine (1000 mg/m2 days 1 and 8) every 21 days for two cycles. Grade 3 and 4 toxicities were more frequent in the investigational arm (86.5% vs. 46.3%; P , .001), including two deaths possibly related to treatment toxicity. The PFS at 3 years for the 515 patients enrolled

CHAPTER 3

Invasive Cervical Cancer

favored the investigational arm (74.4% vs. 65.0%; P 5 .029) and the overall hazard of progression was 0.68 (95% CI, 0.49 to 0.95; P 5 .0227), and the hazard of death was 0.68 (95% CI, 0.49 to 0.95; P 5 .0224). Despite these survival figures, the incorporation of gemcitabine into chemoradiation protocols has not been met with great enthusiasm worldwide. Currently, NRG Oncology (the former GOG and RTOG) in collaboration with the Australian-New Zealand Gynecologic Oncology Group (ANZGOG) is studying the value of four cycles of adjuvant carboplatin plus paclitaxel in this population in the phase III randomized study known as the OUTBACK Trial (NCT01414608). The trial has fully enrolled and results are anticipated following the occurrence of the protocol-specified number of events.

Neoadjuvant Chemotherapy and Other Novel Treatment Approaches Although multimodality therapy has emerged as the standard of care of patients with locally advanced disease, chemoradiation has some shortcomings related to access, efficacy, and tolerability in certain populations. Neoadjuvant chemotherapy is the most studied alternative treatment modality for FIGO stages IB2 to IVA. Other modalities under investigation include proton beam therapy, CyberKnife radiosurgery, IMRT, radiosurgery, radiohyperthermia, and the incorporation of antiangiogenesis and other targeted agents into chemoradiation protocols. Kagei and colleagues treated 25 patients with FIGO stage IIB to IVA disease with external-beam radiation therapy plus proton beam irradiation. The median total tumor dose was 86 Gy. At a median follow-up period of 139 months (range, 11 to 184 months), the 10-year OS rates were 89% for stage IIB and 40% for stages IIIB/IVA. Grade IV GI and GU toxicities were reported in 4% of patients. Choi and colleagues treated 30 women with isolated paraaortic nodal metastases with the CyberKnife. Grade III to IV toxicity requiring hospitalization occurred in one patient. The 4-year OS and 4-year local control rates were 50.1% and 67.4%, respectively. A nonrandomized trial comparing 135 women with locally advanced disease treated with IMRT using FDG-PET/CT simulation to 317 nonIMRT patients was reported to have had no significant impact on recurrence-free survival, although the grade III to IV bowel and bladder toxicities were reportedly higher in the non-IMRT cohort (P 5 .0351). Although the radiobiologic rationale for these three investigational modalities is promising, there have been no randomized trials for the population under discussion. As a result of limited access to sophisticated radiotherapy centers in resource-poor areas of the world, neoadjuvant chemotherapy has emerged as a viable alternative for treatment of women with locally advanced lesions. This approach was popularized by Sardi and colleagues in their “Buenos Aires protocol.” In one of the first prospective randomized studies of neoadjuvant chemotherapy in early-stage cervical cancer, Sardi and colleagues reported their final results in 205 cases of stage Ib carcinoma of the cervix. Patients were treated with RH followed by 50-Gy radiotherapy to the pelvis with or without neoadjuvant chemotherapy. In patients with stage Ib1, neoadjuvant chemotherapy did not improve overall resectability or survival

compared with those not receiving chemotherapy. In patients with stage Ib2, there was 83.6% (51 of 61) partial or complete response to chemotherapy. OS after 9 years of follow-up was 61% for the control group (no chemotherapy) and 80% for the neoadjuvant group (P , .01). Resection was possible in 85% of the control group and 100% in the neoadjuvant group. Patients who responded to neoadjuvant therapy had an OS of 88% compared with 23% for nonresponders. Of interest, the stage Ib1, neoadjuvant groups had an 82% OS compared with 80% for stage Ib2. The control groups’ survival rates were 77% and 61%, respectively. Neoadjuvant chemotherapy improved resectability and survival in the patients with stage Ib2. All patients received postoperative radiation. The Cochrane Collaboration visited this subject originally in 2004 and returned to it recently. In their 2010 report, the authors identified 1072 patients from six trials (Table 3.22). Although PFS was significantly improved with neoadjuvant chemotherapy (HR, 0.76; 95% CI 0.62 to 0.94; P 5 .01), no OS benefit was observed (HR, 0.85; 95% CI 0.67 to 1.07; P 5 .17). Neoadjuvant chemotherapy was associated with a significant decrease in adverse pathologic findings, including lymph node status and parametrial infiltration. Total cisplatin dose and schedule did not influence the findings, nor did stage of disease. The authors concluded that it remains unclear whether neoadjuvant chemotherapy consistently offers a benefit over surgery alone for patients with early-stage or locally advanced cancer. The latest Cochrane Collaboration review of six randomized trials of neoadjuvant chemotherapy with surgery for women with untreated early or locally advanced cervical cancer providing PFS data (n 5 1027) and OS data (n 5 1071) was reported by Rydzewska et al. in 2012. Both parameters were significantly improved among patients receiving neoadjuvant chemotherapy (hazard of progression, 0.75; 95% CI 0.61 to 0.93; P 5 .008) and hazard of death 0.77; 95% CI, 0.62 to 0.96; P 5 .02). The authors emphasized that despite the favorable results associated with neoadjuvant chemotherapy, their analysis was based on a small number of trials, and further research is clearly warranted. A Cochrane Collaboration review identified six RCTs of radiotherapy versus radiohyperthermia for patients with locally

TABLE 3.22 Neoadjuvant Chemotherapy

Plus Surgery Versus Surgery Alone: Hazard Ratios and Confidence Intervals for Overall Survival Study (Year)

Patients (n)

95% CI

Sardi et al. (1997)

210

0.53

0.31, 0.92

Katsumata (2006)

134

1.12

0.56, 2.22

Cai (2006)

106

0.74

0.33, 1.65

Napolitano (2003)

288

0.84

0.51, 1.40

Total

930

0.85

0.67, 1.07

CI, Confidence interval; HR, hazards ratio. Modified from Rydzewska L, Tierney J, Vale CL, Symonds PR: Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer, Cochrane Database Syst Rev 1:CD007406, 2010.

CHAPTER 3

advanced cervical carcinoma during the period from 1987 to 2009. Seventy-four percent of patients treated had FIGO stage IIIB tumors. The HRs for 3-year local recurrence and 3-year survival favored the 43°C hyperthermia arms (HR, 0.48; 95% CI 0.37 to 0.63; P , .001 and HR 0.6; 95% CI 0.45 to 0.99; P 5 .05, respectively). There were no significant differences in acute or late-grade III to IV toxicity. The review did indicate that these studies were limited by small numbers and important methodologic flaws. Finally, a recent Cochrane Collaborative study focusing on the impact of hysterectomy for women with locally advanced disease treated with radiotherapy or chemotherapy or both was reported by Kokka et al. Seven randomized trials were identified involving 1217 patients. Although individual trials did not report a survival advantage among women undergoing hysterectomy after radiotherapy or concurrent chemoradiation, the meta-analysis of three trials (n 5 571) of neoadjuvant chemotherapy and hysterectomy versus radiotherapy alone found that women who received neoadjuvant chemotherapy plus hysterectomy had a lower risk of death (HR, 0.71; 95% CI, 0.55 to 0.93). Currently, the phase 3 randomized INTERLACE trial (NCT01566240) is enrolling women with locally advanced disease and randomizing them to concurrent standard chemoradiation preceded by or without neoadjuvant chemotherapy. Targeted therapy has been studied in two chemoradiation protocols. In 2012, the GOG reported in the phase I protocol 9918 that the addition of anti-epithelial growth factor therapy using cetuximab (400 mg/m2 loading dose followed by 250 mg/ m2) to cisplatin-based chemoradiation was tolerable, but when added to extended-field radiation therapy for treatment of nodal metastases, there were eight dose-limiting toxicities, making the combination not feasible. In RTOG 0417, the antiangiogenesis agent bevacizumab (10 mg/kg IV every 2 weeks) was added to 49 patients treated with cisplatin-based chemoradiation for FIGO stage IB to IIIB disease. The 3-year OS, disease-free survival, and locoregional failure rates were 81.3%, 68.7%, and 23.2%, respectively. The paraaortic nodal failure rate at 3 years was 8.4%. Two ongoing phase 3 randomized clinical trials for women with locally advanced cervical cancer include the CALLA study (NCT03830866) which is studying concurrent chemoradiation with and without the anti-PD-1 checkpoint inhibitor, durvalumab, and the NRG-GY006 study (NCT02466971) which is studying chemoradiation with and without the ribonucleotide reductase inhibitor, triapine.

Suboptimal Treatment Situations Several clinical situations pose unique challenges in the management of cervical cancer, causing some patients with invasive cancer of the cervix to receive suboptimal treatment: 1. Cancer in a cervical stump 2. Simple hysterectomy in the setting of invasive cervical cancer 3. Poor vaginal geometry for intracavitary radiation. Cancer that occurs in a cervical stump is fortunately a diminishing problem because supracervical hysterectomies are performed less frequently. Carcinoma occurring in a cervical stump presents a special problem because often an optimal dose of intracavitary radium cannot be applied as a result of the

Invasive Cervical Cancer

insufficient place to insert the central tandem, which contributes significantly to the radiation dose to the central tumor and to the pelvic sidewall. Radical surgery is also more difficult; the bladder and rectum firmly adhere to the stump and may adhere to each other. Also, the ureters are more difficult to dissect cleanly from the parametrial tissue because of fibrosis from the previous surgery. The net result is an increase in the risk of significant surgical complications involving the ureters, bladder, and rectum. In modern gynecologic surgery, supracervical hysterectomy is rarely indicated, although in recent years, concerns regarding pelvic support and even sexual function have prompted some surgeons to consider the procedure. In a report of the MD Anderson Hospital experience with 263 patients with carcinoma of the cervical stump, Miller and colleagues noted a 30% complication rate after full therapy with radiation. Urinary and bowel complications result from postsurgical adhesions; the absence of the uterus, which acts as a shield; and a tendency to emphasize external radiation therapy. We have had a similar experience, resulting in a preference for radical trachelectomy in patients with cancer of the cervical stump in whom stage and medical conditions allow. The increased technical difficulty of performing such a procedure seems to be outweighed by the low complication rate and comparable survival of patients. A simple hysterectomy performed for invasive cervical cancer is not adequate therapy for most patients. This situation may occur because of poor preoperative evaluation or because the surgery was performed under emergency conditions without an adequate preoperative cervical evaluation. Such a situation may occur in a patient presenting with acute abdomen from ruptured tuboovarian abscesses. In any event, if an extensive cancer is found in the cervix, the prognosis is poor because optimal irradiation cannot be given with the cervix and uterus absent. An even more ominous situation occurs when a hysterectomy is performed with a “cut through” of the cancer—that is, the hysterectomy dissection passes through the cancer. The prognosis is uniformly poor in this event. In the examples just given, surgical cures are not obtained, and the probability of curative radiotherapy is greatly diminished. In 1968, Durrance reported survival rates of 92% to 100% using postoperative radiation therapy in selected patients with presumed stages I or II disease after suboptimal surgery. Excellent survival rates were also reported by Andras and colleagues in 148 patients who had invasive cervical carcinoma found incidentally in the hysterectomy specimen. Of these patients, 126 were treated with postoperative radiation therapy. Patients with microscopic disease confined to the cervix had a 96% 5-year survival rate. Those with gross tumor confined to the cervix had an 84% 5-year survival. Patients with tumor cut through at the margins of surgical resection, but with no obvious residual cancer, had a 5-year survival rate of 87%. Patients with obvious residual pelvic tumor had a 47% 5-year survival rate. In 1986, Heller and colleagues reviewed the literature and reported equivalent survival rates in 35 patients who were also treated mainly with radiation. Orr and colleagues have preferred radical parametrectomy, upper vaginectomy, and lymphadenectomy as the treatment of

CHAPTER 3

Invasive Cervical Cancer

choice after a simple hysterectomy. We also prefer this approach, particularly because many of these patients are young and desirous of preserving optimal sexual function. We are also concerned about postoperative small bowel adhesions and the difficulty of delivering effective irradiation to the medial parametria in the absence of a uterus. Survival rates with either approach appear to be exceptionally good; undoubtedly, this clinical situation creates a bias for smaller lesions that may be easier to eradicate. Adequate radiotherapy is also compromised in patients who have a vagina or cervix that cannot accommodate a complete intracavitary radiation application. This situation is encountered with atrophic stenotic pelvic structures. These patients are treated by inserting the tandem and ovoids in a compromised manner, such as insertion of the ovoids singly or independently of the central tandem. In any event, standard optimal doses are usually not obtained, and the possibility of sustaining a radiation injury is increased.

NEUROENDOCRINE AND OTHER UNCOMMON TUMORS OF THE CERVIX Neuroendocrine (small cell) cervical cancer (Fig. 3.36) is a rare malignancy, representing fewer than 5% of all cases of cervical cancer. These tumors provide a therapeutic challenge for the clinician because they are characterized by frequent and early nodal and distant metastases. The pathologist’s dilemma results from the large number of pathologic entities all described as “small cell cancers,” including fully differentiated small cell nonkeratinizing SCC, reserved cell carcinoma, and neuroendocrine (oat cell) carcinoma. Neuroendocrine carcinomas, which can be identified by characteristic light and electron microscopic criteria, are indistinguishable from oat cell cancers of the lung. In addition, they appear to have the poorest prognosis of the various small cell cancers. Therefore, it is important to distinguish this particular subtype of cancer from the rest and to consider innovative approaches to treatment. Neuroendocrine markers are commonly used to assist in classification, with up to 80% of tumors staining for synaptophysin, chromogranin,

Figure 3.36 Small cell carcinoma. (Courtesy of Ibrahim Ramzy, MD, University of California, Irvine [UCI], College of Medicine.)

or CD56 (neural cell adhesion molecule). At least in one series, Pap smear results were abnormal in only one of seven patients. Abeler and colleagues reported on 26 cases of true neuroendocrine cervical carcinoma. The 5-year survival rate was 14% despite aggressive therapy, including surgery, radiation, and chemotherapy. Viswanathan and colleagues observed a 66% relapse rate, with a course frequently characterized by the development of widespread hematogenous metastases. Locoregional recurrence outside irradiated fields was also frequently observed. In the group studied, the OS rate at 5 years was only 29%, with none of the patients who had disease more extensive than FIGO stage Ib1 or clinical evidence of lymph node metastases surviving their disease. In our experience in the 1980s with 14 patients in stage Ib or IIa treated by RH with postoperative radiation therapy, all 14 have experienced recurrence, 12 before the 31st month after therapy. Innovative approaches to treating this subset of unfortunate patients are under study. Recently, Chan and colleagues updated our series and performed a multivariate analysis of different prognostic factors among 34 patients. His group documented that only those with early lesions amenable to extirpation were curable. The role of primary or postoperative radiation with or without chemotherapy is unclear and yields uniformly poor results, particularly in patients with advanced lesions. Hoskins and colleagues treated 31 patients with small cell neuroendocrine carcinoma (SCNEC) using protocols containing etoposide, cisplatin, and radiation therapy with concurrent chemotherapy with and without the addition of carboplatin and paclitaxel. The reported 3-year failure-free rate for patients with early-stage disease (stages I and II) was 80%. Chang and colleagues have reported that regimens containing a combination of vincristine, doxorubicin, and cyclophosphamide or cisplatin and etoposide constitute active adjuvant therapies after RH. Zivanovic and colleagues examined the outcomes of 17 patients with SCNEC. The estimated 3-year PFS and OS rates were 22% and 30%, respectively. Median OS rates for early-stage disease (IA1 to IB2) were 31.2 months and 6.4 months for those with advanced-stage disease (IIB-IV; P 5 .034). In the early-stage disease group, the 3-year distant recurrence-free survival rates were 83% for patients who received platinum-based combination chemotherapy and 0% for those who did not receive chemotherapy as part of their initial treatment (P 5 .025). These data support the role of chemotherapy for distant control as an addition to radiation therapy for local control. Of interest, combined modality treatment with definitive chemotherapy and radiotherapy are used in the current management of small cell lung cancer, with surgical resection playing a limited role in patients with stages I and II disease. It is unclear which patients, if any, should undergo RH for SCNEC of the cervix. Zivanovic and colleagues advise proceeding with combined modality therapy when the diagnosis is established by cervical biopsy, holding surgery in reserve to be used in the adjuvant setting if necessary. It should be recognized that there are advocates of primary RH for patients with early-stage tumors. Finally, a recent case report by Lyons et al. describing the objective response when a neuroendocrine cervical cancer

CHAPTER 3

Invasive Cervical Cancer

harboring a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was treated with a mitogen-activated protein kinase (MEK) inhibitor emphasizes a potential role for biomarker testing to further guide therapy. Provision of the molecular phenotype of these (and other) tumors is likely to provide the basis for future personalized therapy.

GLASSY CELL CARCINOMA, CARCINOSARCOMA, LYMPHOMA, AND MELANOMA Glassy cell carcinoma of the cervix has also been classically regarded as a poorly differentiated adenosquamous carcinoma, which is infrequently diagnosed and associated with a poor outcome regardless of the modality of therapy. Many recurrences occur in the first year after therapy, and most have occurred by 24 months. Reported survival rates are more encouraging than are those associated with neuroendocrine carcinomas; rates have been seen to be as high as 50% for stage I disease in some series. In the SEER report of 6549 cases of cervical carcinoma from 1973 to 1977, there were only 36 cases of cervical sarcoma, which is an incidence of 0.55%. Ninety-six cases of cervical sarcoma were reviewed by Rotmensch and colleagues, and no clear statement could be made regarding management, although surgery was consistently used for early-stage lesions. Laterza and colleagues reviewed the literature and described the outcomes of 33 patients with carcinosarcoma of the cervix, including two of their own (Fig. 3.37). Of 16 patients with stage I disease, eight were reported to be NED (no evidence of disease) after a variety of treatment modalities, including surgery, radiation, or chemotherapy, alone or in combination. The impact of radiotherapy on survival is uncertain. Given the propensity for distinct histologic subtypes to respond to systemic regimens irrespective of organ site of origin (e.g., SCNECs of the cervix and lung, malignant germ cell tumors of the ovary and testis), ifosfamide-based regimens, particularly ifosfamide plus paclitaxel, may be expected to

Figure 3.37 Carcinosarcoma. (From Laterza R, Seveso A, Zefiro F, et al: Carcinosarcoma of the uterine cervix: case report and discussion, Gynecol Oncol 107[1 suppl]:S98–S100, 2007.)

Figure 3.38 Lymphoma. (From Szánthó A, Bálega J Já, Csapó Z, et al: Primary non-Hodgkin’s lymphoma of the uterine cervix successfully treated by neoadjuvant chemotherapy: case report, Gynecol Oncol 89: 171–174, 2003.)

exhibit some activity in this disease, similar to what has been reported in carcinosarcoma of the uterine corpus. Biomarker profiling may also be of value to understand the clinical behavior of these rare cancers. In a small series of three women with cervical carcinosarcoma, Gan et al. reported high levels of bcl-2 and surviving expression and decreased apoptosis using an apoptosis index. Dysregulation of apoptosis may facilitate the aggressive behavior of carcinosarcoma. In contrast to systemic lymphomas, fever, night sweats, and weight loss rarely have been reported in cervical lymphoma (Fig. 3.38). Most present with abnormal vaginal bleeding or discharge, but pelvic pain and dyspareunia may also be present. The differential diagnosis of cervical lymphomas should include benign chronic inflammations, poorly differentiated and small cell cervical carcinomas, sarcomas, and lymphomalike lesions. Immunophenotyping can be used to make the diagnosis. The prognosis of extranodal lymphomas is usually poorer than that of nodal lymphomas as a result of inaccurate or delayed diagnosis. Early-stage diagnosis of cervical lymphoma has been associated with favorable outcomes. Some authors have suggested that surgical resection in localized lymphoma may improve survival, although this is unclear. The CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen is the most commonly used regimen. Malignant melanoma of the uterine cervix is a rare manifestation (Fig. 3.39). A careful survey should be done of the patient’s skin and mucous membranes for a possible primary site. Almost 90% of the patients are asymptomatic, and vaginal bleeding is the main complaint among 10%. Most lesions present as an exophytic polypoid cervical mass with obvious coloring. Immunohistochemistry can be used to identify melanin granules, and positive staining for S100, HMB 45, or Melan-A can help in establishing the diagnosis. Although there is little consensus on the best approach for therapeutic management, the majority of patients have undergone RH with or without PL and upper vaginectomy. The efficacy of radiation therapy has not been established, although it has been used in the adjunctive

CHAPTER 3

Invasive Cervical Cancer

Figure 3.39 Melanoma. (From Kristiansen SB, Anderson R, Cohen DM: Primary malignant melanoma of the cervix and review of the literature, Gynecol Oncol 47:398–403, 1992.)

and palliative settings. Likewise, the use of adjuvant chemotherapy is under debate. To date, there have been no reports of immunotherapy, including the use of interferon, for this disease. The 5-year survival rate is very poor, not exceeding 40% of stage I and 14% of stage II. The therapeutic landscape of cutaneous melanoma has been transformed with the introduction of checkpoint inhibitors (e.g., anti-CTLA-4 ipilimumab and the antiprogrammed cell death 1 nivolumab and pembrolizumab). To date, there have been no reports of the efficacy of breaking immune tolerance in cervical melanoma, but we may anticipate that they will be forthcoming.

SURVIVAL RESULTS AND PROGNOSTIC FACTORS FOR EARLY-STAGE AND LOCALLY ADVANCED DISEASE For early-stage tumors, results may imply that one form of therapy (i.e., radical surgery vs. radiotherapy) has advantages over the other, but considering the rather wide dispersion that, in fact, may be unrelated to treatment, we must maintain collective open-mindedness about the efficacy of individual therapeutic regimens. The best available figures for the two methods give results that are almost identical, and because the presence of other factors affects the samples being compared, large differences would be necessary to be significant. Individual physicians will probably continue to decide on the basis of personal preferences and comparison of complications and later disabilities. The recovery rates of patients with operative SCC of the cervix depend on many factors, including the histologically documented extent of the carcinoma. Baltzer and associates studied 718 surgical specimens of patients with SCC of the cervix. Lymphatic and blood vessel invasion significantly influenced survival, blood vessel invasion being much more ominous. In their study, whereas 70% of the patients who demonstrated blood vessel invasion succumbed to the disease, 31% of the patients demonstrating only

lymphatic invasion succumbed to the disease process. Other studies have not found prognostic significance for vascular invasion. A definite linkage was noted between the size of the carcinomas and the frequency of metastases. Fuller and colleagues drew similar conclusions. In their study of 431 patients who underwent RH for stages Ib or IIa carcinoma of the cervix at Memorial SloanKettering Cancer Center, they found 71 patients who had nodal spread that correlated closely with increased primary tumor size, extracervical extension of tumor, and the presence of adenocarcinoma. Although these factors were recognized as having prognostic significance, the authors were unable to demonstrate that these detrimental effects could be overcome by postoperative pelvic radiation. Patients receiving postoperative irradiation therapy seemed to have some better local control, but the problem of systemic spread of disease resulted in little overall improvement in survival. In a similar study, Abdulhayogu and associates reported on a series of patients with negative lymph nodes at the time of RH who subsequently developed recurrent disease. They too pointed out the histologic architecture of invasion as an important prognostic indicator. Recurrence was more likely in patients who had deep invasion of the cervical stroma, especially when it extended to the serosal surface (even when the parametria were not involved). Again, the volume of tumor correlated with the eventual prognosis for the patient. They suggested that these patients were in need of postoperative therapy, and radiation therapy for local control was recommended in the absence of any other demonstrated effective adjuvant modality for this set of circumstances. Gauthier and colleagues had similar results and, in a multifactorial analysis of clinical and pathologic factors, demonstrated that the depth of stromal invasion is the single most important determinant of survival. The role of intraperitoneal tumor spread was evaluated by an Italian group. They evaluated 208 patients with advanced local disease who received neoadjuvant chemotherapy. There were 183 clinically responsive patients who underwent radical surgery; 7 (4%) and 13 (7%) showed macroscopic and microscopic peritoneal tumor, respectively. Multivariant analysis showed that the peritoneal tumor involvement, stage, pathologic parametrial involvement, and LNM were independent factors associated with survival. About one-quarter of those with pelvic LNM had intraperitoneal involvement compared with only 6% of node-negative patients. If intraperitoneal disease was present, survival was similar, irrespective of stage (Ib to IIb compared with III to IVa). A study from Austria evaluated 166 patients with stage Ib cancers treated with RH. In a multivariant analysis, microvessel density, lymph node involvement, tumor size, and postoperative radiation remained independent prognostic factors for survival. LSI failed to be a prognostic factor. Of interest, patients with negative lymph nodes but increased microvessel density had similar survival to patients who were node positive but with low microvessel density. A study from Norway evaluated HPV DNA in 97 patients with squamous carcinoma (all stages). When corrected for stage and age, the prognosis was significantly poorer for HPV-18- and -33–positive tumors; however, overall, when all HPV-positive tumors were compared with HPV-negative tumors, no survival difference was noted.

CHAPTER 3

When age was evaluated in the Annual Report, the OS rate in stage I decreased with age. Patients between 15 and 39 years of age in stage II had a worse survival rate compared with older patients. This was true for patients 30 to 49 years of age with stage IV cancers compared with patients of other ages. Mitchell and colleagues reviewed 398 patients with stages I to III cervical cancer of whom 338 patients were 35 to 69 years of age, and 60 patients were 70 years of age or older. Although elderly patients had a higher rate of comorbidity resulting in more frequent treatment breaks and less ability to receive definitive therapy with intracavity radiation, the 5-year actuarial disease-free and causespecific survival rates were comparable between the two groups.

RECURRENT AND ADVANCED CARCINOMA OF THE CERVIX It is estimated that approximately 35% of patients with invasive cervical cancer will have recurrent or persistent disease after therapy. The diagnosis of recurrent cervical cancer is often difficult to establish (Table 3.23). The optimal radiation therapy most patients receive makes cervical cytologic findings difficult to evaluate. This is especially true immediately after completion of radiation therapy. Suit, using mammary carcinomas in C3H mice, demonstrated that persistence of histologically intact cancer cells in irradiated tissue was not indicative of the regrowth of a tumor. Radiobiologically, a viable cell is one with the capacity for sustained proliferation. A cell would be classified as nonviable if it had lost its reproductive integrity, although it could carry out diverse metabolic activities. This reproductive integrity was demonstrated by the transplantation “take” rate when histologically viable tumor cells were transplanted into a suitable recipient. It was evident from these experiments in mice that relatively normal-appearing cancer cells can persist for several months after radiation therapy but that these cells are “biologically doomed.” Thus, cytologic evaluation of a patient immediately after radiation therapy may erroneously lead to the supposition that persistent disease exists. In addition, subsequent evaluation of the irradiated cervix is difficult because of the distortion produced in the exfoliated cells, often called the radiation effect. Thus, histologic confirmation of recurrent cancer is essential. This can be accomplished by punch or needle biopsy of suspected areas of malignancy when they are accessible. An interval of at least 3 months should elapse after completion of radiation therapy. The clinical presentation of recurrent cervical cancer is varied and often insidious. Many patients develop a wasting syndrome with TABLE 3.23 MD Anderson Hospital Central

Recurrence Rate for Carcinoma of the Cervix After Treatment With Radiation Therapy Stage

Patients (%)

1.5

IIb

IIIa

7.5

IIIb

Invasive Cervical Cancer

severe loss of appetite and gradual weight loss over a period of weeks to months. This is often preceded by a period of general good health after completion of radiation therapy. Because most recurrences of cancer occur within 2 years after therapy, the period of good health rarely lasts more than 1 year before the symptoms of cachexia become evident. Diagnostic evaluation at this time of suspected recurrence may include a chest radiograph and CT scan and complete blood count, blood urea nitrogen, creatinine clearance, and liver function tests. Autopsy studies of the location of advanced recurrent and persistent disease have been reported (Figs. 3.40 and 3.41). After RH, about one-fourth of recurrences occur locally in the upper part of the vagina or the area previously occupied by the cervix. The location of recurrence after radiation therapy showed a 27% occurrence in the cervix, uterus, or upper vagina; 6% in the lower two-thirds of the vagina; 43% in the parametrial area, including the pelvic wall; 16% distant; and 8% unknown. Often one notes the development of ureteral obstruction in a patient who had a normal urinary tract before therapy. Although ureteral obstruction can be caused by radiation fibrosis, this is relatively rare, and 95% of the obstructions are caused by progressive tumor. Central disease may not be evident, and in the absence of other findings, a patient with ureteral obstruction and a negative evaluation for metastatic disease after therapy should undergo exploratory laparotomy and selected biopsies to confirm the diagnosis of recurrence. Patients with ureteral obstruction in the absence of recurrent malignancy should be considered for urinary diversion or internal antegrade ureteral stents. The definition of primary healing after radiation therapy is a cervix covered with normal epithelium or an obliteration of the vaginal vault without evidence of ulceration or discharge. On rectovaginal examination, the residual induration is smooth with no nodularity. The cervix is greater than 2.5 cm in width, and there is no evidence of distant metastasis. The definition of persistent disease after radiation therapy is as follows: 1. Evidence of a portion of the tumor that was clinically present before treatment or 2. Development of a new demonstrable tumor in the pelvis within the treatment period. The definition of recurrence after radiation therapy is a regrowth of tumor in the pelvis or distally, which is noted after complete healing of the cervix and vagina. Recurrence after surgery is defined as evidence of a tumor mass after all gross tumor was removed and the margins of the specimen were free of disease. Persistent disease after surgery is defined as persistence of gross tumor in the operative field or local recurrence of tumor within 1 year of initial surgery. A new cancer of the cervix would be a lesion that occurs locally at least 10 years after primary therapy. The triad of weight loss accompanied by leg edema and pelvic pain is ominous. Leg edema is usually the result of progressive lymphatic obstruction, occlusion of the iliofemoral vein system, or both. The clinician should consider the possibility of thrombophlebitis, but recurrent cancer is more likely. Patients characteristically describe pain that radiates into the upper thigh either to the anterior medial aspect of the thigh or posteriorly into the buttock. Other patients describe pain in the

CHAPTER 3

Invasive Cervical Cancer Skull: 0.6% Pituitary: 0.6%

Thyroid: 0.6% Clavicle: 0.6% Rib: 2.4% Bronchus: 1.8% Adrenal: 1.8% Liver: 16.4% Pancreas: 2.4% Kidney: 3.0% Abdominal scar: 0.6% Ileum: 1.2% Vein: 1.2%

Supraclavicular: 0.6% Lung: 14% Pleura: 4.9% Heart: 3.0% Stomach: 0.6% Spleen: 1.2% Skin: 1.2% Forearm: 0.6% Large bowel: 7.2% Vertebra: 9.2% Ureter: 2.4% Femur: 0.6% Urethra: 1.2% Vulva: 1.2%

Tibia: 1.2%

Figure 3.40 Metastatic sites of treated patients with cervical cancer and the percentage of involvement. (From Henriksen E: The lymphatic spread of carcinoma of the cervix and of the body of the uterus; a study of 420 necropsies, Am J Obstet Gynecol 58:924–942, 1949.)

groin or deep-seated central pelvic pain. The appearance of vaginal bleeding or watery, foul vaginal discharge strongly suggests a central recurrence (Table 3.24). These lesions are among the more readily detectable recurrent cervical cancers, and histologic confirmation is easily obtained. Fewer than 15% of patients with recurrent cervical cancer will develop pulmonary metastasis. When this does occur, patients will complain of cough, hemoptysis, and occasionally chest pain. In many cases, there will be enlargement of supraclavicular lymph nodes, especially on the left side. Needle aspiration of enlarged lymph nodes can be accomplished easily and avoids the necessity for an open biopsy of the area. In almost every case, the diagnosis of recurrent cervical cancer must be confirmed histologically. CT-directed needle biopsies have provided us with a tool that avoids the necessity of more elaborate operative procedures. In addition to the standard radiographic evaluations, such as IVP and chest radiograph, the clinician may find more sophisticated studies such as

lymphangiography and MRI helpful in localizing deep-seated areas of recurrent cervical cancer. Bony metastases presenting clinically are particularly rare. In a study of 644 patients with invasive cervical carcinoma, Peeples and colleagues were able to find only 29 cases of remote metastases. Of these, 15 were to the lungs and only 12 were to the bone, which is an incidence of 1.8%. No bony metastases were found at initial staging and diagnosis. The earliest discovery of bone metastasis came 8 months after diagnosis. Therefore, a bone survey was not recommended as part of the staging examination for cervical cancer. Blythe and associates reported on 55 patients who were treated for cervical carcinoma and who developed bony metastases. Radiographs were diagnostic in all except two of the patients. In 15 patients, a combination of radioactive scans and radiographs was used to establish the diagnosis. The most common mechanism of bony involvement from carcinoma of the cervix was extension of the neoplasia from periaortic nodes,

Invasive Cervical Cancer

CHAPTER 3

Dura: 0.8%

Skull: 1.6% Brain: 0.8%

Parotid: 0.1% Cervical: 0.1% Supraclavicular: 1.6% Clavicle: 0.8% Rib: 3.2% Bronchus: 0.8%

Adrenal: 1.6% Liver: 24.5% Gallbladder: 0.8% Kidney: 1.6% Ileum: 3.2%

Lung: 13.9% Pleura: 2.4% Skin: 0.8% Heart: 1.6% Spleen: 1.6% Vertebra: 8.1% Forearm: 0.8% Sigmoid: 6.5%

Ureter: 1.6% Femur: 0.8% Urethra: 2.4%

Tibia: 0.8%

Figure 3.41 Metastatic sites of untreated patients with cervical cancer and the percentage of involvement. (From Henriksen E. The lymphatic spread of carcinoma of the cervix and of the body of the uterus; a study of 420 necropsies, Am J Obstet Gynecol 58:924–942, 1949.)

TABLE 3.24 Signs and Symptoms of

Recurrent Cervical Cancer

Weight loss (unexplained) Leg edema (excessive and often unilateral) Pelvic or thigh–buttock pain Serosanguineous vaginal discharge Progressive ureteral obstruction Supraclavicular lymph node enlargement (usually on the left side) Cough Hemoptysis Chest pain

with involvement of the adjacent vertebral bodies. The longest interval from the primary diagnosis until the discovery of bony metastases was 13 years. Of the patients, 69% were diagnosed within 30 months of initial therapy, and 96% died within 18 months. Of the 36 patients treated with radiation therapy, four received complete relief of symptoms, 24 gained some relief, and eight received no relief.

Van Herik and colleagues examined the records of 2107 cases of cervical cancer for recurrence after 10 years. Sixteen (0.7%) patients had a recurrence 10 to 26 years after the initial therapy. Of these patients, 25% had bony metastasis or extension of the recurrence into bone. The finding of metastasis after 10 years correlates with the findings of Paunier and associates, who indicated that 92.5% of deaths resulting from carcinoma of the cervix occur in the first 5 years after diagnosis. In addition, their cumulative death rate curve was flat after 10 years. Deaths resulting from cancer of the cervix occur most frequently in the first year of observation and decrease thereafter. About half of all the deaths occur in the first year after therapy, 25% in the second year, and 15% in the third year, for a total of 85% by the end of the third year. Because more than threefourths of the recurrences are clinically evident in the first 2 years after initial therapy, posttreatment evaluation done at frequent intervals during this critical period is mandatory. The patient should be examined every 3 to 4 months, and cervical cytologic testing should be done at these visits. In addition,

CHAPTER 3

Invasive Cervical Cancer

particular attention should be paid to the parametria on rectovaginal examination to detect evidence of progressive disease. For several months after the completion of radiation therapy, the examiner may observe a progressive fibrosis in the parametria, creating the so-called horseshoe fibrosis. The amount of fibrosis may sometimes be alarming, but smoothness of the induration should be reassuring when compared with the nodular presentation of recurrent parametrial malignancy. Parametrial needle biopsies, with the patient under anesthesia, may be helpful when the palpatory findings are equivocal. Generous use of endocervical curettage at these follow-up visits is recommended, especially when central failure is suspected after radiation therapy. Every follow-up examination should include careful palpation of the abdomen for evidence of periaortic enlargement, hepatomegaly, and unexplained masses. Every follow-up examination should begin with a careful palpation of the supraclavicular areas for evidence of nodal enlargement. This frequently omitted portion of the examination will sometimes reveal the only evidence of recurrent disease. The prognosis for patients with recurrent or advanced cervical cancer depends on the location of the disease. Of patients with recurrent cervical cancer, the most favorable for therapy after primary irradiation are those with a central recurrence. These patients are candidates for curative radical pelvic surgery, including pelvic exenteration. There will be further discussion of this group of patients later in this chapter. With the advent of sophisticated methods of radiation therapy, including improved methods of brachytherapy and supervoltage external irradiation therapy, patients with pure central recurrence have become a rarity. Isolated lung metastases from pelvic malignancies have responded in very selected cases to lobectomy. Gallousis reported metastases to the lung from cervical cancer in 1.5% of 5614 cases reviewed, with solitary nodules present in 25% of the cases. A surgical attack for isolated pulmonary recurrence should be considered, especially if the latent period has been longer than 3 years. Other patients who deserve serious consideration are those with radiation bowel injury. Over the past decade, the limits of human tolerance to radiation therapy have been reached, with treatment techniques for advanced disease that include large extended fields to the periaortic area. Many patients with advancedstage primary lesions have been treated with large doses of pelvic radiation (6000 to 7000 cGy), often after intraabdominal surgery. With these techniques, standard radiation therapy can lead to a small but significant number of patients with chronic radiation injury to the large or small bowel. These patients often develop cachexia, which is indistinguishable from the clinical presentation of recurrent and progressive malignancy. These patients are often quickly and superficially diagnosed as having recurrent disease, and no further investigation is initiated. Careful investigation of these patients reveals a history of postprandial crampy abdominal pain causing anorexia and weight loss. The diagnostic evaluations discussed previously reveal no conclusive evidence of persistent malignancy. In most cases, these patients can be returned to health with appropriate bowel surgery, including internal bypass procedures. In every patient suspected of recurrent malignancy, an effort should be made to confirm this suspicion by biopsy (histologic confirmation), and patients who do not

have a recurrence and who have radiation bowel injury should be identified.

Management and Prognosis Persistent or recurrent carcinoma of the cervix is a discouraging clinical entity for the clinician, with a 1-year survival rate between 10% and 15%. Treatment failures are, as expected, much more common in patients with more advanced stages of the disease; therefore, most patients are unlikely candidates for a second curative approach with radical pelvic surgery. Cases of curative therapy applied to isolated lung metastases or lower vaginal recurrences are reported but occur rarely. Unfortunately, most recurrences are suitable for palliative management only.

Surgical Therapy: Radical Hysterectomy RH has been reported as therapy for patients with a small recurrent cervical carcinoma after radiation. Coleman’s series of 50 patients from the MD Anderson Hospital were treated with RH (type II or III). Severe postoperative complications occurred in 42% of these patients. Of these patients, 28% developed urinary tract injury. The survival rate was 90% at 5 years for patients with lesions smaller than 2 cm as opposed to 64% in patients with larger lesions. Excessive morbidity can be limited if an omental pedicle is placed at the operative site at the end of the procedure, bringing in a new blood supply to the operative field that has undergone previous radiation therapy.

Pelvic Exenteration In 1948, Brunschwig introduced the operation of pelvic exenteration for cancer of the cervix (Fig. 3.42). Since then, extensive

Figure 3.42 Specimen from an anterior exenteration done for recurrent cervical carcinoma; the specimen consists of the uterus, vagina, and bladder. (The anterior wall has been opened to expose bullous edema of the trigone.)

CHAPTER 3

experience with pelvic exenteration has been accumulated, and the techniques and patient selection have steadily improved so that now, 50 years later, this procedure has attained an important role in the treatment of gynecologic malignancies for a selected group of patients. It is now accepted as a respectable procedure that can offer life to selected patients when no other possibility of cure exists. The criticism of this procedure has been lessened by steadily improving mortality and morbidity and a gratifying 5-year survival record. Most important, however, is that patients who survive this procedure can be rehabilitated to a useful and healthful existence. Although pelvic exenteration has been used for various pelvic malignancies, its greatest and most important role is in the treatment of advanced or recurrent carcinoma of the cervix. Total exenteration (Fig. 3.43) with removal of the pelvic viscera, including the bladder and rectosigmoid, is the procedure of choice for carcinoma of the cervix recurrent or persistent within the pelvis after irradiation. In select cases, the procedure may be limited to anterior exenteration (Fig. 3.44) with removal of the bladder and preservation of the rectosigmoid or posterior exenteration (Fig. 3.45) with removal of the rectosigmoid and preservation of the bladder. Cogent objections have been raised regarding these limited operations, especially in patients with carcinoma of the cervix recurrent after irradiation, because of the increased risk of an incomplete resection. In addition, patients in whom the bladder or rectum is preserved often have multiple complications and malfunctioning of the preserved

Invasive Cervical Cancer

Urostomy

Shaded tissue within the dashed outline is permanently removed. Figure 3.44 Anterior exenteration with removal of all pelvic viscera except the rectosigmoid. The urinary stream is diverted into an ileal or sigmoid conduit or a continent pouch. (Modified from DiSaia PJ, Morrow CP, Townsend DE: Cancer of the vulva, Calif Med 118:13–18, 1973.)

Colostomy

Colostomy Urostomy

Low colonic anastomosis Shaded tissue within the dashed outline is permanently removed. Unshaded tissue within the dashed outline is first removed and then reconstructed. Figure 3.43 Total exenteration with removal of all pelvic viscera. Fecal stream is diverted via a colostomy, and urinary diversion is via an ileal or sigmoid conduit or a continent pouch. (Modified from DiSaia PJ, Morrow CP, Townsend DE: Cancer of the vulva, Calif Med 118:13–18, 1973.)

Low colonic anastomosis Shaded tissue within the dashed outline is permanently removed. Unshaded tissue within the dashed outline is first removed and then reconstructed. Figure 3.45 Posterior exenteration with removal of all pelvic viscera except the bladder. The fecal stream is diverted via a colostomy. (Modified from DiSaia PJ, Morrow CP, Townsend DE: Cancer of the vulva, Calif Med 118:13–18, 1973.)

CHAPTER 3

Invasive Cervical Cancer

organ. Consequently, some surgeons have completely abandoned subtotal exenterations, and most oncologists use them very selectively. One of the greatest technical advances in the evolution of pelvic exenteration is the intestinal conduit for diversion of the urinary stream. Originally, Brunschwig transplanted the ureters into the left colon just proximal to the colostomy, thus creating the so-called wet colostomy. The complication rate from this procedure, especially electrolyte imbalance and severe urinary tract infections, was unacceptable. Bricker popularized the use of an ileal segment conduit for urinary diversion. The incidence of both postoperative pyelonephritis and hypochloremic acidosis has been greatly reduced. Furthermore, the patients are dry and comfortable and therefore more easily rehabilitated. More recent developments have resulted in several techniques for creation of a continent reservoir, again using a segment of bowel (Fig. 3.46). Another significant advancement

in surgical technique of these patients is the use of the intestinal stapling device. Whereas a permanent colostomy was a standard part of the exenterative procedure, today, it is rare. In many, if not most, cases, reanastomosis with the end-to-end anastomosis stapler can be performed, and the fecal stream continues through the anus.

Patient Selection Only a few patients with recurrent cancer of the cervix are suitable for this operation (Table 3.25). Metastases outside the pelvis, whether manifested preoperatively or discovered at laparotomy, are an absolute contraindication to pelvic exenteration. The triad of unilateral leg edema, sciatic pain, and ureteral obstruction is pathognomonic of recurrent and unresectable disease in the pelvis. The triad must be complete, however, to be entirely reliable. Weight loss, cough, anemia, and other aberrations suggestive of advanced disease are not

C Figure 3.46 A–C, Construction of an Indiana pouch from the colon and the terminal ileum. (From Amis ES, Newhouse JH, Olsson CA: Continent urinary diversions: review of current surgical procedures and radiologic imaging, Radiology 168:395–401, 1988.)

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.25 Survival After Pelvic Exenteration Author(s) (Year)

Institution

Patients Treated

Operative Deaths (%)

No. Surviving 5 Yearsa (%)

Douglas and Sweeney (1975)

New York Hospital

1 (4.3)

5 (22)

Parsons and Friedell (1964)

Harvard University

112

24 (21.4)

Brunschwig (1965)

Memorial Hospital

535

86 (16)

108 (20.1)

Bricker (1967)

Washington University

153

15 (10)

53 (34.6)

Krieger and Embree (1969)

Cleveland Clinics

4 (11)

13 (37)

Ketcham et al. (1970)

National Cancer Institute

162

12 (7.4)

62 (38.2)

Symmonds et al. (1975)

Mayo Clinic

198

16 (8)

64 (32.3)

Morley and Lindenauer (1976)

University of Michigan

1 (2.9)

21 (62)

Rutledge et al. (1977)

MD Anderson Hospital

296

40 (13.5)

99 (33.4)

Averette et al. (1984)

University of Miami

—

1966–1971

4 (28.5)

5 (36)

—

1971–1976

15 (33.3)

10 (22)

—

1976–1981

4 (12.1)

19 (58)

—

6 (9.2)

15 (23)

Lawhead (1989)

Memorial Hospital

6 (9.2)

15 (23)

1972–1981

—

Soper et al. (1989)

Duke University

5 (7.2)

28 (4.5)

Shingleton et al. (1989)

University of Alabama

143

9 (6.3)

71 (50)

Sharma et al. (2005)

Roswell Park Cancer Institute

2 (4.2)

16 (33)

Fotopoulou et al. (2010)

Virchow University Hospital Berlin

47b

4 (8.5)

25 (53.2)c

Total

—

2012

248 (12.3)

663 (33.7)

In almost every series, the operative death rate and the 5-year survival rate improved dramatically in the later years of each series. Includes eight vaginal cancers. c Five-year survival not reached and therefore not included in the total. a b

sufficient justifications by themselves to discontinue efforts toward surgical management. Obesity, advanced age, and systemic disease may interdict extensive surgery in direct relation to the severity of these factors. Some patients are unsuitable because of psychological reasons, and a number of women who are otherwise candidates for pelvic exenteration elect to accept the fate of unresected recurrence. If the time from primary treatment to recurrence is short (,2 years), this usually indicates aggressive biologic activity of the tumor, and resectability is usually limited. Evaluation studies before surgery include chest radiography, CT scan of the abdomen and pelvis with intravenous contrast, creatinine clearance, liver function tests, and assessment of the patient’s hemostatic mechanism. Any suspected disease outside the pelvis noted on any of the diagnostic studies should prompt an attempt at confirmation using a fine-needle biopsy technique. Bone survey and liver scan are not part of the “routine” evaluation. Preparation for pelvic exenteration is often traumatic to patients with recurrent cervical cancer, especially when the procedure is aborted. The increased use of CT-directed fine-needle aspirants has contributed greatly to lowering the fraction of patients explored who are found to be unexenterable. At laparotomy, the entire abdomen and pelvis are explored for evidence of metastatic and intraperitoneal cancer (Fig. 3.47). The

liver should be carefully inspected visually and by palpation. The lymph nodes surrounding the lower aorta are the first to be sampled if the exploration of the abdomen has revealed no evidence of disease. If the lower aortic area findings are negative, a bilateral PL is performed.

Morbidity and Mortality Most of the morbidity and mortality directly related to exenteration occur within the first 18 months after the procedure. Many of the complications can be sequelae to any major surgery. These include cardiopulmonary catastrophes such as pulmonary embolism, pulmonary edema, myocardial infarction, and cerebrovascular accidents. The length of these surgical procedures and the magnitude of blood loss definitely increase the incidence of cardiovascular complications. This category of complications usually occurs within the first week after the procedure. Then there is a period when sepsis is the greatest threat to the patient’s health and life. This sepsis usually originates in the pelvic cavity with occurrence of a pelvic abscess or, more commonly, diffuse pelvic cellulitis. One of the most serious postoperative complications of exenteration is small bowel obstruction related to the denuded pelvic floor. In the past decade, several techniques have been used in an effort to avoid the adherence of small bowel to this large raw surface, including mobilization of omentum (Fig. 3.48) or abdominal

CHAPTER 3

Invasive Cervical Cancer

2. Laparotomy with careful search for peritoneal, liver, and other visceral implants

3. Selective periaortic lymphadenectomy

4. Bilateral pelvic lymphadenectomy

5 5. Cardinal ligament involvement with sidewall clearance evaluation

5 1. Biopsy of central recurrence in uterus or vagina

Figure 3.47 Steps in evaluation of a patient for an exenterative procedure. (Courtesy of A. Robert Kagan, MD, Los Angeles, CA.)

Figure 3.48 The omentum has been detached from the right transverse colon and the greater curvature of the stomach, keeping the left gastroepiploic vessels intact and creating a large “tongue of omentum” to cover the pelvic floor.

CHAPTER 3

Invasive Cervical Cancer

Figure 3.49 A, Lateral view of recurrent cancer involving the cervix and upper vagina with extension into the bladder and rectum. The stippled area indicates tissue to be removed by exenteration. B, A lateral view after pelvic viscera have been removed. The omental “carpet” is used to keep the intestines out of the pelvis during immediate postoperative period. With time, the omental “carpet” will descend into the pelvis, and the “carpet” will adhere to the pelvic floor. C, Urinary conduit and colostomy diversion after exenteration. Dotted areas of the sigmoid, bladder, and internal genitalia have been removed.

wall peritoneum to cover the pelvic floor (Fig. 3.49). When small bowel obstruction does occur, it is appropriately treated with conservative therapy. However, half these patients come to reoperation, and the mortality rate of this group is approximately 50% in some series. The risk of bowel obstruction is increased by the presence of pelvic infection. Both conditions predispose to the development of small bowel fistulas, which always require reoperation and frequently are fatal. In general, complications are more common in patients who have recurrence after radiation therapy. Irradiated tissue is less likely to produce good wound healing, and the formation of granulation tissue is severely retarded. The long-term morbidity from exenteration is predominantly related to urinary diversion. After the period of susceptibility to sepsis has passed, urinary obstruction and infection become the major nonneoplastic life-threatening complications. Pyelonephritis is common and should be treated promptly and vigorously. Periodic IVPs can be obtained to assess the collecting system for hydronephrosis. A mild degree of obstruction is frequently retained after construction of an ileal conduit, but progressive hydronephrosis will require correction to salvage renal function. The incidence of complications appeared to be less in patients in whom an unirradiated portion of bowel had been used for construction of the conduit.

Survival Results The 5-year cumulative survival rate after pelvic exenteration varies in the literature from 20% to 62% (see Table 3.27). Reported survival rates depend greatly on the circumstances of

patient selection for exenteration. Cumulative survival rates are always improved when no patient is exenterated who has a positive pelvic node after pelvic irradiation. In general, however, both morbidity and mortality and the 5-year survival rate have improved steadily over the past 2 decades. The mortality rate in most centers is now well below 5%, and morbidity has been similarly lowered. In 2009, 60 years after the first description of pelvic exenteration, Marnitz and colleagues surveyed and compared practice patterns in the United States and Germany. The number of exenterations performed in the 21st century was comparable in both countries, with centrally recurrent cervical cancer or persistent tumor after chemoradiation being the main indication. Whereas PET-CT is more commonly used in the United States, MRI is the preferred tool in Germany. Surgical staging is more commonly performed in the United States (61% vs. 32%). Exenteration for FIGO stage IVA disease was more commonly recommended in Germany (43% vs. 0%), as was the operation in the setting of fistulae involving the bladder or rectum (61% vs. 29%). In Germany, interdisciplinary treatment with general surgeons, urologists, plastic surgeons, and radiation oncologists is more common. Although there is a consensus to administer adjuvant therapy after exenteration for patients with positive margins or positive lymph nodes, adjuvant therapy is more frequently recommended in Germany (93%) than in the United States (74%). In 2017, Graves et al. interrogated the National Cancer Database from 1998 to 2011 and identified 517 women who had

CHAPTER 3

Invasive Cervical Cancer

undergone pelvic exenteration. Among 313 patients with clinical follow-up recorded, the median OS was 24 months. Stage, lymph node status (median OS node-positive, 17.9 months; median OS node-negative, 73.2 months), health insurance status, and histologic type (median OS SCC 24.2 months; median OS adenocarcinoma, 61.8 months) were significantly associated with survival. For vaginal reconstruction, vascularized muscle flaps are preferred to fill the empty pelvis, and developments in bioengineering tissue are likely to have applications in neovaginal creation. De la Garza and colleagues reported the successful performance of a total pelvic exenteration with a split-thickness skin graft neovagina, continent orthotopic neobladder, and rectal anastomosis, resulting in no external ostomies and adequate sexual function.

Radiation With recurrent disease outside the initial treatment field, irradiation is frequently successful in providing local control and symptomatic relief. External irradiation in moderate and easily delivered doses is usually effective in relieving pain from bone metastases. A dose of 3000 cGy delivered over 2 to 3 weeks is often sufficient to relieve pain from vertebral column or longbone metastases. Höckel and associates reported their experience with a combined operative and radiotherapy (CORT) for recurrent tumors infiltrating the pelvic wall. Although the combination therapy is not new, these authors surgically remove the recurrence more radically than previously reported. The bony pelvis and neurovascular support of the leg is preserved. Implantation of guide tubes, which exit from the skin for brachytherapy, is done after resection of the tumor. Considerable pelvic reconstruction is usually done. Although the indications and procedure are evolving, in the first 48 patients treated, survival probabilities are 50% and 44% after 3 and 5 years, respectively. Reirradiation of pelvic recurrences of cervical cancer occurring within the previously treated field is a subject of some controversy. The results after reirradiation of patients with recurrent cervical malignancy have varied considerably. Truelsen reported a 3-year cure rate of 1.7%. Murphy and Schmitz reported a 9% salvage rate in 1956, and Nolan and associates reported on the use of 60Co teleradiation with a 25% salvage rate. At the Roswell Park Memorial Institute, Murphy and Schmitz adopted the policy of reirradiating patients with recurrence, delivering a full or almost full course for a second time. Among the highly selected series of 46 patients, 9% to 10% were living and well at the end of 5 years. Only seven patients had biopsyproven recurrences before treatment. Others have shown that the results of reirradiation depend on many factors, including the site of recurrence, initial clinical stage, and initial dose of radiation therapy. Careful perusal of these reports suggests that most patients who benefited from reirradiation were those who received less than optimal radiation during initial therapy. This set of circumstances has become rare in recent times, when more sophisticated radiotherapy is being delivered in many areas of the United States. Therefore, reirradiation for recurrent disease is

usually not a worthwhile consideration. The potential for necrosis and fistula formation with even moderate doses of reirradiation in the pelvis by external or interstitial sources can give very unfavorable results. Recurrence after RH has been treated with radiation. In a study from Holland, 271 patients were treated with RH, and 27 recurred with 14 limited to the pelvis. Of note, adjuvant radiotherapy had been administered in 14 (52%) of the 27. In the four patients with isolated pelvic recurrence, only one died of disease, but all of the other patients with recurrences died of disease. The survivors were treated with radiation. In a study from the MD Anderson Cancer Center, 50 patients had recurrence after RH and were treated with radiation. OS rate was 33%. In the 16 patients with central disease, 12 (69%) remained disease free. The survival rate of 29 patients with squamous carcinoma was 51% compared with 14% for the 14 patients with adenocarcinoma (P 5 .05).

Chemotherapy The management of disseminated cervical cancer has improved with the development of modern chemotherapy. Fig. 3.17 reviews the treatment of advanced or recurrent disease. Because concurrent platinum-based chemoradiation has become the standard of care for locally advanced disease, many recurrent tumors may therefore be platinum resistant. The GOG has completed eight multicenter, phase III randomized trials to study platinum-based therapies for recurrent and/or metastatic disease (Table 3.26). Drug discovery for the most part has fed into these phase III trial designs through the GOG’s phase II series dedicated to exploring the activity and tolerability of cytotoxic compounds in cervical cancer. The early trials of the GOG for recurrent and metastatic cervical carcinoma were designed to evaluate cisplatin dosing, schedules, and analogs. The next two trials evaluated the addition of ifosfamide, bleomycin, and mitolactol to cisplatin-based therapies. Among some of the lessons learned during the 1980s and 1990s governing chemotherapy for recurrent cervical cancer were that platinum-based therapies were most effective and that cisplatin was more active than carboplatin (19% vs. 15%, respectively). Two ways through which the RR could be increased without prolongation in survival included increasing the platinum dose and/or adding ifosfamide to cisplatin. As a consequence of these first five phase III randomized clinical trials, single-agent cisplatin at 50 mg/m2 emerged as the standard for recurrent disease, with a documented 19% RR on a 21-day schedule. The combined regimen of cisplatin in combination with paclitaxel in GOG 169 yielded an impressive 36% RR, improvement in PFS, but no significant impact on OS compared with single-agent cisplatin. The next trial, GOG 179, compared single-agent cisplatin with cisplatin plus topotecan. The improvements observed in RR, PFS, and OS all favored the combined regimen, leading to FDA approval of the cisplatin 50 mg/m2 plus topotecan 1.75 mg/m2 days 1 to 3 in this population. In both GOG 169 and GOG 179, RRs were decreased in patients who had received prior platinum (Table 3.27). Because GOG 179 was conducted during the era of chemoradiation and GOG

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.26 Eight Phase III Randomized Trials in Recurrent Cervical Cancer Conducted by the

Gynecologic Oncology Group

OBJECTIVE RESPONSE GOG Protocol

Study Chair

Bonomi et al.

PR %

CR %

Overall %

Median Duration of Response (months)

Median PFS (months)

Year

Arms

Patients (n)

1985

Cisplatin 50 mg/m2 IV q21d

150

10.7

20.7

4.9

7.1

Cisplatin 100 mg/m2 IV q21d

166

18.7

12.7

31.4

4.1

Cisplatin 20 mg/m2 IV 3 5 days q21d

128

16.4

8.6

4.8

6.1 Median Survival (months)

110

Thigpen et al.

McGuire et al

Omura et al.

1989

1997

Cisplatin 50 mg/m2 24 h continuous infusion

156

5.5

6.4

Cisplatin 1 mg/min rapid infusion

164

4.5

6.2

Median PFI (months)

Median Survival (months)

Carboplatin 340 to 400 mg/ m2 IV q28d

175

9.7

5.7

15.4

2.7

6.2

Iproplatin 230–270 mg/m2 IV q28d

177

6.8

10.8

5.5

Median PFS (months)

Median Survival (months)

Cisplatin 50 mg/m2 IV q21d

140

11.4

6.4

17.8

3.2

Cisplatin 50 mg/m2 IV 1 mitolactol180 mg/m2 PO days 2, 6 q21d

147

11.6

9.5

21.1

3.3

7.3

Cisplatin 50 mg/m2 IV 1 ifosfamide 5 g/m2 24-h infusion 1 MESNA 6 g/m2 q21d

151

18.5

12.6

31.1 P 5 .004

4.6 P 5 .003

8.3

Median Survival (months) 149

Bloss et al.

2002

Cisplatin 50 mg/m2 IV 1 ifosfamide 5 g/m2 24 h infusion 1 MESNA 6 g/m2 q21d

146

32.2

4.6

8.5

Bleomycin 30 units 24-h infusion followed by cisplatin 50 mg/m2 IV 1 ifosfamide 5 g/m2 24-h infusion 1 MESNA 6 g/m2 q21d

141

32.1

5.1

8.4

Median Survival (months) (Continued)

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.26 Eight Phase III Randomized Trials in Recurrent Cervical Cancer Conducted by the

Gynecologic Oncology Group—cont’d

OBJECTIVE RESPONSE GOG Protocol 169

Study Chair Moore et al.

Year 2004

Arms Cisplatin 50 mg/m2 IV q21d Paclitaxel 135 mg/m2 24-h infusion 1 cisplatin 50 mg/m2 IV q21d

Patients (n) 134

PR % 13

CR % 6

Overall % 19

Median Duration of Response (months) 2.8

130

36 P 5 .002

4.8 P , .001

Median PFS (months) 8.8 9.7

Median Survival (months) 179

Long et al.

2005

Cisplatin 50 mg/m2 IV q21d

145

2.9

6.5

Topotecan 0.75 mg/m2 days 1–3 1 cisplatin 50 mg/m2 IV q21d

148

26 P 5 .004

4.6 P 5 .014

9.4 P 5 .017

MVAC q4wk

4.4

9.4 Median OS (months)

204

Monk et al.

2009

Paclitaxel 135 mg/m2 24-h infusion 1 cisplatin 50 mg/m2 q21d

103

26.2

2.9

29.1

5.82

12.87

Vinorelbine 30 mg/m2 days 1 and 8 1 cisplatin 50 mg/ m2 q21d

108

18.5

7.4

25.9

3.98

9.99

Gemcitabine 1000 mg/m2 days 1 and 8 1 cisplatin 50 mg/m2 q21d

112

21.4

0.9

22.3

4.7

10.28

Topotecan 0.75 mg/m2 days 1–3 1 cisplatin 50 mg/m2 q21d

111

21.6

1.8

23.4

4.57

10.25

CR, Complete response; GOG, Gynecologic Oncology Group; IV, intravenous; MVAC, methotrexate, vinblastine, doxorubicin, cisplatin; NS, not significant; PFS, progression-free survival; PR, partial response; q, every.

TABLE 3.27 Association of Prior Platinum

Exposure With Response Rates in Gynecologic Oncology Group (GOG) 169 and GOG 179 GOG 179

No Prior Cisplatin (%)

Prior Cisplatin (57% of Patients) (%)

Cisplatin

Cisplatin 1 topotecan

GOG 169 Cisplatin

No Prior Cisplatin 26

Prior Cisplatin (27% of Patients) 5

Cisplatin 1 paclitaxel

169 was under way before the adoption of multimodality therapy, 57% of patients on GOG 179 received radiosensitizing platinum compared with 27% on GOG 169. GOG 204 compared four platinum-based doublets using paclitaxel, topotecan, gemcitabine, and vinorelbine. Because this study was activated before the data from GOG 179 were mature,

cisplatin plus paclitaxel was selected as the control arm, primarily because of the 36% RR observed in GOG 169. None of the experimental arms outperformed the reference arm (Table 3.28 and Fig. 3.50). GOG-0204 established cisplatin plus paclitaxel as the chemotherapy standard for recurrent/metastatic disease not amenable to pelvic exenteration. For this reason, cisplatin plus paclitaxel has been selected as the control arm for the succeeding trial, which was activated in April 2009 (GOG 240). In GOG 240, the experimental arms were designed to answer two critical questions. The first is a chemotherapy question and concerns whether nonplatinum agents would have greater activity in the recurrent setting given the increased usage of platinum-based chemoradiation initially for locally advanced cancers. Two phase II experiences using nonplatinum doublets have been described. In the United Kingdom, the Scotcerv trial piloted gemcitabine plus Taxotere, which, when presented at American Society of Clinical Oncology (ASCO), was not deemed to be suitable for further development. Tiersten and colleagues reported on their experience with the nonplatinum doublet topotecan plus paclitaxel. It is important to note that

CHAPTER 3

Invasive Cervical Cancer

TABLE 3.28 Objective Response by Treatment Regimen in Gynecologic Oncology Group 204 Tumor Response

Cis 1 Pac (%)

Cis 1 Vin (%)

Cis 1 Gem (%)

Cis 1 Topo (%)

Total

3 (2.9)

8 (7.4)

1 (0.9)

2 (1.8)

27 (26.2)

20 (18.5)

24 (21.4)

24 (21.6)

50 (48.4)

46 (42.6)

54 (48.2)

53 (47.8)

203

23 (22.3)

34 (31.5)

33 (29.5)

32 (28.8)

122

Odds ratioa

—

1.17

1.43

1.34

—

95% CI

—

0.54, 2.58

0.65, 3.19

0.61, 2.98

—

Odds ratios for response are provided for the reference arm, Cis 1 Pac, to the experimental therapies. CI, Confidence interval; Cis, cisplatin; CR, complete response; Gem, gemcitabine; Pac, paclitaxel, PD, progressive disease; PR, partial response; SD, stable disease; Vin, vinorelbine. Modified from Monk BJ, Sill MW, McMeekin DS, et al: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 27:4649–4655, 2009. a

1.0 0.9

Treatment CIS + PAC CIS + VIN CIS + GEM CIS + TOP

Proportion surviving

0.8 0.7

Alive Dead Total 74 103 29 85 108 23 92 112 20 89 111 22

0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

Months on study Figure 3.50 Gynecologic Oncology Group 204 Survival Curve. (From Monk BJ, Sill MW, McMeekin DS, et al: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 27:4649–4655, 2009.)

the regimen was active in previously irradiated patients (RR, 26%) with acceptable toxicities. The laboratory work by Bahadori and colleagues demonstrating synergy between paclitaxel and microtubule-inhibiting agents (e.g., topotecan or vinorelbine) underscored this regimen’s potential. This nonplatinum doublet is being studied by the Arbeitsgemeinschaft Gynakologische Onkologie (AGO). The second question addressed by GOG 240 involves targeted therapy. Tumor angiogenesis as measured by microvessel quantification has been shown to be a prognostic factor in cervical cancer. A small case series by Wright and colleagues described the successful combination of bevacizumab with cytotoxic agents in the recurrent and metastatic setting among previously irradiated patients. Of note, the antiangiogenesis agent bevacizumab in combination with chemotherapy has been FDA approved firstand second-line therapy for metastatic colorectal cancer and untreated non-small-cell lung cancer (NSCLC). The drug has also been studied by the GOG in primary advanced and platinum-sensitive recurrent ovarian carcinoma. A phase II evaluation of bevacizumab at 15 mg/kg q21 days was undertaken

within the GOG (protocol 227C). The 26% RR of bevacizumab among previously irradiated patients was among the highest RRs noted within the GOG’s phase II experience for recurrent cervical cancer (Fig. 3.51). Given the potential shared tumor biology between NSCLC and cervical cancer, the activity of platinum plus paclitaxel with bevacizumab in NSCLC supported the inclusion of this regimen as one of the experimental arms in GOG 240. Assuming no interaction between the nonplatinum doublet and bevacizumab, a 2 3 2 factorial design was selected to answer both the chemotherapy question and the antiangiogenesis question. The schema for GOG 240 appears in Fig. 3.52. This study also prospectively evaluated important prognostic factors—including African American race, performance status greater than 0, pelvic disease, prior radiosensitizer, and time interval from diagnosis to first recurrence less than 1 year—that have been recently reported by Moore and colleagues in a multivariate pooled analysis of three prior phase III studies in this population (Table 3.29). At 173 deaths in February 2012, the preplanned interim analysis occurred and was noteworthy for demonstrating that

100

CHAPTER 3

Invasive Cervical Cancer 1.0 Proportion progression free

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

12 Months on study

Figure 3.51 Progression-free survival curves of bevacizumab from Gynecologic Oncology Group protocol 227C superimposed over progression-free survival curves of other agents studied by the Gynecologic Oncology Group in this patient population. (From Monk BJ, Sill MW, McMeekin DS, et al: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 27:4649–4655, 2009.)

GYNECOLOGIC ONCOLOGY GROUP PROTOCOL 240 A randomized phase III trial of cisplatin plus paclitaxel with and without bevacizumab versus the nonplatinum doublet, topotecan plus paclitaxel, with and without NCI-supplied bevacizumab, in stage IVb, recurrent, or persistent carcinoma of the cervix. Activation Date – April 6, 2009 Target Accrual = 450 Study Chair: Krishnansu S. Tewari, MD ([emailprotected]) Statistician: Michael Sill, PhD Pathologist: Helen Michael, MD Co-Chairs: Harry J. Long, MD (Medical Oncology), Richard T. Penson, MD (Quality of Life), Michael J. Birrer, MD, PhD (Translational Research) Scientific Collaborations: Steven Waggoner, MD. David H. Moore, MD. Kathleen M. Darcy, PhD, Bradley J. Monk, MD

PRIMARY OBJECTIVES

1. To determine whether the addition of bevacizumab to chemotherapy improves overall survival 2. To determine whether the nonplatinum chemotherapy doublet consisting of topotecan plus paclitaxel improves overall survival compared with the regimen involving cisplatin plus paclitaxel 3. To determine the frequency and severity of adverse events as assessed by CTCAE version 3.0 for the regimens administered

SECONDARY OBJECTIVES

1. To estimate and compare the progression-free survival of patients treated by the regimens investigated on this study 2. To estimate and compare the proportion of patients with tumor responses by the regimens investigated on this study

HEALTH-RELATED QUALITY OF LIFE OBJECTIVES To determine whether the addition of bevacizumab to chemotherapy or the substitution of cisplatin with topotecan improves the health-related QoL as measured by the FACT-Cx TOI and produces favorable toxicity profiles

REGIMEN I

ELIGIBILITY Primary stage IVB or recurrent or persistent carcinoma of the cervix Measureable disease GOG PS 0-1 Cycles repeated q21 days to progression or toxicity

R A N D O M I Z E

Paclitaxel 135 mg/m2 IV 24h d1 CDDP 50 mg/m2 IV d2 OR Paclitaxel 175 mg/m2 IV 3h 1 CDDP 50 mg/m2 IV d2 OR Paclitaxel 175 mg/m2 IV 3h d1 CDDP 50 mg/m2 IV d1

REGIMEN II

Paclitaxel 135 mg/m2 IV 24h d1 CDDP 50 mg/m2 IV d2 Bevacizumab 15 mg/kg d2 OR Paclitaxel 175 mg/m2 IV 3h d1 CDDP 50 mg/m2 IV d2 Bevacizumab 15 mg/kg d2 OR Paclitaxel 175 mg/m2 IV 3h d1 CDDP 50 mg/m2 IV d1 Bevacizumab 15 mg/kg IV d1

REGIMEN III

Paclitaxel 175 mg/m2 IV 3h d1 Topotecan 0.75 mg/m2 30min d1–3

REGIMEN IV

Paclitaxel 175 mg/m2 IV 3h d1 Topotecan 0.75 mg/m2 30min d1–3 Bevacizumab 15 mg/kg IV d1

Gynecologic Oncology Group US NIH, 2010.

Figure 3.52 Gynecologic Oncology Group 240 Schema.

EXPLORATORY OBJECTIVE A: PROGNOSTIC MARKERS FOR PREDICTIVE MODELING To evaluate the impact of age, race, performance status, stage, histology, grade, disease site, prior chemotherapy with primary radiation, and time to recurrence on RR, PFS, and OS

EXPLORATORY OBJECTIVE B: IMPACT ON SMOKING To determine the prevalence of active smoking extent of nicotine dependence and to determine if smoking is an independent risk factor for PFS in this cohort

TRANSLATIONAL RESEARCH OBJECTIVES 1. To isolate circulating tumor cells recovered from blood and determine their association to measures of clinical outcome 2. To correlate angiogenesis markers in plasma, biomarkers of hypoxia, and single nucleotide polymorphisms with measures of clinical outcome 3. To develop an optimal prognostic model for PFS and OS using clinical covaniates, smoking status, and various biomarkers

CHAPTER 3

TABLE 3.29 Multivariate Analysis of

Prognostic Factors of Treatment Response in Recurrent, Persistent, and Metastatic Cervical Carcinoma OR

95% CI

P-Value

Race: Black vs. non-Black

0.49

0.28–0.83

.008

GOG performance 1 or 2 vs. 0

0.60

0.38–0.94

.027

Site of disease: pelvic vs. nonpelvic

0.58

0.38–0.90

.015

Radiosensitizer: yes vs. no

0.52

0.32–0.85

.009

First recurrence within 1 year of diagnosis: yes vs. no

0.61

0.39–0.95

.027

Odds ratio (OR) in favor of treatment response estimated from logistic regression model, adjusted for covariates. CI, Confidence interval; GOG, Gynecologic Oncology Group. From Moore DH, Tian C, Monk BJ, et al: Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study, Gynecol Oncol 116:44–49, 2010.

the substitution of topotecan for cisplatin did not significantly improve OS in the GOG 240 population, even among those who were platinum-naïve. However, at 276 deaths in December 2012, the database was locked again and a second analysis performed. In February 2013, the NCI issued a press release indicating that the open-label, multinational, multi-center, phase III, randomized clinical trial, GOG protocol 240, had met its primary endpoint with the arms administering the fully humanized, antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab being associated with a significant survival advantage when compared to chemotherapy alone. The rationale to target tumor angiogenesis in cervical cancer was based on clinical, pathologic, and molecular phenomenon that characterize HPV-induced cervical carcinogenesis along with therapeutic gains observed with antiangiogenesis drugs in phase I (e.g., the fungal derived TNP-470 molecule) and phase II (bevacizumab; oral VEGF receptor tyrosine kinase inhibitor, pazopanib) trials in the recurrent cervical cancer population. In GOG 240, patients were treated every 21 days until progression.

Proportion surviving

1: Chemo 2: Chemo + Bev

0.8 0.7

Events, n (%) Median OS, mos

0.6 0.5

Chemotherapy (n = 225)

Chemotherapy + Bev (n = 227)

140 (62)

131 (58)

13.3

17.0

HR = 0.71 (97% CI; 0.54–0.94) P = 0.0035

0.4

Median follow-up 20.8 mo

0.3 0.2 0.1 0.0 0

101

The ASCO accepted the abstract for the General Plenary 2013 but made a rare exception to their embargo policy and released the abstract into the public domain in March 2013, 3 months before the Annual Meeting. Importantly, the incorporation of bevacizumab (15 mg/kg) with cisplatin–paclitaxel and with topotecan–paclitaxel led to a significant 3.7-month improvement in OS (17 vs. 13.3 months; HR, 0.71; 98% CI, 0.54 to 0.95; one-sided P 5 .004), a significant improvement in PFS (8.2 vs. 5.9 months; HR, 0.67; 95% CI, 0.54 to 0.82; two-sided P 5 .002), and superior objective response rate (ORR) (48% vs. 36%; relative probability of response, 1.35; 95% CI, 1.08 to 1–1.68; two-sided P 5 .008) (Fig. 3.53). Each of these gains was clinically meaningful and was not accompanied by a significant deterioration of QoL when measured by three QoL instruments that had undergone prior prospective validation in this population. For example, using the mean functional assessment of cancer therapy for cervical cancer trial outcome index, QoL with bevacizumab scored 1.2 points lower on average (98.75% CI, 4.1 to 1.7; P 5 .3) which was not statistically significant as prior studies had indicated a difference of at least 3 points on this instrument to be indicative of a significant difference. A vaginal fistula rate of 8.6% was observed among patients who received bevacizumab, all of whom had been previously irradiated. The results of GOG-240 led directly to US FDA approval on August 14, 2014 (without an Oncology Drugs Advisory Committee [ODAC]) for the population studied, as well as approval by regulatory agencies throughout the world, including the United Kingdom’s Cancer Drug Fund; the European Union’s European Medicines Agency; Swissmedic; and the Ministries of Health in Israel, Australia, Hong Kong, 5 Middle Eastern nations, Brazil, and 10 Latin American countries, including Mexico. The NCCN Cervical Cancer Treatment Guidelines have listed both bevacizumab-containing triplets studied in GOG 240 (cisplatin–paclitaxel–bevacizumab and topotecan–paclitaxel– bevacizumab) as category 1. A final analysis of OS was reported in 2017 when the protocol-specified number of 348 deaths had been reached. The median OS still favored the arms incorporating bevacizumab (16.8 vs. 13.3 months; HR 0.77; 95% CI, 0.62 to 0.95; P 5 .007).

1.0 0.9

Invasive Cervical Cancer

Months on study Figure 3.53 Gynecologic Oncology Group 240 phase III randomized trial: progression n 5 free survival for chemotherapy versus chemotherapy plus bevacizumab.

102

CHAPTER 3

Invasive Cervical Cancer

The median OS among radiation-naïve patients who received bevacizumab was superior to that of those radiation-naïve patients treated with chemotherapy alone (24.5 vs. 16.8 months; HR 0.64; 95% CI, 0.37 to 1.10; P 5 .11). Finally, in an analysis of post-progression survival, there was no evidence of a negative impact associated with bevacizumab use (median OS approx. 7 to 8 months; HR 0.83; 95% CI, 0.66 to 1.05; P 5 .06). Among the tertiary endpoints of GOG-0240 was the prospective evaluation of clinical prognostic factors previously identified in a pooled analysis of prior GOG studies in this population. With equal weights assigned to performance status, time to recurrence, prior platinum exposure, pelvic disease, and African American ethnicity (likely a surrogate for limited access to healthcare), patients were separated into three risk categories: low-risk (0 to 1 factor), mid-risk (2 to 3 factors), and high-risk (4 to 5 factors). For the entire study population, these “Moore criteria” were prospectively validated in GOG-0240. Interestingly, while there appeared to be limited survival benefit attributed to bevacizumab use among low-risk patients (HR 0.96; median OS 22.9 vs. 21.8 months), mid-risk and high-risk patients appeared to derive benefit (HRs 0.673 and 0.536, respectively). These findings call into question whether low-risk patients by the Moore prospectively validated scoring system should be treated with bevacizumab with its attendant risk of fistula (approximately 8% among those previously irradiated) without any survival benefit. At the very least, low-risk patients (as well as mid-risk and highrisk patients) should be counseled regarding these data. Because glandular carcinomas comprise only 25% of cervical cancer, it was not surprising that GOG-0240 was underpowered to critically evaluate the impact of bevacizumab among women with adenocarcinoma of cervix. To increase the sample size in an exploratory analysis, Seamon et al. combined squamous histologies from GOG-0240 (i.e., SCC and adenosquamous carcinoma) in one ancillary data analysis, and also combined glandular histologies (i.e., adenocarcinoma plus adenosquamous carcinoma) in a second ancillary data analysis. No significant differences in median OS were observed when comparing adenocarcinoma to combined squamous histologies or when SCC was compared with combined glandular histologies. Based on these results and the observation that both HPV-16 (predominantly found in squamous tumors) and HPV-18 (found in glandular tumors) contain the same oncogenes (i.e., E6 and E7) that drive tumor angiogenesis, it is reasonable not to withhold bevacizumab among women with recurrent/metastatic cervical adenocarcinoma. The translational science endpoint in GOG-0240 involved the enumeration of circulating tumor cells (CTCs) pre-cycle 1 and 36 days post-cycle 1. Not only were CTCs detected in the majority of patients, but it was found that among those with high CTCs (i.e., above the median of 7 CTCs/sample), the median PFS for those who received chemotherapy plus bevacizumab was significantly higher than those patients with high CTCs who received chemotherapy alone (median PFS 10.8 vs. 6.9 months). If these findings were to be prospectively validated in a forthcoming randomized trial, CTCs would represent predictive biomarker that could be obtained via a non-invasive liquid biopsy. The Japanese Clinical Oncology Group (JCOG) protocol 0505 demonstrated significant non-inferiority with substitution

of carboplatin for cisplatin to mitigate toxicity in the platinumdoublet for recurrent/metastatic disease. The study demonstrated significant non-inferiority (HR 0.994; 90% CI, 0.789 to 1.253; P 5 .032) with a median OS for cisplatin plus paclitaxel of 18.3 months and for carboplatin plus paclitaxel, 17.5 months. Bevacizumab was not studied in this trial. Interestingly, among patients who were cisplatin-naïve (i.e., had not received prior CDDP-radiosensitizing chemoradiation for locally advanced disease prior to recurrence), the median OS with carboplatin plus paclitaxel was inferior (i.e., 13.0 months vs. 23.2 months) (HR 1.571; 95% CI, 1.062 to 2.324). This trial would support using the cisplatin-paclitaxel-bevacizumab triplet for recurrent/ metastatic disease that is platinum-naïve. Otherwise, carboplatin-paclitaxel-bevacizumab may be considered for patients previously treated with cisplatin-based chemoradiation.

Immunotherapy for Advanced Cervical Cancer The rationale to study immunotherapy for treatment of advanced disease is predicated on the observation that nearly every case of cervical cancer is driven by high-risk HPV infection. Interrogation of the Cervical Cancer Genome Atlas has been noteworthy for novel amplifications identified in the immune targets, programmed death-ligand 1 (PD-L1) and PD-L2. Interestingly, amplification of immunologic sequences appears to be triggered by viral integration into the genome. Whereas 0% of normal cervical tissue expresses the immune checkpoint, PD-L1, 19% to 88% of SCCA of the cervix and 14% of adenocarcinoma of the cervix express PD-L1; 29% of squamous lesions also express PD-L2. Other immune inhibitory molecules, including CTLA-4 and TIM-3, are also expressed in cervical carcinomas. Importantly, SCCs arising in the head and neck have shown promising results in phase III randomized clinical trials studying immunologic checkpoint blockade. In addition, the composition of the tumor microenvironment impacts prognosis with increased tumor infiltrating lymphocytes (TILs) associated with improved survival. The appearance of mature M1 macrophages, CD81 cells, CD41 cells, and Tregs also track with better prognosis. Finally, cervical cancers have an increased total mutational burden with 5 to 6 mutations per mega-base, providing a relatively large neoantigen substrate.

Pembrolizumab—The First US FDA Approved Immunotherapy for Cervical Cancer Pembrolizumab, an anti-PD-1 checkpoint inhibitor, prevents binding of PD-L1 and PD-L2 on the tumor to the PD-1 receptors on T cells. The cervical cancer cohort of the KeyNote-158 basket trial (NCT02628067) enrolled women with recurrent/metastatic cervical cancer that had progressed following systemic therapy. Patients were treated with pembrolizumab 200 mg intravenously every 21 days until disease progression. The primary endpoint, ORR, was correlated with the combined positive score (CPS) of PD-L1 expression. The CPS is described by an equation in which the sum of PD-L1 positive tumor cells, lymphocytes, and macrophages are divided by the total number of tumor cells and multiplied by 100. Among 77 patients with PD-L1 positive tumors, the ORR was 14.3% (95% CI, 7.4 to 24.1) and included 2.6% complete responses. At the time of review by the US FDA, the median

CHAPTER 3

duration of response in months had not been reached, although over 90% of responders remained progression-free for at least 6 months. On June 12, 2018, pembrolizumab became the first immunotherapy approved for cervical cancer, together with its companion diagnostic, PD-L1 IHC 22C3 through the FDA’s accelerated approval program. Patients who progress on first-line systemic therapy (e.g., platinumbased chemotherapy doublets with or without bevacizumab) who have a CPS score $1 may be treated in the second line with pembrolizumab. The confirmatory phase III randomized trial, KeyNote-826 (NCT03635567), is studying chemotherapy with and without pembrolizumab in the first-line setting and has fully enrolled. In this trial, inclusion of bevacizumab is according to the investigator. A second phase III, randomized, frontline trial, BEATcc (NCT03556839), is evaluating the tolerability and safety of chemotherapy plus bevacizumab with and without the anti-PD-L1 molecule atezolizumab. Finally, in the second-line setting, the phase III, randomized clinical trial, EMPOWER Cervical-1 (NCT03257267), is comparing the activity of the anti-PD-1, cemiplimab, to physician’s choice chemotherapy among patients who have progressed on platinum-containing systemic therapy for recurrent disease.

Anti-PD-1 and Anti-CTLA-4 Combinations Inhibition of the PD-1/PD-L1 pathway will not activate tumor immunity as expected if the required CD81 T cells are not present in the cancer tissue. However, simultaneous inhibition of the B7-CTLA-4 pathway by an anti-CTLA-4 antibody can increase the number of activated CD81 T cells in lymph nodes, followed by an increase in the number of activated CD81 T cells infiltrating into tumor tissues, thereby enhancing the antitumor effects. In addition, anti-CTLA-4 antibody therapy may be effective against regulatory T cells in the cancer immunosuppressive microenvironment. In the CheckMate-358 study (NCT02488759), women with advanced SCC of the cervix who had received up to two prior lines of therapy for recurrent/metastatic disease were treated with one of two different combinations of the anti-PD-1, nivolumab, and the anti-CTLA-4, ipilimumab. Objective responses ranged from 31.6% to 45.8% for patients who had not received prior systemic therapy (median PFS 8.5 to 13.8 months), and from 23.1% to 36.4% for those who had (median PFS 3.6 to 5.8 months). The duration of response for previously treated patients ranged from 9.5 to 14.6 months, while that for treatment-naïve patients had not been reached at the time of data presentation at the 2019 European Society for Medical Oncology (ESMO) Congress in Barcelona. These provocative data underscoring the activity of combined checkpoint blockade in this disease were indirectly validated at the 2020 Virtual ESMO Congress where O’Malley et al. reported that the combination of the anti-PD-1, balstilimab, and the antiCTLA-4, zalifrelimab (NCT03495882), was active in patients who had received one or more prior lines of therapy for recurrent/metastatic cervical cancer (ORR 20% with 5% complete response and 15% partial response; median duration of response not reached at the time of presentation.) Importantly, responses with the combination were observed among patients with adenocarcinoma and

Invasive Cervical Cancer

103

adenosquamous carcinoma, as well as among patients who were PD-L1 negative.

Adoptive T Cell Therapy Studying autologous TILs at the NCI, Stevanovic et al. obtained tumor from nine heavily pretreated patients with advanced cervical cancer. After isolating the TILs and expanding them with young TILs and enriched T cells, a conditioning regimen was used for reinfusion. T cell infusion was preceded by lymphocyte-depleting chemotherapy and followed by administration of aldesleukin. Three patients experienced objective tumor responses (two complete responses and one partial response). At the time of publication, the two complete responses were ongoing at 22 and 15 months after treatment. Importantly, HPV reactivity of T cells in the infusion product correlated positively with clinical response. Patients whose serum showed no reactivity did not respond to a single infusion of HPV-TILs. At present, the phase II LN-145 autologous TILs study using interleukin-2 (NCT03108495) is being conducted as part of several distinct cohorts in order to determine the efficacy, tolerability, and feasibility of rolling out this novel therapeutic platform into the community.

Tissue Factor as a Target Tissue factor is highly expressed in cervical carcinoma and is upregulated in metastatic lymph nodes and distant disease. Using the tissue factor-directed antibody-drug conjugate (ADC), tisotumab vedotin, Coleman reported encouraging results from the innovaTV-204 study (NCT03438396) at the 2020 Virtual ESMO Congress. The ORR was 24% by blinded radiology review and included seven complete responses. The median duration of response was 8.3 months at a median follow-up of 10 months. The ocular adverse events (grade 1, 25%; grade 2, 27%; grade 3, 2%) resolved in 85% of cases and are thought to be related to the linker in the ADC. This novel therapy is being studied in the ongoing innovaTV 205/GOG-3024/ENGOT-cx8 trial (NCT03786081) in which all patients are evaluated by an ophthalmologist prior to treatment initiation and placed on an active eye care plan.

Anti-HER Strategies Five percent of cervical carcinomas are HER21 as assessed by 31 immunohistochemistry ($30% intense, uniform staining) and/or FISH HER2 amplification using the CEP17 control (HER2/CEP17 $2.0). In the SUMMIT phase II basket trial (NCT01953926), Oaknin et al. reported that oral neratinib 240 mg/day with mandatory loperamide prophylaxis for cycle 1 was associated with an ORR of 25% among 16 patients with HER2 mutant cervical cancer with disease progression after platinum-based systemic therapy. In this study, the median PFS was 7.0 months and the median OS was 16.8 months, with mild-to-moderate diarrhea, nausea, and decreased appetite being reported among 38% to 75% of patients. At present the HER-Seq blood-based screening study (NCT03786107) is being conducted to identify patients with HER2 mutations for continued enrollment into the SUMMIT study. For the bibliography list, log onto www.expertconsult.com http://www.expertconsult.com&

BIBLIOGRAPHY General Observations ACOG Committee Opinion No. 436: evaluation and management of abnormal cervical cytology and histology in adolescents, Obstet Gynecol 113:1422, 2009. Andersen BL, Lachenbruch PA, Andersen B, et al: Sexual dysfunction and signs of gynecologic cancer, Cancer 57:1880, 1986. Barnholtz-Sloan J, Patel N, Rollison D, et al: Incidence trends of invasive cervical cancer in the United States by combined race and ethnicity, Cancer Causes Control 20:1129, 2009. Boon ME, de Graaff Guilloud JC, Kok LP, et al: Efficacy of screening for cervical squamous and adenocarcinoma: the Dutch experience, Cancer 59:862, 1987. Christopherson WM, Parker JE, Mendez WM, et al: Cervix cancer death rates and mass cytologic screening, Cancer 26:808, 1970. Coppleson M, Reid B: The etiology of squamous carcinoma of the cervix (editorial), Obstet Gynecol 32:432, 1968. Hildesheim A, Brinton LA, Mallin K, et al: Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer (see comments), Epidemiology 1:266, 1990. McDougall JA, Madeline MM, Daling JR, et al: Racial and ethnic disparities in cervical cancer incidence rates in the United States, 1992–2003, Cancer Causes Control 18:1175, 2007. Pagliusi SR, Aguado MT: Efficacy and other milestones for human papillomavirus vaccine introduction, Vaccine 23:569, 2004. Piper JM: Oral contraceptives and cervical cancer, Gynecol Oncol 22:1, 1985. Siegel R, Ward E, Brawley O, et al: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths, CA Cancer J Clin 61:212, 2011. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 72:7-33, 2022. Seibel MM, Freeman MG, Graves WL: Carcinoma of the cervix and sexual function, Obstet Gynecol 55:484, 1980. Tavassoli FA, Devilee Peter, editors: World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of the Breast and Female Genital Organs, Lyon, 2003, IRC Press. Vinh-Hung V, Bourgain C, Vlastos G, et al: Prognostic value of histopathology and trends in cervical cancer: a SEER population study, BMC Cancer 7:164, 2007. Weijmar Schultz WCM, Van De Wiel HBM, Bouma J: Psychosexual functioning after treatment for cancer of the cervix: a comparative and longitudinal study, Int J Gynecol Cancer 1:37, 1991. West RR: Cervical cancer: age at registration and age at death, Br J Cancer 35:236, 1977.

Human Papillomavirus Kurtycz DFI, Smith M, He R, et al: Comparison of methods trial for high-risk HPV, Diagn Cytopathol 38:104, 2009. Narimatsu R, Patterson BK: High-throughput cervical cancer screening using intracellular human papillomavirus E6 and E7 mRNA quantification by flow cytometry, Am J Clin Pathol 123:716, 2005. Stillman MJ, Day SP, Schutzbank TE: A comparative review of laboratorydeveloped tests utilizing Invader HPV analyte-specific reagents for the detection of high-risk human papillomavirus, J Clin Virol 45:S73, 2009. zur Hausen H: Papillomaviruses in the causation of human cancers: a brief historical account, Virology 384:260, 2009.

Microinvasive Carcinoma of the Cervix Argenta PA, Kubicek GJ, Dusenberry KE, et al: Widespread lymph node metastases in young women with FIGO stage IA1 squamous cervical cancer, Gynecol Oncol 97:659, 2005.

Benedet JL, Anderson GH, Boyes DA: Colposcopic accuracy in the diagnosis of microinvasive and occult invasive carcinoma of the cervix, Obstet Gynecol 65:557, 1985. Bisseling KC, Bekkers RL, Rome RM, et al: Treatment of microinvasive adenocarcinoma of the uterine cervix: a retrospective study and review of the literature, Gynecol Oncol 107:424, 2007. Boutselis JG, Ullery JC, Charmer L: Diagnosis and management of stage Ia (microinvasive) carcinoma of the cervix, Am J Obstet Gynecol 110:984, 1971. Boyce DA, Worth AJ: Treatment of early cervical neoplasia: definition and management of preclinical invasive carcinoma, Gynecol Oncol 12:317, 1981. Boyce DA, Worth AJ, Fidler HK: The results of treatment of 4389 cases of preclinical cervical squamous carcinoma, J Obstet Gynaecol Br Commonw 77:769, 1970. Burghardt E, Girardi F, Lahousen M, et al: Microinvasive carcinoma of the uterine cervix, Cancer 67:1037, 1991. Cairns M, Cuschieri KS, Cubie HA, et al: High-risk HPV genotyping in the follow-up of women treated conservatively for microinvasive cervical cancer, Int J Gynecol Cancer 20:154, 2010. Ceballos KM, Shaw D, Daya D: Microinvasive cervical adenocarcinoma (FIGO stage IA tumors): results of surgical staging and outcome analysis, Am J Surg Pathol 30:370, 2006. Copeland LJ, Silva EE, Gershenson DM, et al: Superficially invasive squamous cell carcinoma of the cervix, Gynecol Oncol 45:307, 1992. Costa S, Marra E, Martinelli GN, et al: Outcome of conservatively treated microinvasive squamous cell carcinoma of the uterine cervix during a 10-year follow-up, Int J Gynecol Cancer 19:33, 2009. Creasman WT, Fetter BF, Clarke-Pearson DL, et al: Management of stage Ia carcinoma of the cervix, Am J Obstet Gynecol 153:164, 1985. Creasman WT, Parker RT: Microinvasive carcinoma of the cervix, Clin Obstet Gynecol 16:261, 1973. Creasman WT, Zano RJ, Major FJ, et al: Early invasive carcinoma of the cervix (3–5 mm invasion): risk factors and prognosis, Am J Obstet Gynecol 178:62, 1998. Girardi F, Burghardt E, Pickel H: Small stage Ib cervical cancer, Gynecol Oncol 55:427, 1994. Gurgel M, Bedone AJ, Androde L, et al: Microinvasive carcinoma of the uterine cervix: histological findings on cone specimens related to residual neoplasia on hysterectomy, Gynecol Oncol 65:437, 1997. Halzer E: Microinvasive carcinoma of the cervix: clinical aspects, treatment, and follow-up. In Burghardt E, Halzer E, editors: Minimal Invasive Cancer, Philadelphia, 1982, WB Saunders. Hasumi K, Sakamoto A, Sugano H: Microinvasive carcinoma of the uterine cervix, Cancer 45:928, 1980. Hopkins MP, Morley GW: Squamous cell cancer of the cervix: prognostic factors related to survival, Int J Gynecol Cancer 1:173, 1991. Hopkins MP, Morley GW: Squamous cell carcinoma of the cervix: clinical pathological features related to survival, Am J Obstet Gynecol 164:1520, 1991. Koliopoulos G, Sotiriadis A, Kyrgiou M, et al: Conservative surgical methods for FIGO stage IA2 squamous cervical carcinoma and their role in preserving women’s fertility, Gynecol Oncol 93:469, 2004. Kolstad P: Follow-up study of 232 patients with stage Ia1 and 411 patients with stage Ia2 squamous cell carcinoma of the cervix (microinvasive carcinoma), Gynecol Oncol 33:265, 1989. Lee SJ, Kim WY, Lee JW, et al: Conization using electrosurgical conization and cold coagulation for International Federation of Gynecology and Obstetrics stage IA1 squamous cell carcinomas of the uterine cervix, Int J Gynecol Cancer 19:407, 2009.

e2 Lee SW, Kim YM, Son WS, et al: The efficacy of conservative management after conization of patients with stage IA1 microinvasive cervical carcinoma, Acta Obstet Gynecol Scand 88:209, 2009. Leman MH, Benson WL, Kurman RJ, et al: Microinvasive carcinoma of the cervix, Obstet Gynecol 48:571, 1976. Lohe KJ: Early squamous cell carcinoma of the uterine cervix. I, Gynecol Oncol 6:10, 1978. Lohe KJ: Early squamous cell carcinoma of the uterine cervix. III, Gynecol Oncol 6:51, 1978. Lohe KJ, Burghardt E, Hillemanns HG, et al: Early squamous cell carcinoma of the uterine cervix II, Gynecol Oncol 6:31, 1978. Maiman MA: Superficially invasive squamous cell carcinoma of the cervix, Obstet Gynecol 72(3 Pt 1):399, 1988. Mestwerdt G: About the micro-carcinoma of the uterine cervix: colposcopy, cytology, histology and treatment, An Bras Ginecol 59:181, 1965. Miroshnichenko GG, Parva M, Holtz DO, et al: Interpretability of excision biopsies of the cervix: cone biopsy and loop excision, J Low Genit Tract Dis 13:10, 2009. Morice P, Piovesan P, Rey A, et al: Prognostic value of lymphovascular space invasion determined with hematoxylin-eosin staining in early stage cervical carcinoma: results of a multivariate analysis, Ann Oncol 14:1511, 2003. Mota F: Microinvasive squamous carcinoma of the cervix: treatment modalities, Acta Obstet Gynecol Scand 82:505, 2003. Östör AG, Rome RM: Microinvasive squamous cell carcinoma of the cervix: a clinicopathologic-pathologic study of 200 cases with long-term follow-up, Int J Gynecol Cancer 4:257, 1994. Park JY, Kim DY, Kim JH, et al: Human papillomavirus test after conization in predicting residual disease in subsequent hysterectomy specimens, Obstet Gynecol 114:87, 2009. Poynor EA, Marshall D, Sonoda Y, et al: Clinicopathologic features of early adenocarcinoma of the cervix initially managed with cervical conization, Gynecol Oncol 103:960, 2006. Roche WD, Norris HJ: Microinvasive carcinoma of the cervix: the significance of lymphatic invasion and confluent patterns of stromal growth, Cancer 180:180, 1985. Rogers LJ, Luesley DM: Stage IA2 cervical carcinoma: how much treatment is enough? Int J Gynecol Cancer 19:1620, 2009. Salani R, Puri I, Bristow RE: Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients evaluating the predictive value of conization margin status, Am J Obstet Gynecol 200:182. e1–e5, 2009. Sedlis A, Gall S, Tsukoda Y, et al: Microinvasive carcinoma of the uterine cervix: a clinical pathologic study, Am J Obstet Gynecol 133:67, 1979. Seski JC, Abell MR, Morley GW: Microinvasive squamous carcinoma of the cervix, Obstet Gynecol 50:410, 1977. Sevin BU, Nadji M, Averette HE, et al: Microinvasive carcinoma of the cervix, Cancer 70:2121, 1992. Simon NL, Gore H, Shingleton HM: Study of superficially invasive carcinoma of the cervix, Obstet Gynecol 68:19, 1986. Takeshima N, Yanoh K, Tabatat T, et al: Assessment of the revised International Federation of Gynecology and Obstetrics staging for early invasive squamous cervical cancer, Gynecol Oncol 74:165, 1999. Tsukamoto N, Kaku T, Matsukuma K, et al: The problem of stage Ia (FIGO 1985) carcinoma of the uterine cervix, Gynecol Oncol 34:1, 1989. Van Nagell JR Jr, Greenwell N, Powell DF, et al: Microinvasive carcinoma of the cervix, Am J Obstet Gynecol 145:982, 1983. Yasgashi N, Sata S, Inque Y, et al: Comparative surgical treatment in cervical cancer with 3–5 mm stromal invasion in the absence of

confluent invasion and lymph-vascular pace involvement, Gynecol Oncol 54:333, 1994.

Clinical Profile of Invasive Cancer Acs J, Hildesheim A, Reeves WC, et al: Regional distribution of human papillomavirus DNA and other risk factors for invasive cervical cancer in Panama, Cancer Res 49:5725, 1989. Barron BA, Richart RM: A statistical model of the natural history of cervical carcinoma based on a prospective study of 557 cases, J Natl Cancer Inst 41:1343, 1968. Berman ML, Keys H, Creasman W, et al: Survival and patterns of recurrence in cervical cancer metastatic to periaortic lymph nodes, Gynecol Oncol 19:8, 1984. Brinton LA. Epidemiology of cervical cancer: overview. IARC Sci Publ 119:3-23, 1992. Brinton LA: Oral contraceptives and cervical neoplasia, Contraception 43:58l, 1991. Burger MP, Hollema M, Gouw AS, et al: Cigarette smoking and human papillomavirus in patients with reported cervical cytological abnormality, Br Med J 306:749, 1993. Chu J, White E: Decreasing incidence of invasive cervical cancer in young women, Am J Obstet Gynecol 157:1105, 1987. Daling JR, Sherman KJ, Hislop TG, et al: Cigarette smoking and the risk of anogenital cancer, Am J Epidemiol 135:180, 1992. Delgado G, Bundy BN, Fowler WC Jr, et al: A prospective surgical pathological study of stage I squamous carcinoma of the cervix: a Gynecologic Oncology Group study, Gynecol Oncol 35:314, 1989. Gagnon F: The lack of occurrence of cervical carcinoma in nuns, Proc Second Natl Cancer Conf 1:625, 1952. Henriksen E: The dispersion of cancer of the cervix, Radiology 54: 812, 1950. Henriksen E: Distribution of metastases in stage I carcinoma of the cervix, Am J Obstet Gynecol 80:919, 1960. Henriksen E: The lymphatic spread of carcinoma of the cervix and of the body of the uterus: a study of 420 necropsies, Am J Obstet Gynecol 58:924, 1949. Hopkins MP, Morlay GW: Squamous cell carcinoma of the cervix: clinical pathological features related to survival, Am J Obstet Gynecol 164:1520, 1991. Mvula M, Iwasaka T, Matsuo N, et al: Detection of human papillomavirus types 16 and 18 in primary and metastatic lesions of cervical carcinomas, Gynecol Oncol 53:156, 1994. Reeves WC, Brinton LA, Garcia M, et al: Human papillomavirus infection and cervical cancer in Latin America, N Engl J Med 320: 1437, 1989. Simons AM, Philips DH, Coleman DV: Damage to DNA in cervical epithelium related to smoking tobacco, Br Med J 306:1444, 1993. Slattery ML, Robison LM, Schuman KL, et al: Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer, JAMA 261:1593, 1989. Ursin G, Peters RK, Henderson BE, et al: Oral contraceptive use and adenocarcinoma of cervix, Lancet 344:1390, 1994. Wagner AE, Pappas L, Ghia AJ, et al: Impact of tumor size on survival in cancer of the cervix and validation of stage IIA1 and IIA2 subdivisions, Gynecol Oncol 129:517–521, 2013.

Glandular Tumors of the Cervix Angel C, Dubeshter B, Lin JY: Clinical presentation and management of stage I cervical adenocarcinoma: a 25-year experience, Gynecol Oncol 44:71, 1992. Anton-Culver H, Bloss JD, Bringman D, et al: Comparison of adenocarcinoma and squamous cell carcinoma of the uterine cervix: a

e3 population based epidemiologic study, Am J Obstet Gynecol 166:1507, 1992. Berek JS, Castaldo TW, Hacker NF, et al: Adenocarcinoma of the uterine cervix, Cancer 48:2734, 1981. Boon ME, Baak JP, Kurver PJ, et al: Adenocarcinoma in situ of the cervix, Cancer 48:768, 1981. Brand E, Berek JS, Hacker NF: Controversies in the management of cervical adenocarcinoma, Obstet Gynecol 71:261, 1988. Chen RW, Change DY, Yen ML, et al: Prognostic factors of primary adenocarcinoma of the uterine cervix, Gynecol Oncol 69:157, 1998. Davidson SE, Symonds RP, Lamont D, et al: Does adenocarcinoma of uterine cervix have a worse prognosis than squamous carcinoma when treated by radiotherapy? Gynecol Oncol 33:23, 1989. Duk JM, Aalders JG, Fleuren GJ, et al: Tumor markers CA 125, squamous cell carcinoma antigen, and carcinoembryonic antigen in patients with adenocarcinoma of the uterine cervix, Obstet Gynecol 73:661, 1989. Eifel PJ, Burke TW, Delclos L, et al: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter, Obstet Gynecol 41:199, 1991. Eifel PJ, Burke TW, Morris M, et al: Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma, Gynecol Oncol 59:38, 1995. Eifel PJ, Morris M, Oswald MJ, et al: Adenocarcinoma of the uterine cervix, Cancer 65:2507, 1990. El-Ghobashy AA, Shaaban AM, Herod J, et al: The pathology and management of endocervical glandular neoplasia, Int J Gynecol Cancer 15:583, 2005. Hopkins MP, Morlay GW: Comparison of adenocarcinoma and squamous cell carcinoma of the cervix, Obstet Gynecol 77:912, 1991. Hopkins MP, Schmidt RW, Roberts JA, et al: The prognosis and treatment of stage I adenocarcinoma of the cervix, Obstet Gynecol 72:915, 1988. Kaku T, Kamura T, Sakai K, et al: Early adenocarcinoma of the uterine cervix, Gynecol Oncol 65:281, 1997. Kilgore LC, Soong SJ, Gore H, et al: Analysis of prognostic features in adenocarcinoma of the cervix, Gynecol Oncol 31:137, 1988. Kjorstad KE, Bond B: Stage Ib adenocarcinoma of the cervix: metastatic potential and patterns of dissemination, Am J Obstet Gynecol 150: 297, 1984. Kleine W, Rau K, Schwoeorer D, et al: Prognosis of the adenocarcinoma of the cervix uteri: a comparative study, Gynecol Oncol 35: 145, 1989. Lai CH, Hsueh S, Hong JH, et al: Are adenocarcinomas and adenosquamous carcinomas different from squamous carcinomas in stages IB and II cervical cancer patients undergoing primary surgery? Int J Gynecol Cancer 9:28, 1999. Matthews CM, Burke TW, Tomos C, et al: Stage I cervical adenocarcinoma: prognostic evaluation of surgically treated patients, Gynecol Oncol 49:19, 1993. McHale MT, Le TD, Burger RA, et al: Fertility sparing treatment for in situ and early invasive adenocarcinoma of the cervix, Obstet Gynecol 98:726, 2001. Moberg PJ, Einborn N, Silfversward C, et al: Adenocarcinoma of the uterine cervix, Cancer 57:407, 1986. Östör A, Rome R, Quinn M: Microinvasive adenocarcinoma of the cervix: a clinicopathologic study of 77 women, Obstet Gynecol 89:88, 1997. Parazzin IF, LaVecchia C: Epidemiology of adenocarcinoma of the cervix, Gynecol Oncol 39:4, 1990. Prempree T, Amornmarn R, Wizenberg MJ: A therapeutic approach to primary adenocarcinoma of the cervix, Cancer 56:1264, 1985.

Raju KS, Kjorstad KE, Abeler V: Prognostic factors in the treatment of stage 1b adenocarcinoma of the cervix, Int J Gynecol Cancer 1:69, 1991. Rose PG, Reale FR: Case report: serous papillary carcinoma of the cervix, Gynecol Oncol 50:361, 1993. Rutledge FN, Gutierrez AG, Fletcher GH: Management of stage I and II adenocarcinomas of the uterine cervix on intact uterus, AJR Am J Roentgenol 102:161, 1968. Schorge JO, Lee KR, Flynn CE, et al: Stage IA1 cervical adenocarcinoma: definition and treatment, Obstet Gynecol 89:88, 1997. Yamakawa Y, Forslund O, Teshima H, et al: Human papillomavirus DNA in adenocarcinoma and adenosquamous carcinoma of the uterine cervix detected by polymerase chain reaction (PCR), Gynecol Oncol 53:190, 1994. Young RH, Scully RE: Invasive adenocarcinoma and related tumors of the uterine cervix, Semin Diagn Pathol 7:205, 1990.

Uncommon and Neuroendocrine Tumors of the Cervix Abeler VM, Holm R, Nesland JM, et al: Small cell carcinoma of the cervix, Cancer 73:672, 1994. Barrett RJ, Davos I, Leuchter RS, et al: Neuroendocrine features in poorly differentiated and undifferentiated carcinomas of the cervix, Cancer 60:1089, 1987. Cetinkava K, Benzer E, Dervisoglu H: Primary mucosal malignant melanoma of the cervix: case report and review of the literature, Tumori 101(5):e147–e150, 2015. Chan JK, Loizzi V, Burger RA, et al: Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis, Cancer 97:568, 2003. Gan XL, Li JK, Yu TH, et al: High expressions of bcl-2 and surviving, and decreased apoptosis in uterine cervical carcinosarcoma compared to cervical squamous cell carcinoma, Arch Gynecol Obstet 284:175–181, 2011. Hoskins PJ, Wong F, Swenerton K, et al: Small cell carcinoma of the cervix treated with concurrent radiotherapy, cisplatin, and etoposide, Gynecol Oncol 56:218, 1995. Lewandowski GS, Copeland LJ: Case report: a potential role for intensive chemotherapy in the treatment of small cell neuroendocrine tumors of the cervix, Gynecol Oncol 48:127, 1993. Lotocki RJ, Krepart GV, Paraskevas M, et al: Glassy cell carcinoma of the cervix: a bimodal treatment strategy, Gynecol Oncol 44:254, 1992. Lyons YA, Frumovitz M, Soliman PT: Response to MEK inhibitor in small cell neuroendocrine carcinoma of the cervix with a KRAS mutation, Gynecol Oncol Rep 25:28–29, 2014. Morris M, Gershenson DM, Eifel P, et al: Treatment of small cell carcinoma of the cervix with cisplatin, doxorubicin, and etoposide, Gynecol Oncol 47:62, 1992. Pazdur R, Bonomi P, Slayton R, et al: Neuroendocrine carcinoma of the cervix: implications for staging and therapy, Gynecol Oncol 12:120, 1981. Sheets EE, Berman ML, Hrountas CK, et al: Surgically treated, earlystage neuroendocrine small-cell cervical carcinoma, Obstet Gynecol 71:10, 1988. Stoler MH, Mills SE, Gersell DJ, et al: Small-cell neuroendocrine carcinoma of the cervix, Am J Surg Pathol 15:28, 1991. Tamimi HK, Ek M, Hesla J, et al: Glassy cell carcinoma of the cervix redefined, Obstet Gynecol 71:837, 1988. Viswanathan AN, Deavers MT, Jhingran A, et al: Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence, Gynecol Oncol 93:27, 2004.

Staging Belenson JL, Goldberg MI, Averette HE: Para-aortic lymphadenectomy in gynecologic cancer, Gynecol Oncol 7:188, 1979.

e4 Brenner DE, Whitley NO, Prempree T, et al: An evaluation of the computed tomographic scanner for the staging of carcinoma of the cervix, Cancer 50:2323, 1982. Buchsbaum HJ: Extrapelvic lymph node metastases in cervical carcinoma, Am J Obstet Gynecol 133:814, 1979. Burke TW, Heller PB, Hoskins WJ, et al: Evaluation of the scalene lymph nodes in primary and recurrent cervical carcinoma, Gynecol Oncol 28:312, 1987. Childers JM, Hatch K, Surwitt EA: The role of laparoscopic lymphadenectomy in the management of cervical carcinoma, Gynecol Oncol 47:38, 1992. Childers JM, Hatch K, Tran AN, et al: Laparoscopic para-aortic lymphadenectomy in gynecologic malignancies, Obstet Gynecol 82:741, 1993. Choi HJ, Ju W, Myung SK, et al: Diagnostic performance of computer tomography, magnetic resonance imaging, and positron emission tomography or positron emission tomography/computed tomography for detection of metastatic lymph nodes in patients with cervical cancer: meta-analysis, Cancer Sci 101(6):1471–1479, 2010. Dargent D: Laparoscopic surgery and gynecologic cancer, Curr Opin Obstet Gynecol 5:294, 1993. Delgato G, Smith JP, Ballantyne AJ: Scalene node biopsy in carcinoma of the cervix: pelvic and para-aortic lymphadenectomy, Cancer 35: 784, 1975. Fuller AF Jr, Elliott N, Kosloff C, et al: Determinants of increased risk for recurrence in patients undergoing radical hysterectomy for stage IB and IIa carcinoma of the cervix, Gynecol Oncol 33:34, 1998. Havrilesky LJ, Kulasingam SL, Matchar DB, et al: FDG-PET for management of cervical and ovarian cancer, Gynecol Oncol 97:183, 2005. Kidd EA, Siegel BA, Dehdashti F, et al: Lymph node staging by positron emission tomography in cervical cancer: relationship to prognosis, J Clin Oncol 28(12):2108–2113, 2010. Kidd EA, Siegel BA, Dehdashti F, et al: Pelvic lymph node F-18 fluorodeoxyglucose uptake as a prognostic biomarker in newly diagnosed patients with locally advanced cervical cancer, Cancer 116:1469, 2010. Kupets R, Covens A: Is the International Federation of Gynecology and Obstetrics staging system for cervical carcinoma able to predict survival in patients with cervical carcinoma? An assessment of clinimetric properties, Cancer 92:796, 2001. Lagasse LD, Creasman WT, Shingleton HM, et al: Results and complications of operative staging in cervical cancer: experience of the Gynecologic Oncology Group, Gynecol Oncol 9:90, 1980. Lanciano RM, Won M, Hanks GE: A reappraisal of the international federation of gynecology and obstetrics staging system for cervical cancer, Cancer 69:482, 1992. Memarzadeh S, Natarajan S, Dandade DP, et al: Lymphovascular and perineural invasion in the parametria: a prognostic factor for early-stage cervical cancer, Obstet Gynecol 102:612, 2003. Nelson JH Jr, Macasaet MA, Lu T, et al: The incidence and significance of para-aortic lymph node metastases in late invasive carcinoma of the cervix, Am J Obstet Gynecol 118:749, 1974. Potish RA, Twiggs LB, Prem KA, et al: The impact of extra-peritoneal surgical staging on morbidity and tumor recurrence following radiotherapy for cervical carcinoma, Am J Clin Oncol 7:245, 1984. Vandeperre A, Van Limbergen E, Leunen K, et al: Para-aortic lymph node metastases in locally advanced cervical cancer: comparison between surgical staging and imaging, Gynecol Oncol 138:299–303, 2015.

Treatment of Early-Stage Disease Abbe R: The use of radium in malignant disease, Lancet 2:524, 1913. Alberts DS, Martimbeau PW, Surwit EA, et al: Mitomycin C, bleomycin, vincristine, and cis-platinum in the treatment of advanced

recurrent squamous cell carcinoma of the cervix, Cancer Clin Trials 4:313, 1981. Alberts DS, Garcia D, Mason-Liddil N: Cisplatin in advanced cancer of the cervix: an update, Semin Oncol 18:11, 1991. Ampil F, Datta R, Datta S: Elective postoperative external radiotherapy after hysterectomy in early-stage carcinoma of the cervix: is additional vaginal cuff irradiation necessary? Cancer 60:280, 1987. Anderson B, LaPolla J, Turner D, et al: Ovarian transposition in cervical cancer, Gynecol Oncol 49:206, 1993. Andras EJ, Fletcher GH, Rutledge F: Radiotherapy of carcinoma of the cervix following simple hysterectomy, Am J Obstet Gynecol 115:647, 1973. Artman LE, Hoskins WJ, Bibro MC, et al: Radical hysterectomy and pelvic lymphadenectomy for stage IB carcinoma of the cervix: 21 years’ experience, Gynecol Oncol 28:8, 1987. Bali A, Weekes A, van Trappen P, et al: Central pelvic recurrence 7 years after radical vaginal trachelectomy, Gynecol Oncol 96:854, 2005. Bandy LC, Clarke-Pearson DL, Soper JT, et al: Long-term effects on bladder function following radical hysterectomy with and without postoperative radiation, Gynecol Oncol 26:160, 1987. Barnes W, Waggoner S, Delgado G, et al: Manometric characterization of rectal dysfunction following radical hysterectomy, Gynecol Oncol 42:116, 1991. Barton DPJ, Cavanagh D, Roberts WS, et al: Radical hysterectomy for treatment of cervical cancer: a prospective study of two methods of closed-suction drainage, Am J Obstet Gynecol 166:533, 1992. Bernardini M, Barrett J, Seaward G, et al: Pregnancy outcomes in patients after radical trachelectomy, Am J Obstet Gynecol 189:1378, 2003. Bianchi UA, Sartori E, Pecorelli S, et al: Treatment of primary invasive cervical cancer; considerations on 997 consecutive cases, Eur J Gynaecol Oncol 9:47, 1988. Bloss JD, Berman ML, Mukherejee J, et al: Bulky stage IB cervical carcinoma managed by primary radical hysterectomy followed by tailored radiotherapy, Gynecol Oncol 47:21, 1992. Bonfiglio M: The pathology of fracture of the femoral neck following irradiation, AJR Am J Roentgenol 70:449, 1953. Bosch A, Marcial VA: Carcinoma of the uterine cervix associated with pregnancy, AJR Am J Roentgenol 96:92, 1966. Brack CB, Everett HC, Dickson R: Irradiation therapy for carcinoma of the cervix: its effect on urinary tract, Obstet Gynecol 7:196, 1956. Bremer GL, van der Putten HW, Dunselman GA, et al: Early stage cervical cancer: aborted versus completed radical hysterectomy, Eur J Obstet Gynecol Reprod Biol 47:147, 1992. Brenner DE, Gillette AW, Jones HW 3rd, et al: Simultaneous radiation and chemotherapy for advanced carcinoma of the cervix, Gynecol Oncol 26:381, 1987. Brookland RK, Rubin S, Danoff BF: Extended field irradiation in the treatment of patients with cervical carcinoma involving biopsy-proven para-aortic nodes, Radiat Oncol Biol Phys 10: 1875, 1984. Brown JV, Fu YS, Berek JS: Ovarian metastases are rare in stage I adenocarcinoma of the cervix, Obstet Gynecol 76:623, 1990. Burghardt E, Baltzer J, Tulusan AH, et al: Results of surgical treatment of 1028 cervical cancers studied with volumetry, Cancer 70:648, 1992. Carenza L, Nobili F, Giacobini S: Voiding disorders after radical hysterectomy, Gynecol Oncol 13:213, 1982. Chambers SK, Chambers JT, Holm C, et al: Sequelae of lateral ovarian transposition in unirradiated cervical cancer patients, Gynecol Oncol 39:155, 1990. Chapman JA, Mannel RS, DiSaia PJ, et al: Surgical treatment of unexpected invasive cervical cancer found at total hysterectomy, Obstet Gynecol 80:931, 1992.

e5 Choo YC, Wong LC, Wong KP, et al: The management of intractable lymphocyst following radical hysterectomy, Gynecol Oncol 24:309, 1986. Corn BW, Hanlon AL, Pajak TF, et al: Technically accurate intracavitary insertions improve pelvic control and survival among patients with locally advanced carcinoma of the uterine cervix, Gynecol Oncol 53:294, 1994. Covens A, Shaw P, Murphy J, et al: Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA–B carcinoma of the cervix? Cancer 86:2273, 1999. Creasman WT, Soper JT, Clarke-Pearson D: Radical hysterectomy as therapy for early carcinoma of the cervix, Am J Obstet Gynecol 155:964, 1986. Currie DW: Operative treatment of carcinoma of the cervix, J Obstet Gynaecol Br Commonw 78:385, 1971. Czesnin K, Wronkowski Z: Second malignancies of the irradiated area in patients treated for uterine cervix cancer, Gynecol Oncol 6:309, 1978. Dargent D, Enria R: Laparoscopic assessment of the sentinel lymph nodes in early cervical cancer. Technique: preliminary results and future developments, Crit Rev Oncol Hematol 48:305, 2003. Darlin L, Persson J, Bossmar T, et al: The sentinel node concept in early cervical cancer performs well in tumors smaller than 2 cm, Gynecol Oncol 117:266, 2010. Delgato G, Caglar H, Walker P: Survival and complications in cervical cancer treated by pelvic and extended field radiation after para-aortic lymphadenectomy, AJR Am J Roentgenol 130:141, 1978. Diakomanolis E, Haidopoulos D, Rodolakis A, et al: Laser CO2 conization: a safe mode of treating conservatively microinvasive carcinoma of the uterine cervix, Eur J Obstet Gynecol Reprod Biol 113:229, 2004. DiSaia PJ, Bundy BN, Curry SL, et al: Phase III study on the treatment of women with cervical cancer, stage IIb, IIIb, and IVa (confined to the pelvis and/or periaortic nodes), with radiotherapy alone versus radiotherapy plus immunotherapy with intravenous Corynebacterium parvum: a Gynecologic Oncology Group study, Gynecol Oncol 26:386, 1987. DiSaia PJ: Surgical aspects of cervical carcinoma, Cancer 48:548, 1981. DiSaia PJ: The case against the surgical concept of en bloc dissection for malignancies of the reproductive tract, Cancer 60:2025, 1987. Dottino PR, Plaxe SC, Beddoe AM, et al: Induction chemotherapy followed by radical surgery in cervical cancer, Gynecol Oncol 40:7, 1991. Durance FY: Radiotherapy following simple hysterectomy in patients with stage I and II carcinoma of the cervix, Am J Roentgenol Radium Ther Nucl Med 102:165, 1968. Einstein MH, Kadish AS, Burk RD, et al: Heat shock protein (HSP)based immunotherapy (HspE7) for treatment of CIN III (NCI 5850, NYGOG), Gynecol Oncol 96:912a, 2005. Falk V, Lungren N, Quarfordt L, et al: Primary surgical treatment of carcinoma stage I of the uterine cervix, Acta Obstet Gynecol Scand 61:481, 1982. Feder BH, Syed AMN, Neblett D: Treatment of extensive carcinoma of the cervix with the “transperineal parametrial butterfly”: a prelimary report on the revival of Waterman's approach., Int J Radiat Oncol Biol Phys 4:735, 1978. Fletcher GH, Rutledge FN: Extended field technique in the management of the cancers of the uterine cervix, AJR Am J Roentgenol 114: 116, 1972. Forney JP: The effect of radical hysterectomy on bladder physiology, Am J Obstet Gynecol 138:374, 1980. Fotiou S, Tserkezoglou A, Hatzieleftheriou G, et al: Class III vs. class II radical hysterectomy in stage IB cervical carcinoma: a comparison of morbidity and survival, Int J Gynecol Cancer 7:117, 1997.

Fujii S: Original film of the Okabayashi’s radical hysterectomy by Okabayashi himself in 1932, and two films of the precise anatomy necessary for nerve-sparing Okabayashi’s radical hysterectomy clarified by Shingo Fujii, Int J Gynecol Cancer 18:383, 2008. Gallion HH, van Nagell JR Jr, Donaldson ES, et al: Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel-shaped cervical cancer, Cancer 56:262, 1985. Garcia F, Petry KU, Muderspach L, et al: ZYC101a for treatment of highgrade cervical intraepithelial neoplasia: a randomized controlled trial, Obstet Gynecol 103:317, 2004. Giaroli A, Sananes C, Sardi JE, et al: Lymph node metastases in carcinoma of the cervix uteri: response to neoadjuvant chemotherapy and its impact on survival, Gynecol Oncol 39:34, 1990. Gilinsky NH, Burns DG, Barbezat GO, et al: The natural history of radiation-induced proctosigmoiditis: an analysis of 88 patients, Q J Med 205:40, 1983. Gil-Moreno A, Diaz-Feijoo B, Roca I, et al: Total laparoscopic radical hysterectomy with intraoperative sentinel node identification in patients with early invasive cervical cancer, Gynecol Oncol 96:187, 2005. Gortzak-Uzan L, Jimenez W, Nofech-Mozes S, et al: Sentinel lymph node biopsy vs. pelvic lymphadenectomy in early stage cervical cancer: is it time to change the gold standard? Gynecol Oncol 116: 28, 2010. Grosu AL, Piert M, Weber WA, et al: Positron emission tomography for radiation treatment planning, Strahlenther Onkol 181:483, 2005. Hatch KD, Parham G, Shingleton HM, et al: Ureteral strictures and fistulae following radical hysterectomy, Gynecol Oncol 19:17, 1984. Heller PB, Barnhill DR, Mayer AR: Cervical carcinoma found incidentally in a uterus removed for benign indications, Obstet Gynecol 67:187, 1986. Herzog TJ: New approaches for the management of cervical cancer, Gynecol Oncol 90:S22, 2003. Hopkins MP, Morley GW: Radical hysterectomy versus radiation therapy for stage IB squamous cell cancer of the cervix, Cancer 68:272, 1991. Hreschyshn MM, Aron BS, Boronow RC, et al: Hydroxyurea or placebo combined with radiation to treat stages IIIb and IV cervical cancer confined to the pelvis, Int J Radiat Oncol Biol Phys 5:317, 1979. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer, N Engl J Med 350:2335, 2004. Husseinzadeh N, Van Aken ML, Aron B: Ovarian transposition in young patients with invasive cervical cancer receiving radiation therapy, Int J Gynaecol Cancer 4:61, 1994. Inoue T, Morita K: 5-year results of postoperative extended-field irradiation on 76 patients with nodal metastases from cervical carcinoma stages Ib to IIIb, Cancer 61:2009, 1988. Ito E, Saito T: Nerve-preserving techniques for radical hysterectomy, Eur J Surg Oncol 30:1137, 2004. Jackson KS, Das N, Naik R, et al: Laparoscopically assisted radical vaginal hysterectomy vs. radical abdominal hysterectomy for cervical cancer: a matched controlled study, Gynecol Oncol 95:655, 2004. Jakobsen A, Bichel P, Ahrons S, et al: Is radical hysterectomy always necessary in early cervical cancer? Gynecol Oncol 39:80, 1990. Jensen PT, Groenvold M, Klee MC, et al: Early-stage cervical carcinoma, radical hysterectomy, and sexual function: a longitudinal study, Cancer 100:97, 2004. Johnston CM, Dottino PR, Heller DS, et al: Case report: recurrent cervical squamous cell carcinoma in an ovary following ovarian conservation and radical hysterectomy, Gynecol Oncol 41:64, 1991. Jolles CJ, Freedman RS, Hamberger AD, et al: Complications of extendedfield therapy for cervical carcinoma without prior surgery, Radiat Oncol Biol Phys 12:179, 1986.

e6 Kagan AR, Nussbaum H, Gilbert H, et al: A new staging system for irradiation injuries following treatment for cancer of the cervix uteri, Gynecol Oncol 7:166, 1979. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical cancer, N Engl J Med 340:1154, 1999. Khorram O, Stern JL: Case report: bleomycin sclerotherapy of an intractable inguinal lymphocyst, Gynecol Oncol 50:244, 1993. Kim DS, Moon H, Hwang YY, et al: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib, IIa, and IIb with bulky tumor, Gynecol Oncol 29:321, 1988. Kim RY: Radiotherapeutic management in carcinoma of the uterine cervix: current status, Int J Gynecol Cancer 3:337, 1993. Kinney WK, Alvarez RD, Reid CC, et al: Value of adjuvant whole-pelvis irradiation after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: a matchedcontrol study, Gynecol Oncol 34:258, 1989. Kinney WK, Egorshin EV, Ballard DJ, et al: Long-term survival and sequelae after surgical management of invasive cervical carcinoma diagnosed at the time of simple hysterectomy, Gynecol Oncol 44:24, 1992. Kirsten F, Atkinson KH, Coppleson JV, et al: Combination chemotherapy followed by surgery or radiotherapy in patients with locally advanced cervical cancer, Br J Obstet Gynaecol 94:583, 1987. Kramer C, Peschel RE, Goldberg N, et al: Radiation treatment of FIGO stage IVa carcinoma of the cervix, Gynecol Oncol 32:323, 1989. Krebs HB, Helmkamp BF, Sevin BU, et al: Recurrent cancer of the cervix following hysterectomy and pelvic node dissection, Obstet Gynecol 59:422, 1982. Landoni F, Maneo A, Colombo A, et al: Randomized study of radical surgery versus radiotherapy for stage IB–IIA cervical cancer, Lancet 350:535, 1997. Larson DM, Malone JM, Copeland LJ, et al: Ureteral assessment after radical hysterectomy, Obstet Gynecol 69:612, 1987. Larson DM, Stringer CA, Copeland LJ, et al: Stage Ib cervical carcinoma treated with radical hysterectomy and pelvic lymphadenectomy: role of adjuvant radiotherapy, Obstet Gynecol 69:378, 1987. Lee Y, Wang KL, Lin MH, et al: Radical hysterectomy with pelvic lymph node dissection for treatment of cervical cancer: a clinical review of 954 cases, Gynecol Oncol 32:135, 1989. Lin LY, Wu JH, Yang CW, et al: Impact of radical hysterectomy for cervical cancer on urodynamic findings, Int Urogynecol J 15:418, 2004. Lin YS, Tzeng CC, Huang KF, et al: Sentinel node detection with radiocolloid lymphatic mapping in early invasive cervical cancer, Int J Gynecol Cancer 15:273, 2005. Liu W, Meigs JW: Radical hysterectomy and pelvic lymphadenectomy, Am J Obstet Gynecol 69:1, 1955. Maas CP, Trimbos JB, DeRuiter MC, et al: Nerve sparing radical hysterectomy: latest developments and historical perspective, Crit Rev Oncol Hematol 48:271, 2003. Madhu J, Cooke KJ, Flam M, et al: Preliminary results of concomitant radiotherapy and chemotherapy in advanced cervical carcinoma, Gynecol Oncol 28:101, 1987. Mann WJ, Chumas J, Amalfitano T, et al: Ovarian metastases from stage Ib adenocarcinoma of the cervix, Cancer 60:1123, 1987. Mann WJ, Vogel F, Pastner B, et al: Management of lymphocysts after radical gynecologic surgery, Gynecol Oncol 33:248, 1989. Martinez-Palones JM, Gil-Moreno A, Perez-Benavente MA, et al: Intraoperative sentinel node identification in early stage cervical cancer using a combination of radiolabeled albumin injection and isosulfan blue dye injection, Gynecol Oncol 92:845, 2004.

Maruyama Y, Donaldson E, van Nagell JR, et al: Specimen findings and survival after preoperative 252Cf neutron brachytherapy for stage II cervical carcinoma, Gynecol Oncol 43:252, 1991. Massi G, Savino L, Susini T: Schauta-Amreich vaginal hysterectomy and Wertheim–Meigs abdominal hysterectomy in the treatment of cervical cancer: a retrospective analysis, Am J Obstet Gynecol 168:928, 1993. McCall ML: A modern evaluation of the radical vaginal operation for carcinoma of the cervix, Am J Obstet Gynecol 85:295, 1963. McIntyre JF, Eifel PJ, Levenback C, et al: Ureteral stricture as a late complication of radiotherapy for stage IB carcinoma of the uterine cervix, Cancer 75:837, 1995. Miller BE, Copeland LJ, Hamberger AD, et al: Carcinoma of the cervical stump, Gynecol Oncol 18:100, 1984. Mitra S: Radical vaginal hysterectomy and extraperitoneal lymphadenectomy in cervical cancer, Zentralbl Gynakol 73:574, 1951. Monk BJ, Cha DS, Walker JL, et al: Extent of disease as an indication for pelvic radiation following radical hysterectomy and bilateral pelvic lymph node dissection in the treatment of stage IB and IIa cervical carcinoma, Gynecol Oncol 54:4, 1994. Monk BJ, Wang J, Im S, et al: Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of the Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial, Gynecol Oncol 96:721, 2005. Montana GS, Fowler WC, Varia MA, et al: Carcinoma of the cervix, stage III, Cancer 57:148, 1986. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high risk cervical cancer, N Engl J Med 340:1137, 1999. Morrow CP: Is pelvic radiation beneficial in the postoperative management of stage Ib squamous cell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? Gynecol Oncol 10:105, 1980. Nam JH, Kim JH, Kim DY, et al: Comparative study of laparoscopicovaginal radical hysterectomy and abdominal radical hysterectomy in patients with early cervical cancer, Gynecol Oncol 92:277, 2004. Navratil E, Kastner H: Our experiences with 977 Amreich operations in the treatment of invasive carcinoma of the cervix, Wien Med Wochenschr 116:1012, 1996. Niikura H, Okamura C, Akahira J, et al: Sentinel lymph node detection in early cervical cancer with combination of 99mTc phytate and patent blue, Gynecol Oncol 94:528, 2004. Nolan JF, Anson JH, Steward M: A radium applicator for use in the treatment of cancer of the uterine cervix, AJR Am J Roentgenol 79: 36, 1958. Oonk MHM, van de Nieuwenhof HP, de Hullu JA, et al: The role of sentinel node biopsy in gynecologic cancer: a review, Curr Opin Oncol 21:425, 2009. Orr JW, Wilson K, Bodiford C: Corpus and cervix cancer: a nutritional comparison, Am J Obstet Gynecol 153:775, 1985. Owens S, Robert WS: Ovarian management at the time of radical hysterectomy for cancer of the cervix, Gynecol Oncol 35:349, 1989. Panici PB, Greggi S, Scambia G, et al: High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: a preliminary report, Gynecol Oncol 41:212, 1991. Panici PB, Scambia G, Baiocchi G, et al: Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer: prognostic factors for response and survival, Cancer 67:372, 1991. Park TK, Choi DH, Kim SN, et al: Role of induction chemotherapy in invasive cervical cancer, Gynecol Oncol 41:1007, 1991.

e7 Park TK, Lee SK, Kim SN, et al: Combined chemotherapy and radiation for bulky stages I–II cervical cancer: comparison of concurrent and sequential regimens, Gynecol Oncol 50:196, 1993. Patsner B: Closed-suction drainage versus no drainage following radical abdominal hysterectomy with pelvic lymphadenectomy for stage IB cervical cancer, Gynecol Oncol 57:232, 1995. Patsner B, Sedlacek TV, Lovecchio JL: Para-aortic node sampling in small (3 cm or less) stage IB invasive cervical cancer, Gynecol Oncol 44:53, 1992. Perez CA, Breaux S, Askin F, et al: Irradiation alone or in combination with surgery in stages Ib and IIa carcinoma of the uterine cervix: a nonrandomized comparison, Cancer 43:1062, 1979. Perez CA, Breaux S, Madoc-Jones H, et al: Correlation between radiation dose and tumor recurrence and complications in carcinoma of the uterine cervix: stages I and IIa, Int J Radiat Oncol Biol Phys 5:373, 1979. Petersen LK, Mamsen A, Jakobsen A: Carcinoma of the cervical stump, Gynecol Oncol 46:199, 1992. Photopulos GJ, Vander Zuang R, Miller B, et al: Vaginal radiation brachytherapy to reduce central recurrence after radical hysterectomy for cervical carcinoma, Gynecol Oncol 38:187, 1990. Photopulos GJ, Van der Zwaag R: Class II radical hysterectomy shows less morbidity and good treatment efficacy compared to class III, Gynecol Oncol 40:21, 1991. Piver MS: Extended field irradiation in the treatment of patients with cervical carcinoma involving biopsy proven para-aortic nodes, Int J Radiat Oncol Biol Phys 10:1993, 1984. Piver MS, Barlow JJ: High dose irradiation to biopsy-confirmed aortic node metastases from carcinoma of the uterine cervix, Cancer 39: 1243, 1977. Piver MS, Rutledge FN, Smith PJ: Five classes of extended hysterectomy of women with cervical cancer, Obstet Gynecol 44:265, 1974. Plante M, Renaud MC, Hoskins IA, et al: Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of earlystage cervical cancer—a series of 50 pregnancies and review of the literature, Gynecol Oncol 98:3, 2005. Pomel C, Atallah D, le Bouedec G, et al: Laparoscopic radical hysterectomy for invasive cervical cancer: 8-year experience of a pilot study, Gynecol Oncol 91:534, 2003. Potish R, Adcock L, Jones TJ Jr, et al: The morbidity and utility of periaortic radiotherapy in cervical carcinoma, Gynecol Oncol 15:1, 1983. Puthawala A, Syed AM, Nalick R, et al: Integrated external and interstitial radiation therapy for primary carcinoma of the vagina, Obstet Gynecol 62:367, 1983. Raspagliesi F, Ditto A, Fontanelli R, et al: Nerve-sparing radical hysterectomy: a surgical technique for preserving the autonomic hypogastric nerve, Gynecol Oncol 93:307, 2004. Remy JC, DiMaio T, Fruchter RG, et al: Adjunctive radiation after radical hysterectomy in stage Ib squamous cell carcinoma of the cervix, Gynecol Oncol 38:161, 1990. Rettenmaier MA, Casanova DM, Micha JP, et al: Radical hysterectomy and tailored postoperative radiation therapy in the management of bulky stage Ib cervical cancer, Cancer 63:2220, 1989. Roman LD, Morris M, Mitchell MF, et al: Prognostic factors for patients undergoing simple hysterectomy in the presence of invasive cancer of the cervix, Gynecol Oncol 50:179, 1993. Rose PG, Bundy BN, Watkins ED, et al: Concurrent cisplatin based radiotherapy and chemotherapy for locally advanced cervical cancer, N Engl J Med 340:1144, 1999. Roy M, Plante M, Renaud MC, et al: Vaginal radical hysterectomy versus abdominal radical hysterectomy in the treatment of earlystage cervical cancer, Gynecol Oncol 62:336, 1996.

Rubin SC, Brookland R, Mikuta JJ, et al: Para-aortic nodal metastases in early cervical carcinoma: long-term survival following extended field radiotherapy, Gynecol Oncol 18:213, 1984. Russell AH: Contemporary radiation treatment planning for patients with cancer of the uterine cervix, Semin Oncol 21:30, 1994. Rutledge FN, Wharton JT, Fletcher GH: Clinical studies with adjunctive surgery and irradiation therapy in the treatment of carcinoma of the cervix, Cancer 38:596, 1976. Sakuragi N, Todo Y, Kudo M, et al: A systematic nerve-sparing radical hysterectomy technique in invasive cervical cancer for preserving postsurgical bladder function, Int J Gynecol Cancer 15:389, 2005. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous nonsmall cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial–E499. ASCO 2005 Annual Meeting, Abstract #LBA4. Sardi JE: Neoadjuvant chemotherapy in locally advanced carcinoma of the cervix-uterus, Gynecol Oncol 38:486, 1990. Sardi JE, di Paola GR, Cachau A, et al: A possible new trend in the management of the carcinoma of the cervix uteri, Gynecol Oncol 25:139, 1986. Sardi JE, Giaroli A, Sananes C, et al: Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage IB squamous carcinoma of the cervix: the final results, Gynecol Oncol 67:61, 1997. Sardi JE, Sanaes CE, Giarolic AA, et al: Neoadjuvant chemotherapy in cervical carcinoma stage IIB: a randomized control trial, Int J Gynecol Cancer 8:441, 1998. Scharge JO, Molpus KL, Koelliker D, et al: Stage IB and IIa cervical cancer with negative lymph nodes: the role of adjuvant radiotherapy after radical hysterectomy, Gynecol Oncol 66:31, 1997. Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy, Gynecol Oncol 73:177, 1999. Seibel M, Freeman MG, Graves WL: Sexual function after surgical and radiation therapy for cervical carcinoma, South Med J 75:1195, 1982. Sekiba K: Radical hysterectomy for cancer of the uterine cervix, Semin Surg Oncol 1:95, 1985. Seski JC, Diokno AC: Bladder dysfunction after radical abdominal hysterectomy, Am J Obstet Gynecol 128:643, 1977. Silva LB, Silva-Filho AL, Traiman P, et al: Sentinel node detection in cervical cancer with 99mTc-phytate, Gynecol Oncol 97:588, 2005. Slater JD, Slater JM, Wahlen S: The potential for proton beam therapy in locally advanced carcinoma of the cervix, Int J Radiat Oncol Biol Phys 22:343, 1991. Soisson AP, Soper JT, Berchuck A, et al: Radical hysterectomy in obese women, Obstet Gynecol 80:940, 1992. Soisson AP, Soper JT, Clarke-Pearson DL, et al: Adjuvant radiotherapy following radical hysterectomy for patients with stage Ib and IIa cervical cancer, Gynecol Oncol 37:390, 1990. Spirtos NM, Eisenkop SM, Schlaerth JB, et al: Laparoscopic radical hysterectomy (type III) with aortic and pelvic lymphadenectomy in patients with stage I cervical cancer: surgical morbidity and intermediate follow-up, Am J Obstet Gynecol 87:340, 2002. Stallworthy J: Radical surgery following radiation treatment for cervical carcinoma, Ann R Coll Surg Engl 34:161, 1964. Steed H, Rosen B, Murphy J, et al: A comparison of laparoscopicallyassisted radical vaginal hysterectomy and radical abdominal hysterectomy in the treatment of cervical cancer, Gynecol Oncol 93:588, 2004.

e8 Stehman FB, Bundy BN, DiSaia PJ, et al: Carcinoma of the cervix treated with radiation therapy. I: a multi-variate analysis of prognostic variables in the Gynecologic Oncology Group, Cancer 67: 2776, 1991. Stehman FB, Rose PG, Greer BE, et al: Innovations in the treatment of invasive cervical cancer, Cancer 98(Suppl 9):2052, 2003. Surwit EA, Manning MR, Aristizabal SA, et al: Interstitial thermoradiotherapy in recurrent gynecologic malignancies, Gynecol Oncol 15:95, 1983. Syed AMN, Feder BH: Technique of afterloading interstitial implant, Radiol Clin 46:458, 1977. Tabata M, Ichinoe K, Sakuragi N, et al: Incidence of ovarian metastasis in patients with cancer of the uterine cervix, Gynecol Oncol 28:255, 1987. Tanguay C, Plante M, Renaud MC, et al: Vaginal radical trachelectomy in the treatment of cervical cancer: the role of frozen section, Int J Gynecol Pathol 23:170, 2004. Thomas GM, Dembo AJ: Is there a role for adjuvant pelvic radiotherapy after radical hysterectomy in early stage cervical cancer? Int J Gynecol Cancer 1:1, 1991. Trimbos JB, Maas CP, Deruiter MC, et al: A nerve-sparing radical hysterectomy: guidelines and feasibility in Western patients, Int J Gynecol Cancer 11:180, 2001. Ungar L, Palfalvi L, Hogg R, et al: Abdominal radical trachelectomy: a fertility-preserving option for women with early cervical cancer, Br J Obstet Gynecol 112:366, 2005. Weems DH, Mendenhall WM, Bova FJ, et al: Carcinoma of the intact uterine cervix, stages Ib–IIa–b, 6 cm in diameter: irradiation alone vs. preoperative irradiation and surgery, Radiat Oncol Biol Phys 11:1911, 1985. Wharton JT, Jones HW 3rd, Day TG Jr, et al: Preirradiation celiotomy and extended field irradiation for invasive carcinoma of the cervix, Obstet Gynecol 49:333, 1977. Yabuki Y, Asamoto A, Hoshiba T, et al: Dissection of the cardinal ligament in radical hysterectomy for cervical cancer with emphasis on the lateral ligament, Am J Obstet Gynecol 164:7, 1991. Yessian A, Magistris A, Burger RA, et al: Radical hysterectomy followed by tailored postoperative therapy in the treatment of stage IB2 cervical cancer: feasibility and indications for adjuvant therapy, Gynecol Oncol 94:61, 2004. Zander J, Baltzer J, Lohe KJ, et al: Carcinoma of the cervix: an attempt to individualize treatment: results of a 20-year cooperative study, Am J Obstet Gynecol 139:752, 1981.

Survival Results and Prognostic Factors Abdulhayoglu G, Rich WM, Reynolds J, et al: Selective radiation therapy in stage Ib uterine cervical carcinoma following radical pelvic surgery, Gynecol Oncol 10:84, 1980. Adcock L, Julian TM, Okagaki T, et al: Carcinoma of the uterine cervix FIGO stage Ib, Gynecol Oncol 14:199, 1982. Alvarez RD, Soong SJ, Kinney WK, et al: Identification of prognostic factors and risk groups in patients found to have nodal metastasis at the time of radical hysterectomy for early-stage squamous carcinoma of the cervix, Gynecol Oncol 35:130, 1989. Baltzer J, Lohe KJ, Kopcke W, et al: Histological criteria for prognosis in patients with operative squamous cell carcinoma of the cervix, Gynecol Oncol 13:184, 1982. Barber HRK, Brunschwig A: Gynecologic cancer complicating pregnancy, Am J Obstet Gynecol 85:156, 1963. Berman ML, Bergen S, Salazar H: Influence of histological features and treatment on the prognosis of patients with cervical cancer metastatic to pelvic lymph nodes, Gynecol Oncol 39:127, 1990.

Burghardt E, Baltzer J, Tulusan AH, et al: Results of surgical treatment of 1028 cervical cancers studied with volumetry, Cancer 70:648, 1992. Burke TW, Hoskins WJ, Heller PB, et al: Prognostic factors associated with radical hysterectomy failure, Gynecol Oncol 26:153, 1987. Chan JK, Loizzi V, Burger RA, et al: Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis, Cancer 97:568, 2003. Chen RJ, Lin YH, Chen CA, et al: Influences of histologic type and age on survival rates for invasive cervical carcinoma in Taiwan, Gynecol Oncol 73:184, 1999. Cooper RA, Wilks DP, Logue JP, et al: High tumor angiogenesis is associated with poorer survival in carcinoma of the cervix treated with radiotherapy, Clin Cancer Res 4:2795, 1998. Davidson B, Goldberg I, Kopolovic J: Angiogenesis in uterine cervical intraepithelial neoplasia and squamous cell carcinoma: an immunohistochemical study, Int J Gynecol Pathol 16:335, 1997. Dawlatly B, Laire O, Cross PA, et al: Prognostic factors in surgicallytreated stage IB–IIB squamous cell carcinoma of the cervix with positive lymph nodes, Int J Gynecol Cancer 8:467, 1998. Delgado G: Prospective surgical pathological study of disease free interval in patients with stage Ib carcinoma of the cervix: a GOG study, Gynecol Oncol 38:352, 1990. Delgado G, Bundy B, Aino R, et al: Prospective surgery pathological study of disease-free interval in patients with stage IB squamous cell carcinoma cervix, Gynecol Oncol 38:352, 1990. Dellas A, Moch H, Schultheiss E, et al: Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations, Gynecol Oncol 67:27, 1997. Dobbs SP, Hewett PW, Johnson IR, et al: Angiogenesis is associated with vascular endothelial growth factor expression in cervical intraepithelial neoplasia, Br J Cancer 76:1410, 1997. Fiorica JV, Roberts WS, Greenberg H, et al: Morbidity and survival patterns in patients after radical hysterectomy and postoperative adjuvant pelvic radiotherapy, Gynecol Oncol 36:343, 1990. Francke P, Maruyama J, vanNagell J, et al: Lymphovascular invasion in stage IB cervical carcinoma: prognostic significance and role of adjuvant radiotherapy, Int J Gynecol Cancer 6:208, 1996. Fuller AF, Elliott N, Kosloff C, et al: Lymph node metastasis from carcinoma of the cervix, stages Ib and IIa: implications for prognosis and treatment, Gynecol Oncol 13:165, 1982. Gauthier P, Gore I, Shingleton HM, et al: Identification of histopathologic risk groups in stage Ib squamous cell carcinoma of the cervix, Obstet Gynecol 66:569, 1985. Greggi S, Benedett P, Amoroso M, et al: Intraperitoneal tumor spread in locally advanced cervical carcinoma undergoing neoadjuvant chemotherapy, Int J Gynecol Cancer 8:207, 1998. Hagmar B, Christensen JJP, Johansson B, et al: Implications of human papillomavirus type for survival in cervical squamous cell carcinoma, Int J Gynecol Cancer 5:341, 1995. Hopkins MP, Morley GW: Squamous cell cancer of the cervix: prognostic factors related to survival, Int J Gynecol Cancer 1:173, 1991. Hopkins MP, Morley GW: Stage IB squamous cell cancer of the cervix: clinicopathologic feature related to survival, Am J Obstet Gynecol 164:1520, 1991. Inoue T, Morita K: The prognostic significance of number of positive nodes in cervical carcinoma stages Ib, IIa, and IIb, Cancer 65:1923, 1990. Kosary CL: FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973–1987 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina, Semin Surg Oncol 10:31, 1994.

e9 Lanciano RM, Martz K, Montant GS, et al: Influence of age, prior abdominal surgery, fraction size, and dose on complications after radiation therapy for squamous cell cancer of the uterine cervix, Cancer 69:2124, 1992. Look KY, Brunetto VL, Clarke-Pearson DL, et al: An analysis of cell type in patients with surgically staged IB carcinoma of the cervix, Gynecol Oncol 63:304, 1996. Lovecchio JL, Averette HE, Donato D, et al: 5-year survival of patients with periaortic nodal metastases in clinical stage Ib and IIa cervical carcinoma, Gynecol Oncol 34:43, 1989. Manetta A, Delgado G, Petrilli E, et al: The significance of para-aortic node status in carcinoma of the cervix and endometrium, Gynecol Oncol 23:284, 1986. Mitchell PA, Waggoner S, Rotsnensch J, et al: Cervical cancer in the elderly treated with radiation therapy, Gynecol Oncol 71:291, 1998. Montana GS, Fowler WC, Varia MA, et al: Analysis of results of radiation therapy for stage II carcinoma of the cervix, Cancer 55:956, 1985. Obermair A, Wanner C, Bilgi S, et al: Tumor angiogenesis in stage IB cervical cancer: correlation of microvessel density with survival, Am J Obstet Gynecol 178:314, 1998. Orlandi C, Costa S, Terzano P, et al: Presurgical assessment and therapy of microinvasive carcinoma of the cervix, Gynecol Oncol 59:255, 1995. Pecorelli S: FIGO annual report on the results of treatment in gynaecological cancer, J Epidemiol Biostat 3:5, 1998. Perez CA, Grigsby PW, Nene SM, et al: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone, Cancer 69:2796, 1992. Peterient DG, Hartenback EM, Thomas GM: Para-aortic lymph node evaluation in cervical cancer: the impact of staging upon treatment decisions and outcome, Int J Gynecol Cancer 8:353, 1998. Prempree T, Patanaphan V, Scott R: Radiation management of carcinoma of the cervical stump, Cancer 43:1262, 1979. Rutledge FN, Mitchell MF, Munsell M, et al: Youth as a prognostic factor in carcinoma of the cervix: a matched analysis, Gynecol Oncol 44:123, 1992. Sardi JE, di Paola GR, Giaroli A, et al: Results of a phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix uteri, Gynecol Oncol 31:256, 1988. Stockler M, Russell P, McGaham S, et al: Prognosis and prognostic factors in node-negative cervix cancer, Int J Gynecol Cancer 6:477, 1996. Thomassen LV, Warshaw J, Lawhead RA, et al: Invasive cervical cancer in young women, J Reprod Med 37:901, 1992. Tinga DJ, Timmer PR, Bouma J: Prognostic significance of single vs. multiple lymph node metastases in cervical carcinoma stage Ib, Gynecol Oncol 39:175, 1990. Ulfelder H, Smith CJ, Costello JB: Invasive carcinoma of the cervix during pregnancy, Am J Obstet Gynecol 98:424, 1967. Wang PH, Liu YC, Lai CR, et al: Small cell carcinoma of the cervix: an analysis of clinical and pathological findings, Eur J Gynaecol Oncol 19:189, 1997. Zaino RJ, Ward S, Delgado G, et al: Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, Cancer 69:1750, 1992.

Postsurgical Adjuvant Therapy Shibata K, Kajiyama H, Terauchi M, et al: Feasibility and effectiveness of postoperative adjuvant concurrent chemoradication therapy in Japanese patients with high-risk early-stage cancer of the uterine cervix, Int J Clin Oncol 13:233, 2008. Takeshima N, Umayahara K, Fujiwara K, et al: Treatment results of adjuvant chemotherapy after radical hysterectomy for intermediate- and high-risk stage IB-IIA cervical cancer, Gynecol Oncol 103:618, 2006.

Radical Trachelectomy Burnett AF, Stone PF, Duckworth LA, et al: Robotic radical trachelectomy for preservation of fertility in early cervical cancer: case series and description of technique, J Minim Invasive Gynecol 16:569, 2009. Cibula D, Slama J, Fischerova D: Update on abdominal radical trachelectomy, Gynecol Oncol 111:S111, 2008. Cibula D, Slama J, Svarovsky J, et al: Abdominal radical trachelectomy in fertility-sparing treatment of early-stage cervical cancer, Int J Gynecol Cancer 10:1407, 2009. Einstein MH, Park KH, Sonoda Y, et al: Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes, Gynecol Oncol 112:73, 2009. Nishio H, Takuma F, Kameyama K, et al: Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women, Gynecol Oncol 115:51, 2009. Pareja R, Rendon GJ, Vasquez M, et al: Immediate radical trachelecotmy versus neoadjuvant chgemotherapy followed by conservative surgery for patients with stage IB1 cervical caner with tumors 2 cm or larger: a literature review and analysis of oncological and obsteretrical outcomes, Gynecol Oncol 137:574–580, 2015. Plante M: Vaginal radical trachelectomy: an update, Gynecol Oncol 111: S105, 2008. Ramirez PT, Schmeler KM, Malpica A, et al: Safety and feasibility of robotic radical trachelectomy in patients with early-stage cervical cancer, Gynecol Oncol 116:512, 2010. Vieira MA, Rendon GJ, Munsell M, et al: Radical trachelectomy in early-stage cervical cancer: a comparison of laparotomy and minimally invasive surgery, Gynecol Oncol 138:585–589, 2015.

Nerve-Sparing Radical Hysterectomy Cibula D, Abu-Rustum NR, Benedetti-Panici P, et al: New classification system of radical hysterectomy: emphasis on a three-dimensional anatomic template for parametrial resection, Gynecol Oncol 122: 264–288, 2011. Dursun P, Ayhan A, Kuscu E: Nerve-sparing radical hysterectomy for cervical carcinoma, Crit Rev Oncol Hematol 70:195, 2009. Fujii S: Anatomic identification of nerve-sparing radical hysterectomy: a step-by-step procedure, Gynecol Oncol 111:S33, 2008. Querleu D, Morrow CP: Classifcation of radical hysterectomy, Lancet Oncol 9:297–303, 2008. Roh JW, Lee DO, Suh DH, et al: Efficacy and oncologic safety of nervesparing radical hysterectomy for cervical cancer: a randomized controlled trial, J Gynecol Oncol 26:90–99, 2015. Skret Magierlo J, Narog M, Kruczek A, et al: Radical hysterectomy during the transition period from traditional to nerve-sparing technique, Gynecol Oncol 116:502, 2010. Van den Tillaart SA, Kenter GG, Peters AA, et al: Nerve-sparing radical hysterectomy: local recurrence rate, feasibility, and safety in cervical cancer patients stage IA to IIA, Int J Gynecol Cancer 19:39, 2009.

Laparoscopic Radical Hysterectomy With Pelvic Lymphadenectomy Canton-Romero JC, Anaya-Prado R, Rodriguez-Garcia HA, et al: Laparoscopic radical hysterectomy with the use of a modified uterine manipulator for the management of stage IB1 cervix cancer, J Obstet Gynaecol 30:49, 2010. Chen Y, Xu H, Li Y, et al: The outcome of laparoscopic radical hysterectomy and lymphadenectomy for cervical cancer: a prospective analysis of 295 patients, Ann Surg Oncol 15:2847, 2008. Faer AN, Escobar PF: Laparoscopic sing-site surgery (LESS) in gynecologic oncology: technique and initial report, Gynecol Oncol 114:157, 2009.

e10 Malzoni M, Tinelli R, Cosentino F, et al: Laparoscopic radical hysterectomy with lymphadenectomy in patients with early cervical cancer: our instruments and technique, Surg Oncol 18:289, 2009. Ramirez PT, Slomovitz BM, Soliman PT, et al: Total laparoscopic radical hysterectomy and lymphadenectomy: the M.D. Anderson Cancer Center Experience, Gynecol Oncol 102:252, 2006.

Robotic-Assisted Laparoscopic Radical Hysterectomy With Pelvic Lymphadenectomy Cantrell LA, Mendivil A, Gehrig PA, et al: Survival outcomes for women undergoing type III robotic radical hysterectomy for cervical cancer: a 3-year experience, Gynecol Oncol 117:260, 2010. Estape R, Lambrou N, Diaz R, et al: A case matched analysis of robotic radical hysterectomy with lymphadenectomy compared with laparoscopy and laparotomy, Gynecol Oncol 113:357, 2009. Lowe MP, Chamberlain DH, Kamelle SA, et al: A multi-institutional experience with robotic-assisted radical hysterectomy for early stage cervical cancer, Gynecol Oncol 113:191, 2009. Maggioni A, Minig L, Zanagnolo V, et al: Robotic approach for cervical cancer: comparison with laparotomy—a case control study, Gynecol Oncol 115:60, 2009. Sert B: Robotic port-site and pelvic recurrences after robot-assisted laparoscopic radical hysterectomy for a stage IB1 adenocarcinoma of the cervix with negative lymph nodes, Int J Med Robotics Comput Assist Surg 6(2):132–135, 2010. Shafer A, Boggess JF: Robotic-assisted endometrial cancer staging and radical hysterectomy with the da vinci surgical system, Gynecol Oncol 111(Suppl 2):S18, 2008. Shazly SA, Murad MH, Dowdy SC, et al: Robotic radical hysterectomy in early stage cervical cancer: a systematic review and metaanalysis, Gynecol Oncol 138:457–471, 2015.

Recurrent and Advanced Carcinoma of the Cervix Alberts DS, Garcia D, Mason-Liddil N: Cisplatin in advanced cancer of the cervix: an update, Semin Oncol 18(1 Suppl 3):11, 1991. Ampil FL: Stage IVa carcinoma of the cervix, Radiat Med 8:184, 1990. Barter JF, Soong SJ, Hatch KD, et al: Diagnosis and treatment of pulmonary metastases from cervical carcinoma, Gynecol Oncol 38:347, 1990. Bassan JS, Glaser MG: Bony metastasis in carcinoma of the uterine cervix, Clin Radiol 33:623, 1982. Blythe JG, Cohen MH, Buchsbaum HJ, et al: Bony metastases from carcinoma of cervix: occurrence, diagnosis, and treatment, Cancer 36:475, 1975. Bricker EM: The radical evisceration of the pelvis organs in advanced and relapsed carcinoma, Arch Gynakol 204:1–24, 1967. Burke TW, Hoskins WJ, Heller PB, et al: Clinical patterns of tumor recurrence after radical hysterectomy in stage Ib cervical carcinoma, Obstet Gynecol 69:382, 1987. Christopherson WM, Lundin FE Jr, Mendez WM, et al: Cervical cancer control: a study of morbidity and mortality trends over a twenty-one-year period, Cancer 38:1357, 1976. Coleman DL, Gallup DG, Wolcott HD, et al: Patterns of failure of bulky-barrel carcinomas of the cervix, Am J Obstet Gynecol 166:916, 1992. Coleman RL, Keeney ED, Freedman RS, et al: Radical hysterectomy for recurrent carcinoma of the uterine cervix after radiotherapy, Gynecol Oncol 55:29, 1994. Delgato G, Goldson AL, Ashayeri E, et al: Intraoperative radiation in the treatment of advanced cervical cancer, Obstet Gynecol 63:246, 1984. El-Minawi MF, Perez-Mesa CM: Parametrial needle biopsy follow-up of cervical cancer, Int J Obstet Gynecol 12:1, 1974.

Flint A, Terhart K, Murad TM, et al: Confirmation of metastasis by fine needle aspiration biopsy in patients with gynecologic malignancies, Gynecol Oncol 14:382, 1982. Fotopoulou C, Neumann U, Kraetschell R, et al: Long-term clinical outcome of pelvic exenterationin patients with advanced gynecological malignancies, J Surg Oncol 101:507–512, 2010. Gallousis S: Isolated lung metastases from pelvic malignancies, Gynecol Oncol 7:206, 1979. Hartenbach EM, Saltzman AK, Carter JR, et al: Nonsurgical management strategies for the function complications of ileocolonic continent urinary reservoirs, Gynecol Oncol 59:358, 1995. Ketcham AS, Deckers PJ, Sugarbaker EV, et al: Pelvic exenteration for carcinoma of the uterine cervix. A 15-year experience, Cancer 26: 513–521, 1970. Kreiger JS, Embree HK: Pelvic exenteration, Cleve Clin Q 36:1–8, 1969. Larson DM, Copeland LJ, Stringer CA, et al: Recurrent cervical carcinoma after radical hysterectomy, Gynecol Oncol 30:381, 1988. Layfield LJ, Heaps JM, Berek JS: Fine-needle aspiration cytology accuracy with palpable gynecologic neoplasms, Gynecol Oncol 40:70, 1991. Lifshitz S, Railsback LD, Buchsbaum HJ: Intra-arterial pelvic infusion chemotherapy in advanced gynecologic cancer, Obstet Gynecol 52:476, 1978. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al: 13-cis-retinoic acid plus interferon 2a: highly active systemic therapy for squamous cell carcinoma of the cervix, J Natl Cancer Inst 84:241, 1992. Long HJ 3rd, Bundy BN, Grendys EC Jr, et al: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study, J Clin Oncol 23:4626, 2005. Look KY, Blessing JA, Muss HB, et al: 5-Fluorouracil and low-dose leucovorin in the treatment of recurrent squamous cell carcinoma of the cervix, Am J Clin Oncol 15:497, 1992. Monk BJ, Huang HQ, Cella D, et al: Quality of life outcomes from a randomized phase III trial of cisplatin with or without topotecan in advanced carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 23:4617, 2005. Monk BJ, Solh S, Johnson MT, et al: Radical hysterectomy after pelvic irradiation in patients with high-risk cervical cancer or uterine sarcoma: morbidity and outcome, Eur J Gynecol Oncol 14:506, 1993. Montana GS, Martz KL, Hanks GE: Patterns and sites of failure in cervix cancer treated in the USA in 1978, Int J Radiat Oncol Biol Phys 20:87, 1991. Moore DH, Plessing JA, McQuellon RP, et al: Phase III study of cisplatin with or without paclitaxel in stave IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 22:3113, 2004. Morris M, Blessing JA, Monk BJ, et al: Phase II study of cisplatin and vinorelbine in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 22:3340, 2004. Murphy WT, Schmitz A: The results of reirradiation of cancer of the cervix, Radiology 67:378, 1956. Mutch DG, Bloss JD: Gemcitabine in cervical cancer, Gynecol Oncol 90:S8, 2003. Ng HT, Kan YY, Chao HT, et al: The outcome of the patients with recurrent cervical carcinoma in terms of lymph node metastasis and treatment, Gynecol Oncol 26:355, 1987. Omura GA: Current status of chemotherapy for cancer of the cervix, Oncology 6:27, 1992. Park RC, Thigpen JT: Chemotherapy in advanced and recurrent cervical cancer, Cancer 71(Suppl 4):1446, 1993. Parsons L, Friedell GH: Radical surgical treatment of cancer of the cervix, Proc Natl Cancer Conf 5:241–246, 1964.

e11 Paunier JP, Delclos L, Fletcher GH: Causes, time of death, and sites of failure in squamous-cell carcinoma of the uterine cervix on intact uterus, Radiology 88:555, 1967. Peeples WJ, Inalsingh CH, Hazra TA, et al: The occurrence of metastasis outside the abdomen and retroperitoneal space in invasive carcinoma of the cervix, Gynecol Oncol 4:307, 1976. Potter ME, Alvarez RD, Gay GL, et al: Optimal therapy of pelvic recurrence after radical hysterectomy for early stage cervical cancer, Gynecol Oncol 37:74, 1990. Rettenmaier MA, Moran MF, Ramsinghani NF, et al: Treatment of advanced and recurrent squamous carcinoma of the uterine cervix with constant intra-arterial infusion of cisplatin, Cancer 61:1301, 1988. Rubin SC, Hoskins WJ, Lewis JL: Radical hysterectomy for recurrent cervical cancer following radiation therapy, Gynecol Oncol 27:316, 1987. Russell AH, Tong DY, Figge DC, et al: Adjuvant postoperative pelvic radiation for carcinoma of the uterine cervix: pattern of cancer recurrence in patients undergoing elective radiation following radical hysterectomy and pelvic lymphadenectomy, Radiat Oncol Biol Phys 10:211, 1984. Saphner T, Gallion HH, Van Nagell JR, et al: Neurologic complications of cervical cancer: a review of 2261 cases, Cancer 64:1147, 1989. Shield PW, Wright RG, Free K, et al: The accuracy of cervicovaginal cytology in the detection of recurrent cervical carcinoma following radiotherapy, Gynecol Oncol 41:223, 1991. Sommers GM, Grigsby PW, Perez CA, et al: Outcome of recurrent cervical carcinoma following definitive irradiation, Gynecol Oncol 35:150, 1989. Suit HD, Howes AE, Hunter N: Dependence of response of a C3H mammary carcinoma to fractionated irradiation on fractionation number and intertreatment interval, Radiat Res 72:440, 1977. Sutton GP, Blessing JA, McGuire WP, et al: Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group Study, Am J Obstet Gynecol 168:805, 1993. Terada K, Morley GW: Radical hysterectomy as surgical salvage therapy for gynecologic malignancy, Obstet Gynecol 70:913, 1987. Tewari KS, Monk BJ: Gynecologic Oncology Group trials of chemotherapy for metastatic and recurrent cervical cancer, Curr Oncol Rep 7:419, 2005. Thigpen T, Shingleton H, Homesley H, et al: Cis-platinum in the treatment of advanced or recurrent squamous cell carcinoma of the cervix, Cancer 48:899, 1981. Thomas GM: Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery, Gynecol Oncol 27:254, 1987. Truelsen F: Injury of bones by roentgen treatment of the uterine cervix, Acta Radiol 23:581, 1942. Van Herik M, Decker DG, Lee RA, et al: Late recurrence in carcinoma of the cervix, Am J Obstet Gynecol 108:1183, 1970. Welander CE, Homesley HD, Barrett RJ: Combined interferon alpha and doxorubicin in the treatment of advanced cervical cancer, Am J Obstet Gynecol 165:284, 1991.

Locally Advanced Disease Duenas-Gonzalez A, Zarba JJ, Patel F, et al: Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant emcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix, J Clin Oncol 29:1678–1685, 2011.

Fernandez-Otz A, Crook J: The role of intensity modulated radiotherapy in gynecological radiatoherapy: present and future, Rep Pract Oncol Radiother 18:363–370, 2013. GOG protocol 9918. ClinicalTrials.gov Identifier: NCT00104910; Farley JH (study chair). Kagei K, Tokuuye K, Okumura T, et al: Long-term results of proton beam therapy for carcinoma of the uterine cervix, Int J Radiat Oncol Biol Phys 55:1265, 2003. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma, N Engl J Med 340:1154, 1999. Kokka F, Bryant A, Brockbank E, et al: Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer, Cochrane Database Syst Rev CD010260, 2015. Ly Y, Wang F, Yang L, et al: Intensity-modulated whole pelvic radiotherapy provides effective dosimetric outcomes for cervical cancer treatment with lower toxicities, Cancer Radiother 18:745–752, 2014. Monk BJ, Tewari KS, Kow WJ: Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions, J Clin Oncol 27:2952, 2007. Moore KN, Sill MW, Miller DS, et al: A phase I trial of tailored radiation therapy with concomitant cetuximab and cisplatin in the treatment of patiens with cervical cancer: a Gynecologic Oncology Group study, Gynecol Oncol 127:456–461, 2012. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer, N Engl J Med 340:1137, 1999. NCI Clinical Announcement: http://www.cancer.gov/newscenter/ cervicalcancer, 1999. NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. V1. www.nccn.org, 2010. Peters III WA, Liu PY, Barrett II RJ, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in highrisk early-stage cancer of the cervix, J Clin Oncol 18:1606, 2000. Portelance L, Winter K, Jhingran A, et al: Post-operative pelvic intensity modulated radiation therapy (IMRT) with chemotherapy for patients with cervical carcinoma/RTOG 0418 phase II study, Int J Radiat Oncol Biol Phys 75:S640–S641, 2009. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer, N Engl J Med 340:1144, 1999. RTOG protocol 0417. ClinicalTrials.gov Identifier: NCT00369122; Schefter TE (PI). Rydzewska L, Tierney J, Vale CL, et al: Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer, Cochrane Database Syst Rev (20):CD007406, 2010. Rydzewska L, Tierney J, Vale CL, et al: Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer, Cochrane Database Syst Rev (12):CD007406, 2012. Schefter T, Winter K, Kwon JS, et al: RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma, Int J Radiat Oncol Biol Phys 88:101–105, 2014. Whitney CW, Sause W, Bundy BN, et al: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study, J Clin Oncol 17: 1339, 1999.

e12 Recurrent/Metastatic/Persistent Disease AGO protocol IFG-01-0106. A prospective, randomized phase III study to compare the effects of paclitaxel and topotecan to those of cisplatin and topotecan for treatment of patients with recurrent or persistent cervical cancer. (F. Thiel, study chair). Bahadori HR, Green MR, Catapano CV: Synergistic interaction between topotecan and microtubule-interfering agents, Cancer Chemother Pharmacol 48:188, 2001. Bloss JD, Blessing JA, Behrens BC, et al: Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 20:1832, 2002. Bonomi P, Blessing JA, Stehman FB, et al: Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 3:1079, 1985. Cetina L, Crombet T, Jimenez-Lima R, et al: A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent, or metasatic cervical cancer, Cancer Biol Ther 16:684–689, 2015. GOG protocol 240: A randomized phase III trial of cisplatin plus paclitaxel with and without bevacizumab versus the non-platinum doublet, topotecan plus paclitaxel, with and without bevacizumab, in stage IVB, recurrent or persistent carcinoma of the cervix. (Tewari KS, study chair). JCOG0505: Trial of cisplatin plus paclitaxel versus carboplatin plus paclitaxel regimens for stage IVB, persistent, or recurrent cervical cancer. (R. Kitagawa and T. Kamura, study chairs). www.clinicaltrials.gov. Long HJ 3rd, Bundy BN, Grendys EC, et al: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study, J Clin Oncol 23:4626, 2005. Maciag PC, Radulovic S, Rothman J: The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix, Vaccine 27:3975–3983, 2009. Maljekal TT, Bajaj J, Giri V, et al: The role of Notch signaling in human cervical cancer: implications for solid tumors, Oncogene 27:5110–5114, 2008. McGuire WP III, Arseneau J, Blessing JA, et al: A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study, J Clin Oncol 7:1462, 1989. Monk BJ, Sill MW, Burger RA, et al: Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 27:1069, 2009. Monk BJ, Sill MW, McMeekin DS, et al: Phase III trial of four cisplatincontaining doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 27:4649, 2009. Moore DH, Blessing JA, McQuellon RP, et al: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 22:3113, 2004. Moore DH, Tian C, Monk BJ, et al: Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 116:44, 2010. Olsauskas-Kuprys R, Zlobin A, Osipo C: Gamma secretase inhibitors of Notch signaling, Onco Targets Ther 6:943–955, 2013. Omura GA, Blessing JA, Vaccarello L, et al: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide

in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol 15:165, 1997. Qui JT, Ho KC, Lai CH, et al: Supraclavicular lymph node metastases in cervical cancer, Eur J Gynaecol Oncol 28:33, 2007. Rice AE, Latchman YE, Balint JP, et al: An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression, Cancer Gene Ther 22(9): 454–462, 2015. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer, N Engl J Med 355:2542, 2006. Stevanovic S, Draper LM, Langhan MM, et al: Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells, J Clin Oncol 33:1543–1550, 2015. Symonds R, Davidson S, Chan S, et al: SCOTCERV: a phase II trial of docetaxel and gemcitabine as second-line chemotherapy in cervical cancer, J Clin Oncol ASCO Annual Meeting Proceedings 25(Pt 1):18S, Abstract no. 5548, 2007. Takano M, Kikuchi Y, Kita T, et al: Complete remission of metastatic and relapsed uterine cervical cancers using weekly administration of bevacizumab and paclitaxel/carboplatin, Onkologie 32:595, 2009. Tewari KS, Monk BJ: Beyond platinum for metastatic and recurrent carcinoma of the cervix, Onkologie 32:552, 2009. Tewari KS, Monk BJ: Gynecologic Oncology Group trials of chemotherapy for metastatic and recurrent cervical cancer, Curr Oncol Rep 7:419, 2005. Tewari KS, Monk BJ: Recent achievements and future developments in advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group, Semin Oncol 36:170, 2009. Tewari KS, Monk BJ: The rationale for the use of non-platinum chemotherapy doublets for metastatic and recurrent cervical carcinoma, Clin Adv Hematol Oncol 8:108, 2010. Tewari KS: A critical need for reappraisal of therapeutic options for women with metastatic and recurrent cervical carcinoma: commentary on Gynecologic Oncology Group Protocol 204. Am J Hematol Oncol 9:31-34, 2010. Tewari KS: Patients with metastatic/recurrent cervical cancer should be treated with cisplatin plus paclitaxel. Expert Panel. Clin Ovarian Cancer 4:90-93, 2011. Thigpen JT, Blessing JA, DiSaia PJ, et al: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study, Gynecol Oncol 32:198, 1989. Tiersten AD, Selleck MJ, Hershman DL, et al: Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical carcinoma, Gynecol Oncol 92:635, 2004. Tinker AV, Ellard S, Welch S, et al: Phase II study of temsirolimus (CCI779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clincial Trials Group (NCIC CTG IND 199), Gynecol Oncol 130:269–274, 2013. Veeraraghavalu K, Pett M, Kumar RV, et al: Papillomavirus-mediated neoplastic progression is associated with reciprocal changes in JAGGED1 and manic fringe expression linked to notch activation, J Virol 78:8687–8700, 2004. Wiggins DL, Granai CO, Steinhoff MM, et al: Tumor angiogenesis as a prognostic factor in cervical carcinoma, Gynecol Oncol 56:353, 1995. Wright JD, Viviano D, Powell MA, et al: Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer, Gynecol Oncol 103:489, 2006. Yang W, Song Y, Lu YL, et al: Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlateds with impaired cell-

e13 mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia, Immunology 139:513–522, 2013. Yeasmin S, Nakayama K, Rahman MT, et al: Expression of nuclear Notch3 in cervical squamous cell carcinomas and its association with adverse clinical outcomes, Gynecol Oncol 117:409–416, 2010.

Pelvic Recurrence After Suboptimal Surgery Brin EN, Schiff M Jr, Weiss RM: Palliative urinary diversion for pelvic malignancy, J Urol 113:619, 1975. Coddington CC, Thomas JR, Hoskins WJ: Percutaneous nephrostomy for ureteral obstruction in patients with gynecologic malignancy, Gynecol Oncol 18:339, 1984. Höckel M, Baussmann E, Mitze M, et al: Are pelvic side-wall recurrences of cervical cancer biologically different from central relapses? Cancer 74:648, 1994. Feuer GA, Fruchter R, Seruri E, et al: Selection for percutaneous nephrostomy in gynecologic cancer patients, Gynecol Oncol 42:60, 1991. Ijoz T, Eifel PJ, Burke T, et al: Radiation therapy of pelvic recurrence after radical hysterectomy for cervical carcinoma, Gynecol Oncol 70:241, 1998. Orr JW, Ball GC, Soong SJ, et al: Surgical treatment of women found to have invasive cervix cancer at the time of total hysterectomy, Obstet Gynecol 68:353, 1986. Samlal RAK, Van der Velden J, Van E, et al: Recurrent cervical carcinoma after radical hysterectomy: an analysis of clinical aspect and prognosis, Int J Gynecol Cancer 8:78, 1998.

Pelvic Exenteration Averette HE, Lichtinger M, Sevin BU, et al: Pelvic exenteration: a 15year experience in a general metropolitan hospital, Am J Obstet Gynecol 150:179, 1984. Barber HRK: Relative prognostic significance of preoperative and operative findings in pelvic exenteration, Surg Clin North Am 49: 431, 1969. Barber HRK, Jones W: Lymphadenectomy in pelvic exenteration for recurrent cervix cancer, JAMA 215:1949, 1971. Behtash N, Mousavi A, Tehranian A, et al: Embryonal rhabdomyosarcoma of the uterine cervix: case report and review of the literature, Gynecol Oncol 91:452, 2003. Berman ML, Lagasse LD, Watring WG, et al: Enteroperineal fistulae following pelvic exenteration: a 10-point program of management, Gynecol Oncol 4:368, 1976. Bricker EM: Bladder substitution after pelvic evisceration, Surg Clin North Am 30:1511, 1950. Bricker EM, Butcher HR, McAfee A: Results of pelvic exenteration, Arch Surg 73:661, 1956. Brunschwig A: What are the indications and results of pelvic exenteration? JAMA 194:274, 1965. Brunschwig A, Pierce VK: Necropsy findings in patients with carcinoma of the cervix: implications for treatment, Am J Obstet Gynecol 56: 1134, 1948. Carlson JW, Soisson AP, Fowler JM, et al: Rectus abdominis myocutaneous flap for primary vaginal reconstruction, Gynecol Oncol 51: 323, 1993. Creasman WT, Rutledge F: Is positive pelvic lymphadenectomy a contraindication to radical surgery in recurrent cervical carcinoma? Gynecol Oncol 2:282, 1974. De la Garza J, Wilson SS, Behbakht K: Total pelvic exenteration with a split-thickness skin graft neovagina, continent orthotopic neobladder and rectal reanastomosis, resulting in no external ostomies and adequate sexual function, Gynecol Oncol 115:312, 2009. Gruessner SE, Omwandho CO, Dreyer T, et al: Management of stage I

cervical sarcoma botryoides in childhood and adolescence, Eur J Pediatr 163:452, 2004. Hancock KC, Copeland LJ, Gershenson DM, et al: Urinary conduits in gynecologic oncology, Obstet Gynecol 67:680, 1986. Hatch KD, Shingleton HM, Potter ME, et al: Low rectal resection and anastomosis at the time of pelvic exenteration, Gynecol Oncol 32: 262, 1988. Hoffman MS, Lynch CM, Gleeson NC, et al: Colorectal anastomosis on a gynecologic oncology service, Gynecol Oncol 55:60, 1994. Hökel M, Schlenger K, Hamm H, et al: Five year experience with combined operative and radiotherapeutic treatment of recurrent gynecologic tumors infiltrating the pelvic wall, Cancer 77:1918, 1996. Iavazzo C, Vorgias G, Akrivos T: Laparoscopic pelvic exenteration: a new option in the surgical treatment of locally advanced and recurrent cervical carcinoma, Bratisl Lek Listy 109:467, 2008. Irvin W, Presley A, Anderson W, et al: Leiomyosarcoma of the cervix, Gynecol Oncol 91:636, 2003. Jurado M, Alcazar JL, Martinez-Monge R: Resectability rates of previously irradiated recurrent cervical cancer (PIRCC) treated with pelvic exenteration: is still the clinical involvement of the pelvis wall a real contraindication? A twenty-year experience, Gynecol Oncol 116:38, 2010. Ketcham AS, Deckers PJ, Sugarbaker EV, et al: Pelvic exenteration for carcinoma of the uterine cervix: a 15-year experience, Cancer 26:513, 1970. Lambaudie E, Narducci F, Leblanc E, et al: Robotically-assisted laparoscopic anterior pelvic exenteration for recurrent cervical cancer: report of three first cases, Gynecol Oncol 116:582, 2010. Lawhead RA: Pelvic exenteration for recurrent or persistent gynecologic malignancies: a 10-year review of the Memorial SloanKettering Cancer Center experience (1972–1981), Gynecol Oncol 33:279, 1989. Lee JW, Kim YT, Min YH, et al: Granulocytic sarcoma of the uterine cervix, Int J Gynecol Cancer 14:553, 2004. Lichtinger M, Averette H, Girtanner R, et al: Small bowel complications after supravesical urinary diversion in pelvic exenteration, Gynecol Oncol 24:137, 1986. Lim PC: Robotic assisted total pelvic exenteration: a case report, Gynecol Oncol 115:310, 2009. Magrina JF: Types of pelvic exenterations: a reappraisal, Gynecol Oncol 37:363, 1990. Marnitz S, Dowdy S, Lanowska M, et al: Exenterations 60 years after first description: results of a survey among US and German Gynecologic Oncology Centers, Int J Gynecol Cancer 19:974, 2009. Morley GW, Lindenauer SM: Pelvic exenteration therapy for gynecologic malignancies: an analysis of 70 cases, Cancer 38:581, 1976. Morley GW, Lindenauer SM, Young D: Vaginal reconstruction following pelvic exenteration, Am J Obstet Gynecol 116:996, 1973. Ng C, Amis S: Radiology of continent urinary diversion, Contemp Urorad 29:557, 1991. Orr JW, Shingleton HM, Hatch KD, et al: Urinary diversion in patients undergoing pelvic exenteration, Am J Obstet Gynecol 142: 883, 1982. Park TK, Choi DH, Kim SN, et al: Role of induction chemotherapy in invasive cervical cancer, Gynecol Oncol 41:1007, 1991. Penalver M, Averette H, Sevin BU, et al: Gastrointestinal surgery in gynecologic oncology: evaluation of surgical techniques, Gynecol Oncol 28:74, 1987. Roberts WS, Cavanagh D, Bryson SC, et al: Major morbidity after pelvic exenteration: a seven year experience, Obstet Gynecol 69: 617, 1987.

e14 Rutledge FN, Burns BC Jr: Pelvic exenteration, Am J Obstet Gynecol 91:692, 1965. Rutledge FN, McGuffee VB: Pelvic exenteration: prognostic significance of regional lymph node metastasis, Gynecol Oncol 26:374, 1987. Rutledge FN, Smith JP, Wharton JT, et al: Pelvic exenteration: analysis of 296 patients, Am J Obstet Gynecol 129:881, 1977. Schneider A, Kohler C, Erdemoglu E: Current developments for pelvic exenteration in gynecologic oncology, Curr Opin Obstet Gynecol 21:4, 2009. Sharma S, Odunsi K, Driscoll D, et al: Pelvic exenterations for gynecological malignancies: twenty-year experience at Roswell Park Cancer Institute, Int J Gynecol Cancer 15:475, 2005. Shingleton HM, Soong SJ, Gelder MS, et al: Clinical and histopathologic factors predicting recurrence and survival after pelvic exenteration for cancer of the cervix, Obstet Gynecol 73:1027, 1989. Snijders-Keilholz A, Ewing P, Seynaeve C, et al: Primitive neuroectodermal tumor of the cervix uteri: a case report changing concepts in therapy, Gynecol Oncol 98:516, 2005. Soper JT, Berchuck A, Creasman WT, et al: Pelvic exenteration: factors associated with major surgical morbidity, Gynecol Oncol 35:93, 1989. Spahn M, Weiss C, Bader P, et al: The role of exenteration surgery and urinary diversion in persistent or locally recurrent gynecological malignancy: complications and survival, Urol Int 85(1):16–22, 2010. Stanhope CR, Symmonds RE, Lee RA, et al: Urinary diversion with use of ileal and sigmoid conduit, Am J Obstet Gynecol 155:288, 1986. Swan RW, Rutledge FN: Urinary conduit in pelvic cancer patients: a report of 16 years’ experience, Am J Obstet Gynecol 119:6, 1974. Symmonds RE, Pratt JH, Webb MJ: Exenteration operations: experience with 198 patients, Am J Obstet Gynecol 121:907, 1975. Walton LA: The stress of radical pelvic surgery: a review, Gynecol Oncol 7:25, 1979. Wheelers CR Jr: Incidence of fecal incontinence after coloproctostomy below five centimeters in the rectum, Gynecol Oncol 27:373, 1987. Wheelers CR Jr: Recent advances in surgical reconstruction of the gynecologic cancer patient, Curr Opin Obstet Gynecol 4:91, 1992.

Nonepithelial Tumors of the Cervix (Sarcoma, Lymphoma, and Melanoma) Abdul-Karim RW, Bazi TM, Sorensen K, et al: Sarcoma of the uterine cervix: clinicopathologic findings in three cases, Gynecol Oncol 26: 103, 1987.

Akine Y, Arimoto H, Ogino T, et al: Carcinoma of the uterine cervix treated by irradiation alone: result of treatment at the National Cancer Center, Tokyo, Acta Oncol 29:747, 1989. Brand E, Berek JS, Nieberg RK, et al: Rhabdomyosarcoma of the uterine cervix: sarcoma botryoides, Cancer 60:1552, 1987. Dursun P, Gultekin M, Bozdag G, et al: Primary cervical lymphoma: report of two cases and review of the literature, Gynecol Oncol 98:484, 2005. Kristiansen SB, Anderson R, Cohen DM: Case report: primary malignant melanoma of the cervix and review of the literature, Gynecol Oncol 47:398, 1992. Laterza R, Seveso A, Zefiro F, et al: Carcinosarcoma of the uterine c ervix: case report and discussion, Gynecol Oncol 107:S98, 2007. Lee JM, Lee KB, Nam JH, et al: Prognostic factors in FIGO stage IBIIA small cell neuroendocrine carcinoma of the uterine cervix treated surgically: results of a multi-center retrospective Korean study, Ann Oncol 19:321, 2008. Montag RW, D’Abaing G, Schlaerth JB: Embryonal rhabdomyosarcoma of the uterine corpus and cervix, Gynecol Oncol 25:171, 1986. Mordel N, Mor-Yosef S, Ben-Baruch N, et al: Malignant melanoma of the uterine cervix: case report and review of the literature, Gynecol Oncol 32:375, 1989. Mousavi AS, Fakor F, Nazari Z, et al: Primary malignant melanoma of the uterine cervix: case report and review of the literature, J Low Genit Tract Dis 10:258, 2006. Muntz HG, Ferry JA, Flynn D, et al: Stage IE primary malignant lymphomas of the uterine cervix, Cancer 68:2023, 1991. Perren T, Farrant M, McCarthy K, et al: Case report: lymphomas of the cervix and upper vagina: a report of five cases and a review of the literature, Gynecol Oncol 44:87, 1992. Rotmensch J, Rosensheim NB, Woodruff JD: Cervical sarcoma: a review, Obstet Gynecol Surg 38:456, 1983. Szantho A, Balega JJ, Csapo Z, et al: Primary non-Hodgkin’s lymphoma of the uterine cervix successfully treated by neoadjuvant chemotherapy: case report, Gynecol Oncol 89:171, 2003. Zivanovic O, Leitao MM Jr, Park KJ, et al: Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy, Gynecol Oncol 112:590, 2009.

e15

NEW REFERENCES Cervical Cancer Treatment Paradigms: 1. Tewari KS, Monk BJ: Evidence-based treatment paradigms for management of invasive cervical carcinoma, J Clin Oncol 37:2472–2489, 2019.

Cancer Statistics 2022:

11. FDA Safety Communication: Caution When Using Robotically Assisted Surgical Devices in Women’s Health Including Mastectomy and Other Cancer-Related Surgeries. https://www.fda.gov/medicaldevices/safety-communications/caution-when-using-robotically-assisted-surgical-devices-womens-health-including-mastectomy-and.

Radical Trachelectomy:

1. Siegel RL, Miller KD, Fuchs HE, Jemal A: Cancer statistics, CA Cancer J Clin 72:7–33, 2022.

1. Smith ES, Moon AS, O’Hanlon R, et al: Radical trachelectomy for the treatment of early-stage cervical cancer: a systematic review, Obstet Gynecol 136:533–542, 2020.

FIGO Staging:

Pelvic Exenteration:

1. Bhatla N, Berek JS, Fredes MC, et al: Revised FIGO staging for carcinoma of the cervix uteri, Int J Gynaecol Obstet 145:129–135, 2019.

1. Graves S, Seagle BLL, Strohl AE, et al: Survival after pelvic exenteration for cervical cancer: a National Cancer Database Study, Int J Gynecol Cancer 27:390–395, 2017.

GOG-0233/ACRIN Study:

JCOG Trial for Recurrent/Metastatic:

1. Atri M, Zhang Z, Dehdashti F, et al: Utility of PET-CT to evaluate retroperitoneal lymph node metastasis in advanced cervical cancer: results of ACRIN6671/GOG0233 trial, Gynecol Oncol 142:413–419, 2016.

1. Kitagawa R, Katsumata N, Shibata T, et al: Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the Open-Label Randomized Phase III Trial JCOG0505, J Clin Oncol 33:2129–2135, 2015.

LACC Trial:

GOG-0240 Citations:

1. Ramirez PT, Frumovitz M, Pareja R, et al: Minimally invasive versus abdominal radical hysterectomy for cervical cancer, N Engl J Med 379;1895–1904, 2018. 2. Tewari KS. Minimally invasive surgery for early-stage cervical carcinoma: Interpreting the Laparoscopic Approach to Cervical Cancer Trial Results, J Clin Oncol 37:3075–3080, 2019. 3. Melamed A, Margul DJ, Chen L, et al: Survival after minimally invasive radical hysterectomy for early-stage cervical cancer, N Engl J Med 379;1905–1914, 2018. 4. Cusimano MC, Baxter NN, Gien LT, et al: Impact of surgical approach on oncologic outcomes in women undergoing radical hysterectomy for cervical cancer, Am J Obstet Gynecol, 221:619. e1–e24, 2019. 5. Paik ES, Lim MC, Kim MH, et al: Comparison of laparoscopic and abdominal radical hysterectomy in early stage cervical cancer patients without adjuvant treatment: ancillary analysis of a Korean Gynecologic Oncology Group Study (KGOG 1028), Gynecol Oncol 154:547–553, 2019. 6. Kim SI, Cho JH, Seol A, et al: Comparison of survival outcomes between minimally invasive surgery and conventional open surgery for radical hysterectomy as primary treatment in patients with stage IB1-IIA2 cervical cancer, Gynecol Oncol 153;3–12, 2019. 7. Doo DW, Kirkland CT, Griswold LH: Comparative outcomes between robotic and abdominal radical hysterectomy for IB1 cervical cancer: results from a single high volume institution, Gynecol Oncol 153:242–247, 2019. 8. Uppal S, Gehrig P, Vetter MH, et al: Recurrence rates in cervical cancer patients treated with abdominal versus minimally invasive radical hysterectomy: a multi-institutional analysis of 700 cases, J Clin Oncol 38:1030–1040, 2020. 9. National Cancer Registration and Analysis Service: Comparisons of OS in Women Diagnosed With Early Stage Cervical Cancer During 2013-2016, Treated by Radical Hysterectomy Using Minimal Access or Open Approach. 2019. https://bgcs.org.uk/news/ncrascervical-cancer-radical-hysterectomy-analysis.html. 10. Notice to SGO Members: Emerging Data on the Surgical Approach for Radical Hysterectomy in the Treatment of Women With Cervical Cancer. https://www.sgo.org/clinical-practice/guidelines/notice-to-sgomembers-emerging-data-on-the-surgical-approach-for-radicalhysterectomy-in-the-treatment-of-women-with-cervical-cancer/.

1. Tewari KS, Sill MW, Penson RT, et al: Bevacizumab for advanced cervical cancer: final OS and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240), Lancet 390:1654–1663, 2017. 2. Tewari KS, Sill MW, Monk BJ, et al: Circulating tumor cells in advanced cervical cancer: NRG Oncology - Gynecologic Oncology Group Study 240 (NCT 00803062). Mol Cancer Ther 19:2363-2370, 2020. 3. Seamon LG, Java JJ, Monk BJ, et al: Impact of tumour histology on survival in advanced cervical carcinoma: an NRG Oncology/Gynaecologic Oncology Group Study, Br J Cancer 118:162–170, 2018. 4. Tewari KS, Sill MW, Monk BJ, et al: Prospective Validation of pooled prognostic factors in women with advanced cervical cancer treated with chemotherapy with/without bevacizumab: NRG Oncology/GOG Study, Clin Cancer Res 21:5480–5487, 2015. 5. Penson RT, Huang HQ, Wenzel LB, et al: Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240), Lancet Oncol 16:301–311, 2015.

Rationale to Study Immunotherapy: 1. Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization of cervical cancer. Nature 543:378-384, 2017. 2. Ojesina AI, Lichtenstein L, Freeman SS, et al: Landscape of genomic alterations in cervical carcinomas, Nature 506:371–375, 2014.

Checkpoint: 1. Chung HC, Ros W, Delord JP, et al: Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study, J Clin Oncol 37:1470–1478, 2019. 2. Wei SC, Anang NAAS, Sharma R, et al: Combination anti–CTLA-4 plus anti–PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies, Proc Natl Acad Sci USA 116:22699–22709, 2019. 3. Naumann RW, et al: ESMO 2019—LBA62, NCT02488759. 4. O’Malley DM, et al: ESMO 2020—LBA 34, NCT03104699 & NCT03495882

e16 TILs: 1. Stevanovic S, Pasetto A, Helman SR, et al: Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer, Science 356:200–205, 2017. 2. Stevanovic S, Draper LM, Langhan MM, et al: Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells, J Clin Oncol 33:1543–1550, 2015.

Tissue Factor and Tisotumab Vedotin: 1. Zhao X, Cheng C, Gou J, et al: Expression of tissue factor in human cervical carcinoma tissue, Exp Ther Med 16:4076–4081, 2018. 2. Coleman Rl, et al: ESMO 2020—LBA32, NCT03438396

Anti-HER2: 1. Zammataro L, Lopez S, Bellone S, et al: Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy, Proc Natl Acad Sci USA 116:22730–22736, 2019. 2. Amant F, Coosemans A, Debiec-Rychter M, et al: Clinical management of uterine sarcomas, Lancet Oncol 10:1188–1198, 2009.

3. Oaknin A, Friedman CF, Roman LD, et al: Neratinib in patients with HER2-mutant, metastatic cervical cancer: findings from the phase 2 SUMMIT basket trial, Gynecol Oncol 159:150, 2020.

New References for New Section by Dr Creasman: Management of Microinvasive Disease: 1. Spoozak L, Lewin S, Burke W, et al: Microinvasive adenocarcinoma of the cervix, AJOG 206:80.e1–e6, 2012. 2. Sia T, Chen Z, Melamed, et al: Trends in Use and effect on survival of simple hysterectomy for early-stage cervical cancer, Obstet Gynecol 134:1132, 2019. 3. Hou J, Goldberg GL, Qualls C, et al: Risk factors for poor prognosis in microinvasive adenocarcinoma of uterine cervix (IA1 and IA2), Gynecol Oncol 121:135, 2011. 4. Buchanan T, Pierce J, Graybill W, et al: Why do we continue to overtreat stage Ia carcinoma o the cervix, AJOG 217:413–417, 2017. 5. Lim CS, Alexander-Sefre F, Allam M, et al: Clinical value of immunohistochemically detected lymphovascular space invasion in early stage cervical cancer, Ann Surg Oncol 15:2581, 2008.

4 Endometrial Hyperplasia, Estrogen Therapy, and the Prevention of Endometrial Cancer Kari L. Ring, MD, MS, JoAnn V. Pinkerton, MD, NCMP, Lisa M. Landrum, MD, PhD, Rosemary E. Zuna, MD, Linda R. Duska, MD, MPH OUTLINE Introduction, 104 Endometrial Hyperplasia: Pathologic Diagnostic Criteria, 106 Clinical Presentation, 108 Management Decisions for Endometrial Intraepithelial Neoplasia, 109 Management of Endometrial Hyperplasia Without Atypia, 110 Prevention of Endometrial Cancer, 111

INTRODUCTION The endometrium is a dynamic tissue in reproductive age women. It is continuously cycling in response to hormonal, stromal, and vascular influences, with the ultimate goal of implanting an embryo and supporting the nutritional needs of the developing pregnancy. While estrogen stimulation is associated with the growth of proliferative endometrium (Fig. 4.1), progesterone produced by the corpus luteum after ovulation inhibits proliferation and stimulates formation of secretory endometrium (Fig. 4.2). Without conception and human chorionic gonadotropin (hCG) production, the corpus luteum fails to produce progesterone, and hormonal withdrawal allows endometrial breakdown and menses to occur. In contrast, continuous estrogen exposure bypasses the normal recycling of the endometrium and allows uninhibited endometrial growth, with the potential for neoplastic change. Unopposed estrogen is not the only etiology of endometrial cancer, and it is important to note that a percentage of endometrial cancers will occur that are not hormonally driven. In fact, over the past decade, we have come to better understand the molecular foundations of endometrial cancer with four distinct molecular subtypes defined by The Cancer Genome Atlas (TCGA). This understanding has evolved from the traditional type I (estrogen excess) and type 2 (estrogen independent) dichotomy to a molecular classification that is more diagnostically reproducible, more prognostic, and more predictive of response to therapy. The new classification has also changed the way in which we think about the etiology of endometrial cancer. Estrogen excess is the primary etiology of many, but not all cases of endometrial cancer. While traditionally we thought of estrogen excess in its many forms (obesity, polycystic ovary syndrome [PCOS], unopposed pharmaceutical estrogen compounds) as the primary cause of type I endometrial cancers, we now consider estrogen 104

Benefits and Risks of Menopausal Hormone Therapy, 112 Risk Modification with Hormone Therapy: Options and Opportunities, 120 Nonhormone Therapies for Menopausal Symptoms, 121 Menopausal Hormone Therapy for Endometrial and Breast Cancer Survivors, 121

excess being most important in those tumors that are copy number low (low mutational burden) endometrial tumors. These are also the tumors that often present with or have concurrent preinvasive lesions and are most responsive to hormonal treatment. This new classification better defines these estrogen-related tumors with respect to prognosis as well as potential targeted treatments. Importantly, a certain percentage of estrogen-driven tumors will also be mismatch repair deficient (MMRd). Historical data support the conclusion that unopposed estrogen stimulation yields a continuous spectrum of change from proliferative endometrium to benign endometrial hyperplasia (Fig. 4.3) and subsequently through many variations of endometrial hyperplasia until a malignant neoplasm develops. Endometrial cancer is defined by the ability to invade local tissue and metastasize (Fig. 4.4). Pre-malignant endometrial lesions may pre-date or co-exist with malignant endometrial cancer. Moreover, the histologic diagnosis of pre-malignant lesions can be made difficult by multiple factors including insufficient sampling or incorrect histologic interpretation. The development of new diagnostic subtypes (for example, endometrial intraepithelial neoplasia, or EIN) and novel diagnostic criteria have been helpful in better defining not only the diagnosis of pre-malignant lesions but also their propensity to progress to or be associated with a malignancy. EIN is primarily caused by estrogen excess but responds to progesterone more frequently in premenopausal than in postmenopausal women. This dichotomy is multifactorial and deserving of further study. Progesterone therapy may also be effective initially but lose its effectiveness over time; research is needed to potentiate continued progesterone effectiveness in those women who either wish to preserve the corpus for fertility or are not reasonable candidates for definitive surgical therapy.

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

Figure 4.1 Proliferative endometrium. Simple tubular endometrial glands are set in a prominent stroma. This pattern is associated with normal estrogen stimulation in a cycling woman (hematoxylin and eosin, 1003 original magnification).

Figure 4.2 Secretory endometrium. Endometrial glands are present with a sawtooth pattern. Each gland is an individual unit set in endometrial stroma. The epithelium has intracytoplasmic glycogen secretion that is eventually extruded into the gland lumen (hematoxylin and eosin, 1003 original magnification).

The molecular classification of these lesions may assist us in a better understanding of which lesions will be most responsive to hormonal therapy alone, and which would benefit from the addition of other targeted agents. Understanding the clinical situations in which excess unopposed estrogen may exist helps the clinician better predict which women are at risk for endometrial cancer and provides windows of opportunity for implementation of prevention strategies. The obesity epidemic has certainly contributed to the rising incidence of endometrial cancer in the US and other developed countries. Delays in childbearing in combination with a younger age of diagnosis has also led to more women with

105

Figure 4.3 Benign endometrial hyperplasia (formerly simple hyperplasia without atypia). The endometrium shows an increase in the glandular epithelium usually caused by unopposed estrogen stimulation. This results in irregular and unpredictable gland outlines that are often cystic. There is abundant stroma, so that the gland-to-stromal ratio is little altered from normal (hematoxylin and eosin, 1003 original magnification).

Figure 4.4 Endometrioid adenocarcinoma. Well-differentiated (International Federation of Gynecology and Obstetrics G1) endometrioid adenocarcinomas typically show a “back-to-back” glandular arrangement with little intervening stroma. The glands are lined by tall columnar cells (hematoxylin and eosin, 2003 original magnification).

pre-malignant or malignant endometrial lesions wishing to preserve fertility. Many female cancers contain estrogen receptors (ERs). The question of the role of hormone replacement therapy (estrogen with or without progestogen) in developing or stimulating cancers and its use for cancer survivors remains confusing, conflicting, and controversial. In the past, unopposed menopausal estrogen use contributed to the development of endometrial cancer. Today, we understand the importance of combining estrogen with a progestogen (progestin or progesterone) for women with

106

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

an intact uterus. There are many Food and Drug Administration (FDA)-approved oral and transdermal therapies for hormone therapy (HT), that are available in varying doses. However, other modern trends are complicating the use of postmenopausal HT. Treatment of gynecological cancers may have a significant impact on women and their quality of life. Early menopause (surgical or induced) has been shown in epidemiologic studies to have more health risk while acute onset of menopausal symptoms may be more debilitating than those seen with natural menopause. Understanding menopause and the benefits and risk of menopausal hormone use will help clinicians work with oncologists to respond to women’s menopausal concerns and improve quality of life for women at risk of or having survived cancer. Data to provide definitive guidance regarding hormone replacement therapy is often lacking as the studies may be small or retrospective in nature. Menopausal symptoms of hot flashes, night sweats, and genitourinary syndrome of menopause may be more severe in women treated for cancer and the associated stress associated with diagnosis and treatment strategies may exacerbate the severity. Current literature suggests that it is important to include in decision making for an individual woman: what is known about the oncologic characteristics of the cancer, therapies used, grade and stage of the tumor including time of remission; information about the specific considered menopausal HT such as dose, formulation, use of estrogen alone or with a progestogen and duration of use; and lastly any endocrine characteristics such as hormone receptor status for the cancer, prior or future use of aromatase inhibitors, selective estrogen receptor modulators (SERMS), or other therapies. Due to a lack of large, randomized clinical trials showing safety of menopausal hormones in female cancers, specialists must rely on preclinical research, case reports, retrospective studies, any randomized controlled trials (RCTs), and meta-analyses to help predict the risks and benefits of menopausal HT for any given clinical scenarios. We will provide information about the known advantages and disadvantages for women with endometrial and breast cancer or whom are BRCA positive.

This entity is very different from EIN and represents the precursor lesion for uterine serous endometrial cancer.

Traditional Endometrial Hyperplasia The traditional classification of endometrial hyperplasia divides hyperplasia into four categories based on architectural structure and cytologic features. The architecture is either simple or complex, and the cytologic features are described as with or without atypia. This yields four separate diagnoses (Table 4.1): simple hyperplasia without atypia (see Fig. 4.3), complex hyperplasia without atypia, simple hyperplasia with atypia, and complex hyperplasia with atypia (AEH) (Fig. 4.5). The terms adenomatous and cystic-glandular hyperplasia have been discarded, and when the abbreviation AEH is used, it refers to atypical endometrial hyperplasia (AEH), which reflects the two categories of hyperplasia with cytologic atypia (simple hyperplasia or complex hyperplasia with atypia). The presence of cytologic atypia is the most important criteria for progression to adenocarcinoma or the coexistence of endometrioid adenocarcinoma. The rates of coexisting endometrioid adenocarcinoma with AEH are reported to be as low as 13% and as high as 43%. Clinically, the term complex atypical hyperplasia (CAH) is used to describe hyperplasia that has both cytologic and architectural atypia and is the category most likely to progress (or be concurrent with) an invasive lesion. TABLE 4.1 Classification of Endometrial

Hyperplasia

Simple hyperplasia Complex hyperplasia (adenomatous) Simple atypical hyperplasia Complex atypical hyperplasia (adenomatous with atypia) From World Health Organization, Kurman RJ, editor: Blaustein’s pathology of the female genital tract, ed 4, Springer, 1994, NewYork.

ENDOMETRIAL HYPERPLASIA: PATHOLOGIC DIAGNOSTIC CRITERIA There are currently two systems of nomenclature for endometrial precursors, the 1994 World Health Organization (WHO94) schema and the EIN system. Recently, the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncology published their Committee Opinion endorsing the EIN system. The EIN system is both more reproducible and better associated with malignant potential. It also gives direction for therapeutic options. As pathologists and clinicians become more familiar with this nomenclature, most pathologists are reporting both the EIN diagnosis as well as the traditional hyperplasia categories. Since most historical data still utilize the hyperplasia nomenclature, we will discuss both nomenclatures below, and when discussing studies, will use the nomenclature utilized in the specific study. Additionally, it is critical to introduce the concept of EIC, endometrial intraepithelial carcinoma.

Figure 4.5 Endometrial intraepithelial neoplasia (formerly atypical complex hyperplasia). The tissue shows a marked increase in the gland-tostromal ratio with complex glandular outlines and nuclear atypia in the lining epithelium (hematoxylin and eosin, 1003 original magnification).

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

Traditionally, the results of the retrospective “expert” review from Dr. Kurman’s group has been used to predict malignant capability of endometrial cancer precursors. From this classic study came the estimation that the risk of progression of CAH to endometrial cancer is 29%. Although this study added significantly to our understanding of the natural history of endometrial cancer precursors, it also had some significant limitations, including: the low number of patients with CAH (35), the retrospective nature, the fact that a year elapsed between the endometrial biopsy and the hysterectomy specimen, and the fact that only one pathology “expert” reviewed all the diagnoses. Recognizing these limitations, a prospective study of AEH (both simple and complex) was undertaken by the Gynecologic Oncology Group (GOG). This study had two primary endpoints: to determine the reproducibility of the diagnosis when made in the “real-life” community setting, and to prospectively determine the concurrent/progression rate of AEH. Women with the community diagnosis of AEH who agreed to have a hysterectomy within 12 weeks of diagnosis of AEH were enrolled; the preoperative biopsy did not have to be reviewed by a GOG pathologist to allow study entry. Both the preoperative biopsy and the postoperative hysterectomy specimen were submitted to the GOG “expert” pathology panel for review. The study population included 302 eligible cases with a median age of 57 years; 31% were 50 years of age or younger. The endometrial biopsy specimens were re-reviewed by three gynecologic pathologists independently (study panel diagnosis) in a blinded protocol. The “expert” reviewers agreed to categorize the endometrium as normal (cycling, menstrual, or atrophic), nonatypical hyperplasia (disordered proliferative, simple or complex hyperplasia), atypical hyperplasia (simple or complex), adenocarcinoma, or inadequate for evaluation. Two of three study pathologists had to agree on one of the above five diagnoses for a study panel diagnosis to be established. Correct diagnosis was determined by consensus agreement on the hysterectomy specimen during a simultaneous panel review with a multiheaded microscope. The results found only 40% of the cases had all three pathologists in agreement. The reproducibility was lowest for the diagnosis of AEH (kappa 0.28), and better for adenocarcinoma (kappa 0.51). Reproducibility was best for dilation and curettage (D&C) (kappa 0.47; confidence interval [CI] 0.41:0.53) compared with small sampling devices (kappa 0.26 to 0.36). In addition to the lack of agreement among experts, there was a lack of agreement with the original diagnosis of the enrolling institution. Two of three study panel members agreed with the referring institution diagnosis of AEH in only 38% of cases. The study panel diagnosis was less severe in 25% of cases and more severe (adenocarcinoma) in 29% of cases. It is in large part because of the lack of reproducibility in the diagnosis of this pre-malignant lesion that the new nomenclature EIN is important. Another important outcome of this study was the finding that 43% of the enrolled participants were found to have adenocarcinoma in their uterus at the time of hysterectomy. This number is obviously far higher than the 29% result from Dr. Kurman’s study. This number is arguably more accurate than 29%, given the prospective nature of the trial, the inclusion of

107

multiple expert reviewers, and the required 12-week interval between biopsy and hysterectomy. Perhaps most alarming, the uterine examination revealed the presence of some risk factors for metastatic disease present in 43 cases, including myometrial invasion or high-grade lesions. There were 123 patients that were determined to have endometrial cancer. Sixty-five percent (80/123) were confined to the endometrium; 77 of these cases had grade 1 disease and so were likely cured with hysterectomy alone. However, 31% had myoinvasive disease, and 10.6% had myoinvasion to the outer third. Eight of 123 endometrial cancer cases had endometrial cancers that were grades 2 or 3. These findings suggest a certain percentage of women with a preoperative diagnosis of AEH will have endometrial cancer with high risk factors at the time of hysterectomy. These women would have benefitted from surgical staging with a gynecologic oncologist to best treat their cancer and better inform the need for adjuvant therapy. The findings of this critical study have changed the clinical management of women with AEH. First, given the higher-thanexpected rate of concurrent endometrial cancer, most providers now recommend definitive hysterectomy for AEH provided the patient has completed childbearing and is a surgical candidate. Second, gynecologic oncologists either routinely perform sentinel node dissection on women with AEH or send frozen section with node dissection based on uterine factors. Third, women with AEH need to be carefully counseled with respect to ovarian preservation, given the high rate of concurrent endometrial cancer.

Endometrial Intraepithelial Neoplasia In 2014, the World Health Organization (WHO) recognized that the goal of all classification schemas should be to bifurcate at clinical decision points. The new classification system of EIN attempts to simplify the previous hyperplasia designation into a binary system that aligns with clinical options and implications. The system is therefore divided into two categories: hyperplasia without atypia (indicative of hormonal milieu, and can be followed with hormonal therapy) and EIN. The EIN system developed by the International Endometrial Collaborative Group classifies endometrial precursors based on their clonal origin, noninvasive growth patterns, and risk of concurrent carcinoma. For a diagnosis of EIN to be made, the following criteria must be met: area of glands exceeds the stroma, cytology differs between the crowded focus and the normal background endometrium, the size of the lesion exceeds 1 mm, and benign pathology with overlapping features such as polyps or effects of exogenous estrogen can be eliminated. There is evidence that the clinical outcome prediction and the interobserver reproducibility using EIN is improved over the 1994 WHO schema. EIN encompasses most of what was previously called CAH, but also includes cytologically bland proliferations which are morphologically distinct from the background endometrium (and would have been called SH or CH in the past). One study showed that EIN includes: 50% to 65% of what was previously called CAH, 45% to 60% of complex hyperplasia without atypia cases, and 5% to 10% of what was previously called simple hyperplasia.

108

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

One multicenter trial of 477 patients compared the WHO 1994 criteria to the EIN. When using WHO criteria, 13% of atypical hyperplasia (AH) progressed, and 2.3% of non-AH progressed. When using EIN, 19% of EIN progressed and 0.6% of non-EIN progressed. The sensitivity of EIN to detect a premalignant lesion was 92%, compared to 67% for the WHO criteria and 46% when using CAH alone. In a regression analysis, EIN was the strongest predictive index of future carcinoma. The EIN diagnosis is more objective than the previous AEH diagnosis, allowing better reproducibility. The morphometric D score combines three quantitative variables in a mathematic formula; a score of less than 1 connotes a high rate of progression to endometrial cancer. The three variables include: stromal contribution, glandular complexity, and gland pleomorphism. The D score measurements were initially obtained objectively, but have been shown to correlate well with subjective interpretations. The EIN system also acknowledges the clonal presentation of endometrial cancer precursors. There are also molecular alterations associated with EIN. Loss of PTEN and PAX2 have been correlated with EIN lesions. Additionally, dissection and molecular testing have proven that PTEN/PAX2-negative areas represent distinct clones within the endometrium with malignant potential.

Endometrial Intraepithelial Carcinoma Serous carcinomas of the uterus arise in a background of atrophic endometrium. These cancers are not associated with excess estrogen and have been classified as type II (estrogen independent) endometrial cancers. Serous carcinoma is less likely to be identified at an early stage compared with endometrioid histologic types. These lesions are typically associated with mutations in the p53 tumor suppressor gene that results in accumulation of inactive p53 protein in the cell (Fig. 4.6). Unlike normal cells

Figure 4.7 Endometrial intraepithelial carcinoma. This is the precursor lesion for serous carcinoma of the endometrium with markedly atypical, crowded epithelium with little architectural abnormality. This lesion is often observed on the surface of otherwise benign endometrial polyps (hematoxylin and eosin, 1003 original magnification).

or most endometrioid cancers, immunostaining with antibodies to p53 will be positive in the majority of serous cancers. Endometrial hyperplasia is not a precursor to serous carcinoma. Rather, the precursor has been identified as EIC. Serous EIC (Fig. 4.7) can even be multifocal with disease found in the ovaries, fallopian tubes, and peritoneal cavity when no invasive component is found in the uterus. Comprehensive surgical staging is recommended because of the difficulty in establishing the diagnosis of invasive cancer intraoperatively. Postoperative therapy can be recommended after adequate histologic evaluation.

CLINICAL PRESENTATION

Figure 4.6 p53 Immunostain of endometrial intraepithelial carcinoma. Endometrial serous carcinoma is typically accompanied by p53 mutations that allow accumulation of p53 protein in the cells that can be identified by immunostaining. Normal cells do not stain positively for p53 because the amount of normal protein is below the threshold of the staining test (immunoperoxidase stain for p53 with 3,3'-Diaminobenzidine [DAB] chromogen, 2003 original magnification).

Women with EIN have a similar clinical presentation to those who have endometrial cancer with respect to symptoms. Preand perimenopausal women may present with irregular menses or oligomenorrhea consistent with a pattern of anovulatory cycles. Postmenopausal women may present with postmenopausal bleeding or an incidentally found thickened endometrial stripe. EIN may also present as atypical glandular cells on cytology in a woman who may or may not be symptomatic, or endometrial cells on cytology in a woman who is not menstruating at the time of cytology collection. Similar to endometrial cancer, investigation of new or unusual bleeding patterns or cytology findings as described previously with endometrial sampling is warranted. There is evidence of exogenous or endogenous unopposed estrogen stimulation of the endometrium in most women with EIN, although EIN may be related to other factors. The most common causes of excess estrogen are obesity, polycystic ovarian disease, or a prolonged perimenopause with anovulatory bleeding patterns. Other rarer causes of estrogen excess include ovarian sources (such as an estrogen producing ovarian tumor) or adrenal causes. The classic presentation of a granulosa cell

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

tumor of the ovary is a solid ovarian mass associated with abnormal uterine bleeding. Approximately 4% to 6% of endometrial cancers may be due to an underlying hereditary cause, with Lynch syndrome accounting for the majority of these cases. Patients with Lynch syndrome have also been documented to have EIN alone and in association with cancer at the time of diagnosis. Previous studies suggest that Lynch syndrome–associated endometrial cancers appear to follow a similar stepwise continuum from EIN to cancer as that of sporadic cancers; however, the distinct molecular steps may be different for the two tumor types. Patients with Cowden syndrome carry a germline pathogenic variant in PTEN and are also at an increased lifetime risk for endometrial cancer. Given that PTEN somatic variants were the most common alteration seen in endometrial cancers in the Cancer Genome Atlas, it is no surprise that women born with a germline pathogenic variant in this gene are at an increased lifetime risk of endometrial cancer. Whether there is the same stepwise progression in these patients is largely unknown. Office endometrial biopsy has replaced the D&C procedure for the diagnosis of endometrial hyperplasia or carcinoma; however, consideration of D&C is still recommended when considering conservative management to ensure accurate diagnosis. Historically, there was thought to be potential benefit of curettage as therapy, as well as providing more tissue for accurate histologic diagnosis. The use of “hormonal curettage” in which medical therapy with progesterone is followed by a withdrawal bleed provides the same benefit without the surgical cost or risk.

MANAGEMENT DECISIONS FOR ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA The patient’s age, desire for fertility, medical comorbidities, and personal preferences play a role in the management of these lesions. Total extrafascial hysterectomy with consideration of bilateral salpingo-oophorectomy (BSO) is generally recommended for women who are postmenopausal without a medical contraindication for surgery given that EIN is commonly found with coexisting cancer at the time of hysterectomy. Premenopausal women who have completed childbearing should also be counseled for hysterectomy, with or without BSO. As previously discussed, the GOG reported that 43% of 306 women who had a community-based diagnosis of AEH on endometrial biopsy and proceeded without medical treatment to hysterectomy had endometrial cancer on final pathology. Although 63% (77 of 123) of the cancers identified were grade I lesions confined to the endometrium, 31% were myoinvasive, and 11% had deep myometrial invasion into the outer 50% of the myometrium. It is possible that future validation of a new EIN scoring system or another molecular marker will allow more precise predictability for the neoplastic potential of EIN and the coexistence of cancer before hysterectomy. For the purpose of discussion of the available evidence, the nomenclature used in the particular trial will be discussed, recognizing the preferred classification now is EIN. The complexity of the surgical management of EIN is underappreciated. The recommendation is that the patient should

109

be informed of the increased risk of underlying malignancy and hysterectomy is required for the final diagnosis. The patient should also be counseled regarding ovarian retention or oophorectomy based on her age, family history, and other medical conditions or comorbidities. Intraoperative frozen section may be used to help guide the decision for oophorectomy; however, even with a diagnosis of invasive endometrioid adenocarcinoma of the uterus, the risk of adnexal metastasis is low at 5%. Genetic counseling and testing for Lynch syndrome may also be reasonable as a factor to consider in this decision-making process. For the vast majority of patients with EIN, lymphadenectomy and complete surgical staging results in overtreatment and increased surgical risk. Endometrial cancers associated with EIN are usually low-grade, early-stage lesions with a low risk of lymphatic metastasis. Sentinel lymph node mapping has become standard of care in the surgical staging of endometrial cancers and previous retrospective studies have evaluated routine sentinel lymph node mapping in AEH. Touhami and colleagues reviewed 120 patients with AEH who underwent surgical staging with hysterectomy and sentinel lymph node mapping. Overall, 53% of patients were found to have endometrial cancer on final pathology and the majority of cases had stage IA disease. No patients with AEH had positive lymph nodes. The authors concluded that sentinel lymph node mapping can safely be omitted for patients with AEH only and no preoperative findings concerning for invasive carcinoma. The risk of a high-risk uterine cancer in women with a biopsy of EIN ranges from 5% to 7%. In the event that high-grade cancer or deep myometrial invasion is found on final pathology that was not seen on frozen section or frozen section was omitted, reoperation may be offered for comprehensive surgical staging and removal of retained ovaries. Staging can usually be accomplished minimally invasively. This should be necessary in approximately 15% of the cases when cancer is identified and depends on the entire health history of the individual. Staging based on intraoperative assessment of myometrial invasion and grade of tumor is an appropriate strategy for institutions experienced in this approach. Supracervical hysterectomy, morcellation, and endometrial ablation are unacceptable for treatment of AEH because of the high prevalence of occult endometrial cancer in these patients. Women who desire childbearing, refuse hysterectomy, or are medically inoperable can be treated hormonally with systemic progesterone therapy or a levonorgestrel-releasing intrauterine device. Although there are no evidence-based guidelines to outline ideal candidates for conservative management with hormonal therapy for EIN specifically, National Comprehensive Cancer Network (NCCN) does outline candidates for con servative management options for endometrial cancer (Version 1.2021), and these recommendations can be extrapolated for EIN. The diagnosis of EIN should be made on a D&C specimen to ensure adequate sampling of the endometrium and should be confirmed by expert pathology review. The American College of Obstetrician and Gynecologists (ACOG) Committee Opinion on Endometrial Intraepithelial Neoplasia (Number 631 May 2015) goes further to recommend consideration of hysteroscopy

110

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

with D&C to include any discrete lesions as well as the background endometrium to ensure accurate diagnosis. For lowgrade endometrial cancer, imaging with pelvic ultrasound or pelvic MRI is recommended to rule out myoinvasive disease. While there are not specific recommendations for EIN, transvaginal ultrasound is frequently performed during clinical evaluation of these patients. In 2012, a systematic review identified 391 subjects from 45 studies with hyperplasia or grade 1 endometrial cancer who desired fertility and were treated with progestins. Seventy-eight percent of patients demonstrated a response to therapy with 53% of patients demonstrating a durable, complete response. The complete response rate was significantly higher for those with hyperplasia at 65% than for those women with carcinoma (48%). Systemic progesterone therapy in the form of Megestrol 160 mg/day, in divided doses, has shown moderate success in the treatment of CAH with a response rate of 75% to 85%. Compliance with systemic progesterone therapy may be impaired by adverse effects of the treatment. Most commonly noted side effects that lead to decreased compliance include irregular vaginal bleeding, nausea, and weight gain, a particularly difficult treatment-related issue in an already obese patient population. Indeed, a recent qualitative analysis of cancer patients showed that almost half of patients reported nonadherence to oral anticancer regimens, including hormonal therapies. Side effect management emerged as one the key topics for non-adherence to oral medication. Local therapy of the endometrium with a levonorgestrelreleasing intrauterine device has emerged as the preferred management strategy for most patients and has been evaluated in both the retrospective and prospective setting. In a multicenter randomized trial in Norway, 170 women with endometrial hyperplasia were randomized to one of three treatment arms: levonorgestrel intrauterine system (LNG-IUS), oral MPA 10 mg administered 10 days per cycle, or continuous oral MPA 10 mg/day for 6 months. At the end of 6 months, women in all treatment regimens showed significant therapeutic response, but the highest numbers of responders were noted in the LNG-IUS group (100%) and the continuous MPA group (96%) compared with the cyclical MPA group (69%). Gallos et al. reported a 12-year comparative cohort study of 344 patients with endometrial hyperplasia who received conservative management with progestins for complex or AEH because of desire for fertility or who were medically unsuitable for surgery. For the group of women treated with LNG-IUS (n 5 250), 94.8% achieved regression of hyperplasia compared with 84% of women treated with oral progestins. Of note, the patients with a body mass index of 35 or greater were most likely to have a relapse of hyperplasia or fail to regress to a normal endometrium. Pal and colleagues reported an 80% response rate with a levonorgestrel-releasing intrauterine device (IUD) in patients with CAH. In this cohort, body mass index (BMI) was not related to response to IUD; however, increased uterine size was a marker of non-response. Most recently, a phase II prospective trial of the levonorgestrel IUD in women with CAH and earlystage endometrial cancer reported a response rate of 90.6% in

patients with CAH with a primary endpoint of pathologic response at 12 months. Importantly, quality of life was not significantly negatively affected. From a pathologic standpoint, the majority of responders had evidence of progesterone effect on biopsy by 3 months, while only 25% of non-responders demonstrated pathologic progesterone effect. An important focus of future studies includes identifying markers for non-response to progesterone therapy in EIN and endometrial carcinoma, and several prospective studies are ongoing to evaluate whether the addition of other targeted therapies may improve response rates in this patient population. It is interesting to note that older (postmenopausal) women are less likely to respond to progesterone therapy. In one retrospective study of 41 postmenopausal women with AH and endometrial cancer who were treated with the levonorgestrel IUD, a complete response was noted in only 50%. Additionally, 4 of 18 patients with a complete response later experienced relapse of hyperplasia or cancer. It is important to discuss with patients that frequent followup visits and resampling are needed with hormonal management to ensure response to therapy. There are no evidence-based guidelines for frequency and length of surveillance with hormonal therapy in EIN; however, there is consensus that regular sampling for at least the first year is needed in order to document response and follow-up schedule can again be extrapolated from NCCN guidelines for low-grade endometrial cancer (Version 1.2021). In general, response to hormonal therapy is seen by 6 months of treatment. Endometrial evaluation every 3 to 6 months with endometrial biopsy or D&C is recommended. If there is complete response by 6 to 12 months, conception is encouraged with continued progestin therapy recommended if the patient is not planning to actively try to conceive. In general, if hormonal therapy is utilized for fertility sparing indication, then completion hysterectomy, bilateral salpingectomy with or without oophorectomy should be considered after childbearing is complete. If there is no response at 6 to 12 months of hormonal therapy on pathologic review, hysterectomy should be considered for medically operable patients. Lifelong prevention strategies must be emphasized with patients and the diagnosis of EIN allows for important counseling on risk reduction. In conclusion, management decisions in women with EIN are complex and require an understanding of the risk of invasive endometrial adenocarcinoma, the reproductive desires of the patient and her comorbidities, and the risks for surgical management. Ideally, minimally invasive techniques can be used to complete hysterectomy with BSO. The finding of adenocarcinoma in the uterus requires consultation with a gynecologic oncologist to determine whether observation, reoperation for surgical staging, or adjuvant therapy based on uterine factors should be considered.

MANAGEMENT OF ENDOMETRIAL HYPERPLASIA WITHOUT ATYPIA The diagnosis of simple or complex hyperplasia without atypia, now collectively referred to as hyperplasia without atypia, requires hormonal management and is not an indication for

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

TABLE 4.2 Hormonal Treatment for

Endometrial Intraepithelial Neoplasiaa Hormonal Agent

Dosage and Length

Medroxyprogesterone acetate

10–20 mg/day or cyclic 12–14 days/month

Depot medroxyprogesterone

150 mg intramuscularly every 3 months

Micronized vaginal progesterone

100–200 mg/day or cyclic 12–14 days/month

Megestrol acetate

40–200 mg/day

Levonorgestrel intrauterine system

52 mg in steroid reservoir over 5 years

Previously known as atypical endometrial hyperplasia.

Modified from Committee on Gynecologic Practice, Society of Gynecologic Oncology. Endometrial intraepithelial neoplasia. ACOG Committee Opinion No. 631: American College of Obstetricians and Gynecologists, Obstet Gynecol 125(5):1272–1278, 2015 and Trimble CL, Method M, Leitao M, et al: Management of endometrial precancers. Society of Gynecologic Oncology Practice Committee, Obstet Gynecol 120: 1160–1175, 2012.

hysterectomy. These lesions are generally reversible with progestogen (synthetic progestin or progesterone). The classification of progestogens is seen in Table 4.2. Progestins may be given cyclically or continuously. Women, including teenagers, who are premenopausal and sexually active, are usually best treated with a regimen that provides contraception such as Depo-Provera or oral contraceptives. Women who want to conceive are likely to be anovulatory and require ovulation induction agents after withdrawal bleeding is produced with a progestogen. Reassurance can be obtained from a reduction of menstrual flow and a bleeding pattern that is appropriately timed with the cyclic therapy. It is extremely important to counsel anovulatory women about the lifelong risk of endometrial cancer and methods for surveillance and prevention. Twenty-five percent of endometrial cancers occur in the premenopausal age range, and 5% are in women 40 years of age and younger. These cancers may be part of the PCOS or the anovulatory transition before menopause, and are all theoretically preventable with proper counseling and active management. There is a dramatic rise in the incidence rate of endometrial hyperplasia and endometrial cancer at 45 years of age and peaking at 65 years of age. This is likely because of the combined effects of estrone (estrogen) production in the peripheral adipose tissue, particularly in obese women, and to the absence of progesterone that is caused by the loss of ovulatory function in menopause.

PREVENTION OF ENDOMETRIAL CANCER In premenopausal women, use of progestin containing contraception decreases risk for EIN and endometrial cancer, due to suppression of endometrial proliferation. Combined oral contraceptive pill (OCP) use is associated with a decreased lifetime risk of endometrial cancer with a 30% to 50% risk reduction in large epidemiologic studies. In addition, progestin-only contraception, including oral progestins, depot medroxyprogesterone acetate (depo-MPA), and

111

progestin containing implants decrease incidence of endometrial cancer by as much as 80%. In Lynch syndrome, progestin use, with both depo-MPA and OCPs, has been shown to have tissue effect in a prospective intermediate biomarker study. In Lynch patients treated with 3 months of hormonal therapy, there was a decrease in endometrial epithelial proliferation and microscopic changes in the endometrium seen with progestin response. In postmenopausal women, endometrial stimulation by estrogens unopposed by progestins leads to endometrial hyperplastic conditions in a dose- and time-dependent manner. Experimental evidence has been obtained from prospective clinical trials conducted to identify the appropriate doses and schedules of hormone replacement therapies. Kurman reported a randomized trial of 1176 postmenopausal women receiving 1 mg of estradiol orally and either placebo or various doses of norethindrone acetate. Women treated with estradiol alone (247 evaluable participants) for 12 months had a 12.2% rate of simple hyperplasia without atypia, 1.6% had complex hyperplasia without atypia, and 0.8% had CAH. Norethindrone acetate at all doses used in this trial nearly eliminated that risk. The North American Menopause Society supports the addition of a progestogen whenever estrogen is prescribed for menopausal symptoms in women with an intact uterus for the prevention of estrogen-induced hyperplasia and adenocarcinoma. Unfortunately, progestogen has undesirable side effects, and women have been known to discontinue this component of their prescribed hormone replacement (see Table 4.2). The prevention of endometrial cancer has been complicated by the publication and early closure of the estrogen plus progestin (E 1 P) component of the Women’s Health Initiative (WHI). However, the WHI trial with conjugated equine estrogen (CEE) alone versus placebo had a very different outcome. There was a nonsignificant reduction in breast cancer risk (P 5 .06), and the cardiovascular heart disease (CHD) risk was unaffected (hazards ratio [HR], 0.91; confidence interval [CI] 0.75 to 1.12), strokes were increased (HR, 1.39; CI 1.10 to 1.77), and hip fractures were reduced (HR, 0.61; CI 0.41 to 0.91). This places women with intact uteruses and their physicians in a difficult situation of balancing the risks. Unopposed estrogen use gives a woman a relative risk (RR) of endometrial cancer of three times the general population for less than 5 years of use and RR of 10 after 10 years of use. The risk decreases but remains elevated after discontinuing the drug. Alternatively, other progestins and progesterone formulations are available that may carry a different but as yet unknown risk of breast cancer. Micronized progesterone is available as oral 100- or 200-mg capsules (Prometrium) and has been approved by the FDA for use in combination with estrogen for relief of menopausal symptoms. The dosage of 200 mg for 12 days/month in a cyclic fashion causes withdrawal bleeding in a predictable manner. The regimen of CEE 0.625 mg/day with oral micronized progesterone at a dose of 200 mg/day for 12 days/month failed to see any increase in endometrial hyperplasia with 3 years of follow-up. A vaginal progesterone gel is available that is only FDA approved for infertility use but has been studied in small numbers of menopausal women. An additional

112

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

alternative is to use the LNG-IUS (Mirena is FDA-approved for contraceptive use only) and unopposed estrogen, which has been studied prospectively in menopausal women. These women were only followed for 1 year, and they were able to convert proliferative endometrium to atrophic endometrium while using continuous estradiol 50 mcg/day via the transdermal route. The official position statement of the North American Menopause Society is that a progestogen should be added to estrogen therapy for all postmenopausal women with intact uteruses. The type, route, or regimen can be individualized to minimize side effects while providing adequate endometrial protection. Further discussion of hormone replacement therapy is discussed at length later. For both premenopausal and postmenopausal women, obesity remains one of the most important and modifiable risk factors for EIN and endometrial cancer. Indeed, women with class III–IV obesity with a BMI of at least 40 kg/m2 have a tenfold increased lifetime risk of endometrial cancer with a known increase in obesity-related premenopausal endometrial cancer cases in recent years. Lifestyle counseling and interventions are an important part of endometrial cancer prevention in this patient population; however, lifestyle changes remain one of the most difficult interventions to employ. A prospective randomized biomarker study of metformin and lifestyle intervention for the prevention of endometrial cancer in obese women demonstrated this, as 576 women were approached and only 52 patients attended the initial screening and 26 patients completed the study. This prospective evaluation showed significant decrease in weight with lifestyle intervention, but not metformin alone. In addition, there was no significant change in endometrial proliferation with either intervention, but overall initial proliferation rates were low. Bariatric surgery may be indicated for some patients and prospective evaluation shows that weight loss associated with bariatric surgery led to resolution of atypical hyperplasia both with and without progestin therapy in patients who had abnormal endometrial pathology prior to bariatric surgery. MacKintosh and colleagues prospectively evaluated patients with endometrial biopsy prior to and following gastric bypass. Six of 72 women enrolled had atypical hyperplasia at enrollment and prior to bariatric surgery. Five patients had resolution of atypical hyperplasia at 12 months following surgery. In addition, weight loss with bariatric surgery was associated with a molecular response in the endometrium with decrease in endometrial proliferation, oncogenic signaling, and hormone receptor expression. Lastly, there were decreases in circulating biomarkers of insulin resistance and inflammation. It is clear that obesity and excess circulating estrogen increases the risk for EIN and endometrial cancer; however, the interplay with other molecular factors are still largely unknown. Further studies are needed to better understand the molecular markers for potential risk of progression to EIN and cancer in obesity in order to better address prevention strategies moving forward. In addition, a collaborative, multi-specialty approach is needed in lifestyle interventions including dieticians, psychotherapy, and bariatric surgery for improved engagement and success for lifestyle interventions.

BENEFITS AND RISKS OF MENOPAUSAL HORMONE THERAPY Menopausal HT remains the gold standard for relief of menopausal symptoms (hot flashes, night sweats, and sleep disruption); reduction of bone loss and osteoporotic fracture risk; and, when used locally, relief of genitourinary syndrome of menopause (vaginal atrophy, urinary symptoms). Menopausal symptoms can be long lasting. As an example, vasomotor symptoms were shown in a longitudinal US study (SWAN) to last a median of 7.4 years, with ethnic variation from 5 years for Asians, 7 years for Caucasians, 9 years for Hispanics, and 10 years for African American women. HT is felt to have the most benefits in symptomatic healthy women initiating HT when under age 60 or within 10 years of menopause onset. In general, initiating systemic HT in women who are older than 60 years is not recommended. HT is generally recommended for 3 to 5 years or to consider discontinuation by around the age of 60. Risks of HT appear to vary depending on type, dose, duration, route of administration; the timing of initiation, and whether a progestogen is needed. Progestogens protect against endometrial hyperplasia and cancer that can occur from chronic unopposed exposure to estrogens. Estrogen therapy used alone is recommended for women who have had a hysterectomy, whereas combined estrogen-progestogen therapy is needed for women with an intact uterus. When combined with estrogen therapy, progestogens are given either sequentially or continuously. Sequential treatment typically results in withdrawal bleeding similar to a menstrual period, whereas continuous progestogen therapy eventually leads to cessation of bleeding. Women with cancer, and those who are at risk for cancer, require a complex evaluation of the risks and benefits of hormonal therapy at the time of natural or induced (surgically or medically) menopause. These women may also consider alternatives to hormones for symptom management and prevention of osteoporosis and heart disease. The data describing risks, benefits, and alternatives for all menopausal women in general and women with or at risk for gynecologic or breast cancers are discussed in the following sections.

Hot Flashes Although the underlying physiology leading to vasomotor symptoms (hot flashes, night sweats, sleep disturbances) remains incompletely understood, abnormal functioning occurs in the thermoregulatory nucleus of the hypothalamus which regulates perspiration and vasodilatation. Core body temperature is normally maintained in a regulated range, called the thermoregulatory zone. It is hypothesized that women who experience more severe vasomotor symptoms have a narrower thermoregulatory zone than those without symptoms; minimal changes in core body temperature may lead to hot flashes or cold chills. Various hormones and neurotransmitters modulate hot flush frequency. Of these, estrogens play a vital role. Hot flashes are characterized by a sudden increase of blood flow, often to the face, neck, and chest that may last 1 to 5 minutes, associated with the sensation of extreme heat or sweating,

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

and may cause significant sleep disruption leading to fatigue and mood disturbances. Although approximately 75% of women have hot flashes, only 25% are bothersome enough for women to seek treatment. HT remains the most effective treatment for hot flashes. In a meta-analysis of 24 randomized controlled trials with over 3000 women combined, a 75% reduction in hot flashes was found with estrogen alone or combined with progestin compared to placebo. The use of non-hormonal treatments for hot flashes and vaginal dryness is discussed in depth later.

Critical Assessment of Risk/Benefit Ratio of Hormone Therapy: The Women’s Health Initiative Data Early observational studies suggested protection of cardiovascular disease (CVD) and dementia with the use of HT. However, in 2002, the first findings from the large randomized controlled trial, the WHI, found hormone replacement increased the risk of CVD, blood clots, stroke, and breast cancer, with more dementia found in the trial of women over age 65. Both the estrogen/progestin trial and the estrogen alone trials were stopped early to prevent possible harm. The combined therapy trial (estrogen-progestin therapy EPT], CEE with 2.5 mg of medroxyprogesterone acetate) was stopped at a median of 5.6 years when excess risks were found annually of coronary heart disease events of 0.6/1000 women, stroke 0.9/1000 women, and breast cancer 0.9/1000 women. The estrogen alone trial (ET, CEE 0.625 mg) for women without a uterus was stopped at median 7.2 years due to increased risk of stroke annually of 1.2/1000 women over placebo with no cardiovascular benefit seen. Subsequent post hoc analyses based on age and time from menopause onset found a higher risk of CHD and stroke in women who initiated HT after age 60, with more risk if starting after age 70. No increased risk of CHD or stroke was seen for those starting under age 60 or within 10 years of menopause onset, with a nonsignificant decrease in CHD for the estrogen alone group. To explore the timing of HT initiation among WHI participants, Rossouw and colleagues looked specifically at the effect of HT on stroke and CHD rates across categories of age and years since menopause in the combined (EPT plus ET) trial. Women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause. In evaluating data by age, for the age group of 50 to 59 years, the hazard ratio for CHD was 0.93, or two fewer events per 10,000 person years; for the age group 60 to 69 years, 0.98 or 1 fewer event per 10,000 person years; and for those 70 to 79 years, 1.26 or 19 extra events per 10,000 person years. HT increased the stroke risk— the hazard ratio was 1.32—and this risk did not vary significantly by age or time since menopause. Evidence is insufficient to determine that either ET or EPT should be initiated or continued for primary or secondary CHD prevention. The 2013 ACOG committee report, reaffirmed in 2016, recommended that HT should not be used for the primary or secondary prevention of CHD, but rather women should be

113

prescribed estrogen or estrogen plus a progestogen (when a uterus is present) at the onset of moderate or severe menopausal symptoms. The dose should be the lowest necessary to achieve the symptom control desired, and the duration of therapy should be 5 years or less. However, they recommended against routine discontinuation at age 65; instead, individual consideration of risks and benefits. The risks of venous thromboembolic disease (VTE) are doubled when oral estrogen is used, with less risk if transdermal therapy is used and/or if lower doses are prescribed. Fewer cases of type 2 diabetes were seen in the treated groups in the WHI. An increased risk of dementia was seen in women in the WHI who were age 65 or older. Post hoc analysis with long-term follow up did not show any increased risk of loss of cognition in women who started therapy between the ages of 50 to 59. In the randomized controlled ELITE trial (Early versus late postmenopausal treatment with estradiol) of 643 postmenopausal women who received either 1 mg estradiol plus 45 mg progesterone gel sequentially for 10 days each cycle with uterus or placebo, oral estradiol therapy showed less progression of subclinical atherosclerosis (measured as carotid artery intima media thickness or CIMT) than those on placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. These findings support the “timing hypothesis” of cardiovascular benefit and a possible cognitive benefit if HT is started closer to menopause onset (within 10 years) or when women are less than age 60. The lower absolute risks for younger women suggest that younger symptomatic women are most likely to have benefits exceed risks for menopausal HT. Cumulative 18-year follow up of WHI participants (off therapy) found that all-cause mortality, cardiovascular, and total cancer mortality were similar between the HT and placebo groups. Breast cancer mortality at 18 years was elevated (HR 1.44) in the CEE/MPA group, which was statistically a nonsignificant increase, while a significant reduction in breast cancer mortality (HR 0.55) was noted in the CEE-alone group. A significant reduction (HR 0.85) in mortality from Alzheimer disease or dementia was seen with use of HT.

Cardiovascular Disease and Stroke CVD risk factors for women include nonmodifiable risk factors such as age and family history of CVD. Modifiable risk factors include hypertension, dyslipidemia, obesity, diabetes/glucose intolerance, smoking, poor diet, and lack of physical activity. Vasomotor symptoms have been linked to indices of subclinical CVD; however it is not clear if vasomotor symptoms are markers for CVD or have a causative effect on CVD. Early menopause before the age of 50 has been shown to increase the risk of CVD with those under age 40 found to be twice as likely to have a cardiovascular event before the age of 60. Interpersonal violence, such as survivors of intimate partner violence, sexual abuse or assault, or human trafficking, has an association with increased risk of heart disease and should be considered when identifying risk factors for CVD. Cardiovascular risk reduction recommendations include smoking cessation, exercise, and weight control along with

114

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

blood pressure (BP) and cholesterol management. A healthy diet should be recommended, preferably plant-based or Mediterranean-like diet, high in vegetables, fruits, nuts, whole grains, lean vegetable or animal protein (preferably fish), and vegetable fiber. Central fat distribution, i.e., truncal obesity, correlates positively with increases in total cholesterol, triglyceride, and low-density lipoprotein (LDL) cholesterol levels, and negatively correlates with HDL (protective) levels. More than 5% weight loss has been shown to improve BP, LDL-C, triglycerides, and glucose levels among obese or overweight individuals, and to delay the development of type 2 diabetes. Physical activity of 150 minutes/week of moderate intensity or 75 minutes/week of vigorous intensity is recommended, along with strength training. After menopause as estrogen levels decline, HDL levels decrease and total cholesterol levels increase, leading to a doubling of the risk of CHD for women by age 60. Dietary modification and statin therapy (when needed) can reduce LDL levels leading to a reduction in CVD. Women who smoke should be strongly advised to quit with consideration of behavioral modification, nicotine replacement, or other drug treatments. Aspirin is not recommended for primary prevention of heart disease in women less than 65 unless health benefits are judged to outweigh risks. Aspirin lowered the risk of stroke by 17% (RR, 0.83; CI 0.69 to 0.99; P 5 .04) in a RCT of 39,876 healthy women aged 45 or older who received 100 mg or aspirin or placebo on alternate days for 10 years. Benefit in prevention of myocardial infarction was only found in women aged 65 years of age and older at enrollment (RR, 0.66; CI 0.44; 0.97; P 5 .04). The American College of Cardiology 2019 recommendations suggest considering low-dose aspirin for primary prevention only for higher-risk women ages 40 to 70 years who are not at increased bleeding risk and not to start or use it routinely for primary prevention or for those aged over 70 years or if there is an increased risk of bleeding regardless of age.

Cardiovascular Disease and Cancer Risk Cardiotoxicity can develop during or after cancer treatment. Heart damage caused by chemotherapy-induced cardiotoxicity has been shown to reduce quality of life and increase the risk of death from cardiac-related causes. Potential causes include chemotherapy, radiation therapy to the chest due to the proximity of the heart and lung to the radiation field, molecular therapy, monoclonal antibodies, and drugs used to prevent cancer recurrence. Congestive heart failure is the most serious cardiotoxicity related to cancer treatment, while pericarditis (inflammation of the heart muscle) and coronary artery disease can occur. Less commonly, changes in BP (low or high), or arrhythmias or valvular disease can occur. Women who have additional cardiovascular risk factors appear to be at highest risk including those with history of smoking, obesity, high fat diet, sedentary or inactive lifestyle, or family history of heart disease. The largest study used the Surveillance, Epidemiology and End Results (SEER) database looking at deaths from CVD (including CHD, hypertension, cerebrovascular disease, blocked arteries, and damage to the aorta). Analyses were

adjusted for age, race and sex, looking at 28 different types of cancer. Among the 3,234,256 cancer patients, 38% (1,228,328) died from cancer and 11% (365,689) died from CVD—76% due to heart disease. The risk of dying from CVD was highest in the first year after a cancer diagnosis and for patients younger than 35 years. The majority of CVD deaths occurred in patients with cancers of the breast (a total of 60,409 patients) and prostate (84,534 patients), as these are among the most commonly diagnosed cancers. In 2012, 61% of all cancer patients in the study who died from CVD were diagnosed with breast, prostate, or bladder cancer. The proportion of cancer survivors dying from CVD was highest in bladder (19% of patients), larynx (17%), prostate (17%), womb (16%), bowel (14%), and breast (12%). Those who died were more likely to have the most aggressive and hardto-treat cancers including cancers of the lung, liver, brain, stomach, gallbladder, pancreas, esophagus, ovary, and multiple myeloma. Thus cancer survivors from breast, larynx, skin, Hodgkin lymphoma, thyroid, testis, prostate, endometrium, bladder, vulva, and penis were about as likely to die of cardiovascular diseases as to die of their initial cancer. A second study, the Framingham Heart Study, evaluated data over 15 years from 12,712 participants (average age 51) without CVD or cancer at study initiation. The American Heart Association/American College of Cardiology’s Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator and biomarkers were used to measure cardiovascular risk. During the study 1670 cancer cases were identified (19% gastrointestinal; 18% breast; 16% prostate; 11% lung). Increased risk of CVD factors of age, sex, hypertension, and smoking were independently associated with cancer. Those with a 10-year ASCVD risk of 20% or higher were more than three times as likely as those with 10year ASCVD risk of 5% or lower to develop any type of cancer. Those who developed CVD (myocardial infarction, congestive heart failure, or atrial fibrillation) had a 7-fold increased risk for subsequent cancer while those with elevated brain natriuretic peptide (BNP) were more likely to get cancer than participants with low levels of BNP. Increasing awareness of these risks will hopefully lead to healthier lifestyle behaviors by cancer survivors and increased awareness by their providers about their increased risk of CVD, particularly if cancer survivors have underlying risk factors for CVD.

Osteoporosis Osteoporosis is a disease characterized by low bone mass, microarchitectural deterioration of bone tissue, and a decline in bone quality leading to increased bone fragility and risk of fractures, particularly of the spine, hip, shoulder, and wrist. Peak bone mass occurs before the age of 30, then begins to decrease around age 45. Menopause induces an accelerated bone loss, followed by a slower rate of bone loss. Within the first 5 years of menopause, women can lose up to 20% of bone mineral density (BMD) and up to 30% by age 80. Risk factors for osteoporosis (Table 4.3) include low body weight, history of eating disorder or prior gastric bypass, advancing age, either parent with prior hip fracture, history of smoking or excess alcohol, some long-term medications such as corticosteroids

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

115

TABLE 4.3 Medications and Medical Conditions Associated with Bone Loss or Fracture Risk Medications Medications Associated with Bone Loss Glucocorticoids for .3 months Heparin long-term high-dose therapy, possibly warfarin, low-molecularweight heparins less likely Excess thyroid hormone supplementation/thyroid-stimulating hormone oversuppression Immunosuppressive agents (e.g., cyclosporine) Gonadotropin-releasing hormone agonists or antagonists Anticonvulsants: phenytoin, phenobarbital, carbamazepine, and primidone Cytotoxic agents: methotrexate, Ifosfamide, Imatinib Intramuscular medroxyprogesterone after 2 years Aromatase inhibitors Excess Vitamin A Increased Risk of Fracture in Observational Studies Proton pump inhibitors and H2 blockers Thiazolidinediones used for diabetes SGLT2-inhibitors Insulin with hypoglycemia Selective serotonin-reuptake inhibitors Selective norepinephrine-reuptake inhibitors Tricyclic antidepressants Antiretroviral therapy (HIV) Medications Which Minimize Bone Loss Thiazide diuretics Estrogen Selective estrogen receptor modulators (SERMS) Possibly Statins and Betablockers

Nutritional Disorders Eating disorders/female athlete triad Weight loss/malnutrition Vitamin D deficiency, Chronic renal disease Hypercalciuria Gastrointestinal Diseases Malabsorption syndromes: celiac disease Inflammatory bowel disease Chronic liver disease: biliary cirrhosis Autoimmune Disorders Rheumatoid arthritis Ankylosing spondylitis Multiple sclerosis Lupus Hematologic Disorders Systemic mastocytosis, sickle cell disease Hematological malignancies: lymphoma, leukemia, multiple myeloma Medical Procedures Associated with Bone Loss Gastric bypass, Gastrectomy Solid organ transplant Others Stroke Parkinson disease Polio Spinal cord injuries Frailty

Medical Conditions Genetic Disorders Osteogenesis imperfecta Hypophosphatasia Thalassemia Hemochromatosis Endocrinologic Disorders Ovarian insufficiency Type 1 and type 2 diabetes mellitus Hyperthyroidism/thyrotoxicosis Primary hyperparathyroidism Hypercortisolism, Cushing syndrome Low levels of estrogen/early menopause Source: National Osteoporosis Foundation. www.nof.org; https://www.nof.org/patients/what-is-osteoporosis/accesed 12-230-2020.

or aromatase inhibitors, and medical problems such as rheumatoid arthritis. Postmenopausal women $50 years but less than 65 years of age should undergo clinical assessment for osteoporosis and fracture risk, including a detailed history and physical examination including height measurement, and assessment of osteoporosis risk factors. Measurement of bone density should be considered for those with significant risk factors including those with prior fragility fractures, use of significant amounts of cigarettes or alcohol, and certain medical conditions or medications associated with bone loss. For postmenopausal women aged 65 and older, screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures is recommended.

The National Osteoporosis Foundation and the North American Menopause Society recommend that BMD be considered in the following groups of postmenopausal women: • with a history of fracture since menopause • with known medical causes of bone loss or fracture, regardless of age • age 65 and older, regardless of clinical risk factors • age 50 and over with one or more of these additional risk factors • body weight less than 127 lb. [57.7 kg] or BMI less than 21 kg/m2 • history of hip fracture in a parent • current smoker • alcohol intake of more than two units per day • discontinuing estrogen with additional risk factors for fracture

116

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

Additional risk factors to consider include early menopause whether induced, surgical, or due to primary ovarian insufficiency, without the use of estrogen to age of natural menopause. A chronic daily dose of prednisone of $5 mg is considered the threshold for assessment and clinical intervention to prevent or treat glucocorticoid-induced osteoporosis. Commonly used medications associated with bone loss include anticonvulsants (phenytoin), anticoagulants, chemotherapeutic drugs, gonadotropin releasing hormone agonists, depo medroxyprogesterone acetate, cyclosporine A, tacrolimus, lithium, and aromatase inhibitors. The most common test used to identify loss of bone quantity and assess risk of fracture is a dual energy x-ray (DEXA) machine, which measures bone density, usually at the lumbar spine and hip although the radius can be used. Two scores are provided, a T-score and a Z-score: • A T-score, used for the postmenopausal population, compares current BMD to the mean peak BMD in a normal, young-adult female population, expressed in standard deviation (SD) units. The reference database is White women. Degenerative arthritis in lumbar spine can lead to false positive due to increased density. • A Z-score, preferred for premenopausal women and useful to identify concern about secondary osteoporosis which requires evaluation, compares the BMD to the mean BMD of a reference population of the same sex, age, and ethnicity, expressed in SD units. Although bone density is not routinely recommended for premenopausal women, a low Zscore on DEXA or fragility fracture should lead to further evaluation. The most widely used assessment tool to calculate fracture risk, valid for postmenopausal women older than 40 years, is the FRAX tool, accessible online, available for multiple countries/ ethnicities and in different languages (http://www.shef.ac.uk/ FRAX/. The FRAX algorithm uses multiple clinical risk factors (sex, age, height, weight, prior fracture, parental history of hip fracture, use of steroids, cigarette and alcohol intake, presence of rheumatoid arthritis or other secondary causes of bone loss) and (optionally) the BMD at the femoral neck (hip) to estimate the risk of fracture. A 3% risk of hip fracture or a 20% risk of a major osteoporotic fracture within the next 10 years should lead to consideration of treatment to prevent fractures. Data from the Third National Health and Nutrition Examination Survey (NHANES III) found the highest risk of osteoporosis was among non-Hispanic White and Asian women and lowest among non-Hispanic Black women. Fracture rates do not always correlate with BMD across ethnic groups. For example, Chinese American women typically have lower BMD than White American women, but lower rates of femoral neck and forearm fracture. For a given bone density, fracture risk is much higher in a woman at age 80 than for a woman who is in her 50s. After an osteoporotic fracture occurs, another fracture is five times more likely within the first year; this risk remains elevated over time if no treatment is given. Severe osteoporosis is used to describe women with a T-score below -2.5 with a prior fragility fracture, which is defined as a fracture resulting from a fall from a standing height or lower without major trauma.

Osteoporosis Prevention An inadequate supply of calcium over a lifetime contributes to the development of osteoporotic fractures. Low calcium intake appears to be associated with low bone mass, more rapid bone loss, and higher fracture rates. Exercise appears to decrease fracture risk through improved bone mass during premenopause, by helping prevent bone loss in postmenopausal women, while building stronger muscles and improved balance lowers risk of falls and fractures. Despite controversy about potential cardiac risk from excess supplemental calcium, all women should get lifelong adequate daily amounts of calcium and vitamin D, engage in regular strength training, weight bearing exercise, or exercise against resistance three times per week, avoid smoking and excess alcohol, and minimize risks of falls as they age. Current recommendations are for 1200 mg of calcium/day (as much from diet as possible) and 800 to 1200 IU/day of vitamin D3. Candidates for BMD testing include women age 65 and older, a fragility fracture after age 40 (wrist, vertebral, shoulder, or hip), family history of mother or father with hip fracture, use of systemic glucocorticoid therapy for 3 months or longer, and increased risk or history of falls. Low BMD and presence of prior fragility fracture are the most significant risk factors for predicting future osteoporotic fractures. Breast cancer survivors are considered at higher risk for osteoporosis due to potential for early surgical or induced menopause, and the use of aromatase inhibitors leading to significantly lowered estrogen levels. In addition to calcium, vitamin D, and strength building exercise, bone density and/or fracture risk assessment should be offered. Therapy with bisphosphonates (oral or intravenous) or denosumab are recommended for patients with a T-score less than -2.0 SD, a T-score less than -1.5 SD with one additional risk factor, or those with 2 or more risk factors if DEXA is not available. Pharmacologic Therapies and Osteoporosis: Hormones The beneficial effects of estrogen in preventing or treating postmenopausal osteoporosis are well recognized. As estrogen levels decline, bone-remodeling rates increase and favor bone resorption over bone formation. HT has been shown to reduce the rate of bone resorption and results in an increase in BMD. No clear differences in bone density responses have been seen among varying estrogen preparations or routes of administration, although higher doses are more effective at preventing bone loss. In the WHI RCT trials of both women on estrogen alone (conjugated estrogen CEE 0.625 mg/day) and combined with progestin (medroxyprogesterone acetate MPA 2.5 mg/ day), a significant 34% reduction in hip fractures was seen in a healthy low-fracture-risk population. Even lower doses such as oral daily 0.5-mg estradiol, 0.3-mg doses of CEE, or transdermal estradiol patch 0.014 mg/day have been effective at preventing bone loss. Pharmacologic Therapies and Osteoporosis: Selective Estrogen-receptor Modulators Selective estrogen-receptor modulators, SERMs or estrogen agonists/antagonists, are estrogen-like compounds that act as weak estrogen agonists and estrogen antagonists, depending on the

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

particular SERM and the target tissue. The SERM raloxifene (Evista) binds with high affinity to ERs and promotes estrogenlike activity on bone with studies confirming prevention of bone loss and vertebral fracture. Raloxifene at 60 mg/day improved bone density at 3 years by 2.6% at lumbar spine and 2.1% at femoral neck (P , .001) with a significant reduction in new clinical vertebral fractures of 68%. Raloxifene is most appropriate for prevention and treatment of vertebral fractures, as it has not been found to prevent nonvertebral or hip fractures. Similar to estrogen, bone loss resumes when raloxifene therapy is stopped. In addition to its bone effects, raloxifene reduces risk of breast cancer in high-risk women. In postmenopausal women with osteoporosis, raloxifene significantly reduced the overall incidence of invasive breast cancer by 76% after 3 years and 72% after 4 years. In the 4-year extension of the MORE trial, the risk was 59% lower after 8 years of raloxifene therapy, primarily ER positive invasive breast cancer. In the STAR trial (NSABP Study of Tamoxifen and Raloxifene) of 19,747 postmenopausal women (mean age 58.5 years) at increased risk for developing breast cancer, raloxifene was found to be as effective as tamoxifen in reducing the risk of invasive breast cancer among women at high risk of invasive breast cancer. Side effects include an increase in hot flashes of 2 to 3 per day and an increased risk of leg cramps and thromboembolic events; it is thus contraindicated in patients with a history of VTE. Raloxifene has been tested up to 6 months with vaginal estrogen without proliferative effects on endometrium based on transvaginal ultrasound and endometrial biopsy, but in one study when combined with oral estradiol, an increase in endometrial hyperplasia was seen. A review of six studies of combining raloxifene with systemic estrogen showed a benefit on quality of life, treatment satisfaction, and vaginal dryness; however, an increase in endometrial thickness has been reported as soon as 3 months with endometrial proliferation. Two cases were reported with endometrial hyperplasia, both after 24 weeks. Raloxifene prevents osteoporosis for postmenopausal women and may be the best choice for women with an elevated risk of breast cancer, few vasomotor symptoms, and low risk of VTE. It appears to be safe to combine with vaginal estrogen but not with systemic estrogen due to increased cases of endometrial hyperplasia. Tamoxifen is approved for prevention and treatment after breast cancer and decreases the incidence of recurrent breast cancer. Although not approved to prevent bone loss, tamoxifen is a partial agonist in bone with prevention of bone loss in postmenopausal (but not premenopausal) women at the lumbar spine and hip. Although tamoxifen is an antiestrogen in breast tissue, it paradoxically has estrogen-like properties in the endometrium and increases the risk of endometrial cancer. Potential side effects with tamoxifen include an increased risk of endometrial polyps, endometrial cancer (adenocarcinoma of the endometrium and rare reports of mixed mesodermal sarcoma), and an increased incidence of venous thromboembolic events, pulmonary embolism, and stroke in women over 50. The expected annual rate of endometrial cancer in breast cancer patients is 1 per 1000. Patients taking tamoxifen have an excess risk of 2 per 1000 or a total risk of 3 per 1000 per year.

117

The risk of endometrial cancer in postmenopausal tamoxifen users in the STAR trial was RR 2.54, but was higher at RR 5.4 for women over 50, with longer durations of use or prior endometrial thickening before beginning tamoxifen. Tamoxifen use after breast cancer was traditionally for 5 years but may now be extended to 10 years for some women based on new data demonstrating additional benefit. Women taking tamoxifen should be informed about the risks of endometrial proliferation, endometrial hyperplasia, endometrial cancer, and uterine sarcomas. Studies on the appropriate monitoring of women on tamoxifen have demonstrated that transvaginal ultrasonography and routine annual endometrial biopsies increase a woman’s risk due to the procedures. The current recommendation is to “do no harm” by conducting a routine annual gynecologic examination with cervical cytology and inquire about symptoms. Abnormal vaginal bleeding, bloody vaginal discharge, staining, or spotting should be investigated. According to ACOG (Committee opinion 336), unless the patient is at high risk of endometrial cancer, routine endometrial surveillance has not proved to be effective in increasing the early detection of endometrial cancer in women using tamoxifen and is not recommended. If AEH or neoplasia develops, appropriate gynecologic management should be instituted, and the use of tamoxifen should be reassessed. The effect of tamoxifen on the vagina is mixed with some estrogenic effects but also adverse reports of dyspareunia, leucorrhea, or vaginal dryness. Hot flashes are reported but were only bothersome enough to seek treatment in a small percentage. There does appear to be an association with cataracts. Ospemifene is a SERM which is FDA approved for the treatment of postmenopausal dyspareunia. Beneficial effects were found for improvement in dyspareunia with improvements in vaginal maturation index (increases of superficial and intermediate cells) compared to placebo, as well as improvements in vaginal pH. In an open label clinical extension trial of 52 weeks, ospemifene did not increase the risk of endometrial proliferation on endometrial biopsy. No increased risk of stroke or VTE was seen over placebo, but concern remains about potential VTE risk. No exacerbation of hot flushes was reported in RCTs. Ospemifene has shown preclinical effects on bone density and the breast but no phase III RCT data are available.

Bone Specific Pharmacologic Therapies for Treatment of Osteoporosis The primary goal of osteoporosis treatment is fracture prevention in women with low BMD or risk factors for fracture. Approximately 25% of all White women older than 60 years of age have spinal compression fractures resulting from osteoporosis. The risk of hip fracture is 20% by the age of 90 years, and hip fractures are about 2.5 times more common in women than in men. An increased rate of loss of both cortical and cancellous bone is associated with menopause. An excess mortality rate associated with hip fracture is 12% to 20% during the first year after the injury. Fewer than half of patients with hip fractures ever return to their prefracture activity level. Many require assistance, lose their independence, and require long-term domiciliary care. Vertebral fractures may be asymptomatic in 50%,

118

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

but successive fractures can lead to loss of height, kyphotic distortion of posture, and chronic back pain. Approximately 10% of patients with hip fractures die of surgical or other complications within 6 months of fracture. Given the many health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures by slowing or stopping bone loss, improving bone strength, and by minimizing falls that contribute to fractures. Prevention and treatment decisions occur over the lifespan for postmenopausal woman as their risk for fracture increases with age and propensity for falling. A number of medications are approved by the FDA for the prevention or treatment of osteoporosis. FDA-approved therapies include antiresorptive agents that reduce bone resorption such as HT, SERMS, bisphosphonates, RANK ligand inhibitors, and anabolic agents that stimulate bone formation which includes recombinant parathyroid hormone (PTH 1–34), teriparatide, and a newer synthetic analog, abaloparatide, modified to potentiate the anabolic effect. The newest approved therapy, romosozumab, is a humanized monoclonal antibody that binds and inhibits the activity of the protein sclerostin. Romosozumab both increases bone formation and decreases bone formation with a significant reduction in vertebral fracture, superior to the active comparator alendronate. In general, anabolic agents are used for more severe osteoporosis and are more likely to be prescribed by specialists in skeletal health. Bisphosphonate therapy is not recommended in premenopausal women due to unknown long-term effects in bone and concern about potential teratogenic effects if women become pregnant. Bisphosphonates, such as alendronate 70 mg weekly (Fosamax, Binosto), risedronate 35 mg oral weekly (Actonel, Atelvia delayed release), ibandronate (Boniva) 150 mg monthly, and zoledronate (Reclast) 5 mg intravenously over greater than 15 minutes every year, act by preventing bone resorption by blocking the action of osteoclasts. These agents chemically bind to calcium hydroxyapatite in bone. The oral bisphosphonates display poor bioavailability and therefore are taken on an empty stomach with adequate water for proper dissolution and absorption. Gastrointestinal side effects (reflex, esophagitis, and esophageal ulcers) have been a primary concern for patients taking oral bisphosphonates. Bisphosphonate therapy accumulates in the skeleton to create a reservoir that continues to be released after cessation of treatment. There is concern that prolonged therapy with bisphosphonates may lead to oversuppression of bone remodeling, which allows microdamage to accumulate and increase skeletal fragility. This has led to the concept of “drug holidays” for selected patients, where residual fracture reduction occurs after the initial 3- to 5-year course of therapy. If a drug holiday is offered, periodic re-evaluation is needed, sooner for drugs with lower skeletal affinity such as ibandronate and for women at higher risk. Denosumab (subcutaneous injection 60 mg every 6 months) is a fully human monoclonal antibody which binds to and inhibits RANK ligand. Osteoclast development and activity is inhibited, leading to decreases in bone resorption and increased BMD with reduced vertebral and hip fractures. Following

discontinuation of denosumab, rapid bone loss occurs and there are case reports of vertebral fractures occurring after discontinuation. Regular subcutaneous injections every 6 months are recommended with consideration of giving an antiresorptive agent such as a bisphosphonate for a year to maintain the gains when denosumab therapy is stopped. Parathyroid hormone-receptor agonists including teriparatide and abaloparatide are anabolic agents which activate osteoblastic bone formation through interactions with the PTH receptor, leading to increased trabecular mass and microarchitecture. In women with postmenopausal osteoporosis, teriparatide (Forteo) at 20 or 40 mg/day was associated with major reductions in risk of vertebral and nonvertebral fractures. The second anabolic agent, abaloparatide (Tymlos), is a modified synthetic analog of parathyroid hormone-related peptide (PTHrP) to potentiate the anabolic effect. Subcutaneous abaloparatide at 80 mcg/day reduced the RR of vertebral, nonvertebral, major osteoporotic, and clinical fractures compared with placebo and reduced the risk of major osteoporotic vertebral and nonvertebral fractures compared with teriparatide. Side effects of these agents include hypercalcemia, dizziness, leg cramps, nausea, and headache. Following therapy with these anabolic agents, switching to either bisphosphonate or denosumab therapy preserves BMD gains. Toxicity studies with both therapies in rats have shown an increased risk of osteosarcoma leading to concern and boxed warnings on the product labeling about increase of malignant bone tumors in rats. Women at increased risk of osteosarcoma should not use these, although no clear association in humans has been seen. Cumulative use for more than 2 years is not recommended due to the potential for side effects. Romosozumab, a humanized antibody that binds sclerostin, is approved for the treatment of postmenopausal women at high risk for fracture. It binds and inhibits the activity of the protein sclerostin with a dual effect on bone, both increasing bone formation and decreasing bone breakdown. Romosozumab has been shown to be more effective than alendronate in preventing vertebral and nonvertebral fractures among women with osteoporosis. Treatment effects wane after 12 months and either denosumab or alendronate are then used to maintain bone effects. Romosozumab carries a boxed warning on its label about potential increased risks for myocardial infarction, stroke, and CV death. It should not be used in women with a cardiovascular event within the previous year. Two uncommon adverse events have been reported for almost all pharmacologic therapies: osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFFs). ONJ is defined as exposed necrotic bone in the maxillofacial region usually occurring after dental procedure that fails to heal after 8 weeks; it may be associated with pain, paresthesia, soft tissue ulceration and swelling, and loosening of teeth. It has been described with many chronic osteoporotic therapies with higher rates seen in cancer patients receiving higher-dose bisphosphonates. AFFs are stress fractures, may be bilateral, and are typically associated with minimal to no trauma. Prodromal pain has been described. A greater risk has been found with longer bisphosphonate use—5 to 9 years compared with shorter use

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

(,2 years). Bone specialists are recommended for management for women with severely low T-scores (less than -3.0 SD), lack of response to therapy with progressive decline of bone density, occurrence of new fractures, and to evaluate and manage secondary osteoporosis such as hyperparathyroidism.

Genitourinary Syndrome of Menopause Lubricants and moisturizers are recommended first line for cancer patients to relieve vulvovaginal and urinary symptoms. If symptoms persist, individual discussion, which should involve the oncologist, is needed about the risks and benefits of low-dose vaginal estrogen therapies which increase the number of superficial cells to restore the vaginal epithelium and normalize vaginal pH, leading to improved health of the vagina. Low dose vaginal estrogen decreases not only the genitourinary

119

symptoms but also the risk of recurrent vaginitis and urinary tract infections, improves or resolves dyspareunia, and improves symptoms of urinary urgency (Table 4.4). Despite the boxed warning found on all systemic and vaginal estrogen products, there is no evidence that low-dose vaginal estrogens increase the risk of breast or endometrial cancer, CHD, stroke, or VTE. The first few applications of vaginal estrogen to atrophic vaginal tissues transiently increase the circulating estrogen levels. The least systemic absorption occurs with the vaginal estradiol ring (7.5 mg released daily), and the newer 4 mg vaginal estradiol suppositories. Low systemic absorption is also seen with twice weekly administration of 10 mg vaginal estradiol tablets and suppositories and when conjugated estrogen and estradiol creams are dosed at 0.5 mg daily. Progestogens are not generally recommended for endometrial protection based on

TABLE 4.4 Recommendations for Local Hormone Therapy Based on Female Cancer Type and Characteristics Patient Population

Recommendation

General guidelines

Individualize therapy

Notes

Use nonhormonal therapy as first line Involve treating oncologist in decisions regarding HT use Avoid off-label medications (vaginal testosterone, estriol) Consider laser therapy, with appropriate counseling regarding limited data on use Further Recommendations After Above General Guidelines Have Been Considered and Nonhormonal Therapies Have Failed Breast Cancer ER1 breast cancer, on tamoxifen

If favorable factors, local HT is an option

Tamoxifen is an ER antagonist in breast tissue; any absorbed estrogen may be blocked

ER1 breast cancer, on aromatase inhibitor (AI)

Caution in considering local HT; review with oncologist; consider switching to Tamoxifen

AIs block conversion of androgen to estrogen; goal is very low serum estradiol levels; GSM symptoms often severe

Triple-negative breast cancer

Local HT is an option; counsel on limited data

No known negative effects; data limited

Uterine Cancer Type I (estrogen-dependent) endometrial cancer Type II (estrogen-independent) endometrial cancer

Prematurely closed randomized trial with HT vs placebo showed no increased recurrence risk, small sample size Local HT is an option; counsel on limited data

Uterine carcinosarcoma

No known negative effects; data limited

Endometrial stromal sarcoma

Caution in considering local HT; counsel on limited data

Hormonally active tumor; data limited

Uterine leiomyosarcoma

Caution in considering local HT; counsel on limited data

Tumor is often ER/PR1; data limited

Local HT is an option; consider systemic HT if premenopausal or postmenopausal with symptoms.

Survival benefit and improved relapse-free survival seen in symptomatic pre- and postmenopausal patients on systemic HT after surgery

Caution in considering local HT; counsel on limited data

Hormonally active tumor; data limited

Local HT is an option

No known risks; data limited

Ovarian Cancer High-grade serous

Endometrioid Sex cord stromal (e.g., granulosa cell) Germ cell

Crean-Tate: GSM in female cancer patients: focus on vaginal hormonal therapy, Am J Obstet Gynecol 2020. ER, Estrogen receptor; GSM, genitourinary syndrome of menopause; HT, hormone therapy; PR, progesterone receptor.

120

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

12-month safety data from clinical trials. Any postmenopausal spotting or bleeding should be evaluated with an examination, transvaginal ultrasound, and endometrial biopsy as appropriate. There remains concern that even small increases in circulating estrogen levels that occur with vaginal estrogen therapies could lower the effectiveness of aromatase inhibitors. Therapies beyond vaginal estrogens include an oral selective ER modulator, ospemifene, and a daily intravaginal dehydroepiandrosterone suppository—both approved for treatment of dyspareunia. Neither has been well studied in breast cancer patients or those on aromatase inhibitors. Vaginal testosterone and the use of intravaginal energy-based therapies (vaginal laser and radiofrequency-based devices) are in clinical trials. The use of vaginal estrogen alone improves dyspareunia but does not always resolve the sexual dysfunction complaints after early menopause due to BSO. Testosterone in physiologic doses has been demonstrated in clinical trials to help with decreased sexual desire, arousal, and orgasmic response, but at present, there is no FDA approval for libido for postmenopausal women. Although the efficacy and safety of testosterone treatment in 814 postmenopausal women with hypoactive sexual desire not receiving estrogen therapy was shown using a transdermal testosterone patch (150 or 300 mcg/day) or placebo, it did not receive FDA approval. At 24 weeks, efficacy was measured, and the group of women receiving 300 mcg/day of testosterone reported significantly greater sexual satisfaction compared with the placebo group and the group treated with 150 mcg/day of testosterone. The rate of adverse events related to androgens, specifically unwanted hair growth, was also highest in this group. The concern was that breast cancer was diagnosed in four women treated with testosterone compared with none of the women who received placebo. A more recent trial of transdermal gel was discontinued despite improved efficacy over placebo at 12 weeks when no significant improvement was maintained at 6 months. Intravaginal testosterone has also been tested, but remains a concern due to possible systemic absorption and unclear risks. Some studies suggest antiproliferative effects of testosterone in the breast; however, androgen receptors are widely expressed in breast cancer. Some studies suggest that testosterone and its metabolite dihydrotestosterone may stimulate breast cancer proliferation. Short-term transdermal testosterone therapy with doses that result in the premenopausal physiologic range have not shown increased risk of breast cancer. There are no good RCTs of the safety of supraphysiologic concentrations of testosterone (such as pellets and injections) and thus their use is not recommended due to concerns about increased risk due to high prolonged dosing. The long-term effects of testosterone, including effects on the breasts, remain unclear. For premenopausal women, there are two FDA-approved treatments, flibanserin and bremelanotide, both approved to treat acquired, generalized hyposexual desire disorder in premenopausal, but not postmenopausal, women.

Special Populations Early Menopause Early menopause, due to either surgical or induced menopause (chemotherapy, pelvic irradiation) or primary ovarian

insufficiency (genetic or autoimmune causes), has been shown in epidemiologic studies to increase health risks including CVD, osteoporosis and fractures, genitourinary syndrome of menopause including sexual concerns, and cognitive challenges including Parkinson disease and dementia. Despite the lack of long-term randomized clinical trials, taking HT to the expected natural age of menopause (range 51 to 52) decreases these risks to those of the normal population. In younger women, higher doses of estrogen may be needed to protect against bone loss or provide symptom relief. For some, the use of oral contraceptives provides symptom relief, cycle control, and protection against unexpected pregnancy if spontaneous ovulation should occur.

Elevated Risk of Breast Cancer Consideration of risk of breast cancer should be taken into account in decisions about the use of HT. Women with a firstdegree relative with breast cancer are twice as likely to develop breast cancer. Risks for women with family members with breast cancer can be calculated using the Gail Model or more extended Tyrer-Cuzick models. However, in the large WHI trial, the RR of breast cancer with combined estrogen and progestin therapy was similar regardless of presence of family history of breast cancer. A meta-analysis of 1100 women with BRCA1 or 2 mutation and intact breasts (three cohort studies) who underwent risk-reducing BSO found no excess risk of the HT beyond their baseline increased risk of breast cancer. Thus, these women should be counseled about risks and benefits of HT with consideration to using low-dose therapy, including a progestogen if uterus is present, to expected age of natural menopause.

RISK MODIFICATION WITH HORMONE THERAPY: OPTIONS AND OPPORTUNITIES Use of Lower Doses and Different Formulations Lower doses of HT relieve menopausal symptoms but may take up to 6 to 8 weeks to provide symptom relief. Benefits include less risk of breast tenderness and bleeding and fewer VTEs. Oral estrogens increase the sex hormone binding globulin levels, triglyceride levels, and C-reactive protein. These increases can be avoided through the use of transdermal therapies. Observational studies suggest a lower risk of both VTE and stroke with transdermal use, particularly with the use of lower-dose transdermal therapy. The lowest approved dose is a 0.014 mg weekly estradiol patch, tested in women over age 60 and approved to prevent osteoporosis, but also shown to improve hot flashes. Transdermal therapy is often most appropriate for women with obesity, metabolic syndrome, hypertriglyceridemia, or low libido. Progestogens (synthetic progestins and progesterone) are used primarily to protect against endometrial cancer in women with a uterus but may also relieve hot flashes when used alone. Observational studies suggest potentially lower risk of VTE and breast cancer and less negative effects on mood and lipids levels with micronized progesterone; however, adequate doses are needed to protect against uterine neoplasia. A newer formulation includes a combination of 0.45 mg CEE with a specific

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

selective ER modulator, bazedoxifene 20 mg. This is an oral, non-progestogen–containing HT which relieves vasomotor symptoms and prevents bone loss, with breast tenderness and bleeding profile similar to placebo. Multicenter randomized trials provide 2 years of safety data without increased risk of endometrial or breast neoplasia. Many women request “bioidentical hormones.” There are many FDA-approved bioidentical hormones available including those which are systemic dosing delivered estradiol either orally or transdermally (weekly and twice weekly patches, a ring, spray, gel, or lotion), or vaginal locally dosed estradiol (cream, ring, tablet, or suppository), oral progesterone, and an oral combination capsule (1 mg estradiol with 100 mg progesterone). For women requesting non-FDA–approved compounded bioidentical HT, prescribers should note that there are safety concerns including minimal government regulation and monitoring and the potential for either over or under dosing, impurities, and sterility concerns. Additionally, these compounded agents lack a label which outlines the risks. Medical societies and the National Academy of Science (NASEM) recommend their use only for women with allergies to approved therapies or with a medical need for an unusual, non-FDA–approved dosing formulation or regimen, and not just because of patient request, as there is much unsubstantiated publicity of improved safety or efficacy for these products.

Discontinuation of Hormone Therapy Up to 8% or more of women may continue to have hot flashes for 20 or more years after menopause. The decision to continue or stop HT should include assessment of the health and risks for the individual women, including hot flash relief, protection against bone loss and fracture, and quality of life. However, it is important to remember that the risks of HT increase with both age and longer durations of use and appear to lessen with estrogen alone, particularly use of transdermal estrogen alone. Controversy continues regarding the safety of longer-term HT (beyond 3 to 5 years). After discontinuation of HT, vasomotor symptoms may return in up to 50% of women. Neither stopping “cold turkey” nor tapering gradually has been proven superior. Many clinicians have found that a gradual taper over 6 months to a year may be more successful in women who have recurrent bothersome hot flashes. Once stopped, protection against osteoporosis is lost rapidly.

NONHORMONE THERAPIES FOR MENOPAUSAL SYMPTOMS For symptomatic menopausal women who desire to avoid HT or who have a history of or elevated risk of CVD, stroke, VTE, breast or uterine cancer, or other contraindications to HT, there are nonhormonal options. Lifestyle changes not well proven include the use of fans, cool nightly indoor temperatures, layered clothing, cooling gel bed toppers, while avoiding heat trapping nightclothes and blankets, spicy foods, alcohol, cigarettes, and hot beverages. Most nonprescription therapies that have not

121

been found to significantly improve, or be clinically more effective than placebo, in randomized blinded controlled trials include black cohosh, evening primrose oil, red clover, vitamin E, ginseng, and flax seed. Phytoestrogens and isoflavones have shown mixed results, but concern exists about potential estrogenic effects. Complementary therapies found in randomized trials to have potential benefit include hypnosis, mindfulness, and cognitive behavioral therapy, while acupuncture, weight loss, stress reduction yoga, and exercise have less clear benefits but minimal harm. Most effective are pharmacologic therapies including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, gabapentinoids, clonidine, and oxybutynin. The doses effective to relieve hot flashes are lower than those needed to treat depression, with a rapid onset of action, often within 2 weeks. The only currently FDAapproved nonhormone treatment for vasomotor symptoms is a low-dose paroxetine mesylate at 7.5 mg/day. Due to its effect on inhibiting cytochrome CYP2D6, paroxetine decreases the conversion of tamoxifen to its active metabolite and thus is not recommended for tamoxifen users. Emerging therapies which appear effective at relieving moderate to severe vasomotor symptoms in testing for relief of these symptoms include stellate ganglion blockade (C6–T2), neurokinin receptor antagonists such as fezolinetant, and estetrol or E4, a fetal estrogen.

MENOPAUSAL HORMONE THERAPY FOR ENDOMETRIAL AND BREAST CANCER SURVIVORS The effect of estrogen on different tissues is not straightforward. There are effects from ERs (ERa and ERb) which bind to estrogen response elements in target genes. However, their effects can be modulated by transcription factors, estrogenindependent activation, or by growth factor receptors. There are many potential interactions and thus simply the presence or absence of estrogen and its receptor does not predict the effects of estrogen in a given cell type. Having said this, the presence of estrogen or progesterone receptors in tumors is a key part of the prognostic factor for hormone sensitive cancers and is used to determine adjuvant therapy. ERa is felt to induce estrogendependent proliferation, whereas ERb can inhibit it, but this does not take into account the complex interactions occurring at the cellular level including estrogen signaling, receptor interactions, and tissue-specific effects. Decisions about the use of systemic or local vaginal therapies are thus complicated by the need to relieve symptoms and improve quality of life without increasing the risk of recurrence.

Hormone Therapy for Endometrial Cancer Survivors Providers are often reluctant to prescribe any type of HT to endometrial cancer survivors due to concern of promoting a recurrence. With 25% of patients premenopausal at the time of diagnosis, it is not unusual for women with endometrial cancer to have more severe menopausal symptoms with the abrupt withdrawal of estrogen at the time of surgical menopause following removal of the uterus, fallopian tubes, and both ovaries. There are some data to help guide decisions about how best to

122

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

TABLE 4.5 Hormone Therapy in Selected Cancers Consider to Natural Age of Menopause BRCA 1/2 mutation without breast cancer Lynch Syndrome

Contraindicated or Relatively Contraindicated Due to Lack of Data Invasive breast cancer ER positive ER triple negative

Hormone Therapy Breast cancer

Consider in Selected Women

Gynecologic cancers

Early endometrial cancer (E2 dependent, type I)—consider with progestogen Early endometrial cancer (E2 independent, type II) Prior use of oral contraceptive pills and EPT decrease incidence

Advanced endometrial cancer (E2, dependent, type 1) Advanced endometrial cancer (E2 independent, type II) Endometrial stroma sarcoma Endometrioid adenocarcinomas Uterine serous carcinoma Clear cell carcinoma Carcinosarcoma Uterine leiomyosarcoma

Ovarian cancer (epithelial, germ cell tumor)

Sertoli Leydig, granulosa cell endometrioid ovarian cancer

EPT, Estrogen-progestin therapy; ER, estrogen receptor.

relieve the menopausal symptoms and health risks of early menopause (Table 4.5). In a prospective, double blind clinical trial by the GOG conducted to evaluate the risk of estrogen therapy in women after treatment of endometrial adenocarcinoma, 1236 patients with stage I–II endometrial cancer were followed for a median of 35.7 months after being treated with a hysterectomy and bilateral oophorectomy. In women assigned to estrogen therapy (n 5 618, CEE 0.625 mg/day), 14 (2.3%) developed disease recurrence, compared to 12 (1.9%) in the placebo group (n 5 618) for a HR of 1.27 (80% CI, 0.916 to 1.77). There was no significant difference in disease recurrence (2.3% versus 1.9%), development of new malignancies (1.3% versus 1.6%), allcause mortality (4.2% versus 3.1%), or death from endometrial cancer (0.8% versus 0.6%). Unfortunately, the study did not meet its target accrual due to premature closure following the release of the initial findings from the WHI trial. However, the results of the study do suggest that estrogen replacement is safe in this group of patients. The results of the study also suggested that racial disparities in outcome may exist. With a median follow-up of 3 years, recurrent disease was noted in 5 of 56 Black patients on the estrogen arm compared with only 8 of 521 White patients, giving a RR of recurrence among Black patients in the estrogen arm of 11.2 (95% CI, 2.86 to 43.59; P 5 .0005) after adjusting for age, BMI, and tumor grade. It is important to note that this study was underpowered for the endpoints of new breast cancers or recurrence of endometrial cancers but did raise concern of risk of estrogen for Black women after treatment of early endometrial cancer. A meta-analysis of 5 observational studies that included this RCT found no significant increased risk of recurrence of endometrial cancer among survivors who received estrogen therapy. A Cochrane review found insufficient high-quality evidence to inform decisions on using HT for endometrial cancer survivors but did not find evidence of significant harm in early-stage,

low-risk endometrial cancer survivors. ACOG in their Practice Bulletin #149 states “Estrogen therapy for the management of menopausal symptoms in the survivors of early-stage endometrial cancer can be considered after thorough counseling about the risks and benefits.” A 2020 clinical practice statement from Society for Gynecologic Oncology in partnership with The North American Menopause Society states that “based on available evidence, use of estrogen therapy in patients with early-stage endometrial cancer (I-II) is reasonable and should be individualized in patients experiencing significant menopause symptoms following appropriate counseling regarding risks and benefits of HT.” Despite a lack of level I RCT evidence, the risk/benefit profile of HT appears to be favorable for women with early-stage endometrial cancer (level II evidence), particularly after early surgical menopause. The optimal time to begin estrogen therapy after treatment has not been determined. Although theoretically a possible advantage, it does not appear that the addition of a progestogen would be safer for women than estrogen alone, using the lowest dose to meet the treatment need. Some suggest waiting for at least 2 years because most patients who will develop recurrences will have done so but this may be difficult with early surgical menopause health risks and more severe symptoms. The decision to prescribe estrogen must be individualized based on symptom control and quality of life concerns and include shared decision making with informed discussion of the potential risks of recurrence or new cancers. Ovarian conservation may be an option for some women with early cancers. In the analysis of the SEER database, the SGO stated “ovarian preservation at the time of hysterectomy for stage I endometrial cancer had no effect on cancer-specific (HR 5 0.58; 95% CI, 0.14 to 2.44) or overall (HR 5 0.68; 95% CI, 0.34 to 1.35) survival.” Similarly, the 2019 NCCN guidelines state that “ovarian conservation may be safe in select women with early stage endometrioid cancer.” In premenopausal women with stage IA to B endometrial cancer, data suggest

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

that ovarian preservation in women followed up to 16 years was not associated with an increased risk of cancer-related mortality. High-risk women in whom estrogen therapy should be avoided include those with high-grade endometrioid adenocarcinomas, uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, and uterine leiomyosarcoma. There are no data supporting hormone use in these survivors, nor in late-stage endometrial cancer (stage III–IV); consequently HT is NOT recommended for these women. Uterine sarcomas have been shown to express estrogen and progesterone receptors and to respond to anti-estrogen therapy. There are no data about the safety of HT for women with uterine sarcomas and thus HT is not recommended. Instead, women at high risk should be offered the tested and effective nonhormone therapy options reviewed earlier for vasomotor symptoms, and candidates should be identified through bone density testing to determine those who need treatment to prevent bone loss.

Hormonal Therapy for Women With or at Risk for Breast Cancer Women who are at elevated risk of breast cancer or are breast cancer survivors have difficult decisions to make regarding loss of estrogen with menopause or their medical or surgical treatments. For women who have had breast cancer, systemic HT is generally contraindicated. Despite retrospective studies suggesting no increased risk or benefit of HT after breast cancer, two prospective clinical trials have led to the current recommendations to avoid systemic estrogen therapy for breast cancer survivors. In 1997, two RCTs were started in Sweden to assess the risks of HT after a diagnosis of breast cancer. Interestingly, these similarly designed trials in a homogenous population of Swedish women arrived at different conclusions. The HABITS (Hormonal Replacement Therapy After Breast Cancer—Is It Safe?) trial was designed as a randomized, nonplacebo, noninferiority study to compare combined estrogen– progesterone treatment for menopausal symptoms with best management without HT in women previously treated for stage 0 to 2 breast cancer. Patients were treated for 2 years and then asked to stop treatment. After a median follow-up of 4 years, there was an increased risk of a new breast cancer event in the HT group compared with the group without HT with a relative hazard of 3.5 (CI 1.5 to 8.1). Of 219 patients in the HT group, 26 new breast cancer events were noted. In the no HT group, there were eight new breast cancer events in 215 women. This corresponds to an absolute difference of 14% in the cumulative incidence of a new breast cancer event at 5 years. Based on these findings at the interim analysis, the decision was made that HT represented an unacceptable risk for women with a history of breast cancer, and the trial was terminated in 2003. The Stockholm trial was a randomized open study in postmenopausal women with a history of breast cancer randomized to receive HT with a cyclic estrogen–progesterone regimen for 5 years (n 5 188) or no HT (n 5 190). In contrast to the HABITS trial, the Stockholm trial found that the risk of breast cancer recurrence was not associated with the use of HT in patients with early-stage breast cancer with a risk hazard of 0.82 (CI 0.35

123

to 1.9). Despite these findings, the Stockholm steering committee prematurely closed this trial based on considerations related to patient safety and difficulty recruiting patients in light of the HABITS results. It is unclear why these two similarly designed studies arrived at different conclusions, but with significant heterogeneity between the two studies (P 5 .02), it is unlikely that this can be explained by chance alone. It should be noted that the proportion of lymph-node positive patients was higher in the HABITS trial compared with the Stockholm trial (26% vs. 16%, respectively). Furthermore, only 21% of patients in the HABITS trial received adjuvant tamoxifen therapy compared with 52% of patients in the Stockholm trial. The distinctions in these clinical characteristics may have contributed to the differences in results of the two studies. Both studies found no increased mortality from breast cancer or other causes from HT. These studies, in addition to more recent studies suggesting increased risk of breast cancer with HT, particularly estrogen combined with progestogen therapy, and studies suggesting increased risk of breast cancer with even low-dose estrogen therapy and longer durations of use, have led to the current recommendations that systemic HT should be avoided in breast cancer survivors. For some women with a low risk of recurrence and severe menopausal symptoms which do not respond to the many nonhormone options, individual evaluation and discussion about symptom relief versus potential risks may be indicated. Low-dose vaginal estrogen may be considered after consultation with the patient’s breast oncologist. Further discussion of hormonal therapy for women at elevated risk for breast cancer is presented below.

Hormone Therapy in Women With Hereditary Cancer Syndromes BRCA1 or BRCA2 Gene Women with a genetic predisposition (BRCA1 or BRCA2 gene or other genes) are at higher risk of developing familial breast and ovarian cancer. Following genetic counseling and testing, risk-reducing bilateral salpingo-oophorectomy (RRSO) between ages 35 and 45 (35 to 40 years for BRCA1 carrier mutations and 40 to 45 years for BRCA2 mutation carriers) or upon completion of childbearing, is recommended to decrease the risk of high-grade serous cancer of ovarian, tubal, and peritoneal origin, improve overall survival, and potentially reduce breast cancer. However, RRSO leads those with BRCA mutation carriers to a premature or early surgical menopause. A prospective longitudinal cohort study of 872 BRCA 1 mutation carriers followed for a mean of 7.6 years with either estrogen alone with or without a progestogen, found no increase in breast cancer incidence compared to never users (10.3% versus 10.7%, P 5 .89). For women with prior hysterectomy, estrogen alone resulted in a nonsignificant 8% reduction in breast cancer per year of use. A meta-analysis of three trials with 1100 women found no higher breast cancer risk in BRCA1 and BRCA2 mutation carriers receiving HT after RRSO (HR 5 0.98; 95% CI 0.63 to 1.52). Again a slight nonsignificant benefit in breast cancer risk reduction was seen for those on estrogen alone compared to estrogen plus progesterone HT formulation (OR 5 0.53; 95%

124

CHAPTER 4

Endometrial Hyperplasia, Estrogen Therapy, and the Prevention

CI 0.25 to 1.15). This reduction is consistent with findings reported in the estrogen alone trial of the WHI. Based on these results, HT use after RRSO in BRCA 1 and BRCA2 mutation carries does not affect breast cancer risk. Comparison of the different HT types suggests that estrogen alone should be related to the lowest breast cancer risk. Shortterm HT after RRSO has many health benefits and does not appear to impact breast cancer risk reduction in BRCA mutation carriers. The risk associated with progestogens is minimized for women who have undergone risk-reducing mastectomy and not an issue for hysterectomized women. For women under the natural age of menopause (51 to 52), HT is recommended due to the increased health risks seen with early menopause including risks of CVD, osteoporotic fractures, mood disorders and cognitive changes, dementia, and genitourinary and sexual concerns. After age 51 to 52, the decision to continue HT should be re-evaluated and usually only continued for persistent severe vasomotor symptoms unresponsive to nonhormone therapies. For women who are hysterectomized, estrogen-only therapy is recommended. For women with a uterus, the lowest effective dose of estrogen is combined with either a low-dose progestin or micronized progesterone or use of the new progestin-free tissue selective estrogen complex (CEE/bazedoxifene) both of which protect the uterus but minimize the negative additive effect of progestogen. The risks of longer duration past the natural age of menopause and the safest therapy for women with an intact uterus are not known.

For BRCA mutations carriers with a personal history of breast cancer, HT is not recommended due to an increased risk of recurrence. An open label, randomized, noninferiority trial of women with prior breast cancer found an elevated hazard ratio for recurrence in those randomized to HT (estrogen alone or with progestogen) for vasomotor symptom management of 2.4 (95% CI 1.3 to 4.2). Even for women with triple negative breast cancer, HT is not recommended due to the higher risk in general of recurrent or new breast cancers. Little data are available about the risks and benefits of the ever-increasing genetic mutations identified with the newer expanded panels.

Lynch Syndrome Women without uterine or breast cancer who have undergone prophylactic hysterectomy and BSO for Lynch syndrome can be considered for estrogen alone therapy to relieve menopausal symptoms. It is possible there may be colon cancer risk reduction as demonstrated in the WHI. In the secondary analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, current HT users (47.1% had undergone hysterectomy) compared with never users had a reduced risk of colorectal cancer, improved colorectal cancer-specific survival, and reduction in all-cause mortality. If the uterus remains intact, there are no data to help guide decision making in this group of mutation carriers. The SGO recommends that women with Lynch syndrome be counseled similar to the general population regarding the use of HT. For the bibliography list, log onto www.expertconsult.com.

BIBLIOGRAPHY Diagnostic Criteria and Clinical Presentation Amant F, Moerman P, Neven P, et al: Endometrial cancer, Lancet 366(9484):491–505, 2005. Ambros RA, Sherman ME, Zahn CM, et al: Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation, Hum Pathol 26(11): 1260–1267, 1995. Antunes CMF, Stolley PD, Rosenshein NB, et al: Endometrial cancer and estrogen use, N Engl J Med 300(1):9–13, 1979. Baak JP, Mutter GL, Robboy S, et al: The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system, Cancer 103(11):2304–2312, 2005. Bergeron C, Nogales FF, Masseroli M, et al: A multicentric European study testing the reproducibility of the WHO classification of endometrial hyperplasia with a proposal of a simplified working classification for biopsy and curettage specimens, Am J Surg Pathol 23(9):1102, 1999. Chamlian DL, Taylor HB: Endometrial hyperplasia in young women, Obstet Gynecol 36(5):659–666, 1970. Committee Opinion No. 631: Endometrial intraepithelial neoplasia, Obstet Gynecol 125(5), 2015. Crosbie EJ, Zwahlen M, Kitchener HC, et al: Body mass index, hormone replacement therapy, and endometrial cancer risk: a metaanalysis, Cancer Epidemiol Biomarkers Prev 19(12):3119–3130, 2010. Dashti SG, Chau R, Ouakrim DA, et al: Female hormonal factors and the risk of endometrial cancer in lynch syndrome, JAMA 314(1):61–71, 2015. Dottino JA, Zhang Q, Loose DS, et al: Endometrial biomarkers in premenopausal women with obesity: an at-risk cohort, Am J Obstet Gynecol 224(3):278.e1–278.e14, 2020. Emge LA: Endometrial cancer and feminizing tumors of the ovaries; significance of their coexistence, Obstet Gynecol 1(5):511–515, 1953. Ferenczy A: Pathophysiology of endometrial bleeding, Maturitas 45(1):1–14, 2003. Gallup DG, Stock RJ: Adenocarcinoma of the endometrium in women 40 years of age or younger, Obstet Gynecol 64(3):417–420, 1984. Huang M, Djordjevic B, Yates MS, et al: Molecular pathogenesis of endometrial cancers in patients with Lynch syndrome, Cancer 119(16):3027–3033, 2013. Kurman R, Carcangiu M, Herrington CS, et al, editors: WHO Classification of Tumours of Female Reproductive Organs, Lyon: International Agency for Research on Cancer 2014. Kurman RJ, Kaminski PF, Norris HJ: The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients, Cancer 56(2):403–412, 1985. Levine DA, Getz G, Gabriel SB, et al: Integrated genomic characterization of endometrial carcinoma, Nature 497(7447):67–73, 2013. Lu KH, Broaddus RR: Endometrial cancer, N Engl J Med 383(21): 2053–2064, 2020. Lu KH, Schorge JO, Rodabaugh KJ, et al: Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer, J Clin Oncol 25(33):5158–5164, 2007. Maxwell GL, Risinger JI, Gumbs C, et al: Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias, Cancer Res 58(12):2500–2503, 1998.

Mutter GL, Lin MC, Fitzgerald JT, et al: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers, JNCI 92(11):924–930, 2000. Mutter GL, Zaino RJ, Baak JPA, et al: Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia, Int J Gynecol Pathol 26(2):103–114, 2007. Ordi J, Bergeron C, Hardisson D, et al: Reproducibility of current classifications of endometrial endometrioid glandular proliferations: further evidence supporting a simplified classification, Histopathology 64(2):284–292, 2014. Parkash V, Fadare O, Tornos C, et al: Committee Opinion No. 631: Endometrial intraepithelial neoplasia, Obstet Gynecol 126(4):897, 2015. Pavlakis K, Messini I, Vrekoussis T, et al: PTEN-loss and nuclear atypia of EIN in endometrial biopsies can predict the existence of a concurrent endometrial carcinoma, Gynecol Oncol 119(3): 516–519, 2010. Raffone A, Travaglino A, Mascolo M, et al: TCGA molecular groups of endometrial cancer: pooled data about prognosis, Gynecol Oncol 155(2):374–383, 2019. Trimble CL, Kauderer J, Zaino R, et al: Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study, Cancer 106(4):812–819, 2006. Usubutun A, Mutter GL, Saglam A, et al: Reproducibility of endometrial intraepithelial neoplasia diagnosis is good, but influenced by the diagnostic style of pathologists, Mod Pathol 25(6):877–884, 2012. Walsh CS, Blum A, Walts A, et al: Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening, Gynecol Oncol 116(3):516–521, 2010. Wood GP, Boronow RC: Endometrial adenocarcinoma and the polycystic ovary syndrome, Am J Obstet Gynecol 124(2):140–142, 1976. Zaino RJ III: Endometrial hyperplasia: is it time for a quantum leap to a new classification? Int J Gynecol Pathol 19(4):314–321, 2000. Zaino RJ, Kauderer J, Trimble CL, et al: Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study, Cancer 106(4):804–811, 2006.

Management Decisions for Endometrial Intraepithelial Neoplasia and Endometrial Hyperplasia Without Atypia Acosta-Torres S, Murdock T, Matsuno R, et al: The addition of metformin to progestin therapy in the fertility-sparing treatment of women with atypical hyperplasia/endometrial intraepithelial neoplasia or endometrial cancer: little impact on response and low live-birth rates, Gynecol Oncol 157(2):348–356, 2020. Baker J, Obermair A, Gebski V, et al: Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature, Gynecol Oncol 125(1):263–270, 2012. Baker WD, Pierce SR, Mills AM, et al: Nonoperative management of atypical endometrial hyperplasia and grade 1 endometrial cancer with the levonorgestrel intrauterine device in medically ill postmenopausal women, Gynecol Oncol 146(1):34–38, 2017. Buttini MJ, Jordan SJ, Webb PM: The effect of the levonorgestrel releasing intrauterine system on endometrial hyperplasia: an Australian study and systematic review, Aust N Z J Obstet Gynaecol 49(3):316–322, 2009. Chiva L, Lapuente F, González-Cortijo L, et al: Sparing fertility in young patients with endometrial cancer, Gynecol Oncol 111(Suppl 2):S101–S104, 2008.

e2 El Behery MM, Saleh HS, Ibrahiem MA, et al: Levonorgestrel-releasing intrauterine device versus dydrogesterone for management of endometrial hyperplasia without atypia, Reprod Sci 22(3): 329–334, 2015. Gallos ID, Ganesan R, Gupta JK: Prediction of regression and relapse of endometrial hyperplasia with conservative therapy, Obstet Gynecol 121(6):1165–1171, 2013. Gonthier C, Walker F, Luton D, et al: Impact of obesity on the results of fertility-sparing management for atypical hyperplasia and grade 1 endometrial cancer, Gynecol Oncol 133(1):33–37, 2014. Gunderson CC, Fader AN, Carson KA, et al: Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review, Gynecol Oncol 125(2):477–482, 2012. Hubbs JL, Saig RM, Abaid LN, et al: Systemic and local hormone therapy for endometrial hyperplasia and early adenocarcinoma, Obstet Gynecol 121(6):1172–1180, 2013. Indermaur MD, Shoup B, Tebes S, et al: The accuracy of frozen pathology at time of hysterectomy in patients with complex atypical hyperplasia on preoperative biopsy, Am J Obstet Gynecol 196(5):e40–e42, 2007. Jacoby VL, Grady D, Wactawski-Wende J, et al: Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women’s Health Initiative Observational Study, Arch Intern Med 171(8):760–768, 2011. Koh WJ, Abu-Rustum NR, Bean S, et al: Uterine Neoplasms, version 1.2018, NCCN Clinical Practice Guidelines in Oncology, J Natl Compr Canc Netw 16(2):170, 2018. Koskas M, Bendifallah S, Luton D, et al: Safety of uterine and/or ovarian preservation in young women with grade 1 intramucous endometrial adenocarcinoma: a comparison of survival according to the extent of surgery, Fertil Steril 98(5):1229–1235, 2012. Lee TS, Lee JY, Kim JW, et al: Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage endometrial cancer: a Korean Gynecologic Oncology Group study, Gynecol Oncol 131(2):289–293, 2013. Montz FJ, Bristow RE, Bovicelli A, et al: Intrauterine progesterone treatment of early endometrial cancer, Am J Obstet Gynecol 186(4):651–657, 2002. Orbo A, Vereide A, Arnes M, et al: Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial, BJOG 121(4):477–486, 2014. Pal N, Broaddus RR, Urbauer DL, et al: Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device, Obstet Gynecol 131(1):109–116, 2018. Park JY, Kim DY, Kim JH, et al: Long-term oncologic outcomes after fertility-sparing management using oral progestin for young women with endometrial cancer (KGOG 2002), Eur J Cancer 49(4):868–874, 2013. Parker WH, Broder MS, Chang E, et al: Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study, Obstet Gynecol 113(5):1027–1037, 2009. Rocca WA, Grossardt BR, de Andrade M, et al: Survival patterns after oophorectomy in premenopausal women: a population-based cohort study, Lancet Oncol 7(10):821–828, 2006. Shan B-e, Ren Y-l, Sun J-m, et al: A prospective study of fertilitysparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young women, Arch Gynecol Obstet 288(5):1115–1123, 2013.

Touhami O, Grégoire J, Renaud MC, et al: The utility of sentinel lymph node mapping in the management of endometrial atypical hyperplasia, Gynecol Oncol 148(3):485–490, 2018. Trimble CL, Method M, Leitao M, et al: Management of endometrial precancers, Obstet Gynecol 120(5):1160–1175, 2012. Ushijima K, Yahata H, Yoshikawa H, et al: Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women, J Clin Oncol 25(19):2798–2803, 2007. Vetter MH, Smith B, Benedict J, et al: Preoperative predictors of endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia or complex atypical hyperplasia, Am J Obstet Gynecol 222(1):60.e1–60.e7, 2020. Watson CH, Fish LJ, Falkovic M, et al: Adherence to oral anticancer therapeutics in the gynecologic oncology population, Obstet Gynecol 136(6):1145–1153, 2020. Westin SN, Fellman B, Sun CC, et al: Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer, Am J Obstet Gynecol 224(2):191.e1–191.e15, 2020. Wildemeersch D, Dhont M: Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system, Am J Obstet Gynecol 188(5):1297–1298, 2003. Wright JD, Buck AM, Shah M, et al: Safety of ovarian preservation in premenopausal women with endometrial cancer, J Clin Oncol 27(8):1214–1219, 2009.

Prevention of Endometrial Cancer Adams TD, Stroup AM, Gress RE, et al: Cancer incidence and mortality after gastric bypass surgery, Obesity 17(4):796–802, 2009. Cao Z, Zheng X, Yang H, et al: Association of obesity status and metabolic syndrome with site-specific cancers: a population-based cohort study, Br J Cancer 123(8):1336–1344, 2020. Chin J, Konje JC, Hickey M: Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen, Cochrane Database Syst Rev (4):CD007245, 2009. Collaborative Group on Epidemiological Studies on Endometrial Cancer: Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies, Lancet Oncol 16(9): 1061–1070, 2015. Furness S, Roberts H, Marjoribanks J, et al: Hormone therapy in postmenopausal women and risk of endometrial hyperplasia, Cochrane Database Syst Rev (2):CD000402, 2009. Iversen L, Sivasubramaniam S, Lee AJ, et al: Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study, Am J Obstet Gynecol 216(6):580.e1–580.e9, 2017. Jaakkola S, Lyytinen H, Pukkala E, et al: Endometrial cancer in postmenopausal women using estradiol–progestin therapy, Obstet Gynecol 114(6):1197–1204, 2009. Kurman RJ, Félix JC, Archer DF, et al: Norethindrone acetate and estradiol-induced endometrial hyperplasia, Obstet Gynecol 96(3):373–379, 2000. Lu KH, Loose DS, Yates MS, et al: Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus Depo-Provera for prevention of endometrial cancer in women with Lynch syndrome, Cancer Prev Res 6(8):774–781, 2013. MacKintosh ML, Derbyshire AE, McVey RJ, et al: The impact of obesity and bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk, Int J Cancer 144(3):641–650, 2019.

e3 Manson JE, Chlebowski RT, Stefanick ML, et al: Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative Randomized Trials, JAMA 310(13):1353–1368, 2013. Raudaskoski T, Tapanainen J, Tomás E, et al: Intrauterine 10mg and 20mg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response, BJOG 109(2):136–144, 2002. Schmandt RE, Iglesias DA, Co NN, et al: Understanding obesity and endometrial cancer risk: opportunities for prevention, Am J Obstet Gynecol 205(6):518–525, 2011. Sjöström L, Gummesson A, Sjöström CD, et al: Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial, Lancet Oncol 10(7):653–662, 2009. Soini T, Hurskainen R, Grénman S, et al: Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland, Obstet Gynecol 124(2 PART 1):292–299, 2014. Symer MM, Wong NZ, Abelson JS, et al: Hormone replacement therapy and colorectal cancer incidence and mortality in the prostate, lung, colorectal, and ovarian cancer screening trial, Clin Colorectal Cancer 17(2):e281–e288, 2018.

Benefits and Risks of Estrogen Replacement Therapy and Risk Modification Adler RA, El-Hajj Fuleihan G, Bauer DC, et al: Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research, J Bone Miner Res 31(1):16–35, 2016. Anastasilakis AD, Polyzos SA, Makras P, et al: Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases, J Bone Miner Res 32(6):1291–1296, 2017. Avis NE, Crawford SL, Greendale G, et al: Duration of menopausal vasomotor symptoms over the menopause transition, JAMA Intern Med 175(4):531–539, 2015. Barnabei VM, Cochrane BB, Aragaki AK: Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative, Obstet Gynecol 105(5):1063–1073, 2005. Bernhardt L, Lawson CA. Early menopause and risk of cardiovascular disease: an issue for young women, Lancet Public Health 4(11):e539–e540, 2019. Bhupathiraju SN, Grodstein F, Stampfer MJ, et al: Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study, Menopause (New York, N. Y.) 26(6):603–610, 2018. Blümel JE, Castelo-Branco C, Chedraui PA, et al: Patients’ and clinicians’ attitudes after the Women’s Health Initiative study, Menopause 11(1):57–61, 2004. Canonico M, Scarabin PY: Oral versus transdermal estrogens and venous thromboembolism in postmenopausal women: what is new since 2003? Menopause 23(6):587–588, 2016. Cody JD, Richardson K, Moehrer B, et al: Oestrogen therapy for urinary incontinence in post-menopausal women, Cochrane Database Syst Rev (4):CD001405, 2009. Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, et al: Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women, Maturitas 91:93– 100, 2016. Committee Opinion No. 556: Postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism, Obstet Gynecol 121(4):887–890, 2013.

Cosman F, Crittenden DB, Adachi JD, et al: Romosozumab treatment in postmenopausal women with osteoporosis, N Engl J Med 375(16):1532–1543, 2016. Crandall CJ, Hovey KM, Andrews CA, et al: Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study, Menopause (New York, N. Y.) 25(1):11–20, 2018. Davis SR, Baber R, Panay N, et al: Global consensus position statement on the use of testosterone therapy for women, J Clin Endocrinol Metab 104(10):4660–4666, 2019. Espeland MA, Rapp SR, Manson JE, et al: Long-term effects on cognitive trajectories of postmenopausal hormone therapy in two age groups, J Gerontol A Biol Sci Med Sci 72(6):838–845, 2017. Ettinger B, Black DM, Mitlak BH, et al: Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene results from a 3-year randomized clinical trial, JAMA 282(7):637–645, 1999. Farr JN, Khosla S: Skeletal changes through the lifespan—from growth to senescence, Nat Rev Endocrinol 11(9):513–521, 2015. Felix AS, Bower JK, Pfeiffer RM: High cardiovascular disease mortality after endometrial cancer diagnosis: results from the Surveillance, Epidemiology, and End Results (SEER) Database, Int J Cancer 140(3):555–564, 2017. FitzGerald G, Compston JE, Chapurlat RD, et al: Empirically based composite fracture prediction model from the Global Longitudinal Study of Osteoporosis in Postmenopausal Women (GLOW), J Clin Endocrinol Metab 99(3):817–826, 2014. Force UPST: Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force Recommendation Statement, JAMA 318(22):2224–2233, 2017. Force UPST: Screening for osteoporosis to prevent fractures: US Preventive Services Task Force Recommendation Statement, JAMA 319(24):2521–2531, 2018. Fournier A, Berrino F, Clavel-Chapelon F: Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study, Breast Cancer Res Treat 107(1):103–111, 2008. Genazzani AR, Gaspard U, Foidart JM: Oral investigational drugs currently in phase I or phase II for the amelioration of menopausal symptoms, Expert Opin Investig Drugs 28(3):235–247, 2019. Gera R, Tayeh S, Chehade He-H, et al: Does transdermal testosterone increase the risk of developing breast cancer? A systematic review, Anticancer Res 38(12):6615–6620, 2018. Hodis HN, Mack WJ, Henderson VW, et al: Vascular effects of early versus late postmenopausal treatment with estradiol, N Engl J Med 374(13):1221–1231, 2016. Hoover R, Gray LA, Cole P, et al: Menopausal estrogens and breast cancer, N Engl J Med 295(8):401–405, 1976. Imtiaz B, Tuppurainen M, Rikkonen T, et al: Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study, Neurology 88(11):1062–1068, 2017. Islam RM, Bell RJ, Green S, et al: Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data, Lancet Diabetes Endocrinol 7(10):754–766, 2019. Kanis JA, Odén A, McCloskey EV, et al: A systematic review of hip fracture incidence and probability of fracture worldwide, Osteoporos Int 23(9):2239–2256, 2012. Lavasani S, Chlebowski RT, Prentice RL, et al: Estrogen and colorectal cancer incidence and mortality, Cancer 121(18):3261–3271, 2015. Lee AW, Ness RB, Roman LD, et al: Association between menopausal estrogen-only therapy and ovarian carcinoma risk, Obstet Gynecol 127(5):828–836, 2016.

e4 Lethaby A, Ayeleke RO, Roberts H: Local oestrogen for vaginal atrophy in postmenopausal women, Cochrane Database Syst Rev 2016(8):CD001500-CD, 2016. Li CI, Beaber EF, Tang MTC, et al: Effect of depo-medroxyprogesterone acetate on breast cancer risk among women 20 to 44 years of age, Cancer Res 72(8):2028–2035, 2012. Lindsay R, Silverman SL, Cooper C, et al: Risk of new vertebral fracture in the year following a fracture, JAMA 285(3):320–323, 2001. Lyon FA, Frisch MJ: Endometrial abnormalities occurring in young women on long-term sequential oral contraception, Obstet Gynecol 47(6):639–643, 1976. Maclennan AH, Broadbent JL, Lester S, et al: Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes, Cochrane Database Syst Rev 2004(4):CD002978-CD, 2004. Manson JE, Aragaki AK, Rossouw JE, et al: Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative Randomized Trials, JAMA 318(10): 927–938, 2017. Martino S, Cauley JA, Barrett-Connor E, et al: Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene, JNCI 96(23):1751–1761, 2004. McClung MR, Grauer A, Boonen S, et al: Romosozumab in postmenopausal women with low bone mineral density, N Engl J Med 370(5):412–420, 2014. Neven P, Quail D, Marin F, et al: Comparing raloxifene with continuous combined estrogen–progestin therapy in postmenopausal women: review of Euralox 1, Maturitas 52(2):87–101, 2005. Pinkerton JV: Hormone therapy for postmenopausal women, N Engl J Med 382(5):446–455, 2020. Pinkerton JV, Conner EA: Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators, Climacteric 22(2):140–147, 2019. Pinkerton JV, Harvey JA, Lindsay R, et al: Effects of bazedoxifene/ conjugated estrogens on the endometrium and bone: a randomized trial, J Clin Endocrinol Metab 99(2):E189–E198, 2014. Portman DJ, Gass MLS, on behalf of the Vulvovaginal Atrophy Terminology Consensus Conference P: Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and The North American Menopause Society, Menopause 21(10): 1063–1068, 2014. Pursnani A, Massaro JM, D’Agostino RB Sr, et al: Guideline-based statin eligibility, cancer events, and noncardiovascular mortality in the Framingham heart study, J Clin Oncol 35(25):2927–2933, 2017. Rahn DD, Carberry C, Sanses TV, et al: Vaginal estrogen for genitourinary syndrome of menopause: a systematic review, Obstet Gynecol 124(6):1147–1156, 2014. Rossouw JE, Anderson GL, Prentice RL. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial, JAMA 288(3):321–333, 2002. Rossouw JE, Prentice RL, Manson JE, et al: Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause, JAMA 297(13):1465–1477, 2007. Santen RJ, Mirkin S, Bernick B, et al: Systemic estradiol levels with low-dose vaginal estrogens, Menopause (New York, N. Y.) 27(3):361–370, 2020. Sarrel PM, Sullivan SD, Nelson LM: Hormone replacement therapy in young women with surgical primary ovarian insufficiency, Fertil Steril 106(7):1580–1587, 2016.

Shumaker SA, Legault C, Kuller L, et al: Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study, JAMA 291(24):2947–2958, 2004. Simon JA, Lin VH, Radovich C, et al: One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus, Menopause 20(4):418–427, 2013. Skorupskaite K, George JT, Veldhuis JD, et al: Neurokinin 3 receptor antagonism reveals roles for neurokinin B in the regulation of gonadotropin secretion and hot flashes in postmenopausal women, Neuroendocrinology 106(2):148–157, 2018. Stuenkel CA, Davis SR, Gompel A, et al: Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab 100(11):3975–4011, 2015. Surgically confirmed gallbladder disease, venous thromboembolism, and breast tumors in relation to postmenopausal estrogen therapy, N Engl J Med 290(1):15–19, 1974. Taylor HS, Tal A, Pal L, et al: Effects of oral vs transdermal estrogen therapy on sexual function in early postmenopause: ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), JAMA Intern Med 177(10):1471–1479, 2017. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel: The 2017 hormone therapy position statement of The North American Menopause Society, Menopause 24(7):728–753, 2017. Thurston RC: Vasomotor symptoms: natural history, physiology, and links with cardiovascular health, Climacteric 21(2):96–100, 2018. Vinogradova Y, Coupland C, Hippisley-Cox J: Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases, BMJ 364:k4810, 2019. Vinogradova Y, Coupland C, Hippisley-Cox J: Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases, BMJ 371:m3873, 2020. Weiss NS, Sayvetz TA: Incidence of endometrial cancer in relation to the use of oral contraceptives, N Engl J Med 302(10):551–554, 1980. Women’s Health Initiative Steering Committee: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial, JAMA 291(14):1701–1712, 2004. Zeleke BM, Davis SR, Fradkin P, et al: Vasomotor symptoms and urogenital atrophy in older women: a systematic review, Climacteric 18(2):112–120, 2015.

Nonhormone Therapies for Menopausal Symptoms Cruz VL, Steiner ML, Pompei LM, et al: Randomized, double-blind, placebo-controlled clinical trial for evaluating the efficacy of fractional CO2 laser compared with topical estriol in the treatment of vaginal atrophy in postmenopausal women, Menopause 25(1): 21–28, 2018. Digesu GA, Tailor V, Preti M, et al: The energy based devices for vaginal “rejuvenation,” urinary incontinence, vaginal cosmetic procedures, and other vulvo-vaginal disorders: an international multidisciplinary expert panel opinion, Neurourol Urodyn 38(3):1005–1008, 2019. Franco OH, Chowdhury R, Troup J, et al: Use of plant-based therapies and menopausal symptoms: a systematic review and metaanalysis, JAMA 315(23):2554–2563, 2016.

e5 Guthrie KA, LaCroix AZ, Ensrud KE, et al: Pooled analysis of six pharmacologic and nonpharmacologic interventions for vasomotor symptoms, Obstet Gynecol 126(2):413–422, 2015. Joffe H, Guthrie KA, LaCroix AZ, et al: Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial, JAMA Intern Med 174(7):1058–1066, 2014. Johnson A, Roberts L, Elkins G: Complementary and alternative medicine for menopause, J Evid Based Integr Med 24:2515690X19829380, 2019. Ruanphoo P, Bunyavejchevin S: Treatment for vaginal atrophy using microablative fractional CO2 laser: a randomized double-blinded sham-controlled trial, Menopause 27(8):858–863, 2020.

Estrogen Replacement Therapy for Endometrial and Breast Cancer Survivors ACOG committee opinion: Hormone replacement therapy in women treated for endometrial cancer, Int J Gynecol Obstet 73(3):283–284, 2001. Armstrong K, Schwartz JS, Randall T, et al: Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: a decision analysis, J Clin Oncol 22(6):1045–1054, 2004. Barakat RR, Bundy BN, Spirtos NM, et al: Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I or II endometrial cancer: a Gynecologic Oncology Group Study, J Clin Oncol 24(4):587–592, 2006. Cauley JA, Norton L, Lippman ME, et al: Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation, Breast Cancer Res Treat 65(2):125–134, 2001. Chapman JA, DiSaia PJ, Osann K, et al: Estrogen replacement in surgical stage I and II endometrial cancer survivors, Am J Obstet Gynecol 175(5):1195–1200, 1996. Chlebowski RT, Aragaki AK, Anderson GL: Menopausal hormone therapy influence on breast cancer outcomes in the Women’s Health Initiative, J Natl Compr Canc Netw 13(7):917, 2015. Collaborative Group on Hormonal Factors in Breast Cancer: Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence, Lancet 394(10204):1159–1168, 2019. Crean-Tate KK, Faubion SS, Pederson HJ, et al: Management of genitourinary syndrome of menopause in female cancer patients: a focus on vaginal hormonal therapy, Am J Obstet Gynecol 222(2): 103–113, 2020. del Carmen MG, Rice LW: Management of menopausal symptoms in women with gynecologic cancers, Gynecol Oncol 146(2):427–435, 2017. Deli T, Orosz M, Jakab A: Hormone replacement therapy in cancer survivors–review of the literature, Pathol Oncol Res 26(1):63–78, 2020. Fahlén M, Fornander T, Johansson H: Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial, Eur J Cancer 49(1):52–59, 2013. Faubion SS, Larkin LC, Stuenkel CA, et al: Management of genitourinary syndrome of menopause in women with or at high risk for breast cancer: consensus recommendations from the North American Menopause Society and the International Society for the Study of Women’s Sexual Health, Menopause 25(6):596–608, 2018. George S, Feng Y, Manola J, et al: Phase 2 trial of aromatase inhibition with letrozole in patients with uterine leiomyosarcomas expressing estrogen and/or progesterone receptors, Cancer 120(5):738–743, 2014.

Hadji P, Aapro MS, Body JJ, et al: Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG, J Bone Oncol 7:1–12, 2017. Holmberg L, Iversen OE, Rudenstam CM, et al: Increased risk of recurrence after hormone replacement therapy in breast cancer survivors, JNCI 100(7):475–482, 2008. Ibeanu O, Modesitt SC, Ducie J, et al: Hormone replacement therapy in gynecologic cancer survivors: why not? Gynecol Oncol 122(2):447–454, 2011. Kotsopoulos J, Gronwald J, Karlan BY, et al: Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers, JAMA Oncol 4(8):1059–1065, 2018. Kotsopoulos J, Lubinski J, Neuhausen SL, et al: Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers, Gynecol Oncol 100(1):83–88, 2006. Marchetti C, Iadarola R, Palaia I, et al: Hormone therapy in oophorectomized BRCA1/2 mutation carriers, Menopause 21(7): 763–768, 2014. Pettersson B, Bergström R, Johansson EDB: Serum estrogens and androgens in women with endometrial carcinoma, Gynecol Oncol 25(2):223–233, 1986. Pinkerton JV, Santen RJ: Managing vasomotor symptoms in women after cancer, Climacteric 22(6):544–552, 2019. Rampurwala M, Wisinski KB, O’Regan R: Role of the androgen receptor in triple-negative breast cancer, Clin Adv Hematol Oncol 14(3):186–193, 2016. Rebbeck TR, Friebel T, Wagner T, et al: Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group, J Clin Oncol 23(31):7804–7810, 2005. Shapiro S, Kelly JP, Rosenberg L, et al: Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens, N Engl J Med 313(16):969–972, 1985. Shim SH, Lee SJ, Kim SN: Effects of hormone replacement therapy on the rate of recurrence in endometrial cancer survivors: a metaanalysis, Eur J Cancer 50(9):1628–1637, 2014. Singh P, Oehler MK: Hormone replacement after gynaecological cancer, Maturitas 65(3):190–197, 2010. Sinno AK, Pinkerton J, Febbraro T, et al: Hormone therapy (HT) in women with gynecologic cancers and in women at high risk for developing a gynecologic cancer: a Society of Gynecologic Oncology (SGO) clinical practice statement: this practice statement has been endorsed by The North American Menopause Society, Gynecol Oncol 157(2):303–306, 2020. Trinh XB, Peeters F, Tjalma WAA: The thoughts of breast cancer survivors regarding the need for starting hormone replacement therapy, Eur J Obstet Gynecol Reprod Biol 124(2):250–253, 2006. Vehmanen L, Elomaa I, Blomqvist C, et al: Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status, J Clin Oncol 24(4):675–680, 2006. Vogel VG, Costantino JP, Wickerham DL, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial, JAMA 295(23):2727–2741, 2006. Yue X, Utsunomiya H, Akahira JI, et al: Expression of steroid and xenobiotic receptor in uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma, Oncol Lett 5(3):835–839, 2013.

5 Adenocarcinoma of the Uterine Corpus and Sarcomas of the Uterus William T. Creasman, MD, David S. Miller, MD, FACOG, FACS, Ramez N. Eskander, MD, Matthew Powell, MD

OUTLINE Incidence, 125 Epidemiology, 126 Diagnosis, 130 Prognostic Factors, 138 Treatment, 145 Antiangiogenic Therapy in Endometrial Cancer, 157

Uterine Sarcoma, 167 Incidence and Epidemiology, 167 Leiomyosarcoma, 167 Endometrial Stromal Sarcoma, 172 Other Sarcomas, 174

KEY POINTS 1. Adenocarcinoma of the endometrium is the most common gynecologic malignancy, with both rising incidence and mortality. 2. Classically, endometrial cancer is divided into two histologic types: type I is endometrioid, and type II consists of uterine serous carcinoma, clear cell (CC), and other more aggressive histologic types, although the molecular classification is emerging as an important paradigm. 3. The mainstay of treatment is surgery with removal of the uterus, cervix, fallopian tubes, and ovaries with incorporation of sentinel lymph node biopsy. 4. Adjuvant therapy is sometimes given. Radiation, chemotherapy, or a combination of both is used depending on the clinical scenario. 5. Some endometrial cancers (5%) result from inherited deoxyribonucleic (DNA) mismatch repair defects, known

as Lynch syndrome. All patients with endometrial cancer should be evaluated for this possibility. 6. Immunotherapy has been identified as an effective treatment strategy in patients with recurrent mismatch repair deficiency/microsatellite instability-high endometrial cancer. 7. Uterine sarcomas are uncommon tumors. The most common tumors are leiomyosarcomas (LMSs; 59%) and endometrial stromal sarcomas (ESSs; 33%). Other sarcomas comprise less than 8% of the remaining. 8. The standard treatment for any sarcoma is removal of the uterus, fallopian tubes, and ovaries. 9. The prognosis of LMSs is poor; even at an early stage, adjuvant therapy has not been shown to affect survival. 10. ESSs are often hormonally responsive.

INCIDENCE

of patients with endometrial cancer; however, there was a decline in incidence during the late 1980s. More recently, deaths from uterine cancer have increased. In 1990, the American Cancer Society estimated 4000 deaths from this cancer, increasing to 10,470 in 2016, and most recently 12,940 in 2021. Despite an overall improvement in cancer-related survival, endometrial cancer mortality continues to rise (Siegel, 2021, #2597). The increasing prevalence of overweight and obesity in women, especially in developed countries, may explain a component of the increased incidence of endometrial cancer. In the United States, approximately 57% of all endometrial cancers are attributed to obesity, with the risk of endometrial cancer increasing by more than 50% for each 5-unit increase in body mass index (BMI) (Bhaskaran, Douglas, et al., 2014; Lu and

In the United States, cancer of the uterine corpus is the most common malignancy unique to women. It was estimated by the American Cancer Society that uterine cancer will develop in approximately 66,570 women in 2021 in the United States, making it the fourth most common cancer in women behind breast, lung, and colorectal cancer (Siegel 2021, #2597; Siegel, et al., 2020) (Fig. 5.1). Importantly, however, when corrected for hysterectomy rates, uterine cancer becomes the second most commonly diagnosed cancer among women. The increased incidence of carcinoma of the endometrium has been apparent only during the past 3 decades. In reviewing the predicted incidence for the 1970s, the American Cancer Society noted a 1.5-fold increase in the number

125

126

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Cervix

Deaths New cases

Ovary Leukemia Uterine Colorectal Lung Breast 0

20,000

40,000

60,000

80,000 100,000 120,000 140,000 160,000 180,000 200,000 220,000

Figure 5.1 Common new cancer cases and deaths in women for 2010 in the United States. (Modified from American Cancer Society: Cancer Facts and Figs. Atlanta, 2010, American Cancer Society.)

Broaddus, 2020). Importantly, rate increases appear greatest in the non-endometrioid, type 2, endometrial cancers, including grade III endometrioid, serous, clear cell, and carcinosarcoma histologies, potentially reflecting the relevance of alternate factors independent of BMI (Mullins and Cote, 2019).

EPIDEMIOLOGY Endometrial adenocarcinoma (AC) occurs during the reproductive and menopausal years. The mean age for patients with AC of the uterine corpus is 63 years; most patients are between the ages of 50 and 59 years (Fig. 5.2). Approximately 5% of women

3500 Surgical 3000

Clinical

Patients (n)

2500 2000 1500 1000 500 0

will have AC before the age of 40 years, and 20% to 25% will be diagnosed before menopause. Bokhman suggested that there are two pathogenic types of endometrial cancer. The first type arises in women with obesity, hyperlipidemia, and signs of hyperestrogenism, such as anovulatory uterine bleeding, infertility, late onset of menopause, and hyperplasia of the stroma of the ovaries and endometrium. The second pathogenic type of disease arises in women who have none of these disease states or in whom the disease states are not clearly defined. Bokhman’s data suggest that patients with the first pathogenic type mainly have well differentiated or moderately differentiated tumors, superficial invasion of the myometrium, high sensitivity to progestins, and a favorable prognosis (85% 5-year survival rate in his material). The patients who fall into the second pathogenic group tend to have poorly differentiated tumors, deep myometrial invasion, a high frequency of metastatic disease in the lymph nodes, decreased sensitivity to progestin, and poor prognosis (58% 5-year survival rate). Multiple risk factors for endometrial cancer have been identified, and MacMahon divides them into three categories: • Variants of normal anatomy or physiology • Frank abnormality or disease • Exposure to external carcinogens Obesity, nulliparity, and late menopause are variants of normal anatomy or physiology classically associated with endometrial carcinoma. These three factors are evaluated in regard to the possible risk of developing endometrial cancer (Table 5.1). If a patient is nulliparous and obese and reaches TABLE 5.1 Endometrial Cancer Risk Factors

15–29 30–39 40–49 50–59 60–69 70–79 Age group (years)

80+

Figure 5.2 Carcinoma of the corpus uteri; patients treated in 1999 to 2001. Age distribution by mode of staging. (Modified from Creasman WT, Odicino F, Maisonneuve P, et al: Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer, Int J Gynecol Obstet 95:S105–S143, 2006.) Clarke et al. J Clin Oncol 2019

Risk Factors

Risk

Obesity

2.5–4.53

Nulliparity Compared with one child

Compared with five or more children

Late menopause

2.43

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

TABLE 5.2 Multiple Risk Factors RISK Nulliparous Top 15% in weight Menopause at 52 years

Parous 53 more than

Lower two thirds in weight Menopause before 49 years

menopause at age 52 years or older, she appears to have a fivefold increase in the risk of endometrial cancer above that of a patient who does not satisfy these criteria (Table 5.2). The type of obesity in patients with endometrial cancer has been evaluated. In a study from the University of South Florida, it was noted that women with endometrial cancer had greater waist-to-hip circumference ratios, abdomen-to-thigh skin ratios, and suprailiac-to-thigh skin ratios than those of matched control women. As these ratios increased, the relative risk (RR) of endometrial cancer increased. The researchers concluded that upper-body fat localization is a significant risk factor for endometrial cancer. In a large multicenter case-control study of 403 endometrial cancer cases and 297 control cases, Swanson and associates confirmed and amplified these findings. Women whose weight exceeded 78 kg had a risk 2.3 times that of women weighing less than 58 kg. For women weighing more than 96 kg, the RR increased to 4.3. Upper-body obesity (waistto-height ratio) was a risk factor independent of body weight. Patients in the highest quartile of both weight and waist-tothigh circumference had a risk of 5.8 times. The amount of body fat has been associated with decreased circulating levels of both progesterone and sex hormone–binding proteins. There was a strong inverse association between sitting height and risk of endometrial cancer. This may be related to sex hormone– bound globulin (SHBG), which appears to be depressed in women with endometrial cancer. The level of SHBG is progressively depressed with increasing upper-body fat localization. With lower SHBG, there is a higher endogenous production of non–protein-bound estradiol. Because endometrial cancer is related to obesity, dietary habits appear to be important. Data suggest that the levels of estriol, total estrogens, and prolactin were lower and those of SHBG were higher in postmenopausal women who were vegetarians. In a case-control study, Levi and colleagues evaluated dietary factors in 274 patients with endometrial cancer and 572 control subjects from two areas in Switzerland and northern Italy. Extensive dietary history was obtained. Their data confirmed the relationship between obesity and endometrial cancer. In relation to diet, they noted an increased association with total energy intake. After correction for total energy intake, a risk was present with the frequency of consumption of most types of meats, eggs, beans, added fats, and sugar. Conversely, significant protection was noted with an elevated intake of most vegetables, fresh fruits, whole grain bread, and pasta. This reflected a low risk with increased intake of ascorbic acid and beta-carotene. Of dietary interest is that the intake of olive oil seemed beneficial in Switzerland but resembled other added fats in Italian women. It has been previously noted that the amount and type of dietary fat influence

127

estrogen metabolism because estrogen reabsorption from the bowel seems to be increased by diets rich in beef or fats. Diabetes mellitus and hypertension are frequently associated with endometrial cancer. Elwood and colleagues reported a RR of 2.8 associated with a history of diabetes after controlling for age, body weight, and socioeconomic status. High levels of insulin-like growth factor I, coupled with elevated estrogen levels, are thought to have neoplastic potential that accounts for the observed increased risk of endometrial cancer. High blood pressure is prevalent in older obese patients but does not appear to be a significant factor by itself, even though 25% of patients with endometrial cancer have hypertension or arteriosclerotic heart disease. As extensively detailed in Chapter 4, the relationship of unopposed estrogen and endometrial cancer is well documented. Fortunately, the addition of a progestin appears to be protective. The adequacy of progesterone is important in prevention of endometrial cancer. In a study from Sweden, at the end of 5 years, excess risk of endometrial cancer was 6.6, but with combined estrogen progestin (E 1 P), the RR was 1.6 for 11 to 15 days of progestin, 2.9 for 10 days of use, and 0.2 if continuous E 1 P was given. The Million Women study from the United Kingdom reported its findings of endometrial cancer and hormone replacement therapy (HRT). This study, which first reported on HRT and breast cancer, has been severely criticized mainly on methodologic factors. The study had an average follow-up of 3.4 years, during which 1320 incident endometrial cancers were diagnosed. At time of recruitment, 22% of HRT users (total number was 320,953 women) last used continuous combined therapy, 45% last used cyclic combined therapy with progestogen usually added for 10 to 14 days per month, 19% last used tibolone, and 4% used estrogen alone. Compared with nonusers, the RRs of endometrial cancer were 0.71, confidence interval (CI) 0.56 to 0.90, P 5 .005; 1.05, CI 0.91 to 1.22; 1.79, CI 1.43 to 2.25, P , .001; and 1.45, CI 1.02 to 2.06, P 5 .04, respectively. Of note, the adverse effects of tibolone and estrogen only were greatest in the nonobese women, and the beneficial effects of combined HRT were greatest in obese women. Although the risk of unopposed estrogen is present, women taking estrogen who develop endometrial cancer appear to have favorable prognostic factors. Several, but not all, studies suggest that risk factors such as multiparity and obesity are lower in the estrogen users. Stage of disease and histologic grade appear to be lower in estrogen users. With correction for stage and grade, estrogen users still have less myometrial invasion than non-estrogen users do. The poor prognostic subtypes, such as clear cell carcinoma, appear less frequently in estrogen users. As a result, survival rates with estrogen-related endometrial cancer are much better than those of non–estrogen-related cancers. Data indicate that the use of combination oral contraceptives decreases the risk for development of endometrial cancer. The Centers for Disease Control and Prevention evaluated endometrial cancer cases of all women aged 20 to 54 years from eight population-based cancer registries and compared them with control patients selected at random from the same centers. A comparison of the first 187 cases with 1320 control cases showed

128

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

that women who used oral contraceptives at some time had a 50% reduction in the risk of developing endometrial cancer compared with women who had never used oral contraceptives. This protection occurred in women who used oral contraceptives for at least 12 months, and protection continued for at least 10 years after oral contraceptive use. Protection was most notable for nulliparous women. These investigators estimated that about 2000 cases of endometrial cancer are prevented each year in the United States by past or current use of oral contraceptives. Of interest, cigarette smoking appears to decrease the risk for developing endometrial cancer, although given the multiple cancers and other diseases associated with smoking this would not be advocated as a risk-reducing measure. In a population-based case-control study of women aged 40 to 60 years, Lawrence and associates found a significant decline in RR of endometrial carcinoma with increased smoking (P . .05). Incidence and survival are higher in White women compared with Black women. Reasons for these differences are unexplained. An analysis of the Gynecologic Oncology Group (GOG) database evaluated this factor in 600 White and 91 Black women with clinical stage I or stage II endometrial cancer. A larger number of the African American women were diagnosed after age 70 years, and they had a higher proportion of serous and clear cell histologies; Black women also had more advanced disease, higher grade, vascular space involvement, depth of invasion, and lymph node metastases than the White women did. The survival rate (5-year) was 77% for White women and 60% for Black women. Survival difference remained even in high-risk groups such as grade III tumors (59% vs. 37%, respectively). Clarke and colleagues suggest that hysterectomy-corrected incidence rates of uterine corpus cancer were similar among non-Hispanic White and Black women and lower among Hispanics and Asian/Pacific Islanders (Clarke, Devesa, et al., 2019). Furthermore, non-endometrioid carcinoma and sarcoma rates were highest in non-Hispanic Black women, with the lowest survival rates in this population irrespective of stage at diagnosis or histologic subtype, highlighting the importance of continued investigation into racial and ethnic differences in oncologic outcome (Clarke, Devesa, et al., 2019). In non-Hispanic Black patients, the overall 5-year survival rate was 63.2%, compared to 86.1% in non-Hispanic White patients, and 81.4% in Hispanic patients (Fig. 5.3). Data emerging from this study additionally suggest that the increase in non-endometrioid cancer cases, combined with stable rates of endometrioid cancers argue against the obesity epidemic as the sole driver of the rising uterine cancer incidence (Clarke, Devesa, et al., 2019). Tamoxifen is used to prevent or treat breast cancer. Tamoxifen was first introduced in clinical trials in the early 1970s and was approved in 1978 by the US Food and Drug Administration (FDA) for treatment of advanced breast carcinoma in postmenopausal woman. Tamoxifen, although labeled an antiestrogen, is known to have estrogenic properties and truly is a weak estrogen. Women receiving tamoxifen also appear to have some protection from osteoporosis and heart disease (decreased lactate dehydrogenase and cholesterol), similar to women receiving estrogen replacement therapy. Extensive experience with this drug has been reported. It is estimated that more than 4 million

women in the United States have taken tamoxifen for almost 8 million women-years of use. One of its major benefits is that in women taking tamoxifen, there has been a substantial decrease in the incidence of a second cancer in the opposite breast compared with similar women who were taking a placebo. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) has produced an important meta-analysis of 194 randomized trials of adjuvant chemotherapy or endocrine therapy with at least 15 years of follow-up. The analysis evaluated the effects of adjuvant tamoxifen on breast cancer recurrence and survival. It was shown that 5 years of tamoxifen therapy, compared with no adjuvant therapy, reduced the 15-year probability of breast cancer recurrence (from 45% to 33%) and breast cancer mortality (from 35% to 26%). In addition, tamoxifen has been shown to provide a preventive benefit in women at risk for developing breast cancer. There has been a considerable amount of discussion in the literature concerning the association of tamoxifen with endometrial cancer. At least three studies (Fisher and colleagues; Powels and colleagues; Veronesi and colleagues) evaluating the prophylactic use of tamoxifen in women without breast cancer have reported an association between tamoxifen use and endometrial cancer. In addition, several cases of endometrial cancer have been described in women receiving tamoxifen. In a prospective, randomized study of the National Surgical Adjuvant Breast and Bowel Project (NSABP), 2843 patients with nodenegative estrogen receptor–positive invasive breast cancer were randomly assigned to receive a placebo or 20 mg/day of tamoxifen. An additional 1220 tamoxifen-treated patients were registered and given the drug. The average time in the study was 8 years for the randomly assigned patients and 5 years for the registered patients. Of the 1419 patients randomly assigned to tamoxifen, 15 developed uterine cancer, of which two were sarcomas. One patient randomly assigned to receive tamoxifen did not take the drug and developed endometrial cancer 78 months after randomization. In the placebo group, two developed endometrial cancer; however, both were receiving tamoxifen at the time of their uterine malignant disease. One patient had a breast recurrence and was prescribed tamoxifen, and the other was given tamoxifen after colon cancer. Two of the patients with endometrial cancer had been taking tamoxifen for only 5 and 8 months before their diagnosis of uterine disease was made. Five patients in the tamoxifen group developed endometrial cancer after the drug had been discontinued for 7 to 73 months. In the registered patients who received tamoxifen, eight uterine tumors (seven endometrial) were subsequently diagnosed. Three of these patients had been taking tamoxifen for less than 1 year (2 months, 2 months, and 9 months). The authors determined the average annual hazards ratio (HR) of endometrial cancer per 1000 women in their population of patients. This was 0.2 per 1000 in the placebo group and 1.6 per 1000 for the randomized tamoxifen-treated patients. In the registered patients receiving tamoxifen, the average annual hazard rate was 1.4 per 1000, similar to that of the randomized tamoxifentreated group. The hazard rate of endometrial cancer in the placebo group was low compared with the Surveillance, Epidemiology, and End Results (SEER) data and with previous

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Non-Hispanic White Non-Hispanic Black Hispanic Non-Hispanic Asian/Paccific Islander

129

Figure 5.3 Trends in age-adjusted incidence rates of microscopically confirmed uterine corpus cancer by race and ethnicity: (A, B) overall and by (C, D) endometrioid and (E, F) nonendometrioid subtypes, (A, C, E)

NSABP randomized tamoxifen–placebo studies; these data suggest that the average annual hazard rate is 0.7 per 1000. These data, based on a limited number of patients with endometrial cancer while receiving tamoxifen, suggest that there may be an RR of 2.3 for development of endometrial cancer while receiving tamoxifen. This does not take into account the well-known fact that women who develop breast cancer are at an increased risk for development of endometrial cancer irrespective of subsequent treatment. A RR of 1.72 to more than

3 has been reported. The risks and benefits of the prevention of recurrences and new breast cancer in comparison to new endometrial cancers were evaluated in the NSABP study. The benefits suggest that 121 fewer breast-related events per 1000 women treated with tamoxifen were seen compared with 6.3 endometrial cancers per 1000 women. Therefore, the benefit from tamoxifen is apparent. It was initially suggested that the rate of endometrial cancers associated with tamoxifen use might be equal to that associated

130

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

with unopposed estrogen replacement therapy. Because tamoxifen is a weak estrogen, similar characteristics of endometrial cancer were also implied (i.e., well-differentiated superficially invasive cancers). Barakat and associates reviewed five studies, including the study by Magriples, the NSABP, their own data from Memorial Sloan-Kettering Hospital, and two studies from overseas. A total of 103 patients were evaluated in regard to histologic features, grade of tumor, International Federation of Gynecology and Obstetrics (FIGO) staging, and deaths from uterine cancer; an increase was not found in poor prognostic histologic findings, tumor differentiation, or stage compared with what would be expected in a similar group of non– tamoxifen-treated patients with uterine cancer. Jordan, in an evaluation of the SEER data and of tamoxifen-associated endometrial cancer in the literature, reported similar findings. It is suggested that all women, irrespective of whether they are taking tamoxifen, should have yearly gynecologic examinations. The endometrium should be evaluated, via biopsy, if the patient is symptomatic. We concur with the American College of Obstetricians and Gynecologists (ACOG) committee opinion that recommends against endometrial sampling or ultrasound evaluation of the endometrium just because an individual is taking tamoxifen. This possible concern of tamoxifen and endometrial cancer may lessen in the near future because the aromatase inhibitors (AIs) may appear to be better than tamoxifen in the prevention of recurrent or contralateral breast cancer. Several clinical trials have demonstrated the comparable if not greater efficacy of AIs compared with tamoxifen. Although tamoxifen remains an option for adjuvant therapy for postmenopausal women, AIs are thought to be more effective in preventing breast cancer recurrence in the first 2 years after surgery. AIs reduce estrogen levels in postmenopausal women by inhibiting or inactivating aromatase, the enzyme that synthesizes estrogens from circulating androgens. AIs should be avoided in premenopausal women, including those who have experienced chemotherapyinduced amenorrhea. Whereas tamoxifen is a partial agonist, AIs are not agonists and are not associated with estrogenic-related thromboembolic events and uterine cancers. The activity of third-generation agents anastrozole, letrozole, and exemestane is generally considered comparable. Although AIs are associated with a significant risk of osteoporosis, they do not increase the risk of gynecologic problems. In one large adjuvant therapy trial (the Anastrozole, Tamoxifen Alone or in Combination Trial [ATAC]), anastrozole was associated with fewer cerebrovascular events (2.0% vs. 2.8%), endometrial cancers (0.2% vs. 0.8%), thromboembolism (3% vs. 4%), and vaginal bleeding (5% vs. 10%) compared with tamoxifen. The role of AIs as prophylaxis has been studied, showing a reduction in new breast cancers relative to placebo, although there are no AIs approved by the US FDA for this indication. Although the majority of endometrial cancer cases are sporadic, hereditary endometrial cancer has been identified in association with hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch II syndrome. This is an autosomal-dominant inherited cancer that involves a germline mutation in one of the genes in the DNA mismatch repair (MMR) gene family, which includes MSH2, MLH1, PMS2, and MSH6.

Fortunately, HNPCC accounts for only 1% to 5% of all colorectal cancers but it is associated with a 39% to 54% lifetime risk of developing colon cancer. There is a lifetime risk of 30% to 61% of developing endometrial cancer in those with HNPCC. There is also an increased risk of ovarian cancers and other non-gynecologic cancers. In a study by Lu and associates, they noted that about half the time, the endometrial or ovarian cancer occurs prior to the colon cancer. In both instances, the age at diagnosis was in the early 40s. There was a median of 11 years between the gynecologic cancer and colon cancer diagnosis. About 14% of the time, the gynecologic and colon cancers were diagnosed simultaneously. Several “red flags” should prompt an evaluation for HNPCC. These include any individual with a personal or family history of colon cancer at an early age of onset (usually before age 50 years) or endometrial cancer at an early age of onset (premenopausal or before age 50 years) and two or more HNPCC-related cancers in an individual or family. Assessing a patient’s risk for hereditary cancer is an important process, beginning with screening for the “red flags” of hereditary colon (and endometrial) cancer. Individuals with any of the “red flags” should enter into a discussion about genetic testing to determine if this is appropriate for them. Medical management strategies can be tailored depending on the genetic testing results and may include increased surveillance, chemoprevention, and prophylactic surgery. The Cancer Study Consortium suggests colonoscopy every 1 to 3 years beginning at age 25 years in individuals with this hereditary disorder. The data suggest that if surveillance is done, survival rates are improved. Women should be offered surveillance with ultrasound and endometrial sampling from age 25 to 35 years, although there are no data to suggest this will improve survival if endometrial cancer is diagnosed by these means. As reported by Schmeler and colleagues, risk-reducing surgery consisting of removal of the uterus, fallopian tubes, and bilateral ovaries has been shown to decrease the risk of uterine and ovarian cancer in these high-risk patients. Incorporation of MMR immunohistochemical (IHC) testing of all endometrial cancer specimens is now advocated to both inform therapeutic strategies, and to simultaneously assess for the possibility of underlying Lynch syndrome versus somatic or epigenetic alterations.

DIAGNOSIS Routine screening for uterine AC and its precursors is not recommended. Women receiving HRT (estrogen and progesterone) do not need endometrial biopsy before institution of therapy or during replacement therapy unless abnormal bleeding occurs. Monthly withdrawal bleeding after progestin is not considered abnormal bleeding. However, breakthrough bleeding should be evaluated. The use of continuous estrogen alone increases the risk of AC. Estrogen plus progesterone appears to decrease the risk of AC and therefore is the preferred treatment. In asymptomatic high-risk patients, periodic evaluation may be advisable. All postmenopausal women with uterine bleeding must be evaluated for endometrial cancer, although only 20% of these patients will have a malignant

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

genital neoplasm. As the patient’s age increases after menopause, there is a progressively increasing probability that her uterine bleeding is caused by endometrial cancer. Feldman and associates found that age was the greatest independent risk factor associated with endometrial cancer or complex hyperplasia. In women aged 70 years or older, the odds ratio was 9.1. If complex hyperplasia was present, the odds ratio increased to 16. When a woman was older than 70 years, her chance of having cancer when vaginal bleeding was present was about 50%. If she was also nulliparous and had diabetes, the risk was 87%. A perimenopausal patient who may have abnormal uterine bleeding indicative of endometrial cancer is frequently not evaluated because the patient or her physician interprets her new bleeding pattern as resulting from menopause. During this time in a woman’s life, the menstrual periods should become progressively lighter and farther apart. Any other bleeding pattern should be evaluated with carcinoma of the endometrium in mind. A high index of suspicion must be maintained if the diagnosis of endometrial cancer is to be made in a young patient. Prolonged and heavy menstrual periods and intermenstrual spotting may indicate cancer, and endometrial sampling is advised. Most young patients who develop endometrial cancer are obese, often with anovulatory menstrual cycles. Historically, fractional dilation and curettage (D&C) has been the definitive diagnostic procedure used in ruling out endometrial cancer. Today, most advocate the routine use of the endometrial biopsy as an office procedure to make a definitive diagnosis and spare the patient hospitalization and need for anesthetic. Several studies have indicated that the accuracy of the endometrial biopsy in detecting endometrial cancer is approximately 90%. Cytologic detection of endometrial cancer by routine cervical Papanicolaou (Pap) smear has generally been poor in comparison with the efficacy of the Pap smear in diagnosing early cervical neoplasia. Several studies in the literature indicate that only one-third to half of the patients with AC of the endometrium have abnormal Pap smear results on routine cervical screening. The main reason for the poor detection with the cervical Pap smear is that cells are not removed directly from the lesion. When a cytologic preparation is obtained directly from the endometrial cavity, malignant cells are present in higher numbers than those found if routine cervical or vaginal smears are obtained. Techniques that obtain only a cytologic preparation are generally inadequate if they are used alone. Several commercial apparatuses are available for sampling the endometrial cavity on an outpatient basis. If diagnosis of endometrial cancer can be made on an outpatient basis, the patient can avoid hospitalization and a minor surgical procedure. Devices that remove tissue for histologic evaluation have generally been good if tissue is obtained from the endometrial cavity. Stovall and colleagues used the Pipelle instrument to evaluate 40 patients known to have endometrial cancer. Ninety percent of the women were postmenopausal. Only in one patient was cancer not identified with the Pipelle. This patient had a prior D&C that revealed a grade I lesion. The Pipelle diagnosis was atypical adenomatous hyperplasia, and the hysterectomy specimen revealed a focus of AC in situ. The pathologist noted

131

that the obtainable tissue was acceptable for analysis in 100% of patients. Discomfort was recorded as mild in 80%, and only two patients (5%) reported severe pain. Goldchmit and coworkers reported similar accuracy with the Pipelle in 176 consecutive patients undergoing D&C. Whereas endometrial biopsy and D&C appear to be equivalent in terms of diagnosing cancer, the accuracy of endometrial biopsy appears to be inferior to D&C in predicting final post-hysterectomy tumor grade. In a recent study by Leitao and colleagues, 18% of endometrial biopsy specimens were upgraded on final hysterectomy specimen, but only 9% of D&C specimens were upgraded. In symptomatic patients in whom inadequate tissue (or no tissue at all) is obtained for pathologic evaluation or in patients with persistent postmenopausal bleeding and non-diagnostic endometrial biopsy, a D&C must be considered. Hysteroscopy has been suggested as an adjuvant in making the diagnosis of endometrial cancer and in establishing the extent of disease. Hysteroscopy has been used frequently in the evaluation of patients with abnormal uterine bleeding and has the advantages of allowing the physician to see the pathologic lesion and direct biopsy, identify other competing diagnoses (fibroids, polyps), and perform the procedure on an outpatient basis. Clark and colleagues analyzed data from 65 primary studies on the use of hysteroscopy to diagnose endometrial cancer and endometrial disease (cancer, hyperplasia, or both), including more than 26,000 women. All of the patients had abnormal premenopausal or postmenopausal uterine bleeding. Using endometrial histologic findings as a reference, a positive hysteroscopy result was associated with a 72% probability of endometrial cancer, but a negative result reduced this probability to 0.6%. The corresponding probabilities for endometrial disease were 55% with a positive result and 3% with a negative result. The accuracy of hysteroscopy tended to be higher among postmenopausal women and in an outpatient setting. They concluded that hysteroscopy is highly accurate and thereby clinically useful in diagnosing endometrial cancer in women with abnormal uterine bleeding and is moderately useful in diagnosing endometrial disease. Because many patients with endometrial cancer can be diagnosed with outpatient office biopsy, this remains the preferred first diagnostic step. If the biopsy result is negative and further evaluation is needed, we proceed to hysteroscopy with endometrial curettage. With its use, surgeons can direct biopsies of focal lesions that might be missed by D&C. Hysteroscopy can also be used to evaluate the endocervical canal. Ultrasonography has been suggested as a diagnostic tool in evaluating women with irregular bleeding, particularly postmenopausal patients (Fig. 5.4). The endometrial stripe as seen with transvaginal ultrasonography appears to be indicative of endometrial thickness. Several studies suggest that if a thin endometrial stripe is present, a histologic diagnosis is not necessary because atrophic endometrium would be present. Granberg and associates evaluated 205 women with postmenopausal bleeding, 30 postmenopausal asymptomatic women, and 30 postmenopausal patients with known endometrial cancer. In the two groups of 60 patients, the endometrial thickness was 3.2 (mean) versus 17.7, respectively. In the group of 205 women, 18

132

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

C Figure 5.4 A, Ultrasound image of the uterus showing the “triple line” indicating the thickness of the endometrium. B, Ultrasound of the uterus showing a “thickened endometrium” of more than 10 mm. C, Saline instillation of the endometrial cavity notes a well-defined submucous fibroid and not thickened endometrium.

were found to have endometrial cancer. No cancers were present in the endometrium that had an endometrial thickness of 8 mm or less. There was considerable overlap of endometrial thickness by all histologic groups. The authors noted that if a cutoff of 5 mm was used, no false-negative findings were present. With this measurement, the positive predictive value was 87%, with specificity of 96% and sensitivity of 100% for identifying endometrial abnormalities. It has been suggested that if

ultrasonography could save a large number of endometrial biopsies, there would be a large cost savings with less discomfort to the patient. As previously noted, significant pain with the newer disposable endometrial biopsy techniques affects only a small number of patients, and a certain number of patients, because of considerable endometrial thickness, will require endometrial sampling anyway. Clark and colleagues investigated the cost-effectiveness of initial diagnostic strategies for

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

postmenopausal bleeding. A decision analytic model was constructed to reflect current service provision, which evaluated 12 diagnostic strategies using endometrial biopsy, ultrasonography (4- and 5-mm endometrial thickness cutoff), and hysteroscopy. Diagnostic probability estimates were derived from systematic quantitative reviews, clinical outcomes from published literature, and cost estimates from local and National Health Service sources. The main outcome measure was the cost per additional life year gained (£/LYG). Compared with carrying out no initial investigation, a strategy based on initial diagnosis with ultrasonography using a 5-mm cutoff was the least expensive (£11,470/LYG). Initial investigation with endometrial biopsy or ultrasonography using a 4-mm cutoff was comparably cost-effective (,£30,000/LYG vs. ultrasonography with a 5-mm cut off). The strategies involving initial evaluation with test combinations or hysteroscopy alone were not costeffective. They concluded that women presenting for the first time with postmenopausal bleeding should undergo initial evaluation with ultrasonography or endometrial biopsy. Unfortunately, endometrial cancer has been identified when the endometrial thickness is less than 5 mm. Although studies may evaluate several hundred patients, most do not have many cancer patients included. Wang and associates reviewed the ultrasounds of 52 women who were diagnosed with serous uterine cancer, clear cell and other high-grade carcinomas. Of the 52, 34 (65%) had a thickened endometrium measuring 5 mm or more; in nine (17%) the endometrium was less than 5 mm, and in an additional nine women (17%) the endometrium was indistinct. In the women with a non-thickened endometrium, other ultrasound abnormalities were noted: intracavitary fluid or lesion, myometrial mass, enlarged uterus, or adnexal mass. With the increasing incidence of type 2 endometrial cancers, the use of ultrasound as a triage mechanism may become less reliable. Multiple factors can affect endometrial thickness. These include estrogen use, estrogen 1 progestin use, BMI, diabetes, poor histotype, race, and postmenopausal status. The Committee on Gynecologic Practice of the ACOG issued an opinion on the role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. They concluded that women with postmenopausal bleeding may be assessed initially with either endometrial biopsy or transvaginal ultrasonography. This initial evaluation does not require performance of both tests. Transvaginal ultrasonography can be useful in the triage of patients in whom endometrial sampling was performed but tissue was insufficient for diagnosis. When transvaginal ultrasonography is performed for patients with postmenopausal bleeding and an endometrial thickness of less than or equal to 4 mm is found, endometrial sampling is not required. Meaningful assessment of the endometrium by ultrasonography is not possible in all patients. In such cases, alternative assessment should be completed. When bleeding persists despite negative initial evaluations, additional assessment is required, especially to rule out a type 2 carcinoma. The reliability of determining endometrial thickness in postmenopausal patients does not appear to be applicable to women taking tamoxifen. In all studies, the endometrium in a tamoxifen-treated patient is considerably thicker than in a

133

non–tamoxifen-treated patient. Histologic evaluation revealed an atrophic endometrium in a large number of these tamoxifen-treated patients. Lahti and colleagues evaluated 103 asymptomatic postmenopausal patients (51 receiving tamoxifen and 52 control participants) with ultrasonography, hysteroscopy, and endometrial histologic examination. In the tamoxifen group, 84% had an endometrial thickness on ultrasonography of 5 mm or more versus 19% in the non-tamoxifen group (51% vs. 8% .10 mm, respectively). Hysteroscopy findings noted that 28% of uterine mucosa was atrophic versus 87% in the non-tamoxifen control group. Histopathologic examination noted atrophic endometrium in 60% of tamoxifen-treated patients versus 79% of control subjects. The biggest difference between the two groups was the finding of polyps in 18% of the tamoxifen group versus 0% of the control group; this appears to be a frequent finding in the tamoxifen-treated patient. So-called mega-polyps measuring up to 12 cm have been described. Other uterine diseases have been attributed to tamoxifen, including increased uterine volume, lower impedance to blood flow in uterine arteries, endometriosis, focal peri-glandular condensation of stromal cells, and epithelial metaplasia. Data now suggest that the markedly thickened endometrium (#40 mm) in patients receiving tamoxifen is not thickened endometrium but proximal myometrium. Ultrasonography has also been evaluated as a means for determining depth of myometrial invasion. Gordon and associates studied 15 known patients with endometrial cancer by ultrasonography and magnetic resonance imaging (MRI). By use of criteria of greater than 50% myometrial wall involvement as deep invasion and less than 50% as superficial invasion, ultrasonography was judged to be more accurate than MRI in five studies; MRI was better in three, both were equally accurate in four, and neither was accurate in three. It has been suggested by some that ultrasonography can accurately predict myometrial invasion in about 75% of cases. Although knowing the depth of invasion preoperatively would be important information to the clinician, the data from studies as noted before would currently appear to be too premature or too costly to use routinely and use may be further limited for type 2 carcinomas as prior studies have excluded or only had limited numbers included in the cited studies. Evaluation of depth of myometrial invasion intraoperatively with gross examination or frozen section is preferred over preoperative radiographic assessment. An exception to the above exists in patients who desire and are appropriate candidates (type 1 carcinomas) for fertility preserving management, where MRI can be obtained to inform myometrial invasion or cervical involvement. In a prospective study of 101 patients with histologically confirmed endometrial cancer, MRI had a sensitivity and specificity of 89% and 100%, respectively, in determining myometrial invasion (Vasconcelos, et al., 2007).

Pathology Careful evaluation of the uterus by the pathologist is essential for proper diagnosis and treatment of corpus cancer (Fig. 5.5). Gross inspection of a bivalved uterus at the time

134

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

13 14

4 3 2

10 9

1 6

Figure 5.5 Pathologic evaluation of endometrial cancer. (Courtesy of Paul Underwood, MD.)

Pelvic organs

of hysterectomy can offer an impression of the size of the lesion, its location (involvement of fundus, lower uterine segment, or cervix), and the depth of tumor penetration into the myometrium (depth of invasion). A clinically enlarged uterus may be caused by increasing tumor volume, but this should not be the only gauge for significant local disease. Obviously, many patients can have enlarged uteri because of factors other than AC. Carcinoma of the endometrium may start as a focal discrete lesion, as in an endometrial polyp. It may also be diffuse in several different areas, in some situations involving the entire endometrial surface. As the tumor grows, it can become larger or spread within the endometrium or myometrium. Endometrial cancer may disseminate to regional lymph nodes, by embolization or direct extension into the pelvis or vagina, or hematogenously to distant organs (Fig. 5.6). The risk of spread is related to several factors, including depth of invasion into the myometrium, tumor grade, and histologic type. Further adding to the complexity, is the observation that type 2 carcinomas may not have grossly visible tumor but can be deeply infiltrative microscopically.

Lymph nodes

Aortics Common iliacs Loose cancer cells in peritoneal cavity

Hypogastrics External iliacs

Small bowel implants

Involved ovary Extension to broad ligament

Vagina

Obturator

Inguinals Paracervical

Figure 5.6 Spread pattern of endometrial cancer with particular emphasis on potential lymph node spread. Pelvic and periaortic nodes are at risk, even in stage I disease.

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

135

TABLE 5.3 Endometrial Carcinoma Subtypes Type

Number (%)

Endometrioid

6231 (84)

Adenosquamous

317 (4.2)

Mucinous

74 (0.9)

Uterine papillary serous

335 (4.5)

Clear cell

185 (2.5)

Squamous cell

28 (0.04)

Other

285 (3.8)

From Creasman WT, Odicino F, Maisonneuve P, et al: Carcinoma of the corpus uteri, Int J Gynecol Obstet 83(Suppl 1):79–118, 2003. No abstract available.

Endometrioid AC, the most common histologic type, is usually preceded by a predisposing lesion, atypical endometrial hyperplasia (Table 5.3). Only hyperplasia with cellular atypia is considered a true “precancerous” precursor of AC of the endometrium. For most patients with endometrioid-type tumors, particularly grade I or II lesions, and hyperplasia, hyperestrogenism is the etiologic basis. Pathologically, endometrial cancer is characterized by the presence of glands in an abnormal relationship to each other, with the hallmark of little, if any, intervening stroma between the glands. There can be variations in the size of the glands, and infolding is common. The cells are usually enlarged, as are the nuclei, along with nuclear chromatin clumping and nucleolar enlargement. Mitosis may be frequent. Differentiation of AC (grades I, II, or III) is important prognostically and is incorporated into FIGO surgical staging (Fig. 5.7). Most studies suggest that 60% to 65% of all endometrial cancers are of the endometrioid subtype. For almost a century, it has been recognized that a squamous component may be associated with an AC of the endometrium. This occurs in about 25% of patients. Historically, patients with a squamous component were further stratified according to whether the squamous component appeared benign (designated adenoacanthoma [AA]) or malignant (designated adenosquamous carcinoma [AS]). It was suggested that AA indicated a good prognosis and those with AS had a poor survival. Today, this distinction has been questioned concerning its prognostic importance. Zaino and coworkers, in reporting data from the GOG, suggest that the notation of squamous component irrespective of differentiation does not affect survival. Patients with clinical stage I and stage II cancers were evaluated, and 456 with typical AC and 175 with squamous differentiation (AC 1 SQ) were identified. The latter were subdivided into 99 with AA and 69 with AS. Multiple known prognostic factors were compared with differentiation of glandular and squamous component of the tumor. Age, depth of myometrial invasion, architecture, nuclear grade, and combined grade were similar for AC and AC 1 SQ, although patients with AA were better differentiated than those with AS and had less myometrial invasion. Both glandular and squamous differentiation correlated with

C Figure 5.7 Histologic patterns of differentiation in endometrial carcinoma. A, Well-differentiated (G1). B, Moderately differentiated (G2). C, Poorly differentiated (G3). (Courtesy of Gregory Spiegel, MD.)

frequency of pelvic and paraaortic node metastasis. Nodal metastasis, when it was stratified for grade and depth of invasion, was similar in AC and AC 1 SQ patients. The differentiation of squamous component is closely correlated with the differentiation of the glandular element, and the glandular element is a better predictor of outcome. It would therefore appear that the previous designation of AA and AS has no added predictive property than differentiation of glandular component and probably should be dropped as a diagnostic term. The authors

136

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Figure 5.8 High-power view of well-differentiated secretory carcinoma invading the inner third of the myometrium. (Courtesy of William M. Christopherson, MD, Louisville, KY.)

suggest the term squamous differentiation instead, with differentiation of the glandular component noted as the important prognostic factor. Secretory AC (Fig. 5.8) is an uncommon type of endometrial cancer. It usually represents well-differentiated carcinoma with progestational changes. It is difficult to differentiate from secretory endometrium. Survival is good and comparable to that associated with the pure AC. Although it is an interesting histologic variant, the separation of the entity as it relates to treatment and survival is probably not warranted. Increasing emphasis has been placed on the importance of uterine serous carcinoma (USC). This subtype represents approximately 5% to 10% of all ACs but is highly aggressive, representing up to 40% of endometrial cancer-related deaths. Unlike the more common variants, USC is not associated with hyperestrogenism and frequently develops in the setting of atrophic endometrium. It is more commonly seen in older and non-White patients. Hendrickson, in the early 1980s, noted that in more than 250 endometrial cancers, only 10% had histologic features of USC, but these accounted for 50% of all treatment failures. The histopathologic appearance resembles a high-grade serous carcinoma of the ovary that has a propensity for vascular or lymphatic vascular space involvement (LVSI), as well as extrauterine spread, which can occur in the absence of myometrial invasion. Well-formed papillae are lined by neoplastic cells with grade III cytologic features (Fig. 5.9). Differentiation between papillary architecture and syncytial metaplasia with benign endometrial alterations must be made because the papillary architecture alone does not designate USC. The uterus may appear grossly normal, without a visible lesion, but can have extensive myometrial invasion. Most USC are aneuploid and have a high S-phase and can be pure or admixed with other histologic types (endometrioid, clear cell, carcinosarcoma). USC commonly arise in endometrial polyps, with varying degrees of myometrial invasions. Current models of pathogenesis hypothesize that USC is a progressive lesion, arising from endometrial intraepithelial carcinoma (EIC), a

Figure 5.9 Serous adenocarcinoma. The similarity to ovarian carcinoma is apparent. (Courtesy of Gregory Spiegel, MD.)

Figure 5.10 Clear cell carcinoma of the endometrium. Clear cell component is quite evident. (Courtesy of Gregory Spiegel, MD.)

finding supported by molecular assessments of paired EIN and USC tissue samples (Zheng, Xiang, et al., 2011; Tolcher, Swisher, et al., 2015). Clear cell carcinomas (Fig. 5.10) are also infrequent, accounting for 1% to 6% of all endometrial cancer, with distinct histologic criteria. Clear cell tumors are characterized by large polyhedral epithelial cells that may be admixed with typical non–clear cell ACs. Some authorities accept the mesonephritic-type hobnail cells as part of this pattern, but others believe that this histologic type should be excluded from the clear cell category. Silverberg and DeGiorgi and Kurman and Scully suggested a worse prognosis for clear cell AC than for pure AC. This was confirmed in studies by Christopherson and coworkers. Even in stage I disease, only 44% of patients with clear cell carcinomas survive 5 years. Neither the FIGO classification nor nuclear grade correlates with survival. Photopulos and associates, in a review of their material, noted that patients with this entity were older and tended to have a worse prognosis. They did note that patients with stage I clear cell carcinomas had a 5-year survival rate similar to that of patients with stage I pure AC of the endometrium.

CHAPTER 5

Endometrium Stage Ib

Adenocarcinoma and Sarcoma of the Uterine Corpus Endocervical glands

Stage Ia Stage Ic

Myometrium Stage IIb

Stage IIa

Stage IIb

Stage IIa Endocervical stroma Endocervical canal

Stage IIa: Endocervical glandular involvement only Stage IIb: Cervical stroma invasion

Stage Ia: Tumor limited to endometrium Stage Ib: Invasion to less than half the myometrium Stage Ic: Invasion to more than half the myometrium

Stage II

Stage I

Pelvic nodes

Periaortic nodes

Positive cytology

Stage IIIa

Stage IIIb

Stage IIIc

Omentum

Inguinal nodes Stage IVa

Stage IVb

137

138

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Tumor Grade In addition to histologic type, pathologists assign a measure of tumor differentiation, known as grade, to endometrial cancers. Grade I lesions are well differentiated, frequently associated with estrogen excess, closely resemble hyperplastic endometrium, and are generally associated with a favorable prognosis. Grade III lesions are poorly differentiated, do not resemble normal endometrium, and frequently have a poorer prognosis. Grade II tumors are moderately differentiated and have an intermediate prognosis. Both architectural criteria and nuclear grade are used to classify. Architectural grade is related to the proportion of solid tumor growth, with grade I having an AC with less than 5% of the tumor exhibiting solid sheets, grade II having 6% to 50% of the neoplasm arranged in solid sheets of neoplastic cells, and grade III having greater than 50% of the neoplastic cells in solid masses. Regions of squamous differentiation are excluded from this assessment. The FIGO rules for grading state that notable nuclear atypia, inappropriate for architectural grade, raises the grade of a grade I or grade II tumor by one. By convention, serous and clear cell histologies are considered grade III or highgrade tumors.

PROGNOSTIC FACTORS After hysterectomy and lymph node assessment, clinical-pathologic characteristics are commonly used to predict risk of recurrence and to optimize therapy. Multiple factors have been identified for endometrial carcinoma that have prognostic value (Table 5.4). Essentially all reports in the literature agree stage (extent of disease spread), tumor grade, and depth of invasion are important prognostic considerations. Before 1988, endometrial cancer was clinically staged with stage assignments based on uterine size and clinical extent of disease. Because of

TABLE 5.4 Prognostic Factors in Endometrial Adenocarcinoma Histologic type (pathology) Histologic differentiation Stage of disease Myometrial invasion Peritoneal cytology Lymph node metastasis Adnexal metastasis

the considerable discrepancy between the clinical extent of disease spread and pathologic spread noted after surgical staging, FIGO adopted a surgical-pathologic staging classification in 1988. In 2009, FIGO updated the staging system (Table 5.5). FIGO staging classification attempts to categorize patients into prognostic groups based on extent of disease and tumor grade.

Stage of Disease: Depth of Invasion, Cervical Involvement, Adnexal Involvement, and Nodal Metastasis Staging of patients with malignancies is designed to have prognostic value by classifying the extent of tumor. The survival rate in regard to stage of disease has been consistent, and Table 5.6 and Fig. 5.11 show the 5-year survival rate reported by FIGO (FIGO 1988 staging). The pattern of disease spread in endometrial cancer was evaluated in a prospective study performed by the GOG (GOG protocol 33) and reported by Creasman and colleagues. This study is required reading for physicians who care for patients with endometrial cancer. GOG protocol 33 was a surgical-pathologic study of 621 patients with clinical stage I

TABLE 5.5 2009 International Federation of Gynecology and Obstetrics Staging System for Carcinoma of the Endometrium Stage Ia

Tumor Contained to the Corpus Uteri Ia

No or less than half myometrial invasion

Invasion equal to or more than half of the myometrium

Stage II Stage III

Tumor invades the cervical stroma but does not extend beyond the uterusb Local and/or regional spread of tumorc

IIIa

Tumor invades the serosa of the corpus uteri and/or adnexa

IIIb

Vaginal and/or parametrial involvement

IIIc

Metastases to pelvis and/or paraaortic lymph nodes IIIcl

Positive pelvic nodes

IIIc2

Positive paraaortic lymph nodes with or without positive pelvic lymph nodes

Tumor invades bladder and/or bowel mucosa and/or distant metastases

Stage IVa IVa

Tumor invasion of bladder and/or bowel mucosa

IVb

Distant metastases, including intraabdominal metastases and/or inguinal lymph nodes

Includes grades I, II, or III. Endocervical glandular involvement only should be considered as stage I and no longer as stage II. c Positive cytology has to be reported separately without changing the stage. a b

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

cytology, and LVSI. Because of this study, FIGO accepted a surgical-based staging system, including lymphadenectomy, of endometrial cancer in 1988. For endometrial cancer, FIGO staging reflects the progression of disease within the uterus and at extrauterine sites. Approximately 75% of patients with endometrial cancer present with disease limited to the uterus (Table 5.7). For stage I disease, depth of tumor invasion into the myometrium is an important prognostic factor. The degree of myometrial invasion is a consistent indicator of tumor virulence (Fig. 5.12). DiSaia and associates noted that recurrences were directly related to depth of myometrial invasion in patients with stage I cancer treated primarily with surgery (Table 5.8). The Annual Report of FIGO demonstrated a decrease in the survival rate as myometrial penetration increased (Table 5.9). Lutz and coworkers determined that the depth of myometrial penetration was not as important as the proximity of the invading tumor to the uterine serosa. Patients whose tumors invaded to within 5 mm of the serosa had a 65% 5-year survival rate, but patients whose tumors were more than 10 mm from the serosa had a 97% survival rate. The depth of myometrial invasion is associated with the other prognostic factors, such as tumor grade. As noted by DiSaia and associates, the survival rate of patients with poorly differentiated lesions and deep myometrial invasion is poor in contrast to that of patients who have well-differentiated lesions but no myometrial invasion. This suggests that virulence of the tumor may vary considerably, and as a result, therapy should depend on the combination of prognostic factors. Location of the tumor within the endometrial cavity is important because tumors low in the cavity may involve the cervix

TABLE 5.6 5-Year Survival in Endometrial

Cancer: Surgical Stage Stage

Patients (n)

5-Year Survival (%)

1063

2735

1219

IIa

364

IIb

426

IIIa

484

IIIb

IIIc

293

IVa

IVb

160

From Pecorelli S, editor: FIGO annual report, years 1996–1998, Int J Gynecol Obstet 83:95, 2003.

endometrial cancer who were uniformly treated with total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), peritoneal cytologic evaluation, and selective pelvic and paraaortic lymphadenectomy. Before this study, it was presumed most patients with endometrial cancer were at risk for nodal metastases, and nearly all patients required some form of pelvic radiation therapy (either preoperatively or postoperatively). The study demonstrated important relationships between pathologic factors and risk of nodal disease. For example, factors associated with nodal disease included higher tumor grade, deeper myometrial invasion, cervical involvement, (1) 100

Stage Ia (n 1063) Stage Ib (n 2735) Stage Ic (n 1219) Stage IIa (n 364) Stage IIb (n 426)

Proportion surviving

Stage IIIa (n 484)

Stage IIIc (n 293) 40

Stage IIIb (n 73)

Stage IVb (n 150) Stage IVc (n 47)

0 0

139

Years after diagnosis Figure 5.11 Carcinoma of the corpus uteri for patients treated in 1990 to 1992 (International Federation of Gynecology and Obstetrics). Survival by surgical stage (n 5 5694). (From Pecorelli S, editor: FIGO Annual Report, years 1996–1998, Int J Gynecol Obstet 83:95, 2003. © International Federation of Gynecology and Obstetrics.)

140

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

TABLE 5.7 Distribution of Endometrial

Carcinoma by Stage (Surgical) Stage

Patients (%)

3839 (73)

574 (11)

III

694 (13)

166 (3)

From Pecorelli S, editor: J Epidemiol Biostat 6:47, 2001.

Myometrial invasion Endometrium only

Inner half

Outer half

Cervical or extrauterine involvement

Grade 1 Grade 2 Grade 3 Low risk

Intermediate risk

High risk

Figure 5.12 Risk assignment based on surgical staging and extent of disease in patients with endometrial cancer.

TABLE 5.8 Relationship Between Depth of Myometrial Invasion and Recurrence in Patients With Stage I Endometrial Carcinoma Endometrial only

7/92 (8%)

Superficial myometrium

10/80 (13%)

Medium myometrium

2/17 (12%)

Deep myometrium

15/33 (46%)

Modified from DiSaia PJ, Creasman WT, Boronow RC, et al: Risk factors in recurrent patterns in stage I endometrial carcinoma, Am J Obstet Gynecol 151:1009, 1985.

TABLE 5.9 Relationship Between Depth of Myometrial Invasion and 5-Year Survival Rate (Stage I) Stage

Patients

5-Year Survival (%)

IaGI

698

IbGI

1030

IcGI

442

IaGII

229

IbGII

1307

IcGII

485

IaGIII

IbGIII

280

IcGIII

247

From Pecorelli S, editor: FIGO annual report, years 1996–98, Int J Gynecol Obstet 83:95, 2003.

earlier than fundal lesions. The prognosis for women with cervical stromal involvement (stage II) is worse than those with stage I disease. Cervical involvement is often a surrogate marker for extrauterine disease spread or for risk of local recurrence. Data from GOG 33 showed that those with disease of the lower uterine segment had a higher incidence of pelvic lymph node metastases (16%) than did those with only fundal disease (8%). There is a similar frequency of paraaortic nodal metastases: a 16% incidence from disease of the lower uterine segment and a 4% incidence when only fundal disease is present. Previously, endocervical curettage (ECC) was commonly used to determine whether the patient had cervical involvement. Many falsepositive results occur with this technique, however. In addition, the prognostic significance of endocervical glandular spread (formerly stage IIa) has been challenged. The new surgical staging adopted by FIGO in 2009 includes only patients with cervical stromal invasion in the stage II category. In some cases, cervical biopsy or ECC is required in the pretreatment planning of a patient with suspected cervical involvement. Patients with stage III or IV disease may have a heterogeneous mix of disease characteristics. It is well recognized that endometrial cancer can and frequently does metastasize to the adnexa. Patients with adnexal or serosal involvement are categorized as having stage IIIA disease and are considered to have a higher risk of peritoneal recurrence. In GOG 33, 5% of patients had adnexal involvement. Adnexal metastasis was significantly associated with involved pelvic (32%) and paraaortic (20%) lymph nodes. In a large surgical trial comparing laparoscopy with open staging (GOG Lap 2 trial), 5% of the 2616 patients enrolled were found to have stage IIIa disease (FIGO 1988 staging). In an analysis of 222 patients with clinical stage I carcinoma of the endometrium reported by DiSaia and colleagues, 16 (7%) were found to have metastasis in the adnexa. This finding correlated with many but not all of the other prognostic factors. Spread to the adnexa did not seem to be related to the size of the uterus. The grade of the disease did not appear prognostically important in regard to this in that 6% of patients with grade I tumors had adnexal disease compared with only 10% if poorly differentiated carcinoma was present. The depth of invasion did appear to be significant, however, in that 4% of patients with only the endometrium involved had adnexal spread compared with 24% who had adnexal metastases if deep myometrial invasion was present. If tumor was limited to the fundus of the uterus, only 5% of patients had disease in the adnexa; however, if the lower uterine segment or the endocervix was involved, one-third had spread to the adnexa. When metastasis was present in the adnexa, 60% of patients had malignant cells in the peritoneal cytologic fluid compared with only 11% if the adnexa were not involved. Recurrences appeared in only 14% of these individuals who did not have metastasis to the adnexa compared with recurrences in 38% of patients with adnexal metastasis. Metastatic spread to lymph nodes (stage IIIc) has prognostic and therapeutic implications. It is clear that lymph node dissection, to date, is the most sensitive way to identify nodal disease. The GOG 33 study demonstrated that as the depth of tumor invasion or tumor grade increased, the frequency of pelvic and

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

TABLE 5.10 Grade Versus Positive Pelvic

and Aortic Nodes Grade (n)

Pelvic Nodes (%)

Aortic Nodes (%)

GI (180)

5 (3)

3 (2)

GII (288)

25 (9)

14 (5)

GIII (153)

28 (18)

17 (11)

Modified from Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987.

TABLE 5.11 Maximal Invasion and Node

Metastasis

Maximal Invasion (n)

Pelvic Nodes (%)

Aortic Nodes (%)

Endometrium only (87)

1 (1)

Superficial muscle (279)

15 (5)

8 (3)

Intermediate muscle (116)

7 (6)

1 (1)

Deep muscle (139)

35 (25)

24 (17)

Modified from Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987.

paraaortic nodal metastases also increased (Tables 5.10 and 5.11). For all 621 patients, 58 (9%) had positive pelvic nodes, and 34 (6%) had positive paraaortic nodes. Patients with grade I, II and III tumors had pelvic nodal metastases of 3%, 9%, and 18% respectively. Similarly, patients with no myometrial invasion, inner one-third, middle one-third, and outer one-third invasion had 1%, 5%, 6%, and 25% pelvic nodal disease, respectively. The highest risk group included patients with grade III tumors and outer one-third invasion who had pelvic nodal involvement in 34% of cases (Table 5.12). Without a lymph node dissection, one may grossly estimate the probability of nodal involvement based on these data to select for or against the use of adjuvant therapy. This strategy potentially results in undertreatment or overtreatment of patients, however. In two large prospective randomized trials, routine lymphadenectomy

TABLE 5.12 Frequency of Pelvic and

Paraaortic Nodal Diseasea

141

resulted in the identification of more patients with nodal disease (9% to 13%) compared with when only clinically suspicious nodes were removed (1% to 3%). It is clear that patients with nodal disease have a poorer prognosis (3- to 5-year survival rate of 50% to 75%) and different patterns of failure (nodal, distant) than patients with negative nodes (3- to 5-year survival rate of 80% to 95%, vaginal cuff failures predominate). Patients with nodal involvement include those with pelvic nodal disease (IIIc1) or paraaortic involvement (IIIc2). The sub-staging was created in 2009 given the belief of different outcomes associated with different levels of nodal involvement. The number of involved nodes and the extent of resection of grossly involved nodes also affect outcome. In addition, Mariani and McMeekin have suggested that patients with positive nodal disease plus other stage III defining features (adnexal or serosal involvement) have a much poorer prognosis than those with nodal disease only. Patients with stage IV or distant disease spread (intraperitoneal, lung, liver) have a particularly poor prognosis, with 5-year survival rate of less than 20%. The extent of surgical resection has been suggested to alter the prognosis in patients with advanced-stage disease. As with ovarian cancer, the extent of resection of disease reflects the biology of the tumor, aggressiveness of the surgery, and response to postoperative therapies.

Tumor Grade The degree of histologic differentiation (tumor grade) of endometrial cancer is a sensitive indicator of prognosis and is included in FIGO stage assignment. The Annual Report on the Results of Treatment in Gynecological Cancer has evaluated survival in regard to grade in patients with clinical stage I AC of the endometrium (Table 5.13). Tumor grade is inversely related to survival; as grade increases, survival decreases. In their review of 244 patients with stage I disease, Genest and colleagues noted that patients with grade I disease had a 5-year survival rate of 96%. This dropped to 79% and 70% for grade II and grade III, respectively. Data presented by Morrow for outcomes in patients enrolled on GOG 33 show that recurrence-free survival markedly diminishes with increasing grade, with progression-free survival (PFS) at 48 months being approximately 95%, 85%, and 68% for grade I, II, and III tumors, respectively. Grade of tumor also correlates with other factors of prognosis. Table 5.14 shows the relationship between differentiation of the tumor and depth of myometrial invasion as reported by Creasman from the GOG 33 study. As the tumor becomes more poorly differentiated, the chances of deep myometrial

GRADE Depth of Invasion

Grade I (n 5 180)

Grade II (n 5 288)

Grade III (n 5 153)

Endometrium only (n 5 86)

0%/0%

3%/3%

0%/0%

Inner third (n 5 281)

3%/1%

5%/4%

9%/4%

Middle third (n 5 115)

0%/5%

9%/0%

4%/0%

Outer third (n 5 139)

11%/6%

19%/14%

34%/23%

Pelvic nodal positivity/paraaortic nodal positivity.

Modified from Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987.

TABLE 5.13 Relationship Between Tumor

Differentiation and 5-Year Survival Rate, Stage I (Surgical) Grade

Survival (n 5 5017) (%)

III

From Pecorelli S, editor: FIGO annual report, years 1996–98, Int J Gynecol Obstet 83:95, 2003.

142

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

TABLE 5.14 Correlation of Differentiation

and Myometrial Invasion in Stage I Cancer GRADE Myometrial Invasion

I (%)

II (%)

III (%)

None

Superficial

Mid

Deep

Modified from Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987.

involvement increase. However, exceptions can occur: Patients with a well-differentiated lesion can have deep myometrial invasion, but patients with a poorly differentiated malignant neoplasm might have only endometrial or superficial myometrial involvement.

Lymphovascular Space Involvement Hanson and colleagues described 111 patients with stage I endometrial cancer and found capillary-like space (CLS) involvement in 16. This was most frequently found in patients with poorly differentiated tumors with deep invasion. These patients had a 44% recurrence rate compared with 2% if the CLS was not involved. This was an independently significant prognostic factor. In the GOG study of 621 patients, it was shown that 93 (15%) had CLS involvement. The incidences of pelvic and paraaortic node metastases were 27% and 19%, respectively. This compares with a 7% occurrence of pelvic node metastasis and a 3% occurrence of paraaortic node metastasis when there is no CLS involvement. In risk models predicting risk of recurrence in node-negative, early-stage endometrial cancer, the GOG has suggested that LVSI is an important risk factor. In the Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, LVSI was considered a factor associated with distant site of failure. In a pooled analysis of the PORTEC-1 and 2 trials, including 926 tumor samples, substantial LVSI using a 3-tiered approach, had the strongest impact on the risk of distant metastases (HR 4.5; 95% CI 2.4 to 8.5). Furthermore, in multivariate analysis (including prognostic variables such as age, depth of invasion, grade, and treatment), substantial LVIS remained the strongest independent prognostic factor for pelvic recurrence (HR 6.2; 95% CI 2.4016), distant metastases (HR 3.6; 95% CI 1.9 to 6.8), and overall survival (OS; HR 2.0; 95% CI 1.3 to 31) (Bosse, Peters, et al., 2015). Tumor Size Schink and coworkers evaluated tumor size in 91 patients with stage I disease. The incidence of lymph node metastases in patients with tumor size less than 2 cm was only 6%. If the tumor was larger than 2 cm in diameter, there were nodal metastases of 21% and up to 40% if the entire endometrium was involved. Patients with lesions greater than 2 cm in size and less

than half myometrial invasion had no nodal metastasis. Using multivariate analysis, the authors showed that tumor size was an independently significant prognostic factor. Watanabe and associates did not find cancer size was predictive of lymph node metastasis. Gynecologic oncologists from the Mayo Clinic have developed a risk model predicting nodal metastases and have suggested that grade I and II tumors that are smaller than 2 cm are particularly low risk for nodal disease.

Peritoneal Cytology The importance of peritoneal cytology in endometrial cancer is controversial. In GOG 33, 76 patients (12%) had malignant cells identified by cytologic examination of peritoneal washings. Of these patients, 25% had positive pelvic nodes compared with 7% of patients in whom no malignant cells were found in peritoneal cytologic specimens (P . .0001). It is true that peritoneal cytology, to a certain degree, mimics other known prognostic factors—that is, if peritoneal cytologic specimens are positive, other known poor prognostic factors may also be identified. In addition, data from GOG 33 also suggested that the RR for recurrence with positive cytology was 2.4 (P 5 .02). Given the relationship of positive cytology with other known risk factors, it is important to evaluate data sets coming from patients who undergo complete surgical staging. Saga and colleagues reported on a series of 307 patients (32 with positive cytology, 275 with negative cytology) with endometrioid-type cancer, all who underwent complete staging and had negative lymph nodes. The authors reported that 5-year survival rate was 87% with positive cytology compared with 97% with negative cytology. Most patients with positive cytology received chemotherapy postoperatively. Havrilesky et al. reported on experience from Duke University. Patients with positive cytology alone (n 5 37) were compared with patients with adnexal or serosal involvement (n 5 20). The 5-year survival rate was similar between the groups (62% positive cytology, 68% adnexal or serosal disease), but in a multivariable analysis, cytology was an independent predictor of recurrence and poorer survival. This study included patients with nonendometrioid histologies, and lymphadenectomy was not routinely performed. In another review of the literature, Wethington demonstrated that in endometrioid-type tumors with low risk factors (superficial invasion, grade I or II) the recurrence rate was only 4%. By comparison, 32% of patients with highergrade tumors or deeper invasion and positive cytology had a recurrence. These results suggest that for at least a subset of cytology patients, the risk of recurrence approximates that driven by other uterine factors (depth of invasion, tumor grade). In 2009, FIGO dropped cytology as a stage IIIa defining characteristic. Milosevic and colleagues reviewed 17 studies. In 3820 patients, the prevalence of positive cytologic findings was 11%. The three largest studies totaling more than 1700 patients (Haroung and associates, Turner and colleagues, Morrow and coworkers) using multivariate analysis noted that the finding of malignant cells on cytologic examination was independently significantly associated with either recurrence or

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

reduced survival. Pooled odds ratio for the entire series was 4.7 (CI 3.5 to 6.3) for disease recurrence. All studies note the highest correlation of malignant cytologic specimens with extrauterine disease. An alternate observational retrospective cohort analysis of 16,851 women using the National Cancer Database (NCDB) similarly found positive cytology to be associated with compromised 4-year OS in patients with stage I to II disease (Seagle, Alexander, et al., 2018). Additional studies have confirmed these findings (Garg, Gao, et al., 2013). It does appear that with multivariate analysis, the presence of malignant cells is an important prognostic factor even when disease is limited to the uterus in all histologic subtypes, although as noted previously, it is no longer incorporated into the FIGO staging algorithm. Optimal therapy has not been determined to date. Historically, intraperitoneal 32P or oral progestins have been used to manage disease in patients with positive cytology. Today, uterine risk factors are largely used to define postoperative adjuvant therapy independent of cytology status and, increasingly, in otherwise low-risk patients (endometrioid-type tumors, negative nodes), observation is often considered. Chemotherapy has also been used in the adjuvant setting for patients with positive cytology, with retrospective studies suggesting a potential benefit.

Molecular Indices Hormone receptors. Historically, estrogen and progesterone receptors were the first “targets” in the molecular biology of endometrial cancer. Using multivariate analysis to analyze hormone receptor status, Creasman and associates noted that in stage I and stage II cancers, progesterone receptor–positive status was a highly significant, independently prognostic factor in endometrial cancer. Without progesterone receptor status in the model and with the evaluation of estrogen receptor status, estrogen receptor–positive status was an independent prognostic factor but not to the degree of progesterone receptor– positive status. Hormone receptor status may closely mirror grade, however. Thankfully, we have seen a transition from disease homogeneity to molecular granularity in the endometrial cancer space, with an explosion of research into the molecular makeup of this disease. Cytogenetic studies have described gross chromosomal alterations, including changes in the number of copies of specific chromosome. The extent of abnormalities in a given tumor is relatively low. About 80% have normal diploid DNA content. Aneuploidy in 20% is usually associated with high-grade, extrauterine disease, high-risk histology, and poor prognosis. Socalled loss of heterozygosity occurs at a relatively low frequency compared with other solid tumors. When chromosomal loss of heterozygosity does occur, underlying molecular genetic defects have been observed on 17p and 10q that correlate with mutational inactivation of TP53 and PTEN, respectively. Individual tumors with a greater number of gains and losses are associated with a poorer prognosis, and some changes seen in cancer are also present in atypical hyperplasia but not simple hyperplasia.

143

Mutational activation or aberrant expression of some oncogenes has been described but to a lesser degree than tumor suppressor genes. The RAS gene family is the most commonly identified oncogene aberration in human cancers and is present in 10% to 30% of endometrial cancers. This mutation appears to occur early in the neoplastic process, and the incidence is the same in endometrial hyperplasia. Correlation of RAS mutation to survival has produced conflicting results. About 10% to 15% of endometrial cancer overexpress ERBB2 (HER2/neu). Overexpression appears to be confined to high-grade or advancedstage tumors. More specifically ERBB2 amplification is most common in USC, occurring in 25% to 45% of these tumors, although estimates of overexpression range from 14% to 80% (Santin, et al., 2005, Buza, et al., 2013, Cancer Genome Atlas Research, et al., 2013). This significant variation is likely related to methodology, criteria used to define overexpression, and interpretation. More recently, a multi-institutional cohort study of 169 patients with stage 1 USC identified that HER2 overexpression (26% HER2-positive; defined as 31 IHC of fluorescent in situ hybridization [FISH] positive), was associated with a significantly higher risk of disease recurrence, and compromised PFS and OS in multivariate models, despite similar rates of adjuvant therapy with carboplatin and paclitaxel (Erickson, 2020, #2598). The FMS oncogene encodes a tyrosine kinase, which serves as a receptor for macrophage colony-stimulating factor (mCSF). Expression of FMS correlates with advanced-stage, highgrade, and deep myometrial invasion. Expression of C-MTC, which has been observed in normal endometrium and endometriosis, has a higher expression in secretory endometrium. Several studies suggest amplification is present in a fraction of endometrial cancers. Mutation of TP53 tumor suppressor gene, the most common genetic abnormality currently recognized in human cancers, is present in 10% to 30% of endometrial cancers. Overexpression or mutation (or both) is associated with prognostic factors. In a study of more than 100 endometrial hyperplasia specimens, TP53 mutation was not present. PTEN mutation analysis in endometrial cancer indicates that this gene is somatically inactivated in 30% to 50% of all tumors, the most frequent molecular genetic alteration defined in endometrial cancer. There does appear to be a correlation between microsatellite instability (MSI) and PTEN mutation. PTEN mutation is observed in 20% of endometrial hyperplasia, suggesting that this is an early event in the development of some type I endometrial cancers. Inherited mutations in gene encoding DNA mismatched repair proteins, including MLH1, PMS2, MSH2, and MSH6, are responsible for HNPCC, for which endometrial cancer is the second most common cancer in women with these mutations. Cancers in these individuals are characterized by frame shift mutations in multiple microsatellite repeat sequences throughout the genome. This mismatch repair deficiency (dMMR) is seen in approximately 20% to 30% of sporadic endometrial cancers, the vast majority of which are endometrioid histology. In these sporadic cancers, acquired mutation in mismatched

144

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

repair genes is rare, although epigenetic silencing of MLH1 can be seen. Endometrial cancers that exhibit dMMR tend to be type I. dMMR can be identified in some cases of complex hyperplasia associated with endometrial cancer but is not seen in USC, and uncommonly in clear cell uterine cancer. Importantly, dMMR, which is defined using immunohistochemistry, does not equate to MSI, which is determined using PCR-based assessments of five microsatellite markers. Cancer specimens with two or more of the five markers exhibiting instability are defined as MSI-high based on the National Cancer Institute Workshop guidelines (Buhard, Cattaneo, et al., 2006). Type I endometrial cancers are commonly described to include tumors seen in obese and nulliparous women, are well differentiated, are superficially invasive, and frequently carry a good prognosis. These tumors also share several common molecular changes and tend to have the following genetic features: diploid, low allelic imbalance, MLH1 methylation, KRAS, and PTEN mutations. In contrast, type II endometrial cancers are associated with poor prognostic pathologic features, have aneuploid, high allelic imbalance, KRAS, TP53, and HER2/neu changes. The Cancer Genome Atlas (TCGA) Research Network has further improved our understanding of the molecular characteristics of endometrial cancer following the publication of a pivotal paper describing molecular alterations identified in endometrial cancer samples (Cancer Genome Atlas Research, et al., 2013). A total of 373 endometrial cancer samples were evaluated using array- and sequencing-based technologies, including low-grade and high-grade endometrioid histologies as well as serous uterine carcinomas. The authors described four molecular groups, including (1) POLE (ultramutated) tumors (~7%), (2) microsatellite unstable tumors (hypermutated, MSI-high mostly as a result of MLH1 promoter methylation) (~28%), (3) copy-number low tumors, mostly endometrioid histology (~39%), and (4) a copynumber high (serous-like) cohort with frequent P53 mutations (26%). POLE-mutant tumors were found to have significantly better PFS, while copy-number high tumors were associated with the worst prognosis. The TCGA additionally confirmed the frequency of PI(3)K/AKT pathway mutations, which occurred more frequently in endometrioid endometrial cancers (93%), than any other tumor type examined by the TCGA. In the TCGA analysis, almost all USC cases clustered into a mitotic transcriptional profile, with evidence of mRNA changes associated with cell cycle dysregulation, including in CCNE1, PIK3CA, MYC, and CDKN2A. Although informative and clinically relevant, the data generated in the TCGA necessitate use of data-intensive and cost-prohibitive methodology. Alternate pragmatic and potentially generalizable methods have been developed to allow for patient classification similar to the initial TCGA publication. Talhouk and colleagues were successful in replicating the molecular classification of the TCGA using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) which includes: (1) mismatch repair protein IHC, (2) POLE mutational analysis, (3) and p53 IHC as a surrogate for copy-number status (Talhouk, McConechy, et al., 2015). Initial assessment was based on MMR status, with dMMR

tumors classified as dMMR and MMR proficient (pMMR) tumors tested for POLE mutations. POLE mutants were classified as POLE exonuclease domain mutations, with POLE wild-type tumors examined for p53 status. pMMR, POLE wild-type tumors were classified as p53 wild-type or p53 abnormal (null/ missense mutations). The ProMisE classifier was subsequently validated in a large cohort series, confirming the prior TCGA findings that POLE mutations had the best prognosis and p53 mutants the worst. The NRG Oncology/GOG 210 study was an observational study that collected tissue, serum, and urine on over 5500 endometrial cancer patients, correlated with clinical and pathologic data. This dataset has resulted in numerous publications and continues to identify relevant molecular, clinical, and prognostic factors in endometrial cancer care. A molecular classification for risk prediction was developed using 982 tumor samples from GOG 210. Investigators assessed MMR defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity at microsatellite repeats. Using four classifications (dMMR copy number altered [can], copy number stable, and POLE mutant), the authors were able to stratify patients by PFS and OS. The classification system remained statistically significant in multivariable analyses. CNA had the worst PFS and cancer-specific survival, whereas the POLE group had the best outcomes. Research continues in an effort to identify molecular markers that may augment clinical-pathologic information in establishing risk and informing adjuvant therapy. Other cancer types (breast, prostate, bladder) have well-validated disease-specific nomograms predicting risk and benefit to adjuvant therapy. Similarly developed and validated models for endometrial cancer are needed. Emerging data in the endometrial cancer space include the PORTEC-3 molecular classification for high-risk endometrial cancer (Leon-Castillo, et al., 2020). Investigators looked to examine prognosis and impact of chemotherapy for predefined molecular subgroups (abstracted from the TCGA endometrial) using 423 patient samples, 103 of which had stage IIIc disease. Submitted tissue specimens were evaluated using p53 IHC, MMR IHC, as well as POLE exonuclease domain DNA sequencing. Samples were then classified as p53 abnormal, POLE-ultramutated, dMMR, or no specific molecular profile (NSMP). Five-year recurrence free survival (RFS) was 48% for patients with p53abn EC, 98% for POLE-mutated EC, 72% for dMMR EC, and 74% for NSMP EC (P , .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P 5 .019); 100% versus 97% for patients with POLEmutated EC (P 5 .637); 68% versus 76% (P 5 .428) for dMMR EC; and 80% versus 68% (P 5 .243) for NSMP EC. The application of the predefined molecular subgroups to the PORTEC-3 dataset suggest a potential predictive capacity of EC molecular classification in identifying the benefit of chemotherapy over radiation. The ongoing PORTEC-4a trial looks to capitalize on these findings by comparing standard adjuvant brachytherapy with individualized treatment algorithms based on integrated molecular profiling. Furthermore, the suggestion of limited benefit of adjuvant chemotherapy in the dMMR cohort enrolled on PORTEC-3 catalyzed the development of novel trials

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

examining adjuvant immune checkpoint inhibitors following radiation versus radiation alone.

Relevant Biomarkers in Endometrial Cancer and Treatment Options Endometrial Cancer Biomarker

Potential Treatment Implications

HER2-positive (defined as 31 IHC of FISH positive) Mismatch repair deficiency (dMMR) POLE mutated

Incorporation of anti-HER2 treatments: Trastuzumab Immune checkpoint inhibition: Pembrolizumab Immune checkpoint inhibition: Pembrolizumab Immune checkpoint inhibition: Pembrolizumab Hormonal Therapy (monotherapy or combination regimens)

TMB-high (.10 mutations/ Mb) Estrogen and Progesterone receptor positive

FISH, Fluorescent in situ hybridization; IHC, immunohistochemical.

Correlation of Multiple Prognostic Factors GOG protocol 33 detailed the extent of disease identified at surgery and correlated this with outcomes. Although single factors were associated with recurrence, the combination of factors could also establish risk. For example, Morrow showed that patients with no risk factors (LVSI, cervical involvement, adnexal involvement, nodal disease) had a very low risk of recurrence, but 20% with one, 43% with two, and 63% with three or more factors recurred. In multivariate analysis, patients with disease limited to the uterus were at increased risk for recurrence if there were deep myometrial invasion, vascular space involvement, or positive washings. Data from three randomized trials evaluating the use of postoperative pelvic radiation therapy have been useful in shaping models predicting risk of recurrence after surgery. Aalders identified a subset of the 95 of 540 (18%) patients enrolled in a randomized trial of vaginal cuff brachytherapy (VCB) with or without pelvic radiation therapy with grade III tumors and any myometrial invasion to be particularly notable for risk of recurrence. Patients with these factors had a pelvic recurrence rate of 20% with vaginal brachytherapy alone compared with 5% with the combination of pelvic and vaginal radiation. It is interesting that approximately 15% of patients with these tumor characteristics failed at a distant site, regardless of radiation technique. The PORTEC trial compared pelvic radiation therapy with observation after hysterectomy without lymph node dissection in patients with endometrial cancer. In this trial of 714 patients, a subset of patients with grade III tumors (10%), age older than 60 years (72%), or greater than 50% depth of invasion (59%) was identified in which having two of three factors defined a high-risk group. The locoregional failure rate was 23% in this group who underwent surgery followed by observation compared with 5% after pelvic radiation therapy. There was no difference in distant sites of recurrence (~5% each group) or in cancer-related deaths (8% observation, 11% radiation). The GOG conducted a randomized trial (GOG 99) of observation versus pelvic radiation in a group of patients with surgically

145

TABLE 5.15 High-Intermediate Risk Model:

Early-Stage Endometrial Cancer Age

Risk Factor

Any age 1 3 factors $50 years 1 2 factors $70 years 1 1 factor

LVSI Grade II or III tumor Outer one-third invasion

LVSI, Lymphovascular space invasion. Modified from Keys HM, Roberts JA, Brunetto VL, et al: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 2004;92:744–751.

documented negative nodes and any amount of myometrial invasion. Depending on patient age and number of risk factors (LVSI, grade I or II tumor, outer one-third myometrial invasion) (Table 5.15), a high-intermediate (H-IR) risk group could be identified. The H-IR group accounted for one-third of all patients enrolled but two-thirds of recurrences. Perhaps equally important was the identification that two-thirds of the patients enrolled who did not have H-IR features had an incredibly low risk of recurrence (2% to 3%), suggesting that in addition to defining high-risk groups, low-risk groups who may avoid postoperative adjuvant therapy may also be identified. The value of risk models is that they can be applied to an individual patient incorporating all of the information (age, uterine characteristics) to provide a reasonable estimate of risk of recurrence and probability of benefit of selected adjuvant therapy.

TREATMENT Surgical Management of Endometrial Cancer Sampling of the endometrium in symptomatic postmenopausal patients is recommended as the first diagnostic technique. If histologic findings are “negative,” the patient is observed. An endometrial curettage is recommended if the patient continues to be symptomatic after the negative endometrial biopsy result. After a tissue diagnosis of endometrial cancer is established, the patient should be assessed for surgical options of therapy. Most patients require routine complete blood counts (CBC), metabolic profile, and a metastatic evaluation with chest radiography. Routine use of computed tomography (CT) or MRI scans has not shown to be useful and should be reserved for patients with high-risk tumor types, evidence of intraperitoneal disease, positive chest radiograph, or clinical evidence of metastatic disease. Most patients with endometrial cancer are candidates for definitive surgery, including surgical staging. Routes of hysterectomy include vaginal, abdominal, laparoscopic (total or assisted), and robotic and have broadened the surgical options for patients. The surgical evaluation of most patients with endometrial cancer requires a thorough inspection of the peritoneal cavity, collection of cytologic washings, and sentinel lymph node (SLN) dissection in addition to hysterectomy. Cytologic evaluation of peritoneal fluids, or washings, has been a common surgical step in staging endometrial cancer because of associations with extrauterine disease and prognosis. After the peritoneal cavity is

146

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

opened, an assessment of the amount of peritoneal fluid in the pelvis is made. If none is present, approximately 100 mL of normal saline solution is injected into the pelvis and aspirated. This can be done with the suction irrigation device at the time of minimally invasive surgical staging. Peritoneal cytologic evaluation may be performed in patients undergoing surgery for endometrial cancer, although FIGO no longer uses cytology as a stage-defining characteristic. Omental biopsy may be considered in patients with gross spread to the omentum or adnexa or in cases with high-risk histologies such as serous or clear cell tumors. In a large GOG study of 621 staged patients, 6% of patients with clinical stage I disease were noted to have intraperitoneal disease. The definitive treatment for patients with endometrial cancer is hysterectomy. The hysterectomy should be extrafascial, and removal of the upper vagina does not appear to decrease vault recurrences (Fig. 5.13). Extirpation of the uterus removes the primary tumor and can provide important information that can be used to estimate risk of spread to lymph nodes or risk of recurrence. Removal of the adnexa is thought to be important given that approximately 5% of endometrial cancers have metastatic disease to the ovaries, fallopian tubes, or both. In addition, synchronous ovarian and endometrial cancers are not infrequent, particularly in younger patients. Historically, total hysterectomy and BSO have been the hallmarks of therapy for endometrial cancer. There are no data to suggest that the route of hysterectomy influences RFS or OS outcomes for patients; as such, the approach (robotic, laparoscopic, or abdominal) that is the safest and facilitates rapid recovery is recommended. Minimally invasive surgical approaches are preferred given the reduced morbidity and rapid recovery without decrement in oncologic outcome, as supported by the LAP-2 publications. Several studies note the role of vaginal hysterectomy in highly selected patients with endometrial cancer for whom surgical staging cannot be performed safely using alternate approaches (significant cardiopulmonary medical comorbidities, advanced age). Because factors associated with the choice of

Figure 5.13 Total abdominal hysterectomy and bilateral salpingo-oophorectomy showing large polypoid adenocarcinoma of the endometrium with deep myometrial invasion.

vaginal hysterectomy (morbid obesity, medical comorbidities) are often associated with favorable uterine characteristics (lowgrade lesions, smaller uterus), it is not surprising that survival rates are comparable to those of the abdominal approach. Chan and coworkers reviewed 51 medically compromised patients treated with vaginal hysterectomy and reported 3- and 5-year disease-specific survival rates of 91% and 88%, respectively. Of note, approximately 50% of women could not have the ovaries removed at the time of vaginal hysterectomy. Assessment of lymph nodes is also not feasible with the vaginal approach and should be a component of patient counseling. Smith evaluated 63 patients with obesity or medical comorbidities and found that vaginal hysterectomy was safe and well tolerated in this patient population. Vaginal hysterectomy may represent a reasonable option for patients who may not tolerate other approaches or for whom surgical staging is not being considered (atypical hyperplasia, some patients with grade I cancers). Over time, there has been a more widespread use of lymphadenectomy in the management of patients with endometrial cancer. Lymph node dissection provides the best estimate of spread of disease (vs. palpation or use of imaging studies), the lymph node status is prognostically important (as evident from the different survival rates seen with different stages of disease), and patients who are found to have positive or negative nodes receive different postoperative therapy versus patients with unknown status of lymph nodes. This may be particularly relevant in the context of recent clinical trials suggesting survival benefits with incorporation of adjuvant chemotherapy in patients with node positive endometrial cancer. Unfortunately, complete pelvic and/or paraaortic lymphadenectomy is associated with intraoperative and postoperative complications including nerve and vascular injury, lymphocyst formation, lymphedema, and neuralgia and is difficult to accomplish in morbidly obese patients (Cardosi, Cox, et al., 2002; Abu-Rustum, Alektiar, et al., 2006). Furthermore, two large prospective phase III trials failed to show a survival advantage with incorporation of lymph node dissection into the surgical staging algorithm. In a large multicentric study (A Study in the Treatment of Endometrial Cancer [ASTEC]), 1408 patients were randomly assigned to TAH or BSO with or without pelvic lymphadenectomy (PLA). With a median follow up of 37 months, there was no difference in survival between the two groups. This was an intent-to-treat study and has been criticized as having a relatively large noncompliance in regard to lymphadenectomy and subsequent therapy. In the lymphadenectomy arm, almost half had no nodes or a small number (#9) removed. This study was further complicated by the fact that many of these patients were secondarily randomly assigned into a postoperative radiation study, not taking into consideration surgical findings. para-aortic lymphadectomy (PALA) was not the standard management, although some patients had these nodes removed. The second study was published by Panici and colleagues. The Italian study randomly assigned 514 stage I patients to systematic PLA or no lymphadenectomy. Although 13% of patients in the lymphadenectomy arm had known metastasis versus 3% in the no-lymphadenectomy arm, there was no difference in recurrence or OS. The protocol required a minimum of 20 lymph

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

nodes to be removed; however, the lymphadenectomy was limited to the pelvis, although PALA could be removed at the discretion of the surgeon. Postoperative radiation was left to the discretion of the treating physician. Adjuvant therapy was similar in the two groups. Whether or not this had an effect on survival is unknown because this was not standardized. In an effort to mitigate adverse events associated with comprehensive lymphadenectomy, while recognizing the prognostic value of defining lymph node status, investigators explored the role of sentinel lymph node dissection in the management of patients with endometrial cancer. The initial feasibility of sentinel lymph node dissection in endometrial cancer was described in retrospective, single institution studies and smaller prospective trials (Barlin, Khoury-Collado, et al., 2012; Darai, Dubernard, et al., 2015). The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was designed to estimate the sensitivity and negative predictive value of sentinel-lymph-node mapping using robotic assisted fluorescence imaging of the tracer indocyanine green (ICG) in detecting lymphatic metastases in patients with endometrial cancer (Table 5.16) (Rossi, Kowalski, et al., 2017). This multicenter, cohort study enrolled a total of 385 patients with endometrial cancer of any histology, and clinical stage 1 disease, without physical examination or radiographic imaging suggestive of extrauterine disease. Investigators injected ICG into the cervix at a dose of 0.5 mg/mL by diluting 1 mL of the stock solution (2.5 mg/ mL) into 4 mL of sterile water. A spinal needle was used to inject 1 mL (0.5 mg) of the ICG solution into the uterine cervix at 3 and 9 o’clock of the ectocervix to a 1 cm depth, achieving a total dose of 1 mg. Successful mapping was defined by observing a channel leading from the cervix directly to at least one candidate lymph node in at least one hemi-pelvis. Identified sentinel lymph nodes were then retrieved and labelled for location (Fig. 5.14). Completion bilateral lymphadenectomy (removal of all remaining non-sentinel lymph node tissue within the relevant nodal basins) was then done on all patients according to the GOG surgical handbook. PLA was required in all

147

patients, with PALA at the discretion of the operating physician. Excellent surgical quality control was incorporated into this trial. Pathologists assessed SLNs for metastases by hematoxylin and eosin (H&E) staining, followed by pancytokeratin AE1 and AEs IHC ultra-staging if H&E assessment was negative. Importantly, 102 patients (29%) had high-grade histology (grade III endometrioid, serous and clear cell cancer). Mapping identified at least one SLN in 293 (86%) of 340 patients. Two of three patients with a mapped isolated paraaortic lymph node had metastatic disease, with otherwise negative pelvic LN. They found an impressive 97.2% sensitivity and 99.6% negative predictive value (Rossi, Kowalski, et al., 2017). In this large study, SLN mapping was not successful in 13.8% of eligible patients. Following publication of the FIRES trial, SLN dissection was adopted into the staging algorithm for endometrial cancer (both minimally invasive and open approaches), with the NCCN recognizing SLN dissection as an appropriate surgical option (Category 2A). It should be emphasized that the success of SLN mapping is dependent on appropriate application of the algorithm, which includes completion of side-specific comprehensive lymph node dissection in cases of failed mapping and the removal of any suspicious appearing LN irrespective of mapping. Lastly, in cases where SLN mapping is not successful, providers can use uterine factors to guide and inform need for nodal assessment. An unanticipated consequence of incorporating SNL dissection into uterine cancer care has been the identification of isolated tumor cells (ITCs) (,0.2 mm) on pathologic nodal evaluation. In the FIRES trial, 19 patients had low-volume disease identified in the SLN, with 10 subjects having ITCs. ITCs do not upstage patients (N0(i1)), and to date, studies suggest no difference in outcome based on choice of adjuvant therapy (Plante, Stanleigh, et al., 2017). In a large, multi-institutional, retrospective study of 175 patients with stage I/II endometrioid endometrial cancer and SLN ITCs, adjuvant therapy did not impact oncologic outcomes (RFS), suggesting observation may be a reasonable approach in this setting (Backes, 2021, #2599).

TABLE 5.16 Findings From Three Pivotal Sentinel Lymph Node Clinical Trials FIRES (Rossi, 2017, #2479)

n 5 385 82% endometroid 12% serous 4% carcinosarcoma 2% clear cell

Successful mapping of at least one SLN in 86% of patients (52% bilateral)

Sensitivity 97%

NPV 99.6%

False negative rate 3%

SENTOR (Cusimano, 2021, #2601)

n 5 156 42% endometrioid (22.5% grade III) 33% serous 11% carcinosarcoma 2% clear cell

Successful mapping of at least one SLN in 97.4% (77.6% bilaterally)

Sensitivity of 96.3%

NPV 99.2%

False negative rate 3.7%

SHREC (Persson, 2019, #2602)

n 5 257 23% serous 5% clear cell 5% carcinosarcoma 65% endometrioid (13.3% grade III)

Successful bilateral mapping in 82% (95% with reinjection)

Sensitivity of 98%

NPV 99.5%

False negative rate 3.5%

148

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Figure 5.14 Fluorescence imaging of the tracer indocyanine green (ICG) in detecting sentinel lymph nodes with processing. (From Lu, Karen H., Broaddus, Russell R., Endometrial Cancer, November 19, 2020, N Engl J Med 2020; 383:2053–2064; with permission)

Longer follow-up time and sample sizes are required to confirm these findings. When comprehensive lymphadenectomy is required, the retroperitoneal spaces in the pelvis are opened in routine fashion. The vessels are outlined, and the lymph node–bearing tissue

along the external iliacs from the bifurcation to the inguinal ligament is removed. The obturator fossa anterior to the obturator nerve is cleaned of lymphoid tissue. Lymph nodes along the common iliacs are also removed. The left and right paraaortic nodes are approached by retracting the small intestine into the upper abdomen and incising the peritoneum over the upper common iliac artery and lower aorta. The main vessels are outlined, and the ureter is retracted laterally. On the right, the tissue overlying the vena cava and the aorta are removed en bloc, beginning at the bifurcation of the aorta and extending caudad. On the left, the left common nodes are frequently quite lateral. Using this technique, one should have a total of 20 to 30 pelvic and paraaortic lymph nodes available for histologic evaluation. The upper limit of the dissection (unless enlarged nodes are noted above this area) is usually the inferior mesenteric artery (IMA), but some surgeons suggest that a comprehensive lymphadenectomy should extend to the level of the renal vessels. In the context of prior studies suggesting two nodal drainage basins—pelvic and paraaortic—the initial adoption of sentinel LN algorithms was accompanied by a concern for paraaortic failures in patients with negative pelvic sentinel LN. Prior studies indicated that when lymph nodes are positive, approximately 50% to 60% of the time paraaortic nodes are involved. In a retrospective study from the Mayo Clinic, 137 patients at high risk for nodal involvement who underwent PALA (PAL1) were compared with those who did not undergo surgical evaluation of the paraaortic nodes (PAL2). The 5-year survival rate was 85% for PAL1 patients compared with 77% for PAL 2 patients. In 51 patients with pelvic or paraaortic node metastasis, survival was 77% for PAL1 patients compared with 42% in the PAL 2 group. It is generally thought that the rate of isolated paraaortic lymph node metastasis is less than 5%; metastasis isolated to the paraaortic lymph node and metastasis above the IMA are seen. Mariani and colleagues reported on a study of 482 patients with endometrial cancer at the Mayo Clinic. A total of 281 underwent lymphadenectomy to the renal vessels, and 22% had positive lymph nodes; of these, 51% had both positive pelvic and paraaortic nodes, 33% had positive pelvic nodes only, and 16% had isolated involvement of the paraaortic nodes. Of note, 46% of those with isolated paraaortic lymph nodes were only positive above the IMA, and 77% had at least one metastatic node located above the level of the IMA. However, the authors do report that there were no positive lymph nodes detected in those with grade I or II tumors with a tumor size of smaller than 2 cm with less than 50% invasion, raising the question of the benefit of lymphadenectomy in the truly low-risk group. Abu-Rustum and colleagues demonstrated a 1% risk of isolated paraaortic lymph node metastasis in both the low- and high-grade tumors. In a meta-analysis which included 3536 patients in six studies, investigators showed higher positive pelvic nodal detection rates, no difference in paraaortic nodal detection rates, and no difference in overall recurrence or nodal recurrence rates in SLN compared with complete lymphadenectomy (Bogani, Murgia, et al., 2019). Specific to high-risk histology, a prospective study examined women with grade III endometrioid, serous, clear cell, and carcinosarcoma by SLN biopsy followed by full pelvic and

Adenocarcinoma and Sarcoma of the Uterine Corpus

CHAPTER 5

paraaortic lymphadenectomy; they found 95% sensitivity and 98% negative predictive value and bilateral mapping rates of 58% and unilateral mapping rates of 40%, supporting the use of SLN in high-risk patients (Soliman, Westin, et al., 2017). Since 1988 when FIGO changed endometrial staging from clinical to surgical, the debate as to whether the lymphadenectomy is only diagnostic, which is an important determinate, or whether

it could also be therapeutic has persisted. Kilgore and associates, in evaluating 649 patients, noted that those who underwent multiple-site lymph node removal had significantly better survival rates than those patients who had no lymph nodes removed (Figs. 5.15 and 5.16). Lymph node removal resulted in a better survival rate than for those without lymph node removal plus postoperative radiation. Cragun and colleagues reported

1 0.9

Proportion surviving

0.8 Low risk, multiple nodes (n 137)

0.7

Low risk, no nodes (n 135)

0.6

High risk, multiple nodes (n 67)

0.5

High risk, no nodes (n 57)

0.4 0.3 0.2 0.1 0 0

Survival (years) Figure 5.15 Survival by nodes sampled and risk groups: multiple-site pelvic node sampling versus no nodes. Low-risk group, P 5 .026; high-risk group, P 5 .0006. (From Kilgore LC, Partridge EE, Alvarez RD, et al: Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling, Gynecol Oncol 56:29, 1995.)

1 0.9

Proportion surviving

0.8 0.7 0.6

Low risk, multiple nodes, no RT (n 74)

0.5

Low risk, no nodes, WP RT (n 17)

0.4

High risk, multiple nodes, no RT (n 17) High risk, no nodes, WP RT (n 14)

0.3 0.2 0.1 0 0

149

Survival (years) Figure 5.16 Survival comparisons of multiple-site pelvic node sampling with whole-pelvic (WP) radiation therapy (RT): multiple nodes without RT versus no nodes plus WP RT. Low-risk group, P 5 .003; high-risk group, P 5 .041. (From Kilgore LC, Partridge EE, Alvarez RD, et al: Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling, Gynecol Oncol 56:29, 1995.)

150

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

that patients with grade III or poorly differentiated cancers with more than 11 lymph nodes removed had an improved survival (HR, 0.25) and PFS (HR, 0.26) compared with those with fewer than 11 lymph nodes removed. However, the number of lymph nodes removed was not predictive of survival outcome in those with grade I and II tumors. This association between lymphadenectomy and improved survival remained when controlling for adjuvant radiation treatment, emphasizing the impact of extensive lymph node dissection. A retrospective review by Chan and colleagues of more than 12,000 patients showed an increased 5-year survival rate for the intermediate- and high-risk group that underwent an extensive lymph node dissection. However, there was no benefit of nodal dissection seen in the low-risk group. Removal of nodes involved by tumor has been supported as a therapeutic option. In a study reported by Havrilesky et al., 91 patients were identified with stage IIIc disease. There were 39 with microscopic involvement of the lymph nodes and 52 with grossly enlarged nodes. After surgery, 92% received some type of adjuvant therapy with 85% receiving radiation therapy. The survival rate (5 years) was 58% in the 39 with microscopic lymph nodes, 48% in 41 patients with grossly positive lymph nodes completely resected, and only 22% in the 11 with unresected lymph nodes. The authors believed that these data suggested a therapeutic benefit for lymphadenectomy. Similarly, in a small study of 41 patients, Bristow and coworkers noted disease-free survival (DFS) was improved if patients with bulky adenopathy underwent complete resection of involved nodes compared with patients who had gross residual disease in lymph nodes remaining after surgery (37.5 vs. 8.8 months; P 5 .006). Onda and colleagues carried out thorough pelvic and paraaortic lymphadenectomies on 173 patients with stage I to III endometrial cancer. The average numbers of lymph nodes removed were 38 pelvic and 29 paraaortic. There were 30 patients (17%) with positive nodes: 10 to pelvis only, two paraaortic only, and 18 with metastasis to both pelvic and paraaortic nodes. Selected patients received radiation therapy with extended fields, combination chemotherapy, or both. In the 10 patients with only pelvic metastasis, the 5-year survival rate was 100%; it was 75% in those with paraaortic involvement. The authors suggest that, although postoperative treatment may contribute to these excellent results, systematic pelvic and PALA was a contributing factor. One of the important effects of lymph node dissection is that it identifies that most patients with negative lymph nodes are at very low risk for recurrence. As such, lymph node dissection has allowed for modifications of postoperative therapy away from pelvic radiation. In one study, Mohan and associates evaluated 159 stage I patients who had full PLA and received vaginal brachytherapy rather than the more traditional pelvic radiation. In general, vaginal brachytherapy is a quicker therapy (1 to 3 days vs. 5 to 6 weeks for pelvic radiation) and is associated with fewer side effects. In the Mohan study, the 15-year OS was 92%, and the recurrence rate was 4%, all at distant sites. Podratz and associates reviewed four studies that used thorough lymphadenectomies in moderate- and high-risk patients who did not receive postoperative radiation therapy.

There were 20 recurrences (7%) in 305 patients; only five recurrences were local or regional, with four being in the vagina. Those four did not receive postoperative brachytherapy but were salvaged with subsequent radiation. The disadvantages of a lymph node dissection include that the performance of lymph node dissection requires a specially trained surgeon, has the potential to increase complications, as previously discussed, and has not been prospectively validated to improve outcomes. Two phase III trials compared the use of lymph node dissection or not in patients with endometrial cancer with no identifiable improved outcome with lymph node dissection. The Cochrane Database concluded that there was no overall statistical difference between PFS and OS in patients who had a lymphadenectomy versus those who did not but did report more morbidity for those patients who had a lymphadenectomy. Cochrane only considered the ASTEC and the Panici trial in reaching this conclusion. Patients with stage II carcinoma of the endometrium, because of extension of disease into the endocervix, will have a greater propensity for lymph node metastasis. For example, in the GOG 33 protocol, 16% of patients with cervical involvement had positive pelvic lymph nodes versus 8% with a fundal location of tumor. Even in patients with occult cervical involvement, 19% of patients had lymph node metastases. In addition, parametrial and vaginal involvement are thought to be more common when the cervix is involved. As such, surgery in the form of radical hysterectomy and lymphadenectomy can be considered when there is gross cervical involvement with tumor. Because many cases of cervical involvement are occult and only recognized after surgery, simple hysterectomy with lymph node sampling (SLN algorithm) appears to be adequate surgery in most cases. Postoperative radiation therapy can be planned, depending on surgical-pathologic findings, including use of pelvic radiation or VCB, both, or neither. Currently, a minimally invasive approach to endometrial cancer staging is advocated given similar oncologic outcomes with reduced intra- and perioperative morbidity. A large GOG study, led by Walker and colleagues (GOG LAP2), compared laparoscopy versus laparotomy in the surgical management of endometrial cancer. Patients were randomly assigned between laparoscopic versus open laparotomy surgical staging. Laparoscopy was initiated and completed without conversion in 74%. Conversion from laparoscopy to laparotomy was secondary to poor visibility in 15%, metastatic cancer in 4%, and bleeding in 3%. Patients randomly assigned to undergo laparoscopy had significantly fewer moderate to severe postoperative (14% versus 21%) complications and similar rates of intraoperative complications. Length of hospital stay was significantly shorter for those randomized to undergo laparoscopy (median 3 days vs. 4 days), but operative time was significantly longer (median, 204 vs. 130 minutes). Pelvic and paraaortic nodes were removed in 92% of patients undergoing laparoscopy and 96% of patients undergoing laparotomy, and cytology was performed in 96% versus 98%. Neither treatment arm demonstrated an improved ability to detect metastatic disease. Quality-of-life evaluation found a better body image and return to normal activities for

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

the patients undergoing laparoscopy. Laparoscopic surgical staging is feasible and safe for patients with uterine cancer and results in fewer complications and shorter hospital stays. Recurrence rates were lower than anticipated; the estimated 3-year recurrence rate was 11% with laparoscopy and 10% with laparotomy, and the estimated 5-year OS rate was almost identical in both arms (90%). Today, advancements of laparoscopic surgery, including use of a robotic surgical platform, have permitted minimally invasive approaches with a reduction in conversion rates to open laparotomy. Robotic surgery offers three-dimensional graphics, visual magnification, improved ergonomics, masking of operating physician tremor, and greater dexterity of surgical instruments. Robotic surgery has expanded the application of laparoscopy, especially in obese patients or patients in whom a vaginal component is more difficult. Although the majority of studies comparing conventional laparoscopy to robotic assisted laparoscopic surgery in the endometrial cancer space have been retrospective, small randomized prospective trials have been performed. Multiple retrospective trials suggest similar oncologic outcomes. Mäenpää and colleagues randomly assigned 101 endometrial cancer patients to conventional laparoscopy and robotic assisted laparoscopic surgery. The robotic approach was associated with a significant reduction in operative time, total time spent in the operative theater, and in conversions to laparotomy (Maenpaa, et al., 2016). Certainly, cost considerations must be accounted for given the large upfront capital costs associated with acquisition of robotic surgical equipment. Increasing data suggest that even in grade I disease, as noted on endometrial biopsy, a significant number of patients have full surgical staging findings that would have an impact on further therapy. Ben-Shachar and colleagues, in evaluating 181 grade I endometrial cancers, found that 19% had grade change on hysterectomy specimen, 11% had extrauterine disease, 4% had lymph node metastasis, and 26% on final evaluation had high-risk intrauterine factors. Of note, the authors believed because of full surgical staging that 12% needed and received adjuvant therapy, and 17% who may have received postoperative treatment did not based on full surgical findings. Geisler and associates found in 349 patients that of those with grade I lesions, 16% had positive nodes and 3% had positive paraaortic nodes only. Of all positive nodes, 31% occurred in grade I lesions. As a result of these and other studies, it is advocated that all patients with endometrial cancer should have the benefit of surgical staging, which includes peritoneal cytology, TAH, and BSO, with SLN dissection. Obviously, complete evaluation of the entire peritoneal cavity and its contents should be performed, and any suspicious areas should be pathologically evaluated.

Radiation Therapy Radiation therapy remains a cornerstone of adjuvant therapy for endometrial cancer and has evolved considerably over time. Historically, nearly all patients received some form of preoperative or postoperative radiation therapy given the perception that risk for recurrence was high. Whereas GOG 33 defined

151

TABLE 5.17 Radiation in Early-Stage

Carcinoma of the Endometrium

Local Recurrence (%)

Survival (%)

Surgery 1 VCB (n 5 277)

Surgery VCB 1 RT (n 5 263)

Surgery (n 5 300)

14b

Surgery 1 RT (n 5 354)

Surgery (n 5 202)

Surgery 1 RT (n 5 190)

Surgeryc(n 5 454)

Surgery 1 RT (n 5 452)

Aalder

Creutzberg (PORTEC)

Keyes (GOG 99)

ASTEC/NCIC CTG EN.5

ASTEC, A Study in the Treatment of Endometrial Cancer; GOG, Gynecologic Oncology Group; NCIC CTG EN.5, National Cancer Institute of Canada Clinical Trials Group Endometrial Cancer 5 trial; PORTEC, PostOperative Radiation Therapy in Endometrial Cancer; RT, pelvic radiation therapy; VCB, vaginal cuff brachytherapy. a P , .01. b P , .001. c 50% received vaginal brachytherapy. d P 5 .038.

relationships between depth of invasion and tumor grade and extrauterine spread after surgical staging, it also showed that most patients were not at risk for extrauterine disease spread. As such, the routine use of pelvic radiation therapy became increasingly questioned. To date, four large prospective randomized studies have compared external beam pelvic radiation with observation or vaginal brachytherapy in women with endometrial cancer (Table 5.17). Aalders and colleagues compared VCB with or without pelvic radiation in 540 patients with early-stage endometrial cancer. Patients did not undergo lymph node dissection. The addition of pelvic radiation therapy reduced local failures (2% vs. 7%), but there was no difference in 5-year survival between groups (89% pelvic, 91% brachytherapy). Onsrud et al. updated the long-term follow-up for these patients. After a median 20.5 years of follow-up, no statistically significant difference was revealed in OS between treatment groups. However, women younger than age 60 years had significantly higher mortality rates after external-beam radiotherapy (EBRT) (HR, 1.36; 95% CI, 1.06 to 1.76) than the control group. The risk of secondary cancer increased after EBRT, especially in women younger than age 60 years (HR, 2.02; 95% CI, 1.30 to 3.15). The authors concluded that there was no survival benefit of external pelvic radiation in early-stage endometrial carcinoma. In women younger than age 60 years, pelvic radiation decreased survival and increased the risk of secondary cancer. Thus, adjuvant EBRT should be used with caution, especially in women with long life expectancies. In the Dutch PORTEC trial, Creutzberg et al. enrolled 714 patients with grade I lesions with greater than 50% myometrial invasion, grade II lesions with any amount of invasion, or grade III with less than 50% invasion. Patients were randomly assigned

152

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

postoperatively to receive either external radiation or observation. None of the patients were surgically staged, and all histologies were eligible. In the 654 eligible for follow-up, local and regional recurrences were less frequent in the radiation therapy group (4% vs. 14%) than in the observational group, but the 5-year survival rates were similar, 81% versus 85%, respectively. As published by Creutzberg et al., after 15 years, there remained no survival advantage and a trend for long-term risk of second cancers. The GOG performed a phase III trial, GOG protocol 99, of surgery with or without adjuvant external beam pelvic radiation in intermediate-risk endometrial ACs. These included all women with any degree of myometrial invasion, any grade, and no evidence of lymph node metastasis (stage IB, IC, IIA occult, and IIB occult). All patients were required to have surgical staging with histologic evaluation of the lymph nodes. A total of 202 patients received no radiation (no adjuvant therapy [NAT]), and 190 received pelvic radiation. The median follow-up period was 69 months. The reported recurrence rate was 15% in the NAT group compared with 6% to 8% in the radiation group (P 5 .007). Local recurrences were 9% versus 2%, respectively. The OS at 48 months was 86% for NAT and 92% for radiation, with intercurrent diseases accounting for half or more of the deaths in both groups. Deaths from disease were 8% in both the NAT versus radiation group. Grade III and IV toxicity by treatment was 5% versus 14% in the NAT and radiation, groups, respectively. Twelve of the 13 women who had isolated vaginal recurrences, and were initially randomized to the NAT arm were treated with radiation, and five have died of disease. Importantly, GOG 99 allowed for the identification of a H-IR subgroup, in a post-hoc manner, that appeared to derive the greatest benefit from pelvic radiation. In the H-IR cohort, the recurrence rate was 27% in the observation arm, versus 13% after pelvic radiation. All other eligible patients were considered low–intermediate risk and had recurrence rates less than 1% to 3% regardless of the use of radiation therapy. H-IR was defined using a combination of age, grade, presence of LVSI, and depth of invasion. Data from a pooled trial of the Medical Research Council (MRC), ASTEC and National Cancer Institute of Canada Clinical Trials Group Endometrial Cancer 5 (NCIC CTG (EN.5) randomized trials also showed no survival advantage for adjuvant EBRT in the treatment of endometrial cancer (5-year survival rate ~84% both groups). In this study including 906 patients randomly assigned to pelvic radiation or observation, 30% of patients underwent lymphadenectomy, and 50% received vaginal brachytherapy. Pelvic radiation reduced local failures (6% with observation vs. 3% after pelvic radiation). In a subsequent Cochrane review on the use of adjuvant radiation therapy for stage I endometrial cancer, the authors concluded that there is no survival advantage with routine use of pelvic radiation therapy and that benefits must be balanced against the toxicity and morbidity of therapy. Essentially all studies evaluating pelvic radiation therapy show improved local control rates compared to observation. The local control, however, is largely a result of reduction in vaginal cuff recurrences. A considerable amount of data has been collected to evaluate vaginal recurrence and survival rate with surgery alone

TABLE 5.18 Survival Rate in Stage I

Carcinoma of the Endometrium With Regard to Grade and Treatment SURVIVAL Grade

Surgery Only (%)

Combined Therapy (%)

1295/1375 (94)

2284/2389 (96)

488/510 (96)

1490/1721 (87)

III

100/135 (74)

398/498 (80)

From Pettersson F, editor: Annual report on the results of treatment in gynecological cancer, vol 21, Stockholm, 1991, International Federation of Gynecology and Obstetrics.

TABLE 5.19 Recurrences in Stage I

Carcinoma of the Endometrium With Regard to Depth of Invasion and Treatment Recurrence

Surgery and Radium

Surgery and External Radiation

Endometrium only

6/88 (7%)

0/4 (0%)

Inner and mid thirds

3/68 (4%)

9/29 (31%)

Outer third

3/9 (33%)

11/24 (46%)

Modified from DiSaia PJ, Creasman WT, Boronow RC, et al: Risk factors in recurrent patterns in stage I endometrial carcinoma, Am J Obstet Gynecol 151:1009, 1985.

or combined therapy when mainly preoperative application of brachytherapy and surgery were used. Data have also been evaluated concerning the grade of the tumor (Table 5.18) and, in some instances, the depth of myometrial involvement (Table 5.19). In patients who had postoperative radiation, there appeared to be a lower incidence of vaginal vault recurrences, although there does not appear to be much difference in the grade I and grade II lesions. Vaginal vault recurrence did not appear to affect survival. Results of a randomized prospective trial comparing adjuvant EBRT versus vaginal brachytherapy in 427 patients with intermediate-risk early-stage endometrial cancer have been reported (PORTEC-2). No differences in recurrence rate (vaginal failure 2% with pelvic radiation, 0.9% with vaginal brachytherapy) or OS (3-year survival rate ~90% both groups) were observed between the two treatment arms, suggesting that patients with intermediate-risk early-stage endometrial cancer can be treated with adjuvant vaginal brachytherapy alone. Although these findings have led many clinicians in the United States to move away from the routine use of EBRT in early-stage endometrial cancer, it is important to note that in the patients who did not undergo a lymph node dissection, pelvic failure rates were higher in the vaginal brachytherapy group (3.5% vs. 0.7%), and the study excluded higher-risk patients such as those with grade III or deeply invasive tumors. An additional study comparing pelvic radiation followed by VCB to VCB alone for “medium-risk” endometrial cancer by Sorbe et al. showed results similar to PORTEC-2, demonstrating that pelvic radiation reduced locoregional relapse rates (1% vs. 5%, P 5 .013) with no difference in OS. Sorbe et al. also reported a randomized trial of vaginal brachytherapy versus no further treatment in patients with low-risk endometrial cancer (grade I or

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

II endometrioid cancer with ,50% invasion). There was no significant reduction in vaginal recurrence in the group receiving brachytherapy (3% vs. 1%). GOG protocol 249 was designed to determine whether adjuvant chemotherapy could improve cancer outcomes in patients with H-IR endometrial cancer (Randall, et al., 2019). This was based on the observation that both PORTEC-1 and GOG protocol 99 reported distant failure rates of 20% to 30% in highrisk patients. Eligible patients had International Federation of Gynecology and Obstetrics (2009) stage I endometrioid histology with H-IR criteria, stage II disease, or stage I to II serous or clear cell tumors. A total of 601 patients were randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m2 (3 hours) plus carboplatin (area under the curve [AUC], 6) every 21 days for three cycles (Randall, et al., 2019). With a median follow-up of 53 months, the 60-month RFS was 0.76 for RT and 0.76 for brachytherapy followed by chemotherapy (HR 0.92; 90% CI 0.69 to 1.23). Furthermore, no difference in 60-month OS was identified between study arms (HR 1.04; 90% CI 0.71 to 1.52). Pelvic or paraaortic nodal recurrences were more common in the chemotherapy arm, 9% versus 4%. Ironically, patients with serous cancer accounted for 15% of patients enrolled on GOG 249, and although the expectation was that chemotherapy may benefit patients with this high-risk histology, there was no significant difference in PFS or OS when chemotherapy was combined with VCB. Two additional pivotal clinical trials looked to better define the utility of radiation and chemotherapy in the management of locally advanced endometrial cancer. GOG protocol 258 was developed in an effort to address local recurrences, reported to occur in up to 20% of patients treated on the chemotherapy arm of GOG 122 (Matei, Filiaci, et al., 2019). The experimental arm was supported by prior studies, including RTOG-9708, which examined adjuvant cisplatin 50 mg/m2 intravenously on days 1 and 29 plus volume-directed radiation therapy (45 Gray 6 brachytherapy) followed by paclitaxel 175 mg/m2 and carboplatin AUC 5 every 21 days for four cycles. GOG 258 enrolled a total of 813 patients with stage III or IVa endometrioid endometrial cancer, as well as stage I or II serous or clear cell carcinoma with positive washings. Patients were randomized to combined chemoradiation which consisted of cisplatin 50 mg/m2 on days 1 and 29 together with volume-directed external beam radiation therapy, followed by carboplatin AUC of 5 to 6 plus paclitaxel at a dose of 175 mg/m2 every 21 days for four cycles, with GCSF support or a chemotherapy-only regimen consisting of carboplatin AUC of 6 plus paclitaxel at a dose of 175 mg/m2 every 21 days for six cycles. In the chemoradiotherapy group, external beam radiation therapy was delivered to the pelvis with or without paraaortic fields. The planned total dose was 45 Gy in 25 fractions at 180 cGy per fraction. Intensity modulated radiotherapy and vaginal brachytherapy were allowed only in the chemoradiotherapy group (Matei, Filiaci, et al., 2019). Nearly all enrolled patients (98%) had no gross residual disease, and 94% underwent some degree of lymph node assessment. At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse free was 59% (95% CI, 53 to 65) in the

153

chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy only group (HR 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; HR 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph node recurrence (11% vs. 20%; HR 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; HR 1.36; 95% CI, 1.00 to 1.86). Furthermore, assessment of quality-of-life endpoints suggested both acute and long-term toxic effects of combination chemoradiation therapy, suggesting that chemotherapy alone was the most appropriate adjuvant regimen in this patient population. In an analogous manner, PORTEC-3 was designed to compare adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiation alone in women with high-risk endometrial cancer. Eligible women had FIGO 2009 stage I, grade III endometrioid carcinoma with deep myometrial invasion or lymph-vascular space invasion (or both), stage II or III endometrioid AC, or stage I to III with serous or clear cell histology. Nearly half of the women enrolled on this trial had stage I or II disease. Patients were randomly assigned (1:1) to receive radiotherapy alone (48.6 Gy in 1.8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) (de Boer, Powell, et al., 2018). A total of 686 women were enrolled, with investigators showing an improvement in 5-year failure free survival in the chemoradiotherapy arm (HR 0.71, 95% CI 0.53 to 0.95; P 5 .022), but no significant improvement in OS (HR 0.76, 95% CI 0.54 to 1.06; P 5 .11) (de Boer, Powell, et al., 2018). Grade 3 or worse adverse events were significantly more common in the chemoradiotherapy arm. When specifically examining patients with stage III disease, the investigators showed a more pronounced FFS advantage (HR 0.66, 95% CI 0.45 to 0.97) with a non-significant trend toward improved OS (HR 0.71, 95% CI 0.45 to 1.11). An updated post-hoc survival analysis of PORTEC-3, completed at a median follow-up of nearly 73 months suggested both a significant OS and failure-free survival advantage with chemoradiotherapy (de Boer, Powell, et al., 2019). This advantage appeared to be most pronounced in patients with stage III disease, as well as those with serous histology. Taken together, the results of GOG 258 as well as PORTEC-3 highlight the importance of chemotherapy in the management of patients with stage III endometrial carcinoma. Conversely, the results of GOG 249 and PORTEC-3 suggest that the addition of chemotherapy to radiation in patients with stage I or II disease may confer limited benefit with additional treatment-related toxicity.

Chemotherapy The role of chemotherapy in the treatment of endometrial cancer continues to evolve. Traditionally reserved for patients with recurrent or metastatic disease, chemotherapy has become increasingly used in the first-line management of patients with advanced-stage and high-risk early-stage disease. Historically,

154

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

radiation therapy has been the adjuvant of choice for patients at risk of recurrence. Although the overall prognosis of patients in adjuvant radiation trials has been favorable, approximately 20% of patients have a recurrence at distant sites, demonstrating the need for effective systemic therapy, as previously discussed.

Drug Development Phase II studies have identified several single agents with modest activity in patients with advanced or recurrent endometrial cancer. In a report of the GOG experience, Thigpen and colleagues noted that 37% with advanced or recurrent cancer experienced an objective response with use of singe agent doxorubicin. Unfortunately, responses lasted only 7 months. The Eastern Cooperative Oncology Group achieved only a 19% response rate in its doxorubicin trial; however, a lower dosage was used than that in the GOG study. Although response rates to the single agent were initially promising, few patients achieved a complete response. Likewise, phase II studies identified platinum agents (cisplatin, carboplatin) and taxanes (paclitaxel) to have significant activity. Combining two or more active agents has been an important strategy in the management of endometrial cancer. Phase III studies have shown better response rates when the agents were combined compared with used alone. Several chemotherapy combinations have been used in recurrent or advanced endometrial cancer. The GOG, in a randomized trial, GOG protocol 107, compared doxorubicin with or without cisplatin. The combination produced tumor response in 66% versus 35% for the single agent, with median progression-free intervals of 6.2 and 3.9 months, respectively. The GOG reported a 45% response rate (22% complete response) for the combination of doxorubicin and cisplatin in advanced or recurrent endometrial cancer compared to 17% response for doxorubicin alone. The European Organization for Research and Treatment of Cancer Gynecological Cancer Cooperative Group (EORTCGCCG) compared doxorubicin alone with doxorubicin and cisplatin. The reported response rates were 17% and 57%, respectively. The GOG (GOG protocol 163) compared doxorubicin and cisplatin with doxorubicin and paclitaxel (24-hour infusion) plus filgrastim in advanced or recurrent endometrial cancer. A total of 317 patients were randomly assigned to the two regimens. Response rates were similar (40% vs. 43%). Median PFS was 7.2 versus 6 months, and median OS was 12.6 versus 13.6 months. Toxicities were also similar. GOG protocol 177, a phase III study, compared doxorubicin plus cisplatin with or without paclitaxel plus filgrastim (TAP) in advanced endometrial cancer. There were 273 women registered, and objective responses were 57% versus 34% (P , .01); PFS (median, 8.3 vs. 5.3 months, P , .01) and OS (median, 15.3 vs. 12.3 months, P 5 .037) were improved with the triple combination TAP regimen. This study marked for the first time a statistically significant improvement in response rate, PFS, and OS with a combination regimen in endometrial cancer. However, the three-drug regimen required a 2-day treatment and the use of growth factors on day 3 and was associated with moderate peripheral neuropathy. Based on the difficulties associated with the triplet regimen, particularly neuropathy and need for growth factors, Miller and

colleagues developed and completed GOG protocol 209, which randomized patients to the three-drug TAP regimen or combination carboplatin plus paclitaxel (TC) (Miller, Filiaci, et al., 2020). TC was previously shown to be active in phase II endometrial cancer trials. GOG protocol 209 enrolled 1381 women over approximately 6 years. TC was found to be noninferior to TAP with respect to OS (median 37 vs. 41 months, respectively; HR 1.002, 90% CI 0.9 to 1.12) and PFS (median 13 vs 14 months; HR 1.032; 90% CI 0.93 to 1.15) (Miller, Filiaci, et al., 2020). Neutropenic fever was similar between treatment arms, although sensory neuropathy, grade 3 or greater thrombocytopenia, emesis, diarrhea, and metabolic toxicities were more frequent in the TAP arm. These findings established carboplatin and paclitaxel as the preferred systemic regimen for the treatment of metastatic or recurrent endometrial cancer, and as the backbone for future clinical trials.

Advanced Disease Drug development trials are designed to assess the efficacy of new drugs or combinations in patients with metastatic or recurrent disease. Treatment of patients with stage III or IV disease depends largely on the extent of surgical resection. Patients with stage III or IV disease and resection to less than 1 to 2 cm residual may be treated with curative intent chemotherapy, radiation, or a combination of the two. The GOG, in protocol 122, studied patients with stage III or IV endometrial cancer with 2 cm or less residual disease (distant metastases were excluded). After surgery, patients were randomly assigned to receive doxorubicin and cisplatin every 3 weeks for eight courses or whole-abdominal radiation with 3000 cGy to the whole abdomen. A boost to the pelvic and paraaortic lymph node region (1500 cGy) could be given for positive nodes. As reported by Randall et al., 2 years after therapy, the OS rate was improved by 11%, and the cancer-free survival rate was improved by 13% with chemotherapy compared with those treated with radiation therapy. Side effects were more common in the chemotherapy-treated patients, and chemotherapy was established as the preferred regimen for these patients. In an effort to build on improvements noted with the firstline chemotherapy into the management of patients with advanced endometrial cancer, the GOG performed a randomized trial (GOG 184) comparing volume-directed radiation (pelvic radiation with or without extended field to cover paraaortic lymph nodes) followed by six cycles of doxorubicin–cisplatin with or without paclitaxel chemotherapy. The results showed no improvement in PFS with the addition of paclitaxel to pelvic radiation plus cisplatin and doxorubicin except in patients with gross residual disease. Although the results of GOG 184 may seem to conflict with the results of GOG 177, several important observations can be made. First, the addition of pelvic radiation therapy may supplant the benefit of adding paclitaxel to the two-drug regimen seen in GOG 177. Second, this trial demonstrates the feasibility of combining multiagent cytotoxic chemotherapy with adjuvant radiation. The role of radiation therapy in advanced disease was subsequently addressed in GOG 258 and PORTEC-3 as previously described.

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Factors associated with response to chemotherapy have been studied. Behbakht and colleagues evaluated prognostic factors in 137 patients with advanced disease (stage III and stage IV). Multivariate analysis noted age, parametrial involvement, and abdominal metastasis as significant prognostic indicators. An increased frequency of advanced stage was also noted with USC histology. Unfortunately, multiple therapies were used, and conclusions concerning treatment cannot be made. Kadar and associates evaluated 58 patients with surgical stage III and stage IV disease. Extrapelvic peritoneal metastasis and positive peritoneal cytologic findings affected survival. If either of these factors was present, the 2-year survival rate was only 25% compared with 83% if they were not present. Postoperative therapy varied, but it did not appear to have any effect on survival.

Adjuvant Therapy: High-Risk Disease Given the results of GOG 122, new considerations for chemotherapy in a variety of settings have been considered. The Japanese GOG group performed a randomized trial of chemotherapy (at least three cycles of cyclophosphamide, doxorubicin, cisplatin [CAP regimen]) versus pelvic radiation in patients with endometrial cancer. Most patients had stage Ic or II disease (75%), but patients with IIIa and IIIc disease were included. For all patients, there was no difference in PFS or OS between the regimens. The study did identify a group of patients with higher risk features (Ic or grade III, stage II or III with depth of invasion .50%) for whom PFS and OS were significantly improved in the chemotherapy arm. Maggi and colleagues performed a similar study comparing five cycles of CAP chemotherapy with pelvic radiation in 340 patients with endometrial cancer. In this trial, 62% of patients had stage IIIa to IIIc disease. The 5-year PFS and OS were not statistically different between the groups. Neither of these studies used paclitaxel, an agent that in phase II and III studies appears to offer improved efficacy. The role of adjunctive chemotherapy in addition to surgery and radiation therapy has been addressed by the GOG in patients with high-risk stage I and occult stage II endometrial cancers. Morrow et al. reported on 181 patients treated with TAH and BSO, peritoneal cytologic evaluation, and selective pelvic and PALA followed by external irradiation (pelvic with or without extended field) and were then randomly assigned to receive doxorubicin 60 mg/m2 every 3 weeks for eight doses. Patients participating in the doxorubicin arm of the protocol had a higher incidence of metastases to pelvic nodes (20% vs. 10%) than did those in the no doxorubicin arm; otherwise, the risk factors were equal between the two groups. There were recurrences in 22 of 92 (23%) in the doxorubicin arm versus recurrences in 23 of 89 (26%) in the non-doxorubicin arm. Of patients with recurrences, those who received doxorubicin had a greater chance of metastasis to the abdomen than did those not receiving it (40% vs. 17%). However, distant metastases occurred more frequently without the use of doxorubicin than with it (56% vs. 18%). The small sample size (and reduced power), the heterogeneous population, and the use of single-agent doxorubicin (as opposed to combination therapy) are weaknesses of the study. The Radiation Oncology Group (RTOG) and the EORTC have both published data on patients

155

with high-risk early-stage endometrial cancers treated with adjuvant radiation therapy with or without adjuvant platinum-based chemotherapy. Both trials suggest that adjuvant radiation combined with adjuvant chemotherapy in high-risk early-stage endometrial cancers is feasible and may result in better OS. Based on the experience with current studies, GOG protocols 249 and 258 as well as PORTEC-3 were developed and completed, with findings as previously reviewed.

Hormones Progestins have been used for more than 30 years, and the objective responsiveness of recurrent carcinoma of the endometrium to these hormones has been substantiated (Fig. 5.17). Historically, approximately one-third of all patients with recurrent carcinoma of the endometrium are said to respond to the hormone, although patients with well-differentiated tumors have a response rate much higher than that of patients with moderately or poorly differentiated lesions. The GOG described 420 patients with advanced or recurrent endometrial carcinoma treated with medroxyprogesterone acetate (MPA) 50 mg three times a day. Of the 219 patients with objective measurable disease, there were only 17 complete responders (8%) and 13 partial responders (6%). More than half of the patients had stable disease, and one-third progressed. The median survival time was 10.5 months. Grade I lesions responded more frequently than poorly differentiated carcinomas. GOG protocol 81 was a randomized phase III trial that examined MPA at 1000 mg/day compared with 200 mg/day. In almost 300 patients, there was no difference in response rate or survival between the two groups. Lentz, in GOG 121, explored highdose megestrol acetate (800 mg/day) in patients with advanced or recurrent endometrial carcinoma. Of 58 patients, 13 (24%)

Figure 5.17 Patient with right hilar metastases that resolved completely on progestin therapy.

156

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

responded; 6 (11%) had a partial response. Four of the responses lasted more than 18 months and were primarily seen in grade I and grade II lesions. Considerable interest has been shown in the presence of specific estrogen and progesterone receptors in neoplastic human uterine tissue. These receptors are definitely present and vary from tumor to tumor. It has been shown that there is a greater number of both estrogen and progesterone receptors in well-differentiated lesions than in poorly differentiated ones (Table 5.20). In a small group of patients, it was noted that about one-third of those with recurrent cancer had a positive receptor site analysis to both estrogen and progesterone. The receptor data may therefore correlate with clinical findings of responsiveness to progesterones in patients with recurrent cancer. Preliminary data suggest an excellent correlation (Table 5.21). Kauppila noted from five studies in the literature that 89% of progesterone receptor–positive tumors were hormonally responsive compared with only 17% of progesterone receptor– negative tumors. The GOG noted that 4 of 10 (40%) estrogen receptor–positive, progesterone receptor–positive tumors responded to progestins compared with 5 of 41 (12%) progesterone receptor–negative tumors. Progestin therapy may be administered in several different ways: MPA (Depo-Provera), 400 mg intramuscularly at weekly intervals; oral MPA (Provera) in the range of 150 mg/day; and megestrol acetate (Megace) 160 mg/day are recommended progestins. Progestins are continued indefinitely if an objective response is obtained. If progression of disease is noted, progestins should be discontinued, and chemotherapy should be considered. Progestins have been evaluated as adjunctive therapy in the hope of preventing recurrences. Lewis and coworkers, in a randomized study, treated endometrial cancer patients postoperatively with MPA or placebo. The 4-year survival rate was similar in the two groups. Kauppila, in describing more than 1100 patients who received adjunctive progestin therapy for 2 years TABLE 5.20 Correlation of Tumor

Differentiation With Receptor Content Differentiation

ER and PR Positive (%)

Well

28/40 (70)

Moderate

21/38 (55)

Poor

11/27 (41)

ER, Estrogen receptor; PR, progesterone receptor. From Creasman WT, Soper JT, McCarty KS Jr, et al: Influence of cytoplasmic steroid receptor content on prognosis of early stage endometrial carcinoma, Am J Obstet Gynecol 151:922, 1985.

TABLE 5.21 Response to Progestin

Therapy in Regard to Receptor Content Receptor Content

Progestin Response (%)

Positive

44/55 (80)

Negative

4/76 (5)

Based on papers by Ehrlich et al., Benraad et al., Creasman et al., Kauppila, Pollow et al., and Quinn et al.

after surgery and radiation therapy, found that even in stage I low-grade tumors, recurrences did appear; it was their belief that prophylactic progestins were not of benefit to these patients. In a prospective study of 363 patients with stage I disease who received adjuvant MPA for 12 months, DePalo and colleagues compared survival with that of 383 patients with stage I disease who did not receive MPA postoperatively; there was no difference in survival between the two groups. In a British study in which 429 patients with stage I or stage II cancers were randomized between postoperative MPA and observation, no difference in survival was seen after 5 years. A Cochrane Database review concluded that current evidence did not support the use of adjuvant progestin therapy in the primary treatment of endometrial cancer. With only modest response to progestins, other hormonal agents have been evaluated. Tamoxifen has been shown to bind estrogen receptors and thereby block access of the estrogen into the nucleus. It has also been suggested that tamoxifen can increase the number of progesterone receptors in vivo. Combined results of several small studies noted a response rate of 22% (complete response rate of 8%) in 257 patients. These studies suggest that grade I lesions are more responsive than other grades of tumors. Progestins plus tamoxifen have been evaluated in combination in recurrent carcinoma of the endometrium. Tamoxifen, 40 mg/day, with intermittent Provera, 200 mg/day on alternate weeks, had a 33% response rate with a median PFS of 3 months and median survival of 13 months (GOG 119). A phase II trial of megestrol acetate, 160 mg orally for 3 weeks, alternating with tamoxifen, 40 mg/day for 3 weeks, until disease progression showed an overall response rate of 27% with a median PFS of 2.7 months and median OS of 14 months (GOG 153). The response rate was 38% in patients with histologic grade I tumors, 24% in those with grade II, and 22% among patients with grade III. Although tamoxifen is theoretically attractive (it causes an increase in progesterone receptors for better progestin effect), studies of small groups of patients have not produced favorable results. The use of tamoxifen is interesting in view of the reports of endometrial cancer in patients taking tamoxifen. This is in contrast to in vitro data suggesting that tamoxifen does not stimulate and in fact may inhibit established endometrial cell line growth. Gonadotropin-releasing hormone (GnRH) analogues have been evaluated in the treatment of endometrial cancer in a small number of patients. These analogues suppress gonadotropins with a reduction in estrogen but not cortisol levels. Gallagher and associates treated 17 patients with recurrent endometrial cancer who had received previous progesterone therapy; 6 (35%) had a response that continued for a median of 20 months. Further study is needed, but it appears that GnRH analogues may have a direct inhibitory effect on cancer cells. More recently investigators have explored hormonal agents in combination with targeted therapy. As detailed in the TCGA endometrial, PI3K/AKT/mTOR pathway mutations were identified more frequently in endometrial cancer than any other solid tumor. Single-agent mTOR inhibitor studies suggested meaningful clinical benefit rates (CBRs), ranging from 20% to 80%, although objective responses were limited and of short

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

duration (Slomovitz, Lu, et al., 2010; Colombo, McMeekin, et al., 2013). Given the suspected cross-regulation between the ER and PI3K/AKT/mTOR pathways, Slomovitz and colleagues examined combination letrozole and everolimus in patients with recurrent, metastatic endometrial cancer (excluding carcinosarcoma and sarcoma), and up to two prior lines of cytotoxic therapy (Slomovitz, Jiang, et al., 2015). A total of 38 patients were enrolled, with a reported CBR of 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, 7 to 29 cycles). The objective response rate (ORR) was 32% (11 of 35 patients; nine complete responses and two partial responses; median, 15 cycles; range, 8 to 29 cycles). Twenty percent of patients (7 of 35 patients) were taken off treatment after a prolonged complete response and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity (Slomovitz, Jiang, et al., 2015). Serous histology was the best predictor of lack of response, and on translational studies, patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Based on these findings, GOG protocol 3007 was developed comparing combination letrozole and everolimus to the GOG 153 regimen of alternating megestrol acetate and tamoxifen. Preliminary results reported that 24% of patients receiving everolimus plus letrozole and 22% of patients receiving the alternating regimen of tamoxifen and megestrol had a response, with median PFS of 6.4 and 3.8 months, respectively. Extrapolating from the breast cancer space, where Palbociclib, a CDK4/6 inhibitor is approved in hormone receptor positive, HER2 negative advanced or metastatic breast cancer in combination with an AIs, Oza and colleagues randomized patients with metastatic or recurrent estrogen receptor positive endometrial cancer and at least one prior line of systemic therapy to placebo plus letrozole versus Palbociclib plus letrozole. The median PFS was more than doubled in the letrozole plus palbociclib arm when compared to control, 8.3 months versus 3.0 months (HR 0.58; 95% CI 0.32 to 0.98). Furthermore, the disease control rate in the combination arm was nearly 64%, compared to 38% with placebo plus letrozole. It is anticipated that a phase III trial will be designed to confirm these findings.

ANTIANGIOGENIC THERAPY IN ENDOMETRIAL CANCER Within the GOG, several phase II trials of single-agent cytotoxic chemotherapy in the second-line setting have been completed, with response rates of approximately 15%. In an effort to expand therapeutic options, cooperative group studies have explored antiangiogenic therapy with bevacizumab in patients with advanced stage or recurrent disease. A single arm, phase II study conducted by the GOG (GOG 229-E) examined bevacizumab at a dose of 15 mg/kg given intravenously every 3 weeks in patients with persistent or recurrent endometrial cancer and two or less prior lines of chemotherapy (Aghajanian et al., 2018). A total of 56 patients were enrolled, with 52 eligible and evaluable. A promising 6-month PFS rate of 40.4% was identified, with median PFS and OS of 4.2 and 10.5 months, respectively.

157

Importantly, no gastrointestinal fistulae or perforations were reported on study (55.8% received prior radiation therapy). These results prompted further investigation of antiangiogenic therapy in this disease setting. The therapeutic benefit of bevacizumab in the front-line treatment of advanced-stage, metastatic, or recurrent endometrial cancer was then examined in the phase II GOG 86P study (Aghajanian et al., 2018). This 3-arm study randomized 349 patients to either: (1) carboplatin (C) 1 paclitaxel (P) 1 bevacizumab versus (2) CP 1 temsirolimus versus (3) C 1 ixabepilone 1 bevacizumab. As presented at the ASCO 2015 annual meeting, the CP 1 bevacizumab triplet regimen compared favorably to the other treatment arms, with a 59.5% ORR (24.7% with complete response). In addition, when compared to a matched group from GOG protocol 209 (CP arm), the triplet regimen of CP 1 bevacizumab showed a significant improvement in OS (34 vs. 22.7 months; P , .039). Grade $3 adverse events occurring in greater than 5% of patients on the CP 1 bevacizumab regimen were limited to hypertension and proteinuria (Aghajanian et al., 2018). Furthermore, an Italian study presented at the 2015 ASCO annual meeting reported the triplet regimen of CP 1 bevacizumab was superior to CP alone in patients with recurrent endometrial cancer; ORR 71.7% versus 54.3%, median PFS 13 versus 8.7 months, median OS 23.5 versus 18 months, respectively (Lorusso et al., J Clin Oncol, suppl; abstr 5502). Despite the promising results reported above, antiangiogenic therapy has not received US FDA approval in the endometrial cancer space.

Immunotherapy Significant enthusiasm emerged following the identification of immunotherapy as an effective treatment strategy in patients with endometrial cancer. Initially catalyzed by the clinical observation of one dramatic responder in two separate colorectal cancer clinical trials, the efficacy of immunotherapy, particularly in dMMR solid tumors, was described in patients with colon cancer as well as a mixed dMMR solid tumor population (Diaz and Le, 2015; Le, Durham, et al., 2017). These findings led to US FDA accelerated approval of the anti-PD-1 antibody pembrolizumab (MK-3475, Keytruda) in May 2017 as monotherapy in patients with dMMR or microsatellite instabilityhigh (MSI-H) solid tumors, whose disease has progressed following prior therapy, and who have no satisfactory alternative treatment options. This remarkable achievement represented the first disease-site agnostic and histology independent cancer drug approval, in which treatment is based on a shared tumor biomarker rather than on the anatomic site of origin. The phase II KEYNOTE-158 study ultimately included 27 different tumor types, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common (Marabelle, et al., 2020). In the entire population, the ORR was 34.3% (95% CI, 28.3% to 40.8%), the median PFS was 4.1 months (95% CI, 2.4 to 4.9 months), and the median OS was 23.5 months (95% CI, 13.5 months to not reached). Within the endometrial cancer cohort (n 5 49), the ORR was 57.1% (95% CI 42.2 to 71.2) and, importantly, the median OS and median duration of response were not reached (Marabelle, et al., 2020).

158

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Despite these findings, and dramatic progress in the dMMR/ MSI-H populations, response to single-agent checkpoint inhibition in pMMR or microsatellite stable endometrial cancer has been limited. As detailed in several single-agent trials, response rates have ranged from 6% to 20%, with short-lived PFS gains (Ott, Bang, et al., 2017; Oaknin, 2019; Konstantinopoulos, Luo, et al., 2019; Yoland Catherine Antill, 2019). In an effort to improve response rates and oncologic outcomes in this patient population, clinical trialists are examining novel combinatorial approaches in conjunction with immune checkpoint inhibition (Table 5.22). In order to improve response to checkpoint inhibition, investigators are assessing combination regimens involving cytotoxic chemotherapy and PD-1/PD-L1 inhibition. Although no randomized controlled trials comparing single-agent checkpoint inhibition to combination regimens with cytotoxic agents have reported in patients with gynecologic malignancies, preclinical data as well as emerging clinical data support such an approach (Zitvogel, Kepp, et al., 2011; Postow, Callahan, et al., 2015). Several preclinical studies have suggested that cytotoxic chemotherapy may result in robust immune stimulation (Zitvogel, Kepp, et al., 2011) (see Table 5.22). The anti-tumor effects of cytotoxic chemotherapy may additionally be immunologic, with a reduction in regulatory T-cell activity and an enhanced presentation of tumor cell specific antigens (Zitvogel, Kepp, et al., 2011; Apetoh, Ladoire, et al., 2015; Galluzzi, et al., 2015). There are currently four prospective, phase III clinical trials examining the impact of the addition of an immune checkpoint inhibitor to standard 3-weekly carboplatin 1 paclitaxel (Table 5.23). NRG GY018 (NCT03914612) was designed to evaluate the therapeutic impact of pembrolizumab, when given in combination with chemotherapy in both pMMR and dMMR cohorts in the front-line, adjuvant setting, or in patients who completed adjuvant therapy $12 months prior to study entry. Enrolled patients are required to have central MMR IHC assessment prior to randomization, which will also permit correlation of local and central testing results. Eligibility requirements include measurable stage III or IVa disease as well as stage IVb or recurrent disease, irrespective of RECIST measurable lesions. TABLE 5.22 Rational for Immunotherapy

Combinations in Endometrial Cancer Combination

Rational

Immunotherapy 1 Chemotherapy

Immune cell stimulation Immunogenic cell death Enhanced presentation of tumor specific antigens Increased T-cell activation by DCs

Immunotherapy 1 Antiangiogenic Therapy

Reduction in Treg activity Reversal of immunosuppressive effects of vascular endothelial growth factor Improved T-cell trafficking and infiltration of CD81 T cells and macrophages into the tumor bed Increased immune cell recruitment

Immunotherapy 1 PARPi

Increased tumor-infiltrating lymphocytes Enhance DNA damage, with increased CD81 T Potential synergy with PARPi

DC, Dendritic cell; PARPi, poly (ADP-ribose) polymerase inhibitors.

In an analogous manner, the RUBY trial (NCT03981796) is randomizing patients with advanced stage or recurrent endometrial cancer to a carboplatin 1 paclitaxel backbone, with or without Dostarlimab (IgG4 anti-PD-1). Although similar in design, the RUBY study permits enrollment of patients with carcinosarcoma histology and does not mandate a minimum number of dMMR endometrial cancer patients. The AtTEnd trial (NCT03603184) was designed to determine if the addition of atezolizumab (IgG1 anti PD-L1) to carboplatin and paclitaxel, and then continued as maintenance will translate into improved cancer outcomes when compared to placebo in patients with advanced stage or recurrent endometrial cancer and measurable disease. It is anticipated that a total of 550 patients will be enrolled on study, with co-primary endpoints of OS and PFS. Lastly, DUO-E (NCT04269200) is a 3-arm study which expands the therapeutic question by adding olaparib, an oral poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), to immunotherapy in the maintenance setting (see Table 5.23). There is mounting evidence to support the rationale of Poly (ADP-ribose) polymerase inhibitors (PARPi) in combination with immunotherapy. The accumulation of DNA errors in homologous recombination deficiency (HRD) tumors, which appears to be prevalent in endometrial cancer, may result in somatic mutations and neoantigen production triggering an immune response (Birkbak, Kochupurakkal, et al., 2013). In fact, BRCA mutated tumors have been found to have an increased tumor mutation burden, CD31 and CD81 immune cell infiltration, and increased expression of PD-L1 and PD-1 in the intraepithelial and peritumoral immune cell compartment compared to non-BRCA mutated tumors (Strickland, Howitt, et al., 2016) (Siedel et al., 2021). There is also strong scientific and therapeutic rational for combining immune checkpoint inhibitors and antiangiogenic therapy (see Table 5.23). Completion and presentation of results from both the IMpower150 (NSCLC) and IMmotion151 (renal cancer) studies suggest added therapeutic efficacy with the addition of atezolizumab (anti-PDL1) to a bevacizumab-containing regimen with acceptable toxicity (Socinski, Jotte, et al., 2018; Rini, Powles, et al., 2019). The translational and mechanistic rationale of this approach stems from data in the melanoma and renal cell cancer arena. In an early study examining the combination of ipilimumab (Anti CTLA-4) and bevacizumab in patients with metastatic melanoma, Hodi et al. reported that on treatment biopsies demonstrated increased CD81 and macrophage cell infiltration in tumor beds (Hodi, Lawrence, et al., 2014). Wallin et al. detailed, in a cohort of 10 subjects with metastatic renal cell carcinoma treated on GP28328, that combination atezolizumab and bevacizumab resulted in increased intratumoral CD81 T-cells, with a related increase in intra-tumoral MHC-1, natural killer cells, Th1, T-effector markers, and chemokines (CX3Cl1; fractalkine) (Wallin, Bendell, et al., 2016). These synergistic effects are hypothesized to stem from the proinflammatory impact of vascular endothelial growth factor (VEGF) blockade, as well as hypoxia in the tumor microenvironment. Aside from its direct antiangiogenic effects, bevacizumab may result in more robust anti-tumor immunity by inhibiting VEGF-related T-reg function while promoting immune cell trafficking and T-cell priming/activation. Thus, the

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

combination regimen may enhance the immunogenic response in patients with advanced-stage or recurrent EC. Additionally, no concerning safety signals have emerged across clinical trials examining this therapeutic drug combination in conjunction with cytotoxic chemotherapy. Although no phase III studies have specifically examined bevacizumab in the endometrial cancer space, alternate multitargeted antiangiogenic tyrosine kinase inhibitors (TKIs) have shown significant promise. Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) 1 to 3, fibroblast growth factor receptor (FGFR) 1 to 4, platelet derived growth factor (PDGFR)a, and the oncogenes RET and KIT (Matsui, Yamamoto, et al., 2008). Early phase II clinical trials of lenvatinib, as monotherapy, in patients with recurrent endometrial cancer showed a response rate of 14.3%, with a median PFS of 5.6 months (95% CI 8.8 to 21.4) (Vergote, 2020, #2600). In an effort to augment response, lenvatinib was combined with pembrolizumab in a phase II, open label, single arm, multicenter clinical trial (Study 111/Keynote 146) (Makker, Rasco, et al., 2019). A total of 53 enrolled patients were included in the analysis, with the primary endpoint defined as the proportion of patients with an objective response (complete or partial response) at the week 24 tumor assessment as assessed by investigators according to irRECIST. Eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for MSI or PD-L1 expression), had a good performance status, and no more than two previous systemic therapies (Makker, Rasco, et al., 2019). The ORR was 39.6% (n 5 21; 95% CI 26.5 to 54.0), although serious treatment-related adverse events (TRAEs) occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial hemorrhage) (Makker, Rasco, et al., 2019). The most frequently reported any-grade TRAEs were hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%). The most common grade 3 TRAEs were hypertension (34%) and diarrhea (8%). At the 2019 European Society of Medical Oncology (EMSO) meeting, Makker et al. presented updated outcomes data on a total of 108 patients treated with the combination regimen (Makker, 2019). In the cohort of patients who were not MSI-H or dMMR (n 5 94), the ORR was 38.9% (7.4% complete response and 31.5% partial response; 95% CI 29.7 to 48.7). Strikingly, although nearly half of the enrolled patients had received two or more prior treatment regimens, the median duration of response was 21.2 months (7.6 – not reached [NR]) (Makker, 2019). Once again, however, toxicity remained an issue with TRAEs occurring in 105 (97%) patients (90% # grade 3, 7% $ grade 4). TRAEs led to study-drug interruption of one or both drugs in 78 (72%) patients and resulted in dose reductions of lenvatinib in 70 (65%) subjects on trial; 20 (19%) patients discontinued one or both drugs due to a TRAE. Analogous to the earlier study, the most common $ grade 3 adverse events were hypertension (32%), fatigue (8%), and diarrhea (7%). Despite issues with tolerability, and the frequent need for dose interruption or dose reduction, these clinical findings reflected remarkable progress when compared to historical controls in the endometrial cancer space. On September 17, 2019,

159

the US FDA granted accelerated approval to the combination of pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. This approval was conducted under Project Orbis and allowed simultaneous review and approval in the United States, Australia, and Canada. Subsequently, Keynote 775 was developed (NCT03517449). This parallel, open label, multicenter phase III study randomized patients to receive either pembrolizumab and lenvatinib or physician’s choice chemotherapy (doxorubicin or paclitaxel), with a total target accrual of 827 patients. The co-primary endpoints of this trial were PFS (determined by blinded independent central review) and OS. As detailed at the 2020 Society of Gynecologic Oncology Virtual Annual Meeting, Keynote 775 met its co-primary endpoints with a significant improvement in both PFS and OS, as well as ORR, favoring combination lenvatinib plus pembrolizumab over physician’s choice chemotherapy. Approximately 84% of patients enrolled on trial were pMMR, 40% had prior radiation therapy, and 30% had serous or clear cell histology. The median PFS in the pMMR population was 6.6 months versus 3.8 months, and in the all-comer population 7.2 months versus 3.8 months, favoring lenvatinib plus pembrolizumab. Analogously, median OS in the pMMR cohort was 17.4 months versus 12 months, and in the all-comer cohort 18.3 months versus 11.4 months, favoring the novel drug combination. Importantly, treatment-related side effects remained an issue, with 89% of patients on lenvatinib 1 pembrolizumab experiencing a grade 3 or greater adverse event, and 65% requiring a dose reduction. Fourteen percent of patients on the new combination regimen discontinued therapy of both agents due to treatment emergent adverse events. The ENGOT-EN9/LEAP-001 study (NCT03884101) is a phase III, randomized, open-label, active-controlled trial comparing combination therapy with pembrolizumab and lenvatinib to carboplatin and paclitaxel in patients with newly diagnosed stage III to IV or recurrent EC (see Table 5.23) (Marth, 2019). Approximately 720 patients not previously treated with systemic chemotherapy (except as part of a chemoradiation regimen), antiangiogenic agents, PD-1 or PD-L1 inhibitors, or other Tcell receptor–targeted agents will be randomized 1:1 to each arm. Patients will be stratified by pMMR versus dMMR, and pMMR patients will be further stratified by ECOG performance status (0 vs. 1), measurable disease (yes vs. no), and prior chemoradiation (yes vs. no). This trial may reflect a paradigm shift in endometrial cancer therapeutics, as the findings may lead to the replacement of cytotoxic chemotherapy in the frontline setting.

Special Circumstances Multiple Malignant Neoplasms Simultaneous or subsequent primary cancers involving the breast, ovary, and large intestines occur more frequently in patients with endometrial cancer than might be expected. The reverse also appears to be true, in that women with breast or ovarian cancer have a higher-than-expected risk for development of

160

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

TABLE 5.23 Phase III Combination Immunotherapy Trials in Patients With Advanced Stage

and Recurrent Endometrial Cancer Study

Drug Regimen

Anticipated Accrual

Study Endpoint

NRG GY018 (NCT03914612)

Carboplatin 1 Paclitaxel 1 Placebo vs. Carboplatin 1 Paclitaxel 1 Pembrolizumab

N 5 590 (pMMR) N 5 220 (dMMR)

Investigator assessed PFS

RUBY (NCT03981796)

Carboplatin 1 Paclitaxel 1 Placebo vs. Carboplatin 1 Paclitaxel 1 Dostarlimab

N 5 470

Investigator assessed PFS

AtTEnd (NCT03603184)

Carboplatin 1 Paclitaxel 1 Placebo vs. Carboplatin 1 Paclitaxel 1 Atezolizumab

N 5 550

Investigator assessed PFS and OS

ENGOT-EN9/LEAP-001 (NCT03884101)

Pembrolizumab 1 Lenvatinib vs. Carboplatin 1 Paclitaxel

N 5 720

BICRa assessed PFS

DUO-E (NCT04269200)

Carboplatin 1 Paclitaxel 1 placebo vs. Carboplatin 1 Paclitaxel 1 Durvalumab vs. Carboplatin 1 Paclitaxel 1 Durvalumab 1 Olaparib

N 5 699

Investigator assessed PFS

dMMR, Mismatch repair deficiency, OS, overall survival, PFS, progression-free survival, pMMR, mismatch repair proficient a Blinded independent central review.

subsequent primary cancers of the endometrium. As a result, the recommendation in a patient with one of these malignant neoplasms is to evaluate the other organ sites at the time of diagnosis or during follow-up visits. Appropriate screening, such as mammography, should be emphasized. Simultaneous malignant neoplasms of the ovary and endometrium are noted in about 5% of patients with carcinoma of the uterus and 10% to 20% of ovarian carcinomas (Zaino, Whitney, et al., 2001). Ovarian involvement in cases in which endometrial cancer is present has been reported to be as high as 40% in autopsy specimens and 15% of specimens obtained at the time of hysterectomy and BSO. In approximately one-third of cases of endometrioid carcinoma of the ovary, endometrial carcinoma has also been noted. When the occurrence is simultaneous, the question arises whether these are synchronous neoplasms or one is metastatic from the other. It appears that if metastasis is present, it is more common for it to go from the endometrium to the ovary than from the ovary to the endometrium. Metastasis to the ovary is suspected if the endometrial carcinoma involves significant myometrium, particularly with lymphatic or vascular channel invasion, or if the tumor is on the ovarian surface. If, however, the corpus carcinoma is small and limited to the endometrium or superficial myometrium, with associated atypical hyperplasia, and the ovarian tumor is centrally located, the tumors are probably independent of each other. Most common tumors are the endometrioid type, but they can occasionally be of different histologic types in the two organs. Historically, studies based on morphologic and pathologic criteria suggested that most of the synchronous ovarian and corpus carcinomas are independent primary tumors. The survival of patients with what is believed to be

multiple primaries mimics the excellent prognosis of the individual cancer, suggesting that the two tumors are probably each stage I and not reflective of stage III disease. This has certainly been true when the simultaneous endometrial and ovarian carcinomas are of the endometrioid type. In one study, the survival was 100% of the 16 patients described. It appears that when such a situation is encountered (i.e., when there is no evidence of direct extension of either tumor), myometrial invasion is usually absent or superficial, there is no lymphatic or blood vessel invasion, there is atypical hyperplasia of the endometrium frequently associated with the cancer, both tumors are usually confined to the primary sites and have minimal spread, and tumor is predominantly within the ovary or the endometrium. Whether the histologic type is uniform or dissimilar, therapy should be appropriate for stage I disease, which in many instances may be treated adequately with surgery only (hysterectomy and BSO with appropriate surgical staging). More recently, however, the results of molecular studies have shown that most synchronous endometrial and ovarian cancers share clonal origins, irrespective of clinicopathologic features (Chao, Wu, et al., 2016; Schultheis, Ng, et al., 2016). In a recent assessment of 22 cases of synchronous endometrial and ovarian cancer, clonal origin was confirmed in all cases by at least one shared mutation in PTEN, AKT1, PIK3CA, KRAS, TP53, and ARID1A, irrespective of clinicopathologic features (Hajkova, et al., 2019). Even in those clinical cases, with low-grade, early-stage tumors, previously classified as independent primaries by conventional morphologic criteria, a clonal origin was suggested by next-generation sequencing assessment. Although interesting, these findings are unable to define “directionality,” and clinical outcomes, even in the context of suspected metastatic disease remain excellent.

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Uterine Serous Carcinoma Much debate has surrounded the biology and clinical behavior of USC tumors, although therapeutic gains have been achieved. There is a common perception that USC tumors behave differently than similarly staged patients with endometrioid tumors. Given the relative rarity of USC tumors, most outcome studies are based on retrospective series covering a long time period using variable levels of surgical staging and a variety of postoperative therapies. Older studies that did not include comprehensive surgical staging suggest that nearly 50% of “early-stage” cases of USC recur. One explanation for this finding is that for USC, extrauterine disease spread is common at diagnosis, even in clinically stage I disease. One of the larger series by Goff and associates identified 50 patients with USC, 33 pure USC and 17 admixed with other histologic types. Unlike endometrioid tumors, USC tumors have a greater frequency of disease spread at presentation. In the Goff series, 72% had extrauterine disease; lymph node metastasis was found in 36% with no myometrial invasion, 50% with less than half invasion, and 40% with outer half invasion. Of particular significance was the fact that 14 patients (28%) had disease limited to the endometrium, and within this cohort, 36% had lymph node metastasis, 43% had intraperitoneal disease, and 50% had positive peritoneal cytologic findings, essentially equal to the findings in patients with outer-half myometrial invasion. In this study, the only significant predictor of extrauterine disease was LVSI. The propensity for extrauterine spread even in the absence of invasion is not an unusual feature in USC tumors. Chan evaluated 100 patients with USC tumors and identified 12 without myometrial invasion who had complete staging. Of these patients, six were found to have extrauterine disease spread. A pooled analysis of several studies (Table 5.24) showed that approximately 50% of cases will be upstaged with comprehensive staging. It is not surprising that if patients with USC tumors do not undergo surgical staging, unrecognized

TABLE 5.24 Upstaging of Serous Carcinoma

of the Uterus Author

Patients (n)

Patients Upstaged (%)

Mallipeddi

Lee

Carcangiu

Cirisano

Gehrig

Kato

Sutton

Gallion

Chen

Goff

Sherman

Frank

Ward

Total

339

190 5 56%

161

disease spread will be a common occurrence, and survival for “early-stage” patients will be poorer. Some suggest that in appropriately staged patients, outcomes of USC tumors are comparable to patients with high-risk endometrioid tumors. Creasman and colleagues using the FIGO Annual Report database compared patients with surgically staged I USC and CC carcinomas with those with GIII endometrioid cancers. Of 3996 surgically stage I cancers, there were 148 USC, 59 CC (5% of all stage I), and 325 GIII endometrioid (8%) cancers. These were more Ia cancers (no myometrial invasion) with UPC and CC than GIII. Five-year survival rates for USC and CC were 72% and 81% respectively, compared with 76% for GIII lesions. Postoperative radiation therapy improved survival somewhat (6% to 8%), but the difference was not significant. The role of chemotherapy was not defined in this study because few patients received cytotoxic chemotherapy. Huh et al. reported on 60 patients with comprehensively staged stage I USC cases and showed that 5-year OS for patients treated by surgery alone was 66%, and it was 59% by radiation alone. Of interest, there were no recurrences in a small group (n 5 7) treated with chemotherapy. Nickels Fader evaluated data from a pooled multi-institutional dataset of 206 surgically staged, stage I to II USC patients. A variety of postoperative therapies were used, including observation after surgery, chemotherapy, radiation, and combinations of chemotherapy and radiation. Of all patients 21% recurred, including 11% of patients with no myometrial invasion. In select situations, specifically, patients with USC confined to an endometrial polyp, and comprehensively staged, the utility of adjuvant therapy is less clear. Retrospective studies suggest that a large proportion of early-stage USC may be confined to a polyp (Hui, Kelly, et al., 2005). Retrospective studies of comprehensively staged, stage Ia USC found no recurrences in patients with polyp-confined disease (Hui, Kelly, et al., 2005). Reflecting the limitations of data abstracted from retrospective reviews, conflicting outcomes were identified in a separate patient cohort, where a 9.4% recurrence rate (n 5 3/32) was noted in stage Ia polyp-confined USC (Chang-Halpenny, Natarajan, et al., 2013). After appropriate counseling, and shared decision making, observation may be an appropriate option in this specific patient population. The peritoneal cavity and distant sites (lung, liver) are common sites of failure in USC tumors. In an effort to improve peritoneal coverage, whole-abdominal radiation has been studied extensively in this disease. In a small phase II study of wholeabdominal radiation, Sutton reported 5-year PFS of only 38% in stage I or II disease. In GOG 122 (whole-abdominal radiation vs. chemotherapy), chemotherapy was superior for all patients, including the subset with USC and CC tumors (approximately 21%). Given the histologic similarity and propensity for intraperitoneal disease spread like ovarian cancer, investigators have advocated use of systemic chemotherapies active in ovarian cancer for USC tumors. Levenback and colleagues from MD Anderson treated 20 patients with USC using cisplatin, doxorubicin, and cyclophosphamide. This included patients with measurable disease (advanced and recurrent disease) and adjuvant

162

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

therapy. Only two of 11 patients with measurable disease had an objective response. The 5-year survival rate for all patients was 23%. Paclitaxel and carboplatin have been increasingly used, and several series suggest improvements in outcomes with this regimen. For example, Huh et al. demonstrated no recurrences in 12 patients with stage I disease treated with platinumbased therapy, and Kelly showed that 0 of 15 patients had a recurrence with Ib USC tumors treated with platinum chemotherapy compared with 10 of 13 who did not receive chemotherapy. In a review of the GOG phase III experience of advanced or recurrent endometrial cancers by McMeekin et al., there was no difference noted in response rate to chemotherapy based on histologic type, endometrioid versus USC/CC. In GOG protocol 249, 15% of enrolled patients had stage I or II USC or CC endometrial cancer as outlined previously. Although the expectation was that chemotherapy may benefit patients with this high-risk histology, there was no significant difference in FFS, OS, or rates of distant recurrence when chemotherapy was combined with VCB, although this was not a statistically planned subset analysis. Post-hoc analysis of the PORTEC-3 study, however, appeared to suggest benefit of combined modality chemoradiotherapy over radiation therapy alone in patients with stage III disease, as well as those with USC. Additionally, subset analysis of USC patients enrolled and treated on GOG 258 suggested no statistically significant difference between arms, calling into question the value of radiation therapy in this disease histology. With advancements in molecular characterization, our understanding of USC has evolved, helping identify novel therapeutic targets. USC are characterized by alterations in TP53, PI3K/AKT/mTOR pathway, CCNE1, and FBXW7, with copy number alterations and evidence of cell cycle aberrations. Furthermore, ERBB2 was found to be focally amplified in up to 45% of USC tumors, though estimates for HER2 overexpression vary significantly (14%–80%), which may result from variable methodologies, and criteria used to define expression (Santin, et al., 2005; Buza, English, et al., 2013; Zhao, Choi, et al., 2013). Alterations in mismatch repair genes, as well as those involved in homologous recombination have also been identified in USC. In a large population-based study of 1083 women with known germline BRCA mutations who underwent risk-reducing salpingo-oophorectomy, 5 subsequently developed serous or serous-like uterine cancer. Four of these cases occurred in BRCA1 carriers, higher than the expected 0.34 cases, suggesting a possible association between BRCA1 and USC (Shu, Pike, et al., 2016). Biomarker-driven approaches to therapy were examined in a prospective phase II trial examining trastuzumab in combination with carboplatin and paclitaxel in HER2/neu overexpressing uterine serous cancer (Fader, Roque, et al., 2018). Sixty-one patients with primary stage III or IV or recurrent HER2/neu-positive disease were enrolled on trial. Median PFS was 8.0 months in the control arm versus 12.6 months with addition of the anti-HER2 agent (P 5 .005; HR 0.44; 90% CI, 0.26 to 0.76). The results of this trial led to a National Comprehensive Cancer Network (NCCN) compendium listing of a trastuzumab-containing regimen in the

treatment of endometrial cancer. More recently, Fader et al. reported on OS, showing a striking benefit in patients with stage III or IV disease treated with trastuzumab in combination with chemotherapy (25.4 months (control) versus not reached (experimental, P 5 .041, HR 5 0.49, 90% CI 0.25 to 0.97) (Fadera, 2020). Based on these findings, carboplatin, paclitaxel plus trastuzumab should be considered a preferred regimen for HER2 positive advanced or recurrent USC.

Uterine Clear Cell Carcinoma Uterine clear cell carcinoma is an uncommon but aggressive histology, accounting for approximately 1% to 5% of endometrial cancers, with recent studies suggesting a frequency of up to 10% (de Boer, Powell, et al., 2019). Although aggressive in clinical behavior, clear cell carcinoma of the endometrium has been difficult to study in a prospective manner due to its low frequency, necessitating the use of retrospective studies and unplanned analysis of cohorts enrolled on prospective trials. In a pooled analysis of GOG trials examining various chemotherapy regimens in patients with advanced-stage or recurrent endometrial cancer, clear cell histology accounted for 4% of cases, and was associated with poorer PFS and OS, although pooled response rate to the various chemotherapy regimens was 32% (McMeekin, et al., 2007). Efforts to better understand the molecular aberrations associated with clear cell endometrial cancer have led to interesting findings. LaGallo and colleagues examined somatic mutational profiles by whole exome and targeted sequencing in 63 cases of clear cell endometrial cancer. Frequent somatic mutations were identified in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%) (Le Gallo, Rudd, et al., 2017). Based on patterns of MSI and mutations in seven genes, the authors suggested that a subset of clear cell uterine cancer molecularly resembled USC or endometrioid endometrial cancer. Although clear cell uterine carcinomas may appear to be confined to the uterus on clinical examination, a significant proportion may be upstaged at the time of surgery. In a retrospective series of 574 patients, including 18 with clear cell carcinoma (3%), 39% of clear cell cancers were upstaged to stage III or IV following surgery, with 45% having extra-uterine disease despite inner one-half myometrial invasion (Cirisano, et al., 1999). These findings highlight the importance of comprehensive staging in patients with clear cell carcinoma, and additionally suggest that preoperative CT imaging of the chest, abdomen, and pelvis may be informative in excluding extrauterine disease and to assist in surgical planning. The utility of omentectomy as a part of surgical staging of clear cell uterine cancer has been debated, with retrospective series reporting omental involvement in 6% to 10% of cases (Saygili, Kavaz, et al., 2001; Kaban, Topuz, et al., 2018). Adjuvant chemotherapy is commonly considered, even in patients with early-stage (stage I to II) clear cell uterine carcinoma. The NCCN recommends adjuvant therapy, including chemotherapy with or without pelvic radiation as well as VCB for all patients with stage Ib disease or greater with observation

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

being limited to those with comprehensively staged, stage Ia disease and no residual carcinoma in the hysterectomy specimen (Koh, Abu-Rustum, et al., 2018). Unfortunately, appropriately powered prospective studies are lacking, and retrospective trials have called into question the utility of adjuvant therapy in patients with stage I to II disease. One study, which included a cohort of 22 patients with stage I to II uterine clear cell carcinoma, suggested no differences in recurrence rate or death between the group receiving adjuvant therapy versus observation (Thomas, Mariani, et al., 2008). Conversely, multiple retrospective studies have suggested a benefit with incorporation of adjuvant brachytherapy in patients with early-stage uterine clear cell carcinoma (Barney, Petersen, et al., 2013; Townamchai, Berkowitz, et al., 2013). In the adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3) trial, 62 women with clear cell uterine cancer were randomized to radiotherapy or radiotherapy with chemotherapy (chemoradiotherapy), with no significant difference between arms in patients with early stage disease (de Boer, Powell, et al., 2018). Unlike patients with stage I to II disease, the utility of chemotherapy for those with stage III or IV clear cell uterine cancer is more clearly defined. Several GOG phase III chemotherapy trials included patients with advanced stage or recurrent uterine clear cell cancer, with response rates approximating 30% in this histology (McMeekin, et al., 2007). GOG protocol 210, a surgical and pathologic study that enrolled women with biopsy-proven endometrial cancer, of all histologies, who were deemed candidates for hysterectomy with BSO as well as pelvic and paraaortic lymphadenectomy, has provided valuable information with respect to clear cell histology (Creasman, Ali, et al., 2017). A total of 5866 women with endometrial cancer were accrued, including 311 (5.3%) with uterine clear cell carcinoma. Thirty-three percent of women with clear cell carcinoma had outer one-half and/or serosal involvement, with positive pelvic nodal rates of 20.1% and paraaortic nodal rates of 12.4%, once again reinforcing the importance of surgical staging. Aside from systemic therapy, management options for patients with recurrent clear cell uterine cancer include surgical resection and/or radiation. Unfortunately, response rates are limited, and enrollment in clinical trial should be prioritized. Given the promising efficacy signals of immune checkpoint combinations in patients with clear cell histology, it will be interesting to see if sufficient patients will be accrued to current phase III immunotherapy trials to help inform future treatment.

Carcinosarcoma Clinical profile. Most patients with uterine carcinosarcoma present with postmenopausal bleeding. As in other cases of postmenopausal bleeding, histologic evaluation by endometrial biopsy or curettage is mandatory and will establish the diagnosis. Not infrequently, a large polypoid mass may extend from the endometrial cavity protruding through the cervical os, which can be easily biopsied (Fig. 5.18). Carcinosarcomas have both malignant epithelial and mesenchymal elements, but on small biopsies, the epithelial component may be the only one

163

Figure 5.18 Uterine carcinosarcoma with a polypoid mass filling the uterine cavity and with deep myometrial invasion. (Courtesy of Dr. Pablo Souza, University of Oklahoma.)

Figure 5.19 Close-up view of specimen in Fig. 5.18 showing carcinosarcoma with tumor filling the endometrial cavity. (Courtesy of Dr. Pablo Souza, University of Oklahoma.)

recognized preoperatively (Figs. 5.19 and 5.20). Some patients may present without bleeding but with an enlarging pelvic mass as a result of tumor and hematometrium. Patients with advanced-stage disease may present similarly to patients with ovarian cancer with pleural effusions, ascites, adnexal masses, and evidence of intraperitoneal disease spread. Preoperative assessment with CT imaging of the chest, abdomen, and pelvis is usually recommended given the propensity for extrauterine spread. For common endometrial cancers, routine preoperative CT scans have not been shown to alter clinical management, but data are limited for patients with carcinosarcoma. Surgical management. The surgical management for patients with uterine carcinosarcoma should include collection of cytologic washings, hysterectomy with BSO, and pelvic and paraaortic lymph node evaluation using the sentinel lymph node approach, if appropriate. Patients with carcinosarcoma of the uterus should be staged according to the 2009 FIGO staging system for endometrial cancer. Extrauterine disease spread in carcinosarcoma is not uncommon. In one analysis of the SEER data from 1988 to 2004, 40% of cases were classified as having stage III or IV disease. When gross extrauterine disease is encountered, efforts at complete cytoreduction are encouraged in a manner analogous to that employed in patients with ovarian cancer.

164

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

B Figure 5.20 Photomicrograph of carcinosarcoma of the uterus. Within the tumor are two discrete malignant populations: a high-grade epithelial component (A) and a stromal component (B). (Courtesy of Dr. Pablo Souza, University of Oklahoma.)

The GOG prospectively evaluated disease distribution in 530 patients with clinical stage I or II uterine sarcomas. All patients underwent collection of pelvic washings, hysterectomy, and pelvic and paraaortic lymph node dissection. In the subgroup of 301 patients with carcinosarcoma, extrauterine disease was found commonly; 21% were identified with positive cytologic

washing, 37% had myometrial invasion into the outer half of the myometrium, 12% had adnexal metastases, and 17% had nodal involvement. Compared with a similar surgical staging study conducted by the GOG evaluating endometrial cancer patients, positive cytology was found in only 12%, deep myometrial invasion in 22%, adnexal involvement in 5%, and nodal metastases in 9% of cases (Table 5.25). For carcinosarcoma, after surgical staging, 59% were stage I, 21% were stage II, 9% were stage III, and 11% were stage IV. In almost every case, when extrauterine metastases are encountered, only the epithelial component of the tumor was present. Carcinosarcomas frequently carry a poor prognosis. In some cases managed without complete surgical staging, unrecognized disease spread may account for poorer outcomes. For example, in the 1988 to 2004 SEER database, of 3962 cases of carcinosarcoma, only 53% underwent lymph node dissection. For patients with apparent uterine confined disease, 5-year cancer-specific survival was 59% for stage Ia (no myometrial invasion), 54% for stage Ib, and 38% for stage Ic. Even in series with uniform use of staging, recurrences are common, indicating that unrecognized disease spread occurs frequently. In the GOG series, 53% of all patients with carcinosarcoma and 40% with stage I disease had a recurrence within 3 years of diagnosis. As in endometrial cancer, survival was related to the presence of nodal metastases, depth of myometrial invasion, and to whether the lower uterine segment or cervix was involved. Patients with adnexal involvement also had a poor prognosis. Ferguson reported a series of 42 patients in stage I who all underwent pelvic nodal dissection and found 3-year DFS and OS were 42% and 62%, respectively, even though nearly all patients received some form of postoperative adjuvant therapy. Although many believe carcinosarcoma to actually represent a metaplastic high-grade or undifferentiated endometrial cancer (and not a true sarcoma), some data indicate a different clinical behavior between uterine carcinosarcoma and highgrade (grade III, serous, or clear cell) endometrial cancers. Amant and colleagues compared 104 patients with grade III, UPSC, or clear cell endometrial cancers with 33 patients with carcinosarcoma. Among patients with stage I or II disease, patients with carcinosarcoma had a poorer survival rate and a higher incidence of pulmonary metastases. Carcinosarcoma was also an independent predictor of survival with a HR of 3.2 for recurrence compared with the other histologies. In a population-based comparison between carcinosarcoma and grade III endometrioid cancers, patients with carcinosarcoma had

TABLE 5.25 Frequency and Distribution of Disease Spread in Patients With Uterine Malignancies Carcinosarcoma (%) (n 5 301)

Leiomyosarcoma (%) (n 5 59)

Endometrial Adenocarcinoma (%) (n 5 621)

Deep myometrial invasion

—

Positive peritoneal cytology

Adnexal involvement

Nodal metastases

3.5

From Major FJ, Blessing JA, Silverberg SG, et al: Prognostic factors in early-stage uterine sarcoma: a Gynecologic Oncology Group study, Cancer 71:1702, 1993; Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987.

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

165

Adjuvant Therapy

poorer survival compared with endometrioid cancers when compared stage by stage. For example, the 5-year survival rate was 38% versus 68% for patients with stage Ic disease. Some have argued that based on the differences in clinical behavior, carcinosarcoma should be studied separately from high-risk endometrial cancers. Patterns of failure after surgery alone or after adjuvant therapies can help to inform how to best direct therapies for patients with cancers. For example, local therapies such as pelvic radiation may reduce local (vaginal or pelvic) failures but have no or minimal effect on the frequency that cancers recur at distant sites (lung, liver, abdominal cavity). In the GOG protocol 20, 40% of patients received postoperative pelvic radiation therapy, with 17% of these patients having a recurrence in the pelvis, 16% at an extrapelvic location, and 19% in the lung (Table 5.26). In the 60% of patients who received no radiation, 24% had a pelvic recurrence, 24% had an extrapelvic recurrence, and 10% recurred in the lung. In the GOG trial, therapy was not randomized but was selected by the physician. Pelvic recurrences usually develop within the first 12 to 18 months after diagnosis and surgery. In a series of 23 carcinosarcoma patients with surgically staged, stage I disease who received no postoperative therapy, 11 patients were noted to have recurrence. The median time to recurrence in these patients was 13 months, and patterns of failure showed that three patients had an isolated pelvic recurrence, three had an isolated distant recurrence, and five had both local and distant failures.

Postoperative radiation therapy or chemotherapy have been used to reduce the risk of recurrence in patients with uterine carcinosarcoma. In older studies, all types of uterine sarcomas were commonly grouped together so that the effect of therapy on a particular histologic type of sarcoma was largely unknown. Historically, radiation therapy has been most commonly used in an effort to reduce pelvic failures. When radiation therapy is given, 4500 to 6000 cGy to the pelvis has been advocated, with some also recommending intravaginal brachytherapy to deliver a boost to the vaginal cuff or entire vagina. Preoperative radiation is infrequently used and typically reserved for cases with bulky cervical involvement or parametrial extension. Several series have shown improved rates of local control with the use of radiation without necessarily improving survival rates compared with patients managed without radiation. In a GOG protocol 20 that included patients with stage I or II uterine sarcomas of all types, 156 patients were randomly assigned to postoperative treatment with doxorubicin or not. Pelvic radiation was permitted at the physician’s discretion. In this study, which included 93 patients with carcinosarcoma, 47% of patients’ disease recurred with or without the use of pelvic radiation therapy (Table 5.27). Pelvic radiation did appear to reduce local recurrences. Similarly, there was not a statistically significant difference in recurrence rates, PFS, or survival in patients who did or did not receive doxorubicin. More recently, EORTC enrolled 224 patients with stage I or II

TABLE 5.26 Patterns of Failure in Uterine Sarcomas CARCINOSARCOMA (N 5 301) Site of First Failure

LEIOMYOSARCOMA (N 5 59)

No Radiation (n 5 182)

Radiation (n 5 119)

No Radiation (n 5 46)

Radiation (n 5 13)

Pelvis

24%

17%

Extrapelvic

24%

16%

29%

Lung

10%

19%

37%

54%

Other

11%

15%

Adapted from Major FJ, Blessing JA, Silverberg SG, et al: Prognostic factors in early-stage uterine sarcoma: a Gynecologic Oncology Group study, Cancer 71:1702, 1993.

TABLE 5.27 Gynecologic Oncology Group Randomized Trial of Doxorubicin Versus No Further

Therapy in Completely Resected Stage I and Stage II Uterine Sarcoma: Rates of Recurrence Adjuvant Doxorubicin (n 5 75)

No Chemotherapy (n 5 53)

CS (n 5 90)

39%

51%

LMS (n 5 52)

44%

61%

ADJUVANT DOXORUBICIN (N 5 75)

NO CHEMOTHERAPY (N 5 53)

All sarcoma types (n 5 156) All sarcoma types (n 5 156)

Radiation (n 5 31)

No Radiation (n 5 44)

Radiation (n 5 28)

No Radiation (n 5 53)

39%

43%

57%

51%

Radiation 6 Chemotherapy (n 5 59) 47%

No Radiation 6 Chemotherapy (n 5 97) 47%

CS, Carcinosarcoma; LMS, leiomyosarcoma. Modified from Omura GA, Blessing JA, Majors F, et al: A randomized clinical trial of adjuvant Adriamycin in uterine sarcoma: a Gynecologic Oncology Group study, J Clin Oncol 3:1240, 1985.

166

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

uterine sarcomas (including 91 with carcinosarcoma) and randomly assigned patients to observation versus pelvic radiation therapy after surgery. For the group as a whole, there was no difference in DFS or OS between the two treatment groups. For patients with carcinosarcoma, improved local control was noted with pelvic radiation therapy. The study found that after observation, 47% of patients with carcinosarcoma developed a local recurrence versus 24% after pelvic radiation. Distant sites of failure remained a significant problem regardless of treatment (35% after radiation; 29% with observation). Because a common site of failure is at a distant site from the pelvis, the use of adjuvant local irradiation, although improving local control, may ultimately have no effect in increasing the OS rate. Systemic therapy using chemotherapy with or without radiation has been evaluated in the adjuvant setting. The selection of drugs or regimens likely to be beneficial is based on information from studies performed with patient populations with advanced or recurrent disease. To date, ifosfamide, cisplatin, and paclitaxel have shown the most promise for development for carcinosarcomas. Kanjeekal and colleagues reviewed the literature on the chemotherapy for uterine sarcomas and noted that for carcinosarcoma, the most promising regimens would likely include platinum-based combinations. Drawing on experience from patients with advanced and recurrent carcinosarcoma, which found that the combination regimen of ifosfamide and cisplatin produced nearly a doubling in response rate and a modestly prolonged PFS compared with ifosfamide alone (GOG protocol 107), the GOG initiated a randomized trial comparing three cycles of ifosfamide and cisplatin with whole-abdominal radiation therapy (WART) (GOG protocol 150). Eligible patients could have had stage I to IV disease provided no residual disease greater than 1 cm remained after surgery. For the group as a whole, stage was one of the most important prognostic factors, with 37% of patients with stage I disease versus 80% with stage IV disease having a recurrence by 5 years. The crude 5-year rate of recurrence rate was 58% for patients treated by WART versus 52% for chemotherapy. After adjusting for stage and age, the recurrence rate was 29% lower for chemotherapy; however, the results did not achieve statistical significance (relative hazard, 0.789; CI 0.48 to 1.04; P 5 .245). Despite this, the authors concluded the results supported further evaluation of combination chemotherapy in future research trials. A retrospective review by Makker and colleagues of 49 patients with stage I to IV disease treated by radiation alone versus chemotherapy 6 radiation suggested that the inclusion of chemotherapy into an adjuvant regimen improved PFS and OS compared with chemotherapy alone. See result of GOG 261 below that included all stages of patients with uterine carcinosarcoma.

Management of Advanced Stage or Recurrent Disease Not unlike with surgical development, the development of chemotherapy in uterine sarcomas began with studies combining all uterine sarcoma types. This strategy appeared justified because, regardless of tumor type, about half the patients with early-stage uterine sarcoma developed a recurrence. Given its

importance in patients with soft tissue sarcomas, doxorubicin has been used extensively in patients with uterine sarcomas. The GOG performed a randomized trial comparing doxorubicin with or without DTIC (dimethyl triazenoimidazole carboxamide) in 226 patients with stage III, stage IV, and recurrent sarcomas of the uterus. There was no difference in response rate, PFS, or survival between doxorubicin and doxorubicin plus DTIC-treated groups. Response rate for leiomyosarcoma was 25% versus 15% for carcinosarcoma, and survival time of patients with leiomyosarcoma was significantly longer than that of patients with other cell types. This study was important because it suggested that there was a difference between sarcoma types and response to different agents. With the recognition that there are differences in prognosis and response between the histologic types, carcinosarcoma and leiomyosarcoma are now studied in separate chemotherapy trials. The first GOG trial to evaluate carcinosarcomas as a separate group was reported by Thigpen and coworkers (GOG 26-C). This phase II study evaluated cisplatin in 28 patients with advanced or recurrent disease who had received prior chemotherapy and had measurable disease. The response rate was 18%, with two patients obtaining a complete response. A subsequent phase II study used cisplatin in a similar group of 63 patients who had not received prior chemotherapy and noted a response rate of 19% (8% complete response). As a result of activity seen in soft tissue sarcomas, ifosfamide was selected for evaluation in uterine sarcomas. Using ifosfamide with the uroprotective agent mesna (2-mercaptoethane sodium sulfate), Sutton reported for the GOG on 28 patients with advanced or recurrent carcinosarcoma who had not received prior chemotherapy (GOG 87-B). He described a 32% response rate, including 18% of patients with a complete response. Given these promising results, interest in studying combination regimens in this disease resurfaced. The GOG evaluated ifosfamide and mesna with and without cisplatin in patients with advanced, persistent, or recurrent carcinosarcomas in a phase III study (GOG 108). The study evaluated 194 patients and found that response rate for ifosfamide alone was 36% compared to 54% for the combination. Patients treated with cisplatin had a modest improvement in median PFS (6 vs. 4 months), but there was no statistically significant improvement in survival (ifosfamide, 9 months vs. ifosfamide plus cisplatin, 10 months, median survival). The combination regimen produced greater incidences of neutropenia, anemia, and peripheral neuropathy. Paclitaxel has been evaluated in 44 patients with advanced or recurrent disease who all had received one prior chemotherapy regimen. Curtin et al. for the GOG reported an 18% response rate with acceptable toxicity. The GOG has subsequently conducted a phase III trial comparing ifosfamide with and without paclitaxel (GOG 161). This trial enrolled 179 eligible patients with stage III, IV, or recurrent carcinosarcoma who had not received prior chemotherapy. The combination regimen produced higher response rates (45% vs. 29%), longer PFS (median, 5.8 months vs. 3.6 months), and longer survival times (median, 13.5 months vs. 8.4 months). There was a 31% decrease in the HR of death (0.69; 95% CI 0.49 to 0.97; P 5 .03). The combination regimen

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

produced more neuropathy and thrombocytopenia and required 3 days for infusion. Because there is interest in improving convenience and cost and reducing toxicity, other regimens have been evaluated in patients with carcinosarcoma. Powell reported on a phase II study, GOG 232-B, evaluating the combination of paclitaxel with carboplatin in 46 patients with advanced or recurrent carcinosarcoma. The response rate was 54% (13% complete response), and 59% of patients completed six or more cycles of therapy. These findings catalyzed the development and completion of GOG 261, a phase III trial that compared ifosfamide–paclitaxel with mesna to combination carboplatin plus paclitaxel in untreated patients with stage I to IV uterine carcinosarcoma. A total of 449 eligible patients were enrolled, with reported median OS of 37 months for patients treated with carboplatin plus paclitaxel compared to 29 months for the ifosfamide–paclitaxel with mesna arm (HR 0.87; 90% CI 0.70 to 1.075; P , .01 for noninferiority). Median PFS additionally favored the carboplatin-paclitaxel arm (16 vs. 12 months; HR 0.73; P , .01 for noninferiority). Both study arms experienced a similar decline in quality of life and increased neurotoxicity, although there was an increase in hematologic toxicity in the carboplatin-paclitaxel arm. The results of GOG 261 established carboplatin and paclitaxel as the preferred systemic regimen for patients with uterine carcinosarcoma.

UTERINE SARCOMA Classification Sarcomas are uncommon tumors arising from mesenchymal elements and are distinguished from carcinomas that arise from epithelial elements. Uterine sarcomas are thought to arise primarily from two tissues: endometrial stroma and the uterine muscle itself. When endometrial mesenchymal tissue undergoes malignant transformation, it may be accompanied by a malignant epithelial component (carcinosarcoma [CS], formerly referred to as malignant mixed Müllerian tumor), it may be associated with a benign-appearing epithelial component (adenosarcoma), or it may have no recognizable epithelial component (endometrial stromal sarcoma [ESS]). Tumors arising from malignant transformation of uterine smooth muscle are known as uterine LMSs. Other sarcomas, such as angiosarcoma and fibrosarcoma, arise in supporting tissues and are rare.

INCIDENCE AND EPIDEMIOLOGY The SEER database notes that LMSs account for 59% of 8365 cases reported. ESSs are represented by 33%, and other sarcomas account for 8%. The peak age for all sarcomas was 45 to 54 years with the peak age for LMS being slightly older than 55 years. In previous editions, classification of sarcomas included CS, LMS, and ESS as the three most common uterine sarcomas with CS being the most common. Convincing evidence now suggest that CSs are not true sarcomas but are derived from epithelial cells and therefore are now included as a type 2 endometrial cancer category. Although there are minor other types of uterine sarcoma, their occurrence is such that they will not be included in this chapter.

167

Sarcomas arising within the uterus are relatively rare and account for 3% to 8% of uterine cancers. According to the SEER, the age-adjusted incidences for all sarcomas (per 100,000 women age 35 years and older) in US women were 2.68 for Native American, Asian, and Hispanic; 3.58 for White; and 7.02 for Black women. By comparison, the incidence for epithelial uterine cancers, per 100,000 women, is roughly 9 for Black women and 20 for White women. Uterine sarcomas represented 8% of primary uterine malignancies in the most recent analysis of the SEER database. Harlow and coworkers had previously reported from SEER databases covering 1973 to 1981 that suggested an annual incidence of only 1.7 cases per 100,000 women. Sarcomas have been traditionally thought to represent only 3% to 5% of all uterine tumors. The increasing incidence of uterine sarcomas noted in the SEER studies may reflect better diagnosis and perhaps a true increase in an aging population. The type and frequency of uterine sarcomas are related to both age and race. LMS can occur at an early age, has an incidence plateau in middle age, and declines thereafter. In a large prospective surgical-pathologic study conducted by the GOG evaluating patients with all types of sarcomas, the median age of patients with LMS was 55 years compared with 65 years for those with CS. Brooks and coworkers suggested that White women were older at the time of diagnosis of their sarcomas compared with Black women. Using SEER data (1992 to 1998), Sherman and Devesa reported on racial differences in uterine malignancies. They found that for all histopathologic categories, the age-adjusted incidence of uterine cancers (per 100,000 women) was 23 for non-Hispanic White, 14 for White Hispanic, and 15 for Black women. In contrast, LMSs are more common in Black women. For LMSs, ESSs, and adenosarcomas combined, the incidence was 1.24 for Black versus 0.79 for non-Hispanic White women. Harlow and associates found the same trend reporting on an earlier SEER data set. It has also been suggested that Black patients present with stage I disease less commonly than White patients. Given that uterine sarcomas are rare and form a heterogeneous group, little is known about other risk factors favoring development of these tumors.

LEIOMYOSARCOMA Clinical Profile Many of these patients experience perimenopausal bleeding, are found to have a pelvic mass on examination, and will be thought to have uterine leiomyomas. Giuntoli and coworkers, reporting on the Mayo Clinic experience of 208 patients with uterine LMS collected over a 23-year period, found that vaginal bleeding was the most common symptom (56%) followed by a palpable pelvic mass (54%) and pelvic pain (22%). A commonly described “clinical pearl” has been the relationship of a rapidly enlarging uterus to LMS. The data to support such an observation are mixed, however. Parker and associates evaluated 1332 patients who underwent surgery for presumed leiomyoma. In the group of 371 patients who had rapid uterine growth, only one case (0.2%) of LMS was identified. Similarly, in a subgroup of 198 patients who had carefully documented rapid uterine growth, no cases of LMS were found. Leibsohn

168

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Figure 5.21 Photomicrograph of uterine leiomyosarcoma demonstrating the malignant lesion at the top right, normal endometrium at the bottom left, and normal myometrium between them.

and coworkers reported on 1432 patients undergoing hysterectomy for bleeding related to uterine leiomyomas and identified 7 (0.49%) patients with LMS. Because LMS arises within the uterine smooth muscle, biopsy of the malignant tissue is difficult, and many lesions are found only at final pathology. In Leibsohn et al.’s series none of the seven patients with LMS were identified on preoperative biopsy and in only three cases was there an intraoperative suspicion of sarcoma. Various authors have reported that LMS may be present in the submucosa of the uterus in 30% to 50% of patients, but even at that, biopsy diagnosis is not easily accomplished. Schwartz and coworkers described the tumors to be both broad based and pedunculated and that in 19 of 20 cases, the LMS was confined to one mass. Because of the difficulty in establishing a preoperative diagnosis and the high frequency of uterine leiomyoma in the population, it is not unexpected that several case reports have detailed the finding of LMSs in patients who have undergone conservative management of symptomatic leiomyomas by myomectomy, after Lupron treatment before myomectomy, and after vascular embolization of presumed leiomyomas. These cases speak to the importance of pretreatment counseling of patients who undergo such therapies. There is considerable discussion about the histologic criteria necessary for the diagnosis of LMS (Fig. 5.21). LMSs must be distinguished from a variety of benign smooth muscle tumors

(Table 5.28). The predominant differentiating features between benign and malignant tumors include mitotic activity (as gauged by the number of mitotic figures per 10 high-power fields [hpf]), cellular atypia, and necrosis. Leiomyoma, cellular leiomyoma, and bizarre leiomyoma (also called atypical or symplastic leiomyoma) are considered to be benign. These entities are distinguished from LMS mainly by the mitotic count of the tumor. Although cellular leiomyomas and bizarre leiomyomas may appear at first sight to be malignant, they contain fewer than 5 mitoses/10 hpf on histologic evaluation, and the prognosis is excellent with surgery only. Smooth muscle tumors of uncertain malignant potential (STUMP) include a group of smooth muscle tumors with 5 to 9 mitoses/10 hpf that can exhibit a variable behavior. Intravenous leiomyomatosis is a rare smooth muscle tumor characterized by nodular masses of histologically benign smooth muscle cells growing within venous channels that are lined by epithelium; arteries are not involved. Treatment involves surgical removal, and the prognosis is good. Recurrences are unusual and are usually managed successfully with further surgical excision. Benign metastasizing leiomyoma is another rare condition in which smooth muscle tumor deposits are found in the lung, lymph nodes, or abdomen and appear histologically like a benign leiomyoma. Most women have a history of pelvic surgery for benign leiomyomas years before these metastatic sites are recognized. Surgical excision has been the primary treatment. Norris and Taylor believed that mitotic count was extremely important in that if fewer than 10 mitoses/10 hpf were identified, the lesion was benign regardless of the degree of cellular atypia; if more than 10 mitoses/10 hpf were present, the prognosis was grave. More recently, Norris and Taylor stated that tumors with fewer than 5 mitoses/10 hpf rarely metastasize. In a follow-up study from the Armed Forces Institute of Pathology, O’Connor and Norris evaluated 73 smooth muscle tumors of the uterus with 5 to 9 mitotic figures/10 hpf but lacking cytologic atypia. They concluded that the metastatic rate was too low to consider these as being sarcoma. Several of their patients were treated only with myomectomies with excellent results. Lissoni and colleagues have suggested extending this philosophy to additional patients. Kempson and Bari believe that the mitotic count is important but state that prognosis is poor if more than 5 mitoses/10 hpf are identified. Their experience with tumors containing 5 to 9 mitoses/10 hpf indicates that the tumors usually behave

TABLE 5.28 Metastatic Potential of Smooth Muscle Tumors of the Uterus Mitotic Figures/10 hpf

Atypiaa

Diagnosis

Metastatic Potential

1–4

Any degree

Leiomyoma

Very low

5–9

None

Leiomyoma with high mitotic activity

Very low

5–9

Grade I

Smooth muscle tumor of uncertain malignant potential

Low

5–9

Grade II or III

Leiomyosarcoma

Moderate

$10

Grade I

Leiomyosarcoma

High

$10

Grade II or III

Leiomyosarcoma

Very high

Grade based on a scale of I to III.

From O’Connor DM, Norris HJ: Mitotically active leiomyomas of the uterus, Hum Pathol 21:223, 1990.

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

aggressively and will metastasize. These authors believe that the degree of cellular atypia is of limited value by itself in determining the malignancy of smooth muscle tumors. In tumors with higher mitotic counts, there were usually a greater number of very atypical cells. This atypia was also seen in tumors with 5 to 9 mitoses/10 hpf. Tumors with fewer than 5 mitoses/10 hpf were thought to be benign regardless of the atypia of the cells. None of Kempson and Bari’s patients with fewer than 5 mitoses/10 hpf had disease outside the uterus, but distant disease was a common finding if more than 5 mitoses/10 hpf were noted. The presence of coagulative necrosis, especially with diffuse significant atypia, suggests strongly that the lesion is a LMS regardless of the mitotic count. However, Silverberg believes that the mitotic count alone cannot be used as a strict histologic criterion because he had patients with fewer than 10 mitoses/10 hpf who succumbed to their disease. He emphasized that the grade of the tumor, which reflects the cytologic atypia, is a better criterion than mitotic count alone. Toledo and Oliva point out that mitotic rate alone is not sufficient to predict prognosis. Although mitotic rate and nuclear atypia are important features, tumor cell necrosis is a unique feature of LMS. Most uterine LMS with necrosis will show high mitotic rate and atypia. Essentially all investigators note the gravity of the situation if intravascular invasion or disease outside the uterus is found. Silverberg believes that the single most important prognostic indicator is the menopausal status of the patient. Women who are premenopausal when the diagnosis is made tend to have a much better prognosis than that of women who are postmenopausal, even when criteria such as blood vessel invasion, growth pattern, grade, and mitotic counts are considered. LMSs occur in young patients and tend to be more localized when they are first diagnosed, and they probably exhibit a slower growth pattern than CSs or ESSs do.

Surgical Management Planning the surgical management of LMS is difficult because many cases go unrecognized preoperatively. Patients commonly undergo myomectomy or hysterectomy for presumptive leiomyomas, which are subsequently identified as a sarcoma. When a preoperative diagnosis is known, hysterectomy should be performed. Retention of the ovaries in premenopausal patients has not shown to worsen outcome in several retrospective series and may be considered. Surgical staging with lymph node dissection is controversial, but most authorities tend to recommend biopsy of suspicious nodes only; use of sentinel lymph nodes could be considered given the possibility of carcinosarcoma on the final pathology, but data is lacking to support routine use. When LMS is recognized postoperatively, re-exploration for the purposes of completing surgical staging is not recommended. After diagnosis, evaluation of the chest with chest radiography or CT is reasonable given the propensity of spread to the lungs. Goff and colleagues found that 10% of patients with LMS had lung metastases at presentation. Several reports have appeared in the medical as well as lay literature in which women with a preoperative diagnosis of leiomyoma were treated with minimally invasive surgery including morcellation, and the final pathology noted a uterine

169

malignancy. Most of these cancers were LMS. Because preoperative diagnosis of LMS is imprecise compared with other uterine malignancies and LMS more frequently occurs in peri- or early menopause, a benign preoperative diagnosis could be easily made. These cases have resulted in disseminated disease with poor prognosis. As a result, several studies have evaluated the incidence of malignancy associated with a hysterectomy or myomectomy done for presumed benign disease. In reported studies of women undergoing hysterectomy or myomectomy for a myometrial mass, the prevalence of sarcoma is about 1 in 500 (0.2%) in most studies and reviews. Most sarcomas were LMS. The largest study of unexplained malignancy in women undergoing morcellation was from the US insurance database including 232,882 women undergoing minimally invasive hysterectomy and noted morcellation was performed in 36,470 (15.7%). Among those in which morcellation was performed, 99 cases (0.34%) of uterine cancer were found. The prevalence of cancer in this series for women younger than the age of 40 years was 1 in 1500 and 1 in 1100 for women 40 to 44 years of age. Unfortunately, histology of uterine cancer cases was not reported. Data from a national US hospital database of 41,777 women undergoing myomectomy included 3220 who underwent power morcellation, and 0.09% had uterine cancer. Occult uterine cancer was 1 in 2337 in women younger than 40 years, 1 in 702 in those age 40 to 49 years, 1 in 154 in those age 50 to 59 years, and 1 in 31 in women age 60 years or older. Studies have noted morcellation is associated with the worst prognosis with uterine sarcoma. A meta-analysis of four observational studies in women with uterine sarcoma found morcellation compared with no morcellation was associated with higher recurrence rate (61% vs. 39%) and mortality rate (48% vs. 29%). In response to the above data, the US Food and Drug Administration initially issued a guideline that power morcellation should not be used in peri- and postmenopausal women (November 2014). In February 2020, after careful examination of data, the US FDA updated the 2014 safety communication, indicating that power morcellation for myomectomy or hysterectomy be performed only with a tissue containment system, and in appropriately selected patients. Wright et al. using a Markov model suggest that morcellation may be beneficial in women younger than the age of 40 years and not beneficial in older women. Contained morcellation in a containment bag is a potential technique that can be employed to help mitigate risk. Importantly, however, the above findings highlight the importance of comprehensive preoperative counseling and shared decision making, as occult LMS cannot be definitively excluded prior to surgical resection. Data on patterns of spread for LMS are limited by the rarity of the tumor. Goff and coworkers found that 16 of 21 patients had stage I disease at surgery, and only patients with disseminated intraabdominal disease had nodal involvement. Giuntoli and coworkers reported that only 34 of 208 patients in the Mayo Clinic series had pelvic nodal dissections performed, and of the four with positive nodes, extrauterine disease was reported in three. The GOG sarcoma study on patterns of spread found that in 59 surgically staged patients, 5% had positive extrauterine spread to peritoneal cytology, 3% had adnexal involvement, and 3.5% had nodal metastases (Table 5.29). After surgical staging,

170

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

TABLE 5.29 Federation of International

Gynecologists and Obstetricians 2009 Staging Classification for Uterine Sarcomas Stage I (tumor limited to uterus)a IA: ,5 cm tumor size IB: $5 cm tumor size For Leiomyosarcoma IA: tumor limited to endometrium or endocervix without myometrial invasion IB: tumor invades ,50% myometrium IC: tumor invades $50% myometrium For Endometrial Stromal Sarcoma and Adenosarcoma Stage II (tumor extension into the pelvis) IIA: adnexal involvement IIB: other extrauterine pelvic disease Stage III (tumor invades abdominal tissues) IIIA: one site of involvement IIIB: .1 site of involvement IIIC: metastasis to pelvic and/or paraaortic lymph nodes Stage IV (tumor invades bladder and/or rectum, and/or distant metastasis) IVA: involvement of bladder and/or rectum IVB: distant metastasis

a For stage I disease, two substages are used based on tumor type. Modified from Mutch DG: Meeting Report—the new FIGO staging system for cancers of the vulva, cervix, endometrium and sarcomas, Gynecol Oncol 115:325–328, 1990 and FIGO Committee: FIGO staging for uterine sarcomas, Int J Gynecol Obstet 104:179, 2009.

83% were stage I, and only 13% of patients were upstaged based on biopsies. In 2009, the FIGO introduced a new staging system for LMS, ESS, and adenosarcoma. For LMS, stage reflects tumor size and extrauterine spread (see Table 5.29). Leiomyosarcomas most commonly spread hematogenously. Corscaden and Singh reported the results of autopsies of 15 patients who died of LMS of the uterus. Of these patients, 100% had intraabdominal visceral involvement, 80% had lung or pleural metastases, 40% had paraaortic nodal involvement, 33% had renal metastases, and 20% had liver metastases. In the GOG study, the most common first site of recurrence was the lung (41%), and only 13% had a pelvic failure (Table 5.30). The prognosis for LMS is poor, even for early-stage disease. Vardi found that of the total group of 32 patients, 44% died of disease within the first 3 years after diagnosis. There was a 63.6% 5-year survival rate in women in whom diagnosis was made while they were premenopausal compared with a 5.5%

5-year survival in postmenopausal women. The GOG found that only 31% of patients remained disease free at 3 years. Gadducci and coworkers found that 39% of patients with stage I or II disease had a recurrence, with a median time to recurrence of 18 months. Berchuck and coworkers reported that only 29% of patients with stage I or II disease remained free of disease, with a median follow-up period of 7.5 years. Although almost all deaths and recurrences are during the 4 years after diagnosis, Gallup and coworkers reported a recurrence 25 years after initial therapy. Contrary to an older perception, these data indicate that LMSs have a poorer prognosis than CSs. Predictors of outcome have been assessed by several groups. The GOG found that patients with greater numbers of mitoses were associated with an increased risk of recurrence such that 79% of patients with more than 20 mitoses/hpf recurred compared with 61% with 10 to 20 mitoses/hpf. Patients who present with extrauterine disease also have a very poor prognosis. Berchuck and coworkers found no survivors beyond 2 years in this group of patients. Gadducci and coworkers assessed 126 patients collected from a multi-institutional study and identified stage, mitotic count, and age as independent prognostic factors predicting recurrence. Giuntoli and coworkers found that high grade, advanced stage, and having had ovaries removed at surgery were independent predictors of poorer survival.

Adjuvant Therapy For patients with LMS, no adjuvant therapy has been shown to be effective in prolonging survival. As with other high-risk uterine cancers, LMSs have been managed postoperatively by radiation therapy or chemotherapy. Berchuck and coworkers found that among patients receiving any form of adjuvant therapy, 83% recurred compared with 68% who underwent surgery alone. Given the propensity for hematogenous spread, radiation does not adequately address the high frequency of distant sites of failure (lung, liver, abdominal cavity). Supporters of radiation note that pelvic control may be obtained, which can prevent bulky pelvic recurrences and improve patient comfort and quality of life. The GOG reported that only three of 13 patients who received radiation remained without recurrence, but no pelvic failures were seen. Giuntoli and coworkers performed a subset analysis within their large series of patients, identifying 31 patients who received adjuvant radiation therapy. In a comparison with 31 well-matched patients who did not receive radiation, there was not a statistically significant difference in survival between the groups, although the 5-year survival rate for those receiving radiation was 60% compared with 40% without radiation therapy. In the only prospective randomized

TABLE 5.30 Frequency and Distribution of Disease Spread in Patients With Uterine Malignancies

Deep myometrial invasion

Carcinosarcoma (%) (n 5 301) 37

Leiomyosarcoma (%) (n 5 59) —

Endometrial Adenocarcinoma (%) (n 5 621) 22

Positive peritoneal cytology

Adnexal involvement

Nodal metastases

3.5

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

trial, the EORTC showed in the subgroup of 103 patients with LMS, there was no improvement of local control with radiation (local recurrence: 20% after radiation vs. 24% after surgery alone). Of note, most patients developed distant sites of failure. Given the importance of distant failures in this disease, chemotherapy has been used to manage LMSs. In the GOG adjuvant trial evaluating the role of doxorubicin with or without radiation, 61% of patients with LMS treated without doxorubicin compared with 44% who received chemotherapy had a recurrence. This study was too small to specifically evaluate the importance that histology played in response to therapy. With the identification of an active combination regimen of docetaxel plus gemcitabine for patients with advanced or recurrent disease, early data suggest that this regimen may hold promise in an adjuvant setting. In one series of 18 patients with stage I or II LMS, 59% remain progression free at 3 years. Hensley et al. reported results of a phase II study of 23 patients with completely resected LMS treated with four cycles of gemcitabine and docetaxel. In patients with uterus-limited disease, the 2-year PFS rate was 59%. GOG 277 evaluated 47 women with uterine-limited disease with four cycles of doxorubicin followed by four courses of gemcitabine and docetaxel. At a median follow-up period of 27.4 months, a 78% 2-year PFS was noted with a median PFS of 39.3 months. Hensley and coworkers more recently enrolled 46 patients with resected uterus-limited high-grade uterine LMS who received four cycles of gemcitabine and docetaxel. If confirmed disease free after four cycles, they then received four cycles of doxorubicin. At 2 years, PFS was 78% of patients; it was 57% at 3 years. Bevacizumab was added to the gemcitabine–docetaxel regimen in 25 women with combined complete and partial response of 44%. GOG 250 enrolled 107 patients with chemotherapy naïve, metastatic and unresectable uterine LMS in a phase III placebo-controlled study to evaluate the addition of bevacizumab to gemcitabine and docetaxel. The addition of bevacizumab failed to improve PFS, OS, or ORR, and the trial was terminated early for futility (Hensley, Miller, et al., 2015). GOG protocol 277 was subsequently designed to compare adjuvant chemotherapy (four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin) to observation in patients with uterine-confined high-grade leiomyosarcoma (Hensley, Enserro, et al., 2018). Unfortunately, only 38 of the target 216 patents were enrolled on study, despite international collaboration, and the study was closed due to accrual futility. Importantly, however, restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm and the restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. These findings called into question the benefit of adjuvant therapy in patients with disease confined to the uterus, although it is notable that the small sample size precluded robust statistical comparison (Hensley, Enserro, et al., 2018). Multiple single agents have been tried and have been unsuccessful. Recently, there has been an increased interest in the

171

study of biologic targets, with modest results. Multikinase inhibitors that affect the VEGF pathway to date have been unsuccessful as monotherapy, although novel combinations are being examined. The combination of sorafenib (multikinase inhibitor of VEGFR, PDGFR, KIT, FLT3 and RAF) plus dacarbazine was examined in patients with recurrent sarcoma (including LMS) and 0 to two prior lines of treatment (D’Adamo, et al., 2019). At the completion of the trial, 17 out of 37 patients had disease control at 18 weeks, which was considered a positive result. Although the trial met its primary endpoint, defining the relative contribution of each agent in a single-arm study is impossible and therefore superiority to either single-agent drug is not proven (D’Adamo, et al., 2019).

Management of Recurrent Disease Data from randomized phase III trials conducted by the GOG, which included advanced and recurrent uterine sarcomas of all types, helped to identify the differential sensitivity of LMSs compared with CSs to different agents. In the trial comparing doxorubicin with and without dacarbazine (DTIC), patients with LMSs were found to have longer survival times compared with patients with other types when treated with a doxorubicin-containing regimen. In a subsequent study using doxorubicin with or without cyclophosphamide, histologic type was not found to be a prognostic indicator. Given that 80% of all patients died of disease within 2 years, the GOG adopted a strategy of performing phase II trials with the hope of identifying active agents that could later be tested in randomized studies. The rarity of LMSs, however, has made randomized study of this tumor more difficult. Historically, doxorubicin and ifosfamide have demonstrated the most activity in patients with recurrent disease with responses ranging from 25% to 33% for doxorubicin and 18% for ifosfamide when used as single agents. Sutton et al. and the GOG published the results of a phase II study combining ifosfamide and mesna and doxorubicin, showing an overall response rate of 30%. The duration response was 4 months, and the regimen resulted in substantial toxicity. Paclitaxel has been studied in LMSs, with an 8% response seen in patients who had received prior chemotherapy and a 9% response in those who were chemotherapy naïve. The combination of gemcitabine with docetaxel showed a 53% response rate in a small phase II trial of patients that included 29 patients with uterine LMS. This regimen was subsequently evaluated in two phase II trials. In one trial of 39 patients with advanced or recurrent LMS who had received no prior chemotherapy, the regimen produced a 36% response rate and a median PFS of 4.4 months. In a similar population of 48 patients who had received one prior chemotherapy regimen, a 27% response rate was noted. In both studies, myelosuppression was the most common toxicity. Targeted biologic agents are also being explored, although no agent has yet to demonstrate activity in this tumor type. A randomized trial comparing the docetaxel plus gemcitabine regimen with or without bevacizumab (GOG 277) was completed and terminated due to futility, failing to show a benefit with the addition of the antiangiogenic agent. Alternate drugs including pazopanib and trabectedin have shown promise and are currently NCCN compendium listed

172

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

for the treatment of uterine leiomyosarcoma. Pazopanib, an oral multi-targeted TKI (VEGFR, PDGFR, FGFR, and KIT), was the first TKI approved for the treatment of multiple subtypes of soft tissue sarcoma, including uterine leiomyosarcoma. The PALLETTE study was a phase III, double-blind, placebocontrolled clinical trial comparing pazopanib to placebo in patients with recurrent soft tissue sarcoma (antiangiogenesis naïve) (van der Graaf, et al., 2012). On trial cross-over was not permitted for patients enrolled to the placebo arm. A total of 369 patents were randomly assigned to receive pazopanib (n 5 246) or placebo (n 5 123). Median PFS was 4.6 months (95% CI 3.7 to 4.8) for pazopanib compared with 1.6 months (0.9 to 1.8) for placebo (HR 0.31, 95% CI 0.24 to 0.40; P , .0001). OS was 12.5 months (10.6 to 14.8) with pazopanib versus 10.7 months (8.7 to 12.8) with placebo (HR 0.86, 0.67 to 1.11; P 5 .25). Forty-three percent of enrolled patients had leiomyosarcoma, and 56% had received two or more lines of prior therapy. In the leiomyosarcoma cohort, median PFS was 4.6 versus 1.9 months for pazopanib and placebo, respectively (HR 0.37; 95% CI 0.23 to 0.60). A post-hoc subgroup analysis of uterine sarcoma patients treated on both the PALETTE trial and prior pazopanib phase II study suggested that patients randomized to receive pazopanib had a significantly longer PFS (3.0 vs 0.8 months, P , .001) and median OS (17.5 vs. 7.9 months, P 5 .038) (Lee, Jones, et al., 2019). Trabectedin was examined in patients with metastatic or recurrent leiomyosarcoma or liposarcoma. Trial 1 randomized 518 patients (2:1, open-label) to trabectedin or dacarbazine intravenously every 3 weeks (Demetri, von Mehren, et al., 2016). Eligibility mandated unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) and previous treatment with an anthracycline- and ifosfamide-containing regimen or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. Seventy-three percent of enrolled patients had leiomyosarcomas and 27% liposarcomas, with 89% receiving two or more prior chemotherapy regimens. Trabectedin was associated with a significant improvement in PFS over dacarbazine (4.2 vs. 1.5 months; HR 0.55, 85% CI 0.44 to 0.70). There was no significant difference in OS between treatment arms. Although olaratumab was granted accelerated approval by the US FDA in 2016 for the treatment of soft tissue sarcoma following promising results of a phase II trial, the confirmatory phase III ANOUNCE trial failed to confirm these findings, leading to withdrawal of approval. Interestingly, the efficacy of single agent doxorubicin in this study was greater than that seen in any prior trial in the recurrent setting. Lastly, novel approaches to the treatment of uterine leiomyosarcoma are being developed, pivoting toward signals derived from molecular characterization of this disease histology. Emerging data suggest that a subset of uterine leiomyosarcomas may harbor HRD and a BRCAness phenotype, analogous to that seen in ovarian cancer. Phase II studies are examining combination regimens, including temozolomide and olaparib, in an effort to capitalize on the promise of synthetic lethality in this disease setting. Patients with late recurrences of LMS in the form of isolated pulmonary metastases are candidates for thoracotomy and

sequential resection of the lesions. Five-year survival rates of 30% to 50% have been reported after such therapy. Furthermore, stereotactic body radiotherapy (SBRT) can be used for local disease control and management of oligometastatic disease.

ENDOMETRIAL STROMAL SARCOMA Clinical Profile Endometrial stromal tumors are rare mesenchymal tumors composed of cells that resemble endometrial stromal cells of the proliferative endometrium. The most common symptom of ESS is irregular vaginal bleeding. Asymptomatic uterine enlargement, pelvic pain, or a palpable mass are also common symptoms. The tumors are generally soft, fleshy, smooth, polypoid masses that may protrude into the endometrial cavity. The multiple-polyp form of the neoplasm has also been described, as has the characteristic yellow color of many of these lesions. On occasion, the uterine wall is diffusely enlarged by tumor without the presence of an obvious tumor mass. Preoperative diagnosis remains challenging because endometrial biopsy may not identify the lesion in many cases. In the past, endometrial stromal tumors were largely grouped as either endolymphatic stromal myosis or ESS. Endolymphatic stromal myosis was distinguished from stromal sarcomas by the minimal extent of tumor infiltration into the myometrium, the lack of metastases, and an indolent clinical behavior. There was significant histologic overlap between the two entities that made diagnosis difficult, however. Currently, endometrial stromal tumors are classified into two groups based on their metastatic potential. Stromal nodules are benign proliferations with the appearance indistinguishable from endometrial stroma of proliferative endometrium. They tend to be well-circumscribed lesions smaller than 15 cm and do not demonstrate infiltrating margins or vascular space invasion. They behave like benign lesions without reported recurrences or metastases. Stromal sarcomas represent the second type of stromal neoplasm. Stromal sarcomas demonstrate local invasiveness or vascular and lymphatic space involvement and infiltrate and separate the muscle fibers of the uterus. Stromal sarcomas have traditionally been divided into low- and high-grade ESSs, largely based on the mitotic activity. Today there is a greater recognition that most high-grade tumors should be classified as undifferentiated endometrial sarcomas. Low-grade endometrial stromal sarcoma (LGESS), previously described as endolymphatic stromal myosis, can have an infiltrating growth pattern that on gross examination can project out in a wormlike fashion into the myometrium or into pelvic blood vessels. On microscopic examination, there is little or no cellular atypia, and there are few if any mitoses (Figs. 5.22 and 5.23). Although metastasis can occur, the clinical course is usually indolent, and surgery alone is usually adequate treatment. Low-grade sarcomas may recur, but their clinical course is marked by late recurrences, typically more than 5 years from diagnosis, with recurrences up to 25 years having been reported. In a review of 72 cases of LGESS, 88% of patients remained alive at 80 months. High-grade ESS traditionally has been distinguished from LGESS by having 10 or greater mitoses per 10 hpf based on work by Norris and Taylor. From a review of 17 stromal sarcomas,

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

Figure 5.22 Low-power photomicrograph of a low-grade endometrial stromal sarcoma with invasion into the myometrium.

Figure 5.23 High-power view of low-grade endometrial stromal sarcoma shown in Fig. 5.2.

Kempson and Bari noted that 10 tumors contained more than 20 mitoses/10 hpf, and 9 of 10 patients died of disease. Seven patients had tumors that contained 5 mitoses or fewer/10 hpf, and none have developed a recurrence. Kempson and colleagues subsequently reviewed 109 cases of ESS and found that stage was the predominant predictor of behavior, even more so than the number of mitoses. For example, disease in 45% of stage I patients with rare mitosis and minimal atypia recurred. In this series, as long as the stromal cells appeared bland (similar to normal proliferative endometrial stromal cells), the 10 mitoses/10 hpf cutoff was not predictive of recurrence or survival. Leath and colleagues demonstrated that the clinical behavior of highgrade endometrial stromal sarcoma (HGESS) is frequently aggressive, with more patients presenting with advanced stage (extrauterine disease, 61% vs. 32%) and poorer survival compared with LGESS. Today there is a belief that many HGESS tumors are in fact undifferentiated endometrial sarcomas. These tumors show myometrial invasion and nuclear pleomorphism and have a high mitotic rate and extensive necrosis but lack smooth muscle or endometrial stromal differentiation.

Surgical Management The standard management for patients with stromal sarcoma is hysterectomy and BSO. The role of nodal dissections is

173

unresolved, largely because there is a scarcity of data when complete surgical staging has been performed. Goff and associates found no nodal disease, but only seven patients were evaluated. In the GOG surgical staging series, 52 stromal sarcomas were included, but the frequency of nodal disease was not reported. Data suggest that BSO should be performed. Several investigators have suggested that recurrences were higher in patients who had ovaries preserved. In 2009, the FIGO introduced a new staging classification for ESSs (see Table 5.30). Patients with LGESS tend to present with disease confined to the uterus, with stage I or II disease being reported in approximately 70% of series. In contrast, patients with HGESS had stage I or II disease in 40% to 50% of cases. In a retrospective review of 52 cases of LGESS by Piver and colleagues, 47% of stage I patients developed recurrence after surgery. Despite this, the 5-year survival rates were 88% for stage I and 100% for stage II patients. Gadducci and coworkers evaluated 66 patients with stromal sarcomas, including 26 with LGESS and 40 with HGESS. For 20 patients with stage I or II low-grade tumors, 25% recurred (median follow-up period, 86 months), all in the pelvis. The median time to recurrence was 36 months, with a range of 4 to 108 months. For LGESS, 5-year survival rates have ranged from 80% to 100% even though 20% to 40% of patients eventually have a recurrence. Piver and coworkers reported on patterns of failure in stage I patients whose disease recurred, with 12 of 19 recurrences being in the pelvis, 3 of 19 being at distant sites, and 4 of 19 with combined pelvic and distant failures. The prognosis for HGESS is comparable to LMSs. Gadducci and coworkers reported 5-year DFS rate of only about 20% for this group of patients. The median time to recurrence is shorter than with LGESS, with a median time of 7 months. Mitotic count was an independent predictor of survival with patients with 10 to 20 mitoses/10 hpf having a 2-year DFS of approximately 60% compared with approximately 10% if there were 20 mitoses or more/10 hpf. Other investigators have suggested 5-year survival rate between 20% and 55% for HGESS. Recurrences in the pelvis, abdomen, and lung are commonly seen, with the majority including at least some distant site of failure. A study of 24 patients with HGESS from the Mayo Clinic found that prognosis was related to the extent of disease, size of primary tumor, and grade. Mitotic count was not a prognostic factor, nor was DNA pattern.

Adjuvant Therapy As with other uterine sarcomas, adjuvant therapy has been evaluated to reduce recurrences. Gadducci and coworkers had no recurrences in five patients with low-grade disease who received adjuvant therapy versus 5 of 15 (33%) who did not. In the Piver et al. study, five patients with low-grade disease received postoperative pelvic radiation, and no recurrences were seen. Piver et al., noting the sensitivity of advanced or recurrent disease to progestins, suggested that adjuvant progestin therapy may be an effective strategy. In the large multi-institutional series by Leath and coworkers, 30 of 72 patients received adjuvant hormonal therapy and survival curves suggested a possible benefit associated with its use. Berchuck and coworkers reported recurrence rates of 57% with adjuvant chemotherapy or radiation therapy versus 56%

174

CHAPTER 5

Adenocarcinoma and Sarcoma of the Uterine Corpus

who did not receive adjuvant therapy in 25 patients with stage I ESS (high and low grade). Gadducci and coworkers noted no benefit to adjuvant therapy in stage I or II high-grade tumors. Given the rarity of ESS, no prospective study has been performed to identify active agents to be used in adjuvant treatment. As with other sarcoma types, radiation therapy may have a role in reducing pelvic recurrences but with an unknown effect on survival.

Management of Recurrent Disease Although initial studies did allow for patients with ESS, the small numbers of such patients included does not allow for interpretation of results. Low-grade endometrial sarcomas have a high frequency of progestin receptors, making progestational agents reasonable. Piver and associates found that progestins produced a 46% response rate in a small number of patients with LGESS treated at recurrence. Responses lasted from 2 to 104 months. Recurrences of LGESS should be considered for local resection when they develop in the pelvis. For HGESS, limited success has been reported with drugs commonly used for uterine sarcomas including ifosfamide and doxorubicin.

OTHER SARCOMAS Clement and Scully described 100 cases of adenosarcoma of the uterus. This is an unusual tumor with low malignant potential. Similar to other endometrial lesions, adenosarcoma usually presents with abnormal vaginal bleeding. On gross evaluation, the tumor is usually a polypoid mass that can fill the endometrial cavity. Involvement of the cervix and myometrium is less commonly seen. In 2009, the FIGO introduced a new staging classification for adenosarcomas (see Table 5.30). Histologic evaluation notes benign or atypical neoplastic glands with a sarcomatous stroma. In 78% of patients, the sarcomatous stroma was homologous. The stromal mitotic rate was 1 to 40/10 hpf. Extensive stromal fibrosis was common. Myometrial invasion was present in only 15, and it was deeply invasive in only four. Recurrence became apparent in 23 patients and in one-third appeared 5 years after diagnosis. Recurrence was confined to the vagina, pelvis, or abdomen, with two exceptions. Of those with recurrence, only 11 died with tumor. Only the presence of myometrial invasion was associated with an increased risk of recurrence. A variant of AC is a pattern that has been called adenosarcoma with sarcomatous overgrowth. This is characterized by overgrowth of the neoplasm by a pure sarcomatous component occupying at least 25% of the lesion. It is an ominous feature with reported recurrence rates exceeding 50% compared with the usual adenosarcoma. Pure heterologous uterine sarcomas are rare. Of these, rhabdomyosarcoma is the most common followed by chondrosarcoma and osteosarcoma. Rhabdomyosarcoma is derived from primitive myogenic precursors and is the most common soft tissue tumor in children and adolescents; 21% occur in genitourinary sites, and 20% of these in the uterus. Therapy has evolved from radical surgery and radiation therapy to more reliance on chemotherapy. Some authors have reported successful preservation of reproductive functions.

Follow-Up for Patients With Endometrial Cancer After surgery, with or without adjuvant therapy, patients with endometrial cancer should enter a routine surveillance program. We advocate for patients to be seen every 3 months for the first 2 years and then every 6 months for the subsequent 3 years, followed by annual visits thereafter. Most recurrences manifest within 2 years, making closer surveillance during this time reasonable. Surveillance visits should include a focused review of systems (questions related to pelvic, leg, or back pain; vaginal bleeding; urinary changes; changes in bowel habits) and physical examination, including pelvic examination. Routine Pap smear collection of the vaginal cuff is controversial. Some have suggested that routine Pap smears are not cost-effective and that most recurrences are clinically palpable or associated with patient symptoms. In addition, after radiation (vaginal or pelvic), vaginal cuff recurrences are uncommon, and radiation may produce cytologic changes occasionally difficult to classify. Most low- and intermediate-risk patients do not require routine, scheduled imaging studies to evaluate for recurrence. Patients with new complaints or worsening of abdominal and pelvic complaints may be considered for additional studies (CT scans, colonoscopy). It has been suggested by some that CA-125 can be used to monitor therapy in patients with advanced or recurrent AC of the endometrium, much as is done in ovarian cancer. Niloff and colleagues and others have noted that CA-125 is elevated in as many as three-fourths of these patients. Data are limited in regard to monitoring. Fanning and Piver did note in 21 women that clinical response, in addition to subsequent relapse, correlated with CA-125 levels of patients with advanced or recurrent disease. Monitoring with CA-125 is helpful, primarily in patients with high risk for recurrent disease, and in patients with recurrent disease receiving therapy who have a proven elevation of their serum value. In patients with USC, preoperative CA-125 levels may reflect extrauterine involvement, and have been shown to correlate with known prognostic parameters. Although most patients with endometrial carcinoma do not experience recurrence or die of disease, the number of endometrial cancer deaths has risen over the past several years. Patients identified with recurrence are assessed for treatment options. Long-term disease control of recurrent disease is a function of site of recurrence. Patients with recurrence at a distant site or with multiple sites of recurrence are best treated with systemic therapy, as discussed earlier, in an effort to control disease, although novel treatment approaches have afforded these patients prolonged and durable responses not seen with prior cytotoxic or hormonal therapy regimens. Isolated vaginal cuff recurrences may occur, particularly in patients in whom postoperative radiation was not used. Provided no other disease spread is noted, up to 80% of patients with vaginal cuff recurrences can achieve long-term disease control with the use of surgery, radiation therapy, or both. Patients with pelvic sidewall or isolated paraaortic recurrences may have long-term disease control, but overall prognosis is poorer than with vaginal recurrence. Rarely, patients with vaginal or pelvic recurrence after radiation therapy may be offered pelvic exenteration with the hopes of cure. For the bibliography list, log onto www.expertconsult.com http://www.expertconsult.com&.

BIBLIOGRAPHY Incidence and Epidemiology American Cancer Society: Cancer Facts and Figs, Atlanta, 2016, American Cancer Society. Antunes CMF, Strolley PD, Rosenshein NB, et al: Endometrial cancer and estrogen use (report of a large case-control study), N Engl J Med 300:9, 1979. Barakat RR: The effects of tamoxifen on the endometrium, Oncology (Huntingt) 9:129, 1995. Barakat RR, Eonf G, Curtin JP: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histological features, Gynecol Oncol 55:164, 1994. Beresford SA, Weiss NS, Voigt LF, et al: Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestogen therapy in postmenopausal women, Lancet 349:458, 1997. Bokhman JV: Two pathogenetic types of endometrial carcinoma, Gynecol Oncol 15:10, 1983. Brinton LA, Berman ML, Mortel R, et al: Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study, J Obstet Gynecol 167:1317, 1992. Burstein HJ, Prestrud AA, Seidenfeld J, et al: American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer, J Clin Oncol 28:3784, 2010. Creasman WT, Odicino F, Maisonneuve P, et al: Carcinoma of the corpus uteri, Int J Gynaecol Obstet 95:S105, 2006. Duffy SR, Distler W, Howell A, et al: A lower incidence of gynecologic adverse events and interventions with anastrozole than with tamoxifen in the ATAC trial, Am J Obstet Gynecol 200:80.e1, 2009. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials, Lancet 365:1687, 2005. Elwood JM, Cole P, Rothman KJ, et al: Epidemiology of endometrial cancer, J Natl Cancer Inst 59:1055, 1977. Evans-Metcalf ER, Brooks SE, Reale FR, et al: Profiles of women 45 years of age and younger with endometrial cancer, Obstet Gynecol 91:349, 1998. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in tamoxifen treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14, J Natl Cancer Inst 86:527, 1994. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study, J Natl Cancer Inst 90:1371, 1998. Gunter MJ, Hoover DR, Yu H, et al: A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer, Cancer Epidemiol Biomarkers Prev 17:921, 2008. Hoover R, Fraumeni JF, Everson R, et al: Cancer of the uterine corpus after hormonal treatment for breast cancer, Lancet 1:885, 1976. Kaku T, Matsumura M, Sakai K, et al: Endometrial carcinoma in women 65 years of age or older: a clinicopathologic study, Eur J Gynaecol Oncol 17:357, 1996. Killackey MA, Hakes TB, Pierce VK: Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens, Cancer Treat Rep 69:273, 1985. Lawrence C, Tessaro I, Durgerian S, et al: Smoking, body weight, and early stage endometrial cancer, Cancer 59:1665, 1987.

Levi F, Franeschi S, Negri E, et al: Dietary factors and the risk of endometrial cancer, Cancer 71:3775, 1993. Lu KH, Dinh M, Kohlmann W, et al: Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome, Obstet Gynecol 105:569, 2005. MacMahon B: Risk factors for endometrial cancer, Gynecol Oncol 2:122, 1974. MacMahon B: Overview of studies on endometrial cancer and other types of cancer in humans: perspective of an epidemiologist, Semin Oncol 24:S1, 1997. Magriples U, Naftolin F, Schwartz PE, et al: High grade endometrial carcinoma in tamoxifen treated breast cancer patients, J Clin Oncol 11:485, 1993. Million Women Study Collaborators: Endometrial cancer and hormone replacement therapy in the Million Women Study, Lancet 365:1543, 2005. Novak E, Yui E: Relationship of endometrial hyperplasia to adenocarcinoma of the endometrium, Am J Obstet Gynecol 32: 674, 1936. Nyholm NCV, Neilsen AL, Norup P: Endometrial cancer in postmenopausal women with and without previous estrogen replacement treatment: comparison of clinical and histopathological characteristics, Gynecol Oncol 49:229, 1993. Schapira DV, Kumar NB, Lyman GH, et al: Upper-body fat distribution and endometrial cancer risk, JAMA 266:1808, 1991. Schmeler KM, Lynch HT, Chen LM, et al: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome, N Engl J Med 354:261, 2006. Smith DC, Prentice R, Thompson DJ, et al: Association of exogenous estrogen and endometrial carcinoma, N Engl J Med 293:1164, 1975. Smith IE, Dowsett M: Aromatase inhibitors in breast cancer, N Engl J Med 348:2431, 2003. Swanson CA, Potischman N, Wilbanks GD, et al: Relationship of endometrial cancer risk to past and contemporary body size and body fat distribution, Cancer Epidemiol Biomarkers Prev 2:321, 1993. Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability, J Natl Cancer Inst 96:261, 2004. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women, Lancet 352:93, 1998. Weiderpass E, Adami HO, Baron JA, et al: Risk of endometrial cancer following estrogen replacement with and without progestins, J Natl Cancer Inst 91:1131, 1999.

Screening and Diagnosis, Surgery, and Prognostic Factors Abu-Rustum NR, Gomez JD, Alektiar KM, et al: The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes, Gynecol Oncol 115:236, 2009. Ambros RA, Kurman RJ: Identification of patients with stage I uterine endometrial adenocarcinoma at high risk of recurrence by DNA ploidy myometrial invasion and vascular invasion, Gynecol Oncol 45:235, 1992. American College of Obstetricians and Gynecologists: The role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. ACOG Committee Opinion No. 440, Obstet Gynecol 114:409, 2009. American College of Obstetricians and Gynecologists: ACOG Committee Opinion No. 601: tamoxifen and uterine cancer, Obstet Gynecol 123:1394–1397, 2014.

e2 American College of Obstetricians and Gynecologists: Endometrial cancer. ACOG Practice Bulletin No. 149, Obstet Gynecol 125:1006– 1026, 2015. Ayhan A, Turner R, Turner ZS, et al: Correlation between clinical and histopathologic risk factors; i.e., lymph node metastasis in early endometrial cancer, Int J Obstet Gynecol 4:306, 1994. Baak JPA, Snijders WP, Van Diest PJ, et al: Confirmation of the prognostic value of the ECPI-1 score in FIGO stage I endometrial cancer patients with long follow up, Int J Gynecol Cancer 5:112, 1995. Boren T, Lea J, Kehoe S, et al: Lymph node metastasis in endometrioid adenocarcinomas of the uterine corpus with occult cervical involvement, Gynecol Oncol 127:43–46, 2012. Boruta DM, Gehrig PA, Nickles Fader A, et al: Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review, Gynecol Oncol 115:142, 2009. Bourne TH, Campbell S, Steer CV, et al: Detection of endometrial cancer by transvaginal ultrasonography with color flow imaging and blood flow analysis, Gynecol Oncol 40:253, 1991. Bristow RE, Zahurak ML, Alexander CJ, et al: FIGO stage IIIC endometrial carcinoma: resection of macroscopic nodal disease and other determinants of survival, Int J Gynecol Cancer 13:664, 2003. Britton LC, Wilson TO, Gaffey TA, et al: DNA ploidy in endometrial carcinoma: major objective prognostic factor, Mayo Clin Proc 65: 643, 1990. Bryant MK, Dickinson A, Kehoe HK, et al: Lymphadenectomy for the management of endometrial cancer, Cochrane Database Syst Rev (1):CD007585, 2010. doi:10.1002/14651858.CD007585.pub2. Cacciatore B, Lehtovirta P, Wahlstrom T, et al: Preoperative sonographic evaluation of endometrial cancer, Am J Obstet Gynecol 160:133, 1989. Carcangiu ML, Chambers JT: Uterine papillary serous carcinoma, Gynecol Oncol 47:298, 1992. Chan JK, Loizzi V, Youssef M, et al: Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium, Gynecol Oncol 90:181, 2003. Chen JL, Trost DC, Wilkinson EJ: Endometrial papillary carcinoma: two clinical pathological types, Int J Gynecol Pathol 4:279, 1985. Clark T, Barton P, Coomarasamy A, et al: Investigating postmenopausal bleeding for endometrial cancer: costeffectiveness of initial diagnostic strategies, BJOG 113:502, 2006. Clark TJ, Voit D, Gupta JK, et al: Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia a systematic quantitative review, JAMA 288:1610, 2002. Cohn DE, Horowitz NS, Mutch DG, et al: Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer? Gynecol Oncol 87:243, 2002. PMID:12468320. Coleman RL, Schink JC, Miller DS, et al: DNA flow cytometric analysis of clinical stage I endometrial carcinomas with lymph node metastases, Gynecol Oncol 50:20–24, 1993. Connell PP, Rotmensch J, Waggoner S, et al: Significance of adnexal involvement in endometrial carcinoma, Gynecol Oncol 74:74, 1999. Creasman W: Revised FIGO staging for carcinoma of the endometrium, Int J Gynaecol Obstet 105(2):109, 2009. Creasman WT, DeGeest K, DiSaia PJ, et al: Significance of true surgical pathologic staging: a Gynecologic Oncology Group study, Am J Obstet Gynecol 181(1):31, 1999. Creasman WT, DiSaia PJ, Blessing J: Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals, Am J Obstet Gynecol 141:921, 1981.

Creasman WT, Kohler MF, Odicino F, et al: Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium, Gynecol Oncol 95:593, 2004. Creasman WT, McCarty KS Sr, McCarty KS Jr: Clinical correlation of estrogen, progesterone binding proteins in human endometrial adenocarcinoma, Obstet Gynecol 55:363, 1980. Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987. Creasman WT, Rutledge FN: The prognostic value of peritoneal cytology in gynecologic malignant disease, Am J Obstet Gynecol 110:773, 1971. Creasman WT, Soper JT, McCarty KS Jr, et al: Influence of cytoplasmic steroid receptor content on prognosis of early stage endometrial carcinoma, Am J Obstet Gynecol 151:922, 1985. Dasarahally S, Mohan MA, Samuels MA, et al: Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma, Gynecol Oncol 70:165, 1998. Dijkhuizen FP, Mol BW, Brölmann HA, et al: The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis, Cancer 89:1765, 2000. DiSaia PJ, Creasman WT, Boronow RC, et al: Risk factors in recurrent patterns in stage I endometrial carcinoma, Am J Obstet Gynecol 151:1009, 1985. Dotters DJ: Preoperative CA125 in endometrial cancer. Is it useful? Am J Obstet Gynecol 182:1328, 2000. Eltabbakh GH, Moore AD: Survival of women with surgical stage II endometrial cancer, Gynecol Oncol 74:80, 1999. Feldman S, Cook EF, Harlow BL, et al: Predicting endometrial cancer among older women who present with abnormal vaginal bleeding, Gynecol Oncol 56:376, 1995. Giatromanolaki A, Sivridis E, Brekken R, et al: The angiogenic “vascular endothelial growth factor/flk-1(KDR) receptor” pathway in patients with endometrial carcinoma prognostic and therapeutic implications, Cancer 92:2569, 2001. Giusa-Chiferi MG, Goncalves WJ, Baracat EC, et al: Transvaginal ultrasound, uterine biopsy and hysteroscopy for postmenopausal bleeding, Int J Gynaecol Obstet 55:39, 1996. Goff BA, Kato D, Schmidt RA, et al: Uterine papillary serous carcinoma: patterns of metastatic spread, Gynecol Oncol 54:264, 1994. Goldchmit R, Katz Z, Blickstein I, et al: The accuracy of endometrial Pipelle sampling with or without sonographic measurement of endometrial thickness, Obstet Gynecol 82:727, 1993. Goldstein SR: Unusual ultrasound appearance of the uterus in patients receiving tamoxifen, Am J Obstet Gynecol 170:447, 1994. Gordon AN, Fleischer AC, Dudley BS, et al: Preoperative assessment of myometrial invasion of endometrial adenocarcinoma by ultrasound and MRI, Gynecol Oncol 34:175, 1989. Granberg S, Wikland M, Karlson B, et al: Endometrial thickness as measured by endovaginal ultrasound for identifying endometrial abnormality, Am J Obstet Gynecol 164:47, 1991. Grice J, Ek M, Greer B, et al: Uterine papillary serous carcinoma: evaluation of long-term survival in surgically staged patients, Gynecol Oncol 69:69, 1998. Grimshaw RN, Tupper WC, Fraser RC, et al: Prognostic value of peritoneal cytology in endometrial carcinoma, Gynecol Oncol 36:97, 1990. Hanson NB, van Nagell JR Jr, Powell DE, et al: Prognostic significance of lymph-vascular space invasion in stage I endometrial cancer, Cancer 55:1753, 1985.

e3 Havrilesky LJ, Alvarez Secord A, Bae-Jump V, et al: Outcomes in surgical stage I uterine papillary serous carcinoma, Gynecol Oncol 105:677, 2007. Havrilesky LJ, Cragun JM, Calingaert B, et al: Resection of lymph node metastases influences survival in Stage III endometrial cancer, Gynecol Oncol 99:689, 2005. Havrilesky LJ, Cragun JM, Calingaert B, et al: The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer, Gynecol Oncol 104:401, 2007. Huang YW, Liu JC, Deatherage DE, et al: Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer, Cancer Res 69:9038, 2009. Huang YW, Luo J, Weng YI, et al: Promoter hypermethylation of CIDEA, HAAO and RXFP3 associated with microsatellite instability in endometrial carcinomas, Gynecol Oncol 117:239, 2010. Huh WK, Powell M, Leath CA III, et al: Uterine papillary serous carcinoma: comparisons of outcomes in surgical stage I patients with and without adjuvant therapy, Gynecol Oncol 91:470, 2003. Kadar N, Homesley HD, Malfetano JH: Prognostic factors in surgical stage III and IV carcinoma of the endometrium, Obstet Gynecol 84:983, 1994. Kadar N, Malfetano JH, Homesley HD: Determinants of survival of surgically staged patients with endometrial carcinoma histologically confined to the uterus, Obstet Gynecol 80:655, 1992. Kauppila A: Oestrogen and progestin receptors as prognostic indicators in endometrial cancer, Acta Oncol 28:561, 1989. Kilgore LC, Partridge EE, Alvarez RD, et al: Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling, Gynecol Oncol 56:29, 1995. Konski A, Poulter C, Keys H, et al: Absence of prognostic significance, peritoneal dissemination and treatment advantage in endometrial cancer patients with positive peritoneal cytology, Int J Radiat Oncol Biol Phys 4:49, 1988. Lancaster JM, Powell CB, Kauff ND, et al: Society of Gynecologic Oncologists Education Committee. Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions, Gynecol Oncol 107:159, 2007. Langer RD, Pierce JJ, O’Hanlan KA, et al: Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease, N Engl J Med 337:1792, 1997. Leitao MM Jr, Kehoe S, Barakat RR, et al: Comparison of D&C and office endometrial biopsy accuracy in patients with FIGO grade 1 endometrial adenocarcinoma, Gynecol Oncol 113:105, 2009. Levenback C, Burke TW, Silva E, et al: Uterine papillary serous carcinoma treated with PAC, Gynecol Oncol 46:317, 1992. Lo SST, Cheng DKL, Ng TY, et al: The prognostic significance of positive peritoneal cytology in endometrial cancer, Int J Gynecol Cancer 6:473, 1996. Lurain JR, Rice BL, Rademaker AW, et al: Prognostic factors associated with recurrence in clinical stage I adenocarcinoma, Obstet Gynecol 78:63, 1991. Lurain JR, Rumsey NK, Schink JC, et al: Prognostic significance of positive peritoneal cytology in clinical stage I adenocarcinoma of the endometrium, Obstet Gynecol 74:175, 1989. Lutz MH, Underwood PB Jr, Kreutner A Jr, et al: Endometrial carcinoma: a new method of classification of therapeutic and prognostic significance, Gynecol Oncol 6:83, 1978. Mariani A, Dowdy S, Cliby WA, et al: Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging, Gynecol Oncol 109:11, 2008. Mariani A, Webb MJ, Galli L, et al: Potential therapeutic role of paraaortic lymphadenectomy in node-positive endometrial cancer, Gynecol Oncol 348:2000.

Mariani A, Webb MJ, Keeney GL, et al: Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 182:1506, 2000. Mariani A, Webb MJ, Keeney GL, et al: Stage IIIC endometrioid corpus cancer includes distinct subgroups, Gynecol Oncol 87:112, 2002. Matsushima-Nishiu M, Unoki M, Ono K, et al: Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN, Cancer Res 61:3741, 2001. Matthews RP, Hutchinson-Colas J, Maiman M, et al: Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women, Gynecol Oncol 65:265, 1997. McMeekin DS, Lashbrook D, Gold M, et al: Analysis of FIGO Stage IIIc endometrial cancer patients, Gynecol Oncol 81:273, 2001. Milosevic MF, Dembo AD, Thomas GM: Clinical significance of malignant peritoneal cytology in stage I endometrial carcinoma, Int J Gynecol Cancer 2:225, 1992. Morrow CP, Bundy BN, Homesley HD, et al: Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: a Gynecologic Oncology Group study, Gynecol Oncol 36:166–171, 1990. Morrow CP, Bundy BN, Kurman RJ, et al: Relationship between surgical pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium, Gynecol Oncol 40:55, 1991. Mutter GL, Lin MC, Fitzgerald JT, et al: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers, J Natl Cancer Inst 92:924, 2000. Nickles Fader A, Starks D, Gehrig PA, et al: An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC), Gynecol Oncol 115:244, 2009. Nordström B, Strang P, Lindgren A, et al: Endometrial carcinoma: the prognostic impact of papillary serous carcinoma (UPSC) in relation to nuclear grade, DNA ploidy and p53 expression, Anticancer Res 16:899, 1996. Onda T, Yeshikawa H, Mizutani K, et al: Treatment of node positive endometrial cancer with complete node dissection, chemotherapy and radiation therapy, Br J Cancer 75:183, 1997. Onsrud N, Aalders J, Abeler V, et al: Endometrial carcinoma with cervical involvement (stage II): prognostic factors in value of combined radiological surgical treatment, Gynecol Oncol 13:76, 1982. Panici PB, Basile S, Maneschi F, et al: Systematic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial, JNCI 100:1707, 2008. Pfisterer J, Kommoss F, Sauerbrei V, et al: Prognostic value of DNA ploidy and S-phase fraction in stage I endometrial carcinoma, Gynecol Oncol 58:149, 1995. Pisani A, Barbuto DA, Chen D, et al: HER-2/neu, p53, and DNA analysis as prognosticators for survival in endometrial carcinoma, Obstet Gynecol 85:729, 1995. Podratz KC, Mariani A, Webb MJ: Staging and therapeutic value of lymphadenectomy in endometrial cancer, Gynecol Oncol 70:163, 1998. Podratz KC, Wilson TO, Gaffey TA, et al: DNA analysis facilitates the pretreatment identification of high-risk endometrial cancer patients, Am J Obstet Gynecol 168:1206, 1993. Pollow K, Manz B, Grill JH: Estrogen progesterone receptors in endometrial carcinoma. In Jasonni VM, editor: Steroids and Endometrial Cancer, New York, 1989, Raven Press, p 101. Quinn MA, Couchi M, Fortune V: Endometrial carcinoma: steroid receptors and response to medroxyprogesterone acetate, Gynecol Oncol 21:314, 1985.

e4 Rosenberg P, Boeryd B, Simonsen E: A new aggressive treatment approach to high grade endometrial cancer of possible benefit to patients with stage I uterine papillary cancer, Gynecol Oncol 48:32, 1993. Rutledge FN: The role of radical hysterectomy in adenocarcinoma of the endometrium, Gynecol Oncol 2:331, 1974. Saga Y, Imai M, Jobo T, et al: Is peritoneal cytology a prognostic factor of endometrial cancer confined to the uterus? Gynecol Oncol 103:277, 2006. Schink JC, Lurain JR, Wallemark CB, et al: Tumor size in endometrial cancer: a prospective factor for lymph node metastases, Obstet Gynecol 70:216, 1987. Seamon LG, Bryant SA, Rheaume PS, et al: Comprehensive surgical staging for endometrial cancer in obese patients: comparing robotics and laparotomy, Obstet Gynecol 114:16, 2009. Sherman ME, Sturgeon S, Brinton LA, et al: Risk factors and hormone levels in patients with serous and endometrioid uterine carcinomas, Mod Pathol 10:963, 1997. Smith RA, Cokkinides V, Brooks D, et al: Cancer screening in the United States, 2010: a review of current American Cancer Society guidelines and issues in cancer screening, CA Cancer J Clin 60:99, 2010. Smith SM, Hoffman MS: The role of vaginal hysterectomy in the treatment of endometrial cancer, Am J Obstet Gynecol 197:202.e1, 2007. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al: Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities, JAMA 280:1510, 1998. Soper JT, Creasman WT, Clarke-Pearson DL: Intraperitoneal chromic phosphate P-32 suspension therapy in malignant peritoneal cytology and endometrial carcinoma, Am J Obstet Gynecol 153: 191, 1985. Sorbe B, Risberg B, Thonthwaite J: Nuclear morphometry and DNA flow cytometry as prognostic methods for endometrial carcinoma, Int J Gynecol Cancer 4:94, 1994. Stovall TG, Photopulos GJ, Poston WM, et al: Pipelle endometrial sampling in patients with known endometrial carcinoma, Obstet Gynecol 77:954, 1991. Susini T, Rapi S, Savino L, et al: Prognostic value of flow cytometric deoxyribonucleic acid in endometrial carcinoma: comparison with other clinical-pathologic parameters, Am J Obstet Gynecol 170:527, 1994. Takeshima N, Hirai Y, Yano K, et al: Ovarian metastasis in endometrial carcinoma, Gynecol Oncol 70:183, 1998. Thornton JE, Ali S, O’Donovan P, et al: Flow cytometric studies of ploidy and proliferative indices in the Yorkshire trial of adjuvant progestogen treatment of endometrial cancer, Br J Obstet Gynaecol 100:253, 1993. Todo Y, Kato H, Kaneuchi M, et al: Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis, Lancet 375:1165, 2010. Trimble EL, Kosary C, Park RC: Lymph node sampling and survival in endometrial cancer, Gynecol Oncol 71:340, 1998. Turner DA, Gershenson DM, Atkinson N, et al: The prognostic significance of peritoneal cytology for stage I endometrial cancer, Obstet Gynecol 74:775, 1989. Varner RE, Sparks JM, Cameron CD, et al: Transvaginal sonography of the endometrium in postmenopausal women, Obstet Gynecol 78:195, 1991. Veljovich DS, Paley PJ, Drescher CW, et al: Robotic surgery in gynecologic oncology: program initiation and outcomes after the first year with comparison with laparotomy for endometrial cancer staging, Am J Obstet Gynecol 198:679.e1, 2008.

Walker JL, Piedmonte MR, Spirtos NM, et al: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: gynecologic Oncology Group Study LAP2, J Clin Oncol 27:5331, 2009. Walker JL, Piedmonte MR, Spirtos NM, et al: Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2, J Clin Oncol 30(7):695–700, 2012. Wang J, Wieslander C, Hansen G, et al: Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers, Gynecol Oncol Apr 101(1):120, 2006. Weber AM, Belinson JL, Bradley LD, et al: Vaginal ultrasonography versus endometrial biopsy in women with postmenopausal bleeding, Am J Obstet Gynecol 177:924, 1997. Wethington SL, Barrena Medel NI, Wright JD, et al: Prognostic significance and treatment implications of positive peritoneal cytology in endometrial adenocarcinoma: unraveling a mystery, Gynecol Oncol 115:18, 2009. Yazigi R, Piver MS, Blumenson L: Malignant peritoneal cytology as prognostic indicator in stage I endometrial cancer, Obstet Gynecol 62:359, 1983.

Pathology Abeler UA, Kjorstad KE: Endometrial adenocarcinoma with squamous cell differentiation, Cancer 69:488, 1992. Alberhasky RC, Connely PJ, Christopherson WN: Carcinoma of the endometrium. IV: mixed adenosquamous carcinoma, Am J Clin Pathol 77:655, 1982. Aozasa K, Saeki K, Ohasawa M, et al: Malignant lymphoma of the uterus, Cancer 72:1959, 1993. Benedetti-Panici P, Maneschi F, Cutillo G, et al: Anatomical and pathological study of retroperitoneal nodes in endometrial cancer, Int J Gynecol Cancer 8:322, 1998. Chambers JT, Merino M, Kohorn EI, et al: Uterine papillary serous carcinoma, Obstet Gynecol 69:109, 1987. Chen JL, Trost DC, Wilkinson EJ: Endometrial papillary carcinoma: two clinical pathological types, Int J Gynecol Pathol 4:279, 1985. Christopherson WN, Alberhasky RC, Connely PJ: Carcinoma of the endometrium. I: a clinicopathological study of clear cell carcinoma and secretory carcinoma, Cancer 49:1511, 1982. Christopherson WN, Alberhasky RC, Connely PJ: Carcinoma of the endometrium. II: papillary adenocarcinoma: a clinicopathological study of 46 patients, Am J Clin Pathol 77:534, 1982. Connely PJ, Alberhasky RC, Christopherson WN: Carcinoma of the endometrium. III: analysis of 865 cases of adenocarcinoma and adenocanthoma, Obstet Gynecol 59:569, 1982. Eifel P, Hendrickson M, Ross J, et al: Simultaneous presentation of carcinoma involving the ovary and uterine corpus, Cancer 50:163, 1982. Gitsch G, Friedlander ML, Wain GV, et al: Uterine papillary serous carcinoma, Cancer 75:2239, 1995. Goff BA, Kato D, Schmidt RA, et al: Uterine papillary serous carcinoma: patterns of metastatic spread, Gynecol Oncol 54:264, 1994. Hendrickson MR, Longacre TA, Kempson RL: Uterine papillary serous carcinoma revisited, Gynecol Oncol 54:261, 1991. Hendrickson MR, Ross J, Eifel PJ, et al: Adenocarcinoma of the endometrium: analysis of 256 cases of carcinoma limited to the uterine corpus, Gynecol Oncol 13:373, 1982. Jeffrey JF, Krepart GV, Lotocki RJ: Papillary serous adenocarcinomas of the endometrium, Obstet Gynecol 67:670, 1986. Kaku T, Tsukamoto N, Hachisuga T, et al: Endometrial carcinoma associated with hyperplasia, Gynecol Oncol 60:22, 1996.

e5 Kandoth C, Schultz N, Cherniack AD, et al: Integrated genomic characterization of endometrial carcinoma, Nature 497:67–73, 2013. Klein Z, Markovitch O, Altaras M, et al: Advanced endometrial adenocarcinoma following endometrial ablation: a case report and review of the literature, Int J Gynecol Cancer 7:163, 1997. Kurman RJ, Scully RE: Clear cell carcinoma of the endometrium: analysis of 21 cases, Cancer 37:872, 1976. Ng ABP, Reagan JW: Incidence and prognosis of endometrial carcinoma by histologic grade and extent, Obstet Gynecol 35:437, 1970. Ng ABP, Reagan JW, Storaasli JP, et al: Mixed adenosquamous carcinoma of the endometrium, Am J Clin Pathol 59:765, 1973. Parkash V, Carcangiu ML: Uterine papillary serous carcinoma after radiation therapy for carcinoma of the cervix, Cancer 69:496, 1992. Photopulos GJ, Carney CN, Edelman DA, et al: Clear cell carcinoma of the endometrium, Cancer 43:1448, 1979. Salazar OM, DePapp EW, Bonfiglio TA, et al: Adenosquamous carcinoma of the endometrium, Cancer 40:119, 1977. Schwartz Z, Ohel G, Birkenfeld A, et al: Second primary malignancy in endometrial carcinoma patients, Gynecol Oncol 22:40, 1985. Silverberg SG, Bolin MG, DeGiorgi LS: Adenoacanthoma and mixed adenosquamous carcinoma of the endometrium, Cancer 30:1307, 1972. Silverberg SG, DeGiorgi LS: Clear cell carcinoma of the endometrium: clinical-pathological and ultra-structural findings, Cancer 31:1127, 1973. Sivridis E, Fox H, Buckley CH: Endometrial carcinoma: two or three entities? Int J Gynecol Cancer 8:183, 1998. Umpierre SA, Burke TW, Tornos C, et al: Immunocytochemical analysis of uterine papillary serous carcinomas for estrogen and progesterone receptors, Int J Gynecol Pathol 13:127, 1994. Zaino RJ, Kurtman R, Herbald D, et al: The significance of squamous differentiation, Cancer 68:2293, 1991. Zaino RJ, Unger ER, Whitney C: Synchronous carcinomas of the uterine corpus and ovary, Gynecol Oncol 19:329, 1984.

Treatment and Recurrence Aalders J, Abeler V, Kolstad P, et al: Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients, Obstet Gynecol 56(4):419–427, 1980. Aghajanian C, Sill MW, Darcy KM, et al: Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study, J Clin Oncol 29:2259–2265, 2011. Abstract/ FREE Full Text. Arneson A: Clinical results and histological changes following irradiation treatment of cancer of the corpus uteri, AJR 36:461, 1936. ASTEC/EN.5 Study Group, Blake P, Swart AM, et al: Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRCASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis, Lancet 373(9658):137, 2009. Ball HG, Blessing JA, Lentz SS, et al: A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study, Gynecol Oncol 62:278, 1996. Barrena Medel NI, Bansal S, Miller DS, et al: Pharmacotherapy of endometrial cancer, Expert Opin Pharmacother 10:1939, 2009. Behbakht K, Jordan EL, Casey C, et al: Prognostic indicators of survival in advanced endometrial cancer, Gynecol Oncol 55:363, 1994. Benedetti Panici P, Basile S, Maneschi F, et al: Systematic pelvic lymphadenectomy versus no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial, J Natl Cancer Inst 100:1707, 2008.

Benraad TJ, Friberg LG, Koenders AJ, et al: Do estrogen and progesterone receptors (E2R and PR) in metastasizing endometrial cancer predict the response to gestagen therapy? Acta Obstet Gynecol Scand 59:155, 1980. Ben-Shachar I, Pavelka J, Cohn DE, et al: Surgical staging for patients presenting with grade 1 endometrial carcinoma, Obstet Gynecol 105:487, 2005. Chambers JT, Chambers SK, Kohorn EI, et al: Uterine papillary serous carcinoma treated with intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide, Gynecol Oncol 60:438, 1996. Chan JK, Cheung MK, Huh WK, et al: Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients, Cancer 107:1823, 2006. Chan JK, Lin YG, Monk BJ, et al: Vaginal hysterectomy as primary treatment of endometrial cancer in medically compromised women, Obstet Gynecol 97(5 Pt 1):707, 2001. Chen SS: Operative treatment in stage I endometrial carcinoma with deep myometrial invasion and/or grade 3 tumor surgically limited to the corpus uteri: no recurrence with only primary surgery, Cancer 63:1843, 1989. Chi DS, Welshinger M, Venkatraman ES, et al: The role of surgical cytoreduction in stage IV endometrial carcinoma, Gynecol Oncol 67:56, 1997. Childers JM: Laparoscopic lymph node sampling, Oper Tech Gynecol Surg 1:22, 1996. Cliby WA, Clarke-Pearson DL, Dodge R, et al: Acute morbidity and mortality associated with selective pelvic and para-aortic lymphadenectomy in the surgical staging of endometrial adenocarcinoma, J Gynecol Tech 1:19, 1995. COSA-NZ-UK Endometrial Cancer Study Groups: Adjuvant medroxyprogesterone acetate in high risk endometrial cancer, Int J Gynecol Cancer 8:387, 1998. COSA-NZ-UK Endometrial Cancer Study Groups: Pelvic lymphadenectomy in high-risk endometrial cancer, Int J Gynecol Cancer 6:102, 1996. Cragun JM, Havrilesky LJ, Calingaert B, et al: Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer, J Clin Oncol 23:3668, 2005. Creutzberg CL, van Putten WLJ, Koper PCM, et al: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial, Lancet 355:1404, 2000. Creutzberg CL, Nout RA, Lybeert MLM, et al: Fifteen-year radiotherapy outcomes of the Randomized PORTEC-1 Trial for Endometrial Carcinoma, Int J Radiat Oncol Biol Phys 81(4): e631–e663, 2011. Creutzberg CL, van Putten WLJ, Warlam-Rodenhuis CC, et al: Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the postoperative radiation therapy in endometrial carcinoma trial, J Clin Oncol 22:1234, 2004. DeCruze SB, Green JA: Hormone therapy in advanced and recurrent endometrial cancer: a systematic review, Int J Gynecol Cancer 17:964, 2007. Dizon DS, Blessing JA, McMeekin DS, et al: Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic Oncology group trial 129P, J Clin Oncol 27:3104, 2009. Ehrlich CE, Young PCM, Cleary RE: Cytoplasmic progesterone and estriol receptors in normal, hyperplastic, and carcinomatous endometria: therapeutic implications, Am J Obstet Gynecol 141:539, 1981.

e6 Elliott P, Green D, Coates M, et al: The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer, Int J Gynecol Cancer 4:84, 1994. Fanning J, Firestein S: Prospective evaluation of the morbidity of complete lymphadenectomy in endometrial cancer, Int J Gynecol Cancer 8:270, 1998. Fanning J, Piver MS: Serial CA125 levels during chemotherapy for metastatic or recurrent endometrial cancer, Obstet Gynecol 77:278, 1991. Fiorica JV, Brunetto VL, Hanjani P, et al: Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 92:10–14, 2004. Fleming GF, Brunetto VL, Cella D, et al: Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 22:2159, 2004. Fleming GF, Filiaci VL, Bentley RC, et al: Phase III randomized trial of doxorubicin 1 cisplatin versus doxorubicin 1 24-h paclitaxel 1 filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study, Ann Oncol 15:1173, 2004. Greven K, Winter K, Underhill K, et al: Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/ paclitaxel chemotherapy following surgery for patients with highrisk endometrial cancer, Gynecol Oncol 103:155, 2006. Hogberg T, Signorelli M, de Oliveira CF, et al: Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer—results from two randomised studies, Eur J Cancer 46:2422–2431, 2010. Homesley HD, Filiaci V, Gibbons SK, et al: A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study, Gynecol Oncol 112:543, 2009. Huh WK, Straughn JM Jr, Mariani A, et al: Salvage of isolated vaginal recurrences in women with surgical stage I endometrial cancer: a multiinstitutional experience, Int J Gynecol Cancer 17:886, 2007. Kauppila A: Progestin therapy of endometrial, breast, and ovarian carcinoma, Acta Obstet Gynecol Scand 63:441, 1984. Keys HM, Roberts JA, Brunetto VL, et al: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 92:744, 2004. Kilgore LC, Partridge EE, Alvarez RD, et al: Adenocarcinoma of the endometrium: survival comparison of patients with and without pelvic node sampling, Gynecol Oncol 56:26, 1995. Kistner RW: The effects of progesteronal agents on hyperplasia and carcinoma in situ of the endometrium, Int J Gynaecol Obstet 8: 561, 1970. Kitchener H, Swart AM, Qian Q, et al: Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study, Lancet 373:125, 2009. Klopp A, Smith BD, Alekitiar K, et al: The role of postoperative radiation therapy for endometrial cancer: executive summary of an American Society for Radiation Oncology evidence-based guideline, Pract Radiat Oncol 4(3):137–144, 2014. doi:10.1016/j.prro.2014.01.003. Kohorn EI: Gestagens and endometrial carcinoma, Gynecol Oncol 4:398, 1976. Kong A, Johnson N, Kitchener HC, et al: Adjuvant radiotherapy for stage I endometrial cancer: an updated Cochrane systematic review and meta-analysis, J Natl Cancer Inst 104:1625–1634, 2012. Kornblith AB, Huang HQ, Walker JL, et al: Quality of life of patients with endometrial cancer undergoing laparoscopic International

Federation of Gynecology and Obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study, J Clin Oncol 27:5337, 2009. Larson DM, Broste SK, Krawisz BR: Surgery without radiotherapy for primary treatment of endometrial cancer, Obstet Gynecol 91:355, 1998. Larson DM, Johnson K, Olson FA: Pelvic and para-aortic lymphadenectomy for surgical staging of endometrial cancer: morbidity and mortality, Obstet Gynecol 79:998, 1992. Leijon T, Rosenberg P, Boeryd B: Total abdominal hysterectomy and bilateral salpingo-oophorectomy: a sufficient treatment for patients with low risk endometrial carcinoma, Int J Gynecol Oncol 7:376, 1997. Lentz SS: Advanced and recurrent endometrial carcinoma: hormonal therapy, Semin Oncol 21:100, 1994. Lentz SS, Brady MF, Major FJ, et al: High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 14:357, 1996. Lewis GC, Slack NH, Mortel R, et al: Adjuvant progestogen therapy in primary definitive treatment of endometrial cancer, Gynecol Oncol 2:368, 1974. Lin LL, Mutch DG, Rader JS, et al: External radiotherapy versus vaginal brachytherapy for patients with intermediate risk endometrial cancer, Gynecol Oncol 106(1):215, 2007. Lincoln S, Blessing JA, Lee RB, et al: Activity of paclitaxel as a secondline chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 88:277, 2003. Lowe MP, Johnson PR, Kamelle SC, et al: A multiinstitutional experience with robotic-assisted hysterectomy with staging for endometrial cancer, Obstet Gynecol 114(2 Pt 1):236, 2009. Macdonald RR, Thorogood J, Mason MK: A randomized trial of progestogens in the primary treatment of endometrial carcinoma, Br J Obstet Gynaecol 95:166, 1988. Maggi R, Lissoni A, Spina F, et al: Adjuvant chemotherapy vs. radiotherapy in high-risk endometrial carcinoma: results of a randomized trial, Br J Cancer 95:266, 2006. Martin-Hirsch PL, Jarvis G, Kitchener H, et al: Progestagens for endometrial cancer, Cochrane Database Syst Rev (2):CD001040, 2000. Massi G, Savino L, Susini T: Vaginal hysterectomy versus abdominal hysterectomy for the treatment of stage I endometrial adenocarcinoma, Am J Obstet Gynecol 174:1320, 1996. McMeekin DS, Filiaci VL, Aghajanian C, et al: A randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic Oncology Group trial, Gynecol Oncol 134:438, 2014. (abstract LBA 431). McMeekin DS, Filiaci VL, Thigpen JT, et al: The relationship between histology and outcome in advanced and recurrent endometrial cancer patients participating in first-line chemotherapy trials: a Gynecologic Oncology Group study, Gynecol Oncol 106: 16, 2007. Miller DS, Filiaci VL, Mannel RS, et al: Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol 20;38(33):3841–3850, 2020. Miller DS, Fleming G, Randall ME: Chemo- and radiotherapy in adjuvant management of optimally debulked endometrial cancer, J Natl Compr Canc Netw 7(5):535, 2009. Mohan DS, Samuels MA, Selim MA, et al: Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma, Gynecol Oncol 70:165, 1998.

e7 Morris M, Alvarez RD, Kinney WK, et al: Treatment of recurrent adenocarcinoma of the endometrium with pelvic exenteration, Gynecol Oncol 60:288, 1996. Nout RA, Smit VTHBM, Putter H, et al: Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial, Lancet 375:816, 2010. Nout RA, Putter H, Jürgenliemk-Schulz IM, et al: Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial, J Clin Oncol 27:3547, 2009. Onsrud M, Cvancarova M, Hellebust TP, et al: Long-term outcomes after pelvic radiation for early-stage endometrial cancer, J Clin Oncol 31(31):3951–3956, 2013. Orr JW, Holloway RW, Orr PF, et al: Surgical staging of uterine cancer: an analysis of perioperative morbidity, Gynecol Oncol 42:209, 1991. Pecorelli S, editor: FIGO annual report, years 1996–1998, Int J Gynecol Obstet 79–118, 2003. Podratz KC, Mariani A, Webb MJ: Staging and therapeutic value of lymphadenectomy in endometrial cancer, Gynecol Oncol 70:163, 1998. Powell MA, Filiaci VL, Rose PG, et al: A phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group (GOG) study, J Clin Oncol 28(16):2727–2731, 2010. Randall ME, Filiaci V, McMeekin DS, et al: Phase III trial: Adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer. J Clin Oncol 20;37(21):1810–1818, 2019. Randall ME, Filiaci VL, Muss H, et al: Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 24:36, 2006. Scholten AN, van Putten WLJ, Beerman H, et al: Postoperative radiotherapy for stage I endometrial carcinoma: long-term outcome of the randomized Portec Trial with central pathology review, Int J Radiat Oncol Biol Phys 63:834, 2005. Selman AE, Fowler JM, Martinez-Monge R, et al: Doxorubicin and/or cisplatin based chemotherapy for the treatment of endometrial carcinoma with retroperitoneal lymph node metastases, Int J Gynecol Cancer 8:423, 1998. Seski JC, Edwards CL, Gershenson DM, et al: Adriamycin and cyclophosphamide chemotherapy for disseminated endometrial cancer, Obstet Gynecol 58:88, 1981. Sorbe B, Horvath G, Andersson H, et al: External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma—a prospective randomized study, Int J Radiat Oncol Biol Phys 82:1249–1255, 2012. Sorbe B, Nordström B, Mäenpää J, et al: Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized study, Int J Gynecol Cancer 19:873–878, 2009. Straughn JM Jr, Huh WK, Kelly J, et al: Conservative management of stage I endometrial carcinoma after surgical staging, Gynecol Oncol 84:194, 2002. Straughn JM Jr, Huh WK, Orr JW, et al: Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy, Gynecol Oncol 89:295, 2003. Susumu N, Sagae S, Udagawa Y, et al: Randomized phase III trial of pelvic radiotherapy vs. cisplatin-based combined chemotherapy in patients with intermediate and high-risk risk endometrial carcinoma: a Japanese Gynecologic Oncology Group study, Gynecol Oncol 108:226, 2008.

Sutton G, Axelrod JH, Bundy BN, et al: Adjuvant whole abdominal irradiation in clinical stage I and II papillary serous or clear cell carcinoma of the endometrium: a phase II study of the Gynecologic Oncology Group, Gynecol Oncol 100:349, 2006. Thigpen JT, Blessing J, Homesley H, et al: Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 33:68, 1989. Thigpen JT, Blessing J, Lagasse LD, et al: A Phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group study, Am J Clin Oncol 3:253, 1984. Thigpen JT, Blessing JA, DiSaia PJ, et al: A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study, J Clin Oncol 12:1408, 1994. Thigpen JT, Brady MF, Alvarez RD, et al: Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group, J Clin Oncol 17:1736–1744, 1999. Thigpen JT, Brady MF, Homesley HD, et al: Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a gynecologic oncology group study, J Clin Oncol 22:3902–3908, 2004. Thigpen JT, Buchsbaum HJ, Mangan C, et al: Phase II trial of Adriamycin in treatment of advanced or recurrent endometrial carcinoma, Cancer Treat Rep 63:21, 1979. Watanabe M, Aoki Y, Kase H, et al: Low risk endometrial cancer: a study of pelvic lymph node metastasis, Int J Gynecol Cancer 13:38, 2003. Whitney CW, Brunetto VL, Zaino RJ, et al: Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol 92:4–9, 2004. Zanetta G, Gabrielle GL, Cappellini A, et al: Conservative management of endometrial carcinoma with prolonged preservation of the uterus in a young patient, Int J Gynecol Cancer 7:332, 1997. Zanotti KM, Belinson JL, Kennedy AW, et al: The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma, Gynecol Oncol 74:272, 1999.

Carcinosarcoma Amant F, Cadron I, Fuso L, et al: Endometrial carcinosarcomas have a different prognosis and pattern of spread compared to high-risk epithelial endometrial cancer, Gynecol Oncol 98:274, 2005. Arrastia CD, Fruchter RG, Clark MC, et al: Uterine carcinomas: incidence and trends in management and survival, Gynecol Oncol 65:158, 1997. Bansal N, Herzog TJ, Seshan VE, et al: Uterine carcinosarcomas and grade 3 endometrioid cancers-evidence for distinct tumor behavior, Obstet Gynecol 112:64, 2008. Callister M, Ramondetta LM, Jhingran A, et al: Malignant mixed müllerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome, Int J Radiat Oncol Biol Phys 58:786, 2004. Chauveinc L, Deniaud E, Plancher C, et al: Uterine sarcomas: the Curie Institut experience—prognostic factors and adjuvant treatments, Gynecol Oncol 72:232, 1999. Chi DS, Mychalczak B, Saigo PE, et al: The role of whole-pelvic irradiation in the treatment of early-stage uterine carcinosarcoma, Gynecol Oncol 65:493, 1997.

e8 Connor JP, Andrews JI, Anderson B, et al: Computed tomography in endometrial cancer, Obstet Gynecol 95:692, 2000. Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study, Cancer 60:2035, 1987. Curtin JP, Blessing JA, Soper JT, et al: Paclitaxel in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study, Gynecol Oncol 83:268, 2001. D’Angelo E, Prat J: Uterine sarcomas: a review, Gynecol Oncol 116:131, 2010. Ferguson SE, Tornos C, Hummer A, et al: Prognostic features of surgical stage I uterine carcinosarcoma, Am J Surg Pathol 31:1653, 2007. Hannigan EV, Freedman RS, Elder KW: Treatment of advanced uterine sarcoma with adriamycin, Gynecol Oncol 16:101, 1983. Hannigan EV, Freedman RS, Rutledge FN: Adjuvant chemotherapy in early uterine sarcoma, Gynecol Oncol 15:56, 1983. Homesley H, Filiaci V, Markman M, et al: Phase III trial of ifosfamide with and without paclitaxel in advanced uterine carcinosarcoma: a GOG study, J Clin Oncol 25:526, 2007. Kanjeekal S, Chambers A, Fung MFK, et al: Systemic therapy for advanced uterine sarcoma: a systematic review of the literature, Gynecol Oncol 97:624, 2005. Le T, Krepart GV, Lotocki RJ, et al: Malignant mixed mesodermal ovarian tumor treatment and prognosis: a 20 year experience, Gynecol Oncol 65:237, 1997. Leath CA III, Numnum TM, Kendrick JE IV, et al: Patterns of failure for conservatively managed surgical stage in uterine carcinosarcoma—implications for adjuvant therapy, Int J Gynecol Cancer 19:888, 2009. Major FJ, Blessing JA, Silverberg SG, et al: Prognostic factors in early stage uterine sarcoma, Int J Gynecol Pathol 11:75, 1992. Major FJ, Blessing JA, Silverberg SG, et al: Prognostic factors in earlystage uterine sarcoma: a Gynecologic Oncology Group study, Cancer 71:1702, 1993. Makker V, Abu-Rustum NR, Alektiar KM, et al: A retrospective assessment of outcomes of chemotherapy-based versus radiationonly adjuvant treatment for completely resected stage I-IV uterine carcinosarcoma, Gynecol Oncol 111:249, 2008. Marchese MJ, Liskow AS, Crum CP, et al: Uterine sarcomas: a clinicopathologic study, 1965-1981, Gynecol Oncol 18:299, 1984. Muss HB, Bundy BN, DiSaia PJ, et al: Treatment of recurrent or advanced uterine sarcoma: a randomized trial of doxorubicin versus doxorubicin and cyclophosphamide, Cancer 55:1648, 1985. Nemani D, Mitra N, Guo M, et al: Assessing the effects of lymphadenectomy and radiation therapy in patients with uterine carcinosarcoma: a SEER analysis, Gynecol Oncol 111:82, 2008. Omura GA, Blessing JA, Majors F, et al: A randomized clinical trial of adjuvant Adriamycin in uterine sarcoma: a Gynecologic Oncology Group study, J Clin Oncol 3:1240, 1985. Omura GA, Major FJ, Blessing JA, et al: A randomized study of adriamycin with and without demethyl triazenoimidazole carboxamide in advanced uterine sarcomas, Cancer 52:626, 1983. Reed NS, Mangioni C, Malmstrom H, et al: Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874), Eur J Cancer 44:808, 2008. Sartori E, Bazzurini L, Gadducci A, et al: Carcinosarcoma of the uterus: a clinicopathological multicenter CTF study, Gynecol Oncol 67:70, 1997. Spanos WJ, Peters LJ, Oswald MJ: Patterns of recurrence in malignant mixed Müllerian tumor of the uterus, Cancer 57:155, 1986.

Sutton G, Brunetto VL, Kilgore L, et al: A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: a Gynecologic Oncology Group study, Gynecol Oncol 79:147, 2000. Sutton GP, Blessing JA, Rosenshein N, et al: Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study, Am J Obstet Gynecol 12:161, 1989. Thigpen JT, Blessing JA, Beecham J, et al: Phase II trial of cisplatin as first line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study, J Clin Oncol 9:1962, 1991. Thigpen JT, Blessing JA, Orr JW, et al: Phase II trial of cisplatin in the treatment of patients with advanced or recurrent mixed mesodermal sarcomas of the uterus: a Gynecologic Oncology Group study, Cancer Treat Rep 70:271, 1986. Van Rijswijk REN, Tognon G, Burger CW, et al: The effect of chemotherapy on the different components of advanced carcinosarcomas (malignant mixed mesodermal tumors) of the female genital tract, Int J Gynecol Cancer 4:52, 1994. Wolfson A, Brady M, Rocereto T, et al: A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma of the uterus, Gynecol Oncol 107:177, 2007. Wolfson AH, Wolfson DJ, Sittler SY, et al: A multivariate analysis of clinicopathologic factors for predicting outcome in uterine sarcomas, Gynecol Oncol 52:56, 1994.

Classification DiSaia PJ, Pecorelli S: Gynecological sarcomas, Semin Surg Oncol 10: 369, 1995. Kempson RL, Hendrickson MR: Smooth muscle, endometrial stromal, and mixed Müllerian tumors of the uterus, Mod Pathol 13:328, 2000. McCluggage WG: Uterine carcinosarcomas are metaplastic carcinomas, Int J Gynecol Cancer 12:687, 2002. Ober WB: Uterine sarcomas: histogenesis and taxonomy, Ann N Y Acad Sci 75:568, 1959. Wada H, Enomoto T, Fujita M, et al: Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors, Cancer Res 57:5379, 1997. Zhe J, Ogata S, Tamura G, et al: Carcinosarcomas (malignant Müllerian mixed tumors) of the uterus and ovary: a genetic study with special reference to histogenesis, Int J Gynecol Pathol 22:368, 2003.

Incidence and Epidemiology Brooks SE, Zhan M, Cote T, et al: Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999, Gynecol Oncol 93:204, 2004. Curtis RE, Freedman DM, Sherman ME, et al: Risk of malignant mixed Müllerian tumors after tamoxifen therapy for breast cancer, J Natl Cancer Inst 96:70, 2004. Harlow BL, Weiss NS, Lofton S: The epidemiology of sarcomas of the uterus, J Natl Cancer Inst 76:399, 1986. Meredith RF, Eisert DR, Kaka Z, et al: An excess of uterine sarcomas after pelvic irradiation, Cancer 58:2003, 1986. Sherman ME, Devesa SS: Analysis of racial differences in incidence, survival, and mortality for malignant tumors of the uterine corpus, Cancer 98:176, 2003. Zelmanowicz A, Hildesheim A, Sherman ME, et al: Evidence for a common etiology for endometrial carcinomas and malignant mixed Müllerian tumors, Gynecol Oncol 69:253, 1998.

e9 Leiomyosarcoma Amada S, Nakano H, Tsuneeyoshi M: Leiomyosarcoma versus bizarre and cellular leiomyomas of the uterus: a comparative study based on the MIB-1 and proliferating cell nuclear antigen indices, p53 expression, DNA flow cytometry, and muscle specific actins, Int J Gynecol Pathol 14:134, 1995. Bell SW, Kempson RL, Hendrickson MR: Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases, Am J Surg Pathol 18:535, 1994. Berchuck A, Rubin SC, Hoskins WJ: Treatment of uterine leiomyosarcoma, Obstet Gynecol 71:845, 1988. Blom R, Guerrieri C, Stal O, et al: Leiomyosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases, Gynecol Oncol 68:54, 1998. Bogani G, Cilby UA, Aletti GD: Import of morcellation on survival outcome of patients with unexpected uterine leiomyosarcoma, Gynecol Oncol 137:167, 2015. Cadducci A, Landoni F, Sartori E, et al: Uterine leiomyosarcoma: analysis of treatment failures and survival, Gynecol Oncol 62:25, 1996. Clement PB: Intravenous leiomyomatosis of the uterus, Pathol Annu 2:153, 1988. D’Angelo A, Amso NM, Wood A: Uterine leiomyosarcoma discovered after uterine artery embolization, J Obstet Gynaecol 23:686, 2003. Evans HL, Chawla SP, Simpson C, et al: Smooth muscle neoplasms of the uterus other than ordinary leiomyoma: a study of 46 cases, with emphasis on diagnostic criteria and prognostic factors, Cancer 62:2239, 1988. Gadducci A, Landone F, Sartore E, et al: Uterine leiomyosarcoma: analysis of treatment failures and survival, Gynecol Oncol 62:25, 1996. Gal AA, Brooks JJ, Pietra GG: Leiomyomatous neoplasms of the lung, Mod Pathol 2:209, 1989. Gallup DG, Blessing JA, Anderson W, et al: Evaluation of paclitaxel in previously treated leiomyosarcoma of the uterus: a gynecologic oncology group study, Gynecol Oncol 89:48, 2003. Giuntoli RL, Metzinger DS, DiMarco CS, et al: Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy, Gynecol Oncol 89:460, 2003. Goff BA, Rice LW, Fleischhacker D, et al: Uterine leiomyosarcoma and endometrial stromal sarcoma: lymph node metastases and sites of recurrence, Gynecol Oncol 50:105, 1993. Hensley ML, Blessing JA, DeGeest K, et al: Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study, Gynecol Oncol 109:323, 2008. Hensley ML, Blessing JA, Mannel RS, et al: Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial, Gynecol Oncol 109:329, 2008. Hensley ML, Ishill N, Soslow R, et al: Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study, Gynecol Oncol 112:563, 2009. Hensley ML, Maki R, Venkatranab E, et al: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial, J Clin Oncol 20:2824, 2002. Leibsohn S, d’Ablaing G, Mishell DR, et al: Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas, Am J Obstet Gynecol 76:162, 1990. Levenback C, Rubin SC, McCormack PM, et al: Resection of pulmonary metastases from uterine sarcomas, Gynecol Oncol 45:202, 1992.

Lissoni A, Cormio G, Bonazzi C, et al: Fertility-sparing surgery in uterine leiomyosarcoma, Gynecol Oncol 70:348, 1998. Maki R: Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future, Oncologist 12:999, 2007. Mayerhofer K, Obermair A, Windbichler G, et al: Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases, Gynecol Oncol 74:196, 1999. Meyer WR, Mayer AR, Diamond MP, et al: Unsuspected leiomyosarcoma: treatment with a gonadotropin-releasing hormone analogue, Obstet Gynecol 75:529, 1990. Mutch DG: Meeting Report—The new FIGO staging system for cancers of the vulva, cervix, endometrium and sarcomas, Gynecol Oncol 115:325, 2009. Nordal RN, Kjorstad KE, Stenweg AE, et al: Leiomyosarcoma and endometrial stromal sarcoma of the uterus, Int J Gynecol Cancer 3:110, 1993. O’Connor DM, Norris HJ: Mitotically active leiomyomas of the uterus, Hum Pathol 21:223, 1990. Oliva E, Young RH, Clement PB, et al: Cellular benign mesenchymal tumors of the uterus: a comparative morphologic and immunohistochemical analysis of 33 highly cellular leiomyomas and six endometrial stromal nodules, two frequently confused tumors, Am J Surg Pathol 19:757, 1995. Parker WH, Fu YS, Berek JS: Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma, Obstet Gynecol 83:414, 1994. Peters WA, Howard DR, Anderson WA, et al: Uterine smooth muscle tumor of uncertain malignant potential, Obstet Gynecol 83:1015, 1994. Rose PG, Blessing JA, Soper JT, et al: Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study, Gynecol Oncol 70:267, 1998. Schwartz LB, Diamond MP, Schwartz PE: Leiomyosarcomas: clinical presentation, Am J Obstet Gynecol 168:180–183, 1993. Silverberg SG: Leiomyosarcoma of the uterus, Obstet Gynecol 38:613, 1971. Sutton G, Blessing JA, Ball H, et al: Phase II Trial of paclitaxel in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study, Gynecol Oncol 74:346, 1999. Sutton G, Blessing JA, Malfetano JH, et al: Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study, Gynecol Oncol 62:226, 1996. Sutton G, Blessing JA, McGuire W, et al: Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus, Gynecol Oncol 36: 295, 1990. Thigpen JT, Blessing JA, Wilbanks GD: Cisplatin as second line chemotherapy in the treatment of advanced or recurrent leiomyosarcoma of the uterus, Am J Clin Oncol 9:18, 1986. Thigpen T, Blessing JA, Yordan E, et al: Phase II trial of etoposide in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study, Gynecol Oncol 63:120, 1996. Toledo G, Oliva E: Smooth muscle tumors of the uterus: a practical approach, Arch Pathol Lab Med 132:595, 2008. Wright JD, Tergas Al, Burk WM, et al: Unexpected gynecologic malignancy undergoing minimally invasive hysterectomy using morcellation, JAMA 312:1253, 2014. Wright JD, Tergas Al, Cui R: Use of electric power morcellation and prevalence of underlying cancer in women who undergo myomectomy, JAMA Oncol 1(1):69-77, 2015. Zivanovic O, Leitao MM, Iasonos A, et al: Stage-specific outcomes of patients with uterine leiomyosarcoma: a comparison of the

e10 International Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems, J Clin Oncol 27:2066, 2009.

Endometrial Stromal Sarcoma Bohr L, Thomsen CF: Low-grade stromal sarcoma: a benign appearing malignant uterine tumour: a review of current literature. Differential diagnostic problems illustrated by four cases, Eur J Obstet Gynecol Reprod Biol 39:63, 1991. Chang KL, Crabtree GS, Lim-Tan SK, et al: Primary uterine endometrial stromal neoplasms: a clinicopathologic study of 117 cases, Am J Surg Pathol 14:415, 1990. DiSaia PJ, Morrow CP, Boronow R, et al: Endometrial sarcoma: lymphatic spread pattern, Am J Obstet Gynecol 130:104, 1978. DeFusio PA, Gaffey TA, Malkasian GD, et al: Endometrial stromal sarcomas: review of Mayo Clinic experience, 1945–1980, Gynecol Oncol 35:8, 1989. FIGO Committee: FIGO Staging for uterine sarcomas, Int J Gynecol Obstet 104:179, 2009. Gadducci A, Sartori E, Landoni F, et al: Endometrial stromal sarcoma: analysis of treatment failures and survival, Gynecol Oncol 63:247, 1996. Leath CA III, Huh WK, Hyde J Jr, et al: A multi-institutional review of outcomes of endometrial stromal sarcoma, Gynecol Oncol 105:630, 2007. Lehrner LM, Miles PA, Enck RE: Complete remission of widely metastatic endometrial stromal sarcoma following combination chemotherapy, Cancer 43:1189, 1979. Lin YC, Kudelka AP, Tresukosol D, et al: Case report: prolonged stabilization of progressive endometrial stromal sarcoma with prolonged oral etoposide therapy, Gynecol Oncol 58:262, 1995. Lissoni A, Cormio G, Perego P, et al: Conservative management of endometrial stromal sarcoma in young women, Int J Gynecol Oncol 7:364, 1997. Nordal RR, Kristensen GB, Kaeren J, et al: The prognostic significance of surgery, tumor size, malignancy grade, menopausal status, and DNA ploidy in endometrial stromal sarcoma, Gynecol Oncol 62: 254, 1996. Norris HF, Taylor HB: Mesenchymal tumors of the uterus. I: a clinical and pathological study of 53 endometrial stromal tumors, Cancer 19:755, 1966. Piver MS, Rutledge FN, Copeland L, et al: Uterine endolymphatic stromal myosis: a collaborative study, Obstet Gynecol 64:173, 1984. Scribner DR, Walker JL: Case report: low-grade endometrial stromal sarcoma preoperative treatment with Depo-Lupron and Megace, Gynecol Oncol 71:458, 1998.

Other Sarcomas Clement PB: Müllerian adenosarcoma of the uterus with sarcomatous overgrowth: a clinicopathological analysis of 10 cases, Am J Surg Pathol 13:28, 1989. Clement PB, Scully RE: Müllerian adenosarcoma of the uterus: a clinical pathological analysis of 100 cases with review of the literature, Hum Pathol 21:363, 1990. Hammerman RM, Runowicz CD: Conservative management of uterine rhabdomyosarcoma, Obstet Gynecol 92:669, 1998. Kaku T, Silverberg SG, Blessing J, et al: Adenosarcoma of the uterus: a Gynecologic Oncology Group clinicopathologic study of 31 cases, Int J Gynecol Pathol 11:75, 1992. Krivac TC, Seidman JD, McBroom JW, et al: Uterine adenosarcoma with sarcomatous overgrowth versus uterine carcinosarcoma: comparison of treatment and survival, Gynecol Oncol 83:89, 2001.

Zaloudek CJ, Norris HJ: Adenofibroma and adenosarcoma of the uterus: a clinicopathologic study of 35 cases, Cancer 48:354, 1981. Oaknin A, Sullivanc RJ, Pothuri B, et al: Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-h and MSS endometrial cancer, Gynecol Oncol 154(1):17, 2019. Fader AN, Roque DM, Siegel E, et al: Randomized Phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxeltrastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress Her2/Neu (NCT01367002): Updated overall survival analysis. Clin Cancer Res 1;26(15):3928–3935, 2020. Abu-Rustum NR, Alektiar K, Iasonos A, et al: The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center, Gynecol Oncol 103(2):714–718, 2006. OBJECTIVES: To describe the incidence of symptomatic postoperative lower-extremity lymphedema in women treated for uterine corpus cancer, and to evaluate its relationship to regional lymph node removal and postoperative therapy. METHODS: A retrospective chart review of all patients with uterine corpus cancer managed over a 12-year period (1/93–12/04). All patients had a hysterectomy as part of their therapy. We identified patients with leg lymphedema—as described by the physician or reported by the patient—through medical records. We excluded cases of leg edema that developed secondary to medical conditions such as cardiovascular and renal disease, venous thrombosis, and end-stage recurrent malignancy. Lymphedema dermal changes and related fibrosis were graded using the common terminology criteria for adverse events. RESULTS: In all, 1289 patients with uterine corpus malignancy were evaluated. We excluded other chronic lower-extremity edema that was related to a variety of medical conditions in 74 patients (5.7%). With a median follow-up of 3 years (interquartile range, 1.1 to 5.4 years), new symptomatic post-treatment lower-extremity lymphedema was noted in 16 patients. Patients who had lymph nodes removed at initial surgery had a higher rate of developing lymphedema (16/670, 2.4%) than those who did not (0/619, 0%) (P 5 .0001). Furthermore, symptomatic lymphedema was limited to patients who had 10 or more regional lymph nodes removed 16/469 (3.4%). Lymphedema was noted at a median of 5.3 months after surgery (range, 1 to 32 months). Lymphedema was unilateral in 11 patients (69%) and bilateral in 5 (31%); moreover, it was considered grade 1 in 12 patients (75%) and grade 2 in 4 (25%). Age, weight, stage, type of hysterectomy, and type of postoperative adjuvant therapy were not associated with lymphedema. CONCLUSIONS: To date, this is the largest series evaluating symptomatic lower-extremity lymphedema in women with uterine corpus cancer. Patients who had 10 or more regional lymph nodes removed at initial surgery appeared to be at higher risk for developing new symptomatic leg lymphedema. Patients undergoing surgery with lymphadenectomy for uterine corpus malignancy should be informed about the possibility of postoperative new symptomatic leg lymphedema. A prospective evaluation of leg lymphedema is needed to accurately determine the incidence, severity, and risk factors of this complication. Apetoh L, Ladoire S, Coukos G, et al: Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol 26(9):1813–1823, 2015.

e11 Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies. The present review aims to summarize the immune-mediated effects of chemotherapeutic agents and their clinical relevance, the biological and clinical features of immune checkpoint blockers, and finally, the preclinical and clinical rationale for novel therapeutic strategies combining anticancer agents and immune checkpoint blockers. Barlin JN, Khoury-Collado F, Kim CH, et al: The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes, Gynecol Oncol 125(3):531–535, 2012. OBJECTIVE: To determine the false-negative rate of a surgical sentinel lymph node (SLN) mapping algorithm that incorporates more than just removing SLNs in detecting metastatic endometrial cancer. METHODS: A prospective database of all patients who underwent lymphatic mapping for endometrial cancer was reviewed. Cervical injection of blue dye was used in all cases. The surgical algorithm is as follows: (1) peritoneal and serosal evaluation and washings; (2) retroperitoneal evaluation including excision of all mapped SLNs and suspicious nodes regardless of mapping; and (3) if there is no mapping on a hemi-pelvis, a side-specific pelvic, common iliac, and interiliac lymph node dissection (LND) is performed. Paraaortic LND is performed at the attendings’ discretion. The algorithm was retrospectively applied. RESULTS: From 9/2005–4/2011, 498 patients received a blue dye cervical injection for SLN mapping. At least one LN was removed in 95% of cases (474/498); at least one SLN was identified in 81% (401/498). SLN correctly diagnosed 40/47 patients with nodal metastases who had at least one SLN mapped, resulting in a 15% false-negative rate. After applying the algorithm, the false-negative rate dropped to 2%. Only one patient, whose LN spread would not have been caught by the algorithm, had an isolated positive right paraaortic LN with a negative ipsilateral SLN and pelvic LND. CONCLUSIONS: Satisfactory SLN mapping in endometrial cancer requires adherence to a surgical SLN algorithm and goes beyond just the removal of blue SLNs. Removal of any suspicious node along with side-specific lymphadenectomy for failed mapping are an integral part of this algorithm. Further validation of the false-negative rate of this algorithm is necessary. Barney BM, Petersen IA, Mariani A, et al: The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer, Int J Radiat Oncol Biol Phys 85(1):109–115, 2013. OBJECTIVES: The optimal adjuvant therapy for International Federation of Gynecology and Obstetrics (FIGO) stage I papillary serous (UPSC) or clear cell (CC) endometrial cancer is unknown. We report on the largest single-institution experience using adjuvant high-dose-rate vaginal brachytherapy (VBT) for surgically staged women with FIGO stage I UPSC or CC endometrial cancer. METHODS AND MATERIALS: From 1998 to 2011, 103 women with FIGO 2009 stage I UPSC (n 5 74), CC (n 5 21), or mixed UPSC/ CC (n 5 8) endometrial cancer underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant high-dose-rate VBT. Nearly all patients (n 5 98, 95%) also underwent extended lymph node dissection of pelvic and paraaortic

lymph nodes. All VBT was performed with a vaginal cylinder, treating to a dose of 2100 cGy in 3 fractions. Thirty-five patients (34%) also received adjuvant chemotherapy. RESULTS: At a median follow-up time of 36 months (range, 1 to 146 months), two patients had experienced vaginal recurrence, and the 5-year Kaplan Meier estimate of vaginal recurrence was 3%. The rates of isolated pelvic recurrence, locoregional recurrence (vaginal1pelvic), and extrapelvic recurrence (including intra-abdominal) were similarly low, with 5-year Kaplan-Meier estimates of 4%, 7%, and 10%, respectively. The estimated 5-year overall survival was 84%. On univariate analysis, delivery of chemotherapy did not affect recurrence or survival. CONCLUSIONS: VBT is effective at preventing vaginal relapse in women with surgical stage I UPSC or CC endometrial cancer. In this cohort of patients who underwent comprehensive surgical staging, the risk of isolated pelvic or extrapelvic relapse was low, implying that more extensive adjuvant radiation therapy is likely unnecessary. Bhaskaran K, Douglas I, Forbes H, et al: Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults, Lancet 384(9945):755–765, 2014. BACKGROUND: High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterization of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS: With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then nonlinear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS: 5.24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1.62, 99% CI 1.56 to 1.69; P , .0001), gallbladder (1.31, 1.12 to 1.52; P , .0001), kidney (1.25, 1.17 to 1.33; P , .0001), cervix (1.10, 1.03 to 1.17; P 5 .00035), thyroid (1.09, 1.00 to 1.19; P 5 .0088), and leukemia (1.09, 1.05 to 1.13; P # .0001). BMI was positively associated with liver (1.19, 1.12 to 1.27), colon (1.10, 1.07 to 1.13), ovarian (1.09, 1.04 to 1.14), and postmenopausal breast cancers (1.05, 1.03 to 1.07) overall (all P , .0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0.98, 0.95 to 1.00; premenopausal breast cancer 0.89, 0.86 to 0.92) and in neversmokers (prostate 0.96, 0.93 to 0.99; premenopausal breast cancer 0.89, 0.85 to 0.94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0.99, 0.93 to 1.05; oral cavity 1.07, 0.91 to 1.26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION: BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups.

e12 FUNDING: National Institute for Health Research, Wellcome Trust, and Medical Research Council. Birkbak NJ, Kochupurakkal B, Izarzugaza JM, et al: Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations, PLoS One 8(11):e80023, 2013. BACKGROUND: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying diseaseassociated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. METHODS AND RESULTS: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. CONCLUSIONS: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms. Bogani G, Murgia F, Ditto A, et al: Sentinel node mapping vs. lymphadenectomy in endometrial cancer: a systematic review and meta-analysis, Gynecol Oncol 153(3):676–683, 2019. Sentinel node mapping is increasingly being utilized for endometrial cancer staging. However, only limited evidence supporting the adoption of sentinel node mapping instead of conventional lymphadenectomy is still available. Here, we aimed to review the current evidence comparing sentinel node mapping and lymphadenectomy in endometrial cancer staging. This systematic review was registered in the International Prospective Register of Systematic Reviews. Six comparative studies were included. Overall, 3536 patients were included: 1249 (35.3%) and 2287 (64.7%), undergoing sentinel node mapping and lymphadenectomy, respectively. Pooled data suggested that positive pelvic nodes were detected in 184 out of 1249 (14.7%) patients having sentinel node mapping and 228 out of 2287 (9.9%) patients having lymphadenectomy (OR: 2.03; (95%CI: 1.30 to 3.18); P 5 .002). No difference in detection of positive nodes located in the paraaortic was observed (OR: 93 (95%CI: 0.39 to 2.18); P 5 .86). Overall recurrence rate was 4.3% and 7.3% after sentinel node mapping and lymphadenectomy, respectively (OR: 0.90 (95%CI: 0.58 to 1.38); P 5 .63). Similarly, nodal recurrences were statistically similar between groups (1.2% vs. 1.7%; OR: 1.51 (95%CI: 0.70 to 3.29); P 5 .29). In conclusion, our meta-analysis underlines that sentinel node mapping is non-inferior to standard lymphadenectomy in terms of detection of paraaortic nodal involvement

and recurrence rates (any site and nodal recurrence), while, focusing on the ability to detect positive pelvic nodes, sentinel node mapping could be considered superior to lymphadenectomy. Further randomized studies are needed to assess long-term effectiveness of sentinel node mapping. Bosse T, Peters EE, Creutzberg CL, et al: Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer—a pooled analysis of PORTEC 1 and 2 trials, Eur J Cancer 51(13):1742–1750, 2015. BACKGROUND: Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence. METHODS: In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomized to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n 5 714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n 5 427). In tumor samples of 926 (81.2%) patients with endometrioid tumors LVSI was quantified using 2-, 3-, and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis. RESULTS: Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n 5 44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4 to 8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4 to 16), distant metastasis (HR 3.6 CI 1.9 to 6.8), and overall survival (HR 2.0 CI 1.3 to 3.1). Only EBRT (HR 0.3 CI 0.1 to 0.8) reduced the risk of pelvic regional recurrence. CONCLUSIONS: Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis, and overall survival. Therapeutic decisions should be based on the presence of substantial, not “any” LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI. Buhard O, Cattaneo F, Wong YF, et al: Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors, J Clin Oncol 24(2):241–251, 2006. PURPOSE: Human gastrointestinal tumors with inactivated DNA mismatch repair system (microsatellite instability [MSI] tumors) have distinct molecular and clinicopathologic profiles, and are associated with favorable prognosis. There is evidence suggesting that colorectal cancer patients with MSI tumors respond differently to adjuvant chemotherapy as compared with patients with non-MSI tumors. Finally, determination of the MSI status has clinical application for assisting in the diagnosis of suspected hereditary cases. It is thus becoming increasingly recognized that testing for MSI should be conducted systematically in all human cancers potentially of this type. We recently described a pentaplex polymerase chain reaction of five mononucleotide repeats to establish the MSI status of human tumors, and showed that this assay was 100% sensitive and specific. Moreover, these markers are quasimonomorphic in germline DNA of the white population (i.e., individuals of Eurasian origin), and could be used for tumor MSI determination without the requirement for matching normal DNA in this group. PATIENTS AND METHODS: In this study, we analyzed a comparable panel of five mononucleotide markers in germline DNA from 1206

e13 individuals encompassing 55 different populations worldwide. Results: With the exception of two Biaka Pygmies and one San individual for whom three markers showed variant alleles (three cases [0.2%]), the remaining 1203 individuals showed no alleles of variant size (1055 cases [87.5%]), or only one (122 cases [10.1%]) or two (26 cases [2.2%]) markers with variant alleles. All 60 MSI tumors investigated display instability in at least four of the five markers. CONCLUSION: We demonstrated that tumor MSI status can be determined using the pentaplex reaction for all human populations without the need for matching normal DNA. Buza N, English DP, Santin AD, et al: Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice, Mod Pathol 26(12):1605–1612, 2013. HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely—at least in part— resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases—85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component—were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients’ medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/ or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended, due to the significant heterogeneity of HER2 protein expression. Marth CV, Rubio MJ, Makker V, et al: ENGOT-EN9/LEAP-001: a phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced endometrial cancer, Ann Oncol 30(Suppl 5), 2019. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al: Integrated genomic characterization of endometrial carcinoma, Nature 497(7447):67–73, 2013. We performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and approximately 25% of high-grade endometrioid tumors had extensive copy number alterations, few DNA methylation changes, low estrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumors had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS and novel mutations in the SWI/SNF chromatin remodeling complex gene ARID5B. A subset of endometrioid tumors

that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumors. Cardosi RJ, Cox CS, Hoffman MS: Postoperative neuropathies after major pelvic surgery, Obstet Gynecol 100(2):240–244, 2002. OBJECTIVE: To estimate the incidence, etiology, and outcome of neuropathies after major gynecologic surgery and to recommend management and prevention strategies for these complications. METHODS: The medical records of women who suffered neuropathy after major pelvic surgery between July 1995 and June 2001 were reviewed. Mechanism of injury, treatment, and outcome were determined from the patient charts. RESULTS: Twenty-three of 1210 patients undergoing major pelvic surgery during the defined period suffered a postoperative neuropathy for an incidence of 1.9%. Neurologic injury involved the obturator (n 5 9), ilioinguinal/iliohypogastric (n 5 5), genitofemoral (n 5 4), femoral (n 5 3), and lumbosacral nerve plexus (n 5 2) in these women. Etiologies were a result of direct surgical trauma, stretch injury, suture entrapment, or were retractor related. All patients with motor deficits were treated with physiotherapy, and pharmacologic or surgical management was used in women with sensory deficits or pain. Seventy-three percent of the women experienced full recovery; the only patients with persistent symptoms were those with unrepaired nerve transection or injury to the lumbosacral plexus. Both time to diagnosis and time to resolution varied widely. CONCLUSION: Neuropathies are infrequently associated with major pelvic surgery. We observed a 73% complete recovery rate, and time to resolution varied depending on the severity of injury. Physical therapy plays a valuable role in managing these patients, but some may require surgery for relief of their symptoms. Chang-Halpenny CN, Natarajan S, Hwang-Graziano J: Early stage papillary serous or clear cell carcinoma confined to or involving an endometrial polyp: outcomes with and without adjuvant therapy, Gynecol Oncol 131(3):598–603, 2013. OBJECTIVE: To investigate clinical outcomes of stage IA uterine papillary serous (UPSC) and clear cell carcinoma (CC) arising from or associated with a polyp. METHODS: From 1995 to 2011, we identified 51 cases of stage IA UPSC (67%), CC (8%), or mixed histology (26%) endometrial cancer. Of these, 32 had disease confined to polyp (seven with no residual disease after hysterectomy), 14 had surface spread, 1 had myometrial invasion (MMI), and 4 had both. The majority of patients did not receive adjuvant therapy (80%). Patients given adjuvant treatment (either platinum-based chemotherapy alone, radiation alone, or a combination of the two) had incomplete staging or abnormal cytology. RESULTS: At mean follow-up of 58.3 months, only 4 patients had progressed, via pelvic adenopathy, carcinomatosis, or both. There were no vaginal cuff recurrences. Kaplan-Meier 5-year estimates were pelvic control of 92.1%, disease-free survival 93%, and OS 80.6%. Only 9% (3/32) of cases confined to polyp progressed. One responded to salvage chemoradiation, but two died despite salvage. Only 5% (1/19) of cases with surface and MMI progressed. On univariate analysis, only MMI and abnormal/positive cytology were significantly associated with increased pelvic recurrence (MMI P 5 .0059, cytology P 5 .0036) and worse DFS (MMI P 5 .0018, cytology P 5 .0054).

e14 Two patients given adjuvant treatment developed new gynecologic malignancies. CONCLUSION: In our study, patients with limited UPSC/CC disease involving a polyp who have complete workup did well without adjuvant therapy, with recurrence rates similar to UPSC/CC stage IA disease. Late and extensive pelvic relapses may occur in the few who do relapse. Chao A, Wu RC, Jung SM, et al: Implication of genomic characterization in synchronous endometrial and ovarian cancers of endometrioid histology, Gynecol Oncol 143(1):60–67, 2016. OBJECTIVES: Synchronous endometrial and ovarian carcinomas (SEOCs) present gynecologic oncologists with a challenging diagnostic puzzle: discriminating between double primary cancers and single primary cancer with metastasis. We aimed to determine the clonal relationship between simultaneously diagnosed endometrial and ovarian carcinomas. METHODS: Fourteen pairs of SEOCs of endometrioid type and two pairs of SEOCs with disparate histologic types (control for dual primary tumors) were subjected to massively parallel sequencing (MPS) and molecular inversion probe microarrays. RESULTS: Thirteen of the 14 pairs of SEOCs harbored somatic mutations shared by both uterine and ovarian lesions, indicative of clonality. High degree of chromosomal instability in the tumors from 10 patients who received adjuvant chemotherapy, of whom 9 had synchronous carcinomas with significantly overlapping copy number alterations (CNAs), suggestive of single primary tumors with metastasis. The clonal relationship determined by genomic analyses did not agree with clinicopathological criteria in 11 of 14 cases. Minimal CNAs were identified in both ovarian and endometrial carcinomas in 4 patients, who did not receive adjuvant chemotherapy and experienced no recurrent diseases. In contrast, two of the 10 patients with chromosomally unstable cancers developed recurrent tumors. CONCLUSION: Our findings support a recent paradigm-shifting concept that most SEOCs originate from a single tumor. It also casts doubt on the clinicopathological criteria used to distinguish between dual primary tumors and single primary tumor with metastasis. Testing of CNAs on SEOCs may help determine the need of adjuvant therapy. Cirisano FD Jr, Robboy SJ, Dodge RK, et al: Epidemiologic and surgicopathologic findings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma, Gynecol Oncol 74(3):385–394, 1999. PURPOSE: The aim of this study was to identify similarities and differences in epidemiologic and surgicopathologic staging results for papillary serous (PS) and clear cell (CC) endometrial cancers compared with endometrioid (EM) carcinoma of the endometrium. METHODS: Clinical and surgicopathologic data were retrospectively collected on 574 clinical stage I-II endometrial cancer patients, including 53 PS and 18 CC (based on postoperative histology), undergoing hysterectomy at Duke University Medical Center between 1967 and 1990. All staging material was available and reexamined prior to this analysis, and FIGO surgical staging was retrospectively assigned. PS and CC histologic subtypes were compared both as a common category and as discrete categories versus EM, EM grade 1 (EM1), EM grade 2 (EM2), and EM grade 3 (EM3). Fisher’s exact test was used to compare proportions with unordered categories (232 tables), while the chi(2) test for trend was used to compare proportions in 332 tables with ordered categories. Differences in medians were compared with the Wilcoxon rank-sum test. RESULTS: PS tumors accounted for 8%, CC for 2%, and EM for 90% of cases. Overall, 14% of tumors were changed to a different

postoperative histology including 64% of PS, 50% of CC, and 8% of EM. Postoperative histology changes were 4% for EM1 and 21% for EM3. PS, CC, and EM3 had more surgical sampling performed than for other EM. Rates for lymph node dissections were similar for EM3 (81%), PS (72%), and CC (67%) tumors, although metastases were more frequent for PS and CC compared with EM3. When PS tumors were confined to the endometrium, paraaortic metastases occurred in 13%. LVSI increased with EM grade and was highest for PS and CC. Upstaging to surgical stage III-IV occurred in 47% of PS, 39% of CC, and 12% of EM. The majority of PS and CC tumors were confined to the inner one-third of the myometrium, compared with EM tumors, where grade correlated with depth of myometrial invasion. Extrauterine metastases occurred in 55% of PS and 45% of CC tumors confined to the inner one-half, compared with 17% of EM3. CONCLUSION: Frequent changes from preoperative to postoperative histology and grade may contribute to misassignment of preoperative and intraoperative risk as determined by depth of myometrial invasion for PS and CC patients. The higher frequency of extrauterine metastases in PS and CC tumors compared with EM3, despite similar surgical sampling rates, supports a more virulent behavior. The poor correlation between depth of myometrial invasion and risk for extrauterine metastases helps to explain poorer survival in PS and CC patients, in addition to more frequent upstaging. These results support routine extended surgical staging for women with preoperative or intraoperative diagnosis of PS and CC tumors. Intraoperative assessment of tumor grade and histology may be indicated and warrants further investigation. Clarke MA, Devesa SS, Harvey SV, et al: Hysterectomy-corrected uterine corpus cancer incidence trends and differences in relative survival reveal racial disparities and rising rates of nonendometrioid cancers, J Clin Oncol 37(22):1895–1908, 2019. PURPOSE: Uterine corpus cancer incidence rates have been projected to increase, a prediction often attributed to the obesity epidemic. However, correct estimation of these rates requires accounting for hysterectomy prevalence, which varies by race, ethnicity, and region. Here, we evaluated recent trends in hysterectomy-corrected rates by race and ethnicity and histologic subtype and estimated differences in relative survival by race and ethnicity, subtype, and stage. METHODS: We estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System. Hysterectomy-corrected agestandardized uterine corpus cancer incidence rates from 2000 to 2015 were calculated from the SEER 18 registries. Incidence rates and trends were estimated separately by race and ethnicity, region, and histologic subtype. Five-year relative survival rates were estimated by race and ethnicity, histologic subtype, and stage. RESULTS: Hysterectomy-corrected incidence rates of uterine corpus cancer were similar among non-Hispanic whites and blacks and lower among Hispanics and Asians/Pacific Islanders. Endometrioid carcinoma rates were highest in non-Hispanic whites, whereas nonendometrioid carcinoma and sarcoma rates were highest in non-Hispanic blacks. Hysterectomy-corrected uterine corpus cancer incidence increased among non-Hispanic whites from 2003 to 2015 and among nonHispanic blacks, Hispanics, and Asians/Pacific Islanders from 2000 to 2015. Overall incidence rates among non-Hispanic blacks surpassed those of non-Hispanic whites in 2007. Endometrioid carcinoma rates rose among non-Hispanic blacks, Hispanics, and Asians/Pacific Islanders but were stable among non-Hispanic whites; however, nonendometrioid carcinoma rates rose significantly among all women. Non-Hispanic blacks had the lowest survival rates, irrespective of stage at diagnosis or histologic subtype. CONCLUSION: Among all women, rates of nonendometrioid subtypes have been rising rapidly. Our analysis shows profound racial

e15 differences and disparities indicated by higher rates of nonendometrioid subtypes and poorer survival among non-Hispanic black women. Colombo N, McMeekin DS, Schwartz PE, et al: Ridaforolimus as a single agent in advanced endometrial cancer: results of a singlearm, phase 2 trial, Br J Cancer 108(5):1021–1026, 2013. BACKGROUND: This open-label, multicenter, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. METHODS: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary endpoint was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more. RESULTS: In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anemia (27%) and hyperglycemia (11%). CONCLUSION: Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted. Creasman WT, Ali S, Mutch DG, et al: Surgical-pathological findings in type 1 and 2 endometrial cancer: an NRG Oncology/ Gynecologic Oncology Group study on GOG-210 protocol, Gynecol Oncol 145(3):519–525, 2017. OBJECTIVE: To report clinical and pathologic relationships with disease spread in endometrial cancer patients. METHODS: Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and paraaortic lymphadenectomy. From 2003 to 2007, open eligibility enrollment was conducted, and from 2007 to 2011, eligibility was restricted to enrich underrepresented patients or those at high risk. RESULTS: This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell, and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell, and carcinosarcoma) had a much greater propensity for extant disease. CONCLUSIONS: This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell, and carcinosarcoma,

surgical pathological findings substantiate the categorization of poor histotypes for these cancers. D’Adamo DR, Dickson MA, Keohan ML, et al: A phase II trial of sorafenib and dacarbazine for leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors, Oncologist 24(6):857–863, 2019. BACKGROUND: Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS: Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1000 mg/m(2) intravenously (later reduced to 850 mg/m(2)). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS: The study included 37 patients (19 female); median age was 55 years (range 26–87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m(2), only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION: This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE: Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity. Darai E, Dubernard G, Bats AS, et al: Sentinel node biopsy for the management of early stage endometrial cancer: long-term results of the SENTI-ENDO study, Gynecol Oncol 136(1):54–59, 2015. OBJECTIVE: We report the long-term results of the SENTI-ENDO study evaluating the impact of sentinel lymph node (SLN) biopsy on management and survival in patients with early stages of endometrial cancer (EC). METHODS: Patients with FIGO stage I-II EC underwent pelvic SLN biopsy after cervical dual injection (technetium and patent blue) and systematic pelvic node dissection. This study is a secondary endpoint reporting the long-term recurrence free survival (RFS) and the impact of the SLN procedure on adjuvant therapies. RESULTS: The median follow-up was 50 months (range: 3 to 77 months). Eighteen of the 125 patients (14.4%) experienced a recurrence. The 50-month recurrence-free survival (RFS) was 84.7% with no difference between patients with and without detected SLN (P 5 .09). Among patients with detected SLN (111), no difference in RFS was observed between those with and without positive SLN (P 5 .5). In the whole population, adjuvant therapy was performed in low-, intermediate-, and high-risk groups in 31 of 64 patients (48.4%), 28 of 37 patients (75.7%), and 14 of 17 patients (82.3%), respectively

e16 (P 5 .0001). For the 111 patients with detected SLN, EBRT was performed in 27 of the 89 with negative SLN and in 11 of the 14 with positive SLN (P 5 .001). Chemotherapy was performed more frequently in patients with positive SLN (6/12, 50%) than in patients with negative SLN (7/56, 12.5%) (P 5 .009). CONCLUSIONS: Our results support the impact of SLN biopsy on surgical management and indications for adjuvant therapies. Further studies are required to assess the clinical impact of the SLN biopsy in early-stage EC. de Boer SM, Powell ME, Mileshkin L, et al: Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial, Lancet Oncol 19(3):295–309, 2018. BACKGROUND: Although women with endometrial cancer generally have a favorable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. METHODS: PORTEC-3 was an open-label, international, randomized, phase 3 trial involving 103 centers in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48.6 Gy in 1.8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m(2) given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m(2)) using a biased-coin minimization procedure with stratification for participating center, lymphadenectomy, stage of cancer, and histological type. The coprimary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on December 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials. gov, number NCT00411138. RESULTS: 686 women were enrolled between November 23, 2006 and December 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60.2 months (IQR 48.1 to 73.1). 5-year overall survival was 81.8% (95% CI 77.5 to 86.2) with chemoradiotherapy versus 76.7% (72.1 to 81.6) with radiotherapy (adjusted hazard ratio [HR] 0.76, 95% CI 0.54 to 1.06; P 5 .11); 5-year failure-free survival was 75.5% (95% CI 70.3 to 79.9) versus 68.6% (63.1 to 73.4; HR 0.71, 95% CI 0.53 to 0.95; P 5 .022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (P , .0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; P , .0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity. INTERPRETATION: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year

overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L’Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute. de Boer SM, Powell ME, Mileshkin L, et al: Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial, Lancet Oncol 20(9):1273–1285, 2019. BACKGROUND: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. METHODS: In the multicenter randomized phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0 to 2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48.6 Gy in 1.8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m(2) given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m(2) given intravenously), by use of a biased coin minimization procedure with stratification for participating center, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analyzed according to the first site of recurrence. Survival endpoints were analyzed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyze patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. FINDINGS: Between November 23, 2006 and December 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72.6 months (IQR 59.9 to 85.6), 5-year overall survival was 81.4% (95% CI 77.2 to 85.8) with chemoradiotherapy versus 76.1% (71.6 to 80.9) with radiotherapy alone (adjusted hazard ratio [HR] 0.70 [95% CI 0.51 to 0.97], P 5 .034), and 5-year failure-free survival was 76.5% (95% CI 71.5 to 80.7) versus 69.1% (63.8 to 73.8; HR 0.70 [0.52 to 0.94], P 5 .016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21.4%; 95% CI 17.3 to 26.3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29.1%; 24.4 to 34.3) in the radiotherapy-alone group (HR 0.74 [95% CI 0.55 to 0.99]; P 5 .047). Isolated vaginal recurrence was the first site of recurrence in one patient (0.3%; 95% CI 0.0 to 2.1) in both groups (HR 0.99 [95% CI 0.06 to 15.90]; P 5 .99), and isolated pelvic recurrence was the first site of recurrence in three women (0.9% [95% CI 0.3 to 2.8]) in the chemoradiotherapy group versus four (0.9% [95% CI 0.3 to 2.8]) in the radiotherapy-alone group (HR 0.75 [95% CI 0.17 to 3.33]; P 5 .71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the

e17 chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (P 5 .24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (P 5 .002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. INTERPRETATION: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial, J Clin Oncol 34(8):786–793, 2016. PURPOSE: This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. PATIENTS AND METHODS: Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary endpoint was overall survival (OS), secondary endpoints were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response, as well as safety and patient-reported symptom scoring. RESULTS: A total of 518 patients were enrolled and randomly assigned to either trabectedin (n 5 345) or dacarbazine (n 5 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 vs. 1.5 months; hazard ratio, 0.55; P , .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 vs. 12.9 months; hazard ratio, 0.87; P 5 .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. CONCLUSION: Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant endpoint, this study supports the activity of trabectedin for patients with these malignancies. Diaz LA Jr, Le DT: PD-1 blockade in tumors with mismatch-repair deficiency, N Engl J Med 373(20):1979, 2015. Fader AN, Roque DM, Siegel E, et al: Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal

growth factor receptor 2/neu, J Clin Oncol 36(20):2044–2051, 2018. PURPOSE: Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. METHODS: Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary endpoint was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. RESULTS: From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival-related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P 5 .005; hazard ratio [HR], 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment (P 5 .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease (P 5 .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. CONCLUSION: Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Galluzzi L, Buqué A, Kepp O, et al: Immunological effects of conventional chemotherapy and targeted anticancer agents, Cancer Cell 28(6):690–714, 2015. The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological “side” effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. Garg G, Gao F, Wright JD, et al: Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer, Gynecol Oncol 128(1):77–82, 2013. OBJECTIVE: In light of the recent changes in the International Federation of Gynecology and Obstetrics (FIGO) staging system, the objective of this study was to determine the prognostic significance of positive peritoneal cytology (PPC) among patients with early-stage endometrial cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with stage I/II endometrial cancer who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analyses used Chi-square test, Kaplan-Meier log rank, and Cox proportional hazards models.

e18 RESULTS: A total of 14,704 patients were identified: 14,219 with negative peritoneal cytology (NPC) and 485 with positive peritoneal cytology. More patients with PPC compared to those with NPC were diagnosed with high-risk factors such grade III disease (40.2% vs. 23.8%, P , .0001), and unfavorable histologic types such as clear cell/ serous carcinoma (17.5% vs. 7.5%, P # .0001) and carcinosarcoma (9.3% vs. 5.6%, P , .0001). When compared to patients with negative peritoneal cytology, survival was significantly worse among patients with positive peritoneal cytology (P , .0001): 5-year disease specific survival 95.1% versus 80.8% in endometrioid adenocarcinoma; 78.0% versus 50.4% in clear cell/serous cancer; and 64.7% versus 32.3% in carcinosarcoma. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of poor survival (P , .0001) in all histologic types examined. CONCLUSION: PPC is an independent risk factor in patients with early-stage endometrial cancer. Although no longer a part of the current FIGO staging criteria, peritoneal cytology status should still be considered for accurate risk-stratification of these patients. Hajkova N, Tichá I, Hojný J, et al: Synchronous endometrioid endometrial and ovarian carcinomas are biologically related: a clinico-pathological and molecular (next generation sequencing) study of 22 cases, Oncol Lett 17(2):2207–2214, 2019. The criteria for distinction between independent primary tumors and metastasis from one site to the other in synchronous endometrioid endometrial and ovarian carcinoma (SEO) has been a matter of dispute for a long time. In our study we performed a comprehensive clinicopathological and molecular analysis of 22 cases of SEO. Based on conventional clinicopathological criteria the cases were classified as independent primary tumors (10 cases) and metastasis from one location to the other (12 cases). All tumors were analyzed by NGS with a panel of 73 genes (219 kbp). Clonal origin was confirmed in all cases by at least one shared mutation in PTEN, AKT1, PIK3CA, KRAS, TP53, and ARID1A. Two patients carried germline pathogenic mutation in cancer-predisposing genes BRCA1 or BARD1. Microsatellite instable phenotype was detected in 5/22 (22.7%) SEO, but in one case only in the endometrial tumor. In conclusion, our results showed that all 22 SEOs were clonally related, irrespective of their clinicopathological features. Even low-grade and low-stage tumors classified as independent primaries, according to the conventional morphological criteria, have a clonal origin. From the practical point of view, only the conventional morphological criteria should be used for the classification (staging) of these tumors. However, molecular profiling of these tumors may have prognostic and predictive meaning. Hensley ML, Enserro D, Hatcher H, et al: Adjuvant gemcitabine plus docetaxel followed by doxorubicin versus observation for high-grade uterine leiomyosarcoma: a phase III NRG Oncology/Gynecologic Oncology Group Study, J Clin Oncol 36(33):JCO1800454, 2018. PURPOSE: We conducted a randomized phase III trial to determine whether adjuvant chemotherapy improves survival in women with uterine leiomyosarcoma. METHODS: Women with uterus-confined, high-grade leiomyosarcoma who were confirmed disease free by imaging were randomly assigned to four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin, or to observation. All were followed for evidence of recurrence. The primary end point was overall survival (OS). RESULTS: With international collaboration, 38 of the targeted accrual of 216 patients were enrolled, after which the study was closed by the National Cancer Institute for accrual futility. Twenty patients were assigned to chemotherapy, 18 to observation. Among the 17 patients treated with at least one cycle of chemotherapy, grade 3 or 4 toxicities were observed in 47%; among the 18 patients assigned to observation, one had grade 3 hypertension. There were six deaths (chemotherapy,

n 5 5; observation, n 5 1), all due to disease. The restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm. There were eight recurrences in each arm. The restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. Neither survival outcome comparison was considered statistically robust, due to the small sample size. CONCLUSION: Despite international collaboration to test the role of adjuvant chemotherapy in uterine-confined leiomyosarcoma, this study was closed for accrual futility. Although the sample size precludes robust statistical comparison, observed OS and recurrence-free survival data do not show superior outcomes with adjuvant chemotherapy. Hensley ML, Miller A, O’Malley DM, et al: Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study, J Clin Oncol 33(10):1180–1185, 2015. PURPOSE: Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabinedocetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs. RESULTS: In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n 5 54) and gemcitabine-docetaxel plus bevacizumab (n 5 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P 5 .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P 5 .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab. CONCLUSION: The addition of bevacizumab to gemcitabinedocetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard firstline treatment for uLMS. Hodi FS, Lawrence D, Lezcano C, et al: Bevacizumab plus ipilimumab in patients with metastatic melanoma, Cancer Immunol Res 2(7):632–642, 2014. Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade

e19 with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n 5 1), hepatitis (n 5 2), and uveitis (n 5 2). Ontreatment tumor biopsies revealed activated vessel endothelium with extensive CD8(1) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(1/2)/CD45RO(1) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. Hui P, Kelly M, O’Malley DM, et al: Minimal uterine serous carcinoma: a clinicopathological study of 40 cases, Mod Pathol 18(1):75–82, 2005. The term “minimal uterine serous carcinoma” has been proposed to include serous carcinomas with invasion limited to the endometrium (superficial serous carcinoma), and those without stromal invasion (intraepithelial serous carcinoma or endometrial intraepithelial carcinoma). Both lesions display similar cytological and immunohistochemical profiles of a typical invasive serous carcinoma with a high nuclear grade and an overexpression of mutant p53 protein. We studied the clinicopathologic features of 40 cases of minimal uterine serous carcinoma. All patients were postmenopausal and underwent hysterectomy and surgical staging procedures. There were nine cases of intraepithelial serous carcinoma and 31 cases of superficial serous carcinoma. Five intraepithelial serous carcinomas and 16 superficial serous carcinomas exclusively involved an endometrial polyp. A total of 18 minimal uterine serous carcinomas also involved, in addition to a polyp, the endometrium proper in the form of intraepithelial serous carcinoma (13 cases) and superficial serous carcinoma (five cases). Overall, minimal uterine serous carcinomas were found to involve an endometrial polyp in 88% of the cases (35/40) and were confined to the polyp in 53% (21/40). Extrauterine tumors were present in 45% of the cases (18/40). In all, 22 patients with tumor limited to their uteri demonstrated an overall survival of 94% (2 to 73 months of follow-up). Eight of 18 patients with extrauterine tumors died of their malignancy (1.5 to 62 months of follow-up). In conclusion, a significant majority of minimal uterine serous carcinomas involve an endometrial polyp. Complete surgical staging is important to predict the prognosis. When the lesion is confined to an endometrial polyp and/or the endometrium proper, the clinical outcome is excellent. Siedel JH, Ring KL, Hu W, et al: Clinical significance of homologous recombination deficiency score testing in endometrial cancer. Gynecol Oncol 160(3):777–785, 2021. Kaban A, Topuz S, Erdem B, et al: Is omentectomy necessary for nonendometrioid endometrial cancer, Gynecol Obstet Invest 83(5):482–486, 2018. BACKGROUND: In subtypes of non-endometrioid endometrium cancers (non-ECC), it is not clear whether the omentectomy is a part of debulking if visual assessment is normal. Recently, the ESMOESGO-ESTRO Endometrial Consensus Conference Working Group in their report titled “Endometrial Cancer: diagnosis, treatment and follow-up” recommended that omentectomy be performed in the serous subtype, but not in carcinosarcoma, undifferentiated endometrial carcinoma, or clear cell. In this study, the question is

whether omentectomy should be a part of a staging procedure in patients with non-ECC. Besides, the sensitivity and specificity of the visual assessment of omentum were analyzed. METHODS: Patients diagnosed with non-ECC in 2 gynecological oncology clinics between 2005 and 2015 were retrospectively reviewed. Occult (absence of visible lesions) and gross (presence of visible lesions) omental metastasis rates of histological subtypes were analyzed. RESULTS: We identified 218 patients with non-ECC. Thirty-four of them (15.1%) had omental metastases and 44.1% of these metastases (n 5 15) were occult metastases. The sensitivity of the surgeon’s visual assessment of an omentum (positive or negative) was 0.55. The highest rate of omental metastasis was found in carcinosarcoma followed by serous, mixed subtypes, and clear-cell (20.4, 17.3, 16.6, 10.0%, respectively). Adnexal metastasis was the only factor associated with occult omental metastasis (P 5 .003). CONCLUSION: Omental metastases occur too often to omit omentectomy during surgical procedures for non-ECC regardless of histological subtypes, and visual assessment is insufficient in recognizing the often occult metastases. Omentectomy should be a part of the staging surgery in patients with non-ECC. Koh WJ, Abu-Rustum NR, Bean S, et al: Uterine neoplasms, Version 1.2018, NCCN clinical practice guidelines in oncology, J Natl Compr Canc Netw 16(2):170–199, 2018. Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately twothirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations. Konstantinopoulos PA, Luo W, Liu JF, et al: Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer, J Clin Oncol 37(30):2786–2794, 2019. PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase epsilon) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary endpoints were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/ kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary endpoint of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing

e20 as of data cutoff date. Responses were observed in the absence of PDL1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/nonPOLE-mutated ECs was low. Le DT, Durham JN, Smith KN, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science 357(6349):409–413, 2017. The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-ofconcept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progressionfree survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repairdeficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin. Le Gallo M, Rudd ML, Urick ME, et al: Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing, Cancer 123(17):3261–3268, 2017. BACKGROUND: The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. METHODS: We conducted whole exome sequencing of paired tumornormal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-ofinterest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats. RESULTS: Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC). CONCLUSION: Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene, Cancer 123:3261–3268. 2017. American Cancer Society. Lee ATJ, Jones RL, Huang PH: Pazopanib in advanced soft tissue sarcomas, Signal Transduct Target Ther 4:16, 2019. Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft

tissue sarcoma (STS). Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors, preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways. Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma, pazopanib was investigated in STS. A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes. The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts. At present, there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy, limiting the clinical effectiveness and cost-effectiveness of the drug. In this review, we summarize the preclinical and clinical data for pazopanib, outline the evidence base for its effect in STS, and explore reported studies that have investigated putative biomarkers. León-Castillo A, de Boer SM, Powell ME, et al: Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy, J Clin Oncol 38(29):3388–3397, 2020. PURPOSE: The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS: Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLEultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary endpoint was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS: Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n 5 93; 23%), POLEmut (n 5 51; 12%), MMRd (n 5 137; 33%), and NSMP (n 5 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P , .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P 5 .019); 100% versus 97% for patients with POLEmut EC (P 5 .637); 68% versus 76% (P 5 .428) for MMRd EC; and 80% versus 68% (P 5 .243) for NSMP EC. CONCLUSION: Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients. Lu KH, Broaddus RR: Endometrial cancer, N Engl J Med 383(21): 2053–2064, 2020. Mäenpää MM, Nieminen K, Tomás EI, et al: Robotic-assisted vs traditional laparoscopic surgery for endometrial cancer: a randomized controlled trial, Am J Obstet Gynecol 215(5):588.e581–588.e587, 2016. BACKGROUND: Previous studies comparing robotic-assisted laparoscopic surgery to traditional laparoscopic or open surgery in gynecologic oncology

e21 have been retrospective. To our knowledge, no prospective randomized trials have thus far been performed on endometrial cancer. OBJECTIVE: We sought to prospectively compare traditional and robotic-assisted laparoscopic surgery for endometrial cancer. STUDY DESIGN: This was a randomized controlled trial. From December 2010 through October 2013, 101 endometrial cancer patients were randomized to hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy either by robotic-assisted laparoscopic surgery or by traditional laparoscopy. The primary outcome measure was overall operation time. The secondary outcome measures included total time spent in the operating room, and surgical outcome (number of lymph nodes harvested, complications, and recovery). The study was powered to show at least a 25% difference in the operation time using 2-sided significance level of .05. The differences between the traditional laparoscopy and the robotic surgery groups were tested by Pearson chi(2) test, Fisher exact test, or Mann-Whitney test. RESULTS: In all, 99 patients were eligible for analysis. The median operation time in the traditional laparoscopy group (n 5 49) was 170 (range 126 to 259) minutes and in the robotic surgery group (n 5 50) was 139 (range 86 to 197) minutes, respectively (P , .001). The total time spent in the operating room was shorter in the robotic surgery group (228 vs 197 minutes, P , .001). In the traditional laparoscopy group, there were 5 conversions to laparotomy vs none in the robotic surgery group (P 5 .027). There were no differences as to the number of lymph nodes removed, bleeding, or the length of postoperative hospital stay. Four (8%) vs no (0%) patients (P 5 .056) had intraoperative complications and 5 (10%) vs 11 (22%) (P 5 .111) had major postoperative complications in the traditional and robotic surgery groups, respectively. CONCLUSION: In patients with endometrial cancer, robotic-assisted laparoscopic surgery was faster to perform than traditional laparoscopy. Also total time spent in the operating room was shorter in the robotic surgery group and all conversions to laparotomy occurred in the traditional laparoscopy group. Otherwise, the surgical outcome was similar between the groups. Robotic surgery offers an effective and safe alternative in the surgical treatment of endometrial cancer. Makker V, Rasco D, Vogelzang NJ, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial, Lancet Oncol 20(5):711–718, 2019. BACKGROUND: Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study. METHODS: In this open-label, single-arm, phase 2 study done at 11 centers in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immunerelated Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096.

FINDINGS: Between September 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumor activity data (December 15, 2017), median study follow-up was 13.3 months (IQR 6.7 to 20.1). 21 (39.6% [95% CI 26.5 to 54.0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial hemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events. INTERPRETATION: Lenvatinib plus pembrolizumab showed antitumor activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomized phase 3 study. FUNDING: Eisai and Merck. Marabelle A, Le DT, Ascierto PA, et al: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/ mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study, J Clin Oncol 38(1):1–10, 2020. PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an antiprogrammed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. PATIENTS AND METHODS: Eligible patients with histologically/ cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary endpoint was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. CONCLUSION: Our study demonstrates the clinical benefit of antiprogrammed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

e22 Matei D, Filiaci V, Randall ME, et al: Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer, N Engl J Med 380(24):2317–2326, 2019. BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary endpoint) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary endpoints included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.). Matsui J, Yamamoto Y, Funahashi Y, et al: E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition, Int J Cancer 122(3):664–671, 2008. E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF, and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC(50) value of 5.2 nM and it was almost identical for VEGF-driven one (IC(50) 5 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC(50) 5 2200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCFproducing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors. McMeekin DS, Filiaci VL, Thigpen JT, et al: The relationship between histology and outcome in advanced and recurrent endometrial

cancer patients participating in first-line chemotherapy trials: a Gynecologic Oncology Group study, Gynecol Oncol 106(1):16–22, 2007. OBJECTIVES: To explore associations between histology and outcome in advanced or recurrent endometrial cancer patients participating in Gynecologic Oncology Group chemotherapy trials. METHODS: Age, race, performance status, histologic type (serous5S; clear cell5CC; endometrioid5E), disease stage, and prior radiation were evaluated using various analytic methods to evaluate the probability of response and identify independent predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: Single agent or combination chemotherapy regimens including doxorubicin (A) (12%), doxorubicin/cisplatin (AP) (63%), doxorubicin/paclitaxel (AT) (13%), and paclitaxel/doxorubicin/ cisplatin (TAP) (11%) were used among 1203 patients treated on 4 randomized clinical trials. Breakdown of disease stage was 7.8% stage III, 22.8% stage IV, and 69.4% recurrent disease. Histologic distribution was 18% S, 3.7% CC, 8.5% mixed, 51.7% E, and 18.1% other. More S/CC patients enrolled on trials with advanced stage (III-IV) disease (as opposed to recurrent disease) compared to E patients (45% vs. 24%, P , .05). Overall response rate was 42% (E 5 44%, S 5 44%, CC 5 32%). Histologic type was not an independent predictor of response. Independent predictors of PFS included race, performance status, disease stage, and CC histology. Histology was also an independent predictor of OS; the relative hazard ratio for S histology was 1.2 (1.02 to 1.4; P 5 .03), and for CC was 1.51 (1.1 to 2.07; P 5 .01). CONCLUSION: In patients with advanced/recurrent endometrial cancer treated with A, P, and/or T, response was not associated with histology. This exploratory analysis does not support exclusion of S tumors in future trials. Poorer PFS and OS were observed in CC compared to other types, but a lack of benefit from chemotherapy was not shown, and as this histology represents such a small fraction, it does not seem feasible to have separate chemotherapy trials for CC. Miller DS, Filiaci VL, Mannel RS, et al: Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209), J Clin Oncol 38(33):3841–3850, 2020. PURPOSE: Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS: GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m(2) and cisplatin 50 mg/m(2) (day 1), followed by paclitaxel 160 mg/m(2) (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m(2) and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS: From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 vs. 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 vs. 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade greater than 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (P 5 .40). More grade $ 3 thrombocytopenia (23% vs. 12%),

e23 vomiting (7% vs. 4%), diarrhea (6% vs. 2%), and metabolic (14% vs. 8%) toxicities were reported with TAP. Neutropenia (52% vs. 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION: With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer. Mullins MA, Cote ML: Beyond obesity: the rising incidence and mortality rates of uterine corpus cancer, J Clin Oncol 37(22):1851–1853, 2019. Ott PA, Bang YJ, Berton-Rigaud D, et al: Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 Study, J Clin Oncol 35(22):2535–2541, 2017. PURPOSE: The multicohort phase Ib KEYNOTE-028 (NCT02054806) study was designed to evaluate the safety and efficacy of pembrolizumab, an anti-programmed death 1 monoclonal antibody, in patients with programmed death ligand 1 (PD-L1) -positive advanced solid tumors. The results from the advanced endometrial cancer cohort are reported. PATIENTS AND METHODS: Female patients with locally advanced or metastatic PD-L1-positive endometrial cancer who had experienced progression after standard therapy were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until progression or unacceptable toxicity. Primary efficacy endpoint was objective response rate by RECIST (version 1.1). Secondary endpoints included safety, duration of response (DOR), progression-free survival, and overall survival. The data cutoff was February 17, 2016. RESULTS: Of 75 patients screened, 36 (48.0%) had PD-L1-positive tumors, and 24 (32.0%) were enrolled. Fifteen (62.5%) of these 24 patients had received at least two previous lines of therapy for advanced disease. Three patients (13.0%) achieved confirmed partial response (95% CI, 2.8% to 33.6%); the median DOR was not reached. Two patients were still receiving treatment and exhibiting continued response at time of data cutoff. Three additional patients (13.0%) achieved stable disease, with a median duration of 24.6 weeks. One patient who achieved partial response had a polymerase E mutation. Thirteen patients (54.2%) experienced treatment-related adverse events (AEs), with fatigue (20.8%), pruritus (16.7%), pyrexia (12.5%), and decreased appetite (12.5%) occurring in $ 10% of patients. Grade 3 treatment-related AEs were reported in four patients. No patient experienced a grade 4 AE, and no patient discontinued treatment because of an AE. CONCLUSION: Pembrolizumab demonstrated a favorable safety profile and durable antitumor activity in a subgroup of patients with heavily pretreated advanced PD-L1-positive endometrial cancer. Plante M, Stanleigh J, Renaud MC, et al: Isolated tumor cells identified by sentinel lymph node mapping in endometrial cancer: does adjuvant treatment matter? Gynecol Oncol 146(2):240–246, 2017. OBJECTIVE: To evaluate the outcome and the role of adjuvant treatment in the management of patients with endometrial cancer and isolated tumor cells (ITCs) identified by SLN mapping. METHODS: This single center study identified all patients undergoing hysterectomy, salpingo-oophorectomy, lymphadenectomy, and SLN mapping for endometrial cancer between November 2010 and December 2015. Data was prospectively collected. Progression-free survival was analyzed according to the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 519 patients were included. Overall, 85 patients (16.4%) were found to have SLN metastases of which 43 (51%) were macrometastasis, 11 (13%) micrometastasis (MM), and 31 (36%) ITC. Eleven (35%) patients with ITCs received adjuvant chemotherapy ÔÇ± whole pelvic radiation therapy (WPRT), 10 (32%) received WPRT, and 10 (32%) received either no adjuvant treatment or vault

brachytherapy (VBT) only. ITC patients received significantly less chemotherapy (P 5 .0001) and WPRT (P 5 .007) compared to patients with macrometastasis. Of note, ITC were not considered node positive in our study. With a median follow-up of 29 months (range: 0 to 67), the progression free survival (PFS) at 3 years for the ITC patients was 95.5%, similar to node negative (87.6%) and micrometastasis patients (85.5%), but statistically better than patients with macrometastasis (58.5%) (P 5 .0012). Only 1/31 patients with ITC recurred (IB, 7cm carcinosarcoma) despite adjuvant treatments. None of the ITC patients with endometrioid histology recurred (0/28) and none of the ITC patients who did not receive adjuvant treatment or VBT recurred (0/10). CONCLUSIONS: Patients with endometrial cancer found to have SLN ITCs have an excellent outcome. The use of adjuvant treatment should be tailored to uterine factors and histology and not solely based on the presence of ITCs. Patients with ITCs and otherwise low-risk uterine disease probably derive little benefit from receiving additional treatments. More studies are needed to confirm our results. Postow MA, Callahan MK, Wolchok JD: Immune checkpoint blockade in cancer therapy, J Clin Oncol 33(17):1974–1982, 2015. Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have demonstrated promise in a variety of malignancies. Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. Combination approaches involving CTLA-4 and PD-1/PDL1 blockade are being investigated to determine whether they enhance the efficacy of either approach alone. Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation. Randall ME, Filiaci V, McMeekin DS, et al: Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer, J Clin Oncol 37(21):1810–1818, 2019. PURPOSE: The primary objective was to determine if vaginal cuff brachytherapy and chemotherapy (VCB/C) increases recurrence-free survival (RFS) compared with pelvic radiation therapy (RT) in highintermediate and high-risk early-stage endometrial carcinoma. PATIENTS AND METHODS: A randomized phase III trial was performed in eligible patients with endometrial cancer. Eligible patients had International Federation of Gynecology and Obstetrics (2009) stage I endometrioid histology with Gynecologic Oncology Group protocol 33-based high-intermediate-risk criteria, stage II disease, or stage I to II serous or clear cell tumors. Treatment was randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m(2) (3 hours) plus carboplatin (area under the curve, 6) every 21 days for three cycles. RESULTS: The median age of the 601 patients was 63 years, and 74% had stage I disease. Histologies included endometrioid (71%), serous (15%), and clear cell (5%). With a median follow-up of 53 months, the 60-month RFS was 0.76 (95% CI, 0.70 to 0.81) for RT and 0.76 (95% CI, 0.70 to 0.81) for VCB/C (hazard ratio, 0.92; 90% confidence limit, 0.69 to 1.23). The 60-month overall survival was 0.87 (95% CI, 0.83 to 0.91) for RT and 0.85 (95% CI, 0.81 to 0.90) for VCB/C (hazard ratio, 1.04; 90% confidence limit, 0.71 to 1.52). Vaginal and distant

e24 recurrence rates were similar between arms. Pelvic or paraaortic nodal recurrences were more common with VCB/C (9% vs. 4%). There was no heterogeneity of treatment effect with respect to RFS or overall survival among clinical or pathologic variables evaluated. CONCLUSION: Superiority of VCB/C compared with pelvic RT was not demonstrated. Acute toxicity was greater with VCB/C; late toxicity was similar. Pelvic RT alone remains an effective, well-tolerated, and appropriate adjuvant treatment in high-risk early-stage endometrial carcinomas of all histologies. Rini BI, Powles T, Atkins MB, et al: Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial, Lancet 393(10189):2404– 2415, 2019. BACKGROUND: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. METHODS: In this multicenter, open-label, phase 3, randomized controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centers and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomization (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PDL1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. FINDINGS: Of 915 patients enrolled between May 20, 2015, and October 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11.2 months in the atezolizumab plus bevacizumab group versus 7.7 months in the sunitinib group (hazard ratio [HR] 0.74 [95% CI 0.57 to 0.96]; P 5 .0217). In the ITT population, median overall survival had an HR of 0.93 (0.76 to 1.14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3 to 4 adverse events; 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related allgrade adverse events, which led to treatment-regimen discontinuation. INTERPRETATION: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favorable safety profile. Longerterm follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. FUNDING: F Hoffmann-La Roche Ltd and Genentech Inc.

Rossi EC, Kowalski LD, Scalici J, et al: A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study, Lancet Oncol 18(3):384–392, 2017. BACKGROUND: Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. METHODS: In the FIRES multicenter, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardized cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without paraaortic lymphadenectomy. 18 surgeons from ten centers (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by hematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. FINDINGS: Between August 1, 2012, and October 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and paraaortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97.2% (95% CI 85.0 to 100), and a negative predictive value of 99.6% (97.9 to 100). The most common grade 3 to 4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). Twenty-two patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. INTERPRETATION: Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. FUNDING: Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology. Santin AD, Bellone S, Van Stedum S, et al: Determination of HER2/ neu status in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry and fluorescence in situ hybridization, Gynecol Oncol 98(1):24–30, 2005. OBJECTIVE: To evaluate and compare HER2/neu protein overexpression and gene amplification in uterine serous papillary endometrial cancer (USPC).

e25 STUDY DESIGN: Immunohistochemical (IHC) and fluorescent in situ hybridization (FISH) assays were used to analyze and compare HER2/neu protein expression and gene amplification, respectively, in paraffin blocks from 26 women harboring stage IA to IV USPC treated at the University of Arkansas for Medical Sciences from 1997 to 2004. Chromosome 17 polysomy status by FISH was also assessed in all specimens. RESULTS: Moderate-to-strong expression of HER2/neu protein was noted in 16 (62%) of 26 USPC samples evaluated, with 7 (27%) samples showing moderate staining (21) and 9 (35%) showing strong staining (31) for HER2/neu. Amplification of the ERBB2 gene by FISH was observed in 11 of the 26 (42%) cases. Protein overexpression and gene amplification were found to correlate in 100% (9 of 9) of the 31 positive tumors and 2 out of 7 (29%) of the 21 positive tumors. Heterogeneity was noted in 3 cases in the amplification of the HER2/neu gene within the same tumor samples with pockets of amplified tumor cells amidst nonamplified tumor cells. None of the 10 USPC cases scored by IHC as 0 or 11 was found positive for ERBB2 amplification by FISH. CONCLUSIONS: Amplification of the HER2/neu oncogene represents a common finding in USPC. FISH analysis should be used for confirmation of gene amplification in USPC showing 21 expression of HER2/neu. Prior screening and selection of appropriate immunohistochemistry-positive areas may be beneficial in the selection of some USPC patients undergoing FISH analysis. Saygili U, Kavaz S, Altunyurt S, et al: Omentectomy, peritoneal biopsy and appendectomy in patients with clinical stage I endometrial carcinoma, Int J Gynecol Cancer 11(6):471–474, 2001. The aim of this study was to evaluate whether omentectomy, appendectomy, and peritoneal biopsy should be a routine part of staging surgery in endometrial carcinoma. Data of 97 patients who had been diagnosed with clinical stage I endometrial carcinoma were reviewed. Associations in the data obtained, pelvic and paraaortic lymph node status, depth of myometrial invasion, grade, and histology were investigated. The chi-square (chi2) test was used for statistical analysis. Of 97 patients, six (6%) had omental metastases, which was microscopic in four. There was a statistically significant relationship between omental metastasis and tumor grade (P , .01). Deep myometrial invasion was significantly more common in patients with omental metastases. Tumor was found in one of 55 appendectomy specimens (2%). Omentectomy may be included in surgical staging in patients with deeply invasive or grade 3 endometrial cancer because of the possibility of omental metastasis in spite of what appears to be stage I disease in laparotomy. In other cases, omentectomy and appendectomy and biopsies from peritoneal sites should be performed in the presence of grossly suspicious disease. Schultheis AM, Ng CK, De Filippo MR, et al: Massively parallel sequencing-based clonality analysis of synchronous endometrioid endometrial and ovarian carcinomas, J Natl Cancer Inst 108(6):djv427, 2016. Synchronous early-stage endometrioid endometrial carcinomas (EECs) and endometrioid ovarian carcinomas (EOCs) are associated with a favorable prognosis and have been suggested to represent independent primary tumors rather than metastatic disease. We subjected sporadic synchronous EECs/EOCs from five patients to whole-exome massively parallel sequencing, which revealed that the EEC and EOC of each case displayed strikingly similar repertoires of somatic mutations and gene copy number alterations. Despite the presence of mutations restricted to the EEC or EOC in each case, we observed that the mutational processes that shaped their respective genomes were consistent. High-depth targeted massively parallel sequencing of sporadic synchronous EECs/ EOCs from 17 additional patients confirmed that these lesions are

clonally related. In an additional Lynch syndrome case, however, the EEC and EOC were found to constitute independent cancers lacking somatic mutations in common. Taken together, sporadic synchronous EECs/EOCs are clonally related and likely constitute dissemination from one site to the other. Seagle BL, Alexander AL, Lantsman T, et al: Prognosis and treatment of positive peritoneal cytology in early endometrial cancer: matched cohort analyses from the National Cancer Database, Am J Obstet Gynecol 218(3):329.e1–329.e15, 2018. BACKGROUND: While positive peritoneal cytology is no longer included among the endometrial cancer staging criteria, Federation International de Gynecologie et Obstetrique recommends continued collection of pelvic washings for cytology to produce additional data that may be used to determine the significance of positive cytology for prognosis and treatment of endometrial cancer. OBJECTIVES: The objectives of the study was to validate that positive cytology is a predictor of decreased survival in early endometrial cancer and to test whether adjuvant chemotherapy for positive cytology is associated with increased survival. STUDY DESIGN: We performed an observational retrospective cohort analysis of the 2010–2013 National Cancer Database including women with cytology status and Federation International de Gynecologie et Obstetrique stage IA-II endometrial cancer. Overall cohort and matched cohort survival analyses were performed with and without imputation of missing data. We also performed survival analyses of women with positive cytology grouped by chemotherapy exposure. Multivariable Cox proportional-hazards regressions were performed to adjust for possible confounders. A variety of sensitivity analyses, including robustness of results to possible unmeasured confounding, were reported. RESULTS: A total of 16,851 women including 953 with positive cytology were included. Four-year overall survival was 79.5% (range, 76.2% to 83.0%) for women with stage I/II with positive cytology vs 92.2% (range, 91.5% to 92.9%), 83.3% (range, 81.6% to 84.9%), and 86.8% (range, 85.1% to 88.5%) for stage IA, IB, and II with negative cytology, respectively (P # .001). Positive cytology was associated with decreased survival (hazard ratio [95% confidence interval], 1.85 [range, 1.54 to 2.21], P , .001). For women with Federation International de Gynecologie et Obstetrique grade 1/2 endometrioid adenocarcinoma, the hazard of death associated with positive cytology was similar (hazard ratio [95% confidence interval], 1.85 [1.28 to 2.67], P , .001). Use of adjuvant chemotherapy by women with positive cytology was associated with increased survival (hazard ratio [95% confidence interval], 0.62 [0.40 to 0.95], P 5 .03). CONCLUSION: Positive peritoneal cytology was associated with decreased overall survival of women with Federation International de Gynecologie et Obstetrique stage I/II endometrial cancer, including low-grade endometrioid endometrial cancer. Treatment of women with stage I/II endometrial cancer and positive cytology with adjuvant chemotherapy was associated with increased survival. Shu CA, Pike MC, Jotwani AR, et al: Uterine cancer after riskreducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations, JAMA Oncol 2(11):1434–1440, 2016. IMPORTANCE: The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA1 women), the role of concomitant hysterectomy is controversial. OBJECTIVE: To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA1 women after RRSO without hysterectomy. DESIGN, SETTING, AND PARTICIPANTS: This multicenter prospective cohort study included 1083 women with a deleterious

e26 BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA11; 453, BRCA21; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0 to 8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression. MAIN OUTCOMES AND MEASURES: Incidence of uterine corpus cancer in BRCA1 women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database. RESULTS: Among the 1083 women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 to 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8 to 3.7; P 5 .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serouslike) endometrial carcinomas were observed (4 BRCA11 and 1 BRCA21) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1 to 56.9; P , .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2 to 35.5; P 5 .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA11 tumors. CONCLUSIONS AND RELEVANCE: Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/ serous-like endometrial carcinoma was increased in BRCA11 women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA11 women. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020, CA Cancer J Clin 70(1):7–30, 2020. Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by longterm declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008–2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual

declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers. Slomovitz BM, Jiang Y, Yates MS, et al: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma, J Clin Oncol 33(8):930–936, 2015. PURPOSE: The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. PATIENTS AND METHODS: Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary endpoint was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease ($ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. RESULTS: Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, 7 to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, 8 to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. CONCLUSION: Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way. Slomovitz BM, Lu KH, Johnston T, et al: A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma, Cancer 116(23):5415–5419, 2010. BACKGROUND: Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110alpha catalytic subunit of phosphatidylinositol-3-kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up-regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR. METHODS: A single-institution, open-labeled, phase 2 study of everolimus in patients with measurable recurrent EC who had failed at least 1 and no more than 2 prior chemotherapeutic regimens was performed. Everolimus was administered at a dose of 10 mg orally daily for 28-day cycles. Patients were treated until disease progression or toxicity. The primary endpoint was clinical benefit response (CBR), defined as a confirmed complete or partial response or prolonged stable disease (SD) ($8 weeks). Inclusion was limited to patients with endometrioid histology. RESULTS: A total of 35 patients were enrolled (median age, 58 years; range, 38 to 81 years). A total of 81 cycles were administered. Twelve of 28 (43%) evaluable patients had not developed disease progression at

e27 the time of the first objective evaluation (8 weeks). All these patients had SD (median, 4.5 cycles; range, 2 to 10 cycles). Six of the 28 (21%) patients had a confirmed CBR at 20 weeks of therapy. Patients with CBR discontinued treatment because of toxicity (6 patients), disease progression (5 patients), and noncompliance (1 patient). Seven patients were unevaluable after receiving # 1 cycle because of toxicity (5 patients) or noncompliance (2 patients). The most common drugrelated toxicities were fatigue, anemia, pain, lymphopenia, and nausea. CONCLUSIONS: Everolimus demonstrated encouraging single-agent CBR in pretreated patients with recurrent endometrioid EC. Future studies will evaluate this agent in combination with hormonal and/or cytotoxic therapy. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for first-line treatment of Metastatic Nonsquamous NSCLC, N Engl J Med 378(24):2288–2301, 2018. BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This openlabel, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-smallcell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary endpoints were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS: In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to –0.74; P , .001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P , .001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P 5 .02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS: The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .). Soliman PT, Westin SN, Dioun S, et al: A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer, Gynecol Oncol 146(2):234–239, 2017.

OBJECTIVE: Sentinel lymph node (SLN) mapping continues to evolve in the surgical staging of endometrial cancer (EC). The purpose of this trial was to identify the sensitivity, false negative rate (FNR), and FN predictive value (FNPV) of SLN compared to complete pelvic and paraaortic lymphadenectomy (LAD) in women with high-risk EC. METHODS: Women with high-risk EC (grade 3, serous, clear cell, carcinosarcoma) were enrolled in this prospective surgical trial. All patients underwent preoperative PET/CT and intraoperative SLN biopsy followed by LAD. Patients with peritoneal disease on imaging or at the time of surgery were excluded. Patients were evaluable if SLN was attempted and complete LAD was performed. RESULTS: 123 patients were enrolled between 4/13 and 5/16; 101 were evaluable. At least 1 SLN was identified in 89% (90); bilateral detection 58%, unilateral pelvic 40%, paraaortic only 2%. Indocyanine green was used in 61%, blue dye in 28%, and blue dye and technetium in 11%. Twenty-three pts. (23%) had $ 1 positive node. In 20/23, $ 1 SLN was identified and in 19/20 the SLN was positive. Only 1 patient had bilateral negative SLN and positive non-SLNs on final pathology. Overall, sensitivity of SLN was 95% (19/20), FNR was 5% (1/20), and FNPV was 1.4% (1/71). If side-specific LAD was performed when a SLN was not detected, the FNR decreased to 4.3% (1/23). CONCLUSION: This prospective trial demonstrated that SLN biopsy plus side-specific LAD, when SLN is not detected, is a reasonable alternative to a complete LAD in high-risk endometrial cancer. Strickland KC, Howitt BE, Shukla SA, et al: Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/ PD-L1 in high grade serous ovarian cancer, Oncotarget 7(12): 13587–13598, 2016. Immune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) have demonstrated remarkable efficacy against hypermutated cancers such as melanomas and lung carcinomas. One explanation for this effect is that hypermutated lesions harbor more tumor-specific neoantigens that stimulate recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), which is counterbalanced by overexpression of immune checkpoints such as PD-1 or PD-L1. Given that BRCA1/2-mutated high-grade serous ovarian cancers (HGSOCs) exhibit a higher mutational load and a unique mutational signature with an elevated number of larger indels up to 50 bp, we hypothesized that they may also harbor more tumorspecific neoantigens, and, therefore, exhibit increased TILs and PD-1/ PD-L1 expression. Here, we report significantly higher predicted neoantigens in BRCA1/2-mutated tumors compared to tumors without alterations in homologous recombination (HR) genes (HR-proficient tumors). Tumors with higher neoantigen load were associated with improved overall survival and higher expression of immune genes associated with tumor cytotoxicity such as genes of the TCR, the IFNgamma and the TNFR pathways. Furthermore, immunohistochemistry studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased CD31 and CD81 TILs, as well as elevated expression of PD-1 and PD-L1 in tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed that both BRCA1/2-mutation status and number of TILs were independently associated with outcome. Of note, two distinct groups of HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) were defined. These findings support a link between BRCA1/2-mutation status, immunogenicity, and survival, suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PDL1 inhibitors compared to HR-proficient HGSOCs.

e28 Talhouk A, McConechy MK, Leung S, et al: A clinically applicable molecular-based classification for endometrial cancers, Br J Cancer 113(2):299–310, 2015. BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. METHODS: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. RESULTS: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis, and p53 immunohistochemistry as a surrogate for “copy-number” status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement, and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined “high-risk” group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffinembedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials. Thomas M, Mariani A, Wright JD, et al: Surgical management and adjuvant therapy for patients with uterine clear cell carcinoma: a multi-institutional review, Gynecol Oncol 108(2):293–297, 2008. OBJECTIVE: To assess the role of surgical staging, adjuvant therapy, and cytoreduction in uterine clear cell carcinoma (UCCC). METHODS: A retrospective review was conducted at 2 major gynecologic cancer centers of all primary UCCC between 1982 and 2004. RESULTS: UCCC was confirmed in 99 patients. The 5-year overall survival (OS) was 79%, 77%, 47%, and 21% for stages I to IV respectively. Sixty-nine patients had no gross evidence of extra-uterine disease, but 36 (52%) were upstaged at surgery. For those 22 patients with stages I and II disease who had a systematic lymphadenectomy (LND) (.20 lymph nodes), no lymphatic (LF), peritoneal (PF), or hematological (HF) failures were noted. Radiation (RT) improved PFS (67% vs. 36%, P 5 .02), and reduced pelvic sidewall recurrences (18% vs. 53%, P 5 .04) and vaginal failures (VF) (7% vs. 35%, P 5 .04) for 45 patients at risk for LF (positive nodes or suboptimal LND). Thirty-nine patients with stages IIIC and IV disease were separately analyzed. Patients with no visible residual disease after cytoreduction had a significant improvement in median PFS (17 vs. 7 months, P , .001) and OS (40 vs. 18 months, P 5 .02) compared to patients with any residual disease after surgery. CONCLUSION: Comprehensive surgical staging with a systematic LND is essential to accurately define early-stage UCCC. Vaginal brachytherapy may be adequate adjuvant therapy for stages I and II

UCCC confirmed by systematic LND. Patients at risk for LF appear to benefit from pelvic RT. An effort at cytoreduction to no visible residual disease should be made in advanced UCCC when feasible. Tolcher MC, Swisher EM, Medeiros F, et al: Characterization of precursor lesions in the endometrium and fallopian tube epithelium of early-stage uterine serous carcinoma, Int J Gynecol Pathol 34(1):57–64, 2015. To determine if selected cases of uterine serous carcinoma (USC) arise from tubal rather than endometrial epithelium. Bilateral fallopian tubes from 38 women with pure USC were entirely submitted for histopathologic examination using the protocol Sectioning and Extensively Examining the FIMbria (SEE-FIM). Non-neoplastic endometrium was extensively sampled. Immunohistochemistry for p53 was performed on all paraffin blocks of fallopian tube and nonneoplastic endometrium. Endometrial intraepithelial carcinoma (EIC) was present in 22 cases (58%). Endometrial p53 foci were identified in 3 patients. There were 11 cases (29%) with fallopian tube involvement; 9 of 11 had tubal wall invasion or lymphatic involvement without serous tubal intraepithelial carcinoma (STIC) and were, therefore, classified as metastatic from the endometrium. STIC was identified in 3 patients (8%). There were 3 cases with tubal p53 foci in non-neoplastic epithelium. EIC was present in 58% of patients, further supporting EIC as a precursor lesion to USC. STIC was present in 8%, suggesting that the fallopian tube may in fact represent the primary lesion in a minority of patients with USC. This finding may account for the early multifocal disease distribution observed in these patients. Townamchai K, Berkowitz R, Bhagwat M, et al: Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer, Gynecol Oncol 129(1):18–21, 2013. OBJECTIVE: To report clinical outcomes following adjuvant highdose-rate (HDR) vaginal brachytherapy (VB) for early-stage uterine papillary serous (UPSC) and clear cell (CC) endometrial cancer. METHODS: A retrospective study of Stage I and II papillary serous and clear cell endometrial cancer treated with post-operative HDR VB between October 2005 and May 2012 was performed. A total of 37 patients were identified, 26 with UPSC, 9 with CC, and 2 with mixed UPSC/CC. After total hysterectomy and bilateral salpingooophorectomy, VB was administered without external-beam radiation with a dose of 24 Gy in 6 fractions prescribed to the vaginal surface. Chemotherapy was given to 30 patients (75%). RESULTS: The median follow up time was 24.8 months (range, 2.0 to 71.5 months). Four patients relapsed, 2 with UPSC and 2 with CC. The initial site of relapse was concurrent vagina, pelvic/paraaortic nodes and abdominal wall (1), pelvic/paraaortic nodes (1), and paraaortic nodes alone (2). The 2-year vaginal-control rate was 96.8%. The pelvic-control rate including vaginal and nodal relapse was 93.5%. The 2-year disease-free and overall survival rates were 89.3% and 100%, respectively. CONCLUSION: HDR VB as the sole adjuvant treatment modality for early-stage UPSC/CC is associated with a low rate of vaginal relapse and excellent survival outcomes. This novel low-dose regimen for VB is safe and effective. Makker V, Aghajanian C, Oaknin A, et al: Lenvatinib (LEN) and pembrolizumab (PEMBRO) in advanced endometrial cancer (EC), Ann Oncol 30(Suppl 5):404–405, 2019. van der Graaf WT, Blay JY, Chawla SP, et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial, Lancet 379(9829):1879–1886, 2012. BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic

e29 soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. METHODS: This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic softtissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomization system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. FINDINGS: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n 5 246) or placebo (n 5 123). Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) for pazopanib compared with 1.6 months (0.9 to 1.8) for placebo (hazard ratio [HR] 0.31, 95% CI 0.24 to 0.40; P , .0001). Overall survival was 12.5 months (10.6 to 14.8) with pazopanib versus 10.7 months (8.7 to 12.8) with placebo (HR 0.86, 0.67 to 1.11; P 5 .25). The most common adverse events were fatigue (60 in the placebo group [49%] vs. 155 in the pazopanib group [65%]), diarrhea (20 [16%] vs. 138 [58%]), nausea (34 [28%] vs. 129 [54%]), weight loss (25 [20%] vs. 115 [48%]), and hypertension (8 [7%] vs. 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. INTERPRETATION: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. FUNDING: GlaxoSmithKline. Vasconcelos C, Félix A, Cunha TM: Preoperative assessment of deep myometrial and cervical invasion in endometrial carcinoma: comparison of magnetic resonance imaging and histopathologic evaluation, J Obstet Gynaecol 27(1):65–70, 2007. This study aimed to evaluate the accuracy of magnetic resonance imaging (MRI) in the detection of deep myometrial invasion and cervical extension by endometrial carcinoma. This prospective study included 101 patients with histologically documented endometrial carcinoma, between July 1998 and April 2004. The findings of preoperative pelvic MRI were compared with histological diagnosis. From 101 cases studied by pelvic MRI, 43 were classified as deep myometrial invasion ($50% of myometrium), where the pathological evaluation confirmed as having deep myometrial invasion. Cervical extension in the MRI study was found in 19 cases. Pathologic study found cervical extension and/or invasion in 31 cases including all cases identified by MRI. The accuracy, sensitivity, and specificity of MRI were 95%, 89%, 100%, detecting deep myometrial invasion and 88%, 61%, 100%, detecting cervical invasion, respectively. The high accuracy achieved makes MRI an adequate method for determining the depth of myometrial and cervical invasion in endometrial carcinoma. Vergote I, Powell MA, Miller DS, et al: A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: angiopoietin-2 as a predictive marker for clinical outcomes, Proc Am Soc Clin Oncol 31(Suppl 15):5520, 2013. Wallin JJ, Bendell JC, Funke R, et al: Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma, Nat Commun 7:12624, 2016. Anti-tumor immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In

preclinical models tumor-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab, and after the addition of atezolizumab. We discover that intra-tumoral CD8(1) T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8(1) T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration. Antill YC, Kok PS, Robledo K, et al: Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: the phase II PHAEDRA trial (ANZGOG1601), J Clin Oncol 37(15):5501, 2019. Zaino R, Whitney C, Brady MF, et al: Simultaneously detected endometrial and ovarian carcinomas—a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study, Gynecol Oncol 83(2):355–362, 2001. OBJECTIVES: The coexistence of carcinomas of the endometrium and ovary occurs in about 10% of women with ovarian carcinoma. It is often unclear whether this represents synchronous primary tumors or metastasis from endometrium to ovary, or from ovary to endometrium; consequently, staging, therapy, and expected outcome are uncertain. The Gynecologic Oncology Group sought to study patients with simultaneously detected adenocarcinomas in the endometrium and ovary with disease grossly confined to the pelvis to explore the possible correlation among discrete tumor subsets, natural history, and survival. METHODS: Between 1985 and 1991, 85 patients were prospectively enrolled, of whom 74 were eligible. All were initially treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging laparotomy, with radiation and chemotherapy left to the discretion of the treating physician and patient. Fifteen pathologic variables were examined to identify differences in tumor behavior. RESULTS: Of the 74 patients, 23 (31%) had microscopic spread of tumor in the pelvis or abdomen. Sixty-four (86%) patients had endometrioid carcinomas in both the endometrium and the ovary, and endometriosis was found in the ovary of 23 (31%) patients. There was concordance between the histologic grade of the tumor in the ovary and the uterus in 51 (69%) patients. The estimated probability of recurrence 5 years following staging surgery is 15.1% (95% confidence interval (CI): 8.7% to 25.2%). The presence of metastasis discriminated two groups of patients that experienced different probabilities of recurrence within 5 years: 10.0% (95% CI: 4.32% to 21.3%) for those with tumors confined to the uterus and ovary and 27.1% (95% CI: 13.0% to 48.5%) for those with metastasis (hazard ratio 5 4.6, P 5 .006). The histologic grades of ovarian and uterine tumors also distinguished groups of patients with different probabilities of recurrence at 5 years: 8.0% (95% CI: 2.8% to 21.3%) for those patients with no more than grade 1 disease at either site and 22.4% (95% CI: 11.8% to 38.4%) for those with a higher grade in either the ovary or the endometrium (hazard ratio 5 3.1, P 5 .047). The estimated overall probability of surviving 5 years is 85.9% and that of surviving 10 years is 80.3%. CONCLUSION: The prognosis for women with simultaneously detected carcinomas in the uterus and ovary with gross disease

e30 confined to the pelvis is surprisingly good, particularly for those with disease microscopically limited to the uterus and ovary or of low histologic grade. Zhao S, Choi M, Overton JD, et al: Landscape of somatic singlenucleotide and copy-number mutations in uterine serous carcinoma, Proc Natl Acad Sci USA 110(8):2916–2921, 2013. Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copynumber variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer. Zheng W, Xiang L, Fadare O, et al: A proposed model for endometrial serous carcinogenesis, Am J Surg Pathol 35(1):e1–e14, 2011. Endometrial serous carcinomas constitute no more than 10% of endometrial adenocarcinomas, but frequently present at an advanced stage and have a significantly worse prognosis than the more common low-grade and intermediate-grade endometrioid adenocarcinomas. The neoplasm’s potential for rapid tumor progression and the high

mortality that is associated with advanced-stage disease underscore the importance of understanding endometrial serous carcinogenesis so that its precancers can be diagnosed and an effective therapeutic intervention can be administered. In this study, the authors summarize the current state of knowledge on endometrial serous carcinogenesis and propose a model for its development based on recent work from our group and published data from other researchers. In this model, endometrial serous carcinoma arises predominantly in the resting endometrium, manifesting first as p53 immunoreactive, morphologically normal endometrial cells (p53 signatures), evolving to endometrial glandular dysplasia (which is the first morphologically identifiable precursor lesion), then to serous endometrial intraepithelial carcinoma (a carcinoma with a noninvasive growth pattern in the uterus but which is not infrequently associated with extrauterine disease), and finally into fully developed serous carcinoma. Endometrial glandular dysplasia is a lesion, which can be diagnosed by routine microscopic evaluation, whose ablation or removal may potentially offer the opportunity to prevent the development of the associated malignancy. The diagnostic criteria, practical applicability, and evidentiary basis for the delineation of this lesion are studied. Zitvogel L, Kepp O, Kroemer G, et al: Immune parameters affecting the efficacy of chemotherapeutic regimens, Nat Rev Clin Oncol 8(3):151–160, 2011. The outcome of chemotherapy can be influenced by the host immune system at multiple levels. Chemotherapy can kill cancer cells by causing them to elicit an immune response or alternatively, by increasing their susceptibility to immune attack. In addition, chemotherapy can stimulate anticancer immune effectors either in a direct fashion or by subverting immunosuppressive mechanisms. Beyond cancer-cell-intrinsic factors that determine the cytotoxic or cytostatic response, as well as the potential immunogenicity of tumor cells, the functional state of the host immune system has a major prognostic and predictive impact on the fate of cancer patients treated with conventional or targeted chemotherapies. In this review, we surmise that immune-relevant biomarkers may guide personalized therapeutic interventions including compensatory measures to restore or improve anticancer immune responses.

6 Invasive Cancer of the Vulva Thomas J. Herzog, MD, Caroline C. Billingsley, MD

OUTLINE Invasive Squamous Cell Carcinoma, 176 Technique of Inguinofemoral Lymphadenectomy, 185 Very Early Vulvar Carcinoma, 195 Paget Disease, 196

Melanoma, 198 Sarcoma, 202 Bartholin Gland Carcinoma, 202 Basal Cell Carcinoma, 203

KEY POINTS 1. Invasive vulvar cancer is a relatively rare tumor, accounting for 4% of all female genital malignant neoplasms. 2. Squamous cell carcinoma of the vulva develops by human papillomavirus- (HPV-) dependent and HPV-independent pathways. 3. Sentinel lymph node biopsy represents the largest innovation in the care of vulvar cancer patients in the past decade.

4. The standard of care is pelvic lymph node irradiation for patients with positive inguinal nodes. 5. Recurrences may be local or distant, and more than 80% will occur in the first 2 years after therapy, demanding initial close follow-up.

Invasive vulvar cancer is a relatively rare tumor, accounting for 4% of all female genital malignant neoplasms with the American Cancer Society projecting just over 6120 cases resulting in 1350 deaths in 2020 in the United States. Except for the rare sarcomas, the peak incidence is in women between 65 and 75 years old (Fig. 6.1); in some series, almost half are 70 years of age or older. Although classically a disease of elderly women, the trend in recent years is an increasing prevalence among younger women, which cannot be accounted for by immune suppression alone. Human papillomavirus (HPV) is a key agedependent risk factor that causes preinvasive disease in the form of vulvar intraepithelial neoplasia (VIN) that is often associated with a history of tobacco use. HPV-related VIN lesions are rarer in older women, and these malignancies may be associated with chronic vulvar dystrophies, such as lichen sclerosis, although a direct association remains unproven. No race or culture is spared, and gravidity and parity appear unrelated in the pathogenesis of this neoplasm. Vulvar cancer is common in poor and elderly women in most parts of the world, and this has led to the hypothesis that inadequate personal hygiene and medical care are contributing factors in disease development. Younger patients frequently have early stromal invasion associated with diffuse VIN. Choo found 17 patients younger than age 35 with invasive carcinoma of the vulva. Of these, eight had microinvasion. Al-Ghamdi and coworkers evaluated 21 patients younger than age 40 with invasive vulvar cancer and found that most, but not all, had associated HPV. Outcomes in

these populations were excellent. Lanneau and colleagues have corroborated these results in 56 women younger than age 45 years with squamous cell carcinoma (SCC) of the vulva. They concluded that vulvar cancer in this population is associated with early-stage disease, HPV, VIN, and smoking. SCC of the vulva develops by HPV-dependent and HPVindependent pathways. The association between HPV and both preinvasive and invasive urogenital lesions has been well described. Susceptibility of the cervical, vaginal, and vulvar epithelium is referred to as the “field effect,” which is more pronounced in tobacco users and in patients who are immunocompromised, such as those with HIV/AIDS or organ transplants. The association of condyloma acuminatum with vulvar carcinoma is well known, but no cause-and-effect relationship has been confirmed yet. HPV infection has been reported to be attributed to vulvar tumorigenesis from 30% to 69% of cases, with Faber et al. reporting almost 40% of vulvar cancers resulting from HPV infection in a meta-analysis of over 5000 vulvar cancers, with the most common high-risk HPV strains being HPV 16, 33, and 18. Although the incidence of vulvar cancer has remained relatively stable over the past several decades, the incidence of VIN has increased, especially that associated with HPV. Hoang and coworkers contrast these multicentric HPV related precursors with VIN of the differentiated type that occurs in postmenopausal women, often in a background of lichen sclerosis or chronic inflammatory dermatoses associated with a high number of somatic mutations, particularly in TP53. Sznurkowski pointed out 175

176

CHAPTER 6

Invasive Cancer of the Vulva Age group (years)

600 Patients (n)

500 400 300 200 100

+ 80

–7

9 70

–6

9 60

–5

–4 40

–3 30

–2

15–29 30–39 40–49 50–59 60–69 70–79 80+ Total

Patients (n)

Percentage (%)

22 97 188 227 332 505 280 1651

1.3 5.9 11.4 13.7 20.1 30.6 17.0 100.0

Age group (years) Figure 6.1 Carcinoma of the vulva: patients treated from 1999 to 2001. (Adapted from Beller U, Quinn MA, Benedet JL, et al: Carcinoma of the vulva. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer, Int J Gynaecol Obstet 95(Suppl 1):S7–S27, 2006.)

the need to better understand the relationship between vulvar cancer and HPV for not only causation but also for developing potential therapeutics. Increasing adoption of routine HPV prophylactic vaccination can reduce the burden of HPV-related vulvar dysplasia and subsequent cancer development. Many previously reported associated features seen in patients with vulvar cancer, such as diabetes, obesity, hypertension, and arteriosclerosis, may just reflect the increased incidence of these diseases associated with aging.

INVASIVE SQUAMOUS CELL CARCINOMA Histology The overwhelming majority of vulvar cancer is squamous in origin. Table 6.1 depicts the incidence of vulvar neoplasia from several studies in the literature. The following discussion focuses mainly on SCC because of its preponderance, but as a generalization, the other lesions can be treated similarly, except as noted.

Clinical Presentation and Diagnosis

Figure 6.2 Squamous cell carcinoma arising in a bed of lichen sclerosis.

Squamous cell vulvar cancer usually arises from an area of intraepithelial neoplasia that develops into a small nodule that can ulcerate (Figs. 6.2 and 6.3). Alternatively, small, warty, or cauliflower-like TABLE 6.1 Incidence of Vulvar Neoplasms by Histologic Type Tumor Type

Incidence (%)

Squamous

86.2

Melanoma

4.8

Sarcoma

2.2

Basal cell

1.4

Bartholin gland Squamous

0.4

Adenocarcinoma

0.6

Adenocarcinoma

0.6

Undifferentiated

3.9

1.2

Based on 1378 reported cases. Modified from Plentl AA, Friedman EA: Lymphatic system of the female genitalia, Philadelphia, 1971, WB Saunders.

Figure 6.3 Small, well-localized lesion of the vulva.

CHAPTER 6

Invasive Cancer of the Vulva

177

TABLE 6.2 Signs and Symptoms of Vulvar

Cancer

Sign or Symptom

Incidence (%)

Pruritus

45.0

Mass

45.0

Pain

23.0

Bleeding

14.0

Ulceration

14.0

Dysuria

10.0

Discharge

8.0

Groin mass

2.5

TABLE 6.3 Indications for Excisional Biopsy of Vulvar Lesions . Change in surface area of nevus 1 2. Change in elevation of a lesion: raised, thickened, or nodular 3. Change in color: especially brown to black 4. Change in surface: smooth to scaly or ulcerated 5. Change in sensation: itching or tingling

growths evolve, and these may be confused with condyloma acuminatum. Long-term pruritus or a lump or mass on the vulva is present in more than 50% of patients with invasive vulvar cancer (Table 6.2). Biopsy must be performed of all suspicious lesions of the vulva, including lumps, ulcers, and pigmented areas, irrespective of symptoms (Table 6.3). A significant delay in diagnosis and appropriate treatment is common. Several series of carcinoma of the vulva report delays of 2 to 16 months after onset of symptoms before medical attention is sought. Further delay occurs when medical treatment of vulvar lesions continues without biopsy for definitive diagnosis. Fortunately, vulvar cancer is often indolent, extends slowly, and metastasizes fairly late. Hence, there is an opportunity for preventing the development of advanced stages of this disease through patient and physician education.

Location and Spread Pattern Primary disease can appear anywhere on the vulva. Approximately 70% arise primarily on the labia. Disease more commonly occurs on the labia majora; however, it may appear on the labia minora, clitoris, or perineum. The disease is usually localized and well demarcated, although it can occasionally be so extensive that the primary location cannot be determined (Fig. 6.4). Multifocal growth pattern in invasive SCC of the vulva is uncommon, except for so-called “kissing lesions” that can occur. Verrucous carcinoma of the vulva (Fig. 6.5) is a special and unusual variant of SCC that is locally invasive but nonmetastasizing. The lesion, which may involve the cervix, vagina, and the vulva, presents as a warty, fungating, ulcerated mass with a bulky, elevated appearance reminiscent of a benign HPV lesion. Identification of this variant is important because the biologic behavior of the disease influences therapy. Condyloma

B Figure 6.4 A, Large ulcerating squamous cell malignancy of the vulva with destruction of the clitoris and the urethra. B, Large exophytic squamous cell carcinoma of the vulva.

may initially be diagnosed on microscopic examination, but distinction from ordinary condylomata is aided by the absence of fibrovascular cores within the proliferating papillary masses of tumor. There is usually a uniform lack of malignant features histologically. Adequate material, including underlying stroma for pathologic evaluation, is necessary to differentiate verrucous carcinoma from condyloma. Tumor may invade deeply into the underlying tissue, often requiring extensive surgery, and has a propensity to recur locally. Woodruff reported no nodal metastases in 27 patients, including a literature review,

178

CHAPTER 6

Invasive Cancer of the Vulva

Figure 6.7 Lymphatic drainage of the external genitalia.

Figure 6.5 Verrucous carcinoma of the vulva.

who were treated with radical vulvectomy and inguinal lymphadenectomy. As a result, a more conservative approach is advocated with wide local excision and tumor-free margins as the therapeutic aim. Lymphadenectomy is of questionable value except when nodes are obviously involved. Historically, it has been thought that radiotherapy is contraindicated because of its ineffectiveness, and reports have indicated that it can incite more aggressive behavior by this tumor. Fundamental to the understanding of therapy for invasive cancer of the vulva is thorough knowledge of the lymphatic drainage of this region. In general, the four histologic types of invasive cancer primarily metastasize via the lymphatic route (Fig. 6.6). Lymphatic drainage of the external genitalia begins with minute papillae that connect to a multilayered meshwork

Figure 6.6 Photomicrograph of a tumor nodule invading a vulvar lymphatic.

of fine vessels that extend over the entire labium minus, the prepuce of the clitoris, the fourchette, and the vaginal mucosa up to the level of the hymenal ring (Fig. 6.7). Ultimately, drainage proceeds to the superficial inguinal nodes, followed by the deeper inguino-femoral nodes. Drainage is usually limited initially to the medial upper quadrant of the femoral node group. The nodes are medial to the great saphenous vein above the cribriform fascia and in turn may drain secondarily to the deep femoral group. The next echelon of nodes is the pelvic/iliac nodes. The inguinofemoral lymph nodes are contained in the femoral triangle, for which the boundaries include the inguinal ligament superiorly, the medial border of the adductor longus muscle medially, and the medial border of the sartorius muscle laterally. From lateral to medial, the contents of the femoral triangle are the femoral nerve and its terminal branches, the femoral artery, the femoral vein and its proximal tributaries (i.e., the great saphenous vein and deep femoral veins), and the inguinal lymph nodes and lymphatics. The superficial inguinal lymph nodes are located immediately beneath the integument and Camper fascia, with an average of 8 to 10 in number. Most authors agree that these nodes are the primary drainage for the vulva, thereby containing the sentinel lymph node (SLN) (Fig. 6.8). The deep femoral nodes, which are by classic teaching located beneath the cribriform fascia, are the secondary node recipients and are involved before drainage into the deep pelvic nodes. The Cloquet node, the last node of the deep femoral group, is located just beneath the Poupart ligament. The multilayered meshwork of lymphatics on the vulva itself is always limited to an area medial to the genitocrural fold (Fig. 6.9). Lymphatic drainage of the vulva occurs via a progressive systematic mechanism, and therapy can be planned according to where in the lymphatic chain the tumor is present. Very posterior lesions that approach and involve the anus may not have the same lymphatic drainage as a

CHAPTER 6

Superficial iliac circumflex vein Oblique group of nodes

Inguinal ligament Superficial epigastric vein Saphenous-femoral junction

Vertical group of nodes

Great saphenous vein

Figure 6.8 The superficial inguinal lymph nodes can be divided into the horizontal group and the perpendicular group.

Iliac Obturator Deep Superficial

Invasive Cancer of the Vulva

179

lower margin of the fossa ovalis under the fascia cribrosa. The clinical implication is that a carefully performed deep femoral lymphadenectomy does not require removal of the fascia lata (cribriform fascia) because no lymph nodes are to be found between the femoral vein and artery lateral to the artery or distal to the lower margin of the fossa ovalis beneath the cribriform fascia. They also found that the node of Cloquet or Rosenmüller, which is the uppermost node among the deep femoral lymph nodes, was absent in 54% of dissections. Borgno and colleagues also demonstrated that during surgery, when traction is persistently applied to the lymphovascular fat tissue above the cribriform fascia, all inguinal nodes can be removed. No nodal tissue was found when the cribriform fascia and the fat beneath were submitted separately for pathologic review. Hudson and colleagues confirmed this finding in cadaveric dissections, and Micheletti and coworkers found supporting evidence with embryologic studies. Although lymphatics draining from the clitoris directly to the deep pelvic lymph nodes are described, their clinical significance appears to be minimal. It is unusual to find a case in which metastasis is present in the pelvic lymph nodes without metastatic disease in the inguinal lymph nodes even when the clitoris is involved. Curry and associates noted clitoral involvement in 58 patients; none had positive deep pelvic nodes without concomitant inguinal node involvement. Similar results were observed in a study by Ericksson and coworkers of 38 patients with carcinomas of the clitoris; they found also that the deep inguinal or femoral nodes were never positive in the absence of positive superficial inguinal nodes. The incidence of positive inguinal and pelvic nodes varies considerably, as noted in Table 6.4. Unfortunately, most of these studies were unstaged, although, in general, the larger the tumor, the greater the propensity for inguinal and pelvic node metastases. Morley noted a 21% incidence of lymph node involvement with a T1 lesion (,2 cm in diameter) versus 45% with a T2 lesion (.2 cm but limited to the vulva). Malfetano and colleagues reported that the incidence of inguinal node metastases in patients with stage III and stage IV lesions was 53% and 90%, respectively. Clinical evaluation of the groin is somewhat more accurate than tumor size. Homesley found that approximately 24% of patients with clinically nonsuspicious nodes had positive nodes when dissected, and approximately 75% of patients with suspicious (palpable, fixed, or TABLE 6.4 Incidence of Positive Nodes

Figure 6.9 Lymphatic spread of a vulvar malignancy. See the text for details.

Series

vulvar cancer involving the labia or clitoris. Lymphatics drain to the mesorectal (inferior rectal) lymph nodes, followed by the inguino-femoral nodes, and finally to the pelvic nodal chain. Borgno and colleagues examined 100 inguinal lymphadenectomy specimens at autopsy and demonstrated that the deep femoral nodes are always situated within the openings in the fascia at the fossa ovalis, and no lymph nodes are distal to the

Cases (n)

Positive Groin or Pelvic Nodes (%)

Positive Pelvic Nodes (%)

Morley (1976)

374

37.0

—

Curry et al. (1980)

191

30.0

4.7

Simonsen (1984)

122

50.0

10.0

Sutton et al. (1991)

150

24.0

—

Homesley (1994)

277

29.2

—

Creasman et al. (1997)

1553

31.0

—

180

CHAPTER 6

Invasive Cancer of the Vulva

TABLE 6.5 Groin Node Versus Tumor

TABLE 6.6 Federation of International Gynecologists and Obstetricians Staging of Invasive Cancer of the Vulva

Diameter Feature

Positive Groin Nodes

Tumor Diameter #2.0 cm

190

.2.0 cm

390

163

Invasion #5 mm

272

.5 mm

286

137

Clinical Examination N0-1

477

114

N2-3

111

Stage

Description

Tumor confined to the vulva

Staging Many staging systems have been applied to invasive cancer of the vulva. Significant discrepancy exists between clinical and surgical-pathologic evaluation of lymph node status, specifically regarding clinical impression of lymph node positivity. Iversen demonstrated that overdiagnosis (clinically suspicious but pathologically negative nodes) occurred in 40 of 258 patients (15%). Of the 100 patients with metastasis to the inguinal lymph nodes, lymph node involvement was clinically unsuspected in 36 patients. Patients with “micrometastasis” (lymph node involvement not suspected clinically but positive microscopically) had a significantly better survival rate than did those with gross metastasis. These repeated findings suggest that staging be based on surgical-pathologic evaluation instead of clinical evaluation alone. The Federation of International Gynecologists and Obstetricians’ (FIGO) staging of vulvar cancer dates to 1969. In 1988, FIGO replaced the clinical staging system with a surgicalpathologic, or tumor–node–metastasis (TNM) classification system. The most recent 2009 FIGO staging for carcinoma of the vulva (Table 6.6) further characterizes the number and type of lymph node metastases. Previous studies noted decreased survival among individuals with bilateral lymph node metastasis;

Lesions #2 cm in size confined to the vulva or perineum and with stromal invasion #1.0 mma; no nodal metastasis

Lesions .2 cm in size confined to the vulva or perineum with stromal invasion greater than 1.0 mma; no nodal metastasis

Tumor of any size with extension to adjacent perineal structures (1⁄3 lower urethra, 1⁄3 lower vagina, anus); no nodal metastasis

III

Tumor of any size with or without extension to adjacent perineal structures (1⁄3 lower urethra, 1⁄3 lower vagina, anus) with positive inguinofemoral lymph nodes IIIA

From Homesley HD, Bundy BN, Sedlis A, et al.: Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecol Oncol 49:279, 1993.

ulcerated) groins had positive nodes. Table 6.5 demonstrates the association between inguinal lymph node involvement and tumor size, depth of invasion, and clinical examination. Of note, these data did not evaluate laterality or unifocal versus multifocal lesions. The application of SLN dissection has been integrated into the formal staging for vulvar cancer to decrease morbidity associated with a full inguino-femoral lymphadenectomy. The distribution of sentinel nodes has been evaluated and found that 100% of sentinel nodes are located over or medial to the femoral vessels. Rob and colleagues reported that in almost 60 vulvar cancer patients with tumors less than 4 cm, sentinel nodes were located superficially in almost 85% of cases, while the remainder were found deep to the cribriform fascia.

(i) With 1 lymph node metastasis ($5 mm), or (ii) With 1–2 lymph node metastasis(es) (,5 mm)

IIIB

(i) With $2 lymph node metastases ($5 mm), or (ii) With $3 lymph node metastases (,5 mm)

IIIC

With positive nodes with extracapsular spread Tumor invades other regional (2⁄3 upper urethra, 2⁄3 upper vagina) or distant structures

IV IVA

Tumor invades any of the following: (i) Upper urethra or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or (ii) Fixed or ulcerated inguinofemoral lymph nodes

IVB

Any distant metastasis, including pelvic lymph nodes

The depth of invasion is defined as the measurement of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. a

thus, laterality was incorporated into the staging system. However, recent studies have demonstrated that the number of lymph node metastases and extracapsular spread are predictive of survival regardless of laterality. Some reports in the literature use older staging systems, and thus data must be evaluated within the context of the staging system used. Donaldson and colleagues demonstrated that lesion size predicted incidence of lymph node metastasis (19% metastasis for lesion ,3 cm and 72% for lesion .3 cm). Likewise, tumor grade correlated with node metastasis (one-third of welldifferentiated tumors had metastasis compared with 75% for poorly differentiated lesions). Of 38 patients, 11 (29%) had node involvement if invasion of the primary lesion was 5 mm or smaller compared with 17 of 28 (61%) if invasion was larger than 5 mm. If the tumor did not involve lymphatic or vascular spaces, only 2 of 33 (6%) had positive nodes, but 26 of 33 patients (79%) with lymphatic or vascular space involvement had metastasis to the regional lymph nodes. None of 25 patients with lesions invading less than 5 mm and without lymphatic or vascular space involvement had lymph node metastasis. Depth of tumor invasion is related to risk of nodal metastasis as well. In superficially invasive disease (, 1 mm), the risk of nodal spread is low, roughly 1% (Stehman et al., 2006). As invasion deepens, so does the risk of nodal spread. Gonzales et al. reported at 2 mm depth of invasion, the nodal spread risk

CHAPTER 6

increases to 7% to 8%, at 3 mm invasion the nodal metastasis is 12% to 17%, and at 5 mm depth of invasion, nodal spread approaches 17%. These data are important for staging recommendations, as minimally invasive disease of 1 mm or less, or stage 1A, are not recommended to undergo surgical lymph node dissection (LND) given the low risk of nodal spread (, 1%). Given the increased risk of nodal spread to 8% for stage IB patients (with depth of invasion of more than 1 mm), lymphadenectomy is recommended. Tabbaa and associates reported the largest cohort study to evaluate the effect and prognostic performance of the 2009 FIGO staging. They reported FIGO stage I, II, III, and IV 5-year overall survival (OS) rates of 84%, 75%, 48%, and 9%, respectively. The 5-year OS rate was 85% for patients without LN metastasis, and for patients with three or more lymph node metastases, the 5-year OS rate was 30%. They surmised that bilateral nodal disease does not appear to impact cause-specific survival, justifying its omission from the 2009 staging system, and that separating node-positive stage III from node-negative stage II cases appears justified.

Molecular Markers and Tumor Etiology Meaningful interpretation of the molecular landscape in which vulvar SCC develops remains a challenge. Immunohistochemistry (IHC) has been utilized to investigate molecular pathological markers and oncologic outcomes; however, results have been conflicting or not particularly impactful for patient management. There are two clear subtypes of vulvar SCC based on etiology: HPV-dependent and HPV-independent. Recent molecular data from the AGO-CaRE-1 trial have suggested three molecular subtypes of vulvar SCC, with differences in prognosis. Woelber et al. found that while HPV-independent cancers were often associated with the vulvar dermatoses of lichen sclerosis and harbored TP53 mutations, HPV-dependent cancers were shown to over-express p16, which was suggested as a surrogate marker for HPV-induced malignant transformation. Of the 648 tumor samples analyzed, they found that p16 IHC was positive in 30.2%, and HPV DNA was detected in 74.8% of the p161/p53-negative tumors, with HPV 16 as the most common subtype (85.1%). p53 IHC was positive in 31.3%. They found a large third molecular group, however, in which neither p16 nor p53 over-expression was noted. Additionally, they found that these molecular subgroups had different prognostic implications. Patients with p161 cancers were younger (63 vs. 70 years for p16- cancers), had lower rates of lymph node involvement (29% vs. 39.7%), and had lower recurrence rates. Oncologic outcomes were impacted as well, as the p161 group had significantly improved 2-year disease-free survival (DFS) (65.5% vs. 47%, P , .001) and 2-year OS (82.7% vs. 70.4%, P 5 .003) compared to p531 group. A third molecular subtype of vulvar SCC was identified in the AGO-CARE-1 translational data. This subgroup was found to be both p16 and p53 negative on IHC. This subgroup was found to have an intermediate prognosis with a 2-year DFS of 53% and 2-year OS of 72.6%. More studies are needed to investigate this third subgroup of vulvar SCC. The authors conclude that there is a clear positive prognostic impact on oncologic outcomes based on HPV presence, and

Invasive Cancer of the Vulva

181

while p53/p16 IHC biomarker data may not guide treatment at this point, it can offer prognostic information and guide more (in p531 tumors) or less intense surveillance practices.

Sentinel Lymph Node Biopsy Sentinel lymph node biopsy (SLNB) represents the most significant innovation in the care of patients with vulvar cancer in the past decade. The use of the SLN technique in the evaluation of vulvar cancer was first described in the late 1970s based initially on the experience in penile cancers, followed by the successes reported in breast cancer and melanoma. The past 20 years have witnessed a myriad of reports featuring SLN techniques in the management of gynecologic cancers, including vulvar cancer, that have provided experienced clinicians with a standard of care option for surgical lymph node management in appropriately selected patients. The concept of SLNs depends on reliable prediction of a tracer substance identifying the primary nodal drainage of the tumor. The assumption is that if the SLN is negative for malignancy, then the other nodes will be negative, thus precluding the need for full nodal dissection and thereby significantly reducing the procedural related short-term infection, wound breakdown, and long-term edema associated with inguinal femoral lymph node dissection (IFLND). The modern SLN concept requires a team comprised of the surgeon, the radiologist, and the pathologist. A 0.2 to 0.5 cc injection of radiocolloid (99mTc-SC filtered or unfiltered) is administered peri-lesionally, subcutaneously, and intradermally, and the images can be viewed online in the operating room (or hard copy films can be prepared). The surgeon prepares 2.5 mL of 1% lymphazurin (isosulfan blue) and using a 25-gauge needle, the dye is injected into the dermis at the junction of the tumor and normal vulvar skin. Gentle massage at the injection site helps with dye uptake. The dye is visible in the field for 30 to 45 minutes following injection, and the groin incision should be made a minimum of 5 minutes following injection of dye. The surgeon reports the location of the sentinel, whether it was hot or cold by the Geiger counter, whether it was blue or not blue, consistency (i.e., firm vs. soft), and size. Midline lesions require bilateral groin dissection, and therefore the primary lesion must be injected at the two points closest to the respective groin. Only approximately 30% of early-stage vulvar cancers have positive nodes with IFLND, thus exposing many women to ostensibly an unnecessary morbid procedure wherein historically up to two-thirds of patients experience lymphedema. More recently, Carlson and colleagues published the results of the Lymphedema and Gynecologic (LEG) study (Gynecologic Oncology Group [GOG] 244) and reported the incidence of lymphedema in vulvar cancer patients at 43%. Therefore, reducing the radicality of groin lymphadenectomy by SLNB merits implementation as a reliable alternative to full nodal dissection that requires balancing the slightly higher groin recurrence rates of SLNB versus the significantly greater morbidity of IFLND. Concerns raised in adopting SLNB as the standard of care include, first, the reliability of SLN detection. How feasible is this technique in terms of how often one detects an SLN, and

182

CHAPTER 6

Invasive Cancer of the Vulva

which technique should be used in terms of injection site and tracer selection? Second, what is the reliability of a negative SLN to predict that all the other inguinal nodes are likewise negative for malignancy? In other words, what is the potential for a falsenegative result, whereby an SLNB does not demonstrate metastases, but additional groin dissection discovers lymphatic spread? Finally, what is the groin recurrence rate? This question is critical because untreated groin metastases will result in groin recurrences that are most often fatal. It is important to recall that the gold standard for the rate of groin relapse in a nodenegative groin is historically 0% to 2% based on Homesley et al.’s GOG experience and others. The data for detection rate, sensitivity, or false-negative results can be considered from the perspective of each groin, viewed as a separate entity, or from the patient’s perspective, whereby the outcomes of SLNB are considered for both groins as a unit. Another important concept is the role of nodal ultrastaging with very fine sectioning and use of IHC as an adjunct to conventional staining, in which the SLN is subjected to far greater scrutiny in terms of pathologic sectioning than nodes removed via traditional IFLND. Ultrastaging is comprised of bisecting the sentinel node on the long axis and then preparing 2 to 3 mm slices that can then be stained with hematoxylin & eosin and IHC for cytokeratin AE1:AE3. Isolated tumor cells (ITC) are single cells or clusters less than 0.2 mm, and micrometastases are denoted when the tumor is greater than 0.2 mm but less than 2 mm. Nodal yield from traditional IFLND is much greater in number, and these nodes are not usually subjected to these laborintensive techniques because of time and resource constraints. Also, a statistical concept known as the false-negative predictive value (FNPV), defined as 1- Negative predictive value, needs to be understood to properly consider the burgeoning SLNB literature in the management of vulvar cancer. Several small studies were instrumental in establishing the feasibility of SLNB, with the original lymphatic mapping data being published by Levenback and colleagues in 1994. Recent studies have continued to demonstrate improved outcomes for SLNB over time. Initial mapping studies of SLNB in vulvar cancer evaluated 21 patients with isosulfan blue dye only, and an SLN was identified in only 86% of patients and 66% of groins. Addition of lymphoscintigraphy (LSG) with radiolabeled technetium significantly improved the SLN detection rate. A collective review of the literature in 2002 noted a detection rate of 92% with the combined technique. One of the first large prospective multicenter observational trials to assess SLNB was the GROINSS-V I study reported by Van der Zee and associates that included 403 assessable patients using the combined technique. Eligible patients had T1 or T2 lesions smaller than 4 cm, invasion greater than 1 mm, and clinically nonsuspicious inguinofemoral lymph nodes. SLNB was performed, and if the SLN result was negative, then an IFLN was not performed; only when SLN metastases were identified was an IFLND performed either at the time of surgery based on frozen section or subsequently based on final pathologic analysis of the SLN. A total of 623 groins in 403 patients were evaluated. The authors selected 276 selected patients with

unifocal vulvar disease and a negative SLN to describe in detail, and the 3-year survival rate was 97%, with a mean follow-up of 35 months. Adjuvant radiotherapy was administered to the groin and pelvis when more than one lymph node demonstrated metastasis or extracapsular nodal tumor growth was identified. Those who underwent SLNB had an FNPV of 2.9% with a false-negative rate of 6%. The groin recurrence rate for those with negative SLNs was 2.3% (6 of 259 patients). Patients with unifocal lesions had only a 2% recurrence rate compared with 12% for those with multifocal lesions on the vulva. Lymphedema was noted in 2% for SLNB versus 25% in those with positive SLN who underwent full IFLND. Wound breakdown and recurrent cellulitis occurred in 12% and 0.4% versus 34% and 16% for SLNB versus completion IFLND procedures, respectively. Ultrastaging with three sections per mm was performed only on SLNs that were negative on routine histopathologic examination. Ultrastaging significantly increased detection of nodal metastases. Routine pathologic examination detected 95 (58%) of the 163 groins with metastatic SLNs, and ultrastaging detected the remaining 68 (42%) groins demonstrating metastatic SLNs. A subset analysis of the GROINSS-V I study conducted by Oonk and colleagues demonstrated that the risk of non-SLN metastases increased with increasing size of SLN metastasis (4.2% with ITC and up to 62.5% with SLN metastases .10 mm). Also, the risk of non-SLN metastases was higher when the SLN was found to be positive with routine pathology rather than with ultrastaging. The 5-year disease-specific survival rates were 97% for women with ITC in the SLN, 88% for those with SLN metastases smaller than 2 mm, 70% for those with metastases measuring 2 to 5 mm, and 69% for those with metastases larger than 5 mm. No cutoff provided complete assurance that the non-SLNs would be free of metastases, thus given the high risk of mortality if such nodes are missed, additional groin treatment remains the current recommendation for all patients with SLN involvement. GOG 173 reported by Levenback and associates included 452 women who underwent SLNB followed by IFLND irrespective of SLNB findings. Eligibility criteria included SCC confined clinically to the vulva with at least 1 mm of invasion and tumor size up to 6 cm in greatest diameter. Patients with groin nodes that were clinically suggestive of cancer were excluded. Every woman underwent intraoperative lymphatic mapping using isosulfan blue dye; however, 2 years into the study, the protocol was amended to require preoperative LSG and intraoperative radiolocalization, which previously had been optional. Nodes were subjected to ultrastaging by serially sectioning them into 3-mm blocks with at least two sections 40 microns apart per block. The use of frozen section was discouraged. If routine hematoxylin and eosin staining was negative for metastatic disease on the first slide, IHC cytokeratin staining was performed on the second slide. A total of 772 groin dissections were performed (bilateral 5 320 and unilateral 5 132) in 452 women, of whom 418 exhibited at least one SLN. Incidence of node positivity among women with at least one SLN identified was 32%. Of the 132 women with positive nodes, 11 had falsenegative findings on SLNB (8.3%; 90% confidence interval

CHAPTER 6

[CI], 4.7% to 13.4%); thus, the sensitivity was 92%. The negative predictive value (NPV), was 96.3%. Importantly, this study showed that the false-negative rate for SLNB increased significantly when tumor size was 4 cm or larger (7.4% vs. 2% for tumors ,4 cm). They also demonstrated a favorable FNPV of 3.7%, which was the primary statistical endpoint of this trial. This FNPV is comparable to that observed in breast cancer, but salvage rates for that disease are more favorable. This study highlighted the role of pathologic analysis as 23% of the positive nodes were missed on conventional staining and required IHC to detect cancer. SLN ultrastaging is also important via step sectioning, which significantly increases the chance of finding metastases, according to Puig-Tintore et al. Coleman et al. published a subset analysis of patients from GOG 173 that examined the importance of the location of the primary tumor relative to the midline and the role of LSG, which was optional in this study. A total of 234 patients were eligible, with 64 having lateral lesions (.2 cm from midline) and thereby undergoing only unilateral IFLND after SLNB; the 105 women with midline and 65 with near-midline lesions (,2 cm distance from midline) underwent bilateral completion IFLND. Bilateral groin drainage using LSG was discovered in 22% of lateral, 58% of near-midline, and 70% of midline tumors. At mapping, no SLNs were found in contralateral groins among patients with near-midline and midline tumors who had unilateral-only LSGs, yet groin metastases were found in four of 32 patients with midline tumors undergoing contralateral dissection; none were found in 27 patients with near-midline tumors. They concluded that the likelihood of detectable bilateral drainage using preoperative LSG decreases as a function of distance from midline. Patients with near-midline primary tumors exhibiting unilateral drainage on LSG may safely undergo unilateral SLN. Further validation of this concept is indicated. A Cochrane review of SLNB in vulvar cancer management was reported by Lawrie et al. that assessed the diagnostic test accuracy of various techniques using traceable agents for SLNB to diagnose groin lymph node metastasis in women with FIGO stage IB or higher vulvar cancer. A total of 34 studies evaluating 1614 women and approximately 2396 groins were included in the analysis. Use of blue dye only provided a sensitivity of 0.94 (68 women; 95% CI 0.69 to 0.99); for mixed tracers, sensitivity was 0.91 (679 women; 95% CI 0.71 to 0.98); and for technetium only, it was 0.93 (149 women; 95% CI 0.89 to 0.96). Sensitivity for combined tests was 0.95 (390 women; 95% CI 0.89 to 0.97). NPVs for all index tests exceeded 95%. Mean detection rate for blue dye alone was 82%, compared with 95%, 96%, and 98% for mixed tests, technetium only, and combined tests, respectively. It was estimated that for 100 women hypothetically undergoing SLNB assuming groin metastases prevalence of 30% for the combined or technetium only tests, one and two women with groin metastases might be “missed,” and for mixed tests, three women with groin metastases would occur as false-negative results. This review concluded that there are only minor differences in diagnostic test accuracy between the technetium and combined tests. Combined testing may reduce the number of false-negative results compared with technetium alone. It must be recognized that there is a learning curve to successful

Invasive Cancer of the Vulva

183

SLNB, and combined tests may further increase detection for less experienced surgeons. Blue dye alone may be associated with more false negatives (FNs) compared with tests that include technetium. They further concluded that SLNB would reduce the need for full IFLND by 70% in patients with early vulvar cancer, but long-term survival data are needed. A systematic review was presented by Meads et al. to assess the accuracy of SLNB with technetium 99 and/or blue dye– enhanced LSG. A total of 29 studies that included 1779 women were analyzed. Most studies used technetium-99 combined with blue dye. Pooling when appropriate revealed mean SLN detection rates of 94% for technetium, 69% for blue dye alone, and 98% for both. SLNB revealed a pooled sensitivity of 95% (95% CI 92% to 98%) with an NPV of 97.9% in studies using technetium with blue dye, ultrastaging, and IHC with inguinal lymphadenectomy as reference. Less morbidity was reported for those undergoing SLNB. The authors concluded that SLNB should be done in carefully selected patients with technetium and blue dye with ultrastaging and IHC. They further concluded that patients must make an informed choice between the slightly higher groin recurrence rates of SLNB versus the higher morbidity with full lymphadenectomy. Another systematic review by Hussanzade et al. included 49 studies and reported a false-negative rate by patient and groin perspectives of 8%. Pooled NPVs were 97% for patient- and groin-based analyses. They pointed out that those with palpable groin nodes had lower detection rates and sensitivity with SLNB. They concluded that SLNB with radioactive tracer plus blue dye was accurate in appropriately selected patients with exclusion of those with clinically suspicious inguinal nodes. They also raised the concern of an increased FN rate for midline tumors. Slomovitz and colleagues performed a review that declared SLNB as the standard of care for early-stage vulvar cancer secondary to lymphedema rates of 30% to 70% after traditional IFLND combined with the robust prospective data from GOG 173 and the GROINSS-V I studies that confirmed the feasibility and utility of SLNB with similar false-negative rates of 6% for tumors smaller than 4 cm. Important differences between these studies include the fact that GROINSS-V I had smaller tumors (T1 or T2 ,4 cm) versus GOG 173, in which T1 and T2 tumors measuring 2 to 6 cm were included. Mapping techniques also differed because GROINSS-V I required both dye and tracer and a minimum threshold of 10 cases for skill verification versus blue dye only, which was initially required with no skill verification in GOG 173. The authors concluded that the groin relapse rate attributable to a false-negative SLNB for primary vulvar tumors smaller than 4 cm was less than 3%. Covens and associates convened a working group panel that performed an additional systematic review with meta-analysis. They reported a per groin detection rate for SLNB using radiocolloid tracer and blue dye of 87% and a false-negative rate of 6.4%. They recommended SLNB for women with unifocal tumors smaller than 4 cm with clinically nonsuspicious groin nodes, provided that conditions of specific infrastructure and SLN experience and volume are met. The groin recurrence rates are 6.6% for superficial IFLND and 1.4% for complete IFLND

184

CHAPTER 6

Invasive Cancer of the Vulva

versus 3.4% for SLNB. Expert panel recommendations from this paper included using radiocolloid with blue dye and not using blue dye alone secondary to low detection rates. Four quadrant intradermal injections into normal tissue at the margins of the tumor were recommended. Near-infrared tracers (e.g., indocyanine green [ICG]) and the role of frozen sections require further study. Radiocolloids can be injected 30 minutes to 24 hours before surgery, depending on the size of the radiocolloid and manufacturer directions, and blue dye should be injected in the same location as the radiocolloid after induction of anesthesia. A node that has more than five times the background radioactivity should be used to identify an SLN. Pathologically, the panel advocated for SLN ultrastaging by serially sectioning into 3-mm blocks and at least two sections 40 mm apart from each block. If routine hematoxylin and eosin staining is negative for metastatic disease on the first slide, IHC cytokeratin staining should be performed subsequently. Finally, the panel endorsed omission of IFLND in the contralateral side to a positive node when the SLN has been negative in that contralateral side, although they acknowledged that data are limited. Some issues with SLNB remain less clear, but data are emerging. What is the risk of contralateral non-SLN metastasis in patients with unilaterally positive SLNs? Woelber and colleagues addressed this question in 140 patients, 124 with bilateral and 16 with unilateral SLN dissection. A median number of two SLNs with a range of one to seven per groin were dissected. Of 33 patients with unilaterally positive SLNs, 28 (85%) underwent complete bilateral IFLND despite a contralateral negative SLN, and none demonstrated contralateral non-SLN metastasis. Of the remaining five patients, three received postoperative radiotherapy to the groins. One woman (3.6%), however, did develop groin recurrence in the initially SLN-negative, fully dissected groin after 19 months. These data support the omission of contralateral IFLND if negative contralateral SLN is found, but clearly, further study is needed before altering current guidelines that mostly advocate for bilateral IFLND in these circumstances because these numbers are small and possibly confounded by groin irradiation. Another unanswered question with SLNB heretofore has been the effect on long-term survival. This issue was recently addressed by te Grootenhuis and associates, who reported the long-term follow-up from the GROINSS-V I study with a median follow-up period of 105 months. The overall local vulvar recurrence rates were 27% at 5 years and 40% at 10 years after primary treatment. These recurrence rates are high considering that these were patients with unifocal tumors smaller than 4 cm. Notably, 89% of patients underwent wide excision versus only 10% who underwent radical vulvectomy for the primary tumor. For SLNB-negative patients, recurrence rates were 25% and 36% at 5 and 10 years, respectively, but SLNB- positive patients demonstrated 33% and 46% recurrence rates at 5 and 10 years, respectively. A total of 39 (15%) SLNB-negative patients underwent IFLND secondary to a local recurrence. The isolated groin recurrence rates were 2.5% for SLNB-negative patients and 8% for SLNB-positive patients at 5 years of follow-up. The overall 10-year disease-specific survival rates were 91% for SLNB-negative patients versus 65% for SLNB-positive patients.

For all patients, 10-year disease-specific survival rate decreased from 90% for patients without a local recurrence to 69% for those with a local recurrence. Klapdor and colleagues reported on a subgroup analysis of the AGO-CaRE-1 study and compared oncologic outcomes of patients with tumors less than 4 cm who underwent SLN dissection or radical lymphadenectomy with negative findings for SLN and LN metastases (N 5 556). While the full IFLND group had larger tumors (20 mm vs. 13 mm, P , .001) and deeper invasion (4 mm vs. 3 mm, P 5 .002), the isolated groin recurrence rates did not differ between groups (SLN 3% vs. IFLND 3.4%, P 5 0.845). Multivariate analysis after controlling for tumor characteristics revealed no statistical difference in progression-free survival (PFS) (hazard ratio [HR] 0.97, 95% CI 0.51 to 1.82) or OS (HR 0.69, 95% CI 0.26 to 1.84) between SLN dissection and radical IFLND in node-negative patients with tumors less than 4 cm. Additional questions with SLNB remain, including optimal imaging techniques such as ultrasonography, computed tomography (CT), magnetic resonance imaging, positron emission tomography/CT, and most recently, single-photon emission computed tomography (SPECT) preoperatively, that would best exclude clinically suspicious nodes that are thought to considerably increase the FN rate for SLNB. Nodes that are totally replaced by tumor may not be identified by mapping because of blockage of lymphatic channels by tumor, thereby resulting in a falsenegative result. The role of prior local recurrences and prior SLNB also is poorly understood in terms of the accuracy of repeating SLNB. Furthermore, the clinical consequences of micrometastases are unclear. As SLN metastasis size increases, the probability of non-SLN metastases increases, which correlates with decreasing survival. SNLB appears to be cost-effective in separate reports (McCann et al. and Erickson et al.); nonetheless, Sutton and associates performed a model-based economic analysis that clearly showed that IFLND was most cost-effective and dominated all other strategies considering 2-year OS, but when morbidity-free outcomes were considered, then SLNB using a combined identification technique with ultrastaging and IHC was superior. Future directions in optimizing SLNB will include development of novel tracers and dyes such as fluorescent dyes (e.g., ICG) for enhanced SNL identification. Additionally, GROINSSV-II-GOG270 has recently resulted and investigated the role of adjuvant groin irradiation as a substitute for completion IFLND in those with positive SLNB. It is noteworthy that this trial suspended accrual in 2010 (after 54 months of inclusion) because of higher than allowable groin recurrences in the cohort of patients with positive SLNB who received adjuvant radiotherapy. At the time of suspension, 9 groin recurrences were identified in 82 such patients. Extensive analysis of these cases revealed that tumor metastases size ($2 mm) and extranodal extension were associated with a statistically higher rate of groin recurrence. The trial was reopened for accrual after amending the eligibility criteria with only those with micrometastases (#2 mm) remaining eligible for radiation (50 Gy); those with macrometastases (.2 mm) were to undergo IFLND. The results of this trial were recently presented at the Society of Gynecologic Oncology Annual Meeting in March 2020 by Slomovitz, van der Zee, Oonk and colleagues. Overall, this trial

CHAPTER 6

represents the largest prospective surgical trial in vulvar cancer to date, with 1540 eligible patients enrolled. There were 1218 patients with a negative SLN and 322 with a positive SLN. In the SLN-negative group, after a median follow-up of 24.3 months (0 to 73.7), 171 patients experienced a recurrence (14%), 14 of those who also experienced a groin recurrence (1 patient had an isolated pelvic node recurrence). Of the 36 isolated groin recurrences (2.9% at 2 years; 95% CI 2.1% to 4.1%), 10 had protocol violations (including 1 incomplete treatment of the groin, 1 primary tumor .4 cm, 3 with not all SLNs on imaging removed, and 2 with false-negative pathology). With the protocol violations excluded, there was a 2.2% (95% CI 1.4 to 3.1) isolated groin recurrence rate among negative SLN patients. Overall, the disease-specific survival was 97.9% at 2 years for the negative SLN group. The investigators conclude that omitting IFLND in patients with vulvar cancer less than 4 cm and a negative SLN is safe. There were 160 patients with a positive micrometastasis on SLN. After a median follow up of 23.9 months (range 0.3 to 68.4 months), 127 patients underwent radiotherapy, 15 patients underwent an IFLND (4 of which also had radiation), and 18 patients had no treatment for various reasons. Excluding those patients who also had an IFLND, patients with positive micrometastatic SLNs experienced an isolated groin recurrence after 2 years at a rate of 1.8% in the radiation group as opposed to 15.4% in the no adjuvant therapy group (P 5 .009). The mean size of metastasis in the radiation group was 0.76 mm compared to 0.63 mm in the no radiation group (P 5 .87). There were 162 patients with positive macrometastatic SLNs, of which 50 were prescribed just radiation prior to the protocol amendment, and 115 patients who underwent IFLND after the protocol amendment (ultimately 52 underwent radiation, 104 underwent IFLND, and 6 patients had no treatment). After 22.5 months median follow up (range 0 to 40.5), in patients with a positive macrometastatic LN, the isolated groin recurrence rate at 2 years was 25.0% in the radiation group compared to 8.2% in IFLND group (P 5 .012). The investigators conclude that radiation to the groin in patients with SLN metastasis #2 mm results in very low groin recurrence rate (1.6%), the toxicity of radiation was minimal in most patients and with less frequent long-term morbidity compared to IFLND, and finally for patients with SLN metastasis greater than 2 mm, radiation with a total dose of 50 Gy is not a safe alternative to IFLND. The next question to be answered is whether chemoradiation is a safe alternative to IFLND in patients with macrometastatic SLNs. This question is being addressed in the upcoming GROINSS-V III prospective phase II trial in which radiation boost to 56 Gy with weekly cisplatin will be prescribed to this patient population. In summarizing, if an SLN is not identified and in any case in which the mapping procedure appears inadequate, SNLB should be abandoned in favor of complete IFLND. Patient selection is crucial to success. Patients should have a negative metastatic workup. Table 6.7 summarizes factors that affect the success of SNLNB. Ideal candidates have unifocal T1 or T2 primary tumors smaller than 4 cm in diameter and clinically nonsuspicious groin nodes. SNLB performance characteristics from select studies are summarized in Table 6.8. The standard

Invasive Cancer of the Vulva

185

TABLE 6.7 Factors Influencing Sentinel Lymph Node Biopsy Success Vulvar tumor size Unifocal versus multifocal vulvar tumor Previous primary resection Previous groin dissection Palpable groin nodes Tracer: dye versus radiocolloid versus ICG Radiopharmaceutical dose Lateral versus midline lesion Ultrastaging Cytokeratin IHC Subcutaneous injection Operator experience ICG, Indocyanine green; IHC, immunohistochemistry.

TABLE 6.8 Select Studies of Sentinel Lymph Nodes Author, Study, Year

Patients (n)

SLN Detection Rate (%)

Sensitivity (%)

NPV (%)

Van der Zee et al., GROINSS-V I, 2008

403

NRa

Levenback et al., GOG 173, 2012

452

96b 98c

Lawrie, review, 2014

1614 (aggregated)

Meads, review, 2014

1779 (aggregated)

97.7

97.9

Hussanzade, review, 2013

981 (aggregated)

94.4

Covens, review, 2015

1087 (aggregated)

Combined Tc and blue dye. Overall. c Tumors ,4 cm. GOG, Gynecologic Oncology Group; GROINSS-V I, GROningen INternational Study on Sentinel nodes in Vulvar cancer I; NR, not reported; NPV, negative predictive value; SLN, sentinel lymph node. a

has been that if a positive SLN is found on one side, then a complete groin dissection should be done bilaterally; however, emerging evidence supports omission of full contralateral IFLND if the contralateral SLN is negative. Fig. 6.10 proposes a potential management algorithm for SLNB. Clearly, these management schemes require individualization and constant vigilance of emerging literature that may alter recommendations.

TECHNIQUE OF INGUINOFEMORAL LYMPHADENECTOMY Although most women with clinical early-stage vulvar cancer will be candidates for SLN identification, complete inguinofemoral

186

CHAPTER 6

Invasive Cancer of the Vulva

Unilateral SLN Positive

Lateral lesion >2 cm from the midline

Vulvar lesion Unifocal,

Disaia and Creasman Clinical Gynecologic Oncology - PDFCOFFEE.COM (2025)

References