Handbook

for
PRINCIPLES AND PRACTICE OF
GYNECOLOGIC ONCOLOGY
Third Edition
Editors
Douglas A. Levine, MD
Director, Gynecologic Oncology
Head, Gynecology Research Laboratory
Professor, Obstetrics and Gynecology
Laura and Isaac Perlmutter Cancer Center
NYU Langone Health
New York, New York

Stéphanie L. Gaillard, MD, PhD

Assistant Professor
Oncology
Gynecology and Obstetrics
Johns Hopkins School of Medicine
Baltimore, Maryland

Lilie L. Lin, MD
Associate Professor
Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas

Dennis S. Chi, MD
Ronald O. Perelman Chair in Gynecologic Surgery
Deputy Chief
Head of Ovarian Cancer Surgery
Gynecology Service
Department of Surgery
Memorial Sloane Kettering Cancer Center
New York, New York

Andrew Berchuck, MD
Director
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Director
Gynecologic Cancer Program
Duke Cancer Institute
Duke University Medical Center
Durham, North Carolina

Don S. Dizon, MD, FACP

Professor of Medicine, Brown University
Director of Women’s Cancers, Lifespan Cancer Institute
Director of Medical Oncology, Rhode Island Hospital
Providence, Rhode Island

Catheryn Yashar, MD
Professor
Chief of Breast and Gynecologic Services
Medical Director La Jolla
University of California, San Diego
San Diego, California
Handbook for
PRINCIPLES AND PRACTICE OF
GYNECOLOGIC ONCOLOGY
Third Edition
Acquisitions Editor: Nicole Dernoski
Development Editor: Sean McGuire
Editorial Coordinator: Anthony Gonzalez
Marketing Manager: Tyrone Williams
Production Project Manager: Bridgett Dougherty
Design Coordinator: Steve Druding
Manufacturing Coordinator: Beth Welsh
Prepress Vendor: SPi Global

Third Edition

Copyright © 2021 Wolters Kluwer

Copyright © 2015 Wolters Kluwer. Copyright © 2010 Lippincott Williams & Wilkins, a Wolters Kluwer business. All rights
reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any
means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval
system without written permission from the copyright owner, except for brief quotations embodied in critical articles and
reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government
employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two
Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at
shop.lww.com (products and services).

9 8 7 6 5 4 3 2 1

Printed in China

Cataloging-in-Publication data available on request from the Publisher.

ISBN-13: 978-1-9751-4106-6

This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any
warranties as to accuracy, comprehensiveness, or currency of the content of this work.

This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient
and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history,
laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this
work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this
work including all medical judgments and for any resulting diagnosis and treatments.

Given continuous, rapid advances in medical science and health information, independent professional verification of
medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made
and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are
advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify,
among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or
contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic
range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury
and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to
or use by any person of this work.

shop.lww.com
 This book is dedicated to all those who care

for our patients on the wards and in the operating rooms,

and to our families who support us.

 CONTRIBUTORS

Stefany Acosta-Torres, MD
Clinical Fellow
Gynecology and Obstetrics
Johns Hopkins School of Medicine
Baltimore, Maryland

Monica Avila, MD
Fellow
Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas

Christine Chin, MD
Assistant ProfessorRadiation Oncology
Vagelos College of Physicians and Surgeons
Columbia University Irving Medical Center
Ney York, New York

Stéphanie L. Gaillard, MD, PhD

Assistant Professor
Oncology
Gynecology and Obstetrics
Johns Hopkins School of Medicine
Baltimore, Maryland

Deanna Gerber, MD
Assistant Professor
Obstetrics and Gynecology
Laura and Isaac Perlmutter Cancer
NYU Langone Health
New York City, New York

Kari Hacker, MD, PhD

Assistant Professor
Obstetrics and Gynecology
Laura and Isaac Perlmutter Cancer
NYU Langone Health
New York City, New York

Douglas A. Levine, MD
Director, Gynecologic Oncology
Head, Gynecology Research Laboratory
Professor, Obstetrics and Gynecology
Laura and Isaac Perlmutter Cancer Center
NYU Langone Health
New York, New York

Lilie L. Lin, MD
Associate Professor
Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas

Melissa H. Lippitt, MD, MPH

Clinical Fellow
Gynecology and Obstetrics
Johns Hopkins School of Medicine
Baltimore, Maryland

Jonathon Posey, MD
Research Coordinator
Oncology
Johns Hopkins School of Medicine
Baltimore, Maryland

Christina H. Son, MD
Assistant Professor
Radiation & Cellular Oncology
University of Chicago
Chicago, Illinois

Elaine M. Walsh, MB, BCh, PhD

Clinical Fellow
Oncology
Johns Hopkins School of Medicine
Baltimore, Maryland

Erica Weston, MD, MHS

Clinical Fellow
Gynecology and Obstetrics
Johns Hopkins School of Medicine
Baltimore, Maryland
 PREFACE

Medicine is a field in continual evolution, and gynecologic oncology is no exception. Indeed,

the field is constantly changing as new data are published that further our understanding and
treatment approaches to these cancers. As a result, we have created the PPGO Handbook as a
complement to its parent textbook, Principles and Practice of Gynecologic Oncology,
seventh edition. We have designed this handbook with an eye toward students, residents,
nurses, and anyone new to gynecologic oncology who needs to rapidly acquire basic
familiarity with the field, a summary of newer developments that have taken place since
publication of the textbook, and who desire such critical information all in one place.
The PPGO Handbook has been shortened from the key chapters in the parent textbook,
with an emphasis on introductory and summary information. It is organized by chapter, with
each of the major cancer sites covered. In addition, we cover the basics of oncology practice
to get the reader oriented not only to the field of gynecologic oncology but to the practice of
cancer medicine. To help our readers, we have highlighted key points from each chapter to
ensure that the most important information stands out and incorporated treatment algorithms,
where appropriate. Finally, a few suggested articles for reading are listed at the end of each
chapter, and more extensive references can be found in the parent textbook. When desired,
trainees can move easily from chapters in this handbook to the comprehensive chapters in the
larger textbook for greater detail.
Several of the chapters in this new edition were coauthored by oncology fellows and
colleagues and we extend our thanks to them for their contributions. Our trainees lend an
invaluable perspective on the information that fellows want to see in a clinical handbook.
We hope this handbook will meet its goals as a convenient introduction to a field that is
exciting and changing rapidly—and one which we hope they will find as rewarding as we
have.
 ACKNOWLEDGMENTS

First and foremost, we thank the authors of Principles and Practice of Gynecologic
Oncology, seventh edition, from whose excellent chapters the current handbook chapters in
large part are derived. We also thank the oncology fellows who helped create new content
and ensure that we are addressing those areas of most importance and interest. We are also
grateful to Sean McGuire, Development Editor, and Nicole Dernoski, Acquisitions Editor, of
Wolters Kluwer, for their expert oversight and guidance throughout the development of this
edition. We very much appreciate all of our wonderful trainees who provide motivation for
teaching and learning every day. We give thanks to all of our patients who are our inspiration
and our teachers as well.
 CONTENTS

Contributors

Preface

Acknowledgments

1 Principles of Systemic Therapy in Gynecologic Cancer

2 Biologic and Physical Aspects of Radiation Oncology
3 Clinical Genetics of Gynecologic Cancer
4 Preinvasive Lesions of the Genital Tract
5 The Vulva
6 The Vagina
7 The Uterine Cervix
8 The Corpus: Epithelial Tumors
9 The Corpus: Mesenchymal Tumors
10 Ovarian Cancer (Including the Fallopian Tube)
11 Nonepithelial Ovarian Cancer
12 Molar Pregnancy and Gestational Trophoblastic Neoplasms
Index
 1 Principles of Systemic Therapy in
Gynecologic Cancer

Introduction
Key Points
The principles of modern systemic therapy require a working knowledge of
growth characteristics of normal and tumor tissues.

Tumor Biology
Development of cancer is the product of biologic insults exerted individually and collectively
on the genome, the proteome, via modulation of the microenvironment or evasion of the
immune system. For example, insults to master regulatory genes responsible for safeguarding
cellular integrity (such as p53, BRCA1/BRCA2, myc, ras, or src) result in well-characterized
downstream aberrations to cell signaling. Hanahan and Weinberg described the six basic
hallmarks of cancer that not only define its behavior, including distinctive and
complementary capabilities that enable tumor growth and metastatic dissemination, but also
provide a roadmap for drug development against key regulatory/survival processes in cancer
cells (Fig. 1.1). Cancer, and gynecologic cancers in particular, show clonal and genomic
diversity, with resulting cellular heterogeneity in space and time, leading to considerable
differences in clinical behavior.
FIGURE 1.1 Hallmarks of cancer and therapeutic targets in gynecologic
cancers. (Reprinted from Hanahan D, Weinberg RA. Hallmarks of cancer: the
next generation. Cell. 2011;144:646–674, with permission from Elsevier.)

The rationale to explain the impact of systemic therapy partially rests on our ability to exploit
differences in the growth kinetics of normal versus malignant cells. Three normal cell
populations can be distinguished based on growth patterns. Static cells are well differentiated
and rarely undergo cellular division. Expanding cells retain the capacity to grow but are
normally quiescent in their adult state. Renewing cells exist in a continuous proliferative state
with cell division balanced by terminal differentiation. These patterns of normal cell growth
partially explain some of the toxic effects of cytotoxic therapy and why some tissues are
commonly spared. Renewing cell populations with constant turnover are most susceptible to
acute injury from chemotherapy or irradiation. This is reflected by the frequent occurrence of
dose-limiting bone marrow suppression, mucositis, azoospermia, and alopecia during
cytotoxic drug treatment, with relative sparing of nonproliferative compartments, such as
brain, muscle, kidney, bone, and oocytes. However, even nondividing tissues can experience
late chronic effects related to DNA damage.
 Targeted and precision therapies seek to exploit cancer evolution and cellular
heterogeneity and therefore predominantly affect cancer cells more than normal cells.
Targeted therapies inhibit the growth of cancer cells by interfering with specific molecules
needed for carcinogenesis and progression and by identifying oncogenic drivers critical for
cancer growth. In this way, both antiangiogenic agents and agents targeting the DNA repair
pathway have been shown to be effective in ovarian cancers.

Gompertzian Growth of Tumors

The exponential enlargement of tumors has been characterized in a pattern termed
gompertzian growth. This describes a pattern of exponential growth during initial cell
divisions that slows as the tumor grows. The importance of this pattern is to recognize that
exponential growth is not strictly maintained throughout a tumor’s history. Other potentially
important implications of gompertzian growth include the following: (i) metastatic spread
may occur even before detection of the primary lesion and (ii) at later stages, even a small
number of doublings may produce a marked change in tumor size.

Host–Tumor Interactions
It has been increasingly recognized that host–tumor interactions and the tumor
microenvironment play a complex role in tumor growth, development, and metastasis. Tumor
growth is dependent on the manipulation of host factors, including evasion of immune
surveillance and promotion of angiogenic pathways to provide nutrients and oxygen.
Targeting these signaling networks supporting tumor growth can be an effective therapeutic
strategy.

The Cell Cycle

Another important aspect critical to understand cancer biology and the effect of systemic
therapy on tumor growth is the cell cycle (Fig. 1.2). Cells can remain in a postmitotic
compartment (G0) for an extended period of time; at this point, the cell is not cycling, though
it is capable of reentering the cell cycle when triggered by growth factors.
FIGURE 1.2 Cell cycle regulation. Cyclins and CDKs promote cell cycle
progression and are mediated by inhibitory molecules.

Cell cycling begins at the G1 checkpoint, which is associated with diverse cellular processes
including protein and RNA synthesis and DNA repair. After G1, cells enter the synthetic
phase (S), marked by replication and resulting in the creation of complete copy of cellular
DNA. Cells then enter the G2 checkpoint, allowing another control point prior to entering
active mitosis (M) consisting of prophase, metaphase, anaphase, and telophase. After M,
cells can further differentiate, stop cycling, or divide once more.
Most chemotherapeutic agents disrupt this process by inhibiting or interfering with DNA,
RNA, or protein synthesis. In addition, rapidly proliferating cells are characterized by a short
G1 checkpoint and are more sensitive to chemotherapy’s effects. Cell cycle–specific agents
commonly used in gynecologic cancers include antifolates (G1, S), doxorubicin (S), platinum
compounds (G1, G2, S), taxanes (M), and bevacizumab (G0, G1, S, G2).

Pharmacologic Principles of Systemic Therapy

Key Points
 The route of administration depends on many factors that are drug specific
(solubility, requirements for activation) and patient specific (feasibility,
tolerability).
The maximal effectiveness of an agent depends on optimizing the area under the
drug concentration-time curve (AUC) at critical tumor sites.
The inactivation and excretion of therapeutic agents occur primarily by the liver,
kidneys, and body tissues, with lesser elimination through the stool.
Understanding potential of drug–drug interactions is critical as they may increase
the risk of more serious toxicities or reduce therapeutic effectiveness.
Dosing of chemotherapy must consider the setting and objective of treatment.
More intense regimens are best utilized in the adjuvant or neoadjuvant setting.

Systemic Therapy Settings

Adjuvant therapy refers to the initial use of systemic therapy after surgery and/or
radiotherapy has been performed with curative intent, and there is no evidence of residual
disease. Adjuvant therapy is considered if the subsequent risk for recurrence after initial
definitive therapy is relatively high (generally >20%), but it is not routinely recommended
when the risk of recurrence is less than 10%.
Neoadjuvant therapy generally refers to the use of systemic therapy in the management
of locally advanced disease in situations where it would be difficult to perform immediate
surgery or radiation. In some clinical situations, response to initial systemic therapy can lead
to improved surgical outcomes and a reduction in morbidity.
Concurrent chemotherapy with radiation (chemoradiation) refers to the use of
chemotherapy to sensitize tumors to the effects of radiation generally delivered with curative
intent. This has been most extensively studied in the primary management of locally
advanced cervical cancer. In general, the duration of chemotherapy coincides with the
duration of external beam radiation. Although the preferred weekly dose of chemotherapy
might appear to be low, these regimens generally exceed the overall dose intensity of
chemotherapy used to treat advanced disease, and patients require monitoring to avoid
cumulative toxicity and treatment interruptions.
Maintenance therapy refers to the concept of continuing systemic therapy after definitive
treatment in order to prevent disease recurrence either by killing residual slowly dividing
cells, preventing cell turnover by inhibitory signaling, or through immunologic control.
Maintenance therapy involves either prolonged courses of cytotoxic therapy or, more
recently, molecularly targeted agents as a means of extending periods of disease control with
the intention of prolonging survival without compromising quality of life. The rationale for
maintenance therapy stems from the fact that for many advanced cancers, recurrence rates
after definitive therapy are high, suggesting that a dormant population of cells remain and
ultimately lead to disease progression. Maintenance treatment administered during periods of
remission could provide a means of extending the interval between courses of chemotherapy
and potentially extend survival.
Systemic Therapy Objectives
Although certain general principles guide the clinician in choosing the appropriate classes of
drugs or combinations, the decision to use these agents must be considered carefully. The
critical factors involved in formulating a recommendation are reviewed in Table 1.1.

TABLE 1.1 Important Considerations before Using Antineoplastic Drugs

The likelihood of achieving clinical benefit influences the choice of treatment and the
acceptance of potential toxicity. Primary tumors can generally be grouped according to the
likelihood of achieving a durable response. There is a group of tumors for which primary
chemotherapy has been curative in the majority of patients, including choriocarcinoma and
ovarian germ cell tumors. These patients should be treated aggressively with curative intent.
Toxicity in this setting is acceptable, assuming that it is reversible, as the probability of long-
term survival is high.
A second group, including advanced epithelial ovarian carcinoma, has high response
rates to primary therapy (>75%), with prolongation of disease-free and median overall
survival, but without curative benefit. Patients with these tumors usually benefit from therapy
in terms of extended survival or quality-adjusted survival, and they should receive primary
treatment at full doses unless contraindicated.
 A third group of cancers, including advanced (or recurrent) endometrial cancer, cervical
cancer, low-grade serous carcinoma, and uterine carcinosarcoma (mixed müllerian tumors),
have intermediate or lower response rates to primary chemotherapy, with shorter duration of
remission and limited improvement in overall survival. Treatment with an initial course of
therapy is reasonable, with careful monitoring of toxicity and response. Other tumors,
including uterine leiomyosarcoma, are more resistant to primary therapy, achieving a low
frequency of objective response without prolongation of survival. In this setting, the use of
chemotherapy should be carefully considered and particular emphasis placed on including
these patients in well-structured clinical trials to evaluate innovative treatments.
In patients with recurrent or progressive disease after prior chemotherapy, the
expectations of response are reduced due to the emergence of drug resistance and the impact
of prior therapy and/or disease on performance status and vital organ function. As such,
treatment goals are usually aimed at control or palliation, with attention to quality of life and
control of symptoms. In this population, the frequency of stable disease usually exceeds the
objective response rate. With appropriate chemotherapy regimens that avoid cumulative
toxicity, patients without further disease progression may remain on therapy for prolonged
periods of time with an acceptable quality of life.
The appropriate therapeutic regimen should be selected using practice guidelines and the
results of randomized trials. A number of combination chemotherapy regimens have been
evaluated and are considered “standard of care” for the primary management of advanced-
stage or recurrent disease. Although tumor response is often increased with combination
therapy, long-term outcomes may be similar for patients who receive optimal single-agent
sequential therapy. As such, single-agent therapy may be a reasonable option for patients
unable to tolerate combination regimens.

Systemic Chemotherapy
We are in the midst of an important transition from conventional cytotoxic agents to new
strategies that incorporate mechanism-based molecular-targeted therapeutics. Even with these
changes in our treatment paradigm, several conventional cytotoxic agents maintain a central
role in the care of women with gynecologic cancers. On the basis of a combination of
intrinsic and acquired factors, the majority of advanced tumors eventually demonstrate broad
resistance to conventional cytotoxic chemotherapy, and there has been renewed interest in
novel biologic and immunologic approaches with non–cross-resistant mechanisms. Certain
cancers, such as choriocarcinoma, can be cured with a single application of a single drug.
However, the majority of cancers are intrinsically less sensitive and require multiagent
chemotherapy over multiple cycles to achieve clinical benefit. Distribution of treatment over
multiple cycles allows for host recovery while still achieving the cumulative cell kill required
for tumor regression and cure.
Cytotoxic agents commonly used in the treatment of gynecologic malignancies, and their
toxicities and emetogenic potential are listed in Table 1.2.
TABLE 1.2 Common Cytotoxic Agents Used in the Treatment of
Gynecologic Malignancies
Chemotherapy Dose Intensity and Density
The dose and frequency of drug administration can contribute to the overall effectiveness of a
treatment regimen, as well as the spectrum and severity of toxicity (Fig. 1.3). Dose intensity
is a standardized measure of the amount of drug administered over time. Preclinical studies
demonstrate a sigmoidal relationship between dose and tumor response. The hypothesis that
greater dose intensity would produce greater benefit has been evaluated. However, within
dose ranges that are achievable in the clinical setting, prospective trials of both platinums and
taxanes have failed to demonstrate improvements in either disease-free or overall survival
with increased dose intensity regimens. Dose intensity is limited by acute (single cycle) and
cumulative (multicycle) nonhematologic and hematologic toxicities.
FIGURE 1.3 Theoretical dose–response curve. The vertical axis is the tumor
response and the horizontal axis is the log of the dose. A hypothetical dose–
response curve is illustrated by the green line. The blue line represents a highly
responsive tumor (e.g., choriocarcinoma), in which the dose–response curve is
shifted to the left. The red line represents a resistant tumor (e.g., previously
treated cervical cancer) in which treatment response is diminished.

By contrast, “dose-dense” therapy, in which agents are sequentially administered at maximal

tolerated doses using short cycle intervals, has been favorably evaluated in the adjuvant
therapy of breast cancer and ovarian cancer, though at a cost of increased hematologic
toxicity.

Intraperitoneal Chemotherapy
Intracavitary chemotherapy has been used for tumors confined to the peritoneum, pleura, or
pericardium. Drug clearance from a body cavity is delayed compared to clearance from the
systemic circulation, resulting in prolonged exposure to higher concentrations of active
agents. However, penetration of peritoneal tumor nodules by passive diffusion is limited;
thus, intracavitary chemotherapy is reserved for patients with minimal residual disease after
primary therapy.
Cisplatin has been the most extensively studied agent for intraperitoneal delivery in
gynecologic malignancies and is part of the standard of care regimen approved for the
primary treatment of small-volume residual ovarian cancer following initial cytoreductive
surgery. In contrast, paclitaxel is poorly absorbed from the peritoneal compartment,
suggesting that patients might benefit from combined intravenous and intraperitoneal
administration to optimize tumor drug exposure.

Targeted Therapy
Exploration of the biologic mechanisms associated with tumor growth, maintenance,
metastasis, and resistance to chemotherapy has led to the development of molecular-targeted
therapeutics. In general, novel targeted agents exhibit toxicities that are distinct from
conventional cytotoxic chemotherapy, often sparing proliferative compartments, such as bone
marrow and mucosal epithelium. However, there is still the potential for serious toxicity,
including drug interactions, alterations in hepatic or renal function, bleeding, thrombosis,
pneumonitis, leukoencephalitis, and autoimmunity.

DNA Damage Repair Pathways and PARP Inhibitors

One targeted pathway of interest in gynecologic malignancies is the DNA repair and
homologous recombination (HR) pathway, and up to 50% of women with high-grade serous
ovarian cancers (HGSOC) have evidence of homologous recombination deficiency (HRD).
In the DNA repair pathway, important targets in ovarian cancer, particularly in HGSOC, are
the BRCA1 and BRCA2 genes. Mutations in these genes predispose germline carriers to
breast and ovarian cancer as well as many other malignancies, and the diagnosis of HGSOC
should lead to germline testing for all patients. There are also a subset of tumors that harbor
other non–BRCA1/BRCA2 mutations in the HR pathway including RAD51, PALB2, CHEK2,
Mre11 complex, and BARD1 (Fig. 1.4). These tumors have features and behavior similar to
BRCA-related cancers, including improved survival rates and HGSOC histology.
FIGURE 1.4 DNA repair pathway and therapeutic targets in cancer.

Germline and somatic testing for BRCA1/BRCA2 mutations not only provides important
information about predisposition but is also a predictive biomarker for poly(ADP-ribose)
polymerase (PARP) inhibitor therapy in women with HGSOC. Impaired DNA repair due to
pathogenic BRCA1/BRCA2 mutations can be leveraged into therapeutic effect by blocking
PARP, another major enzyme in DNA repair. The simultaneous promotion of DNA double-
strand breaks (DSBs) and hindrance of DSB repair by PARP inhibition, dubbed “synthetic
lethality,” has led to the approval of PARP inhibitors for the treatment of BRCA1/BRCA2–
mutated ovarian cancer. The ability to leverage deficiencies in HR has been shown to extend
beyond BRCA1/BRCA2 mutations: non–BRCA HRD–mutated tumors also appear to derive
benefit from PARP inhibition, although the benefit does not appear to be as robust. In
addition, several PARP inhibitors have been FDA approved as maintenance treatment in
platinum-sensitive ovarian cancers, irrespective of BRCA1/BRCA2 status.

Antiangiogenic Therapy
Vascular endothelial growth factor (VEGF) is a key driver of angiogenesis and is important
for tumor growth, survival, and metastasis. VEGF overexpression has been demonstrated in
endometrial, epithelial ovarian and cervical cancers and is thought to be responsible for some
pathognomonic features of ovarian cancer such as ascites, caused by VEGF overexpression
leading to capillary leakiness. In gynecologic cancers, inhibition of tumor-associated
angiogenesis with the use of bevacizumab, a humanized anti-VEGF antibody, has resulted in
improvements in survival in several large randomized clinical trials.

Endocrine Therapy
Endocrine therapy is an attractive targeted therapeutic strategy in treating gynecologic
cancers. In endometrial cancer, a significant proportion of type 1 tumors express estrogen
receptor (ER) or progesterone receptor (PR), which may be useful as prognostic biomarkers.
To date, the agents that have been investigated in this setting include progestogens, selective
ER modulators (SERMs), aromatase inhibitors (AIs), and GnRH inhibitors. The most
common endocrine treatment has been progestational agents, which demonstrate antitumor
response and clinical benefit especially in patients with well-differentiated, PR-positive
tumors. Efforts continue to refine the role of hormonal therapy in endometrial cancer in the
primary and advanced settings.

Immunotherapy
Emerging data that immunity may be sufficient to destroy tumors by recognizing antigens on
tumor cells has provided the impetus to develop new strategies for immunotherapy (Fig. 1.5).
CTLA-4 blockade activates CD4+ and CD8+ T effector cells by removing an inhibitory
checkpoint on proliferation and function. Programmed cell death protein-1 (PD-1) is a
negative regulator of cell activation, expressed on B and T lymphocytes, which binds
programmed cell death ligand-1 (PD-L1). Certain epithelial cancers, including ovarian
cancers, express PD-L1, which may be prognostic in some tumor types. PD-1 blockade has
been shown to activate antitumor immunity, resulting in the approval of PD-1 and PD-L1
inhibitors for multiple tumor types.
FIGURE 1.5 Immune response and targets of immunotherapy in gynecologic
cancers.

The presence of tumor-infiltrating lymphocytes (TILs) predict for PD-1 and PD-L1
expression. POLE ultramutation, microsatellite instability (MSI), and DNA mismatch repair
(MMR) deficiency are associated with high neoantigen loads, high levels of TILs, and PD-1
and PD-L1 overexpression, which in turn are associated with favorable outcomes. The anti–
PD-1 antibody, pembrolizumab, was the first FDA-approved tissue-agnostic drug based on
data showing improved efficacy in patients with MSI-high or MMR-deficient tumors. Tumor
mutation burden (TMB) is another genomic biomarker of response to anti–PD-1 therapy
measuring the total number of mutations per coding area within a tumor genome.
The data for immune checkpoint inhibitors in gynecologic cancer is increasing and
continues to be an area of ongoing investigation. To date, clinical trials using checkpoint
inhibitors in gynecologic cancer have shown positive results in endometrial cancers, and
studies are yielding interesting results in both ovarian and cervical cancers. There are several
agents in active development as single agents, or in combination with chemotherapy, targeted
agents, monoclonal antibodies, and vaccines.
Absorption, Distribution, and Drug Interactions
Drugs may be administered orally, intravenously, intramuscularly, intra-arterially, or
intraperitoneally. The selection of the most appropriate route is dependent on drug solubility,
the requirements for drug activation, tolerance levels of local tissue, individual patient
feasibility (usually based on values and preferences), and the optimal tumor drug exposure.
Ultimately, maximal effectiveness depends on optimizing the area under the drug
concentration–time curve (AUC) at critical tumor sites.
The extent of drug binding to serum proteins may also impact tumor drug exposure.
Many chemotherapy agents are lipophilic and highly protein bound in plasma, particularly to
albumin. The unbound “free” drug mediates toxicity, meaning that any condition associated
with variability in protein binding can impact cumulative drug exposure. For example, the
toxicity of chemotherapy is frequently accentuated in patients with poor nutritional status,
which is associated with reduced protein levels.
During routine care, patients may receive a variety of drugs, including antiemetics,
antihistamines (H1 and H2), steroids, nonsteroidal anti-inflammatory agents, anticoagulants,
narcotics, and antimicrobial agents. Particular attention should be placed on drugs that could
alter renal function, such as aminoglycoside antibiotics, nonsteroidal anti-inflammatory
agents, and diuretics, in patients with reduced fluid intake.
The increasing utilization of oral chemotherapy and oral molecular-targeted agents
requires an understanding of drug bioavailability. Increased attention has been focused on
drug metabolism and potential interactions at the level of cytochrome P450 (CYP) isozymes,
particularly CYP3A4, which is potentially linked to the metabolism of nearly half of all
pharmaceutical agents. Drugs that are substrates for the same isozyme may competitively
inhibit metabolism, but these interactions are usually not of clinical consequence. Drugs that
directly inhibit CYP isozymes without being a substrate for that isozyme are more likely to
have clinical consequences. These include “azole” drugs and erythromycin. Other drugs act
as inducers of CYP isozymes by increasing gene expression or protein levels, such as
glucocorticoids, barbiturates, and rifampin, which can increase the net activity of CYP3A4,
resulting in decreased concentrations of susceptible compounds. Among the anticancer
agents that are substrates for CYP3A4 are cyclophosphamide, ifosfamide, docetaxel,
etoposide, paclitaxel (also CYP2C8), vincristine, vinblastine, tamoxifen, and gefitinib.
In addition to drug–drug interactions, food can also affect drug absorption and
metabolism. Grapefruit juice, for example, reduces small bowel enterocyte CYP3A4 protein
content. Therefore, after the ingestion of grapefruit juice, drugs that are substrates for
CYP3A4 have decreased first pass metabolism and greater oral bioavailability resulting in
increased serum levels.
Owing to the diversity and rapid adoption of new chemotherapy and nonchemotherapy
compounds, information regarding drug interactions is best obtained from online databases
(www.medicalletter.com; www.micromedex.com; www.druginteractioninfo.org/Home.aspx)
or from the drug manufacturer.
Renal Excretion
The inactivation and excretion of therapeutic agents occur primarily by the liver, kidneys,
and body tissues, with lesser elimination through the stool. Table 1.3 lists drugs that require
modification in the setting of renal or hepatic dysfunction.

TABLE 1.3 Modifications in the Setting of Renal and Hepatic

Dysfunction

While any impairment of normal liver or kidney function can alter drug metabolism and
excretion, the most common problem encountered in the setting of gynecologic cancer is
acute or chronic renal insufficiency due to tumor-mediated obstruction, drug-induced
toxicity, advanced age, or preexisting comorbidities. In addition, serum creatinine levels can
be inappropriately low as a consequence of reduced muscle mass, malnutrition, or alterations
in fluid balance, and any of the standard formulae will overestimate glomerular filtration rate
(GFR). This has potential clinical consequences for drugs such as carboplatin, where dosing
is based on renal clearance.
In most cases, it is sufficient to estimate GFR rather than obtain a precise measurement.
Several methods are available to estimate GFR, but the Cockcroft-Gault is the most
commonly used for drug dose calculation. Formerly, the Jelliffe formula was also commonly
used specifically for gynecologic malignancies (Table 1.4). All of these formulae are based
on stable normalized biologic parameters and are less useful in the setting of dynamic
changes following acute renal injury or nonrenal fluctuations in serum creatinine and fluid
status, such as those that might occur in the postoperative setting or in the presence of large-
volume ascites or in patients with abnormal muscle mass. While urine collection for the
measurement of creatinine clearance might be thought to provide a better estimate of GFR, it
is also subject to great variability in clinical practice. Specific guidelines exist for modifying
drug doses for patients with renal impairment, with special attention to a growing list of
agents with renal-dominant clearance.

TABLE 1.4 Commonly Utilized Formulae to Estimate Creatinine

Clearance (CrCl, mL/min)

Metabolism and Pharmacogenomics

With the expanded knowledge of metabolic pathways and awareness of polymorphisms in
key enzymes, it is sometimes possible to identify individuals with a dramatic increased risk
of toxicity. Table 1.5 shows examples of pharmacogenomic variants affecting chemotherapy
metabolism. Because of the low prevalence and low predictive value (patients without
variants may still experience significant toxicity), testing for these variants prior to initiation
of treatment is controversial and has not been widely adopted.
 Pharmacogenomic Variants Affecting Cytotoxic
TABLE 1.5 Chemotherapy Metabolism

Drug Resistance and Tumor Cell Heterogeneity

Key Points
The emergence of drug resistance limits the curative potential of chemotherapy.
Treatment monitoring often encompasses repeat measurements of tumor sites
identified on imaging. The common standard to interpret tumor measurements on
clinical trial utilizes RECIST criteria.
Chemotherapy can result in significant toxicities. Patient education and provider
knowledge are key to managing the complications of treatment.

The curative potential of systemic therapy is limited by the emergence of drug resistance,
which can be either intrinsic or acquired, and may involve one drug or multiple agents
(pleiotropic resistance). Intrinsic drug resistance is likely due to the clonal selection of tumor
subpopulations that have survived previous chemotherapy exposure or have innate resistance
to chemotherapy. In contrast, acquired drug resistance develops through somatic mutations,
regulation of gene expression, or other phenotypic alterations. Of these, acquired resistance
mechanisms may have a reversible component that could influence the timing and selection
of subsequent chemotherapy.
There are two major patterns of drug resistance in gynecologic oncology: (i) pleiotropic
drug resistance associated with the overexpression of membrane-associated transport
proteins, such as MDR1 (P170 glycoprotein) and (ii) resistance due to reduced cellular
uptake as a result of the loss of membrane transport proteins, increased detoxification of
intermediates by glutathione production, increased damage tolerance due to defective
detection and/or apoptotic signaling, and expanded capacity of DNA repair. These second
mechanisms are predominantly responsible for resistance to alkylating agents, including the
platinum compounds (Table 1.6).

TABLE 1.6 Specific Mechanisms of Tumor Drug Resistance

Monitoring of Tumor Response
Generally accepted criteria for the evaluation of response are necessary to facilitate treatment
decisions and comparisons among different regimens. The Response Evaluation Criteria In
Solid Tumors (RECIST) are the most commonly used criteria in current clinical trials of
chemotherapy and targeted therapy. RECIST 1.1 is based on the prospective designation of at
least one “target lesion” that measures at least 1 cm in one dimension, as well as “nontarget
lesions” that are used to corroborate response (Table 1.7).

TABLE 1.7 Overall Disease Response Categories (RECIST 1.1 and

iRECIST)
The summary response designation within RECIST 1.1 integrates the findings from target
and nontarget lesions, as well as serum tumor markers (if applicable). Serum tumor markers
are not sufficient to declare response but, if initially elevated, must normalize to designate a
complete response. In the case of ovarian cancer, international criteria to declare disease
progression on the basis of a serial elevation in CA-125 have been widely adopted, but there
is incomplete agreement on criteria to define a partial response during treatment.
With the advent of immunotherapy, new response evaluations have been developed. The
novel mechanisms of action of these drugs, with immune and T-cell activation, lead to
unusual patterns of response that may resemble tumor flare but are more pronounced and
occur more frequently than in solid tumors. The iRECIST criteria have been developed for
the evaluation of immune-based therapeutics and are based on the standard RECIST 1.1
criteria but allow for evaluation of unconfirmed progression of disease (or
“pseudoprogression”) prior to disease response.

Management of Toxicity
Key Points
Bone marrow toxicity is the most common serious toxicity of chemotherapy.
 Effective antinausea therapy is critical and should be tailored to the emetogenic
potential of the regimen.
Carboplatin hypersensitivity reactions typically occur with the second dose of the
second course of therapy and may be severe.

Toxicity Assessment, Dose Modification, and Supportive Care

Chemotherapeutic regimens are universally toxic, with a narrow therapeutic index. Initial
dosing is based on body surface area, weight, renal function, and hepatic function. However,
patient tolerance of treatment varies widely, and it is necessary to monitor toxicity with
ongoing modifications to avoid serious acute and cumulative side effects.
The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute has
developed a detailed and comprehensive set of guidelines for the description and grading of
acute and chronic organ-specific toxicities. The current version of the Common Terminology
Criteria for Adverse Events (CTCAE) is available in electronic format from CTEP
(http://ctep.info.nih.gov). Basic hematologic parameters are summarized in Table 1.8.

TABLE 1.8 CTCAE Grading of Myelosuppression

Bone Marrow Toxicity

Bone marrow toxicity is the most common dose-limiting side effect associated with cytotoxic
drugs, and neutropenia is the most common manifestation of bone marrow toxicity, occurring
7 to 14 days after the initial drug treatment and persisting for 3 to 10 days. For purposes of
dose modification, the absolute neutrophil count is preferred to total white blood count.
Dose-limiting thrombocytopenia is less common than neutropenia, but it may be problematic
with carboplatin.
Radiation, alkylating agents (e.g., melphalan and carboplatin), and other DNA-damaging
agents (e.g., nitrosoureas and mitomycin C) can have cumulative long-term effects on the
bone marrow. Most other agents, including the taxanes and topotecan, show no evidence of
cumulative toxicity and can be administered for multiple cycles without any dose
modification.
In view of the frequent occurrence of neutropenia and the risk of infectious
complications, utilization of granulocyte colony–stimulating factors (G-CSF), including
filgrastim or the longer-acting polyethylene glycol (PEG)-filgrastim, has increased.
Guidelines for hematopoietic growth factor use are shown in Table 1.9. Although these
agents promote more rapid granulocyte recovery, avoiding potential complications and
facilitating the maintenance of dose intensity, their use has not been shown to improve long-
term survival for patients with gynecologic cancer, compared to conservative management
with dose reduction and cycle delay. In addition, G-CSF is not effective in the management
of thrombocytopenia and may actually increase the degree of thrombocytopenia by the
diversion of immature marrow elements.

TABLE 1.9 Important Considerations before Using Antineoplastic Drugs

Gastrointestinal Toxicity
There are three major categories of nausea and vomiting: anticipatory, occurring prior to the
actual administration of chemotherapy; acute onset, beginning within 1 hour of
chemotherapy administration and persisting for less than 24 hours; and delayed, beginning
more than 1 day after chemotherapy administration and persisting for several days.
The antiemetic regimen is tailored to the emetogenic potential of the treatment, which
reflects the incorporation of specific drugs, as well as the dose and schedule of drug
administration. Table 1.2 categorizes chemotherapy agents according to their emetic
potential. Mild nausea and vomiting can often be managed effectively with H1 antihistamines
(diphenhydramine), phenothiazines (prochlorperazine or thiethylperazine), steroids
(dexamethasone or methylprednisolone), benzamides (metoclopramide), or benzodiazepines
(lorazepam). For drugs with more severe emetogenic potential, a 5-hydroxytryptamine (5-
HT3) receptor antagonist, such as ondansetron or granisetron, should be given prior to
chemotherapy and repeated at 8- to 12-hour intervals. This may be combined with
dexamethasone or the neurokinin-1 receptor antagonist, aprepitant. Longer-acting 5-HT3
antagonists such as palonosetron are also available, which require only a single dose prior to
chemotherapy. Anticipatory nausea and vomiting can become a significant problem during
repeated cycles of chemotherapy and can sometimes be modulated by pretreatment with
benzodiazepines, such as lorazepam.
Diarrhea, oral stomatitis, esophagitis, and gastroenteritis are also potential problems.
Patients with significant oral or esophagogastric symptoms may have their symptoms
managed with oral viscous lidocaine (2%), other topical anesthetics, or parenteral narcotics in
severe cases. In general, dose-limiting mucosal injury is uncommon with platinum-based
combinations, taxanes, and other single agents used in the treatment of gynecologic cancer.
In refractory cases of mucositis, patients should be screened for secondary infectious
complications, such as candidiasis and herpes simplex.

Alopecia
Scalp alopecia is one of the most emotionally taxing side effects of chemotherapy. Aside
from long-lasting alopecia that follows cranial irradiation, it is almost always reversible, but
it can be a major deterrent to successful chemotherapy. A variety of physical techniques have
been devised to minimize alopecia, including scalp tourniquets and ice caps designed to
decrease scalp blood flow. Although partially effective, they are rarely successful with
extended chemotherapy.

Skin Toxicity
Skin toxicities that occur during chemotherapy include allergic or hypersensitivity reactions
(HSRs), skin hyperpigmentation, photosensitivity, radiation recall reactions, nail
abnormalities, folliculitis, palmar–plantar erythrodysesthesia (PPE, hand–foot syndrome),
and local extravasation necrosis.
PPE is a reversible but painful erythema, scaling, swelling, or ulceration involving the
hands and feet. This occurs more often with regimens such as prolonged oral etoposide,
weekly and continuous-infusion 5-fluorouracil, capecitabine, and PEG-liposomal
doxorubicin, where it has emerged as a major dose-limiting toxicity.
 Extravasation necrosis is a serious complication seen after tissue infiltration of vesicant
drugs such as doxorubicin, and vincristine. These drugs should always be administered
through a freely flowing intravenous line with careful monitoring. Caution is also required
during utilization of central venous ports, as malfunctions in the needle, hub, or tubing can be
associated with gradual extravasation that will not be apparent for several hours. Any
suspected infiltration should prompt immediate removal of the intravenous line and
application of cold packs to the infiltrated area every 6 hours for 3 days. Small series have
reported a limited experience with local infiltration or topical application of steroids, N-
acetylcysteine, dimethyl sulfoxide, and hyaluronidase with variable results, and
recommendations are imprecise. However, single or multiple intravenous doses of
dexrazoxane, a topoisomerase II catalytic inhibitor, appear to offer specific protection against
injury from anthracyclines, including doxorubicin and daunorubicin. Skin necrosis from
some extravasations may eventually require surgical debridement and skin grafting.

Neurotoxicity
Peripheral neuropathy is the most common neurotoxicity encountered in gynecologic
oncology and is a particular risk with the administration of cisplatin and paclitaxel. Although
less common with carboplatin than cisplatin, neuropathy can still occur, particularly in
combination with paclitaxel. Peripheral neuropathy generally begins with symptoms of
paresthesia (numbness and tingling) accompanied by a loss of vibration and proprioception in
longer nerves associated with the feet and hands. It then progresses to functional impairment,
with gait unsteadiness and loss of fine motor coordination, such as trouble buttoning clothes
and writing. In moderate cases with paclitaxel and other nonplatinum agents, this is almost
always reversible but may require several months posttherapy for substantial improvement.
In more severe cases, symptoms may persist for the lifetime of the patient. If related to
cisplatin, neuropathy can continue to progress after therapy has been discontinued, with long-
term persistence of symptoms. Cisplatin has also been associated with permanent ototoxicity
and, at higher doses, with a loss of color vision and autonomic neuropathy.
Patients with underlying neurologic problems, such as diabetes, alcoholism, or carpal
tunnel syndrome, are particularly susceptible to neurotoxicity, and substitution of docetaxel
for paclitaxel can be a useful strategy in some situations. All patients who receive potentially
neurotoxic therapy should be routinely queried regarding symptoms so that severe damage
can be avoided.
There has been an interest in agents that might prevent nerve damage, encourage
recovery, or ameliorate symptoms. However, thus far, studies have been inconclusive.
Clinical management of painful paresthesias has been reported with duloxetine, amitriptyline,
gabapentin, and pregabalin.

Genitourinary Toxicity
Renal toxicity is a well-recognized side effect of cisplatin, even though only a small fraction
of cisplatin is cleared by renal excretion. By contrast, carboplatin undergoes extensive renal
clearance with little risk of toxicity. Careful attention to hydration status and saline-driven
urinary output before, during, and immediately after cisplatin therapy is required to reduce
the risk of renal failure.
Hemorrhagic cystitis can be seen with cyclophosphamide or ifosfamide, attributed to the
metabolite acrolein. With moderate-dose cyclophosphamide, this complication can be
prevented by maintaining a high urinary output, which reduces the overall urothelial
exposure to the toxic metabolites. The risk of cystitis is essentially 100% with ifosfamide
unless there is simultaneous administration of mesna, which binds and neutralizes acrolein in
the urine.

Hypersensitivity Reactions
Paclitaxel is formulated in Cremophor EL, a mixture of polyoxyethylated castor oil and
dehydrated alcohol, which has been associated with mast cell degranulation and clinical
HSR. Over 80% of reactions to paclitaxel occur within minutes during either the first or the
second cycle of drug administration and can usually be managed with prophylactic
medication (corticosteroids, histamine H1/H2 blockade, etc.) followed by rechallenge at a
lower rate of infusion. Similar reactions, albeit at lower frequencies, have been reported with
docetaxel and PEG-liposomal doxorubicin, which are not formulated in Cremophor EL.
Emerging data with nanoparticle albumin-bound (NAB)-paclitaxel indicate a marked
reduction in the risk of HSR.
With improved survival and an increased utilization of second-line therapy, patients can
also experience more traditional allergic reactions to selected chemotherapy agents.
Carboplatin, an organoplatinum compound, has emerged as a major source of late allergic
reactions. These occur most often during the second cycle of a second course of therapy,
suggesting a process of antigen recall and priming of the immune response. Patients
receiving the second course of carboplatin-based therapy should be closely monitored for
early signs of hypersensitivity to avoid more serious reactions. Unlike the situation with
paclitaxel, carboplatin reactions are not readily prevented or circumvented with prophylactic
medication, although inpatient and outpatient strategies for desensitization are successfully
utilized for patients who are responding to re-treatment. However, the desensitization routine
must generally be repeated with each cycle of treatment.

Toxicities of PARP Inhibitors

The most common toxicities seen with PARP inhibitors are fatigue and hematologic toxicities
(anemia in 18% to 25%, neutropenia in 7% to 20%, and thrombocytopenia in 2% to 28%).
There are some variations in other toxicities between the agents currently being used in
ovarian cancer: 9% grade 3 hypertension with niraparib and 5% to 13% grade 3 transaminitis
with rucaparib. In addition, there has been a 0.5% to 1.5% risk of MDS/AML reported with
PARP inhibitors and a less than 1% risk of pneumonitis.

Toxicities of Antiangiogenic Agents (VEGF Inhibitors)

The most common toxicities observed with VEGF inhibitors are hypertension, proteinuria,
and bleeding, which are known side effects of bevacizumab treatment. There are also
increased risks of potentially serious thromboembolic events and gastrointestinal (GI)
complications, namely, bowel perforation and fistula formation, especially in patients with GI
involvement or who have been treated with prior radiation. Medical history of hypertension
is an independent predictive risk factor for the development of high-grade hypertension
during bevacizumab treatment.

Immune Mediated Toxicities

In patients treated with immune checkpoint agents, the most common grade 3 to 4 adverse
events are reported as enterocolitis, dermatitis, hepatitis, neuropathies, endocrinopathies, and
hypophysitis, but any autoimmune process can potentially occur. Significant progress has
been made in standardizing treatment approaches to the unique adverse events common to
checkpoint blockade, and many centers now have immune toxicity specialists to assist with
acute management of these toxicities. In addition, the National Comprehensive Cancer
Network (NCCN) has issued clinical practice guidelines in partnership with the American
Society of Clinical Oncology (ASCO) for management of immunotherapy-related toxicities.
These guidelines can be found at
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf.

Other Significant Toxicities

These include cardiac toxicity from cumulative doxorubicin exposure, radiation recall
vasculitis from doxorubicin, pulmonary fibrosis from bleomycin, gonadal dysfunction in
premenopausal women from alkylating agents, and secondary acute leukemia from the
chronic administration of alkylating agents, particularly melphalan in ovarian cancer.

Suggested Readings
Chu E, DeVita VT. Physicians’ Cancer Chemotherapy Drug Manual 2019. Burlington, MA: Jones & Bartlett Learning;
2018.
FIGO Cancer Report 2018. Int J Gynecol Obstet. 2018;143(2):1–158.
Khalique S, Hook JM, Ledermann JA. Maintenance therapy in ovarian cancer. Curr Opin Oncol. 2014;26(5):521–528.
Lee CW, Matulonis UA, Castells MC. Rapid inpatient/outpatient desensitization for chemotherapy hypersensitivity:
Standard protocol effective in 57 patients for 255 courses. Gynecol Oncol. 2005;99:393–399.
Li YF, Fu S, Hu W, et al. Systemic anticancer therapy in gynecological cancer patients with renal dysfunction. Int J Gynecol
Cancer. 2007;17:739–763.
Markman M. Intraperitoneal antineoplastic drug delivery: Rationale and results. Lancet Oncol. 2003;4:277–283.
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors.
European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National
Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216.
 2 Biologic and Physical Aspects of
Radiation Oncology

Introduction to Radiobiology
Key Points
The clinical utility of ionizing radiation (IR) is based on a therapeutic ratio that is
present given that IR’s ability to destroy targeted tumor tissue is greater than its
toxicity to surrounding normal tissues.
IR exerts its deleterious effects by creating free radicals that cause lethal DNA
damage, although hypofractionated regimens may exert additional biologic effects
via endothelial cell damage and enhanced antitumor immunity.
The four classic factors termed the “4 Rs” of radiobiology, (i) repair, (ii)
repopulation, (iii) reassortment, and (iv) reoxygenation, provide a rationale and
framework for the fundamental basis of using fractionated radiotherapy.

Radiobiology is the study of how ionizing radiation (IR) interacts with living things. In the
delivery of IR to target tumor tissue, normal tissues within the radiation field may also be
affected. The size, location, and histology of the tumor, as well as surrounding normal
tissues, must be considered in the determination of total dose and dose per fraction that will
be delivered to optimize tumor eradication while minimizing risk of injury to surrounding
normal tissues.

Dose–Response Relationship and the Therapeutic Ratio of IR

The dose–response relationship of IR on tumor and normal tissues can be depicted as a pair
of sigmoidal curves. At low doses of IR, there is little effect on tumor control as well as low
risk for normal tissue complications. Both tumor control and normal tissue complications
increase with higher doses of IR. For a given dose of IR, however, the probability of tumor
kill is greater than the probability of normal tissue damage, and the dose–response curve of
tumor control is shifted to the left of the normal tissue complication curve (Fig. 2.1). It is in
this dose range that the therapeutic ratio of IR can be exploited to control tumor with an
acceptable toxicity profile. Radiosensitizing drugs that preferentially radiosensitive tumors
may be used to shift the tumor control curve further to the left and potentially widen the
therapeutic radio of IR. Conversely, radioprotectors may be used to shift the normal tissue
complication curve to the right.
FIGURE 2.1 Theoretic curves for tumor control and complications as a function
of radiation dose both with and without chemotherapy. TR, therapeutic ratio, or
the difference between tumor control and complication frequency. Source: Perez
CA, Thomas PRM. Radiation therapy: Basic concepts and clinical implications.
In: Sutow WW, Fernbach DJ, Vietti TJ, eds. Clinical Pediatric Oncology, 3rd ed.
St. Louis, MO: Mosby; 1984:167.

Interaction of IR with Tissue and Cell Death

Radiation is considered ionizing if it deposits sufficient energy into tissue to eject electrons
from atoms and generate ions. The Compton process is the dominant interaction at the high
energies of IR used in radiation therapy (RT). In the Compton process, IR transfers its energy
to outer shell electrons and causes their ejection. These liberated electrons serve as the main
mediators of IR-induced tissue damage through their interaction with intracellular water and
generation of hydroxyl radicals. The indirect effect of creating highly reactive hydroxyl
radicals is what ultimately causes oxidative stress and DNA damage. For conventionally
fractionated IR doses, DNA is the major target of IR-generated free radicals. Free radical
damage to DNA may result in cross-links, base damage, single-strand breaks, and double-
strand breaks (DSBs). DSBs can result in chromosomal and chromatid aberrations that if not
fixed by the cell may result in mitotic catastrophe, the predominant mechanism of cell death
whereby cells die as a result of trying to replicate. Other mechanisms of cell death following
irradiation include apoptosis (programmed cell death), autophagy, or replicative senescence
whereby cells permanently exit the cell cycle.
When a high dose of radiation is given in a single fraction, such as for stereotactic
radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), lethal DNA damage may
not be the only resulting biologic effect. Other proposed effects include radiation-induced
damage to tumor microvasculature, apoptosis of irradiated endothelial cells, or enhancement
of antitumor immunity. These additional mechanisms of action may explain the excellent
clinical outcomes seen with SRS and SBRT.

Cell Survival Curves and Tumor Control Probability

The gold-standard technique used to measure IR-induced cell kill is the clonogenic assay
(Fig. 2.2). This assay measures cell death through mitotic catastrophe following exposure to
different IR doses. An aliquot with a known quantity of cells is plated on growth media and
allowed to incubate. The number of colonies formed is determined and used to calculate a
plating efficiency, as not all cells may successfully replicate. The experiment is repeated, but
prior to incubation the cells are irradiated. The number of colonies formed divided by the
starting number of cells and again divided by the plating efficiency is used to determine the
ratio of surviving cells as a result of a given IR dose. The experiment is repeated over a range
of doses and yields a cell survival curve that models cell survival (on a logarithmic scale on
the y-axis) as a function of radiation dose.
FIGURE 2.2 Clonogenic survival curves. A: Clonogenic survival assay to
determine plating efficiency and surviving fraction with different IR doses. B:
The surviving fraction is the plotted logarithmically on the y-axis and the
corresponding IR dose is plotted linearly on the x-axis. Source: From Chi D,
Berchuk A, Dizon DS, Yashar CM, eds. Principles and Practice of Gynecologic
Oncology, 7th ed. Philadelphia, PA: Wolters Kluwer; 2017.

The log cell kill model describes cell kill in the simplest terms and highlights the logarithmic
nature of fractionated radiation cell kill. A typical course of RT is given in 10 to 40 fractions
administered over 2 to 8 weeks. With each fraction of treatment, a fixed percentage of cells
will be killed. The D0 is the dose of radiation where 1/e (37%) of cells survive or 63% of
cells are killed. For most tumors, the D0 is estimated to be 1 to 2 Gy, and therefore in
fractionated external beam radiation, we typically deliver 1.8 to 2 Gy with each fraction. The
dose to kill 90% of cells is called the D10 and is related to D0 by the following formula: D10 =
2.3 × D0. A tumor with 109 cells will require 10 decades of cell kill for a 90% chance of
tumor control (10 decades of kill × D10 = total dose for 90% tumor control).
The shape of the cell survival curve is best described by the linear– quadratic model with
DNA as the lethal target (Fig. 2.3). Radiation exerts most of its deleterious effects by causing
breaks in two chromosomes. The linear component of cell kill (also known as α kill) is due to
two breaks caused by a single ejected electron. Cell kill is proportional to dose (D) and is
dominant at lower doses. Cell kill may also occur as a result of two separate chromosome
breaks due to two separate ejected Compton electrons (β kill). This is dominant at higher
doses accounting for the quadratic portion of the survival curve where cell kill is proportional
to D2. Because β kill results from two separate hits, it is more easily repaired.

FIGURE 2.3 Cell killing by radiation is largely due to aberrations caused by

breaks in two chromosomes. The dose–response curve for HDR irradiation is
linear quadratic: the two breaks may be caused by the same electron (dominant at
low doses) or by two different electrons (dominant at higher doses). For LDR
irradiation, where radiation is delivered over a protracted period, the principal
mechanism of cell killing is by the single electron. Source: From Chi D,
Berchuk A, Dizon DS, Yashar CM, eds. Principles and Practice of Gynecologic
Oncology, 7th ed. Philadelphia, PA: Wolters Kluwer; 2017.
Biologically Equivalent Dose
Both the total dose of radiation and how fast it is delivered can produce very different
outcomes. The same holds true for fractionated courses of radiation. The linear–quadratic
equation can be used to derive an equation to be used as a guide to predict various biologic
endpoints and is given by the following equation:

BED is the biologically equivalent dose, D is the total dose, d is the dose per fraction, and α/β
is the dose where the alpha component of cell kill equals the beta component. These formulae
are useful for conversion between different fractionation schemes: between standard and
hypofractionation or between high-dose rate (HDR) and low-dose rate (LDR). This
conversion is important so that doses can be compared between regimens.

Factors Influencing Tissue Sensitivity to Radiation Therapy

The clinical utility of RT is dependent on how tumor and normal tissues differentially interact
with IR. There are four classic factors termed the “4 Rs” of radiobiology, (i) repair, (ii)
repopulation, (iii) reassortment, and (iv) reoxygenation, that form the basis of using
fractionated radiotherapy to exploit the therapeutic ratio of IR.

Repair
Radiobiologically, tumor and normal tissues have a differential capacity for DNA damage
repair that can be exploited to widen the therapeutic ratio of IR. A consequence of genomic
instability within cancer cells is decreased DNA damage repair capacity compared to normal
tissues. Following higher doses of IR, the repair processes in response to DNA damage are
overwhelmed and cell death occurs in an exponential manner. However, at low doses of
fractionated IR, normal tissue cells are able to repair DNA damage more effectively than
cancer cells in the hours prior to delivery of the next fraction of IR (Fig. 2.4). This sublethal
damage repair is reflected in the “shoulder” region of the survival curve and is often wider in
normal tissues than for cancer cells. The dose range of IR within the shoulder region is often
within the clinically relevant doses of D0. By fractionating radiation treatments, the shoulder
of the cell survival curve is repeated, and by doing this, we are able to amplify the ability of
normal tissue to repair and tolerate IR damage while tumor cells are preferentially killed.
FIGURE 2.4 Difference in cell survival curves for acute and late radiation
effects with single or multifractionated doses of irradiation.

Repopulation
The time allotted for repair also needs to be balanced against the concept of tumor
repopulation. Following exposure to IR, tumors may undergo accelerated repopulation in
response to stress. Avoidance of treatment breaks is paramount to optimize patient outcomes.
Clinical data for cervical cancer has shown that prolonged treatment package time greater
than 8 weeks negatively impacts pelvic disease control.

Reassortment
The cell cycle is an ordered set of events that results in cell growth and division into two
daughter cells. The steps are G1–S–G2–M. G1 stands for “GAP 1,” and S phase stands for
“synthesis” and is the point at which DNA replication occurs. The intrinsic sensitivity to IR
varies throughout the cell cycle. Late S phase is the most radioresistant phase of the cell cycle
since the DNA repair machinery for replication can also repair radiation damage. The G2
stage stands for “GAP 2,” and M phase stands for “mitosis” and is when nuclear division
occurs. M phase is the most radiosensitive phase of the cell cycle and is an important reason
why rapidly dividing cells such as cancers are radiosensitive. Fractionation of IR over
multiple days will allow different populations of tumor cells to be in G2–M radiosensitive
phase during exposure to IR. Furthermore, IR-induced DNA damage will activate cell cycle
checkpoints, namely, the G2–M checkpoint, that will stall a fraction of cells in a
radiosensitive phase of the cell cycle.

Reoxygenation
Oxygen alters sensitivity to IR as it is known to chemically modify and fix radiation-induced
DNA damage, making it irreparable. This is known as the oxygen fixation hypothesis.
Therefore, under anoxic conditions, DNA damage repair would be expected to increase
considerably and make cells relatively resistant to IR. Tumor hypoxia can be categorized as
either acute or chronic. Acute hypoxia due to temporary vasospasms and malformed tumor
vasculature may fluctuate day to day throughout a course of fractionated radiation. Chronic
hypoxia due to limits in the physical distance oxygen is able to diffuse over makes tumor
cells further from central vasculature relatively resistant to IR.

Introduction to Radiation Physics

Key Points
The most common forms of radiation used in radiation therapy are photons (x-
and γ-rays) and electrons.
X- and γ-rays differ in their source of production: x-rays are artificially produced,
whereas γ-rays arise through the natural process of radioactive decay within the
nucleus of an atom.
Exposure is the amount of ionization produced in air by photons, and its unit is
roentgen (R).
Radiation deposits energy in tissue by transferring energy from photons to ionized
particles, which in turn transfer energy to the medium (usually tissue). The SI unit
for absorbed dose is the gray (Gy).

Radiation physics is the study of the interaction of radiation with matter. In the treatment of
patients with radiation, this matter is either tumor tissue or normal tissues.

Common Forms of Radiation Used in Radiation Therapy

Radiation is a term that refers to “energy in transit.” Specifically, radiation of sufficient
energy to cause ionization of the atoms that it interacts with, called IR, is used for RT. IR
used in RT comes in many forms including x-rays, γ-rays, neutrons, electrons, and protons.
X- and γ-rays are forms of electromagnetic radiation similar to visible light and are also
known as photons. They travel with a much shorter wavelength than visible light, that is,
with greater energy. The difference between x- and γ-rays is only their respective origins.
Modern radiotherapy treatment machines termed linear accelerators or LINACs create x-rays
artificially by bombarding an atom or tungsten target with high-speed electrons. LINACs can
produce both photon and electron beams of different energies depending on their
construction. There is an increased penetration as the energy of x- or γ-rays is increased. The
x-rays produced by LINACs are much more penetrating than cobalt (60Co) γ-rays. While x-
rays are artificially produced, γ-rays arise through the natural process of radioactive decay
within the nucleus of an atom. These radioactive isotopes can occur naturally or be created
artificially. Examples include the brachytherapy sources cesium (137Cs) and iridium (192Ir) as
well as cobalt (60Co) teletherapy treatment machines.
Electrons are negatively charged particles and will usually only penetrate a few
millimeters to centimeters in tissue. Similar to photons, the higher the energy of the electron,
the farther it will penetrate into the tissue. However, unlike photons, the skin dose increases
with increasing energies rather than decreases. Electrons are used to treat tumors or tissues
close to the skin surface such as superficial inguinal nodes and tumors of the skin, including
vulvar cancers.
Protons and other heavy charged particles such as neutrons with a high linear energy
transfer coefficient when compared to high-energy photons are more efficient at transferring
and depositing their energy in tissue. Protons are positively charged particles that have a
characteristic Bragg peak that describes the depth at which the majority of a proton’s energy
is deposited. Prior to the depth of the Bragg peak, only a very small amount of energy is
deposited. Furthermore, the width of the treatment dose depth may be finely controlled,
making protons an attractive option for tumors adjacent to critical structures.

Units Used in Radiation and Radiation Therapy

Exposure is the amount of ionization produced in air by photons, and its unit is the roentgen
(R). The SI unit for exposure is coulomb per kilogram (C/kg) with 1 R = 2.58 × 10−4 C/kg
air. Kerma is the kinetic energy release per unit mass and defines the transfer of energy from
photons to directly ionized particles. These directly ionized particles, in turn, transfer some of
their energy to the medium (usually tissue). This transfer of energy is defined as the absorbed
dose to the medium from the radiation beam. The SI unit for kerma is joule per kilogram
(J/kg) or gray (Gy). The SI unit for absorbed dose is also joule per kilogram or gray, which
has replaced the previously used term “rad.” Often, the term centigray (cGy) is used. The
cGy is equivalent to the rad, and 1 gray equals 100 cGy. Table 2.1 lists some basic units of
radiation and RT, both in historic context and in terms of modern SI units.

TABLE 2.1 SI Units for Radiation Therapy

Radioactive Isotopes
As mentioned before, γ-rays are typically derived from radioactive isotopes, for example,
60Co. Electrons or beta particles also come from radioactive isotopes. Radioactivity is the

result of an atom changing its “energy” state, usually to a lower “energy” state, by the
emission/absorption/internal conversion of photons or electrons in the atom. Table 2.2 lists
many of the more common radioactive isotopes and their physical properties. Use of radium
226 (226Ra) sources is now historic.

TABLE 2.2 Physical Properties and Uses of Brachytherapy Radionuclides

Radioactivity, or activity, is denoted by the symbol, A, and is defined as the number of
disintegrations per unit of time. The equation describing radioactive decay is A = Aoe−λt,
where Ao is the initial activity, λ is the decay constant, and t is some unit of time later. Other
important units for radioactivity and radioactive decay are the half-life (T1/2) and the average
life (Ta). The half-life is the amount of time necessary to reduce the original amount of
material by half. T1/2 is related to the decay constant by T1/2 = 0.693/λ. Ta is related to the
decay constant and the half-life by Ta = 1/λ = 1.44 T1/2. Cesium 137 (137Cs) has replaced
radium as a safer, equally effective radioisotope. It is typically used for LDR gynecologic
brachytherapy in tandem and ovoid and cylinder applicators. Iridium 192 (192Ir) comes in
various activities and can be used for interstitial and intracavitary gynecologic implants. It is
the primary isotope for HDR applications.

Radiation Production
Key Points
Intensity-modulated radiation therapy (IMRT) is accomplished by using small
computer-controlled leaves in the head of the machine (multileaf collimators or
MLCs) to block the beam in different patterns, modulating beam intensity and
creating multiple complex treatment fields. The result is improved target coverage
and increased sparing of normal tissues.
Image-guided radiation therapy (IGRT) refers to the imaging of treatment fields
prior to treatment delivery in order to precisely align the patient and improve
treatment accuracy.

Linear Accelerators
LINACs produce radiation by accelerating an initial beam of electrons across a variable
electric field. This electron beam can be adjusted to control its shape and intensity before
delivery to the patient. Alternatively, the electron beam can be directed to a tungsten target.
The electron–target interaction creates a forward scattered photon beam or x-ray. The
resulting photon beam can then be modified by the machine using filters and collimators to
produce the desired radiation field shape.
Photon beams of different energies have a different absorbed dose pattern within tissues.
This pattern is normally characterized as a percent depth dose or variation of dose as a
function of depth within tissue. The higher-energy photons deposit dose at greater depths,
and less dose is deposited at shallow depths. This is called “skin sparing” and is a
characteristic of high-energy photons. Modern LINACs come equipped with multileaf
collimators (MLCs) and asymmetric jaws to control the shape of the radiation beam directed
before it reaches the patient. MLCs are small (projected size at the patient approximately 1
cm), adjustable collimators built into the LINAC gantry that work together to create a shaped
opening mimicking the effects of a poured block. With the advent of computer-controlled
motion of the MLCs, the radiation field can be controlled to produce an intensity-modulated
radiation therapy (IMRT) treatment. In IMRT, the MLCs are used to create many small fields
of radiation within a larger treatment field. This adaptability allows the radiation treatment
planner to create and deliver very complex treatment fields that improve target coverage
while attempting to spare normal tissues.
IMRT for gynecologic cancers has been shown to significantly reduce toxicity compared
to standard 3D-conformal RT. The phase III RTOG 1203 trial compared patient-reported
acute gastrointestinal (GI) and urinary toxicity and health-related quality of life in women
with cervical and endometrial cancer treated with either IMRT or standard four-field RT.
Between baseline and end of RT, the mean EPIC bowel scores and urinary scores declined
less in patients who received IMRT (23.6 vs. 18.6 points, p = 0.048 and 10.4 vs. 5.6 points, p
= 0.03, respectively). Women who received IMRT were less likely to report frequent or
almost constant diarrhea at the end of RT (33.7% vs. 51.9%, p = 0.01) and were less likely to
be taking antidiarrheal medications four or more times daily (7.8% vs. 20.4%, p = 0.04).
Figure 2.5 shows a side-by-side comparison of IMRT and conventional four-field pelvic
irradiation plans.

FIGURE 2.5 Intensity-modulated radiotherapy (IMRT) and four-field (4-F)

plans for (A) a large involved uterus and (B) a small uninvolved uterus. Source:
From Forrest J, Presutti J, Davidson M, et al. A dosimetric planning study
comparing intensity-modulated radiotherapy with four-field conformal pelvic
radiotherapy for the definitive treatment of cervical carcinoma. Clin Oncol.
2012:24:e63–e70, with permission from Elsevier.

Due to the highly precise and conformal nature of IMRT delivery, organ and tissue
motion is a significant concern and potential obstacle to the widespread implementation of
IMRT for gynecologic cancers. The Radiation Therapy Oncology Group (RTOG) has
published guidelines for the delineation of target volumes and normal structures, margin size,
and dose–volume constraints in the postoperative setting for both early-stage cervical and
endometrial cancers. The RTOG (Lim et al.) has also developed an MRI atlas to improve
target volume delineation for the intact cervix when treating with IMRT. Gaffney et al. have
also published an atlas for the contouring of the vulva and inguinal regions for radiotherapy
in both the definitive and postoperative settings for locally advanced vulvar cancers.
A relatively new and increasingly relevant technology in RT is image-guided radiation
therapy (IGRT). Modern LINACs have added onboard imaging that allows the treatment
fields to be recorded electronically at every treatment setup using an electronic portal
imaging device. By comparing computer-generated radiographs (DRRs or digitally
reconstructed radiographs) with the actual patient images, discrepancies in field shape and
patient setup can be corrected before the delivered treatment. This type of corrective behavior
before treatment is the foundation of IGRT. The latest variations on IGRT are the addition of
computed tomography (CT) scanners or magnetic resonance imagers within the LINAC to
verify more completely the correct alignment of the patient on the treatment table prior to
treatment. This may be particularly helpful in the management of intact cervical cancer given
the significant uterine and cervical interfraction motion and tumor regression that can be
observed.

Computerized Dosimetry
In a modern radiotherapy department, computers are necessary to accurately calculate the
absorbed doses to tissues. These absorbed doses within tissues are termed isodoses or lines of
the same dose. To initiate this process, CT images are acquired of the area of interest at a
pretreatment planning session or simulation. These scans are typically obtained on the CT
simulator. Treatment targets such as pelvic lymph nodes, the uterus, or the vagina are
identified through contouring on these images, as are normal tissues such as the
rectosigmoid, bladder, or small bowel. Dose goals are identified for the targets and normal
tissues. A dosimetrist uses this information to design the radiation treatment plan, which is
reviewed by the treating physician and a physicist. The goal of treatment planning is to treat
the target to a specified dose while minimizing dose to adjacent normal tissues.
Figure 2.6 illustrates the gross tumor volume (GTV), the clinical tumor volume (CTV),
the planning target volume (PTV), and the treated volume. The CTV includes all of the GTV
plus possible microscopic extensions. An internal target volume (ITV) may also be used for
the primary target (i.e., uterus/cervix in the definitive setting for cervical cancer or the vagina
and paravaginal tissues in the postoperative setting). This is created by simulating a patient
with a full bladder and then subsequently with an empty bladder and contouring a CTV target
on each scan followed by booleaning the two volumes together to create the ITV. The PTV
includes all of the CTV plus a margin to account for possible geometric uncertainties of the
patient or treatment margin. The irradiated volume includes all of the PTV plus any margins
that might be included in the treatment plan to provide minimum dose coverage to the PTV.

FIGURE 2.6 Schematic representation of “volumes” in radiation therapy. The

treatment portal volume includes the GTV, potential areas of local and regional
microscopic disease around the tumor (clinical), and a margin of surrounding
normal tissue (planning). Source: From Perez CA, Purdy JA. Rationale for
treatment planning in radiation therapy. In: Levitt SH, Khan FM, Potish RA, eds.
Levitt and Tapley’s Technological Basis of Radiation Therapy: Practical and
Clinical Applications, 2nd ed. Philadelphia, PA: Lea & Febiger; 1992. Modified
in Perez CA, Brady LW, Roti JL. Overview. In: Perez CA, Brady LW, eds.
Principles and Practice of Radiation Oncology, 3rd ed. Philadelphia, PA:
Lippincott-Raven Publishers; 1998:1, with permission.

Brachytherapy Principles
Key Points
Brachytherapy delivers a concentrated dose of radiation to immediately adjacent
tissues by implanting temporary or permanent radioactive sources within a
patient.
In gynecologic malignancies, temporary implants are used most frequently and
are categorized as interstitial (sources are directly inserted into tumor-bearing
tissues) or intracavitary (sources are placed into naturally occurring body cavities
or orifices such as the vagina or uterus).
Dose rate is the amount of dose delivered over an interval of time. LDR is defined
as 40 to 100 cGy per hour. HDR is defined as 20 to 250 cGy per minute.

Brachytherapy is a term with Greek roots where “brachy” means “short distance.” With
brachytherapy, a highly concentrated dose of radiation is delivered to immediately
surrounding tissues within millimeters to several centimeters of the applicators that carry the
radioactive sources. This allows for a high dose of radiation to be delivered to the tumor
while relatively sparing nearby normal tissues such as the rectosigmoid, bladder, and small
bowel.
There are different types of brachytherapy or radioactive implants. For gynecologic
carcinomas, temporary implants are used most frequently and are categorized as interstitial or
intracavitary. With interstitial brachytherapy, the radioactive sources are transiently inserted
into tumor-bearing tissues directly through placement in hollow needles or tubes. With
intracavitary brachytherapy, radioactive sources are placed into naturally occurring body
cavities or orifices such as the vagina or uterus using commercially available hollow
applicators such as a vaginal cylinder or tandem and ovoids. Permanent interstitial implants
entail the insertion of radioactive seeds (iodine 125 [125I], gold 198 [198Au], and palladium
103 [103Pd]) directly into tumor-bearing tissues to emit radiation continuously as they decay
to a nonradioactive form.
Dose rate is also an important variable in brachytherapy. Traditional LDR irradiation has
been used for decades in gynecologic cancers using 226Ra and 137Cs sources for intracavitary
insertions and low-activity 192Ir sources for interstitial insertions. HDR brachytherapy has
gradually been introduced over the last several decades and entails the use of a highly
radioactive (10-Ci) 192Ir source. Standard ranges for LDR are 40 to 100 cGy per hour and for
HDR 20 to 250 cGy per minute (1,200 to 15,000 cGy per hour). Pulsed dose rate uses a
medium-strength 192Ir source of 0.5 to 1.0 Ci with dose rates of up to 3 Gy per hour and
delivers the treatment in a “pulsed” method over only 10 to 30 minutes of each hour as
opposed to LDR techniques, which deliver 30 to 100 cGy per hour continuously over several
days. PDR was developed to combine the isodose optimization of HDR brachytherapy with
the biologic advantages of LDR. HDR techniques, however, have gained increasing
acceptance due to several inherent advantages. Given the shortened treatment time, there is a
greater degree of certainty that applicator displacement as a function of time will be
decreased. New systems allow more flexibility for dose optimization and improved dose
distributions that may better spare normal tissues. Lastly, because HDR is delivered over a
few fractions, the interval of time between fractions may theoretically allow for
reoxygenation of hypoxic cells and is a potential radiobiologic advantage.
The term “afterloading” refers to an unloaded applicator that has radioactive sources
introduced after insertion was popularized by Henschke. Nearly all modern brachytherapy
programs exploit afterloading. This sequence allows for more careful and accurate applicator
placement than earlier “hot-loaded” applicators that were placed in the operating room
preloaded with radium. Remote afterloading, which eliminates all personnel exposure, entails
the use of a computer-driven machine to insert and retract the source(s), which are attached
to a cable.

Clinical Applications of Brachytherapy

Key Points
Patterns of Care Studies have revealed that brachytherapy is the single most
important treatment factor for locally advanced cervical cancer with respect to
survival and pelvic control.
The Manchester system approach for prescribing brachytherapy dose relied on
predetermined doses and dose rates directed to fixed points in the pelvis such as
points A and B.
Although prescription to point A has been used historically, CT or MR image-
guided brachytherapy with dose prescribed to a high-risk clinical target volume
has come into favor.

Brachytherapy Systems for the Treatment of Cervical Cancer

Brachytherapy is essential in the treatment of many gynecologic cancers. When curative
treatment is planned, patients with cervical carcinoma treated with definitive irradiation
should receive a combination of external beam irradiation and brachytherapy. Even with
IMRT and the ability to customize and escalate dose to specific volumes, brachytherapy
cannot be replaced. The efficacy of brachytherapy is attributable to the ability of radioactive
implants to deliver a higher concentrated radiation dose to tumor “inside out” due to the close
proximity of the radioactive source(s) to the tumor. Intracavitary brachytherapy for cervical
carcinoma was profoundly impacted by the development of various “systems” that attempted
to combine empiricism with a more scientific and systematic approach. Three systems
developed in Europe, including the Paris system, the Stockholm system, and the Manchester
system, are an integral part of modern brachytherapy.

The Manchester System

The Manchester system standardized treatment with predetermined doses and dose rates
directed to fixed points in the pelvis. The fixed points A and B were selected on the theory
that the dose in the paracervical triangle impacted normal tissue tolerance rather than the
actual doses to the bladder, rectum, and vagina. The paracervical triangle was described as a
pyramidal-shaped area with its base resting on the lateral vaginal fornices and its apex
curving around with the anteverted uterus. “Point A” was defined as 2 cm lateral to the
central canal of the uterus and 2 cm from the mucous membrane of the lateral fornix in the
axis of the uterus (Fig. 2.7). It often correlates anatomically with the point of crossage of the
ureter and uterine artery and was taken as an average point from which to assess dose in the
paracervical region. “Point B” was located 5 cm from midline at the level of point A and was
thought to correspond to the location of the obturator lymph nodes. To achieve consistent
dose rates, a set of strict rules dictating the relationship, position, and activity of radium
sources in the uterine and vaginal applicators was devised. The amount of radium would vary
based on ovoid size and uterine length such that the same dose would be delivered to point A
regardless of patient and tumor factors. The amount of radium per ovoid varied by size so as
to obtain a uniform dose rate at the ovoid surface. Vaginal packing was used to limit the
bladder and rectum dose to less than 80% of point A. External beam irradiation with a
midline block in place was later used to deliver a cumulative dose of 6,000 R to point B.
FIGURE 2.7 The Manchester system. Definitions of points A and B in the
classical Manchester system are found in the text. In a typical application, the
loading of intrauterine applicators varied between 20 and 35 mg of radium and
between 15 and 25 mg of radium for each vaginal ovoid. The resultant treatment
time to get 8,000 R at point A was 140 hours. Source: From Meredith WJ.
Radium Dosage: The Manchester System. Edinburgh, UK: Livingstone; 1967,
with permission.

The Manchester system is the basis for contemporary intracavitary techniques and dose
specification. With current LDR applications using cesium rather than radium, it is
considered standard to have a point A dose rate of 50 to 60 cGy per hour and to deliver a total
dose of 85 Gy to point A and 60 Gy to point B when combined with external beam therapy
while limited the normal tissues to less than 80% of point A dose.

The Fletcher (M.D. Anderson) System

The Fletcher system was established at M.D. Anderson Hospital in the 1940s. The Fletcher
applicator was subsequently developed and remains an integral part of gynecologic
brachytherapy. The Fletcher system combined many elements of the Paris and Manchester
system including using the largest sized ovoid possible, positioned as far laterally and
cephalad as possible, to deliver the highest tumor dose at depth for a given mucosal dose.
The Fletcher colpostats were in fact a further evolution of the Manchester ovoids. They were
made with the same diameters of 2, 2.5, and 3 cm but were more cylindrical than Manchester
“ovoids” and were attached to handles with shielding in the direction of the bladder and
rectum. Initially, these were preloaded with radium, but later an afterloading model was
developed and loaded instead with 137Cs. Recommended loadings were 15, 20, and 25 mg of
radium for the 2-, 2.5-, and 3-cm colpostats, respectively, and 5 to 10 mg for the mini-ovoids.
Recommended tandem loadings were usually 15–10–10 mg of radium with the amount of
radium in the tandem usually greater than that in the ovoids.
On review of implant films, it was recommended to keep the tandem in the axis of the
pelvis, equidistant from the sacral promontory and pubis and the lateral pelvic walls, to avoid
overdosage to the bladder, sigmoid, or one ureter. The tandem was recommended to bisect
the ovoids on the AP films and bisect their height on lateral films. The flange of the tandem
was to be flush against the cervix and the ovoids surrounding it, verified by confirming the
proximity of the applicators to the radiopaque cervical seeds. Vaginal packing was used to
hold the system in place and to displace the bladder and rectum.
The M.D. Anderson approach to treatment specification reflects a policy of treating
advanced cervical carcinoma to normal tissue tolerance. This includes integrating standard
loadings and mg-hours with calculated doses to the bladder, rectum, sigmoid, and vaginal
surface. The activity in the ovoids is limited by the vaginal surface dose, which is kept below
140 Gy. The calculated bladder and rectal doses are noted and are sometimes used to limit the
duration of the intracavitary system, with the combined external beam and implant doses for
the bladder kept at less than 75 to 80 Gy and for the rectum at less than 70 to 75 Gy. Mg-Ra-
eq hours are usually limited to 6,000 to 6,500 after 40 to 45 Gy external beam. In a
retrospective review of cervical cancer patients treated definitively at M.D. Anderson, the
median total dose to point A from external beam and intracavitary irradiation was 87 Gy, and
the median doses to the bladder and rectum were 68 and 70 Gy. The total dose delivered to
the vaginal surface was limited to 120 to 140 Gy or 1.4 to 2.0 times the point A dose. These
total doses to point A and the vagina, bladder, and rectum are used as contemporary
guidelines for determining implant duration and therefore dose.

Limitations of Point A
The failure of localization radiographs to show the surface of the ovoids made
implementation of the initial definition of point A difficult. Therefore, the definition of point
A was modified in 1953 to be “2 cm up from the lower end of the intrauterine source and 2
cm laterally in the plane of the uterus,” as the external os was assumed to be at the level of
the vaginal fornices. This definition, however, becomes problematic when the cervix
protrudes between the ovoids. This causes a resultant increase in dose rate at point A because
point A lies in the higher-dose “bulge” around the ovoids. The variation of point A often
occurs in a high-gradient region of the isodose distribution. A consistent location for dose
specification should fall sufficiently superior to the ovoids where the dose distribution runs
parallel to the tandem. In patients with deep vaginal fornices, reverting to use of the ovoid
surface rather than the exocervix can help to solve this problem. It has therefore become clear
over time that points A and B are not anatomic sites. Point A does not maintain a constant
relationship to tumor or normal tissue anatomy and is present in a steep dose gradient that is
sensitive to displacement.

Contemporary Dose Specification for Cervical Cancer

2D orthogonal film-based dose distribution analysis, in which single or multiple reference
points are chosen on films at the interface of the organs closest to the applicators, is
inadequate for gynecologic brachytherapy. Tumor reference points such as point A do not
give sufficient information about the dose distribution throughout the tumor volume or within
organs at risk (OARs) such as the bladder and rectosigmoid. Additionally, there is no
recognition of the volume of tumor and normal tissues receiving these doses.
With the advent of MRI- and CT-compatible applicators, and the presence of CT and MR
simulators in radiation oncology, 3D image-guided brachytherapy is becoming the standard.
Image-based brachytherapy entails defining both the disease and the OARs and then shaping
the dose distribution to optimally cover disease and exclude the normal tissues. Directly
relating the intracavitary system to the anatomy through use of CT and MRI is the next step
in the lineage of dosimetric systems.
While CT is excellent for delineating normal pelvic organs, it is unable to clearly define
tumor in the cervix or vagina. The value of MR in the imaging of gynecologic cancers lies in
its multiplanar capability and superior soft tissue resolution compared to CT, enabling
delineation of tumor within the cervix, uterus, and vagina as well as within the parametrial
and vaginal tissues. Tumors of the cervix display moderately increased signal on T2-
weighted images relative to normal cervical stroma, permitting more accurate delineation of
tumor volume. This is an advantage during brachytherapy, as one can assess the proximity of
the tumor to the applicator and the subsequent dose distribution throughout the tumor volume
while limiting dose to the adjacent normal OARs.
The Gynecologic GEC-ESTRO working group developed guidelines for recording and
reporting 3D image-based treatment planning for cervical cancer brachytherapy. They
describe a methodology using MRI at the time of brachytherapy to define the GTV and CTV.
The GTV at the time of brachytherapy is defined as residual tumor following external beam
radiation on clinical examination, as well as the high-signal regions on T2 fast–spin-echo
(FSE) images in the cervix and paracervical tissues. The high-risk clinical target volume
(HR-CTV) includes GTV as well as the entire cervix and the extra cervical tumor spread at
the time of brachytherapy. The HR-CTV encompasses tissues with a major risk of local
recurrence because of residual macroscopic disease, which require a high dose of radiation
similar to that delivered traditionally to point A (Fig. 2.8). The intermediate-risk clinical
target volume (IR-CTV) is defined as encompassing the HR-CTV with a margin of 5 to 15
mm and refers to tissues carrying significant microscopic tumor load. Doses of
approximately 60 Gy are intended for this volume.

FIGURE 2.8 MRI image-guided brachytherapy. Axial (A) and sagittal (B) MRI
images with MRI-compatible applicator in place with contours of the GTV and
HR-CTV as well as the rectum, sigmoid, and bladder.

Dose–volume parameters are defined for GTV, HR-CTV, IR-CTV, and the OARs. For the
rectum, contouring includes the outer wall from the anorectal junction to the rectosigmoid
flexure, and the sigmoid contour continues alone until the sigmoid is approximately 2 cm
from the uterus. The outer contours of the bladder should also be defined. D100 and D90, as
well as V100, should be reported as well as the minimum dose in the most irradiated tissue
volumes for 0.1, 1, and 2 cc of the OARs. The radiobiologic model equivalent dose (EQD2)
is used to sum the external beam and HDR doses together over the course of treatment so that
a cumulative biologically weighted dose is available.
ICRU 38 system is a dose reporting system (Fig. 2.9). This was developed so that
comparisons could be made between centers using different brachytherapy systems. It
provides definitions for determining dose to the bladder and rectum in addition to other
characteristics of the implant.

FIGURE 2.9 Reference points for bladder and rectal brachytherapy doses
proposed by the ICRU, Report 38.
Brachytherapy Applicators for Cervical Cancer
It is important to select the appropriate applicator to accommodate patient anatomy and
disease. Furthermore, attention to the details of implant geometry is key in order to achieve
optimal outcomes and local control. Imaging should always be obtained following applicator
placement to assess applicator geometry and the need for adjustment to ensure optimum
placement.

Intracavitary Applicators: LDR and HDR

There are various LDR applicators for intracavitary brachytherapy. The best known are the
Fletcher-Suit and Henschke tandem and ovoid (colpostat) applicators. In the 1970s, the
Delclos mini-ovoid was developed for use in narrow vaginal vaults. The mini-ovoids do not
have shielding added inside the colpostat, and this together with their smaller diameter
produces a higher surface dose than regular ovoids. Fletcher tandems are available in four
curvatures, with the greatest curvature used for larger cavities measuring greater than 6 cm. A
flange with keel is added to the tandem once the uterine canal is sounded, which
approximates the exocervix and defines the length of source train needed. The keel prevents
rotation of the tandem after packing. The distal end of the tandem near the cap is marked so
that rotation of the tandem after insertion can be assessed. The Henschke tandem and ovoid
applicator were initially unshielded, but later modified with rectal and bladder shielding. The
Henschke applicator may be easier to insert into shallow vaginal fornices compared to
Fletcher ovoids.
The Fletcher-Suit-Delclos tandem and cylinder applicator accommodates narrow vaginas
where ovoids may be contraindicated and allow treatment of varying lengths of the vagina
when mandated by vaginal spread of disease. The cylinders vary in size from 2 to 5 cm to
accommodate varying vaginal sizes. Use of vaginal cylinders may lead to a higher rate of
local failure as the dose to the lateral cervix and pelvic sidewall is reduced in the absence of
ovoids, which produce the optimum pear-shaped distribution. These patients also tend to be
treated to lower total doses due to the proximity of the rectum and bladder. There is less of a
dose gradient between the vaginal mucosa and the bladder and rectum than in a patient with a
wider vagina. Additionally, packing cannot be used with cylinders to decrease the rectal and
bladder doses. Vaginal cylinders increase the length of the vagina and rectum treated with an
associated increase in complications including vaginal fistulas, rectal ulcers, and strictures.
For both vaginal cylinders and mini-ovoids, lower doses should be prescribed as both
applicators have no shielding. Interstitial implantation should also be a consideration for
patients with a narrow vagina or with distal vaginal disease.
The tandems and ovoids used with HDR are variations of the traditional Fletcher and
Henschke LDR applicators but are lighter, narrower, and smaller (Fig. 2.10). Tandems and
cylinders are also available for HDR. Rectal and bladder displacement is often not possible,
although a posterior speculum blade to displace the rectum can be used if there is no
posterior vaginal disease.
FIGURE 2.10 HDR tandems and ovoids.

The ring applicator, which is an adaptation of the Stockholm technique, has become a
popular applicator. Its ease of insertion and predictable geometry make it a popular
alternative to tandems and ovoids. The ring applicator is ideal for patients without lateral
vaginal fornices (Fig. 2.11). The plastic caps that come with the ring applicator place the
vaginal mucosa 0.6 cm from the source path, compared to caps for the ovoids, which place
the vaginal mucosa from the source path at a distance of 1 to 1.5 cm. The short distance from
the ring to the vaginal mucosa can result in very high surface doses if fixed weighting is
nonoptimized. The lateral dwell positions are activated on each side of the ring, but not all, in
order to minimize dose to the rectum and bladder. The shape of the isodose curves with ring
applicators compared tandems and ovoids will differ. The ring applicator may be adapted to
accommodate needles for patients with bulky tumors.
FIGURE 2.11 Tandem and ring applicator with an associated rectal retractor.

Interstitial Applicators: LDR and HDR

The shape of the reference pear-shaped isodose achieved with tandem and ovoids can be
altered to some degree, but may not be able to encompass a bulky tumor, particularly when
there is bulky parametrial or vaginal disease. Furthermore, interstitial implantation may be
indicated in patients with anatomical distortion such as an obliterated endocervical canal or
narrow vagina or recurrent disease. Interstitial implantation is used in less than 10% of
patients with gynecologic cancers, and they are typically performed in higher-volume
centers. The ABS has recently published consensus guidelines for LDR and HDR interstitial
brachytherapy for cervical and vaginal cancers.
The development of prefabricated perineal templates, through which stainless steel
needles were inserted and afterloaded with 192Ir or 125I, was pivotal in advancing interstitial
techniques for the treatment of cervical and vaginal cancers. Rather than performing a
freehand implant, the template concept allows for a more predictable distribution of needles.
The MUPIT (Martinez Universal Perineal Interstitial Template; Beaumont Hospital, Royal
Oak, MI) and the Syed-Neblett (Best Industries, Springfield, VA) are two well-known
commercially available template systems (Fig. 2.12).
FIGURE 2.12 A: Martinez Universal Perineal Interstitial Template (MUPIT). B:
Diagrammatic representation in coronal and sagittal planes of the same template.

Templated interstitial implants may be particularly well-suited for treatment of vaginal

disease, as the vaginal obturator needles can be loaded to encompass disease from the
fornices to the introitus. Additionally, obturator needles can be advanced directly into the
cervix and help to prevent central cold spots, especially if an intrauterine tandem is not used.
Use of an intrauterine tandem along with interstitial needles has been statistically associated
with improvement in overall survival in stage IIIB cervical cancer, as more peripheral
needles may be used to implant the parametria, which is often underdosed in intracavitary
approaches.

Dose–Fractionation Schemes
There is no consensus regarding the optimal dose per fraction and number of fractions;
however, the choice is dependent on the external beam dose, whether central shielding is
used, and the total dose to normal tissues. Currently, the most common approach in the
United States is to use five fractions of 5 to 6 Gy (two fractions delivered per week) in
combination with whole pelvis irradiation of 45 to 50 Gy. The goal is to deliver 80 to 90 Gy
to the high-risk CTV while limiting dose to the rectum and sigmoid (D2cc to 70 to 75 Gy)
and bladder (D2cc 80 to 90 Gy).

Sequencing with External Beam

In cervical and vaginal cancers, the role of external beam irradiation is to shrink bulky tumor
prior to implantation and bring any gross residual disease within the range of the high-dose
intracavitary dose distribution, improve tumor geometry by shrinking tumor that may distort
anatomy and prevent optimal brachytherapy, and sterilize paracentral and nodal disease that
lies beyond reach of the intracavitary system. In nonbulky disease presentations, HDR
insertions are often integrated early in the treatment course after approximately 20 Gy of
external beam RT. Alternatively, some institutions choose to take the whole pelvis to 40 to 45
Gy before proceeding with HDR insertions. Compressing the duration of treatment to less
than 7 to 8 weeks is desirable to optimize pelvic control and survival. HDR and external
beam fractions should not be given on the same day.

Midline Blocks
Use of midline blocks is controversial, but may be used during external beam to avoid
regions of overdosing to the bladder and rectosigmoid adjacent to the brachytherapy implant
and to deliver an adequate dose to potential tumor-bearing regions outside of the implant
high-dose region. The use of a midline block will influence the HDR fraction size as well as
whole pelvis dose. Studies have recommended avoiding a combination of parametrial boost
doses of ≥54 Gy and a cumulative rectal biologically effective dose (CRBED) of ≥100 Gy3.
Given the potential risk for toxicity, some would advocate abandoning the midline block in
favor of other options, such as dose-painting IMRT.

Parametrial and Nodal Boosting

Parametrial boosting is often recommended for patients with bulky parametrial or sidewall
disease after completion of the whole pelvis field and midline block fields, as the parametria
are a common site of failure. The need for boosting is based on the degree of disease
regression following whole pelvic radiation. Residual parametrial disease after 40 to 45 Gy
whole pelvis treatment should be boosted up to 60 to 62 Gy in small volumes combining the
external beam doses with implant doses. When there is uterosacral space involvement,
thought should be given to the use of a supplemental posterior oblique external beam boost.

Brachytherapy for Endometrial Cancer

Hysterectomy is the cornerstone of treatment for endometrial carcinoma. Vaginal
brachytherapy (VBT) may be indicated in the adjuvant setting based on high-intermediate
pathologic risk factors. Most VBT for endometrial cancer is performed with vaginal cylinders
(available in diameters of 2 to 5 cm) using HDR techniques; however, sometimes ovoids may
be used. For vaginal cylinders, the dose distribution should ideally conform to the shape of
the cylinder; however, sometimes the cylinder may not be in close approximation with all of
the vaginal mucosa in the setting of a wide vaginal apex or if the cuff has been closed with
“dog ears.”
Dose is typically specified either at the vaginal applicator surface (mucosal surface) or at
a depth of 0.5 cm from the applicator. Prior studies have revealed that 95% of the vaginal
lymphatic channels are located within 3 mm of the vaginal surface and dose prescription to a
depth of less than 5 mm may be adequate. Typically, the length of the vagina treated is 4 to 5
cm and perhaps longer when treating with brachytherapy alone. Distal vaginal recurrences
are very rare (0.5% to 1%), and therefore it is not suggested to treat more than the upper half
of the vagina routinely. Total vaginal surface doses of 50 to 80 Gy are reported most
frequently in the literature. When used with external beam, cumulative doses of 60 to 100 Gy
at the vaginal surface are reported in the literature. Doses in excess of 80 Gy to the vaginal
mucosa are not necessary in the setting of adjuvant therapy and can be associated with
increased morbidity. Whether a vaginal cuff boost is routinely necessary in addition to
external beam radiation to the pelvis for early-stage endometrial cancer is debatable. The
rationale for a boost is that doses in excess of 45 to 50 Gy may be necessary to control
microscopic tumor cells that may be present in the hypoxic vaginal cuff.
For patients with medically inoperable endometrial cancer, MRI or CT should be
performed to determine the uterine wall thickness. Per the ABS guidelines, patients with
stage I, grade 1 to 2 disease with minimal myometrial invasion on imaging can undergo
brachytherapy alone. External beam should be added if patients have deep myometrial
invasion or stage II or III disease. Tandems and ovoids or ring may be appropriate if the
uterine cavity is small; otherwise, for a large uterus, a special uterine applicator such as the
dual or triple tandems or Simon Heyman capsules should be considered to achieve better
coverage of the endometrial cavity.
Patients with an isolated vaginal recurrence from endometrial cancer usually benefit from
both external beam and brachytherapy. Doses in excess of 80 Gy may lead to better local
control in these patients. In patients with residual vaginal disease less than 0.5 cm in
maximum thickness, vaginal cylinders or ovoids can be used, whereas in patients with
thicker lesions following external beam, interstitial techniques are needed. Laparotomy or
laparoscopy or image-guided brachytherapy may be required to help guide optimum needle
placement for apical lesions.

Radiation-Induced Tissue Effects

Key Points
Acute effects of radiation are due to the inherent sensitivity of the irradiated tissue
and the kinetics of the affected cell population as a whole.
Late effects of radiation are due to damage at the capillary level where there is
endothelial cell proliferation, resulting in less diffusion of oxygen into tissues and
resulting fibrosis.
The volume of tissue irradiated, as well as the dose, dose rate, and fractionation
scheme, will affect both acute and late toxicities.

Radiation-Induced Tissue Effects

Side effects that develop within 3 months of radiation completion are termed acute side
effects. Those that develop later than 3 months after completion of therapy are termed late or
chronic effects. These late effects are due to damage at the capillary level resulting in less
diffusion of oxygen into the tissues and subsequently fibrosis. The response of a tissue or
organ to radiation depends on two factors: (i) the inherent sensitivity of the individual cells
and (ii) the kinetics of the cell population as a whole. These factors combine to account for
the substantial variation in response to radiation characteristic of different tissues.
Additionally, the volume of tissue irradiated, dose, dose rate, and fractionation scheme will
affect both acute and late toxicities. The addition of chemotherapy or other systemic agents;
medical comorbidities such as diabetes, hypertension, collagen vascular diseases, and Crohn
disease; as well as social risk factors such as smoking may all have an impact on toxicity as
well. The tolerance doses for tissues are described by the TD 5/5 (probability of a 5% risk of
complications within 5 years of the completion of radiation) and TD 5/50 (probability of a
50% risk of complications within 5 years).

Skin
Treatment of abdominopelvic tumors with skin-sparing high-energy photons often results in
minimal skin reaction. Skin reactions are more likely to develop in skin folds such as the
inguinal creases or intergluteal fold. When treating the vulvar and inguinal regions with
electrons, however, there can be marked skin reactions. Erythema is the first visible skin
reaction and is usually seen around the 3rd week of radiation. Other skin reactions include
dry desquamation and moist desquamation, which occur after the 4th week of radiation.
Return of the epidermis can take 2 to 3 weeks. Late manifestations of radiation on the skin
include depigmentation, subcutaneous fibrosis, dryness and thinning with the loss of apocrine
and sebaceous glands, thinning or loss of hair, and telangiectasias. Necrosis of the skin is rare
and generally occurs only with doses of radiation in excess of 60 Gy.

Vagina
There are few noticeable acute reactions when treating the upper two-thirds of the vagina
with radiation. White-yellow vaginal discharge may appear due to mucositis of the vaginal
mucosa. This can be evident during radiation and continue for several weeks after radiation.
The lower third of the vagina, however, is less tolerant of radiation and can become quite
irritated due to irradiation of the nearby vulva and urethra. The tolerance doses of the upper
and lower vagina are in the range of 120 to 150 Gy versus 80 to 90 Gy, respectively. Vaginal
narrowing and shortening are late sequelae of radiation. Use of a vaginal dilator or
intercourse two to three times a week can help to keep the vagina open. Use of lubrication
with intercourse as well as estrogen cream will also help to build up the vaginal mucosa to
make intercourse more comfortable. Necrosis of the vagina is rare and more commonly
involves the introitus than the vaginal apex due to the vascular supply of the vagina.
Hydrogen peroxide douches, antibiotics and hyperbaric oxygen therapy, and Trental
(pentoxifylline) can help the vaginal tissues to heal, and pain management may be indicated.

Bladder
Acute and transient radiation cystitis may be observed with moderate doses of irradiation
(>30 Gy). Patients will report urinary frequency, urgency, as well as mild dysuria and
decreased bladder capacity. Higher radiation doses may cause more severe symptoms of
cystitis and spasms of the bladder musculature. It is important to rule out the presence of a
concomitant bacterial infection. Radiation cystitis is characterized by the presence of white
cells and red cells without bacteria on urinalysis.
Doses above 60 Gy can cause chronic cystitis, telangiectasias, hematuria, fibrosis, and
decreased bladder capacity. Rarely, bladder neck contractures as well as fistulas may occur.
Fistulas are more likely to occur if there is invasion of the bladder wall by tumor or in the
setting of interstitial implants. Hyperbaric oxygen therapy can be helpful with hemorrhagic
cystitis, as can pentosan polysulfate (Elmiron), which has been used for interstitial cystitis.

Small and Large Intestine

The acute effects of radiation on the intestine are due to the inherent radiation sensitivity of
the rapidly dividing undifferentiated crypt of Lieberkühn cells. The normal lining of the GI
tract is a self-renewing tissue. The mature cells at the surface of the villi are repeatedly
sloughed and replaced by the cells that originate in the crypts. These undifferentiated crypt
cells are the most sensitive to radiation and are preferentially depleted, leading to loss of
mature replacement cells at the surface of the villi. This leads to loss of absorptive function
and results in fluid and nutrient wasting, diarrhea, and dehydration. This constellation of
symptoms is termed acute radiation enteritis.
It is common to observe watery diarrhea with intermittent abdominal cramping starting in
the second or third week of abdominal or pelvic irradiation. Increased peristalsis, disturbance
of the absorption mechanisms, and a decreased transit time also occur. Patients may also
report increased flatulence and gas pain. Concurrent 5-fluorouracil (5-FU), taxanes, or
gemcitabine can worsen small bowel toxicity. Implementation of a low-residue diet,
hydration, and use of antimotility agents can be very helpful. Mucosal healing will occur
within 10 to 14 days once radiation is terminated, and symptoms will accordingly improve.
The late effects of radiation on the small bowel can be a continuation of the acute effects.
Some patients will experience chronic diarrhea. Areas of narrowing corresponding to regions
of high dose or adhesions can occur in the small bowel loops and lead to partial obstruction
of the small bowel. Small bowel obstructions occur in approximately 5% of irradiated
patients. Small bowel doses should be limited to 45 to 50 Gy with a 60 Gy maximum. The
absolute volume of small bowel receiving greater than 15 Gy should be less than 120 cc
when delineating individual loops of bowel. If the entire peritoneal space is defined, the
volume of small bowel receiving greater than 45 Gy should be less than 195 cc.
When the rectum is included in the irradiated volume, there is rectal discomfort with
tenesmus and mucous production, sometimes mixed with blood in the stools. Hemorrhoids
may worsen during radiation. Late radiation effects with high enough doses include
temporary or permanent ulceration and bleeding due to telangiectasias. Fibrosis, stenosis,
perforation, and fistula formation are rarer.
Ovaries
In premenopausal patients treated with definitive irradiation, the ovaries will be irradiated
incidentally and ovarian failure will occur. Hot flashes and other menopausal symptoms can
begin to develop during radiation. Alternatively, the ovaries can also be elevated out of the
radiation field and placed above the true pelvis to attempt to avoid them when treating
cervical cancer. The dose necessary to castrate a woman depends on her age: a larger dose is
required during the period of more active follicular proliferation. A single dose of 4 to 8 Gy
or fractionated doses of 12 to 20 Gy (depending on age) are known to produce permanent
castration and sterility in most patients.

Bone Marrow/Pelvic Bones

The lymphocytes are the most radiosensitive cells in the bone marrow. The rate of fall of the
various components of the marrow is a function of the half-lives of the mature cells. These
half-lives are as follows: erythrocytes—120 days; granulocytes—6.6 hours; and platelets—8
to 10 days. Pelvic irradiation may cause transient lymphopenia. This is even more of an issue
when whole abdominal or extended field irradiation is used due to the increased bone
marrow in the radiation fields. Prior or concurrent chemotherapy will also lead to increased
bone marrow toxicity. The frequent monitoring of the CBC is considered standard of care
with pelvic or abdominal irradiation.
Insufficiency fractures can also develop in irradiated pelvic bones. These most
commonly involve the sacrum and ileum, followed by the pubic bones and, rarely, the
acetabulum. MRI is the best imaging modality to detect them and rule out recurrent disease.
Symptoms from these changes in the pelvic bones will often improve over time, but patients
may also suffer future symptoms from the exacerbation of these fractures or the development
of new fractures over time. Femoral neck complications can include avascular necrosis as
well as fracture. This is a rare complication following the irradiation of the inguinal nodes,
and hip replacement surgery is required to resolve these problems.

Liver
Veno-occlusive disease is the pathologic entity caused by radiation to the liver, resulting in
necrosis and atrophy of the hepatic cells. During radiation, the liver enzymes may be
elevated. Signs of radiation hepatitis can include a marked elevation of alkaline phosphatase
(3 to 10 times normal) with much less elevation of the transaminases (normal to two times
normal). The TD 5/5 for whole liver is 30 Gy. Small portions of the liver can receive up to 70
Gy.

Kidney
The kidneys are very sensitive to small doses of radiation, and a common goal is to avoid
greater than 18 to 20 Gy whole kidney dose. When delivering whole abdominal or para-
aortic irradiation, the kidneys are at risk and the equivalent of one kidney must be spared.
Functional changes have been described after exposure of the kidney to more than 20 Gy, and
signs and symptoms of renal dysfunction can follow; these include hypertension, leg edema,
and a urinalysis showing albuminuria and low specific gravity. A normocytic, normochromic
anemia may also appear.

Doses to Bladder and Rectosigmoid—LDR

The bladder and rectosigmoid are the organs of concern in the setting of combined external
beam irradiation and brachytherapy. Maximum bladder doses of 75 to 80 Gy and rectal doses
of 70 to 75 Gy are guidelines. The ratio of dose to the rectal point or bladder point to the dose
at point A is also important, with a low incidence of rectal (0.3% vs. 5%) and bladder (2% vs.
2% to 5%) complications when this ratio is less than 80%. The volume of rectum and bladder
irradiated is an important variable in the development of complications in addition to the
cumulative dose.

Doses to Bladder and Rectosigmoid—HDR

Compared to LDR, the therapeutic range is narrower, and the risk of complications seems to
rise faster than the rate of improved tumor control. The most important factor in late
complication development is the dose per fraction and the number of fractions. Fowler has
speculated that if only 80% of the tumor dose is received by the critical normal tissues, then 4
to 6 HDR fractions can be used safely. The doses to the normal critical structures should be
less than the dose at point A, in the range of 50% to 80%. CT scanning after applicator
placement is exceedingly helpful and much more reliable in assessing the proximity of the
sigmoid to the tandem and in manipulating the dose distribution. The EQD2 limit to D2cc is
70 to 75 Gy for the rectum and sigmoid and for the bladder 80 to 90 Gy.

Future Focus
Reducing treatment-related morbidity while improving local control and cure rates continues
to be the primary goal in the treatment of patients with a gynecologic cancer. MRI-guided
brachytherapy has shown to decrease complications and increase local control. The GEC-
ESTRO guidelines for defining and contouring tumor volumes and normal tissues on MRI
scans are being used worldwide and were incorporated in the EMBRACE I and II studies.
SBRT, a relatively novel advancement in radiation delivery technique, has been increasingly
used to treat macroscopic pelvic and para-aortic nodes and oligometastatic disease, however,
it remains investigational. More prospective trials with long-term follow-up data are needed
to fully evaluate the benefit of SBRT for gynecologic cancers.

Suggested Readings
Beriwal S, Demanes DJ, Erickson B, et al. American Brachytherapy Society consensus guidelines for interstitial
brachytherapy for vaginal cancer. Brachytherapy. 2012;11:68–75.
Dimopoulos JCA, Petrow P, Tanderup K, et al. Recommendations from Gynecological (GYN) GEC-ESTRO Working
 Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer
brachytherapy. Radiother Oncol. 2012;103(1):113–122.
Gaffney DK, King B, Viswanathan AN, et al. Consensus recommendations for radiation therapy contouring and treatment of
vulvar carcinoma. Int J Radiat Oncol Biol Phys. 2016;95(4):1191–1200.
Georg P, Lang S, Dimopoulos J, et al. Dose–volume histogram parameters and late side effects in magnetic resonance
image-guided adaptive cervical cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2011;79(2):356–362.
Georg P, Potter R, Georg D, et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic
resonance image-guided adaptive cervix cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2012;82(2):653–657.
Haie-Meder C, Potter R, Van Limbergen E, et al. Recommendations for Gynecological (GYN) GEC-ESTRO Working
Group (I): Concepts and terms in 3D image-based 3D treatment planning in cervix cancer brachytherapy with emphasis
on MRI assessment of GTV and CTV. Radiother Oncol. 2005;74:235–245.
Klopp AH, Yeung AR, Deshmukh S, et al. Patient-reported toxicity during intensity-modulated radiation therapy: NRG
oncology RTOG 1203. J Clin Oncol. 2018;36(24):2538–2544.
Lim K, Small W Jr, Portelance L, et al. Consensus guidelines for delineation of clinical target volume for intensity-
modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys.
2011;79:348–355.
Nag S, Chao C, Erickson B, et al. The American Brachytherapy Society recommendations for low-dose-rate brachytherapy
for carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2002;52:33–48.
Potter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy
combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical
cancer. Radiother Oncol. 2011;100:116–123.
Potter R, Haie-Meder C, Van Limbergen E, et al. Recommendations for Gynecological (GYN) GEC ESTRO Working Group
(II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy—3D volume parameters
and aspects of 3D image-based anatomy, radiation physics radiobiology. Radiother Oncol. 2006;78:67–77.
Schwarz JK, Beriwal S, Esthappan J, et al. Consensus statement for brachytherapy for the treatment of medically inoperable
endometrial cancer. Brachytherapy. 2015;14(5):587–599.
Small W Jr, Beriwal S, Demanes D, et al. American Brachytherapy Society consensus guidelines for adjuvant vaginal cuff
brachytherapy after hysterectomy. Brachytherapy. 2012;11:58–67.
Small W Jr, Erickson B, Kwakwa F. American Brachytherapy Society survey regarding practice patterns of post-operative
irradiation for endometrial cancer: Current status of vaginal brachytherapy. Int J Radiat Oncol Biol Phys.
2005;63(5):1502–1507.
Small W Jr, Mell L, Anderson P, et al. Consensus guidelines for the delineation of the clinical target volume for intensity
modulated pelvic radiotherapy in the postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol
Phys. 2008;71(2):428–434.
Small W Jr, Mundt A. Gynecologic Pelvis Atlas. RTOG Radiation Therapy Oncology Group; 2007.
http://www.rtog.org/gynatlas/main.html
Viswanathan A, Beriwal S, DeLosSantos J, et al. American Brachytherapy Society consensus guidelines for locally
advanced carcinoma of the cervix. Part II: High-dose-rate brachytherapy. Brachytherapy. 2012;11:47–52.
Viswanathan AN, Erickson B, Gaffney DK, et al. Comparison and consensus guidelines for delineation of clinical target
volume for CT- and MR-based brachytherapy in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys.
2014;90:320–328.
Viswanathan AN, Lee LJ, Eswara JR, et al. Complications of pelvic radiation in patients treated for gynecologic
malignancies. Cancer. 2014;120:3870–3883.
 3 Clinical Genetics of Gynecologic Cancer

Genetics in Clinical Practice of Gynecology Oncology

The identification of BRCA1 in 1994 and BRCA2 in 1995 has introduced a new component to
the practice of gynecologic oncology. Genetic testing for predisposition to ovarian cancer
became available by 1996 and is now well established. There are at least six genes for
ovarian cancer susceptibility presently in clinical use (BRCA1, BRCA2, MLH1, MSH2,
PMS2, and MSH6). BRCA1 and BRCA2 are responsible for the hereditary breast–ovarian
cancer syndrome (approximately 15% of all ovarian cancers), and MLH1, MSH2, PMS2, and
MSH6 are responsible for Lynch syndrome (2% of ovarian cancers, previously referred to as
hereditary nonpolyposis colorectal cancer [HNPCC]) (Tables 3.1 and 3.2). Other genes, such
as RAD51C, RAD51D, and BRIP1, have more modest risks for ovarian cancer, and risk-
reducing strategies are recommended. Current strategies for prevention include risk-reducing
surgery and chemoprevention with oral contraceptives. Screening for ovarian cancer is
widespread, but it has been proven to be ineffective for the general population and has
received a D grade (recommends against) from the U.S. Preventive Services Task Force.

TABLE 3.1 Lifetime Risks of Cancers Associated with Specific Genes

aMismatch repair genes MLH1, MSH2, MSH6, and PMS2.

NI, not increased.

TABLE 3.2 Genes Associated with Common Cancers

Ovarian Cancer
Key Points
Twenty to twenty-five percent of all ovarian cancers are associated with a
germline or somatic BRCA1, BRCA2, or related mutation.
Risk-reducing bilateral salpingo-oophorectomy is an effective method of ovarian
cancer risk reduction for mutation carriers.
Ovarian cancer screening is not effective for the general, average-risk population.

Genetic Epidemiology
Approximately 20% to 25% of all women with invasive ovarian cancer carry a germline or
somatic BRCA1, BRCA2, or related mutation, and offering genetic testing to all woman
diagnosed with invasive epithelial ovarian cancer (with the exception of mucinous cancers) is
now a standard recommendation. In the event of a positive genetic test, testing should be
extended to all unaffected relatives. However, if there is no living affected relative, then
testing may begin with an unaffected woman in the proper clinical context (strong family
history of cancer).
The frequency of BRCA mutations among ovarian cancer patients is not the same for all
ethnic groups. In some populations, there are recurrent (founder) mutations. In these
populations, the overall frequency of BRCA mutations tends to be high, and one, or a small
number, of specific mutations will account for a large proportion of mutations. For example,
approximately 30% to 40% of Jewish women with ovarian cancer carry one of the three
founder mutations (two in BRCA1 and one in BRCA2). The frequency of BRCA mutations
has been estimated at 1 in 12 cases of ovarian cancer in French Canadians and 1 in 6 cases in
Pakistan. In these populations, it may be possible to offer testing for a limited number of
mutations. The excess risk of ovarian cancer in Jewish families with multiple cases of breast
or ovarian cancer appears to be almost entirely due to the three Jewish founder mutations.
Among women with a BRCA mutation, the ovarian cancer incidence is much greater than
expected. If a founder mutation is not identified through screening of a Jewish family, a
different (nonfounder) mutation will be found in approximately 2% to 4%.
In the ethnically mixed populations of North America, approximately 20% to 25% of all
patients with invasive ovarian cancer carry a germline or somatic mutation in BRCA1,
BRCA2, or related genes. However, the range of mutations is wide, and genetic testing must
be comprehensive (full genomic screening with rearrangement testing). Among BRCA1
carriers, the risk of ovarian cancer is significant in women above the age of 40
(approximately 1% per year), and preventive measures must be initiated early. Women who
carry a pathogenic mutation in the BRCA1 gene have a lifetime risk of approximately 40%
for developing invasive ovarian cancer. Among BRCA2 carriers, the risk is lower and is less
likely to occur below age 50. A meta-analysis estimated the risk of ovarian cancer to be 16%
for BRCA2 carriers. Also, among BRCA2 carriers, the risk of ovarian cancer may vary with
the position of the mutation. Other genes that have been implicated in breast cancer risk may
increase the risk of ovarian cancer; these include BRIP1, RAD51C, RAD51D, and possibly
PALB2. Genes previously thought to increase the risk of ovarian cancer have more recently
been found to have insufficient evidence and include NBN, CHEK2, and BARD1. ATM likely
has an increased risk of uncertain magnitude. Population-based research findings have led
many experts to suggest multigene panel testing in women who do not have mutations in
BRCA1 or BRCA2 or as the first approach to genetic testing in affected probands. Variants of
uncertain significance (VUSs) should be considered as negative, and no clinical action
should be based on these findings. Women with VUSs should be encouraged to contact their
appropriate providers to obtain updated risk classification every few years. When VUSs are
reclassified, most become benign variants.

Pathology and Surgical Presentation of Hereditary Ovarian

Cancer
Ovarian cancers that occur in women with a BRCA mutation appear to be similar to their
sporadic counterparts with the exception that mucinous tumors and tumors of low malignant
potential (or “borderline” tumors) are rarely observed in women with a BRCA mutation. The
majority of BRCA-linked ovarian cancers are poorly differentiated. In most of the studies to
date, the proportion of endometrioid and clear cell carcinomas associated with BRCA
mutations may be overrepresented due to inaccurate historical diagnoses or stochastic
association. Most hereditary ovarian tumors present at an advanced surgical stage, but stage I
or stage II tumors are now being discovered in the context of high-risk screening programs,
or as an incidental finding associated with a risk-reducing salpingo-oophorectomy (RRSO) in
an asymptomatic woman. Several studies have reported on the presence of early ovarian
cancers among pathology specimens obtained at the time of risk-reducing surgery. The
frequency of occult malignancy ranges between 2% and 10%. Some of these early tumors are
identified in the distal fallopian tube, supporting the hypothesis that this may be a site of
origin for most ovarian/fallopian tube cancers. It is necessary that the fallopian tube have
near complete removal (at least the distal two-thirds) and serial sectioning (SEE-FIM
protocol) when an RRSO is performed.
Clinical Outcome and Treatment Effects
A number of studies have reported that the survival of patients with BRCA-associated ovarian
cancer is improved, compared to women with sporadic ovarian cancer. A study of
consecutive cases of ovarian cancers that compared BRCA-associated cancer to sporadic
ovarian cancers from the same institution found that BRCA mutation status was a favorable
and independent predictor of survival for women with advanced disease. It is clear that
improved survival rate is most likely the result of a better response of BRCA-associated
tumors to current DNA damaging therapies and less likely a factor of improved surgical
outcomes as a result of different patterns of tumor invasion. A large meta-analysis found that
overall survival is improved for women with BRCA2 mutations and over time the
improvements seen for women with BRCA1 mutations return to that of sporadic ovarian
cancer. With the advent and widespread use of poly-ADP ribose polymerase (PARP)
inhibition for women with BRCA-associated ovarian cancer, these epidemiologic findings
may become outdated. All women with ovarian cancer should have germline and somatic
testing for BRCA mutations since current treatment approaches include PARP inhibition for
maintenance therapy after the completion of initial chemotherapy based on recently
completed clinical trials. Clinical molecular testing for homologous recombination deficiency
(HRD) can further stratify patients to identify women who will have the greatest benefit from
PARP inhibition in the maintenance setting.

Risk-Reducing Bilateral Salpingo-Oophorectomy

In 1995, a consensus panel of the NIH recommended RRSO for high-risk women at age 35
years or after childbearing is complete. It seems logical that this procedure should eliminate
the incidence of ovarian cancer, but there are two reasons for the potential failure of RRSO.
First, it is possible that the removed ovaries or fallopian tubes contain foci of occult
carcinoma and that the cancer had spread locally to the peritoneum at the time of the
resection. Secondly, it is possible that cancer arises in the peritoneum from shed fallopian
tube cells after salpingo-oophorectomy. The peritoneum is derived from coelomic epithelium,
of the same embryologic origin as the surface epithelium of the ovary. Considering the recent
understanding that high-grade serous ovarian cancer likely originates in the distal fallopian
tube, it is becoming increasingly difficult to justify a de novo origin for high-grade serous
carcinoma in the peritoneum.
Approximately 1 in 345 to 1 in 800 women have a BRCA1 or BRCA2 mutation associated
with hereditary breast and ovarian cancer. Hereditary breast and ovarian cancer syndrome is
seen in all racial and ethnic groups. However, several racial and ethnic groups have
experienced a marked increase in the population frequency of specific mutations, known as
founder mutations. Best known of the founder mutations are collectively found in 1 of 40
individuals of Eastern European Jewish (Ashkenazi) heritage. Increased incidence of BRCA
mutations has also been seen in individuals of Icelandic, Swedish, Dutch, Polish, French
Canadian, and Hungarian descent. The vast majority of deleterious mutations in BRCA1 and
BRCA2 are nonsense mutations that lead to a premature stop codon and a truncated protein.
The other development causing profound changes in genetic testing for hereditary breast and
ovarian cancer is the advent of massively parallel sequencing technology, frequently termed
next-generation sequencing. This sequencing technology allows for testing of multiple
putative tumor suppressive genes at the same time that BRCA1 and BRCA2 are sequenced.
One issue with multiplex cancer susceptibility testing is that many panels include genes
based on molecular pathway inference, as opposed to actual clinical data. As the cancer risks
for many of these genes are uncertain, testing for them may increase the potential for false
positives and inappropriate clinical action without benefitting the patient.
Kauff et al. followed 170 BRCA carriers for an average of 2 years. They observed 1
peritoneal cancer among 98 women who chose RRSO versus 5 ovarian/peritoneal cancers in
72 women with intact ovaries. In a historical cohort study of 551 BRCA1 and BRCA2
carriers, Rebbeck et al. reported that the incidence of ovarian or peritoneal cancer was
diminished by 96% (95% confidence interval [CI]: 84% to 99%) in women who underwent
risk-reducing oophorectomy, compared to those with intact ovaries.
Finch et al. followed 1,045 women with a mutation who underwent a bilateral RRSO and
compared the cancer risk with that in 783 women who did not undergo the procedure. The
overall reduction in cancer risk associated with bilateral salpingo-oophorectomy was 80%
(hazard ratio = 0.20; 95% CI, 0.07 to 0.58; p = 0.003). The estimated cumulative incidence of
peritoneal cancer was 4.3% at 20 years after salpingo-oophorectomy.
An additional benefit of risk-reducing oophorectomy is a marked reduction in the risk of
breast cancer, though more recent reports suggest that this may be limited to women with
BRCA2 mutations. Oophorectomy performed at a relatively early age (<40) is associated with
a greater degree of protection than is surgery performed near the age of menopause, and the
protective effect is evident for 15 years postoophorectomy.
Several organizations have proposed guidelines for offering genetic risk assessment for
hereditary breast and ovarian cancer syndrome. For the gynecologic oncologist, the most
relevant guidelines are those published by the ACOG (Table 3.3), the Society of Gynecologic
Oncology (SGO), and the NCCN. Briefly, all of these guidelines state that hereditary cancer
risk assessment is a process that (i) should include assessment of risk, education, and
counseling; (ii) should be conducted by a physician, genetic counselor, or other provider with
experience in cancer genetics; and (iii) may include genetic testing after appropriate
counseling and consent is obtained.

TABLE 3.3 The ACOG Criteria for Offering Genetic Evaluation for
Hereditary Breast and Ovarian Cancer Syndrome
aClose relative is defined as a first-degree relative (mother, sister, daughter), second-degree relative (grandmother,
granddaughter, aunt, niece), or third degree (first cousin, great-grandparent, or great-grandchild).
Source: Adapted from ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol.
2009;113:957–966.

With evidence suggesting the distal fallopian tube epithelium is the cell of origin for pelvic
serous cancer, some professional societies have suggested a role for risk-reducing
salpingectomy with delayed oophorectomy as a bridging strategy for women with BRCA1
and BRCA2 mutation who are not ready to proceed with oophorectomy. However, caution is
warranted with this approach since there are no clear data demonstrating that salpingectomy
with delayed oophorectomy reduces the risk of pelvic serous cancer. Once a woman with
BRCA mutation enters the risk period for gynecologic cancer, RRSO remains the
recommended standard risk reduction strategy. Ongoing and approved (planned) clinical
trials are testing the hypothesis that bilateral salpingectomy with delayed oophorectomy is
not inferior to RRSO and will improve estrogen deprivation symptoms.
Several studies have demonstrated that risk-reducing mastectomy (RRM) in women with
BRCA1 or BRCA2 mutation is associated with at least a 90% reduction in the risk of new
breast cancer. Importantly, the impact on life expectancy may be markedly less, as the
majority of these cancers in women undergoing both mammography and breast MRI will be
diagnosed at a curable stage.

Hormone Replacement Therapy

Premenopausal oophorectomy is associated with the induction of acute menopause. There is
concern that the use of hormone replacement therapy in these women may be associated with
an increased risk of breast cancer or may offset the protective effect of the oophorectomy
itself. Rebbeck et al. estimated the effect of oophorectomy on breast cancer risk in a study of
462 BRCA1 and BRCA2 carriers. They found that the odds ratio for breast cancer associated
with oophorectomy in the entire study group was 0.40 (95% CI: 0.18 to 0.92) and was 0.37
(95% CI: 0.14 to 0.96) in the subgroup of women with oophorectomy who used hormone
replacement therapy. Hormone replacement therapy is likely safe in mutation carriers and
does not seem to reduce the breast cancer protection offered by premenopausal
oophorectomy.

Oral Contraceptives and Tubal Ligation

A protective effect of oral contraceptives against ovarian cancer has been reported in BRCA
carriers. In a matched case–control study of 799 ovarian cancer cases and 2,424 controls, 3 to
5 years of oral contraceptive use was associated with a 64% reduction in the risk of ovarian
cancer (p = 0.0001). In a second, smaller study, 6 or more years of use of oral contraceptives
was associated with a decreased in risk of 38% (OR = 0.62; 95% CI: 0.35 to 1.09). Tubal
ligation has been found to be protective against ovarian cancer in the general population.
There is some evidence that it is also effective among BRCA1 carriers. Oral contraceptives
should be considered in mutation carriers who have not undergone RRSO. When caring for
women with BRCA1 or BRCA2 mutations, it is important, however, to consider both breast
and ovarian cancer risk. A meta-analysis found that neither BRCA1 (summary relative risk =
1.09; 95% CI, 0.77 to 1.54) nor BRCA2 (summary relative risk = 1.15; 95% CI, 0.61 to 2.18)
mutation carriers demonstrated a statistically significant increased risk of breast cancer with
oral contraceptive use. Given the data currently available, it likely makes sense to counsel
patients that oral contraceptives are generally safe for BRCA1 and BRCA2 carriers and have a
significant benefit on ovarian cancer risk.

Screening for Hereditary Ovarian Cancer

Screening for ovarian and fallopian tube cancer in the general population using serial CA-
125 levels and transvaginal ultrasound, or similar approaches, is not recommended. Recently,
two large randomized trials of ovarian cancer screening in women not known to be at
inherited risk have failed to demonstrate a reduction in ovarian cancer mortality through early
detection.
Two prospective trials specifically targeting women at familial/inherited risk have also
been completed, UK Familial Ovarian Cancer Screening Study (UKFOCSS) and GOG-199.
Until final results are available from UKFOCSS and GOG-199, given the lack of evidence
with respect to benefit, transvaginal ultrasound and CA-125 determinations cannot be
recommended as an alternative to RRSO in a woman with a mutation in BRCA1 or BRCA2
once she enters the risk period for ovarian cancer. Until an effective early detection method
has been identified for hereditary ovarian cancer, risk-reduction methods should be
recommended (Table 3.4).
TABLE 3.4 Risk-Reduction Recommendations for Carriers of BRCA1 and
BRCA2 Mutations

Source: Adapted from National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology.
Genetic/Familial High-Risk Assessment: Breast and Ovarian. 2016. Version 2.2016.

Endometrial Cancer
Key Points
Lynch syndrome (previously known as hereditary nonpolyposis colon cancer
[HNPCC] syndrome) increases the risks of both endometrial and colon cancer in
women.
Prophylactic hysterectomy is an effective method of endometrial cancer risk
reduction for mutation carriers.
Endometrial cancer screening remains unproven in patients with Lynch syndrome.
Risk-reducing bilateral salpingo-oophorectomy should be performed at the time
of prophylactic hysterectomy in most Lynch syndrome patients.

Genetic Epidemiology
The most important factor in the etiology of endometrial cancer is prolonged estrogen
exposure, but inherited factors are important for a small proportion of cases (approximately
5%). Susceptibility genes for endometrial cancer include the four mismatch repair genes
(MSH2, MLH1, PMS2, and MSH6), EPCAM, PTEN, and possibly BRCA1. These genes are
responsible for the Lynch syndrome, Cowden syndrome, and hereditary breast–ovarian
cancer syndrome, respectively. The Breast Cancer Linkage Consortium reported that some
endometrial cancers were due to mutations in BRCA1, but none were due to mutations in
BRCA2. However, two smaller studies (one on patients with serous endometrial tumors and
one on patients with endometrial carcinomas in general) concluded that the risk of
endometrial carcinoma in women with a germline BRCA1 mutation was not increased. These
findings suggest that it is likely that some cases of endometrial carcinoma are due to an
inherited BRCA1 mutation, but the penetrance of BRCA1 mutations for endometrial
carcinoma is low, and the hereditary fraction is small. Data suggest that the excess risk of
endometrial cancer among BRCA carriers often can be attributed to past tamoxifen use and
not to the effect of the gene.
Somatic mutations in PTEN are common in endometrial cancers, and rare inherited
constitutional mutations in PTEN are present in women with endometrial cancer. In the latter
case, endometrial cancer is seen in the context of Cowden syndrome—a rare dominant
disease of the skin that is associated with increased risks of cancer of the breast, the thyroid
gland, and the endometrium.
Women in families with Lynch syndrome are at an elevated risk for both endometrial and
ovarian cancers. This syndrome is characterized by an autosomal dominant inherited
tendency to develop colon and other cancers. The colon cancers tend to be of young onset
and right sided and are often multicentric. Individuals in families with Lynch syndrome are at
risk for a range of cancer types, and endometrial cancer is also a common site of cancer
among women. Genes that are responsible for the repair of mismatched DNA (mismatch
repair) are defective in families with this syndrome. MSH2, MLH1, PMS2, MSH6, and
EPCAM are the five major genes responsible for it. The risk of colon cancer is high in
families with a mutation in any of these genes, and the lifetime risk for endometrial cancer in
women from these families is reported to be from 40% to 60%. The risk of endometrial
cancer also depends on which gene carries the mutation. Mutations in MSH2 and MSH6 have
been implicated in most Lynch syndrome families with endometrial cancer, but families with
MLH1 mutations have been reported as well. Germline mutations in MSH6 are relatively rare
in Lynch syndrome but are overrepresented in families with multiple cases of endometrial
cancer. Goodfellow et al. reported that an inactivating germline MSH6 mutation was present
in 7 of 441 women with unselected endometrial cancer (1.6%). Cancers were diagnosed in
women with mutations on average 10 years earlier than in women without mutations.
Most Lynch syndrome endometrial cancers have endometrioid histology, though 15% or
more will be serous carcinoma, clear cell carcinoma, and carcinosarcomas. In one study, all
of the nonendometrioid tumors occurred in patients with MSH2 mutations. Lynch syndrome
endometrial cancers are most commonly stage I and frequently have lower uterine segment
involvement and tumor-infiltrating lymphocytes. Women with Lynch syndrome also have an
approximate 5% to 10% lifetime risk for developing ovarian cancer. The ovarian cancers
seen in Lynch syndrome are more likely to present at stage I and less likely to be of serous
histology. Recent data suggest that the risk of ovarian cancer associated with germline
mutations in MSH6 and PMS2 are sufficiently low that removal of the ovaries may be
reconsidered in young women.
Clinical Care and Treatment
The majority of tumors from individuals from Lynch syndrome families demonstrate
microsatellite instability (MSI). MSI is a feature of tumors that are genetically unstable,
associated with error-prone DNA replication during cell division. Approximately one-quarter
of women with nonhereditary endometrial cancer (sporadic cancer) have tumors that
demonstrate MSI. If the mutation is present in the germline, it may be transmitted from
parent to child. In this case, genetic counseling is warranted. It is not necessary that genetic
counseling be undertaken when the mutation is limited to the tumor tissue only, as this
situation does not pose a risk to relatives. Individuals with an inherited mutation in one of the
mismatch repair genes are also at risk for additional cancers, including ovarian, gastric,
urologic tract, and small bowel cancers, but the risk for these is much less than the risk of
colon or endometrial cancer. In a study that examined 101 women with Lynch syndrome who
had developed both GI cancer and gynecologic cancer, half of the women presented first with
their gynecologic cancer.
While family history remains an important component in identifying individuals who
may be at risk for Lynch syndrome, tumor testing for evidence of mismatch repair defects
can be useful for triaging which patients may be at risk for having one of the germline DNA
mismatch repair mutations. These tumor tests include immunohistochemistry (IHC) for one
of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and MSI analysis. In
2014, the ACOG published a practice bulletin, recommending an IHC-based algorithm, for
assessing the possibility of Lynch syndrome in newly diagnosed endometrial tumors (Fig.
3.1). For IHC tests, the absence of a specific mismatch repair protein can focus sequencing
efforts to a particular gene, which may reduce costs. Other screening approaches that have
been previously employed include routine IHC testing of tumors in women who are under
age 50 or who have tumors with morphologic features of DNA mismatch repair deficiency
such as tumor-infiltrating lymphocytes, lower uterine segment involvement, or
dedifferentiated histology. As our understanding of the genomic and pathogenic
manifestations of Lynch syndrome tumors expands, and the approaches to molecular
medicine advance, the system of screening will continue to evolve.
FIGURE 3.1 Algorithm for using IHC evaluation of mismatch repair protein
expression to triage endometrial tumors for the possibility of Lynch syndrome.
Source: Adapted from ACOG Practice Bulletin No. 147: Lynch syndrome.
Obstet Gynecol. 2014;124:1042–1054.

Guidelines for screening and prevention of Lynch syndrome–associated cancers have been
published and should be reviewed with patients when the diagnosis of Lynch syndrome is
made (Table 3.5). No studies have examined the mortality impact of annual endometrial
sampling in women with Lynch syndrome. Consensus guidelines currently recommend
consideration of surveillance with endometrial biopsy for evaluation of the uterus and
chemoprevention with progesterone-based contraceptives. The data to support these
recommendations are limited. Because of the high lifetime risk of endometrial cancer in
women with mutations in the mismatch repair genes, risk-reducing hysterectomy with BSO
should be considered. A multi-institutional retrospective study of women with Lynch
syndrome demonstrated that the incidence of endometrial cancer fell from 33% to 0% in
women who underwent hysterectomy, and the incidence of ovarian cancer fell from 5.4% to
0% in women who underwent salpingo-oophorectomy.

TABLE 3.5 Risk-Reduction Recommendations for Women with Lynch

Syndrome
Sources: Adapted from ACOG Practice Bulletin No. 147: Lynch syndrome. Obstet Gynecol. 2014;124:1042–1054 and
National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk
Assessment: Colorectal. 2016. Version 1.2016. http://www.nccn.org

Suggested Readings
Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA.
2000;283:2260–2265.
Eisen A, Lubinski J, Klijn J, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation
carriers: An international case–control study. J Clin Oncol. 2005;23:7491–7496.
Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube and peritoneal cancers
in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296:185–192.
Goodfellow PJ, Buttin BM, Herzog TJ, et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an
unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003;100:5908–5913.
Kauff ND, Mitra N, Robson ME, et al. Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast
cancer families. J Natl Cancer Inst. 2005;97:1382–1384.
Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 mutation. N
Engl J Med. 2002;346:1609–1615.
Levine DA, Lin O, Barakat RR, et al. Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol.
2001;80:395–398.
Liede A, Karlan BY, Baldwin RL, et al. Cancer incidence in a population of Jewish women at risk of ovarian cancer. J Clin
Oncol. 2002;20:1570–1577.
Moslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian
cancer. Am J Hum Genet. 2000;66:1259–1272.
Narod SA, Risch H, Mosleh R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med.
1998;339:424–428.
Phelan CM, Kwan E, Jack E, et al. A low frequency of non-founder mutations in Ashkenazi Jewish breast-ovarian cancer
families. Hum Mutat. 2002;20:352–357.
Piver MS, Jishi MF, Tsukada Y, et al. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a
family history of ovarian cancer. A report from the Gilda Radner Family Ovarian Cancer Registry. Cancer.
1993;71:2751–2755.
Powell CB, Kenley E, Chen LM, et al. Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: Role of serial
sectioning in the detection of occult disease. J Clin Oncol. 2005; 23:127–132.
Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 and BRCA2 mutation. N
Engl J Med. 2002;346:1616–1622.
Risch HA, McLaughlin JR, Cole DEC, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a
population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68:700–710.
Thompson D, Easton D; Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2
mutation carriers. Am J Hum Genet. 2001;68:410–419.
Whittemore AS, Balise RR, Pharoah PD, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or
BRCA2 mutations. Br J Cancer. 2004;91:1911–1915.
 4 Preinvasive Lesions of the Genital Tract

Pathogenesis and Diagnosis of Preinvasive Lesions of

the Lower Genital Tract
The high level of public and professional attention to preinvasive lesions of the lower genital
tract is due to increasing knowledge surrounding pathogenesis and the availability of
preventative vaccines. Over the past 40 years, there has been a marked increase in the
number of patients in North America and Western Europe diagnosed with human
papillomavirus (HPV)-associated disease. This increase is due partly to a heightened
awareness of various clinical and pathologic manifestations of HPV infections and the
increased use of highly sensitive tests for the detection of HPV infections and cervical cancer
precursors. In addition, a true increase in the prevalence of HPV infections appears to have
taken place. Recent data suggest that over 90% of sexually active men and women will
become infected with HPV at some point in their lives.

Cervix—Squamous Lesions
It has long been recognized that invasive squamous cell carcinomas of the cervix are
associated with lesions that are histologically and cytologically identical to invasive cervical
carcinoma but lack invasion of the subepithelial stroma. It also became clear that there were
squamous epithelial abnormalities with less severe histologic and cytologic features. These
lesions were referred to as dysplasia and were often divided into three grades: mild,
moderate, or severe. It was also recognized that dysplastic lesions and invasive carcinoma
form a pathologic continuum rather than a series of discrete steps. In 1973, Richart proposed
that the term cervical intraepithelial neoplasia (CIN) be used to encompass all forms of
cervical cancer precursor lesions. These lesions were graded on a scale of 1 to 3, with 1
representing mild dysplasia and 3 representing severe dysplasia. Most recently, the College
of American Pathologist and the American Society for Colposcopy and Cervical Pathology
(ASCCP) recommended a new nomenclature to describe cervical lesions: the Lower
Anogenital Squamous Terminology (LAST). Under this standardized system, all HPV-related
preinvasive lesions of the lower genital tract should be classified as either low-grade
squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions
(HSIL).

Cervix—Glandular Lesions
Interest in glandular lesions of the cervix has been stimulated by an apparent increase in the
number of women, especially those under the age of 35, diagnosed with invasive
adenocarcinoma of the cervix and glandular precursor lesions. The absolute number of
women diagnosed with invasive adenocarcinomas has not increased but instead the number
of women with invasive squamous cell carcinomas has decreased, resulting in a relative
increase. There is considerable evidence indicating that adenocarcinoma in situ (AIS) is a
precursor for invasive adenocarcinoma of the cervix, but there is little evidence to support
such a role for lower-grade glandular abnormalities. The majority of preinvasive glandular
lesions are solitary, but multifocal or “skip” lesions may occur in 10% to 15% of cases.

Vulva and Vagina

The nomenclature used for preinvasive lesions of the vulva and vagina parallels that used for
the cervix. In the 1980s, many clinicians and pathologists began to apply the intraepithelial
neoplasia terminology widely used to describe cervical cancer precursors to the vulva. Thus,
the term vulvar intraepithelial neoplasia (VIN), together with a grade of 1 to 3, was adopted.
More recently, pathologists have transitioned to a two-category system. Usual-type VIN
describes less aggressive lesions associated with HPV infection, whereas differentiated VIN
is not associated with HPV infection and is more likely to progress to invasive carcinoma.
The term vaginal intraepithelial neoplasia (VAIN), together with a grade of 1 to 3, has been
used to describe preinvasive lesions of the vagina. With the introduction of LAST, these
lesions are now characterized as low- or high-grade SIL. It is important to note that data
suggesting a continuum between all grades of vaginal preinvasive lesions and invasive
squamous cell carcinoma are significantly less compelling than those for the cervix.

Natural History of Preinvasive Lesions of the Lower

Genital Tract
Key Points
Dysplasia refers to cytologic and histologic abnormalities and is a precursor to
invasive squamous cell carcinoma of the cervix.
The time required for progression from dysplasia to carcinoma is controversial.
A smaller portion of vulvar carcinomas arise from precursor lesions.

Cervix
A variety of epidemiologic and long-term follow-up studies support the concept that certain
epithelial lesions are precursors of invasive squamous cell carcinoma of the cervix. A number
of follow-up studies clearly demonstrate that, once established, high-grade cervical dysplasia
has significant potential for progression to invasive cancer (estimated at 30% if untreated).
Many prospective studies have investigated the relationships between different grades of
CIN. These studies have calculated different estimates of the frequency of mild dysplasia, the
likelihood of progression from low-grade to high-grade precursors, and the time required for
progression from preinvasive to invasive lesions. Until recently, it was believed that it took
many years for a low-grade lesion to progress to a high-grade lesion. Mathematical modeling
studies based on the prevalence of cytologic abnormalities in an unscreened population
suggested that it takes on average almost 5 years for mild dysplasia to progress to severe
dysplasia. More recent studies contradict this model and suggest that high-grade lesions can
develop quite rapidly after an incident HPV infection. A prospective study of college students
found that the median length of time from the first detection of an HPV infection to the
detection of CIN 2,3 was only 14.1 months. Data from HPV vaccine trials confirm that CIN
2,3 lesions can develop quite rapidly after initial HPV infections. Due to concern for
progression from CIN 1 to CIN 2,3, low-grade lesions have traditionally been treated.
However, prospective studies have shown that many low-grade CIN 1 lesions spontaneously
regress and have a low chance of progressing to CIN 2,3 or squamous cell carcinoma.
Whether CIN 2,3 can spontaneously regress remains controversial (Table 4.1).

Vulva
Studies on the natural history of VIN lesions are much fewer than for CIN. Thus, the
relationships between VIN and invasive squamous cell carcinoma of the vulva are less well
understood than those documented between CIN and invasive squamous cell carcinoma of
the cervix. Unlike the cervix, in which the majority of carcinomas are associated with high-
grade dysplasia, only one-third to one-half of invasive vulvar squamous carcinomas have a
coexisting VIN 3 lesion. A review of six published follow-up studies found that only 16 of
330 patients (4.8%) with VIN progressed to invasive cancer. Most of the patients in these
follow-up studies were treated for their VIN or followed for relatively short periods of time,
which limits our understanding of the natural history of these lesions.

Risk Factors for the Development of Lower Genital

Tract Cancers and Preinvasive Lesions of the Lower
Genital Tract
Key Points
Smoking and number of sexual partners are the greatest risk factors for cervical
cancer and its precursors.
HPV infection is acquired through sexual contact and is necessary for the
development of cervical cancer and its precursors.
The majority of HPV-infected women spontaneously clear their infections within
1 to 2 years.

Cervix
Risk Factors
A large number of epidemiologic studies have analyzed risk factors for the development of
cervical cancer and its precursors. Risk factors are similar for both cervical cancer and its
precursor lesions, but the degree of association is much stronger for cervical cancer than for
precursor lesions. The major risk factors found in most studies are markers of sexual
behavior and include number of sexual partners, early age of first pregnancy and first
intercourse, sexually transmitted diseases, and parity. In addition, lower socioeconomic class,
cigarette smoking, oral contraceptive (OCP) use, specific HLA-DR haplotypes, and
immunosuppression are associated with both cervical cancer and dysplasia.

Human Papillomavirus
Over the last 15 years, considerable evidence has accumulated implicating HPV in the
pathogenesis of cervical cancer and dysplasia. Epidemiologic and molecular studies have
found that there is a consistent and strong relationship between HPV infection and cervical
neoplasia, that the temporal sequence between the infection and the development of cancer is
correct, the association between HPV and cervical cancer is relatively specific, and that the
epidemiologic findings are consistent with the natural history and biologic behavior of HPV
infections and cervical cancer.
Epidemiologic studies clearly demonstrate a strong and consistent association between
specific types of HPV DNA and invasive cervical cancer and its precursor lesions.
Additionally, HPV exposure and infection precede the development of cervical disease.
When combined with the enormous body of molecular evidence demonstrating a role for
HPV in the development of cervical cancer and CIN, these findings clearly indicate that HPV
infection, acquired through sexual contact, is a “necessary cause” of both CIN and invasive
cervical cancer. Based on these data, the International Agency for Research on Cancer of the
World Health Organization has classified HPV 16 and 18 and all of the other “high-risk”
types of HPV as carcinogens in humans.

Smoking and Oral Contraceptives

In addition to risk factors associated with sexual behavior, several other risk factors have also
been associated with the development of cervical cancer. Current cigarette use increases the
prevalence and persistence of HPV infection, particularly high-risk types. Additionally,
cigarette smoking results in higher HPV viral loads. Smoking is a strong and consistent risk
factor for both cervical dysplasia and invasive cancer. The use of combined OCPs has also
been linked to the development of cervical cancer and its precursors in some studies. A large
population-based study that pooled data from epidemiologic studies involving over 50,000
women showed an increased risk of preinvasive and invasive cervical disease in current OCP
users, but the possible confounding effects of sexual activity were not fully controlled for.
More recent large trials have not demonstrated that OCP use is an independent risk factor for
cervical disease.
Immunosuppression
Because cell-mediated immunity is important in clearing HPV infections, women with
inherited or acquired defects in T-cell function are at increased risk of developing cervical
dysplasia and squamous cell carcinoma. Immunosuppression is a strong risk factor for the
development of both CIN and cervical cancer; solid organ transplant recipients and HIV-
infected women have higher rates of preinvasive HPV-associated lesions. In studies of renal
transplant patients, transplant recipients have a relative risk of 13.6 for the development of
CIN 3 compared to women in the general population. A Swedish study of solid organ
transplant recipients found that the rates of vulvar malignancy were more than 25 times
higher than that of the general population. Additionally, a large cohort study of American
transplant recipients demonstrated that the rate of vulvar malignancy was higher in the
women than was that of cervical cancer. This may reflect improved cervical cancer
surveillance in this patient population.
Over the last decade, it has become widely accepted that there is an association between
cervical disease and infection with HIV. In a large prospective U.S.-based study, CIN 3 or
worse was found in 5% of HIV-infected women compared to 2% of HIV-negative women.
Invasive cervical cancers that develop in HIV-infected women act aggressively and respond
poorly to standard forms of therapy. CD4 count and HIV RNA levels correlate with high-risk
HPV positivity, and invasive cervical cancer has been designated as an AIDS case–defining
illness by the Centers for Disease Control and Prevention. Treatment of HIV-positive women
with highly active antiretroviral therapy (HAART) is associated with better CIN outcomes
and improves life expectancy in HIV-positive women but has not been shown to change the
incidence or persistence of HPV infections.

Human Papillomavirus
Classification
Papillomaviruses are a diverse group of viruses that are widely distributed in mammals and
birds. They are double-stranded DNA viruses that infect epithelial cells of skin and mucous
membranes. To date, 120 papillomavirus types have been identified. Over 40 types of HPV
that infect the epithelium of the anogenital tract have been described, and these different
types of HPV tend to be associated with different types of epithelial lesions. HPV 6 and 11
are the most common HPV types found in association with benign exophytic condylomata of
the male and female anogenital tracts in adults, whereas cervical dysplasia is associated with
different HPV types.

TABLE 4.1 Natural History of CIN Is Dependent on Lesional Grade

HPV types are categorized into “high risk” or “low risk” based on the relative risk of being
associated with cancer (Table 4.2). A meta-analysis of the distribution of HPV types in CIN
2,3 lesions demonstrated that HPV 16 is identified in 45.3%, HPV 18 in 6.9%, and HPV 31
in 8.6%.

TABLE 4.2 Classification of Anogenital HPV Types

aClassified as “low risk” based on other data.

Reprinted with permission from Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human
papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518.

Virology
Papillomaviruses are naked DNA viruses composed of a double-stranded circular DNA
genome and a protein coat containing 72 capsomeres of the viral L1 and L2 capsid proteins.
The 8,000 base pair genome contains eight open reading frames encoding the viral proteins
E1, E2, E4, E5, E6, E7, L1, and L2. The oncogenic potential of HPV types is attributed to the
ability of viral E6 and E7 to interact with cellular tumor suppressor genes. E7 binds to Rb,
leading to E2F release and dysregulation of the cell cycle. E7 expression also leads to
chromatin remodeling and genomic instability. E6 binds to p53 leading to p53 degradation,
decreased cellular apoptosis, and increased cellular proliferation. Together, these proteins
alter cell cycle regulation and lead to increased proliferation.

Transformation
With prolonged viral infection, the HPV genome can become inserted into the host cell
genome. This integration of the viral genome into the host DNA is considered a necessary
step for cervical carcinogenesis with integrated viral DNA found in more than 80% of
invasive cervical cancers.
Prevalence and Transmission of HPV Infections
HPV is the most common of all sexually transmitted infections. The National Health and
Nutrition Examination Study (NHANES) found that the overall prevalence of HPV infection
was 42.5% in women aged 14 to 49 years with the highest prevalence in college-age women
(Fig. 4.1). It is estimated that greater than 80% of all American men and women will acquire
an HPV infection at some point in their lifetime.

Figure 4.1 U.S. prevalence of HPV infections in women. Source: Reprinted with
permission from Harir S, Unger ER, Sternberg M, et al. Prevalence of genital
human papillomavirus in the United States, the National Health and Nutrition
Examination Survey, 2003–2006. J Infect Dis. 2011;204:566–573.

Both genital and nongenital HPV appear to be transmitted predominately through close
“skin-to-skin” or “mucosa-to-mucosa” contact, and transmission is facilitated by minor
trauma at the site of inoculation. The importance of sexual transmission is highlighted by
studies of young women initiating sexual activity. In a study of 604 women attending a
university, HPV DNA was detected by PCR in 3% of women reporting no prior vaginal
intercourse, 7% of women with 1 male sexual partner, 33% of women with 2 to 4 partners,
and 53% of women with 5 or more male partners.

Outcome After Exposure to HPV

Infection with a high-risk anogenital HPV in most women leads to a transient productive
viral infection that lasts for a period of months to years. The vast majority of HPV-infected
women spontaneously clear their infections within 1 to 2 years, but up to one-third will
develop cytologic abnormalities while infected. Studies have estimated that 40% to 70% of
young women will clear HPV infections within 1 year and less than 20% of women remain
HPV DNA positive after 24 months of follow-up (Table 4.3). Older women are much less
likely to spontaneously clear HPV infections.

TABLE 4.3 HPV Persistence

Sources: Richardson H, et al. The natural history of type-specific human papillomavirus infections in female university
students. Cancer Epidemiol Biomarkers Prev. 2003;12:485–490; Ho GY, et al. Natural history of cervicovaginal
papillomavirus infection in young women. N Engl J Med. 1998;338:423–428; Dalstein V, et al. Persistence and load of
high-risk HPV are predictors for development of high-grade cervical lesions: A longitudinal French cohort study. Int J
Cancer. 2003;106:396–403; Bae J, et al. Natural history of persistent high-risk human papillomavirus infections in Korean
women. Gynecol Oncol. 2009;115:75–80.

It is possible that women who appear to have cleared their HPV infection and become HPV
DNA negative continue to have a latent, undetectable infection. Reactivation of latent
infections could explain the increase in the prevalence of HPV among cytologically negative
older women and recurrent infections with the same HPV subtype (Fig. 4.2).
Figure 4.2 Prevalence of HPV DNA positivity in women with normal cervical
cytology. The estimate is based on a meta-analysis that included published
studies from all regions of the world. Source: Adapted with permission from de
Sanjose S, Diaz M, Casellsague X, et al. Worldwide prevalence and genotype
distribution of cervical HPV DNA in women with normal cytology: A
metaanalysis. Lancet Infect Dis. 2007;7(7):453–459.

Although spontaneous clearance can continue to occur even after 24 months, clinically
significant persistent infections are defined as infections that last at least 2 years. These long-
term, persistent infections occur in only about 10% of infected individuals. Although newer
studies suggest that CIN 2,3 lesions can develop within a relatively short period of time after
initial infection, lesions that do not persist for at least 2 years are unlikely to have clinical
significance.

Screening for Cervical Cancer and Its Precursors

Key Points
Cervical cytology has reduced the incidence of cervical cancer by almost 80% in
 the United States. .

Cervical screening should begin at age 21 years regardless of age at first sexual
intercourse.
Liquid-based Pap smears have the advantage of providing reflex HPV testing in
women with atypical squamous cells of undetermined significance (ASC-US).

Cytology-based cervical cancer screening programs were first introduced in the mid-20th
century and are widely recognized as reducing the incidence of and mortality from invasive
cervical cancer. Strong evidence for their effectiveness comes from a comparison of
incidence and mortality trends of invasive cervical cancer with screening activity in a given
country or region.

Accuracy of Cervical Cytology

Despite the proven effectiveness of cervical cytology in reducing the incidence of cervical
cancer, the accuracy of cervical cytology has been questioned recently due to the low
sensitivity of a single Pap smear. A number of factors influence the variable false-negative
rate of cervical cytology including sampling errors, processing factors, and interobserver
variability. Since the majority of CIN and cancers develop in the transformation zone,
sampling the endocervical canal reduces the false-negative rate. Thus, sampling devices have
been specifically designed to sample this area including an endocervical brush or a cell
broom. Other important factors for reducing the false-negative rate are the rapid fixation of
cells to prevent artifactual changes secondary to air-drying and the use of a cytology
laboratory with stringent quality control standards.
The use of cervical cytology has reduced the incidence of cervical cancer by almost 80%
in the United States over the last three decades. The effectiveness of cervical cytology is
attributable to the fact that invasive cervical cancer usually requires many years to develop
from CIN 2,3 lesions. If cervical cytology is performed on a routine basis, it is unlikely that a
CIN 2,3 lesion will remain undetected, although such cases do rarely occur. The current
unified screening recommendation from various professional societies including the
American Cancer Society, the American College of Obstetricians and Gynecologists, and the
ASCCP advise initiating cervical cancer screening at age 21 years regardless of the age at
first sexual intercourse or other risk factors. Screening with a Pap smear alone should occur
every 3 years if normal until age 30. Because the prevalence of HPV DNA positivity is much
higher in young women, the 2012 Consensus Guidelines do not recommend the routine use
of HPV testing in women aged 21 to 29. After 30 years of age, the interval between
screenings can be extended to 5 years with cervical cytology (Pap smear) and HPV DNA
cotesting. The current screening guidelines state that cervical cancer screening may stop after
age 65 in women with adequate negative prior screens, but this has become somewhat
controversial. Up to 20% of cervical cancers in the United States are diagnosed over the age
of 65, and some groups recommend extending the age for screening Pap smears or screening
based on specific risk factors in this age group of women. Routine screening is not
recommended for women who have undergone a hysterectomy for benign indications and
who have no prior history of CIN 2,3.

Liquid-Based Cytology
Liquid-based cytology (LBC) is now widely used in the United States for cervical cancer
screening. When it was first introduced, LBC was believed to provide a significant advantage
compared to conventional cervical cytology with respect to sensitivity. However, when all of
the studies comparing LBC with conventional cytology are considered and combined, there
is no evidence that LBC reduces the proportion of unsatisfactory slides nor that it has better
performance than conventional cytology with respect to the identification of women with
CIN 2,3.
While there is no evidence that LBC is either more sensitive or more specific than
conventional cytology, there are other advantages of LBC. The greatest of these appears to be
the availability of residual fluid for “reflex” HPV testing in women with atypical squamous
cells of undetermined significance (ASC-US). Moreover, most cytologists agree that it is
easier to evaluate LBC specimens than conventional cytology specimens.

HPV Testing
The use of HPV testing alone has demonstrated slightly better detection rates and
associations with future development of CIN than Pap testing alone, but specificity may be
lower. In April 2014, the FDA approved HPV testing alone as a screening method to
determine which women require additional diagnostic testing. Women infected with high-risk
HPV 16 or 18 subtypes should be referred for immediate colposcopy, and women with other
high-risk subtypes should have a Pap smear performed with those results indicating whether
colposcopy is recommended. Women with negative HPV testing can have routine screening.
As mentioned above, HPV testing alone is not recommended for screening women younger
than 30 due to high rates of HPV infection.
Cotesting with a Pap smear and HPV testing is the recommended approach to cervical
cancer screening in women over the age of 30. Cotesting improves detection of CIN 2,3 and
lowers the false-negative rate when compared to cytology alone. Cotesting also improves
detection of glandular lesions.

Terminology of Cytology Reports

The Bethesda system terminology is used for reporting cervical cytology results in the United
States. The Bethesda system underwent significant modifications in 2001 (Table 4.4) and was
most recently updated in 2014. The major features of the Bethesda system are that it requires
(i) an estimate of the adequacy of the specimen for diagnostic evaluation (i.e., is the
transformation zone sampled); (ii) a general categorization of the specimen as being
“negative for intraepithelial lesion or malignancy,” as having an “epithelial cell abnormality,”
or as “other” (i.e., having endometrial cells in a woman 40 years of age and older); and (iii) a
descriptive diagnosis that includes a description of epithelial cell abnormalities. The terms
low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial
lesion (HSIL) are used to designate cytologic changes that correlate with CIN 1 and CIN 2,3,
respectively. In addition, the Bethesda system attempts to separate epithelial changes
secondary to inflammation or repair from those associated with cervical cancer precursors
whenever possible. Nondiagnostic squamous cell abnormalities are included in a category of
atypical squamous cells (ASC). ASC specimens have features suggestive, but not diagnostic,
of a SIL. This category is further subdivided into two subcategories: ASC-US (atypical
squamous cells of undetermined significance) and ASC—cannot exclude HSIL (ASC-H).
The risk of a woman with ASC-US having biopsy-confirmed CIN 2,3 is approximately 7% to
17%, and the risk for a woman with ASC-H is approximately 40%. Nondiagnostic glandular
cell abnormalities are included in a category of atypical glandular cells (AGC). This
category is further subdivided into either not otherwise specified or AGC—favor neoplasia.

TABLE 4.4 The 2001 Bethesda System

Reprinted with permission from Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: Terminology for
reporting results of cervical cytology. JAMA. 2002;287:2114.

Use of Colposcopy
Over the last 25 years, colposcopy combined with colposcopically directed cervical biopsies
has become the primary modality by which women with abnormal Pap smears are evaluated.
Colposcopy consists of viewing the cervix with a long-focal-length, dissecting-type
microscope after a solution of dilute (4%) acetic acid has been applied. The acetic acid
solution acts to remove and dissolve the cervical mucus and causes CIN lesions to become
whiter than the surrounding epithelium (acetowhite) by dehydrating the cells. This coloration
allows the colposcopist to identify and biopsy epithelial lesions. In addition to identifying
acetowhite areas, colposcopy also allows for the detection of blood vessel patterns that can
indicate high-grade CIN lesions and invasive cancers. Colposcopy and appropriately directed
biopsy have greatly facilitated the management of patients with preinvasive lesions of the
cervix because it allows the clinician to rule out invasive cancer and determine the limits of
preinvasive disease.

Management of Cytologic Abnormalities and CIN

Key Points
Complete recommendations and management algorithms are available at
www.asccp.org.
Over 90% of LSIL will spontaneously clear in adolescents.
A diagnosis of HSIL confers a significant risk for CIN 2,3 and invasive cervical
cancer.
Due to their high rate of clearance of HPV infections and cervical dysplasia,
women aged 21 to 24 are considered a “special population,” and they are
managed less aggressively than older women with the same findings.

In 2006, the ASCCP sponsored a consensus workshop to update the 2001 Consensus
Guidelines for the Management of Women with Cytological Abnormalities and Cervical
Cancer Precursors. In 2012, the ASCCP worked with 23 other national organizations on a
revision of the 2006 guidelines for management of abnormal screening tests and CIN/AIS.
These guidelines are widely used in the United States and are evidence based, with each
recommendation accompanied by a grading of both the strength of the recommendation and
the strength of the data supporting the recommendation. The complete recommendations and
management algorithms are available at www.asccp.org. New Risk-Based Management
Consensus Guidelines are expected to be published in 2020.

Atypical Squamous Cells of Undetermined Significance

A vexing group of patients for both clinicians and cytologists are those with atypical cervical
cytology (i.e., not normal) but who lack the characteristic features of SIL or cancer. A
cytologic result of ASC-US is the least reproducible cytologic category. Approximately one-
half of all women diagnosed with CIN 2,3 have ASC-US as their initial abnormal cervical
cytology result. Although the risk that a woman with ASC-US has invasive cervical cancer is
quite low (~1/1,000), the large number of women with this cytology interpretation (2.3
million annually) guarantees that each year approximately 2,300 women with invasive
cervical cancer will have only equivocal results on their cervical cytology (Fig. 4.3).
Therefore, women with ASC-US need to receive follow-up evaluation, but consideration
should be given to preventing unnecessary inconvenience, anxiety, cost, and discomfort.
Figure 4.3 Distribution of abnormal cervical cytology. Source: Adapted with
permission from Davey DD, Neal MH, Wilbur DC, et al. Bethesda 2001
implementation and reporting rates: 2003 practices of participants in the College
of American Pathologists Interlaboratory Comparison Program in
Cervicovaginal Cytology. Arch Pathol Lab Med. 2004;128:1224–1229.

Two methods are recommended for the management of women with ASC-US: reflex HPV
DNA testing or repeat cervical cytology. A number of studies have directly compared the
sensitivity and specificity of these two options for identifying women with CIN 2,3. In every
study, HPV DNA testing identified more cases of CIN 2,3 than did a single repeat cervical
cytology but referred approximately equivalent numbers of women for colposcopy. The 2012
ASCCP Consensus Conference concluded that HPV DNA testing is the preferred approach to
managing women with ASC-US and immediate colposcopy is no longer recommended.
Figure 4.4 provides the algorithm recommended for the management of women in the
general population with ASC-US. Due to the high prevalence of HPV infection and high
rates of spontaneous clearance among women aged 21 to 24 years, repeat cytology at 12
months is recommended over reflex HPV testing in this population.
Figure 4.4 ASCCP guidelines for the management of women with atypical
squamous cells of undetermined significance (ACS-US) on cytology. Source:
Reprinted with permission from Massad LS, Einstein MH, Huh WK, et al. 2012
updated consensus guidelines for the management of abnormal cervical cancer
screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 suppl
1):S1–S27.

Management options for pregnant patients with ASC-US are identical to those for
nonpregnant patients with the exception that endocervical curettage (ECC) should be
deferred and it is acceptable to postpone colposcopic examination until the patient is 6 to 8
weeks postpartum.

Atypical Squamous Cells—Cannot Exclude HSIL

The prevalence of biopsy-confirmed CIN 2,3 is considerably higher among women referred
for the evaluation of ASC-H cervical cytology than it is for women referred for the
evaluation of ASC-US. Therefore, colposcopy is recommended regardless of HPV status. If
CIN is not identified following an adequate colposcopy with negative ECC, follow-up
utilizing repeat cytology with HPV testing at 6 and 12 months or an excisional procedure is
recommended. For women aged 21 to 24 years, adequate colposcopy with cytology is
recommended every 6 months for 2 years rather than an excisional procedure.

Low-Grade Squamous Intraepithelial Lesions

As with ASC-US, there is considerable variation between populations and laboratories in the
rates at which LSIL is reported. A cytologic result of LSIL is a very specific indicator of the
presence of high-risk types of HPV. In the Atypical Squamous Cells of Undetermined
Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS),
approximately 80% of the women referred for the evaluation of LSIL were high-risk HPV
DNA positive. A cytologic result of LSIL is a poor predictor of the grade of CIN that will be
identified on cervical biopsy with CIN 2,3 identified in approximately 25% of women with
LSIL on cervical cytology. Based on this information, the 2012 Consensus Guidelines
recommend that all women older than 24 with a cytologic result of LSIL be referred for a
colposcopic evaluation (Fig. 4.5). This allows women with significant disease to be rapidly
identified and reduces the risk of women being lost to follow-up. A diagnostic excisional
procedure is not required when a woman with LSIL cytology is found to have an
unsatisfactory colposcopic examination. For women with LSIL who have had cotesting as
part of standard screening and are found to be HPV negative, repeat cotesting at 1 year is
preferred over colposcopy.
Figure 4.5 ASCCP guidelines for the management of women with low-grade
squamous intraepithelial lesions (LSIL). Source: Reprinted with permission
from Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus
guidelines for the management of abnormal cervical cancer screening tests and
cancer precursors. J Low Genit Tract Dis. 2013;17(5 suppl 1):S1–S27.

The risk of invasive cervical cancer is very low in young women, and prospective studies
have shown that over 90% of LSIL will spontaneously clear over a period of years.
Therefore, women aged 21 to 24 years with LSIL are considered to be a “special population”
and should have repeat Pap testing at yearly intervals for 2 years. Another “special
population” is postmenopausal women with LSIL. In some studies, the prevalence of HPV
DNA in postmenopausal women with LSIL is lower than in premenopausal women, and the
prevalence of CIN 2,3 also declines in postmenopausal women with LSIL. Therefore, the
2012 Consensus Guidelines indicate that postmenopausal women with LSIL without HPV
testing can have repeat cytology at 6 and 12 months, HPV testing, or colposcopy. For
pregnant women with LSIL, colposcopy is preferred without ECC unless the woman is aged
21 to 24 years.
High-Grade Squamous Intraepithelial Lesions
The cytologic result of HSIL is uncommon and accounts for only about 0.7% of all cervical
cytology results but confers a significant risk for CIN 2,3 and invasive cervical cancer. CIN
2,3 or cancer is identified in a single colposcopic biopsy or a loop electrosurgical excisional
procedure (LEEP) specimen in approximately 60% and 90% of women with HSIL.
Therefore, women with a cytologic result of HSIL should be referred for either a colposcopic
evaluation or an immediate diagnostic excisional procedure. Subsequent management
depends on whether or not the patient is pregnant, whether the patient is aged 21 to 24 years,
and whether the colposcopic examination is satisfactory.

Biopsy-Confirmed CIN 1
Women with a histologically confirmed CIN 1 lesion represent a heterogeneous group. A
number of studies have clearly demonstrated a high level of variability in the histologic
diagnosis of CIN 1. In ALTS, only 43% of biopsies that were originally diagnosed as CIN 1
at the clinical centers were subsequently classified as CIN 1 by the reference pathology
committee with 41% downgraded to normal and 13% upgraded to CIN 2,3. Additionally,
there is a very high rate of spontaneous regress of CIN 1 in the absence of treatment. One
prospective Brazilian study found that 90% of LSIL lesions spontaneously regressed within
24 months. Other recent studies indicate that CIN 1 only rarely progresses to CIN 2,3. Since
the risk of an undetected CIN 2,3 or glandular lesion is expected to be higher in women
referred for the evaluation of an HSIL or AGC on cytology, women with CIN 1 preceded by
ASC-H or HSIL cervical cytology should be managed more aggressively than women with
CIN 1 preceded by ASC-US or LSIL cytology with cotesting at 12 and 24 months or a
diagnostic excision procedure. For CIN 1 preceded by ASC-US or LSIL, cotesting at 12
months can be followed by return to routine screening if both tests are normal.
If CIN 1 persists for at least 2 years, continued follow-up or treatment is acceptable.
Randomized controlled clinical trials comparing cryotherapy, laser ablation, and LEEP for
treating biopsy-confirmed CIN have reported no significant differences in either
complication rates or success rates. Before treating any grade of CIN using an ablative
modality such as cryotherapy, it is important to perform endocervical sampling in order to
assure that an unsuspected lesion is not present in the endocervical canal.

Biopsy-Confirmed CIN 2,3

Women with an untreated histologically confirmed CIN 2,3 lesion are felt to have a
significantly high risk of progressing to invasive cervical cancer. Therefore, these lesions
warrant routine treatment. Initial treatment may involve an excisional or ablative procedure.
In patients with recurrent CIN (either CIN 1 or CIN 2,3), an excisional treatment modality
with either LEEP or cold knife cone is recommended. Additionally, a diagnostic excisional
procedure is recommended for all women with biopsy-confirmed CIN 2,3 and an
unsatisfactory colposcopic examination. The risk of recurrent CIN 2,3 or invasive cancer
remains elevated for many years after treatment. The 2012 Consensus Guidelines recommend
that women should be followed with cotesting at 12 and 24 months after treatment for CIN
2,3. If any test is abnormal, colposcopy with ECC is recommended. Once two consecutive
negative cytology results are obtained, repeat testing at 3 years followed by routine screening
is recommended. When CIN is identified at the margins of a diagnostic excisional procedure,
a 4- to 6-month follow-up visit with cytology and endocervical sampling is recommended.

Atypical Glandular Cells and Adenocarcinoma In Situ

Patients with AGC are at risk for both cervical and endometrial abnormalities. For women
under age 35, colposcopy with ECC should be performed. For women older than 35 or any
woman with abnormal vaginal bleeding in the setting of AGC, an endometrial biopsy should
be performed in addition to colposcopy and ECC. For women with AGC–NOS who are not
found to have high-risk findings, cotesting at 12 and 24 months is recommended. For high-
grade (CIN 2+) squamous lesions, standard recommendations can be followed. For negative
colposcopic findings after AGC favor neoplasia or AIS on Pap smear, a diagnostic excisional
procedure is recommended.
Patients with biopsy-proven AIS are known to have both multifocal disease and a risk of
invasive adenocarcinoma when thoroughly sampled. Therefore, excision is required for all
patients. Hysterectomy is the preferred treatment but must be preceded by an excisional
biopsy that can exclude invasion requiring a more radical procedure. For women with AIS
who desire fertility preservation, a cold knife cone biopsy with negative margins is an
acceptable alternative to hysterectomy. Other forms of excision procedures may be
considered as long as they produce a specimen that is not fragmented.

Vulvar and Vaginal Intraepithelial Neoplasia

VIN and VAIN require more individualization and creativity in treatment. Most VIN is
detected at the time of biopsy for a suspicious lesion. Definitive treatment should be
complete excision, although positive margins for a low-grade lesion could be observed.
Higher-grade VIN should be completely excised with negative margins. VAIN treatment
must be more tailored to the disease location and patient. Low-grade lesions can be followed
akin to biopsy-proven CIN 1. VAIN 2,3 should be treated, and simple excision is the
preferred method as it provides a specimen in which to rule out invasive disease. Topical
treatment with intravaginal 5-FU has been used, but it is associated with serious adverse
events and is not recommended as an initial choice of therapy. Laser ablation is a reasonable
alternative to excision for diffuse lesions or lesions in regions that are challenging to resect.

HPV Vaccination
Key Points
Prophylactic vaccination is an important element in cervical cancer prevention.
HPV vaccination is approved for males and females ages 9 to 45.
HPV vaccination is nearly 100% effective against target subtypes and has cross-
 coverage against some off-target subtypes.
Current HPV vaccines are not therapeutic and are much less effective in people
with preexisting infection.

Infection with HPV is necessary for the development of almost all preinvasive cervical and
vaginal lesions. HPV infection is also present in roughly half of preinvasive vulvar disease. It
is the most commonly diagnosed sexually transmitted disease, with an overall lifetime
prevalence of 80% and a point prevalence of 40%. With our current understanding of the role
of HPV in preinvasive and invasive disease, prophylactic vaccination has emerged as an
important element in cervical cancer prevention. Currently, three vaccines are approved in
the United States for the prevention of cervical cancer. All three vaccines contain virus-like
particles (VLPs) generated from recombinant viral L1 capsid proteins. The newest vaccine,
Gardasil 9 (Merck & Co., Inc., Whitehouse Station, NJ, USA) is a 9-valent vaccine
composed of VLPs developed from HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The
quadrivalent vaccine, Gardasil (Merck & Co., Inc., Whitehouse Station, NJ, USA), contains
VLPs to HPV types 6, 11, 16, and 18 and the bivalent vaccine, Cervarix (GlaxoSmithKline,
Rixensart, Belgium), contains VLPs to HPV types 16 and 18.
The FDA originally approved the quadrivalent vaccine in 2006 for girls and women aged
15 to 25 years for the prevention of cervical cancer caused by HPV types 16 and 18;
precancerous genital lesions caused by HPV types 6, 11, 16, and 18; and genital warts caused
by HPV types 6 and 11. In 2008, the quadrivalent vaccine was also approved for the
prevention of vaginal and vulvar cancer. The following year, its use was expanded to the
prevention of genital warts due to HPV type 6 and 11 in boys and men aged 15 to 25. The
FDA further expanded the indications to include the prevention of anal cancer and associated
premalignant lesions caused by these same HPV types. In 2018, the FDA again expanded
indications to include men and women up to the age of 45. The federal advisory committee
on immunization practices (ACIP) recommends routine vaccination of all 11- and 12-year-
old boys and girls with the 9-valent series. Adolescents can receive a series of two shots
between the ages of 9 and 14. Older patients receive a three-shot vaccination series. The
ACIP recommendations for the bivalent and quadrivalent vaccine mirror those for the 9-
valent vaccine, except the bivalent vaccine is not approved for use in males.
In an international trial, the quadrivalent vaccine was 99% effective in preventing HPV
16 and 18 preinvasive or invasive lesions in women who were HPV naive at baseline. The
vaccine was also extremely effective in preventing CIN 1, vulvar dysplasia, and vulvar
condyloma. In the 4-year follow-up of a bivalent HPV vaccine trial, efficacy against HPV
16– and HPV 18–mediated CIN 3 lesions was 100% in women who were HPV negative at
the time of vaccination. The vaccine was also effective against other lesions caused by HPV
types 31, 33, and 45, which are closely related to HPV 16 and 18. In women who were HPV
negative at the time of vaccination, there was 93% efficacy against all CIN 3, irrespective of
HPV type, and 100% efficacy against all AIS. High rates of efficacy even in non–HPV 16–
or non–HPV 18–mediated lesions suggest that the vaccine provides some cross-protection
against closely related HPV types. Vaccination with the current products has not been shown
to be therapeutic against preexisting HPV infections. Therefore, the HPV vaccine is most
effective if it is administered prior to the onset of sexual activity.

Suggested Readings
Appleby P, Beral V, Berrington de Gonzalez A, et al. Cervical cancer and hormonal contraceptives: Collaborative reanalysis
of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24
epidemiological studies. Lancet. 2007;370:1609.
Arbyn M, Bergeron C, Klinkhamer P, et al. Liquid compared with conventional cervical cytology: A systematic review and
meta-analysis. Obstet Gynecol. 2008;111:167.
de Sanjose S, Diaz M, Castellsague X, et al. Worldwide prevalence and genotype distribution of cervical human
papillomavirus DNA in women with normal cytology: A meta-analysis. Lancet Infect Dis. 2007;7:453.
Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical
cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5, suppl 1):S1–S27.
Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with
cervical cancer. N Engl J Med. 2003;348:518.
Richardson H, Kelsall G, Tellier P, et al. The natural history of type-specific human papillomavirus infections in female
university students. Cancer Epidemiol Biomarkers Prev. 2003;12:485.
Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical
Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of
cervical cancer. J Low Genit Tract Dis. 2012;16(3):175–204.
Sideri M, Jones RW, Wilkinson EJ, et al. Squamous vulvar intraepithelial neoplasia; 2004 modified terminology. ISSVD
Vulvar Oncology Subcommittee. J Reprod Med. 2005;50:807.
Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: Terminology for reporting results of cervical cytology.
JAMA. 2002;287:2114.
Solomon D, Schiffman M, Tarrone R. Comparison of three management strategies for patients with atypical squamous cells
of undetermined significance: Baseline results from a randomized trial. J Natl Cancer Inst. 2001;93:293.
Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: Realistic
estimates from the ASCUS-LSIL Triage Study. JAMA. 2001;285:1500.
The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study
(ALTS) Group. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous
intraepithelial lesions: Baseline data from a randomized trial. J Natl Cancer Inst. 2000;92:397.
Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women.
N Engl J Med. 2006;354:2645.
Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J
Infect Dis. 2005;191:731.
 5 The Vulva

Introduction
Malignant tumors of the vulva account for 6% of all cancers of the female genital tract, with
an estimated 6,070 new cases and 1,280 deaths occurring in 2019. The majority of women
with vulvar cancer initially present with symptoms such as irritation, pruritus, pain, or a mass
lesion that does not resolve. Less common symptoms include vulvar bleeding or discharge,
dysuria, or an enlarged groin lymph node. Diagnosis is frequently delayed due to a
combination of patient and physician factors, with one report noting 88% of patients had
experienced symptoms for more than 6 months prior to diagnosis. While the traditional
therapeutic approach to vulvar cancer has been radical surgical excision of the primary tumor
and inguinal femoral lymph nodes, a more tailored individualized approach with
multidisciplinary input to vulvar cancer management, often employing multiple modalities in
an effort to achieve excellent disease control with better cosmetic results and sexual/organ
function preservation, is now the norm.

Histology
Over 90% of malignant vulva tumors are squamous cell carcinoma (SCC) followed by
malignant melanoma. HPV (human papillomavirus) 16 is most commonly associated with
the usual type of VIN (uVIN) associated with cancer (2017, 2011). Differentiated VIN
(dVIN) is not usually associated with HPV (2011). Table 5.1 shows the differences between
uVIN and dVIN. There are three main histologic subtypes of vulvar SCC: warty, basaloid,
and keratinizing, of which basaloid and warty types are more commonly associated with
preceding vulvar intraepithelial neoplasia (VIN) (2005). Basal cell carcinoma,
adenocarcinomas (derived from the Bartholin gland, eccrine sweat glands, Paget disease, or
ectopic breast tissue), and a host of very rare soft tissue sarcomas such as leiomyosarcomas,
malignant fibrous histiocytomas, liposarcomas, angiosarcomas, rhabdomyosarcomas,
epithelioid sarcomas, and Kaposi sarcomas may also arise on the vulva. Finally, the vulva
may be secondarily involved with malignant disease originating in the bladder, anorectum, or
other genital organs.

TABLE 5.1 Comparison of uVIN and dVIN: HPV and Non–HPV-Related

Primary Vulvar Malignancies
uVIN, usual vulvar intraepithelial neoplasia; dVIN, differentiated vulvar intraepithelial neoplasia; HPV, human
papillomavirus; STI, sexually transmitted infection; VIN, vulvar intraepithelial neoplasia; SCC, squamous cell carcinoma;
IHC, immunohistochemistry. Adapted from Hoang LN, Park KJ, Soslow RA, et al. Squamous precursor lesions of the
vulva: Current classification and diagnostic challenges. Pathology. 2016;48(4):291–302. doi: 10.1016/j.pathol.2016.02.015.

Anatomy
The vulva consists of the external genital organs including the mons pubis, labia minora and
majora, clitoris, vaginal vestibule, perineal body, vaginal introitus, and their supporting
subcutaneous tissues. The Bartholin glands, two small mucus-secreting glands, have ducts
opening onto the posterolateral portion of the vestibule. The perineal body is a 3- to 4-cm
band of skin and subcutaneous tissue located between the posterior extensions of the labia
majora and the anus; it forms the posterior margin of the vulva.
The vulva has a rich blood supply derived primarily from the internal pudendal artery
and the superficial and deep external pudendal arteries. The innervation of the vulva is
derived from L1 (ilioinguinal nerve), L1–2 (genitofemoral nerve), and S2–4 (pudendal
nerves). The vulva lymphatics run anteriorly through the labia majora, turn laterally at the
mons pubis, and drain primarily into the superficial inguinal lymph nodes. The superficial
inguinal lymph nodes are located within the femoral triangle, which is formed by the inguinal
ligament superiorly, by the sartorius muscle laterally, and by the border of the adductor
longus muscle medially. Lymphatic drainage proceeds from the superficial to the deep
inguinal (or femoral) nodes and then into the pelvic lymph node basin (Fig. 5.1). There are
usually three to five deep nodes, the most superior of which is Cloquet node located under
the inguinal ligament. The vulvar lymphatic channels do not cross the midline, unless the site
lesion involves midline structures (the clitoris or perineal body). Drainage from midline
lesions can be bilateral. Several small lymphatics may drain from the clitoris under the pubic
symphysis directly into the pelvic nodes.

FIGURE 5.1 The lymphatic drainage of the vulva initially flows to the
superficial inguinal nodes and then to the deep femoral and iliac groups.
Drainage from midline structures may flow directly beneath the symphysis to the
pelvic nodes. Source: Modified from DiSaia PJ, Creasman WT, Rich WM. An
alternative approach to early cancer of the vulva. Am J Obstet Gynecol.
1979;133:825.

Epidemiology
Key Points
Vulvar cancer is more common in menopausal women.
Human papillomavirus (HPV) is found in 55% to 60% of invasive tumors.
All suspicious lesions should be biopsied in the office, if possible.
Vulvar dystrophies may be precursor lesions of invasive disease.

Most vulvar cancers occur in postmenopausal women, although more recent reports suggest a
bimodal age distribution with a trend toward younger age at diagnosis. Risk factors for
vulvar cancer include a history of genital condylomata, a previously abnormal Papanicolaou
smear, a history of smoking, and chronic immunosuppression. Both chronic vulvar
inflammatory lesions, such as vulvar dystrophy or lichen sclerosis, and squamous
intraepithelial lesions, particularly carcinoma in situ, have been suggested as precursors of
invasive squamous cancers.
HPV DNA has been isolated from both invasive and carcinoma in situ lesions, with HPV
type 16 being the most common subtype. Of these, 30% to 40% of cases of vulvar cancer are
attributable to HPV, and 76% to 87% are attributable to VIN lesions (2017). The rising
incidence of HPV-related VIN among young women may explain the trend toward younger
age at diagnosis of invasive vulvar cancers. Other infectious agents that have been proposed
as possible etiologic agents in vulvar carcinoma include granulomatous infections and herpes
simplex virus.

Clinical Presentation
The classic presentation of vulvar cancer is persistent vulvar pruritus and a recognizable
lesion. Optimal management for any patient presenting with a suspicious lesion is to proceed
directly to biopsy under local analgesia. Tissue biopsies should include the cutaneous lesion
in question and contiguous underlying stroma so that the presence and depth of invasion can
be accurately assessed. The goals of immediate evaluation with outpatient biopsy are to avoid
delay in the planning of appropriate therapy. The presentation in advanced disease is
generally dominated by local pain, bleeding, and surface drainage from the tumor.
Diagnostic Evaluation
Initial evaluation should include a detailed physical examination with measurements of the
primary tumor, assessment for extension into midline structures or adjacent mucosal or bony
structures, and possible involvement of the inguinal lymph nodes. Because neoplasia of the
female genital tract is often multifocal, a meticulous evaluation of the vagina and cervix—
including cervical cytologic screening—should always be performed in women with vulvar
neoplasms. Fine needle aspiration biopsy from sites of suspected metastases may eliminate
the need for surgical exploration in some patients with advanced tumors and may assist in
radiotherapy planning, particularly in the extent of radiotherapy fields as well as the total
dose of radiotherapy.

Staging Systems
The International Federation of Gynecology and Obstetrics (FIGO) adopted a modified
surgical staging system for vulvar cancer in 1989, which was most recently modified in 2009
(Table 5.2). The TNM classification scheme is correlated with the updated FIGO staging
system (Table 5.3). Nodal status is determined by the surgical evaluation of the groin, most
recently involving sentinel node sampling. The presence or absence of distant metastases is
based on an unspecified diagnostic workup tailored to the patient’s clinical presentation.

TABLE 5.2 FIGO Staging of Carcinoma of the Vulva (Updated 2009)

aThe 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.
Source: Reprinted with permission from Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and
endometrium. Int J Gynaecol Obstet. 2009;105:103–104.

TABLE 5.3 American Joint Committee on Cancer (AJCC) Staging of

Vulvar Cancer (7th Edition)
aFIGO no longer includes Stage 0 (Tis).
bThe 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.
cFIGO uses the classification T2/T3. This is defined as T2 in TNM.
dFIGO uses the classification T4. This is defined as T3 in TNM.
Source: Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al., eds. AJCC
Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.

Patterns of Spread
Vulvar cancers metastasize in three ways: (i) local growth and extension into adjacent organs;
(ii) lymphatic embolization to regional lymph nodes in the groin; and (iii) hematogenous
dissemination to distant sites. Descriptive definitions of local extension are clinically useful
in that local surgical resection with a wide margin is almost universally feasible in women
with T1 or T2 tumors, occasionally possible in those with T3 lesions, and impossible in those
with T4 tumors without resorting to an exenterative operation, depending on the location of
the lesion. More recent experience with intraoperative mapping has demonstrated that
lymphatic drainage from most vulvar sites proceeds initially to a “sentinel” node located
within the superficial inguinal group.
Inguinal node metastasis can be predicted by the presence of certain parameters,
including lesion diameter greater than 2 cm, poor differentiation, increasing depth of stromal
invasion, and invasion of lymphovascular spaces. Clinically important observations
regarding nodal metastases include the following: (i) the superficial inguinal nodes are the
most frequent site of lymphatic metastasis; (ii) in-transit metastases within the vulvar skin are
exceedingly rare, suggesting that most initial lymphatic metastases represent embolic
phenomena; (iii) metastasis to the contralateral groin or deep pelvic nodes is unusual in the
absence of ipsilateral groin metastases; and (iv) nodal involvement generally proceeds in a
stepwise fashion from the superficial inguinal to the deep inguinal and then to the pelvic
nodes. Spread beyond the inguinal lymph nodes is considered distant metastasis.

Pathology
Key Points
Squamous cell carcinoma is the most common histologic subtype.
Melanoma is the second most common subtype, and 25% may be nonpigmented.
The risk of lymph node metastases is negligible when the depth of invasion is less
than or equal to 1 mm.
Paget disease of the vulva has a high likelihood of recurrence and may be
associated with underlying adenocarcinoma.

The majority of vulvar squamous carcinomas arise within areas of epithelium involved by
some recognized epithelial cell abnormality. Approximately 60% of cases have adjacent VIN.
In cases of superficially invasive squamous carcinoma of the vulva, the frequency of adjacent
VIN approaches 85%. Lichen sclerosus, usually with associated squamous cell hyperplasia,
and/or VIN, can be found adjacent to vulvar SCC in 15% to 40% of the cases.
Vulvar SCC precursors can be considered in two distinct groups: those associated with
HPV, usually associated VIN, and those that are not (e.g., those associated with lichen
sclerosus, chronic granulomatous disease).

Vulvar Carcinomas
Squamous Cell Carcinomas
The term microinvasive carcinoma is not recognized as meaningful in reference to the vulva
because there are no commonly agreed upon pathologic criteria established for this term.
However, a substage of FIGO stage I, stage IA, is defined as a solitary squamous carcinoma
of the vulva measuring 2 cm or less in diameter with clinically negative nodes, with depth of
tumor invasion 1 mm or less. Tumors with a depth or thickness of 1 mm or less carry little or
no risk of lymph node metastasis. Stage I squamous carcinomas of the vulva, with a reported
depth or thickness of 5 mm or more, have a lymph node metastasis rate of 15% or higher. In
addition to tumor stage and depth or thickness, other pathologic features include
lymphovascular space invasion (LVSI), growth pattern of the tumor, grade of the tumor, and
tumor type.
In a multivariable retrospective analysis of 39 cases of vulvar squamous carcinoma, in
addition to clinical stage, and when corrected for treatment modality, pattern of tumor
invasion, depth of tumor invasion, and lymph node status were all found to be significant
prognostic factors. In addition, desmoplasia (a fibroblastic stromal tumor response) has been
correlated with a higher risk of lymph node metastasis and poorer survival.
Verrucous carcinoma of the vulva is an exophytic-appearing growth that can be locally
destructive. Clinically, it may resemble condyloma acuminatum. Because of its excellent
prognosis, strict histologic criteria should be used in the diagnosis of verrucous carcinoma.
Verrucous tumors may be associated with HPV type 6 or its variants.

Adenocarcinoma and Carcinoma of the Bartholin Gland

Most primary adenocarcinomas of the vulva arise within the Bartholin glands. Invasive
vulvar Paget disease has been associated with underlying adenocarcinoma. Primary
malignant tumors arising within the Bartholin glands include adenocarcinoma and SCC,
which occur with approximately equal frequency. Carcinoma of the Bartholin glands
generally occurs in older women and is rare in women younger than 50. In clinical practice, it
is generally advisable to excise an enlarged Bartholin gland in a woman 50 years of age or
older, especially if there is no known history of prior Bartholin cyst. If a cyst is drained and a
palpable mass persists, excision is also indicated.
 Primary carcinomas within the Bartholin glands are characteristically deep in location
and difficult to detect in their early growth. Approximately 20% of women with primary
carcinoma of the Bartholin glands have metastatic tumor to the inguinofemoral lymph nodes
at the time of primary tumor diagnosis.

Vulvar Paget Disease and Paget-Like Lesions

Vulvar Paget disease typically presents as an eczematoid, red, weeping area on the vulva,
often localized to the labia majora, perineal body, clitoral area, or other sites. This disease
typically occurs in older, postmenopausal Caucasian women and may be associated with an
underlying primary adenocarcinoma. Invasive Paget disease 1 mm or less in depth of
invasion has reportedly little risk for recurrence.

Vulvar Malignant Melanoma

Malignant melanoma of the vulva accounts for approximately 9% of all primary malignant
neoplasms on the vulva, and vulvar melanoma accounts for approximately 3% of all
melanomas in women. This tumor occurs predominantly in Caucasian women, and the mean
age at diagnosis is 55 years. Although usually pigmented, approximately one-fourth are
nonpigmented, amelanotic melanomas.
The level of invasion and tumor thickness are essential measurements in evaluating
malignant melanoma. Malignant melanomas that have a thickness of less than 0.75 mm have
little or no risk for metastasis and tumors up to 1 mm in thickness are generally considered to
have minimal risk of recurrence. Melanomas of 1.49 mm thickness or less also correlate with
good prognosis. A poor prognosis is correlated with thickness greater than 2 mm, or mitotic
count exceeding 10/mm2. Other poor prognostic factors include minimal or nil inflammatory
reaction and surface ulceration.

Metastatic Tumors to the Vulva

Most metastatic tumors to the vulva involve the labia majora or Bartholin glands. Metastatic
tumors account for approximately 8% of all vulvar tumors, and in approximately one-half of
the cases, the primary tumor is in the lower genital tract, including the cervix, vagina,
endometrium, and ovary. In approximately 10% of the cases, the primary site of the
metastatic tumor cannot be identified.

Prognostic Factors
Prognosis has been most extensively evaluated in women with SCC. The major prognostic
factors in vulvar cancer—tumor diameter, depth of tumor invasion, nodal spread, and distant
metastasis—have been incorporated into the current FIGO staging system. Risk of local
recurrence, although clearly associated with tumor size and extent, is also related to the
adequacy of the surgical resection margins. Several retrospective studies have confirmed an
increased incidence of local recurrence in patients with microscopic margins less than 8 mm
in formalin-fixed tissue specimens.
The single most important prognostic factor in women with vulvar cancer is metastasis to
the inguinal lymph nodes, and most recurrences will occur within 2 years of primary
treatment. The presence of inguinal node metastases portends a 50% reduction in long-term
survival. Because the clinical prediction of lymph node spread is inaccurate, node status is
best determined via surgical biopsy. Prognostic issues that appear to be important in
evaluating lymphatic involvement are (i) whether nodal spread is bilateral or unilateral, (ii)
the number of positive nodes, (iii) the volume of tumor in the metastasis, and (iv) the level of
the metastatic disease. Multiple positive nodes, bilateral metastases, involvement beyond the
groin, and bulky disease are associated with poor prognosis.

Treatment
Key Points
Treatment should be individualized based on lesion location.
Partial radical vulvectomy with inguinal lymphadenectomy through separate
incisions is the treatment of choice for stage IB and some stage II tumors.
Combined chemotherapy and radiation therapy are indicated for more advanced
lesions and those that involve vital structures where primary resection would be
morbid.
Postoperative inguinal and pelvic irradiations are indicated for most patients with
positive nodes.

The development of the radical vulvectomy with bilateral inguinofemoral lymphadenectomy

during the 1940s and 1950s was a dramatic improvement over prior surgical options and
greatly enhanced survival, particularly for women with smaller tumors and negative lymph
nodes. Long-term survival of 85% to 90% can now be routinely obtained with radical
surgery. However, radical surgery can be associated with postoperative complications such as
disfigurement, wound breakdown, and lymphedema.
More recently, surgical emphasis has evolved to an individualized approach for tumors at
either end of the spectrum. Many gynecologic oncologists believe that smaller vulvar tumors
can be acceptably managed by less radical surgical approaches and have proposed more
limited resections for certain subsets considered to represent early or low-risk disease. In the
late 2000s, sentinel lymph node biopsy (SLNB) has emerged as an alternative standard of
care to traditional lymphadenectomy, resulting in decreased postoperative morbidity without
compromising detection of lymph node metastases (2008, 2011, 2012). The obvious
advantages of such an approach are retention of a significant portion of the uninvolved vulva,
less operative morbidity, and fewer late complications. In contrast, radical surgery is
frequently ineffective in curing patients with bulky tumors or positive groin nodes.
Multimodality programs that incorporate radiation, surgery, and chemotherapy are now being
investigated in women with these high-risk tumors based upon success with similar
approaches in women with squamous cancers of the cervix.

Early Tumors
Tumors demonstrating early invasion of the vulvar stroma (≤1 mm) have minimal risk for
lymphatic dissemination. Excisional procedures that incorporate a 1-cm unfixed normal
tissue margin are likely to provide a curative result. Patients in this category represent the
only subset for whom evaluation of the groin lymph nodes is unnecessary. After primary
therapy, these patients should undergo frequent follow-up examinations.

Stage I and II Cancers

Traditional management of stage I and II vulvar cancers has been radical vulvectomy with
bilateral inguinofemoral lymphadenectomy. The operation removes the primary tumor with a
wide margin of normal skin, along with the remaining vulva, dermal lymphatics, and regional
nodes. This approach provides excellent long-term survival and local control in
approximately 90% of patients. Disadvantages of radical surgery include the loss of normal
vulvar tissue with alterations in appearance as well as changes in sexual and organ, a 50%
incidence of wound breakdown, a 30% incidence of groin complications (breakdown,
lymphocyst, and lymphangitis), and a 10% to 15% incidence of lower extremity
lymphedema. Most recently, a radical local resection can be undertaken along with sentinel
lymph node (SLN) excision as an alternative to traditional lymphadenectomy. This involves
resecting the primary lesion with a 1- to 2-cm margin of normal tissue carrying the dissection
to the deep perineal fascia. This partial radical vulvectomy should not be confused with the
concept of wide excisional biopsy, which is used primarily as a diagnostic procedure. For
lesions greater than 2 cm from the midline, ipsilateral sampling is suggested while lesions
less than 2 cm should undergo bilateral SLN sampling, this results from findings of the
Gynecologic Oncology Group (GOG) 137 study, where cutaneous lymphatic mapping was
used to define and target the true sentinel groin nodes. In this study, which examined 452
patients with clinically negative groin lymph nodes and T2 (primary 2 to 6 cm) SCC of the
vulva with at least 1 mm invasion, the sensitivity of the SLNB was 92%, and the negative
predictive value (NPV) was 96%. In patients with tumors less than 4 cm, the NPV was even
higher at 98%. Another study, GROINSS-V evaluated 41 patients noting NPV for SLNB of
95% to 99%, suggesting that only 1% to 5% of vulvar cancers metastasize to non-SLNs
(2010). These studies suggest lymphatic metastases may ultimately be reduced to the biopsy
of one or two identifiable nodes in well-selected patients. Further, in an attempt to reduce
treatment-related morbidity, the classic radical operation has been replaced by the use of
“triple-incision” techniques that separate the vulvectomy incision from the groin incisions.
Additionally, postoperative therapy, primarily irradiation, should be considered in the
10% to 20% of patients with negative margins based on other factors like close tumor
margins, LVSI, tumor size, spray pattern of invasion, or positive nodes with the
understanding that this will further increase the incidence of lymphedema. For tumors with
positive margins, reexcision is considered, and those with reexcised negative margins can be
observed or irradiated based on factors discussed above, while reexcised positive margins
require radiotherapy (2018). Tumors that cannot be reexcised are treated with external beam
radiotherapy (1997). With limited resection, survival of 90% or better is attainable for
patients with stage I vulva carcinoma with acceptable anatomic appearance and function. In
patients with positive sentinel nodes, chemoradiation can be undertaken, or a contralateral
inguinal lymphadenectomy can be performed followed by chemoradiation if greater than two
nodes are positive or a single node holds greater than 2 mm of disease (2007).
In summary, therapy for women with stage I and II cancers must be individualized to the
patient and the location and size of her tumor. Radical vulvectomy provides excellent local
control and long-term survival but has significant morbidity and detrimental, long-term
sexual function effects. More conservative approaches appear safe in most stage I settings
and may be applicable in some stage II patients, particularly if these patients are compliant
with follow-up. The groin node assessment can be limited to a “sentinel” node identified by
intraoperative mapping as predictors of nodal spread in well-selected patients.

Stage III and IV Cancers

By definition, stage III tumors extend to adjacent mucosal structures or the inguinal lymph
nodes. Many are bulky, but some are of limited volume but considered high stage because of
proximity to critical central structures. Some of these primary tumors can be curatively
resected by radical operations, such as radical vulvectomy or some variation of the pelvic
exenteration and vulvectomy. Recent therapeutic efforts have focused on combined modality
treatment programs involving sequenced radiation therapy or chemoradiotherapy and radical
surgery. There are now ample data from retrospective series, and a few prospective trials,
from which to conclude that vulvar cancers are radioresponsive and that function-sparing
operations are feasible in selected patients with advanced disease who receive combined
modality treatment (see Radiation Therapy section). A similar experience has been reported
for patients with stage IVA tumors. Ultraradical (exenteration) resection may also be
considered for selected patients.

Node-Positive Cancers
Patients who have radiographic evidence of nodal involvement should undergo bilateral
inguinofemoral lymphadenectomy as initial therapy and if found to be node positive—
particularly more than one positive node—will benefit from postoperative chemoirradiation
including the groin and lower pelvis. Radiation therapy was demonstrated to be superior to
surgery in the postoperative management of patients with positive pelvic nodes through the
GOG 37 study. This trial randomized patients with groin node-positive vulvar cancer to
postoperative radiation (45 to 50 Gy) versus ipsilateral pelvic node resection after radical
vulvectomy and inguinal lymphadenectomy. At a median survivor follow-up of 74 months,
the relative risk of progression was 39% in the radiation arm. The 6-year cancer-related death
rate was significantly higher for pelvic node resection compared with radiation, 51% and
29%, respectively. In a recent update, there was a persistent 6-year overall survival benefit
for the radiation arm in patients with clinically suspected or fixed ulcerated nodes, as well
patients with two or more positive groin nodes. Several management options are available for
patients found to have positive nodes; however, if postoperative radiotherapy to the inguinal
nodes is deemed necessary, it would be reasonable to limit resection to grossly positive
nodes. Excellent local control and minimal morbidity have been achieved when selective
inguinal lymphadenectomy and tailored postoperative adjuvant therapy were administered to
carefully selected patients.

Recurrent Cancer
Regardless of initial treatment, vulvar cancer recurrences can be categorized into three
clinical groups: local (vulva), groin, and distant. The reported experience with local
recurrence on the vulva is surprisingly good. Recurrence-free survival can be obtained in up
to 75% of cases when the recurrence is limited to the vulva and can be resected with a gross
clinical margin. Recurrences in the groin have, in the past, been deemed to be universally
fatal; however, a few patients may be salvaged by combined modality therapy utilizing
chemoradiation following surgical resection of residual bulky disease (Table 5.4). Patients
who develop distant metastases are candidates for systemic cytotoxic therapy, which is
largely palliative. Patients should be considered for mutation testing including testing for PD-
L1, which may make them eligible for some immunotherapies.

TABLE 5.4 Unanticipated Groin Failure in Patients with Negative

Superficial Lymphadenectomy

Source: Moroney JW, Kunos C, Wilkinson EJ, et al. Chapter 19: Vulva. In: Principles and Practices of Gynecologic
Oncology, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:543.

Surgical Techniques
Radical Vulvectomy and Bilateral Inguinofemoral
Lymphadenectomy
The traditional incisions for radical vulvectomy and bilateral lymphadenectomy described as
a “butterfly” or a “longhorn” approach have largely been abandoned.

Partial Radical Vulvectomy

In procedures used to resect small vulvar cancers, incisions are devised to allow for at least a
2-cm resection margin encompassing the primary lesion (Fig. 5.2). Dissection is carried to
the deep perineal fascia. Recent data suggest that a 1-cm unfixed tissue margin may be
adequate for some tumors. Most radical wide excision sites can be closed primarily. Some
form of inguinal lymphadenectomy, performed through a separate incision, is generally
combined with radical hemivulvectomy. The necessary extent of the groin dissection is an
area of current investigation. Wound breakdown, usually of minor degree, is reported in
approximately 15% of cases.
FIGURE 5.2 Planned resection of a left labial squamous carcinoma and adjacent
carcinoma in situ by radical wide excision. A 2-cm margin is outlined. Rhomboid
flap repair using a V incision is anticipated. Source: Reprinted with permission
from Burke TW, Morris M, Levenback C, et al. Closure of complex vulvar
defects using local rhomboid flaps. Obstet Gynecol. 1994;84:1044.

Triple-Incision Techniques
This resection allows complete removal of the vulvar skin in a manner identical to that
achieved with radical vulvectomy; however, bilateral inguinofemoral lymphadenectomy is
accomplished via separate incisions parallel to the inguinal ligaments. The three-incision
concept preserves the radicality of the vulvar resection while retaining skin over the groin,
and the incidence of major wound breakdown is reduced.

Management of the Groin

Excisional Biopsy
Most preoperative diagnostic dilemmas related to enlarged groin nodes can be resolved
simply and accurately using fine needle aspiration biopsy. However, selective excision of
groin lymph nodes may be considered when fine needle aspiration biopsy results are negative
or equivocal or to remove bulky positive nodes before beginning a course of combined
modality therapy.

Superficial Inguinal Lymphadenectomy

Superficial inguinal lymphadenectomy involves the removal of the 8 to 10 lymph nodes that
lie superficial to the cribriform fascia and surrounding the branches of the saphenous vein.
This is a more meticulous and complete lymphatic dissection than that described for
excisional biopsy.

Deep Inguinal (Femoral) Lymphadenectomy

The deep inguinal (femoral) lymph nodes lie medial to the femoral vein beneath the
cribriform fascia. This space contains three to five nodes, the channels of which course
beneath the inguinal ligament and continue in the pelvis as the external iliac nodal chain. The
most superior deep inguinal node is known as Cloquet node.
Surgical removal of the deep nodes is performed as an extension of a superficial
lymphadenectomy rather than as an isolated procedure. The usual approach is to open the
cribriform fascia along the sartorius muscle at the time of the superficial lymphadenectomy.
Because all of the deep nodes are consistently located medial to the femoral vein, some
surgeons have recommended eliminating the removal of the entire cribriform fascia.
Sentinel Lymph Node Mapping and Biopsy
The concept of a “sentinel lymph node” suggests that the SLN is the first lymph node in the
lymphatic pathway and the initial site of metastasis. The use of an intraoperative blue dye
staining technique along with lymphoscintigraphy (LSG) using radioactive 99mTc
administered shortly before surgery, combined with the intraoperative use of a handheld
gamma probe, produces the highest sensitivity of SLN identification.
Because SLNs are subjected to a more rigorous pathologic (ultrastaging) examination,
SLNB can allow for the detection of smaller tumor foci compared to complete groin node
dissection and traditional pathologic examination. Factors that may contribute to the failure
of SLN identification include the following: midline location for the primary tumor and/or
stasis of lymph flow from a node completely replaced by tumor. On a subset analysis of 234
patients in the GOG 137 study who underwent SLN localization with both blue dye and LSG,
LSG demonstrated bilateral lymphatic draining in 22% of patients with lateral tumors (>2 cm
from midline) versus 69% with midline tumors. None of the 64 patients with lateral tumors
had contralateral groin lymph node involvement, whereas 12% of patients with midline
tumors had contralateral groin lymph node metastases despite unilateral lymphatic drainage
detected by LSG. These findings suggest that unilateral SLN localization can only be safely
utilized in patients with lateral primaries and unilateral drainage on LSG. Given the poor
prognosis associated with groin relapse, selection of patients who are appropriate candidates
for SLN identification and biopsy should be conducted carefully by experienced, well-trained
gynecologic oncologists. The ongoing GROINSS-VII (GOG 270) study is evaluating the use
of radiotherapy versus inguinal lymphadenectomy in patients with known SLNB metastases.
Surgical Resection for Recurrent Disease
The site, extent, and volume of recurrent vulvar cancer have important implications for both
resectability and potential for cure. Surgical therapy plays a curative or palliative role in
selected subsets of patients with recurrent disease.

Radical Wide Excision

As many as 75% of patients with recurrent disease limited to the vulva can be salvaged by
radical wide excision or reexcision of the tumor. Surgical principles for recurrent vulvar
tumors are identical to those for primary tumors: wide excision with a measured normal
tissue margin of at least 2 cm. Particular attention is also focused on obtaining a clear deep
margin.

Pelvic Exenteration
Selected patients have achieved long-term survival after pelvic exenteration for vulvar
recurrences extending to the vagina, proximal urethra, or anus. The surgical approach in
these cases should be individualized to the size and location of the recurrent tumor, prior
therapies, and the age and overall health of the patient. Patients considered for pelvic
exenteration should have a thorough preoperative evaluation to exclude the presence of
regional and/or distant metastases.

Resection of Groin Recurrence

Surgical resection should be viewed with caution in the previously irradiated patient. Cure is
unlikely with resection alone, and wound healing is impaired. The debility caused by a
combination of unresolved recurrence and surgical wound breakdown is worse than that of
progressive recurrence alone. Patients who develop groin recurrence without a history of
prior irradiation should be considered for surgical resection in combination with preoperative
or postoperative radiation therapy ± concurrent chemotherapy. Isolated groin recurrence is a
rare event, so the data to support the efficacy of this treatment are anecdotal.

Radiation Therapy
Treating Locally Advanced Disease in the Vulva
Following initial resection of a vulvar primary, multiple surgicopathologic features have been
identified that are associated with a higher risk of local recurrence including tumor size,
nodal status, margin status (<8 mm on fixed tissue), LVSI, and deep tumor penetration.
Although many local recurrences may be controlled with additional surgery or radiotherapy,
salvage surgery is often morbid, and local recurrences may provide additional opportunity for
regional and distant tumor spread. While no prospective trials of postoperative vulvar site
radiotherapy have been completed, adjuvant radiation of the primary tumor bed in selected
patients with close margins or with other high-risk features does improve local tumor control
and can be considered compared to close observation or reexcision.
Alternatively, in patients who present with more advanced primary tumors, radiation
therapy may be delivered preoperatively or in the definitive setting. Several investigators
have reported excellent responses and high local control rates after preoperative treatment of
advanced tumors with relatively modest doses of radiation therapy followed by local
resection. More recently, a number of published series have suggested the therapeutic benefit
of concurrent chemoradiation, typically followed by limited surgical resection, in addressing
locally advanced disease (Table 5.5). Randomized trials of the role of chemoradiation have
not been done in vulvar cancer. However, recent trials that demonstrated improved local
control and survival when concurrent cisplatin-containing chemotherapy was added to
radiation treatment of cervical cancers suggest that this approach may also be useful for
women with other locally advanced lower genital tract neoplasms. A concern though may be
the postoperative morbidity associated with trimodality therapy.

TABLE 5.5 Concurrent Chemoirradiation in the Management of Locally

Advanced or Recurrent Carcinoma of the Vulva

5-FU, 5-fluorouracil; Mito, mitomycin C; CDDP, cisplatin; RT, radiation therapy.

Source: Adapted from Moroney JW, Kunos C, Wilkinson EJ, et al. Chapter 19: Vagina. In: Principles and Practices of
Gynecologic Oncology, 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2013:547.

The most compelling initial data in support of concurrent chemoradiation in the management
of locally advanced disease come from a large prospective phase II trial performed by the
GOG. In the GOG 101 study, 71 evaluable patients with locally advanced T3 or T4 disease
who were deemed not resectable by standard radical vulvectomy underwent preoperative
chemoradiation. Chemotherapy consisted of two cycles of 5-fluorouracil and cisplatin.
Radiation was delivered to a dose of 47.6 Gy, using a planned split-course regimen, with part
of the radiation given twice daily during the 5-fluorouracil infusion. Patients underwent
planned resection of the residual vulvar tumor, or incisional biopsy of the original tumor site
in the case of complete clinical response, 4 to 8 weeks after chemoradiotherapy. A complete
clinical tumor response was noted in 33/71 (47%) patients. Following vulvar excision or
biopsy, 22 patients (31%) were found to have no residual tumor in the pathologic specimen.
With a median follow-up interval of 50 months, 11 patients (16%) have developed locally
recurrent disease in the vulva.
Encouraged by the impressive outcome of their initial chemoradiation protocol, the GOG
conducted a second phase II prospective trial to examine a more intensive chemoradiation
regimen. In the GOG 205 study, the total radiation dose was increased to 57.6 Gy at 1.8 Gy
daily over 32 fractions. Chemotherapy consisted of weekly cisplatin (40 mg/m2). As with the
GOG 101 study, patients underwent a planned surgical resection of residual tumor or biopsy
to confirm complete clinical response 6 to 8 weeks after completion of chemoradiation. Out
of 58 evaluable patients, 37 patients achieved a complete clinical response (64%), and 29 of
these 37 patients (78%) also demonstrated a complete pathologic response. Among all
evaluable patients, the complete pathologic response rate was 50% (29/58). With a median
follow-up of 24.8 months, four patients (7%) have developed recurrent or persistent disease
in the vulva. The superior results of this study compared to that of GOG 101 supports a dose–
response curve for SCC of the vulva to radiotherapy. A 2011 Cochrane review showed when
comparing primary surgery to chemoradiation, there was no difference in OS in patients with
vulvar SCC (2011).

Treatment of Regional Disease

Although radical inguinal lymphadenectomy has historically been considered the treatment
of choice for regional management of invasive vulvar carcinoma, a number of retrospective
studies have suggested that regional prophylactic radiation therapy is an effective method of
preventing groin recurrences with minimal morbidity. The GOG tried to define the optimal
approach to clinically negative inguinal nodes in a trial that randomized patients between
inguinal node irradiation and radical lymphadenectomy (followed by inguinopelvic
irradiation in patients with positive nodes) after resection of the primary tumor. This study
was closed after entry of only 58 patients when there appeared to be a higher rate of groin
recurrence in the radiation treatment arm. However, this study has been criticized because the
treatment protocol did not use CT-based radiotherapy planning and recommended
combination photon and electron prescribed to a depth of 3 to 4 cm and likely delivered an
inadequate dose to the inguinal nodes.
While the role of prophylactic radiotherapy in the undissected but high-risk groin
remains unresolved, there is strong evidence that adjuvant radiation therapy improves
regional tumor control and survival in patients who have documented nodal metastases
following inguinal node dissection. The critical role of radiation therapy was not appreciated
until 1986, when results of a prospective GOG trial in 114 patients with inguinal metastases
were published. In that study, all patients underwent radical vulvectomy and inguinal
lymphadenectomy. Patients who had positive inguinal nodes were randomized
intraoperatively to receive either pelvic node dissection or postoperative irradiation to the
pelvis and inguinal nodes. This trial was closed before the projected accrual goal because an
interim analysis revealed a statistically significant overall survival advantage for the radiation
treatment arm (p = 0.03). The differences between the 2-year survival rates of patients treated
with radiation therapy or pelvic dissection were most marked for patients presenting with
clinically positive nodes (59% and 31%, respectively) and for those with two or more
positive groin nodes (63% and 37%, respectively). There was no significant difference in
survival between the treatment groups for patients with only one microscopically positive
node, although the authors commented that the number of patients in this subset was
insufficient for reliable analysis. The most striking difference in the patterns of recurrence for
the two treatment groups was the much larger number of inguinal failures among patients
who were treated with surgery alone (Fig. 5.3). These groin recurrences were rarely if ever
salvageable. The vulva, regardless of tumor pathologic risk factors, was not included in the
radiation treatment fields in this study, and approximately 9% of patients in both treatment
arms had recurrences at the primary site at the time of the analysis, raising the question of
whether selective radiation to the vulva may have decreased local recurrences. The role of
adjuvant radiation for patients with a single positive groin node following a complete
inguinal node dissection remains unresolved.

FIGURE 5.3 Sites of disease recurrence in patients treated with adjuvant

radiation therapy to the pelvis and inguinal region or with pelvic node dissection
following radical vulvectomy and bilateral inguinal lymphadenectomy. Source:
Modified from Homesley HD, Bundy BN, Sedlis A, et al. Radiation therapy
versus pelvic node resection for carcinoma of the vulva with positive groin
nodes. Obstet Gynecol. 1986;68:733, with permission.

Successful use of concurrent chemoradiation following radical hysterectomy in cervical

cancer patients with positive lymph nodes suggests that concurrent chemoradiotherapy might
improve outcomes for patients with node-positive vulvar cancer. The GOG opened a phase
III, prospective, randomized study (GOG 185) to compare inguinofemoral irradiation alone
or in combination with weekly cisplatin for 6 weeks in patients with vulvar cancer and
positive groin nodes. Unfortunately, this study was closed due to lack of accrual.
The role of preoperative chemoradiation has been assessed in patients who present with
bulky, unresectable inguinal adenopathy at the time of presentation. In the GOG 101 study of
preoperative chemoradiation for locoregionally advanced vulvar cancer, there was a cohort of
42 evaluable patients with N2 or N3 nodal disease that were deemed initially unresectable.
Two patients (5%) had nodal disease that remained unresectable after combined
chemotherapy and radiation therapy. The surgical specimen showed histologic clearance of
nodal disease in 15 patients (36%). At a median follow-up of 78 months, only 1/37 (3%)
patients relapsed in the groin. For patients who are not able to undergo surgical resection,
higher doses delivered to the groin nodes are needed to control gross disease. This is best
determined close to the completion of their initial planned radiotherapy to prevent a gap
between any additional radiotherapy to boost the nodes, and therefore close multidisciplinary
communication is encouraged. This study, while nonrandomized, provides further evidence
of the efficacy of combined chemoradiotherapy in the management of locoregionally
advanced vulvar cancer and in patients with significant regional adenopathy. Given the high
risk of distant relapse with node-positive vulvar cancer, especially in those with greater than
or equal to two involved nodes, adjuvant concurrent chemotherapy in addition to radiation
should be considered for such high-risk patients. In patients with positive inguinal nodes, the
risk of pelvic node involvement is approximately 30%.

Radiation Therapy Technique

Techniques commonly used for the treatment of vulvar carcinoma reflect the need to
encompass the lower pelvic and inguinal nodes as well as the vulva while minimizing the
dose to the femoral heads, bowel, and other normal tissue. Historically, treatments were
planned using two-dimensional or three-dimensional planning with an anterior field that
encompasses the inguinal regions, lower pelvic nodes, and vulva and a more narrow posterior
field that encompassed the lower pelvic nodes and vulva but excluded the majority of the
femoral heads with subsequent boosting of disease in the vulva and groin nodes with electron
fields. This type of therapy, however, is associated with significant skin fibrosis and femoral
neck fractures. The introduction of CT simulation for radiotherapy planning has increased the
ability to spare adjacent critical normal tissues while escalating doses to the nodes as well as
primary vulva if necessary through the use of intensity-modulated radiation therapy (IMRT).
There is, however, a steep learning curve for the use of IMRT for vulvar cancers given the
relative rarity of the disease and thus judicious identification of the at-risk regions to treat is
imperative as recurrences in field are almost never salvageable. Additionally, compared to
conventional three-dimensional conformal therapy, IMRT can achieve a more conformal and
homogenous dose distribution, resulting in decreased toxicity to normal tissue, particularly in
large women where significantly decreased doses to normal tissue including the skin, bowel,
and femoral heads can be observed. Initial single-institution experience with preoperative
IMRT in conjunction with chemotherapy for locally advanced vulvar cancer has been
positive, with no documented grade 3 or higher gastrointestinal or genitourinary toxicity and
excellent rates of pathologic response (48.5% with complete pathologic response). An expert
consensus contouring atlas and guidelines for vulva IMRT has recently published. In
addition, the GOG is currently conducting a phase II trial examining the efficacy of cisplatin
and gemcitabine with concurrent IMRT for the primary treatment of locally advanced SCC of
the vulva.

Acute Complications of Radiation Therapy

Acute dermatologic reactions are brisk with radiotherapy, and doses of 35 to 45 Gy routinely
induce confluent moist desquamation depending on the patient’s body habitus and tumor
location. However, with adequate local care, this acute reaction usually resolves within 3 to 4
weeks following completion of therapy. Sitz baths, aluminum acetate solution (astringent),
water-based emollient creams, and treatment of possible superimposed Candida infection or
narcotics all help to minimize the discomfort. Providing flexibility, treatment in a frog-leg
position is recommended to minimize the dose and ensuing skin reaction on the medial
thighs; care must then be taken, however, to deliver an adequate dose to the vulvar skin,
especially when using IMRT. Dose verification strategies, such as thermolucent dosimeters,
should be routinely used and skin bolus included if the dose is inadequate to at-risk regions.
Although most patients will develop confluent mucositis by the 4th week of treatment, this is
usually tolerated if the patient is warned in advance and assured that the discomfort will
resolve after treatment is completed. Although a treatment break is occasionally required,
delays should be minimized because they may allow time for the repopulation of tumor cells.

Late Complications of Radiation Therapy

The morbidity and risk of late complications depend on the technique of radiotherapy (IMRT
vs. 2D/3D) as well as the extent of surgery, if performed. If the vulva is treated, late
complications on the underlying bladder and rectum would mirror complications seen with
postoperative radiation for endometrial or cervical carcinoma including cystitis and proctitis.
Irradiation to the vagina during vulvar irradiation can lead to shortening, narrowing,
decreased lubrication, and sexual dysfunction in addition to skin fibrosis. Use of a vaginal
dilator, especially in younger patients, should be considered posttreatment. Patients are often
elderly and may have complicating medical conditions, such as diabetes, multiple prior
surgeries, and osteoporosis, that may complicate the care of the vulvar region. The
contribution of concurrent chemotherapy to local morbidity is not yet clearly defined but may
contribute to bowel and bone complications.
The incidence of lower extremity edema after inguinal irradiation alone is negligible.
Although radiation therapy likely contributes to the incidence of peripheral edema following
radical node dissection, no difference was evident in a GOG randomized study. In general,
with careful treatment planning technique, the risk of major late complications following
regional nodal radiation, either electively or adjuvant to lymph node dissection, can be low.

Chemotherapy
Squamous Cell Carcinoma
Squamous carcinoma is the only cell type for which reproducible information exists on the
value of cytotoxic therapy. Several drugs have undergone phase II testing in squamous vulvar
cancer. Only doxorubicin and bleomycin appear to have activity as single agents. Cisplatin
has notably little activity in vulvar and vaginal squamous tumors. This lack of activity,
however, is based on the treatment of refractory patients only. No trials of this agent as a
presurgical cytoreductive regimen have been attempted. With the impressive results obtained
with concurrent cisplatin-based chemotherapy and radiation therapy in locally advanced
squamous cancer of the cervix, one must consider a similar approach in the patient with
locally advanced squamous cancer of the vulva. Several drug combinations have also been
used in squamous vulvar cancer. Toxicity with these regimens has been reported as tolerable.
There are some increasing reports of the concomitant use of cytotoxic therapy with
irradiation, usually as primary therapy in advanced and inoperable disease. Cisplatin-based
combination therapy with agents such as 5-fluorouracil and, in the current GOG study,
gemcitabine has been used to good effect. The largest experience in vulvar cancer was
recently reported by the GOG and is noted above.

Results of Therapy
The overall results of therapy for women with squamous cancers of the vulva are excellent.
Approximately two-thirds of patients present with early-stage tumors. Five-year survival
rates of 80% to 90% are routinely reported for stage I and II diseases, respectively. As
anticipated, survival rates for patients with advanced disease are poor: 60% for stage III cases
and 15% for stage IV (Fig. 5.4). The survival rate for women with nodal spread is one-half
that of women without nodal disease who have similarly sized primary tumors (Fig. 5.5).
FIGURE 5.4 Invasive squamous vulvar carcinoma. Survival by FIGO stage.
Source: Patients treated at M. D. Anderson Cancer Center 1944–1990; data
courtesy of F. N. Rutledge.
FIGURE 5.5 Invasive squamous vulvar carcinoma. Survival of patients with
positive nodes. Source: Data courtesy of F. N. Rutledge.

Management of Other Vulvar Malignancies

Malignant Melanoma
Malignant melanoma is the second most common vulvar malignancy. The primary treatment
modality for vulvar melanoma is radical surgical excision. Because most failures are distant,
ultraradical local resection does not appear to enhance survival. Depth of invasion and the
presence of ulceration are significant prognostic factors and should be considered in
treatment planning. Locke et al. reported that none of the patients with lesion depth of less
than or equal to 1.75 mm experienced a recurrence and suggested that these patients could be
treated with wide local excision. In contrast, all patients with lesion depth of greater than
1.75 mm recurred despite radical tumor excision. Lymphadenectomy can be avoided in
patients with superficial melanomas for whom the risk of metastatic disease is negligible.
SLN identification and biopsy may have a role, although data regarding SLNB for vulvar
melanomas are limited. Radiation therapy may be useful in enhancing local and regional
control for some high-risk patients.
Systemic chemotherapy, in either an adjuvant or salvage setting, is considered palliative,
but responses are truly rare, and adverse effects may be significant. Biologic and
immunologic approaches to the treatment of malignant melanoma are currently being
evaluated.
Overall survival rates in women with vulvar melanoma are approximately 50%. Patients
with superficial lesions have an excellent chance for cure after surgical resection, but patients
with deeper lesions or metastases at the time of diagnosis have a more dismal prognosis.
Immunotherapies including CTLA-4 inhibitors and PD-1/PD-L1 inhibitors are approved for
metastatic melanoma and could be considered.

Verrucous Carcinoma
Verrucous carcinomas are locally invasive and rarely metastasize. Consequently, treatment by
radical wide excision is usually curative. Local recurrence can occur, especially when the
tumor has been inadequately resected. Radiation therapy is generally not recommended due
to published reports of anaplastic transformation and widespread metastases following
radiotherapy.

Basal Cell Carcinoma

Basal cell carcinomas should be removed by excisional biopsy using a minimum surgical
margin of 1 cm. Lymphatic or distant spread is exceedingly rare. In patients who are poor
surgical candidates or with lesions where resection would cause undue morbidity,
consideration can be given to primary radiation therapy. Large retrospective reviews
demonstrate 5-year local control rates of over 90% in previously untreated lesions.

Adenocarcinoma
Despite the paucity of data regarding the evaluation and treatment of vulva adenocarcinoma,
resection of localized disease by radical wide excision, hemivulvectomy, or radical
vulvectomy seems appropriate. The incidence of groin node metastases is approximately
30%. Some form of inguinal lymphadenectomy should be included with primary surgical
resection. Radiation therapy may have a role in enhancing local control for women with
small margins, unresectable disease, large primary tumors, or inguinal metastases.

Paget Disease
Paget disease should be resected with a wide margin, but recurrences are common. If
underlying invasion is suspected, the deep margins should be extended to the perineal fascia.
Repeat local excision of recurrent disease is usually effective in the absence of invasion.

Vulvar Sarcomas
All types of vulva sarcoma are rare, but leiomyosarcoma, malignant fibrous histiocytoma,
and rhabdomyosarcoma predominate. Cures have occasionally been obtained with aggressive
resection of either primary or locally recurrent disease. The results of regional and systemic
therapy for leiomyosarcoma are disappointing; however, rhabdomyosarcoma seems to be
more responsive to both chemotherapy and radiation than other soft tissue sarcomas. The
current treatment of choice is to combine chemoradiation with limited surgical resection of
residual disease.

Future Directions
Vulvar cancer is an uncommon neoplastic disease, and its relative rarity is a major obstacle in
designing prospective randomized trials. Current trends in its management are focusing on a
more individualized approach that emphasizes conservative vulva surgical resection when
feasible, the use of reconstructive procedures to preserve or restore vulva function, potential
reduction in groin complications through SLNB, and multimodality therapy for advanced or
disseminated disease (Fig. 5.6).
FIGURE 5.6 Management of invasive vulvar cancer. Source: Reprinted with
permission from Markman M, ed. Atlas of Cancer, 2nd ed. Philadelphia, PA:
Springer; 2008.

Suggested Readings
American Cancer Society. Cancer Facts & Figures 2019. Atlanta, GA: American Cancer Society; 2019.
Arvas M, Kahramanoglu I, Bese T, et al. The role of pathological margin distance and prognostic factors after primary
surgery in squamous cell carcinoma of the vulva. Int J Gynecol Cancer. 2018;28(3):623–631. doi:
10.1097/IGC.0000000000001195.
Beriwal S, Shukla, G, Shinde A, et al. Preoperative intensity modulated radiation therapy and chemotherapy for locally
advanced vulvar carcinoma: Analysis of pattern of relapse. Int J Radiat Oncol Biol Phys. 2013;85(5):1269–1274.
Coleman RL, Ali S, Levenback CF, et al. Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva
always necessary? An analysis from Gynecologic Oncology Group (GOG) 173. Gynecol Oncol. 2013;128:155–159.
Faber MT, Sand FL, Albieri V, Norrild B, Kjaer SK, Verdoodt F. Prevalence and type distribution of human papillomavirus
in squamous cell carcinoma and intraepithelial neoplasia of the vulva. Int J Cancer. 2017;141(6):1161–1169.
Faul CM, Mirmow D, Huang Q, Gerszten K, Day R, Jones MW. Adjuvant radiation for vulvar carcinoma: Improved local
control. Int J Radiat Oncol Biol Phys. 1997;38(2):381–389. doi: 10.1016/S0360-3016(97)82500-X.
Gonzalez Bosquet J, Magrina JF, Magtibay PM, et al. Patterns of inguinal groin metastases in squamous cell carcinoma of
the vulva. Gynecol Oncol. 2007;105:742–746. doi: 10.1016/j.ygyno.2007.02.014.
Hoang LN, Park KJ, Soslow RA, Murali R. Squamous precursor lesions of the vulva: Current classification and diagnostic
challenges. Pathology. 2016;48(4):291–302. doi: 10.1016/j.pathol.2016.02.015.
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. 2008;17:1611.
Kunos C, Simpkins F, Gibbons H, et al. Radiation therapy versus pelvic node resection for carcinoma of the vulva with
positive groin nodes: An update of a Gynecologic Oncology Group study. Obstet Gynecol. 2009;114(3):537–546.
Levenback CF, Ali S, Coleman RL, et al. Lymphatic mapping and sentinel lymph node biopsy in women with squamous
cell. Carcinoma of the vulva: A Gynecologic Oncology Group study. J Clin Oncol. 2012;30:3786–3791.
Locke J, Karimpour S, Young G, et al. Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Biol Phys.
2001;51(3):748.
Medeiros F, Nascimento AF, Crum CP. Early vulvar squamous neoplasia: Advances in classification, diagnosis, and
differential diagnosis. Adv Anat Pathol. 2005;12(1):20–26.
Monk BJ, Burger RA, Lin F, et al. Prognostic significance of human papillomavirus DNA in vulvar carcinoma. Obstet
Gynecol. 1995;85:709.
Oonk MH, van Hemel BM, Hollema H, et al. Size of sentinel-node metastasis and chances of non-sentinel-node
involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study.
Lancet Oncol. 2010;11:646–652.
Shylasree TS, Bryant A, Howells REJ. Chemoradiation for advanced primary vulval cancer. Cochrane Database Syst Rev.
2011;(4):CD003752. doi: 10.1002/14651858.CD003752.pub3.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11.
Silverman MK, Kopf AW, Gladstein AH, et al. Recurrence rates of treated basal cell carcinomas. Part 4: X-ray therapy. J
Dermatol Surg Oncol. 1992;18(7):549.
Van Der Zee AG, Oonk MH, De Hullu JA, et al. Sentinel node dissection is safe in the treatment of early-stage vulvar
cancer. J Clin Oncol. 2008;26:884–849. doi: 10.1200/JCO.2007.14.0566.
 6 The Vagina

Anatomy
The vagina is a muscular dilatable tubular structure averaging 7.5 to 8.5 cm in length that
extends from the cervix to the vulva. It lies dorsal to the bladder and urethra and ventral to
the rectum. The upper portion of the posterior wall is separated from the rectum by a
reflection of peritoneum, the pouch of Douglas. The vaginal wall is composed of three layers:
the mucosa, muscularis, and adventitia. The inner mucosal layer is formed by a thick,
nonkeratinizing, stratified squamous epithelium.
The lymphatics in the upper portion of the vagina drain primarily with the cervix; the
upper anterior vagina drains along cervical channels to the internal iliac and parametrial
nodes, while the posterior vagina drains into the inferior gluteal, presacral, and anorectal
nodes. The distal vaginal lymphatics follow drainage patterns of the vulva into the inguinal
and femoral nodes before coursing to the pelvic nodes. Bilateral pelvic nodes should be
considered to be at risk in any invasive vaginal carcinoma, and bilateral groin nodes should
be considered to be at risk in lesions involving the distal third of the vagina.

Epidemiology and Etiologic Risk Factors

Key Points
Eighty to ninety percent of vaginal neoplasms represent metastases from other
primary gynecologic (cervix or vulva) sites, involving the vagina by direct
extension or lymphatic routes.
Peak incidence of vaginal carcinoma is in the sixth and seventh decades of life;
however, it is increasingly seen in younger women, possibly due to human
papillomavirus (HPV) infection.

Primary vaginal cancer, defined as a lesion arising in the vagina without involvement of the
cervix or vulva, is a rare entity, representing only 1% to 2% of all female genital neoplasms.
In 2016, 1,293 new cases of primary vaginal cancer were identified and 386 deaths occurred
from this disease in the United States (2019). Most vaginal neoplasms, 80% to 90%,
represent metastases from other primary gynecologic (cervix or vulva) and nongynecologic
sites, involving the vagina by direct extension or lymphatic or hematogenous routes.
Carcinoma of the vagina is considered to be associated with advanced age, with the peak
incidence occurring in the sixth and seventh decades of life. However, vaginal cancer is
increasingly being seen in younger women, possibly due to HPV infection or other sexually
transmitted diseases. Only about 10% of patients are 40 years of age or younger. A decrease
in the incidence of primary vaginal tumors has been noted in recent years, possibly because
of early detection with cervical cytology or more rigid diagnostic criteria, which have
eliminated from this category primary cancers arising from adjacent organs, such as the
cervix, vulva, or endometrium.

Vaginal Intraepithelial Neoplasia and Squamous Cell

Carcinoma
Approximately 80% to 90% of vaginal neoplasms are squamous cell carcinomas (SCC), and
the incidence of this histology increases with age. Potential risk factors for vaginal SCC
include prior history of HPV infection, cervical intraepithelial neoplasia (CIN), vulvar
intraepithelial neoplasia (VIN), immunosuppression, and possibly previous pelvic irradiation.
HPV is the likely etiologic agent of SCC and its precursor lesion, vaginal intraepithelial
neoplasia (VaIN). One population-based case–control study of 156 women with SCC in situ
or invasive vaginal cancer demonstrated the presence of HPV DNA in over 80% and 60% of
these two respective patient groups.
In studies reporting on groups of women with VaIN and SCC of the vagina, the following
risk factors have been identified: five or more sexual partners, first sexual intercourse before
age 17, smoking, low socioeconomic status, a history of genital warts, prior abnormal
cytology, and prior hysterectomy. There is also evidence that in utero exposure to
diethylstilbestrol (DES) doubles the risk of development of VaIN. The putative mechanism is
an enlargement of the transformation zone at risk, which is then consequently at risk for
infection with HPV.
Patients with previous cervical carcinoma have a substantial risk of developing vaginal
carcinoma, presumably because these sites share exposure and/or susceptibility to
endogenous or exogenous carcinogenic stimuli. About 10% to 50% of patients with VaIN–
carcinoma in situ (CIS) or invasive carcinoma of the vagina have undergone prior
hysterectomy or radiotherapy (RT) for CIS or invasive carcinoma of the cervix. The interval
from therapy for cervical cancer or preinvasive disease to the development of carcinoma of
the vagina averages nearly 14 years.

Clear Cell Adenocarcinoma

An increased incidence of clear cell adenocarcinoma (CCA) of the vagina in young women
related to in utero exposure to DES during the first 16 weeks of pregnancy was first reported
in 1971. Specific suggested mechanisms of carcinogenesis focus on the retention of nests of
abnormal cells of müllerian duct origin, which, after stimulation by endogenous hormones
during puberty, are transformed into adenocarcinomas. The median age at diagnosis in the
DES-exposed patients is 19 years, whereas prior to this report, most patients with CCA of the
vagina were elderly. Hicks and Piver noted that 60% of CCA patients had been exposed to
DES or similar agents in utero, that most cases involved the anterior upper third of the
vaginal wall, and that DES-associated CCA cases had been reported from ages 7 to 34
(median, 19 years). Fortunately, the incidence of this tumor has decreased in recent years and
may decrease even more since the practice of prescribing DES during pregnancy has been
discontinued.

Melanoma
Malignant melanoma is a very rare cancer of the vagina with less than 300 cases reported to
date. Primary vaginal malignant melanoma accounts for less than 3% of all vaginal
neoplasms. The mean age of diagnosis is approximately 60 years, and these cases are
reported predominantly in Caucasian women. The most common location is the lower third
and the anterior vaginal wall, although oftentimes it is multifocal.

Sarcomas
Sarcomas represent 3% of primary vaginal cancers and are most common in adults, with
leiomyosarcoma representing 50% to 65% of vaginal sarcomas. Malignant mixed müllerian
tumor (carcinosarcoma), endometrial stromal sarcoma, and angiosarcoma are less common.
Embryonal rhabdomyosarcoma (RMS)/sarcoma botryoides is a rare, malignant pediatric
tumor, and RMS arising in the female genital tract accounts for less than 4% of all pediatric
RMS. Prior pelvic RT is a risk factor, particularly for mixed mesodermal tumors and vaginal
angiosarcomas. Histopathologic grade appears to be the most important predictor of
outcome.

Natural History
Key Points
The majority of vaginal primaries occur in the upper third or at the apex of the
vault, most commonly in the posterior wall, and as a result careful examination
including rotation of the speculum so that the posterior blade does not obscure
this region is critical.
If positive biopsies of the cervix or the vulva return at the time of initial diagnosis,
the tumor cannot be considered to be a primary vaginal lesion.
There is a significant risk of nodal metastasis for patients with disease beyond
stage I.

The majority (57% to 83%) of vaginal primaries occur in the upper third or at the apex of the
vault, most commonly in the posterior wall; the lower third may be involved in as many as
31% of patients. Lesions confined to the middle third of the vagina are uncommon. The
location of the vaginal carcinoma is an important consideration in planning therapy and
determining prognosis. Vaginal tumors may spread along the vaginal walls to involve the
cervix or the vulva. However, if biopsies of the cervix or the vulva are positive at the time of
initial diagnosis even if the bulk of disease is in the vagina, by convention the tumor cannot
be considered a primary vaginal lesion for staging purposes, as cervical and vulvar cancer are
much more common. A lesion on the anterior wall may infiltrate the vesicovaginal septum
and/or the urethra; those on the posterior wall may eventually involve the rectovaginal
septum and subsequently infiltrate the rectal mucosa. Lateral extension toward the
parametrium and paracolpal tissues is not uncommon in more advanced stages of the disease.
There is a significant risk of nodal metastasis for patients with disease beyond stage I.
Although data on staging lymphadenectomy are sparse, two studies reported a significant
incidence of nodal disease in early-stage vaginal carcinoma. In the series by Al-Kurdis and
Monaghan, the incidence of pelvic nodal metastasis was 14% and 32% for stages I and II,
respectively, whereas in the series by Davis et al., the incidence was 6% and 26% for stages I
and II, respectively. The incidence is expected to be higher for stage III, although no
substantial data are available. The incidence of clinically positive inguinal nodes at diagnosis
reported by several authors ranges from 5.3% to 20%.
Distant metastasis may occur, primarily in patients with advanced disease at presentation
or those who recurred after primary therapy. In the series by Perez et al. (1999), the incidence
of distant metastasis was 16% in stage I, 31% in stage IIA, 46% in stage IIB, 62% in stage
III, and 50% in stage IV.

Clinical Presentation
Vaginal Intraepithelial Neoplasia—Carcinoma In Situ
VaIN most often is asymptomatic. In modern practice, VaIN is usually detected by cytologic
evaluation performed following hysterectomy as part of a surveillance strategy in patients
with a history of CIN or invasive cervical carcinoma. In these cases, VaIN has a predilection
for involvement of the upper vagina, likely secondary to a “field effect.” It should be noted
that evidence-based guidelines do not support routine cytologic studies following
hysterectomy for noncervical pathology. Rather, surveillance cytology post hysterectomy
should be limited to those patients with a prior history of CIN or invasive cervix cancer.

Invasive Squamous Cell Carcinoma

In patients with invasive disease, irregular vaginal bleeding, often postcoital, is the most
common presenting symptom, followed by vaginal discharge and dysuria. Pelvic pain is a
relatively late symptom generally related to tumor extent beyond the vagina. Other symptoms
like urinary obstruction can occur for lesions approximating the urethra.

Other Histologies
The most common presenting symptom in patients with CCA is vaginal bleeding (50% to
75%) or abnormal discharge. More advanced cases may present with dysuria or pelvic pain.
Embryonal RMS, the most common malignant vaginal tumor in children, presents as a
protruding, edematous grapelike mass. Ninety percent of these sarcomas present before the
age of 5 years.

Diagnostic Workup
In general, in patients with suspected vaginal malignancy, thorough physical examination
with detailed speculum inspection, digital palpation, colposcopic and cytologic evaluation,
and biopsy constitutes the most effective procedure for diagnosing primary, metastatic, or
recurrent carcinoma of the vagina. In order to obtain a biopsy, examination under anesthesia
is recommended for the thorough evaluation of all of the vaginal walls and local extent of the
disease, primarily if the patient is in great discomfort because of advanced disease. Biopsies
of the cervix, if present, are recommended to rule out a primary cervical tumor. The
speculum must be rotated as it is slowly withdrawn from the vaginal fornix so that the total
vaginal mucosa may be visualized, and, in particular, so that posterior wall lesions, which
occur frequently, are not overlooked.
The patient with a history of preinvasive or invasive carcinoma of the cervix found to
have abnormal cytology following prior hysterectomy or RT should be offered vaginoscopy
with the application of acetic acid to the entire vault, followed by biopsies as indicated by
areas of white epithelium (“acetowhite” areas), mosaicism, punctation, or atypical
vascularity. Application of half-strength Schiller iodine following the application of acetic
acid to determine if the Schiller-positive (nonstaining) areas correspond with the acetowhite
areas is another method of identifying high-risk regions requiring biopsy.

Staging
At present, primary malignancies of the vagina are all staged clinically. In addition to a
complete history and physical examination, routine laboratory evaluations including
complete blood cell count with differential and platelets and assessment of renal and hepatic
function should be undertaken. In order to determine the extent of disease, the following tests
are allowed by International Federation of Gynecology and Obstetrics (FIGO) criteria: chest
and skeletal radiograph, a thorough bimanual and rectovaginal examination, cystoscopy,
proctoscopy, and intravenous pyelogram. It can be difficult even for the experienced
examiner to differentiate between disease confined to the mucosa (stage I) and disease spread
to the submucosa (stage II).
Although advanced imaging techniques do not change the FIGO stage, they are important
for determining the overall treatment plan. Pelvic computed tomography (CT) scan is
generally performed to evaluate inguinofemoral and/or pelvic lymph nodes, as well as extent
of local disease. In patients with vaginal melanoma or sarcoma, chest, abdomen, and pelvic
CT scans are often part of the workup. Magnetic resonance imaging (MRI) is superior to CT
imaging for evaluation of vaginal cancers due to the soft tissue resolution, predominantly the
T1-weighted images with contrast and T2-weighted images. Additionally, water-based gel
placed in the vagina prior to imaging helps distend the walls allowing visualization of the
extent of disease, particularly smaller lesions, and acts as a contrast on T2-weighted imaging
as the gel is bright compared to the tumor or soft tissue. MR imaging is helpful for radiation
oncologists to identify the extent of primary disease and is often repeated during the course
of external beam RT to aid in planning a brachytherapy boost or an external beam boost if
brachytherapy cannot be performed. Tumors less than 5 mm in size may be treated
sufficiently with intracavitary brachytherapy (ICB) compared to interstitial brachytherapy
(ITB). Positron emission tomography with computed tomography (PET/CT) is helpful in
evaluating the extent of nodal disease and presence of distant metastases and is useful in
planning external beam RT particularly the extent of fields and/or nodal boosts.
The two commonly used staging systems for carcinoma of the vagina are the FIGO
(Table 6.1) and the American Joint Commission on Cancer (TNM) (Table 6.2) classifications.
According to FIGO guidelines, patients with tumor involvement of the cervix or vulva should
be classified as primary cervical or vulvar cancers, respectively, given the rarity of vaginal
cancers.

TABLE 6.1 FIGO Staging System for Carcinoma of the Vagina

Source: From FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer of the vagina, fallopian tube,
ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet. 2009;105(1):3–4, with permission.

TABLE 6.2 American Joint Commission on Cancer (AJCC, 7th Edition)

Staging of Vaginal Cancer
Source: Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al., eds. AJCC
Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.

Pathologic Classification
Squamous Cell Carcinoma
The most common malignant tumor of the vagina is SCC, representing about 80% to 90% of
primary vaginal cancers. These tumors occur in older women and are most often located in
the upper, posterior wall of the vagina. For a neoplasm to be considered a vaginal primary,
there must not be involvement of the cervix or vulva or a history of cervical cancer for 5
years prior to the diagnosis. Histologically, keratinizing, nonkeratinizing, basaloid, warty, and
verrucous variants have been described. Tumors may also be graded as well, moderately, or
poorly differentiated, based on a combination of cytologic and histologic features. However,
there is little correlation between tumor grade and survival.
Verrucous carcinoma is a rare distinct variant of well-differentiated SCC, usually with the
appearance of a large, well-circumscribed, soft, cauliflower-like mass. Verrucous carcinoma
may recur locally after surgery but rarely metastasizes.
VaIN is a precursor of SCC and is graded from 1 to 3, based on the thickness of epithelial
involvement. Alternatively, VaIN can be classified as low or high grade. High-grade lesions
indicate involvement of the outer third of the mucosa and include CIS, which encompasses
the entire thickness of the epithelium. The true incidence of VaIN and its rate of progression
to invasive carcinoma is unclear, ranging in several series from 9% to 28%. High-risk HPV
was noted in 35% of VaIN 1 and 94% of VaIN 3 lesions. Comparison of the distribution of
HPV types in the vagina, vulva, and cervix suggests that VaIN is more closely related to CIN
than to VIN.

Clear Cell Adenocarcinoma and Vaginal Adenosis

DES-associated CCA has a predilection for the upper third of the vagina and the exocervix. It
is frequently located at or near the lower margin of the zone of glandular tissue in the vagina
or cervix. Most CCAs are exophytic and superficially invasive. About 97% will be associated
with mucosal adenosis. CCA is mainly composed of clear and hobnail-shaped cells. The
major determinant of outcome in CCA is stage, but some pathologic features are statistically
associated with better outcome, including a tubulocystic growth pattern, size less than 3 cm2,
and less than 3 mm of stromal invasion.
Vaginal adenosis is a condition in which müllerian-type glandular epithelium is present
after vaginal development is complete. Although adenosis is the most common histologic
abnormality in women exposed to DES in utero, it is not strictly confined to this population.
Atypical adenosis of tuboendometrial type appears to be a precursor lesion of CCA.

Other Adenocarcinomas
Primary adenocarcinoma of the vagina is rare and occurs predominantly in postmenopausal
women.

Melanoma
Malignant melanoma of the vagina accounts for less than 3% of vaginal neoplasms. In
contrast to SCC, the most common locations of vaginal melanoma are the lower third and the
anterior vaginal wall. Grossly, these tumors are typically pigmented and show considerable
variation in size, color, and growth patterns, being polypoid or nodular in the majority of
cases. Immunohistochemical stains are frequently positive for S100 protein, HMB-45, and
melan-A. Tyrosinase and MART-1 are useful markers when S100 is negative or only focally
positive. Tumor thickness correlates with prognosis and may be measured by the method of
Breslow.

Mesenchymal Tumors
Embryonal RMS is a rare pediatric tumor. The botryoid variant, or sarcoma botryoides, is the
most common malignant vaginal tumor in infants and children. Ninety percent of cases occur
in children younger than 5 years of age. Sarcoma botryoides has a characteristic macroscopic
appearance consisting of multiple gray-red, translucent, edematous, grapelike masses that fill
the vagina and may protrude from it.
Leiomyosarcoma is the most common vaginal sarcoma in adults. Smooth muscle tumors
3 cm or greater in diameter have an increased risk of recurrence. Although they may
originate in any part of the vagina, most are submucosal.

Prognostic Factors Influencing Choice of Treatment

Key Points
Primary malignancies of the vagina are all staged clinically.
The most common malignant tumor of the vagina is SCC.
VaIN is a precursor of SCC.
Exposure to DES in utero is associated with the development of CCA.
Stage of disease is the dominant prognostic factor in terms of outcome.
Vaginal melanoma has a higher propensity for the development of distant
metastases, and these patients do more poorly than patients with SCC.

Invasive Squamous Cell Carcinoma

Stage of disease is the dominant prognostic factor in terms of outcome. In the report by
Creasman et al. (1998), the 5-year survival rate was 96% for patients with stage 0, 73% for
stage I, 58% for stage II, and 36% for those with stage III and IV diseases, respectively. In
the series by Perez et al., including 165 patients with primary vaginal carcinomas treated with
definitive RT, the 10-year actuarial disease-free survival (DFS) was 94% for stage 0, 75% for
stage I, 55% for stage IIA, 43% for stage IIB, 32% for stage III, and 0% for those with stage
IV.
The impact of lesion location has been controversial. Several investigators have shown
superior survival and decreased recurrence rates for patients with cancers involving the
proximal half of the vagina when compared with those in the distal half or those involving
the entire length of the vagina. In addition, lesions of the posterior wall have a worse
prognosis than those involving other vaginal walls (10-year recurrence rates of 32% and
19%, respectively), which probably reflects the greater difficulty of performing adequate
brachytherapy procedures in this location.
 The prognostic importance of lesion size has also been controversial. Chyle et al. (1996)
noted that lesions measuring less than 5 cm in maximum diameter had a 20% 10-year local
recurrence rate compared to 40% for those lesions larger than 5 cm. Similarly, in the Princess
Margaret Hospital experience and more recently in the Stanford experience, tumors larger
than 4 cm in diameter fared significantly worse than smaller lesions (1995, 2013). Other data
suggest that disease volume, a likely surrogate for stage or lesion size, adversely impacted
survival as well as local control.
Several series have shown histologic grade to be an independent, significant predictor of
survival. Chyle et al. (1996) also noted histology was a significant predictor of outcome, with
a higher incidence of local recurrence in patients with adenocarcinoma compared with SCC
(52% and 20%, respectively, at 10 years), as well as a higher incidence of distant metastases
(48% and 10%, respectively) and lower 10-year survival rate (20% vs. 50%).

Other Histologies
An increased propensity for distant metastases to the lung and supraclavicular nodes has been
reported in patients with CCA. Stage, tubulocystic pattern, size less than 3 cm, and depth of
invasion less than 3 mm were all noted to be associated with superior survival.
Vaginal melanoma has a higher propensity for the development of distant metastases, and
affected patients have poor prognosis compared to those patients with SCC.
Patients with malignant mesenchymal tumors of the vagina do worse than those with
invasive SCC. Specific, adverse prognostic factors for vaginal sarcoma identified by
Tavassoli and Norris included infiltrative versus pushing borders, high mitotic rate of 5 or
more mitoses per 10 HPFs, size greater than 3 cm in diameter, and cytologic atypia.

General Management: Treatment Options and

Outcome by FIGO Stages
Key Points
Treatment options for VaIN range from partial or complete vaginectomy to more
conservative approaches such as local excision, electrocoagulation, laser
vaporization, topical 5% fluorouracil, or ICB.
Surgery may be preferable in select stage I and II patients with small, superficially
invasive SCC lesions at the apex and upper third of the posterior or lateral vagina.
External beam radiotherapy (EBRT) in conjunction with brachytherapy is
advisable in patients with deeply infiltrating or poorly differentiated stage I and II
lesions and in all patients with stage III to IVA disease.
Consideration should be given to delivering cisplatin-based chemotherapy
concurrently with RT in patients with advanced vaginal cancer.
Vaginal Intraepithelial Neoplasia—Carcinoma In Situ
VaIN has been approached both surgically and medically by multiple investigators. The
degree of VaIN and the age and general health of the patient are important treatment
considerations. For low-grade squamous intraepithelial lesion (VaIN1), vaginal cotesting is
widely accepted with potential for repeat colposcopy if abnormal. If persistent LSIL/VaIN1
beyond 2 years without prior HSIL or cancer, it would be reasonable to extend the screening
interval to every 2 to 3 years. VaIN2 is known as an equivocal diagnosis and has the potential
to regress. However, VaIN2 with positive p16 staining should be considered a true precancer
and should be treated—if p16 staining is negative, it would be reasonable to manage
conservatively (2007). For high-grade squamous intraepithelial lesion (VaIN3), a variety of
treatment options are acceptable. Treatment options range from partial or complete
vaginectomy to more conservative approaches such as local excision, electrocoagulation,
laser vaporization, topical 5% fluorouracil (5-FU) administration, or ICB. For patients in
whom invasive disease cannot be ruled out, as well as for those who fail conservative
therapy, surgical resection remains the treatment of choice. Overall, the reported control rates
are very similar among the different approaches, ranging from 48% to 100% for laser, 52% to
100% for colpectomy, 75% to 100% for topical 5-FU, and 83% to 100% for RT. After
treatment for p16+ VaIN2 or HSIL, cotesting in 12 months is reasonable and subsequent
colposcopy if the result is HPV+ or there is at minimum LSIL lesion.
Partial colpectomy is favored by many for the treatment of focal VaIN without any prior
history of pelvic RT. Patients who have received prior pelvic RT, wherein partial colpectomy
would have high risk of fistula formation, may benefit from a medical approach with topical
application of 5-FU. This acts by inciting a desquamation of the vaginal squamous
epithelium, which later re-epithelializes with presumably normal cells. Several schedules of
topical 5-FU have been reported; however, one preferred schedule is one-third applicator
weekly for 10 weeks. Regardless of which 5-FU application schedule is chosen, it is
important that the perineal skin be protected with a topical ointment, such as zinc oxide, to
prevent painful vulvar erosions. More recently, investigators have demonstrated the
feasibility and efficacy of topical imiquimod in the treatment of VaIN, with cure rates of up
to 86% reported in small single-institution studies. Imiquimod is a heterocyclic
imidazoquinoline amine that acts through toll-like receptor 7 to induce cytokine expression
and subsequent activation of both the innate and adaptive immune responses. This topical
medication is generally well tolerated with the majority of side effects limited to mild skin
reactions, such as redness, swelling, itching/burning, tenderness, and flaking.
Partial or total vaginectomy has been considered by many to be an acceptable treatment
for VaIN. However, one of its main drawbacks is shortening or stenosis of the vagina,
frequently with poor functional results. Prior RT is probably a contraindication to
vaginectomy owing to significantly increased morbidity. Control rates of 66% to 100%
following partial colpectomy have been achieved.
RT has a long history of documented efficacy with control rates ranging between 80%
and 100%, and a significantly better therapeutic ratio than other modalities. Using
conventional low dose rate (LDR) ICB techniques, the entire vaginal mucosa should receive
between 50 and 60 Gy, given the high incidence of multicentricity; the area of involvement
should receive 70 to 80 Gy, in one or two implants, prescribed to the mucosal surface. Higher
doses may cause significant vaginal fibrosis and stenosis. Perez et al. (1999) reported only
one distal local failure in the 20 patients treated for CIS. A more recent publication from
Blanchard et al. (2011) reported only one “in-field” recurrence in 28 patients treated with
LDR brachytherapy for VaIN3. Pelvic recurrences or distant failures have not been observed
in the absence of invasive component after ICB.
There have been some reports in the literature regarding the use of high dose rate (HDR)
ICB for patients with VaIN3; however, data are limited, and there is a lack of consensus
regarding fraction schedules. Based on the excellent local control and functional results
obtained with LDR-ICB, this remains the treatment of choice when definitive RT is used,
unless unavailable.

Invasive Squamous Cell Carcinoma

Surgical Approach and Outcomes
In general, SCC of the vagina has been treated with RT given the morbidity associated with
surgery particularly with large lesions given the location. However, several surgical series
have reported acceptable outcomes in well-selected patients, with survival rates after radical
surgery for stage I disease ranging from 75% to 100%. Situations in which surgery may be
the preferred treatment include selected stage I and II patients with lesions at the apex and
upper third of the posterior or lateral vagina that could be approached with radical
hysterectomy, upper vaginectomy, and pelvic lymphadenectomy, providing adequate margins
for very superficial lesions. Lesions in the lower third of the vagina would require
vulvovaginectomy in addition to dissection of inguinofemoral nodes to achieve negative
margins. If the margins are found to be close or positive after resection, adjuvant RT is
recommended. However, for lesions at other sites, and those cases requiring more extensive
resection, primary RT is the treatment of choice since it offers excellent results. Exenteration
should be reserved for those with central failure after RT or as primary therapy in those with
disease not fixed to the bone and have a contraindication to RT (i.e., prior RT).
Advanced-stage patients should receive primary RT, combined with concurrent
chemotherapy, if possible. This is based on extrapolation from the data in cervical cancer,
given the true benefit of concurrent chemotherapy in this population is unknown due to the
lack of randomized data.

Radiotherapy Techniques and Outcome

STAGE I
In patients with stage I lesions, usually 0.5 to 1 cm thick that may involve one or more
vaginal walls, it is important to individualize radiotherapy techniques to obtain optimal
functional results. Superficial lesions (<0.5 cm thick) can be adequately treated with ICB
alone using afterloading vaginal cylinders, assuming there is no evidence of nodal disease on
imaging. The entire length of the vagina is generally treated to a mucosal dose of 60 to 65 Gy
(LDR), and an additional mucosal dose of 20 to 30 Gy is delivered to the area of tumor
involvement. For lesions thicker than 0.5 cm at the time of implantation, it is advisable to
combine ICB and ITB with a single-plane implant to increase the depth dose and limit
excessive irradiation to the vaginal mucosa. An additional 15 to 20 Gy at a depth of 0.5 cm
beyond the plane of the implant will be delivered with the ITB such that the base of the
tumor receives between 65 and 70 Gy, with the involved vaginal mucosa receiving an
estimated 80 to 100 Gy. The proximal and distal vaginal mucosal doses should be limited to
140 and 100 Gy, respectively. The optimal fractionation schedule and dose for HDR
brachytherapy remain to be defined, especially for HDR monotherapy. The HDR dose
schedules proposed in the American Brachytherapy Society consensus guidelines are for
HDR brachytherapy combined with EBRT and are based on empirical protocols or
extrapolated from LDR parameters.
For larger, more infiltrating, or poorly differentiated tumors, EBRT should be given in
combination with brachytherapy given the higher risk of lymph node metastasis. The initial
EBRT fields are treated to 45 to 50 Gy and tailored to the location of the initial tumor and
should include the inguinal region if the disease extends to the mid to low vagina. If there is
extensive common iliac nodal disease, the fields should encompass the low para-aortic region
or at least 2 to 3 cm above the most superior extent of nodal disease. Intensity-modulated
radiotherapy (IMRT) techniques can be considered particularly if the inguinal region needs to
be treated. Chyle et al. (1996) recommended EBRT in addition to brachytherapy for stage I
disease to cover at least the paravaginal nodes and, in larger lesions, to cover the external and
internal iliac nodes. About 95% to 100% of local control has been achieved with
intracavitary and interstitial techniques, with 5-year survival for patients with stage I disease
treated with RT alone ranging from 70% to 95% (Table 6.3).

TABLE 6.3 FIGO Stage I and II Vaginal Cancers: Treatment Approach

and Results
aFour patients received adjuvant irradiation.
St, stage; RT, radiotherapy; S, surgery; surv., survival; DSS, disease-specific survival.
Source: Adapted from Cardenes VR, Schilder JM, Emerson R. Chapter 20: vagina. In: Barakat RB, Berchuck A, Markman
M, et al., eds. Principles and Practices of Gynecologic Oncology, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2013:573.

STAGE II
Patients with stage IIA tumors have more advanced paravaginal disease without parametrial
infiltration to the sidewall. Treatment is a combination of external beam RT and
brachytherapy depending on the location and extent of disease as above. After the initial
EBRT, a combination of LDR-ICB, LDR-ITB, HDR-ICB, or HDR-ITB or pulsed dose rate
may be used depending on institutional preference. The modality used should aim for 25 to
35 Gy (if using HDR, use conversion for equivalent dose at 2 Gy [EQD2]) 0.5 cm beyond the
deep margin of the tumor in addition to the whole pelvis dose to a total tumor dose of 70 to
80 Gy, depending on tumor response and vaginal tolerance. The upper vagina has a greater
tolerance than the lower vagina. Double-plane or volume implants may be necessary for
more extensive disease. Perez et al. (1999) demonstrated that in stage IIA, the local tumor
control was 70% (37 of 53) in patients receiving brachytherapy combined with EBRT,
compared with 40% (4 of 10) in patients treated with either brachytherapy or EBRT alone.
The superiority of the combination of EBRT and brachytherapy over EBRT or brachytherapy
alone has been shown in other series as well. Furthermore, recent SEER analysis by Orton et
al. demonstrated that patients who received brachytherapy as a component of their treatment
had a significantly decreased risk of death for all FIGO stages (2016).
Patients with stage IIB, with more extensive parametrial infiltration, will receive 40 to 50
Gy to the whole pelvis with consideration of a parametrial boost for bulky disease or with a
poor response. An additional boost of 30 to 35 Gy EQD2 will be given with LDR or HDR
interstitial and ICB to deliver a total tumor dose of 75 to 80 Gy to the vaginal tumor and 60
to 65 Gy to parametrial and paravaginal extensions. Patients with lesions limited to the upper
third of the vagina can be treated with an intrauterine tandem and vaginal ovoids or cylinders
if the patient still has a uterus. The locoregional control in patients with stage IIB in the series
by Perez et al. was also superior with combined EBRT and brachytherapy (61% vs. 50%,
respectively).
The 5-year survival for patients with stage II disease treated with RT alone ranges
between 35% and 70% for stage IIA and 35% and 60% for stage IIB. The results of several
series published in the literature using different treatment approaches for stage I and II
vaginal cancers are shown in Table 6.3.

Stages III and IVA

Generally, patients with stage III and IVA disease will receive 45 to 50 Gy EBRT to the
pelvis and, in some cases, additional parametrial dose to deliver up to 60 Gy to the pelvic
sidewalls. Ideally, ITB boost is performed, if technically feasible, to deliver a minimum
tumor dose of 75 to 80 Gy. If brachytherapy is not feasible or if the lesion is in the posterior
vaginal wall, a shrinking field technique can be used, with fields defined using the three-
dimensional (3D) treatment planning capabilities to deliver a tumor dose around 65 to 70 Gy.
An alternative approach is intensity-modulated RT (IMRT) using multiple beams of varying
intensity that conform the high-dose region to the shape of the target tissues, with more
adequate sparing of the surrounding normal tissues, primarily the bladder, rectum, and small
bowel. Simultaneous integrated boost can also be considered to deliver higher central doses
to the gross disease. Careful accounting of organ motion with daily image guidance should be
performed. Depending on the location of the disease, use of an endorectal balloon or
endovaginal obturator could be considered.
The overall cure rate for patients with stage III disease is 30% to 50%. Stage IVA
includes patients with rectal or bladder mucosa involvement or, in most series, positive
inguinal nodes. Although some patients with stage IVA disease are curable, many patients are
treated palliatively with EBRT only. Pelvic exenteration can also be curative in highly
selected stage IV patients with small-volume central disease. Table 6.4 shows the treatment
results with different therapeutic modalities, including four series that reported the use of
primary surgery in highly selected patients with advanced disease. However, each of these
series reported a far greater number of patients with similar stage disease treated with RT,
which represents the preferred approach in contemporary practice. In 2016, the Korean
Radiation Oncology Group performed a retrospective review of 148 patients with advanced
disease treated with radiotherapy noting that higher stage showed worse survival outcome
and higher severe late toxicity with a 5-year OS of 68% (2016). This was followed up in
2018 by a retrospective review by the Japanese Radiation Oncology Group noting a 5-year
OS of 75% for stage IV disease for patients receiving 3D conformal RT and brachytherapy
(2018). These data highlight that personalized and precise radiation treatment of advanced-
stage vaginal cancer is crucial.

TABLE 6.4 FIGO Stage III and IV Vaginal Cancers: Outcome with
Radiotherapy with/without Surgery
aTwenty patients with stages III and IV were treated with chemotherapy (5-FU ± mitomycin-C) and radiotherapy.
St, stage; RT, radiotherapy; S, surgery; surv., survival; DSS, disease-specific survival.
Source: Adapted from Cardenes VR, Schilder JM, Emerson R. Chapter 20: vagina. In: Barakat RB, Berchuck A, Markman
M, et al., eds. Principles and Practices of Gynecologic Oncology, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2013:573.
External Beam Radiotherapy
EBRT is recommended in patients with deeply infiltrating or poorly differentiated stage I
lesions and in all patients with stage II to IVA diseases. Either 3D conformal therapy or
IMRT can be considered for treatment of primary vaginal cancer with contouring of target
tissues and organs at risk (see Chapter 2).
Treatment should include the external/internal iliacs and obturator nodes to a dose of 45
Gy and can include the inguinal region if the mid to low vagina is involved. If there are
involved or suspicious lymph nodes, we recommend treating an additional echelon of nodes
above the involved region. Gross nodes should be treated to a dose of 60 to 66 Gy depending
on the size and proximity to critical structures. High-energy photons (≥10 MV) are usually
preferred. Fiducials should be placed prior to CT simulation to delineate the distal and
proximal extent of disease. The lower border of the field should be at least 3 cm below the
distal extent of disease or should treat the entire vagina to the introitus if there is lack of
clarity regarding the extent of involvement. Historically, treatment portals covered at least the
true pelvis with 1.5- to 2.0-cm margin beyond the pelvic rim; however, in the era of CT
simulation, the regional nodes that are being targeted should be contoured as per the RTOG
Gyn contouring guidelines (2019). Superiorly, the field extends to either L4–5 or L5–S1 to
cover the pelvic lymph nodes (some choose to cover the common iliacs in more advanced
disease or if there is involvement of the external or internal iliac nodes, which may extend
the superior border to as high as L3) and extends distally to the introitus to include the entire
vagina. Lateral fields, if used, should extend anteriorly to adequately include the external
iliac nodes, anterior to the pubic symphysis, and at least to the junction of S2–3 posteriorly.
In patients with tumors involving the middle and lower vagina without nodal
involvement, the bilateral inguinofemoral lymph node regions should be treated electively to
45 to 50 Gy. Planning CT is recommended to determine adequately the depth of the
inguinofemoral nodes. A number of techniques have been used to treat the areas at risk
without overtreating the femoral necks. Some of the most commonly used techniques include
the use of unequal loading (2:1, AP/PA), a combination of low- and high-energy photons (4
to 6 MV, AP, and 15 to 18 MV, PA), or equally weighted beams with a transmission block in
the central AP field, utilizing small AP photon or electron beams to deliver a daily boost to
the inguinofemoral nodes, or, more recently, the use of IMRT. If inguinal nodes are being
treated, it is our preference to use IMRT to spare the femoral heads from high doses. When
using IMRT, it is advisable that the radiation oncologist and radiation team have experience
and recognize the importance of adequate target delineation, as well as a quality assurance
program that takes into account target shrinkage and interfractional/intrafractional motion.
For instance, we recommend simulating patients with both a full and empty bladder. If there
is significant gas in the rectum, this can be decompressed with a rectal tube prior to
simulation. If there is significant stool that cannot be evacuated, we would recommend
contouring the CTV volume several centimeters into the rectum and approximately 1.5 cm
anterior to the posterior rectal wall. Or if the rectum is very empty, the CTV should be
contoured several centimeters into the posterior bladder. Furthermore, daily kilovoltage
imaging should be utilized with or without daily cone beam CT (CBCT) imaging. CBCT
could be considered daily for the first 2 weeks to evaluate the extent of organ motion if there
is a concern with subsequent tailoring of treatment per the imaging observations.
For patients with positive pelvic nodes or for those patients with advanced disease not
amenable to interstitial implant, additional boost to the areas of gross disease, as defined by
CT scan, should be given using conformal therapy to deliver a total dose between 65 and 70
Gy, when feasible, with high-energy photons. Boost to the areas of gross nodal disease, as
defined by CT scan, should be given using small fields (similar to the parametrial boost with
midline shielding) to deliver a total dose between 60 and 66 Gy with high-energy photons
depending on the size and location to critical structures. In patients with clinically palpable
inguinal nodes, additional doses of 15 to 20 Gy (calculated at a depth determined by CT
scan) are necessary with reduced portals. This can generally be achieved by using low-energy
photons and/or electron beam (12 to 18 MeV) or IMRT techniques. Although the role of
IMRT for treatment of vaginal cancer remains undefined, its benefit in reducing GI, GU, and
bone marrow toxicity while providing excellent local tumor control has been well
documented in other gynecologic sites. M.D. Anderson reported on the use of IMRT in 13
patients with very advanced vaginal cancer or with extensive rectovaginal septum
involvement that precluded brachytherapy. At 18-month median follow-up, there were no
pelvic recurrences, although two patients did develop fistulas after treatment. Recently,
Stanford University published their experience with the use of IMRT in 10 patients with
vaginal SCC showing excellent locoregional control with no grade 3 or 4 toxicities.
Overall treatment time (7 to 9 weeks) has been found to be a significant treatment factor
predicting tumor control, although this has not been universally recognized.

Low Dose Rate Intracavitary Brachytherapy

VaIN and small T1 lesions with less than a 0.5-cm depth can be adequately treated with ICB
alone. LDR-ICB is performed using vaginal cylinders loaded with cesium-137 (137Cs)
radioactive sources. Ninety-five percent of vaginal lymphatic channels are located within a 3-
mm depth from the vaginal surface, confirming the adequacy of prescribing the dose to a
depth of 5 mm for superficially invasive lesions.
It is recommended that the largest possible diameter that can be comfortably
accommodated by the patient should be used to improve the ratio of mucosa-to-tumor dose
and eliminate vaginal rugations. In general, the vulva is sutured closed for the duration of the
implant in order to secure the position of the applicators.
In patients with upper vagina lesions with less than a 0.5-cm depth of invasion, vaginal
colpostats alone (after hysterectomy) or in combination with intrauterine tandem, loaded with
137Cs sources similar to that used in treatment of cervical cancer, can be used, if the patient

still has a uterus, to treat the proximal vagina to a minimum dose of 65 to 70 Gy, estimated to
0.5 cm depth, including the contribution of EBRT if given. When indicated, the remainder of
the vagina can be treated by performing a subsequent implant using vaginal cylinders
(generally 50 to 60 Gy prescribed to the vaginal surface).

High Dose Rate Intracavitary Brachytherapy

The International Commission on Radiation Units and Measurements defines HDR
brachytherapy as exceeding 12 Gy/h. HDR-ICB is typically performed with a 10 Ci single
iridium-192 (192Ir) source (microSelectron HDR, Nucletron). The applicators are similar to
those described for LDR. Generally, the number of insertions ranges from 1 to 6 (median, 3),
with the dose per fraction ranging from 300 to 800 cGy (median, 700 cGy), depending on if
the dose is prescribed to the vaginal surface or 5 mm below the mucosal surface.
Complication analyses from retrospective data show no significant differences between the
HDR and the LDR. The choice of vaginal cylinder mirrors the LDR technique in that the
cylinder chosen should be the largest comfortable for the patient. CT or MR planning should
be considered to confirm the extent of treatment as well as to ensure adequate approximation
of the cylinder with the vagina as air gaps can occur. Dose target remains the same (EQD2),
but the prescription dose may be at the surface or 5 mm below the mucosal surface. Since the
cylinder is in the vagina for only a short time (15 to 45 minutes), it is usually held in place by
an immobilization board or stretch netting, rather than a vaginal stitch. Multichannel vaginal
cylinders can also be utilized that allow for asymmetric treatment of the vagina; contouring
of a treatment volume should be considered in this situation with verification using CT or
MR imaging with each fraction.

Interstitial Brachytherapy
ITB is a critical component in the treatment of more advanced primary vaginal carcinomas,
typically in combination with EBRT and/or ICB. If a patient is identified to likely need ITB
after EBRT and the resources to do such therapy are not available at the initial treating
institution, the patient should be sent to a regional center performing such therapies to be
evaluated as early on as possible during treatment or before treatment initiation. Coordination
of ITB can be challenging so planning far in advance is recommended. Temporary implants
are more commonly used in the curative treatment of larger gynecologic malignancies.
Permanent implants are performed at select institutions typically for smaller-volume disease.
When performing an interstitial procedure, freehand implants or template systems designed
to assist in preplanning and to guide and secure the position of the needles in the target
volume can be employed. The commercially available templates generally consist of a
perineal template, vaginal obturator, and 17-gauge hollow guides of various lengths that can
be afterloaded with 192Ir sources. The vaginal obturator is centrally drilled so that it can allow
the placement of a tandem to be loaded with 137Cs sources or to accommodate the HDR 192Ir.
This makes it possible to combine an interstitial and intracavitary application simultaneously.
The major advantage of these systems is greater control of the placement of the sources
relative to tumor volume and critical structures owing to the fixed geometry provided by the
template. Several institutions are providing individualized 3D printed templates for single
use. In order to improve the accuracy of target localization and needle placement as well as to
improve avoidance of normal structures, performing ITB under transrectal ultrasound, CT,
MRI-planned implants with endorectal coil, laparotomy, and laparoscopic guidance have all
been described in the literature.
Tewari et al. described results in 71 patients who underwent ITB with (61 patients) or
without (10 patients) EBRT. Each implant delivered a total tumor dose reaching 80 Gy
integrated with EBRT. Local control was achieved in 53 patients (75%). By stage, 5-year
DFS rates included stage I, 100%; stage IIA, 60%; stage IIB, 61%; stage III, 30%; and stage
IV, 0%. Significant complications occurred in nine patients (13%) and included necrosis (n =
4), fistulas (n = 4), and small bowel obstruction (n = 1).

Role of Chemotherapy and Radiation

The control rate in the pelvis for stage III and IV patients has been historically low, and about
70% to 80% of the patients have persistent disease or recurrent disease in the pelvis in spite
of high doses of EBRT and brachytherapy. Contemporary series, however, demonstrate
higher rates of local control and survival in advanced-stage patients likely due to improved
staging and RT techniques such as IMRT and image-guided brachytherapy, which allow for
dose escalation and shrinking treatment volumes, thereby sparing greater normal tissue
(2018). Distant failures occur in about 25% to 30% of the patients with locally advanced
tumors; therefore, there is a need for better approaches to the management of advanced
disease such as the use of concomitant chemoradiotherapy. Agents such as 5-FU, mitomycin,
and cisplatin have shown promise when combined with RT, with complete response rates as
high as 60% to 85%, but long-term results of such therapy have been variable, in part owing
to the advanced stage of the patients included in these small studies. Extrapolating from
published data on locally advanced cervical cancer demonstrating an advantage in
locoregional control, overall survival, and DFS for patients receiving cisplatin-based
chemotherapy concurrently with RT as well as data on locoregionally advanced vulvar
cancer, consideration should be given to a similar approach in patients with advanced vaginal
cancer. New directions involve the evaluation of immunotherapy in the treatment of
advanced vaginal cancer with several trials currently under way. In particular for patients
with PD-L1–positive cancers (staining of >1%), anti–PD-1 or anti–PD-L1 therapies should
be considered.

Patterns of Failure in Squamous Cell Carcinoma

At least 85% of patients who recur will have a component of locoregional failure, and the
vast majority of these recurrences will be confined to the pelvis and vagina. The rate of
locoregional recurrence in stage I is approximately 10% to 20% versus 30% to 40% in stage
II. The pelvic control rate for patients with stage III and stage IV is relatively low, and about
50% to 70% of the patients have recurrences or persistence in spite of well-designed RT. The
median time to recurrence is 6 to 12 months. Tumor recurrence is associated with a dismal
prognosis, with only a few long-term survivors after salvage therapy. Failure in distant sites
alone or associated with locoregional failure does occur in about 25% to 40% of patients with
locally advanced tumors.

Treatment Complications
Key Points
At least 85% of patients who recur will have a component of locoregional failure,
with the vast majority of these recurrences being confined to the pelvis and
vagina.
The median time to recurrence is 6 to 12 months.
Tumor recurrence is associated with a dismal prognosis.
Acute radiation toxicity usually resolves within 2 to 3 months after completion of
therapy.

The anatomic location of the vagina places the lower gastrointestinal and genitourinary tracts
at greatest risk for complications after surgery or RT.
Acute toxicities from therapy depend on the extent of RT. If brachytherapy alone is used,
the toxicities are minimal; however, if the treatment is a combination of EBRT and
brachytherapy, toxicities can include edema, erythema, moist desquamation, and confluent
mucositis with or without ulceration if the low vagina is being treated. There can also be
diarrhea, cystitis, fatigue, as well as nausea/vomiting if concurrent chemotherapy is
delivered. Additionally, the severity of the acute effects varies in intensity and duration
depending upon patient age, hormonal status, tumor size, stage, RT dose, and personal
hygiene. These effects usually resolve within 2 to 3 months after the completion of therapy.
Late effects include the development of vaginal atrophy, fibrosis, and stenosis.
Telangiectasias are commonly seen in the vagina. Care should be taken in treating these if
symptomatic as they can precipitate vaginal necrosis. Vaginal narrowing or shortening,
paravaginal fibrosis, loss of elasticity, and reduced lubrication often result in dyspareunia and
sexual dysfunction, and patients are encouraged to use a vaginal dilator regularly to help
prevent fibrosis and vaginal narrowing. More severe complications include necrosis with
ulceration that can progress to fistula formation (rectovaginal, vesicovaginal, and
urethrovaginal). Most series report major complication rates (>Gr 2) of 16% to 17% at 10
years. The effects of chemotherapy on the incidence of late complications, if any, are unclear.
(See Chapter 2 for greater discussion of acute and late toxicities and management.)
The RT tolerance limit of the surface of the proximal vagina is 120 to 150 Gy. The distal
vaginal tolerance is lower and should be limited to surface doses of less than 80 to 90 Gy. In
addition, the posterior wall of the vagina is more prone to radiation injury than the anterior
and lateral walls, and the dose should be kept below 80 Gy in order to minimize the risk of
rectovaginal fistula.

Clear Cell Carcinoma of the Vagina

Stage I CCA of the vagina can be adequately managed with surgery depending on the
location and extent of disease, with one series of 142 cases noting an 8% risk of recurrence
after radical surgery (n = 117) and an 87% survival. As the majority of CCAs occur in the
upper third of the vault, the largest series addressing the surgical approach to these lesions
have advocated radical hysterectomy, pelvic and para-aortic lymphadenectomy, and sufficient
colpectomy to achieve negative margins. Wharton et al. advocate intracavitary or
transvaginal irradiation for the treatment of small tumors because this may yield excellent
tumor control with a functional vagina and preservation of ovarian function. A combination
of wide local excision and extraperitoneal node dissection followed by brachytherapy is an
acceptable alternative for patients desirous of fertility preservation. Treatment should be
individualized given the rarity of this disease.
Most patients with stage II vaginal CCA should be treated with combination EBRT and
brachytherapy; however, small, easily resectable lesions in the upper fornix might undergo
resection, allowing better preservation of coital and ovarian function.

Nonepithelial Tumors of the Vagina

Key Point
As distant disease is the predominant pattern of failure in patients with vaginal
melanoma, quality of life should be optimized by offering management with wide
excision followed by RT and avoiding disfiguring radical surgery.

Melanoma of the Vagina

Vaginal melanoma is an exceedingly rare entity, and with its propensity to develop distant
metastases and its lack of a recognized precursor lesion, it has presented therapeutic
challenges with generally disappointing results irrespective of treatment modality. Because
vaginal melanoma was deemed a relatively radioresistant tumor, radical surgery had been the
treatment of choice in operable patients. However, most series report 5-year survival rates of
5% to 30% regardless of radicality of surgery. As distant disease is the predominant pattern
of failure in these patients, quality of life should be optimized by wide excision followed by
RT to affect local control, while obviating the need for radical surgery.
Recent retrospective data also suggest that vaginal melanoma may be radioresponsive
and possibly radiocurable. Volumes and doses of irradiation are similar to those used for
epithelial tumors, ranging from 50 Gy for subclinical disease to 75 Gy for gross tumors;
consideration should be made for hypofractionated regimens. Several series have now shown
that prolonged local control can be obtained with RT as an adjunct to more limited surgery, or
even with RT alone, primarily in patients with lesions ≤3 cm in diameter. The use of systemic
chemotherapy has been very disappointing in the limited published data. Immunotherapies
have been very promising in melanoma, although there are limited data on the use of
immunotherapy for mucosal melanomas. Multidisciplinary management should be
considered for these patients with early enrollment onto clinical trials particularly for those
with advanced disease. Due to an extremely high risk of local recurrence of distant
metastasis, the prognosis of vaginal melanoma continues to be very poor regardless of
treatment delivered.
There is lack of consensus as to the benefit of adjuvant therapy for stage II or III
melanomas after surgical excision (2013). Recently, agents targeting T-cell response have
proven promising in the treatment of melanoma. Ipilimumab, anti–cytotoxic T-lymphocyte
antigen (CTLA) leading to T-cell stimulation, was the first therapy to result in OS
improvement at 2 and 4 months in chemotherapy-naive and previously treated melanoma
(2010, 2011). Antiprogrammed cell death protein-1 (PD-1) agents have also shown efficacy
in early phase I trials (2012). The combination of both anti-CTLA and anti–PD-1 agents is
now being explored, and it has yet to be shown if these responses will be mirrored in vaginal
melanomas.

Sarcomas of the Vagina

Sarcomas represent 3% of vaginal primaries with leiomyosarcoma representing 50% to 65%
of vaginal sarcomas, with the majority arising from the posterior vaginal wall.
Histopathologic grade appears to be the most important predictor of outcome. Radical
surgical resection, such as posterior pelvic exenteration, offers the best chance for cure for
vaginal leiomyosarcomas. Sarcomas are relatively resistant to chemotherapy, and the most
common site of failure is the pelvis. In 50% of patients with recurrence, it is the only site of
failure. Five-year survival rates are generally better in patients with leiomyosarcoma than in
patients with carcinosarcoma. Adjuvant RT seems to be indicated in patients with high-grade
tumors and locally recurrent low-grade sarcomas.
Embryonal RMS of the vagina, the most common pediatric vaginal tumor, is
appropriately managed through the use of multimodality therapy. A series of reports from the
Intergroup Rhabdomyosarcoma Study Group have reported survival rates in excess of 85%
utilizing VAC chemotherapy and wide excision with or without adjuvant RT, sparing the
great majority of patients from exenterative surgery. However, due to the high rates of local
recurrence in patients who did not receive adjuvant RT in the IRS III and IV trials, the recent
Children’s Oncology Group ARST0331 study amended their protocol to require adjuvant RT
at week 13 for all patients with vaginal primaries. This study is closed to accrual and
currently completing follow-up assessments.

Salvage Therapy
This group represents a heterogeneous population and treatment should be individualized.
Local recurrences should be confirmed by biopsy, and further workup should establish the
extent of disease, particularly if salvage local therapy is considered. In most cases, only
patients with small-volume local recurrences and no metastatic disease are curable.
Generally, patients with isolated pelvic or regional recurrences after definitive surgery
who have not received prior RT are managed with EBRT, often in conjunction with
brachytherapy. Concurrent cisplatin-based chemotherapy may also be recommended, and
extrapolation from the available data for locally advanced cervical and vulvar cancer
suggests that a combined modality approach with chemoradiotherapy may improve the
locoregional control and survival in patients with isolated pelvic recurrences. Salvage options
for patients with central recurrence after definitive or adjuvant RT are limited to radical
surgery, usually exenterative or, in selected patients with small-volume disease, reirradiation
using interstitial radiation implants or IMRT or proton therapy. In patients with small, well-
defined vulvovaginal or pelvic recurrences, reirradiation using primarily interstitial
techniques has been attempted with control rates between 50% and 75% and grade 3 or
higher complication rates between 7% and 15%. Recently, stereotactic body irradiation using
high-dose, localized therapy has been reported with acceptable palliative outcomes and
toxicity; however, studies are few, small, and retrospective.

Palliative Therapy
Radiotherapy
At the present time, there is no curative option for patients who present with stage IVB
disease. Many of these patients suffer from severe pelvic pain or bleeding. Palliative
radiation with either ICB (for vaginal bleeding) or EBRT can result in good tumor regression
and excellent palliation of symptoms. The RTOG published on a palliative schedule that is
well tolerated with good symptomatic results. The treatment is 370 cGy BID for 2 days.
Three courses are delivered, with a field reduction on the third. Combination with Taxol
chemotherapy has been reported as well.

Chemotherapy in Advanced and Recurrent Vaginal Cancer

Treatment of recurrent or metastatic disease is confined to a handful of phase II clinical trials
and anecdotal reports. In general, regimens that are active in cervical cancer are usually
active in vaginal cancer. Regimens including cisplatin, mitoxantrone, 5-FU, mitomycin C,
bleomycin, vincristine, and MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)
have been reported with varying success. Currently, no evidence exists to suggest diagnosis
of a recurrence via periodic follow-up after treatment leads to improved prognosis. NCI has
no recommended interval for periodic follow-up but recommend cytology and imaging as
seen fit by physical findings. However, American College of Radiology (ACR)
Appropriateness Criteria recommend follow-up once every 3 months for the first 2 years out
from treatment and then observation at longer intervals after. This stems from retrospective
series resulting in a 70% to 80% relapse rate typically within the first 2 years of initial
treatment (2007). Given the high risk of secondary malignancies particularly in women with
HPV-related cancers, screening for secondary cancers should be considered.
Suggested Readings
Beriwal S, Demanes DJ, Erickson B, et al. American Brachytherapy Society consensus guidelines for interstitial
brachytherapy for vaginal cancer. Brachytherapy. 2012;11:68–75.
Blanchard P, Monnier L, Dumas L, et al. Low-dose-rate definitive brachytherapy for high-grade vaginal intraepithelial
neoplasia. Oncologist. 2011;16:182–188.
Carrascosa LA, Yashar CM, Paris KJ, et al. Palliation of pelvic and head and neck cancer with paclitaxel and a novel
radiotherapy regimen. J Palliat Med. 2007;10:877–881.
Chaudhuri S, Das D, Chowdhury S, et al. Primary malignant melanoma of the vagina: A case report and review of literature.
South Asian J Cancer. 2013;2:4.
Chang JH, Jang WI, Kim YB, et al. Definitive treatment of primary vaginal cancer with radiotherapy: Multi-institutional
retrospective study of the Korean Radiation Oncology Group (KROG 12-09). J Gynecol Oncol. 2015;27(2):e17.
Chyle V, Zagars GK, Wheeler JA, et al. Definitive radiotherapy for carcinoma of the vagina. Int J Radiat Oncol Biol Phys.
1996;35:891–905.
Creasman WT, Phillips JL, Menck HR. The National Cancer Data Base report on cancer of the vagina. Cancer.
1998;83:1033–1040.
Daling JR, Madeleine MM, Schwartz SM, et al. A population-based study of squamous cell vaginal cancer: HPV and
cofactors. Gynecol Oncol. 2002;84(2):263.
Division of Cancer Prevention and Control, Centers for Disease Control and Prevention. Vaginal and Vulvar Cancers
Statistics. (May 21, 2019). Retrieved from https://www.cdc.gov/cancer/vagvulv/statistics/index.htm
Frank SJ, Jhingran A, Levenback C, et al. Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J
Radiat Oncol Biol Phys. 2005;62:138–147.
Hiniker SM, Roux A, Murphy JD, et al. Primary squamous cell carcinoma of the vagina: Prognostic factors, treatment
patterns, and outcomes. Gynecol Oncol. 2013;131(2):380–385.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl
J Med. 2010;363:711–723.
Iavazzo C, Pitsouni E, Athanasiou S, et al. Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia. Int J
Gynecol Obstet. 2008;101:3–10.
Ikushima H, Wakatsuki M, Ariga T, et al. Radiotherapy for vaginal cancer: A multi-institutional survey study of the
Japanese Radiation Oncology Study Group. Int J Clin Oncol. 2018;23:314–320. doi: 10.1007/s10147-017-1205-z.
Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immunotherapy of Cancer consensus statement on tumour
immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol. 2013;10:588–598.
Kirkbride P, Fyles A, Rawlings GA, et al. Carcinoma of the vagina-experience at the Princess Margaret Hospital (1974–
1989). Gynecol Oncol. 1995; 56:435–443.
Kucera H, Vavra N. Radiation management of primary carcinoma of the vagina: Clinical and histopathological variables
associated with survival. Gynecol Oncol. 1991;40:12–16.
Kunos CA, Debernardo E, Radivoyevitch T, et al. Hematological toxicity after robotic stereotactic body radiosurgery for
treatment of metastatic gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2012;84:e35–e41.
Kunos CA, Fabien J, Zhang Y, et al. Gynecologic cancer. In: Simon S. Lo, Bin S. Teh, Jiade J. Lu, et al., eds. Stereotactic
Body Radiation Therapy. Berlin, Germany: Springer; 2012:211–225.
Magné N, Pacaut C, Auberdiac P, et al. Sarcoma of the vulva, vagina and ovary. Best Pract Res Clin Obstet Gynaecol.
2011;25(6):797–801.
Murakami N, Kasamatsu T, Sumi M, et al. Radiation therapy for primary vaginal carcinoma. J Radiat Res.
2013;54:931–937.
Orton A, Boothe D, Williams N, et al. Brachytherapy improves survival in primary vaginal cancer. Gynecol Oncol.
2016;141:501–506. doi: 10.1016/j.ygyno.2016.03.011.
Perez CA, Grigsby PW, Garipagaoglu M, et al. Factors affecting long-term outcome of irradiation in carcinoma of the
vagina. Int J Radiat Oncol Biol Phys. 1999;44:37–45.
Robert C, Thomas L, Bodarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl
J Med. 2011;364:2517–2526.
Rtog. GYN, Retrieved May 21, 2019, www.rtog.org/CoreLab/ContouringAtlases/GYN.aspx
Spanos W Jr, Guse C, Perez C, et al. Phase II study of multiple daily fractionations in the palliation of advanced pelvic
malignancies: Preliminary report of RTOG 8502. Int J Radiat Oncol Biol Phys. 1989;17:659–661.
Strander B, Andersson-Ellstrom A, Milsom I, Sparen P. Long term risk of invasive cancer after treatment for cervical
intraepithelial neoplasia grade 3: Population based cohort study. BMJ. 2007;335(7629):1077.
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J
Med. 2012;366:2443–2454.
Vera R, Eifel PJ, Jhingran A, et al. Intensity-modulated radiation therapy (IMRT) in the treatment of carcinoma of the
vagina. Int J Radiat Oncol Biol Phys. 2007;69:S396.
Wee WW, Chia YN, Yam PK. Diagnosis and treatment of vaginal intraepithelial neoplasia. Int J Gynecol Obstet.
2012;117:15–17.
Wharton JT, Routledge FN, Gallager HS, et al. Treatment of clear cell adenocarcinoma in young females. Obstet Gynecol.
1975;45:365–368.
Xia L, Han D, Yang W, et al. Primary malignant melanoma of the vagina: A retrospective clinicopathologic study of 44
cases. Int J Gynecol Cancer. 2014;24:149–155.
 7 The Uterine Cervix

Epidemiology
Worldwide, cervical cancer is the fourth most common cancer (after breast, colorectal, and
lung) in women and is the leading cause of death of women from cancer in developing
countries. In 2018, over 500,000 new cases and 300,000 deaths occurred due to cervical
cancer, with the majority of cases in developing countries lacking access to routine
Papanicolaou (Pap) smear screening. In the United States, cervical carcinoma is the 15th
most common malignant tumor, and in 2018, an estimated 13,240 women were expected to
be diagnosed with invasive cervical cancer, while 4,170 women were estimated to die from
the disease. While the incidence and mortality of this disease in North America have declined
during the last half-century, Black and Hispanic women continue to be disproportionately
affected, especially in the southern United States.

Risk Factors and Etiology

Key Points
Cervical cancer is a sexually transmitted disease associated with chronic infection
by oncogenic types of human papillomavirus (HPV).
Tobacco smoking may be a cofactor for the development of high-grade cervical
dysplasia in women who have chronic HPV infections.
HPV 16 and 18 account for approximately 70% of cervical cancers.

Because cervical cancer is a sexually transmitted disease associated with chronic infection by
oncogenic types of HPV, risk factors include early age at onset of sexual activity, multiple
pregnancies, long duration of oral contraceptive use, other sexually transmitted infections,
immunosuppressed states, and multiple sexual partners. Tobacco smoking is also a risk factor
and may be a cofactor for development of high-grade cervical dysplasia in women who have
chronic HPV infections.

Human Papillomavirus
HPV is a double-stranded DNA virus, with more than 30 recognized oncogenic and more
than 70 nononcogenic strains of HPV being described to date. In the United States, HPV 16
and 18 are the predominant strains, accounting for approximately 70% of cervix cancers.
High-risk HPV genotypes code for three early proteins (E5, E6, and E7) with cellular
growth–stimulating and cellular growth–transforming properties. The E6 protein binds to
p53, results in chromosomal instability, activates telomerase, inhibits apoptosis, and results in
cellular immortalization. The E7 protein binds to retinoblastoma protein (Rb), inactivating
the Rb-related pocket proteins, activates cyclins E and A, inhibits cyclin-dependent kinase
inhibitors, and also results in cellular immortalization. HPV E6 and HPV E7 lead to dysplasia
and malignant transformation of cervical epithelium. High-risk HPV types are identified in a
high percentage of patients with adenocarcinoma or small cell carcinoma of the cervix in
addition to the more common squamous carcinoma.
Cellular and humoral immune responses are likely to be involved in the resolution of
HPV infection, and deficiencies, such as caused by human immunodeficiency virus (HIV)
infection, may result in more rapid progression to dysplasia and carcinoma.
Almost 50% of women will be infected with HPV within 4 years after the onset of sexual
activity, with prevalence peaking between 25 and 35 years of age. Despite a high prevalence
of HPV, only 5% to 15% will develop cervical dysplasia.

Concurrent Infection with HPV and Human

Immunodeficiency Virus
HIV is a sexually transmitted virus that results in a decline in circulating CD4+ cells over
time. Concurrent infection with HIV and HPV is associated with lower rates of regression of
low-grade lesions and may result in more rapid progression from chronic HPV infection to
dysplasia and cancer. While HIV+ patients with concurrent HPV infection must be followed
closely and aggressively treated for squamous intraepithelial lesions, multiple studies suggest
that antiretroviral therapy does increase likelihood of regression of CIN 1 disease.

Anatomy
The cervix is an extension of the lower uterine segment of the uterus and is approximately 3
to 4 cm in length. The external cervical os connects to the endocervical canal, the internal
cervical os, and the endometrial canal.
The cervix is lined by squamous and columnar cells; the transition from columnar cells to
squamous cells occurs in the transformation zone. This region is at higher risk of abnormal
changes and most cervical dysplasias and invasive cancers arise from here. The endocervix
contains mostly mucinous glandular epithelium.
The uterus has five ligamentous attachments: the round, broad, utero-ovarian, cardinal,
and uterosacral ligaments. Within the broad ligament are extraperitoneal connective tissues,
known as the parametrium. The blood supply of the uterus is mainly through the uterine
artery, originating from the anterior division of the hypogastric artery. The lymphatics of the
cervix drain into the paracervical and parametrial lymph nodes and to the internal, external,
and common iliac chains. The obturator lymph nodes are the most medial portion of the
external iliac nodal region and lie along the obturator internus. Other lymphatic drainage
routes include the inferior and superior gluteal lymph nodes and the superior rectal, presacral,
and para-aortic lymph nodes. The innervations of the cervix are from the sacral roots (S2–4).

Natural History
Key Points
An interval of epithelial dysplastic changes, typically in the transformation zone,
known as cervical intraepithelial neoplasia (CIN), precedes the development of
invasive cancer.
The reported rate of progression of carcinoma in situ (CIS) to invasive cancer
ranges from 12% to 22%.
The pattern of lymphatic metastases is generally predictable and orderly, starting
from the obturator to the common iliacs and para-aortic regions. However, in rare
circumstances, high common iliac or para-aortic lymph node regions may be the
initial site of nodal spread. Spread beyond the para-aortic region may occur via
the thoracic duct and subsequently to the left supraclavicular region.
The most common sites of hematogenous spread include the lung, mediastinum,
bone, and liver.
Most recurrences occur in the first 24 months, with a median of 17 months.

Preinvasive Disease
Cervical cancer is preceded by an interval of epithelial dysplastic changes, most commonly
within the transformation zone. Low-grade dysplasia (CIN 1) is confined to the basal one-
third of the epithelium, and most low-grade lesions will regress to normal in about 24
months. Full-thickness involvement is known as CIN 3 or CIS. Overall, the reported rate of
progression of CIS to invasive cancer ranges from 12% to 22%.

Patterns of Spread
Cervical cancer can spread through direct extension to the endocervix, lower uterine
segment, parametrium, and vagina. In very advanced cases, it can invade the bladder or
rectum. Lymphatic spread is via the parametrial, obturator, and internal, external, and
common iliac lymph nodes. The pattern of spread is usually predictable and orderly as the
rate of para-aortic lymph node metastasis is very rare if the pelvic nodes are spared. The
overall risk of pelvic lymph node metastasis in tumors confined to the cervix (FIGO stage
IB) is about 17%. The risk of para-aortic nodal metastasis is higher with advanced stage, with
rates of 16% to 25% for tumors extending outside the cervix. The most common sites of
hematogenous spread include the lung, mediastinum, bone, and liver. Most recurrences occur
in the first 24 months with a median of 17 months.

Clinical Presentation and Diagnostic Evaluation

Key Points
The two primary means of obtaining and diagnosing cervical dysplasia are the
conventional Papanicolaou smear and the liquid-based thin-layer preparation.
The combination of negative cytology and HPV testing carries a high negative
predictive value of over 95% regarding the development of CIN 3 or invasive
cancer.
HPV testing is more sensitive in detecting high-grade disease compared to
conventional smears, but it has a lower specificity rate.
Indications for colposcopy are based on abnormal Pap findings, HPV testing, age,
and persistent abnormality on repeat testing (for instance, persistent CIN 1, 2, or 3
on cytology or atypical squamous cells of uncertain significance [ASCUS] smears
with positive high-risk HPV testing), but colposcopy can also be performed for an
abnormal-appearing cervix, persistent postcoital bleeding or discharge, or in utero
exposure to diethylstilbestrol (DES).

Preclinical Invasive Disease

Screening
Multiple studies have demonstrated that cervical cancer screening reduces cervical cancer
mortality. The two available screening tests include the Pap test (either the conventional
smear or a liquid-based thin-layer preparation) and HPV testing. The frequency of screening
and the test used depends on age, prior screening results, and immunocompetency.
The combination of negative cytology and HPV testing carries a high negative predictive
value of over 95% regarding the development of CIN 3 or invasive cancer, providing great
reassurance for low-risk women and lengthening the interval of screening in that population
to 3 years.
HPV testing is much more sensitive in detecting high-grade disease compared to
conventional smears but with a lower specificity rate. Screening women younger than 30
years may lead to unnecessary testing as many HPV infections are transient, and most
women will not develop dysplasia with HPV infection. In low-grade squamous intraepithelial
lesion (LSIL), more than 85% of cases test positive for HPV. Therefore, the American
Society for Colposcopy and Cervical Pathology (ASCCP) recommends screening with
cytology alone in women less than 30 years of age. However, the ASCCP does recommend
HPV reflex testing for findings of ASCUS.
The American Cancer Society (ACS) updated their cervical cancer screening guidelines
in 2015. The current recommendation is to start cytologic screening at age 21. For women
aged 21 to 29 years, Pap testing should be performed every 3 years, with reflex HPV testing
only after abnormal Pap results. From ages 30 to 65, combination HPV and cytology
screening (cotesting) every 5 years is preferred, but cytology alone every 3 years is
acceptable. For women older than age 65, screening can be discontinued in those who have
had regular cervical cancer testing in the past 10 years with normal results. For those who
have a history of “serious cervical precancer,” testing should be continued for 20 years after
the diagnosis regardless of age at final testing.
According to the ACS, women with HIV infection, immunosuppression, or in utero DES
exposure will require more frequent screening. Women who have undergone hysterectomy do
not require screening unless there is a history of cervical cancer or other “serious precancer”
lesions. Guidelines from ACOG are similar to the ACS recommendations.

Colposcopy
Colposcopy examines the lower genital tract including the vulva, vagina, and epithelium of
the cervix and opening of the endocervix. The use of acetic acid and Lugol solution assists in
highlighting abnormal changes that could signify high-grade disease such as acetowhite
plaques and vascular abnormalities (punctations, mosaicism, and abnormal branching).
Punch biopsies and endocervical curettage can be performed at this time. Indications for
colposcopy include an abnormal-appearing cervix, persistent postcoital bleeding or
discharge, abnormal screening test (depending on extent of cytologic abnormality,
persistence of abnormality over time, age, and HPV testing results), or in utero exposure to
diethylstilbestrol. Adequate colposcopic examination mandates full visualization of the entire
transformation zone and junction of squamous and glandular cells.

Cone Biopsy
Cervical conization refers to the surgical removal of the squamocolumnar junction. This may
be done in the operating suite through a classical cold knife conization technique or as an
outpatient using thermal cautery with loop excision (loop electrosurgical excision procedure,
or LEEP). Indications for conization include inadequate colposcopy; positive ECC; persistent
CIN 1 (usually >1 year); CIN 2, 3 or CIS; and discrepancy between cytologic, colposcopic,
and pathologic findings.

Clinical Disease
Symptoms and Complaints
The most common presentations of invasive cervical cancer are abnormal vaginal bleeding,
postcoital bleeding, and vaginal discharge. As the tumor enlarges, it can cause local
symptoms such as pelvic pain and difficulty with urination or defecation. If disease
metastasizes to regional lymph nodes, back pain, leg swelling (especially unilateral), and
neuropathic pain may occur. Local extension can cause urinary or rectal symptoms, in
addition to pain.

Physical Findings
The most common finding on physical examination is an abnormal lesion on the cervix that
can be necrotic and friable. Determination of parametrial, sidewall, uterosacral ligament, as
well as vaginal involvement must be done through a rectovaginal examination. Other areas of
concern are the superficial groin and femoral lymph nodes and the supraclavicular region.

Staging
Key Points
Cervical cancer is now staged by physical examination, surgical findings, and
radiographic evaluation.
Major changes to FIGO staging in the 2018 update include the following: lateral
extent of disease is no longer considered in 1A disease; 1B disease is now divided
into three size groupings (<2 cm, ≥2 and <4 cm, and >4 cm); and IIIC is a new
grouping that takes into account pelvic (IIIC1) and para-aortic (IIIC2) nodal
involvement noted on imaging and pathologic evaluation, denoted with an r or p,
respectively.
Positron emission tomography (PET) has emerged as a superior method of
imaging nodal disease in cervical cancer, while magnetic resonance imaging
(MRI) provides enhanced information on local extension of disease.

Laboratory Studies
A baseline complete peripheral blood count is indicated to evaluate for anemia, which might
warrant correction prior to treatment initiation. Serum chemistries with attention to serum
creatinine are essential to evaluate for renal failure or assess renal function in patients who
will receive cisplatin-based chemoradiotherapy. Additional tests should include liver function
tests and urinalysis.

Radiographic Studies
Cervical cancer is now staged by physical examination, surgical findings, and radiographic
evaluation. Computed tomography (CT) and MRI are used extensively to delineate disease
extent and improve treatment planning. Several studies and a meta-analysis have shown an
increased sensitivity for MRI as compared with CT for the evaluation of tumor size, uterine
body involvement, and parametrial and vaginal extension.
Modern imaging techniques, such as CT and MRI, have low sensitivities for detecting
disease in the para-aortic nodes less than 1 cm. PET has emerged as a superior method of
imaging nodal disease in cervical cancer. The reported sensitivity is about 85% to 90% and
the specificity about 95% to 100%. Both CT and MRI can be useful for detecting
hydronephrosis due to tumor or nodal bulk; corresponding abnormalities in serum creatinine
may suggest a need for ureteral stent placement in preparation for cisplatin administration.

FIGO and American Joint Committee Commission on Cancer

Staging
Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging is most commonly
used and was recently updated in 2018; comparison of the 2018 and 2009 staging is shown in
Table 7.1.

TABLE 7.1 FIGO 2018 Staging of Carcinoma of the Uterine Cervix

aImaging and pathology can be used, where available, to supplement clinical findings with respect to tumor size and extent,
in all stages.
bThe involvement of vascular/lymphatic spaces does not change the staging. The lateral extent of the lesion is no longer
considered. 1B is now divided into three size categories.
cAdding notation of r(imaging) and p(pathology) to indicate the findings that are used to allocate the case to stage IIIC. The
type of imaging modality or pathology technique used should always be documented.
*denotes change in definition from prior staging system (FIGO 2009).
Source: From Bhatla N. Cancer of the cervix uteri. Int J Gynaecol Obstet. 2018;143(suppl. 2):22–36.

Major changes to the FIGO system in 2018 include the following: stage 1A disease no longer
takes into consideration extension or width of the lesion; stage IB is now classified into three
different size groupings; and stage III now includes pelvic and para-aortic nodal involvement
as seen on imaging. The most important change has been the incorporation of pathologic
findings and imaging modalities (PET, CT, MRI, etc.) to determine FIGO staging. Previously,
imaging (with the exception of chest x-ray and intravenous pyelogram) and surgical findings
(as well as image-guided biopsies) were not used to determine clinical FIGO staging with the
rationale that this allowed for standardization of staging across varying resource settings.
However, in practice, many clinicians used this additional information to aid in treatment
decisions. The recent inclusion of advanced imaging and surgical techniques to FIGO staging
may limit robust comparison of management and outcomes of cervical cancer patients.
Additionally, while the radiographic detection of nodal metastases is prognostic, it is unclear
whether this is true for local extension of disease (such as parametrial involvement) noted on
imaging alone.
A TNM (tumor, node, metastasis) staging system is proposed by the American Joint
Committee Commission on Cancer (AJCC) and is mainly used in documenting findings on
surgical and pathologic evaluations as the pathologic stage of the disease. The AJCC eighth
edition staging does not yet reflect changes in the 2018 FIGO staging system. If there is
ambiguity regarding the correct stage when two qualified professionals evaluate the patient,
the lower stage is assigned.

Pretreatment Nodal Staging

The role of surgical staging for locally advanced cervical cancer remains unclear. Some
centers advocate for pretreatment nodal sampling or debulking surgeries. The rationale is
twofold: (i) therapeutic benefit in patients with large nodes that may be difficult to control
with radiotherapy and (ii) to evaluate for the presence of nodal disease in making a primary
treatment recommendation (i.e., surgery vs. radiation) or to assist in treatment planning for
the radiation oncologist (i.e., coverage of the para-aortic nodal region). The presence of
lymph node metastases has a significant impact on progression-free and overall survival.
Pretreatment knowledge of nodal spread could potentially direct treatment in a manner that
could improve outcomes. Given the limitations of imaging in reliably detecting nodal
micrometastases, surgical staging has been used. For further discussion, please see “Elective
Para-aortic Lymph Node Radiation.”

Pathology
Key Points
Squamous CIS is a precursor lesion of invasive squamous carcinoma.
 Untreated squamous CIS results in invasive carcinoma in about one-third of cases
over a period of 10 years.
Adenocarcinoma accounts for 20% to 25% of cervical carcinomas and is
associated with HPV (usually type 18, but sometimes type 16).
Adenosquamous carcinomas appear to be either histologically more aggressive or
diagnosed at a later stage than adenocarcinomas of the uterine cervix.

Squamous Cell Carcinoma

Preinvasive Disease
Squamous CIS is a precursor lesion of invasive squamous carcinoma, characterized by full-
thickness atypia of the epithelium in the absence of normal maturation of squamous
epithelium; there is no breach of the underlying basement membrane. There may also be
involvement of endocervical glands.

Microinvasive Carcinoma
Microinvasive squamous carcinoma is associated with squamous intraepithelial neoplasia,
and it is characterized by small nests of cells that have escaped the basement membrane of
the surface or glandular epithelium. Microinvasive carcinoma often displays cells that are
larger, with more abundant eosinophilic cytoplasm than cells in the adjacent dysplasia.
A diagnosis of microinvasive squamous carcinoma of the cervix requires a loop
electrosurgical excisional procedure or conization biopsy that encompasses the entire lesion
and has negative margins (Fig. 7.1).
FIGURE 7.1 HPV changes. This squamous epithelium displays cells with large
halos surrounding atypical nuclei (“koilocytotic atypia”).

Invasive Squamous Cell Carcinoma

Invasive cervical carcinoma arises from high-grade dysplasia, which may be detected up to
10 years before invasive carcinoma develops. Untreated squamous CIS results in invasive
carcinoma in about one-third of cases over a period of 10 years. Invasive carcinoma occurs
most often after the age of 40 years, although it may be seen in younger women. It is
associated with HPV infection in more than 99% of cases. Tumors may present as firm,
indurated masses, or they may be ulcerated or polypoid. Microscopically, there are irregular,
haphazardly infiltrating nests of cells with eosinophilic cytoplasm and enlarged, atypical,
hyperchromatic nuclei.
Lymphatic and vascular space invasion may be present, especially in more deeply
invasive tumors. Invasive squamous carcinomas are also graded 1 to 3 (well, moderately, and
poorly differentiated), although histologic grade may not correlate with prognosis. Grade 2
tumors represent the majority of invasive squamous carcinomas of the uterine cervix and are
usually nonkeratinizing squamous carcinomas with nuclear pleomorphism, numerous
mitoses, and an infiltrative pattern. Grade 3 (poorly differentiated) tumors either have smaller
cells without neuroendocrine differentiation or are pleomorphic with anaplastic nuclei and
sometimes a tendency to form spindle cells that must be distinguished from sarcoma by
positive cytokeratin stains.

Adenocarcinoma
While the incidence of squamous carcinoma of the cervix has decreased in the past decades
owing to cytologic screening, the number of cases of cervical adenocarcinoma has increased.
Adenocarcinoma accounts for 20% to 25% of cervical carcinomas.
Adenocarcinoma in situ (AIS) is a precursor of invasive adenocarcinoma. It is found
adjacent to many invasive adenocarcinomas, often accompanied by squamous dysplasia.
Both AIS and invasive adenocarcinoma of the cervix are associated with HPV (usually type
18, but sometimes type 16).
AIS is characterized by preservation of the overall endocervical gland architecture.
However, endocervical glands and surface epithelium are replaced to varying degrees by
cells displaying atypia. Most adenocarcinomas in situ occur near the transformation zone,
and skip lesions are unusual.

Other Epithelial Tumors

Adenosquamous carcinoma is a tumor composed of admixed malignant glandular and
squamous elements. One multi-institutional study found that adenosquamous carcinomas
were more commonly associated with higher tumor grade and vascular invasion than
adenocarcinomas. They also appear to be either histologically more aggressive or diagnosed
at a later stage than adenocarcinomas of the uterine cervix.

Small Cell Carcinoma

Most neuroendocrine tumors seen in the uterine cervix represent small cell carcinomas. Even
a small component of small cell carcinoma is associated with adverse outcome.
Morphologically, these tumors are identical to those seen in small cell carcinoma of the lung.
They are aneuploid tumors that show a strong association with type 18 HPV.
Immunohistochemical stains for neuroendocrine markers, such as chromogranin and
synaptophysin, may be helpful in the diagnosis. CD56 (neural cell adhesion molecule) is a
sensitive marker for the diagnosis of small cell cancer in the cervix.

Mixed Epithelial, Mesenchymal Tumors, and Other Malignant

Tumors
Uncommon malignant tumors of the cervix include sarcomas, malignant mixed müllerian
tumors, endometrial stromal sarcomas, melanomas, granulocytic sarcomas, primitive
neuroectodermal tumors, desmoplastic small round cell tumors, and primary germ cell
tumors. Primary extranodal lymphomas of the uterine cervix are usually diffuse B-cell
neoplasms.

Prognostic Factors
Key Points
Size of the primary tumor, depth of stromal invasion, lymphovascular invasion,
and parametrial involvement have been correlated with disease-free survival in
patients undergoing radical hysterectomy (RH).
Lymph node involvement is generally considered the most significant negative
prognostic factor.

Tumor Size, Volume, and Margin Status

The size of the primary tumor, depth of stromal invasion, and parametrial involvement have
been correlated with disease-free survival in patients undergoing RH. Lymphovascular space
invasion and depth of cervical stromal invasion have also been associated with significantly
worse prognosis.
Size has also been correlated with increased pelvic failure rates in patients treated
definitively with radiation. In patients with stage IB cervical cancer treated surgically, with or
without RT, positive margin status conveyed a hazard ratio of 3.92 compared to negative
margins. Margin status (distance in millimeter in patients with close margins) was
significantly associated with an increased recurrence rate. In this series, postoperative RT
eliminated local recurrences in patients with close margins and halved the recurrence rate in
patients with positive margins.

Stage
The FIGO stage is universally accepted for its prognostic significance. Previous FIGO
staging (2009) did not take into account important prognostic information such as nodal
status. Given the importance of nodal status, FIGO acknowledged this discrepancy (as well
as the widespread use of imaging in determining management) by incorporating radiographic
nodal involvement into the 2018 staging update.

Nodal Status
Lymph node involvement is, in most studies, the most significant negative prognostic factor.
Reports emphasize higher 5-year survival rates (90% or higher) among surgically treated
patients with no evidence of metastasis in the regional nodes, compared to patients with
positive pelvic (50% to 60%) or para-aortic nodes (20% to 50%).

Lymphovascular Space Invasion

Lymphovascular space invasion (LVSI) proved to be a significant prognostic factor in a
surgical–pathologic study of 542 patients completed by the Gynecologic Oncology Group
(GOG). Disease-free survivals were 77% and 89%, respectively, in patients with and without
LVSI. Furthermore, LVSI was shown to correlate with pelvic adenopathy and with time to
recurrence.

Hypoxia and Anemia

Both hypoxia and anemia have been independently correlated in multiple studies with
adverse outcomes in patients with cervical cancer. The data regarding anemia’s impact are
largely retrospective, while hypoxia has been studied through direct tumor measurements in
patients treated definitively with surgery as well as with radiation therapy. Studies have not
confirmed the hypothesis of a direct correlation between anemia and tumor hypoxia, and the
relationship between these two prognostic factors is complex. Several authors have suggested
that a lower hemoglobin level could also be a marker for more aggressive disease as opposed
to a physiologic variable that could be manipulated for therapeutic benefit. Indeed, a recent
large retrospective study of more than 2,000 women found that after accounting for other
prognostic factors, there was no correlation between local recurrence and anemia. While
historically it was recommended that hemoglobin less than 10 g/dL should be corrected,
many practitioners typically transfuse only when patients are symptomatic or at a
hemoglobin level of less than 8 g/dL.

Histopathology
Conflicting data exist regarding the prognostic significance of adenocarcinoma as compared
with squamous cell carcinoma, with some studies suggesting similar survival rates for
comparable stages and others suggesting inferior survival in the adenocarcinoma subgroup.
There is evidence that adenosquamous carcinoma is either a histologically more aggressive
tumor than cervical adenocarcinoma or is diagnosed later in the disease course.
Higher tumor grade and vascular invasion are statistically more common in
adenosquamous carcinoma than adenocarcinoma of the cervix. The presence of small cell
neuroendocrine carcinoma in any amount, even when associated with other types of
neoplasm, is an independent prognostic factor associated with aggressive tumor behavior.

General Management and Results of Treatment

Key Points
A 9-valent vaccine targeting HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 is
now recommended for all males and females starting at 11 or 12 years of age.
Though the vaccine is approved for men and women up to the age of 45,
generally, the vaccine is not recommended for those older than 26 years. The 9-
valent vaccine covers nearly 90% of cervical cancers
Receipt of the vaccine does not alter frequency or type of screening for cervical
cancer.
Severe dysplasia/CIN and CIS are adequately managed with local therapies such
as conization, laser ablation, cryotherapy, or a simple hysterectomy.
Stage IA1 carcinoma without LVSI is usually treated with conization or
hysterectomy.
Stage IA2 squamous cell carcinoma is treated with modified (type II) radical
hysterectomy (MRH) and pelvic lymphadenectomy, although curative-intent RT is
an equivalent option.
Radical surgery and definitive chemoradiation have similar good outcomes for
stage IB to IIA nonbulky tumors.
Bulky IB (FIGO 2018 IB3), IIB, IIIB, and IVA tumors are treated with curative-
intent chemoradiation.

Prevention: HPV Vaccination

There are now three FDA-approved HPV vaccines that have been shown in randomized
clinical trials to be highly effective in protecting against high-risk HPV infections. Gardasil-9
(9-valent covering HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58), Gardasil (quadrivalent
vaccine covering types 6, 11, 16, and 18), and Cervarix (bivalent vaccine covering types 16,
18) all protect against HPV types 16 and 18, the cause of 70% of cervical cancers and 50% of
precancerous cervical lesions. The remaining HPV types covered by the 9-valent vaccine (31,
33, 45, 52, 58) contribute to another 20% of cervical cancer cases. HPV 6 and 11 are
responsible for approximately 90% of genital warts. In addition to cervical cancer prevention,
the vaccines are intended to prevent anal, vulvovaginal, penile, and oropharyngeal cancers.
Vaccine doses should be administered two to three times depending upon age of initiation.
Epidemiologic studies have demonstrated decrease in the rates of preinvasive disease
following implementation of vaccination programs; recent studies now also demonstrate
reduction in cervical cancer rates. Since efficacy decreases in those with active HPV
infection and the vaccine does not protect against all known HPV types, general screening
guidelines should still be followed in women who have received the vaccine.

Severe Dysplasia and Carcinoma In Situ

Patients with severe dysplasia/CIN and CIS have essentially no risk of lymphatic
involvement and are often treated with local therapies such as conization, laser ablation,
cryotherapy, or a simple hysterectomy. These various techniques have comparable efficacy.
Patients with HIV infection, high HPV viral load, positive margins, older age, and residual
high-risk infection following conservative management have a higher recurrence rate.
Reported rates of recurrent CIS and invasive cancer following therapeutic conization are low
(<5%).
Factors associated with persistent disease or invasive cancer following cold knife
conization include residual CIN 3, positive ectocervical and endocervical margins,
multiquadrant disease, age greater than 50, and positive endocervical curettings. Patients with
positive ECC after conization or positive endocervical margins on a cone specimen for CIS
should have repeat conization prior to hysterectomy to avoid inappropriate treatment for
invasive disease.
Since patients with CIS have virtually no risk of pelvic adenopathy, it is also appropriate
to treat with only intracavitary RT. Tumor control rates of 100% have been reported. Grigsby
and Perez successfully treated 21 such patients with a single intracavitary implant, delivering
a mean point A dose of 46.12 Gy; no treatment sequelae were observed.

Stage IA
The concept of “microinvasion” (equating to FIGO stage IA) should define tumors that
penetrate the basement membrane but have little or no risk of nodal involvement or
dissemination. All tumors with depth ≥5 mm are considered stage IB tumors.
Stage IA1 carcinoma is usually treated with conization or extrafascial hysterectomy. The
control rate approaches 100%. Absence of LVSI plays a key role in opting for the
conservative management of patients with MID as its presence may herald a higher incidence
of lymphatic involvement as well as tumor recurrence. Patients with IA1 disease with LVSI
should undergo MRH and pelvic lymphadenectomy.
Patients with FIGO IA2 disease are not candidates for conservative surgical approaches
in most circumstances. The recommended treatment for stage IA2 squamous cell carcinoma
is a modified (type II) RH and pelvic lymphadenectomy, although curative-intent RT is an
equivalent option. The average pelvic lymphatic metastasis rate from reported data is 5% to
13%. In patients who are medically inoperable, intracavitary RT may be used, with several
series documenting excellent outcomes and low complication rates.

Adenocarcinoma Early Disease

The incidence of cervical adenocarcinoma has increased in the past 40 years. Almost all AIS
lesions are associated with HPV, with 18 being the predominant type. The management of
AIS is controversial. The term “microinvasion” may be inaccurate in describing glandular
lesions as an accurate measurement of depth of invasion in glands may be difficult. The
overall rate of residual disease in hysterectomy specimens after conization with negative
margins is 25% and with positive margin is around 50%. Given the critical role of margin
status postconization, a cold knife technique may be preferred in patients with AIS. The
recommended surveillance after conization for AIS includes cytology and ECC every 4
months. The most successful conservative management protocols require negative margins
and no LVSI, and careful counseling and follow-up are warranted.

Stages IB to IIA (Nonbulky)

Stage IB is now divided into IB1 (lesions confined to the cervix and <2 cm in size), IB2 (≥2
and <4 cm), and IB3 (≥4 cm). Lesions less than 4 cm and selected IIA lesions without
extensive vaginal involvement can be treated with either RH and pelvic lymphadenectomy
(followed by tailored chemoradiation as indicated by surgical findings) or primary radiation.
Surgery is the preferred option in younger women as ovarian function and vaginal length, and
thus sexual function, can generally be maintained. Transposition of the ovaries to the
abdominal wall or the gutters away from the radiation field may prevent radiation-induced
ovarian failure. Retention of ovarian function following transposition and postoperative
radiation has been reported to range from 53% to 71%. The rate of ovarian metastasis is very
low in squamous cell carcinoma (<1%), and thus, salpingo-oophorectomy is not generally
required. Of note, recent data from both a randomized trial and national US hospital-based
registry data suggest that open abdominal RH is superior to minimally invasive radical
surgery techniques in terms of disease-free and overall survival in patients with early-stage
cervical cancer (please see “Surgery” section).
Radical surgery and definitive chemoradiation have similar good outcomes. Typically, 5-
year survival for patients with disease confined to the cervix is 85% to 90% and for upper
vaginal involvement is 65% to 75%. In a prospective study of RH ± RT (patients with
parametrial involvement, deep stromal invasion, and/or positive nodes received postoperative
RT) versus RT alone, no difference was seen in disease-related outcome. In the RH arm, 54%
(62 out of 114) and 84% (40 out of 55) of stages IB1 and IB2 (using FIGO 2009 staging)
received postoperative RT, respectively. Severe morbidity was seen in 28% in the surgical
arm (mostly combined surgery and RT) compared to 12% in the RT arm.
Stage I patients who undergo radical surgery and are found to have poor prognostic
pathologic features should receive adjuvant RT to decrease their risk for local recurrence.
This high-risk group of patients is defined by the presence of two more of the following risk
factors: lymphovascular space involvement, greater than one-third stromal invasion, and
tumor size greater than 4 cm. In a prospective study of adjuvant RT versus observation in this
group of high-risk stage IB patients after surgery, adjuvant RT decreased the rate of local
recurrence by 46% and progression-free survival by 42% at 10-year median follow-up for
patients still alive at last contact.

Fertility-Sparing Surgery/Radical Vaginal and Abdominal

Trachelectomy
Almost 30% of women diagnosed with cervical cancer will be less than 40 years of age and
40% will have early stage I disease. Preservation of fertility can be a major consideration in
treatment if an acceptable oncologic outcome can be obtained. Recently, there have been
major advances in fertility-sparing surgery (FSS) in women with early-stage cervical cancers
using a procedure that involves transvaginal resection of cervical and paracervical tissues
(vaginal radical trachelectomy) and proximal vaginal, placement of a permanent cerclage at
the cervicouterine junction, and a laparoscopic pelvic lymphadenectomy.
The overall recurrence rate in the literature is about 4%, comparing favorably with
standard treatment. Appropriate lesions include FIGO stage IA1 without extensive LVSI and
IA2 or IB1 lesions (<2 cm in size) with limited endocervical involvement. A review reported
that of patients electing FSS, 43% attempt conception, 70% conceive, 49% deliver at term,
and 15% have cervical stenosis causing infertility.

Bulky IB Carcinoma of the Cervix

Bulky endocervical tumors and the so-called barrel-shaped cervix cancers have a higher
incidence of central recurrence, pelvic and para-aortic lymph node metastasis, and distant
dissemination. As discussed above, of the stage I patients with tumors greater than 4 cm
randomized to surgery (vs. radiotherapy), 84% required postoperative RT due to risk factors,
suggesting that definitive radiotherapy (typically with concurrent chemotherapy) can provide
equivalent disease control with decreased treatment-related toxicity. Therefore, patients with
bulky disease confined to the cervix are generally managed with definitive chemoradiation.
Historically, adjuvant extrafascial hysterectomy following preoperative RT was an
accepted treatment approach. The GOG performed a randomized trial in which 256 eligible
patients with carcinomas of the cervix ≥4 cm were treated with external beam and
intracavitary radiation with or without extrafascial hysterectomy. The 3-year disease-free
survival and overall survival rates were 79% and 83%, respectively, and were virtually
identical in the irradiation-alone and the combined irradiation and surgery groups. The
incidence of progression was somewhat higher in the irradiation-alone group (46%)
compared to the combined therapy group (37%) (p = 0.07). However, it appears that surgery
does not contribute to increased survival compared to RT alone in patients with “bulky” stage
IB disease. Furthermore, combined modality therapy was associated with a higher incidence
of any reported adverse effects compared to RT alone (63% vs. 56%). Therefore, adjuvant
hysterectomy is generally only indicated in instances where there is insufficient
brachytherapy dose administered to the primary tumor.

Stages IIB, III, and IVA

Most patients in the United States with stage IIB disease are treated with curative-intent
chemoradiation. With RT alone, the 5-year survival rate has historically been 60% to 65%,
and the pelvic failure rate 18% to 39%. Similarly, most patients with stage III and IVA
tumors are best treated with concurrent chemoradiation. Based on multiple randomized
clinical trials (Table 7.2), concurrent chemotherapy with irradiation is considered the
standard of care. Although the studies used a variety of agents, the de facto standard has
become once-weekly cisplatin at a dose of 40 mg/m2 for six cycles. Other chemotherapy
agents used successfully include 5-FU, mitomycin, carboplatin, paclitaxel, and epirubicin.
Considering all eligible patients with stage IIB to IVA carcinomas enrolled in GOG 85, a
55% survival rate with platinum-based chemotherapy with RT was demonstrated after a
median follow-up of 8.7 years. In this same group of patients, GOG 120 found a 66%
survival rate with platinum-based chemoradiation. A recent randomized trial from India also
demonstrated improved survival specifically in patients with IIIB tumors with the addition of
weekly cisplatin.

TABLE 7.2 Randomized Trials of Chemoradiation for Locally Advanced

Cervical Cancer
EFRT, extended field radiation therapy; WPRT, whole pelvic radiation therapy; 5-FU, 5-fluorouracil; SH, simply
hysterectomy; RH, radical hysterectomy.
*Indicates p-value <0.05 for comparison between arms.

More recently, an international phase III randomized trial investigated the addition of
concurrent and two additional cycles of adjuvant gemcitabine to cisplatin-based radiation in
stage IIB to IVA disease. At 3-year follow-up, progression-free and overall survivals were
higher in the gemcitabine arm compared to the standard regimen of cisplatin-based
chemoradiation. This study, however, has been criticized for its statistical design, significant
acute toxicity, and the paucity of late toxicity follow-up data.
The value of adjuvant chemotherapy following cisplatin-based chemoradiation in locally
advanced patients is currently being explored in the OUTBACK study. This prospective,
randomized, phase III trial endorsed by the GOG and RTOG randomizes patient to adjuvant
carboplatin and paclitaxel or no additional therapy following primary cisplatin-based
chemoradiation. The primary outcome to be addressed in this trial is improvement in overall
survival.

External Irradiation Alone

Rarely, brachytherapy procedures cannot be performed due to medical reasons or unusual
anatomic configuration of the pelvis or the tumor (e.g., extensive lesion and inability to
identify the cervical canal, presence of a fistula). These patients may be treated with higher
doses of external irradiation alone, although the results are inferior to those obtained with
combined external beam and intracavitary irradiation.

Unusual Clinical Situations

Invasive Carcinoma Treated by Simple Hysterectomy
Although uncommon, cervical cancer can be diagnosed incidentally after simple
hysterectomy in patients operated on for what is felt to be CIS, “microinvasive” disease,
incorrectly diagnosed endometrial carcinoma, or for “benign” indications. If only
microinvasive carcinoma is found, with no evidence of LVSI, no additional therapy is
necessary. However, in patients with more advanced disease, simple extrafascial abdominal
hysterectomy is not curative because the paravaginal/paracervical soft tissue, vaginal cuff,
and pelvic lymph nodes are not removed.
While technically difficult, an additional radical operation after previous simple
hysterectomy may be appropriate for selected patients. An alternative approach favored by
some is the use of adjuvant pelvic RT in patients with invasive disease, especially if restaging
scans suggest nodal disease. In an exhaustive review of the literature comparing a series of
patients having reoperation with radical parametrectomy and lymph node dissection (LND)
versus those having postoperative RT, the weighted average 5-year survivals favored RT
(68.7% vs. 49.2%).
If the postoperative RT approach is chosen, RT should be administered immediately after
recovery from operation, as prognosis is worse if therapy is delayed. The potential
contribution of concurrent platinum-based chemotherapy must be considered, particularly in
view of the randomized study of patients treated after RH with high-risk features (Fig. 7.2).
FIGURE 7.2 The influence of type of treatment on disease-free survival in
patients undergoing RH with and without RT and those who had simple
hysterectomy followed by adjuvant RT. (Kaplan-Meier analysis, p = not
significant.) Source: From Munstedt K, Johnson P, von Georgi R, et al.
Consequences of inadvertent, suboptimal primary surgery in carcinoma of the
uterine cervix. Gynecol Oncol. 2004;94:515–520.

Small Cell Carcinoma of the Cervix

Small cell carcinomas account for less than 3% of cervical neoplasms and are not often
confined to the cervix and surrounding tissues at diagnosis. Lymph node involvement is
present in over 50%, and vascular invasion is frequently present. One small retrospective
study suggested no patient with greater than stage IB1 survived, and even for stage IB1
patients, the survival was much worse than would be expected in more common histologies.
Given the propensity for distant metastasis, the use of combination cisplatin-based
chemotherapy (such as cisplatin and etoposide, a regimen used in small cell lung cancer) has
been widely accepted in these patients. Prophylactic cranial RT has also been given following
this chemoradiation in the absence of progression, although this is controversial.

Surgery
Key Points
Class I extrafascial hysterectomy is the most common hysterectomy performed
for a variety of gynecologic disorders.
Class II or MRH involves resection of the parametrial tissue medial to the ureter
and a 1- to 2-cm vaginal margin.
Class III or radical abdominal hysterectomy involves resection of parametrial
tissue to the pelvic sidewall along with a 2- to 3-cm vaginal margin. Minimally
invasive techniques are associated with worse outcomes compared to open
techniques based on randomized and large hospital-based registry data.
The standard approach to pelvic lymph node evaluation is pelvic (with or without
para-aortic) lymphadenectomy, but sentinel lymph node biopsy is currently being
studied.

A generally accepted classification of types of hysterectomy is given in Table 7.3 and

described below.

TABLE 7.3 Types of Abdominal Hysterectomy

Note: Type IV, extended RH (partial removal of bladder or ureter), in addition to type III.
Source: From Stehman FB, Perez CA, Kurman RJ, et al. Chapter 31—Uterine cervix. In: Hoskins WJ, Perez CA, Young
RC, eds. Principles and Practice of Gynecologic Oncology, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2000:864.

Class I Extrafascial Hysterectomy

This is the most common hysterectomy performed for a variety of gynecologic disorders. It
consists of removing the uterus and cervix with very little removal of vaginal mucosa. This
hysterectomy is adequate for the treatment of stage IA1 and advocated by some for stage
IA2. This procedure can be accomplished abdominally, vaginally, or laparoscopically.

Class II or Modified Radical Hysterectomy

MRH involves dissection of the uterine artery at its junction with the ureter. The parametrial
tissue is resected medial to the ureter. The ureterosacral ligaments are isolated, and the
proximal portions medial to the ureter are resected. A 1- to 2-cm vaginal margin is resected
along with the cervix. A pelvic lymphadenectomy is typically performed along with MRH.
Type II MRH is reserved for microscopic or smaller tumors depending on the surgeon’s
experience and preference.

Class III or Radical Abdominal Hysterectomy

The RH differs from the MRH in the amount of dissection and resection. The ureters are
dissected to their insertion into the bladder trigone. The cardinal ligaments are resected to the
pelvic sidewall. The ureterosacral ligaments may be either dissected to their attachment or in
select cases resected midway to their attachment. Resection of 2 to 3 cm of proximal vagina
is usual, but the operation can be tailored according to tumor size and patient anatomy.
Recently published data suggest superior disease-free and overall survival using open
techniques as compared to minimally invasive techniques. In one study by Ramirez et al.,
over 600 patients (>90% had disease confined to the cervix <4 cm in size) were randomized
to laparoscopic versus open radical abdominal hysterectomy. Three-year disease-free survival
was 91% versus 97% (hazard ratio for disease recurrence or death from cervical cancer, 3.74;
95% CI, 1.63 to 8.58), and overall survival was 94% versus 99% (hazard ratio for death 6.00;
95% CI, 1.77 to 20.30) favoring open radical abdominal hysterectomy.

Class IV or Extended Radical Hysterectomy

Extended radical hysterectomy (ERH) involves complete dissection of the ureter off the
vesicouterine ligament, sacrifice of the superior vesical artery, and resection of three-fourths
of the vagina. The risk of bladder dysfunction and fistula formation is greatly increased
compared to type I to III hysterectomies. There is little indication for ERH in the era of
modern RT and chemosensitization for locally advanced tumors.

Class V Hysterectomy
Type V hysterectomy is rarely performed and involves resection of the distal ureter or
bladder with reimplantation of the ureter if needed.

Pelvic Exenteration
Total pelvic exenteration (TPE) is mainly used for select stage IVA patients or for those with
limited central recurrences following treatment with prior RT. It involves en bloc removal of
the bladder, uterus, rectum, vagina, and, at times, vulva, depending on the extent of
recurrence. The procedure can be tailored to remove only the anterior or posterior structures
including the bladder (anterior exenteration) or rectum (posterior exenteration). Reported 5-
year survival outcomes are approximately 40%, ranging from 18% to 70% in the literature.
Sidewall extension, metastatic disease, and hydronephrosis are possible contraindications
to the procedure. Perioperative complications can include bleeding, infection, cardiac and
pulmonary complications, gastrointestinal and urinary leaks, fistulas, bowel obstruction, and
reconstruction flap failure. Sexual dysfunction and psychosocial effects are often longer-term
sequelae that can be permanent. The mortality rate from TPE is about 5%, even with careful
patient selection.

Lymph Node Evaluation

Pelvic lymphadenectomy is the standard approach for lymph node evaluation. Inclusion of
the para-aortic region depends upon risk of involvement and intraoperative findings. For
further indications and its role in treatment, please see section “Pretreatment Nodal Staging.”
Sentinel lymph node biopsy can be considered in select patients with the rationale that it may
decrease morbidity and operative time. In this technique, blue dye and radiocolloid are
injected into the cervical region at multiple sites; all mapped sentinel nodes, as well as
suspicious nonsentinel lymph nodes, should be removed. Lack of sentinel node detection in a
hemipelvis necessitates a complete lymphadenectomy on that side. A growing body of data
suggests high rates of detection, sensitivity, and negative predictive value, with the best
results in patients with tumors less than 2 cm in size. A large meta-analysis reported that
sensitivity was 100% and sentinel nodes were detected in greater than 95% of these cases.

Radiation Therapy
Key Points
Radiation portals are designed to encompass gross disease and regional areas at
risk for microscopic spread.
Extended field radiation therapy (EFRT) can be used either prophylactically or
therapeutically to treat the lymph nodes located in the para-aortic chain.
Multiple randomized trials demonstrate that pelvic RT combined with platinum-
based chemotherapy is superior to RT alone in patients with locally advanced
disease.
Brachytherapy is an integral component of definitive chemoradiation by allowing
for the delivery of high doses of radiation safely to the tumor.
Standard doses to the whole pelvis with external beam radiation therapy (EBRT)
are 45 to 50.4 Gy, and are combined with low–dose rate (LDR), pulse–dose rate,
or high–dose rate (HDR) brachytherapy. Intensity-modulated radiation therapy
(IMRT) may allow for dose intensification to nodal disease and potentially
improve toxicity compared to conventional techniques.
Historically, brachytherapy doses have been prescribed to a defined point in
relation to the brachytherapy apparatus, point A. In LDR brachytherapy, point A
receives 40 to 55 Gy, resulting in a total dose of 85 to 90 Gy (including EBRT)
depending on tumor stage.
Image-guided brachytherapy (IGBT) uses three-dimensional (3D) imaging (most
commonly CT and/or MRI) to define a tumor target volume and create an optimal
 radiation plan that allows for dose escalation to tumor and reduction of dose to
normal tissues. HDR brachytherapy is generally used with IGBT to deliver a
cumulative dose of ≥80 to 90 Gy EQD2 to the target volume over four to six
treatments.

External Irradiation
Standard Fields (3D-Conformal Radiation)
Treatment of invasive carcinoma of the uterine cervix requires delivery of adequate doses of
irradiation to the pelvic lymph nodes. Standard radiation fields include four fields to
encompass the pelvic region: an anterior beam (anteroposterior), posterior beam
(posteroanterior), and two lateral beams. The superior border of the pelvic portal should be at
the L4–5 interspace to include the external iliac and hypogastric lymph nodes. Some have
recommended extension of the superior border to the confluence of the common iliac artery
and veins and should be considered, especially in those patients with positive nodes in the
external and internal iliac region. For patients with positive common iliac nodes, superior
border should include the low para-aortics to the level of L2. This increase in the superior
border will expose more normal tissue to irradiation, however. If there is no vaginal
extension, the lower margin of the portal is at the midportion to inferior border of the
obturator foramen or 3 to 4 cm below any visible or palpable disease, whichever is lower.
When there is vaginal involvement, the field should extend distally beyond the tumor a
minimum of 3 to 4 cm, although some contend that the entire length of the vagina should be
treated down to the introitus. It is important to identify the distal extension of the tumor in
some manner at the time of initial simulation, for example, with a radiopaque marker in the
vagina, or by placement of fiducial markers, particularly as tumor regression over the course
of therapy may make identification of the initial distal extent of disease difficult to determine
at the time of brachytherapy. Often, vaginal extension will not be clearly defined by CT scan
but may be better appreciated on MRI. Placement of ultrasound gel or KY jelly in the vagina
can aid in visualization of vaginal disease. In patients with involvement of the distal third of
the vagina (stage IIIA), portals should cover the inguinal lymph nodes because of the
increased probability of metastases. The lateral portal anterior margin is placed 1 cm anterior
to the pubic symphysis to include the anterior extent of the external iliac nodes. The posterior
margin usually covers at least 50% of the rectum in stage IB tumors and extends to cover the
entire sacrum in patients with more advanced tumors (Fig. 7.3B). Routinely placing the
posterior border at S3 interspace (to cover the uterosacral ligament and presacral nodes) may
result in inadequate coverage of the planning target volume. Ideally, 3D imaging with CT,
MRI, or both will be used to ensure adequate coverage. Contouring of the structures at risk
with blocks based on these contours forms the mainstay of current therapy—3D conformal.
FIGURE 7.3 Standard fields for external beam whole pelvis radiation therapy.
A: Anteroposterior field. B: Lateral field. Source: From Kunos CA, Abdul-
Karim FW, Dizon DS, et al. Cervix uteri. In: Chi D, Berchuck A, Dizon DS, et
al., eds. Principles and Practice of Gynecologic Oncology, 7th ed. Philadelphia,
PA: Wolters Kluwer; 2017:491.

Intensity-Modulated External Radiation Therapy

IMRT refers to the delivery of 7 to 9 converging radiation beams with varying intensity
patterns that create a dose distribution that allows for a steeper dose gradient and improved
conformality around the target volume. This enables coverage of the target to the prescribed
dose while minimizing doses to normal surrounding structures. Treatment planning is most
commonly based on 3D imaging utilizing CT. MRI and PET images can be fused with
planning CT scans to assist in delineating the treatment volume (Fig. 7.4).
FIGURE 7.4 This figure shows dose distribution from extended field RT given
with a four-field isocentric technique with all fields treated in continuity. The
AP–PA fields (A) are weighted 70:30 in relation to the lateral fields (B), limiting
the dose to the kidneys, as shown in the DVH in Figure 7.5. This patient had a
large pelvic mass, compromising the ability to spare the rectum and bladder.

Published benefits of IMRT include the ability to preferentially limit the dose of radiation to
normal tissues, safely deliver higher tumor doses, and enable treatment and retreatment of
tumors that are not otherwise treatable. For example, in patients with bulky, unresectable
lymph nodes, IMRT can be utilized to boost dose to the involved nodes. While a small
prospective RTOG study found that the use of a para-aortic field using conventional
techniques was associated with a very high rate of severe toxicity, more modern studies
suggest that IMRT may be associated with lower toxicity. For instance, a small, single-
institution, prospective Chinese study by Du et al. compared treatment of para-aortic node
metastasis with IMRT versus conventional para-aortic field irradiation. The investigators
found significantly higher rates of tumor response and overall survival at 2 and 3 years,
accompanied by lower hematologic and gastrointestinal toxicity rates, in patients treated with
IMRT. Despite the higher dose being delivered in IMRT patients, IMRT provided better
critical organ sparing than the conventional RT technique.
Results of a randomized trial (TIME-C) comparing IMRT to conventional planning in the
postoperative setting suggest a reduction in acute toxicity with IMRT, but limitations to this
trial include short follow-up and low utilization of concurrent chemotherapy. Therefore,
results may not be applicable in the setting of definitive radiotherapy, in which chemotherapy
is typically administered and target volumes are much larger. There is an ongoing
randomized trial from India (PARCER) exploring the use of IMRT specifically for
postoperative cervical cancer patients with a primary endpoint of late gastrointestinal
toxicity; preliminary reports suggest a higher rate of chemotherapy use in this patient
population. In the definitive setting, IMRT may be most beneficial in instances where gross
nodal disease requires higher doses or the inguinal or para-aortic regions require treatment.
To date, the weight of opinion does not support the ability of IMRT techniques to replace
intracavitary brachytherapy for the treatment of cervical cancer.
A concern and possible pitfall of IMRT for gynecologic cancers includes the problem of
target motion due to variability in rectal and bladder filling. Other concerns include an
increase in the incidence of secondary radiation-induced malignancies, limitations of imaging
in accurately defining pelvic disease, increased dose heterogeneity, and problems with quality
assurance. IMRT should only be undertaken in a facility with sufficient experience in
treatment planning and delivery; the utilization of cone beam CT and other imaging
techniques can be used to verify and account for intrafraction changes in patient and target
volume setup.

Extended Field Radiation Therapy

EFRT can be used either prophylactically or therapeutically to treat the lymph nodes located
in the para-aortic chain. The para-aortic chain is surrounded by organs of limited radiation
tolerance, that is, the spinal cord, kidneys, and small intestine; thus, there are concerns
regarding its use related to increased acute and late toxicities. Conventional techniques for
treatment include the use of opposed anterior and posterior fields and a four-field technique
(AP:PA and opposed laterals). Careful determination of the kidney location with an
intravenous pyelogram or CT scan and knowledge and respect of normal tissue tolerance
limits (kidneys, small bowel, and spinal cord) are critical when designing fields and beam
weighting. A dose–volume histogram (DVH) of such a treatment is shown in Figure 7.5.
IMRT may also be used to create a conformal plan that spares surrounding normal tissue.
FIGURE 7.5 This DVH from an extended field RT plan plots the volume of
various organs or structures versus the dose received. It shows excellent
coverage of tumor and nodal regions, while the normal structures, for example,
the kidneys, spinal cord, etc., receive limited dose. This provides quantitative
measures of dose distribution for use in evaluating and comparing treatment
plans.

ELECTIVE PARA-AORTIC LYMPH NODE IRRADIATION

As described above, the para-aortic region is generally not included in patients receiving
definitive radiotherapy, and thus occult involvement of lymph nodes in this region is a
potential cause of treatment failure. Even in the modern era, surgical studies have
demonstrated an approximately 20% false-negative rate for para-aortic node detection in
patients with pelvic nodal involvement on PET. Surgical staging is considered at some
institutions to determine whether the para-aortic region requires treatment. Elective treatment
of this region via EFRT is an alternative strategy that seeks to avoid the risks and treatment
delays associated with surgical staging. Retrospective and prospective data suggest that
EFRT can be delivered safely and with reasonable efficacy in high-risk patients. An older
randomized RTOG study demonstrated a survival benefit to EFRT compared to pelvic RT in
the absence of chemotherapy, while RTOG 90-01 showed that pelvic RT combined with
platinum-based chemotherapy was superior to EFRT (without chemotherapy) in patients with
locally advanced disease.
In the setting of concurrent chemotherapy, there are no randomized data studying the
impact of elective EFRT in those at highest risk of occult para-aortic nodal involvement.
More contemporary retrospective studies demonstrate significant benefit with the use of
elective irradiation in the setting of involved pelvic lymph nodes. One recent study from
Taiwan reported a benefit in cancer-specific survival with the use of EFRT in patients with
common iliac or three or more pelvic lymph nodes involved. Thus, possible indications for
consideration of elective EFRT include involvement of any common iliac or multiple pelvic
lymph nodes.

THERAPEUTIC PARA-AORTIC LYMPH NODE IRRADIATION

Data from the GOG suggest that patients with stage IB, II, III, and IVA cervical cancers will
have spread to the para-aortic lymph nodes in 5%, 16%, 25%, and 13%, respectively. Tumor
involvement in para-aortic lymph nodes is uncommon (although possible) in the absence of
pelvic lymph node metastasis. The degree to which RT demonstrates curative potential in this
group of patients is quite variable and is mostly related to selection factors in the patient
population so treated.
Therapeutic EFRT in patients with para-aortic metastases appears to be efficacious,
resulting in long-term survival rates of 25% to greater than 50%. Chemotherapy can feasibly
be added to EFRT in these patients, although at the expense of increased acute toxicity. A
Korean study demonstrated that with concurrent cisplatin-based chemotherapy, 3-year overall
survival in patients with para-aortic nodal disease was 69%. Indeed, even in patients with
para-aortic and left supraclavicular fossa metastases, 3-year survival in this study was still
49%, suggesting that patients with advanced nodal disease still benefit from curative
chemoradiotherapy.

Brachytherapy
Brachytherapy refers to the placement of radioactive sources at a short distance from the
intended target. Brachytherapy allows the delivery of high doses of radiation safely and has
been a major factor in the ability of RT to cure cervical cancer. For general details on
brachytherapy, please refer to Chapter 2.
The use of imaging to delineate a 3-D target volume (rather than a point in relation to the
apparatus) is becoming more common and is referred to as IGBT. In IGBT, cross-sectional
imaging such as CT or MRI is utilized to contour a high-risk clinical target volume (HR-
CTV), which is inclusive of the cervix and gross tumor that is present on imaging and
physical examination. Use of HDR and the addition of interstitial needles can improve the
ability to shape the dose distribution to the HR-CTV and allow for superior sparing of the
bowel, bladder, sigmoid, and rectum (Fig. 7.6).

FIGURE 7.6 Dose distribution for a standard versus optimized brachytherapy

plan demonstrating improved sparing of organs at risk (rectum and bladder) as
well as improved coverage of the target (red). Isodose lines: blue 75%, cyan
100%, white 200%, and yellow 300%. Source dwell times and positions are
shown on the right. (Source: Reprinted from Tanderup K, Nielsen SK, Nyvang
G, et al. From point A to the sculpted pear: MR image guidance significantly
improves tumour dose and sparing of organs at risk in brachytherapy of cervical
cancer. Radiother Oncol. 2010;94:173–180, with permission from Elsevier.)

Image guided intensity modulated External beam radiochemotherapy and M RI based

adaptive BRAchytherapy in locally advanced CErvical cancer (EMBRACE) is a large
international prospective study of MRI-guided brachytherapy. Data from EMBRACE have
provided a wealth of information to guide radiation oncologists in optimizing outcomes for
locally advanced cervical cancer patients, including recommended dose–volume metrics for
normal organs, dose–response of cervical cancer tumors for local control, and techniques for
incorporating MRI in the planning process. Due to the high spatial resolution available with
MRI, the “gold standard” in IGBT is to obtain MRI with the brachytherapy apparatus in
place and use T2-weighted sequences to delineate the HR-CTV. However, due to logistic
concerns and limited availability of MRI, many radiation oncologists will utilize diagnostic
MRI obtained prior to the procedure in conjunction with CT-based planning. Another
component of IGBT is its adaptive nature; the HR-CTV is contoured based on extent of gross
disease on imaging at the time of brachytherapy (there is no inclusion of initial areas of
disease or of areas at risk outside the cervix).
Although EMBRACE describes excellent clinical outcomes of local control greater than
90% and grade 3 to 4 toxicities less than 10%, it must be noted that the use of MRI and even
CT may be unrealistic in resource-limited settings around the United States and globally.

Doses of Irradiation
Invasive carcinoma of the cervix is treated with a combination of whole pelvis and
intracavitary or interstitial brachytherapy techniques. Standard doses to the whole pelvis
(with or without para-aortic radiation) with EBRT are 45 to 50.4 Gy, delivered by a four-field
box or IMRT technique.
This is generally followed by LDR or HDR brachytherapy. In LDR intracavitary therapy,
there are one to two insertions to a dose of approximately 40 to 55 Gy prescribed to point A,
depending on tumor stage (volume). Usual doses to point A from both the external irradiation
to the whole pelvis and the LDR intracavitary brachytherapy range from 70 Gy for small (1
cm) stage IB tumors to 90 Gy for stage IIB or IIIB tumors.
HDR brachytherapy doses can also be prescribed to point A, with commonly used
fractionation regimens of 6 Gy per fraction for 5 fractions or 7 Gy per fraction for 4 fractions.
If IGBT is used, the dose is prescribed to the 3D target volume. Dose received by 90% of the
volume (D90) is a commonly used metric to evaluate for adequate coverage of the target. The
goal D90 is at least 80 Gy EQD2 with data from EMBRACE suggesting that doses greater
than 90 Gy may provide improved local control in the setting of MRI guidance.
In some patients with parametrial or pelvic sidewall involvement, an additional external
beam parametrial dose is administered after consideration of the contribution of dose
delivered by the brachytherapy.

Overall Treatment Time

Several studies have demonstrated lower pelvic tumor control and survival rates after
definitive RT in invasive carcinoma of the uterine cervix when the overall treatment time is
prolonged. Combining the published results, one can suggest that pelvic control will suffer at
an approximate rate of 1% per day that treatment extends beyond 52 days. Recent data
suggest a benefit with even shorter treatment times of less than 49 days.

Chemotherapy
Chemotherapy is increasingly utilized in the management of cervical cancer, both in primary
management and for recurrent and metastatic disease. Cisplatin-based regimens are generally
administered concurrently with radiotherapy; most commonly weekly cisplatin is used.
Multiple randomized trials have demonstrated a survival benefit with the use of cisplatin in
definitive radiotherapy, and a 2010 meta-analysis concludes that there was a 6% absolute
benefit in 5-year survival in patients receiving chemoradiation versus radiation alone. In
patients with renal insufficiency, carboplatin can be used as an alternative agent.
Conventional agents that are able to induce a response rate of at least 20% in measurable
disease include cisplatin, paclitaxel, topotecan, ifosfamide, doxorubicin, epirubicin, and
vinorelbine. Doublets that combine these agents with cisplatin result in a doubling of
response rate and improved progression-free survival but little or no improvement in overall
survival when compared to cisplatin as a single agent. Three- and four-drug chemotherapy
regimens further increase the response rate without improvement in overall survival at the
expense of increased toxicity. For further discussion, please see “Treatment of Recurrent
Carcinoma of the Cervix.”

Combined Modality Treatment

Adjuvant Hysterectomy after Radiation Therapy
The use of adjuvant hysterectomy postradiation therapy (AHPRT) has been explored to
decrease the incidence of pelvic recurrence; however, its use remains controversial because
overall survival appears to be unaffected. A randomized trial to address this question was
performed by the GOG in 256 patients with cervix cancers more than 4 cm in size who were
randomized to curative doses of pelvic RT with brachytherapy versus preoperative doses of
RT and brachytherapy plus AHPRT. The relapse rate was significantly lower in the AHPRT
arm versus RT alone (27% vs. 14%). The incidence of progression was somewhat higher in
the RT-alone group at 46% versus 37% (p = 0.07) in the AHPRT group. However, no overall
survival advantage was seen. The use of AHPRT may be considered in patients where there
is concern that inadequate radiation therapy has been delivered to areas at risk due to
anatomic or tumor factors precluding optimal brachytherapy implantation.

Adjuvant Postoperative Pelvic RT

Key Points
Early-stage cervical cancer patients at intermediate (presence of two out of three
risk factors of large tumor size, lymphovascular invasion, and deep stromal
invasion) or high (positive nodes, margins, or parametria) risk of recurrence
require postoperative radiation
A phase III GOG trial in women with intermediate-risk cervical cancer treated
with RH ± RT showed a 46% reduction in the risk of recurrence in the RT arm
compared to the observation arm (p = 0.007) and a reduction in the risk of
progression or death (p = 0.009).
A phase III intergroup trial in high-risk women treated with RH and postoperative
radiation ± chemotherapy showed a significant improvement in 3-year survival
with concurrent cisplatin/5-fluorouracil and irradiation followed by adjuvant
 chemotherapy compared with pelvic irradiation alone (87% vs. 77%,
respectively).
An ongoing randomized cooperative group trial is presently investigating the
benefit of adjuvant carboplatin and taxol chemotherapy following postoperative
chemoradiation in women with high-risk cervical cancer.

The most common failure pattern following radical surgery for cervical carcinoma is pelvic
relapse. Based on an extensive GOG clinicopathologic study, groups of patients with
intermediate and high risk of recurrence were identified. Intermediate-risk criteria relate to
tumor size, depth of stromal invasion, and LVSI. High-risk criteria include positive pelvic
nodes, close or positive margins, and parametrial extension. Retrospective and prospective
data suggest that adjuvant pelvic RT significantly improves pelvic control rates and disease-
free survival in patients with risk factors for recurrence who have completed radical surgery.
The role of chemotherapy, particularly in high-risk patients, has also become established.

Intermediate Risk, Node Negative

The GOG conducted a phase III trial comparing RH alone to RH and postoperative pelvic RT
in patients with node-negative stage IB cervical carcinomas, with prognostic features
correlated with an intermediate risk of recurrence (GOG 92). Eligibility criteria for this study
are given in Table 7.4. There was a 46% reduction in the risk of recurrence in the RT arm
compared to the observation arm (p = 0.007) and a reduction in the risk of progression or
death (p = 0.009). Among patients with adenocarcinoma or adenosquamous histologies, only
8.8% recurred in the RT arm versus 44% in the observation arm. There was a strong trend
toward improved survival in the RT arm, but this did not reach statistical significance (p =
0.074). There is a now an ongoing GOG trial randomizing this patient population to
postoperative radiation with or without concurrent chemotherapy.

TABLE 7.4 GOG-92 Eligibility Criteria

Management of patients with tumors greater than 4 cm (FIGO 2018 IB3) is somewhat
controversial in that some favor initial surgery followed by adjuvant RT while others
recommend curative-intent chemoradiation to avoid the use of two local modalities. This is
based on a finding from a randomized study (mentioned above) demonstrating a high rate
(84%) of postoperative radiotherapy required in patients with tumors greater than 4 cm.

Node-Positive/High-Risk Patients
Spread of disease to the pelvic lymph nodes is a poor prognostic sign. An intergroup study
was conducted by the Southwest Oncology Group (SWOG), GOG, and RTOG in women
with FIGO stages IA2, IB, or IIA carcinoma of the cervix and found to have involvement of
the pelvic lymph nodes, involvement of the parametria, or positive surgical margins at time
of primary RH. All patients underwent total pelvic lymphadenectomy with confirmed
negative para-aortic lymph nodes. One hundred twenty-seven patients were randomized
between pelvic EBRT with 5-FU infusion and cisplatin, and 116 were treated with pelvic
external beam irradiation alone. The median follow-up for survivors was 43 months. Three-
year survival was significantly improved with concurrent cisplatin/5-fluorouracil and
irradiation followed by adjuvant chemotherapy compared with pelvic irradiation alone (87%
vs. 77%, respectively). Chemotherapy appeared to reduce both pelvic and extrapelvic
recurrences.

Close or Positive Margins/Parametrial Involvement

Eighty-five percent of patients accrued on the SWOG/GOG/RTOG Intergroup study were
eligible based on pelvic node involvement. Only 5% of patients accrued to this intergroup
study had positive margins. Nevertheless, patients with positive or close margins and/or
parametrial involvement are considered to be at high risk and, based on this randomized trial,
should be considered for adjuvant chemoradiation.

Radiation Therapy Dose and Technique

Vaginal intracavitary RT alone can be appropriate for patients with CIS with minimally
invasive carcinoma at the vaginal margin of resection as the only risk factor. Outpatient HDR
brachytherapy is commonly employed because it prevents the prolonged immobilization
required for LDR brachytherapy. The historic dose per fraction for vaginal cylinder
brachytherapy is 7 Gy/fraction for 3 fractions prescribed at 0.5 cm depth to the upper portion
of the vagina (typically the proximal 3 to 5 cm). This is extrapolated from the endometrial
cancer setting. Due to concerns for long-term toxicity, many practitioners use a more
prolonged fractionation scheme at a lower dose per fraction. In the cervical cancer setting,
total dose and number of fractions may require modification depending upon the extent of
residual disease and use of external beam radiation.
When external RT is used, patients generally should not receive more than 45 Gy to the
whole pelvis. Doses up to 50.4 Gy are acceptable when treating smaller fields that minimize
small bowel. Brachytherapy or small-field external beam boosts can be given, within
tolerance, to increase dose to the central pelvis. In the postoperative setting, a brachytherapy
boost using a vaginal cylinder may be considered for close or positive margins.

Chemotherapy in Combinations for Localized Carcinoma of

the Cervix: Neoadjuvant Chemotherapy Followed by
(Chemo)Radiotherapy
Randomized trials of neoadjuvant chemotherapy (NACT) followed by radiation versus
radiation alone in patients with locally advanced cervical cancer (mainly stages III and IV)
have been disappointing, in terms of both complete response rates and increase in survival. A
meta-analysis of 18 randomized clinical trials of NACT, including 2,074 patients, compared
NACT followed by RT to RT alone and demonstrated no advantage of NACT with regard to
progression-free survival, locoregional disease-free survival, metastasis-free survival, or
overall survival. NACT followed by RT for patients with locally advanced cervical cancer
should not be performed based on existing data.
Multiple modern prospective studies have evaluated tolerability and response rates to
NACT prior to chemoradiation. The rationale for this includes intensification of systemic
therapy earlier in the treatment course to address micrometastatic disease. A British phase II
study demonstrating good response rates and acceptable toxicity forms the basis for the
multi-institutional INTERLACE trial randomizing patients to chemoradiation with or without
neoadjuvant dose-dense weekly carboplatin and paclitaxel. Concerns of this approach include
the delay of definitive therapy, and this approach should not be routinely used in patients
until further evidence demonstrates its safety.

Neoadjuvant Chemotherapy Followed by Surgery

Numerous nonrandomized studies reported in the 1990s suggested that NACT followed by
surgery might be an attractive approach, and some but not all of the randomized trials show a
trend in favor of this combined approach. A meta-analysis of 5 randomized clinical trials and
872 patients who received NACT followed by surgery ± RT was compared to RT alone.
There was a significant improvement in progression-free survival, locoregional disease-free
survival, metastasis-free survival, and overall survival for those who were resectable
following NACT. A more contemporary randomized trial from Tata Memorial randomized
632 patients with stage IB2, IIA, or IIB (FIGO 2009 staging) cervical squamous cell
carcinoma to neoadjuvant carboplatin and paclitaxel followed by radical surgery versus
chemoradiation with weekly cisplatin. Disease-free survival (the primary endpoint) was
superior in patients receiving standard chemoradiation. Moreover, 21% of patients in the
surgery arm were unresectable following chemotherapy and crossed over to receive definitive
chemoradiation, while another 23% required postoperative radiotherapy due to the presence
of high risk features.

Adjuvant Chemotherapy
Several nonrandomized studies suggest a beneficial effect of adjuvant chemotherapy given
after radical surgery in patients at high risk for recurrence. Two randomized trials with a very
limited number of patients have tried to evaluate the effect of adjuvant chemotherapy in
patients with high-risk cervical cancer after RH. The results of both studies were
inconclusive. An ongoing randomized cooperative group trial is presently investigating the
benefit of adjuvant carboplatin and taxol chemotherapy following postoperative
chemoradiation in women with early-stage high-risk cervical cancer.

Treatment of Recurrent Carcinoma of the Cervix

The main cause of death among women with cervical cancer is uncontrolled disease in the
pelvis. However, a subset of patients with recurrent disease confined to the pelvis following
definitive local therapy is potentially curable. Additionally, select patients with limited sites
of metastatic disease may benefit from aggressive local therapy for long-term disease control,
although this is controversial.
When curative-intent salvage treatment is contemplated, the local recurrence should be
biopsy proven, and the patient should be evaluated for regional and distant metastases by
physical examination and imaging. PET/CT may be the most accurate test in terms of
assessing metastasis prior to embarking on local salvage therapy. Generally, patients with
pelvic or regional recurrences after definitive surgery alone are managed with RT or
chemoradiation, often with brachytherapy. Salvage options for patients with central
recurrence after definitive or adjuvant RT are limited to radical, usually exenterative, surgery
and, in select patients, reirradiation using interstitial radiation implants or highly conformal
EBRT or IMRT. Chemotherapy-responsive patients can obtain meaningful palliation in many
cases (Table 7.5).

TABLE 7.5 Randomized Studies of Cisplatin-Based Combinations versus

Single-Agent Cisplatin in Patients with Advanced Cervical
Cancer
ap = 0.03.
bNumbers evaluable for response.
cp = 0.004.
dp < 0.01.
CR, complete response; PR, partial response; MMC, mitomycin C; VCR, vincristine; BLM, bleomycin; CDDP, cisplatin
(dose in all studies and in all arms 50 mg/m2); DVA, vindesine; DBD, dibromodulcitol; IFOSF, ifosfamide.
In addition to cytotoxic therapies, targeted agents against molecular signaling pathways have
also been studied in the setting of recurrent cervical disease. Bevacizumab is a recombinant
antibody against the vascular endothelial growth factor, a known driver of tumor progression.
GOG 240 randomized patients with advanced disease to cisplatin and paclitaxel with or
without bevacizumab; final results demonstrated improved survival in patients receiving
bevacizumab (16.8 vs. 13.3 months). Notably, the fistula rate was 15% in patients receiving
bevacizumab.
The development of immune checkpoint inhibitors has also provided another viable
systemic therapy option in patients who have failed standard chemotherapeutic regimens.
Pembrolizumab is an antiprogrammed cell death 1 (PD-1) antibody that was approved by the
FDA in 2018 after the phase II KEYNOTE-158 study demonstrated activity in cervical
cancer patients who were PD-L1–positive. In the KEYNOTE study, response rate was 13.3%
at a median follow-up time of 10.3 months. Pembrolizumab is now recommended for those
who are PD-L1 positive and have disease progression on or after chemotherapy.

Complications and Sequelae of Treatment

Key Points
Complications following RH include ureteral injuries, vesicovaginal or
ureterovaginal fistulas (1% to 2% of cases), bladder atony (5%), lymphocyst
formation (1.6%), and lymphedema (3.6%).
Radiotherapy to the pelvis will result in ovarian failure. Ovarian transposition
may be considered in select patients with squamous cell carcinoma.
Grade 2 or higher late sequelae of pelvic RT occur in 5% to 15% of cases and may
include chronic proctosigmoiditis, rectal stricture, rectal ulcer, bowel obstruction,
malabsorption syndrome, chronic cystitis, bladder contracture, urethral stricture,
incontinence, vaginal stenosis/fibrosis, dyspareunia, vault necrosis, and
rectovaginal or vesicovaginal fistulae.
Concurrent chemoradiation results in additional acute hematologic toxicity
although most phase III studies show no significant increase in late toxicity.

Surgery Related
Common complications after conization include infection, bleeding, damage to surrounding
structures (bladder, rectum, and vagina), and cervical incompetence with risk of preterm
labor in future pregnancies. RH and lymphadenectomy may result in additional
complications. Urologic complications, such as ureteral injuries or
vesicovaginal/ureterovaginal fistulas, are reported in 1% to 2% of cases; this rate may
increase in patients requiring postoperative RT. The majority of vesicovaginal fistulas heal
spontaneously with continuous bladder drainage for 6 to 8 weeks and treatment of any
underlying infection. Conservative management can include ureteral stenting and drainage of
the urinary system via percutaneous nephrostomy, which may lead to healing of the fistula.
Surgical repair may be required for those refractory to conservative management. Fistulas
that occur following pelvic RT are less likely to heal with conservative management and may
require earlier surgical treatment. As surgical repair after RT has a lower success rate, urinary
diversion may be required as definitive treatment.
After pelvic LND, lymphocyst formation is about 1.6%, and the lymphedema rate is
about 3.6%. The hypogastric plexus, located at the sacral promontory, contains sympathetic
fibers that fuse with parasympathetic fibers located in the parametrium and allows for bladder
contraction and compliance. Surgical disruption of this plexus results in bladder atony and
dysfunction in about 5% of patients, possibly requiring continuous or intermittent drainage
for a few weeks.
Rectal function can also be impacted by RH. In a study of patient-reported outcomes of
rectal function after RH in 48 patients, 18% had constipation, 33% required chronic straining,
and 60% required laxative or manual assistance with defecation. The incidence of chronic
constipation was more than 20%.

Radiation Therapy Related

Acute effects during external pelvic RT most typically include diarrhea and bladder irritation.
These are usually self-limited and can be managed effectively with conservative measures,
such as dietary or behavioral modification. Most late gastrointestinal and urologic
complications occur within the first 3 years after RT, with an overall fistula rate of about 2%.
Factors that may increase the rate of fistula are combined treatment (surgery and RT),
smoking, thin habitus, inflammatory bowel diseases, and diabetes and other vasculopathies.
Possible late sequelae of pelvic RT by site are as follows:
1. Rectosigmoid complications: chronic proctosigmoiditis, rectal stricture, and rectal
ulcer
2. Small intestine complications: obstruction and malabsorption syndrome
3. Genitourinary (GU) complications: chronic cystitis, bladder contracture, urethral
stricture, and incontinence
4. Vaginal complications: vaginal stenosis/fibrosis, dyspareunia, vault necrosis, and
rectovaginal or vesicovaginal fistulae
5. Musculoskeletal complications: pelvic insufficiency fracture
6. Other complications: ovarian failure, lower extremity edema
There is approximately a 5% rate of major late sequelae in patients with stage I cervical
carcinoma treated with RT and a rate of approximately 10% in patients with stage II to IVA
diseases. Grade 2 complications are seen in 10% to 15% of patients with all stages treated
with RT alone. Risk is related to a number of factors, mainly dose and volume treated. A
greater incidence of pelvic complications has been consistently observed in patients treated
with higher doses to the whole pelvis (above 40 to 50 Gy). Injury to the gastrointestinal tract
is the most frequent late complication of RT for cervical cancer.
Combined Modality Related
Irradiation Followed by Surgery
One larger retrospective series of patients with stage IB cervical carcinoma treated with RT
reported an incidence of major complications at 3 and 5 years of 7.7% and 9.3%,
respectively; the actuarial risk of major complications was 14.4% at 20 years. The rate of
fistula formation was doubled in those who underwent adjuvant hysterectomy (5.3% vs.
2.6%). In a GOG study, 256 patients with stage IB carcinomas of the cervix—4 cm confined
to cervix—were treated either with external RT and intracavitary irradiation or with external
RT and a lower dose of intracavitary irradiation followed by an extrafascial hysterectomy.
The toxicities were similar in both groups, with grade 3 and 4 toxicities of about 10% in each
arm.

Surgery Followed by Irradiation

Radical surgery may result in intestinal adhesions to denuded surfaces in the pelvis, with an
increase in complications if postoperative RT is also administered. The GOG demonstrated a
significant increase in grade 2 late complications among patients undergoing pre-RT surgical
staging, particularly with a transperitoneal approach compared with a retroperitoneal
approach. Pretreatment laparotomy also increased the rate of fistula formation (5.2% vs.
2.9%) and small bowel obstruction (14.5% vs. 3.7%). An extraperitoneal approach to lymph
node staging lessens these complications.
In a randomized study of postoperative RT versus no further treatment (NFT) after RH,
grade 3 to 4 GU toxicities were noted in 3.1% versus 1.4% in the RT as compared to the NFT
arm, respectively. Similarly, grade 3 and 4 GI toxicities were 3.1% versus 0.8%, respectively.
Overall grade 3 and 4 toxicities were 6% in the RT group versus 2.1% in the NFT arm.
Methods to decrease the volume of small bowel irradiated will further lessen enteric
morbidity. Figures 7.7 and 7.8 show the effect of treating patients in the prone position with a
full bladder as a means of limiting the volume of small bowel irradiated. Similarly, IMRT
techniques can also be used to limit doses to normal tissues.
FIGURE 7.7 A, B: Lateral radiographs with and without bladder distension in a
patient with contrast in the small intestine.

FIGURE 7.8 A, B: Anteroposterior radiographs with and without bladder

distension in a patient with contrast in the small intestine.

Concurrent Chemoradiation
Concurrent chemoradiation results in additional acute hematologic toxicity. A major concern
has been the possible need to delay treatment, thus potentially compromising outcomes.
Typical RT fields include pelvic bone marrow, and strategies to reduce risk of toxicity
include use of IMRT as well as functional imaging to identify active bone marrow. The use of
granulocyte colony–stimulating factor (G-CSF) for neutropenia should ideally be avoided
during chemoradiation; however, its use may be necessary in patients with prolonged
neutropenia that affects treatment delivery. G-CSF should not be administered concurrently
with radiotherapy (i.e., therapy should be held).
Although some early series suggested that concurrent chemotherapy increased late
complications in patients receiving curative-intent RT, most studies suggest no significant
impact.

Thromboembolic Complications
In one series of patients who underwent radical surgery for cervical and uterine malignancies,
postoperative thromboembolic complications occurred in 7.8% of patients despite regular use
of low-dose heparin and antiembolism stockings. A second series noted a 16.7% incidence of
thromboembolic complications in 48 patients who received chemoradiation therapy without
surgery. Brachytherapy alone is associated with a very low rate of thromboembolic
complications: 0.3% in one series.
Erythropoietin has been utilized to maintain normal hemoglobin levels during
chemoradiation. However, reports of increased incidence of thromboembolic complications
have been noted in patients who receive erythropoietin during RT, and its routine use should
be discouraged.

Suggested Readings
Bhatla N, Aoki D, Sharma D, et al. FIGO Cancer Report 2018: Cancer of the cervix uteri. Int J Gynecol Obstet.
2018;143(suppl 2):22–36.
Bipat S, Glas AS, van der Veldern J, et al. Computed tomography and magnetic resonance imaging in staging of uterine
cervical carcinoma: A systematic review. Gynecol Oncol. 2003;91(1):59.
Bishop AJ, Allen PK, Klopp AH, et al. Relationship between low hemoglobin levels and outcomes after treatment with
radiation or chemoradiation in patients with cervical cancer: Has the impact of anemia been overstated? Int J Radiat
Oncol Biol Phys. 2015;91(1):196–205.
Blitz S, Baxter J, Raboud J, et al. Evaluation of HIV and highly active antiretroviral therapy on the natural history of human
papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women. J
Infect Dis. 2013;208:454–462.
Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients:
Results of a comprehensive meta-analysis. J Natl Cancer Inst. 2005;97:489–498.
Delgado G, Bundy B, Zaino R, et al. Prospective surgical-pathological study of disease-free interval in patients with stage IB
squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol. 1990;38:352–357.
Du XL, Sheng XG, Jiang T, et al. Intensity-modulated radiation therapy versus para-aortic field radiotherapy to treat para-
aortic lymph node metastasis in cervical cancer: Prospective study. Croat Med J. 2010;51:229–236.
Dueñas-González A, Zarbá JJ, Patel F, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus
cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in
patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011;29:1678–1685.
Eifel PJ, Morris M, Wharton JT, et al. The influence of tumor size and morphology on the outcome of patients with FIGO
stage IB squamous cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1994;29:9.
Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent
anogenital diseases. N Engl J Med. 2007;356:1928–1943.
Haie-Meder C, Potter R, Van Limbergen E, et al. Recommendation from Gynecological (GYN) GEC ESTRO Working
Group. Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy with emphasis on MRI
assessment of GTV and CTV. Radiother Oncol. 2005;74:235–245.
International Agency for Research on Cancer (IARC), World Health Organization. Cancer Fast Sheets: Cervical Cancer.
http://gco.iarc.fr/today/data/factsheets/cancers/23-Cervix-uteri-fact-sheet.pdf
Keys HM, Bundy BN, Stehman FB, et al. Radiation therapy with and without extrafascial hysterectomy for bulky stage IB
cervical carcinoma: A randomized trial of the Gynecologic Oncology Group. Gynecol Oncol. 2003;89:343–353.
Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage IB-IIA cervical
cancer. Lancet. 1997;350:535–540.
Leblanc E, Narducci F, Frumovitz M, et al. Therapeutic value of pretherapeutic extraperitoneal laparoscopic staging of
locally advanced cervical carcinoma. Gynecol Oncol. 2007;105:304–311.
Lécuru F, Mathevet P, Querleu D, et al. Bilateral negative sentinel nodes accurately predict absence of lymph node
metastasis in early cervical cancer: results of the SENTICOL study. J Clin Oncol. 2011;29(13):1686–1691.
Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical
cancer. N Engl J Med. 2018;379:1905–1914.
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. 2009;27:1069–1074.
Morice P, Rouanet P, Rey A, et al. Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy
with no hysterectomy in patients with a (clinical and radiological) complete response after chemoradiation therapy for
stage IB2 or II cervical cancer. Oncologist. 2012;17(1):64–71.
Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation
for high-risk cervical cancer. N Engl J Med. 1999;340:1137–1143.
National Cancer Institute. Cancer Advances in Focus: Cervical Cancer.
http://www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/cervical
Peters WA III, Liu PY, Barrett RJ, 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. 2000;18:1606–1613.
Potter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working
group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy—3D dose volume
parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol. 2006;78:67–77.
Ramirez P, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N
Engl J Med. 2018;379:1895–1904.
Rob L, Robova H, Halaska MJ, et al. Current status of sentinel lymph node mapping in the management of cervical cancer.
Expert Rev Anticancer Ther. 2013;13(7):861–870.
Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced
cervical cancer. N Engl J Med. 1999;340:1144–1153.
Rotman M, Pajak TF, Choi K, et al. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and
bulky IB and IIA cervical carcinoma. JAMA. 1995;274:387.
Rotman M, Sedlis A, Piedmonte MR, et al. A phase III randomized trial of postoperative pelvic irradiation in stage IB
cervical carcinoma with poor prognostic features: Follow-up of a Gynecologic Oncology Group study. Int J Radiat
Oncol Biol Phys. 2006;65:169–176.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11.
Stehman FB, Bundy BN, DiSaia PH, et al. Carcinoma of the cervix treated with irradiation therapy. I. A multi-variate
analysis of prognostic variables in the Gynecologic Oncology Group. Cancer. 1991;67:2776.
Surveillance, Epidemiology, and End Results Program, National Cancer Institute. Cancer Stat Facts: Cervical Cancer.
 https://seer.cancer.gov/statfacts/html/cervix.html
Tanderup K, Nielsen SK, Nyvang G, et al. From Point A to the sculpted pear: MR image guidance significantly improves
tumour dose and sparing of organs at risk in brachytherapy for cervical cancer. Radiother Oncol. 2010;94:173–180.
Tierney J; the Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy for
locally advanced cervical cancer: A systematic review and meta-analysis of individual patient data from 21 randomized
trials. Eur J Cancer. 2003;39: 2470–2486.
 8 The Corpus: Epithelial Tumors

Introduction
In the United States, endometrial cancer (EC) is the most prevalent of all gynecologic
malignancies. It is estimated that 65,620 new cases of EC will be diagnosed in 2020, and
account for an estimated 12,590 deaths. Factors influencing its rising incidence include
prolonged life expectancy, earlier diagnosis, and obesity. Currently, endometrial
adenocarcinoma is the fourth most common cancer in females, behind breast, colorectal, and
lung cancers. It is the sixth leading cause of death from malignancy in women. The lifetime
risk of EC is 3.1% among American women, with a 0.6% lifetime mortality risk.
In 67% of all cases, the tumor is confined to the uterine corpus at the time of diagnosis,
and survival rates of 95% or more are expected. In the past 50 years, the treatment of this
cancer has evolved from a regimen of preoperative radiation therapy followed by
hysterectomy 6 weeks later, to individualized management consisting of surgical treatment
with or without additional therapy depending on whether various risk factors are identified.
Currently, EC is surgically staged using the 2009 International Federation of Gynecology and
Obstetrics (FIGO) staging system (Table 8.1).

TABLE 8.1 FIGO Staging of Carcinoma of the Endometrium (Updated

2009)
aG1, G2, or G3.
bEndocervical glandular involvement only should be considered as stage I and no longer as stage II.
cPositive cytology has to be reported separately without changing the stage.
Source: From Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol
Obstet. 2009;105:103–104, with permission.

Epidemiology and Risk Factors

Key Points
Type I cancers are estrogen related, and type II cancers are not.
Type II cancers represent the more aggressive phenotypes.
There is a high risk of an invasive cancer in the presence of biopsy-proven
complex atypical hyperplasia (CAH).

Two broad histologic categories of EC have been described (Table 8.2), termed type I and II
carcinomas. They appear to have different patterns of molecular alterations that underlie their
pathogenesis and clinical outcomes.
TABLE 8.2 Comparison between Type I and Type II Endometrial Cancers

Type I ECs are associated with unopposed estrogen exposure and are often preceded by
premalignant disease. They are usually early stage at diagnosis, are low-grade tumors
(predominantly of endometrioid histology), and carry a favorable prognosis. Obesity and
family history remain two of the strongest risk factors for EC. Hereditary cancers are most
clearly linked to Lynch syndrome (formerly termed hereditary nonpolyposis colorectal cancer
[HNPCC]), an autosomal dominant cancer susceptibility syndrome. Diabetes and
hypertension, once thought to be risk factors for EC, are probably surrogates for obesity; as a
result, they probably should not be considered as important independent risk factors. Finally,
tamoxifen (a common agent for the treatment of breast cancer) is a risk factor for the
development of type I endometrial carcinoma, though the benefits of treatment (for breast
cancer) far outweigh the risk of disease.
In contrast, type II ECs represent estrogen-independent tumors and are associated with a
more aggressive clinical course. Unlike type I tumors, there is no readily observed
premalignant phase. Uterine serous carcinoma, clear cell carcinoma, and perhaps grade 3
tumors constitute these histologic phenotypes (Table 8.2).
The molecular defects associated with ECs are stratified between type I and type II
cancers. Type I cancers frequently have PTEN, KRAS, CTNNB1, and PIK3CA mutations, and
this is also varied by race, whereas type II cancers are more likely to have TP53 mutations or
amplification of ERBB2 (HER2). Among women belonging to families with the autosomal
dominant Lynch syndrome, the most common extracolonic malignancy is endometrial
carcinoma with a lifetime risk of 40% to 60%.

Pathology of Preinvasive Disease

The current classification of endometrial hyperplasia accepted by the World Health
Organization (WHO) divides hyperplasia on the basis of cytologic features into hyperplasia
without atypia and atypical endometrial hyperplasia (AEH), with atypia being the most
concerning cytologic feature. Atypical hyperplasia is also referred to as endometrial
intraepithelial neoplasia (EIN). Endometrial hyperplasia appears to arise as a result of
unopposed and prolonged estrogen stimulation. Therefore, some hyperplasias may regress if
the estrogenic stimulus is removed.
The probability of progression to adenocarcinoma is related to the degree of cytologic
atypia. While progression occurs rarely for patients with hyperplasia without atypia
(incidence is 1% and 3%, respectively), progression from atypical hyperplasia is much
higher; approximately 33%. However, coexistent adenocarcinoma may be present in over
40% of hysterectomies performed to treat atypical hyperplasia.
Mutter et al. proposed the alternative classification of hyperplasia based on a
combination of morphologic, molecular, and morphometric information. This resulted in the
use of a new term, endometrial intraepithelial neoplasia (EIN), as the histopathologic
presentation of a monoclonal endometrial preinvasive glandular proliferation that is
considered the immediate pathologic precursor of endometrioid endometrial adenocarcinoma.
Approximately 25% to 33% of women with an EIN diagnosis will be diagnosed with
endometrial carcinoma within 1 year, and for those who do not develop cancer within 12
months, there is a 45-fold increased risk of future EC. Correspondingly, absence of an EIN
lesion in an initial representative biopsy, including those with only benign hyperplasia,
confers very high (99%) negative predictive value for concomitant or future adenocarcinoma.
In contrast, endometrial intraepithelial carcinoma (EIC) has been recognized as a
histologically distinctive lesion that is proposed to represent a form of intraepithelial tumor. It
appears to be the likely precursor to serous carcinoma of the endometrium.

Pathology of EC
Uterine tumors are classified based on a relatively simple classification scheme and
accommodates the vast majority of endometrial carcinoma. It has been shown to accurately
distinguish prognostic classes of endometrial neoplasms.
The differentiation of a carcinoma is expressed as its grade. Both architectural criteria
and nuclear grade are used to determine grade. The architectural grade is determined based
upon the amount of the tumor growth in solid sheets (Table 8.3). Grade 1 lesions are well
differentiated and are generally associated with a good prognosis. The FIGO rules for
grading state that notable nuclear atypia, inappropriate for architectural grade, raises the
grade of a grade 1 or grade 2 tumor by 1. Though FIGO did not define notable nuclear atypia,
it has been interpreted to include tumors with a majority of cells having nuclei of grade 3,
which portends a significantly worse behavior and justifies upgrading by one grade. Some
cell types (i.e., serous and clear cell) are not easily architecturally graded because their
growth patterns are architecturally limited, and in these cases, the nuclear grading is more
universally applicable. In instances where two distinctive cell types are identified within a
single tumor (mixed carcinomas), classification is generally based on the components that
constitute at least 5% of the tumor, according to the most recent WHO classification
guidelines.

TABLE 8.3 Histologic Grade and Depth of Invasion

Source: Reprinted from Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial
cancer: A Gynecologic Oncology Group study. Cancer. 1987;60:2035–2041, with permission.

Molecular Alterations in the Pathogenesis and Progression of

Endometrial Adenocarcinoma
Deletions or mutations of the PTEN gene and microsatellite instability (MSI) due to
hypermethylation of the promoter for the mismatch repair (MMR) gene, MLH1, are both
relatively common and early events in the development of a significant proportion of
endometrioid adenocarcinomas. In contrast, these molecular alterations do not appear critical
in the pathogenesis of serous or clear cell carcinoma. There are relatively few data to inform
the importance of MSI as a prognostic factor in EC, although defects in MMR systems are
associated with responsiveness to immunotherapy.
Mutations in the p53 gene are found with high frequency not only in invasive serous
carcinoma but also in EIC, the noninvasive precursor of serous carcinoma, suggesting that a
different pathway is followed in the development of this type of endometrial
adenocarcinoma. These mutations appear to be an early event in the development of serous
carcinoma but a late event in endometrioid carcinomas for which it serves as an indicator of
poor prognosis. In addition to the very frequent overexpression of p53 protein in serous
carcinoma, it has also been related to high FIGO stage, clear cell histology, higher histologic
grade, and increasing depth of myometrial invasion.
The KRAS, CTNNB1 (β-catenin), PIK3CA, and FGFR2 genes are also commonly
mutated in EC.

Cell Types
Endometrioid
Endometrioid adenocarcinoma is the most common form of carcinoma of the endometrium,
constituting 75% to 80% of cases. It varies from well differentiated to undifferentiated.
Characteristically, the glands of endometrioid adenocarcinoma are formed of tall columnar
cells that share a common apical border. With decreasing differentiation, there is a
preponderance of solid growth rather than gland formation.
Foci of squamous differentiation are found in about 10% to 25% of endometrial
adenocarcinomas. In a Gynecologic Oncology Group (GOG) study of early-stage disease, it
was noted that these tumors with squamous regions behave in a fashion similar to
endometrioid carcinomas without squamous differentiation. Pure squamous carcinoma of the
endometrium is extremely rare, representing less than 1% of endometrial carcinoma, and
with only about 60 reported cases.

Serous
Serous carcinoma of the endometrium closely resembles serous carcinoma of the ovary and
fallopian tube because its papillary growth and cellular features are similar. It is usually
found in an advanced stage in older women, when comprehensive surgical staging is
performed. Serous carcinomas most often arise from a background of atrophy or polyps
rather than hyperplasia. Serous carcinoma represents about 10% of endometrial carcinomas.
The tumors often deeply invade the myometrium, and unlike typical endometrioid
adenocarcinoma, there is a propensity for peritoneal spread.
Unfortunately, advanced-stage disease or recurrence is common even when serous
carcinomas are apparently only minimally invasive or even confined to the endometrium in
polyps. Since the metastatic disease is often identified only microscopically, about 60% of
patients are upstaged following complete surgical staging. Wheeler et al. stressed the
prognostic importance of meticulous surgical–pathologic staging. They and others found that
serous carcinoma truly confined to the uterus had an overall excellent prognosis, while those
with extrauterine disease, even if only microscopic in size, almost always suffered recurrence
and death from tumor.
Other Cell Types
Clear cell adenocarcinoma of the endometrium represents approximately 4% of all uterine
tumors. It is generally recognized and defined on the basis of the distinctive clearing of the
cytoplasm of neoplastic cells. These are biologically aggressive neoplasms with 5-year
survival of approximately 40% regardless of stage. These results are attributed to a high
propensity for extrauterine spread and frequent recurrence. In fact, occult extrauterine
metastasis is present in 40% of patients with disease clinically confined to the uterus.
Mucinous adenocarcinoma is rare in the endometrium, representing approximately 1% of
endometrial adenocarcinomas. Mucinous carcinoma of the endometrium has the same
prognosis as common endometrial carcinoma. If an endometrial carcinoma manifests two or
more different cell types, each representing at least 5% or more of the tumor, the term mixed
cell type is appropriate.
Malignancies in other organs may metastasize to the endometrium. The most common
extragenital sites are the breast, stomach, colon, pancreas, and kidney, although any
disseminated tumor could involve the endometrium. The ovaries are the most likely
gynecologic sources of metastasis.
Cancers of an identical cell type may be discovered in the ovary and endometrium
simultaneously. Usually, the primary site is assigned to the area having the largest tumor
mass and most advanced stage. In certain situations, primary malignancies in the
endometrium and ovary may coexist. This “field effect” of the “extended müllerian system”
may occur in 15% to 20% of endometrioid carcinomas of the ovary. In a review of a GOG
study of 74 patients with simultaneously detected endometrial and ovarian carcinoma with
disease grossly limited to the pelvis, only 16% of women suffered a recurrence of disease,
with a median follow-up of 80 months. This group of patients was atypical, with 86% having
endometrioid histology in both sites. Recurrence was statistically related to the presence of
microscopic metastases or high histologic grade. Recent data suggests that synchronous
tumors of the ovary and endometrium are clonally related, indicating shared origin.

Cancer Prevention and Screening for EC

Key Points
All women should be encouraged to promptly report abnormal vaginal bleeding.
Women taking tamoxifen (usually as breast cancer prevention or treatment) do not
require endometrial screening in the absence of symptoms.

Many cases of EC develop by way of a precursor lesion. Estrogen-related cancers frequently

develop secondary to atypical endometrial hyperplasia. Serous tumors also may develop EIC
through a precursor lesion. Prompt recognition of precursor lesions with institution of proper
treatment will prevent cancers and their sequelae. Many ECs may be preventable, particularly
those that are estrogen related.
 Because 95% of endometrial carcinomas occur in women 40 years and older and because
endometrial hyperplasia, the precursor state, tends to be a premenopausal and
perimenopausal condition, it is appropriate to evaluate individuals past their fourth decade of
life if there is abnormal bleeding. Similarly, a higher degree of suspicion should be held for
younger patients with high-risk characteristics including significant obesity, polycystic
ovarian syndrome/chronic anovulation, or tamoxifen exposure.
Evaluation can be by endometrial biopsy or by dilation and curettage (D&C) if the
biopsy is unsuccessful or the results are unclear. Patients with atypical hyperplasia may be
treated by hysterectomy or by periodic use of progestins, depending on age and reproductive
desires. Hysterectomy is the preferred treatment in the patient with atypical endometrial
hyperplasia. This approach not only cures the usual presenting symptoms of abnormal
bleeding but confers prophylaxis against the almost 30% risk of later developing endometrial
carcinoma. Since coexistent invasive EC may be present in up to 40% of women with
atypical hyperplasia, frozen section and surgical staging should be available at the time of
hysterectomy.
Those with AEH treated with progestins should have a D&C performed before treatment
to rule out occult carcinoma not detected by biopsy. A progestin should be administered at
least 10 to 14 days each month, if not continuously, and endometrial biopsies should be
performed at 3- to 4-month intervals to assess treatment results. Women with a uterus should
never be prescribed estrogen-only preparations of hormone replacement therapy because
unopposed estrogen greatly increases their risk of EC. The addition of progestins to the
regimens of patients treated with exogenous estrogen may prevent endometrial hyperplasia
and subsequent cancer and may protect against the development of carcinoma.
Women taking tamoxifen and having their uterus intact should be informed of the
increased risk of EC. Education regarding the onset of vaginal bleeding is important, and
patients should be advised to report symptoms early. All women on tamoxifen who present
with abnormal vaginal bleeding should be investigated promptly. However, screening of
asymptomatic women on tamoxifen therapy with ultrasound or endometrial biopsies is not
recommended.
Considering the available knowledge about the disease and available tests, it seems
unlikely that screening would be generally advised in the near future. This has also been the
view in statements from official organizations such as the Union for International Cancer
Control and the American Cancer Society (ACS). The ACS does recommend annual
endometrial biopsies starting at age 35 for women known to have or be at risk for HNPCC.
Obese patients should be counseled that a healthy diet and regular exercise could reduce their
risk of EC (in addition to other known benefits).

Clinical Presentation and Diagnostic Workup

Key Points
All postmenopausal bleeding should be evaluated.
Endometrioid adenocarcinoma is likely to present with disease confined to the uterus, while
serous and clear cell tumors are more likely to have extrauterine spread and pre-operative
imaging is warranted.
Approximately 90% of patients will present with abnormal vaginal discharge, of which
80% will report abnormal bleeding (usually postmenopausal) and 10% show leukorrhea.
Other signs and symptoms of more advanced disease include pelvic pressure and other
symptoms indicative of uterine enlargement or extrauterine tumor spread (abdominal
bloating, pain, shortness of breath).
The standard method of assessing uterine bleeding is EMB or D&C. Results of
endometrial biopsies correlate well with endometrial curettings.
After the diagnosis of endometrial carcinoma has been histologically confirmed, the
patient should undergo a thorough clinical evaluation consisting of a physical examination
and careful medical history, complete blood count, liver and renal function tests, and chest x-
ray. Further imaging can be guided by the risk of extrauterine spread. In general, women with
well-differentiated endometrioid tumors do not need to undergo an extensive metastatic
workup. However, patients with high-grade tumors should undergo further evaluation. This
may include body imaging by computed tomography (CT) with or without 18F-
fluorodeoxyglucose–positron emission tomography (PET), or magnetic resonance imaging
(MRI) of the pelvis (particularly indicated if cervical involvement is suspected). In addition,
a CA-125 may be useful for nonendometrioid tumors; if elevated, it becomes a way to
evaluate progress during treatment and, subsequently, during surveillance.
Preoperative assessments of lymph node involvement have been proposed by some
authors as useful techniques to assess for metastasis. However, only a few pretreatment
imaging tests have been described. Both CT and MRI are extensively used to assess nodal
spread of disease in patients with malignant tumors, including EC. The GOG conducted a
prospective assessment of PET/CT in patients with endometrial and cervical cancer (GOG
233). In both diseases, the addition of PET scanning to CT scan increased the detection of
lymph node metastases. It is not clear if these results have been translated into routine
clinical practice.

Pathologic Factors of Prognostic Significance

The importance of uterine and extrauterine risk factors is determined by how they affect the
probability of retroperitoneal lymph node involvement and subsequent survival.

FIGO Stage
The prognostic utility of surgical–pathologic stage has been confirmed in multiple studies of
large numbers of patients, using both univariate and multivariate analyses. FIGO stage is
often the single strongest predictor of outcome for women with endometrial adenocarcinoma
in studies using multivariate analyses. Although the FIGO clinical staging system of 1971
was generally useful, retrospective comparison of the two methods demonstrated the clear
superiority of surgical–pathologic staging over clinical staging in predicting outcome.

TABLE 8.4 Grade, Depth of Invasion, and Pelvic Node Metastasis

Source: From Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer: A
Gynecologic Oncology Group study. Cancer. 1987;60:2039–2041, with permission.

Histologic Cell Types

The histologic classification of endometrial adenocarcinoma is important because it has
consistently been recognized as an important predictor of biologic behavior and probability
of survival. Endometrioid adenocarcinoma accounts for the majority of tumors in the corpus
and, fortunately, usually has a relatively good prognosis.
Adenocarcinoma with squamous differentiation is similar to typical endometrioid
adenocarcinoma with respect to the distribution by age and frequency of nodal metastasis but
is associated with a slightly increased probability of survival. Serous carcinoma is an
aggressive tumor, with overall survival (OS) rates varying from 40% to 60% at 5 years. Clear
cell carcinoma is also a highly aggressive tumor, with 5-year survival rates of 30% to 75%.

Grade
The degree of histologic differentiation has long been considered one of the most sensitive
indicators of tumor spread. The GOG and other studies have confirmed that as grade
becomes less differentiated, there is a greater tendency for deep myometrial invasion (Table
8.3) and, subsequently, higher rates of pelvic and paraaortic lymph node involvement (Tables
8.4 and 8.5). In fact, 50% of grade 3 lesions have greater than one-half myometrial invasion,
with pelvic and paraaortic lymph node involvement approaching 30% and 20%, respectively.
Survival has also been consistently related to histologic grade, and in a GOG study of more
than 600 women with clinical stage I or occult stage II endometrioid adenocarcinoma, the 5-
year relative survival was as follows: grade 1, 94%; grade 2, 84%; and grade 3, 72%.
TABLE 8.5 Grade, Depth of Invasion, and Aortic Node Metastasis

Source: From Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer: A
Gynecologic Oncology Group study. Cancer. 1987;60:2039–2041, with permission.

Myometrial Invasion
The depth of myometrial invasion should be recorded in all pathology reports, preferably in
both millimeters and in the percentage of total myometrial thickness. Extension of tumor into
adenomyosis is not regarded as invasion. Deep myometrial invasion is one of the more
important factors correlated with a diminished probability of survival and is associated with a
higher probability of extrauterine tumor spread, treatment failure, and recurrence. In a GOG
study of over 400 women with clinical stage I and occult stage II endometrioid
adenocarcinoma, the 5-year relative survival was 94% when tumor was confined to the
endometrium, 91% when tumor involved the inner third of the myometrium, 84% when the
tumor extended into the middle third, and 59% when the tumor invaded into the outer third of
the myometrium. Although the depth of invasion is often inversely related to the degree of
differentiation, myometrial invasion is an independent predictor of outcome for women with
early-stage endometrial carcinoma.

Lymphovascular Space Invasion

Several studies have suggested that lymphovascular space invasion (LVSI) is a strong
predictor of recurrence and death and is independent of depth of myometrial invasion or
histologic differentiation. Zaino et al. found that vascular invasion was a statistically
significant indicator of death from tumor in early clinical stage but not in early surgical stage
endometrial adenocarcinoma. This suggests that lymphatic invasion helps to identify patients
likely to have spread to lymph nodes or distant sites but that its importance is diminished for
those in whom thorough sampling of nodes has failed to identify metastasis. Lymphovascular
space invasion or capillary-like space involvement with tumor exists in approximately 15%
of uteri containing adenocarcinoma. Nodal metastases are more common when capillary
invasion is identified. Capillary invasion is identified in 35% to 95% of serous carcinomas of
the endometrium, where it has generally been associated with an elevated risk of tumor
recurrence or death from disease.

Peritoneal Cytology
About 12% to 15% of patients who undergo surgical staging have positive peritoneal
cytology. Of these, 25% have metastases to pelvic lymph nodes, and 19% have metastases to
paraaortic lymph nodes. In addition, 35% of patients with extrauterine disease (adnexal,
nodal, or intraperitoneal spread) have positive cytologic washings. However, 4% to 6% of
patients with positive washings have no evidence of extrauterine disease. Published opinions
are mixed about the significance of this finding. Several small series show no outcome
differences. However, two large series show peritoneal cytology to be, by itself, a poor
prognostic factor. Nonetheless, in 2009, FIGO removed peritoneal washings as a formal
component of EC staging and suggests that positive cytology should be reported separately
but does not affect stage.

Pelvic and Paraaortic Lymph Nodes

In the 1987 GOG study of 621 clinical stage I and occult stage II patients, 70 (11%) had
metastases to pelvic or paraaortic lymph nodes. Of this number, 22 patients had metastases to
both the pelvic and paraaortic regions and 12 had metastases to the paraaortic nodes only.
The highest rate of paraaortic node metastases (32%) occurred if pelvic nodes were involved.
The frequency of pelvic and paraaortic nodal metastases with respect to depth of invasion
and grade is shown in Tables 8.4 and 8.5.

Determining the Surgical Procedure

Key Points
Surgical staging is a critical component for the proper diagnosis and management
of all endometrial carcinomas.
FIGO stage is the most powerful predictor of prognosis.
Surgical staging is feasible by minimally invasive techniques.

Contemporary management for most patients with EC remains surgical. Although the
tradition has been to do this abdominally, minimally invasive management has increasingly
been integrated into the forefront of surgical staging. Surgery for EC includes, at the
minimum, an initial surgical exploration with collection of peritoneal fluid for cytologic
evaluation (intraperitoneal cell washings), thorough inspection of the abdominal and pelvic
cavities with biopsy or excision of any extrauterine lesions suspicious for tumor, and total
extrafascial hysterectomy with bilateral salpingo-oophorectomy (BSO). The uterus should be
observed for tumor breakthrough of the serosal surface. To complete the surgical staging of
EC, the removal of bilateral pelvic and paraaortic lymph nodes is traditionally required.
While the current FIGO staging system removed the status of cytology as a stage-defining
criterion, it remains an important piece of information, especially in women with high-risk
histologies (e.g., serous carcinoma) with very early-stage disease.
In cases with gross omental or intraperitoneal disease spread, cytoreductive surgery is
often performed, especially if the surgeon believes a complete or optimal cytoreduction is
possible. This may require total omentectomy, radical peritoneal stripping, and, occasionally,
bowel resection.
In cases complicated by medical comorbidity, advanced age, or obesity, or when nodal
dissection cannot or will not be performed, total vaginal hysterectomy with or without
laparoscopic assistance may be utilized. Following surgical assessment, patients may be
classified based on pathologic features as to their risk of recurrence, and those deemed to be
at sufficient risk may be offered adjuvant therapies. An algorithm for surgical approach can
be found in Figure 8.1.
FIGURE 8.1 Surgical management of early-stage endometrial cancer (stages I
and II). Patients with stage I and II endometrial cancers are treated with total
hysterectomy (TH), BSO, peritoneal cytology, and pelvic and paraaortic
lymphadenectomy. Many advocate lymphadenectomy when feasible for all
patients with early-stage endometrial cancer regardless of grade or depth of
myometrial invasion. Source: From Markman M, ed. Atlas of Cancer, 2nd ed.
Philadelphia, PA: Current Medical Group; 2008.

Nonsurgical Management
Patients with significant medical comorbidities who are not acceptable candidates for surgery
(e.g., markedly advanced age, diminished performance status, or severe cardiac/pulmonary
disease) may be managed by alternative means. Importantly, obesity in and of itself should
not preclude surgical management. Patients who are obese but otherwise surgical candidates
may undergo an abdominal panniculectomy to enhance surgical exposure to facilitate
hysterectomy and nodal dissection. Primary radiation therapy without surgery has been used
and is discussed later in this chapter.
Approximately 5% of women with EC are diagnosed under the age of 40. For some of
these patients, the standard treatment of hysterectomy is unacceptable due to desires to
maintain fertility. Ideally, eligibility for nonoperative management should be limited to
patients without myometrial invasion. Pelvic MRI may be useful to better assess for
myometrial involvement. In patients who are offered nonsurgical treatment, progestational
therapy, delivered orally or intrauterinely, has been successful in reversing malignant changes
in up to 76% of cases. Increasingly, there has been a consideration for progestin-based
intrauterine devices, although the data are limited. In a 2012 systematic review of the
literature, 74% of atypical endometrial hyperplasia and 72% of grade 1 EC patients achieved
a pathologic complete response (CR) for 6 months or longer with oral progestins. The range
of CRs was 50% to 95% for atypical endometrial hyperplasia and 50% to 100% for grade 1
cancer. The mean time required to achieve the CR was 9 months. Of the 22 patients reported
with grade 1 cancer treated with progesterone-releasing intrauterine device, 68% achieved a
CR. Because response may be temporary or incomplete, periodic sampling of the
endometrium is advised.

Surgical Recommendations
The contemporary management of EC continues to evolve, and the indications for lymph
node dissection remain controversial. For most patients, however, comprehensive staging
most accurately assigns stage and associated prognosis. Staging also allows for a more
tailored approach to the use of adjuvant therapies. Patients who a priori are deemed not to be
candidates for staging should be considered for vaginal or laparoscopic-assisted vaginal
hysterectomies. Laparoscopic techniques have been shown to result in comparable surgery to
open procedures. For patients with resectable intraperitoneal disease, cytoreductive surgery
may improve outcomes.

Nodal Dissection
The value of surgical staging is a source of controversy and has been the subject of increased
scrutiny and debate over the last decade. Proponents of routine surgical staging suggest that
the ability to identify otherwise unrecognized disease spread to the nodes changes the
postoperative therapies that are given and is the most accurate way to assess risk. Most
controversial is the assertion that surgical staging has a therapeutic benefit independent of the
node status (positive or negative for metastatic disease). Fundamentally, surgeons must
determine for themselves whether or not surgical staging has sufficient value to offer it to all
patients or only to those selected based on risk factors identified preoperatively and
intraoperatively. The principal risks attributable to nodal dissections include increased
operative time, potential for blood loss associated with vascular injury, genitofemoral nerve
injury with resulting numbness and paresthesias over medial thighs, lymphocyst formation,
and lymphedema. In general, the risks associated with nodal dissections are low and
acceptable. The principal advantage of comprehensive staging is that the physician and
patient are provided with the greatest amount of information. In the contemporary
management of EC, this information results in less use of radiation and substitution of
vaginal cuff brachytherapy for pelvic radiation.
The importance, extent, and technique of nodal dissection are hotly debated. Questions
relate to which patients should be offered and could benefit from surgical staging (all, some,
or none) and what is the optimal surgical procedure to be performed (biopsy of
enlarged/visible nodes, full lymphadenectomy, or sentinel lymph node biopsy). Controversy
also exists between those surgeons who perform only pelvic dissections and those who
advocate pelvic and paraaortic nodal dissection.

Arguments against Routine Nodal Dissection

Most patients with EC will present with low-risk features. In the entire GOG 33 study
population of 621 patients, 75% had grade 1 to 2 tumors, and 59% had inner one-third or less
myometrial invasion. Only 9% of patients had positive lymph nodes. The Post Operative
Radiation Therapy in Endometrial Cancer (PORTEC) trial evaluated patients with stage IC,
grade 1; stages IB and IC, grade 2; or stage IB, grade 3 who underwent hysterectomy without
lymph node dissection and compared observation to postoperative pelvic radiation. This
patient population managed without nodal dissection and had favorable outcomes with or
without radiation therapy (5-year survival rates of 85% observation, 81% with pelvic
radiation).
Two randomized trials comparing hysterectomy with or without lymphadenectomy have
been reported. A Study in the Treatment of Endometrial Cancer (ASTEC) randomized
patients with EC treated with hysterectomy to pelvic lymphadenectomy or not. Following
surgery, patients with stage I and IIA diseases were then randomized again to observation or
pelvic radiation therapy if they had grade 3, serous, or clear cell histology; more than 50%
myometrial invasion; or endocervical glandular invasion (stage IIA). Treatment centers were
also permitted to use vaginal cuff brachytherapy regardless of pelvic radiation assignment.
The results show no evidence of benefit in terms of overall or recurrence-free survival for
pelvic lymphadenectomy in women with early EC.
A similar study was performed by Italian investigators. In this trial, 514 patients were
assigned to hysterectomy with or without pelvic lymphadenectomy (LND). Patients were
required to have myometrial invasion, and patients with grade 1 tumors and less than 50%
invasion were excluded. In the no-LND group, 22% of patients had nodal dissections due to
clinical suspicion with 14% of these cases, or 3% of the entire no-LND arm, having node-
positive disease. In the LND group, the median number of nodes removed was 26. Paraaortic
dissection could be performed at the surgeon’s discretion and was done in 26% of cases. In
the LND group, 13% were found to have positive nodes. Postoperative therapy was not
protocol prescribed, but the use of radiation therapy was more common in the no-LND group
(25% vs. 17%). The 5-year disease-free survival (DFS) was 81% in both groups, and 5-year
survival was 90% in the no-LND group versus 86% in the LND group (hazard ratio [HR] 1.2,
p = 0.5). The authors concluded that pelvic lymphadenectomy could not be recommended as
a routine procedure for therapeutic purposes.

Arguments for Selective Nodal Dissection

Increasingly, some form of nodal assessment has been integrated into the upfront
management of EC, and nodal assessment has been incorporated into the staging of EC since
1988. Surgical staging is the most accurate way to determine the extent of disease spread.
Palpation of lymph nodes is not sufficiently accurate.
Based on pathologic information available at the time of surgery, the risk for nodal
metastasis may be estimated. Physicians who selectively perform nodal dissections
frequently do so based on the presence of uterine risk factors, which suggest the potential for
nodal disease. In the surgical–pathologic study GOG 33, pelvic and paraaortic nodal diseases
were more frequent with increasing grade (% pelvic nodal metastases: 3% grade 1, 9% grade
2, 18% grade 3), depth of invasion (1% endometrium only, 5% inner 1/3, 6% middle 1/3,
25% outer 1/3 myometrial invasion), and LVSI (27% with LVSI, 7% without LVSI). Pelvic
and paraaortic nodal metastases were also more common with cervical involvement, when
peritoneal cytology was positive, and when extranodal (adnexal, intraperitoneal sites) disease
was found.
In 2000, the Mayo group described a model that could classify a group with a low risk of
nodal disease spread and high DFS based on frozen section evaluation of the uterus. Mariani
et al. determined that patients with grade 1 or 2 histology, myometrial invasion less than
50%, and tumor size less than 2 cm were at a low risk for lymph node involvement. In this
large series of 381 patients with grade 1 or 2 endometrioid EC and less than 50% myometrial
invasion, no patients with tumor size less than 2 cm had lymph node involvement. Of the
patients with tumors greater than 2 cm, 8 of 107 (7%) had lymph node involvement. Overall,
grade 1 and 2 tumors had 4% (5/126) and 7% (4/61) lymph node involvement, respectively.
Given these findings, the authors recommended consideration of lymph node sparing
surgeries in patients with grade 1 or 2 tumors of endometrioid histology, tumor size less than
2 cm, and myometrial invasion less than 50%. These findings have further been validated in
subsequent retrospective studies.

Arguments for Routine Nodal Dissection

Many gynecologic oncologists have moved toward performing uniform comprehensive
surgical staging for nearly all patients with EC. The rationale for uniform staging includes the
lack of a patient population for whom nodal disease is so low that nodes should be omitted,
the inaccuracy of preoperative or intraoperative assessments predicting the risk for nodal
disease, the potential for therapeutic benefit in node-positive and node-negative patients, and
the lack of significant morbidity associated with the procedure. Postoperative adjuvant
decisions are best made with the most complete information. If nodal assessment is the
predominant factor by which to categorize patients into risk groups, routine nodal dissection
is the best method by which to determine which few patients will require adjuvant therapy.

Alternatives to Lymphadenectomy
Given the debate as to the value of lymphadenectomy, alternative strategies have been
evaluated. The concept of sentinel LN suggests that regional nodal spread first moves to a
“sentinel” node for which markers (dye, lymphoscintigram, gamma counter) make apparent.
This concept has been accepted into practice for breast cancer and melanoma. By selectively
resecting the sentinel LN, the most “at-risk” node is evaluated only, thus reducing morbidity,
length of surgery, and blood loss. Investigators at Memorial Sloan Kettering have performed
a series of sentinel node mapping surgeries on 266 patients, followed by lymphadenectomy.
Using a cervical injection technique, they reported sentinel detection was possible in 84% of
cases, 12% had positive nodal disease, and metastatic cells were three times more likely in
sentinel nodes than in nonsentinel nodes. In a meta-analysis of 26 series on sentinel LN
dissection, Kang estimated that the detection rate for sentinel LN was 78% and the sensitivity
was 93%. In a disease where baseline rates of nodal involvement are 10%, this translates to
approximately 1% false-negative rate.

Minimally Invasive Surgery for EC

Minimally invasive management of EC has increasingly been integrated into standard
practice. Laparoscopic techniques are utilized in the initial treatment of EC (laparoscopic-
assisted vaginal hysterectomy, total laparoscopic hysterectomy), to stage patients with
laparoscopic pelvic and paraaortic nodal dissection, and to restage patients following
incomplete surgical staging.
The largest and most comprehensive data set to date comes from the large prospective
randomized trial conducted by the GOG (LAP2 trial). The study was designed to compare
laparoscopic hysterectomy with comprehensive surgical staging to the traditional laparotomy
technique (using a 2:1 randomization favoring the laparoscopic arm) to determine the
complete staging rates, safety, short-term surgical outcomes, and long-term cancer recurrence
and survival. The study enrolled 920 patients to the open arm and 1,696 to laparoscopy. The
rate of conversion from laparoscopy to open procedure was 26% and was most frequently
related to poor visibility (15%), extrauterine cancer spread (4%), and bleeding (3%). The
conversion rate increased with an increasing patient obesity. Median number of removed
nodes was similar between each technique, as were the frequencies of patients found to have
positive lymph nodes. Complication rates (combined rates of vascular, urinary, bowel, nerve,
or other complications) for those who had an open procedure were 7.6%, compared to 9.5%
of patients randomized to laparoscopy. Of the 1,242 patients randomized to laparoscopy who
had the procedure successfully completed laparoscopically, the complication rates were
4.9%. Comparing patients who underwent open surgery versus successful completion of
laparoscopy, operative time was longer (median, 70 minutes), but hospital time was shorter
(2 vs. 4 days) with laparoscopy. Postoperative arrhythmia, pneumonia, ileus, antibiotic use,
and any complication greater than grade 2 were lower in the laparoscopic group. The authors
concluded that laparoscopic surgical staging is an acceptable and possibly a better option,
particularly when the surgery can be successfully completed laparoscopically. In a
subsequent evaluation of recurrence and survival data from the GOG LAP2 trial published in
2012, 3-year recurrence rates were 11.4% with laparoscopy versus 10.2% with open surgery,
and 5-year survival was 90% in each arm.
Laparoscopic surgery has demonstrated an important role in the management of EC. The
demonstration of comparable surgical endpoints (similar numbers of nodes removed, similar
frequency of positive nodes) along with shortened hospital stay and quicker recovery
compared to open procedures suggests that appropriate patients should be counseled
regarding this option.
Robotic surgery may represent the next step forward in minimally invasive surgery. Since
FDA approval for hysterectomy and myomectomy procedures in 2005, there has been an
increasing utilization of robotic surgery within gynecologic oncology practice. A number of
retrospective series have described robotic experience or compared outcomes to laparoscopy
and/or open procedures. Proposed robotic surgery advantages include improved visualization
with 3D optics, “wristlike” motion of instruments that allow for greater dexterity, reduction
in tremor, an easier learning curve for adoption compared to straight-stick laparoscopy, and
more comfortable ergonomics. Published data suggest comparable outcomes with respect to
blood loss, nodal counts, and operative time compared to laparoscopy, with several series
suggesting lower postoperative complications compared to open surgery. Robotic surgery
may offer unique opportunities for obese patients.

Surgical Management of Intraperitoneal Disease

In patients with distant metastasis, there may be limited role for surgery such as to provide
control of vaginal bleeding. The value of extensive cytoreductive surgery in EC has not been
well studied. Several retrospective reports suggest that survival correlates with volume of
residual disease. Shih et al. reported on 58 patients with stage IV endometrioid disease, of
whom 9 had no gross residual, 11 had less than 1 cm residual, and 32 had residual greater
than 1 cm. The median survival for the entire population was 19 months; however, median
survival was 42 months for patients with no gross residual disease. In a multivariate analysis
of these data, residual disease and use of adjuvant chemotherapy were independently
associated with survival. In patients with serous histology, similar improvements were seen
with optimal debulking of intraperitoneal disease.

Role of Adjuvant Therapy

Key Points
 Women with a very low risk of EC do not require any postoperative treatment. In
these patients, the risks of therapy outweigh the minimal benefits associated with
treatment.
Adjuvant radiation for early-stage disease can reduce local recurrence with no
appreciable effect on OS.
Intravaginal radiation therapy is probably sufficient for comprehensively staged
patients with early-stage disease.
Chemotherapy is preferable to whole abdominal radiation in advanced-stage
disease.
Combination therapy is currently being studied in advanced-stage disease.

A postoperative treatment plan should take into account the prognostic factors determined by
the surgical–pathologic staging. Patients can be classified into three categories: those who
show a high rate of cure without postoperative therapy, those with a low rate of cure without
postoperative therapy, and those who demonstrate a reduced rate of surgical cure and may
benefit from additional therapy. The postoperative treatment plan should also consider the
available postoperative treatment methods and their morbidities. Chemotherapy as adjuvant
treatment for patients with stage III and IV endometrial carcinomas is recently supported by
data from GOG 122 and is discussed separately. Adjuvant radiation therapy is continually
evolving, and currently, intravaginal brachytherapy and external beam whole-pelvic therapy
with or without an extended field are commonly employed.

Adjuvant Radiation Therapy

Radiation therapy plays a significant role in the management of EC. It is often used as an
adjuvant treatment after surgery or as definitive treatment for patients who are medically
inoperable or with local recurrence. In the past, most patients were treated with preoperative
intracavitary brachytherapy with or without external beam radiotherapy followed by
hysterectomy. This approach is not without merit, especially in patients with gross cervical
involvement. However, most patients nowadays undergo surgery first; then, depending on the
prognostic features obtained from the pathology review, the need for radiotherapy is
determined.
It should be noted that patients with very low risk disease (grade 1 or 2, disease limited to
the endometrium, without high-risk histology) should not receive adjuvant radiation therapy.
A 2012 Cochrane meta-analysis showed that adjuvant pelvic radiation therapy in these
patients resulted in a 2.5-fold higher risk of death compared to observation alone (relative
risk 2.64, 95% CI: 1.05 to 6.66). Although brachytherapy may be a more reasonable
approach to adjuvant treatment, it is also associated with side effects, including genitourinary
symptoms (e.g., vaginal dryness, incontinence) that raise significant doubts about the risk-
benefit relationship.

Early-Stage Disease
Most of the data on adjuvant radiation in EC pertain to patients with early-stage (I and II)
disease. The role of radiation in this group of patients, however, has been undergoing
significant scrutiny in the last 10 years. The questions to be resolved are elucidating the
benefits of radiation, clarifying which patients will be best served by this additional therapy,
and determining the most appropriate radiation strategy.
Two prospective randomized trials compared surgery alone to surgery and postoperative
external beam radiation. The first trial was conducted by the GOG (GOG 99). In this trial,
390 patients with stage IB and IIB ECs who underwent a total abdominal hysterectomy and
BSO and pelvic/paraaortic lymph nodes sampling were randomized to observation (n = 202)
or postoperative pelvic radiation (n = 190). With a median follow-up of 69 months, the 4-
year survival rate was 92% in the irradiation arm, compared with 86% in the observation arm
(p = 0.6). The 2-year estimated progression-free survival (PFS) rate was 97% versus 88% in
favor of the irradiation arm (p = 0.007), with the greatest decrease seen in vaginal/pelvic
recurrences. The second trial was the PORTEC study, in which 714 patients with stage IB
grades 2 and 3 and stage IC grades 1 and 2 were randomized after total abdominal
hysterectomy and BSO and no lymph node sampling to observation (n = 360) or pelvic
radiation (n = 354). With a median follow-up of 52 months, the 5-year vaginal/pelvic
recurrence rate was 4% in the radiation arm compared to 14% in the observation arm (p <
0.001). The corresponding 5-year survival rates were 81% and 85%, respectively (p = 0.37).
Despite the fact that adjuvant radiation significantly improved locoregional control, most
of the debate focuses on the lack of improvement in OS. In addition, many of the patients
who develop local recurrence after surgery alone may be salvaged with subsequent radiation.
Even in patients who ultimately die from EC, the most common cause is distant rather than
local relapse.
An update with a median follow-up of 13.3 years has been published recently. The
actuarial 15-year locoregional recurrence was statistically different at 6% versus 15% for
those with adjuvant irradiation compared to observation with no statistical difference in OS
or failure-free survival, distant metastases, or secondary cancers. Most recurrences in the
observation arm were vaginal (11% of the 15%).
In a follow-up study including 427 patients with higher-risk disease (age >60 years plus
grades 1 to 2 and outer 50% invasion, or grade 3 with inner 50% invasion, or stage IIA [1988
FIGO] disease), the PORTEC 2 study compared pelvic radiation therapy to vaginal
brachytherapy. None of the patients underwent nodal assessment, and 5-year PFS (78% to
83%) and survival (80% to 85%) suggested that in this population, vaginal brachytherapy
was equivalent to pelvic radiation.

Type of Radiation
There are two types of radiation (intravaginal brachytherapy and external beam radiation)
that could be used either alone or in combination for early-stage EC.

INTRAVAGINAL BRACHYTHERAPY ALONE OR COMBINED WITH PELVIC RADIATION

In a historically important trial, Aalders et al. reported on 540 patients with stage IB-IC EC
who underwent TAH/BSO without LN sampling and postoperative intravaginal
brachytherapy to 60 Gy. The patients were then randomized to observation or to
supplemental pelvic radiation to 40 Gy. A significant reduction in local recurrence rates has
been seen with the addition of pelvic radiation to intravaginal brachytherapy (1.9% vs. 6.9%,
p < 0.01). With regard to OS, there was no significant difference between the two treatments,
but in the subset of patients with grade 3 disease and deep myometrial penetration, there was
a survival advantage (cause-specific survival) of 18% versus 7% in favor of the pelvic
radiation arm.

I
With the increase in surgical lymph node staging, the use of postoperative intravaginal
brachytherapy alone regained its appeal. The rationale was that full surgical lymph node
staging could potentially eliminate the need for pelvic radiation, while vaginal brachytherapy
could still address the risk of vaginal cuff recurrence. Several reports in the past 5 years
showed a very low rate of recurrence either in the vagina or in the pelvis with such an
approach.
From the above discussion, it is clear that the options available for patients with early-
stage endometrioid EC are numerous. Perhaps, it is better to consider different options based
on the following factors: stage and grade, whether surgical lymph nodes staging was done,
and the risk of nodal versus vaginal recurrence. The therapeutic ratio of adjuvant external
beam radiation is very likely to benefit from the advances in intensity-modulated radiation
therapy by providing the most conformal dose distribution to the tumor volume while sparing
the surrounding normal structures.

Advanced-Stage Disease
For patients with more advanced disease (stage III and cytoreduced stage IVA disease), the
standard of care has evolved from radiation therapy to the increased use of platinum-based
chemotherapy. However, in light of the benefits of local control with radiation therapy,
combined modality is often administered.

Chemotherapy
The data to support chemotherapy initially come from the GOG 122 trial, which included
396 patients with stage III and optimally debulked stage IV disease who were randomly
assigned to treatment with whole-abdomen radiation (n = 202) or to doxorubicin–cisplatin
(AP) chemotherapy (n = 194). With a median follow-up of 74 months, there was significant
improvement in both PFS (50% vs. 38%; p = 0.007) as well as OS (55% vs. 42%; p = 0.004),
respectively, in favor of chemotherapy.
However, a separate study showed that radiation therapy was at least equivalent to
chemotherapy. In this study, which included stage I patients, patients were randomly assigned
to radiation therapy or doxorubicin– cisplatin–cyclophosphamide (TAP). With a median
follow-up of 95.5 months, the 5-year DFS was 63% in both arms (p = 0.44), and the 5-year
OS rate was 69% in the radiation arm compared to 66% in the chemotherapy arm (p = 0.77).
As the follow-up study to GOG 122, GOG 184 evaluated the combination of irradiation
and chemotherapy in 552 women with stage III and IV diseases. Of note, after 66 patients
were enrolled, those with upper abdominal disease were excluded from the study. Treatment
consisted of tumor volume-directed irradiation (51% received 5,040 cGy pelvis irradiation
alone, and 49% received 4,320 to 4,350 cGy of extended field for positive paraaortic disease
or undissected paraaortics) followed by randomly assigned treatment with AP or TAP. TAP
did not improve the risk of recurrence compared to AP, nor did it improve the recurrence-free
survival, and it was associated with a worse toxicity profile.
On the basis of these data, AP was the preferred adjuvant chemotherapy regimen.
However, on the basis of GOG 209, carboplatin and paclitaxel are now the more routinely
administered regimen. In this trial, almost 1,300 women with recurrent or advanced EC
(including stage III disease) were randomly assigned to TAP or carboplatin plus paclitaxel.
As presented at the 2012 Society of Gynecologic Oncologists Annual Meeting, women who
were treated with carboplatin and paclitaxel had a similar overall response rate to those
treated with TAP (51% in both arms). In addition, survival results were no different (PFS, 13
months in each arm; OS 37 vs. 40 months, respectively). However, carboplatin and paclitaxel
were significantly more tolerable.

Special Situations
Serous and Clear Cell Histologies
Serous cancer and, to a lesser extent, clear cell cancer tend to spread in a fashion similar to
ovarian cancer with a high propensity for upper abdominal relapse. Therefore, whole-
abdomen radiation and chemotherapy have both been studied in this group of patients.
Patients with early-stage disease who are surgically staged can be treated with intravaginal
radiation given with carboplatin/paclitaxel chemotherapy, while those with advanced stage
are given tumor-directed radiation and/or chemotherapy.

Definitive Radiation for Inoperable Disease

Patients with medically inoperable stage I to II uterine cancers are usually treated in a fashion
similar to those with cervical cancer by using intracavitary applicators with or without pelvic
radiation. For patients with clinical stage I grade 1 or 2 and no evidence of myometrial
invasion or lymph node metastasis on MRI, intracavitary brachytherapy alone is sufficient.
More recently, high-dose-rate brachytherapy is also being employed.

Surveillance
Key Points
Routine physical examination in combination with prompt reporting of symptoms
is probably the best method for detecting recurrent disease.

The frequency and extent of follow-up visits and surveillance tests for patients with a history
of gynecologic cancer have traditionally been based on arbitrary guidelines that have been
established and perpetuated at various institutions throughout the United States. Since the
majority of patients with EC will do well, and there is no clear evidence that early detection
of disease recurrence will improve outcome, it has become necessary to reevaluate the
practice of routine intensive surveillance in women with a history of EC.
Physicians should educate patients regarding the signs and symptoms of recurrent disease
and act promptly to evaluate symptomatic patients with diagnostic tests targeted toward the
symptoms. Obtaining Pap smears routinely at each follow-up visit does not appear to be
beneficial. Elevated levels of the tumor-associated antigen CA-125 have been documented in
patients with advanced/recurrent EC; however, the value of surveillance CA-125 levels is
limited and best reserved for patients with an elevated value at initial diagnosis. Based on the
knowledge that the majority of recurrences occur within the first 3 years after surgery, it is
recommended that patients undergo semiannual pelvic examinations for 3 years and then
annually thereafter. There is no evidence in the literature that routine chest x-rays improve
survival and Pap smears do not improve the outcome of patients with isolated vaginal
recurrences.

Complications of Radiation
Pelvic Radiation
In the PORTEC randomized trial, the overall (grades 1 to 4) rate of late complications was
26% in the RT group compared to 4% in the observation group (p < 0.0001). Most of the late
complications in the RT group, however, were grades 1 and 2 (22%), and only 3% were
grades 3 and 4. It is also important to note that many patients in this trial were treated with
AP/PA fields where the overall rate of complications was 30% compared to 21% for those
treated with the four-field box technique (p = 0.06).

Intravaginal Brachytherapy
The main advantage of intravaginal brachytherapy is its ability to deliver a relatively high
dose of radiation to the vagina while limiting the dose to the surrounding normal structures
such as bowels and bladder. This advantage is manifested with the low rate of severe late
toxicity seen with this treatment technique ranging from 0% to 1%. But such a low rate of
severe complications cannot be taken for granted because special attention needs to be paid
to the depth of prescription, dose per fraction, the length of vagina treated, and the diameter
of the cylinder used.

Treatment of Recurrent Disease

Key Points
Radiation therapy is useful for local recurrences in patients who have not been
irradiated previously.
Surgery is an excellent option for isolated disease that can be completely resected.
Hormonal therapy is often active in patients with well-differentiated tumors.
Multiagent chemotherapy is more active than single agents, and the optimal
combination is under active investigation.

Patients with recurrent EC must be fully evaluated for sites of recurrent disease. Depending
on the site of the recurrence and prior therapy, patients may be treated for palliation or for
cure. Treatment may consist of irradiation, surgery, endocrine therapy, or cytotoxic
chemotherapy. These agents may be used singly or in combination. It is uncommon for
patients with recurrent disease to be cured unless the recurrence is only in the vaginal cuff or
central pelvis.
For women with an isolated vaginal recurrence who have not received prior radiotherapy,
salvage radiotherapy is an excellent choice for treatment. As demonstrated in PORTEC 1,
87% of women with an isolated recurrence treated by radiotherapy had a CR. Vaginal
recurrences within a previously irradiated field carry a worse prognosis. In PORTEC 1, the 3-
year OS rate in this patient population was 43%, much lower than the 65% reported for
radiotherapy-naive patient with isolated vaginal recurrences. Despite the lower rate of
response to radiotherapy and higher risk of side effects, this option should not be completely
excluded from the list of treatment options but likely needs to be administered at a
specialized center capable of tailoring the approach to minimize toxicity to normal,
surrounding tissues.

Systemic Therapies
Endocrine Therapy
Hormonal agents have been found to be valuable, particularly in the patient with recurrent
disease, and reviews of their use have been extensively published. Response rates to a variety
of endocrine agents including progestins, antiestrogens, and aromatase inhibitors are
presented in Table 8.6. The overall response to progestins is approximately 25%. A higher
dose of progestin does not appear to increase the response rate. Tamoxifen has been
investigated in patients with recurrent disease in several studies. Results have varied, but in
general, response rates have been modest in untreated patients. The possibility of alternating
tamoxifen with megestrol acetate in order to exploit the recruitment of progesterone receptors
by tamoxifen has also been tested with some success by the GOG.

TABLE 8.6 Response to Endocrine Therapy

NA, not available; SERM, selective estrogen receptor modulator.

Adjuvant and Advanced Disease

Chemotherapy for adjuvant and advanced disease has been evaluated in multiple clinical
trials. Trials have compared chemotherapy to radiation as well as to other therapeutic
regimens. Discussed earlier, GOG 122, which was one of the first studies to compare RT to
chemotherapy, demonstrated improved PFS and OS in patients treated with chemotherapy for
their advanced-stage EC. GOG 258, a randomized phase III trial of cisplatin and volume-
directed radiation followed by carboplatin/paclitaxel versus chemotherapy alone for
optimally debulked advanced EC was recently completed. This study found no differences in
recurrence-free survival reported, but significantly more vaginal and pelvic or paraaortic
recurrences were reported in the chemotherapy group. There were more distant recurrences in
the combined chemoradiotherapy group.

Cytotoxic Chemotherapy
Both single-agent and combination regimens are capable of inducing objective responses, yet
the median time to treatment failure is on average 3 to 6 months, and the OS of patients with
metastatic EC is generally less than 12 months. The role of chemotherapy in the recurrent
disease setting remains palliative, and minimizing side effects is of equal importance when
selecting a regimen.
Metastatic/Recurrent Disease
A wide variety of single agents have been tested. Despite the number of drugs evaluated, the
most commonly used single agents today based on response rates of at least 20% include
cisplatin, carboplatin, doxorubicin, epirubicin, ifosfamide, docetaxel, paclitaxel, and
topotecan. Frequent variability in response rate has been noted for the same agent and is
probably related to several factors, including prior treatment, performance status, extent of
disease, histologic subtype, and the response criteria used for evaluation. No current data
suggest that dose–response relationships exist for single-agent therapy and doses and
schedules are generally adjusted to minimize toxicity for an individual patient (Table 8.7).

TABLE 8.7 Single-Agent Trials

95% CI, the 95% confidence interval for complete and partial response; CR, complete response; NS, not stated; Nr, not
reported; PR, partial response.

Combination Therapy
The results of treatment with combination regimens are presented in Table 8.8. The results of
GOG 107 comparing doxorubicin (60 mg/m2 every 3 weeks) with the same doxorubicin dose
and cisplatin (50 mg/m2 every 3 weeks) in 223 patients with advanced or recurrent EC have
shown a significantly higher response rate for the combination (42% vs. 25%, p = 0.004) but
a PFS and OS of 5.7 versus 3.8 months and 9.2 versus 9.0 months, respectively. This study
confirms a higher response rate with combination therapy, but the difference in PFS is
modest and likely not clinically meaningful; the OS is identical in the two groups.

TABLE 8.8 Randomized Trials of Combination Chemotherapya

aAll trials were conducted in chemotherapy-naive patients, and each regimen is given on a q3 wk schedule.
CYS, cyclophosphamide; DOX, doxorubicin; CIS, cisplatin; PAC, paclitaxel, CR, complete response; PR, partial response.

The GOG conducted a randomized trial (GOG 163) for patients with primary stage III and IV
or recurrent EC with measurable disease comparing doxorubicin and cisplatin to doxorubicin
with 24-hour paclitaxel and granulocyte colony–stimulating factor (G-CSF). There were no
significant differences in response rate (40% vs. 43%), PFS (median, 7.2 vs. 6.0 months), or
OS (median, 12.6 vs. 13.6 months) for arms 1 and 2, respectively. The disadvantage of GOG
163 was the lack of platinum in the taxane-containing arm, however. The addition of a taxane
was subsequently studied in GOG 177 evaluating doxorubicin (60 or 45 mg/m2 in patients
with prior radiotherapy) with cisplatin (50 mg/m2) as the standard arm versus paclitaxel (160
mg/m2) with doxorubicin (45 mg/m2) and cisplatin (50 mg/m2) (TAP regimen) and G-CSF as
the investigational regimen. Overall, TAP chemotherapy increased 12-month survival to 59%
compared to 50% with doxorubicin and cisplatin with a HR of 0.75 (0.56 to 0.998). Although
the TAP regimen produced an improvement in response rate and PFS, survival was
minimally increased, and it is associated with greater toxicity.
GOG 209, a randomized trial comparing TAP with carboplatin and paclitaxel (TC)
revealed that the doublet regimen was not inferior to TAP in terms of PFS (median PFS of
TAP vs. TP: 13.5m vs. 13.3m; HR 1.03) and OS (40.3m vs. 35.5m; HR 1.05). The toxicity
profile of TC was favorable.
Based on GOG 209, carboplatin and paclitaxel are now the more routinely administered
regimen.

Serous and Clear Cell Histologies—Chemotherapy

Serous cancer and to a lesser extent clear cell cancer tend to spread in a fashion similar to
ovarian cancer, with a high propensity for upper abdominal relapse. With whole-abdomen
radiotherapy, the rate of relapse is still substantial, indicating the need for effective systemic
therapy. Based on the response rates of paclitaxel and carboplatin in other tumors of serous
histology, trials investigating paclitaxel and carboplatin in uterine serous carcinomas have
reported response rates of 60% to 70%. Recognizing the limits of retrospective studies, data
support the potential benefit of a regimen of platinum-based chemotherapy with cuff
irradiation in patients with uterine serous carcinomas. Randomized prospective data are
needed to accurately define the best approach in these patients.

Targeted Therapy
Historically, ECs have been classified into two types: type I and type II; however, The
Cancer Genome Atlas has noted that reclassification by molecular grouping may be more
appropriate. The four molecular groups are (i) POLE (ultramutated), (ii) microsatellite
unstable tumors, (iii) copy number high tumors with TP53 mutations, and (iv) copy number
low tumors. Biologic agents targeting molecular components are currently under
development, and focus has centered on histologic subtype and/or biomarker-driven patient
stratification.
The PI3K/AKT/PTEN pathway is the most commonly altered pathway in type I EC, and
inhibitors for this pathway have been investigated. Temsirolimus, ridaforolimus, and
everolimus have all shown activity both as single agents and as combination therapy.
MSI is found in 20% to 45% of type I tumors and is caused by inactivation of DNA
repair genes such as MLH1, MSH2, MSH6, and PMS2. Defects in MMR systems may alter
response to chemotherapy and radiation. These tumors are responsive to immunotherapy,
which is now FDA-approved for this indication.
Mutations of p53 appears to be an early event in the development of serous carcinoma
but are not often found in type I ECs. Lundgren et al. studied p53 in relation to
clinicopathologic variables in 376 consecutive patients with all stages of EC and found that
p53 overexpression was a strong significant factor with regard to relapse-free survival in
univariate analysis, but it failed to retain its significance in a multivariate analysis.
HER-2/neu is frequently overexpressed or amplified in 10% to 30% of type I and 40% to
80% of type II ECs and has been associated with advanced stage, decreased differentiation,
aggressive histology, and deep myometrial invasion. In a recent phase II study, the use of
trastuzumab combined with carboplatin/paclitaxel has been recently shown to increase PFS
in advanced and recurrent serous tumors.
Alterations in the RAS/RAF/MEK pathway have also been studied in ECs. The GOG has
explored the oral MEK inhibitor, selumetinib, in pretreated patients with EC and found
adequate RRs but frequent and severe side effects, which halted the trial.
Overexpression of VEGF has been associated with poor prognostic factors in EC. The
treatment of recurrent ECs with VEGF inhibitors has revealed mixed results. Bevacizumab
was investigated as treatment in patients with recurrent or persistent measurable EC after
receiving one or two prior lines of treatment. Of 52 evaluable patients, 13.5% had objective
response, while 40.4% had a progression-free interval of at least 6 months. However, in GOG
86P the addition of bevacizumab to carboplatin/paclitaxel offered no PFS benefit, but there
was noted to be an improvement in median OS in the bevacizumab/carboplatin/paclitaxel
arm when compared to historical controls. Tumors with CTNNB1 mutations appeared to have
the most favorable responses to bevacizumab.
Other treatments under investigation include tyrosine kinase receptor inhibitors,
metformin, and PARP inhibitors.

Immunotherapy in Management of Patients with

Uterine Cancer
Checkpoint inhibitors have demonstrated efficacy in treatment of several cancers. A phase II
trial of pembrolizumab was conducted in patients with MMR–deficient tumors. The authors
reported that MMR-deficient cancers had higher objective response rates and improved PFS.
Multiple studies have addressed the role of immunotherapy in EC and consistently show
favorable response in MSI tumors.

Future Directions
In 2001, the National Cancer Institute convened an expert panel to develop a national 5-year
plan for research priorities in gynecologic cancers. The resulting report, Priorities of the
Gynecologic Cancer Progress Review Group (PRG), specified that understanding tumor
biology was the central key toward controlling gynecologic cancers. Now, nearly a decade
later, some hope for a better understanding of EC at a genetic and molecular level is being
realized. The GOG 210 study, a prospective surgical–pathologic study that created an
annotated tissue repository from over 6,000 patients with more than 36,000 specimens,
serves as a resource for discovery and validation of predictive and prognostic biomarkers. In
addition, The Cancer Genome Atlas project has completed an analysis of more than 500 EC
cases (endometrioid and serous types). It is expected that the knowledge from these data sets
will drive clinical research and patient care for the next decade. Increasingly, we can expect
that therapies offered to our patients will be based on a more complete understanding of
pathways and that therapies may be matched to address specific genetic changes.

Summary
EC is the most common gynecologic malignancy, and an understanding of presentation,
surgical management, and treatment options is required for gynecologic oncologists. Surgical
therapy is the mainstay of EC, with lymphadenectomy and laparoscopy commonly
integrated. A thorough knowledge of the relationships between uterine factors and
extrauterine disease spread is essential. Surgical staging defines extent of disease and largely
defines risk of recurrence. Radiation is associated with better local control but with no
improvement in survival for patients with stage I and II ECs in randomized trials.
Chemotherapy is increasingly integrated into upfront management of advanced-stage EC and
may have a role in early-stage disease. Combination therapy with radiation and
chemotherapy is under evaluation. Targeted agents hold promise; however, a better
understanding of molecular and genetic changes is required to improve efficacy.

Suggested Readings
Alektiar KM, McKee A, Venkatraman E, et al. Intravaginal high-dose-rate brachytherapy for Stage IB (FIGO Grade 1, 2)
endometrial cancer. Int J Radiat Oncol Biol Phys. 2002;53:707–713.
ASTEC Study Group; Kitchener H, Swart AM, Qian Q, et al. Efficacy of systematic pelvic lymphadenectomy in
endometrial cancer (MRC ASTEC trial): A randomised study. Lancet. 2009;373(9658):125–136.
Connor JP, Andrews JI, Anderson B, et al. Computed tomography in endometrial cancer. Obstet Gynecol. 2000;95:692–696.
Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer: A Gynecologic
Oncology Group study. Cancer. 1987;60:2035.
Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients
with stage-1 endometrial carcinoma: Multicentre randomised trial. PORTEC Study Group. Post Operative Radiation
Therapy in Endometrial Carcinoma. Lancet. 2000;355:1404–1411.
Creutzberg CL, van Putten WL, Koper PC, et al.; PORTEC Study Group. Survival after relapse in patients with endometrial
cancer: Results from a randomized trial. Gynecol Oncol. 2003;89:201–209.
Dizon DS. Treatment options of advanced endometrial carcinoma. Gynecol Oncol. 2010;117: 373–381.
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. 1994;86:527.
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.
2004;22:2159–2166.
Horowitz NS, Peters WA III, Smith MR, et al. Postoperative high dose-rate intravaginal brachytherapy combined with
external beam irradiation for early-stage endometrial cancer: A long-term follow-up. Int J Radiat Oncol Biol Phys.
 1994;30:831–837.
Kadar N, Homesley H, Malfetano J. Positive peritoneal cytology is an adverse risk factor in endometrial carcinoma only if
there is other evidence of extrauterine disease. Gynecol Oncol. 1992;46:145–149.
Kang S, Yoo HJ, Hwang JH, et al. Sentinel lymph node biopsy in endometrial cancer: Meta-analysis of 26 studies. Gynecol
Oncol. 2011;123:522–527.
Kelly MG, O'Malley DM, Hui P, et al. Improved survival in surgical stage I patients with uterine papillary serous carcinoma
(UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol. 2005;98(3):353–359.
Khoury-Collado F, Murray MP, Hensley ML, et al. Sentinel lymph node mapping for endometrial cancer improves the
detection of metastatic disease to regional lymph nodes. Gynecol Oncol. 2011;122:251–254.
Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarcinoma in breast cancer patients: Findings from the National
Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994;86:527–537.
Kurman R, Kaminski P, Norris H. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in
170 patients. Cancer. 1985;56:403–411.
Latif NA, Haggerty A, Jean S, et al. Adjuvant therapy in early-stage endometrial cancer: A systematic review of the
evidence, guidelines, and clinical practice in the U.S. Oncologist. 2014;19(6):645–653.
Lu K, Dinh M, Kohlman W, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis
colorectal cancer syndrome. Obstet Gynecol. 2005;105: 569–574.
Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: A
paradigm shift in surgical staging. Gynecol Oncol. 2008; 109:11–28.
Norris HJ, Tavassoli FA, Kurman RJ. Endometrial hyperplasia and carcinoma, diagnostic consideration. Am J Surg Pathol.
1988;7:839.
Nout RA, Smit VT, 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.
2010;375:816–823.
Picchio M, Mangili G, Samanes Gajate AM, et al. High-grade endometrial cancer: Value of [(18)F]FDG PET/CT in
preoperative staging. Nucl Med Commun. 2010;31(6):506–512.
Rockall AG, Sohaib SA, Harisinghani MG, et al. Diagnostic performance of nanoparticle-enhanced magnetic resonance
imaging in the diagnosis of lymph node metastases in patients with endometrial and cervical cancer. J Clin Oncol.
2005;23:2813–2821.
Shih KK, Gardner G, Barakat R, et al. Surgical cytoreduction in stage IV endometrioid endometrial carcinoma. Gynecol
Oncol. 2011;122:608–611.
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. 1994;12:1408.
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. 2006;106:812–819.
Wheeler D, Bell K, Kurman R, et al. Minimal uterine serous carcinoma: Diagnostic and clinicopathologic correlation. Am J
Surg Pathol. 2000;24:797–806.
Zaino RJ, Kurman RJ, Diana KL, et al. Pathologic models to predict outcome for women with endometrial adenocarcinoma.
Cancer. 1996;77:1115–1121.
 9 The Corpus: Mesenchymal Tumors

Mesenchymal tumors are rare malignancies that account for approximately 7% to 8% of all
uterine cancers. Unlike most endometrial adenocarcinomas, uterine sarcomas are generally
aggressive, and overall mortality rates approached 90% in early reports. Though current
literature suggests that uterine carcinosarcoma is better classified as an epithelial metaplastic
carcinoma of the uterus rather than a sarcoma, uterine carcinosarcoma will be described in
this chapter for historical reasons.
The World Health Organization classification of mesenchymal uterine corpus tumors is
summarized in Table 9.1. Uterine sarcomas are a heterogeneous group with regard to clinical
presentation, response to therapy, and outcomes.

TABLE 9.1 WHO Classification of Mesenchymal Tumors of the Uterine

Corpus
Source: From WHO classification of tumours of the uterine corpus. In: Kurman RJ, Carcangiu ML, Herrington CS, et al.,
eds. WHO Classification of Tumours of Female Reproductive Organs, 4th ed. Lyons, France: IARC Press; 2014:122, with
permission.

Epidemiology and Risk Factors

Key Points
Leiomyosarcomas are the most common uterine mesenchymal tumor when
excluding carcinosarcomas.
Uterine sarcomas are more common in African American women.
 Prior radiotherapy is a risk factor for carcinosarcoma and undifferentiated
sarcoma.

The most common uterine sarcomas are carcinosarcomas and leiomyosarcomas. When
carcinosarcomas are excluded, leiomyosarcomas represent more than two-thirds of uterine
mesenchymal tumors (Fig. 9.1). Endometrial stromal sarcomas (ESS) account for 25% of
true uterine sarcomas and are currently divided into low grade, high grade, and
undifferentiated sarcomas. Patients with carcinosarcomas and adenosarcomas tend to be older
at the time of diagnosis compared to those with leiomyosarcomas and ESS.

FIGURE 9.1 Histologic distribution of uterine sarcomas in series with at least

100 cases including carcinosarcomas (A) and excluding carcinosarcomas (B).
ESS, endometrial stromal sarcoma; CS, carcinosarcoma; LMS, leiomyosarcoma.

Women with carcinosarcomas are more likely to be of African American descent than those
with endometrial adenocarcinomas. The age-adjusted incidence of uterine sarcomas in
African American women is approximately twice that of Caucasian women.
Carcinosarcomas and leiomyosarcomas constitute about 4% and 1.5% of all uterine
malignancies, respectively. The risk profile of carcinosarcomas closely parallels that of
endometrial adenocarcinomas with regard to obesity, diabetes, anovulation, and low parity,
providing additional support that they be regarded as “metaplastic” endometrial carcinomas
instead of true sarcomas.
Possible risk factors for uterine sarcoma are prior radiation exposure, hormone exposure,
tamoxifen use, and hereditary predisposition. Prior exposure to pelvic radiotherapy is thought
to increase the risk of developing subsequent carcinosarcoma and undifferentiated sarcoma.
Carcinosarcomas in previously irradiated patients also tend to present in advanced stage,
perhaps because radiotherapy is often associated with cervical stenosis and, thus, no telltale
uterine bleeding. The association with hormone exposure is strongest for leiomyosarcoma.
The risk of uterine cancer is increased with tamoxifen use and modified by duration of use. A
significant association was seen with more than 4 years of tamoxifen use (OR, 6.6; 95%
confidence interval [CI], 2.0 to 21.1), whereas use of tamoxifen for 2 years or less was not
associated with an increased risk (OR, 2.1; 95% CI, 0.4 to 11.6). There may be a small risk of
uterine sarcomas associated with hereditary nonpolyposis colorectal cancer and hereditary
retinoblastoma.

Clinical Presentation
Vaginal bleeding is the most common presenting symptom in women with uterine sarcomas
in general and is nearly universal in those with carcinosarcomas. Vaginal bleeding occurs in
as few as 50% of women with leiomyosarcomas, however. A typical presentation of
carcinosarcoma is vaginal bleeding associated with a protuberant, fleshy mass from the
cervix. These neoplasms arise in the endometrial lining but often grow in an exophytic
pattern within the endometrial cavity (Fig. 9.2).

FIGURE 9.2 Exophytic pattern of growth in carcinosarcoma.

Uterine enlargement and a presumptive diagnosis of uterine leiomyomata are nearly universal
findings in patients with leiomyosarcoma. The incidence of leiomyosarcoma in all patients
with the clinical picture of myomas is less than 1% but increases with age, and an enlarging
pelvic mass in a postmenopausal female is suspicious for a malignant process.

Diagnosis and Evaluation

Vaginal bleeding in a postmenopausal female should be evaluated with endometrial sampling
and possibly transvaginal ultrasound. Whereas the diagnosis of carcinosarcoma is confirmed,
or at least suggested, at the time of endometrial biopsy or curettage, leiomyosarcomas are
rarely diagnosed before hysterectomy.
Laparoscopy has become a standard and preferred approach in the management of benign
and malignant gynecologic conditions. Morcellation is often not done in women with
carcinosarcoma because they are often older and may have a preoperative diagnosis.
Morcellation of uterine leiomyosarcoma is associated with a worsened outcome. The 5-year
overall survival (OS) was 46% after morcellation compared to 73% in those not morcellated
(p = 0.04). The true impact of morcellation of uterine leiomyosarcomas is difficult to fully
understand because of the very small cohorts and overall poor quality of published reports.
There is literature to support that the combination of serum lactate dehydrogenase and
dynamic magnetic resonance imaging may help to evaluate uterine lesions for
leiomyosarcoma. Controversy regarding the use of morcellation has heightened the
awareness of these issues and led to cautionary statements from the government and
professional societies. As of August 2018, the U.S. Food and Drug Administration (FDA)
warns against using laparoscopic power morcellators in gynecologic operations to treat
patients with suspected or confirmed cancer and in the majority of women undergoing
myomectomy or hysterectomy for uterine fibroids.

Staging and Prognosis

The International Federation of Gynecology and Obstetrics (FIGO) devised a sarcoma-
specific staging system in 2009 for leiomyosarcoma, ESS, and adenosarcoma (Tables 9.2 and
9.3). Carcinosarcomas are staged using the system for endometrial carcinoma. Figure 9.3
depicts the stage distribution for newly diagnosed uterine sarcomas using older staging
criteria. The majority of ESS, leiomyosarcomas, and adenosarcomas appear confined to the
uterus and/or cervix. Carcinosarcomas and undifferentiated sarcomas have a much greater
propensity for metastatic spread at time of presentation. A nomogram for leiomyosarcomas is
also available online at https://www.mskcc.org/nomograms/uterine. Although more accurate
than the current staging systems, it does require further development and validation.

TABLE 9.2 The 2009 FIGO Staging System for Uterine

Leiomyosarcomas and ESS
Source: From D’Angelo E, Prat J. Uterine sarcomas: A review. Gynecol Oncol. 2010;116:131–139, with permission.

TABLE 9.3 The 2009 FIGO Staging System for Uterine Adenosarcomas
Source: From D’Angelo E, Prat J. Uterine sarcomas: A review. Gynecol Oncol. 2010;116:131–139, with permission.
FIGURE 9.3 Stage distribution of the more common uterine sarcomas. ESS,
endometrial stromal sarcoma; LMS, leiomyosarcoma; AS, adenosarcoma; UUS,
undifferentiated uterine sarcoma; CS, carcinosarcoma.

Staging systems and nomograms have limited prognostic capabilities because they rely on
anatomic, clinical, and pathologic criteria that have not been consistently associated with
outcome. A better molecular understanding may provide greater prognostication. Expression
patterns of estrogen receptor (ER), progesterone receptor (PR), β-catenin, cyclooxygenase-2,
and bcl-2 have all been reported to be associated with survival in leiomyosarcoma.

Pathology and Molecular Genetics

Malignant mesenchymal tumors can be classified into pure mesenchymal tumors and tumors
with a mixed epithelial and mesenchymal component. In the first group, the most common is
leiomyosarcoma, followed by ESS, and, rarely, others including rhabdomyosarcoma,
liposarcoma, angiosarcoma, chondrosarcoma, osteosarcoma, and alveolar soft part sarcoma.
Mixed epithelial and mesenchymal tumors include carcinosarcoma and adenosarcoma. In
addition, there are three rare mesenchymal tumors occurring in the uterus: uterine tumors
resembling ovarian sex cord tumors (UTROSCTs), perivascular epithelioid cell tumors
(PEComas), and inflammatory myofibroblastic tumor. The malignant potential of these
tumors is highly variable.

Leiomyosarcoma and Other Smooth Muscle Tumors

Leiomyosarcomas are malignant smooth muscle tumors that usually arise de novo. Recent
studies have shown that some tumors display areas with benign morphology, suggesting
some progression from leiomyoma to leiomyosarcoma; however, clonality studies only
support this progression in a small percentage of cases. Microscopically, most
leiomyosarcomas are overtly malignant and have hypercellularity, coagulative tumor cell
necrosis, abundant mitoses (more than 10/10 high-power fields [hpf]), atypical mitoses,
marked cytologic atypia, and infiltrative borders. The three most important criteria are
coagulative tumor cell necrosis, high mitotic rate, and significant cytologic atypia.
Some smooth muscle tumors have histologic features that are not worrisome enough to
render an unequivocal diagnosis of sarcoma. These tumors can be classified as atypical
leiomyomas, smooth muscle tumors with low malignant potential (low probability of an
unfavorable outcome), or smooth muscle tumors of uncertain malignant potential (STUMP)
(insufficient numbers have been studied to predict their behavior). Figure 9.4 summarizes the
classification of uterine smooth muscle tumors based on their histologic characteristics. It is
recommended that unusual cases be reviewed by a gynecologic pathologist. Histologic
parameters of leiomyosarcomas that have been shown to be prognostic indicators include
grade, mitotic rate, extensive tumor cell necrosis, lymphovascular invasion, and ER/PR
status.
FIGURE 9.4 Uterine smooth muscle tumors (excluding epithelioid and myxoid
types and cervical tumors). AWD, alive with disease; DOD, dead of disease; hpf,
high-power fields; LMP, low malignant potential; NED, no evidence of disease;
SMT, smooth muscle tumor.

Carcinosarcoma
Uterine carcinosarcomas, also called malignant mixed müllerian tumors, are lesions
containing carcinomatous and sarcomatous elements. Numerous studies have shown that
these tumors are clonal malignancies derived from a single stem cell and should be
considered epithelial metaplastic carcinomas. Microscopically, these tumors have a typical
biphasic pattern with carcinomatous and sarcomatous elements. The carcinoma is usually
high grade; the sarcomatous component is always high grade and may be homologous or
heterologous. Homologous elements are those components that are native to the uterine body
and most commonly are high-grade fibrosarcomas, although other varieties such as
undifferentiated sarcoma may be found as well. Heterologous elements are those components
that are not normally found within the uterus. Heterologous elements are seen in half of the
cases. The most common heterologous sarcoma is rhabdomyosarcoma, followed by
chondrosarcoma, and, less often, osteosarcoma and liposarcoma.
Most studies suggest that the behavior of carcinosarcomas is predicted by the
carcinomatous component. Tumors typically metastasize through lymphatic channels similar
to endometrial carcinomas. Most metastases and recurrences are composed of pure
carcinoma. In two recent studies, adverse prognostic factors included the following:
heterologous elements (in stage I tumors) and high percentage of sarcomatous component in
the main tumor and in the recurrences. Data from The Cancer Genome Atlas indicate that
approximately 90% of carcinosarcomas harbor TP53 mutations.

Endometrial Stromal Neoplasms

In the most recent (2014) WHO publication, endometrial stromal tumors are reclassified as
endometrial stromal nodules, low-grade ESS, high-grade ESS, or undifferentiated uterine
sarcoma. Both endometrial stromal nodules and low-grade ESS are composed of cells
identical to those found in the stroma of proliferative endometrium, whereas high-grade ESS
and undifferentiated sarcomas are composed of cells with cytologic atypia. The differential
diagnosis between an endometrial stromal nodule and an ESS is important, because the
nodules are always benign. Stromal nodules are the least common of the pure endometrial
stromal neoplasms. It is impossible to render a definitive diagnosis based upon curettage
material alone; final diagnosis requires a hysterectomy specimen.
Low-grade ESS is characterized by uniformly bland cells resembling endometrial stromal
cells. Most have fewer than 10 mitoses per 10 hpf. Low-grade ESS is usually positive for ER,
PR, and CD10, and approximately 50% have cytogenetic abnormalities involving
rearrangements of chromosomes 6, 7, and 17. The most characteristic translocation of these
tumors, t(T7;17) (Tp15;q21), generates a fusion of the JAZF1 and JJAZ1 genes.
The newly described entity of “high-grade ESS” is an infiltrative tumor showing
confluent destructive growth, often invading deeply into the myometrial wall. These tumors
have areas of high-grade cytology with a brisk mitotic count of greater than 10 mitoses per
10 hpf, necrosis, and often lymphovascular invasion. High-grade ESS typically harbors the
YWHAE-FAM22 genetic fusion as a result of t(10;17) (q22;p13) translocation.
Undifferentiated endometrial sarcomas have cytologic atypia to the extent that they
cannot be recognized as arising from endometrial stroma. Morphologically, these high-grade
lesions resemble undifferentiated mesenchymal tumors and behave as high-grade sarcomas.
Undifferentiated uterine sarcomas are usually seen in patients older than 50 years, have a
recurrence rate of over 85%, and are usually fatal.

Müllerian Adenosarcoma
Müllerian adenosarcomas are mixed müllerian tumors composed of malignant stromal and
benign epithelial components. Microscopically, the tumors have a benign epithelial
component usually covering the surface of the polyps and in the form of benign glands
uniformly distributed throughout the tumor. The mesenchymal component is usually a low-
grade sarcoma that resembles endometrial stroma. Minimal criteria include at least one of the
following: two or more stromal mitoses/10 hpf, marked stromal hypercellularity, and
significant stromal cell atypia. A minority of cases have “sarcomatous overgrowth,” when
more than 25% of the tumor is composed of pure sarcoma. In these cases, the sarcoma is
typically high grade, and the lesions are aggressive. Most adenosarcomas without stromal
overgrowth express ERs in the sarcomatous component, and this may be used for therapeutic
purposes. Besides stromal overgrowth, the other histologic features associated with decreased
survival are lymphovascular or myometrial invasion.

Surgery
Key Points
Surgery, typically hysterectomy, is a cornerstone of treatment for uterine sarcoma.
Lymphadenectomy is considered standard of care for carcinosarcoma.
Surgical cytoreduction and surgery for recurrent disease may be considered in
highly select cases.

Surgery is a cornerstone in the treatment of uterine sarcomas. A total hysterectomy (never

supracervical) must be performed in the majority of malignant mesenchymal tumors of the
uterus, including leiomyosarcoma, undifferentiated sarcoma, or carcinosarcoma. Uterine
preservation is an option in younger women who wish to preserve fertility and are diagnosed
with STUMP or other atypical leiomyomata of the uterus. The risk of ovarian metastasis is
very low in leiomyosarcoma, and oophorectomy is not recommended in premenopausal
women with leiomyosarcoma. Occult ovarian metastasis in carcinosarcoma is approximately
12%, so bilateral salpingo-oophorectomy should be recommended. Oophorectomy in ESS
may be associated with a decrease in recurrence but is not associated with OS since these
patients generally do very well.
Lymph node metastasis in adult soft tissue sarcomas is less than 3%, with some variation
among histologic types. There is no clear benefit to routine lymphadenectomy in patients
with leiomyosarcoma confined to the uterus and clinically normal lymph nodes.
Lymphadenectomy is considered standard for carcinosarcoma, in which the overall and
occult rates of lymph node metastasis are 27% and 20%, respectively.
Surgical cytoreduction and surgery for recurrent disease may be considered in highly
select cases. Complete gross resection in leiomyosarcoma with extrauterine metastasis was
found on multivariate analysis to be independently associated with progression-free survival.
Cytoreductive surgery for recurrent disease is considered if there has been a relatively long
disease-free interval and sites of recurrence seem amenable to complete surgical resection.
The approach to carcinosarcomas is often extrapolated from data for endometrial carcinomas.

Radiation Therapy
Key Points
Radiation therapy for carcinosarcoma can provide good local control but does not
impact OS due to distant failure.
 The role of radiation therapy remains undefined for leiomyosarcoma and
endometrial stromal sarcoma.

Since the utilization of radiation therapy for patients with uterine sarcomas has been almost
exclusively in the postoperative setting (Fig. 9.5), the role of primary or palliative
radiotherapy will not be presented. As they are more fully explored in the chapter on
epithelial tumors of the corpus, a detailed discussion of the techniques and complications of
adjuvant radiation therapy will not be discussed in this section.

FIGURE 9.5 Adjuvant management algorithm for patients with

leiomyosarcoma, endometrial stromal sarcoma, and high-grade undifferentiated
sarcoma. aConsider adjuvant chemotherapy or pelvic RT for particularly high-
risk features. bFor isolated extrauterine disease, tumor-directed RT may be
appropriate, but in general, systemic chemotherapy should be given for
advanced-stage disease. Source: Adapted from NCCN practice guidelines in
oncology v.5.2019; UTSARC-2/3.

Uterine Sarcomas
Because of the rarity of uterine sarcomas, most literature is retrospective and has often had to
combine many types of sarcomas to attain numbers sufficient for evaluation. Thus, most of
these retrospective studies have not achieved statistical power to reach definite conclusions.
Currently, there is one completed prospective phase III clinical trial that focused on the role
of adjuvant radiation therapy for patients with all three main cell types of uterine sarcomas
(protocol 55874 of the European Organization for Research and Treatment of Cancer
[EORTC]). Those subjects in EORTC 55874 with surgical stage I or II disease were
randomized to either no further treatment or external beam irradiation of the whole pelvis.
For carcinosarcomas, there were 2 of 46 (4.4%) in the adjuvantly irradiated arm and 11 of 45
(24.4%) in the observation subset with isolated local relapses. For leiomyosarcomas, 1 of 50
(2%) in the radiotherapy group and 7 of 49 (14.3%) in the untreated cohort developed
isolated local failures. Though local control was improved in both subtypes, patients with
isolated local failures evaluated in EORTC 55874 are in the minority for both
carcinosarcomas and leiomyosarcomas. The patients treated postoperatively had a
nonsignificant median survival advantage of 8.5 years versus 6.7 years for the observational
cohort with a hazard ratio of 1.02 (95% CI: 0.68 to 1.53, p = 0.92).
Data from the nonrandomized review of the Surveillance, Epidemiology, and End Results
(SEER) analyses of 2,677 cases of all types of uterine sarcomas did demonstrate a
statistically significant improvement in survival favoring adjuvant radiotherapy for stage II,
III, and IV (but not stage I) uterine sarcomas.
The GOG has previously conducted two prospective clinical trials involving selected
patients with uterine sarcomas. The earliest study reported on 156 evaluable patients with
surgically staged I or II sarcomas of the uterus (GOG 20). Radiotherapy did not seem to
affect recurrence in general. However, there was a notable decrease in vaginal recurrences in
patients with carcinosarcomas. Furthermore, there was a significant reduction in pelvic
relapses (10%) in treated patients compared with those untreated (23%) (Table 9.4). The
second main GOG trial for patients with uterine sarcomas involved a clinicopathologic
evaluation of patients with clinical stages I and II diseases (GOG 40). Although adjuvant
pelvic external beam therapy was not mandated in this surgical trial, there appeared to be a
possibility that adjuvant radiation plays a role in reducing pelvic relapses.

TABLE 9.4 Sites of First Recurrence for Nonleiomyosarcomas

RT, radiation therapy.

Source: Modified from Hornback NB, Omura G, Major FJ. Observations on the uterine sarcomas of adjuvant radiation
therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys. 1986;12:2127–2130.

A recently published retrospective review has the largest number to date of patients with
uterine sarcomas, with 3,650 evaluable patients. There was no significant impact on OS for
patients receiving predominantly postoperative pelvic radiation therapy versus those
receiving no adjuvant therapy. However, there was a statistically significant reduction in local
recurrence rate in the adjuvantly irradiated cohort, which was preserved on subset analyses of
patients with carcinosarcoma (p < 0.001), leiomyosarcoma (p < 0.01), and ESS (p < 0.05).
Further studies are needed to evaluate the role of adjuvant “volume-directed” radiation
therapy for patients with uterine sarcomas.

Uterine Carcinosarcomas
Other reports have been limited to one histologic type of sarcoma. The most common of
these have evaluated uterine carcinosarcomas, which are more appropriately considered
metaplastic carcinomas. Results are inconsistent with some studies demonstrating no benefit
for radiotherapy, while others have shown a significant impact of adjuvant pelvic
radiotherapy on the survival for patients with carcinosarcomas.
GOG 150 is the only randomized phase III prospective trial of adjuvant radiotherapy in
carcinosarcomas. This study compared whole-abdominal irradiation to three cycles of
cisplatin–ifosfamide chemotherapy with respect to recurrence rates, disease free, and OS.
Eligible were patients with carcinosarcomas confined to the abdomen who underwent
optimal surgical debulking with no postsurgical residual disease greater than 1 cm. After
adjusting for stage and age at diagnosis, there was a diminution in death rate reduction of
29% for those receiving chemotherapy compared with radiotherapy (HR = 0.712, 95% CI:
0.484 to 1.048, p = 0.085, two-tail test). Of interest is the fact that those patients who
received adjuvant radiotherapy had more late complications, mainly gastrointestinal, than
those having cytotoxic therapy (p < 0.001). In addition, two patients undergoing radiotherapy
died as a direct result of radiation-induced hepatitis.
Based on the results of GOG 150, the role of adjuvant radiotherapy for the management
of patients with carcinosarcomas continues to remain uncertain. Since there were more
vaginal failures in the chemotherapy arm of GOG 150 and other sites of relapse were similar
or less common in frequency (abdominal recurrences) than those in the radiotherapy arm,
perhaps postoperative vaginal brachytherapy (either high- or low-dose rate) with
chemotherapy should be considered for any patient having optimally debulked
carcinosarcomas in future trials (Table 9.5).

TABLE 9.5 Patterns of Failure in GOG 150

aSome patients had multiple sites of relapse.
n, total number of cases in each arm; WAI, whole-abdominal irradiation.
Source: Modified from Wolfson AH, Brady MF, Rocereto T, et al. A Gynecologic Oncology Group randomized phase III
trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as postsurgical therapy in stage I–IV
carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007;107:177–185.

A review of the nonrandomized SEER database of 2,461 women with carcinosarcomas from
1973 to 2003 included 890 patients who had received adjuvant radiotherapy. The overall 5-
year survival rates of those receiving radiotherapy versus no irradiation were 41.5% and
33.2%, respectively (p < 0.001). Furthermore, a significant improvement in survival in this
study was observed for all stages of disease, including stage IV. Finally, there have been
several published retrospective reports suggesting that combined adjuvant radiotherapy and
chemotherapy may impart even longer survival, especially for stage I and II diseases.
As there were more vaginal failures in the CT arm of GOG 150, and other sites of relapse
(abdominal recurrences) were similar or less common in frequency than those in the RT arm,
it may be reasonable to consider postoperative VBT with CT (of greater than three cycles) for
any patient with optimally debulked CS in future trials.

Uterine Leiomyosarcomas
The most common uterine sarcoma excluding carcinosarcoma is leiomyosarcoma. There are
currently no randomized phase III trials that demonstrate any impact of adjuvant radiation
therapy on locoregional relapse or survival. The overall pelvic/extrapelvic relapse rates are
approximately 16.6% and 42.0% for patients with uterine leiomyosarcoma. There still
remains a paucity of information that specifies between upper abdominal and extra-
abdominal distant sites of tumor involvement. The respective pelvic/extrapelvic percentages
were 18.5% (22/119)/41.2% (49/119) for nonirradiated and 12.9% (8/62)/43.5% (27/62) for
patients treated with postoperative radiotherapy. From this overview, it does not appear that
postoperative radiotherapy has any real effect on reducing recurrences for patients with
uterine leiomyosarcoma.
However, two of the listed series combined to yield an 11.1% (4/36) pelvic relapse rate
with radiation versus 61.1% (22/36) without the implementation of adjuvant radiation
therapy. However, the major problem is that the majority of these patients have distant extra-
abdominal metastases, such as the lung, despite having local control. This would suggest that
adjuvant systemic therapy must be added in order to have an impact on the outcome of these
patients. The role of adjuvant radiotherapy in leiomyosarcoma remains undefined.

Endometrial Stromal Sarcomas

The total pelvic and extrapelvic rates of relapse for patients with ESS are 42.2% and 33.3%,
respectively. There was a 33.3% (6/18) pelvic recurrence rate of which the majority did not
undergo any radiation therapy. This latter finding initially suggested that postoperative
external pelvis radiotherapy could be considered for the subset of patients with low-grade
ESS.
A more recent report retrospectively reviewed 28 patients with ESS of which 19 were
low grade and 9 high grade. Fifty percent of the patients in this series underwent adjuvant
pelvic radiotherapy with no difference in the survival of the patients. In addition, almost 30%
of those receiving adjuvant radiotherapy relapsed within the treatment field. However, a more
recent small series of 13 patients with all stages of ESS showed that the 10 patients
undergoing adjuvant radiation therapy had an 89% locoregional control rate versus 50%
locoregional control for the 3 not receiving any radiotherapy. No direct survival benefit has
been associated with the use of postoperative RT in either EES or UUS. Thus, the role of
radiotherapy for patients with ESS remains uncertain.

Chemotherapy
Key Points
Combined chemotherapy is more effective than single agents.
Active agents are different for carcinosarcoma and leiomyosarcoma.
Hormonal therapy is effective for endometrial stromal sarcoma.

Uterine sarcomas, although far less common than endometrial carcinomas, exhibit two
features that increase the need for systemic therapy: a recurrence rate of at least 50%, even in
early-stage disease, and a high propensity for distant failure. The comparatively low
incidence of uterine sarcomas has made randomized controlled trials difficult. Crucial to the
understanding of the use of chemotherapy in uterine sarcomas is the observation that these
neoplasms are heterogeneous. The first two subtypes, carcinosarcomas and leiomyosarcomas,
constitute 90% of cases entered into clinical trials. These two histologic subtypes are usually
the only uterine sarcomas with sufficient numbers to permit meaningful phase III studies;
however, as these two histologic subtypes appear to respond differently to chemotherapy,
they should be studied separately.

Chemotherapy: Limited Disease

Uterine sarcoma has a high rate of distant metastases even in the absence of intraperitoneal or
lymph node metastases. It has been concluded that this is due to the high rate of
hematogenous and lymphatic dissemination. Even for surgical stage I disease, the recurrence
is as high as 53%. The largest randomized trial to date of adjuvant chemotherapy versus no
further therapy in patients with uterine sarcoma did not segregate histologic subtypes.
Although the recurrence rate and median survival of patients treated with doxorubicin
compared to no therapy were 41% versus 53% and 73 months versus 55 months,
respectively, this phase III GOG trial of 156 evaluable patients concluded that there was no
significant difference. As with advanced disease, more recent trials began to segregate the
histologic subtypes.

Uterine Carcinosarcomas
A GOG study reported by Sutton et al. in 2005 of 65 patients with completely resected stage I
and II carcinosarcomas of the uterus treated with adjuvant ifosfamide and cisplatin reported
2- and 5-year survival rates of 82% and 62%, respectively. Since more than half of the
recurrences involved the pelvis, the study suggested that a combined sequential approach
with chemotherapy and radiotherapy might be beneficial for this group of patients, which
should be verified in randomized phase III study.
GOG 150, a phase III study of patients with stage I to IV uterine carcinosarcoma who
had undergone complete gross resection, compared whole-abdominal radiation with three
cycles of cisplatin and ifosfamide as adjuvant therapy. There was a trend toward improved
outcome in the chemotherapy group with recurrence and estimated death 21% and 29%
lower, respectively, compared to the radiotherapy group.

Leiomyosarcomas
Two factors continue to limit the study of adjuvant therapy in patients with uterine
leiomyosarcomas: the relatively low frequency of the disease, which makes it difficult to
complete randomized trials in a reasonable period of time, and the lack of highly active
agents. The Sarcoma Alliance for Research through Collaboration conducted a phase II
adjuvant therapy trial (SARC005) of gemcitabine and docetaxel followed by doxorubicin for
women with uterus-limited leiomyosarcoma and reported a progression-free survival at 2 and
3 years of 78% and 50%, respectively. A phase III multicenter randomized trial (GOG 277)
compared gemcitabine and docetaxel followed by doxorubicin to the current standard
approach of observation, in order to determine if adjuvant chemotherapy improves outcomes
for patients with uterus-limited high-grade leiomyosarcoma. Despite international
collaboration, this study was closed for accrual futility. The observed OS and recurrence-free
survival data did not show superior outcomes with adjuvant chemotherapy. Observation
remains the standard of care in this setting.

Chemotherapy: Advanced or Recurrent Disease

Leiomyosarcomas
Numerous single agents have been and continue to be tested in patients with
leiomyosarcomas. Doxorubicin and ifosfamide are the most active agents investigated as
primary single-agent chemotherapy in advanced and recurrent uterine leiomyosarcomas.
Combination chemotherapy yields greater response rates.
In 1996, using a combination of ifosfamide and doxorubicin, the GOG demonstrated an
overall response of 30% in patients with advanced leiomyosarcoma with no history of prior
treatment. Gemcitabine plus docetaxel was proven highly active and tolerable (40% overall
response rate) in treated and untreated patients with leiomyosarcomas. The response rate of
this doublet was 36% as initial therapy and 27% in the second-line setting. Given the paucity
of survival data available from the randomized trials to compare various chemotherapy
regimens, a pooled analysis showed that patients who received first- or second-line
chemotherapy for the treatment of metastatic leiomyosarcoma had a higher response rate
with combination chemotherapy than with single-agent chemotherapy.

Uterine Carcinosarcomas
Several drugs have been studied in this group of tumors as single agents. However, only three
drugs have demonstrated clear-cut activity: ifosfamide, cisplatin, and paclitaxel. Of the three
drugs given as a single agent, ifosfamide is the most active single agent studied to date, with
a response rate of 36%. In patients with prior chemotherapy, cisplatin produced an 18%
response in 28 patients. A repeat trial in patients with no prior chemotherapy documented
essentially the same response rate of 19% among a larger group of patients. Paclitaxel, as a
single agent, was associated with a response rate of 21% in a group of 33 patients with
uterine sarcoma who had prior chemotherapy, with an 8% response rate in patients who failed
appropriate local therapy. Doxorubicin, generally regarded as the most active agent in soft
tissue sarcomas, unfortunately demonstrated inconsistent activity in three trials of patients
with carcinosarcomas.
A phase II study of carboplatin and paclitaxel as first-line chemotherapy for women with
advanced uterine carcinosarcoma reported an overall response rate of 54%, with a favorable
toxicity profile. The GOG evaluated the addition of cisplatin to ifosfamide in 194 eligible
carcinosarcoma patients and found that this improved the overall response rate from 36% to
54% and prolonged the median progression-free interval by an absolute 2 months. However,
this advantage was not associated with a significant OS gain. More recently, and based upon
the finding of moderate activity (18% response rate) of paclitaxel for this disease, the GOG
carried out a phase III trial of ifosfamide with or without paclitaxel in advanced uterine
carcinosarcomas. The group found that the addition of paclitaxel produced a 45% response
rate compared with 29% in the ifosfamide single-agent arm with OS significantly improved.
There was a significant decrease in the hazard of death and progression but more sensory
neuropathy, as expected. A recent meta-analysis supports the use of combination
chemotherapy in advanced or recurrent carcinosarcoma with a reduction in the risk of death
and disease progression compared to single-agent therapy. In order to determine the best
first-line chemotherapy doublet, the GOG has conducted a noninferiority phase III trial, GOG
261, comparing carboplatin and paclitaxel with ifosfamide and paclitaxel. The combination
of carboplatin and paclitaxel was not inferior to ifosfamide and paclitaxel for OS with longer
PFS and similar QOL and neurotoxicity. These results establish carboplatin and paclitaxel as
the new standard regimen for women with uterine CS.

Endometrial Stromal Sarcoma

In recurrent stromal sarcoma, reports support hormone therapy for patients with low-grade
subgroup and chemotherapy for high-grade tumors. Randomized phase III trials with stromal
sarcomas are limited due to the rarity of this disease. The GOG reported a phase II study of
ifosfamide treatment in 21 cases with high- or low-grade, recurrent or metastatic ESS, with
an overall response of 33%. Another noncontrolled study observed a 50% response rate to
doxorubicin therapy in 10 patients with recurrent ESS. Interest in ESS continues owing to the
difference in the prognosis of patients with low-grade disease, high-grade disease, versus
those with undifferentiated endometrial sarcomas. There are no prospective trials of CT
specifically for high-grade undifferentiated endometrial sarcoma. Case reports of response to
ifosfamide- and doxorubicin-based regimens have been documented. Gemcitabine plus
docetaxel may also have activity in high-grade undifferentiated endometrial sarcoma. Owing
to the paucity of data available to guide systemic treatment, patients with these tumors should
be encouraged to participate in clinical trials.

Hormonal Therapy
Although the role of hormonal therapy is clear in breast and endometrial cancers, it has not
been extensively evaluated in mesenchymal uterine tumors. Few uterine sarcomas contain
sufficient ER or PR protein to influence therapy, the only exception being low-grade ESS or
stromal nodules. Uniquely, low-grade ESS are hormonally responsive in roughly two-thirds
of cases, and long-term maintenance therapy should be beneficial. Progestins, gonadotropin-
releasing hormone analogs, or aromatase inhibitors have been used in the treatment of
patients with advanced or recurrent stromal sarcomas. Several papers reported that long-term
use of tamoxifen for the treatment of breast cancer was related to the development of uterine
sarcomas, likely secondary to the stimulatory estrogenic effects of tamoxifen on the uterus. It
is therefore reasonable to avoid ER replacement therapy for these patients.

Biologic Therapy
Because of the high recurrence rate and poor response to radiotherapy and chemotherapy,
biologic therapy may have more promise in uterine sarcoma. The recent advances in the
biology of uterine sarcoma related to probable treatments have concentrated on tyrosine
kinase receptors, vascular endothelial growth factor, and the phosphatidyl-3-kinase
(PI3K)/Akt pathway. The results of a GOG phase II trial of pazopanib in previously treated
uterine carcinosarcoma indicate very limited activity. A phase III, placebo-controlled trial of
gemcitabine and docetaxel with or without bevacizumab as first-line therapy for advanced or
recurrent leiomyosarcoma failed to show benefit. Advances in the understanding of the
biology of uterine sarcomas may provide more treatment targets and make long-term control
of the disease possible.

Systemic Therapy Summary

The current role of chemotherapy in the management of uterine sarcomas involves the
treatment of patients with advanced or recurrent disease, and an emphasis on palliative intent.
In leiomyosarcomas, the active drugs are doxorubicin, ifosfamide, gemcitabine, and
docetaxel. For carcinosarcomas, the drugs of choice are now carboplatin and paclitaxel.
Hormonal therapy, including progestational agents, gonadotropin-releasing hormone analogs,
and aromatase inhibitors, has a role in the treatment of advanced or recurrent ESS. The use of
hormonal agents in the treatment of other histologic subtypes has not been well studied.

Conclusions
There has been a slow evolution in the understanding of the basic science of sarcomas. The
majority are felt to be sporadic with no specific etiology, and most have complex karyotypes.
However, in an increasing number of sarcomas, specific chromosomal translocations
resulting in fusion genes that are constitutive and involve the activation of transcription
factors have been identified.
Adjuvant chemotherapy no longer appears appropriate in early-stage, resected
leiomyosarcomas, despite high rates of recurrence. Clinical trials are possible in subsets of
uterine sarcomas. Carboplatin and paclitaxel are the new standard of care for advanced
uterine carcinosarcoma. A basic understanding of uterine sarcomas and their differences will
help to guide surgical and adjuvant therapy as well as palliative treatment in patients with
these rare neoplasms; this knowledge is critical in the practice of gynecologic oncology.

Suggested Readings
Berchuk A, Rubin SC, Hoskins WJ, et al. Treatment of endometrial stromal tumors. Gynecol Oncol. 1990;36:60–65.
Chi DS, Mychalczak B, Saigo PE, et al. The role of whole-pelvic irradiation in the treatment of early-stage uterine
carcinosarcoma. Gynecol Oncol. 1997;65:493–498.
Ferguson SE, Tornos C, Hummer A, et al. Prognostic features of surgical stage I uterine carcinosarcoma. Am J Surg Pathol.
2007;31(11):1653–1661.
Hensley ML, Blessing JA, Mannel R, 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. 2008;109:329–334.
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.
2018:JCO1800454. doi: 10.1200/JCO.18.00454 [Epub ahead of print].
Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma:
Results of a phase II trial. J Clin Oncol. 2002;20:2824–2831.
Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: Results of a
phase 2 trial (SARC 005). Cancer. 2013;119:1555–1561.
Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine
carcinosarcomas: A Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:526–531.
Major FJ, Blessing JA, Silverberg SG, et al. Prognostic factors in early-stage uterine sarcoma: A Gynecology Oncology
Group Study. Cancer. 1993;71:1702–1709.
Meredith RJ, Eisert DR, Kaka Z, et al. An excess of uterine sarcomas after pelvic irradiation. Cancer. 1986;58:2003–2007.
Norris HJ, Taylor HB. Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal
tumors. Cancer. 1966;19:755–766.
Powell MA, Filiaci VL, Hensley ML, et al. A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus
paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I–IV, persistent or recurrent carcinosarcoma of
the uterus or ovary: An NRG Oncology trial. J Clin Oncol. 2019;37(15 suppl):5500–5500. doi:
10.1200/JCO.2019.37.15_suppl.5500.
Reed NS, Mangioni C, Malmström H, et al. Phase III randomized study to evaluate the role of adjuvant pelvic radiotherapy
in the treatment of uterine sarcoma stages I and II: An EORTC Gynaecological Cancer Group Study (protocol 55874).
Eur J Cancer. 2008;44(6):808–818.
Silverberg SG, Major FJ, Blessing JA, et al. Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A
Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol. 1990;9:1–19.
Sutton G, Brunetto VL, Kilgore L, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcomas of the
uterus: A Gynecologic Oncology Group Study. Gynecol Oncol. 2000;79:147–153.
Sutton G, Kauderer J, Carson LF, et al. Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II
carcinosarcomas (mixed mesodermal tumors) of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol.
2005;96:630–634.
U.S. Food & Drug Administration. Laparoscopic power morcellators. https://www.fda.gov/medical-devices/surgery-
devices/laparoscopic-power-morcellators; Accessed October 5, 2019.
Wolfson AH, Brady MF, Rocereto TF, et al. A gynecologic oncology group randomized trial of whole abdominal irradiation
(WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcomas of the uterus.
Gynecol Oncol. 2007;107(2):177–185.
Young RH, Prat J, Scully RE. Endometrial stomal sarcomas of the ovary: A clinicopathologic analysis of 23 cases. Cancer.
1984;53(5):1143–1155.
Zivanovic O, Jacks LM, Iasonos A, et al. A nomogram to predict postresection 5-year overall survival for patients with
uterine leiomyosarcoma. Cancer. 2012;118:660–669.
 10 Ovarian Cancer (Including the Fallopian
Tube)

Introduction
Note: In this chapter, which will address epithelial ovarian cancer only, “ovarian cancer” will
generally refer to a müllerian cancer arising in the peritoneum, fallopian tube, or ovary.
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the
United States and Europe. Ovarian cancer is the fifth most common cause of cancer death in
women in the United States, where 1 in 70 women will be diagnosed and 1 in 100 women
will die of the disease.
Worldwide, ovarian cancer is the eighth most common form of cancer in women. In
general, the highest incidence rates are found in Europe and North America, and the lowest
rates in sub-Saharan Africa. In the United States, rates for black women are about two-thirds
of those for white women, and rates for women of Asian/Pacific Islander descent are similar
to those of black women. Rates of hysterectomy and oophorectomy in a population will
affect the rate of ovarian cancer; 40% to 50% of women in the United States have a
hysterectomy by 60 to 70 years of age, and about half of them have their ovaries removed at
the same time.
Despite some apparent advances in therapy, survival in the United States from ovarian
cancer has increased only 22% over the past three decades. Small but significant
improvements in survival have been noted for white women but not for black women.
Overall 5-year relative survival rates were 44% for white women and 36% for black women
during 2003– 2009. Outcomes in black women are worse even when controlling for age,
stage, and histology.

Risk Factors
Key Points
Risk factors for ovarian cancer include increasing age, nulliparity, and family
history.
Use of oral contraceptives and tubal ligation are protective.
Carriers of BRCA1 or BRCA2 mutations have a 20% to 40% lifetime risk of
ovarian cancer and should consider prophylactic salpingo-oophorectomy (see
Chapter 3: Clinical Genetics of Gynecologic Cancer).
Established risk factors for ovarian cancer are listed in Table 10.1 alongside protective
factors. Aside from having a first-degree relative with the disease, age is the most important
risk factor for ovarian cancer (Fig. 10.1). Fifty percent of all U.S. cases occur in women over
the age of 65. Older women have a worse prognosis overall (Fig. 10.2), which is in part
because they have an increased incidence of high-stage and high-grade disease at the time of
diagnosis (Table 10.2). However, age remains a poor prognostic factor even when adjusted
for stage, grade, histologic cell type, race, and surgical treatment.

TABLE 10.1 Established Factors Associated with Ovarian Cancer Risk

FIGURE 10.1 Incidence of invasive and borderline ovarian tumors in the United
States by age. Source: Sherman ME, Berman J, Birrer MJ, et al. Current
challenges and opportunities for research on borderline ovarian tumors. Hum
Pathol. 2004;35:961–970.
FIGURE 10.2 Disease-specific survival of patients based on age at diagnosis.
Source: Chan JK, Urban R, Cheung MK, et al. Ovarian cancer in younger vs.
older women: A population-based analysis. Br J Cancer. 2006;95:1314–1320.

TABLE 10.2 Incidence of Stage and Grade by Age Grouping in SEER Data
1988–2001
Source: Adapted from Chan JK, Urban R, Cheung MK, et al. Ovarian cancer in younger vs. older women: A population-
based analysis. Br J Cancer. 2006;95:1314–1320.

Approximately 15% to 20% of cases of invasive epithelial ovarian cancer are the result of
autosomal dominant high-penetrant genetic factors, predominantly germline mutations in the
BRCA1 or the BRCA2 genes. The BRCA1 and BRCA2 gene products function in the cellular
response to DNA damage. The lifetime risk of ovarian cancer for women with BRCA1
mutations and BRCA2 mutations has been estimated to be 40% and 20%, respectively. Risk
may be reduced by prophylactic salpingo-oophorectomy. Survival for women with ovarian
cancer related to a BRCA1 or BRCA2 mutation is longer than for women with a similar stage
cancer and no mutation. Issues related to BRCA mutations as well as mutations in genes
involved in the mismatch repair pathway are discussed in Chapter 3. BRCA1 or BRCA2 is the
most common identified genetic mutation in ovarian cancer patients (14% to 18%) followed
by mutations in genes linked to Lynch syndrome (also known as hereditary nonpolyposis
colorectal cancer [HNPCC] syndrome), which include mutations of MLH1, MSH2, MSH6,
and PMS2. In addition to a predisposition to develop colorectal and endometrial cancer,
women with Lynch syndrome have a 10% to 13% lifetime risk for developing ovarian cancer.
There have been no consistent relationships reported of specific dietary components to
ovarian cancer risk. Although some studies had implicated a diet high in meat and animal fat
or a diet high in lactose, most large recent studies have failed to demonstrate any relationship
between the consumption of animal foods and the development of ovarian cancer. There does
appear to be a modest inverse correlation between moderate physical activity and ovarian
cancer risk, and obesity has consistently shown a positive association with ovarian cancer
risk.
 Women who use oral contraceptives (OCPs) for at least 5 years reduce their risk of
ovarian cancer by an average of 50%, with a concomitant decrease in mortality. Case–control
analyses have consistently documented that users of OCPs have a 30% to 60% decreased risk
of developing ovarian cancer than do women who have never used OCPs. Tubal ligation is
also protective. Some reports have suggested an increased risk with use of fertility-inducing
drugs such as clomiphene, but most recent studies have found either a weak association or no
association between infertility treatment and development of ovarian cancer. There appears to
be a modest association between hormone replacement therapy (HRT) and risk of ovarian
cancer. Progestins have been proposed to be protective against ovarian cancer, and the risk of
ovarian cancer may be greater for estrogen-only HRT than for estrogen–progestin
combinations. However, current clinical practice is to prescribe HRT to patients with severe
postmenopausal symptoms and to administer it at the lowest effective dose for less than 5
years.
Although several early studies showed substantial increases in ovarian cancer risk linked
to use of fertility drugs, subsequent studies have generally not confirmed an association, at
least for invasive cancers. There are, however, lingering concerns regarding whether fertility
medications might increase the risk of borderline ovarian cancers, especially given results
from a recent large Dutch cohort study. Whether this reflects a biologic relationship or
merely increased medical surveillance among infertility patients has yet to be determined.

Pathology
Key Points
High-grade serous histology accounts for the majority of epithelial ovarian
cancers.
Most serous ovarian cancers originate in the distal fallopian tube from serous
tubal intraepithelial carcinoma (STIC) lesions.
Borderline tumors are usually confined to the ovary and have a better prognosis.
Primary mucinous ovarian cancers can be difficult to distinguish from metastases
to the ovary from other sites.

Ovarian carcinoma includes many histologic subtypes (Table 10.3). Approximately half of all
ovarian tumors are of epithelial origin and account for 90% of malignant ovarian tumors,
while high-grade serous histology accounts for the majority of epithelial ovarian cancers.
Most recently, there have been new insights into the origin of serous “ovarian” cancer. A
putative precursor lesion in the fallopian tube, serous tubal intraepithelial carcinoma (STIC),
has been identified, and it is now believed that most serous “ovarian” cancer originates in the
distal fallopian tube as STIC lesions. However, it is often not possible to clearly identify
where the serous tumor originated.

Histologic Classification of Common Epithelial Tumors of the

TABLE 10.3 Ovary

aOrigin of müllerian mucinous tumors is not definitively known.

Source: Cobb L, Gaillard S, Wang Y, et al. Adenocarcinoma of Mullerian origin: Review of pathogenesis, molecular
biology, and emerging treatment paradigms. Gynecol Oncol Res Pract. 2015;2:1. DOI: 10.1186/s40661-015-0008-z.

Most of the remaining cell types of ovarian carcinomas appear to have other precursor
lesions. Nearly all clear cell carcinomas and a large proportion of endometrioid carcinomas
arise in endometriosis and appear to progress through a hyperplasia–borderline tumor–
carcinoma sequence. Similarly, mucinous carcinomas most probably transit through a
mucinous cystadenoma–borderline tumor–intraepithelial carcinoma sequence before invasion
occurs (though the majority are metastases from mostly gastrointestinal sites—see Mucinous
Tumors section below). Such tumors are much more likely to be diagnosed while still
confined to the ovary, and they therefore constitute more curable ovarian carcinomas.
Low-grade serous carcinoma is a recently described and relatively small subset of
ovarian serous carcinoma that also often appears to follow a stepwise progression from
borderline tumor to invasive carcinoma.

Serous Tumors
Approximately 20% of serous tumors are malignant, 2% are borderline tumors, and 78% are
benign. The mean age for patients with cancer is 56 years. Patients with benign and
borderline tumors are generally younger, with mean ages at diagnosis of 45 and 48 years,
respectively. Approximately one in six serous adenomas are bilateral compared to one-third
of stage I serous adenocarcinomas. Those of higher stage are bilateral in two-thirds of cases.
A recent Stanford series showed a 55% bilateral rate in serous borderline tumors. Borderline
tumors that are confined to the ovary are associated with a survival that approaches 100%.
The 10-year survival for women with tumors that have associated noninvasive peritoneal
lesions still exceeds 95%, while for those with invasive implants, it is 67%. Micropapillary
serous tumors are a subtype of borderline tumors that are particularly likely to be associated
with invasive implants and therefore have a worse prognosis. Microinvasion (defined
variously as a maximal invasive focus size of 2, 3, or 5 mm or an area of 10 mm2) can be
found in up to 10% of borderline tumors. The overall prognosis for the patient with
microinvasion in a borderline tumor is currently considered to be no different than that of a
borderline tumor without microinvasion. Borderline serous tumors may also spread to lymph
nodes, but this does not appear to worsen the overall good prognosis.
Serous adenocarcinomas range in size from small (2 to 3 cm) to quite large. They often
present as solid masses bounded by a capsule, often containing areas of necrosis and
hemorrhage. The ovary from which the neoplasm has arisen is frequently not apparent
grossly or microscopically. The gross appearance of a typical high-grade serous carcinoma
(HGSC) is not distinctive, and it may be mimicked by other high-grade epithelial ovarian
neoplasms, granulosa cell tumors, and carcinomas metastatic to the ovary. The tumor may
appear as large sheets of polygonal cells growing autonomously without stromal support or
as broad to fine clusters of cells related to papillae that irregularly dissect through the stroma,
accompanied by a host desmoplastic response. The nuclei are typically large and
pleomorphic, with variably sized nucleoli and numerous mitotic figures. Grading of epithelial
ovarian cancer has transitioned from a three-grade system to effectively a binary system
(high grade and low grade) in the last two decades. Former grade 2 and 3 tumors are now
grouped and considered high grade, while grade 1 tumors are considered to be low grade. In
contrast to HGSC, low-grade neoplasms are characterized by cells with only mild-to-
moderate nuclear atypia, evenly distributed chromatin, variable nucleoli, and fewer than 10
mitoses/10 hpf. Micropapillary architecture is frequently observed. The binary system
separates over 90% of advanced-stage serous carcinomas into the high-grade group. This
distribution is reflected in the overall behavior of advanced-stage serous carcinoma, which is
associated with a 5-year survival of approximately 25%. In contrast, the 5- and 10-year
survivals for women with advanced-stage low-grade serous carcinoma are approximately
85% and 50% to 60%, respectively. Serous carcinomas frequently stain positively with
immunohistochemistry for WT1 and cytokeratin (CK) 7 and negative or only focally positive
for CK20 and calretinin. A panel that includes these antibodies is frequently employed to
evaluate a carcinoma whose primary site is uncertain. Pancreatic and breast carcinomas have
the same CK7/20 profile, and thus, other markers are needed for these sites. GCDFP-15
(gross cystic disease fluid protein 15) is often positive in breast carcinoma and only rarely
positive in ovarian carcinoma.

Mucinous Tumors
Primary ovarian mucinous carcinomas are rare, and approximately 70% of those that involve
the ovary are metastatic from other sites. Therefore, initial workup for a mucinous “ovarian”
carcinoma warrants a full gastrointestinal workup (including colonoscopy and EGD). While
metastatic mucinous tumors are often bilateral, primary ovarian mucinous tumors are
typically unilateral. While mucinous carcinomas with secondary spread to the ovary are
much more commonly encountered than primary ovarian mucinous carcinomas, the
distinction can be difficult to make because the ovarian metastasis may be the presenting site
of disease. Typical pathologic features of metastatic mucinous carcinomas are bilateral,
smaller size (typically <10 cm), ovarian surface involvement, a nodular pattern of
involvement, and an infiltrative pattern of stromal invasion. However, some metastatic
mucinous carcinomas, especially those derived from the colorectum, pancreaticobiliary tract,
appendix, and endocervix, can exhibit deceptive patterns of invasion. Immunohistochemical
analysis with antibodies such as CK7, CK20, CDX-2, and p16 can be useful for identifying
some metastatic mucinous carcinomas; however, the utility of currently available markers is
limited due to overlapping immunoprofiles of primary ovarian mucinous tumors with other
mucinous tumors, particularly those of upper gastrointestinal tract origin.
Primary ovarian mucinous tumors include three types: cystadenomas (81%; these are
benign), borderline tumors (13%), and primary ovarian mucinous carcinomas (5%). The
mean age for patients with mucinous adenocarcinoma is 52 years, which, as with serous
adenocarcinoma, is greater than the mean age of patients with benign and borderline tumors
(44 and 49 years, respectively). These masses are multicystic mucinous masses with smooth
capsules and can grow to extremely large sizes, being among the largest of any recorded
tumor in the body. They may contain solid areas and regions of necrosis, and rupture with
surface involvement can occur. A thick tenacious mucinous material may fill the cysts.
Most primary mucinous ovarian cancers are stage I cancers. There are also two types of
borderline mucinous tumors: the endocervical type and the gastrointestinal type (which is
more common). Both types of borderline mucinous tumors are almost always stage I and
have close to 100% survival.
Pseudomyxoma peritonei is a clinicopathologic syndrome in which mucinous ascites is
accompanied by low-grade neoplastic mucinous epithelium intimately associated with pools
of extracellular mucin and fibrosis. It was thought that this syndrome sometimes resulted
from mucinous ovarian tumors, but now it is believed to be derived universally from
appendiceal low-grade (adenomatous) mucinous tumors; the ovarian involvement is
secondary.

Endometrioid Tumors
Invasive endometrioid ovarian cancer accounts for about 10% of all ovarian carcinomas and
occurs most often in perimenopausal patients. Approximately 10% to 40% of cases are
associated with endometriosis. When controlled for stage, the survival rate for endometrioid
tumors is similar to that of serous adenocarcinoma in some studies but better in others. Up to
25% of patients of reproductive age with an endometrioid endometrial cancer have a
synchronous early-stage endometrioid ovarian cancer, though it is often difficult to determine
pathologically whether concurrent ovarian and endometrial endometrioid tumors
alternatively represent metastases. The presence of concurrent endometrial hyperplasia in the
ovarian specimen or clonally related tumors helps to establish the diagnosis of metastases.
While the absence of these features cannot rule out metastases, their absence may represent a
true synchronous primary tumor.
Clear Cell Tumors
Advanced clear cell carcinomas are unusual in the United States. Clear cell carcinoma is
more common in Japan, where it accounts for about 20% of ovarian carcinomas. Even in
Japan, early-stage clear cell carcinoma is more common than advanced-stage disease; in one
review, stage I made up 51% of clear cell disease, stage II 13%, stage III 30%, and stage IV
6%. About half of cases are associated with endometriosis. Clear and “hobnail” cells are the
microscopic hallmark, but the diagnosis rests upon architecture as well as optically clear
cytoplasm. When present, the clear appearance of the cytoplasm results from glycogen that
has leached as the tissue specimen is prepared for microscopic examination. The hobnail
cells contain bulbous nuclei that protrude into the lumen at the apparent cytoplasmic limits of
the cell. See Implications of Clear Cell and Mucinous Histology section later in this chapter
for more details.

Carcinosarcoma
Although previously thought to be rare, carcinosarcomas constitute about 6% of ovarian
carcinomas in the United States and 2.5% in Thailand. The mean age at diagnosis, 66 years,
is slightly higher than that for HGSC. These tumors are typically large, ranging from 15 to 20
cm in diameter. The stage distribution is identical to that of HGSC. The morphology is
similar to its uterine counterpart. The characteristic microscopic feature is an intimate
admixture of malignant epithelial and stromal elements. The malignant epithelial element is
most commonly a HGSC but can be of any of the surface epithelial cell types of ovarian
tumors. The stromal component usually contains sheets of hyperchromatic rounded to
spindled cells with marked nuclear atypia and a high mitotic index. Heterologous elements,
most commonly cartilage, osteoid, and rhabdomyoblasts, are commonly found, and, as in the
uterine counterpart, their frequency depends on the diligence with which they are sought.

Mixed Carcinoma
Perhaps, as many as 10% of all ovarian tumors of common epithelial origin are mixed, when
defined as a carcinoma in which more than 10% of the neoplasm exhibits a second histologic
cell type. One common specific malignant combination is mixed clear cell and endometrioid
carcinoma, both being related to endometriosis.

Fallopian Tube Carcinoma

The National Cancer Institute defines fallopian tube carcinoma as cancer that arises in the
lining of the fallopian tube. It is important to note that most HGSCs (that were previously
considered primary ovarian carcinoma) actually develop in the distal fallopian tube from the
precursor lesion: STIC. As such, the incidence of the diagnosis of fallopian tube carcinoma
has increased dramatically. While most fallopian tube neoplasms display papillary serous
histology, mucinous or endometrioid histology are very rarely observed. In the absence of a
STIC lesion, fallopian tube carcinoma that has spread to the ovary is indistinguishable as
primary ovary or primary fallopian tube carcinoma. This distinction is irrelevant from a
clinical perspective since both fallopian tube and ovarian epithelial carcinoma are treated in
the same manner.

Primary Peritoneal Serous Carcinomatosis

Primary peritoneal carcinoma is defined by the Gynecologic Oncology Group (GOG) as
follows: (i) ovaries are of normal size or enlarged by a benign process; (ii) ovarian
involvement is absent or limited to the surface and/or superficial cortex with no tumor nodule
within the ovarian cortex exceeding 5 × 5 mm; (iii) serous histology; and (iv) volume of
extraovarian disease significantly exceeds that of ovarian disease. The pathology and
response to treatment of peritoneal serous carcinomas are essentially identical to that of
ovarian serous carcinomas. It has recently become apparent that the tubal fimbriae may be an
important source of carcinomatosis in the absence of the typical features of primary tubal
carcinomas (i.e., a dilated fallopian tube with a large mucosal lesion). Because the gross and
microscopic characteristics, as well as spread, of carcinoma of the fallopian tube are identical
to those of the ovary, the determination of the site of origin of a tumor that forms a solid or
cystic tubo-ovarian mass is arbitrary. The fallopian tube may actually be the source of many
HGSCs that are considered primary to the ovary.

Diagnosis and Clinical Evaluation

Approximately 75% to 85% of patients with epithelial ovarian cancer are diagnosed at an
advanced stage when their disease has spread throughout the peritoneal cavity. Symptoms
that have been shown to be more likely in women with ovarian cancer than the general
population are new and persistent symptoms of bloating, pelvic or abdominal pain, difficulty
eating, early satiety, or urinary urgency or frequency. Several organizations, including the
Gynecologic Cancer Foundation, the Society of Gynecologic Oncologists, and the American
Cancer Society, released a consensus statement in June 2007 that urges women to seek
medical attention if they have any of these symptoms. However, there is no evidence that
increased awareness of these symptoms and their relation to risk of ovarian cancer will shift
diagnosis early enough to affect mortality.
The diagnosis of early-stage ovarian cancer (when the tumor is still confined to the
pelvis) is usually discovered incidentally during a workup for other conditions. When an
incidental ovarian mass is discovered, the approach varies depending on whether the woman
is premenarchal, premenopausal, or postmenopausal. A complex (based on ultrasound
findings) adnexal mass in a premenarchal or postmenopausal woman has a higher likelihood
of being a malignant tumor than the same mass in a premenopausal woman, and surgical
exploration is usually indicated in these populations. However, in premenopausal woman, the
vast majority of adnexal masses are not malignant (approximately 95% are benign) and can
represent many benign conditions. These masses are commonly due to either follicular or
corpus luteum cysts (functional cysts). The vast majority of these functional cysts will
regress in one to three menstrual cycles, and, consequently, the initial approach to
management for a palpable adnexal mass less than 8 cm in size in a premenopausal woman is
to repeat the pelvic examination and imaging studies in 1 to 2 months.
Ovarian carcinomas are distinctive by virtue of their propensity to exfoliate malignant
cells into the peritoneal cavity. There, the cells follow the normal circulation of peritoneal
fluid along the right paracolic gutter and to the undersurface of the right hemidiaphragm,
where they may implant and grow as surface nodules. The omentum is also a frequent site of
involvement, and, indeed, all intraperitoneal (IP) surfaces are at risk. Ovarian cancer may
also spread via the retroperitoneal lymphatics that drain the ovary. These follow the ovarian
blood supply in the infundibulopelvic ligament to terminate in lymph nodes lying along the
aorta and vena cava up to the level of the renal vessels. Lymph channels also pass laterally
through the broad ligament and parametrial channels to terminate in the pelvic sidewall
lymphatics, including the external iliac, obturator, and hypogastric chains. Spread may also
occur along the course of the round ligament, resulting in involvement of the inguinal
lymphatics.
Preoperative evaluation of the ovarian cancer patient is shown in Figure 10.3. CT scans
of the chest, abdomen, and pelvis are usual. Brain scans and bone scans are unnecessary
unless suggested by the patient’s symptoms; metastases to these sites are extremely
uncommon, particularly at the time of diagnosis. If there is concern for a gastrointestinal
primary based on bowel symptoms or heme-positive stools, barium enema or colonoscopy
can be useful. Because of the association of ovarian cancer with breast cancer and because
metastatic breast cancer can produce intra-abdominal carcinomatosis as well, mammography
is often performed.
FIGURE 10.3 Suspicious symptoms/palpable mass or ascites.

Serum CA-125 level should be measured. It has been demonstrated that fewer than 1% of
normal nonpregnant women have serum CA-125 levels greater than 35 U/mL. In contrast,
80% to 85% of patients with epithelial ovarian cancer have elevated serum levels.
Unfortunately, the percentage of women with an elevated CA-125 level is lower in stage I
disease, limiting the usefulness of the marker as a screening test. The serous histologic subset
of ovarian cancer has the highest incidence of elevated CA-125 levels (>85%), whereas
mucinous tumors are associated with a low incidence of abnormally elevated serum CA-125
levels. In postmenopausal women with asymptomatic pelvic masses, an elevated serum CA-
125 (>65 U/mL) had a sensitivity of 97% and a specificity of 78% for ovarian cancer. In
contrast, in premenopausal women, there is a higher prevalence of nonmalignant conditions
that can produce elevated serum CA-125 levels (e.g., pregnancy, endometriosis, uterine
fibroids, and pelvic inflammatory disease). It is important to note that tumor markers differ
for germ cell and sex cord stromal tumors (please refer to the respective chapters).

Screening
Key Points
Ovarian cancer has a low prevalence: 1 case/2,500 women per year.
Screening with pelvic exam, transvaginal ultrasound, and CA-125 has not been
shown to be effective in any group of women, including BRCA mutation carriers.

Despite decades of large trials, no current screening modalities (CA-125, pelvic ultrasound,
pelvic examinations), either individually or in combination, have been shown to decrease the
risk of death from ovarian cancer. Difficulties with developing effective screening techniques
include the need for surgery to evaluate a positive test (and the risks of any surgical
procedure) and the fact that slow-growing tumors detected on screening are often borderline
(which are not likely to be lethal) or already in an advanced stage (which are difficult to
cure). Additionally, because ovarian cancer has such a low prevalence (1 case/2,500 women
per year), screening low-risk asymptomatic women requires a test or combination of tests
with very high sensitivity and specificity and high positive and negative predictive values.
Several studies have shown that, if asymptomatic women were screened for ovarian cancer,
between 5 and 33 operations would be required to find one invasive ovarian cancer. This
situation is primarily caused by the high false-positive rates of ultrasound and CA-125 in
benign disease.
A representative large multimodal screening trial, the National Cancer Institute (NCI)-
sponsored Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, enrolled
over 74,000 women aged 55 to 74 years from 1993 through 2000. Women were randomly
assigned to either observation or baseline measurements of CA-125 levels and transvaginal
ultrasonography followed by annual CA-125 readings for 6 years and transvaginal ultrasound
for 4 years. Baseline screening in the 28,816 women randomized to screening who received
at least one test detected 29 neoplasms (26 ovarian, 2 fallopian, and 1 primary peritoneal).
Nine were of low malignant potential. Only two of the invasive cancers were stage I; one of
these was a granulosa cell tumor. Five hundred seventy surgical procedures, including 325
laparotomies, were performed. The authors calculated the positive predictive value for
invasive cancer of an abnormal CA-125 as 3.7%, of an abnormal transvaginal ultrasound as
1.0%, and of having both tests abnormal as 23.5%. However, if only subjects in whom both
tests were abnormal had been evaluated, 12 of the 20 invasive cancers would have been
missed.
The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which ran
between 2001 and 2005, assessed the effect of screening on disease mortality in more than
200,000 postmenopausal women. Women were randomized to (i) annual multimodal
screening (MMS), (ii) annual transvaginal ultrasound screening, or (iii) no screening. In the
MMS group, they annually measured CA-125 and used the risk of ovarian cancer algorithm
(ROCA) for an interpretation of rises in CA-125 over time. ROCA is a computer-based
algorithm devised to increase the sensitivity and specificity of CA-125 by looking at the
changes in levels of CA-125 over time for an individual, instead of using a single cutoff
value as the basis for deciding whether additional tests are needed. Using ROCA in the MMS
group, women were triaged to annual screening versus repeat CA-125 versus repeat CA-125
and transvaginal ultrasound. The group did not find a significant reduction in ovarian cancer
mortality with the use of any screening technique. The mortality reduction with MMS was
15% (CI: 3 to 30, p = 0.21), and the reduction with ultrasound alone was 11% (CI: 7 to 27, p
= 0.21). The results suggest that most of the disease detected with MMS was low-volume
disease. In a post hoc analysis, there was evidence of a significant mortality reduction (28%)
in the patients who had multimodality screening after 7 years (after excluding prevalent
cases), but given the primary analysis did not identify a significant reduction in mortality, this
finding is essentially hypothesis-generating. No stage-shift was observed in patients screened
with ultrasound alone; 641 patients needed to be screened to prevent one cancer death.
Criticisms of the study included the exclusion of primary peritoneal cancers from the main
analysis, the persistence of high mortality from ovarian cancer despite screening (53% of
patients died within 2.3 years of diagnosis), and the potential of lead-time bias associated
with early detection. The study results are planned to be reanalyzed after a longer follow-up
interval, which should give us data that could help us assess the value of the screening
approaches.
At this time, routine screening, with serum CA-125 or ultrasound, of the general
population should not be performed because of the risks of performing needless procedures
without proven benefit. Even in women with a positive family history of ovarian cancer or
known BRCA mutations, there is no evidence that screening can affect mortality from this
disease. Despite the absence of benefit, given the significant prevalence of disease and high
mortality rate, screening, with serum CA-125 and pelvic ultrasound, is commonly performed
in patients considered at high risk until/unless they opt for a prophylactic bilateral salpingo-
oophorectomy.
Surgical Staging and the Role of Lymph Node
Sampling
Key Points
Important prognostic factors for women with ovarian cancer include surgical
stage, volume of residual disease after surgery, and tumor grade.
Surgical staging procedures include hysterectomy, bilateral salpingo-
oophorectomy, omentectomy, pelvic and para-aortic lymphadenectomy (if
enlarged nodes or if tumor is presumed to be stage 1), and peritoneal biopsies.

Patients newly diagnosed with ovarian cancer usually undergo surgery for the purpose of
pathologic diagnosis, cytoreduction, symptom relief, and staging. The International
Federation of Gynecology and Obstetrics (FIGO) staging system requires that surgery be
performed to confirm the histologic diagnosis and to determine the true extent of the disease
(the full FIGO staging system for ovarian carcinomas is presented in Table 10.4).

TABLE 10.4 Carcinoma of the Ovary: 2014 FIGO Staging System

aIncludes extension of tumor to capsule of the liver and spleen without parenchymal involvement of either organ.
bParenchymal metastases are stage IVB.
Source: Mutch DG, Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer. Gynecol Oncol.
2014;133:401–404, with permission.

The initial surgical approach to a suspicious adnexal mass, confined to the ovary, is often
performed laparoscopically (depending on the size of the mass). On entering the abdomen,
aspiration of ascites or peritoneal lavage should be performed to obtain specimens for
cytologic examination. The mass is then removed, usually as a unilateral salpingo-
oophorectomy. An encapsulated adnexal mass should be removed intact, if possible, since
rupture and spillage of malignant cells within the peritoneal cavity will increase the patient’s
stage and may adversely affect her prognosis (for laparoscopic procedures, the specimen can
be placed in an endoscopic bag and be removed through one of the port sites). Once a
diagnosis of ovarian cancer is confirmed, based on pathologic frozen section, surgical staging
procedure is performed either laparoscopically or via laparotomy (for disease that has already
spread beyond the adnexa, typically a laparotomy with a vertical incision is performed in
order to fully access both the pelvis and the upper abdomen).
For tumors presumed to be confined to the ovary, surgical staging includes omentectomy;
peritoneal biopsies from the pelvis, right and left paracolic gutters, and the undersurfaces of
the right and left hemidiaphragms; and completion hysterectomy and removal of the
contralateral fallopian tube and ovary in women who do not desire fertility (in select patients,
fertility-sparing surgery may be permissible). In presumed early-stage disease, several reports
have demonstrated that the pelvic lymph nodes are involved by ovarian cancer at the same
frequency as are para-aortic nodes and suggest the need for comprehensive nodal sampling.
As such, currently complete pelvic and para-aortic lymphadenectomy should be performed in
patients with presumed disease confined to the ovary. Adhesions should also be biopsied
since they may represent occult areas of microscopic disease. A complete abdominal
exploration should also be carried out, including the evaluation of all intestinal surfaces, and
any suspicious areas should be biopsied.
In contrast, for patients with disease that has already spread beyond the ovary/pelvis,
surgical approach is focused on removing all visible (macroscopic) evidence of disease. In
these patients, a complete surgical cytoreduction (also referred to as debulking) procedure
should be performed with the goal of removing all visible tumor. Instead of the complete
lymphadenectomy that is recommended for presumed early-stage patients, in patients with
disease that has spread outside of the ovary, only enlarged/suspicious nodes should be
removed due to the increased morbidity with complete lymphadenectomy and no proven
survival benefit as demonstrated in a recent randomized control trial (LION trial). While this
procedure is typically performed with open laparotomy, the National Comprehensive Cancer
Network (NCCN) guidelines state that laparoscopic debulking surgery may be permissible in
certain cases but conversion to laparotomy should be performed if complete gross resection
(removal of all visible tumor) cannot be accomplished in a minimally invasive fashion.
Minimally invasive surgery may also be used as an initial step to whether complete
cytoreduction can be performed prior to converting to a laparotomy procedure.

Prognostic Factors
The 5-year survival of patients with epithelial ovarian cancer is directly correlated with the
tumor stage (Fig. 10.4). Prognosis for stage I disease has been reported to be from 60% to
over 80% and is strongly dependent on tumor grade and whether the patient was fully staged
(as patients with apparent stage I disease may have stage III disease found with careful
surgical exploration and lymph node sampling). Similarly, initial studies of patients with
stage II disease reported the range of 5-year survivals from 0% to 40%. However, stage II
disease frequently is upstaged to stage III disease, particularly when patients present with
large-volume disease in the pelvis. The small numbers of patients who are found to have
stage II disease following completion of a comprehensive laparotomy have a 5-year survival
rate of approximately 80%. Patients with stage III disease have a 5-year survival rate of
approximately 15% to 30%, whereas patients with stage IV disease have a 5% 5-year
survival rate.

FIGURE 10.4 Carcinoma of the ovary; patients treated from 1996 to 1998.
Survival of FIGO stage. Source: Heintz AP, Odicino F, Maisonneve P, et al.
Carcinoma of the ovary. Int J Gynecol Obstet. 2003;83:135–166, with
permission.

In women with advanced-stage disease, the removal of tumor implants is an essential

component of treatment in advanced ovarian cancer as there is an inverse relationship with
the amount of residual tumor and survival in these patients. The approach to a patient with
advanced-stage disease includes an assessment of whether or not a complete gross resection
of tumor is feasible. Complete gross resection is defined as resection to microscopic disease
(which should be the goal of any ovarian cancer debulking procedure though is not always
feasible); optimal cytoreduction is defined as residual disease that is less than 1 cm, and gross
residual disease is defined as remaining disease that is greater than 1 cm. It is essential for
surgeons to evaluate and record the amount of residual disease in the operative report given
that the terminology and definitions have shifted over time. A meta-analysis of 81 studies
showed that survival is associated with the amount of residual disease, with a median OS of
22.7 months for patient cohorts in which 25% or fewer were maximally cytoreduced (≤3 cm
residual tumor) and a median OS of 33.9 months for patient cohorts with 75% or greater rates
of maximal cytoreduction. Each 10% increase in the proportion of patients who were
maximally cytoreduced was associated with a 5.5% increase in median cohort survival time.
In general, the histologic type has less prognostic significance than other clinical factors,
such as stage, volume of disease, and histologic grade. However, there is a high correlation
between histologic type, stage, and grade. The histologic grade of the tumor is a particularly
important prognostic and decision-making factor in patients with early-stage ovarian cancer.
In surgically staged patients from the FIGO database, the overall 5-year survivals are 87%,
82%, and 69% for stage I grade 1, 2, and 3 tumors, respectively.

Treatment
Treatment of ovarian cancer is based on histologic subtype and stage of disease. Examples of
management algorithms for serous and endometrioid ovarian cancer are shown in Figure
10.5.
FIGURE 10.5 Postoperative chemotherapy.

Early-Stage Ovarian Cancer

Although the benefits of chemotherapy in advanced-stage ovarian cancer have been well
demonstrated, they have been much harder to show in early-stage disease. The number of
patients available is smaller and the prognosis better than with more advanced-stage disease,
making adequately powered randomized trials difficult to complete. Some patients treated
postsurgically with observation alone may be salvaged with chemotherapy after recurrence.
In addition, early-stage epithelial ovarian cancer is composed of a different mix of grades and
histologies than is advanced-stage disease, in particular a much larger percentage of
mucinous, and clear cell carcinomas and a smaller percentage of serous carcinomas. The
current standard of care for most early-stage ovarian cancer patients is chemotherapy. This is
based on the positive results of the combined ACTION and ICON 1 trials, which randomized
women with early-stage disease to chemotherapy versus no postoperative treatment (Fig.
10.6).
FIGURE 10.6 Kaplan-Meier curves for overall survival in early-stage ovarian
cancer patients treated with adjuvant chemotherapy (solid line) and no adjuvant
chemotherapy (dotted line). Source: Trimbos JB, Parmar M, Vergote I, et al.
International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant
Chemotherapy in Ovarian Neoplasm Trial: Two parallel randomized phase III
trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J
Natl Cancer Inst. 2003;95:105–112.

The benefit of adjuvant chemotherapy was found to be restricted to patients with incomplete
surgical staging. Incompletely staged patients with a poorly differentiated grade III tumor
were found to derive the greatest benefit from adjuvant chemotherapy. Duration of therapy
for early-stage disease remains controversial. The GOG randomized 427 eligible patients
with early-stage disease to receive either three or six cycles of carboplatin/paclitaxel
chemotherapy in GOG 157. Overall 5-year survival was 84% for stage I disease and 73% for
stage II disease and did not differ by treatment regimen (HR 1.02). After adjusting for initial
FIGO stage and tumor grade, the recurrence rate was 24% lower for patients receiving six
cycles (HR 0.76), though it was not statistically significant. However, in a subsequent
subgroup analysis from this study, patients with high-grade serous histology who received six
cycles had reduced recurrence risk compared to those who received three cycles (HR 0.33,
95% CI: 0.14 to 0.77, p = 0.04). This benefit was not observed in patients with other
histologic types (HR 0.92, 95% CI: 0.60 to 1.49). Therefore, six cycles of adjuvant
chemotherapy are recommended for patients with early-stage high-grade serous tumors,
while three cycles are acceptable for patients with other histologic types.
At this time, it is recommended that patients with comprehensively staged stage IA or IB
grade 1 epithelial ovarian cancer receive no postoperative chemotherapy. Patients with grade
3 or stage IC disease have a relapse risk of at least 20%, and this can be reduced with
platinum-based chemotherapy. Carboplatin/paclitaxel for three to six cycles is the usual
treatment in the United States. Based on the low frequency of early-stage disease, future data
to better address which women with early-stage ovarian cancers actually derive benefit from
therapy will be difficult to generate.

Early-Stage Fallopian Tube Carcinomas

Unlike ovarian carcinoma, in which two-thirds of patients present with advanced-stage
disease, about half of patients diagnosed with fallopian tube carcinoma using traditional
criteria have been diagnosed in stage I or II. No meaningfully sized series to inform about the
benefits of treatment exist, and these tumors are treated the same as early-stage ovarian
cancers. As advanced-stage fallopian tube carcinomas appear to respond to platinum-based
therapies in a manner similar to that of ovarian carcinomas, adjuvant chemotherapy is
currently used for early-stage fallopian tumor in most situations.

Advanced Epithelial Ovarian Cancer

Key Points
Cytoreductive surgery is standard in the management of ovarian cancer, with the
goal being complete resection of all visible tumor.
Six cycles of carboplatin/paclitaxel is standard therapy for most women with
advanced-stage ovarian cancer in the United States (administered either in the
adjuvant setting or as neoadjuvant and adjuvant therapy with an interval
cytoreductive surgery).
Recent trials (GOG 218 and ICON 7) have shown statistically significant but
modest benefit with the addition of bevacizumab to frontline therapy.
Intraperitoneal (IP) therapy may benefit women who have had an optimal
cytoreductive surgery.
Advanced-stage clear cell and mucinous tumors appear to be relatively
chemotherapy resistant.

Cytoreductive Surgery
The majority of cases of ovarian cancer are not diagnosed until the disease has spread beyond
the ovary. Often, patients with advanced disease will present with an abdomen distended with
ascites and obviously bulky tumor masses in the pelvis and upper abdomen. Surgery is
indicated in these patients for three reasons: (i) to obtain tissue for a diagnosis, (ii) to
improve symptoms, and/or (iii) for cytoreduction. Surgery alone is never curative in
advanced disease and therefore should only be attempted as part of a treatment plan including
postoperative chemotherapy. The goal of surgical cytoreduction in patients with advanced-
stage III/IV ovarian cancer should be a complete resection of all visible tumor (see Table
10.5).

TABLE 10.5 Terms and Definitions for Ovarian Cancer Cytoreductive

Surgery

Survival is associated with the amount of residual disease after cytoreductive surgery. In the
largest (4,312 women) phase III ovarian cancer trial performed to date (GOG 182), the
Gynecological Cancer InterGroup studied the addition of a third chemotherapy group to the
standard carboplatin and paclitaxel regimen in women with stage III/IV ovarian cancer.
Although the addition of a third drug did not show any benefit, the extent of cytoreductive
surgery was shown to be significantly correlated with progression-free survival (PFS) and
overall survival (OS). Patients with FIGO stages III and IV who had no macroscopic disease
at the end of surgery, minimal residual disease (<1 cm), or gross residual disease had a
median PFS of 29, 16, and 13 months, respectively, and a median OS of 68, 44, and 30
months, respectively. A meta-analysis of 81 studies by Bristow and colleagues also showed
that survival is associated with the amount of residual disease, with a median OS of 22.7
months for patient cohorts in which 25% or fewer were maximally cytoreduced (≤3 cm
residual tumor) and a median OS of 33.9 months for patient cohorts with 75% or greater rates
of maximal cytoreduction. Each 10% increase in the proportion of patients who were
maximally cytoreduced was associated with a 5.5% increase in median cohort survival time.
Even in patients with FIGO stage IV disease, cytoreduction to microscopic disease should be
the primary goal at initial surgery. A positive association of stage IV disease optimally
debulked to microscopic residual disease with longer survival was confirmed by review of
three prospective phase III Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) trials
(AGO-OVAR3, AGO-OVAR5, AGO-OVAR7). However, patients with very extensive
carcinomatosis and extensive upper abdominal disease and/or mesenteric involvement tend to
obtain limited benefit from primary cytoreductive procedures, as residual disease will likely
remain.
Neoadjuvant ChemotherapySurgery prior to chemotherapy, for diagnosis and tumor
debulking, has been the standard in the United States. However, since optimal cytoreduction
is associated with improved outcomes, for patients in whom optimal cytoreduction is not
thought possible at an initial surgery, the benefit of a brief induction course of chemotherapy
(neoadjuvant chemotherapy typically consisting of three cycles of platinum/taxane
chemotherapy) prior to debulking surgery has been explored. The CHORUS and
EORTC55971 trials randomized patients to neoadjuvant chemotherapy followed by interval
cytoreduction versus primary surgery followed by adjuvant chemotherapy. Both studies
found no significant difference in PFS or OS between the groups. Both studies also suggested
an improved rate of optimal cytoreduction after neoadjuvant chemotherapy. However,
critiques of these studies include the low rate of complete cytoreduction in the primary
surgery arm (in both studies) and the high mortality rate (CHORUS), the latter, which may
reflect the overall morbidity and poor performance status of those enrolled. These critiques
fuel an ongoing debate on the role of neoadjuvant chemotherapy in ovarian cancer care. This
approach clearly seems appropriate in patients who are poor surgical candidates at
presentation due to comorbidities or tumor sites that are thought to be unresectable in the
upfront setting. However, despite improvements in rates of optimal cytoreduction,
neoadjuvant therapy does not appear to improve overall survival. An ongoing international
study entitled Trial on Radical Upfront Surgery in Advanced Ovarian Cancer (TRUST) may
help to answer these questions.
Interval Cytoreductive SurgeryInterval debulking is a term traditionally used to describe
surgery performed in the middle of a chemotherapy course for patients in whom initial
debulking surgery was attempted but was unsuccessful and whose disease appears to be
responding to therapy. Interval debulking is also sometimes referred to as cytoreductive
surgery after neoadjuvant chemotherapy without attempted primary cytoreductive surgery.
There is conflicting evidence from two large prospective randomized trials (EORTC and
GOG) as to whether interval debulking can improve survival in certain patients with
advanced ovarian cancer, with an EORTC trial showing substantial benefit and a GOG trial
showing no benefit in either PFS or OS. Select patients may benefit from interval debulking
depending on the aggressiveness of the initial cytoreductive surgery, the geographic
distribution and size of the remaining disease, and the response to the initial several cycles of
chemotherapy.

Second-Look Surgery
The term second-look laparotomy/laparoscopy refers to an abdominal procedure after
chemotherapy to assess whether or not residual disease remains. At least half of patients in
clinical complete remission with a normal CA-125 level will have residual disease at
laparotomy. Second-look procedures used to be routine and provided important information
about the natural history of ovarian cancer. However, although surgery is the most accurate
way to assess the response to therapy, there is no evidence that any type of routine surgical
procedure after initial chemotherapy prolongs overall survival or that any further therapy
administered to patients with clinically inapparent residual disease will prolong survival.
Moreover, even patients with negative second-look laparotomy have a 50% recurrence risk.
This type of procedure is therefore no longer standard practice.

Chemotherapy
The current standard for a patient with disease that appears resectable, and is an operative
candidate, is initial aggressive surgery with the goal of accomplishing complete tumor
cytoreduction with no visible residual disease.
For patients who undergo primary surgery, the surgery alone is rarely curative for women
with advanced-stage ovarian carcinoma, even when there is no residual disease; thus,
adjuvant chemotherapy is required. The standard postoperative chemotherapy regimen in the
United States is currently six cycles of a combination of a taxane and platinum agent,
frequently intravenous carboplatin/paclitaxel. Various dosing strategies including IP
chemotherapy are options for adjuvant treatment. Because there is no one universal approach,
treatment may be tailored to the patient’s clinical situation (see Table 10.6).

TABLE 10.6 Acceptable Primary Systemic Therapy Regimens by Stage

according to National Comprehensive Cancer Network
(NCCN) Guidelines (Version 3.2019)
aConsideration for PARP inhibitor maintenance therapy following completion of chemotherapy for patients with BRCA
mutation–associated disease.
Platinum agents represent the most active group of chemotherapy drugs in the treatment of
ovarian cancer. Multiple randomized trials comparing carboplatin to cisplatin in ovarian
carcinoma have been performed, and both individual studies and meta-analyses have
confirmed that there is no difference in efficacy between the two agents. Therefore, in
general, carboplatin, which is less emetogenic and produces less neurotoxicity and
nephrotoxicity than cisplatin, is the first-line platinum agent in the treatment of ovarian
cancer in the United States. No evidence supports the use of doses of cisplatin above 50 to
100 mg/m2 every 3 weeks or carboplatin AUC 5 to 7.5 every 3 weeks. Weekly carboplatin is
also an acceptable option, and the MITO 7 trial showed that a weekly regimen is efficacious
and has less toxicity than the standard every-3-week dosing. However, weekly dosing of
carboplatin is often reserved for patients for whom the standard every-3-week dosing may
cause significant toxicity such as elderly or otherwise frail patients.
Of note, in patients with extensive tumor burden (ascites, poor performance status and
several comorbidities, obesity, and older age), neoadjuvant chemotherapy (discussed above)
is a very reasonable choice (same drugs used for adjuvant chemotherapy are used in the
neoadjuvant setting).

ADDITION OF A TAXANE TO PLATINUM CHEMOTHERAPY

In the 1980s, a great deal of excitement was generated by the demonstration that single-agent
paclitaxel had substantial activity against platinum-resistant ovarian cancer.
A number of randomized trials were rapidly launched comparing platinum-based
regimens with and without taxane in the first-line treatment of ovarian cancer. The results of
the first two of these trials completed (GOG 111 and OV-10) clearly demonstrated that
combination chemotherapy with paclitaxel and cisplatin prolongs both progression-free and
overall survival as compared with cyclophosphamide/cisplatin. However, the other two trials
did not clearly support the addition of paclitaxel to frontline therapy. GOG 132 compared
single-agent paclitaxel to single-agent cisplatin to the combination of cisplatin and paclitaxel.
The response rate to single-agent paclitaxel in patients with measurable disease was
significantly lower than to either of the platinum-containing regimens (42% vs. 67%, p <
0.01). However, there was no difference in overall survival (30.2, 25.9, and 26.3 months)
between the regimens. It is possible that sequential therapy with platinum and taxane would
produce the same results as combined therapy, but this has not been prospectively
demonstrated, and combination platinum/taxane therapy remains the standard in the United
States.

ALTERNATE TAXANES/TAXANE SCHEDULES

Docetaxel plus carboplatin has been prospectively compared to paclitaxel plus carboplatin.
There were no apparent differences in progression-free or overall survival between the two
drugs. Docetaxel was associated with less neurotoxicity but more myelotoxicity. It represents
an attractive option for patients with or at risk for neurotoxicity. Albumin-bound paclitaxel
(NAB-paclitaxel) has been shown to have activity in ovarian cancer but has not been
compared with paclitaxel. Its use is sometimes considered for patients with hypersensitivity
to other taxanes.
Higher doses or more prolonged infusions of paclitaxel have not been shown to be of
benefit. Several trials tested the effects of weekly administration (often called “dose dense”)
of paclitaxel with every 3-week carboplatin: JGOG 3016 (Japanese trial), GOG 262 (all
patients had the option to receive bevacizumab), and ICON 8. While JGOG 3016 showed a
survival benefit in the weekly Taxol group, GOG 262 and ICON 8 (included a neoadjuvant
arm) did not confirm these results. The reasons for the lack of improvement with weekly
paclitaxel in GOG 262 and ICON 8 may be due to differences in patient or disease
characteristics, though in GOG 262, there did appear to be a benefit of weekly paclitaxel in
the subgroup of patients who did not receive bevacizumab. While MITO 7 also utilized
weekly paclitaxel, it used a lower dose of paclitaxel than the above studies and incorporated
weekly carboplatin.

ADDITION OF A THIRD CYTOTOXIC AGENT TO FRONTLINE CHEMOTHERAPY

Adding a third cytotoxic agent to frontline chemotherapy does not improve outcomes. An
international multiarm randomized study was led by the GOG (GOG 182–ICON 5) to
definitively answer this question. A total of 4,312 advanced-stage ovarian cancer patients
were randomized to carboplatin/paclitaxel or carboplatin/paclitaxel combined with
gemcitabine, liposomal doxorubicin, or topotecan. PFS was not statistically different among
any of the combination regimens studied.

INTRAPERITONEAL CHEMOTHERAPY
IP chemotherapy provides a means by which high concentrations of drugs and long durations
of tissue exposure can be attained at the peritoneal surface. As progression of disease within
the peritoneal cavity remains the major source of morbidity and mortality in ovarian cancer,
it is a theoretically attractive approach in the treatment of this disease. It should be noted that
(i) the theoretical benefit is only for very small tumor volumes and (ii) agents that do not
reach therapeutic systemic levels when given by the IP route need to be administered
intravenously as well. For a given dose of cisplatin, peak concentrations are higher with
intravenous cisplatin, and this has resulted in somewhat decreased toxicity in a randomized
comparison of the same doses of cisplatin given intraperitoneally versus intravenously,
including less hearing loss and neuromuscular toxicity. However, the amount of cisplatin
recovered in the urine, reflecting total systemic exposure, is similar between intravenous and
IP administration. Similarly, carboplatin administered IP at an AUC of 6 has been shown to
give an AUC in the peritoneal cavity approximately 17 times higher than intravenous
administration, while producing a very similar serum AUC. Randomized data show that IP
carboplatin produces benefits similar to those seen with IP cisplatin, yet cisplatin remains the
standard platinum drug for IP administration. For paclitaxel, on the other hand, there is low
systemic absorption of IP paclitaxel; thus, IV administration has been incorporated into the
standard IP regimen. Significant levels of paclitaxel persist in the peritoneal cavity 1 week
after drug administration.

CLINICAL USE OF IP THERAPY FOR OVARIAN CANCER

Numerous prospective randomized clinical trials have tested the benefit of IP cisplatin in the
treatment of ovarian cancer; the three largest are summarized in Table 10.7. In January 2006,
the NCI issued a clinical alert suggesting the use of IP cisplatin chemotherapy in women with
optimally cytoreduced ovarian cancer. A meta-analysis of eight trials comparing IP to
intravenous platinum-based chemotherapy (all but one used cisplatin) showed an average
21.6% decrease in the risk of death (HR 0.79). As the expected median duration of survival
for women with optimally cytoreduced ovarian cancer receiving standard treatment is
approximately 4 years, this size reduction in death rate was estimated to translate into about a
12-month increase in overall median survival. Despite these results, IP therapy has not yet
been consistently adopted for the treatment of women with optimally cytoreduced ovarian
cancer in the United States and has not been widely adopted internationally. There are several
reasons for this. First, IP therapy, as used in the reported trials, is technically demanding.
Administration of paclitaxel over 24 hours, which has been used to reduce the neurotoxicity
when paclitaxel is combined with cisplatin, is inconvenient and, if it requires hospitalization,
expensive. Use of IP catheters is not routine in many oncology practices and is associated
with a number of complications including intestinal injury, catheter blockage, and infections.
Second, all of the large randomized studies used cisplatin in both the IP and intravenous
arms, whereas carboplatin, which is less toxic and easier to administer, has become the
standard intravenous platinum agent in the treatment of ovarian cancer. IP carboplatin can be
safely used and appears to have favorable pharmacokinetics (pharmacologic advantage
combined with good systemic drug exposure) and was included in the 3-armed RCT, GOG
252. GOG 252 randomized women who had maximal cytoreductive surgery to the (i) IV
carboplatin arm, IV paclitaxel 80 mg/m2 weekly + IV carboplatin (AUC 6) every 3 weeks;
(ii) IP carboplatin arm, IV paclitaxel 80 mg/m2 weekly + IP carboplatin (AUC 6); or (iii) IP
cisplatin arm day 1 IV paclitaxel 135 mg/m2 + day 2 IP cisplatin 75 mg/m2 + day 8 IP
paclitaxel 60 mg/m2 every 3 weeks. All arms received bevacizumab 15 mg/kg IV every 3
weeks. None of the regimens in GOG 252 showed a PFS or OS advantage; however, PFS and
OS were prolonged in all the arms and toxicity and patient reported outcomes favored the IV
carboplatin arm.

TABLE 10.7 Selected Randomized Trials of Intraperitoneal versus

Intravenous Chemotherapy in Optimally Debulked Ovarian
Cancers
In conclusion, the heterogeneity and toxicity of the IP regimens used have left some
confusion as to what the most important elements of the ideal IP therapy regimen are and
what could be modified to improve safety and tolerability while maintaining efficacy. Despite
these uncertainties, a potential 1-year survival advantage is certainly meaningful, and the
option of IP therapy should be discussed with healthy patients who have optimally debulked
ovarian cancer. Ongoing trials may clarify the benefit of simplified, less toxic regimens.

PROLONGATION OF PRIMARY THERAPY/MAINTENANCE THERAPY

Many women with ovarian cancer have an excellent response to first-line chemotherapy, but
most will nonetheless relapse and die of their disease. Further therapy after a clinical
complete remission would clearly be warranted if an effective treatment could be found. In
an effort to improve survival outcomes, studies have evaluated a number of treatment
strategies including prolongation of primary therapy or consolidation therapy (treatment with
other modalities following primary cancer therapy) with chemotherapy (such as topotecan or
epirubicin), whole-abdominal radiotherapy, IP delivery of radioactive isotypes or
chemotherapy, and high-dose chemotherapy with stem cell support. However, none of these
approaches have produced any convincing survival benefit to date in the general population.
An initial study (SWOG/GOG S9701) of maintenance therapy intravenous paclitaxel 175
mg/m2 every 4 weeks was halted early by its data and safety monitoring board after a
planned interim efficacy analysis showed an improvement in PFS for patients receiving 12
months versus 3 months of maintenance therapy (PFS 28 vs. 21 months, respectively).
Overall survival was not different between the treatment arms, and rates of peripheral
neuropathy were higher in patients receiving extended therapy. A subsequent study, GOG
212, randomized women in clinical complete remission after primary therapy for stage III or
IV disease to maintenance paclitaxel polyglumex, maintenance paclitaxel, or observation.
This study showed no overall survival advantage with maintenance taxane therapy.
Maintenance therapy with paclitaxel after completion of primary chemotherapy is not
generally recommended.
Another approach for maintenance therapy has focused on combining newer molecular
targeted agents with frontline chemotherapy. The most promising agent to date has been
bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). It
has produced single-agent response rates in the range of 20% in the setting of recurrent
ovarian cancer and has improved survival when combined with chemotherapy in the
treatment of metastatic colon cancer and lung cancer. Two large randomized trials, GOG 218
and ICON 7, tested the addition of bevacizumab to frontline therapy followed by greater than
12-month maintenance therapy with bevacizumab alone. Results from GOG 218 showed a
significant improvement in PFS (3.8 months) with the addition of bevacizumab to upfront
intravenous chemotherapy when the bevacizumab was continued as a maintenance regimen
after chemotherapy. Because blocking VEGF inhibits the formation of ascites in preclinical
studies, a retrospective subset analysis of GOG 218 examined whether the presence of ascites
might affect the benefit from bevacizumab. Patients with no ascites (n = 221) had no
improvement with bevacizumab in either PFS (adjusted hazard ratio [AHR] 0.81) or OS
(AHR 0.94), whereas those with ascites had significant improvement in both PFS (AHR
0.71) and OS (AHR 0.82).
In the ICON 7 trial, restricted mean PFS for the control group was 20.3 versus 21.8
months in those receiving bevacizumab (restricted mean was reported due to nonproportional
hazards). Benefits were greater among patients at high risk for disease progression as
demonstrated by an analysis of a predefined subgroup of 502 patients with poor prognosis
disease (stage IV or stage III with over 1.0 cm residual disease; similar to the population of
GOG 218 as a whole). In this subgroup analysis, a significant restricted mean OS difference
was observed: 34.5 months for standard therapy versus 39.3 months with bevacizumab.
Bevacizumab is currently approved for use in combination with six cycles of chemotherapy
and as maintenance therapy after chemotherapy in the United States and Europe. The clinical
results are modest, and this approach has not been universally adopted. Unanswered
questions include whether a similar benefit would be seen if bevacizumab were to be given
only following completion of platinum/taxane–based chemotherapy because the trial did not
include a treatment group who received only maintenance bevacizumab. Furthermore, neither
study demonstrated an overall survival benefit. It is also unclear whether bevacizumab given
as part of initial treatment is more favorable than bevacizumab given in the recurrent setting.
In considering whether to use bevacizumab in the initial treatment setting, the modest PFS
benefit, burden of continued therapy, and potential risks (e.g., hypertension, bleeding,
thromboembolic disease, bowel perforation) must be weighed on an individual basis.
A randomized controlled trial of another antiangiogenic agent, pazopanib, which is a
tyrosine kinase inhibitor of the VEGF receptor, demonstrated an improved PFS (18 vs. 12
months) with the addition of pazopanib maintenance therapy, but no OS benefit was
observed.
The SOLO1 study compared olaparib maintenance versus placebo after upfront
chemotherapy in BRCA1- or BRCA2-positive patients. Patients who received maintenance
olaparib had improved PFS compared to those who received placebo (hazard ratio for disease
progression or death 0.30; 95% CI: 0.23 to 0.41, p < 0.001). While patients with both
germline and somatic mutations were eligible, the study only included two patients with
somatic mutations. Based on this study, olaparib maintenance therapy should be offered to
patient with germline or somatic BRCA mutations after completion of primary
chemotherapy.

Management of Borderline Tumors

Key Points
Surgery is the primary management for borderline tumors.
There is no evidence that postoperative chemotherapy improves outcomes for
women with borderline ovarian cancer even with advanced-stage disease.
Borderline tumors may recur after 10 to 15 years.
Twenty to thirty percent of ovarian tumors diagnosed as borderline at the time of
frozen section examination may return as invasive carcinomas on final pathology.

Borderline tumors constitute 10% to 20% of ovarian malignancies. Twenty to thirty percent
of ovarian tumors diagnosed as borderline of any histologic subtype at the time of frozen
section examination prove to be invasive carcinomas on final pathology.
Most are of serous or mucinous histology, and most are diagnosed at an early stage. Even
when they present with more advanced-stage disease, they progress very slowly. A review of
borderline tumors entered into the NCI SEER database between 1988 and 1997 showed 10-
year relative survival rates of 99% for stage I, 98% for stage II, 96% for stage III, and 77%
for stage IV disease. Borderline tumors are particularly likely to affect young women (Fig.
10.1), in whom therapeutic decisions regarding fertility-sparing, premature hormonal
deprivation, and adjuvant chemotherapeutic treatments are particularly pertinent.
Surgery is the cornerstone of treatment for early-stage as well as advanced-stage ovarian
borderline tumors. There is no evidence that a conservative surgical approach (performing
unilateral salpingo-oophorectomy or even cystectomy in some cases for very young patients)
has an adverse effect on survival in patients with stage I borderline tumors. Even though
patients treated with a unilateral oophorectomy have a higher recurrence rate than patients
treated with a total hysterectomy and bilateral oophorectomy, effective surgery for recurrent
disease leads to equivalent survival.
Serous borderline tumors can now be subclassified into two categories that are based on
the presence of peritoneal implants (noninvasive or invasive). For patients with either no
implants or noninvasive implants, survival is close to 100%, though there is a small long-
term risk of developing invasive serous carcinoma (typically low grade) when noninvasive
implants are present. Chemotherapy is not indicated for borderline tumors with either no
implants or noninvasive implants. However, when invasive implants are identified,
management follows recommendations for invasive low-grade serous carcinoma (based on
stage of disease).
Of note, over 90% of serous borderline ovarian tumors are estrogen receptor positive, and
there are case reports of major responses to tamoxifen, leuprolide, and anastrozole.
Approximately 5% to 10% of early-stage serous borderline tumors will ultimately recur,
either as borderline tumors or low-grade carcinomas. Recurrences can present 10 to 15 years
after the initial diagnosis, making long-term follow-up necessary.
Most mucinous borderline ovarian tumors are stage I and present as large unilateral
ovarian masses; bilaterality suggests the possibility of metastatic tumor from another site.
Appendectomy and evaluation of the GI tract should be performed to rule out a primary
gastrointestinal tumor. Advanced-stage pure borderline mucinous tumors are exceedingly
uncommon.

Implications of Clear Cell Histology

The implications of clear cell histology in early disease are not clear; in some reports, it
seems to portend a high risk of recurrence, and in others, it appears to have little prognostic
significance. However, it has become increasingly clear that advanced-stage clear cell tumors
may not respond well to platinum chemotherapy. For example, the Hellenic Cooperative
Oncology Group reviewed outcomes for women with an advanced clear cell carcinoma of the
ovary treated on protocols from 1987 to 2003 (n = 35) and compared them to outcomes for
women with serous tumors treated on the same trials. Response rates were 45% versus 81%
(p = 0.008), and median survival was 25.1 versus 49.1 months (p = 0.141) in clear cell versus
serous tumors, respectively. Clinical data regarding differential chemotherapy sensitivity to
various agents of clear cell carcinomas are sparse and inconsistent. There are few reports of
therapies effective specifically for clear cell carcinomas. The Japanese Gynecologic
Oncology Group (JGOG 3017) performed a randomized phase III study comparing paclitaxel
plus carboplatin with cisplatin plus irinotecan for the frontline therapy of clear cell
carcinoma, and results showed no differences in OS or PFS between the arms. Among the
nonplatinum agents used in primary and secondary resistant cases in the MITO 9 analysis,
gemcitabine appeared to have better activity (response rate [RR] 66%) than topotecan (RR
33%) or liposomal doxorubicin (RR 10%). It has also been hypothesized that antiangiogenic
agents will benefit women with clear cell carcinomas, but this remains unproven.
Interestingly, multiple reports suggest that women with clear cell carcinomas are more likely
to have a thromboembolic event. Clear cell carcinomas may also be associated with
hypercalcemia related to paraneoplastic expression of parathyroid hormone–related peptide.

Implications of Mucinous Histology

Early-stage mucinous tumors tend to be low grade and have a good prognosis. They are
unlikely to have metastasized to lymph nodes, and lymph node dissection is generally not
needed in presumed stage IA mucinous tumors. Advanced-stage mucinous tumors are
uncommon in the United States and are difficult to distinguish from mucinous tumors
metastatic from other sites (most commonly in the GI tract). They respond poorly to
chemotherapy and are associated with a short survival. Investigators from The Royal
Marsden Hospital reviewed outcomes for all patients with stage III or IV mucinous epithelial
ovarian cancer (n = 27, 19 with measurable disease) treated with first-line platinum-based
therapy at their unit between 1992 and 2001 and compared outcomes in patients with
nonmucinous epithelial ovarian cancer. Patients with mucinous cancers experienced poorer
response rates (26% vs. 65%, respectively) and median overall survival was shorter (12 vs.
37 months, p < 0.001, respectively). Disease progression while on platinum-based
chemotherapy was high (63%) for mucinous cancers.
Based on histologic similarities between mucinous ovarian cancers and colorectal
carcinomas, an international trial was launched to compare carboplatin/paclitaxel with or
without bevacizumab with capecitabine/oxaliplatin with or without bevacizumab in the
frontline therapy of stage II to IV or recurrent mucinous carcinomas. Unfortunately, this trial
was closed because of poor enrollment. Of the 16 patients accrued, only 5 were deemed to
have correct stage and histology on central pathology review, illustrating some of the
difficulties in both clinically identifying and studying advanced mucinous ovarian cancer.
Thus, an ongoing debate remains as to whether mucinous ovarian cancer should be treated
with a GI chemotherapy regimen or a platinum/taxane regimen.

Implications of Carcinosarcoma
Ovarian carcinosarcomas tend to present with advanced disease, and early-stage tumors are
unusual. Ovarian carcinosarcoma occurs at a slightly older age and has a worse prognosis
overall than epithelial ovarian cancer without sarcomatous differentiation, with a median OS
in the range of 9 to 24 months. A SEER database review found a 5-year survival of 65.2% for
stage I ovarian carcinosarcoma (vs. 80.6% for stage I serous tumors) and of 18.2% for stage
III ovarian carcinosarcoma (vs. 33.3% for stage III serous ovarian cancer). Adjuvant
chemotherapy is also generally recommended, although there is controversy regarding
whether these tumors should be treated as carcinomas or sarcomas. Retrospective series have
suggested that platinum-containing regimens produce higher response rates than
nonplatinum-containing regimens, but the optimal regimen remains unknown, and it is
unknown whether the percentage of sarcomatous histology in the tumor should influence
choice of regimen. Current studies addressing this question are ongoing.

Follow-Up of Patients in Remission

National Comprehensive Cancer Network (NCCN) Guidelines for follow-up of patients with
ovarian cancer who enter a clinical complete remission include a history and clinical exam
every 2 to 4 months for 2 years, then 3 to 6 months for 3 years, then annually after 5 years, +/
− CA-125 or other tumor markers at every visit if initially elevated, and imaging only as
clinically indicated. Pelvic exam should be performed periodically. A rise in CA-125 in
patients with a history of high-grade serous cancer is fairly specific for recurrence,
particularly if the pretreatment CA-125 was significantly elevated and a second confirmatory
CA-125 shows that the titer is continuing to rise. However, the utility of starting therapy
based on the asymptomatic rise in CA-125 in an asymptomatic patient is unclear. A multi-
institutional European study showed that patients who started therapy based on CA-125
monitoring rather than symptom development did not live longer and received on average 5
months more chemotherapy and quality of life measures were lower. Whether to monitor
CA-125 as part of surveillance should be actively discussed between the patient and treating
physician.

Treatment of Persistent/Recurrent Disease

Key Points
Recurrent ovarian cancer is generally incurable, but patients who recur more than
6 months after completion of primary therapy are considered to have a platinum-
sensitive recurrence.
Patients who recur fewer than 6 months after completion of primary
chemotherapy are considered to be platinum resistant.
Patients with recurrent epithelial ovarian cancer may have significant benefit from
further chemotherapy.
Combination therapy produces higher response rates than single-agent
chemotherapy in women with platinum-sensitive disease, but data regarding
overall survival benefit are conflicting.
The value of secondary cytoreductive surgery is limited to patients who have had
long treatment free intervals and for whom complete cytoreduction is feasible.

Second-Line Chemotherapy
Ovarian cancer that is refractory to primary chemotherapy or recurs at some point after
primary chemotherapy is generally not curable. However, some patients benefit from further
treatment, in particular those who relapse after a substantial disease-free interval. The GOG
defines ovarian cancers with progression on platinum-based therapy as “platinum refractory,”
those that recur less than 6 months after completion of platinum-based therapy as “platinum
resistant,” and those that recur more than 6 months after completing treatment with a
platinum-based regimen as “platinum sensitive” (more accurately “potentially platinum
sensitive”). Women with primary platinum-refractory therapy have a very poor prognosis,
and response to any subsequent treatment is unlikely. General principles of treating recurrent
disease include the following:
1. In women with platinum-sensitive disease, most data suggest that platinum compounds
are the most active single agents, though platinum-sensitive tumors are more sensitive
than platinum-resistant tumors to any cytotoxic agent tested to date.
2. In women with platinum-sensitive disease, platinum-based combinations of cytotoxic
agents produce superior response rates and PFS compared with single-agent platinum
therapy; the effect on overall survival is less certain, and toxicity may be increased.
 3. In women with platinum-resistant disease, combination cytotoxic therapy is not of
proven benefit.
4. In women with platinum-resistant disease, no single agents except possibly taxanes
have consistently produced response rates over 20%. The addition of bevacizumab to
single-agent chemotherapy has doubled the response rate and the PFS.
5. Treatment must be recognized as primarily palliative, and decisions about treatment
regimens should include patient convenience and toxicity as well as efficacy.

Treatment of Platinum-Sensitive Disease

Several randomized trials comparing platinum-containing combinations including paclitaxel,
gemcitabine, and liposomal doxorubicin to single-agent platinum therapy produce superior
PFS to single-agent platinum therapy in the setting of platinum-sensitive disease. As a group,
they show a superior response rate and superior PFS with combination therapy. Results
regarding any benefit to overall survival are conflicting, and any such benefit is probably
small. The addition of bevacizumab to a platinum doublet has demonstrated a 4-month
increased benefit in PFS but no OS benefit in the OCEANS trial, which tested gemcitabine
and carboplatin ± bevacizumab or placebo continued as maintenance until progression.
Similarly, in GOG 213, carboplatin, paclitaxel plus bevacizumab, given concurrently with
chemotherapy and continued as maintenance, was tested against carboplatin and paclitaxel
alone and showed a 3.8-month PFS benefit in the bevacizumab-containing arm (13.8- vs.
10.4-month PFS).
Secondary debulking surgery has been hypothesized to be of benefit in this group, and
the DESKTOP III randomized trial comparing secondary cytoreduction plus chemotherapy
versus chemotherapy alone showed improved PFS with surgery (hazard ratio 0.66). OS data
are pending for this trial. Of note, inclusion criteria were an excellent performance status,
ascites ≤500 mL, and complete gross resection at initial surgery.
Repeated courses of carboplatin-based therapy place patients at risk for hypersensitivity
reactions. The incidence in patients treated with seven or more cycles of platinum-based
therapy (typically the second dose of the second regimen) has been reported to be 27%. The
reactions that occur during drug infusion are associated with flushing, nausea, and
hypertension. A number of desensitization protocols have been published and appear to be
generally effective; moreover, not all patients allergic to carboplatin will be allergic to
cisplatin. However, the reactions are frightening and may be fatal, and desensitization
protocols are time consuming for the patient and decrease the convenience of carboplatin
therapy. Routine use of diphenhydramine premedication has been reported to produce a
nonsignificant decrease in reaction rate.

Treatment of Platinum-Resistant Disease

Response rates to any conventional single-agent therapy in this group of women are 10% to
20%; median PFS is 3 to 4 months, and median overall survival is 9 to 12 months. A list of
agents with some activity in the treatment of platinum-resistant recurrent ovarian cancer is
shown in Table 10.8. At this time, pegylated liposomal doxorubicin is one of the agents
commonly used in this setting, based on the ease of administration and tolerable toxicity. The
addition of bevacizumab to single-agent chemotherapy has doubled the response rate and the
PFS duration for each single-agent chemotherapeutic agent and provided a substantial quality
of life benefit. Specifically, adding bevacizumab to chemotherapy in this setting
demonstrated approximately a 3-month benefit in PFS with a 2% rate of bowel perforation.

TABLE 10.8 Agents in Treatment of Platinum-Resistant Ovarian Cancer

(Preferred Regimens according to NCCN Guidelines Version
3.2019)

Hormonal therapies, such as tamoxifen, have also been tested. Response rates to hormonal
treatment by modern standards are hard to gauge, as most of the trials are quite old; however,
it does appear that selected patients, perhaps those with borderline or low-grade tumors, may
respond and toxicities are minimal.

PARP Inhibitors
(Please see Chapter 1 for an introduction to PARP inhibitors)
PARP inhibitors can be used in three settings: (i) frontline maintenance therapy for
BRCA mutation carriers (germline or somatic mutations), (ii) recurrent platinum-sensitive
maintenance therapy, and (iii) recurrent treatment for BRCA mutation carriers (germline or
somatic). (See Table 10.9 for FDA approval details for PARP inhibitors.)

TABLE 10.9 FDA Indications for PARP Inhibitors (as of 02/2019)

Each only indicated as monotherapy at this time.

aRequires companion diagnostic.
bFor patients in complete or partial remission after platinum-based chemotherapy.

The evidence supporting the use of olaparib in upfront maintenance therapy in BRCA-
positive patients (SOLO1) is described above, in the Prolongation of Primary
Therapy/Maintenance Therapy section. Prior to the results of SOLO1, PARP inhibitors were
primarily used in the recurrent setting. A randomized placebo-controlled phase II trial (Study
19) tested olaparib 400 mg BID as maintenance therapy versus placebo in 265 women with
platinum-sensitive relapsed high-grade serous ovarian carcinomas who were in partial or
complete response following their last platinum-containing regimen. Median PFS was
significantly longer with olaparib than with placebo (8.4 vs. 4.8 months, p < 0.001); this was
more pronounced in the group with a germline or tumor BRCA mutation (11.2 vs. 4.3
months, p < 0.0001). A phase III randomized controlled trial of olaparib maintenance therapy
versus no further treatment (SOLO2) demonstrated a PFS benefit with the addition of
olaparib maintenance in women with platinum-sensitive recurrent epithelial ovarian cancer
and either a germline or somatic BRCA mutation.
Niraparib is also FDA approved for maintenance therapy in women with platinum-
sensitive recurrent ovarian cancer who have response to recurrence therapy. This approval is
based on the results of the NOVA trial, which showed improved PFS in women who received
niraparib maintenance compared to those who received placebo (12.9 vs. 3.8 months among
women without a germline BRCA mutation and 21.0 vs. 5.5 months in women with a
germline BRCA mutation). Rucaparib was also tested as a maintenance therapy for women
with platinum-sensitive disease in the ARIEL3 trial. This study showed a PFS benefit of 5.4
months in the intention to treat population with larger benefits seen in women with BRCA
mutations (11.2 month PFS benefit) or homologous recombination–deficient (HRD)
carcinoma (8.2 month PFS benefit).

Suggested Readings
Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous
cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335(26):1950–1955. DOI:
10.1056/NEJM199612263352603.Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in
ovarian cancer. N Engl J Med. 2006;354:34–43. DOI: 10.1097/01.ogx.0000206353.22975.c5.
Bell J, Brady MF, Young RC, et al. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and
paclitaxel in early stage epithelial ovarian carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol.
2006;102:432–439.
Buys SS, Partridge E, Greene MH, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO)
cancer screening trial: Findings from the initial screen of a randomized trial. Am J Obstet Gynecol.
2005;193:1630–1639.
Cobb L, Gaillard S, Wang Y, et al. Adenocarcinoma of Mullerian origin: Review of pathogenesis, molecular biology, and
emerging treatment paradigms. Gynecol Oncol Res Pract. 2015;2:1. DOI: 10.1186/s40661-015-0008-z.
Gershenson DM. Management of borderline ovarian tumours. Best Pract Res Clin Obstet Gynaecol. 2017;41:49–59. DOI:
10.1016/j.bpobgyn.2016.09.012.
Harter P, et al. A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms. N Engl J Med.
2019;380:822–832. DOI: 10.1056/NEJMoa1808424.
Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian
cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. Lancet. 2015;386:249–257.
Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus
moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage
III ovarian carcinoma: An intergroup study of the gynecologic oncology group, Southwestern Oncology Group, and
Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19(4):1001–1007. DOI: 10.1200/JCO.2001.19.4.1001.Moore
K, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med.
2018;379(26):2495–2505. DOI: 10.1056/NEJMoa1810858.
National Academies of Sciences, Engineering, and Medicine. Ovarian Cancers: Evolving Paradigms in Research and Care.
Washington, DC: The National Academies Press; 2016. https://doi.org/10.17226/21841.
Pinsky PF, et al. Extended mortality results for ovarian cancer screening in the PLCO trial with median 15 years follow-up.
Gynecol Oncol. 2016;143(2):270–275. DOI: 10.1016/j.ygyno.2016.08.334.
Trimble CL, Kosary C, Trimble EL. Long-term survival and patterns of care in women with ovarian tumors of low
malignant potential. Gynecol Oncol. 2002;86:34–37.
Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N
Engl J Med. 2010;363:943–953.Walker JL, Brady MF, Wenzel L, et al. Randomized trial of intravenous versus
intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: An NRG oncology/gynecologic
oncology group study. J Clin Oncol. 2019;37(16):1380–1390. DOI: 10.1200/JCO.18.01568.
 11 Nonepithelial Ovarian Cancer

Overview
Key Points
Nonepithelial ovarian cancers predominantly consist of germ cell tumors and sex
cord–stromal tumors.
The most common malignant germ cell tumors in females are (i) dysgerminomas,
(ii) immature teratomas (ITs), and (iii) yolk sac tumors.
The most common malignant sex cord–stromal tumor in females is adult
granulosa cell tumor.

The World Health Organization classification of tumors of the ovaries divides ovarian tumors
predominantly into epithelial tumors, germ cell tumors, and sex cord–stromal tumors. Germ
cell tumors are derived from primordial germ cells of the ovary. Sex cord–stromal tumors are
derived from the sex cord cells including granulosa cells, Sertoli cells and the stromal cells
(mesenchyme of the embryonic gonads) that include theca cells, fibroblasts, and Leydig
cells.

Germ Cell Tumors

Pathology and Epidemiology
Key Points
Germ cell tumors account for 2% to 3% of all ovarian cancers and usually occur
in girls or young women.
The majority of germ cell tumors are large and unilateral.

The current World Health Organization classification of ovarian germ cell tumors includes
dysgerminoma, yolk sac tumor, embryonal carcinoma, nongestational choriocarcinoma,
mature teratoma, immature teratoma, and mixed germ cell tumors. Overall, ovarian germ cell
tumors account for 20% to 25% of all ovarian neoplasms, but only 3% to 5% of these are
malignant.

Dysgerminoma
Dysgerminoma is the most common ovarian malignant germ cell tumor but only represents
1% to 2% of all ovarian malignant tumors. The mean patient age at presentation is 22 years.
Most dysgerminomas are seen in patients with a normal karyotype, but it is the most frequent
neoplasm in patients with gonadal dysgenesis.
On gross examination, dysgerminomas are usually large, white to gray, fleshy lobulated
masses. About 10% of dysgerminomas are bilateral on gross examination, and another 10%
have microscopic involvement of the contralateral ovary. Prominent hemorrhage, necrosis, or
cystic changes are not expected and, if present, suggest a mixed germ cell tumor.
Microscopically, dysgerminomas display nests and cords of primitive-appearing germ cells
with clear to eosinophilic cytoplasm and prominent cytoplasmic borders. The number of
mitotic figures does not have any therapeutic or prognostic significance.
Dysgerminomas contain cytoplasmic glycogen that can be demonstrated with a periodic
acid–Schiff stain. In addition, they stain diffusely for placenta-like alkaline phosphatase
(PLAP). Because dysgerminoma is the only ovarian germ cell tumor that displays c-kit
staining, positive stains for this marker (and nuclear transcription factor OCT3/OCT4) can
also help to confirm the diagnosis. Tumors may also stain positively for human chorionic
gonadotropin (hCG) due to the presence of syncytiotrophoblast cells within these tumors.
Poor fixation can result in artifacts that mimic embryonal carcinoma and yolk sac tumor
histology.

Yolk Sac Tumor

Yolk sac tumors (formerly known as endodermal sinus tumor) are primitive germ cell tumors,
which have the capacity to differentiate into endodermal structures. The mean age of
presentation is 19 years of age, and they rarely occur beyond age 40.
Yolk sac tumors are typically large and unilateral, with a smooth external surface. On
sectioning, these neoplasms are solid and cystic and tan to gray in color, commonly with
hemorrhage and necrosis. The cut surface may appear mucoid or gelatinous. Yolk sac tumors
display many different histologic patterns. The most common is the reticular or microcystic
pattern. The tumor has a meshlike pattern, and it displays a network of flattened or cuboidal
epithelial cells with varying degrees of atypia. The endodermal sinus (festoon) pattern
contains Schiller-Duval bodies (Fig. 11.1), which have a central capillary surrounded by
connective tissue and a peripheral layer of columnar cells. When present, Schiller-Duval
bodies are diagnostic of yolk sac tumor but are not present in all yolk sac tumors. Yolk sac
tumors generally, though not always, display cytoplasmic staining for cytokeratin and α-
fetoprotein (AFP).
FIGURE 11.1 Schiller-Duval bodies, papillary structures with central blood
vessels, are seen in the endodermal sinus pattern of yolk sac tumor.

Embryonal Carcinoma
Embryonal carcinoma is rarely seen in the ovary, either as pure embryonal carcinoma or as a
component of a mixed germ cell tumor. On gross examination, embryonal carcinoma
characteristically displays areas of hemorrhage and necrosis. Microscopically, this tumor is
composed of very crowded cells that display overlapping nuclei in paraffin sections. The
nuclei are very pleomorphic, and they contain large, prominent nucleoli. The mitotic rate is
high in these tumors. Glandular, solid, and papillary patterns may be seen. Vascular invasion
is common. Embryonal carcinoma stains positively for PLAP, keratin AE1/AE3, CD30, and
OCT3/ OCT4. Syncytiotrophoblast cells may be present, resulting in positive stains for hCG,
but, if not accompanied by cytotrophoblast cells, do not indicate the presence of a
choriocarcinoma component.

Choriocarcinoma
Primary nongestational ovarian choriocarcinomas are rare. It is most often seen as a
component of mixed germ cell tumors of the ovary. On gross examination, choriocarcinomas
are often large with a solid or solid and cystic cut surface, often with abundant hemorrhage
and necrosis. Microscopically, these neoplasms show a plexiform pattern composed of an
admixture of syncytiotrophoblast and cytotrophoblast cells. Numerous mitoses are usually
easily identified in the histologic specimen. These tumors produce hCG due to the presence
of syncytiotrophoblast cells. Choriocarcinoma may also stain for cytokeratins, epithelial
membrane antigen, and carcinoembryonic antigen. Nongestational choriocarcinoma must be
distinguished from gestational choriocarcinoma because the former has a worse prognosis
and requires more aggressive therapy. The identification of paternal genetic material
indicates that the tumor is of gestational origin.

Mixed Germ Cell Tumors

Mixed germ cell tumors of the ovary contain two or more different types of germ cell
neoplasm, either intimately admixed or as separate foci within the tumor. They are much less
common in the ovary than in the testis, accounting for only about 8% of malignant ovarian
germ cell tumors.
The diagnosis and prognosis of malignant mixed germ cell tumors depend on adequate
tumor sampling in order to detect small areas of different types of germ cell tumor because
the types of tumor identified may affect therapy and prognosis.

Teratomas
Teratomas are germ cell tumors that contain tissue derived from two or three embryonic
layers; however, monodermal teratomas with tissue of only one type, such as thyroid tissue
(struma ovarii), also exist. Teratomas represent approximately 95% of ovarian germ cell
tumors, although the majority of teratomas are benign. Teratomas are subclassified according
to whether the tumor elements represent mature or immature tissue types. Immature
teratomas represent about 3% of all ovarian teratomas but are the second most common
malignant ovarian germ cell tumor.
Most teratomas are mature cystic teratomas that contain differentiated tissue components
such as skin, cartilage, glia, glandular elements, and bone. Any tissue type present in adults
may be represented in teratomas. Mature cystic teratomas represent benign neoplasms unless
they contain a somatic malignancy such as squamous carcinoma, papillary thyroid
carcinoma, or other non–germ cell tumors arising in differentiated elements of the teratoma.
Malignant transformation is seen in 0.2% to 1.4% of mature teratomas.
Immature teratomas typically present before age 30. Immature teratomas are typically
unilateral, large, predominantly solid, fleshy and gray-tan in color. Areas of hemorrhage and
necrosis are common. Microscopically, these tumors contain a variety of mature and
immature tissue components. The immature elements almost always consist of immature
neural tissue in the form of small round blue cells focally organized into rosettes and tubules
(Fig. 11.2). There is a correlation between disease prognosis and the degree of immaturity in
the teratoma. Immature teratomas are graded on either a two-tiered or three-tiered grading
system based on the proportion of immature neuroectodermal components (Table 11.1).

FIGURE 11.2 Ovarian immature teratoma. Immature neural tissue forms

tubules.

TABLE 11.1 Grading of Immature Teratomas

In patients whose neoplasm has disseminated beyond the ovary, the grade of the tumor
metastasis is important in predicting survival and determining treatment. Occasionally,
patients may have peritoneal implants that contain only mature glial tissue, but genetic data
suggest that these mature glial implants may represent a metaplastic phenomenon rather than
actual tumor implants. It is extremely important to sample peritoneal disease thoroughly in
order to identify foci of immature teratoma.

Clinical Features
Key Points
Most patient with germ cell tumors present with abdominal pain and a palpable
abdominal mass.
Patients with germ cell tumors typically present with stage I disease.
hCG and AFP are useful tumor markers for some subsets of germ cell tumors.

Malignant germ cell tumors of the ovary occur mainly in girls and young women, typically
between the ages of 10 and 30. Ninety percent of patients are under 40 years old at diagnosis.
All of the germ cell tumors present with similar clinical symptoms. Abdominal pain
associated with a palpable pelvic–abdominal mass is present in approximately 85% of
patients. Approximately 10% of patients present with acute abdominal pain, usually caused
by rupture, hemorrhage, or ovarian torsion. This finding is somewhat more common in
patients with yolk sac tumor or mixed germ cell tumors. Less common signs and symptoms
include abdominal distention (35%), ascites (20%), fever (10%), and vaginal bleeding (10%).
Additionally, the majority of ovarian germ cell tumors are unilateral except for
dysgerminomas. Bilateral involvement occurs in 10% to 15% of dysgerminoma patients.
Many germ cell tumors possess the unique property of producing biologic markers that
are detectable in serum. The development of specific and sensitive radioimmunoassay
techniques to measure hCG and AFP led to dramatic improvement in patient monitoring.
Serial measurements of serum markers aid the diagnosis and, more importantly, are useful for
monitoring response to treatment and detection of subclinical recurrences. Table 11.2
illustrates typical findings in the sera of patients with various tumor histologic types. Yolk
sac tumors and choriocarcinoma are prototypes for AFP and hCG production, respectively.
Embryonal carcinoma can secrete both hCG and AFP, but most commonly produces hCG.
Mixed tumors may produce either, both, or none of the markers, depending on the type and
quantity of elements present. Dysgerminoma is commonly devoid of hormonal production,
although a small percentage of tumors produce low levels of hCG. The presence of an
elevated level of AFP or high level of hCG (>100 U/mL) denotes the presence of tumor
elements other than dysgerminoma. Although immature teratomas are associated with
negative markers, a few tumors can produce AFP. A third tumor marker is lactic
dehydrogenase, which is frequently elevated in patients with dysgerminoma or other germ
cell tumors. Unfortunately, it is less specific than hCG or AFP, which limits its usefulness.
CA-125 can also be nonspecifically elevated in patients with ovarian germ cell tumors.

TABLE 11.2 Serum Tumor Markers in Malignant Germ Cell Tumors and
Sex Cord-Stromal Tumors of the Ovary

Management
Key Points
The majority of patients with ovarian germ cell tumors survive their disease with
the judicious use of surgery and cisplatin-based combination chemotherapy.
 Fertility-sparing surgery procedures enable a large proportion of young women
with early-stage disease to preserve their reproductive potential.
Adjuvant chemotherapy, with bleomycin, etoposide, and cisplatin (BEP), is
recommended for most patients (with the exception of patients with grade 1
immature teratoma or stage IA dysgerminoma).

Surgery
Malignant germ cell tumors generally spread in one of two ways: along the peritoneal surface
or through lymphatic dissemination. They more commonly metastasize to lymph nodes than
epithelial tumors. The stage distribution is also very different from that of epithelial tumors.
In most large series, approximately 60% to 70% of tumors will be stage I, with stage III
accounting for 25% to 30% of tumors. Stages II and IV are relatively uncommon.
The initial treatment approach for a patient suspected of having an ovarian germ cell
tumor is surgery, both for diagnosis and for therapy. A thorough determination of disease
extent by inspection and palpation should be made. The type of primary operative procedure
depends upon the surgical findings and desire for fertility. Because many of these patients are
young women, for whom the preservation of fertility is a priority, minimizing the surgical
resection while ensuring the removal of tumor bulk must be thoughtfully balanced.
Surgical staging information is essential for determining the extent of disease, providing
prognostic information, and guiding postoperative management. It is of critical importance
for those patients with early clinical disease in order to detect the presence of occult or
microscopic metastases.
All ovarian tumors, including germ cell tumors, use the same staging system as defined
by the International Federation of Gynecology and Obstetrics (Table 11.3). Principles of
surgery and staging include the recommendation that a gynecologic oncologist perform the
surgery. Typically, an open laparotomy is used although minimally invasive techniques may
be used for select patients. There are no trials that evaluate open versus minimally invasive
techniques in germ cell tumors. Standard staging includes peritoneal cytology, hysterectomy,
bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node dissection. If there is
no evidence of extrapelvic disease, then random staging biopsies should be performed
including of the omentum and peritoneal surfaces. It is important to complete a
lymphadenectomy, especially in patients with apparent stage I dysgerminomas as isolated
lymph node metastases are seen in up to a third of patients.

TABLE 11.3 FIGO Staging for Ovarian, Fallopian Tube, and Primary
Peritoneal Cancer
Source: Adapted from Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary,
fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124:1–5.

Many patients may undergo their initial surgery with a general gynecologist and are
inadequately staged. Upon referral of such a patient, the gynecologic oncologist is faced with
the dilemma of inadequate staging information. In such cases, postoperative studies including
computed tomography of the abdomen are recommended. If histopathologic and limited
anatomic information from the first surgery clearly indicates the use of systemic
chemotherapy, reexploration solely for the purpose of precise staging information is
generally not advised. Reoperation to complete comprehensive staging may be appropriate
under clinical circumstances where careful surveillance after complete staging may be a
reasonable alternative to chemotherapy.
For women who desire future fertility, fertility-sparing unilateral salpingo-oophorectomy
with preservation of the contralateral ovary and uterus can usually be performed. As noted
previously, bilateral ovarian involvement is rare, except in pure dysgerminoma. If the
contralateral ovary appears grossly normal on careful inspection, it should be left
undisturbed. However, in the case of pure dysgerminoma, biopsy may be considered because
occult or microscopic tumor involvement occurs in a small percentage of patients.
Unnecessary biopsy may result in future infertility due to peritoneal adhesions or ovarian
failure. If the contralateral ovary appears abnormally enlarged, a biopsy or ovarian
cystectomy should be performed. If frozen examination reveals a dysgenic gonad, or if there
are clinical indications suggesting a hermaphrodite phenotype, then bilateral salpingo-
oophorectomy is indicated. It is difficult to establish this diagnosis on frozen section;
therefore, this determination should be made by determining a normal female karyotype
preoperatively. If a benign cystic teratoma is found in the contralateral ovary, an event that
can occur in 5% to 10% of patients, then ovarian cystectomy with the preservation of the
remaining normal ovarian tissue is recommended. Additionally, even if both ovaries are
removed, a hysterectomy does not necessarily need to be performed. With current assisted
reproduction technologies involving donor oocyte and hormonal support, a woman without
ovaries could potentially sustain a normal intrauterine pregnancy.

Cytoreductive Surgery
If widely spread tumor is encountered at initial surgery, it is recommended that the same
principles concerning primary cytoreductive surgery applied in the surgical management of
advanced epithelial ovarian cancer be followed. As much tumor should be resected as is
technically feasible and safe. Patients with completely resected disease do better than those
with bulky postoperative residual disease. However, as with epithelial tumors, the relative
influence of tumor biology, surgical skill, and aggressiveness remain uncertain. Germ cell
tumors, especially dysgerminomas, are generally much more chemosensitive than epithelial
ovarian tumors. Therefore, aggressive resection of metastatic disease in these cases is
questionable. Even in the face of extensive metastatic disease, it is generally possible to
perform a fertility-sparing procedure with preservation of a normal contralateral ovary.
 The value of secondary cytoreductive surgery in the management of nonepithelial
ovarian tumors is even less clear. The finding of a residual mass after completion of
chemotherapy is less common in patients with ovarian germ cell tumors than in men with
testis cancer, because women are likely to have considerable tumor cytoreduction at the time
of the diagnostic surgical procedure and thus enter chemotherapy with significantly less
tumor burden. In patients with bulky dysgerminoma, residual masses after chemotherapy are
very likely to represent desmoplastic fibrosis. Although a number of patients with pure
ovarian immature teratomas or mixed germ cell tumors have persistent mature teratoma at the
completion of chemotherapy, the majority are left with multiple small peritoneal implants
rather than with a dominant mass. However, occasional patients who have received
chemotherapy for immature teratoma or mixed germ cell tumors containing teratoma will
have bulky residual teratoma after chemotherapy. There are anecdotal reports of progressive
mature teratoma in ovarian germ cell tumor patients after chemotherapy. Considering this
information, it may be appropriate to resect persistent masses in patients with negative
markers after chemotherapy for germ cell tumors containing immature teratoma. If viable
malignant neoplasm is found, additional chemotherapy should be considered. However, if
only mature teratoma is resected, observation is generally recommended.

Chemotherapy
The recommended treatment for most patients with malignant germ cell tumors is adjuvant
chemotherapy with three cycles of bleomycin, etoposide, and cisplatin (BEP), except in
patients with grade 1 immature teratoma or stage IA dysgerminoma. Based on promising
results obtained in men with testicular cancer, a prospective Gynecologic Oncology Group
(GOG) study evaluated three cycles of BEP in patients with ovarian germ cell tumors. The
regimen was highly effective, with 89 of 93 enrolled patients free of disease at follow-up.
Although randomized trials have not been feasible, these data (and others from single-
institution and retrospective studies) have led to the widespread adoption of BEP for these
patients.
It is extremely important that women receive the full chemotherapy doses without dose
reduction and remain on schedule. Avoiding delays in treatment and dose reductions is
important to maintain the curative potential of systemic chemotherapy. Most patients are
young and will not develop neutropenic fever or infection. However, if a prior cycle was
complicated by neutropenic fever or in unusually ill patients who are at a higher risk of
myelosuppressive complications, the administration of hematopoietic growth factors is
reasonable. Modern antiemetic therapy has greatly lessened chemotherapy-induced emesis.
Bleomycin can cause pulmonary fibrosis, and therefore pulmonary function testing should be
obtained prior to starting bleomycin and should be repeated as clinically indicated. Findings
of early bleomycin lung disease include a lag or diminished expansion of one hemithorax or
fine basilar rales that do not clear with cough. These findings can be very subtle but if present
mandate immediate discontinuation of bleomycin. Cisplatin is associated with nephrotoxicity,
ototoxicity, and peripheral neuropathy. Nephrotoxicity can be minimized by ensuring
adequate hydration during and immediately after chemotherapy and by avoidance of
aminoglycoside antibiotics. A recognized late effect of chemotherapy used for the treatment
of ovarian germ cell tumors is the risk of secondary malignancies. The epipodophyllotoxins,
including etoposide, are associated with the development of acute myelogenous leukemia
(AML). Morphologically, these leukemias are monocytic or myelomonocytic (M4 or M5).
Characteristic chromosomal translocations (mostly involving the 11q23 region) are
frequently, but not always, present. Leukemia after etoposide treatment occurs within 2 to 3
years, compared to alkylating agent–induced AML, which has a longer latency period. This
treatment complication appears to be dose and schedule dependent. In the GOG protocol
testing the efficacy of BEP in women with ovarian germ cell tumors, one case of AML was
recorded among 91 patients treated.
Although ovarian dysfunction or failure is a risk of chemotherapy, the majority of
survivors can anticipate normal menstrual and reproductive function. Factors such as older
age at initiation of therapy, greater cumulative drug dose, and longer duration of therapy have
adverse effects on future gonadal function.

Surveillance
GOG 9901 reported that among 132 survivors of ovarian germ cell tumors treated with
surgery and platinum-based chemotherapy, 71 patients had fertility-sparing procedures. Of
those potentially fertile survivors, 62 (87.3%) maintained menstrual periods and 24 patients
reported a total of 37 successful pregnancies. Although the survivors reported an increased
incidence of gynecologic problems and diminished sexual pleasure, they also tended to have
stronger, more positive relationships with their significant others.
As with any group of patients with a history of pelvic surgery, patients with malignant
ovarian germ cell tumors may develop functional cysts in the residual ovary. A trial of oral
contraceptives and serial ovarian surveillance with sonography is helpful in distinguishing
functional cysts from tumor recurrence.
Surveillance visits are important to monitor for disease recurrence. According to the
National Comprehensive Cancer Network (NCCN) guidelines, in patients with a
dysgerminoma, physical exam and serum markers (if initially elevated at diagnosis) should
be performed every 2 to 3 months during year 1, every 3 to 4 months during year 2, every 6
months from years 3 to 5, and then annually after 5 years. Additionally, radiographic imaging
with a CT of the abdomen/pelvis should be performed every 3 to 4 months during year 1,
every 6 months during year 2, annually during year 3 to 5, and then as clinically indicated
after 5 years.
In women with nondysgerminoma germ cell tumors, physical exam and serum markers
(if initially elevated at diagnosis) should be performed every 2 months during year 1 to 2,
every 4 to 6 months during year 3, every 6 months during year 4 to 5, and then annually after
5 years. Additionally, radiographic imaging with an CT of the abdomen/pelvis should be
performed every 3 to 4 months during year 1, every 4 to 6 months during year 2, every 6 to
12 months during years 3 to 5, and as clinically indicated after 5 years. Additionally, a chest
x-ray may also be performed during years 1 to 2.

Management of Residual or Recurrent Disease

The large majority of patients with ovarian germ cell tumors are cured with surgery and
platinum-based chemotherapy. However, a small percentage of patients have persistent or
progressive disease during treatment or recur after the completion of treatment. Most
recurrences occur within 24 months of primary treatment, and nearly all cause-specific deaths
occur within 5 years of diagnosis. The management of recurrent disease is complex and is
preferably performed in a specialized center. Data to guide the management of patients with
recurrent ovarian germ cell tumors are scant and largely extrapolated from the clinical
experience with testicular cancer. In general, options include an alternative platinum-based
regimen (such as vinblastine, ifosfamide, and cisplatin) or consideration of a high-dose
chemotherapy regimen with stem cell rescue.

Special Considerations for Dysgerminoma

Dysgerminoma is the female equivalent of seminoma. This disease differs from its
nondysgerminomatous counterparts in several respects. First, it is more likely to be localized
to the ovary at the time of diagnosis (stage I). Bilateral involvement is more common, as is
spread to retroperitoneal lymph nodes. While it is less relevant now than before the era of
modern chemotherapy, dysgerminoma is very sensitive to radiation.
As many as 75% to 80% of dysgerminoma patients used to be considered stage I at
diagnosis. With more precise surgical staging, the true figure is probably somewhat lower.
Currently, patients with well-staged IA dysgerminoma can be observed after unilateral
salpingo-oophorectomy, regardless of the size of the primary tumor. Careful follow-up is
required, because as many as 15% to 25% of patients will experience a recurrence. With the
tumor’s chemosensitivity, virtually all dysgerminoma patients can be cured successfully at
the time of recurrence, if detected early.
Dysgerminoma is very responsive to cisplatin-based chemotherapy, even more so than
other germ cell tumors. Therefore, less toxic chemotherapy has been considered. An
alternative regimen tested by the GOG consists of a 3-day regimen with carboplatin and
etoposide. In the prospective trial, all 39 patients enrolled with stage IB to III pure
dysgerminoma remained free of disease at a median follow-up of 7.8 years. This regimen
may be a reasonable alternative for select patients in whom minimizing toxicity is a priority
although there are fewer survival data with this alternative regimen.
The implications of elevated hCG or AFP levels in patients with dysgerminoma should
be emphasized. These tumor markers are usually increased in patients with
nondysgerminomatous tumors. Therefore, AFP elevation denotes the presence of elements
other than dysgerminoma, and treatment should be tailored accordingly. An elevated hCG
level can be seen occasionally in pure dysgerminoma. This finding should not alter therapy,
but prompt re-examination of the tumor specimen to determine whether
syncytiotrophoblastic cells are present or if the tumor contains nondysgerminomatous
elements.

Sex Cord–Stromal Tumors

Pathology, Epidemiology, and Clinical Features
Key Points
The sex cord–stromal tumors account for approximately 7% of all ovarian
neoplasms.
The most common malignant sex cord–stromal tumor is adult granulosa cell
tumors.
The clinical presentation of patients with sex cord–stromal tumors is frequently
governed by their clinical manifestation resulting from endocrine abnormalities.

Beneath the surface epithelium, the intraovarian matrix, which supports the germ cells,
consists of cells originating from the sex cords and mesenchyme of the embryonic gonad.
Granulosa cells and Sertoli cells are derived from the sex cord cells, whereas the pluripotent
mesenchymal cells are the precursors of theca cells, Leydig cells, and fibroblasts. Neoplastic
transformation of these cellular components, either singly or in various combinations
collectively, results in neoplasms that are termed sex cord–stromal tumors. The current World
Health Organization classification (Table 11.4) of ovarian sex cord–stromal tumors includes
pure sex cord tumors (adult granulosa cell tumors, juvenile granulosa cell tumor, Sertoli cell
tumors, and sex cord tumors with annular tubules), pure stromal tumors (fibroma,
fibrosarcoma, thecoma, Leydig cell tumor, steroid cell tumor), and mixed sex cord–stromal
tumors (Sertoli-Leydig cell tumors).

TABLE 11.4 WHO Classification of Sex Cord–Stromal Tumors and Mixed

Sex Cord–Stromal Tumors
Adult Granulosa Cell Tumor
Adult granulosa cell tumors constitute 5% of all ovarian malignancies but account for
approximately 70% of malignant sex cord–stromal tumors. The peak incidence for these
tumors occurs during the perimenopausal decade. Adult-type granulosa cell tumors are
frequently large, averaging 10 to 15 cm in diameter, and greater than 95% are unilateral.
They are predominately cystic, with numerous loculi filled with fluid or blood and separated
by solid tissue. The solid tissue may be gray–white or yellow and soft or firm. Microscopic
examination reveals a population of granulosa cells often with an additional component of
theca cells, fibroblasts, or both. There can be a variety of growth patterns that occur and are
often admixed. The most common pattern is a diffuse pattern, in which the tumor cells grow
in sheets. A minority of tumors actually display a microfollicular pattern, which is
characterized by Call-Exner bodies in which granulosa cells surround small spaces
containing eosinophilic secretions. Call-Exner bodies are pathognomonic for adult granulosa
cell tumors. A mutation in FOXL2 is present in 97% of adult granulosa cell tumors and
absent in other tumors.
The majority of patients with adult granulosa cell tumors present with one or a
combination of the following symptoms: abnormal vaginal bleeding (including
postmenopausal bleeding), abdominal distention, and abdominal pain. Due to the production
of estrogen, many patients will have endometrial hyperplasia, and the frequency of
concurrent endometrial adenocarcinoma ranges from 3% to 27%.
Adult granulosa cell tumors are low-grade malignancies with propensity to remain
localized and demonstrate indolent growth. Ninety percent are diagnosed at stage I. A unique
feature of granulosa cell tumors is that they can recur at extended time intervals from primary
therapy. For patients who recur, the median time to recurrence is 6 years, and the median
survival after recurrence is 5.6 years.
Useful serum markers for adult granulosa cell tumors include inhibin B and anti-
Müllerian hormone. These markers can be useful both in diagnosis and surveillance.

Juvenile Granulosa Cell Tumor

Overall, juvenile granulosa cell tumors account for about 5% of all granulosa cell tumors.
However, juvenile granulosa cell tumors account for approximately 90% of the granulosa cell
tumors diagnosed in prepubertal girls and women less than 30 years of age. Like adult
granulosa cell tumors, juvenile granulosa cell tumors tend to be large, with diameters
averaging greater than 10 cm. Most are both solid and cystic, but some are uniformly solid or
cystic. The solid areas are yellow or tan. The cysts may contain hemorrhagic fluid.
Microscopic examination typically reveals a nodular or diffuse growth punctuated, in most
cases, by follicles of varying sizes and shapes. The follicles are lined with cells with
abundant eosinophilic cytoplasm and the follicles are filled with basophilic secretions. The
cells have hyperchromatic nuclei which almost always lack grooves. There are frequent
mitotic figures. Call-Exner bodies are rarely encountered.
The majority of prepubertal patients present with clinical evidence of isosexual
precocious pseudopuberty with elevated serum estradiol levels. Compared to adult granulosa
cell tumors, juvenile granulosa cell tumors are characteristically aggressive in advanced
stages, and the time to relapse is generally within 3 years of initial diagnosis.

Sertoli Cell Tumor

Sertoli cell tumors are rare. Mean age at presentation is 30 years but they can present at any
age. Sertoli cell tumors are typically unilateral, large tumors averaging 8 cm. They are
typically solid, lobulated, and yellow. Sertoli cell tumors may be arranged in a variety of
patterns, but most commonly in a tubular pattern, as hollow or solid tubules. The majority of
Sertoli cell tumors are well differentiated and are rarely malignant.
Evidence of estrogen production is observed in approximately two-thirds of cases.
Estrogen excess may cause isosexual precocious puberty in prepubertal girls, menstrual
disorders in women diagnosed during the reproductive decades, and postmenopausal
bleeding in older women.

Sex Cord Tumor with Annular Tubules

These tumors are rare, constituting less than 1% of sex cord–stromal tumors. Approximately
a third of sex cord tumor with annular tubules occur in association with Peutz-Jeghers
syndrome (PJS). The PJS-associated tumors are small (often not visible), solid, and yellow.
The non–PJS-associated neoplasms are typically greater than 3 cm and are solid and cystic or
mostly cystic and tan or yellow. The tumors are characterized microscopically by the
presence of simple and complex annular tubules. The tumor characteristically has a relatively
long doubling time, a propensity for lymphatic dissemination, and an aptness to remain
lateralized.
Abnormal vaginal bleeding is common causing menstrual irregularities if diagnosed
during the reproductive decades or postmenopausal bleeding. Almost all tumors associated
with PJS are benign. However, in the cases associated with PJS, up to 15% of patients may
also develop adenoma malignum of the cervix, a neoplasm that defies early diagnosis and is
associated with a relatively high mortality rate. Patients with sex cord tumor with annular
feature without PJS have a clinical malignancy rate of approximately 20%.

Fibroma
A fibroma is a benign stromal tumor composed of spindled to ovoid fibroblastic cells
producing collagen. They are the most common pure ovarian stromal tumor, accounting for
4% of all ovarian neoplasms. These hormonally inactive tumors are seldom bilateral and vary
in size. The ovarian capsule is usually smooth and intact and on cut section surfaces are
typically hard, chalky, and white or yellowish white. Areas of edema and cystic degeneration
may be present, especially when the tumor is large. Hemorrhage or necrosis can be present
usually secondary to torsion. Approximately 10% of fibromas are densely cellular with scant
collagen. In the presence of only mild nuclear atypia, these are known as cellular fibromas.
In women with ovarian fibromas that are larger than 10 cm, approximately 10% to 15%
of women will have ascites. Although rare, about 1% of women with fibromas may present
with Meigs syndrome. Meigs syndrome presents with a benign adnexal mass, ascites, and
pleural effusion that resolve after removal of the mass.

Fibrosarcoma
Compared to fibromas, fibrosarcomas are highly malignant neoplasms distinguished by their
greater cellular density and marked pleomorphism.

Thecoma
Thecomas are almost invariably clinically benign. They account for approximately 1% of
ovarian neoplasms, and the majority of patients are in their 6th and 7th decade at the time of
diagnosis. The majority of thecomas are unilateral. They are usually 5 to 10 cm in diameter,
often solid and yellow but occasionally focally white. Cystic degeneration, hemorrhage,
necrosis, and calcification are uncommon. Thecomas are composed of cells with appreciable
pale gray cytoplasm intersected by hyaline plaques.
Thecomas typically produce estrogen and are considered to be among the most
hormonally active of the sex cord–stromal tumors. The primary presenting signs and
symptoms are abnormal vaginal bleeding and/or pelvic mass. Up to 20% of patients with a
thecoma may present with a synchronous endometrial cancer secondary to excess estrogen.

Leydig Cell Tumor

Leydig cell tumors account for 20% of steroid cell tumors. They are a steroid cell tumor
composed of Leydig cells, as proven by the presence of cytoplasmic crystals of Reinke.
These tumors are usually small and solid. They range from red-brown to yellow to
occasionally black. Histologically, they are typically composed of a monotonous proliferation
of cells with abundant eosinophilic cytoplasm but occasionally may have pale, lipid-rich
cytoplasm.
The initial clinical manifestations are usually consistent with a hyperandrogenic state.
Overt signs of virilization are observed in over 80% of the patients.

Steroid Cell Tumor

Steroid cell tumors constitute only 0.1% of all ovarian neoplasms. Mean age at presentation
is 43 years old. They are defined by being a tumor composed entirely of cells resembling
steroid-secreting cells that lack Reinke crystals. Mean diameter is 8.4 cm. They are similar in
appearance to Leydig cell tumors but hemorrhage is more common.
Patients typically present with clinical signs and/or symptoms of androgen excess
ranging from heterosexual precocity in prepubertal girls to amenorrhea, hirsutism, and
virilization during the reproductive and postmenopausal ages, which prompt the majority of
patients to seek medical advice.

Sertoli-Leydig Tumor
Sertoli-Leydig tumors account for less than 0.2% of all ovarian tumors. As implied by their
designation, the tumors contain both Sertoli and Leydig cell elements. The average patient
age at diagnosis is approximately 25 years old. The majority of these tumors are unilateral.
The size ranges from 2 to 35 cm with a mean of 12 to 14 cm. Grossly, they are solid, often
yellow, and lobulated. Well-differentiated Sertoli-Leydig cell tumors are characterized by a
predominately tubular pattern. A nodular architecture is often conspicuous, with fibrous
bands intersecting lobules composed of small, round, hollow, or—less often—solid tubules,
separated by Leydig cells.
The most frequent complaints at the time of presentation are menstrual disorders,
virilization, and nonspecific symptoms resulting from abdominal mass. Frank virilization
occurs in 35% of the patients with Sertoli-Leydig cell tumors, and another 10% to 15% have
some clinical manifestations consistent with androgen excess. Only 2% to 3% of Sertoli-
Leydig cell tumors have demonstrable extraovarian spread at the time of detection. The more
favorable prognosis reflects the abrupt onset of androgenic manifestations that promote
prompt medical assessment.
Management
Key Points
Surgery remains the cornerstone of treatment, and surgical resection alone is
sufficient for sex cord–stromal tumors lacking malignant potential.
Fertility-sparing surgery procedures enable a large proportion of young women
with early-stage disease to preserve their reproductive potential.
Postoperative adjunctive therapy should be considered for patients with metastatic
disease and Sertoli-Leydig cell tumors with poor differentiation.

The definitive management of sex cord–stromal tumors is dependent on one or more of the
following: surgical stage, histologic subtype, patient’s age and desire for fertility
preservation, and various prognostic factors. Surgical resection alone is sufficient for sex
cord–stromal tumors lacking malignant potential. Postoperative adjunctive therapy should be
considered for patients with advanced disease.

Surgery
Surgery remains the cornerstone of treatment for patients with sex cord–stromal tumors.
Peritoneal washings should be collected for cytologic assessment and inspection of the entire
abdominal/pelvic cavity. Resection of the ovarian tumor constitutes sufficient therapy for the
essentially benign neoplasms (thecomas, fibromas, Leydig cell tumors, Sertoli cell tumors).
Sex cord tumors with annular tubules associated with PJS are also considered benign and can
be similarly managed, but it is imperative that the endocervix be evaluated and subsequently
monitored for the potential development of an adenoma malignum of the cervix.
In patients with a histologic confirmation of granulosa cell tumor, intermediate or poorly
differentiated Sertoli-Leydig cell tumor, sex cord–stromal tumor with annular tubules
independent of PJS, and steroid cell tumors NOS, surgical staging is required. This includes
multiple peritoneal biopsies, omentectomy, and resection of grossly suspicious pelvic or para-
aortic lymph nodes. There appears to be little benefit to performing routine
lymphadenectomy in the absence of suspicious lymph nodes. For older patients or those with
advanced-stage disease or bilateral ovarian involvement, abdominal hysterectomy and
bilateral salpingo-oophorectomy are usually indicated. However, in women who desire
fertility preservation, in the absence of extraovarian disease, conservation of the uterus and
contralateral ovary is reasonable. If the uterus is preserved, it is important to perform a
thorough curettage in all patients with estrogen-producing tumors to ensure there is no
endometrial hyperplasia or carcinoma.

Chemotherapy
For patients with stage II to IV disease, the recommended adjuvant treatment is platinum-
based chemotherapy. There are limited data to guide primary treatment, and acceptable
options include BEP (bleomycin, etoposide, cisplatin) or paclitaxel/carboplatin. In women
with stage I, high-risk disease (ruptured stage IC disease or poorly differentiated stage I),
treatment options include either observation or platinum-based chemotherapy, and treatment
decisions should be individualized.
The GOG 115 study reported the largest series of women with ovarian sex cord–stromal
tumors treated with four cycles of BEP. This chemotherapy combination was considered
beneficial, but longer follow-up is important given the prolonged natural history of these
tumors. More recently studies have shown taxanes to be active in sex cord–stromal tumors.
Retrospective data support the use of a platinum/taxane-based chemotherapy regimen with
cancer outcomes similar to combination BEP but with fewer side effects. There is an ongoing
GOG randomized phase II study to evaluate paclitaxel and carboplatin versus BEP in patients
with sex cord–stromal tumors (GOG 264). The common side effects of BEP are discussed
previously in this chapter. Additionally, antiangiogenesis drugs have also been reported to
have activity in the treatment of recurrent sex cord–stromal tumors of the ovary.
In women with recurrent disease, options for treatment include additional cytotoxic
therapy including taxanes, platinum/taxane therapy, and
vincristine/dactinomycin/cyclophosphamide (VAC). Hormonal therapy, including aromatase
inhibitors, leuprolide acetate (specifically for recurrent granulosa cell tumors), or tamoxifen,
can be used. Bevacizumab as a single agent was shown to be active in recurrent sex cord–
stromal tumors in GOG 251. Lastly, palliative localized radiation therapy may also play a
role in the management of recurrent disease.

Specific Considerations for Granulosa Cell Tumors

Women with granulosa cell tumors typically do well after primary surgical resection.
Considerable rationale exists for the utilization of hormone-based approaches to advanced or
recurrent granulosa cell tumors. In one study, 58% of granulosa cell tumors expressed steroid
hormone receptors. A variety of hormonal therapies have been utilized (including
medroxyprogesterone acetate, GnRH antagonists, and aromatase inhibitors). A systematic
review assessing response to hormone therapy in patients with advanced-stage or recurrent
granulosa cell tumors reported a 25% complete response and 45% partial response rate.

Surveillance
Surveillance visits are important for monitoring for disease recurrence in malignant sex cord–
stromal tumors. According to the NCCN guidelines, physical exam should be performed as
clinically indicated based on stage. For women with early-stage, low-risk disease, exams can
be done every 6 to 12 months and in women with high-risk disease exams can be done every
4 to 6 months. Additionally, serum tumor markers can also be checked if they were elevated
at diagnosis. Routine radiographic imaging should be reserved for patients with symptoms,
elevated biomarkers, or suspicious findings on physical exam.
Suggested Readings
Brown J, Brady WE, Schink J, et al. Bevacizumab shows activity in treating recurrent sex cord stromal ovarian tumors:
Results of a phase II trial of the Gynecologic Oncology Group. Cancer. 2014;120(3):344–351.
de Wit R, Stoter G, Kaye SB, et al. Importance of bleomycin in combination chemotherapy for good-prognosis testicular
nonseminoma: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary
Tract Cancer Cooperative Group. J Clin Oncol. 1997;15:1837–1843.
Einhorn LH, Brames MJ, Juliar B, et al. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell
tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol. 2007;25:513–516.
Einhorn L, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors.
N Engl J Med. 2007;357:340–348.
Gershenson DM, Miller AM, Champion VL, et al. Reproductive and sexual function after platinum-based chemotherapy in
long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group Study. J Clin Oncol.
2007;25(19):2792–2797.
Gershenson DM, Morris M, Cangir A, et al. Treatment of malignant germ cell tumors of the ovary with bleomycin,
etoposide, and cisplatin. J Clin Oncol. 1990;8:715–720.
Homesely HD, Bundy BN, Hurteau JA, et al. Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa
cell tumors and other stromal malignancies: A Gynecologic Oncology Group Study. Gynecol Oncol. 1999;72:131–137.
Horwich A, Sleijfer DT, Fossa SD, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin,
etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: A Multiinstitutional
Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol.
1997;15:1844–1852.
Marina NM, Cushing B, Giller R, et al. Complete surgical excision is effective treatment for children with immature
teratomas with or without malignant elements: A Pediatric Oncology Group/Children’s Cancer Group Intergroup Study.
J Clin Oncol. 1999;17:2137–2143.
Murugaesu N, Schmid P, Dancey G, et al. Malignant ovarian germ cell tumors: Identification of novel prognostic markers
and long-term outcome after multimodality treatment. J Clin Oncol. 2006;24:4862–4866.
Williams SD, Blessing JA, DiSaia PJ, et al. Second-look laparotomy in ovarian germ cell tumors: The Gynecologic
Oncology Group experience. Gynecol Oncol. 1994;52:287–291.
Williams S, Blessing JA, Liao SY, et al. Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and
bleomycin: A trial of the Gynecologic Oncology Group. J Clin Oncol. 1994;12:701–706.
 12 Molar Pregnancy and Gestational
Trophoblastic Neoplasms

Epidemiology
Key Points
Gestational trophoblastic disease (GTD) originates from the placental trophoblast.
GTD includes both benign and malignant pathologic processes.
The frequency of molar pregnancy in Asia is 7 to 10 times greater than in the
United States or Europe.
One in three pregnancies in women over the age of 50 is molar.
Gestational trophoblastic neoplasms most commonly follow a molar pregnancy
but may develop after any gestation.

Gestational trophoblastic disease (GTD) originates from the placental trophoblast, which is
derived from the outermost layer of the blastocyst called the trophectoderm. The trophoblast
is composed of three cell types—cytotrophoblast, syncytiotrophoblast, and intermediate
trophoblast (Fig. 12.1). All three types can proliferate to produce GTD lesions.
FIGURE 12.1 A schematic representation of trophoblastic subpopulations in the
placenta and fetal membranes. (Reprinted with permission from Shih IM,
Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like
lesions. Int J Gynecol Pathol. 2001;20(1):31–47.)

GTD comprises a diverse range of both benign and malignant pathologic processes including
the following:
Complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM)
Invasive mole
Choriocarcinoma
Placental site trophoblastic tumor (PSTT)
Epithelioid trophoblastic tumor (ETT)
Whereas both complete and PHMs are benign processes that generally resolve after uterine
evacuation, they have the potential to persist despite attempts at evacuation and become
invasive. Collectively, invasive mole, choriocarcinoma, PSTT, and ETT are malignant
processes and referred to as gestational trophoblastic neoplasia (GTN); these disease
processes have varying propensities for both local invasion and metastasis.
The reported incidence of GTN varies dramatically in different regions of the world. The
frequency of molar pregnancy in Asian countries is 7 to 10 times greater than the reported
incidence in North America or Europe. Whereas hydatidiform mole occurs in Taiwan in 1 per
125 pregnancies, the incidence of molar gestation in the United States is about 1 per 1,500
live births. Despite this geographic variation, the risk of hydatidiform moles has not been
linked to any specific ethnic or racial differences, cultural factors, or differences in reporting
of hospital-based and population-based data.
Increased risk for complete mole has been linked to diets deficient in vitamin A and
animal fat, as well as extremes of maternal age (teenage women and women over the age of
40). Women over 40 years of age have a 5- to 10-fold greater risk of CHM. In fact, one out of
three pregnancies in women over 50 years of age is molar, and the risk of developing GTN is
significantly increased as well. Interestingly, neither age nor diet appears to play a role in the
development of partial mole. However, the risk for both complete and partial molar
pregnancies is also increased in women with a history of prior spontaneous abortion and
infertility.
The risk of a second complete molar pregnancy is 1%, approximately 10- to 20-fold
higher than the risk of molar pregnancy in the general population. The risk of a third mole is
15% to 20%, regardless of a change in partner. Postmolar GTN develops in approximately
15% of patients after a complete molar evacuation and 1% to 5% following a partial molar
pregnancy. It is important to note that although GTN most commonly follow a molar
pregnancy, they may develop after any gestation including a normal delivery, ectopic
pregnancy, or miscarriage.
Molar Pregnancy
Key Points
Hydatidiform moles may be categorized as either complete or partial based upon
gross morphology, histopathology, and karyotype.
Most complete moles have a 46,XX karyotype with entirely paternal
chromosomes.
Most partial moles have a triploid karyotype.
Complete moles often present with bleeding and a markedly elevated human
chorionic gonadotropin (hCG).
Partial moles generally present as a missed or incomplete abortion.

Complete Hydatidiform Mole

A complete mole is characterized by trophoblastic hyperplasia with no formation of a fetus
secondary to excess paternal genetic material. The chorionic villi have generalized swelling
and diffuse trophoblastic hyperplasia, and the implantation site trophoblast has diffuse,
marked atypia. Complete moles have no identifiable embryonic or fetal tissues. Complete
moles usually have a 46,XX karyotype, with a 46,XY karyotype present in only 10% of
cases. The molar chromosomes are derived entirely from paternal (androgenetic) origin.
Most cases of 46,XX complete moles appear to arise from an anuclear ovum that has been
fertilized by a haploid (23X) sperm, which then duplicates its own chromosomes. In contrast,
complete moles that possess a 46,XY karyotype arise from the fertilization of an anuclear
ovum by two sperm. Therefore, chromosomes in the complete mole are entirely of paternal
origin, other than mitochondrial DNA, which is of maternal origin.
Vaginal bleeding is the most common presenting symptom in patients with a complete
mole, with onset between weeks 6 and 16 of the pregnancy. The finding of a markedly
elevated hCG value is suggestive of the diagnosis, with serum hCG levels of greater than
100,000 frequently detected. In the presence of significantly elevated hCG levels, symptoms
such as excessive uterine enlargement for gestational age, hyperemesis gravidarum,
thyrotoxicosis, and preeclampsia may be present, although they are less common now than in
previous years due to earlier detection.
The diagnosis of complete mole is made via ultrasonography, which is a sensitive and
reliable technique for diagnosis. Because of marked swelling of the chorionic villi, a
complete mole produces a characteristic vesicular sonographic pattern known as a
“snowstorm” appearance. When this sonographic pattern is identified in conjunction with an
elevated hCG value and absence of fetus, molar pregnancy is the most likely diagnosis.

Partial Hydatidiform Mole

In contrast to a complete mole, a partial mole contains fetal/embryonic tissue along with
trophoblastic hyperplasia. This is due to its triploid karyotype, which results from the
fertilization of an apparently normal ovum by two sperm. Partial moles are characterized by
the following pathologic features: (i) varying-sized chorionic villi with focal swelling and
focal trophoblastic hyperplasia; (ii) focal, mild atypia of implantation site trophoblast; (iii)
marked villous scalloping and prominent stromal trophoblastic inclusions; and (iv)
identifiable fetal or embryonic tissues (Fig. 12.2). If an identifiable fetus is present in a
partial mole, there are generally stigmata of triploidy including growth retardation and
multiple congenital anomalies. The presence of Ki-67, proliferating cell nuclear antigen, and
p53 is significantly higher in GTD compared with normal tissue and can differentiate
between GTD and spontaneous abortion. Florescence in situ hybridization can also be used to
differentiate between partial moles (triploid) and hydropic abortus (diploid).

FIGURE 12.2 Photomicrograph of a partial hydatidiform mole demonstrating

varying-sized chorionic villi with focal swelling and focal trophoblastic
hyperplasia.

Patients with a partial mole generally present with the signs and symptoms of a missed or
incomplete abortion. Partial moles do not present with markedly elevated hCG values as
often as patients with complete moles. Sonographic findings significantly associated with the
diagnosis of a partial mole include focal cystic changes in the placenta and enlarged
gestational sac. The final diagnosis of a partial mole is usually made after histologic review
of curettage specimens.

Surgical Evacuation
Key Points
Surgical evacuation is the treatment of choice for molar pregnancy.
The use of prophylactic chemotherapy at the time of surgery remains
controversial.
After molar evacuation, women should be followed with hCG levels until the
levels have been normal for at least 6 months.
Women should avoid pregnancy during the period of hormonal follow-up. Unless
contraindicated, oral contraceptive pills should be prescribed.

After diagnosis of a molar pregnancy, the patient should be carefully evaluated to identify the
potential presence of medical complications including preeclampsia, electrolyte imbalance,
hyperthyroidism, and anemia because any of these may complicate a planned surgical
evacuation.
Suction curettage is recommended in most patients because it is a highly effective
therapeutic option with minimal perioperative risks. Hysterectomy is an option for women
who no longer desire fertility and are at high a priori risk for development of GTN (age >40,
hCG > 100,000).
As the cervix is being dilated, the surgeon may encounter brisk uterine bleeding.
Therefore, all patients should be typed and crossed for blood products in advance. Shortly
after commencing suction evacuation, uterine bleeding is generally well controlled, and in
most cases, the uterus will rapidly regress in size. IV oxytocin should be started at the onset
of the procedure and continued postoperatively for several hours. When suction evacuation is
thought to be complete, a sharp curettage should be gently performed to remove any residual
chorionic tissue.
Patients who are Rh negative should receive Rh immune globulin at the time of
evacuation because Rh D factor is expressed on trophoblast.
Medical induction of labor or hysterotomy is not recommended because of increased risk
of maternal morbidity, including blood loss, incomplete evacuation requiring surgical
intervention, and the need for cesarean delivery in subsequent pregnancies.

Risk of Postmolar GTN

Postmolar GTN develops in approximately 15% of patients after a complete molar
evacuation and in 1% to 5% following a partial molar pregnancy. Factors that predispose to
postmolar tumors include signs of marked trophoblastic proliferation; these include hCG
level of more than 100,000 mIU/mL, uterine size greater than that at gestational age, and
theca lutein cysts more than 6 cm in diameter. Women who have at least one of these risk
factors have a 40% chance of developing postmolar GTN, compared with a 4% risk in those
with none of these factors. An increased risk of postmolar GTN has also been observed in
women over 40 years of age and in women with multiple molar pregnancies.

Role of Prophylactic Chemotherapy

The use of prophylactic chemotherapy at the time of molar evacuation remains controversial.
In one trial, chemoprophylaxis significantly reduced the incidence of postmolar tumor from
15%–20% to 3%–8%. However, routine administration of chemotherapy exposes all patients
to toxicity while benefiting only a relative few. Furthermore, all patients who are found to
have persistent postmolar GTN with serial hCG testing can be cured with chemotherapy. In
light of this, most institutions reserve the use of chemoprophylaxis to patients who are at
particularly high risk for GTN or are unable or unwilling to comply with serial hCG assays.

Hormonal Follow-Up
After molar evacuation, patients should be followed with weekly hCG values until they are
normal for 3 weeks and then with monthly values until they are normal for at least 6 months.
After achieving nondetectable hCG levels, the risk of relapse appears to be very low.
All patients should be encouraged to use effective contraception during the entire interval
of follow-up. Oral contraceptive pills are the contraception of choice because they also have
the added benefit of hormonal suppression of the hypothalamic–pituitary–ovarian axis. This
mitigates the risk of having an erroneously elevated hCG assay due to cross-reactivity with
endogenous LH. Intrauterine devices should not be inserted until the patient achieves normal
hCG levels because of the risk of uterine perforation, bleeding, and infection if residual
tumor is present. Patients who have an absolute contraindication to oral contraceptives
should be educated about the importance of barrier protection.

Pregnancy after Hydatidiform Mole

Women should be counseled to wait at least 6 months from time of hCG normalization to
become pregnant. For all future pregnancies, pathologic examination of the placenta and
other products of conception and measurement of hCG 6 weeks postpartum are
recommended. In general, patients with a prior history of a complete or partial mole can
anticipate normal reproduction in the future. However, they are at increased risk of
developing molar disease in later conceptions. After having one molar pregnancy, the risk of
subsequent molar pregnancy increases to 1% or 10- to 20-fold higher risk than the general
population. An ultrasound should be performed in the first trimester of any subsequent
pregnancy to confirm normal gestational development. An hCG measurement should also be
obtained 6 weeks after the completion of any future pregnancy to exclude occult
trophoblastic disease.
Gestational Trophoblastic Neoplasms
Key Points
The diagnosis of GTN should be considered in any woman in the reproductive
age group with unexplained systemic or pulmonary symptoms.
Metastases are very vascular and bleed easily. Biopsy should be avoided. If
deemed necessary, it should be approached with caution.
Staging differs from that of most common solid tumors and involves a “risk
score.”
GTN are highly curable with chemotherapy, even in the presence of widespread
metastases.

Clinical Presentation
The clinical presentation of GTN depends on the extent of disease and histopathology. There
are no signs or symptoms to differentiate between postmolar GTN and GTN arising after a
nonmolar pregnancy event. GTN should be considered in patients who present with
postpartum bleeding and uterine subinvolution. Uterine perforation and metastases can cause
abdominal pain, hemoptysis, or melena. Symptoms suggesting pulmonary involvement
include dyspnea, cough, and chest pain. Symptoms of brain metastases include headaches,
vomiting, seizures, headache, hemiparesis, speech disturbances, and visual disturbances.

Diagnosis and Evaluation

The components needed to diagnose postmolar GTN include at least one of the following: (i)
less than 10% decline in four measurements taken over 3 weeks on days 1, 7, 14, and 21; (ii)
hCG rise of greater than 10% increase in three measurements taken over 2 weeks on days 1,
7, and 14; (iii) hCG persistence for 6 months after molar evacuation; (iv) histopathologic
diagnosis of choriocarcinoma; or (v) presence of metastatic disease.
When the diagnosis of GTN is suspected or established, a metastatic workup is initiated.
All patients should undergo a complete history and physical examination; baseline hCG
level, hepatic, thyroid, and renal function tests; CBC and type and screen; and imaging
studies for organ sites at risk for metastasis. The most common metastatic sites are the lung
(80%), vagina (30%), brain (10%), and liver (10%). Radiologic studies should start with a
chest x-ray, and if abnormal, a CT or MRI of the chest should be performed followed by CT
scans of the abdomen, pelvis, and brain. If the chest x-ray is normal and there are no
symptoms of metastasis, other sites of metastasis are rarely present.
Because fragile vessels perfuse trophoblastic tumors, metastases are often hemorrhagic,
making biopsy of any suspected metastases high risk.

False-Positive hCG Tests

Although accurate measurements of hCG levels are invaluable in diagnosing and later
monitoring GTD, some patients may also have a false-positive elevation in serum hCG
measurement owing to the presence of circulating heterophilic antibody, called “phantom
hCG.” This is more of a historical problem as modern assays rarely demonstrate cross-
reactivity with heterophilic antibody. In order to avoid unnecessary treatment, the possibility
of false-positive hCG measurement should be assessed by sending both serum and urine
samples to a reference hCG laboratory. Patients with phantom hCG generally have no
measurable hCG in a parallel urine sample. In addition, serial dilution of the serum sample
would not show a decrease in the detected antibody.
Many hCG assays also have a degree of cross-reactivity with luteinizing hormone.
Following multiple courses of combination chemotherapy, ovarian steroidal function may be
damaged, particularly in patients in their late 30s and 40s. This may cause luteinizing
hormone levels to rise, and owing to cross-reactivity, the patient may be falsely thought to
have persistent low levels of hCG. Patients who receive combination chemotherapy should
therefore be placed on oral contraceptives to suppress luteinizing hormone levels and prevent
problems with cross-reactivity, even in the presence of ovarian failure.
hCG molecules in GTN are more degraded or heterogeneous in serum than they are in
normal pregnancy. Trophoblastic disease samples contain high proportions of free β-hCG,
nicked hCG, hyperglycosylated hCG, and β-core fragment. When diagnosing and monitoring
patients with GTN, it is therefore desirable to use an assay that detects not only intact hCG
but also all of its metabolites and fragments.

Pathologic Considerations
GTN includes invasive mole, choriocarcinoma, PSTT, and ETT (Table 12.1).
Invasive mole is a benign tumor that arises from myometrial invasion of a mole via
direct extension through tissue or venous channels.
Choriocarcinoma does not contain chorionic villi but is composed of sheets of both
anaplastic cytotrophoblast and syncytiotrophoblast. Direct invasion of the
myometrium and vasculature is common, resulting in metastasis to the lungs, brain,
liver, pelvis, vagina, kidney, intestines, and spleen.
PSTT is uncommon and is composed almost entirely of mononuclear intermediate
trophoblast. Therefore, it does not contain chorionic villi. It has a high risk of
lymphatic invasion. Measurement of serum hCG is not reliable in PSTT because
secretion occurs focally. Instead, human placental lactogen is secreted by PSTT and
should be drawn in any patient in whom this diagnosis is suspected.
ETT is also a rare malignant tumor that arises from neoplastic transformation of
chorion-type intermediate trophoblast. These lesions appear as nodules of
mononuclear intermediate trophoblast, surrounded by hyalinized EM within
extensive necrotic tissue and with preserved blood vessel structure.

Clinicopathologic Features of Gestational Trophoblastic

TABLE 12.1 Diseases
ECM, extracellular matrix; ETT, epithelioid trophoblastic tumor; hCG, human chorionic gonadotropin; IT, intermediate
trophoblast; PSTT, placental site trophoblastic tumor.
Source: Adapted from Lurain JR. Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and
diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol.
2010;203(6):531–539, with permission.

Staging System
In 2002, the International Federation of Gynecology and Obstetrics (FIGO) adopted a
combined anatomic staging and modified World Health Organization (WHO) risk factor
scoring system for GTN. The FIGO stage (Table 12.2) is designated by a Roman numeral
followed by the modified WHO score (Table 12.3) designated by an Arabic numeral,
separated by a colon. PSTT and ETT are classified separately. Treatment of GTN is based on
the classification into risk groups defined by the stage and scoring system.

TABLE 12.2 FIGO Anatomic Staging for Gestational Trophoblastic

Neoplasia

Source: Adapted from FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer of the vagina,
fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet. 2009;105:3–4, with permission.

TABLE 12.3 Prognostic Scoring System for Gestational Trophoblastic

Tumors
Note: Total score is obtained by adding the scores for each prognostic factor. Format for reporting stage and prognostic
score: list stage as represented by Roman numerals I–IV followed by the total prognostic score in Arabic numerals,
separated by a colon, for example, stage II: 4, stage IV: 9. FIGO, International Federation of Gynecology and Obstetrics;
GI, gastrointestinal; WHO, World Health Organization.
Source: Modified from FIGO staging for gestational trophoblastic neoplasia 2000. Int J Gynaecol Obstet. 2002;77:285–
287, with permission.

A prognostic score of 7 or greater is considered “high-risk” and identifies the subset of

patients in whom intensive combination chemotherapy is recommended. However, patients
with a risk score of 5 to 6 appear to have more treatment failures, and there is discussion that
these patients should be separated out into an “intermediate-risk” category. To date, no
changes have yet been made to the current staging system.
In general, patients with stage I disease have a low-risk score, and patients with stage IV
disease have a high-risk score. Therefore, the distinction between low-risk and high-risk
primarily applies to stages II and III.

Management
Key Points
Most patients will be cured with chemotherapy, regardless of stage.
Low-risk patients (prognostic score ≤6) should be treated with single-agent
chemotherapy.
High-risk patients (prognostic score ≥7) should receive combination
chemotherapy.
The use of etoposide appears to improve outcomes in high-risk patients but carries
 a risk of secondary malignancies, including leukemia.

Low-Risk Disease
Table 12.4 reviews the New England Trophoblastic Disease Center (NETDC) protocol for
the management of stage I and low-risk metastatic disease (stages II and III, score <7).

TABLE 12.4 Treatment Protocols for Low-Risk GTN

aPatients should be restaged if they experience progression on their prior line of treatment.
EMA-CO, etoposide, methotrexate, actinomycin D, Cytoxan, Oncovin.

For stage I disease, the selection of treatment is based mainly on the patient’s desire to
preserve fertility. If the patient no longer wishes to retain fertility, hysterectomy with
adjuvant single-agent chemotherapy is also an option as primary treatment. Chemotherapy
may be safely administered postoperatively without increasing the surgical complication rate.
For women with persistent GTD, a second curettage can be considered if their WHO risk
score is low (<5).
Single-agent chemotherapy is the preferred treatment in patients with low-risk disease.
Methotrexate (MTX) and actinomycin D (ACT D) are the two most commonly used single
agents in the treatment of GTN. Multiple series have shown impressive efficacy of a single-
agent regimen, with survival rates ranging from 77% to 100%. Chemotherapy is continued
until hCG levels become normal, and then one additional dose is administered.
Although multiple treatment protocols have been described, the 5-day MTX or ACT D
protocols or the 8-day MTX–folinic acid protocol are more effective than weekly MTX or
biweekly single-dose ACT D protocols. Side effects include stomatitis, mucositis, pleuritis,
conjunctivitis, and rash. ACT D is associated with alopecia, whereas MTX is not.
Patients categorized as having low-risk metastatic GTN (FIGO stage II or III, score <7)
can be optimally treated with primary single-agent chemotherapy (Table 12.4). Summarizing
the experience from four centers, single-agent chemotherapy induced complete remission in
128 (87%) of 147 patients with low-risk metastatic GTN, and all but 2 patients who were
resistant to single-agent chemotherapy later achieved remission with combination
chemotherapy.
HCG assays are obtained every 2 weeks at the start of each treatment cycle. If a good
response to initial therapy is followed by hCG plateau (<10% decrease over two treatment
cycles), a change to the alternate single-agent chemotherapy (i.e., if MTX was used, change
to ACT D) along with hysterectomy should be considered. If a good response to initial
therapy is followed by a rapid rise in hCG level (>10% change) or there is a poor response to
initial therapy, a change from single-agent to combination chemotherapy should be
implemented along with consideration of hysterectomy.
Approximately 50% of patients with high-risk metastatic disease will eventually require
some form of surgical intervention. Thoracotomy has a limited role in the management of
stage III GTN and should be performed only in the setting of serious diagnostic doubt or a
nidus of persistent viable tumor despite administration of chemotherapy. Fibrotic nodules
may persist indefinitely on the chest radiograph after complete hCG remission is achieved. If
a metastasis is persistent on radiography, but is of questionable viability, either a scan with a
radioisotope-labeled antibody to hCG or a PET scan may be useful.
Hysterectomy may be required in patients with metastatic GTN to control uterine
hemorrhage or sepsis or to debulk a large uterine tumor burden, which could contribute to
chemoresistance. Angiographic embolization can also be effective in the management of
profuse uterine bleeding in lieu of hysterectomy, especially in those patients who are
hemodynamically stable and wish to retain their fertility potential.

High-Risk Disease
Table 12.5 outlines the NETDC protocol for the management of high-risk GTN. Patients with
high-risk metastatic GTN (FIGO stage IV and stages II to III score ≥7) should be treated with
multiagent chemotherapy with or without adjuvant surgery or radiation therapy.

TABLE 12.5 Treatment Protocol for High-Risk GTN

EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; MTX, methotrexate; EP, etoposide,
cisplatin; EMA-EP, etoposide, methotrexate, actinomycin D, cisplatin; BEP, bleomycin, etoposide, cisplatin; ICE,
ifosfamide, carboplatin, etoposide; TP/TE, paclitaxel, cisplatin, etoposide.

EMA-CO, a combination regimen that includes etoposide, MTX, ACT D, cyclophosphamide,

and vincristine (Oncovin), is currently the preferred treatment for patients with high-risk
metastatic GTN. A 71% to 78% complete response rate and 85% to 94% long-term survival
rate have been achieved using EMA-CO. For patients with extensive metastatic disease with
prognostic score greater than 12 with significant risk for hemorrhage at metastatic sites,
induction therapy with etoposide and cisplatin may be considered.
In general, combination chemotherapy is administered every 2 weeks, or as frequently as
toxicity permits, until the patient attains three consecutive normal hCG values. After normal
hCG levels are achieved, two to three additional courses of chemotherapy are administered to
reduce the risk of relapse. Because of the curative potential of chemotherapy in GTN, every
effort should be made to continue therapy on schedule. Granulocyte growth factors may be
considered as secondary prophylaxis for neutropenic fever or neutropenia-associated
treatment delays.
For patients presenting with brain metastases, intensified dosing of MTX may be
considered. Alternatives include whole brain radiation or surgical excision with stereotactic
radiotherapy. Intrathecal MTX may also be used in some centers.
In the setting of an incomplete response to combination chemotherapy or relapsed
disease, etoposide/platinum-based regimens with bleomycin, ifosfamide, or paclitaxel should
be used (Table 12.5). Resection of chemotherapy-resistant disease may be considered, if
feasible.
PSTT and ETT
Nonmetastatic PSTT and ETT should generally be treated with primary hysterectomy
because these tumors respond less well to chemotherapy. For metastatic PSTT and ETT, the
optimal chemotherapy regimen remains to be defined. EMA-EP or a paclitaxel/cisplatin–
paclitaxel/etoposide doublet is the treatment of choice. The survival rate is approximately
100% for nonmetastatic disease and 50% to 60% for metastatic disease.

Follow-Up
All patients with GTN who enter remission should be followed with weekly hCG tests until
normal for 3 consecutive weeks and then monthly for 12 months as the risk of relapse is
about 3% in the first year after completing therapy. Patients should be encouraged to use
contraception during the entire interval of follow-up.

Quiescent GTD
Some women with a history of GTD or spontaneous abortion may have a consistent, low
level of hCG, typically less than 200 mIU/mL. This may persist for months despite no
evidence of active disease. It is believed that this “quiescent GTD” is due to individual, slow-
growing syncytiotrophoblastic cells with limited invasive potential. For women who present
with this clinical scenario, chemotherapy is not indicated. Close follow-up in this setting with
administration of combined oral contraceptive pills and routine hCG assays is usually the
management of choice. Consistent follow-up is crucial as almost one-quarter of these women
will go on to develop GTN, diagnosed by a concomitant increase in hCG and
hyperglycosylated hCG. Only once GTN is diagnosed should patients undergo active
treatment.

Recurrent GTN
Mutch and colleagues reported recurrences after initial remission in 2% of patients with
nonmetastatic GTN, 4% of patients with good prognosis metastatic GTN, and 13% of
patients with poor prognosis disease. Relapses developed within 3 and 18 months in 50% and
85% of patients, respectively. Most patients with stages I, II, and III GTN who develop
recurrence are subsequently cured.
For patients who recur after combination chemotherapy (usually EMA-CO), remission
may be possible with EMA-EP. Bower et al. reported that EMA-EP induced remission alone
or in conjunction with surgery in 16 (76%) of 21 patients who were resistant to EMA-CO.

Pregnancies after GTN

Patients with successfully treated GTN can also generally expect normal reproduction in the
future despite exposure to drugs that have ovarian toxicity and teratogenic potential. The
frequency of congenital malformations or obstetric complications does not appear to be
increased. Patients are advised to delay conception for 1 year after completing chemotherapy
to allow for uninterrupted hCG surveillance and to permit the elimination of mature ova that
may have been damaged by exposure to cytotoxic drugs. Occasionally, patients will become
pregnant before the recommended 12-month follow-up period has elapsed. When a patient’s
hCG level reelevates after completing chemotherapy, the use of ultrasound can help the
clinician to distinguish between an intercurrent pregnancy and disease recurrence.

Suggested Readings
Berkowitz RS, Cramer DW, Bernstein MR, et al. Risk factors for complete molar pregnancy from a case control study. Am J
Obstet Gynecol. 1985;152(8):1016–1020.
Brown J, Naumann RW, Seckl MJ, Schink J. 15 years of progress in gestational trophoblastic disease: Scoring,
standardization, and salvage. Gynecol Oncol. 2017;144(1):200–207.
Kashimura Y, Kashimura M, Sugimori H, et al. Prophylactic chemotherapy for hydatidiform mole: Five to 15 years of
follow up. Cancer. 1986;58(3):624–629.
Lurain JR. Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and diagnosis of gestational
trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol. 2010;203(6):531–539.
Lurain JR. Gestational trophoblastic disease II: Classification and management of gestational trophoblastic neoplasia. Am J
Obstet Gynecol. 2011;204(1):11–18.
 INDEX

A
Adenosarcoma. See Müllerian adenosarcoma
Adjuvant hysterectomy post–radiation therapy (AHPRT)
Adjuvant postoperative pelvic RT, cervical cancer
close or positive margins/parametrial involvement
intermediate risk, node negative
node-positive/high-risk patients
radiation therapy dose and technique
Adjuvant therapy
Adult granulosa cell tumors
Alopecia
American Joint Commission on Cancer (AJCC) staging system
vaginal cancer
vulvar cancer
ASC. See Atypical squamous cells (ASC)
Atypical squamous cells (ASC)
categories
cervical intraepithelial neoplasia
cannot exclude HSIL
undetermined significance
liquid-based cytology
B
Bethesda system terminology
Bleomycin
Bone marrow toxicity
Borderline ovarian tumors
management
mucinous tumor
risk factors
serous tumor
Brachytherapy. See also Radiation therapy
afterloading
cervical cancer
 dose specification points
dose–fractionation schemes
endometrial carcinoma
external beam irradiation
Fletcher system
interstitial applicators: LDR and HDR
intracavitary applicators: LDR and HDR
limitations
Manchester system
midline blocks
parametrial and nodal boosting
sequencing with external beam
dose rate
endometrial cancer
principles
radionuclides
BRCA mutations
breast cancer
endometrial cancer
ovarian cancer
genetic epidemiology
hereditary
lifetime risks
oral contraceptives
patient survival
premenopausal oophorectomy
tubal ligation
C
Cancer Therapy Evaluation Program (CTEP)
Capecitabine
Carboplatin
Carcinosarcoma
diagnostic evaluation
epidemiology
nodal involvement
pathology
risk factors
staging
therapy
 chemotherapy
radiation therapy
vaginal bleeding
Cervical cancer. See also Human papillomavirus (HPV)
brachytherapy applicators
dose–fractionation schemes
endometrial carcinoma
interstitial applicators: LDR and HDR
intracavitary applicators: LDR and HDR
midline blocks
parametrial and nodal boosting
sequencing with external beam
brachytherapy systems
dose specification points
Fletcher system
limitations
Manchester system
cervix, anatomy
chemotherapy
clinical disease
physical findings
symptoms and complaints
colposcopy
combined modality treatment
adjuvant chemotherapy
adjuvant hysterectomy post–radiation therapy
adjuvant postoperative pelvic RT
neoadjuvant chemotherapy
cytologic screening
accuracy
Bethesda system terminology
liquid-based cytology
epidemiology
external beam irradiation
human papillomavirus
hysterectomy
abdominal hysterectomy
class V
extended radical hysterectomy
extrafascial hysterectomy
 modified radical hysterectomy
radical abdominal hysterectomy
immunosuppression
management
bulky IB carcinoma
dysplasia/CIN
external irradiation alone
HPV vaccination
stage IA
stage IB to IIA (non-bulky)
stages IIB, IIIB, and IVA
natural history
preinvasive disease
spreading patterns
oral contraceptives
pathology
adenocarcinoma
malignant tumors
small cell carcinoma
squamous cell carcinoma
pelvic exenteration
preinvasive disease
colposcopy
conization biopsy
cytology
HPV testing
screening
prognostic factors
FIGO stage
histopathology
hypoxia and anemia
lymphovascular space invasion
nodal status
tumor size, volume, and margin status
radiation therapy
brachytherapy
external irradiation
irradiation dose
treatment time
recurrent carcinoma
 risk factors
HIV
human papillomavirus
smoking
staging
laboratory studies
pretreatment nodal staging
radiographic studies
TNM staging system
treatment complications
combined modality related
radiation therapy related
surgery related
thromboembolic complications
unusual clinical situations
invasive carcinoma
small-cell carcinomas
Cervical intraepithelial neoplasia (CIN)
colposcopy
cytologic abnormalities, management
atypical glandular cells
atypical squamous cells
biopsy-confirmed CIN 1
biopsy-confirmed CIN 2,3
high-grade squamous intraepithelial lesions
low-grade squamous intraepithelial lesions
HPV infection
immunosuppression
lesional grade
vs. VIN lesion
Chemoradiation. See Concurrent chemotherapy
Chemotherapy
advanced-stage corpus cancer
carcinosarcoma
cell cycle
cervical cancer
cytotoxic
combination therapy
single-agent trials
endometrial stromal tumors
 germ cell tumors
intraperitoneal
leiomyosarcomas
serous and clear cell histology
sex cord-stromal tumors
uterine carcinosarcomas
Choriocarcinoma
CIN. See Cervical intraepithelial neoplasia (CIN)
Cisplatin
Clear cell adenocarcinoma (CCA)
vaginal cancer
DES–associated CCA
incidence
stage I and II
vaginal adenosis
Clear cell carcinoma
histology
pathology
vaginal cancer
Clear cell histology
Common Terminology Criteria for Adverse Events (CTCAE)
Complete hydatidiform mole (CHM)
diagnosis, hCG values
epidemiology
Concurrent chemotherapy
Concurrent chemotherapy with radiation (chemoradiation)
Corpus uteri
epithelial tumors See (Endometrial carcinoma)
mesenchymal tumors See (Uterine sarcomas)
Cyclophosphamide
D
Dacarbazine
Dihydropyrimidine dehydrogenase (DPD)
Docetaxel
Doxorubicin
Dysgerminoma
chemotherapy
clinical features
lymphadenectomy at stage I
 serum tumor markers in
special considerations for
staining
surveillance
E
Embryonal carcinoma
Endocrine therapy
Endometrial carcinoma
adjuvant radiation therapy
advanced-stage disease
early-stage disease
brachytherapy
definitive radiation, inoperable disease
diagnostic evaluation
epidemiology and risk factors
tamoxifen
type I and type II
genetics
clinical care
genes associated
genetic epidemiology
lifetime risks
treatment
immunotherapy
incidence
nodal disease
pathology
cells
hyperplasia
molecular alterations
preinvasive disease
prevention and screening
prognostic factors
adnexal involvement
FIGO stage
grade
histologic cell types
lymphovascular space invasion
myometrial invasion
 pelvic and paraaortic lymph nodes
peritoneal cytology
radiation complications
intravaginal brachytherapy
pelvic radiation
whole abdomen radiation
recurrent disease, treatment
serous and clear cell histology
staging
stromal tumors
biologic therapy
chemotherapy
hormonal therapy
management algorithm
pathology
radiation therapy
surgical management
surgical procedure
algorithm
cytologic evaluation
hysterectomy
minimally invasive management
nodal dissection
nonsurgical management
postoperative surveillance
surgical recommendations
systemic therapy
cytotoxic chemotherapy
endocrine therapy
Endometrial stromal tumors
Endometrioid cancer
adenocarcinoma
Epithelial ovarian cancer. See also Endometrial carcinoma
chemotherapy
consolidation
front-line chemotherapy
interval debulking
intraperitoneal chemotherapy
maintenance therapy
platinum agents
 primary therapy prolongation
taxane/platinum therapy
taxanes/taxane schedules
cytoreductive surgery
intraperitoneal chemotherapy
carboplatin
cisplatin vs. intravenous route
clinical use
paclitaxel
Etoposide
Extended radical hysterectomy (ERH)
External beam radiotherapy
External irradiation
elective para-aortic lymph node irradiation
extended field radiation therapy
intensity-modulated external radiation therapy
standard fields (3d-conformal radiation)
therapeutic para-aortic lymph node irradiation
Extravasation necrosis
F
Fallopian tube cancer
pathology
treatment
Fibromas
Fibrosarcoma
FIGO staging system
endometrial carcinoma
gestational trophoblastic neoplasms
anatomic staging system
WHO prognostic scoring system
ovarian cancer
vaginal cancer, SCC
chemotherapy
external beam radiotherapy
high dose-rate intracavitary brachytherapy
interstitial brachytherapy
low dose-rate intracavitary brachytherapy
radiation therapy techniques and outcome
surgical approach and outcomes
Fletcher (M.D. Anderson) system
5-Fluorouracil
G
Gastrointestinal toxicity
Gemcitabine
Genetics
clinical practice
endometrial cancer
clinical care
genes associated
genetic epidemiology
lifetime risks
treatment
ovarian cancer
bilateral salpingo-oophorectomy
clinical outcome
epidemiology
genes associated
hormone replacement therapy
lifetime risks
oral contraceptives
pathology and surgical presentation
screening
treatment effects
tubal ligation
Genitourinary toxicity
Gestational trophoblastic neoplasms (GTN)
diagnostic evaluation
epidemiology
false-positive hCG tests
hCG test
management
high-risk disease
low-risk disease
molar pregnancy See (Molar pregnancy)
pathologic considerations
quiescent GTD/GTN
recurrent GTN
staging system
 subsequent pregnancies
GOG-92 eligibility criteria
Granulocyte colony-stimulating factors (G-CSF)
Granulosa cell tumors
adult
juvenile
special considerations for
H
Hemorrhagic cystitis
Hereditary nonpolyposis colorectal cancer (HNPCC)
High-grade squamous intraepithelial lesions (HSIL)
Host–tumor interactions
HPV. See Human papillomavirus (HPV)
Human chorionic gonadotropin (hCG)
gestational trophoblastic neoplasms
molar pregnancy
complete hydatidiform mole
hormonal follow-up
partial hydatidiform mole
prophylactic chemotherapy
Human papillomavirus (HPV)
infection
anogenital HPV
cervical intraepithelial neoplasia
classification
prevalence
transformation
transmission
virology
persistence
vaccination
5-Hydroxytryptamine (5-HT3) receptor antagonist
Hyperplasia
preinvasive disease
progression
treatment
Hypersensitivity
Hysterectomy
cervical cancer
 abdominal hysterectomy
class V
extended radical hysterectomy
extrafascial hysterectomy
modified radical hysterectomy
radical abdominal hysterectomy
endometrial hyperplasia
extrafascial
laparoscopic
limitation
tamoxifen
total vaginal
I
ICRU 38 system
Ifosfamide
Image-guided radiation therapy (IGRT)
Immature ovarian teratomas
age factor
grading system
neural tissue
three-tiered grading system
Intensity-modulated radiation therapy (IMRT)
International Federation of Gynecology and Obstetrics (FIGO). See FIGO staging system
Intraperitoneal chemotherapy
Intraperitoneal disease, surgical management of
Intravaginal brachytherapy
complications
pelvic radiation
surgical staging
Irinotecan
J
Juvenile granulosa cell tumor
L
Leiomyosarcomas
diagnosis
epidemiology
management algorithm
pathology
 risk factors
staging and prognosis
therapy
chemotherapy
radiation therapy
Leydig cell tumors
Linear accelerators
Liquid-based cytology (LBC)
Lower genital tract cancers. See Cervical cancer; Vaginal cancer; Vulvar cancer
Low-grade squamous intraepithelial lesions
Lymph node metastasis
Lymphovascular space invasion (LVSI)
Lynch syndrome
clinical care and treatment
epidemiology
genes associated
M
Maintenance therapy
Manchester system
Martinez Universal Perineal Interstitial Template (MUPIT)
Mesenchymal tumors. See Uterine sarcomas
Mitomycin
Mixed epithelial/stromal tumors. See Carcinosarcoma; Müllerian adenosarcoma
Mixed germ cell tumors
Modified radical hysterectomy (MRH)
Molar pregnancy
complete hydatidiform mole
epidemiology
hormonal therapy
partial hydatidiform mole
prophylactic chemotherapy
surgical evacuation
Mucinous tumors
adenocarcinoma
metastasis
pathology
types
Müllerian adenosarcoma
pathology
 risk factors
N
Neoadjuvant chemotherapy
Neurotoxicity
New England Trophoblastic Disease Center (NETDC) protocol
stage I GTN
stage IV GTN
Nodal dissection
Nonepithelial ovarian cancer
germ cell tumors
choriocarcinoma
clinical features
dysgerminomas
embryonal carcinoma
epidemiology
immature teratomas See (Immature ovarian teratomas)
management
mixed
pathology
teratomas
yolk sac tumors
sex cord–stromal tumors See (Sex cord–stromal tumors)
O
Ovarian cancer. See also Epithelial ovarian cancer
diagnosis
genetics
bilateral salpingo-oophorectomy
clinical outcome
epidemiology
genes associated
hormone replacement therapy
lifetime risks
oral contraceptives
pathology and surgical presentation
screening
treatment effects
tubal ligation
germ cell tumors See (Nonepithelial ovarian cancer)
 histology, implications
clear cell tumor
mucinous tumor
pathology
clear cell tumors
endometrioid tumors
fallopian tube carcinoma
mixed carcinoma
mucinous tumors
primary peritoneal serous carcinomatosis
serous tumors
preoperative evaluation
remission, follow-up patients
risk factors
age
BRCA2 mutation
dietary components
hormone replacement therapy
oral contraceptives
screening
second-look laparotomy/laparoscopy
surgical staging
FIGO staging system
prognostic factors
treatment
borderline tumors
early-stage fallopian tube carcinomas
early-stage ovarian cancer
persistent/ recurrent disease
Ovarian germ cell tumors
choriocarcinoma
clinical features
dysgerminomas
embryonal carcinoma
epidemiology
immature teratomas
management
chemotherapy
cytoreductive surgery
surgical treatment
 mixed
pathology
teratomas
WHO classification
yolk sac tumors
Oxaliplatin
P
Paclitaxel
gynecologic malignancies
Palmar-plantar erythrodysesthesia (PPE)
Partial hydatidiform mole (PHM)
chorionic villi
p53
pathologic features
sonographic findings
PEGylated liposomal doxorubicin
Pelvic radiation
Pemetrexed
Peripheral neuropathy
Peritoneal serous carcinomatosis
Platinum-resistant ovarian cancer
Preinvasive lesions
cervix See also ( Cervical cancer)
glandular lesions
human papillomavirus
immunosuppression
natural history
risk factors
smoking and oral contraceptives
squamous lesions
vagina
vulva
natural history
pathogenesis and diagnosis
vulva intraepithelial neoplasia
Q
Quiescent gestational trophoblastic neoplasms
R
Radiation therapy
bladder
irradiation doses
rectosigmoid-HDR
rectosigmoid-LDR
bone marrow
brachytherapy principles See also ( Brachytherapy)
carcinosarcoma
cervical cancer
brachytherapy
external irradiation
irradiation dose
treatment time
endometrial carcinoma
advanced-stage disease
early-stage disease
stromal tumors
endometrial stromal tumors
external beam irradiation See (External beam radiotherapy)
kidney
large intestine
leiomyosarcomas
liver
ovaries
pelvic bones
radiation physics
common forms
energy in transit
radioactive isotopes
SI units
radiation production
computerized dosimetry
linear accelerators
radiation-induced tissue effects
radiobiology
biologically equivalent dose
cell cycle
cell survival curve
dose–response relationship
interaction with tissue and cell death
 reassortment
reoxygenation
repair
repopulation
therapeutic ratio
tumor control probability
skin
small intestine
uterine sarcoma
vagina
vulvar cancer
acute complications
chemoirradiation
late complications
regional disease
surgico-pathologic features
technique
Recurrent gestational trophoblastic neoplasms
Response Evaluation Criteria in Solid Tumors (RECIST)
S
Scalp alopecia
Schiller-Duvall bodies
Sclerosing stromal tumors
Serous carcinoma
chemotherapy
pathology
targeted therapy
Sertoli-Leydig tumors
Sex cord tumor with annular tubules
Sex cord–stromal tumors
adult granulosa cell tumors
with annular tubules
clinical features
epidemiology
fibroma
fibrosarcoma
juvenile granulosa cell tumor
leydig cell tumors
management
 chemotherapy
specific considerations for granulosa cell tumors
surgical stage
mixed
pathology
sertoli cell tumors
Sertoli-Leydig tumor
steroid cell tumor
surveillance
thecoma
WHO classification of
Skin toxicity
Squamous cell carcinoma (SCC)
FIGO staging, vaginal cancer
chemotherapy
external beam radiotherapy
high dose-rate intracavitary brachytherapy
interstitial brachytherapy
low dose-rate intracavitary brachytherapy
radiation therapy techniques and outcome
surgical approach and outcomes
vaginal cancer
vulva
chemotherapy
histology
pathology
prognosis
Steroid cell tumors
Systemic therapy
absorption, distribution, and drug interactions
cell cycle
cytotoxic agents
drug intensity and density
host–tumor interactions
immunotherapy
intraperitoneal chemotherapy
metabolism
objectives
pharmacogenomics
pharmacologic principles of
 renal excretion
settings
targeted therapy
antiangiogenic therapy
DNA damage repair pathways
endocrine therapy
PARP inhibitors
toxicity management
antiangiogenic agents
bone marrow toxicity
Cancer Therapy Evaluation Program
cardiac toxicity
dose modification
gastrointestinal toxicity
genitourinary toxicity
hypersensitivity
immune mediated toxicities
myelosuppression, CTCAE grading
neurotoxicity
PARP inhibitors
scalp alopecia
skin toxicity
tumor
biology
gompertzian growth of
growth
tumor drug resistance
tumor response monitoring
T
Tamoxifen
Temozolomide
Teratomas
classification
immature teratomas
age factor
grading system
neural tissue
three-tiered grading system
mature cystic
Theca cell tumors
Thecoma
Topotecan
Tumor drug resistance, specific mechanisms of
U
Uridine diphospho-glucuronosyl-transferase 1A1 (UGT1A1)
Uterine cancer
Uterine carcinosarcomas, chemotherapy
Uterine sarcomas
carcinosarcoma See (Carcinosarcoma)
diagnosis
endometrial stromal tumors See (Endometrial carcinoma)
epidemiology
histologic distribution
leiomyosarcomas See (Leiomyosarcomas)
Müllerian adenosarcoma See (Müllerian adenosarcoma)
pathology
carcinosarcoma
endometrial stromal neoplasms
leiomyosarcoma
Müllerian adenosarcoma
smooth muscle tumors
prognosis
risk factors
staging
surgery
therapy
biologic therapy
hormonal therapy
radiation therapy
vaginal bleeding
WHO classification, of mesenchymal tumor
V
Vaginal cancer
anatomy, vagina
clear cell carcinoma
clinical presentation
diagnostic workup
 epidemiology and etiologic risk factors
clear cell adenocarcinoma
melanoma
sarcomas
squamous cell carcinoma
vaginal intraepithelial neoplasia
natural history
nonepithelial tumors
melanoma
sarcomas
palliative therapy
pathologic classification
clear cell adenocarcinoma
melanoma
mesenchymal tumors
squamous cell carcinoma
vaginal adenosis
preinvasive lesion
salvage therapy
American joint commission on cancer
computed tomography scan
FIGO staging system
positron emission tomography
vaginal intraepithelial neoplasia
staging See (Squamous cell carcinoma (SCC))
treatment
choice, prognosis
complications
Vaginal intraepithelial neoplasia (VAIN)
FIGO staging
squamous cell carcinoma
clinical presentation
epidemiology and etiologic risk factors
grading
Vinblastine
Vincristine
Vinorelbine
Vulvar cancer
chemotherapy
clinical presentation
diagnostic evaluation
epidemiology
histology
malignancies, management
adenocarcinoma
basal cell carcinomas
malignant melanoma
Paget disease
verrucous carcinomas
vulvar sarcomas
pathology
adenocarcinoma
malignant melanoma
metastatic tumors
Paget disease
squamous cell carcinomas
preinvasive lesion
natural history
vulvar intraepithelial neoplasia
prognostic factors
radiation therapy
acute complications
chemoirradiation
late complications
regional disease
surgico-pathologic features
technique
results of therapy
spreading patterns
staging systems
American joint committee
FIGO
surgical techniques
groin management
radical vulvectomy and bilateral lymphadenectomy
radical wide excision
recurrent disease
triple incision techniques
treatment
future aspects
 microinvasive tumors
node positive cancers
recurrent cancer
stage I and II cancers
stage III and IV cancers
vulva
anatomy
blood supply
lymphatic drainage
Vulvar intraepithelial neoplasia (VIN)
W
Whole abdomen radiation
Y
Yolk sac tumor