Cancer of the Uterus, 1st Edition

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 Cancer of the

UTERUS edited by

GEORGE C O U K O S , M.D ., P H .D
Assistant Professor, Department of Obstetrics and Gynecology
Division of Gynecologic Oncology
Hospital of the University of Pennsylvania
and
Director, Gynecologic Malignancy Research Program
Abramson Family Cancer Research Institute
Philadelphia, Pennsylvania, U.S.A.

ST EPH E N C . R U B I N , M.D .
Chief of the Division of Gynecologic Oncology
and
The Franklin Payne Professor of Obstetrics and Gynecology
University of Pennsylvania
Philadelphia, Pennsylvania, U.S.A.

M ARCEL D EKKER N EW Y ORK

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Although great care has been taken to provide accurate and current information,
neither the author(s) nor the publisher, nor anyone else associated with this
publication, shall be liable for any loss, damage, or liability directly or indirectly
caused or alleged to be caused by this book. The material contained herein is not
intended to provide specific advice or recommendations for any specific situation.

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ISBN: 0-8247-5415-8

Marcel Dekker, 270 Madison Avenue, New York, NY 10016

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Copyright © 2005 by Marcel Dekker. All Rights Reserved.

Neither this book nor any part may be reproduced or transmitted in any form or by
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PRINTED IN THE UNITED STATES OF AMERICA

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To Alessandra, Dimitri and Alex

G.C.

To Anne, Mike and Ellie

S.C.R.
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Preface

Cancers of the uterine corpus represent the most common gyne-

cologic malignancies, with an estimated yearly incidence of
40,000 new cases in the United States, which is among the
highest worldwide. A substantial increase in uterine cancers
may be seen in the near future as a result of the epidemic of obe-
sity and diabetes in the Western world. These statistics create
a pressing need to understand the molecular basis of uterine
cancers, improve their prevention and optimize their therapy.
We are extremely excited and humbled by the opportu-
nity to invite a group of distinguished scientists and clinicians
to discuss systematically the important basic, translational
and clinical advances made in this field and review the many
controversies still surrounding the management of uterine
cancers. Dr. Goodfellow and colleagues discuss the current
understanding of the molecular events underlying endome-
trial cancer and the identification of two distinct molecular
phenotypes of endometrial cancer. Dr. Bandera reviews the
role of the environmental and genetic factors modulating the
risk of uterine cancer and discusses the counseling of women
at risk for uterine cancer based on molecular epidemiology
data. The molecular characterization of uterine cancers has
unveiled novel targets for molecular therapy. Dr. Coukos and
colleagues discuss these in relation to current compounds
emerging from the industry pipeline. Understanding endome-
trial cancer and uterine sarcomas at the molecular level
forces a rethinking of their pathologic classification, as it will
be discussed by Drs. Kurman and colleagues and Dr.

v
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vi Preface

Kempson, respectively. Although the role of steroid hormones

in the pathogenesis of endometrial neoplasia is well estab-
lished, the significance of steroid receptors as prognostic or
disease classification biomarkers guiding therapy remains
controversial and is discussed by Dr. Leslie and colleagues.
Finally, Dr. Barakat reviews the effects of tamoxifen and
other selective estrogen receptor modulators on the uterus
and the management of patients receiving these drugs.
Important controversies remain in the clinical manage-
ment of uterine cancers. Dr. Cooper and colleagues review
the work up and management of abnormal uterine bleeding,
while Dr. Randall and Bowman argue the case of conservative
management of early endometrial cancer and its precursor
lesions. Dr. Chu reviews the prognostic factors affecting out-
come in patients with early stage endometrial cancer and dis-
cusses the rationale for surgical staging and different surgical
approaches to define the optimal surgical management of
early endometrial cancer. The public demand for minimally
invasive surgical approaches has created a pressing need to
define the value of laparoscopic approaches to uterine cancer
surgery. Dr. Walker and colleagues review these issues in
detail and present outcome evidence from recent studies.
Although high survival rates are attainable in early stage
endometrial cancer, approximately 20% of newly diagnosed
patients will have regional or distant spread of disease. Dr.
Bristow and colleagues discuss the rationale and outcomes rel-
evant to primary cytoreductive surgery for patients with stage
III and IV disease. In addition, they review the recent litera-
ture addressing the surgical management of uterine papillary
serous carcinoma, making the case that this histotype war-
rants aggressive management even in early stage.
One of the most controversial topics in the field of gyne-
cologic oncology is the postoperative management of patients
with endometrial cancer and uterine sarcomas. Dr. Grisby
reviews radiation therapy recommendations for patients who
are surgically staged and for those who have incomplete sur-
gical staging, based on the results of existing prospective ran-
domized studies or retrospective studies. He also describes
the use of irradiation alone for medically inoperable patients
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Preface vii

and provide the techniques for both external irradiation and

high dose rate brachytherapy.
The restored life expectancy of patients with early stage
uterine cancer poses important questions on the safety of
estrogen replacement therapy in this population. Dr.
Runowicz and colleagues review the risks and benefits of
estrogen replacement therapy in endometrial cancer sur-
vivors.
Recurrence is not uncommon in patients presenting ini-
tially with high risk early stage or advanced disease. There is
a recognized role for surgery in carefully selected patients. Dr.
Penalver and colleagues review the indications, technique,
outcome, and complications of exenterative surgery for recur-
rent endometrial cancer in previously irradiated patients,
and discuss palliative surgery approaches. In addition, Dr.
Lu and colleagues discuss the medical management of recur-
rent endometrial cancer, reviewing the evidence on
chemotherapy and hormonal therapy. Finally, Dr. Harris and
colleagues review the postoperative radiation treatment of
advanced and recurrent endometrial carcinoma, discuss pal-
liative radiation therapy, and discuss the role of high dose
radiation in this setting.
Uterine sarcomas represent a challenging group of
tumors owing to their rarity and heterogeneity. Dr. Sutton
and colleagues review the management of mixed müllerian
mesodermal tumors, endometrial stromal sarcoma and
leiomyosarcoma. They discuss the role of staging for appar-
ently early disease and that of debulking for advanced sarco-
mas. They also discuss adjuvant therapies for early stage
disease and the management of advanced disease.
We are grateful to all colleagues, friends, and authors for
their time, wisdom, and technical expertise. We hope that this
monograph will fill an important gap in the field of transla-
tional and clinical gynecologic oncology and provides the
reader useful information for the management of these
tumors.

George Coukos
Stephen C. Rubin
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Acknowledgments

The editors gratefully acknowledge Jerry and Lucille

Francesco and the St. Martha Foundation for their generous
support of our translational research program in gynecologic
cancers. We would also like to acknowledge Carmen Lord,
our editorial assistant, for her tireless efforts on behalf of this
text.

ix
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Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1. Molecular Genetics of Uterine Malignancies . . . . . 1

Paul J. Goodfellow
Introduction . . . . 1
Genetic and Environmental Factors . . . . 3
Summary . . . . 17
References . . . . 19

2. Endometrial Cancer in the Hereditary

Nonpolyposis Colorectal Cancer Syndrome . . . . 35
Christina A. Bandera
Introduction . . . . 35
Clinical and Pathologic Features of
HNPCC-Related Cancers . . . . 36
Genetic Basis of HNPCC . . . . 39
Identifying the HNPCC Syndrome . . . . 40
Counseling Regarding Screening and Prevention . . . . 44
Conclusion . . . . 47
References . . . . 48

3. Steroid Hormone Receptors in the Normal

Endometrium and in Endometrial Cancer . . . . . 53
Kimberly K. Leslie, Suzy Davies, Meenakshi Singh,
and Harriet O. Smith
Introduction: Endometrial Cancer and the Link to
Steroid Hormones and Steroid Receptors . . . . 53
xi
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xii Contents

Hormone Receptors in the Normal Endometrium . . . . 54

Hormonal Effects and Hormone Receptors in
Endometrial Cancer . . . . 56
Ligand Binding Assays and Immunohistochemistry
to Determine Steroid Receptor Status . . . . 58
Cross-Talk and Expression in Endometrial Glands
and Stroma . . . . 61
Genomic Effects of SRs . . . . 62
Receptor Isoforms . . . . 63
Non-Genomic Effects of Steroid Hormones Through
Membrane and Cytosolic Receptors . . . . 67
References . . . . 68

4. The Effects of Tamoxifen on

the Endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Richard R. Barakat
Introduction . . . . 79
Endometrial Carcinoma . . . . 80
Histology of Tamoxifen-Associated
Uterine Cancer . . . . 82
The Role of Screening . . . . 86
References . . . . 90

5. Pathology of Endometrial Hyperplasia

and Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Brigitte M. Ronnett, Jeffrey D. Seidman, Richard J. Zaino,
Lora Hedrick Ellenson, and Robert J. Kurman
Classification . . . . 93
Precursors of Endometrial Carcinoma . . . . 96
Endometrioid Carcinoma . . . . 108
Serous Carcinoma . . . . 124
Clear Cell Carcinoma . . . . 131
Mixed Types of Carcinoma . . . . 133
Malignant Mesodermal Mixed Tumor
(MMMT)/Carcinosarcoma . . . . 134
Undifferentiated Carcinoma . . . . 136
Molecular Genetics of Endometrial Cancer . . . . 136
References . . . . 142
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Contents xiii

6. Pathology of Uterine Sarcomas . . . . . . . . . . . . . . 149

Michael R. Hendrickson, Teri A. Longacre,
and Richard L. Kempson
Classification of Uterine Mesenchymal, Mixed
Mesenchymal, and Epithelial Neoplasms . . . . 149
Endometrial Stromal Sarcoma (ESS) . . . . 150
Uterine Neoplasms with Sex Cord-like Elements . . . . 158
Leiomyosarcoma . . . . 162
Undifferentiated ESS . . . . 170
Miscellaneous Pure Sarcomas . . . . 171
Mixed Müllerian Neoplasms . . . . 171
Adenosarcoma . . . . 172
Carcinosarcoma . . . . 176
References . . . . 180

7. Clinical Evaluation of Abnormal

Uterine Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Jay M. Cooper and Barbara J. Stegmann
Definition . . . . 195
History and Physical Examination . . . . 196
Etiology . . . . 197
Diagnosis . . . . 206
References . . . . 223

8. Conservative Treatment of Endometrial

Hyperplasia and Early Endometrial Cancer . . 229
Genesis Bowen and Thomas Randall
Introduction . . . . 229
Clinical Characteristics . . . . 230
Progestin Therapy . . . . 232
Anticipation of Treatment Failure . . . . 237
Treatment Regimens . . . . 240
References . . . . 242

9. The Surgical Management of Early

Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . 245
Christina S. Chu
Introduction . . . . 245
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xiv Contents

Staging . . . . 246
Prognostic Factors . . . . 248
Surgical Approaches . . . . 260
Conclusions . . . . 263
References . . . . 264

10. The Role of Laparoscopy in the Management

of Endometrial Cancer . . . . . . . . . . . . . . . . . . . . 275
Joan L. Walker and Robert S. Mannel
Demand for Laparoscopic Surgery . . . . 275
Surgical Techniques for Laparoscopic Treatment of
Endometrial Cancer . . . . 280
Current Treatment Algorithms Utilizing Laparoscopy
in EC . . . . 284
Surgical Candidate Selection . . . . 284
Training . . . . 288
Potential Benefits of Laparoscopic Surgery . . . . 289
Complications of Laparoscopy . . . . 291
References . . . . 297

11. The Role of Primary Surgery in Advanced

Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . 305
Robert E. Bristow and F.J. Montz
Introduction . . . . 305
Theoretical Basis for Cytoreductive Surgery . . . . 306
Stage III Endometrial Cancer . . . . 307
Stage IV Endometrial Cancer . . . . 312
Uterine Papillary Serous Carcinoma/
Cancer (UPSC) . . . . 317
Conclusion . . . . 320
References . . . . 320

12. Surgical Management of Recurrent

Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . 327
Nicholas Lambrou, Luis Mendez, and Manuel Penalver
Introduction . . . . 327
Pelvic Exenteration . . . . 329
Palliation . . . . 337
References . . . . 338