A Practical Approach to

Gynecologic Oncology
A Practical Approach to
Gynecologic Oncology

Editors
Partha Basu
Head, Department of Gynecologic Oncology
Chittaranjan National Cancer Institute
Kolkata

Anita Singh
Associate Professor
Department of Obstetrics and Gynecology
Patna Medical College Hospital
Patna

Alka Pandey
Consultant Obstetrician and Gynecologist
Uma Foundation
Patna

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A Practical Approach to Gynecologic Oncology

© 2005, Partha Basu, Anita Singh, Alka Pandey
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or
transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or
otherwise, without the prior written permission of the editors and the publisher.

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under Delhi jurisdiction only.

First Edition: 2005

ISBN 81-8061-494-8
Typeset at JPBMP typesetting unit
Printed at Gopsons Papers Ltd, A-14, Sector 60, Noida 201 301, India
 Contributors

Alka Pandey K Uma Devi

Consultant Obstetrician and Gynecologist Consultant Gynecologic Oncologist
Uma Foundation Department of Gynecologic Oncology
Patna Kidwai Memorial Institute of Oncology
Bangalore
Amita Maheshwari Kasturi Lal
Assistant Surgeon Medical Director
Gynecologic Oncology Services Pain and Palliation Clinic
Tata Memorial Hospital Jammu and Kashmir
Mumbai
Kumar T Bhowmik
Anila S Kapadia Consultant and Head
Consultant Gynecologic Oncologist Department of Radiotherapy
Former Head of Department of Safdarjung Hospital and
Gynecologic Oncology Vardhman Mahaveer Medical College
New Delhi
Gujarat Cancer Research Institute
Ahmedabad
Lakshmi Seshadri
Professor and Head, Obstetrics and Gynecology II
Anita Singh Christian Medical College
Associate Professor Vellore
Department of Obstetrics and Gynecology
Patna Medical College Hospital Mridul Gehlot
Patna Professor, Obstetrics and Gynecology
SMS Medical College, Jaipur
Bhagyalaxmi Nayak Unit Head, Gynecologic Oncology Unit
Lecturer
Division of Gynecologic Oncology Neerja Bhatla
Acharya Harihar Regional Cancer Center Additional Professor
Department of Obstetrics and Gynecology
Cuttack
All India Institute of Medical Sciences
New Delhi
Bhawna Malhotra Singh
Senior Research Scientist
Partha Basu
All India Institute of Medical Sciences
Head, Department of Gynecologic Oncology
New Delhi Chittaranjan National Cancer Institute
Kolkata
Hemant B Tongaonkar
Professor and Head Prabir Chaudhuri
Gynecologic Oncology Services Consultant Radiation Oncologist
Tata Memorial Hospital Chittaranjan National Cancer Institute
Mumbai Kolkata
vi A Practical Approach to Gynecologic Oncology

Pradip Das Shanti Roy

Senior Medical Officer Former Professor and Head
Department of Gynecologic Oncology Department of Obstetrics and Gynecology
Chittaranjan National Cancer Institute Patna Medical College Hospital
Kolkata Patna

Pravas M Patnaik Srabani Mittal

Professor and Head School for Cervical Cancer Prevention
Division of Radiation Oncology Chittaranjan National Cancer Institute
Acharya Harihar Regional Cancer Center Kolkata
Cuttack
Suparna Mazumdar
Prerna Garg Head
Department of Obstetrics and Gynecology Department of Radiology
Safdarjung Hospital and Vardhman Mahaveer Chittaranjan National Cancer Institute
Medical College Kolkata
New Delhi
Sushil K Giri
Rama Joshi Associate Professor and Head
Consultant Gynecologic Oncologist Division of Gynecologic Oncology
Indian Railway Cancer Institute Acharya Harihar Regional Cancer Center
Varanasi Cuttack

Ranajit Mandal Uttam D Bafna

Consultant Gynecologic Oncologist Associate Professor and Head
Chittaranjan National Cancer Institute Department of Gynecologic Oncology
Kolkata Kidwai Memorial Institute of Oncology
Bangalore
Satish Jain
Medical Director and Chief of Surgery and Veena Jain
Surgical Oncology Chief of Gynecologic Oncology
Mohan Dai Oswal Cancer Treatment and Mohan Dai Oswal Cancer Treatment and
Research Foundation Research Foundation
Ludhiana Ludhiana

Shakuntala Chhabra
Professor and Head
Department of Obstetrics and Gynecology
Mahatma Gandhi Institute of Medical Sciences
Sevagram, Wardha
 Preface

It is often said about textbooks that they fail to recommend treatment even ten
years after it’s been proved to be efficacious and continue to advocate therapy
upto ten years after it’s been shown to be useless! A Practical Approach to Gynecologic
Oncology has been conceived and designed to provide the updated knowledge
about the management of different gynecologic cancers based on the best available
evidence.
The knowledge and practice of gynecologic oncology is no longer limited to
treating women suffering from cancers of the genital tract. Very few subspecialties
deal with such wide-ranging issues, encompassing prevention and early detection
of cancers to palliative care. It is crucial that the medical students as well as the
practicing gynecologists and gynecologic oncologists keep themselves abreast of
the latest developments in the area.
The chapters in the book are written in a lucid, coherent manner, never losing
the focus on the practical management issues. Our principle is not to weigh down
the readers with volumes of information, but to make them understand the
principles based on which treatment decisions are made. All the authors contributing
to this manual have extensive experience in the subject and have made substantial
inputs in the area they have dealt with. It has been our endeavor to present as
much information and statistics relevant to Indian subcontinent. We are certain
the book will prove immensely beneficial to students and practicing gynecologists
in making informed decisions and offering better care to the women.
The editors would like to express sincere gratitude to the contributing authors
for their excellent effort without which the book would not have seen the light of
the day. We owe a special debt of gratitude to our publishers for organizing the
entire production of this book.
As a first effort the editors are likely to make mistakes or judgmental errors.
We will deeply appreciate any suggestions or criticisms to improve the quality of
this book.
Partha Basu
Anita Singh
Alka Pandey
 Contents

1. Principles of Surgical Management of Gynecological Cancers 1

Hemant B Tongaonkar, Amita Maheshwari
2. Principles of Chemotherapy in Gynecologic Cancers 23
Alka Pandey, Partha Basu
3. Principles of Radiation Therapy in Gynecologic Cancers 35
Sushil K Giri, Prabir Chaudhuri, Pravas M Patnaik, Bhagyalaxmi Nayak
4. Tumor Markers in Gynecologic Cancers 45
Veena Jain, Satish Jain
5. Vulvar Intraepithelial Neoplasia 56
Mridul Gehlot
6. Cancer of Vulva 64
Rama Joshi, Partha Basu
7. Cancer of Vagina 80
Uttam D Bafna
8. Cervical Intraepithelial Neoplasia 84
Ranajit Mandal, Srabani Mittal
9. Cancer of Uterine Cervix 100
Partha Basu, Pradip Das
10. Cancer of Endometrium 124
Anita Singh, Alka Pandey
11. Sarcoma of Uterus 137
Alka Pandey, Anita Singh
12. Gestational Trophoblastic Neoplasia 141
K Uma Devi
13. Epithelial Ovarian Cancer 153
Anila S Kapadia, K Uma Devi
14. Germ Cell and Stromal Tumors of Ovary 172
Neerja Bhatla, Bhawna Malhotra Singh
15. Cancer of Fallopian Tube 190
Alka Pandey
16. Pregnancy Associated with Gynecologic Cancers 194
Lakshmi Seshadri
x A Practical Approach to Gynecologic Oncology

17. Imaging in Gynecologic Cancers 198

Suparna Mazumdar
18. Genetic Factors in Gynecologic Cancers 206
Shakuntala Chhabra
19. Evidence-based Medicine in Gynecologic Oncology 215
Kumar T Bhowmik, Prerna Garg
20. Hormone Replacement Therapy in Patients Treated for 220
Gynecologic Malignancies
Kasturi Lal, K Uma Devi
21. Care of a Terminally-ill Gynecologic Cancer Patient 225
Shanti Roy
Index 233
 Principles of Surgical
1 Management of
Gynecological Cancers
• Hemant B Tongaonkar • Amita Maheshwari

INTRODUCTION have significant negative impact on the self

During the past 30 years there have been
several changes in the management of
gynecologic cancers, which has led to an
improved outcome. The management of most
gynecologic malignancies requires a multi-
disciplinary approach that includes surgery,
chemotherapy and radiotherapy. The role of
pathologists and radiologists is critical to
optimize outcomes. Over a period of time the
field of Gynecologic Oncology has established
its identity and now been recognized as a
separate subspecialty.
Quality of life has become a very important
factor in deciding the extent of surgical proce-
dures for patients affected by a variety of
cancers. In recent years, more attention has
focused on preserving organ function,
cosmesis and reproductive function. As the
survival rates have improved in recent years
with improved treatment of cancer, the
patients are more and more interested in
preserving their fertility potential.
The primary end point of cancer treatment
is cure. However, the radicality of cancer
treatment can lead to impaired sexual and
reproductive function, unacceptable cosmetic
appearance, altered body image, severe
impairment or loss of organ function and a
variety of long-term side effects which can
esteem and the psyche of the patient. This, in
addition to the psychological impact of
suffering from cancer, can lead to serious loss
of quality of life of these patients.
Surgery is the mainstay of the treatment
for gynecologic cancers and until recently was
the only treatment that could cure patients
with cancer. The surgical management of
gynecologic cancers has changed drastically
over the last several decades. Advances in
surgical techniques and a better under-
standing of the pathogenesis and patterns of
spread of individual cancers should allow
more appropriate selection of cases suitable
for radical procedures and to perform
successful resections for an increased number
of patients. The surgeons must be familiar
with the natural history of individual cancers
and with the principles and potentialities of
different treatment modalities. A thorough
knowledge of pelvic anatomy especially the
lymphatic drainage of genital tract is
mandatory to dictate the extent of the
procedure and will prevent inappropriate or
overenthusiastic attempts at an impossible
surgical cure, e.g. pelvic exenteration is
inappropriate in a patient with positive pelvic
nodes. On the other hand, surgeons must be
very careful not to undertreat the cancer,
which may lead to a tragic recurrence of an
2 A Practical Approach to Gynecologic Oncology
otherwise curable disease. The development
of alternate treatment strategies that can
control microscopic disease has prompted
surgeons to reassess the magnitude of surgery
necessary.
Surgical interventions are usually needed
at some point during the course of most
gynecologic cancers. Surgery is the mainstay
of treatment for endometrial and vulvar
cancers, while it has a role in the management
of precancerous, preinvasive and early
invasive cervical lesions. In ovarian cancer
the role of surgery is for diagnosis, staging and
treatment and its contribution is as significant
as that of chemotherapy.
With the emergence of effective alternative
nonsurgical treatment modalities in recent
years and with better understanding of the
disease, there has been a dramatic paradigm
shift in the radicality of surgery for many
cancers—leading to organ and function
preservation with a better quality of life,
without compromising survival. With better
understanding of the biological behavior and
mechanisms of spread, the surgery for cancers
at many sites has been downscaled without
affecting the end-results. In gynecologic
oncology too many new and innovative
techniques and approaches have been devised
aiming at preserving fertility potential.
Surgery has an important role for early
diagnosis and prevention, for diagnosis and
staging, as primary therapy, as a part of
multimodality treatment, as salvage therapy,
for metastatic disease, for reconstruction and
for palliation.
The principles of surgery for various
subsites in gynecological cancers are described
below.
CERVICAL CANCER
Traditionally, the role of surgery in cervical
cancer has been virtually limited to pre-
invasive and early invasive stages of this
cancer. In recent years, however, numerous
studies have been undertaken to define the
role of surgery in locally advanced cervical
cancer.
In patients with stage IA1 cervical squa-
mous carcinoma, simple hysterectomy or cone
biopsy with negative surgical margins are
virtually curative in all patients. Absence of
lymphovascular invasion in these patients
makes routine pelvic lymphadenectomy
unnecessary. Patients with stage IA2 lesions
can be treated with primary radical (class II
or III) hysterectomy with pelvic lympha-
denectomy or primary intracavitary radiation
therapy with equivalent results.
Retrospective data from case control and
nonrandomized studies showed that stage IB/
IIA cancer of the cervix can be treated with
either radical hysterectomy (class III) with
pelvic lymphadenectomy or radical radiation
therapy (external beam therapy plus
brachytherapy) with equally good results (70-
85% five-year survival). However, the
evidence of equivalence of these two modali-
ties was not forthcoming from randomized
clinical trials. In 1997, Landoni reported a
randomized trial of 343 patients with stage
IB/IIA carcinoma cervix, which showed that
these two modalities were equally effective
in controlling the disease judged by the
disease free and total survival as well as by
the relapse rates.1 The choice of treatment
should be influenced by selection criteria such
as age, ovarian preservation, comorbid
conditions, potential late side effects, the
patient’s wish as well as the availability of
expertise in radical surgery or radiation
therapy. This trial also conclusively showed
that surgery has a survival advantage
over radiation therapy for patients with
adenocarcinoma cervix.
There are several advantages of surgery in
the management of early stage disease.
Surgery removes the whole disease and allows
 Principles of Surgical Management of Gynecological Cancers 3
histopathological examination of the primary
as well as the lymph nodes for prognostication
and to define presence of risk factors for
relapse so that adjuvant treatment can be
administered and tailored as per the perceived
risk to these patients. It is the only modality
which can accurately assess the presence of
metastases in the lymph nodes. Ovaries can
be preserved in young premenopausal women
whereas the premature loss of ovarian
function is unfortunate sequelae of radiation
therapy. Vagina is left more pliable after
surgery with post-therapy sexual function
much better than that after radiation therapy.
Treatment period is short, surgical complica-
tions are minimal in experienced hands and
are usually early and easily correctable.
Excellent survival and quality of life are
reported after surgical treatment of early stage
cervical cancer.
Since Meigs2 first described the procedure
of radical hysterectomy, a number of technical
modifications have been devised with the aim
of reduction of morbidity without compro-
mising radicality of the procedure. One of the
major morbidities of radical hysterectomy is
the bladder dysfunction secondary to damage
to the autonomic nerve pathways, which is
reported in up to 10 to 30 percent of patients
undergoing this procedure, depending on the
radicality of the surgery. With the aim of
reducing this morbidity, Yabuki et al (1996)
pioneered a nerve sparing radical hystere-
ctomy technique wherein they performed an
anatomically defined nerve sparing resection
without compromising the radicality.3 Their
work has been followed by similar efforts by
other authors. Hoeckel et al (1998) and
Possover et al (2000) have confirmed the
value of nerve sparing techniques, reporting
a significant reduction in bladder function
impairment. 4,5 Recently, Raspaglieri et al
reported their experience in a small number
of patients and concluded that it was possible
to reduce the morbidity of radical hystere-
ctomy consistently by preserving the
hypogastric autonomous nerves.6 However,
further prospective studies looking at
oncological end points as well as morbidity
assessment are necessary.
Para-aortic lymph node sampling is
performed in selected cases (stage IB2-IIA).
Approximately 5 to 10 percent of patients with
stage IB disease have para-aortic lymph node
metastases. Metastasis to these nodes
is considered a contraindication to radical
hysterectomy and these patients are best
treated with extended-field radiotherapy with
concomitant platinum based chemotherapy.
Over a period of time, several other surgical
procedures have evolved for the treatment of
early stage cervical cancer. These include
laparoscopic radical hysterectomy,7 radical
vaginal hysterectomy (Schauta-Amereich),8
and fertility-sparing radical trachelectomy.
It is estimated that 10 to 15 percent of
cervical cancer cases are presently diagnosed
in young women in the childbearing years,
in whom removal of uterus will deprive them
of an opportunity of having babies.9 Thus, the
radical trachelectomy procedure, which
allows preservation of the body of the uterus,
thereby preserving reproductive function
seems to be a significant advance in the
management of these young women with
cervical cancer. This procedure was first
described by Dargent in 199410 and the initial
skepticism about it is slowly being replaced
by acceptance and optimism. Trachelectomy
is usually preceded by a laparoscopic pelvic
node dissection and on confirmation of
absence of metastatic involvement of lymph
nodes, trachelectomy is proceeded with. It is
essential to confirm adequate disease free
margins after trachelectomy by frozen section
examination. If adequate margins cannot be
obtained, a complete radical vaginal or
abdominal hysterectomy is required. The
4 A Practical Approach to Gynecologic Oncology
recently published results of radical
trachelectomy from four centres show that
the majority of the patients undergoing this
procedure had stage IB1 or less squamous
carcinoma, without vascular space invasion
and less than two cm in size.11-14 The overall
recurrence rate in the four published series is
3.1 percent (4 of 130 patients), which is similar
to the one reported after radical hystere-
ctomy. The obstetric outcome in the reported
data is also encouraging. Most women were
delivered by cesarian section. All authors have
reported increased incidence of premature
labour, probably due to chorioamnionitis
consequent to inadequate mucus plug. To
overcome this problem, Dargent has been
performing the Saling procedure at 14 weeks,
wherein the external os is covered with vaginal
mucosa to prevent ascending infection.
Although the oncological and obstetric
outcome appears to be favorable and the
morbidity of the procedure is low, the number
of patients who have undergone this pro-
cedure is still small. This procedure needs to
be tested in a prospective randomized trial
with a larger number of patients in order to
define its exact role.
The management of stage IB2 cervical
cancer has been a matter of great debate. The
survival of these patients is relatively poor
(approximately 60% five-year survival)
with the standard treatment of radical surgery
or radiation therapy, consequent upon the
higher incidence of pelvic lymph node
metastases and potential systemic spread.
Keys et al (1998) observed benefit of addition
of extrafascial hysterectomy to radiation
therapy and morbidity is increased with the
combination of the two modalities. 15
Recently published randomized trials have
demonstrated that addition of concurrent
cisplatin chemotherapy to radiation therapy
improves survival compared to radiation
therapy alone. On the other hand, Sardi et al
reported a statistically significant improve-
ment in survival using neoadjuvant chemo-
therapy prior to radical surgery versus radical
surgery alone in these patients (80% vs 61%),
increased resectability and lower pelvic
relapses. 16 A meta-analysis of all trials
comparing neoadjuvant chemotherapy plus
surgery versus radiation therapy showed a
superior survival outcome in the former
group.17 However, there has never been a
direct comparison of concurrent chemo-
radiation therapy and neoadjuvant chemo-
therapy followed by surgery. Two such
trials—one conducted by EORTC and one at
the Tata Memorial Hospital, Mumbai are
currently underway.
Selected patients of stage IV, with no
parametrial invasion may be treated with
primary exenterative surgery, the extent of
which (anterior, posterior or total) would
depend on the extent of the lesion. The
management of recurrent and metastatic
cervical cancer is quite well-defined. Patients
with predominantly central recurrence after
radical radiation therapy with no spread to
the pelvic side wall, no extrapelvic disease
and good performance status should be
offered the option of salvage surgery. The
extent of surgery may vary from extrafascial
hysterectomy to radical hysterectomy to
exenterative surgery, depending on the extent
of the disease and the degree of fibrosis and
devascularization. The actual extent of
resection, i.e. total/anterior/posterior
depends on the extent and location of the
disease. Anterior exenteration is done in
patients who have disease limited to the
vesicovaginal space, whereas tumors in the
rectovaginal space can be treated with
posterior exenteration. More extensive tumors
need total exenteration. Any tumor that is
2 to 3 cm above the levator muscle can be
managed by supralevator exenteration while
more advanced disease may require
 Principles of Surgical Management of Gynecological Cancers 5
infralevator exenteration with pelvic floor
reconstruction. The aim of exenterative
surgery should always be resection of the
tumor with adequate tumor-free margins,
which is confirmed by intraoperative frozen
section. With improved radiation therapy
techniques, the number of patients with
isolated central recurrence is slowly dimi-
nishing, but there remains a small group of
such patients for whom this procedure offers
the only chance of cure. Careful selection of
patients is essential for good survival outcome
as well as for minimal morbidity. Counseling
of the patient including psychosexual
counseling and stoma clinic advice prior to
exenterative surgery is mandatory. This
surgery should be undertaken only in centres
with facilities and expertise for this surgery
available and only by teams who have the
experience and commitment to look after the
long-term rehabilitation of these patients.
Excellent survivals have been reported from
various centers in recent years. 18-20 The
mortality rates, which were overwhelmingly
high once upon a time, have now reduced
considerably due to improved surgical
techniques, decreased operating time and
blood loss, improved anastomotic techniques,
blood component therapy, parenteral nutri-
tion, better control of infection and excellent
intensive care facilities. The quality of life of
the patients who have undergone total pelvic
exenteration can be improved by doing a
stapled low rectal anastomosis and construct-
ing a continent urinary reservoir in suitable
patients. Sexual rehabilitation with vaginal
reconstruction has assumed a very important
role since many patients are sexually active
prior to surgery and every effort should be
made to maintain sexual function following
exenteration. With this, exenterative pro-
cedures have gained wide acceptance in the
minds of both patients and doctors. No patient
who qualifies for this surgery should be
denied the benefit of it.
EPITHELIAL OVARIAN CANCER
Surgery remains the mainstay of the multi-
disciplinary approach to the management of
ovarian cancer and is the hallmark method of
establishing the diagnosis, staging the disease
and therapeutic removal of the disease. The
appropriate surgical management of ovarian
cancer requires not only the technical ability
needed to perform the surgical procedures but
a comprehensive understanding of the
biological behavior and natural history of the
disease.
The most important preoperative diagno-
stic investigations for ovarian cancer are
peritoneal fluid cytology in the presence of
ascites and imaging studies. Ultrasonography
and/or CT scan of the abdomen and pelvis
are the usual imaging modalities used to
document an ovarian mass and its extent of
spread. However, these modalities are only
suggestive of ovarian cancer and do not give
us histological diagnosis. Fine-needle
aspiration cytology of the mass is strictly
contraindicated in patients with early stage
disease due to the risk of disseminating the
cancer cells throughout the peritoneal cavity
but may be used for establishing a diagnosis
in patients in whom the disease is already
disseminated. In early stage ovarian cancer,
exploratory laparotomy remains the only
method of establishing the histological diagno-
sis.
The standard of care for early stage
epithelial ovarian cancer is primary surgery
followed by adjuvant chemotherapy in the
high-risk group of patients. The primary
surgery should include total abdominal
hysterectomy, bilateral salpingo-oophore-
ctomy, omentectomy, pelvic and para-aortic
lymphadenectomy and comprehensive
6 A Practical Approach to Gynecologic Oncology
surgical maneuvers. Surgical staging must
evaluate sites of potential spread of ovarian
cancer, as accurate staging is critical to plan
optimum treatment and predict survival.
Ovarian cancer is a surgicopathologically
staged disease 21 and failure to stage the
disease properly at primary laparotomy may
result in understaging in nearly 30 percent of
patients. It is a grievous error to assume that
negative inspection and palpation indicate the
absence of disease spread in ovarian cancer.
In nearly 50 percent patients with diaphra-
gmatic metastases, 45 percent with omental
metastases and 33 percent with lymph node
metastases, the metastases are not clinically
evident by inspection or palpation and hence
biopsy of these potential tumor-bearing areas
is advocated. Pelvic lymphadenectomy and
para-aortic lymph node sampling is an
integral part of surgical staging for early stage
ovarian cancer. Although the true incidence
of lymph node metastasis in early stage
ovarian cancer is unknown, it has been
reported to the tune of 18 to 25 percent
depending on the extent of lymphadenectomy
and extent of sampling. It is important to do
a systematic lymphadenectomy, since
microscopic metastases have been reported
to be present in 33 percent patients with
palpably normal nodes.22
Approximately 3 to 15 percent of patients
with epithelial ovarian cancer are younger
than 40 years at the time of diagnosis and
nearly eight percent of all stage I epithelial
ovarian cancers occur in women less than
35 years of age, in whom fertility preservation
may be an important issue. The standard
treatment for early stage ovarian cancer
includes total abdominal hysterectomy with
bilateral salpingo-oophorectomy. Conserva-
tive surgery may be offered to selected
patients with stage IA grade I-II cancers
wishing to preserve their fertility if adequate
comprehensive surgical staging has been
performed in them. Frozen section facility is
essential to rule out advanced disease
intraoperatively. The criteria for conservative
surgery in patients with early stage ovarian
cancer have been defined by McHale and
DiSaia (1999). If the disease is truly limited to
one ovary, prognosis is excellent and
conservative surgery may be advised in
suitable patients.23 Even in stage IB patients,
uterus may be preserved if the option of
surrogacy is considered for future. The risk of
occult malignancy in contralateral ovary is
quite low, in the range of 5 to 7 percent.24
Routine biopsy of apparently normal looking
ovary is not recommended since microscopic
foci of cancer can still be missed and it can
lead to iatrogenic adhesions and infertility.23
Recent studies have shown that the recurrence
rate for patients undergoing conservative
surgery is not different from those undergoing
radical surgery.24,25 Since both these studies
included patients with stage IC disease, it is
proposed that the indications of conservative
surgery may be expanded to include patients
with stage IC disease. However, this is highly
controversial, and the long-term results need
to be assessed in a larger number of patients
before such recommendation can be made.
Conservative surgery has no role in patients
with advanced epithelial ovarian cancer.
Successful obstetric outcome has been
reported after conservative surgery. However,
the chance of successful pregnancy is reduced
after adjuvant chemotherapy due to
premature ovarian failure in some women.
There is no consensus on the need for removal
of the other ovary after childbearing, but it
appears to be preferable.24-25 It is essential to
counsel the prospective candidates for
conservative surgery regarding all these
factors preoperatively. With more widespread
use of laparoscopic techniques in the surgical
treatment of ovarian cancer it remains to be
seen whether the fertility rate will improve
 Principles of Surgical Management of Gynecological Cancers 7
due to lesser surgical tissue trauma and
reduced adhesions.
Spillage during surgery or intraoperative
cyst rupture is considered to be an adverse
prognostic factor. However, the evidence for
or against it was inconclusive and ambiguous.
Recent evidence has indicated that spillage
during surgery for stage I epithelial ovarian
cancer is harmful and should be avoided at
all costs.26 In this study, rupture before surgery
(hazard ratio 2.65) and rupture during surgery
(hazard ratio 1.64) were found to be impo-
rtant independent prognostic parameters
affecting outcome. Besides, with tumor
spillage, many patients may be subjected to
adjuvant therapy that otherwise would not
have been administered. This information is
extremely important in today’s era of
laparoscopic surgery where spillage during
laparoscopic surgery should be strongly
condemned.
Primary cytoreductive surgery followed by
adjuvant chemotherapy is the standard of care
in advanced epithelial ovarian cancer.
Complete removal of all visible and palpable
tumor is the aim of cytoreductive surgery.
Maximal tumor cytoreduction has been
shown to confer both theoretical and clinical
benefit even when all tumor cannot be
removed. Although there are no randomized
trials designed directly to assess the impact
of cytoreductive surgery, the evidence for the
benefits of cytoreductive surgery are in
retrospective studies are so strong that it is
accepted as the standard of care. It was
Munnell in 1968 that introduced the concept
of “Maximal surgical effort” but it was not
until 1975, when the residual tumor after
cytoreductive surgery was quantified and
correlated with survival. 27 Since then,
improved survival with more aggressive
cytoreduction has been a consistent and
reproducible observation. Other authors have
correlated the total volume of residual disease
and the number of residual lesions to
survival.28-31 The definition of optimal level of
cytoreduction has been based on the diameter
of the residual disease. Various cut off values
from 0 to 3 cm have been used to divide the
optimal and suboptimal groups for
prognostication. The initial Gynecologic
Oncology Group (GOG) studies showed that
surgical cytoreduction to 2 cm or less residual
disease resulted in a significant survival
benefit but all residual diameters greater than
2 cm resulted in equivalent survival rates and
that if the cytoreduction did not achieve a
residual of 2 cm or less, aggressive cytore-
duction was a futile exercise.32 Subsequent
studies showed that even within the subgroup
of patients with a residual disease of 2 cm or
less, those with no visible disease had a better
survival, forcing GOG to make the reco-
mmendation that residual disease diameter of
1 cm or less probably represented optimal
cytoreduction.32,33 The present understanding
of the disease defines optimal cytoreduction
as “no visible or palpable disease at the end
of cytoreductive surgery.” The probability of
presence of disease at the second look surgery
has also been found to correlate strongly with
the amount of residual disease at the end of
the primary cytoreductive surgery in a large
pooled data of 1797 patients from 25 series.34
Hoskins et al in their GOG study have further
tried to clarify the role of primary cyto-
reductive surgery. They demonstrated that
patients who had small volume disease at the
beginning of cytoreduction had a better
survival than those who were cytoreduced to
small volume disease.31 Although this study
did not show the lack of effectiveness of the
cytoreductive surgery, it showed that other
factors like tumor biology were equally
important. However, after a review of all
available data and evidence, the National
Institute of Health Management Development
Conference on Ovarian Cancer (1994)
8 A Practical Approach to Gynecologic Oncology
recommended “aggressive efforts at maximal
cytoreduction are important since minimal
residual tumor is associated with improved
survival”.35
One of the most difficult judgments in the
management of advanced epithelial ovarian
cancer is to determine the degree of
aggressiveness of cytoreduction. The factors
that need to be taken into consideration while
making this decision are location and extent
of the disease, the general condition of the
patient, the skill and knowledge of the
surgeon and the potential benefits of adjuvant
therapy. Bowel and urinary tract resections,
splenectomy, partial hepatectomy, aggressive
para-aortic and pelvic lymphadenectomy
appear to be justified only if they allow the
surgeon to reach an optimal cytoreductive
residual status and must be balanced against
the perioperative morbidity of the procedure.
It makes little sense to do aggressive organ
resections if there is bulk disease elsewhere
that is unresectable. The role and extent of
retroperitoneal (pelvic and para-aortic)
lymphadenectomy in patients with advanced
epithelial ovarian cancer has been a matter of
great debate. It was not clear whether the
survival benefit seen in some of the
retrospective studies was due to selection of
patients with better tumor biology. An early
report of a recent randomized trial comparing
systematic pelvic and para-aortic lympha-
denectomy versus resection of bulky nodes
only, in optimally cytoreduced stage III/IV
patients showed a statistically significant
improvement in survival in the former
group.36 In view of this, it is recommended
that systematic pelvic and para-aortic
lymphadenectomy should be performed as a
part of optimal cytoreduction.
Numerous trials and meta-analyses have
tried to look at the actual survival benefit
accrued with primary cytoreductive surgery,
with conflicting results.28, 30, 37-41 These studies
indicate that the cytoreductive surgery has
only a small impact on survival in patients
with advanced ovarian cancer. Despite the
lack of prospective randomized trials that
clearly prove the efficacy of the procedure,
there seems little doubt that patients who
undergo optimal cytoreduction have higher
complete and overall responses to chemo-
therapy, a greater likelihood of a negative
second look evaluation and improved
survival rates. Cytoreductive surgery
influences prognosis and although it is not
the only factor affecting patients’ chances of
cure, it is a very important part of therapy. It
is true that tumor biology does play an
important role in the ultimate outcome—the
survival benefit for patients with small
residual disease probably reflects the tumor
biology and suggests that less invasive
tumors may be more chemotherapy sensitive
than those tumors in which optimal
cytoreduction was not possible. However, the
GOG studies reflected 32, 42, 43 that technical
ability to resect the disease may be as
important as the biological factors associated
with bulky disease. Besides, the relative
contribution of tumor biology vis-a-vis cyto-
reductive surgery has never been established.
In future, cytoreductive surgery will remain
an important part of therapy for patients with
advanced epithelial ovarian cancer. Newer
technological advances will help us to achieve
optimal cytoreduction in a greater number
of patients, and also to identify patients who
are not likely to benefit from cytoreductive
surgery.
In the management of advanced epithelial
ovarian cancer, the percentage of patients
whose disease can be successfully cytoreduced
to an optimal residual status ranges from 20
to 95 percent. In the hands of a trained
gynecologic oncologist, this figure would be
approximately 50 to 70 percent, which means
that a significant number of patients are left
 Principles of Surgical Management of Gynecological Cancers 9
with a suboptimal residual disease at the end
of primary surgery. In those patients who
cannot be optimally cytoreduced upfront,
adding another surgical cytoreductive effort
after three cycles of chemotherapy has been
shown to impart a survival benefit (33%
reduction in the risk of dying at 2 years).44 The
GOG is presently conducting a similar study
with paclitaxel and cisplatin chemotherapy. It
is rather tempting to extrapolate these results
to the group of patients without cytoreductive
surgery, i.e. those with clinically unresectable
disease. This approach of neoadjuvant
chemotherapy followed by interval surgery is
likely to increase the rate of optimal cyto-
reduction, improve survival, reduce the
morbidity of surgical debulking, improve the
quality of life and be more cost-effective. This
approach although yet unproven in
randomized clinical trials holds promise in
developing countries like India. These two
approaches of primary debulking surgery and
interval debulking surgery in patients with
stage III C/IV epithelial ovarian cancer are
presently being compared in a randomized
EORTC trial.
The role and benefit of aggressive cyto-
reductive surgery in patients with stage IV
disease is less clear. Patients with only pleural
effusion or supraclavicular lymph node
metastasis may be treated on the lines of
stage III disease. Extensive cytoreduction is of
no benefit in presence of lung or liver
metastases. As opposed to earlier reports,
however, recent data has now confirmed the
significant survival advantage associated with
optimal surgical cytoreduction followed by
cisplatin based chemotherapy.45-47 Bristow et
al (1999) confirming these findings also
concluded that even in patients with unrese-
ctable liver metastases, optimal debulking of
extrahepatic disease is associated with
significant survival benefit.48
Some interesting publications have shown
that the survival of patients with epithelial
ovarian cancer is linked to the subspecialty
training of the operating surgeon, this effect
being most pronounced for patients with stage
III ovarian cancer,49 with a 25 percent and 32
percent reduction in the risk of death
compared with surgery performed by a
general gynecologist or a general surgeon.
Optimal surgical staging as well as optimal
cytoreductive surgery has been found to be
performed more frequently by a specialist
gynecologic oncologist.29 Management by a
specialist has been found to be an independent
prognostic factor in two large studies
with more than 1,800 patient with ovarian
cancer.50, 51
The role of second look surgery outside the
setting of clinical trials is presently
controversial. With the advent of newer more
effective chemotherapy regimens, the number
of patients achieving complete response has
increased considerably. There has also been
an increase in the number of patients who
experienced clinical relapse after surgically
confirmed complete response, indicating poor
prognostic impact of second look surgery.
Confirmation of negative findings at second
look laparotomy (SLL) no longer dictates
continuation or otherwise of chemotherapy,
since the value of consolidation therapy is yet
unproven. Besides, no significant survival
benefit has been demonstrated with any
salvage therapy for patients with evidence of
residual disease at SLL. In view of this, second
look surgery is no longer considered a part of
the routine standard of care. However, it may
still have a beneficial role in patients at a high-
risk of recurrence, who are medically fit and
who desire more accurate prognostication
and/or aggressive treatment of their cancer,
especially in view of the encouraging reports
with consolidation chemotherapy.52
10 A Practical Approach to Gynecologic Oncology
Because primary cytoreductive surgery
appears to have a significant impact on
survival, many authors recommend secondary
cytoreduction for women with persistent or
recurrent ovarian cancer. Secondary cyto-
reduction can be accomplished with accept-
able morbidity in a majority of patients who
are candidates for it, but whether it imparts
any significant survival benefit needs to be
determined. It is important to determine
preoperatively whether the patient is likely to
derive survival advantage from secondary
cytoreduction. Patients with progressive
disease during chemotherapy or those with
residual disease at the conclusion of chemo-
therapy or those who experience a relapse very
shortly after completion of the primary
treatment have limited life expectancy and are
not likely to benefit from surgery and in the
absence of effective second line chemotherapy,
secondary cytoreductive surgery should not
be offered to them. Secondary cytoreduction
at the time of second look surgery for clinical
complete responders should be advocated
only if optimal cytoreduction is possible and
then too, it imparts maximum benefit when
all visible disease can be resected. Patients who
relapse after a long relapse free interval (>12
months) are also likely to be benefited by a
repeat cytoreductive effort. The ability to
resect all gross disease at secondary cyto-
reduction may be a reflection of the inherent
biology of the tumor rather than the skill of
the surgeon. The single most important factor
responsible for the failure of secondary
cytoreductive surgery is the lack of effective
second line therapy. Retrospective reviews
with a strong selection bias suggest a survival
benefit when the disease can be reduced to a
microscopic level at the time of secondary
cytoreductive surgery.53-56 The precise role of
secondary cytoreductive surgery vis a vis its
impact on survival is presently being
evaluated in a randomized study “Late
relapse of ovarian cancer: Surgery or not
(LAROCSON).”
Most patients of advanced ovarian cancer
who fail to respond to the primary treatment
have an unrelenting disease progression
leading to death. Progressive cancer usually
results in symptoms associated with
conditions such as intestinal obstruction,
ascites, pleural effusion, and ureteric
obstruction. The option of surgical manage-
ment must be carefully considered especially
since it may the only option for longer
symptom-free interval. The decision to
operate depends on the estimate that the
patient will recover from the surgery and live
long enough to enjoy the benefits of the
surgery. The decision must be balanced
against the estimate of risk of surgical
complications and operative mortality. Any
decision regarding palliative surgery in such
patients must be made after weighing the pros
and cons carefully and after discussing the
clinical situation and expected benefit/risk
with the patient and asking her to make an
informed choice.
The laparoscopic approach for treatment
of ovarian cancer should not be considered
standard at present but may be employed in
research setting in selected patients.
Borderline ovarian tumors (Tumors of low
malignant potential): Conservative surgery
can be safely offered to patients with
borderline tumors. The majority of borderline
tumors are diagnosed in stage I, are
uncommonly bilateral except in the serous
variety and have excellent prognosis with a
very low relapse rate of less than 5 percent.57
Besides, comprehensive surgical staging in
apparently stage I tumors is not mandatory
because of the low yield of upstaging and
chemotherapy is rarely, if at all used in the
management of these tumors.58 These patients
can be treated effectively with unilateral
salpingo-oophorectomy. Tazelaar et al (1985)
 Principles of Surgical Management of Gynecological Cancers 11
found no evidence of microscopic disease in
grossly normal ovaries that were bivalved in
61 patients with stage I low malignant pote-
ntial tumors of the ovary.59 In the literature,
some patients with borderline epithelial
ovarian cancer have been treated with ovarian
cystectomy with preservation of normal
ovarian parenchyma, with recurrence rates
equivalent to those after salpingo-oopho-
rectomy.60,61 Excellent fertility results have
been reported in patients with borderline
tumors who have undergone conservative
surgery. Ovulation induction and IVF have
been used with good success rates in patients
unable to conceive naturally.61,62
ENDOMETRIAL CANCER
Surgery is the main modality of treatment for
endometrial cancer. Total abdominal hystere-
ctomy, bilateral salpingo-oophorectomy along
with pelvic and para-aortic node sampling is
the treatment of choice for stage I patients,
while radical hysterectomy with pelvic
lymphadenectomy and para-aortic node
sampling is the preferred treatment for
stage II patients who have involvement of
cervix. Postoperative radiation therapy is
reserved for those with infiltration of myo-
metrium or cervical stroma. There is no effe-
ctive systemic adjuvant therapy for endo-
metrial cancer. Some use progestational agents
to this effect but the objective response rates
are poor. Advanced endometrial cancer is very
difficult to treat effectively and one can only
offer palliative symptomatic treatment to them
most of the times.
There is controversy regarding the extent
of surgery in stage I endometrial cancer. A
routine pelvic and para-aortic staging lympha-
denectomy is often recommended. Optimal
management of lymph node is still contro-
versial. Although lymphadenectomy in
patients with endometrial cancer has the
ability to determine prognosis and guide
treatment, whether it also has a therapeutic
role is not clear. Some authors claim a survival
benefit because they found a higher cancer
specific survival rate than in the reported
series of patients treated with total abdominal
hysterectomy and pelvic radiotherapy in
selected patients. Kilgore et al63 reported a
retrospective series of endometrial cancer
patients undergoing multiple site pelvic and
para-aortic lymphadenectomy compared with
a group of patients who underwent limited
or no lymph node sampling. Patients were
divided into a low-risk group with disease
apparently confined to the uterus, and a high-
risk group, in which disease spread outside
the uterus. Analysis revealed a significantly
better survival in patients with lymphadene-
ctomy when compared with no lymphadene-
ctomy group. Survival was also improved in
the low-risk group, compared with the high-
risk group, with or without radiotherapy and
for poorly differentiated tumors when
multiple site lymph nodes were sampled.
Webb et al64 showed a significantly improved
overall survival in patients with para-aortic
metastases who underwent para-aortic
lymphadenectomy when compared with
patients who had a sampling only (< 5 lymph
nodes obtained). On the other hand, Candiani
et al65 evaluated the patients as a function both
of different surgical treatments and of risk
factors by histology and concluded that
lymphadenectomy is useful for prognostic
purposes but does not confer a therapeutic
benefit. Similar observation was made by
others also.66-70 However, these retrospective
studies and comparison with historical
controls were subject to selection bias. Some
recent studies have shown that a formal
lymphadenectomy may directly impact both
recurrence rates and overall survival,71 with
the effect being most pronounced in patients
with stage IAG3, IBG2-3, IC, vascular space
invasion, adnexal involvement and high-risk
12 A Practical Approach to Gynecologic Oncology
cell types. In view of this, it appears logical to
add pelvic lymphadenectomy and para-aortic
lymph node sampling to the surgical chores
in patients with endometrial cancer. A
spectrum of surgical approaches exists for
evaluating the lymph nodes, ranging from
palpation to selective nodal sampling to
complete lymphadenectomy. Selective lymph
node sampling based on nodal enlargement
also does not appear to be effective. Creasman
et al72 and Chuang et al73 both reported that
less than 30 percent of lymph node metastases
are clinically detected on palpation. Girardi
et al74 indicated that 47 percent of the lymph
node metastases occurred in nodes that were
less than 1 cm. These data suggest that
retroperitoneal palpation is not an accurate
method for retroperitoneal evaluation. Some
authors have used intaroperative frozen
section to assess lymph node metastasis,75 but
at least five to seven percent of patients with
high-risk factors will be missed even on
extensive intraoperative frozen section
analysis.76
Various reports indicate that patients with
grade I Stage IA disease are at low risk for
lymph node metastases and probably do not
benefit from routine pelvic and para-aortic
lymphadenectomy.77,78 Similarly, the manage-
ment of patients with gross intra-abdominal
metastases is unlikely to be changed by pelvic
and para-aortic lymphadenectomy.79 So the
patients most likely to be benefited from pelvic
and para-aortic lymphadenectomy are those
with high-risk endometrial histopathology
without clinical or gross surgical evidence of
extrauterine metastases.79 Various pre- and
intra-operative factors including histopatho-
logic grade,80 cervical cytology,81 and gross
depth of myometrial invasion82 can be used
to identify high-risk patients who may benefit
from more aggressive surgical staging
including lymphadenectomy. Knowing the
status of the para-aortic nodes is important for
high-risk cases because identification of para-
aortic disease may potentially lead to cure
with extended field radiotherapy.
In 1988, FIGO recognized the importance
of myometrial invasion, depth of cervical
invasion, site of metastasis and result of
peritoneal cytology and redefined the staging
of endometrial carcinoma and abandoned
clinical staging of endometrial carcinoma in
favor of surgical staging. 83 An increased
understanding of the biologic behavior,
assists in the detection of extrauterine
disease, potentially facilitates management
decisions, and certainly improves communica-
tion regarding treatment results of patients
within a specific surgical stage. Surgical
staging provides the most accurate method
of defining extrauterine disease, need of
postoperative treatment, and a reasonable
estimate of prognosis. The importance or
benefit of extensive surgical staging has been
championed by a number of authors, 84-90
doubted by some,91, 92 and denied by others.93
Surgical staging is important and may help in
omitting unnecessary pelvic radiotherapy for
some and directing therapy for others.
Surgical staging consists of meticulous
exploration of the abdominal and pelvic
cavities and organs with biopsies if necessary,
peritoneal cytology, para-aortic lymph node
(PAN) biopsy, pelvic lymph node dissection,
excision of any suspected extrauterine lesions,
extrafacial hysterectomy and bilateral
salpingo-oophorectomy. Uterine histopatho-
logic characteristics and intraoperative
findings continue to provide the primary
indications for surgical staging in endometrial
cancer. The uterine specimen should be
opened and the tumor size, depth of myome-
trial involvement, and cervical extension
should be assessed.
The diagnosis of stage II endometrial can-
cer may be made preoperatively on fractional
curettage but the definitive diagnosis of cer-
 Principles of Surgical Management of Gynecological Cancers 13
vical involvement is often made postopera-
tively. As the incidence of pelvic lymph node
metastasis is reported to be up to 36.5 percent94
in patients with stage II disease, any treatment
protocol should include treatment of these
lymph nodes. Radical hysterectomy with
bilateral pelvic lymphadenectomy and para-
aortic lymph node sampling may improve
survival especially in patients with more
extensive cervical involvement.
Treatment for stage III endometrial carci-
noma must be individualized but initial
surgical evaluation should be done if possible
to know the occult lymph node metastases and
extent of intraperitoneal spread. In the
presence of an adnexal mass, surgery should
be done first, to determine the nature of the
adnexal mass and to remove the bulk of the
disease. The presence of parametrium exte-
nsion may require preoperative radiotherapy.
The aim of the surgery should be removal of
all macroscopic tumor tissue, which is the
most important prognostic factor in these
patients. The surgery should include removal
of any enlarged pelvic and para-aortic lymph
nodes. If all gross disease can be resected from
the pelvis, a thorough surgical staging is
indicated. Aalders et al reported a 5-year
survival rate of 40 percent for patients with
surgicopathologic stage III disease95 compared
with 16 percent for patients with clinical stage
III. Patients treated with combined surgery
and radiotherapy do better than patients who
receive radiotherapy.
The use of laparoscopy in the management
of gynecologic malignancies has significantly
increased over the last five years. The safety
and adequacy of pelvic and para-aortic
lymphadenectomy have been established by
several investigators. Patients with carcinoma
of the endometrium are treated by laparo-
scopically assisted vaginal hysterectomy in
conjunction with laparoscopic pelvic and para-
aortic lymphadenectomy. Malur et al (2001)
compared a laparoscopic-vaginal approach
with the conventional abdominal approach for
treatment of patients with FIGO stage I-III
endometrial cancer. They showed that the
yield of pelvic and para-aortic lymph nodes,
duration of surgery, and incidences of
postoperative complications were similar for
both groups. Overall and recurrence-free
survival did not differ significantly for both
groups. But blood loss and transfusion rates
were significantly lower in the laparoscopic
group.95 Eltabbakh et al (2001) investigated the
feasibility and safety of laparoscopic
management of obese women with early stage
endometrial cancer and compared the surgical
outcome, cost, hospital stay, postoperative
pain control, time to return to full activity and
to work, and overall satisfaction among these
women and those managed by laparotomy.
They concluded that patients with early stage
endometrial cancer can be safely managed
through laparoscopy with excellent surgical
outcome, shorter hospitalization, and less
postoperative pain than those managed
through laparotomy.96 Similar conclusions
were drawn by others.97 In view of this, it
appears that the laparoscopic approach for
treatment of endometrial cancer is associated
with lower perioperative morbidity compared
with the conventional abdominal approach.
However, the selection of patients for
laparoscopy should be done considering
optimal benefit and safety.
In patients with significant comorbid
conditions, some authors have advocated
vaginal hysterectomy with bilateral salpingo-
oophorectomy, pelvic washings by colpotomy
and extraperitoneal pelvic and para-aortic
lymph node dissection. 98 However, no
randomized study has yet been undertaken
to compare this approach with laparoscopic
or abdominal techniques.
14 A Practical Approach to Gynecologic Oncology
CANCER OF THE VULVA
Over the past 100 years the treatment of vulvar
cancer has evolved dramatically. The most
significant advance regarding conservatism in
gynecologic oncology is seen in vulvar cancer,
where the cosmetically and functionally
compromising procedure like radical
vulvectomy with groin node dissection is now
rarely advocated.
Way (1948) established that a very wide
resection of vulvar lesion was vital to the
chances of cure from cancer of the vulva and
therefore radical excision was performed even
for small tumors.99 With the pioneering work
of Way, en-bloc radical vulvectomy and
bilateral ilioinguinal lymphadenectomy
became the standard treatment for most
patients with operable vulvar cancer.
However, this led to devastating mutilation
especially in young patients and compromised
the cosmesis and sexual function, besides
causing serious alternations in body image.
This provided a stimulus for developing an
alternative conservative approach to early
vulvar cancer, which aimed at conservation
of body image and sexual function by
retaining large areas of vulvar tissue including
mons veneris and clitoris whenever possible.100
Conservative surgery can reduce sexual
dysfunction and urethral/anal problems,
provided local control and survival not
compromised. Surgery is now almost always
limited to ipsilateral wide local excision in case
of small lateral lesions.101
Today, an individualized approach is advo-
cated by most for treatment of early invasive
vulvar cancer.102-107 Most T1 and selected T2
lesions can be controlled locally with a radical
wide local excision. A wide and deep excision
of the lesions is performed with the incision
extended down to the inferior fascia of uro-
genital diaphragm and/or pubic periosteum.
An effort should be made to remove the lesion
with a 2 cm margin of normal tissue in all
directions unless this would require sacrifice
of urethra or anus. Heaps et al (1990)
suggested that although it has been customary
to aim for 2 to 3 cm margin, a minimum of 1
cm might be adequate. Small T1 lesions that
invade 1 mm or less may be managed by local
excision alone because the risk of regional
spread is low.108 Patients with more invasive
lesions must have a concomitant treatment of
groin nodes. Radical local excision is most
appropriate for lesions on the lateral or
posterior aspects of the vulva, where
preservation of clitoris is possible.
The major deterrent for conservative
surgery is the multicentricity of invasive
cancer in 20 to 30 percent cases. However,
Hoffman (1992) demonstrated that conserva-
tive surgery led to comparable local control
and survival to radical vulvectomy in well-
selected patients.109 Other authors have also
shown that these conservative approaches
result in survival comparable with that after
more radical operations and fears of an
increased local recurrence rate as a result
of less radical surgery proved to be unwarran-
ted.102, 110
It was believed in the past that without an
en-bloc resection, the intervening tissue left
between the primary tumor and the regional
nodes may contain microscopic tumor foci in
draining lymphatics. However, it is now
known that squamous carcinomas spread by
embolization and not be permeation and
experience with a separate incision technique
for node dissection has confirmed that
metastases rarely occur in the skin bridge in
patients without clinically suspicious nodes
in the groin.111
From the evidence in the literature, it
appears that all patients with a depth of
invasion more than 1 mm require inguino-
femoral lymphadenectomy. Presently,
inguinofemoral lymphadenectomy can be
avoided safely only in patients with lesions
 Principles of Surgical Management of Gynecological Cancers 15
less than 2 cm in size and with depth of
invasion of less than 1 mm. It is also clear
that if the primary lesion is unilateral, uni-
lateral lymphadenectomy may be adequate.
The risk of contralateral lymph node meta-
stases in patients with negative ipsilateral
nodes in T1 lesions is negligible.
Sentinel Node Biopsy
An approach aimed at avoiding or down-
scaling the morbid lymphadenectomy in those
who do not need it, is under active investi-
gation at present. It is of particular interest in
vulvar cancer, since the ilioinguinal lympha-
denectomy practised for this cancer is one of
the most morbid surgical procedures due to
poor wound healing and it is important to
perform it only in patients who absolutely
need it. Levenback et al (1995) and DeCesare
et al (1997) using isosulfan blue dye and
lymphoscintigraphy (technetium 99-m labeled
sulfur colloid) respectively demonstrated the
feasibility of mapping and identification of
the sentinel node in patients with invasive
stage I vulvar cancer.112, 113 De Hullu et al (2000)
using a combination of these two methods
concluded that accurate identification of the
sentinel node was feasible in all patients and
even after step sectioning and immuno-
histochemistry staining for cytokeratin, only
four of the 102 negative sentinel nodes were
found to be metastatic.114 Similar findings have
been reported in patients with invasive
cervical cancer by several investigators—
either at open surgery 115 or laparoscopically.116
Results from prospective randomized trials
should provide interesting data in the near
future, which will guide us regarding
incorporation of this procedure in routine
clinical practice.
Large T2 and T3 lesions should be managed
by radical vulvectomy and bilateral
inguinofemoral lymphadenectomy. It may be
necessary to do partial resection of vagina or
distal urethra, if these are involved. It may be
possible to extend the indications of radical
local excision to selected T2 patients, with
results equivalent to those after radical
vulvectomy.117
The pelvic nodes need to be addressed in
all patients with positive inguinal nodes.
Some authors suggest pelvic lymphadene-
ctomy only in the presence of multiple (3 or
more) positive nodes.118-120
Adequate surgical clearance of the primary
tumor when it involves the anus, rectum,
rectovaginal septum or proximal urethra
would warrant an exenterative surgical
procedure including radical vulvectomy and
bilateral inguinal lymphadenectomy. In view
of the magnitude of the surgery with its
consequent morbidity and mortality and the
psychosexual problems associated with it,
attempts have been made to downsize the
disease with radiation therapy or chemo-
radiation and then get an adequate surgical
clearance with radical vulvectomy or radical
wide local excision.104, 121-125
CONCLUSION
The treatment results of gynecological cancers,
with the exception of ovarian cancer have
improved considerably with more effective
primary and adjuvant therapy. This has
prompted the practicing physician to devise
treatment protocols with more emphasis on
preservation of quality of life. With more and
more women in the childbearing age being
diagnosed with gynecological cancers, fertility
preservation has become an important issue
in young women afflicted with these cancers
and has resulted in redefining the treatment
of these cancers. Although the conservative
approach appears to be justified in well-
selected patients, it remains to be seen how
much these indications for conservative
surgery can be expanded without jeopardizing
the survival of these patients. While the
16 A Practical Approach to Gynecologic Oncology
western world is busy with advanced
molecular, biological and genetic approaches
to improve the end results of gynecological
cancers, the emphasis in our country should
be to ensure that all the unfortunate women
afflicted with gynecological cancers should
have the benefit of early diagnosis, optimum
staging and state-of-the-art treatment in order
to improve their outcome.
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 2 Principles of Chemotherapy
in Gynecologic Cancers
INTRODUCTION
A fine balance is maintained between the cell
proliferation and the cell loss in our body.
Cancer cells are characterized by the loss of
the regulatory mechanisms that control the
cycles of growth, maturation, senescence and
finally death of individual cells. Surprisingly,
the malignant cells do not proliferate at a rate
higher than their normal counterparts. The
normal response to the growth stopping
signals and the process of programmed cell
death (apoptosis) are deranged in these
abnormal cells, leading to the accumulation
of cells that go on replicating.
A new armamentarium was added to the
fight against cancer during the middle of last
century when it was demonstrated that
nitrogen mustard (a byproduct of mustard
gas used in first world war) was effective
against lymphomas and other solid tumors.1
Since then a large number of drugs with
various mechanisms of actions have been
discovered and they have radically changed
the survival of at least some of the
malignancies. The search is still going on for
the ideal chemotherapeutic agent that will
selectively kill or inhibit the growth of only
the neoplastic cells leaving the normal cells
unharmed.
• Alka Pandey • Partha Basu
CELL KINETICS AND TUMOR BIOLOGY
Cellular Kinetics of Normal Tissues
In adult human body the tissues have variable
capacity to proliferate and grow. Depending
on the proliferative activities, the tissues are
divided into the following three categories:
• Static: Some of the well-differentiated cells
like striated muscles and neurons stop
dividing after the initial period of proli-
feration during the fetal life.
• Expanding: Cells of kidney and liver have
the capacity to proliferate only under
special stimuli-like injury. Otherwise they
remain quiescent throughout the adult life.
• Renewing: The cell populations of gastro-
intestinal mucosa, bone marrow, sperma-
tozoa, etc. have very high turn-over. There
is constant division and formation of new
cells on one hand and constant cell loss on
the other.
Understanding of the characteristics of
normal cellular growth pattern is essential to
appreciate the common toxicities associated
with the use of chemotherapeutic drugs. As
the cytotoxic drugs act on the actively dividing
cells, normal cells with high proliferative
capacities are worst affected. This pheno-
menon can explain many of the common side
24 A Practical Approach to Gynecologic Oncology
effects of chemotherapy, like bone marrow
depression, oral mucositis, azoospermia, etc.
Phases of Cell Cycle
A proliferating cell goes through the
following phases of cell cycle (Fig. 2.1):
• M phase (Mitotic phase): Mitotic phase is the
point of chromosomal division.
• G 1 phase (Post-mitotic phase): This is a
variable stage when cellular activities,
protein and RNA synthesis and DNA
repair occurs. The cell after this phase either
re-enters the next phase of cell cycle (S
phase) or differentiates.
• S phase (DNA synthesis phase): In this phase
new DNA is synthesized and chromo-
somes are duplicated.
• G2 phase (Post-synthetic phase): The cell is
prepared for mitosis through synthesis of
Fig. 2.1: Phases of cell cycle
specialized protein and RNA. The mitotic
spindle apparatus is manufactured. At this
phase the cell has haploid number of
chromosomes with twice the DNA of a
normal cell.
• G0 phase (Resting phase): This is the quiescent,
non-dividing state of the cell. The cell stops
dividing temporarily or permanently and
is inactive metabolically. From this
phase the cell enters G 1 phase after a
variable period of time, if it starts dividing
again.
Normal tissues have huge number of cells
in the G0 phase of the cell cycle in contrast to
tumor cells where more cells are in the active
phase of cell division. Dividing tumor cells
are most sensitive to cytotoxic agents
whereas cells in the G0 phase are relatively
insensitive.
 Principles of Chemotherapy in Gynecological Cancers 25

Characteristics of Table 2.1: Classification based on

Growth of Tumor Cells mechanism of action
Mechanism Example
In normal tissues equilibrium is maintained
between death of the existing cells and new 1. Damage to DNA
template:
cell production. This finely regulated equili-
• DNA alkylation • Nitrogen mustards
brium is disturbed in cancerous growths (cyclophosphamide,
leading to the uninhibited proliferation of Ifosfamide)
cells. • Nitrosoureas (carmus-
Earlier it was considered that all the tine, lomustine)
neoplastic cells in a tumor are in the process • Thiotepa, busulfan,
of dividing, with no cell in the resting phase. mitomycin C
According to this concept the growth of the • Platinum coordi- • Cisplatin, carboplatin
nation cross-linking
tumor follows an exponential (logarithmic)
• Double strand • Antibiotics (doxorubi-
pattern and the doubling time of the cleavage via cin, daunorubicin)
proliferating cancer cells is constant forming topoisomerase II • Podophyllotoxins
a straight line on a semilog plot.2 (etoposide)
In reality human tumors have both • Single strand clea- • Topotecan, irinotecan
proliferating and nonproliferating cell vage via topoiso-
populations. Instead of the expected straight merase I
line growth on a semilog plot, the tumors • Blocking RNA syn- • D-actinomycin,
thesis by intercalation mithramycin
follow a sigmoid growth curve known as
• Unknown • Bleomycin
Gompertzian growth curve. Initially the cells mechanism
accumulate slowly in number because the 2. Antimetabolites (inhibition of following enzymes):
number of dividing cells is small. The growth • Di-hydrofolate • Methotrexate
rate is maximum at about one-third the reductase
maximum tumor volume when there is a rapid • DNA polymerase • Cytosine arabinoside
accumulation of cells. As the tumor expands, • Ribonucleotide • Hydroxyurea
it outgrows its blood supply. This leads to reductase
3. Damage to the mitotic spindle:
anoxia, slowing of cell cycles, exit of some
• Vinca alkaloids • Vincristine, vinblastine
cells to the G0 nonproliferating phase and cell • Taxanes • Taxols, taxotere
necrosis. Because of this there is gradual 4. Inhibition of protein
slowing of the rate of growth, almost to a synthesis: • L-Asparaginase
plateau, as the tumor reaches a critical mass. 5. Hormone antagonists: • Tamoxifen, flutamide
6. Biological response
CLASSIFICATION OF modifiers: • Interferons, interleu-
ANTICANCER DRUGS kins, levamisole

Anticancer drugs can be classified based on

their chemical nature, mechanism of action
and cell cycle effects.
Classification Based on Chemical Nature
and Mechanism of Action (Table 2.1)
Cytotoxic drugs containing reactive alkyl
groups capable of forming covalent bonds
with DNA are called alkylating agents. The
cross-links formed with the DNA prevent cell
multiplication. Some of the alkylating agents
can break the DNA strands resulting in death
of the cell. Platinum complexes like cisplatin
and carboplatin form strong covalent bonds
26 A Practical Approach to Gynecologic Oncology
giving rise to inter-strand cross-links similar
to the alkylating agents.
The antimetabolites inhibit the replication
or repair of DNA by either inhibition of the
enzymes needed for DNA replication or
incorporation of the drug (or its derivative)
directly into DNA. The ability of this group
of cytotoxic agents to inhibit DNA synthesis
makes them most effective in the S phase of
cell growth. Methotrexate exerts its anti-
metabolic action through tight but reversible
binding to dihydrofolate reductase enzyme,
making it ineffective. The cytotoxic activity
of 5-fluorouracil is related to competitive
inhibition of thymidylate synthetase enzyme
by one of its derivatives.
The antitumor antibiotics are natural
products of metabolism of various microbes,
mostly fungi. By virtue of their structures,
the antibiotics can intercalate between the base
pairs of the DNA (doxorubicin, daunorubicin,
d-actinomycin, bleomycin), bind to DNA
(mitomycin) or generate toxic oxygen-free
radicals that cause DNA breaks (doxorubicin,
daunorubicin). The damage to the DNA
results in inhibition of RNA synthesis, protein
and glutathione synthesis, defective mitosis
and high rate of mutation.
Anticancer drugs like vinca alkaloids
(vincristine and vinblastine) and taxanes
(paclitaxel, docetaxel) target the microtubules
of the cells. The vinca alkaloids disrupt the
microtubules comprising the mitotic spindle
and cause metaphase arrest of the dividing
cells. The taxanes induce polymerization of
the tubulin and stabilize the microtubules.
These effects cause sustained mitotic block at
the metaphase.
Irinotecan, a synthetic derivative of the
natural product camptothecin inhibits the
enzyme topoisomerase I. Topoisomerase I is
essential for the DNA replication and its
inactivation results in single strand breaks of
the DNA. Etoposide produces DNA strand
breaks by inhibiting the topoisomerase II
enzyme.
Classification Based on
Cell Cycle Effects
The mechanisms of action of the cytotoxic
drugs vary widely. Some of them target the
cells at specific phases of the cell cycle and
the effectiveness of many of them is
dependent on the proliferative capacity of the
cells. 3 Based on these features the anti-
neoplastic drugs are classified as follows:
• Cell cycle nonspecific: These compounds kill
cells in all phases of the cell cycle whether
they are proliferating (G1-M) or not (G0).
Some of them are proliferation dependent
(cyclophosphamide, cisplatin), others are
not (paclitaxel, topotecan).
• Cell cycle specific—phase specific: These
compounds are toxic to neoplastic cells in
certain phases of the cell cycle. They tend
to be most effective against tumors with
high proportion of actively dividing cells
and rapid rate of proliferation. Examples
of this group of drugs are hydroxyurea and
methotrexate that are toxic to cells in early
S phase, paclitaxel and vincristine that are
effective against M phase and doxorubicin
that has a greater effect in the late S phase.
• Cell cycle specific—non-phase specific: These
compounds kill proliferating neoplastic
cells in preference to resting cells and are
non-phase specific, e.g. anthracycline
antibiotics, chlorambucil, cisplatin.
DETERMINANTS OF RESPONSE TO
ANTICANCER DRUGS
The clinical criteria for evaluation of response
to chemotherapy are as follows:
• Complete response: Hundred percent dis-
appearance of all objective signs of cancer,
both clinical and radiological
 Principles of Chemotherapy in Gynecological Cancers
• Partial response: Tumor regression of 50 to
99 percent in the diameters of measurable
tumor and the absence of appearance of
new lesions or tumor progression else-
where
• Stationary disease: <25 percent increase in
size and less than 50 percent regression
• Progressive disease: >25 percent increase in
size of measurable tumor.
Cure probably requires complete eradi-
cation of tumor cells from a malignant growth.
Certain pharmacokinetic principles of the
chemotherapeutic drugs, the innate properties
of the malignant cells and a few host factors
determine the response to therapy.
First Order Kinetics
Cytotoxic drug follows first order kinetics.
This signifies that at a given dose, in a given
tumor the drug will kill a constant percentage
of cells, regardless of the total burden of
tumor cells. Therefore a drug that kills 90
percent of the tumor cells will kill this fraction
regardless of the size of the tumor. ‘One log’
kill signifies 90 percent reduction in number
of cells in a tumor and ‘two log’ signifies 99
percent reduction.
The first order kinetics explains why
repetitive cycles are necessary for complete
tumor eradication. For example, if a cytotoxic
agent is effective in killing the population of
cells of a tumor by 1 log, a single cycle will
reduce the number of cells of a tumor
weighing 1 gm from 109 to 108 cells (10% of
the pretreatment number will be left behind).
Without further therapy the tumor would re-
grow very soon.
Growth Fraction
Growth fraction is the proportion of cancer
cells that are actively proliferating and it
represents the dividing cells likely to be
sensitive to chemotherapy. Small tumors have
the largest growth fraction due to the optimal
27
supply of oxygen and nutrients. So the best
opportunity to achieve total cell kill is at the
early portion of the growth curve. At the
other extreme of the curve total number of
the cells may be large, but the growth fraction
is minimum due to large population of anoxic
or necrosed, nonproliferating cells. This is the
reason why anticancer drugs achieve poor
response in a large tumor.
A major rationale for giving chemotherapy
in cycles is that the tumor shrinkage allows
circulation to improve, thus causing the resting
cells (resistant to chemotherapy) to enter the
proliferating pool. The increased growth
fraction makes them sensitive to the cytotoxic
agents in the next cycle.
Tumor Doubling Time
The time required to double the size of a
tumor is known as tumor doubling time and
it varies with the nature of the tumors.
Lymphomas and malignant mesenchymal
tumors have doubling time of less than 50
days whereas, epithelial tumors have
doubling time varying from 50 to 100 days.
The doubling time of metastatic tumors is
faster than the primary tumors. In general,
by the time a mass is radiologically visible
(0.5 cm diameter) it has already undergone
nearly 27 doublings. A mass can be clinically
detected when it has a size of at least 1 cm
and by that time the tumor has completed 30
doublings. So the tumors that are apparently
detected ‘early’ are not so from the point of
view of growth kinetics. With only three
more doublings a 1 cm tumor will be a huge
8 cm mass.
This concept has led to the use of adjuvant
therapy (chemotherapy after surgery/
radiation) in early stages of disease, where
residual disease of low volume (even if not
visible radiologically) is suspected. This also
explains the rationale behind continuation of
chemotherapy for few cycles beyond clinical
and radiological remission of tumor.
28 A Practical Approach to Gynecologic Oncology
Total Tumor Burden
Tumor size is another limiting factor to
successful chemotherapy in malignant disease.
In general, large bulky tumors are not curable
with drugs. Drugs may not be able to
penetrate into a solid tumor in amounts
sufficient to kill the cells. Most cells in a bulky
tumor may be in a nonproliferative stage at
the time of treatment and thus escape the
cytotoxic effect of the chemotherapeutic
agents. They survive to re-establish the tumor
mass. Also the longer a tumor has been
present the greater likelihood that it has
already metastasized.
Tumor Heterogeneity
Tumors are heterogeneous populations of
cells. Some of these cells are proliferating,
some can proliferate but are dormant and
others are dying. The fact that tumors are
not uniform must be considered. For therapy
to be completely effective the most invasive
metastatic cells must be killed.
Host Factors
Included among these is the general status of
the patient. The “Karnofsky patient per-
formance status” (Table 2.2) is a useful index
to evaluate whether or not the disease is
progressing, both during and after therapy.
In general, if the patient’s performance status
is below 40 percent it is less likely that his or
her clinical condition can be markedly
improved with chemotherapy. The best
chance for increasing survival time is when
treatment begins early. Also important is the
patient’s immune status. The status of a
patient’s cell-mediated immunity (i.e. the
effect initiated by activated macrophages,
cytolytic T-lymphocytes, and natural
killer cells) is the most important factor in the
immune response to malignant cells.
Antibody-dependent cell-mediated cytotoxi-
Table 2.2: The Karnofsky performance status score
Performance status Karnofsky score
Asymptomatic and fully active 100
Asymptomatic, fully ambulatory, 80-90
restricted in physically
strenuous activity
Symptomatic, ambulatory, 60-70
capable of self care, more than 50%
of working hours spent out of bed
Symptomatic, limited self care, 40-50
spends more than 50% of waking
hours in bed, but not bed-ridden
Completely disabled, no self-care, 20-30
bed-ridden
city (so-called ADCC reactions) also plays a
role in tumor cell killing. Circulating antigen-
antibody complexes (“blocking factors”) may
inhibit the cell mediated killing of cancer cells.
The blood supply and site of neoplasm is also
important. If any drug is to be effective, it
must be present in sufficient concentrations
at the site of its action. In cancer chemo-
therapy, this means that tumor cells, even if
very sensitive to the administered drug,
cannot be destroyed unless they have a
reasonable access to blood supply. Failure of
drug therapy may occur when tumors
metastasize into the pleural space or the CNS.
DRUG RESISTANCE
Drug resistance is one of the most important
problems with cancer chemotherapy. As many
as 40 to 45 percent of the cancers may have
or may develop resistance to anticancer
drugs. There are several different biochemical
mechanisms by which tumor cells develop
resistance to anticancer drugs. These include:
• Decreased intracellular drug levels: This could
result from increased drug efflux or
decreased inward transport. Among the
drugs which become resistant by this
mechanism are the anthracyclines, dacti-
nomycin, vinca alkaloids and podo-
phyllotoxins.
 Principles of Chemotherapy in Gynecological Cancers
• Increased drug inactivation: Included in this
group are the alkylating agents, antimeta-
bolites and bleomycin.
• Deceased conversion of drug to an active form:
This mechanism is most common among
the antimetabolites which must be
converted to the active metabolites before
they are active.
• Altered amount of target enzyme or receptor: In
the methotrexate resistant tumors there is
increased production of the target enzyme
dihydrofolate reductase.
• Decreased affinity of target enzyme or receptor
for the drug: Examples of this group of drugs
are the antimetabolites and hydroxyurea.
• Enhanced repair of the drug-induced defect: The
alkylating agents typically show resistance
by this mechanism although other
mechanisms are also important with these
drugs.
• Multidrug resistance (MDR): This is a
phenomenon whereby tumors become
resistant to several, often unrelated drugs
simultaneously. The multidrug resistance
(MDR) gene encodes an ATP-dependent
efflux pump, called p-glycoprotein, that
may become amplified in drug resistant
tumors. The intracellular concentrations of
the drugs are reduced leaving them
ineffective. MDR occurs between several
different stucturally unrelated antitumor
agents that apparently have different
mechanisms of action.
TOXICITY
Cytotoxicity to normal tissues is a major
limiting factor in patient chemotherapy.
Severe systemic disability, advanced age,
poor nutritional status, direct organ
involvement by primary or secondary tumor
enhance the severity of the side effects of
chemotherapy.4,5
The cytotoxic drugs have narrow thera-
peutic index. Therefore, treatment has to be
29
a balance between toxic effects and efficacy.
The actively proliferating normal cells of the
body cannot escape the harmful effects and
that is the primary reasons of the adverse
effects seen with the anticancer drugs. The
higher is the growth potential of the normal
tissue, greater is the adverse effect. Hair
follicles, bone marrow, mucous membrane of
the gut, etc. are most commonly affected.
Adverse effects of chemotherapeutic
regimes can be minimized by giving combi-
nations of drugs that require smaller doses
of individual drugs. Intermittent high doses
are more effective and better tolerated.
The common side effects of cytotoxic drugs
are listed below.
1. Bone marrow toxicity: Destruction of the
actively proliferating precursor cells leads
to decreased RBC, WBC and platelet
counts resulting in anemia, infection and
hemorrhage. The myelosuppressive effect
can be counteracted by recombinant
cytokines that stimulate cell production in
bone marrow, e.g. granulocyte colony
stimulating factor (G-CSF) and erythro-
poietin.
Autologous bone marrow trans-
plantation allows higher dosages of
myelosuppressive drugs and increases cure
rate.
2. Gastrointestinal (GI) tract toxicity: Nausea
and vomiting occur very frequently due
to stimulation of vomiting center in CNS
and not due to direct GI toxicity. They can
be managed by centrally-acting antie-
metics.
Stomatitis, dysphagia, diarrhea, pain
and GI bleeding may occur due to damage
to the proliferating mucosa of the GI tract.
3. Hair follicle toxicity: Many of the chemo-
therapeutic drugs cause partial or complete
alopecia (hair loss) due to the damage to
the hair follicles. Hair regrows normally
after completion of chemotherapy.
30 A Practical Approach to Gynecologic Oncology
4. Reproductive toxicity: The cytotoxic drugs
may act on the ovaries causing menstrual
irregularities, amenorrhea and rarely
premature menopause. The effects of the
drugs on pregnancy have been discussed
in details later.
5. Immunosuppression: Most of the agents
lower cellular and to a lesser extent
humoral immunity which are fortunately
recovered after cessation of therapy.
6. Hepatic toxicity: Long-term use of metho-
trexate may induce hepatic fibrosis and can
progress to frank cirrhosis.
7. Pulmonary toxicity: Bleomycin, alkylating
agents and nitrosoureas cause interstitial
pneumonitis with pulmonary fibrosis.
8. Cardiac toxicity: Doxorubicin may cause
severe cardiomyopathy. Paclitaxel causes
arrhythmias.
9. Genitourinary toxicity: Cisplatin can cause
renal tubular toxicity associated with
azotemia and magnesium wasting.
Methotrexate can cause precipitate in the
renal tubules casing oliguric renal failure.
Cyclophosphamide in high doses for
prolonged periods causes hemorrhagic
cystitis.
10.Neurotoxicity: Cisplatin, vinca alkaloids and
paclitaxel are associated with peripheral
neuropathy most commonly sensory type.
They can cause loss of vibratory sense, high
frequency hearing and deep tendon
reflexes. ACTH analogues and Amifostine
are being evaluated as treatment for
neuropathy.
11.Carcinogenicity: Cancer patients treated by
chemotherapy have an increased incidence
of second malignancies. Alkylating agents
are major offenders. Anthracyclines and
procarbazine are also mutagenic and
carcinogenic. One common example of
second malignancy is leukemia following
treatment with alkylating agents.6
The World Health Organization’s common
toxicity scores are described in Table 2.3.
CHEMOTHERAPY IN PREGNANCY
The reported incidence of pregnancy with
cancer is less that one in 1000.7 Among the
gynecologic cancers, cervical and ovarian
cancers are more commonly associated with
pregnancy. Prescribing cytotoxic drugs for the
treatment of malignancy to a pregnant woman
willing to continue with the pregnancy is a
contentious issue for an oncologist. The drugs
are known to cause teratogenicity and
abortion, particularly if administered during
the first trimester. At the same time the
prognosis of the disease may be compromized
if definitive therapy is delayed till the birth
of a healthy baby. Thus the decision to initiate
chemotherapy in a pregnant patient is always
a difficult one.
Physiologic changes in pregnancy alter the
pharmacokinetics of the cytotoxic drugs. The
plasma volume increases due to considerable
increase in body water. This results in larger
dilutional space for the water soluble drugs.
An increased distribution volume reduces the
peak plasma concentration of a drug following
bolus administration. This can alter both the
efficacy and the toxicity of the drugs. The
drug distribution is also affected due to the
altered plasma concentrations of albumin and
proteins.
Almost all the chemotherapeutic drugs
enter the fetus through the placenta. The
effects of the cytotoxic drugs depend on the
timing of such exposure. During the first
trimester when the organogenesis occurs,
drugs can either cause abortion or produce
congenital malformations. After the first
trimester the drugs rarely cause significant
malformations but may impair fetal growth
and development. As the neuronal growth
 Principles of Chemotherapy in Gynecological Cancers 31

Table 2.3: WHO common toxicity criteria

Toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Hematologic
WBC >4.0 3.0-3.9 2.0-2.9 1.0-1.9 <1.0
Platelet WNL 75,000-normal 50,000-74,900 25,000-49,900 <25,000
Hb (%) WNL 10.0-normal 8.0-10.0 6.5-7.9 <6.5

Gastro-intestinal
Vomiting None 1 episode in 24 2-5 episodes in 6-10 episodes in >10 episodes
hours 24 hours 24 hours 24 hours
Diarrhea None Increase of 2-3 Increase of 4-6 Increase of 7-9 Increase of >9
stools per day stools per day, stools per day, stools per day,
moderate severe cramping needs paren-
cramping teral support
Stomatitis None Painless ulcer, Painful erythema, Painful erythema, Requires
erythema ulcer, can eat ulcer, cannot eat parenteral or
enteral support
Bilirubin WNL – <1.5 × normal 1.5-3 × normal >3 × normal

Renal
Creatinine WNL <1.5 × normal 1.5-3 × normal 3.1-6 × normal >6 × normal
Hematuria Negative Microscopic only Gross, no clots Gross with clots Requires
transfusion

Pulmonary
Pulmonary None Asymptomatic, – Radiographic –
fibrosis radiographic changes with
changes only symptoms
Dyspnea None Asymptomatic Dyspnea on Dyspnea at Dyspnea at rest
with abnormal significant normal activity
PFT exertion
Cardiac
Dysrhythmias None Asymptomatic, Persistent, no Requires Hypotension,
transient therapy required treatment ventricular
tachycardia,
fibrillation

Neurologic
Sensory None Mild paresthesia, Moderate Paresthesia –
Loss of deep paresthesia, interfering with
tendon reflex mild to moderate function, severe
objective sensory objective
loss sensory loss
Motor None Subjective Mild objective Objective Paralysis
weakness only weakness, no weakness with
significant impairment of
impairment of function
function
32 A Practical Approach to Gynecologic Oncology
in the brain continues even after first
trimester the exposure to the anticancer drugs
during second or third trimester may cause
brain damage. The list of adverse effects of
cytotoxic drugs in pregnancy is provided in
Table 2.4. The approximate incidence of fetal
malformations after exposure to chemo-
therapy during the first trimester is 15
percent.8 The rate drastically comes down to
approximately one percent if the chemo-
therapy is given in second and third
trimester. Antimetabolites are the most
potent teratogens.
Table 2.4: Adverse effects of antineoplastic
agents on the fetus and neonate
• Immediate adverse effects
• Spontaneous abortion
• Teratogenesis
• Low birth weight
• Preterm delivery
• Long-term complications
• Carcinogenesis
• Sterility
• Retarded physical and/or mental growth and
development
• Mutation
Management of cancer associated with
pregnancy needs an individualized approach
and a multidisciplinary team will be best suited
to handle such patients. The patient and her
relatives need to be counseled properly and
they should be encouraged to actively
participate in making treatment decisions. If
cure is a realistic goal, therapy should not be
withheld or modified to compromise the cure.
If possible, chemotherapeutic drugs should
be avoided in first trimester of pregnancy. If
it is unavoidable to give chemotherapy in
first trimester, folate antagonists should
be avoided. Single or combination chemo-
therapies in the standard dosages may be
given in second and third trimester without
significant risk of teratogenicity.
COMBINATION CHEMOTHERAPY
Antineoplastic agents are often used in
combination.9 The use of combinations of
drugs in cancer chemotherapy has been one
of the major advances made in this field.
Combination chemotherapy has several
important advantages. It usually results in a
decreased incidence of resistance. Secondly,
there is often a greater than additive or
synergistic effect of the drugs. This can be
explained by the first order kinetics principle
followed by the cytotoxic drugs to kill the
tumor cells. If drug A kills 90 percent of the
cells (1 log kill), combining drug B with A
will kill 90 percent of the 10 percent left after
A alone, resulting in a cell kill of 99 percent
(2 log kill). Similarly, combining drug C with
drugs A and B will achieve almost complete
eradication of tumor (99.9 percent, 3 log kill).
Finally, by using drugs with different types
of toxic effects the overall toxicity is
decreased. There are three generally accepted
guidelines for choosing drugs for combination
chemotherapy.
• Select drugs that are active against the
tumor when used alone
• Select drugs with different mechanisms of
action (to avoid combined resistance)
• Select drugs with minimally overlapping
toxicities.
ADJUVANT CHEMOTHERAPY AND
NEOADJUVANT CHEMOTHERAPY
Adjuvant therapy is defined as administration
of chemotherapeutic agents after removal of
the primary tumor, at which point no evidence
of residual disease exists. This has the
theoretical advantage of eliminating any
microscopic residual or metastatic cells thus
improving on the survival of the patient. This
is being used commonly for ovarian cancer
with established improvement in survival.
 Principles of Chemotherapy in Gynecological Cancers 33

Neoadjuvant chemotherapy has been chemotherapy is given prior to the surgery

introduced relatively recently. It is also called
primary or induction therapy. Neoadjuvant
chemotherapy refers to chemotherapy that is
administered prior to local therapy in patients
with localized disease for whom complete
effective treatment does not exist. Here
or radiotherapy. This can make an unresec-
table tumor operable. The other advantage
is the ability to monitor drug sensitivity in
the intact primary tumor allowing one to
determine what definitive local therapy could
be used.

Table 2.5: Chemotherapeutic drugs used in gynecologic cancers

Drugs Common treatment Common toxicities Diseases treated
schedules
1. Alkylating agents
• Cyclophosphamide 1.5-3.0 mg/kg/day p.o Myelosuppression, cystitis Breast, ovary, softtissue
10-50 mg/kg IV every + bladder fibrosis, sarcomas
every 1-4 weeks alopecia, hepatitis ame-
norrhea, azoospermia
2
• Iphosphamide 1.0 or 1.2g/m /day × 5 days Myelosuppression Cervix, ovary
2
With mesna: 200 mg/ m bladder toxicity,
Immediately before and CNS dysfunction,
4 and 8 hr after renal toxicity
iphosphamide
2. Alkylating-like agents
• Cis-dichlorodiamino 10-20 mg/m2/day × 5 days Nephrotoxicity, tinnitis and Ovarian and germ
Platinum (cisplatin) every 3 weeks or 50-75 and hearing loss, nausea cell carcinomas,
2
mg/m every 1-3 weeks and vomiting, cervical cancer
Myelosuppression,
Peripheral neuropathy
2
• Carboplatin 300-400 mg/m /day × 5 Less neuropathy, Ovarian and germ
days every 3-4 weeks ototoxicity, and nephro- cell carcinomas
toxicity than cisplatin;
more hematopoietic
Toxicity, especially throm-
bocytopenia
Than cisplatin
3. Antitumor antibiotics
2
• Actinomycin D 0.3-0.5 mg/m IV × 5 days Nausea and vomiting,skin Germ cell ovarian tumors,
every 3-4 weeks necrosis, mucosal ulcer- choriocarcinoma,
ation myelosuppression soft tissue sarcoma
2
• Bleomycin 10-20 units/m 1-2 times/ Fever, dermatologic Cervix, germ cell
/week to total dose of reactions, pulmonary ovarian tumors,
400 units; for effusions: toxicity, anaphylactic malignant effusions
60-120 units reactions
2
• Mitomycin-C 10-20 mg/m every Myelosuppression, local Breast, cervix, ovary
6-8 weeks vesicant, nausea and
vomiting, mucosal ulcer-
ations, nephrotoxicity
Contd...
34 A Practical Approach to Gynecologic Oncology

Contd...
Drugs Common treatment Common toxicities Diseases treated
schedules
2
• Doxorubicin 60-90 mg/m every Myelosuppression, alo- Ovary, breast, endo-
2
3 weeks or 20-35 mg/m pecia, cardiotoxicity, local metrium
every day × 3 every vesicant, nausea and
3 weeks vomiting, mucosal
ulcerations
4. Antimetabolites
• 5-fluorouracil 10-15 mg/kg/week Myelosuppression, Breast, ovary
nausea and vomiting
anorexia, alopecia
• Methotrexate Oral: 15-40 mg/day Mucosalulceration,
× 5 days;
2
IV: 240 myelosuppression
mg/m with leucovorin Choriocarcinoma,
hepatotoxicity, allergic
pneumonitis; breast, ovary
with intrathecal:
2
meningeal irritation
• Hydroxyurea 1-2 gm/m /daily for Myelosuppression, Cervix
2-6 weeks vomiting, anorexia
5. Plant alkaloids
• Vincristine 0.01-0.03 mg/kg/week Neurotoxicity,alopecia, Ovarian germ cell,
myelosuppression, sarcoma
2
neurotoxicity
• Epipodophyllotoxin 300-600 mg/m divided Myelosuppression, Ovarian germ cell,
(Etoposide) over 3-4 days every alopecia, hypotension choriocarcinoma
3-4 weeks 2
• Paclitaxel 135-250 mg/m as a Myelosuppression, Ovarian cancer,
3 to 24-hour infusion alopecia allergic breast cancer
every 3 weeks reactions, cardiac
arrhythmias

REFERENCES neoplasticagents.In: Parrillo JE, Masur H,

1. Burchenal JH. The historical development
of cancer chemotherapy. Semin Oncol
1977;4:135.
2. Skipper HE. Historic milestones in cancer
biology: A few that are important to cancer
treatment (revisited). Semin Oncol 1979;
6:506-14.
3. Baserga R. The relationship of the cell cycle
to tumour growth and control of cell
division: A review. Cancer Res 1965; 25:581.
4. Calabrest P, Parks RE Jr. Chemotherapy of
neoplastic diseses. In: Goodman LS, Gilman
A, (Ed): Goodman and Gilman’s The
Pharmacological Basis of Therapeutics. 6th
ed. New York: Macmillan 1980:1249.
5. Kaufman D, Rosen N,Young RC. Clinical
consequences and management of anti-
(Eds): The Critically Immunosuppressed
Patient: Diagnosis and Management.
Rockville, Maryland: Aspen Press, 1986.
6. Schilsky RL, ErlichmanC. Late compli-
cations of chemotherapy: Infertility and
carcinogenesis. In: Chabner BA, (Ed):
Pharmacologic Principles of Cancer
Treatment. Philadelphia: WB Saunders,
1982:109-31.
7. Potter JF, Schoeneman M. Metastasis of
maternal cancer to the placenta and fetus.
Cancer 1979; 25: 380-8.
8. Doll DC, Ringenberg QS, Yarbro JW.
Management of cancer during pregnancy.
Arch Intern Med 1988; 148: 2058-64.
9. Frei E III. Combination cancer therapy.
Presidential address. Cancer Res 1972; 32:
2593-607.
 3 Principles of Radiation
Therapy in Gynecologic Cancers
• Pravas M Patnaik • Bhagyalaxmi Nayak
INTRODUCTION
Carcinoma of the female genital tract
constitutes 30 percent of all cancers in India
and accounts for more than 50 percent of
cancers in the females. 1 In developing
countries the incidence of carcinoma cervix is
highest among the gynecologic malignancies
followed by carcinoma of ovary. Radio-
therapy plays an integral part in the
management of gynecological malignancies
in addition to surgery and chemotherapy.
Teletherapy (External beam radiation
therapy) and brachytherapy are the two
methods of radiation used in the management
of gynecologic cancers. The radiation used
may be gamma rays, X-rays or electrons.
Concurrent chemoradiation therapy (CCRT)
has produced better results in the manage-
ment of some of the gynecologic neoplastic
diseases, particularly that of cervical cancer.
BASICS OF RADIATION THERAPY
Radiotherapy is defined as a modality for the
treatment of malignant and rarely non-
malignant conditions by ionizing radiations.
Such radiations are capable of causing
ionization of the target molecules by removal
of an electron from the atom, leaving a
positively charged ion. Ionising radiations are
divided into two main groups:
• Sushil K Giri • Prabir Chaudhuri
• Electromagnetic radiations, e.g. gamma
rays and X-rays
• Particulate radiations, all charged and
uncharged particles with definite mass, e.g.
electrons, protons, alpha particles, neu-
trons, negative pimesons, etc.
Radiations that originate from the decay
of atomic nuclei like Cobalt 60, Cesium 137 ,
Iridium192, Radium226 are termed gamma rays.
The unstable atoms found in nature come to
a stable state by emitting radiations. This
process is known as radioactive decay and
such atoms as radioactive.
X-rays are emitted when high-energy
charged particles (e.g. electrons) bombard a
suitable target such as tungsten. Machines
such as betatron and linear accelerator can
generate electrons at high accelerations and
thus the X-rays generated by these machines
are quite high in energy. Gamma rays and
X-rays are collectively termed as photons.2
The second International Congress of
Radiology (1928) adopted ionization of air as
the measurable effect of radiation. The unit
of radiation was accepted as Roentgen.
Roentgen is defined as the amount of
radiation associated with corpuscular
emission per 0.001293 g of air, which produces
ions carrying one electrostatic unit of charge
in air. Calibration of the machines using this
unit became difficult once the high-energy
machines came into use. Presently, radiation
36 A Practical Approach to Gynecologic Oncology
is measured by the absorbed dose, defined
as the energy deposited by the radiation beam
per unit of mass as it passes through a
medium. The unit of absorption of ionizing
radiation in the biological material is
expressed in terms of rad that represents the
absorption of 0.01 joule energy per kilogram
of the medium. The more frequently used SI
unit for the same is called Gray (Gy) and 1
Gy = 100 rad or 100 centiGray (cGy).
MECHANISMS OF ACTION OF
RADIATION
The DNA is the principal cellular target for
ionizing radiation. Radiation produces
damage by direct as well as indirect effects
with the molecules. In case of direct effect,
radiation can interact directly with the critical
target molecules in the cell, causing ionisation
and excitation, which lead to biochemically
abnormal DNA. Indirectly, radiation
produces biological damage through the free
hydroxyl radicals (OH –) generated by
electrolysis of water. These free-radicals are
highly reactive because they have an unpaired
electron in the outer shell. They produce
damage to DNA by formation of organic
peroxide.
These direct and indirect effects of
radiation on DNA lead to cell death by two
methods:
• Apoptosis or programmed cell death,
where cells die immediately without
attempting cell division. Apoptosis is
characterized by chromatin condensation
and segmentation, fragmentation of the
nuclei and shrinkage of the cells.
• Cell necrosis or mitotic cell death, where
the cells sustaining severe DNA damage
loose their reproductive integrity and
proliferative potential. They die while
attempting division. The cell membranes
rupture, lysosomal enzymes are released
and nuclear chromatins are degraded.
Radiation-induced lethality is not instan-
taneous. The cells may continue functioning
and may even undergo a few cycles of
division before biological death occurs.
A single exposure of radiation kills a fixed
proportion of cells, although the number of
lethal and sublethal events could be
distributed throughout the cell population.
It is recommended that to maximize the
tumor response and to minimize the normal
tissue reactions, the total radiation dose must
be fractionated over a period of time. This
provides an opportunity for the normal tissue
to repair the sublethal damages and time for
the tumor cells to reassert themselves in to a
radiosensitive phase of cell cycle.
Fractionations may be of various types;
conventional fractions (about 2 Gy per day,
5 days in a week), hyperfractions, hypo-
fractions, accelerated hyperfractions, etc. The
dependency of biologic effectiveness on
degree of fractionation is known as ‘dose-
time relationship.’
Radiosensitivity is the response of the
tumor to irradiation that can be measured by
the extent of regression and length of time of
required for that. Radiosensitivity depends
on tissue oxygenation, volume of tumor at
the time of initial therapy and the dose
limiting factor, i.e. the tolerance of surroun-
ding normal tissue to radiation (Table 3.1).
Generally, the faster and more complete is
the tumor response, the greater is the chance
of curability, assuming that there is no distant
metastasis.
Table 3.1: Maximum tolerance dose of
radiation to different pelvic organs
Organ Maximum tolerable dose
Cervix and uterus 200-300 Gy
Vaginal mucosa 160-200 Gy
Rectosigmoid and large bowel 50-60 Gy
Small bowel 45-50 Gy
Urinary bladder 55-60 Gy
 Principles of Radiation Therapy in Gynecologic Cancers
FACTORS INFLUENCING THE
BIOLOGICAL EFFECTS OF IONIZING
RADIATIONS
Linear Energy Transfer
Linear energy transfer (LET) is defined as
the energy transfer per unit length of the
particle tract. The absorption of radiation in
the tissues and subsequent ionization along
the tracts of the ionizing particles depend on
the energy and charge possessed by the
particles. Photons give rise to fast electrons
that have negative charge but very small mass.
Such radiations are sparsely ionizing, low
linear energy transfer (LET) radiations.
Neutrons give rise to recoil protons that also
carry unit electric charge but have mass nearly
2000 times that of the electrons. Radiations
involving neutron particles are densely
ionizing and have high LET.
Radiosensitizers and Radioprotectors
Radiosensitizers are agents those potentiate
the action of radiation therapy. They are
chemotherapeutic agents like bleomycin,
cisplatin, 5-FU, paclitaxel, to name a few, and
nonchemotherapeutic agents like nitro-
imidazole group of drugs. Oxygen is one of
the most potent radiosensitizers. Well-
oxygenated cells are much more sensitive to
radiation than the hypoxic cells. Oxygen reacts
with the free radicals generated by radiation
and produces an organic peroxide that can
irreversibly change the chemical composition
of the DNAs exposed to radiation. In absence
of oxygen many of the ionized target
molecules could repair themselves to restore
normal function. The large tumors have
central cores of necrotic hypoxic tissue that
are insensitive to radiation. Hyperthermia
also enhances the effect of radiation.
Radioprotector, like amifostine reduces the
intensity of radiation toxicity. Amifostine is
metabolized to the active derivative by the
37
membrane-bound alkaline phosphatase
enzyme. The enzyme is selectively available
in the normal cells and is absent in neoplastic
cells. So the active metabolites are transported
into the normal cells that are selectively
protected from the radiation effects.
Rationale for Fractionation of the
Radiation Dose
The radiation dose required to eradicate a
tumor is delivered in small daily increments
or fractions over days or weeks. The
rationale for fractionation is based on the
differential response between the normal
tissue and the tumor tissue. The interval
between the fractions allows the normal cells
to repair sublethal damage and repopulate.
As opposed to that, during the interval the
tumor cells become more susceptible to
radiation damage due to reoxygenation and
redistribution of the cells to the more
sensitive phases of the cell cycles.
MODES OF ADMINISTRATION
OF RADIATION
External Beam Radiation
Therapy or Teletherapy
Two types of units are used for the purpose
of External Beam Radiation Therapy (EBRT),
also known as teletherapy. These are tele-
cobalt units with Cobalt60 sources emitting
gamma rays and linear accelerator units
producing photons and electrons. The
Cobalt60 teletherapy machines and the high-
energy X-ray generators like linear acce-
lerators have become the mainstay of external
radiation therapy. These machines are capable
of producing gamma rays or X-rays of more
than million electron volts (MeV) and are
known as mega-voltage machines. These
machines can treat deep-seated tumors
without significant toxicity to the surrounding
normal tissues. The linear accelerators
38 A Practical Approach to Gynecologic Oncology
produce two X-ray beams (6 MV and 18 MV)
and multiple energy electron beams (6 to 20
MeV). Machines emitting proton and neutron
beams have also been developed and are in
use in some selective centers. Conventionally,
the patient is treated five times a week over
a period of five to six weeks with each fraction
of 1.8 to 2.0 Gy.
Brachytherapy
The Greek word ‘brachy’ means ‘short
distance.’ This is the modality of treatment
in which radiation is delivered by placing the
radioactive isotopes in and around the tumor.
With this type of treatment, the absorbed
dose falls off very rapidly with increasing
distance from the sources. As a result, a very
high-dose of radiation can be delivered to
the tumor tissue without much significant
damage to the surrounding normal tissues.
Brachytherapy and teletherapy are comple-
mentary to each other.
Radioactive sources used for the purpose
of brachytherapy are Ra226, Co60, Cs137, Ir192,
I125 , etc.
The isotopes used are available in the forms
of tubes, needles, pallets, wires or seeds.
Depending on the lesion being treated, mode
of brachytherapy varies. Some of the common
modes are:
• Intracavitary
• Interstitial
• Surface dose applications
• Intraluminal
In intracavitary brachytherapy the natural
cavities of the body are used for temporary
insertion of isotopes close to the tumor, e.g.
cavities of uterus and vagina are used for
treating cancer cervix. In interstitial implant
brachytherapy the isotope is surgically
embedded into the tumor bearing tissue, e.g.
paracervical tissue in cancer cervix, vulvar
tissue in cancer vulva.
In surface dose applications (also called
mould brachytherapy) a mould is prepared
of acrylic compound to fit into the body
contour of the part to be treated. The radio-
active sources are mounted on this mould,
which is then applied in close proximity to
the tumor bearing area. Such types of mould
are commonly used to treat cancer of vagina.
Depending upon the rate at which the
absorbed dose is delivered to the prescription
point, the brachytherapy techniques are
classified as:
• Low dose rate (LDR): Dose rate 0.4 to
2 Gy/hr
• Medium dose rate (MDR): Dose rate 2 to
12 Gy/hr
• High dose rate (HDR): Dose rate more than
12 Gy/hr, usually in the region of 150 Gy/
hr.
• Pulsed dose rate (PDR): An HDR machine
is used for a series of short exposures every
hour to simulate a LDR exposure rate.
The preloaded or ‘hot source’ technique
of positioning the radioactive sources during
the operative procedure has become obsolete.
Only afterloading brachytherapy is practised
these days to minimize personnel exposure.
There are two methods of afterloading
brachytherapy applications; manual after-
loading and remote afterloading. The remote
afterloading techniques have now replaced
the manual afterloading techniques for better
dose distribution and better radiation protec-
tion for the staff involved in the procedure.
In remote afterloaders the applicators are
applied to the patient first and dummy
sources are inserted. The correctness of the
application is verified and the patient is
transferred to the treatment room. Once
correctly checked, the dummy sources are
removed and the applicator is connected to
the machine catheters. The machine drives the
source into the applicators after the machine
is programmed for source positions and time.
When a single source is being used, it is made
to dwell on the applicator at different
 Principles of Radiation Therapy in Gynecologic Cancers
positions for various lengths of time so as to
give simulation of multisource system.
The treatment by interstitial implants can
be temporary or permanent using the sources
like Ir192, I 125 or Au198 seeds. The seeds are
injected through a special gun to the affected
volume and left there to decay. In general,
the temporary implants are considered
superior because of the control on dose and
distribution of sources.
Treatment Planning and Simulation
The radiation oncologist in consultation with
the gynecologic oncologist identifies the
problem and develops an overall treatment
approach. CT scan, MRI scan, etc. determine
the anatomic extent of the known tumor. A
three-dimensional, anatomically accurate
treatment program is planned using a
computerized radiation treatment planning
system (TPS). The TPS calculates radiation
dose distribution in the patient’s body (two-
dimensional or three-dimensional) for a given
treatment plan and gives a visual display on
the screen with the option of having a hard
copy through the printer or the plotter. Thus,
one gets a three-dimensional distribution of
the dose in the patient demonstrating the
conformal approach of the planning.
With modern radiation unit it is possible
to deliver exact doses to exact site. Use of
simulator in treatment planning is of great
value. Simulator is an apparatus that uses a
diagnostic X-ray tube but mimics the
functions of a radiation treatment unit in
terms of its geometrical, mechanical, and
optical properties. The main function of a
simulator is to display the treatment field so
that the target volume may be accurately
encompassed without delivering excessive
irradiation to surrounding normal tissue.3 The
hard copy of the patient’s film serves as a
reference in case of future need.
39
RADIATION FOR CERVICAL CANCER
All cervical cancers, except stages I and IIA
are primarily treated with radiation therapy.
Large tumor burden even in stage I or IIA
calls for treatment of the entire pelvis with
radiotherapy. Radiation is planned to
eradicate tumor from the cervix, paracervical
tissue as well as from the pelvic lymph nodes.
Teletherapy
Majority of the cases are treated with a
combination of external beam radiotherapy
(EBRT) and intracavitary brachytherapy. A
dose of 45 to 50 Gy is delivered by EBRT
over five weeks, with daily fraction of 1.8 to
2.0 Gy, five fractions per week. As the tumor
shrinks making introduction of the uterine
and vaginal applicators easy, rest of the dose
is delivered by brachytherapy.
For EBRT either a two-field technique
(anterior and posterior) or a four-field
technique (anterior, posterior and two lateral
fields) is used. A four-field technique can
substantially reduce the volume of tissue
irradiated. So the damage to the normal tissue
is less. A simulation X-ray is taken to ensure
that the radiation field encompasses inferiorly
the inferior border of obturator foramen,
superiorly the L4 and L5 interface and laterally
1.5 cm beyond the pelvic brim. Para-aortic
nodes are included in the planning field in
extended field radiation therapy, the role of
which is still controversial. Extended field
radiotherapy has high morbidity without any
significant improvement in survival, hence not
commonly advocated.
Brachytherapy
Three different systems of administration
were developed to treat cervical cancer by
intracavitary brachytherapy:
• The Paris system
• The Stockholm system
• The Manchester system
40 A Practical Approach to Gynecologic Oncology
The Manchester system was the first
system designed to meet certain dosimetric
specifications and this system is used in
modified form in most centers. In the
Manchester system the applicator and loading
system was based on a dosimetric field
quantity to specific reference points in the
pelvis (points A and B), rather than milligram
hours (Fig. 3.1). Point A was defined as 2 cm
above the lateral fornix and 2 cm lateral to
the axis of the intrauterine canal. It
corresponds to the parametrial tissue. Point
B was defined as 3 cm lateral to point A at
the same horizontal level. Point B represents
the position of the lymph nodes in the pelvis.
The definition of point A was subsequently
modified. According to the new definition
point A is located 2 cm above the external os
and 2 cm lateral to midline.
The total dose to point A (EBRT and
brachytherapy combined) required for control
of central disease varies from 75 Gy for stage
IA disease to 90 Gy for stage III disease. The
dose prescribed to point B is between 45 and
65 Gy depending on the volume and extent
of the tumor.
The present day brachytherapy technique
for cancer cervix applies a hollow tube in the
Fig. 3.1: Position of points A and B and their relations
to the intrauterine tandem and vaginal colpostats
uterus (tandem) and intravaginal receptacles,
which are subsequently loaded with
radioactive sources ( 137Cs, 192Ir). The most
commonly used applicator for treatment of
cancer cervix is Fletcher-Suit-Delcos system.
Brachytherapy can be delivered by either
low dose rate (LDR) or by high dose rate
(HDR) technique. LDR brachytherapy has
been conventionally used and delivers 40 to
60 cGy per hour. The total tumoricidal dose
is delivered in 72 to 96 hours in one or two
sittings.
The HDR brachytherapy machines are
capable of delivering 0.5 to 5.0 Gy per minute.
The HDR regimens vary widely from center
to center. Many centers use 5 fractions of 5.5
to 6.0 Gy each to point A after 45 Gy EBRT to
the pelvis. Number of fractions varies from 2
to 13 in different centers.
HDR brachytherapy has tumor control and
complication rates comparable to LDR with
the following additional advantages:
• Treatment planning and dosimetry—can be
more accurate
• Patient immobilization time—very short
• Patient discomfort—minimum
• General anesthesia—not required
• Hospital admission or operating room set-
up—not required
• Radiation exposure to the medical staff—
virtually nil.
Interstitial template therapy is used in
patients in whom intracavitary tandem and
colpostats cannot be placed. Interstitial
needles are held in place by a template sewn
to the perineal skin. Once the applicators are
in place, Iridium192 tubes are inserted into
various needles by after loading technique.
The parametrial radiation is significantly
increased by this method.
Concurrent Chemoradiotherapy (CCRT)
The use of chemotherapy along with radio-
therapy is defined as concurrent chemoradio-
 Principles of Radiation Therapy in Gynecologic Cancers
therapy (CCRT). The use of chemotherapy
drugs in concurrence with radiation has
proved to be effective in cervical cancer4 with-
out significant increase in toxicity. The means
by which RT and CT interact are as follows:
• Modify radiation induced damage
• Inhibit repair of radiation-induced damage
• After drug delivery recruits cell to growth
phase when they are more sensitive to
radiation
• Enable small field size for radiotherapy.
As a single agent cisplatin is commonly
used at the dose of 40 to 50 mg/ m2 weekly
along with external radiotherapy. Brachy-
therapy is employed after chemoradiation. In
various trials, it has been observed that
cisplatin based chemotherapy given con-
currently with pelvic radiotherapy in cases
of cancer cervix improves disease free and
overall survival. No such benefit is achieved
with neo-adjuvant chemotherapy (chemo-
therapy prior to radiation).
RADIATION FOR
ENDOMETRIAL CANCER
Cancer of the uterine corpus is commonly
detected in the postmenopausal women. The
treatment planning of carcinoma of the uterine
corpus is based on the stage and other risk
factors. Surgery remains the main modality
for curable tumors and radiotherapy remains
as an adjuvant treatment. Radiation therapy
is used as an alternative primary modality
for the inoperable uterine malignancies.
Depending on the surgicopathological
features indicating the likelihood of relapse,
adjuvant treatment is offered.5
• Low risk disease: Grade I or II tumors,
lesions confined to uterine cavity without
myometrial invasion. Low risk disease
does not require any adjuvant treatment.
• Intermediate risk disease: Grade I or II
tumors, lesions confined to uterus with
41
myometrial invasion of less than half of its
depth. In such cases postoperative intra-
vaginal brachytherapy is indicated because
of 10 percent chance of vaginal recurrence.
• High risk disease: All grade III tumors,
tumors with myometrial invasion more
than half of its depth, cervical extension,
adnexal spread, lymph node metastasis are
included in this group. These group need
adjuvant radiotherapy, both EBRT and
brachytherapy.
Postoperative radiation reduces the risk of
pelvic recurrence in the medium and high risk
cases. But any clear advantage of this mode
of therapy in terms of reduction of mortality
is yet to be proved.
Postoperative irradiation is delivered four
to six weeks after total hysterectomy and
bilateral salpingo-oophorectomy. The target
volume is the pelvis and the vagina. The
prescribed dose is 46 Gy to this volume in
23 fractions over four and a half weeks. (i.e.
five fractions per week). The technique is a
four-field box technique with tele-cobalt with
blocks to shield part of the intestine and head
of femur. After a two weeks rest, the dose is
completed with brachytherapy using high
dose rate with two sequences of 7 Gy at the
surface of the vagina one week apart.
RADIATION FOR OVARIAN CANCER
The advent of the new chemotherapeutic
agents has reduced the role of radiation to a
considerable extent in cases of cancers of the
ovary. However, most of the ovarian cancers
are relatively radiosensitive and radiation
may help in reduction of masses which are
least responding to chemotherapeutic agents.6
Due to early dissemination of the disease
in the peritoneal cavity, whole abdominal
radiation has to be given for tumor control.
The recurrence free survival of postoperative
radiation depends on the amount of residual
42 A Practical Approach to Gynecologic Oncology
disease and is no better than adjuvant
chemotherapy. The toxicities are more with
radiation. Whole abdominal radiation can be
delivered either by the moving-strip
technique or by the open-field technique.
Randomized trials did not find any difference
between the two techniques.
Whole abdominal radiation has been tried
after surgery and chemotherapy either as
multimodality sequential therapy or as
salvage therapy for residual disease. The
randomised trials have failed to demonstrate
any benefit of the sequential use of
postoperative CT followed by RT over
postoperative CT alone.
The present role for radiotherapy is
generally limited to the palliation of recurrent
cancers not responsive to chemotherapy.
RADIATION FOR GESTATIONAL
TROPHOBLASTIC DISEASE
Patients with metastasis to brain and liver may
be given radiotherapy for palliation. The
recommended treatment to whole brain is
30 Gy in 10 fractions in two weeks in cases of
brain metastasis and in case of liver metastasis
the recommended dose is 20 Gy in 10 fractions
in two weeks. The intention of treatment is
to achieve palliative relief by reducing the risk
of hemorrhage.
Primary role in the management of gesta-
tional trophoblastic disease with radiotherapy
is not found.
RADIATION FOR VULVAR CANCER
The role of radiotherapy as primary mode of
management in cases of carcinoma of vulva
is limited, as surgery remains the mainstay
of management. Still radiation can play a
significant role in the management of vulvar
cancers in the following situations:
• If the inguinal lymph nodes are positive
radiation to pelvis reduces the regional
recurrence and improves survival
• If the surgical margins are positive or if
there are multiple local recurrences
• If the disease involves urethra (beyond the
lower third) or the anus preoperative
radiation can avoid exenteration
• In selected patients with clinically negative
groin nodes radiation to the groin can avoid
inguinal lymphadenectomy.
Radiation doses of 45 to 50 Gy in five to
six weeks of time are needed in the treatment
of bulky tumor, otherwise inoperable. Pre-
operative radiotherapy dose in those cases
with involvement of urethra or anus is usually
30 Gy in 15 fractions in three weeks time.
Concurrent use of chemotherapy with
cisplatin or 5-FU has found to give encou-
raging response rates.
RADIATION FOR VAGINAL CANCER
Cancers of the upper portion of the vagina
with intact uteri or large carcinomas of the
vault or vaginal wall are usually treated with
radiotherapy in the same technique as that of
carcinoma cervix, i.e. EBRT followed by
brachytherapy. Early stage of carcinoma of
the vagina may be well managed with
brachytherapy only.
Following ERBT, supplementary dose to
the tumor-bearing area can be delivered with
interstitial perineal implant (with or without
the intracavitary RT) in the situations like
advanced parametrial or local infiltration
(stages IIIB and IVA), distorted cervi-
couterine configuration, etc. Homogenous
dose delivery to the tissue can be achieved
with the advent of afterloading transperineal
perforated templates. Two different systems
currently used for this purpose are Martinez
Universal Perineal Interstitial Template
(MUPIT) and the Syed-Neblett system.
Iridium192 and Iodine125 are the isotopes used
for this procedure. The minimum dose
delivered by the MUPIT system is 25 to 30
Gy after the EBRT dose of 40 to 45 Gy. In
 Principles of Radiation Therapy in Gynecologic Cancers
Syed-Neblett system, the ERBT dose to
whole pelvis is 50 Gy with a central block
after 40 Gy. This is followed by two
interstitial implants with or without ICRT.
Additional dose of 40 to 60 Gy to point A
and 25 to 35 Gy to the parametrium is
delivered. The implant procedure may take
a time period of three to six days and may
cause pain and discomfort. Associated
complications are the risk of pelvic infection,
bladder and rectum perforation. The patient
should be adequately covered with hydration,
antibiotics, weak opioids, coanalgesics, etc.
PALLIATIVE RADIOTHERAPY
Metastases at distant sites or local recurrences
are seldom curable. Palliative RT is somewhat
tried in cases of brain metastasis or bone
metastasis to achieve some symptomatic relief
for the patient to improve the quality of life
(QOL), to alleviate the pain or sometimes to
control the hemorrhage, etc. Recommended
dose is 30 Gy in 10 fractions in a period of
two weeks or 20 Gy in five fractions in one
week according to the suitability.
COMPLICATIONS OF RADIOTHERAPY
An EBRT causes minimal complications. Mild
degree of tenesmus and diarrhea is often
noticed in the 3rd week of treatment. Low
residue, milk-free diet and the use of related
drugs can manage the condition.
Structures with poor tolerance suffer most
from the radiotherapy-induced morbidities
and is due to the factors like proximity of
certain sources to some of the vital structures
and the degree of integral dose received by
the pelvis (integral dose is measured by the
product of the weight of the tissue irradiated
and the average dose received by it). During
brachytherapy it is always very important to
remember the anatomical relation of the
ovoids to the rectum and the trigone of
bladder. In retroverted uterus, the intra-
43
uterine tube lies very close to rectosigmoid
junction and rectum. Sometimes, a small
intestinal loop within the pelvis may be
overdosed, as it comes very close to the
intrauterine source causing watery diarrhea,
occasional perforation and stricture formation
later on. Such complication can be avoided
by raising the foot end of the bed during the
procedure, which will help the small intestinal
loop to recede into the abdomen. Placement
of a good pack between the ovoid and
anterior rectal wall reduces the rectal dose
and thus rectal complications. Continuous
drainage of the urinary bladder with a Foley’s
catheter during the procedure will help to
minimize the bladder dose. Thus, it is
observed that simple precautions are very
much helpful in avoiding unwanted radiation
induced complications.
Radiation induced complications are
classified into three grades, which are Grade
I, Grade II and Grade III reactions.
Grade I complications are temporary and
respond to usual conventional treatments.
Grade II complications are more severe in
degree of intensity but are still manageable
with nonsurgical forms of treatment. These
are telangiectasia and bleeding from the blad-
der, rectal ulceration and long-standing
tenesmus, chronic diarrhea, subacute intesti-
nal obstruction.
Grade III reactions are those, which do not
respond to conventional treatment but require
surgical correction. These are contracted blad-
der, rectal stricture, rectosigmoid stricture,
rectosigmoid ulceration and bleeding,
rectovaginal and vesicovaginal fistulae, etc.
Pelvic irradiation in menstruating women
leads to suppression of ovarian functions
inducing menopause in most patients. Radia-
tion may lead to discomfort and woodiness
in the pelvic region due to the development
of fibrosis in parametrium. Poor sexual
life is often reported in patients of pelvic
44 A Practical Approach to Gynecologic Oncology
irradiation due to dyspareunia from narrow-
ing of the vagina. It is not very uncommon to
find post-radiation therapy patients present-
ing with bilateral lower limb edema due to
lymphatic obstruction.
If planning of radiation dosage is done
properly not more than 15 to 20 percent of a
patient population should suffer from the
reactions. Chances for morbidity is consi-
derably increased in association with sys-
temic diseases like diabetes, leprosy, hyper-
tension, peripheral vascular diseases, steroid
retention enema may help in intractable tenes-
mus and rectal bleeding.
REFERENCES
1. Kilara G. Radiation therapy in gynecologi-
cal cancers. In: Principles and Practice of
Obstetrics and Gynecology for Post-gradu-
ates, 2nd edn. Jaypee Brothers. 2003;
523-26.
2. Disaia PJ, Creasman WT. Basic principles
of gynaecologic radiotherapy. In: Clinical
Gynaecologic Oncology 5th edn. Mosby
Year Book: St Louis 1997;617-31.
3. Harold D’ Souza, T Ganesh, RC Joshi, R
Kumar. Teletherapy concepts and equip-
ment. In: Textbook of Radiation Oncology:
Principle and Practice. GK Rath, BK
Mohanti, (Eds): BI Churchill Livingstone:
New Delhi, 2000;112-29.
4. National Cancer Institute. Concurrent
chemoradiation for cervical cancer. Clinical
announcement. Washington, D.C., February
22, 1999.
5. SK Giri, Jita Parija, Nayak BL. Endometrial
carcinoma In: Principles and Practice of
Obstetrics and Gynaecology for post-
graduates, 2nd edn. Jaypee Brothers.
2003;517-22.
6. John E Byfield, Conley G Lacey. Principles
of radiation therapy. In: Synopsis of
Gynaecologic Oncology, 5th edn. Churchill
Livingstone, 1998;439-97.
 4 Tumor Markers in
Gynecologic Cancers
INTRODUCTION
Tumor markers are biological substances that
are closely associated with the process of
carcinogenesis. Considering the clinical utility
of these markers in the diagnosis and
management of cancer, lot of cancer research
is directed toward the evolution of new
tumor markers. In last 30 years, since the
introduction of diagnostic immunology, a
large number of tumor markers have been
evaluated and applied in clinical practice.
A tumor marker is defined as a substance
that is produced by the body (host) in
response to cancer or by the cancer tissue
itself. Tumor markers can be measured
quantitatively by specific laboratory tests.
The qualitative procedures like Pap smear,
detection of fecal occult blood or immuno-
staining of cells in tissue section are not
included in tumor markers. The tumor
markers are usually released into circulation
and measured in blood. In addition, these
tumor markers can be measured in tissues and
body fluids including urine and cerebrospinal
fluid. In recent years, the definition of tumor
marker has been expanded to include
molecular markers and genetic markers
(chromosomal aberrations and oncogenes).
The researches on tumor markers started
more than a century ago with the discovery
of Bence-Jones protein in 1848. In later part
• Veena Jain • Satish Jain
of the last century a number of tumor markers
like AFP (Alpha-fetoproteins), CEA (Carcino-
embryonic antigen) and SCC (Squamous cell
carcinoma antigen) were introduced into
clinical practice. The tumor markers are
usually tumor-associated cell surface antigens
or intracellular proteins. Certain enzymes or
hormones associated with neoplasms also act
as tumor markers. They can be detected by
various specific and sensitive techniques like
radioimmunoassay (RIA), immunoradio-
metric assay (IRMA), enzyme-linked
immunosorbent assay (ELISA), enzyme
immunoassay (EIA) and radioreceptor assay
(RRA). The classification of tumor markers
is shown in Table 4.1.
CLINICAL UTILITY OF TUMOR MARKERS
A tumor marker can be a useful tool in
management of various gynecologic cancers
in the following clinical settings:
• Screening
• Early diagnosis
• Prognosis and assessment of therapeutic
efficacy
• Early detection of residual or recurrent
disease.
The clinical utility of a tumor marker
depends upon the characteristics of the tumor
markers such as specificity, sensitivity and
correlation of tumor marker level with the
46 A Practical Approach to Gynecologic Oncology

Table 4.1: Classifications of tumor markers Tumor Marker as a Screening Test

Tumor markers type Example Screening aims to identify the persons with
1. Enzymes • Lactate dehydrogenase high risk of having a disease before the
• Alkaline phosphatase appearance of symptoms, either from the
• Prostatic acid phosphatase
(PAP)
general population or from population at risk.
2. Hormones • Human chorionic gonadotro- The screen positive persons need to undergo
phins (hCG). further diagnostic tests for confirmation of
• Calcitonin disease. The accuracy of a screening test is
• Adrenocorticotropic evaluated by its sensitivity, specificity,
hormone (ACTH)
negative and positive predictive values.
3. Glycoproteins
a. Oncofetal • Alpha fetoprotein (AFP)
Whereas high sensitivity indicates that a test
(expressed in • Carcinoembryonic antigen is capable of identifying correctly high
normal cells at (CEA) number of true positive cases, high specificity
embryonic or • Tissue polypeptide (specific) implies the capability of a test to correctly
fetal stage but antigen (TPA, TPS) exclude high number of true negative cases.
not in adult • Cytokeratin-18
Positive predictive value is the percentage of
stage)
b. Others • Breast cancer antigen patients with positive test truly harboring the
(CA-15.3) disease. A screening test with a high negative
• Ovarian cancer antigen predictive value will have very few true
(CA-125) positive cases among those tested negative.
• Colorectal and pancreatic However, the ultimate test of effectiveness
cancer antigen (CA-19.9)
of a tumor marker as a screening test would
4. Miscellaneous • Host products that increase
group in response to tumors be its ability to reduce the mortality from the
• Serum ferritin levels disease under consideration. CA-125 is yet
• Cytokine levels to be accepted as a perfect screening test for
• Glycolipids ovarian cancer because there is still no
5. Molecular and • HPV DNA in carcinoma concrete evidence that screening the
genetic markers Cervix
population for ovarian cancer using the test
• Mutations of oncogenes and
tumor suppressor genes reduces mortality.
• BRCA-1
• BRCA-2 Tumor Marker as a Diagnostic Test
• C-erb
• C-myc In lesions detected clinically and/or
• p53 radiologically, tumor marker levels may help
confirm the diagnosis of a cancer. Estimation
tumor burden. An ideal tumor marker should of serum beta hCG level for confirming the
have 100 percent sensitivity and specificity. diagnosis of gestational trophoblastic disease
That is feasible if a tumor marker is produced is a classic example of using tumor marker as
only by cells of a specific tumor, as soon as a diagnostic test. Unfortunately, other tumor
the malignant process starts and not be markers do not have similar high diagnostic
present in normal individuals or in benign accuracy. Negative result of tumor marker
conditions. Unfortunately no tumor marker assay does not exclude presence of a
identified till date fulfills that criteria. malignancy with confidence.

Tumor Marker as a Prognostic Test
Extreme elevation of levels of tumor marker
often indicates a poor prognosis and in some
malignancies may indicate the need for more
aggressive therapy. Once the diagnosis is con-
firmed, estimation of tumor marker is of
immense help in prediction of drug response.
Since the numerical value of marker concen-
tration correlates well with the amount of
tumor burden, the rate of fall of these levels
provide useful information regarding
response to treatment and drug therapy.
Thus, the profile of tumor marker levels as a
function of time can provide critical informa-
tion about the cancer status. A rapid decline
in tumor marker suggests that the treatment
regimen has been successful.
Tumor Marker for Follow up
After Treatment
The most useful clinical application of tumor
marker is the follow up of treated cancer
patients to detect the residual tumor or early
recurrence. Persistent high level of marker
after completion of treatment correlates well
with persistent disease that may not be
clinically or radiologically obvious. During
follow up a measurable rise in tumor marker
levels in treated patients with normal levels
is a strong indication of recurrence of disease.
Often this increase is observed several
months before the demonstration of the
clinical recurrences.
Search is still going on for agents that
would foot the bill for an ideal tumor marker.
The new agents have to undergo rigorous
clinical trials to prove their low false-positivity
or false-negativity before being inducted in
routine clinical practice. Analytical results
performed must be equivalent when tested
at different laboratories and reproducible.
The method of assays should be simple, so
that facilities are available for the population
Tumor Markers in Gynecologic Cancers 47
at large. In addition cost effectiveness is an
important issue especially in developing
countries.
TUMOR MARKERS FOR
INDIVIDUAL MALIGNANCIES
Ovarian Epithelial Tumors
Carcinoma Antigen-125
Carcinoma antigen-125 (CA-125), described
by Bast et al in 1983, is the most widely
employed marker for epithelial (most
commonly serous) ovarian cancer. CA-125 is a
high molecular weight (>200 kD) glycoprotein
expressed on the surface of celomic
epithelium and is recognized by the murine
(developed in mice) monoclonal antibodies
OC-125.1 CA-125 antigen is identified in fetus
in the derivatives of celomic epithelium,
e.g. peritoneum, pleura, peri-cardium and
amnion. In an adult it has been detected in
epithelium of fallopian tube, endometrium
and endocervix but is not expressed in normal
adult or fetal ovarian epithelium.
Serum levels of CA-125 are determined by
radioimmunoassay. A cut off value of 35 IU/
ml or lower in the serum is considered
normal. Still three percent of normal healthy
women have serum concentration of CA-125
more than 35 IU/ml and 0.8 percent may have
level higher than 65 IU/ml without any
obvious pathology.2-4
Elevated serum levels of CA-125 are seen
in 80 percent of women with epithelial cancers
of ovary and 26 percent of the women with
benign ovarian tumors. 5-8 Many non-
neoplastic conditions may be associated with
elevated CA-125 levels. These include first
trimester pregnancy, menstruation, endo-
metriosis, adenomyosis, uterine fibroids,
acute salpingitis, hepatic disease (e.g.
cirrhosis) and any condition associated with
inflammation of peritoneum, pericardium or
48 A Practical Approach to Gynecologic Oncology
pleura. CA-125 levels are elevated in cancers
other than that of ovaries. These are maligna-
ncies of endometrium, endocervix, fallopian
tube, breast, pancreas, stomach, liver, bile
duct, colon and lung. CA-125 is thus a tumor
associated but not tumor-specific tumor
marker.
Estimation of CA-125 in serum has been
widely tried as a screening test for carcinoma
ovary. Though, nearly 90 percent patients
with advanced epithelial ovarian malignancies
(Stage II and above) have serum concen-
trations of CA-125 more than 35 IU/ml, among
patients with early disease confined to ovary
(Stage I) only 50 percent show increased
levels.1
In a Swedish study CA-125 was measured
annually in 550 women older than 40 years.9
If the levels were more than 30 IU/ml,
sequential CA-125 levels were obtained more
frequently, i.e. every three months along with
pelvic examinations and transabdominal
ultrasound performed every 6 months. Only
six ovarian cancers were detected out of 175
women with elevated CA-125 levels.
Combined serum CA-125 (>35 IU/ml) and
pelvic examination as screening test for
ovarian cancer has a specificity of 99.6 percent
and a positive predictive value of 6 to 25
percent.10 Due to low prevalence of disease
in patients without a family history of ovarian
cancer, screening these women using USG
and CA-125 together has a very low positive
predictive value.11-13 Since the screen positive
women have to undergo laparotomy/ laparo-
scopy (surgical procedure) for confirmation
of diagnosis of ovarian cancer, the positive
predictive value of a screening test for ovarian
cancer should be high (at least 10%). 14
Considering the high false-positive results,
routine screening for ovarian cancer is not
yet advocated. Screening may be more
effective in women with family history of
ovarian cancer.15 The impact of screening on
morbidity and mortality in this high-risk
group is not well established.
In young patients CA-125 assays should be
carried out when patient is not menstruating
as markedly elevated levels may be seen
during menses. In women with pelvic mass,
serum concentrations of more than 35 IU/ml,
65 IU/ml and 95 IU/ml can distinguish
malignancies from benign diseases with 82
percent, 93 percent and 96 percent accuracy,
respectively.16,17 Studies suggest that various
CA-125 cut off levels ranging from 65 to 200
IU/ml are necessary to distinguish benign
cyst from malignant cyst in premenopausal
women.18 Moreover, rising values on serial
CA-125 assay is an indicator that a malignancy
may be present. A stable or declining level
suggests a non-malignant lesion.
One of the useful qualities of CA-125 in
clinical practice is that its serum level
correlates well with tumor burden in 80 to
95 percent of the cases. A study that
evaluated CA-125 as a prognostic marker
observed that patients with CA-125
concentrations more than 450 IU/ml had a
very poor median survival of 9 months as
compared to patients with CA-125 concentra-
tions less than 55 IU/ml. The second group
had a better median survival of 23 months.19
Another study did not find independent
prognostic effect of preoperative CA-125
levels on survival, after adjusting for other
factors by multivariate analysis.20 However,
postoperative CA-125 level is an independent
prognostic variable.21
Serum CA-125 levels decline after removal
of tumor and have a half-life of 4.5 days.
Postoperative serum CA-125 level predicts
two years overall survival (87% with levels
less than 35 IU/ml to 30% if level is more
than 65 IU/ml).22 Rate of fall after start of
chemotherapy is also an important prognostic
factor and most studies have shown that
serum CA-125 levels after three cycles of

chemotherapy are accurate predictors for the
probability of a patient achieving a complete
remission. 21 The efficacy of CA-125 for
identifying progression and non-progression
during first line chemotherapy is 90.5 per-
cent.23
Nearly 50 percent of the patients with
normal CA-125 show disease at second look
laparotomy, thereby indicating that normal
levels do not rule out the presence of disease.24
Normal levels after three cycles of chemo-
therapy cannot be used as a guide for
treatment decision because of lack of its
predictive value. In patients with normal CA-
125 values after treatment, more than one
subsequent elevated CA-125 levels are highly
predictive of active disease.25,26 This rise in
CA-125 may precede the clinical and
radiological evidence of recurrence by three
to six months.
Other Markers
Since CA-125 estimation has low accuracy as
a screening test, studies are ongoing to find
more sensitive tumor markers for ovarian
cancer screening. Macrophage colony-
stimulating factor (M-CSF) has been detected
in epithelial ovarian tumors and in the serum
or ascitic fluid of 70 percent patients with
diagnosed carcinomas.21 Serum M-CSF levels,
together with CA-125 levels may be more
predictive than CA-125 levels alone.27 OVX-I
is a newly developed antibody that may also
complement CA-125.28 A panel of CA-125, M-
CSF and OVX-I has been shown to identify
early stage ovarian cancer with extremely
high sensitivity and moderate specificity in
preliminary studies.29 In early stage disease
at least one of the three markers was elevated
in 76 percent cases.
The addition of other new tumor markers
like CA-15.3 or TAG-72.3 to CA-125 has
shown to improve the specificity. In clinical
Tumor Markers in Gynecologic Cancers 49
situations with inconclusive or negative CA-
125 serum values, another tumor marker
CASA (Cancer Associated Serum Antigen)
may be of help.30
In ovarian cancer mutation of the p53
tumor suppressor gene is the most important
genetic alteration associated with high grade
tumor and poor survival. Presence of BRCA-
I and BRCA-II mutations carry a lifetime risk
of 10 to 42 percent (more with BRCA-I
mutations) of developing ovarian cancers.65
K-ras mutations are seen in 40 percent cases
of advanced stage mucinous ovarian tumor.
Some growth factors and cytokines are also
under research for their association with
ovarian cancer. These are epithelial growth
factor (EGF), tumor necrosis factor (TNF-β),
vascular epithelial growth factor (VEGF), etc.
Ovarian Germ Cell Tumors
Germ cell tumors originate from the
primordial germ cells of the ovary. The
majority of malignant germ cell tumors
produce tumor markers. These tumor
markers are very useful for diagnosis and for
monitoring the disease after treatment.
Various tumor markers associated with
germ cell tumors of ovary are α-fetoprotein
(AFP), β human chorionic gonadotropin (β-
hCG), human placental lactogen (HPL),
pregnancy specific β1-glycoprotein, trans-
ferrin, α 1-antitrypsin, carcinoembryonic
antigen (CEA), alkaline phosphatase enzyme,
lactate dehyrogenase enzyme, CA-125 and
neuron- specific enolase.31 The various tumor
markers in different histologic subtypes of
germ cell tumors are shown in Table 4.2.
AFP is most commonly used marker for
germ cell tumors because of its association
with endodermal sinus tumors, malignant
teratomas and embryonal carcinomas. The
upper normal values of AFP are 5 ng/ml.
The other non-neoplastic and neoplastic
50 A Practical Approach to Gynecologic Oncology
Table 4.2: Biological markers of malignant germ cell tumors
Tumor types AFP hCG
Dysgerminoma – +
Endodermal sinus tumor + –
Immature teratoma + –
Embryonal carcinoma + +
Choriocarcinoma – +
Mixed + +
disorders, where it may be raised are
hepatitis, cirrhosis of liver, gastrointestinal
malignancies, breast cancer and primary or
metastatic hepatic tumors.32 Lactate dehydro-
genase (LDH) is a glycolytic enzyme. Serum
LDH has been found to be markedly elevated
in patients with ovarian dysgerminoma and
sharply returns to normal level following
treatment. LDH can also be demonstrated by
histochemical method within the tumor cells.33
Although the markers are important in
diagnosis of germ cell tumors, their most
reliable use is in monitoring the response to
therapy and detection of early recurrences.
Ovarian Granulosa Cell Tumors
Serum inhibin concentrations are elevated
(>122 IU/L) in women with granulosa cell
tumor (100%) or mucinous cystadeno-
carcinoma (89%). Patients with benign
ovarian tumors also have elevated serum
concentration (30%) of inhibin. 40 Serum
inhibin levels are useful for detection of
relapse. Although numbers are small, serum
inhibin is a nearly perfect marker for moni-
toring of patients with granulosa cell tumors.41
Mullerian inhibiting substance (MIS) which
is usually undetectable in females before
puberty is raised in patients with granulosa
cell tumors. The levels falls dramatically after
surgery.42 MIS may be an effective marker for
granulosa cell tumor and Sertoli-Leydig cell
tumor to observe the response to treatment
and detect early recurrence.43
34-39
LDH CA-125 Others
+ + ALP +
+ +
+ + CA-19.9 +
– +
– +
+ +
Gestational Trophoblastic Tumors
Gestational trophoblastic tumor is a malignant
tumor where nearly an ideal tumor marker
is available and that marker is serum β hCG.
With the exception of germ cell tumors, only
benign or malignant trophoblastic cells
produce β hCG. If normal pregnancy is
excluded, β hCG is highly sensitive and
specific tumor marker for trophoblastic
disease. Only 10,000 tumor cells are required
to produce a detectable level of hCG in
serum. Estimation of β hCG is of central
importance in the diagnosis, treatment, follow
up and detecting early recurrence of
gestational trophoblastic disease.
hCG is a placental hormone consisting of
α and β chains. The a chain shows cross
reaction with pituitary hormone, e.g.
luteinizing hormone (LH) and thyroid-
stimulating hormone (TSH). β subunit (β hCG)
does not cross react with these hormones and
is estimated by technique of radioimmu-
noassay.45 Normal levels of β subunit in adult
non-pregnant females are 5 to 8 mIU/ml.
After complete evacuation of hydatidiform
mole, serum concentrations of β hCG fall
rapidly with a half-life of 12 to 20 hours and
levels come back to normal in 8 to 10 weeks.46
Persistence may indicate local or less often
metastatic disease. Marked elevation (>40,000
mIU/ml) indicates high risk group, thereby
the need for aggressive therapy.47 Elevated
cerebrospinal fluid (CSF) concentration of β
hCG is associated with choriocarcinoma and

a serum/CSF ratio of less than 60:1 indicates
the presence of metastasis to the central
nervous system (positive predictive value
86%, negative predictive value 100%).48, 49
After the initiation of therapy a good
response can be documented by a prompt 1
log or greater reduction in titer in 18 days.
Plateau or rise in levels during therapy
demands an alternative therapy. Three
consecutive serum hCG levels done at
intervals of one month are diagnostic of
complete remission.
Cervical Cancers
For cervical cancers cytology (Pap smear)
followed by colposcopy-guided biopsy is the
best method for screening and early detection
of primary cancer. Tumor markers may be
useful for monitoring the clinical course of
therapy and early detection of recurrence for
which cytologic examination is not very
effective. Human Papilloma Virus (HPV)
subtypes and viral load, squamous cell
carcinoma antigen (SCC-Ag) and tissue
polypeptide antigen (TPA) have been tried
for this purpose in cervical cancer.
HPV Subtypes and Viral Load
A causal association exists between HPV
infection and invasive carcinoma of cervix.
HPV DNA has been identified in more than
95 percent of cervical carcinomas.50 Types 16,
18, 31, 35 and 39 are commonly associated
with high grade and invasive cervical cancer.51
HPV 16 is associated with large cell
keratinizing tumor and with low recurrence
rate while HPV 18 is more virulent and
associated with poorly differentiated
carcinoma. 52-54 With HPV 18 there is an
increased incidence of lymph node involve-
ment, poor response to treatment and high
rate of disease recurrence. In two studies of
Tumor Markers in Gynecologic Cancers 51
patients with histologically negative lymph
nodes, investigators have reported higher
rates of disease recurrence when PCR assay
of the lymph nodes were strongly positive
for HPV DNA.55,56
Squamous Cell Carcinoma Antigen
Squamous cell carcinoma antigen (SCC-Ag)
is a 48 kD neutral isoelectric subfraction of
tumor antigen 4 (TA-4).57 It is found in the
cytoplasm of keratinizing and large cell
nonkeratinizing squamous cell carcinoma, but
not in the small cell, nonkeratinizing type.58
SCC-Ag serum concentration can be positive
also in squamous cell carcinoma of the lung,
esophagus, vulva and oropharynx. Adeno-
carcinoma and small cell carcinoma of lung,
adenocarcinoma of stomach and colon and
hepatocellular carcinoma are also associated
with elevated SCC-Ag. Less than five percent
of normal healthy subjects, both men and
women, have a serum concentration more than
2.0 ng/ml.
The serum concentration of SCC-Ag in
patients with squamous cell carcinoma of the
cervix is stage dependent. SCC-Ag levels
higher than 2.5 ng/ml are seen in 0 to
16 percent of precancers, 29 to 34 percent of
stage I, 59 to 64 percent of stage II, 85 to
86 percent of stage III and 80 to 85 percent of
stage IV cervical cancers.59 SCCAg provides
a potential means of monitoring patients for
recurrent carcinoma, because 82 percent of
patients with recurrent disease will be
positive.60 However, investigators disagree
about the independent predictive value of this
test.
Tissue Polypeptide Antigen
The tissue polypeptide antigen (TPA) is a
single chain polypeptide with a molecular
weight of 45 kDa. The reported sensitivity of
52 A Practical Approach to Gynecologic Oncology
TPA in detecting cervical cancer varies from
28 to 34 percent and the specificity approaches
96 percent. Its usefulness has been evaluated
in early stage carcinoma cervix with otherwise
low risk prognostic factors to detect early
recurrence.61
Carcinoembryonic antigen (CEA), a
glycoprotein with a molecular weight of 200
kDa is elevated in about 35 percent of patients
with squamous cell carcinoma of uterine
cervix.62 Pretreatment CEA levels correlate
well with the stage of disease.
Presence of high risk HPV is an important
but not the only factor for cervical carci-
nogenesis. Research is ongoing to delineate
these molecular markers, acting as cofactors
for carcinogenesis. In cervical adenocarci-
noma over expression of HER-2/neu is seen
in 25 percent cases and its presence is strongly
associated with advance stage. Other non-
HPV related molecular abnormality seen in
cervical cancer is expression of cell cycle genes
such as bcl-1 and bcl-2.
Endometrial Cancer
There is no tumor specific marker available
for endometrial cancer. Combination assay
of several tumor markers including cancer
antigen 125 (CA-125) is of some diagnostic
value. If raised, can be used for follow up of
cases.63 In endometrial carcinoma estrogen
and progesterone receptor assay has been
found to be of some prognostic significance.
When extrauterine disease is present, the five
years overall survival rates are 67 percent and
62 percent for patients with tumors positive
for estrogen and progesterone receptors
respectively. The survival rates are 36 percent
and 21 percent respectively for those patients
in whom the estrogen and progesterone
receptors are absent.64
Among the genetic markers in endometrial
cancers, presence of p53 mutations confers a
poor prognosis. Over expression of HER-2/
neu has been associated with advanced stage,
deep myometrial invasion and poor survival.
CONCLUSION
In summary a variety of biochemical and
molecular tumor markers are available at
present which can be used for screening,
diagnosis, assess response to treatment and
prognosis and follow up of cancer patients.
Prior to their use in clinical practice one must
be aware of their potential usefulness and
limitations. For screening purposes no ideal
tumor marker is available, yet most of them
are very useful for follow up after treatment
and early detection of recurrence. Availability
of molecular markers in future may be of help
in detection of high risk population where
other diagnostic tests may be applied. In
previously diagnosed cases of cancer,
detection of poor prognostic group may help
to initiate more aggressive therapy. Whatever
their application, evaluation of cost effective-
ness of these tumor markers is an important
aspect for consideration in developing
countries.
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56 A Practical Approach to Gynecologic Oncology
Vulvar Intraepithelial
5 Neoplasia
INTRODUCTION
A plethora of terms has been applied to vulvar
inflammatory or preneoplastic lesions; these
include leukoplakia, lichen sclerosus, Bowen’s
disease, neurodermatitis, hyperplastic
dystrophy etc. Looseness of the terminology
led to a wide range of treatments including
radiotherapy and wide local excision of
lesions with unproven malignant potential.
A commonly used term to represent vulvar
preneoplastic conditions is ‘dystrophy’ that
suggests impaired nutrition or vasculariza-
tion. There is no evidence of these processes
in the etiology of vulvar dermatoses and the
malignant potentials of various types of
dystrophies are not similar.
Considering all these confusions and ambi-
guities in the nomenclature the International
Society for the Study of Vulvovaginal
Diseases (ISSVD) recommended a new system
of nomenclature that was subsequently
accepted by World Health Organization.1 This
classification is based on both the findings of
gross appearance and histopathology in
contrast to the previous classification that was
based solely on histological findings.
NOMENCLATURE
The latest ISSVD classification of vulvar
disease is described in Table 5.1. In most
instances a clinical diagnosis can be made on
the basis of gross inspection alone. However,
• Mridul Gehlot
Table 5.1: Classification of vulvar disorders
1
(ISSVD, 1989)
I. Non-neoplastic epithelial disorders
A. Lichen sclerosus
B. Squamous cell hyperplasia (formerly known as
hypertrophic dystrophy)
C. Other dermatoses
The current classification recommends that li-
chen sclerosus with associated squamous cell
hyperplasia should be reported as such rather
than as a ‘mixed dystrophy’.
II. Mixed non-neoplastic and
neoplastic epithelial disorders
When lichen sclerosus or squamous hyperplasia
is associated with vulvar intraepithelial neopla-
sia (VIN), both diagnoses should be reported.
III. Intraepithelial neoplasia
A. Squamous Intraepithelial Neoplasia
VIN I (Mild dysplasia)
VIN II (Moderate dysplasia)
VIN III (Severe dysplasia or carcinoma in situ)
B. Nonsquamous Intraepithelial Neoplasia
Paget’s disease
Melanocytic proliferations
(melanocarcinoma in situ)
* VIN III encompasses Bowen’s disease, erythropla-
sia of Querat, and carcinoma in situ, simplex type.
Bowenoid papulosis is not a histopathologic diag-
nosis, but a clinical presentation.
this is not always possible and a histologic
diagnosis is required for the correct classi-
fication of disease. This is important, since
the management of the patient will vary
significantly depending upon the final
diagnosis.

NON-NEOPLASTIC EPITHELIAL
DISORDERS
Lichen Sclerosus
Lichen sclerosus was first described by Henri
Hallopeau in 1897 who referred to it as lichen
planus atrophicus. Though most commonly
seen in the genital area in women, it may also
be found on other sites of the body. Lichen
sclerosus is primarily a disease of the
postmenopausal woman, however, it can be
seen at any age and not uncommonly in
children.
Pruritus is the most common symptom and
is observed in 99 percent of the patients with
the disease. Vulvar irritation, burning and
dyspareunia are the other common
symptoms. The lesions characteristically look
like dry parchment paper with atrophy of the
labia. The labia minora undergoes adhesion
to adjacent majora. Edema, scarring and
agglutination of prepuce and frenulum
gradually convert the glans of clitoris into
pale amorphous tissue. These structural
alterations are clinical hallmarks of lichen
sclerosus. Lesions are often bilaterally
symmetrical and may involve the perianal
region.
A strong relationship between the presence
of lichen sclerosus and invasive squamous cell
carcinoma of the vulva was suggested in the
first part of last century. Later on, enough
evidences were gathered to prove that the
risk of a woman with lichen sclerosus
developing invasive squamous cell carcinoma
of the vulva is extremely small, varying
between 2 and 5 percent. Currently, the
appropriate treatment for lichen sclerosus is
one of the high potency corticosteroids,
clobetasol propionate applied on the vulva
twice daily for one month; then at bedtime
for two months; and then twice weekly for
three months. Following this routine, a
complete remission of symptoms is observed
Vulvar Intraepithelial Neoplasia 57
in about 80 percent of the women studied.
The patient may be advised to use the
clobetasol as needed once or twice a week.
If the patient has persistent debilitating
pruritus 5 mg of triamcinolone suspension
diluted in 2 ml of normal saline can be injected
subcutaneously beneath the skin of both labia
majora. Lichen sclerosus in the child is usually
treated with local application of steroids
aimed primarily at relief of pruritus.
Squamous Cell Hyperplasia
Squamous cell hyperplasia (formerly known
as hyperplastic dystrophy or leukoplakia) is
a common non-neoplastic epithelial disorder
of the vulva and unlike lichen sclerosus it is
more commonly seen in premenopausal
women. It is related to chronic irritation and
may be caused by candidiasis, HPV infection
or other dermal abnormalities. Physiologic or
psychogenic sweat, psychogenic pruritus,
pruritus as the result of systemic disease and
chronic exposure to chemicals can also give
rise to squamous hyperplasia. Pruritus is the
commonest symptom.
Characteristic clinical appearance is a pink-
red vulva with overlying gray-white keratin.
Areas most frequently involved on the vulva
are the prepuce, labia majora, interlabial sulci,
outer aspect of the labia minora, and the
posterior commissure.
Microscopic findings consist of elongation,
widening of the rete ridges and irregular
thickening of the malpighian layer of rete
ridges (acanthosis), hyperkeratosis and
chronic inflammation in dermis.
The risk of development of invasive cancer
for women with squamous cell hyperplasia
without intraepithelial neoplasia is minimal.
Squamous cell hyperplasia is often observed
adjacent to invasive squamous cell cancer.
Women with squamous cell hyperplasia
occurring in the background of lichen
sclerosus are at higher risk of developing
58 A Practical Approach to Gynecologic Oncology
invasive cancer and require histologic
assessment.
Topical corticosteroids and relief of itching
with antihistaminics are the mainstay of
therapy for squamous cell hyperplasia. The
fluorinated compounds (fluocinolone) in
cream or ointment vehicles, applied twice
daily will generally cure the lesion. Any cause
of chronic irritation should be identified and
treated.
VULVAR INTRAEPITHELIAL NEOPLASIA
Over the last few decades the incidence of
VIN has increased primarily because of
correct classification of disease and increased
detection.2 The term vulvar intraepithelial
neoplasia (VIN) has replaced the very wide
range of confusing terms used in the past
like atypical hyperplastic dystrophy,
Bowen’s disease, Bowenoid papulosis and
leukoplakia.
Histology
The VIN is characterized in the similar way
to its cervical counterpart that the cells are
neoplastic and limited by the boundaries of
the epithelium. Histologically the epithelium
shows abnormal maturation, loss of polarity,
pleomorphism, coarse nuclear chromatin,
irregularities of nuclear membrane and
mitotic figures. There may be acanthosis,
hyperkeratosis and parakeratosis.
• VIN I: The atypical cells are limited to the
lower one-third of the epithelium
• VIN II: The atypical cells are limited to the
lower two-third of the epithelium
• VIN III: Loss of maturation occurs across
the full thickness of the epithelium and
there may be bizarre mitotic figures with
significant pleomorphism.
Unlike cervical intraepithelial neoplasia the
natural history of VIN as a biologic
continuum, that may end in invasive cancer,
is not well established. VIN can be multi-
centric with coexisting cervical intraepithelial
neoplasia (CIN) or vaginal intraepithelial
neoplasia (VAIN). Younger women are more
likely to have multicentric lesions.
Etiopathology
The HPV DNAs have been identified in
vulvar intraepithelial neoplasia suggesting an
etiologic connection. However, the causal
association is not as high as it is with cervical
neoplasia, though upto 80 percent of the VIN
III lesions have been found to be HPV DNA
positive.3 There has been a significant increase
in the incidence of the disease in younger
women over the past 2-3 decades. The
majority of these cases are associated with
HPV 16 subtype infection.
Common STDs like herpes simplex,
condyloma acuminata, gonorrhea, syphilis,
trichomoniasis and gardenella vaginalis may
co-exist with VIN. Patients seropositive for
herpes simplex are at greater risk of VIN-III.
Immunosuppressed patients like those with
systemic lupus erythematosus (SLE) or
patients undergoing renal transplantation
have increased risk of developing VIN. As
with CIN, smokers are at high risk of
developing VIN and invasive cancer of vulva.
There are two types of VIN:
1. Bowenoid type: It is more warty, more
common in younger age group and
multicentric in origin. This variety is
commonly associated with HPV infection.
2. Basaloid type: It occurs more commonly in
older age group and presents as unifocal
disease. The etiology is not known.
Malignant Potential
Malignant potential of VIN varies widely
across the studies (1-10%), primarily because
of different classifications, different follow
up methods and different follow-up
durations. VIN III has been consistently
 Vulvar Intraepithelial Neoplasia 59

found to have high progression rate to cancer. The colposcopic classification of vulvar
Many authors refuse to accept VIN I and II abnormalities by Coppleson (1992) is as
as true cancer precursors. follows:
1. Color
Symptoms and Signs a. Normal b. White
c. Acetowhite d. Red
Although a large proportion of patients with
e. Brown
VIN can be asymptomatic most of them
2. Blood Vessels
present with pruritus or pain. On clinical
a. Absent b. Punctation
examination there will be raised thickened
c. Mosaic d. Atypical
area with color change (red, brown, white,
3. Surface Configuration
gray). The surface may be smooth or
a. Flat
irregular. There may be small ulcers due to
b. Raised
scratching. Hairless skins of interlabial
c. Micropapillary
groove, posterior fourchette and perineum
d. Microcondylomatous
are more frequently affected. Multifocal
e. Villiform
lesions may be present in 30 to 40 percent of
4. Topography
VIN cases.
a. Unifocal
Diagnosis b. Multifocal
c. Multi-sited, e.g. perineum,
In the vast majority of the cases the condition urethral, vaginal, cervical.
may be diagnosed clinically. But a tissue If colposcope is not available the examina-
diagnosis is essential for management and tion of vulva can be satisfactorily done using
sometimes to rule out early malignancies. a hand held magnifying glass under good
Examination of vulva using a colposcope light source.
(vulvoscopy)4,5 is extremely useful to identify
the appropriate area to direct the biopsy from. Toludine Blue Test
Vulvoscopy should also be done routinely
with colposcopy even in asymptomatic It is an extremely valuable diagnostic aid used
women. to delineate suspicious skin areas for biopsy.6
Toludine blue is a nuclear stain. In normal
Vulvoscopy keratin layer there are no surface nuclei. So
the dye does not stain the skin when used on
Vulvoscopy is the magnified visualization of
a normal skin surface. Nuclear material is
the vulva with colposcope. It works in the
present on the surface when there is an
same principle as colposcopy. The VIN
abnormality of squamous cell maturation in
becomes white with application of 3 to
VIN. So a positive stain indicates suspicious
5 percent acetic acid. However, the waiting
area.
time after applying acetic acid is longer (2-3
minutes). The density of aceto-whitening
Biopsy of Vulva
varies with higher grade of lesion and
vascular abnormalities like coarse punctations Vulval biopsy is a minor procedure. A biopsy
or mosaics may be present in high grade can be taken under local anesthesia (1%
lesions. lignocaine) injected in subepithelial layer or
60 A Practical Approach to Gynecologic Oncology
prilocaine cream applied 10-15 minutes before
the procedure. Biopsy should be considered
in the following situations:
• Lesions that are raised, red or pigmented.
• Lesions are surrounded by either
thickened skin or color changes.
• Presumed genital warts that fail to respond
to two or three office treatments.
• Vulvar changes that do not respond to
medical therapy, such as squamous cell
hyperplasia and lichen sclerosus.
• When any suspicion of neoplasia exists, e.g.
Surface ulceration, rapidly progressing,
etc.
Keys Cutaneous Punch, a dermatological
instrument is used to core out a small circular
plug of skin. A small wedge biopsy taken with
a knife is also adequate. Usually the biopsy is
taken from the margin of the lesion and from
the most suspicious area.
MANAGEMENT OF VIN
Principles
The optimum management of VIN is still a
matter of considerable debate because of the
uncertain natural history of the disease.
Various treatment options, ranging from the
conservative to the radical procedures have
been tried. It must be remembered that many
patients will be young and the emotional
trauma of any procedure is considerable.
The topographic distribution of the disease
induces an element of variability. Its presence
in either hair or non hair-bearing areas has
an influence on the type of procedure per-
formed.
The vulvar skin is of a stratified squamous
type that possesses a number of appendages,
including sweat glands, pilosebaceous ducts
that lead to hair follicles deep in the reticular
dermis, sebaceous glands and other
specialized structures such as Bartholin’s
gland and duct. An appreciation of the
extension of VIN into any of these skin
appendages is important because a failure to
destroy VIN in any of these structures would
run the risk of recurrence. Mean depth of hair
follicle involvement is about 1 mm. Removal
of VIN to a depth of 1 mm in non-hairy skin
and 2 mm in hairy skin would be appropriate
for successful treatment.
The options for treating VIN are:
1. Conservative management.
2. Wide local excision using a knife or laser.
3. Skinning vulvectomy and skin grafting.
4. Simple vulvectomy.
5. Wide local excision with vaginal advance-
ment.
6. Laser treatment.
7. Medical therapy (5- fluorouracil).
Before any treatment option is embarked
upon, preoperative vulvoscopy and biopsy are
essential to aid the decision as to which
method will be employed to treat the VIN.
Conservative Management
A study of the natural history of VIN shows
that there is a low risk of progression and,
indeed, there are case reports of spontaneous
regression of VIN in young women. When
an expectant policy is undertaken, the patient
must be willing to attend for long-term
follow-up, and this will involve frequent bio-
psies and vulvoscopy to exclude malignancy.
The patient has to be aware of the commit-
ment that is necessary for this conservative
observation of the lesion. Vulvoscopy and
mapping of lesions is performed at each visit,
and any new lesions or existing lesions that
alter in appearance must be biopsied.
Wide Local Excision
(Using either Knife or Laser)
Wide local surgical excision is used to treat
unifocal or multicentric lesions in non-hairy

or hairy areas. Primary closure is usually
obtained. However, in treating lesions in the
perianal region, where there is less laxity than
in the surrounding tissue, the wound may be
grafted or left to heal by secondary intention.
Wide local excision using a laser is very
popular because it employs the unique
properties of this modality, namely, removal
of precision-measured portions of tissue
involved with VIN and minimal trauma.7
Skinning Vulvectomy with Skin Grafting
The technique has been recommended
primarily for use in young women with
multicentric disease that extends into the hair-
bearing areas of the vulva, it is also useful in
cases where there is a wide area of unifocal
disease and where excision with primary
closure would be technically difficult.8 The
procedure does involve more prolonged
hospitalization because a second scar usually
results from removal of the graft from either
the medial aspect of the thigh or the anterior
abdominal wall. This scarring can, in itself,
produce problems in young women but it
does give a better functional and cosmetic
vulvar result. The technique involves mapping
the vulvar lesion and performing excision
with a wide margin through the relatively
avascular plane between the dermis and the
subcutaneous tissue. Hemostasis is carefully
maintained with diathermy, and the
subcutaneous tissue is preserved as a graft
bed. The clitoris is preserved and lesions on
the glans can be shaved with a scalpel blade.
Using a dermatome with mineral-oil
lubrication and skin traction, a graft is taken
from one of the areas mentioned above and
an occlusive dressing is applied to the donor
site. The graft is kept moist by saline irrigation
and is applied to the graft bed without
excessive tension; it is sutured in place with
polyglycolic sutures. The graft is incised to
allow serosanguinous exudate to drain away
Vulvar Intraepithelial Neoplasia 61
and a foam-rubber pressure bandage is
applied. The postoperative regime includes
an indwelling suprapubic catheter, antibiotic
cover, subcutaneous heparin and bed rest for
up to 1 week. Once the dressing has been
removed, sitz baths are given three times
daily.
Simple Vulvectomy
A simple vulvectomy is a mutilating proce-
dure for a young woman to undergo and it
does not significantly reduce the recurrence
rate. It is associated with a high incidence of
postoperative psychosexual problems9 and is
generally no longer popular for VIN.
Wide Local Excision with
Vaginal Advancement
The use of a technique in which the lesion is
locally and widely excised with the
advancement of the vaginal mucosa to cover
the defect, presents many advantages. It
involves a two-part procedure in which the
area of VIN 3 is first outlined, using vulvo-
scopy and excised and then the vagina is
undercut and advanced. The technique is
especially suitable for lesions that involve
the vaginal introitus, fourchette, or labia
minora and in those cases where the
perineum is involved to within 1.5 cm of the
anal margin.
Laser Vaporization
The technique involves the use of laser
ablation of tissue up to a precise depth so that
the VIN within the surface epithelium and
pilosebaceous ducts can be eradicated.
Reid et al (1985) 10,11 have described the
existence of three surgical planes within the
vulva that need to be identified for efficient
laser vaporization, each having specific
morphologic characteristics. Destruction of
the first plane removes only the surface
62 A Practical Approach to Gynecologic Oncology
epithelium to the level of the basement
membrane. Each passage of the laser beam
will reveal bubbles of silver opalescence
beneath the charred surface squames and this
is associated with a distinctive crackling
sound as the prickle layer is destroyed. Moist
gauze is used to wipe away these cells and
immediately the smooth intact surface of the
papillary dermis is exposed.
The second surgical plane involves removal
of both the epidermis and the loose network
of fine collagen and elastin fibers that
comprise the papillary dermis. If the zone of
coagulation necrosis lies within the papillary
dermis there will be only minimal thermal
injury to the underlying reticular dermis. In
cases of extensive condylomata, destruction
upto this level is sufficient.
The third surgical plane involves the
destruction of the epidermis, the upper
portions of the pilosebaceous duct and a part
of the reticular dermis. There are the mid-
reticular layers with their coarse collagen
bundles that can be seen through the
operating microscope as gray-white fibers
“resembling water-logged cotton threads”.
After wiping the area with iced saline, the
bright alabaster-white cover of other basal
collagen plates becomes recognizable and this
also reveals the network of prominent
arterioles and venules that run horizontal to
the epithelial surface. Moving the beam slowly
will uncover skin appendages within the deep
reticular dermis. Once these have been
uncovered, hair follicles and sweat glands
will become readily visible as tiny refractile
granules that resemble grains of sand. The
third surgical plane represents the deepest
level from which optimum healing will occur.
Regeneration will occur from the keratino-
cytes within the skin appendages. Laser
vaporization of the third surgical plane would
certainly be sufficient to ablate VIN.
Post-Operative Care After
Laser Vaporization
After treatment, the area should be infiltrated
with bupivacaine. To prevent super infection,
the patient is asked to bathe in a sitz bath at
least three times a day. Where extensive areas
have been laser treated, use of a suprapubic
catheter is recommended. A prophylactic
antibiotic is usually employed in such circum-
stances. Washing the vulva with tepid salt
water or taking sitz baths and the application
of antibacterial cream are the most important
methods for reducing postoperative infection
and for promoting satisfactory and rapid
healing. Patients are seen at 2 weeks intervals
until the 6th postoperative week. This enables
the physician to assess healing, prevent or
release adhesion formation and treat by the
application of 85 percent trichloroacetic acid
any recurrent warts that may occur within
this period. Patients are then seen at 4 months,
at 1-year and thereafter at 1 year intervals.
Medical Therapy
Medical treatment of VIN includes the use
of chemotherapy in the forms of 5-FU,
dinitrochlorobenzene (DNCB) cream and
interferon. Photodynamic therapy involving
photochemical destruction of cells sensitized
with a light-activator compound, such as
hematoporphyrin is undergoing trials at this
time. Initially encouraging reports for 5-FU
treatment have been displaced by later
evidence suggesting that it is of very little
use in VIN treatment. Of women undergoing
5-FU treatment for vulvar lesions, 75 percent
stop treatment after 10 days as a result of
discomfort and ulceration.
REFERENCES
1. Ridley CM, Frankman Q, Jones ISC and
Wilkinson EJ. New nomenclature for vulvar

disease. International Society of the study of
Vulvar Diseases. Hum Pathol 1989;20:495.
2. Sturgeon SR, Brinton CA, Devesa SS and
Kurman RJ. In situ and invasive vulvar cancer
trends (1973-1987). Am J Obstet Gynecol
1992;166(5):1482.
3. Park JS, Jones RW, Mclean MR, et al. Possible
aetiological heterogeneity of vulvar intra-
epithelial neoplasia. A correalation of
pathologic characteristics with human papi-
llomavirus detection by in situ hybridization
and polymerase chain reaction. Cancer
1991;67(6):1599.
4. Coppleson M, Pixley EC. Colposcopy of vulva
and vagina. In: Coppleson M (Ed): Gyne-
cological Oncology, (2nd edn). Edinburgh:
Churchill Livingstone. Vol 1:325.
5. Singer A, Monaghan JM. Vulvar intra-
epithelial neoplasia. ‘Lower genital tract
precancer colposcopy, pathology and
treatment’. Blackwell science 1994;177-226.
6. Collins CG, Hansen LH, Theriot E. A clinical
stain for use in selecting biopsy sites in patients
Vulvar Intraepithelial Neoplasia 63
with vulvar disease. Obstet Gynecol
1996;28:158.
7. Kelly JL, Burke TW, Tornos C, et al. Minimally
invasive vulvar carcinoma: An indication for
conservative surgical therapy. Gynecol Oncol
1992;44:240.
8. Rutledge F, Sinclair M. Treatment of intra-
epithelial carcinoma of the vulva by skin
excision and graft. Am J Ostet Gynecol 1968;
102:806.
9. Theusen B, Andreasson B and Bock JE. Sexual
function and somatophysic reactions after
local excision of vulvar intraepithelial neo-
plasia. Acta Obstet Gynecol Scand 1992;
71(2):126.
10. Reid R. Superficial laser vulvectomy III, a new
surgical technique for appendage conserving
ablation of refractory condyloma and vulvar
intraepithelial neoplasia. Am J Obstet
Gynecol 1985;152(5):504.
11. Simonsen EF. The CO 2 laser used for
carcinoma in situ/Bowen’s disease (VIN) and
lichen sclerosus in the vulvar region. Acta
Obstet Gyneocol Scand 1989;68(6):551.
64 A Practical Approach to Gynecologic Oncology
6 Cancer of Vulva
INTRODUCTION
Cancer of the vulva is a relatively rare disease
of women and accounts for approximately
4 percent of Gynecologic malignancies. 1
Squamous cell carcinoma accounts for
approximately 90 percent of these cases and
the rest are melanomas, adenocarcinomas,
basal cell carcinomas and sarcomas. Over the
past two decades, the incidence of in situ
vulvar cancer has more than doubled in many
of the developed countries but the rate of
invasive squamous cell carcinoma has
remained stable.2
The traditional therapy for vulvar
carcinoma has been radical surgery that
provides excellent local tumor control and is
curative for many patients. Recent areas of
investigation have focused on the develop-
ment of less aggressive surgical approaches
for the patients with early cancers and
multimodal therapeutic approaches for
patients with advanced or metastatic cancers.
The principles of management of women with
vulvar cancer are evolving with a trend
towards individualization of treatment and
preservation of sexual function.
EPIDEMIOLOGY AND RISK FACTORS
The age-standardized incidence rates of
cancer of vulva are 0.5-2/100,000 female
populations all over the world. The black
population of United States has a slightly
• Rama Joshi • Partha Basu
Table 6.1: Age standardized incidence rates of
3
vulvar cancer in different Indian cancer registries
Registry Age-standardized incidence
of vulvar cancer
Ahmedabad 0.6/100,000
Bangalore 0.5/100,000
Chennai 0.6/100,000
Delhi 0.5/100,000
higher incidence. The age standardized
incidence rates of vulvar cancer from various
cancer registries in India are given in
Table 6.1.
Most of the vulvar cancers occur in post-
menopausal women although recent reports
suggest a trend towards younger age at
diagnosis.4 The disease is most commonly
seen in women in their seventh decade of life.
The relationship of invasive disease to vulvar
dystrophy and to vulvar intraepithelial
neoplasia (VIN) is controversial. The VIN has
traditionally been considered to have low
malignant potential with progression to
invasive disease in elderly or immunosup-
pressed.5 The relatively stable incidence of
invasive cancer despite a steady increase in
patients diagnosed with VIN could suggest
that either the etiologic factors for the two
conditions are different or the early detection
and effective treatment of VIN have preven-
ted a significant increase in the incidence of
invasive disease.

Jones et al in an observational study of
women with carcinoma in situ of vulva
(VIN III) found that 7 out of 8 (87.5%)
untreated cases progressed to invasive
carcinoma within eight years. Compared to
that only 4 of 105 (3.8%) treated women with
vulvar in situ cancer eventually developed
invasive cancer over the period of 7-18 years.6
Vulvar cancer has been reported to be more
common in patients who are obese, hyper-
tensive, diabetic or nulliparous.7,8 However,
more recent publications have not confirmed
the prognostic significance of these factors.9
A second primary neoplasia, usually pre-
invasive or invasive cervical cancer has been
reported in up to 22 percent of cases. 10,11
Establishment of Human Papilloma Virus
(HPV) as the initiator of cervical cancer has
led investigators to look for HPV infections
in patients with vulvar neoplasms also. HPV-
16 or other HPV subtypes are found in 80 to
90 percent of VIN lesions. However, the
association of HPV with vulvar cancer is not
as strong as it is in cervical cancer. Only 30-
50 percent of invasive vulvar carcinomas
are associated with evidence for HPV
infection. 12-16 The patients with invasive
squamous cell carcinoma of the vulva can be
divided into two etiological groups: one that
is associated with HPV infection and another
that is not.13,15,17 HPV positive tumors tend
to occur in younger women (35-55 yrs), are
often associated with VIN, frequently
multifocal and have less keratin than HPV
negative tumors. Patients with HPV positive
tumors are more likely to have coexisting
cervical intraepithelial neoplasia (CIN) and
the risk factors typically associated with
cervical cancers (multiple sex partners, early
age at first intercourse, low socio-economic
status and smoking).17-20 In contrast, HPV
negative tumors usually occur in women older
than 55 years. They are often associated with
vulvar inflammation or Lichen Sclerosis but
Cancer of Vulva 65
rarely with VIN, generally unifocal and
usually well differentiated with exuberant
keratin formation.13-16 Lee and colleagues
found miss-sense mutations of p53 gene in 4
(44%) of the nine HPV negative tumors but
in only one (8%) of 12 HPV positive tumors.21
They postulated that the alteration of the cell-
division regulatory activity of p53 tumor
suppressor gene initiates the vulvar cancer.
The alteration of p53 gene can be either due
to point mutations or due to inactivation by
E6 onco-protein produced in HPV infected
cells.
PATHOLOGY
Squamous cell Carcinoma
Most of the vulvar malignancies originate
from the squamous epithelium. Squamous
neoplasms arise most commonly on labia
minora, clitoris, fourchette, perineal body or
medial aspect of labia majora; areas where
keratinized stratified squamous epithelium
joins with the non keratinized squamous
epithelium of the vestibule. The squamous cell
carcinomas may present as nodules, ulcers or
hyperkeratotic white plaques. These lesions
are microscopically subdivided into warty
and basaloid types depending on the degree
of differentiation. The warty lesions have
greater degree of differentiation and the
basaloid lesions have lesser degree of
differentiation. Rarer forms include giant cell
carcinoma and lymphoepithelioma like
carcinoma.
The well differentiated squamous cell
cancer of vulva infiltrates as a compact well
circumscribed mass in continuity with the
overlying epithelium. There are no satellite
infiltrations separate from the main mass
and vascular invasion is rare. Stromal desmo-
plastic (fibroblastic) reaction is minimal. The
poorly differentiated type has trabecular
pattern characterized by fingerlike projec-
66 A Practical Approach to Gynecologic Oncology
tions of poorly differentiated cells deep into
the stroma. There are multiple islands of
cancer cells separate from the main mass. The
poorly differentiated type is associated with
a strong desmoplastic stromal response and
vascular space involvement is quite common.
Most of the vulvar malignancies have both
compact (well differentiated) and trabecular
(poorly differentiated) growth patterns
combined in varying proportions. Gyneco-
logic Oncology Group (GOG) proposed the
following grading system for vulvar
squamous cell carcinoma.
• Grade 1 tumors are composed of well
differentiated cells and contain no poorly
differentiated element.
• Grade 2 tumors contain both patterns,
with poorly differentiated portions making
up one third or less of the tumor.
• Grade 3 tumors also contain both
components, with the poorly differentiated
portions comprising more than one third
but less than one half of the tumor.
• Grade 4 tumors have one half or more of
the tumor composed of the poorly
differentiated elements.
Other Histologic Forms of Vulvar Carcinoma
Verrucous carcinoma is a rare, very well
differentiated form of vulvar carcinoma that
usually presents in fifth or sixth decade of
life as a large locally invasive lesion.22 On
microscopic examination the tumor has a
papillary, exophytic appearance. The tumor
cells retain the normal appearance of
maturation and demonstrate minimal atypia.
Lymph node metastasis from verrucous
carcinoma is rare even with extensive local
invasion.
Basal cell carcinoma of the vulva is typically
found in the elderly women and is charac-
terized by a small (2 cm or less in diameter),
firm, well circumscribed growth in the labia
majora. Microscopically such tumor comprises
of small epithelial cells with small
hyperchromatic nuclei.
Malignant melanomas of the vulva account
for approximately 2 to 4 percent of primary
vulvar malignancies and 1 to 3 percent of all
melanomas arising in women.23,24 Vulvar
melanomas most frequently occur in women
older than 60 years of age though 10 to 20
percent occur in women younger than 40
years. 17 Approximately half of the vulvar
melanomas involve labium majus but may also
arise on labium minus, clitoris and perineum.
Approximately 5 percent of vulvar cancers are
anaplastic carcinomas that may consist of large
immature cells, spindle sarcomatoid cells or
small cells. Vulvar carcinomas consisting of
small cells may resemble small cell anaplastic
carcinoma of the lung or Merkel’s cell tumors
and have demonstrated aggressive biologic
behavior in the few cases reported till
date.25
The diagnosis of Bartholin’s gland carci-
noma is based on clinical findings of
tumor arising in the anatomical location of
Bartholin’s gland. The histology usually
reveals adenocarcinoma but squamous cell
carcinoma, transitional cell carcinoma and
adenoid cystic carcinoma have also been
reported.26
Though majority of the primary adeno-
carcinomas of vulva arise from Bartholin’s
glands, they can also originate from the skin
appendages like sweat glands and Skene’s
glands. Primary adenocarcinomas of the vulva
may be associated with Paget’s disease of
vulva.
Patterns of Spread
Vulvar cancer spreads by
1. Local growth and direct extension to
involve adjacent organs such as vagina,
urethra and anus
2. Embolization to regional lymph nodes in
the groin

3. Hematogenous dissemination to distant
sites including the lungs, liver and bone
Lymphatic metastasis may occur early in
the disease. A more precise understanding
of the lymphatic drainage of the vulva has
been key to developing an individualized
surgical approach to vulvar cancer. Parry-
Jones demonstrated systematic lymphatic
drainage of the vulva with the help of
lymphatic dye studies. He showed that the
lymphatic fluids drain from the lateral sites
of vulva to the ipsilateral superficial group of
inguinal nodes located between Camper’s
fascia and fascia lata.27 The lymphatics are
drained from the superficial inguinal nodes
to the deep inguinal (femoral) nodes that are
located medial to the femoral vein. The most
cephalad of the femoral node group is the
Cloquet’s node situated beneath the inguinal
ligament. Metastases to the femoral nodes
have been reported without the involvement
of superficial inguinal nodes. From the
inguinal nodes tumor spreads to the pelvic
group of nodes, most frequently to the
external iliac group.
No lymphatic channels are located beyond
labio-crural fold and crossover drainage to
opposite groin bypassing the ipsilateral groin
is rare. On the other hand, drainage from the
midline tumors can be bilateral with some
channels from clitoral area and Bartholin’s
glands draining directly to the pelvic nodes.
The reported overall incidence of lymph
node involvement in operable vulvar cancers
is approximately 30 percent. Size of the lesion
is one of the important factors predicting
lymph node metastases. The incidence of
nodal metastases is less than 5 percent if the
size of the lesion is 1 cm or less. More than
half of the cases with size of lesion greater
than 4 cm will have nodal metastasis.28
Other than tumor size, factors predictive
of lymph node metastasis are depth of
Cancer of Vulva 67
invasion, tumor thickness and presence or
absence of lympho-vascular space invasion
(LVSI).29
Metastases to pelvic nodes are uncommon
with overall reported frequency being
approximately 9 percent.30 The pelvic node
metastases are rare in the absence of clinically
suspicious groin nodes and 3 or more positive
groin nodes.31 Approximately 20 percent of
the patients with positive groin nodes have
positive pelvic nodes.
Hematogenous spread usually occur late
in the course of vulvar cancer and is rare in
the absence of lymphnode metastasis. Hema-
togenous spread is uncommon in patients with
one or two positive groin nodes, but is more
common in patients with three or more
positive nodes.30
PROGNOSTIC FACTORS AND STAGING
The prognosis of vulvar squamous cell carci-
noma depends on size, tumor depth, vascular
invasion, node involvement and tumor diffe-
rentiation (grading). The depth of invasion
is defined as the measurement from epithelial
stromal junction of the most superficial
adjacent dermal papillae to the deepest point
of invasion.32,33 Some authors designated
3 mm or 5 mm of stromal invasion as micro-
invasive and recommended omission of
inguinal lymphadenectomy in these tumors.
However, it was observed later that 10-20
percent of these tumors had lymph node
metastasis. Considering the very low
possibility of nodal metastasis International
Federation of Gynecology and Obstetrics
(FIGO) defined solitary squamous carcinoma
of vulva measuring 2 cm or less in diameter
with clinically negative nodes and depth of
tumor invasion 1 mm or less as stage IA
(micro-invasive tumors). 27 Microinvasive
tumors are commonly seen in younger
women and are often associated with other
68 A Practical Approach to Gynecologic Oncology

neoplasia of the lower genital tract.
The single most important prognostic factor
of vulvar cancer is lymph node metastasis.
The determinants of long term survival are
the number of nodes involved, whether they
are involved unilaterally or bilaterally and
whether the pelvic nodes are also involved.
A clinical staging system based on TNM
classification was adopted by the International
Federation of Gynecology and Obstetrics
(FIGO) in 1969. The staging was based on a
clinical evaluation of primary tumor and
regional lymph nodes and a limited search
for distant metastases.
However, several studies have demons-
trated poor correlation between clinical
assessment of inguinal lymph nodes and
pathologic findings. 35-37 In a study of 588
patients with tumors that invaded 5 mm or
deeper, Homesley and colleagues reported
that 24 percent of those with clinically
negative nodes had histologic evidence of
inguinal lymph node metastases and 24
percent of patients with suspicious but mobile
nodes had no nodal metastasis on post-
operative histology. 36 This led the cancer
committee of FIGO to introduce a surgical
staging for vulvar cancer in 1988. The FIGO
clinical staging system was modified to
incorporate the more accurate information
gained from surgical assessment of regional
lymph nodes. The staging system was revised
again in 1994 to create a separate stage IA for
minimally invasive lesions. The details of the
staging systems are given in Table 6.2.
The Gynecologic Oncology Group (GOG)
staged patients according to new FIGO
criteria and reported 5 year survival rates of
98 percent, 85 percent, 74 percent and 31
percent for stages I, II, III, IV respectively.29
Number of positive nodes correlates well with
the survival. The patients with one
microscopically positive node have good
prognosis regardless of the stage of disease.31
Patients with more than two positive nodes
have poor prognosis. The five year survival
rate for positive pelvic nodes is significantly
low and reported to be 11 percent.30

Table 6.2: FIGO Staging for vulvar cancer (1994)

FIGO stage TNM Clinical/Pathologic Findings

Stage 0 Tis Carcinoma in situ, intraepithelial carcinoma

Stage I T1N0M0 Tumor < 2 cm in greatest diameter, confined to
vulva or perineum; nodes are negative
IA T1aN0M0 As above with stromal invasion <1.0 mma
IB T1bN0M0 As above with stromal invasion >1 mm
Stage II T2N0M0 Tumor confined to vulva and/or perineum,
> 2cm in greatest dimension, nodes are negative
Stage III T3N0M0 Tumor of any size with
T3N1M0 1. Adjacent spread to lower urethra
T1N1M0 and/or vagina and/or anus and/or
T2N1M0 2. Unilateral regional lymph node metastasis
Stage IVA T1N2M0 Tumor invades any of the following:
T2N2M0 upper urethra, bladder mucosa, rectal mucosa,
T3N2M0 pelvic bone and/or
T4, any N, M0 bilateral regional node metastasis
Stage IVB Any T, any N, M1 Any distant metastasis including pelvic lymph nodes
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.

CLINICAL FEATURES
Squamous cell carcinoma is predominantly a
disease of postmenopausal women with the
mean age at diagnosis of 65 years. Most of
the patients present with a vulvar lump or
mass. There is often a long history of pruritus
due to co-existent vulvar dystrophy. Less
commonly presenting symptoms include
vulvar bleeding, discharge or dysuria.
Occasionally a large metastatic mass in the
groin may be the initial presenting symptom.
On physical examination, the lesion is
usually raised and may be fleshy, ulcerated,
leukoplakic or warty in appearance. Warty
carcinomas account for approximately 20
percent of all cases and the incidence is on
the rise. Most of the squamous carcinomas of
the vulva occur on labia majora. Labia minora,
clitoris, and perineum also may be the
primary sites. Approximately 10 percent of
the lesions are too extensive to determine the
site of origin and 5 percent have multi-focal
disease.
As part of the clinical assessment, the groin
lymph nodes should be evaluated carefully
and complete pelvic examination performed.
A Papanicolaou smear should be taken from
the cervix and colposcopy of cervix and vagina
should be peformed because of the common
association with other squamous intraepithe-
lial neoplasms of the lower genital tract.
Diagnosis of invasive vulvar lesions
requires a wedge biopsy of the lesion with
surrounding skin and with underlying dermis
and connective tissue for adequate patholo-
gical evaluation. The procedure can be
performed under local anesthesia. Excision
biopsy is preferred for lesions smaller than 1
cm in diameter.
MANAGEMENT
Principles of Management and
the Changing Trends
Cancer of Vulva 69
The principles guiding the management of
women with vulvar cancer are evolving
towards a more conservative approach as
many of the cases are being diagnosed in
younger age group and at early stages.
Radical vulvectomy with en bloc bilateral
dissection of the groin and pelvic nodes was
introduced in 1950s and became the standard
treatment for most patients with operable
vulvar cancer as it was found to improve the
survival significantly.38-40 Pelvic exenteration
was combined with this dissection if the
disease involved anus, proximal urethra or
rectovaginal septum. Over the last few
decades the treatment of vulvar cancer,
particularly of the early stages has undergone
a major paradigm shift from a radical surgical
approach to tissue-sparing surgery and
preservation of sexual function. The key
changes introduced in the principles of
management of vulvar cancer and their
rationale are as follows:
• Less radical approach to the management of
vulvar growth in selected cases: Wide local
excision of growth keeping 1 cm of clear
margin all around is preferred to radical
vulvectomy if the tumor is less than or
equal to 2 cm. The wide excision is carried
down to the inferior fascia of the uro-
genital diaphragm. This conservative
surgery has the advantages of less opera-
tive morbidity and preservation of the
sexual function, particularly if the clitoris
can be preserved. Lesions on the posterior
or lateral aspects of vulva can be best
treated by local excision. The local
recurrence rate in properly selected cases
of wide local excision is same as radical
vulvectomy (Table 6.3).
• Preservation of Clitoris in small periclitoral
growth: In young patients with periclitoral
lesions consideration must be given to treat
the primary lesion with a small field of
radiation therapy as small vulvar lesions
respond very well to approximately 5 Gy
70 A Practical Approach to Gynecologic Oncology

Table 6.3: Incidence of local invasive recurrence contralateral groin is very rare if the
after radical local excision and radical vulvectomy for ipsilateral groin does not show any meta-
T1 squamous cell carcinoma of the vulva stasis (Table 6.4). Bilateral inguino-femoral
No. Recurrencea Dead of lymph node dissection should be done if
disease the lesion is bilateral or involves the clitoris
or anterior labia minora. However, in case
Radical local 165 12 (7.2%) 1 (0.6%)
excision of doubt one should settle for bilateral
dissection as patients who develop
Radical 365 23 (6.3%) 2 (0.5%)
vulvectomy recurrence in the undissected groin have
very high mortality rates.
ap = 0.85 • Avoiding dissection of fascia lata: The inguinal
lymph nodes are situated between the
external radiation. Biopsy should be
fascia of Camper and the fascia lata.
performed after therapy to document
Dissection of fascia lata lateral to the
absence of residual disease.
femoral vessels is not required and
• More conservative surgical approach to groin:
transposition of the sartorius muscle is no
Ipsilateral inguino-femoral lymph node
longer indicated. However, the femoral
dissection is mandatory in all cases of
nodes medial to the femoral vein should
vulvar cancer except stage IA (stromal
always be removed along with the inguinal
invasion less than or equal to 1 mm). In
nodes.
stage IA disease the risk of inguino-femoral
• Identification of Sentinel node: The concept
lymph node metastasis is very low (<1%)
of identifying single or multiple sentinel
and nodal dissection is not necessary. In
lymph node(s) was introduced to limit the
well lateralized primary tumors contra-
extent of dissection of inguino-femoral
lateral groin node dissection should be
lymph nodes and the resulting morbidity.
done if the ipsilateral inguino-femoral
There is a theoretical possibility that if the
nodes have metastasis. Metastasis to
sentinel node(s) can be identified and found
Table 6.4: Incidence of positive contralateral nodes negative, there is very little risk of tumor
in patients with lateral T1 squamous cell vulvar deposits in the deeper nodes. So the patient
carcinomas and negative ipsilateral nodes can be spared of the morbidity of full groin
dissection. Techniques employing techne-
Author Unilateral Contralateral Percent-
lesions nodes positive age tium-99m (Tc-99m) sulfur colloid and
isosulfan blue dye are utilized to identify
Magrina 77 2 2.6 sentinel nodes in the inguinal lymphatic
et al, 197941 beds. Technetium-99m sulfur colloid is
Iversen 112 0 0 injected intradermally at the tumor margins
et al, 198142
90-180 min preoperatively followed by a
Buscema 38 0 0
similar injection of isosulfan blue dye
et al, 198143
(alternatively methylene blue) 5-10 min
Hacker 60 0 0
before the groin dissection. A handheld
et al, 198444
collimated gamma counter is employed to
Struyk 53 0 0
et al, 198945 identify Tc-99m-labeled sentinel nodes.
Lymphatic tracts that had taken up blue
Total 380 2 0.59
dye and their corresponding sentinel node

are also identified and retrieved. The
sentinel nodes are subjected to rigorous
pathologic examination with multiple step
sections. A number of studies have tried
to determine the ability of the sentinel
nodes to predict metastasis to the inguinal
lymphatics.46,47 These studies concluded
that sentinel nodes can be identified in
nearly all cases using Tc-99m and if the
sentinel nodes are negative for metastasis,
the probability of the nonsentinel nodes
to harbor metastasis is almost nil (very high
negative predictive value). Reports from
larger studies are awaited before the
modification of groin node dissection
based on the sentinel node status is
recommended in routine clinical practice.
• Omitting pelvic lymph node dissection: The
possibility of the pelvic lymph nodes
harboring disease is very low in the
absence of groin node metastasis. Pelvic
node dissection is no longer deemed
necessary if the groin nodes are found to
be free of tumor deposits. If the groin
nodes are positive the pelvic nodes can be
surgically removed or can be treated with
radiotherapy. In a Gynecologic Oncology
Group trial patients with positive groin
nodes after radical vulvectomy and
bilateral inguino-femoral lymphadenec-
tomy were randomized to either pelvic
node dissection or postoperative irradi-
ation of pelvic and inguinal nodes. The
study observed a statistically significant
improvement of survival in the radiation
group.48
• Modifications of incisions for lymphadenectomy
and vulvectomy: The original Stanley Way
technique of en bloc radical vulvectomy
and groin dissection used a butterfly
incision that had a very high incidence of
wound breakdown and postoperative
morbidity. This has been modified to use
two separate incisions for groin dissection
Cancer of Vulva 71
and a third incision for vulvectomy. During
groin dissection the subcutaneous fat above
the Camper’s (superficial) fascia is
preserved while raising the skin flaps so
that their blood circulation is maintained.
These modifications have significantly
reduced the rate of postoperative wound
breakdown from 50 percent for butterfly
incisions to 10-20 percent for the triple
incisions. Primary closure of the vulvar
incision is possible and recurrence over the
skin bridge between the vulvar incision and
groin incisions is seen rarely.
• Multimodality approach: Multi-modality
treatment approaches including radiation
therapy, surgery and chemotherapy are
being investigated for improving the
survival in women with high-risk
advanced stage disease. Radiation can help
preserve the vulva in young women with
a small lesion around the clitoris.
Management of Early Vulvar Cancer
The approach to the management of such
patients with T1 vulvar carcinoma must be
individualized with emphasis on performing
the most suitable conservative surgery with-
out compromising the cure of the disease.
• Principles of management of Microinvasive
Tumors: Tumors demonstrating early
invasion of the vulvar stroma (<1 mm) have
minimal risk for lymphatic dissemination.
Excisional biopsy that incorporates a 1 cm
normal tissue margin all around the lesion
is likely to provide a curative resection.49
Considering the minimal risk of nodal
metastasis groin lymph node dissection can
be ignored in these patients.
Microinvasive carcinoma tends to arise
in young women with multifocal pre-
invasive disease of the lower genital tract.
Such lesions are commonly associated with
HPV infections. Consequently, the cervix,
72 A Practical Approach to Gynecologic Oncology
vagina and vulva must be carefully
evaluated by Colposcopy before surgery
and during followups.
• Principles of management of Stage I and II
vulvar cancers: Radical vulvectomy
combined with bilateral inguino-femoral
lymphadenectomy is the traditional
management of stages I and II vulvar
cancers. This approach provides excellent
long term survival and local control in
80-90 percent of the patients. 50,51 The
disadvantages of this surgery include loss
of normal vulvar tissue with alteration in
appearance and sexual function. This is
associated with significant postoperative
morbidity also. The post operative
complications include high incidence of
wound breakdown (50%), groin compli-
cations (lymphangitis, lymphocyst and
wound break down) and lymph-edema leg
(10-15%).52 Approximately 10-20 percent of
these patients with positive regional nodes
require post operative radiation therapy
that further increases the morbidity. 48
Radical local excision instead of radical
vulvectomy is most appropriate for the
early lesions on the lateral or posterior
aspect of vulva, where preservation of
clitoris is feasible. In young patients with
periclitoral lesions consideration must be
given to treat the primary lesion with a
small field of radiation.
• Technique for radical local excision: Radical
local excision implies a wide and deep
surgical excision of primary tumor with
surgical margins of at least 1 cm. The
primary tumor should be resected with
1-2 cm healthy margin and incision must
be carried down to the inferior fascia of
the urogenital diaphragm. The surgical
defect is closed in two layers.
• Management of groin lymph nodes in early
cancers: Appropriate groin lymph node
dissection is the single most important
factor in decreasing the mortality from
early vulvar cancer. All patients with more
than 1 mm of stromal invasion require
inguinofemoral lymphadenectomy. It is not
necessary to perform bilateral groin node
dissection when the lesion is unilateral and
well lateralized. Lesions involving anterior
labia minora, clitoris or perineal body
should have bilateral dissection because of
the more frequent contra-lateral lymph
flow from these regions.53 In patients with
negative inguinal nodes no further
dissection or postoperative therapy is used.
Patients with positive nodes can undergo
additional node dissection of contralateral
groin or be treated with postoperative
irradiation or both. The likely benefit of
postoperative radiation therapy to the groin
and low pelvis has been demonstrated
when more than one groin nodes are
positive.48 The risk of chronic groin compli-
cations and lymphedema is related to the
extent of groin node dissection. Patients
with superficial or deep lymphadenectomy
followed by irradiation have the greatest
likelihood of morbidity.
In an attempt to reduce morbidity of
inguinofemoral node dissection, potential
for cutaneous lymphatic mapping to define
and target the true sentinel nodes has been
discussed before.
Management of Stage III and IV
Vulvar Cancer
• Principles of surgery for advanced disease:
Primary tumors that involve anus, rectum,
recto-vaginal septum, or proximal urethra
can be adequately resected only by
combining pelvic exenteration with radical
vulvectomy and bilateral groin node
dissection. Such procedures have substan-
tially increased risk of acute and long term
complications. Surgery alone is not curative
for patients with the bulky, fixed or

ulcerated groin nodes. For this reason
investigators have explored the use of
combined treatment modality approach to
spare critical structures in patients with
locally advanced disease. Treatment of
T3/T4 tumors or bulky positive groin nodes
needs to be individualized.
• Role of radiotherapy in advanced cancer: Some
cases of T3 tumors that minimally involve
external urethra or anus can undergo initial
radical vulvectomy. In patients with
adequate tumor free margin the local
recurrence rate can be reduced significantly
with postoperative radiation therapy. The
vulva should receive the total dose of 50-
65 Gy depending on the proximity of the
disease to surgical margins. In early 1980s
some investigators reported successful
organ sparing surgery with preoperative
radiation therapy without compromise in
local control.54 Hacker and Colleagues
reported pathological complete response
on vulvectomy specimen in 4 of the 8
patients after radiotherapy and 7 of these
8 patients had local control of disease.55
Boronow et al reported 75.6 percent 5 year
survival in 37 primary vulvar cancer cases
with preoperative radiation therapy. 56
There was pathological complete response
in 42.5 percent of the cases.
• Role of chemoradiation: More recently con-
current chemoradiation is being investi-
gated in this setting. Most of the investi-
gators have used combination of cisplatin,
5FU, and mitomycin C chemotherapeutic
agents in concurrence with radiation
therapy. Better response rates as compared
to radiation alone have been reported by
most studies, though the studies have
included small number of patients.
Benedetti–Panici and colleagues investi-
gated the role of neoadjuvant chemo-
therapy of 2-3 cycles of cisplatin, blomycin
and methotrexate followed by radical
Cancer of Vulva 73
surgery.57 The authors reported 10 percent
(2 of 21 patients) partial response in vulvar
tumors and 67 percent (14 of 21 patients)
partial responses in the regional nodes
respectively. Ninety percent of the locally
advanced vulvar tumors were considered
operable following neoadjuvant chemo-
therapy. But the 3 year survival rate was
only 24 percent.
Management of Recurrent Vulvar Cancer
Vulvar cancer recurrences can be categorized
into local vulvar recurrences, regional and
distant recurrences. Local vulvar recurrences
are frequently observed in patients with
primary lesions larger than 4 cm in diameter.
Local recurrences can be successfully
managed with repeat wide excisions. The
recurrence free survival of upto 75 percent
has been reported when the recurrence is
limited to vulva and resected with optimal
margins.60,61 These optimal surgical excisions
often require gracilis myocutaneous graft to
cover the defect.
Radiation therapy, particularly combination
of interstitial needles and external-beam
therapy has been used to treat vulvar recur-
rences successfully but at the cost of high
morbidity of severe radiation necrosis.
Recurrence in the groin is difficult to manage
and is fatal most of the times. Combination
of surgery and radiation therapy has been
used for the management of groin recurrence
and chemotherapy is largely palliative for
distant recurrences.
Surgical Techniques
The surgical approach for radical vulvectomy
and bilateral Inguinofemoral lymphadenec-
tomy can be:
• Either the en-bloc approach through a
‘Butterfly’ incision or ‘Longhorn’ incision
• Or the separate incision approach (‘triple
74 A Practical Approach to Gynecologic Oncology
incision technique’) involving three
separate incisions, one for radical vulvec-
tomy and one for each groin dissection.
The second approach is most widely used
currently. The first approach is only reserved
for large tumors on the mons pubis or when
the groin nodes are fixed to the overlying
skin.
Technique of Groin Node Dissection
• In triple incision technique the incision for
groin node dissection is made separately
on either side along the medial four fifths
of the line drawn between anterior
superior iliac spine and pubic tubercles. For
en bloc dissection with a single incision the
classical Stanley Ways’ butterfly incision
has been replaced by longhorn incision to
allow primary skin closure.
• The abdominal incision is carried down to
the aponurosis of external oblique muscle
around 2 cm above the inguinal ligament.
• Skin flap is raised over the femoral triangle
with preservation of subcutaneous fat
above the superficial (camper’s) fascia.
Preservation of subcutaneous tissue above
superficial fascia can significantly reduce
the incidence of skin necrosis.
• The fatty tissues between the superficial
fascia and fascia lata are removed over the
femoral triangle. This contains the super-
ficial inguinal nodes.
• Saphenous vein is tied off at the apex of
femoral triangle and at its point of entry
into the femoral vein.
• Anatomic boundaries of superficial inguinal
node dissection are inguinal ligament
superiorly, border of sartorius muscle
laterally and the border of adductor longus
muscle medially. The anterior limit is
superficial subcutaneous fascia (camper’s
fascia) and posterior limit is cribriform
fascia overlying the femoral artery, vein
and deep nodes.
• Lymphadenectomy specimen is developed
by continuing the inferior dissection along
the borders of the sartorius and adductor
longus muscles. As the dissection proceeds,
the specimen is mobilized off the cribriform
fascia.
• There are usually one to three femoral
lymph nodes situated medial to the
femoral vein in the opening of fossa ovalis.
The fascia is opened medial to the vein and
adjacent nodes are removed.
• Skin is closed with either sutures or staples.
• Routinely closed suction drain is placed
within the lymphadenectomy site and left
in place until the drainage is less than 25
ml/day for two consecutive days.
Technique of Radical Vulvectomy
• Radical vulvectomy is accomplished using
two elliptical incisions – an inner one placed
at the vaginal introitus and an outer one
placed at labiocrural folds and across the
mons pubis and perineal body.
• The anterior incision on mons pubis
extends through the superficial fascia to the
pubic symphysis and the lateral incisions
are carried to the level of deep perineal
fascia so that bulbocavernosus muscles and
vestibular bulbs are removed with the
specimen.
• Either of the two incisions, medial and
lateral may require to be modified to clear
the primary tumor with surgical margins
of at least 1 cm.
• Distal half of the urethra may be resected
without compromising the continence of
urinary bladder.
• Care is taken to ligate the clitoral vessels
and the internal pudendal vessels.
• Vulvar defect is closed keeping the drain
in place.
• Closure of large defects will include the
following options depending upon location
 Cancer of Vulva 75

of the defect and size.
a. Full thickness skin flaps. Rhomboid flaps
are best suited for covering large defects
of posterior vulva.
b. Unilateral or bilateral gracilis myocuta-
neous grafts most suitable for covering
extensive defect from Mons pubis to
perineal area. These are particularly
useful for those who had prior surgical
resection or radiation
c. Area may be left open to granulate,
especially when the defect is around
urethra. Granulation usually takes 6 to
8 weeks and will avoid urethral
deviation.
Management of Rare Vulvar
Malignancies
Non squamous vulvar malignancies are rare
and the available definitive information
regarding the treatment is relatively less and
based on small case series.
Malignant Melanoma
Malignant melanoma is the second most
common vulvar malignancy. 62,63 Typical
presentations include an asymptomatic
pigmented lesion or a mass with itching, pain
or bleeding. Melanomas may arise from
either existing pigmented vulvar lesion or as
new primary lesion. These occur predomi-
nantly in postmenopausal women and the
most common sites of the lesion are labia
minora and clitoris.
There are three basic histologic types. The
most common is the superficial spreading
melanoma, which tends to remain relatively
superficial early in its development. The
lentigo maligna melanoma is a flat freckle,
which may become quite extensive but also
tends to remain superficial. The most
aggressive lesion is the nodular melanoma
which is a raised lesion that penetrates deeply
and may metastasize widely.
Melanomas are staged according to one of
the three available microstaging systems
(Table 6.5) based on depth of local invasion
or tumor thickness. FIGO staging used for
squamous lesions is not applicable to mela-
nomas as the prognosis in FIGO is correlated
with diameter of the lesion not the depth of
penetration.
The major treatment modality for vulvar
melanoma is surgical. Radical vulvectomy and
inguinofemoral lymphadenectomy has been
the treatment of choice. In vulvar melanoma
too there is a trend towards more conserva-
tive resection. Lesions with less than 1mm of
invasion may be treated with radical local
excision alone. Lymphadenectomy can be
avoided in such patients as the risk of nodal
metastasis is negligible. For melanomas with
greater depth of invasion inguino-femoral
lymphadenectomy is mandatory.
As melanomas commonly involve the
clitoris and labia minora, care should be taken
to obtain adequate vagino-urethral margin at
resection as this is the common site of failure.
Podratz et al. reported significantly better

Table 6.5: Microstaging systems for vulvar melanomas

Clark et al64 Chung et al62 Breslow65

I Intraepithelial Intraepithelial <0.76 mm

II Into papillary dermis <1 mm from granular layer 0.76-1.50 mm
III Filling dermal papillae 1.1-2 mm from granular layer 1.51-2.25 mm
IV Into reticular dermis > 2 mm from granular layer 2.26-3.0 mm
V Into subcutaneous fat Into subcutaneous fat >3 mm
76 A Practical Approach to Gynecologic Oncology
10-year survival rate of 61 percent in patients
with lateral lesions as compared to 37 percent
survival rate for medial lesions (p = 0.027).63
Usually pelvic node metastasis does not
occur in the absence of groin node metastases.
There appears to be no advantage of
performing pelvic lymphadenectomy in these
patients as prognosis in patients with positive
pelvic nodes is very poor.
Though radiation therapy has shown the
complete response and tumor control in 50
to 70 percent of patients with local
recurrences, it has rarely been used in pri-
mary treatment of vulvar melanoma. Systemic
chemotherapy either as adjuvant or salvage
setting is generally palliative.
Verrucous Carcinoma
Verrucous carcinomas are locally invasive and
rarely metastasizing.66 Grossly the tumors
have cauliflower like appearance and micro-
scopically may resemble giant condyloma
accuminatum. Adequate biopsy from the base
of the lesion is required to differentiate these
lesions and confirm the diagnosis.
Treatment by radical wide excision is
curative. The metastasis to regional lymph-
nodes is rare but has been reported. In the
presence of regional nodal metastasis, radical
vulvectomy and bilateral inguinofemoral
lymphadenectomy is the standard treatment.
Radiation therapy is reported to induce
anaplastic transformation with subsequent
regional and distant metastasis and is
contraindicated.67 Local recurrence can occur
which is usually seen following inadequate
resection, will further necessitate surgical
excision including exenteration.
Basal Cell Carcinoma
Presentation of vulvar lesions is similar to
basal cell carcinoma at other sites as rodent
ulcer. These lesions are commonly situated
on anterior part of labia majora. They are
locally aggressive and radical local excision
with minimum surgical margin of 1 cm is
usually the optimal treatment. Lymphatic and
distant spread is rare. Local recurrence may
occur and is commonly observed in tumors
removed with suboptimal surgical margins.
Rarely malignant squamous components
have been reported in basal cell carcinomas
that behave aggressively and treatment in
these patients is advocated on the lines of
squamous cell carcinomas.
Paget’s Disease
Paget’s disease presents as a ‘weeping ecze-
matous lesion’ of vulva that causes intense
itching. This condition is associated with
underlying invasive adenocarcinoma in about
15 percent of the patients.68 The condition is
similar to Paget’s disease of breast. The
development of invasive adenocarcinoma at
sites other than the vulva has been reported
in 30 percent of these patients.
Adenocarcinomas
Adenocarcinomas usually occur either in
association with Paget’s disease or arise in
Bartholin’s gland. Though the data for treat-
ment evaluation of adenocarcinoma are
limited, radical vulvectomy is the appropriate
treatment and should be combined with groin
node dissection as reported incidence of groin
node metastasis is around 30 percent. For
patients with larger tumors and inguinal node
metastasis; postoperative radiation therapy
may improve local control.
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Melanoma of the vulva: An update. Gynecol
Oncol 1983;16:153.
64. Clark WH, From L, Bernardino EA, Mihm MC.
The histogenesis and biologic behavior of
primary human malignant melanomas of the
skin. Cancer Res 1969;29:705.
65. Breslow A. Thickness, cross-sectional area
and depth of invasion in the prognosis of cuta-
neous melanoma. Ann Surg 1970;172:902.
66. Gallousis S, Verrucous carcinoma: Report of
three vulvar cases and a review of the
literature. Obstet Gynecol 1972;40:502.
67. Demian SDE, Bushkin FL, Echevarria RA.
Perineural invasion and anaplastic transfor-
mation of verrucous carcinoma. Cancer
1973;32:395-99.
68. Creasman WT, Gallager HS, Rutledge F.
Paget’s disease of the vulva. Gynecol Oncol
1975;3:133.
 7 Cancer of Vagina
INTRODUCTION
Primary carcinoma of the vagina is one of the
rare gynecological malignancies accounting
for 1 to 2 percent of all gynecological
malignancies. Vaginal cancer represents one
of the most challenging therapeutic problems
in gynecologic oncology because of its very
close proximity to the urinary bladder
anteriorly and rectum posteriorly. Most of
the malignancies of vagina are secondary from
the cervix. Malignancies of the urinary blad-
der, rectum, vulva may also involve vagina
by direct infiltration. Vagina may also be
involved by metastases from endometrium,
ovary and gestational trophoblastic tumor.
Because of the rarity of vaginal cancer
International Federation of Gynecologists and
Obstetricians (FIGO) recommended that any
vaginal cancer extending to the cervix should
be considered primarily of cervical origin.
Similarly a tumor that involves the vulva and
vagina should be classified as vulval
carcinoma. Any new cancer developing in the
vagina at least five years after the cervical
cancer should be considered as a new primary
lesion and not a recurrence.
HISTOLOGY AND LYMPHATIC
DRAINAGE OF VAGINA
The vaginal wall is composed of three layers,
i.e. the mucosa, the muscularis and the
adventitia. The inner mucosal layer is formed
by a thick, non-keratinizing, stratified,
squamous epithelium overlying a basement
• Uttam D Bafna
membrane containing many papillae. The
epithelium normally contains no glands. The
middle muscularis layer is composed of
smooth muscle fibers arranged circularly on
the inner side and longitudinally on the outer
side. The adventitia is thin, outer connective
tissue layer.
The upper portion of the vagina drains
mainly via the lymphatics of the cervix to the
pelvic nodes. The lymphatics from the lower
portion of the vagina drain cephalad into the
cervical lymphtics or follow the drainage
pattern of the vulva to the groin nodes.
ETIOLOGY
Vaginal cancers are commonly seen in the 6th
decade. The exact cause is unknown, although
HPV has been implicated. Vaginal tissues are
relatively immune to malignancy unlike
cervical cancer, which is one of the common
cancers in the developing countries. The
transformation zone in the cervix with
metaplastic cells is more susceptible to mali-
gnant transformation than the mature vaginal
mucosa lined by stratified squamous epithe-
lium.
Chronic trauma due to pessary or any
other reason, has been implicated although
this has not been substantiated. Twenty to
thirty percent of the vaginal cancers occur
after hysterectomy for benign reasons.
The natural history of preinvasive vaginal
lesions, vaginal intraepithelial lesions (VAIN),
has not been well-documented unlike cervical

cancer. Histologically VAIN is similar to
cervical intraepithelial neoplasia (CIN) with
three grades—VAIN I, II and III. Vaginal
intraepithelial neoplasias are rare lesions and
are known to have higher malignant potential
than vulval intraepithelial neoplasias (VIN).
About 30 to 40 percent of vaginal cancer
occur after hysterectomy for benign conditions
as reported by various authors.1-3
SIGNS AND SYMPTOMS
Vaginal discharge, which is often bloody is the
most common symptom. Some patients
present with urinary symptoms. Pap smear
is effective in detecting vaginal cancer in
asymptomatic women. Therefore, it is
recommended that Pap smear should be done
every 2 to 3 years even in patients who had
hysterectomy for benign disease. Most
lesions are situated in the upper 1/3rd of the
vagina, usually in the posterior wall. This
could be probably due to the fact that this
area is most exposed to the posterior vaginal
fornix pool collection. The diagnosis is often
missed as the lesion may be obscured by the
blade of the vaginal speculum.
HISTOLOGIC DISTRIBUTION
Squamous cell carcinoma accounts for almost
85 percent of all vaginal cancers, while
adenocarcinoma accounts for 5 to 6 percent.
Other rare histologies are melanoma, sarcoma
and miscellaneous malignancies.
FIGO STAGING
Vaginal cancer is clinically staged as per the
International Federation of Obstetrics and
Gynecology (FIGO) guidelines based on the
findings at general physical and pelvic
examination. Investigations recommended by
the FIGO for the purposes of staging include
cystoscopy, proctosigmoidoscopy, intra-
venous pyelography, chest X-ray and bone
Cancer of Vagina 81
scan. These investigations should be used
judiciously depending on the clinical findings
and the symptoms. The FIGO staging is
shown in the Table 7.1.
Table 7.1: FIGO staging of vaginal cancer
• Stage 0 : Vaginal carcinoma in situ (VAIN III),
carcinoma confined to the vaginal mucosa with
intact basement membrane.
• Stage I : The carcinoma is confined to the vaginal
wall.
• Stage II: The carcinoma has involved the
subvaginal tissue but has not extended to the pelvic
wall.
• Stage III: The carcinoma has extended to the pelvic
wall.
• Stage IVa: The carcinoma has involved the bladder
or rectal mucosa.
• Stage IVb: The carcinoma has spread outside the
true pelvis.
It is difficult to determine accurately any
spread to the subvaginal tissue, hence the
FIGO staging is highly subjective.
PATTERN OF SPREAD
Direct spread occurs to the adjacent organs.
Lymphatic spread is to the pelvic and later to
the para-aortic nodes. Lymphatic spread from
the lower 3rd of vagina may involve the
inguinofemoral nodes. Hematologic spread
is rare and the commonly involved sites are
the lungs, liver and bone.
TREATMENT
Vaginal Intraepithelial Neoplasia
Vaginal intraepithelial neoplasias (VAINs) are
difficult to manage by surgical excision
because of close proximity to the bladder and
the rectum. Most cases are considered to be
extensions of CIN onto the vagina. Residual
CIN lesions present at the vaginal vault may
be hidden behind the suture line and are
82 A Practical Approach to Gynecologic Oncology
difficult to manage. It is important to rule out
invasive disease by doing multiple punch
biopsies, especially when the lesion is
extensive or multifocal.
The treatment options include partial or
total vaginectomy, laser excision or radio-
therapy depending on the anatomy of the
lesion, local expertise and facility for treat-
ment.
Local application of 5 fluorouracil has been
tried with varied results.
Invasive Vaginal Cancer
Most cases are treated using radiotherapy and
surgery is limited to select patients with very
early disease.
Radiotherpy
Due to anatomical considerations salvage of
bladder and rectal functions is possible only
with radiotherapy in most of the cases.
Radiotherapy consists of external beam
radiotherapy and brachytherapy (vaginal
ovoids, vaginal cylinders or interstitial
implants). Most cases should receive a mid
tumor dosage of more than 75 Gy as lesser
doses are unlikely to achieve local tumor
control. There is little place for using external
beam radiotherapy alone and most cases
should be treated using combination of
external beam radiotherapy and brachy-
therapy. The incidence of significant long-term
complications is around 10 percent and
includes vaginal stenosis, vesicovaginal or
rectovaginal fistulae and rectal stricture.
As in cervical cancer most cases with
primary vaginal cancers are treated with
concomitant chemoradiation these days.
Weekly cisplatin in the dosage of 40 mg/m2
for five to six cycles is the currently preferred
regimen. Combination chemotherapy has not
shown significant survival benefit in cervical
cancer, and it significantly adds to the toxicity.
Surgery
Surgery has a limited role in the management
of vaginal cancer. Those with stage I lesions
involving the upper vagina can be managed
with radical hysterectomy, pelvic lympha-
denectomy and partial vaginectomy with 2 cm
tumor-free margins. Anterior vaginal wall
lesions are generally managed by radio-
therapy due to close proximity to the urinary
bladder. Lesions smaller than 2 cm confined
to the vaginal wall (stage I) involving mid-
vaginal tube, can be managed by wide local
excision with adequate tumor-free margins
prior to radiotherapy to achieve better local
control rates. Laxity of vaginal walls is an
important consideration while deciding in
favor of surgery. In the presence of vaginal
wall stenosis and fibrosis radiotherapy is
considered to be a better option. Lesions
involving lower 2 to 3 cm of posterior vagina
can be treated with radical vulvectomy,
bilateral groin lymphadenectomy and lower
vaginectomy.
Patients presenting with vesicovaginal or
rectovaginal fistulae should be considered for
exenterative surgery, if the pelvic side walls
are not involved. Distant metastasis (extra-
pelvic) is a contraindication for exenterative
surgery.
SURVIVAL
Overall survival for stage I disease is
approximately 70 to 80 percent.4,5 There is
inconsistency in the reporting of survival for
stages II and III disease because of difficulty
in assigning the correct stage clinically.
Prognostic Factors
The FIGO stage is the most important
prognostic factor. Tumor grade has also been
reported to be an important prognostic factor
with poorly differentiated tumors not faring
well.

UNCOMMON VAGINAL TUMORS
Leimyosarcoma
Primary therapy is surgical excision. Adjuvant
radiotherapy and chemotherapy have been
advocated for high grade tumors. Most
commonly used chemotherapeutic drugs are
ifosfamide and adriamycin used in combi-
nation.
Tumor grade is important prognostic factor
apart from the stage.
Rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft
tissue tumor in children. Vagina is the second
most common site after head and neck. More
than 90 percent of the tumors occur in children
younger than 3 years. Its origin is from the
primitive mesenchymal tissue.
Typically patients present with “grape-like”
vaginal mass and bleeding. Tumors are most
commonly confined to the anterior vaginal
wall.
Treatment consists of surgical excision with
preservation of reproductive function.
Surgical excision is difficult in children and
needs extraoperative skill and judgment.
Usually the tumor is excised without excision
of the vaginal walls. Adjuvant chemotherapy
most commonly consists of combination of
vincristine, actinomycin D and cyclopho-
sphamide. The survival rates are over
90 percent following treatment.
Cancer of Vagina 83
Clear Cell Adenocarcinoma
This rare tumor has been associated with
maternal ingestion of diethylstilbestrol (DES)
and it typically affects young women. This
tumor has become even rarer as DES is no
longer used.
Melanoma
Primary malignant melanoma of vagina is rare
and is considered the most aggressive
gynecological malignancy. The outlook is
bleak, whatever the type of treatment. Surgical
excision, radiotherapy and chemotherapy
have all been used with poor outcome.
REFERENCES
1. Bell J et al. Vaginal cancer after hysterectomy
for benign disease, value of cytologic
screening. Obstet and Gynecol 1984;
64: 699.
2. Benedet JL et al. Primary invasive cancer
of vagina. 1983 Obstet and Gynecol 1983;
62: 715.
3. Peters et al. Micro invasive cancer of vagina
a distinct clinical entity. Am J Obstet Gynecol
1985; 153:505.
4. Eddy GL, Marks RD, JR Miller et al. Primary
invasive vaginal carcinoma. Am J Obstet
Gynecol 1991;165: 292.
5. Perez CA, Camel HM. Long term follow up
in radiation therapy of cancer of vagina.
Cancer 1982; 49:1308.
 8 Cervical Intraepithelial
Neoplasia
• Ranajit Mandal • Srabani Mittal

ANATOMY AND PHYSIOLOGY cervix enlarges and the columnar epithelium

OF CERVICAL EPITHELIUM of the lower part of endocervical canal comes
out on the ectocervix. This condition is called
A thorough knowledge of anatomy and
ectropion or ectopy. It is sometimes erro-
histology of the normal cervical epithelium is
neously called erosion.
essential to understand the pre-neoplastic
Since the columnar epithelium cannot
changes of cervical cancer. Both stratified
withstand the acidic vaginal milieu, it is
squamous and columnar epithelium cover the
eventually replaced by squamous epithelium
cervix. Normally ectocervix is covered by the
arising from the proliferation of sub-epithelial
stratified, nonkeratinizing, glycogen contain-
reserve cells. The process is called metaplasia
ing squamous epithelium. Multiple (15-20)
and the newly formed epithelium is known
layers of cells are orderly arranged on the
as metaplastic epithelium. The new squamo-
basement membrane forming basal, para-
columnar junction between the columnar
basal, intermediate and superficial layers
epithelium and the metaplastic squamous
from below upwards. The columnar epithe-
epithelium is situated at the external cervical
lium consists of single layer of tall, mucin
os. The area between the original squamo-
secreting cells with dark staining nuclei close
columnar junction and the new squamo-
to the basement membrane. The columnar
columnar junction is called the transformation
epithelium invaginates into the connective
zone (TZ).
tissue (stroma) to form the crypts, more
At menopause the cervix shrinks due to
commonly known as glands. These two types
the paucity of endogenous estrogen. As a
of epithelia meet at the squamocolumnar
result the squamocolumnar junction moves
junction that is normally placed at the external
upwards into the endocervical canal.
os.
The location of the squamocolumnar
CERVICAL PRECANCER:
junction varies depending upon the woman’s
TERMINOLOGY AND DEFINITIONS
age and menopausal status. During childhood
and premenarche the original squamo- Cervical cancer is considered to develop
columnar junction is located very close to the through well-defined precursor lesions.
external os. At puberty and during childbirth, Starting from the early part of twentieth
under the influence of excess estrogen the century the nomenclature for cervical

precancer has undergone a series of changes.
The term carcinoma in situ (CIS) was
introduced in 1932 to denote those lesions in
which the undifferentiated neoplastic cells
involve the full thickness of the epithelium
without disrupting the basement membrane.1
The term dysplasia was introduced in late
1950s to designate the cervical epithelial
atypia that is intermediate between normal
epithelium and CIS.2 Dysplasia was later
categorized into mild, moderate and severe
– depending on the degree of involvement
of the epithelial thickness by the dysplastic
cells.
Dysplastic epithelium is characterized by
irregularities of shape and size of the cells,
abnormal nuclear size, increased nuclear
chromatin, loss of polarity and increased
number of mitotic figures. When this
neoplastic change is limited to the lower third
of the epithelium the condition is called mild
dysplasia. In moderate dysplasia the epi-
thelial changes are limited to the lower two-
third. Involvement of the entire thickness of
the epithelium except the most superficial
layer is designated as severe dysplasia.
In the late 1960s, the cervical intraepithelial
neoplasia (CIN) terminology was introduced
in which the cervical precancers were
categorized into three grades: CIN I, CIN II
and CIN III.3 In this nomenclature CIS and
severe dysplasia were together grouped as
CIN III. The terms mild and moderate
dysplasia were replaced by CIN I and CIN II
respectively.
In the 1980s, koilocytic atypia associated
with human papilloma virus (HPV) infection
was recognized. Koilocytes are atypical cells
with enlarged hyperchromatic nuclei, fine
granular chromatin and perinuclear halo in
the cytoplasm are pathognomonic of HPV
infection.
In 1988, the Bethesda system proposed to
replace the terms dysplasia/CIS or CIN with
Cervical Intraepithelial Neoplasia 85
a new nomenclature. Cellular changes
associated with HPV infection or mild
dysplasia (CIN I) were grouped as low grade
squamous intraepithelial lesions (LSIL),
whereas high grade squamous intraepithelial
lesions (HGSIL) included moderate dysplasia
(CIN II) and severe dysplasia/CIS (CIN III).4
NATURAL HISTORY OF CERVICAL
PRECANCER LESIONS
Persistent infection with the oncogenic
subtypes of human papilloma virus (HPV)
happens to be the necessary causal agent for
cervical carcinogenesis.5 The DNA of any of
the oncogenic sub-types of HPV (16, 18,31,
33,35,39,45,51,52,56,58,59 and 68) is recovered
from almost all high grade CIN and invasive
cancer.6 Women infected with oncogenic HPV
types have relative risks of 40-180 for deve-
lopment of high grade cervical neoplasia.7
HPV 16 and 18 are the main viral genotypes
found in cervical cancers worldwide.
HPV infection is transmitted through sexual
contact and the risk factors therefore
are closely related to sexual behavior (e.g.
lifetime, number of sexual partners, sexual
intercourse at an early age). Although the
prevalence of HPV infection varies in
different regions of the world, it generally
reaches a peak of about 20-30 percent among
women aged 20-24 years, with a subsequent
decline upto the age of 40-45 years, but then
may begin to increase slowly again.8 In most
women, HPV infections are transient. About
80 percent of the young women who become
infected with HPV will clear the infection
within 12-18 months. Only 10-20 percent
women who have persistent infection may
finally develop cervical neoplasia.9
HPV infection is believed to start in the
basal cells or parabasal cells of the metaplastic
epithelium. If the infection persists, integration
of viral genome into the host cellular genome
may occur resulting in the expression of E6/
86 A Practical Approach to Gynecologic Oncology
E7 oncoproteins. The E6 oncoprotein binds
and inactivates host tumor suppressor protein
p53, thus preventing the repair of genetic
damage and the programmed cell death
(apoptosis). E7 oncoprotein similarly acts on
tumor suppressor protein pRb and promotes
host cell (and also viral) DNA synthesis. The
combined effect leads to the development of
abnormal dysplastic epithelium. If the
neoplastic process continues uninterrupted,
the early low-grade lesions may eventually
involve the full thickness of the epithelium.
Subsequently the disease may traverse the
basement membrane and become invasive
cancer. The invasion may then affect blood
and lymphatic vessels and the disease may
spread to the lymph nodes and distant
organs.
It is evident that majority of the low grade
CIN lesions regress spontaneously within a
relatively short period of time and do not
progress to high grade lesions. On the
contrary, high grade CIN lesions have
increased probability of progressing to overt
disease although a small proportion may
persist or regress. The mean time interval for
progression of cervical precancer to cancer is
10 years.
Available studies suggest that the risk of
progression to invasive disease increases with
the grade of lesion. The relative risk (RR) of
progression and regression calculated after
2 years of follow up of moderate and severe
dysplasias (with mild dysplasia taken as the
baseline category) showed that the RR of
developing carcinoma in situ (CIS) from
moderate dysplasia was 8.1 and from severe
dysplasia was 22.7. The relative risks of
developing invasive cancer for moderate
dysplasia and severe dysplasia were 4.5 and
20.7 respectively.10
The results of a pooled analysis of studies11
published between 1950 and 1993 are given
in the Table 8.1 below.
Table 8.1: Regression, persistence and
progression probabilities of CIN
CIN Regres- Persis- Progres- Progres-
cate- sion tence sion to sion to
gory CIN 3 invasive
cancer
CIN1 57% 32% 11% 1%
CIN 2 43% 35% 22% 1.5%
CIN 3 32% 56% – 12%
SCREENING AND EARLY DETECTION OF
CERVICAL CANCER
Screening is defined as application of a simple
and rapid test on the asymptomatic, high-risk
population to identify the presence of a
disease. In the context of cervical cancer
prevention, the aim of screening is to detect
precancer lesions and treat them before they
progress to invasive cancer. In developed
countries, introduction of Pap smear to screen
sexually active women annually or once in
2-5 years has resulted in large decline in
cervical cancer incidence and mortality over
the last 40 years.
Cytology Based Screening
Successful cytology based screening program
demands a wide range of resources, logistics
and high level of organizational capabilities.
Such program requires a relatively
sophisticated infrastructure, highly trained
personnel, adequately equipped laboratories,
and facilities to recall the screen positive
women at a later date. It is very difficult to
meet these criteria in developing countries
with highly limited resources. Pap smear
cytology was introduced as a screening test
in routine clinical practice without any
randomized trial to evaluate its efficacy. The
ability of the test to reduce the incidence of
cervical cancer has traditionally been accepted
as the proof of its effectiveness.
The screening program in a developing
country can only afford low intensity

screening (i.e. women within a limited age
group will be screened using the test less
frequently). For such screening protocol it is
essential that the test should have high
sensitivity with reasonably good specificity.
The sensitivity of cytology to detect precancer
lesions when objectively assessed by various
studies proved to be inconsistent and often
unacceptably low. A pooled analysis of
various studies 12 concluded that the
sensitivities of cytology (at ASCUS/CIN I
threshold) to detect high grade lesions ranged
from 30-87 percent (mean 47%). In another
meta-analysis13 the estimated mean sensitivity
was 58 percent and the mean specificity was
found to be 69 percent. Due to the poor sensi-
tivity of cytology and the logistic constraints
of implementing a cytology based screening
program, alternative means of controlling the
disease in the low resource set-ups have been
explored over the last two decades.
Role of Health Education
The survival from invasive cancer cervix
depends mainly on the stage at the time of
detection and treatment. In developing
countries most of the cases present at an
advanced stage when mostly palliative
treatment is possible. This is due to the lack
of knowledge among women about disease
symptoms, inherent fear of the disease and
low priority for women’s health in the family.
Health education to make women aware
of the early symptoms is likely to achieve
down-staging of the disease resulting in
reduction of mortality. This hypothesis was
tested in a community trial in India where
women in a defined geographic area received
health education on early symptoms of
cervical cancer. When compared with a
control group who did not receive the
awareness messages, the intervention group
had higher number of women presenting at
an early stage. This finally resulted in a
Cervical Intraepithelial Neoplasia 87
statistically significant difference in the
mortality rate from cervical cancer between
the two groups (5.1/105 in the intervention
group vs. 8.2/105 in the control group).14 Such
a health education program does not require
much infrastructure or logistics support for
implementation. It is imperative that facilities
for clinical examination of the symptomatic
women should also be made along with the
awareness program.
Clinical Downstaging
As an alternative to cytology it was proposed
in the early 1980s that the health workers may
be trained to perform naked eye speculum
examination of the uterine cervix under a
good light source and designate the findings
as ‘normal’ or ‘abnormal’. 15 Those with
abnormal findings need further investigation
or examination by gynecologists. It was
expected that ‘downstaging’ would achieve
a stage shift of the disease towards an early
one at diagnosis.16
The apparently simple technique has been
evaluated by a number of studies done in
Indian subcontinent. Some of the studies
have used two different thresholds of criteria
for referral: Low threshold criteria (cervicitis,
polyp, wart, bleeding on touch, bleeding
erosion, hypertrophied elongated cervix,
congested stippled cervix, growth, ulcer) and
high threshold criteria (bleeding on touch,
bleeding erosion, hypertrophied elongated
cervix, congested stippled cervix, growth,
ulcer). It has been convincingly demonstrated
that ‘downstaging’ is quite inefficient to
detect either cervical cancer or precancer and
also cannot achieve any stage shift of the
disease.
Proportion of Cervical cancers with Normal
Visual Inspection Findings in Various Indian
Studies are as follows:
Nene (1997) 14 14% (Low threshold)
Nene (1997) 29% (High threshold)
88 A Practical Approach to Gynecologic Oncology
Wesley (1997)17 46% (High threshold)
Basu (2002)18 14% (Low threshold)
Basu (2002) 28% (High threshold)
‘Downstaging’ is unlikely to achieve the
objective of cost-saving as at least half of the
women need to be subjected to further
investigation. The cost of locating and moti-
vating such a high proportion of women
would offset the cost saving achieved by
avoiding cytology. To achieve any significant
reduction in mortality ‘downstaging’ has to
be repeated at a very frequent interval (once
a year) that will again raise the cost of the
program.
Visual Inspection after Application
of Acetic Acid (VIA)
Visual inspection with acetic acid (VIA) is
currently being investigated as the most
promising low technology alternative to Pap
smear for cervical cancer prevention in low-
resource settings. VIA involves naked eye
examination (without magnification) of the
uterine cervix after application of freshly
prepared 3-5 percent acetic acid, under a good
light source. Acetic acid intravital staining is
routinely used in colposcopic examinations to
see abnormal epithelium. Acetic acid causes
dehydration of the cells and some coagulation
of the cellular proteins, thereby reducing the
transparency of the epithelium and turning it
white. These changes are more pronounced
in the neoplastic epithelium because of its
higher nuclear density and consequent high
concentration of protein. High grade of
intraepithelial lesions take up a dense white
colour due to its high content of nuclear
protein.
The results are reported based on the
findings observed one minute after
application of acetic acid and are categorized
as negative, positive or invasive cancer. The
details of the classification of VIA findings
are given in following Table 8.2.
Table 8.2: Criteria for categorizing VIA test results
VIA category Description
Negative No acetowhite lesions
Transparent lesions or faint patchy
lesions without definite margins
Nabothian cysts taking up aceto-
whitening
Faint line like acetowhitening at the
junction of columnar and squamous
epithelium
Acetowhite lesions far away from
the transformation zone
Positive Distinct, opaque acetowhite area
Margin should be well-defined,
may or may not be raised
Abnormality close to the squamo-
columnar junction in the transfor-
mation zone and not far away from
the os
Invasive cancer Obvious growth or ulcer in the
cervix
Acetowhite area may not be visible
because of bleeding
VIA can be a potential alternative to
cytology as a screening test suitable for low-
resource settings. The test is relatively simple
in terms of administration and interpretation
and can be performed by trained health
workers and technicians. This test is not
dependent on laboratories or trained cyto-
pathologists, so rarely available in the
developing countries. The instant availability
of the test results can save the logistic problem
of recalling the positive women and
transporting them to the clinic for further
evaluation.
Recent studies in various settings have
proved that VIA can detect cervical precursor
lesions missed by Pap smears and its
sensitivity is comparable to that of cervical
cytology or even better in some of the studies.
The primary pitfalls of VIA are that the test
suffers from a high proportion of false
positive referrals for colposcopy and is likely
to miss many of the endocervical lesions.
 Cervical Intraepithelial Neoplasia 89

The sensitivity of VIA for detection of CIN epithelium and neoplastic epithelium contain
II, III and invasive cancer ranged from 67.4- little or no glycogen. As a result they remain
96.8 percent and the specificity ranged from unstained.
64.1-92.2 percent in various studies. Some of Lugol’s iodine solution (Composition:
the initial studies suffered from verification 4 gms iodine, 6 gms potassium iodide, 100 ml
bias as only the test positive women were of water) is applied to cervix to look for iodine
subjected to the reference investigation of non-uptake areas. The test outcome criteria
colposcopy and/or biopsy. These studies are of VILI are described in Table 8.4:
more likely to reflect the true sensitivity of
the test. Table 8.3 lists the results of some of Table 8.4: Criteria for categorizing VILI test results
the studies done without verification bias. VILI category Description
Though VIA has its limitations in terms of Negative Squamous epithelium turns ma-
low specificity and failure to evaluate the hogany brown and columnar
endocervical diseases, it is likely to find a epithelium does not change
place as an alternative low technology and color
low cost screening tool in developing Patchy, indistinct, colorless or
countries where it is not feasible to introduce partially brown areas in trans-
cytology screening of acceptable quality for formation zone
many years to come. Furthermore, in Leopard skin appearance (yel-
low dots in brown background)
developed countries, it may be useful as an
Thin or patchy iodine non-up-
adjunct test to improve the sensitivity of take areas with angular or
cervical cytology. digitating margins located away
from squamo-columnar junc-
Visual Inspection with Lugol’s Iodine (VILI) tions
Positive Well-defined, bright mustard
Schiller’s iodine test was introduced in 1930s yellow/saffron yellow iodine
to identify cervical neoplasia even before the non-uptake areas touching the
advent of Pap smear.23 Normal squamous squamo-columnar junction
epithelium of cervix has abundant glycogen Invasive cancer Obvious growth or ulcer in the
in the cells that are stained by iodine to cervix
produce a dark brown mahogany color. The Iodine non-uptake area may not
columnar epithelium, immature metaplastic be visible because of bleeding

Table 8.3: Performance of VIA and cytology in detection of CIN II and above
lesions in different studies without verification bias
Author Sensitivity Specificity
VIA Cytology VIA Cytology
19
Belinson et al
2001(cytology: Thinprep, threshold >ASCUS) 71% 94% 74% 78%
20
University of Zimbabwe/JHPIEGO (1999) 77% 44% 64% 91%
(cytology: conventional, threshold >LGSIL)
21
Sankaranarayanan et al 2003 (cytology: conventional, 83% 82% 87% 88%
threshold >Atypia)
22
Basu et al 2003 56% 30% 82% 92.3%
90 A Practical Approach to Gynecologic Oncology
Sankaranarayanan et al evaluated the test
performance of VILI in a study that was free
from verification bias. They observed a
sensitivity of 87.2 percent and a specificity of
84.7 percent for the detection of CIN II and
worse lesions.21 A recently concluded study
in Kolkata observed similar performance of
VILI in the detection of CIN II and worse
lesions. The sensitivity and specificity
observed in the Kolkata study were 78.1
percent and 88.3 percent respectively. These
initial results suggest that VILI can prove to
be another useful low-technology method for
cervical cancer screening in limited resource
settings.
Detection of DNA of Oncogenic
Subtypes of HPV
A persistent high-risk HPV infection is
necessary for the development, maintenance
and progression of a high grade cervical
cancer precursor lesion. The detection of
oncogenic HPV in nearly all cervical cancers
establishes the rationale for utilization of high
risk HPV testing in cervical cancer screening.
The high prevalence of HPV infection in the
younger women precludes the use of this test
in women aged less than 30 years.
Hybrid capture II (Digene Diagnostics) is
currently the only assay that is commercially
available and has been extensively tried in
studies all over the world. Table 8.5 cervical
cells around the os are collected in a liquid
collection medium using a cytobrush. The cells
are lysed to release the denatured viral DNA
if present. Synthetic HPV RNA probes are
added to the solution so that they hybridize
with the viral DNAs present. The solution is
then added to a specially designed microplate
lined with antibodies against RNA-DNA
hybrids. The antibodies can recognize RNA-
DNA hybrids if present and capture them.
The immobilized hybrids of RNA-DNA are
reacted with a second antibody conjugated
to alkaline phosphatase. A chemoluminescent
substrate is added. As the substrate is cleaved
by the bound alkaline phosphatase conjugate,
light is emitted. The intensity of the emitted
light is proportional to the amount of viral
DNA in the specimen and is measured by a
luminometer. Emitted light intensity is
expressed in relative light units (RLU) that is
the ratio of light produced by each sample
divided by the mean level of light produced
by three positive controls of 1 pg HPV 16
DNA per ml. An RLU value of more than 1 is
usually taken as the cutoff value for positive
detection. It is a non-radioactive, repro-
ducible, relatively rapid, liquid hybridization
assay designed to detect 13 oncogenic HPV
subtypes (16, 18, 31, 33, 35,39, 45, 51, 52, 56,
58, 59, 68).
HPV DNA test can be used for primary
cervical screening, as an adjunct to cytology
or for triaging of ASCUS/borderline cytology
smears for referral to colposcopy.
A number of studies have evaluated the
performance of HPV DNA testing as a
primary screening test in developed as well
as low-middle income countries. The
performance of HPV testing was compared
with conventional cervical cytology in most
of these studies.
HPV test can be combined with cytology
to enhance the efficiency of the screening
program. The high sensitivity and the high
negative predictive value of the combined
testing strategy can reduce the frequency of
screening and make the program more cost-
effective.
The ASCUS (Atypical Squamous Cells of
Undetermined Significance) or LSIL smears
comprise of 5-10 percent of all the smears in
the cytology screening programs of the
developed countries. ASCUS/LSIL smears
have very low predictive values for the
detection of high grade lesions. Referring all
such cases for colposcopy will overwhelm the
colposcopy services and will result in high
 Cervical Intraepithelial Neoplasia 91

Table 8.5: Performance of hybrid capture II

for detection of high-grade SIL/cancer
Study Test Sensitivity Specificity NPV PPV
Schiffman-Costa Pap only 78 94 18 99.6
24
Rica HPV only 88 89 12 99.8
Pap + HPV 94 90 9 99.9
19
Belinson-China Pap only 94 78 16 99.7
HPV only 95 85 23 99.8
Pap + HPV 100 68 6 100
25
Petry-Germany Pap only 52 99 11 99.8
HPV only 96 96 8 100
Pap + HPV 100 95 7 100

number of unnecessary biopsies. If the women • CIN or cancer on cytology

with equivocal pap results are subjected to
HPV DNA testing and only the test positives
are referred for colposcopy, the number of
referrals will be much less. To prove this
hypothesis a large randomized trial has
recently been concluded.26 Three thousand
four hundred eighty-eight women with a
community-based ASCUS interpretation were
randomized to immediate colposcopy, triage
based on enrollment HPV DNA testing, or
conservative management based on repeat
cytology. Recruitment of LSIL cases was
stopped in the midway based on the
observation that a very high percentage (80%)
of this group was HPV positive and were
ultimately referred for colposcopy. The trial
concluded that HPV testing is significantly
more sensitive than repeat cytology for
detecting CIN III lesions, while referring the
same number of women to colposcopy.
COLPOSCOPY IN THE
MANAGEMENT OF CIN
For confirmation of diagnosis, all screen posi-
tive women need to undergo colposcopy that
can confirm/validate the presence of a lesion.
Indications for Colposcopy
• Suspicious looking cervix on naked eye
examination.
• Persistence of inflammatory appearance of
smear despite adequate treatment
• Positive results on screening tests other
than cytology (VIA, VILI, HPV DNA
detection)
• Monitoring after treatment of CIN, regard-
less of treatment methods.
The Instrument
A colposcope is a low power, stereoscopic,
binocular microscope with a variable intensity
light source. Hinselmann (1925) first devised
the instrument and established the foundation
for the practice of colposcopy.
Modern colposcopes usually have 6x to 40x
adjustable magnification. A magnification
range of 6x to 15x is usually adequate. Lower
magnification yields a wider view and greater
depth of field for examination of cervix.
However, higher magnifications may be
required to reveal finer features such as
abnormal blood vessels.
Colposcopes should be focused by
adjusting the distance between the lens and
the organ of the woman being examined. The
focal length of a colposcope is either 250 or
300 mm.
Colposcopic Appearance of Normal Cervix
On colposcopy squamous epithelium appears
smooth and translucent with a pinkish tinge.
Columnar epithelium is deep red in color and
92 A Practical Approach to Gynecologic Oncology
has a villous or grape like appearance. The
most crucial part of cervix for colposcopic
evaluation is the transformation zone where
cervical intraepithelial neoplasia (CIN) and
cervical carcinoma arise. Unless the
colposcopist can adequately examine the
entire transformation zone (TZ) the
examination is inadequate or unsatisfactory.
The TZ is characterized by the presence of
tongue shaped extension of faint acetowhite
immature epithelium, crypt openings,
nabothian follicles and islands of columnar
epithelium. The inner limit of TZ is the
squamocolumnar junction and the outer limit
is the furthest extension of the metaplastic
epithelium evidenced by the presence of crypt
openings.
A wide range of colposcopic appearances
may be seen during different phases of
metaplasia. In the earliest phase, the villi
widen, flatten and fuse together. As metaplasia
progresses, the fused columnar epithelium
forms tongue like projections pointing
towards the external os. The fully mature
epithelium resembles the original native
epithelium except for the presence of some
crypt openings and nabothian follicles. The
metaplastic epithelium may become white on
application of acetic acid due to the high
chromatin content of the immature cells. The
aceto-whitening is thin, often translucent and
may have a very fine network of capillaries
forming fine mosaics. Metaplastic epithelium
is often devoid of glycogen and may not take
iodine stain. The typical blood vessels in the
normal epithelium are long regular branching
vessels with gradually decreasing caliber or
a network of regular branching vessels.
Colposcopic Appearance of Cervical
Intraepithelial Neoplasia (CIN)
Colposcopic diagnosis of CIN requires
recognition of important features like intensity
of aceto-whitening, color tone, margin and
surface contour of acetowhite areas, vascular
pattern and iodine staining. The presumptive
dignosis of CIN can be made depending upon
the presence of one or more of these features
on the transformation zone of cervix.
Colposcopic diagnosis should be confirmed
by taking directed biopsy.
Abnormal Vascular Patterns
At the beginning, normal saline should be
applied to the cervix to wipe the mucus or
any discharge. This facilitates the evaluation
of surface features and atypical vessels.
Vascular pattern is best studied under green
filter and high magnification. The abnormal
vascular features suggestive of cervical
intraepithelial neoplasia are the atypical blood
vessels, punctations and mosaics.
The atypical vessels are characterized by
varying intercapillary distance, irregularities
in shape and caliber and abrupt appearance
and disappearance. The atypical vessels can
have the characteristic shapes resembling
hairpin, corkscrew, tendril, waste-thread or
root. Presence of abnormal vessels always
signifies high grade lesion with a strong
probability of invasion.
The looped capillaries in the stroma when
viewed end on, appear as dots on the surface
of the ectocervix. Such appearance is known
as punctation. The dots may be thin and
evenly placed producing a delicate stippling
effect. Such an appearance is known as fine
punctation and may be associated with
infection or metaplasia.
Mosaics are the networks of blood vessels
that appear in close proximity to one another
and give the appearance of cobblestones on
colposcopy. When the blood vessels are of
fine caliber and evenly spread out, the
appearance is called fine mosaic that signifies
metaplasia or low-grade lesion.
Advanced neoplastic change is charac-
terized by formation of new vessels that are
fragile, unevenly placed and raised from the
 Cervical Intraepithelial Neoplasia 93

surface. Such vessels form coarse punctations
or coarse mosaics in the background of dense
acetowhite epithelium.
Acetowhite Epithelium
The appearance of well demarcated, opaque,
acetowhite area close to or abutting the
squamocolumnar junction in the trans-
formation zone after application of acetic acid
is the hallmark of colposcopic diagnosis of
CIN. The grade of CIN will depend on the
rapidity of appearance and the density of
acetowhite area. The higher-grade lesions are
more likely to turn dense white rapidly. The
margins of neoplastic lesions are clear-cut and
straight and sometimes may be elevated from
the surface.
If a crypt is involved with high-grade
lesion, it may have thick, dense acetowhite
rim. Such appearance is called cuffed crypt
opening.
Appearance after Lugol’s Iodine Application
Lugol’s iodine solution if applied abundantly
to the whole cervix and vagina, the glycogen
rich normal epithelium will stain mahogany
brown or black, whereas, dysplastic epithe-
lium containing little or no glycogen will not
take any stain and remains mustard or saffron
yellow. Columnar epithelium does not take
any stain with iodine and immature
metaplastic epithelium only takes partial stain.
Atropic epithelium also stains partially with
iodine that makes interpretation difficult in
postmenopausal women.
At the end of colposcopy the colposcopist
should try to arrive at a provisional diagnosis.
A scoring or grading system may be used to
interpret colposcopic findings more syste-
matically and in a more objective manner. One
such scoring system, modified Reid’s scoring
system is described in Table 8.6.

Table 8.6: Modified Reid’s scoring system

Feature 0 point 1 point 2 points
Color of acetowhite Low intensity acetowhitening; Shiny grey Dull, oyster white
(AW) area shiny, snow white; indistinct
AW; AW beyond transformation
zone
Margin and Feathered margins; angular, Regular lesions with Rolled, peeling edges
surface jagged lesion; flat lesions with smooth straight outlines
configuration indistinct margins; condylo-
matous or micropapillary
surface
Vessels Fine/uniform vessels; poorly Absent vessels Well-defined coarse
formed patterns of fine punctation or coarse
punctuations and/or fine mosaic
mosaic; vessels beyond the
margin of transformation zone;
fine vessels within micro-
condylomatous or micro-
papillary lesions
Iodine staining Positive iodine uptake giving Partial iodine uptake by Negative iodine uptake
mahogany brown color; a lesion scoring 4 or more by a lesion scoring 4
negative uptake of lesions points on above three more points on the
scoring 3 points or less on categories; variegated or above micropapillary
above three categories speckled appearance three criteria
Scoring: A score of 0-2 points = Likely to be CIN I; 3-4 points = Overlapping lesion: likely to be CIN I-II; 5-8
points = Likely to be CIN II-III lesions.
94 A Practical Approach to Gynecologic Oncology
TREATMENT OF CERVICAL PRECANCER
Principles
Cervical intraepithelial neoplasia is usually
treated conservatively either by destroying
the abnormal epithelium (ablative techniques)
or by removing the diseased part (excisional
techniques). Ideally, the entire diseased
portion including the extension into the
crypts should be treated leaving a healthy
margin of about 2 mm. Cytology report, histo-
logic grade, extent of the lesion and
completeness of colposcopic assessment are
important parameters based on which
treatment decisions are made.
Cryotherapy
Crisp et al in 1967 first reported cryotherapy
as a simple and safe alternative to knife
conization for the treatment of cervical
intraepithelial neoplasia. The technique was
widely used as an outpatient procedure in
the 1970s. Cryotherapy lost its popularity
following the introduction of the loop excision
procedure in early 1980s by Rene Cartier. The
main drawbacks of cryotherapy were, failure
to deliver a piece of tissue for further
histopathological evaluation and unacceptable
recurrence rates following treatment of CIN
III. The interest in the technique was revived
with the realization that the technique may
be suitable in the cervical cancer control
programs of the low resource set-ups. The
low cost, low complication rate and simplicity
of the procedure make it very attractive for
use in such set-ups.
The cryotherapy unit consists of a
compressed gas cylinder (nitrous oxide or
carbon dioxide), cryo-gun with multiple cryo-
probes, pressure gauge and gas conveying
tube. Carbon dioxide or nitrous oxide gas
freezes when released through the nozzle of
cryogun to the atmospheric pressure (freezing
point of carbon dioxide is –60° C and of nitrous
oxide –90° C). This forms an ice-ball that
brings down the temperature of the tissue in
contact to below –20 ° C. This results in
crystallization of the intracellular water. The
spear-like crystals of water pierce the cell
membrane and cause irreversible damage and
cell death (cryonecrosis).
Adequate punch biopsies should be
obtained from the abnormal area prior to
cryotherapy. All cervical precancer lesions
cannot be treated by cryotherapy. The
eligibility criteria for cryotherapy are as
follows:
• The entire lesion is located in the ectocervix
without extension to the vagina and/or
endocervix.
• The lesion can be adequately covered by
the largest available cryotherapy probe
• The lesion does not occupy more than 75%
of the transformation zone
• Any grade of CIN can be treated provided
other eligibility criteria are fulfilled
• There is no evidence of invasive cancer.
• The woman is not pregnant
• There is no evidence of pelvic inflammatory
disease.
After reassessing the lesion by colposcopy,
cryoprobe with appropriate diameter is
selected to cover the lesion completely. The
cryogun along with tube is attached to the
gas cylinder. At the beginning of the
procedure the pressure of the gas cylinder
should be checked by the pressure gauge so
that it is between 40 to 70 kg/sq cm.
Cryoprobe surface is wiped with saline to
ensure adequate thermal contact with the
cervix. The probe-tip is then firmly applied
with the center of the tip on the external os.
One must ensure that the vaginal walls are
not in contact with the probe-tip. As the gas
starts flowing, ice-ball is seen forming at the
tip of the cryoprobe. Freezing should be done
in two cycles of three minutes with five
minutes of thawing in between. When
adequate freezing has been achieved the
 Cervical Intraepithelial Neoplasia 95

margin of the ice-ball extends 4-5 mm beyond heavier bleeding. A small number of patients
the outer edge of the cryo-tip. This will ensure may develop infection, requiring antibiotics.
that the cryonecrosis occurs down to ade- Cervical stenosis may be seen as a late
quate depth. Some authors observed that complication of cryotherpy. The external
single cycle of 3 minutes of freezing is as cervical os is narrowed to such an extent that
effective as double cycle of freezing.27 a Q-tipped cotton swab cannot be introduced.
If the eligibility criteria are strictly adhered This can very rarely lead to hematometra or
to, cryotherapy is as effective as laser pyometra. No effect on fertility or labor has
vaporization or loop excision methods. The been observed.
most important determinant of success of
cryotherapy is the size of the lesion. The Large Loop Electrocoutery
comparisons of results of cryotherapy by Excision Procedure (LEEP)
grades of CIN and size of the lesions are
Diathermy loops have been used for many
given in Tables 8.7 and 8.8.
years to remove small and large lesions of
cervix. In the early 1980s Rene Cartier used
Table 8.7: Success rates of cryotherapy
in different grades of CIN small loops to obtain biopsies from lesions
on the cervix. A few years later Prendeville
Author CIN I CIN II CIN III
(%) (%) (%)
and his team used large diathermy loops
28 simultaneously to obtain adequate biopsy and
Ostergard (1980) 93.7 92.5 81.4 achieve complete treatment.
29
Creasman (1984) 94.6 92.8 82.3
30 In electro-surgery the electrical energy is
Andersen (1988) – 92.7 77.0
Benedet (1987)31 95.1 95.7 – transformed into heat and light energies. The
heat from a high voltage electrical arc bet-
Table 8.8: Success rates of cryotherapy ween the operating electrode and tissue allows
in different sizes of CIN lesions the operator to cut by vaporizing the tissue or
Author Lesion Lesion Lesion to coagulate by dehydrating the tissue.
in 1 in 1-2 in more The cutting electrodes are loops made up
quadrant quadrant than 2 of very fine (0.2 mm cross-sectional diameter)
of cervix of cervix qua- stainless steel or tungsten wires. The width
drants of the loops varies from 15 to 25 mm and the
of cervix depth (the height from the cross bar to the
(%) (%) (%) farthest point of the wire arc) varies from 15
Townsend and 95.2 92.9 88.3 to 22 mm. The appropriate size of the loop is
chosen to achieve adequate depths and width
32
Richart (1983)
29
Creasman (1984)
33
91.8 87.7 85.4 of cut depending on the size and position of
Bryson (1985) 96.1 91.0 – the lesion.
Indications of LEEP are as follows:
During the procedure the patient may feel 1. Treatment of CIN lesions
a little discomfort or cramp in the lower 2. The lesion extends into the endocervical
abdomen. Less than 5 percent of women expe- canal and a satisfactory assessment cannot
rience significant pain. After the procedure be made colposcopically
most of the women will have a watery 3. Cytology is repeatedly abnormal sugges-
discharge per vagina for 2 to 3 weeks. Rarely ting high grade lesions without there being
this may be associated with spotting or any colposcopic abnormality
96 A Practical Approach to Gynecologic Oncology
4. Cytology suggests a higher grade lesion
than do colposcopy or biopsy
5. Abnormal glandular lesion is suggested on
cytology or colposcopy
6. Endocervical curettage reveals abnormal
histology.
Consent of the patient is taken prior to
treatment. She is placed in the lithotomy
position, and an insulated (preferred) Cusco’s
or Graves’ speculum is used to expose the
cervix. Colposcopic assessment is repeated
and Lugol’s iodine is applied to delineate the
margin of the lesion clearly. Local anesthetic
agent (5-10 ml of 1% xylocaine or similar
agent) is injected into the stroma of the
ectocervix (just beneath the epithelium) in a
ring pattern at the periphery of the lesion. A
smoke evacuation system is attached to the
speculum. Non-cooperative patients or those
with large lesions will require general
anesthesia.
Modern electrosurgical generators have the
facility to combine cutting waveform with
coagulation waveform producing what is
known as the blended electrical current. This
type of current is desirable while performing
LEEP as it minimizes bleeding in the surgical
field while cutting. The power setting
depends on the size of the electrode being
used. The most commonly used power setting
is a blend of 50 watts of coagulation current
and 50 watts of cutting current.
An appropriate sized loop is chosen to
encompass the entire lesion for removal in
one pass, although this is not always feasible.
If the diameter of a lesion exceeds the width
of the largest loop, the lesion must be
removed with multiple passes. The loop is
introduced into the tissue 5 mm outside the
outer margin of the lesion. The loop is
directed gradually into the cervix until the
cross bar nearly comes in contact with the
epithelial surface. Then the loop is guided
along parallel to the surface till the opposite
outer margin of the lesion is reached and is
gradually withdrawn keeping it at right
angles to the surface. The operator should
simply provide directional guidance and
allow the loop to cut its own way without
pushing it. Once the specimen has been
removed and placed in formalin, the defect
is carefully fulgurated using a ball electrode.
Severe perioperative bleeding occurs in less
than 2 percent of cases and this bleeding can
usually be controlled by applying monsel’s
paste or silver nitrate applicator sticks or by
fulguration. Rarely placement of lateral
sutures is required.
If the procedure is performed under local
anesthesia then few women may experience
transitory pain. Postoperative pain is rare and
if it occurs it is usually similar to cramps.
The chances of postoperative infection is
very less and can be reduced by delaying
treatment till complete resolution of any
existing PID, cervicitis, trichomoniasis or
bacterial vaginosis.
Cervical stenosis is one of the long-term
sequelae of the procedure and is seen in less
than 2 percent of the cases.
LEEP is a simple and inexpensive method
of treatment of cervical precancers. Most of
the cases can be done in an office setting using
local anesthesia. However, the inflexibility of
the loop does not allow fashioning an incision
around the lesion. This results in removal of
the abnormality in multiple pieces that the
pathologists find difficult to orientate.
Various authors have observed high inci-
dences of positive margin (up to 40%) in the
excised specimens after LEEP. Murdoch, et al
in a follow-up study of such incompletely
excised lesions did not find a high failure
rate in patients with incompletely excised
diseases. Based on this evidence they conclu-
ded that such cases with positive cone margins
can be followed up without resorting to repeat
treatment. The failure rate of LEEP varies
between 4-10 percent in various studies.34
 Cervical Intraepithelial Neoplasia 97

A randomized clinical trial was done by is exposed by a Sim’s speculum after putting
Mitchell et al to compare the effectiveness of the patient in the lithotomy position. The
cryotherapy, laser vaporization and LEEP.35 patient is recolposcoped and site of the lesion
Women with biopsy proved CIN were is confirmed. To reduce bleeding, the two
randomly allocated to the different treatment decending branches of cervical arteries are
groups and were stratified by grades of CIN, occluded by two lateral stitches. With a tissue
lesion size and endocervical gland involve- forceps the cervix is grasped peripheral to the
ment. They observed no statistically lesion and drawn down, the ectocervical
significant difference in failure rates between incision is made with a pointed knife
the three treatment groups (Table 8.9). completely circumscribing the transformation
zone and the lesion. It is often easier to begin
Table 8.9: Comparisons of treatment the incision posteriorly and then carry it on
options for CIN anteriorly. Manipulating the cone with a tissue
Cryo- Laser LEEP forceps, a vertical incision is made into the
therapy vapori- cervix, angled towards the upper part of the
zation
endocervical canal so as to remove a conical
N = 139 N = 121 N = 130
block of tissue. A depth of cut between 15
Free of disease and 20 mm will clear most endocervical
at 1 year 74% 83% 83%
Persistent lesion
lesions. Local hemostasis can be achieved by
(detected within cauterizing the base or by applying a few
6 months) 7% 4% 4% stitches at the margin.
Recurrent lesion The most common complications of knife
(detected after conization are peroperative and post-
6 months) 19% 13% 13% operative hemorrhage.
Complications 2% 4% 8%
Peri/postoperative
Hysterectomy
bleeding 0 1% 3%
The indications of hysterectomy in the
Cold Knife Cone Biopsy management of cervical intraepithelial
neoplasia are as follows:
For years, the standard therapy for treating
• Associated gynecological conditions
CIN and conserving the cervix was cold knife
requiring removal of uterus
cone biopsy. Currently this procedure is
• Persistent abnormal smear following
reserved only for the treatment of
excision or ablative treatment
microinvasive cancer where evaluation of the
• Lesion extending to the vagina
margin is of prime importance. Excising the
• Where there are doubts about compliance
abnormality with a knife avoids the thermal
to regular follow-up.
artifact of diathermy excision and allows
If hysterectomy is required after conization
proper pathological evaluation of the margins.
it should either be done within 72 hours or
If facilities for LEEP are not available, cold
should be delayed for 6 weeks.
knife conization can still be performed on the
cases not suitable for cryotherapy.
MANAGEMENT OF CIN IN PREGNANCY
Reversible short acting analgesics, such as
midazolam, is given first to make the patient The occurrence of cervical precancer in
semiconscious and free from pain. The cervix pregnancy is relatively rare. Figures from
98 A Practical Approach to Gynecologic Oncology
larger centers in UK suggest an incidence of
one case of CIN III per 750 pregnancies.36 All
abnormal smears in pregnancy should be
evaluated by colposcopy. The colposcopic
interpretation of findings during pregnancy
is difficult due to the progestogenic effect and
subsequent decidualization of cervix. More-
over, the increased vascularity of the cervix
makes any kind of biopsy and treatment
procedure hazardous due to higher incidence
of bleeding complications.
During pregnancy, it is often a practice to
rely on colposcopy diagnosis alone, without
biopsy confirmation unless an invasive lesion
is suspected. If the colposcopic features are
suggestive of low-grade disease only, a repeat
assessment is advised at 12 weeks post-
partum, by which time the cervix is
completely involuted. If a high grade lesion
is suspected on colposcopy, the woman is
recalled 6 weeks after delivery for repeat
colposcopy and biopsy. However, if there is
any suspicion of invasion a colposcopically
directed punch biopsy should be obtained.
In the rare instances when colposcopy is not
adequate or the punch biopsy does not yield
adequate tissue for evaluation, a cone biopsy
is performed.
Vaginal delivery may be allowed in
presence of CIN and these women are
subjected to re-assessment at 8-12 weeks post
partum when the lesion is treated by the usual
methods.
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12. Nanda K, McCrory DC, Myers ER, et al.
Accuracy of the papanicolaou test in
screening for and follow-up of cervical
cytologic abnormalities: A systematic review.
Ann Intern Med 2000;132:810-19.
13. Fahey MT, Irwig L, Macaskill P. Meta-
analysis of Pap test accuracy. Am J Epide-
miol 1995;141:680-9.
14. Nene BM, Deshpande S, Jayant K, et al. Early
detection of cervical cancer by visual
inspection: A population-based study in
rural India. Int J Cancer 1997;68:770-3.
15. World Health Organization. Control of
cancer of the cervix, a WHO meeting. Bull
WHO 1986;64:607-18.

16. Stjernsward J, Eddy D, Luthra U, et al.
Plotting a new course for cervical cancer
screening in developing countries. World
Health Forum 1987;8:42-5.
17. Wesley R, Sankaranarayanan R, Mathew B,
et al. Evaluation of visual inspection as a
screening test for cervical cancer. Br J Cancer
1997;75:436-40.
18. Basu P, Sankaranarayanan R, Mandal R,
et al. Evaluation of downstaging in the
detection of cervical neoplasia in Kolkata,
India. Int J Cancer 2002;100:92-6.
19. Belinson J, Qiao YL, Pretorius R, et al. Shanxi
province cervical cancer screening study: A
cross sectional comparative trial of multiple
techniques to detect cervical neoplasia.
Gynaecol Oncol 2001;83:439-44.
20. University of Zimbabwe/JHPIEGO Cervical
Cancer Project. Visual inspection with acetic
acid for cervical cancer screening: Test
qualities in primary-care setting. Lancet
1999;353:869-73.
21. Sankaranarayanan R, Wesley R,
Somanathan T, et al. Test characteristics of
visual inspection with 4% acetic acid (VIA)
and Lugol’s Iodine (VILI) in cervical cancer
screening in Kerala, India. Int J Cancer 2003;
106:404-8.
22. Basu PS, Sankaranarayanan R, Mondal R,
et al. Visual inspection with acetic acid and
cytology in the early detection of cervical
neoplasia in Kolkata, India. Int J Gynecol
Cancer 2003;13:626-32.
23. Schiller W. Early diagnosis of carcinoma of
cervix. Surg Gynaecol Obstet 1933;66:
210-20.
24. Schiffman M, Herrero R, Hildeschein A,
et al. HPV DNA testing in cervical cancer
screening: Results of high risk province in
Costa Rica. JAMA 2000;283:87-93.
25. Petry K-U, Menton S, Menton M, et al.
Inclusion of HPV testing in routine cervical
cancer screening for women above 29 years
in Germany: Results for 8468 patients. Br J
Cancer 2003;88:1570-77.
26. ALTS Study group, Solomon D, Schiffman
M, Tarone R. Comparison of three manage-
ment strategies for patients with atypical
Cervical Intraepithelial Neoplasia 99
squamous cells of undetermined signi-
ficance: Baseline results from a randomized
study. J Natl Cancer Inst 2001;93:252-3.
27. Boonstra H, Koudstaal J, Oosterhuis JW, et al.
Analysis of cryolesions in uterine cervix;
application techniques, extension and
failures. Obstet Gynecol 1990;75:232-9.
28. Ostergard DR. Cryosurgical treatment of
cervical intraepithelial neoplasia. Obstetrics
and Gynaecology 1980;56:231-3.
29. Creasman WT, Hinshaw WM, Clarke-
Pearson D. Surgery in the management of
cervical intraepithelial neoplasia. Obstet
Gynaecol 1984;63:145-9.
30. Andersen ES, Thorup K, Larsen G. The
results of cryosurgery for cervical intra-
epithelial neoplasia. Gynaecol Oncol 1988;
30:21-5.
31. Benedet JL, Miller DM, Nickerson KG, et al.
The results of cryosurgical treatment of
cervical intraepithelial neoplasia at one, five
and ten years. Am J Obstet Gynaecol 1987;
157:268-73.
32. Townsend DE, Richart RM. Cryotherapy
and carbon dioxide laser management of
cervical intraepithelial neoplasia: A control-
led comparison. Obstet Gynaecol 1983;61:
75-8.
33. Bryson SCP, Lenehan P, Lickrish GM. The
treatment of Grade III cervical intraepithelial
neoplasia with cryotherapy: An 11year
experience. Am J Obstet Gynaecol 1985;151:
201-6.
34. Murdoch JB, Morgan PR, Lopes A,
Monaghan JM. Histological incomplete
excision of CIN after large loop excision of
the transformation zone (LLETZ) merits
careful follow-up, not retreatment. B J Obstet
Gynecol 1992;99:990-3.
35. Mitchell MF, Cantor SB, Brookner C, et al. A
randomized controlled trial of, cryotherapy,
loop electrosurgical excision and laser
vaporization for the treatment of cervical
intraepithelial lesions of the cervix. Obstet
Gynecol 1998;92:737-44.
36. Shepherd J. Cancer complicating pregnancy.
In: Shepherd J, Monaghan J (eds). Clinical
Gynaecological Oncology. Blackwell Scienti-
fic Publications, Oxford 1990.
 9 Cancer of
INTRODUCTION
Reduction of mortality from cancer cervix in
many of the developed nations through
organized screening programs is probably the
greatest triumph of cancer public health till
date. Robert Hull in 1851 first used a vaginal
speculum to diagnose a strange new uterine
disease and this was the only method to detect
cancer of cervix for a long time.1 Aurel Babes
of Bucharest in 1927 first came out with the
idea that cells can be scrapped from cervix/
vagina and examined under microscope to
detect neoplastic changes. Unfortunately, his
work did not get enough attention. The
potential of exfoliative cytology in early
detection of cervical cancer was appreciated
when George Papanicolaou, Professor of
Anatomy at New York published an
illustrated monograph ‘Diagnosis of uterine
cancer by the vaginal smear’ with Herbert Traut
in 1943. By the 1960s cervical cytological
screening became widespread and was
instrumental in bringing down the incidence
of cervical cancer in the countries where the
programs were successfully implemented.
Unfortunately millions of women residing in
the low resource countries are still deprived
of the benefits of screening. As a result cancer
of uterine cervix is the most common cancer
Uterine Cervix
• Partha Basu • Pradip Das
among women in the developing countries
and still causes loss of more than 3.4 million
woman-years of life before 70 years of age each
year worldwide.2
INCIDENCE AND MORTALITY PATTERNS
The population based cancer registries collect
information on all new cancer cases diagnosed
among the population within a defined
geographical area. Using the available
statistics the number of new and prevalent
cervical cancer cases and mortality from the
disease have been estimated, though many of
the developing countries are either not
represented or can not provide good quality
data. The worldwide burden of new cervical
cancer cases around the year 2000 was 471,000,
of which 380,000 (81%) were in the deve-
loping countries. The developing countries
accounted for 194,000 (82%) of the 233,000
deaths from this disease in the same year.3
Cancer of cervix has been reported as
the commonest cancer by nine (Calcutta,
Bhopal, Nagpur, Aurangabad, Pune, Barshi,
Bangalore, Chennai, Karunagappally) out of
total thirteen population based cancer regis-
tries in India. The crude and age standardized
incidence rates in Indian registries are given
in Figure 9.1.
 Cancer of Uterine Cervix 101

Fig. 9.1: Incidence rates of cervical

cancer in India (1988-92)4

The data from the Indian registries show The advanced stage at first diagnosis
that the incidence rates start increasing from (ranging from 70–95% in different centers)
the age group 30 to 34 years and reach a peak accounts for the poor survival of the cervical
between the ages of 55 to 65 years. cancer patients in India.
Estimates of survival from cervical cancer
are available from some of the population RISK FACTORS
based cancer registries in the developing
countries. The survival estimates provide an Infection with certain oncogenic strains of
important index of quality of cancer detection Human Papilloma Virus (HPV) has been
and management services in the area. The established, as the necessary cause to initiate
five-year age-standardized relative survival the cascade of events that leads to cervical
rates in cervical cancer patients in some neoplasia including cancer.6 HPV infection is
selected developing countries are given in unlikely to be sufficient by itself to cause high
Table 9.1. grade precancers and cancers. It is not yet
clear why only a very small percentage of
Table 9.1: Five-year age-standardized relative
5
women infected by this ubiquitous virus tend
survival rates in cervical cancer patients to have persistent infection that progress to
Population 5-year survival (%) develop cancer. There are several risk factors
Shanghai, China 61.9 for the disease that either predispose the
Cuba 54.3 individual to HPV infection or potentiate the
Bangalore, India 39.9 HPV mediated cellular changes.
Barshi, India 32.0
Bombay, India 49.5 Sexual Behavior
Madras, India 56.7
Rizal, Philippines 28.0 Domenico Rigoni-Stern, an Italian physician,
Chiang Mai, Thailand 64.9 in the middle of 19th century, first suspected
Singapore 65.0 the relationship of cervical cancer with sexual
102 A Practical Approach to Gynecologic Oncology
practice. He observed from the mortality
records that cervical cancers occurred much
more frequently in married than unmarried
women. The relationship of cervical cancer
with sexual behavior is supported by the fact
that disease is rare in nuns and virgins.
Studies conducted in 1990s have highlighted
early age at coitus as an important risk factor
after adjusting for confounding variables.7,8
Multiple sex partners as a potential
independent risk factors has been extensively
studied. The risk of development of cervical
cancer is elevated by 2 to 4 times if a woman
reports having more than one sexual partners.
Higher the number of partners, the higher is
the risk.8,9
Studies carried out at different parts of
India also highlighted sexual behavior as an
important contributing factor in the process
of cervical carcinogenesis.10
Socio-Demographic Factors
The incidence of cervical cancer varies widely
according to the geographic distribution. The
highest rates have been reported from Latin
America and the lowest from United States
(Whites) and Jews of Israel. Women belong-
ing to the low socio-economic strata are at
much higher risk of developing the disease.
Though some (not all) of the studies have found
geographical distribution as an independent
risk factor, low socio-economic status is likely
to be the surrogate for other risk factors like
poor hygiene, sexual behavior, etc.
Menstrual Hygiene and
Reproductive Factors
Few studies revealed a significant risk
associated with the use of unclean cloth as
compared to the use of sanitary napkins even
after adjustment with other confounding
factors. A report from WHO also suggests
genital hygiene to be an important component
associated with cervical neoplasia.11
Some of the recent studies have revealed
multiparty to be an independent risk factor.7
Deliveries conducted by untrained birth
attendants in poor hygienic conditions can
also predispose to develop cancer of cervix.
Contraceptives
There is conclusive evidence that there is no
strong association (positive or negative)
between HPV positivity and use of oral
contraceptive pills (OCP).12 Long term use of
OCP could be a co-factor that increases risk
of cervical cancer by up to four-fold in women
positive for oncogenic HPV DNA.13
Contrary to common beliefs use of condoms
does not give adequate protection against
HPV infection as the virus harbors in the skin
of the genital area not covered by condoms
and can be transmitted from there.
Use of Tobacco
An exhaustive review of the relationship of
cervical neoplasia and smoking revealed
positive association and there is a dose
response relationship. Smoking promotes
carcinogenic events by increasing the
duration of oncogenic HPV infections and
decreasing the possibility of their clearance.14
There is hardly any information about this
association in Indian context and it will be
interesting to look into the effect of the
chewable forms of tobacco that are so widely
used in our country.
Dietary Factors
High plasma levels of antioxidants may reduce
the risk of cervical intraepithelial neoplasia
(CIN) independent of HPV infection.
Lycopene and probably vitamin A may play
a protective role in the early stages of cervical
carcinogenesis15 and vitamins C and E appear
to independently exert protective effects
against development of CIN.16,17

Sexually Transmitted Infections
other than HPV
In the past a strong association was presumed
between Herpes Simplex Virus-II (HSV-II)
infection and cancer cervix. The association
became weak and inconsistent when HPV
infection was taken into account. Similarly,
other sexually transmitted infections act as
surrogates for HPV infection. However, in
one well-designed prospective study
antibodies to Chlamydia trachomatis were
significantly associated with the risk of
developing high grade CIN. The authors
postulated that Chlamydia trachomatis could be
a co-factor in the pathogenesis of cervical
cancer.18
PATHOLOGY
Histologically cervical cancers can be classified
into squamous cell carcinoma, adenocarci-
noma, adenosquamous carcinoma and other
rare varieties. Squamous cell carcinoma is the
most common type. In the last few decades
the relative proportion of adenocarcinoma has
increased accounting for 10-30 percent of all
cervical cancers. It is not clear whether this is
due to the absolute increase in the incidence
of adenocarcinoma in the young or due to
the decrease in squamous cell carcinoma as a
result of screening, which is more efficient in
identifying the squamous precancers.
Squamous Cell Carcinoma
Invasive squamous cell cancers are composed
of compact masses or nests of squamous
epithelium with varying degree of kerati-
nazation and intervening stroma. The
individual cells are oval or polygonal showing
considerable variation in size, shape and
nuclear pleomorphism. The system of classi-
fication of squamous cell cancers has gone
through considerable changes over the years
and the current classification is based on the
Cancer of Uterine Cervix 103
degree of differentiation that has direct
relationship to response to treatment and
survival. 19 Well-differentiated tumors are
composed predominantly of mature squa-
mous cells with abundant keratin and pearl
formation. There is minimal mitotic activity.
The moderately differentiated carcinomas are
composed of cells with less abundant
cytoplasm and higher mitotic activities. Cell
borders are less distinct, intercellular bridges
are scanty and the nuclei display greater
pleomorphism. The poorly differentiated
tumors form solid sheets of small oval cells
with abundant mitotic activity and minimal
or no keratinization.
Adenocarcinoma
Adenocarcima of cervix can be of following
varieties depending on their architectural
patterns.
Minimal deviation adenocarcinoma (adenoma
malignum): This most well differentiated
variety of adenocarcinoma has little or no
cytological atypia. The glandular crypts are
more complex in pattern, often sharply
angulated and extend to a much greater depth
into the stroma as compared to normal crypts.
It is often difficult to detect this neoplasm in
a superficial biopsy.
Mucinous adenocarcinoma: This is the most
common variety and the well differentiated
type is formed of branching clefts lined by
single or stratified layers of mucus secreting
columnar cells containing intra-glandular
mucin. As the degree of differentiation
diminishes the tumor may still retain the
glandular architecture but the cellular atypia
increases and mucin secretion diminishes. In
the poorly differentiated variety the
glandular architecture may be completely lost
and the cells form solid nests or islands
resembling squamous cell cancer.
Endometrioid adenocarcinoma: This type of
tumor develops either in cervical endometrio-
104 A Practical Approach to Gynecologic Oncology
tic focus or from metaplastic endometrial
epithelium in the cervix. The tumors are
histologically identical to the tumors arising
in the endometrium. The degree of differen-
tiation of the tumor depends on the propor-
tion of solid areas. In well differentiated
tumors less than 10 percent of the tumor is
solid and the remainder forms glands. If 10
to 50 percent of the tumor consists of solid
areas it is moderately differentiated. The
poorly differentiated tumor has more than
half of its area composed of solid sheets of
cells.
Clear cell adenocarcinoma: These neoplasms
are of Müllerian origin and comprise of cells
that have clear or eosinophilic granular
cytoplasm. Often the cells have characteristic
‘hobnail’ shapes with prominent nuclei and
scanty cytoplasm.
Other Histological Variants
of Cervical Cancer
Verrucous carcinoma: Verrucous carcinoma is
a distinct type of well differentiated squamous
cell cancer that is locally invasive and rarely
metastasize. Microscopically the tumor is
exophytic with hyperkeratotic surface
composed of rounded papillary projections
that lack central fibro-vascular core. The last
feature is particularly useful in distinguishing
this cancer from condyloma acuminatum.
Adenosquamous carcinoma: This histological
type exhibits both glandular and squamous
differentiation. A variant of poorly diffe-
rentiated adenosquamous carcinoma
characterized by sheets of cells having
moderate amount of cytoplasm with a ground
glass appearance is called Glassy-cell
carcinoma.
Neuroendocrine tumors: Tumors pre-
viously known as ‘small cell carcinoma’ are
composed of a heterogenous group of tumors
many of which display neuroendocrine
differentiation. According to the suggestion
of a study group the neuroendocrine tumors
of the cervix are subdivided into typical
carcinoid, atypical carcinoid, large cell
neuroendocrine carcinoma and small cell
carcinoma.20 Very rarely these tumors can
give rise to endocrine syndromes like
carcinoid syndrome, Cushing’s syndrome or
hypoglycemia.
There has been sporadic reports of other
rare varieties of tumors of cervix like leio-
myosarcoma, rhabdomyosarcoma, lym-
phoma and malignant mixed mesodermal
tumors.
CLINICAL PRESENTATIONS
Symptoms
The most common presenting symptom of
cervical cancer is abnormal vaginal bleeding.
There may be postcoital bleeding, inter-
menstrual bleeding, menorrhagia or post-
menopausal bleeding. Many patients complain
of profuse watery or yellowish discharge,
often malodorous and sometimes mixed with
blood. Locally advanced tumor involves the
lumbosacral or sciatic nerve roots and gives
rise to back pain radiating towards the legs
or deep boring pain in the pelvis. Patients
may present with symptoms of anemia,
edema, weight loss, fatigue or other
constitutional symptoms. Bladder and rectal
symptoms like hematuria or rectal bleeding
appear if the tumor involves these structures.
Patients may present with renal failure at the
end stage.
Physical Signs
A speculum examination of the cervix is
enough to diagnose cancer of this organ most
of the time. There may be exophytic,
ulcerative or endophytic growth on the cervix
that bleeds to touch. Sometimes the cervix
may be congested, eroded or have irregular

surface. Rarely the growth may be entirely
hidden inside the canal. No growth will be
visible but the cervix will be expanded and
firm. Extension of growth to the vagina can
be both seen and felt. Infiltration of base of
bladder may be suspected if there is extensive
involvement of anterior vaginal wall. Rectal
examination is mandatory to assess the lateral
extension of the tumor on to the parametrium
and to assess involvement of rectal mucosa.
Examination of abdomen for ascitis or mass,
palpation of groins and supraclavicular
regions for any palpable lymph nodes should
also be done.
DIAGNOSTIC EVALUATION
Cytology
Cytology has very little role to play if there
is gross abnormality of the cervix. A Pap
smear may be taken if the cervix looks
unhealthy and there is no obvious growth. It
is advisable to refer the woman for
colposcopy in such situations even if the
cytology result is negative. The false negative
rate of Pap smear in the presence of invasive
cancer is up to 50 percent.23
Colposcopy
Colposcopy may be helpful in the diagnosis
of very early invasive cancer when there is
no visible growth on the cervix. Dense
acetowhite lesion with atypical blood vessels
is the hallmark of invasive lesions. The
acetowhite area is large, thick, often
obliterates the external os and may have
raised margin. The atypical blood vessels are
characterized by absence of normal bran-
ching, sudden appearance and disappearance
and great variation in caliber. They may take
the forms of tendrils, corkscrews, waste
threads and other bizarre branching patterns.
Diagnosis of adenocarcinoma through
colposcopy is more difficult. They usually
Cancer of Uterine Cervix 105
present as densely white islands in the
columnar epithelium. The lesions may be
elevated, may have a papillary pattern and
often have abnormal vessels on the surface.
The glandular lesion may entirely be hidden
inside the canal or may be associated with
squamous precancer lesions on the ectocervix.
Colposcopic examination is essential prior to
surgery to assess the lower limit of vaginal
extension. It is not unusual to find high grade
intraepithelial neoplasia in the vagina, not
apparent clinically, in association with cervical
cancer.
Biopsy
Histopathology is confirmatory of diagnosis
of any cancer and cancer cervix is no
exception. Obtaining a piece of tissue with a
punch biopsy forceps from a growth is easy
because of the friable nature of the tumor.
The biopsy material should be collected from
the margin of the growth rather than from
its center where tissue may be necrotic and
unsuitable for evaluation. If there is colpo-
scopic suspicion of invasive lesion in the
absence of an obvious growth multiple punch
biopsies should be taken from the most
abnormal areas.
On colposcopy if there is a high grade
precancer lesion whose endocervical limit is
not visible or if the cytology report indicates
high grade squamous or glandular lesion in
the absence of a visible abnormality,
endocervical curettage should be performed.
With this technique some of the invasive
lesions can be detected without resorting to
cone biopsy.
Invasive cancer may be a chance diagnosis
on a conization specimen removed for the
treatment of CIN. That is the precise reason
why a cone of tissue should be excised and
submitted for histologic evaluation in the
following situations to treat CIN lesions:
106 A Practical Approach to Gynecologic Oncology
• The endocervical extent of the lesion is not
visualized (there is always a possibility that
an invasive focus may be present at the
innermost part)
• Lesion is very large covering more than
75 percent of the transformation zone (such
a lesion has a high possibility of having an
invasive focus)
• The colposcopic features are suspicious of
invasion even though the punch biopsy
indicates CIN
• Cytology indicates glandular lesion
Conization is mandatory if the punch
biopsy report is microinvasive cancer (see
later). A thorough evaluation of the cone
specimen is the only way to rule out a focus
with more extensive invasion.
Lymphangiogram
Pedal lymphangiogram to detect pelvic and
para-aortic node metastases is not an accurate
test and suffers from poor sensitivity (as low
as 50%). Fatty degeneration, fibrosis or
infection of the lymph nodes can give false
positive results that can be as high as
30 percent. The test is tedious and is no longer
recommended in routine clinical practice.
Computed Tomographic (CT) Scan
The CT scan as a noninvasive procedure is
often done as pretreatment evaluation. Nodes
exceeding 1 cm diameter are usually
considered positive. CT scan is more efficient
in detecting metastatic para-aortic nodes
rather than the pelvic nodes. Matsukuma et
al evaluated the accuracy of CT scan in the
diagnosis of pelvic and para-aortic lym-
phnode metastases from cancer cervix. CT
scan could detect 71.4 percent para-aortic
meta-stases and had high specificity.22 CT scan
has the additional advantage of evaluating
the liver and the urinary tract.
Magnetic Resonance Imaging (MRI)
The MRI can be helpful in estimating the
volume of tumor and depth of invasion, the
parametrial spread and metastatic tumor in
pelvic and para-aortic nodes preoperatively.
Correct identification of the parametrial
spread in bulky tumors by MRI scan can
identify the candidates suitable for primary
surgery. MRI is safe for pregnant women.
Positron Emission Tomography (PET) Scan
For this imaging technique radionuclide
labeled analogue of glucose (fluorodeoxy-
glucose) is injected into the body. The
chemical is concentrated in the cancer cells
because of their high affinity towards glucose.
The positrons emitted by the radionuclides
concentrated in the tissues help to delineate
the extent of the disease. The technique has
reasonably good sensitivity and very high
specificity to detect para-aortic node
metastases.
Fine Needle Aspiration Cytology (FNAC)
FNAC of retroperitoneal nodes done under
the guidance of CT scan or ultrasonography
has an accuracy of 70-90 percent. An
unequivocal positive FNAC report precludes
the need of biopsy from the nodes.
MODES OF SPREAD
Cervical cancer spreads by means of direct
infiltration into surrounding structures,
lymphatic permeation, lymphatic metastases
or through blood circulation.
Direct Invasion
The neoplastic cells penetrate the basement
membrane to infiltrate the underlying stroma
and sets the malignant process in motion.
Gradually the tumor extends beyond the
cervix to involve the vagina below, the corpus
of the uterus above, the uterosacral and
Mcenrodt’s ligaments on either side to reach
the pelvic sidewalls. The malignant process

may extend further to involve the urinary
bladder in front and the rectum behind.
Lymphatic Spread
Malignant cells usually spread to the regional
lymph nodes as small emboli. Sometimes such
tumor emboli are held up in the lymphatic
vessels and grow to become the foci of
discontinuous parametrial involvement.23 The
lymphatic spread in cervical cancer occurs in
a very orderly fashion from the main tumor
to the parametrial nodes, then to the nodes
in the pelvic sidewalls (obturator, internal iliac
and external iliac) and finally to the common
iliac and para-aortic nodes. From the para-
aortic nodes spread can occasionally occur
along the thoracic duct to the left supra-
clavicular lymph nodes. Obturator nodes are
the most commonly affected and they may
be involved without the parametrial nodes
being affected. Very rarely tumor cells can
reach the common iliac and the para-aortic
lymph nodes directly by the posterior cervical
trunk.
Ovarian involvement in cervical cancer is
uncommon and most likely occurs through
the lymphatic channels. In a Gynecologic
Oncology Group (GOG) study the reported
incidence of ovarian metastases in cervical
cancer stage IB is 0.5 percent with squamous
cancer and 1.7 percent with adenocarcinoma.
Hematogenous Dissemination
The most common organs for hematogenous
spread are the lungs, bones and liver (in that
order of frequency) though any organ in the
body may be affected.
STAGING
Clinical Staging
Majority of the cases of cancer cervix all over
the world are treated by radiation and
chemotherapy or radiation alone. So staging
Cancer of Uterine Cervix 107
of the disease is based primarily on clinical
assessment. Examination under anesthesia
is not routinely required for staging and
should be reserved only for the non-
cooperative patients. X-ray of chest and
intravenous urography are the radiologic
investigations required. Cystoscopy and
rectosigmoidoscopy should be done if there
are suggestive symptoms and/or clinical
suspicion of involvement of bladder and
rectum. Involvement of bladder and rectal
mucosa should be confirmed by biopsy and
bullous edema of bladder and mucosal
swelling of rectum are not accepted as
evidence of infiltration of these organs.
Clinical staging of cancer cervix was done first
by the League of Nations in 1929. Since then
the staging system has gone through several
modifications and the last revision was done
in 1995 by International Federation of
Obstetrics and Gynecology (FIGO) in
collaboration with World Health Organization
(WHO) and International Union Against
Cancer (UICC). The details of the current
FIGO staging are given in Table 9.2.
Table 9.2: Carcinoma of cervix uteri: FIGO
Nomenclature (Montreal, 1994)
24
Stage 0: Carcinoma in situ, CIN III (preinvasive
disease)
Stage I: Carcinoma strictly confined to the cervix
(extension to the corpus would be disre-
garded.
IA: Invasive carcinoma that can be
diagnosed only by microscopy.
Invasion to the stroma is limited to
a maximum depth of 5 mm from the
basement membrane of the epithe-
lium with a maximum horizontal
extension of 7 mm. Involvement of
venous or lymphatic vascular
spaces does not change the allot-
ted stage. All macroscopically vis-
ible lesions even with superficial
invasion should be staged as IB.
Contd...
108 A Practical Approach to Gynecologic Oncology
Contd...
IA1: Measured stromal invasion of
<3 mm in depth
IA2: Measured stromal invasion of
>3 mm and <5 mm in depth
IB: Clinically visible lesions limited to
cervix or preclinical lesions greater
than IA
IB1: clinically visible lesion <4 cm
in greatest dimension
IB2: clinically visible lesion >4 cm
in greatest dimension
Stage II: Cervical carcinoma extends beyond the
uterus but not to the pelvic wall or to the
lower third of the vagina
IIA: No obvious parametrial involve-
ment
IIB: Obvious parametrial involvement
Stage III: The carcinoma has involved the lower
third of vagina or it has extended to the
pelvic wall evidenced by lack of cancer-
free space between the tumor and the
pelvic wall. All cases of hydronephrosis
or non-functioning kidneys are included
in this stage, unless they are known to be
due to other cause.
IIIA: Tumor involves lower one third of
vagina with no extension to pelvic
sidewall
IIIB: Extension to pelvic side wall or hy-
dronephrosis or non-functioning
kidney
Stage IV: The carcinoma invades the mucosa of
bladder or rectum or extends beyond the
true pelvis
IVA: Spread of growth to bladder or rec-
tum
IVB: Spread to distant organs
Surgical Staging
Since the large majority of cervical cancer
cases will never have surgery as part of their
treatment, surgical staging does not have
much relevance. It is well known that the
discrepancy between clinical staging and
pathological assessment of the extent of
disease after surgery can range between 20
and 40 percent. 25 In the 1970s a group of
surgeons tried pretreatment staging laparo-
tomy with the hope that the accurate know-
ledge of status of lymph nodes, particularly
of the para-aortic nodes will help to
individualize the radiation therapy and
improve survival. The initial transperitoneal
approach was associated with unacceptably
high rate of small bowel complications (fistula,
obstruction and post-radiation enteritis)
when followed by radiation. This approach
was abandoned in favor of an extra-perito-
neal approach performed by stripping the
peritoneum from the anterior and lateral
abdominal wall through a left lateral J-shaped
incision or a midline incision. The incidence
of serious complications after radiation with
this approach is much less as compared to the
transperitoneal approach. Para-aortic node
metastases is observed in 5-20 percent
(average 16%) of clinically stage II disease and
15-38 percent (average 28%) of stage-III
disease.26 There is no evidence till date that
surgical staging followed by irradiation of the
metastatic para-aortic nodes gives any
survival advantage over the current standard
treatment protocols based on clinical
staging.27
PROGNOSTIC FACTORS
A major area of research in cervical cancer
has been to look into the possible factors that
can predict the response to treatment and the
survival so that the patients can be indivi-
dualized for therapy. Wide range of factors
(related to the patient, to the primary tumor
and to the biology of the tumor) that may
have significant effects on treatment outcome
have been extensively studied.
Lymph Node Metastases
Regional and distant lymph node spread of
the disease is the most reliable prognostic
indicator for cancer cervix. Clinical stage
correlates so well with the probability of
nodal involvement that it is considered a
 Cancer of Uterine Cervix 109

surrogate for nodal metastases as a prognostic
parameter.
The frequency of pelvic node metastases
in different stages is given in Figure 9.2. The
frequency of node involvement and survical
correlated well with the stage of disease.
Frequency of para-aortic lymph node
involvement in stages II and III is shown in
Table 9.3. Para-aortic nodes are involved in
less than 5 percent cases of stage I.
Involvement of lymph nodes makes a lot
of difference in the disease free and overall
survival of the disease. The 5-year survival
of surgically treated cases without any lymph
node metastases is around 90 percent. The
survival reduces significantly if there is pelvic
lymph node metastases (50-60%) or even
further if there is para-aortic node metastases
(20-45%) in postoperative specimens.
Figure 9.3 shows the cumulative results from
references on the 5-year survival by stages
of the node positive cases.
The number of positive nodes and the size
of the metastatic nodes are also important
prognostic parameters. In a retrospective
study on patients who received postoper-
ative radiation, the survival rate was
87 percent when only one lymph node was
affected as compared to 24 percent when
multiple nodes were involved.29
Size of Primary Tumor
Tumor volume is a determinant of response
to treatment in all stages of cancer. This has
practical implication in the management of the
disease. Burghardt and his associates
extensively studied the association of volume

21
Table 9.3: Frequency of para-aortic lymph node metastases in stages-II and III cervical cancer
Stage II Stage III
Author Explored Positive (%) Explored Positive (%)
Sudarsanam (1978) 43 7 16.3 19 3 15.8
Nelson (1977) 63 9 14.3 39 15 38.5
Berman (1984) 265 43 16.2 180 45 25
Hughes (1980) 80 14 17.5 96 23 24
Ballon (1981) 48 9 18.8 24 4 16.7

Fig. 9.2: Frequency of pelvic lymph node metastases in cervix cancer28

110 A Practical Approach to Gynecologic Oncology
Fig. 9.3: Five years survival by stage and node status28
to the response to therapy in microinvasive
carcinoma. They observed that the rate of
recurrence after conservative treatment was
very low if the total volume of the tumor was
less than 400 mm.3,30
For frankly invasive cancers, both
squamous and adenocarcinomas, the incre-
asing tumor diameter is associated with
reduced 5 year survival. Kristensen et al
observed 94.8 percent survival rate for stage
IB tumors less than 2 cm diameter compared
with 47.4 percent for tumors of diameter
> 4 cm (p <0.00001).31 The bulky tumors have
higher propensity to metastasize to the pelvic
lymph node.
Histologic Type and
Differentiation of Tumor
Most authors have reported a worse prog-
nosis for cervical adenocarcinoma as
compared to its squamous counterpart when
matched stage for stage. Since most
adenocarcinomas grow endophytically (barrel
shaped) they are detected later. They also
have a greater propensity to metastasize to
the lymph nodes.32 Small cell carcinoma of
cervix has the worst prognosis among all
histologic types as they usually are not con-
fined to cervix at the time of initial diagnosis.
Lymph node involvement is found in 50-
60 percent of patients with this histologic
variety and vascular invasion is the norm.33
Histological grades of tumors are impor-
tant prognostic indicators when all histologic
varieties are considered together. Differen-
tiation of tumor correlates well with the
outcome of adenocarcinoma of cervix but not
so much with the outcome of its squamous
counterpart.
Depth of Stromal Invasion
Kristensen et al observed that on univariate
analysis depth of stromal invasion along with
the tumor size was the most significant
influencing factor for 5-year relapse-free
survival in stage IB cancer cervix. In their
series of 125 patients 5-year relapse-free
survivals were 94.7 percent, 73.3 percent,

57.1 percent and 33.3 percent for depth of
invasion <10 mm, 11-15 mm, 16-20 mm and
>20 mm respectively (p<0.00001).31
Lymph-Vascular Space Invasion
Lymph-vascular space (LVS) involvement is
defined as presence of viable tumor inside a
space lined by endothelial cells within the
histological structure of the cervix. This fea-
ture is an independent risk factor in progno-
sis and survival of invasive cervical cancer.
Though this feature has been ignored in the
current FIGO staging system, many authors
observed that LVS involvement substantially
increases the risk of metastases to the lymph
nodes. Attempts have been made to quantify
the LVS involvement and correlate that with
the risk of lymph node metastases.34
PRINCIPLES OF
SURGICAL MANAGEMENT
Historical Background
Ernst Wertheim of Vienna was an assistant
to Schauta and did not agree with his chief in
his opinion that removal of pelvic lymph
nodes was of no value. Schauta believed that
lymphadenectomy could never be complete
and would cause higher morbidity. Wertheim
performed the first radical abdominal
hysterectomy in 1898 and combined selective
pelvic lymphadenectomy to enhance the
radicality of the operation. The Wertheim’s
technique achieved credibility as he published
the results of 500 such operations in 1911. In
the early part of twentieth century
radiotherapy was the mainstay of treatment
of cervical cancer. The interest in surgical
techniques was resurrected in late 1930s by
European surgeons like Bouwdijk, Bonney
and Taussig. Meigs from Boston refined the
Wertheim’s technique by introducing
systematic lymphadenectomy prior to
hysterectomy, dissection of paravesical and
Cancer of Uterine Cervix 111
pararectal spaces and releasing the ureters
extensively from their surrounding tissues.
Using this technique Meigs reported 5 years
survival of 75 percent for stage I and
54 percent for stage II in the year 1945. In
1954 Mitra from Calcutta described a modi-
fication of Schauta’s radical vaginal hyste-
rectomy by adding extra-peritoneal pelvic
lymph node dissection through two separate
groin incisions. He achieved a 5-year survival
rate of 61 percent. However, the operation
did not become popular because of the
necessity to make three separate incisions for
an operation that did not have any substantial
advantage over the Wertheim’s technique.
Types of Hysterectomy for Cervical Cancer
Piver et al published a comprehensive list of
all the different classes of hysterectomies
practised for the management of cervical
cancer. 35 They categorized hysterectomies
into the following classes depending on the
extent of radicality of surgery.
Class I (total extra-fascial hysterectomy):
Uterus and cervix are removed with a small
cuff (1-2 cm) of vagina in a plane outside the
pubo-cervical fascia. The trigone of bladder
and the ureters are not disturbed from their
beds. This surgery is suitable for stage IA1
cancer.
Class II (modified radical hysterectomy):
Ureters are dissected in the para-cervical
tunnel to the point of entry into the bladder
but are kept attached to the pubo-vesical
ligaments. Ureters are retracted to remove
the medial parts of the cardinal ligaments,
proximal part of uterosacral ligaments and
the upper part of vagina. Stage IA2 cervical
cancer is usually treated by this method.
Class III (radical hysterectomy): This
operation consists of resection of the
parametrial tissues from the lateral pelvic
walls, complete dissection of pelvic ureters
from their beds, more extensive mobilization
112 A Practical Approach to Gynecologic Oncology
of the bladder and rectum and removal of
2-3 cm vaginal cuff. Uterosacral ligaments are
removed from their sacral attachments. Stage
IB cervical cancer is treated by this method
of surgery but the cardinal ligaments and the
uterosacral ligaments are not that extensively
dissected nowadays. Pelvic node dissection
is performed along with hysterectomy.
Class IV (extended radical hysterectomy):
This procedure requires more extensive
mobilization of bladder and rectum, sacrifice
of superior vesical artery and removal of
three quarters of vagina. This surgery is
sometimes practiced for small central
recurrence after radiation.
Class V (partial exenteration): This class of
hysterectomy differs from class IV procedure
in that the involved portions of distal ureter
or bladder are excised as well. This operation
for locally advanced disease is rarely
performed and has been replaced by
radiotherapy.
Preparation for Surgery
All routine investigations are done prior to
surgery for assessment of patient’s fitness for
general anesthesia. Blood is kept cross-
matched to be available at the time of surgery
if required. Bowel preparation is done before
surgery as an empty colon facilitates pelvic
surgery and minimizes postoperative
discomfort. Patient is put on liquid diet 1-2
days prior surgery and bowel is evacuated
using Polyethylene glycol (Peglec) or other
purgatives on the day before surgery. To
reduce the risk of thromboembolic
complications subcutaneous heparin (5000
units) is administered twice a day starting
from 1-2 hr before operation. Low Molecular
Weight Heparins (LMWH) have the
advantages of better bio-availability, conve-
nient once a day dosing and better effective-
ness to prevent deep venous thrombosis
and pulmonary embolisms. Prophylactic
antibiotics (Cefuroxime or cefotaxim with
metronidazole) are administered during
induction of anesthesia). Surgery is done
under general anesthesia that may be
combined with epidural analgesia that is
continued after operation for post-surgery
pain relief.
Incision
A transverse muscle cutting (Maylard’s or
Cherney’s) incision gives best exposure to the
lateral pelvic walls. A midline vertical incision
can also be used particularly if aortic node
sampling is intended.
Para-aortic Lymphadenectomy
Para-aortic lymph node dissection is not
routinely done along with radical hyster-
ectomy for stage IB1 cancer as the incidence
of para-aortic nodal metastasis is negligible.
Patsner et al did para-aortic lymph node
sampling in 125 cases of stage IB 1 cancer
(tumor 3 cm or less) and found para-aortic
node metastasis in only 2 patients.36 In stages
IB2 and IIA extended field radiation is used
to take care of the para-aortic node
metastases instead of doing surgical resection
of these nodes. In fact, presence of clinically
or radiologically suspicious paraaortic lymph
nodes is a contraindication to radical surgery.
Gross metastases to para-aortic lymph nodes
are usually excluded either prior to surgery
by CT scan or by palpation after opening the
peritoneum. Some surgeons do para-aortic
lymph node sampling and send the tissue for
frozen section biopsy. If the report is positive
the operation is abandoned.
Pelvic Lymphadenectomy
Hoskins compiled the published reports of
more than 1000 stage IB cervical cancers and
observed that the 17 percent of them had
positive pelvic lymph nodes.37 The therapeutic

value of pelvic lymphadenectomy is not
established as no randomized clinical trial has
been done to prove its efficacy. A study
compared radical hysterectomy and selective
lympa-denectomy (only suspicious nodes
removed) with radical hysterectomy and
systematic lymphadenectomy (all nodes
removed). The mortality rate in node positive
patients in the first group was 71 percent and
in the second group was 39 percent.38 The real
value of pelvic lymphadenectomy is to
identify the high risk group (with positive
nodes) who needs adjuvant therapy.
Steps of Pelvic Lymphadenectomy
The round ligament is clamped and ligated
at the junction between middle and lateral
third. The retroperitoneal space is opened,
the peritoneum over the great vessels is gently
retracted and the loose areolar tissues are
gently retracted to develop the paravesical
space anteriorly and the pararectal space
posteriorly. The ureter can be seen attached
to the medial leaf of the peritoneum. The
infundibulo-pelvic ligament is ligated and cut
keeping adequate distance from the ureter.
If the ovary has to be preserved the utero-
ovarian ligament and the medial fallopian
tube are clamped and ligated. Lymph node
dissection is started from the external iliac
group at its most distal point where the
external iliac vessels leave the pelvis. With
gentle blunt and sharp dissection the fatty
tissues and the lymph nodes surrounding the
adventitia of these vessels are removed. The
vessels are retracted medially to remove the
lateral chain. Care is taken to preserve the
genito-femoral nerve lateral to the artery. The
external iliac vein is retracted above and
laterally to expose the obturator nodes which
are pulled medially to expose the obturator
nerve underneath. The obturator nodes are
removed in continuity with the internal iliac
nodes at the bifurcation of the common iliac
Cancer of Uterine Cervix 113
vessels. The retroperitoneal space is opened
further cranially to expose and remove the
common iliac lymph nodes around the
common iliac artery. After completion of
lymphadenectomy the uterine artery can be
easily identified as the tortuous penultimate
branch of anterior division of the internal iliac
artery. This vessel is ligated at its origin.
Extraperitoneal Approach to Pelvic
Lymphadenectomy
Bilateral pelvic lymphadenectomy can be
performed first, before doing the hyster-
ectomy trans-peritoneally. The inferior
epigastric vessels and the round ligaments are
ligated and cut and the peritoneum is
retracted medially to expose the pelvic
sidewalls. The advantages of this technique
are:
• This gives excellent exposure to lateral
pelvic wall
• There is less trauma to the serosa of the
intestines
• Prolonged exposure of intraperitoneal
organs is avoided
• Intestinal functions return more promptly
in the postoperative period
The only disadvantage of this technique is
that the transperitoneal exploration of the
abdomen is delayed till the lymphadenectomy
is completed. But exploration of abdominal
cavity seldom provides extra information that
would change the course of surgery.
Steps of Radical Hysterectomy
The uterovesical fold of peritoneum is incised
and the bladder is reflected down-wards with
sharp dissection of its attachment to expose
the upper part of vagina. The ureter is freed
from its facial attachment to the peritoneal
fold prior to its entry into the ureteric tunnel.
A right angle clamp is gently introduced into
the ureteric tunnel above the ureter and the
114 A Practical Approach to Gynecologic Oncology
roof of the tunnel along with the uterine
vessels is divided laterally. The freed ureter
is rolled down laterally and the bladder is
mobilized further down to expose 2-3 cm of
vagina and the medial part of the Mcenrodt’s
ligament.
The peritoneum of the pouch of Douglas is
incised between the two uterosacral ligaments
to enter the prerectal space. With sweeping
movement of fingers the rectum is pushed
behind to expose the uterosacral ligaments
which are dissected as posteriorly as possible
carefully protecting the ureter and the rectum.
The ureter is lifted up laterally using a sling
to clamp and cut the cardinal ligament as
laterally as possible. Removing adequate
length of vagina becomes easy after this. The
bladder may have to be mobilized further if
necessary.
The vault of the vagina is closed using
interrupted sutures. The area in the pelvis is
not reperitonealized. Most surgeons prefer
to put a closed suction drain in the pelvis that
is left in situ until there is less than 20 ml
drainage in 24 hours.
The postoperative care is routine as for any
major surgery. Normally the patient can be
put on oral feed on the next day. The bladder
is drained for 5-7 days using Foley catheter.
If possible an ultrasound should be done 6-8
hours after removal of catheter to estimate
the residual urine volume. If it is more than
150 ml recatheterization is required.
Preservation of the Ovaries
During radical hysterectomy of post-
menopausal women ovaries are routinely
removed as they are of little value. The risk
of metastases to the ovaries in stage IB
squamous cell cervical cancer is less than 0.5%.
The risk is slightly higher (less than 2.0%) with
adenocarcinoma. In premenopausal women
ovaries are preserved if they are found to be
grossly normal. Some consider glandular
histopathology to be a contraindication for
ovarian preservation.39
To save the ovaries from radiation if
required postoperatively, they are transposi-
tioned in the paracolic gutter above the iliac
crest away from the radiation field. There are
some concerns against this practice. After
transpositioning, up to 20 percent of the ova-
ries undergo premature ovarian failure even
without irradiation and 40 percent after irra-
diation. The transpositioned ovaries have
higher incidence of cyst formation that is
sometimes painful but rarely require laparo-
tomy.
Management of Microinvasive Cancer
The FIGO cancer committee, in 1985 modified
the definition of stage IA (microinvasive
cancer) by subdividing it into stages IA1 and
IA2. The stage IA1 lesions were described as
those with minimal microscopically evident
stromal invasion and stage IA2 lesions were
described as those with a measurable depth
of invasion of 5 mm or less with the maximum
horizontal spread of 7 mm. In a review of
10 published studies Piver et al observed that
the incidence of nodal metastases was
0.21 percent when the invasion of stroma was
3 mm or less. If the stromal invasion was at
depth of 3.1-5 mm nodal metastases was seen
in 6.8 percent cases and the difference was
highly statistically significant (p<.0005).40
Other subsequent studies also indicated that
the risk of extrauterine disease is significantly
high (8-10%) if the stromal invasion is more
than 3 mm and such patients are not suitable
for conservative treatment.
Based on this principle microinvasive
carcinoma stage IA1 can be treated by cone
biopsy. If the margins of the cone are free of
disease and the depth of invasion does not
exceed 3 mm, no further treatment is
necessary. Cold knife conization is preferred
as the margins will be free of burning artifact

and can be assessed better. Pelvic lymph node
dissection is not necessary as the possibility
of metastasis is very low (<1%). If the margin
is involved and the cone biopsy does not
show more extensive invasion, hysterectomy
should be done. Prior to hysterectomy it is
better to do a repeat conization to exclude
frank invasion in the lesion left behind. Some
surgeons prefer extrafascial hysterectomy as
routine therapy for stage IA 1 unless the
patient is keen to maintain fertility.41
Stage IA2 carcinoma is treated by radical
hysterectomy and bilateral pelvic lympha-
denectomy. A more conservative hyster-
ectomy (Piver Class II) may be adequate.
Radical trachelectomy may be performed
in a few selected patients of stage IA2 desirous
of preserving fertility. Pelvic lymph node
dissection is done first (laparoscopically or
by open method) to exclude metastasis that
is a contraindication to this conservative
surgery. Radical trachelectomy consists of
radical excision of the cervix with a vaginal
cuff in continuity with the cardinal ligament
through the vaginal route. A circlage suture
is applied to the isthmus and the transected
vaginal margin is anastomosed with the body
of the uterus.
In medically unfit patients brachytherapy
alone can be used to treat IA cancer.
The survival rate for microinvasive
cancer if assessed and treated properly is 98-
99 percent.
Management of Stage IB1 and IIA Cancer
There have been a number of prospective
studies and prospective randomized studies
to prove that there is no significant difference
in outcome of patients of stage IB1 and IIA
cancer treated by irradiation alone or radical
hysterectomy followed by radiation therapy
based on pathological findings. The cure rates
in these studies are around 85 percent.42,43
Surgery has the following advantages over
radiotherapy:
Cancer of Uterine Cervix 115
• Ovarian function can be preserved in young
women
• Vaginal pliability and function better
retained so sexual function is better pre-
served
• Radiation treatment remains as option in
case of recurrence
• Accurately evaluate the spread of disease
including metastasis to the lymph nodes.
This gives the opportunity to identify the
high risk group that requires adjuvant
therapy.
• Long term complications of radiotherapy
are avoided.
The most frequently practised surgical
procedure for stages IB1 and IIA cervical
cancer is a modification of Wertheim’s
operation. The parametria and the uterosacral
ligaments are removed short of their distal
attachments instead of trying to dissect right
up to their attachments to pelvic walls. The
ureters are mobilized keeping the blood
supply to the terminal part intact.
Highly selected patients with stage IB1
tumor <2 cm may be candidates for radical
trachelectomy and pelvic lymph node
dissection.44
Postoperative pelvic irradiation is given to
patients if the lymph nodes have metastatic
disease. However, there is no clear-cut
evidence till date that this approach signi-
ficantly improves survival. The other indi-
cations for post operative radiotherapy are
involved or close vaginal margin, deep
stromal invasion and evidence of lympho-
vascular space involvement.
Management of Stage IB Bulky Tumor
Bulky stage IB (IB2) tumors have higher chance
of having pelvic and para-aortic lymph node
metastasis and are considered unsuitable
for surgery. Finan et al. observed positive
pelvic nodes in 15.5 percent of patients with
stage IB1 cancers versus 43.8 percent with stage
IB2. Para-aortic node metastasis was present
116 A Practical Approach to Gynecologic Oncology
in 1.8 percent of stage IB1 and 6.3 percent of
stage IB2 cancers.45
Bulky stage IB endocervical tumors more
commonly seen in adenocarcinoma have a
higher propensity for central recurrence after
radiotherapy. Extrafascial hysterectomy has
been advocated for such tumors after
radiotherapy based on the survival advantage
observed in a few non-randomized study.46,47
PRINCIPLES OF RADIOTHERAPY FOR
CANCER CERVIX
Historical Perspectives
Two discoveries made at the end of nine-
teenth century are considered epoch making
for the management of cancer patients. The
first one was in 1895 when Roentgen
discovered X-rays and the second one was in
1898 when Curies reported the discovery of
radium. In the second and third decades of
twentieth century a number of reports were
published about the efficacy of ionizing
radiations, either using X-ray generated by
X-ray generators operating at 800 to 1000 kV
or by intracavitary radium use. Coutard
developed a protracted, fractionated dose
scheme using X-ray in 1934 that still remains
the basis of current radiation therapy. 48
Artificially produced radioactive nuclide 60Co
that emitted high energy photons (g rays)
was first used for tele-therapy in Canada in
1951. The new gene-ration radiation therapy
machines called linear accelerator (linac)
accelerate electrons to strike a metal target
at a very high energy level. This emits a special
X-ray beam that is highly penetrating. The
linac can also generate photons.
The chief modalities of present day radia-
tion treatment of cancer cervix are external
photon beam treatment and brachytherapy.
External beam irradiation is used to treat the
pelvic lymph nodes, common iliac lymph
nodes, paraaortic lymph nodes and the lateral
parametria. The tumor in the cervix, vagina
and medial parametria are taken care of by
the brachytherapy. Stage IA1 can be treated
by brachytherapy only. For all other stages a
judicial combination of the two treatment
modalities are used.
External Beam Irradiation
External radiation is delivered prior to
brachytherapy so as to reduce the size and
vascularity of tumor to make brachytherapy
application easier. Radiation is usually
delivered using four fields (one anterior, one
posterior and two lateral portals). This four -
field technique is used to deliver minimum
radiation exposure to bladder, rectum and
head of femur. The lateral portals may be
omitted if the inter-field distance is <18 cm.
The extent of the field of radiation depends
on the intended area to be treated. Normally
the pelvic radiation field extends superiorly
to the inter-space between the fourth and fifth
lumber vertebrae (L4-5) to include the
external and internal iliac lymph nodes. This
limit is extended to the interspace between
L2-3 vertebrae if the common iliac glands
have to be irradiated. The superior extent of
the field is extended to the upper margin of
twelfth vertebral body when para-aortic
lymph nodes have to be included. The lateral
extent of the portal is 2 cm beyond the widest
diameter of the pelvic outlet on either side.
If there is no vaginal extension the lower
margin of the portal is at the inferior border
of the obturator foramen. In case of vaginal
extension of the tumor the entire length of
vagina upto the introitus is taken into the
portal. For stage IB disease a 15 cm x 15 cm
portal at the surface is sufficient. For more
advanced stages larger portals (18 cm x 15
cm at the surface) are required. The anterior
margin of the lateral portal is placed at the
pubic symphisis. The posterior margin is
planned in such a way as to cover 50 percent
of the rectum in stage IB tumor and it extends
to the sacral hollow in patients with more
advanced tumor.
A linear accelerator or other megavoltage

equipment is used for external radiation to
provide about 9.0 Gy radiation per week at a
daily fraction of 1.8 Gy.
Brachytherapy
The word ‘brachy’ in Greek means ‘short
distance’. Brachytherapy implies placing
radioactive sources in contact with or very
close to the target tissue. High doses of
radiation may be safely delivered by this
technique to a well-localized target region
over a short time. Implants for brachytherapy
are classified into High Dose Rate (HDR) and
Low Dose Rate (LDR) depending on the rate
at which the absorbed dose is delivered to
the prescribed point. Dose rates of 0.4 to 2.0
Gy/hour are delivered in LDR brachytherapy
so that the treatment time is 24-72 hours. An
HDR brachytherapy implant uses dose rates
more than 12 Gy/hour and the total dose can
be delivered in few minutes.
The HDR is comparable to LDR brachy-
therapy in cure and complication rates.49 The
stage-wise comparison of 5-yr survival using
the two techniques is shown in Table 9.4. The
HDR technique has the following advantages
over its counterpart:
• Treatment planning and dosimetry are
more exact
• Short patient immobilization time and less
patient discomfort
• General anesthesia or operating room not
required and hospitalization not necessary
• Radiation exposure of medical personnel
is almost nil.
Table 9.4: High dose rate (HDR) versus low dose
rate (LDR) intracavitary brachytherapy for carcino-
50
ma cervix
Stage Number of patients (HDR/LDR)
HDR LDR
5 year (%)
survival rate
I 160/422 76.9 71.6
II 358/796 58.1 54.4
III 386/588 38.1 38.4
IV 66/50 15.2 10.0
Cancer of Uterine Cervix 117
Isotopes used for LDR brachytherapy are
137
Cs (Caesium) and for HDR brachytherapy
60
Co (Cobalt). 192Ir (Iridium) isotopes are used
both for LDR and HDR therapy. Cervical
intracavitary brachytherapy is delivered using
a variety of applicators that include an
intrauterine tandem and a pair of colpostats
in the vaginal fornices. After each brachy-
therapy placement radiographs should be
obtained and computerized dosimetry should
be done to calculate doses to critical structures
– vagina, bladder and rectum. Doses to pelvic
points A and B are calculated to ensure
delivery of adequate dose to eradicate the
tumor. Point A is located 2 cm cephalad to
cervical os and 2 cm lateral to the uterine canal
approximately at the crossing of ureter and
uterine artery. Point B is 5 cm lateral to the
center of the pelvis at the same level as point
A and the anatomic landmark for obturator
nodes and lateral parametrium. Most centers
use after-loading applicators. Interstitial
implants using 137Cs needles or 192Ir plastic
catheters are used infrequently for cervix
cancer (to treat parametrial extension or
localized residual tumor).
Radiation Doses
The optimal dose for treatment of invasive
cancer of cervix is delivered using a judicial
combination of whole pelvis external beam
irradiation and intracavitary brachytherapy.
Stage IA1 may treated by brachytherapy only
if the patient is found medically unfit for
surgery. To treat this stage the radiation
doses to point A are either 60 Gy in one
insertion or 75-80 Gy in two insertions.
For other stages 40 to 45 Gy whole pelvis
irradiation is delivered using anteroposterior
and posteroanterior portals with or without
lateral portals in conventional fractions.
Additional parametrial dose (using midline
rectangular block) is delivered to complete
50 Gy for stages IB and IIA, and 55 Gy for
118 A Practical Approach to Gynecologic Oncology
more advanced stages. This is combined with
one or two intracavitary applications of
approximately 40-50 Gy (to point A) depend-
ing on the tumor volume.
Extended Field Radiation
Standard pelvic radiation is likely to spare
the para-aortic node metastases in 17 percent
with stage IIB disease and 29 percent with
stage III disease (Table 9.3) resulting in high
distant failure rates. Prophylactic extended
field irradiation to the para-aortic region in
advanced cancer is justified and the compli-
cation rate is within the acceptable limit. The
Radiation Therapy Oncology Group (RTOG)
in Unite States conducted a randomized trial
of prophylactic para-aortic radiation (45 Gy)
in patients with stage IB/IIA bulky disease(>4
cm) or IIB cervical cancer. They observed a
significantly improved survival rate in the
extended field radiation group (66% vs 55%).51
PRINCIPLES OF CHEMOTHERAPY
FOR CANCER CERVIX
The 5-year survival rates achieved with
radiation therapy for the locally advanced
cervix cancer is suboptimal (<50%). Most
treatment failures (70%) are due to persistent
or recurrent tumors in the pelvis. Local
control can not be improved any further by
radiation because the higher doses of radiation
to the critical organs are associated with high
morbidity. Both neoadjuvant (chemotherapy
prior to definitive radiotherapy or surgery)
and concomitant chemotherapy with radia-
tion have been extensively tried for cervix
cancer. Adjuvant chemotherapy after radia-
tion has seldom been tried as the compro-
mised vascularity of the tissue after radiation
greatly reduces the drug penetration
resulting in poor response.
Neoadjuvant Chemotherapy
Till date all the randomized trials have shown
that neoadjuvant chemotherapy in spite of
significant response rates either has worse
local control and survival or has no difference
in disease-free or overall survival when
compared with radiation alone.52,53
Neoadjuvant chemotherapy delays the
primary therapy and can induce cross-
resistance to further radiotherapy.
Concomitant Chemoradiation
Cisplatin acts like a radiosensitizer in vivo and
in vitro with documented activity against
squamous cell carcinoma. It has the ability to
inhibit repair of sublethal radiation damage.
In squamous cell cancer of cervix the drug
has consistently shown 20-25 percent response
rate. The initial phase II studies using this
drug alone or in combination with other
chemotherapeutic agents (5-FU, hydroxyurea,
bleomycin, etoposide, etc.) concomitantly
with radiotherapeutic agents showed enco-
uraging results. The theoretical advantages
of concurrent chemoradiation are; synergistic
action between chemotherapy and radio-
therapy leads to increased tumor kill; it
produces no delay in starting the definitive
radiotherapy, there is no time gap to induce
cross resistance and possibility of eradicating
the subclinical metastases.
Over the last decade several randomized
studies have been done to evaluate the
efficacy of different combinations and regimes
of cytotoxic drugs used concomitantly with
radiation.
A Gynecologic Oncology Group (GOG)
trial recruited 368 patients with stages IIB,
III or IVA and negative para-aortic nodes on
surgical staging. The patients were
randomized to receive either irradiation with
hydroxyurea (80 mg/kg twice weekly during
external beam radiation) or irradiation with

cisplatin (50 mg/m 2 on days 1 and 29 of
external beam radiation) plus continuous
infusion of 5 FU (1,000 mg/m2/day on days
2-5 and 30-33 of external beam radiation). At
a median follow up of 8.7 years the irradiation
and cisplatin/5 FU group demonstrated a
superior progression free survival (p=0.033)
and superior overall survival (p=0.018).54
Another important GOG trial randomized
para-aortic node negative stage IIB, III, IVA
patients to three groups. The first group
(n=173) received cisplatin (50 mg/m2 on days
1 and 22) plus 5 FU (1,000 mg/m2/day on
days 2-5 and 23-26) plus hydroxyurea (2 gm/
m2 twice weekly for 6 weeks) during external
beam therapy. The second group (n=176)
received weekly cisplatin (40 mg/m2 weekly
for 6 weeks) along with external radiation
and the third group (n=177) received
hydroxyurea 3 gm/m2 twice weekly for 6
weeks during external irradiation. Both the
cisplatinum based regimes demonstrated
superior progression free interval at a median
follow up of 35 months. Weekly cisplatin regi-
men reduced the risk of death by 39 percent
and the three drug regimen reduced the risk
by 42 percent. The study did not find any
significant survival advantage of using
multiple drugs over cisplatin alone and the
toxicities were higher in the multiple drug
regimes.55
An RTOG trial randomized patients with
clinical stages IB to IVA to irradiation alone
group (n=193) and irradiation with cisplatin
plus 5 FU group (n=195). The second group
received cisplatin 75 mg/m2 on day 1 every 3
weeks followed by 5 FU 1000 mg/m2/day for
4 days continuous infusion. At a median 43
months of follow up survival was superior in
the chemoradiation group (p=0.004) with a
41 percent reduction of risk of death.56
A trial by the SouthWest Oncology Group
(SWOG) recruited stages IA2, IB and IIA
disease with pelvic lymph node involvement,
Cancer of Uterine Cervix 119
parametrial involvement or positive resection
margins at the primary radical hysterectomy
but negative common iliac or para-aortic
lymph nodes. The patients were randomized
to receive irradiation with cisplatin plus 5 FU
or to irradiation alone. This study also
demonstrated that concurrent chemo-radia-
tion is the treatment of choice for post-
operative patients with any of the above high
risk features.57
Based on the available evidence chemo-
radiation using weekly cisplatin has become
the standard treatment of locally advanced
cancer cervix in most centers.
MANAGEMENT OF CERVICAL CANCER
IN PREGNANCY
Parametrial assessment is often inaccurate in
pregnancy. MRI can safely be used in
pregnancy to assess the tumor volume,
parametrial and nodal spread.
Stage IB1 or IIA
Stage IB1 or IIA patients with early pregnancy
can be treated with Wertheim’s operation
with the fetus inside the uterus. If the
gestational age is 34 weeks or more the baby
is delivered by caesarean section (In early
cervical cancer lower segment cesarean section
can be safely done and gynecologists are more
conversant with that technique) and
Wertheim’s operation is done in the same
sitting. In early third trimester pregnancy if
the fetal lung maturity is doubtful a planned
delay of few weeks can be done when
corticosteroids are administered to accelerate
the lung maturity. Lecithin/sphingomyelin
ratio to be determined to ensure lung
maturity before doing cesarean section
followed by radical hysterectomy. The
surgical procedure is slightly more difficult
due to increased vascularity though the
reported complication rates are same as with
non-pregnant uterus.
120 A Practical Approach to Gynecologic Oncology
Stage IB2 and Above
External beam radiation is started first and
spontaneous abortion occurs after an average
33 days in first trimester and 44 days during
second trimester. If abortion has not occurred
by the time of brachytherapy, hysterotomy
should be done. If the pregnancy is 34 weeks
and above the fetus is delivered by classical
cesarean section as the lower segment is more
vascular and friable. If the gestational period
is around 30 weeks treatment can be held up
for a few weeks to allow the fetus to have
lung maturity.
FOLLOW UP
First follow up is after 1 month of completion
of treatment. If there is persistent disease
patients treated by radiotherapy should be
assessed monthly for the next 3 months to
assess the regression. After complete
regression of tumor the patients are assessed
every 3 months for the first 2 years during
which most of the recurrences (80%) occur.
After that patients are seen at 6 months
interval until 5 years. Then yearly follow up
is done.
At each follow up the patients are asked
about the symptoms suggestive of recurrence
or treatment complications. Palpation of
supraclavicular and inguinal lymph nodes
should be done routinely followed by
abdominal and rectovaginal examination. Pap
smear should be done at each visit in patients
treated by surgery alone. Value of cytology
after radiation therapy is doubtful. If there is
any evidence of recurrence of tumor it should
be biopsied. Routine chest radiograph or
abdominal CT scan are not indicated.
Management of Recurrent Cervical Tumor
Treatment of recurrent cervical cancer
depends on the primary therapy and the site
of recurrence.
Total pelvic exenteration that includes
radical resection of uterus, urinary bladder,
vagina, rectosigmoid colon and anus is the
only surgical treatment of choice of a small
subgroup of patients who have central
recurrence. The pelvic side walls should be
free of tumor, there should not be any
evidence of disease remote from the central
recurrence and the patients general condition
should be suitable to stand such an extensive
surgery. Mean operative mortality of pelvic
exenteration has been reported to be
12.1 percent and the mean 5-year survival
following this operation is 35.2 percent.26
Pelvic recurrence of disease after primary
surgery should be treated by radiotherapy
(external beam followed by brachytherapy by
using ovoid vaginal applicators).
Chemotherapy can be tried in pelvic
recurrences after radiotherapy that are not
amenable to surgery or if there are distant
metastases. Role of chemotherapy in either
situation is purely palliative to achieve relief
of symptoms and prolongation of life.
Complete responses are unusual. The most
preferred schedule is Cisplatin alone
administered every 3 weeks at the dose of 50
mg/m2.
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10 Cancer of Endometrium
Anita Singh, Alka Pandey

INTRODUCTION risk areas identified are United States and

Canada. In the developing countries incidence
In the early 1970s the use of estrogen became
rates are about 4-5 times lower than the
very popular as the ‘rejuvenating’ drug. The
developed country. The incidence of the
use of unopposed estrogen led to a surge of
disease in India is among the lowest in the
endometrial adenocarcinoma and since then
world (Table 10.1). However registration
the causal association of this particular cancer
deficiency and failure to distinguish between
with endogenous or exogenous estrogen has
corpus cancer and cancer cervix should be
been established. Endometrial cancer is the
considered while interpreting the data.
most frequently occurring gynecological
Urban population shows 20-40 percent
malignancy in many of the developed
higher incidence in comparison to rural
countries. The mortality from this cancer is
population. Developing countries are showing
quite low even in these high incidence
a rising trend. Of the new cases diagnosed
countries. As it is a slow growing neoplasia,
worldwide 30 percent are from these
about 80 percent of the cases are confined to
countries. 5 The incidence of endometrial
the uterus at the time of initial diagnosis.
cancer is double in whites than in blacks.1,2
EPIDEMIOLOGY
ETIOLOGY AND RISK FACTORS
The epidemiological data for endometrial
cancer have offered the most important and Majority of the endometrial cancers are due
definite etiological clues. It is primarily a to prolonged exposure to estrogen, either
disease of the affluent society. The highest endogenous or exogenous, in the absence of

Table 10.1: Trends in age standardized incidence rate

1-4
(/100,000 women) of endometrial cancer in selected areas

Recent Data
1960 1965 1970 1975 1980
NY State 12.0 — 12.7 18.8 16.7
Japan 2.0 1.3 1.3 2.0 2.8
India (Bombay) — 1.5 1.3 1.4 2.0
UK (Oxford) — 9.1 9.4 10.7 10.4
USA (Hawaii caucasian) 15.6 17.5 28.8 34.8 23.4

the protective effects of progestins. Many of
the identified risk factors for the disease are
associated with states giving rise to high
hormonal milieu in the body. There is a sub-
group of women suffering from the disease
in whom there is no evidence of exposure to
high level of estrogen (nonestrogen dependent
tumors). Based on this observation Bockman
suggested two types of endometrial carci-
noma.
Type 1 (estrogen dependent types):
Tumors associated with obesity, hyper-
lipidemia and signs of hyperestrogenism. The
tumors are often associated with endometrial
hyperplasia and are well or moderately differ-
entiated. The invasion of myometrium is
superficial and they are highly sensitive to
progestogens having a favorable prognosis
(5 years survival of 85%).
Type 2 (estrogen independent types):
Tumors that arise in women with atrophic
endometrium tend to be poorly differentiated
with deep myometrial invasion. Such tumors
have high frequency of lymph node meta-
stasis, decreased sensitivity to progestins and
poor prognosis (5 years survival of 58%).
The risk factors associated with endo-
metrial cancers are as follows.
Socioeconomic Indicators
Carcinoma endometrium is found more
commonly in the affluent class of women. The
reasons may be more widespread use of
hormone replacement therapy and high
prevalence of overweight.6,7
Weight
Aromatization of androstenedione secreted
from the adrenal glands to estrone in the
adipose tissues is the major source of estro-
gens after menopause when progesterone is
almost completely lacking.8 The association
between weight and endometrial cancer risk
has generally been explained in terms of an
Cancer of Endometrium 125
increased availability of unopposed peripheral
estrones in these obese women due to
abundance of adipose tissues. A lower concen-
tration of sex hormone binding globulin in
obese women leads to an increased availability
of peripheral estrogens to hormone responsive
tissues. 9 The risk of endometrial cancer
increases proportionate to the degree of
obesity. The relative risk is 2 times if the
woman is 5-10 kg overweight and the risk rises
to 10 times if the woman is overweight by
more than 25 kg.
Menstrual Factors
Late menarche offers protective effect on
endometrial carcinoma. Amenorrhea or
irregular menstrual cycle is associated with
anovulation and unopposed estrogen stimu-
lation leading to increased risk of endo-
metrial hyperplasia and endometrial cancer.
An association between endometrial cancer
and delayed menopause is confirmed from
various studies.
Pregnancy and Fertility
Nulliparous women have been found to be
at increased risk of endometrial cancer. In
young women a strong direct association
between endometrial cancer and Stein-
Leventhal syndrome as well as other
conditions associated with infertility has been
reported.10,11
Estrogen Replacement Therapy
Large amount of data available in the late
1970s and early 1980s confirmed the
association between estrogen use and
endometrial cancer. The overall evidence
suggests that the risk is 3-4 times greater in
ever users of estrogen as compared to the
never users. The risk rises with the duration
of use and dose. In women who have used
high dose estrogen for 10 years or more there
126 A Practical Approach to Gynecologic Oncology
is more than 10 fold increase in the risk.12 The
relative risk for exogenous estrogens tends
to be smaller in overweight women than that
in leaner women. 13,14 The addition of
progestins to estrogens for at least 10 days
of each treatment cycle has been shown to
protect against endometrial hyperplasia, an
endometrial cancer precursor.15
Antiestrogens
Tamoxifen, the widely used antiestrogen to
treat breast cancer patients has been found
by some authors to be associated with an
increased risk of adenocarcinoma of endo-
metrium. The National Surgical Adjuvant
Breast and Bowel Project (NSABP) randomly
allocated the node-negative, estrogen receptor
positive breast cancer patients to either
treatment by tamoxifen or to the placebo
group.16 They observed a 7.6 times increased
risk of endometrial cancer in the intervention
arm. A potential carcinogenic effect of
tamoxifen on endometrium at least in
postmenopausal women is biologically
plausible. It has been observed that tamoxifen
binds to estrogen receptors in the endo-
metrium and stimulates its growth by its
inherent weak estrogenic properties.
However, two randomized controlled trials
and a recent case control study using the
Surveillance, Epidemiology and End Results
Study (SEER) database indicate that when
confounding factors have been corrected an
increased risk of endometrial cancer in
patients on tamoxifen does not appear to
exist.17 On the basis of currently available
evidence the yearly evaluation of endo-
metrium of the patients on tamoxifen is not
warranted unless they are symptomatic.
Combined Oral Contraceptive Pill
The use of combined oral contraceptive pills
decreases the risk of developing endometrial
cancer. Protection is about 50 percent for
women who had used pills versus never users
and it increases with the duration of use.18
The reduced risk seems to persist for at least
10-15 years after the use of pills is stopped.
PATHOLOGY
Endometrial Hyperplasia
Endometrial hyperplasia is considered to be
the precursor of endometrial carcinoma. The
International Society of Gynecological
Pathologists classification of the various types
of hyperplasia is described in Table 10.2. In
simple hyperplasia of the endometrium the
glands are dilated and increased in number
and the stroma also is proliferated. The glands
may be cystic giving rise to cystic glandular
hyperplasia. Complex hyperplasia is
characterized by the presence of irregular
glands with marked structural complexity and
a back to back crowding. There may be strati-
fication of the epithelial cells and papillary
infoldings. The characteristic features of
atypical hyperplasia are nuclear atypia,
abnormal mitotic figures, loss of polarity, pro-
minent nucleoli and hyperchromatic changes
in the nuclei with clumping of the chromatin.
One percent of simple and three percent
of complex hyperplasias may progress to
malignancy. These figures rise to 8 percent and
29 percent when the simple and complex
hyperplasias become atypical. Atypical
hyperplasia often coexists with frank invasive
carcinoma. Clinically the patients may present
with irregular vaginal bleeding that may be
profuse at times. This is generally preceded
by amenorrhea.
Management of endometrial hyperplasia
depends on the age and histology. Young
patients with hyperplasia without atypia
should be managed by medical therapy and
followed up. They can be advised combined
oral contraceptive pills for 3-6 months.
Resampling of endometrium should be done

Table 10.2: International Society of Gynecological Pathologists classification of
noninvasive endometrial proliferation
Histologic diagnosis Cytologic atypia
Hyperplasia
Simple Absent
Complex Absent
Simple with atypia Present
Complex with atypia Present
every 6 months. Patients can also be put on
medroxyprogesterone acetate 10-20 mg orally
per day for 10 days in the second half of the
cycle for 3-6 months. In patients desiring
pregnancy ovulation should be induced by
clomiphene or gonadotrophins.
If hyperplasia is associated with atypia a
thorough fractional curettage is indicated to
rule out invasive lesion that may coexist in
nearly 20 percent of these cases.
For young women with endometrial
hyperplasia and atypia a higher dose of
medroxyprogesterone is recommended.
Medroxyprogesterone should be started at a
dose of 20 mg daily with gradual increase up
to 60 mg daily depending on the response
observed on periodic endometrial sampling.
Peri- and postmenopausal women with
hyperplasia and no atypia should also be
managed conservatively with progestins.
This age group of women with atypical
hyperplasia may be initially managed with
progestins. However, due to the high risk of
malignant changes hysterectomy is preferred,
particularly if follow up is not assured.
Endometrial Polyps
Endometrial polyps are focal overgrowths of
endometrial gland along with stroma. Very
rarely there is active proliferation of the
glands and the malignant potential of such
conditions is almost nil. This is found not
infrequently in women between the age of
40-50 years. Sometimes they may be associated
Cancer of Endometrium 127
Architectural pattern
Regular
Irregular glands crowded back to back
Regular
Irregular glands crowded back to back
with postmenopausal bleeding or abnormal
uterine bleeding but most of the time they are
asymptomatic. A polyp may be confused with
a malignant growth on hysteroscopy and
should be biopsied. Polyps giving rise to
symptoms have to be removed.
Histologic Subtypes of
Invasive Endometrial Cancer
Adenocarcinomas arise from the glandular
elements of the endometrium. Most
endometrial carcinomas arise in the upper
region of the uterus as a focal lesion though
it may arise anywhere including the lower
part close to the internal os. Endometrioid
adenocarcinoma occurs in 90 percent of all the
cases. Benign squamous differentiation is
found in 20-25 percent of such tumors. These
are known as adenoacanthomas. If the
squamous component is malignant the
histological variety is called adenosquamous
carcinoma that is rarely found. Other rare
tumors are papillary serous carcinoma that is
very aggressive and has a poor prognosis.
Clear cell carcinoma resembles renal cell
carcinoma and also has poor prognosis.
Squamous carcinoma is rare and the cervical
primary must be excluded. Metastatic spread
to the endometrium may be directly from
another pelvic malignancy or rarely from a
distant site such as breast.
Histologic Grading of Endometrial Cancer
The FIGO 1988 staging system has graded the
128 A Practical Approach to Gynecologic Oncology

endometrial cancers into 3 groups depending International Federation of Obstetrics and

on the degree of differentiation.
• Grade 1: 5 percent or less of nonsquamous,
nonmorular solid growth pattern
• Grade 2: 6-50 percent of nonsquamous,
nonmorular solid growth pattern
Grade 3: More than 50 percent of nonsqua-
mous, nonmorular solid growth pattern.
PATTERNS OF SPREAD AND STAGING
Endometrial cancer is a slow growing tumor
and is confined to the uterus in vast majority
of the cases at the time of diagnosis. The
modes of spread can be as follows:
• The tumor frequently infiltrates the
myometrium and can extend to the serosal
surface of the uterus or into the para-
metrium.
• Direct spread to the cervix and along the
fallopian tubes to the ovaries and peritoneal
cavity can also occur.
• Lymphatic spread occurs to the pelvic and
para-aortic nodes. From the region of the
cornu the tumor cells may follow the
lymphatics along the round ligament to
reach the inguinal nodes rarely.
• Hematogenous spread is uncommon and
is usually to the lungs.
Gynecology (FIGO) modified the pre-existing
clinical staging system in the year 1988 to
incorporate the three most important
prognostic parameters—the grade of tumor,
the depth of myometrial invasion and the
involvement of pelvic and para-aortic lymph
nodes. Table 10.3 describes the details of the
FIGO surgical staging.
Surgical staging is extremely important
when one considers the poor correlation
of the clinical staging and the postoperative
pathological findings. Surgical technique
identifies patients with extra uterine disease
and identifies patients with uterine risk factors
including deep myometrial invasion, cervical
extension and lymph vascular invasion an has
a significant impact on treatment decision.
PROGNOSTIC FACTORS
To individualize therapy for the best results it
is very important to look into the prognostic
factors.
Age
Younger women with endometrial cancer fare
better than older women as they tend to have
more of the well-differentiated tumors.

Table 10.3: 1988 FIGO Surgicopathological staging for endometrial carcinoma

Stage Ia G123 Tumor limited to endometrium
Ib G123 invasion to less than one half of the myometrium
Ic G123 invasion to more than one half of the myometrium
Stage IIa G123 Endocervical glandular involvement only
IIb G123 Cervical stromal invasion
Stage IIIa G123 Tumor invades serosa and/or adnexa and/or positive peritoneal cytology
IIIb G123 Vaginal metastasis
IIIc G123 metastasis to pelvic and/or para-aortic lymph nodes
Stage IVa G123 Tumor invasion of the bladder and/or bowel mucosa
IV b Distant metastasis including intra-abdominal spread and/or inguinal lymph
nodes involvement.
[G1: Grade 1, G2: Grade 2, G3: Grade 3]
 Cancer of Endometrium 129

Histopathologic Types Table 10.4: Relationship between depth of myometrial

invasion and grade with 5 years survival rate in
The prognosis does not depend on the stage-I tumors19
squamous component of the tumor, either
Stage Survival 5 yrs
benign (adenoacanthoma) or malignant
(adenosquamous). The grade of the adeno- IaG1 94%
matous component in these subtypes does IbG1 92%
affect prognosis. Papillary serous and clear cell IcG1 87%
histological types confer a poor prognosis but IaG2 89%
fortunately are infrequent. IbG2 87%
IcG2 84%
Histologic Grade IaG3 83%
Degree of histologic differentiation of IbG3 76%
IcG3 68%
endometrial cancer has long been accepted
as one of the most sensitive indicators of
prognosis. As the tumor looses its differen- deep myometrial invasion, lymph vascular
tiation the chances of deep myometrial space involvement and positive peritoneal
involvement and lymph node metastasis cytology tend to have an increased risk of
increases. The chances of survival decreases lymph node metastasis. The Table 10.5 shows
with the more advanced grade of tumor. the risk of pelvic nodal metastasis with grade
The 5-year survival rate for surgically staged of tumor and myometrial invasion. Para-aortic
stage-I tumors is 92 percent for grade 1 and node metastasis is observed in nearly
only 74 percent for grade 3.19 25 percent cases of stage-I disease with grade
3 tumors or with deep myometrial invasion.
Myometrial Invasion
Table 10.5: Pelvic lymph node metastasis in
The degree of myometrial invasion is a
surgical stage-I metastasis20
consistent indicator of tumor virulence. As
the depth of myometrial invasion increases Parameter Metastasis (%)
there is a greater chance of having extra- Grade 1 1.2
uterine disease. When grade and depth of Grade 2 5.4
Grade 3 25.7
invasion are evaluated separately the depth
Limited to endometrium 0.0
of invasion appears to be more important
Superficial myometrial invasion 5.5
prognostic factor than the grade of the tumor Intermediate myometrial invasion 23.1
(Table 10.4). Deep myometrial invasion 33.3

Peritoneal Cytology
Cytologic evaluation of peritoneal fluid is an
independent prognostic factor and also
appears to correlate with other prognostic
factors such as depth of myometrial invasion
and lymph node metastasis.
Lymph Node Metastasis
Patients with poorly differentiated cancers,
papillary serous and clear cell carcinomas,
Stage of Disease
The extent of the tumor is the most important
prognostic variable for endometrial cancers
as is for any malignant neoplasm. Prognosis
for women with cervical involvement is much
worse than the earlier lesions. A tumor lying
low in the cavity involves the cervix earlier
and carries worse prognosis. Adnexal
metastasis substantially increases the risk of
130 A Practical Approach to Gynecologic Oncology
metastasis to both pelvic and para-aortic
lymph nodes.
Lymphovascular Space Invasion
Lymphovascular space involvement is found
to be associated with a very high recurrence
rate.
Tumor Size
The lymph node metastasis rate increases with
the size of the tumor.
Steroid Receptors
Receptors for both estrogen as well as
progesterone are present in approximately
7 percent of the endometrial carcinomas.
Presence of progesterone receptors has been
linked to improved disease free as well as
overall survivals. In a prospective study the 3
years disease free survival for the endometrial
cancer patients having progesterone receptor
levels greater than 100 fmol/mg of protein
was 93 percent, whereas those having receptor
levels less than 100 fmol/mg was 36 percent.21
The relationship of estrogen receptor status
with the prognosis is not clearly established.
DNA Ploidy of the Tumor
DNA ploidy and the fraction of cells in the S
phase are the prognostic factors that correlate
strongly with stage and tumor grade. Most
endometrial cancers are diploid but
aneuploidy indicates advanced disease and a
poor prognosis. A raised fraction of cells in
the S phase also indicates a poorer prognosis.
Oncogene Amplification/Expression
Mutations in codon 12 or 13 of the K-ras
oncogene have been reported. Over expression
of HER-2/neu oncogene has been identified
in 10-15 percent of endometrial adeno-
carcinomas. Alteration of tumor suppression
gene p53 has been associated with papillary
serous type, advanced stage and poor
prognosis.
DIAGNOSIS
Nearly 75 percent of cases of endometrial
carcinoma are seen in postmenopausal women
and the most common symptom is post-
menopausal bleeding. All women presenting
with abnormal uterine bleeding in the peri-
and postmenopausal period must be
investigated although only about 20 percent
of postmenopausal bleedings are due to
malignancy.
On physical examination in vast majority
of cases no gross evidence of disease is noted.
Uterus may be of normal size or bulky.
Sometimes uterus may be irregular; there may
be blood stained discharge from the external
cervical os or purulent discharge due to the
presence of pyometra. Occasionally an
adnexal mass or ascitis may be seen.
Women presenting with abnormal
bleeding need to be investigated to exclude
obvious pathology in the lower genital tract.
An abnormality in either cervix, vagina or
vulva can be identified on gross inspection.
If no obvious pathology is found in the lower
genital tract the women should have further
evaluations for endometrial pathology.
Endometrial Sampling
Women presenting with abnormal uterine
bleeding should have sampling of the endo-
metrium using Pipelle’s or other curetting
devices. This is a simple, cheap, reliable and
convenient office procedure. Novak was the
first person to use his uterine curette for
outpatient uterine sampling. Since then many
devices have evolved for endometrial
sampling.
Diagnostic accuracy of endometrial
sampling to detect endometrial carcinoma is
93-100 percent.

Endometrial Curettage
Although fractional curettage historically was
the procedure of choice to diagnose
endometrial cancer, currently endometrial
sampling has replaced this procedure as a
quick and sensitive method for diagnosis.
Endometrial aspiration sometimes may fail
due to cervical stenosis, inadequate material,
frank bleeding, pyometra and too much
discomfort of the patients. In such cases the
patients should have dilatation and curettage
of the endometrium under anesthesia. If
endometrial pathology is not present in the
biopsy specimen and the patient has no further
bleeding no additional diagnostic tests need
to be performed. If the patients continues to
be symptomatic then further evaluation of
endometrial cavity is needed.
Hysteroscopy
It is a safe, reliable and quick office procedure.
It provides inspection of endometrial features
like color, vascularity, thickness and necrotic
areas or growths. It is an excellent method for
targeted biopsy that one may miss at dilatation
and curettage or endometrial aspiration.
Accuracy of hysteroscopy in detecting
endometrial cancer varies from 85-92.5
percent. Combined use of hysteroscopy and
histopathology gives 100 percent accuracy in
the diagnosis of endometrial neoplasia and its
precursors. Small uterine polyps and
submucous fibroids also can be diagnosed by
hysteroscopy.
Transvaginal Ultrasound (TVS)
During the recent past the increased use of
vaginal ultrasound to evaluate endometrial
thickness has been advocated. The risk of
endometrial cancer is very low if the
endometrial thickness is less than 4-5 mm
(including both endometrial layers) in
postmenopausal women. The thickness of
Cancer of Endometrium 131
more than 10 mm goes in favor of malignancy.
The assessment of endometrial thickness as a
diagnostic test for endometrial cancer suffers
from high false positivity as several other
conditions may increase the endometrial
thickness like endometrial polyp, submucous
fibroids, endometrial hyperplasia, tamoxifen
treatment, etc.
Hydroultrasound
In the presence of thickened endometrium, a
hydroultrasound helps to rule out false-
positive results. This is accomplished by
instilling a small volume of saline into the
endometrial cavity during sonography. This
separates the endometrial surfaces and can
reveal submucous myoma and pedunculated
polyps.
Magnetic Resonance Imaging (MRI)
It is useful in detecting the extent of
growth, myometrial invasion and lymph node
involvement prior to surgery. It is an
expensive method. A high index of suspicion
must be maintained if the diagnosis of
endometrial cancer is to be made in the young
patients. Cytologic detection of endometrial
cancer by routine Pap smear has generally
been poor.
TREATMENT
Endometrial cancer like other pelvic malig-
nancies in general has a propensity to meta-
stasize to regional lymph nodes. Since current
imaging modalities are suboptimal in
detecting these metastases a significant
number of patients with apparent stage-I
carcinoma of endometrium are clinically
understaged. This has led FIGO to recommend
surgical staging of these patients. Hence,
surgery remains the most widely accepted
treatment of endometrial cancer.
132 A Practical Approach to Gynecologic Oncology
Management of Stage-I
For staging laparotomy a vertical incision
should be made for adequate exploration of
the abdominal cavity. About 100 ml of normal
saline should be instilled in the abdomen and
aspirated for cytology. Total abdominal
hysterectomy (extrafascial, Piver class I)
should be performed and the specimen to be
sent for frozen section biopsy if possible. If
the myometrial invasion is less than 50 percent
and the tumor is known to be grade 1 pelvic
or para-aortic lymphadenectomy is not
required. In grade 2 or 3 tumors or if the
myometrial invasion is more than 50 percent
there is considerable chance of metastasis in
the lymph nodes hence pelvic and para-aortic
lymphadenectomy is recommended.
If the disease is limited within the uterus,
patients with grade 1 or grade 2 disease have
minimal (4%) chance of recurrence. So
surgical treatment alone is sufficient in the
above-mentioned groups of patients.
In patients with grade 3 tumors having
superficial muscle involvement the chance of
recurrence after surgery is 14 percent and
those with significant muscle involvement
extending to outer one half, the recurrence
rate is 42 percent. Whole pelvis irradiation (40-
50 Gy) is recommended following surgery in
patients with grade 3 tumors with any amount
of muscle involvement.
Laparoscopic approach for surgical staging
and pelvic lymphadenectomy combined with
vaginal hysterectomy is an attractive alterna-
tive to the traditional surgical approach 22
particularly because many of the patients are
grossly obese.23,24 Bloss et al have reported that
cure rates of vaginal and abdominal surgery
are comparable while morbidity and mortality
rates were lower with vaginal hysterectomy.25
Levandoski et al reported 12.5 percent
complication rate and Dasarahally Mohan et
al reported 13.8 percent complication rate of
lymphadenectomy, of which the most
common was leg edema. 26,27 Removal of
vagina does not reduce vault recurrence in
stage-I carcinoma endometrium and therefore
it is not recommended.
A substantial proportion of patients of
stage-I endometrial cancer are unfit for
surgery. For them radiation therapy is the
only curative treatment. Otto Lehoczky et al
used intracavity radiation alone for stage-I
endometrial cancer.28 The estimated doses
delivered to point A and to point B were 80
and 20 Gy respectively. The corrected 5 years
survival rate for stage-Ia was 76 percent and
for stage-Ib was 72 percent (Table 10.6). Grade
had a profound effect on survival. The total
failure rate was 24 percent. Most of the
recurrences occurred in pelvis.
Table 10.6: Survival rate in stage-I carcinoma
endometrium with regard to grade and treatment29
Grade Surgery Combined therapy
1 1295/1374—94% 2284/2389—96%
2 488/510—96% 1490/1721—87%
3 100/135—74% 398/498—80%
Management of Stage-II
Incidence of positive pelvic lymph nodes
increases from 10 percent in stage-I to
36 percent when the disease extended to the
cervix.30 The reported overall 5 years survival
rates of 40-60 percent are significantly poorer
than 70-90 percent rates achieved in patients
with stage-I disease.31 Histologic grade, extent
of cervical involvement and depth of myo-
metrial invasion contribute to the prognosis
of stage-II endometrial cancers. Reviews have
concluded that radical hysterectomy does not
improve patient’s survival and often increases
patient morbidity. 32 It appears that total
hysterectomy and bilateral salpingo-
oophorectomy with pelvic and para-aortic
lypmphadenectomy would be adequate
surgery in most cases when the amount of
cervical involvement is limited.

Patients with cervical involvement and
extrauterine pelvic spread would definitely
benefit from external radiation therapy.
Several published randomized clinical trials
have failed to demonstrate any benefit of
preoperative brachytherapy. Therefore in
endometrial carcinoma hysterectomy and
bilateral salpingo-oophorectomy with
lymphadenectomy together with post-
operative whole pelvic irradiation is the
treatment of choice. Postoperative whole
pelvis external beam irradiation usually
involves the delivery of 45-50 Gy in 1.8 Gy
daily fractions over 5-6 weeks. A number of
studies have shown that the incidence of
vaginal recurrence in patients with tumors
apparently confined to the uterus can be
reduced from 15-1.2 percent by postoperative
radiation. Postoperative vaginal irradiation is
most often administered using colpostats to
deliver a surface dose of 60-70 Gy to upper
vagina. Lotocki et al have noted that pre-
operative vaginal vault radiation also
decreased the incidence of vaginal recurrence
significantly and improved 5 years survival
from 75-90 percent. 33 Primary surgery
followed by postoperative irradiation is
preferred to preoperative irradiation as more
accurate surgical staging of the disease is
possible.
Management of Stage-III and IV
Relatively few cases are diagnosed in the late
stages of endometrial cancer; 3-13 percent in
stage-III and 3-8 percent in stage-IV. 5 years
survival in stage-III ranges from 4-36 percent
whereas 5 years survival in stage-IV disease
is approximately 10 percent. Great variations
in the site of extrauterine tumor extension and
the medical condition of the patients lead to
greatly individualized treatment regimens. If
the disease is only in fallopian tube and ovary
then the prognosis is better than when the
disease has spread to other pelvic structures.
Cancer of Endometrium 133
Radiotherapy alone or surgery combined with
radiotherapy, progestogens or chemotherapy
are the treatment modalities available for the
advanced tumors.
Extended field radiation appears to
improve survival in patients with endometrial
cancer and positive para-aortic lymph nodes.
Patients with papillary serous cancer and
stage-III and IV disease require whole
abdomen irradiation. Whole abdomen
irradiation is delivered as 30 Gy (daily
fractions of 1.5 Gy) with kidney shielding at
15-20 Gy along with additional 15 Gy to the
para-aortic lymph nodes and 20 Gy to the
pelvis.
While intraperitoneal radioactive isotopes
can theoretically deliver a grater dose to upper
abdomen than external beam therapy the
distribution of isotope can be quite variable
and uncertain.34 In addition most patients with
peritoneal metastasis are at risk for vaginal
and pelvic recurrences and thus require pelvic
external beam therapy and brachytherapy to
the vault. The probability of enteric injury is
substantial with external beam doses of 50 Gy
given after isotope therapy.35
Chemotherapy as a modality of treatment
of advanced endometrial cancer either alone
or in combination with other modalities has
very limited role. The most extensively tried
chemotherapeutic drugs are doxorubicin,
cisplatin and carboplatin. These drugs have a
response rate of approximately 25-30 percent
that last for a very short period. GOG
randomized trial compared doxorubicin with
or without cisplatin in advanced or recurrent
endometrial carcinoma. 36 The objective
response was 66 percent for combination
therapy compared to 35 percent for single
agent. The median progression free survivals
were 6.2 months and 3.9 months for
combination and single agent respectively.
Progestins have been evaluated as
adjuvant therapy in the hope of preventing
134 A Practical Approach to Gynecologic Oncology
recurrences without any established benefit.
Objective responses have been seen after
treatment by progestins of advanced or
recurrent endometrial cancers, particularly
those positive for steroid receptors. A review
of literature observed that 89 percent of pro-
gesterone receptor positive tumors res-
ponded to progestins, compared with only
17 percent of the receptor negative tumors.
Progesterone can be administered as depot
medroxyprogesterone acetate (Provera) –
400 mg IM weekly or oral Provera—150 mg/
day or Megestral acetate 160 mg/day. If there
is an objective response the progestin therapy
can be continued indefinitely. Complete
remission of lung metastasis has also been seen
with progestin alone.37
Tamoxifen has been evaluated in combina-
tion with progestins in recurrent cancer of
endometrium but the results have not been
encouraging. Recently GnRH analogous are
being evaluated for treatment of endometrial
cancer with inconclusive results.
RECURRENT ADENOCARCINOMA
OF ENDOMETRIUM
A recurrence is defined as regrowth of
endometrial cancer after an apparently
complete remission following primary treat-
ment lasting for at least 6 months. Probable
mechanisms of vaginal recurrence of adeno-
carcinoma of the endometrium following
completion of primary therapy have been
described and include direct implantation of
tumor cells at surgery and retrograde
lymphatic or venous spread.38 It has been
reported that the majority of recurrences
occur within 2 yrs of primary therapy.39
Therapy of recurrent disease is individua-
lized. Majority of the cases who have not been
irradiated before are treated by radiation
therapy; external beam therapy to the whole
pelvis and additional brachytherapy to bring
the vaginal surface dose to 100 Gy. Surgery
plays a minor but significant part in cases of
localized operable recurrent disease. In
patients with central disease exenterative
surgery may be required. Many authors have
advocated the use of progestational agents in
the therapy of patients with advanced and
recurrent endometrial cancer. However, pa-
tients with recurrent disease have undifferen-
tiated tumors and a low progesterone receptor
activity. In addition recurrences in the
previously irradiated field reduces the chance
for hormonal response. At times the recurr-
ences in lung respond well to progestogens.
The 5 years survival rate is higher in patients
with grade 1 and 2 tumors who receive pro-
gestogens.
Certain chemotherapeutic agents such as
cyclophosphamides, 5 fluorouracil, doxo-
rubicin and paclitaxel have been used in the
treatment of advanced recurrent endometrial
cancer either as a single agent or in combi-
nation.
FOLLOW UP AFTER TREATMENT
Patients should be examined every 3 months
for the first 2 years and 6 monthly thereafter.
Obtaining a history and physical examination
are the most effective methods of follow up.
Chest X-ray every 6 monthly should be done.
Serum CA-125 measurement has been
suggested as post-treatment surveillance if the
pretreatment levels were high.
Estrogen replacement therapy after
surgical treatment of low risk early stage
endometrial cancer in women is safe.
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hospital for cancer. 949-1965 Obst and Gynae
49-609-608,1977.
32. Pagel J, Bock JE. Endometrial cancer a review.
Dan Med Bull 1984;31:333-45.
33. Lotocki RJ, Copeland LJ, De Petrillo AD,
Muirhead W. Stage-I, endometrial adeno-
carcinoma treatment results In 835 patients. Am
J Ob and Gyn 1981;146:141-45.
34. Leichner PK, Rosen Shein NB, Lubel SA, Orda
SE. Distribution and tissue dose of intra-
peritoneally administered radioactive chro-
mium phosphate. In New Zealand White Rab-
bits. Radiology 1980;134:720-34.
35. Julian CG, Inal Singh, CHA Burnett IS.
Radioactive phosphorous and external
radiation as an adjuvant in surgery for ovarian
carcinoma. Obst and Gynae 52:155-60.
36. Thigpen JT, et al. Phase III trial of doxorubicin
+/- cisplatin in advanced or recurrent
endometrial carcinoma. A Gynecologic
Oncology Group (GOG) study. [Abstract]. Proc
Am Soc Clin Oncol 1993; 12:261
37. Alders JG, Abellar, P Kotrtad. Stage-IV
endometrial carcinoma a clinical and
histopathological study of 83 patients Gynae
Onco 1984-17,75-84.
38. Cetledge R, Tan FN, Fletcher SK. Vaginal
Matastasis from adenocarcinoma of the corpus
uteri. Am J Obst Gynae 1958;75:167-74.
39. Prem KA. Adenocarcinoma of the endome-
trium with special reference to vaginal
involvement. Univ Minn Med Bull 1958; 1299:
512-28.

11
INTRODUCTION
Uterine sarcomas represent only 1 to 3 percent
of all female genital tract neoplasms and 3 to
7 percent of uterine neoplasms. 1 There
prognosis is poor with 2 years survival rate
below 50 percent and 5 years survival rate of
only about 30 percent.2,3 Uterine sarcomas
represent a heterogeneous group of tumors.
Tumors arising from the myometrium are
leiomyosarcomas and those from the uterine
mucosa are either endometrial stromal
sarcoma or carcino-sarcomas or mixed
mesodermal sarcomas.
PATHOLOGICAL CLASSIFICATION
Sarcomas have been classified on the basis of
histological features by several authors. The
simple classification that has been accepted by
the Gynecologic Oncology Group for the sake
of uniformity of reporting is as follows.
• Leiomyosarcoma: Leiomyosarcoma arises
from the uterine muscle itself.
• Endometrial stromal sarcomas: They arise
from the endometrial glands and stroma
• Mixed homologous müllerian sarcomas
(carcino-sarcoma): These tumors have mali-
gnant epithelial elements as well as mali-
gnant homologous sarcomatous elements.
• Mixed heterologous müllerian sarcomas (mixed
mesodermal sarcoma): These tumors have
histologic evidence of tissues not normally
found in the uterus
• Other uterine sarcomas.
Sarcoma of Uterus 137
Sarcoma of Uterus
• Alka Pandey • Anita Singh
Mixed homologous müllerian sarcomas
and mixed heterologous müllerian sarcomas
fall under the common category of malignant
mixed müllerian tumors (MMT).
ETIOLOGY AND RISK FACTORS
There are many common risk factors
between the uterine sarcomas and the
adenocarcinomas—like obesity, hypertension,
diabetes and unopposed estrogen stimulus.
The association of these risk factors with
sarcomas is not as strong as in adenocarci-
noma. Previous exposure to irradiation,
particularly for the treatment of cervical cancer
has been found to increase the risk of
developing sarcoma of the uterus. The
proportion of sarcomas of all uterine cancers
in the black women is higher as compared to
the white women primarily due to the less
incidence of adenocarcinoma in this popula-
tion and not due to an absolute increase in
number of disease.
Malignant transformation of leiomyoma to
leiomyosarcoma is found very rarely (< 0.5%).
INCIDENCE
Malignant mixed müllerian tumors are the
most common variety of uterine sarcomas
followed by leiomyosarcomas whereas the
mean age for patients with mixed mesodermal
tumors is mid 60s.
138 A Practical Approach to Gynecologic Oncology
PATHOLOGY AND CLINICAL FEATURES
Leiomyosarcoma (LMS)
These are rare female neoplasms that account
for about 1 percent of all uterine malignancies
and for approximately 25 percent of uterine
sarcomas.4 According to recent definition,
uterine smooth muscle tumors with 5 or more
mitosis per 10 high power field (HPF)
and nuclear atypia are defined as LMS. 5-7
Incidence of sarcomatous change in benign
uterine leiomyoma is reported to be 0.13 to
1.18 percent.
The mean age for patients with leiomyo-
sarcomas is the mid 50s. The usual presenting
symptoms of uterine LMS are abnormal
vaginal bleeding and pelvic or abdominal
pain. Less common symptoms include weight
loss, weakness, lethargy, rapidly enlarging
pelvic mass and fever.5,7,8
The most important prognostic factor for
LMS is the extent of tumor at diagnosis. The
other prognostic factors are age at diagnosis,
grade, growth pattern, blood vessel invasion
and mitotic count. Invasion of tumor cells into
vascular space decreases survival.
The LMS has the following variants:
• Intravenous leiomyomatosis: There is growth
of worm like, histologically benign smooth
muscle into the venous channels of broad
ligament and then into the uterine and iliac
veins. 9-11 Estrogen may stimulate the
proliferation of these tumors. Treatment is
total abdominal hysterectomy and bilateral
salpingo-oophorectomy with removal of as
much tumor as possible. Prognosis is
excellent.
• Benign metastasizing leiomyomata: It
produces benign metastasis to lung or
lymph nodes. Estrogen has stimulating
effect on these tumors. Hysterectomy and
salpingo-oophorectomy along with resec-
tion of pulmonary metastasis and medical
treatment with progestins have amelio-
rating effect.
• Leiomyomatous peritonealis disseminata: They
most frequently occur in patients who have
recently been pregnant or have a long
history of oral contraceptive use. This is a
rare condition characterized by benign
smooth muscle nodules scattered through-
out the peritoneal cavity on peritoneal
surfaces.11 The clinical outcome is favorable.
Treatment is hysterectomy, salpingo-
oophorectomy, omentectomy and excision
of as much gross disease as possible.
• Myxoid leiomyosarcoma: It is aggressive
tumor with poor survival. It has a gross
gelatinous appearance and apparent
circumscribed border. Microscopically it
has a myxoematous stroma and it exten-
sively invades adjacent tissues and blood
vessels. Hysterectomy is the main treatment
as it does not respond to chemotherapy or
radiotherapy.
• Leiomyoblastoma: It is a low grade tumor
with excellent prognosis. Treatment is
hysterectomy.
Endometrial Stromal Sarcoma (ESS)
They often present with irregular vaginal
bleeding, abdominal pain and rapidly grow-
ing uterus in women between 45 to 50 years
of age. The cells of these tumors resemble
endometrial stroma. They may be of the
following three types depending on the
mitotic count and atypia.
• Endometrial stromal nodule: It is a benign,
well circumscribed tumor having less than
3 mitotic figures (MF)/10 HPF
• Low grade stromal sarcoma: Microscopically
it has a mitotic rate less than 10 MF/10 HPF.
Spread is confined to pelvis in two-third of
cases. It follows an indolent course.
Recurrences occur late. Treatment is by
hysterectomy and bilateral salpingo-
oophorectomy. Pelvic irradiation may be
given for inadequately excised tumor

• Endometrial stromal sarcoma: It is very
aggressive, has poor prognosis and has
mitotic count more than 10 MF/10 HPF.
Treatment again is with hysterectomy and
bilateral salpingo-oophorectomy. Radio-
therapy, chemotherapy or both may be
added to surgery.
Malignant Mixed Müllerian Tumor (MMT)
These are histologically a mixture of
carcinoma and sarcoma. Carcinomatous
element is usually glandular whereas the
sarcomatous element may resemble the
normal endometrial stroma. The stromal
element may be homologous that is composed
of malignant cells derived from types that are
normally found in uterus such as leiomyo-
sarcomas, fibrosarcomas and endometrial
stromal sarcomas or they may be undiffe-
rentiated. If the elements are not related to
normal uterine tissue as with rhabdo-
myosarcomas, osteosarcomas and chondro-
sarcomas then the tumor is described as
heterologous. They may be associated with
diabetes, obesity and hypertension. A history
of previous irradiation may be present. The
tumor grows as a large polypoidal mass filling
and distending the uterine cavity. It is a very
aggressive tumor and the myometrium is
invaded in almost all cases. It presents with
postmenopausal bleeding, vaginal discharge
and passage of tissue per vagina. De Saia et al
found 53 percent 2 years survival when the
disease was confined to the uterus, 8.5 percent
2 years survival when it extended into the
vagina and there were no survivors when the
disease spread outside the uterus. 12
Hematogenous metastasis to the lung, pleura,
vagina and omentum are common. Pelvic
recurrence is commonest within first
18 months of surgery.
Adenosarcoma is a variety of mixed
mesodermal tumor of low grade malignancy
Sarcoma of Uterus 139
and in it only the stromal element is malignant.
Recurrence may occur several years after
hysterectomy.
STAGING AND MEDIAN SURVIVAL
There is no separate staging system for uterine
sarcomas and the International Federation of
Obstetrics and Gynecology (FIGO) staging
system for endometrial cancers is followed.
The survival depends on the stage. These
tumors have high recurrence rate and a high
propensity to develop extrapelvic recurrence
after treatment. The median survival is worst
for leiomyosarcoma (20.6 months) and best for
MMT with homologous elements (62.6
months).
MANAGEMENT
The treatment of uterine sarcomas continues
to be a challenge. Surgery constitutes the
mainstay of therapy. Surgical exploration and
thorough evaluation of peritoneal cavity and
the extent of the tumor should be done. The
surgical management comprises of hysterec-
tomy with bilateral salpingo-oophorectomy
and pelvic lymphadenectomy. Although
adjuvant radiotherapy may reduce the risk of
local recurrence in patients with localized
mixed müllerian tumors and endometrial
stromal sarcomas but it has not proved of
much help in early leiomyosarcomas because
pulmonary metastasis is more common in
them than pelvic recurrences.
In general chemotherapy has not proved its
role in treatment of uterine sarcomas. In a
randomized GOG study single agent doxo-
rubicin adjunctively was shown to have no
significant impact on survival in patients with
uterine sarcomas.12 Doxorubicin in combina-
tion with dacarbazine (DTIC), cisplatin,
cyclophosphamide and vincristine has been
tried without significant improvement in long-
term survival. Sutton reporting for GOG
140 A Practical Approach to Gynecologic Oncology
demonstrated modest activity of ifosamide
against LMS.13 Ifosamide with doxorubicin
showed an overall response rate of 33.3
percent with few patients showing grade IV
neutropenia and grade V cardiac toxicity.
A recent trial of GOG with combination of
chemotherapy hydroxyurea, dacarbazine and
etoposide exhibited overall response rate of
18.7 percent with quite acceptable toxicity.
About 50 percent uterine sarcomas recur
Table 11.1: Uterine sarcomas: Survival rate in
terms of stage, treatment and pathology
Stage Histologic type (N)
I MMT
LMS
ESS
II-IV MMT
LMS
ESS
REFERENCES
1. Babib A, Vongtoma V, Kurohara S, Webster J.
Radiotherapy in the treatment of sarcomas of
the corpus uteri cancer 1969;24:724-729.
2. Moskovie E, Macsweeney E, Law M, Price A.
Survival pattern of spread and prognostic
factors in uterine sarcoma—Study of 76
patients. Br J Radiol 1993;66:1009-15.
3. Olab KS, Gec I I Blunt S, Dunn JA, Kelly K,
Chann KK. Retrospective analysis of 318 cases
of uterine sarcomas. Eur J Cancer 1991;27:
1095-99.
4. Norris HJ, Zaludek CJ. Mesenchymal tumors
of uterus. In: Blaustein A (Ed). Pathology of
Female Genital Tract, 2nd edn. New York:
Springer-Verlag 1982;352-92.
5. Zaludek C, Norris HJ. Mesenchymal tumors of
the uterus. In: Kurman RJ (Ed). Blaustein
Pathology of Female Genital Tract, 4th ed. New
York:Springer-Verlag 1999;487-528.
6. Hendrickson MR, Kempson RL. Surgical
pathology of uterine corpus. In: Bennington JL
(Ed): Major Problems in Pathology. Phila-
delphia: Saunders 1980;12:468-529.
after treatment. The most common sites are
abdomen and lungs.
SURVIVAL RATE
Uterine sarcomas have a poor prognosis even
if they are detected early. Because of the rarity
of the tumors very limited experience has been
gathered about their natural history and the
optimal management even in the referral
center.
5-year survival rate
Surgery Surgery+RT RT
52% 48% 29%
58% 75% 33%
47% 88% 50%
5% 16% 0%
0% 13% 0%
0% 33% 0%
7. Barter JF, Smith EB, Szpak CAH, Shaw W,
Clarke Pearson DL, Creasman WT. Leiomyo-
sarcomas of the uterus—clinicopathology
study of 21 cases. Gynaecol Oncol 1985; 21:
220-27.
8. Schwartz Z, Dgani R, Lancet M, Kessler I.
Uterine sarcoma in Israel study of 104 cases.
Gynaecology Oncology 1985; 20:354-63.
9. Norris HJ, Parmley J. Mesenchymal tumors of
the uterus V intravenous leiomyomatosis. A
clinical and pathology study of 14 cases. Cancer
1975;36:2164-78.
10. Evans AT III Symonds RE, Gaffey TA.
Recurrent pelvic intravenous leiomyomatosis.
Obst and Gynae 1981;57:260-64.
11. Tavossoli FA, Norris HJ. Peritoneal myo-
matosis peritonealis disseminata—A clinico-
pathology study of 20 cases with ultrastructural
observations. Int J Gynae Pathol 1982;1:59-74.
12. Disaia PJ, Castro JR, Rutlez FM. Mixed
mesodermal sarcomas of the uterus. Am J Roen
Genol 1973;117:632-36.
13. Sutton GP, Blessing JA, Barrett RJ, Mc Gehec
R. Phase II trial of ifosamide and mesna in
leiomyosarcomas of the uterus—AGOG Study.
Am J Obst and Gyn 1992;166:556-59.

12 Trophoblastic Neoplasia
INTRODUCTION
Gestational trophoblastic neoplasia (GTN),
referred by Hertig as “God’s first cancer and
man’s first cure” is a spectrum of tumors
originating from the trophoblastic cells of the
human placenta.1 The inter-related spectrum
of tumors includes hydatidiform mole,
invasive mole, placental site trophoblastic
tumor and choriocarcinoma. The disease is
unique by virtue of developing from an
allograft (the abnormal conceptus) and its
secretion of human chorionic gondotrophin
(hCG), a marker that provides a sensitive and
specific means to detect and monitor the
course of this potentially fatal disorder.
The trophoblast originates from the outer
cell mass of the pre-implantation embryo. It
is uniquely devoid of transplantation antigens
(both HLA and ABO) and as a result is not
vulnerable to maternal immune rejection.2-4
The normal trophoblast invades with
impunity the maternal decidua, decidual
vessels as well as the connective tissues of
the subjacent myometrium.5, 6 The trophoblast
maintains a steady, low volume embolic
stream directed from the inter-villous blood
spaces into the maternal pulmonary
circulation. Only a small proportion of the
emboli finds its way into the systemic
vasculature. 7 Morphologically, even the
normal trophoblast reflects its invasive and
metastatic properties. The neoplasms arising
Gestational
• K Uma Devi
from the trophoblast have the propensity to
invade the surrounding structures and
metastasize at a relatively earlier stage.
Fortunately, most of these tumors can be
cured, if treated properly, even after distant
metastasis.
HYDATIDIFORM MOLE
Hydatidiform mole is a general term that
includes two distinct entities—complete mole
and partial mole.
Pathology
Complete hydatidiform mole is an abnormal
conceptus without any identifiable embryo or
fetus. It is characterized by loss of villous
vasculature leading to gross hydropic
swelling and central cistern formation. There
is pronounced cytotrophoblastic and syncytio-
trophoblastic hyperplasia. Usually the
complete mole has 46XX karyotype and all the
chromosomes are of paternal origin, a
phenomenon called androgenesis. 8 The
complete mole arises from fertilization of a
defective ovum (with absent or inactivated
nucleus) by a haploid sperm which then
duplicates its own chromosomes.9 About 10
percent of the complete moles have 46XY
chromosomal patterns that result from
fertilization of an empty ovum with two
sperms.10
142 A Practical Approach to Gynecologic Oncology
Partial hydatidiform mole has a persistent
embryonic or fetal element and a placenta
with a mosaic of normal appearing villi
alternating with areas of focal villous swelling
and trophoblastic hyperplasia. Micro-
scopically the partial moles have scalloping
of chorionic villi and trophoblastic stromal
inclusions, both of which are absent in
complete moles. Usually the partial mole has
a triploid karyotype that results from
fertilization of an apparently normal ovum
by two sperms. 9 Fetuses identified with
partial moles generally exhibit the features of
triploidy, for example, growth retardation,
hydrocephalus, microphthalmos and
syndactyly of the hands and feet.10-12
In about 15 percent cases hydatidiform
mole can lead to an invasive mole that can
invade the myometrium or metastasize (in less
than 5% cases) or both.13 Postmolar GTN rarely
occurs after partial mole (2-4%).
Postmolar GTN is more frequently seen if
the following high risk factors are present at
the time of diagnosis of hydatidiform mole:14
• Maternal age more than 40 years
• Excessive uterine enlargement
• Serum hCG level more than 100,000 mIU/
ml
• Theca lutein cysts greater than 6 cm in
diameter
• Toxemia, hyperthyroidism and coagulopathy
• Trophoblastic embolization
• Previously treated choriocarcinoma
Epidemiology and Risk Factors
The incidences of gestational trophoblastic
diseases vary widely across different regions
of the world. The Asian countries have much
higher incidence of molar pregnancies as
compared to Europe or America. The
frequency of hydatidiform moles is one per
125 pregnancies in Taiwan as compared to
one in 1500 live births in United States.
Nutritional factors are primarily responsible
for such regional variations. Case-control
studies have shown that women whose diet
is poor in carotene and animal fat are at a
much higher risk of having molar
pregnancies.15 The variation in dietary habits
can explain the regional variation of frequency
of the abnormal pregnancies. Another
important risk factor for molar pregnancies
is advanced maternal age. The risk of
complete molar pregnancies is 5-10 times
higher in women above 40 years of age.
Women who have had 2 or more spontaneous
abortions are at 3 times higher risk of having
complete mole as compared to those who do
not have any miscarriages. Infertile women
are also at a higher risk.
Clinical Signs and Symptoms
of Molar Pregnancy
The patients with molar pregnancy will
present most commonly with vaginal
bleeding in the first half of pregnancy. The
bleeding may be long-standing, excessive and
there may be history of spontaneous passage
of grape-like typical molar tissue. The blood
retained in the uterine cavity may get oxidized
and the leaking blood may have the typical
color of prune-juice. The patients are often
anemic due to chronic blood loss and may
present in an exsanguinated state. Due to
trophoblastic proliferation and accumulation
of blood in the uterine cavity, the uterus may
be disproportionately enlarged relative to the
period of gestation. Nearly 50 percent of the
patients with molar pregnancy have enlarged
(> 6 cm in diameter) theca lutein cysts that
regress within 2-4 months of molar
evacuation. The cystic change in the ovaries
is the result of hyperstimulation from high
circulating levels of hCG. Enlarged theca
lutein cysts may give rise to a constant, dull,
aching pain in the lower abdomen. Elevated

β-hCG may cause hyperemesis gravidarum
and toxemia early in the pregnancy (before
24 weeks of gestation). A small proportion of
the patients suffering from trophoblastic
disease may have raised serum thyroid
hormone levels giving rise to the clinical
features of hyperthyroidism. One has to be
vigilant as some of these patients may develop
thyroid storm (hyperthermia, delirium, coma,
cardiovascular collapse) during evacuation
under general anesthesia. Administration of
β-adrenergic blocking agents may be life
saving in such situations. Some patients may
have chest pain and respiratory distress due
to trophoblastic emboli in the lung.
Patients with partial moles most often
present with signs and symptoms of missed
abortion or an incomplete abortion. Serum
hCG level is not as elevated as in complete
molar pregnancy. As a result hyperemesis,
toxemia or hypothyroidism are rarely seen.
Diagnosis
Ultrasonography is reasonably accurate in
detecting molar pregnancy. In fact, due to
wide spread use of routine ultrasonography
in pregnancy, molar pregnancies are often
detected in the first trimester even before the
symptoms appear. The absence of fetus along
with the typical vesicular sonographic pattern
(snow-storm appearance) can confirm the
diagnosis of complete hydatidiform mole.
Focal cystic spaces in the placenta are seen on
ultrasonography in partial moles. The ratio
of the transverse to antero-posterior
diameter of the gestational sac more than 1.5
should alert the sonologist about the
possibility of partial mole.
Treatment
Molar pregnancy can be removed either by
suction and evacuation or by hysterectomy
with the mole in situ. The patient should be
Gestational Trophoblastic Neoplasia 143
carefully evaluated for hypertension,
electrolyte imbalance, hyperthyroidism and
anemia. Necessary steps should be taken to
correct such medical complications. The
patient’s reproductive preference is a crucial
factor in decision-making.
If the patient no longer desires to maintain
fertility hysterectomy may be performed.
Although, hysterectomy eliminates the risks
of local invasion, it does not prevent
metastases. Prominent theca lutein cysts may
be aspirated at the time of surgery.
Oophorectomy should not be done for theca
lutein cysts.
If the patient desires to preserve fertility,
suction evacuation is the preferred method
of evacuation regardless of period of
gestation and uterine size. Cervix can be
primed with prostaglandin E2. Oxytocin can
be employed to stimulate uterine contraction
during suction evacuation. At the completion
of evacuation, sharp curettage should be
performed to look for residual tissues. Both
the specimens of suction and sharp curetting
are submitted separately for pathologic
review.
Role of prophylactic chemotherapy, as a
routine, at the time of molar evacuation
remains controversial. Goldstein et al treated
247 patients having complete molar pregnancy
with single dose of Actinomycin D prophy-
lactically at the time of evacuation or hysterec-
tomy.16 On follow-up only 10 patients (4%)
developed local invasion without a single case
of distant metastasis. In comparison, 160 out
of total 858 patients (18.6%) developed
persistent GTN in the group that did not
receive prophylactic chemotherapy. Other
investigators have reported that such
treatment does not reduce the risk of
postmolar tumor but increases the rate of
complication.17 Kim et al demonstrated in a
randomized prospective trial that prophylac-
tic chemotherapy significantly reduces the risk
144 A Practical Approach to Gynecologic Oncology
of developing persistent GTN after complete
mole if the high risk factors mentioned
previously are present. Chemoprophylaxis did
not significantly reduce the risk of persistent
disease in patients with low risk complete
moles. 18 Based on the available evidences
prophylactic chemotherapy is advised in
patients with complete moles having any of
the high risk factors mentioned earlier,
particularly when follow-up is not assured.
Follow-up
All patients should be followed up with
weekly β-hCG radio-immunoassay after
molar evacuation or hysterectomy until the
values are normal for 3 consecutive weeks. The
test is performed monthly after that until
results are normal for consecutive six months.
Patients are advised to use oral contraceptives
or barrier methods to avoid pregnancy for 1
year following normalization of the β-hCG
level. Oral contraceptive pills are preferred as
they are more effective and there is no
evidence that the risk of postmolar GTN is
higher in the pill users specially if the pills
contain estrogen less than 50 mg. Many hCG
assays have some cross reactivity with
luteinizing hormone (LH). Following
chemotherapy ovarian steroidal levels may
be depressed resulting in elevation of LH
levels. This may result in false positive β-hCG
assay. Oral contraceptives suppress the LH
level and prevent problems with cross
reactivity.
MALIGNANT GESTATIONAL
TROPHOBLASTIC NEOPLASIA
Malignant gestational trophoblastic tumors
are uncommon solid tumors that include
choriocarcinoma, invasive mole and placental
site trophoblastic tumor. These tumors can
progress, invade, metastasize and kill, if
untreated. GTN is currently known to be the
most curable gynecological malignancy even
with widespread dissemination.17 They are
highly chemosensitive. The results have been
significantly improved through aggressive use
of multimodality therapy, such as single and
combination chemotherapy regimens, surgery
and radiotherapy.19
Pathology
Choriocarcinoma is a malignant neoplasm of
cytotrophoblastic and syncytiotrophoblastic
elements without villous formation. It usually
progresses and metastasizes and is fatal
without treatment. It can occur after a
hydatidiform mole, a nonmolar abortion or a
term pregnancy.
Hydatidiform mole can lead to an invasive
mole that can invade the myometrium,
metastasize or both. It sometimes progresses
and metastasizes but usually regresses
spontaneously.
Placental site trophoblastic tumor (PSTT) is
composed mainly of cytotrophoblastic
mononuclear intermediate cells arising from
the placental implantation site. It does not
contain chorionic villi and secrete only small
amounts of hCG.13 They metastasize rarely,
usually late in the course of disease. The tumor
is not sensitive to chemotherapy and is cured
by hysterectomy.
Metastatic Sites
Gestational trophoblastic neoplasia may
present with the signs and symptoms of
distant metastasis. Choriocarcinoma is noto-
rious for widespread metastasis as they
tend to invade the vessels relatively early in
the course of disease. The common sites of
metastasis of GTN are listed in Table 12.1.20

Table 12.1: Common sites of metastasis in GTN
Site Relative incidence of metastasis
Lungs 80 %
Vagina 30 %
Pelvis 20 %
Brain 10 %
Liver 10 %
Bowel, kidney, spleen <5%
Others <5%
The metastatic deposits contain fragile
blood vessels that bleed easily. Sometimes the
patient may present with abnormal bleeding
from the metastatic sites without any history
of molar pregnancy. Only a high index of
suspicion can prompt the physician to go for
β-hCG assay that can clinch the diagnosis.
Symptoms and Signs
During follow-up of a molar pregnancy if the
β-hCG level does not come down to normal
within 8 weeks or rises at any point of time,
malignant GTN is diagnosed after exclusion
of normal pregnancy. Usually the patient is
amenorrhic or may have irregular vaginal
bleeding. There may be subinvolution of
uterus and abdominal pain due to large theca
lutein cysts. Rarely, trophoblastic tumor may
perforate the myometrium producing
intraperitoneal hemorrhage. There may be a
highly vascular, red vaginal nodule either in
the fornices or in the suburethral region
causing irregular vaginal bleeding. Such
nodules should not be biopsied due to the
risk of severe hemorrhage. The patients with
malignant GTN may present with hemoptysis
and chest pain due to pulmonary metastasis,
headache, seizures and hemiplagia due to
intracerebral metastasis or epigastric pain due
to hepatic metastasis.
Diagnosis
All patients with malignant GTN should
undergo careful metastatic work-up before
Gestational Trophoblastic Neoplasia 145
starting the treatment. Histological verifica-
tion of disease is not required. A complete
clinical history and general physical
examination is followed by measurement of
serum β-hCG titer, hepatic, thyroid and renal
function tests and a complete hemogram. The
metastatic work-up should include chest
X-ray and ultrasonography of abdomen and
pelvis. Abdominal ultrasonography is fairly
accurate to detect hepatic metastasis. Pelvic
ultrasonography can detect the presence of
large tumor in the uterus and also the theca
lutein cysts. Bulky tumor in the uterus may
not respond adequately to chemotherapy and
may require hysterectomy to reduce the tumor
burden. CT scan is much more accurate than
X-ray to detect pulmonary metastasis. Still the
routine use of chest CT to screen for small
pulmonary metastases is not recommended to
stage patients or to assign initial therapy. CT
scan should be done to exclude cranial
metastasis if suspected from symptoms and
signs. HCG levels in CSF may be high in
presence of cranial metastasis.21
Prognostic Scoring System and Staging
A scoring system has been designed by
including several prognostic risk factors to
predict response to chemotherapy and
individualize treatment.
There are currently three prognostic
scoring systems available for malignant
gestational trophoblastic disease.22,23
• The World Health Organization (WHO)
scoring system
• The National Institute of Health (NIH)
prognostic classification
• The International Federation of Gynecology
and Obstetrics (FIGO) staging system
WHO developed a prognostic scoring system
based on the one proposed by Bagshawe.24 This
has been found to predict reliably the resistance
to chemotherapy. The details of the scoring
system are described in Table 12.2.
146 A Practical Approach to Gynecologic Oncology

Table 12.2: WHO modified prognostic

25
in the United States separate patients with
scoring system metastatic disease into “Good” and “Poor”
Prognostic factors Score prognostic categories.26,27 This classification is
simple and very convenient to design
0 1 2 3
Age (Years) < 39 > 39
treatment protocols.
Antecedent The NIH clinical classification of GTN is
Pregnancy H Mole Abortion Term described in Table 12.3.
Interval (Months)* <4 4-6 7-12 >12 A staging system of GTN based on
3 3 4 4 5 5
hCG (IU/litres) < 10 10 - 10 10 – 10 >10 anatomic extent of the disease in combination
ABO Groups O×A B with prognostic factors was recommended by
(female × male) A×O AB FIGO in 1992. The details are given in Table
Largest tumor
12.4.
including uterine
tumor < 3 cm 3-5 cm >5 cm
Table 12.4: FIGO staging of malignant GTN
Site of tumor Lung, Spleen, GI tract, Brain
vagina kidney liver Stage I: Disease confined to uterus
No. of metastasis Ia Disease confined to uterus with no risk fac-
identified 1-4 5-8 >8 tor.
Prior Ib Disease confined to uterus with one risk
chemotherapy Single Multiple factor
drug drugs Ic Disease confined to uterus with two risk fac-
tors
* Interval between end of antecedent pregnancy and Stage II: GTN extending outside uterus but limited to
start of chemotherapy genital structures (adnexa, vagina, broad
[The total score for a patient is obtained by adding the ligament)
individual score for each prognostic factor. 0-4: Low IIa GTN involving genital structures without any
risk, 5-7: Middle risk, 8 or more: High risk] risk factor
IIb GTN involving genital structures with one
risk factor
The NIH clinical classification used by
IIc GTN involving genital structures with two
majority of the trophoblastic disease centers risk factors
Stage III: GTN extending to lungs with or without
Table 12.3: NIH clinical classification of GTN
known genital tract involvement
I. Non-metastatic GTN IIIa GTN extending to lungs with genital tract
II. Metastatic GTN involvement with no risk factor
Low risk group (good prognosis) IIIb GTN extending to lungs with or without
• Low Pretreatment b-hCG titer (<100,000 IU/L involvement of genital tract and with one risk
urine or <40,000 mIU/ml serum) factor
• Symptoms present for <4 months IIIc GTN extending to lungs with or without
• No brain or liver metastases involvement of genital tract and with two risk
• No prior chemotherapy factors
• Antecedent pregnancy event is not term deliv- Stage IV: All other metastatic sites
ery (i.e. mole, ectopic or spontaneous abortion) IVa All other metastatic sites without risk factors
High risk group (poor prognosis) IVb All other metastatic sites with one risk factor
• long duration (last pregnancy >4months) IVc All other metastatic sites with two risk fac-
• Symptoms present for >4 months tors
• Presence of brain or liver metastases [Risk factors: 1) β-hCG >100,000 mIU/ml and 2) dura-
• Unsuccessful prior chemotherapy tion of disease > 6 months from termination of ante-
• Antecedent term pregnancy cedent pregnancy]

Management
Chemotherapy is the sheet anchor of
management of GTN. An optimal regimen
should maximize response rate with minimal
morbidity. Careful clinical staging and prog-
nostic scoring have led to more appropriate
individualization of therapy. Single agent
chemotherapy is recommended for low risk
disease resulting in reduced toxicity, while
multi-agent chemotherapy is reserved to treat
high risk patients. Patients who fail to respond
to one single agent are switched to the other
single agent. Patients who develop resistance
to two single-agent chemotherapy regimens
are then treated with combination chemo-
therapy used for high risk disease. Surgery is
generally reserved for patients resistant to
chemotherapy.
Non-metastatic GTN
Majority of the patients with non-metastatic
GTN achieve sustained remission with single
agent chemotherapy. Most centers have
reported essentially 100 percent cure rates for
patients with non-metastatic disease using
single drug regimes. Methotrexate and
actinomycin-D have been the principal agents
utilized for therapy of this disease. 26-33
Bagshawe and his colleagues first combined
high dose methotrexate with folinic acid to
reduce toxicity and obtained a complete
remission in 90.2 percent patients with non-
metastatic GTN.34 Since then, this has been the
most widely accepted protocol of single drug
therapy for malignant GTN, specially non-
metastatic type. The detailed protocol is
described in Table 12.5.
A single cycle of methotrexate and folinic
acid (day 1 to day 8) is administered for non-
metastatic gestational trophoblastic disease
and β-hCG regression is followed. If the
patient has a progressive decrease in β-hCG
level and extended remission, no further
Gestational Trophoblastic Neoplasia 147
Table 12.5: Protocol for therapy with methotrexate
in combination with folinic acid
Day Time Tests and Therapy
1 Morning CBC, Platelet count, AST
Evening Methotrexate 1.0 mg/kg IM/IV
2 Evening Folinic acid, 0.1 mg/kg IM
3 Morning CBC, Platelet count, AST
Evening Methotrexate 1.0 mg/kg IM/IV
4 Evening Folinic acid, 0.1 mg/kg IM
5 Morning CBC, Platelet count, AST
Evening Methotrexate 1.0 mg/kg IM/IV
6 Evening Folinic acid, 0.1 mg/kg IM
7 Morning CBC, Platelet count, AST
Evening Methotrexate 1.0 mg/kg IM/IV
8 Evening Folinic acid, 0.1 mg/kg IM
[CBC: Complete blood count, AST: Aspartate ami-
notransferase]
therapy is given. If β-hCG level plateaus for
more than 3 consecutive weeks or begins to
rise again, patients are treated with another
cycle of methotrexate with folinic acid. If the
total leucocyte count or the platelet count goes
down the administration of chemotherapy
should be deferred until the total leucocyte
count is >2000/mm3 and platelet count is
>100,000/mm3.
Some clinical trials have administered
methotrexate and folinic acid in repetitive
cycles until remission is achieved, followed
by two cycles of maintenance chemotherapy.
However, for non-metastatic GTN mainte-
nance chemotherapy is rarely advocated.
Actinomycin-D is as effective as metho-
trexate as the first line of treatment for non-
metastatic GTN. Still most oncologists utilize
the drug as salvage therapy for non-metastatic
GTN after failure of initial methotrexate
regimen. If the response to two consecutive
courses of methotrexate-folinic acid is
unsatisfactory, the patient is considered
resistant to the drug. Actinomycin is given
intravenously in doses of 10 to 13 μg/kg per
day for five days repeated at 12 to 14 days
interval. Actinomycin-D is the appropriate
148 A Practical Approach to Gynecologic Oncology
therapeutic agent for patients with compro-
mised liver and renal functions. In a Gyne-
cologic Oncology Group (GOG) study, 94
percent patients with non-metastatic GTN
achieved remission with actinomycin-D alone
at a dose of 1.25 mg/m2 IV every 14 days after
a median of four pulses.30
The majority of patients can retain
childbearing capacity and often have normal
pregnancy after chemotherapy.
Hysterectomy alone can be offered as first
line of management in elderly patients not
desirous of fertility. Hysterectomy may be
combined with adjuvant single agent
chemotherapy as the first line of treatment
for non-metastatic GTN with either of the
high risk factors. Most clinicians advocate that
chemotherapy should be administered at the
time of surgery to reduce the likelihood
of disseminating viable tumor cells. Hysterec-
tomy is useful in selected patients with bulky
disease to decrease the amount of chemo-
therapy required for remission and to salvage
patients who have failed initial chemotherapy.
Hysterectomy should be performed in all cases
of placental site trophoblastic tumors as they
are resistant to chemotherapy and rarely
spread outside uterus.
All patients with non-metastatic GTN
should be followed up with weekly measure-
ment of β-hCG levels until they are normal
for 3 consecutive weeks. Then serum hCG
should be estimated monthly until levels are
normal for 12 consecutive months. The patient
should be advised contraception (pill or ba-
rrier contraceptives) during the entire period
of follow-up.
Metastatic “Low Risk” GTN
The treatment with chemotherapy is very
similar for patients with non-metastatic
trophoblastic tumors and for patients with low
risk metastatic trophoblastic tumors. 32, 33
Single agent chemotherapy courses (metho-
trexate alone or with folinic acid, actinomycin-
D) are administered and repeated every
12-14 days. If there is a resistance to single
agent chemotherapy combination chemo-
therapy is used. The details of the combination
therapy protocols are discussed later.
The role of surgery in treating patients with
good prognostic metastatic disease depends
on the location of the tumor, the response to
chemotherapy and the patient’s reproductive
status. Unlike the case in non-metastatic
disease, these patients with disease in the
uterus also have metastases. Therefore,
hysterectomy is not likely to be curative.
Hysterectomy in this setting has usually been
reserved for patients with the drug-resistant
focus in the uterus or if there is excessive
bleeding from the uterine growth. A
persistent isolated pulmonary metastasis
occurs on occasion and in this case, resection
may prove to be curative.
Patients with metastatic GTN in the “low
risk” group should be monitored by weekly
measurement of β-hCG titers until they
are normal for 3 consecutive weeks and
thereafter monthly for 12 consecutive months.
Effective contraception during the entire
follow-up interval is essential.
Metastatic “High Risk” GTN
The randomized trial of Gynaecologic
Oncology Group (GOG) and the experience
at the New England Trophoblastic Disease
Centre strongly suggest that the chemo-
therapy of choice in a patient with a WHO
prognostic score of more than 6 is the
traditional MAC regime of chemotherapy
(Table 12.6). However, this therapy is
inadequate for patients with prognostic scores
of 8 or above (ultra-high risk patients).
Superior results in these patients have been
achieved with EMA-CO regime (with a

remission rate upto 83 percent in patients with
“high-risk” GTN).34-38 The EMA-CO regime
consists of two courses (Table 12.7). Course
one is given on days 1 and 2 after hospital
admission; course two is given on day 8 and
hospital administration is not mandatory. The
next cycle is started a week after the day 8.
Complete blood count, platelet count, liver
and renal function tests and serum β-hCG are
performed before each cycle. Two to three
cycles of maintenance chemotherapy is given
after β-hCG comes to normal.
Table 12.6: MAC III regime
Days Drugs
1, 3, 5, 7 Methotrexate 1.0 mg/Kg IM
2, 4, 6, 8 Folinic acid 0.1 mg/Kg IM
1-5 Act D 12 ug/Kg IV
Cyclophosphamide 3 mg/kg IV
Cycles repeated every 14-21 days
Table 12.7: EMA-CO regime
Course 1: (EMA)
2
Day 1 Etoposide 100 mg/m IV infusion in 200 ml
Normal saline over 30 minutes
Actinomycin-D 0.5 mg IV bolus
2
Methotrexate 100 mg/m IV bolus followed
2
by 200 mg/m square IV infusion over 12
hours.
2
Day 2 Etoposide 100 mg/m IV infusion in 200ml
Normal saline over 30 minutes
Actinomycin-D 0.5 mg IV bolus
Folinic Acid 15 mg IM every 12 H for 4 doses
beginning 24 hr after starting Methotrexate
Course 2: (CO)
2
Day 8 Vincristine 1.0 mg/m IV bolus
2
Cyclophosphamide 600 mg/m IV infusion in
normal saline
Next cycle started 1 week after day 8
Some of the patients with high risk disease
fail to achieve complete remission with EMA-
CO. These patients can be salvaged with a
regimen containing cisplatin or carboplatin in
combination with other agents. One such
Gestational Trophoblastic Neoplasia 149
regime is EMA-CE. Etoposide, Methotrexate,
Act-D are administered as in day 1 to day 2 of
EMA-CO regime and on day 8 cisplatin
100 mg/m 2 infused with normal saline for
2 hours. Etoposide 100 mg/m2 is administered
in saline infusion, 250 ml over 30 minutes.
Radiation therapy has limited role in the
management of metastatic GTN. Whole brain
radiation therapy in combination with
systemic chemotherapy has been successful in
patients presenting with brain involvement.39,
40
30-36 Gy is given simultaneously with the
initiation of chemotherapy.
The use of radiation therapy for liver
metastasis is controversial. Hammond et al
proposed a dose 20 Gy over 10 days to reduce
the risk of liver hemorrhage.41
Surgery may play an important role in the
cure of patients with recurrent or resistant
metastatic GTN. Hammond et al demons-
trated that hysterectomy performed
coincident with the initiation of systemic
chemotherapy significantly reduced the
duration of hospitalization and the amount of
chemotherapy needed to achieve remission.42
Still hysterectomy is usually reserved for low
risk metastatic GTN only. Although there was
a suggestion of benefit in patients with poor
prognosis disease who underwent initial
hysterectomy, the differences did not appear
to be significant when compared with similar
patients who did not undergo hysterectomy
and it is unclear whether the procedure has
an influence on their survival.40
Thoracotomy may be indicated in the
patients with persistent solitary pulmonary
metastases limited to one lung despite prior
chemotherapy without any evidence of
metastatic disease elsewhere in the body.
However, the patient must be in a good
surgical risk, the primary malignancy must be
controlled and the urinary hCG below 1000
mIU/ml. Wedge resection is the surgical
150 A Practical Approach to Gynecologic Oncology
procedure of choice so as to preserve as much
normal pulmonary tissue as possible.
Successful surgical extirpation of all
residual tumors should result in the β-hCG
levels returning to normal within 4 to 10 days
after the operation.42 Depending on the β-hCG
level after thoracotomy additional courses of
chemotherapy should be given to achieve
complete remission.
Craniotomy is rarely of value in the
management of tumor in the brain but may
be necessary in emergency situations caused
by intracerebral hemorrhage.
Patients with “High Risk” metastatic
disease are monitored with weekly measure-
ment of β-hCG titers until they are normal
for 3 consecutive weeks and then monthly
until they are normal for 24 months with
appropriate contraception.
SUBSEQUENT PREGNANCIES
Patients with complete molar pregnancies can
anticipate normal reproduction in the future.43
Limited data are available concerning the
subsequent pregnancy experience in patients
with partial mole. Ultrasonography during the
first trimester of any later pregnancy is
recommended to confirm normal fetal deve-
lopment. Furthermore, the placenta or
chorionic tissues from subsequent pregnancies
should undergo pathologic review. β-hCG
levels should be measured six weeks after the
completion of any future pregnancy to exclude
occult trophoblastic disease.
Patients with GTN who are successfully
managed with chemotherapy can also expect
normal reproduction in the future.44,45 The
growth and development of these children
were also evaluated through adolescence and
proved to be normal. Although chemo-
therapeutic agents are known to have
teratogenic and mutagenic potential, the
frequency of congenital malformation in
subsequent pregnancies was not increased.
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2. Bulmer JW, Johnson PM. Antigen Expression
by trophoblast populations in human placenta
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Placenta 1985;6:127.
3. Sunderland CA, Redman WG, Stirrat GM.
Characterization and localization of HLA
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4. Szulman AE. The A, B and H Blood-group
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5. Kurman RJ, Young RN, Norris HJ. Immuno-
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6. Pijnenberg R, Bland JM, Robertson WB, et al.
The pattern of interstitial trophoblast invasion
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7. Covone AE, Johnson PM, Mutton D, et al.
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8. Kajii T, Ohama K. Androgenic origin of
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9. Yamashita K, et al. Human lymphocytic
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10. Pattilo RA, et al. Genesis of 46 XY Hydatidi-
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11. Szulman AE, Surti U. The syndromes of hydati-
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12. Doshi N, Surti U, Szulman AE. Morpholologic
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13. Finkler NJ, Berkowitz RS, et al. Clinical
experience with placental site trophoblastic
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14. Bagshawe KD. Risk and prognostic factors in
trophoblastic neoplasia. Cancer 1976;38:
1373-85.
15. Berkowitz RS, Cramer DW, Bernstein MR,
Cassells S, Driscoll SG, Goldstein DG. Risk
factors for complete molar pregnancy from a
case control study. Am J Obstet Gynecol
1985;152:1016.
16. Goldstein DP, Berkowitz RS, Bernstein MR.
Management of molar pregnancy. J Reprod
Med 1981;26:208.
17. Goldstein DP, Berkowitz RS. Gestational
Trophoblastic Neoplasms-Clinical Principles of
Diagnosis and Management. Philadelphia:WB
Saunders Co, 1982;301.
18. Kim DS, Moon H, Kim KT, Moon YJ. Hwang
YY. Effects of prophylactic chemotherapy for
persistent trophoblastic disease in women with
complete hydatidiform mole. Obstet Gynecol
1986;67:690-94.
19. Berkowitz RS, Goldstein DP. Pathogenesis of
gestational trophoblastic neoplasms. Pathobiol
Ann 1981;11:391-411.
20. Goldstein DP. Prevention of gestational
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in molar pregnancies. Obstet Gynecol 1974;43:
475-79.
21. Berkowitz RS, et al. Cerebrospinal fluid human
chorionic gonadotropin levels in normal preg-
nancy and choriocarcinoma surg. Gynecol
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22. Duboc-Lissoir J, et al. Metastatic gestational
trophoblastic disease: A comparison of prog-
nostic classification. Gynecol Oncol 1992;45:
40-45.
23. Mortakis AE, Broga CA. “Poor Prognosis”
metastatic gestational trophoblastic disease:
The prognostic significance of the scoring
system in predicting chemotherapy failure.
Obstet Gynaecol 1990;76:272-77.
24. Bagshawe KD. Risk and prognostic factors in
troploblastic neoplasia. Cancer 1976;192:
1373.
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25. World Health Organisation Scientific Group on
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trophoblastic disease, Geneva (692): Technical
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26. Wong LC, et al. Methotrexate with citrovorum
factor rescue in gestational trophoblastic
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1985;152:59.
27. Hammond CB, Parker TR. Diagnosis and
treatment of trophoblastic disease. Obstet
Gynecol 1970;35:132.
28. Goldstein DP, et al . Methotrexate with citro-
vorum factor rescue for gestational tropho-
blastic neoplasm. Obstet Gynecol 1978;51:93.
29. Holmesley, et al. Weekly Methotrexate for non-
metastatic gestational trophoblastic disease
(Abstract). Gynecol Oncol 1987;26:411.
30. Hammond CB, et al. Primary chemotherapy for
non-metastatic gestational trophoblastic
neoplasms. Am J Obstet Gynecol 1967;98:81.
31. Petrilli ES, et al. Single dose actinomycin-D
treatment for non-metastatic gestational
trophoblastic disease. Cancer 1987;60:2173.
32. Berkowitz RS, et al. Methotrexate with
citrovorum factor rescue for non-metastatic
gestational trophoblastic neoplasms. Obstet
Gynaecol 1979;54:725-28.
33. Osathanondh R, et al. Actinomycin-D as the
primary agent for gestational trophoblastic
disease. Cancer 1975;36:863.
34. Berkowitz RS, Goldstein DP, Bernstein MR. Ten
year’s experience with methotrexate and folinic
acid as primary therapy for gestational
trophoblastic disease. Gynecol Oncol 1986;
23: 111.
35. Bagshawe KD. Treatment of high risk chorio-
carcinoma. J Reprod Med 1984;29:813.
36. Newlands ES, Bagshawe KD. Anti-tumor
activity of the epipodophyllin derivative
VP16-213 (Etoposide:NSC-141540) in gesta-
tional choriocarcinoma. Eur J Cancer 1980;
16:401.
37. Surwit EA. Management of high risk gesta-
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1987;32:657-62.
38. Wong LC, et al. Primary oral etoposide therapy
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Obstet Gynaecol 1985;152:59.
152 A Practical Approach to Gynecologic Oncology
39. Weed JC Jr, Hammond CB. Cerebral metastatic
choriocarcinoma: Intensive therapy and
prognosis. Obstet Gynecol 1980;55:89.
40. Hammond CB, Soper JJ. Poor Prognosis,
metastatic choriocarcinoma: Intensive therapy
and prognosis. Obstet Gynecol 1984;27:228.
41. Tomodal Y, et al. Surgical indications for resec-
tion in pulmonary metastasis of choriocar-
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42. Hammond CB, et al. The role of operation in
the current therapy of gestational tropho-
blastic disease. Am J Obstet Gynaecol 1980; 136:
844-58.
43. Berkowitz RS, et al. Reproductive experience
after complete and partial molar pregnancy and
gestational trophoblastic tumors. J Reprod Med
1991:36:3-8.
44. Walden PAM, Bagshaw KD. Reproductive
performance of women successfully treated for
gestational trophoblastic tumors. Am J Obstet
Gynecol 1978;125:1108-14.
45. Song H-Z, et al. Pregnancy outcomes after
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J Obstet Gynecol 1988;158:538-45.
 13 Epithelial Ovarian Cancer
INTRODUCTION
Ovarian cancer may occur at any age and it is
said that ovaries may become too old to
function but never too old to produce tumors.
Neoplasms with a great diversity of histologic
appearance and biologic behavior can be seen
in the ovary. Epithelial cancers are most
common among the histologic varieties and
they account for 4 percent of all cancers among
women worldwide. More than 80 percent of
the ovarian tumors registered in the hospital-
based registries in Mumbai, Bangalore and
Chennai are of epithelial origin.1 In spite of
recent advances in the diagnostic and
therapeutic methods, the overall survival for
patients with epithelial ovarian cancer has not
changed significantly over the past several
decades. This is because more than 70 percent
of such cancers are diagnosed after the disease
has already spread beyond ovaries.
EPIDEMIOLOGY AND RISK FACTORS
There is a regional variation of the incidence
of the disease all over the world though it is
not as dramatic as cervical cancer. Japan has
one of the lowest incidences of ovarian
cancers whereas the incidence is higher
among women of the Nordic countries. 2
United States Whites have a higher incidence
compared to the Black population. The age-
standardized incidences of ovarian cancers in
different population-based registries in India
• Anila S Kapadia • K Uma Devi
vary from 3.6-9.6 per 100,000 women (Table
13.1). In all these registries ovarian cancer is
the second leading cancer of the female genital
tract next to cancer cervix. According to the
hospital-based cancer registry data ovarian
cancer ranks fifth among all the cancers in
females in India.1
Table 13.1: Age-standardized incidence
(per 100,000) of ovarian cancer from
different Indian registries
Registry site Age-standardized incidence
(per 100,000)
Ahmedabad 3.6
Bangalore 5.1
Chennai 5.5
Mumbai 8.0
Nagpur 9.6
Epithelial cancers of ovary are primarily
seen in women older than 50 years and the
incidence increases with age till the age of 75
years. In the age group of 40-50 years, the
incidence is 15.7/100,000. The rate doubles
after the age of 50 to about 35/100,000. Highest
incidence rates are found between 65 - 85 years
of age (54/100,000).
High gravidity, hysterectomy, female
sterilization and oral contraceptive use are
associated with reduced risk of ovarian cancer.
Infertility and late age at menopause are
associated with increased risk. Though these
factors are related to each other, each of them
has been found to be independently associated
154 A Practical Approach to Gynecologic Oncology
with ovarian cancer risk after adjusting for the
effects of the other factors.
Menstrual Factors
Parazzini et al 3 studied the influence of
various menstrual factors on the risk of
epithelial ovarian cancer. They reported that
the risk increased with later age of menopause
and with early menarche. Booth et al 4
observed that women having their meno-
pause at the age of 50 years or later had nearly
3 times the risk of women who were
menopausal before the age of 45 years. They
did not find any relation to the age at
menarche.
Reproductive Factors
Multiparity is associated with a decreased risk
of ovarian cancer. The risk of ovarian cancer
is 30-60 percent less in ever-pregnant women
as compared to nulligravid women. Each
additional pregnancy lowers a woman’s risk
by approximate 10-15 percent.5 A case-control
study has observed that women having their
first pregnancy after the age of 35 years had
significantly higher risk of ovarian cancer
(Relative Risk 4.1) than women with first
pregnancy before the age of 20 years.4 Some
reduction in risk has been noted in women
who have breastfed, but there is no evidence
that the protective effect increases with the
duration of breastfeeding.
Infertility
Infertile women have been noted to have a
higher risk of ovarian cancer and one study
showed a six fold higher risk in women who
did not conceive even after unprotected
sexual intercourse for 10 or more years (when
compared to women without fertility pro-
blems).4 Whitemore and colleagues6 found
higher incidence of ovarian cancer in women
who have undergone ovulation induction as
compared to women who have not used
fertility agents.
Oral Contraception
Use of oral contraceptive pills is associated
with significant reduction of risk. The earlier
the age of first use and the longer the duration
of use the lesser is the risk. The risk reduction
is estimated to be in the range of 30 to
60 percent depending upon duration of use.7
Tubal Ligation
Hankinson and colleagues found strong
inverse correlation between tubal ligation and
the subsequent development of ovarian
cancer. 8 There is some evidence that
hysterectomy gives a protective effect even
after one or both ovaries are left behind.
Dietary Factors
The increased dietary fat intake noted in
industrialized societies is associated with an
increased incidence of ovarian cancer,
compared to that seen in population with
lower per capita fat consumption.9 Some
studies that looked into the role of dietary fat
as risk factor for ovarian cancer have been
inconclusive and the association of other
dietary factors to ovarian cancer is not at
present considered well-established. Coffee
use has been debated as a risk factor.10
Chemical Carcinogens
Use of asbestos in talc as a causative factor is
also conflicting. Woodruff et al suggested their
hypothesis of migration of chemical
carcinogens from vagina to the pelvic
peritoneum.11 Booth et al in their case-control
study did not find any consistent trend of
increasing risk with increasing frequency of
talc use in the genital area.4

Hereditary Factors
Familial ovarian cancers are rare and account
for less than 5 percent of all epithelial ovarian
cancers. The estimated lifetime risk of any
woman developing ovarian cancer is 1 in 55
(1.8%). Women who have one first-degree
relative with ovarian cancer have 4.5 times
(8%) lifetime risk of developing the same
cancer. The lifetime risk is much higher (55%)
if there are two or more first-degree relatives
affected by ovarian cancer. These facts
establish the familial inheritance of epithelial
ovarian cancer as an autosomal dominant
disease with variable penetrance. Three pat-
terns of hereditary ovarian cancer syndromes
are found: site specific ovarian cancer synd-
rome; breast/ovarian cancer syndrome;
hereditary non-polyposis colorectal cancer
occurring primarily with endometrial
carcinoma but also with ovarian cancer (Lynch
syndrome II).
ETIOPATHOGENESIS
Based on the observations of the risk factors
of ovarian cancers a few theories have been
postulated to explain the origin of the epi-
thelial cancers.
Incessant Ovulation
Fathalla postulated that inhibition of ovula-
tion, as induced by pregnancy and oral
contraceptives is the factor that protects
against ovarian cancer.12 Tubal ligation and
hysterectomy induce premature ovarian
failure in some women due to compromised
blood flow and thus reduce the risk. The
epithelial lining of the ovary may be sensitive
to the constant trauma of ‘incessant ovulation’,
which in turn can act as a promoting factor in
the carcinogenic process. The proliferation of
the epithelium associated with reparative
process can stimulate mutations. Therefore the
greater the total number of ovulatory cycles
Epithelial Ovarian Cancer 155
in a woman’s lifetime, the greater is the risk of
developing epithelial ovarian cancer. Further
observation and study of this interesting
hypothesis is necessary.
Genetic Alterations
Cytogenetic studies of ovarian carcinoma have
identified complex aneuploid karyotypes with
numerous structural abnormalities most
commonly affecting chromosomes 1, 3, 6, 11,
17, 19.13 The most frequently observed onco-
gene abnormality reported to date is amplifi-
cation or over expression of HER-2/neu that
is present in one-third of invasive epithelial
ovarian cancers. Mutation of p53 gene is the
most frequent genetic change to be described
in epithelial ovarian cancers.14
BRCA-1, the breast cancer susceptibility
gene is located on chromosome 17q12-21.
Inheritance of BRCA-1 mutation will predis-
pose some women to ovarian cancer as well.
An analysis of the 132 breast/ovarian cancer
families (with no breast cancer in males) of the
Gilda Radner Familial Ovarian Cancer registry
demonstrated that 88 percent of the families
were linked to the BRCA-1 gene. Out of the
families of the same registry, with three or
more cases of ovarian cancer and no breast
cancer below the age of 50 years (fitting into
the site-specific ovarian cancer category), 78
percent were linked to the BRCA-1 gene.15
Easton estimated that for women with BRCA-
1 mutation the lifetime risk of developing
ovarian cancer is 63 percent by age 70.16
Clonal Origin
The observation of same allelic deletions,
X-chromosome inactivations and p53 gene
mutations in tissues from the cancers of the
ovaries and from the multiple sites of
metastases led Jacobs et al to conclude that
ovarian cancers have unifocal or monoclonal
origins.17 The practical significance of this
finding is that the prophylactic oophorectomy
156 A Practical Approach to Gynecologic Oncology
would not be effective if the origins of ovarian
cancers were from polyclonal peritoneal meso-
thelioma.
SCREENING FOR EPITHELIAL
OVARIAN CANCER
The 5 years survival rate for stage-I epithelial
ovarian carcinoma is approximately 85-90
percent, compared to that, the 5 years survival
for stage-III is less than 20 percent. So there is
a theoretical probability that if a stage shift of
ovarian cancer can be achieved through some
form of screening, the mortality from the
disease can be reduced. Though there are some
evidences to suggest that there may be
premalignant precursors in certain ovarian
cancers, the natural history of such precursors
is still not well known. Unlike cervical cancer
there is still no efficient test to detect the
disease at the precursor stage. The effective-
ness of any screening program is evaluated
by its capability to reduce mortality from the
disease and also by the program cost-effective-
ness. Randomized clinical trials designed to
determine the impact of ovarian cancer scree-
ning on mortality are currently in progress.
Initial results may be encouraging but not yet
convincing enough to recommend ovarian
cancer screening for the general population.
Screening may be justified only in the high-
risk group of women having strong family
history of ovarian or breast cancer (as
discussed before), though the survival benefit
of such a strategy is yet to be established.
The details of the screening methods are as
follows.
Clinical Pelvic Examination
Routine pelvic bimanual examination has been
recommended in conjunction with cervical
screening with the objective that asymp-
tomatic ovarian masses can be picked up. The
effectiveness of this examination in terms of
disease pick up rate or improvement of
survival from the disease is not yet proved.
CA-125
The biochemical marker that has been most
thoroughly investigated in ovarian cancer is
the CA-125 antigen. CA-125 is a high
molecular weight glycoprotein recognized by
the OC-125 monoclonal antibody that has
established value in preoperative diagnosis
and monitoring of ovarian cancer.
Serum levels of CA-125 are elevated (grea-
ter than 35 IU/ml) in more than 85 percent of
women with clinically apparent epithelial
ovarian cancer. There is a definite correlation
with stage. Serum levels are elevated in more
than 90 percent of women with FIGO stage-II,
III and IV disease but only in 50 percent of
stage-I disease.18
CA-125 is also elevated in some benign
conditions and other cancers like breast, lung,
pancreas and colorectal cancers.19 The benign
conditions that can cause elevated levels of
CA-125 are pregnancy, menstruation, endo-
metriosis, pelvic inflammatory disease
(tuberculosis), hepatic disease (cirrhosis of
liver) and fibroid uterus.
Several studies have evaluated CA-125
estimation as the primary screening test. In the
Stockholm study, 5500 apparently healthy
women over the age of 40 had annual serum
CA-125 estimation.20 Those with elevated
levels were followed up for a median duration
of 35 months by repeat CA-125 estimation,
clinical examination and ultrasonography. If
the CA-125 level doubled or was more than
95 IU/ml or if an adnexal mass was detected
on ultrasound or pelvic examination, the
patient underwent laparotomy. Elevated CA-
125 levels were found in 175 women and
among them 6 ovarian cancers were detected
and only 2 of them were in stage-IA. Ovarian
cancer was detected in 3 women with normal
CA-125 levels. Data from such studies prove

that CA-125 has a sensitivity of 70-80 percent
at 1 year after screening. The high false
positivity of the test will result in unnecessary
investigations and surgical interventions.
Several major prospective studies
investigated CA-125 levels as an initial test to
screen for ovarian cancer. Jacob et al screened
22,000 healthy postmenopausal women (>45
years of age) with a serum CA-125 measure-
ment.21 Those patients with values greater than
or equal to 30 IU/ml were recalled for abdomi-
nal-pelvic ultrasound.
Patients with an abnormal ultrasound were
explored surgically. In this series, 41 of 22,000
women underwent surgical exploration and
11 ovarian cancers were found. This protocol
achieved specificity of 99.9 percent and
positive predictive value of about 27 percent.
Multiple tumor markers such as CA-15.3,
TAG-72, M-CSF (Macrophage colony stimula-
ting factor), OVX1, UGF (urinary gonado-
tropin fragment), NBK 70, etc. have been
investigated. Some of them have shown
promising results for their consistent associa-
tion with all histologic types of ovarian tumor
(NBK 70) and ability to detect small volume
early stage disease (UGF).
Ultrasonography
A pelvic mass arising from the ovaries having
any of the following features should be
suspected to be malignant:
• Complex heterogeneous appearance sug-
gesting both solid and cystic components
• Thick septa
• Surface papillations
• Bilateral tumors
Higgins et al were the first to demonstrate
the safety and feasibility of transvaginal
sonography (TVS) in the assessment of ovarian
size or morphology and currently this is the
most effective method available for ovarian
cancer screening.22 An ovarian volume of
Epithelial Ovarian Cancer 157
20 cm3 or greater in premenopausal women
and of 10 cm3 or greater in postmenopausal
women is considered abnormal.
The introduction of the color Doppler blood
flow imaging is an important complement to
the transvaginal sonography. The process of
neovascularization in ovarian carcinogenesis
is associated with development of low resis-
tance blood flow pattern, which helps in
distinguishing benign from malignant. The
sensitivity of transvaginal ultrasound for
detecting ovarian cancers is reported to be
nearly 100 percent. The technique still suffers
from lack of specificity.
Weiner et al demonstrated low vascular
resistance (high blood flow: pulsatility index
< 1) in 15 of 16 ovarian cancers while 35 of 36
benign ovarian tumors had normal vascular
flow pattern.23 This data is very encouraging,
but color Doppler ultrasonography is expen-
sive, technically difficult and time consuming
to be used as primary screening tool for
ovarian cancer.
Multimodal Approach
Using the two tests sequentially can reduce
the false-positive rates of CA-125 and ultra-
sonography. In a randomized trial in United
Kingdom 22000 women aged 45 years or more
were assigned to a screening group (N=10958)
and a control group of routine pelvic
examination (N=10977).24 The screening group
had annual measurement of CA-125 for
consecutive 3 years, pelvic ultrasonography
if the CA-125 was 30 IU/ml or higher and
referral to a gynecologist if the ovarian volume
was 8.8 ml or more on ultrasonography.
CA-125 was elevated in 468 women and out
of them 29 were referred for surgery. Cancer
was detected in 6 of them and 23 had false-
positive results leading to unnecessary laparo-
tomies. Ovarian cancer was detected in 10
additional women in the screened group
during a 7-year follow up period. In the
158 A Practical Approach to Gynecologic Oncology
control group 20 cancers were detected. In the
screened group the median survival of the
cancer cases was 72.9 months, significantly
higher as compared to the median survival in
the control group (41.8 months). However, the
number of deaths were not significantly
different among the two study arms. This trial
and similar other trials proved the feasibility
of using CA-125 and ultrasonography sequen-
tially to detect ovarian cancers in the asymp-
tomatic population. Larger trials are required
to establish a distinct survival advantage.
Management of Women at
High-risk of Ovarian Cancer
The definition of high-risk women for ovarian
cancer is based on family history. Any of the
following criteria should be fulfilled to
designate a family as high risk:
• Two or more women with ovarian cancer
who are first-degree relatives
• One woman with ovarian cancer and one
woman with breast cancer diagnosed
under 50 years who are first-degree
relatives
• One woman with ovarian cancer and two
women with breast cancer diagnosed
before 60 years of age who are first-degree
relatives
• Three women with colorectal cancer with
at least one case diagnosed before 50
years, one case of ovarian cancer and all
these women are first degree relatives.
Women who appear to be high risk for
ovarian or breast cancer should undergo
genetic counseling and if the risk appears to
be substantial, they may be offered genetic
testing for BRCA-1 and BRCA-2 mutations.
Women with BRCA mutations who wish to
preserve fertility, may be offered oral
contraceptives if they are not interested in
immediate pregnancy. Screening for ovarian
cancer should be confined to those women
who are at a high risk, either because they
belong to families fulfilling any of the above-
mentioned criteria or are known to have
BRCA-1/BRCA-2 mutations or both. The
protocol for screening of these high-risk
women is annual testing with both CA-125
and TVS.
Women who have finished childbearing can
undergo prophylactic bilateral salpingo-
oophorectomy. They should be counselled
that this operation does not offer absolute
protection because peritoneal carcinomatosis
may still occur.
PATHOLOGY
The most useful classification of ovarian
neoplasms is based on the presumed cell of
origin. Thus the most widely used contem-
porary classification (developed and updated
by World Health Organization and Internatio-
nal Federation of Gynecology and Obstetrics)
is histogenetic. In this scheme, there are three
major categories: epithelial tumors; germ cell
tumors and sex cord stromal tumors. The
present chapter deals with the commonest
variety of them, i.e. epithelial tumors.
Epithelial tumors arise from the coelomic
epithelium or mesothelium, covering the
ovary. The histologic patterns of this category
of tumors resemble the epithelia of different
parts of the genital tract. The appearance of
serous tumors is similar to tubal epithelium,
endometrioid tumors to the endometrium and
mucinous tumors to the endocervical epithe-
lium. Also included in this group are the clear
cell tumors, transitional cell tumors and
undifferentiated carcinoma.
Each of these varieties of tumors except
undifferentiated carcinoma is divided into
benign, borderline and malignant types. The
borderline tumors have low malignant
potential and rarely spread beyond the
ovaries. They are more commonly seen in
premenopausal women and have very good
prognosis.

The serous epithelial tumors are the
commonest variety of ovarian tumors compri-
sing nearly one-third of all. Half of these
tomours are benign. The benign tumors are
bilateral in 15-20 percent cases and comprise
of unilocular or multilocular cysts with focal
papillary projections. The cysts are lined by
cuboidal epithelial cells often with cilia
(similar to the epithelium of fallopian tube).
In the borderline type of serous epithelial
tumors the cysts and papillae are lined by
stratified columnar epithelium of varying
thickness without any stromal invasion.
Malignant serous epithelial tumors account for
40-50 percent of all ovarian cancers. Nearly
half of such tumors are bilateral. On gross
appearance the tumor may have cystic areas
but the solid components are predominant.
The microscopic appearance may vary from
fine papillae comprising of well-differentiated
cells to solid sheets of anaplastic cells.
The mucinous tumors are the second most
common variety (12-15% of all ovarian
tumors) and majority of them (75%) are
benign. Grossly the tumors are multiloculated
and contain mucinous material. Microscopi-
cally the cysts are lined by a single layer of
columnar cells that have the nuclei at the base
and the mucin droplets at the apex. The
borderline tumors may have stratification of
cell layers with mild to moderate nuclear
atypia without any invasion of the stroma. The
malignant mucinous tumors constitute
10 percent of all ovarian cancers and are
bilateral in less than 10 percent cases.
Endometrioid tumors are mostly malignant,
often bilateral and are frequently associated
with ovarian or pelvic endometriosis.
Most of the clear cell tumors are malignant
and usually affect perimenopausal and
postmenopausal women. Grossly the tumors
are solid with few cystic areas. Microscopically
the ‘hobnail cells’ are distinctive of clear cell
carcinoma. These cells have highly pleomor-
Epithelial Ovarian Cancer 159
phic nuclei surrounded by glycogen rich clear
cytoplasm.
Benign transitional cell (Brenner) tumors are
not so common and are often associated with
other epithelial tumors, more frequently
mucinous tumors. The tumors are solid, firm
and have a whorled appearance on cut surface.
Microscopically, they are composed of nests
of transitional epithelium scattered in a fibrous
stroma. Transitional cell carcinoma may
coexist with benign transitional tumor or may
have the malignant component alone.
About 10-15 percent of the ovarian cancers
are undifferentiated or have minor areas of
differentiation. Such tumors often have
extensive peritoneal metastasis by the time
they are detected.
Histologic grade of tumor has been proved
to predict both relapse free and overall
survival. The criteria for grading are usually
different for different types of epithelial
tumors. Serous tumors with mild to moderate
atypia or less than 10 mitoses per 10 high
power field are designated as low grade. High
grade serous tumors have severe atypia or
more than 10 mitoses per 10 high power fields.
Gradation of mucinous cancers does not
correlate well with the prognosis. Endome-
trioid cancers are graded in the same way as
cancers of endometrium. If the proportion of
solid tumor area is less than 5 percent the
tumor is graded 1. If the percentage is between
5-50 percent the tumor is grade 2 and if it
exceeds 50 percent the tumor is graded as
grade 3. Clear cell, transitional cell and
undifferentiated cancers are always conside-
red as high grade neoplasms.
SYMPTOMS AND SIGNS
Ovarian cancer is often asymptomatic at the
early stage. Vague abdominal discomfort,
dyspepsia and other mild digestive disturban-
ces may be present for a long time and these
160 A Practical Approach to Gynecologic Oncology
symptoms are usually overlooked as indiges-
tion. Thus the ovarian cancer ‘nurtures in the
sea of antacids’. Heaviness of lower abdomen
and enlargement of abdomen occur when
tumor reaches a diameter of 15 cm and begins
to rise out of pelvis. Gross enlargement of
abdomen and pressure symptoms like urinary
symptoms and constipation often occur with
gross ascitis and huge pelvic tumor. Weight
loss is frequently seen because of nausea and
anorexia. Rare paraneoplastic manifestations
like migratory thrombophlebitis, dermato-
myositis and cerebellar degeneration may
occur.
Bladder should be emptied before pelvic
examination. Ascites may be present. A mass
may be palpable in upper abdomen because
of deposits in the omentum. The mass arising
from pelvis may be palpable on abdominal
examination, may be of varying sizes and
with restricted mobility. Sometimes the mass
may be felt in any of the iliac fossa.
On vaginal examination, separate adnexal
mass may be palpable. At times it is adherent
to the uterus and the uterus may not be
palpated separate from the mass. The mass is
often fixed to the lateral pelvic walls. Nodula-
rity may be felt in the pouch of Douglas indica-
ting disseminated disease.
Rectal examination is a must, as it helps to
assess the posterior uterine surface, the utero-
sacral ligaments, the pouch of Douglas and
the parametrium.
If the tumor is bilateral and mobile, breast
and gastrointestinal tract should be investi-
gated, as the tumor may be metastatic. Pedal
edema and pleural effusions may be present.
PATTERNS OF SPREAD
The origin of epithelial ovarian carcinoma is
obscure. Stromal inclusions are formed by the
invaginations of germinal epithelium during
ovulatory processes and these inclusions may
be the precursor lesions. Ovarian carcinoma
is thought to arise within the substance of the
ovary, beneath the surface capsule. The spread
patterns are retrospective constructs from
surgical and autopsy observations. It can
spread via direct extension, intraperitoneal
dissemination, retroperitoneal dissemination
or distant metastases.
Direct Extension
Once the cancer cells penetrate the ovarian
capsule, spread can occur by direct extension
to surrounding organs such as the fallopian
tube, uterus, bladder, cul-de-sac peritoneum,
or rectosigmoid colon. Direct extension is not
a prerequisite for other spread patterns but
usually occurs simultaneously with them.
Intraperitoneal Dissemination
Exfoliated cancer cells can implant and grow
on visceral and peritoneal surfaces. This
process may occur in the absence of capsular
rupture. Some investigators reported positive
peritoneal cytology without gross capsular
penetration or rupture. Perhaps the most
common and widely recognized spread
pattern is intraperitoneal dissemination.
Retroperitoneal Dissemination
The tendency of ovarian cancer to metastasize
to retroperitoneal lymph nodes has been noted
for many years. Autopsy studies by several
authors have demonstrated lymph node
metastases in 65-80 percent of cases. Burghardt
et al reported positive pelvic lymph nodes in
61.8 percent of the cases and para-aortic lymph
nodes in 41.4 percent of cases. They observed
that the para-aortic lymph nodes were
involved only in the presence of pelvic lymph
node metastases.25
Lymphatic drainage of the ovaries is
primarily to the common iliac and para-aortic
lymph nodes. When these nodes are involved,

tumor emboli can pass in a retrograde fashion
to the external iliac and inguinal lymph nodes.
Tumor emboli can also enter lymphatic chan-
nels that anastomose with uterine lymphatics
in the broad ligaments, leading to the involve-
ment of internal iliac and obturator lymph
nodes. The tumor emboli may reach the
inguinal nodes via the round ligament lym-
phatic network. Supraclavicular, axillary and
cervical lymph node metastases may occur
rarely.
Distant Metastases
It occurs usually in advanced disease process,
rarely in the absence of advanced intra-
peritoneal disease. The most common sites of
distant metastases are the liver (34%) and the
lung (27%). Tumor implants on the liver
capsule can directly invade the liver pare-
nchyma. Tumor that involves the dia-
phragmatic lymphatics can invade the pleural
space. Other distant metastatic sites include
bone, skin and brain.
STAGING OF MALIGNANT OVARIAN
TUMORS
Ovarian cancers are staged based on the
findings of systematic surgical exploration of
the abdominal cavity combined with the
results of preoperative investigations to rule
out extra-abdominal metastases. International
Federation of Gynecology and Obstetrics
(FIGO) introduced the current surgical staging
in 1987 (Table 13.2). The rationales for surgical
staging are as follows:
• When a rigorous staging laparotomy is
performed, a substantial number of patients
initially felt to have localized disease are
upstaged.
• Some investigators have reported that
31 percent of women were upstaged
following surgical staging and 77 percent
Epithelial Ovarian Cancer 161
of those upstaged patient actually had
stage-III disease.26
The reported survival rates for surgically
staged stage-I cancers are substantially higher
compared to the survival rates reported
earlier based on clinical staging. This is
because surgical staging reflects the true
disease status more accurately.
Table 13.2: FIGO surgical staging of ovarian cancer
(Am J Obstet Gynecol 1987; 156: 263)
Stage Description
Stage-I Growth limited to the ovaries.
Stage-IA Growth limited to one ovary; no ascites
present containing malignant cells; no
tumor on the external surfaces; cap-
sule intact.
Stage-IB Growth limited to both ovaries; no as-
cites present containing malignant
cells; no tumor on the external sur-
faces; capsules intact.
Stage-IC* Tumor either stage IA or stage IB but
with tumor on the surface of one or both
ovaries; or with capsule ruptured; or
with ascites present containing malig-
nant cells or with positive peritoneal
washings.
Stage-II Growth involving one or both ovaries
with pelvic extension.
Stage-IIA Extension and/or metastases to the
uterus and/or tubes.
Stage-IIB Extension to other pelvic tissues.
Stage-IIC* Tumor either stage-IIA or stage-IIB but
with tumor on the surface of one or both
ovaries; or with capsule(s) ruptured; or
with ascites present containing malig-
nant cells or with positive peritoneal
washings.
Stage-III Tumor involving one or both ovaries
with peritoneal implants outside the
pelvis and/or positive retroperitoneal or
inguinal nodes; superficial liver me-
tastasis equals stage-III; tumor is lim-
ited to the true pelvis but with histo-
logically verified malignant extension
to small bowel or omentum.
Contd...
162 A Practical Approach to Gynecologic Oncology
Contd...
Stage Description
Stage-IIIA Tumor grossly limited to the true
pelvis with negative nodes but with his-
tologically confirmed microscopic
seeding of abdominal peritoneal sur-
faces.
Stage-IIIB Tumor of one or both ovaries; histo-
logically confirmed implants of
abdominal peritoneal surfaces, none
exceeding 2 cm in diameter; nodes
negative.
Stage-IIIC Abdominal implants 2 cm in diameter
and/or positive retroperitoneal or
inguinal nodes.
Stage-IV Growth involving one or both ovaries
with distant metastasis; if pleural effu-
sion is present, there must be positive
cytologic test results to allot a case to
stage-IV; parenchymal liver metasta-
sis equals stage IV.
*The operative note should indicate whether rupture
of the capsule was (1) spontaneous or (2) caused by
the surgeon and whether the source of the malignant
cells detected was (1) peritoneal washings or
(2) ascites.
MANAGEMENT
The cornerstone of any scheme of manage-
ment for ovarian malignancy is surgery. Not
only surgery is the most effective treatment
but also it plays a primary role in establishing
the diagnosis and determining the extent of
the disease. The information obtained
following a thorough surgical exploration
forms the basis upon which adjuvant therapy
can most accurately be planned and prognosis
can be judged.
Principles of Surgical Management
Basic principles of surgical treatment are to
remove the primary lesion and all metastases
without putting patient’s life in jeopardy.
Comprehensive surgical staging with total
abdominal hysterectomy and bilateral
salpingo-oophorectomy should be done for
early stage ovarian cancer except those in
whom fertility preservation is to be conside-
red. The contralateral ovary should be
removed, as there is increased risk of develo-
ping carcinoma in the uninvolved ovary
especially in serous and endometrioid cancer.
Occult metastasis or primary ovarian cancer
may be present in the other ovary that may
not be detectable even in wedge biopsy.
The reasons for removal of the uterus are
as follows:
• Uterus may be involved by lymphatic
metastases
• There may be serosal implants
• Patients with ovarian cancer have a propen-
sity to develop subsequent müllerian
primaries
• It is easier to assess the pelvis on postopera-
tive follow up, when the uterus is absent,
• Estrogen replacement therapy is simplified
as progesterone need not be added
• The organ is dispensable when fertility is
not a consideration.
The uterus and the contralateral ovary may
be preserved in women willing to preserve
fertility with stage-IA disease without any of
the high-risk factors (Table 13.3).
Table 13.3: Prognostic factors for early
stage epithelial tumors
Risk factors High-risk features
Histologic type Clear cell/ undifferentiated
Histologic grade of High grade
tumor
Capsule Involved with surface
excrescences
Ascites Ascites present with
malignant cells in the fluid
Adhesions Dense adhesions
Tumor ploidy Aneuploid tumor

Removal of the uterus and the left over
ovary may be considered after childbearing
in these cases.
Surgical Procedures for Ovarian Cancer
Include the Following:
• Surgical staging for presumed localized
stage-I and II diseases.
• Primary optimal debulking surgery for
advanced stage-III and IV diseases.
• Interval debulking after primary chemo-
therapy in advanced stage disease.
• Secondary debulking for recurrent disease.
• Second look laparoscopy/laparotomy.
• Palliative surgery.
Primary Surgery for
Early Stage Ovarian Cancer
Staging procedure is most important for early
ovarian cancers especially when the disease
is at a first glance limited to one or both
ovaries. The steps of staging laparotomy are
as follows:
• An infraumbilical midline or paramedian
incision extended to 1-2 inches above the
umbilicus is must for adequate assessment
in patients whose preoperative evaluations
suggest probable diagnosis of ovarian
cancer. By chance, if a low transverse
incision is made, the rectus muscles should
be divided for proper exposure.
• Ascitic fluid, particularly from the pouch
of Douglas should be sent for cytology. In
absence of ascites, the abdominal washings
with normal saline are taken from the pouch
of Douglas, both paracolic gutters, under
surface of diaphragm and from the rest of
the abdominal cavity. A simple rubber
catheter attached to a 50 cc syringe can be
used to rinse the subdiaphragmatic surface
and collect the washings.
• Careful inspection and palpation of all
peritoneal surfaces including the under-
surface of diaphragm, the surface of liver,
Epithelial Ovarian Cancer 163
the small and large bowel, their mesente-
ries, stomach and omentum should be done.
Biopsies are taken from all suspicious areas
and also from the adhesions. Multiple
biopsies are taken from the parietal perito-
neum, peritoneum of the pouch of Douglas
and paracolic gutters even if there are no
visible tumors.
• In most patients with early epithelial ova-
rian cancer, bilateral salpingo-oophorec-
tomy and total hysterectomy should be
done along with complete removal of pelvic
disease. The infundibulopelvic ligament
and broad ligament should be resected
widely on affected side to ensure complete
removal of ovarian disease. The ureter
needs to be visualized prior to that.
• The omentum is lifted gently in cranial
direction exposing the attachment of
infracolic omentum to transverse colon. The
infracoloic omentum is resected from the
transverse colon close to its attachment.
• The retroperitoneal spaces should be explo-
red to evaluate the pelvic lymph nodes. Any
enlarged nodes should be removed and
pelvic lymphadenectomy is done. The
nodal involvement varies from 15 percent
for stage-I to 40 percent to 60 percent in
stage-III.
• The enlarged para-aortic lymph nodes
should be removed.
Cytoreductive Surgery for Advanced Cases
In 1968 Munnell’s introduced the term
“maximum surgical effort” and reported an
improved survival for patients who had
undergone complete surgical clearance of
disease in ovarian cancer.27
The advantages of surgical debulking of
tumor in a patient with advanced ovarian
cancer are as follows:
• Large tumors have necrotic areas with less
vascular supply where chemotherapy
drugs cannot reach effectively. Removal of
164 A Practical Approach to Gynecologic Oncology
bulk of the mass will enhance the delivery
of chemotherapy.
• The cells in a large tumor are in the resting
phase of the growth cycle and are resistant
to chemotherapy.
• Immunologic competence of the patient is
enhanced leading to improved responsi-
veness to chemotherapy.
• Relieves intestinal obstruction and impro-
ves gastrointestinal function resulting in
improved nutritional status.
• By removing large tumor and omental cake
the amount of ascites will decrease and at
times disappear.
Primary optimal cytoreductive surgery in
ovarian carcinoma of any stage includes total
abdominal hysterectomy with bilateral
salpingo-oophorectomy, infracolic omen-
tectomy, pelvic and para-aortic lymphade-
nectomy with no residual disease or residual
disease measuring less than 1 cm. Survival is
significantly better only if the initial
cytoreduction leaves tumors of less than 1-2
cm in diameter. Patients who have cytoreduc-
tion that leaves behind residual tumors of
more than 2 cm diameter do not have any
survival advantage. That is why initial surgery
should be avoided if it is not possible to
perform initial surgical cytoreduction to an
optimum level. Unfortunately, it is often
difficult to assess the operability of the tumor
preoperatively, either by clinical examination
or by imaging techniques. The inoperable
cases should be subjected to primary
chemotherapy after the diagnosis is establi-
shed by fine-needle aspiration cytology
(FNAC). If after opening the abdomen it is
found that optimum debulking is not possible
in spite of aggressive surgery, only those
tumors should be removed that can be tackled
without major organ resection or without
causing undue morbidity to the patient.
The technique of en-bloc resection of
advanced pelvic disease was first described
by Hudson in 1968.28 The steps of this proce-
dure are as follows:
• Round ligament and infundibulopelvic
ligaments are divided and ligated.
• Pelvic peritoneum is then circumferentially
opened from the symphysis pelvis
anteriorly to the rectosigmoid posteriorly.
• The peritoneum is dissected free in a lateral
to medial direction including that covering
the dome of the bladder and the pelvic
sidewalls.
• The uterine arteries are divided and ligated
at their origins at the internal iliac artery.
• Ureters are mobilized laterally.
• The anterior vaginal fornix is exposed by
further dissection of the bladder anteriorly
and opened transversely.
• Hysterectomy can be performed in a
retrograde fashion.
• Development of retrorectal space will allow
elevation of the rectum, uterus and tumor
from the sacral hollow.
• Assessment of the need for rectosigmoid
resection depends on the tumor mobility
and invasion.
• The anastomosis can then be completed and
covered by a loop colostomy.
• If the omentum is replaced by a large tumor
deposit (omental cake), it is separated from
the greater curvature of the stomach by
ligation of the right and left gastroepiploic
arteries and ligation of the short gastric
arteries and supracolic omentectomy is
performed.
• The laparotomy should be completed with
an assessment of retroperitoneal nodes and
removal of the significantly enlarged ones.
• Griffiths reported that patients who were
left with no residual disease have median
survival of 34 months compared to patients
with residual disease of more than 2 cm.
whose median survival is 11 months.29

Secondary Cytoreductive Surgery
Secondary cytoreductive surgery is defined as
removal of residual tumor after full course of
chemotherapy following suboptimal
debulking or as removal of recurrent growth
after primary therapy. Secondary cytoreduc-
tion may also be necessary if resectable bulky
disease is observed during second look laparo-
tomy. The advantages of secondary cytoreduc-
tion are not clear-cut in all such clinical
situations. Cytoreductive procedure does give
a survival advantage if it can be done
successfully after chemotherapy in sub-
optimally debulked patients. The effectiveness
of secondary debulking followed by second-
line chemotherapy in recurrent disease is
dependent on the disease-free interval before
relapse. Longer the interval better is the
survival. Cytoreductive surgery is most
appropriate in recurrent cases with long
disease-free interval (1 year or more). Patients
having progressive disease while receiving
chemotherapy have a very dismal pro-
gnosis and secondary cytoreduction is not
advisable.
The optimal candidates for secondary cyto-
reduction are:
• Patients in whom the interval between
complete remission andrelapse is 12months
or more
• Patients who responded to prior chemo-
therapy
• Patients with resectable residual/recurrent
disease
• Relatively young patients with high perfor-
mance status.
Interval Cytoreductive Surgery
The term is characteristically used for an
operation performed after a short course (2-3
cycles) of induction chemotherapy in patients
who had unresectable tumors initially. The
Epithelial Ovarian Cancer 165
removal of the tumor may be facilitated by the
reduction of the mass due to prior chemo-
therapy.
Second Look Laparotomy/Laparoscopy
Second look laparotomy is performed to
determine the response in a patient who has
completed a prescribed course of chemo-
therapy after primary surgery and has no
clinical or radiological evidence of disease.
Despite the advent of modern diagnostic
methods such as CT scan, ultrasound, etc.
second look surgery remains the most
sensitive and specific method to determine the
response to treatment. The abdomen is opened
through midline longitudinal incision. The
entire abdominal cavity is inspected carefully,
including undersurface of diaphragm, the root
of mesentery, all parietal and visceral
peritoneal surfaces. Peritoneal wash for
cytology and liberal biopsies are taken from
all previous disease sites, from adhesions and
from suspicious areas. If no macroscopic
disease is found pelvic and para-aortic lymph
node dissection and omentectomy are done,
if not done before.
Second look laparotomy has high progno-
stic value and resection of macroscopic tumors
found at surgery may be possible. However,
till date there is very little evidence that the
procedure or the therapeutic measures done
on the basis of the findings influence the
patient’s survival significantly. Negative
second look laparotomy without any micro-
scopic disease will have good prognosis but
30-50 percent of them may have recurrence in
5 years.
If microscopic disease is detected, then
additional therapy in the form of intra-
peritoneal chemotherapy and radiation should
be planned. The prognosis is poor if macro-
scopic disease is found. Secondary cyto-
166 A Practical Approach to Gynecologic Oncology
reduction should be performed if surgically
resectable. If surgically unresectable, then
salvage chemotherapy should be considered.
The laparoscope can be used immediately
before planned laparotomy. If gross disease
is detected and secondary resection of tumor
is not possible, then laparotomy can be
avoided.
Chemotherapy in
Epithelial Ovarian Cancer
In the year 1952 Seligmen et al first described
the use of intravenous hemisulfur mustard in
a variety of malignancies including ovarian
cancers.30 They noted decrease in ascites in
65 percent of women with disseminated
ovarian cancers. Since then numerous chemo-
therapeutic agents, either singly or in combi-
nation, have been tried as adjuvant or neoadju-
vant treatment in early and advanced ovarian
cancer. The idea of postoperative adjuvant
chemotherapy did not arise until late 1960s.
The initial therapeutic protocols used alkyla-
ting agents, like melphalan for adjuvant
therapy. Though the responses were fair to
good across various studies, melphalan was
found to induce secondary cancer like
leukemia in many of the treated patients. The
advent of cisplatin in the late 1970s brought a
paradigm change in the chemotherapeutic
management of epithelial ovarian cancers. The
introduction of paclitaxel in the 1990s added
another effective armament against the
disease.
Adjuvant Chemotherapy for
Early Stage Ovarian Cancer
According to current recommendations, all
patients with epithelial ovarian cancers, except
those with FIGO stage-IA well-differentiated
tumors are candidates for adjuvant chemothe-
rapy. Chemotherapy may be avoided in
patients with stage-IB well-differentiated
cancer if staging laparotomy has been done in
the proper way. Very few randomized
controlled studies have been done to look into
the role of chemotherapy in surgically staged
early ovarian cancers. The Italian Gynecologic
Oncology Group randomly allocated the
surgically staged IA and IB epithelial ovarian
cancers (histological grade 2 or 3) into the
treatment arm (cisplatin 50 mg/m2 every 28
days for 6 cycles) and the follow up alone
arm.31 After a median follow up of 69 months
the 5-year disease free survival was 83 percent
for the treatment arm and 64 percent for the
follow up arm. However, no significant
difference in overall survival was noted
between the two arms. Five years survival was
87 percent in the treated group and 81 percent
in the follow up group. The same group
studied the roles of adjuvant cisplatin (50 mg/
m 2 every 28 days for 6 cycles) and
intraperitoneal radiation with 32P (15 mCi of
chromic phosphate) in surgically staged-IC
tumors (any grade). The 5-year disease free
survival was much better in the cisplatin arm
but the overall 5-year survivals were again
similar between the two groups. Substantial
morbidity is associated with intraperitoneal
32
P due to small bowel complications. No
randomized study has compared surgery
along with surgery plus chemotherapy for
stage-IC cancer. Combination chemotherapy
with cisplatin/carboplatin and paclitaxel is
often suggested even for early stage ovarian
cancer. This recommendation is based on
extrapolation from data on advanced ovarian
cancers rather than any firm clinical evidence.
The results from randomized studies are
awaited to prove that such an approach has a
survival advantage over no treatment or single
agent treatment. Early phase trials are going
on to look into the pharmacokinetics,
maximum tolerable dose, response rate and
feasibility of intraperitoneal administration of
carboplatin or paclitaxel in early stage ovarian

cancer after surgery. Higher peak peritoneal
concentration can be achieved at a comparati-
vely lower dose with this route of administra-
tion and the initial responses are encouraging.
Adjuvant Chemotherapy for
Advanced Stage Ovarian Cancer
Systemic chemotherapy is the treatment of
choice in advanced epithelial cancer of ovary
even after surgical removal of all visible
tumors. A major concern in the management
of advanced ovarian cancer is that in spite of
introduction of new chemotherapeutic agents
and new combinations, the overall survival
has remained almost unchanged over the last
few decades, particularly for the suboptimally
debulked disease.
The most commonly used regime before the
advent of paclitaxel was a combination of
cisplatin (75 mg/m2 IV infusion over 4 hours)
and cyclophosphamide (750 mg/m2 IV) both
on day 1, repeated every 3 weeks usually for
6 cycles. The overall response rate achieved
with cisplatin-based combinations is 70-
80 percent and a complete clinical response is
seen in 40-50 percent cases. Addition of
doxorubicin (50 mg/m2 IV infusion on day 1)
gives a small survival benefit. The drug is not
routinely used these days because this small
survival advantage is not clinically relevant
and the drug is cardiotoxic.
Paclitaxel was initially used for the plati-
num resistant tumors as the drug does not
develop cross-resistance with the platinum
compounds. The Gynecologic Oncology
Group first did a randomized controlled trial
comparing the combination of cisplatin (75
mg/m2) and paclitaxel (135 mg/m2 infusion
over 24 hours) with the standard cisplatin-
cyclophosphamide regime. A total of 386
patients with suboptimally debulked (>1 cm
residual disease) stage-III and stage-IV tumors
were recruited between the years 1990 and
1992.32 The paclitaxel combination had signifi-
cantly better response rate, longer progression
Epithelial Ovarian Cancer 167
free interval and improved median survival.
Among the 218 measurable diseases patients,
the clinical complete response rate was 31
percent in the cisplatin-cyclophosphamide
arm and 51 percent in the cisplatin-paclitaxel
arm. Severe alopecia, febrile neutropenia and
allergic reactions were more common in the
paclitaxel arm.
Similar results were reported by other
randomized trials comparing the two combi-
nations.33 The clear advantage of the combina-
tion has resulted in its acceptance as the
standard level of care for advanced ovarian
cancers in many centers.
A European-Canadian randomized trial
compared a 3 hours infusion of paclitaxel at a
dose of 175 mg/m2 to the 24 hours infusion at
a dose of 135 mg/m2 in 382 patients with
relapsed ovarian carcinoma.34 No difference
was found between the two schedules.
Because the high dose/short infusion time
schedule appears to be marginally more
effective and suitable for out patient adminis-
tration, it has become the standard regime for
paclitaxel administration.
Carboplatin is the second-generation
platinum analog with less gastrointestinal side
effects, nephrotoxicity, neurotoxicity and
ototoxicity as compared to cisplatin. This drug
has become the preferred agent for combina-
tion with paclitaxel in most clinics due to its
lower toxicity. A few randomized trials
comparing cisplatin and paclitaxel with
carboplatin and paclitaxel observed this
benefit of carboplatin without any difference
in the progression-free survival between the
two combinations. The myelosuppressive
effect of carboplatin is the dose limiting
toxicity.35,36
New Agents for Chemotherapy
in Ovarian Cancer
The drugs that have shown encouraging
results in the phase II trials are the
Topoisomerase I inhibitors (topotecan and
168 A Practical Approach to Gynecologic Oncology
irinotecan), 2’,2’-Difluorodeoxicytidine
(Gemcitabine) and Docetaxel (Taxotere).
Topotecan has been most extensively studied
among these drugs. It has been found to be
effective in producing response in ovarian
cancers refractory to platinum compounds
and paclitaxel. Carmichael et al did a
randomized trial comparing topotecan (1.5
mg/m2/day over 30 minutes for 5 days) with
paclitaxel (175 mg/m 2 over 3 hours)
administered to patients who failed a
platinum based regimen. The response rate
and the progression free interval were
significantly higher in the topotecan treated
groups.37 Gemcitabine and Docetaxel have
been tried on patients refractory to platinum-
based regimes and both the drugs have
shown response in 20-30 percent of cases.
High Dose Chemotherapy and Autologous
Bone Marrow Transplant
The use of high dose chemotherapy followed
by hematopoietic reconstitution with
autologous bone marrow transplant (ABMT)
is being tested in advanced ovarian cancer
patients. Another option for hematopoietic
rescue after megadose chemotherapy is with
peripheral blood stem cells reinfusion. The
drugs used for this purpose are cyclo-
phosphamide, melphalan, carboplatin and
mitoxantrone. Several phase I-II clinical trials
are ongoing.
Place of Neoadjuvant Chemotherapy
Primary optimum cytoreductive surgery
(leaving residual tumors less than 2 cm) may
not be feasible in many of the advanced cases
of ovarian cancers, either because the tumor
is unresectable or because the poor general
condition will not permit major surgery. In
such patients neoadjuvant chemotherapy
(chemotherapy as the initial treatment)
followed by surgery has been found to have
better results compared to suboptimal
debulking and chemotherapy. The tissue
diagnosis is established by fine needle
aspiration cytology or by cytology of the
ascitic fluid. Advantages of neoadjuvant
chemotherapy are that the patient’s condition
will improve for subsequent cytoreductive
surgery and less extensive surgery may be
necessary for obtaining optimal cytoreduc-
tion. However, no randomized controlled
trial has evaluated neoadjuvant chemotherapy
and interval debulking with primary
debulking followed by adjuvant chemo-
therapy.
Optimal Number of Cycles
of Chemotherapy
Six cycles of chemotherapy should be
administered for optimal treatment of ovarian
cancer after complete debulking. There is not
enough evidence to suggest that increasing the
number of cycles will have any survival adva-
ntage. For suboptimally debulked patients
chemotherapy should be administered till a
clinically complete response is obtained
(including normalization of serum CA-125
level) and has to be continued for 3 more
cycles. The patient should receive at least 6
cycles. If the disease progresses while the
chemotherapy is being administered
consideration should be given to change of
regime.
Radiotherapy
The value of radiotherapy in advanced
ovarian cancer is quite limited. This is evident
as the optimal dose required to achieve tumor
control of even microscopic disease (40 to 50
Gy) is substantially greater than the maximum
dose tolerated by liver and kidney. Whole
abdomen radiation is applicable to patients
with no residual disease and is recommended

by some authorities as consolidation after
chemotherapy.38 It does not appear to enhance
survival and is associated with significant
morbidity, typically small bowel injury.39
Management of Borderline
Epithelial Ovarian Cancer
The diagnosis must be confirmed by examina-
tion of multiple sections from the original
ovarian tumor and every effort should be
taken to rule out invasion. In mucinous tumors
a single specimen may have benign, borderline
and invasive pathology. In the vast majority
of the patients the borderline tumors are
detected in stage-I for which the standard
treatment is bilateral salpingo-oophorectomy
along with hysterectomy and thorough
surgical staging. For women desirous of
preserving fertility unilateral salpingo-
oophorectomy along with surgical staging is
also sufficient if the other ovary is grossly
normal. There is no proven role of chemothe-
rapy in the early stages. Though rare, the
borderline tumors may present in advanced
stage with tumor extension limited within the
abdomen (extra abdominal metastasis rarely
found). In these cases the treatment of choice
is surgery. Chemotherapy may be tried but the
response is usually poor. Long-term follow up
is necessary after treatment. The recurrent
cases may have borderline or invasive disease.
In both the cases surgery followed by chemo-
therapy is the standard management. The
long-term survival for surgically staged stage-
I borderline ovarian tumors is nearly
100 percent. Even for advanced stages the
survival is between 80–90 percent.
Protocol for Follow up After Treatment
Second look laparotomy may be the best tool
to identify persistent disease following
primary therapy. Unfortunately recurrent
disease develops in 30–50 percent of patients
Epithelial Ovarian Cancer 169
with negative second look laparotomy. There
is no convincing evidence that the treatment
decisions made on the basis of the findings
of this procedure significantly alters the
survival, hence less invasive methods are
preferred for the follow up of the patients.
Clinical Pelvic Examination
For the first two years the woman should be
seen every 3 months. During each visit
complete history should be taken and a
thorough physical, bimanual pelvic and
rectovaginal examination should be done.
Pelvic examination has been found to be as
effective as ultrasonography and CT scan in
detecting early pelvic recurrences.
CA-125 Estimation
It is a very important tumor marker for
monitoring the disease. During the first 2
years of follow up CA-125 should be repeated
every 3 months if the pretreatment level was
high. Persistently elevated CA-125 levels have
been associated consistently with persistence
of disease, even if the clinical examination is
normal. Elevated CA-125 preceded disease
recurrence by 1-14 months with a mean of 5
months. The degree of elevation by itself does
not precisely predict the amount of residual
disease. Normal levels may also accompany
disease with tumor of 2 cm or greater in one-
third or more cases. A 50 percent rise in the
CA-125 level above normal range at two
occasions is considered as a likely indication
of recurrence. Histologic confirmation or
clinical evidence of disease is necessary before
any salvage chemotherapy. At times cytology
of ascites fluid, if present may help in
establishing the diagnosis.
Ultrasound
Ultrasound is a relatively inexpensive, non-
invasive imaging technique and can be
170 A Practical Approach to Gynecologic Oncology
repeated at each follow up visit. However, the
sensitivity of the technique to detect low
volume peritoneal disease and early lymph
node recurrence is not satisfactory.
CT Scan and MRI
CT scan is not a very sensitive test to detect
early recurrences in ovarian cancers due to its
inability to pick up disease less than 2 cm
diameter and to detect growth at the apex of
the vagina. MR imaging has better resolution
and is more efficient in identifying the early
recurrences, but it is much more costly than
ultrasound or CT scan. CT scan/MRI are
reserved for investigating the cases in whom
the CA-125 level is elevated during follow up.
After the initial 2 years of normal follow-
up, the follow up interval can be prolonged to
4-6 months.
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 Germ Cell and
14 Stromal Tumors of Ovary
• Neerja Bhatla • Bhawna Malhotra Singh
INTRODUCTION
Non-epithelial tumors of the ovary comprise
all neoplasms derived from the primitive germ
cells of the embryonic gonad. This group
consists of several histologically different
tumor types and are broadly of two categories:
germ cell tumors and sex cord-stromal cell
tumors. During the last two decades, the
nomenclature and histologic criteria for the
various non-epithelial neoplasms of the ovary
have been standardized. Also, the manage-
ment of malignant ovarian germ cell and
stromal cell tumors has evolved a great deal.
Recent developments in chemotherapy have
dramatically changed the prognosis of these
cancers and favored the fertility-preserving
surgery for many of these tumors.
INCIDENCE AND CLINICAL PROFILE
Ovarian germ cell tumors account for 20-25
percent of all ovarian neoplasms and only
about 3 percent of these are malignant.1 Most
of these neoplasms occur in young women and
hence their management involves decisions
concerning preservation of reproductive
function. Most of these lesions are found in
the second and third decades of life therefore
these neoplasms are the most frequently
encountered ovarian malignancies in young
females. In a series by Norris and Jensen, germ
cell tumors comprised 80 percent of
preadolescent malignant ovarian tumors, the
rest were sex-cord stromal tumors. 2 The
proportion of malignant epithelial ovarian
tumors rises with increasing age, while that
of non-epithelial tumors declines with age.
The majority of these neoplasms present
with a palpable abdominal mass and/or pain.
Ovarian germ cell tumors are usually rapidly
growing abdominal masses, often associated
with considerable discomfort and abdominal
pain with the exception of benign cystic
teratomas, which are often asymptomatic and
diagnosed incidentally. Acute onset pain may
be caused by torsion, rupture or hemorrhage
in the neoplasm. One of the classically descri-
bed signs of a dysgerminoma is hemoperi-
toneum resulting from rupture of the capsule
of the rapidly enlarging tumor.
CLASSIFICATION
Though all the histologic subtypes of non-
epithelial ovarian tumors have been described
for almost a century, there was no uniformity
in nomenclature because of the rarity of these
neoplasms and the multiplicity of histologic
patterns. In 1973, the World Health Organiza-
tion introduced the current classification
system, which is shown in Tables 14.1 and
14.2.3

Table 14.1: World Health Organization
classification of germ cell tumors
Dysgerminoma
Endodermal sinus tumors
Embryonal carcinoma
Polyembryoma
Choriocarcinoma
Teratomas
Immature
Mature (dermoid cyst)
Mesodermal (struma ovarii, carcinoid)
Mixed forms
Gonadoblastoma
Table 14.2: World Health Organization
classification of sex-cord stromal tumors
Granulosa stromal cell tumors
1. Granulosa cell tumors
2. Thecoma – fibroma
Androblastomas; Sertoli-Leydig cell tumors
1. Well-differentiated (Pick’s adenoma, Sertoli cell
tumor)
2. Intermediate differentiation
3. Poorly differentiated
4. With heterologous elements
Lipid cell tumors
Gynandroblastoma
Unclassified
Dysgerminoma
Pure dysgerminoma is the most common
malignant ovarian germ cell tumor, account-
ing for approximately 2 percent of all ovarian
malignancies. 4 It is also the commonest
ovarian malignancy in children and young
females and the commonest component of
mixed germ cell tumors of the ovary.
Dysgerminoma may occur at any age from
infancy to old age, but approximately 80-90
percent occur in the second and third decades
of life.5 Dysgerminoma is one of the most
common malignant ovarian neoplasms
associated with pregnancy and has also been
reported to be found incidentally at cesarean
section. The majority present at a relatively
Germ Cell and Stromal Tumors of Ovary 173
early stage (80-90% in stage I) and approxi-
mately 10-15 percent of patients with
dysgerminoma have bilateral ovarian involve-
ment.5 Despite the short duration of symp-
toms, the tumor is often large indicating rapid
growth.
Pathology
Dysgerminoma consists of germ cells that have
not differentiated to form embryonic or extra-
embryonic structures. Grossly, the tumor may
be firm or fleshy, pale or cream colored, with
lobulated external as well as cut surfaces.
Microscopically, it consists of undifferentiated
germ cells with stroma almost always
infiltrated with lymphocytes and often
contains granulomas. Occasionally, it contains
isolated syncytiotrophoblastic giant cells
capable of producing human chorionic
gonadotropin (hCG).
About 5 percent of dysgerminomas occur
in girls with chromosomal abnormalities and
gonadal dysgenesis. In these cases, the
dysgerminoma often develops in a pre-
existing gonadoblastoma in dysgenetic
gonads. Therefore, karyotype should be
obtained in young females with pelvic mass
associated with sexual abnormality or primary
amenorrhea. If the results show the presence
of Y-chromosome (testicular feminization or
pure/mixed gonadal dysgenesis), both the
gonads should be removed at surgery
especially when they are dysgenetic.
Twentyfive to fifty percent of these cases will
develop gonadal malignancy, usually
gonadoblastoma or dysgerminoma.6
Ovarian dysgerminoma has a predilection
for early lymphatic spread to the pelvic, para-
aortic, mediastinal and supraclavicular
lymph nodes. This is in contrast to typical
surface spread of epithelial ovarian tumors.
Hematogenous spread to other organs like
liver, lungs and bones occurs late.
174 A Practical Approach to Gynecologic Oncology
Endodermal Sinus Tumor
(Yolk Sac Tumor)
Endodermal sinus tumor is the second most
common form of malignant germ cell tumor
and a common component of mixed germ cell
tumors. In adults, endodermal sinus tumor
accounts for approximately 10-15 percent of
all ovarian germ cell tumors. In children it is
relatively more common, comprising up to
22 percent in a series reported by Kurman and
Norris.7 Endodermal sinus tumor is also called
yolk sac tumor as it is related histologically to
yolk sac endoderm.
Most of the endodermal sinus tumors are
confined to one ovary when diagnosed but are
usually large, measuring more than 10 cm
mostly. They are characterized by rapid
growth and early metastasis. These neoplasms
invade the surrounding structures leading to
extensive involvement of intra-abdominal
structures with tumor deposits. They also
metastasise via lymphatic system. These
tumors are capable of producing alpha-
fetoprotein (AFP) resulting in elevation of
serum AFP in most of the cases.
Pathology: Grossly endodermal sinus tumors
are gray-yellow in color with areas of
hemorrhage and cystic gelatinous changes.
They are considered to originate from germ
cells that differentiate into extra-embryonal
yolk sac. The typical perivascular invaginated
papillary structures with central blood vessels
(Schiller-Duval bodies) resemble endodermal
sinuses of the rat yolk sac. The tumor consists
of scattered tubules lined by single layers
of cuboidal cells, loose reticular stroma,
numerous scattered para-aminosalicyclic-
positive globules and the characteristic
Schiller-Duval bodies.
Embryonal Carcinoma
Embryonal carcinoma is an uncommon germ
cell tumor accounting for less than 5 percent
of all malignant germ cell tumors.8 In spite of
being one of the most virulent malignant
neoplasms of the ovary it is usually diagnosed
at stage I confined to one ovary.
Pathology: Embryonal carcinoma is composed
of embryonal cells, embryoid bodies and
syncytiotrophoblastic giant cells. It probably
develops from primordial germ cells before
there is much differentiation towards either
embryonic or extra-embryonic tissue. The
tumor consists of large primitive cells with
occasional papillary or gland-like formations.
Scattered throughout the tumor are multi-
nucleated giant cells that resemble syncytial
cells. The large primitive cells contain AFP and
the syncytiotrophoblast-like cells contain hCG.
Because of elevated hCG in most of these cases,
the patients manifest hormonal abnormalities
like precocious puberty, irregular uterine
bleeding or amenorrhea.
Polyembryoma
As the name suggests, polyembryoma consists
of numerous embryoid bodies resembling
morphologically normal embryos. It is a rare
ovarian germ cell neoplasm with only a few
cases reported. In most cases, it has been
associated with other germ cell elements,
mainly immature teratoma. Polyembryoma is
a highly malignant tumor and presents mostly
with invasion of adjacent structures and
metastases that are mainly confined to the
abdominal cavity.
Choriocarcinoma
Pure choriocarcinoma of the ovary can be ges-
tational or non-gestational in origin. Gesta-
tional ovarian choriocarcinoma may be pri-
mary choriocarcinoma associated with ova-
rian pregnancy, or metastatic choriocarcinoma
from a primary gestational choriocarcinoma
arising in other parts of the genital tract,
mainly the uterus. It is the non-gestational

choriocarcinoma of the ovary that is a germ
cell tumor differentiating in the direction of
trophoblastic structures and arising admixed
with other neoplastic germ cell elements. Non-
gestational choriocarcinoma can be diagnosed
with certainty only in a patient who is sexu-
ally inactive or immature or unable to con-
ceive.9
Non-gestational pure ovarian choriocar-
cinoma is a rare, highly malignant tumor.10 In
most cases, the tumor is admixed with other
neoplastic germ cell elements and their presence
is diagnostic of non-gestational choriocar-
cinoma. Non-gestational choriocarcinoma
usually arises from a teratoma as a component
of a mixed germ cell tumor. The distinction
between gestational and non-gestational
choriocarcinoma is extremely important due to
the poorer prognosis of the latter.
Similar to other malignant germ cell
neoplasms, this tumor occurs in children and
young females, with 50 percent of cases
reported in prepubescent girls. The average
age at presentation is 13.9 years. 10 The
predominant presenting symptom is lower
abdominal pain with other complaints
including bleeding per vaginum, amenorrhea,
nausea, vomiting, weight loss and dysuria.
The duration of symptoms range from 1 to 16
weeks.
Choriocarcinoma secretes hCG. It may
manifest in prepubescent girls as isosexual
precocious puberty with breast development,
growth of sexual hairs and uterine bleeding.
Sexually active women may be misdiagnosed
as having ectopic pregnancy. Estimation of
urinary or plasma hCG levels is useful in
diagnosis and follow-up of these patients.
Pathology: The histological features of an
ovarian choriocarcinoma are identical to those
of a uterine gestational choriocarcinoma with
both malignant cytotrophoblast and syncytio-
trophoblast being present.11
Germ Cell and Stromal Tumors of Ovary 175
Teratoma
Teratomas account for approximately
15 percent of all ovarian tumors. Table 14.3
shows the World Health Organization
classification.3
Mature teratomas are ovarian teratomas
containing mature tissue of ectodermal,
mesodermal or endodermal origin. They may
be cystic or solid.
Table 14.3: World Health Organization
classification of teratomas
Mature teratoma
Cystic
Solid
Monodermal or highly specialized
Struma ovarii and carcinoid
Others
Immature teratoma
Low grade
High grade (based on the amount of neural tissue
present)
Mature teratoma with malignant transformation
(malignant change in a mature element of tissue)
Mature Cystic Teratoma
Mature cystic teratoma, commonly called
dermoid cyst, is one of the most common
ovarian neoplasms and also accounts for more
than 95 percent of all ovarian teratomas.
Though they may occur at any age, these
neoplasms are the most common ovarian
tumors in women in the second and third
decades of life. They account for 70 percent of
benign ovarian neoplasms among women
younger than 30 years.12 Thus, they are the
most common ovarian neoplasms during
pregnancy, accounting for 24-40 percent of all
ovarian tumors encountered in pregnancy.13
They are generally asymptomatic, detected on
ultrasonography or occasionally on physical
examination, unless complications occur. They
may be incidentally diagnosed during
176 A Practical Approach to Gynecologic Oncology
investigation of infertility in young women.
These slow-growing benign lesions may
manifest symptoms related to their size.
Torsion is the most frequent complication and
tends to be more common during pregnancy
and puerperium and more common in
children and young patients. Rarely, rupture
may occur leading to shock and hemorrhage
followed by chemical peritonitis secondary to
intra-abdominal spill of the cholesterol-laden
debris or there may be a chronic presenta-
tion.14 Rupture tends to occur more commonly
in large sized tumors. Infection is an un-
common complication and occurs in approxi-
mately 1 percent of patients.
Mature cystic teratomas occur bilaterally in
10-15 percent of patients, therefore the
management of the contralateral ovary is of
great importance. The characteristic gross
appearance and contents of the tumor leads
to an easy preoperative and peroperative
diagnosis.
Pathology: Mature cystic teratomas may
contain tissue derived from all three germ cell
layers. The most common elements are
ectodermal derivatives such as skin, hair,
sebaceous or sweat glands and teeth.
Grossly mature cystic teratomas are usually
multicystic and contain hair admixed with
sticky, keratinous and sebaceous debris.
Occasionally, well-formed teeth are seen along
with cartilage or bone. A true dermoid cyst
consists of only ectodermal derivatives of skin
and skin appendages on histology. However,
other mature tissues like gastrointestinal or
respiratory epithelium may be present in
mature cystic teratomas.
Mature Solid Teratoma
Mature solid teratoma is a very uncommon
type of ovarian teratoma, composed entirely
of mature tissues. Although the neoplasm is
considered benign, it may be associated
occasionally with peritoneal implants
consisting of mature glial tissue. The teratoma
is usually unilateral.
Monodermal or highly specialized teratomas
a. Struma ovarii
Struma ovarii is an uncommon type of
teratoma. This neoplasm consists predomi-
nantly or entirely of thyroid parenchyma,
unlike small foci of thyroid tissue in benign
cystic teratomas. One fourth of the patients
with struma ovarii manifest clinical hyper-
thyroidism. This neoplasm is usually
benign but may undergo malignant trans-
formation.
b. Carcinoid tumors
Primary carcinoid tumors of the ovary
usually arise in the gastrointestinal or
respiratory epithelium of the mature cystic
teratoma. These neoplasms are uncommon
and many occur in post-menopausal
women. One-third of the patients with
carcinoid tumors of the ovary have typical
carcinoid syndrome, despite the absence of
metastases.
Mature Cystic Teratoma with
Malignant Transformation
Malignant transformation of the germ cell
elements of mature teratomas is reported to
occur in 0.17-2 percent of patients.13,15 Typically
post-menopausal patients develop malignant
transformation and present with abdominal
pain. An abdominal mass or vaginal bleeding
may also be present. It has been suggested that
larger mature cystic teratomas (more than
6 cm size) are at greater risk for malignant
transformation.16,17
Pathology: Grossly, mature cystic teratomas
may contain solid tissue with evidence of
hemorrhage and necrosis. The malignant
tissue is mostly located within the solid areas
and is often associated with hemorrhage and

necrosis.18 It may be squamous carcinoma,
adenocarcinoma, sarcoma or carcinoid
tumors, out of which squamous carcinoma is
the most common malignant element in 83
percent of cases.15
The tumor spreads by peritoneal implanta-
tion. The prognosis of these patients is poor
and is related to the histopathology and the
stage of the disease. Women with squamous
cell pathology and stage I disease have been
reported to have a better survival and prog-
nosis as compared to women with unusual
histopathology (adenocarcinoma, sarcoma or
carcinoid) and spread beyond the ovaries.13,16,18
Immature Teratoma
Immature teratomas are the third most com-
mon malignant germ cell tumors containing
variable amounts of immature tissue derived
from the three germ cell layers, ectoderm,
mesoderm and endoderm. These tumors have
been known as solid teratomas, malignant ter-
atomas, teratoblastoma or embryonal ter-
atoma.
Immature teratomas represent approxi-
mately 1 percent of all ovarian teratomas and
usually occur in children and young women
with a reported mean age of 17 to 20 years.18
They are almost never seen after menopause.
This is in contrast to mature cystic teratomas,
which may occur at all ages and have been
reported in postmenopausal women also.
Generally, older patients tend to have lower
grade tumors compared with younger
patients.
Pathology: Morphologically, immature
teratomas are solid but they may also contain
fluid-filled cysts. Histologically, they consist
of tissue derived from all germ layers. Most
commonly the immature elements are of
neuroepithelial origin. According to Norris et
al, the quantity of immature neural tissue
alone determines the grade of the tumor.
Germ Cell and Stromal Tumors of Ovary 177
Grade 1 is defined as neuroepithelium absent
or limited to one low magnification field.
Grade 2 is defined as neuroepithelium present
but not exceeding three low magnification
fields. Tumor is grade 3 if immaturity and
neuroectoderm are prominent, the latter
occupying four or more low power fields. The
grade of the teratoma determines the survival:
the higher the grade, the worse the prognosis.
Survival of women with immature teratoma
stage I was 100 percent in grade 1, 90 percent
in grade 2 and 33 percent in grade 3.19 Multiple
sections of the primary lesion and wide
sampling of the peritoneal implants are
necessary to appropriately grade the tumor.
Usually, implants and metastases are
better differentiated than the primary ovarian
tumor.
Unlike mature cystic teratomas, immature
teratomas are almost always unilateral, with
80 percent of these tumors diagnosed in stage
IA. Though almost never bilateral, peritoneal
implants may be present at the time of initial
surgery. The prognosis is closely correlated
with the histologic grade of the primary tumor
and the implants.
Mixed Germ Cell Tumors
Mixed germ cell tumor is the term used for
germ cell tumors composed of two or more
malignant germ cell elements. It is not unusual
to find three or four different germ cell
elements in a mixed germ cell tumor. Dys-
germinoma is the most common component
reported in 70-80 percent of mixed germ cell
tumors. 1,20 Endodermal sinus tumor and
immature teratoma are the next common
elements found in 70 percent and 53 percent
of these neoplasms respectively. Embryonal
carcinoma and choriocarcinoma are seen only
infrequently. The most common combination
is dysgerminoma and endodermal sinus
tumor. The most significant component
usually predicts the outcome and prognosis,
178 A Practical Approach to Gynecologic Oncology
therefore therapy and follow-up should be
determined by it.
Sex-cord Stromal Tumors
Sex-cord stromal tumors account for 5 percent
of all ovarian tumors and 5-10 percent of all
ovarian cancers. These include all tumors
containing granulosa cells, theca cells,
luteinized theca cells, Sertoli cells, Leydig cells
and fibroblasts of the gonadal stroma. These
neoplasms are slow-growing tumors with a
tendency to recur late. The average time to
recurrence is between 5 and 10 years after the
initial diagnosis.
Granulosa – Stromal Cell Tumors
Granulosa cell tumors and thecoma-fibromas
together constitute the granulosa-stromal cell
group. These neoplasms may occur at any age,
from prepubescent to post-menopausal. Most
granulosa and theca cell tumors produce
estrogen but a few may be androgenic. The
majority (80-85%) of them are palpable on
abdominal or pelvic examination. Occa-
sionally an unsuspected tumor is detected
during hysterectomy done for abnormal ute-
rine bleeding due to endometrial hyperplasia
or carcinoma.
Granulosa Cell Tumors
Granulosa cell tumors of the ovary are
uncommon neoplasms with a wide spectrum
of clinical presentations. They represent more
than 70 percent of malignant sex-cord stromal
tumors and less than 5 percent of all malignant
ovarian tumors. These tumors may occur at
any age from the first to the tenth decade of
life, but the average age of diagnosis is 52
years. Only about 5 percent of granulosa cell
tumors occur before puberty.21
Patients with granulosa cell tumors may
present with non-specific symptoms such as
abdominal pain or heaviness, bloating or
distension, or awareness of an abdominal
mass. Seventy percent of these tumors secrete
estrogens and hence may manifest symptoms
of hyperestrogenism and consequent
endometrial stimulation. Vaginal bleeding is
common in postmenopausal women due to
stimulation of the endometrium. An endo-
metrial carcinoma, usually well-differentiated,
may develop in approximately 10 percent of
patients with granulosa cell tumors.1,21 Other
estrogenic effects include tenderness or
swelling of the breasts and vaginal cytology
showing an increase in maturation of the
squamous cells. Some (about 15%) patients
present with an acute abdomen due to
hemoperitoneum consequent to internal
tumor rupture and hemorrhage.
Pathology: Most granulosa cell tumors grossly
have both solid and cystic components with
areas of hemorrhage. The solid tumors may
be soft or firm, depending upon the relative
amounts of neoplastic cells and fibrotheco-
matous stroma. Depending upon the lipid
content of the cells, they may be yellow or gray
in color. The cystic component of the tumor is
generally filled with serous fluid or clotted
blood. These tumors are usually unilateral
with an average diameter of 12 cm.
The granulosa cells in these neoplasms may
demonstrate one of several characteristic
patterns, including microfollicular, macro-
follicular, insular or trabecular. Typical Call-
Exner bodies are usually seen in the micro-
follicular pattern. Less commonly, these
tumors may be less well-differentiated with
sarcomatoid pattern. The histologic subtype
does not predict prognosis but high nuclear
grade, atypia and a high mitotic index are
associated with a poor clinical outcome. 22
Fujimoto et al reported that both high mitotic
index (>4 per 10 HPF) and lymphovascular
space involvement are independent prog-
nostic factors of poor prognosis and a high rate
of recurrence.23

Immunohistochemical staining for inhibin
may help in the pathological diagnosis of
granulosa cell tumors as this would rarely be
noted in other ovarian tumors. Inhibin
positivity might also correlate with a favor-
able prognosis since tumors at stage I or II are
more likely to stain for inhibin than those at
higher stages.24
Two histologically and clinically distinct
subtypes of granulosa cell tumors are
described: adult and juvenile granulosa cell
tumors.
Adult Granulosa Cell Tumors
These account for approximately 95 percent
of all granulosa cell tumors. They occur more
commonly in postmenopausal women and are
the most common estrogen-producing tumors.
Rarely, the tumor may be androgenic result-
ing in hirsute changes. Histologically,
fibrothecomatous components are common
and the cytoplasm is usually scanty. The typi-
cal coffee-bean grooved cells are present.
Mature follicles and Call-Exner bodies are
common. Abnormal histology of the endo-
metrium is not uncommon in these patients
due to endometrium stimulation. A high inci-
dence of endometrial hyperplasia, also with
atypia or even carcinoma of the endometrium
has been reported.
Juvenile Granulosa Cell Tumors
The majority of juvenile granulosa cell tumors
occur in young adults, with less than 5 per-
cent presenting before puberty. Although
adult granulosa cell tumors may occur in
childhood, it is infrequent to detect a juvenile
granulosa cell tumor in older patients. Most
of the juvenile granulosa cell tumors in chil-
dren induce pseudopuberty through active
estrogen production resulting in the develop-
ment of breasts and sexual hairs. Irregular
uterine bleeding may also be present.
Germ Cell and Stromal Tumors of Ovary 179
The histological appearance is distinctive in
juvenile granulosa cell tumors. The thecoma-
tous component is predominant with tumor
cells larger than in adult granulosa cell tumors,
with abundant cytoplasm and hyperchromatic
nuclei. The nuclei are oval and the cellular
grooving and the presence of Call-Exner bod-
ies are not characteristic. The tumors appear
to be less well-differentiated than the adult
type, but the prognosis is good with high cure
rates.
True granulosa cell tumors are low-grade
malignancies with the majority of them
confined to one ovary at the time of diagnosis.
They are found to be bilateral in only 2-5
percent of patients. Late recurrences are
typical of granulosa cell tumors and they often
appear more than 5 years after initial therapy.
Some recur as late as 20 years after the initial
diagnosis. Nevertheless, the prognosis for
these patients with relapses is excellent with
long-term survival rates in the range of 75-
90 percent for all stages.
Thecoma-Fibroma
Thecomas are infrequently seen sex-cord
stromal tumors of the ovary consisting of
neoplastic cells containing moderate to large
amounts of lipid. These neoplasms are solid,
yellow-colored tumors almost always
confined to one ovary. Histologically, they
may contain both granulosa cells and a
fibromatous component. If more than a very
small component of granulosa cells is present,
the term granulosa cell tumor is generally
applied. The term theca cell tumor or thecoma
is essentially reserved for neoplasms that
consist entirely of benign theca cells. If clusters
of lutein cells are present, the term luteinized
thecoma is often used.
Fibromas may arise from ovarian stromal
cells and differentiate in the direction of
collagen-producing fibroblasts. Tumors with
histology in between that of thecoma and
180 A Practical Approach to Gynecologic Oncology
fibroma may be designated as thecoma-
fibromas. These neoplasms are benign and
almost always unilateral.
Sertoli-Leydig Cell Tumors
Sertoli-Leydig cell tumors of the ovary
originate from the specialized gonadal stroma
and consist of Sertoli cells or Leydig cells in
varying proportions and degrees of differen-
tiation. They are also known as androblas-
tomas or arrhenoblastomas. These neoplasms
account for less than 0.5 percent of all ovarian
tumors.
Sertoli-Leydig cell tumors are classically
described as masculinizing tumors but some
of these may not have endocrine manifestation
and some may even be accompanied by
estrogenic symptoms. Though most often
found in young women in third decade of life,
these tumors may occur at all ages. Classically,
a patient with Sertoli-Leydig cell tumor
presents with progressive masculinization
that is heralded by hirsutism, temporal
balding, hoarseness of voice and clitorome-
galy. Others may manifest with secondary
amenorrhea, breast atrophy or a marked
increase in libido.
Sertoli-Leydig cell tumors have low
malignant potential. The histological degree
of differentiation of the tumors predicts the
prognosis. The overall 5-year survival rate of
patients with Sertoli-Leydig cell tumors has
been reported to be more than 70-90 percent.
Young and Scully reported in their series of
220 Sertoli-Leydig cell tumors that none of the
27 well-differentiated tumors and only 4 of 100
tumors of intermediate differentiation were
clinically malignant. 25 Well-differentiated
tumors are almost always pure, without
heterologous or retiform components. They
contain pure Sertoli cell tumors as well as
tumors with a significant Leydig cell compo-
nent, known as well-differentiated Sertoli-
Leydig cell tumors.
Sertoli Cell Tumor
Sertoli cell tumors are of interest clinically
because, in contrast to other tumors in this
category, they tend to be estrogenic rather than
androgenic. These tumors are rare. Evidence
of estrogen production is associated with two-
third of them. These may result in isosexual
precocity. All well-differentiated Sertoli cell
tumors are unilateral and almost always
confined to the ovary.
Pathology: Typically they are solid yellow
tumors with an average diameter of 9 cm.
Microscopically, Sertoli cell tumors contain
hollow or solid tubules lined by columnar to
cuboidal cells with moderate amounts of pale
or slightly eosinophilic cytoplasm. They may
simulate prepubertal testicular tubules or the
atrophic tubules of an adult testis.
Heterologous Sertoli-Leydig Cell Tumor
Heterologous Sertoli-Leydig cell tumors are
also noteworthy since they may feature
mucinous epithelium, carcinoid, skeletal
muscle and/or cartilage resulting in a confu-
sing histologic picture and misdiagnosis.
These neoplasms account for approximately
20 percent of all Sertoli-Leydig cell tumors and
do not differ significantly from other Sertoli-
Leydig cell tumors without a heterologous
component.
The heterologous elements that occur are
of two basic types: endodermal elements
characterized by gastrointestinal type
epithelium, sometimes with foci of carcinoid
or mesenchymal elements in the form of
immature skeletal muscle or cartilage.26 The
endodermal elements are typically found in
tumors of intermediate differentiation and
mesenchymal elements are found in poorly
differentiated tumors. The degree of differ-
entiation is more significant in determining the
prognosis than the type of heterologous
component.

Retiform Sertoli-Leydig Cell Tumor
The recently recognized retiform variant of
Sertoli-Leydig cell tumor is often confused
with more common epithelial tumors of the
ovary and is also less often androgenic than
are other Sertoli-Leydig cell tumors.
Androgenic manifestations are present in only
25 percent of cases as opposed to 50 percent
for Sertoli-Leydig cell tumors as a group.26
Gynandroblastoma
A rare sex-cord stromal tumor of the ovary
containing unequivocal granulosa cell
elements along with Sertoli cell tubules and
Leydig cells has been designated as gynand-
roblastoma. Essentially, it is a combination of
granulosa cell and Sertoli-Leydig cell tumors.
These mixed tumors can be associated with
either estrogen or androgen production and
they behave as low-grade malignancies similar
to their individual components.
Lipid Cell Tumors
Lipid cell tumors are also designated as hilus
cell tumors, stromal luteomas or Leydig
tumors. These neoplasms are composed of
lipid containing polygonal cells, found
commonly in the medulla or hilus regions of
the ovaries. Neoplasms that are small in size
(generally less than 8 cm) are expected to
behave in a benign fashion, while tumors with
a microscopic cellular pleomorphism with
high mitotic activity or those that have spread
to contiguous organs at the time of initial
diagnosis should be considered malignant.
They are mostly unilateral.
Gonadoblastoma
Gonadoblastoma is a rare ovarian neoplasm
representing both components, i.e. germ cell
neoplasms and sex-cord stromal cell tumors.
It consists of germ cells resembling those of
dysgerminoma and stromal cells, which
Germ Cell and Stromal Tumors of Ovary 181
resemble those of a granulosa or Sertoli cell
tumor.
Gonadoblastoma is a unique neoplasm that
mostly develops in dysgenetic gonads asso-
ciated with sex chromosome abnormality. The
chromosomal analysis of women with
gonadoblastoma usually shows either 45, X or
45X/46XY pattern. These women presents
with primary amenorrhea, with or without
virilization and developmental genital abno-
rmality. Most women with gonadoblastoma
are phenotypic females but some may be
phenotypic males with cryptorchidism and
hypospadias. Gonadoblastoma may be
detected in an otherwise asymptomatic female
in gonadectomy specimen done in XY females
or may present as a pelvic tumor.
Gonadoblastoma is associated with
dysgerminoma in half the patients and with
other more malignant germ cell neoplasms
uncommonly. The contralateral gonad may
harbor a microscopic germ cell malignancy.
The prognosis of patients with gonado-
blastoma is excellent, even when associated
with dysgerminoma, if the tumor as well as
the contralateral gonad are excised. Metastasis
is a late occurrence.
DIAGNOSIS
Most women with germ cell or stromal tumors
are diagnosed in the same fashion as those
with epithelial ovarian neoplasms. They
present with abdominal pain/discomfort,
distension or a pelvic mass. However an
ovarian tumor in childhood/adolescence or in
a young woman points more towards a non-
epithelial neoplasm. Also, the associated
history of primary amenorrhea and the
presence of genital anomaly or signs of
virilization favor the diagnosis of an ovarian
germ cell malignancy. Elevated specific tumor
markers and abnormal sex chromatin studies
are highly suggestive of specific types of germ
cell neoplasm.
182 A Practical Approach to Gynecologic Oncology

Evaluation of women suspected to have a the uterus is to be considered. Ten percent of

non-epithelial ovarian neoplasm is the same
as that for all women presenting with a pelvic
mass. This includes a complete physical
examination with pelvirectal examination
(internal pelvic examination may be omitted
in sexually inactive women), ultrasound of the
pelvis and chest X-ray. Initial laboratory
investigations include routine hematological
and serum chemistry evaluation. Relevant
tumor markers should be assayed, especially
when age and ultrasonographic findings point
towards a malignant germ cell neoplasm.
Though the ultrasound features are not
distinguishable from other ovarian neoplasms,
large mostly solid ovarian mass or the
presence of thick septae and echoic foci along
with doppler flow ultrasonography showing
low resistive index are consistent with germ
cell or stromal cell neoplasms.
A significant number of women with gra-
nulosa cell tumors of the ovary demonstrate
signs/symptoms of increased estrogen
production. This is manifested as increased
endometrial thickening on ultrasonography.
In these women, preoperative investigation
should also include endometrial biopsy espe-
cially in young women where preservation of
granulosa cell tumors are associated with
concomitant endometrial adenocarcinoma
and as many as 50 percent are reported to have
endometrial hyperplasia.21
Biologic Serum Markers
Many malignant germ cell tumors have
various serum markers for monitoring their
clinical status such as α-fetoprotein, β-human
chorionic gonadotropin (β-hCG), human
placental lactogen (HPL), pregnancy-specific
β1-glycoprotein, fibronectin, transferrin, α-1-
antitrypsin, lactate dehydrogenase (LDH),
cancer antigen 125 (CA-125) and neuron-
specific enolase.27-29 Of all these different
markers, only AFP and β-hCG are routinely
monitored. Although serum markers are of
value in diagnosis of germ cell tumors of the
ovary, their most effective use is in monitoring
response to therapy and detecting recurrences
early during follow-up. The clinically relevant
biologic markers in malignant germ cell
tumors are summarized in Table 14.4.
1. α-fetoprotein (AFP)
Endodermal sinus tumor and embryonal
carcinoma are capable of synthesizing
α-fetoprotein (AFP). AFP can be monitored

Table 14.4: Biologic markers in germ cell tumors

Tumor type Histological AFP β– hCG Others
grading
Dysgerminoma Malignant - +/- CA-125, LDH, ALP, Calcium,
Neuron-specific enolase
Endodermal sinus tumor Malignant + -
Embryonal carcinoma Malignant + +
Polyembryoma Malignant + +
Choriocarcinoma Malignant - +
Teratoma, mature Benign
Immature Malignant +/- +/- CA-125, LDH,
CA-19-9, CEA,
Neuron-specific enolase
Mixed germ cell tumor Malignant +/- +/-

as a tumor marker in these patients and in
mixed germ cell tumors with endodermal
sinus tumor or embryonal carcinoma
component.
There may be histologically detectable
small foci of endodermal sinus tumor
within the immature teratoma. These
patients show a moderate elevation of the
AFP level (less than 100 ng/ml). Elevated
serum AFP has been reported in 4 of 12
patients with pure immature teratoma.30
The upper normal limit of AFP is 5 ng/ml.
2. β-Human chorionic gonadotropin (β-hCG)
Human chorionic gonadotropin (hCG) is
composed of α- and β-glycoprotein chains;
the α-chain is similar to that of other
glycoprotein hormones and the β-chain is
structurally distinguishable and measured
by radioimmunoassay. Elevated levels of
β-hCG are demonstrated in all cases of
ovarian choriocarcinoma, in most cases of
embryonal carcinoma31 and in some cases
of pure dysgerminoma and mixed germ cell
tumor.32-35 It should be noted that β-hCG
levels are lower in non-gestational than in
gestational choriocarcinoma.20
3. Cancer antigen 125 (CA-125)
CA-125 is an antigen associated with a high-
molecular weight glycoprotein expressed in
the coelomic epithelium during embryonic
development. It is demonstrated in the
majority of epithelial ovarian carcinomas
and has also been reported in malignant
germ cell tumors of the ovary especially
those with pure dysgerminoma and
immature teratoma.36
4. Lactate dehydrogenase (LDH)
Lactate dehydrogenase (LDH) is a
glycolytic enzyme with increased activity
in malignant tissues. Elevated serum LDH
in patients with ovarian dysgerminomas
before treatment has been shown to return
to normal levels following treatment.35, 37
We have seen very high levels of LDH in a
Germ Cell and Stromal Tumors of Ovary 183
pregnant woman with advanced ovarian
dysgerminoma, which sharply declined
following surgery and postoperative
chemotherapy.
5. Alkaline phosphatase
A high alkaline phosphatase (ALP) activity
has been demonstrated in dysgerminoma
tumor cells.35
6. Neuron-specific enolase
Recently, neuron-specific enolase has been
identified as a serum tumor marker in
patients with germ cell tumors. Raised
neuron-specific enolase levels were
reported in 4 of 8 patients with immature
teratomas and 5 of 6 patients with dys-
germinomas.29
7. Calcium
Hypercalcemia has rarely been described
in association with dysgerminoma that did
not recur after removal of the dysger-
minoma.38
8. Inhibin
Inhibin is a non-steroidal polypeptide
hormone that is secreted by granulosa cells
of the ovary. This hormone is secreted
during the reproductive years but not in
postmenopausal women. Inhibin has been
suggested as a tumor marker for granulosa
cell tumors since serum levels have been
found to be elevated several fold. However,
it is not specific as elevated inhibin levels
have been described with other ovarian
neoplasms like mucinous epithelial
tumors.39 Nevertheless, serum inhibin levels
may have a potential role as a marker for
monitoring patients with granulosa cell
tumors on therapy and for the early
detection of tumor recurrence. This is
especially true in postmenopausal women
who should otherwise have undetectable
inhibin levels. But in a young woman with
granulosa cell tumor and a remaining ovary
the interpretation of inhibin levels is more
difficult as values vary significantly during
184 A Practical Approach to Gynecologic Oncology
the menstrual cycle. Inhibin level is at its
nadir immediately after menses and hence
measurement at this time is recommended
for follow-up of young patients.
MANAGEMENT
Mature Cystic Teratomas of the Ovary
These being the most common benign germ
cell tumors of the ovary in women of
reproductive age, future fertility is a major
concern. Surgical management must focus on
preserving ovarian tissue and minimizing
adhesion formation. Experienced laparoscopic
surgeons should consider laparoscopy as an
alternative to laparotomy in the management
of these benign tumors. Spillage of the contents
may be minimized by the use of endobags for
retrieval of the specimen. If unintentional
spillage occurs, this should be managed with
copious saline irrigation until the returning
fluid is clear. The reported incidence of post-
operative chemical peritonitis is very low
(0.2%).40
The management of the contralateral ovary
is of great importance because of bilaterality
in 10 to 15 percent of patients. Since ultrasound
is a good predictor of the presence of a mature
cystic teratoma, careful inspection of the
contralateral ovary at the time of surgery is
all that is recommended. Incising the normal
ovary to look for macroscopic tumor may
result in hemorrhage and adhesion formation,
hence is not recommended.
Premenopausal women with bilateral or
multiple mature cystic teratomas should be
followed after cystectomy for any recurrence
or the development of other germ cell tumors.
Chapron el al demonstrated that 2 (4%) of their
48 patients with mature cystic teratomas were
detected to have another mature cystic
teratoma within 9 months, 1 in the ipsilateral
and 1 in the contralateral ovary.41 If the final
pathology on cystectomy specimen reveals an
immature teratoma, reoperation with
unilateral salpingo-oophorectomy and staging
laparotomy is recommended.
An annual pelvic ultrasound appears to be
appropriate postoperative surveillance
following cystectomy. Patients who develop
germ cell malignancy usually become
symptomatic with abdominal pain and
distension.
MANAGEMENT OF MALIGNANT GERM
CELL NEOPLASMS
Primary Surgery
Laparotomy is initially indicated for both
diagnosis and treatment of young women
suspected of having a germ cell malignancy.
The standard surgical staging including
peritoneal cytology, multiple biopsies of the
pelvic and abdominal peritoneum, omentum
and retroperitoneal lymph nodes, is important
to determine the extent of disease. Unilateral
salpingo-oophorectomy with preservation of
the contralateral normal ovary and the uterus
is the appropriate surgical management for
most patients, because bilateral ovarian
involvement with tumor is rare except in pure
dysgerminoma. If a bilateral salpingo-oopho-
rectomy is necessary because of bilateral
involvement, advanced disease or dysgenetic
gonads, the uterus may still be preserved for
donor oocyte transfer to achieve a normal
intrauterine pregnancy.
If metastases are encountered during the
primary surgery, the same principles of
cytoreductive surgery that have been applied
in the surgical management of epithelial
ovarian cancers are followed with resection of
as much tumor as is technically feasible and
safe. Optimal cytoreduction is important as
patients with bulky residual disease have sub-
optimal response to chemotherapy when
compared with those with minimal residual
disease (82% versus 55%).42

As germ cell tumors, especially dys-
germinomas, are very chemosensitive,
aggressive resection of metastatic disease is
generally not advisable. Ovarian cystectomy
of one or both ovaries is also an attractive
option for patients who have bilateral tumors
and are desirous of conception. Combining
ovarian cystectomy with postoperative
chemotherapy would, of course, be most
applicable for patients with dysgerminoma.
Patients to be considered for treatment with
surgery alone are those who have well-
documented state IA, grade 1 pure immature
teratoma or stage I pure dysgerminoma. For
all other patients with malignant germ cell
neoplasms, postoperative chemotherapy is
currently the standard of care.
Chemotherapy of Dysgerminoma
Though dysgerminoma is exquisitely radio-
sensitive and radiation therapy has been the
traditional postoperative treatment for several
decades with excellent survival rates, the
patient’s fertility is almost always lost.
Chemotherapy has essentially replaced
radiotherapy as the postoperative treatment
of choice for patients with dysgerminoma;
radiotherapy may be used as a salvage option
in selected patients.
The current gold standard chemothera-
peutic regimen is the combination of
bleomycin, etoposide and cisplatin (BEP) with
overall disease-free survival rates of greater
than 95 percent.43 Three to four cycles of this
regimen are adequate, but for patients with
bulky residual tumor, 5 to 6 cycles may be
indicated.
Chemotherapy of
Non-dysgerminomatous Tumors
Before the advent of combination chemo-
therapy, the prognosis for patients with non-
dysgerminomatous tumor was very dismal.
Postoperative treatment with radiotherapy or
Germ Cell and Stromal Tumors of Ovary 185
single-alkylating agent chemotherapy also
resulted in an equally dismal survival rates.
Combination chemotherapy in the form
of VAC regimen (Vincristine, dactinomycin
and cyclophosphamide) or VBP regimen
(Vinblastine, bleomycin and cisplatin)
produced a high proportion of cures in stage I
disease.43 Later, etoposide-containing regi-
mens revealed excellent activity and results
in patients with non-dysgerminomatous
tumors, making BEP (bleomycin, etoposide
and cisplatin) the popular regimen. Three or
four cycles of BEP resulted in sustained
remission in 96 percent of patients who had
completely resected stage I, II or III disease.44
This is the current gold standard chemo-
therapeutic regimen, but for patients with
bulky residual tumor, 5 to 6 cycles may be
indicated.
For choriocarcinomas the recommended
therapy is EMA-CO (etoposide, methotrexate,
actinomycin-D, cyclophosphamide and
vincristine).
Secondary Surgery
The role of secondary cyoreduction following
chemotherapy is uncertain. If a patient has an
isolated focus of persistent tumor after first-
line chemotherapy, then surgical resection
should be considered before changing the
chemotherapeutic regimen.
Second-look laparotomy is performed to
assess the disease status after a fixed interval
of chemotherapy. It may be unnecessary in
patients with early stage germ cell neoplasm
who had complete resection or who had
positive tumor markers. In a review of
experience with second-look laparotomy, the
findings were negative in 52 of 53 patients.45
It currently seems appropriate to reserve the
procedure for those patients who have
advanced disease negative tumor markers at
the start of chemotherapy.
186 A Practical Approach to Gynecologic Oncology
Salvage Therapy
Salvage therapy has a role in patients with
malignant ovarian germ cell tumors with
persistent, progressive or recurrent tumor after
initial chemotherapy. The most popular current
regimen includes ifosfamide, cisplatin and
either vinblastine or etoposide for platinum-
sensitive tumors, with complete response in 25
to 36 percent to chemotherapy alone or to
chemotherapy followed by surgical resection.43
For patients with platinum-resistant tumors
(progressive disease during platinum-based
chemotherapy or relapses within 6-8 weeks of
stopping therapy), dose intensification with
autologous bone marrow rescue is a reasonable
treatment option. Complete response was
reported in 52 percent of 29 patients with
refractory germ cell tumor.46
Management of Ovarian
Sex-cord Stromal Tumors
Surgery remains the mainstay of treatment for
patients with sex-cord stromal tumors of the
ovary. Conservative surgery with unilateral
salpingo-oophorectomy seems to be appro-
priate management for young patients with
stage IA disease. For older patients or those
with advanced stage disease, bilateral
salpingo-oophorectomy along with hystere-
ctomy is usually indicated. A careful
exploration and surgical staging procedure
must be performed in all patients. In a patient
with granulosa cell tumor, if conservative
surgery without hysterectomy is conte-
mplated, an endometrial sampling should be
performed to exclude the possibility of a
concurrent endometrial carcinoma.
Optimal cytreduction in advanced disease
is a major prognostic factor. Hence, every
effort should be made to resect any visible dis-
ease beyond the ovaries. Available data do not
demonstrate a consistent benefit of post-
operative chemotherapy in women with
advanced disease. However, most authors still
suggest that a multi-drug regimen of chemo-
therapy should be used in women with dis-
ease outside the ovary. A cisplatinum-based
regimen with etoposide (with or without
bleomycin) is preferred, pending an evalua-
tion of the benefit of paclitaxel. Currently, BEP
regimen appears to be the most popular post-
operative treatment for patients with sex-cord
stromal tumors.
The patients for postoperative chemo-
therapy include patients with stage I poorly-
differentiated Sertoli-Leydig cell tumors, or
those Sertoli-Leydig cell tumors that contain
heterologous elements or metastatic tumors of
any histologic type.
Reproductive Function and
Late Sequelae Following Treatment
Although ovarian dysfunction or failure is a
risk of chemotherapy, most survivors with
ovarian preservation at surgery resume
normal menstrual and reproductive function
following chemotherapy.20,43,47,48 Patients who
are premenarchal at the time of diagnosis may
anticipate normal menarche with regular
menses. Most postmenarchal patients report
a return to regular menstruation during or
after completion of chemotherapy with delays
ranging from 0 to 6 months.47,48
Fertility-preserving surgery followed by
chemotherapy even in advanced-stage
malignant germ cell tumors of the ovary, is
effective in conserving the reproductive
function of women. 47,48 In a series of 106
patients with malignant germ cell neoplasms
of ovary, 38 attempted conception following
treatment. Twenty-nine achieved at least one
pregnancy (76%). Among the patients who
conceived, 20 were stage I, one was stage II
and eight were stage III. Follow-up of the born
children revealed no evidence of congenital
anomalies.47
Other reported long-term sequelae include
functional cysts in the residual ovary, risk of

secondary malignancies and premature
ovarian failure. Factors such as older age at
chemotherapy, greater cumulative drug dose
and longer duration of therapy may have an
adverse effect on future gonadal function.
CONCLUSION
The key difficulty in the management of ova-
rian germ cell and sex-cord stromal tumors is
that it is rare for the diagnosis to be known
preoperatively. Hence, intraoperative deci-
sions should be conservative in young
patients. A second procedure after histopatho-
logical diagnosis is preferable to inappropri-
ate aggressive surgery.
Fertility-preserving surgery followed by
appropriate chemotherapy should remain the
standard of care even for women with
advanced disease. Currently, BEP is the most
effective and popular chemotherapy regimen.
Patients with positive tumor markers should
receive one or two cycles of chemotherapy
after normalization of serum levels, but in
patients without measurable disease or
elevated serum tumor markers, it is more
difficult to determine the precise duration of
treatment. Studies on late effects of treatment
show that reproductive potential can be
preserved in most young patients with ovarian
germ cell and sex-cord stromal cell tumors.
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190 A Practical Approach to Gynecologic Oncology
15
Reynaud in 1847 gave the first gross
description of fallopian tube cancer which is
rarest of all gynecological malignancies. The
first case was reported in 1888 by Orth.
INCIDENCE
Primary fallopian tube malignancy comprises
approximately 0.3 to 1.1 percent of cancers
of female genital tract.1, 2 The annual incidence
of epithelial fallopian tube carcinoma is 3-4
per million women per year. Peak incidence
occurs between the ages of 60 and 64 years.
The incidence is significantly higher in
caucasian women than in African Americans.
Chronic tubal inflammation commonly coex-
ists in fallopian tubes that contain carcinoma.3,4
Whether there is an etiologic relationship
between the two conditions is still unclear.
CLINICAL FEATURES
The most frequently occurring symptoms are
vaginal bleeding, discharge and pelvic pain.
Primary fallopian tube carcinoma must be
considered in the differential diagnosis when
post-menopausal bleeding persists after a
negative curettage. The presence of pain is
highly significant since cancers of ovary,
endometrium, and cervix do not cause pain
until their diagnosis is all too obvious. The
syndrome of “hydrops tubae profluens” was
described by Latzko in which a patient pre-
sents with pelvic mass, profuse watery or
Cancer of
Fallopian Tube
• Alka Pandey
honey colored vaginal discharge and pelvic
pain that is greatly relieved by the sudden
disappearance of the mass. It is rarely
encountered but is almost pathognomonic.
Pelvic mass is the most common physical
finding occurring in approximately 65 percent
of patients. 5 Ascites may be present in
15 percent of cases.
DIAGNOSIS
Preoperative diagnosis is made in less than
three percent of the patients due to low index
of suspicion by the medical practitioners.
The effectiveness of cytologic diagnosis
from cervical and/or vaginal pool samples is
widely variable and has been reported
as 40 to 60 percent in women with tubal
cancers. 1,6 The usual ultrasound finding
reveals a sausage-shaped mass with internal
projections into a fluid-filled lumen giving a
characteristic shape.7 Successful preoperative
diagnosis of primary fallopian tube carcinoma
using transvaginal color and pulsed Doppler
ultrasound has recently been reported by
Kurjak and coworkers.8 Elevated levels of
Ca-125 are not very specific.
STAGING
FIGO in 1991 promulgated following staging
system for tubal carcinoma.9
• Stage 0 : Carcinoma in situ (limited to
tubal mucosa).

• Stage I : Growth limited to the fallo-
pian tubes.
• Stage IA : Growth limited to one tube
with extension into the sub-
mucosa and/or muscularis but
not penetrating the serosal
surface, no ascites.
• Stage IB : Growth limited to both tubes
with extension into the
submucosa and/or muscularis
but not penetrating the serosal
surface. No ascites.
• Stage IC : Tumor either stage IA or IB
with tumor extension through
or on to the tubal serosa or
with ascites present contain-
ing malignant cells or with
positive peritoneal washings.
• Stage II : Growth involving one or both
fallopian tubes with pelvic
extension.
• Stage IIA : Extension and/or metastasis
to the uterus and/or ovaries.
• Stage IIB : Extension to other pelvic
tissues.
• Stage IIC : Tumor either stage IIA or IIB
and with ascites present con-
taining malignant cells or with
positive peritoneal washing.
• Stage III : Tumor involving one or both
fallopian tubes with perito-
neal implants outside of the
pelvis and/or positive retro-
peritoneal or inguinal nodes.
Superficial or inguinal nodes.
Superficial liver metastases
equal stage III. Tumor seems
limited to the true pelvis with
negative nodes but with histo-
logically proved malignant
extension to the small bowel
or omentum.
• Stage IIIA : Tumor grossly limited to the
true pelvis with negative
nodes but with histologically
Cancer of Fallopian Tube 191
confirmed microscopic seed-
ing or abdominal peritoneal
surfaces.
• Stage IIIB : Tumor involving one or both
tubes with histologically con-
firmed implants on abdominal
peritoneal surfaces, none ex-
ceeding 2 cm in diameter.
Lymph nodes negative.
• Stage IIIC : Abdominal implants greater
than 2 cm in diameter and/or
positive retroperitoneal or
inguinal nodes.
• Stage IV : Growth invading one or both
fallopian tubes with distant
metastases. If pleural effusion
is present, there must be posi-
tive cytology to be stage IV.
Parenchymal liver metastases
equal stage IV.
PATTERNS OF SPREAD
Studies from the literature indicate that the
pattern of spread of fallopian tube carcinoma
is similar to ovarian carcinoma with both
intra-peritoneal and lymphatic commonly
encountered. 1,10 di-Re and coworkers 11
observed an increase in nodal metastasis rates
with stage of disease and grade, the
percentage of patients with positive nodes
was 33, 66 and 80 percent for stages I, II and
III-IV diseases respectively. Patients with
negative nodes had a survival of 76 months
compared with only 33 months if nodal
metastasis was present.
PROGNOSTIC FACTORS
In view of the inherent difficulties of studying
such a rare disease the role of prognostic
factors assumes a greater importance—stage
is the most consistent prognostic factor
associated with survival.10, 12-15 Although initial
tumor burden does not have predictive
significance, regarding survival, residual
192 A Practical Approach to Gynecologic Oncology
disease after cytoreduction is a strong
prognostic factor of survival. 10,13,15,16 Other
important prognostic factor is presence of
ascites.10 Peters and colleagues 15 analyzing
stage 1 disease, observed statistically
significant increase in the risk of death with
invasion of more than 50 percent of the tubal
muscularis. No association between grade
and survival was observed by several
investigators.10,14,18
TREATMENT
Initial management is by surgery. Since
fallopian tube carcinoma is rarely diagnosed
preoperatively the surgeon is usually
confronted with the diagnosis intra-
operatively. The new FIGO staging system
requires a cytologic analysis of either ascitic
fluid or pelvic and abdominal washings,
abdominal hysterectomy and bilateral
salpingo-oophrectomy, omentectomy and
selective pelvic and paraaortic lymphadene-
ctomy with selective peritoneal biopsies. In
apparent early stage disease there may be up
to 33 percent incidence of nodal metastasis, 11
highlighting the importance of selective pelvic
and paraaortic lymph adenectomy. For
advanced disease cytoreductive surgery is
performed. Eddy and coworkers, 13 found
that median survival of patients with no gross
residual disease was 30 months as compared
to 17 months in patients whose largest tumor
diameter was greater than 2 cm.
Radiation Therapy
Abdominopelvic irradiation has been used as
postoperative adjuvant treatment for patients
with fallopian tube carcinoma. 10,14,17 This
approach has given better survival than
radiation confined to pelvis alone. While
fallopian tube cancer is sensitive to radiation
therapy the dose that may be delivered safely
to the upper abdomen using conventional
fractionation is less than that required to
eradicate macroscopic disease. If post-
operative abdominopelvic irradiation is to be
recommended for more advanced disease it
should be reserved for those with microscopic
or no residual disease in the upper abdomen
and less than 1 cm residuum in the pelvis.
Chemotherapy
Cyclophosphamide, melphalan and thiotepa
were among the frequently used single agents
in early cytotoxic treatment of tubal carci-
noma.18-20
Peters and colleagues20 demonstrated that
multiagent chemotherapy with cysplatin
achieved an 81 percent objective response rate
whereas multiagent therapy without cisplatin
achieved a 29 percent response rate and single
agent therapy other than cisplatin achieved a
9 percent response rate. During the passed
decade as experience increased it is obvious
from the literature that fallopian tube cancers
respond well to chemotherapy. Multidrug
regimens containing cisplatin seems to be
more active than nonplatinum single agents
or multidrug regimens without cisplatin.
Sequential therapy seems to be very pro-
mising. One report of sequential therapy from
Toronto suggested that it was superior to
whole abdominopelvic radiotherapy alone.21
Over all survivals for sequential therapy were
54 percent for stage I, 68 percent for stage II,
28 percent for stage II and 25 percent for
stage IV. The over all survival was signi-
ficantly influenced by treatment, with 5 year
survival of 84 percent following sequential
therapy compared with 37 percent for the
historic cohort treated with radiation alone.
The overall toxicity was deemed acceptable.
Role of hormone therapy in fallopian tube
cancer is not clear.

PROGNOSIS
Although most of the larger series have
reported recurrent disease later than 5-years
after therapy more than 80 percent of the
recurrences occur by the third year from the
onset of treatment.22 The larger series which
reported staging similar to the current FIGO
system observed that the 5-year survival was
61 percent for stage I, 40 percent for stage II
and 17 percent for stage III and IV.10,14,19,23 In
two reports there were no 5 years survivors
in stage IV.
Other malignant fallopian tube neoplasms
are malignant mixed tumors primary leio-
myosarcoma, trophoblastic disease and
immature teratoma.
REFERENCES
1. Sedis A. Primary carcinoma of fallopian tube.
Obst and Gyne Survey 1961;16:209-26.
2. Rosenblatt KA, Weiss NS, Schwartz SM.
Incidence of malignant fallopian tube tumors.
Gynecol Oncol 1989;35:236-39.
3. Shiller HM, Silver Berg. Staging and prognosis
in primary carcinoma of the fallopian tube.
Cancer 1971;28:389-95.
4. Tamimi HK, Figge DC. Adenocarcinoma of
the uterine tube potential for lymph node
metastasis. Am J Obst Gyne 1981;141:132-37.
5. Nordin AJ. Primary carcinoma of the fallopian
tube—A 20 years literature review. Obst Gyne
Survey 1994;49:349-61.
6. Johnson GA. Primary malignancy of fallopian
tube. A clinical review of 13 cases. J Surg
Oncology 1983;24:304.
7. Ajjimakron S, Bhamaraparvati Y. Trans-
vaginal ultrasound and the diagnosis of
fallopian tube carcinoma. J Clinical Ultra-
sound 1991;19:116-19.
8. Kurjak A, Kupesic I, Lijas M, et al. Preoperative
diagnosis of primary fallopian tube carci-
noma 1998;68:29.
9. Petterson F. Staging rules for gestational
trophoblastic tumors and fallopian tube
cancer. Acta Obst Gyne Scandinavia 1992;
71:244-45.
Cancer of Fallopian Tube 193
10. Podratz KC Podczska ES, Gaffey TA, et al.
Primary carcinoma of fallopian tube. Am J
Obstet Gynecol 1986;154:1319-26.
11. Di RE E, Grosso G, Raspaglicsi F, Baiochhi G.
Fallopina tube cancer—incidence and role of
lymphatic spread. Gyne Oncology 1996;62:
199-202.
12. Rosen AC, Ktein M, Hafner E, et al. Manage-
ment and prognosis of primary fallopian tube
carcinoma. Gyne Obstet Invest 1999;47:45-51.
13. Eddy GL, Copeland IJ, Gerhenson DN, et al.
Fallopian tube carcinoma. Obst Gyne 1984;
64:546-52.
14. McMurray Er Jacobs AJ, Perez CA, et al.
Carcinoma of the fallopian tube management
and sites of failure. Cancer 1986;58:2070-75.
15. Peters WA, Anderson WA, Hopkins MP, et al.
Prognostic features of carcinoma of the
fallopian tube. Obst Gyne 1988;71:757-62.
16. Barkat RR, Rubin SC, Saigo PE, et al. Cisplatin-
based combination chemotherapy in carci-
noma of the fallopian tube. Gyne Onco 1991;
42:156-60.
17. Benede JL, White GW, Fairey RN, Boyes DA.
Adenocarcinoma of the fallopian tube
experience with 41 patients. Obst and Gyne
1977;50:654-57.
18. Rose PG, Piver Ms Taulcada. Fallopian tube
cancer—The Rosewell Park experience.
Cancer 1990;66:2661-67.
19. Peters WA, Anderson WA, Hopkins MA.
Results of chemotherapy in advanced cancer
of fallopian tube. Cancer 1989;63:836-39.
20. Brown MD, Kohorn EI, Kapp DS, et al.
Fallopian tube carcinoma. Int J Radiat Oncol
Biol Phys 1985;11:483-90.
21. Rawlings O, Bush R, Dembo A, et al. Fallopian
tube cancer. Survival following radiation and
chemotherapy. Proceedings of International
Gynecologic Cancer Society. 3rd Biennial
meeting 1991, Cauirs—Australia.
22. Semrad N, Watring W, Fu YS, et al. Fallopian
tube carcinoma common extraperitoneal
recurrence. Gyne Onco 1986;24:230-35.
23. Brown MD, Kohorn EJ, Kapp DS, et al.
Fallopian tube carcinoma. Int J Radiation
Oncol Biol Physi 1985;11:483-90.
194 A Practical Approach to Gynecologic Oncology
Pregnancy Associated with
16 Gynecologic Cancers
INTRODUCTION
Pregnancy associated with gynecological
cancers are not often seen. The situation is
encountered rarely and therefore has to be
handled by a team of senior consultants with
experience. Of the gynecological cancers,
cervical and breast cancers are the ones seen
most often in pregnancy. Rarely one may
encounter ovarian cancer.
INCIDENCE OF CANCER IN PREGNANCY
• CIN—1.3/1000
• Invasive cervical cancer—1/1000
• Breast cancer—0.33/1000
• Ovarian cancer—0.1/1000
From Allen HH, Nisker JA (Eds). Cancer in
pregnancy: Therapeutic guidelines, 1996.1
Cancer of the vulva and fallopian tube along
with pregnancy are so rare that figures are
not available. Theoretically endometrial
cancer cannot coexist with pregnancy.
There are several issues that are peculiar
to pregnancy with cancer and these have to
be addressed with due consideration. The
evaluation of the cancer and treatment may
affect the fetus, clinical assessment of the
cancer may be difficult because of the growing
uterus. Surgery may pose increased risk to
the mother and the course of the disease may
be affected by the pregnancy.
Until recently, it was felt that the hormonal
milieu associated with pregnancy may
• Lakshmi Seshadri
adversely affect the course of cancer by
stimulating its growth and rapid spread. But
no concrete evidence is available to prove that
pregnancy has an adverse biological effect on
gynecological cancers.2 Thus the prognosis is
same as in the non-pregnancy women.
EVALUATION
Clinical evaluation of the disease and clinical
staging may be interfered by the enlarging
uterus. In the first trimester, it is not too
difficult but in second and third trimesters,
assessment of parametrium, nodal disease, etc.
become difficult.
Various imaging modalities have to be
used for assessment and preoperative evalua-
tion of cancers. It is well known that these can
have a deleterious effect on the fetus. The
effects are gestational age-dependent.3 Any
insult during the peri-implantation stage can
be lethal. During the embryonic period of
organogenesis, exposure to agents can lead to
a teratogenic effect. Insults during early fetal
stage cause growth disturbances where as
during the late fetal stage, they cause subtle
anomalies, sterility and childhood malign-
ancies in the offspring .
Radiation upto 0.1 Gy is considered safe.
Doses more than 1 Gy can cause fetal death.
Doses between these two can cause various
deleterious effects. Ultrasound scans are
considered safe in pregnancy4 and are used
extensively to evaluate the extent of disease,
 Pregnancy Associated with Gynecologic Cancers 195
nodal metastasis, etc. Information obtained by
ultrasound scan is adequate in most situations.
In the second half of pregnancy, the large
uterus may interfere with evaluation of pelvic
structures. Computerized tomography deli-
vers doses often ranging from 8-1.3 Gy and
the dose may be more if contrast is used.
Hence they are not recommended for use in
pregnancy. 5 Magnetic resonance imaging
(MRI) delivers non-ionizing radiation and so
far no deleterious effect on fetus has been
reported with its use.6 Due to its superior
resolution and multiplanar images, this has
become a very popular method of evaluation.
MANAGEMENT
Treatment of malignancies with radiotherapy
or chemotherapy can also affect the fetus.
Surgery for malignancies in pregnancy is not
associated with significant increase in
mortality or morbidity. Altered anatomy and
increased vascularity should be borne in mind.
Lateral tilt should be maintained during the
surgical procedures.
Small doses of radiotherapy can give rise
to genetic damage and therefore is contra-
indicated.7 Radiation to supradiaphragmatic
structures can deliver 1.2-1.7 percent of total
dose to pelvis and can be lethal.
All chemotherapeutic agents are theore-
tically mutagenic and teratogenic and cannot
be used during the period of organogenesis.
Absorption and distribution of drugs are also
altered in pregnancy. Most of the data on
effects of chemotherapeutic agents on the fetus
are from animal studies and cannot be directly
extrapolated to humans. In general teratogenic
effects, growth restriction, reduced intellectual
development and childhood malignancies are
known to occur.8 Most drugs are secreted in
breast milk and so breastfeeding is considered
unsafe but platinum and taxol have been used
after first trimester with reasonable safety.
Recent review noted that there is an increased
rate of prematurity with chemotherapy.9
Preinvasive Cervical Cancer
This is fairly common in pregnancy. Manage-
ment remains a challenge due to increased
bleeding with biopsy, preterm labor and
infection. Abnormal Papanicolau’s smear
should be followed by colposcopy. Biopsy is
taken if high-grade lesion is suspected but
endocervical curettage should be avoided.
Ablation or excision should be postponed until
after delivery. If microinvasive cancer is
suspected, LEEP or shallow cone may be per-
formed to exclude invasive cancer. Conization
is associated with hemorrhage (9-13%), spo-
ntaneous pregnancy loss (3.6-8%) and pre-
mature delivery (12%). If invasive cancer is
excluded, definitive management can be
deferred.
Invasive Cervical Cancer
Invasive cancers FIGO stage-Ia2 and above if
diagnosed before 24 weeks are managed with
surgery or RT without consideration for the
pregnancy. If diagnosed after 24 weeks, it may
be possible to wait till fetal maturity, deliver
the baby and then institute definite treatment
(Figs 16.1 A and B).
Classical cesarean section is usually
recommended but recent studies have shown
that vaginal delivery is possible if the growth
is not too big.10 Increased risk of hemorrhage
and infection have been reported. Episiotomy
site recurrences are well known;11 therefore
episiotomy must be avoided. If lower segment
is not infiltrated or very vascular, lower
segment cesarean section may be performed.
Recently neoadjuvant chemotherapy with
platinum to shrink the tumor and deferred
radiotherapy after delivery has been under
trial but only small series are available.12
Survival of women with invasive cervical
196 A Practical Approach to Gynecologic Oncology

Invasive cancers < 24 weeks

Ia2 - IIa
II b

External RT Radical hysterectomy with lymphadenectomy External RT

Abortion Abortion
(Spontaneous or induced)

Intracavitary RT Intracavitary RT
(A)

Invasive cervical cancer > 24 weeks

Ia2 - IIa IIb

C. Section at maturity C. Section at term

RT Radical surgery RT
(B)

Figs 16.1A and B: Management of invasive cervical cancer

cancer in pregnancy is the same as that in non-
pregnant women, stage for stage.13
Ovarian Cancer
Ovarian cancer is rare in pregnancy and
when encountered is generally in early stage.
Epithelial ovarian cancers of early stage
(stage-I) can be treated with unilateral or
bilateral adnexectomy.14 Chemotherapy can be
postponed until delivery at maturity. Those
with advanced disease, if in the first trimester,
will need termination of pregnancy and defi-
nitive surgery and chemotherapy. If late in
pregnancy, neoadjuvant chemotherapy with
platinum and taxol may be given for three
cycles.15 Surgery and three more courses of
chemotherapy may be deferred until delivery.
Germ cell tumors cannot be managed on
similar lines because the tumors are aggressive
and chemotherapy cannot be delayed. 16
Therefore, if diagnosed early in pregnancy,
termination and definitive chemotherapy are
mandatory. If late in pregnancy, unilateral
salpingo-oophorectomy followed by three
cycles of chemotherapy may be given.
Breast Cancer
Contrary to popular belief,17 prognosis and
survival does not worsen with pregnancy. In
women above 35 years of age, it is three times
more common. If breast cancer is diagnosed
in first trimester termination of pregnancy and
definitive treatment are indicated. If pre-
gnancy is more advanced, lumpectomy and
 Pregnancy Associated with Gynecologic Cancers 197
lymphadenectomy may be performed and
radiotherapy and chemotherapy delayed till
delivery.
In women with past breast cancer pre-
gnancy does not increase recurrence rates.18
CONCLUSION
Management of pregnant women with gyne-
cologic malignancy is difficult and challe-
nging. If requires a good understanding of the
effects of treatment on the fetus. A multi-
disciplinary approach with involvement of
obstetrician, oncologist and neonatologist is
required. Treatment has to be individualized
and the couple will have to be counselled and
the mother’s views and opinion must be taken
into consideration.
REFERENCES
1. Allen HH, Nisker JA (Eds). Cancer in preg-
nancy: Therapeutic guidelines. Mt Kisco, NY:
Futura Publishing 1986.
2. Disaia PJ, Creaseman WT (Eds). Cancer in
pregnancy. Clinical Gynecologic Oncology.
Mosby Inc, Philadelphia, 2002; 439.
3. Mayr NA, Wen B Chen, Saw CB. Radiation
therapy during pregnancy. Obstet Gynecol
Clin North Am 1998; 25:301.
4. Pelsany RE. Diagnostic imaging modalities
during pregnancy . Obstet Gynecol Clin North
Am 1998; 25:287.
5. Moore MM, Shearer DK. Fetal dose estimate
for CT pelvimetry. Radiology 1989; 171:265.
6. Rofsky NM, Pizzarello DJ, Weinreb JC, et al.
Effect on fetal mouse development of expo-
sures to MR imaging and gadopentetate
dimeglumine. J Magn Reson Imaging 1994;
4:805.
7. Kinlen LJ, Acheson ED. Diagnostic irradiation:
Congenital malformations and spontaneous
abortion. Br J Radiol 1968; 41:648.
8. Doll RC, Ringenperg OS, Yarbo JW. Anti-
neoplastic agents and pregnancy. Semin Oncol
1989; 16: 337.
9. Ward RM, Bristow RE. Cancer and pregnancy:
Recent developments. Curr Opin Obstet
Gynecol 2002; 14:613.
10. Lee RB, Neglia W, Park RC. Cervical carcinoma
in pregnancy. Obstet Gynecol 1981; 58:584.
11. Cilby WA, Dodson MK, Podratz KC. Cervical
cancer complicated by pregnancy: Episiotomy
site recurrence following vaginal delivery.
Obstet Gynecol 1994; 84:179.
12. Tewari K, Cappuccini F, Gampino A, et al.
Neoadjuvant chemotherapy in the treatment of
locally advanced cervical carcinoma in
pregnancy. Cancer 1998; 82:1529.
13. Creaseman WT, Rutledge F, Fletcher G.
Carcinoma of the cervix associated with
pregnancy. Obstet Gynecol 1970; 36:495.
14. Boulay R, Podczaski E. Ovarian cancer
complicating pregnancy. Obstet Gynecol Clin
North Am 1998; 25:385.
15. Anderson LE, Elia G, Garfinkel D, et al.
Platinum chemotherapy during pregnancy for
serous cystadenocarcinoma of the ovary.
Gynecol Oncol 1993; 49:92.
16. Malone JM, Gershenson DM, Creasy RK, et al.
Endodermal sinus tumor of the ovary
associated with pregnancy. Obstet Gynecol
1986; 68:865.
17. Petrek JA. Breast cancer during pregnancy.
Cancer 1994; 74:518.
18. Gilber S, Coates AS, Golhirsch A, et al. Effect
of pregnancy on overall survival after diagnosis
of early stage breast cancer. J Clin Oncol 2001;
19:1671.

17 Gynecologic Cancers
Imaging techniques have come a long way
since the days W. Roentgen discovered
X-rays way back in 1895. There have been
rapid strides since then and the entire gamut
of radiological investigations that are being
routinely used for imaging apart from
conventional X-rays are ultrasonography,
color Doppler studies, computed tomography,
magnetic resonance imaging, radioisotope
scanning, positron emission tomography, etc.
The female genital tract is no exception
to this barrage of investigations and an
important role is played by them in early
detection, diagnosis, staging and management
of gynecological tumors.
There is however, no substitute for an
active interaction between the clinician and
radiologist regarding the patient for an
appropriate diagnosis as the female genital
tract is a complex system changing in the
various stages of a woman’s life—in fact going
through different phases in a month itself.
GYNECOLOGIC IMAGING
Conventional
Plain X-ray Abdomen
It may help to confirm the presence of any
pelvic mass by demonstrating a homogenous
soft tissue mass, in the pelvis which may
extend into the abdomen and displace gas
filled bowel. There may be radiological
evidence of ascites—loss of clarity of visceral
Imaging in
Suparna Mazumdar
outline, haziness and lateral bowing of body
wall lines. The spine and pelvis should be
examined for neoplastic involvement.
Calcification present in the pelvis may be
pointer for pelvic pathology—benign as well
as malignant, e.g. uterine fibroids, ovarian
dermoids, ovarian fibroma, ovarian carci-
noma.
Chest X-ray
It is indicated to assess distant spread of
disease—commonly in trophoblastic tumors.
Three types of metastases are seen:
a. Discrete (single or multiple)
b. Multiple ill-defined (snowstorm)
c. Arterial emboli giving a picture of infarc-
tion.
IVU
The intravenous urogram is performed to
demonstrate distortion, deviation or obstru-
ction of urinary tract by a pelvic mass and to
show any resulting hydronephrosis/urinary
residue/vesical or ureteric invasion.
Barium Enemas
They may be helpful to demonstrate adjacent
bowel involvement.
Hysterosalpingogram
No significant role nowadays.

Lymphography
Previously done to demonstrate many of the
lymph nodes to which uterine or ovarian
cancers metastasize. The glands remained
visible for many months.
Ultrasonography, computed tomography
and magnetic resonance imaging have almost
eliminated the need for these investigations.
Modern Imaging
Ultrasonography
Introduced in the 1950’s, it became a practical
imaging tool in cardiology and obstetrics in
the 1960’s. However, with the advent of real-
time imaging in the 1970s it has developed into
a major imaging tool. It is considered to be
the initial and basic imaging modality in
evaluating a patient with a pelvic mass and
may be used as a guidance of aspiration/
biopsy procedures. The development of high
frequency vaginal probes has improved the
detail and diagnostic accuracy in many cases.
Technique
The standard transabdominal sonogram is
performed with a distended bladder, to
provide an acoustic window. The distended
bladder displaces the bowel loops out of the
pelvis and keeps the target organs at a depth
of about 10 cm which keeps them all within
the focal zone of the standard 3.5 MHz
transducers usually used. In patients who
cannot adequately hold their urine, obese
patients and patients with retroverted uterus
transabdominal sonography has limitations.
These can be overcome by the use of
transvaginal sonography where the bladder
must be kept empty. The frequency range is
from 5-7.5 MHz. Since the organs are closer to
the probe, the details are better and distinction
between bowel and adnexal masses easier. The
endometrial anatomy is also better appre-
Imaging in Gynecologic Cancers 199
ciated. However, its limitations are restricted
field of view, especially in large masses,
limited availability in our country and lack of
enterprise.
The two methods are therefore comple-
mentary.
Color Doppler: The technique is used mainly
with transvaginal probes for the study of
pelvic vessels. The common, external and
internal iliac vessels may be assessed by a
transabdominal approach however, the
uterine and ovarian arteries are better
demonstrated by transvaginal US with color
flow Doppler. Optimal signal recording
methods are used. Normally the uterine
arteries are seen coursing along the lateral
aspects of the uterine body. Its branches and
the ovarian artery are seen in the broad
ligament and superior aspect of the ovary
respectively. Normal venous structure are
usually seen in association. The normal
Doppler spectra varies throughout the cycle,
particularly in the ovarian artery.
Duplex ultrasound has no established role
in the assessment either of cervical carcinoma
or pelvic metastatic disease. In ovarian cancers
it has been suggested that malignant tumors
show neovascularity and higher diastolic
flow and consequently lower resistance
and pulsatility indices than benign tumors.
However, currently color Doppler has neither
the sensitivity nor specificity to distinguish
between benign and malignant tumors. Their
is limited role in screening for first order
relatives of ovarian cancer though there is a
high false positive detection rate, particularly
in premenopausal patients using both CA 125
and US. In malignant trophoblastic disease it
appears to be of value in determining
prognosis and treatment planning. There is
significant increase in myometrial and
endometrial blood flow with high systolic
velocity and low resistance index.1
200 A Practical Approach to Gynecologic Oncology
Hysterosalpingo-contrast sonography: The use of
echo-enhancing agents along with trans-
vaginal scan has developed as a new technique
to study the endometrial cavity and patency
of tubes but has not replaced X-ray hystero-
salpingograms.
Normal anatomy of female genital tract on USG:
The vagina is seen as a double walled
structure, flattened in the sagittal plane. The
vesicovaginal and vaginorectal septae are not
greater than 5 mm thick.
The uterus varies in shape and size
throughout life. The normal postpubertal
nulliparous uterus measures 8 cm in length,
4 cm in width and 5 cm in diameter.
Multiparity increases each dimension by
1 cm. The postmenopausal uterus atrophies
gradually and ranges from 3.5-6.5 cm in length
and 1.2-1.8 cm in AP diameter over the age
of 65 years.2
The normal myometrium is homogenous
and hypoechoic. The normal endometrial
cavity is seen as a thin echogenic line and the
appearance varies with the menstrual cycle—
the upper limit of maximum thickness is
considered to be up to 13 mm in a menstrua-
ting woman. The postmenopausal endome-
trium is thin (2-3 mm) and considered to be
abnormal if greater than 5 mm.2
The cervix is seen as a bulge into the vaginal
lumen.
The ovaries are ellipsoid structures with
their cranio-caudal axes parallel to the internal
iliac vessels which lie posteriorly and serve
as reference. The normal ovary has a
relatively homogenous cortex with a central
more echogenic medulla. Well-defined cystic
follicles may be seen in the cortex. The
appearance of the ovary varies with age and
phase of the menstrual cycle. Ovarian volume
is considered to be the best method
for determining ovarian size. In a normal
menstruating woman, ovarian volume is
accepted to have a volume of 10 + 3.9 cc. In
postmenopausal women, the upper limit has
been stated to be 2.5 cc (2.9 + 2.2 cc using
TVS).1,2
The fallopian tube usually cannot be ide-
ntified sonographically unless it is surrounded
by fluid. It is about 8-10 mm wide and the
lumen cannot be seen unless filled with fluid.
Computed Tomography
Computed tomography is an important
imaging tool for evaluating patient with
suspected pelvic disease because it provides
excellent cross-sectional display of bony and
soft-tissue pelvic structure.
A successful CT examination of pelvis
requires complete opacification of alimentary
tract—this is achieved by oral contrast to the
patient. Intravenous contrast is also admi-
nistered to opacify the vessels so as to be able
to differentiate better from enlarged nodes. A
delayed set of images is taken through the
urinary bladder for better assessment of
urinary wall—for routine studies, contiguous
1 cm transaxial scans will suffice.3
Magnetic Resonance Imaging
In recent years the clinical utility of MRI in
pelvic imaging has been better defined—it has
certain unique features such as its ability to
produce multiplanar images, superior and
inherent contrast sensitivity, the fact that it
is nonionizing and can distinguish vascular
from non-vascular structures without the use
of IV contrast material.
Respiratory motion artifact which
degrades image elsewhere is absent in the
pelvis. As in CT scan an oral contrast agent
can aid in the differentiation of bowel. A
variety of radiofrequency receiver coils are
used—a body coil provides the largest field
of view and an intraluminal one yields the best
anatomic detail-phased array multicoils
combine both and have become the receiver
of choice. Both T1 and T2 weighted sequences

are required for lesion characterization and
detection. High cost, slow spread of technical
expertise in the community as well as absence
of unequivocal indications have delayed the
widespread acceptance of MR.
Female genital anatomy is best displayed
on T2 images—both sagittal and axial planes
are important. The endometrium is a high
signal intensity stripe sharply demarcated
from hypointense deeper myometrium at the
junctional zone. The rest of the myometrium
is of intermediate signal intensity. The cervix
is again hypointense. Depending on the level
the cervix is bordered by vaginal fornices,
vesicovaginal septum, parametrial tissues
including cardinal ligaments, uterosacral
ligaments and paracervical venous plexus and
posteriorly the cul-de-sac. The ovaries have a
low signal intensity central stroma with
numerous hyperintense follicular cysts.
Round ligaments are also hypointense
structures coursing towards the inguinal
canal. Normal fallopian tubes are not usually
depicted unless dilated with fluid or blood.
COMMON PELVIC MALIGNANCIES
AND THEIR IMAGING
Cervical Cancer
Cervical cancer is usually detected by an ab-
normal Papanicolaou smear or by discover-
ing a cervical mass associated with vaginal
discharge or bleeding. The role of imaging is
predominantly in staging the disease.
A routine chest X-ray is indicated.
Role of USG is limited. It may detect the solid
hypoechoic mass in the retrovesical region,
associated hydrometra/hematometra/
pyometra. It can detect any pelvic or para-
aortic lymphadenopathy, hydronephrosis as
an indirect evidence of parametrial spread,
rarely ascites or hepatic metastases. Local
invasion into ureter, urinary bladder base or
Imaging in Gynecologic Cancers 201
rectum may be better demonstrated by
transrectal US.
Computed Tomography is an excellent comple-
mentary staging procedure in advanced
disease with an overall accuracy of 58 to
88 percent. In the detection of pelvic lymph
node metastases it has an overall accuracy of
65 to 80 percent and 80 to 90 percent in
detecting para-aortic lymph nodes.4 The classic
CT appearance is a solid mass enlarging the
cervix greater than 3.5 cm and containing
hypodense areas from necrosis, ulceration and
diminished postcontrast enhancement.
Uterine enlargement with collection within it
maybe noted. The features of cervical cancer
on CT scan are as follows:
Stage I
i. Intact peripheral cervix borders
ii. Absence of parametrial soft tissue mass
iii. Intact periureteral fat planes.
Stage II
i. Disruption of peripheral cervix margins
ii. Prominent parametrial soft tissue strands
iii. Obliteration of periureteric fat planes
iv. An eccentric parametrial soft tissue mass.
Stage III
This is usually detected by presence of soft
tissue extension upto obturator internus or
piriformis muscle(pelvic sidewall). Hydro-
nephrosis or pelvic lymphadenopathy also
indicate IIIb disease. When the parametrial
mass is within 2-3 mm of the pelvic sidewall,
even though there is intervening fat plane it is
labelled as IIIb.
Stage IV
i. Focal loss of perivesical/perirectal fat
plane with wall thickening
ii. Nodular indentations of bladder/ rectum
wall
iii. Intraluminal mass.
CT scan is also useful in screening patients
with known or suspected recurrence.
202 A Practical Approach to Gynecologic Oncology
MRI may become the procedure of choice
to differentiate Stage Ib from Stage IIb cervical
cancer because of its higher overall accuracy
in evaluating parametrial tumor extension and
higher predictive value for detecting tumor
confined to the cervix. It may also be more
useful for detecting recurrence from
posttreatment fibrosis and to monitor the
effects of RT/CT. On T2 weighted images the
lesion is seen as a high signal intensity lesion
in the normal hypointense cervical stroma.
Tumor as small as 2 cc can be visualized. In
advanced disease it can accurately predict
parametrial extension (abnormal high
intensity) disruption of low signal intensity
ring of cervix, invasion of vagina, adjacent
pelvic muscles, urinary bladder, rectum and
metastases to lymph nodes and bone. MRI has
a high accuracy using 1 cm as cut-off for
minimum axial nodal diameter. It can also
give information about tumor size and
vascular encasement. Accurate staging of
cancer cervix is crucial for deciding the mode
of treatment. Some centers use CT to assess
patients with tumor of suspected clinical stage
II and above. Some others use MRI for the
initial staging and follow-up though investi-
gation cost is often a limitation in many
countries like ours where clinical staging with
a complementary sonography is mostly used
in many cases.
Endometrial Cancer
A chest skiagram is indicated to rule out sec-
ondaries or co-morbid pulmonary conditions.
Skeletal radiography and scintigraphy may be
indicated for bony metastases.
Ultrasound (Transvaginal) reveals widening of
the central echogenic endometrial stripe. The
endometrium is measured as the double layer
thickness at the widest part of the cavity in a
longitudinal plane. Double layer thickening
greater than 5 mm in postmenopausal women
is considered abnormal. If the woman is on
estrogen therapy upto 7 mm is considered
normal. Endovaginal USG may be an useful
tool for screening—80 to 90 percent of patients
with postmenopausal bleeding do not have
endometrial cancer. Depth of myometrial
invasion may be classified as superficial if
there is focal thinning of inner hypoechoic
myometrium while obliteration indicates
deeper(> 50%) invasion. Accuracy varies from
68 to 69 percent.5,6 Saline infusion sonography is
coming up as a new technique. The value of
ultrasound in detection of lymph node meta-
stases or cervical invasion is not established.
Color Doppler may detect any abnormal vascu-
larity in the tumor or decreased pulsatility
index in the uterine artery but does not seem
to offer a better detection of premalignant and
malignant lesions than normal ultrasound.7
CT shows a diffuse or focal enlargement of
uterus with a poorly enhancing lesion. Rarely
fluid in the cavity may be present. Involve-
ment of cervix is indicated by cervical
enlargement (>3.5 cm with a heterogenous
stroma). Parametrial extension or trans-serosal
spread to ovaries or tubes makes the disease
stage III. CT may also detect omental spread
or hepatic metastases. The accuracy ranges
widely from 58-86 percent in staging.
The limitations of CT scan are differentia-
ting endometrial cancer from leiomyomas and
difficulty in detecting depth of myometrial
invasion.
MRI tumors are hyperintense on T2 images
(isointense on T1) compared to myometrium
with heterogeneity in larger tumors. Large
tumors also often are seen as polypoid mass
expanding the endometrial cavity. Secondary
signs of small tumors include increased thick-
ness or lobulation of endometrium.
In myometrial invasion there is disruption
of junctional zone—intact outer 2/3 myome-

trium (Stage Ib) or >50 percent invasion (Stage
Ic).
Cervical invasion (Stage II) is best seen on
sagittal contrast enhanced T2 images.
Extra uterine disease (Stage III) is detected
by transmyometrial extension/adnexal mass/
vaginal metastases/lymphadenopathy.
Stage IV disease shows vesical/rectal/
distant spread. Overall accuracy is about
85-94 percent in staging (contrast enhanced).4
The clinical utility of preoperative radio-
logic staging is not established. The cancer is
definitively staged at surgery (FIGO classi-
fication). CT may be used to screen patients
with advanced disease who are not surgical
candidates. Recurrence may be evaluated by
USG or CT/MRI as per availability of facilities
at the center.
Gestational Trophoblastic Disease
The role of radiological evaluation is in
detecting distant metastases (lung/brain/
liver) by X-ray, USG or CT.
For the local disease the commonly used
modality is USG. Sonographically H. mole
presents a classic pattern of solid collection of
echoes with multiple anechoic spaces—a vesi-
cular pattern in the uterine cavity (snowstorm
appearance). In early pregnancy transvaginal
sonography may help.
Doppler studies reveal a low flow high impe-
dance state.
CT is used for imaging persistent local pelvic
and metastatic GTD. Classically eccentric
hypodense foci strongly enhancing, are seen
in myometrium/endometrium associated
with bilateral multilocular theca-lutein cysts.
Dilated uterine arteries may be seen in the
parametrium. Hypervascular metastases may
be detected in liver or lung, etc.
MRI shows the primary lesion as a medium
intensity mass on T1 and a heterogenous high
Imaging in Gynecologic Cancers 203
and low signal intensity on T2 images.
Multiple vessels along with intra-lesional
hemorrhage may be seen. The zonal anatomy
of uterus is obscured. Tumor penetration
through uterus can be seen.
Ovarian Tumors
It is the commonest cause of death from gy-
necological malignancies in women. The life-
time risk of ovarian cancer in women is
1.5 percent. Efforts have therefore been di-
rected to develop methods of early diagnosis.
Ultrasonography is the first line of investigation.
The features of malignant tumor are large
(> 4 cm) complex cysts with solid component,
thick septae often with debris. Walls are
irregular, with poor definition and ascites,
pelvic sidewall omental fixation, metastatic
nodes may be present. In young females
benign tumors are 5 times more common
whereas in postmenopausal women the ratio
of benign to malignant is 2: 1.
Other associated features often detected by
ultrasound are obstructive uropathy, perito-
neal implants, hepatic and rarely splenic meta-
stases, pleural effusion.
Transvaginal color Doppler may reveal neo-
vascularity and low pulsatility index. It can
also be used for screening of unilocular
postmenopausal cysts less than 5 cm which
are likely to be benign.
The commonest tumors are epithelial tumors
of which serous cystadenomas and carcinomas
comprise of 30 percent of all ovarian neo-
plasms. They are usually large multilocular
cystic masses with multiple papillary projec-
tions arising from the cyst wall and thick
septae (> 3 mm). Echogenic solid loculations
and ascites maybe there.
Mucinous tumors are the second most
common and have a similar appearance.
Penetration of the tumor capsule may lead to
intraperitoneal spread of mucin secreting
cells–pseudomyxoma peritonei—looks like
204 A Practical Approach to Gynecologic Oncology
ascitic fluid with septations and low level
echogenic materials in it.
The other epithelial tumors are:
• Endometroid tumors which may be bilateral,
have associated endometrial carcinoma and
are usually cystic with papillary projections.
• Clear cell carcinomas—often bilateral com-
plex masses.
• Brenner tumors are rare and commonly
benign. They appear as solid hypoechoic
masses and may have calcification.
Germ cell tumors comprise of teratomas (dermoid
and immature), dysgerminoma and yolksac tumor.
• Dermoids are usually benign—a predo-
minantly cystic mass with an echogenic
mural nodule, the dermoid plug, is specific.
A fat-fluid or hair-fluid level is also specific.
Sometimes a mixture of hair and sebum
may give rise to a highly echogenic shado-
wing mass hidden among bowel loops.
• Dysgerminomas occur in young women and
are echogenic solid masses.
• Yolk sac tumors occur in young females less
than 20 years of age and appear similar.
Sex-cord stromal tumors comprise of the
following:
• Granulosa cell tumor usually are unilateral
and found in postmenopausal women.
Small masses are usually solid but large
masses are multiloculated and cystic.
• Sertoli-Leydig cell tumor are rare and appear
similar.
• Thecomas and fibromas classically appear
as hypoechoic attenuating masses (like
Brenner’s or fibroids). Fibromas may have
associated pleural effusion and ascites
(Meig’s syndrome).
• Metastatic tumors arise mostly from the
breast and gastrointestinal tract or may be
lymphoma. They are bilateral solid masses,
(Krukenberg’s tumors).
CT and MRI are used to demonstrate local and
distant disease spread like pelvic organ
involvement, pelvic side-wall invasion, peri-
toneal implants(> 5 mm) in cul-de-sac,
hepatorenal pouch, paracolic gutters, sub-
phrenic space, porta hepatis, greater omentum
and small bowel mesentery. Lymphatic spread
can occur as also hematogenous metastases to
liver and spleen late in the disease process.
CT is currently recommended as the imaging
modality of choice for staging. It is also used
to diagnose persistent or recurrent disease and
to monitor response to therapy.
Uncommon and Rare Tumors
Sarcomas
Uterine—On USG appear similar to rapidly
growing and degenerative fibroids often with
evidence of local invasion and distant meta-
stases.
Vaginal—MRI or CT preferred to detect size,
location, local extent and lymphadenopathy.8
Vulval Neoplasms
Rarely imaging is requested—transperineal
USG or MRI may be done.
Carcinoma Fallopian Tube
USG/ CT/MRI demonstrate a solid adnexal
mass may be inseparable from ovary—usually
diagnosed at surgery.
Carcinoma Vagina
MRI preferred to CT for evaluation of local
tumor extent and for staging purposes.
CONCLUSION
Ultrasound is the primary imaging investi-
gation of choice as it is accurate, inexpensive
and does not entail radiation hazards. It can
be repeated at frequent intervals if necessary.
CT is valuable where obesity, previous
surgery or radiation and an unstable bladder

preclude satisfactory ultrasound imaging. It
is valuable for staging malignant gyneco-
logical tumors. Cystic and solid masses are
well distinguishable. Calcification in a mass,
e.g. dermoids as also fatty components present
in teratodermoids are detectable. Ascites, local
involvement of bladder, rectum, muscles and
ureters are well assessed. Pelvic and
retroperitoneal lymhadenopathy along with
distant metastases can all be identified in one
sitting.
MRI in our country is still an expensive
option not readily available at all centers. It
can delineate anatomy and pathologic condi-
tions in the pelvis with greater intrinsic soft-
tissue contrast than USG or CT. Currently it
has the greatest accuracy as well as greatest
potential utility in the staging of cervical
carcinoma. Endometrial carcinoma can also be
staged with reasonable accuracy. Newer
techniques and new contrast agents are
contributing to the rapid pace of advancement
in the field of MRI of the pelvis.
REFERENCES
1. Rumack CM, Wilson SR, Charbonneau JW.
Diagnostic Ultrasound, Mosby, 1991,vol 1.
Imaging in Gynecologic Cancers 205
2. Sutton D. A Textbook of Radiology and
Imaging, 4th Edn. Churchill Livingstone, 1987;
vol 2.
3. Haaga JR, Lanzieri CF, Sartoris DJ, et al.
Computed tomography and magnetic
resonance imaging of the whole body, 3rd Edn.
Mosby 1994; vol 2.
4. Lee KT Joseph, Sagel S Stuart, Stanley J Robert,
et al. Computed tomography with MRI
correlation, Lippincott Raven 1998; vol 2.
5. Fistonic I, Hodek B, Klaric P, et al. Transvaginal
sonographic assessment of premalignant and
malignant changes in the endometrium
in postmenopausal bleeding. J of Clinical
Ultrasound 1997; no 8, vol 25.
6. Lindgren R, Mattson LA, Anderson K, et al.
Transvaginal ultrasonography and endo-
metrial histology in peri and postmenopausal
women on hormone replacement therapy.
British J of Obstetrics and Gynaecology
1999;106: 421-426.
7. Vaento MH, Perihonen JP, Makinen JI, et al.
Screening for endometrial cancer in asympto-
matic women with conventional and color
Doppler sonography. British J of Obstetrics and
Gynaecology 1999;106:14-20.
8. Petterson H, Allison D, Hricack H, et al. The
encyclopedia of medical imaging. The NICER
Institute 1999; vol IV:2.
206 A Practical Approach to Gynecologic Oncology
Genetic Factors in
18 Gynecologic Cancers
INTRODUCTION
Over the past years significant progress has
been made in identifying the role of genetic
factors in carcinogenesis.1 All cancers can be
called genetic, caused by inborn or acquired
errors in the genes that lead to uncontrolled
cell growth. Estimated 5-10 percent are truly
hereditary due to an abnormal single gene that
runs in the family. It is important to try to
determine which cancers are more likely to be
inherited. Some general characteristics of
hereditary cancers include multiple cases of
the same or related cancers in more than one
generation of one side of the family and a
single individual with more than one type of
cancer.2 To date numerous genes which are
involved in both tumor neovascularization
(angiogenesis) and tumor cell invasion have
been identified and most of them are
expressed to some extent under normal
physiological conditions also. However, little
is known about how these genes co-express
in these settings.3 Many (but not all ) of the
oncogenes identified in human tumors have
been found to be related to viral oncogenes
isolated from RNA tumor viruses. The
demonstration that genes from a virus could
change a normal cell into a malignant one has
established that genes could act as central
controllers of malignant conversion.4
• Shakuntala Chhabra
MOLECULAR CARCINOGENESIS
Genes related to cancer are of two distinct
types, oncogenes and tumor suppressor genes.
They have opposite effects in carcinogenesis.
Most oncogenes are mutated forms of normal
genes called proto-oncogenes that are in-
volved in the control of cell proliferation and
differentiation. The products of proto-
oncogenes promote growth. The products of
tumor suppressor genes normally block ab-
normal growth and malignant transformation.
They contribute to malignancy only when the
function of both alleles is lost. In other words,
in contrast to mutations in proto-oncogenes,
which are dominant in their action, mutations
in tumor-suppressor genes are recessive.4
It was in the 1970s that Lynch and Fraumeni
had identified several families in which
multiple cases of epithelial ovarian cancer had
occured. Families in which one relative had
ovarian or endometrial cancer and two or more
first degree relatives had cancer of the colon
were classified as Lynch II syndrome families.
The genes responsible for Lynch II syndrome
(Nonpolyposis colorectal cancer in association
with endometrial, stomach, breast cancer and
less frequently ovarian cancer) have been
mapped to short arm of chromosomes 2 and 3
which also function as tumor suppressor
genes.4

In 1990, linkage analysis of a small family
cohort of breast cancer families identified a
potential susceptibility gene on chromosome
17 near the genetic marker D17S74 on 17q21.
In 1994, it was named BRCA1 and it did not
appear to be a member of a known gene
family. To construct the gene from the region
identified by the linkage studies, investigators
used known sequences of DNA called yeast
artificial chromosomes (YACs), bacterial
artificial chromosomes (BACs) and cosmids
(small fragments of DNA of known
sequence).6 BRCA1 appears to be responsible
for some aspect of cell cycle control necessary
for early embryo development. It is a nuclear
phosphoprotein that is phosphorylated in
S and M phases. Until recently, over 50 muta-
tions have been described in the BRCA1 gene
in breast/ovarian cancer. Different types of
mutations may explain the differences in the
risk of developing cancer in different families,
though the reason is still unknown.
A second breast susceptibility gene was
identified in 1995. The initial progress towards
identifying this gene was made by the linkage
analysis of 22 families. This gene, named
BRCA2, is located on 13q between markers
13S260 and 13S271. BRCA2 is estimated to
confer a lifetime ovarian cancer risk of
10-20 percent. More than 100 mutations have
been identified and continue to be recorded.6
The hereditary breast cancer and ovarian
cancer syndrome (HBOC) includes genetic
alterations of various susceptibility genes such
as TP53, ATM, PTEN or MSH2, MLH1, PMS1,
PMS2, MSH3 and MSH6, BRCA1 and BRCA2.
Germline mutations of the cancer-suscepti-
bility genes BRCA1 and BRCA2 seem to be
the major etiology of the HBOC.7
SELECTED ONCOGENES RELATED TO
PELVIC MALIGNANCIES
A list of oncogenes that are mutated in various
pelvic malignancies is produced in Table 18.1
Genetic Factors in Gynecologic Cancers 207
Table 18.1: List of oncogene mutations in
pelvic malignancies4
Neoplasia Oncogenes
Embryonal ovarian carcinoma c-K-ras2
Squamous cervical carcinoma c- myc
c-Ha-ras
Endometrial adenocarcinoma c-myc
c-neu
Ovarian epithelial carcinoma c-myc
c-K-ras2
Choriocarcinoma c-fms
Individual cancers are discussed below.
Ovarian Cancer
The proliferation of epithelium for repair of
ovarian defect after ovulation under the
influence of growth factors secreted by
surrounding cells may provide an opportu-
nity for mutations resulting in somatic activa-
tion of oncogenes and inactivation of tumor
suppressor genes. The genes involved include
genes for growth factors (M-CSF, TGF-B),
genes for growth factor receptors (fms, erbB),
genes involved in transcriptional regulation
(Myc, p53) and loss of heterozygosity (LOH)
at various loci.
For studying genetic events that are impor-
tant in the pathogenesis of ovarian cancer,
researchers tried to understand the role of two
novel receptor tyrosine kinases; H-Ryk and
discoidine domain receptor isolated in cell sig-
naling. The second more direct approach has
been to use allele loss as a tool to isolate po-
tential tumor suppressor genes that are impor-
tant in the pathogenesis of ovarian cancer.8
It is thought that primary genetic factor is
responsible for 5-10 percent of ovarian cancers
which are called hereditary.6 Li et al reported
that familial occurrence of ovarian cancer may
result from genetic susceptibility of ovarian
tissue to hormonal or other carcinogenic
influences.9 Alternatively, the genetic defect
may induce a hormonal imbalance which is
208 A Practical Approach to Gynecologic Oncology
potentially carcinogenic. The etiologic
mechanisms may be clarified by the use of
family clusters for laboratory investigations of
hormonal, immunologic, cytogenetic, or other
factors which may be involved in ovarian
carcinogenesis.
Pattern of involvement suggests activity of
a dominant gene with variable penetrance,
or possibly a polygenic mechanism. No
evidence of genetic diseases such as Peutz-
Jeghers syndrome predisposing to ovarian
tumor have been found.10
The ovarian tumors available for histologic
review have been predominantly serous
cystadenocarcinoma, usual cell type in familial
ovarian carcinoma, which also represents
about one-half of all ovarian cancers.11-13 The
tumors in these families have generally been
diagnosed after age 35, although younger
women with undifferentiated carcinoma have
also been reported.14,15 In some instances, the
pattern of familial occurence has seemed
consistent with the activity of an autosomal
dominant gene transmitted through men or
women.11,12
Baker et al have reported c-myc ampli-
fication, not detected in normal ovarian tissue,
benign adenomas, and tumors of low
malignant potential are present in 29 percent
of ovarian carcinomas. 16 Another study,
reported the amplification in 50 percent
patients with ovarian cancer. This observation
supports the theory that different genetic
alterations account for the development of
benign vs malignant ovarian neoplasms.
Abnormalities of other oncogenes, such as ras
gene deletions amplification and point
mutation and fos gene overexpression, have
also been reported.6 Sato et al have studied
37 ovarian neoplasms with several DNA
probes and found allelic losses on 6q, 13q and
19q in serous carcinomas.17 They found fewer
allelic losses in mucinous type tumors.The
chromosomal arm 6q is an important region
with a high frequency of allele loss in epithelial
ovarian cancers. By detailed mapping
researchers have identified a 3cM region on
6q 27 between D6S297 and D6S264 containing
a putative tumor suppressor gene. The gene
for p90 Rsk-3 (RPS6KA2) is a candidate tumor
suppressor gene in ovarian tumors.8 Sasano
et al have found homogenous deletions of the
RB gene in more than 4 percent, and Mazars
et al have found Tp53 gene mutations in
36 percent ovarian carcinomas with most
mutations clustered in axons 5 and 7. Marks
et al have found high levels of mutant Tp53
protein in more than 50 percent of the ovarian
cancer tumors, which was undetectable in
benign gynecologic tissue samples. Over-
expression of Tp53 protein was found to
correlate closely with the presence of Tp53
gene mutation in the tumors. Such studies
suggest that the Tp53 gene through deletion
or point mutation plays a role in the develop-
ment or progression of some ovarian cancers.18
Numerous other reports have identified
activation of other oncogenes in ovarian
cancer. Reported overexpression of erb-b2
(HER2/neu) with and without gene ampli-
fication correlates with poor clinical outcome
suggesting possible clinical use of this
molecular marker in future treatment plans.
Using Southern blot analysis Slamon et al have
found erb-b2 amplification in 26 percent
primary ovarian malignant neoplasms and
12 percent cases showed erb-b2 expression
without evidence of gene amplification.19
McFadyen et al conducted a comprehensive
immunohistochemical investigation, into the
presence of cytochrome p450 CYP1 B1 in
primary and metastatic ovarian cancers and
found increased expression of CYP1 B1 in the
majority of ovarian cancers investigated (92%),
with no detectable CYP1 B1 in normal ovary.20
An altered mutant of the normal BRCA1
gene may be passed from generation to
generation in families which may predispose

a woman to development of breast or ovarian
cancer. The data also suggest that in families
in which disease is not linked to BRCA1 other
genes as yet unknown may be responsible for
ovarian cancer. In spite of lack of conclusive
evidence, linkage studies have indicated that
the risk of ovarian cancer by age 70 for BRCA
1 carriers is around 63 percent. Mutations in
the BRCA1 gene can lead to a 44 percent
lifetime risk while mutations in the BRCA2
gene infer a 15-20 percent lifetime risk.4
The carcinogenesis of ovarian cancer does
involve inactivation of tumor suppressor
genes as well. Several tumor suppressor genes
have been identified by strategies such as
positional cloning and differential expression
display. Further research is warranted to
understand fully their contribution to the
pathogenesis of sporadic ovarian cancer.21
All said common ovarian malignancies are
those that arise due to somatic mutation
occuring in ovarian cells with an initially
normal genome and not always due to
inherited genetic abnormalities. Further
ovarian cancers are heterogeneous group of
cancers composed of a variety of histologic
subtypes. Some neoplasms with the same
histologic features often have divergent
clinical behavior, suggesting that genetically
these lesions may not be same. Studies are
needed to correlate specific molecular markers
with histologic subtypes and clinical behavior.
There has been controversy for decades as to
whether the patterns of development in
ovarian cancer support the multifocal concept.
Mok et al have reported nine cases with
widespread abdominal carcinomatosis in
which the pattern of Tp53 gene expression was
identical in cancer cells from different sites in
the same patient, suggesting a unifocal
origin. 22 Tsao et al used X chromosome
inactivation as a molecular marker and
showed similar results.23
Genetic Factors in Gynecologic Cancers 209
In view of the high risk of ovarian cancer in
patients with a family history, it is reasonable
to commence screening for these cancers at an
early age. Although prospective studies are
needed to determine the value of pelvic
examination, transvaginal ultrasonography,
and CA125 in BRCA1 carriers, in the interim
the use of these modalities seems reasonable,
particularly in young women who wish to
maintain fertility.
Often, women in these families request
bilateral oophorectomy upon completion of
their child-bearing and before natural
menopause, as a prophylactic measure.
However, there are reports of disseminated
intra-abdominal malignancy resembling
ovarian carcinoma following prophylactic
oophorectomy.24 So there is some doubt about
the efficacy of oophorectomy as a preventive
strategy. Possible explanation is that the pelvic
peritoneum shares the same embryologic
origin as the ovarian epithelium. However in
at least a few of these cases careful retro-
spective examination of the ovaries has
revealed the presence of microscopic foci of
cancer that were not appreciated at the time
of the initial pathologic examination. This may
occur because a single section is all that usually
is examined in a normal appearing ovary.
When prophylactic oophorectomy is per-
formed the pathologist should be alerted as
to the indication for surgery and multiple
sections should be examined from each ovary
to exclude the presence of occult carcinoma.
The molecular genetic events that determine
progression of ovarian cancer are still not fully
characterized. Any method that enables the
early detection of ovarian cancer would lead
to a significant decrease in the incidence.18
FALLOPIAN TUBE CARCINOMA
Fallopian tube carcinoma is uncommon and
not much is known because the presentation
210 A Practical Approach to Gynecologic Oncology
is similar to ovarian cancer and intra
abdominal picture may also be deceptive for
knowing whether it is primary ovarian or
fallopian tube carcinoma.
Hellstrom 25 had found that 1) p53 immu-
nopositivity without detectable p21/WAF1
immunostaining did not correlate with Tp53
mutations in the conserved domains; 2)
mutations in Tp53 occurred in two metastasis/
recurrences but not in their corresponding
primary tumors; 3) in two cancers a Tp53
mutation was observed in the primary tumor
but not in the metastases/recurrences; 4)
constant denatural gel electrophoresis seems
to be more sensitive than single-stranded
conformation polymorphism in detecting
Tp53 mutations; and 5) in the nine cases
studied, p53 immunoreactivity and/or Tp53
mutation analysis did not correlate with tumor
progression, survival, or response to treat-
ment.25
ENDOMETRIAL CANCER
It is estimated that as many as 6 percent of all
endometrial cancers have a heritable
component. The majority of patients with
heritable endometrial cancer are from a group
of women of families with hereditary
nonpolyposis colorectal cancer syndrome
(HNPCC) (Lynch syndrome type II). The two
hereditary cancer syndromes known to cause
endometrial cancers are HNPCC and Cowden
syndrome. Only 1 percent of all cases of
endometrial cancer are explained by genetic
factors. Individuals with HNPCC have up to
an 80 percent lifetime risk for the development
of colon cancer, 60 percent lifetime risk for
endometrial cancer, 19 percent lifetime risk for
stomach cancer, a 9 percent lifetime risk for
ovarian cancer, and slightly increased risk for
brain, pancreas, transitional cell carcinomas of
the ureter and renal pelvis.2
Several small studies have identified
alterations of oncogenes, such as the ras group,
K-ras, c-fms, and c-erb-1 that may play a role
in the development and progression of
endometrial carcinoma. Okamoto et al studied
24 cases of endometrial adenocarcinoma for
allelic losses and found loss of heterozygosity
in seven cases, five of which lost loci on 17p,
which harbours the Tp53 gene.26 Risinger et
al have reported Tp53 gene point mutations
in 14 percent cases.27 Between 5 percent and
50 percent of endometrioid endometrial
cancers over express the p53 protein. This does
not occur in endometrial hyperplasia,
indicating that p53 mutations may be a late
event in the genesis of endometrial cancer. The
expression of p53 appears to be inversely
proportional to Bcl-2 expression and may also
be associated with a poorer prognosis. Further
p21 and p185 have also been associated with
endometrial cancer.
The molecular events that lead to the
development of endometrial cancer are poorly
understood. So investigators are searching for
tumor suppressor genes and several have been
associated. Regions of loss include 3p, 10q,
17p, and 18q papillary serous cancers often
show loss on 1p.
Approximately 6 percent of patients with
endometrial cancer have a germline mutation
in one of the mismatch repair genes that may
be due to a primary mutation in one of these
genes. When there is a primary mutation this
may represent a germline mutation and
therefore be an inherited form of endometrial
cancer.
Phosphate and tension homologue (PTEN)
is a recently identified tumor suppressor gene
inactivated in a wide variety of human
cancers, including endometrial cancers.
Mutation of the PTEN has been reported in
approximately 50-83 percent of endometrial
adenocarcinoma. Studies show that PTEN and
p27 are differentally expressed in endomet-
rioid type carcinoma compared with those of
the serous type and suggest that the cyclin

dependant kinase inhibitor, p27 is a down-
stream target of PTEN dependant cell cycle
arrest in endometrial carcinoma.28
Several studies looking for loss of hetero-
zygosity have identified loss on 10q25- 10q26
PTEN gene has been isolated from the 10q23-
10q24 region and appears to be mutual in 35
percent of endometrial cancers. Oncogenes
associated with endometrial cancers include
the K-rasgene, which is mutated between
10 percent and 30 percent of the time.
Preliminary studies suggest that this is an
early event in the genesis of endometrial
cancers. Her-2/neu is also associated with
endometrial cancers.
In a study of abnormalities of the APC/
beta-catenin pathway in the development of
endometrial cancer Moreno-Bueno et al
(2002) 29 have found a high prevalence of
alterations in molecules of the APC/beta-
catenin pathway, but only mutations in beta-
catenin gene are associated with aberrant
nuclear localization of beta-catenin. The
activation of the APC/beta-catenin signalling
pathway due to beta-catenin mutations has
been implicated in the development of a
subset of endometrial carcinomas. However,
upto 25 percent of endometrial cancers have
beta-catenin nuclear accumulation without
evidence of beta-catenin mutations, suggest-
ing alterations of other molecules that can
modulate the Wnt pathway, such as APC,
gamma-catenin, AXIN1 and AXIN2.
It has been recommended that oral
contraceptives might be given to patients with
history of ovarian/breast cancer in the family,
since some studies suggest protective effect
against sporadic ovarian and endometrial
cancer. However, the effect of oral contracep-
tives on familial ovarian and endometrial
cancer is uncertain. Moreover, any benefits
against ovarian and endometrial cancer may
be offset by an increased risk of breast cancer
in these women.
Genetic Factors in Gynecologic Cancers 211
CERVICAL CANCER
Recent report from the Swedish national can-
cer registry indicates that there may be some
genetic component to cervical cancer because
mothers and sisters of individuals with cervi-
cal cancer have been found twice as likely to
develop cervical cancer themselves.2
Although a common point of integration
has not been found, HPV sequences have been
found integrated near cellular oncogenes
c-myc and N-myc in at least a few cervical
cancer cell lines; in most cases, integration
interrupts the E1 and E2 open reading frames
but leaves E6 and E7 open reading frames
intact. The proteins encoded by E6 and E7 of
oncogenetic HPV strains can effectively
immortalize primary keratinocytes.
A study by Van Trappen et al (2000) 3
revealed a significant co-expression between
the angiogenesis inhibitor TSP-2 and most
other genes analyzed in normal cervical tissue.
In cervical cancer, a strong upregulation of
VEGF-C and MMP-9 mRNA, with a highly
significant co-expression between MMP-9 and
VEGF189 was found.
Polymorphism of the p53 gene, codon 72,
is also considered a risk factor in the develop-
ment of cervical carcinoma by some, but is
contradicted by others. Some results indicate
that women homozygotic for arg/arg in codon
72 of the p53 gene are at an increased risk for
the development of cervical adenocarcinoma.
However, this genetic disposition seems to be
unrelated to the HPV infection.30 All said for
this cancer hereditary is presently rare, al-
though it can occur as a complication of the
genetic skin conditions ectodermal dysplasia
and dyskeratosis congenita.
VULVOVAGINAL CANCER
Worshum (1991)31 had found that vulval
cancers tend to contain certain consistent
chromosomal abnormalities, including losses
212 A Practical Approach to Gynecologic Oncology
of chromosomes 3p, Sp. and 22q and gains of
3q and 11q. Losses of 10q and 18q were found
only in cases that exhibited biologically
aggressive behavior.
There is molecular evidence that vulval
intraepithelial neoplasia (VIN) is the precur-
sor of VIN-associated vulval squamous cell
carcinoma (VSCC), that multifocal disease
may arise via either different clones or a single
clone and that continued divergent clonal
evolution may occur in vulval neoplasia.32 The
transcriptional regulators aryl hydrocarbon
receptor (AHR) and aryl hydrocarbon receptor
nuclear translocator (ARNT) modulate the
transcription of genes involved in cellular
differentiation and proliferation.33
GESTATIONAL TROPHOBLASTIC
NEOPLASIA (GTN)
Complete hydatidiform mole is considered to
be exclusively of paternal origin, in which all
46 chromosomes (almost always XX) are
derived most likely from duplication of the
haploid spermatozoa or failure of the second
meiotic division.34-37 The occurrence of 2
trophoblastic neoplasms in homozygous twins
is unlikely to be a random event. This finding
suggests the existence of a maternal genetic
factor(s) that interfere with female meiosis and
favor the production of ova with absent or
inactivated nuclei. The presence of trans-
location chromosomes in a few affected
women and the association, reported in epi-
demiologic studies, between older maternal
age and the development of hydatidiform
mole are consistent with this hypothesis.38-40
BREAST CANCER
The familial risk of breast cancer has been
examined from several points of view. The
mother-daughter relationship has been
calculated in two ways, first an expected
number of mother-daughter pairs calculated
for a lineage with a specific number of
daughters accomplished by using the rate for
mothers and the rate for daughters in the
lineage. The total expected of 6.3 pairs for all
lineages has not been significantly different
from the nine pairs actually found. Second, the
overall rate of breast cancer amongst
daughters of women with breast cancer was
3.2 percent and the rate in daughters of women
without breast cancer was 2.2 percent.41
Slamon et al (1989) 19 have reported a
28 percent incidence of amplification of
HER-2/neu in breast cancers. Patients with
multiple copies of the gene in DNA from their
tumors had a shorter time to relapse as well as
a shorter overall survival indicating that gene
amplification was prognostic for disease
behavior in these individuals. Moreover, mul-
tivariate survival analysis showed HER-2/neu
amplification to be more predictive for clinical
outcome than all other known prognosticators
with the exception of positive lymph nodes.
Other studies reported that over-expression of
the normal, nonmutated, HER-2/neu gene
could induce transformation in NIH 3T3 cells.42
The altered neu gene was capable of inducing
malignant transformation in breast epithelium
of the mouse in a single-step fashion.
Until recently, over 50 mutations have been
described in the BRCA1 gene in breast cancer.
BRCA2 carriers have a 80 to 90 percent lifetime
risk for development of breast cancer. Physical
examination, mammography, xenography,
and thermography provide a means for early
diagnosis.
CONCLUSION
Cancer is a genetic disorder in which the
normal control of cell growth is lost. The basic
mechanism in all cancers is mutation, either
in the germline or, much more frequently, in
somatic cells. Much remains to be learned
about the genetic processes of carcinogenesis
and about the environmental factors that can
alter DNA and thus lead to malignancy. It is

likely that new insights into the fundamental
role of DNA changes in carcinogenesis will
lead in the near future to improved and more
specific ways of prevention and treatment of
malignant disease.
Genetic counseling and identification of
high-risk families may be essential to provide
the best method for genetic testing by explain-
ing the sensitivity and specificity of the meth-
ods. Genetic testing may be limited to mem-
bers of families with a strong history and that
testing be performed in conjuction with estab-
lished research programs by trained profes-
sionals aware of genetic, clinical and psycho-
logical implications of the testing and of the
technical limitations of the testing methods.
The protocol for managing individuals with
suspected genetic susceptibility to cancer
should be similar to the approach long used
by genetic conusellors for other inherited dis-
orders.
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 Evidence-based Medicine
19 in Gynecologic Oncology
Kumar T Bhowmik, Prerna Garg

INTRODUCTION replaces them with new ones that are more

The Medical Profession is increasingly coming
under scrutiny. With the revolution in
Information Technology, the patients and
their relatives today are much better infor-
med and have an unlimited access to under-
standable medical literature. Pressures of
mounting litigation are making the practice
of medicine more defensive and consequently
more costly, as healthcare systems attempt
to play safe. Resources being scarce in our
country, the healthcare delivery system is not
optimum. But the society now expects the best
possible medical care, and has started
demanding so. How do we respond to this
scenario? Evidence-based medicine (EBM)
could be a way out.
DEFINITIONS
EBM was defined by David Sackett (1996) as
‘the conscientious, explicit and judicious use of
current best evidence in making decisions about
care of individual patients’. EBM is the
integration of best research evidence with
clinical expertise and patient values.
By best research evidence we mean clinically
relevant research, which may be from basic
sciences, but more commonly from patient-
centered research into the various compo-
nents of health care delivery. New evidence
from clinical research invalidates previously
accepted diagnostic tests and treatments and
powerful, accurate, efficacious and safer.
By clinical expertise we mean the ability to
use our clinical skills and past experience to
identify each patient’s health state and
diagnosis, risks and benefits of interventions,
individual’s personal values and expectations.
Lacking clinical expertise, medical practice
runs the risk of becoming tyrannized by exter-
nal evidence, as the best of external evidence
may not be suitable or appropriate for an indi-
vidual patient.
By patient values we mean the preferences,
concerns and expectations each patient brings
to a clinical situation.
There is an increasing need for the clinician
for valid information about diagnosis,
prognosis, therapy and prevention. Our
textbooks being out of date are inadequate
for information, frequently wrong and
ineffective and too variable in their validity
for practical clinical use. There is a disparity
between diagnostic skills and clinical
judgment, which increases with experience
and knowledge, while clinical performance
declines. There is also the lack of time for
adequate searching and assimilation of
evidence.
PRACTICE OF EBM
The full-blown practice of EBM comprises of
five steps, which are as follows:
216 A Practical Approach to Gynecologic Oncology
• Converting the need for information about
prevention, diagnosis, prognosis, therapy,
causation, etc. into an answerable question.
• Tracking down the best evidence with
which to answer that question.
• Critically appraising that evidence for its
validity, impact and applicability.
• Integrating the critical appraisal with
clinical expertise and with patients’ biology,
values and circumstances.
• Evaluating the effectiveness and efficiency
in executing the previous four steps and
seeking ways to improve them for the next
time.
Every time we see a patient we need new
information about some aspect of diagnosis,
prognosis or management. The problems that
clinicians face in shaping answerable
questions are that we are puzzled by a patient
and do not know where to start, that we have
trouble in asking the question and that we
have more questions than time. It would be
important to basically follow these guidelines
when attempting to frame answerable
questions such as to which question is most
important to the patients’ well-being, which
question is most relevant to our learners’
needs, which question is most feasible to
answer within the time we have available,
which question is most interesting, and which
question is most likely to recur in our practice?
SOURCES OF EVIDENCE
Where does one find the best evidence? Our
traditional textbooks are not the source. Only
some parts of a textbook are going to be
current, but we do not have the means of
knowing which parts. For a textbook to be
relied upon as a source of current best
evidence, they should be revised at least once
a year, be heavily referenced so that the
reader can get to the original source of
information and determine the date of a
claim, and the evidence in support of a
statement should be selected according to the
clear cut principles of evidence. A better way
would be to invest in evidence databases.
Medline, the first electronic medical literature
database, has become too huge for effectively
getting exactly what we want. Today, there
are specialized clinical research databases
which yield clinically useful information, like
‘The Cochrane Library’ and ‘Best Evidence’.
Another way could be by investing in
evidence-based journals and on-line services.
How does one carry out a search? After
defining the answerable clinical question, one
is required to select the most likely source
from which the information will be available.
Then a search strategy has to be designed.
The evidence that is found as a result of the
search is to be summarized and applied.
However, if the yield is poor, then the second
most likely resource is to be selected, a new
search strategy designed, summarize the
evidence and apply the evidence.
The next area is how to critically appraise
the evidence generated and how to apply it
in practice. If we are looking at individual
studies, it would have to be determined
whether the assignment of patients to be
treated were randomized, whether the
randomization list was concealed, whether
the follow-up was sufficiently long and
complete, and whether all the patients were
analyzed in the groups to which they were
randomized. We would also have to look and
see if the patients and clinicians were kept
blind to treatment, if the groups were treated
equally and whether the groups were similar
at the start of the trial. It would then require
assessment as to whether the study patients
results would be applicable to our patients
and if the study was feasible in our setting.
Evaluation of our performance in our own
continuing professional development is
 Evidence-based Medicine in Gynecologic Oncology 217
important. Self evaluation of our abilities in
asking answerable questions, searching,
critically appraising and integrating the
evidence is the cornerstone of successful
practice of EBM. Joining an EBM Group or
subscribing to EBM Journals may be of help
in refining our use of EBM.
BASIC TOOLS OF EBM
There are 3 basic tools that can assist the
medical profession in the practice of EBM-
randomized clinical trials, systematic reviews
and clinical practice guidelines.
A clinical trial is defined as a prospective
study comparing the effect and value of
intervention(s) against a control in human
beings. A clinical trial must employ one or
more intervention technique, which may be
prophylactic, diagnostic or therapeutic agents,
devices, regimens, procedures, etc. and must
follow the principles of good clinical practice
(GCP). Well-done prospective randomized
trials with good statistical power can provide
answers to clinical problems for which no
clear-cut answers are available. Clinical trials
are the very basis of EBM, as it is primary data.
The term ‘systematic review’ implies that
a review has been prepared using some kind
of systematic approach to minimize biases and
random errors. A systematic review of
research evidence is a fundamental scientific
activity. Through critical exploration, evalu-
ation and synthesis, the systematic review
separates the insignificant, unsound or
redundant studies from salient and critical
studies. In a systematic review, the author
takes into account the entire body of evidence
within limits of feasibility, and designs the
review in the same way an investigator would
design a formal study. The protocol goes so
far as to specify in advance, precisely what the
clinical question is for which the review is
being done, what literature search strategy
will be used, prescribe analytic and statistical
techniques and handle each piece of evidence
using specific eligibility criteria. A systematic
review differs from a traditional review, which
uses a narrative format, and inclusion of
studies is rarely exhaustive, as also a strong
reviewer bias in the selection of studies. It is
quite like a meta-analysis, where synthesis of
primary data that match strict inclusion
criteria is done. A systematic review could be
used in place of a new study, and can establish
the generalization of scientific findings,
usually not possible with a single study. A
systematic review can establish a consistency
of relationship as also enhance the statistical
power of findings.
Clinical practice guidelines (CPG) is
systematically developed statements to assist
provider and patients decisions about
appropriate health care measures for a specific
clinical situation. From the evidence-based
perspective, CPG is one of the most efficient
tools to organize the best available evidence
to be considered in clinical decision-making.
CPG is intended to guide clinical practice, not
replace clinical judgment. Three basic methods
are used for CPG development- expert
opinion, consensus and evidence-based
methods. Evidence-based CPG (EB-CPG) is
currently the best available method. The
scientific method at the heart of the EB-CPG
is the systematic review. CPG helps organize
the evidence around a specific clinical
problem, as available medical literature is
poorly organized for clinical decision-making.
EB-CPG is usually developed by doing a
systematic review to generate clinical
recommendations, which are then reviewed
by external experts and vetted by the
practitioners before being formally adopted.
Usually, a multi-disciplinary disease site
218 A Practical Approach to Gynecologic Oncology
group identifies the clinical question; a group
of methodologists are responsible for getting
the scientific evidence, while a CPG
development group examines the evidence
and makes the recommendations. Practitioner
feedback is obtained to establish acceptability
of the guidelines. This whole process is formal,
explicit, reproducible, and is tempered by
clinical experience and judgment.
CHALLENGES TO THE PRACTICE OF EBM
The examination of the concepts and the
practice of EBM by clinicians and academics
have thrown up negative as well as positive
reactions. There are three limitations in every
branch of medicine—the shortage of coherent
and consistent scientific evidence, difficulties
in applying any evidence to the care of the
individual patient and barriers to any practice
of high-quality medicine. There are some more
limitations which are unique to the practice
of EBM. Essentially the need to develop new
skills in searching and critically appraising
evidence is a major hurdle in the practice of
EBM. Also clinicians do not have adequate
time at their disposal to apply these skills.
And, then the evidence that EBM actually
works has been rather slow in coming.
EBM reinforces the need for clinical and
communication skills, that are required to
gather and critically look at patient history,
examination and decide on appropriate
therapeutic options. It forms an efficient basis
for lifelong learning. It also helps in identifying
gaps in present day knowledge and provides
the impetus for designing trials to answer
these gaps. Determining what is the best
evidence is the biggest scientific challenge as
no statements are accepted unless based on
evidence. To remain current with the explo-
sion of new knowledge is a challenge. As of
now the main thrust of EBM is on therapeutics,
for diagnostics it is limited to precision and
accuracy.
Gynecologic oncology has always been in
the forefront of EBM as the methods of
randomized clinical trials are the standard
approach to prove that new treatments work.
Further it is a known fact that patients get the
best care when they are followed according
to protocols of proven effectiveness. Also
clinical practice guidelines form the very basis
for the practice of gynecologic oncology.
The need of the hour is to build a better
knowledge base through which EBM can
provide better insights into the whole gamut
of patient care services. EBM dispels the older
norm of practice based on infallible authori-
ties and brings about increasing democra-
tization of the practice of medicine. Medicine
requires being practiced based on evidence
and not on authority. We need to move away
from an era of authoritarian medicine to an
era of authoritative medicine. Is not it the
present times an impetus for us to usher in
Evidence-based Health Care!
Levels of Evidence
• I—Evidence is obtained from meta-
analysis of multiple, well-designed,
controlled studies. Randomized trials have
low false-positive and low false-negative
errors (high power)
• II—Evidence is obtained from at least one
well-designed experimental study.
Randomized trials have high false-positive
and/or false-negative errors (low power)
• III—Evidence is obtained from well-
designed quasi-experimental studies such
as nonrandomized, controlled, single-
group, pre-post, cohort, time or matched
case-control series
• IV—Evidence is obtained from well-
designed, non-experimental studies, such
 Evidence-based Medicine in Gynecologic Oncology 219
as comparative and correlational descrip-
tive and case studies
• V – Evidence is obtained from case records
and clinical examples.
Grades of Recommendation
Level Basis of Recommendation
A There is evidence of type I or consis-
tent findings from multiple studies of
type II, III or IV
B There is evidence of types II, III or IV,
and findings are generally consistent
C There is evidence of types II, III or IV,
but findings are inconsistent
D There is little or no systematic empi-
rical evidence.
BIBLIOGRAPHY
1. Covell DG, Uman GC, Manning PR. Informa-
tion needs in office practice: Are they being
met? Ann Intern Med 1985;103:596-99.
2. Evidence-based medicine working group.
Evidence-based medicine. A new approach to
teaching the practice of medicine. JAMA
1992;268:2420-25.
3. Oxman A, Guyatt GH. The science of review-
ing research. Ann NY Acad Sci 1993;703:
125-34.
4. Saackett DL, Rosenberg WMC, Gray JAM,
Haynes RB, Richardson WS. Evidence-based
medicine: What it is and what it isn’t. BMJ
1996;312:71-72.
5. Sackett DL. Using evidence-based medicine to
help physicians keep up-to-date. Serials
1997;9:178-81.
220 A Practical Approach to Gynecologic Oncology
Hormone Replacement Therapy
20 in Patients Treated for
Gynecologic Malignancies
INTRODUCTION
Successful treatment of patients with gyne-
cological cancers has resulted in an ever
increasing population of cancer survivors,
following treatment for breast, cervix, endo-
metrial and ovarian cancer, these survivors
may experience menopausal symptoms or
express concern about the prevention of
cardiac disease and osteoporosis. At the
present time, estrogren replacement therapy
(ERT) alone or in combination with pro-
gesterone (HRT) is considered by many to be
contraindicated in these patients. Because of
the fear that estrogen may accelerate the
growth of occult metastasis. However, one
needs to understand the epidemiologic studies
on the increased occurrence of endometrial
and ovarian cancer at the time of climacteric
and the increased frequencies if these cancers
in nulliparaous women were taken as
evidence for a potential role for steroid
hormones in the development of these
cancers. Due to the shared epidemiologic and
genetic risk factors, women with ovarian
cancer and endometrial cancer may also be at
risk for breast cancer, thus complicating
consideration for ERT or HRT in these
patients.
• Kasturi Lal • K Uma Devi
HORMONE RECEPTORS IN
GYNECOLOGIC CANCERS
Breast and endometrial cancers are known to
be hormone-dependent and a number of
studies have established the relationship
between the presence of estrogen and
progesterone receptors in the malignant
tissues and their relation to the prognosis of
the disease. As compared to that, studies of
sex steroid receptor status in normal and
neoplastic ovarian surface epithelium are
limited. Many investigators have assayed
estradiol receptor (ER) and the progesterone
receptor (PR) concentration in benign,
borderline and malignant ovarian tumors
and correlated receptor levels to age,
menopausal status, tumor type, degree of
tumor differentiation and survival status.1-5
Receptor-positive ovarian cancers contained
significantly low ER and PRS when compared
to the receptor possible breast and endometrial
carcinoma. Several investigators found that 35-
89 percent of ovarian epithelial cancers
appeared positive for the ER and about 35-91
percent were PR positive.2-7 The ER and PR
status of ovarian epithelial cancers has also
been correlated with prognosis. Bizzi et al
observed an association between presence of
ER and improved survival. 8 However, the
 Hormone Replacement Therapy in Patients Treated for Gynecologic Malignancies
biologic significance of these receptors
remains to be established.
Both ERs and PRs are expressed in normal
squamous mucosa of the cervix. ER is most
prominent in parabasal and intermediate
cells.9 In a study of 83 cervical cancer cases (75
squamous cell carcinoma and 8 adeno-
carcinoma) 56 percent were ER-positive and
58 percent PR-positive.10 The receptor levels
did not correlate with tumor stage or histo-
logic grade. Receptor status was not related
to overall or disease free survival.
HRT IN INDIVIDUAL CANCERS
Breast Cancer
The increasing incidence of breast cancer, in
addition to its earlier detection and treatment,
has produced an enlarging population of
women for whom HRT remains problematic.
Although breast cancer is considered to be a
contraindication for estrogen therapy, the
prohibition of HRT significantly diminishes
the quality of life for breast cancer survivors.
A major concern in the use of estrogen
replacement remains the potential of occult,
residual disease. Dormant tumor cells,
contained by host factors, may be activated
by exogenous estrogens and may further
potentiate this risk. However, there is indirect
proof that endogenous and exogenous estro-
gens do not influence the biologic behavior of
breast cancer.11
Randomized, prospective studies will
ultimately be necessary to resolve this issue.
Any possible benefit must be balanced by a
thorough discussion of current knowledge
and its deficits. No patients can be guaranteed
protection from the recurrence of disease.
Cervical Cancer
The age distribution of cervical cancer patients
is bimodal, with peaks at 35 to 39 years and
221
60 to 64 years12. The traditional treatment for
cervical cancer has been surgery and radiation
therapy. Although young patients with
disease limited to the cervix and selected
patients with stage IIA disease may be treated
with radical surgery and ovarian conservation,
patients with bulky carcinomas or stage II or
stage IV disease are often treated definitely
with radiation therapy. Patients usually
receive 40 to 50 Gy to pelvis followed by
intracavitary radiation. Administration of 5 to
6.25 Gy to the pelvis results in radiation
castration in more than 90 percent of patients.13
Ovarian preservation may be accompanied by
a significant failure rate.14 Many patients may
be accompanied by a treatment induced
menopause and they require estrogen
replacement therapy (ERT) or hormone
replacement therapy (HRT) to prevent
vasomotor symptoms, osteoporosis and
reduce vaginal stenosis and thereby facilitate
follow up examination.15 Five years disease
free survival is not different between the
patients treated with HRT and without HRT.
The long-term rectal, vesical and vaginal
postradiation therapy complications are
significantly lower in the patients treated with
estrogens. Several studies reported that the
endometrium is not always ablated after
standard radiation therapy for cervical carci-
noma.16,17 It is recommended that patients who
receive HRT after radiation therapy should
receive a combination of estrogen and proge-
stational agent to avoid endometrial stimu-
lation from unopposed estrogen therapy.
Endometrial Cancer
The use of estrogen replacement represents a
significant change in the approach to women
previously treated for endometrial cancer. The
majority of patients with early endometrial
carcinomas are successfully treated with
surgery, the risks and benefits of hormonal
222 A Practical Approach to Gynecologic Oncology
replacement in these patients have been
re-examined. For many women, the improve-
ment in quality of life and reduction in osteo-
porosis and coronary artery disease outweigh
the risk of stimulating occult tumor growth.
As a result, there is increasing acceptance of
estrogen replacement in selected patients.
However, several small studies have failed
to reveal an increase in recurrence or death
rate of women given ERT or HRT after
treatment of endometrial cancer.18-23 These
studies are methodologically limited by their
small sample size, short follow-up and
retrospective trial design.
Three retrospective studies have suggested
that hormone replacement therapy is not
detrimental to patients in following treatment
for endometrial cancer. Creasman and
colleagues retrospectively studied 221 patients
treated for stage I endometrial adeno-
carcinoma. Forty-seven patients received ERT
after their cancer therapy and 174 patients did
not. Risk factors for recurrence were similar
between both groups. The estrogen-treated
group experienced a significant improvement
in disease free survival as compared with
those patients not receiving HRT. The authors
concluded that there was no contraindication
to HRT in stage I endometrial cancer patients
who have completed therapy.
Lee and co-workers reported on 44 patients
placed on ERT after treatment of endometrial
cancer. The patients were at low-risk for
recurrence because of strict selection criteria,
which included well-differentiated tumors,
superficial invasion and no evidence of
metastatic disease. Treatment was started with
the first year after therapy in 57 percent of the
patients. The dose of conjugated ERT ranged
from 0.625 mg to 1.25 mg daily for 25 days
and 15 patients also took progesterone (34%).
The sample size was too small to achieve a
statistically significant difference.
Chapman et al retrospectively reviewed 123
women with stage I and II endometrial cancer
treated between 1984-1994. Sixty-two of these
women received ERT,were compared with 61
women not given HRT. There was no
statistically significant difference in disease
free survival between the two groups.
However, the patients receiving ERT had
earlier stage of disease and a lesser extent of
myometrial invasion.
A committee of gynecologic practice of the
American College of Obstetrician and Gyne-
cologists concluded that no definitive data
support specific recommendations regarding
the use of estrogen in women previously
treated for endometrial cancer. The opinion
states that estrogen use in women previously
treated for endometrial carcinoma should be
selective, based on prognostic indicators and
the risk that the patient is willing to assume.
The prognostic factors include stage of disease,
depth of myometrial invasion, tumor grade
and cell type.
However there exist no definitive data on
which to base specific recommendations about
estrogen replacement in patients previously
treated for endometrial cancer. The GOG has
recently opened a prospective, double-blinded
trial of ERT versus placebo in women with
stage I and II endometrial adenocarcinoma.
Patients are randomised to receive either
0.625 mg of CEE or placebo for a period of
3 years because patients with ovarian and
endometreial cancers are at increased risk for
breast cancer, it is important to examine the
data on estrogens and breast cancer risk.
Ovarian Cancer
The role of ERT or HRT in the pathogenesis of
ovarian cancer is still unknown.24 A recent
meta-analysis, however, revealed that the use
of ERT or HRT was associated with an
increased risk for invasive ovarian cancer (RR
 Hormone Replacement Therapy in Patients Treated for Gynecologic Malignancies
1.27; 95% CT, 1.05-1.27), especially for patients
with more than 10 years of use.25 These results
are consistent with epidemiologic data that
support a role for estrogen as a risk factor for
ovarian cancer. Early menarche and late
menopause result in a long term exposure to
estrogen.26 There is a sharp slowing in the
prevalence rate of ovarian cancer, at meno-
pause, when there is a sharp decrease in hor-
mone production.
Although ovarian epithelial carcinomas
have been reported to possess ER and PRs, the
biologic significance of these receptors
remains to be established. Clinical data
regarding risks of hormonal replacement in
patients previously treated for ovarian cancer
are limited. A retrospective study by Eles et al
revealed that HRT given to patients with
ovarian cancer within one year of surgical
treatment did not adversely affect the survival
or relapse rates.27 However, the study was
limited by its small sample size, short follow-
up period and its bias towards giving HRT to
younger subjects with earlier disease, who
inherently may have a better survival rate.
A randomized control trial of ERT in
ovarian cancer survivors by Guidozzi and
Daponiote concluded that postoperative ERT
did not have a negative influence on the
disease-free interval and overall survival of the
survivors of ovarian cancer. 28 However, this
study was limited by its small sample size. To
date, no evidence indicates that the estrogen
stimulate the growth of the ovarian cancer.
Therefore the authors believe, that ovarian
cancer should not be considered a
contraindication for estrogen replacement
therapy or HRT.
However, women with ovarian cancer
share epidemiologic and genetic traits with
breast cancer patients, especially with the
inherited familial syndrome (BRCA-1/2),
survivors of ovarian cancer are thus at an
223
increased risk for breast cancer. ERT or HRT
for these patients is an especially complex
issue in light of the total body of indirect
evidence on the relationship between estrogen
and breast cancer. Based on the limited data,
a definitive statement of the safety of ERT or
HRT for survivors of ovarian cancer awaits a
large, prospective, randomized, controlled
trial.
The most prudent approach with this popu-
lation is to consider alternative treatments
until the ongoing randomized clinical trials
have been evaluated, with an adequate long
term follow-up.29 Prevention of cardiac disease
and osteoporosis, must be given the high
priority. Diet and exercise are essential
component of the counseling provided to
patients after cancer therapy. Non-hormonal
alternatives to prevent disease and to manage
symptoms should be offered to patients.
REFERENCES
1. Abu Jawdeh GM, et al. Estrogen receptor
expression, is a common feature of ovarian
borderline tumors. Gynaecol Oncol 1996;
60:301.
2. Harding M, et al. Estrogen and progesterine
receptors in ovarian cancer 1990;65:486.
3. Iversen OE, et al. Steroid receptor content in
human ovarian tumors: Survival of patients
with ovarian carcinoma related to steroid
content. Gynae Oncol 1982;23:65.
4. Schwartz PE, et al. Estrogen receptors in
ovarian epithelial carcinoma. Obst Gynaecol
1982;59:229.
5. Vierikko P, et al. Cytosol and nuclear estrogen
and progestin receptors and 17-beta hydroxy-
sterpoid dehydrogenasae activity in non-
disasesd tissue and in benign and malignant
tumors of the human ovary. Int J of Cancer
1983;32:413.
6. Schwartz PE, et al. Histopathologic correlation
of estrogen and progestrin receptors protein in
epithelial ovarian carcinomas. Obst Gynaecol
1985;66:428.
224 A Practical Approach to Gynecologic Oncology
7. Sutton GP, et al. Estrogen and progesterine
receptors in epithelial ovarian malignancies.
Gynae Oncol 1986;23:176.
8. Bizzi, et al. Steroid receptors in epithelial
ovarian carcinoma, relation to clinical para-
meters and survival. Cancer Res 1988; 48;622.
9. Satyaswaroop PG, et al. Estrogen like effects of
tamoxifen on human endometrial carcinoma,
transplanted in nude mice. Cancer Res 1984;
44:4006.
10. Scambia G, et al. Steroid hormone receptors in
the carcinoma cervix, lack of response to an
antioestrogen. Gynaec Oncol 1990;37:323.
11. Disaia PJ. Hormone replacement therapy in
patients with breast cancer, A Reappraisal.
Cancer 1993;71:1490.
12. Hatch KD. Cervical cancer. In Berek JS, Hacker
NF (Eds). Practical Gynae Oncol 2nd ed
Baltimore:Williams & Wilkins 1994;243.
13. Peck WS, et al. Castration of female by irradia-
tion the results in 334 patients. Radiology 1940;
34:176.
14. Husseinzadeh N, et al. The preservation of
ovarian function in young women undergoing
pelvic radiation therapy. Gynaecol Oncol
1984;18:373.
15. Hartman P, et al. Vaginal stenosis following
irradiation therapy for carcinoma of the Cevix
Uterei Cancer 1972;30:426.
16. Mckay MJ, et al. Persisting cyclic uterine
bleeding in patients treated with radical
radiation therapy and hormonal replacement
for carcinoma of cervix. Int J Radiation and
Biophysics 1990;18:921.
17. Barnhill D, et al. Persistence of endometrial
activity after radiation therapy for cervical
carcinoma. Obst and Gynaecol 1985;66:805.
18. Baker DP. Estrogen replacement therapy in
patients with previous endometrial carcinoma.
Com Ther 1990;16:28-35.
19. Byrant GW. Administration of estrogen to
patients with a previous diagnosis of endo-
metrial adenocarcinoma (Letter). South Med J
1990;83:725-26.
20. Champan JA, et al. Estrogen replacement in
stage I and II endometrial cancer survivors. Am
J Obs Gynae 1996;175:1195-1200.
21. Crcasman WT, et al. Estrogen replacement
therapy in patients treated for endometrial
cancer. Gynae Oncol 1990;36:189-91.
22. Gitsch G, et al. Endometrial cancer in premeno-
pausal women 45 yrs and younger. Obst and
Gynaecol 1995;85:504-08.
23. Lee R B, et al. Hormone replacement therapy
following treatment for stage I endometrial
cancer. Oncol 1990;36:189-91.
24. Hempling RE, et al. Hormone replacement
therapy as a risk factor for epithelial ovarian
cancer; results of a case-control study. Obst
Gynaecol 1997;89:1012-16.
25. Garg PP, et al. Hormone replacement therapy
and the risk of epithelial ovarian carcinoma; a
meta-analysis. Obst Gynae 1998;92:472-79.
26. Spicer DC, et al Prevention of breast cancer
through reduced ovarian steroid exposure.
Acta Oncol 1992;31:167-74.
27. Eles RA, et al. Hormone replacement therapy
and survival after surgery for ovarian cancer.
B M J 1991;302:259-62.
28. Guidozzi F Daponte A Estrogen replacement
therapy for ovarian carcinoma survivors: A
randomised controlled trial. Cancer 1999; 86:
1013-18.
29. Cass I, Runouriz CD. Non-hormonal alternatives
to treating menopausal symptoms. Am J
Managed Care 1998;4:732-39.
 Care of a Terminally-Ill Gynecologic Cancer Patient
Care of a Terminally-Ill
21 Gynecologic Cancer Patient
INTRODUCTION
A terminally ill patient may be defined as one
in whom the condition is clearly deteriorating
or has become static inspite of appropriate
therapy and there is no scope for curative
treatment. Such patients need a good pallia-
tive care, which includes physical, psycho-
logical, emotional, spiritual and existential
care to provide maximum comfort and
satisfaction to the patient. The attempt should
be to improve the quality of life keeping her
pain free.
The World Health Organization defined
palliative care as follows:1
Palliative care is the active total care of patients
whose disease is not responsive to curative
treatment. Control of pain of other symptoms, and
of psychological, social, and spiritual problems is
paramount. The goal of palliative care is
achievement of the best possible quality of life for
patients and their families.
Principles of palliative care are:
• Affirm life and regard dying as a normal
process
• Neither hasten nor postpone death
• Provide relief from pain and other
distressing symptoms
• Integrate the psychological and spiritual
aspects of patient care
• Offer a support system to help patients live
as actively as possible until death
• Offer a support system to help the family
225
• Shanti Roy
during the patient’s illness and in their
bereavement.
Effective treatment modalities, i.e. radio-
therapy, chemotherapy and surgery offer the
best chance of symptom relief in a patient
who is good responder but in non-responders
the therapeutic approach may do more harm
than good. Hence, tailoring of management
according to individual needs is important
and the investigative procedures should be
minimally utilized.
KEY ASPECTS OF TERMINAL CARE
Diagnosis
It involves assessment of patient’s symptoms
and other problems, nature and extent of the
neoplastic process. The palliative care giver
has to recognize the support of the family
members and other support systems.
Therapeutic Possibilities
These are implemented according to the diag-
nosis with or without further investigations.
The therapeutic option chosen takes maxi-
mum care for the quality of life and the
facilitation of freedom. The selected approach
should not waste patient’s time, resources
and personal energy.
Relevant anti-tumor treatment, e.g. radio-
therapy, chemotherapy or surgery should be
strongly considered because the control of
neoplastic process generally offers the best
226 A Practical Approach to Gynecologic Oncology
chance of symptom relief. The patient should
be adequately informed about the possible
advantages and disadvantages of the various
treatment options and her choice should be
respected. The physician, however, should not
compromise his or her better judgement or
conscience in the face of patient or family
pressure.2
Evaluation of Outcome
The informed patient is the best judge but
observations of the medical and nursing staffs
are also important. Imminent death should be
clearly recognized. This may be indicated by
a change in the progress of the disease, an
irreversible change in the function of the
critical organs and a rapid deterioration in
strength or physical performance in the
absence of reversible factors, e.g. anemia,
septicemia, hypercalcemia, etc. When the
patient is clearly dying, it may not be medi-
cally wise to treat anemia, septicemia, etc.
although medically-possible.
MANAGEMENT OF MAJOR SYMPTOMS
Accurate assessment of symptoms requires
skill, patience, active listening and uncondi-
tional regard for the patient. The patient is
always right about symptoms.3-7 Irrespective
of the cause, symptom relief is essential.
Pain Management
The options for pain management should be
readily available to all patients with advanced
gynecological cancer.
The American Society of Clinical Oncology4
has developed guidelines for cancer pain
assessment and treatment. Pain management
may be considered in the following steps:
1. Reduction of noxious stimulus at the periphery:
This is possible by adequate understanding
of the mechanisms of pain stimulus in the
individual patient. A careful history, physi-
cal examination and other investigations if
necessary provide a guide to the likely
mechanism. Pain may be caused by treat-
ment or it may arise from soft tissue
distortion or infiltration, bone involvement,
neural involvement, muscle spasm,
infection within or near tumor masses,
intestinal colic or sheer pressure. The
treatment varies according to cause and
specific therapeutic measures should
be considered if possible. For pain relief
non-steroidal anti-inflammatory drugs
(NSAID), paracetamol and low-dose corti-
costeroids will be helpful depending upon
the cause. If the patient is unable to take
the drugs orally, rectal preparation may be
helpful.
2. Raising the pain threshold: Comfort, care,
concern, diversion and relaxation raise the
pain threshold while depression, anxiety,
loneliness and isolation lower the pain
threshold.
3. Reduction of pain perception: This is achieved
by careful and precise use of opioid drugs
which should be given regularly and at
fixed intervals rather than haphazardly for
severe pain stimulus. A range of opioids
are available, e.g. codeine, meperidine,
methadone, dextropropoxyphene, mor-
phine, etc. Morphine sulphate is most
commonly used and is best given at every
four hours with a double dose at bed time
and a break of 8 hours overnight. The dose
has to be titrated starting from a small dose
and gradually increasing till the patient gets
pain relief. The starting dose for oral
morphine varies from 5 mg to 10 mg accord-
ing to weight and age of the patient, which
is repeated in 1 to 2 hours if pain is not
relieved. During the next 24 to 48 hours the
correct daily dose is determined. Controlled
released morphine tablets are also available
which are given every 12 hours. They
should not be used for uncontrolled or
 Care of a Terminally-Ill Gynecologic Cancer Patient
unstable pain or for patients with extensive
upper abdominal disease, as drug absorp-
tion may be disturbed. When oral route is
not possible then subcutaneous route
should be used and the conversion ratio of
oral to subcutaneous is 3:1. Occasionally,
the rectal route may be more useful. There
is usually no need for the intramuscular
route. Intravenous route can be hazardous
as acute tolerance develops.
Some types of pain are relatively un-
responsive to opioids as that caused by bone
metastases, nerve irritation, or extreme
muscle spasm. In such cases other drugs are
essential as adjuncts to morphine
Hepatic impairment, if severe, interferes
with morphine metabolism to glucuronides
while renal impairment interferes with
excretion of these metabolites. Dose reduc-
tion is essential in both these situations. Side
effects of morphine includes mainly consti-
pation and occasionally nausea. A laxative
having softening and stimulant properties
should be combined with morphine.
4. Use of other strong opioids: Oxycodone has
analgesic effect similar to morphine and is
most often used in a dose of 5 to 15 mg every
4-6 hours. Some patients tolerate oxycodone
better than morphine. Meperidine (Pethidine)
is of very little value in palliative care. At
high doses, the drug is clearly neurotoxic
and can add much to the distress of dying
patients.4 Heroin offers no advantage over
morphine except higher solubility. Its
efficiency depends on metabolism to
morphine. Methadone is occasionally useful,
but difficult to use because its sedative
action outlasts its analgesic activity.
Transdermal preparations of opioids such as
fentanyl are very convenient if used
correctly. Codeine combined with aspirin,
acetaminophen or dextropropoxyphene is
useful for mild pain.
227
Fecal impaction may occur due to
opioids, if not given with laxative and can
cause nausea, pelvic and abdominal pain,
and occasionally diarrhea, abdominal
distension and confusion in an elderly
patient.
5. Recognition and correct treatment of neuropathic
pain: Neuropathic pain results from irrita-
tion or destruction of peripheral nerves
secondary to disease or its therapy. It is
generally difficult to treat. The quality of
neuropathic pain varies, e.g. burning,
lancinating, anesthetic, or hyperesthetic.
For such pain an opioid is used in combi-
nation with tri-cyclic antidepressants,
anticonvulsants, corticosteroids, or oral
anesthetic agents. Regional blockade with
local anesthetic techniques may have to
be considered. Epidural morphine with
marcaine is useful for carefully selected
patients.2
Management of Lumbosacral Plexopathy
The lumbosacral plexus can be compressed or
invaded by a malignant tumor. The compres-
sion can also result by an abscess or
hematoma. Fibrosis may occur due to radia-
tion. All these can cause plexopathy. The lum-
bosacral plexus lies in the retroperitoneal
space medial to the iliopsoas muscle and lat-
eral to the cervix. The Lumbar portion
(L1-4) forms the femoral nerve and the sacral
portion (L5-S3) forms the sciatic nerve.8
Pain is the first sign of lumbosacral plexo-
pathy and usually precedes the weakness and
sensory dysfunction by weeks to months.
The pain occurs in the lumbosacral area or is
referred to the leg along the sensory distri-
bution of the nerve routes. Compression of the
upper plexus leads to hip flexor weakness and
difficulty in climbing steps and paresthesia in
the anterior thigh. The involvement of lower
part may lead to foot-drop, pelvic tilt and
228 A Practical Approach to Gynecologic Oncology
sensory loss in the thigh, sole and perineum.
The diagnosis requires CT scan or magnetic
resonance imaging of the pelvis.
Management of lumbosacral plexopathy
requires treatment of the underlined cause, i.e.
anti-tumor therapy, drainage of abscess or
hematoma, antibiotics, etc. The symptom
management includes use of dexamethasone,
acetaminophen, NSAIDS and opioids.
Anticonvulsants, antidepressants and trans-
cutaneous electronic nerve stimulation (TENS)
should be given in accordance with require-
ment.
Treatment of Psoas Muscle Spasm
This can occur due to infiltration by tumor or
compression by nodal disease or benign space-
occupying lesion. The main symptom is severe
pain in abdomen, iliac, or inguinal region with
radiation to the hip or posterior thigh. The hip
is usually held in a fixed flexed position and
external or internal rotation of the hip is
extremely painful. Anti-tumor treatment (i.e.
radiotherapy, chemotherapy or surgery when
appropriate) together with early symptom
management is essential. For symptom
management a combination of drugs is given
which includes acetaminophen or NSAIDS,
opioids, diazepam and dexamethasone. The
goal is the relief of suffering. The suffering is
not only due to pain but also due to anxiety
and depression, which require proper treat-
ment.
Gastrointestinal Symptoms
Gastrointestinal symptoms are only next to
pain among the symptoms of advanced mali-
gnancy and may be a major source of distress.
These can arise from the cancer itself or by its
treatment. Precise diagnosis and correct
management is important for each symptom.9
Oral: Oral candidiasis and mucositis may be
most distressing. Candidiasis is treated by
antifungal agents nystatin mouthwashes
(every 2-3 hours), amphotericin lozenges, or
ketoconazole tablets. Pain from mucositis
caused by radiotherapy may be relieved by
sucralfate suspension and by acetaminophen
with morphine (orally or subcutaneously) if
necessary. Vitamins also are helpful in
stomatitis and glossitis in seriously malno-
urished patients.
Anorexia: It is very common and can be due
to variety of causes. Serious nutritional
deficiency can occur. Small meals, good mouth
care, emotional support and nutritional
supplementation are helpful. Progestins may
be added to increase weight.
Nausea and Vomiting: Nausea and vomiting are
common in advanced gynecological cancer.
When vestibular mechanisms are suspected
or when no specific pathway can be identified,
relatively nonsedating antihistamines
(e.g. cyclizine and meclozine), that act directly
on the vomiting center and the vestibular cen-
ter, may be useful. When anxiety dominates
the scene, anxiolytics may be crucial in
reducing the nausea. Chemotherapy induced
nausea responds to ondansetron, a 5-HT
(serotonin) receptor agonist. Constipation can
occur with ondansetron. Nausea associated
with decreased gut motility responds to
metoclopramide or domperidone, which
promote gastric emptying and increase gut
motility. Metoclopramide or domperidone
should not be used in patients with very high
gastrointestinal obstruction because vomiting
will be aggravated. Dexamethasone is also
useful in suppressing nausea but the lowest
possible dose, e.g. 2 mg should be used and
as an adjunct to other therapy, but not in
patients with history of peptic ulcer, tubercu-
losis or diabetes mellitus.
Constipation: Constipation is a common
symptom and may be due to a change of diet,
inactivity, opioids or from tumor related
intestinal obstruction. The treatment is by
 Care of a Terminally-Ill Gynecologic Cancer Patient
glycerine or stimulant suppositories, enema’s,
large bowel stimulants and occasionally by
small bowel flushers or manual removal of
impacted feces. The choice depends upon the
individual problem. Constipation resulting
from intestinal obstruction as a direct effect
of tumor or adhesions requires either relief
of the obstruction by medical or surgical
means or acceptance as an end-stage mani-
festation.
Bowel obstruction: Bowel obstruction is most
common in ovarian cancer and the instance
varies from 14.6 percent18 to 42 percent.19,20
Surgery may be considered for these patients
if positive benefit is expected. Poor pro-
gnostic factor includes hypoalbuminemia,
raised blood urea nitrogen, raised serum
alkaline phosphatase, obstruction associated
with abnormal abdominal X-ray or the
presence of massive ascites or palpable
abdominal masses.10,11
With end stage obstruction, a totally
symptomatic approach developed at St.
Christopher’s Hospice12 is useful which avoids
use of nasogastic tube and intravenous fluids.
It relies on careful mouth care, with a little food
and drink as desired. The patient remains
mildly dehydrated which helps in reducing
gastrointestinal secretions and the amount of
vomiting. Medications are used with care.
Complete bowel obstruction: The surgical
correction or bypass depends on the location
of the obstruction, the extent of the cancer and
the estimated time of survival. If surgery is
not indicated, medical management should be
undertaken. Steroids are given if not contra-
indicated as they reduce pain and edema and
relief occurs in reversible cases. If irreversible,
care is taken for pain and nausea with appro-
priate drug, parenteral fluids are reduced or
stopped to decrease gastrointestinal secretion.
Somatostatin 300 to 600 mg subcutaneously
per day is given to reduce secretions in large
229
volume vomiting cases having high obstruc-
tion. If vomiting of large volumes persists
despite the above measures, a skinny naso-
gastric tube may be considered or a percuta-
neous gastrostomy may be performed to
enable decompression. Gastrostomy in such
cases is very helpful and makes the life of a
terminally-ill patient more comfortable.
Partial obstruction: It may be confused with
motility disorder but there is more vomiting,
more pain and characteristic bowel sounds in
partial obstruction. For single level obstru-
ction, surgery should be considered. If surgery
is not possible then steroids, metoclopramide,
antispasmodics, analgesics and gentle enemas
will help.
Motility disorders: It is diagnosed by progre-
ssive and worsening constipation. There is a
little or no vomiting, minimal abdominal
distention and diminished or absent bowel
sounds. It can occur due to invasion of the
myenteric plexus or bowel wall, radiotherapy
and neuropathy from chemotherapy. The
treatment is bowel stimulation by cisapride or
other prokinetic agents and senna. The lower
bowel is emptied by enema and surgery is
considered for single loop of bowel involve-
ment.
Diarrhea, fistula and tenesmus: Most often
diarrhea is a sign of fecal impaction. True
diarrhea can occur when bowel wall is
involved in tumor. Loperamide is useful.
Fistula’s between bowel and bowel, bowel
and skin and with other pelvic organs can
occur in some patients with advanced gyne-
cological malignancy. Surgery is the best
treatment. If surgery is not feasible then
judicious use of bulking agents, somatostatin,
metronidazole, catheters, skin care and
constant emotional support are helpful in
management of such cases.
Tenesmus can be troublesome. Antispa-
smodics, calcium channel blockers and drugs
used for neuropathic pain may be helpful.
230 A Practical Approach to Gynecologic Oncology
Abdominal Distension and Ascites
Abdominal distension may occur due to large
tumor, obstructed bowel or ascites and can
cause severe distress. For intractable ascites,
recurrent paracentesis has a definite place.
Diuretics may help initially. Corticosteroids
in very low doses may also be tried as they
reduce production. For distress, a combination
of acetaminophen and a low-dose of opioid2
should be used. Systemic or intraperitoneal
cytotoxics are often helpful but their use is
limited in a late stage patient.
Dyspnea
Dyspnea can be caused by pleural effusion,
bronchial obstruction, diffuse lung involve-
ment, reduced expansion due to massive
ascites, bronchial asthma, chronic obstructive
airway disease, cardiac failure and respiratory
infection. After proper diagnosis, the cause
should be properly treated. If the dyspnea is
not reversible then careful use of
morphine considerably improves dyspnea.13
Anxiolytics, e.g. 2 mg diazepam orally or
0.5 mg lorazepam sublingually may provide
significant relief in anxious patients.
Urinary Tract Symptoms
In advanced gynecological cancer, urinary
tract symptoms are very common. Hydro-
nephrosis may require nephrostomy or stent
insertion if life expectancy is at least for several
months. In other cases for short-term
treatment short courses of oral corticosteroids,
e.g. dexamethasone, 4 mg daily for 3 to 5 days
may provide significant reduction in serum
creatinine level and improved quality of life.
Bladder symptoms may be relieved by
NSAIDS and anticholinergic drugs. Catheteri-
zation may be required in many cases. Renal
failure when present requires dose readjust-
ment of many drugs.
Edema
Edema is caused by venous or lymphatic
obstruction. It may respond to small doses of
diuretics or careful massage toward the trunk
beginning at the top of the leg. Systematic
bandage of the legs may improve the patient’s
comfort. Compression bandages should not be
used when legs are grossly edematous because
it further impedes venous circulation.
Weakness
With large tumor load, weakness is a domi-
nant symptom. Other causes of weakness in
advanced gynecological malignancy are nutri-
tional deficiencies, hypotension, hypokalemia,
hyperglycemia, hypercalcemia, hypoadrenal-
ism, renal failure, infection and anemia. Many
of these causes can be appropriately treated.
Transfusion is justified only if the hemoglo-
bin is very low with extreme weakness.
Hypercalcemia
Hypercalcemia is often associated with bony
metastases. The symptoms may be aggra-
vation of bone pain, lethargy weakness,
constipation, severe nausea, vomiting and
confusion. The distressing symptoms should
be reversed if possible. The treatment consists
of pamidronate 30-60 mg by intravenous
infusion in 250 ml of crystalloid over 4-8 hours.
Improvement occurs within 2-3 days and lasts
for 2-3 weeks when pamidronate infusion may
be repeated. Treatment however may not be
justified for a patient who is close to death.
Care Close to Death
When death is imminent the goal is dignity
and peace and is best provided by control of
major symptoms. The indicated drugs should
be used in correct dose either subcutaneous
or rectally. In cases of extreme distress direct
 Care of a Terminally-Ill Gynecologic Cancer Patient
sedation may be justified. Anxiolytics of the
benzodiazepine group is preferable, sub-
lingual lorazepam 0.5-2.5 mg every 4 to
6 hours or parenteral midazolam 2 to 5 mg
subcutaneously or intramuscularly or clona-
zepam subcutaneously or sublingual may
provide adequate sedation. Large doses of
opioids should be avoided.
CONCLUSION
No person should die in despair. The physician
should assist the patient to center hope not on what
will fail in the end (e.g. chemotherapy, radiotherapy,
surgery) but on what will not fail—such as the
physician’s commitment to care, the control of pain
and other symptoms, and the intrinsic value of the
patient as a unique individual. No patient should
die with hope focused on the next course of
chemotherapy or on another surgical intervention.
Unrealistic expectations may increase, not relieve,
suffering.14
Nothing should be said or done by doctors
to induce despair, either by encouraging false
hope or by failure to offer skilled care. Instead,
all should be said and done to facilitate the
emergence of a final integrity and wholeness,
no matter what the preceding shape of the
patient’s life has been. This is real hope rooted
in reality, which is abiding. Good palliative
care is concerned with enrichment of life, even
when facing death, the human task that is
common to all.2
Hospice care precludes the use of curative
treatment at life’s end stages. Complex equip-
ments and tubes of all sorts should be avoided
if possible as it will facilitate maximum physi-
cal contact with loved ones.2 A clear therapeu-
tic plan should be presented. Respect for in-
dividual religious and cultural customs is
mandatory. Good symptomatic relief and
basic care in accord with human dignity
should be provided throughout the course of
the illness. It is crucial to recognize when the
231
time has come to allow a patient to die but
deliberate acceleration of death is not neces-
sary.
REFERENCES
1. World Health Organization. Cancer pain relief
and palliative care. WHO: Geneva, 1991.
2. Jonathan S Berek, Eli Y Adashi, Paula A
Hillard. Novak’s Gynecology. Williams and
Wilkins 1996;1303-1319.
3. Twycross RG, Lack SA. Therapeutics in
terminal cancer. In: Pain Relief, 2nd ed.
London: Churchill Livingstone 1990.
4. Doyle D, Hanks GW, MacDonald N. Oxford
Textbook of Palliative Medicine. Oxford:
Oxford University Press 1993.
5. Billings JA. Outpatient management of advan-
ced cancer. Philadelphia: JB Lippincott, 1985.
6. Walsh TD. Symptom Control. Oxford:
Blackwell Scientific 1989.
7. Hanks GW, Justin DM. Cancer pain
management. Lancet 1992; 339:1031-39.
8. Greed Pettigrew L, Glass JP, Maor M, Zornoza
J. Diagnosis and treatment of lumbosacral
plexopathies in patients with cancer. Arch
Neurol 1984; 41:1282-5.
9. Twycross RG, Lack SA. Control of alimentary
symptoms in far advanced cancer. London:
Churchill Livingstone, 1986.
10. Krebs HB, Goplerud DR. Surgical management
of bowel obstruction in advanced ovarian
carcinoma. Obstet Gynecol 1983; 61(3):327-30.
11. Fernandes JR, Seymour RJ, Suissa S. Bowel
obstruction in patients with ovarian cancer: A
search for prognostic factors. Am J Obstet
Gynecol 1988; 158:344-9.
12. Baines M, Oliver DJ, Carter RL. Medical
management of intestinal obstruction in
patients with advanced malignant disease.
Lancet 1985; 2:990-3.
13. Cowcher KC, Hanks GW. Long-term manage-
ment of respiratory symptoms in advanced
cancer. J Pain Symptom Manage 1990;5:320-30.
14. Cassell EJ. The nature of suffering and the goals
of medicine. N Engl J Med 1982;306(11):
639-45.
 Index 233

Index

A endometrial sampling steroid receptors 130

130 tumor size 130
Abdominal distension and ascites
hydroultrasound 131 treatment 131
230
hysteroscopy 131 Cancer of fallopian tube 190
Actinomycin-D 147
magnetic resonance clinical features 190
Adenocarcinoma 103
imaging (MRI) 131 diagnosis 190
Adenosquamous carcinoma 104
transvaginal ultrasound incidence 190
Adjuvant chemotherapy 32
(TVS) 131 patterns of spread 191
Adult granulosa cell tumors 179
epidemiology 124 prognosis 193
Adverse effects of antineoplastic
etiology and risk factors 124 prognostic factors 191
agents on the fetus and
staging 190
neonate 32 antiestrogens 126
treatment 192
Alkylating agents 33 combined oral
chemotherapy 192
cyclophosphamide 33 contraceptive pill 126
radiation therapy 192
iphosphamide 33 estrogen replacement
Cancer of the vulva 14
Alkylating-like agents 33 therapy 125 Cancer of uterine cervix 100
carboplatin 33 menstrual factors 125 clinical presentations 104
cis-dichlorodiamino 33 pregnancy and fertility physical signs 104
platinum (cisplatin) 33 125 symptoms 104
Antimetabolites 34 socioeconomic indicators diagnostic evaluation 105
5-fluorouracil 34 125 biopsy 105
hydroxyurea 34 weight 125 colposcopy 105
methotrexate 34
follow up after treatment 134 computed tomographic
Antineoplastic drugs 26
pathology 126 (CT) scan 106
Antitumor antibiotics 33
patterns of spread and cytology 105
actinomycin D 33
staging 128 fine needle aspiration
bleomycin 33
prognostic factors 128 cytology (FNAC) 106
doxorubicin 34
age 128 lymphangiogram 106
mitomycin-C 33
DNA ploidy of the tumor magnetic resonance
Apoptosis 23
130 imaging (MRI) 106
histologic grade 129 positron emission tomo-
B graphy (PET) scan 106
histopathologic types 129
Basics of radiation therapy 35 lymph node metastasis incidence and mortality
Bilateral salpingo-oophorectomy patterns 100
129
6 modes of spread 106
lymphovascular space
Biologic serum markers 182 direct invasion 106
invasion 130
hematogenous dissemina-
myometrial invasion 129
C tion 107
oncogene amplification/ lymphatic spread 107
Cancer of endometrium 124 expression 130 pathology 103
diagnosis 130 peritoneal cytology 129 principles of surgical
endometrial curettage 131 stage of diseases 129 management 111
234 A Practical Approach to Gynecologic Oncology

historical background 111 pattern of spread 81 based on cell cycle effects 26

hysterectomy for cervical signs and symptoms 81 based on chemical nature and
cancer 111 survival 82 mechanism of action 25
incision 112 treatment 81 Classification of vulvar disorders
management of micro- Cancer of vulva 64 56
invasive cancer clinical features 68 intraepithelial neoplasia 56
114 epidemiology and risk factors mixed non-neoplastic 56
management of stage IB 64 neoplastic epithelial disorders
bulky tumor 115 FIGO staging for vulvar 56
management of stage IB cancer 68
1 non-neoplastic epithelial
and IIA cancer 115 management 69
disorders 56
para-aortic lymphadenec- management and the
Clear cell adenocarcinoma 104
tomy 112 changing trends 69
Clinical utility of tumor markers
pelvic lymphadenectomy management of early
vulvar cancer 71 45
112
management of rare classifications of tumor
preparation for surgery
vulvar malignancies markers 46
112
75 tumor marker as a diagnostic
preservation of the
management of recurrent test 46
ovaries 114
vulvar cancer 73 tumor marker as a prognostic
radical hysterectomy 113
management of stage III test 47
prognostic factors 108
and IV vulvar cancer tumor marker as a screening
depth of stromal invasion
72 test 46
110
surgical techniques 73 tumor marker for follow-up
histologic type and
pathology 65 after treatment 47
differentiation of
prognostic factors and staging Colposcope 59
tumor 110
67 Colposcopic classification of
lymph-vascular space
Carcinoma of the female genital vulvar abnormalities 59
invasion 111
tract 35 Colposcopy in the management
risk factors 101
Cell carcinoma 76 of CIN 91
contraceptives 102
Cell kinetics and tumor biology colposcopic appearance of
dietary factors 102
23 cervical intraepithelial
mestrual hygiene and
Cell necrosis 36
reproductive factors neoplasia (CIN) 92
Cellular kinetics of normal tissues
102 colposcopic appearance of
23
sexual behavior 101 normal cervix 91
Cervical cancer 2
sexually transmitted indications for colposcopy 91
Cervical precancer 84
infections other than definitions 84 Colpotomy 13
HPV 103 terminology 84 Common pelvic malignancies
socio-demographic factors Characteristics of growth of and their imaging 201
102 tumor cells 25 cervical cancer 201
use of tobacco 102 Chemotherapeutic drugs used in endometrial cancer 202
staging 107 gynecologic cancers 33 gestational trophoblastic
clinical staging 107 Chemotherapy of dysgerminoma disease 203
surgical staging 108 185 ovarian tumors 203
Cancer of vagina 80 Chemotherapy of non- uncommon and rare tumors
etiology 80 dysgerminomatous tumors 204
FIGO staging 81 185 Concurrent chemoradiation
histologic distribution 81 Choriocarcinoma 174 therapy (CCRT) 35
histology and lymphatic Classification of anticancer drugs Concurrent chemoradiotherapy
drainage of vagina 80 25 40

Conservative surgery 6
Craniotomy 150
D ultrasonography 157
Determinants of response to
anticancer drugs 26
complete response 26
partial response 27
progressive disease 27
stationary disease 27
Drug resistance 28
Dysgerminoma 173
Dyspnea 230
E sources of evidence 216
Edema 230
Embryonal carcinoma 174
Endodermal sinus tumor
(Yolk sac tumor) 174
Endometrial cancer 11, 210
Epithelial ovarian cancer 153
chemotherapy 166
epidemiology 153
etiopathogenesis 155
clonal origin 155
genetic alterations 155
incessant ovulation 155
management 162
pathology 158
patterns of spread 160
direct extension 160
distant metastases 161
intraperitoneal
dissemination 160
retroperitoneal
dissemination 160
radiotherapy 168
risk factors 153
chemical carcinogens 154
dietary factors 154
hereditary factors 155
infertility 154
menstrual factors 154
oral contraception 154
reproductive factors 154
tubal ligation 154
screening 156
CA-125 156
clinical pelvic
examination 156
multimodal approach 157
symptoms and signs 159
Epithelial ovarian cancer 5
Evidence-based medicine (EBM)
215
basic tools of EBM 217
challenges to the practice of
EBM 218
definitions 215
levels of evidence 218
practice of EBM 215
External beam radiation therapy
35, 37
Factors influencing the biological
effects of ionizing
radiations 37
linear energy transfer 37
radiosensitizers and
radioprotectors 37
rationale for fractionation of
the radiation dose 37
F
Fallopian tube carcinoma 209
First order kinetics 27
Folinic acid 147
G 194
Gastrointestinal symptoms 228
Genetic counseling 213
Gestational trophoblastic
neoplasia 141
Gompertzian growth curve 25
Gonadoblastoma 181
Granulosa cell tumors 178
Growth fraction 27
Gynandroblastoma 181
Gynecologic imaging 198
computed tomography 200
conventional 198
barium enemas 198
chest X-ray 198
hysterosalpingogram 198
Index 235
IVU
lymphography 199
plain X-ray abdomen 198
magnetic resonance imaging
200
modern imaging 199
color Doppler 199
ultrasonography 199
Gynecologic oncology 1
H
Histologic forms of vulvar
carcinoma 66
Hormone receptors in
gynecologic cancers 220
HRT in individual cancers 221
Hydatidiform mole 141
clinical signs and symptoms
of molar pregnancy 142
diagnosis 143
epidemiology and risk factors
142
follow-up 144
pathology 141
treatment 143
Hypercalcemia 230
I
Imaging in gynecologic cancers
198
Incidence of cancer in pregnancy
Interstitial template therapy 40
Invasive vaginal cancer 82
Ionising radiations 35
electromagnetic radiations 35
particulate radiations 35
J
Juvenile granulosa cell tumors
179
K
Karnofsky performance status
score 28
Key aspects of terminal care 225
diagnosis 225
236 A Practical Approach to Gynecologic Oncology
evaluation of outcome 226
therapeutic possibilities 225
L ovary 184
Late sequelae 186
Lipid cell tumors 181
M Partial hepatectomy 8
Malignant gestational tropho-
blastic neoplasia
144
diagnosis 145
metastatic sites 144
pathology 144
prognostic scoring system
and staging 145
symptoms and signs 145
Management of borderline
epithelial ovarian cancer 169
Management of cervical cancer in
pregnancy 119
Management of CIN in
pregnancy 97
Management of major symptoms
226
management of lumbosacral
plexopathy 227
pain management 226
Management of malignant germ
cell neoplasms 184
Management of ovarian sex-cord
stromal tumors 186
Management of recurrent cervical
tumor 120
Management of VIN 60
conservative management 60
laser vaporization 61
local excision with vaginal
advancement 61
medical therapy 62
post-operative care after laser
vaporization 62
principles 60
simple vulvectomy 61
skinning vulvectomy with
skin grafting 61
wide local excision 60
Manchester system 40
Martinez universal perineal
interstitial template 42
Mature cystic teratomas of the
Mechanisms of action of radiation
36
Metastatic “high risk” GTN 148
Metastatic “low risk” GTN 148
Minimal deviation
adenocarcinoma 103
Mixed germ cell tumors 177
Modes of administration of
radiation 37
brachytherapy 38
external beam radiation
therapy or teletherapy 37
treatment planning and
simulation 39
Molecular carcinogenesis 206
Moving-strip technique 42
Mucinous adenocarcinoma 103
Mustard gas 23
N Polymerization of tubulin 26
Neoadjuvant chemotherapy 32
Nerve sparing techniques 3
Non-epithelial tumors 172
classification 172
incidence and clinical profile
172
Nonmetastatic GTN 147
Non-neoplastic epithelial
disorders 57
lichen sclerosus 57
squamous cell hyperplasia 57
O concomitant chemoradiation
Oncogene mutations 207
Open-field technique 42
Optimal cytoreduction 10
Oral mucositis 24
P
Paget’s disease 76
Palliative radiotherapy 43
Papanicolaou smear 69
Para-aortic lymph node (PAN)
biopsy 12
Para-aortic lymph node sampling
6
Para-aortic lymphadenectomy 5
Para-aortic node sampling 11
Para-aortic staging
lymphadenectomy 11
Phases of cell cycle 24
G phase (resisting phase) 24
0
G phase (post-mitotic phase)
1
24
G phase (post-synthetic
2
phase) 24
M phase (mitotic phase) 24
S phase (DNA synthesis
phase) 24
Plant alkaloids 34
etoposide 34
paclitaxel 34
vincristine 34
Planus atrophicus 57
Polyembryoma 174
Pregnancy associated with
gynecologic cancers 194
evaluation 194
management 195
breast cancer 196
invasive cervical cancer
195
ovarian cancer 196
preinvasive cervical
cancer 195
Primary cytoreductive surgery 7
Principles of chemotherapy for
cancer cervix 118
118
neoadjuvant chemotherapy
118
Principles of radiotherapy for
cancer cervix 116
brachytherapy 117
extended field radiation 118
external beam irradiation 116
historical perspectives 116
radiation doses 117
 Index 237

R breast cancer 212 hysterectomy 97

Radiation for cervical cancer 39
brachytherapy 39
teletherapy 39
Radiation for endometrial cancer
Radiation for gestational
trophoblastic disease 42
Radiation for ovarian cancer 41
Radiation for vaginal cancer 42
Radiation for vulvar cancer 42
Radiation-induced lethality 36
Recurrent adenocarcinoma of
endometrium 134
Repetitive cycles 27
Role of chemoradiation 73
S gastrointestinal (GI) tract
Salvage therapy 186
Sarcoma of uterus 137
etiology and risk factors 137
incidence 137
management 139
pathological classification
137
pathology and clinical
features 138
staging and median survival
139
survival rate 140
Screening and early detection of
cervical cancer 86
clinical downstaging 87
cytology-based screening 86
detection of DNA of
oncogenic subtypes of
HPV 90
role of health education 87
visual inspection after
application of acetic acid
88
visual inspection with Lugol’s
iodine (VILI) 89
Second look laparotomy (SLL) 9
Secondary cytoreductive surgery
10
Selected oncogenes related to
pelvic malignancies 207
cervical cancer 211
gestational trophoblastic
neoplasia (GTN) 212
ovarian cancer 207
vulvovaginal cancer 211
Semilog plot 25
Sentinel node 70
Sentinel node biopsy 15
Sertoli cell tumor 180
Sertoli-Leydig cell tumors 180
Sex-cord stromal tumors 178
Side effects of cytotoxic drugs 29
bone marrow toxicity 29
carcinogenicity 30
cardiac toxicity 30
toxicity 29
genitourinary toxicity 30
hair follicle toxicity 29
hepatic toxicity 30
immunosuppression 30
neurotoxicity 30
pulmonary toxicity 30
reproductive toxicity 30
Squamous cell carcinoma 65, 103
Staging of malignant ovarian
tumors 161
Subsequent pregnancies 150
Surgical staging 12
Syed-Neblett system 42
T Vulvar intraepithelial neoplasia
Taxanes 26
Technetium 99-m labeled 15
Technetium-99m sulfur colloid
70
Teratoma 175
Thecoma-fibroma 179
Total tumor burden 28
Toxicity 29
cytotoxicity 29
Treatment of cervical precancer
94
cold knife cone biopsy 97
cryotherapy 94
large loop electrocoutery
excision procedure (LEEP)
95
principles 94
Treatment of psoas muscle spasm
228
Treatment planning system (TPS)
39
Tumor doubling time 27
Tumor heterogeneity 28
Tumor markers 45
Tumor markers for individual
malignancies 47
cervical cancers 51
endometrial cancer 52
gestational trophoblastic
tumors 50
ovarian epithelial tumors 47
carcinoma antigen-125 47
other markers 49
ovarian germ cell tumors 49
ovarian granulosa cell tumors
50
U
Urinary tract symptoms 230
V
Verrucous carcinoma 76, 104
Vinca alkaloids 26
58
diagnosis 59
etiopathology 58
histology 58
symptoms and signs 59
Vulvar melanoma 76
Vulvoscopy 59
W
Weakness 230
WHO common toxicity criteria
31