Ranu Patni

Editor

Current Concepts in
Endometrial Cancer

123
Current Concepts in Endometrial Cancer
Ranu Patni
Editor

Current Concepts
in Endometrial Cancer
Editor
Ranu Patni
Gynecologic Oncology
Bhagwan Mahaveer Cancer Hospital
and Research Centre
Jaipur
India

ISBN 978-981-10-3107-6    ISBN 978-981-10-3108-3 (eBook)

DOI 10.1007/978-981-10-3108-3

Library of Congress Control Number: 2017933280

© Springer Nature Singapore Pte Ltd. 2017

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This book is dedicated to all my patients who have provided me the incentive to
write about the dilemmas in managing endometrial carcinoma. Dr. Sushila
Kothari, my maternal aunt, deserves a special mention as she braved this disease
very positively for almost twelve years after having been diagnosed in stage IV.
Preface

Of all gynecological malignancies, endometrial carcinoma is the most consistent in

presentation, easy to diagnose and has a largely favorable outcome. At the same
time, it has had a turbulent evolutionary journey and the most varied management
protocols across institutions and individuals. Editing a book on this challenging
topic has been a very satisfying experience.
This book is a genuine venture to provide a comprehensive coverage of the
“Cinderella” of gynecological cancers, i.e., endometrial carcinoma. All ten chapters
in this book are written by well-known specialists having vast experience in the
fields of gynecologic oncology, gynecology, pathology, etc. The experience of the
authors reflects in their writing. Basics as well as current facts and evidence-based
practices have been incorporated in each chapter. There is a full chapter on “mini-
mally invasive surgery” which is fast becoming the preferred mode of treatment of
this disease.
The initial chapter will take the reader through a brief account of evolving concepts
over time and gives an overview of the subject. The next few chapters will focus on
epidemiology, prevention, pathophysiology, and diagnostic workup. The following
chapters will deal with stagewise management of this malignancy and delineate the
role of minimally invasive surgery. Lastly, one chapter is dedicated to future perspec-
tives including surgical advancements, targeted therapies, and other developments in
the offing. Each chapter carries a summary in the beginning to give the reader an idea
of the content to follow. Illustrations add interest and color to the text.
I sincerely hope that this book will benefit medical undergraduates, postgradu-
ates, and students as well as practitioners of gynecologic oncology thereby contrib-
uting to successful management and better outcomes in patients suffering from
endometrial carcinoma.
I wish to acknowledge and thank all the authors for their contribution to this book
without which this project would not have been possible. I extend special thanks and
gratitude to Dr. Hemant Tongaonkar for his consistent encouragement and to Dr.
Somashekhar for his helpful advice time and again. I am also thankful to Mr.
Ramcharan for drawing the illustrations for my chapter in the book. Last but not the
least, I heartily acknowledge the unconditional support provided by my family espe-
cially my husband, Dr. Rajeev, and my children, Prannay and Pallavi, in this venture.

Jaipur, India Ranu Patni

vii
About the Editor

Dr. Ranu Patni is a prominent gynecologic oncolo-

gist with more than 15 years of experience in “gyne-
cologic oncology.” After postgraduate work in
obstetrics and gynecology, her quest for clinical, sur-
gical, and academic excellence led her to constantly
upgrade her skills through trainings from reputed
international and national institutions, including
King George V Hospital (Sydney, Australia) and
Tata Memorial Hospital (Mumbai). She has been a
pioneer in establishing the concept of “gynecologic
oncology” and “menopausal medicine” in the state
of Rajasthan, India.
Her surgical skills are backed not only by a large number of gynecological can-
cer surgeries including those on many challenging endometrial cancer patients but
also by very competitive long-term results. She is well known for her age-­appropriate
approach to individual patients and routinely adopts evidence-based fertility preser-
vation techniques and hormonal conservation measures.
She also has a keen interest in research and dissemination of knowledge among
the medical fraternity as well as the public. She has organized and participated in
numerous national and international conferences/workshops, contributed chapters
to books of national repute, published papers in national and international journals,
and edited and peer-reviewed papers for prominent journals, is an active member of
many academic societies, and has been a principal investigator in large multicentric
clinical trials on “postmenopausal osteoporosis.”
A unique feature of Dr. Patni’s career is her passion for public health education.
Over the past 20 years, she has repeatedly engaged in efforts to educate the public,
especially women, about the preventive and therapeutic aspects of various health
issues.

ix
Contents

1 Endometrial Carcinoma: Evolution and Overview������������������������������    1

Ranu Patni
2 Epidemiology and Prevention of Endometrial Carcinoma������������������   11
Simmi Pokharna
3 Premalignant Conditions of the Endometrium ������������������������������������   19
Kusum Lata and Neerja Bhatla
4 Pathophysiology of Endometrial Carcinoma����������������������������������������   29
Arpita Jindal
5 Diagnosis and Pre-management Workup of Endometrial
Carcinoma������������������������������������������������������������������������������������������������   41
P. Veena and Amita Maheshwari
6 Surgical Management of Early-Stage Endometrial Cancer����������������   55
Hemant Tongaonkar, Samar Gupte, Devyani Mahajan,
and Jyoti Kulkarni
7 Minimally Invasive Surgery for Endometrial Cancer��������������������������   67
S.P. Somashekhar
8 Endometrial Cancer: Advanced Stage��������������������������������������������������   91
Rama Joshi
9 Recurrent Endometrial Cancer��������������������������������������������������������������  107
Yogesh Kulkarni and Harshavardhan
10 Newer Perspectives in the Management of Endometrial Cancer��������  117
Sampada Dessai and Anant Ramaswamy

Index������������������������������������������������������������������������������������������������������������������  127

xi
Endometrial Carcinoma: Evolution
and Overview 1
Ranu Patni

The uterus with its lining, i.e., the endometrium, is a very expressive organ. It mani-
fests its suffering through a variety of symptoms pertaining to benign as well as
malignant diseases. Pathophysiological behavior of the uterus and endometrium can
be aptly described as follows:

With life in it, it grows.

With death in it, it throws.
But, when it weeps
It shows, it shows, it shows!

This book focuses on one of the most dreaded maladies of the uterus originating
from the endometrium, i.e., the endometrial carcinoma. This chapter will give, the
reader, an overview about endometrial carcinoma with the aim of creating a will to
read on in order to gain maximum possible knowledge about this condition.
According to Seibold and Wolf (1973), reproductive cancers were rare in nonhu-
man primates. They reported one ovarian adenocarcinoma, no endometrial carci-
noma, and no breast cancers in 1065 nonhuman primate necropsies [1]. Currently, it
is the fourth most common cancer in women worldwide. According to the current
Surveillance, Epidemiology, and End Results (SEER) fact sheets released in April
2016 based on data review from 1975 to 2013, the number of estimated new detected
cases of endometrial carcinoma in 2016 is 60,050. This constitutes 3.6 % of all new
cancer cases. Similarly, the number of estimated deaths due to endometrial carci-
noma in 2016 is 10,470 which is 1.8 % of all cancer deaths. Median age at diagnosis
is 62 years and the median age of death is 70 years as per SEER database. Five-year
survival based on statistics from the year 2006 to year 2012 is 81.7 %. The 5-year
relative survival has been more or less constant over the last three or four decades

R. Patni
Gynecologic Oncology, Bhagwan Mahaveer Cancer Hospital & Research Centre,
Jaipur, Rajasthan, India
e-mail: ranupatni1@[Link]

© Springer Nature Singapore Pte Ltd. 2017 1

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_1
2 R. Patni

89
88
87
86
85
84
Relative survival (in percentage)
83
82
81
80
79
1975 1990 2004 2007

Graph 1.1  Five-year relative survival trend in endometrial carcinoma based on SEER database

Table 1.1  Number of cases and number of deaths per 100,000 persons by race/ethnicity: endome-
trial carcinoma based on SEER database
Race/ethnicity Number of cases Number of deaths
All races 25.4 4.5
White 26.0 4.1
Black 24.6 7.9
Asian/Pacific Islander 20.3 2.9
American Indian/Alaska Native 21.3 3.6
Hispanic 21.4 3.6
Non-Hispanic 25.9 4.5

(Graph 1.1). SEER database, 2016, also reiterates the old fact that the number of
new cases per 100,000 persons is higher in white race (26.0) compared to black race
(24.6) or Asians/Pacific Islanders (20.3) and American Indians/Alaska Natives
(21.3). However, the number of deaths per 100,000 is higher in black race (7.9)
compared to white race (4.1), Asians/Pacific Islanders (2.9), and American Indians/
Alaska Natives (3.6) (Table 1.1). A small study comparing African-American and
Caucasian patients found no clear differences in global gene expression profiles
suggesting that environmental or social issues played a greater role in explaining
disparity [2].
The Indian Council of Medical Research (ICMR) has published a 3-year report of
population-based cancer registries (PBCRs) (2012–2014) from Bengaluru, India, in
March 2016. On comparing the AARs (age-adjusted rates) per 100,000 persons, cancer
of the corpus occupied the top three places in Chennai (6.0), Delhi (5.5), and
Thiruvananthapuram districts (5.1). On analyzing the trends of endometrial carcinoma
over time, PBCRs showed a significant increase in annual average of AARs for both
three and five years in the metropolitan cities of Bengaluru, Chennai, Delhi and Mumbai.
Changing reproductive trends leading to prolonged estrogen exposure might be
responsible for the increasing incidence of certain reproductive cancers in females.
These include reduced age at menarche, delayed age at first pregnancy, less number
of pregnancies, increased incidence of infertility, higher use of OCs/HRT, and
1  Endometrial Carcinoma: Evolution and Overview 3

increased number of ovulations. However, it is not practical to divert current repro-

ductive practices to those of our ancestors, e.g., early first birth, having more chil-
dren, etc. At the same time, healthy lifestyle and dietary habits should be promoted.
Evolutional and designed changes in microanatomical and hormonal milieu of
human physiology need to proceed while debating their social desirability.
According to Henderson et al. (1982), women with endometrial carcinoma typi-
cally exhibit signs of high estrogen effect and higher plasma estrogen levels as com-
pared to controls. The association of obesity with endometrial carcinoma supports
this hypothesis called as “estrogen excess hypothesis” [1]. Endometrial glandular
proliferation is inhibited by endogenous progesterone in premenopausal women.
Endometrial proliferation is markedly reduced in premenopausal women receiving
a synthetic progestin and in untreated postmenopausal women [3].
Women’s Health Initiative (n = 16,608), a double-blind placebo-controlled trial,
showed that after 5.6 years’ median intervention and 13 years’ median cumulative
follow-up there were fewer endometrial carcinoma and statistically nonsignificant
reduction in deaths from endometrial carcinoma in the combined hormone therapy
compared with the placebo group [4].
A meta-analysis of 30 studies showed that the relative risk of ever users of unop-
posed estrogen therapy was 2.3 compared to nonusers, and it increased to 9.5 in
users of 10 or more years [5].
The potential of anti-aromatase agents in management and the role of hormone
receptors and immunohistochemical (IHC) markers in diagnosis as well as prognos-
tication of endometrial carcinoma were also studied over a period of time.
Given the favorable responses to aromatase inhibitor therapy, as seen in women
with endometrial carcinoma, these treatments may be of interest as preventive and
adjunctive therapies for lesser proliferative lesions of the endometrium [6]. An
overexpression of endometrial aromatase may underlie pathogenesis of endometrial
polyps at least in a subset of cases [7].
Immunohistochemical analysis of endometrial carcinoma differentiating between
various grades and histological types can be useful in identifying high-risk cases.
Halperin et al found that the endometrioid G1–G2 cases showed increased immuno-
reactivity for ER, PR, and bcl-2 (85.7 %, 78.6 %, and 42.8 % respectively), and low
expression of p53 (14.3 %) and HER-2/neu (14.3 %). In contrast, the serous papil-
lary endometrial carcinoma cases showed immunonegativity for ER, PR, and bcl-2
and high immunoreactivity for p53 (81.8 %) and HER-2/neu (45.4 %). The endo-
metrioid G3 cases demonstrated an intermediate immune profile characterized by
immunonegativity for ER, PR, and HER-2/neu, low immunoreactivity for bcl-2
(7.1 %), and high expression of p53 (57.1 %) [8].
A review and meta-analysis report showed that in patients with endometrial car-
cinoma, higher level of ER and PR predicted favorable survival and increased level
of HER2 was associated with poorer survival. All of the three hormone receptors
had prognostic value for survival [9].
Precursor lesions like atypical endometrial hyperplasia (AEH) or endometrial
intraepithelial carcinoma (EIC) frequently precede estrogen-related or serous endo-
metrial carcinomas. However, prevalence of endometrial carcinoma is low (5 per
4 R. Patni

1000 women >45 years). Hence, standardized screening is not effective. At the

same time, recognizing these precursor lesions and timely treatment will prevent
these cancers. The American College of Obstetricians and Gynecologists (ACOG)
and the Society of Gynecologic Oncology (SGO) do not recommend routine screen-
ing for uterine cancer. The American Cancer Society does recommend annual endo-
metrial biopsies starting at age 35 for women known to have a risk for Lynch
syndrome.
Timely assessment of symptomatic and high-risk patients is the key to correct
diagnosis and management of endometrial carcinoma. When endometrial carci-
noma was clinically staged (FIGO 1971), fractional dilatation and curettage was
used to evaluate abnormal bleeding. This permitted the assessment of cervical tissue
and endometrial tissue from all walls and surfaces of the uterus. Currently office
endometrial biopsy has largely replaced D&C. The results of both methods corre-
late well and the accuracy to detect cancer is 91–99 % [10]. Hysteroscopy-guided
biopsy is the standard practice used to evaluate abnormal uterine bleeding in many
centers especially in postmenopausal women (Fig. 1.1). There is no substantial evi-
dence to show that it improves the sensitivity to detect hyperplasia or cancers.
Retrospective studies have suggested increased incidence of positive peritoneal
cytology on hysterectomy after hysteroscopic evaluation. However, no prospective
studies have been performed till date. Positive peritoneal cytology, independently, is
not recognized as a stage-defining feature under the FIGO 2009 staging system
[11].
There is very little role of preoperative imaging in patients with endometrial
carcinoma, as surgery is essentially the same for stages 1, 2, and 3. Imaging studies
have significant limitations in detecting nodal disease, which is microscopic in 90 %

Fig. 1.1 Hysteroscopy-
guided biopsy
1  Endometrial Carcinoma: Evolution and Overview 5

of cases [12]. Imaging studies may be more helpful in assessing extrauterine spread
in serous and clear cell carcinomas, in determining operability to some extent, and
in counseling young women opting for fertility-conserving surgery. In a small pro-
spective series by Signorelli et al., a high negative predictive value for FDG PET/CT
(93 %) was shown in high-risk endometrial carcinoma patients [13]. The GOG 233
trial is an ongoing prospective assessment of PET/CT in patients with endometrial
and cervical cancer. Biomarker, CA 125, may be used to predict the presence of
extrauterine disease. Ideally, serum biomarkers should be tested in endometrial
tissue.
The management of endometrial carcinoma has progressed from an era when
pre- and postoperative radiotherapy was combined with simple hysterectomy to the
present times of primary comprehensive surgical staging. The staging system given
by FIGO has evolved over time from clinical staging in 1971 to surgico-­pathological
staging in 1988 and finally surgical staging in 2009 (Fig. 1.2). In the small number
of patients in whom primary radiotherapy is given, clinical staging (FIGO 1971) is
applied and noted. Standard surgical procedure includes obtaining peritoneal fluid

DISEASE
INVADING
MYOMETRIUM DISEASE EXTENDING INTO
CERVICAL STROMA

Stage II
Stage IA Stage IB

DISEASE INVADING
SEROSA AND ADNEXA
DISEASE EXTENDING INTO
VAGINA AND PARAMETRIUM

Stage IIIB
Stage IIIA

DISEASE AFFECTING
LYMPH NODES

DISEASE AFFECTING
LYMPH NODES
DISEASE INVADING
BLADDER AND BOWEL
MUCOSAE

Stage IIIC Stage IVA

Fig. 1.2  Endometrial carcinoma: stages I to IV A

6 R. Patni

for cytology, exploring the abdomen and pelvis, biopsy/excision of suspicious

extrauterine lesions, total hysterectomy with bilateral salpingo-oophorectomy, and
retroperitoneal (pelvic and para-aortic) lymphadenectomy (Figs. 1.3 and 1.4). There
is increasing trend of surgically reducing the disease to no residual volume like in
ovarian cancer.
Minimally invasive surgery is fast becoming the standard practice especially in
obese patients. In patients with severe medical comorbidity, advanced age, obesity,
or inability to perform nodal dissection, vaginal hysterectomy with or without lapa-
roscopic/robotic assistance may be done. Based on pathological features in final
histopathology report, patients may be classified according to their risk of recur-
rence and adjuvant therapy offered to those at sufficient risk. Primary radiation

Fig. 1.3 Retroperitoneal
lymph nodes

SUPERIOR MESENTRIC ARTERY

LEFT URETER

LEFT OVARIAN VEIN

PARA AORTIC LYMPH NODES LEFT OVARIAN ARTERY
RIGHT URETER
INFERIOR MESENTRIC ARTERY

LEFT COMMON ILIAC VESSELS

HYPOGASTRIC ARTERY
AND NODES
EXTERNAL ILIAC NODES
OBTURATOR NODES

GENITOFEMORAL NERVE

COMMON ILIAC ARTERY

EXTERNAL ILIAC ARTERY

INTERNAL ILIAC ARTERY
EXTERNAL ILIAC VEIN

OBTURATOR NERVE

URETER
SUPERIOR VESICAL ARTERY

Fig. 1.4  Pelvic lymph

node dissection
1  Endometrial Carcinoma: Evolution and Overview 7

therapy or hormonal therapy may be used for patients not suitable for primary sur-
gery. Progestational therapy is given in younger patients desiring fertility conserva-
tion. Radiotherapy, chemotherapy, or hormonal therapy may be given in disseminated
or non-resectable disease [14].
It is indeed a challenge to identify patients who are likely to benefit from lymph-
adenectomy and from adjuvant therapies. Current trends suggest a less frequent use
of pelvic radiation therapy or no use of any radiation [15]. The PORTEC study
published in 2000 showed that postoperative radiotherapy in stage 1 endometrial
carcinoma reduces locoregional recurrence but has no impact on overall survival.
Radiotherapy increases treatment-related morbidity and is not indicated in patients
with stage 1 endometrial carcinoma below 60 years and in patients with grade 2
tumors with superficial myometrial invasion [16]. In 2012, a Cochrane systematic
review and meta-analysis published by Kong A et al. showed similar results with
EBRT [17]. Continued efforts to minimize the morbidity associated with EBRT led
to further research and modifications in the adjuvant radiotherapy protocol. The
PORTEC 2 study showed that vaginal brachytherapy (VBT) is effective in ensuring
vaginal control, with fewer gastrointestinal toxic effects than with EBRT, and VBT
should be the adjuvant treatment of choice for patients with endometrial carcinoma
of high-­intermediate risk [18].
Also, there have been significant developments in chemotherapy in endometrial
carcinoma. There is increasing use of combination chemotherapy in advanced and
recurrent disease along with a promise of better outcomes in adjuvant setting.
Pooled analysis of NSGO-EC-9501/EORTC 55991 and MaNGO ILIADE-III stud-
ies showed that addition of adjuvant chemotherapy to radiotherapy improves
progression-­free survival in operated endometrial carcinoma patients with no resid-
ual tumor and high-risk profile [19]. PORTEC 3 is an intergroup trial investigating
survival improvement with adjuvant chemotherapy given during and after pelvic
radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk
endometrial carcinoma (HR-EC). Accrual was completed in December 2013.
Toxicity and 2-year HRQL (health-related quality of life) results showed that CTRT
for high-­risk endometrial carcinoma causes significantly higher adverse events
(AE) and symptom ratings and reduced HRQL during and after treatment as com-
pared with RT, but with recovery over time, without differences in grade >/= 3AE at
2 years [20]. NCCN guidelines have updated treatment recommendations to assign
a greater role to chemotherapy in primary (category 2B) as well as adjuvant setting.
A section on sentinel lymph node mapping has also been included in these guide-
lines (NCCN guidelines version 2.2016).
The current challenge in management of endometrial carcinoma is to understand
the tumor biology, utilize it to predict recurrence as well as survival, and exploit the
genetic changes to define postoperative therapies with least toxicity. Targeted thera-
pies based on molecular changes in patients with advanced or recurrent disease are
currently under development in many clinical trials. These will help in individual-
izing therapy based on personal genotypic and phenotypic profile. P13K/AKT/
8 R. Patni

mTOR inhibitors, anti-HER-2/neu antibodies, biguanide (metformin), PARP inhibi-

tors, etc. may hold promise in the future. It is also hoped that with evolution of
understanding of molecular pathways, treatment based on histology may become
available so as to provide better management and outcomes for poor prognosis
endometrial carcinoma like serous carcinoma, clear cell carcinoma, and
carcinosarcoma.
A Talhouk et al. have recently proposed a new system for classification of endo-
metrial carcinoma based on molecular categories identified in The Cancer Genome
Atlas (TCGA). This pragmatic molecular classification tool based on mismatch
repair protein immunohistochemistry, POLE mutational analysis, and p53 IHC as a
surrogate for “copy number” status can provide independent prognostic information
beyond established risk factors [21].
With the background of the above evolutionary journey and overview, this book
will further provide a detailed account of various aspects of endometrial carcinoma
in its different chapters. “Uterine sarcoma” being a separate entity has not been
covered in the text. Although “radiotherapy” and “chemotherapy” as treatment
modalities have been described as appropriate, their detailed accounts are out of
scope of this book.
I wish for a fruitful reading experience for the readers.

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Epidemiology and Prevention
of Endometrial Carcinoma 2
Simmi Pokharna

Abstract
The objective of this chapter is to review the evidence related to the epidemiol-
ogy of endometrial carcinoma and subsequent protective factors.
The majority of the cancers that occur in the body of uterus are endometrial
cancers mostly adenocarcinomas. It is the fourth most common cancer in women,
worldwide.
It is mainly a disease of high-income countries. Risk increases with transition
from lower- to high-income economies and with age as majority of cases are
diagnosed after menopause.
Obesity and physical inactivity are also important risk factors. As worldwide
obesity epidemic shows no signs of abetting, as compared to other cancers, the
relative risk of obesity-related deaths is highest in endometrial cancers.
Preventive strategies and early detection are required to reduce the burden of
a disease whose incidence and mortality rates are on the rise.
As symptoms present at relatively early stages, it is generally diagnosed early
and 5-year survival rate is high.

Endometrial cancer is the fourth most common cancer in women worldwide and the
most common gynaecological malignancy in the United States. It accounts for
4–8 % of all cancers and is fourth after breast, colon and lung cancer [2]. It is esti-
mated that a woman born in the United States in 2011 has a lifetime risk of 1 in 39
of developing endometrial carcinoma [1].
However, in India and Southeast Asia as a whole, the incidence and rates of
endometrial carcinoma are lower. In developed countries, the incidence is 12.9 per

S. Pokharna, MS (*)
Obstetrics and Gynecology, Aditya Hospital, Jaipur, Rajasthan, India
e-mail: adityahospital111@[Link]

© Springer Nature Singapore Pte Ltd. 2017 11

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_2
12 S. Pokharna

100,000 women and mortality rate is 2.4 per 100,000. In developing countries the
incidence is 5.9 per 100,000 with a mortality rate of 1.7 per 100,000 [19]. Lower
rates in this part of the world may be explained by difference in the distribution of
known risk factors amongst different races [2].
Worldwide, 290,000 women were diagnosed with endometrial carcinoma in
2008, accounting for nearly 5 % of all new cases of cancer in women [22]. The
incidence has been increasing by 0.8 % each year since 1998 [3]. The reasons for
this may be a result of a marked increase in the risk factors. Overall mortality and
morbidity is low because normally the patients present at an earlier stage with
abnormal uterine bleeding.
There are two types of endometrial carcinomas:

1. Type I, which are oestrogen dependent, low grade and endometrioid and account
for 85 % of endometrial carcinomas and have better prognosis. These cancers are
oestrogen driven and have hyperplastic endometrium.
2. Type II, which are oestrogen-independent, high-grade and serous or clear cell
tumours with late-stage diagnosis and have poor prognosis [1]. These cancers are
mostly related to ageing. Recent studies suggest that the two types of endome-
trial carcinomas share many common etiological factors. So type II tumours may
not be completely oestrogen independent [5, 20].

Most of the risk factors of endometrial cancers are based on increased oestrogen
exposure. Independent of this, there are certain clearly discernable demographic
patterns which shall be elaborated further in this chapter (Table 2.1).

Table 2.1  Risk factors of endometrial carcinoma

Risk factors Salient features
Age Peak between 55 and 70 years
Race More in White race and less in Indians and South Asians
Obesity BMI >30 kg/m2
Diet High in fat and low in fibre
Diabetes mellitus Increases the risk two- to threefold
Parity More in nulliparous and infertile women
Hypertension As common association with obesity and diabetes (corpus cancer
syndrome)
Menstrual history Early menarche, late menopause, long menstruation span
Hyperoestrogenic states Oestrogen replacement therapy without progesterone, PCOS and
oestrogen-producing tumours
Lynch syndrome Inherited autosomal dominant disease
Use of tamoxifen High index of suspicion is warranted in tamoxifen users
Family history Family history of endometrial, ovarian and breast cancers
Molecular alterations Mutation of the PTEN and p53 genes is a frequent event in
endometrial cancers [1]
2  Epidemiology and Prevention of Endometrial Carcinoma 13

Endometrial cancers are age dependent. The risk of developing endometrial

cancers increases with advancing age. The peak of occurrence is between 55 and
70 years of age and the average age is 61 years. More than 90 % of the patients are
over the age of 50. Only 5 % or less develops before the age of 40 [3]. A woman
under the age of 40 has 1 in 1423 chances of developing the disease but a woman
older than 70 has a risk of 1 in 81 [9].
Race, as stated before, White women are more likely to be afflicted as compared
to African, Asian, Hispanic, Chinese or Japanese women. In general, incidence is
higher in North America, Australia and Europe than in South Asia, Central America
and Africa. But once the women from other regions start living in the United States,
the incidence of acquiring the disease increases as compared to those who choose to
remain in the country of their origin. However, once the disease occurs, morbidity
and mortality rates in Afro-American women are more than in White and Asian
women [1].
Obese women have a higher risk of endometrial carcinomas. Nearly 70 % of the
patients are obese women. With increase in BMI, the risk of getting the disease and
concurrent morbidity and mortality also increase [17]. With a BMI of >30 kg/m2,
the risk is 3 times and it becomes 4 times with BMI of >32 kg/m2. A BMI of
>35 kg/m2 will increase the risk of developing endometrial carcinomas to 6 times
as compared to a woman of BMI 23 kg/m2 [1, 12]. An abrupt increase in weight
gain, especially during early adulthood, is also predictive of increased risk. Upper
body obesity is also a risk factor independent of body weight. Both obesity and
distribution of adipose tissue accumulated during adult life increase the risk of
endometrial carcinoma substantially. In addition morbidly obese women have high-
est risk of cancer-related deaths [1, 17]. As compared to other cancers, the relative
risk of obesity-­related deaths is highest in endometrial cancers [6].
Obesity increases endogenous oestrogen by peripheral conversion of androstene-
dione to oestrogen by aromatase in adipose tissues. This increases the endometrial
exposure to endogenous oestrogen and decreases serum sex-binding globulins,
thereby leading to hyperoestrogenic state [1, 6].
A diet high in carbohydrates and high glycaemic index influences insulin secre-
tion and insulin-like growth factors, which may exert relevant effects on obesity and
diabetes mellitus. Both of these are important risk factors for endometrial carci-
noma [7]. Food rich in fat and red meat significantly increases the risk [6].
Diabetes mellitus is an independent risk factor, and an increased incidence of
type II diabetes mellitus is noted in patients of endometrial cancers since many
years [1]. There is also a strong relationship between increased insulin resistance
and endometrial cancer. An obese, diabetic menopausal woman has 2–3 times more
risk of developing endometrial cancer [3].
Hypertension is often associated with obesity and hence also termed a risk factor
[3]. The presence of a triad of obesity, diabetes and hypertension in a woman
increases the risk of endometrial cancer and is commonly termed corpus cancer
syndrome.
Parity has a positive association with the risk of development of endometrial
cancer. Nulliparous women are 2–3 times more at risk than parous women. The
14 S. Pokharna

observed beneficial effects of pregnancies may be related to a strong exposure to

progesterone during pregnancies [8]. Moreover, childbearing at an older age is asso-
ciated with a lower risk. According to a study, women who give birth at age 40 or
even more have 44 % less chances of disease when compared to women who had
their last childbirth at age 25. The reduced risk persists for many years [4, 9].
Infertility, which may be a manifestation of nulliparity, has a three- to fivefold
increase in the risk for disease as compared to fertile women although treatment for
infertility may alter the woman’s cancer risk [1].
Menstrual history also plays a role in risk development. The extremes of spec-
trum, i.e. early menarche (11–12 years) and late menopause (more than 50 years),
have both been associated with increased risk [1]. The longer the menstruation span,
the greater is the risk. The increase in menstruation span may be related to an accu-
mulation of PTEN or p53 mutation [5].
Most of the risk factors are associated with exposure to excessive oestrogen
(hyperoestrogenic states). The initial cases of endometrial carcinoma were reported
relating to oestrogen replacement therapy (ERT) without concomitant progesterone.
ERT increased the risk 4.5–8 times [3]. The risk which persisted for many years
even after the treatment was stopped. In addition the risk increased with longer
duration and higher dosages of oestrogen. A single year of unopposed oestrogen use
increased the risk by 40 % of baseline [1].
Oestrogen-producing tumours were first reported by Schroeder in 1992 to be
related to endometrial cancers. Since then, a large number of patients (6–12 %) with
oestrogen-producing tumours have been found to have developed endometrial car-
cinoma [1].
Polycystic ovary syndrome is also related with risk of endometrial carcinoma.
Elevated endogenous oestrogen levels along with certain comorbidities prevalent in
PCOS like obesity, insulin resistance, type II diabetes mellitus and hypertension
lead to an increase in the risk. Chronic anovulation leading to proliferative endome-
trial pathologies, polyps, hyperplasia and unopposed oestrogen exposure all cause
an increase in the risk of development of endometrial carcinoma [11].
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an
inherited autosomal dominant disease in which women are at a risk of more than
one primary cancer of colon, rectum, ovaries, small intestine, renal pelvis or endo-
metrial cancer developing in their lifetime. Thirty-nine percent of these women may
develop endometrial carcinoma by the age of 70 [1, 3].
A strong association has been found between endometrial cancer and BRCA
mutation gene carriers. But it is difficult to differentiate whether there is an increased
susceptibility on account of BRCA mutation or a consequence of tamoxifen usage
in BRCA carriers with a history of breast carcinoma. Since 1985 multiple authors
have confirmed the relation between endometrial carcinoma and the duration and
use of tamoxifen. As the benefits of tamoxifen to breast cancer patients outweigh
the risk of endometrial cancer, a high index of suspicion and close monitoring is
warranted in tamoxifen users complaining of abnormal uterine bleeding [10].
Altered levels of hormones like prolactin and [Link] may also play a role in risk
of endometrial cancer by causing obesity and menstrual dysfunction [6].
2  Epidemiology and Prevention of Endometrial Carcinoma 15

Use of talc for pelvic hygiene is also associated with increase in risk of
endometrial carcinoma [5, 19].
Karen Lu and Brian M. Slomovitz in Katz Gynaecology have defined the molec-
ular alterations present in endometrial cancers. PTEN mutations are frequently seen
in endometrioid endometrial carcinoma and have also been seen in complex endo-
metrial hyperplasia. Microsatellite instability occurs in 25–30 % of all endometrial
cancers and is the result of either germline mutations in DNA mismatch repair pro-
teins (MLH1, MSH2 or MSH6) or more frequently from the somatic methylation of
the MLH1 promoter. In contrast to endometrioid endometrial cancers, uterine papil-
lary serous carcinomas have a high frequency of p53 mutations. HER-2/neu ampli-
fication is seen in 10–20 % of uterine papillary carcinomas and is likely associated
with advanced age and poor prognosis of this histology [13].
Recent studies suggest that biomarkers like progesterone receptors, insulin-like
growth factor I, retinaldehyde dehydrogenase type II, secreted frizzled-related pro-
tein 4 and anti-LeY monoclonal antibodies may be promising tumour markers.
Adiponectin secreted by adipose cells is decreased in obesity and may be a marker
for endometrial cancer. Leptin, another adipose-derived hormone, is also implicated
in proliferation of the endometrium [6]. A five-panel biomarker (prolactin, GH,
eotaxin, E-selectin and [Link]) has also been used to diagnose the risk of endome-
trial cancer [6, 18].
HE-4 marker, a human epididymis-specific 4-disulphide core protein, a precur-
sor of human epididymis protein, provides 46 % sensitivity for diagnosis and prog-
nosis of endometrioid adenocarcinoma of endometrium in all stages of cancer and
has a specificity of 95 %. Human serum amyloid apolipoprotein (SAA) is overex-
pressed and actively secreted by grade 3 endometrioid adenocarcinoma and serous
papillary carcinoma of endometrium [21].
Endometrial carcinoma is a very common malignancy affecting a large number
of women across the globe. An understanding of the epidemiology will aid not only
in diagnosis but also in treatment and development of preventive regimens. Though
endometrial cancer is less common in India and other developing countries, increase
in longevity and changing lifestyles have increased the possibilities of rise in cases
of endometrial cancers.
There are certain protective factors which can help in reducing the risk of endo-
metrial cancers (Table 2.2):

(i) Weight loss remains the key to protection from endometrial carcinoma. It
helps in reversal of hormonal imbalances and dysregulation of IGF/insulin
pathway. The fact that so many diagnosed cancers of endometrium are associ-
ated with obesity leads us to hypothesize that a large portion of these cancers
might be preventable by weight loss.
(ii) Prolonged use of oral contraceptive pills has long been known to decrease the
risk of endometrial carcinoma by 40 % even up to 15 years after the discon-
tinuation. This protection increases with the length of use. Four years of
usage has been known to reduce the risk by 56 %, 8 years by 67 % and
12 years by 72 % [1, 3].
16 S. Pokharna

Table 2.2  Preventive factors in endometrial carcinoma

1 Weight reduction
2 Physical exercises
3 Oral contraceptive pills
4 Intrauterine devices
5 Good monitoring of diabetes mellitus
6 Metformin
7 Breastfeeding
8 Oestrogen with concomitant progesterone in hormone replacement therapy
9 High consumption of coffee, whole grains, vegetable and food rich in lutein and high fibre
10 Avoiding use of talc

(iii) Recent studies indicate that intrauterine devices may also be associated with
decreasing the risk. The protective effect of IUD may be through the intense
inflammatory response that leads to lysosomal and inflammatory actions,
which may be responsible for early elimination of hyperplastic endometrium.
Complete shedding of endometrium decreases hyperplasia and thereby
reduces the risk of endometrial carcinoma [1, 5, 15, 16].
(iv) Hormonal IUDs help in reversal of endometrial hyperplasia and thus substan-
tially reduce the incidence of this potentially preventable disease. Further
studies are required for levonorgestrel-containing devices in obese patients
[1, 15, 16].
(v) Active cigarette smoking has been found to have a beneficial effect in regard
to the risk of developing endometrial cancer especially in postmenopausal
women. This may be because of reduction in circulating oestrogens. Smoking
causes reduction in body weight and induces early menopause. It is not seen
in passive smokers. However, the protection is far outweighed by other health
hazards associated with cigarette smoking and tobacco use [1, 6, 14, 18].
(vi) Metformin, an oral hypoglycaemic agent, lowers blood glucose by increas-
ing its uptake. It seems to be a logical choice for prevention of endometrial
cancer. Based on preclinical data, the Gynecologic Oncology Group is
considering examination of metformin for the treatment of endometrial
cancer [18].
(vii) Coffee also probably protects against endometrial cancer. Coffee drinking
has been associated with higher sex hormone-binding globulin (SHBG),
which reduces free oestradiol and stimulates synthesis of oestrogen metabo-
lites, thus inhibiting oestrogen-mediated carcinogenesis. High coffee con-
sumption has been associated with low levels of C-peptide and higher levels
of adiponectin [22].
(viii) Encouragement of breastfeeding also has a preventive effect on the occur-
rence of endometrial cancers.
(ix) Judicious advice of HRT with concomitant progesterone weighs the risks of
usage with non-usage. Progesterone as a differentiating factor may hold the
key to the protective measures.
2  Epidemiology and Prevention of Endometrial Carcinoma 17

As the epidemiology and risk factors of occurrence of endometrial carcinomas

are better known, mortality and morbidity relating to the disease may be signifi-
cantly reduced by certain preventive measures.
Since endometrial carcinomas often present as postmenopausal bleeding or
abnormal uterine bleeding, it is easier to diagnose in earlier stages as compared to
other malignancies. It has been shown that 9 % of women in their early 50s with
postmenopausal bleeding had endometrial carcinoma, while 60 % of women in their
80s with postmenopausal bleeding had endometrial cancers [7]. All women with
postmenopausal bleeding and any patient with premenopausal abnormal uterine
bleeding especially those with high risk (e.g. obese, diabetic, infertile) should
undergo transvaginal ultrasound and thereafter endometrial biopsies. Fifty percent
of the females may be diagnosed by routine Pap smear.
Women on tamoxifen should also undergo screening regularly by TVS and
biopsy if needed. This evaluation is to be continued even after discontinuation of
tamoxifen.
Endometrial biopsies have 99.6 % and 91 % detection rate in premenopausal and
postmenopausal women, respectively. The specificity of endometrial biopsy is 98 %
and sensitivity is 99 % [3].
All obese, diabetic postmenopausal women should be advised to maintain a
healthy weight and do regular exercise for at least 30 min per day with an increase
in routine physical activity. A sedentary lifestyle and physical inactivity have to be
avoided.
There should be a controlled diet which is low in fats and high in fibre. Food with
high glycaemic index is to be avoided. Coffee, whole grains, vegetables and food
rich in lutein are inversely associated with cancer risk [6].
By lifestyle modification, improving technique of early detection and providing
timely therapy, we can look forward to longer and healthier outcomes for possible
patients and survivors. Risk assessment and proper clinical staging of disease are
required for proper management.

References
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Endometrial Cancer. https:/[Link]. doi:10.3843/GLOWM.10236.
2. Chhabra S, Tembhare A. Current status of endometrial carcinoma. J MGIMS.
2009;14(ii):18–23.
3. Pant AC, Bristow RE. In Joseph Hurt K, Guile MW, Bienstock JL, editors. Chapter cancer of
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4. Setiawam VW, Hannah P, et al. Evidence for a link between obesity and the risk of cancer.
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5. Cramer DW. The epidemiology of endometrial and ovarian cancer. Haematol Oncol Clin
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7. Galeone C, Augustin LSA, et al. Dietary glycaemic index, glycaemic load and the risk of
endometrial cancer; a case control study and meta analysis. Eur J Cancer Prev. 2013;
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8. Balasubramaniam G, Sushama S. Hospital-based study of endometrial cancer survival in
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11. Pal L. Polycystic ovary syndrome-current and emerging concepts. Chap, 18 Lauren W milman
and Anuja Dokras. Springer [India] Ltd., New Delhi: p. 303–16.
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Epidemiol. 2008;18(6):492–9.
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analysis of prospective observational studies. Lancet. 2008;371(9612):569–79.
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Premalignant Conditions
of the Endometrium 3
Kusum Lata and Neerja Bhatla

Abstract
In developed countries, endometrial carcinoma is the most common female
genital tract malignancy. It is showing an increasing trend in India as well. It is
now recognized that a precursor lesion usually precedes it. The distinction
between endometrial hyperplasia and true precancerous lesions is of utmost
importance to provide appropriate intervention. At present, the endometrial
intraepithelial neoplasia (EIN) classification best fits this requirement as com-
pared to the more widely used four-class World Health Organization schema
(1994), which does not distinguish between atypical hyperplasia and precan-
cerous lesions.
The diagnosis of premalignant lesions is made by dilatation and curettage or
endometrial suction curette, but the accuracy of both in diagnosing precancer
and excluding concurrent carcinoma is unclear. Hysteroscopy with directed
biopsy improves the sensitivity of diagnosis. Total hysterectomy for endometrial
intraepithelial neoplasia allows definitive assessment of a possible concurrent
carcinoma and effectively treats premalignant lesions. However, for women who
wish to retain their childbearing potential, systemic or local progestin therapy
has a role as an alternative to hysterectomy.

K. Lata
Sitaram Bhartia Institute of Science and Research, New Delhi, India
N. Bhatla (*)
Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences,
New Delhi, India
e-mail: Neerja.bhatla07@[Link]

© Springer Nature Singapore Pte Ltd. 2017 19

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_3
20 K. Lata and N. Bhatla

Introduction

Globally, endometrial cancer is the fifth most common cancer in women, affecting
318,000 women every year [1]. While it is the most common female genital tract
malignancy in the West, accounting for almost half of all new gynecologic cancers
[2], in India, the incidence is low with an age-standardized incidence rate of 4.6 per
100,000 population [3].
Two main types of endometrial cancer are recognized: type 1 cancers that consti-
tute 80–90 % of cases are estrogen-dependent endometrioid adenocarcinomas with
good prognosis. On the other hand, type 2 tumors which are non-estrogen depen-
dent are found to be more aggressive with poor prognosis carrying a high risk of
relapse and metastasis.
The most common type of endometrial carcinoma is the endometrioid subtype
(approximately 80–85 % of cases), which is preceded by a precursor lesion. Excess
estrogenic stimulation of the endometrium, with consequent proliferative glandular
epithelial changes, has been associated with both endometrioid endometrial carci-
noma and its precursor lesions. Risk factors known to predispose to the develop-
ment of endometrial carcinoma are obesity, unopposed estrogen therapy, diabetes
mellitus, and nulliparity. Women most commonly present with abnormal uterine
bleeding, whether in the form of menorrhagia, metrorrhagia, or postmenopausal
bleeding, while some may present with abnormal Pap smear, i.e., atypical glandular
cells or atypical endometrial cells, detected on routine Pap smear.

Endometrial Hyperplasia Classification Systems

Currently there are two systems of endometrial precancer classification: (1) the
WHO 1994 schema and (2) the endometrial intraepithelial neoplasia (EIN) diagnos-
tic schema developed by the International Endometrial Collaborative Group [2].
The WHO 1994 schema classifies histology based on glandular complexity and
nuclear atypia into four categories of risk classification: (1) simple hyperplasia, (2)
complex hyperplasia, (3) simple hyperplasia with atypia, and (4) complex hyperpla-
sia with atypia. These categories, being descriptive in nature, make interpretation
more subjective. Importantly, this classification does not provide specific manage-
ment algorithms. Due to poor reproducibility of the WHO classification [3, 4], the
EIN schema was introduced to improve clinical management.
There are three categories in EIN schema based on pathologic criteria [5, 6]: (1)
benign (benign endometrial hyperplasia), (2) premalignant (endometrial intraepi-
thelial neoplasia), and (3) malignant (endometrial adenocarcinoma, endometrioid
type, well differentiated). Tables 3.1 and 3.2 show the diagnostic criteria and defini-
tions of EIN, respectively. Using this classification, pathologists can classify the
lesion more accurately, and clinicians can guide treatment appropriately. It has been
shown to be a good prognostic tool in several retrospective studies and one prospec-
tive study [7–9], with better interobserver reproducibility than the WHO 1994
schema. Figures 3.1 and 3.2 are images of benign endometrial hyperplasia and
endometrial intraepithelial neoplasia, respectively.
3  Premalignant Conditions of the Endometrium 21

Table 3.1  Diagnostic criteria for endometrial intraepithelial neoplasia [6, 7]

Functional
Nomenclature Topography category Treatment
Benign endometrial Diffuse Prolonged Hormonal therapy,
hyperplasia estrogen effect symptomatic
Endometrial intraepithelial Focal progressing to Precancerous Hormonal therapy or
neoplasia diffuse surgery
Endometrial adenocarcinoma, Focal progressing to Malignant Surgery, stage based
endometrioid type, well diffuse
differentiated

Table 3.2  Definitions of endometrial intraepithelial neoplasia criteria [6, 7]

Criteria Comments
Architecture Area of glands greater than stroma (volume percentage stroma less
than 55 %)
Cytology Cytology differs between architecturally crowded focus and
background
Size greater than 1 mm Maximum linear dimension exceeds 1 mm
Exclude mimics Benign conditions with overlapping criteria (i.e., basalis, secretory,
polyps, repair)
Exclude cancer Carcinoma if maze-like glands, solid areas, or appreciable cribriform

Fig. 3.1  Benign endometrial hyperplasia (Picture courtesy of Dr. Sandeep Mathur)

Precancer Diagnosis: Endometrial Sampling and Imaging

The management of patients with premalignant endometrial lesions requires accu-

rate diagnosis of a precancer lesion and exclusion of coexisting carcinoma to pre-
vent any under- or overtreatment. Ideally, it should be possible to make this diagnosis
22 K. Lata and N. Bhatla

Fig. 3.2  Endometrial intraepithelial neoplasia (Picture courtesy of Dr. Sandeep Mathur)

preoperatively. However, it has been seen that in approximately 40 % of patients

who had a diagnosis of endometrial intraepithelial neoplasia diagnosis by endome-
trial suction curette, the diagnosis changed to carcinoma after hysterectomy [8, 10],
making exclusion of concurrent carcinoma a challenge.
Both dilatation and curettage (D&C) and endometrial suction curette have pit-
falls in diagnosing precancer and excluding concurrent carcinoma. Both have sam-
pling limitations: approximately 60 % of D&C specimens sample less than one half
of the uterine cavity [11]. For women undergoing hysterectomy as a definitive man-
agement for premalignant lesions, the technique of sampling does not matter as
much since hysterectomy eliminates the risk of failure to diagnose an endometrial
cancer. Dilation and curettage and endometrial suction curette sampling devices
have been reported to yield equal rates of cancer detection in patients with abnormal
uterine bleeding [12]. The more accurate diagnosis of uterine lesions is made by
hysteroscopy with directed biopsy as it helps in visual assessment of the background
epithelium also [13–15]. It gives the best opportunity to confirm the diagnosis of a
true premalignant endometrial lesion and exclude an associated endometrial carci-
noma. Currently available diagnostic methods provide very little amount of endo-
metrial tissue making cancer risk assessment less feasible. So it has been suggested
that the assessment of sample adequacy should be included in the diagnostic scheme
as is done for cervical cytology specimens.
In women with postmenopausal bleeding, transvaginal ultrasonography (TVS) is
the most common employed imaging modality due to high specificity in excluding
carcinoma. Endometrial sampling is not recommended if endometrial thickness is
found to be 4 mm or less because of the very low risk of uterine malignancy in these
patients [16]. An endometrial thickness greater than 4 mm in a patient with post-
menopausal bleeding requires additional evaluation (such as sonohysterography,
3  Premalignant Conditions of the Endometrium 23

office hysteroscopy, or endometrial biopsy) to adequately visualize endometrial

thickness. The significance of an endometrial thickness greater than 4 mm in an
asymptomatic, postmenopausal patient has not been established, and this finding
need not routinely trigger evaluation [16].
Unlike postmenopausal women, the role of TVS is limited in premenopausal
women as endometrial thickness is not static during different phases of the men-
strual cycle and may overlap with women having carcinoma.
The role of tumor markers for endometrial carcinoma is not well established. An
inexpensive, sensitive, and specific serum test, which would be the most attractive
approach to screen women for endometrial cancer, has still not been discovered.
Raised serum CA 125 usually signifies an advanced disease and a poor prognosis
but has limited role in monitoring treatment response. The serum markers CA 19-9,
CA 15-3, and CA 72-4 and CEA levels are raised in endometrial cancer patients in
22–24 %, 24–32 %, 22–32 %, and 14–22 % of cases, respectively [17]. It has been
seen that only a combination of CA 125 and CA 19-9 has a role in posttreatment
surveillance due to high sensitivity (83.3 %) for detection of recurrence, with only
12.8 % of false-positive cases [17]. Tumor markers should be used in conjunction
with other modalities, such as ultrasound and high-resolution MRI to attain high
specificity.

Management of Endometrial Intraepithelial Neoplasia

Management of a newly diagnosed case of endometrial intraepithelial neoplasia has

the following main objectives: (1) to exclude a concurrent adenocarcinoma, (2) to
minimize the risk of delayed discovery of an occult carcinoma, and (3) to prevent
progression to endometrial cancer.

Nonsurgical Management Options

Nonsurgical management is advised to patients (1) whose clinical, radiological, and

pathological assessment suggests endometrial hyperplasia without any evidence of
malignancy and (2) who desire future fertility (3) or patients with sufficient medical
comorbidities precluding surgical management.
Presently nonsurgical management options include hormonal therapy and endo-
metrial ablation. Endometrial ablation using thermal or electrical cautery devices
has been employed for non-precancerous endometrial lesions, but it is not recom-
mended for the treatment of atypical endometrial hyperplasia (AEH)/endometrial
intraepithelial neoplasia (EIN). The completeness of ablation cannot be guaranteed
via any method, and subsequent adhesions may make the cavity less accessible for
follow-up surveillance.
Several studies have evaluated the use of hormonal treatment to induce
regression of hyperplasia. Progestins are widely used with acceptable toxicity
profile. Progesterone counteracts the mitogenic effects of estrogens and induces
24 K. Lata and N. Bhatla

secretory differentiation [22]. Treatment with progestins may be an option for

any patient who wants to retain childbearing, any patient with a hyperplastic or
precancerous lesion who desires uterine preservation, and most elderly patients
with medical comorbidities having diagnosis of endometrial intraepithelial neo-
plasia, a low-­grade malignancy, or both. Although the efficacy of progesterone
is well recognized, the exact dose and duration has not been specified till date
[23–25]. Neither has the frequency been determined whether treatment should
be cyclic or continuous. The appropriate length of follow-up after treatment also
is still debatable.
Table 3.3 shows commonly used progestin regimes. Medroxyprogesterone ace-
tate and megestrol acetate, with different doses and schedules, are the most common
progestin therapies used in the clinical setting. Regression of hyperplasia (simple,
complex, and atypical) has been observed in 80–90 % of individuals receiving
medroxyprogesterone acetate (10 mg daily for 12–14 days per month) or micron-
ized progesterone in vaginal cream (100 mg for 12–14 days per month) when treated
for 3 months as shown in Table 3.3 [26–28]. Long-term systemic medical treatment
to prevent reappearance of endometrial intraepithelial neoplasia requires awareness
of concomitant adverse effects. Edema, gastrointestinal disturbances, and thrombo-
embolic events are infrequent with these treatments, thereby making medical man-
agement a suitable therapeutic option for patients for whom surgical management is
not desired. However, if endometrial intraepithelial neoplasia is present, there is a
higher incidence of failure of medical management and subsequent development of
cancer [29].
The levonorgestrel-releasing intrauterine system (levonorgestrel IUS) is another
preferred option in these cases. The greatest advantage is a onetime insertion and
the IUS is effective for a period of 5–7 years. Local-acting progesterone has an
effect on the endometrium that is several times stronger than that exerted by sys-
temic products and has a decreased systemic effect. A systematic review and meta-
analysis found a pooled regression rate of 69 % (95 % confidence interval, 58–83)
in 14 studies (n = 189) of women with atypical hyperplasia treated with oral proges-
tins [30].
Follow-up and surveillance is important and is done by serial endometrial sam-
pling every 3–6 months, but the appropriate frequency has not yet been
determined.

Table 3.3  Hormonal treatment for endometrial intraepithelial neoplasia

Hormonal agent Dosage and length
Medroxyprogesterone acetate 10–20 mg/day, or cyclic 12–14 days per month
Depot medroxyprogesterone 150 mg intramuscularly, every 3 months
Micronized vaginal progesterone 100–200 mg/day or cyclic 12–14 days per month
Megestrol acetate 40–200 mg/day
Levonorgestrel intrauterine system 52 mg in a steroid reservoir over 5 years
Modified from Trimble et al. [31]
3  Premalignant Conditions of the Endometrium 25

Surgical Assessment and Management Options

In a woman who does not desire future fertility, total hysterectomy is the most
preferred treatment option as it fulfills all the three objectives stated above. It
gives a definitive diagnosis of possible concurrent carcinoma and effectively
treats premalignant lesions. Hysterectomy can be performed via abdominal,
vaginal, or minimally invasive procedures with or without bilateral salpingo-
oophorectomy. Supracervical hysterectomy, morcellation, and endometrial
ablation should not be performed for treatment of endometrial intraepithelial
neoplasia because of concerns about underlying carcinoma [17]. Removal of the
cervix and lower uterine segment along with the uterine corpus permits staging
of any incidentally discovered cancer and reduces the risk of leaving behind
residual disease. The possible need for additional surgery to complete surgical
staging in case a carcinoma is identified should be explained to the patient
clearly.
Intraoperatively, management may be altered based on intraoperative assess-
ment and pathologic review. The specimen should be examined for gross evi-
dence of a tumor or myoinvasion, which may require frozen section. This can
help guide decisions about the need for comprehensive surgical staging, but the
diagnostic accuracy of frozen section should be kept in mind as it varies from
institution to institution. The correlation between frozen section and final pathol-
ogy for histology, grade, and depth of myometrial invasion has been reported to
be as high as 97.5 %, 88 %, and 98.2 %, respectively [18]. Furthermore, high-risk
disease is detected more efficiently in frozen section compared with low-risk
disease [19].
Comprehensive surgical staging with pelvic and para-aortic lymph node dissec-
tion at the time of hysterectomy for endometrial intraepithelial neoplasia is not rec-
ommended as it may result in overtreatment and increased surgical risk for a vast
majority of patients. The risk of a concurrent high-risk uterine carcinoma with fea-
tures like high-grade tumor, deep invasion, or lymphovascular space invasion, in
women with a biopsy diagnosis of endometrial intraepithelial neoplasia, is approxi-
mately 10 % [10, 20].
Vaginal hysterectomy may be performed if the need for comprehensive surgical
staging is excluded completely, as this is not feasible with a vaginal approach.
Bilateral salpingo-oophorectomy is not absolutely required, especially in premeno-
pausal women, and, in fact, removal of both ovaries in premenopausal or perimeno-
pausal women without a confirmed gynecologic malignancy may increase overall
morbidity and mortality [21].
As far as prevention is concerned, a healthy lifestyle, including adequate physi-
cal activity, daily exercise, healthy diet, and control of weight and blood sugar lev-
els, is essential. Because endometrial intraepithelial neoplasia is often an antecedent
of endometrial cancer, clinicians may counsel patients about weight loss or bariatric
surgery to reduce the risk of progression/recurrence as obesity is one of the major
risk factors for endometrial cancer.
26 K. Lata and N. Bhatla

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cer incidence and mortality worldwide 2012. IARC Cancer Base 11. Lyon, France: International
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Int. 2010. Article ID 862908, 26 pages doi:10.1155/2010/862908.
3. Julka PK, Manoharan N, Rath GK. Cancer incidence and mortality in Delhi UT Urban.
New Delhi: Delhi Cancer Registry; 2008 & 2009.
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the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study.
Cancer. 2006;106:804–11.
5. Mutter GL, Baak JP, Crum CP, Richart RM, Ferenczy A, Faquin WC. Endometrial precancer
diagnosis by histopathology, clonal analysis, and computerized morphometry. J Pathol.
2000;190:462–9.
6. Mutter GL. Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The
Endometrial Collaborative Group. Gynecol Oncol. 2000;76:287–90.
7. Baak JP, Mutter GL, Robboy S, van Diest PJ, Uyterlinde AM, Orbo A, et al. The molecular
genetics and morphometry based endometrial intraepithelial neoplasia classification system
predicts disease progression in endometrial hyperplasia more accurately than the 1994 World
Health Organization classification system. Cancer. 2005;103:2304–12.
8. Mutter GL, Kauderer J, Baak JP, Alberts D. Biopsy histomorphometry predicts uterine myoin-
vasion by endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol
Group Hum Pathol. 2008;39:866–74.
9. Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL. Prediction of endometrial
carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol.
2005;18:324–30.
10. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke 2nd JJ, et al. Concurrent endo-
metrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a
Gynecologic Oncology Group study. Cancer. 2006;106:812–9.
11. Stock RJ, Kanbour A. Prehysterectomy curettage. Obstet Gynecol. 1975;45:537–41.
12. Ben-Baruch G, Seidman DS, Schiff E, Moran O, Menczer J. Outpatient endometrial sampling
with the Pipelle curette. Gynecol Obstet Investig. 1994;37:260–2.
13. Leitao MM Jr, Han G, Lee LX, Abu-Rustum NR, Brown CL, Chi DS, et al. Complex atypical
hyperplasia of the uterus: characteristics and prediction of underlying carcinoma risk. Am
J Obstet Gynecol. 2010;203:349.e1–6.
14. Bedner R, Rzepka-Gorska I. Hysteroscopy with directed biopsy versus dilatation and curettage
for the diagnosis of endometrial hyperplasia and cancer in perimenopausal women. Eur
J Gynaecol Oncol. 2007;28:400–2.
15. Allison KH, Reed SD, Voigt LF, Jordan CD, Newton KM, Garcia RL. Diagnosing endometrial
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The role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. Obstet
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19. Morotti M, Menada MV, Moioli M, Sala P, Maffeo I, Abete L, et al. Frozen section pathology
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20. AlHilli MM, Podratz KC, Dowdy SC, Bakkum-Gamez JN, Weaver AL, McGree ME, et al.
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Pathophysiology of Endometrial
Carcinoma 4
Arpita Jindal

Abstract
Endometrial adenocarcinoma may be preceded by endometrial hyperplasia.
Oestrogen has been associated with increased endometrial hyperplasia and
adenocarcinoma.
It is divided into two classes, type I and type II, each with different patho-
physiology, genetic alterations and prognosis.
Histologically endometrioid morphology accounts for 75–80 % of cases.
In addition to tumour type, the tumour grade and surgical stage influence the
prognosis.
Immunohistochemistry is useful in the diagnosis of endometrial carcinomas
only in some specific situations.

Premalignant Lesions of the Endometrium

Endometrial Hyperplasia

Endometrial hyperplasia is a term which denotes a proliferative lesion of the endo-

metrium with architectural complexity and cytologic atypia (Fig. 4.1). This process
is usually diffuse but it can occur focally. The most widely used WHO classification
is a four-tier system which takes into consideration the atypia and the architecture
[1]. Recent studies have shown that the cytologic atypia rather than the complex
architecture determines the risk of progression. Atypical hyperplasia has a 40 % risk

A. Jindal, MD
Sawai Man Singh Medical College and attached hospitals, Jaipur, India
e-mail: drarpitajindal@[Link]
© Springer Nature Singapore Pte Ltd. 2017 29
R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_4
30 A. Jindal

as compared to non-atypical/simple hyperplasia which has only 10 % chances of

progression [2]. The most acceptable classification of endometrial hyperplasia is
given in Table 4.1.

Pathophysiology

Oestrogen replacement therapy has been shown to have a strong association with the
development of endometrial carcinoma, and the factors which decrease the exposure
of the endometrium to oestrogen have decreased the risk of endometrial carcinoma
including the addition of progestin to oestrogen replacement therapy [4, 5]. Atypical
endometrial hyperplasia has been associated with a number of genetic alterations
including mutation in the PTEN tumour suppressor gene and KRAS oncogene and
microsatellite instability [6]. These are the most common genetic alterations in endo-
metrioid carcinoma, which support atypical hyperplasia as a precursor lesion.

Fig. 4.1  Endometrium – simple hyperplasia

Table 4.1  World Health Hyperplasia(typical)

Organization classification of   Simple hyperplasia without atypia
endometrial hyperplasia [3]   Complex hyperplasia without atypia
Atypical hyperplasia
  Simple atypical hyperplasia
  Complex atypical hyperplasia
4  Pathophysiology of Endometrial Carcinoma 31

Endometrial carcinoma

Definition
Endometrial carcinoma is a malignant epithelial tumour, arising in the endometrium
with glandular differentiation, but it may have variable morphology.

Pathophysiology of Endometrial Carcinoma

A number of studies have demonstrated the association of oestrogen with the devel-
opment of endometrial carcinoma. Exogenous oestrogen without progesterone has
been associated with increased adenocarcinoma. The excess risk can be signifi-
cantly reduced by the concomitant administration of progestins [4, 5]. There has
been a conflicting data on the risk of endometrial cancer with the use of tamoxifen
[7]. Obesity has been a well-defined risk factor too, due to increased availability of
oestrogen as a result of aromatization of androgens in the adipose tissue [8].
Prolonged exposure to oestrogen due to chronic anovulation in nullipara, late meno-
pause and early menarche may be related to increased risk [9].
Endometrial carcinoma can be divided into two categories based on clinicopath-
ologic and molecular genetic features referred to as type I and type II. Type I is
associated with unopposed oestrogen stimulation and is often accompanied by atyp-
ical hyperplasia. It is usually a low-grade carcinoma of favourable prognosis and
more commonly occurs in perimenopausal white women. Type II has no association
with exogenous oestrogen or endometrial hyperplasia. It is usually high grade and
has an unfavourable prognosis and occurs in postmenopausal women, often of
African-American or Asian descent [4, 5, 10–12].

Macroscopy

Endometrial carcinoma presents as an exophytic mass, usually seen in an enlarged

uterus, or the tumour presents as a diffuse thickening of the endometrium with a
shaggy, glistening and tan surface and presents more frequently on the posterior
than on the anterior wall [13]. The tumour may be focal, at times presenting as pol-
ypoidal mass. Myometrial invasion usually appears as firm grey-white area in the
form of linear extensions. The tumour may penetrate the serosa, and extension into
the cervix is common.

Microscopy

Endometrial carcinoma has various histological types based on the cell morphology
(Table 4.2).
32 A. Jindal

Table 4.2 Histological Endometrioid adenocarcinoma

classification of endometrial  Variant with squamous differentiation
carcinoma [14]  Villoglandular variant
 Secretory variant
 Ciliated cell variant
Mucinous adenocarcinoma
Serous adenocarcinoma
Clear cell adenocarcinoma
Mixed cell adenocarcinoma
Squamous cell carcinoma
Transitional cell carcinoma
Small cell carcinoma
Undifferentiated carcinoma

Table 4.3  FIGO – grading of endometrial carcinoma [12]

Grade 1 Less than 5 % of solid areas (excludes squamous differentiation)
Grade 2 6–50 % solid areas
Grade 3 More than 50 % solid areas
The tumour grade is increased by one if the nuclei are enlarged with prominent nucleoli (excluding
serous or clear cell differentiation)

Endometrioid Adenocarcinoma
Endometrioid adenocarcinoma is the most common type accounting for almost
three-fourths of the cases [11]. It resembles a proliferative phase endometrium
with small, back-to-back glands without the stroma intervening. The grade of
the tumour is based on nuclear features and architectural pattern. The nuclear
grade is determined by the variation in nuclear size and shape, nucleoli and
distribution of chromatin. The architecture grade and pattern are seen as how
well the gland formation is seen as compared to solid clusters of tumour cells.
Glandular complexity may be seen as luminal budding, papillae and cribriform
patterns. Mitotic activity usually increases with the increase in nuclear grade
and is an independent variable. The grading of the tumour is done according to
the degree of gland formation by the tumour (Table 4.3). In grade 1 lesions,
nuclei of the lining epithelial cells are uniform with minimal atypia and small
discrete nucleoli (Fig. 4.2). The degree of tumour necrosis is usually mild to
moderate. Marked amount of necrosis is unusual, even in high-grade endome-
trioid adenocarcinoma (Fig. 4.3).

Variants
Different morphologic patterns of endometrioid adenocarcinoma are seen including
villoglandular, secretory, ciliated cell and adenocarcinoma with squamous differen-
tiation. These patients share similar epidemiologic characteristics of typical endo-
metrioid carcinoma, and these patterns may be seen in association with the usual
form of endometrioid cell type.
4  Pathophysiology of Endometrial Carcinoma 33

Fig. 4.2  Photomicrograph of endometrioid adenocarcinoma – grade 1

Endometrioid Adenocarcinoma with Squamous Differentiation

Endometrioid adenocarcinoma may contain squamous epithelium. The proportion
of squamous element can be variable. At least 10 % of the tumour should have a
squamous element in a well-sampled tumour to qualify as endometrioid carcinoma
with squamous differentiation. There are no differences in clinical features of this
34 A. Jindal

Fig. 4.3  Photomicrograph of endometrioid adenocarcinoma – grade 3 (high grade)

variant. It is graded on the basis of glandular component of the tumour as well,

moderately or poorly differentiated. The treatment of this variant is the same as for
endometrioid carcinoma of comparable stage.

Villoglandular Carcinoma
This variant displays papillary architecture with cells resembling usual endometri-
oid carcinoma. The papillary fronds comprise delicate fibrovascular cores covered
by columnar cells with oval nuclei that generally show mild to moderate nuclear
atypia. Occasionally high-grade nuclear atypia is seen where one has to differentiate
it from serous carcinoma as both have distinct papillary pattern. Mitosis is variable
and myometrial invasion is usually superficial.

Secretory Carcinoma
This variant appears histologically similar to secretory phase endometrium with
columnar cells that have abundant vacuolated cytoplasm. They may have a cribri-
form or villoglandular pattern. Glands are back to back with presence of stromal
invasion. Cellular atypia is minimal. The neoplasm is of low grade, and the progno-
sis is good. It is important to differentiate it from clear cell carcinoma.

Ciliated Cell Carcinoma

This is a rare variant of endometrioid carcinoma. Ciliated cells may be seen occa-
sionally in endometrioid adenocarcinoma, but the majority of the malignant glands
should be lined by ciliated cells to categorise it as this variant. One has to be just
careful that endometrial proliferations with cilia may be carcinomatous too.
4  Pathophysiology of Endometrial Carcinoma 35

Mucinous Carcinoma
Mucinous carcinoma is an adenocarcinoma with abundant intracellular mucin. To cat-
egorise it as mucinous carcinoma, more than 50 % of the cell population must contain
mucin which should be PAS positive and diastase resistant. Its appearance is similar to
the mucinous endocervical adenocarcinoma, and it has to be differentiated from the
clear cell carcinoma where the pattern is usually papillary or solid as compared to
glandular in this variant. Endometrioid and clear cell adenocarcinoma may have large
amounts of intraluminal mucin, but only mucinous adenocarcinoma contains the mucin
within the cytoplasm. They tend to be of low grade with a good prognosis.

Serous Carcinoma
Serous carcinoma usually involves older women and is uncommon as compared to
endometrioid carcinoma. It often displays papillary architecture like the variants of
endometrioid carcinoma, but the papillae here have broad cores, and the pattern
may be even solid. The cytologic atypia is marked (Fig. 4.4). Psammoma bodies
may be present. These tumours are aggressive and have a poor prognosis. They are
considered as high-grade neoplasms and are not graded. These tumours have a pre-
dilection for peritoneal spread, akin to ovarian serous adenocarcinoma [15].

 lear Cell Carcinoma

C
The prevalence of clear cell carcinoma is low and like serous carcinoma occurs in
elderly women. It may exhibit solid, tubular, papillary and cystic pattern with typi-
cally hobnail-shaped cells. Nuclear atypia is moderate to marked. The clear cyto-
plasm is the result of glycogen present in the cells which can be demonstrated by

Fig. 4.4  Photomicrograph of serous adenocarcinoma – nuclei are typically poorly differentiated,
macronucleoli
36 A. Jindal

PAS staining with diastase digestion. They are not graded; per se they are high-­
grade tumours with aggressive behaviour and poor prognosis.

 quamous Cell Carcinoma

S
Endometrial squamous cell carcinoma (SCC) is extremely rare. To qualify it as
squamous cell carcinoma, there should be no connection with the squamous epithe-
lium of the cervix, squamous cell carcinoma should not be present in the cervix, and
endometrial carcinoma should not be present in the endometrium. A strong associa-
tion with pyometra and cervical stenosis and ichthyosis uteri has been seen in post-
menopausal women. Primary SCC of the endometrium is an aggressive tumour and
is associated with deep myometrial invasion and extrauterine extension.

 ransitional Cell Carcinoma

T
Transitional cell carcinoma in the endometrium is extremely uncommon. In this
90 % or more is composed of cells resembling urothelial transitional cells. It is
found admixed with another type of carcinoma, usually endometrioid. The immu-
noprofile supports Müllerian rather than urothelial differentiation.

 mall Cell Carcinoma

S
Small cell carcinoma is an uncommon tumour of the endometrium. It resembles
small cell carcinoma of the lungs and other organs. These are positive for neuroen-
docrine markers and for cytokeratin.

Undifferentiated Carcinoma
The tumour lacking any evidence of differentiation is defined as undifferentiated
carcinoma as per WHO. These tumours have to be differentiated from small cell
neuroendocrine tumours, large cell lymphoma, lymphoepithelioma-like carcinoma
and undifferentiated component of other endometrial carcinomas.

Immunohistochemistry of Endometrial Carcinomas

Interpretation of tumour type in endometrial carcinoma can be difficult especially

when biopsy material is scant, or there is abundant necrosis or poorly preserved
architectural and cytologic detail. Some cases are morphologically ambiguous,
even in a well-preserved biopsy specimen. In such circumstances, immunostains
are useful.
Endometrial carcinomas usually express pan-cytokeratins, EMA, CA125,
Ber-EP4, B72.3, CK7 and vimentin, whereas they are usually negative for CK20,
WT1 and CEA (carcinoembryonic antigen). Endometrioid endometrial carcino-
mas express ER and PR. Squamous differentiation in endometrioid carcinomas
often shows strong positivity with CEA. The serous carcinomas show strong p53
expression (intense nuclear staining of almost all nuclei) [16]. Only in some
specific situations is immunohistochemistry of importance in the diagnosis of
endometrial carcinomas. Importance of IHC lies in distinguishing endometrial
and cervical adenocarcinoma in biopsies and curettings. To distinguish
4  Pathophysiology of Endometrial Carcinoma 37

endometrioid endometrial carcinoma from endocervical adenocarcinoma, ER,

PR and P16 have been shown to be useful [17–19]. Most of the endocervical
adenocarcinomas are HPV (human papilloma virus) related, and they express
diffuse, moderate to strong P16 expression. Finally, an important difference
between the immunophenotype of endometrial with ovarian and tubal serous car-
cinoma is the WT1 expression. Seventy percent of ovarian and tubal serous car-
cinomas express WT1 as against at most 20–30 % of endometrial serous
carcinomas [20–22].

Prognostic Factors of Endometrial Carcinoma

Postoperative study of hysterectomy specimen in endometrial carcinoma requires

evaluation of features (Tables 4.4 and 4.5) like cervical involvement, adnexal involve-
ment, depth of myometrial involvement, histology type, grade and lymphovascular
invasion. Myometrial invasion is an important issue. FIGO divides stage I tumours on
the basis of the depth of invasion into IA (limited to the endometrium), IB (invasion
of less than half of the myometrium) and IC (invasion of more than half of the myo-
metrium) [23, 24]. Positive peritoneal cytology, pelvic and para-aortic lymph node
metastasis and parametrial involvement are important extrauterine factors.

Table 4.4 Important Cervical involvement

parameters to be evaluated in Tubes and ovaries
surgical specimen Parametrium
Depth of invasion
Histologic type
Histologic grade
Lymphovascular invasion
Peritoneum/omentum
Regional lymph nodes

Table 4.5  FIGO – staging I Tumour limited to the endometrium

of endometrial carcinoma [25]   IA No or less than half myometrial invasion
  IB Invasion equal to or more than half of the myometrium
II Tumour invades cervix, but does not extend beyond the
uterus
III
  IIIA Tumour invades the serosa and/or adnexae
  IIIB Vaginal involvement and/or parametrial involvement
  IIIC Metastases to pelvic and/or para-aortic lymph nodes
IV
  IVA Tumour invasion of bladder and/or bowel mucosa
  IVB Distant metastasis including intra-abdominal
metastases and/or inguinal nodes)
Endocervical gladular involvement only should be considered as
stage I and no longer as stage II. Positive cytology has to be
reported separately without changing the stage
38 A. Jindal

Genetics of Endometrial Carcinoma

A number of cancer-causing genes have been analysed in endometrial carcinoma.

PTEN tumour suppressor gene has been the most frequently altered gene
studied in endometrioid carcinoma [26, 27]. PTEN mutations are as well docu-
mented in endometrial hyperplasia with and without atypia too [28]. Another
molecular alteration in endometrioid endometrial cancers includes microsatel-
lite instability. It is found in tumours of patients affected by hereditary nonpol-
yposis colorectal carcinoma. Few oncogenes are altered in endometrial
carcinoma like mutation in the KRAS proto-oncogene. Mutation in the CTNNB1
gene too has been noted in tumours with squamous differentiation. Other onco-
genes have been found to be overexpressed like EGFR, c-Myc, CFMS, HER2/neu
and BCl2 [29–32].
In contrast to endometrioid carcinoma, mutations in KRAS and PTEN appear to
be uncommon in serous carcinoma, and microsatellite instability has not been
detected in this type of tumour.
The most common genetic alteration in type 2 serous carcinomas is in p53, the
tumour suppressor gene. Other frequent genetic alterations are inactivation of p16
and overexpression of HER2/neu [33].

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Diagnosis and Pre-management Workup
of Endometrial Carcinoma 5
P. Veena and Amita Maheshwari

Abstract
• Advanced age, postmenopausal status, obesity, polycystic ovarian syndrome/
chronic anovulation, and tamoxifen use are the important risk factors for
endometrial carcinoma (EC).
• Transvaginal ultrasonography is the imaging modality of first choice while
evaluating women with postmenopausal bleeding.
• Office endometrial biopsy (EB) is the first step for evaluating the endome-
trium among women with postmenopausal bleeding.
• Once diagnosis of EC is confirmed, MRI is the most effective imaging modality
for pre-management staging of EC especially in early stages, whereas CECT is
effective in determining peritoneal deposits and parenchymal liver deposits.
• PET-CT is found to be effective for distant metastases, more so in recurrent
diseases.

Abbreviations

ACOG American College of Obstetricians and Gynecologists

ASR Age-standardized rate
ATLAS trial Adjuvant tamoxifen: longer against shorter trial
CECT Contrast-enhanced computed tomography
EB Endometrial biopsy

P. Veena, MD, DNB

Department of Obstetrics and Gynecology, JIPMER, Pondicherry, India
A. Maheshwari, MD (*)
Gynecologic Oncology, Tata Memorial Hospital, Mumbai, India
e-mail: maheshwariamita@[Link]

© Springer Nature Singapore Pte Ltd. 2017 41

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_5
42 P. Veena and A. Maheshwari

EC Endometrial carcinoma
ESMO European Society for Medical Oncology
FDG PET [18F] 18-2-Fluoro-2-deoxy-D-glucose positron emission tomography
FIGO International Federation of Gynecology and Obstetrics
HNPCC Hereditary nonpolyposis colon cancer
MRI Magnetic resonance imaging
NCCN National Comprehensive Cancer Network
TVUS Transvaginal ultrasound
USG Ultrasonography

Introduction

The incidence of endometrial cancer is very low in India; the highest age-­
standardized rate (ASR) was observed in Delhi (ASR = 4.3) and Bangalore (ASR =
4.2), while in Mumbai it was 2.8 per 100,000 vs 25.1 per 100,000 in the western
world [1]. Endometrial carcinoma is essentially a disease of postmenopausal
woman, with median age at cancer diagnosis of 60 years. Usually it is diagnosed
early as it is symptomatic in early stages, and diagnosis is easily accomplished.

Diagnosis

The most common symptom among women with endometrial carcinoma is abnormal
uterine bleeding, mainly postmenopausal bleeding. Evaluation for this symptom can
be done in different ways to gain different information and are enumerated below:

• History and clinical examination

• Pap smear
• Office endometrial biopsy
• Transvaginal ultrasound
• Color Doppler
• Sonohysterogram
• Hysteroscopy and guided biopsy
• Dilatation and curettage
• CECT of the abdomen and pelvis
• MRI of the abdomen and pelvis

History and Clinical Examination

Postmenopausal bleeding is an important symptom which needs to be evaluated

thoroughly. Among women with postmenopausal bleeding, age and the duration
from the menopause are directly proportional to the risk of endometrial carcinoma
5  Diagnosis and Pre-management Workup of Endometrial Carcinoma 43

(9 % at 50 years, 16 % in 60 years, 28 % in 70 years, and 60 % in 80 years) [2]. Even
though endometrial carcinoma mainly occurs in postmenopausal women, it is vital
to note that 25 % of the cases occur in premenopausal women and 5 % occur in
women who are <40 years old [3]. Any irregular bleeding in these women should be
investigated thoroughly after ruling out pregnancy-related conditions.
A thorough clinical history identifies women at increased risk of endometrial
cancer. Any condition which leads to prolonged unopposed estrogen exposure of the
endometrium puts the woman at an increased risk of endometrial hyperplasia and
endometrial carcinoma. Chronic anovulation due to polycystic ovarian syndrome is
an important cause [4]. Other hyperestrogenic states are morbid obesity (aromatiza-
tion of androgens to estradiol and the conversion of androstenedione to estrone in
peripheral adipose tissue), exogenous estrogen intake as in hormone replacement
therapy, estrogen-secreting tumors of the ovary, and diabetes mellitus [5].
Tamoxifen use in women with breast cancer is an important risk factor for endo-
metrial cancer. Tamoxifen, being a selective estrogen receptor modulator, has anti-
estrogenic action on tissues like the breast and estrogenic action on the endometrium.
In standard doses used in adjuvant treatment of breast cancer, it is known to cause
endometrial hyperplasia and polyps, invasive endometrial carcinoma, and uterine
sarcoma. Tamoxifen is known to cause subepithelial stromal hypertrophy, which
gives a false impression of a thick endometrium on ultrasonography [6] (Fig. 5.1).
Hence, in asymptomatic women, there is a poor correlation between ultrasono-
graphically measured endometrial thickness and abnormal pathology, and screening
them has not shown to be beneficial. Thus, evaluation of the endometrium should be
performed only in postmenopausal women with abnormal uterine bleeding. However,
the risk of developing endometrial carcinoma is estimated to be only 1.26 for 1000
patient-years after 5 years of tamoxifen intake. Further, based on the findings of the
ATLAS study [7], ACOG recommends that tamoxifen use may be extended to
10 years rather than 5 years [8]. ACOG does not recommend screening in premeno-
pausal women and asymptomatic postmenopausal women taking tamoxifen [8].

Fig. 5.1 Tamoxifen-induced
cystic hyperplasia of the
endometrium
44 P. Veena and A. Maheshwari

Family history of malignancies among other members should not be overlooked,

especially endometrial, breast, and colon cancers. Lynch syndrome or HNPCC
(hereditary nonpolyposis colon cancer) is known to be associated with 40–60 %
increased risk of endometrial malignancy, and 5 % of all endometrial cancers may
be attributed to it. Germline mutation in one of four genes in the DNA mismatch
repair family MLH1, MSH2, MSH6, or PMS2 is known to be associated with Lynch
syndrome. Endometrial cancer occurs at an earlier age in these women, 47 years
when compared to 60 years in general population [9]. Although BRCA1 and
BRCA2 are known to be significantly associated with breast and ovarian cancers,
lifetime risk of endometrial carcinoma is not increased in these women [10].
General examination should focus on detecting anemia, icterus, edema, and
supraclavicular and inguinal lymph node enlargement. Clinical examination should
aim at ruling out obvious causes of postmenopausal bleeding like those caused by
lesions of the vulva, vagina, and cervix. This can be effectively done by visual
inspection of the external genitalia in good light followed by a speculum examina-
tion. This should be followed by a bimanual examination to look for uterine size,
tenderness, and irregularity, to rule out benign lesions, more so in premenopausal
women. A rectovaginal examination aids in assessing the pouch of Douglas, the
parametrium, and the adnexal pathology.

Pap Smear

If clinical examination does not reveal any obvious cause of postmenopausal bleeding,
a Pap smear should be taken before doing the bimanual examination. Atypical glandu-
lar cells (AGC) reported on Pap smear are known to be associated with endocervical,
endometrial, ovarian, or fallopian tube cancers 3–17 % of the time. These women
should undergo a fractional curettage and pelvic imaging to rule out these cancers [11].

Office Endometrial Biopsy

The first step in the evaluation of the endometrium is invariably an office endome-
trial biopsy. Different devices which are available for performing the same are
Novak curette, Pipelle endometrial suction curette, and Vabra aspirator (Fig. 5.2).
Multiple studies have been done to determine the better device among these three,
but it has been found that the accuracy for diagnosis of endometrial cancer is almost
similar among these three (Novak curette, 67–97 %; Pipelle endometrial suction
curette, 79–94 %; Vabra aspirator, 80–98 %) [12].
The success of the procedure is affected by many factors like cervical stenosis,
alteration of the endometrial cavity by the submucous fibroids, and the size of the
lesion itself. The yield of office endometrial biopsy can be increased by combining it
with office hysteroscopy especially in small lesions [12]. False-negative rate of office
endometrial biopsy is around 10 %, so further evaluation is recommended if the results
come back as normal with persistent symptoms or abnormal pelvic imaging [13].
5  Diagnosis and Pre-management Workup of Endometrial Carcinoma 45

Fig. 5.2  Endometrial biopsy curettes

Fig. 5.3 Thickened
endometrium by
ultrasonogram

Transvaginal Ultrasound

Transvaginal ultrasound (TVUS) examination is a useful adjunct to office endome-

trial biopsy in the initial evaluation of endometrial pathology. The endometrium is
usually evaluated by examining the thickness and morphology. Endometrial thick-
ness of more than 5 mm is abnormal in postmenopausal women [14] (Fig. 5.3).
A normal TVUS decreases the pretest probability of endometrial cancer from 10
to 1 % posttest among postmenopausal women with vaginal bleeding [15].
Endometrial thickness is dynamic in premenopausal women; nevertheless, trans-
vaginal ultrasound examination can be helpful in diagnosing benign conditions like
fibroids and adenomyosis which can also present with abnormal uterine bleeding.
At this juncture, it is prudent to mention that 17 % of type II endometrial cancers
will have a thin endometrium as these cancers develop in a background of atrophy
[16]. TVUS has good negative predictive value (99 %) but a poor positive predictive
46 P. Veena and A. Maheshwari

value (57 %) in the diagnosis of endometrial cancer which further decreases to 37 %
in women taking hormone replacement therapy [15].
Endometrial thickness can be morphologically classified as diffuse or focal.
Diffuse endometrial thickness may be due to endometrial hyperplasia or carci-
noma, and a non-focal blind biopsy is sufficient for diagnosis, whereas focal
endometrial biopsy can be due to lesions like polyps, either benign or malignant,
and requires hysteroscopic-guided biopsy. Other morphological features described
by researchers to indicate malignancy are heterogeneous and hyperechoic with
irregular borders. It is recommended that combined assessment of endometrial
thickness and morphology should be done to improve detection of endometrial
pathology [17].

Color Doppler

Color Doppler used along with TVUS aids in the diagnosis of endometrial malig-
nancy. The pattern of vascularity in the thickened endometrium or a focal lesion
helps in distinguishing between malignant and benign conditions. Broad-based
lesions with diffuse high level of vascularity indicate malignant lesions, and single
feeding vessel in the stalk of a focal lesion with low vascularity indicates a benign
condition like polyps [18]. When Doppler analysis was compared to conventional
gray-scale TVUS, researchers found that abnormal endometrial thickness alone is a
better predictor of endometrial pathology than Doppler analysis [19].

Sonohysterography

Transvaginal ultrasound examination is performed after installing sterile normal

saline into the endometrial cavity to enable better visualization of lesions like endo-
metrial polyps, submucous fibroids, adhesions, and others. This is especially recom-
mended in women who are on tamoxifen as they tend to have endometrial polyps
[14]. Sonohysterography accurately identifies endometrial pathology with reported
sensitivities of 89–98 % and specificities of 46–88 % with a good negative predic-
tive value for detecting malignancy. But the positive predictive value for cancer
prediction is very poor (16 %) which implies that it is very good at detecting benign
conditions [20].

Hysteroscopy and Guided Biopsy

Hysteroscopy enables visualization and guided biopsy especially in small early

lesions which can be easily missed on routine office endometrial biopsy (Fig. 5.4).
It is also useful in evaluating falsely thickened endometrium of women on
tamoxifen which is due to subendometrial edema [14]. Hysteroscopy has good sen-
sitivity and specificity at 86 % and 99 %, respectively. Like other modalities
5  Diagnosis and Pre-management Workup of Endometrial Carcinoma 47

Fig. 5.4 Hysteroscopic
image of endometrial
malignancy

described above, the negative predictive value of hysteroscopy for detecting malig-
nancy is up to 99 % with positive predictive value of 72 % [21].

Dilatation and Curettage

Dilatation and curettage was the recommended diagnostic test for evaluation of abnor-
mal bleeding before office endometrial biopsy took over. Currently the indications for
dilatation and curettage are inability to perform office endometrial biopsy due to patient
distress, cervical stenosis, and anatomical factors like submucous fibroids. It is a day
care procedure done under anesthesia, either local (paracervical block) or general.
Hysteroscopic visualization during the procedures enables sampling of smaller lesions.

CECT, MRI, and PET-CT of the Abdomen and Pelvis

None of these imaging tests are indicated in screening or diagnosis of endometrial

cancer. They are useful in pre-management workup of the patients as discussed in
the next section.

Pre-management Workup

In a patient who is diagnosed with endometrial cancer, pre-management workup is

essentially directed toward assessing the clinical stage of disease to decide the mode
of initial treatment. In patients for surgery, pre-op workup also aims at determining
medical fitness for surgery and deciding the extent of surgery. NCCN (2016) and
ESMO 2015 [22] recommend following investigations in the initial evaluation of
endometrial cancer (Table 5.1).
48 P. Veena and A. Maheshwari

Table 5.1  Initial evaluation of endometrial cancer (NCCN 2016 and ESMO 2015 [22])
Recommended Optional
Clinical and gynecological Genetic counseling in women <50 years and in those with family
examination history of endometrial cancer and colon cancer
Histopathology of Cervix biopsy or MRI in suspected cases of cervical involvement
endometrial biopsy
CBC including platelets CA-125 (optional), MRI, CECT in suspected extrauterine disease
Chest X-ray FDG PET-CT ([18F] 2-fluoro-2-deoxy-D-glucose positron
emission tomography) in suspected distant metastases
Liver function and renal Immunohistochemistry (IHC) and microsatellite instability (MSI)
function tests screening to identify individuals at risk for Lynch syndrome

Table 5.2  Staging of endometrial cancer (FIGO: 2009) [23]

Stage I Tumor confined to the corpus uteri
IA NO or less than half myometrial invasion
IB Invasion equal to or more than half of the myometrium
Stage II Tumor invades cervical stroma, but does not extend beyond the uterus
Stage Local and/or regional spread of the tumor
III IIIA Tumor invades the serosa of the corpus uteri and/or adnexa
IIIB Vaginal and/or parametrial involvement
IIIC Metastasis to pelvic and/or para-aortic lymph nodes
C1 Positive pelvic nodes
C2 Positive para-aortic lymph nodes with or without positive pelvic
lymph nodes
Stage Tumor invades bladder and/or bowel mucosa and/or distant metastases
IV IVA Tumor invasion of bladder and/or bowel mucosa
IVB Distant metastases, including intra-abdominal metastases

Staging of Endometrial Cancer

Endometrial cancer is generally staged according to the International Federation of

Gynecology and Obstetrics (FIGO) system [23]. In May 2009, a new staging system
was published, replacing the previous staging of 1988 (Table 5.2).

Imaging in the Pre-op Workup of Endometrial Cancer

Although staging of endometrial cancer is recommended to be done surgically,

imaging plays an important role in the treatment planning and predicting prognosis
of the disease. Pre-op staging also helps in determining the need for lymphadenec-
tomy, radical hysterectomy, and preoperative radiotherapy and in assessing for hor-
monal treatment in women who are desirous of further childbearing. Various
imaging modalities like TVUS, Doppler, CECT, MRI, and FDG PET have been
studied in predicting the extent of disease.
5  Diagnosis and Pre-management Workup of Endometrial Carcinoma 49

TVUS

Tumor spread within the uterus can be assessed by TVUS by the virtue of its high
resolution, but extrauterine spread and nodal involvement cannot be assessed effi-
ciently owing to its poor tissue penetration. Researchers have found high levels of
accuracy in detecting deep myometrial invasion (99 %) and cervical extension
(96 %) using TVUS [24]. In another study where TVUS was compared with MRI,
the accuracy of TVUS for detecting deep myometrial invasion was 68 %, and cervi-
cal extension was 69 % [25]. This wide variation in reported accuracies can be
attributed to operator expertise, technical factors, and patients’ body habitus.
Researchers have even studied intrauterine sonography using high-frequency
micro-­tip probe inserted transcervically and have reported improved accuracy in
assessing depth of myometrial invasion when compared to TVUS [26].

Doppler

Inconclusive data exist in the literature regarding the use of Doppler in pre-op stag-
ing of endometrial cancer. Some researchers have found it to be useful in predicting
deep myometrial invasion, but not for tumor grade or nodal spread [19]. Yet others
have reported a statistically significant association between pelvic lymph node
metastases and vascular density [27].

Magnetic Resonance Imaging (MRI)

MRI is the most important imaging investigation for pre-op staging of EC. The accu-
racy of MRI in determining myometrial invasion, cervical involvement, and extra-
uterine spread is reportedly better than that of CECT or TVUS [28] (Figs. 5.5 and 5.6).
These investigators have also compared MRI with visual inspection of a surgical
specimen in evaluation of myometrial invasion and cervical involvement and found that
MRI is 90 % accurate in predicting myometrial invasion and 80 % accurate for cervical
involvement. Errors in assessing myometrial invasion can occur in women with fibroids
and adenomyosis and in women with distension of the endometrial cavity. They also
mention that contrast-enhanced MRI (gadolinium) performs better than plain MRI.
Evaluation of lymph nodes by MRI was improved by addition of ferumoxtran-10,
which evaluates nodal function rather than size [29] as normal-sized nodes can har-
bor micro-metastatic disease, whereas enlarged nodes may be reactive in nature.

CECT

CECT has a limited role in evaluating patients with early disease. Advantage of
CECT is that its resolution is not compromised by bowel or patient motion when
compared to MRI, and this property enables CECT to reliably detect distant paren-
chymal metastases, peritoneal implants, and malignant ascites [30]. Table 5.3
50 P. Veena and A. Maheshwari

Focal invasion

Fig. 5.5  MRI showing superficial myometrial invasion

Endometrial mass
with deep myometrial
invasion.
(more than 50%)

Invasion into cervical

stroma

Fig. 5.6  MRI showing deep myometrial invasion and cervical stromal involvement

Table 5.3  Accuracy of imaging in the workup of endometrial Ca

Imaging modality Cervical stromal involvement % Myometrial invasion % Distant spread
USG [27] 69 68 Poor
MRI [30] 80 90 Good
CECT [31] 58 76 Good
5  Diagnosis and Pre-management Workup of Endometrial Carcinoma 51

summarizes three important modalities in the pre-management evaluation of

endometrial carcinoma.

PET

Positron emission tomography (PET) with the radioactive glucose analogue 18-2-flu-
oro-2-deoxy-D-glucose (FDG PET [18F]) has been used in various malignancies to
detect nodal involvement, but it was not found to be useful in early endometrial cancer
because of its limited ability in detecting micro-metastases in normal-sized nodes
with sensitivity for nodal metastases of 63 % and a specificity of 98 % [32]. However,
when used along with CECT or MRI, FDG PET images performed better in detecting
extra-pelvic and nodal metastases, and currently research is ongoing regarding the
role of fusion PET-CT scanning for pre-op staging of endometrial Ca [33].

Workup for Fertility-Preserving Therapy

Around 4 % of patients with endometrial carcinoma are <40 years of age, and
majority of them may be desirous of future childbearing. The standard approach for
the management of endometrial cancer in young women of childbearing age is hys-
terectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy.
Although this treatment is highly effective, it also results in a permanent loss of
reproductive potential. In such patients, fertility-preserving approach using high-­
dose oral progestins could be considered when the tumor is of low grade and con-
fined to the endometrium. D&C is superior to Pipelle biopsy in terms of accuracy of
the tumor grade, and the initial stage should be confirmed by an enhanced pelvic
magnetic resonance imaging (MRI) to exclude overt myometrial invasion, as well
as adnexal or pelvic nodes involvement. Patients should be informed that this is a
nonstandard approach, and they should be willing to accept close follow-up during
and after the treatment. They should also be informed of the need for future hyster-
ectomy in case of failure of the treatment and/or after pregnancies [22].

Conclusion
Diagnosis of endometrial carcinoma is easily accomplished by simple modalities
like transvaginal ultrasonography and endometrial biopsy. Advanced imaging
techniques like MRI, CECT, and FDG PET have no role in diagnosis but serve
to stage the disease preoperatively to optimize treatment.

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Surgical Management of Early-Stage
Endometrial Cancer 6
Hemant Tongaonkar, Samar Gupte, Devyani Mahajan,
and Jyoti Kulkarni

Abstract
Most endometrial cancers are diagnosed with early-stage/uterus-confined d­ isease
and are usually cured by surgery alone.
Extrafascial hysterectomy with bilateral salpingo-oophorectomy along with
comprehensive surgical staging including pelvic and para-aortic lymphadenec-
tomy (except in low-risk disease) and peritoneal wash cytology remains the
mainstay of surgical treatment of endometrial carcinoma.
Ovarian preservation may be done in young patients with low-stage, ­low-­grade
endometrial cancer after thorough counselling.
Minimally invasive surgery is recommended in low- to intermediate-risk
patients with early-stage endometrial carcinoma in a skilled set-up.
Tumour stage and pathological tumour grade appear to be the most important
factors influencing lymph node metastasis.
Sentinel node mapping for uterine cancer is currently being widely studied.

H. Tongaonkar (*) • S. Gupte

PD Hinduja National Hospital and Research Centre, Mumbai, India
Hinduja Healthcare Surgical, Mumbai, India
e-mail: htongaonkar@[Link]
D. Mahajan
Gynaecologic Oncology, PD Hinduja National Hospital and Research Centre,
Mumbai, India
J. Kulkarni
Consultant Gynecologist, Mumbai, India

© Springer Nature Singapore Pte Ltd. 2017 55

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_6
56 H. Tongaonkar et al.

Introduction

Endometrial cancer is the most common malignancy of the female genital tract in
developed countries and fourth most common cancer in women after breast, lung
and colorectal cancers. The incidence rate in India is much lower, it being the third
commonest gynaecological cancer in India after cervical and ovarian cancers.
Most cancers are diagnosed with uterus-confined disease, which are usually
cured by surgery alone. The presence of extrauterine disease significantly affects
recurrence rates and survival, which emphasizes the importance of sites of disease
spread and provision of appropriate adjuvant post-operative therapy.
The surgical management of early endometrial cancer has evolved over the past
two decades, with introduction of comprehensive surgical staging to identify patients
with extrauterine disease and an emphasis on individualization of treatment based on
clinicopathological risk groupings and risk of recurrence. Surgical approaches aimed
at limiting morbidity and improving quality of life in these patients without affecting
cure rates are now introduced at specialist centres. Several other such approaches are
being investigated for their safety and efficacy before they can be considered a part
of standard clinical practice. In this chapter, we review the current “state of the art”
of surgical management of early stage endometrial cancer.

Assessment of Early-Stage Endometrial Cancer

Accurate assessment of tumour stage and histology is essential to plan optimum

therapy for patients with early stage endometrial cancer.
Although endometrial cancer is generally diagnosed with the help of pelvic
ultrasonography followed by hysteroscopic evaluation and endometrial biopsy or
curettage, additional imaging may be considered in order to better define the myo-
metrial invasion, cervical, ovarian, peritoneal, nodal involvement and distant spread.
An MRI is most accurate in defining the local extent of the disease within the uterus
[1], while a CT scan [2] or a PET-CT scan is necessary to define extrauterine spread
of the disease [3–6]. However, since endometrial cancer is a surgically staged dis-
ease, it is not mandatory to do these pre-operative imaging studies, since these
imaging studies have been rarely found to alter the management of patients with
uterine cancers especially of the endometrioid variety [7].
Pre- and intraoperative assessment of histology in terms of histological subtype
and the tumour grade by an experienced oncopathologist cannot be overemphasized
as the management strategy, and prognosis depends on these factors [8, 9].

Surgical Management of Apparent Stage I Endometrial Cancer

Extrafascial hysterectomy with bilateral salpingo-oophorectomy along with com-

prehensive surgical staging including pelvic and para-aortic lymphadenectomy and
peritoneal wash cytology remains the mainstay of treatment of endometrial cancer.
6  Surgical Management of Early-Stage Endometrial Cancer 57

The need for a comprehensive staging is based on the fact that nearly 20 % of
women believed pre-operatively to have early stage uterine cancer are found to have
advanced (stage III–IV) disease [10]. It is no longer considered necessary to remove
a vaginal cuff along with extrafascial hysterectomy at surgery.
Radical hysterectomy for stage II endometrial cancer has not been found to
impart survival benefit as compared to extrafascial hysterectomy but was associated
with more adverse events. However, radical hysterectomy is recommended in the
presence of parametrial spread.
Ovarian preservation may be done in young patients with endometrial cancer who
are more likely to have low-stage, low-grade tumours, after a thorough discussion of
the benefits and risks of preserving the adnexa. This is important to avoid an early
surgical menopause and the early and late consequences thereof. Before contemplat-
ing ovarian preservation, it is essential to rule out a synchronous ovarian cancer or
ovarian metastases from endometrial cancer intraoperatively. Numerous studies have
reported that ovarian preservation may be safe and has no adverse impact on overall
survival of these young patients with early stage endometrial cancer [11]. Ovarian
preservation is not recommended in patients with family history of breast/ovarian/
uterine cancers, in non-endometrioid histology and in advanced stages.
Omentectomy is also considered a part of the standard surgical protocol for pap-
illary serous carcinomas especially where peritoneal implants may be present.
However, it is not recommended for clear cell carcinomas.
Current literature suggests that management of women by a gynaecologic oncol-
ogist in high-volume institutions results in improved disease-specific survival [12].

Surgical Approach

Surgery may be carried out by the open, laparoscopic or robotic approach.

Traditionally, surgical staging of endometrial cancer has been accomplished by
laparotomy. Many prospective and retrospective studies in 1990s demonstrated fea-
sibility of laparoscopic surgery for endometrial cancer [13, 14]. Numerous random-
ized controlled trials have compared the surgical- and disease-related outcomes
after open versus laparoscopic surgery for endometrial cancer. The largest amongst
these, the LAP-2 study, accrued 2626 patients of stage I–IIA endometrial cancer,
who were randomized to open (n = 920) versus laparoscopic (n = 1696) [15]. All
patients underwent hysterectomy, bilateral salpingo-oophorectomy, pelvic and
para-aortic lymphadenectomy and peritoneal cytology. The laparoscopic arm was
associated with a longer operative time but a shorter post-operative stay. The post-­
operative adverse events were similar in both the arms, with a lesser incidence of
moderate to severe side effects in the laparoscopic arm (14 % vs. 21 %, p < 0.0001).
Although there was a high (25.8 %) conversion rate to laparotomy in the laparos-
copy arm, there was no significant difference in the overall detection of advanced-­
stage disease between the two arms. The high rate of conversion to laparotomy was
more related to the lymphadenectomy part of the surgery and dependent on the
learning curve of the operator. Long-term outcomes of the LAP-2 study published
58 H. Tongaonkar et al.

in 2012 showed a non-inferiority (defined as no more than 40 % increase in the risk
of recurrence with laparoscopy compared to laparotomy) of recurrence-free interval
(HR for laparoscopy vs. laparotomy 1.14) and equivalent estimated overall survival
(89.8%) [16].
Two meta-analyses have compared the outcomes between the two approaches.
Zullo et al. [17] in a meta-analysis of eight trials concluded that the estimated blood
loss and the post-operative complications were significantly lower in the laparo-
scopic arm, while the operative time was significantly longer in the laparoscopy
arm. Intraoperative complications were no different in the two groups and were
related to the training of the operative surgeon [17]. The updated meta-analysis
published by Palomba in 2009 observed that there was no difference in the adverse
events as well as in the disease-free survival, overall survival or cancer-related sur-
vival [18]. Although there is a paucity of published data from RCTs comparing
robotic with open/laparoscopic approach, one expects the results of robotic approach
to be equivalent to the older approaches. However, the cost [19, 20], limited avail-
ability and learning curve [21, 22], along with lack of significant measurable bene-
fits to the patient, are limiting factors to recommend routine robotic surgery in all
patients.
The findings of the randomized trials and the meta-analysis provide definitive
evidence of short-term safety benefit and cost-effectiveness of laparoscopic surgery
in all patients, including those with co-morbidities, obesity and advanced age, along
with similar recurrence-free and overall survival [23, 24]. From the available evi-
dence, one can conclude that minimally invasive surgery is recommended and in
fact considered the preferred surgical approach in low- to intermediate-risk patients
with early stage endometrial cancer, provided the surgeon is trained in advanced
surgical techniques needed to perform retroperitoneal lymphadenectomy. The
extrapolation of the same to high-risk patients is debatable.
In patients who are medically unfit to undergo standard open or minimally inva-
sive surgery for endometrial cancer, vaginal hysterectomy with bilateral salpingo-­
oophorectomy may be considered, especially in low-risk patients who may not need
systematic lymphadenectomy [25]. For some women who are old, obese or have
severe medical co-morbidities, the risk associated with open or laparoscopic surgi-
cal staging may overweigh its potential benefit [12]. The vaginal approach does not
allow a thorough exploration of the abdominal cavity, peritoneal washings, lymph-
adenectomy and omentectomy and hence is not suitable for patients at risk of extra-
uterine disease. Several studies have reported similar survival rates with vaginal
hysterectomy versus abdominal hysterectomy for early stage endometrial cancer in
patients with a high surgical risk [26–28].

Lymphadenectomy

The indications, extent and therapeutic impact of lymphadenectomy remains one of

the most controversial and contentious issues in management of endometrial cancer.
Undoubtedly, it is an integral part of the comprehensive surgical staging,
6  Surgical Management of Early-Stage Endometrial Cancer 59

endometrial cancer being a surgico-pathologically staged cancer. Currently, a sys-

tematic pelvic and para-aortic lymphadenectomy is the only way to accurately iden-
tify the presence of nodal disease in women with endometrial cancer [29, 30].
Nearly 20 % of patients with endometrial cancer are understaged in the absence of
systematic lymphadenectomy [10]. It is also useful for prognostication (90 % 5-year
survival in node-negative versus 54 % for node-positive patients) and for appropri-
ate triage of patients for adjuvant therapy as the results of lymphadenectomy can
identify patients at high risk of recurrence and guide the decision about appropriate
adjuvant therapy (radiation therapy, chemotherapy, etc.). It thereby helps to indi-
vidualize treatment and prevent unnecessary overtreatment or inappropriate under-
treatment. The therapeutic value of lymphadenectomy, however, remains unclear
and debated.

Risk of Lymph Node Metastases

Endometrial cancer is a surgico-pathologically staged cancer. The GOG 33 proto-

col, a prospective surgico-pathological study published in 1987, clearly showed the
limitations of clinical staging compared with surgico-pathological assessment.
Metastatic disease was identified in a significant percentage of patients, when com-
prehensive staging was performed in apparently stage I patients with disease con-
fined to the uterus. Based on this, the FIGO changed over to a surgical staging
system for endometrial cancer in 1988 [31].
Tumour stage and pathological tumour grade appear to be the most impor-
tant factors influencing lymph node metastases. Creasman et al. [10] reported
that the overall incidence of lymph node metastases in clinically uterus-con-
fined endometrial cancer was about 3 % in grade I, 9 % in grade II and 18 % in
grade III tumours and less than 5 % in <50 % myometrial invasion, 15 % of
grade I–II tumours with >50 % myometrial invasion or grade III with <50 % of
myometrial invasion and >40 % in grade III >50 % myometrial invasion.
Boronow et al. noted that patients with outer one third of myometrial involve-
ment had a 25 % incidence of pelvic node metastases and 17 % para-aortic
lymph node ­metastases as compared to only 1 % incidence of nodal metastases
in patients without m ­ yometrial invasion [32]. Chi et al. reporting on the inci-
dence of lymph node metastases in patients with surgically staged endometri-
oid endometrial cancer confirmed that as the tumour grade increased, the risk
of myometrial invasion also increased. In their series, no patient with grade I
tumour on final pathology and only 2 % of patients with no myometrial inva-
sion had lymph node ­metastases [33].
An intraoperative assessment of histological subtype, grade and depth of myo-
metrial invasion in the operative specimen of hysterectomy visually and by frozen
section examination is found to be fairly accurate (84–88 % accuracy) and often
recommended to better define the risk of regional and distant spread and has the
ability to identify patients who will benefit from systematic lymphadenectomy and
adjuvant therapy [34].
60 H. Tongaonkar et al.

Indications for Lymphadenectomy

Patients with stage I endometrial cancer are stratified into different risk groups
according to their risk of extrauterine spread and relapse. This risk stratification also
serves as an aid to guide optimum adjuvant therapy. Although various risk stratifica-
tion models are available, the one defined by endometrial cancer consensus confer-
ence guidelines probably defines the risk groups best and is given below:

Low risk Stage I endometrioid, grade I–II, <50 % myometrial invasion,

LVSI – ve
Intermediate risk Stage I endometrioid, grade I–II, > 50 % myometrial invasion,
LVSI – ve
High-intermediate risk Stage I endometrioid, grade III, <50 % myometrial invasion,
regardless of LVSI status
Stage I endometrioid, grade I–II, LVSI +ve, regardless of depth of
invasion
High risk Stage I endometrioid, grade III, >50 % myometrial invasion,
regardless of LVSI status
Stage II
Stage I with non-endometrioid histology

Patients with low-risk endometrial cancer have a low risk of lymph node involve-
ment and do not benefit with systematic lymphadenectomy, and hence it is not rou-
tinely recommended in them [25, 35, 36].
Patients with intermediate-, high-intermediate- and high-risk endometrial cancer
have a higher probability of having extrauterine disease and also have demonstrated
survival benefit with systematic lymphadenectomy. Hence, a comprehensive pelvic
and para-aortic lymphadenectomy is recommended in them for staging and thera-
peutic planning purposes [25].

Extent of Lymphadenectomy

In published literature, the extent of lymphadenectomy for endometrial cancer has

been extremely variable, ranging from no lymphadenectomy to pelvic and/or para-­
aortic lymph node sampling to a comprehensive pelvic and para-aortic lymphade-
nectomy. Although there is no standard definition of “optimum lymphadenectomy”
for endometrial cancer, it is clear that lymph node sampling has a low sensitivity for
detecting lymph node metastases, since para-aortic lymph nodes may be involved in
the absence of positive pelvic nodes [10].
The question of the optimal extent of lymphadenectomy was answered in a ret-
rospective study of 281 patients with endometrial cancer who underwent compre-
hensive pelvic and para-aortic lymphadenectomy. Twenty-two percent of patients
with high-risk endometrial cancer had lymph node metastases – 51 % of these had
metastases in both pelvic and para-aortic nodes, 33 % had positive pelvic nodes
only, while 16 % had isolated positive para-aortic nodes in the absence of metastatic
6  Surgical Management of Early-Stage Endometrial Cancer 61

pelvic nodes, with majority of patients with para-aortic metastatic nodes (77 %)
having positive nodes above the level of inferior mesenteric artery [37]. On the other
hand, they also found that patients with low-risk disease had no lymph node metas-
tases and did not benefit from a systematic lymphadenectomy. Similar findings have
been reported by other authors [38]. This suggests that para-aortic nodes should be
removed whenever lymphadenectomy is indicated and that it is essential to extend
the upper limit of lymphadenectomy to the level of renal vessels.
There are two ways to judge the adequacy of lymphadenectomy. The more accu-
rate way is to perform a complete pelvic and para-aortic lymphadenectomy as per
the anatomic templates. The other is to measure the lymph node count in the surgi-
cal specimen, which is a surrogate marker for adequacy of lymph node dissection (it
has been shown that patients with more than 10–12 nodes removed during lymph-
adenectomy have an improved survival). In the collated data of 16,995 patients of
endometrial cancer from two randomized controlled trials and seven observational
studies, Kim et al. demonstrated an improved overall survival with systematic
lymphadenectomy (i.e. removal of more than 10–11 nodes) in patients with inter-
mediate- and high-risk endometrial cancer but limited survival benefit in low-risk
patients [39–41]. Based on this, lymph node counts have become a surrogate for
adequacy of lymphadenectomy with the recommendation that more than ten nodes
should be removed in an adequate lymphadenectomy [42, 43].

Does Lymphadenectomy Improve Survival?

Two randomized studies [44, 45] comparing systematic pelvic lymphadenectomy to

no lymphadenectomy in the surgical management of patients with endometrial can-
cer demonstrated that lymphadenectomy improved surgical staging but had no
impact on overall survival.
However, despite the randomized trials showing no survival benefit with com-
prehensive surgical staging, controversy still exists regarding the role of lymph-
adenectomy, mainly due to the criticisms of the ASTEC trial [46]. This trial was
criticized for a faulty trial design, a high rate of crossover to radiation therapy
and selection bias. Neither trial included para-aortic lymphadenectomy, and the
ASTEC trial also had low lymph nodal counts. This omission of para-aortic
lymphadenectomy may have negated the therapeutic effect of lymphadenectomy
since more than half of the patients with positive pelvic nodes have para-aortic
nodal metastases, and about 10 % of lymph node metastases occur exclusively in
the para-aortic region without pelvic lymph nodal involvement as shown by the
sentinel node studies [47]. Removal of para-aortic lymph nodes could probably
explain the significant effect of para-aortic lymphadenectomy as shown by Todo
et al. [48]. They analyzed their study of intermediate and high-risk patients who
underwent surgery with pelvic lymphadenectomy with or without para-aortic
lymphadenectomy. Those who had para-aortic lymphadenectomy had a survival
benefit as compared to those who did not [48]. The findings of this SEPAL study,
similar to the ASTEC trial, suggested that the survival effect of
62 H. Tongaonkar et al.

lymphadenectomy is rather limited in low-risk patients but is quite substantial in

the intermediate- or high-risk patients, with reduction in the risk of death (HR
0.44, p < 0.0001). In the ASTEC trial, patients were secondarily randomized to
radiation therapy based on uterine pathology only without considering the nodal
status, leaving some patients with metastatic nodes with no adjuvant therapy. The
clinical benefit of triage to adjuvant therapy was obscured as 50 % of patients
with lymph node metastases were randomized to no adjuvant therapy. Besides,
the lymphadenectomy versus no lymphadenectomy arms were unbalanced in
terms of high-risk criteria, with the lymphadenectomy arm having a greater per-
centage of patients with high-risk histology, high-grade tumours, presence of
lymphovascular invasion and deep myometrial invasion. Lastly, this trial did not
address the issue of benefit from para-aortic lymphadenectomy as patients under-
went para-­aortic node palpation with selective sampling rather than systematic
lymphadenectomy.
Retrospective data suggests that patients undergoing systematic lymphadenec-
tomy had improved survival over those who had limited or no lymphadenectomy
[43]. An analysis of 42,184 patients from the SEER database revealed that system-
atic lymphadenectomy was associated with overall and cancer-specific survival
benefit (HR 0.81 and 0.78, respectively), and removal of more than 11 nodes was
associated with HRs of 0.74 and 0.69, respectively [49]. Although statistically sig-
nificant, the retrospective nature of the data was subject to selection bias and stage
migration. Trimble et al., using a large national database, reported benefit with
lymphadenectomy in grade III tumours only [50].

Sentinel Node Mapping

The lymphatic drainage of uterus is complex, with several anatomical areas at risk
for metastases. The sentinel node is defined as the first node in the lymphatic basin
that receives the lymphatic flow. If the SLN is negative for metastatic disease, other
nodes in the template are expected to be free of disease involvement. The advantage
of SLN biopsy is the potential for improved diagnostic accuracy with use of ultrast-
aging while lowering morbidity [51, 52]. Sentinel node biopsy in particular has the
advantage of limiting the risk of lymphedema, which is seen in 6–38 % of patients
following pelvic lymphadenectomy [53, 54].
Sentinel node mapping for uterine cancer was first described by Burke et al. [55].
They reported on 15 patients who had SLN mapping followed by complete pelvic
and para-aortic lymphadenectomy. They reported an overall SLN detection rate of
67 %. Four patients had positive lymph nodes – two of these were detected by SLN
mapping with blue dye, one had a positive non-sentinel node and one had bulky
nodes without dye uptake. Khoury-Collado et al. (2011) could successfully identity
the sentinel node in 84 % of the cases in their study of 266 cases of endometrial
cancer, with 12 % incidence of metastatic nodes and 3 % metastatic nodes being
confirmed by immunohistochemistry [56]. Ballester et al. [51] in their multicentre
SENTI-ENDO trial showed that 10 % of low-risk and 15 % of intermediate-risk
patients were upstaged using the sentinel node technique [51].
6  Surgical Management of Early-Stage Endometrial Cancer 63

The greatest challenge in using the SLN technique in endometrial cancer is to

identify the optimum injection site that properly represents the drainage of the
tumour. Most large series till date have used cervix as the injection site. In recent
times, endometrial site of injection using the hysteroscopic, ultrasound-guided,
laparoscopic and open approaches has been investigated. Hysteroscopy allows
injection of the tracer in the mucosal space just around the tumour and at least con-
ceptually should be the best way to delineate the drainage of the tumour.
Hysteroscopic injection also allows a complete detection of the drainage of the uter-
ine corpus directed to both pelvic and para-aortic nodes, thereby decreasing the
false-negative rates. The first report of hysteroscopy-guided SLN technique by
Nilkur et al. [47] showed a detection rate of 82 % with no false negatives.
Subsequently, Maccauro et al. [57] and Raspagliesi et al. [58] reported a detection
rate of 100 % with no false negatives [57, 58]. Presently, however, there is no defi-
nite evidence that these technically more demanding injection approaches have a
definite benefit over cervix as the injection site [59].

Para Aortic Lymphadenectomy

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Minimally Invasive Surgery
for Endometrial Cancer 7
S.P. Somashekhar

Abstract
Objectives in improving cancer treatment can be categorized as those that
improve efficacy and those that lessen morbidity.
Minimally invasive surgery seeks to decrease morbidity from surgery while
maintaining at the very least equivalent efficacy. Laparoscopic method is estab-
lished as a standard technique with the landmark trial of GOG LAP2.
Robotic approach further enhances the benefits of laparoscopy with similar
results especially in obese women. However, randomized trials are awaited in
this regard. Early case series thus far reported suggest robotic surgery for endo-
metrial cancer is feasible.
Main advantages of robotic technology over laparoscopy include 3D vision
with better camera, more flexible instruments, less conversion rate, ease of sur-
gery, surgeon’s comfort, and shorter learning curve.
Current limitations of robotic surgery are mostly due to mechanical/energy
source-related instrument problems, high cost, and longer operating time.
The extent of surgery depends on the stage and extent of disease.
Adjuvant treatment is offered based on surgical stage and adverse factors.
Chemoradiation shows promising results in high-risk and advanced-stage
disease.
Systemic treatment of metastatic and relapsed disease may consist of endo-
crine therapy or cytotoxic chemotherapy.

S.P. Somashekhar, MS, MCh (Onco), [Link]

Manipal Comprehensive Cancer Center, Manipal Hospital,
HA-Airport road, Bangalore 560017, India
e-mail: somusp@[Link]

© Springer Nature Singapore Pte Ltd. 2017 67

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_7
68 S.P. Somashekhar

Introduction

Endometrial cancer is the sixth most common malignancy among females world-
wide. In developed countries, endometrial cancer is the fourth most common cancer
in women [1]. Endometrial cancer is common in western women, and the rates are
very high; however, in India, the rates are as low as 4.3 per 100,000 (Delhi) [2].
More than 90 % of cases occur in women older than 50 years of age, with a median
age of 63 years. Chronic estrogen exposure is the most common risk factor followed
by genetic predisposition (10 %), e.g., HNPCC/Lynch syndrome and chronic liver
disease like cirrhosis. Most cases of endometrial cancer are diagnosed in early
stages since abnormal uterine bleeding is the presenting symptom in 90 % of cases.
Endometrial cancer is staged according to the International Federation of
Gynecology and Obstetrics (FIGO 2009) system [3]. Preoperative imaging is not
mandatory. Dynamic contrast-enhanced magnetic resonance imaging (MRI) is the
best tool to assess the cervical involvement [4, 5]. In a few studies, MRI has been
shown to accurately evaluate the depth of myometrial invasion. A prospective collab-
orative trial, comparing MRI and ultrasonography (US), reported that the accuracy of
US is comparable to that provided by MRI [6], but US is highly operator dependent.
CA-125 marker is raised in extrauterine disease and is a bad prognostic marker.
Multiple factors have been identified for high risk of recurrence in apparent
early-stage disease: histological subtype, grade 3 histology, myometrial invasion
≥50 %, lymphovascular space invasion (LVSI), lymph node metastases, and tumor
diameter >2 cm. In this regard, stage I can be subdivided into three risk categories:

Low risk: stage IA (G1 and G2) with endometrioid type

Intermediate risk: stage IA G3 with endometrioid type and stage IB (G1 and G2)
with endometrioid type
High risk: stage IB G3 with endometrioid type, all stages with non-endometrioid
type

Two main clinicopathological types of endometrial cancer have been recognized,

corresponding to estrogen-dependent, more common endometrioid (type 1) and estro-
gen-independent non-endometrioid carcinomas (type 2). Type 2 endometrial cancer
carries bad prognosis. Both type 1 and type 2 have different etiopathogenesis through
different molecular pathways. Unlike typical (or “prototypical”) tumors, several cases
still remain morphologically ambiguous, indeterminate, or hybrid adenocarcinomas,
requiring immunohistochemistry (ER, PR, p53, p16, PTEN) and eventually mutational
analysis to allow for a correct interpretation.

Surgical Treatment

The surgical approach for the treatment of endometrial cancer has traditionally
been laparotomy. Nevertheless, in the last 15 years, the use of minimally invasive
techniques has been widely accepted by many authors. A recent publication of the
7  Minimally Invasive Surgery for Endometrial Cancer 69

Gynecologic Oncology Group (GOG) LAP2 study has shown similar operative
outcomes in the minimally invasive surgery and in the laparotomy group.
Laparoscopy seems to provide equivalent results in terms of disease-free survival
and overall survival compared with laparotomy, with further benefits: shorter hos-
pital stay, less use of pain killers, lower rate of complications, and improved qual-
ity of life. A potential enhancement to laparoscopy has been provided by the
robotic approach with a high “benefit” in obese women. Since 2002, the use of
robotic-assisted laparoscopy has advanced rapidly, particularly in the United
States. The largest published series of robotic surgery was reported in 2011 by
Paley et al. [10]. The major complication rate was significantly less with robotic
surgery (20 % vs. 6.4 %) compared with laparotomy, particularly related to wound
complications and infections.

Surgical Treatment in Stage I Endometrial Cancer

The standard surgical approach for stage I endometrial cancer consists of total
hysterectomy and bilateral salpingo-oophorectomy (BSO) with or without lymph-
adenectomy [I, A]. Lymphadenectomy could be important in determining a
patient’s prognosis and in tailoring adjuvant therapies. Hence, many authors sug-
gest a complete surgical staging for intermediate high-risk endometrioid cancer
(stage IA G3 and IB) [II, B]. Randomized trials have failed to show a survival or
relapse-free survival benefit in stage I endometrial cancer [I, A], and the role of
systematic pelvic lymphadenectomy is an issue of current debate. In an Italian
study, 514 patients with stage I endometrial cancer were randomized to receive
lymphadenectomy or not (excluding stage IA–IB G1 and non-endometrioid histo-
type). In this study, systematic lymphadenectomy did not improve disease-free or
overall survival [11]. In the ASTEC trial, 1408 women with malignancies confined
to the uterus were randomized. In this trial, there was no evidence of a benefit on
overall survival or recurrence-free survival when pelvic lymphadenectomy was
carried out [12]. The authors concluded that routine systematic pelvic lymphade-
nectomy cannot be recommended in women with stage I endometrial cancer,
unless enrolled in clinical trials. However, the design of these studies has not
addressed the most important impact of lymphadenectomy in the high-risk popula-
tion in order to identify patients who can safely avoid or benefit from adjuvant
treatment. A large retrospective study published in 2010, comparing systematic
pelvic lymphadenectomy vs. systematic pelvic and para-aortic lymphadenectomy
(SEPAL) study, has suggested that overall survival was significantly longer in
patients undergoing pelvic and para-aortic lymphadenectomy [13]. The SEPAL
study suggests that high-risk patients may benefit from aggressive surgery. Sentinel
lymph node identification in endometrial cancer has been described with interest-
ing preliminary results, which deserve further investigation in properly designed
clinical studies. Further randomized trials will be focused on investigating the role
of lymphadenectomy for patients with high-risk endometrial cancer to direct sub-
sequent treatment and the role of sentinel node biopsy.
70 S.P. Somashekhar

Surgical Treatment in Stage II Endometrial Cancer

Traditionally, the surgical approach consists of radical hysterectomy with bilateral

salpingo-oophorectomy and systematic pelvic lymphadenectomy with or without
para-aortic lymphadenectomy. In stage II, lymphadenectomy is recommended to
guide surgical staging and adjuvant therapy.

Robotic-Assisted Surgery for Endometrial Cancer

The benefits of robotic surgery as a minimally invasive surgical technique parallel

those of traditional laparoscopy, with the added advantages of overcoming several
barriers to the use of laparoscopy.

Basics of Robot

Surgeon performs surgery using a computer that remotely controls very small
instruments attached to the robot. It allows surgeons to perform delicate operations
by manipulating the robotic arms, which translate the surgeon’s hand movements
into smaller and smoother strokes. It has revolutionized the field of surgery by
allowing the surgeon to perform less-invasive and complex surgical procedures that
were once only possible with open surgery. Robotic machine has three parts – sur-
geon’s console (Fig. 7.1), patient cart (Fig. 7.2), and optical cart. Surgeon’s console
contains 3D monitor and joysticks which control the instruments. Patient cart has
four arms for the instrument and camera. With changing technology, improved ver-
sions of robot have better surgeon’s console and patient cart.
Robotic surgery enables surgeons to be more precise, advancing their technique
and enhancing their capability in performing complex minimally invasive surgery.
Binocular stereoscopic 3D vision with stability of camera and 10× magnification
allows the surgeon better visualization of the anatomy, which is especially critical
when working around delicate and confined structures like in the pelvis, chest, or
abdomen. This allows surgeons to perform radical cancer surgeries with superior
oncological outcome.
It mimics the human hand in its flexible movement and also overcomes limita-
tions of it, like 7° of movement and elimination of hand tremors. Despite the wide-
spread use of laparoscopic surgery, adoption of laparoscopic techniques, for the
most part, has been limited to a few routine procedures. This is due mostly to the
limited capabilities of traditional laparoscopic technology, including standard video
and rigid instruments. Surgeons have been slow to adopt laparoscopy for complex
procedures because they generally find that fine-tissue manipulation such as dissect-
ing and suturing to be more difficult. Intuitive technology, however, enables the use
of robot for complex procedures. The robot allows for 7° of motion vs. the limited
4° of motion in laparoscopy. Robotic technology eliminates the fulcrum effect of
laparoscopy (the robotic arms imitate the movements of the surgeon’s hand).
7  Minimally Invasive Surgery for Endometrial Cancer 71

Fig. 7.1 Surgeon’s
console

Motion scaling and precision of surgical movements during robotic surgery

improve the quality of surgery. Extremely easy and fast suturing and knotting and
multitasking instrumentations decrease operative time. Surgeon sits and operates at
ease with less fatigue, translating to safe surgery.

Surgical Technique

Preoperative Preparation

Patient takes clear liquids a day prior to surgery. Proctoclysis enema and two
Dulcolax (bisacodyl) tablets are given per oral a night before the surgery. We do not
administer Peglec which causes dilatation of the bowel.
Port placement (Figs. 7.3 and 7.4) and instrumentation (Fig. 7.8)
72 S.P. Somashekhar

Fig. 7.2  Patient cart

Fig. 7.3 Abdominal
marking of port placement
7  Minimally Invasive Surgery for Endometrial Cancer 73

Fig. 7.4  Port placement

Vaginal-Cervical Ahluwalia Retractor-Elevator (VCARE) uterine manipulator is

fixed to the cervix after placing patient in lithotomy position. Intraoperatively, it
helps in manipulating the uterus. A 12 mm camera port is placed 3 cm above the
umbilicus in the midline with optical trocar. The rest of the ports are placed after
insufflating the abdomen with gas and marking the port measurements. Arm-one
(8 mm) port is placed on patient’s right side, 3–5 cm below and at least 8 cm lateral
to the camera port. Arm-two (8 mm) port is placed on patient’s left side, 8 cm lateral
and 3–5 cm below the level of the camera port. Arm-three (8 mm) port is placed on
patient’s right side, 2 cm above the anterior superior iliac spine and 8 cm away from
the first port. Assistant port (12 mm) is placed on patient’s left side, slightly cepha-
lad to the camera port on an arc at the midpoint between the camera port and the
instrument arm-two port.
Zero-degree scope is used for all the steps, except for para-aortic lymph node
dissection where 30° down scope is used. In arm-one hot shears (monopolar curved
scissors), in arm-two fenestrated bipolar forceps, and in arm-three prograsp forceps
is used (Figs. 7.5 and 7.6, 7.7).
After placing all the ports, the patient is positioned before docking the robot.
Head end side is lowered completely, and all the bowel loops are taken toward the
upper abdomen. Pelvic wash is given and fluid is taken for cytological examination
(Fig. 7.8).

Surgical Steps

Dissection is done in a circular fashion from one round ligament to the other.
74 S.P. Somashekhar

Figs. 7.5 and 7.6  Patient positioning and Docking in progress

Fig. 7.7  Post docking

Fig. 7.8  Robotic instruments

with endowrist technology
7  Minimally Invasive Surgery for Endometrial Cancer 75

Fig. 7.9  Pelvic lymphadenectomy – distal boundary

Fig. 7.10  Pelvic lymphadenectomy – lateral and proximal boundary

Step 1: The uterus is retracted to the patient’s left side with the help of uterine
manipulator. Dissection starts with incising the peritoneum over the infundibulopel-
vic triangle, isolating the ureter and ovarian pedicle. Then, the round ligament is
transected near the inguinal ring with hot shear (monopolar diathermy). Incision is
extended anteriorly into the anterior leaf of the broad ligament up to the lateral
uterovesical junction. Coagulate and transect the right uterine pedicle and cardinal
ligament. Pay careful attention to the course of the ureter.
Step 2:The urinary bladder is lifted up with third arm, and the uterus is retro-
verted with the help of uterine manipulator and second arm. The vesicouterine
groove is identified and the bladder is dissected away from the uterus, and adhesions
if any are dissected with the cold knife (hot shear).
76 S.P. Somashekhar

Step 3: Left-side isolation of the ureter and dissection of the round ligament are
done similar to step 1. Both side ovarian pedicles are coagulated with bipolar dia-
thermy but not divided until complete dissection is done.
Step 4: Posterior part dissection is done by separating the rectum from the uterus
with the division of the uterosacral ligaments on either side. The course of the ureter
must be noted during this step.
Step 5: Anterior and posterior colpotomies are done by incising over the colpot-
omy ring. Finally, both the ovarian pedicles are divided. Specimen is delivered
through the vagina by pulling out the uterine manipulator, and abdominal pneumatic
pressure is maintained by packing the vagina with an adequate size ball made of
mop inside a surgical hand glove.
Step 6: Bilateral pelvic lymphadenectomy (Figs. 7.11 and 7.12) is done by expos-
ing the pararectal and paravesical spaces. Separate specimen bag is used for each
side of the lymph nodes, and specimen is delivered through the vagina. Para-­aortic
lymph node dissection is done when indicated. The vaginal cuff is closed with a
15 cm long self-retaining polydioxanone (monofilament, violet) barb suture, and
uterosacral ligaments are included laterally.
The role of systematic pelvic lymphadenectomy is an issue of current debate.
Excision of suspicious or enlarged nodes is important to exclude metastasis. A more
selective and tailored lymphadenectomy approach is now recommended to avoid
systematic overtreatment [6]. No randomized trial data support full lymphadenec-
tomy [7] although some retrospective studies have suggested that it is beneficial [8].
A subset of patients may not benefit from lymphadenectomy, but it is difficult to
preoperatively identify these patients because of the uncontrollable variable of
change in grade and depth of invasion in final histopathology.
As the grade of the tumor increases, accuracy of intraoperative evaluation of
myometrial invasion by gross examination decreases. Therefore, frozen section
examination for evaluation of the histology, size of primary, grade, and depth of
invasion is important. Pending further trials, pelvic lymphadenectomy is done in all
patients. Para-aortic lymphadenectomy is indicated in high-risk patients.

Fig. 7.11  Pelvic lymphadenectomy – inferior boundary

7  Minimally Invasive Surgery for Endometrial Cancer 77

Fig. 7.12  Completed paraortic lymphadenectomy with critical structures

Anatomical spaces in pelvic dissection:

1. Paravesical space
2. Pararectal space

Anatomical boundaries:

Distal – deep circumflex iliac vein

Proximal – common iliac vessels
Laterally – genitofemoral nerve
Inferiorly – obturator fossa (Figs. 7.9 and 7.10)

Para-aortic Lymphadenectomy

Boundaries
Superiorly – renal vein
Inferiorly – common iliac vessels
Laterally – ureter

Evolving Evidence

Efficacy of Laparoscopy

The Gynecologic Oncology Group (GOG) has completed a phase III randomized
study (lamina-associated polypeptide 2 (LAP2)) comparing laparoscopy vs.
78 S.P. Somashekhar

laparotomy in endometrial cancer [9]. Patients with clinical stage I–IIA uterine can-
cer were randomly assigned to laparoscopy (n = 1696) or open laparotomy (n = 920),
including hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and
para-aortic lymphadenectomy. Laparoscopy was initiated in 1,682 patients and com-
pleted without conversion in 1,248 patients (74.2 %). Conversion from laparoscopy
to laparotomy was secondary to poor visibility in 14.6 %, metastatic cancer in 4.1 %,
bleeding in 2.9 %, and other causes in 4.2 %. Laparoscopy had fewer moderate to
severe postoperative adverse events than laparotomy (14 % v 21 %, respectively;
P = .0001) but similar rates of intraoperative complications, despite having a signifi-
cantly longer operative time (median, 204 v 130 min, respectively; P = .001).
Hospitalization of more than 2 days was significantly lower in laparoscopy vs. lapa-
rotomy patients (52 % v 94 %, respectively; P = .0001). They concluded that laparo-
scopic surgical staging for uterine cancer is feasible and safe in terms of short-term
outcomes and results in fewer complications and shorter hospital stay. Time to recur-
rence was the primary end point, with non-inferiority defined as a difference in recur-
rence rate of less than 5.3 % between the two groups at 3 years. The recurrence rate
at 3 years was 10.24 % for patients in the laparotomy arm, compared with 11.39 %
for patients in the laparoscopy arm, with an estimated difference between groups of
1.14 % (90 % lower bound, −1.278; 95 % upper bound, 3.996) [10]. Although this
difference was lower than the pre-specified limit, the statistical requirements for non-
inferiority were not met because of a lower-than-expected number of recurrences in
both groups. The estimated 5-year overall survival was almost identical in both arms
at 89.8 %. These results, combined with previous findings from this study of improved
QOL and decreased complications associated with laparoscopy, are reassuring to
patients and allow surgeons to reasonably suggest this method as a means to surgi-
cally treat and stage patients with presumed early-stage endometrial cancers.
Another prospective randomized trial is ongoing at Australian and the UK insti-
tutions, the Laparoscopic Approach to Cancer of the Endometrium (LACE) trial
anticipated to randomize 590 patients to total laparoscopic hysterectomy and lymph
nodal staging vs. standard, open surgery [11].
Disadvantages of laparoscopy:

• Steep learning curve

• Limited dexterity
• Counterintuitive motion
• Two-dimensional field
• Limited depth perception
• Ergonomic difficulty

Evidence for Robotic-Assisted Surgery

Obesity
Endometrial cancer is particularly suited for robotic surgery for several reasons. The
majority of women with endometrial cancers are obese and at greater risk for
7  Minimally Invasive Surgery for Endometrial Cancer 79

postoperative wound complications and would benefit from a minimally invasive

procedure with smaller incisions, resulting in less risk for wound problems.
However, at the same time, obesity increases the degree of difficulty of management
via laparoscopy, maybe to the extent that the level of difficulty may become prohibi-
tive in accomplishing the operation. In a retrospective comparison of obese women
and morbidly obese women undergoing traditional laparoscopic approach vs.
robotic-­assisted approach, better surgical outcomes were observed in the group
undergoing robotic-assisted laparoscopy [12]. The group who underwent the proce-
dure robotically had significantly shorter operating time, less blood loss, improved
lymph node count, and shorter hospital stay suggesting that robotic-assisted lapa-
roscopy greatly facilitates laparoscopic surgery in obese patients. In obese patients
with greater abdominal surface area, adequate spacing between the ports and in turn
clashing of the arms are seldom a problem.
Bernardini et al. [13] studied women with clinical stage I or II endometrial can-
cer and a BMI greater than 35 kg/m2 treated with robotic surgery at their institution
between November 2008 and November 2010. These patients were compared with
a historical cohort of similar patients who underwent laparotomy. A total of 86
women were analyzed in this study (robotic surgery, 45; laparotomy, 41). The over-
all intraoperative complication rate was 5.8 %. There was no statistical difference in
age, number of comorbidities, BMI, prior abdominal surgery, and operative compli-
cations between the women who underwent robotic surgery vs. laparotomy.
Postoperative complication rates were higher in the laparotomy group (44 % vs.
17.7 %; P = 0.007), and hospital length of stay was also higher in the laparotomy
group (4 vs. 2 days; P = 0.001). There was no difference in rates of (pelvic) lymph
node dissection; however, para-aortic node dissection was more common in the
robotic surgery group.

Learning Curve

An analysis of robotic-assisted hysterectomy with lymphadenectomy vs. total lapa-

roscopic hysterectomy with lymphadenectomy and laparotomy with total abdomi-
nal hysterectomy with lymphadenectomy was done by Lim PC et al. [14]. Data
were categorized by chronologic order of cases into groups of 20 patients each. The
learning curve of the surgical procedure was estimated by measuring operative time
with respect to chronologic order of each patient who had undergone the respective
procedure. Analysis of operative time for robotic-assisted hysterectomy with bilat-
eral lymph node dissection with respect to chronologic order of each group of 20
cases demonstrated a decrease in operative time: 183.2 (69) min (95 % CI, 153.0–
213.4) for cases 1–20, 152.7 (39.8) min (95 % CI, 135.3–170.1) for cases 21–40,
and 148.8 (36.7) min (95 % CI, 130.8–166.8) for cases 41–56. For the groups with
laparoscopic hysterectomy with lymphadenectomy and traditional total abdominal
hysterectomy with lymphadenectomy, there was no difference in operative time
with respect to chronologic group order of cases. It was concluded that the learning
curve for robotic-assisted hysterectomy with lymph node dissection seems to be
80 S.P. Somashekhar

easier compared with that for laparoscopic hysterectomy with lymph node dissec-
tion for surgical management of endometrial cancer.

Survival Analysis

Retrospective study was conducted at two academic centers to compare the sur-
vival of women with endometrial cancer managed by robotic- and laparoscopic-
assisted surgery [15]. A total of 183 women had robotic-assisted surgery and 232
women had laparoscopic-assisted surgery. With a median follow-up of 38 months
(range 4–61 months) for the robotic and 58 months (range 4–118 months) for the
traditional laparoscopic group, there were no significant differences in survival
(3-year survival 93.3 and 93.6 %), DFS (3-year DFS 83.3 and 88.4 %), and tumor
recurrence (14.8 and 12.1 %) for robotic and laparoscopic groups, respectively.
Univariate and multivariate analysis showed that surgery is not an independent
prognostic factor of survival. Robotic-assisted surgery yields equivalent oncologi-
cal outcomes when compared to traditional laparoscopic surgery for endometrial
adenocarcinoma.
A retrospective chart review was performed for all consecutive endometrial ade-
nocarcinoma patients surgically staged with robotic-assisted laparoscopy at the
University of North Carolina Hospital from 2005 to 2010 [16]. Demographic data,
5-year survival, and recurrence-free intervals were analyzed. Surgical staging was
85.2 % for stage IA, 80.2 % for stage IB, 69.8 % for stage II, and 69 % for stage
III. Projected 5-year survival was 88.7 % for all patients included in the study.
Nearly 82 % of cases were endometrioid adenocarcinoma, with papillary serous,
clear cell, or mixed histology comprising 17.4 % of cases. Median follow-up time
was 23 months, with a range of 0–80 months. Among stage IA, IB, II, and III
patients, projected overall survival was 94.2 %, 85.9 %, 77.4 %, and 68.6 %, respec-
tively. The results from this study demonstrate that robotic-assisted surgical staging
for endometrial cancer does not adversely affect rates of recurrence or survival.
These findings provide further evidence that robotic-assisted laparoscopic surgical
staging is not associated with inferior results when compared to laparotomy or tra-
ditional laparoscopy.
Advantages of robotic technology:

• Binocular stereoscopic 3D vision.

• Stable, high-definition camera with 10× magnification.
• EndoWrist instrumentation – increased dexterity.
• Extremely easy and fast suturing and knotting intracorporeally.
• Surgeons sit and operate at ease with arms rested.
• Multitasking instrumentations.
• Option of harmonic scalpel.
• Three arms in addition to camera arm.
• Filters human tremor.
• Ergonomic with equal access with both left- and right-sided ports.
7  Minimally Invasive Surgery for Endometrial Cancer 81

Efficacy of Robotic Surgery

In our prospective randomized study [17] of 50 consecutive patients with carcinoma

endometrium, estimated blood loss (81.28 ml), hospital stay (1.94 days), and peri-
operative complications were significantly less in robotic-assisted group in com-
parison to open method. Mean number of lymph nodes removed were 30.56 vs. 27.6
which is suggestive of significant difference statistically. Operative time decreased
as the experience of the surgeon increased but still significantly remained higher
than the open procedure after 25 robotic-assisted surgeries. All robotic surgeries
were completed successfully without converting to open method. Robotic-assisted
staging procedure for endometrial cancer is feasible without converting to open
method, with the advantages of decreased blood loss, short duration of hospital stay,
and less postoperative minor complications.
A cohort study [18] was performed by prospectively identifying all patients with
clinical stage I or occult stage II endometrial cancer who underwent robotic hyster-
ectomy and lymphadenectomy from 2006 to 2008 and retrospectively comparing
data using the same surgeons’ laparoscopic hysterectomy and lymphadenectomy
cases from 1998 to 2005, prior to their robotic experience. Patient demographics,
operative times, complications, conversion rates, pathologic results, and length of
stay were analyzed. One hundred and eighty-one patients (105 robotic and 76 lapa-
roscopic) met inclusion criteria. There was no significant difference between the
two groups in median age, uterine weight, bilateral pelvic or aortic lymph node
counts, or complication rates in patients whose surgeries were completed minimally
invasively. Despite a higher BMI (34 vs. 29, P < 0.001), the estimated blood loss
(100 vs. 250 ml, P < 0.001), transfusion rate (3 % vs. 18 %, RR 0.18, 95 % CI
0.05–0.64, P = 0.002), laparotomy conversion rate (12 % vs. 26 %, RR 0.47, 95 %
CI 0.25–0.89, P = 0.017), and length of stay (median 1 vs. two nights, P < 0.001)
were lower in the robotic patients compared to the laparoscopic cohort. The odds
ratio of conversion to laparotomy based on BMI for robotics compared to laparos-
copy is 0.20 (95 % CI 0.08–0.56, P = 0.002). The mean skin to skin operating time
(242 vs. 287 min, P < 0.001) and total room time (305 vs. 336 min, P < 0.001) was
shorter for the robotic cohort. It was concluded that robotic hysterectomy and
lymphadenectomy for endometrial cancer can be accomplished in heavier patients
and result in shorter operating times and hospital length of stay, lower transfusion
rate, and less frequent conversion to laparotomy when compared to laparoscopic
hysterectomy and lymphadenectomy.
Magrina et al. [19] did a prospective analysis of 67 patients undergoing robotic
surgery for endometrial cancer between March 2004 and December 2007.
Comparison was made with similar patients operated between November 1999 and
December 2006 by laparoscopy (37 cases), laparotomy (99 cases), and vaginal/
laparoscopy approach (vaginal hysterectomy, bilateral adnexectomy/laparoscopic
lymphadenectomy) (47 cases) and matched by age, body mass index (BMI), histo-
logical type, and International Federation of Gynecology and Obstetrics (FIGO)
staging. Mean operating times for patients undergoing robotic, laparoscopy, vagi-
nal/laparoscopy, or laparotomy approach were 181.9, 189.5, 202.7, and 162.7 min,
82 S.P. Somashekhar

respectively (p = 0.006); mean blood loss was 141.4, 300.8, 300.0, and 472.6 ml,
respectively (p < 0.001); mean number of nodes was 24.7, 27.1, 28.6, and 30.9,
respectively (p = 0.008); and mean length of hospital stay was 1.9, 3.4, 3.5, and
5.6 days, respectively (p < 0.001). There were no significant differences in intra- or
postoperative complications among the four groups. The conversion rate was 2.9 %
for robotic and 10.8 % for the laparoscopy group (0.001). There were no differences
relative to recurrence rates among the four groups: 9 %, 14 %, 11 %, and 15 % for
robotics, laparoscopy, vaginal/laparoscopy, and laparotomy, respectively. It was
concluded that robotics, laparoscopy, and vaginal/laparoscopy techniques are pref-
erable to laparotomy for suitable patients with endometrial cancer. Robotics is pref-
erable to laparoscopy due to a shorter hospital stay and lower conversion rate and
preferable to vaginal/laparotomy due to a reduced hospitalization.
Ran et al. recently reported a meta-analysis which included 22 studies [20].
These studies involved a total of 4420 patients, 3403 of whom underwent both
robotic surgery and laparoscopy and 1017 of whom underwent both robotic sur-
gery and laparotomy. The estimated blood loss (p = 0.01) and number of conver-
sions (p = 0.0008) were significantly lower, and the number of complications
(p < 0.0001) was significantly higher in robotic surgery than in laparoscopy. The
operating time (OT), length of hospital stay (LOHS), number of transfusions, and
total lymph nodes harvested (TLNH) showed no significant differences between
robotic surgery and laparoscopy. The number of complications (p < 0.00001),
LOHS (p < 0.00001), EBL (p < 0.00001), and number of transfusions (p = 0.03)
were significantly lower, and the OT (p < 0.00001) was significantly longer in
robotic surgery than in laparotomy. The TLNH showed no significant difference
between robotic surgery and laparotomy. Conclusions: Robotic surgery is gener-
ally safer and more reliable than laparoscopy and laparotomy for patients with
endometrial cancer. Robotic surgery is associated with significantly lower EBL
than both laparoscopy and laparotomy; fewer conversions but more complications
than laparoscopy; and shorter LOHS, fewer complications, and fewer transfusions
but a longer OT than laparotomy.

Limitations of Robotic Surgery

Apart from the absence of level 1 evidence regarding robotic-assisted laparoscopy

for endometrial cancer, there are other limitations of robotic-assisted surgery to
consider. These limitations can be categorized as physical limitations of the da Vinci
System and cost considerations.
The limitations of robotic technology include: [21]

• Additional surgical training

• Increased costs and operating room time
• Bulkiness of the devices
• Instrumentation limitations (e.g., lack of a robotic suction and irrigation device,
size, cost)
7  Minimally Invasive Surgery for Endometrial Cancer 83

• Lack of haptics (tactile feedback)

• Risk of mechanical failure
• Limited number of energy sources (i.e., less than with conventional
laparoscopy)
• Not designed for abdominal surgery involving more than two quadrants (the
device needs to be re-docked and repositioned to operate in the quadrants it is not
facing)

The development of the da Vinci Xi, with a longer reach and improved range, has
in general enabled para-aortic lymph node dissection without much difficulty.
Robotic surgical systems are designed with features intended to minimize the
potential effects of mechanical failures on patients [21]. Such features include sys-
tem redundancy, so-called “graceful” performance degradation or failure, fault tol-
erance, just-in-time maintenance, and system alerting. In simplified terms, there are
several mechanical checks and balances built into current robotic surgical systems
so that the risk of mechanical failure is minimized.
Also as a result of the robotic arms being limited in its ability to reach away or in
the cephalad direction, the placements of the ports are typically higher in a patient
than compared to traditional laparoscopy in order to have access to both the pelvis
and to the upper abdomen. These incisions, some of which are placed above the
umbilicus, may be a cosmetic concern for some patients.
The absence of haptics or tactile feedback is also an important consideration in
robotic-assisted surgery. Currently, there is no ability for the surgeon at the sur-
geon’s console to receive tactile feedback regarding the “firmness of tissue” or the
degree of tension one is exerting on tissue as would be the case in an open laparot-
omy or traditional laparoscopy procedure in which the surgeon is actually touching
the tissue or holding instruments that are in direct contact with the patient; however,
most surgeons would agree that as one gains more experience with the robot, the
surgeon is able to use visual cues which enable a “virtual” tactile feel.
Another limitation of the robot already discussed has been in the bulkiness of
the arms of the robot holding the robotic instruments. These have a greater propen-
sity to clash if not positioned with adequate spacing in between, a situation that
sometimes cannot be avoided in small, petite patients, but is seldom a problem for
most endometrial cancer patients. Truncal obesity resulting in a greater abdominal
surface area ironically results in an advantage, overcoming this limitation for many
patients with endometrial cancers. The recent generation da Vinci Xi system which
has a longer reach and thinner arms has improved many of the limitations dis-
cussed above.

Surgical Treatment in Stage III–IV Endometrial Cancer

Maximal surgical debulking is indicated in patients with a good performance status

and resectable tumor [III, B]. For distant metastatic disease, palliative surgery could
be considered in patients with a good performance status. When surgery is not
84 S.P. Somashekhar

Table 7.1  Stage wise treatment protocol for endometrial cancer

Adjuvant
Stage Surgical treatment treatment
I IA Hysterectomy + BSO
G1–G2
IA G3 Hysterectomy + BSO + bilateral pelvic and para-aortic
lymphadenectomy
IB Hysterectomy + BSO + bilateral pelvic and para-aortic
G1–G3 lymphadenectomy
II Hysterectomy + BSO + bilateral pelvic and para-aortic
lymphadenectomy
III Maximal surgical cytoreduction with good performance
status
IV IVA Anterior and posterior pelvic exenteration
IVB Systemic therapy with palliative surgery

feasible due to medical contraindications (5–10 % of patients), or because of irre-

sectable disease, external radiotherapy with or without intracavitary brachytherapy
to the uterus and vagina is suitable for individual clinical use [IV, B] (Table 7.1).

Adjuvant Treatment

Adjuvant treatment for endometrial cancer is offered based on surgical stage and
adverse factors.

Radiotherapy

In 2009, a randomized trial compared vaginal brachytherapy vs. observation in

stage IA G1–2 endometrial cancer with a similar overall recurrence rate, survival,
and late toxic effect in the two groups. The optimal adjuvant treatment (Table 7.2)
of intermediate-risk endometrial cancer is still to be defined. External beam radia-
tion has been shown to reduce the rate of locoregional recurrence in intermediate-­
risk endometrial cancer. However, three large randomized studies (PORTEC-1 [13],
GOG 99 [14], and ASTEC MRC-NCIC CTG EN.5 [15]) failed to demonstrate that
radiation improves overall or disease-specific survival. A randomized clinical trial
(PORTEC-2) comparing vaginal brachytherapy and external beam radiation in
intermediate-risk patients showed that the two radiation therapies were equally
effective but that the quality of life was better in the vaginal brachytherapy arm [16].

Chemotherapy

Platinum-based chemotherapy can be considered in stage I G3 with adverse risk

factors (patient age, lymphovascular space invasion, and high tumor volume) and in
7  Minimally Invasive Surgery for Endometrial Cancer 85

Table 7.2  Risk stratification and adjuvant Rx

Risk Category Extent of disease Adjuvant treatment
Low Risk Superficial invasion No further Rx
(<1/2)
Low grade (1/2)
Intermediate Risk High Grade Vaginal Brachytherapy
Deep Invasion
LVSI
Negative Lymph
Nodes
High Risk Positive Lymph Nodes External pelvic irradiation and vaginal
Stage II brachytherapy – /+CT
CT + Extended field
UPSC, CCCa
RT
Positive P- A LNs
PORTEC II Trial

patients with stage II–III endometrial cancer [II, B]. Maggi et al. conducted a ran-
domized trial in 345 high-risk patients comparing five courses of cisplatin, doxoru-
bicin, and cyclophosphamide with external pelvic radiation. The authors reported
no difference between therapies in terms of PFS or overall survival [17], a result
which is also related to the insufficient sample size. A Japanese multicenter ran-
domized trial compared whole-pelvic irradiation with three or more courses of
cyclophosphamide, doxorubicin, and cisplatin chemotherapy in patients with old
stage IC–IIIC endometrioid adenocarcinoma. No difference in overall survival,
relapse rate, or PFS was observed [18]. In a subgroup analysis, chemotherapy
appeared superior to pelvic radiotherapy in patients aged >70 years with outer half
myometrial invasion, those with grade 3, those with stage II, or those with stage I
disease and positive peritoneal cytology.

Combined Radiotherapy and Chemotherapy

Two randomized clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO

ILIADE-III) were undertaken to clarify whether the sequential use of chemotherapy
and radiotherapy improved PFS over radiotherapy alone in high-risk endometrial
cancer patients (stage I–IIA, IIIC, any histology). The results of the two studies
were pooled for analysis [19]. The combined modality treatment was associated
with 36 % reduction in the risk of relapse or death [hazard ratio (HR) 0.64, 95 %
confidence interval (CI) 0.41–0.99; P = 0.04]. Cancer-specific survival was signifi-
cantly different (HR 0.55, 95 % CI 0.35–0.88; P = 0.01) and favored the use of
adjuvant chemotherapy in addition to radiotherapy. The ongoing PORTEC-3 study
is comparing radiotherapy with the concomitant and sequential use of chemother-
apy and radiotherapy in patients with endometrioid stage I G3, stage II–III, and any
stage serous and clear-cell carcinomas. Current evidence does not support the use of
progestins in the adjuvant treatment of endometrial cancer [I, A].
86 S.P. Somashekhar

Locoregional Recurrence

The standard treatment of vaginal recurrence in women who have not taken prior
RT is radiotherapy (external beam plus vaginal brachytherapy) with high rates of
local control, complete response (CR), and a 5-year survival of 50 %. For central
pelvic recurrence, the treatment of choice is surgery or radiotherapy (no prior RT),
while for regional pelvic recurrences, it is radiotherapy (no prior RT), associated
with chemotherapy/hormone therapy.

Advanced Disease

There is no agreement on the standard treatment of women with advanced endome-

trial cancer. Typically, a combination of surgery, radiotherapy, and/or chemotherapy
is employed.
In the GOG-122 trial, there were 396 patients with stage III and optimally deb-
ulked stage IV disease who were randomized to whole abdominal radiation or to
doxorubicin-cisplatin chemotherapy; there was a significant improvement in both
PFS (50 % vs. 38 %; P = 0.07) and overall survival (55 % vs. 42%; P = 0.004) in
favor of chemotherapy [20].

Treatment of Metastatic Disease and Relapse

Systemic treatment of metastatic and relapsed disease may consist of endocrine

therapy or cytotoxic chemotherapy. Hormonal therapy is recommended for endo-
metrioid histologies only and involves mainly the use of progestational agents;
tamoxifen and aromatase inhibitors are also used. The main predictors of response
in the treatment of metastatic disease are well-differentiated tumors, a long disease-­
free interval, and the location and extent of extrapelvic (particularly pulmonary)
metastases. The overall response to progestins is ∼25 %. Single cytotoxic agents
have been reported to achieve a response rate up to 40 % in chemotherapy-naïve
patients with metastatic endometrial cancer. Among those, platinum compounds,
anthracyclines, and taxanes are most commonly used alone and in combination
[21]. In nonrandomized trials, paclitaxel with carboplatin or cisplatin demonstrated
a response rate of >60 % and a possibly prolonged survival compared with historical
experience with other non-paclitaxel-containing regimens. Based upon these results,
many consider that paclitaxel-based combination regimens are preferred for first-­
line chemotherapy of advanced and recurrent endometrial cancer. The GOG has
completed accrual to a non-inferiority randomized phase III study evaluating carbo-
platin/paclitaxel vs. cisplatin/doxorubicin/paclitaxel in patients with stage III, IV, or
recurrent endometrial cancer (GOG 209), and published results should be available
soon. Preliminary results showed that the two-drug regimen was as good as the
three-drug regimen in terms of activity against the cancer and overall survival,
whereas it was less toxic. Endometrial cancer recurring after first-line chemother-
apy is largely a chemoresistant disease. Various agents have been tested in a number
7  Minimally Invasive Surgery for Endometrial Cancer 87

of small phase II trials in patients previously exposed to chemotherapy. Only pacli-

taxel has consistently shown a response rate of >20 %. Preliminary data for several
molecularly targeted agents for endometrial cancer are emerging. The PI3K/Akt/
mTOR pathway is frequently upregulated in women with endometrial cancer
because of loss of the tumor suppressor gene PTEN. Inhibitors of the mammalian
target of rapamycin (mTOR) have shown promising early results. The mTOR inhib-
itor temsirolimus was associated with a 24 % response rate in chemotherapy-naïve
patients. In patients with previous treatment, a 4 % response rate with disease stabi-
lization in 46 % has been reported [22]. A recent phase II clinical trial demonstrates
that single-agent ridaforolimus has antitumor activity in women with advanced
endometrial cancer, most of whom had received two prior chemotherapy regimens
[23]. The study met its primary end point, as 29 % of patients achieved a clinical
benefit, defined as an objective response or prolonged stable disease of 16 weeks or
more. Ridaforolimus also showed an acceptable toxic effect profile. Unfortunately,
predictive factors have not yet been identified to select patients most likely to ben-
efit from mTOR inhibitor therapy.

Serous Carcinoma and Clear-Cell Carcinoma

Serous and clear-cell carcinoma requires complete staging with total hysterectomy,
bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omen-
tectomy, appendectomy, and peritoneal biopsies. They are more aggressive with
higher rates of metastatic disease and lower 5-year survival rates [I, A]. There is
considerable evidence from retrospective series that platinum-based adjuvant che-
motherapy for early (stage I and II) disease improves PFS and overall survival [III,
B] [24]. Platinum-based chemotherapy is recommended in patients with stage III or
IV [I, A]. The same chemotherapy regimens usually employed for epithelial ovarian
cancer can be considered in women with advanced or recurrent serous or clear-cell
uterine cancer. Historically serous endometrial cancers have not been considered to
be hormone responsive.

Prognosis

Endometrial cancer is generally associated with a favorable prognosis. In the

EUROCARE-4 study, age-adjusted 5-year relative survival estimates reached 76 %
in 1995–1999 and 78 % in 2000–2002 in Europe. Survival for patients treated in
2000–2002 was highest generally in Northern Europe (especially in Sweden) and
lowest in Eastern Europe (Czech Republic and Poland) [25]. A key factor leading to
this good prognosis is that most cases are diagnosed at an early stage. The most
important prognostic factors at diagnosis are stage, grade, depth of invasive disease,
LVSI, and histological subtype. Endometrial tumors have a 5-year survival of 83 %
compared with 62 % for clear-cell and 53 % for papillary carcinomas. LVSI is pres-
ent in 25 % of cases. Five-year overall survival is 64 and 88 % with or without LVSI,
respectively.
88 S.P. Somashekhar

Given the importance of tumor stage for both prognosis and adjuvant treatment, it
is necessary to compare the performance of the 1988 and 2009 FIGO staging sys-
tems. Based on the 2009 system, survival was 89.6 and 77.6 % for stage IA and
IB. The newly defined stage IIIC substages are prognostically different. Survival for
stage IIIC1 was 57 % compared with 49 % for stage IIIC2 [26]. The first Indian pro-
spective randomized trail comparing open and robotic assisted surgery in endome-
trial cancers revealed that minimally invasive method is similar to open method with
respect to oncological outcomes. It has the additional benefit of decreased blood loss,
shorter duration of hospital stay and less postoperative complications [27].

Follow-Up and Long-Term Implications

Most recurrences will occur within the first 3 years after treatment. The suggested
frequency of follow-up is every 3–4 months with physical and gynecological exami-
nation for the first 2 years and then with a 6-month interval until 5 years. Further
investigations can be carried out if clinically indicated. PET/CT has been shown to
be more sensitive and specific than CT alone for the assessment of suspected recur-
rent endometrial cancer. The utility of Pap smears for the detection of local recur-
rences has not been demonstrated.

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Endometrial Cancer: Advanced Stage
8
Rama Joshi

Abstract
For patients with stage III/IV endometrial carcinoma, prognosis remains poor
and an optimum therapy is yet to be established. Treatment is individualized
based on disease extent at presentation, patient’s performance status, and hor-
monal status of the tumor. Surgery is often the mainstay of treatment in stage III
disease. The role of adjuvant radiotherapy in conferring survival is controversial.
Chemotherapy is fast emerging as an effective adjuvant treatment for advanced
endometrial cancer. Hormonal therapy with variable response rates has been
used for metastatic and recurrent endometrial carcinoma. The GOG continues to
investigate multimodality therapy.

Endometrial carcinoma is the most common malignancy of the female genital tract
in the western world and the fourth most common cancer in the women after breast,
lung, and colorectal cancer. Developing countries and Japan have incidence rates
4–5 times lower than western industrialized nations with the lowest rates being in
India and South Asia [1].
In 2/3 cases of endometrial cancer, the tumor is confined to the corpus at the time
of diagnosis where uncorrected survival rates of 75 % or more are expected [2].
In patients of advanced endometrial cancer with documented extrauterine disease of
stage III or IV, the prognosis remains poor.

R. Joshi, MBBS, MS
Department of Gynae Oncology, Fortis Memorial Research Institute, Gurgaon, India
e-mail: [Link]@[Link]

© Springer Nature Singapore Pte Ltd. 2017 91

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_8
92 R. Joshi

In the past 50 years, the treatment of endometrial cancer has evolved from a
regime of preoperative intracavitary radium packing or external pelvic radiation
therapy (RT) followed in 6 weeks by hysterectomy to customized treatment pro-
gram of primary surgery where hysterectomy with bilateral salpingo-oophorectomy
and surgical staging has now become the standard of care management. The adju-
vant treatment is employed subject to the stage of the disease and other histological
risk factors. The patients of endometrial cancer are staged according to FIGO 2009
(Table 8.1) [3].
In the past 30 years, the role of chemotherapy has emerged, and various chemo-
therapeutic regimes have been tried and tested as the adjuvant treatment in primary
setting.

Diagnosis and Staging Studies

The diagnosis of endometrial cancer is confirmed by the histopathology of endome-

trial curettage/endometrial biopsy. Thorough evaluation of patient, including com-
plete physical examination, and metastatic workup can define the extrauterine
spread of the disease within the pelvis or outside the pelvis, in the abdomen, and in
supraclavicular or inguinal nodal areas. These patients often have comorbid condi-
tions of obesity, diabetes, and hypertension which require to be evaluated prior to
the treatment decision of the disease.
The workup includes imaging ultrasonography (USG), magnetic resonance
imaging (MRI), CA125, and PET–CT when indicated. The ultrasonography and
magnetic resonance imaging appear to be able to diagnose the myometrial invasion
and lymph node metastasis with accuracy of 75–95 % [4–7]. The only way of accu-
rately diagnosing the depth of myometrium invasion is by histological examination
of the hysterectomy specimen.
Serum levels of CA125 are elevated in most of the patients with advanced or
metastatic endometrial cancer [8]. Multivariate analysis showed lymph node metas-
tasis had the most significant effect on elevation of CA125 levels (>40 u/ml), the
sensitivity and specificity for screening lymph node metastasis being 78 % and
84 %, respectively. Thus, preoperative CA125 levels greater than 40 u/ml can be
considered as an indication for full surgical staging with pelvic and para-aortic
lymphadenectomy in endometrial cancer [9] and may be helpful in monitoring clin-
ical response [10, 11].

Predicting Factors for Advance Stage

The two large prospective surgical staging GOG trials reported in 1984 and 1987
[12, 13] were the landmark trials in defining the prognostic factors of endometrial
carcinoma and the current treatment approach for the patients of endometrial
cancer.
8  Endometrial Cancer: Advanced Stage 93

Table 8.1  AJCC tumor–node–metastasis (TNM) and International Federation of Gynecology and
Obstetrics (FIGO) surgical staging systems for endometrial cancer
Primary tumor (T)
TNM FIGOa
categories stages Surgical–pathological findings
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tisb Carcinoma in situ (preinvasive carcinoma)
T1 I Tumor confined to the corpus uteri
T1a Ia Tumor limited to the endometrium or invades less than one-half of
the myometrium
T2 II Tumor invades stromal connective tissue of the cervix but does not
extend beyond the uterusc
T3a IIIIA Tumor involves the serosa and/or adnexa (direct extension or
metastasis)d
TBb IIIB Vaginal involvement (direct extension or metastasis) or parametrial
involvement
IIIC Metastases to pelvic and/or para-aortic lymph nodesd
IV Tumor invades the bladder and/or bowel mucosa and/or distant
metastases
T4 IVA Tumor invades the bladder mucosa and/or bowel (bullous edema is
not sufficient to classify a tumor as T4)

Regional lymph nodes (N)

TNM FIGO Surgical–pathological findings
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 IIIC1 Regional lymph node metastasis to pelvic lymph nodes (positive pelvic nodes)
N2 IIIC2 Regional lymph node metastasis to para-aortic lymph nodes, with or without
positive pelvic nodes

Distant metastasis (M)

TNM FIGO
categories stage Surgical–pathological findings
M0 No distant metastasis
M1 IVB Distant metastasis (includes metastasis to the inguinal lymph nodes,
intraperitoneal disease, or lung, liver, or bone). It excludes metastasis to
the para-aortic lymph nodes, vagina, pelvic serosa, or adnexa
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original and primary source for this information is the AJCC Cancer Staging Manual, seventh
edition (2010), published by Springer Science+Business Media, LLC (SBM) (for complete infor-
mation and data supporting the staging tables, visit [Link])
Any citation or quotation of this material must be credited to the AJCC as its primary source.
(continued)
94 R. Joshi

Table 8.1 (continued)
Reprinted from: Pecorelli et al. [74] (Copyright 2009, with permission from International
Federation of Gynecology and Obstetrics)
a
Either G1, G2, or G3
b
Note: FIGO no longer includes stage 0 (Tis)
c
Endocervical glandular involvement only should be considered as stage I and no longer as stage II
d
Positive cytology has to be reported separately without changing the stage

In addition to intrauterine risk factors of histological type, grade, myometrial

invasion, isthmus–cervix extension, and vascular space invasion, the extrauterine
factors of adnexal metastasis, intraperitoneal spread, pelvic node metastasis, and
para-aortic node metastasis are important in defining the adjuvant treatment.
Predicting factors help in selecting the patients who are likely to have advanced
disease at presentation and should undergo the extensive surgical staging. The high-­
risk factors usually modify the survival by either lymph node metastasis or extra-
uterine spread of the disease.
The following factors can predict the advanced stage of the disease:

1. FIGO stage is the strongest single predictor of outcome in women with endome-
trial carcinoma as shown in multivariate analysis [14]. The probability of pelvic
and para-aortic lymph node involvement and subsequent survival can be deter-
mined by the uterine risk factors as well as the extrauterine risk factors.
2. Histologic cell types

The cell type has consistently been recognized as an important factor in predicting
the biological behavior of the disease and thus survival. The majority of the uterine
corpus tumors are endometrioid adenocarcinoma and usually have relatively good
prognosis. Adenocarcinoma with squamous differentiation and villoglandular car-
cinoma behave similarly with respect to the frequency of nodal metastasis and sur-
vival to that in endometrioid adenocarcinoma.
Serous carcinoma often has low survival rates from 40 to 60 % at 5 years [15–
22]; clear cell carcinoma also has very aggressive behavior with a reported 5-year
survival rate of 30–75 % [23–30] as the disease is often advanced at presentation.

3. Grade

The degree of histological differentiation is considered to be the most sensitive indi-

cators of tumor spread to either lymph nodes or extrauterine sites. High-grade
tumors will have deeper myometrial invasion and increased incidence of pelvic and
para-aortic nodal metastasis (Table 8.2). More than half of grade 3 lesions are
reported to have >50 % myometrial invasion, 30 % involvement of pelvic, and 20 %
involvement of the para-aortic lymph nodes. Survival has also been consistently
related to histological grade [13].
8  Endometrial Cancer: Advanced Stage 95

Table 8.2  Histological grade and depth of invasion grade and no. of patients
Depth Grade 1 (%) Grade 2 (%) Grade 3 (%) Total (% of total)
Endometrium only 44 (24) 31 (11) 11 (7) 86 (14)
Superficial 96 (53) 131 (45) 54 (35) 281 (45)
Middle 22 (12) 69 (24) 24 (16) 115 (19)
Deep 18 (10) 57 (20) 64 (42) 139 (22)
Total 180 (100) 288 (100) 153 (100) 621 (100)
Reprinted from Creasman et al. [13]

4. Myometrial invasion

The depth of myometrial invasion is one of the most important factors, and deep
myometrial invasion has high probability of extrauterine disease spread including
lymph node metastasis and treatment failure [12, 31, 32].

5. Isthmus–cervix extension

Site of the tumor within the uterus is important in predicting the nodal metastasis.
Fundal lesions have 8 % pelvic nodal metastasis and 4 % para-aortic nodal metasta-
sis. In addition, lower uterine segment lesions will have 16 % risk of positive pelvic
node and 14 % risk of positive para-aortic nodes [13].

6. Lymphovascular invasion

The lymphatic invasion helps to identify the patients with lymph nodal metastasis
and is a strong predictor of tumor recurrence. Vascular space invasion is reported in
15 % of uterus-confined adenocarcinoma [13] with pelvic node positivity in 27 %
and para-aortic nodal positivity in 19 %, which is 4–6 times higher in comparison to
lymphovascular space-negative patients.

7. Adnexal involvement

The clinical stage I and occult stage II patients have tumor spread to adnexa in 6 %
[13] where pelvic and para-aortic nodal metastasis is reported in 32 % and 20 %
cases, respectively, which is four times greater than in patients without adnexal
metastasis.

8. Intraperitoneal spread

Gross intraperitoneal spread of the disease in absence of adnexal involvement cor-

relates well with higher incidence of involvement of pelvic and para-aortic nodes in
about 50 % of patients and 23 % patients, respectively [13, 33, 34]. The pelvic and
para-aortic nodal positivity in absence of peritoneal spread is 7 and 4 % only.
96 R. Joshi

Table 8.3  Frequency of nodal metastasis among risk factors

Risk factors No. of patients Pelvic no. (%) Aortic no. (%)
Histology
Endometrioid adenocarcinoma 599 56 (9) 30 (5)
Others 22 2 (9) 4 (8)
Grade
1 well 180 5 (3) 3 (2)
1 moderate 288 25 (9) 14 (5)
3 poor 153 28 (18) 17 (11)
Myometrial invasion
Endometrial 87 1 (1) 1 (1)
Superficial 279 15 (5) 8 (3)
Middle 116 7 (6) 1 (1)
Deep 139 35 (25) 24 (17)
Site of tumor
Fundus 524 42 (8) 20 (4)
Isthmus–cervix 97 16 (16) 14 (14)
Capillary-like space involvement
Negative 528 37 (7) 19 (9)
Positive 93 21 (27) 15 (19)
Other extrauterine metastases
Negative 586 40 (7) 26 (4)
Positive 35 18 (51) 8 (23)
Peritoneal cytology
Negative 537 38 (7) 20 (4)
Positive 75 19 (25) 14 (19)
Reprinted from Creasman et al. [13]

9. Pelvic and para-aortic lymph node metastasis

The frequency of pelvic and para-aortic nodal metastasis has been correlated well to
various pathological risk factors as shown in Table 8.3. Para-aortic nodal metastasis
was in 35 % of the cases where pelvic nodes were positive.

10. Ploidy and steroid receptors

Ploidy has remained the strong predictor of disease outcome. Diploid tumors
show higher survival rates than aneuploid tumors [35]. Positivity and quantity of
estrogen receptors and progesterone receptors have been correlated well with
clinical stage, histological grade, absence of vascular invasion, and better out-
come [36].
8  Endometrial Cancer: Advanced Stage 97

Treatment of Advanced Stage

Advanced stage endometrial cancer patients have stage III or stage IV disease.
These have increased risk of locoregional as well as distant recurrence and poor
prognosis. The use of multimodal approach in the treatment is required which can
prevent these recurrences and thus improve survival. These patients may benefit
from chemotherapy, tumor-directed radiation therapy, hormonal therapy, or com-
bined treatment. Chemotherapy is regarded as the foundation of adjuvant treatment
in advanced stage endometrial cancer.

Treatment of Stage III

Majority of the patients presenting with early-stage disease have good prognosis
and survival [37]. Approximately 5–10 % of patients of endometrial cancer present
in clinical stage III disease [38]. The patients in stage III include the heterogeneous
group of patients of extrauterine disease involving the adnexa, serosa, vagina, or
retroperitoneal pelvic or para-aortic nodes with varying risks.

Surgery

Patients presumed to be in advance stage are shown in Table 8.4. Surgery is the
mainstay of treatment [38] and requires the following surgical procedures:

• Type I hysterectomy
• Type II hysterectomy when the cervix is involved by the disease
• Bilateral salpingo-oophorectomy
• Peritoneal washings for cytological study
• Pelvic and para-aortic lymphadenectomy
• Resection of grossly enlarged nodes when present (Figs. 8.1 and 8.2)
• Omental biopsy
• Omentectomy when histology is serous, clear cell, or poorly differentiated
carcinoma
• Biopsy of any suspicious peritoneal nodule/lesion

Table 8.4  Risk factors in Uterine factors Extrauterine factors

endometrial cancer
Histological type Adnexal metastasis
Grade Intraperitoneal spread
Myometrial invasion Positive peritoneal cytology
Isthmus–cervix extension Pelvic node metastasis
Vascular space invasion Aortic node metastasis
98 R. Joshi

Fig. 8.1  Bulky ­para-aortic

nodal disease in
endometrial cancer stage
IIIC2

Fig. 8.2  Status post nodal

mass excision in endometrial
cancer stage IIIC2

Adjuvant Treatment

Patients with extrauterine disease confined to the adnexa or lymph nodes may be
treated with systematic therapy and pelvic- or extended-field tumor-directed radia-
tion therapy (RT).
The GOG 33 trial documented the 5-year survival rate of 36 % [39] for patients
receiving para-aortic radiation therapy for para-aortic node positivity. The radiation
dose which ranged from 4500 to 5015 cGy was delivered to the nodal area from the
pelvic brim. In the same series, the 5-year survival rate for patients with para-aortic
and pelvic nodal disease was 43 % compared with 47 % for those with para-aortic
8  Endometrial Cancer: Advanced Stage 99

nodal disease, though the difference was of no statistical significance [39]. Another
series of 18 patients showed significantly better 5-year survival rate of 67 % in
patients with para-aortic microscopic disease compared to 17 % for patients with
gross nodal disease [40].
Adjuvant chemotherapy and hormonal therapy in stage III and IV endometrial
cancer are discussed later in the chapter.

Treatment of Stage IV

The treatment of stage IV disease must be individualized. This usually involves

multimodality treatment of surgery, radiation therapy, chemotherapy, and hormonal
therapy. Endometrial cancer involving the bladder or rectum is uncommon and usu-
ally requires some type of modified pelvic exenteration with or without adjuvant
radiation or chemotherapy.

Surgery

Cytoreductive surgery plays an important role in the management of stage IV endo-

metrial cancer. The importance of cytoreductive surgery was studied in some series
(Table 8.5) [41–43]. In these series, the successful cytoreduction was found to be a
significant prognostic variable on multivariate analysis. Young age of <58 years and
good performance status were also predictive of survival [41] in stage IV disease.
Importance of aggressive surgery with the optimal status of cytoreduction has
been correlated with the improved survival in addition to the tumor biology [42].
The optimal status of cytoreduction was defined as the largest residual tumor nodule
of diameter ≤2 cm. Surgery in these patients may include radical pelvic resection
and some type of modified pelvic exenteration (Figs. 8.3, 8.4, 8.5 and 8.6). The radi-
cal pelvic resection and extended pelvic resection with or without pelvic radiation
or chemotherapy in conjunction with intraoperative radiation have also been
described [44].

Table 8.5  Surgical cytoreduction for stage IV endometrial cancer

n of
Study patients Residual tumor diameter Median survival (mos)
Goff et al. (1994) [43] 47 Resected 18
Unresected 8
Chi et al. (1997) [42] 55 ≤ 2 cm 31
>2 cm 12
Unresected 3
Bristow et al. (2000) [41] 65 Microscopic 40
≤ 1 cm 15
>1 cm 11
100 R. Joshi

Fig. 8.3  Specimen of

endometrial cancer
involving the adnexa
uterine surface and pelvic
peritoneum

Fig. 8.4  No residual status

postsurgical cytoreduction
following radical pelvic
resection

Chemotherapy
For improving the outcome of patients, chemotherapy was combined to the adjuvant
radiation therapy as safety and efficacy of chemoradiation was established in cervi-
cal carcinoma patients [45–48]. The chemotherapy was combined to radiation ther-
apy for improving survival in advanced endometrial cancer. Different combination
chemotherapy schedules are shown in Table 8.6 [49–53]. These studies are limited
with their small sample size.
The randomized phase III GOG trial [54] assessed optimal adjuvant therapy for
patients with stage III and stage IV disease having minimal residual disease and was
8  Endometrial Cancer: Advanced Stage 101

Fig. 8.5 Endometrial
disease involving the
adnexa, pelvic peritoneum,
and rectosigmoid. The
specimen of modified
posterior exenteration

Fig. 8.6  No gross residual

disease status following
modified posterior
exenteration as
cytoreductive procedure

randomly assigned to either whole abdominal radiation therapy or seven cycles of com-
bined doxorubicin (60 mg/m2) and cisplatin (50 mg/m2) chemotherapy. This study
reported improved progression-free survival (PFS) and overall survival (OS) in patients
receiving combination chemotherapy as compared to whole abdominal radiation ther-
apy (RT) arm and has since established the role of adjuvant multiagent systemic chemo-
therapy in advanced endometrial cancer patients with the curative intent and raised the
issue of appropriate combination of chemotherapy and radiation therapy [54].
Another GOG study compared the two chemotherapeutic arms of cisplatin, doxo-
rubicin, paclitaxel, and cisplatin and doxorubicin arms. The three-drug regimen arm
showed improved survival but with increased toxicity of peripheral neuropathy [55].
GOG 209 compared the outcome of chemotherapeutic regimes of carboplatin
and paclitaxel versus cisplatin, doxorubicin, and paclitaxel which reported similar
102 R. Joshi

Table 8.6  Phase I and II trials evaluating combination chemotherapy and radiation therapy in the
management of stage III/IV and high-risk endometrial carcinoma patients
Study Stages Patients Regimen Comments
Duska et al. III/IV, 20 TAC f/b 45 Gy WPRT SBO X2; 13 NED at
(2005) [33] HR median follow-up of 16
mos
Soper et al. III/IV 10 30 Gy WART + CDDP f/b 7 of 10 patients received
(2004) [34] Dox + CDDP CT; grade 4 neutropenia,
10 of 10 patients; 5
episodes of FN; median
survival, 14 mos
Bruzzone III/IV 45 CDDP + Epidox + Grade 4 neutropenia, 8 %
et al. (2004) cyclophosphamide f/b 9-year PFS, 30 %; OS,
[35] 50 Gy WPRT 53 %
Frigerio HR 13 Paclitaxel + 50 Gy WPRT Minimal toxicity; no
et al. (2001) survival data
[36]
Greven et al. HR 46 45 Gy WPRT + CDDP f/b Grade 4 hematologic
(2004) [37] CDDP + paclitaxel toxicity: RT, 2 %; CT,
62 %; 2-year DFS, 83 %;
OS, 90 %
CT regimens: Duska et al. [33], TAC paclitaxel (160 mg/m2), Dox (45 mg/m2), carboplatin (AUC
5); Soper et al. [34], CDDP (15 mg/m2) with RT, Dox (50 mg/m2), CDDP (50 mg/m2); Bruzzone
et al. [35], CDDP (50 mg/m2), Epidox (60 mg/ m2), cyclophosphamide (600 mg/m2); Frigerio et al.
[36], paclitaxel (60 mg/m2); Greven et al. [37], CDDP (50 mg/m2) on days 1 and 28 of WPRT,
CDDP (50 mg/m2), paclitaxel (175 mg/m2)
Abbreviations: AUC area under the concentration–time curve, CDDP cisplatin, CT chemotherapy,
DFS disease-free survival, Dox doxorubicin, Epidox epidoxorubicin, f/b followed by, FN febrile
neutropenia, HR high-risk endometrial cancer (papillary serous, clear cell, advanced stage), NED
no evidence of disease, OS overall survival, PFS progression-free survival, RT radiotherapy, SBO
X2 two small-bowel obstruction events, WART whole abdominal radiotherapy, WPRT whole pelvic
radiotherapy

outcomes with less toxicity in carboplatin and paclitaxel chemotherapy arm and
reported the response rate of 40–62 % and overall survival of 13–29 months [56].

 ormonal and Chemohormonal Therapy

H
The role of hormonal therapy in metastatic endometrial cancer has been primarily eval-
uated in endometrioid adenocarcinoma expressing estrogen (ER) and progesterone
receptors (PR), not in the papillary serous carcinoma, clear cell, and poorly differenti-
ated carcinoma. Well-differentiated tumors with expression of ER/PR and location and
extent of extrapelvic metastasis are the main predictors of hormonal treatment response.
Progestational agents are mainly used in the treatment of advanced stage endo-
metrial cancer [57]. Medroxyprogesterone acetate (MPA), megestrol acetate, and
hydroxyprogesterone caproate have shown the response rates of 14–53 %, 11–56 %,
and 9–36 %, respectively [57–65]. The responses are usually of short duration, the
median being 4 months [66].
8  Endometrial Cancer: Advanced Stage 103

Tamoxifen and aromatase inhibitors have also been used as the hormonal ther-
apy. Tamoxifen has been studied in combination of progestational agents [67, 68].
The response rate was not significantly different when treated with megestrol ace-
tate as the single agent compared with those treated with combination of tamoxifen
and megestrol acetate [69]. Sequential hormonal treatment of megestrol acetate in
the dose of 80 mg twice daily for 3 weeks, alternating with tamoxifen 20 mg daily
for 3 weeks, reported an overall response rate of 26 % [70]. Another GOG study
reported a response rate of 33 % with progression-free survival of 3 months and
median overall survival of 13 months when tamoxifen was given in the dose of
20 mg daily combined with medroxyprogesterone acetate 100 mg twice daily in
alternate week [71].
The combination hormonal therapy is the potential treatment alternative in
selected asymptomatic advanced endometrial cancer patients expressing estrogen
and progesterone receptors. The adjuvant therapy with hormonal agents has not
been compared with chemotherapy in advanced disease.
Combination chemohormonal therapy has been studied in some phase II trials
[72, 73]. A response rate of 40–50 % was noted which was similar to the response
rates reported by combination chemotherapeutic treatment. Further randomized tri-
als are required to establish the superiority of either chemohormone or paclitaxel-­
containing combination chemotherapy.
Intraoperative/specimen photographs of the advanced endometrial cancer
patients in stage III and stage IV disease contributed by author of the chapter

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motherapy in radically operated advanced ovarian cancer. Gynecol Oncol. 1999;72:215–9.
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Recurrent Endometrial Cancer
9
Yogesh Kulkarni and Harshavardhan

Abstract
Women who present with recurrent disease are not curable. Treatment options
are dependent on prior therapy.
For women who did not receive radiation after primary surgery and who pre-
sented with isolated vaginal recurrence, RT rather than surgery or medical treat-
ment is preferred (Grade 2C). For women who decline RT or are not candidates
for RT, surgical resection is a reasonable alternative.
Surgery is the treatment of choice for patients with prior radiation and isolated
vaginal recurrence, if surgery is feasible and patient is fit to undergo surgery
(Grade 2C). For women who are not surgical candidates (due to disease location
or medical contraindications), re-irradiation can be considered provided that
local expertise is available (Grade 2C).
For women who are not candidates for local therapy, medical treatment is
recommended.
For chemotherapy naïve patients, a platinum-based combination regimen
rather than endocrine therapy or single-agent chemotherapy (Grade 2B) is
preferred.
Carboplatin and paclitaxel are the preferred combination regime.
For some women with recurrent endometrial cancer, endocrine therapy is a
reasonable alternative to combination chemotherapy as initial treatment if any of
the following factors are present: grade 1 or grade 2 endometrial cancer, tumors
positive for estrogen (ER) and progesterone (PR) receptors, and women without

Y. Kulkarni, MD, DNB (*) • Harshavardhan, MS, DNB Surgical Oncology Trainee
Kokilaben Dhirubhai Ambani Hospital & Research Centre, Mumbai, India
e-mail: dryogik@[Link]

© Springer Nature Singapore Pte Ltd. 2017 107

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_9
108 Y. Kulkarni and Harshavardhan

(or with minimal) cancer-related symptoms. If endocrine therapy is adminis-

tered, megestrol acetate alternating with tamoxifen is preferred (Grade 2C).
Disease progression on endocrine therapy – chemotherapy given
Second-line chemotherapy – relapse interval is taken into account. For a long
treatment-free interval (e.g., ≥6 months), platinum-based combination chemo-
therapy rather than single-agent therapy is used (Grade 2C).
For relapse within 6 months of completion of first-line chemotherapy – single-­
agent chemotherapy
Women, who relapse following first- or second-line chemotherapy, have a
poor prognosis. The median overall survival in clinical trials of first- or second-­
line agents is generally 12 months or less.

Introduction

Seventy to eighty percent of endometrial cancers are diagnosed at an early

stage. As a result, treatment with surgery with or without adjuvant radiation
results in fewer treatment failures. Treating women with recurrent endometrial
cancer can be challenging, and clear understanding of the management options
is essential.
Factors that impact survival in patients with recurrent endometrial cancer
include site of relapse, prior radiation exposure, time to relapse, and the histologi-
cal type/grade of tumor. A longer disease-free interval, type I/grade I endometrioid
carcinoma, and isolated site of recurrence are associated with prolonged survival
in recurrent endometrial carcinoma cases. Non-endometrioid histology and high-­
grade tumors have a worse prognosis than endometrioid carcinoma. Women with
endometrial carcinoma who did not receive radiation therapy after primary surgery
and with isolated vault recurrences are appropriate candidates for radiation ther-
apy [1].
Aalders et al. [2] reported a large series of 379 recurrent endometrial carcinoma
cases from the Norwegian Radium Hospital. Local recurrence was observed in
50 % of cases, distant metastasis was seen in 29 %, and 21 % of patients had both
local and distant relapse. The time to detect the recurrence was 14 months for
patients with local recurrence and 19 months for those with distant recurrence.
Three-fourths (76 %) of the recurrences were detected within 3 years. The disease
was symptomatic only in 68 % of patients. Among the patients with local recur-
rence, 36 % were asymptomatic, 37 % had vaginal bleeding, and 16 % had pelvic
pain.
A diagnosis of endometrial cancer generally portends a favorable prognosis. A
majority (75 %) are diagnosed in FIGO stage I and have a 5-year survival of 85 %.
Women diagnosed in FIGO stage II have a 5-year survival of 75 %, 40 % for FIGO
stage III, and 20 % for FIGO stage IV [3, 4].
The reported recurrence rate for endometrial carcinoma is 6–14 %, and almost
80 % of recurrences are seen within 3 years of completion of treatment [5, 6].
9  Recurrent Endometrial Cancer 109

Isolated Vaginal Vault Recurrences

These are the recurrences which are most amenable to treatment, possibly even with
a curative intent. Prior to initiation of any kind of therapy, metastatic workup is
necessary. PET/CT scans achieve this in the best possible way.
Treatment approaches usually vary with prior history of radiation therapy:

No Prior Radiation Therapy

Evidence in support of radiation therapy for isolated vaginal vault recurrences

comes in from a multi-institutional study in the United States which identified 69
patients diagnosed with stage I endometrial carcinoma who were treated without
adjuvant radiation and who went on to develop an isolated vaginal recurrence [6].
Radiation therapy controlled 81 % of these vault recurrences.
In the Danish endometrial cancer study in which low-risk patients were followed
without radiation, 17 vaginal recurrences were reported, and 15 of these (88.2 %)
responded completely to radiation therapy. By contrast, none of the seven patients
with a pelvic recurrence could be cured [7].

Prior Radiation Therapy

Vaginal recurrences are less common in women treated with prior RT, but are asso-
ciated with a poor prognosis. In the PORTEC trial, there were only seven vaginal
recurrences out of 354 women treated with RT [8]. However, the actuarial OS rate
at 3 years among these patients was 43 %. Treatment options among these women
depend on whether surgery is an option or no.

Operative Candidates  Pelvic exenteration may be required as prior radiotherapy,

and surgery might have rendered anatomical planes obsolete. However, the decision
to proceed with pelvic exenteration should be considered carefully due to the asso-
ciated short- and long-term morbidity, including urinary tract and bowel dysfunc-
tion, the need for diversion (colostomy and/or nephrostomy), and sexual dysfunction.
Wide excision and primary closure might be possible in a few cases.
The reported 5-year OS rates for pelvic exenteration range from 14 to 50 %. In
the largest series of 44 women with recurrent endometrial cancer, the median OS
was 10.2 months, and 5-year OS was 20 % [9]. In a more recent review, Khoury-­
Collado F et al. describe their experience with 21 patients and report an overall
5-year survival of 40 % [10].

Nonoperative Candidates  In general, reradiating is not an option for women with

a vaginal recurrence, particularly after pelvic radiation, given the risks to the normal
surrounding tissue. However, tailored treatment approaches may allow for
110 Y. Kulkarni and Harshavardhan

r­e-­treatment with limited toxicity to surrounding normal tissue. As an example, a

case series of 27 patients treated with stereotactic RT after conventional RT found
no serious (grade 3, 4, or 5) toxicity associated with re-treatment, and a 96 % symp-
tomatic response (measured by reduced tumor size, decrease in pain, or decrease in
bleeding) was reported [11]. Unfortunately, due to limited experience, the practice
is not universal, and some form of medical treatment is recommended.

Systemic Recurrence: Role of Surgery

Surgery – in combination with radiation, chemotherapy, or hormonal therapy – may

play a role in selected patients with recurrent endometrial cancer, particularly if all
R0 status can be achieved.
Johns Hopkins Medical Center has reported complete cytoreduction in 23
patients (66 %) [12]. Median OS was 39 months compared to 13.5 months in resid-
ual disease group. Completeness of salvage surgery and residual disease was sig-
nificantly associated with survival. A smaller study from MSKCC also had the same
conclusions [13].
Ideal candidates for this approach are patients with long disease-free interval
(>2 years) and oligometastases.

Systemic Recurrence: Role of Hormonal Therapy

Progestational Agents  Both parenteral and oral have been used in patients with
recurrent and metastatic endometrial cancers. The objective response rate, however,
has been of the order of 15–20 %. Features that predict a better response are hor-
mone receptor expression, low-grade histology, and a long disease-free interval.
The GOG randomized 299 patients with advanced or recurrent endometrial cancer
to receive either 200 mg/d or 1,000 mg/d of oral MPA. Overall response was better
with the low-dose regime (25 % vs 15 %). Median survival durations were
11.1 months and 7 months (low vs high dose). Patients with poorly differentiated or
PR-negative tumors had only an 8–9 % response rate [14]. Progestins are to be con-
tinued lifelong in responders. Adverse effects from progestin include weight gain,
edema, thrombophlebitis, tremor, headache, and hypertension. There is also an
increased risk of thromboembolism.

Tamoxifen  Tamoxifen is a first-generation selective estrogen response modulator

(SERM) and inhibits the binding of estradiol to uterine ER, presumably blocking
the proliferative stimulus of circulating estrogens. Dose is 20 mg daily or twice
daily and is continued for as long as the disease is responding. Adverse effects
include hot flashes, vaginal dryness, DVT, and increased risk of cardiovascular
events. Moore et al. [15], in a review of literature, reported a pooled response rate of
22 % for single-agent tamoxifen.
9  Recurrent Endometrial Cancer 111

Aromatase Inhibitors  These have a response rate of only about 10 % in recurrent
and metastatic endometrial cancers, but the majority of patients in the reported stud-
ies have had high-grade, hormone receptor-negative cancers, where the likelihood
of response is low [16].

Systemic Recurrence: Role of Cytotoxic Chemotherapy

The role of cytotoxic chemotherapy in recurrent endometrial cancers is palliative at

best. Considerations to be noted prior to initiation include:

• Performance status
• Comorbidities such as obesity, diabetes mellitus, and cardiovascular disease
• Pelvic radiation – can limit bone marrow reserve
• Prior therapy with cytotoxic agents

Initial Therapy

Platinum-based combination is preferred. The two most commonly used regimens

to treat recurrent endometrial cancer are:

• Carboplatin plus paclitaxel

• The triple drug combination of cisplatin, doxorubicin, plus paclitaxel (TAP)

A 2012 meta-analysis [18] of trials that compared administration of two or more

agents (“more intensive” regimens) to one agent or two agent combinations (“less
intensive” regimens):

• Improvement in PFS from 6 to 7 months (HR 0.82, 95 % CI 0.74–0.90) and OS

from 9 to 10.5 months (HR 0.86, 95 % CI 0.77–0.96) in favor of “more intense
regimens.”
• “More intensive” chemotherapy significantly increased the risk of serious nausea
and vomiting (odds ratio [OR] 2.64, 95 % CI 1.71–4.09) and diarrhea (OR 2.25,
95 % CI 1.09–4.63) (Figs. 9.1, 9.2, 9.3, 9.4, 9.5, and 9.6).

Cisplatin, Doxorubicin, Plus Paclitaxel  GOG 177 enrolled 273 women with pre-
viously untreated stage III/IV or recurrent endometrial cancer and randomized them
to treatment with AP (cisplatin [50 mg/m2] plus doxorubicin [60 mg/m2] adminis-
tered on day 1 every 3 weeks) or to TAP (doxorubicin [45 mg/m2 on day 1], cispla-
tin [50 mg/m2 on day 1] plus paclitaxel [160 mg/m2 over 3 h on day 2] every 3
weeks) [17]. Compared to AP, TAP resulted in:
112 Y. Kulkarni and Harshavardhan

Fig. 9.1 Anterior
exenteration for a case of
recurrent endometrial
carcinoma treated
primarily by radiation

Fig. 9.2  Ileal conduit with

ureteric anastomosis

Fig. 9.3  Ileal conduit

9  Recurrent Endometrial Cancer 113

Fig. 9.4  Recurrence on

liver surface in a case of
papillary serous
adenocarcinoma of
endometrium

Fig. 9.5 Para-aortic
nodal recurrence in
endometrial carcinoma
case after 3 years

• Overall response rate (ORR) – 57 % vs 34 %

• PFS – 8 months vs 5 months
• OS −15 months vs 12 months
• TAP – increased incidence of grade 3 neuropathy (12 % vs 1 %)

Carboplatin Plus Paclitaxel  GOG 209 (which was not included in the 2012 meta-­
analysis) administered carboplatin (area under curve = 6) plus paclitaxel (175 mg/m2)
every 21 days and was compared to TAP in a trial that enrolled 1300 women with
chemotherapy naive stage III, IV, or recurrent endometrial carcinoma [17]:

• ORR – 51 % in both arms

• PFS – 13 months in both arms
• OS – 37 months vs 40 months (AP vs TAP)
114 Y. Kulkarni and Harshavardhan

Fig. 9.6 Complete
retroperitoneal node
dissection in endometrial
carcinoma with isolated
nodal recurrence

• A statistically significant reduction in the incidence of grade 2 or greater toxicity,

including sensory neuropathy (19 % vs 26 %), thrombocytopenia (12 % vs
23 %), emesis (4 % vs 7 %), diarrhea (2 % vs 6 %), and metabolic derangements
(8 % vs 14 %)

Second-Line Therapy

For women who have received adjuvant chemotherapy, the approach to second-line
treatment depends on the interval between the end of adjuvant treatment and the
diagnosis of relapse:
9  Recurrent Endometrial Cancer 115

• Greater than 6 months – repeat treatment with a platinum-based combination

• Short treatment-free interval (<6 months) – single-agent therapy rather than a
combination chemotherapy regimen. Commonly used agents include:
–– Doxorubicin
–– Ifosfamide
–– Ixabepilone
–– Docetaxel
–– Topotecan
–– Oxaliplatin

Novel Agents

• Bevacizumab
• Temsirolimus

References
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Newer Perspectives in the Management
of Endometrial Cancer 10
Sampada Dessai and Anant Ramaswamy

Abstract
CT, MRI, or PET have similar efficacy in detecting extrauterine disease and
should be performed when extrauterine disease is suspected in carcinoma
endometrium.
Systematic lymphadenectomy is associated with an improvement in overall
survival in patients with intermediate- or high-risk endometrial cancer.
Adjuvant RT and chemotherapy in stage I disease with intermediate- or high-­
risk features prevent recurrence but are not associated with improvement in over-
all survival.

Introduction

Endometrial cancer is the commonest female malignancy in the western world, but
in India, it ranks third after breast and cervical cancer, respectively. Incidence of
endometrial cancer in India is 12,335 cases per year, and 4773 persons die because
of this malignancy every year [1]. Advances in endometrial cancer at a national
level are slow to occur in view of its rarity. However, management of this cancer
remains challenging. The aim of this chapter is to comprehensively describe the
advances in the management of endometrial cancer.

S. Dessai (*)
Department of Gyn Oncology, Malabar Cancer Centre, Thalassery, India
e-mail: sampadads@[Link]
A. Ramaswamy
Department of Medical Oncology, TMH, Mumbai, India

© Springer Nature Singapore Pte Ltd. 2017 117

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3_10
118 S. Dessai and A. Ramaswamy

Methods

A PubMed search was carried out using the following MeSH terms and filters,
“endometrial neoplasm’s”[MeSH Terms] OR (“endometrial”[All Fields] AND
“neoplasms”[All Fields]) OR “endometrial neoplasms” [All Fields] OR
(“endometrial”[All Fields] AND “cancer”[All Fields]) OR “endometrial cancer”[All
Fields]) AND ((Clinical Trial[ptyp] OR Comparative Study[ptyp] OR Meta-­
Analysis[ptyp]) AND “2010/07/19”[PDat]: “2015/07/17”[PDat] AND
“humans”[MeSH Terms] AND English[lang]).
Eight hundred and sixty-one articles were available for selection. These articles
were manually screened, and relevant articles are compiled under the subheadings
of surgical, medical, and radiation oncology.

Recent Perspective in Imaging

Imaging in Carcinoma Endometrium

Detection of extrauterine disease mandates an imaging in carcinoma endometrium.

CECT has been traditionally used for this purpose. Whether PET-CT or PET-CECT
would improve the rate of detection of extrauterine disease is an open question. A
part of this question with regard to nodal involvement was answered by Kitajima
et al. [2]. A cohort of 41 patients underwent CECT, PET-CT, and PET-CECT. The
sensitivity and specificity of PET-CECT, PET-CT, and CECT were 61.4 % and
98.1 %, 52.3 % and 96.8 %, and 40.9 % and 97.8 %, respectively. The authors con-
cluded that PET-CECT was not significantly superior to PET-CT for nodal staging
of uterine cancer. Nodal metastasis cannot be excluded even if PET-CECT findings
are negative. A systematic review and meta-analysis were performed by Chang
et al. to assess the performances of PET or PET-CT in detecting pelvic and/or para-­
aortic lymph nodal metastasis [3]. The sensitivity and specificity of PET or PET-CT
scans in the detection of nodal metastasis (pelvic and/or para-aortic LN) were
63.0 % and 94.7 %, respectively. Chang et al. concluded that it may help surgeons
in selecting appropriate patients for pelvic and/or para-aortic lymphadenectomy.
The value of 18 FDG-PET in preoperative risk determination and prognosis was
evaluated in a systematic review by Ghooshkhanei et al. [4]. Pooled mean SUVmax
in patients with high-risk factors [grade 3, lymphovascular invasion (LVI), cervical
invasion (CI), myometrial invasion (MI) ≥ 50 %] was statistically higher than those
in patients without risk factors. Higher preoperative SUVmax was predicted for a
lower disease-free survival. However, these findings need large multicentric studies
for confirmation.
The current NCCN guidelines suggest that CT, MRI, or PET can be performed
as clinically indicated when extrauterine disease is suspected in carcinoma endo-
metrium. On the basis of evidence, it seems that PET-CECT is slightly better in
identifying patients with extrauterine nodal disease than CECT.
10  Newer Perspectives in the Management of Endometrial Cancer 119

Recent Perspective in Surgical Oncology

Fertility-Preserving Surgery

Fertility-preserving surgery seems an option for FIGO stage IA endometrial cancer.

Laurelli et al. selected patients with age ≤40 years, without Lynch II syndrome,
with G1 and ER+/PR+ endometrioid histology, without myometrial invasion, with-
out multifocal tumor, without node metastasis, without ovarian mass, and with nor-
mal serum CA 125 for fertility-preserving surgery. They underwent hysteroscopic
ablation of the lesion and the myometrial tissue below, followed by either oral
megestrol acetate 160 mg/day for 6 months or 52 mg levonorgestrel-medicated
intrauterine device for 12 months. Only one patient out of 14 recurred within a
median follow-up of 40 months [5]. The Turkish gynecologic oncology group also
collected their data on fertility-preserving strategy in early endometrial cancers.
They had 43 patients, and with average follow-up of 50 months, 81.4 % patients
were disease-free, and 41.9 % patients had conceived [6].
NCCN currently recommends that fertility-preserving treatment can be provided
in selected patient cohorts. These patients include those with stage IA G1 endome-
trioid histology, with endometrial cancer limited to the endometrium, without any
myometrial invasion, without Lynch type 2 syndrome or any other genetic syndrome,
without any extrauterine disease, and without any medical contraindication for pro-
gesterone therapy. These patients need to be counseled that this is not the standard
option, and if they still insist, it can be offered. If post 6 months they have a complete
response, then they should be encouraged for conception with continuous
surveillance.

Extent of Surgery

Prediction of Lymph Nodal Disease

Nomograms
The role of complete prophylactic lymphadenectomy in early stage endometrial cancer
is a matter of controversy. Around 5–10 % of early stage endometrial cancers harbor
lymph nodal metastasis. Hence, it would be useful to know if we can identify patients
who may benefit from lymphadenectomy either preoperatively or intraoperatively. The
prediction of nodal disease preoperatively by PET scan has been discussed in the above
section. In this section, we would look at other characteristics which have been reported
to be important predictors of lymph nodal metastasis. Bendifallah et al. validated two
nomograms made and were internally validated by ALHilli et al. [7]. The overall rate
of lymphatic spread was 9.9 %. Predictive accuracy was 0.65 (95 % Cl, 0.61–0.69) for
the full nomogram and 0.71 (95 % Cl, 0.68–0.74) for the alternative nomogram. The
correspondence between recurrence rate and the nomogram prediction suggested only
a moderate calibration of the nomograms. The authors concluded that additional
parameters are needed to improve upon the accuracy of the nomograms.
120 S. Dessai and A. Ramaswamy

In India, patients are commonly seen after incomplete staging surgery, i.e., only
TAH-BSO without lymph node dissection. Whether to do para-aortic nodal staging
in them is a matter of debate in this situation. Kang et al. addressed this issue and
tried to prepare a web-based nomogram which could be utilized to individualize
treatment in such cases [8]. Four variables – deep myometrial invasion, non-­
endometrioid subtype, lymphovascular space invasion, and log-transformed CA-125
levels – were part of the nomogram. It showed good discrimination. The nomogram
is available on the website ([Link] It can
be helpful in individualizing treatment in these patients.

Sentinel Lymph Node

Sentinel lymph node procedure is one of the known ways of predicting lymph node
status. It has established itself in breast cancer, melanoma, and carcinoma vulva.
The utility of sentinel lymph node dissection in endometrial cancers was studied by
Kang et al. in 2011in a meta-analysis [9]. The detection rate and the sensitivity were
78 % (95 % CI=73–84 %) and 93 % (95 % CI=87–100 %), respectively. Paracervical
injection technique was associated with the increase in detection rate (P = 0.031).
While hysteroscopic injection technique and the subserosal injection technique
were associated with decrease in detection rate and decreased sensitivity, respec-
tively, if they were not combined with other injection techniques. The authors con-
cluded that SLN biopsy had shown good diagnostic performance, but this should be
interpreted with caution.
Ballester et al. evaluated sentinel lymph node in presumed low- and intermediate-­
risk endometrial cancers. The detection rates in low and intermediate risk were
61.2 % and 37.1 %, respectively. 21.4 % and 21.2 % of patients in low risk and
intermediate risk were upstaged by the procedure. Ultrastaging detected metastases
which were undetected by conventional histology in 42.8 % of patients [10].
A repeat systematic review and meta-analysis of sentinel LN sampling by Ansari
et al. revealed a detection rate of 77.8 % and sensitivity of 89 % [11]. Similar to
Kang’s review, it also observed that paracervical injections were associated with
higher detection rates [9]. The authors concluded that sentinel node mapping was
feasible in endometrial cancer. Using blue dye, radiotracer, and cervical injection
can optimize the sensitivity and detection rate of this technique.
All these reviews had concluded that a large study would be required to con-
firm these benefits of these techniques. The SENTI-ENDO study was reported by
Daraï et al. in 2015 [12]. It was a study evaluating the impact of sentinel lymph
node dissection on adjuvant therapy. There was no difference in recurrence-free
survival (RFS) whether sentinel LN was detected or not in patients with stage I–II
endometrial cancer. Similarly there was no difference in RFS in patients whether
the sentinel LN detected was negative or positive. Adjuvant therapies were more
frequently administered in patients with a sentinel lymph node-positive status. It
seems that these adjuvant therapies may have altered the course of sentinel lymph
node-­positive cases.
10  Newer Perspectives in the Management of Endometrial Cancer 121

The current NCCN guidelines suggest doing sentinel lymph node dissection as
category 3 recommendation.

Role of Lymphadenectomy

The role of lymphadenectomy has also been debated in endometrial cancers espe-
cially after the publication of ASTEC studies. Kim et al. did a systematic review and
meta-analysis to address this issue. In all the studies, systematic lymphadenectomy
improved overall survival, compared with unsystematic lymphadenectomy (hazard
ratio, 0.89; 95 % confidence interval, 0.82–0.97). The systematic lymphadenectomy
was associated with an improvement in overall survival in patients with intermediate-
or high-risk endometrial cancer (hazard ratio, 0.77; 95 % confidence interval, 0.70–
0.86). No such benefit was seen in those with low-risk endometrial cancer (hazard
ratio, 1.14; 95 % confidence interval, 0.87–1.49) [13]. The impact of systematic
lymphadenectomy was studied by Angioli et al. Lymphadenectomy had no negative
influence on global health status [14]. Hence, systemic lymphadenectomy should be
performed in patients with intermediate to high risk of lymph nodal metastasis.
The current NCCN guideline suggests doing pelvic and para-aortic lymph node
removal for staging in patients with high-risk factors.

Technique of Surgery

 aparoscopic Versus Open Surgery

L
Lu et al. reported a randomized study comparing the outcomes of open versus lapa-
roscopic surgery in endometrial cancers [15]. Laparoscopic surgery was found to be
a safe and reliable alternative to laparotomy, with significantly reduced hospital stay
and postoperative complications; however, it did not seem to improve the overall
survival and 5-year survival rate. A Cochrane review done on the same topic too had
similar conclusions [16]. In early stage carcinoma, laparoscopy was associated with
similar overall and disease-free survival. Laparoscopy had reduced operative mor-
bidity and hospital stay. There was no difference in severe postoperative morbidity
between the two techniques.

 obotic Versus Laparoscopic Surgery

R
Gala et al. did a systematic review of robotic versus laparoscopic versus laparotomy
in endometrial cancer [17]. They revealed that, compared with open surgery, robotic
surgery has a shorter hospital stay. The learning curve seems to be lower for robotic
surgery than for laparoscopy. There was a conflicting data regarding comparison of
robotics and laparoscopy. He concluded that whether to select laparoscopy or
robotic surgery should be individualized for a patient taking into consideration sur-
geons’ proficiency and equipment available.
122 S. Dessai and A. Ramaswamy

Recent Perspective in Radiation Oncology

Radical Radiation

Surgery is the standard treatment option in endometrial cancer. Radical radiation is

an option in patients with medically inoperable endometrial cancers. A retrospec-
tive experience with radical radiation was published by Podzielinski [18]. The
median PFS and OS were 43.5 and 47.2 months, respectively. Majority of patients
in this review died due to comorbidities. Among the surviving patients, only 16 %
had recurrence.
NCCN recommends a tumor-directed RT in medically inoperable patients.
However, in these patients, control of comorbidities seems to be an important
aspect of management.

Adjuvant Radiation

Sorbe et al. reported a randomized study of intermediate-risk endometrial cancer

randomized postsurgery between vaginal brachytherapy and external beam radia-
tion. Five-year locoregional relapse rates were 1.5 % after EBRT + VBT and 5 %
after VBT alone (p = 0.013), and 5-year overall survival rates were 89 % and 90 %,
respectively (p = 0.548). There was no survival benefit associated with EBRT
+VBT, and it had incremental complications. Hence, the author concluded that
combined RT should probably be used for high-risk cases with two or more high-­
risk factors. VBT alone should be the adjuvant treatment option for purely medium-­
risk cases [19].
A Cochrane review was done by Kong et al. to address the issue of adjuvant RT
in stage I endometrial cancer. EBRT significantly reduced locoregional recurrence
compared with no EBRT or VBT alone (P < .001), but there was no improvement
in OS or endometrial cancer-specific survival or distant recurrence rates. EBRT in
addition increased risk of severe acute toxicity, severe late toxicity, and reduced
quality of life scores [20].
The NCCN recommends the use of external RT and vaginal brachytherapy on the
basis of risk stratification. To summarize, in the absence of risk factors for recur-
rence, observation is recommended; in case of intermediate risk, vaginal brachy-
therapy is recommended; and in case of high-risk status, both EBRT and vaginal
brachytherapy are recommended.

Recent Perspective in Medical Oncology

Adjuvant Chemotherapy

Endometrial cancers with poor differentiation, deep myometrial invasion, and high-­
grade histologies or with advanced disease are associated with poor prognosis.
Adjuvant radiation has shown to improve locoregional control rates in these patients,
but not overall survival. Whether addition of adjuvant chemotherapy helps in
10  Newer Perspectives in the Management of Endometrial Cancer 123

improving outcomes in these patients is not known. A combined analysis of two

randomized studies evaluating adjuvant chemotherapy was reported by Hogberg
et al. In both these studies, patients with high-risk features were randomized to
either adjuvant RT or adjuvant RT + sequential chemotherapy. In the combined
analysis, overall survival was not improved by adjuvant chemotherapy (HR 0.69, CI
0.46–1.03, P = 0.07); however, it had significant impact on cancer-specific survival
(CSS) (HR 0.55, CI 0.35–0.88, P = 0.01). The chemotherapy used in these studies
was paclitaxel+ carboplatin or doxorubicin + carboplatin or paclitaxel + epirubicin
or doxorubicin + cisplatin [21].
Two drug regimens have been used as adjuvant therapies; whether addition of a
third agent would improve the outcomes is not known. Addition of an anthracycline
to paclitaxel and carboplatin has been tried. In a feasibility study, the combination
of paclitaxel 150 mg/m2, epirubicin 50 mg/m2, and carboplatin AUC 4 was associ-
ated with a response rate of 74 % and median survival of 37 months [22]. Similar
efficiency has also been shown for doxorubicin (45 mg/m2), cisplatin (50 mg/m2),
and paclitaxel (160 mg/m2) [23]. These studies need evaluation in large multicentric
studies prior to their routine use.
NCCN recommends adjuvant chemotherapy in advanced endometrial cancer
and stage IB with high-risk features and stage II G3.

Palliative Chemotherapy

Palliative chemotherapy in recurrent, metastatic, and advanced endometrial cancer

is associated with an increment in overall survival. A Cochrane review showed that
treatment consisting of chemotherapy regimen has better overall survival (OS) (haz-
ard ratio (HR) 0.86, 95 % confidence intervals (CI) 0.77–0.96, P = 0.005) and
progression-­free survival (PFS) (n = 1526, HR 0.82, 95 % CI 0.74–0.90, P < 0.0001).
But these regimens are associated with more serious side effects. There was no
particular single agent or doublet regimen which would be labeled as a regimen with
better response rates [24].
Multiple newer agents including lapatinib, gefitinib, and aflibercept have been
tested, but none of them had a survival benefit [25–29].

Palliative Hormonal Therapy

Hormonal therapy has been used in endometrial cancer. The resistance to these
does develop over time. m-TOR inhibitors have been suggested – in such situa-
tions. The addition of temsirolimus and everolimus to aromatase inhibitors has
shown promising activity in phase II studies [30, 31]. Fulvestrant, an estrogen
receptor inhibitor, was tested in phase II studies, but it failed to improve the
results [32].

Conclusion
In the last 5 years, the treatment of endometrial cancer has shown minimal progress.
Major advances have been reported in minimal invasive techniques.
124 S. Dessai and A. Ramaswamy

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Index

A B
Advanced stage endometrial cancer Bilateral salpingo-oophorectomy (BSO), 69
diagnosis, 92
lymph node metastasis, 92
multivariate analysis, 92 C
myometrial invasion, 92 Chemotherapy
prognostic factors advanced stage endometrial cancer,
adnexal involvement, 95 97–102
FIGO stage, 94 combined radiotherapy, 85
histological grade, 94, 95 cytotoxic (see Cytotoxic chemotherapy)
histologic cell types, 94 locoregional recurrence, 86
intraperitoneal spread, 95 medical oncology, 124–125
isthmus-cervix extension, 95 metastatic and relapsed disease, 86
lymphovascular invasion, 95 MIS, 85
myometrial invasion, 95 non-resectable disease, 7
pelvic and para-aortic nodal palliative, 125
metastasis, 96 platinum-based, 84–85, 87
ploidy and steroid receptors, 96 Ciliated cell carcinoma, 34
serous carcinoma, 94 Clear cell carcinoma, 35–36
serum levels, 92 Combination chemohormonal
stage III disease therapy, 103
adjuvant chemotherapy, 99 Corpus cancer syndrome, 13
hormonal therapy, 99 Cytoreductive surgery, 99
para-aortic radiation therapy, 98 Cytotoxic chemotherapy
risk factors, 97 carboplatin plus paclitaxel, 115–116
surgery, 97–98 cisplatin plus doxorubicin, 113, 115
systematic therapy, 98 cisplatin plus paclitaxel, 113, 115
stage IV disease metastatic disease and relapse, 86
chemotherapy, 99, 100 platinum-based combination, 113
combination chemohormonal
therapy, 103
cytoreductive surgery, 99 E
hormonal therapy, 102–103 Early-stage endometrial cancer
radiation therapy, 98, 101 extrafascial hysterectomy, 56
tamoxifen and aromatase histology assessment, 56
inhibitors, 103 laparoscopic surgery, 58
surgical staging systems, 93–94 lymphadenectomy, 58–63
tumor-node-metastasis, 92, 93 omentectomy, 57
Aromatase inhibitors, 113 ovarian preservation, 57

© Springer Nature Singapore Pte Ltd. 2017 127

R. Patni (ed.), Current Concepts in Endometrial Cancer,
DOI 10.1007/978-981-10-3108-3
128 Index

Early-stage endometrial cancer (cont.) imaging studies, 5

pelvic and para-aortic lymphadenectomy, 56 immunohistochemistry of, 36–37
peritoneal wash cytology, 56 incidence of, 42
radical hysterectomy, 57 locoregional recurrence, 7
randomized trials, 58 MIS (see Minimally invasive surgery
stage I disease (MIS))
adnexal involvement, 95 molecular categories, 8
extrauterine spread and relapse, 60 pathophysiology
FIGO, 37 macroscopy, 31
high risk, 68 myometrial invasion, 31
intermediate risk, 68 obesity, 31
low risk, 68 type I, 31
platinum-based chemotherapy, 84–85 type II, 31
robotic hysterectomy, 81 pelvic lymph node dissection, 6
RT, 124 pre-and postoperative radiotherapy, 5
serous and clear-cell carcinoma, 87 pre-management workup, patients
surgical management, 56–57 CECT, 49–51
surgical treatment, 69 cervical stromal involvement, 49, 50
stage II disease Doppler, 49
adnexal involvement, 95 fertility-preserving therapy, 51
radical hysterectomy, 57 imaging accuracy, 48–50
robotic hysterectomy, 81 initial evaluation, 47, 48
surgical treatment, 70 magnetic resonance imaging, 49, 50
surgical staging, 57–58 positron emission tomography, 51
tumour stage, 56 superficial myometrial invasion, 49, 50
uterus-confined disease, 56 TVUS, 49
vaginal hysterectomy, 58 progestational therapy, 7
Endocrine therapy prognostic factors of, 37
disease progression, 110 retroperitoneal lymph nodes, 6
megestrol acetate, 110 stages, 5, 48
metastatic disease and relapse, 86 symptoms, 42
Endometrial cancer tumor biology, 7
clinical examination, 42–44 Endometrial intraepithelial neoplasia (EIN)
combination chemotherapy, 7 schema, 22
definition, 31 benign, 20, 21
diagnosis definitions, 20, 21
chronic anovulation, 43 diagnostic criteria, 20, 21
Color Doppler, 46 hormonal treatment, 24
dilatation and curettage, 47 levonorgestrel-releasing intrauterine
family history of malignancies, 44 system, 24
guided biopsy, 46–47 malignant, 20
hysteroscopy, 46–47 management of, 23
office endometrial biopsy, 44, 45 nonsurgical management, 23–24
Pap smear, 44 pathologic criteria, 20
postmenopausal bleeding, 42–43 premalignant, 20
sonohysterography, 46 progestin regimes, 24
tamoxifen-induced cystic Endometrioid adenocarcinoma
hyperplasia, 43 ciliated cells, 34
transvaginal ultrasound clear cell carcinoma, 35–36
examination, 45–46 epidemiologic characteristics, 32
FIGO grading, 32, 37 grade 1, 32, 33
genetics of, 38 grade 3, 32, 34
histological types, 31, 32 morphologic patterns, 32
history, 42–44 mucinous carcinoma, 35
Index 129

proliferative phase endometrium, 32 G

SCC, 36 Genetics, endometrial carcinoma, 38
secretory phase endometrium, 34
serous carcinoma, 35
small cell carcinoma, 36 H
with squamous differentiation, 33–34 Hereditary nonpolyposis colorectal cancer
transitional cell carcinoma, 36 (HNPCC), 14, 44, 68
tumour necrosis and grading, 32 Hormonal therapy, 7, 23, 86, 102–103
undifferentiated carcinoma, 36 aromatase inhibitors, 113
villoglandular carcinoma, 34 parenteral and oral drugs, 112
Epidemiology, endometrial cancer progestational agents, 112
clinical staging, 17 tamoxifen, 112
controlled diet, 17 Hyperplasia, endometrium
diabetic postmenopausal women, 17 EIN diagnostic schema, 20–24
early detection, 17 premalignant lesions, 29–30
endometrial biopsies, 17 WHO schema
protective factors complex hyperplasia, 20
breastfeeding, 16 complex hyperplasia with atypia, 20
cigarette smoking, 16 glandular complexity, 20
coffee drinking, 16 nuclear atypia, 20
diabetes mellitus, 16 poor reproducibility, 20
hormonal IUDs, 16 simple hyperplasia, 20
hormone replacement therapy, simple hyperplasia with atypia, 20
concomitant progesterone, 16
intrauterine devices, 16
metformin, 16 I
oral contraceptive pills, 15, 16 International Federation of Gynecology and
physical exercises, 15, 16 Obstetrics (FIGO) grading, 32, 37, 94
weight loss, 15, 16 Intracavitary brachytherapy, 84
women on tamoxifen, 17
risk factors
age dependent, 12, 13 L
assessment, 17 Laparoscopic surgery
diabetes mellitus, 12, 13 cost-effectiveness, 58
diet, 12, 13 vs. open surgery, 57, 123
family history, 12 vs. robotic surgery, 79, 80, 123
HNPCC, 12, 14 safety benefit, 58
hyperoestrogenic states, 12, 14 Lymphadenectomy
hypertension, 12, 13 adjuvant therapy, 70
infertility, 12, 14 BSO, 69
menstrual history, 12, 14 distal boundary, 75
microsatellite instability, 15 incidence, 59
molecular alterations, 12 indications, 60
obesity, 12, 13 inferior boundary, 76
oestrogen-producing tumours, 12, 14 intraoperative assessment, 59
parity, 12–14 lateral and proximal boundary, 75
polycystic ovary syndrome, 12, 14 limited survival benefit, 61
race, 12, 13 lymph node dissection, 61
tamoxifen usage, pelvic hygiene, 12, 15 pararectal and paravesical spaces, 76
Estrogen replacement therapy (ERT), 14, 30 pathological tumour grade, 59
patient’s prognosis, 69
pelvic/para-aortic lymph node sampling,
F 25, 37, 56, 59–61, 76, 77, 87, 92,
Fertility-preserving therapy, 51 96, 120, 123
130 Index

Lymphadenectomy (cont.) pathological features, 6

randomized controlled trials, 61 preoperative preparation technique
robotic-assisted hysterectomy, 79, 81 medications, 71
role of, 123 patient positioning, 73, 74
sentinel node mapping, 62–63 port placement, 71–73
serous and clear-cell carcinoma, 87 proctoclysis enema, 71
surgical staging, 70 robotic instruments, 73, 74
surgico-pathologically staged cancer, 58–59 zero-degree scope, 73
survival benefit, 61–62 prognosis, 87–88
tumour stage, 59 robotic surgical systems, 70–71, 78–83
Lynch syndrome, 4, 12, 14, 44, 68 serous and clear-cell carcinoma, 87
stage I
high risk, 68
M intermediate risk, 68
Management, endometrial cancer low risk, 68
description, 119 surgical treatment
imaging in, 120 complication rate, 69
medical oncology, 124–125 laparoscopy, 69
PubMed search, 120 laparotomy, 68
radiation oncology for stage I, 69
adjuvant radiation, 124 for stage II, 70
radical radiation, 124 tumor diameter, 68
surgical oncology, 121–123 uterine manipulator, 75
Medical oncology vesicouterine groove, 75
adjuvant chemotherapy, 124–125 Mucinous carcinoma, 35
hormonal therapy, 125
palliative chemotherapy, 125
Minimally invasive surgery (MIS) O
adjuvant treatment Oestrogen-producing tumours, 12, 14
advanced disease, 86 Office endometrial biopsy, 4, 44, 45, 47
chemotherapy and radiotherapy, 85
locoregional recurrence, 86
metastatic and relapsed disease, 86–87 P
platinum-based chemotherapy, 84–85 Palliative hormonal therapy, 125
radiotherapy, 84, 85 Platinum-based chemotherapy, 84–85, 87
risk stratification, 84, 85 Polycystic ovary syndrome, 12, 14
vaginal recurrence, 86 Postmenopausal bleeding, 17, 22–23, 42–44
anterior and posterior colpotomies, 76 Precancer diagnosis
bilateral pelvic lymphadenectomy, 76, 77 dilatation and curettage, 22
clinical use, 83–84 endometrial sampling and imaging, 21–23
clinicopathological types, 68 postmenopausal bleeding, 22
efficacy of laparoscopy, 77–78 tumor markers, 23
external radiation therapy, 83–84 Premalignant lesions
follow-up and long-term implications, 88 assessment and management, 25
histological subtype, 68 endometrial precancer classification, 20
lymph node metastases, 68 hyperplasia classification systems
lymphovascular space invasion, 68 (see Hyperplasia, endometrium)
maximal surgical debulking, 83 intraoperative assessment, 25
medical comorbidity, 6 morcellation and endometrial ablation, 25
myometrial invasion, 68 pathophysiology, 30
ovarian pedicles, 76 precancer diagnosis, 21–23
para-aortic lymphadenectomy, 76, 77 supracervical hysterectomy, 25
Index 131

surgical staging, 25 Surgical oncology

type 1 and 2 tumors, 20 early-stage/uterus-confined disease (see
vaginal hysterectomy, 25 Early-stage endometrial cancer)
Progestational therapy, 7, 112 fertility-preserving surgery, 121
lymphadenectomy, 123
lymph nodal disease
R nomograms, 121–122
Radiation therapy (RT) sentinel lymph node procedure, 122–123
advanced stage endometrial cancer technique of
stage III disease, 100 laparoscopic vs. open surgery, 123
stage IV disease, 99, 103 robotic vs. laparoscopic surgery, 123
chemotherapy, 85 Surveillance, epidemiology and end results
MIS, 83–84 (SEER) database
tumor-directed, 97, 98 abnormal uterine bleeding, 4
vaginal vault recurrences, 111 anti-aromatase agents, 3
Recurrent endometrial cancer aromatase inhibitor therapy, 3
bevacizumab, 117 hysteroscopy-guided biopsy, 4
cytotoxic chemotherapy immunohistochemical analysis, 3
anterior exenteration, 113, 114 lymphadenectomy, 62
carboplatin plus paclitaxel, 115–116 precursor lesions, 3
cisplatin plus doxorubicin, 113, 115 reproductive trends, 2
cisplatin plus paclitaxel, 113, 115 survival trend, 2
platinum-based combination, 113 timely assessment, 4
diagnosis, 110 Women’s Health Initiative, 3
hormonal therapy
aromatase inhibitors, 113
parenteral and oral drugs, 112 T
progestational agents, 112 Tamoxifen, 112
tamoxifen, 112 induced cystic hyperplasia, 43
isolated vaginal vault recurrences, 111–112 The Cancer Genome Atlas (TCGA), 8
second-line therapy, 116–117 Transitional cell carcinoma, 36
surgery role, 112
temsirolimus, 117
women, treatment, 110 U
Robotic-assisted surgery Undifferentiated carcinoma, 36
applications, 70 Uterine sarcoma, 8, 43
binocular stereoscopic 3D vision, 70
efficacy of, 81–82
vs. laparoscopic surgery, 123 V
learning curve, 79–80 Vaginal brachytherapy (VBT), 7, 124
limitations of, 82–83 Vaginal-cervical Ahluwalia retractor-elevator
motion scaling and precision, 71 (VCARE) uterine manipulator, 73
obesity, 78–79 Vaginal vault recurrences, isolated
survival analysis, 80 pelvic exenteration, 111
radiation therapy, 111
tailored treatment approaches, 111–112
S Villoglandular carcinoma, 34
Secretory carcinoma, 34
Sentinel node mapping for uterine cancer, 62–63
Serous carcinoma, 8, 15, 35, 37, 38, 87, 94, 102
Small cell carcinoma, 36 W
Squamous cell carcinoma (SCC), 36 WHO schema classification, 20, 29