Review Article

CURRENT
STATUS
OF
ENDOMETRIAL
( RISK TO RECURRENCE )
CHHABRA

S*,

TEMBHARE

CARCINOMA

A **
ABSTRACT

In some parts of world endometrial cancer (En Ca) accounts for 4-8% of all Ca, fourth
position aftger breast, colon lung cancers, in others is less common, lowest rates in India, Southeast
Asia. Morbidity, mortality is low because most patients present at early stage for abnormal bleeding
though pain also could be there. It was believed that En Ca represents a continuum from benign
cystic hyperplasia to complex atypical hyperplasia (CAH), but recent concepts are En hyperplasia
& Ca may be two different entities.
Screening for En Ca is not cost effective; therefore assessing risk is essential. It needs to be
clinically staged for appropriate management. In 94% and 75% cases of atypical hyperplasia and
well differentiated En Ca in younger women who wish to preserve their fertility progestins result in
complete regression of disease respectively. Studies have shown that patients of hyperplasia without
atypia respond well (>80%) to progestin, are not at increased risk of Ca but with atypia 50%
respond. Treatment is mainly surgical, based on stage. Radiotherapy, Chemotherapy (hormones
and cytotoxic drugs) are needed in advanced cases.

differences in the distribution of known risk

factors among different races6. Creaseman et al4
have reported that 75% women are postmenopausal,
only 3-10% less than 40 years.
Overall morbidity and mortality of En
Ca is low because most patients present at early
stage because of abnormal bleeding7, but it is
associated with an approximately fourfold
increase in mortality with ovarian cancer and
twofold increase in mortality with breast cancer.

Introduction
In some parts of the world endometrial
cancer (En Ca) accounts for 4-8% of all Ca, fourth
position after breast, colon and lung cancers
and approximately 7400 die form the disease1,2,
in other parts it is the second most common
malignancy in female hereditary non-polyposis
colorectal cancers (HNPCC)3 or the most common
gynaecological cancer (Gyn ca)4 and the fourth
leading Ca in comen with 35000 new cases and
3000 deaths each year in the United States5.
However in some parts En Ca is less common,
lowest rates are from India, Southeast Asia as a
whole4. Some studies have examined differences
in En Ca risk among ethnic groups in the United
States which do not seem to be explained by

Risk /Protective Factors

Increased or prolonged estrogen exposure,
either because of early menarche or late menopause,
obesity, nulliparity, anovulation, estrogen producing
neoplasms or unopposed exogenous estrogen
including tamoxifen therapy place a woman at
increased risk of En Ca, though 35% patients

* Director Prof. ** Resident, Deptt. of Obs & Gyne,

MGIMS

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Chhabra S et al

growth factor I, retinaldehyde dehydrogenase

type II, secreted frizzled-related protein 4 and
anti-LeY monoclonal antibodies (diagnosed by
immunocytochemical cytology) whose expression
is altered in cases of endometrial hyperplsia or
cancer may be promising early stage tumor
markers17. Polycystic ovary disease and subfertility
have been found significantly more in cases with
cytological atypia; however, they not significant
in cases with carcinoma.

with En Ca show no signs of obesity or hyperestrogenism. Hormone replacement therapy (HRT)

with estrogen is associated with an eightfold
increased incidence but the addition of progestin
decreases this risk dramatically8. Epidemiological
studies indicate that estrogens, endogenous and
exogenous, have a major role in En Ca9. Diabetes
has also been associated with increased risk of
En Ca in some epidemiological studies. The high
diabetes prevalence and mortality among women
with En Ca suggests that weight control and
regular physical activity are important10. Women
with En Ca show higher mean BMI and Waist
Hip Ratio (WHR) than who do not have11. With
family history of En Ca or breast Ca, risk is more.
Radiation, hypertension are also predisposing
factors12,13. Given the observed association between
obesity and En Ca, it is important to understand
how weight loss among obese women may affect
their risk of developing En Ca13.

Screening, Symptoms, Signs and Diagnosis

Population screening for En Ca is not cost
effective; therefore assessing the risk is essential.
If there are symptoms, but an adequate pelvic
examination is not possible or the woman has risk
factors, transvaginal ultrasonography (TVS) is
advocated. Perimenopausal women with abnormal
uterine bleding(AUB), Postmenopausal Bleeding
(PMB), low abdominal pain with a enlarged
uterus need to be evaluated. En Ca, precancerous
conditions typically result in endometrium
greater than 10-12mm. The risk of ca is around
5% in women who have endometrial fluid on
ultrasound. Sonohysterography can distinguish
endometrium from small polyps & leiomyomas
which are sometimes missed during endometrial
biopsy18, however because of possibilities of
peritoneal dissemintion of malignant cells,
sonohysterography and hysteroscopy are not
advocated. A patient who has AUB and a
thickened endometrium should be rebiopsied if
initial biopsy is negative or nondiagnostic. Gull
et al19 have evaluated 394 women with PMB and
reported relative risk for En Ca 63.9% compared
with 22.7% in the age-matched general population.
Thegold standard continues to be histopathology
of En and the final histopathology of the
hysterectomy specimen. Endometrial/endocervical

Low parity, lactation, use of combined

oral contraceptives (COC), a diet low in fat and
high in plant foods, and physical activity decrease
the risk13, OCP use for 5 yers or more reduces
the risk by 50%14. Weiderpass et al14 have reported
10% decreased risk per year of COC utilization
for atypical hyperplasia as well as for all grades
of invasive cancers. The risk is slightly less in
cigarette smokers15.
Pathogenesis
Earlier it was hypothesized that En Ca
represents a continuum from benign cystic
hyperplasia to complex atypical hyperplasia
(CAH), however Berek et al16 have suggested that
En hyperplasia & Ca may be two different entities,
the distinguishing feature being the presence or
absence of cytologic atypia. Recent studies suggest
that biomarkers progesterone receptor, insulin-like
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Current Status of Endometrial carcinoma (Risk to Recurrence)

curettage is also warranted in asymptomatic

postmenopausal women who have endometrial
cells on Paps smear. Some opine that D and C is
a blind technique that often samples less than half
the endometrium. MRI has an overall accuracy
for deep myometrial invasion with sensitivity of
88-90%, especially contrast enhanced MRI20.
Elevated CA 125 levels correlate well with the
clinincal course and help in diagnosis of recurrent
tumor but may be normal in small recurrences22.
Leeuw et al21 have reported that the Micro
satellite instability (MSI) analysis and immunohistochemical examinations using hMLH1,
hMSH2, and hMSH6 are highly effective. MSI
has been found in approximately 30% cases.

cases of atypical hyperplasia and well differentiated

En Ca in younger women who wish to preserve
their fertility respectively24. However, medical
therapy may not be justified if fertility is not an
issue, especially if risk factors are present. The
cytostatic agents most frequently used are
medroxyprogesterone acetate, megestrol & 17
hydroxyl progesterone. Recent studies reveal that
progestin alone is as effective as either tamoxifen
or gonadotropin- releasing hormone (GnRH)
analogues plus progestins25. The duration of
therapy varies from three months to one year or
longer medroxyprogesterone acetate, in a dosage
of 10mg daily, or norethindrone acetate, in a
dosage of 2.5mg daily for a minimum of 12 to 14
days per month.

Types

Studies have shown that patients of

hyperplasia without atypia respond well (more
than 80%) to progestin and are not at increased
risk of Ca but with atypia only 50% show
response and Ca develops in 25%, in 50% with
adenomatous hyperplasia and atypia. Actually
30 to 50% women could have simultaneous
invasive ca26. However, some reports reveal that
complex atypical hyperplasia (CAH) also
regresses and only 10-12% ultimately progress
to Ca27.

Most patients with En Ca are adenocarcinoma

(61-71%), some adenosqamous Ca; adenoacanthoma
(14-24%) and rest are papillary serous tumour &
clear cell carcinoma22.
STAGING
En Ca need to be clinically staged for
appropriate management. FIGO advocates surgical
staging also in addition to clinical. Surgical
staging is by laparotomy with details of possible
invsion and thorough bilateral pelvic and
paraaortic lymph-node sampling23. Patients
with superficial invasion) of uterus and grade
I pathology have a very low risk of pelvic or
para-aortic metastasis, those with intermediate
risk (one-half invasion and grade 2 histology
intermediate) have 3 to 6% of pelvic nodal
involvement and 2% risk of para-aortic metastasis.

THERAPY
Surgery
Treatment is mainly surgical, the extent
based on the stage of disease. Pelvic and para-aortic
lymphadenectomy need to be performed in the
intermediate and high risk cases. Some recommend
para-aortic node dissection, if there are
suspiciously enlarged pelvic nodes, gross adnexal
metastasis or when there is outer one third
myometrial invasion28. While lymph nodes that
are suspicious on palpation or grossly enlarged

Prevention
Treatment with progestins results in
complete regression of disease in 94% and 75%
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Chhabra S et al

Laparoscopic management
Laparoscopic surgical staging is believed
to be as safe as an open procedure. The five year
survival rate of 93-95% is also comparable to the
traditional staging laparotomy & hysterectomy30
however significant complications can occur
and careful selection is essential. Gynaecology
oncology group(GOG) has initiated a study for
the feasibility and efficacy of laparoscopic
surgical staging and therapy of E Ca31.

are important, fewer than 10% of patients with

lymphnode involvement have grossly enlarged
nodes. Therefore, it is important to determine
the need for lymphadenectomy based on clinical
and histologic factors. Some believe that the high
risk factors for pelvic lymph node metastasis
include deddifferentiation, deep myometrium
invasion, cervical involvement, positive peritoneal
cytology, adnexal metastasis and distant spread.
There are reports that pelvic lymphadenectomy
does not improve the prognosis22.

Chemotherapy
Because tumor response to cytotoxic
chemotherapy has been poor, chemotherapy is
used only as adjuvant or palliation. Progestins
have been used to treat recurrent disease, but the
response rates have been poor32. Systemic
chemotherapy is reserved in case of disseminated
primary disease or extrapelvic recurrence and
although the combination of cisplatin and
doxorubicin is commonly used. carboplatin and
paclitaxel combination represent an efficacious,
low-toxicity regimen30.

Radiotherapy
Pelvic radiotherapy (RT) is advocated
but increases treatment related morbidity.
Servere complications have been reported in 3%
and 20% in mild. Extended-field radiation
should be considered only for patients with
histologically positive lymph nodes. Papillary and
clear cell types need to be treated like ovarian
carcinoma.
In stage II disease with preoperative
brachytherapy followed by appropriate surgery,
five years disease free survival (DFS) is 80-90% in
most studies. Some believe that post operative
radiation should be considered in high risk
histologic types either simple vaginal vault
irradiation or external pelvic irradiation with or
without extended abdominal irradiation (based
on the extent of disease).17 The addition of vginal
cuff brachytherapy boost to pelvic radiation for
pelvic control or disease free survival is not
recommended29.

Prognosis and Recurrence

Factors which affect prognosis are age,
medical conditions, tumour size, stage, and
abnormalities on pelvic examination, tumour
grade, and histologic subtype. Some studies have
revealed that there is no association between
recurrence and the clinicopathologic variables
such as age at diagnosis, body mass index (BMI),
histologic grade of tumor, histologic type, stage,
depth of myometrial invasion, or whether the
patient received adjuvant radiotherapy33. Cervical
involvement carries worse prognosis, with 5 year
DFS ranging from 45-60%24. In adenocarcinoma
and adenocanthoma with appropriate management.
5 years Disease Free Survival (DFS) is 88-91%,
with adenosquamous tumours, 62% and 45%

Stage III & IV cases are usually treated

with individualized multimodal approach, with
post operative pelvic radiotherapy, or using
initial cytotoxic or hormonal therapy with or
without radiation with local control of pain or
bleeding.
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Current Status of Endometrial carcinoma (Risk to Recurrence)

5. Walsh C, Holschneider C, Hoang Y et al. Co-existing

ovarian malgnancy in young women with
endometrial cancer. Obstetrics and Gynaecology
2005; 106: 693-9.

with papillary serous tumours, clear-cell carcinoma

respectively. Patients with locally advanced disease
have aq 5 year survival of 4-44%. In most patients
with recurrence, the disease recurs at a distant site
and is thus incurable. Total pelvic exenteration
is an option for patients who have a vaginal cuff
recurrence after radiation therapy. Offering HRT
to survivors is controversial. Additionally 75% of
En Ca present with localized disease with potential
for significant survival. So the balance of potential
and theoretical risk of disease recurrence with
HRT against the believed benefits is crucial37.
Further it is currently believed that the recurrence
ca may not be neocarcinogenesis, but is the
clinical manifestation of micrometastasis that were
either not detected or not treated successfully at
the time of initial therapy2.
En Ca is less common in developing
countries including India, however longetivity is
increasing, so the number of elderly women is
going to be more with possibilities of more cases
of En Ca. Suspicion helps in timely diagnosis
and therapy with better survival. However there
are grey areas, so research needs to be continued.

6. Setiawan, Veronica wendy 1: Pike, Malcolm C. 1:

Kolonel, Laurence N, 2: Nomura, Abraham M. 2:
Goodman, Marc T. 2: Henderson, Brian E, 1:
Racial/Ethnic Differences in Endometrial
Cancer Risk: The Multiethnic Cohort Study. Am J.
of Epidemiology 165(3), 2007, 262-27.
7.

David S, Miller Should we ofer HRT to ovarian

and endometrial cancer survivors? Curr Opin Obstet
Gynaecol, 2001; 10(1): 9-14.

8. Bergan L. Beilen M.L.R. Galee M.P.W, YHollera

H. Benraade JK. Van leeuwen E. Risk &
Prognosis of endometrial carcinoma after - for
breast carcinoma. The Lancet; 2000, 356-881.
9. Wild SH, Finalyson AR, Bryden JR, Lee RJ, Bishop
JL, Byrne CD and Brewster DH. Cancer,
cardiovascular disease and diabetes mortality
among women with a history of endometrial
cancer. Br J Cancer (2007), 96, 1747-1749.
10. Kristin E, Anderson, Elizabeth Anderson, Pamela
J. Mink, Ching Pong Hong, Lawerence H. Kushi
Thomas A, Sellers, DeAnn Lazovich, and Aaron
R, Folsom. Diabetes and Endometrial Cancer in
the lowa womens Health Study. Cancer Epidemiology,
Biomarkers and Prevention 10, 611-616, 2001.

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