EPIDEMIOLOGY AND MOLECULAR

PATHOGENESIS OF ENDOMETRIAL

CANCER

DR. N. SRAVANTHI

Incidence

Estimated new cases and deaths from endometrial (uterine corpus)

cancer in the United States in 2015

New cases: 54,870.

Deaths: 10,170.

Most common gynecologic malignancy in the United States and

accounts for 6% of all cancers in women.

Cancer Facts and Figures 2015. Atlanta

American Cancer Society, 2015.

Developed countries

Most common malignancy of female genital tract

Fourth most common cancer in women

(Breast>Lung>Colorectal)

Developing countries

4-5 times lower rates

India & South-Asia with lowest rates

GLOBOCAN – 2012Estimated age standardized incidence and mortality rates:

women (WORLD)

GLOBOCAN – 2012Estimated age standardized incidence and mortality rates:

women (INDIA)Incidence Mortality 5-year prevalence

GLOBOCAN – 2012Estimated age standardized incidence and mortality rates: women

WORLD INDIA

SEER Stat Fact Sheets: Endometrial

Cancer

● Constitutes 3.2% of all new cancer cases

● 1.5% of all cancer deaths

● 5-years survival rate of 81.5%

SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Females.

Rates are Age-Adjusted

Lifetime Risk of Developing Cancer: Approximately 2.7 percent of

women will be diagnosed with endometrial cancer at some point

during their lifetime, based on 2009-2011 data.

Prevalence of this cancer: In 2011, there were an estimated

610,804 women living with endometrial cancer in the United

States.

Surveillance, Epidemiology, and End Results Program

AGE

Most frequently diagnosed among women

aged 55-64.

Median age at diagnosis is 62years.

SURVIVAL For endometrial cancer, 67.9% are diagnosed at the local

stage.

The 5-year survival for localized endometrial cancer is 95.1%.

Overall 5-year survival rate is 81.5%.

(Based on data from SEER 18 2004-2010)

SEER 18 2004-2010, All Races, Females by SEER

Summary Stage 2000

5-year relative survival rates in the US by FIGO stage

Stage 5-year survival rate

I-A 88%

I-B 75%

II 69%

III-A 58%

III-B 50%

III-C 47%

IV-A 17%

IV-B 15%

“Survival by stage of endometrial cancer”.

American cancer society. March 2014

Mortality

The percent of endometrial cancer deaths is

highest among women aged 65-74.

Median age at death is 71 years

SEER 18 U.S. 2007-2011, All Races, Females

Risk factors

CHARACTERISTICS RELATIVE RISK

Nulliparity 2-3

Late Menopause (>52years) 2.4

Obesity (21-50 lb overweight ) 3

Obesity (>50 lb overweight) 10

Diabetes Mellitus 2.8

Unopposed Estrogen Therapy 4 - 8

Tamoxifene 2 .3

Atypical Endometrial Hyperplasia 8 - 29

Lynch II Syndrome 20

ROLE OF ESTROGEN Estrogen stimulation – growth & proliferation of endometrium

Progesterone (Corpus luteum) – inhibits proliferation of the

endometrium & stimulates secretions in the glands &

predecidual changes

Continuous estrogen stimulation of the endometrium bypasses

the normal recycling of the endometrium.

Transitions in women’s life – with absence of ovulation

predisposes to unopposed estrogen stimulation e.g. menarche,

menopause, PCOS & obesity.

ESTROGENS

Mitogenic effect on

endometrium

Higher rate of proliferation

Increased frequency of

Spontaneous mutations

Presence of estrogens may

facilitate “Clonal

expansion” of the genetic

damage occurred

PROGESTINS

Down regulate estrogen

receptor levels

Decrease proliferation

Increase Apoptosis

TAMOXIFENE

selective estrogen receptor modulators or SERMs.

acts like estrogen on some tissues in the body, such as the

uterus,

Blocks the effects of estrogen on other tissues, such as

the breast.

Used to prevent breast cancer in women who are at high risk

for the disease.

Relative risk of 2-3 for development of endometrial cancer while

receiving Tamoxifene

Obesity

Peripheral conversion of androgens secreted in adrenals &

ovaries into estrone (by the enzyme aromatase).

Amount of body fat – associated with decreased circulating

levels of both progesterone & Sex- hormone binding

globulin (SHBG).

Lower SHBG – Higher endogenous production of non-

protein bound estradiol.

PROTECTIVE FACTORS Combination oral contraceptives

(0.5 relative risk when used at least for 12months)

Addition of progestin appears to be protective

PROTECTIVE FACTORS Physical activity

Pregnancy and breast-feeding

Diet

low in saturated fats and high in fruits and vegetables

soy - based foods

Smoking – Lowers estrogen & protects against endometrial cancer

(But cannot be encouraged as a protective measure for obvious reasons)

Molecular PathogenesisTYPE I

(Endometrioid)

TYPE II

(Non - Endometrioid)

75% - 85% cases 15%

Younger women Older women

Perimenopausal Postmenopausal

H/o Unopposed Estrogen Therapy Without Estrogenic stimulus

Better differentiated Less differentiated

More favorable prognosis Poorer prognosis

Microsatellite instability & mutation in PTEN, PIK3CA, K - ras &

β - catenins

P-53 mutations & chromosome instability

TCGA – The Cancer Genome Atlas Project

Four broad categories of endometrial cancers were identified

1. Microsatellite instability cancers :

• Predominantly Endometrioid tumors.

• Mutation rates 10 fold higher

• Frequent K-ras mutation

2. Microsatellite stable cancers – Low CNV:

• High frequency mutation in beta-catenins (CTNNB1-

involved in cell-cell adhesions & WNT Signaling

pathway

TCGA – The Cancer Genome Atlas Project

3. Microsatellite stable cancers – High CNV:

• Frequent TP53 mutations

• Serous & Grade 3 Endometrioid tumors

• Share molecular features with High grade serous ovarian ca

& basal like breast Ca

4. Ultrahigh mutation rate cancers (more than 100 fold) –

• Mutation in POLE – a catalytic subunit of DNA polymerase

epsilon

• Also been associated in colorectal cancers.

LYNCH SYNDROME

In the United States, about 140,000 new cases of colorectal

cancer are diagnosed each year. Approximately 3 to 5

percent of these cancers are caused by Lynch syndrome.

Characterized by an increased risk for colon cancer and

cancers of the endometrium, ovary, stomach, small

intestine, hepatobiliary tract, urinary tract, brain, and skin.

LYNCH SYNDROME

Hereditary Non - Polyposis Colorectal cancer (HNPCC)

Autosomal dominant pattern of inheritance

caused by a germline mutation (i.e. pathogenic variant

in the germline) in a mismatch repair genes (MSH2,MLH1

MSH6, MSH3, PMS1 & PMS 2) and associated with tumors

exhibiting microsatellite instability (MSI).

Most cases result from alterations in MSH2 and MLH 1

Loss of mismatch repair

Mutator Phenotype

Accumulation of genetic mutations

through out the genome (in repetitive

DNA sequences -MICROSATELLITES )

Accumulation of Mutations in

Tumor-suppressor gene

Accelerated malignant

transformation

LYNCH SYNDROME – Genetic screening

Analysis of cancers for microsatellite instability

MSI (Microsatellite instability) seen in >90% of colonic

cancers % in >75% of endometrial cancers

Overall only 20%-25% of endometrial cancers exhibit MSI -

Majority of cases – Silencing of MLH 1 gene because of a

promoter methylation rather than germline mutation.

LYNCH SYNDROME

Following life time risks for cancer are seen:

o 52%-82% for colorectal cancer (mean age at diagnosis 44-61 years);

o 25%-60% for endometrial cancer in women (mean age at diagnosis

48-62 years);

o 6% to 13% for gastric cancer (mean age at diagnosis 56 years); and

o 4%-12% for ovarian cancer (mean age at diagnosis 42.5 years;

approximately 30% are diagnosed before age 40 years).

Mean age of onset of endometrial cancer – Before

menopause(often before 40years)

Clinical features are similar to the sporadic cases.

Well differentiated & Endometrioid type & early stages.

Survival is approximately 90%

SURVEILLANCE & PREVENTION IN

HIGH RISK POPULATION

Annual

Pelvic examination

Transvaginal Ultrasound

Endometrial biopsy – Beginning from 30 -35years of Age.

Guidelines for the clinical management of Lynch syndrome (HNPCC)

J Med Genet 2007; 44:353 – 362

Role of hysterectomy!!

THANK YOU