L3 - Pathology of the female reproductive tracts

Question 1

What do over 80% of women with endometrial cancer present with?

Answer 1

Post menopausal bleeding

Question 2

Endometrium

Answer 2

Composed of glands in a specialised storm with a specialised blood supply

Growth, maturation and regression of all three components is co-ordinated during each menstrual cycle

Question 3

Endometrial cancer

Answer 3

The predominant endometrial cancer arises in the glands of the endometrium

Malignant neoplasm of glandular epithelium = adenocarcinoma

Question 4

Adenocarcinomas

Answer 4

Adenocarcinomas arising at different sites in the body have different risk factors, pathogenesis, appearances, genetic abnormalities, behaviour, prognosis and treatment

Among adenocarcinomas arising at a single site there are multiple subtypes, initially divided by different appearances and increasingly supplemented by understanding molecular genetic pathogenesis

Question 5

Subtypes of endometrial adenocarcinoma by morphology

Answer 5

Endometrioid

Serous

Clear cell

Mixed (components of the previous 3)

Undifferentiated

Carcinosarcomas

Question 6

Why the adenocarcinoma subtypes are named endometrioid, serous, clear cell

Answer 6

Endometrioid cancers show differentiation that resembles endometrial glands

Serous cancers were thought to resemble Fallopian tube epithelium

Clear cell cancers have clear cytoplasm

Question 7

Adenocarcinoma subtypes with similar appearance and the same names occur at other sites

Answer 7

E.g. there is a clear cell carcinoma of the ovary

They are NOT the same disease

If a tumour has spread to other sites it can be very difficult to work out which is the site of origin and which is the site of metastasis

Question 8

Demographic and histologic studies suggest was about endometrial adenocarcinoma?

Answer 8

That there are two types of women that get it

Question 9

The two groups differ with respect to?

Answer 9

Cause

Age

Morphologic types of tumour

Molecular genetic abnormalities

Precursor lesions

Prognosis and treatment

Question 10

Molecular pathology

Answer 10

The cancer genome atlas (TCGA) published an integrated genomic classification of endometrial cancer in 4 groups

Based on integrated genomic, transcriptomic and proteomic characterisation of c370 endometrial carcinomas

Question 11

TCGA Endometrial cancers

Answer 11

1. Ultramutated cancers (DNA pol epsilon mutations) 7%
2. Hypermutated cancers (defective mismatch repair and micro satellite instability) 28%
3. Endometrial cancers with low frequency of DNA copy number alterations 39%
4. Endometrial cancers with high frequency of DNA copy number alterations 26%

Question 12

Precursor lesions in endometrial adenocarcinoma

Answer 12

In the cerivix, we recognise a precursor lesion to invasive squamous cell carcinoma

Cervial Intra-Epithelial neoplasia (CIN)

The disease process is called dysplasia

Question 13

Much less is known about precursor lesions in the endometrium

Answer 13

It is assumed that the common (endometrioid) form of endometrial carcinoma has its origin in a lesion called atypical hyperplasia

This is supported by temporal genetic and morphologic continuity with endometrioid endometrial adenocarcinoma

Question 14

The women at risk of endometrial adenocarcinoma

Answer 14

Most common invasive cancer of the female genital tract in UK

4th most common cancer in women in the UK (breast, lung, colorectum)

Lifetime risk of 1 in 46

Usually arises in postmenopausal women

Peak incidence in the 55-65 y/o age group

Most common presenting feature is postmenopausal bleeding (80%)

Question 15

Endometrial cancer by age

Answer 15

Starts properly rising above 40yrs

Peaks at 60-64

Then decreases

Question 16

Risk factors for endometrial cancer

Answer 16

Endogenous hormones and reproductive factors

Excess body weight

Diabetes mellitus and insulin

Exogenous hormones and modulators

Ethnicity

Familial (Cowden’s syndrome; HNPCC)

Smoking not a risk

Question 17

Endogenous hormones

Answer 17

Excess exposure to oestrogen unopposed by progestogens

Overweight increases oestrogen levels in post menopausal women

Overweight can disrupt ovulation and progestogen production in pre-menopausal women

PCOS

Some rare ovarian neoplasms can produce oestrogens

Question 18

Reproduction

Answer 18

Pregnancy and parity reduce the risk of endometrial cancer

Mechanism includes the break from unopposed oestrogen during pregnancy and the removal of abnormal cells at delivery

Early menarche and late menopause increase risk (reduced by 7% for each year fewer)

Question 19

Excess body weight

Answer 19

34% endometrial cancers are linked to excess body weight

2-3 times increased risk in overweigh women

Increased risk begins with a moderately elevated BMI

Central adiposity (waist circumference and waist:hip ratios) may be more important than BMI

Question 20

Diabetes mellitus and insulin

Answer 20

Women with diabetes mellitus have a two-fold increased risk of endometrial cancer

Hard to separate effect of insulin from excess body weight but a probably direct effect

Insulin and insulin-like growth factors may increase the effects of oestrogen on the endometrium

Question 21

Exogenous hormones and modulators

Answer 21

HRT
-unopposed oestrogen (RR 6.0)

Tamoxifen (RR 2.0)

Question 22

Ethnicity

Answer 22

US studies show endometrial carcinoma is less common in African American women

• 13 per 10^5 in African-American women
• 23 per 10^5 in white

BUT this group has higher mortality (x4)

Many variables involved

• later stage at diagnosis
• unfavourable type
• sociodemographic factors and treatment
• co-morbidities

Question 23

3 tumour-specific parameters

Answer 23

Tumour type

Tumour grade

Tumour stage

Question 24

Grading of neoplasms

Answer 24

Grading reflects how much a tumour resembles its parent tissue

Has to be done on tissue under a microscope

Many use a three-point system

Well differentiated - Grade 1

Moderately differentiated - Grade 2

Poorly differentiated - Grade 3

Question 25

Grading of endometrial carcinoma

Answer 25

Normal endometrial epithelium matures to form glands

Adenocarcinoma also forms glands

The fraction of the tumour forming glands is estimated as a percentage (then divided into 3 groups)

Tumour grade affects prognosis

Question 26

Staging systems

Answer 26

For all neoplasma a T N M system exists

T for tumour: local spread

N for nodes: lymph node deposits

M for metastasis: metastatic deposits

For gynaecological tumours a different system called FIGO is usually used

Question 27

Spread of the endometrial carcinoma

Answer 27

Because endometrium has its own storm, initially malignant glands invade endometrial storm

Then spreads into the myometrium

Down into the cervix

Where it reaches vessels and spreads via lymphatics or veins to nodes or vagina

Question 28

FIGO staging of endometrial carcinoma

Answer 28

Stage 1: confined to corpus

Stage 2: Involving cervix

Stage 3: Serosa/adnexa/vagina/lymph

Stage 4: Bladder, bowel, distant metastasis