3. Pathology of the female reproductive tract 3

Question 1

What is the most common presentation of endometrial cancer?

Answer 1

post-menopausal bleeding - 80% of women with endometrial cancer present with this

Tells us that most women with endometrial cancer are post-menopausal and that we should always investigate post menopausal bleeding

Question 2

Describe the endometrium

Answer 2

Composed of glands in a specialised stroma with a specialised blood supply
Growth, maturation and regression of all three components is co-ordinated during each menstrual cycle

Question 3

What tissue type most commonly gives rise to 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

*morphology means microscopic appearance

Question 6

What do endometrioid adenocarcinomas look like?

Answer 6

Endometrioid because it looks like endometrium

Named for the resemblance of malignant glands to ordinary endometrial glands

Question 7

Why are the adenocarcinoma subtypes named endometrioid, serious, clear cell?

Answer 7

Endometrioid cancers show differentiation that resembles endometrial glands

Serous cancers were thought to resemble Fallopian tube epithelium

Clear cell cancers have clear cytoplasm

Question 8

Why is naming adenocarcinomas tricky?

Answer 8

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

We know that there are different microscopic morphologic types of endometrial adenocarcinoma.
Does the appearance of the tumours reflect any biological difference in their cause and behaviour?

Question 9

How do the two main groups of women with endometrial adenocarcinoma differ?

Answer 9

The two groups differ with respect to
Cause
Age
Morphologic types of tumour
Molecular genetic abnormalities
Precursor lesions
Prognosis and treatment

Question 10

Type 1 of women who typically get endometrial cancer

Answer 10

50s – 60s
Obesitycommon
Estrogenic stimulation common
Endometrial background -anovulatory
Precursor lesion - EIN, atypical hyperplasia
Transition - Slow
Type - Endometrioid
Molecular genetics -MSI, PTEN, PAX2 loss
Familial - HNPCC
Spread - Lymph nodes
Concurrent ovarian ca is common
Prognosis - Good

Question 11

Type 2 of women who get endometrial cancers

Answer 11

60s – 70s
Obesity uncommon
Estrogenic stimulation uncommon
Endometrial background- atrophic
Precursor lesion - EIC
Transition - unknown
Type- Serous, mixed
Molecular genetics - P53 mut, 1p deletion, PAX2 loss

Spread- Peritoneum
Concurrent ovarian ca is uncommon
Prognosis is poor

Question 12

What is the TCGA

Answer 12

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 13

TCGA endometrial cancers

Answer 13

Ultramutated cancers (DNA pol epsilon mutations) 7%

Hypermutated cancers (defective mismatch repair and microsatelite instability) 28%

Endometrial cancers with low frequency of DNA copy number alterations 39%

Endometrial cancers with high frequency of DNA copy number alterations 26%

Question 14

Precursor lesions in endometrial adenocarcinoma

Answer 14

In the cervix, we recognize a precursor lesion to invasive squamous cell carcinoma
Cervical Intra-Epithelial Neoplasia (CIN)
The disease process is called dysplasia

How do we detect CIN and treat it to prevent cervical carcinoma?

Question 15

Most common type of precursor lesion in endometrium

Answer 15

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 16

The women at risk of endometrial adenocarcinoma

Answer 16

Most common invasive cancer of the female genital tract in UK
Fourth 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 (c80%)

Question 17

Risk factor for endometrial cancer

Answer 17

Endogenous hormones and reproductive factors
Excess body weight
Diabetes mellitus and insulin
Exogenous hormones & modulators
Ethnicity
Familial (Cowden’s syndrome; HNPCC)
Smoking not a risk

Question 18

How do endogenous hormones contribute to endometrial cancer risk?

Answer 18

Excess exposure to estrogen unopposed by progestagens
Overweight increases estrogen levels in post menopausal women
Overweight can disrupt ovulation and progestagen production in pre menopausal women
Polycystic ovarian disease
Some rare ovarian neoplasms can produce estrogens

Question 19

Reproduction as a risk factor for endometrial cancer

Answer 19

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 20

Excess body weight as a risk factor for endometrial cancer

Answer 20

c 34 % endometrial cancers are linked to excess body weight
2-3 times increased risk in overweight women
Increased risk begins with a moderately elevated BMI
Central adiposity (waist circumference and waist:hip ratios) may be more important than BMI

Question 21

Diabetes mellitus as a risk factor for endometrial cancer

Answer 21

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 estrogen on the endometrium

Question 22

Exogenous hormones and modulators as a risk factor

Answer 22

Hormone replacement therapy
- Unopposed estrogen (RR 6.0)
Tamoxifen (RR 2.0)

Question 23

Ethnicity as a risk factor

Answer 23

US studies show endometrial carcinoma is less common in African American women
13 per 105 in African-American women
23 per 105 in white 
BUT this group has higher mortality (x4)
Many variables involved
Later stage at diagnosis
Unfavourable tumour type
Sociodemographic factors and treatment
Comorbidities

Question 24

Parameters informing behaviour and treatment

Answer 24

There are three tumour-specific parameters
Tumour type
Tumour grade
Tumour stage

Question 25

Grading neoplasms

Answer 25

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 26

Grading endometrial carcinoma

Answer 26

Normal endometrial epithelium matures to form glands
Adenocarcinomas also form glands
The fraction of the tumour forming glands is estimated as a percentage
(then divided into three groups)
Tumour grade affects prognosis

Question 27

Staging systems

Answer 27

For all neoplasms 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 28

Spread of endometrial carcinoma

Answer 28

Because endometrium has its own stroma, initially malignant glands invade endometrial stroma
Then spreads into the myometrium
Down into the cervix
Where it reaches vessels and spreads via lymphatics or veins to nodes or vagina

Question 29

FIGO staging of endometrial carcinoma

Answer 29

Stage 1: Confined to corpus
Stage 2: Involving cervix
Stage 3: Serosa/Adnexa/Vagina/Lymph Nodes
Stage 4: Bladder, Bowel, Distant Metastasis

Question 30

Endometrial cancer overview

Answer 30

Over 80% of women with endometrial cancer present with post menopausal bleeding
Most ‘endometrial cancers’ arise from endometrial glands and are adenocarcinomas
There are several different types of adenocarcinoma – the most common is called endometrioid because it resembles endometrial glands

Question 31

How can other types of endomtrial (non endometrioid) adenocarcinomas be recognised?

Answer 31

Other types of endometrial adenocarcinoma can be recognized microscopically
These may have distinct molecular abnormalities and behaviour
Recognizing different types of adenocarcinoma benefits patients since it informs likely prognosis and treatment

Question 32

Endometrioid cancer precursors

Answer 32

Endometrioid cancer has a precursor lesion called atypical hyperplasia
Tumour grading estimates the degree to which the neoplasm matures and informs prognosis and treatment
Tumour staging demonstrates the extent to which a neoplasm has spread and informs prognosis and treatment