3. Pathology of the female reproductive tract 3 Flashcards
What is the most common presentation of endometrial cancer?
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
Describe the endometrium
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
What tissue type most commonly gives rise to endometrial cancer
The predominant endometrial cancer arises in the glands of the endometrium
Malignant neoplasm of glandular epithelium = adenocarcinoma
Adenocarcinomas
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.
subtypes of endometrial adenocarcinoma by morphology
Endometrioid Serous Clear cell Mixed (components of the previous 3) Undifferentiated Carcinosarcomas
*morphology means microscopic appearance
What do endometrioid adenocarcinomas look like?
Endometrioid because it looks like endometrium
Named for the resemblance of malignant glands to ordinary endometrial glands
Why are the adenocarcinoma subtypes named endometrioid, serious, clear cell?
Endometrioid cancers show differentiation that resembles endometrial glands
Serous cancers were thought to resemble Fallopian tube epithelium
Clear cell cancers have clear cytoplasm
Why is naming adenocarcinomas tricky?
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?
How do the two main groups of women with endometrial adenocarcinoma differ?
The two groups differ with respect to Cause Age Morphologic types of tumour Molecular genetic abnormalities Precursor lesions Prognosis and treatment
Type 1 of women who typically get endometrial cancer
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
Type 2 of women who get endometrial cancers
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
What is the TCGA
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
TCGA endometrial cancers
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%
Precursor lesions in endometrial adenocarcinoma
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?
Most common type of precursor lesion in endometrium
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
The women at risk of endometrial adenocarcinoma
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%)
Risk factor for endometrial cancer
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
How do endogenous hormones contribute to endometrial cancer risk?
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
Reproduction as a risk factor for endometrial cancer
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)
Excess body weight as a risk factor for endometrial cancer
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
Diabetes mellitus as a risk factor for endometrial cancer
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
Exogenous hormones and modulators as a risk factor
Hormone replacement therapy
- Unopposed estrogen (RR 6.0)
Tamoxifen (RR 2.0)
Ethnicity as a risk factor
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
Parameters informing behaviour and treatment
There are three tumour-specific parameters
Tumour type
Tumour grade
Tumour stage
Grading neoplasms
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
Grading endometrial carcinoma
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
Staging systems
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
Spread of endometrial carcinoma
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
FIGO staging of endometrial carcinoma
Stage 1: Confined to corpus
Stage 2: Involving cervix
Stage 3: Serosa/Adnexa/Vagina/Lymph Nodes
Stage 4: Bladder, Bowel, Distant Metastasis
Endometrial cancer overview
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
How can other types of endomtrial (non endometrioid) adenocarcinomas be recognised?
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
Endometrioid cancer precursors
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
