Gynaecopathology - Endometrial Cancers

Question 1

What are the symptoms that are associated with uterine cancer

Answer 1

Bleeding

But this can be linked with menopausal women, perimenopausal, or even irregular inter-menstrual bleeding.

Question 2

What is menopause

Answer 2

A conclusion of a long process where we start seeing reduction of hormonal stimulation, so for a certain period of time women may have irregular periods - it is difficult to define a certain time period.

Question 3

What is the myometrium

Answer 3

The thick, muscular middle layer of the uterine wall composed primarily of smooth muscle cells, responsible for uterine contractions during menstruation

Question 4

What is the Stratum Basalis

Answer 4

The deeper, permanent layer of the uterine lining (endometrium) that remains intact during menstruation and serves to regenerate the stratum functionalis (the superficial, shed layer) after each menstrual cycle

Question 5

What is Stratum Functionalis

Answer 5

This is the functional layer, that will change and increase in thickness and increase in complexity of the glands as well as the complexity of the stroma component

Question 6

What are the 3 components of the stratum functionalis

Answer 6

1) The glands

2) The stroma

3) Vascular components which can include inflammatory cells.

Question 7

How are endometrial carcinomas diagnosed

Answer 7

On the basis of morphology

There would also be more frequent bleeding

Question 8

Why is it hard to get a good prognosis on ovary cancer

Answer 8

They are only diagnosed at a later stage due to how hard the symptoms are to spot.

Question 9

What are the risk factors for women developing endometrial cancer younger than age 40

Answer 9

• morbid obesity
• chronic anovulation
• hereditary syndromes

Question 10

How does high BMI lead to endometrial carcinomas

Answer 10

Increased risk of dysregulated endometrial stimulation or hormonal stimulation.

This leads to a lesion that is considered peri-neoplastic such as endometrial hyperplasia.

If this is not treated, it would lead to more endometrial carcinomas

Question 11

What are the symptoms of endometrial carcinomas

Answer 11

• Symptoms are clearer in peri-menopausal or menopausal women as bleeding is more easily associated with this disease rather than having period. But bleeding is still a very vague symptom as this can be caused by:
• a polyp in the endometrial cavity
• a polyp in the cervix
• a random rupture gland
• an Infection

Testing must be done along with some imaging and hysterectomy

Question 12

What are Type 1 endometrial carcinoma tumours

Answer 12

• Low grade
• oestrogen related
• often clinically indolent
• Histotype: endometrioid carcinoma

– cancer that closely resembles the endometrial lining

• the most common type comprising of 75-80%
• affects post-menopausal women
• More frequent in women with increased BMI.

Question 13

What are Type 2 endometrial cancer

Answer 13

• High grade
• Unrelated to oestrogen stimulation
• Aggressive
• Histotype: serous papillary carcinoma 5-10% and clear cell carcinoma 3-5%, affecting post menopausal women (70-80 years of age)

Question 14

What is an endometrioid carcinoma

Answer 14

It is an oestrogen driven carcinoma of the endometrium that has a well-defined precursor lesion

Atypical hyperplasia/endometrioid intraepithelial neoplasia - increased growth and number of cells.

They are arranged in glands (There would be crowding of these glands) sharing similar molecule alterations.

Question 15

What are the risk factors for endometrioid carcinoma

Answer 15

• Higher risk of oestrogen (early menarche/late menopause)
• Nulliparity (anovulatory cycles)
• Obesity
• Tamoxifen
• PCOS

Question 16

What therapy can be administered to these women

Answer 16

Progesterone therapy - these changes would regress
- Exogenous progesterone
- Mirena coil

Question 17

What is Endometrial Intraepithelial Neoplasia (EIN)

Answer 17

This is clonal proliferation of endometrial glands, considered to be a premalignant condition due to its strong association with concurrent and/or subsequent endometrioid Type 1 adenocarcinoma of the endometrium.

Question 18

What is the histology of EIN

Answer 18

There are focal areas of crowding of the glands.

Sometimes there is multiple layers that tend to be rounder rather than columnar.

Sometimes there would be mitotic activity

Question 19

What is the histological criteria of diagnosing EIN

Answer 19

• At least 1mm in greatest linear dimension
• Architecture (area of glands exceeds area of endometrial stroma)
• Cytology (difference in nuclear and cytoplasmic appearance between the abnormal and background endometrium)
• Exclusion of cancer, as well as benign condition mimicking EIN, is an important part of accurate diagnosis.

Question 20

What is endometrial stroma

Answer 20

The connective tissue framework beneath the epithelial lining of the endometrium, the inner lining of the uterus, and is a natural part of the uterus

Question 21

What is the architecture of endometrioid carcinoma

Answer 21

• Confluent or back-to-back glands lack intervening stroma
• Cribriform or microacinar pattern
• Complex papillary, micropapillary or villoglandular

Area of squamous metaplasia, mitotic activity (women in menopause should not be having mitotic activity).

It would have more atypia and a more complex structure in general.

Question 22

What are the cytological features of endometrioid carcinoma

Answer 22

• Resembles proliferative type endometrium with varying degrees of atypia
• Cellular/nuclear enlargement
• Nuclear rounding (not elongated) with large nucleoli with loss of polarity

Question 23

What is the staging system that is used for endometrial cancer

Answer 23

FIGO system

Question 24

What does the FIGO system cover

Answer 24

Talks about the depth of invasion of the tumour within the myometrial wall (the wall of the uterus) - if ti above or below 50%

If it tumour extends to the cervix (if it goes down to the cervix, it gets access to the lymphatics that are around the cervix) which can spread to the lymph nodes in the pelvis.

If it goes into the serosa, it can spread to the other organs.

Question 25

What classifies as lymph-vascular invasion?

Answer 25

When the tumour can become invasive and penetrate the myometrium, and then the lymphatics. This type of invasion would define a more aggressive therapeutic strategy including radiotherapy after surgery

Question 26

What is a serous carcinoma

Answer 26

This is associated with the Type 2 model - This type of tumour grows in papilla and the cells are more distorted than the ones that are seen in endometrial carcinoma. - High grade carcinoma affecting postmenopausal (older than type 1), nonobese women, oestrogen independent

Question 27

What is the architecture of serous carcinoma

Answer 27

- Complex papillary, solid or glandular architecture; similar to ovarian/tubal high grade serous carcinoma - The cells that are seen are more bluish, have more nucleoli and high mitotic activity. They have a much messier arrangement.

Question 28

What is the genetics behind serous carcinoma

Answer 28

- Often harbours mutations in the TP53 (strong and diffuse or complete absence of IHC) - Alteration of PI3K/AKT/mTOR and MAPK pathways – the mutation in P53 is the driving mechanism for serous carcinoma

Question 29

What is the prognosis for serous carcinoma

Answer 29

It is worse than endometrioid carcinoma - even if it was only contained in a polyp and not infiltrative in the wall of the uterus, ti would still have very poor prognosis. It would not stop that tumour from potentially metastasising later on

Question 30

What is clear cell carcinoma

Answer 30

a type of cancer, often appearing in the kidneys or female reproductive organs, where the cancer cells appear clear or "bubble-like" when viewed under a microscope It is less frequent but affects elderly patients This type of tumour is also solid rather than growing in glands

Question 31

What are the characteristics for clear cell carcinoma

Answer 31

- Characteristic morphology clear to eosinophilic cells - Solid architecture more common than papillary - HNF-1B, napsin A and AMACR positive – these are markers that are immunohistochemistry markers. - It must be negative for oestrogen and progesterone. - Within this histotype there can be very different genetic abnormalities - can be any of the 4 molecular subtypes of endometrial carcinoma. This can affect the prognosis

Question 32

What is the significance of POLE mutations in Endometrial carcinoma

Answer 32

POLE mutations cause an accumulation of small mutations, making tumours highly antigenic. They tend to present early, respond well to treatment, and have an excellent prognosis

Question 33

Why doe POLE-mutations have better prognosis

Answer 33

Because they are more antigenic, allowing the immune system to detect and target them more effectively

Question 34

What happens if POLE is wild-type in endometrial cancer classification

Answer 34

The tumour is evaluated for MMR deficiency, which can also guide treatment and prognosis

Question 35

What causes MMR deficiency in endometrial cancer

Answer 35

it can be due to epigenetic silencing (e.g., MLH1 promoter methylation) or inherited mutations, such as those found in Lynch Syndrome

Question 36

What is Lynch Syndrome and how is it related to endometrial cancer

Answer 36

Lynch Syndrome is a genetic condition that increases the risk of several cancers, including colorectal, gastric, and endometrial cancer, due to inherited MMR defects

Question 37

What if both POLE and MMR are normal

Answer 37

The next step is to check for p53 status

Question 38

What does a mutated p53 gene indicate in endometrial cancer

Answer 38

It is a marker for serous carcinoma, which is more aggressive and has a poorer prognosis

Question 39

What does it mean if POLE, MMR and p53 are all normal

Answer 39

There is no clear molecular abnormality, so treatment relies on histology and clinical judgment. Prognosis is harder to predict.

Question 40

What role does the POLE gene play in DNA replication

Answer 40

POLE encodes DNA polymerase epsilon, responsible for leading strand DNA replication and includes a proofreading exonuclease domain to maintain low mutation rates

Question 41

How do POLE mutations affect endometrial cancer prognosis

Answer 41

They improve prognosis by increasing immune due to high mutation loads and regulating cellular metabolism through AMF/AMFR signalling

Question 42

What is AMF/AMFR signalling

Answer 42

a pathway where the autocrine motility factor (AMF), a protein secreted by cancer cells, binds to its receptor, the autocrine motility factor receptor (AMFR), leading to increased cell motility, proliferation, and potentially tumor invasion and metastasis

Question 43

What types of cancer have been associated with POLE mutations

Answer 43

Colorectal Pancreatic Ovarian Gliomas Endometrial cancers

Question 44

What is the current molecular classification of endometrial cancer

Answer 44

Group 1: Pole mutated - good prognosis Group 2: MMR deficient (MMRd) - intermediate prognosis Group 3: Low copy number alteration - intermediate prognosis Group 4: p53 mutant - poor prognosis

Question 45

Why do POLE-mutated tumours evoke a stronger immune response

Answer 45

Due to ultra-high mutation rates that create neoantigens recognisable by the immune system

Question 46

What is the challenge with sampling in endometrial biopsy using pipelle

Answer 46

Small sample sizes can lead to inaccurate diagnosis; serous carcinoma often yields very little tissue, making detection harder

Question 47

How does a sample volume affect endometrial cancer diagnosis

Answer 47

Larger tissues samples are more likely to confirm cancer presence; insufficient tissue may lead to false negatives, especially in aggressive types (serous carcinoma).