Week 6 - D - Uterine cancer - Polpys, Hyperplasia, Endometrioid&Serous Carcinoma, Lynch Syndrome,Other Uterine Tumours

Question 1

What is an endometrial polyp?

Answer 1

An endometrial polyp is a growth in the uterine cavity originating from the endometrial lining itself - malignancy is rare but can happen

Question 2

How is an endometrial polyp different from fibroids? What are uterine fibroids also known as?

Answer 2

An endometrial polyp originates from the endometrial cells A uterine fibroid originates from the smooth muscle of the uterus - also known as leiomyoma

Question 3

What are the symptoms of endometrial polyps and when do they occur?

Answer 3

Polyps are often associated with abnormal uterine bleeding. They can cause bleeding in between periods (intermenstrual bleeding or spotting), irregular periods (metorrhagia), post-coital bleeding (bleeding following intercourse) and post-menopausal bleeding. Occasionally endometrial polyps can also cause severe cramping during menses (dysmenorrhea). Usually occur in women nearing menopause or after menopause

Question 4

Which hormone are uterine polyps sensitive to?

Answer 4

No definitive cause of endometrial polyps is known, but they appear to be affected by hormone levels and grow in response to circulating estrogen

Question 5

Another cause of dyfunctional uterine bleeding is endometrial hyperplasia It can be classified as simple, complex, simple atypical or complex atypical When does it usually progress to cancer?

Picture shows diffence between simple, complex and atypical

Answer 5

Endometrial hyperplasia can progress to cancer usually if it is complex atypical (can progress if simple or complex without atypia but less common)

Question 6

Which is normal, simple or complex?

Answer 6

Normal endometrium - picture on the left Middle - simple endometrial hyperplasia - glands are hyperplastic with a few angular irregularities Right - complex endometrial hyperplasia - overcrowded glands - dont look atypical Complex atypical on left- atypical and overcrowded

Question 7

What is endometrial hyperplasia caused by? How does endometrial hyerplasia usually present?

Answer 7

It is usually caused by excess oestrogen without progesterone ie anovulatory cycles - if no egg is produced there is no corpus luteum to produce progesterone Therefore the oestrogen continues to cause uterine proliferation until it eventually breaksown causing irregular bleeidng Endometrial hyperplasia usually presents with abnormal uterine bleeding (dysfunctional uterine bleeding or postmenopasual bleeding)

Question 8

What thickness of endometrium suggest endometrial cancer pre and post menopausal?

Answer 8

Premenopasual - greater than 16-20mm Post menopasua - greater than 4mm thick if not on hormones

Question 9

Endometrial hyperplasia occurs when the endometrium, the lining of the uterus, becomes too thick. It is not cancer, but in some cases, it can lead to cancer of the uterus. Diagnosing endoemtrial hyperplasia is done using TVUS To distinguish the hyperplasia from cancer, what is carried out?

Answer 9

The only way to tell for certain that cancer is present is to take a small sample of tissue from the endometrium and study it under a microscope. This can be done with an endometrial biopsy, dilation and curettage, or hysteroscopy.

Question 10

As endometrial hyperplasia is usally due to the lack of progesterone, what is the recommended treatment?

Answer 10

Probably IUS but any cyclical progesterone really

Question 11

As stated complex atypical endometrial hyperplasia is the most likely to progress to cancer

What is the mutation that is common in this type of hyperplasia usually causative of endometrioid endometrial carcinoma?

Answer 11

PTEN mutation

Mutation of the PTEN tumor suppressor gene is a frequent event in endometrioid carcinomas

Question 12

What age group is the peak incidence of endometrial carcinoma?

Answer 12

The peak incidence of endometrial carcinoma is ages 50-60 years (it is uncommon below the age of 40)

Question 13

Cancer of the womb (uterus) is a common cancer that affects the female reproductive system. It’s also called uterine cancer and endometrial cancer. Abnormal vaginal bleeding is the most common symptom of womb cancer. If you have postmenopausal vaginal bleeding, or notice a change in the normal pattern of your period, visit your GP. List other condition that the post menopausal bleeding may be due to again?

Answer 13

Endometriosis Fibroids Polyps Endometrial hyperplasia (non cancerous)

Question 14

In young women, consider underlying predisposition e.g. polycystic ovary syndrome or Lynch syndrome What are the signs of polycystic ovarian syndrome?

Answer 14

Polycystic ovarian syndrome - Three main signs are usually - irregular menstrual periods, polycystic ovaries, excess androgen – high levels of “male hormones” in your body, which may cause physical signs such as excess facial or body hair

Question 15

Lynch syndrome is also known as Hereditary nonpolyposis colorectal cancer (HNPCC) WHat are the two most common cancers in this condition? What is the mode of inheritance?

Answer 15

Colorectal cancer is most common Endometrial cancer is the second most common cancer in HNPCC Lynch syndrome is an autosomal dominant genetic condition that has a high risk of colon cancer[1] as well as other cancers including endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin

Question 16

There are two main groups of endometrial cancer with different precursor lesions State the two groups and their precursor lesions?

Answer 16

Endometroid carcinoma - precursor atypical hyperplasia Serous carcinoma - precursor serous intraepithelial carcinoma

Question 17

Endometrial carcinoma generally presents with abnormal bleeding - usually post menopausal How does endometrial carcinoma look macroscopically? How does it look microscopically?

Answer 17

Macroscopic - large uterus, polypoid Micrscopically - mostly adenocarcinoma and most are well differentiated

Question 18

Two main clinico‐pathological types 1. Endometrioid (and mucinous) 2. Serous (and clear cell) How common are both types of endometrial cancer? WHat are the precursor lesions again?

Answer 18

Type 1 * Endometrioid (and mucinous) adenocarcinoma - accounts for 80% of endometrial cancers * Precursor - atypical hyperplasia Type 2 * Serous (and clear cell) adenocarcinoma - accounts for 20% of endometrial cancer * Precurosr - serous intraepithelial carcinoma

Question 19

What are type 1 tumours related to? (hormone, mutations (3 different associations), precursor)

Answer 19

Type 1 tumours- related to unopposed oestrogen and associated with atypical hyperplasia as a precursor lesion Usually have a PTEN, K-ras, PIK3CA mutations

Question 20

What are the type 2 tumours related to? (hormone?, age affected?, mutation?)

Answer 20

Type 2 endometrial carcinomas are not associated with unopposed oestrogen levels

It affects elderly post menopasual women and has an associated with p53 mutations (TP53 - tumour protein 53)

Question 21

Type 1 tumours are also associated with a molecular genetic change causing microsatellite instability (MSI) MSI results from imparied DNA Mismatch repair and therefore leaves you in a state of hypermutability (predisposing to mutation) What syndrome discussed earlier is caused by impaired DNA mismatch repair causing microsatellite instability (MSI)?

Answer 21

This would be Lynch syndrome Hereditary non polyposis colorectal cancer (HNPCC) - causes colorectal cancer as well as many other cancers, endometrial being second most common

Question 22

Endometrial carcinoma type 1 - associated with PTEN, K-Ras, PIK3CA mutations and microsatellite instability

Microsatellite instability due to:

• * Germline mutation of mismatch repair genes (Lynch syndrome)

Which type of endometrial carcinoma is associated with

• * unopposed oestrogen?
• * Atypical hyperplasia?
• * p53 mutation?
• * Is usually superficial?

Answer 22

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Question 23

What is a well known risk factor or endometrial cancer? (not a hormone, more sort of lifestyle aimed)

Answer 23

Obestiy is a well known risk fator for endometrial cancer This excess risk is associated with the endocrine and inflammatory effects of adipose tissue. (Physical inactivity is linked to breast, colon and endometrial cancers)

Question 24

How does the endocrine and inflammatory effects of the adipose tissue cause breast cancer? (focus on the effect of oestogen due to increased adipose tissue on this card)

Answer 24

Adipocytes express aromatase which converts ovarian androgens into oestrogens and oestrgoen causes endometrial proliferation Sex hormone binding globulin is also lower in obese people and therefore there is more free unbound oestrogen circulating

Question 25

How does the endocrine and inflammatory effects of the adipose tissue cause breast cancer? (focus on the effect of insulin due to increased adipose tissue on this card)

Answer 25

Insulin action is often altered in obese people The levels of insulin binding globulin are reduced and there is therefore more free insulin. Insulin/insulin like growth factors (IGF) exert a proliferative effect on the endometrium as well

Question 26

Now discuss how the increase in adipocytes due to obesity increases the risk of endometrial cancer - both oestrogen and insulin effect

Answer 26

Oestrogen * Adipocytes express aromatase that converts ovarian androgens to oestrogen - oestrogen promtoes endometrial proliferation * Sex hormone binding globulin (SHBG) reduced in obese therefore more free circualating oestrgoen Insulin Insulin action often altered in obese. Insulin binding globulin levels reduced & free insulin is elevated. Insulin/IGF exert proliferative effect onendometrium

Question 27

What lifestyle change is associated with a reduction in the risk of endometrial cancer?

Answer 27

Weight loss

Question 28

Apart from unopposed oestrogen and obesity, state some other risk factors for endometrial cancer? What is the drug used to treat brest cancer that can increase the risk of endometrial cancer?

Answer 28

* PCOS * Lynch Syndrome * Age * Nullparity * Diabetes * Endometrial hyerplasia (also polyps and fibroids) * HRT where oestrogen only (only give this in thos who have had a ysterectomy) This drug would be tamoxifen

Question 29

Lynch syndrome (Hereditary non-polyposis colorectal cancer) is a cancer predisposition syndrome - high risk of colorectal cancer. High risk of endometrial cancer (lifetime risk 28%) and an increased probability of developing ovarian cancer. What is the inheritance of this condition? What is the mutation in this condition?

Answer 29

This is an autosomal dominant genetic condition The mutation in this condition is due to an impaired DNA mismatch repair leading to microsatellite instability -this predisposes to genetic mutability

Question 30

Due to the inheritance of a defective DNA mismatch repair gene. Autosomal dominant inheritance. Immunohistochemistry staining of the tumour for mismatch repair proteins can help identify tumours due to Lynch syndrome. What can the cancer be tested for to help with the lynch syndrome identification?

Answer 30

Testing the cancer for microsatellite instability can help with the Lynch syndrome diagnosis

Question 31

Type II endometrial carcinomas include serous and clear cell types What are the mutations here? What is the precursor lesion? Is this more aggresive than Type 1?

Answer 31

Mutations are in the tumour protein 53 (p53 aka TP53) Precursor lesions is serious endometrial intraepithelial carcinoma Spreads along Fallopian tube mucosa and peritoneal surfaces so can present with extrauterine disease It is more aggressive than endometrial/mucinous adenocarcinomas

Question 32

What does endometrioid carcinoma typically infiltrate? (when saying endometrial carcinoma - endometrioid is type 1, serous is type 2)

Answer 32

Typically infiltrates the myometrium Type 2 typically spreads along fallopian tubes or peritoneal spread

Question 33

Prognosis depends on • Stage • Histological grade • Depth of myometrial invasion • Endometrioid carcinoma has good prognosis as usually confined to uterus at presentation What is the usual treatment?

Answer 33

Usual treatment of endometroid carcinoma would be to carry out a total hysterectomy with bilateral salpingo-oopherectomy and/or chemotherapy or radiation

Question 34

The doctor compares the cancerous tissue with healthy tissue. Healthy tissue usually contains many different types of cells grouped together. If the cancer appears similar to healthy tissue and contains different cell groupings, it is called differentiated or a low-grade tumor. If the cancerous tissue looks very different from healthy tissue, it is called poorly differentiated or a high-grade tumor. The cancer’s grade may help the doctor predict how quickly the cancer will spread. How many grades are there for endometrioid cancer?

Answer 34

There are three grades - the lower the grade the better Endometrioid cancers are usually low grade

Question 35

The doctor compares the cancerous tissue with healthy tissue. State the percentages of tumour growth in each of the gradings of endometrial cancer?

Answer 35

Grade 1 - 50% solid tumour growth

Question 36

Serous carcinoma and clear cell carcinoma are not formally graded The staging of endometrial cancers is also done over 4 stages What is stage IA and IB?

Answer 36

Stage IA - cancer is confined to endometrium or has invaded 50% of the myometrium

Question 37

Stage II is when the cancer invades the cervical stroma How is Stage III of endometrial cancer split?

Answer 37

• Stage III - local and or regional spread
• Stage IIIA - Tumour invades serosa of uterus and/or adenexae
• Stage IIIB - Vaginal and/or parametrial involvement
• Stage IIIC1 - Cancer spread to regional pelvic nodes
• Stage IIIC2 - cancer spread to para-aortic lymph nodes

Question 38

Stage IV is split into two also Describe each

Answer 38

Stage IVA - cancer invaded the baldder or rectal mucosa Stage IVB - cancer has distant metastases

Question 39

Run through the staging of endometrial cancer

Answer 39

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Question 40

How do sarcomas arise? What is a carcinoma?

Answer 40

Sarcomas are cancers that start from tissues like muscle, fat, bone, and fibrous tissue (the material that forms tendons and ligaments).

Cancers that start in epithelial cells, the cells that line or cover most organs, are called carcinomas. More than 95% of uterine cancers are carcinomas. If a carcinoma starts in the cervix, it is a cervical carcinoma. Carcinomas starting in the endometrium, the lining of the uterus, are endometrial carcinomas.

Question 41

WHat is the most common uterine sarcoma? (sarcoma - tumour that arises in eg muscle, fat, bone)

Answer 41

The most common uterine sarcoma is the leiomyosarcoma - this is an abnormality of the myometrium Other types include Endometrial stromal sarcoma - this is an abnormality of the endometrium

Question 42

Endometrial stromal sarcoma

• • Low grade endometrial stromal sarcoma
• • High grade endometrial stromal sarcoma (increased atypica, proliferative activity)

What do they often infiltrate?

How do they normally present?

Answer 42

• Often infiltrate the myometrium or lymphovacular spaces
• Can present with abnormal uterine bleeding but normally present at metastases stage - usually to lungs or ovaries
• High-grade ESS means the cancer cells look very different from normal cells, and the tumor is growing quickly. This type of ESS is most often found when the tumor is already large and/or has spread. These tumors are hard to treat.

Question 43

What do carcinosarcomas arise from? Account for <5% of uterine malignancies

Answer 43

These are tumours that have both sarcoma and carcinoma elements Sacroma- arising from connective or any non-epithelial tissue Carcinoma -arising from the epithelial tissue

Question 44

Carcinosarcomas are malignant tumors that consist of a mixture of carcinoma (or epithelial cancer) and sarcoma (or mesenchymal/connective tissue cancer). Carcinosarcomas are rare tumors What is usually the outcome with uterine carcinosarcoma? Is its staging the same or different from endometrial cancers?

Answer 44

It is usually associated with a poor outcome Carcinosarcomas have the same staging as endometrial cancers

Question 45

Leiomyomas are also known as fibroids (uterine leiomyomata) How do they occur?

Answer 45

They occur as tumours of the smooth muscle of the uterus that may grow and bulge into the peritoneum (Subserosal) or the endometrial (submucosal)

Question 46

What is the most common treatment of fibroids in those who are subfertile and wish to have children?

Answer 46

Myomectomy is the treatment of choice in subfertility

Question 47

Leimyosarcoma * A malignant smooth muscle tumour commonly displaying a spindle cell morphology * The most common uterine sarcoma * Accounts for 1-2 % of all uterine malignancies What age group is it common in? What are the symptoms?

Answer 47

Common in those above 50 Most commonly people present with abnormal uterine bleeding, pelvic pain, and palpable pelvic mass

Question 48

Poor prognosis even if confined to uterus at time of diagnosis Overall 5 year survival rates 15-25%, stage is most powerful prognostic factor

How are endometrial stromal sarcomas and leiomyosarcomas staged?

Answer 48

They have a different staging system than endometrial carcinomas (remember serous and clear clear cell endometrial carcinomas arent graded)