Lecture 27 - Ovarian Cancer

Question 1

What are the four stages of ovarian cancer?

Answer 1

Before ovarian cancer: Healthy ovaries
Stage I: Cancer is confined to one or both of the ovaries
Stage II: Cancer spreads within the pelvic
Stage III: Average stage of diagnosis when cancer spreads to other body parts within the abdomen
Stage IV: Cancer spreads beyond the abdomen

Question 2

Is ovarian cancer the same disease?

Answer 2

Molecular and genetic analysis has determined that cancer is not a single disease

Question 3

What are the 5 major histotypes in ovarian cancer (defined by both histology and molecular profiles)?

Answer 3

• High-grade serous carcinoma (>80%)
• Low-grade serous cacinoma
• Endometrioid
• Mucinous
• Clear-cell carcinoma

Question 4

In the past 20 years, how have the survival rates of ovarian cancer changed?

Answer 4

• There has been no change, meaning survival rates have not improved nor have they decreased
• The 5 year survival rate is between 20-40% depending on the histology of cancer

Question 5

Why is it important to learn and identify the different histotypes?

Answer 5

• they all have different metabolic traits

- want to accurately diagnose to provide the proper treatment

Question 6

What are the characteristics of Endometrioid?

Answer 6

• Have tubular glands
• There are solid and cystic regions
• Has an enlarged nuclei and other abnormal features

Question 7

What are the characteristics of Mucinous?

Answer 7

• It has an expansive pattern of invasion
• There are smooth surfaces
• Multi-lobular (several lobes)
• Has a mucin appearance

Question 8

What are the characteristics of Low Grade Serous Carcinoma?

Answer 8

• Glandular lined by bland cells
• Has little mitotic activity
• Has normal nuclear morphology (no enlarged nuclei)

Question 9

What are the characteristics of Clear Cell Ovarian Carcinoma?

Answer 9

• Contains microcystic masses with solid nodules (feels nodule-like)
• Has regions of clear cell-like appearance

Question 10

What are the characteristics of High-Grade Serous Ovarian Carcinoma?

Answer 10

• Has a papillary/micropapillary (nipple like structure) form
• Contains slit-like spaces between cells
• Is glandular and solid

Question 11

What are the Type I tumours in ovarian cancer?

Answer 11

• Endometrioid
• Mucinous
• Clear Cell
• Low grade Serous

Question 12

What are the characteristics of Type I tumours?

Answer 12

• Low grade
• Slow growing
• Encompasses all histologies
• Likely evolve through a step-wise progress from borderline tumours
• Usually chomosomally stable (not picking up mutations frequently)

Question 13

What are Type II Tumours in ovarian cancers?

Answer 13

• Endometrioid
• Carcinosarcoma
• Clear Cell
• High-grade serous carcinoma

Question 14

What are the characteristics of Type II Tumours?

Answer 14

• High-grade
• Evolve rapidly
• Includes: high-grade serous carcinoma, high-grade endometrioid carcinoma, carcinosarcoma, undifferentiated carcinoma and some clear cell carcinomas
• No recognizable precursors in the ovary
• Widespread DNA copy number changes

Question 15

Where are the two locations people have hypothesized ovarian cancer arises from?

Answer 15

• The epithelial cells that line the ovary

- Somewhere on the Fallopian tubes

Question 16

Explain how a normal or mutant stem cell precursor can become ovarian cancer.

Answer 16

• The mutant stem cell precursor becomes entrapped during ovulation when the surface endothelium was remodeled
• Envagination occurs and results in a cortical inclusion cyst: aberrant niche (which could result in Type II tumours)
• The cyst then becomes a Mullerian metaplasia, if it had not differentiated into a Type II tumour cell, before undergoing malignant transformation
• results in Type I tumours

Question 17

Explain how ovarian cancer arises from the Fallopian tubes.

Answer 17

• During ovulation, a rupture in the ovary and some of the cells from the fimbriae enter it
• A normal or mutant stem cell precursor undergoes a p53 signature mutation
• The mutations the lead to STIC which undergoes ectropic implantation
• An aberrant niche forms before undergoing a malignant transformation to become a High-grade serous

Question 18

What stands out when looking at the molecular alterations in the various histotypes of ovarian cancer?

Answer 18

The histotypes all have different molecular feature combinations
eg., High-grade serous carcinoma -> TP53, BRCA1 and P13KCA

Question 19

What was the first line of treatment 30 years ago?

Answer 19

• Debulking surgery - remove tumour
• Chemotherapy - Platinum
• Radiation - Clear cell ovarian cancer

Question 20

What was the second line treatment (recurrent disease) 30 years ago?

Answer 20

• Chemotherapy - Platinum

- Repeat

Question 21

What is the first line of treatment now?

Answer 21

• Neoadjuvant chemotherapy (before surgery)
• Debulking surgery - remove tumour
• Hysterectomy - Removal of uterus
• Unilateral salpingo-oophorectomy - removal of one ovary and Fallopian tube
• Bilateral salpingo-oophorectomy - removal of both ovaries and Fallopian tubes

Question 22

What is the modern day Second line treatment (recurrent sensitive or resistant)?

Answer 22

Recurrent sensitive
- Chemotherapy - carboplatin, paclitaxel, doxorubicin and gemcitabine
Recurrent resistant
- Chemotherapy - non-platinum single agent, gemcitabine, doxorubicin and paclitaxel

Question 23

What is the modern day Third Line treatment (recurrent resistant/sensitive)?

Answer 23

• Chemotherapy

- PARP inhibitor (BRCA1 mutation carriers - once approved)

Question 24

Why are PI3K and Akt signalling important in ovarian cancer?

Answer 24

• PI3K activates AKT downstream
• Akt is the central regulator of signals from the cell surface that leads to proliferation, survival and cell growth
• Akt inhibits the activation of mTOR
• these pathways represent novel targets for the treatment of ovarian cancer and better therapies