Risks, Histology, and Malignant Molecular Markers

Question 1

1/3 cases of TCC are due to what?

Answer 1

cigarette smoking

• increases RR by 2-4x
• patient who quit smoking when diagnosed with TCC do better than those who continue to smoke

Question 2

Exposure to what other substances can cause bladder TCC?

Answer 2

aromatic amines (aniline dyes)
- rubber factory, textile mill, hair dressers

acrolein (from cyclophosphamide)

• known to cause hemorrhagic cystitis
• prevent with mesna (binds to acrolein)

combustion products

pelvic radiation

Question 3

Chronic indwelling catheters, bladder calculi, or chronic UTI’s can lead to this type of cancer?

Answer 3

squamous cell carcinoma

Question 4

What is the parasite, endemic in Egypt, that is known to cause squamous cell carcinoma of the bladder?

Treatment?

Answer 4

Schistosoma haematobium

Tx: Praziquantel

Question 5

What are the 3 primary layers of the bladder?

Answer 5

1. Mucosa
2. Muscularis propria
3. Adventitia

Question 6

The mucosa is subdivided into what two layers?

Answer 6

1. Urothelium

2. Lamina propria

Question 7

What components make up the urothelium?

Answer 7

Glycosaminoglycan layer, uroplakin layer, umbrella cells, intermediate stratum, basal cells

Question 8

Disease that is limited to the urothelium is what stage?

Answer 8

Ta

Question 9

What components make up the lamina propria?

Answer 9

connective tissue and muscularis mucosa

Question 10

These are benign proliferations of urothelial cells in the lamina propria layer

Answer 10

von Brunn’s nests

Question 11

Disease limited to the mucosal lamina propria layer is what stage?

Answer 11

T1

Question 12

What are the sublayers of the muscularis propria?

Answer 12

inner longitudinal

middle circular

outer longitudinal

Question 13

Disease that invades into the muscularis propria is what stage?

Answer 13

T2

Question 14

Disease that invades or penetrates the adventitia layer is what stage?

Answer 14

T3 invades, T4 penetrates

Question 15

What are the high yield tumor suppressor genes mutated in bladder cancers?

Answer 15

1. P53
2. P16 or CDKN2
3. P27 or Kip
4. Retinoblastoma
5. 9q loss

Question 16

P53 gene is located on what x-some?

Answer 16

17p13

Question 17

Function of P53?

Answer 17

normally influences damaged DNA cells towards apoptosis

Question 18

Mutations of p53 signifies what?

Answer 18

High grade TCC

Question 19

Function of p16 (CDKN2)?

Answer 19

normally inhibitor of Cdk4-cyclin D complexes (i.e. indirectly RB protein activation)

Question 20

Location of p16?

Answer 20

9p21

Question 21

Function of p27 (Kip)?

Answer 21

normally inhibitor of Cdk4-cyclin D complexes (i.e. indirectly RB protein activation; same as p16)

Question 22

Mutation of p27 signifies what?

Answer 22

Aggressive TCC

Question 23

Mutation of p16 signifies what?

Answer 23

Not much… >50% of bladder cancers have this mutation

Question 24

Function of RB gene?

Answer 24

normally RB inhibits cell cycle progression through the G1/S restriction point

• must by un-phosphorylated to function
• inactivated by the Cdk4-cyclin D complex

Question 25

Significants of mutated RB?

Answer 25

aggressive TCC

Question 26

Mutation/loss of 9q usually signifies?

Answer 26

low grade superficial TCC

Question 27

Name 3 proto-oncogenes of bladder cancer?

Answer 27

1. FGFR3 (fibroblast growth factor receptor 3)
2. RAS gene family
3. ERBB2 or HER2/neu on 17q12

Question 28

This proto-oncogene is found in the majority of low grade bladder cancers and is a good prognostic marker

Answer 28

FGFR3

Question 29

What is the nuclear proliferation antigen, associated with cell cycle and required for cell proliferation, and when mutated signifies aggressive TCC?

Answer 29

Ki-67 on chromosome 10

Question 30

FISH urinalysis checks for aneuploidy of which chromosomes?

Answer 30

3, 7, 17, and loss of 9p21

• xsome 17 = ERBB2 or HER2/neu
• xsome 9p21 = p16 (CDKN2)

Question 31

Are urine FISH tests sensitive/specific?

Answer 31

Relatively, yes. Sensitivity 50-80%, specificity 90%

• May have positive urine FISH months prior to visualization on cystoscopy
• May have positive results with papillary RCC (chromosome 7, 17)