Colorectal Cancer

Question 1

What are adenomatous polyps?

Answer 1

Precursor lesions for colorectal carcinoma (can be tubular or villous, pedunculated or sessile)

Question 2

What is the risk of early onset colorectal cancer with FAP?

Answer 2

100%

Question 3

What increases the risk of early onset colorectal cancer?

Answer 3

Familial syndromes (e.g. FAP, HNPCC/Lynch syndrome)
Chronic inflammatory bowel disease (more commonly UC)

Question 4

What gene is mutated in FAP?

Answer 4

APC

Question 5

How is FAP inherited?

Answer 5

AD

Question 6

How is FAP treated?

Answer 6

Prophylactic colectomy (curative because the polyps do not invade past the muscular mucosa, and there are no lymphatics in the lamina propria so no opportunity for spread)

Question 7

Describe the histological features of an adenomatous polyp in FAP

Answer 7

Abnormal crypt architecture
Dysplasia (crowded cells with abnormal nuclei, goblet cell depletion, increased or atypical mitoses)
No invasion past muscularis mucosa

Question 8

What are the 3 main colorectal cancer genetic pathways?

Answer 8

Chromosomal instability
Microsatellite instability (MSI)
CpG island methylator phenotype (CIMP)

Question 9

What is HNPCC?

Answer 9

Hereditary nonpolyposis colorectal cancer (aka Lynch syndrome)

Question 10

What is the role of APC loss in the dysplasia-carcinoma sequence for colorectal cancer?

Answer 10

Decreased cell adhesion

Increased cell proliferation

Question 11

What are the most common accumulated mutations in colorectal cancer?

Answer 11

Proto-oncogenes: K-RAS, B-RAF
TSGs: SMAD4/SMAD2, p53
Activation of telomerase

Question 12

Describe the multi-step model for colorectal cancer

Answer 12

Normal epithelium
FIRST HIT APC MUTATION (somatic or familial)
B-CATENIN MUTATION
Dysplastic ACF
Early adenoma
K-RAS MUTATION
Intermediate adenoma
SMAD4 MUTATION
Late adenoma
p52 MUTATION
Carcinoma
OTHER ALTERATIONS
Metastasis

Question 13

What is the most common familial colorectal cancer syndrome?

Answer 13

HNPCC

Question 14

How is HNPCC inherited?

Answer 14

AD

Question 15

What gene is mutated in HNPCC?

Answer 15

DNA mismatch repair gene (MSI)

Question 16

What genetic changes occur in the MSI pathway for colorectal cancer?

Answer 16

Defective DNA mismatch repair due to germline mutation of MSH2 or MLH1
Widespread mutations in DNA microsatellites leads to mutations in wide range of other genes

Question 17

Where do sessile serrated adenomas generally arise?

Answer 17

Proximal colon

Question 18

What histological features are seen in sessile serrated adenomas?

Answer 18

Saw-tooth architecture
Complex branching
"Boot-leg" angulation and dilation at base of crypts
Cytological changes
Increased atypia with dysplasia

Question 19

What mutation is commonly seen in sessile serrated adenomas?

Answer 19

B-RAF (may be precursor to MSI or CIMP)

Question 20

What staging system is used for colorectal cancers and what classifications are there?

Answer 20

Australian ClinicoPathological Staging (ACPS):
A - invades beyond muscularis mucosa
B - invades beyond muscularis propria/externa
C - LN metastases
D - distant metastases
N.B. Used in combination with TNM

Question 21

What is a common site of metastasis for colorectal cancer? Why?

Answer 21

Liver, because portal vein drains the gut

Question 22

What targeted therapies exist for colorectal cancer?

Answer 22

Ab-based therapies that block EGFR signalling

Question 23

Cetuximab

Answer 23

EGFR inhibitor

Question 24

Panitumumab

Answer 24

EGFR inhibitor

Question 25

What genetic mutations suggest poor response to EGFR therapy?

Answer 25

K-RAS

B-RAF

Question 26

What features of colorectal cancer suggest good prognosis?

Answer 26

MSI

High numbers of tumour-infiltrating immune cells