Colorectal Cancer

Question 1

What are the 2 broad classifications of polyps?

Answer 1

Sessile (no stalk)

Pedunculated (stalk)

Question 2

What are the precursor lesions to colorectal cancer i.e. in the dysplasia-carcinoma sequence?

Answer 2

Tubular adenoma - sessile or pedunculated, dysplastic glands
Villous adenoma - usually large & sessile, columnar epithelial extensions
Tubuloadenoma

Question 3

What are factors that increase malignancy risk?

Answer 3

Villous adenoma
Larger polyp size (<1 cm)
Large number of polyps
High grade dysplasia

Question 4

When can early onset colorectal cancer commonly occur?

Answer 4

IBD - particularly ulcerative colitis

Familial syndromes - particularly FAP & Lynch syndrome

Question 5

What is FAP?

Answer 5

Familial adenopolyposis
Autosomal dominant inherited mutation in the APC gene
100% of cases lead to colorectal cancer, usually by late teens/early 20s but definitely by 30
Leads to > 100 polyps but can be thousands

Question 6

What is Lynch Syndrome?

Answer 6

Hereditary non-polyposis colorectal cancer - mot common familial one
Autosomal dominant mutation in DNA mismatch repair gene - leads to widespread mutation (repeats) in DNA microsatelites
Early onset ~45 yrs
Increases risk of extra-colonic cancers i.e. endometrial, ovarian, stomach & SB

Question 7

What are the 3 genetic pathways for colorectal cancer development?

Answer 7

Chromosomal instability - majority of sporadic cases + FAP

Microsatelite instability - Lynch syndrome + some sporadic cases

Methylator phenotype - some sporadic cases

Question 8

What is the dysplasia-carcinoma sequence in colorectal cancer?

Answer 8

Early APC mutation (sporadic or familial) –> down regulation of Beta-catenin, cell proliferation & genome instability

Dysplasia and accumulation of mutations leading to early adenoma through to late adenoma formation
- Mutations often sequential in K-Ras, SMAD4 and p53

Carcinoma in situ
Further mutations allowing invasion & metastitis

Question 9

What is a targeted molecular treatment of colorectal cancer and what is prognostic of its effectiveness?

Answer 9

Monoclonal Abs (cetuximab) to block EGFR receptors that active Ras and MAP-kinase signalling pathways for cell proliferation

Mutations in Ras and B-Raf predict poor response to this treatment as they are activating mutations (doesn’t matter if GF binding the receptor, pathway will always be activated)

Question 10

What is the staging system of colorectal cancer and what are its principles?

Answer 10

Dukes Classification
Dukes A - moderately differentiated and invasion into but NOT THROUGH bowel wall

Dukes B - poorly differentiated and invasion THROUGH bowel wall but not to LNs

Dukes C - metastisis to LNs

Dukes D - distance metastisis