22 - Pathology of Colon Cancer

Question 1

Bowel cancer

Answer 1

• Malignant neoplasm of the bowel (usually large bowel aka colorectal carcinoma)
• Usually adenocarcinoma (gland forming)
• Less common types are lymphomas, GIST, sarcomas, metastases from other organs

Question 2

Neoplastic benign polyps

Answer 2

Hyperplastic polyp

Question 2

Non neoplastic benign polyps

Answer 2

Inflammatory poylp

Question 3

Pre-malignant polyps

Answer 3

• Tubular/tubulovillous/villous adenoma
• Sessile serrated lesion/adenoma

Question 4

Prevalence

Answer 4

• 4000 aus deaths
• Second most common in men (behind prostate)
• Second most common in woman (behind breast)
• More common in men

Question 5

Risk factors

Answer 5

• Family history
• IBD
• Obesity
• Diet high in processed meat
• Alcohol

Question 6

Carcinogenesis

Answer 6

• Multiple non-lethal genetic mutations (variations) or ‘hits’ (Knudson hypothesis)
• Both alleles must be affected before phenotype is altered
• Carcinogenesis is therefore a multistep process at the genetic level

Question 7

Which four classes of regulatory genes do mutations occur in

Answer 7

• Growth promoting proto-oncogenes (gain of function)
• Growth inhibiting tumour suppressor genes (loss of function)
• Genes that regulate cell death (pro-apoptotic)
• Genes involved in DNA repair

Question 8

Mechanisms of genetic change in colon cancers

Answer 8

• Chromosomal instability resulting in high levels of somatic copy number alterations and DNA gains/deletions
• Microsatellite instability (MSI) due to defective DNA mismatch repair (most of these show CpG island hypermethylation)
• Defective DNA polymerase proofreading (most are silent passenger mutations

Question 9

Most common pathways mutated

Answer 9

• Activation of WNT, MAPK, or PI3K pathways leading to growth promotion and anti apoptosis
• Inactivation of TGF-B and p53 inhibitory pathways

Question 10

Colon cancer precursors

Answer 10

• Normal (APC TSG)
• Mucosa at risk (macroscopically normal, beta catenin ])
• Adenoma (Macroscopically small polyp, Histologically low grade dysplasia, K-RAS)
• Advanced adenoma (Larger, irregular polyps, High grade dysplasia, p53)
• Carcinoma (invasion, telomerase)

Question 11

Serrated adenoma

Answer 11

• Most have microsatellite instability
• Macroscopically small polyp
• Histologically serrated architecture
• Acquisition of additional mutations (BRAF)

Question 12

Familial Adenomatous Polyposis (FAP)

Answer 12

• Autosomal dominant
• New germline mutations acquired during embryogenesis
• 100% risk of colon cancer by 40
• Mutation in APC gene at 5q21
• ‘Carpet’ of >100 adenomas increases probability of second, third hits

Question 13

T/F most cases are sporadic rather than familial

Answer 13

TRUE

Question 14

HNPCC (‘Lynch syndrome’ and variants)

Answer 14

• Autosomal dominant
• Fewer adenomatous polyps than FAP, more than sporadic cancers
• Mutations in mismatch repair gene(s) MLH1 or MSH2
• Amsterdam and Bethesda criteria for genetic testing

Question 15

Amsterdam criteria

Answer 15

3 or more family members with CRC (at least one first degree), two successive generations, at least one before age 50, FAP excluded.

Question 16

Bethesda criteria

Answer 16

CRC <50 years, multiple CRC or other associated tumour, high microsatellite histology <60 years, HNPCC diagnosed in first degree relative

Question 17

Chromosomal instability

Answer 17

• Resulting in high levels of somatic copy-number alterations and DNA gains/deletions
• Mostly correlated with development of cancer from conventional dysplastic adenomas
• Majority of sporadic cancers on both left and right side of colon
• Majority have mutations or alterations in APC, TP53, and KRAS
• Patients with FAP develop these cancers young

Question 18

Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR)

Answer 18

• Leading to high mutation rate in a range of genes
• Mostly correlates with development of cancer from serrated polyps
• Subset of sporadic cancers and majority of cancers associated with Lynch syndrome
• Most of these tumours show BRAF mutations and develop CpG island hypermethylation
• More likely to be right sided (more sessile serrated lesions)

Question 19

Two ways chronic inflammation is associated with CRC

Answer 19

• Driver of dysplasia
• Marker of host response

Question 20

IBD

Answer 20

Increases the risk of bowel cancer due to repeated cycles of inflammation, ulceration and epithelial damage leading to increased turnover of epithelium

Question 21

Signs and symptoms of early cancer

Answer 21

• Usually asymptomatic
• Subtle stool blood loss
• Chronic, painless
• From surface ulceration

Question 22

Signs and symptoms of advanced cancer

Answer 22

• Bowel obstruction (constipation/pain)
• Perforation (peritonitis and tumour seeding)
• Severe haemorrhage (anaemia, shock) (due to erosion of large vessels)
• Direct invasion of other organs

Question 23

Diagnosis of colon cancer

Answer 23

• Faecal occult blood testing
• Imaging (CT scan)
• Endoscopy
• Biopsy

Question 24

Benefits of screening

Answer 24

• Reduction in mortality and morbidity
• Cost-effective (cheaper than advanced treatment)
• Procedures for early cancer easier, safer, cheaper than advanced cancer

Question 25

What is required for a screening program to be worthwhile

Answer 25

1. Disease has serious consequences
2. The disease must have a detectable preclinical period
3. High prevalence
4. The test must be sensitive and specific
5. Safe
6. Test is affordable and available
7. Effective treatment exists
8. Treatment is more effective when started earlier