22 - Pathology of Colon Cancer Flashcards
Bowel cancer
- 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
Neoplastic benign polyps
Hyperplastic polyp
Non neoplastic benign polyps
Inflammatory poylp
Pre-malignant polyps
- Tubular/tubulovillous/villous adenoma
- Sessile serrated lesion/adenoma
Prevalence
- 4000 aus deaths
- Second most common in men (behind prostate)
- Second most common in woman (behind breast)
- More common in men
Risk factors
- Family history
- IBD
- Obesity
- Diet high in processed meat
- Alcohol
Carcinogenesis
- 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
Which four classes of regulatory genes do mutations occur in
- 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
Mechanisms of genetic change in colon cancers
- 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
Most common pathways mutated
- Activation of WNT, MAPK, or PI3K pathways leading to growth promotion and anti apoptosis
- Inactivation of TGF-B and p53 inhibitory pathways
Colon cancer precursors
- 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)
Serrated adenoma
- Most have microsatellite instability
- Macroscopically small polyp
- Histologically serrated architecture
- Acquisition of additional mutations (BRAF)
Familial Adenomatous Polyposis (FAP)
- 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
T/F most cases are sporadic rather than familial
TRUE
HNPCC (‘Lynch syndrome’ and variants)
- 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
Amsterdam criteria
3 or more family members with CRC (at least one first degree), two successive generations, at least one before age 50, FAP excluded.
Bethesda criteria
CRC <50 years, multiple CRC or other associated tumour, high microsatellite histology <60 years, HNPCC diagnosed in first degree relative
Chromosomal instability
- 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
Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR)
- 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)
Two ways chronic inflammation is associated with CRC
- Driver of dysplasia
- Marker of host response
IBD
Increases the risk of bowel cancer due to repeated cycles of inflammation, ulceration and epithelial damage leading to increased turnover of epithelium
Signs and symptoms of early cancer
- Usually asymptomatic
- Subtle stool blood loss
- Chronic, painless
- From surface ulceration
Signs and symptoms of advanced cancer
- Bowel obstruction (constipation/pain)
- Perforation (peritonitis and tumour seeding)
- Severe haemorrhage (anaemia, shock) (due to erosion of large vessels)
- Direct invasion of other organs
Diagnosis of colon cancer
- Faecal occult blood testing
- Imaging (CT scan)
- Endoscopy
- Biopsy
Benefits of screening
- Reduction in mortality and morbidity
- Cost-effective (cheaper than advanced treatment)
- Procedures for early cancer easier, safer, cheaper than advanced cancer
What is required for a screening program to be worthwhile
- Disease has serious consequences
- The disease must have a detectable preclinical period
- High prevalence
- The test must be sensitive and specific
- Safe
- Test is affordable and available
- Effective treatment exists
- Treatment is more effective when started earlier
