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Path - Tumours of Small + Large Intestines (ii) (CR adenocarc (risk…
Path - Tumours of Small + Large Intestines (ii)
Adenoma-carcinoma sequence
= the development of carc from an adenomatous lesion
pops that have high prevalence of adenomas have high prevalence of CRC (distributions comparable)
peak incidence of adenomatous polyps precede the peak of CRC
APC mutations (same gene, whether familial or sporadic)
multiple other hits needed (multi-hit hypothesis - cumulative genetic alterations)
inactivation/muation of other APC allele (loss of heterozygosity)
activation of kras (12p)
loss of DCC gene (18q)
loss of p53 (17p)
increased COX expression (PG production increases tumour growth)
activation of telomerase (elongates telomeres, increases cell life)
2 pathways
APC + other hits
microsatellite instability (seen in HNPCC)
CR adenocarc
disease of western world
peak incidence in 70s
if in young person: a/w genetic predisposition or UC
risk factors
adenomatous polyps
heritidary syndromes - FAP + HNPCC
IBD (esp UC)
diet (low fibre, high fat, high carbs, high intake of red meat, low intake of micronutrients, low intake of vits A,C,E)
obesity
physical inactivity
tumours in proximal (right) colon tend to group as polypoid lesions ("cauliflower") - may ulcerate, bleed (iron deficient anaemia), vague pain
iron deficient anaemia in an adult (esp male) - CRC until proven otherwise
tumours in distal (left) colon tend to be annular (ring-shaped), encircling lesions ("Napkin-ring") - cause contraction with signs + symptoms of obstruction
rectal bleeding
blood streaked stool
changed bowel habits
decreased stool calibre (diameter)
lumen in left colon = narrower than lumen on right + faecal matter is solid in left colon
LLQ pain
symptoms
changed bowel habits
blood in stool
iron deficiency anaemia
abdo discomfort/pain
NB: CRC a/w increased risk in Strep Bovis endocarditis (indication of colonoscopy)
may produce mucin
well, moderately or poorly differentiated
invade through bowel wall
mets: nodes, liver, lungs
Dx
colonoscopy + bx
barium enema
occult blood
DRE
CEA
carcinoembryonic antigen
tumour marker
low sensitivity + specificity - not good for dx
better for follow-up: assess resection adequacy + detect early recurrence
radiology NB for staging (e.g. liver US)
prognosis depends on stage, grade (degree of differentiation), location (left sided a/w worse prognosis than right because they tend to be more invasive)
staging
most important prognostic factor
Dukes'
A: confined to wall (not through muscularis propria) - >90% 5 yr survival
B: through muscularis propria - 70% 5yr survival
C: nodal involvement - 30% 5 yr survival
D: distant mets - 5-10% 5yr survival
TNM
Jass score
chemoprevention
COX inhibitors (aspirin, other SNAIDs) reduce rate of CRC by 50%
COX2 has tumourigenesis effects (increased prolif, decreased apoptosis, increased angiogenesis)
Monoclonal Abs
approved to tx metastatic CRC
erbitux (cetuximab) + vectibix (panitumumab) block EGFR signalling
avastin (bevacizumab) blocks growth of blood vessels to tumour
HNPCC
hereditary non-polyposis CRC
aka Lynch syndrome
AD familial syndrome
Colonic carc NOT A/W PREEXISTING ADENOMAS
usually right sided
lower no. of polys than FAP
Lynch syndrome 1: increased risk of colon cancer only
Lynch syndrome 2: increased risk of colon cancer + non-GI cancers (endometrial, ovarian)
defect in MMR genes
repair DNA
microsat instability
microsats = repetitive nucleotide sequences - easy for DNAP to slip + make a coding mistake - MMR proteins meant to proof read + correct these errors
hMSH2, hMLH1, hPSM1, hPMS2
accumulation of mutations