PATHOPHYSIOLOGY OF
RECTAL CANCER
ETIOLOGY
1.DIET
- Low intake of vegetable fibre in diet ---Low stool bulk
- Diet rich in animal fat---Excessive cholestrol and their
metabolites which may be carcinogenic
- Excessive consumption of refined carbohydrate---Prolonged
contact with colonic musosa changes the bacterial flora of the
bowel,thus resulting in production of carcinogenic substances
2.GENETIC
SUSCEPTIBILITY
i) FAMILIAL ADENOMATOUS
POLYPOSIS ( FAP )
- Autosomal dominant hereditary disease
- characterised by presence of numerous adenomatous colorectal
polyps ( or Adenomas ) which have a tendency for progression to
adenocarcinoma
FAP is due to germline mutation in APC ( adenomatous polyposis
coli ) gene located on long arm of chromosome 5
ii) HEREDITARY NON-POLYPOSIS
COLONIC CANCER ( HNPCC or Lynch syndrome )
- Autosomal dominant condition
- Assosiated with multiple primary cancers at different sites (
endometrium,ovary ) including colorectal cancer without evidence of
familial polyposis coli
- Seen in atleast 2 generations of first degree relatives
- HNPCC occurs due to the germline mutation in the mismatched
repais genes, human mutL homolog - hMLH2 located on chromosome 2
and hMLH1 located in chromosome 3 resulting in DNA instability
3.HIGH RISK
CONDITIONS
Presence of certain pre-existing diseases like,
- Inflamatory bowel disease ( especially ulcerative colitis
)
- Diverticular diseases for long duration
- Role of tobaco smoking
- Infection with Streptococcus bovis
PATHOPHYSIOLOGY
MOLECULAR MECHANISM: ADENOMA CARCINOMA SEQUENCE
Sequential multistep mutations in evolution of colorectal cancer
from adenomas is by,
1. Mutational
Pathway ( conventional adenoma 80-90% )
Multiple mutation pathway is generally assosiated with
morphologically identifiable changes of transformation from adenoma
to adenocarcinoma.These changes are under,
i) Loss of tumour supresser APC gene located on the long arm of
chromosome 5.
- Results in translocation of beta catenin to the nucleus where
it activates transcription of other genes,mainly MYC & cyclin
D1, both which stimulate cell proliferation
- This is called APC mutation / beta-catenin mechanism
- observed in 80% of sporadic colonic cancer
ii) Point mutation in K-RAS gene follows loss of APC gene (
10-15% cases of adeno carcinoma )
iii) Deletion of DCC gene located on long arm of chromosome 18 (
60-70% cases of colon cancer )
iv) Loss of p53 tumour suppressor gene ( 70-80% of colon cancer
)
2. MICROSATELLITE
INSTABILITY ( MSI ) MECHANISM ( 10-20% cases of serrated
adenoma )
- Multiple mutation but of different genes
- No morphologically identifiable changes
- Basic mutation is loss of DNA repair gene
- In colonic cancer the DNA repair genes mutated are- TGF-beta
receptor gene (after mutation causes the uncontrolled proliferation
of colonic epithelium in adenoma ) and BAX gene ( after mutation
results in loss of apoptosis and disregulated growth )
- Results in repetative DNA sequences ( ie, microsatellites )
becomes unstable during replication cycle called MICROSATELLITE
INSTABILITY ( hallmark of this pathway )
- This pathway accounts for 10-15% cases of colonic cancer
MORPHOLOGIC PROGRESSION
OF RECTAL CARCINOMA
Mucosa at risk----Early adenoma----Adenoma &
dysplasia----Large adenoma----Carcinoma