Autosomal dominant inherited bowel cancer syndrome due to mutations in mismatch repair genes.
Hereditary non- polyposis colorectal cancer (HNPCC)
Epidemiology: 3% of colorectal cancers
Commonest inherited bowel syndromes.
Genetics:
Due to germline mutation in MMR – majority are MLH1, MSH2, MSH6, PMS2
MMR are tumour-suppressor genes.
When defective, DNA mismatches are no longer repaired, resulting in accumulation of mutations in other genes, leading to tumour formation.
Microsatellite instability (MSI) (only 15% of sporadic show MSI)
Pathology:
LAMPS:
Lymphocytes/lymphoid
Associated cancers
Mucinous/metachronous
Poorly differentiated/proximal
Signet cell/synchronous
Clinical features:
Average age at diagnosis 45 years, mostly proximal colon.
Often multiple (synchronous or metachronous).
Tend to be mucinous, poorly differentiated, signetring appearance, with infiltration by lymphocytes and lymphoid aggregation at margins.
Cancers associated with Lynch syndrome:
C - colorectal 30-75%
O - ovarian 5-10% (of women)
U - uterine 50%
G - gastric 5-10%
R - renal (urothelial)
S - Small bowel and skin
Other – small bowel, pancreas, brain < 5%
Diagnosis
Pedigree/family history
Amsterdam criteria II (50% who meet criteria)
At least 3 relatives with Lynch syndrome associated cancer, one of whom should be a first-degree relative of the other two
At least two successive generations affected
At least one cancer diagnosed before 50
FAP excluded
Tumours verified by pathological examination
Pathological testing
Histologically Bethesda criteria (determine whether to test for MSI) was used to determine who to test
NZ Guidelines now suggest
Test all newly diagnosed cases of colorectal cancer for mismatch repair deficiency preferably on initial biopsy
Immunohistochemistry for MMR proteins or MSI testing are appropriate methodologies.
If performing immunohistochemistry, then use a four-panel test for MLH1, PMS2, MSH2 and MSH6.
If MSH2, MSH6 or PMS2 are abnormal (deficient), then the patient will need genetic testing. For this testing, refer them to the New Zealand Familial Gastrointestinal Cancer Service.
If MLH1 is abnormal (deficient), then you must perform further testing to differentiate a sporadic cancer from a cancer associated with Lynch syndrome .
BRAF V600E mutation analysis → if demonstrates mutant then sporadic
If BRAF V600E is wild-type then perform promoter hypermethylation testing and if negative, then refer the patient to the New Zealand Familial Gastrointestinal Cancer Service.
Conduct BRAF V600E mutation analysis in all newly diagnosed stage IV colorectal cancers
Conduct extended RAS mutation testing before considering treatment with EGFR-targeted monoclonal antibodies
Genetic testing
Costly.
Based on patient factors, family history and tumour factors
Need consent
Surveillance
Reduces risk of colorectal cancer by 63%
Chromoendoscopy increases pick up
Every 2 years from age 25 or 5 years younger than affected relative.
Extracolonic surveillance:
Gastroscopy every 2 years
Annual abdominal ultrasound of renal tracts, pelvis and pancreas
Annual TV US + clinical exam +/- endometrial sampling
Annual LFTs, Ca 19-9, CEA & Ca 125
Annual urinalysis/cytology
Surgery
Prophylactic
Prophylactic colectomy can be discussed.
Subtotal with ileorectal or proctocolectomy. Risk of rectal cancer about 12% at 12 years. Should have annual flexible sigmoidoscopy if ileorectal.
Similar hysterectomy and BSO should be discussed once completed family.
No significant advantage of prophylactic surgery over good-quality surveillance
Treatment
Once diagnosed, decision of segmental colectomy (better function but increased risk of metachronous cancer and need for colonoscopy surveillance)
vs colectomy + ileorectal anastomosis (reduce metachronous risk, easier surveillance)
Risk of metachronous cancer of 16% at 10 years
Medical
MSI reduced when exposed to NSAIDs.
Aspirin from age 25
Adjuvant therapy – only for stage III not stage II.