HNPCC (Lynch Syndrome)

DEFINITION

Hereditary Non-Polyposis Colon Cancer
Better known as Lynch Syndrome, as it involves polyps and more than colon cancer
Lynch I = colorectal cancer at a young age
Lynch II = both colorectal and extracolonic

One of several inherited bowel cancer syndromes
- FAP (see notes)
- Hyperplastic polyposis syndrome
- Peutz-Jehger (see polyps)
- Juvenile polyposis (see polyps)

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EPIDEMIOLOGY

5% rate of Colorectal Ca in the community
5% are inherited.
2% are Lynch syndrome

Risk :
See Screening guidelines

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AETIOLOGY

Genetic
- AD
- Germline mutations in the MMR genes

MMR Genes
These genes correct base-pair mismatch during DNA replications
Or initiate apoptosis when beyond repair.
Also causes changes in sequence repeats at microsatellites
--> microsatellite instability is a hallmark of HNPCC.
-> nb. 25% of CRC shows MSI; in non-HPCC, this is due to methylation of MMR genes, leading to inactivation over time.
--> 2 unstable satellites = MSI-H (high); vs 1 = MSI-L (low)

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BIOLOGICAL BEHAVIOUR

Biological Behavior
Lifetime risk of a cancer = 70-90%
- average age onset 45y
Multiple tumours but major predilection is colon cancer
- and bad ones: signet ring, lymph infiltration, mucinous, poorly differentiated types

Associated tumours
Large bowel 80%
Endometrium 40%
Stomach 15%
Ovary 12%
Urothelium 5% (bladder, renal pelvis)
Other <5% (pancreas, CNS, small bowel)



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MANIFESTATIONS

Amsterdam Criteria

Identifies families at risk of HNPCC
3-2-1 rule
At least 3 relatives with a Lynch-Syndrome associated tumour
At least 2 successive generations
At least 1 diagnosed before age 50
AND
--> 1 must be a first degree relative
--> FAP excluded
--> Tumours pathologically verified

Revised Bethesda Guidelines
Identifies patients with CRC for HNPCC testing from specimens
1. CRC <50y
2. Synchronous or metachronous CRC or HNPCC related tumours
3. CRC <60 with MSH-H
4. 1+ 1st degree relatives with HNPCC tumour diagnosed <50y
5. 2+ 1-2nd degree relatives with HNPCC related tumours at any age


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INVESTIGATIONS

Pathology

Immunohistochemistry

- measures expression of MMR proteins
- loss of staining indicates affected genes
- MLH-1, MSH-2, PMS-2, MSH-6

Microsatellite instability testing
-
performed where family history is indicative.
- virtually all HNPCC are MSH-H

Germline genetic testing

- predictive test offered to family members
- positive family members are offered screening or prevention as appropriate.
--> even if negative, still need surveillance as sensitivity of current test is 80%

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MANAGEMENT

Surveillance


1. Scope 10y earlier than youngest affected relative.
- continue until old age or until mutation excluded (then normal population risk)

2. Little evidence for extracolonic tumours, however options include:
- transvaginal and transabdominal USS annually
- LFTs, CEA, CA19-9, CA125 annually
- urine cytology annually
- CT abdo biannually
- gastroscopy biannually

Management

1. Prophylactic colectomy.
- discuss vs surveillance with pt.
--> subtotal colectomy with ileorectal anastomosis and restorative proctocolectomy

2. Risk of metachronous cancers in a retained rectum is 12% at 12 years.
--> annual rectal surveillance recommended

3. Discuss prophylactic hyesterectomy and BLSO at time of colectomy if family complete.


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REFERENCES