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Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome, also known as Lynch syndrome, is a rare colorectal syndrome that can lead to cancer of the colon.

Hereditary Nonpolyposis Colorectal Cancer Syndrome Inheritance pattern
- autosomal dominant
- syndromal patients have only one functional allele and cancer occurs through loss of heterozygosity (LOH)
- mutations occur in mismatch repair genes (MLH1, MSH 2, MSH6, PMS 1, PMS 2)
- mutations lead to microsatellite instability which are mostly repeats in intronic regions

What to look for?

- you can look for the loss of the genes themselves

- you can look at particular microsatellite loci and see how many have instability
- 0/5 – stable
- 1/5 – low frequency instability
- 2 or greater/5  – high frequency of instability – MSI-H
- microsatellite instability is NOT specific to HNPCC, as it is seen in 10-15 % of sporadic colorectal carcinomas. Sporadic tumors arise in older patients who lack a family history. The activity of the mismatch repair genes in sporadic tumors is lost through hypermethylation

Diagnostic criteria is through the Amsterdam II criteria

Clinical presentation

- development of multiple cancers at an early age, including cancer of the colon, endometrium, renal pelvis and ureter, small bowel, ovary, brain, hepatobiliary tract and sebaceous tumors 

Muir -Torre Syndrome

- sebaceous tumors along with HNPCC type of internal malignancy

Turcot Syndrome

- tumors of the CNS (usually gliobalstomas) and multiple colorectal tumors

Gross Appearance

- predilection for right colon and cecum all the way to the transverse colon
- usually polypoid in appearnace rather than diffuse

Microscopic Appearance

- sporadic tumors have the same features as tumors associated with HNPCC

- proximally located mucinous type of colorectal adenocarcinomas +/- tumor infiltrating lymphocytes

- proximally located, poorly differentiated medullary or undifferentiated colorectal adenocarcinomas – these are well circumscribed and lacking abundant desmoplastic stroma and may contain tumor infiltrating lymphocytes

- adenomas – many have a villous morphology and high grade dysplasia, with rapid progression to carcinoma