Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common type of inherited colorectal cancer and accounts for 3% of new colorectal cancer diagnoses. It is also associated with extracolonic cancers including endometrial, small bowel, ureter, stomach, renal pelvis, ovarian, and hepatobiliary. Variations of HNPCC include Muir-Torre syndrome, which is associated with sebaceous skin tumors, and Turcot syndrome, which is associated with brain tumors such as medulloblastomas and gliomas. Colorectal cancers that arise in the setting of HNPCC have germline mutations in the mismatch-repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or the epithelial cellular adhesion molecule (EPCAM) gene. Such colon cancers are usually right sided. There is also a high prevalence of metachronous colorectal cancers in patients with HNPCC.

The diagnosis of HNPCC can be made using Amsterdam II criteria:

• Three or more relatives with histologically verified HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two
• Cancer involving at least two generations
• One or more cancer cases diagnosed before 50 years of age
• Familial adenomatous polyposis should be excluded in the colorectal cases
• Tumors should be verified by pathologic examination

The revised Bethesda guidelines are used to determine which patients with colorectal cancer should be screened for HNPCC with tumor testing for microsatellite instability.

Confirmation of the diagnosis with genetic testing for a germline mutation in the MMR genes or in the EPCAM gene should be done. Once the diagnosis is made, first-degree family members should be tested.