Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Characteristics
Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant disorder that is strongly associated with a higher incidence of endometrial cancer. 1, 2
Genetic Basis
- Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, PMS2, or deletions in the EPCAM gene 2, 3
- MLH1 and MSH2 mutations account for >90% of Lynch syndrome families with known mutations 2
- MSH6 mutations are responsible for approximately 5-10% of Lynch syndrome cases 2
- The inheritance pattern is autosomal dominant, not recessive 1, 3
Cancer Risk Profile
- Colorectal cancer: 22-80% lifetime risk (varies by specific gene mutation) 3
- Endometrial cancer: 30-60% lifetime risk in women, making it the second most common cancer in Lynch syndrome 2, 3
- Ovarian cancer: Increased risk, but lower than endometrial cancer risk 3
- Other associated cancers include urinary tract, small intestine, gastric, pancreatic, biliary tract, and brain tumors 3
Colorectal Cancer Characteristics
- Predominantly right-sided (proximal) colon cancers, with approximately 70% occurring proximal to the splenic flexure 1, 4
- One-third of the cancers occur in the cecum 4
- More rapid adenoma-to-carcinoma progression (approximately 35 months vs. 10-15 years in sporadic cases) 1, 3
- Distinctive histopathological features including poor differentiation, signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes, and lymphoid host response 1
- Better stage-for-stage survival compared to sporadic colorectal cancer 3
Diagnostic Criteria
- Amsterdam II criteria: Family history of 3 relatives with Lynch syndrome-associated cancer, with one being a first-degree relative of the other two, at least 2 successive generations affected, and at least 1 cancer diagnosed before age 50 3
- Molecular diagnosis through identification of pathogenic germline mutations in MMR genes 1
- Tumors demonstrate microsatellite instability (MSI) and loss of MMR protein expression on immunohistochemistry 2, 3
Management Implications
- Colonoscopy every 1-2 years beginning in the 20s 3
- Consider subtotal colectomy rather than segmental resection for initial colorectal cancer due to high risk of metachronous cancers 1, 4
- Endometrial sampling and transvaginal ultrasound recommended annually for women starting at age 30-35 1
- Prophylactic hysterectomy and oophorectomy have demonstrated efficacy 1
In summary, Lynch syndrome is an autosomal dominant disorder characterized by predominantly right-sided colorectal cancers and significantly increased risk of endometrial cancer, not left-sided colorectal cancers or autosomal recessive inheritance.