Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the inherited gastrointestinal syndromes predisposing to colorectal cancer. The syndrome accounts for approximately 2% to 3% of all colo-
rectal cancers (Westlake et al, 1991; Salovaara et al, 2000). HNPCC is an autosomal dominant heritable syndrome. Therefore, 50% of the children of an affected individual will develop the syndrome. The penetrance of HNPCC has been estimated to be between 80% and 85% (Lynch et al, 1983; Vasen et al, 1996); thus, not all affected individuals will develop cancer in their lifetime.
HNPCC is characterized by early age at onset, excess synchronous and metachronous lesions, right-sided predominance, and extracolonic manifestations. The median age of diagnosis of colorectal cancer in persons with HNPCC is approximately 45 years. Although most patients present with right-sided colon malignancies, up to 40% of patients present with left-sided colorectal tumors. In patients with HNPCC, the risk of developing synchronous colorectal neoplasms has been reported to be as high as 18%, and the risk of developing metachronous lesions has been reported to be 25% to 30% (Aarnio et al, 1995; Lynch and de la Chapelle, 1999; Box et al, 1999). The most common extracolonic tumor in HNPCC is endometrial cancer, which is present in 30% to 40% of affected women (Aarnio et al, 1995; Lynch and de la Chapelle, 1999). Other extracolonic cancers common in the syndrome are transitional cell carcinoma of the renal pelvis and ureter, small bowel adenocarcinoma, and sebaceous skin tumors (Muir-Torre syndrome). Less commonly reported in HNPCC are hepatobiliary, gastric, ovarian, renal cell, bladder, and brain tumors.
At the molecular level, HNPCC is characterized by germline mutations in the mismatch repair genes. These genes include hMLHl, hMSH2, hMSH6, hPMSl, and hPMS2. Mutations in these genes lead to microsatellite instability (MSI), which is found in more than 85% of colorectal tumors from patients with HNPCC (Lynch and de la Chapelle, 1999). A germline mutation in transforming growth factor beta type II has been described in an atypical family (Lu et al, 1998). hMSH6 mutations tend to occur in families with endometrial cancer and in older patients with colorectal cancer.
Pathologically, colorectal cancers from HNPCC patients are characterized by poor differentiation, mucin production, Crohn's-like reaction, and an intense lymphocytic infiltrate (Jass et al, 1994). Even though some of these characteristics (mucin and poor differentiation) indicate a worse prognosis, HNPCC patients with colorectal cancer have been reported to have a better prognosis stage for stage than patients with sporadic colorectal cancer (Watson et al, 1998; Lynch and de la Chapelle, 1999). It is important to note that adenomas do occur in patients with HNPCC. Currently it is believed that adenomas in patients with HNPCC progress to carcinoma more quickly than do adenomas in patients with sporadic colorectal cancer.
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