The lifetime risk of CRC in MLH1 and MSH2 mutation carriers was 68.7% in males and 52% in females. However, in a meta-analysis of three population-based studies and a clinic based study, the lifetime risk of CRC in MLH1 and MSH2 mutation carriers was reported to be 53% in males and 33% in females.[208,209] In a study of 113 families with MSH6 mutation carriers, the estimated cumulative risk of CRC in males was 22% and 10% in females.PMS2 lifetime CRC risk to age 70 has been reported to be 20% in males and 15% in females.
Patients with LS can have synchronous and metachronous colorectal neoplasms and other primary extracolonic malignancies. LS mutation carriers have an increased risk of developing colon adenomas (hazard ratio = 3.4), and the onset of adenomas appears to occur at a younger age than in nonmutation carriers from the same families. Unlike patients with sporadic cancers, whose cancer develops most often in the left side of the colon, approximately two-thirds of LS cancers develop in the right side of the colon, defined as proximal to the splenic flexure.
In addition to CRC, LS patients and their relatives are at risk for a wide variety of other cancers. The most common is endometrial adenocarcinoma, which affects at least one female member in about 50% of LS pedigrees. The lifetime risk of endometrial cancer in MLH1 and MSH2 mutation carriers has been estimated at 44% to 54%.[207,208,209,210] Families with a MSH6 mutation have been reported to have an endometrial cancer predominance. Lifetime risk of endometrial cancer in MSH6 mutation carriers in 113 families was estimated to be 26% at age 70 and 44% at age 80. In PMS2 mutation carriers, the endometrial cancer risk at age 70 has been reported to be 15%. Endometrial cancer can be the index cancer in female LS patients. LS-associated endometrial cancer is not limited to the endometrioid subtype. Endometrial adenocarcinoma, clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed M�llerian tumors are part of the spectrum of uterine tumors in LS. Patients with LS are also at risk for transitional cell carcinoma of the ureters and renal pelvis, and cancers of the stomach, small intestine, liver and biliary tract, brain, and ovary.[214,215,216,217]
Muir-Torre syndrome is considered a variant of LS and includes a phenotype of multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas). The skin lesions and CRC define the phenotype,[218,219] and clinical variability is common. Both mutations in the MSH2 and MLH1 genes have been found in Muir-Torre families.[220,221,222] A study of 1,914 MSH2 and MLH1 unrelated probands found MSH2 to be more common in individuals with the Muir-Torre syndrome phenotype.