Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing
cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed
colorectal cancer using MMR
protein immunohistochemistry, we evaluated MMR
protein expression in a series of
endometrial cancers in the general population. A total of 605 consecutive cases of primary
endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR
proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated
endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2
protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing
hysterectomy specimen. Only 15% of patients had a prior history of
carcinoma, including only 2 patients with prior
colorectal carcinoma. Most (80%) of the
endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2
carcinosarcoma cases. When grading was applicable, 40% of the endometrial
malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the
tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family
cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated
tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated
endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed
endometrial cancers.