Mucinous Differentiation with Tumor Infiltrating Lymphocytes Is a Feature of Sporadically Methylated Endometrial Carcinomas

Defects in the DNA mismatch-repair system are identified in ∼25%-30% of endometrial carcinomas (ECs). Whereas some ECs are due to germline Lynch syndrome (LS)-associated mutations, the majority demonstrate sporadic MLH1 promoter hypermethylation (MLH1hm). MLH1hm characterizes a unique subset of colorectal cancers with a relatively poor prognosis; however, the morphology and behavior of sporadically methylated ECs (SMECs) are less well understood. We herein review the clinicopathologic features of 34 SMECs diagnosed at The University of Virginia and compare them with LS-associated and Lynch-like endometrial cancers. Most SMECs were centered in the uterine fundus (74%) and displayed Grade 1 (35%) or Grade 2 (41%) endometrioid morphology. Mucinous differentiation was present in 50%, and 65% showed tumor-infiltrating lymphocytes. Cases with undifferentiated components or sarcomatous differentiation were relatively rare (9%). Most SMECs presented at stage 1 or 2 (91%). When compared with LS and Lynch-like endometrial cancers, SMECs occurred ∼8 yr later and were significantly more likely to show conventional endometrioid morphology (P=0.04), mucinous differentiation (P=0.002), and tumor-infiltrating lymphocytes (P=0.002). These findings suggest that SMECs constitute a clinicopathologically distinct subset of mismatch-repair-deficient/high-level microsatellite instability tumors. Future studies are needed to further understand the implications of MLH1hm on the prognosis and treatment of endometrial cancer.