---------------------------- 2015 Platform Presentation Winner --------------------------

[1257] Universal Lynch Screening in Endometrial Cancers: An Examination of Immunohistochemical Subgroups and Associated Clinical and Histologic Features

Jaclyn C Watkins, Lynette M Sholl, Brooke E Howitt. Brigham & Women's Hospital, Boston, MA

Background: Endometrial carcinoma (EMC) is the first malignancy diagnosed in 50% of women with Lynch syndrome (LS). Although screening for LS in colorectal cancer (CRC) is widely accepted, universal screening in EMC is still debated.
Design: Our prospective IRB-approved study included all EMC resected from 10/2013-9/2014 (n=125). All tumor slides were assessed for morphologic features including histologic subtype (endometrioid E, serous S, undifferentiated U), grade (G), and tumor infiltrating lymphocytes. Patient age, BMI, and personal or family history (FH) of malignancy were recorded. Immunohistochemistry for MMR proteins MSH2, MSH6, MLH1, and PMS2 was performed.
Results: The average age in our cohort was 62.7y (range 27-87y). Histotypes included E (100; 80%: 78 G1, 17 G2, 12 G3, and 2 biphasic G1/3), S (10; 8%), carcinosarcoma (2; 1.6%), U (2; 1.6%), mixed E and S (7; 5.6%), and other mixed subtypes (3; 2.4%). MMR abnormalities included loss of MSH2/MSH6 (3; 2.4%; all E), loss of MSH6 (1; 0.8%; mixed E and U), or loss of MLH1/PMS2 (20; 16%; 19 pure E and 1 mixed E and U). In cases with MLH1 loss, 1 case (5%) was unmethylated. Patients with presumed LS were overall younger than those with MMR-intact tumors (48.5 vs. 62.8y, p=0.006); however, of the 5 cases with presumed LS (loss of MSH2/MSH6, MSH6 only, or MLH1 without promoter methylation), only 3 were < 50 y, (accounting for 27.3% of EMC in women < 50y). None of the patients had a prior history of cancer. The patient with an unmethylated MLH1 deficient tumor had a paternal history of MLH1 germline mutation, and multiple relatives with CRC and EMC. Of the 4 remaining MMR-deficient cases, 1 had a FH of maternal breast cancer, and another had a FH of maternal breast cancer and multiple maternal relatives with EMC. The remaining 2 had unremarkable FH. Tumors with MLH1 methylation were more likely to be G3 (p=0.006).
Conclusions: Screening guidelines for LS in EMC based on age, FH, and tumor morphology would miss 40% of presumed LS patients at our institution accounting for 4% of EMC. LS-related tumors displayed no prototypical histomorphology. Tumors with MLH1 methylation were the only MMR deficient tumors to display a significantly different morphology, having a statistically significant association with G3 EMC. Our findings support the use of universal screening for LS using MMR IHC in women with EMC.