Tumor lymphocytic infiltration impacts recurrence in endometrioid-type endometrial carcinoma.

Abstract

e15239 Background: Endometrial cancers that have mismatch repair deficiency are associated with higher numbers of tumor-associated lymphocytes, but the clinical significance of this observation is unknown. Our objective was to quantify CD3+ and CD8+ tumor lymphocytes of MMR intact (MMRi) and MMRd endometrioid-type endometrial carcinomas and determine if there was an association with survival. Methods: MMRd was defined as endometrial carcinomas with loss of MLH1 expression due to MLH1 gene methylation and determined by immunohistochemistry. MMRi was defined as positive expression of MLH1, MSH2, MSH6, and PMS2. This was followed by Aperio image-based quantification was used to assess CD3+ and CD8+ lymphocyte populations in different regions of the primary endometrial carcinomas, including tumor periphery (tumor-myometrial interface), tumor center (bounded on all sides by tumor), and tumor hotspot (area with highest number of lymphocytes). Recurrence-free survival was estimated using Kaplan Meier and Cox regression. Median follow up time was 44 months. Results: 180 patients with endometrial carcinoma were analyzed of which 132 were MMRi and 48MMRd. The MMRd group had significantly higher levels of CD3+ and CD8+ lymphocytes regardless of which tumor region was assessed (Figure 1a, P < 0.001). Lymphocyte counts in both MMRd and MMRi groups had wide standard deviations such that there was some overlap in counts between the groups (Figure 1). Both MMRd and higher CD3+ counts were associated with worse recurrence-free survival. CD3+ quantification in the tumor periphery captured 21/23 recurrences (Figure 1b, HR = 8.04; 95% CI: 1.88 -34.31; p = 0.005); this included all of the MMRd cases that recurred and 7 MMRi cases with higher numbers of CD3+ lymphocytes that also recurred. Conclusions: MMRd endometrial cancers have increased numbers of CD3+ lymphocytic infiltrates within the primary tumor. Higher CD3+ infiltration is associated with greater risk of recurrence regardless of tumor location. In predicting tumor recurrence, lymphocytic counts performed better than assessment of MMR. Thus, quantification of CD3+ lymphocytes should be explored as a predictive biomarker.