Clinicopathological characteristics of endometrial carcinomas according to DNA mismatch repair protein status

Author(s)

de Freitas, Daniela ; Aguiar, Fernando Nalesso ; Anton, Cristina ; de Almeida, Danielle Cristina ; Bacchi, Carlos Eduardo ; Carvalho, Jesus Paula ; Carvalho, Filomena Marino

• Document type: Journal article
• Source: HELIYON; v. 9, n. 6, p. 11-pg., 2023-06-01.

Abstract

DNA mismatch repair protein deficiency (MMRd) in endometrial carcinoma is associated with the risk of Lynch syndrome and response to immune checkpoint inhibitors. It is also related to mi-crosatellite instability and corresponds to a molecular subtype of endometrial tumor with an unclear prognosis. Here, we evaluated the clinicopathological characteristics and prognosis of 312 consecutive endometrial carcinoma cases submitted to complete surgical staging at a single institution. We compared MMRd and mismatch repair protein-proficient (MMRp) tumors and examined the effects of the MMR protein loss type (MLH1/PMS2 vs. MSH2/MSH6) and influence of L1CAM and p53 expression. The median follow-up period was 54.5 (range, 0-120.5) months. No difference was observed between MMRd [n = 166 (37.2%)] and MMRp [n = 196 (62.8%)] cases in terms of age, body mass index, FIGO stage, tumor grade, tumor size, depth of myometrial infiltration, or lymph node metastasis. More MMRd than MMRp tumors had endometrioid his-tology (87.9% vs. 75.5%) and despite MMRd had more lymphovascular space invasion (LVSI; 27.2% vs. 16.9%), they presented fewer recurrences and no difference in lymph node metastasis and disease-related death. Relative to those with MLH1/MSH6 loss, tumors with MSH2/MSH6 loss were diagnosed at earlier FIGO stages, were smaller, and had less & GE;50% myometrial inva-sion, LVSI and lymph node metastasis. Outcomes, however, did not differ between these groups. L1CAM positivity and mutation-type p53 expression were more common in MMRp than in MMRd tumors and did not differ between the MLH1/PMS2 and MSH2/MSH6 loss groups. In the entire cohort, L1CAM and mutation p53 expression were associated with worse prognosis, but only non-endometrioid histology, FIGO stage III/IV, and deep myometrial infiltration were significant predictors. In the subgroup of endometrioid carcinomas, only FIGO stage III/IV was associated with poor outcomes. The risk of lymph node metastasis was associated with tumor size, non-endometrioid histology, and multifocal LVSI. For MMRd tumors, only tumor size and myo-metrial invasion depth were predictive of lymph node involvement. In our cohort, MMRd tumors were associated with greater recurrence-free, but not overall, survival. The precise identification of MMRd status, present in a substantial proportion of endometrial cancer cases, is a challenge to be overcome for proper patient management. MMRd status serves as a marker for Lynch syndrome, and a significant number of these tumors are high risk and candidate to immunotherapy. (AU)

• FAPESP's process: 18/06717-8 - Role of adhesion molecules determined by immunohistochemical assays in the prediction of lymph node involvement and prognosis of endometrial carcinomas
• Grantee: Filomena Marino Carvalho
• Support Opportunities: Regular Research Grants