OBJECTIVE: Treatment approaches for endometrial cancer became more personalized in the last decade, mainly due to two key advancements - sentinel lymph node (SLN) mapping and molecular classification. However, their prognostic interaction remains relatively unexplored. METHODS: This retrospective cohort study included patients with endometrial cancer, who underwent surgical treatment including SLN mapping at the Bern University Hospital, Switzerland. Ultrastaging of the SLNs and a molecular analysis on the primary tumor was performed. RESULTS: The study cohort included 206 patients, of which 197 tumor samples underwent molecular classification. 11.2 % were classified as POLEmut, 25.9 % as MMRd, 46.2 % as NSMP, and 16.8 % as p53abn. Overall, 834 SLN were removed. SLN macrometastasis were most prevalent in patients with p53abn tumors (24.2 %), followed by MMRd (13.7 %), NSMP (5.5 %), and POLEmut (0 %) tumors (p = .006). Mean follow-up time was 70.9 months. SLN macrometastasis was significantly associated with a higher risk of recurrence in the entire study cohort (p >
.001) and the NSMP subgroup (p >
.001). In the MMRd subgroup, SLN macrometastasis remained a significant predictor of recurrence (p = .030) and disease-specific death (p = .047) in multivariate Cox regression analysis. For patients with p53abn endometrial cancer, there was no association between SLN macrometastasis and risk of recurrence (p = .618) or disease specific death (p = .798). CONCLUSIONS: SLN macrometastasis is an independent predictor of recurrence and disease-specific death in patients with MMRd endometrial cancer. In the subgroup of p53abn endometrial cancers, SLN macrometastasis did not have an added impact on oncological outcome.