Prognostic impact of tumor budding in endometrial carcinoma within distinct molecular subgroups

Tumor budding is a robust prognostic parameter in several tumor entities but is rarely investigated in endometrial carcinoma. We applied the recently standardized counting method from the International Tumor Budding Consensus Conference for colorectal cancer (ITBCC) on a cohort of 255 endometrial carcinomas with known molecular profiles according to The Cancer Genome Atlas (TCGA) subgroups. Our investigation aims to clarify the potential prognostic role of tumor budding in endometrial carcinoma in contrast to other known prognostic factors, including molecular factors. In addition, the microcystic elongated and fragmented (MELF) pattern and tumor budding were compared with respect to their potential as markers for epithelial-mesenchymal transition (EMT). Tumor budding was found in n = 67 (26.3%) tumors, with a very low mean of 0.7 buds per ×20 HE field. Tumor budding was significantly associated with depth of invasion, nodal status, lymphatic invasion (each p < 0.001), grading (p = 0.004), and vascular invasion (p = 0.01). Tumor budding showed moderate inter-observer-variability with prognostic stratification irrespective of the observer (κ-value = 0.448). In multivariate analysis, tumor budding served as a significant independent prognosticator for worse outcomes in overall and recurrence-free survival (HR 2.376 and 2.736, p < 0.001), but not when the TCGA subgroups entered into the analysis. In consequence, dependency had to be clarified in the subgroup analysis for Polymerase E mutated (POLEmut), mismatch repair deficient (MMRdef), nonspecific mutation profile (NSMP), and P53 aberrant (P53abn) endometrial carcinomas. A particular impact was identified in the intermediate prognostic groups of NSMP and MMRdef carcinomas. Tumor budding outperformed the MELF pattern in single and combined prognostic information. In conclusion, the presence of tumor budding alone is a promising, robust, and easy-to-apply prognostic parameter in endometrial carcinoma. In a morpho-molecular approach, it exerts its prognostic potential in the most clinically relevant subgroups of endometrial carcinoma and serves as a good biomarker for EMT.