Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients

SIMPLE SUMMARY: Rrisk assessment of microsatellite instability (MSI) and copy-number (CN)-low endometrial adenocarcinomas constitutes a major challenge. We aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification, comprehensively analyzing one finding cohort (TCGA-UCEC) and two independent validation cohorts. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor–stroma ratio, tumor-infiltrating lymphocytes (TIL), “microcystic, elongated, fragmented” (MELF) pattern) were analyzed. For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. In MSI tumors, TB (≥3 buds/high-power field) was detected to be an independent prognostic factor for inferior outcomes and lymph node metastases. The finding was confirmed in two validation cohorts. For CN-low tumors, solely WHO grading was independently prognostic with inferior outcomes for high-grade tumors. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management. ABSTRACT: The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor–stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), “microcystic, elongated, fragmented” (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort (n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management.