Validation of Tumor Budding as a Prognostic Factor in Ovarian Clear Cell Carcinoma Using an Independent Cohort.

Ovarian clear cell carcinoma (OCCC) is an endometriosis-related neoplasm, in which traditional histologic grading does not show prognostic significance. Tumor budding was associated with poorer outcomes in OCCC in previous studies. We aimed to evaluate the prognostic significance of tumor budding in OCCC in an independent cohort. Seventy patients diagnosed with OCCC were retrospectively identified. Slides from primary ovarian resections were reviewed by 2 pathologists blinded to outcomes. Tumor budding was defined as single or clusters of <5 tumor cells in peritumoral and/or intratumoral nonhyalinized stroma. Most patients were diagnosed at an early stage (stage I: 69%; II: 20%; III: 10%; IV: 1%). Twenty-one patients experienced recurrences (30%) and 2 progressive disease (3%). At the last follow-up, 52 patients had no evidence of disease, 6 were alive with disease, and 12 died of disease. The median follow-up time was 66.7 mo. Tumor budding was identified in 41 cases (59%) with a kappa coefficient of 0.60. On univariate analysis, tumor budding (P=0.022) and stage (P=0.0005) were associated with shorter progression-free survival (PFS), but only stage was independently associated with shorter PFS on multivariate analysis (P=0.003). Higher stage was the only variable associated with shorter overall survival (P=0.037). Tumor budding was associated with higher stage (P=0.039), absence of endometriosis (P=0.042) and adenofibroma (P=0.046), tumor-associated inflammation (P=0.002), and higher mitotic activity (P=0.022). There was no association between tumor budding and molecular characteristics in 32 cases with somatic tumor sequencing. Tumor budding was not independently associated with worse outcomes in this cohort of OCCC, although it was significantly associated with specific clinicopathologic features, including higher stage. Stage was the only independent variable predictive of poorer survival, which appears to drive the prognostic significance of tumor budding.