Independent Validation of Tumor Budding Activity and Cell Nest Size as Determinants of Patient Outcome in Squamous Cell Carcinoma of the Uterine Cervix.

A novel 3-tiered grading system that combines tumor budding activity and cell nest size has been found to be highly prognostic in squamous cell carcinomas (SCCs) of various sites, including lung, oral cavity, larynx, hypopharynx, and esophagus. A similar grading system has recently been proposed for SCC of the uterine cervix. In this study, we appraise this grading system in an institutional cohort of cervical SCC to assess its prognostic value in an independent dataset. Our study cohort consisted of 94 consecutive, surgically excised, neoadjuvant therapy-naive cases of SCC of the uterine cervix, stage pT1b or higher. Tumor budding activity and cell nest size were scored on each case, the sum of which formed the basis for assigning a grade in the 3-tiered grading system hereafter referred to as the "tumor budding/nest size" (TBNS) system. As individual variables, both high tumor budding and small nest size were each associated with reduced overall survival (OS), disease-specific survival, and disease-free survival. The full TBNS system was associated with decreased OS, disease-specific survival, and disease-free survival independent of patient age, pathologic stage, and regional lymph node status. TBNS grades 1, 2, and 3 subgroups were clearly distinguishable on multivariate analyses (hazard ratio for OS of 2.06 [95% confidence interval: 0.5-8.42] for grade 2 and 4.58 [95% confidence interval: 1.24-16.87] for grade 3 tumors, relative to their grade 1 counterparts [P=0.035]). Higher grade tumors in the TBNS system were significantly correlated with advanced pathologic stage and lymph node metastasis (P=0.044 and 0.04, respectively). Among the other, potentially prognostic factors, higher pathologic stage, and lymph node metastasis were associated with decreased OS (P<0.001 and 0.004, respectively), whereas keratinization, nuclear size, mitotic count, and World Health Organization (WHO) grade were not. In conclusion, the proposed TBNS grading system is an excellent prognostic indicator that may potentially provide information that is useful in clinical decision-making. Our findings validate the previous study that proposed this system for prognostically stratifying cervical SCC patients. If further confirmed, consideration should be given to routinely adding a TBNS grade to pathologic descriptions of cervical SCC.