Tumor Budding Activity is an Independent Prognostic Factor of Recurrence in Human Papillomavirus-Independent p53-Abnormal Squamous Cell Carcinoma of the Vulva

Outcomes of vulvar squamous cell carcinoma (vSCC) are driven by human papillomavirus (HPV) and p53 status. As tumor budding activity (TBA) and tumor-stroma ratio (TSR) are prognostic in other carcinomas, we evaluated their significance in vSCCs. Tumors diagnosed from 1990 to 2022 were identified, and clinicopathologic data, TBA, and TSR were assessed. The cohort included 172 tumors: 73 (42.5%) HPV-associated, 74 (43%) HPV-independent/p53-abnormal, and 25 (14.5%) HPV-independent/p53-wild-type. Median patient age was 69.5 (22 to 98) years. Most tumors were staged as pT1b (132, 76.7%). Lymphovascular invasion (LVI) was present in 25 (14.5%), and lymph node metastases in 24.6% (33/134) of cases with nodal evaluation. The median TBA was 2 (0-45)/1 high-power field (HPF), 4 (0-198)/5 HPF, and 5 (0-304)/10 HPF. The median TSR was 60% (10% to 90%). Seventy (40.7%) patients experienced recurrences (median: 14 mo, 2-141). Increased TBA at ≥20/10 HPF was associated with shorter recurrence-free survival (RFS) in the entire cohort (P=0.002) and HPV-independent/p53-abnormal vSCCs (P=0.003). This association persisted in the HPV-independent/p53-abnormal vSCCs after adjusting for LVI, and T and N categories of pTNM stage (P=0.012), and in the entire cohort after adjusting for tumor subtype and other covariates (P=0.01). TBA was also associated with shorter disease-specific (P=0.048) and overall (P=0.009) survival after adjusting for tumor subtype, LVI, and T and N categories. Our study suggests that high TBA is associated with shorter recurrence-free survival in vSCC, particularly the HPV-independent/p53-abnormal subgroup, as well as with shorter disease-specific and overall survival after adjusting for tumor subtype, LVI, T and N categories. The findings warrant further validation.