Molecular subtypes of stage III vulvar squamous cell carcinoma predict recurrence and survival outcomes.

Although molecular classification has been associated with outcomes in vulvar squamous cell carcinoma (vSCC), its relevance in patients with stage III disease is less well characterized. We evaluated the association between molecular subtype and oncologic outcomes among patients with 2021 FIGO stage III vSCC. We conducted a retrospective study of patients with primary stage III vSCC treated at a single institution from 2000 to 2021. Tumors were classified as HPV-associated (HPV+), HPV-independent/p53 wild-type (HPV-/p53wt), or HPV-independent/p53 mutant (HPV-/p53mut) using HPV RNA in situ hybridization and p16 immunohistochemistry (IHC) for HPV status and p53 IHC as a surrogate for TP53 mutation status. Primary outcomes were recurrence and disease-specific mortality within five years from primary treatment evaluated using Cox proportional hazards and Kaplan-Meier survival analysis. Fifty-two patients had complete molecular data: 32.7% HPV+, 21.2% HPV-/p53wt, and 46.2% HPV-/p53mut. Smoking was associated with HPV+ tumors (p < 0.001). Within five years, 46.2% experienced recurrence (median 11 months, IQR 7.3-29.2). The highest proportion of recurrences occurred in the HPV-/p53mut group, and most groin recurrences occurred in HPV-independent tumors; however, HPV/p53 status was not significantly associated with five-year recurrence (p = 0.22). For disease-specific survival, HPV-/p53mut tumors were associated with a 5.7-fold increased risk of disease-specific death compared with HPV+ tumors (HR 5.70, 95% CI 1.66-19.62). Molecular classification distinguishes clinically meaningful subgroups in stage III vSCC. HPV-independent tumors, particularly those with TP53 mutation, are associated with worse disease-specific survival and supports further evaluation of molecularly informed risk stratification and treatment approaches.