Prognostic implications of HPV and TP53 status in early-stage vulvar squamous cell carcinoma.

OBJECTIVE: To evaluate the prognostic significance of HPV and p53 status in patients with FIGO 2021 stage I vulvar squamous cell carcinoma (vSCC) treated with surgery alone. METHODS: We retrospectively identified patients with stage I vSCC treated surgically between 2000 and 2021 with available tissue for p16 immunohistochemistry (IHC), p53 IHC, and high-risk HPV RNA in situ hybridization. Tumors were classified as HPV+, HPV-/p53 wild-type (wt), or HPV-/p53 mutant (mut). Primary outcomes were 10-year disease-specific survival (DSS) and 5-year recurrence-free survival (RFS). Kaplan-Meier and Cox proportional hazards models were used. RESULTS: Among 195 patients, 176 had evaluable molecular data: 70 (39.8%) HPV+, 40 (22.7%) HPV-/p53wt, and 66 (37.5%) HPV-/p53mut. Most patients (81.3%) had stage IB disease. Ten-year DSS differed significantly by molecular subtype: 93.3% for HPV+, 81.9% for HPV-/p53wt, and 57.8% for HPV-/p53mut tumors (p < 0.001). Compared with HPV+ tumors, HPV-/p53mut tumors were associated with increased disease-specific mortality (adjusted hazard ratio [aHR] 5.43, 95% CI 1.22-24.09). Five-year RFS was 93.6% for HPV+, 52.5% for HPV-/p53wt, and 53.6% for HPV-/p53mut tumors (p < 0.001). Both HPV-/p53wt (aHR 7.57, 95% CI 2.50-22.95) and HPV-/p53mut tumors (aHR 7.70, 95% CI 2.63-22.56) were associated with recurrence. HPV-independent tumors accounted for 90.8% of recurrences and all groin recurrences. A tumor-free margin ≥3 mm was protective and remained significant among HPV-/p53mut tumors. CONCLUSIONS: Molecular classification identifies clinically distinct subgroups within stage I vSCC. HPV-/p53mut tumors demonstrate inferior survival, higher recurrence risk, and increased groin failure. Prospective studies are needed to determine whether molecular classification should inform treatment and surveillance strategies.