LAUSR

INTRODUCTION Based on their etiological relationship with human papillomavirus (HPV), the 2020 WHO classification has divided vulvar squamous cell carcinomas (VSCC) into two distinct types, HPV-associated and HPV-independent, and HPV-independent tumours have recently been divided according to p53 status. Nevertheless, the clinical and prognostic significance of this classification has not been clearly established. We analysed the differential clinical, pathological, and behavioural characteristics of these three types of VSCC in a large series of patients. METHODS AND RESULTS VSCC samples from patients who underwent primary surgery at the Hospital Clinic of Barcelona, Spain, during a 47-year period (January 1975 to January 2022) were analysed (n = 190). HPV detection, p16, and p53 immunohistochemical staining were evaluated. We also analysed recurrence-free survival (RFS) and disease-specific survival (DSS). Thirty-three tumours (17.4%) were HPV-associated and 157 (82.6%) HPV-independent. Of these, 20 showed normal and 137 abnormal p53 expression. The two types of HPV-independent tumours showed worse RFS in the multivariate analysis (hazard ratio [HR] = 3.63; P = 0.023 for the HPV-independent p53 normal VSCC and HR = 2.78; P = 0.028 for the HPV-independent p53 abnormal VSCC). Although the differences were not significant, HPV-independent VSCC had worse DSS than HPV-associated VSCC. Although patients with HPV-independent p53 normal tumours had worse RFS than patients with HPV-independent p53 abnormal tumours, the DSS was better for the former group. Only advanced FIGO stage was associated with worse DSS in multivariate analysis (HR = 2.83; P = 0.010). CONCLUSION The association of HPV and p53 status have prognostic implications, reinforcing a three-tier molecular classification of VSCC (HPV-associated VSCC, HPV-independent VSCC with normal p53, HPV-independent VSCC with abnormal p53).