A review of reviews of the prevalence of molecular biomarkers in vulvar cancer and their implications for prognosis refinement and treatment strategies

Background: To clarify the prevalence and clinical utility of molecular biomarkers in vulvar cancer, we performed a review of systematic and high-quality narrative reviews, complemented by interrogation of public repositories containing genomic datasets. Our objectives were to (i) quantify biomarker prevalence across vulvar cancer subtypes, (ii) evaluate their prognostic and predictive value, and (iii) identify actionable therapeutic targets. Methods: A review of reviews following the Joanna Briggs Institute's Manual for Evidence Synthesis was conducted using MEDLINE, Scopus, Web of Science, and ProQuest from inception to October 1, 2025 (PROSPERO CRD420251080015). Additional genomic data were obtained from cBioPortal, SRA, GEO, EGA, Zenodo. Eligible publications were systematic or high-quality narrative reviews (SANRA ≥8/12) reporting the prevalence or clinical associations of molecular biomarkers in primary or recurrent vulvar malignancies. Systematic reviews were appraised with AMSTAR-2 and narrative reviews with SANRA by two blinded reviewers, with arbitration by a third when needed. Biomarkers' pooled prevalence estimates were generated, and prognostic or predictive associations were synthesized. Public sequencing datasets were examined to identify clinically actionable alterations. Results: Thirteen reviews (four systematic with meta-analysis, and nine narrative) met the inclusion criteria. HPV-independent vulvar tumors showed high pooled prevalences of TP53 mutations (0.57, 95% CI 0.43–0.71) and CDKN2A alterations (0.16, 95% CI 0.09–0.25), both linked to poorer survival and increased recurrence. HPV-associated vulvar squamous cell carcinomas demonstrated strong p16^INK4A overexpression (0.84, 95% CI 0.72–0.94), correlating with more favorable outcomes. Recurrent PIK3CA, HRAS, and FGFR3 variants emerged as potential therapeutic targets. Activating BRAF and c-KIT mutations were frequent in vulvar melanoma, while ERBB2/HER2 amplification was noted in invasive Paget disease. Conclusions: Molecular profiling underscores the biological heterogeneity of vulvar cancer and suggests opportunities for improved risk stratification and targeted therapy. Validation in prospective biomarker-driven trials is needed before routine clinical adoption.