Abstract Background: Vulvar squamous cell carcinoma (VSCC) is molecularly classified into two subtypes in the 2020 WHO Classification of Tumors: HPV-dependent, which is associated with a more favorable prognosis, and HPV-independent, which is more aggressive and typically requires intensified surgical treatment. The HPV-dependent subtype is particularly relevant in South Africa, where the high prevalence of HIV contributes to increased HPV infection rates. While younger women with HPV-associated VSCC may be candidates for conservative surgical management, the global literature supporting this approach is limited, particularly in low-resource settings with high HPV prevalence. Furthermore, South African HPV vaccination guidelines are restricted to school-aged children and have not been updated to reflect international recommendations for individuals living with HIV. The primary aim of this study was to classify VSCC into the three-tiered molecular classification of VSCC: HPV-dependent, p16 positive; and HPV-independent types, p16 negative/TP53 wild-type and p16 negative/TP53 mutant, using p16 and p53 IHC stains. Methods: This retrospective study analyzed cases from Tygerberg Hospital National Health Laboratory Services in South Africa. Tumors were subclassified using p16 and p53 immunohistochemistry (IHC), with HPV genotyping performed where sufficient tissue was available. Data were coded and statistically analyzed to address the study objectives. Results: Of the total cases, 78 (87.6%) were classified as HPV-dependent, 1 (1.1%) as HPV-independent with wild-type p53, and 10 (11.2%) as HPV-independent with mutant p53 expression. The sensitivity of p16 for identifying HPV-dependent tumors was 97.7%, with a specificity of 50%, likely influenced by the small number of HPV-independent cases. A statistically significant association was found between HIV status and HPV-dependent tumors (p 0.001). Conclusion: The predominance of HPV-dependent VSCC in this cohort highlights the importance of adapting clinical management strategies in high HIV-prevalence settings. These findings support the need for broader HPV vaccination policies, particularly for individuals living with HIV, and suggest that conservative surgical approaches may be appropriate in selected cases. This study also establishes a foundation for further research on the molecular pathology of VSCC in sub-Saharan Africa and underscores the feasibility of implementing molecular subclassification in resource-limited environments. Citation Format: Mukuzo Fortunat. Bagula, Rubina Razack, Jenny Butt, Micheline Sanderson. Application of the molecular subclassification of vulvar squamous cell carcinoma in a South African patient cohort abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C042.
Bagula et al. (Thu,) studied this question.