HPV in oropharyngeal squamous papillomas: a missing link in head and neck viral pathogenesis

The role of human papillomaviruses (HPV) in oropharyngeal squamous papillomas remains incompletely defined, in contrast to their established involvement in oropharyngeal squamous cell carcinoma and laryngeal papillomatosis. This study aimed to assess HPV prevalence, genotype distribution, and associated biomarker expression in oropharyngeal papillomas, with particular emphasis on p16 and viral E4 protein immunoexpression. We retrospectively analyzed 51 formalin-fixed paraffin-embedded oropharyngeal squamous papillomas diagnosed between 2015 and 2023. HPV DNA detection and genotyping were performed using the INNO-LiPA assay. Immunohistochemistry for p16 and E4 was correlated with HPV status. For comparison, 20 oropharyngeal squamous cell carcinomas were included as controls, comprising 10 HPV16-positive and 10 HPV-negative cases. HPV DNA was detected in 57% of papillomas, predominantly high-risk genotypes, most frequently HPV16. E4 immunoexpression was observed in 55.5% of evaluable cases and was significantly associated with HPV DNA positivity (p < 0.0001). In contrast diffuse p16 overexpression was uncommon and showed no significant association with HPV detection. The prevailing immunophenotype in HPV-positive papillomas was E4 + /p16-, whereas HPV16-positive carcinomas uniformly exhibited a p16 + /E4- profile. No statistically significant differences in recurrence, dysplasia, or malignant transformation were observed between HPV-positive and HPV-negative papillomas, although adverse events occurred exclusively in high-risk HPV-associated cases. These findings suggest that a substantial subset of oropharyngeal squamous papillomas is associated with productive high-risk HPV infection, biologically distinct from transforming infections seen in carcinoma. While combined E4/p16 immunoprofiling may contributed to lesion characterization and prognostic stratification, its clinical utility warrants validation in larger, prospective cohorts.