Histopathological Features and p16/p62 Expression as Indicators of High-Risk HPV Co-Infection in Anogenital Condyloma Acuminata

Background: Condyloma acuminata (CA) is primarily caused by low-risk human papillomavirus (LR-HPV); however, high-risk HPV (HR-HPV) co-infection is increasingly reported and cannot be reliably distinguished based on clinical appearance alone. Histopathological assessment and selected immunohistochemical markers may help identify lesions with greater biological risk. Objective: To evaluate the association between histopathological features, p16 and p62 expression, and HR-HPV co-infection in anogenital CA. Methods: This cross-sectional study included 81 histopathologically confirmed CA cases. Semi-quantitative scoring was applied to lesion morphology, keratinization patterns, koilocytosis, atypical mitoses, and lymphocytic infiltration. p16 and p62 expression were assessed immunohistochemically. HPV genotyping was performed using real-time PCR. Variables significant in bivariate analysis were entered into multivariate logistic regression. Results: HR-HPV co-infection was detected in 59.3% of cases, with HPV-16 as the most frequent genotype. Hyperkeratosis (aOR = 4.29; p = 0.039) and atypical mitotic activity (aOR = 14.29; p < 0.001) were independently associated with HR-HPV co-infection. Parakeratosis and koilocytosis showed inverse associations. p16 and p62 were not independent predictors, although p16 block positivity correlated with high p62 expression (p < 0.001). Conclusion: Certain histopathological features, particularly atypical mitoses and hyperkeratosis, are associated with HR-HPV co-infection in anogenital CA. Routine histopathological evaluation may therefore provide practical clues to identify lesions that warrant closer clinical attention, while p16 and p62 offer complementary biological information. Plain Language Summary: Condyloma acuminata, also known as genital warts, is usually caused by low-risk types of human papillomavirus (HPV). However, some genital warts also contain high-risk HPV types that are associated with a greater chance of developing serious disease. These high-risk infections cannot always be recognized by visual examination alone, especially in healthcare settings without access to specialized HPV tests. In this study, we examined genital wart tissue under a microscope for features that might indicate a high-risk HPV infection. We focused on visible changes in the skin cells, such as abnormal cell division and thickening of the outer skin layer. We also studied two laboratory markers, p16 and p62, which reflect how cells respond to HPV infection. We found that abnormal cell division and certain keratinization changes were more common in warts with high-risk HPV. In contrast, p16 and p62 alone could not reliably identify high-risk HPV. These results show that routine microscopic examination can still provide useful clues about which genital warts may require closer medical attention. This is particularly valuable in settings where advanced HPV testing is unavailable, helping doctors and pathologists determine which patients may benefit from closer monitoring.