HPV42: From a Low-Risk Genotype to a Potentially Oncogenic Virus

Human papillomavirus 42 (HPV42), initially classified as a low-risk (LR) genotype isolated from benign vulvar papillomas, has long been associated with benign lesions such as anogenital warts. However, recent studies have uncovered its unexpected oncogenic potential, challenging its traditional classification. HPV42 has been identified as a causative driver of digital papillary adenocarcinoma (DPA), a rare and aggressive cutaneous tumor, and is also linked to high-grade squamous intraepithelial lesions (HSIL) in the cervix and anus, as well as frequent infections in the oropharyngeal region. The molecular hallmarks of HPV42-induced carcinogenesis, including interactions with key tumor suppressor pathways and genomic integration, share striking similarities with high-risk (HR) HPV genotypes. This review synthesizes current evidence on the clinicopathological features, oncogenic mechanisms, epidemiological characteristics, and diagnostic implications of HPV42-associated diseases. We also discuss the need for re-evaluating HPV42's risk classification and its implications for prevention and clinical management. A comprehensive understanding of HPV42's pathogenic spectrum is crucial for addressing the unmet clinical needs in diagnosing and treating its associated lesions and tumors.