HUMAN PAPILLOMAVIRUS–ASSOCIATED CUTANEOUS AND ANOGENITAL LESIONS: A SYSTEMATIC REVIEW OF HISTOPATHOLOGICAL AND MOLECULAR FEATURES

Abstract

Background: Human papillomaviruses (HPVs) are epitheliotropic DNA viruses associated with lesions ranging from self-limited cutaneous warts to high-grade intraepithelial neoplasia and invasive squamous cell carcinoma. Their biological effects differ substantially between keratinized skin and the anogenital tract, making combined morphological and molecular interpretation important. Objective: To systematically synthesize histopathological and molecular features of HPV-associated cutaneous and anogenital lesions, with emphasis on genotype distribution, p16, p53, Ki-67, E6/E7 transcription, viral integration, and host genomic alterations. Methods: A structured review of literature published from January 2005 through 19 September 2026 was undertaken using 12 predefined evidence searches. The search generated 120 records; after removal of 14 duplicates, 106 unique records were screened. Sixty records were excluded at title/abstract stage, 46 full-text reports were assessed, 16 were excluded with prespecified reasons, and 30 original human studies entered qualitative synthesis. Meta-analysis was not performed because of heterogeneity in anatomical sites, viral assays, biomarker thresholds, and outcomes. Results: Cutaneous wart studies demonstrated broad genotype diversity. In histologically confirmed common warts, causative HPV was identified in 122 of 126 evaluable lesions in one series, with HPV27 predominating; a contemporary plantar-wart cohort reported overall HPV detection of 81.2%, with HPV1 accounting for 36.1%. Among 331 squamous cell carcinomas, koilocytes were present in 15.1%, rising to 38.1% in nail lesions and 60.0% in genital lesions. Bowen disease showed strong site dependence, with HPV DNA detected in 66.7% of genital versus 8.3% of extragenital lesions. Anogenital neoplasia showed stronger transforming signatures: p16 sensitivity approached 100% with specificity of 96–98.7% for HPV-associated vulvar carcinoma in selected studies; p16/E6-E7 concordance in anal SCC reached 96%. Penile SCC segregated into HPV-associated and HPV-independent pathways, with p53 providing additional stratification in the latter. Genomic studies identified HPV integration and recurrent host alterations involving pathways such as NOTCH1, FAT1, TP53, CDKN2A, CASP8, and chromatin-remodeling genes. Risk-of-bias assessment showed a low overall risk in 7 studies (23.3%), some concerns in 21 studies (70.0%), and high risk in 2 studies (6.7%); the principal concerns related to retrospective sampling, selected populations, small rare-tumor cohorts, and incomplete control of confounding. Conclusion: HPV-associated cutaneous and anogenital lesions are biologically heterogeneous. Histopathology remains the diagnostic foundation, while site-appropriate use of p16, p53, Ki-67, HPV DNA/RNA testing, and genomic profiling refines etiological classification. Evidence of viral transcription or pathway disruption is more informative for assigning HPV-driven carcinogenesis than viral DNA detection alone.