FROM BENIGN WARTS TO SQUAMOUS NEOPLASIA: HISTOPATHOLOGICAL AND MOLECULAR FEATURES OF HPV-ASSOCIATED CUTANEOUS AND ANOGENITAL LESIONS-A SYSTEMATIC REVIEW

Abstract

Background: Human papillomaviruses (HPVs) comprise a genetically diverse group of epitheliotropic viruses associated with benign, premalignant, and malignant lesions of cutaneous and anogenital epithelia. Although characteristic microscopic changes such as papillomatosis, hyperkeratosis, koilocytosis, and epithelial dysplasia can suggest HPV infection, the relationship between morphology, HPV genotype, transcriptionally active viral infection, and host-cell biomarkers varies considerably by anatomical site and lesion type. Objective: To systematically synthesize the histopathological and molecular findings of HPV-associated cutaneous and anogenital lesions, with particular emphasis on HPV genotype distribution, p16INK4a, p53, Ki 67, E6/E7 expression, and viral DNA/RNA detection. Methods: A systematic literature search was conducted for studies available up to June 2026. The review followed the PRISMA 2020 framework. Search concepts combined human papillomavirus/HPV with terms relating to cutaneous warts, epidermodysplasia verruciformis, cutaneous squamous cell carcinoma, condyloma, vulvar, anal and penile squamous lesions, histopathology, HPV genotype, p16, p53, Ki-67, E6/E7, polymerase chain reaction, and in situ hybridization. Ninety-five records were identified. After removal of 6 duplicates, 89 records underwent title and abstract screening. Fifty-two records were excluded and 37 reports were sought for retrieval. One report could not be retrieved, leaving 36 full-text reports for eligibility assessment. Fifteen full text reports were excluded with documented reasons, and 21 studies were included in the qualitative synthesis. Owing to substantial clinical and methodological heterogeneity, meta-analysis was not undertaken. Results: The included studies showed distinct biological patterns across cutaneous and anogenital disease. Benign cutaneous warts demonstrated papillomatosis, acanthosis, hyperkeratosis, hypergranulosis, and variably conspicuous koilocytosis, with HPV1, HPV2, HPV27, and HPV57 among the principal genotypes. Epidermodysplasia verruciformis showed enlarged keratinocytes with blue-gray cytoplasm and abnormal keratohyalin granules and was predominantly associated with beta-HPVs. Transcriptionally active high-risk alpha-HPV was uncommon in ordinary non-anogenital cutaneous squamous cell carcinoma. In contrast, high grade anogenital intraepithelial lesions and subsets of vulvar, anal, and penile squamous cell carcinoma were characterized by oncogenic HPV, particularly HPV16, diffuse block-type p16 expression, increased proliferative activity, and E6/E7 transcription. HPV-independent vulvar and penile carcinomas more frequently exhibited keratinizing differentiation and abnormal p53-associated pathways. Conclusion: HPV-associated cutaneous and anogenital lesions represent biologically heterogeneous diseases. Histopathology remains central to diagnosis, but molecular classification substantially improves etiological assignment in high-grade and malignant lesions. HPV DNA positivity alone should not be equated with HPV driven neoplasia. Integrated evaluation combining morphology, anatomical site, HPV genotype or transcriptional status, and appropriately interpreted biomarkers provides the most biologically meaningful diagnostic framework.