Carcinogenic mechanisms in penile cancer: HPV, inflammation, and other pathways

Objective: Penile cancer, though rare, carries profound clinical and psychosocial consequences. Its diagnosis often occurs at advanced stages, leading to mutilating surgeries and severe impairment in quality of life. Approximately 95% of penile malignancies are squamous cell carcinomas (SCCs), with a global 5-year cancer-specific survival rate of ~65%. Recent advances have shifted attention from purely oncologic outcomes toward understanding its molecular heterogeneity and etiopathogenesis. Growing evidence supports a dual carcinogenic model involving viral and non-viral pathways, driven respectively by human papillomavirus (HPV) infection and chronic inflammatory dermatoses. The objectives of the study are to synthesize current evidence on the molecular, immunologic, and epigenetic mechanisms underlying HPV-related and HPV-independent penile SCC, emphasizing their epidemiologic relevance, pathogenic interplay, and clinical implications. Materials and Methods: A critical appraisal of epidemiological, molecular, and immunological studies was conducted, and evidence was graded according to the Oxford classification for levels of evidence and strength of recommendation. Systematic searches were conducted in PubMed/MEDLINE, Scopus, Web of Science, and Literatura Latino-Americana e do Caribe em Ciências da Saúde, covering publications from January 2000 to October 2025. Search terms included (“penile cancer” OR “penile carcinoma” OR “penile squamous cell carcinoma” OR “cancer of the penis”) AND (“HPV” OR “human papillomavirus” OR “lichen sclerosus” OR “balanitis” OR “chronic inflammation” OR “carcinogenesis” OR “molecular mechanism” OR “tumor microenvironment” OR “epigenetics” OR “non-coding RNA” OR “APOBEC” OR “immune checkpoint” OR “p16” OR “TP53” OR “E6 oncoprotein” OR “E7 oncoprotein” OR “p16INK4a” OR “viral integration” OR “HPV DNA” OR “E6/E7 mRNA” OR “pRb inactivation” OR “p53 degradation” OR “CDKN2A methylation” OR “DNA methylation” OR “histone modification” OR “miRNA” OR “lncRNA” OR “piRNA” OR “cancer-associated fibroblast” OR “tumor-associated macrophage” OR “immune checkpoint” OR “PD-L1” OR “EBV” OR “HSV” OR “viral co-infection”). Studies were selected according to predefined inclusion criteria (systematic reviews, clinical trials, and cohort studies with histological confirmation) and exclusion criteria (case reports, series with <30 patients, and non-peer-reviewed sources). Evidence quality was graded using the Oxford Centre for Evidence-Based Medicine framework. Results: Two distinct but occasionally overlapping oncogenic mechanisms drive penile carcinogenesis. The HPV-related pathway, responsible for 30–50% of cases, is predominantly associated with HPV-16 and HPV-18. Viral oncoproteins E6 and E7 promote p53 degradation and retinoblastoma (pRb) inactivation, resulting in uncontrolled proliferation and p16^INK4a^ overexpression. Integration of viral DNA into the host genome disrupts regulatory genes and induces epigenetic alterations, including hypermethylation of CDKN2A and global hypomethylation. HPV-positive tumors typically exhibit lower mutational burden, higher immune infiltration, and improved prognosis. Nonetheless, HPV-driven lesions display enrichment of immunosuppressive cells (FoxP3+ regulatory T cells and CD163+ macrophages), and upregulation of immune checkpoints (programmed cell death 1, lymphocyte activation gene-3, T cell immunoglobulin and mucin-domain containing-3), favoring immune exhaustion and tumor persistence. Conversely, the HPV-independent pathway arises primarily from chronic inflammatory and dermatologic conditions such as lichen sclerosus and balanitis. Persistent inflammation generates oxidative stress and DNA damage, driving tumor protein 53 (TP53) mutations and activating nuclear factor kappa B, cyclooxygenase-2, interleukin 6/signal transducer and activator of transcription 3, and transforming growth factor-beta signaling cascades. These molecular events establish a tumor-promoting microenvironment characterized by angiogenesis, epithelial-mesenchymal transition, and immune evasion. Genetic susceptibility through polymorphisms in DNA repair (TP53, breast cancer gene 2, excision repair cross-complementing 4) and immune-regulatory genes modulates individual risk. In addition, dysregulation of non-coding RNAs (miR-21, miR-223, miR-744-5p), APOBEC3-mediated mutagenesis, and viral co-infections (herpes simplex virus, Epstein-Barr virus) contribute to genomic instability and disease progression. Conclusion: Penile carcinogenesis represents a multifactorial process involving viral, inflammatory, and host-genetic interactions that converge on immune evasion and genomic instability. HPV-driven and inflammation-mediated pathways may act synergistically, amplifying oncogenic potential through shared inflammatory and epigenetic circuits. Integration of HPV testing, p16 immunohistochemistry, and molecular profiling into clinical practice is instrumental for accurate classification, prognostic refinement, and the development of precision-based prevention and treatment strategies. Public health efforts focused on HPV vaccination, early circumcision, and management of chronic inflammatory conditions remain critical to reducing incidence and mortality, particularly in high-burden regions such as Latin America and sub-Saharan Africa.