From HPV Detection to Cancer Prevention: The Role of Infection Persistence, Genotype, and Anatomical Site in HPV-Associated Cancers

Background/Objectives: Most HPV infections are transient, but persistent high-risk infection, particularly with HPV16, is among the most important determinants of progression to HPV-associated precancer and cancer. The role of genotype, infection persistence, and anatomical site varies across cervical, oropharyngeal, anal, vaginal, vulvar, and penile cancers. This review synthesizes evidence to clarify how these factors shape cancer risk and prevention. Methods: This structured narrative review used iterative, topic-specific searches in PubMed, Scopus, Web of Science, and Google Scholar without a publication-year restriction and was limited to English-language sources. Search terms were adapted to each database and thematic question. Original empirical studies and secondary data analyses informed direct quantitative discussion, whereas reviews, meta-analyses, guidelines, consensus statements, and authoritative reports were used principally for context. Evidence was synthesized qualitatively because study designs, populations, anatomical sites, assays, outcomes, and clinical purposes differed substantially; no new meta-analysis was performed. Results: The most developed longitudinal and screening evidence concerned cervical cancer, whereas evidence for several non-cervical sites was smaller and more heterogeneous. HPV16 was the most important genotype in most cancers examined. The role of HPV18 and other high-risk genotypes varied depending on the cancer site, tissue type, and geographic region. Most transient infections do not lead to cancer; however, persistent high-risk HPV infection, particularly HPV16, was associated with high-grade lesions and an increased risk of cancer. Vaccination was associated with a reduction in high-grade lesions and invasive cancer in population-based studies. Self-sampling and urine testing had practical value when individuals with positive results proceeded to triage, treatment, and follow-up. Conclusions: Three key questions exist for assessing the risk of HPV-associated cancers: Where has the persistent infection occurred? Which genotype is involved? And can the healthcare system intervene before progression to cancer? In cervical cancer, vaccination, screening, triage, and treatment are linked within the most developed prevention pathway. For anal cancer, prevention is more strongly focused on high-risk groups and diagnostic capacity. In oropharyngeal cancer, HPV is important for understanding etiology and prognosis, but there is still no established population screening pathway. Evidence for vaginal, vulvar, and penile cancers must be interpreted separately by site.