HPV-Associated Oropharyngeal Squamous Cell Carcinoma and Persistent Oral High-Risk HPV Detection: A Narrative Review of Longitudinal Assessment, Diagnostic Evaluation, and Surveillance.

Currently, no validated population-based screening strategy uses persistent oral high-risk human papillomavirus (HPV) detection to identify individuals at clinically meaningful risk of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). This narrative review evaluates sampling strategies, virologic assays, liquid-biopsy biomarkers, adjunct biomarkers, and integrative approaches across three clinical contexts: longitudinal oral HPV assessment; diagnostic evaluation and HPV attribution in suspected or newly diagnosed OPSCC; and treatment monitoring and post-treatment surveillance in established HPV-associated OPSCC. The literature published from January 2020 through June 2026 and identified in PubMed was synthesized by clinical context, specimen source, biological target, study population, and intended use. Repeated detection of the same high-risk HPV genotype in serial oral specimens provides a pragmatic measure of persistent oral HPV detection but does not establish uninterrupted infection, sustained viral oncogene transcription, malignant transformation, or future OPSCC risk. Oral HPV DNA, oral E6/E7 mRNA, tumor-tissue HPV testing, and plasma circulating tumor HPV DNA represent distinct biological and clinical signals. Plasma circulating tumor HPV DNA has the most mature evidence for treatment monitoring and post-treatment surveillance in established HPV-associated OPSCC, not population screening. Clinical translation requires standardized longitudinal protocols, validation in intended-use populations, actionable management pathways, and incremental predictive value for proposed risk-stratification models.