Circulating biomarkers in HPV-associated oropharyngeal cancer: Clinical applications of liquid biopsy in diagnosis, prognosis, and surveillance.

Oropharyngeal squamous cell carcinoma (OPSCC), particularly the HPV-associated subtype, represents a growing public health burden worldwide. While HPV-positive OPSCC carries a better prognosis, challenges persist in early detection, treatment response monitoring, and recurrence surveillance. Traditional tissue biopsy remains the diagnostic gold standard but is invasive, limited by sampling bias, and unsuitable for dynamic disease monitoring. This review synthesizes current evidence on the role of liquid biopsy including circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), circulating HPV DNA (ctHPV-DNA), circulating tumor cells (CTCs), exosomes, and microRNAs (miRNAs) in the diagnosis, prognostication, and surveillance of OPSCC. A literature review of human studies evaluating circulating biomarkers in OPSCC was performed. Eligible studies included prospective and retrospective investigations using liquid biopsy components for diagnostic, prognostic, or treatment-monitoring applications in HPV-positive or HPV-negative OPSCC. Among the circulating analytes, ctHPV-DNA has emerged as the most robust biomarker in HPV-positive OPSCC, offering high sensitivity and specificity for diagnosis and recurrence detection. Multiple studies support its utility in minimal residual disease (MRD) detection, often predicting recurrence months before clinical evidence. Saliva, plasma, and novel fluids like surgical lymphatic drainage have been evaluated as sampling sources. Additionally, ctDNA somatic mutations, gene methylation signatures, CTC counts, and exosomal miRNAs are being explored for their potential in personalized disease stratification and treatment monitoring. Liquid biopsy is a promising adjunct to tissue biopsy in OPSCC, particularly in HPV-driven disease. Its minimally invasive nature, dynamic tumor tracking capability, and expanding analytical platforms position it as a transformative tool in head and neck oncology. Standardization, assay optimization, and large-scale validation are required before routine clinical integration.