HPV-positive oropharyngeal squamous cell carcinoma: risk-adapted treatment strategies and biomarker-guided individualization

Abstract

Oropharyngeal squamous cell carcinoma (OPSCC) has undergone a major epidemiologic shift driven by the rising incidence of human papillomavirus (HPV)-associated disease. HPV-positive OPSCC represents a distinct clinical entity with improved survival, yet marked heterogeneity persists, creating the challenge of minimizing overtreatment while preserving cure in higher-risk patients. This narrative review summarizes current evidence on HPV-driven carcinogenesis and the transition toward biology-driven, risk-adapted management. We review evolving diagnostic frameworks, HPV-specific staging, and emerging de-intensification strategies, including postoperative radiation modification and perioperative immunotherapy. We also assess the role of immune checkpoint inhibitors across disease settings and examine circulating tumor HPV DNA as a precision biomarker for molecular residual disease and surveillance. Collectively, these advances support a shift toward dynamically adaptive treatment paradigms integrating molecular, immune, and clinical risk factors.