Abstract
The rising incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) necessitates advancements in risk stratification to optimize treatment outcomes and improve the quality of life for patients. Despite its favorable prognosis compared to HPV-negative OPSCC, current clinical staging and biomarkers, such as p16 status, are limited in their ability to distinguish between high- and low-risk patients within HPV-associated OPSCC. This limitation results in the overtreatment of low-risk patients, exposing them to unnecessary toxicity, and the undertreatment of high-risk patients who require more aggressive interventions. This review critically evaluates current stratification methods, including clinical assessments, de-escalation trials, and candidate molecular biomarkers for risk stratification. Emerging approaches such as immune markers, viral genomic integration patterns, and other molecular markers offer promising avenues for enhanced prognostic accuracy. By integrating advanced risk stratification methods, tailored treatment approaches may one day be developed to balance oncologic efficacy with reduced treatment-related morbidity. This review underscores the need for continued research into predictive biomarkers and adaptive treatment strategies to better address the diverse risk profiles of HPV-associated OPSCC patients.