Clinical Utility and Limitations of Circulating HPV DNA in Tonsillar Squamous Cell Carcinoma: A Narrative Review

The rising incidence of human papillomavirus (HPV)-positive tonsillar cancer, despite the availability of highly effective treatment modalities, presents an ongoing challenge in the area of disease surveillance. While routine clinical examinations, often supported by CT or even PET imaging, remain the standard approach for monitoring, they may lack sensitivity in detecting early or submucosal recurrences. Consequently, there is a growing need to integrate novel diagnostic tools—such as liquid biopsy—into routine follow-up strategies to enhance the accuracy of disease monitoring. The aim of this study is to provide a comprehensive overview of HPV-positive tonsillar cancer, encompassing its etiology, molecular pathogenesis, disease progression, diagnostic approaches, treatment strategies, and current surveillance practices. Special emphasis is placed on the emerging role of liquid biopsy in disease monitoring, particularly for assessing disease burden and enhancing early detection of local recurrence. The review encompassed studies from diverse sources, including experimental, observational, and clinical research published between 2000 and 2025. Data were collected through comprehensive literature searches using databases such as PubMed, Scopus, and the Cochrane Library with defined inclusion and exclusion criteria. Emerging evidence supports the clinical utility of liquid biopsy—particularly circulating tumor (ct) HPV DNA detection—for monitoring HPV-positive tonsillar cancer. Studies report high specificity (87-100%) and sensitivity (72-100%) for recurrence detection, often identifying disease earlier than imaging. Commercial ctHPV DNA assays have demonstrated strong performance in distinguishing true recurrence from benign HPV presence. However, technical variability, lack of standardization, and reduced sensitivity for non-HPV16 genotypes remain key limitations. Therefore, this review aims to evaluate the clinical application of circulating HPV DNA as a surveillance tool in tonsillar squamous cell carcinoma (TSCC), focusing on its diagnostic performance, current limitations, and integration into real-world practice.