High-Risk HPV Testing in Head and Neck Carcinoma: Key Updates from the 2025 College of American Pathologists Guideline

High-risk human papillomavirus (HPV) plays a significant role in the pathogenesis of certain head and neck (HN) cancers, especially squamous cell carcinomas (SCC) arising in the oropharynx. Distinction between HPV-independent and HPV-associated HNSCC has important implications for clinical management and patient prognosis in specific anatomic subsites of the head and neck. In 2018, the College of American Pathologists (CAP) issued 14 evidence-based guideline statements related to the testing, application, interpretation, and reporting of HPV and surrogate marker testing for HN carcinomas. Since that time, significant amounts of new data have been published which serves as the foundation for the updated 2025 CAP Guideline resulting in 16 evidence-based recommendations. These statements refine issues related to the application of high-risk HPV testing in patients with HNSCC, and they address some issues not fully covered in the 2018 CAP Guideline. This brief review discusses the changes that were made to the original guideline and provides a quick reference for the testing recommendations across head and neck sites.