The Utility of Tumor Tissue–Modified Viral HPV DNA Testing for HPV ‐Associated Non‐Oropharyngeal Squamous Cell Carcinoma of the Head and Neck

Background Tumor tissue–modified viral (TTMV) human papillomavirus (HPV) DNA testing has high diagnostic and surveillance performance in HPV‐associated oropharyngeal squamous cell carcinoma, but its utility in HPV‐associated non‐oropharyngeal (non‐OP) head and neck squamous cell carcinoma (HNSCC) is not well defined. Methods We performed a retrospective cohort study of patients with biopsy‐confirmed HPV‐positive non‐OP HNSCC who underwent TTMV‐HPV DNA testing at a single tertiary academic center from April 2020 to January 2025. Diagnostic performance was assessed for pretreatment testing, and surveillance performance was assessed per test and per patient. Results The diagnostic cohort included 19 patients and demonstrated 80% sensitivity and 100% specificity. The surveillance cohort included 15 patients who underwent 32 tests. Per‐test surveillance sensitivity was 87%, specificity 100%, positive predictive value 100%, and negative predictive value 89%. Per‐patient surveillance sensitivity was 86%, specificity 100%, positive predictive value 100%, and negative predictive value 89%. In two patients, positive surveillance tests preceded clinical or radiographic recurrence by 18 and 110 days. Conclusions TTMV‐HPV DNA testing demonstrated strong diagnostic and surveillance performance in HPV‐associated non‐OP HNSCC and may be a useful adjunct in posttreatment surveillance.