Diagnostic Accuracy of HPV Circulating Tumor DNA Following Non‐Diagnostic FNA of a Cystic Lateral Neck Mass

Background Cystic lateral neck masses in adults commonly represent nodal metastases from HPV‐associated oropharyngeal squamous cell carcinoma (OPSCC) or benign lesions. Because cystic lesions are relatively acellular, fine‐needle aspiration (FNA) is often non‐diagnostic. HPV circulating tumor DNA (ct‐DNA) may aid diagnosis in these cases. Methods We conducted a two‐institution retrospective review of patients with cystic neck masses and non‐diagnostic FNA who underwent pre‐treatment HPV ct‐DNA testing. Sensitivity, specificity, and predictive values were calculated based on final pathology. Results Thirty‐two patients were included. HPV ct‐DNA was positive in 20/32 (62.5%) cases, all of which were HPV‐associated OPSCC. Four patients with negative HPV ct‐DNA were ultimately diagnosed with HPV‐associated OPSCC (sensitivity: 83%, specificity: 100%, PPV: 100%, NPV: 67%). Conclusion HPV ct‐DNA demonstrated high specificity and may complement standard workup in adult cystic neck masses with non‐diagnostic FNA. Positive HPV ct‐DNA results should prompt further evaluation for HPV‐associated OPSCC.