A subset of head and neck squamous cell carcinomas are caused by the human papillomavirus (HPV). This HPV-related form of head and neck squamous cell carcinoma (HPV-HNSCC) has captured the attention of the oncology community for its rising incidence, its link to non-traditional risk factors, and its divergent clinical behavior. To diagnose this special form of head and neck squamous cell carcinoma is to provide important prognostic information and, in some instances, redirect clinical therapy. The diagnosis of HPV-HNSCC is aided by a strong appreciation for its characteristic microscopic findings and by an awareness of aberrant features that set apart a growing list of HPV-HNSCC morphologic variants. This review will delineate the microscopic appearance of HPV-HNSCC, spotlight ways in which the misinterpretation of these microscopic features can lead to diagnostic confusion, offer recommendations for appropriate terminology when diagnosing HPV-HNSCC, and provide examples of specific diagnostic scenarios where HPV testing can inform the diagnostic process.
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