The finding by Hajek et al. [15] that HPV-positive, CYLD-mutant HNSCCs demonstrate a more favorable prognosis than CYLD-wild-type cases suggests that CYLD mutation, or potentially the surrogate of correlated histopathologic features, may inform the clinical phenotype of HPV-positive HNSCC. This evidence concerns the gene CYLD and head and neck squamous cell carcinoma.