In summary, we found that over one in five HPV-positive head and neck carcinomas in our cohort carry CYLD mutations, and that the presence of CYLD mutations defines a subset of HNSCC tumors that often display cylindroma-like histopathologic features and exhibit unusually low TMB and infrequent alterations in PIK3CA. Characterization of HPV-positive, CYLD-mutant carcinoma may assist in classification of HNSCC and potentially inform prognosis and experimental therapies for the patients affected [17, 18], both topics that will require additional study. Here, PIK3CA is linked to adnexal spiradenoma/cylindroma of a sweat gland.