Comparison of CYLD-wildtype HNSCC with cylindroma-like inclusions vs. those without these inclusions revealed that cases with cylindroma-like features showed significantly lower TMB (median 2.6 vs. 4.4 mut/Mb, p = 0.0219), and a lower frequency of PIK3CA (12% [4/34] vs. 35% [150/425], p = 0.0042), KMT2D (3% [1/34] vs. 18% [76/425], p = 0.0284), and FBXW7 genomic alterations (0% [0/34] vs. 13% [53/425], p = 0.0229). The gene discussed is PIK3CA; the disease is adnexal spiradenoma/cylindroma of a sweat gland.