In cases of unknown primary HNSCC, positive p16INK4a expression should be interpreted with caution, as approximately 20% of metastatic squamous cell skin and lung cancers, without associated high-risk HPV, show more than 70% nuclear staining and cytoplasmic positive in the IHC of p16INK4a.39 Here, CDKN2A is linked to head and neck squamous cell carcinoma.