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A significant association between HPV status and p16INK4a immunoreactivity was observed in more than 76% of the HPV-related HNSCCs (P  less then  0.0001). The overexpression of p16INK4a and cytoplasmic NF-κB was more common in low-grade HNSCC tumors. that HPV16, in particular the A2 sublineage, followed by A1 and D2 sublineages are the major agents associated with HNSCCs in Iran. Based on HPV16 predominance and its lineage distribution pattern, it seems that the prophylactic vaccines developed for cervical cancer prevention