In p16+ disease, T4 disease with N1 nodes is Stage III. In p16- disease, that same presentation would be Stage IVA. This reflects the biological sensitivity of HPV-positive tumors to radiotherapy and chemotherapy.

Crucially, the presence of clinical or pathological extranodal extension (ENE) does NOT upstage a p16-positive patient, whereas it is a defining high-risk feature for p16-negative patients. This is one of the most important distinctions in head and neck oncology.

While p16+ patients are downstaged, the standard of care (Concurrent Chemoradiation with High-Dose Cisplatin) has largely remained the same outside of clinical trials. However, the 8th edition allows for more accurate counseling regarding the high probability of cure.