Which statement about HPV-NEGATIVE oropharyngeal squamous cell carcinoma is TRUE?

Correct answer: A. It is strongly associated with tobacco and alcohol use and carries a worse prognosis than HPV-positive disease

• A. CORRECT. HPV-NEGATIVE oropharyngeal cancer is the classic carcinogen-driven disease: older patients, heavy TOBACCO and ALCOHOL exposure (synergistic, not merely additive), field cancerization with multiple genetic hits, and a significantly WORSE prognosis. Its overall incidence has been DECLINING in step with falling smoking rates.
• B. HPV-negative disease occurs in older patients, typically over 60, with a long carcinogen exposure history.
• C. The reverse is true: HPV-positive tumors are markedly more radiosensitive and chemosensitive, with roughly 80–90% 3-year survival versus 50–60% for HPV-negative disease. This is why staging was revised in AJCC 8th edition to separate the two.
• D. It is HPV-POSITIVE disease whose incidence is rising sharply, particularly in younger white men who are non-smokers, and which now accounts for the majority of oropharyngeal cancers in the United States.

Note: ⚠️ Read these stems carefully — the exam frequently swaps 'HPV-positive' and 'HPV-negative' between the stem and the options. p16 immunohistochemistry is the standard surrogate marker for HPV status.