Figure. The multifactorial model of HNSCC carcinogenesis. Tobacco- and alcohol-related head and neck tumors are predominantly negative for HPV. However, there may be a subset of HPV-positive tumors in which the virus may (in E6/E7 expressors) or may not (in E6/E7 non-expressors) play a role in carcinogenesis. In the absence of tobacco and alcohol use, head and neck tumors may or may not be positive for HPV. The virus may function as a carcinogen in those tumors that express E6/E7. Risk factors other than HPV may account for the development of HPV-negative as well as HPV-positive, E6/E7 non-expressing tumors.