Human papillomavirus and diseases of the upper airway: Head and neck cancer and respiratory papillomatosis

Human papillomavirus (HPV) infection is causally associated with benign and malignant diseases of the upper airway, including respiratory papillomatosis and oropharyngeal cancer. Low-risk HPV types 6 and 11 are the predominant cause of papillomatosis, whereas only HPV16 definitively satisfies both molecular and epidemiological causal criteria as a carcinogenic or high-risk type in the upper airway. HPV16 E6/E7 mRNA expression and integration are observed predominantly among oropharyngeal cancers, and experimental models have shown E6/E7 expression to be necessary for the initiation and maintenance of the malignant phenotype of these cancers. From an epidemiological perspective, a strong and consistent association between markers of HPV16 exposure and oropharyngeal cancer has been demonstrated in numerous case-control studies. HPV-positive oropharyngeal cancers have also been shown to be distinct from HPV-negative head and neck squamous cell cancers with regard to risk-factor profiles, molecular genetic alterations, population-level incidence trends over time, and prognosis. Tumor HPV status (as determined by certain HPV16 in situ hybridization assays or certain p16 immunohistochemistry assays) is the strongest determinant of survival for patients with local-regionally advanced oropharyngeal cancer: patients with HPV-positive cancer have at least a 50% improvement in overall survival at 5 years, which is equivalent to an approximate 30% difference in absolute survival. Thus, HPV status determination is now part of the routine diagnostic evaluation for prognostication. Preliminary evidence indicates that a small proportion of head and neck cancers may be caused by additional HPV types (e.g., 18, 31, 33, 35) and that HPV-caused cancers may rarely arise from non-oropharyngeal sites (e.g., the oral cavity, nasopharynx, and larynx). Whether or not HPV vaccination has the potential to prevent oral HPV infections that lead to cancer or papillomatosis in the upper airway is currently unknown, as is the potential for secondary prevention with HPV detection.