Human papillomaviruses (HPVs) are recognized as important causes of cancer of the anogenital tract and may be involved also in the etiology of cancers of the upper aerodigestive tract (UADT). Epidemiological and experimental evidence lend some support to this possibility. Increased risk of cancer of the oral cavity, pharynx, and larynx subsequent to the occurrence of cancer of the cervix has been found and suggests common etiological factors besides smoking. HPV has been found in a substantial proportion of benign UADT lesions, most notably laryngeal papillomas and oral verrucal-papillary lesions. Largest and most accurate case series (i.e., > 15 UADT cancer cases, based on best HPV detection techniques) showed HPV DNA in 46% of cancers of the oral cavity and pharynx, 15% of cancers of the esophagus, and 24% of cancers of the larynx, with however, great discrepancies from one study to another. An additional 14 case series with a comparison group of noncancer patients revealed approximately a 4-fold higher HPV prevalence in UADT cancer tissues than in normal ones. The only two strictly designed case-control studies dealt with cancer of the oral cavity and provided inconclusive results, possibly because of interference of primary treatment with HPV detection in buccal exfoliated cells. An increasing bulk of experimental and in vitro evidence suggests that at least a proportion of UADT cancers harbor a relatively high copy number of HPV DNA. E6/E7 region transcripts and a clonal association with HPV have been demonstrated in these tumors. The combination of a good study design with reliable and noninvasive viral measurement will ultimately allow researchers to elucidate the role of HPV in the development of UADT cancer. Allowance for the strong effect of smoking, alcohol drinking, and betel quid chewing on UADT cancer and exclusion of noncausal associations will be the most difficult challenges of such studies.

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