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High-risk human papillomaviruses are the causative agents of cervical cancer and are also believed to be aetiologically involved in a subset of squamous cell carcinomas of the head and neck region, especially the tonsil. Cervical cancers arise through disruption of the pathways of p53 and the product of the retinoblastoma gene by the human papillomavirus oncoproteins E6 and E7. It is generally assumed that the same pathways are involved in human papillomavirus-induced carcinogenesis at other mucosal surfaces. However, the patterns of expression of cell cycle proteins targeted by human papillomavirus E6 and E7 in cancers from different anatomic sites have been inconsistent, due to either biologic or technological factors. In this study, 73 human papillomavirus, 16-positive cervical squamous cell carcinomas (35 from Australian and 38 from Chinese women) were analysed for the expression of p53, pRb, p16(INK4A), p21(CIP1/WAF1), p27(KIP1) and cyclin D1 by semiquantitative immunohistochemistry. Cervical cancers from Chinese women were found to be significantly more likely to overexpress p53, pRb, p21 and p27 than their Australian counterparts. These findings were compared with those from 31 human papillomavirus 16-positive tonsillar squamous cell carcinomas, all of Australian origin, tested using the same methodology. Comparisons of the tonsillar and combined cervical data showed that tonsillar cancers were significantly more likely to be p53-positive, whereas cervical cancers were significantly more likely to overexpress pRb, p16 and p27. When the tonsillar data were compared with cervical data from Australian women, the associations for p53 and pRb remained. These findings represent new evidence that the molecular pathways to human papillomavirus-induced mucosal cancer may be influenced by anatomic location and ethnicity.

Epidemiological and experimental evidence from Western countries now consistently support an etiological role for human papillomavirus (HPV) in a subset of oropharyngeal squamous cell carcinomas (SCC), especially those originating in the tonsil. The role of HPV in the etiology of tonsil cancer in developing countries such as China has not been investigated. In this study, none of 16 tonsil cancer specimens from Chinese patients were positive for HPV DNA, whereas those from Australian patients using the same methodology gave a positivity rate of 46%. The tumors from Chinese patients, like the Australian HPV-negative subset, significantly overexpressed pRb and cyclin D1 and underexpressed p16(INK4A) (p16). In contrast, the Australian HPV-positive cancers overexpressed p16 and had reduced expression of pRb and cyclin D1. These findings may help explain why China has a relatively low rate of oropharyngeal cancer compared with Australia. They also support the hypothesis that molecular pathways to tonsil cancer mediated by HPV are distinct from those induced by mutagens present in cigarette smoke or alcohol.