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Since 1990, the incidence of oropharyngeal cancers associated with high-risk HPV (HR-HPV) has risen at 5% or more per year in most major countries that have undertaken routine testing for HPV. HPV types 16 and 18 are the most commonly detected, transcriptionally active HR-HPV types in head and neck cancer [69]. Little is known about the significance of HPV in other sub-sites in the head and neck and more so hypopharynx [70]. While HPV-related head and neck cancers are encountered in non-oropharyngeal sites, the incidence of true HPV-related non-oropharyngeal carcinomas is vastly over stated. Some of the reasons given include the differing methods of testing for HPV, occasionally ectopic-displaced tonsillar tissue is encountered in the hypopharynx, tumour migration from Waldeyers’s ring inferiorly to involve the piriform sinus. This suggests that the true incidence of HPV-related head and neck cancer of the oral cavity, larynx and hypopharynx is only about 5% [71]. Analysis of histological biopsy specimens either by pre-treatment or retrospectively have revealed that the p16 expression is not a suitable biomarker [72, 73]. Others have commented that HPV/p16 status should be considered when considering treatment of advanced hypopharyngeal cancer [74, 75]. There are many HPV testing options available, but currently there is no clear consensus on which test or combination of tests is optimal for routine diagnostic use. It is acknowledged that biologically and clinically favourable features are limited to tumours that harbour transcriptionally active, HR-HPV, sometime that occurs predominantly (but certainly not exclusively) in the oropharynx [69, 76].