Global burden of oropharyngeal cancer attributable to human papillomavirus by anatomical subsite and geographic region

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Background

Oropharynx is the middle part of pharynx, including the palatine tonsils, palatoglossal folds, valleculae, base of tongue, posterior pharyngeal wall, and soft palate [12] . Oropharyngeal cancer is tumor arising from the above anatomical subsites, most of which are histologically classified as squamous cell carcinoma (SCC) [2] . Oropharyngeal cancer has several risk factors: tobacco smoking, alcohol consumption, betel quid chewing, and human papillomavirus (HPV) infection, which may exist individually or simultaneously [2] . Globally, approximately 85,000 newly diagnosed oropharyngeal cancer cases occurred per year, of which about 22,000 were HPV positive [3] . In all cases with oropharyngeal cancer, HPV prevalence in tonsillar cancer and base of tongue cancer were the highest [4] .

HPV includes a group of deoxyribonucleic acid (DNA) viruses that are one of the most common sexually transmitted infections worldwide [5] . HPV infects the lower, basal layer epithelial cell, causing warts and cervical cancer [67] . Meanwhile, a certain proportion of anal rectal cancer, vulvar cancer, vaginal cancer, penile cancer, and oropharyngeal cancer are found to be associated with HPV infection [6] . Based on the potential for oncogenesis, HPV are classified as high-risk and low -risk types. High-risk HPV types include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82. Low-risk types such as 6 and 11 do not cause cancers but are the main causes of genital warts [8] . HPV vaccines can effectively prevent HPV-related diseases and the bivalent (2 v), quadrivalent (4 v), and nonavalent (9 v) vaccines can prevent the infection of HPV 16/18, HPV 6/11/16/18, and HPV 6/11/16/18/31/33/35/52/58, respectively [9] .

Prevention and treatment of HPV infection have a substantial effect on the prevention of HPV-related cancers. In public health, attributable fraction (AF) is used to quantify this effect. The AF of HPV is the proportional reduction in cancer cases if HPV infection had been avoided or cured before it causes cancer [10] . Some studies have indicated that for head and neck cancers HPV positivity should be defined as being positive for both HPV DNA and p16 ^INK4a [11] . In recent years, p16 ^INK4a is widely used as a surrogate biomarker to identify transcriptional active HPV infection in oropharyngeal cancer [1213] . Previous meta-analysis calculated AF of HPV as the product of HPV prevalence in cancer cases and p16 ^INK4a positivity in HPV positive cancer cases [4] .

Previous studies published in 2016 and 2017 have estimated global burden of HPV-related oropharyngeal cancer by region and country [1014] . However, data used for previous estimates were derived from studies published before 2012. Due to the limitation of available data, the burden of some countries could not be estimated in these studies. In recent several years, many new publications on HPV prevalence and p16 ^INK4a positivity in oropharyngeal cancer have become available. HPV prevalence varied greatly across different subsites of oropharynx. As anatomical subsites with the highest and second highest HPV prevalence in oropharynx [4] , no study has estimated the global burden of HPV in tonsillar cancer and base of tongue cancer. We conducted this study to update the global burden estimates of oropharyngeal cancer attributable to HPV with the latest data and estimate global burden of tonsillar cancer and base of tongue cancer attributable to HPV, by region and country.