An estimated 7,400 new cases of HPV-associated OPC are diagnosed annually in the United States.3 Prevalence of oral infection is highest among adults in their late 20s and late 50s.14 The disease is more common in men than women (almost 4:1) and in non-Hispanic populations.2,8

HPV-Associated Carcinogenesis in the Oropharynx

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The role of p53/pRb disruption in HPV-positive versus HPV-negative HNSCC is highlighted by different molecular patterns. HPV-positive disease is characterized by wild-type p53, overexpression of p16, and low pRb levels, whereas HPV-negative disease is characterized by p53 mutations, low p16 expression, and high pRb levels.5 Oncogenic transformation involves disruptions of p53 and pRb tumor suppressor proteins that are driven by HPV oncoproteins E6 and E7.4,9 Although both E6 and E7 have oncogenic effects independent of their effects on p53 and pRb, including induction of telomerase activity and inhibition of cell-cycle regulatory and pro-apoptosis proteins, these apparently require additional genetic changes that still are not well understood.10

Clinicopathologic Features

HPV-positive HNSCC presents with a distinct phenotype characterized by location in the oropharynx, poor differentiation, and improved survival with standard therapies compared with HPV-negative HNSCC.5,7 The oropharynx comprises the middle part of the pharynx, including the soft palate, the base of the tongue, and the tonsils.11 Within this area, the anterior tonsillar pillar is the most common location for tumors to appear, most of which are diagnosed at advanced stages (75% stage III/IV).12 Cancers occurring at the base of the tongue generally are asymptomatic until late in progression and are associated with lymph node metastasis (70% ipsilateral cervical lymph node involvement).12 Soft palate tumors usually are found on the anterior surface in early stages, and remain superficial.12 Symptoms of oropharyngeal tumors include pain, dysphagia, weight loss, neck masses, and referred otalgia due to nerve involvement.12

Risk Factors

HPV-positive OPC shares risk factors with the likelihood of HPV oral infection, mostly related to sexual behaviors; this differs from those associated with HPV-negative disease, where tobacco and alcohol use are the predominant risk factors. HPV-positive OPC risk factors include a high number of lifetime sex partners (oral, anal, and/or vaginal), early age (≤17 years) at first intercourse, and irregular or no condom use.5,15 The prevalence of oral HPV infection is about 7% in the general population, including 3.7% with high-risk serotypes; however, this can be as high as 20% among those with more than 20 sex partners or who smoke more than 20 cigarettes daily.

Persistence of HPV infection and HPV-16 seropositivity further increase cancer risk; whether smoking (tobacco or marijuana) and alcohol produce additional cancer risk in HPV-positive patients is still unclear.5,15