Several case histories have been reported in the literature, with the prevalence of HPV DNA detection in cancers ranging from 0% to 100%, depending on the population, combination of topographies, type of specimen, and DNA detection method.8 These studies used a variety of detection techniques, including lower-sensitivity methods (in situ hybridization and Southern blot hybridization) and high-sensitivity methods (polymerase chain reaction [PCR]). Several sampling methods were employed, including biopsies, scrapes, brushes, and oral rinses. Adding to the variability, such storage procedures as fresh, frozen, or formalin-fixed paraffin-embedded samples were used. Clearly, the nonstandardization of these multiple variables has added to the confusion in this field. A systematic meta-analysis reviewed the current available literature in the field to determine the worldwide prevalence of HPV in head and neck squamous cell carcinoma (HNSCC).9 Researchers analyzed 60 relevant studies using PCR detection from 26 countries. In all, 5,046 cases of SCCs, 2,642 oral cancers, 969 oropharyngeal cancers, and 1,435 laryngeal cancers were studied. HPV prevalence was 35.6% in oropharyngeal cancers, 23.5% in oral cancers, and 24.0% in laryngeal cancers. The overall estimated prevalence of HPV in HNSCC was 26%.
New case-control studies provide additional evidence that HPV is an independent risk factor for oral and oropharyngeal squamous cell carcinomas.10 The first indication of this connection came when Finnish researchers noted that 40% of the cancers in their study shared histologic and morphologic similarities with HPV-associated lesions.5 The likelihood of detecting HPV increases with the progression from normal mucosa to premalignant lesions to oral cancer. HPV is two to three times more likely to be observed in precancerous oral mucosa and 4.7 times more likely to be found in oral sqaumous cell carcinoma (OSCC) than in normal mucosa.11
HPV may play a more important role in some tumors than in others.12 For example, HPV-related cancers arise mainly from the tonsils and base of the tongue rather than the ventrolateral tongue, gingivae, cheek, palate, and floor of the mouth.13
Alcohol and smoking are the primary risk factors for HNSCC. The fact that 15% to 20% of patients develop OSCC in the absence of exposure to these agents or without any obvious predisposing genetic defects strongly suggests the possibility of other risk factors, including the presence of HPV.14 Although certain subsets of HNSCC have become less prevalent with the decrease in smoking, rates of oropharyngeal cancers—particularly tongue and tonsillar cancers—have risen steadily among men and women aged 20 to 44 years.15
HPV-associated OSCC may be found in a different population subtype than expected. HPV-associated OSCC patients are often nonsmokers and nondrinkers16 and younger than patients with HPV-negative tumors.17 Additionally, HPV prevalence in OSCC is higher in oral cancer observed in persons younger than age 60 years.18 Patients with HPV 16-positive head and neck tumors were shown to be younger than patients with HPV-negative tumors. The role of marijuana use in HPV-associated OSCC is unclear, as is the possible association with poor oral hygiene.19 Yet another study reported that HPV-positive cancers were independently associated with sexual behavior and exposure to marijuana but not related to tobacco or alcohol use or poor oral hygiene.20
HPV-related diseases are increased in the oral cavity of HIV-positive individuals.21 HIV carriers have more frequent infections and a wider variety of HPV types in addition to an increased frequency of HPV-associated oral lesions.22 Additionally, studies have demonstrated an increase in the incidence of oral warts related to HPV infection since the advent of antiretroviral therapy.23,24 Investigators looked at a subset of 56 patients with oral warts from a group of 2,194 persons who had HIV from 1997 through 1999. An increased incidence of oral warts was associated with a decrease in HIV RNA level and with chronic or previous infection with hepatitis B virus. While no specific association between warts and highly active retroviral treatment was found, a significant reduction in viral load in the previous six months was related to an increased incidence of oral warts. It has been suggested that this phenomenon of increasing incidence of oral warts associated with a decreasing viral load may represent a form of immune reconstitution syndrome.
Lifestyle changes have also been tied to the rise in HPV-associated intraoral infection. An increase in the number of people engaging in premarital sex, multiple sexual partners, and oral sex over the past few decades has likely contributed to increased rates of oral HPV infection.25 In line with this trend, a recent U.S. study has reported an association between oral sex and open-mouthed kissing and the development of oral HPV infection.26 A case-control study demonstrated that a high number (≥26) of lifetime vaginal-sex partners and six or more lifetime oral-sex partners were associated with an increased risk of HNSCC.27