Although screening methods for HPV-OPSCC have not yet been developed, population-based prevention may be achievable through HPV vaccination, but only if concerted efforts are made to increase vaccine uptake in the United States.
Lewis et al comprehensively review current epidemiologic, clinical, prognostic, and treatment considerations for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). As they discuss, the incidence of HPV-OPSCC has increased rapidly over the past several decades in the United States and will soon exceed the incidence of cervical cancer. They state that “the emergence of HPV-OPSCC has been deemed an epidemic of our time.” The designation of HPV-OPSCC as an “epidemic” has numerous important implications, several of which will be discussed in this commentary.
First, the rising incidence combined with the favorable prognosis of HPV-OPSCC implies that the population of HPV-OPSCC survivors is expanding. Therefore, there is an increasing need to understand and address the survivorship considerations that are unique to this population. For example, treatment-related toxicities can greatly affect health-related quality of life (HRQOL); thus, in a population in which the majority of patients will survive for more than 5 years, long-term toxicities emerge as a significant concern. As a result, multiple deintensification trials for HPV-OPSCC treatment are currently underway. In addition, there is preliminary evidence that HRQOL trajectories for HPV-OPSCC patients are distinct from those of their HPV-negative counterparts, with greater declines in HRQOL during the diagnosis and treatment period; further study will be necessary to clarify trends and determinants of HRQOL for these patients. Finally, unlike other head and neck cancers, HPV-OPSCC results from a sexually transmitted infection. The impact of this reality on patients’ psychosocial well-being, including their relationships, has not been well explored.
Second, the current deficits in effective screening for HPV-OPSCC and its early detection will take on increasing importance as projected incidence trends are realized. Higher incidence of disease improves the clinical utility and cost-effectiveness of screening programs, thus underscoring the importance of identifying high-risk populations. Screening for OPSCC is not yet feasible for a number of reasons, including a lack of identifiable premalignant lesions amenable to an oropharyngeal “Pap test equivalent,” the lack of highly sensitive oral and serum markers of HPV-OPSCC, and the relatively low incidence of HPV-OPSCC in the general population. However, the distinct epidemiology of HPV-OPSCC may allow for identification of high-risk groups, likely based on sex, smoking history, and sexual history, in whom screening would be appropriate and cost-effective.
Third, an essential component of managing any epidemic is the development of effective prevention, eg, vaccines. Vaccines against high-risk types of HPV were initially targeted toward cervical disease and have been shown to have efficacy in the prevention of cervical premalignancy and malignancy.[7,8] HPV 16, which causes over 90% of HPV-OPSCCs, is included in bivalent, quadrivalent, and now nine-valent vaccines. Preliminary evidence suggests that these vaccines are effective in preventing oral HPV infection, the presumptive precursor to HPV-OPSCC. However, no prospective clinical trials have been reported, and there are numerous questions regarding the ability of the HPV vaccines to alter the forecasted epidemic of HPV-OPSCC.
The natural history of HPV infection in the oral cavity and oropharynx appears to differ from that of cervical infection. For example, the peak prevalence of cervical HPV infection is shortly after sexual debut, whereas oral HPV infection prevalence is bimodal, with peaks in early and later adulthood.[10,11] Even if vaccination prevents oral HPV infection around the time of sexual debut, it is unknown whether this protection will endure to later adulthood.
Another consideration is the relative contribution of the local compared with the systemic immune response to oral HPV infection; the oral cavity and oropharynx (sampled by oral secretions) are a unique immunologic milieu, and oral tolerance to foreign antigens is well described.[12,13] Whether the systemic and cervical immunity provided by vaccination will extend to the oral cavity is unclear. Therefore, while there is optimism that the vaccine will reduce the future burden of HPV-OPSCCs, there is a significant knowledge gap.
Whether or not the vaccine proves efficacious in preventing HPV-OPSCCs, it unequivocally prevents other HPV-related cancers. Thus, the low compliance with vaccine recommendations in the United States presents a major public health challenge and opportunity. Although vaccination has been recommended since 2006 for 11- to 12-year-old girls, with catch-up vaccination to age 26, and since 2011 for 11- to 12-year-old boys, with catch-up vaccination to age 21, the uptake of HPV vaccination in the United States remains remarkably low. In 2013, among 13- to 17-year-olds in the United States, just 57% of females and 35% of males received at least one dose of the three-dose series, and only 38% of females and 14% of males received all three doses. The most common reasons cited by parents for not vaccinating their children were a lack of knowledge, healthcare provider’s failure to recommend the vaccine, and a belief that the vaccine was not needed or necessary.
Even though discussing the prevention of cancers caused by a sexually transmitted infection in the context of preadolescents may be uncomfortable, increasing vaccination coverage is currently the most promising option for reversing the HPV-OPSCC epidemic, while also preventing a host of anogenital cancers. Indeed, the President’s Cancer Panel Annual Report recently identified HPV vaccination as a national priority, stating that “such a significant opportunity to prevent cancers in the US and around the world is rare.”
Finally, we must not forget the role of tobacco in head and neck cancers, including HPV-OPSCC. Tobacco continues to cause the majority of head and neck cancers, and although patients with HPV-OPSCC are less likely to smoke than those with HPV-negative head and neck cancer, many still report a history of tobacco use.[18-22] Tobacco smoking independently worsens the prognosis of HPV-OPSCCs in a dose-dependent fashion.[18,23] Consequently, many of the deintensification trials summarized by Lewis et al incorporate pack-years of smoking into eligibility criteria. Tobacco smoking also appears to have a role in the early pathogenesis of HPV-OPSCC, in that it independently increases the risk of oral HPV infection,[10,24] as well as the likelihood that these infections will persist. Clearly, tobacco plays a major role in HPV-OPSCC, and we must continue to emphasize tobacco prevention and cessation efforts in the context of head and neck cancer care.
In summary, there is an epidemic of HPV-OPSCC in the United States, which has widespread implications and highlights existing knowledge gaps. There is a need for increased emphasis on understanding survivorship considerations for the growing population of patients with HPV-OPSCC. Although screening methods for HPV-OPSCC have not yet been developed, population-based prevention may be achievable through HPV vaccination, but only if concerted efforts are made to increase vaccine uptake in the United States. Finally, tobacco smoking prevention and cessation must remain at the forefront of the HPV-OPSCC discussion.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Lewis A, Kang R, Levine A, Maghami E. The new face of head and neck cancer: the HPV epidemic. Oncology (Williston Park). 2015;29:616-26.
2. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-301.
3. Sharma A, Mendez E, Yueh B, et al. Human papillomavirus-positive oral cavity and oropharyngeal cancer patients do not have better quality-of-life trajectories. Otolaryngol Head Neck Surg. 2012;146:739-45.
4. Rettig E, Kiess AP, Fakhry C. The role of sexual behavior in head and neck cancer: implications for prevention and therapy. Expert Rev Anticancer Ther. 2015;15:35-49.
5. Fakhry C, Rosenthal BT, Clark DP, Gillison ML. Associations between oral HPV16 infection and cytopathology: evaluation of an oropharyngeal “pap-test equivalent” in high-risk populations. Cancer Prev Res (Phila). 2011;4:1378-84.
6. Gillison ML, Chaturvedi A, Anderson WF, Fakhry C. The epidemiology of HPV-positive head and neck squamous cell carcinoma. J Clin Oncol. 2015. In press.
7. Centers for Disease Control and Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2010;59:626-9.
8. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711-23.
9. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8:e68329.
10. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693-703.
11. Markowitz LE, Sternberg M, Dunne EF, et al. Seroprevalence of human papillomavirus types 6, 11, 16, and 18 in the United States: National Health and Nutrition Examination Survey 2003-2004. J Infect Dis. 2009;200:1059-67.
12. Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunol. 2012;5:232-9.
13. Fakhry C, Marks MA, Gilman RH, et al. Comparison of the immune microenvironment of the oral cavity and cervix in healthy women. Cytokine. 2013;64:597-604.
14. Petrosky E, Bocchini JA, Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64:300-4.
15. Elam-Evans LD, Yankey D, Jeyarajah J, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years––United States, 2013. MMWR Morb Mortal Wkly Rep. 2014;63:625-33.
16. Stokley S, Jeyarajah J, Yankey D, et al. Human papillomavirus vaccination coverage among adolescents, 2007-2013, and postlicensure vaccine safety monitoring, 2006-2014––United States. MMWR Morb Mortal Wkly Rep. 2014;63:620-4.
17. Accelerating HPV vaccine uptake: urgency for action to prevent cancer. A report to the President of the United States from the President’s Cancer Panel. Bethesda, MD: National Cancer Institute; 2014.
18. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.
19. Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100:407-20.
20. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261-9.
21. Hafkamp HC, Manni JJ, Haesevoets A, et al. Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer. 2008;122:2656-64.
22. D’Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol. 2014;32:2408-15.
23. Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol. 2012;30:2102-11.
24. Fakhry C, Gillison ML, D’Souza G. Tobacco use and oral HPV-16 infection. JAMA. 2014;312:1465-7.
25. Beachler DC, Sugar EA, Margolick JB, et al. Risk factors for acquisition and clearance of oral human papillomavirus infection among HIV-infected and HIV-uninfected adults. Am J Epidemiol. 2015;181:40-53.