Latest findings on HPV infection and the risk of oropharyngeal and oral squamous cell cancer

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Latest findings on HPV infection and the risk of oropharyngeal and oral squamous cell cancer

Human papilloma virus (HPV) is causal for cervical and anogenital cancers, and has been identified as a cause of squamous cell cancers in the oropharyngeal region and oral cavity. In the United States, oropharyngeal squamous cell carcinoma (OPSCC) is now the most frequently-occurring cancer associated with HPV.1Van Dyne EA, Henley SJ, Saraiya M, Thomas CC, Markowitz LE, Benard VB. Trends in Human Papillomavirus–Associated Cancers — United States, 1999–2015. MMWR 2018; 67(33);918-24. The interest in HPV infection as a cause of oropharyngeal cancers and oral cancers (OC) has been driven in part by the change in the epidemiology of these cancers, as younger men and women without traditional risk factors (use of tobacco, betel quid, and alcohol consumption) have been diagnosed with these diseases.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8. While many questions remain unanswered, oral health care providers need to be up to date on the latest information regarding prevalence, diagnosis and prevention.

Prevalence of HPV-associated OPSCC and OC

The association of OPSCC and HPV infection is established. Sites include the base of tongue, pharyngeal tonsils, tonsillar pillars, glossotonsillar sulci, the anterior surface of the soft palate and uvula, and the pharyngeal walls.1Van Dyne EA, Henley SJ, Saraiya M, Thomas CC, Markowitz LE, Benard VB. Trends in Human Papillomavirus–Associated Cancers — United States, 1999–2015. MMWR 2018; 67(33);918-24.,2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8. More than 200 types of HPV have been identified, of which 15 are considered oncogenic (causal for cancer).3Javadi P, Sharma A, Zahnd W, Jenkins W. Evolving disparities in the epidemiology of oral cavity and oropharyngeal cancers. Cancer Causes and Control 2017;28(6):635-45. HPV-16 and -18 are high-risk for head and neck cancers, and HPV-16 is most closely associated with risk for OPSCC.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8.,4D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9. HPV is now causal for >70% of OPSCC in the United States, with a much greater prevalence of the disease in males than females.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8.,3Javadi P, Sharma A, Zahnd W, Jenkins W. Evolving disparities in the epidemiology of oral cavity and oropharyngeal cancers. Cancer Causes and Control 2017;28(6):635-45.,5O’Leary ST, Kimberlin DW. Update From the Advisory Committee on Immunization Practices. J Ped Inf Dis Soc 2018;7(3):181-7.,6de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017;141(4):664-70.

HPV-16 is causal for >70% of OPSCC in the United States.

The increased prevalence of HPV-associated OPSCC has been ascribed to changes in sexual behavior since the 1960s, and the burden of OPSCC disease is now shifting to older males.7Chaturvedi A, Zumsteg ZS. A snapshot of the evolving epidemiology of oropharynx cancers. Cancer 2018;124(14):2893-6. Similar patterns are observed in other developed countries, including Canada and in Europe.5O’Leary ST, Kimberlin DW. Update From the Advisory Committee on Immunization Practices. J Ped Inf Dis Soc 2018;7(3):181-7.,8Forte T, Niu J, Lockwood G, Bryant H. Incidence trends in head and neck cancers and human papillomavirus (HPV)-associated oropharyngeal cancer in Canada, 1992–2009. Cancer Causes & Control 2012;23(8):1343-8.,9Schache AG, Powell NG, Cuschieri KS, Robinson M, Leary S, Mehanna H, et al. HPV-related oropharynx cancer in the United Kingdom: an evolution in the understanding of disease etiology. Cancer Res 2016;122(24):6598-06. Globally, 30.8% of cases of OPSCC are attributable to HPV compared to 2.2% for OC.5O’Leary ST, Kimberlin DW. Update From the Advisory Committee on Immunization Practices. J Ped Inf Dis Soc 2018;7(3):181-7. In examining different regions, HPV-positive OPSCC accounts for 37%, 6% and 2% of cases in Western Europe, Eastern Europe and Asia, respectively (p<0.0001).10Mehanna H, Franklin N, Compton N, Robinson M, Powell N, Biswas-Baldwin N, et al. Geographic variation in human papillomavirus-related oropharyngeal cancer: Data from 4 multinational randomized trials. Head Neck 2016;38(Suppl 1):E1863-9. Overall, only 1% of individuals with OC were HPV-positive.

Risk factors for oral HPV infection and OPSCC

For the most recent U.S. national data available (2009-2014), HPV-16 and other HPV that are oncogenic were detected in the oral cavity in 3.5% and 1.1% of adults 20 to 69 years-of-age, respectively, with a low lifetime risk for OPSCC estimated at 1 in 370 individuals in the population.4D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9. Among 50 to 59-year-olds, 8.1% and 2.1% of men, respectively, were infected with oncogenic HPV, including HPV-16, compared to 1.6% and 0.5% of women, respectively. The lifetime risk for OPC for men and women in this age group is estimated at 0.7% and 0.2%, respectively.4D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9. (Figure 1)

Figure 1. Trends in human papillomavirus–associated cancers — United States, 1999–2015.


A risk profile for oral HPV infection has emerged, and includes tobacco use and the number of oral sexual partners over a lifetime.4D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9. Males who are current smokers with a history of at least 5 oral sexual partners are at increased risk of infection, with a prevalence of 14.9% and 3.1% for oncogenic HPV overall and HPV-16, respectively. Males with 2 to 4 lifetime partners are at moderate risk, with a prevalence of 7.3% and 2.2%, respectively, while for nonsmokers the risk is low, with a prevalence of 2.8% and 0.7%. The risk of HPV-16 infection in women is low, with a reported prevalence of 0.1% to 0.4%.4D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9.

Further, while the majority of new oral HPV infections appear to clear within a year, smoking and immunodeficiency (e.g., HIV infection) appear to increase the risk for persistent infection.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8. This may be a key factor in HPV-related disease. In addition, periodontitis was found in a recent study to increase the risk for head and neck cancer more than four-fold, and chronic gingival inflammation to increase the risk for transmission.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8.

A risk profile for oral HPV infection has emerged, and includes tobacco use and the number of oral sexual partners over a lifetime.

Screening for oral HPV infection and OPSCC

At the current time, reliable screening methods are lacking.11Tuhkuri A, Saraswat M, Mäkitie A, Mattila P, Silén R, Dickinson A, Carpén T, Tohmola T, Joenväärä S, Renkonen S. Patients with early-stage oropharyngeal cancer can be identified with label-free serumproteomics. Br J Cancer 2018;119(2):200-12.,12Rosenthal M, Huang B, Katabi N, Migliacci J, Bryant R, Kaplan S, Blackwell T, Patel S, Yang L, Pei Z, Tang YW, Ganly I. Detection of HPV related oropharyngeal cancer in oral rinse specimens. Oncotarget 2017;8(65):109393-401.,13Kreimer AR, Shiels MS, Fakhry C, Johansson M, Pawlita M, Brennan P, Hildesheim A, Waterboer T. Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research. Cancer 2018;124(9):1859-66. Current tests used for screening include immunochemistry to detect p16 protein, and polymerase chain reaction (PCR) to detect HPV DNA and E6/E7 oncoproteins. These oncoproteins are present with high-risk HPV-related OPSCC, and p16 is overexpressed in high-risk HPV infections.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8.,14Windon MJ, D'Souza G, Rettig EM, Westra WH, van Zante A, Wang SJ, Ryan WR, Mydlarz WK, Ha PK, Miles BA, Koch W, Gourin C, Eisele DW, Fakhry C. Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer 2018;124(14):2993-9.,15König F, Krekeler G, Hönig JF, Cordon-Cardo C, Fischer G, Korabiowska M. Relation between Human Papillomavirus positivity and p16 expression in head and neck carcinomas – A tissue microarray study. Anticancer Res 2017;27:283-8. In a systematic review of 8 studies, HPV detection using an oral rinse/swab resulted in false-negatives in 28% of tests.16Gipson BJ, Robbins HA, Fakhry C, D'Souza G. Sensitivity and specificity of oral HPV detection for HPV-positive head and neck cancer. Oral Oncol 2018;77:52-6. It was concluded that this technique was likely of limited value in the general population. In a recent study in individuals with and without OC/OPC, oral rinse samples were analyzed using a test based on the Cobas HPV Test approved by the Food & Drug Administration for testing cervical samples. A specificity of >90% was obtained, however, the test still resulted in a false negative 21% of the time.12Rosenthal M, Huang B, Katabi N, Migliacci J, Bryant R, Kaplan S, Blackwell T, Patel S, Yang L, Pei Z, Tang YW, Ganly I. Detection of HPV related oropharyngeal cancer in oral rinse specimens. Oncotarget 2017;8(65):109393-401. Recently, a promising droplet digital PCR gave a sensitivity and specificity of 92% and 98%, respectively, and results concurred with the presence of p16 protein.17Isaac A, Kostiuk M, Zhang H, Lindsay C, Makki F, O'Connell DA, Harris JR, Cote DW, Seikaly H, Biron VL. Ultrasensitive detection of oncogenic human papillomavirus in oropharyngeal tissue swabs. J Otolaryngol Head Neck Surg 2017;46(1):5. With respect to HPV DNA, while this indicates HPV infection it does not necessarily mean that the HPV is biologically active.2Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8. In addition, based on an apparent low lifetime risk of associated disease in most groups, screening of the general population using oral swabs/rinses may be impractical.4D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9.

Based on an apparent low lifetime risk of associated disease in most groups, screening of the general population using oral swabs/rinses may be impractical.

Treatment for HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC,6de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017;141(4):664-70.,14Windon MJ, D'Souza G, Rettig EM, Westra WH, van Zante A, Wang SJ, Ryan WR, Mydlarz WK, Ha PK, Miles BA, Koch W, Gourin C, Eisele DW, Fakhry C. Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer 2018;124(14):2993-9. with lower rates of local and regional recurrence.6de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017;141(4):664-70. The latest staging classification uses p16 immunostaining to stage tumors and has been found to be effective in determining a prognosis.18Cramer JD, Hicks KE, Rademaker AW, Patel UA, Samant S. Validation of the eighth edition American Joint Committee on Cancer staging system for humanpapillomavirus-associated oropharyngeal cancer. Head Neck 2018;40(3):457-66. In one study, 32% of patients with OPSCC were p16+ve, and the presence of HPV DNA in tumors further enhanced the five-year survival rate in this group.19Nauta IH, Rietbergen MM, van Bokhoven AAJD, Bloemena E, Lissenberg-Witte BI, Heideman DAM, Baatenburg de Jong RJ, Brakenhoff RH, Leemans CR. Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. Ann Oncol 2018;29(5):1273-9.

Treatment for HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC.

Preventing HPV-associated cancers

HPV infection and related cancers can be prevented with vaccination.5O’Leary ST, Kimberlin DW. Update From the Advisory Committee on Immunization Practices. J Ped Inf Dis Soc 2018;7(3):181-7. The World Health Organisation (WHO) recommends vaccination for females 9 to 13 years-of-age.20World Health Organisation. Immunization, Vaccines and Biologicals. Human papillomavirus (HPV). Available at: http://www.who.int/immunization/diseases/hpv/en/. In the United States, routine vaccination for all adolescents at 11 to 12 years-of-age and up to 18 years-of-age is recommended.1Van Dyne EA, Henley SJ, Saraiya M, Thomas CC, Markowitz LE, Benard VB. Trends in Human Papillomavirus–Associated Cancers — United States, 1999–2015. MMWR 2018; 67(33);918-24.,21Centers for Disease Control and Prevention. Recommended immunization schedule for children and adolescents aged 18 years or younger, United States, 2018. Available at: https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html#f14. By 2017, approximately 49% of adolescents in the United States were fully vaccinated against HPV.22Centers for Disease Control and Prevention. More US adolescents up to date on HPV vaccination. CDC reports show encouraging signs for preventing future cancers. August 23, 2018. Available at: https://www.cdc.gov/media/releases/2018/p0823-HPV-vaccination.html. In Sweden, HPV vaccination is provided to pre-adolescent girls, with infection prevention in boys relying on herd immunity (indirect protection of a community due to a high proportion of individuals within that community being immune to that disease, typically through vaccination). In the United Kingdom, as of June 2018, HPV vaccination is recommended for males and females.23Wolff E, Elfström KM, Haugen Cange H, Larsson S, Englund H, Sparén P, Roth A. Cost-effectiveness of sex-neutral HPV-vaccination in Sweden, accounting for herd-immunity and sexual behaviour. Vaccine 2018;36(34):5160-5.,24HPV vaccination recommended in boys in UK. PharmacoEconomics & Outcomes News 2018;808(1):Jul 28.

In the United States, routine vaccination for all adolescents at 11 to 12 years-of-age and up to 18 years-of-age is recommended.

Barriers to vaccination

A recent systematic review of 55 studies examined barriers to HPV vaccination.25Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, Markowitz LE. Prevalence of genital Human Papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, 2003– 2006. JID 2011;204:566-73. For health care professionals, barriers included parental attitudes and concerns, knowledge gaps, time constraints, cost and lack of /inadequate imbursement. Parental barriers included lack of knowledge, safety concerns, religious and cultural norms, perceived low risk of HPV infection and the belief that vaccination would encourage sexual activity, lack of access and distrust. Similar barriers were found in a second review that included studies from several countries.26Ferrer HB, Trotter C, Hickman M,1 Audrey S. Barriers and facilitators to HPV vaccination of young women in high-income countries: a qualitative systematic review and evidence synthesis. BMC Public Health 2014;14:700. (Table 1)

Table 1. Parental barriers to HPV vaccination
Lack of knowledge
Safety concerns
Religious norms
Cultural norms
Perceived low risk of HPV infection
Belief that it encourages sexual activity
Lack of access
Distrust

The role of dental professionals and barriers to patient education

Dental professionals already conduct oral cancer screenings to detect premalignant and malignant lesions. Surveys confirm that current and future dental professionals also believe that it is important to discuss HPV, its relationship to OPC/OC and vaccination, during routine dental visits. While indicating a willingness to do, barriers have also been identified.27Kline N, Vamos C, Thompson E, Catalanotto F, Petrila J, DeBate R, Griner S, Vázquez-Otero C, Merrell L, Daley E. Are dental providers the next line of HPV-related prevention? Providers' perceived role and needs. Papillomavirus Res 2018;5:104-8.,28Thompson EL, Daley EM, Vamos CA, Horowitz AM, Catalanotto FA, DeBate RD, Merrell LK, Griner SB, Vazquez-Otero C, Kline NS. Health literacy approaches to improving communication between dental hygienists and patients for HPV-related oral cancer prevention. J Dent Hyg 2017;91(4):37-45.,29Daley EM, Thompson EL, Vamos CA, Griner SB, Vazquez-Otero C, Best AL, Kline NS, Merrell LK. HPV-related knowledge among dentists and dental hygienists. J Cancer Educ 2018;33(4):901-6.,30Rowan SD, Hu SL, Brotzman JS, Redding SW, Rankin KV, Vigneswaran N. Knowledge assessment of the dental community in Texas on the role of Human Papilloma Virus in oropharyngeal cancer. Tex Dent J 2015;132(8):528-36.,31Lorenzo-Pouso A, Gándara-Vila P, Banga C, Gallas M, Pérez-Sayáns M, García A, Daley EM, Gasamáns I. Human Papillomavirus-related oral cancer: Knowledge and awareness among Spanish dental students. J Cancer Ed May 10, 2018. doi: 10.1007/s13187-018-1373-1. [Epub ahead of print],32Poelman MR, Brand HS, Forouzanfar T, Daley EM, Jager DHJ. Prevention of HPV-related oral cancer by dentists: Assessing the opinion of Dutch dental students. J Canc Educ 2018;33:1347-54. In one survey, the top two barriers were fear of offending patients (58%) and lack of privacy (54%). Others included lack of time (49%), patient factors such as age/gender (29%), inadequate knowledge (26%) and discomfort (20%).27Kline N, Vamos C, Thompson E, Catalanotto F, Petrila J, DeBate R, Griner S, Vázquez-Otero C, Merrell L, Daley E. Are dental providers the next line of HPV-related prevention? Providers' perceived role and needs. Papillomavirus Res 2018;5:104-8. (Figure 2) Suggested methods of increasing patient awareness (such that patients would initiate discussions and making it easier to do so), include waiting room pamphlets and videos, mobile apps, and posters.27Kline N, Vamos C, Thompson E, Catalanotto F, Petrila J, DeBate R, Griner S, Vázquez-Otero C, Merrell L, Daley E. Are dental providers the next line of HPV-related prevention? Providers' perceived role and needs. Papillomavirus Res 2018;5:104-8.

Figure 2. Barriers to discussing HPV with patients


Survey results confirm knowledge gaps. In one US survey, the prevalence of HPV infection was underestimated, 31% knew that most HPV infections would clear in a short time, 43% believed HPV could cause herpes and 9% were unaware that HPV is sexually transmitted.29Daley EM, Thompson EL, Vamos CA, Griner SB, Vazquez-Otero C, Best AL, Kline NS, Merrell LK. HPV-related knowledge among dentists and dental hygienists. J Cancer Educ 2018;33(4):901-6. In another survey, fewer than half of dental professionals could identify the site and age group with the greatest increase in incidence for OPC.30Rowan SD, Hu SL, Brotzman JS, Redding SW, Rankin KV, Vigneswaran N. Knowledge assessment of the dental community in Texas on the role of Human Papilloma Virus in oropharyngeal cancer. Tex Dent J 2015;132(8):528-36. Similar knowledge gaps are found for dental students.31Lorenzo-Pouso A, Gándara-Vila P, Banga C, Gallas M, Pérez-Sayáns M, García A, Daley EM, Gasamáns I. Human Papillomavirus-related oral cancer: Knowledge and awareness among Spanish dental students. J Cancer Ed May 10, 2018. doi: 10.1007/s13187-018-1373-1. [Epub ahead of print],32Poelman MR, Brand HS, Forouzanfar T, Daley EM, Jager DHJ. Prevention of HPV-related oral cancer by dentists: Assessing the opinion of Dutch dental students. J Canc Educ 2018;33:1347-54. Among Spanish and Dutch students, 75% and 87%, respectively, believed HPV was associated with OPC/OC, 49% and 34%, respectively, were aware that an increasing number of cases are associated with nontraditional risk factors, 66% and 75%, respectively, knew that HPV is sexually transmitted, and 37% and 17%, respectively, knew that most infections clear in a short time. In addition, 28% and 29% were unaware of a vaccine, and 68% and 10% believed that antibiotics could cure HPV infection.

Conclusions

HPV oral infection has increased and is now responsible for more than 70% of cases of OPSCC. Knowledge and awareness are lacking among the general public, and patients need to be educated on HPV infection, risk and prevention. Dental professionals and dental students have indicated a willingness to educate patients on the association of HPV infection, risk for oral and oropharyngeal cancer, and prevention. The need for more education and continuing education on the current epidemiology of HPV and information to be provided to patients, as well as training to build communication skills, has been identified.27Kline N, Vamos C, Thompson E, Catalanotto F, Petrila J, DeBate R, Griner S, Vázquez-Otero C, Merrell L, Daley E. Are dental providers the next line of HPV-related prevention? Providers' perceived role and needs. Papillomavirus Res 2018;5:104-8.,31Lorenzo-Pouso A, Gándara-Vila P, Banga C, Gallas M, Pérez-Sayáns M, García A, Daley EM, Gasamáns I. Human Papillomavirus-related oral cancer: Knowledge and awareness among Spanish dental students. J Cancer Ed May 10, 2018. doi: 10.1007/s13187-018-1373-1. [Epub ahead of print],32Poelman MR, Brand HS, Forouzanfar T, Daley EM, Jager DHJ. Prevention of HPV-related oral cancer by dentists: Assessing the opinion of Dutch dental students. J Canc Educ 2018;33:1347-54. Dental students have also identified the need for standardized education in the dental curriculum.31Lorenzo-Pouso A, Gándara-Vila P, Banga C, Gallas M, Pérez-Sayáns M, García A, Daley EM, Gasamáns I. Human Papillomavirus-related oral cancer: Knowledge and awareness among Spanish dental students. J Cancer Ed May 10, 2018. doi: 10.1007/s13187-018-1373-1. [Epub ahead of print],32Poelman MR, Brand HS, Forouzanfar T, Daley EM, Jager DHJ. Prevention of HPV-related oral cancer by dentists: Assessing the opinion of Dutch dental students. J Canc Educ 2018;33:1347-54. Additional information related to HPV should be added to the dental school curriculum. Current and future dental professionals are in a unique position to play a key role in helping to provide patient education to help combat oral HPV infection and related disease.

References

  • 1.Van Dyne EA, Henley SJ, Saraiya M, Thomas CC, Markowitz LE, Benard VB. Trends in Human Papillomavirus–Associated Cancers — United States, 1999–2015. MMWR 2018; 67(33);918-24.
  • 2.Hübbers CU, Akgül B. HPV and cancer of the oral cavity. Virulence 2015;6(3):244-8.
  • 3.Javadi P, Sharma A, Zahnd W, Jenkins W. Evolving disparities in the epidemiology of oral cavity and oropharyngeal cancers. Cancer Causes and Control 2017;28(6):635-45.
  • 4.D'Souza G, McNeel TS, Fakhry C. Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer. Ann Oncol 2017;28(12):3065-9.
  • 5.O’Leary ST, Kimberlin DW. Update From the Advisory Committee on Immunization Practices. J Ped Inf Dis Soc 2018;7(3):181-7.
  • 6.de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017;141(4):664-70.
  • 7.Chaturvedi A, Zumsteg ZS. A snapshot of the evolving epidemiology of oropharynx cancers. Cancer 2018;124(14):2893-6.
  • 8.Forte T, Niu J, Lockwood G, Bryant H. Incidence trends in head and neck cancers and human papillomavirus (HPV)-associated oropharyngeal cancer in Canada, 1992–2009. Cancer Causes & Control 2012;23(8):1343-8.
  • 9.Schache AG, Powell NG, Cuschieri KS, Robinson M, Leary S, Mehanna H, et al. HPV-related oropharynx cancer in the United Kingdom: an evolution in the understanding of disease etiology. Cancer Res 2016;122(24):6598-06.
  • 10.Mehanna H, Franklin N, Compton N, Robinson M, Powell N, Biswas-Baldwin N, et al. Geographic variation in human papillomavirus-related oropharyngeal cancer: Data from 4 multinational randomized trials. Head Neck 2016;38(Suppl 1):E1863-9.
  • 11.Tuhkuri A, Saraswat M, Mäkitie A, Mattila P, Silén R, Dickinson A, Carpén T, Tohmola T, Joenväärä S, Renkonen S. Patients with early-stage oropharyngeal cancer can be identified with label-free serumproteomics. Br J Cancer 2018;119(2):200-12.
  • 12.Rosenthal M, Huang B, Katabi N, Migliacci J, Bryant R, Kaplan S, Blackwell T, Patel S, Yang L, Pei Z, Tang YW, Ganly I. Detection of HPV related oropharyngeal cancer in oral rinse specimens. Oncotarget 2017;8(65):109393-401.
  • 13.Kreimer AR, Shiels MS, Fakhry C, Johansson M, Pawlita M, Brennan P, Hildesheim A, Waterboer T. Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research. Cancer 2018;124(9):1859-66.
  • 14.Windon MJ, D'Souza G, Rettig EM, Westra WH, van Zante A, Wang SJ, Ryan WR, Mydlarz WK, Ha PK, Miles BA, Koch W, Gourin C, Eisele DW, Fakhry C. Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer 2018;124(14):2993-9.
  • 15.König F, Krekeler G, Hönig JF, Cordon-Cardo C, Fischer G, Korabiowska M. Relation between Human Papillomavirus positivity and p16 expression in head and neck carcinomas – A tissue microarray study. Anticancer Res 2017;27:283-8.
  • 16.Gipson BJ, Robbins HA, Fakhry C, D'Souza G. Sensitivity and specificity of oral HPV detection for HPV-positive head and neck cancer. Oral Oncol 2018;77:52-6.
  • 17.Isaac A, Kostiuk M, Zhang H, Lindsay C, Makki F, O'Connell DA, Harris JR, Cote DW, Seikaly H, Biron VL. Ultrasensitive detection of oncogenic human papillomavirus in oropharyngeal tissue swabs. J Otolaryngol Head Neck Surg 2017;46(1):5.
  • 18.Cramer JD, Hicks KE, Rademaker AW, Patel UA, Samant S. Validation of the eighth edition American Joint Committee on Cancer staging system for humanpapillomavirus-associated oropharyngeal cancer. Head Neck 2018;40(3):457-66.
  • 19.Nauta IH, Rietbergen MM, van Bokhoven AAJD, Bloemena E, Lissenberg-Witte BI, Heideman DAM, Baatenburg de Jong RJ, Brakenhoff RH, Leemans CR. Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. Ann Oncol 2018;29(5):1273-9.
  • 20.World Health Organisation. Immunization, Vaccines and Biologicals. Human papillomavirus (HPV). Available at: http://www.who.int/immunization/diseases/hpv/en/.
  • 21.Centers for Disease Control and Prevention. Recommended immunization schedule for children and adolescents aged 18 years or younger, United States, 2018. Available at: https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html#f14.
  • 22.Centers for Disease Control and Prevention. More US adolescents up to date on HPV vaccination. CDC reports show encouraging signs for preventing future cancers. August 23, 2018. Available at: https://www.cdc.gov/media/releases/2018/p0823-HPV-vaccination.html.
  • 23.Wolff E, Elfström KM, Haugen Cange H, Larsson S, Englund H, Sparén P, Roth A. Cost-effectiveness of sex-neutral HPV-vaccination in Sweden, accounting for herd-immunity and sexual behaviour. Vaccine 2018;36(34):5160-5.
  • 24.HPV vaccination recommended in boys in UK. PharmacoEconomics & Outcomes News 2018;808(1):Jul 28.
  • 25.Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, Markowitz LE. Prevalence of genital Human Papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, 2003– 2006. JID 2011;204:566-73.
  • 26.Ferrer HB, Trotter C, Hickman M,1 Audrey S. Barriers and facilitators to HPV vaccination of young women in high-income countries: a qualitative systematic review and evidence synthesis. BMC Public Health 2014;14:700.
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