HPV & Oral Cancer: A Guide for the Dental Team
Dolphine Oda, BDS, MSc, University of Washington School of Dentistry professor and Director of UW's Oral Pathology Biopsy Service, shares what dental teams should know about HPV and oral cancer with the WSDA News.
Originally published in the July 2018 issue of the WSDA News.
Human Papilloma Virus (HPV) and Oropharyngeal squamous cell carcinoma (OPC)
Human papilloma viruses (HPV) are a group of small species-specific, double-stranded DNA viruses that specifically infect epithelial cells of the skin and mucosa, including the oral mucosa (1-7). Over 200 types of HPV are described (2), and are divided into low- and high-risk categories. Low-risk types of HPV (e.g., 6/11, 2/4, 13/32) are associated with venereal and common warts and focal epithelial hyperplasia. High-risk types (e.g., 16, 18, 31, 35, 45), also known as carcinogenic (oncogenic) HPVs, are associated with cervical, oral and oropharyngeal, anal, vaginal, vulva,r and penile squamous cell carcinomas (SCC) (1-6).
Prevalence:
In 2009, a cross-sectional study of the prevalence of oral HPV infection demonstrated that 6.9% of the U.S. population between the ages of 14-69 has HPV in their mouth, and that 1% has the carcinogenic HPV type 16 (6). This study showed that HPV infection is three times more common in males as in females, which corresponds to the clinical incidence of Oropharyngeal squamous cell carcinoma (OPC) being significantly more common in males (1-2, 6). In the last 15 years or so, the incidence of HPV-associated OPC (referred to in this article as HPV+ OPC) has steadily increased, almost doubling from 40% in the year 2000 to 70% in 2009 (7-8). This near doubling is attributed to the increasing incidence of infection with carcinogenic HPV. It is important to note that HPV infection is transient, and that the immune system clears the virus on average within one year (2). For a variety of reasons, this virus may persist in a small number of patients (1-6). Patients with persistent carcinogenic HPV lesions are more likely to progress to epithelial dysplasia and SCC, though this does not always occur. It is also important to note that exposure to carcinogenic HPV does not mean that the exposed person will necessarily develop oral or oropharyngeal SCC. In the U.S., the CDC reports close to 6 million new cases of all types of HPV infection annually (2); of those, only 12,000 develop OPC, and 21,000 develop cervical and other genital cancers, so the overall risk of developing OPC from HPV infection is very small—about two cancer cases per 1,000 infected patients.
Clinical presentation:
The clinical presentation, patient profile, and prognosis of HPV+ OPC are different from that of tobacco-associated oral cavity SCC (referred to in this article as tobacco+OC). HPV+ OPC is believed to be a sexually transmitted disease caused by the same HPV types that cause cervical cancer, especially types 16 and, to a somewhat lesser extent, 18 (1-3). The main modes of transmission are oral-genital sex and, to a lesser extent, deep kissing (1-3). HPV+ OPC patients tend to be young adults, especially young white males (1-6), though the number of young females diagnosed with this condition is also on the rise (7). These patients tend not to smoke or drink (or do so only lightly), and tend to be within the age range of 30-60 or occasionally older (1-3). The posterior mouth, including the oropharynx, tonsillar area, and tongue base, is the most common site of occurrence (7-10). The clinical presentation is also different from tobacco+OC. HPV+ OPC lesions are usually small in size, and often present at more advanced stages of the disease (TNM stages 3 and 4) with unexplained cervical lymphadenopathy (neck mass) (1-3). The lymph nodes are usually large and cystic. Less frequently, patients present with dysphagia, odynophagia, weight loss, otalgia, tonsillar mass, and sore throat (1-3). Otalgia is probably one of the earliest subtle symptoms that are often ignored by both the patient and the provider.
HPV+ OPC survival rate:
The literature consistently demonstrates that patients with HPV+ OPC have a significantly better survival rate than patients with other types of OPC. HPV+ OPC patients usually first present at TNM stages 3 and 4, but despite the more advanced stage of the disease, the prognosis is significantly better than that of patients with HPV negative OPC (three-year survival rates of 74% and 43%, respectively) (6).
In December 2017, the American Joint Committee on Cancer reported that stage 3 HPV+ OPC has a better prognosis than stage 1 tobacco+ OC. This observation led to clinical trials investigating “deintensification” of treatment strategies to reduce treatment-associated morbidity induced by multimodal treatment including surgery, radiation, and chemotherapy (11). Patients with HPV+ OPC have less potential for a second primary SCC and a 60-80% reduction in mortality compared to patients with HPV negative OPC (6). In addition, patients with HPV+ OPC respond better to treatment and have a better prognosis and survival rate than tobacco+ OC (1-8).
Immunization for HPV infection:
Three types of vaccines are available; all are of synthetic derivation and cannot transmit disease (12-15). The first is the bivalent vaccine (Cervarix) against HPV types 16 and 18. The second vaccine (Gardasil) is quadrivalent against HPV types 6/11 (low risk), as well as 16 and 18. The third vaccine (Gardasil 9), used most commonly, is multivalent against nine types of HPV: two are the low-risk types 6/11; and the other seven are oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58. Immunization is recommended for males and females before the age of “risk for exposure,” which is ideally between 11 and 12 years of age, with a range of 9-26 for both males and females (12-15).
The vaccines have historically been administered in three doses 0-6 months apart, which is still recommended (12-15). Although some immunity is achieved after a single injection, two or three doses are recommended depending upon age. Cervarix is more immunogenic following a single dose, and the immune response is longer lasting. On the other hand, three doses are more effective in achieving prolonged immunogenicity. For example, a 2017 Scandinavian study including 9,437 patients with 12 years of follow-up reported that the quadrivalent HPV vaccine (administered in three doses) “shows continued protection in women for at least 10 years, with a trend for continued protection through 12 years of follow-up” (15). The necessity and efficacy of booster doses is not yet adequately studied, and the uptake of HPV vaccines worldwide remains low. While Gardasil 9 is active against seven oncogenic HPV types, immunogenicity and length of protection may be inadequate. Thus, clinical surveillance for genital and oral cancers remains very important to achieve early diagnosis and treatment.
References
1. Vokes EE, Agrawal N, Seiwert TY. HPV-Associated Head and Neck Cancer. J Natl Cancer Inst 2015 ; 107:djv344.
2.Polesky JM and Hirsch MS. Human papilloma virus infections: epidemiology and disease association. Uptodate.com online publication. Dec 2017, edited again May 2018.
3. Haddad RI, Brockstein BE, Brizel DM.et al. Uptodate.com online publication. June 2017, edited again May 2018.
4. David J. Adelstein and Cristina P. Rodriguez. Human Papillomavirus: Changing Paradigms in Oropharyngeal Cancer 2010: Curr Oncol Rep 12:115–120.
5. Blitzer GC, Smith MA, Harris SL, Kimple RJ (2014). Review of the clinical and biologic aspects of human papillomavirus-positive squamous cell carcinomas of the head and neck. It J Radiat Oncol Biol Phys. 2014: Mar 15;88(4):761-70.
6. Poling JS, Ma X J, Bui S et al. Human papillomavirus (HPV) status of non-tobacco related squamous cell carcinomas of the lateral tongue. Oral Oncology 2014 50:306-10.
7. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, Graubard BI, Chaturvedi AK (2009-2010). Prevalence of oral HPV infection in the United States. JAMA. 2012 Feb 15;307(7):693-703.
8. Gillison, M. L. (2007). Current topics in the epidemiology of oral cavity and oropharyngeal cancers. Head & neck, 29(8), 779-792.
9. Wesley R. McIlwain, BS; Amit J. Sood, BA; Shaun A. Nguyen, MD, MA; Terry A. Day, MD. Initial Symptoms in Patients With HPV-Positive and HPV-Negative Oropharyngeal Cancer onlinefirst. JAMA Otolaryngol Head Neck Surg. Published online March 20, 2014.
10. Michaud, D. S., Langevin, S. M., Eliot, M., Nelson, H. H., Pawlita, M., McClean, M. D., & Kelsey, K. T. (2014). High‐risk HPV types and head and neck cancer. International Journal of Cancer.
11. Worden FP, Bradford CR and Eisbruch A. Treatment of locoregionally advanced (stage III and IV) head and neck cancer: the oropharynx. Uptodate.com online publication. September 2017.
12. Lauri E. Markowitz, Eileen F. Dunne, Mona Saraiya, Harrell W. Chesson, C. Robinette Curtis, Julianne Gee, Joseph A. Bocchini, Jr, Elizabeth R. Unger.. Human Papillomavirus Vaccination: Recommendations of the Advisory Committee on Immunization Practices (ACIP).CDC: August 29, 2014 / 63(RR05); 1-30.
13. Tino F. Schwarz, Andrzej Galaj, et al. Ten‐year immune persistence and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in females vaccinated at 15–55 years of age. Cancer Medicine: Open access October 2017. https://doi.org/10.1002/cam4.1155
14. Luciano Mariani and Aldo Venuti. HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future. J Transl Med. 2010; 8:105. Published online.
15. Kjaer SK, Nygård M, Dillner J et al. A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries. Clin Infect Dis. 2018 Jan 18;66(3):339-345.
16. 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 Jul 17;8(7):e68329.
Human Papilloma Virus (HPV) and Oropharyngeal squamous cell carcinoma (OPC)
Human papilloma viruses (HPV) are a group of small species-specific, double-stranded DNA viruses that specifically infect epithelial cells of the skin and mucosa, including the oral mucosa (1-7). Over 200 types of HPV are described (2), and are divided into low- and high-risk categories. Low-risk types of HPV (e.g., 6/11, 2/4, 13/32) are associated with venereal and common warts and focal epithelial hyperplasia. High-risk types (e.g., 16, 18, 31, 35, 45), also known as carcinogenic (oncogenic) HPVs, are associated with cervical, oral and oropharyngeal, anal, vaginal, vulva,r and penile squamous cell carcinomas (SCC) (1-6).
Prevalence:
In 2009, a cross-sectional study of the prevalence of oral HPV infection demonstrated that 6.9% of the U.S. population between the ages of 14-69 has HPV in their mouth, and that 1% has the carcinogenic HPV type 16 (6). This study showed that HPV infection is three times more common in males as in females, which corresponds to the clinical incidence of Oropharyngeal squamous cell carcinoma (OPC) being significantly more common in males (1-2, 6). In the last 15 years or so, the incidence of HPV-associated OPC (referred to in this article as HPV+ OPC) has steadily increased, almost doubling from 40% in the year 2000 to 70% in 2009 (7-8). This near doubling is attributed to the increasing incidence of infection with carcinogenic HPV. It is important to note that HPV infection is transient, and that the immune system clears the virus on average within one year (2). For a variety of reasons, this virus may persist in a small number of patients (1-6). Patients with persistent carcinogenic HPV lesions are more likely to progress to epithelial dysplasia and SCC, though this does not always occur. It is also important to note that exposure to carcinogenic HPV does not mean that the exposed person will necessarily develop oral or oropharyngeal SCC. In the U.S., the CDC reports close to 6 million new cases of all types of HPV infection annually (2); of those, only 12,000 develop OPC, and 21,000 develop cervical and other genital cancers, so the overall risk of developing OPC from HPV infection is very small—about two cancer cases per 1,000 infected patients.
Clinical presentation:
The clinical presentation, patient profile, and prognosis of HPV+ OPC are different from that of tobacco-associated oral cavity SCC (referred to in this article as tobacco+OC). HPV+ OPC is believed to be a sexually transmitted disease caused by the same HPV types that cause cervical cancer, especially types 16 and, to a somewhat lesser extent, 18 (1-3). The main modes of transmission are oral-genital sex and, to a lesser extent, deep kissing (1-3). HPV+ OPC patients tend to be young adults, especially young white males (1-6), though the number of young females diagnosed with this condition is also on the rise (7). These patients tend not to smoke or drink (or do so only lightly), and tend to be within the age range of 30-60 or occasionally older (1-3). The posterior mouth, including the oropharynx, tonsillar area, and tongue base, is the most common site of occurrence (7-10). The clinical presentation is also different from tobacco+OC. HPV+ OPC lesions are usually small in size, and often present at more advanced stages of the disease (TNM stages 3 and 4) with unexplained cervical lymphadenopathy (neck mass) (1-3). The lymph nodes are usually large and cystic. Less frequently, patients present with dysphagia, odynophagia, weight loss, otalgia, tonsillar mass, and sore throat (1-3). Otalgia is probably one of the earliest subtle symptoms that are often ignored by both the patient and the provider.
HPV+ OPC survival rate:
The literature consistently demonstrates that patients with HPV+ OPC have a significantly better survival rate than patients with other types of OPC. HPV+ OPC patients usually first present at TNM stages 3 and 4, but despite the more advanced stage of the disease, the prognosis is significantly better than that of patients with HPV negative OPC (three-year survival rates of 74% and 43%, respectively) (6).
In December 2017, the American Joint Committee on Cancer reported that stage 3 HPV+ OPC has a better prognosis than stage 1 tobacco+ OC. This observation led to clinical trials investigating “deintensification” of treatment strategies to reduce treatment-associated morbidity induced by multimodal treatment including surgery, radiation, and chemotherapy (11). Patients with HPV+ OPC have less potential for a second primary SCC and a 60-80% reduction in mortality compared to patients with HPV negative OPC (6). In addition, patients with HPV+ OPC respond better to treatment and have a better prognosis and survival rate than tobacco+ OC (1-8).
Immunization for HPV infection:
Three types of vaccines are available; all are of synthetic derivation and cannot transmit disease (12-15). The first is the bivalent vaccine (Cervarix) against HPV types 16 and 18. The second vaccine (Gardasil) is quadrivalent against HPV types 6/11 (low risk), as well as 16 and 18. The third vaccine (Gardasil 9), used most commonly, is multivalent against nine types of HPV: two are the low-risk types 6/11; and the other seven are oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58. Immunization is recommended for males and females before the age of “risk for exposure,” which is ideally between 11 and 12 years of age, with a range of 9-26 for both males and females (12-15).
The vaccines have historically been administered in three doses 0-6 months apart, which is still recommended (12-15). Although some immunity is achieved after a single injection, two or three doses are recommended depending upon age. Cervarix is more immunogenic following a single dose, and the immune response is longer lasting. On the other hand, three doses are more effective in achieving prolonged immunogenicity. For example, a 2017 Scandinavian study including 9,437 patients with 12 years of follow-up reported that the quadrivalent HPV vaccine (administered in three doses) “shows continued protection in women for at least 10 years, with a trend for continued protection through 12 years of follow-up” (15). The necessity and efficacy of booster doses is not yet adequately studied, and the uptake of HPV vaccines worldwide remains low. While Gardasil 9 is active against seven oncogenic HPV types, immunogenicity and length of protection may be inadequate. Thus, clinical surveillance for genital and oral cancers remains very important to achieve early diagnosis and treatment.
References
1. Vokes EE, Agrawal N, Seiwert TY. HPV-Associated Head and Neck Cancer. J Natl Cancer Inst 2015 ; 107:djv344.
2.Polesky JM and Hirsch MS. Human papilloma virus infections: epidemiology and disease association. Uptodate.com online publication. Dec 2017, edited again May 2018.
3. Haddad RI, Brockstein BE, Brizel DM.et al. Uptodate.com online publication. June 2017, edited again May 2018.
4. David J. Adelstein and Cristina P. Rodriguez. Human Papillomavirus: Changing Paradigms in Oropharyngeal Cancer 2010: Curr Oncol Rep 12:115–120.
5. Blitzer GC, Smith MA, Harris SL, Kimple RJ (2014). Review of the clinical and biologic aspects of human papillomavirus-positive squamous cell carcinomas of the head and neck. It J Radiat Oncol Biol Phys. 2014: Mar 15;88(4):761-70.
6. Poling JS, Ma X J, Bui S et al. Human papillomavirus (HPV) status of non-tobacco related squamous cell carcinomas of the lateral tongue. Oral Oncology 2014 50:306-10.
7. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, Graubard BI, Chaturvedi AK (2009-2010). Prevalence of oral HPV infection in the United States. JAMA. 2012 Feb 15;307(7):693-703.
8. Gillison, M. L. (2007). Current topics in the epidemiology of oral cavity and oropharyngeal cancers. Head & neck, 29(8), 779-792.
9. Wesley R. McIlwain, BS; Amit J. Sood, BA; Shaun A. Nguyen, MD, MA; Terry A. Day, MD. Initial Symptoms in Patients With HPV-Positive and HPV-Negative Oropharyngeal Cancer onlinefirst. JAMA Otolaryngol Head Neck Surg. Published online March 20, 2014.
10. Michaud, D. S., Langevin, S. M., Eliot, M., Nelson, H. H., Pawlita, M., McClean, M. D., & Kelsey, K. T. (2014). High‐risk HPV types and head and neck cancer. International Journal of Cancer.
11. Worden FP, Bradford CR and Eisbruch A. Treatment of locoregionally advanced (stage III and IV) head and neck cancer: the oropharynx. Uptodate.com online publication. September 2017.
12. Lauri E. Markowitz, Eileen F. Dunne, Mona Saraiya, Harrell W. Chesson, C. Robinette Curtis, Julianne Gee, Joseph A. Bocchini, Jr, Elizabeth R. Unger.. Human Papillomavirus Vaccination: Recommendations of the Advisory Committee on Immunization Practices (ACIP).CDC: August 29, 2014 / 63(RR05); 1-30.
13. Tino F. Schwarz, Andrzej Galaj, et al. Ten‐year immune persistence and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in females vaccinated at 15–55 years of age. Cancer Medicine: Open access October 2017. https://doi.org/10.1002/cam4.1155
14. Luciano Mariani and Aldo Venuti. HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future. J Transl Med. 2010; 8:105. Published online.
15. Kjaer SK, Nygård M, Dillner J et al. A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries. Clin Infect Dis. 2018 Jan 18;66(3):339-345.
16. 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 Jul 17;8(7):e68329.
