The CDC reports that human papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the United States.1 At an estimated 14 million persons newly infected every year, this accounts for most STIs reported.2 Although most HPV infections are cleared by the body's immune system with minimal to no harm, HPV infection accounts for more than 5% of cancers worldwide.1 The association between HPV and cervical cancer is widely recognized. Primary care providers have been working to reduce the risk of HPV-related cervical cancer through early detection and vaccination against the most common high-risk types.
A less familiar association is that between HPV and oropharyngeal cancer, commonly referred to as throat or tonsil cancer (Figure 1). The oropharynx, at the junction of the oral cavity and pharynx, contains lymphoid tissue in the form of tonsils: the paired palatine tonsils located along the lateral pharyngeal walls and the paired lingual tonsils at the base of the tongue. This article focuses on HPV and its association with oropharyngeal squamous cell carcinoma, including epidemiology, risk factors, screening, and management.
Human papillomaviruses are nonenveloped, double-stranded DNA viruses. Of the more than 150 types, or strains, of HPV, 11 types are classified as high-risk for their potential to induce malignancy. Types 16, 18, 31, and 33 are the most prevalent of these. HPV 16 proportionately causes more than 90% of HPV-positive oropharyngeal cancer.1 The virus has a circular genome that is divided into a classification of early and late genes: early genes (E1-E7) serve viral transcription and replication, and late genes (L1 and L2) encode structural capsid proteins.
HPV proteins E6 and E7 are considered oncoproteins and bind tumor suppressor proteins. Both proteins have been established as the key drivers of carcinogenesis in oropharyngeal carcinoma. E6 binds the tumor suppressor protein p53 and marks it for degradation.3 Although the E6 and E7 proteins are expressed in both low- and high-risk HPV types, the proteins expressed in high-risk HPV types bind their tumor suppressor proteins with much higher affinity.3,4
Lymphoid tissue of the tonsils of the oropharynx has a nonkeratinized stratified squamous epithelium. HPV infection begins in the basal epithelial cells of the lymphoid tissue. The tonsil tissue of the oropharynx has involutions creating tonsillar crypts that increase the tonsil's surface area more than 700-fold (Figures 2 and 3). The reticular epithelium within the crypts has a disrupted basal cell layer and basement membrane, which facilitates the trafficking of antigens, lymphocytes, and antigen-presenting cells, and is the proposed site for subsequent neoplasia (Figure 4).5,6
HPV evades the immune system by a number of means. Although HPV infects basal epithelial cells, viral replication only produces high levels of viral proteins in the upper layers of the squamous epithelia during cell differentiation. Moreover, no cytolysis occurs as a consequence of HPV replication and no viral particles are released from the infected cells. The lack of a viremic phase and delayed expression of viral proteins in later stages of epithelial differentiation insulate the infection from the immune response.6 HPV also delays the activation of the immune response by downregulating interferon signaling pathways and the expression of proinflammatory products.7 The same E6 and E7 oncogenes are believed to play a crucial role in this downregulation.
Most HPV infections are cleared in 9 to 18 months. The small percentage that are not cleared become chronic persistent infection.5,7 Literature on cervical HPV reports that about 10% of women fail to clear HPV infections.5,7 A persistent infection is believed to be a risk factor for cancer development because the lack of normal cell death progression provides an increased opportunity for genetic mutations to accumulate.8
Head and neck cancer is the sixth most common cancer worldwide.9 An estimated 45,000 patients were diagnosed with head and neck cancer in the United States in 2015, accounting for about 3% of all malignancies.10,11
Historically, the most common risk factors for head and neck cancer were tobacco and alcohol use.12,13 Although the two habits are often linked, their independent association with head and neck cancer has been confirmed. Clear dose relationships exist for the frequency, duration, and number of pack years of cigarette smoking, and for the amount and duration of alcohol use.11-13
A possible association between HPV and oropharyngeal cancer was suggested as early as 1992, and became widely accepted as proven by 2007. Oropharyngeal squamous cell carcinomas are clinically referred to as HPV-positive or HPV-negative. The incidence of HPV-negative head and neck cancers declined 50% between 1988 and 2004.14 This decline is likely attributable to tobacco cessation efforts over the past 40 years. Studies comparing different nations around the world have shown less of a decline in HPV-negative head and neck squamous cell carcinoma in developing countries, where tobacco cessation programs have not yet been implemented.15
The prevalence of HPV-positive oropharyngeal squamous cell carcinoma in the United States has risen from 20% in the 1980s to more than 70% in 2014.16 If this trend continues, the prevalence of HPV-positive oropharyngeal squamous cell carcinoma will surpass that of HPV-related cervical cancer by 2020.16,17
THE NEW RISK FACTOR: HPV EXPOSURE
Several studies have reviewed the epidemiology and natural history of oral HPV infection.18-20 A cross-sectional study of oral HPV prevalence was conducted as part of the National Health and Nutrition Examination Survey (NHANES) 2009-2010 of men and women ages 14 to 69 years.18 The prevalence of oral HPV infection among men and women was 6.9%, and the prevalence of high-risk type HPV16 oral infection was 1%.18 In comparison, NHANES 2003-2006 data on female genital HPV infection reported a rate of 42.5% in women ages 14 to 59 years.21 The data confirm that oral HPV infection is predominately sexually transmitted, and 80% of sexually active people ages 14 to 44 years have had oral sex with an opposite-sex partner.22 Infection was almost eightfold higher among sexually experienced patients and increased with the number of sexual partners: One in five patients with more than 20 lifetime sexual partners was infected. Oral HPV infection followed a bimodal pattern with respect to age, with peak prevalence of 7.3% among patients ages 30 to 34 years, and 11.4% among those ages 60 to 64 years. Men had a significantly higher prevalence than women: 10.1% compared with 3.6%.18 NHANES did not collect data relevant to nonsexual means of transmission.
In 2007, D'Souza and colleagues published a landmark paper in the New England Journal of Medicine on the association between HPV and oropharyngeal squamous cell carcinoma.23 They found that HPV16 DNA was detected in 72% of patients with newly diagnosed oropharyngeal squamous cell carcinoma. The association increased significantly in patients who had had 26 or more vaginal-sex partners or six or more oral-sex partners. The association was independent of patients' history of tobacco and alcohol use.23
Although the exact course from the time of HPV exposure to the development of oropharyngeal cancer is unknown, HPV exposure likely occurs earlier in life and takes decades to result in cancer.24,25 Interestingly, patients with HPV-positive oropharyngeal squamous cell carcinoma tend to present at a relative young age for head and neck cancer (typically between ages 40 and 55 years), are male, and have no or limited use of tobacco products.26
Although HPV-positive oropharyngeal squamous cell carcinomas typically are discovered at a more advanced stage, treatment response and patient survival are superior, with 3-year survival rates of 82% compared with 57% for patients with HPV-negative oropharyngeal squamous cell carcinomas.27
SCREENING IN PRIMARY CARE
The goal of all cancer screening is to detect cancer early, if possible before symptom onset. In most cases, the earlier a cancer is identified, the more straightforward it is to treat and the more likely for the patient to have a good prognosis. Screening for head and neck cancer primarily depends on a history and physical examination.
The most common presentation for oropharyngeal cancer is a neck mass that represents metastasis to a lymph node. Because metastatic disease may be the first and only presenting symptom, primary care providers must be alert to this finding and initiate the appropriate workup. Other common presenting symptoms include odynophagia, dysphagia, globus sensation, and referred otalgia.28
A suspicious finding on physical examination warrants further diagnostic workup and a referral to an otolaryngologist. An otolaryngologist can perform a more comprehensive head and neck examination, often assisted by flexible nasolaryngoscopy for a more thorough evaluation of the oropharynx, larynx, and hypopharynx (Figure 5). First-line imaging typically consists of an ultrasound or CT and positron-emission tomography (PET)-CT to look for areas of increased metabolic activity and delineate the tumor's morphology (Figures 6 and 7). Metastatic lymphadenopathy is confirmed with fine-needle aspiration.
The National Comprehensive Cancer Network (NCCN) has integrated HPV tumor detection into its guidelines once a tissue biopsy has been taken. Institutions most commonly detect HPV DNA in tumors via polymerase chain reaction (PCR) or in-situ hybridization. P16 is a surrogate marker for HPV status because the P16 protein is overexpressed in HPV-positive oropharyngeal cancers. P16 has been shown to be a statistically significant correlate to the presence of HPV DNA measure by PCR or in-situ hybridization in oropharyngeal squamous cell carcinoma.3 The terms HPV-positive and P16-positive oropharyngeal squamous cell carcinoma often are used interchangeably.
Unlike the Pap test for cervical cancer screening, routine testing for oropharyngeal squamous cell carcinoma has not been developed. Screening has been complicated by the challenges presented by tonsil tissue. A brush or swab of the palatine tonsil is likely to be feasible in any clinic, but to reliably sample the less accessible lingual tonsils of the base of tongue requires more specialized examination by an otolaryngologist. Perhaps more important is the difference in histology of the cervix compared with the tonsils. Cervical epithelium is relatively flat, allowing reliable sampling from the surface. The tonsils contain crypts and invaginations, and the epicenter of tumor growth likely is in the basal epithelial layer at the base of these crypts. A swab or brush of the tonsil surface may simply pass over a premalignant or malignant change within the crypts below.29
Fakhry and colleagues investigated the association between HPV16 infection, cytopathology, and histopathology and concluded that an oropharyngeal “Pap test equivalent” may not be feasible.30 An admitted challenge to the study included the likely inability to sample the relevant tonsillar epithelium in the tonsillar crypts via traditional cytobrush biopsy.
Oral cavity and oropharyngeal screening
A variety of commercially available diagnostic laboratory tests can be found for oral cavity and oropharyngeal screening. These tests are used as an adjunct to the oral examination and are not proven as screening tests. No recommendations exist for saliva testing as a screening test. Furthermore, no blood tests can identify squamous cell carcinoma. HPV antibody serologies can be used to track current or past infection with HPV, but since HPV elicits a strong universal immune response, serology may not be completely reliable.
The benefits of a screening process must be weighed against the risks. Poor screening tests could lead to patient harm through unnecessary diagnostic procedures and treatments. Also, the financial stress of such screenings could prove significant. Thus, the most appropriate screening for head and neck cancer remains a patient history, physical examination, and prompt, appropriate referrals to specialists.
Patients seeking treatment for HPV-related oropharyngeal cancer have two basic options:
- primary chemoradiotherapy
- surgery with adjuvant radiotherapy or adjuvant chemoradiotherapy.
Most tertiary referral centers have multidisciplinary tumor boards consisting of surgical oncologists, radiation oncologists, and medical oncologists, along with other members of the oncologic care team to help direct a patient-centered treatment plan. Many retrospective studies support surgical as well as nonsurgical approaches to treatment.26,27
Treatment morbidity varies depending on patient comorbidities and tumor characteristics and stage. Although many retrospective studies exist for each treatment, no prospective randomized controlled trial has compared surgery and definitive chemoradiotherapy. Thus, there is no gold standard treatment. Patients should be referred for consultations with all members of a head and neck cancer treatment team so they understand all available options and before making medical decisions.
Three HPV vaccines are licensed for use in the United States.31-33 The quadrivalent vaccine (Gardasil) was approved by the FDA in 2006 and prevents infection with HPV types 6, 11, 16, and 18. The bivalent vaccine (Cervarix) was approved in 2009 and prevents infection with HPV types 16 and 18. A 9-valent HPV vaccine, Gardasil 9, approved in late 2014, prevents against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. All the vaccines are composed of virus-like particles and are noninfectious.
The Advisory Committee on Immunization Practices (ACIP) first recommended vaccination for girls in 2007, and extended this recommendation to boys in 2011. Current ACIP recommendations include vaccination of girls at ages 11 to 12 years. In addition, girls and women ages 13 to 26 years who have not started or completed the vaccine series should receive the vaccine.
The quadrivalent or 9-valent vaccines are recommended routinely for boys ages 11 to 12 years. Boys and men ages 13 to 21 years who have not started or completed the vaccine series should receive the vaccine.31-33 In the United States, the vaccines are not licensed or recommended for use in patients older than age 26 years.31-33
All HPV vaccines are administered in a three-dose schedule. The second and third doses are administered 1 to 2 months after the first dose and 6 months after the first dose, respectively. The current cost of each dose is about $150, for a total of about $450 for the series. Many health insurance companies pay for the cost of the vaccination.
Although the first HPV vaccine was approved in 2006 for use in the United States, according to the 2011 National Immunization Survey, about 35% of females ages 13 to 17 years and 1% of males ages 13 to 17 years had completed the vaccination. By comparison, compliance with measles-mumps-rubella and hepatitis B vaccination recommendations were 91% and 92%, respectively.34 The 2013 vaccination rates show 14% of male teens receiving all three doses, and 38% of females receiving all three doses.35
The President's Cancer Panel Report 2012-2013, released in February 2014, recommends focus on three critical goals:36
- Reduce missed clinical opportunities to recommend and administer HPV vaccines
- Increase acceptance of HPV vaccination by parents, caregivers, and adolescents
- Maximize access to HPV vaccination services.
Although the efficacy of the HPV vaccination has been documented as greater than 90% in preventing cervical, anal, penile, vaginal, and vulvar intraepithelial neoplasia, the efficacy in preventing oropharyngeal cancers is unknown. Its safety, however, is well proven.35 Postlicensure monitoring data from 2006 to 2014 indicate that the quadrivalent vaccine is safe, with more than 67 million doses having been administered.35
With the current knowledge about HPV and oropharyngeal squamous cell carcinoma, primary care providers should aim to provide parents with the necessary information to make the decision about HPV vaccination. The CDC has tips available at: www.cdc.gov/vaccines/youarethekey.
HPV is a common STI with a high lifetime rate of exposure. Clear evidence supports HPV as a cause of certain head and neck throat cancers. History and physical examination are the only ways to screen for these relatively asymptomatic cancers; the first presenting sign may be a neck mass. Patients with a concern for throat cancer should undergo prompt referral to a specialist. Vaccines are available against high-risk HPV types that are risk factors for cervical and oropharynx cancer.
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