There has been a significant increase in the incidence of human papillomavirus (HPV)-mediated oropharyngeal cancer in the United States. This entity is most commonly diagnosed in nonsmoking middle-aged white males. The majority of the patients present with asymptomatic, persistent neck masses despite antibiotic therapy. An awareness of this condition and a high degree of suspicion is necessary for timely diagnosis.
HPV-mediated oropharyngeal squamous cell carcinomas (HPV-OPSCCs) are unique biologically and clinically, and affected patients enjoy better outcomes with existing standard therapies than do patients with OPSCC mediated by tobacco exposure. The p16 protein is usually overexpressed in HPV-OPSCC, and its detection on immunohistochemistry is a reliable surrogate marker for this disease. In this review, we discuss current paradigms in the diagnosis and management of HPV-OPSCC, and we emphasize pertinent research questions to investigate going forward, including whether to deintensify treatment in these patients.
There has been a remarkable shift in the epidemiology of head and neck cancer in this country over the past 30 years. While exposure to chemical mutagens such as tobacco and alcohol remains the most common risk factor for squamous cell cancers of the aerodigestive tract, a rapidly expanding subset of head and neck cancers are acquired through human papillomavirus (HPV) infection. The oropharynx is uniquely susceptible to HPV, and now up to 70% of oropharyngeal cancers in the United States are HPV-mediated oropharyngeal squamous cell carcinomas (HPV-OPSCCs).[1,2] HPV-OPSCC is fundamentally distinct (Table 1). Patients with HPV-OPSCC are frequently younger than those with tobacco-mediated oropharyngeal cancer and experience significantly better outcomes with current standard therapies. Thus, there is current impetus for treatment deintensification strategies that maintain optimal cancer outcomes, yet lessen treatment-related side effects.
Epidemiologic Trends of Head and Neck Squamous Cell Carcinoma
Squamous cell cancer of the upper aerodigestive tract accounts for more than 550,000 cancer cases, or 5% of cancer cases, worldwide each year. It is endemic in countries such as India and Brazil where tobacco consumption is the cultural norm. Decreasing tobacco consumption in the United States has led to an overall decline in the incidence of head and neck cancers over the past 3 decades.[4,5] This downward trend is noted for cancers of the oral cavity, larynx, and hypopharynx, since tobacco use remains the primary risk factor for cancers in these sites. However, up to 25% of all head and neck cancers currently diagnosed in the United States are independent of tobacco use. It is now well known that sexually transmitted HPV infection is the main risk factor for this subset of cancers, in which rather specific involvement of the oropharynx (tonsils and base of tongue) is expected, thus adding oropharyngeal cancer to the list of virally mediated malignancies.
Chaturvedi et al reviewed the Surveillance, Epidemiology, and End Results population-based data from the past 30 years and reported on the age-adjusted incidence trends of HPV-related and HPV-unrelated head and neck squamous cell carcinoma (HNSCC). They noted a significant decrease in HNSCC incidence in HPV-unrelated sites (oral cavity, larynx, hypopharynx) in contrast to an impressive increase in the incidence of HNSCC in HPV-related oropharyngeal sites over the same time period. Subset analyses by age group, sex, and race demonstrated that the largest increase in HPV-mediated cancers has occurred in white men in their fourth or fifth decade of life.
The demographic and risk profiles of HPV-positive and HPV-negative HNSCC patients clearly differ. Thus, an HPV-positive patient with HNSCC is more likely to have better dentition, less or no tobacco or alcohol use, greater marijuana use, and greater numbers of oral sex partners than an HPV-negative patient. Furthermore, these risk associations have shown a very strong dose effect, again emphasizing the distinct risk profile of HPV-positive HNSCC patients.
By the year 2020, the annual number of cases of HPV-OPSCC is projected to outnumber the cases of HPV-mediated cervical cancer in the United States. The emergence of HPV-OPSCC has been deemed an epidemic of our time.
Risk Factors for HPV Infection and HPV-OPSCC
HPV infection is the most common sexually transmitted disease in the world. HPV may be transmitted by any type of sexual activity. In the United States alone, it is estimated that 20 million people are currently infected, and 6.2 million acquire a new infection each year. The virus is endemic; more than 50% of persons who are sexually active will have a genital HPV infection at some time during their lives. Seven percent of the population between the ages of 14 and 69 (10% of men and 4% of women) are orally infected at any given time, but only 1% of these infections are caused by high-risk cancer-causing HPV subtypes. Smoking further increases the risk of HPV infection. The specific association of HPV 16 and oropharyngeal cancer was reported as early as 1998, in a study from City of Hope in which 60% to 70% of oropharyngeal cancer cases were HPV-associated.[12,13] Currently, HPV 16 accounts for 90% of high-risk oral HPV infections and confers a 15- to 230-fold increased risk of OPSCC.[8,14,15] A sentinel study by Gillison et al confirmed HPV as the actual trigger and promoter for this cancer phenotype.
HPV-infected persons remain oblivious to the infection, as there are no associated signs or symptoms. No current treatment exists for active HPV infection. However, a majority of those infected will clear the virus within 2 years. It is unknown why chronic infections develop in a small subset of the population that later progress to HPV-OPSCC. An effective screening test for early detection of HPV-OPSCC has not yet been defined, and no validated screening test is available. The difficulty in screening for OPSCC relates to the fact that most of these cancers originate deep in the crypts of the tonsils, which are inaccessible to simple “Pap smear equivalents” that can be readily performed in anatomic areas such as the anus or cervix.
HPV and Virus-Mediated Oncogenesis
HPV is a small DNA virus that is capable of infecting human keratinocytes of the skin and mucous membranes. Although there are more than 100 subtypes of HPV, HPV 16 accounts for 90% of all HPV-related head and neck cancers. HPV encodes several genes that are important in tumorigenesis. Early proteins E6 and E7 are nonstructural oncoproteins (Figure 1). The E6 oncoprotein interferes with the function of tumor-suppressor protein p53 through ubiquitin-mediated p53 degradation. E7 binds to the retinoblastoma tumor-suppressor gene and inhibits its ability to repress the expressions of replication enzyme genes, thus pushing the cell cycle forward. Late proteins L1 and L2 determine the virus subtype and are structural capsid proteins that encapsulate the amplified viral genomes. Virions can then be sloughed off, and the viral life cycle continues. A byproduct of HPV E7–mediated retinoblastoma inhibition is overexpression of p16 protein, a cyclin-dependent kinase inhibitor. A useful surrogate marker for HPV infection is p16 overexpression.
Of all potential sites of head and neck cancer, the palatine and lingual tonsils are preferentially targeted by HPV. The highly specialized reticulated lymphoepithelium of the tonsillar crypts strongly expresses programmed death ligand 1 (PD-L1), which acts to suppress T-cell responses to HPV, thus providing an “immune-privileged” site for initial viral infection and adaptive immune resistance.
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