In the past 30 years, the number of cases of HPV-associated oropharyngeal SCC has increased dramatically. Using several national databases, a data brief published by the CDC in August 2018 reported that HPV-associated oropharyngeal SCC is now the most common cancer caused by HPV.2 Similar to other HPV-related cancers, type 16 is the main culprit of oropharynx malignancy. Therefore, clinicians should be cognizant of the prevalence of oral HPV infections and HPV-associated oropharyngeal SCC. Clinicians who work in primary healthcare settings such as family practice, internal medicine, urgent care, and emergency medicine have the opportunity to recognize this disease early and refer appropriately for timely oncologic management. This article aims to equip frontline clinicians with the knowledge to understand the epidemiology of HPV-associated oropharyngeal SCC and to correctly identify patients who warrant additional workup and referral to an otolaryngology head and neck surgery practice.
EPIDEMIOLOGY OF ORAL HPV INFECTION
HPV is epitheliotropic, meaning it has an affinity for squamous epithelial cells, and different genotypes have a propensity for either cutaneous or mucosal epithelium. A few types are transmitted casually skin-to-skin (common wart) or vertically from mother to baby (respiratory papillomatosis), but 40 types have been identified as sexually transmitted. Transmission of the virus occurs at the interface of epithelial surfaces. In the anogenital region, entry of the virus into the stratified epithelium occurs through microabrasions in the skin or mucosa. The mucosal epithelium of the palatine and lingual tonsils is reticulated, which allows for egress of lymphocytes, but also enables ingress of HPV virion particles without tissue trauma. Figure 2 illustrates how the virus enters the epithelium, attaches to the basement membrane, and integrates into stem cells of the basal layer.3 Viral proteins necessary for transcription, replication, and inhibiting apoptosis are increasingly expressed as the cells differentiate and migrate toward the epithelial surface.4 Virion particles, which transfer the infection during contact, are released as epithelial cells are sloughed off.4
The incident infection goes unnoticed by the recipient because HPV has no viremic phase. The virus is able to temporarily evade immune detection while buried in the stratified epithelium. Similarly, the host will be asymptomatic while the infection persists in a dormant state.
The same 40 genotypes of HPV that affect the anogenital tract can be acquired as oral infections, although the prevalence of oral infections is much less than that of genital infections. The most recent estimate of oral HPV prevalence in the United States is about 11.5%, representing 11 million men and 3.2 million women.5 More than half of the infections are caused by high-risk HPV type 16, with a sixfold higher incidence in men than women.5 High-risk oral HPV infections have a bimodal age distribution observed in men (but not women), with peak prevalence among patients ages 60 to 64 years and a second peak among those ages 30 to 34 years.6 Rates of oral HPV infection are eight times higher in the sexually experienced versus sexually naïve, supporting the concept that oral HPV is not casually transmitted.6
The most strongly and consistently attributed risk factor for acquiring an oral HPV infection is oral sex. A study of young adults ages 18 to 25 years demonstrated that risk of an incident oral HPV infection was significantly increased by recently performed oral sex in the preceding 3 months.7 This study also clarified that oral sex performed by a man on a woman increased the man's risk of oral HPV infection; however, oral sex acts of man to man, woman to man, or woman to woman were not associated with increased risk of oral HPV infection.7
Most infections will be cleared from the body in 1 to 2 years, but a small percentage evade immune clearance and persist for years or decades in a latent stage for reasons that are still unknown. Several studies have concluded that the risk factors for a persistent oral HPV infection include number of lifetime oral sex partners, older age, male sex, and smoking.8,9 Men are three to four times more likely to have an oral HPV infection than women and that difference cannot be explained by men having a higher number of total lifetime sexual partners. It was shown that men have a higher “per partner” prevalence then women, suggesting an inherent risk factor unique to the male sex.8 Men also take almost twice as long as women to clear an oral HPV infection.7 Men appear to be more susceptible to oral HPV infections and have a decreased immune response for clearance of the virus. A persistent oral HPV infection is considered a risk factor for malignant transformation and development of HPV-associated oropharyngeal SCC.9 Why some infections are cleared while others persist, and why some infections remain benign while others transform into malignancy, are questions that cannot yet be answered. Remember that even with the ubiquity of HPV infections, only a very small percentage lead to cancer.
HPV-ASSOCIATED OROPHARYNGEAL SCC
Fewer than 1% of oral HPV infections lead to HPV-associated oropharyngeal SCC, but the exact mechanism of malignant transformation remains elusive. HPV-positive oropharynx tumors do not have one common mutation; rather, many different mutations have been identified that all result in the same cancer. One confirmed step in the carcinogenesis is that HPV oncoproteins E6 and E7 bind to and inhibit tumor-suppressor proteins p53 and pRb, causing unchecked cellular replication and loss of cell cycle control.4
The anatomy of the oropharynx is conducive to cancer development. The palatine and lingual tonsils are components of the Waldeyer ring, a collection of lymphoid tissue lining the upper aerodigestive tract, and act as the first line of defense against ingested or inhaled pathogens. The tonsils have crypts, or invaginations, that increase the epithelial surface of these structures by 700%.10 Tonsillar crypts allow for development of a primary tumor deep within the tonsil, unbeknownst to the patient or healthcare provider. The rich lymphatic supply of the palatine and lingual tonsils also may contribute to early metastases to regional lymph nodes. Unlike HPV disease below the waist, which causes precancerous dysplasia, no evidence exists of a premalignant stage in the development of HPV-associated oropharyngeal SCC.
In the last few decades, the pendulum has shifted from most oropharynx cancers being HPV-negative (no viral cause) to now well over 70% being HPV-positive. In the 1980s, only 16% of oropharynx tumors were HPV-positive, but in the early 2000s, this number jumped to 73%.11 Reduced smoking rates in the United States may have contributed to the decline in HPV-negative tumors and changes in sexual behavior since the sexual revolution may underscore the rising incidence of HPV-positive tumors. Historically, women endured the greatest HPV cancer burden due to high rates of cervical cancer. Over the last 50 years, cervical cancer rates have steadily declined; in the last 15 years, oropharyngeal cancer rates have doubled.12 Moreover, incidence in men only is responsible for a twofold increase.2 The most common cancer caused by HPV is oropharyngeal cancer occurring in men.2,12
HPV-associated oropharyngeal SCC has a relatively indolent course, making the clinical presentation obscure. A patient with yet-to-be-diagnosed HPV-associated oropharyngeal SCC is most commonly a white man ages 55 to 65 years with no past medical history and no tobacco history. Patients do not exhibit the expected symptoms of head and neck cancer such as pain, dysphagia, odynophagia, dysphonia, breathing difficulty, or weight loss. Because the primary tumor in the oropharynx is small and/or asymptomatic, the cancer usually metastasizes to regional cervical lymph nodes before diagnosis. Therefore, the most common presentation and the cardinal sign of HPV-associated oropharyngeal SCC is persistence of a painless neck mass (Figure 3).
When an adult presents to his or her primary care provider with a complaint of a neck mass, history taking is the most important factor in forming a differential diagnosis. Note the pertinent negatives in the history and review of systems such as lack of fever, fatigue, and pain, all of which clinicians would expect to see with an acute infectious process. Consider the presenting signs and symptoms that do not correlate with an upper respiratory infection, pharyngitis, tonsillitis, or sialadenitis. Patients most likely will report feeling well and appear nontoxic, but if they present with a neck mass, have a high suspicion for oropharyngeal SCC.
After careful history taking, perform a physical examination including a meticulous head and neck examination. Inspection and palpation of the oral cavity and oropharynx is paramount. The findings might be normal or reveal an enlarged palatine tonsil or asymmetric appearance of the soft palate. Palpation of the oropharynx may reveal a firm mass in the palatine or lingual tonsil. Several examples of typical oropharynx findings are shown in Figure 4. Thorough palpation of the neck also is important. Metastatic cervical lymphadenopathy from a primary tumor in the oropharynx can present as a single or multiple firm, nontender, enlarged lymph nodes in the unilateral or bilateral upper neck.
Following a comprehensive physical assessment, the next best step is to obtain a neck ultrasound to evaluate for lymphadenopathy and differentiate benign (reactive) nodes from pathologic nodes. If ultrasound reveals an abnormal mass or lymphadenopathy consistent with metastatic disease, refer the patient to otolaryngology. A fine-needle aspiration should be sufficient to diagnose the cause of a neck mass. Core needle biopsy and an open biopsy of a neck mass are both contraindicated if SCC is in the differential. Obtaining a CT neck with contrast is standard of care for evaluation and staging of a primary upper aerodigestive tract malignancy and metastatic cervical lymphadenopathy.
Management of HPV-associated oropharyngeal SCC should be done by an experienced otolaryngology head and neck surgeon with a multidisciplinary team in a comprehensive cancer center. Treatment may include a single modality or combination of surgery, radiation, and chemotherapy depending on the patient's cancer staging at presentation.
A silver lining of HPV-associated oropharyngeal SCC is that patients have a better prognosis compared with patients whose oropharyngeal SCC is not caused by HPV. A landmark paper published in The New England Journal of Medicine proved that HPV status is an independent prognostic factor and HPV-positivity led to increased survival in patients with oropharyngeal cancer.13 All other factors being equal (adjustments for age, race, cancer stage, smoking history, and treatment) patients with HPV-positive tumors had a 58% decrease in risk of death compared with patients whose tumors were HPV-negative.13
A one-time detection of oral HPV is not indicative of a dysplastic or malignant process. Oral HPV presence is clinically irrelevant in the absence of epithelial cell abnormality. The idea of applying a screening tool such as the Pap test to the oropharynx is unfeasible due to the anatomy—the massive epithelial surface area formed by tonsillar crypts prevents thorough cytology sampling or monitoring any lesion. Because no premalignant lesion has been identified, random sampling of tonsillar epithelium would be futile. Using serum testing of HPV antibodies for screening is under investigation; however, it has been estimated that 10,500 people would need to be screened in order to detect one cancer.14 In conclusion, no screening tool exists for HPV-associated oropharyngeal SCC, but evidence is promising for prevention through vaccination.
The HPV vaccine could prevent 92.3% of the 32,500 HPV-induced cancers (all sites) that the CDC estimates will be diagnosed each year.15 Oncogenic HPV types 16 and 18 are the leading cause of cervical and anal cancer, and low-risk types 6 and 11 cause genital warts. Early HPV vaccines included Cervarix, covering HPV type 16 and 18, and Gardasil, covering 16, 18, 6, and 11. Through clinical trials, these vaccines proved effective for the prevention of high-grade cervical lesions, anal dysplasia, and genital warts. No epidemiologic data demonstrate vaccine efficacy in prevention of HPV-associated oropharyngeal SCC specifically, but several studies show its ability to reduce oral HPV infections. And because a persistent infection with HPV type 16 accounts for most oropharyngeal cancers, the vaccine should produce similar protection as it has with anogenital cancers.
The clinical trial of bivalent HPV 16/18 vaccine in women showed that cervical, anal, and oral infections could be prevented.16 Findings highlighted that the vaccine is most effective (all sites combined) in women who have not been exposed to HPV, which supports vaccination at a young age. The vaccine was still moderately efficacious for women who had been exposed to HPV but were without active cervical or anal infection, indicating that vaccination even after exposure may prevent concordant infections at multiple sites.16 Oral HPV infection prevalence was reduced by 93% in women who received the bivalent vaccine.17 The quadrivalent HPV 16/18/6/11 vaccine produced oral site antibodies that were analogous to serum antibody levels, suggesting protection at the oral site in addition to genital sites.18 In a study of men, 96% of the participants developed detectable oral levels of HPV 16-type antibodies after Gardasil vaccination.18 A cross-sectional study of men and women ages 18 to 33 years compared prevalence of HPV 16/18/6/11 type-specific oral infections with vaccination rates and concluded that vaccinated young adults had a 88.2% reduction of oral HPV infections.19 Yet, due to low vaccination rates nationally, the population-level effect of oral HPV infection reduction was only 17%.19
The good news is that HPV vaccination rates in the United States are rising. The latest data from the CDC show a steady increase in HPV vaccination coverage rates per birth cohort.20 Nearly 66% of adolescents ages 13 to 17 years have received at least one dose of the recommended series for their age (68.6% for females and 62.6% for males).20 Additionally, the current HPV vaccine offers broader coverage, protecting against seven known oncogenic types of HPV in addition to the two low-risk types. The only vaccine now available in the United States is Gardasil 9, which covers nine HPV types known to cause cancer, precancerous lesions, and genital warts.
National guidelines recommend that all children receive the HPV vaccine by age 11 or 12 years, although they can start as early as age 9 years.15 If the vaccine series is initiated before age 15 years, only two doses are needed; if initiated at age 15 years or older, three doses are recommended. In October 2018, the FDA announced that HPV vaccination also is approved for men and women ages 27 to 45 years.21 Initially, the vaccine was indicated before sexual debut, but the mounting evidence of multisite efficacy and long-term immunogenicity suggests the vaccine could prevent an array of different diseases at multiple sites at almost any age. Clinicians in all specialties should educate their patients—whether they are adults, teenagers, parents, or children—on the indications for HPV vaccination.
Patients often need to be educated about HPV. In one survey of 308 healthy adults, only 40% had heard of HPV; of those who had heard of the virus, 35.5% were unsure or did not think that it was common among sexually active adults and only 47% identified HPV as a risk factor for head and neck cancer.22 In another group, the majority thought HPV infections were rare in men and thought HPV could be cured with antibiotics—both of which are false.23 Physician knowledge of HPV-associated oropharyngeal SCC also is low. When surveyed, pediatricians, primary care physicians, otolaryngologists, and obstetricians/gynecologists lacked awareness of the primary tumor site (palatine and lingual tonsils), the higher prevalence in men, the sexual transmission, and the availability of a vaccine that targets HPV types associated with oropharynx cancer.24,25 Due to this self-reported lack of knowledge, these topics often are not part of physicians' routine patient counseling about HPV vaccination.25
Further study by the scientific community is ongoing in an attempt to fully understand HPV-associated oropharyngeal SCC. Clinicians should tell patients that:
- HPV infection is common and does not indicate promiscuity.
- Monogamous couples have already been exposed to any HPV infection their partner may carry.
- Exposure to HPV does not equal development of cancer.
- A vaccine for patients ages 9 to 45 years can prevent HPV-associated disease and cancer.
Genital HPV infections are ubiquitous, oral HPV infections are less prevalent, and oropharyngeal cancer is still rare. Yet, the incidence of HPV-associated oropharyngeal SCC is on the rise, especially in older healthy men. The factors most consistently attributed to cancer development are persistent oral HPV infection, male sex, older age, lifetime number of oral sex partners, and smoking. Because no valid screening test exists, early recognition is crucial for appropriate diagnosis and prompt treatment. Unfortunately, HPV-associated oropharyngeal SCC has an indolent and largely asymptomatic course, so identifying it in a primary care setting is challenging. If a patient over age 40 years presents with a neck mass, assume a diagnosis of metastatic oropharyngeal SCC until proven otherwise. Early referral to otolaryngology head and neck surgery is encouraged for an asymmetric tonsil, neck mass of unknown cause, or a confirmed diagnosis of cancer. Physician assistants are in a unique position to educate patients in all healthcare settings about the HPV-associated oropharyngeal cancer epidemic and the significance of HPV above the waist.
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Keywords:Copyright © 2019 American Academy of Physician Assistants
human papillomavirus; HPV; vaccine; oropharyngeal squamous cell carcinoma; physician assistant