Definitive determination of a patient's HPV status is important in order to provide appropriate education about the virus and the implications of a positive diagnosis. The challenge of HPV testing is to differentiate the presence of an incidental virus from one with oncogenic activity. Detection of E6 and E7 oncoprotein mRNA expression is the gold standard against which the sensitivity and specificity of all other tests are evaluated. However, it is costly, requires technical expertise, and has practical limitations within the routine diagnostic setting. Immunohistochemical staining for overexpression of cellular protein p16, HPV DNA in situ hybridization (ISH), and polymerase chain reaction (PCR) are other molecular biology techniques with their own unique strengths and limitations.
Although there is no current standard approach, most HPV detection in clinical samples for diagnostic purposes uses techniques that detect the presence of genomic HPV material. PCR is both highly sensitive and specific; it requires very close attention to tissue handling to avoid false-positive results. ISH is notable for high specificity (except at low viral load) and is optimized for fixed tissue samples; however, it is less sensitive then PCR [48
]. Immunohistochemistry staining for p16 has been increasing in popularity because it is low in cost, a validated independent prognostic biomarker, and correlates strongly with positive high-risk HPV status [49
]. However, given the high sensitivity and limited specificity of p16 staining, it is recommended that interpretation of results be informed by other data such as staining pattern, histology, anatomy of tumor, and clinical characteristics of the patient [48
]. Additional types of HPV-related testing that patients may be aware of are serological testing for HPV antibodies in the blood [52
] and testing for presence of HPV in oral swabs or saliva [54
]. Although these are potentially useful epidemiologic tools that someday may play a role in assessing risk of HPV-related tumors, they are not validated and are not currently used to determine HPV status for clinical purposes.
When a patient with OPC undergoes HPV testing, this should be preceded by discussion of the implications of a positive or negative result for transmissibility, prognosis, treatment, and recurrence risk. Information about HPV can be complex, controversial, and/or limited, and it is constantly changing as new information becomes available; thus, it is important for the provider to provide the most up-to-date information possible, as well as to convey uncertainty when appropriate.
When a patient has been identified as HPV positive, it is essential to address their questions systematically, with an emphasis on clear patient-provider communication to ensure that all questions are answered. Conversely, patients whose tumors test negatively for the virus may be disappointed that they have the “worse kind of tumor” and experience feelings of pessimism. In both cases, patients will require a clear explanation of their expected prognosis and treatment plan, as well as the opportunity to ask questions. To help guide this discussion, we have developed a set of questions and answers based on relevant information from both the Centers for Disease Control and Prevention HPV guidelines [56
] and a set of empirically determined questions answered by a panel of experts from the American Social Health Association [57
]. In addition, we have included supporting and relevant empirical data where appropriate. Although not intended to be comprehensive—and subject to change as additional research becomes available—these questions and answers () can serve as a starting point for providers to develop their own counseling scripts.
Frequently asked questions regarding HPV-positive oropharyngeal cancer
HPV Transmission: “How, When, or From Whom Did I Get HPV?”
HPV is primarily a sexually transmitted virus. It is impossible to know for certain from whom or when one initially acquired HPV because most people do not know they have it. The patient may have been exposed in another relationship months, years, or decades earlier, and the infection may have been dormant (“hidden”) in the meantime. HPV is very common and can be transmitted through vaginal and anal sex. However, oral sex, kissing, and genital-to-genital contact or genital-to-hand-to-oral contact can also allow for transmission to occur.
Human papillomaviruses can either be of the mucosa or cutaneous type. HPV has been reported to have selectivity for the anogenital tract, urethra, skin, larynx, and mucosa of the trachea, bronchi, and oropharynx [58
]. Furthermore, HPV is classified into high-risk types (primarily types 16 and 18) with oncogenic potential and low-risk types associated with genital condylomas. Mechanisms of oropharyngeal HPV transmission remain unclear. Concordance has been reported between maternal and newborn HPV genotypes, suggesting perinatal transmission of infection that can subsequently remain subclinical for an extended period of time [59
]. The evidence on type-specific concordance between couples is mixed owing to variations in recruitment, detection, and specimens tested. However, in a recent study, hygiene habits such as sharing towels or razors was not found to contribute to concordance [60
Hand-to-oral and hand-genital transmission has also been reported in earlier studies [62
] but recent evidence for oral autoinoculation of the virus from anogenital sites is mixed. A recent study found an individual's genital HPV infection to be highly correlated with subclinical oral HPV infection [64
], whereas others have not found concordance within the same patient [65
Risk factors such as oral sex and open-mouthed kissing are associated with oral HPV infection. The odds of contracting oral HPV infection are substantially increased with progressively higher numbers of oral sexual and open-mouthed kissing partners [67
]. However, a recent study called into question whether oral sex is the main transmission mode of oral HPV infection. Between spouses, oral sex was not associated with asymptomatic oral HPV infection; rather, persistent oral HPV infection in one partner was a significant risk factor for oral infection in the other [68
], suggesting that the oral-to-oral route is an important mode of HPV transmission.
HPV Prevention: “How Can I Avoid Transmitting HPV to Others?”
Lifetime mutual monogamy or abstinence are the best possibilities for prevention. This does not mean abstinence from the patient's partner, with whom this infection has likely been shared for a considerable period of time. Most sexually active people will get HPV early in their lifetimes. Condoms prevent many bacterial and viral infections, but if HPV is present on uncovered skin or nongenital mucosal sites such as the oropharynx, transmission is possible. As with all other sexual behaviors, safer sexual practices and fewer sexual partners may be considered the mainstay of prevention. Simple transmission may not be sufficient to lead to cancer and other factors related to genetics, immune function, other STIs and infections, promiscuity, and multiple sexual partners may come into play in progression from infection to cancer.
Clearance of HPV and regression of HPV-associated penile lesions and cervical intraepithelial neoplasia has been reported with consistent condom use [69
]. However, this recommendation may not be practical for individuals in long-term, monogamous relationships or relevant to HPV infection in the oropharynx.
Patients and their partners should be made aware that the oncogenic nature of the disease is not in and of itself contagious. Earlier evidence based on a small study shows specific HPV genetic markers identified among couples in which both members contracted tonsil cancer, associating direct viral transmission with cancer in both exposed parties. This, however, appears to be the exception, not the norm; the vast majority of partners of patients with HPVOPC never develop either oropharyngeal or cervical cancer.
Patients and their partners should be made aware that the oncogenic nature of the disease is not in and of itself contagious. Earlier evidence based on a small study shows specific HPV genetic markers identified among couples in which both members contracted tonsil cancer, associating direct viral transmission with cancer in both exposed parties [71
]. This, however, appears to be the exception, not the norm; the vast majority of partners of patients with HPVOPC never develop either oropharyngeal or cervical cancer. Currently, a multicenter study is being conducted by D'Souza et al. to determine a partner's risk for developing cancer [72
]. For now, the existence and frequency of viral transmission among sexual partners and subsequent cancer development continues to be an active area of investigation. In the meantime, there is little medical justification for counseling HPV-positive patients with OPC on changing their sexual practices and intimate behaviors to modify risk of malignancy in partners.
Duration of HPV Infection and Progression to Cancer: “Will I Always Have HPV?”
A healthy immune system suppresses the virus in most infected persons. It is difficult to predict when HPV is no longer contagious. Experts disagree on whether the virus is eventually eliminated from the body or whether it is reduced to undetectable levels. There are treatments for cancer caused by HPV (discussed below) but not for the presence of the virus itself.
Substantial data exist regarding the outcomes of genital HPV infections among women; however, the natural history of oral HPV infection in men and women is just beginning to be explored. Thus, when answering patient questions related to the timing of infection relative to cancer onset, providers can offer information available from the data on genital HPV infection and cervical cancer. Women are infected soon after their sexual debut, with the highest prevalence seen in women younger than 25 years of age [73
]. Evidence from genital HPV infections show that 90% of women have undetectable levels within 2 years and that those with persisting infections have a higher risk of progression to precancerous cervical lesions that, if left untreated, will progress to invasive cervical cancer within 10–20 years [74
]. Based on the evidence of genital HPV infections at an early age and the late onset of oropharyngeal cancer [75
], it is likely that there is considerable latency between HPV oral infection and the development of OPC, suggesting that in the majority of patients previous exposure—rather than a current partner—is the source of disease.
A recent population-based cross-sectional study examining the epidemiology of oral HPV-16 detected HPV in the saliva of 3% of men and 1% women, corresponding to an estimated 2 million individuals in the U.S. with active salivary expression at any single time [76
]. It is unknown what the absolute risk of OPC is for this small but significant population. There is also a lack of known risk factor modifiers or therapies that can help to prevent persistence of oral HPV, which is believed to be necessary for inducing OPC. Few prospective studies have addressed the natural history of oral HPV infections. However, of these studies, one arbitrarily defined “persistent” HPV infection as present 6 months after baseline [77
], whereas another showed clearance of infection 12 months after the start of the study [68
], suggesting that the time-to-clearance for infected persons can be quite variable. Furthermore, the length of time from initial infection to the start of the study was not available for either study. Thus, further prospective studies are needed to clarify the timing and natural history of persistent oral HPV infection and risk of subsequent head and neck cancer.
Prognosis, Treatment, and Risk of Recurrence for HPV-Positive OPC: “What Are the Best Treatment Options for HPVOPC?”
HPV itself is not directly treated in HPVOPC. The precancerous condition, known as dysplasia, can be detected in the cervix with the Papanicolaou (Pap) test, treated, and monitored accordingly. Although there is currently no method for detecting and treating precancerous lesions in the oral cavity or pharynx, numerous studies have shown that patients with head and neck cancer and HPV respond better to cancer treatment and have significantly better overall survival then HPV-negative patients with OPC. Importantly, as the results of clinical trials focused on HPVOPC become available, it may be possible to treat HPV-positive tumors with less intense treatment regimens. Patients should discuss all treatment options with their provider before deciding on a plan of treatment.
Accumulating evidence suggests that HPV status is an important prognostic factor and HPV positivity predicts favorable outcomes in head and neck cancers treated with surgery, radiation alone, or chemoradiation. A retrospective clinical trial demonstrated that patients with HPV-positive OPC tumors have better 3-year rates of overall survival and a 58% reduction in risk of death after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment [78
]. An earlier prospective clinical trial confirmed the favorable prognostic factor of positive HPV status that could not be explained by differences in treatment regimen or tumor site. HPV positivity conferred an improved response to either chemoradiation (84% vs. 57%) or induction therapy (82% vs. 55%) [79
]. More recently, overall survival and progression-free survival rates in patients with HPVOPC were found to be 79% and 73%, respectively, compared with 31% and 29% in HPV-negative patients with OPC [80
]. However, risk of cancer progression or death increases directly as a function of total pack-years of smoking, regardless of HPV status. Furthermore, smoking during radiation independently increases the risk of death [81
]. Therefore, when counseling patients it is important to consider their current and previous smoking status and implement smoking cessation when appropriate.
The data on recurrence and secondary primary tumor in HPV-positive OPC are mixed; however patients with HPV-positive second primary tumors—although much more rare than HPV-negative second primary tumors—also have improved survival rates. HPV-positive patients who are also tobacco users are at significantly higher risk of disease recurrence than never-tobacco users. Therefore, in order to avoid disease relapse, HPV-positive patients who use tobacco should be counseled on the benefits of cessation [82
]. Furthermore, men with HPVOPC who have never been married may benefit from regular screenings for anal cancer, as this demographic has been shown to have an increased risk for developing primary anogenital cancer within 4–5 years of OPC diagnosis [84
In genetic testing, inheritance or mutation resulting in genetic abnormality predisposes an individual to disease; for many genetic diseases, the outcome determines subsequent interventions or intensified screening practices. For others (e.g., Huntington disease), testing provides prognostic information only. At the time of this article, therapeutic guidelines do not take into account a patient's tumor HPV status [85
], nor does the current staging system reflect the different treatment response and survival of HPV-positive and HPV-negative patients with OPC [86
]. Nonetheless, when deciding between different treatment options, it is important that patients understand how their HPV and smoking status modify prognosis and likely response to therapy.
Partner Notification: “What Should I Tell My Partner About My HPV Status?”
Most sexually active people will eventually be infected with HPV. The majority of infected persons do not develop signs or symptoms; therefore, they do not know they are infected. If the patient decides to tell his or her partner about HPV testing results, it is best for them to talk openly and honestly. Partners who have been together tend to share HPV. This means that the partner likely has HPV already. There is no way to know if the partner gave the patient HPV or vice versa. Because HPV is a common virus and is usually acquired early in life, having an HPV infection does not imply infidelity. It is important to remember that there should be no shame or blame associated with a diagnosis of HPV.
When a patient has suspected OPC and testing for HPV occurs either at the time of biopsy or after, they should be counseled regarding the sexually transmitted nature of the virus. However, it is equally important for the provider to convey any uncertainties about the transmissibility associated with particular sexual behaviors. In the case of HIV, where there are more concrete facts and less uncertainty, the patient is interviewed to elicit information about their partners, who can then be confidentially notified of their possible exposure or potential risk. Infected individuals and their partners are offered a range of medical, prevention, and psychosocial services that can facilitate prevention of transmission, such as positive behavior modification to reduce transmission [54
]. Unlike HIV, there is no evidence to support partner notification of HPV-positive patients or referral for clinical evaluation of their partners. The current ethically acceptable approach to STI testing supports this notion, as notification of partners may cause unnecessary and unethical distress given the absence of clinical standards of treatment [87
]. However, patients may benefit from having an informed discussion with their partner about their diagnosis, which can foster partner support. However, physicians should be aware that partner disclosure may have repercussions for some patients, such as partner rejection or even abuse. Therefore, it is important to support the patient's decision whether or not they choose to notify. If the patient elects to disclose their HPV status, physician should be prepared to provide medical information should the partner seek it.
HPV is neither a necessary nor a sufficient cause of OPC. However, persistent oral HPV infection in partners may increase the risk of developing oral cancer. It is recommended that these individuals use regular dental appointments as important tools for detecting any high-risk HPV-related changes in the oral and oropharyngeal mucosa. Behavioral modifications, such as cessation of alcohol and tobacco use, should be encouraged because they are not only health-enhancing strategies but have been found to significantly decrease the odds of oral HPV persistence [77
]. The available HPV vaccines cover the HPV genotypes found most commonly in the oral mucosa, but their protective effect against oral/oropharyngeal cancer, especially in individuals who have already been exposed to HPV, remains to be demonstrated.
Exposed partners may be considered a high-risk population for developing oropharyngeal cancer. Therefore, screening methods similar to the Pap test for cervical cancer, would be desirable in this population; however, as yet these tests do not exist, and it is not clear that an HPV-induced oropharyngeal precancerous lesion analogous to cervical dysplasia exists [88
]. Furthermore, until there is more data on the natural history of oral HPV infection and how best to prevent the progression of precancer, screening may have limited utility.