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Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer

Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer
Author:
Robert I Haddad, MD
Section Editors:
Bruce E Brockstein, MD
David M Brizel, MD
Marvin P Fried, MD, FACS
Deputy Editor:
Melinda Yushak, MD, MPH
Literature review current through: Jan 2024.
This topic last updated: Jul 07, 2023.

INTRODUCTION — Human papillomavirus (HPV) infection is the most commonly diagnosed sexually transmitted disease in the United States. HPV infection has been etiologically linked with condyloma acuminatum, squamous intraepithelial lesions, and anogenital malignancy, including cervical, vaginal, vulval, penile, and anal carcinoma.

Many patients with oropharyngeal squamous cell carcinomas, particularly those arising in the base of the tongue and in the tonsillar region, do not have the traditional risk factors associated with head and neck cancers (eg, smoking, smokeless tobacco, alcohol consumption). Epidemiologic and molecular studies have identified the HPV 16 genotype of HPV as a causative agent in many of these patients [1]. Other high-risk HPV genotypes, such as HPV 18, 31, or 33, are also causative but are less common. These high-risk HPV infections may also rarely cause cancers at other head and neck sites.

The epidemiology, staging, and clinical presentations of HPV infection in head and neck squamous cell carcinoma of the oropharyngeal and nonoropharyngeal regions are presented here. Other risk factors for head and neck cancer and the treatment approach to HPV associated oropharyngeal squamous cell carcinoma of the head and neck are discussed separately. (See "Epidemiology and risk factors for head and neck cancer", section on 'Risk factors' and "Treatment of human papillomavirus associated oropharyngeal cancer".)

BIOLOGY OF HPV — HPV are small deoxyribonucleic acid (DNA) viruses that are widely distributed in vertebrates. These viruses contain an 8 kilobase long, double-stranded, circular DNA genome. The papillomavirus genome comprises early and late genes that encode early proteins E1-E7 and late proteins L1-L2. The early proteins are nonstructural proteins involved in replication and transcription of the genome (E1-E5) or in host cell tumoral transformation (E6 and E7), whereas L1 and L2 are the structural capsid proteins of the virion.

The HPV E6 and E7 oncogenes encode proteins consisting of approximately 151 and 98 amino acids, respectively. These genes are largely responsible for the onset and persistence of the malignant process in both head and neck and anogenital cancers.

The molecular profiles of HPV associated tumors are distinct from those of non-HPV associated cancers. The absence of genetic or epigenetic alterations in the p53 and pRb pathways in HPV associated head and neck cancers is in sharp contrast to what is observed in non-HPV associated head and neck cancer. In the typical non-HPV associated squamous cell carcinomas, p53 mutations are very frequent, along with decreased levels of p16 and increased levels of pRb. By contrast, HPV associated carcinomas are associated with wild-type p53, down regulation of pRb, and upregulation of p16. These differences in gene expression suggest that HPV associated and non-HPV associated head and neck cancers represent distinct entities.

The virology of HPV and its role in the molecular pathogenesis of malignancy are discussed separately. (See "Virology of human papillomavirus infections and the link to cancer", section on 'Molecular pathogenesis'.)

EPIDEMIOLOGY

HPV associated cancers — Epidemiologic studies have demonstrated that there has been a decrease in the incidence of laryngeal, hypopharyngeal, and oral cavity cancers beginning in the late 1980s [2]. This decline has been associated with the current decrease in smoking, which is the primary risk factor for these cancers.

Oropharyngeal carcinoma

Incidence — Despite the decrease in tobacco use, the incidence of oropharyngeal cancer initially remained constant and then began to rise [1,3,4]. Multiple lines of evidence linked the increase in oropharyngeal cancer to HPV related cancers arising in the base of the tongue and the tonsillar region.

This association is primarily with HPV 16, which is known to be carcinogenic at other sites [5,6]. Initial cohort studies suggested that approximately 50 percent of oropharyngeal cancers were attributable to HPV, while subsequent studies suggest that HPV accounts for 70 to 80 percent of cases in North America and Europe [7]. Analyses of worldwide cancer statistics from 1983 to 2002 have found a significant increase in the incidence of oropharyngeal cancer in males in developed countries, with disease occurring at younger ages, consistent with a role for HPV [8].

The timing between exposure to HPV and the development of oropharyngeal cancer probably exceeds 10 years [9,10]. As an example, the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) identified 638 individuals with head and neck cancer, for whom plasma samples had been obtained an average of six years prior to diagnosis [9]. Among the 135 patients with oropharyngeal cancer, antibodies against the E6 antigen were present in 35 percent, in contrast to 0.6 percent of controls. The prevalence of antibodies against E6 was not elevated in patients with other cancers.

Prevalence of HPV infection — Oncogenic oral HPV infection is detectable in the majority of patients with HPV associated oropharyngeal cancer, but the incidence of such HPV infection in long-term sexual partners is not increased beyond that seen in the general population.

●In the general population, a cross-sectional study of males and females aged 14 to 69 years found that the overall prevalence of HPV DNA in oral exfoliated cells was 6.9 percent, and the prevalence of HPV 16 was 1 percent [11]. HPV prevalence was approximately three-fold more common in males compared with females (10.1 versus 3.6 percent), consistent with the observed sex distribution for HPV associated oropharyngeal cancer.

●A study analyzed oral rinse samples for the presence of HPV in patients with HPV associated oropharyngeal cancer and their long-term sexual partners [12]. In the 164 patients with oropharyngeal cancer, oral HPV was detected in 65 percent of cases, and an oncogenic HPV strain was identified in 61 percent; 88 of 100 positive for oncogenic HPV had HPV 16. Among the 93 partners available for testing, the overall incidence of HPV infection was 4 percent, and only one had the oncogenic HPV 16. These findings suggest that most partners effectively clear any active infection to which they are exposed.

●The presence of HPV 16 in the oral cavity has been associated with the subsequent development of oropharyngeal carcinoma. In a case control study of 132 patients with squamous cell carcinoma of the head and neck, mouthwash samples were available from prior prospective collection, obtained a median of 3.9 years prior to the diagnosis of cancer and analyzed for HPV. HPV was identified in 5 of 25 patients (20 percent) who subsequently developed oropharyngeal carcinoma versus 1 of 75 matched controls without cancer (odds ratio [OR] 22.4, 95% CI 1.8-276.7) [13].

Nonoropharyngeal carcinoma — The prevalence of HPV infection in nonoropharyngeal sites of head and neck cancer (eg, the hypopharynx, larynx, and oral cavity) is less than that seen in oropharyngeal sites of disease, as demonstrated in observational studies [14-17].

●A meta-analysis identified 148 studies, including 12,163 cases of squamous cell carcinoma of the head and neck [14]. The HPV prevalence rates in oropharyngeal, oral cavity, and laryngeal cancers were 46, 24, and 22 percent, respectively, and the prevalence rates of HPV 16 positivity were 41, 15, and 13 percent, respectively.

●In one observational study from the National Cancer Database (NCDB) of over 24,000 patients with squamous cell carcinoma of the head and neck (approximately 60 percent oropharyngeal and 40 percent nonoropharyngeal), 63 percent of oropharyngeal cancers were HPV associated, whereas the rates of HPV positivity among oral cavity, laryngeal, and hypopharyngeal cancers were 11, 11, and 17 percent, respectively [17].

The prognosis of patients with HPV associated nonoropharyngeal carcinoma is discussed separately. (See 'Nonoropharyngeal carcinoma' below.)

HPV vaccination — A nine-valent HPV vaccine is approved by the US Food and Drug Administration (FDA) for the prevention of HPV associated head and neck cancers, including oropharyngeal cancers, among other indications [18]. Further details on indications for and administration of HPV vaccinations are discussed separately. (See "Human papillomavirus vaccination".)

HPV vaccination has been associated with a decrease in the subsequent prevalence of oral HPV infection [19]. As an example, in a population-based study from the National Health and Nutrition Examination Survey (NHANES), 2627 males and females aged 18 to 33 years were analyzed for the presence or absence of HPV in oral washes a mean of four years after vaccination [20]. Based on self-report, 18 percent of the study population had received one or more doses of vaccine. The prevalence of oral infection with HPV types 16, 18, 6, or 11 was 0.11 percent in those who had received vaccine versus 1.61 percent in those who had not been vaccinated. (See "Human papillomavirus vaccination", section on 'Oral disease'.)

CONFIRMING HPV 16 POSITIVITY — Immunohistochemistry (IHC) for p16 is highly sensitive for HPV associated tumors, and we routinely use it as a surrogate for HPV status. If decision-making hinges on HPV status, this diagnosis can be confirmed with either in situ hybridization or polymerase chain reaction (PCR), both of which detect the presence of HPV DNA [21]. Rare cases of HPV associated lesions arising in the head and neck that are high-grade neuroendocrine tumors (small cell carcinomas) have been described [22]. (See "Pathology of head and neck neoplasms" and "Extrapulmonary small cell cancer".)

Although the gold standard for assessing HPV infection in patients with HPV associated head and neck cancer is in situ hybridization or PCR to detect HPV DNA, several biomarkers may serve as surrogates for HPV status or be useful in further refining the risk associated with HPV infection. Common biomarkers commonly used in clinic include IHC to detect p16 expression and/or real-time PCR (RT-PCR) to measure HPV 16 viral load [1,23,24].

The p16 protein functions as a tumor suppressor by binding to the cyclin D1 CDK4/CDK6 complex, preventing phosphorylation of the Rb protein. The p16 protein is overexpressed in HPV associated cancers.

Either HPV status or p16 status can be used as a marker of HPV infection, depending on availability in the treating institution [25]. In one study, tumor samples from over 300 patients with squamous cell carcinoma of the head and neck were assessed for both p16 (strong and diffuse, nuclear and cytoplasmic staining in at least 70 percent of tumor cells) and HPV (by in situ hybridization). Ten percent of those positive by p16 were negative for HPV, and 7 percent of those negative for p16 were positive for HPV [26].

The sensitivity of immunostaining for p16 may be lower on fine needle aspirate samples. In one study of 142 cases of head and neck squamous cell carcinoma that tested positive for HPV by real-time PCR on fine needle aspirate samples, only 33 percent of paired p16 stains met standard thresholds for positivity (had strong and diffuse, nuclear and cytoplasmic staining in at least 70 percent of tumor cells) [27].

The p16 IHC assay is an effective surrogate marker for HPV DNA or RNA status that is associated with improved overall survival (OS) [28]. Testing for both p16 expression and HPV DNA or RNA status may also provide additional information on prognosis [29,30]. As an example, in one multicenter observational cohort study, 7654 patients with oropharyngeal tumors were evaluated for both p16 expression and HPV DNA or RNA status. Tumors that were positive for both tests were associated with better OS (five-year OS 81 percent) compared with tumors that had discordant test results (five-year OS 55 percent for those positive for p16 expression and negative for HPV by DNA/RNA; five-year OS 53 percent for those negative for p16 expression and positive for HPV by DNA/RNA) and tumors that were negative for both tests (five-year OS 40 percent for non-HPV associated disease) [30].

OROPHARYNGEAL CARCINOMA — Oropharyngeal cancer associated with HPV has important differences in its staging and clinicopathologic features compared with oropharyngeal cancer not associated with HPV. These differences have potentially important implications for prognosis and therapy.

Staging — In the eight edition (2017) tumor, node, metastasis (TNM) staging system of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC), separate staging systems were established for HPV associated and non-HPV associated oropharyngeal carcinomas (table 1A-B and table 2A-B) [31,32]. The TNM system for HPV associated disease uses p16 positivity as a surrogate for HPV. The previous seventh edition did not distinguish between HPV associated and non-HPV associated disease.

HPV associated versus non-HPV associated staging systems — The separation of the HPV associated staging system (table 1A-B) from the non-HPV associated staging system (table 2A-B) for oropharyngeal carcinoma is based on differences in the outcome of patients with HPV associated disease compared with those with non-HPV associated disease treated in a similar manner. The staging systems reflect the different biology of the two cancers. This approach was based on an alternative staging system that was developed and validated by ICON-S [7].

The ICON-S study included 1907 patients with HPV associated oropharyngeal cancer (by p16 staining or in situ hybridization) and 696 with non-HPV associated oropharyngeal cancer. The patients with HPV associated disease were divided into a training cohort of 661 patients at one site to develop a new staging system and 1246 at six other centers to validate these results.

●In an analysis from this database, the prognostic utility of the UICC/AJCC 2010 TNM system was applicable only to those with non-HPV associated disease:

•For patients with HPV associated disease, there were no statistically significant differences in overall survival for patients with stage I, II, III, and IVA disease (five-year rates 88, 82, 84, and 81 percent, respectively), although it was significantly lower for those with stage IVB disease (60 percent).

•In contrast, for the 696 patients with non-HPV associated disease, prognosis worsened with increasing stage of disease. The five-year overall survival rates for stage I, II, III, IVA, and IVB were 76, 68, 53, 45, and 34 percent, respectively

●Using an adjusted hazard ratio (HR) model that took into account age, smoking status, and use of cytotoxic chemotherapy, a new ICON-S staging system was proposed for patients with HPV associated oropharyngeal cancer:

•Stage I disease included patients with a T1 or T2 primary tumor and either N0 or N1 nodal disease (including seventh edition AJCC N1, N2A, and N2B), but without distant metastases. The five-year survival rate was 85 percent in the training cohort and 88 percent in the validation cohort.

•Stage II disease included those with a T3 primary and N0 to N2 nodal involvement, as well as those with a T1/T2 primary and N2 lymph node disease but without distant metastases. The five-year survival rate was 78 percent in the training cohort and 81 percent in the validation cohort.

•Stage III disease included all patients with a T4 primary tumor, regardless of nodal status, or N3 nodal involvement, regardless of size of the primary tumor, but without distant metastases. The five-year survival rate was 53 percent in the training cohort and 65 percent in the validation cohort.

•All patients with distant metastases (M1) are classified as stage IV.

•Notably, in the eighth edition AJCC system, N stage differs for clinically versus pathologically staged patients and differs greatly from the seventh edition AJCC system.

Clinical presentation — Multiple studies have characterized the clinical presentation of HPV associated oropharyngeal cancers, including important differences from other head and neck cancers (table 3). The most extensive data come from an analysis by the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S), which included data from 1907 patients with HPV associated oropharyngeal cancer and 696 with non-HPV associated oropharyngeal cancer [7]:

●Age at diagnosis – Patients with HPV associated oropharyngeal cancer are relatively younger than patients with non-HPV associated disease [5-7,33-35], although the incidence is increasing in older adults [36]. In the ICON-S database, the median age for those with HPV associated disease was 57 years versus 61 years in those with non-HPV associated disease [7]. This difference in patient age, along with differences in comorbidity due to the decreased incidence of tobacco and alcohol excess, has major implications for the ability to tolerate treatment, which can in turn affect the prognosis.

●Sex – There is a heavy preponderance of male patients in those with HPV associated oropharyngeal cancer. In the ICON-S database, 84 percent of patients were male; among those with non-HPV associated oropharyngeal cancer, 76 percent were male [7]. The male:female ratio has been somewhat less in other studies, although male sex still predominates.

●Anatomic location – HPV associated tumors predominantly arise in the tonsillar region, the base of the tongue, or soft palate [37], although a small percentage of tumors at other sites are also HPV associated. Why the oropharynx is more susceptible than other head and neck sites to HPV transformation is unclear. Like uterine cervix, the oropharynx offers easy access for infection. The tonsils contain deep invaginations of the mucosal surface believed to favor the capture and processing of antigens, which may facilitate viral access to basal cells.

●Exposures – In contrast to patients with non-HPV associated disease, patients with HPV associated disease are less likely to smoke tobacco or drink alcohol. However, a greater number of sexual partners and/or higher frequency of oral sex may increase the risk of developing HPV associated oropharyngeal cancer [5,38]. (See 'Risk subgroup identification' below.)

●Presenting signs – The most common presenting sign for HPV related oropharyngeal squamous cell carcinoma of the head and neck is an asymptomatic neck mass typically related to cervical lymph node involvement, rather than other signs or symptoms related to the primary tumor in the oropharynx [37]. Further details of other signs and symptoms related to oropharyngeal tumors are discussed separately. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Clinical presentation'.)

●Clinical stage at presentation – HPV associated oropharyngeal cancer is more likely to present with an early-stage primary tumor, even though there is an increased risk of more advanced disease in the neck. In the ICON-S study, the frequency of an early-stage (T1 or T2) primary tumor was significantly higher in those with HPV associated disease (64 versus 44 percent), while the incidence of more advanced nodal involvement (N2 or N3) was significantly higher (69 versus 51 percent) compared with those with non-HPV associated tumors [7]. Of note, this study used AJCC seventh edition to determine stage; many cases identified as N2 or N3 with AJCC seventh edition would be classified as N1 with AJCC eighth edition.

●Second malignancy – A study that included 318 patients with oropharyngeal cancer found that those patients whose tumors were HPV associated based on immunostaining for p16 were significantly less likely to have a second malignancy [39]. The decrease in second malignancies included a history of prior tumors, synchronous lesions, and metachronous second primary lesions (11 versus 20, 1 versus 9, and 6 versus 13 percent, respectively). (See "Second primary malignancies in patients with head and neck cancers".)

●HPV infection of nonoropharyngeal sites – HPV positivity is associated with improved survival for patients with nonoropharyngeal tumors involving certain sites, such as the hypopharynx and larynx. (See 'HPV associated cancers' above and 'Nonoropharyngeal carcinoma' below.)

Risk subgroup identification — Identification of more and less favorable prognostic subgroups, beyond TNM stage, with HPV associated oropharyngeal squamous cell carcinoma (OPSCC) will be important in determining which patients may be candidates for de-intensified therapy to prevent acute toxicities and late complications without compromising overall survival or increasing the risk of locoregional recurrence.

●Smoking – Tobacco smoking is associated with a worse prognosis in patients with HPV associated OPSCC [7,40-42]. In an analysis of patients from two phase III trials (one with radiation therapy [RT] and the other using chemoradiation), the risks of disease progression and death increased progressively with an increasing smoking history; this increase was independent of tumor p16 status and of the specific treatment patients received.

●Retropharyngeal lymphadenopathy – The subset of patients with retropharyngeal lymphadenopathy has a poorer prognosis than those without retropharyngeal involvement. In a retrospective analysis of 185 patients with HPV associated OPSCC, 29 had retropharyngeal adenopathy on radiologic review [43]. There was no difference in locoregional control with definitive RT compared with those not having retropharyngeal involvement. However, these patients had worse overall survival (57 versus 81 percent) and distant failure-free survival (70 versus 91 percent).

●PIK3CA mutated tumors – The presence of a PIK3CA mutation is associated with worsened disease-free survival in patients with HPV associated OPSCC. In an analysis of two prospective phase II trials of 77 patients treated with deintensified chemoradiation, a cohort of 16 patients (21 percent) were identified with PIK3CA mutated tumors using next-generation sequencing [44]. Compared with those with PIK3CA wild-type tumors, patients with a PIK3CA mutation had a worsened three-year disease-free survival (69 versus 93 percent).

●Absolute lymphocyte count – Absolute lymphocyte count (ALC) may be prognostic for patients with OPSCC. In one observational study, high pretreatment ALC was associated with improved overall survival in patients with OPSCC treated with RT (with or without concurrent chemotherapy) [45].

Treatment

Standard approach — Treatment for patients with HPV associated oropharyngeal cancer is similar to those with non-HPV associated oropharyngeal cancers, except in the context of a clinical trial. Although testing for HPV positivity provides prognostic information, there are insufficient data to alter therapy based on HPV status [1]. The treatment of HPV associated and non-HPV associated oropharyngeal cancer is discussed separately.

●(See "Treatment of human papillomavirus associated oropharyngeal cancer".)

●(See "Treatment of early (stage I and II) head and neck cancer: The oropharynx".)

●(See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx".)

Role for treatment deintensification — Treatment deintensification of RT and/or chemotherapy in patients with HPV associated head and neck cancer remain an investigational approach, and further randomized trials are needed before incorporating this approach into the standard of care. Further details on deintensification techniques are discussed separately. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Is there a role for treatment deintensification?'.)

NONOROPHARYNGEAL CARCINOMA — As opposed to oropharyngeal cancer, there are no treatment implications for patients with HPV associated nonoropharyngeal carcinoma, and eighth edition American Joint Committee on Cancer (AJCC) staging remains unchanged.

The implications of p16 positivity in nonoropharyngeal head and neck carcinoma are less clear than for oropharyngeal cancer, and there does not appear to be a characteristic clinical presentation. Available data from retrospective studies suggest that HPV related head and neck cancer has a better prognosis than non-HPV related cancer at the same site [17,26,46,47].

As an example, in an observational study from the National Cancer Database (NCDB) of 24,740 patients with squamous cell carcinoma of the head and neck, 40 percent had disease involving nonoropharyngeal sites (eg, the oral cavity, larynx, or hypopharynx) [17]. HPV positivity was associated with improved overall survival in those with all stages of disease in the hypopharynx (hazard ratio [HR] 0.61) and with advanced-stage cancers in the oral cavity (HR 0.78) and larynx (HR 0.72).

PROGNOSIS

●Prognosis at diagnosis – For patients with HPV associated locoregionally advanced disease, long-term survival rates are approximately 80 percent or higher [6,28,48-52]. (See "Overview of approach to long-term survivors of head and neck cancer", section on 'Prognosis'.)

Despite this apparent biologic aggressiveness of HPV associated cancer manifested by earlier and more extensive lymph node involvement, these tumors have a better prognosis than head and neck cancers not associated with HPV [53]. The improved prognosis for patients with HPV associated oropharyngeal carcinoma has also been observed in subset analyses of large randomized trials [28,50,54].

As an example, the Radiation Therapy Oncology Group (RTOG) 0129 trial included 433 patients with oropharyngeal cancer who were randomly assigned to radiation therapy (RT) with either accelerated fractionation with a concomitant boost or standard fractionation [54]. All patients received concurrent cisplatin while receiving RT. HPV status was assessed in nearly 75 percent of oropharyngeal patients, based on p16 positivity; 68 percent of patients had HPV associated disease. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Radiation therapy schedule'.)

Overall survival was significantly better in patients with HPV associated tumors compared with those who were not HPV associated (eight-year survival rate 71 versus 30 percent, adjusted HR 0.34, 95% CI 0.22-0.52). Similarly, at eight years, progression-free survival and the locoregional failure rate were significantly better for those with HPV associated disease (64 versus 23 percent, adjusted HR 0.43, 95% CI 0.29-0.64, and 20 versus 52 percent, adjusted HR 0.29, 95% CI 0.17-0.48, respectively). The incidence of distant metastases was not significantly lower (10 versus 16 percent, adjusted HR 0.59, 95% CI 0.26-1.35).

●Prognosis at recurrence – Patients with HPV associated oropharyngeal cancer have a significantly better prognosis following relapse (locoregional, distant, or combined) compared with the prognosis following recurrence in patients whose tumor is not associated with HPV.

The impact of HPV status on prognosis following recurrence was demonstrated in a retrospective analysis of patients with locally advanced oropharyngeal cancer and known HPV status from two RTOG trials (RTOG 0129 and RTOG 0522) [55]. In aggregate, these two trials enrolled 1058 patients with oropharyngeal cancer, and HPV status (based on p16 immunohistochemistry) was known for 637.

•Among patients with known p16 status, 181 developed a recurrence, 105 of 450 patients (23.3 percent) of those with a p16 positive tumor compared with 76 of 187 (40.6 percent) with p16 negative tumors.

•There were no significant differences between those with HPV associated disease and those without HPV associated disease in the median time to progression following initial treatment (eight versus seven months), in the pattern of recurrence (locoregional only 55 percent and distant or combined distant plus locoregional 45 percent for the entire cohort), and in initial sites of distant metastases (lung 73 versus 70 percent, bone 14.6 versus 15.2 percent, and liver 8.3 versus 15.2 percent).

•At a median follow-up of four years after first disease progression, patients with a p16 positive tumor had significantly longer overall survival following recurrence (median 2.6 versus 0.8 years, HR 0.49, 95% CI 0.39-0.70).

•Factors at presentation that were significant on multivariate analysis included p16 tumor status, tumor stage, and cigarette pack years. At relapse, progression type (distant versus locoregional) and the use of salvage surgery were also significant prognostic factors.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Laryngeal cancer (The Basics)" and "Patient education: Throat cancer (The Basics)" and "Patient education: Tongue cancer (The Basics)")

SUMMARY

●Cancers associated with HPV infection – Human papillomavirus (HPV) infection is a sexually transmitted virus that is associated with condyloma acuminatum, squamous intraepithelial lesions, and malignancy, including anogenital malignancies (cervical, vaginal, vulval, penile, and anal carcinoma) and head and neck squamous cell carcinoma. (See "Human papillomavirus infections: Epidemiology and disease associations".)

●Biology of HPV – Two viral oncogenes (E6 and E7), which are expressed as a result of high-risk HPV infection, are mainly responsible for malignant transformation and, ultimately, an HPV associated head and neck cancer with a molecular signature distinct from non-HPV associated head and neck cancers. (See 'Biology of HPV' above.)

●Epidemiology of HPV associated head and neck cancer – HPV associated head and neck cancers occur primarily in the tonsils, base of tongue, or soft palate (table 3). HPV associated malignancies account for 70 to 80 percent of oropharyngeal cancers in the United States and Western Europe. High-risk HPV infection may also be causative in some cases of other head and neck cancer sites. (See 'Epidemiology' above.)

●Confirmation of HPV status – We routinely use immunohistochemistry (IHC) for p16 as a surrogate for HPV status, as it is highly sensitive for HPV associated tumors. If decision-making hinges on HPV status, this diagnosis can be confirmed with either in situ hybridization or polymerase chain reaction (PCR). (See 'Confirming HPV 16 positivity' above.)

●Clinical presentation – HPV associated oropharyngeal cancer typically presents in younger patients without a history of excessive exposure to alcohol and tobacco. HPV associated oropharyngeal cancers tend to present with regional cervical lymph node metastases and smaller primary tumors. (See 'Clinical presentation' above.)

●Prognosis – HPV associated oropharyngeal cancer has a better prognosis and response to therapy than non-HPV associated disease. Tumor testing for HPV status should be included in the evaluation of patients with oropharyngeal squamous cell carcinoma. (See 'HPV associated versus non-HPV associated staging systems' above and "Overview of the diagnosis and staging of head and neck cancer", section on 'HPV testing'.)

●Management – The management of HPV associated oropharyngeal cancer follows a similar treatment approach as for non-HPV associated tumors outside the context of a clinical trial, despite the difference in prognosis. (See "Treatment of human papillomavirus associated oropharyngeal cancer" and "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx" and "Treatment of early (stage I and II) head and neck cancer: The oropharynx".)

Treatment deintensification in patients with HPV associated head and neck cancer remains an investigational approach. (See 'Role for treatment deintensification' above.)

●HPV infection in nonoropharyngeal cancers – HPV positivity is much less common in nonoropharyngeal cancers, and its prognostic implications remain unclear, although similar to oropharyngeal cancer, data suggest a relatively favorable prognosis. (See 'HPV associated cancers' above and 'Nonoropharyngeal carcinoma' above.)

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  21. Pannone G, Rodolico V, Santoro A, et al. Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization. Infect Agent Cancer 2012; 7:4.
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  26. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol 2014; 32:3930.
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  28. Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol 2010; 28:4142.
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Topic 3378 Version 64.0

References

1 : HPV-Associated Head and Neck Cancer.

2 : The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms?

3 : Trends in Human Papillomavirus-Associated Cancers - United States, 1999-2015.

4 : HPV-associated cancers in the United States over the last 15 years: Has screening or vaccination made any difference?

5 : Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers.

6 : Human papillomavirus and rising oropharyngeal cancer incidence in the United States.

7 : Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study.

8 : Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers.

9 : Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer.

10 : Absolute Risk of Oropharyngeal Cancer After an HPV16-E6 Serology Test and Potential Implications for Screening: Results From the Human Papillomavirus Cancer Cohort Consortium.

11 : Prevalence of oral HPV infection in the United States, 2009-2010.

12 : Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners.

13 : Associations of Oralα-,β-, andγ-Human Papillomavirus Types With Risk of Incident Head and Neck Cancer.

14 : HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis.

15 : HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients.

16 : Human Papillomavirus Drives Tumor Development Throughout the Head and Neck: Improved Prognosis Is Associated With an Immune Response Largely Restricted to the Oropharynx.

17 : Survival outcomes by high-risk human papillomavirus status in nonoropharyngeal head and neck squamous cell carcinomas: A propensity-scored analysis of the National Cancer Data Base.

18 : Survival outcomes by high-risk human papillomavirus status in nonoropharyngeal head and neck squamous cell carcinomas: A propensity-scored analysis of the National Cancer Data Base.

19 : Projected Association of Human Papillomavirus Vaccination With Oropharynx Cancer Incidence in the US, 2020-2045.

20 : Effect of Prophylactic Human Papillomavirus (HPV) Vaccination on Oral HPV Infections Among Young Adults in the United States.

21 : Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization.

22 : HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior.

23 : Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma.

24 : Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

25 : Human Papillomavirus Testing in Head and Neck Carcinomas: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists Guideline.

26 : p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma.

27 : Real-time PCR HPV genotyping in fine needle aspirations of metastatic head and neck squamous cell carcinoma: Exposing the limitations of conventional p16 immunostaining.

28 : Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial.

29 : Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis.

30 : Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

31 : Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

32 : Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

33 : Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?

34 : Cause-specific mortality in HPV+ and HPV- oropharyngeal cancer patients: insights from a population-based cohort.

35 : Incidence of Oropharyngeal Cancer Among Elderly Patients in the United States.

36 : Trends in Human Papillomavirus-Associated Cancers, Demographic Characteristics, and Vaccinations in the US, 2001-2017.

37 : Presenting symptoms and clinical findings in HPV-positive and HPV-negative oropharyngeal cancer patients.

38 : Oral sexual behaviors associated with prevalent oral human papillomavirus infection.

39 : Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy.

40 : Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer.

41 : E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group.

42 : Combined effects of smoking and HPV16 in oropharyngeal cancer.

43 : Impact of retropharyngeal adenopathy on distant control and survival in HPV-related oropharyngeal cancer treated with chemoradiotherapy.

44 : PIK3CA Mutation in HPV-Associated OPSCC Patients Receiving Deintensified Chemoradiation.

45 : Pretreatment Lymphocyte Count Predicts Benefit From Concurrent Chemotherapy With Radiotherapy in Oropharyngeal Cancer.

46 : Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer.

47 : Immune Response to HPV16 E6 and E7 Proteins and Patient Outcomes in Head and Neck Cancer.

48 : Human papillomavirus and survival of patients with oropharyngeal cancer.

49 : Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial.

50 : Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial.

51 : High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma.

52 : Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial.

53 : Association of Tumor Site With the Prognosis and Immunogenomic Landscape of Human Papillomavirus-Related Head and Neck and Cervical Cancers.

54 : Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity.

55 : Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma.

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