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Human papillomavirus associated head and neck cancer

Robert I Haddad, MD
Section Editors
Bruce E Brockstein, MD
David M Brizel, MD
Deputy Editor
Michael E Ross, MD
Disclosures: Robert I Haddad, MD Nothing to disclose. Bruce E Brockstein, MD Consultant/Advisory Boards:
Novartis [GIST (Imatinib, Mesylate)]. David M Brizel, MD Consultant/Advisory Boards: Pfizer [Radioprotector (IL-11
inhibitor)]. Michael E Ross, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is
Literature review current through: Jun 2015. | This topic last updated: Feb 12, 2015.
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 any of 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 [1,2]. Other high-risk HPV genotypes such as HPV-18, 31, or 33 are
also causative, but are less common. High-risk HPV infection may also rarely cause cancers at
other head and neck sites.
The role of HPV infection in head and neck squamous cell carcinoma is presented here. The
epidemiology and other risk factors for head and neck cancer are discussed separately, as is the
virology of HPV and its relationship to malignancy. (See "Epidemiology and risk factors for head and
neck cancer" and "Virology of human papillomavirus infections and the link to cancer".)
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 is believed to reflect the gradual decrease in smoking, which is the
primary risk factor for these cancers.
Despite the decrease in tobacco use, the incidence of oropharyngeal cancer initially remained
constant and then began to rise [2,3]. 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
[1,3]. Cohort studies from the 1990s suggested that approximately 50 percent of oropharyngeal

cancers were attributable to HPV, while more recent studies suggest that HPV may account for
much as 70 to 80 percent of these cases in North America and Europe [2-4]. Analyses of worldwide
cancer statistics from 1983 to 2002 have found a significant increase in the incidence of
oropharyngeal cancer in men in developed countries, with disease occurring at younger ages,
consistent with a role for HPV [5].
The timing between exposure to HPV and the development of oropharyngeal cancer may exceed
10 years. 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 [6]. 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 this antigen was not elevated in patients with cancer arising in
other sites.
HPV infection may also have a role in other head and neck cancers. Two large studies have
analyzed the incidence of HPV infection in non-oropharyngeal cancer.
In a combined analysis of 683 patients from three RTOG trials, tumor samples were
analyzed by immunohistochemistry (IHC) for p16 and by in situ hybridization (ISH) for high-risk
HPV status [7]. High-risk HPV was present in 28 of 297 analyzed cases (9.4 percent) and p16
was positive in 62 of 322 cases (19.3 percent).
A combined analysis of 1294 patients from Danish Head and Neck Cancer Group
(DAHANCA) trials over a 20-year period used p16 positivity at a marker for HPV infection [8].
The incidence of p16 positivity was significantly less for those with non-oropharyngeal cancers
compared with oropharyngeal cancer (65 of 479 [14 percent] versus 425 of 815 [52 percent]).
Prevalence of oral 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 men and women, aged 14 to 69 years,
studied the prevalence of HPV [9]. The overall prevalence of HPV DNA in oral exfoliated cells
was 6.9 percent, and the prevalence of HPV16 was 1 percent. HPV prevalence was
approximately three-fold more common in men compared with women (10.1 versus 3.6
percent), consistent with the observed sex distribution for HPV associated oropharyngeal
A study analyzed oral rinse samples for the presence of HPV in patients with HPV associated
oropharyngeal cancer and their long-term sexual partners [10].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 HPV16. Among
the 93 partners available for testing, the overall incidence of HPV infection was 4 percent, and
only one had the oncogenic HPV16. These findings suggest that most partners effectively
clear any active infection to which they are exposed.
BIOLOGY OF HPV HPV are small DNA viruses that are widely distributed in vertebrates. These
viruses contain an eight 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 about 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 positive tumors are distinct from those of HPV negative cancers. The
absence of genetic or epigenetic alterations in the p53 and pRb pathways in HPV positive head and
neck cancers is in sharp contrast to what is observed in HPV negative head and neck cancer. In the
typical HPV negative squamous cell carcinomas, p53 mutations are very frequent along with
decreased levels of p16 and increased levels of pRb. In contrast, HPV positive carcinomas are
associated with wild type p53, down regulation of pRb, and upregulation of p16. These differences
in gene expression suggest that HPV positive and HPV negative 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".)
Diagnosis The gold standard for assessing HPV infection is in-situ hybridization or polymerase
chain reaction (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. Real-time PCR to
measure HPV16 viral load and/orimmunohistochemistry to detect p16 expression are commonly
used in the clinic [11].
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
Either HPV status or p16 status can be used as a marker of HPV infection, depending upon
availability in the treating institution. In one multi-institutional trial that included 433 oropharyngeal
patients, samples of 316 patients 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. However, studies using p16 as a surrogate marker for HPV positivity appear
to have demonstrated a similar impact on survival [12]. The p16 status, as assessed by
immunohistochemistry, may provide additional information beyond HPV positivity. In a study
comparing the effect of p16 expression and HPV DNA presence, cases that were HPV positive with
high p16 expression had a better prognosis than those that were HPV positive but with low
expression [13].
Epidermal growth factor receptor The epidermal growth factor receptor (EGFR) is another
important target in head and neck cancer, and assessment of EGFR expression may be a useful
prognostic marker in conjunction with HPV status. (See "Head and neck squamous cell
carcinogenesis: Molecular and genetic alterations", section on 'EGFR and transforming growth

In an organ-sparing therapy trial for advanced oropharyngeal cancer, low EGFR and high p16 (or
high HPV titer) expression were markers of good response to treatment and outcome, whereas high
EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking were
associated with a poor outcome [14]. Another study also identified p16 and EGFR status as a
powerful predictor of survival with the highest survival seen in those patients whose tumor status
was p16 positive/EGFRnegative [15].
In a randomized trial that compared radiation therapy alone with radiation therapy with cetuximab,
an EGFR inhibitor, the benefit of the combined therapy was most significant in patients with
oropharyngeal cancer, which presumably contained a large number of patients with HPV positive
tumors [16]. Additional evaluation is required to determine whether EGFR inhibitors will be useful in
patients with HPV positive oropharyngeal cancer.
OROPHARYNGEAL CARCINOMA Oropharyngeal cancer associated with HPV has important
differences from non-HPV associated disease in its clinicopathologic features. These differences
and their implications for staging and treatment are areas of ongoing research. (See "Treatment of
locoregionally advanced (stage III and IV) head and neck cancer: The oropharynx" and "Treatment
of early (stage I and II) head and neck cancer: The oropharynx".)
Clinicopathologic features Multiple studies have characterized the features of HPV associated
oropharyngeal cancers, including important differences with and other head and neck cancers [2]:
Pathology The vast majority of HPV associated head and neck cancers are squamous cell
carcinomas. Immunohistochemistry (IHC) for p16 is highly sensitive for HPV associated
tumors and we recommend its routine use to determine whether HPV status should be tested
in patients with oropharyngeal cancer. If decision making hinges on HPV status, this diagnosis
should be confirmed with either PCR for HPV or by in situ hybridization [17]. Rare cases of
HPV associated lesions arising in the head and neck that are high-grade neuroendocrine
tumors (small cell carcinomas) have been described [18]. (See "Pathology of head and neck
neoplasms" and "Extrapulmonary small cell cancer".)
Age at diagnosis Patients with HPV positive oropharyngeal cancer are approximately 10
years younger when compared to HPV negative patients [1,3,19]. Many of the patients seen
with this entity are in their late thirties or early forties. This difference in patient age has major
implications in terms of performance status, comorbidities, and thus the ability to tolerate
treatment, which can affect the prognosis.
Anatomic location HPV associated tumors predominantly arise in the base of the tongue or
the tonsillar region, although a small percentage of tumors at other sites are also HPV
positive. Why the oropharynx is more susceptible than other 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.
Clinical stage and prognosis HPV associated oropharyngeal cancer is more likely to
present with an early stage (T1/T2) primary tumor, even though there is relatively advanced
disease in the neck (N2/N3), often with a large cystic lymph node that can sometimes be
mistaken for a cyst (table 1). Despite the biologic aggressiveness of HPV positive cancer,
these tumors have a better prognosis than head and neck cancers not associated with HPV.

As an example, in a secondary analysis of a randomized trial, the incidence of distant

metastases was lower in HPV positive as opposed to HPV negative patients (10 versus 16
percent) [20], although this difference did not persist after adjustment for other prognostic
factors. Similar results were observed in another large retrospective series, in which the
incidence of distant metastases was also lower in HPV positive compared with HPV negative
tumors (10 versus 15 percent, respectively), although the difference was not statistically
significant [21].In the HPV positive group, distant metastases developed later in patients with
an HPV associated cancer and in a much different pattern than in HPV negative patients.
Second malignancy A study that included 318 patients with oropharyngeal cancer found
that those whose tumors were HPV associated based upon immunostaining for p16 were
significantly less likely to have a second malignancy [21]. 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".)
Although laryngeal cancers have been associated with infection with high-risk HPV
genotypes, no correlation has been demonstrated between infection and clinical course in
these patients [22]. (See 'HPV associated cancers' above.)
Staging HPV associated oropharyngeal cancer is currently staged using the same tumor, node,
metastasis (TNM) staging system as for those with HPV negative oropharyngeal cancers (table 1).
However, given the differences in clinical presentation and the natural history of disease, the TNM
staging system for HPV positive disease is under review and may require modification [23].
A single center study of 573 patients with HPV associated disease (defined by positive p16
immunostaining) analyzed the relationship between the Union for International
Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging criteria and prognosis
in patients who were treated with chemoradiation or radiotherapy alone [24]. Conventional stage
groupings (I-IV) did not distinguish different prognoses. Using recursive partitioning analysis, the
study identified three distinct prognostic groups (T1-3N0-2b versus T1-3N2c versus T4 or N3).
Selection of treatment based on the current AJCC system or other biases may have affected the
stage-outcome correlation, although an exploratory adjusted analysis demonstrated only small
effect. The incorporation of the patient-specific factors smoking (20 pack years versus >20 pack
years) and age (70 years versus >70 years) yielded four discrete groups that were prognostic for
survival. As an example, patients grouped as stage 1 with T1-3 disease, N0-N2c, and 20 pack
years of smoking had a five-year overall survival of 89 percent (95% CI 85-93 percent) These
observations require validation from larger series. Regardless of whether this is immediately
incorporated into formal staging systems, this and similar studies shed important light on the design
interpretation of clinical trials.
Therapeutic implications Treatment for patients with HPV associated oropharyngeal cancer
currently is the same as for those with HPV negative 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 upon HPV status. (See "Treatment of locoregionally
advanced (stage III and IV) head and neck cancer: The oropharynx" and "Treatment of early (stage
I and II) head and neck cancer: The oropharynx".)

The treatment of head and neck cancer frequently includes a multimodality approach that may
include chemotherapy, radiation therapy (RT), and/or surgery. The acute and long-term effects of
treatment are potentially severe and include mucositis, swallowing dysfunction, fibrosis, xerostomia,
and severe dental problems. These may be especially problematic given the younger age and
better prognosis in patients with HPV associated oropharyngeal cancer.
Ongoing clinical studies are assessing the role of a reduced dose of RT in this population. In a
multicenter cooperative group study (ECOG1308), 80 patients with stage III or IVA HPV associated
oropharyngeal cancer received induction chemotherapy with three cycles of cisplatin, paclitaxel,
and cetuximab [25]. Patients were then reevaluated clinically. Lower dose RT (54 Gy in 27 fractions)
was given to the 62 patients who had a clinical complete response after induction therapy.
Conventional dose RT (69.3 Gy in 33 fractions) was given to the 15 patients with a clinical partial
response or stable disease. In both groups, RT was given in conjunction with weekly cetuximab.
For patients who had a complete response to the initial induction therapy, the two-year progressionfree survival (primary endpoint of the study) was 80 percent [25]. This result is similar to an earlier
cooperative group trial (E2399), in which the two-year progression-free survival for HPV positive
patients was 84 percent after paclitaxelcarboplatin induction followed by RT (70 Gy) with weekly
paclitaxel [26].
Additional data and longer follow-up will be required before lower dose RT, substitution of radiation
dose by induction chemotherapy, or use of potentially less toxic radiosensitizing drugs can be
considered a standard approach for HPV positive patients. The safety of such changes will need to
be carefully confirmed so as to not compromise the excellent prognosis in these patients. One such
trial, RTOG 1016, comparing radiation with cetuximab to radiation with cisplatin, has completed
accrual. (See "Management and prevention of complications during initial treatment of head and
neck cancer" and "Management of late complications of head and neck cancer and its treatment".)
Prognosis Patients with HPV associated oropharyngeal cancer have a significantly better
prognosis at presentation and after disease recurrence, compared with patients whose disease is
not associated with HPV.
At initial diagnosis Multiple clinical studies have demonstrated that the prognosis for patients
who present with HPV associated oropharyngeal cancer is significantly better than for HPV negative
cancer of a comparable stage [3,27-32].
The impact of HPV status is illustrated a single center cohort of 810 patients with non-metastatic
oropharyngeal cancer (71 percent with HPV associated disease) treated between 2000 and 2010
[33]. The five-year overall survival rates for stages I, II, III, and IVa/b were 88, 78, 71, and 74
percent for those with HPV associated disease, compared with 70, 58, 50, and 30 percent for
stages I to IVa/b in those with HPV unrelated disease.
A similar differential was observed in three large randomized trials in which the oropharyngeal
cancer subsets of patients with advanced head and neck cancer were subsequently analyzed
based upon HPV status:
The RTOG 0129 trial included 433 patients with oropharyngeal cancer were randomly
assigned to radiation therapy with either accelerated fractionation with a concomitant boost or
standard fractionation [20]. All patients received cisplatin (100 mg/m2) while receiving RT. HPV

status was assessed in nearly 75 percent of oropharyngeal patients based upon p16 positivity;
68 percent of patients were HPV positive. (See "Locally advanced squamous cell carcinoma of
the head and neck: Approaches combining chemotherapy and radiation therapy", section on
'RT schedule'.)
Overall survival was significantly better in patients with HPV positive tumors compared with
those who were HPV negative (eight-year survival rate 71 versus 30 percent, adjusted hazard
ratio [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 HPV positive patients (64 versus 23
percent, adjusted HR 0.43 95% CI0.29-0.64, 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).
In the TROG 02.02 trial, patients with head and neck cancer were treated with radiation
therapy plus concurrent cisplatin, with or without the radiosensitizer tirapazamine [28]. HPV
status was assessed in 172 patients with oropharyngeal cancer. Using p16 positivity as a
surrogate for HPV positivity, two-year overall survival was significantly improved (91 versus 74
percent, HR 0.36), as was the failure-free survival (87 versus 72 percent, HR 0.39). Patients
with p16 positive tumors had lower tumor stage (T1-T2), but more extensive nodal disease
(N2-N3) than those with p16 negative tumors (37 versus 15 percent and 86 versus 65
In the TAX 324 trial, patients were treated with either three or two drug induction
chemotherapy followed by concurrent chemoradiotherapy [29]. HPV status was assessed in
111 of the 264 patients with oropharyngeal cancer [30]. Both progression-free and overall
survival rates were significantly improved in HPV positive patients at five years (78 versus 28
percent and 82 versus 35 percent, respectively). The HPV positive group contained a
significantly larger number of patients with early (T1-T2) primary tumors compared with those
with HPV negative disease (49 versus 20 percent); advanced nodal disease was present in
more than three-fourths of patients, regardless of HPV status.
Tobacco smoking is associated with a worse prognosis in patients with HPV associated
oropharyngeal cancer [25,34]. In an analysis of patients from two phase III trials (one with radiation
therapy and the other using chemoradiotherapy), 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.
From time of recurrence Patients with HPV associated oropharyngeal cancer have a
significantly better prognosis following relapse (locoregional, distant, or both) compared with the
prognosis 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
Radiation Therapy Oncology Group trials (RTOG 0129 and RTOG 0522) [35]. In aggregate, these
two trials enrolled 1058 patients with oropharyngeal cancer, and HPV status (based upon p16) 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 in the median time to progression following initial
treatment (eight versus seven months), as was the pattern of recurrence (locoregional only 55
percent and distant or combined distant plus locoregional 45 percent for the entire cohort), and
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).
Survival analysis was carried out with a median follow-up of four years after first disease
progress among surviving patients. Patients with a p16 positive tumor had a significantly
longer overall survival following recurrence (median 2.6 versus 0.8 years, HR 0.49, 95% CI
Factors at presentation that have been identified as significant in multivariate analysis
included p16 tumor status, tumor stage, and cigarette pack years. Subsequently, progression
type (distant versus locoregional) and the use of salvage surgery are also significant
prognostic factors.
NON-OROPHARYNGEAL CARCINOMA The implications of p16 positivity in non-oropharyngeal
head and neck carcinoma are less clear than for oropharyngeal cancer, and there does not appear
to be a characteristic clinical presentation.
Two retrospective series have given somewhat conflicting results in this setting:
In a retrospective analysis from three RTOG studies, patients whose non-oropharyngeal
tumors were positive for p16 had a better prognosis compared with those who were p16
negative (progression-free survival, hazard ratio [HR] 0.63, 95% CI 0.42-0.95, and overall
survival HR 0.56, 95% CI 0.35-0.89) [7]. Although there were trends toward better
progression-free survival and overall survival in patients with high-risk HPV by in situ
hybridization (ISH), there were only limited numbers of such patients and the differences were
not statistically significant. When analyzed by primary tumor site, similar trends were observed
for patients with oral cavity, hypopharyngeal, and laryngeal cancers, although patient numbers
were limited.
In contrast, a retrospective analysis of 1294 patients with non-oropharyngeal cancer from
Danish Head and Neck Cancer Group (DAHANCA) trials compared p16 positive patients with
p16 negative patients and did not identify a significant improvement either in locoregional
control (HR 1.13, 95% CI 0.75-1.70) or overall survival (HR 0.82, 95% CI 0.59-1.16) [8].
SUMMARY 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.
HPV associated head and neck cancers occur primarily in the tonsils and base of tongue.
HPV associated malignancies now account for more than one-half of cancers of the
oropharynx and 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.)
HPV associated head and neck cancers affect younger patients without a history of
excessive exposure to alcohol and tobacco. (See 'Clinicopathologic features'above.)
Two viral oncogenes (E6 and E7), which are expressed as a result of HR HPV infection, are
mainly responsible for malignant transformation and ultimately, an HPV associated head and

neck cancer with a molecular signature distinct from HPV negative head and neck cancers.
(See 'Biology of HPV' above.)
HPV associated oropharyngeal cancers tend to present with regional lymph node
metastases relatively early in the natural history of the disease. Despite this, these cases are
associated with a better prognosis and response to therapy than HPV negative tumors due to
other risk factors. Tumor testing for HPV status may be useful in patients with oropharyngeal
cancer as a prognostic marker.
Although the HPV status of oropharyngeal cancers has significant prognostic implications,
there is insufficient evidence to alter therapy based upon HPV status outside the context of a
clinical trial. (See 'Prognosis' above and 'Therapeutic implications' above.)
HPV positivity is much less common in non-oropharyngeal cancers and its prognostic
implications remain unclear. (See 'HPV associated cancers' above and 'Non-oropharyngeal
carcinoma' above.)
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