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The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to the decreasing incidence of carcinomas in other subsites of the head and neck, in spite of the reduced prevalence of smoking. Human papilloma virus (HPV) infection, and in particular type 16 (HPV-16), is now recognized as a significant player in the onset of HPV positive OPSCC, with different epidemiological, clinical, anatomical, radiological, behavioural, biological and prognostic characteristics from HPV negative OPSCC. Indeed, the only subsite in the head and neck with a demonstrated aetiological viral link is, at present, the oropharynx. These observations lead to questions regarding management choices for patients based on tumour HPV status with important consequences on treatment, and on the role of vaccines and targeted therapy over the upcoming years.
HPV in oropharyngeal cancer:
the basics to know in clinical practice
HPV nel carcinoma dell’orofaringe: le nozioni base da conoscere nella pratica
1Division of Otolaryngology Head and Neck Surgery, European Institute of Oncology, Milano, Italy; 2Department of
Otolaryngology, Head and Neck Surgery, Alexandria University, Alexandria, Egypt; 3Department of Experimental
Oncology, IFOM-IEO Campus, European Institute of Oncology, Milano, Italy
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to the decreasing incidence of carcinomas in other
subsites of the head and neck, in spite of the reduced prevalence of smoking. Human papilloma virus (HPV) infection, and in particular
type 16 (HPV-16), is now recognized as a signicant player in the onset of HPV positive OPSCC, with different epidemiological, clinical,
anatomical, radiological, behavioural, biological and prognostic characteristics from HPV negative OPSCC. Indeed, the only subsite in
the head and neck with a demonstrated aetiological viral link is, at present, the oropharynx. These observations lead to questions regarding
management choices for patients based on tumour HPV status with important consequences on treatment, and on the role of vaccines and
targeted therapy over the upcoming years.
KEY WORDS:                 
L’incidenza del carcinoma spinocellulare dell’orofaringe (OPSCC) è in aumento in contrasto con la diminuzione dell’incidenza di carci-
nomi in altre sedi del distretto cervico-facciale, nonostante la ridotta prevalenza del fumo. L’infezione da Papilloma Virus Umano (HPV),
in particolare di tipo 16 (HPV16), è ora riconosciuto come un importante fattore nell’insorgenza di HPV OPSCC positivo, con diverse
caratteristiche radiologiche, epidemiologiche, cliniche, anatomiche, biologiche e prognostiche rispetto all’HPV OPSCC negativo. In effetti
l’unica sede del distretto cervico-facciale con un collegamento virale eziologico dimostrato è, attualmente, l’orofaringe. Queste osserva-
zioni portano a domande riguardanti le scelte di gestione per i pazienti in base allo stato del tumore HPV con importanti conseguenze sul
trattamento e sul ruolo dei vaccini e terapia mirata per i prossimi anni.
PAROLE CHIAVE: Papilloma Virus Umano • Tumori del distretto cervico-facciale • Tumori dell’orofaringe • Carcinoma spinocellulare •
Prognosi • Trattamento • Prevenzione • Vaccinazione • Studi clinici
Acta Otorhinolaryngol Ital 2014;34:299-309
Head and neck cancer, which includes tumours that arise
from the oral cavity, oropharynx, larynx, hypopharynx
and sinonasal tract, represents a serious health care prob-
lem in many parts of the world, and ranks as the sixth most
common cancer worldwide1. These tumours are linked by
common characteristics including a male predominant ap-
pearance in the 5-6th decade of life, a strong aetiological
link with prior tobacco, alcohol use or betel nut chew-
ing2, and a histopathological resemblance3. About 90%
of head and neck cancers are squamous cell carcinomas
The estimated annual burden of HNSCC is approximately
650,555 incident cases and approximately 300,000 result-
ant deaths45. It is considered the sixth leading cause of
cancer mortality and oropharyngeal squamous cell carci-
noma (OPSCC) accounts for approximately 50,000 inci-
dent cases, which is low in comparison with other head
and neck squamous cell carcinoma (HNSCC)56.
Multiple studies have demonstrated that the incidence of
HNSCC has remained stable or even declined in the late
1980s, due to the gradual decrease in smoking and alco-
hol which are the primary risk factors for these cancers2.
Despite this, the incidence of oropharyngeal squamous
cell carcinoma with different characteristics, particularly
S. Elrefaey etal.
in the base of the tongue and tonsil subsites, has increased
by 2-3% annually during 1973-2001, and then by 5.22%
annually from 2000 to 2004 in the USA7. Similar trends
have been noted in other countries. In particular, one study
suggests that the annual number of HPV-associated oro-
pharyngeal cancers in the United States will overtake the
incidence of invasive cervical cancer cases in the United
States by 20208. There is also a discrepancy in incidence
of OPSCC between developed and developing countries
of oropharyngeal cancer9.
The developing world has a relatively low proportion of
OPSCC (1-10% of HNSCCs), which appears to remain
stable (or even to decrease) over time, while the incidence
of HNSCC has steadily increased in most countries410.
The developed world features a relatively high and vari-
able proportion of OPSCCs (15-30% of HNSCC). For ex-
ample, a central belt of European countries has the highest
OPSCC proportions in the developed world (up to 30%
of HNSCCs) with the remainder of Europe being charac-
terised by slightly lower OPSCC proportions, while the
overall HNSCCs incidence has remained stable or has
even shown a declining trend over the same period4 1112.
These demographic data prompted researchers to search
for further risk factors contributing to the incidence of
The impact of HPV as a risk factor
Most studies have demonstrated that features tobacco and
alcohol consumption are major, common risk factors for
HNSCC, but over the last 10-15 years HPV infection has
been increasingly recognised as a major aetiological fac-
tor for a subset of HNSCCs7-10, including mostly OPSCC.
HPV infection in the aetiology of OPSCC was rst shown
by Gillison etal.13; numerous case series studies conduct-
ed in the late 1990s and 2000s evaluated the prevalence
HPV infection in oropharyngeal cancer using molecular
techniques such as PCR and in situ hybridisation81415. In-
deed, over the last ve years it has become increasingly
clear that HPV plays a pathogenic role in this subset of
head and neck cancers, with distinct epidemiologic, clini-
cal and molecular characteristics. These ndings have
created new opportunities for improved therapy and pri-
mary prevention for these HNSCCs16.
At present, it should be clear that the only subsite in the
head and neck with a demonstrated role for HPV infection
in the aetiology of cancer is the oropharynx, as noted in
the most important report by Gillison et al. 13 and con-
rmed by Stransky etal. in 20111317.
From a biological point of view, HPV is a DNA onco-
virus and is epitheliotropic. There are over 120 differ-
ent HPV subtypes, including the low-risk types such as
HPV6 and HPV11, responsible for benign proliferation
of epithelium, and the high-risk oncogenic types HPV16
and HPV18 which are both well-established initiators of
over 90% of cervical cancers, 70% of anogenital cancers,
5% of non-oropharyngeal SCC 17 and 20-72% of OP-
SCC2 4 1217. The oncogenic nature of high risk HPVs is
due to the immortalising and transforming properties of
HPV oncoproteins E6 and E7, which target the p53 and
pRB tumour suppressor pathways, respectively, rendering
infected cells susceptible to mutations and cancer forma-
tion1819. Since the majority of HPV-HNSCCs are OPSCC,
we will mainly discuss OPSCC.
Classication of oropharyngeal cancer
according to HPV
According to the National Comprehensive Cancer Net-
work (NCCN)20 guidelines, ‘HPV testing is recommend-
ed for all oropharyngeal tumours’. In addition, according
to the US National Cancer Institute (NCI)21 and Cancer
Therapy Evaluation Programme (CTEP) 22, HPV status
must be included as a stratication factor for trials includ-
ing oropharynx cancer patients. Much evidence suggests
that HPV-positive and HPV-negative OPSCCs represent
distinct subgroups of OPSCC, each with unique epide-
miological and biological proles45172123-27.
Differences between HPV positive
and HPV negative OPSCCs
Epidemiological factors
HPV-positive patients tend to be younger with a median
age of diagnosis of 54 years, less exposure to tobacco
and alcohol 28-30, and higher socioeconomic status and
education 31. HPV positivity is less frequent in blacks
than in Caucasians (4% of HNSCC in blacks vs. 34% in
whites)32, with a three fold higher incidence in males than
As in cervical cancer, oral HPV infection appears to be
a sexually-acquired disease. Although the natural history
of oral HPV infection is not well dened, D’Souza and
colleagues recently showed in a case-control study that a
high (≥26) number of lifetime vaginal-sex partners and
6 or more lifetime oral-sex partners were associated with
an increased risk of OPSCC [odd ratio (OR) 3.1 and 3.4,
respectively]35. An increased risk of HPV-associated OP-
SCC in female patients with a history of HPV-associated
anogenital cancers and their male partners is also con-
sistent with HPV transmission to the oropharyngeal cav-
ity3637. The recent increased incidence of this disease may
thus reect societal changes in sexual behaviour that have
occurred over time in the developed world3839.
An important point to mention is that there is no clear
case-control study addressing the evidence for HPV prior
to development of OPSCC (i.e. temporal association),
with the exception of a Scandinavian study by Mork etal.
HPV in oropharyngeal cancer
which showed that the presence of HPV16 L1 antibod-
ies in pre-diagnostic serum samples was associated with a
14.4-fold increased risk of oropharyngeal cancer. Impor-
tantly, the presence of HPV16 antibodies preceded oro-
pharyngeal cancers by more than 10 years, underscoring a
temporal association. These data conrmed that oral HPV
infection increases the risk of developing OPSSC40.
Lastly, it is possible that in addition HPV infection, other
risk factors or cofactors such as genetic susceptibility or
nutritional factors or tobacco and alcohol interaction have
an important role in cancer onset. There is an objective
need for more analytic epidemiological studies in males
and females diagnosed with HPV positive oropharyngeal
cancer younger than 50 years of age40.
Anatomical sites
Several studies have noted an increased incidence of
HPV-associated oropharyngeal cancers, especially tonsil-
lar and tongue cancer. For example, in the USA they have
risen by 3.9% and 2.1% among men and women, respec-
tively, in the age group from 20 to 44 years, between 1973
and 2004241. Similar patterns have been noted in Sweden
for tonsillar cancer which rose 2.9-fold between 1970 and
2001, increasing by 2.6% per year in men and 1.1% in
The preference of HPV for the oropharynx is unexplained,
but may be related to the unique presence of transitional
mucosa in the oropharynx, predominantly found in the
tonsillar tissue and which shows histological similarities
to the cervical mucosa211. Another possibility lies within
the genetic features of HPV16, which accounts for more
than 90-95% of all HPV associated oropharyngeal can-
cers, as it may facilitate survival in the tonsillar crypt
epithelium4344. It is also possible that the invagination of
the mucosal surface of the tonsil may favour virus capture
and maintenance by promoting its access to basal cells
(the only dividing cells in the epithelium)45. If this is true,
tonsillar tissue could be a reservoir for HPV in the upper
aerodigestive tract. This view is partly supported by the
fact that when oral samples are collected by oral rinse, the
detection rate of HPV is much higher than with swabs.
Finally, the persistence of HPV in tonsillar tissue might be
of importance in the immune response to HPV46.
Biological proles
Recent global genomic screening studies searching for a
biological distinction among HPV-positive and negative
OPSCC have shown that HPV-induced carcinogenesis has
a clear impact on the acquisition and maintenance of spe-
cic chromosomal gains and losses within tumour cells,
in which OPSCCs with transcriptionally active HPV-
DNA are characterised by occasional chromosomal loss/
allelic imbalance47. Conversely, those lacking HPV-DNA
are characterised by gross deletions that involve entire or
large parts of chromosomal arms3248.
Furthermore, ploidy studies have conrmed that HPV-
positive tonsillar cancers feature a lower number of chro-
mosomal alterations compared to their HPV-negative
The biology of HPV-positive oropharyngeal cancer is
typied by p53 degradation, retinoblastoma protein (RB)
down-regulation and p16 up-regulation. By contrast, to-
bacco-related oropharyngeal cancer is characterised by
p53 mutations, down-regulation of p16 and RB up-reg-
Interestingly, recent studies observed an inverse correla-
tion between the presence of HPV and p53 mutations17.
Clinical stage at presentation
Multiple studies have shown that HPV-positive tumours
are more likely to present with early T stage (T1-T2)51
and higher N stage (usually cystic and multilevel)52, and
have distinct histological features, such as moderate/poor
tumour differentiation and non-keratinising or basaloid
pathology1419 51. The incidence of distant metastases was
seen to be lower in patients with HPV positive tumours.
Furthermore, metastases developed later and with a very
different pattern from patients with HPV-negative tu-
mours. HPV-positive oropharyngeal cancer had a 28% re-
duction in the risk of death and a 49% reduction in the risk
of disease recurrence53. Secondary primary tumour (SPT)
in patients with HPV-positive cancer is very rare, and has
improved better survival rate compared to patients with
HPV negative tumours45.
Radiological imaging
Recent studies have shown radiological difference be-
tween HPV-positive and HPV-negative oropharyngeal
cancer. Specically, HPV-positive carcinomas often had
small or even occult primary lesions with well-dened
borders and cystic nodal metastases, whereas HPV-nega-
tive primaries more often had poorly dened borders and
invasion of adjacent muscle5254.
Several studies have shown that patients with HPV-pos-
itive oropharyngeal cancer, identied through PCR, in
situ hybridisation or p16 immunohistochemistry on tu-
mour tissues, have a signicantly improved overall and
disease-free survival compared to patients with HPV-
negative oropharyngeal cancer patients295355-61 (TableI).
This holds true even after adjustment for differences in
favourable prognostic factors associated with HPV posi-
tive patients (younger age, better performance status,
fewer comorbidities, less smoking). Ang etal. reported
that these prognostic factors explained only 10% of the
observed survival differences between two subgroups29.
However, other studies reported that survival rates im-
proved among non-smoker HPV positive patients com-
S. Elrefaey etal.
pared to smokers patients even in recurrent tumours,
underscoring once again the benets acquired from
smoking cessation6263.
Why does HPV positive orophrangeal cancer have a bet-
ter prognosis?
1. HPV-positive tumours may harbour fewer or different
genetic alterations, which can be associated with better
response to therapy1764.
2. HPV-positive tumours have higher radiosensitivity,
probably due to intact apoptotic response to radia-
3. The absence of eld cancerisation in HPV-positive tu-
4. Immunologic response may be play a role in the im-
proved response to radio- and chemotherapy in HPV-
positive tumours (due to the stimulation of immune
response directed to viral specic tumour antigens66.
5. Younger age, good performance status, fewer comor-
bidities of HPV-positive oropharyngeal cancer patients
may also contribute to improved survival67.
The impact of HPV on clinical management
The standard treatment for OPSCCs at present is mainly
dependent on the stage of the disease and patient and cli-
nician preferences. Single-modality treatment, in the form
of surgery or radiotherapy, is usually recommended for
early (T1-T2, N0) disease. For advanced stage disease,
standard treatments include chemoradiotherapy with or
without neck dissection, or surgical resection with re-
construction and postoperative chemoradiotherapy, as
required. These current standard methods of treatment
appear to apply to both HPV positive and negative sub-
1) Non-surgical treatment options for OPSCCs
The emergence of HPV-OPSCCs in younger patients
with better prognosis and survival rates in comparison to
non-HPV OPSCCs have prompted clinicians to address
changes in the non-surgical management according to
HPV status2.
Multiple studies 29 58-61 68-70 tackling this issue have con-
cluded that (TablesI,II):
1. Overall survival rates increase with HPV positive sta-
tus, low EGFR and high p1672.
2. Patients with HPV negative disease have a poorer
prognosis, and therefore usually require more intensive
treatment. Studies (TAX 324 61, TROG 02.02 59) have
suggested that for patients with HPV DNA-negative
tumours, treatment intensication improves outcomes
compared to standard treatment, but overall outcome is
still poor.
3. Smoking cessation and strategies to target EGFR and
Bcl-xL70 are important adjuncts in the treatment of oro-
pharyngeal cancer.
4. Achievement of acceptable cure rates with minimal
long-term morbidity with HPV positive oropharyngeal
cancer is possible.
All these data suggest that HPV status can be used in the
clinical decision-making processes to select patients for
less aggressive non-surgical treatment. Thus, assessing
HPV presence is of utmost importance. This is especially
true considering long-term outcomes of HPV-positive
younger patients, since they are at risk of a lifetime com-
promised quality of life as a result of chronic toxicities due
to chemoradiotherapy. p16 immunohistochemistry (IHC)
is a current marker to detect HPV presence. However, it
can be associated with a high rate of false positive/false
negative responses, prompting the need for new surrogate
markers for oral HPV infection. These concerns were also
reported by Rietbergen etal.71 and Bussu etal.72. Thus, in
clinical practice it is not recommended to rely on p16 IHC
alone to screen for HPV positivity.
Currently, there are on-going oncological trials that at-
tempt to answer some questions regarding deintensica-
tion of treatment (TableIII):
1. Can we use neoadjuvant chemotherapy followed by re-
duced radiotherapy dose in HPV positive patients?
2. What is the intensity of adjuvant therapy required in
p16-positive oropharynx cancer patients?
3. Can cetuximab provide selective radiosensitisation
compared with cisplatin?
4. Should the volume treated be reduced by not adminis-
tering prophylactic radiotherapy to areas at risk of mi-
croscopic disease?
5. Is it possible to reduce the dose of radiation therapy
when given with standard doses of chemotherapy?
6. What is the exact role of immune activation in HPV
positive patients?
Table I. Selected studies reporting the association of HPV infection with oropharyngeal cancer prognosis.
Study Author, year # of cases HPV detection Follow-up OS positive vs. negative tumours
ECOG58 2399 Fakhry, 2008 96 HPV16 DNA ISH 2 2-yr survival (95% vs. 62%)
RTOG29 0129 Ang, 2010 323 HPV16 DNA ISH 4.8 3-yr survival (82.4%, vs. 57.1%)
TROG59 02.02 Rischin, 2010 185 p16 IHC 5 2-yr survival (91% vs. 74%)
DHANCA60 6,7 Lassen, 2011 794 p16 IHC 5 (62% vs. 47%)c, (52% vs. 48%)*
TAX61) 324 Posner, 2011 111 HPV16 DNA PCR 5 5 yr survival (82%-35%)
ISH: in situ hybridisation; IHC: immunohistochemistry; PCR: polymerase chain reaction; OS: overall survival; *accelerated radiotherapy; cconventional radiotherapy.
HPV in oropharyngeal cancer
2) Surgical treatment options for OPSCCs
All treatment modalities for OPSCC have similar on-
cological outcomes 73, but functional outcomes have
signicant and critical considerations when managing
younger HPV positive patients with an longer expected
lifetime. While nonsurgical deintensication trials are
Table II. Retrospective analyses of HPV status and/or p16 immunohistochemical staining status as a surrogate biomarker of HPV infection and survival
outcome in Phase III outcome.
Study Treatment Regiment Total
(n included)
Overall Survival Conclusion
RTOG 0129
Ang etal.
radiation + cisplatin
vs. hyperfractionated
radiation + cisplatin
743 (323) HPV+/p16 HPV-/p16
3-yr 73.7% 3 yr 43%
3-yr 74.4% 3 yr 38%
3-yr 82.4% 3 yr 57.1%
3-yr 83.6% 3-yr 51.3%
No survival differences seen between the 2
treatment arms.
Secondary analysis confirmed significantly
improved survival in patients with HPV-
positive tumours vs. HPV-negative disease.
Lassen etal.
195 (156)
219 (175)
5-yr p16+ (70%)
5-yr p16- (40%)
5-yr p16+ (62%)
5-yr p16- (26%)
Improved loco-regional control when
nimorazole was added to radiotherapy
was restricted to p16-negative patients.
Improved survival in p16-positive patients
treated with radiotherapy alone.
Lassen etal.
5 Fractions w/radiation
6 Fractions w/radiation
726 (385)
750 (409)
5-yr p16+ (78%)
5-yr p16- (64%)
5-yr p16+ (62%)
5-yr p16 -(47%)
Accelerated radiotherapy significantly
improves outcome in HNSCC compared to
conventional fractionation. The observed
benefit was independent of tumour p16
status, and the use of a moderately
accelerated radiotherapy regimen seemed
advantageous for
HPV/p16 positive HNSCC.
TROG 02.02
Rischin etal.
Radiation+cisplatin vs.
861 (185) 2-yr p16+ (87%)
2-yr p16- (72%)
2-yr p16+ (91%)
2-yr p16- (74%)
While there was no difference in the
p16-positive group, there was a trend
for improved loco-regional control with
tirapazamine in p16 negative patients.
The study clearly demonstrated that HPV
associated oropharyngeal cancer treated
with a standard regimen of concurrent
cisplatin and radiation has a better outcome
compared with HPV-negative OPSCC.
Table III. On-going clinical trials (
Study ID NCI Trial
Treatment arm Primary
E1308 NCT01084083 Phase II 160 Sequential therapy: cisplatin/paclitaxel/cetuximab
Complete response: IM RT (27 fractions)
Non complete response: IM RT (33 fractions) 1cetuximab
2-yr PFS
J0988 NCT01088802 Phase I/II 60 IMRT (lower dose) + cisplatin Toxicity/LRC
National Cancer
Institute (NCI)
NCT01585428 Phase II -
Fluderabine/cyclophosphamide/ Young TIL
Tumour response /
RTOG 1016 NCT01302834 Phase III 706 IMRT hyperfractionation+cisplatin vs.
IMRT hyperfractionation +cetuximab
5-yr OS
of Michigan
Cancer Center
NCT01663259 - -
Standard dose radiotherapy+cetuximab for stage III/IV
Rate of recurrence
ECOG1308 NCT01084083 Phase II 83 Induction chemotherapy followed by cetuximab With
low dose vs. standard dose IMRT
2-yr PFS
Mount Sinai
School of
NCT01358097 Observational - Biomarkers of immune function as predictors of HNSCC in
response to therapy
OS: overall survival, LRC: loco-regional control; DFS: disease-free survival; IMRT: intensity modulated radiation therapy; PFS: progression-free survival; TIL: tumour infiltrating
S. Elrefaey etal.
showing great promise2958-6170-72, minimally-invasive ap-
proaches, especially transoral robotic surgery (TORS),
have gained more favour by achieving the satisfactory
oncological outcomes without compromising functional
outcome7374. Indeed, three-dimensional visualisation al-
lows the ability to manipulate75 and perform reconstruc-
tion of the oropharynx without the need for mandibulot-
omy and/or pharyngotomy, thus reducing the morbidity
of extensive surgery 76. It also facilitates safer exposure
and resection of the primary tumour, thereby providing
complete pathologic evaluation and impacting the use
of clinically-established adjuvant therapies77. These in-
clude use of concurrent chemotherapy 78 and effective
lower doses of radiotherapy, which contribute to a de-
crease of swallowing dysfunction79. The postoperative
target volume for radiation is typically smaller, and with
modern techniques such as intensity modulated radio-
therapy (IMRT) this procedure can signicantly reduce
the dose delivered to uninvolved normal structures. In
patients requiring postoperative concurrent chemoradia-
tion, this offers the potential to reduce the risk of late
The incorporation of TORS, not only to improve oncolog-
ic results but also to decrease the long-term toxicity risks
caused by non-surgical strategies, is crucial for HPV posi-
tive patients since they typically present at a younger age.
To date, there are few surgical trials investigating the
role of TORS in HPV positive patients. For instance,
Cohen et al. 81 found no differences in oncological out-
comes, overall survival or loco-regional control between
HPV-positive and negative groups patients who under-
went TORS surgery stratied by HPV status. Nonethe-
less, TORS surgery was suitable for both subgroups. The
Mount Sinai group reported no differences in overall
survival or loco-regional control in patients stratied by
smoking status, with the assumption that patients without
a smoking history are predominantly HPV positive82.
The failure to show statistically signicant differences in
HPV-positive and HPV-negative tumours in TORS sur-
gical trials for early T stage differences is unclear. It is
possible that these studies were small and thus lack the
statistical power to show survival differences, or that the
survival advantage in HPV-positive tumours does not ap-
ply to early T-stage tumours that are surgically resected.
Lastly, one may argue that HPV-negative tumours are less
radio-responsive, and surgical resection provides better
prognosis in the cohort being studied83.
New multi-institutional studies are needed to conrm the
exact impact of TORS on the quality of life and survival
outcomes of HPV negative and positive OPSCC patients.
Future directions in HPV-positive OPSCCs
HPV-induced carcinogenesis has been extensively stud-
ied in the most widely accepted HPV-related malignancy,
namely cervical cancer. HPV-associated cancers continu-
ously express the HPV E6 and E7 viral oncogenes even
during advanced stages, and repression of viral oncogene
expression can prevent growth or survival of cervical can-
cer cells84. These ndings raise the possibility that even
late-stage HPV-associated cancers can be treated through
HPV-targeted approaches with drugs that interfere with
the expression or function of the viral oncoproteins or
with therapeutic vaccines that elicit a cytolytic immune
response in cells expressing these oncoproteins.
The world has greatly beneted from vaccine programmes
in controlling the morbidity and mortality of infectious
diseases. Hepatitis B virus (HBV) vaccine, developed for
the prevention of hepatitis B virus infection, is considered
the rst vaccine against a major human cancer, hepatocel-
lular carcinoma85. Recently, a prophylactic HPV vaccine
has been included in national immunisation programmes
of most developed countries with the hope of also be-
ing included in developing countries within the next few
years, with the goal of preventing cervical and other non-
cervical HPV related cancers86.
Two FDA-approved HPV prophylactic vaccines are
currently available87. The quadrivalent vaccine was ini-
tially approved in the US in 2006, and is composed of
four HPV type-specic virus-like particles (VLPs) from
the major capsid protein L1 of HPV types 6, 11, 16 and
18, combined with aluminium phosphate adjuvant. These
are the most common HPV types found in 70% of cer-
vical cancers and 90% of non-cervical cancers87 88. The
bivalent HPV vaccine, approved in 2009, is composed of
two HPV types, 16 and 18, which cause 70% of cervical
cancers 86. The efcacy of the quadrivalent vaccine was
100% in preventing HPV16 and 18 related cervical in-
traepithelial neoplasia (CIN) grades 2/3 and vulvar and
vaginal intraepithelial neoplasia (VIN) 2/3, and 98.9% in
preventing HPV6, 11, 16 and 18 related genital warts89.
The bivalent vaccine is 98.1% efcacious in HPV16 and
18 related CIN 2/3 prevention90.
The Advisory Committee on Immunization Practices
(ACIP) and the Centers for Disease Control and Preven-
tion (CDC) recommends889091:
• routinevaccinationofgirlsaged11or12yearsthatcan
be started at 9 years of age;
• catch-upvaccinationforfemalesaged13-26years;
• routinevaccinationofboysaged11or12years;
• routine vaccination recommended for both men who
have sex with men (MSM) and immunocompromised
individuals aged 22 through 26 years;
• menaged13to21yearswhowerenotpreviouslyvac-
• menaged22to26yearsmayalsoreceivethevaccine;
• canbegiventolactatingwomen, patients withminor
HPV in oropharyngeal cancer
acute illnesses and women with equivocal or abnormal
Pap test.
HPV vaccine should be delivered through a series of 3
intramuscular injections over a 6-month period of time,
at 0, 2 and 6 months for the quadrivalent vaccine and 0,
1 and 6 months for the bivalent one89, inducing strong
immune memory with persistent antibody up to 6.4 years
(bivalent) and up to 9.5 years (HPV16 VLP used in quad-
rivalent) thus entailing long-term duration of protection
against infections caused by pathogenic HPVs and their
disease sequelae92.
The entrance of males into vaccination programmes is
primarily due to the estimation of 7,500 cases of HPV-
related cancer, primarily head and neck and anal can-
cer, which occur in men each year in the United States
alone93. Furthermore, the rates of anal cancer in homosex-
ual males are extremely high, and thus vaccination may
contribute in immunisation with subsequent reduction of
HPV sexual transmission.
In the future, the currently available vaccines may also
show promising results on preventing HPV-associated
OPSCC caused by HPV16, and longitudinal studies com-
paring the incidence of disease before and after the intro-
duction of the vaccine may clarify this issue.
Unfortunately, the prophylactic vaccine is not effective on
established infections and cancer lesions, so the study of
a therapeutic HPV vaccine to treat HPV-associated cancer
remains an area of crucial importance94.
Different immunotherapeutic vaccines targeting E7 and/
or E6 have been developed over the last decade including
peptide/protein, dendritic cell (DC), plasmid DNA and
viral vector-based therapies, but with limited success in
preclinical and clinical phase studies9596. A recent Italian
study developed a promising therapeutic vaccine based
on an integrase defective lentiviral vector (IDLV) to de-
liver a mutated non-oncogenic form of the HPV16 E7
protein, considered as a tumour specic antigen for im-
munotherapy of HPV-associated cervical cancer, fused to
calreticulin (CRT), a protein that is able to activate natu-
ral killer T cells (NKTs). A single intramuscular injection
prevented tumour growth in 90% of early stage tumour-
bearing mice, without adjuvants and/or drug treatments.
These promising results may suggest that a safe antican-
cer immunotherapeutic vaccine may be available in the
future for human use94.
Targeted therapies
Evaluation of epithelial growth factor receptor (EGFR)-
targeted therapies in HNSCC patients have been based
on the observation that EGFR is highly expressed in HN-
SCC, and its over-expression has been associated with
reduced survival in several studies97. For clinical use, EG-
FR can be targeted either by antibodies recognising the
ligand-binding domain of EGFR or by EGRF tyrosine ki-
nase inhibitors (TKIs). Cetuximab is a humanised mouse
anti-EGFR IgG1 monoclonal antibody, offering improved
loco-regional control and overall survival in locally-ad-
vanced HNSCC in combination with radiotherapy98.
Other humanised anti-EGFR antibodies such a panitu-
mumab or zalutumumab are currently being evaluated in
phase II/III clinical trials and may evolve as alternatives
to cetuximab99. Additional prospective clinical trials are
on-going to assess the value of cetuximab in management
of HPV-positive OPSCCs.
To date, the available data corroborate some well-estab-
lished concepts: oropharynx tumours have been steadily
increasing over the last 20 years compared to other can-
cers of the head and neck worldwide, particularly in West-
ern countries. SEER data suggest that about 18% of all
head and neck carcinomas in the USA were located in the
oropharynx in 1973, compared to 31% of such squamous
cell tumours in 2004. Similarly, in Sweden, the proportion
of oropharyngeal cancers HPV positive has steadily in-
creased, from 23% in the 1970s to 57% in the 1990s, and
as high as 93% in 2007. These data indicate that HPV is
now the primary cause of tonsillar cancer in North Amer-
ica and Europe.
The biology of HPV-positive oropharyngeal cancer is
characterised by p53 degradation, retinoblastoma RB
pathway inactivation and p16 up-regulation. In contrast,
tobacco-related oropharyngeal cancer is characterised
by p53 mutation and down-regulation of CDKN2A (en-
coding p16ink4A). HPV-positive oropharyngeal cancer
seems to be more responsive to chemotherapy and radia-
tion than HPV-negative disease.
The choice of the best viral detection method in tumours
is a matter of controversy, and both in-situ hybridisation
and PCR are commonly used; p16 IHC is also being used
to detect HPV infection, but with unreliable results71 72.
Thus, there is clearly a need for new surrogate markers for
HPV infection to give patients the best treatment strate-
The presence of HPV16 can also be thought of as a prog-
nostic marker for enhanced overall and disease-free sur-
vival, but its use as a predictive marker has not yet been
proven. Many questions about the natural history of oral
HPV infection are still under investigation.
Regarding disease management, based on the present in-
formation, we can consider HPV-positive oropharyngeal
cancer as a distinct subset of HNSCC with a more favour-
able outcome. Patients with HPV-positive oropharyngeal
cancer are typically young and in good health. In future
clinical trials, cancer centres should stratify head and
neck patients by HPV status. Regardless of treatment
modality, an opportunity now exists to investigate less in-
tense treatment strategies that do not compromise survival
S. Elrefaey etal.
outcomes, but lower the risk of fatal side effects. Thus,
providing a high level quality of life with the fewest treat-
ment complications are important considerations. Poten-
tial long-term side effects of concurrent chemoradiation
include dysphagia, xerostomia, feeding-tube dependency
from brosis and scarring of the pharyngeal muscles,
chronic aspiration and chronic fatigue.
However, we must always emphasise that the best cure
against cancer is prevention, especially in those malig-
nancies in which the main pathogenic agent is known.
Finally, the authors wish to suggest reader to consult
two very recent and excellent reviews: “New insights
into human papillomavirus-associated head and neck
squamous cell carcinoma” 100 and “Human papilloma
virus (HPV) in head and neck region: review of litera-
List of Abbreviations:
CTEP: Cancer therapy evaluation programme.
DHANCA: Danish Head And Neck Cancer Group.
DNA: Deoxynucleic acid
E6: Early oncoprotein6
E7: Early oncoprotein7
ECOG: Eastern Cooperative Oncology Group
FDA: Food and Drug Administration
EGFR: Epithelia Growth Factor Receptor
HNSCC: Head and Neck Squamous Cell Carcinoma
HPV: Human Papilloma Virus
ISH: in situ hybridization
NCCN: National Comprehensive Cancer Network
PCR: Polymerase Chain Reaction
pRb: retinoblastoma tumour suppressor
OPSCC: OroPharyngeal Squamous Cell Carcinoma
RTOG: Radiation Therapy Oncology Group
TKI: Tyrosine Kinase Inhibitors
TLM: Transoral Laser Microsurgery
TROG: Trans-Tasman Radiation Oncology Group
TORS: Trans Oral Robotic Surgery
USA: United States of America
BCL-XL: B-cell lymphoma-extra large
SEER: Surveillance, Epidemiology and End Results Program
1 Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide
burden of cancer in 2008: globocan 2008. Int J Cancer
2 Sturgis EM, AngKK. The epidemic of HPV-associated oro-
pharyngeal cancer is here: is it time to change our treatment
paradigms? J Natl Compr CancNetw 2011;9:665-73.
3 Johnson N, Franceschi S, Ferlay J, et al. Oral Cavity and
Oropharynx. In: Barnes L, Eve J, Reichart P, etal., editors.
Int. Pathology and Genetics Head and Neck Tumors. Lyon
2005. p.163-208.
4 van Monsjou HS, Balm AJ, van den Brekel MM, etal. Oro-
pharyngeal squamous cell carcinoma: a unique disease on
the rise? Oral Oncol 2010;46:780-5.
5 Mignogna MD, Fedele S, Lo Russo L. The world cancer
report and the burden of oral cancer. Eur J Cancer Prev
6 Horner MJ, Ries LAG, Krapcho M, etal. SEER Cancer Sta-
tistics Review, 1975-2006, National Cancer Institute. Bethes-
da, MD,, based on
November 2008 SEER data submission, posted to the SEER
web site, 2009.
7 Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil
carcinoma: increasing trends in the US population ages 20-
44 years. Cancer 2005;103:1843-9.
8 Chaturvedi AK, Engels EA, Pfeiffer RM, etal. Human papil-
loma virus and rising oropharyngeal cancer in the United
States. J Clin Oncol 2011;29:4294.
9 Sedrak M, Rizzolo D. Understanding the link between hpv
and oropharyngeal cancer. JAAPA 2009;22:42-6.
10 McKean-Cowdin R, Feigelson HS, Ross RK, etal. Declining
cancer rates in the 1990s. J Clin Oncol 2000;18:2258-68.
11 Hammarstedt L, Dahlstrand H, Lindquist D, etal. The inci-
dence of tonsillar cancer in Sweden is increasing. Acta Oto-
laryngol 2007;127:988-92.
12 Robinson KL, Macfarlane GJ. Oropharyngeal cancer inci-
dence and mortality in Scotland: are rates still increasing?
Oral Oncol 2003;39:31-6.
13 Gillison ML, Koch WM, Capone RB, etal. Evidence for a caus-
al association between human papillomavirus and a subset of
head and neck cancers. Natl Cancer Inst 2000;92:709-20.
14 Gillison ML. Human papillomavirus-associated head and
neck cancer is a distinct epidemiologic, clinical, and molecu-
lar entity. Semin Oncol 2004;31:744-54.
15 Singhi AD, Westra WH. Comparison of human papilloma-
virus in situ hybridization and p16 immunohistochemistry in
the detection of human papillomavirus-associated head and
neck cancer based on a prospective clinical experience. Can-
cer 2010;116:2166-73.
16 Adelstein DJ, Rodriguez CP. Human papilloma virus:
changing paradigm in oropharyngeal cancer. Curr Oncol
Rep 2010;12:115-20.
17 Stransky N, Egloff AM, Tward AD, et al. The mutational
landscape of head and neck squamous cell carcinoma. Sci-
ence 2011;333(6046):1157-1160.
18 Oh JE, Kim JO, Shin JY. Molecular genetic characteriza-
tion of p53 mutated oropharyngeal squamous cell carcinoma
cells transformed with human papillomavirus E6 and E7 on-
cogenes. Int J Oncol 2013;43:383-93.
19 Rampias T, Sasaki C, Weinberger P. E6 and E7 gene silenc-
ing and transformed phenotype of human papillomavirus
16 - positive oropharyngeal cancer cells. J Natl Cancer Inst
20 National Comprehensive Cancer Center Network. Practice
guidelines in oncology-Head and Neck Cancers v. 2.2008.
21 National Cancer Institute: PDQ® Oropharyngeal Cancer
Treatment. Bethesda, MD: National Cancer Institute. Date
last modified <02/15/2013>. Available at:
sional. Accessed <02/15/2013>
HPV in oropharyngeal cancer
22 Ansher SS, Scharf R. The Cancer Therapy Evaluation Pro-
gram (CTEP) at the National Cancer Institute. Ann N Y
Acad Sci 2001;949:333-40.
23 Lindel K, Beer KT, Laissue J, et al. Human papillomavirus
positive squamous cell carcinoma of the oropharynx: a ra-
diosensitive subgroup of head and neck carcinoma. Cancer
24 Kreimer AR, Cliffor GM, Boyle P, etal. Human papilloma
virus types in head and neck squamous cell carcinomas
worldwide: a systemic review. Cancer Epidemiol Biomark-
ers Prev 2005;14:467-75.
25 D’Souza G, Dempsey A. The role of HPV in head and
neck cancer and review of the HPV vaccine. Prev Med
26 Llewellyn CD, Linklater K, J Bell, etal. An analysis of risk
factors for oral cancer in young people: a case-control study.
Oral Oncol 2004;40:304-13.
27 Gillison Ml, D’Sousa G, Westra W, etal. Distinct risk factor
profiles for human papillomavirus type 16-positiveand hu-
man papillomavirus type 16-negativehead and neck cancers.
J Natl Cancer Inst 2008;100:407-20.
28 Chaturvedi AK, Engels EA, Anderson WF, etal. Incidence
trends for human papillomavirus related and unrelated oral
squamous cell carcinomas in the United States. J Clin Oncol
29 Ang KK, Harris J, Wheeler R, etal. Human papillomavirus
and survival of patients with oropharyngeal cancer. N Engl
J Med 2010;363:24-35.
30 D’Souza G, Kreimer AR, Clifford GM, et al. Case control
study of human papillomavirus and oropharyngeal cancer.
N Engl J Med 2007;356:1944-56.
31 Benard VB, Johnson CJ, Thompson TD, et al. Examin-
ing the association between socioeconomic status and po-
tential human papillomavirus associated cancers. Cancer
32 Settle K, Posner MR, Schumaker LM, etal. Racial survival
disparity in head and neck cancer results from low prevalence
of human papillomavirus infection in black oropharyngeal
cancer patients. Cancer Prev Res (Phila) 2009;2:776-81.
33 Ryerson AB, Peters ES, Coughlin SS, etal. Burden of potential-
ly human papillomavirus-associated cancers of the oropharynx
and oral cavity in the US, 1998-2003. Cancer 2008;113:2901-9.
34 Sturgis EM, Cinciripini PM. Trends in head and neck can-
cer incidence in relation to smoking prevalence: an emerg-
ing epidemic of human papilloma virus associated cancers?
Cancer 2007;110:1429-35.
35 D’Souza G, Kreimer AR, Viscidi R, etal. Case-control study
of human papillomavirus and oropharyngeal cancer. N Engl
J Med 2007;356:1944.
36 Frisch M, Biggar RJ. Aetiological parallel between ton-
sillar and anogenital squamous-cell carcinomas. Lancet
37 Hemminki K, Dong C, Frisch M. Tonsillar and other upper
aerodigestive tract cancers among cervical cancer patients
and their husbands. Eur J Cancer Prev 2000;9:433-7.
38 Heck JE, Berthiller J, Vaccarella S, et Sexual behaviours
and the risk of head and neck cancers: a pooled analysis
in the International Head and Neck Cancer Epidemiology
(INHANCE) consortium. Int J Epidemiol 2010;39:166-81.
39 Smith EM, Ritchie JM, Summersgill KF, et al. Age,
sexual behaviour, and human papillomavirus infection
in oral cavity and oropharyngeal cancers. Int J Cancer
40 Mork J, Lie AK, Glattre E, etal. Human papillomavirus in-
fection as a risk factor for squamous- 0cell carcinoma of the
head and neck. N Engl J Med 2001;344:1125-31.
41 Hashibe M, Brennan P, Chuang SC, etal. Interaction be-
tween tobacco and alcohol use and the risk of head and neck
cancer: pooled analysis in the International Head and Neck
Cancer Epidemiology Consortium. Cancer Epidemiol Bio-
markers Prev 2009;18:541-50.
42 Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human
papillomavirus as a risk factor for the increase in incidence
of tonsillar cancer. Int J Cancer 2006;119:2620-3.
43 Klussman JP, Weissenborn SJ, Wieland U, etal. Prevalence,
distribution, and viral load of human papillomavirus 16
DNA in tonsillar carcinomas. Cancer 2001;92:2875-84.
44 Joseph AW, D’Souza G. Epidemiology of human papilloma-
virus-related head and neck cancer. Otolaryngol Clin North
Am 2012;45:739-64.
45 Chu A, Genden E, Posner M, etal. A patient centered ap-
proach to counseling patients with head and neck cancer un-
dergoing human papillomavirus testing: a clinician’s guide.
Oncologist 2013;18:180-9.
46 Syrjanen S. HPV infections and tonsillar carcinoma. J Clin
Pathol 2004;57:449-55.
47 Dahlstrand HM, Dalianis T. Presence and influence of hu-
man papillomaviruses (HPV) in tonsillar cancer. Adv Can-
cer Res 2005;93:59-89.
48 Dahlgren L, Mellin H, Wangsa D, etal. Comparative genom-
ic hybridization analysis of tonsillar cancer reveals a differ-
ent pattern of genomic imbalances in human papillomavirus-
positive and -negative tumors. Int J Cancer 2003;107:244-9.
49 Lohavanichbutr P, Houck J, Fan W, etal. Genomewide gene
expression profiles of HPV- positiveand HPV-negative oro-
pharyngeal cancer: potential implications for treatment
choices. Arch Otolaryngol Head Neck Surg 2009;135:180-8.
50 Smeets SJ1, Braakhuis BJ, Abbas S, et al. Genome-wide
DNA copy number alterations in head and neck squamous
cell carcinomas with or without oncogene-expressing hu-
manpapillomavirus. Oncogene 2006;25:2558-64.
51 Huang SH, Perez-Ordonez B, Liu FF, etal. Atypical clini-
cal behaviour of p16-confirmed HPV-related oropharyngeal
squamous cell carcinoma treated with radical radiotherapy.
Int J Radiat Oncol Biol Phys 2012;82:276-83.
52 Goldenberg D, Begum S, Westra WH, et al. Cystic lymph
node metastasis in patients with head and neck cancer: an
HPV-associated phenomenon. Head Neck 2008;30:898-903.
53 Chaturvedi AK. Epidemiology and clinical aspects of
HPV in head and neck cancers. Head and Neck Pathol
54 Cantrell SC, Peck BW, Li G, etal. Differences in imaging
characteristics of HPV-positive and HPV negative oro-
pharyngeal cancers: A blinded matched-pair analysis. AJNR
Am J Neuroradiol 2013;34:2005-9.
55 Olshan AF. Epidemiology, pathogenesis, and prevention of
head and neck cancer. New York: Springer; 2010.
S. Elrefaey etal.
56 Marur S, D’Souza G, Westra WH, et al. HPV-associated
head and neck cancer: a virus-related cancer epidemic. Lan-
cet Oncol 2010;11:781-9.
57 Chung CH, Gillison ML. Human papillomavirus in head and
neck cancer: its role in pathogenesis and clinical implica-
tions. Clin Cancer Res 2009;15:6758-62.
58 Fakhry C, Westra WH, Li S, etal. Improved survival of pa-
tients with human papillomavirus-positive head and neck
squamous cell carcinoma in a prospective clinical trial. J
Natl Cancer Inst 2008;100:261-9.
59 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;28:4142-8.
60 Lassen P, Eriksen JG, Krogdahl A, etal. The influence of HPV-
associated p16 expression on accelerated fractionated radio-
therapy in head and neck cancer: evaluation of the randomised
DAHANCA 6&7 trial. Radiother Oncol 2011;100:49-55.
61 Posner M, Lorche J, Goloubeva O, etal. Survival and human
papillomavirus in oropharynx cancer in TAX324: a subset
analysis from an international phase III trial. Ann Oncol
62 Maxwell JH, Kumar B, Feng FY, etal. Tobacco use in hu-
man papillomavirus-positive advanced oropharynx cancer-
patients related to increased risk of distant metastases and
tumor recurrence. Clin Cancer Res 2010;16:1226-35.
63 Hafkamp HC, Manni JJ, Haesevoets A, etal. Marked differ-
ences in survival rate between smokers and nonsmokers with
HPV16-associated tonsillar carcinomas. Int J Cancer 2008
64 Klussmann JP, Mooren JJ, Lehnen M, etal. Genetic signa-
tures of HPV-related and unrelated oropharyngeal carci-
noma and their prognostic implications. Clin Cancer Res
65 Lindel K, Beer KT, Laissue J, etal. Human papillomavirus
positive squamous cell carcinoma of the oropharynx: a ra-
diosensitive subgroup of head and neck carcinoma. Cancer
66 Vu HL, Sikora AG, Fu S. HPV-induced oropharyngeal can-
cer, immune response and response to therapy. Cancer Lett
67 Ang KK, Sturgis EM. Human papillomavirus as a marker of the
natural history and response to therapy of head and neck squa-
mous cell carcinoma. Semin Radiat Oncol 2012;22:128-42.
68 Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of
HPV-associated p16INK4A expression on response to radio-
therapy and survival in squamous cell carcinoma of the head
and neck. J Clin Oncol 2009;27:1992-8.
69 Lassen P, Eriksen JG, Hamilton-Dutoit S, etal. HPV-associ-
ated p16- expression and response to hypoxic modification
of radiotherapy in head and neck cancer. Radiother Oncol
70 Kumar B, Cordell KG, Lee JS, etal. EGFR, p16, HPV Titer,
Bcl-xL and p53, sex, and smoking as indicators of response
to therapy and survival in oropharyngeal cancer. J Clin On-
col 2008 1;26:3128-37.
71 Rietbergen MM, Snijders PJ, Beekzada D, etal. Molecular char-
acterization of p16-immunopositive but HPV DNA-negative oro-
pharyngeal carcinomas. Int J Cancer 2014;134:2366-72.
72 Bussu F, Sali M, Gallus R, etal. HPV infection in squamous
cell carcinomas arising from different mucosal sites of the
head and neck region. Is p16 immunohistochemistry a reli-
able surrogate marker? Br J Cancer 2013;108:1157-62.
73 Dowthwaite SA, Franklin JH, Palma DA, et al. The role
of transoral robotic surgery in the management of oro-
pharyngeal cancer: a review of the literature. ISRN Oncol
74 Moore EJ, Henstrom DK, Olsen KD, etal. Transoral resec-
tion of tonsillar squamous cell carcinoma. Laryngoscope
75 Park YM, Lee JG, Lee WS, etal. Feasibility of transoral lat-
eral oropharyngectomy using a robotic surgical system for
tonsillar cancer. Oral Oncol 2009;45:e62-6.
76 Genden EM, Sambur IM, de Almeida JR, etal. Human papil-
loma virus and oropharyngeal cell squamous cell carcinoma:
what the clinician should know. Eur Arch Otorhinolaryngol
77 Quon H, Richmon JD. Treatment deintensification strategies
for HPV-associated head and neck carcinomas. Otolaryngol
Clin North Am 2012;45:845-61.
78 Cooper JS, Pajak TF, Forastiere AA, etal. Postoperative con-
current radiotherapy and chemotherapy for high-risk squa-
mous-cell carcinoma of the head and neck. N Engl J Med
79 Ang KK, Trotti A, Brown BW, et al. Randomized trial ad-
dressing risk features and time factors of surgery plus ra-
diotherapy in advanced head-and-neck cancer. Int J Radiat
Oncol Biol Phys 2001;51:571-8.
80 Machtay M, Moughan J, Trotti A, etal. Factors associated
with severe late toxicity after concurrent chemoradiation for
locally advanced head and neck cancer: an RTOG analysis.
J Clin Oncol 2008;26:3582-3.
81 Cohen MA, Weinstein GS, O’Malley BW Jr, etal. Transoral
robotic surgery and human papillomavirus status: Oncologic
results. Head Neck 2011;33:573-80.
82 Stucken C, de Almeida JR, Tong CCL, etal. Transoral ro-
botic surgery for smokers with squamous cell carcinoma of
the oropharynx. In: Multidisciplinary Head and Neck Cancer
Symposium, Phoenix, AZ; 2012.
83 Genden ER. The role of surgical management in HPV-Relat-
ed oropharyngeal carcinoma. Head Neck Pathol 2012;6(Sup-
84 Goodwin EC, Yang E, Lee CJ, et al. Rapid induction of se-
nescence in human cervical carcinoma cells. Proc Nat Acad
Sci USA 2000;97:10978-83.
85 World Health Organization. Countries using Hepatitis B vac-
cine. [cited: July 2012]. Available from:
86 Tota JE, Chevarie-Davis M, Richardson LA, et al. Epi-
demiology and burden of HPV infection and related dis-
eases: implications for prevention strategies. Prev Med
87 Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic
vaccines and the potential prevention of noncervical cancers
in both men and women. Cancer 2008;113:3036-46.
88 Markowitz LE, Dunne EF, Saraiya M, etal. Quadrivalent hu-
man papillomavirus vaccine. Recommendations of the Advi-
sory Committee on Immunization Practices (ACIP). Centers
HPV in oropharyngeal cancer
for Disease Control and Prevention 2007. Available at: http://
cid=rr5602a1_e (Last accessed: Nov 23, 2014).
89 Kjaer SK, Sigurdsson K, Iversen OE, etal. A pooled analy-
sis of continued prophylactic efficacy of quadrivalent human
papillomavirus (Types 6/11/16/18) vaccine against high-
grade cervical and external genital lesions. Cancer Prev Res
90 Centers for Disease Control and Prevention. FDA licensure of
bivalent human papillomavirus vaccine (HPV2,Cervarix) for
use in females and updated HPV vaccination recommenda-
tions from the Advisory Committee on Immunization Practices
(ACIP). MMWR Morb Mortal Wkly Rep 2010;59:626-9.
91 Centers for Disease Control and Prevention. Recommen-
dations on the use of quadrivalent human papillomavirus
vaccine in males-Advisory Committee on Immunization
Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep
92 Stanley M. Potential mechanisms for HPV vaccine-induced
long-term protection. Gynecol Oncol 118(Suppl):S2-7.
93 Centers for Disease Control. Fact sheet on HPV and men.
[Updated: February 23, 2012]. Available from: http://www.
94 Grasso F, Negri DR, Mochi S, etal. Successful therapeutic
vaccination with integrase defective lentiviral vector ex-
pressing nononcogenic human papillomavirus E7 protein.
Int J Cancer 2013;132:335-44.
95 Trimble CL, Frazer IH. Development of therapeutic HPV
vaccines. Lancet Oncol 2009;10:975-80.
96 Bellone S, Pecorelli S, Cannon MJ, et al. Advances in den-
dritic-cell-based therapeutic vaccines for cervical cancer.
Expert Rev Anticancer Ther 2007;7:1473-86.
97 Psyrri A, Sasaki C, Vassilakopoulou M, etal. Future direc-
tions in research, treatment and prevention of HPV-related
squamouscell carcinoma of the head and neck. Head Neck
Pathol 2012;6(Suppl1):S121-8.
98 Bonner JA, Harari PM, Giralt J, etal. Radiotherapy plus ce-
tuximab for squamous- cell carcinoma of the head and neck.
N Engl J Med 2006;354:567-78.
99 Egloff AM, Grandis JR. Targeting epidermal growth factor
receptor and SRC pathways in head and neck cancer. Semin
Oncol 2008;35:286-97.
100 Boscolo-Rizzo P, Del Mistro A, Bussu F, etal. New insights in-
to human papillomavirus-associated head and neck squamous
cell carcinoma. Acta Otorhinolaryngol Ital 2013;33:77-87.
101 Mannarini L, Kratochvil V, Calabrese L, etal. Human Papil-
loma Virus (HPV) in head and neck region: review of litera-
ture. Acta Otorhinolaryngol Ital 2009;29:119-26.
Address for correspondence: Mohssen Ansarin, Division of
Head and Neck Surgery, European Institute of Oncology, via
Ripamonti 435, 20077 Milano, Italy. Tel. +39 02 57489490.
Fax+390255210169. E-mail:
Received: January 14, 2014 - Accepted: April 24, 2014
... factors such as alcohol drinking and tobacco smoking (Kumar et al., 2016). However, despite a decrease in exposure to these factors during the past three decades, the number of new OSCC and OPSCC cases has continued to increase, suggesting other etiological factors, such as infection with human papilloma virus (HPV) and Epstein-Barr virus (EBV), for these cancers (Elrefaey et al., 2014). In fact, HPV and EBV, as two important human oncogenic viruses, have also been implicated in the development of OSCC and OPSCC (Mirzaei et al., 2020); so that, in 2009, the International Agency for Research on Cancer (IARC) classified the sexually transmitted oncogenic viral pathogen HPV-16 as an independent risk factor for OPSCC (Bouvard et al., 2009). ...
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Background: Head and neck squamous cell carcinoma is one of the most important malignancies, worldwide. Oncogenic viruses, such as human papilloma virus (HPV) and Epstein-Barr virus (EBV), are linked to these cancers and studies suggest a possible interaction between HPV and EBV during co-infections to promote oncogenesis. Nonetheless, these reports are controversial and demand more investigations in this regard. The present work to assessed the prevalence of HPV and co-infection with EBV in oral and oropharyngeal squamous cell carcinomas. Methods: Formalin-fixed paraffin-embedded tissues were collected from 166 archived oral and oropharyngeal squamous cell carcinoma samples from Ahvaz Imam Khomeini hospital, Ahvaz, Iran, from March 2013 and December 2019. Nested-PCR was used to detect the viruses and type-specific PCR/nested-PCR and sequencing were performed for virus genotyping. Results: Out of the 166 specimens, 84.33% and 16.42% were from oral cavity and oropharynx, respectively; of which, 32 cases (19.3%) were HPV-positive (16.42% of oral cavity and 34.6% of oropharynx). HPV was detected in 36.36%, 25%, and 16.42% of base of tongue, tonsil, and oral tongue tumors, respectively. HPV was more associated with well differentiated tumors (24;18.04%) in compared to moderately and poorly differentiated ones. Regarding HPV-16 genotyping, 7 (21.8%) out of the 32 samples were found to be HPV-16 (4/26 (15.38%) for oropharynx and 3/140 (2.14%) for oral cavity). Moreover, 90 samples were evaluated for EBV infection and co-infection; of which, 4 (4.4%) subjects tested positive for EBV, including two cases with HPV co-infection. All the positive cases were EBV type B, from oral cavity, and histologically well differentiated. Conclusions: HPV was more associated with oropharyngeal cancer. This association has been linked to various factors such as repeated oral and oropharyngeal exposure to HPV due to change in patterns of sexual behaviors; a phenomenon that may demand routine HPV vaccination.
... Other important risk factors are patients' age, with the average onset around 62 years, two-thirds of oropharyngeal cancer patients being older than 55, exposure to UV radiation, poor diet behavior low in fruits and vegetables, and genetic risk factors. Recently, scientific attention has been distributed towards the HPV infection of the oropharyngeal region due to the significant increase in recent years in developed countries [8,9]. ...
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Background and Objectives: Curcumin (Cc) as an active substance is known for its anti-inflammatory, anticoagulant, antioxidant, and anti-carcinogenic effects, together with its role in cholesterol regulation, and its use in different gastrointestinal derangements. On the other hand, curcumin can be used for its properties as an inactive substance, with Cc particles being more often tested in pharmaceutical formulations for drug delivery, with promising safety records and kinetics. The aim of this research was to obtain and characterize polyurethane microparticles that can be used as a carrier with a controlled Cc release. Materials and Methods: The in vitro samples were characterized by the Zetasizer procedure, and UV–Vis spectroscopy, while the in-vivo measurements on human subjects were performed by non-invasive skin assays (trans-epidermal water loss, erythema, and skin hydration). A total of 16 patients with oropharyngeal cancer stages II and III in equal proportions were recruited for participation. Results: The experimental values of sample characteristics using the Zetasizer identified a mean structural size of 215 nm in the polyester-urethane preparate (PU), compared to 271 nm in the curcumin-based PU. Although the size was statistically significantly different, the IPDI and Zeta potential did not differ significantly (22.91 mV vs. 23.74 mV). The average age during the study period was 57.6 years for patients in the PU group, respectively, and 55.1 years in those who received the curcumin preparations. The majority of oropharyngeal cancers were of HPV-related etiology. There were no significant side effects; 75.0% of patients in the PU group reporting no side effects, compared to 87.5% in the Cc group. The 48 h TEWL measurement at the end of the experiment found a statistically significant difference between the PU and the Cc group (2.2 g/h/m2 vs. 2.6 g/h/m2). The erythema assessment showed a starting measurement point for both research groups with a 5.1-unit difference. After 48 h, the difference between PU and PU_Cc was just 1.7 units (p-value = 0.576). The overall difference compared to the reference group with sodium lauryl sulfate (SLS) was statistically significant at a 95% significance level. Conclusions: Our findings indicate the obtaining of almost homogeneous particles with a medium tendency to form agglomerations, with a good capacity of encapsulation (around 60%), a medium release rate, and a non-irritative potential. Therefore, this polyester-urethane with Cc microparticles can be tested in other clinical evaluations.
... It has also been postulated that HPV-positive tumours harbour fewer genetic mutations or may be more radiosensitive (with an intact apoptotic response), associated with an overall better response to radiotherapy. 41 Genetic susceptibility to HNC has been investigated, 42 with the largest genomewide association study (GWAS) of oral and pharyngeal cancer (6,034 cases and 6,585 controls from Europe, North America and South America), detecting seven unique loci. 43 Of note, oropharyngeal subgroup analysis revealed a strong protective association at chromosome 6p21.32 ...
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Introduction Head and neck cancer appears to be increasing in incidence, with potential changes in aetiology proposed. This paper aims to provide a narrative overview of the epidemiological literature to describe the disease burden and trends in terms of incidence and mortality both in the UK and globally and to review the evidence on current risk factors. Methods A search was performed on multiple databases (PubMed and Epistemonikos), applying filters to identify systematic reviews and meta-analyses which investigated head and neck cancer incidence, mortality and risk factors. International and UK cancer registries and sources were searched for incidence and mortality data. Results Multiple definitions of head and neck cancer are employed in epidemiology. Globally, incidence rates have increased in recent decades, largely driven by oropharyngeal cancer. Mortality rates over the last decade have also started to rise, reflecting the disease incidence and static survival rates. Major risk factors include tobacco smoking alone and in combination with alcohol consumption, betel chewing (particularly in Southeast Asian populations) and the human papillomavirus in oropharyngeal cancer. Conclusions These epidemiological data can inform clinical and preventive service planning for head and neck cancer.
... Oropharyngeal cancer (OPC) includes tumors that arise from the oral cavity, oropharynx, larynx, hypopharynx, and sinonasal tract. The main risk factors are male gender, prior tobacco use, and alcohol use [21]. About 90% of head and neck cancers are squamous cell carcinomas. ...
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The human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. The risk of being infected at least once in a lifetime among both men and women is estimated to be 50%. Although the majority of HPV infections are asymptomatic and improve within 2 years, approximately 10% of individuals develop a persistent infection and have an increased risk of developing carcinomas. The association of HPV and genital cancer is well established. However, there is evidence that HPV may also be associated with other cancers, including those of the gastrointestinal system. The aim of this review is to organize the current evidence of associations between HPV infections and oropharyngeal and gastrointestinal cancers, including the following: oropharyngeal, esophageal, gastric, colorectal, and anal cancers. A comprehensive review of the most up-to-date medical literature concluded that an HPV infection might have a role in the oncogenesis of gastrointestinal tract cancers. HPV may have a causal relationship with oropharyngeal and esophageal squamous cell cancers. However, the association between HPV and gastric and colorectal cancers is weaker. The development of cancer in the oropharyngeal and gastrointestinal tract is usually multifactorial, with HPV having a role in at least a subset of these cancers. HPV infections pose a big challenge due to their burden of infection and their oncogenic potential.
... Genetic variants in ARID5B have also been linked to autoimmune diseases [49,50], suggesting that immune dysregulation may be a plausible pleiotropic mechanism at this locus, especially given the infectious etiology of oropharyngeal carcinoma [51,52]. ...
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Background Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. Methods To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. Results We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Conclusions Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.
... While the classic risk factors are tobacco and alcohol, human papillomavirus (HPV) has emerged in the past few decades as a growing risk factor for these cancers, especially for oropharyngeal squamous cell carcinoma (OPSCC), defining a new subtype of tumor that is distinct from HPV-negative tumors. As a consequence, OPSCC is one of the few cancers with rapidly increasing incidence in recent years, driven predominantly by HPV-positive cases (6,7). ...
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Human papillomavirus (HPV)-positive head and neck cancers, predominantly oropharyngeal squamous cell carcinoma (OPSCC), exhibit epidemiologic, clinical, and molecular characteristics distinct from those OPSCCs lacking HPV. We applied a combination of whole-genome sequencing and optical genome mapping to interrogate the genome structure of HPV-positive OPSCCs. We found that the virus had integrated in the host genome in two thirds of the tumors examined but resided solely extrachromosomally in the other third. Integration of the virus occurred at essentially random sites within the genome. Focal amplification of the virus and the genomic sequences surrounding it often occurred subsequent to integration, with the number of tandem repeats in the chromosome accounting for the increased copy number of the genome sequences flanking the site of integration. In all cases, viral integration correlated with pervasive genome-wide somatic alterations at sites distinct from that of viral integration and comprised multiple insertions, deletions, translocations, inversions, and point mutations. Few or no somatic mutations were present in tumors with only episomal HPV. Our data could be interpreted by positing that episomal HPV is captured in the host genome following an episode of global genome instability during tumor development. Viral integration correlated with higher grade tumors, which may be explained by the associated extensive mutation of the genome and suggests that HPV integration status may inform prognosis. Implications Our results indicate that HPV integration in head and neck cancer correlates with extensive pangenomic structural variation, which may have prognostic implications.
Objetivos: Descrever a mortalidade por câncer da cavidade oral em um hospital referência e analisar fatores associados em pacientes atendidos e acompanhados no período de 2005 a 2010. Métodos: Estudo transversal, descritivo e retrospectivo, construído por meio de dados obtidos entre janeiro de 2005 e dezembro de 2010 do Hospital de Câncer de Londrina. Para coleta de dados, foram utilizados os prontuários dos pacientes diagnosticados com a condição. O desfecho foi o óbito pós diagnóstico de câncer bucal e as variáveis independentes foram: dados demográficos, fatores de risco, dados clínicos relacionados ao tumor e tipo de tratamento. Para a análise estatística dos dados foi realizada a regressão logística para obtenção do Odds Ratio (OR) e intervalo de confiança (IC) à 95%. Resultados: Dos 326 pacientes incluídos, 161 (49,4%) faleceram, sendo que a maioria era do sexo masculino, da cor branca, com nível de escolaridade até o nível fundamental e trabalhadores braçais expostos à radiação solar. Foi verificado que a maioria desses pacientes eram tabagistas e etilistas. Quase que a totalidade dos pacientes que faleceram receberam o diagnóstico inicial de CEC e a localização anatômica do tumor mais frequente foi a língua, seguida pelo soalho bucal e palato mole. As variáveis associadas ao óbitos foram: tabagismo, etilismo, tratamento radioterápico e intervenção cirúrgica. Os pacientes desses grupos apresentaram riscos maiores de óbito. Conclusões: A taxa de letalidade para o câncer bucal foi elevada. Além disso, o óbito apresentou associação significativa com o tabagismo, o etilismo, o tipo de tratamento e o fato do paciente ter passado por intervenção cirúrgica.
Oropharyngeal cancers driven by Human Papilloma Virus are also on the increase. Recent studies are showing that the way people sleep, eat, and exercise may influence the risk of getting head and neck cancer. Disturbed sleep has been shown to increase the levels of interleukin 6 (IL‐). IL‐6 is a protein involved in regulating cell growth and inflammation. Most head and neck cancer patients will lose muscle during treatment. For the patient this means increased risk of a poor outcome, poor swallowing function, reduced ability to carry out activities of daily living, and low mood. In the longer term there is an increased risk of falls, osteoporosis, and fractures. An exercise programme can counter these issues. Patients undergoing head and neck cancer treatment are often malnourished prior to treatment, and virtually all will lose weight during the treatment. The exact amount of protein patients need in their diet remains controversial.
Purpose: To report the prospective results of mucosal sparing radiation (MSRT) in HPV related OPSCC. Methods: From March 2016 through May 2019, patients were enrolled on this IRB approved prospective cohort study at a multi-site institution. Inclusion criteria included p16+ AJCC 7th edition pathologic T1 or T2, N1 to N3, M0 oropharyngeal cancers. Proton therapy (PT) was delivered to at risk nodal regions, excluding the primary mucosal site. Secondary to insurance denial for PT, IMRT was allowed. EORTC-HN35 and PROMIS10 surveys (QOL) and modified barium swallowing impairment profiles (MBSImP) were obtained at baseline prior to RT, then 3 months and 12 months post RT. Kaplan-Meier estimates were calculated for time-to-event clinical outcomes and repeated measures mixed models were utilized for explore changes in QOL over time. Comparison of QOL and swallowing outcomes with standard of care treatment was analyzed. Results: There were 61 evaluable pts with a median follow up of 38 months (range, 10 - 64), 44 (72%) were treated with PT and 17 (28%) were treated with IMRT. The 2-year LC, LRC, DMFS, and OS were 98%, 97%, 98% and 100%, respectively. There were 6 grade ≥3 events related to treatment. Two IMRT patients required PEG tube placement during treatment secondary to significant nausea due to dysgeusia. Patients noted significant QOL improvement over time in the pain, swallowing, speech, social eating, social contact, mouth opening, and use of pain medication domains (all p < 0.02). MBSImP overall severity score as well as oral and pharyngeal impairment scores showed stability with no significant change over time. For the 44 patients treated with PT, the mean D95 to the primary target was 10.7 Gy (SD = 12.5 Gy). Conclusion: MSRT is well tolerated in select resected HPV related OPSCC with a low risk of recurrence at the mucosal primary site, a low rate of PEG tube placement, and few radiation related grade ≥ 3 adverse events.
Epidemiology, Pathogenesis, and Prevention of Head and Neck Cancer provides a current perspective on the epidemiology of head and neck cancer. Cancers of the oral cavity, pharynx, and larynx comprise an important group of tumors with diverse international patterns of incidence and mortality, established associations with tobacco and alcohol use, the human papilloma virus, and potential determinants of genetic susceptibility. Because of these factors, head and neck cancer offers a unique insight into mechanisms of cancer initiation and progression and gene-exposure interaction. This book brings together the latest epidemiologic and molecular genetic evidence regarding the patterns of occurrence and causes of head and neck cancer. In addition, Epidemiology, Pathogenesis, and Prevention of Head and Neck Cancer considers approaches to chemoprevention, and incorporates a multidisciplinary perspective including salient clinical, pathologic, molecular, and epidemiologic contributions.
The entrance to the oral cavity is formed by the lips. The upper lip features the philtrum in the midline. The corners of the lips are called the commissures.
Objective: To study the difference in gene expression between human papillomavirus (HPV)-positive and HPV-negative oral cavity and oropharyngeal squamous cell carcinoma (OSCC). Design: We used Affymetrix U133 plus 2.0 arrays to examine gene expression profiles of OSCC and normal oral tissue. The HPV DNA was detected using polymerase chain reaction followed by the Roche LINEAR ARRAY HPV Genotyping Test, and the differentially expressed genes were analyzed to examine their potential biological roles using the Ingenuity Pathway Analysis Software, version 5.0. Setting: Three medical centers affiliated with the University of Washington. Patients: A total of 119 patients with primary OSCC and 35 patients without cancer, all of whom were treated at the setting institutions, provided tissues samples for the study. Results: Human papillomavirus DNA was found in 41 of 119 tumors (34.5%) and 2 of 35 normal tissue samples (5.7%); 39 of the 43 HPV specimens were HPV-16. A higher prevalence of HPV DNA was found in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88). We found no significant difference in gene expression between HPV-positive and HPV-negative oral cavity cancer but found 446 probe sets (347 known genes) differentially expressed in HPV-positive oropharyngeal cancer than in HPV-negative oropharyngeal cancer. The most prominent functions of these genes are DNA replication, DNA repair, and cell cycling. Some genes differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer (eg, TYMS, STMN1, CCND1, and RBBP4) are involved in chemotherapy or radiation sensitivity. Conclusion: These results suggest that differences in the biology of HPV-positive and HPV-negative oropharyngeal cancer may have implications for the management of patients with these different tumors.
6001 Background: HNSCC are etiologically heterogeneous, with one subset primarily attributable to HPV and another to tobacco and alcohol. Methods: Data from SEER9 program registries were used to investigate the potential influence of HPV on incidence and survival of HNSCC in the US from 1973–2003. HNSCCs (N=58,158) were classified by anatomic site as potentially HPV-R (base of tongue; tonsil; oropharynx; N=16,712) or HPV-U (lip; tongue; gum; floor of mouth; palate; other mouth; hypopharynx; ill-defined sites of lip, oral cavity, and pharynx; N=41,446). Joinpoint regression was used to assess incidence trends and life-table methods were used to compare survival for HPV-R and HPV-U HNSCCs. Results: For HPV-R HNSCCs, age-adjusted incidence increased significantly from 1973–2003 (annual percent change [APC] = 0.65), particularly among males (APC=1.02), whites (APC=0.89), and younger ages (APCs for 30–39 = 1.46; 40- 49=1.92; 50–59=0.61, and =60= -0.66). By contrast, HPV-U HNSCC incidence was stable from 1973–1983 and then decreased significantly from 1983–2003 (APC= -2.42). Mean age at diagnosis was younger for HPV-R HNSCC than HPV-U (61.1 vs. 64.5 years; p<0.001), and from 1973- 2003, decreased significantly for HPV-R, but increased for HPV-U. Improvements in overall survival (OS) were observed for HPV-R (all stages) and HPV-U (regional and distant) HNSCC treated by radiotherapy (RT) from 1973–2003, but were more marked for HPV-R HNSCC, e.g. absolute increase in two-year OS for regional disease of 24.4% (vs. 5.8% for HPV-U). OS for HPV-R (local and regional) was significantly better than HPV-U HNSCC if treated by RT, but worse if not so treated. Conclusions: The proportion of HNSCC that is potentially HPV- R increased in the US from 1973–2003, particularly among recent birth cohorts, perhaps due to changing sexual and smoking behaviors. Recent improvements in locoregional control with RT-based therapy may be due in part to a gradual shift in the etiology of the underlying disease. No significant financial relationships to disclose.