ACTA OTORHINOLARYNGOLOGICA ITALICA 2014;34:299-309
HPV in oropharyngeal cancer:
the basics to know in clinical practice
HPV nel carcinoma dell’orofaringe: le nozioni base da conoscere nella pratica
S.ELREFAEY12, M.A.MASSARO1, S.CHIOCCA3, F.CHIESA1, M.ANSARIN1
1Division of Otolaryngology Head and Neck Surgery, European Institute of Oncology, Milano, Italy; 2Department of
Otolaryngology, Head and Neck Surgery, Alexandria University, Alexandria, Egypt; 3Department 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 signicant 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.
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 (HPV16), 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 worldwide1. 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-
ing2, and a histopathological resemblance3. 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 deaths45. 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)56.
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 cancers2.
Despite this, the incidence of oropharyngeal squamous
cell carcinoma with different characteristics, particularly
S. Elrefaey etal.
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 USA7. 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 20208. There is also a discrepancy in incidence
of OPSCC between developed and developing countries
of oropharyngeal cancer9.
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 countries410.
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 period4 1112.
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 HNSCCs7-10, including mostly OPSCC.
HPV infection in the aetiology of OPSCC was rst shown
by Gillison etal.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 hybridisation81415. 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 HNSCCs16.
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 etal. in 20111317.
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
HPV6 and HPV11, responsible for benign proliferation
of epithelium, and the high-risk oncogenic types HPV16
and HPV18 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-
SCC2 4 1217. 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-
tion1819. Since the majority of HPV-HNSCCs are OPSCC,
we will mainly discuss OPSCC.
Classication 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 stratication 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 proles45172123-27.
Differences between HPV positive
and HPV negative OPSCCs
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 dened, 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-
ity3637. The recent increased incidence of this disease may
thus reect societal changes in sexual behaviour that have
occurred over time in the developed world3839.
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 etal.
HPV in oropharyngeal cancer
which showed that the presence of HPV16 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 HPV16 antibodies preceded oro-
pharyngeal cancers by more than 10 years, underscoring a
temporal association. These data conrmed that oral HPV
infection increases the risk of developing OPSSC40.
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 age40.
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 2004241. 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 mucosa211. Another possibility lies within
the genetic features of HPV16, which accounts for more
than 90-95% of all HPV associated oropharyngeal can-
cers, as it may facilitate survival in the tonsillar crypt
epithelium4344. 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 HPV46.
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-
cic chromosomal gains and losses within tumour cells,
in which OPSCCs with transcriptionally active HPV-
DNA are characterised by occasional chromosomal loss/
allelic imbalance47. Conversely, those lacking HPV-DNA
are characterised by gross deletions that involve entire or
large parts of chromosomal arms3248.
Furthermore, ploidy studies have conrmed 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
typied 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 mutations17.
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
pathology1419 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 recurrence53. 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 tumours45.
Recent studies have shown radiological difference be-
tween HPV-positive and HPV-negative oropharyngeal
cancer. Specically, HPV-positive carcinomas often had
small or even occult primary lesions with well-dened
borders and cystic nodal metastases, whereas HPV-nega-
tive primaries more often had poorly dened borders and
invasion of adjacent muscle5254.
Several studies have shown that patients with HPV-pos-
itive oropharyngeal cancer, identied through PCR, in
situ hybridisation or p16 immunohistochemistry on tu-
mour tissues, have a signicantly improved overall and
disease-free survival compared to patients with HPV-
negative oropharyngeal cancer patients295355-61 (TableI).
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 etal. reported
that these prognostic factors explained only 10% of the
observed survival differences between two subgroups29.
However, other studies reported that survival rates im-
proved among non-smoker HPV positive patients com-
S. Elrefaey etal.
pared to smokers patients even in recurrent tumours,
underscoring once again the benets acquired from
Why does HPV positive orophrangeal cancer have a bet-
1. HPV-positive tumours may harbour fewer or different
genetic alterations, which can be associated with better
response to therapy1764.
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 specic tumour antigens66.
5. Younger age, good performance status, fewer comor-
bidities of HPV-positive oropharyngeal cancer patients
may also contribute to improved survival67.
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
Multiple studies 29 58-61 68-70 tackling this issue have con-
cluded that (TablesI,II):
1. Overall survival rates increase with HPV positive sta-
tus, low EGFR and high p1672.
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 intensication improves outcomes
compared to standard treatment, but overall outcome is
3. Smoking cessation and strategies to target EGFR and
Bcl-xL70 are important adjuncts in the treatment of oro-
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 etal.71 and Bussu etal.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 deintensica-
tion of treatment (TableIII):
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-
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
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
ECOG58 2399 Fakhry, 2008 96 HPV16 DNA ISH 2 2-yr survival (95% vs. 62%)
RTOG29 0129 Ang, 2010 323 HPV16 DNA ISH 4.8 3-yr survival (82.4%, vs. 57.1%)
TROG59 02.02 Rischin, 2010 185 p16 IHC 5 2-yr survival (91% vs. 74%)
DHANCA60 6,7 Lassen, 2011 794 p16 IHC 5 (62% vs. 47%)c, (52% vs. 48%)*
TAX61) 324 Posner, 2011 111 HPV16 DNA PCR 5 5 yr survival (82%-35%)
ISH: in situ hybridisation; IHC: immunohistochemistry; PCR: polymerase chain reaction; OS: overall survival; *accelerated radiotherapy; cconventional 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
signicant and critical considerations when managing
younger HPV positive patients with an longer expected
lifetime. While nonsurgical deintensication 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
Overall Survival Conclusion
radiation + cisplatin
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
Secondary analysis conﬁrmed signiﬁcantly
improved survival in patients with HPV-
positive tumours vs. HPV-negative disease.
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.
5 Fractions w/radiation
6 Fractions w/radiation
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
HPV/p16 positive HNSCC.
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 (ClinicalTrials.gov).
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
J0988 NCT01088802 Phase I/II 60 IMRT (lower dose) + cisplatin Toxicity/LRC
NCT01585428 Phase II -
Fluderabine/cyclophosphamide/ Young TIL
Tumour response /
RTOG 1016 NCT01302834 Phase III 706 IMRT hyperfractionation+cisplatin vs.
IMRT hyperfractionation +cetuximab
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
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 etal.
showing great promise2958-6170-72, minimally-invasive ap-
proaches, especially transoral robotic surgery (TORS),
have gained more favour by achieving the satisfactory
oncological outcomes without compromising functional
outcome7374. Indeed, three-dimensional visualisation al-
lows the ability to manipulate75 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 therapies77. These in-
clude use of concurrent chemotherapy 78 and effective
lower doses of radiotherapy, which contribute to a de-
crease of swallowing dysfunction79. The postoperative
target volume for radiation is typically smaller, and with
modern techniques such as intensity modulated radio-
therapy (IMRT) this procedure can signicantly 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 stratied 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 stratied by
smoking status, with the assumption that patients without
a smoking history are predominantly HPV positive82.
The failure to show statistically signicant 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 studied83.
New multi-institutional studies are needed to conrm 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 cells84. 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 beneted 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 carcinoma85. 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 cancers86.
Two FDA-approved HPV prophylactic vaccines are
currently available87. The quadrivalent vaccine was ini-
tially approved in the US in 2006, and is composed of
four HPV type-specic 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 cancers87 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 efcacy of the quadrivalent vaccine was
100% in preventing HPV16 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 HPV6, 11, 16 and 18 related genital warts89.
The bivalent vaccine is 98.1% efcacious in HPV16 and
18 related CIN 2/3 prevention90.
The Advisory Committee on Immunization Practices
(ACIP) and the Centers for Disease Control and Preven-
tion (CDC) recommends889091:
be started at 9 years of age;
• routine vaccination recommended for both men who
have sex with men (MSM) and immunocompromised
individuals aged 22 through 26 years;
• canbegiventolactatingwomen, patients withminor
HPV in oropharyngeal cancer
acute illnesses and women with equivocal or abnormal
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 one89, inducing strong
immune memory with persistent antibody up to 6.4 years
(bivalent) and up to 9.5 years (HPV16 VLP used in quad-
rivalent) thus entailing long-term duration of protection
against infections caused by pathogenic HPVs and their
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
alone93. 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 HPV16, 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 importance94.
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 studies9596. 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 HPV16 E7
protein, considered as a tumour specic 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 use94.
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 studies97. 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 radiotherapy98.
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 cetuximab99. 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 results71 72.
Thus, there is clearly a need for new surrogate markers for
HPV infection to give patients the best treatment strate-
The presence of HPV16 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 etal.
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
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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+390255210169. E-mail: email@example.com
Received: January 14, 2014 - Accepted: April 24, 2014