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otolaryngologia polska 68 (2014) 213219

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Leading article/Artyku redakcyjny


Review/Praca pogldowa

Human Papillomavirus (HPV) Structure,


epidemiology and pathogenesis
Wirus brodawczaka ludzkiego (HPV) struktura,
epidemiologia i patogeneza
Kamal Morshed 1,*, Dorota Polz-Gruszka 2, Marcin Szymaski 1,
Magorzata Polz-Dacewicz 2
1
2

Katedra i Klinika Otolaryngologii i Onkologii Laryngologicznej Uniwersytetu Medycznego w Lublinie, Poland


Zakad Wirusologii Uniwersytetu Medycznego w Lublinie, Poland

article info

abstract

Article history:

The number of cancers is constantly increasing. An important role in the etiology of

Received: 13.04.2014

many of them is played by the viral factor, by oncogenic viruses, such as the Human

Accepted: 18.06.2014

Papillomavirus. The article shows current epidemiological situation and describes the

Available online: 27.06.2014

structure of the virus and modes of transmission. It also explains the role of HPV infection in cancer with particular emphasis on oropharynx and head and neck cancer.

Keywords:
 HPV
 Oropharynx cancer
 Tumors
 Epidemiology

Summarizing, HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may inuence prognosis and treatment method choices.
2014 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by
Elsevier Urban & Partner Sp. z o.o. All rights reserved.

 Pathogenesis
Sowa kluczowe:
 HPV
 rak czci ustnej garda
 nowotwory
 epidemiologia
 patogeneza

Introduction and epidemiology


The number of cancers is constantly increasing and an
important role in the etiology of many of them is played by

the viral factor by oncogenic viruses. Approximately 20%


of human cancers are associated with viral infections [1]. In
this group there is among others the Human Papillomavirus.
The article describes contemporary epidemiological situation, the structure of the virus, and modes of transmission.

* Corresponding author at: ul. Sapiehy 7, 20-093 Lublin, Poland. Tel.: +48 601959835.
E-mail address: kamal1@op.pl (K. Morshed).
http://dx.doi.org/10.1016/j.otpol.2014.06.001
0030-6657/ 2014 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights
reserved.

214

otolaryngologia polska 68 (2014) 213219

It also explains the role of HPV infection in cancer and


possible clinical implications.
Currently, there is a visible constant increase in the
incidence of malignant tumors. In 2010, 140 000 new cases
and 92 500 deaths were reported. The increase in incidence
compared to previous years amounted to approximately 2.5
thousand new cases. Malignant tumors are the second,
after cardiovascular diseases, cause of death in Poland and
in 2010 they accounted for 26% of deaths in men and 23%
in women. In 2010, in Poland 2709 men were diagnosed
with lip, mouth or throat cancer (this amounted to 9.84% of
all cancers) and 1763 died (3.4%), at the same time 960
women were diagnosed (1.4%) and 464 (1.1%) died. The lip,
oral cavity and throat cancer account for 9.84% of all
cancers in men and 1.4% in women. The incidence of
larynx cancer amounted to 1924 cases, which accounted for
2.75% of all cancers in men. The mortality among men
equaled to 1358 (2.62%) [2]. Oral cancers represent 2.4% of
all cancers in men and 1.1% of cancers in women, which in
turn accounts for approximately 30% of all malignant
neoplasms of head and neck, in comparison malignant
tumors of the mouth and neck represent approximately
12% of all malignant tumors. In Poland, oral cancer is
second to larynx cancer when it comes to malignant
tumors of the head and neck [3].
Squamous cell carcinoma constitutes 90% of all cases of
cancers localized in the oral and oropharyngeal cavity.
Etiology of OSCC is multifactorial, and the factors inuencing it include tobacco smoking, betel chewing, alcohol
drinking, HPV infections, nutritional deciency, poor oral
hygiene, and chronic irritation [46].

Virus structure and genome organization


The papillomaviruses are a big group of small, non-enveloped DNA viruses, which can induce squamous epithelial
tumors (warts and papillomas) in many different anatomical
localizations. A strong correlation between HPV and cancer
of the cervix uteri [7], penis, vulva, vagina, anus and
oropharynx (including base of the tongue and tonsils), oral
cavity, larynx, and hypopharynx has been recorded by the
International Agency for Research on Cancer. Of the estimated 12.7 million new cancers occurring in 2008 worldwide,
4.8% were attributable to HPV infection [7].
Cottontail rabbit papillomavirus was the rst described
papilloma virus. In 1972, the connection between HPV and
skin cancer in epidermodysplasia verruciformis was suggested by Stefania Jaboska and in 1978, Jaboska and Gerard
Orth from the Pasteur Institute, discovered HPV-5 in
skin cancer [8]. In 1977, Harald zur Hausen published
a hypothesis that HPV plays an important role in the cause
of cervical cancer [9]. In 1983 and 1984 zur Hausen and his
collaborators identied HPV16 and HPV18 in cervical cancer
[10] and in the course of the next 12 years of research it has
been recognized as a carcinogen inuencing its development. Subsequent years conrmed the carcinogenicity of
HPV 16 in relation to oropharynx and possibly to the oral
cavity. The research was conducted by IARC (International
Agency for Research on Cancer) [8, 11].

According to recent recommendations of the International Committee on Taxonomy of Viruses (ICTV) [12] this
virus belongs to the Papillomaviridae family, which contains
29 genera (30 genera according to ICTV) formed by 189
papillomavirus (PV) types isolated from humans (120 types),
non-human mammals, birds and reptiles (64, 3 and 2 types,
respectively). To accommodate the number of PV genera
exceeding the Greek alphabet, the prex dyo is used,
continuing after the Omega-PVs with Dyodelta-PVs. The
current set of human PVs are contained within ve genera,
whereas mammalian, avian and reptile PVs are contained
within 20, 3 and 1 genera, respectively [13]. The L1 ORF is
the most conserved region within the genome and has
therefore been used for the identication of new papillomavirus types. A new papillomavirus isolate is recognized if
the complete genome has been cloned and the DNA
sequence of the L1 ORF differs by more than 10% from the
closest known type. Differences in homology ranging between 2% and 10% dene a subtype and those of less than
1% dene a variant [8].
For each genus there are biological properties and characteristics genome organization. Some Alpha-papillomavirus (which among others include types 32, 10, 61, 2, 26, 53,
18, 7, 16, 6, 34, 1, 54) are responsible for mucosal and
cutaneous lesions in humans and primates, high- and lowrisk classication based on molecular biological data: highrisk types (pre- and malignant lesions) immortalize human
keratinocytes; low-risk types (benign lesions) [14].
Beta-papillomaviruses (types 5, 9, 49) are responsible for
cutaneous lesions in humans. Infections exist in latent form
in general population and are activated under conditions of
immune suppression. Gamma-papillomaviruses are responsible for cutaneous lesions in humans, histologically distinguishable by intracytoplasmic inclusion bodies specic for
the type of species. Mu-papillomaviruses are responsible for
cutaneous lesions. Nu-papillomaviruses are responsible for
benign and malignant cutaneous lesions. This genus is
responsible for diseases in humans. Alpha-HPVs infect
mucosal tissue, beta-, gamma-, nu- and mu-papillomaviruses infect the cutaneous site [14].
Delta-papillomavirus, Epsilon-papillomavirus, Zeta-papillomavirus, Eta-papillomavirus, Theta-papillomavirus, Iotapapillomavirus, Kappa-papillomavirus, Lambda-papillomavirus, Xi-papillomavirus Omikron-papillomavirus, and Pipapillomavirus are responsible for diseases in animals [14].
HPV is 4555 nm in diameter and is devoid of cap. The
genetic material is in the form of a double-stranded, circular
DNA which accounts for 1013% of the viron mass. The viral
genome consists of 72008000 base pairs [15] and is organized into three segments; early region (E) which comprises
E1, E2, E4E7 and represents 50% of the genome, the late
region (L) consisting of L1 and L2 which represents 40% of
the genome and the genomic regulatory region (10% of the
genome) [16]. All encoding protein fragments are located on
a single DNA strand. These DNA fragments described as
ORF (Open Reading Form) can be divided into early and late
depending on the time of viral DNA replication occurrence
[8]. Early fragments are involved in the regulation of DNA
replication (E1, E2) transcription (E2) and cell transformation
(E5, E6, E7) and late fragments encode structural proteins of

otolaryngologia polska 68 (2014) 213219

the virion [17]. No enzymes, lipids nor saccharides were


found within the Papillomavirus structure. The virus is stable
at pH = 37, becomes inactivated at 70 8C, and is killed after
30 min in the temperature above 50 8C. It is resistant to
solvents, acids and X-ray. In general, virus infection leads to
the destruction of the cell; however, it may also cause cell
transformation and tumor development. There have been
over 100 different types of viruses identied up to date [18].
Within this group there are 118 types which nucleotide
sequence has been elucidated [14]. They can be divided into
two subgroups: those with low oncogenic potential; 6, 11
[17, 19] and with a high oncogenic potential; 16, 18, 31, 33,
35, 45, 51, 52, 55, 58, 59, 68, 73, 82, 83 [17], some authors also
include 39, 56 and 79 in the high risk type [20]. It is essential
to underline that this division in not clearly established as
there are authors who propose a different qualication: lowrisk types; 6, 11, 42, 43, 44, intermediate risk types 31, 33, 35,
51, 52, and high risk types; 16, 18, 45, 56 [21], or high risk
HPV types; 16, 18, 31, 33 [22].

E1 protein
This protein is necessary for viral DNA replication. It is also
a repressive agent in transcription and inhibits DNA replication, maintaining the episomal copies number within the
cell at the same level [23, 24].

E2 protein
Protein E2 is also involved in the DNA replication process; it
combines with E1 protein and jointly they initiate it,
especially HPV 6, 11, 16 [23]. It is also responsible for coding
proteins which regulate viral DNA transcription [24]. E2 also
plays an important role in cell transformation, initiating and
inhibiting apoptosis, transcriptional regulation, and in the
modulation of the immortalizing and transformation potential of HPV [23, 25, 26]. E2 inactivation affects the development of tumor lesions by promoting the expression of E6
and E7, and active E2 inhibits the transcription of E6 and E7,
causing an increase in p53 expression and apoptosis of the
infected cells [2426]. The two proteins are essential in
maintaining the replication of the virus and synthesis of the
genes through the course of the differentiation process of
the epithelium. They are also necessary for the virus to
complete its replicable cycle [27].

215

implies its role in the staging of the disease. This study


authenticates previously made suggestions for the importance of the E4 biomarker in the diagnosis and diseasestaging, and broadens the E4 approach to include the
conrmation of HPV causality [26].
E4 proteins are visible during the advanced stages of the
infection, approximately at the time of genome amplication initiation. E4 proteins of various papillomaviruses have
an identiable modular framework even though they exhibit
diversity at the primary amino acid sequence level and can
be accrue to high levels in the upper epithelial layers where
virus particles accumulate. Any analyses of E4 function
must take this into consideration. What is more, it has been
stated that E4's potential to disrupt the cellular keratin
network and the accumulation of cornied envelope may
expedite the release of the virus and/or its transmission
[28].

E5 protein
E5 protein is involved in the transformation and participates
in viral DNA replication [23, 24]. This protein also allows for
the infected cell to avoid being recognized by the immune
system [26].

E6 and E7 proteins
E6 and E7 proteins play a central role in HPV-dependent
malignant transformation. They cause the impairment of
the control of cell cycle regulation and cell maturation [24,
25, 29]. E6 connects to the p53 protein, leading to its
proteolytic degradation [25, 26, 30]. Previously, however, E6
connects to the accessory protein (AP), which acts as
a ubiquitin ligase, and the combination of E6+E6+AP with
the degradation area of p53 causes p53 proteolysis and the
elimination of all known functions of p53 [25, 27]. This may
result in an uncontrolled replication of HPV 16 and/or 18
infected cells [23]. E7 protein binds and inactivates the pRb
protein, leading to its degradation, which results in the cell's
loss of control over the cell cycle [30, 31]. E6 and E7
oncoproteins may undergo phosphorylation and to various
degrees bind to the target proteins [23, 25]. E6 and E7
proteins' expression is controlled by E2 protein, a host
cellular protein YY1 and proinammatory cytokines [25].

L1 and L2 proteins
E4 protein
E4 protein is a cytoplasmic protein disturbing the structural
framework of keratin. It is sometimes detected in the cell
nucleus [24, 26] and it inuences the formation of the HPV-1
triggered nodules [23]. Its role in the regulation of cell cycle
may also be possible [24]. As a result of protein E4 activity,
the thickening of the spinous and horned layer of the
epidermis and the koilocytosis of the epidermis occur [26].
E4 protein is expressed at increased levels in cells supporting the viral genome amplication. Its presence in lesions

L1 and L2 proteins are capsid proteins of the virus, wherein


L1 is the major protein and L2 is the minor capsid protein
[23, 25].

Transmission
Papillomaviruses are characterized by epiteliotropizm. Target cells are the cells found in germ layers of the skin and
in mucous membranes; keranocyte or the cell having

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otolaryngologia polska 68 (2014) 213219

potential to differentiate toward keranocyte. Creating capsid


proteins and formation of capsid particles occur only in the
terminally differentiated epithelial cells of the supercial
layer of the epithelium [26, 29] and the full development
cycle can occur only in the differentiating epithelial cells
[32, 33]. Expression of viral proteins is strictly regulated and
combined with squamous cell differentiation. Because the
differentiating cells move toward the surface, that is where
the virus accumulates [17]. DNA replication occurs in the
nucleus of the host cell, and these viruses proliferate only
in differentiating squamous epithelium, making it impossible to conduct research in conventional cell cultures [21],
hence the necessity of using molecular biology methods in
diagnostics and research. Epidermis is composed of the
layered keratinocytes. The deepest layer of cells is located
on the basal membrane, then on the spinosum, granular,
intermediate and horny layer. Only the two rst layers are
capable of divisions. These viruses cause the formation of
warts on the skin, mucous membranes of the oral cavity,
respiratory tract, throat and genitals and also are the cause
of urethral warts. The upper respiratory tract infection is
possible through two mechanisms: transmission from
mother to child by the infected birth canal and through
sexual contacts [17, 34]. Skin injuries, micro injuries of the
epidermis and the mucous membranes, and skin abrasions
[21, 23] are an additional way for the virus to enter the body.
These factors facilitate the penetration of the virus into the
stem cells of the basal layer. Infection causes growth
stimulation and the formation of pathologic cells, additionally in the virus replication, the correlation with differentiating epidermal cells is visible. Virons are also present in
supercial layers, which facilitate the transfer of infection
during contact [16, 17, 21].
American Centers for Disease Control and Prevention
rapport of 2013 shows that HPV constitutes the majority of
newly acquired STI's (sexually transmitted infections).
Approximately 20 million new cases of STI's are reported
annually, among which HPV is the most common sexually
transmitted virus in the USA. Nearly 200 strains of HPV have
been enumerated, majority of which are harmless, however
over 40 of them can infect genital and oral mucosa of both
males and females, and out of all 9 are considered to cause
cancer. Each day approximately 12 000 American residents
aged 1524 are infected with genital HPV. There are many
ways of acquiring oral and oropharyngeal HPV infections
such as sexual contacts, kissing between partners of family
members or autoinoculation. Vertical transmission from
mother to child during childbirth is also possible. Benign
lesions of the upper aerodigestive tract may also be caused
by mucosotropic human papillovirus strains [35].

Clinical signicance of HPV diagnostics


HPV DNA is detected in a number of changes including mild
changes focal epithelial hyperplasia (heck disease), oral
squamous papilloma, oral condyloma acuminate, common
warts (verruca vulgaris), oral lichen planus (HPV types 11
and 16 are commonly found in about 87% of patients), oral
leukoplakia (commonly caused by HPV types 6, 11 and 16)

and malignant changes such as the malignant oral squamous cell carcinoma, which was documented in connection
with 20% of OSCC cases as reported by Syrjanen in 1983 [36].
From a clinical point of view, the conrmation/exclusion
of HPV DNA presence in OPSCC is extremely important as
there exists a relationship between the presence of the virus
in oropharyngeal squamous cell carcinoma and prognosis
and therapy choices. Some authors believe that a more
favorable prognosis concerns the HPV-positive OPSCC
patients. Those patients are considered to respond to
treatment in a better way, they are characterized by higher
survival rates and lower risks of recurrence compared with
HPV-negative patients [37]. What is more, those patients do
not require radiation or chemotherapy [38]. Many authors
suggest testing patients diagnosed with OPSCC for HPV,
which would allow for proper planning of treatment and to
recognize HPV positive squamous cell carcinoma and
HPV negative squamous cell carcinoma as distinct clinical
and pathological entities [36]. It seems that patients with
HPV-positive cancers have better treatment prognosis [39,
40].
The HPV status of the tumor among patients diagnosed
with oropharyngeal cancer is an independent and strong
prognostic factor. HPV-positive cancer has been more frequent among non-smokers and those who have a shorter
history of smoking than among heavy smokers. It was also
connected with other favorable prognostic factors such as
younger age, white race, better performance status, lack of
anemia, and smaller primary tumors. Both groups had the
same tumor HPV status. However, patients with HPVpositive tumors had a 58% reduction of the risk of death
compared with patients with tumors that were HPV-negative and a 51% reduction in the possibility of having
a relapse or dying. After imputation for missing data, the
outcomes were comparable. Tumors were tested not only
for the HPV expression but also for cyclin-dependent-kinase
inhibitor p16, which is a known biomarker of the HPV
oncogenic function, and is effectuated as the outcome of
pRb inactivation by the human papillivirus E7 oncoprotein.
What is more, its presence is only minimally discernible in
HPV-negative tumors because of the genetic or epigenetic
silencing [41, 42].
There is a strong congruency between the HPV status of
the tumor, as specied by in situ hybridization, and p16
expression. HPV-16 in situ hybridization assessment is
sensitive to single viral copies, and a positive outcome is
highly correlated with the HPV E6 and E7 oncogene expression. This is a standard method for determining whether
a tumor is HPV associated [43].
Problematic for this method is the unknown sensitivity
to probing for non-HPV-16 types, which are estimated to be
between 5 and 10% of HPV-positive OSCC [44]. Therefore
incorrect classication of HPV-positive as HPV-negative
tumors may account for a slightly larger reduction in death
risk when the analysis was based on the p16 expression in
comparison to the HPV presence. The effectiveness of p16expression assay is that it is not specic for the HPV type, in
comparison to the in situ hybridization assay; hence p16
expression status is a good replacement for tumor HPV
status [41].

otolaryngologia polska 68 (2014) 213219

The favorable prognosis for HPV-positive cancer in comparison to that for the HPV-negative squamous-cell carcinoma seems to be multifactorial. Recognized favorable
factors connected with the HPV-positive subgroups account
for approximately 10% of the observable difference in the
outcome. Higher local-regional control, which reects
a higher innate susceptibility to radiation or radiosensitization using cisplatin, may result in a greater survival rate
among patients with HPV-positive cancer. Although rates of
response to induction chemotherapy are higher in HPVpositive patients than among HPV-negative ones, treatment
with cisplatin alone did not appear to affect in different
ways the suppression of occult metastases. Second primary
tumors, largely related to smoking, were less common in
patients with HPV-positive tumors, a nding that is sequacious to lower tobacco exposure in this subgroup. However,
death rates from second primary tumors are similar in both
subgroups; thus do not inuence the overall survival rates.
Based on the obtained results, Smith et al. [41] classied
patients with OSCC into three categories taking into account
the risk of death: low risk, with a 3-year rate of overall
survival of 93.0%; intermediate risk, with a 3-year rate of
70.8%; and high risk groups with a 46.2% chances of survival
within the 3-year period. Patients diagnosed with HPVpositive tumors (except for smokers with high nodal stage i.
e. N2b to N3 who were considered to be at an intermediate
risk) were considered to be at low risk, whereas, patients
who were diagnosed with HPV-negative (except nonsmokers
with T2 or T3 tumors considered to be at an intermediate
risk) were considered to be at high risk. Obtained data
indicate that positive and negative HPV statuses and status
concerning tobacco smoking are major, independent of each
other, prognostic factors for patients with OSCC. This may
be caused by the fact that by determining the molecular
prole of cancer the response to therapy also differs.
Obtained results suggest that the therapy for both types of
HPV should vary [41]. Currently, the AJCC staging system
does not mirror the different treatment results and survival
rates for HPV-positive and HPV-negative patients with head
and neck squamous cell cancer [45]. There have been few
cases reported which support inverse connection between
HPV status of the tumor and p-53 inactive mutation
presence in HNSCC. A more advantageous response to
chemotherapy and radiation visible in HPV-positive tumors
in comparison to negative was observed [41]. This may be
caused by the presence of untapped p53 broker apoptosis to
chemotherapy-induced stress [46].
There are many diagnostic materials that could be the
aim of HPV diagnosis: smear tests, frozen intraoperative
material or tissue xed in the form of parafn blocks. It is
impossible to culture the human papillomavirus in cell
cultures; thus the methods applicable in the study and
diagnosis of virus infection are the methods of molecular
biology, mainly PCR (Polymerase Chain Reaction) [47]. The
aim of the PCR technique is to obtain multiple copies of the
DNA sequence sought, by means of repeated replication. In
result, after 20 cycles there is a million-fold increase in the
amount of amplied DNA fragments, which allows for HPV
DNA replication in the examined material [26]. The incidence of HPV detection varies depending on the type of

217

method used and the examined tissue. PCR is the most


sensitive of the all available methods. Quantitative PCR
method has an additional advantage of distinguishing mild
infections from contamination and determining the amount
of viruses in the sample [9]. The largest amount of DNA is
found in the freshly frozen tissue ( 70 8C), as opposed to
tissues preserved in parafn or formalin, as the last two
methods result in DNA degradation, especially during longterm storage [48].
Epidemiological data indicate that smoking is not that
relevant for the development of HPV-positive OSCC, however, our data show that the biological behavior of an HPVpositive tumor may be modied by tobacco use. Genetic
modications caused by tobacco-assisted cancers may result
in HPV-positive tumors being less responsive to treatment.
The probability of such genetic changes seems to be
increasing with the number of pack-years of tobacco smoking [42].

HPV-dependent oncogenesis
Highly oncogenic HPV types: 16 and 18 induce precancerous
lesions, increasing the risk of cancer development. The
transition from dysplasia to invasive cancer appears to be
associated with the integration of viral DNA into the
genome of host cells [16]. Almost all types of HPV replicate
in the host's cell nucleus, apart from the types with low
oncogenic potential which do not bind with the DNA of
host's cells and replicate as outer chromosomal episomes or
plasmids. In case of an infection with HPV-types that have
high oncogenic potential, integration of the viral DNA and
the host's chromosomes occurs [6].
HPV prevalence in squamous cell carcinoma of the oral
cavity and oropharynx is very diverse, ranging from 8% to
74% [15, 49, 50].
HPV 16, which has a high oncogenic potential, is most
frequently isolated in the squamous cell carcinoma of the
head and neck. HPV 16 was found in 60100% of the HPV
positive squamous cell carcinomas; Praetorius et al. [51]
70%, Tachezy et al. [52] 51.5%, Balaram et al., 74%Wilczynski
et al., 64%, Ostwald et al., 62%, Cruz et al., 55%, Koh et al.,
52%, Elamin et al., 50%, Miguel et al., 8%, and Holladay et al.,
19% [all authors cited in accordance with [15]]. Although
these data show extreme values, however the average
prevalence of HPV 16 appears to be approximately 90% of all
HPV types [15, 40].
Squamous cell carcinoma of the oral cavity is most
commonly observed among people above 60 [53]; however,
current data reveal that this cancer occurs in younger and
younger people, Golusiski et al. [5] present the results
concerning the occurrence of cancer in patients under 45
years of age, indicating that they constitute 0.249% of all
cases, and this problem arose a few years ago. In Poland, in
2002, 80.8% of cancers of the oral and oropharynx cavity
concerned patients aged 50 and older, and 19.2% concern
younger patients [54].
Squamous cell carcinoma of the oral and oropharynx
cavity is more frequent among men than women. In the
research conducted by Ritchie et al. [49], men constituted

218

otolaryngologia polska 68 (2014) 213219

64% of all patients, whereas in Ringstrm et al. research


[39], men constituted 72% of all patients.

Summary
HPV infection plays an important role in carcinogenesis of
the oropharynx tumors. The presence of viral genetic
material in the tumor may inuence prognosis and treatment method choices.

Authors' contributions/Wkad autorw


KM, DP-G participated in study design, data collection,
literature search, acceptance of nal manuscript. MSz, MP-D
performed data collection, literature search, acceptance of
nal manuscript.

Conict of interest/Konikt interesu


None declared.

Financial support/Finansowanie
Supported by Ministry of Science and Higher Education
project nr NN403287136.

Ethics/Etyka
The work described in this article has been carried out in
accordance with The Code of Ethics of the World Medical
Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; Uniform Requirements for manuscripts submitted to
Biomedical journals.

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