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Review/Praca poglądowa

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Human Papillomavirus (HPV) – Structure, epidemiology and pathogenesis

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Wirus brodawczaka ludzkiego (HPV) – struktura, epidemiologia i patogeneza

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Kamal Morshed 1,*, Dorota Polz-Gruszka 2, Marcin Szymański 1, Małgorzata Polz-Dacewicz 2 1 2

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

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 influence prognosis and treatment method choices. © 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Polish Otorhinolaryngology – Head and Neck Surgery Society.

 Pathogenesis Słowa kluczowe:  HPV  rak części ustnej gardła  nowotwory  epidemiologia  patogeneza

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Introduction and epidemiology

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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: [email protected] (K. Morshed). http://dx.doi.org/10.1016/j.otpol.2014.06.001 0030-6657/© 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Polish Otorhinolaryngology – Head and Neck Surgery Society. Please cite this article in press as: Morshed K, et al. Human Papillomavirus (HPV) – Structure, epidemiology and pathogenesis. Otolaryngol Pol. (2014), http://dx.doi.org/10.1016/j.otpol.2014.06.001

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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 influencing it include tobacco smoking, betel chewing, alcohol drinking, HPV infections, nutritional deficiency, poor oral hygiene, and chronic irritation [4–6].

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Virus structure and genome organization

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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 first described papilloma virus. In 1972, the connection between HPV and skin cancer in epidermodysplasia verruciformis was suggested by Stefania Jabłońska and in 1978, Jabłońska 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 identified 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 influencing its development. Subsequent years confirmed 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 prefix ‘‘dyo’’ is used, continuing after the Omega-PVs with Dyodelta-PVs. The current set of human PVs are contained within five 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 identification 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% define a subtype and those of less than 1% define 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 classification 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 specific 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 45–55 nm in diameter and is devoid of cap. The genetic material is in the form of a double-stranded, circular DNA which accounts for 10–13% of the viron mass. The viral genome consists of 7200–8000 base pairs [15] and is organized into three segments; early region (E) which comprises E1, E2, E4–E7 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

Please cite this article in press as: Morshed K, et al. Human Papillomavirus (HPV) – Structure, epidemiology and pathogenesis. Otolaryngol Pol. (2014), http://dx.doi.org/10.1016/j.otpol.2014.06.001

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the virion [17]. No enzymes, lipids nor saccharides were found within the Papillomavirus structure. The virus is stable at pH = 3–7, 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 identified 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 qualification: 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].

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E1 protein

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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].

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E2 protein

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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 [24–26]. 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].

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E4 protein

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E4 protein is a cytoplasmic protein disturbing the structural framework of keratin. It is sometimes detected in the cell nucleus [24, 26] and it influences 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 amplification. Its presence in lesions

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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 confirmation of HPV causality [26]. E4 proteins are visible during the advanced stages of the infection, approximately at the time of genome amplification initiation. E4 proteins of various papillomaviruses have an identifiable 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 cornified envelope may expedite the release of the virus and/or its transmission [28].

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E5 protein

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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].

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E6 and E7 proteins

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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 proinflammatory cytokines [25].

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L1 and L2 proteins

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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].

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Transmission

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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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Please cite this article in press as: Morshed K, et al. Human Papillomavirus (HPV) – Structure, epidemiology and pathogenesis. Otolaryngol Pol. (2014), http://dx.doi.org/10.1016/j.otpol.2014.06.001

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potential to differentiate toward keranocyte. Creating capsid proteins and formation of capsid particles occur only in the terminally differentiated epithelial cells of the superficial 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 first 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 superficial 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 15–24 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].

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Clinical significance of HPV diagnostics

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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 confirmation/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 specified 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 classification 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 specific 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].

Please cite this article in press as: Morshed K, et al. Human Papillomavirus (HPV) – Structure, epidemiology and pathogenesis. Otolaryngol Pol. (2014), http://dx.doi.org/10.1016/j.otpol.2014.06.001

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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 reflects 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 finding 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 influence the overall survival rates. Based on the obtained results, Smith et al. [41] classified 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 profile 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 fixed in the form of paraffin 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 amplified DNA fragments, which allows for HPV DNA replication in the examined material [26]. The incidence of HPV detection varies depending on the type of

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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 paraffin 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 modified by tobacco use. Genetic modifications 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].

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HPV-dependent oncogenesis

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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 60–100% 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, Golusiński et al. [5] present the results concerning the occurrence of cancer in patients under 45 years of age, indicating that they constitute 0.24–9% 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

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Please cite this article in press as: Morshed K, et al. Human Papillomavirus (HPV) – Structure, epidemiology and pathogenesis. Otolaryngol Pol. (2014), http://dx.doi.org/10.1016/j.otpol.2014.06.001

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64% of all patients, whereas in Ringström et al. research [39], men constituted 72% of all patients.

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Summary

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

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Authors' contributions/Wkład autorów

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

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Conflict of interest/Konflikt interesu

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None declared.

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Financial support/Finansowanie

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Supported by Ministry of Science and Higher Education project nr NN403287136.

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Ethics/Etyka

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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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r e f e r e n c e s / p i s m i e n n i c t w o

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