Relationship of human papillomavirus with diseases of the oral cavity

Med Clin (Barc). 2019;153(4):157–164

www.elsevier.es/medicinaclinica

Review

Relationship of human papillomavirus with diseases of the oral cavity夽 ˜ a , Laia Capdevila b , Enric Jané-Salas c,∗ Núria Boguná a

Facultad de Medicina y Ciencias de la Salud, Odontología, Universidad de Barcelona, Barcelona, Spain Servicio de oncología médica, Xarxa Sanitària i Social de Santa Tecla, Tarragona, Spain Unidad Medicina Bucal, Departamento de Odontoestomatología, Facultad de Medicina y Ciencias de la Salud, Odontología, Universitat de Barcelona, Oral Health and Masticatory System Group, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), l’Hospitalet de Llobregat, Barcelona, Spain b c

a r t i c l e

i n f o

Article history: Received 10 January 2019 Accepted 18 February 2019 Available online 18 July 2019 Keywords: Human papillomavirus Oropharyngeal squamous cell carcinoma Head and neck squamous cell carcinoma

a b s t r a c t Over the last few decades, the human papillomavirus (HPV) infection has emerged as a new epidemic and become a health issue due to its involvement in several cancers affecting the cervix, the anogenital region and the oropharynx. In this review, we aim to understand and explain the distinctive features of HPVrelated OPSCC (Oropharyngeal Squamous Cell Carcinoma) based on its epidemiological data, risk factors, specific topography, HPV subtypes most frequently involved, HPV-status diagnosis, clinical behaviour, prognosis, treatment, and preventive measures. In addition, the relationship of HPV with the development of other head and neck carcinomas and benign lesions of the oral cavity will also be discussed. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,

El virus del papiloma humano y su relación con la patología de la cavidad oral r e s u m e n Palabras clave: Virus del papiloma humano Carcinoma escamoso de orofaringe Carcinoma escamoso de cabeza y cuello

Durante las últimas décadas, la infección por VPH (Virus del Papiloma Humano) ha emergido como una nueva epidemia y se ha convertido en un problema de salud debido a su asociación con diversos cánceres localizados en el cuello uterino, región ano-genital y orofaringe. En esta revisión, pretendemos entender y explicar las características distintivas de los CEO (Carcinoma Escamoso de Orofaringe) relacionados con el VPH, en términos de epidemiología, factores de riesgo, topografía específica, subtipos de VPH más frecuentemente involucrados, técnicas de detección del VPH, comportamiento clínico, pronóstico, tratamiento y prevención. También se discutirá la relación del VPH con el desarrollo de otros cánceres de cabeza y cuello y con la patología benigna de la cavidad oral. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,

Introduction The first description of cervical cancer was made by Hippocrates more than 2000 years ago.1 In 1842, Rigoni-Stern noticed a greater incidence of this condition among married women, widows and prostitutes, which contrasted with a low frequency of celibate nuns and virgin women.2 Even so, it was not until 1980 when Gissman and Zur Hausen, winner of the Nobel Prize in Medicine in

夽 Please cite this article as: Boguná ˜ N, Capdevila L, Jané-Salas E. El virus del papiloma humano y su relación con la patología de la cavidad oral. Med Clin (Barc). 2019;153:157–164. ∗ Corresponding author. E-mail address: [email protected] (E. Jané-Salas). ˜ S.L.U. All rights reserved. 2387-0206/© 2019 Elsevier Espana,

2008, established a relationship between the human papilloma virus (HPV) and cervical cancer.1 Currently, HPV is also associated with genital, anal, and head and neck cancers. HPV is part of the Papillomaviridae virus family. It is a nonenveloped virus, formed by a 60 nm diameter icosahedral capsid containing a deoxyribonucleic acid (DNA) double-stranded circular molecule of 8000 base pairs. Only one of the chains is used for transcription and it can differentiate 3 genomic regions with approximately 10 open reading frames (ORF), which are nucleotide sequences that can encode a protein.3 Subdivided into:

• Early Region: It encodes non-structural proteins necessary for viral replication (E1, E2, E4–E7). E6 and E7 are oncogenes.

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DNA replication (uninfected cell)

pRB

E2F

Cell proliferation

Cell damage

p53

Apoptosis

E7 DNA replication (infected cell)

pRB

E2F

Cell proliferation E6 Cell damage

p53

Apoptosis

Fig. 1. Comparative diagram showing normal deoxyribonucleic acid (DNA) replication versus the mechanism of the human papilloma virus in the oncogenic process.

• Late Region: It encodes the proteins of the capsid, L1 (major protein) and L2 (minor protein). Both with immunogenic capacity. • Long Control Region: It is a non-coding regulatory region that controls the processes of transcription and replication.4 The Papillomaviridae family is classified according to differences in DNA sequence in genus, species, types, subtypes and variants.3 205 types of HPV have been described in humans to date, all of them with tropism for keratinized or non-keratinized stratified squamous epithelium. Genital HPV (with mucosal tropism) belongs to the alpha genus and HPV associated with epidermodysplasia verruciformis (with cutaneous tropism) to the beta genus.5 HPVs with mucosal tropism can be subdivided into high-risk and low risk types according to their clinical impact6 : ◦ ◦

Low risk: The most common are HPV-6 and 11, which cause genital warts and focal hyperplasia in the oral epithelium. High risk: The most common are HPV-16 and 18, involved in cervical, anal, genital and oral cancer.

HPV is spread by direct contact (skin–skin, skin–mucosa and mucosa–mucosa). Genital HPV infection occurs through sexual transmission and, to a lesser extent, through the birth canal.5,6 Through microtraumas, HPV manages to infect the undifferentiated basal cells and replicates as the differentiated cells reach more superficial layers of the epithelium, thus perpetuating the infection.3 HPV infections can disappear spontaneously in 12–24 months.7 It is believed that infections can be eliminated by the immune system, be self-limiting, or go into a state of latency. Other times, the infections are persistent and can potentially develop malignant lesions, and even cancer.5 Infections that persist may take about 12 years to develop squamous cell carcinoma.8 The mechanisms by which some HPV infections manage to evade the immune system and become malignant are still poorly understood.9 Fortunately, the majority of oral HPV infections (0–80%) are transient, and the persistence of these infections is rare.10 A longer duration of infection of high-risk HPV, especially of HPV-16, has been observed.5 The oncogenic process begins with the integration of highrisk HPV DNA into the genome of the host cell. So, E7 joins the retinoblastoma protein, the protein responsible for regulating the cell cycle, and activate the E2F transcription factor, which in turn initiates DNA replication. In an uninfected cell, p53 should induce cell death. But in the cell with integrated HPV, E6 degrades p53, preventing apoptosis. Thus, the sustained action of the E6 and E7 oncogenes causes a lack of control in the cell cycle and favours the development of a possible cancer4 (Fig. 1). The global prevalence of patients infected with HPV is 9–13% (630 million people) and each year 6 million new cases are diagnosed.11 HPV infection is the most prevalent sexually transmitted infection and it is estimated that the majority of the sexually

active population will be infected during their lifetime.5 There are geographical differences, with underdeveloped countries showing higher figures than the developed ones. The highest figures occur in young women under 25 years of age and the prevalence decreases with age.12 This tendency is reflected only in genital infections, since the geographical distribution is reversed in oral infections. In our setting, according to a retrospective observational study conducted at the Vall d’Hebron Hospital between 2010 and 2011, the incidence of HPV in oral cavity and oropharynx squamous cell carcinomas is 12.3%.13 HPV-16 has the highest prevalence. In fact, the incidence of highrisk HPV infections is higher than that of low-risk HPV infections. HPV types with the highest incidence of infection are 16, 18, 31, 33 and 51.5 The prevalence of HPV infections is higher in the anogenital region than in the oral cavity.14 Regarding HPV in the development of pathology in the oral cavity, the oral manifestations due to its infection are diverse. HPV infection can be subclinical, developing benign or potentially malignant lesions. It can end up causing a squamous cell carcinoma. HPV detected in normal oral mucosa are types 2, 6, 7, 11, 13, 16, 18, 31, 33 and 35.15 HPV signs and symptoms in the oral cavity can be classified as follows: • Subclinical infection: The prevalence of HPV in normal oral mucosa is 11% with an interval of 0–81.1%.11 • Benign lesions: HPV causes asymptomatic lesions predominantly verruciform. These may be single or multiple, with smooth or rough surfaces, and white, pink or red depending on the degree of epithelium keratinization. The benign lesions that HPV causes in the oral cavity include vulgar warts, squamous papilloma, condylomata acuminata, and focal epithelial hyperplasia. These usually appear on the tongue, soft palate and lips. They are mostly related to low-risk HPV (HPV-2, 4, 11, 13 and 32) and, to a lesser extent, to high-risk HPV.11 • Potentially malignant lesions: The role of HPV in these lesions is controversial. According to Syrjänen et al., there is a positive association between HPV and potentially malignant lesions (Odds Ratio = 3.87.15 It is believed that HPV may be involved in the development of leukoplakia, proliferative verrucous leukoplakia, erythroplasia, and oral lichen planus. These lesions are closely related to the high-risk genotypes 16 and 18.11 • Malignant lesions: HPV is associated with head and neck squamous cell carcinoma (HNSCC), originating more frequently in the oropharynx, with type 16 being responsible in most cases16 (Fig. 2). While squamous cell carcinomas of the oral cavity are decreasing, confirming the success of campaigns against smoking and alcohol, Oropharyngeal Squamous Cell Carcinoma (OSCC) associated with HPV (HPV-OSCC) are progressively increasing due to changes in the sexual habits of the population during the last

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Discussion HPV is included in the category of oncogenic viruses and is considered responsible for 5.2% of all cancers.17,18 It is mainly associated with cervical, anal, genital and head and neck cancers.19 Next, the distinctive characteristics of HPV-OSCC are described. Incidence

Fig. 2. Human papilloma virus-related tumour in tonsillar area. Image courtesy of the Medical Oncology Service of Xarxa Sanitària i Social de Santa Tecla, Tarragona.

decades.11 HPV infection has emerged as a new epidemic and its implication in OSCC makes it a distinct clinical entity from HPVnegative OSCC. In this review, we intend to understand and explain the distinctive characteristics of HPV-associated OSCC.

Materials and methods This paper is a PubMed database literature review. The selection of articles began in December 2017 and ended in December 2018. The PICO strategy used to design the research question was the following: – P (Problem): Identify the etiological relationship of HPV with the development of OSCC. – I (Intervention): Analyse HPV-associated OSCC in terms of epidemiology, risk factors, specific topography, HPV subtypes most frequently involved, prevention, behaviour and therapeutic implications. – C (Comparison intervention): Identify the distinctive characteristics of HPV-positive and HPV-negative OSCC. – O (Outcomes): Update on HPV-OSCC to contribute to their early detection and health education of the population. Next, the following search equation was made: (Human papillomavirus OR HPV) AND (Oncogenicity OR Risk factors OR Oral cancer OR Oropharyngeal cancer) NOT Cervical cancer.

HNSCC is the eighth most common cancer in the world and the sixth cause of cancer mortality.20 Each year 500,000–650,000 new cases of HNSCC are diagnosed and cause 300,000–350,000 deaths.7,8,21–23 HNSCC originate in the mucosa of the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx and sinonasal tract. 5–25% of HNSCC are caused by HPV, and of these, 40–90% originate in the oropharynx.17,24,25 The role of HPV in the aetiology of HNSCC has been mentioned in the scientific literature since the 1980s.8,19,26 The published literature is extensive but not uniform in terms of epidemiological data. The figures may vary depending on geographical location, research period, HPV detection methods and different anatomical classifications. There is a great geographical variation with respect to the fraction of OSCC attributable to HPV8 (Fig. 4). The different smoking and alcohol consumption habits are associated with differences in the data according to the geographical area. Since 1980, cases of HPV-negative HNSCC have been reduced by 50%, accompanied by a decrease in smoking and alcohol consumption, while the incidence of HPV-OSCC has increased by 225% in the USA.7,18 In this sense, Spain, together with the Netherlands, boasts the lowest HPV-OSCC figures in Europe and HNSCC remains strongly associated with the smoking and alcohol abuse.20 In contrast, in Scotland, OSCC figures already surpass those of cervical cancer, cutaneous melanoma and oesophageal adenocarcinoma.27 The research period also seems to affect HNSCC viral detection data (Fig. 5). Epidemiological changes around HPV during the last decades are associated to improvements in detection techniques, a better understanding of HPV oncogenesis and an increase in the prevalence of HPV due to changes in sexual behavior.23 It is expected that by 2020, OSCC cases will outweigh the incidence of HPV-associated cervical cancers.7 Patient profile

Results

The increase in the incidence of HPV-OSCC has led to the emergence of a new patient profile of head and neck cancer, which is far from the traditional smoker and drinker.29

A total of 5556 articles were obtained. This initial search without filters was limited by applying selection criteria. For the sole purpose of assessing the current state of affairs, only systematic literature reviews with less than 5 years since publication were included, based on studies with humans, written in English or Spanish and with the text available. All the studies that did not meet these parameters were excluded, leaving a total of 113 results. From this set, 34 articles whose title was not in harmony with the search subject and 36 papers with abstracts that did not fit the subject of study were discarded. Finally, we selected 43 reviews (Fig. 3). In addition, 14 articles published between 2005 and 2018 considered relevant were selected directly in PubMed. In the literature search, two monographic studies of the International Agency for Research on Cancer (IARC) published in 2007 and 2012, as well as the publication HPV and prevention of cervical cancer, of 2008 were also included.

• Sex: HPV-OSCC predominantly affects men, representing more than 70% of cases and with a ratio of 2.8:1.17,21,30 While the anogenital infection mostly affects females, oral HPV infection is 2–3 times more likely in men.31 • Age: HPV-OSCC are usually diagnosed between 40–55 years of age, while HPV-negative patients are usually over 60 years of age.7 • Ethnic group: A higher incidence has been observed in white individuals compared to other ethnic groups, representing 34% and 4% of cases, respectively.7,17 ¨ • Social status: This new ¨ patienthas a higher educational and socioeconomic level. They enjoy a good state of health and a low level of substance abuse. They do not smoke or drink alcohol and, if they do, it is occasional.7,17 • Sexual behaviour: Sexual behaviour is shown as the main risk factor for HPV-OSCC.32 Patients with HPV-positive OSCC have, in general, a risk-related sexual behaviour.17

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Initial search 5.556 articles

Search with filters 113 articles

Abstract-based exclusion 43 articles

Title-based exclusion 79 articles

7 systematic reviews

4 meta-analysis

1 editorial 2 case series studies

43 literature reviews

1 written publication

2 monographs IARC

Fig. 3. On the left, article selection process outline. On the right, literature used for this review according to the type of scientific article.

75% 64.70% 52% 45%

17%

38%

39%

Eastern Europe

Northern Europe

21.90%

6.10% Spain

South Netherlands Europe

Australia

Japan

North America

Taiwan

Fig. 4. Geographical variations of human papilloma virus-associated Oropharyngeal Squamous Cell Carcinoma between the years 2000 and 2015. Chart obtained from the publications of Gillison et al.,14 Stein et al.20 and Chi et al.28

70% 60% 50% 40% 30% 20% 10% 0% pre - 1995

1995 - 1999 North America

2000-2004 Europe

2005 - 2015

Globally

Fig. 5. Epidemiological trends of Human Papilloma Virus-associated Oropharyngeal Squamous Cell Carcinoma in North America, Europe and globally during the last 2 decades. Data obtained from the systematic literature review by Stein et al.20

Risk factors According to a study published in 2010 by INHANCE (International Head and Neck Cancer Epidemiology Consortium), sexual behaviour is closely related to the risk of developing HPVassociated cancer.8 In this sense, changes in sexual and social behaviour may have led to an increase in cases of HPV-OSCC.7,20 On the contrary, there is little evidence linking sexual practices with other head and neck cancers not originated in the oropharynx.8 Among the behaviours associated with an increased risk of developing HPV-positive oropharyngeal cancer are: having had more than 6 sexual partners and more than 4 with habitual oral sex practices, sexual initiation before the age of 18, negligence in the use of sexual protection and a history of sexually transmitted diseases.7,8,18,23,27,31–33 The increased risk of HPV-OSCC also increases in case of having suffered a malignant disease attributed to HPV, having a history of anogenital HPV infection or developing antibodies for highrisk HPV. Specifically, patients with cervical cancer have a 5-fold

increased risk of developing HPV-associated head and neck carcinoma. Likewise, their partners have 2–3 times higher risk of HPV-OSCC.7,18,19,34 There are also other risk factors that may favour HPV infection and its carcinogenesis, such as smoking and alcohol and marijuana consumption.35 Although HPV-OSCC is associated with non-drinking and non-smoking patients, the consumption of these substances plays an important role in the development of HPV-positive and HPV-negative cancers.34 In fact, smoking is an established risk factor for cervical cancer. Tobacco decreases innate and cellular immunity, both systemically and locally, and facilitates infection persistence.36 On the other hand, alcohol acts as a solvent and increases mucosal exposure to HPV and other carcinogens.22 The risk increases with the duration and intensity of both habits, and have a synergistic effect.17,19,23,27 Marijuana and betel also appear as concomitant risk factors in the development of HPVassociated HNSCC.36,37 In addition, there are other common risk factors for all HNSCC, such as following an inadequate diet, acquired or iatrogenic immunosuppression and family history, among others.21,22,38

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Anatomical location The overall fraction of HPV-OSCC is approximately 45.8%, in the oral cavity between 23.5–24.2% and in the larynx between 22.1–24%.39 Paradoxically, in other studies, the figures vary from 18.5 to 22.4%; 4.4–5.9% and 1.7–3.5% in the oropharynx, oral cavity and larynx, respectively.40 These variations between meta-analyses and specific studies can be attributed to the disparity of criteria in the anatomical delimitations, different viral detection techniques and geographical HPV prevalence variations. In 2007, IARC established HPV-16 as the causative agent of oropharyngeal cancer. The lower detection figures for other HNSCC raise doubts about its etiological role in other non-oropharyngeal carcinomas.17,30 It is estimated that OSCC are 5 times more likely to be HPV-positive than those of the oral cavity, larynx and hypopharynx.33 Oropharyngeal cancers are those that derive from the base of the tongue (the posterior third), tonsils, lateral walls of the pharynx (oropharynx) and areas of the nasopharynx that are integrated into Waldeyer’s tonsillar ring.21 80% of OSCC come from the tonsils and the posterior third of the tongue,41 in a ratio of 53.9% and 47.8%, respectively.42 The histological similarities between the oropharyngeal mucosa and that of the cervix indicate an increased susceptibility of these tissues to HPV infection.37 Both mucous membranes have a transition zone between the squamous and columnar epithelium, which would facilitate the access of viral particles to the basal layer.28 There are other reasons that could explain this selective tropism. It is considered that the tonsillar crypts could act as a deposit, trapping HPV particles. Also, “the reticulated epithelium that covers them has intercellular gaps that mimic microlesions of the cervical epithelium (uterine cervix), which would allow viral access to the basal layer”.42 In addition, it is believed that the immunological environment of the oropharynx induces a prolonged inflammatory state, prone to dysplastic changes.17,18,23,31,42,43 Subtypes of human papillomavirus HPV-16 is the genotype established as the causative agent of HNSCC,17 while other high-risk types of are detected in a smaller proportion.26 HPV-16 is associated with 90% of HPV-positive OSCC cases.17,23 According to Kreimer et al., the most prevalent types after HPV-16 are 18, 33 and 35.44 However, a more recent systematic review by Stein et al. indicate that the prevalence of the different genotypes in HPV-OSCC are: 93.10% of HPV-16; a 1.40% of HPV-33; 1.30% of HPV-18; 0.50% of HPV-35 and 4.20% of other genotypes.20 It is suspected that the greater presence of these genotypes in malignant lesions is due to greater activity of the oncogenes E6 and E7.18 Even so, the etiological role of HPV-16 in other HNSCC and the role of other genotypes in OSCC is unknown.38 For now, the identification of the causative subtypes has no clinical relevance and, in many centres, the genotype responsible is not specified.23 Behaviour and therapeutic implications Given that HPV-OSCC are usually small tumours located inside the tonsillar crypts and, therefore, difficult to detect on examination, it is not surprising that patients begin with an asymptomatic neck lymphadenopathy and unknown primary site cancer.45 Sometimes they may have a symptomatic mass in the amygdala or posterior third of the tongue with or without lymphadenopathy.29,46 HPV-positive OSCC are usually diagnosed with low “T” and advanced “N” assessment.17

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HPV-positive OSCC show unique histological characteristics, establishing themselves as distinct entities with respect to HPV-negative OSCC.41 They are usually poorly differentiated, nonkeratinizing, basaloid cell tumors.18,19,47 These types of tumours express messenger ribonucleic acid (mRNA) E6 and E7, as well as normal values of p53 and overexpression of p16.41 There is still no consensus on which technique to use to associate HNSCC with HPV. This affects the heterogeneity of data33 (Table 1). It is important to remember that the presence of viral DNA does not imply a causal relationship between HPV and OSCC.8,26 “It is convenient to distinguish between a driving causative agent and a passenger”.47 Bearing this in mind, an agreement on the most accurate detection tool is essential to be able to compare different studies and homogenize the data.7 An improvement on detection techniques will increase the prevalence of HPV-OSCC in the future.20 Currently, the following HPV detection techniques are used: P16INK4A detection by immunohistochemistry. HPV-DNA detection by polymerase chain reaction. HPV-DNA detection by in-situ hybridization. E6/E7 HPV-mRNA detection by polymerase chain reaction or insitu hybridization. – Other less used techniques: HPV-specific immunoglobulin G and identification of biological markers in oral fluids.

– – – –

HPV(+) diagnosis is a positive prognostic factor, since HPV-OSCC show better results with respect to HPV(−), regardless of the treatment administered.46 This circumstance has not been observed in other HPV(+) HNSCC.30,42 HPV-OSCC have a survival of 82.4% at 3 years and 80% at 5 years, compared to 57.1% and 40% of HPV(−), respectively.29,30,43,46 In addition, HPV-OSCC shows a 58% reduction in the risk of death and 51% of recurrences.43 The implications of HPV in the clinical behaviour of OSCC are little known,51 but it is believed that this type of tumours have a greater sensitivity to chemotherapy and radiotherapy.23 The lower number of mutations and the lower genetic instability in comparison to cancers induced by smoking and alcohol can influence a better prognosis.18 At the same time, the better health conditions enjoyed by patients with an HPV-positive OSCC profile have contributed to better outcomes. Despite this, there are different modifying factors that can alter HPV-OSCC prognosis.52 Smoking can alter the clinical behaviour of these cancers, causing cellular genetic alterations that decrease treatment response. Survival decreases as years of smoking use increase.29,34,35,46 In addition to smoking, a large primary tumour with an advanced “N” category are indicators of poor prognosis.43 The main treatment options for HNSCC are surgery, chemotherapy and radiotherapy.7 Considering the best results in HPV(+) patients, the current trend is to decrease the intensity of the treatment.23 The objective is to reduce the toxicity associated with this type of treatment, preserving efficacy and maintaining good results.53 In this way, the quality of life of these patients is improved, who, due to being younger, will suffer the side effects for a longer time.17 It is estimated that in 80% of HPV-OSCC patients, radiotherapy may be sufficient.41 However, not all HPV(+) patients have the same prognosis54 and, in these patients, a more aggressive treatment has a positive impact.24 For this reason, it is proposed to stratify patients according to their risk, considering factors that can modify the prognosis, such as an advanced disease according to TNM staging (tumour, node, metastasis) and smoking history.52 To this end, we are investigating different biomarkers that can predict the risk of patients.55 Current lines of research study the possibility of modifying TNM staging based on HPV(+)/(−) status and reducing the intensity of treatment optios.18 This would mean a reduction in chemotherapy

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Table 1 Epidemiological data for human papilloma virus-associated head and neck squamous cell carcinoma according to different studies, detection technique, geographical area and location of the head and neck squamous cell carcinoma. [1,0] Study and year of publication

[1,0] Sample

Castellsagué Series of et al.48 . 3680 cases 2016

Ndiaye et al.49 . 2014

Systematic review and metaanalysis (1990–2012), 12,163

[1,0] Location

Kreimer et al.44 . 2005

[0,7-9] Oral cavity

[0,10-12] Larynx

HPV-DNA (+) and mRNA (+) and/or p16 (+)

HPV-DNA (+) and mRNA (+) and p16 (+)

HPV-DNA

HPV-DNA (+) and mRNA (+) and/or p16 (+)

HPV-DNA (+) and mRNA (+) and p16 (+)

HPV-DNA

HPV-DNA (+) and mRNA (+) and/or p16 (+)

HPV-DNA (+) and mRNA (+) and p16 (+)

Europe

22.3%

19.9%

15.9%

7.8%

3.7%

2.1%

4.8%

2.4%

1.2%

Central and South America Asia Africa Total Europe

43%

40.5%

35.5%

8.6%

6.6%

5.2%

8.4%

6.1%

2.8%

20.4% – 24.9% 41.4%

18.4% – 22.4% –

16.5% – 18.5% –

one% 3.4% 7.4% 17.5%

0% 0% 4.4% –

0% 0% 3% –

1.4% 5.5% 5.7% 20.9%

0% 2.7% 3.5% –

0% 0% 1.5% –

60.4%

–

–

13.4%

–

–

18.8%

–

–

14.9%

–

–

33.1%

–

–

32.2%

–

–

51.1% 47.7% – 45.8%

– – – 39.7% *HPV-DNA (+) and p16 (+) –

43.4% – 4.1% 24.2%

–

– – – 16.3% *HPV-DNA (+) and mRNA (+) –

– – – 6.8% *HPV-DNA (+) and p16 (+) –

28.3% – – 22.1%

39.7%

– – – 39.8% *HPV-DNA (+) and mRNA (+) –

–

– – – 8.6% *HPV-DNA (+) and mRNA (+) –

– – – 19.1% *HPV-DNA (+) and p16 (+) –

59.9%

–

–

–

–

–

–

–

–

32.5%

–

–

–

–

–

–

–

–

47.7% 28.2%

– –

– –

– 16%

– –

– –

– 21.3%

– –

– –

47%

–

–

16.1%

–

–

13.8%

–

–

46.3% 36.6%

– –

– –

33% 18.1%

– –

– –

38.2% 48.5%

–

–

35.6%

–

–

23.5%

–

–

24%

–

–

North America Central and South America Asia Oceania Africa Total

Mehanna et al.50 . 2013

[0.4-6] Oropharynx HPV-DNA

Systematic Europe review and metaanalysis (1970–2008), 19,368 North America Other regions Total Systematic Europe review, 5046 North America Asia Other regions Total

HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus. Information obtained from studies by Kreimer et al.,44 Castellsagué et al.,48 Ndiaye et al.49 and Mehanna et al.50

and radiotherapy, as well as opting for minimally invasive surgery based on TORS (transoral robotic surgery).52,54 Prevention There are 2 types of vaccines against HPV: preventive (prophylactic) and therapeutic. • Prophylactic vaccines: They consist of virus-like particles, generated by the major virus capsid protein L1 of the different subtypes to which it is directed. Therefore, they do not contain viral DNA and have no infective or oncogenic capacity, but they do have immunogenicity.23,30 There are 3 vaccines available: ® a) Gardasil (Merck): It is a quadrivalent vaccine that contains virus-like particles of genotypes 6, 11, 16 and 18. Indicated for

both sexes for the prevention of cervical cancer, genital cancer and genital warts.18 ® b) Cervarix (GlaxoSmithKline): It is a bivalent vaccine targeting HPV-16 and HPV-18. Indicated to prevent cervical cancer in women.18 ® c) Gardasil9 (MSD): It is a 9-valent vaccine that immunizes against genotypes 6, 11, 16, 18, 31, 33, 45, 52 and 58. It is indicated for both sexes for the prevention of cervical cancer, anogenital cancer and anogenital warts.56

Vaccination is approved between the ages of 9 and 26 to be administered before sexual initiation.8,31 The age of onset may vary according to the geographical region.57 Thus, it is not useful in already infected subjects.34

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Little research has been conducted on the preventive action of vaccines in HNSCC.17 Nevertheless, the close link between OSCC and HPV-16 suggests that vaccines could reduce its prevalence.34,58 Vaccination against HPV is part of national vaccination programs, 71 countries include it for women (37%) and 11 countries for men (6%).56 However, administration in men would be useful in OSCC, since it predominantly affects males.30 In addition, its low implementation in women has little impact on men.59 On the other hand, a sex-based administration does not protect the homosexual community.60 • Therapeutic vaccines: Presently under research. Their objective is to induce a cellular immune response, so that T cells can destroy virus-infected cells.7,35 Conclusions 1 HPV has established itself as a causative agent for oropharyngeal cancer. 45.8% of OSCC cases are linked to the virus. 80% of OSCC cases originate in the tonsils and the posterior third of the tongue. 2 HPV has not been established as a causative agent in other non-oropharyngeal HNSCC, but the fraction of squamous cell carcinomas associated with HPV is 23.5–24.2% in the oral cavity and 22.1–24% in the larynx. 3 HPV-OSCC predominantly affect young white men with a high socioeconomic status, non-drinkers and non-smokers, and a high-risk sexual behaviour. 4 HPV-16 is the most commonly involved subtype in HPV-OSCC and is associated with 93.1% of cases. 5 Smoking and alcohol, considered traditional risk factors for HNSCC, favour HPV infection and have a negative impact on the prognosis of HPV-associated OSCC. ® ® ® 6 Prophylactic vaccines, Gardasil , Cervarix Y Gardasil9 , can be useful in the prevention of HPV-associated head and neck squamous cell carcinoma but prospective studies on this subject are lacking. Conflict of interest The author declares no conflict of interest in this article. Acknowledgement ˜ Ponsa for his altruistic We wish to thank Dr. Jose María Boguná collaboration. References 1. Gasparini R, Panatto D. Cervical cancer: from hippocrates through Rigoni-Stern to zur Hausen. Vaccine. 2009;27:4–5. 2. zur Hausen H. Papillomaviruses in the causation of human cancers—a brief historical account. Virology. 2009;384:260–5. 3. Harden ME, Munger K. Human papillomavirus molecular biology. Mutat Res Rev Mutat Res. 2017;772:3–12. 4. Cortés J. VPH y prevención del cáncer de cuello de útero—100 preguntas más frecuentes. Madrid: Edimsa; 2008. p. 13–26. 5. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human Papillomaviruses. IARC Monogr Eval Carcinog Risks Hum. 2007;90:47–132. 6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum. 2012;100:255–96. 7. Whang SN, Filippova M, Duerksen-Hughes P. Recent progress in therapeutic treatments and screening strategies for the prevention and treatment of HPVassociated head and neck cancer. Viruses. 2015;7:5040–65. 8. Martín-Hernán F, Sánchez-Hernández JG, Cano J, Campo J, del Romero J. Oral cancer, HPV infection and evidence of sexual transmission. Med Oral Patol Oral Cir Bucal. 2013;18:439–44. 9. Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPV-associated oropharyngeal cancer. Oral Oncol. 2014;50:380–6.

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