Human Papillomaviruses (HPVs) are considered ubiquitous in the sexually active adult population. In recent years, much attention has been paid to the role of HPVs in the development of cervical neoplasia. Less attention is given to HPV-associated head and neck cancers, despite the fact that rates have increased by 225% in recent decades [1].

This paper examines recent epidemiological data while exploring the mechanisms underlying HPV-mediated oncogenesis, the associated risk factors for HPV-positive malignancy and the implications of tumour HPV-status in prognostication and treatment. Vaccination programs are discussed with regard to efficacy and safety, and with reference to public health initiatives both in Ireland and abroad. Finally, recommendations are provided for ways in which the burden of HPV-associated disease can be reduced.

Human Papillomaviruses (HPVs)

Human Papillomaviruses are a sexually transmitted infection, now held to be the most common sexually transmitted disease in the United States [2]. HPVs are considered ubiquitous in the sexually active adult population. Transmission of HPVs occurs via sexual contact, including oral, vaginal and anal sex. Non-sexual, vertical transmission from mother to child can also occur during pregnancy and childbirth [3]. There are over 100 identified strains, which differ substantially in their pathogenecity. Low risk strains include HPV-6 and HPV-11 which are linked with anogenital warts, oral squamous papillomas and recurrent respiratory papillomas. High risk HPV strains include HPV-16, HPV-18, HPV-31, HPV- 33, HPV- 45, HPV-52 and HPV-58. Of these, HPV-16 and HPV-18 are by far the most prevalent [4]. The vast majority of anal cancers (90%) and cervical cancers (99.7%) are attributed to infection with these HPV strains [5]. It is estimated that three of every four new diagnoses of oropharyngeal squamous cell carcinoma (OPSCC) are HPV-positive [6]. HPV-16 is the main causative agent of OPSCC and is mainly seen in patients with limited tobacco or alchol use.

HPV-mediated oncogenesis

HPV-mediated oncogenesis arises from the disruption of DNA repair mechanisms and regulators of the cell cycle which facilitates uncontrolled proliferation and ultimately malignant transformation [4]. Specifically, HPV can integrate into the host DNA genome resulting in abnormal, uncontrolled expression of the viral oncoproteins E6 and E7.7 The oncogenic potential of E6 is related to its ability to inactivate p53, which is a key cellular tumour suppressor protein responsible for cell cycle arrest and apoptosis in the presence of cell injury and DNA damage in particular. Viral inactivation of p53 results in a significant decrease in p53 tumour-suppressing activity. In contrast to non-HPV OPSCC, where carcinogenic exposure causes mutation of the p53 gene, the HPV E6 protein binds p53 and inactivates its transcriptional activity [7]. Similarly, E7 inhibits retinoblastoma protein (pRb) another tumour suppressor protein which prevents abnormal cells from progressing to the synthesis (S) phase of cell division [4]. The inhibition of these tumour suppressor genes in affected epithelial membranes renders cell genomes unstable and susceptible to the development of malignancy [4,5].

HPV and Head & Neck cancer

Head and neck cancers typically arise from the mucosal layers of the lip, oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract and nasopharynx [7]. Squamous Cell Carcinoma (SCC) is the predominant histological type [7]. The oropharynx is by far the most common site of HPV-related SCC, with the lingual and palatine tonsils most often affected [8]. The lymphoid tissues at these sites feature an incomplete basal cell layer and a disrupted, porous basement membrane which facilitates their immunological role. It has been suggested that this cellular layout may contribute to the early metastatic potential of OPSCC tumours [9].  HPV is reliant on the proliferative capacity of these cells in order to cause infection and undergo further viral synthesis [4]. Division of infected cells then allows the virus to spread [4].

The incidence of head and neck cancer has increased so sharply in recent decades it has been described as epidemic [9].  Squamous Cell Carcinoma of the head and neck (HNSCC) is the fifth deadliest cancer worldwide [5] with OPSCC expected to surpass cervical cancer as the most common HPV-related cancer in the United States in the next five years [1]. In the period spanning 1988 to 2004, it is estimated that HPV-associated OPSCC increased by 225% [1]. In Ireland, the National Cancer Registry shows that the incidence of OPSCC in Ireland has doubled in the past two decades, from 50 cases in 1994, to 100 cases in 2012.10 The general consensus attributes this dramatic rise squarely on the shoulders of HPV.

Implications of HPV-status of tumours

HPV-positive SCC demonstrates a malignant process, presentation, treatment response and prognosis distinct from that of HPV-negative SCC [9]. The most common initial symptom of HPV-positive OPSCC is a neck mass. In contrast, HPV-negative OPSCC most often presents with sore throat [11]. The TNM system used to stage tumours and in prognostication is limited in its application to HPV-positive HNC. This system is based on the size of the primary tumour, the extent of nodal spread and the presence of metastasis. Curiously, HPV-positive OPSCC usually presents with smaller primary tumours but more advanced nodal involvement [8]. Compared to HPV-negative tumours, HPV-positive tumours exhibit greater loco-regional control and rarely metastasise. When metastasis does occur however, HPV-positive disease exhibits a tendency to disseminate to multiple organs and unusual sites such as the skin and pancreatic tail [12].

Recent years have seen an increasing incidence of HNSCC in individuals with no history of significant smoking or alcohol use. Traditionally HNSCC has been associated with heavy smoking or tobacco use and alcohol consumption, typically observed in older males in their sixth or seventh decade of life [5,13]. Additional risk factors include chemical exposure (asbestos, chromium, arsenic) and environmental exposure to ionising radiation. In comparison, the new demographic are predominantly Caucasian males, non-smokers, with low alcohol intake, higher educational attainment and higher socioeconomic status [13].

Risk factors for HPV-associated cancer

In stark contrast to the aforementioned rise in HPV-positive OPSCC, there has been a 50% decline seen in rates of HPV-negative HNSCC in the same period [5]. The rise in incidence of HPV-positive OCSCC may be primarily attributed to two behavioural shifts in society. First, the significant decrease in smoking compared to previous generations may make HPV-related cancer more statistically visible. Second, shifts in sexual behaviour, particularly an increase in oral sexual partners and engaging in oral sex at a younger age, may make HPV-related cancer more common [7].

Oral sexual behaviour and a history of multiple vaginal sexual partners in males have both been identified as strong risk factors for HPV-associated disease [9]. It has been suggested that higher rates of HPV-associated OCSCC in men may be due to the greater prevalence of the virus in cervical tissue (compared to penile tissue) which may be transferred when a male performs oral sex on a female [7]. When compared to those without cervical neoplasia, women with cervical cancer were five times more likely to have a husband with over 20 sexual partners in his lifetime [5]. In addition, studies have demonstrated significantly greater incidence of oral, pharyngeal and laryngeal cancers in the husbands of women diagnosed with cervical cancer [5].

Testing for HPV

HPV can be tested for via a number of methods. The most common is polymerase chain reaction (PCR) and tissue-based in situ hybridisation (ISH) [4].  Currently screening is available for cervical and anal cancer however there is no standard protocol for oropharyngeal cancer screening [5].

Treatment options

The HPV status of a tumour is important to prognosis and will influence the course of treatment. Despite the sharp increase in the prevalence of HPV-associated OPSCC, these malignancies show more favourable outcomes with regard to treatment response, recurrence rates and overall survival when compared with HPV-negative OPSCC [9]. HPV-positive OPSCC demonstrates increased sensitivity to chemo- and radiotherapy versus HPV-negative OPSCC thus concomitant chemoradiotherapy has emerged as the current mainstay of treatment [3,7,14]. Chemo-sensitivity is proposed to stem from the presence of wild type P53 in tumour cells, such that the cells retain intact cellular apoptotic pathways [15]. In increased radio-sensitivity is attributed to impaired DNA repair mechanisms in tumour cells [16].

Thoughts regarding best practice in terms of treatment are undergoing a shift. Given the younger, healthier profile of these patients, the harmful but inevitable complications associated with chemotherapy and radiotherapy are becoming less acceptable. Both modalities carry significant burden in terms of associated morbidity. Toxicity-induced sequelae include nephrotoxicity, neutropenia, ototoxicity, osteoradionecrosis and dysphagia amongst many others [17,18]. One study of patients undergoing concurrent chemoradiotherapy found that 43% experienced severe late toxicity [18].

In light of such findings, recent research has begun to focus on the extent to which chemoradiotherapy can be de-intensified without compromising on treatment efficacy [8]. Others have advocated the use of surgery in the management of patients with HPV-positive HNSCC, highlighting the benefits of minimally-invasive transoral robotic surgery and laser microsurgery [17,19].  Where previously highly invasive and often requiring extensive dissection, surgical options for OPSCC have advanced greatly in recent years and may offer comparable oncologic outcomes with potentially better functional outcome [17].

Survival rates

It is difficult to ascertain the extent to which treatment modality influences patient outcome as HPV-positive status confers advantage regardless of the treatment course pursued [20]. The innumerable confounding factors present in the patient population must be acknowledged. For instance, the survival advantage observed in HPV-related malignancy is likely due, in some part, to younger patient age, lower alcohol- and smoking-related morbidity, and the ability to withstand more aggressive treatment [14]. Nevertheless, when these factors are controlled for, the prognostic advantage persists [8]. Two-year survival rate for HPV-positive OPSCC is 95% compared to 62% in HPV-negative OPSCC [3]. A 2012 meta-analysis of 42 studies found the five-year survival rates for patients with HPV-positive HNSCC to be 70-80% compared with 25-40% for patients with HPV-negative HNSCC [14]. HPV-positive OPSCC demonstrates 63% less likelihood of cancer recurrence and overall mortality 53% lower than HPV-negative cohorts [14], findings which parallel with Dayyani et al. who reported similar figures [21].

HPV-Vaccination

There are currently three groups of prophylactic HPV-vaccines available. The bivalent Cervarix targets HPV-16 and HPV-18 and the quadrivalent Gardasil targets HPV-6, HPV-11, HPV-16 and HPV-18. HPV-6 and HPV-11 are most commonly implicated in benign anogenital warts [9]. There also exists a 9-valent vaccine targeting HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58 [22].

The full impact of HPV vaccination programs will not be apparent for decades. Currently, researchers look to the incidence of pre-invasive cervical intraepithelial neoplasia 2 and 3 and adenocarcinoma in situ (collectively referred to as CIN2+) as an indicator of vaccination efficacy [22]. Within 5 years of implementing a free, school based vaccination program, Australia has experienced a huge decrease in external genital warts which is anticipated to translate into similar declines in the rate of cervical cancer in future decades [23].

The efficacy of vaccination in males has also been demonstrated in the literature. A recent study of over 4000 men aged 16-24 found that vaccination led to a 90.4% reduction in external genital lesions (linked to HPV-6, HPV-11, HPV-16 or HPV-18) and demonstrated 89.4% efficacy against condylomata acuminata, a type of genital wart [24]. The authors suggest these effects will likely translate to the prevention of anogenital cancers, intraepithelial neoplasia and oropharyngeal cancers in the future [24].  Notwithstanding this, it will be decades before the true impact of HPV vaccination on malignant disease will be fully established [25].

The Irish HPV Schools Immunisation Programme commenced in May 2010.26 The routine Irish vaccination programme is currently offered to adolescent females in second level education, and involves three doses of the Gardasil vaccine. Uptake of the vaccination in Ireland compares well with international statistics. Based on figures as of June 30th 2015, 84.9% of girls in first year of second level education are recorded as having completed the full course [27]. Uptake of a catch-up vaccine, offered to older adolescents females has been lower, with approximately 44.6% of girls in sixth year completing the course [27].

HPV-vaccine-associated Adverse Drug Events (ADEs)

HPV-vaccinations pose an interesting challenge in the age of immunisation-sceptics. A key criticism is that the long term benefits of the HPV-vaccine “rest on assumptions rather than solid research data” [28]. Critics highlight the necessity for a very narrow margin of tolerance for serious ADRs, especially in the case of vaccines with undetermined benefit [28]. They maintain that there is no evidence to support the claim that either Gardasil or Cervarix can actually prevent any type of cervical cancer, and that no vaccine currently in use can eradicate existing HPV infections or arrest their progression to CIN 2/3 lesions [28]. In addition, HPV vaccines have documented adverse effects in a small minority of recipients, although the majority are considered non-serious. The Irish Medicines Board (IMB) actively monitors the reports of adverse events associated with the HPV vaccine Gardasil. In line with the US Food and Drugs Administration (FDA) and the Therapeutic Good Administration in Australia (TGA), the IMB maintains the safety of Gardasil [26].

As with virtually all vaccines, local injection site reactions can occur including pain, redness and swelling. These are short-lived and spontaneously resolve in the vast majority of recipients [29]. Non-serious adverse events included syncope, dizziness, nausea, fever and urticaria [29]. In the United State as of March 2014, 67 million doses of HPV-vaccines had been administered, with no significant increase in adverse events reported [2]. The US Vaccine Safety Datalink reports no increased risk of Guillain-Barre syndrome, seizures, stroke, venous thromboembolism, anaphylaxis or other allergic reactions, in those who have received the HPV-vaccination [30]. There is also no evidence of a link between HPV vaccines and demyelinating disorders [31].

Parental attitudes

Other less pressing concerns include the belief of some parents that prophylactic vaccination equates to the condoning of sexual behaviour at an earlier age and may promote the practice of unsafe sex [32]. Studies of sexual behaviour in young adolescents following vaccination have found such concerns to be unfounded, with those vaccinated no more likely to engage in sexual activity than their unvaccinated peers [33].

Should males be vaccinated?

When considering HPV and vaccination, much emphasis has been placed on cervical cancer. Virtually all vaccination programmes are aimed, at least in the initial stages, at pre-adolescent females. The suggestion of herd immunity conferred to males via the vaccination of females embodies a number of flaws as it is based on assumptions regarding the sexual activity of males. The National Cancer Institute estimates that over half of the cancers diagnosed in the United States in the next five years will be “oropharyngeal rather than cervical” which demonstrates a clear predominance in males [34].

A universal vaccination policy would carry a number of benefits [35]. Primarily, universal vaccination would reduce the burden of HPV-associated diseases and malignancies in the general population, and facilitate more rapid control of the most common strains in circulation. Such a policy would also reduce the risk posed to males by unvaccinated females and extend protection to men who have sex with men (MSM) who do not benefit from herd immunity [35]. A recent study conducted with MSM in Ireland found that 69% of men tested had detectable HPV DNA [36].

Recommendations

A number of useful recommendations can be drawn from the above literature which could be employed to reduce the burden of HPV-associated cancer, including:

• Extension of HPV vaccination programs to include males and confer protection against HNSCC [4].
• A targeted campaign for MSM, who do not benefit from herd immunity.
• Development of more sensitive screening tools for this group of malignancies, given propensity for unusual metastatic sites.
• Education workshops for primary care clinicians in relation to atypical symptoms associated with HPV-positive HNC.
• Development of a comprehensive staging algorithm for HPV-positive HNSCC [12].

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