|Year : 2014 | Volume
| Issue : 3 | Page : 492-498
Exploring the link between human papilloma virus and oral and oropharyngeal cancers
Shailesh R Khode1, Raghav C Dwivedi2, Peter Rhys-Evans2, Rehan Kazi2
1 Department of ENT-HNS, Faculty of Medicine, MAHSA University College, Kuala Lumpur, Malaysia
2 Department of Head and Neck Surgery, Royal Marsden Hospital, London SW3 6JJ; Department of Head and Neck Surgery, Institute of Cancer Research, London SW3 6JB, United Kingdom
|Date of Web Publication||14-Oct-2014|
Department of Head and Neck Surgery, Royal Marsden Hospital, London SW3 6JJ; Department of Head and Neck Surgery, Institute of Cancer Research, London SW3 6JB
Shailesh R Khode
Department of ENT-HNS, Faculty of Medicine, MAHSA University College, Jalan Elmu off Jalan University College Campus, 59100, Kuala Lumpur
Source of Support: None, Conflict of Interest: None
Squamous cell carcinoma involving the oral cavity (OC) and oropharynx regions are a major cause of morbidity and mortality world-wide. The recent discovery of a strong association between human papilloma virus (HPV) infection and OC and oropharyngeal (OP) cancer has prompted world-wide research into the exact etiology and pathogenesis of these cancers in relation to the HPV. HPV-positive OC/OP cancers generally present at a relatively advanced stage (by virtue of cervical nodal involvement) and are more commonly seen in younger patients without significant exposure to alcohol or tobacco. These factors are implicated in prognosis, regardless of HPV association. In this article, we review the biology and epidemiology, risk factors, association, molecular analyses, treatment response and prognosis of HPV-related cancers. Role of HPV vaccination in HPV-related OC/OP cancers has also been discussed.
Keywords: Head-neck cancer, human papilloma virus, oral cancer, oropharyngeal cancer
|How to cite this article:|
Khode SR, Dwivedi RC, Rhys-Evans P, Kazi R. Exploring the link between human papilloma virus and oral and oropharyngeal cancers. J Can Res Ther 2014;10:492-8
| > Introduction|| |
Head and neck cancer (HNC) is the sixth commonest cancer world-wide. Each year, almost 650,000 patients the world over are diagnosed with HNC and nearly 40% of these patients die from this disease. Approximately 90% of these HNC are squamous cell carcinomas (SCC).  Overall, although the incidence of HNC is declining, we now know numbers of oropharyngeal (OP) cancers is increasing dramatically especially in the younger patients. , Life-style causes such as consumption of tobacco and alcohol are the two main causative factors responsible for approximately 75-80% of all oral cavity (OC)/OP cancers.  Yet there are a significant number of tumors (20%) that appear to have a different etiology. Löning et al. first suggested a causal relationship between human papilloma virus (HPV) and head, neck squamous cell carcinoma (HNSCC) in 1985.  Since then over the last 25 years, molecular and epidemiological studies have clearly identified oncogenic HPV infection as a significant etiological factor for a variety of cancers including that of the head and neck region.
High-risk subtypes of HPV infection (e.g. HPV-16) are strongly associated with cancer risk in OP cancers, especially those arising from tonsil and base of tongue. ,, They are independently associated with a 3-15-fold increase in risk for OC/OP cancers.  Developing a sound, effective and robust strategy to detect and treat oral and OP HPV infections are of great importance to bolster survival figures. The presence of HPV infection has been constantly reported with various topographical subtypes of OC/OP, demographical data of patients, habituation such as smoking and alcohol consumption and clinical staging of the disease. HPV-positive OC/OP cancers generally present at a relatively advanced stage (by virtue of cervical nodal involvement) and are more commonly seen in younger patients without significant exposure to alcohol or tobacco. These factors are implicated in prognosis, regardless of HPV positivity. ,
OC/OP cancers are commonly treated with curative intent by either radiation (with or without concomitant chemotherapy) or surgery (with or without adjuvant radiotherapy). In the current literature, HPV-positive OC/OP cancers appear to be more sensitive to chemo-radiotherapy than HPV-negative tumors.  This phenomenon is thought to result in improved progression-free and overall survival rate. In this article, we review the significant biology and epidemiology, risk factors, association, molecular analyses, treatment response and prognosis of HPV-related oral and OP cancers (OOPC). The role of HPV vaccination for HPV-related OC/OP cancers has also been discussed here.
| > Biology and molecular pathology of hpv|| |
HPV belongs to the papovaviridae family. It is a non-enveloped virus containing a small, circular double-stranded deoxyribonucleic acid (DNA) genome and an icosahedral (20-sided) protein coat. It is the most common sexually transmitted virus and has been implicated in a variety of cutaneous, anogenital and aerodigestive diseases, ranging from skin warts to laryngeal papillomata and carcinoma of cervix [Table 1].
In an article in 1933, Shope and Hurst.  first identified and isolated the papilloma virus particle in rabbit papillomatosis. Many of these benign papillomas in rabbits progressed to malignancy. These viruses are epitheliotropic, meaning they infect cells in the basal layer of squamous epithelia. Currently, sequences for more than 100 different serotypes of HPV have been identiﬁed. They are subdivided on the basis of cutaneous and mucosal site of involvement as high-, intermediate- and low-risk, depending on their association with malignancy [Table 2]. , In this review, attention will mainly focus on the mucosal high-risk serotypes (HPV-16 and HPV-18) that are known to be of significance in OC/OP cancers. Recent data demonstrate the presence of HPV in the oropharynx, specifically in tonsillar carcinomas, suggesting that the oropharynx or Waldeyer's ring may be a favored site for HPV-related oncogenesis. ,,, The reasons for this remain unknown at present.
|Table 2: Different types of HPV categorized according to their level of risk of being associated with malignancy|
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High risk serotypes, HPV-16 and -18, are capable of transforming epithelial cells derived from both the genital and upper aerodigestive tracts.  The transforming potential of high-risk HPVs is largely a result of the function of two viral oncoproteins namely E6 and E7. These are normally under the regulatory control of E2 and E1 inhibitory genes. These genes can be deleted or functionally inactivated on viral integration, leading to unchecked transcription of E6 and E7. The protein products of the E6 and E7 genes can functionally inactivate two key human tumor-suppressor proteins, p53  and pRb (Retinoblastoma protein),  respectively, which help in immortalizing the cell. Expression of E6 and E7 proteins result in the initiation of virus mediated transformation which is associated with the accumulation of p16 1NK4a , a product of CDKN2A regulating pRb activity in the proliferating cell layers of the epithelium. ,,,, It is well documented that continuous expression of E6 and E7 leads to genetic instability in the infected cells which in turn coincides with accumulation of specific (epi-) genetic alterations of cancer genes, helping in the progression to a tumorigenic phenotype. , However, it must be noted that the development of cancer in a HPV infected cell may take over 10 years and essentially requires multiple additive crucial (epi-) genetic alterations. ,
| > Risk-Factors for HPV Positive OOPC|| |
Several studies in the current literature have reported that HPV-positive HNSCCs occur more frequently in non-smokers and non-drinkers. , Lindel et al.  showed that in patients with OC/OP cancers, non-smokers were more likely (approximately 15-fold) to be diagnosed with HPV-positive cancers than smokers.  Those patients who are seropositive to the HPV-16 viral capsid protein have a 2-3-fold increase in risk of HNSCC. , Other case control studies have shown an even stronger association with oral infection by high-risk HPV conferring a 6-14-fold increased risk for OC/OP cancers. ,, Other factors associated with elevated risk of oral HPV infection include the male sex, history of other sexually transmitted diseases, HIV infection and severity of immunosuppression. , Additional high-risk groups for tonsillar cancer include those with a previous history of an HPV-associated malignancy, a history of cervical carcinoma in situ (CIS) in females over 50 years of age and husbands of females with CIS and invasive cervical carcinoma. ,
Several case control studies have reported risk factors, mainly certain sexual behaviors, for infection with high-risk HPV serotypes in patients with HNSCC. , These include: (i) young age at ﬁrst intercourse; (ii) a history of genital warts;  (iii) the number of sexual partners; high lifetime number of sexual partners, ≥26 for vaginal sex and ≥6 for oral sex. , This implies that a history of oral sex has been more strongly associated with the risk for an HPV-positive tumor as compared to vaginal sex. ,, In a hospital-based case-control study of 100 patients with newly-diagnosed OP cancer, D'Souza et al. reported conclusive evidence of an association between HPV infection and OP cancer. This degree of association increased with a high lifetime number of vaginal- or oral-sex partners. 
Syrjδnen  studied married couples with healthy oral mucosa and concluded that the oral route is an important means of HPV transmission between the partners. Similarly, in the study by Mork et al.,  patients who were seropositive for HPV-16 had a 14-fold increased risk of OP cancer. They also importantly concluded that exposure to HPV can precede the appearance of OP cancer by 10 or more years. Schwartz et al.  conducted a population-based case-control study to determine the relation between HPV infection and sexual history by comparing subjects of both sexes who had a history of 15 or more sexual partners to those who had had fewer than 15 sexual partners. Herrero et al.  suggested that the overall risk for cases whose tumors contained HPV type 16 DNA was 2.5 times greater, whereas in those containing HPV type 11 and 6 DNA it was 1.2 and 0.9 times greater, respectively, as compared to patients whose tumor did not contain HPV-DNA. Results presented in all the above studies suggest that sexual behavior is clearly associated with OP cancers. 
| > Association between hpv and cancer sites including lymph nodes|| |
In a number of published studies, PCR-based methods (using head and neck biopsy specimens) have been used to detect HPV-DNA to define the prevalence of HPV infection and its distribution by anatomic site. A total of 60 eligible studies from 26 different countries identified 5046 cases of HNSCC. Of these cases, 2642 involved the oral cavity, 969 the oropharynx and 1435 the larynx. Overall, 26% of all head and neck biopsy specimens were HPV positive and out of these 90% were positive for HPV-type 16. HPV prevalence was higher in OP cancer (36%) (specifically tonsillar region) than oral cancer (23%) and laryngeal cancer (24%) respectively. The biological explanation for this phenomenon remains unclear but it is possible that the mucosa-associated lymphoid tissue in the tonsil/base of the tongue may share similar properties to the squamo-columnar junction of the cervix uteri (main HPV-positive cancer site in the female genital tract). 
A systematic review by Kreimer et al.  showed that the prevalence of HPV-positive oral cancer in Asia and North America was higher than in European countries, while that of OP cancer was higher in North America as compared to Europe and Asia. Although the use of alcohol and tobacco-related products (smoking and chewing) varies by country and culture, these remain the most important causes of HNC world-wide and are also likely to affect the prevalence of OC/OP cancers. In a meta-analysis of oral cancer, HPV was 2-3 times more likely to be detected in precancerous lesions and 4.7 times more likely to be detected in oral cancer than normal oral mucosa.  Various studies have been conducted on HPV subtypes in OOPC type and its prevalence as shown in [Table 3]. Most of the studies showed HPV subtype 16 has maximum prevalence in both OC and OP lesions except the study conducted by Maden et al has HPV subtype 6 in OC and Schwartz et al has subtype 6 in OP. ,,,,,,,,
|Table 3: Various studies on HPV subtype in OOPC type- specific prevalence|
Click here to view
The prevalence rates for HPV in primary OC and OP cancer are 40% and 60% respectively. As HPV positive tumors may have a higher propensity for metastatic spread to the regional lymph nodes, the prevalence rates may be enhanced in lymph node metastases in HPV positive OC/OP cancers.  An HPV detection probe in cervical lymph nodes can help to localize the tumor origin in carcinoma of unknown primary (CUP).
Begum et al.  detected HPV-16 in 71% of metastases from OP carcinomas. They noticed HPV-16 ISH appears to be the most reliable method for detection of HPV related OP cancer, at primary sites and at distant spread. Over expression of the surrogate marker p16 by immuno-histochemistry in cervical lymph node metastases is an additional reliable marker of HPV infection [Figure 1]. 
In retrospective analyses, tonsillectomy has been shown to identify the primary site of CUP as the ipsilateral tonsil in approximately 30% or contralateral tonsil in approximately 10% of cases. , In the study conducted by Strome et al.,  HPV was detected in 46% of patients with tonsillar SCC. Approximately 93% had evidence of HPV in pathologically involved lymph nodes in HPV positive tonsillar carcinoma with regional metastases. This supports the role of HPV in the oncogenesis of OP carcinoma (tonsillar). 
| > Molecular analysis of hpv|| |
The diagnosis of HPV associated SCC should be considered in OC/OP cancers and especially those arising from the lingual and palatine sites i.e. site of origin. Additionally, cancer in young age, cancer in non-alcoholic and non-tobacco chewers and/or smokers, cancer with basaloid histology and immunocompromised host should be considered as highly suspicious group for HPV positive OC/OP cancers. ,,
There are a number of different detection methods and assays available for detection of HPV, but every test has its own analytical sensitivity. , HPV detection methods can either be based on polymerase chain reaction (PCR) assays (e.g. SPF10, GP5+/GP6+-PCR), , DNA hybridization with specific labeled ribonucleic acid probes (e.g. HC2),  in situ-hybridization (ISH) or any combination of the above.  An important factor which affects the sensitivity of a detection method is contamination, either on the instrument or gloves, resulting in false positive results. Recently, a multiplex PCR has been shown to be a very sensitive assay targeted to the L1 region of the viral genome.  In most of the studies, MY09/11 primers were used for detection, which often yields a significant product size of 450 base pairs , [Table 3].
Another standard assay for the detection of HPV DNA has been the southern blot hybridization (SBH). It offers the ability to distinguish between episomal and integrated DNA.  SBH has some technical variability and requires a significant amount of DNA. The advantage of SBH, it is not prone for contamination error.  Theoretically SBH may have a higher specificity but clearly has less sensitivity than PCR.  In a study by Yeudall et al.  utilized both SBH and type-specific PCR for HPV 16/18 and concluded that there was a significant difference in prevalence between the two methods. This raises the further important question of what threshold of HPV detection is needed to infer infection and what level is needed for carcinogenesis. 
ISH is less expensive compared to PCR based techniques but it is only available at a limited number of tertiary referral medical institutes. It involves the use of type-specific labeled DNA probes complementary to HPV sequences for detection.  The possibility of contamination is less in those studies utilizing quantitative PCR techniques with fluorescence.  More recently an algorithm has been developed for satisfactory detection of HPV from paraffin embedded (PE) material which involves a combination of 2 separate tests applied in a definite sequence (p16 INK4a immunostaining followed by HPV-DNA PCR (e.g., GP5+/6+) on the p16 INK4a positive cases).  This sequence has shown to be 100% sensitive and specific in HPV detection from PE specimens. 
| > Treatment and survival|| |
In the majority of studies, patients with HPV positive OP tumors have shown better prognosis when compared to patients with HPV negative tumors. ,, Date has suggested that risk of dying from HPV positive cancer is reduced by 60-80% when compared to HPV negative cancer.  Fakhry et al.  reported for the first time in 2008, the prognostic significance of HPV status in a prospective multi-center phase II clinical trial of HNSCC conducted by Easter co-operative oncology group in which patients received homogenous treatment. Here after 39 months of follow-up (median), risk of progression and death were lowered by 72% and 79% in HPV positive compared to HPV negative patients respectively. 
In another large retrospective study conducted on 45,779 patients divided in three calendar decades, Chaturvedi et al.  in their study have reported a significant 2 years survival benefit of 9.9%, 23.1% and 18.6% for local, regional and distant HPV related OC/OP cancers when compared to 5.6%, 3.1% and 9.9% for HPV non-related cancers when they were treated with radiotherapy and compared. 2 year survival rate for localized HPV positive against HPV negative OC/OP cancer were 75% with radiotherapy and 73.1% without radiotherapy respectively. The reasoning for improvement in survival is still under evaluation. Lindel et al.,  retrospective review of HNC patients who underwent curative radiotherapy, reported significantly improved local control rate and subsequently increased overall survival rate in HPV positive cases. 
The impact of HPV vaccination on OC/OP HPV infection in HNC prevention has yet to be established. At present available vaccines strictly designed for prevention of cervical cancer and genital warts. Widely, HPV infection is sexually acquired therefore vaccination should be done prior to first sexual intercourse to prevent serious HPV related diseases. The data on immunization setting in oral HPV infections are limited to animal models (canine and hamster) only. There is no evidenced based human data available which has shown a protective effect against the development of HPV related oral diseases. ,
At present, various clinical trials on the evaluation of quadrivalent HPV vaccine in the protection of oral HPV infections are also still under evaluation ,,, The
reduction in OC/OP cancer incidence remains to be yet seen and proved.
| > Conclusion|| |
The extensive epidemiological and laboratory evidence strongly suggest that HPV has a strong association with OC/OP, especially tonsillar carcinoma. The most common HPV type associated with cancer in these locations is HPV-16. HPV positive OC/OP cancers have more aggressive biological behavior. They are relatively more common in younger age, less dependent on consumption of alcohol and tobacco and have better survival rates as compared to HPV negative OC/OP cancer. HPV detection in cervical lymph nodes of patients with CUP may be used to diagnose the primary site of tumor with high speciﬁcity for the primary within the oropharynx. The screening of patients for HPV using different detection methods helps to improve treatment protocols and provide important prognostic information. Literature suggests there is an increased "sensitivity" of HPV positive OP tumors to concurrent chemo-radiation and a number of plausible explanations have been offered.
However further studies and research to know the exact etiology and to make definite conclusions about whether, or not, HPV positive patients should receive less or more aggressive therapies. Finally, only time and more studies will demonstrate the impact of HPV vaccination on the incidence of OC/OP cancers and the therapeutic effect of vaccine on already infected patients.
| > Acknowledgment|| |
The authors would like to thank Dr. Kevin J. Harrington for his help in manuscript preparation.
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[Table 1], [Table 2], [Table 3]