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Journal of Cancer Research and Therapeutics
Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI)
ISSN: 0973-1482 EISSN: 1998-4138
Vol. 5, Num. 2, 2009, pp. 71-77
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Journal of Cancer Research and Therapeutics, Vol. 5, No. 2, April-June, 2009, pp. 71-77
Review Article
Role of human papilloma virus in the oral carcinogenesis: An Indian perspective
Chocolatewala Noureen M, Chaturvedi Pankaj
Department of Head and Neck, Tata Memorial Hospital, Mumbai
Correspondence Address:Tata Memorial Hospital, Head & Neck Unit, Dr. E Borges Road, Parel, Mumbai - 400 012
chaturvedi.pankaj@gmail.com
Code Number: cr09022
DOI: 10.4103/0973-1482.52788
Abstract Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the Indian subcontinent. Although tobacco and alcohol are the main etiologic factors for nearly three-fourth of these cancers, no definite etiologic factor can be identified in one-fourth of the cases. There is growing evidence that human papilloma virus (HPV) may act as a cocarcinogen, along with tobacco, in the causation of oral cancers. The role of HPV in the etiology of anogenital cancers has been firmly established, and infection with this virus has also been shown to have prognostic significance. However, there is no clear evidence to support its involvement in oral carcinogenesis.
We searched the PubMed database for all literature published from 1985 to 2008 and performed a systemic review in order to understand the relationship of HPV with oral cancers and its prevalence in various sub-sites in the oral cavity.
Association of HPV is strongest for oropharyngeal cancers, especially cancers of the tonsils, followed by those of the base of tongue. High-risk HPV-16 is the predominant type; it commonly affects the younger age-groups, with males appearing to have a predisposition for infection with this strain. Its prevalence increases from normal to dysplasia and finally to cancer. HPV prevalence has been reported to be twice as high in premalignant lesions as in normal mucosa and is nearly five times higher in OSCC. The overall prevalence of HPV in OSCC ranges between 20-50%. OSCCs associated with HPV have been found to have better outcomes, being more responsive to radiotherapy and showing higher survival rates.
In view of the association of HPV with OSCC, it should be worthwhile to conduct further experimental studies to elucidate its role in oral carcinogenesis.
Keywords: Human papilloma virus, oral cancer, oral cavity
Introduction
Head and neck squamous cell carcinomas (HNSCC) are a biologically heterogeneous group of cancers. They are a major cause of cancer morbidity and mortality worldwide, especially so in the Indian subcontinent. Head and neck cancers, 90% of which are squamous cell carcinomas (SCC), ranks sixth among all malignancies worldwide. [1],[2] In the Indian subcontinent, oral squamous cell carcinoma (OSCC) is the most common malignancy, accounting up to 40-50% of all malignant cancers. [3] Despite advances in treatment, there has been no significant decline in the mortality rate.
The most frequently detected genetic alteration in cancers of the oral cavity is the loss of tumor suppressor protein such as p53, antiproliferative proteins, and the product of the retinoblastoma gene (pRb). This is a result of either genetic mutation or interaction with viral oncoproteins like human papilloma virus (HPV) E6/E7. [4],[5] Any disruption in their activity permits the accumulation of genetic mutations, leading to a carcinogenic phenotype [Figure - 1]. Other viruses/proteins that can bind to the p53 protein and inactivate its function in the regulation of cell proliferation are the SV40 T antigen and the adenovirus E1B protein.
Globally, the main risk factors for oral cancer are tobacco and alcohol. Exposure to one or both of these factors accounts for more than 75% of oral cancers in developed countries. [6] The combined effect is multiplicative rather than additive. [7],[8],[9] Diets lacking in essential micronutrients, exposure to agents such as radiation, poor oral hygiene, genetic susceptibility of the individual, and certain viruses have also been associated with an increased risk of cancer. [10],[11],[12],[13],[14] However, approximately 20% of oral cancers occur in people lacking these established risk factors, [15],[16],[17] and there is strong epidemiologic and experimental evidence indicating that HPV may account for the majority of these cancers. [18],[19],[20] The role of HPV as an etiologic agent in cancer was first recognized in the uterine cervix and is now well established. It has been estimated that HPV infections account for 6% of cancers worldwide. Most HPV-related cancers are anogenital cancers. [21]
Pathogenesis
HPVs are small (55 nm), nonenveloped, icosahedral, epitheliotropic DNA tumor viruses that are acquired early in life. [22],[23],[24],[25] More than 118 HPVs have been completely described. [26] The role of HPV in the development of anogenital cancers has been widely studied. Approximately 50 different types of HPV can infect surfaces in the anogenital region. [27] Many of these types have also been identified in mucosal lesions of the oral cavity, including precancerous lesions and cancer-derived cell lines, as well as in lymph node metastases.
HPVs can be categorized into two major groups based on the oncogenic potential. HPV-6 and -11 are the two most common low-risk types; they account for the majority of genital warts, which rarely progress to malignancy. HPV-16 and -18 are the major high-risk types and predominate in invasive anogenital cancers. [5],[28] As in genital lesions, HPV-16 is the most common type and is associated with a wide range of oral lesions, from benign to premalignant and malignant. [29]
HPVs have been a prime suspect in the etiology of OSCC due to their morphological association with squamous cell carcinomas and their ability to immortalize oral keratinocytes and bring about transformation of epithelial cells. [30] The buccal mucosa, being the site that is most exposed to chemical carcinogens, infections, and trauma, is most vulnerable to carcinogenesis. It has been postulated that abrasions caused due to this continuous exposure might make this mucosal surface more susceptible to HPV by making it easier for the virus to gain entry into the basal cells. [31],[32],[33]
The proposed mechanism of action of HPV in tumorigenesis includes the following [Figure - 1]:
- A breakpoint in the E1/ E2 sequence allows integration of HPV into the host genome and significantly increases its tumorigenicity through upregulation of E6 and E7 encoded in the early open reading frame of the virus.
- Expression of E6 and E7 is negatively regulated by E2 protein, which is also encoded in the early open reading frame of the virus.
- By altering host genome functions, HPV E6 and E7 disrupts the p53 and pRb tumor suppressor genes, as well as numerous cellular proteins involved in carcinogenesis. [4]
- Subsequently, infected cells develop defects in gene expression controlling apoptosis, DNA repair, and cell cycle, thus paving the way for cellular transformation.
Materials and Methods It is unknown whether the physical state of the virus influences tumor biology. Application of a real-time PCR technique in the determination of the physical status of HPV-16 in OSCC samples found that patients who harbored episomal HPV-16 DNA more often had large tumors than did those whose samples contained integrated or mixed forms. [34] They observed no correlation between the physical status of HPV-16 DNA and prognosis in a series of 12 HNSCC patients. [35] Seroreactivity against the viral capsid proteins and oncogenes has been consistently associated with an increased risk of head and neck cancer.
Review of Literature
HPV, a known tumor virus, has been identified as the causative agent in 99.7% of cervical cancers. [36] In recent years, there has been mounting evidence of the role of HPV as the etiologic agent in a subset of head and neck cancers. [37] We searched the PubMed database for literature published from January 1985 through August 2008 reporting any relationship between HPV and normal oral mucosa, leukoplakia, intraepithelial neoplasia (i.e., dysplasia and carcinoma in situ ), verrucous carcinoma, and OSCC. We also searched for reports on the site-wise prevalence of the virus within oral cavity. We performed a systematic review of the available literature to test the hypothesis that HPV infection is a risk factor for OSCC, while addressing its relationship to various oral sites.
An association between HPV and head and neck cancer was first noticed during the 1960s, when there were reports of conversion of recalcitrant laryngeal papillomas to malignancy after radiation therapy. [38],[39] A possible role for HPV in the etiology of cancers at other sites within the head and neck was first suggested by Lüning et al. in 1985. [40]
There is increasing evidence of the role of HPV in the development of OSCC. Although the role is less clear in OSCC than in cervical cancer, HPV DNA has been identified in primary tumors of the tonsil, larynx, hypopharynx, oral cavity, tongue, and nasopharynx, as well as in celllines derived from a variety of head and neck carcinomas and in inverted papillomas that have progressed to SCC. Precancerous lesions and metastatic lymph nodes have also been shown to contain DNA of the same HPV type as in the primary tumor in 76% of the cases, supporting the involvement of HPV in the development of SCC. [41],[42],[43],[44],[45],[46],[47]
The prevalence of HPV in OSCC, which was initially underestimated to be between 20-30%, [48] is now considered to be as high as 50% if not more; in other words, it is likely that every alternate OSCC patient is HPV positive. [49],[50],[51],[52],[53],[54] The association is strongest in the oropharynx, most notably in the tonsil [55],[56],[57],[58],[59] and base of tongue, which present more frequent basaloid morphology and less frequent p53 mutations.
HPV Genotypes Of the HPV family, more than 12 types have been found in oral lesions, including HPVs 1, 2, 4, 6, 7, 11, 13, 16, 18, 30, 32, and 57. [30] HPV-13 and -32 appears to be restricted to oral lesions. Although we found heterogeneity among the various studies [Table - 1], HPV-16 and -18 were detected in 80% of cases, revealing that high-risk HPV viruses were detected 2.8 times more often than the low-risk types in oral carcinomas; the latter appeared to be more often associated with premalignant lesions.
Age / Gender Mucosal cancer occurring in the younger age-groups-with little or no exposure to known risk factors-is increasing in incidence and has long been thought to constitute an etiologically distinct group. [60],[61] The disease may be mutilating and fatal and therefore has tremendous social implications, especially in the young. Controversy exists concerning the prognosis and treatment of these young patients. Although the picture is still not very clear, some studies have documented that high-risk HPV types are three times more likely to be detected in OSCC in young patients than in patients above 60 years of age; [62],[63] this is due to viral transmission by direct physical contact. Tumor site may also vary by age, with a higher frequency of tongue or oral cavity tumors in the younger age-groups. A higher risk of oral cancer has been found to be associated with number of sexual partners, younger age at first sexual intercourse, practice of oral sex, and history of genital warts. [64],[65],[66] However, further investigations are needed to clarify these findings.
Site There has been wide variation in HPV positivity rates in cancers at different sites in the head and neck region. Approximately 25-75% [67] of oropharyngeal cancers have tested HPV positive, with rates in tonsillar cancer being the highest, followed by cancers of the tongue and of the buccal mucosa. In one study, 74% of SCCs removed from the lateral aspect of the tongue were found positive for oncogenic subtypes of HPV, while other authors have reported 72.5-91% prevalence of HPV in tongue cancers. [68],[69],[70] These results suggest that oncogenic HPV should be considered as a risk factor for tongue cancer.
HPV in Oral Premalignant Lesions
The likelihood of detecting HPV increases from normal mucosa to premalignant lesions to oral cancer; HPV is 2-3 times more likely to be detected in precancerous oral mucosa and 4.7 times more likely to be detected in OSCC than in normal mucosa. [70]
A review of 16 studies on leukoplakia revealed that HPV was prevalent in 14.8% of the cases, with the mean age of the patients being 40.7 years. Buccal mucosa, tongue, and palate were the sites commonly harboring these viruses. [71],[72]
In verrucous carcinoma HPV showed a mean prevalence of 27%, demonstrating that the virus has a greater predisposition for buccal mucosa, alveolus, and palate. The commonest genotype was HPV 6/11, being seen in 47% of cases. [69]
Association as Cocarcinogen Certain studies show HPV infection to be associated with an increased risk (up to three times) of OSCC, independent of exposure to alcohol or tobacco, [37],[54] demonstrating that the relative risk of OSCC with HPV infection is equal to or exceeds the risk associated with tobacco and alcohol consumption. Thus, as has been discussed elsewhere, four risk factors have been found to be significantly associated with an increase in HPV detection, i.e., male gender, oropharyngeal tumors, less tobacco usage, and history of oro-genital sex. [59],[73],[74]
Prognosis
Reports on the impact of HPV positivity on prognosis in HNSCC have not been consistent. Pintos and coworkers [75] reported that HPV infection is unlikely to play any role in the prognosis of patients with cancers of the upper aerodigestive tract. Ringstrφm and coworkers, [74] however, observed that HNSCC patients who had HPV-positive tumors had better overall and disease-specific survival than HPV-negative patients.
Several studies have reported that detection of HPV DNA is highly associated with poorly differentiated cancer grade, positive lymph nodes, and late-stage disease. [58],[62],[76] Despite this, improved survival among HPV-positive head and neck cancers has been noted by others. [77] This may suggest that the effects of HPV on the p53 and Rb proteins are not as detrimental as the more classic mutations induced by other known carcinogens, such as tobacco and alcohol. It is possible, for example, that p53 inactivation may depend on the level of HPV E6 present, and that some p53 may ′escape′ inactivation. These residual functional p53 may mediate cellular apoptosis following radiotherapy. Although this is still controversial, the role of p53 in HPV-induced OSCC has been linked with better radiosensitivity of tumor. [78],[79] Some studies also support factors such as genetic predisposition being responsible for the high rate of oral cancers. P53 codon 72 genotype frequencies in Indian oral cancer patients were 0.55(Arg) and 0.45(Pro) in 37/110 patients, suggesting that Arg/Arg genotypes are more susceptible to HPV infection and oral carcinogenesis. [80]
Cell Markers of HPV Infection
HPV DNA has been detected in the full spectrum of disease, including in precancerous lesions, cancer-derived cell lines, and lymph node metastases. HPV viral load-a measure of the amount of viral DNA in the biopsy specimen-alone or in conjunction with well-characterized HPV serological assays, may also clarify the role of HPV in oral carcinoma. Antibodies against HPV E6 and E7 are strong markers of invasive HPV-associated malignancy, [81],[82] unlike antibodies against HPV DNA virus-like particles, which are considered a marker of cumulative, lifetime HPV infection and are associated with HPV-related diseases. [83],[84] These seromarkers were relatively higher among cases having high viral load as compared to those having low viral load.
Survivin expression, an index of apoptosis blockage, is higher in HPV-negative cases than in HPV-positive ones and is also more pronounced in solid tumors. [85],[86] It has been documented that increased survivin is associated with poor prognosis and reduced survival. [87] Thus, HPV-positive oral cancers show relatively good clinical and biomolecular behavior, no recurrence, 5% mortality, and better response to radiotherapy.
HPV Prevalence in Indian Oral Cancers Not much data is available regarding the incidence of HPV-induced oral cancers in the Indian scenario. Whereas the tongue and the floor of the mouth are the common sites for the development of SCC in Western countries, [12] the buccal mucosa is the most common site for SCC in India; this is chiefly attributable to the common habit of placing a tobacco and betel quid in the gingival sulcus. Studies on patients with tobacco-induced OSCC have produced some interesting findings; for example, 33.6% of OSCC patients were HPV positive in Eastern India as compared with 67% in South India and 15% in Western India. [13],[14] HPV infection is more prominent in OSCC cases from India than in patients from other countries; for example, only 23% of Japanese patients, 8-20% of American patients, and 19% of Dutch patients are HPV positive. Apparently, HPV plays a very important role in the development of oral cancers in the Indian population. Among oropharyngeal SCCs that are positive for HPV DNA, 90% show the presence of HPV-16. In a study of 110 patients from Eastern India with tobacco-induced OSCC, out of 37 patients who were HPV positive, HPV-16 was the most frequently involved type (22.7%), followed by HPV-18 (14.5%) and HPV-16/18 coinfection (10%). [80] These findings are in agreement with that of other groups except that of Balaram et al ., [13] whose study was based on a South Indian population.
Future Directions
Although several studies have supported the presence of an association between HPV infection and oral cancers, the significance of HPV in the prognosis of oral cancers has not been firmly established. The reason for this underlying therapeutic benefit may be treatment related. It is interesting to note that overall survival was significantly higher in these HPV-HR compared to HPV-negative cases. [77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88] Future clinical management and treatment decisions may need to take into consideration differences in the extent of disease associated with HPV infection and perhaps recognize virus-related tumors as a separate disease entity.
Understanding the role of HPV in the etiology of oral cancer may be essential in determining prognosis and treatment and for disease prevention. Over the past few years, there have been significant advances in the understanding of the tumor pattern, and various options are now available as far as treatment modalities and techniques of surgical reconstruction are concerned. However, there has been no significant improvement in the 5-year survival of these patients, which continues to be around 40%. Thus, additional information regarding the pathogenesis of these tumors is necessary that would aid us in providing better prognosis for these patients. Various cellular proteins, such as p53, cyclin D1, and p27, have been identified as prognostic markers [89],[90] but none have gained universal acceptance. However, the use of immunohistochemistry, with screening of oral cancers for HPV-16 by PCR for p16 expression as a marker of HPV E7 oncogene activity, has now been extensively studied and should soon find universal acceptance as a method for identifying the etiology of these cancers; this will also have prognostic implications.
The identification of HPV-16 and -18 as the major types causing cervical cancers, and HPV-6 and -11 as causing the majority of genital warts, have resulted in the development of prophylactic vaccines based on their viral capsids; these vaccines have shown beneficial results in clinical trials [91],[92],[93],[94],[95],[96],[97],[98],[99],[100] and should soon become available in the market. This is encouraging and gives us hope that it should be possible to develop such vaccines against head and neck cancers too; it would be especially useful in advanced cases, where its therapeutic benefit when given along with other treatment modalities would result in a better prognosis for the patient.
Conclusions
There has been a rising international recognition of the role of HPV as an etiologic agent in a subset of oral cancers. The HPV detection rate of 20-50% in oral carcinomas is among the highest of any extragenital human malignancy. Given this high rate of positivity, HPV may be recognized as a tumorigenic factor for the development of head and neck cancers.
HPV association has been linked with better overall survival of these patients. It therefore becomes essential to consider cytological screening of patients who may harbor latent high-risk HPV in their oral mucosa. This knowledge would be helpful in certain situations; for example, the detection of HPV in a patient with dysplastic oral will be of great help in guiding decision making. Also, treatment modalities are different for HPV-associated OSCCs vs non-HPV-associated OSCCs.
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