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Journal of Cancer Research and Therapeutics, Vol. 7, No. 3, July-September, 2011, pp. 251-255 Review Article Human papilloma virus: A new risk factor in a subset of head and neck cancers Manisha Bisht1, Sampan Singh Bist2 1 Department of Pharmacology, Himalayan Institute of Medical Sciences, Himalayan Institute Hospital Trust University, Jolly- Grant, Dehradun, India PMID: 22044803 DOI: 10.4103/0973-1482.87004 Keywords: Human papilloma virus, oropharyngeal carcinoma, squamous cell carcinoma Introduction Almost 6.5 lakh patients worldwide are diagnosed with head and neck cancer each year, and nearly 90% of these cancers are squamous-cell carcinomas. [1] Smoking and alcohol are the two main causative factors accounting for approximately 80% of oral, oropharyngeal and laryngeal carcinomas. The association between human papilloma virus (HPV) and head and neck squamous cell carcinoma (HNSCC) has been under investigation for at least 20 years. The morphological similarity of genital and oral HPV associated lesions was one of the early findings that raised the possibility that HPV might be involved in oral and laryngeal squamous cell carcinomas (SCCs). This fact was first postulated in 1983, and later confirmed in 1985. [2] Since then, there is mounting evidence that points to a much stronger association between oropharyngeal carcinomas, especially those of tonsillar origin, and infection with high risk strain of HPV, most commonly HPV-16. [3] This review describes the principles of HPV induced carcinogenesis in HNSCC and its clinical implications. Human Papilloma Virus HPVs are small non-enveloped Deoxyribonucleic acid (DNA) viruses that show particular affinity for human squamous cell epithelium. There are more than 120 different identified strains of HPV. [4] HPVs give rise to a large spectrum of epithelial lesions, ranging from benign hyperplasia (e.g. warts or papillomas) with low malignant potential to precancerous lesions having high malignant potential. HPV-1, 2 and 4 are associated with common warts, whereas HPV-6 and 11 are associated with respiratory papillomas. [5] There is a subgroup of HPVs, the ′high-risk′ HPVs (HPV-16, 18, 33 and 35) which are associated with precancerous lesions. [4] In 1995, the International Agency for Research on Cancer, on the basis of epidemiological and molecular evidence, recognized that mainly two HPV types 16 and 18 were carcinogenic in humans. [6] The genome of HPV consists of double stranded DNA enclosed in a viral capsid and its replication is critically dependent on the host-cell DNA replication machinery. HPV DNA can exist within the human cell in an integrated or an episomal form. Either state can lead to malignant progression. [4] The HPVs genome encodes for several different proteins. L1 and L2 code for the viral capsid proteins while E6 and E7 proteins create a state competent for DNA replication. The oncogenic potential of HPV is attributed to its ability to insert E6 and E7 into host cellular genomes. As a result of this integration, the function of two tumor suppressor genes is abrogated. The E6 protein binds and induces the degradation of the p53 tumor suppressor protein via a ubiquitin-mediated process, while the HPV-E7 protein binds and destabilizes the retinoblastoma (Rb) tumor suppressor protein. [7],[8] This in turn leads to defects in apoptosis, DNA repair mechanism, cell cycle regulation and finally to cellular immortalization, thus inducing the malignant phenotype. L1 protein forms viral capsid proteins that trigger an immune reaction against the virus, but do not contain the rest of the harmful viral genome. This property is being exploited to produce a vaccine against HPV. [5] Molecular Mechanism of Action Functional disruption of tumor suppressor genes p53 and pRb are common finding in SCC. However, there is a difference between the specific mechanism by which HPV inactivates p53 and pRb as compared to the other well known etiological agents of SCC-tobacco and alcohol. Excess alcohol or tobacco exposure produces mutational or epigenetic inactivation of TP53, p16 and RB1 genes in a multistep progression from normal cell to dysplasia to carcinoma. Whereas in HPV-induced tumors, HPV-E6 and E7 proteins inactivate p53 and pRb pathways, without inactivation of their genes, and since pRb negatively regulates p16 expression there is upregulation of its expression. Thus, tobacco/alcohol-associated SCC is associated with downregulation of p16 protein and TP53 gene mutation, whereas HPV-associated SCC is associated with wild-type TP53 and RB1 genes and upregulation of p16 protein levels. [9] In fact, p16 levels are so consistently over expressed that it has been proposed as a surrogate marker for high risk HPV infection that could replace the labour of intensive and expensive process of HPV DNA detection and typing. [10] Epidemiology A wide range of HPV prevalence (0-100%), along with the presence of HPV in normal oral mucosa have been reported in literature. The prevalence of HPV in HNSCC ranges from 11% to 44%. [11] A recent systematic review of literature revealed that the overall prevalence of HPV infection was 25.9% in HNSCC, and it was significantly higher among patients with oropharyngeal SCC (35.6%) as compared to those with oral (23.5%) or laryngeal (24.0%) SCC. [12] When HPV presence is further stratified by tumor site, HPV has been found in 17% - 40% of base of tongue tumors, and in 21-100% of tonsillar tumors with an average prevalence in tonsillar tumor of 50%. [3],[4],[11] In contrast, only 2.3% to 25% of oral cavity SCCs are reported as being positive for HPV. [11] HPV-16 is the most frequently detected HPV type in HNSCC, found in up to 90% of HPV-positive cases. [13] Although HPV-16 is usually found in isolation, there may be concurrent infection with other oncogenic HPV strains such as 18, 33 and 35. HPV-18 has been found in 6-11%, whereas HPV-33 has been isolated in 1-4% of oropharyngeal SCCs. HPV- 35 has been found even less frequently. [14] There also seems to be geographic variation as to which HPV type is most common in tumors. In Greece, HPV-18 was the most common strain isolated, whereas in India, HPV-16 and 18 were found at equal rates. [3] Route of Oral Human Papilloma Virus Transmission The mode of HPV transmission in HNSCC is not very clear. Various theories have proposed and multiple pathways of transmission have been suggested, including perinatal transmission, autoinfection from oral genital contact by hand and sexual transmission by oral genital contact. Several studies suggest that oral HPV infection is sexually acquired. [15] However, transmission of the virus by direct oral contact or by other means could not be excluded. In one study involving married couples with healthy oral mucosa, the results suggested that the oral route is an important means of HPV transmission between partners; one spouse had a 10-fold risk of acquiring oral HPV infection if the other spouse had persistent oral HPV infection. [16] Site of HPV Related Tumor There is evidence that specific epithelial areas of oropharynx such as the squamous columnar junction at the level of the tonsillar crypts, which is similar to the transformation zone of the uterine cervix from which most cervical cancers originate, have a stronger association with HPV due to the easy exposure of the basal cells. [17] It is unclear, however, whether HPV-associated cancer of the tonsils originates from crypt or surface epithelium, although data suggest that HPV inhabits the normal crypt epithelia. [18] The possibility that tonsillar tissue in Waldayer′s ring, which is important as an antigen-presenting site, is the reservoir of HPV, cannot be excluded. Life time risk of head and neck squamous cell carcinoma with human papilloma virus infection It is important to note that most people with HPV infection do not develop cancer. Research in women with cervical HPV infection clearly shows that 80% of women are able to clear the infection spontaneously as a result of normal immune system mechanisms. Similarly, whether persistent HPV infection in the head and neck region is a risk factor for oropharyngeal cancer has not been rigorously demonstrated. One study has shown a 14-fold increase in the risk of oropharyngeal cancer among patients seropositive for HPV-16 L1 protein, which is a measure of lifetime exposure to HPV-16 and suggested that exposure to HPV can precede the appearance of oropharyngeal cancer by 10 or more years. [19] Diagnosis of Human Papilloma Virus Infection The productivity of HPV DNA from oral samples when performing the molecular detection is quite low. It is therefore essential that all the procedures employed are highly sensitive, specific and reliable. The rate of HPV detection in HNSCC varies according to the method used and the tissue examined. Both oral tissue samples and exfoliated cells can be used for the HPV detection. Fresh frozen tissue (−70 o C) offers the highest yield of DNA as opposed to paraffin embedded or formalin fixed tissue, as these latter methods result in degradation of DNA, especially after prolonged storage. [5] Oral mucosal exfoliated cells can be obtained by either superficial brushing/scraping or oral rinse. The latter method is more efficient in terms of cell yield, DNA containing nucleated cells and is less invasive than that of biopsy. [20] Commercial mouthwashes seem to be more efficient than glucose or saline in terms of DNA yield, quality and productivity. [21] Polymerase chain reaction (PCR) is the most sensitive method available for HPV detection. Quantitative PCR offers the additional advantage of differentiating low level infection from contamination, as well as determining the viral load in the specimen. [22] Other methods such as southern blotting and In-situ hybridization should be avoided as they lead to lower HPV rates. However, there are certain inherent limitations in diagnosis of HPV associated oropharyngeal SCC. Firstly, the oral cavity is an extremely rarely a site of HPV related carcinomas, and secondly, detection of HPV DNA does not in itself prove a causal relationship. The mere presence of HPV DNA is not sufficient to relate it with carcinoma; rather, an evidence of biologically active HPV justifies the causation of SCC. Detection of high-risk E6/E7 mRNA or protein would be the ideal test for classifying a tumor as truly HPV-associated, but this determination is not feasible in formalin-fixed, paraffin-embedded tissue. Since the levels of p16 are consistently associated with HPV infection, determination of p16 expression status by immunohistochemistry could serve as a reasonable surrogate marker for biologically relevant high-risk HPV infection. More recently, p16-positive/HPV-negative oropharyngeal SCC has also been isolated and therefore its reliability as a surrogate marker has been challenged. [23] There is still a need to enhance the standardization of the approach in terms of types of oral specimen examined, sampling method applied and HPV molecular assay employed. Classification of Oropharyngeal Squamous Cell Carcinomas HPV-DNA detection per se in an oropharyngeal SCC does not prove causal association. Only transcriptionally, active HPV DNA is biologically and clinically relevant as a risk factor of oropharyngeal SCC. According to one study it was hypothesized that for HPV-DNA-positive cases, p16 expression status would identify those that were biologically relevant. [13] This study delineated three biologically and clinically distinct types of oropharyngeal SCC: Class I, HPV-negative/p16 non expressing; class II, HPV-positive/p16 non expressing; and class III, HPV-positive/p16 expressing oro pharyngeal tumors. Only patients in class III had significantly lower p53 and pRb expression. Thus, only the HPV-positive/p16 expressing oropharyngeal SCC tumors (class III) are said to be the actual HPV associated SCC. Clinic pathologic features of human papilloma virus related oropharyngeal carcinoma [24] HPV + tumors are distinct clinically and pathologically. They are more common in young patients (<40 years) with a male to female ratio of 4:1. They usually present as a small or occult primary tumor with advanced neck disease. Microscopically, they are non-keratinizing squamous cell carcinomas with basaloid features, excessive mitosis and comedo type necrosis. The tumors have a distinct immunohistochemical profile characterized by strong and diffuse p16 reactivity, low or negative p53 staining and high Ki67 labeling scores. HPV + carcinomas are more radio-sensitive and have a better prognosis than the classical keratinizing SCC. Clinical Implication of Human Papilloma Virus Researchers have tried to delineate whether there is a difference in the clinical profile of patients with HPV positive tumors. HPV-associated oral SCC patient′s are often nonsmokers and nondrinkers and on average 5 years younger than their tobacco-use-associated counterparts. [17] There is controversy regarding the issue of whether HPV positivity is more common in patients with a decreased history of tobacco and alcohol consumption. Regardless, HPV has been shown to have an additive or even synergistic effect with tobacco and alcohol in increasing the risk of HNSCC. [14] Various studies have indicated that patient who have had more sexual partners and who engaged in oral sex practices are more likely to have HPV positive tumors. [4],[14] The association of HPV positive tumors with patient′s age, tumor grade, tumor stage or nodal involvement is not well defined. [3],[11] It appears that patients with HPV positive tumors have a better clinical prognosis. [3],[4],[5],[11] In one study, it was seen that the 5-year survival in HPV positive tumors was 79%, significantly higher than HPV negative tumors (20%, P=0.0095). Disease free survival was 75% compared with 15% (P=0.0025). The 5-year local recurrence was 14% compared with 45% (P=0.03). [13] The favorable outcome of HPV-induced oropharyngeal cancers might be attributable to the wild type Rb and p53 genes, absence of field cancerization or an increased radiosensitivity. [25],[26] HPV-positive carcinomas usually do not contain any p53 and Rb mutations, and overexpression of p16 protein has been reported in HPV-associated cancers. The term ′field cancerization′ is used to describe the presence of carcinogen induced early genetic changes in the epithelium which lead to the development of multiple independent lesions. [27] Recently, there is also evidence that HPV positive cell line is extremely cisplatin resistance. [28] p16 and p53 protein expression, and high-risk human papillomavirus (HPV-HR) types have been associated with better survival in head and neck cancer (HNC). Evidence suggests that multiple molecular pathways need to be targeted to improve the poor prognosis of HNC. More recently a study examined the individual and joint effects of tumor markers for differences in predicting HNC survival. It revealed better predictive value of multiple molecular markers in HNC patients. It was seen that p16+/p53-/HPV-HR had best prognosis and the p16−/p53+/HPV- group had the lowest overall survival (84% vs. 60%, P<0.01) and disease-specific survival (86% vs. 66%, P<0.01). [29] Role of Human Papilloma Virus Prevention In recent years, two HPV vaccines have been developed. One of the vaccines is quadrivalent, and protects against HPV types 6, 11, 16 and 18. It is advised for reduction in genital warts along with cervical cancer. The other vaccine protects against HPV types 16 and 18 and is indicated for reduction in precancerous cervical lesions and cancer incidence. The impressive range of protection of these vaccines ranging from 86-100% has been recently reported. [30],[31] It is predicted that prophylactic vaccination against high-risk HPV types will eventually prevent a significant number of cervical carcinomas, although owing to the prolonged course of cervical carcinogenesis, reduction in cancer incidence will not be profound for several years. It is thought that these vaccines might have a broader implication, and also reduce the incidence of oral and genital HPV infection and thereby HPV-related oropharyngeal, anal, vulvar, vaginal and penile cancers. Because HPV seems to be a distinct etiological factor for a certain percentage of head and neck cancer, the possibility that a subset of HNSCC might be prevented by HPV vaccination is worth considering. Potential of Gene Therapy The preventive HPV vaccines may not be useful for the treatment of existing diseases. Therefore, it is necessary to develop effective therapies to take care of already infected patients. One approach is to develop therapeutic HPV vaccination strategies eliciting cytolytic T cell response against high risk HPV-E6 and E7 oncoproteins. This approach, however, has not yet been successful against carcinoma in situ and cervical carcinoma in humans. [32] Another approach is to develop gene therapy directed against HPV-E6 and E7 oncogenes to tackle HPV positive cervical tumors. [33] The various methods include the use of E6 short interfering RNA, antisense RNA to E6 and E7 genes and mutated E2 protein that acts as cancer cell specific inducer of apoptosis. [34] It was found that when E6 and E7 protein expression is suppressed, p53 and Rb protein expression increase, the HPV infected cells undergo apoptosis and tumorigenicity is greatly suppressed. However, further understanding of HPV induced oncogenesis is required, for the appropriate use of gene therapy to treat HPV associated disease in humans. Conclusion Recent data confirms that infection with HPV-16 and to a lesser extent other high risk strains of HPV is an independent risk factor for a subset of oropharyngeal SCCs, especially once arising from the tonsil. Research results also trend in the direction that there is association between riskier sexual behavior, oral HPV infection and HNSCC. HPV-associated oropharyngeal SCCs are likely to have a better prognosis than HPV negative tumors. Molecular classification of tumors is likely to provide important new information that will allow a better estimate of prognosis and may well influence treatment decisions. Since HPV-16-DNA is present in relatively high fraction of HPV-associated HNSCC, effective vaccines targeted against this virus will soon hopefully be a part of the adjuvant therapy used to treat these tumors. However, future research is required to find out the associations of HPV infection with tobacco and alcohol exposure, appropriate screening methods for HPV infection and finally the impact of anti HPV vaccines on HPV-related oropharyngeal carcinoma. References
Copyright 2011 - Journal of Cancer Research and Therapeutics |
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