|Year : 2016 | Volume
| Issue : 2 | Page : 969-974
Systematic meta-analysis on association of human papilloma virus and oral cancer
Nallan C. S. K. Chaitanya, Neeharika Satya Jyothi Allam, DB Gandhi Babu, Shefali Waghray, RK Badam, Reddy Lavanya
Department of Oral Medicine and Radiology, Panineeya Institute of Dental Sciences, Hyderabad, Telangana, India
|Date of Web Publication||25-Jul-2016|
Nallan C. S. K. Chaitanya
Department of Oral Medicine and Radiology, Panineeya Institute of Dental Sciences, Hyderabad - 500 060, Telangana
Source of Support: None, Conflict of Interest: None
Background: Oral cancer is a disease with complex etiology. There is a strong evidence for the role of smoking, alcohol, genetic susceptibility, and indications that DNA viruses could also be involved in oral cancer. Recognized initially as sexually transmitted agent, human papilloma virus (HPV) is now considered a human carcinogen. Papilloma viruses are epitheliotropic viruses. A strong association of cervical cancer has been implicated with high-risk HPV16 and HPV18 infections, establishing the viral pathogenesis of the carcinoma. The etiopathogenesis is still unclear referring mainly to conflicting evidences in the detection of such viruses in oral carcinoma in spite of few studies suggesting their positive correlation.
Aim of the Study: This systematic meta-analysis aimed to provide evidence-based analysis of literature relating oral cancer and HPV, along with identification of reliable diagnostic methodology for identifying HPV in oral and oropharyngeal cancer.
Materials and Methods: A systematic review was performed using PubMed (from the year 1995 to 2015), Medline, Cochrane, ScienceDirect, and the Internet search. Reviewed literature included randomized control trials, cross sectional and cohort studies. Pooled data were analyzed by calculating relative risk and odds ratios (ORs), using a binary random-effects model.
Results: Out of 1497 cases, 588 patients were positive for HPV DNA, detected by various methods. About 39.27% of case samples were positive for HPV DNA. The calculated OR was 2.82 and 95% confidence interval, which showed significantly an increased risk of HPV among case group when compared to that of controls.
Conclusion: The present meta-analysis suggests a potentially significant casual relation between HPV and oral and oropharyngeal cancers.
Keywords: Human papilloma virus, meta-analysis, oral cancer, oropharyngeal carcinoma
|How to cite this article:|
Chaitanya NC, Allam NS, Gandhi Babu D B, Waghray S, Badam R K, Lavanya R. Systematic meta-analysis on association of human papilloma virus and oral cancer. J Can Res Ther 2016;12:969-74
|How to cite this URL:|
Chaitanya NC, Allam NS, Gandhi Babu D B, Waghray S, Badam R K, Lavanya R. Systematic meta-analysis on association of human papilloma virus and oral cancer. J Can Res Ther [serial online] 2016 [cited 2020 Mar 30];12:969-74. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/969/179098
| > Introduction|| |
Cancers occurring in the oral cavity account for 2–3% of all malignancies. Incidence of oral cancer has been increasing in most regions of the world. Tobacco smoking and alcohol consumption are the major causative factors for head and neck squamous cell carcinoma (HNSCC). The exact role of human papilloma viruses (HPVs) in the case of oral squamous cell carcinoma (OSCC) and premalignant continues to be a debated topic despite the well-established fact that the vast majority of cervical squamous cell carcinoma of uteri was attributable to HPV infection.
Across the world, HPV infections are the most common sexually transmitted viral infections. The HPV is a double-stranded DNA virus and its genome contains eight open-reading frames, which are potential coding sites of six early (E) proteins and two late (L) proteins. Over 120 types of HPVs have been identified to date. Most of the HPVs that infect human mucosae belong to alpha papilloma viruses, which include 15 species. HPV infections, have been postulated as a possible risk factor for at least some varieties of oral cancer. Quite a few studies have detected the DNA of HPV in a considerable proportion of malignant tumors of the head and neck cancers, with rates of detection ranging from 0% to 100%.
Various epidemiological studies have evaluated the relation between HPV infection and OSCC using techniques which detect only viral DNA using polymerase chain reaction (PCR), etc., only serological assays using enzyme-linked immunosorbent assay (ELISA), etc., or using both techniques. There were merely few studies which focused on evaluating the reliable diagnostic method in the detection of HPV-related oral and oropharyngeal cancers.
The present study aimed at evaluating the presence of HPV and oral and oropharyngeal cancers, also analyzing various diagnostic methodologies in such association.
| > Materials and Methods|| |
A systematic literature search was performed using PubMed, Cochrane library, EBSCO search, ScienceDirect, and the Internet search, with language restriction to English. The search included published studies which dealt with detection methods of HPV-related oral and oropharyngeal cancers, from January 1995 to June 2015. Literature search was done using keywords such as oral cancer and HPV, oropharyngeal cancer and HPV, and detection method of HPV-related oral cancers.
Randomized controlled trials (RCTs) and case–control studies correlating HPV and oral and oropharyngeal carcinomas and those evaluating various diagnostic methods in the detection of HPV in oropharyngeal carcinomas only were involved in the search. The quality of reviewed literature was assessed by Hadorn et al. criteria.
Articles that were not published in English or where the full text could not be acquired were excluded from the search. Case reports, reviews, non-RCTs, noncase–control studies, and articles that included only cases who tested positive for HPV, studies based on pediatric population, and animals and in vitro studies were not included in the study.
Two separate investigators were involved in retrieving and analyzing the articles, based on inclusion and exclusion criteria.
Flow chart of investigators
Principal investigator and two co-investigators were involved in data extraction, as depicted in the flow chart [Figure 1]. Co-investigator 1 was allotted the task of scrutinizing studies related to the association of oral and oropharyngeal cancer and HPV whereas co-investigator 2 was allotted the task of analyzing studies on various diagnostic methodologies in such association. Both the co-investigators reported to the principal investigator and the principal investigator supervised and further analyzed the data.
All the articles were analyzed and the data were extracted utilizing the eligibility, validity, and design of the study, which included relevance of HPV to oral and oropharyngeal cancers in case and control group, and HPV detection methods. When studies included extraoral and oropharyngeal sites, only areas from oral and oropharyngeal regions were involved. The data were tabulated in excel sheet which included presence/absence of HPV, age, gender, and methodology of detection of HPV by three different sampling techniques, i.e., biopsy, serum analysis, and cytology or CDx brush biopsy or oral swishes, separately for both cases and controls.
The data were analyzed using binary random-effects model.
The primary analysis was to identify the correlation of HPV in oral and oropharyngeal cancer patients. The association between HPV prevalence in oral cancer patients was estimated by calculating relative risk (RR) with 95% confidence interval (95% CI).
The diagnostic methodologies employed for HPV detection such as histopathology, serum analysis, and cytopathology using oral CDx or oral swishes were analyzed taking CI of 95% with P value significance taken as <0.05.
| > Results|| |
Results of search strategies
Out of 1177 publications, related to search strategy, 36 full articles which were related with prevalence of HPV in oral and oropharyngeal cancers and various HPV detection methods were acquired for further inspection. Out of the 36 articles, 11 articles met the criteria of case–control studies.
Human papilloma virus and oral squamous cell carcinoma
The data from the analyzed studies are summarized in [Table 1]. The 11 articles constituted a total sample size of 1497 in case group and 3212 in control group. HPV prevalence across all studies were higher among oral and oropharyngeal cancer samples than in controls except for studies such as Herrero et al. 2003 and Ribeiro et al. 2011. The association between HPV and oral and oropharyngeal cancer was estimated with odds ratio (OR) and RR, at 95% CI. Along with the prevalence, various diagnostic methodologies which included serum analysis, histopathology, and oral CDx were also analyzed. Despite the results, high heterogeneity among the studies was noted due to the usage of various methodologies in the studies for identifying the HPV DNA in case and control groups.
|Table 1: Characteristics of studies evaluating human papillomavirus infection in oral/oropharyngeal cancers and controls|
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Out of 1497 cases, 588 patients were positive for HPV DNA, detected by various methods. About 39.27% of case sample was positive for HPV DNA. The calculated OR was 2.82 and 95% CI, which showed significantly increased risk of HPV among case groups when compared with the controls.
Human papilloma virus detection methodologies
Apart from identifying the prevalence of HPV in oral and oropharyngeal cancers, the present study also analyzed the reliable diagnostic method for identifying HPV in humans, both case and control groups. Both positive and negative samples arrived based on different methodologies, namely serum analysis, histopathological examination, and oral scrapings.
In studies using serology to detect HPV in both case and control groups, using binary random-effects model, the risk for HPV in cancer group was 3.37 (95% CI: 2.30–4.55) [Figure 2]. A study by Xingming Chen et al. showed highest weightage in this category. Serologic examination for identifying HPV in cancer patients when compared to control group was found to be 3.371 times greater in cancer group, which was significant.
|Figure 2: Forest plot showing the prevalence of human papilloma virus in case group by using serum samples. Studies are ordered by year of publication. The square and horizontal line corresponds to the study odds ratio and the 95% confidence intervals. The area of the squares reflects the weight each trial contributes in the meta-analysis. The diamond represents the combined relative risk with its 95% confidence intervals|
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In studies, where biopsy samples were taken for histopathological examination of detection of HPV DNA in both cases and controls, a study by Patrizia et al. in 2013 showed a higher weightage. Heterogeneity in this category was found to be 0%. The calculated risk was 4.895 (95% CI: 3.395–7.058) [Figure 3], which was significant. Through histopathology sampling, prevalence of HPV is found to be 4.895 times greater in cancer patients than control group.
|Figure 3: Forest plot showing the prevalence of human papilloma virus in case group by using biopsy samples. The square and horizontal line corresponds to the study odds ratio and the 95% confidence intervals. The area of the squares reflects the weight each trial contributes in the meta-analysis. The diamond represents the combined relative risk with its 95% confidence intervals|
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In studies using oral scraping, i.e., exfoliated cells, which showed 114 patients out of 1309 in case group were positive for HPV DNA when compared to 30 patients in 3819 of control group. The calculated risk was 6.58 (95% CI: 4.507–9.396) [Figure 4], which was significant. A study done by Rosenquist et al., 2005, had a highest weightage in this category. This showed that oral CDx (cytopathology) was 6.508 times greater in detecting HPV DNA in the samples of case group, when compared to control group.
|Figure 4: Forest plot showing the prevalence of human papilloma virus in case group by using oral scraping samples. The square and horizontal line corresponds to the study odds ratio and the 95% confidence intervals. The area of the squares reflects the weight each trial contributes in the meta-analysis. The diamond represents the combined relative risk with its 95% confidence intervals|
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The results discussed above were analysis of individual diagnostic methodologies compared in case and control group. When comparing serological examination of HPV DNA with histopathological examination, it was found that serology was able to identify HPV DNA, 1.129 times greater than histopathological examination, but it was insignificant. A study done by Gypsyamber et al. in 2007 showed a highest weightage in this category.
In studies comparing histopathology and oral CDx (oral scrapings cytopathology) for examining samples for HPV DNA, though histopathology was able to identify HPV 1.052 times than serology, the risk estimates were not statistically significant. The calculated risk was 1.052 (95% CI: 0.775–1.427). The heterogeneity within the studies was 19%.
Despite these results, there was a high heterogeneity found in the samples, which was varying based on individual category again, ranging from 0% to 47%.
In the present study, a sub-group analysis of topographic association of HPV in cancer patients pertaining to particular site was also done. Topographic locations included the tongue, oropharynx/tonsils, buccal mucosa, dentoalveolar complex, pharynx, larynx, and floor of the mouth. Oropharynx and tonsillar region showed a high association, i.e., 38.29% with HPV DNA followed by tongue, especially posterior region (20.34%) [Figure 5].
|Figure 5: Topographic association of human papilloma virus DNA in cancer patients. The figure shows high prevalence of human papilloma virus DNA to oropharynx and tonsillar region (38.29%), followed by tongue (20.34%) and others. Others include nasopharynx and hypopharynx|
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| > Discussion|| |
Though there is evidence which showed strong association of HPV with cervical cancers, the association of HPV with oral cancers is still debatable. Recently, the prevalence of HPV-associated oral cancers, particularly oropharyngeal group was confirmed. Yet, the role of HPV in causing oral cancers is not certain. The present study showed a strong association between oral and oropharyngeal cancers and the presence of HPV DNA.
HNSCC is the sixth most common human cancer in the developed countries and 50% of all HNSCCs occur in the oral cavity. The present study included 11 studies, in which out of 7880 case group samples, 1509 patients were positive for HPV DNA, i.e., 19% of case sample was positive for HPV DNA.
This was in accordance with various studies (Schwartz et al., 1998; Mork et al., 2001; Herrero et al., 2003; Gypsyamber et al., 2007). However, few studies showed a significant association of HPV to tonsillar area and less clear association to nontonsillar area (Pintos et al., 2008). However, some studies reported low or insignificant association of HPV and oral cancers (Ribeiro et al., 2011). Ribeiro et al. reported a very low prevalence of HPV16 E6 or E7 antibodies (<5%) in both head and neck cancers overall and in cancers of the oropharynx. The present study also showed an increased prevalence of HPV in males and younger age group cases.
HPV involvement in oral cancers was first proposed by Syrjanen et al. 1983. HPV are small DNA viruses, which are etiologically related to virtually all cervical cancers, and early HPV oncoproteins E6 and E7 are responsible for the malignant phenotype, principally through inactivation or suppression of tumor suppressor proteins such as p53 and pRB. HPV had also been associated with head and neck cancers, especially tonsillar region, as the viral DNA, mostly HPV16, has been identified in the specimens of case groups. Though the exact etiopathogenesis is elusive, it is suggested that tonsillar crypts act as reservoirs for HPV and hence the relatively increased prevalence among tonsillar cancers. Recently, it has also been observed that periodontal pockets may act as reservoirs for HPV (Hormia 2005).
In the present study, a subgroup analysis of reliable diagnostic method in identifying HPV DNA in cancer groups was done. The diagnostic methods analyzed include histopathology examination, serology, and oral CDx (scrapings). The present study showed that all the three diagnostic methods, individually, were significant in identifying the HPV DNA in case group when compared to control group. Testing method of HPV assumes critical for estimating the prevalence or association of HPV and oral cancer. Most of the studies used histopathology, which included PCR as gold standard. Various studies have done HPV genotyping, i.e., whether the HPV DNA was a high-risk (HR) type (type 16, 18, and 31/33/35) or a low-risk type (type 6 and 11) (Schwartz et al., 1998). Some of the studies performed serologic examination using ELISA. In studies using oral scrapings, cytopathology was performed by extracting the DNA from the exfoliated cells and subjecting them to PCR analysis.
In the present study, when histopathology and serology were compared in identifying HPV DNA, histopathology was able to identify HPV 1.052 times more than oral CDx, though it was statistically insignificant. This was in accordance with the meta-analysis done by Syrjänen et al., 2011, which suggested that for HPV testing, biopsy samples were more appropriate than exfoliated cell samples. This was in contrast to a study by Smith et al. who detected a 3-fold increased risk for oral cavity and oropharyngeal cancer associated with the detection of HPV DNA in exfoliated cells before treatment. When histopathology and serology were compared, serologic examination showed 1.129 times greater efficiency than histopathology in identifying the HPV DNA, and it was statistically insignificant. In the studies that analyzed the sampling, processing of the samples as well as PCR protocols should be standardized to allow for more precise comparison of the results. Thus, the suitable marker of HPV exposure assessable in case group patients and control group subjects remains elusive, mainly given the biologic variety of individual topographic regions in the oral cavity.
Another subgroup analysis was done in the present study, which was topographic association of HPV and oral and oropharyngeal cancer. Our study showed the highest association to tonsillar and oropharyngeal region, which was 38.29%. This was in agreement to the study done by Schwartz et al., 1998, which suggested that tonsillar carcinomas had the strongest association with serologic evidence of HPV type 16 infections.
The following interpretations were carried out based on those variables without sampling in the study. Few studies have demonstrated high levels of HPV in stage III and IV levels of oral and oropharyngeal cancer, which yet could not be systematically analyzed. Some studies showed case group partners reporting more than one sexual partner in their lifetime were more likely to have HPV DNA in tumors and those engaging in oral sex. Few studies observed that the association of HPV to oral and oropharyngeal cancer was independent of smoking and chewing habits. (Herrero et al. 2003).
| > Conclusion|| |
The present study showed definite prevalence of HPV in the cancer group patients when compared to control group. Along with it, all the three methods are superior in identifying HPV in cancer group, individually, but when one method is compared to another, all three diagnostic methods showed similar accuracy and none was significant over the other. As HPV-related oral cancers are emerging as a separate disease entity, it is needed to understand the importance of HPV investigations in oral cancer. Necessity of mass education on sexual habits should also to be focused.
One shortcoming of the meta-analysis is the heterogeneity in the study samples, especially with the diagnostic methodologies, as there was no standardization in PCR analysis. Most of the studies have focused only on HPV16 or a restricted panel of other HR-HPV genotypes, and hence identification of other HPV variants was not investigated upon. This affected the epidemiological samples. In addition, as most of these studies have failed to bring together the data on age, drinking history, smoking, sexual habits, or other potential risk factors, and considering their heterogeneity, analysis could not be attempted upon the confounding risk factors of HPV.
It is still unclear whether the association of HPV with oral cancer is an incidental finding or a sole etiologic factor. If the etiopathogenesis of HPV-related oral and oropharyngeal cancers is evaluated, then proper preventive and therapeutic aspects can be developed. Role of HPV in field cancerization has to be evaluated. Some of the studies have shown that HPV has an influence on the prognosis of HPV-related cancers. Hence, further research related to prognosis of HPV-related cancers has to be done. RCTs on Indian population are very few, and there is a need for such studies to understand the epidemiology of HPV-related oral and oropharyngeal cancers in India. Further research on the role of HPV vaccine as prophylaxis in HPV-related oropharyngeal cancers is required.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]