Association between helicobacter pylori infection and carcinoma of the larynx or pharynx
JIAN ZHOU, DUO ZHANG, YUE YANG, LIANG ZHOU & LEI TAO
Background: Infection with Helicobacter pylori (H. pylori) plays a role in the development of gastric carcinoma. However, there is controversy as to whether H. pylori infection increases laryngeal or pharyngeal cancers.
Methods: We managed a systematic review of researches related to H. pylori infection in laryngeal or pharyngeal carcinomas, distributed up to December 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were assessed by random effects models or according to heterogeneity I2.
Results: Eleven studies were involved in the meta-analysis. Overall, H. pylori infection was significantly higher in the study group compared with the normal control group (OR = 2.87; 95% CI = 1.71-4.84, I2 = 67.1, P < 0.0001, random effects analysis). The ORs for laryngeal carcinoma were 3.28 (95% CI =1.91-5.63; I2 = 58, P < 0.0001, random effects model). The ORs for pharyngeal cancer were 1.35 (95% CI = 0.86-2.12; P=0.188, random effects model).
Conclusion: This study supported the proposition that Infection with H. pylori was related to laryngeal carcinoma, specifically in the hospital-based control group and diagnosed by PCR or ELISA. Nevertheless, no significant relationship was discovered between H. pylori infection and pharyngeal cancer.
Keywords: Helicobacter pylori, laryngeal cancer, pharynx cancer
Laryngeal carcinoma is one of the common malignancies of the upper aerodigestive tract. It accounts for 25% of all the carcinomas of the head and neck and 2-3% of the carcinomas of the entire body . Tobacco smoking and alcohol consuming are major risk factors for laryngeal and pharyngeal cancer. The other risk factors for instance, microbes, viruses, occupational exposures, gastroesophageal reflux, and genetic inheritance have also been associated with the malignancy .
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It has been verified that H. pylori has an important effect on the pathogenesis of duodenal and gastric ulcers, chronic gastritis, gastric lymphoma, and adenocarcinoma . H. pylori immigration in the upper aerodigestive zone was proved by a previous study .There are some articles studying the association between H. pylori and laryngeal malignancy, the outcomes of which are still conflicting [5–11].
The purpose of this meta-analysis study is to determine whether H. pylori infection is related to cancers of the larynx and pharynx by summarizing proof from published studies.
Material and methods
We made a systematic literature search in Web of Knowledge, PubMed, and Embase for articles published up to December, 2014 by means of related keywords and combinations thereof: for instance, ‘laryngeal cancer,’ ‘larynx carcinoma,’ ‘pharyngeal cancer,’ ‘pharynx carcinoma,’ and ‘helicobacter pylori’. We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) strategies.
Inclusion and exclusion standards
Inclusion standards were the following: (1) diagnoses of laryngeal or pharyngeal cancer, and sources of cases and controls, (2) clear evaluation of the relationship of malignances of the pharynx or larynx with H. pylori infection, (3) satisfactory data for pharyngeal or laryngeal carcinoma cases as well as controls, (4) unequivocal information on the H. pylori detection method used, (5) most updated and latest version of published articles. Exclusion standards were the following: (1) case reports, review articles, and studies not in English, and involving patients with benign sickness, (2) uncontrolled studies, (3) cohort studies, (4) animal studies, (5) and manifold articles providing outcomes from the same study.
The subsequent data were collected from every qualified article: first author’s surname, publication year, city and country of source, amount and type of controls, means of identification of H. pylori, and cases related to smoking or drinking, correspondingly. All studies were studied independently by two authors, and based on consensus.
Meta-analysis was managed using the random fixed effect model to pool individual study evaluations into an overall summary estimate of the associations between H. pylori infection and laryngeal cancer (or pharyngeal cancer). The results were given by 95% confidence interval (CI) and odds ratio (OR). The significance of the OR was decided by the Z test and p < 0.05 was identified as statistically significant. I2 was used to evaluate the heterogeneity between studies. Subsequently, stratified analyses were carried out with regarding to the features of the study (type of carcinoma, sources of controls, methods of diagnosis of H. pylori, and sample sizes). We assessed publication bias with Begg’s funnel plot. The random effects model introduces additional variation across diverse studies. We used the Stata 12.0 (Stata Corporation, College Station, TX, USA) to complete wholly statistical analyses.
As displayed in Figure1, we identified 177 studies by database searches, with 57 containing overlapping details. After subsequent initial screening of the abstracts, 22 entitled articles were selected. Among these 22 studies, two articles were removed owing to absence of controls, and eight were short of necessary statistics. Lastly, 11 articles were involved in this study. Designated characteristics of cases and controls are displayed in Table I. All articles were retrospective in scope. The carcinoma cases were primarily confirmed histologically. Seven researches addressed laryngeal carcinoma alone, and four researches addressed laryngeal cancer or pharyngeal cancer. Hospital-based controls were involved in seven researches, population-based controls were used in two researches and clinic-based controls were included in two researches. The technique of identification of H. pylori varies with authors.
Generally, comparison of H. pylori infection for laryngeal cancer against a local control was statistically significant and favoured laryngeal cancer (OR = 2.87; 95% CI = 1.71-4.84, I2 = 67.1, random effects mode). Table II showed the separate risk assessments of researches assessed in meta-analysis. Selected researches supplied full data on H. pylori infection, by carcinomas, sources of controls, H. pylori diagnosis, and sample magnitude. The results of analyses stratified with these aspects were presented in Table II. Once stratifying for carcinomas, the pooled ORs for laryngeal cancer were 3.28 (95% CI =1.91-5.63; I2 = 58, random effects model) and 1.35 (95% CI = 0.86-2.12; I2 = 0, random effects model) for pharyngeal carcinoma. In the subcategory analysis founded on the basis of controls, significant relations were detected in the hospital-based researches (OR = 3.31; 95% CI =1.49-7.35; I2 =68.2, random effects model) and in the clinic-based researches (OR =2.60; 95% CI = 1.00-6.76; I2 = 62.1, random effects model), but not in the population-based researches (OR = 2.05; 95% CI = 0.70-5.91, random effects models). Significant relations were also detected in the different ways of identifying of H. pylori infection and sample magnitude. In both overall and subcategory analyses, I2 values were 50% or greater and related p values were < 0.005, suggesting significant heterogeneity (Table II)
Sensitivity analysis and publication bias
No publication bias was evident (Figure 2) in meta-analyses of the association between H. pylori and risk of laryngeal or pharyngeal carcinoma, this was established on the basis of Begg’s rank correlation test and Egger’s regression test (Begg’s test, p = 0.876; Egger’s test, p = 0.615). We researched the influence of a single study on the whole meta-analysis assessment. Figure 3 shows the outcomes of this study, in which the meta-analysis estimates were computed omitting one study at a time. The results show that the corresponding pooled ORs were not essentially changed, demonstrating that our results were statistically forceful.
The impact of H. pylori in the pathogenesis of chronic illnesses and cancer of the digestive regions is well acknowledged [20, 21]. H. pylori infection has a prevalence of up to 90% in underdeveloped countries and around 30% in developed countries . The potential for damaging epithelial and mucosal obstacles and inflammation could lead to chronic harm and epithelial cell proliferation resulting in larynx pathology [23, 24]. The possible relationship between H. pylori infection and carcinomas of the larynx or pharynx has been an source of argument for decades. Numerous studies have been performed to demonstrate this cause-and-effect association.
This study combined formerly published data related to the association between H. pylori infection and cancers of the larynx(or pharynx) into a terse assessment of influence. The risk of developing laryngeal cancer is 2.87 times higher for the people infected with H. pylori, than for the control group (95% CI:1.71-4.84, P < 0.0001). This discovery is largely supported by the outcomes of the individual involved researches, except for one research .
A previous (2008) meta-analysis of five studies showed that the risk of developing laryngeal carcinoma is two times higher for the people infected with H. pylori, than for those in the control group , providing an indication that H. pylori infection may be related to an increased risk of laryngeal(or pharynx) carcinoma. Our research studied and analysed the outcomes of 11 researches.
Once the study was stratified by category of carcinoma, there is a higher rate of laryngeal cancer among patients infected with H. pylori than among the general population (OR =3.28, 95% CI = 1.91-5.63). No significant relationship was discovered in pharyngeal cancer, signifying that patients are perhaps more susceptible to laryngeal than pharyngeal neoplasm, or that the small number of pharyngeal cancer patients in this study resulted in such a result. Hospital-based researches (OR = 3.31, 95% CI = 1.49-7.35) reported a higher frequency of H. pylori infection than clinic-based researches (OR =2.60, 95% CI =1.00-6.76). No significant relationship was discovered in population-based controls (OR = 2.05, 95% CI =0.70-5.91, Table II). In the subcategory investigation by sample magnitude, the deviation of the pooled OR in large sample sizes (number of controls and cases≥50) was smaller compared to small-sized sets, signifying that a large sample size with adequate power was an essential to the strategy of meta-analysis. After the study was stratified by H. pylori diagnosis, we found that the best method for detection of H. pylori in the larynx (or pharynx) tissue is PCR with high specificity and sensitivity (OR=7.03, 95% CI = 4.19-11.79). This finding is similar to the research of Gong .
A well-controlled large-scale prospective study is important to completely realize the fundamental relationship between carcinomas of the larynx (or pharynx) and H. pylori infection.
Finally, a number of important limitations need to be considered. Firstly, researches involved in this meta-analysis were published in English only, signifying that a possible language bias existed. Secondly, evident heterogeneity was detected in involved researches. Thirdly, the influence of smoking and alcohol consumption on H. pylori and laryngeal carcinoma was not removed from our study. Nevertheless, it is uncertain whether the H. pylori infection was causal or related to the tobacco and alcohol consumption among most malignancy patients. Fourthly, wholly studies were case-control researches, which are responsive to recall and information and selection bias, and this may influence the outcomes of the present research.
This meta-analysis favours the suggestion that H. pylori infection is related to laryngeal carcinoma, specifically in hospital-based control researches and when diagnosed by PCR and ELISA. Nevertheless, no significant relationship was found between H. pylori infection and pharyngeal cancer. Furthermore, the small number of studies involved in this study led to a large CI in this assessment.
This work was supported by the National Natural Science Foundation of China (grant no. 30801283), the Technology Project of Shanghai (grant nos 09QA1401000, 10QA1405900 and 14411961900), Shanghai’s Health System of Talents Training Plan (grant nos XYQ2011055 and XYQ2011015).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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