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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 297-306  

Is periodontitis a risk factor for lung cancer? A meta-analysis and detailed review of mechanisms of association


1 College of Dental Sciences & Research Centre, Ahmedabad, India
2 New York University College of Dentistry, New York, USA
3 Metropolitan Hospital Center, New York, NY, USA
4 Nitte (Deemed to be University), AB Shetty Memorial Institute Of Dental Sciences(ABSMIDS), Department of Conservative Dentistry And Endodontics, Mangaluru, Karnataka, India

Date of Submission17-Feb-2022
Date of Decision05-Jul-2022
Date of Acceptance23-Aug-2022
Date of Web Publication28-Nov-2022

Correspondence Address:
Dr. Raksha Bhat
Department of Conservative Dentistry and Endodontics, Nitte (Deemed To Be University), Ab Shetty Memorial Institute of Dental Sciences, Mangaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ccd.ccd_117_22

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   Abstract 


Background: Numerous studies have explored the correlation of periodontal disease (PD) with the risk of lung cancers, but the findings were inconsistent. Therefore, we did a meta-analysis to ascertain the correlation of PD with the risk of incident lung cancer. Methods: The authors searched relevant studies in databases (PubMed, Web of Science, Scopus, Embase, and MEDLINE) till November 2020. We registered the study at the International database of Prospectively Registered Systemic Reviews under the CRD42020198119. The summary relative risk (RR) along with a 95% confidence interval (CI) was calculated using fixed-effects models. Results: Twelve studies were included in the qualitative synthesis. The pooled analysis revealed that PD was significantly associated with an increased risk of lung cancer (RR 1.71; 95%CI 1.61–1.81; P < 0.01). Subgroup analysis was performed based on gender distribution, geographic location, and type of studies. Conclusion: From this current evidence, PD is a potential risk factor for the development of lung cancer. The risk for incidence of lung cancer is surged twice in the patients with PD, even though age and smoking are controlled in the studies.

Keywords: Lung cancer, meta-analysis, periodontitis, systemic review


How to cite this article:
Kesharani P, Kansara P, Kansara T, Kini A, Bhat R, Shetty P, Penugonda B. Is periodontitis a risk factor for lung cancer? A meta-analysis and detailed review of mechanisms of association. Contemp Clin Dent 2022;13:297-306

How to cite this URL:
Kesharani P, Kansara P, Kansara T, Kini A, Bhat R, Shetty P, Penugonda B. Is periodontitis a risk factor for lung cancer? A meta-analysis and detailed review of mechanisms of association. Contemp Clin Dent [serial online] 2022 [cited 2023 Jan 28];13:297-306. Available from: https://www.contempclindent.org/text.asp?2022/13/4/297/361981




   Introduction Top


The mouth is a mirror of the body. The most prevalent oral diseases, dental caries, and periodontal diseases (PD) are of microbial origin. More than 700 bacterial species in PD are accountable for different grades of pathogenesis toward the host. Aforesaid literature betrayed the association between PD and diabetes, respiratory diseases, cardiovascular diseases, mental disorders, and pregnancy complications.[1],[2],[3],[4],[5] Moreover, concerning evidence revealed an association between periodontitis and oral cancer, cancer of the head and neck, esophagus cancer, lung, pancreas, colorectal, breast, and hematopoietic cancer.[6],[7],[8],[9],[10],[11],[12],[13] In the United States, the prevalence of periodontitis is 47.2% aged 30 years and older and 70.1% aged 65% and older.[12]

Lung cancer is a terminal illness, with a 5-year mortality rate of almost 89%, accounting for approximately 25% of all cancer deaths.[14] The American Cancer Society estimates that the risk of developing lung cancer in men is 1 in 15, whereas in women as 1 in 17 with an estimated incidence rate of 228,820 cancer cases and 135,720 deaths in 2020. Although tobacco is the foremost conviction, 53% of lung cancer cases in women worldwide are not ascribable to smoking, advocating that other factors may independently increase or modify the risk for lung cancer.[15],[16] Many cohort and case–control studies were executed since the first association between PD and lung cancer was offered and suggested genetic, microbial, and inflammatory links of pathogenesis between these two. Such connections could be due to several mechanisms: (1). Systemic spread of oral bacteria causes damage to distant organ sites, (2). Increase in systemic inflammatory mediators that initiate and promote tumorigenesis, (3). A change in host immunity by autoimmune response produced during PD.[15],[16],[17],[18] However, no study was able to explain the comprehensive mechanism of interrelation between PD and lung cancer.

Focusing on initial detection and anticipation plans to bring down cancer burden are condemnatory, and oral health seems like a field that may have the future to contribute to cancer deterrence. To assess the role of PD on cancer burden, it is essential to determine whether the association detected in population studies is casual. A meta-analysis performed by Zeng et al., including five cohort studies until 2014, concluded that individuals with PD were associated with a 1.24-fold increased risk of developing lung cancer.[9] Pooled results of the previous studies reinforced the hypothesis of an association between periodontitis and all types of cancer. However, the low methodological quality prohibited us from the punctual implementation of the judgment.[12],[17],[18] Even though positive relatedness was found, the validity of the result was limited by the inclusion of high-quality and low-quality studies in a single analysis since low-quality studies showed associations. If the corroboration is adequately strong, endorsements can be made to promote prevention through refinements in the dental coverage and enhance awareness of the risk. Therefore, after more recent studies, a more comprehensive meta-analysis is the lifeblood to provide solid authentication of the association.


   Methods Top


Literature and search strategy

The protocol was designed according to preferred reporting items for systemic review and meta-analysis for protocols and recommendations, and registered at the International database of Prospectively Registered Systemic Reviews under the CRD42020198119.[19]

The targeted review question was: Is PD positively associated with lung cancer? The emphasized question obeyed PECO criteria: The population (P) was patients of any age, the Exposure (E) was the presence of periodontitis, the Comparison (C) was an absence of PD, and the Outcome (O) was patients having lung cancer.

Searched methods for the identification of studies

A comprehensive electronic search of the following databases was conducted: PubMed, MEDLINE database through Ovid interface, EMBASE database through Ovid interface, Scopus, and Web of Science between 1952 and 2020. The search was done using keywords along with Boolean operators “OR” and “AND.” The search string from databases was: “Periodontitis” OR “Periodontal disease” OR “Tooth loss” AND “Lung Cancer.” The reference list of all included studies was scanned for relevant review articles and editorial to identify additional pertinent studies. We coped all references by operating reference manager software (EndNote Basics, Clarivate Analytics). The search was completed on November 31, 2020.

Eligibility criteria

The titles, abstracts, full texts, and appraised studies were independently screened based on the following inclusion criteria: (1). Studies on human subjects, (2). Retrospective and prospective cohorts, and nested case–control studies with available full-text articles, (3). Exposure point is PD regardless of the depth and severity of periodontitis, (4). Description of how confounders were controlled in the analysis, precisely age and smoking, (5). Results reported in terms of adjusted risk ratio (RR) and hazards ratio (HR) associated with a 95% confidence level. In the case of divergence in the article eligibility process, a blinded assessor solved the query.

Data extraction

The data were individualistically collected, and the results were compared. The following data were extracted from each arm of the study: Author's name and year of publication, study design and country of origin, population studied, the sample size in exposure and comparison group, outcome numbers in exposure and comparison group, age and gender, duration of follow-up, methods of determining exposure and outcome, RR or HR associated with 95% confidence interval (CI) and confounder factors controlled for the study.

Outcome measures

The primary outcome was lung cancer risk in patients with periodontitis which was the only outcome measured in the present analysis.

Assessment of methodological quality of studies

The quality of studies was evaluated using the Newcastle-Ottawa Scale.[20] This scale encompasses the assessment of three parts: selection (0–4 stars), compatibility (0–2 stars), and outcome (0–3 stars). The high-quality study consists of 3 or 4 stars in the selection, 1 or 2 in comparison, and 2 or 3 stars in the outcome domain.

Statistical analysis

Relative risk (RR) with a 95% CI was used as a measure of association across the studies. The analysis was performed with the aid of R statistical software version 3.5.3 (Revolution Analytics). Heterogeneity among studies was evaluated by the I2 test (ratio of true heterogeneity to total observed variation) and s2 (among-study variance). I2 values higher than 50% indicate moderate heterogeneity. In the presence of heterogeneity, the effect estimates across studies by use of a random effect model were combined.

All 12 cohorts and case–control studies were included in the final analysis. Because of the increased heterogeneity obtained from the pooled data, separate meta-analyses were carried out, including only high-quality and low-quality trials. The potential heterogeneity was explored by subgroup analysis and sensitivity analysis. Sensitivity analysis was conducted by deleting each study at a time and calculating the summary effect size of the remaining research.


   Results Top


Literature retrieved and study characteristics

Seven hundred and twenty-two citations were identified from the search in the selected databases. After removing duplicates, the articles were narrowed down to 151 articles. Based on the exclusion criteria, a full text of 41 articles was selected for detailed reading. Evaluating the reference lists in the chosen studies, two articles were included. Twelve studies in total met the eligibility criteria [Figure 1]. The variables with missing values for an adjusting variable were not included in the full model analysis.
Figure 1: PRISMA flow diagram, PRISMA: preferred reporting items for systemic review and meta-analysis

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[Table 1] summarizes the detailed characteristics of included studies reporting risk estimates for the correlation between periodontitis and lung cancer.[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32] Eight cohort studies and 1 case–control study of high quality have been reported [Table 2] and [Table 3]. P < 0.05 was considered statistically significant.
Table 1: Characteristics of studies on the association of periodontal disease with lung cancer

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Table 2: Quality assessment of cohort studies using New Castle Ottawa Scale

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Table 3: Quality assessment of case control studies using New Castle Ottawa Scale

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Overall estimates

Pooled results showed that subjects with periodontitis have an increased risk of lung cancer by 1.71 times. (RR 1.71; 95%CI 1.61–1.81; P < 0.01) [Figure 2]. Estimates from the high-quality studies indicate the association becomes stronger than the pooled results from low-quality studies (high-quality studies analysis – RR 1.91; 95%CI 1.77–2.07; P < 0.01 vs. low-quality studies meta-analysis – RR1.45; 95%CI 1.33–1.57; P < 0.01) [Figure 3].
Figure 2: Forest plot for periodontal disease associated with lung risk cancer

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Figure 3: Forest plot of high-quality versus low-quality studies

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Subgroup analysis

Subgroup analysis according to study design [Figure 4] revealed a significant relation of periodontitis with increased risk of lung cancer in prospective cohorts (RR 2.08; 95%CI 1.92–2.24; P < 0.01) than in case–control studies (RR 1.26; 95% CI 1.16–1.37; P = 0.75).
Figure 4: Forest plot of cohort versus case–control studies

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Gender-specific analysis [Figure 5] showed that the association between periodontitis and risk of lung cancer was significant in male and female populations (RR 1.55; 95% CI 1.42–1.70; P < 0.01), women population alone (RR 1.70;95% CI 1.56–1.87; P = 0.02), and men population alone (RR 1.95; 95% CI 1.73–2.20; P < 0.01).
Figure 5: Forest plot of gender-based subgroup analysis

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Seven studies were performed in America, two in Europe, and four in Asia. For subgroup analysis by geographic region [Figure 6], the association observed for the America (RR 2.00; 95% CI 1.86–2.15; P < 0.01) and the Asia (RR 1.29; 95% CI 1.17–1.42; P = 0.09) was significant, however for Europe (RR 1.15; 95% CI 0.82–1.61; P = 0.82), the association was not significant.
Figure 6: Forest plot of location-based subgroup analysis

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Sensitivity analysis

In sensitivity analysis using the leave-one-out approach, the result showed that no individual study altered the pooled RR for lung cancer demonstrating that meta-analysis results were robust.

Survival plot analysis

Based on the results obtained by the survival plot analysis for patients with lung cancer with or without periodontitis included in the present analysis, it was found that patients with periodontitis have 1.31 times more chance of getting lung cancer as compared to patients without periodontitis [Figure 7].
Figure 7: Survival plot analysis

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   Discussion Top


The present meta-analysis of eight cohorts and four case–control studies revealed that individuals with PD are associated with a 1.71-fold increased risk for developing lung cancer. Furthermore, the separate meta-analysis of high-quality studies stipulated around 2-fold intensified in risk of developing lung cancer (RR 1.91; 95%CI 1.77–2.07; P < 0.01). Of the twelve included studies, nine were adjusted for smoking status, ten were adjusted for age, and nine were adjusted for alcohol drinking status, the critical risk factors for lung cancer incidence.

The proposed hypothesis of the mechanism of association between lung cancer and periodontitis is as follows: chronic inflammation is a risk factor in 25% of cancer. Bacteria produce inflammatory mediators and detrimental effects on fibroblasts, epithelium, endothelium, and extracellular matrix by activating immunologic and inflammatory reactions. Rybojad et al. identified microorganisms from the bronchial secretion in 30 lung cancer patients. The most frequently isolated microorganisms were Actinomycosis spp., Peptostreptococcos spp., followed by Eubacterium Lentum, Veillonella Parvula, Provetella spp., Bacteroides Spp., Lactobacillus.[33]

Scannapieco proposed four mechanisms through which periodontal bacteria enter the lung and enhance infection and cancer; first, aspiration: periodontal bacteria can aspirate directly to the lower respiratory tract from salivary secretion. Lung abscesses contain the most type of facultative anaerobic bacteria, enhancing mucosal adhesion where the periodontal bacterial enzymes can modify the mucosal surface, enhance attachment and colonization, and then get aspirated into the lung. Second, poor oral hygiene leads to an increased risk of infection. Porphyromonas gingivalis and Spirochetes alter mucosal epithelium to increase adhesion and colonization of respiratory pathogens. They also secrete enzymes such as mannosidase, fructokinase, and hexosaminidase, which are responsible for increasing the adhesion of bacteria to the mucosa by exposing adhesin receptors on mucosa epithelium. Third, it can also inhibit bacterial clearance as the periodontal bacterial enzymes destroy salivary pellicles on bacteria and resist its clearance. Finally, the cytokines and pro-inflammatory mediators alter respiratory epithelium to enhance bacteria adhesion and decrease its removal.[34]

P. gingivalis causes the production of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, Il-8, tumor necrosis factor α, C-reactive protein (CRP), matrix metalloproteinases. Pine et al. evaluated the association between IL-6, IL-8, and CRP in 123 lung cancer patients using logistic regression models. High serum IL-8 level predicts the subsequent diagnosis of the disease, as it was present 5 years before the diagnosis.[35] IL-6 levels increased in patients who developed lung cancer. IL-6 and IL-8 directly act on lung epithelium via β1 (Nuclear Factor of Kappa light polypeptide gene enhancer in B-cells 1) pathways and induce tumorigenesis.[36] IL-6 plays an important role in tumor initiation and progression. IL-6 causes an increase in reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), thus capable of promoting tumor initiation by altering the epigenetics of certain genes. IL-6 activates tumorigenic-related transcription factors and causes tumor progression.[37]

Periodontal bacteria cause an increase in fibronectin expression, especially in nonsmall-cell carcinoma, by increasing the adhesion of lung carcinoma cells to fibronectin and enhancing tumorigenesis.[38] Fibronectin also interacts with vertebrate androgen receptors by stimulating gonadal steroids and controlled the expression of cyclin D. Cyclin D is a factor in a cell cycle. Due to this mechanism, fibronectin may enhance tumor growth and its resistance to therapy.[39]

Actinomycosis Actinomycetemocomitans produced cytolethal toxins, which directly affect the G2M phase of the cell cycle. Bacterial toxins can disturb the cell cycle, resulting in altered cell growth, abnormal mitosis, and apoptosis.[40]

P. gingivalis plays an important role in the development of lung cancer by acting on (Grainyhead-like 2 [GRHL2] transcription factor). GRHL2 maintains epithelial plasticity and stemness, including self-renewal capacity. The majority of GRHL2 roles are shown to be implicated with carcinogenesis action.[41] It can directly bind to the promoter region of (Ras homology Growth [RhoG] related) and plays an important role in proliferation and metastasis. RhoG is responsible for the regulation of cell shape, attachment, and mobility. GRHL2 enhances cell growth and colony formation by inhibiting cell migration and invasion.[42] GRHL2 causes regulation of epithelial-to-mesenchymal transition (EMT), and it suppresses EMT through inhibiting ZEB1 promoter transactivation. EMT is controlled by a complex network of the transcription factors ZEB1, and ZEB2. The event of cancer progression, metastasis, chemoresistance, and phenotypic plasticity is governed by EMT. Overexpression of GRHL2 causes a reduction of expression of ZEB1 and ZEB2, and increased expression of Octamer-binding transcription factor 4 (Oct-4), which was confirmed by Chen et al., who showed that GRHL2 binds with miR-200 promoter and proximal region of Oct-4 gene promoter to regulate the expression of ZEB and the occurrence of EMT.[43]

During the inflammatory reactions, the cytokines and chemokines increase the expression of NADPH oxidase and nitric oxide synthase, leading to increase production of ROS and RNI. Increased expression of oxygen and nitrogen species identified in cancer.[44]

Treatment for periodontal infection can reduce markers of systemic inflammation and endothelial dysfunction within 2–6 months. Hwang et al. found that the anti-inflammation treatment of PD significantly reduces the risk of developing lung cancer (HR 0.45; 95%CI 0.38, 0.54 P < 0.05).[45],[46]

The present meta-analysis has some possible limitations. First, although most included studies were adjusted for common covariates, including age, smoking, and alcohol consumption, other unmeasured confounding factors such as stress, socioeconomic status, and genetics might affect lung cancer and PD. Second, the result had a wide CI in three studies, which limited the power of analyses.[24],[27],[31] Third, moderate heterogeneity was detected in the pooled analysis. Thus, the subgroup results should be interpreted with caution. Assessment techniques of periodontitis were heterogeneous in included studies, and definitions for categories of PD severity were diverse between the studies. Three studies used an oral examination of periodontal tissue by dentists for assessment of PD, two studies used insurance data to evaluate PD patients, seven studies used health questionnaire forms, which might affect the heterogeneity and precision of our result.[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32] Furthermore, in the literature search for the present analysis, no studies identified with safety outcomes related to lung cancer in periodontitis patients. However, this could be attributed to the focus of the analysis being only on the primary outcome measuring the lung cancer risk in patients with periodontitis.

However, the present meta-analysis has numerous critical strengths. The most significant strength is the large sample size of patients in exposure and control groups included in the cumulative analysis. Second, according to the Newcastle-Ottawa Quality Assessment score, most studies included in the analysis were high-quality studies that controlled for significant confounders such as age, sex, smoking, alcohol, diet, and other comorbidities. Six of the nine cohorts have more than 10 years of follow-up duration. Sufficiently long follow-up is necessary because most lung cancers have a long subclinical period. The results were separately investigated according to the methodological quality of the studies. Third, the most fascinating remark is that association becomes stronger (1.91-fold) when the data were pooled separately from high-quality studies compared to the 1.4-fold increase in the development of lung cancer according to the data pooled from low-quality studies. This is in accordance with a large meta-epidemiological study, which distinctly endorses that systemic reviewers should present meta-analysis confined to studies at low risk of bias for each outcome.[46] One should be attentive when illustrating the data from low-quality studies. Fourth, even though the present meta-analyses employed a moderate heterogeneity, subgroup and sensitivity analysis disclosed coherent results for the connection between PD and lung cancer, which infer the robustness and consistency of the findings.


   Conclusion Top


From the current evidence, PD is a potential risk factor for the development of lung cancer. The risk for incidence of lung cancer is surged twice in the patients with PD, even though age and smoking are controlled in the studies. We impulse health professionals and the general community to be further aware of the potential association between these two. Furthermore, it is assured that the observation of the contemporary meta-analysis could help increase awareness and significance of oral health preservation, which may lead to a downgrade of the risk for developing lung malignancy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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