Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study

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1 Q J Med 2014; 107: doi: /qjmed/hct248 Advance Access Publication 11 December 2013 Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study B.-W. WEN 1 *, C.-S. TSAI 2 *, C.-L. LIN 3, Y.-J. CHANG 4, C.-F. LEE 5, C.-H. HSU 6y and C.-H. KAO 7y From the 1 Department of Family Medicine, Buddhist Tzu Chi General Hospital, Taichung Branch, 2 Department of Otolaryngology, Tung s Taichung MetroHarbor Hospital, 3 Management Office for Health Data, China Medical University Hospital, Taichung, 4 Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, 5 Department of Oral and Maxillofacial Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, 6 Department of Nuclear Medicine, Taipei Medical University Hospital and School of Medicine, College of Medicine, Taipei Medical University, Taipei and 7 Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung and Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan Address correspondence to C.-H. Kao, M.D., Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. d10040@mail.cmuh.org.tw *These authors contributed equally to this work. y These authors contributed equally to this work. Received 29 October 2013 and in revised form 29 November 2013 Summary Aim: Periodontal disease encompasses gingivitis and periodontitis, which exerts systemic effects. We conducted a population-based study to evaluate the association between periodontal disease and the risk of cancer. Methods: We used insurance claims data from 1997 to 2010, accessing a database of 1 million randomly selected insurants in Taiwan. All patients were older than 20 and newly diagnosed with periodontitis between 1 January 1997 and 31 December The comparison cohort comprised patients older than 20, who were newly diagnosed with gingivitis in the same period. Both cohorts were followed until a cancer diagnosis, lost to follow-up, death, termination of insurance, or the end of Results: The incidence rate of cancer was 1.14 times higher in the study cohort than in the comparison cohort [confidence interval (CI) = ]. The adjusted hazard ratio (HR) was 1.05 (95% CI = ). A multivariable analysis showed that the periodontitis patients exhibited an elevated risk of developing oral cancer (adjusted HR = 1.79, 95% CI = ). Conclusion: The findings indicated that patients in the periodontitis cohort exhibited a higher risk of developing oral cancer than those in the gingivitis cohort. Introduction Periodontal disease is described as any inherited or acquired disorder of the tissues surrounding and supporting the teeth (periodontium). 1 This disease can be classified into eight subcategories, including gingival disease, chronic periodontitis and aggressive periodontitis. 2,3 Gingivitis is primarily caused by accumulated dental-bacterial plaque 2 and is the mildest form of periodontal disease. 1 Unnoticed plaque requires 2 3 days to cause gingivitis; 2! The Author Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please journals.permissions@oup.com

2 284 B.-W. Wen et al. adults who exhibit normal gingiva can develop biofilm on the teeth 24 h after conducting oral hygiene procedures (e.g. tooth-brushing) and form gingivitis days after these procedures. 1,4 The worldwide prevalence of periodontal disease as high as 90% and gingivitis affects 50 90% of the adult population. 1 Common symptoms include bleeding and tenderness. 2 Similar symptoms occur in periodontitis, 3 which is an inflammatory disease of the supporting tissues of the teeth caused by specific microorganisms or groups of specific microorganisms, resulting in progressive destruction of the periodontal ligament and alveolar bone with increased probing depth formation, recession, or both. 3 Periodontitis is always preceded by gingivitis, 3 but differs from gingivitis regarding its irreversible course. 2 Approximately 10 15% of gingivitis patients progress to chronic periodontitis; in addition to bleeding and tenderness, 3 this causes tooth mobility and eventually tooth loss if left untreated. 1 The pathogenic bacteria causing periodontitis include Porphyromonas gingivalis, Tannerella forsythia (formerly Bacteroides forsythus) and Treponema denticola. 3 Emerging evidence has suggested that periodontal disease correlates with an increased cancer risk. 5 Population-based studies evaluating the association between periodontal disease and cancer are lacking in Taiwan. Because of the high prevalence of gingivitis and the short time required to progress from normal gingiva to gingivitis, we performed a retrospective study to evaluate the risk of cancer among gingivitis and periodontitis patients. Materials and methods Data sources The National Health Insurance (NHI) program in Taiwan is a universal health insurance system that was implemented in March 1995 by the Bureau of National Health Insurance, Department of Health. At the end of 2009, the NHI program covered 99% of the million people in Taiwan and was contracted with 97% of Taiwanese hospitals and clinics. 6 The NHI program covers comprehensive medical services including inpatient and outpatient care, Chinese medicine, dental care, physical therapy, preventive care, prescription drugs and coverage at various medical institutions. The identifying factors in the patient registration files are scrambled to ensure patient anonymity. This study used a longitudinal, retrospective cohort design, assessing insurance claims data from 1997 to 2010 for 1 million people, who were randomly selected from the insurants in Taiwan. All diagnoses were coded using the International Classification of Disease, ninth revision, Clinical Modification (ICD-9-CM). This study was approved by the Ethics Review Board of China Medical University (CMU-REC ). No written informed consent was obtained from the participants, because the identification numbers used in the National Health Insurance Research Database (NHIRD) assure patient anonymity. Study participants The study patients were older than 20 and newly diagnosed with periodontitis (ICD-9-CM codes and 523.4) between 1 January 1997 and 31 December The comparison cohort included selected patients older than 20 who were newly diagnosed with gingivitis (ICD-9-CM codes and 523.1) in the same period. To ensure that periodontitis and gingivitis were accurately diagnosed, we selected patients who were admitted at least three times for related treatment. The index date was defined as the date of periodontitis or gingivitis diagnosis. Patients diagnosed with malignant cancer (ICD-9-CM codes ) before the index date or lacking sex and age information were excluded. Outcome measures By using the unique patient identification numbers, we linked to the Catastrophic Illness Patient Database to gather histological confirmation of cancer diagnoses. Both cohorts were followed until a malignant cancer diagnosis (ICD-9-CM codes , ), loss to follow-up, death, insurance termination, or the end of The baseline comorbidities were diabetes (ICD-9-CM code 250), hypertension (ICD-9- CM codes ) and hyperlipidemia (ICD-9-CM code 272). Statistical analysis The data analysis involved comparing demographic characteristics and comorbidities by using the chisquare test for categorical variables and the t-test for continuous variables between the study and comparison cohorts. The follow-up time (in personyears) was used to estimate the incidence density rates, comparing the incidence rate ratio (IRR) of the study and comparison cohorts at a 95% confidence interval (CI) based on demographic characteristics and comorbidities. The multivariable Cox proportional-hazard regression model was used to assess the risk of developing malignant cancer associated with periodontitis and gingivitis, and to adjust the demographic characteristics and comorbidities.

3 Cancer, gingivitis and periodontitis 285 Table 1 Demographic characteristics in periodontal disease patients a Periodontal disease P-value Gingivitis (N = ) Periodontitis (N = ) Gender Women (50.7) (49.2) < Men (49.3) (50.8) Age stratified (65.6) (63.1) < (22.9) (23.9) (11.5) 6749 (13.0) Age, mean SD < b Comorbidity Diabetes 7780 (8.07) 4473 (8.64) < Hypertension (17.9) 9805 (18.9) < Hyperlipidemia (12.7) 6434 (12.4) 0.09 a For periodontal disease patients, periodontal disease is divided into two disease groups, including gingivitis patients and periodontal patients. Chi-square test. b t-test. A plotted Kaplan Meier analysis was used to exhibit the probability of remaining free of oral cancer, and a log-rank test was used to evaluate the differences between the study and comparison cohorts. The level of statistical significance was set at P < 0.05 (SAS software, version 9.2, SAS Institute Inc, Cary, NC, USA). Results The study population included periodontitis patients in the study cohort and gingivitis patients in the comparison cohort. The proportional distributions showed that the study cohort comprised more men than the comparison cohort did (50.8% vs. 49.3%, P < ) (Table 1). The age distribution significantly differed, and the study cohort was older than was the comparison cohort ( vs years; P < ). The study cohort exhibited more prevalent comorbidities than did the comparison cohort, including diabetes (8.64% vs. 8.07%) and hypertension (18.9% vs. 17.9%). The IRR of cancer was 1.14 times higher among the study cohort than it was among the comparison cohort (4.84 vs per 1000 person-years, IRR = 1.14, 95% CI = ) (Table 2). However, the adjusted hazard ratio (HR) was nonsignificant, attaining a value of 1.05 (95% CI, ) after controlling for age, sex and comorbidities. A sex-specific analysis indicated that the IRR of cancer was higher among men than that among women (IRR = 1.21, 95% CI = vs. IRR = 1.05, 95% CI = ). Hence, the adjusted HR was 1.22 (95% CI = ) for men compared with women. An age-specific analysis indicated that the IRR decreased as age increased (age 20 49, IRR = 1.16, 95% CI = ; age 50 64, IRR = 1.06, 95% CI = ; age 5 65, IRR = 0.99, 95% CI = ). However, the adjusted HR was 5.80 (95% CI = ) among the 565 group compared with the group. The periodontitis patients who exhibited hypertension were at a higher risk of cancer than were gingivitis patients who lacked hypertension (HR = 1.22, 95% CI = ). Diabetic periodontitis patients were at a higher risk of cancer than were gingivitis patients who lacked diabetes (HR = 1.19, 95% CI = ). Table 3 shows a cancer-type analysis, indicating that the periodontitis patients exhibited the highest risk of developing oral cancer (HR = 1.79, 95% CI = ; Table 3). Table 4 lists the cancer risk among male and female gingivitis and periodontitis patients. The female patients exhibited an increased risk of oral cancer (HR = 2.23, 95% CI = ). The Kaplan Meier analysis indicated a significantly lower oral cancer-free rate in the periodontitis cohort than in the gingivitis cohort (log-rank P < ; Figure 1). Discussion Similar to previous studies, the current findings suggest that oral cancer is more associated with periodontitis patients compared with gingivitis patients. 5,7 Certain studies have used tooth loss as

4 286 B.-W. Wen et al. Table 2 Incidence and adjusted hazard ratio of cancer stratified by sex, age and comorbidity compared between different degrees of periodontal patients Gingivitis Periodontitis IRR b (95% CI) Adjusted HR c (95% CI) Event PY Rate a Event PY Rate a All cancers ( )*** 1.05 ( ) Sex F ( )* 1 (reference) M ( )*** 1.22 ( )*** Age ( )*** 1 (reference) ( )* 3.12 ( )*** ( ) 5.80 ( )*** Comorbidity Diabetes No ( )*** 1 (reference) Yes ( ) 1.19 ( )*** Hypertension No ( )*** 1 (reference) Yes ( ) 1.22 ( )*** Hyperlipidemia No ( )*** 1 (reference) Yes ( ) 0.94 ( ) *P < 0.05, ***P < a Incidence rate, per 1000 person-years. b Incidence rate ratio, per 1000 person-years. c Multivariable analysis including sex, age and the presence of comorbidities. Table 3 Incidence, incidence rate ratio and adjusted hazard ratio of cancer sub-divisions between different degrees of periodontal patients Cancer (ICD-9-CM) Gingivitis Periodontitis IRR b (95% CI) Adjusted HR c (95% CI) Event Rate a Event Rate a Oral ( ) ( )*** 1.79 ( )*** Pharynx ( ) ( )*** 1.26 ( ) Esophagus (150) ( )*** 1.50 ( ) Stomach (151) ( )*** 0.92 ( ) Colon (153, 154) ( )*** 0.95 ( ) Pancreas (157) ( )*** 1.15 ( ) Larynx (161) ( )*** 0.77 ( ) Lung (162) ( )*** 1.08 ( ) Breast (174) ( ) 1.04 ( ) Uterus ( ) ( )*** 1.19 ( ) Prostate (185) ( )*** 1.00 ( ) Bladder (188) ( )*** 0.93 ( ) Kidney (189) ( ) 0.89 ( ) Thyroid (193) ( )*** 0.82 ( ) Hematologic ( ) ( )*** 1.01 ( ) Others ( )* 0.93 ( ) *P < 0.05, ***P < a Incidence rate, per 1000 person-years. b Incidence rate ratio, per 1000 person-years. c Multivariable analysis including sex, age and the presence of comorbidities.

5 Cancer, gingivitis and periodontitis 287 Table 4 Incidence, incidence rate-ratio and adjusted hazard ratio of cancer sub-divisions between different degrees of periodontal patients, in women and in men Cancer (ICD-9-CM) Women Men Gingivitis Periodontitis IRR b (95% CI) Adjusted HR c Gingivitis Periodontitis IRR b (95% CI) Adjusted HR c (95% CI) Event Rate a Event Rate a Event Rate a Event Rate a (95% CI) Oral ( ) ( )*** 2.23 ( )* ( )*** 1.73 ( )*** Pharynx ( ) ( )*** 0.78 ( ) ( )*** 1.39 ( )* Esophagus (150) ( ) 0.87 ( ) ( )*** 1.59 ( )* Stomach (151) ( )*** 1.03 ( ) ( ) 0.86 ( ) Colon (153, 154) ( ) 0.95 ( ) ( )** 0.95 ( ) Pancreas (157) ( )*** 0.99 ( ) ( )*** 1.28 ( ) Larynx (161) ( )*** 0.56 ( ) ( )*** 0.80 ( ) Lung (162) ( )*** 1.11 ( ) ( )*** 1.05 ( ) Breast (174) ( )*** 1.04 ( ) Uterus ( ) ( )*** 1.18 ( ) Prostate (185) ( )*** 1.00 ( ) Bladder (188) ( )*** 1.26 ( ) ( ) 0.83 ( ) Kidney (189) ( )*** 0.76 ( ) ( )*** 1.00 ( ) Thyroid (193) ( )*** 0.73 ( ) ( )*** 1.10 ( ) Hematologic ( ) ( )*** 0.77 ( ) ( )*** 1.25 ( ) Others ( )** 0.84 ( ) ( )*** 0.98 ( ) *P < 0.05, **P < 0.01, ***P < a Incidence rate, per 1000 person-years. b Incidence rate ratio, per 1000 person-years. c Multivariable analysis including sex, age and the presence of comorbidities.

6 288 B.-W. Wen et al. Figure 1. Probability free of oral cancer for patients with periodontitis (dashed line) or with (solid line) gingivitis. a surrogate marker of periodontitis; however, tooth loss is not limited to periodontitis. In Taiwan, dental caries are the primary reason (55.3%) for tooth extraction. 8 Tooth mobility may be the appropriate parameter for measuring periodontitis; based on selfreported tooth-loss indicators, Divaris et al. 9 reported that tooth mobility, rather than tooth loss per se, is associated with squamous cell carcinoma of the head and neck. Other markers, such as the clinical attachment level (CAL), or self-reported periodontal health may be inaccurate; however, the CAL is difficult to measure in certain circumstances 4 and self-reported periodontal health is not concordant with clinical findings. 10 The cohort- and population-based and clinician-oriented design of the current study lend strength to the current findings. Oral cancer is among the 10 most common cancers in the world, 11 representing 7% of all malignant tumors. 11,12 The incidence rate of oral cancer has significantly increased in Taiwan, where men are 10 times more likely to exhibit oral cancer compared with women. Despite improvements in diagnostic and therapeutic modalities, the prognoses of patients diagnosed with oral malignancies remain poor. The 5-year survival rate is 50%, among the lowest rate of all cancers; 13 this may be due to diagnostic delays 12 because most oral cancer patients are in an advanced stage (Stages III and IV) on their first medical visit. 14 Therefore, early diagnosis and treatment are key to improving the survival rate and life quality of oral cancer patients. 14 The risk factors for oral cancer include tobaccos, such as chewing tobacco; 13,15 17 alcohol; 13,15 17 betel quid; 15,17 marijuana; 15 poor nutrition; 13 family history; 13,17 low socioeconomic status; 17 viral infections such as herpes virus or human papilloma virus; 13,15,17 poor oral hygiene; 17 and insufficient fruit and vegetable intake. 18 Smoking, drinking alcohol and chewing betel quid yield a synergistic effect; in Taiwan, those who combined these habits exhibited a 123-fold increase in the incidence of oral cavity cancer compared with those who abstained. 19 An increased risk of oral cancer was associated with using betel quid and an increased rate of smoking among young adults, 20 most of which were male. 21,22 In addition, diabetes is considered a risk factor of oral cancer. 13 The association between periodontitis and oral cancer may relate to similar risk-factor profiles, such as tobacco, 1,3 alcohol, 1 poor nutrition, 1 diabetes, 1,3,17 low socioeconomic status 4 and poor oral hygiene. 4 In Taiwan, chewing betel quid and smoking are highly correlated behaviors, yielding synergistic actions in carcinogenesis. 23 Both smoking and chewing betel quid are associated with metabolic syndrome, 24,25 which is highly related to diabetes. Hyperlipidemia and hypertension are the primary components of metabolic syndrome. These comorbidities were adjusted in the regression models to assess the cancer risks among the periodontitis and gingivitis cohorts. After adjusting for comorbidities (diabetes, hypertension and hyperlipidemia), the increased risk of oral cancer remained significant. In addition, we separately assessed the cancer risk among men and women. The women, who typically exhibit a low prevalence of smoking, alcohol use and chewing betel quid in Taiwan, continued to exhibit an increased risk of oral cancer (Table 4). Poor oral hygiene is a common risk factor of oral cancer and periodontitis, allowing excessive microflora growth that alters the species balance. 26 Oral microorganisms could be involved in the etiology of oral cancer. 26 Periodontitis causes the continued release of bacterial and inflammatory markers into saliva and, to a lesser degree, into blood. 7 Chronic inflammation can lead to carcinogenesis through the release of chemical mediators and the formation of oxidative free radicals. 27 This process may include a receptor for advanced glycation end products (RAGE), which is a multiligand receptor expressed on various cell membranes with ligands that are upregulated in inflammation. RAGE activation may alter cell function, including proliferation, survival, migration, motility and invasiveness. 28 The pathogenic bacteria involved in periodontitis (P. gingivalis) exhibits intense staining in the malignant tissues of oral cancer. 29 Porphyromonas gingivalis could penetrate and invade various epithelial cells, affecting the cell cycle and preventing epithelial cell apoptosis, a mechanism inherent to cancerization. 29

7 Cancer, gingivitis and periodontitis 289 The strength of this study is its large sample and population-based design; these factors increase the generalizability of the results. However, the study is subject to certain limitations. First, the NHIRD did not provide information regarding certain variables relevant to our investigation, such as detailed demographic information concerning smoking habits, alcohol consumption, body mass index, socioeconomic status and family history of systemic diseases, which may be major risk factors of cancer. Thus, our analyses were limited to the available data and we could not conduct sophisticated tests to adjust for unrecorded variables. Second, evidence derived from a cohort study is typically considered to be of inferior methodological quality compared with data obtained during randomized trials because the design of a cohort study design includes biases related to confounder adjustment. Despite our meticulous design and attempts to control the confounding variables, a key limitation was that bias could remain for unmeasured or unknown confounders. Third, although most of the collected data regarding periodontal disease were highly reliable, the diagnoses of periodontitis entirely relied on the ICD-9 codes (particularly 523.3, aggressive and acute periodontitis) recorded in the NHIRD. Therefore, the severity of periodontitis could not be clearly identified and the final diagnoses primarily depended on the judgments of dentists; this may be excessively subjective. In conclusion, the results of this population-based retrospective cohort study indicated that the IRR of cancer was higher among the periodontitis cohort than among the gingivitis cohort, and the periodontitis patients exhibited an elevated risk of developing oral cancer. Although periodontal disease is prevalent in Taiwan, most people remain unaware of this. 30 Treating periodontitis is likely crucial for preventing oral cancer; however, subsequent largescale controlled prospective studies are required to confirm the current findings. Acknowledgments The study was supported in part by grants from China Medical University Hospital (DMR ), Tung s Taichung MetroHarbor Hospital (TTM-TMU-96-06), the Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TD-B ), Taiwan Department of Health Cancer Research Center of Excellence (DOH102-TD-C ) and International Research-Intensive Centers of Excellence in Taiwan (NSC I ). B.-W.W. and C.-H.K: concept and design; C.-S.T., C.-F.L. and C.-H.H: provision of study materials or patient recruitment; C.-L.L. and Y.-J.C.: data collection and/or assembly; all authors: data analysis and interpretation, manuscript composition and final approval of the manuscript. 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