Abstract

Aim: The aim of our study was to evaluate the relationship between routine treatment of periodontal disease (PD) and the subsequent risks for cancers in Taiwan.

Methods: Study participants were selected from the Taiwan National Health Insurance (NHI) system database. The PD with a routine treatment cohort contained 38 902 patients. For each treatment cohort participant, two age- and sex-matched comparison (control) cohort participants were randomly selected. Cox’s proportional hazards regression analysis was used to estimate the effects of PD with treatment on the subsequent risk of cancer.

Results: The overall risk of developing cancer was significantly lower in the treatment cohort than in the patients without treatment (adjusted Hazard ratio = 0.72, 95% confidence interval = 0.68–0.76). The risks of developing most gastrointestinal tract, lung, gynecological and brain malignancies were significantly lower in the treatment cohort than in the comparison cohort. In contrast, the risks of prostate and thyroid cancers were significantly higher in the treatment cohort than in the comparison cohort.

Conclusions: Our findings suggest that PD with treatment is associated with a significantly reduced overall risk of cancer and reduced risks of certain types of cancers.

Introduction

Periodontal disease (PD) is a chronic inflammatory disease that affects the alveolar bone, periodontal ligament, cementum and gingiva. It is most common in adults, and has traditionally been divided into two categories: gingivitis and periodontitis.1 Gingivitis can progress to periodontitis. PD is caused primarily by Gram-negative bacteria. The chronic bacterial infection in PD results in painful and bleeding gums, alveolar bone destruction and odontoseisis, ultimately stimulating the inflammatory response.2 The worldwide prevalence of the disease varies according to geographic location and race. Estimates of the global prevalence of severe PD generally range from 10% to 15%, and prevalences of gingivitis have been reported to up to 90%.2 One study of 8462 Taiwanese patients aged 35–44 years found that 94.8% of them exhibited signs of PD.3

The associations between PD and systemic manifestations of cardiovascular disease and diabetes are well known.4 Evidence also suggests that people with PD may have a higher risk for cancer of the mouth, upper gastrointestinal tract, breast, kidney and hematopoietic tissues.5,6 The inflammatory cells and mediators produced in response to PD may account for these relationships.6 In addition, the inflammation caused by PD may enhance cellular proliferation and mutagenesis, reduce adaption to oxidative stress, promote angiogenesis and inhibit apoptosis.7 Treatment for periodontal infection can reduce markers of systemic inflammation and endothelial dysfunction within 2–6 months.8 Based on these findings, we hypothesized that routine treatment for PD may reduce the risk of cancer. Therefore, we conducted a population based, retrospective cohort study that investigated the relationship between PD with treatment and subsequent cancer risks in Taiwan.

Materials and methods

Data sources

The participants for our study were selected from the Taiwan National Health Insurance (NHI) system. The NHI program is a universal insurance system that was formed by the Taiwan Department of Health in March 1995 from 13 previously existing insurance-related systems. By the end of 2009, the NHI covered ∼99% of the 23.74 million residents of Taiwan.9 The National Health Research Institutes (NHRI) cooperate with the Bureau of NHI to prepare annual data sets for public use that are based on NHI claims data. The data sets available at the time of our study represented the registry of a randomly sampled cohort of 1 000 000 enrollees in the NHI system with claims from 1996 to 2010. We applied the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes to retrieve information based on diagnosis. The database encrypts the patients’ personal information for privacy protection and provides researchers with anonymous identification numbers associated with the relevant claim information, which includes the patient's sex, date of birth, registry of medical services and medication prescriptions. Patient consent is not required for accessing the database. This study was approved by the Institutional Review Board of China Medical University in central Taiwan (CMU-REC-101-012).

Study subjects

Patients who were newly diagnosed and received at least 10 treatments for PD (ICD-9-CM codes 523.4 or 523.5) between 1997 and 2010 were selected as the treatment cohort. The treatments offered to these patients included subgingival curettage (scaling and root planing) and periodontal flap surgery.10 Because the prevalence of PD among the Taiwanese population is ∼95%,3 the comparison cohort consisted of two randomly selected age- and sex-matched people without medical claims for PD care between 1997 and 2010 for each treatment cohort member. The index date was defined as the date of PD diagnosis for follow-up person–years measurements. Patients with a history of cancer (ICD-9-CM codes 140-208) before the index date were excluded from our study.

Outcome measures

To measure the incidence of cancer in the treatment and comparison cohorts, the follow-up endpoint was defined as death, withdrawal from the NHI system, a diagnosis of cancer (ICD-9-CM codes 140-208) or the end of 2010. The histories of diabetes (ICD-9-CM code 250), hypertension (ICD-9-CM codes 401-405) and hyperlipidemia (ICD-9-CM code 272) were based on diagnoses made before the index date.

Statistical analysis

The distributions of sociodemographic and clinical characteristics were compared between the treatment and comparison cohorts, and examined using chi-squared analysis. The sex-, age-, occupation- and comorbidity-specific incidence densities of cancer were measured for both cohorts. To assess the relative incidence in each subgroup between the two cohorts, we measured the ratios of incidence rates. Hazard ratios (HRs) and incidences that were based on a 95% confidence interval (95% CIs) were calculated using the Cox proportional hazards model to assess the association between treatment for PD and the risk of developing cancer. Cancer site-specific incidence rates and HRs were also determined. SAS software version 9.1 (SAS Institute, Carey, NC, USA) was used for all data analyses, and two-sided probability values (P) <0.05 were considered statistically significant.

Results

Our retrospective cohort study included 38 902 participants in the PD with treatment cohort and 77 804 participants in the comparison cohort. The mean age and standard deviation of the treatment cohort was 43.1 ± 13.6 years, and 50.6% of the treatment cohort comprised women (Table 1). The comparison cohort had an age and sex distribution similar to that of the treatment cohort. The majority of the treatment cohort participants were white-collar workers, with a greater tendency to have diabetes, hypertension and hyperlipidemia than the comparison cohort. The overall incidence of cancer was 0.74-fold lower in the treatment cohort than in the comparison cohort (41.3 vs. 55.8 per 10 000 person–years; Table 2). Sex- and age-specific analyses showed that the beneficial effects of treatment for PD increased with age, and occurred more frequently in men than in women. The adjusted HR also increased with age, and was higher in men in the treatment cohort than in their female counterparts. The treatment cohort to comparison cohort IRR of cancer was lower for those with diabetes (0.68; 95% CI = 0.60–0.77) and without hypertension (0.71; 95% CI = 0.69–0.74). However, the adjusted HR was higher for those with both diabetes and hypertension.

Table 1

Comparisons of demographic characteristics and comorbidities between the PD with treatment cohort and the non-treatment comparison cohort

 Periodontal disease
 
P-value 
No treatment
 
Treatment
 
(n = 77 804) (n = 38 902) 
Age, mean ± SD (y) 43.1 13.6 43.1 13.6 0.91 
Stratify age n n  
    20–34 22 110 28.4 10 951 28.2 0.62 
    35–49 33 744 43.4 16 976 43.6  
    50–64 15 075 19.4 7587 19.5  
    65+ 6875 8.84 3388 8.71  
Sex      
    Women 39 352 50.6 19 676 50.6 0.99 
    Men 38 452 49.4 19 226 49.4  
Occupation      
    White-collara 36 263 46.6 24 187 62.2 <0.0001b 
    Blue-collarc 30 637 39.4 9715 25  
    Othersd 10 904 14 5000 12.9  
Comorbidity      
    Diabetes 3850 4.95 2451 6.3 <0.0001b 
    Hypertension 9389 12.1 5474 14.1 <0.0001b 
    Hyperlipidemia 1452 1.87 1314 3.38 <0.0001b 
 Periodontal disease
 
P-value 
No treatment
 
Treatment
 
(n = 77 804) (n = 38 902) 
Age, mean ± SD (y) 43.1 13.6 43.1 13.6 0.91 
Stratify age n n  
    20–34 22 110 28.4 10 951 28.2 0.62 
    35–49 33 744 43.4 16 976 43.6  
    50–64 15 075 19.4 7587 19.5  
    65+ 6875 8.84 3388 8.71  
Sex      
    Women 39 352 50.6 19 676 50.6 0.99 
    Men 38 452 49.4 19 226 49.4  
Occupation      
    White-collara 36 263 46.6 24 187 62.2 <0.0001b 
    Blue-collarc 30 637 39.4 9715 25  
    Othersd 10 904 14 5000 12.9  
Comorbidity      
    Diabetes 3850 4.95 2451 6.3 <0.0001b 
    Hypertension 9389 12.1 5474 14.1 <0.0001b 
    Hyperlipidemia 1452 1.87 1314 3.38 <0.0001b 

SD, standard deviation

aWhite-collar: civil services, institution workers, enterprise, business and industrial administration personnel.

bChi-square test

cBlue-collar: farmers, fishermen, vendors and industrial laborers.

dOthers: retired, unemployed and low-income populations.

Table 2

Incidence and adjusted HR of cancer stratified by sex, age and comorbidity, compared between the PD with treatment cohort and the non-treatment comparison cohort

 Periodontal disease
 
  
 No treatment
 
Treatment
 
  
 Event PY Ratea Event PY Ratea IRRb (95% CI) Adjusted HRc (95% CI) 
Cancer 4183 749 261 55.8 1846 446 535 41.3 0.74 (0.72, 0.77)** 0.72 (0.68, 0.76)** 
Sex         
    Female 1810 390 790 46.3 851 227 663 37.4 0.81 (0.77, 0.85)** 1 (Reference) 
    Male 2373 358 470 66.2 995 218 872 45.5 0.69 (0.65, 0.72)** 1.28 (1.22, 1.35)** 
Age (y)         
    20–34 213 201 261 10.6 130 130 892 9.93 0.94 (0.87, 1.01) 1 (Reference) 
    35–49 1497 345 802 43.3 670 196 339 34.1 0.79 (0.75, 1.83)** 3.71 (3.31, 4.16)** 
    50–64 1471 147 283 99.9 588 83 138 70.7 0.71 (0.66, 0.76)** 8.21 (7.31, 9.23)** 
    65+ 1002 54 914 182.5 458 36 166 126.6 0.69 (0.63, 0.76)** 14.5 (12.8, 16.4)** 
Occupation         
    White-collar 1514 339 452 44.6 1008 279 842 36.0 0.81 (0.77, 0.84)** 1 (Reference) 
    Blue-collar 2069 303 671 68.1 509 110 631 46.0 0.68 (0.63, 0.72)** 1.03 (0.98, 1.10) 
    Others 600 106 137 56.5 329 56 062 58.7 1.04 (0.95, 1.13) 0.99 (0.92, 1.07) 
Comorbidity         
Diabetes         
    No 3818 717 698 53.2 1642 420 607 39.0 0.73 (0.71, 0.76)** 1 (Reference) 
    Yes 365 31 563 115.6 204 25 928 78.7 0.68 (0.60, 0.77)** 1.12 (1.02, 1.23)** 
Hypertension         
    No 3251 666 311 48.8 1349 388 170 34.8 0.71 (0.69, 0.74)** 1 (Reference) 
    Yes 932 82 949 112.4 497 58 365 85.2 0.76 (0.70, 0.82)** 1.12 (1.05, 1.20)** 
Hyperlipidemia         
    No 4089 737 787 55.4 1766 434 711 40.6 0.73 (0.71, 0.76)** 1 (Reference) 
    Yes 94 11 474 81.9 80 11 824 67.7 0.83 (0.68, 1.01) 0.94 (0.80, 1.10) 
 Periodontal disease
 
  
 No treatment
 
Treatment
 
  
 Event PY Ratea Event PY Ratea IRRb (95% CI) Adjusted HRc (95% CI) 
Cancer 4183 749 261 55.8 1846 446 535 41.3 0.74 (0.72, 0.77)** 0.72 (0.68, 0.76)** 
Sex         
    Female 1810 390 790 46.3 851 227 663 37.4 0.81 (0.77, 0.85)** 1 (Reference) 
    Male 2373 358 470 66.2 995 218 872 45.5 0.69 (0.65, 0.72)** 1.28 (1.22, 1.35)** 
Age (y)         
    20–34 213 201 261 10.6 130 130 892 9.93 0.94 (0.87, 1.01) 1 (Reference) 
    35–49 1497 345 802 43.3 670 196 339 34.1 0.79 (0.75, 1.83)** 3.71 (3.31, 4.16)** 
    50–64 1471 147 283 99.9 588 83 138 70.7 0.71 (0.66, 0.76)** 8.21 (7.31, 9.23)** 
    65+ 1002 54 914 182.5 458 36 166 126.6 0.69 (0.63, 0.76)** 14.5 (12.8, 16.4)** 
Occupation         
    White-collar 1514 339 452 44.6 1008 279 842 36.0 0.81 (0.77, 0.84)** 1 (Reference) 
    Blue-collar 2069 303 671 68.1 509 110 631 46.0 0.68 (0.63, 0.72)** 1.03 (0.98, 1.10) 
    Others 600 106 137 56.5 329 56 062 58.7 1.04 (0.95, 1.13) 0.99 (0.92, 1.07) 
Comorbidity         
Diabetes         
    No 3818 717 698 53.2 1642 420 607 39.0 0.73 (0.71, 0.76)** 1 (Reference) 
    Yes 365 31 563 115.6 204 25 928 78.7 0.68 (0.60, 0.77)** 1.12 (1.02, 1.23)** 
Hypertension         
    No 3251 666 311 48.8 1349 388 170 34.8 0.71 (0.69, 0.74)** 1 (Reference) 
    Yes 932 82 949 112.4 497 58 365 85.2 0.76 (0.70, 0.82)** 1.12 (1.05, 1.20)** 
Hyperlipidemia         
    No 4089 737 787 55.4 1766 434 711 40.6 0.73 (0.71, 0.76)** 1 (Reference) 
    Yes 94 11 474 81.9 80 11 824 67.7 0.83 (0.68, 1.01) 0.94 (0.80, 1.10) 

aRate, incidence rate, per 10 000 person–years.

bIRR, incidence rate ratio

cAdjusted HR, adjusted hazard ratio, adjusted for age, sex, occupation, type 2 diabetes mellitus, hypertension and hyperlipidemia.

*P < 0.05, **P < 0.01

Table 3 shows the specific analyses of cancer types. Patients in the PD with treatment cohort had significantly lower risks for malignant tumors in the gastrointestinal tract, the lungs, the female reproductive organs and the brain. In contrast, the male treatment cohort participants had a significantly higher risk of prostate cancer (HR = 2.11, 95% CI = 1.63–2.73). However, the male treatment cohort had a significantly higher percentage of participants that underwent prostate-specific antigen (PSA) testing than did the men in the comparison cohort, regardless of age, with 1.12% vs. 0.35% for 20–34 years, 7.95% vs. 2.93% for 35–49 years, 20.2% vs. 9.44% for 50–64 years and 39.1% vs. 18.7% for 65 years and older, respectively (Table 4). Treatment cohort participants also had a significantly higher risk of thyroid cancer (HR = 1.54, 95% CI = 1.09–2.09; Table 3), and a significantly higher percentage of treatment cohort participants underwent thyroid diagnostic procedures, compared with the comparison cohort (Table 5).

Table 3

Incidence, incidence rate ratio and adjusted HR of subdivision cancers between the periodontal disease (PD) with treatment cohort and the non-treatment comparison cohort

 Periodontal disease
 
  
 No treatment
 
Treatment
 
  
Cancer (ICD-9-CM) Event Ratea Event Ratea IRRb (95% CI) Adjusted HRc (95% CI) 
All 4183 55.8 1846 41.3 0.74 (0.72, 0.77)** 0.72 (0.68, 0.76)** 
Hematologic malignancy (200–208) 158 2.11 82 1.84 0.87 (0.83, 0.91)** 0.84 (0.64, 1.10) 
Head and neck (140–149, 161) 390 5.21 229 5.13 0.99 (0.95, 1.03) 0.97 (0.82, 1.15) 
Esophagus (150) 136 1.82 17 0.38 0.21 (0.20, 0.22)** 0.20 (0.12, 0.34)** 
Stomach (151) 203 2.71 62 1.39 0.51 (0.49, 0.54)** 0.49 (0.37, 0.65)** 
Small intestine (152) 0.11 0.11 1.05 (0.99, 1.11) 1.15 (0.37, 3.53) 
Colon/rectum (153–154) 526 7.02 239 5.35 0.76 (0.73, 0.79)** 0.70 (0.60, 0.82)** 
Liver (155) 643 8.58 185 4.14 0.48 (0.46, 0.51)** 0.44 (0.38, 0.52)** 
Pancreas (157) 74 0.99 28 0.63 0.63 (0.60, 0.67)** 0.55 (0.35, 0.85)** 
Lung (162) 541 7.22 160 3.58 0.50 (0.47, 0.52)** 0.45 (0.38, 0.54)** 
Skin (173) 46 0.61 32 0.72 1.17 (1.11, 1.22)** 1.05 (0.67, 1.66) 
Female breast (174) 421 5.62 273 6.11 1.09 (1.05, 1.13)** 1.06 (0.90, 1.23) 
Gynecology (180–184) 305 4.07 107 2.40 0.59 (0.56, 0.62)** 0.58 (0.46, 0.72)** 
Prostate (185) 98 1.31 152 3.40 2.60 (2.49, 2.72)** 2.11 (1.63, 2.73)** 
Bladder (188) 125 1.67 63 1.41 0.85 (0.81, 0.89)** 0.75 (0.55, 1.01) 
Kidney (189) 91 1.21 54 1.21 1.00 (0.95, 1.04) 0.91 (0.65, 1.28) 
Brain (191) 52 0.69 11 0.25 0.35 (0.33, 0.38)** 0.35 (0.18, 0.67)** 
Thyroid (193) 65 0.87 63 1.41 1.63 (1.56, 1.70)** 1.54 (1.09, 2.09)* 
Others 301 4.02 84 1.88 0.47 (0.45, 0.49)** 0.45 (0.35, 0.58)** 
 Periodontal disease
 
  
 No treatment
 
Treatment
 
  
Cancer (ICD-9-CM) Event Ratea Event Ratea IRRb (95% CI) Adjusted HRc (95% CI) 
All 4183 55.8 1846 41.3 0.74 (0.72, 0.77)** 0.72 (0.68, 0.76)** 
Hematologic malignancy (200–208) 158 2.11 82 1.84 0.87 (0.83, 0.91)** 0.84 (0.64, 1.10) 
Head and neck (140–149, 161) 390 5.21 229 5.13 0.99 (0.95, 1.03) 0.97 (0.82, 1.15) 
Esophagus (150) 136 1.82 17 0.38 0.21 (0.20, 0.22)** 0.20 (0.12, 0.34)** 
Stomach (151) 203 2.71 62 1.39 0.51 (0.49, 0.54)** 0.49 (0.37, 0.65)** 
Small intestine (152) 0.11 0.11 1.05 (0.99, 1.11) 1.15 (0.37, 3.53) 
Colon/rectum (153–154) 526 7.02 239 5.35 0.76 (0.73, 0.79)** 0.70 (0.60, 0.82)** 
Liver (155) 643 8.58 185 4.14 0.48 (0.46, 0.51)** 0.44 (0.38, 0.52)** 
Pancreas (157) 74 0.99 28 0.63 0.63 (0.60, 0.67)** 0.55 (0.35, 0.85)** 
Lung (162) 541 7.22 160 3.58 0.50 (0.47, 0.52)** 0.45 (0.38, 0.54)** 
Skin (173) 46 0.61 32 0.72 1.17 (1.11, 1.22)** 1.05 (0.67, 1.66) 
Female breast (174) 421 5.62 273 6.11 1.09 (1.05, 1.13)** 1.06 (0.90, 1.23) 
Gynecology (180–184) 305 4.07 107 2.40 0.59 (0.56, 0.62)** 0.58 (0.46, 0.72)** 
Prostate (185) 98 1.31 152 3.40 2.60 (2.49, 2.72)** 2.11 (1.63, 2.73)** 
Bladder (188) 125 1.67 63 1.41 0.85 (0.81, 0.89)** 0.75 (0.55, 1.01) 
Kidney (189) 91 1.21 54 1.21 1.00 (0.95, 1.04) 0.91 (0.65, 1.28) 
Brain (191) 52 0.69 11 0.25 0.35 (0.33, 0.38)** 0.35 (0.18, 0.67)** 
Thyroid (193) 65 0.87 63 1.41 1.63 (1.56, 1.70)** 1.54 (1.09, 2.09)* 
Others 301 4.02 84 1.88 0.47 (0.45, 0.49)** 0.45 (0.35, 0.58)** 

aRate, incidence rate, per 10 000 person–years.

bIRR, incidence rate ratio, rate of case group divided by the rate of comparison group.

cAdjusted HR, adjusted hazard ratio, adjusted for age, sex, occupation, type 2 diabetes mellitus, hypertension and hyperlipidemia.

*P < 0.05, **P < 0.01

Table 4

The distribution of PSA between the PD with treatment cohort and the non-treatment comparison cohort

 Periodontal disease
 
P-value 
Variable No treatment
 
Treatment
 
 n n  
PSA      
Age (y)      
    20–34 78 0.35 123 1.12 <0.0001a 
    35–49 988 2.93 1350 7.95 <0.0001a 
    50–64 1423 9.44 1533 20.2 <0.0001a 
    65+ 1286 18.7 1325 39.1 <0.0001a 
 Periodontal disease
 
P-value 
Variable No treatment
 
Treatment
 
 n n  
PSA      
Age (y)      
    20–34 78 0.35 123 1.12 <0.0001a 
    35–49 988 2.93 1350 7.95 <0.0001a 
    50–64 1423 9.44 1533 20.2 <0.0001a 
    65+ 1286 18.7 1325 39.1 <0.0001a 

PSA, prostate-specific antigen

aChi-square test

Table 5

The distribution of thyroid diagnostic procedures between the PD with treatment cohort and the non-treatment comparison cohort

 Periodontal disease
 
P-value 
Variable No treatment
 
Treatment
 
 n n  
Thyroid procedures      
Age (y)      
    20–34 146 0.66 342 3.12 <0.0001a 
    35–49 208 0.62 485 2.86 <0.0001a 
    50–64 128 0.85 294 3.88 <0.0001a 
    65+ 67 0.97 146 4.31 <0.0001a 
 Periodontal disease
 
P-value 
Variable No treatment
 
Treatment
 
 n n  
Thyroid procedures      
Age (y)      
    20–34 146 0.66 342 3.12 <0.0001a 
    35–49 208 0.62 485 2.86 <0.0001a 
    50–64 128 0.85 294 3.88 <0.0001a 
    65+ 67 0.97 146 4.31 <0.0001a 

aChi-square test

Discussion

Cancer has been the leading cause of death in the general population in Taiwan since 1982, and the age-adjusted incidence rate has increased steadily, reaching 276 new cases per 100 000 in 2008.11 However, different trends have been reported based on surveillance epidemiology and end results data, which showed that the overall incidence rates of cancer for all racial and ethnic groups combined decreased by 0.7% per year during 1999–2006.12 Because of such inconsistencies among the results of previous studies and the challenge that rising cancer rates pose to the public health care system, the government of Taiwan has encouraged further population-based investigations of cancer epidemiology and prevention. The Taiwan NHI record databases represent valuable resources for such populated-based studies. We previously used NHI data to evaluate the risk of cancer for patients with Parkinson’s disease, and found that Taiwanese patients with Parkinson’s disease have a lower risk of developing colorectal and lung cancers.13 Because PD is highly prevalent in Taiwan, any significant finding may have a significant impact on efforts to improve public health, and our current study used a similar study design to identify relationships between PD with treatment and the risks of different types of cancer.

We showed that PD with treatment significantly reduced the subsequent risks of certain types of cancer, including malignancies of the gastrointestinal tract, the lungs, the female reproductive organs and the brain. However, prostate and thyroid cancer risks were significantly higher in the PD with treatment group. A relationship between PD and an increased risk of cancer has been proposed in previous studies that investigated both overall and site-specific cancer rates.6 The scientific rationale behind the potential association is that inflammation is a major factor in both PD and cancer,14 and that an increase in systemic circulatory C-reactive protein and other inflammatory markers may contribute to such a relationship.15 This link is also supported by higher incidences of cancer in patients with chronic inflammatory conditions.7 The presence of inflammatory cells and mediators associated with tumors are key indicators of the progression of cancer,16 and associations between certain types of cancer and chronic inflammation have been shown for inflammatory bowel disease and colon cancer, hepatitis B and C infections and liver cancer, Heliobacter pylori-associated ulcers and gastric cancer, human papillomavirus infection and cervical cancer, Epstein–Barr virus infection and Hodgkin's lymphoma, and Burkitt's lymphoma and nasopharyngeal carcinoma.16,17

Previous studies on the association of PD and the overall risk of cancer have been relatively inconclusive, with one study reporting a small increase (odds ratio = 1.14) in the overall risk of cancer,18 and other investigators finding no significant association.19 Previous studies have shown that PD is linked to higher risks of oral cavity, esophagus, stomach, pancreas, lung, breast, kidney and hematopoietic malignancies.18 However, two studies suggested an inverse association between the risk of prostate cancer and the number of teeth lost.18,20 Our results showed that PD with treatment is associated with a significantly lower overall risk of cancer, and reduced risks for malignancies of the digestive system (esophagus, stomach, colon, liver and pancreas), the lungs, the female reproductive organs and the brain were observed separately. Most of these types of cancer were observed to be related to PD in earlier studies. Conversely, our results suggest that PD with routine treatment plays a protective role regarding the development of certain types of cancer. Studies have shown that subgingival scaling in patients with widespread periodontitis reduced inflammatory markers,21 and the efficacy of anti-inflammatory medications in preventing some cancers have been widely discussed,22–24 with most studies suggesting that regular use of aspirin and other non-steroidal anti-inflammatory drugs may reduce the long-term risk of colorectal, esophageal, gastric, biliary, breast and genitourinary cancers. Our results may also suggest that anti-inflammation therapies can effectively reduce cancer risks.

Recent researches connect PD-causing mouth bacteria to tumor growth in the colon and reveal possible treatments that may prevent colon cancer.25,26 Prior work in mouse models has shown that gut bacteria, which include species found in the mouth, can promote the development of colon tumors. A series of genetic studies on human colon biopsies revealed that one family of microbes—Fusobacteria—is present in healthy tissue adjacent to colorectal cancer. Although Fusobacteria start off in the mouth and are frequently associated with PDs, they can migrate through blood vessels to far reach of the colon. Finally, the strain of mouth bacteria that causes PD may have a more lethal health consequence of colon cancer. Because colon cancer is one the most common cancers in the world, therefore our findings based on a national-wide population-based study suggest this bacterial mouth-to-colon relationship is the public health manifestations within Taiwan and globalization.

We also observed significantly higher risks for prostate and thyroid cancers following PD with treatment. However, further analyses revealed significantly higher rates of PSA testing and thyroid diagnostic procedures in the PD with treatment cohort. More regular dental care may provide patients with increased health education, thus encouraging more frequent cancer screenings. The Taiwanese government provides free screening for prostate, cervical, breast and colorectal cancers for all patients with risk indicators, which may have contributed to the more frequent diagnosis of prostate cancer patients in our treatment cohort. Cervical cancer is the most common gynecological cancer in Taiwan,11 and more frequent Papanicolaou smear examinations may result in the identification of a greater number of cervical CIS/CIN/dysplasia cases. CIN and CIS lesions are known to precede invasive tumors in the progression of cervical cancer. Patients often receive treatment before the disease progresses to invasive cancer. However, we did not include CIN or CIS as a study end-point regarding cervical cancer, which may have otherwise led to a decrease in the relative number of cervical cancer cases in our treatment cohort, as well as the total number of gynecological cancer cases. Breast cancer also occurred more frequently in our treatment cohort, but the difference did not reach statistical significance. In contrast, colorectal cancer occurred at a significantly lower frequency, which we did not expect based on our assumption that the treatment cohort received more frequent routine health check-ups. Thus, for colorectal cancer, the anti-inflammatory effect of PD treatment may have overcome the screening effect. Likewise, the anti-inflammatory effects of PD treatment may have counteracted the effect of increased screening for oral cavity, head and neck cancers, which may partially explain the lack of a significant difference in the risks of cancers in these locations between the treatment and comparison cohorts. Regarding the higher incidence of thyroid cancer, however, it is likely that incidental observations of the head and neck regions during routine dental examinations of the oral cavity may have increased opportunities for more prominent neck masses, such as thyroid masses, to be detected.

The strength of our findings lies in the population-based study design, allowing for greater generalization of our findings. However, our study has several limitations. First, information on the lifestyle or behavior of patients is lacking in the NHI database, making it impossible to adjust for health-related factors, such as smoking and alcohol consumption. Second, there are clear evidences that less educated, lower income and in general lower social class patients with higher incidence rate for cancer. However, the above information is also lacking or incorrect in the NHI database. Third, the treatment fee for PD is only partially covered by the NHI, and out-of-pocket costs are high for some PD treatments, resulting in limited treatment options and subsequent negative outcomes for patients who are unable to pay. We attempted to control for this possible confounder using adjustments based on patient occupation. Finally, the evidence derived from a cohort study is generally of a lower methodological quality than that obtained from randomized trials because a cohort study design is subject to many biases related to adjustment for confounders. Despite our meticulous efforts for adequate control of confounding factors, biases may have remained because of immeasurable or unknown confounders. Nonetheless, the data we obtained on PD and cancer diagnoses were highly reliable.

In conclusion, our population based, retrospective cohort study indicated that PD with treatment may reduce the risks of certain types of cancers, as well as the overall risk of cancer. The potential anti-inflammatory effects of routine PD treatment may have contributed to these observations. Further studies are warranted to elucidate the relationships among cancer, PD and effects of PD treatment.

Acknowledgements

Conception/design: I.-M. Hwang, L.-M. Sun and C.-H. Kao; provision of study material or patients: C.-F. Lee and C.-H. Kao; collection and/or assembly of data: C.-L. Lin; and data analysis and interpretation/manuscript writing/final approval of manuscript: all authors.

Funding

The study was supported in part by the study projects (DMR-103-018 and DMR-103-020) in our hospital; Taiwan Ministry of Health and Welfare Clinical Trial and Research Center for Excellence (DOH102-TD-B-111-004), Taiwan Ministry of Health and Welfare Cancer Research Center for Excellence (MOHW103-TD-B-111-03); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Conflict of interest: None declared.

References

1
Armitage
GC
Periodontal diagnoses and classification of periodontal diseases
Periodonto 2000
 , 
2004
, vol. 
34
 (pg. 
9
-
21
)
2
Pihlstrom
BL
Michalowicz
BS
Johnson
NW
Periodontal diseases
Lancet
 , 
2005
, vol. 
366
 (pg. 
1809
-
20
)
3
Lai
H
Lo
MT
Wang
PE
Wang
TT
Chen
TH
Wu
GH
A community-based epidemiological study of periodontal disease in Keelung, Taiwan: a model from Keelung community-based integrated screening programme (KCIS No. 18)
J Clin Periodontol
 , 
2007
, vol. 
34
 (pg. 
851
-
9
)
4
Nesbitt
MJ
Reynolds
MA
Shiau
H
Choe
K
Simonsick
EM
Ferrucci
L
Association of periodontitis and metabolic syndrome in the Baltimore Longitudinal Study of Aging
Aging Clin Exp Res
 , 
2010
, vol. 
22
 (pg. 
238
-
42
)
5
Söder
B
Yakob
M
Meurman
JH
Andersson
LC
Klinge
B
Söder
Periodontal disease may associate with breast cancer
Breast Cancer Res Treat
 , 
2011
, vol. 
127
 (pg. 
497
-
502
)
6
Fitzpatrick
SG
Katz
J
The association between periodontal disease and cancer: a review of the literature
J Dent
 , 
2010
, vol. 
38
 (pg. 
83
-
95
)
7
Coussens
LM
Werb
Z
Inflammation and cancer
Nature
 , 
2002
, vol. 
420
 (pg. 
860
-
7
)
8
Tonetti
MS
D'Aiuto
F
Nibali
L
Donald
A
Storry
C
Parkar
M
, et al.  . 
Treatment of periodontitis and endothelial function
N Engl J Med
 , 
2007
, vol. 
356
 (pg. 
911
-
20
)
9
Cheng
TM
Okma
KGH
Crivelli
L
Taiwan's national health insurance system: high value for the dollar
Six Countries, Six Reform Models: Their Healthcare Reform, Experience of Israel, the Netherlands, New Zealand, Singapore, Switzerland and Taiwan
 , 
2009
New Jersey
World scientific
(pg. 
171
-
204
)
10
Lee
CF
Lin
CL
Lin
MC
Lin
SY
Sung
FC
Kao
CH
Surgical treatment for patients with periodontal disease reduces risk of end-stage renal disease: a nationwide population-based retrospective cohort study
J Periodontol
 , 
2014
, vol. 
85
 (pg. 
50
-
6
)
11
Cancer Statistics Annual Report
Taiwan Cancer Registry
  
http://tcr.cph.ntu.edu.tw/main.php?Page=N2 (3 August 2012, date last accessed)
12
Edwards
BK
Ward
E
Kohler
BA
Eheman
C
Zauber
AG
Anderson
RN
, et al.  . 
Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates
Cancer
 , 
2010
, vol. 
116
 (pg. 
544
-
73
)
13
Sun
LM
Liang
JA
Chang
SN
Sung
FC
Muo
CH
Kao
CH
Analysis of Parkinson's disease and subsequent cancer risk in Taiwan: a nationwide population-based cohort study
Neuroepidemiology
 , 
2011
, vol. 
37
 (pg. 
114
-
9
)
14
Tezal
M
Sullivan
MA
Reid
ME
Marshall
JR
Hyland
A
Loree
T
, et al.  . 
Chronic periodontitis and the risk for tongue cancer
Arch Otolaryngol Head Neck Surg
 , 
2007
, vol. 
133
 (pg. 
450
-
4
)
15
Loos
BG
Systemic markers of inflammation in periodontitis
J Periodontol
 , 
2005
, vol. 
76
 
11 Suppl.
(pg. 
2106
-
15
)
16
Mantovani
A
Allavena
P
Sica
A
Balkwill
F
Cancer-related inflammation
Nature
 , 
2008
, vol. 
454
 (pg. 
436
-
44
)
17
Momin
B
Richardson
L
An analysis of content in comprehensive cancer control plans that address chronic hepatitis B and C virus infections as major risk factors for liver cancer
J Community Health
 , 
2012
, vol. 
37
 (pg. 
912
-
6
)
18
Michaud
DS
Liu
Y
Meyer
M
Giovannucci
E
Joshipura
K
Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study
Lancet Oncol
 , 
2008
, vol. 
9
 (pg. 
550
-
8
)
19
Tu
YK
Galobardes
B
Smith
GD
McCarron
P
Jeffreys
M
Gilthorpe
MS
Associations between tooth loss and mortality patterns in the Glasgow Alumni Cohort
Heart
 , 
2007
, vol. 
93
 (pg. 
1098
-
103
)
20
Hiraki
A
Matsuo
K
Suzuki
T
Kawase
T
Tajima
K
Teeth loss and risk of cancer at 14 common sites in Japanese
Cancer Epidemiol Biomarkers Prev
 , 
2008
, vol. 
17
 (pg. 
1222
-
7
)
21
Rastogi
P
Singhal
R
Sethi
A
Agarwal
A
Singh
VK
Sethi
R
Assessment of the effect of periodontal treatment in patients with coronary artery disease: a pilot survey
J Cardiovasc Dis Res
 , 
2012
, vol. 
3
 (pg. 
124
-
7
)
22
Algra
AM
Rothwell
PM
Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials
Lancet Oncol
 , 
2012
, vol. 
13
 (pg. 
518
-
27
)
23
Flossmann
E
Rothwell
PM
British Doctors Aspirin Trial and the UK-TIA Aspirin Trial
Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies
Lancet
 , 
2007
, vol. 
369
 (pg. 
1603
-
13
)
24
Rothwell
PM
Wilson
M
Elwin
CE
Norrving
B
Algra
A
Warlow
CP
, et al.  . 
Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials
Lancet
 , 
2010
, vol. 
376
 (pg. 
1741
-
50
)
25
Rubinstein
MR
Wang
X
Liu
W
Hao
Y
Cai
G
Han
YW
Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin
Cell Host Microbe
 , 
2013
, vol. 
14
 (pg. 
195
-
206
)
26
Kostic
AD
Chun
E
Robertson
L
Glickman
JN
Gallini
CA
Michaud
M
, et al.  . 
Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment
Cell Host Microbe
 , 
2013
, vol. 
14
 (pg. 
207
-
15
)

Author notes

*I.-M. Hwang and L.-M. Sun are contributed equally for this work.