The association between periodontal disease and cancer: A review of the literature

journal of dentistry 38 (2010) 83–95

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Review

The association between periodontal disease and cancer: A review of the literature Sarah G. Fitzpatrick *, Joseph Katz Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL, USA

article info

abstract

Article history:

Objectives: Periodontal disease has long been linked to many systemic diseases, and recently

Received 11 June 2009

a link between periodontal disease and cancer has been established. The purpose of this

Received in revised form

paper is to review the literature to explore the evidence to date of a relationship between

14 October 2009

periodontal disease and cancer. In addition, the main hypotheses for the association are

Accepted 27 October 2009

discussed along with challenges in evaluating the evidence. Data/sources/study selection: In this review, English-language papers studying the relationship between periodontal disease or tooth loss in humans and increased risk of several types

Keywords:

of cancers along with overall cancer risk between 1990 and April 2009 were reviewed.

Risk factors

Conclusions: The most consistent increased risk was noted in studies of oral and esophageal

Periodontitis

cancers and periodontal disease. Gastric and pancreatic cancers had an association in most

Oncology

but not all studies. Lung, prostate, hematologic and other cancers were less consistently associated or did not have sufficient studies to determine a predictable pattern. Studies to date indicate a positive correlation between several forms of cancer and periodontal disease. # 2009 Elsevier Ltd. All rights reserved.

1.

Introduction

Periodontal disease has been linked to many systemic conditions such as, cardiovascular disease, low-birth weight complications in pregnancy, diabetes, and, pulmonary disease.1 More recently, a link between periodontal disease and cancer has been suggested through several studies looking both at specific types of cancers and at the overall total cancer rate and the relationship to periodontal disease. The scientific rationale behind the proposed association is that inflammation is a major factor in both periodontal disease and cancer.2–4 Oral cancer, gingival squamous cell carcinoma in particular, has been known to mimic advanced periodontal disease in clinical appearance showing similar symptoms of swelling, bleeding, tooth mobility, deep periodontal pockets, and bone

destruction.5 Many cases have been reported of gingival squamous cell carcinoma presenting clinically similar to inflammatory periodontal or periodontal/endodontic lesions.6–12 Cases of other types of cancer mistaken for periodontal disease such as metastatic pancreatic cancer13 and osteogenic sarcoma14 have also been reported. These examples hint that a similar underlying mechanism may be responsible for both periodontal disease and cancer. Review of the pertinent literature reveals major differences in criteria used by the various investigators for the diagnosis and grading of periodontal disease. Furthermore, many potential confounding factors that may influence the validity of the study have not always been considered. The purpose of this paper is to critically review the current literature reporting the association between periodontal disease and several types

* Corresponding author at: Department of Oral and Maxillofacial Diagnostic Sciences, PO Box 100414, Gainesville, FL 32610-0416, USA. Tel.: +1 352 273 6683; fax: +1 352 392 2507. E-mail address: [email protected] (S.G. Fitzpatrick). 0300-5712/$ – see front matter # 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jdent.2009.10.007

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journal of dentistry 38 (2010) 83–95

of cancer along with overall cancer risk and discuss the main hypotheses for the association.

strong trends when these two groups have been separated from each other.

3.1.

2.

In this review, articles were identified by searches on PubMed from 1990 through April 2009 in the English language including humans. We used the following search terms: ‘‘periodontal disease’’, ‘‘periodontitis’’, and ‘‘tooth loss’’ linked with ‘‘cancer studies’’, ‘‘oral cancer studies’’, ‘‘gastrointestinal cancer studies’’, ‘‘lung cancer studies’’, ‘‘pancreatic cancer studies’’, ‘‘prostate cancer studies’’, and ‘‘hematologic cancer studies’’. Studies were also identified from the reference lists of retrieved papers. Case reports were excluded from this study.

3.

Oral cancer

Materials and methods

Results

The studies evaluated in this review varied greatly in design, criteria, and evaluation methods. Several factors were taken into consideration to derive conclusions from these available studies. Study design and sample size were the first factor taken into consideration. All of the studies included fell into the categories of either cohort or case–control studies. Most of the cohort studies included very large numbers of potential subjects; however, some of the numbers of individual cases of specific cancers were very small, numbering in some instances less than 10 cases in tens of thousands of overall subjects. Therefore, though the large cohort studies should be considered to be perhaps more informative than the case–control studies, the small numbers of individual cancers should provoke some reservation. It then seems to follow that when looking at the large cohort information available, the data may be more reliable for subsets such as overall cancer rates where the cancer cases numbered in the hundreds or thousands than for very specific cancers where the numbers of cases are much smaller within the cohort. A second consideration should be the adjustment for confounding factors. Most studies attempted to at least control for major risk factors such as tobacco and alcohol use, therefore for the most part studies could be compared relatively evenly in regards to this factor. The most important variable in the comparison of the studies available was the periodontal disease criteria used and whether or not it specifically measured some form of periodontal disease value or merely relied on missing teeth as a surrogate of presumed presence of periodontal disease. Earlier studies all relied on missing teeth alone as parameters, which of course may be misleading due to the differing reasons that teeth can be lost other than periodontal disease including caries activity and trauma. However, the presence of several large studies using specific parameters measuring periodontal disease gave the most valuable information to draw conclusions from. When analyzing the studies as a whole, striking patterns can be seen differentiating the studies measuring specifically for periodontal disease against the studies measuring for tooth loss, and in many cases the results show

Oral cancer and a link to tooth loss or periodontal disease has been evaluated in several studies.2,4,15–24 Most found a significant increase of oral cancer risk with patients with increased tooth loss or other parameters of periodontal disease even after adjustment for tobacco and alcohol. Perhaps the most informative studies of these are two by Tezal et al., since objective measures of periodontal disease were used in these as opposed to tooth loss as a measurement tool.4,23 The first reported a 5.23-fold increase in risk of tongue cancer with each millimeter of bone loss in periodontal disease patients in a study of men with tongue cancer in Buffalo, New York, and in fact found no association with other parameters of dental disease such as caries or significant prior dental work.4 In an earlier cohort study of a NHANES III data, Tezal et al. found an increased incidence of oral tumors or precancerous oral lesions in patients with greater than 1.5 mm clinical attachment loss.23 The only other study that used a specific periodontal disease indicator was a large cohort study by Michaud et al. and was in fact the only study not finding a significant association; however, two factors should be considered in evaluating this.2 First of all, oral cancer was grouped in with all oropharyngeal cancers in this study and thus no true determination of the risk of oral cancer alone could be determined.2 Secondly, the parameter measuring periodontal disease was less strong than objective measure of clinical attachment loss because it relied on patient reported history of periodontal disease verified by radiographic bone loss.2 Of the studies in this review looking at oral cancer and periodontal disease or missing teeth, eleven found a significant increase in risk of oral cancer (odds ratio [OR] ranging from 1.55 to 8) and one found no significant association (see Table 1). This may indicate that in the case of oral cancer, a valid association is likely present for both tooth loss and periodontal disease.

3.2.

Esophageal cancer

Several studies have found a link between esophageal cancer and missing teeth.2,3,18,19,25–29 It is difficult to determine, however, if this translates to a direct link to periodontal disease because only one of these studies, Michaud et al., used a specific measure of periodontal disease rather than missing teeth, and their large scale cohort study failed to find an association with esophageal cancer either with patient selfreported periodontal disease verified by radiographic bone loss or with missing teeth.2 Hiraki et al. reported a significant association with esophageal cancer similar to their previously mentioned work with head and neck cancer.19 A recent study by Abnet et al. in Iran found that increasing numbers of teeth lost had a direct relationship on the risk of esophageal squamous cell carcinoma noting that edentulous subjects had twice the risk as compared to subjects who lost fewer than 13 teeth.27 Guha et al. showed that missing between 6 and 15 teeth doubled the risk of esophageal cancer when compared with subjects missing less than 5 in two concurrent studies in

Table 1 – Studies linking oral cancer with periodontal disease. Author

Year

Population

Criteria

1986–1990

161 cases oral SCCA and 400 controls in Denmark

Loss of teeth

de Rezende et al.16

2003–2004

CPITNb and DMFTc

FernandezGarrote et al.17 Guha et al.18

1996–1999

50 patients with oral and oropharyngeal squamous cell carcinoma and 50 cancer-free controls 200 cases oral cancer and controls in Cuba

Hiraki et al.19

2001–2005

Dental condition by exam (good, average, poor as measured with tartar, bleeding, mucosal irritation, and caries present) and missing teeth Loss of teeth

Marshall et al.20

1975–1983

924 cases head and neck and esophageal SCCA/928 controls in Europe and 2286 cases and 1824 controls in Latin America 429 cases head and neck cancer out of 5240 cancer patients and 10,480 control patients in Japan 290 subjects and controls in the United States

Michaud et al.2

1986–2004

Rosenquist et al.21

2000–2004

118 cases of oropharyngeal cancer out of 48,328 cohort in United States 132 cases and 320 controls in Sweden

Patient reported history of periodontal disease (validated by radiographic measure of bone loss) and loss of teeth Loss of teeth and radiographic evaluation (amount of marginal bone loss)

Talamini et al.22

1996–1999

132 cases and 148 controls in Italy

Loss of teeth and poor general oral condition (tartar, decayed teeth, and mucosal irritation)

Tezal et al.23

1988–1994

131 oral tumors and 323 oral pre-cancerous lesions out of 13,798 subjects

Clinical attachment loss (CAL)

Tezal et al.4

1999–2005

51 cases and 54 controls in the United States

Mm of alveolar bone loss

Zheng et al.24

1989–1990

404 subjects and control pairs in China

Loss of teeth

a b

Loss of teeth

Odds ratio. WHO guidelines of Community Periodontal Index of Treatment Needs (depth of periodontal pockets on scale of 1–4). WHO guidelines of Decayed, Missing, and Filled Teeth.

Type of Study

Significantly increased risk (OR 2) of developing oral SCCA for patients with fewer than 15 teeth after smoking/EtOH adjustment 76% of subjects in cancer group showed >6 mm pockets compared to 10% of control group (No OR calculated) No association with DMFT

Case–control

Significantly increased risk (OR 2.7) of oral cancer for patients missing 16 or more teeth after smoking/EtOH adjustment Poor oral condition significant increased risk (Europe OR 2.89, LA OR 1.89) of head and neck cancer

Case–control

Significantly increased risk of head and neck cancer to decreased number remaining teeth (OR 1.68 for 0 remaining teeth) after smoking/ EtOH adjustment Significantly increased risk of oral cancer (OR 2.7) with loss of 11 or more teeth after smoking and EtOH adjustment No significant increase in risk for oropharyngeal cancer with history of periodontal disease or increased number of teeth lost Significantly increased risk (OR 3.4) of oral and oropharyngeal cancer for missing over 20 teeth after adjustment for smoking and EtOH Radiographic evidence of increased risk also but not after adjustment for confounders No significant increase in risk of oral cancer to increased missing 16 or more teeth found but poor condition of mouth was associated (OR 4.5) after smoking and EtOH control Significantly increased risk of oral tumor (OR 4.57) and pre-cancerous lesion (OR 1.55) with >1.5 mm CAL both still significant in never smokers (tumors OR 1.63, pre-cancerous OR 1.32) Significantly increased risk (OR 5.23) of tongue cancer with each mm of bone lost after smoking adjustment Significantly increased risk of oral cancer with increased missing teeth (OR 2–3 men, 5–8 women) controlling for smoking and EtOH

Case–control

Case–control

Case–control

Case–control

Cohort

Case–control

Case–control

Cohort

Case–control

Case–control

85

c

Europe 1998–2002 Latin America 1998–2003

Loss of teeth

a

journal of dentistry 38 (2010) 83–95

Bundgaard et al.15

Results

86

Table 2 – Studies linking esophageal cancer and upper GI with periodontal disease. Author Abnet et al.

Year 3

1985–1999

Population

Criteria

No significant association seen for esophageal or gastric cardia cancer with increased loss of teeth

Cohort

Loss of teeth

Significantly increased risk of esophageal cancer (OR 1.3) with increasing tooth loss adjusted for tobacco and EtOH Significant increase in risk of upper GI deaths (OR 1.25 under age 50) with increasing loss of teeth especially in a younger age controlled for smoking and EtOH Significantly increased risk of esophageal SCCA with 32 DMFT compared to <15 (OR 2.10) Also found significant risk with poor oral hygiene and increasing numbers of teeth lost—controlled for smoking Significantly increased risk of esophageal cancer when missing between 6 and 15 teeth (EU OR 3.4, LA OR 2.18) controlled for smoking and EtOH

Cohort

Significantly increased risk for esophageal cancer with increased number of teeth lost (OR 2.36 for 0 teeth remaining) after smoking/EtOH adjustment No significant increase in risk for esophageal cancer with history of periodontal disease or increased number of teeth lost

Case–control

Significantly increased risk (OR 5) for dysplasia in edentulous patients over good oral health

Case–control

Significant increased risk for esophageal dysplasia in patients having lost more but not all teeth -controlled for smoking

Cohort

Abnet et al.26

1986–1991

2625 upper GI deaths in 29,584 cohort in China

Loss of teeth

Abnet et al.27

2003–2007

283 esophageal SCCA and 560 controls in Iran

DMFT and poor hygiene Loss of teeth

924 cases head and neck and esophageal SCCA/928 controls in Europe and 2286 cases and 1824 controls in Latin America

Loss of teeth and dental condition by exam (good, average, poor as measured with tartar, bleeding, mucosal irritation, and caries present) Loss of teeth

Hiraki et al.19

2001–2005

Michaud et al.2

1986–2004

Sepehr et al.28

1995–1996

Wei et al.29

2002

354 esophageal cancers out of 5240 cancer patients and 10,480 control patients in Japan 131 cases of esophageal cancer out of 48,328 cohort in United States

124 cases of precursor esophageal dysplasia vs. 50 control in Iran 724 subjects in China

Patient reported history of periodontal disease (validated by radiographic measure of bone loss) and loss of teeth Poor oral health (rated good, fair, poor, very poor, or prostheses) and loss of teeth Loss of teeth

Cohort

Case–control

Case–control

Cohort

journal of dentistry 38 (2010) 83–95

Loss of teeth

1986–1991

Europe (EU) 1998–2002 Latin America (LA) 1998–2003

Type of study

49 esophageal cancer cases and 66 esophageal/gastric cardia cases out of 29,124 cohort in Finland 620 cases of esophageal cancer in a 28,868 cohort in China

Abnet et al.25

Guha et al.18

Results

Table 3 – Studies linking gastric cancers with periodontitis. Author

Population

Criteria

Abnet et al.3

1985–1999

179 gastric non-cardia and 66 esophageal/gastric cardia in Finland

Loss of teeth

Abnet et al.25

1986–1991

431 gastric cardia and 102 gastric non-cardia cancers in China

Loss of teeth

Demirer et al.30

1987–1988

Hiraki et al.19

2001–2005

Deficient teeth and poor oral hygiene Loss of teeth

Hujoel et al.31

1971–1975, follow-up until 1992

100 cases of adenocarcinoma of stomach and 100 controls in Turkey 702 stomach cancers out of 5240 cancer patients and 10,480 control patients in Japan 8 cases of stomach cancer in 11,328 cohort in United States

Michaud et al.2

1986–2004

106 cases of stomach cancer out of 48,328 cohort in United States

Watabe et al.32

1996–1997

242 cases gastric cancer and 484 controls in Japan

Periodontal exam by Russell index (classified as periodontitis, gingivitis, no periodontitis, or edentulous) Patient reported history of periodontal disease (validated by radiographic measure of bone loss) and loss of teeth Loss of teeth

Results

Type of study

Significantly increased risk of gastric non-cardia cancer (OR 1.65) for loss of all teeth compared to losing less than 10 after adjustment for smoking/EtOH. No significant increased risk for gastric cardia cancer Significantly increased risk for gastric cardia (OR 1.3) and non-cardia cancer (OR 1.8) with increasing tooth loss, controlled for smoking and EtOH Stomach cancer patients were more likely to brush their teeth less frequently and have more deficient teeth than control No significant association between gastric cancer and increased loss of teeth

Cohort

No significant increase in stomach cancer risk for patients with periodontitis found

Cohort

No significant association between stomach cancer and history of periodontal disease or loss of teeth

Cohort

Significant increased risk of gastric cancer with more than 20 teeth lost when compared to none lost (OR 3–4), controlled for smoking

Case–control

Cohort

Case–control Case–control

journal of dentistry 38 (2010) 83–95

Year

87

88

Cohort

Cohort

Case–control

Loss of teeth 1948–1968 and follow-up until 2005 Tu et al.33

Lung cancer number unspecified in 12,223 cohort in Scotland

1986–2004 Michaud et al.2

678 lung cancers out of 48,328 cohort in United States

2001–2005 Hiraki et al.19

909 lung cancers out of 5240 cancer patients and 10,480 control patients in Japan

Patient reported history of periodontal disease (validated by radiographic measure of bone loss) Loss of teeth

Significantly increased risk of lung cancer (OR 1.94) but not significant when limited to non-smokers Significantly increased risk of lung cancer with increased loss of teeth (OR 1.54 for 0 teeth remaining) after adjustment for smoking/EtOH Significantly increased risk of lung cancer (OR 1.36) with history of periodontal disease and persisted after control smoking Significantly increased risk of lung cancer (OR 1.70) with 1–16 teeth compared to 25–32 but did not persist after smoking controlled (OR 0.96) No significant association noted between lung cancer and loss of teeth Periodontal exam by Russell index (classified as periodontitis, gingivitis, no periodontitis, or edentulous) Loss of teeth

Results Population

191 lung and bronchus cancer deaths in 11,328 cohort in the United States 1971–1975, follow-up until 1992 Hujoel et al.

The relationship between lung cancer and periodontitis or missing teeth has also been evaluated several times as well in the literature.2,19,31,33 Again, two studies specifically examined the link using periodontal measures. Hujoel et al. examined the relationship between periodontal disease by clinical examination and lung cancer and reported a strong initial association.31 However, the result was not significant after limiting the effects of never smokers31 which tempers the strength of the association as smoking is such a strong risk factor for lung cancer. Michaud et al. found a significant increased risk in patients with a history of periodontal disease that persisted after controlling for smoking, but for patients with tooth loss they noted a significant increase only before controlling for smoking.2 The other two studies used

Year

Lung cancer

31

3.4.

Author

The association between upper GI and gastric cancers has been evaluated in the context of periodontal disease.2,3,19,25,30– 32 Increased tooth loss as a risk factor seems to exhibit a mixed result in the literature. Abnet et al. found a significantly elevated risk between tooth loss and esophageal squamous cell carcinoma, gastric cardia adenocarcinoma, and gastric non-cardia adenocarcinoma. The strongest association was noted between gastric non-cardia adenocarcinoma and tooth loss in a study originating in China.25 However, in another study in Finland, Abnet et al. found a significant association between tooth loss and gastric non-cardia adenocarcinoma but not with esophageal squamous cell carcinoma or gastric cardia adenocarcinoma.3 Of the studies, there were two large cohort studies that evaluated the relationship between specific periodontal indicators and stomach cancer.2,31 As in oropharyngeal and esophageal cancers, Michaud et al. reported no significant association between stomach cancers and history of periodontal disease verified by radiographic bone loss or with tooth loss as well.2 Hujoel et al. in the NHANES I Epidemiologic Follow-up Study found no significant association between stomach cancer and periodontitis as defined by clinical examination but had a small number of cases within their cohort.31 In review of gastric cancer and periodontal disease or tooth loss studies, four studies found an increased risk of cancer (OR ranging from 1.3 to 1.8), and three did not (see Table 3). Again, as the studies specifically measuring parameters of periodontal disease did not show an association, the evidence as of yet does not support a link from gastric or upper GI cancer with periodontal disease.

Criteria

Upper GI and gastric cancers

Table 4 – Studies linking lung cancer and periodontal disease.

3.3.

Type of study

Europe and Latin America.18 In the same study, other indicators of oral health other than missing teeth were not significantly associated.18 Overall, of studies examining esophageal cancer and periodontal disease or tooth loss, seven found a significant association (OR from 1.25 to 5) (see Table 2), and two studies failed to find a significant increase in risk. This shows that while an association may be present for an increased risk of esophageal cancer for patients with an overall poor oral condition and increased numbers of missing teeth, the evidence does not yet support a specific association to periodontal disease indicators.

Cohort

journal of dentistry 38 (2010) 83–95

89

Cohort

Cohort

Cohort

Loss of teeth 174 cases in 29,104 cohort in Finland 1985–1988 StolzenbergSolomon et al.35

253 cases in 48,328 cohort in United States Michaud et al.34

1971–1975, follow-up until 1992 1986–2004 Hujoel et al.31

12 pancreatic cancer deaths in 11,328 cohort in United States

Loss of teeth

Periodontal exam by Russell index (classified as periodontitis, gingivitis, no periodontitis, or edentulous) Patient reported history of periodontal disease (validated by radiographic measure of bone loss) and loss of teeth Loss of teeth

No significant association found between pancreatic cancer and increased loss of teeth Increased risk noted for pancreatic cancer with patients with periodontal disease (OR 1.77) Significant increased risk of pancreatic cancer with history of periodontitis (OR 1.64) after adjustment for smoking No significant increase in risk for increasing loss of teeth Significant increased risk of pancreatic cancer for edentulous patients compared to patients missing 1–10 teeth (OR 1.63) adjusted for smoking

Results Population

178 cases pancreatic cancer of 5240 cancer patients and 10,480 control patients in Japan 2001–2005 Hiraki et al.

Several investigators examined the relationship between prostate cancer and tooth loss or periodontal disease2,19,31 (see Table 6). Interestingly the two studies which used tooth loss as an indicator actually found an inverse relationship.2,19 Hiraki et al. found that subjects with greater tooth loss actually demonstrated a decreased risk of prostate cancers.19 They speculated that socio-economic status may explain this finding, as a negative association between prostate cancer and socio-economic status has been previously suggested.36 A similar inverse relationship was also reported by Michaud et al.2 Hujoel et al. was the only study to use direct assessment of periodontal state and established a slight positive association between prostate cancer and periodontal disease; however, they had a low sample size (20 cases of patients with prostate cancer) in comparison to the aforementioned studies.31 It does not appear that as of yet a strong association can be made at this time between periodontal disease and prostate cancer.

Year

Prostate cancer

19

3.6.

Author

The link between pancreatic cancer and periodontal disease or tooth loss has had mixed results in several studies.19,31,34,35 Two large cohort studies that used a specific periodontal measure both found significant associations.31,34 Michaud et al. looked at a link between pancreatic cancer and history of periodontal disease and found a significant association between the two, in fact finding a higher association among the non-smokers than the smokers.34 Hujoel et al. found a significant association between pancreatic cancer and periodontitis measured by examination but again had a relatively small number of cases within their cohort.31 Of the other two studies involving loss of teeth, the results were again mixed. A significant association was found between pancreatic cancer and tooth loss by a Finnish study.35 Hiraki et al., however, found no association between pancreatic cancer and tooth loss.19 Overall, for pancreatic cancer and periodontitis, three studies found an increase in risk (OR ranging from 1.63 to 1.77) and one did not (see Table 5). The evidence favoring an association specifically with periodontal disease appears promising for pancreatic cancer when the two studies by Michaud et al. and Hujoel et al. are taken into account.31,34

Criteria

Pancreatic cancer

Table 5 – Studies linking pancreatic cancer and periodontal disease.

3.5.

Type of study

tooth loss as their measure with Hiraki et al. finding a significantly increased risk of lung cancer with increased loss of teeth after adjusting for tobacco and alcohol19 and Tu et al. in the Glasgow Alumni Cohort failing to find an association between increased numbers of missing teeth and lung cancer after controlling for tobacco use.33 Therefore, three out of four authors studying lung cancer and periodontal disease or tooth loss found some level of association (OR ranged from 1.36 to 1.94) although in most cases it did not remain after adjustment for smoking (see Table 4). Overall, this suggests that smoking is a very high confounder of this relationship, and thus there is some reservation in interpreting these results as proof of a link between lung cancer and periodontal disease.

Case–control

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Table 6 – Studies linking prostate cancer and periodontitis. Author

Year 19

Population

Criteria

Results

Hiraki et al.

2001–2005

136 cases of 5240 cancer patients and 10,480 control patients in Japan

Loss of teeth

Hujoel et al.31

1971–1975, follow-up until 1992

20 deaths in 11,328 cohort in United States

Michaud et al.2

1986–2004

541 out of 48,328 cohort in United States

Periodontal exam by Russell index (classified as periodontitis, gingivitis, no periodontitis, or edentulous) Loss of teeth

3.7.

Hematologic cancers

Hematologic cancers in association with periodontal disease have had limited study2,19 (see Table 7). Michaud et al. looked at hematologic malignancy for an association with history of periodontal disease with verified radiographic bone loss and reported an increase with non-Hodgkin lymphoma (NHL), leukemia, and myelomas but only NHL yielded a significant relationship.2 Michaud et al. also evaluated loss of teeth in relationship to hematologic malignancies and found no significant increase in risk.2 Hiraki et al. could not demonstrate an association between lymphomas in general and tooth loss.19 As of yet, there has been insufficient study to conclude if a relationship exists, but as the Michaud study was a cohort study with quite large numbers and found a relationship with NHL after separating out periodontal patients from general tooth loss, the suggestion of a link is an interesting course for future study.

3.8.

Breast cancer

Breast cancer was investigated in two studies (see Table 8) with Hujoel finding a significant association between breast cancer risk and periodontal disease by examination31 but Hiraki finding no association between breast cancer risk and tooth loss.19 The Hiraki et al. study was not specific for periodontal indicators but did have a much higher numbers of breast cancer patients, whereas Hujoel et al. used a specific measure of periodontal disease but had rather low numbers. This may reflect a difference between the tooth loss group and true periodontal disease groups; however, the data seems insufficient to draw a strong conclusion at this point.

3.9.

Other cancers

Hiraki et al. also investigated liver, ovary, uterus, bladder, thyroid, and colon cancer in their study and found no significant associations for these cancers and missing teeth.19 Michaud et al. also studied several other cancers in relationship to a history of periodontal disease and missing teeth and found rectal, bladder, and brain with no significant association found. They also found kidney cancer to have a significant association with history of periodontal disease, and noted an inverse relationship between melanoma and tooth loss.2 Hujoel et al. also looked at colon cancer and

Type of study

Negative (inverse) association to risk of prostate cancer for increased number of teeth lost Increased risk of prostate cancer with patients with periodontitis (OR 1.81)

Case–control

Negative (inverse) association between risk of prostate cancer and number of teeth lost

Cohort

Cohort

periodontitis by examination and found no significant association.31

3.10.

Overall cancer

Several cohort studies have looked at overall cancer rates for a possible link to periodontal disease2,31,33,37 (see Table 9). In these, an interesting pattern has emerged. Again, the two studies which specifically used periodontal measures as criteria both found a positive association with overall cancer rates, and lending more credibility was the large sample size for both.2,31 The Hujoel et al. study found an increase in overall cancer rates for patients with periodontal disease by clinical examination,31 and Michaud et al. found a small but significant increase in overall cancer risk even when adjusted for smoking when looking at patients with reported history of periodontal disease as verified by radiographic bone loss.2 The other two studies both measured missing teeth in relation to overall cancer rates, and neither found an association.33,37 This seems to suggest that while missing teeth may not be an independent risk factor for overall cancer risk, periodontal disease may play a significant part.

4.

Discussion

Several hypotheses are of interest in the potential etiology of a link between, periodontal disease and cancer.

4.1.

Alteration of the oral flora

It has been suggested that carcinogenic metabolic by-products of periodontal disease might account for the relationship between the two diseases. When considering gastric cancers, Abnet et al. argue that the mechanism of increased cancer risk may be an increased production of nitrosamines in situations of poor oral hygiene and that these by-products may function as GI organ specific carcinogens.25 Nitrosamines have been linked to cancers of the stomach and esophagus.38 Heliobacter pylori infection also plays a role in stomach cancers.39,40 The carcinogenic ethanol by-product acetaldehyde has also been studied, as there is a clear link between upper GI cancers and alcohol.41 A study by Homann et al. showed that poor dental status was shown to lead to a 2-fold increase in salivary acetaldehyde production by oral microbes.42 In another study,

Table 7 – Studies linking hematologic cancers and periodontitis. Author Hiraki et al.

19

Michaud et al.2

Year

Population

2001–2005

232 cases of lymphoma of 5240 cancer patients and 10,480 control patients in Japan 934 cases of hematologic cancers out of 48,328 cohort in United States

1986–2004

Criteria

Results

Type of study

No significant increase in risk of lymphoma with increased number of missing teeth

Case–control

Patient reported history of periodontal disease (validated by radiographic measure of bone loss) Loss of teeth

Significant increased risk of NHL with patients reporting periodontal disease history (OR = 1.31) (only NHL was significant out of all heme cancers represented but also had the greatest number of cases) No significant increase in risk noted for hem. cancers with increased loss of teeth

Cohort

journal of dentistry 38 (2010) 83–95

Loss of teeth

Table 8 – Studies linking breast cancer and periodontitis. Author Hiraki et al.

19

Hujoel et al.31

Year

Population

Criteria

2001–2005

756 cases of 5240 cancer patients and 10,480 control patients in Japan

Loss of teeth

1971–1975, follow-up until 1992

19 cancer deaths in 11,328 cohort in United States

Periodontal exam by Russell index (classified as periodontitis, gingivitis, no periodontitis, or edentulous)

Results No significant increase in risk of breast cancer with increased number of missing teeth Increased risk of breast cancer with patients with periodontitis (OR 1.32)

Type of study Case–control

Cohort

91

92

Cohort

Cohort 1986–2004

1948–1968 and follow-up until 2005

Michaud et al.2

Tu et al.33

549 cancer deaths of 12,223 patient cohort in Scotland

1971–1975, follow-up until 1992 Hujoel et al.31

Cabrera et al.

5720 cancer cases out of 48,328 cohort in United States

Periodontal exam by Russell index (classified as periodontitis, gingivitis, no periodontitis, or edentulous) Patient reported history of periodontal disease (validated by radiographic measure of bone loss) Loss of teeth 884 cancer deaths of 11,328 cohort in United States

Significantly increased risk of overall cancer for patients with a history of periodontal disease (OR 1.14) after controlling for smoking No significant increase in risk between cancer deaths and increased missing teeth

Cohort

Cohort

No significant association between cancer mortality and increased number of missing teeth Increased risk of cancer deaths with patients with periodontitis (OR 1.55) Loss of teeth 68 cancer deaths of 1462 women in Sweden 1967–1969, follow-up until 1992–1993

Population Year

37

Author

Table 9 – Studies linking overall cancer rates with periodontitis.

Criteria

Results

Type of study

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Homann et al. showed that certain oral bacterial species had a higher acetaldehyde production capacity including Streptococcus salivarius, Corynebacterium, Stomatococcus, and alpha-hemolysing Streptococcus.43 Other microorganisms have been studied as well as potential carcinogenic agents. There is also some evidence that some strains of candidiasis have been seen in higher frequency in oral cancer patients.44 Viruses may play a role in this also. A suggestion has been made that increased periodontal disease may be associated with infection with cytomegalovirus and/or Epstein-Barr Virus 1 with mixed results.45–47 EBV of course has been linked to cancer including lymphoma and nasopharyngeal carcinoma.39

4.2. Increase in systemic circulatory inflammatory markers This is the basis for the link between periodontal disease and cardiovascular disease and diabetes.4 The presence of inflammatory cells and mediators such as chemokines, cytokines, and prostaglandins associated with tumors represent the main indicators.48 Myeloperoxidase and superoxide dismutase help to regulate inflammation and are found to be elevated in periodontitis, and polymorphisms of these genes have been associated with elevated pancreatic cancer risk.49 This dual condition result of genetic polymorphisms has been suggested for gastric cancer and periodontitis as well.3 Many cancers are linked to local chronic inflammation, including inflammatory bowel disease and colon cancer, Hepatitis C inflammation and liver carcinoma, and H. pylori-associated ulcers and gastric cancer.39,48,50 Also, the immune response mounted to a chronic periodontal infection has been proposed as a potential carcinogenic etiologic factor.2 Also of interest is the relationship between the pro-inflammatory expression of the receptor for advanced glycation end products (RAGE) and esophageal, gastric, colon, biliary, pancreatic, and prostate cancers.51 RAGE has been shown to play a role in the inflammatory processes of oral infections including periodontal disease.52 There are several obstacles in accurately determining a relationship between, periodontal disease and cancer.

4.3.

Methodology

First, there are many potential statistical problems, involved in the measurement of periodontal disease. Studies vary between inclusion, criteria for patients with periodontal disease—some rely on tooth loss as a marker and, others use patient history or clinical or radiographic examination as criteria. The, difficulty in using tooth loss as a variable is that teeth can be lost due either to caries, trauma, or periodontal disease, thus it is difficult to remove caries as a confounding factor in these relationships. A major limiting factor in establishing a solid link between periodontitis and cancer is that many of these studies exclusively used tooth loss as a measure of periodontal disease. Tu et al. point out in a study on overall cancer risk and tooth loss that in fact as the number of teeth that are lost increases, the exposure to periodontal disease may decrease (as edentulous patients no longer have active periodontal disease).33 This is supported in Guha et al.

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where they found that if the missing teeth were over 15 in number the association with esophageal cancer disappeared.18 However, some aspects of these studies support the differentiation of periodontal disease from general poor oral health as an independent risk factor for cancer. A study in Brazil comparing the oral health status of patients with untreated oral and oropharyngeal squamous cell carcinoma with cancer-free patients showed a higher rate of periodontal disease in the cancer patients but similar rates of caries as measured by DMFT and oral hygiene habits.16 This is also supported by the Tezal et al. study in 2007 where other indicators of oral health (i.e. DMFT) were not significantly associated with tongue cancer while millimeters of alveolar bone loss were.4 Even amongst studies that specifically measured for periodontal disease, differences in measurement criteria existed: periodontal disease was measured in varied ways including by clinical attachment loss,23 Russell index31 (which categorized patients into periodontitis, gingivitis, no periodontitis, and edentulous), and patient reported history verified with radiographic bone loss.2 Of these methods the most objective and thus most reliable would be the direct clinical measurement of attachment loss.

4.4.

Confounding factors

Smoking appeared to be the main confounding factor among these studies, especially for cancers strongly linked to tobacco use such as lung cancer. Other potential confounding factors are socio-economic status, diabetes, age, gender and ethnicity,40 along with genetics.27 Dietary factors associated with advanced tooth loss have also been proposed as a potential confounding factor as a lack of fruit and vegetable intake has been shown to be increased with a higher risk of some cancers and patients who have lost many teeth may be less able to include these foods in their diets.40

5.

Conclusions

In summary, the current literature shows that the strongest degree of evidence of association to periodontal disease is with oral cancer. There is also suggestive positive evidence for pancreatic cancer as well as overall cancer rates. Mixed results appear to be present for esophageal, gastric, lung, prostate, breast, hematologic and other cancers in regards to a link specifically to periodontal disease. Additional studies are needed to explore these suggested associations. Consistent and standardized criteria periodontal disease (such as millimeters of alveolar bone loss by clinical examination) and consistent rigorous control of the confounding factors such as smoking and alcohol use will be helpful in establishing a definitive link between periodontal disease and cancer. Given the evidence to date, it would be beneficial to the dental provider to be aware of the real potential that periodontal disease may exist as a risk factor for many forms of malignancy. Thus it may be of real benefit to patients exhibiting periodontal disease who also have concurrent known risk factors for certain types of cancer such as lifestyle factors or family history to consider several steps to reduce the

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risk levels. This may include the possibility of a more frequent periodontal recall schedule to keep the level of disease and inflammation to an absolute minimum and stressing the importance of maintaining regular dental visits and meticulous oral hygiene. In addition, the patients should be encouraged to work with their other medical providers to comply with all appropriate schedules of screening examinations for early detection of malignancy including frequent oral cancer screenings in the dental health setting. Finally, these patients should be encouraged and supported in making positive lifestyle changes that may reduce their cancer risk levels such as tobacco cessation, maximal nutrition and exercise, and elimination of environmental risks. Dental health practitioners have a great opportunity and obligation to assist in preventative medicine by helping their patients obtain the best possible oral health.

references

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