|Year : 2013 | Volume
| Issue : 6 | Page : 706-710
Poor periodontal health: A cancer risk?
KS Rajesh, Deepak Thomas, Shashikanth Hegde, M. S. Arun Kumar
Department of Periodontology, Yenepoya Dental College, Mangalore, Karnataka, India
|Date of Submission||12-Jan-2013|
|Date of Acceptance||18-Jul-2013|
|Date of Web Publication||7-Jan-2014|
Department of Periodontology, Yenepoya Dental College, Nithyanandanagar Post, University Road, Deralakatte, Mangalore 575 018, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Evidence indicates that chronic infections and inflammation are associated with increased risk of cancer development. There has also been considerable evidence that proves the interrelationship between bacterial and viral infections and carcinogenesis. Periodontitis is a chronic oral infection thought to be caused by gram-negative anaerobic bacteria in the dental biofilm. Periodontal bacteria and viruses may act synergistically to cause periodontitis. Many studies have shown that periodontal pockets may act as reservoirs for human papilloma virus, cytomegalovirus, Epstein Barr virus, and suspected agents associated with oral cancer. Periodontitis, characterized by epithelial proliferation and migration, results in a chronic release of inflammatory cytokines, chemokines, growth factors, prostaglandins, and enzymes, all of which are associated with cancer development. This review article intends to shed light on the association between periodontal health and carcinogenesis.
Keywords: Carcinoma, inflammation, microorganisms, poor oral hygiene, virus
|How to cite this article:|
Rajesh K S, Thomas D, Hegde S, Kumar MA. Poor periodontal health: A cancer risk?. J Indian Soc Periodontol 2013;17:706-10
| Introduction|| |
Evidence indicates that chronic infections and inflammation are related with increased cancer risk. There is also considerable evidence connecting the relationship between bacterial and viral infections and carcinogenesis.
Periodontitis is an infectious disease thought to be caused by gram-negative anaerobic microorganisms in the dental biofilm, resulting in inflammation within the supporting structures of the tooth, leading to progressive attachment and bone loss, characterized by pocket formation and recession. Periodontitis leads to epithelial proliferation and migration, which results in the chronic release of inflammatory cytokines, prostaglandins, growth factors, and enzymes, all of which are closely associated with the development of cancer.
Evidence for association
Cancer patients may be in a depressed state of mind, which keeps them from regular brushing of teeth and usage of cleaning aids. The cancer patients may undergo chemotherapy/radiotherapy, which would negatively affect the oral hygiene habits. This may increase the likelihood of gingival bleeding and burden of periodontal infection.,,,
There are many studies indicating that cancer patients are manifested with poor oral health.
Pow et al. (2003), showed that nasopharyngeal carcinoma survivors (1-4 years after radiotherapy) showed compromised oral health.
Shankarapillai et al. (2010), conducted a study on 73 patients diagnosed with acute myeloid leukemia (AML), which showed that about three-quarters of the patients with AML had poor or fair oral hygiene.
There are also studies indicating that poor periodontal health may prove to be a cancer risk. There are sources of evidence that are emerging to associate periodontal health and risk of developing cancer.
Felix et al., in 1986, showed that gingival hypertrophy is the main manifestation of acute monoblastic leukemia (AMoL).
Velly et al. (1998), examined the relationship between dental health variables and the risk of upper aerodigestive tract (UADT) cancers. The study population included 717 cases (cancers of mouth, pharynx, and larynx) and 1434 controls, matched for age, gender, period of admission, and study site. Tobacco and alcohol consumption, diet, and sociodemographic variables were taken into consideration. It was concluded that poor oral hygiene due to infrequent tooth brushing and sores caused by dentures are risk factors for cancer of the mouth and these associations are unlikely to be due to the insufficient control of confounding factors.
Abnet et al. (2001), in his prospective study, evaluated the association between tooth loss and the risk of developing esophageal squamous cell carcinoma, gastric cardia adenocarcinoma or gastric non-cardia adenocarcinoma in a 28,868-person cohort, followed prospectively for 5.25 years. The analytic cohort included 620 esophagus, 431 gastric cardia, and 102 gastric non-cardia cancer cases. In this cohort tooth loss increased the risk of developing upper gastrointestinal cancer. It was hypothesized that this may be related to alterations in the oral bacterial flora and subsequent increases in the in-vivo production of carcinogens, such as, nitrosamines.
Hujoel et al. (2003), studied the association between periodontitis and various types of cancer. Data were available on 11,328 adults (25-74 years), who were diagnosed as dentate individuals with either periodontitis (n = 2092), gingivitis (n = 2603), a healthy periodontium (n = 2,671) or as individuals without teeth (edentulous n = 3,962) at the beginning of the follow-up. The main outcome measure was fatal cancer, as ascertained from the death certificates. Of the different cancer types, lung cancer demonstrated the strongest association.
Stolzenberg-Solomon et al. (2003), investigated prospectively, the relation between dentition history and pancreatic cancer and the association between dentition history and H. pylori seropositivity, in a cross-sectional sample of subjects without cancer (n = 475) from the same cohort. It was seen from this study that tooth loss was associated with pancreatic cancer, but not associated with H. pylori seropositivity.
Tezal et al., conducted a study in the Rosewell Park Cancer Institute, New York, between the years 1999 and 2005. The study showed the direct association between chronic periodontitis and tongue cancer, independent of smoking status, age, gender, race, and the like. After adjusting for the effects of age at diagnosis, smoking status, and number of teeth, each millimeter of alveolar bone loss was associated with a 5.23-fold increase in the risk of tongue cancer.
Tezal et al. (2005), conducted a study on 13,798 subjects aged 20 years and older, with at least six natural teeth, who participated in the Third National Health and Nutrition Examination Survey. Three separate dependent variables were employed: (1) Tumor (non-specific); (2) pre-cancerous lesions, and (3) any oral soft tissue lesion. The independent effect of clinical attachment loss on those three dependent variables was assessed, adjusting for the effects of the number of filled teeth, number of decayed teeth, presence of prosthesis, age, gender, race/ethnicity, education, tobacco, alcohol and occupational hazard. This study suggested the association between periodontal disease and the risk for precancerous lesions and tumors, generating a hypothesis about a possible relationship between periodontal disease and oral neoplasms.
Michaud et al., in his cohort study conducted in 1986, collected data from 51,529 health professionals between the age group of 40 and 75 years. A total of 216 patients were diagnosed with pancreatic cancer during 16 years of follow-up study. They found that men with history of periodontal disease had a 64% increased risk of pancreatic cancer than men with no history of it. Increased severity of periodontitis, that is, recent tooth loss had a greater risk. There was no association found between tooth decay and pancreatic cancer in this study.
Christian Abnet et al., in 2008, conducted a case-control study of pathologically confirmed esophageal squamous cell carcinoma (ESCC) patients and controls, in people living in the high-risk areas of Iran, matched for age, sex, and neighborhood. Subjects with ESCC had significantly more decayed, missing or filled teeth when compared to the controls. Subjects with ESCC were more likely than controls to fail to practice regular oral hygiene. Restricting the analysis to non-smokers did not materially alter the results. Lack of regular oral hygiene practices confirmed greater than a two-fold increased risk of ESCC, notable for three reasons. They were: First, there was no association between oral hygiene and tobacco or opium consumption, so this exposure was not susceptible to confounding by tobacco or opium use. Second, carcinogenic products produced by oral pathogens could affect the esophageal mucosa. Finally, a simple intervention of teaching routine oral hygiene practices led to lower risk of ESCC. The study found a significant association between two markers of poor oral hygiene (larger number of decayed/missing/filled teeth (DMFT) and lack of poor oral hygiene) and risk of ESCC, in a population at a higher risk for ESCC, where many cases occur in 'never-smokers'.
A case-control study with 404 matched cases and controls was conducted in Beijing for assessing the relation between dentition and risk of oral cancer. The oral examination included recording of missing teeth and presence of gingivitis or periodontal disease. Analyses were stratified by gender, for males, a two- to three-fold increase in the risk of oral cancer was observed for any tooth loss, with or without tooth replacement, and a five- to eight-fold increase of risk was found for females.
Michaud et al. carried out a prospective study in 1986, in 48,375 US health professionals aged 40-75 years, over a period of 17.7 years. In addition to the baseline questionnaires, follow-up questionnaires were posted to all living participants every two years and dietary questionnaires every four years. At baseline, the participants were asked whether they had a history of periodontal disease with bone loss. Participants also reported the number of natural teeth at the baseline, and any tooth loss during the previous two years was reported on the follow-up questionnaires. Smoking status and history of smoking were obtained at baseline and in all subsequent questionnaires. The five most common cancers were colorectal (n = 1043), melanoma of the skin (n = 698), lung (n = 678), bladder (n = 543), and advanced prostate (n = 541). After adjusting for the known risk factors, including smoking history and dietary factors, it was found that participants with a history of periodontal disease had an increased risk of total cancer compared with those with no history of periodontal disease. Going by the cancer site, significant associations for those with a history of periodontal disease were noted for lung, kidney, pancreas, and hematological cancers. It was interpreted that periodontal disease was associated with a small, but significant, increase in the overall cancer risk, which persisted in 'never-smokers'. The associations recorded for lung cancer were probably because of residual confounding by smoking. It was suggested that periodontal disease might be a marker of a susceptible immune system or might directly affect cancer risk.
Tezal et al., conducted a study in the Department of Dentistry and Maxillofacial Prosthetics, Rosewell Park Cancer Institute between 1999 and 2005, to assess the effect of chronic periodontitis on head and neck squamous cell carcinoma (HNSCC). Cases were those diagnosed with HNSCC. Controls were those diagnosed negative for malignancy. A total of 473 cases were examined (266 cases and 207 controls). Periodontitis was measured by assessing the alveolar bone loss using panoramic radiography. Each millimeter of alveolar bone loss was associated with more than a four-fold increased risk of HNSCC (Odds ratio 4.76, 95% confidence interval, 3.16-6.01). The strength of association was found to be the greatest in the oral cavity. Patients with periodontitis were more likely to have poorly differentiated oral squamous cell carcinoma than those without periodontitis. This suggested that chronic periodontitis is an independent risk factor for HNSCC and smoking modifies the association.
Another study was conducted by Manish Arora et al., for the exploration of shared genetic risk factors between periodontal disease and cancer in Swedish twins. The authors proposed that both the conditions exhibited common risk factors. They analyzed the association between baseline periodontal disease measured by questionnaires, recorded tooth mobility and incident cancers, identified by linkage with National Registries between 1963 and 2004, in 15,333 Swedish twins. After adjustment of the covariates, baseline periodontal disease was associated with increased risk of several cancers ranging from 15% of the total cancer. This was associated with increased risk of colorectal, pancreatic, and prostate cancers. In the co-twin analysis, dizygotic twins with baseline periodontal disease showed 50% increase in the total cancer risk. In monozygotics, the association was found to be markedly attenuated. Similar patterns emerged for digestive tract cancers, suggesting that shared genetic factors may partially explain the associations between both.
Divaris et al. (2010), conducted a population-based, case-control study of incident squamous cell carcinoma of the head and neck (SCCHN). The Carolina Head and Neck Cancer Study was carried out in 2002-2006 in 46 counties in North Carolina. The controls (n = 1,361) were frequency-matched with the cases (n = 1,289) on age, race, and gender. Oral health was assessed using interview data on tooth loss and mobility, mouthwash use, and frequency of dental visits. Self-reported history of tooth mobility was moderately associated with an increased SCCHN risk. However, the association did not persist among 'never-smokers'. Routine dental visits were associated with 30% risk reduction. The data obtained from this study showed a modest possible association between both.
A study by Grant et al. (2011), showed that low Vitamin D status contributes to the link between periodontal disease and breast cancer.
Sadighi Shamami et al., in his systematic review, selected PubMed articles from1995 to 2010 outlining the recent epidemiological researches pointing to a possible role for tooth loss and periodontal disease in carcinogenesis. Nine out of ten case-control studies reported a significant increase in the risk of oral cancer in patients with periodontitis and one with no significant association. The results indicated that there was a possible link between cancer and severe periodontal disease, after adjustment for smoking and drinking habits.
Bacteria and viruses in periodontitis
Evidence indicates that chronic infections and inflammation may be associated with increased risk of cancer development. Evidence shows that periodontal bacteria and viruses may act synergistically to cause periodontitis.
There are many studies indicating that periodontitis lesions are a source of salivary human cytomegalovirus (HCMV) and Epstein Barr virus (EBV). Saygun et al., in 2005, conducted a study comparing the HCMV and EBV DNA copy counts in periodontitis sites and in whole saliva, and evaluated the potential of periodontal therapy to reduce the salivary level of the two viruses.
Twenty systemically healthy periodontitis patients in the age group of 21-56 years participated in this study. Seven patients, three months after periodontal therapy, were also included in this study. Treatment included both the surgical and nonsurgical phases. The clinical parameters were evaluated. In each patient, virological samples were collected from one periodontal pocket of 6-10 mm and from an adjacent inflamed adjacent pocket and from unstimulated saliva. All the twenty periodontitis patients showed a positive correlation between the gingival tissue and salivary counts of HCMV and EBV DNA. After treatment, both the DNA counts decreased. The HCMV DNA counts decreased 37.5-fold in the subgingival sites and 64.5-fold in saliva. The EBV DNA counts decreased 5.7-fold in the subgingival sites and 12.9-fold in saliva. This study proved the presence of salivary HCMV and EBV in periodontitis lesions.
Hormia et al., in 2005, conducted a study taking gingival biopsies from 38 patients, which were clinically diagnosed as periodontal disease. In the study, high-risk Human Papilloma virus was detected in 26% of the biopsies. The study suggested that a periodontal pocket may serve as a reservoir for HPVs in the oral mucosa.
Another study was conducted by Pradeep et al. in 2006, on the microorganism H. pylori. The purpose was to determine whether dental plaque, poor oral hygiene, and periodontal disease were risk factors for Helicobacter pylori Pylori) infection. It was found that the association of periodontal disease and poor oral hygiene with H. pylori infection was not significant. There was higher prevalence of the microorganism in the dental plaque of patients with gastric H. pylori infection than in the controls, but both the cases and control group had a high positive urease test for H. pylori infection in the plaque (89 and 71%, respectively). H. pylori in dental plaque are seldom eliminated by the H. pylori eradication therapy, and these may act as a source for future reinfection. It is usually present in patients with gastric ulcers and chronic gastritis. It is also believed to be linked with the development of duodenal ulcer and stomach cancer.
Sahin et al., in 2009, conducted a study where whole saliva was collected from 14 periodontitis patients, 15 gingivitis patients, and 13 complete denture wearers. The subjects were systemically healthy and had not received any periodontal treatment for the past three months. Salivary cytomegalovirus was detected in 50% of the periodontitis patients, but not in any gingivitis or denture wearers. The salivary EBV was seen in 79% of the periodontitis patients and a small percentage in gingivitis patients and denture wearers. It was concluded that HCMV and EBV were commonly present in the saliva of periodontitis patients. The periodontal lesions of systemically healthy patients constitute the main origin of HCMV, but do not comprise the sole source of EBV.
Bacteria and the suspected cancers
Helicobacter pylori infection is believed to be linked with gastric cancer and Chlamydia pneumonia infection with lung cancer development. Streptococcus bovis infection is associated with colon cancer. The other bacteria include Salmonella More Details Typhi in gall bladder cancer and hepatobiliary carcinoma.
Viruses and the associated cancers
Epstein Barr virus is believed to be associated with Burkitt lymphoma, Hodgkin Lymphoma, nasopharyngeal carcinoma, and stomach cancer. Human Herpes 8 is associated with Kaposi sarcoma. The Hepatitis B virus has its involvement in liver cancer and human T-lymphocytic virus with adult T-cell leukemia. The cytomegalovirus is associated with cancer of the salivary gland and prostate. The human papilloma virus is linked with cancer of the cervix, vulva, penis, and anus.
Periodontitis is characterized by epithelial proliferation and migration, which results in the chronic release of inflammatory cytokines, chemokines, prostaglandins, growth factors, and enzymes, all of which are closely associated with carcinogenesis. Chronic infections such as periodontitis can play a direct or indirect role in carcinogenesis.
Direct toxic effect of microorganisms
Microorganisms and their products such as endotoxins, enzymes, and metabolic by products, which are toxic to the surrounding cells, may directly induce mutations in the tumor-suppressor genes and proto-oncogenes or alter the signaling pathways that may affect cell proliferation and/or survival of the epithelial cells. Chronic infections with bacteria, notably S. Typhi, can also facilitate tumor development. Several bacterial toxins may interfere with the cellular signaling molecules in a manner that is characteristic of tumor promoters (Pasteurella multocida toxins act as mitogens). This leads to activation of COX2, which is involved in several stages of tumor development, inhibiting apoptosis. These toxins could play an important role in the causation of cancer and its progression.
Several factors influence the progression from viral infection to cancer development. The factors include the host's genetic makeup, mutation occurrence, exposure to cancer causing agents, and immune impairment.
Many viruses like the human cytomegalovirus (HCMV) and Epstein Bar virus (EBV), two members of the herpes viridae family may also mediate oncogenic growth. Herpes viruses are transmitted from person to person during initial stages of primary infection. HCMV is the most common life-threatening infection in HIV patients and EBV is the causative agent of oncogenic growth. Saliva is the main source of its transmission and it resides in marginal and apical periodontitis. Periodontal therapy reduces the EBV.
Viruses typically initiate cancer development by suppressing the host's immune system by causing inflammation over a long period of time or by altering the host's genes.
There are two mechanisms by which virus cause tumors. A direct oncogenic viral mechanism involves either insertion of additional viral oncogenic genes into the host cell or it enhances the already existing oncogenic genes (proto-oncogenes) in the genome. Here the virus infects a cell and express its own genes. The gene products enhance the growth potential of that cell. If a growth enhancing change occurs in the same cell, it may grow into a cancer.
Direct tumor viruses must have at least one virus copy in every tumor cell, expressing at least one protein or RNA that is causing the cell to become cancerous.
Chronic indirect tumor viruses can be lost from a mature tumor that has accumulated sufficient mutations and growth conditions from the chronic inflammation of a viral infection.
Indirect viral oncogenicity involves chronic nonspecific inflammation occurring over decades of infection, as is the case for HCV-induced liver cancer. Here the virus acts as a cofactor for the tumor, but it is not actually present in the tumor cells. It allows viruses such as the EBV and Kaposi's sarcoma-associated herpes virus to act opportunistically and cause uncontrolled cell growth in the absence of normal immune control mechanisms (e.g., the HIV affected).
The EBV may mediate oncogenic growth because of its close relationship with certain tumors arising in the lymphoid tissue, such as, Burkitt lymphoma, Hodgkin disease, and those from the epithelial tissue, such as, nasopharyngeal carcinoma. The salivary gland tissue and ductal epithelial cells are assumed to be the main reservoirs of the herpes virus, which is believed to cause Kaposi sarcoma. Presence of the herpes virus is usually seen in aggressive periodontitis.
Indirect effect through inflammation
Microorganisms and their products activate host cells such as neutrophils, macrophages, monocytes, lymphocytes, fibroblasts, and epithelial cells to,
- Generate reactive oxygen species (ROS) and nitrogen species, reactive lipids and metabolites, and matrix metalloproteases, which can induce DNA damage in epithelial cells
- Produce cytokines, chemokines, growth factors, and other signals that produce an environment for cell survival, proliferation, migration, and angiogenesis, and also help in inhibition of apoptosis.
This environment may help epithelial cells to accumulate mutations and drive these cells to proliferate, migrate, and give them a growth advantage. It has been shown that people with periodontal disease have an increased level of inflammatory markers such as C-reactive proteins in their blood. These markers are a part of an early immune system, which respond to persistent inflammation and have been linked to the development of pancreatic cancer.
Another link was explained between periodontal disease and risk of pancreatic cancer. The high levels of carcinogenic compounds that are present in the mouth of people with periodontal disease increase the risk of cancer. The carcinogenic compounds, namely, nitrosamines and bacteria, react with the digestive chemicals in the gut to create conditions that favor the development of pancreatic cancer.
The shared genetic factors may partially explain the association between cancer and periodontal disease, in the case of digestive tract cancer. There are many other risk factors modifying the development of cancer. Smoking and usage of smokeless tobacco have also proved to be the main risk factors associated with cancer development. The strength of association is higher in a past smoker or a 'never smoker' when compared to current smokers.
Alcoholism along with smoking gives an additive effect in carcinogenesis.
Diet, age, gender, and family history also play an important role in carcinogenesis.
| Conclusion|| |
Summarizing the review, the studies done by various authors throw light on the fact that compromised oral health may prove a risk factor for carcinogenesis. It is essential to explore the association between the two by undertaking a larger number of studies that include other sites. By confirming the association between these two, a message of relevance can be delivered to the community, which may have a potential impact on understanding the etiology of cancer as well as its prevention and control.
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