The Relationship of Periodontal Disease to Oral Squamous Cell Cancer
The identification of periodontal disease (specifically periodontitis; PD) as a risk factor for systemic diseases has generated great interest among the clinical and research communities in dentistry and medicine. Most of the attention has been focused on several chronic, non-communicable diseases, specifically cardiovascular and cerebrovascular disease1Herrera D, Molina A, Buhlin K, Klinge B. Periodontal diseases and association with atherosclerotic disease. Periodontol 2000. 2020;83(1):66-89., diabetes mellitus2Sanz M, Ceriello A, Buysschaert M, Chapple I, Demmer RT, Graziani F, et al. Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol. 2018;45(2):138-49., respiratory disease3Qian Y, Yuan W, Mei N, Wu J, Xu Q, Lu H, et al. Periodontitis increases the risk of respiratory disease mortality in older patients. Exp Gerontol. 2020;133:110878., and cognitive disorders4Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017;9(1):56.. Furthermore the definition of the PD-OSCC relationship challenge to adverse pregnancy outcomes due n part to anatomic proximity, this has been a subject of particular interest5Teshome A, Yitayeh A. Relationship between periodontal disease and preterm low birth weight: systematic review. Pan Afr Med J. 2016;24:215..
Another association that has generated recent attention is the possible influence of oral infection/oral inflammation/PD on the development of various cancers. Defining these relationships is potentially of enormous significance for patients and clinicians when discussing the nature of PD and the need for appropriate treatment. The relationship of PD and cancer includes epidemiologic evidence supporting this association, and proposed mechanisms that would explain this relationship (i.e., biologic plausibility).
What Do We Know About the Relationship of Periodontal Disease and Cancer?
Nwizu and colleagues (2020)6Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: Epidemiologic studies and possible mechanisms. Periodontol 2000. 2020;83(1):213-33. reviewed the linkage between PD and the development of all cancers. PD is a chronic infection of the supporting tissues of the teeth, resulting in a low grade but often persistent host inflammatory and immune response that if untreated can contribute to the systemic inflammatory burden. The potential pathogenic mechanisms include both the role of specific bacteria, and persistent inflammation that occurs in response to the mixed infection.
The review6Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: Epidemiologic studies and possible mechanisms. Periodontol 2000. 2020;83(1):213-33. note that the PD-cancer relationship was not prominently discussed when the field of “Periodontal Medicine” was developing. A Consensus Conference held in 2012 concluded that there was a suggestion of a linkage, but the published data did not allow further discussion of causality. Since that time, additional studies have been published that warrant a closer look at this relationship.
The epidemiological relationship between PD and all cancers has been evaluated using a variety of measures of oral disease, including self-reported history, surrogate markers such a tooth mobility, clinical periodontal parameters, and radiographic bone loss, as well as tooth loss. Systematic reviews/meta-analyses have examined incident cancer occurrence, and total mortality related to cancer. For cancer occurrence, the increased risk associated with periodontal disease in the 7 studies included in their analysis ranged from 1.05 to 1.24, or a 5% to 24% increase. For increased mortality related to PD, in the 6 studies included in that analysis the risk ranged from 1.0 to 1.55, or a 0% to 55% increase.
The Association of Periodontal Disease and Oral Squamous Cell Cancer
Depending upon the country, and the prevalence of existing risk factors, oral squamous cell carcinoma (OSCC) is generally considered to be among the top 10 most common types of malignancy7Rivera C. Essentials of oral cancer. Int J Clin Exp Pathol. 2015;8(9):11884-94.. OSCC is a complex disease, with multiple risk factors (Figure 1); this makes the definition of the PD – OSCC a challenge. Due in part to anatomic proximity, this association has been most extensively studied of all the PD – cancer relationships6Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: Epidemiologic studies and possible mechanisms. Periodontol 2000. 2020;83(1):213-33.. However, challenges exist in interpretation and summation of these studies since the published reports are quite heterogeneous in terms of how PD is defined, with some studies using surrogate markers such as self-report and tooth loss, while others include more quantitative clinical and radiographic data. Variables for OSCC must also be considered and include anatomic location and stage of the disease at the time of diagnosis.
Figure 1: Risk factors for oral squamous cell cancer (OSCC)
OSCC is a complex disease with multiple risk factors. Traditional risk factors include tobacco, alcohol, and betel nut chewing. Other risk factors have been more recently identified, including infection with the human papilloma virus (HPV), inflammation and the oral microbiome. The clinician must consider the potential impact of each risk factor when evaluating each patient.
In sum, most studies report a positive association of PD and OSCC. Meta-analyses have examined the relationship between periodontal disease and cancer of the head and neck8Zeng XT, Deng AP, Li C, Xia LY, Niu YM, Leng WD. Periodontal disease and risk of head and neck cancer: A meta-analysis of observational studies. PLoS One. 2013;8(10):e79017. and the relationship of tooth loss and head and neck cancer9Wang RS, Hu XY, Gu WJ, Hu Z, Wei B. Tooth loss and risk of head and neck cancer: A meta-analysis. PLoS One. 2013;8(8):e71122.,10Zeng XT, Luo W, Huang W, Wang Q, Guo Y, Leng WD. Tooth loss and head and neck cancer: A meta-analysis of observational studies. PLoS One. 2013;8(11):e79074.. Regarding periodontal disease and risk of head and neck cancer, 8 studies were included in the meta-analysis. While a range of measures of PD were used, a significant association between PD and head and neck cancer was observed (odds ratio = 2.63). For tooth loss and the risk for head and neck cancer, two meta-analyses included 9 and 10 studies respectively, with odds ratios of 2.00 and 1.58. For tooth loss, there was generally an association of greater tooth loss and greater risk. Two more recent systematic reviews have been published, confirming these associations. However, even considering the heterogeneity of study designs, and the potential importance of confounders such as smoking and alcohol use, the authors of one systematic review concluded that there was a modest but significant risk of OSCC for persons with PD11Javed F, Warnakulasuriya S. Is there a relationship between periodontal disease and oral cancer? A systematic review of currently available evidence. Crit Rev Oncol Hematol. 2016;97:197-205.. A more recent systematic review identified an association between PD and oral cancer but did not perform a meta-analysis since the authors felt that differences in study design, the periodontal indices that were used, and the location of the oral cancers were variable, so a mathematical summary of the available data was not warranted12Colonia-Garcia A, Gutierrez-Velez M, Duque-Duque A, de Andrade CR. Possible association of periodontal disease with oral cancer and oral potentially malignant disorders: a systematic review. Acta Odontol Scand. 2020;78(7):553-9..
Nwitzu et al6Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: Epidemiologic studies and possible mechanisms. Periodontol 2000. 2020;83(1):213-33. discussed the biological reasons that could explain a relationship of PD and cancer. The two major lines of investigation are the role of the oral microbiome, and the resultant inflammatory response to the mixed infection.
There is a robust literature examining the relationship of the microbiome and cancer13Goodman B, Gardner H. The microbiome and cancer. J Pathol. 2018;244(5):667-76.. This review focused on the potential role of bacteria, and not viruses, but they note that the strong evidence for the role of certain viruses, including the human papilloma virus and hepatitis B virus, in the development of cancer. Goodman and Gardner13Goodman B, Gardner H. The microbiome and cancer. J Pathol. 2018;244(5):667-76. estimated that 20% of all cancers are attributable to infection. They note the particular importance of Helicobacter pylori and F. nucleatum in the development of cancers of the gastrointestinal track.
The examination of the microbial – cancer linkage now focusses on mechanistic studies. In that vein, the presence of a number of Gram-negative anaerobic organisms within the deepened sulcus is important. The sulcus epithelium is often ulcerated, which promotes both local and systemic spread of the microorganisms. This biofilm is resistant to disruption, and the deepened periodontal sulcus is also protective of the biofilm. Specifically,
- Periodontal pathogens produce or release an array of toxic substances, including degradative enzymes and endotoxin that can cause damage to DNA of resident cells, including mutations of genes that suppress development of cancer.
- Periodontal bacteria can activate toll-like receptors, which are present on the surface of many cells of the innate immune system and activate the inflammatory and immune responses. Activation of these receptors can lead to tumor cells evading important anti-tumor defense mechanisms.
- The direct effect of specific bacteria has been implicated in the development and progression of cancers. The oral microflora associated with OSCC differs from that which is found elsewhere in the mouth. As an example, the bacterium F. nucleatum, a component of the pathogenic oral microflora, has been implicated in the development of pre-malignant and malignant lesions of the gastrointestinal system. While mechanisms are being studied, penetration of the lining of the colon, followed by penetration and then stimulation of an inflammatory response with production of growth factors that enhance proliferation of cancer cells has been one area that has received attention14Han YW. Commentary: Oral bacteria as drivers for colorectal cancer. J Periodontol. 2014;85(9):1155-7..
The other aspect of PD that has been implicated in the PD – cancer is inflammation, specifically low-grade inflammation induced by the persistent periodontal infection. Several mechanisms have been proposed that can promote the development of cancer. As examples,
- Inflammation is associated with generation of free radicals and oxygen metabolites, which leads to a state of oxidative stress. This condition can lead to mutations in DNA and disrupted DNA repair, both of which are associated with carcinogenesis.
- Inflammatory cells produce a variety of other mediators, including cytokines, interleukins, and arachidonic acid metabolites, which also contribute to cellular disruption.
- As a result of the above, further recruitment of inflammatory cells will occur, that perpetuates the inflammatory response.
A Focus on the Pathogenic Oral Microflora as Important to the PD-OSCC Relationship
The use of animal models to study the development of OSCC can provide insight into the mechanisms that can explain the role of oral bacteria in development of OSCC15Supsavhad W, Dirksen WP, Martin CK, Rosol TJ. Animal models of head and neck squamous cell carcinoma. Vet J. 2016;210:7-16.. As an example, a model to study the effect of oral bacterial pathogens on OSCC described by Gallimidi and co-workers16Binder Gallimidi A, Fischman S, Revach B, Bulvik R, Maliutina A, Rubinstein AM, et al. Periodontal pathogens Porphyromonas gingivalis and F. nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget. 2015;6(26):22613-23.. demonstrated specific signaling between bacterial and tumor cells. This enhancement of OSCC activity was the result of several mechanisms, including the stimulatory effect of Porphyromonas gingivalis and F. nucleatum on OSCC cells, and proliferation and expression of tumor-associated molecules via cell-to-cell contact of the bacterial and tumor cells.
In a clinical study, the salivary microbiota was examined in different groups of patients, including those without an oral lesion, with a pre-cancerous oral epithelial lesion, and with oral cancer associated with various risk factors such as chewing betel nut and smoking17Lee WH, Chen HM, Yang SF, Liang C, Peng CY, Lin FM, et al. Bacterial alterations in salivary microbiota and their association in oral cancer. Sci Rep. 2017;7(1):16540.. Differences were observed between the microflora in saliva of patients with pre-cancerous lesions and those associated with oral cancer. Using DNA sequencing, higher concentrations of organisms in the Bacillus, Enterococcus and Peptostreptococcus genera were observed. The authors proposed that such an evaluation could eventually lead to a means of predicting which patients are at risk for development of OSCC. Further, a review published in 2019 noted the importance of four bacterial species (P. gingivalis, F. nucleatum, Treponema denticola and Streptococcus anginosus) as potentially involved in the development and progression of OSCC via a variety of mechanisms, including promotion of both cell migration and invasion and prevention of apoptosis, which is programmed cell death18Zhang WL, Wang SS, Wang HF, Tang YJ, Tang YL, Liang XH. Who is who in oral cancer? Exp Cell Res. 2019;384(2):111634..
A study evaluated the microflora that characterized OSCC versus the normal mucosa on the contralateral side of the oral cavity19Zhang L, Liu Y, Zheng HJ, Zhang CP. The oral microbiota may have influence on oral cancer. Front Cell Infect Microbiol. 2019;9:476.. Speciation using DNA sequencing revealed that several bacterial species were abundant in the OSCC lesions, including F. nucleatum, Prevotella intermedia, Aggragatibacter segnis, Capnocytophgia leadbetteri and Peptostreptococcus stomatis. On the genetic level, genes associated with bacterial chemotaxis, and production of lipopolysaccharide, were associated with OSCC lesions, and these genes were increased above what was observed when a lesion as not present. The authors proposed that these data could ultimately be used to design approaches to both prevention and treatment of OSCC. Further, a review by Chattopadhyay and colleagues20Chattopadhyay I, Verma M, Panda M. Role of oral microbiome signatures in diagnosis and prognosis of oral cancer. Technol Cancer Res Treat. 2019;18:1533033819867354. examined specific mechanisms associated with the important periodontal pathogens P. gingivalis and F. nucleatum that can explain their role in development of OSCC. Identification of bacterial species that promote development OSCC, as well a normal or constituent species that do not have this effect, may ultimately be used for both diagnostic and prognostic purposes.
A variety of other direct and indirect mechanisms have been associated with the PD – OSCC linkage. These include:
- Mastication can cause release of pathogenic bacteria that normally reside in the complex subgingival biofilm. This would infer that the mucosal tissue is bathed in saliva containing these microorganisms.
- High levels of matrix metalloproteinase are associated with periodontitis and can be found in both saliva and gingival fluid21Uitto VJ, Suomalainen K, Sorsa T. Salivary collagenase. Origin, characteristics and relationship to periodontal health. J Periodontal Res. 1990;25(3):135-42.. These enzymes are primarily of host origin and can degrade both the extracellular matrix and basement membrane and thereby promote tumor invasion and spread.
- For persons with diabetes, the glycation of proteins has been implicated in the development of many clinical aspects of the disease. These advanced glycation end products (AGEs) represent an end stage in the non-enzymatic joining of proteins and glucose, are present in many types of tissues of persons with diabetes and promote inflammation22Schroter D, Hohn A. Role of advanced glycation end products in carcinogenesis and their therapeutic implications. Curr Pharm Des. 2018;24(44):5245-51.. This upregulation of inflammation, with production of an array of inflammatory mediators, is associated with tissue alteration and destruction23Ramos-Garcia P, Roca-Rodriguez MDM, Aguilar-Diosdado M, Gonzalez-Moles MA. Diabetes mellitus and oral cancer/oral potentially malignant disorders: A systematic review and meta-analysis. Oral Dis. 2021;27(3):404-21.. Therefore, patients with PD and diabetes may be at higher risk for this tumor-promoting activity.
- If periodontitis progresses to tooth loss, the resultant inability to chew properly can modify a person’s diet, leading to a preference for easy to chew soft, carbohydrate-rich foods, and avoidance of healthy, fibrous foods such as fruits and vegetables.
Another Consideration: Use of an Alcohol-containing Mouthrinse
Alcohol, specifically ethyl alcohol or ethanol, which is consumed in alcoholic beverages, is recognized as both a mutagen (altering DNA, which leads to mutations that can cause cancer) as well as a carcinogen (which directly promote the development of cancer). The metabolism of ethyl alcohol occurs in the liver, with production of acetaldehyde. Acetaldehyde is recognized as extremely carcinogenic. A variety of direct effects of alcohol on cellular activity have also been associated with its carcinogenic potential, primarily because of disruption of normal DNA function24Reidy JT, McHugh EE, Stassen LF. A review of the role of alcohol in the pathogenesis of oral cancer and the link between alcohol-containing mouthrinses and oral cancer. J Ir Dent Assoc. 2011;57(4):200-2..
Several mouthrinses that are used as adjuncts in oral hygiene contain alcohol at concentrations as high as 26.9%, and concern has been raised about the concentration of acetaldehyde in saliva after the use of an ethanol-containing mouthrinse. The salivary acetaldehyde concentration was assessed in healthy volunteers who used an alcohol-containing mouthrinse over a to 10-minute period. Concentrations were assessed following the recommended time of exposure (20 ml rinsed for 30 seconds). The level of salivary acetaldehyde reached a peak concentration 2 minutes after rinsing, and the concentrations in saliva was comparable to what would occur after drinking an alcoholic beverage. While the calculated exposure was determined to represent a low public health risk, caution was urged, especially for patients with other risk factors for OSCC25Lachenmeier DW, Gumbel-Mako S, Sohnius EM, Keck-Wilhelm A, Kratz E, Mildau G. Salivary acetaldehyde increase due to alcohol-containing mouthwash use: A risk factor for oral cancer. Int J Cancer. 2009;125(3):730-5..
Several population studies and systematic reviews (some with a meta-analysis) have examined the association of mouthrinse use and OSCC. A systematic review and meta-analysis published in 2012 examined 18 studies and did not find a statistically significant association of oral cancer with use of any mouthrinse, increasing use of mouthrinse, or an alcohol-containing mouthrinse26Gandini S, Negri E, Boffetta P, La Vecchia C, Boyle P. Mouthwash and oral cancer risk quantitative meta-analysis of epidemiologic studies. Ann Agric Environ Med. 2012;19(2):173-80.. To illustrate that there is some confusion about this question, the same authors evaluated these relationships in a database from the International Head and Neck Cancer Epidemiology Consortium. They identified a small but significant increased risk of developing oral and oropharyngeal cancer with use of any mouthrinse (11% and 29% increase, respectively), and a 15% increase if mouthrinse was used for more than 35 years. The authors concluded that there was an association between mouthrinse use and development of head and neck cancer but acknowledged that they could not consider the effect of tobacco and recreational alcohol use on their findings27Boffetta P, Hayes RB, Sartori S, Lee YC, Muscat J, Olshan A, et al. Mouthwash use and cancer of the head and neck: A pooled analysis from the International Head and Neck Cancer Epidemiology Consortium. Eur J Cancer Prev. 2016;25(4):344-8.. Another systematic review included 6 clinical studies28Ustrell-Borras M, Traboulsi-Garet B, Gay-Escoda C. Alcohol-based mouthwash as a risk factor of oral cancer: A systematic review. Med Oral Patol Oral Cir Bucal. 2020;25(1):e1-e12.. One study demonstrated a relationship between use of an alcohol-containing mouthrinse and OSCC, 2 studies found a relationship when there was frequent use of such a mouthrinse, and 3 studies failed to identify any risk. The authors could not identify an increased risk of OSCC with use of an alcohol-containing mouthrinse but concluded that the risk is increased if there are other risk factors for OSCC (i.e., smoking). Yet another recent review concluded that the use of alcohol-containing mouthrinse was not a risk factor for development of OSCC29Aceves Argemi R, Gonzalez Navarro B, Ochoa Garcia-Seisdedos P, Estrugo Devesa A, Lopez-Lopez J. Mouthwash with alcohol and oral carcinogenesis: Systematic review and meta-analysis. J Evid Based Dent Pract. 2020;20(2):101407..
- Considering all the available evidence relating periodontitis to oral cancers/other cancers, there is a suggestion of a positive association.
- Cause and effect cannot be proven with analysis of existing databases, often because the studies were not designed to answer this question. Systematic reviews often include studies that employ a variety of markers for PD, which makes interpretation difficult.
- The importance of related factors, most notably the effect of smoking and alcohol use on the development of OSCC, cannot be overemphasized. Many studies do not adequately control for these confounders. Other secondary confounders such as diet quality, being overweight and frequency of exercise often cannot be assessed from the available databases.
- The ultimate answer to these questions would only be possible with a well-designed and lengthy prospective study. The cost of such a study would be prohibitive, so this question will remain open.
What to Tell Your Patients?
The message to patients should be direct and based on the facts as they are known. There is a suggestion of an association between PD and OSCC, but cause and effect have not been determined. There are several mechanisms that can account for this association (there is biologic plausibility), and the role of pathogenic bacteria in the development of different cancers has received increasing attention. The development of oral cancer is a complex process and well-documented primary risk factors including smoking (which is often accompanied by excessive alcohol intake), HPV infection and betel nut chewing. Further, smoking is recognized as the most important risk factor for PD, so this overlap further complicates an attempt to tease out the effect of PD on OSCC.
For the dental patient who is at risk for development of OSCC, oral health care providers should actively advise patients to reduce risk factors, which include smoking cessation and reduced alcohol intake, as well as secondary risk factors which can include reduction in heavy use of any mouthrinse with a high alcohol content. For the at-risk patient, frequent surveillance and reinforcement of lifestyle changes should be part of the message delivered in the dental office.
Treatment recommendations for the patient with PD should be based on the severity of PD, as well as other patient-specific considerations. Periodontal treatment will improve the status of the periodontium, helping to preserve the dentition, which by itself is an important outcome. Additional benefits, including possibly reducing the risk for certain other systemic diseases such as cardiovascular disease and type 2 diabetes, as well as the risk of OSCC, are considered secondary, but with important consequences. The control of underlying risk factors (i.e., smoking cessation) must also be included in the conversation about how the patient’s self-care can improve both oral and general health. Regarding advice about the use of alcohol-containing mouthrinse, the association with OSCC is not fully defined, but the available evidence argues against this as a primary risk factor. Nevertheless, when evaluating a patient who is considered at risk for OSCC (for example a long-term smoker who is unwilling to quit), the frequent and long-term use of an alcohol-containing mouthrinse should be discouraged.
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