|Year : 2020 | Volume
| Issue : 4 | Page : 209-212
Association of chronic periodontitis and oral cancer: A review on pathogenetic mechanism and clinical implication
RJ Krishnasree1, P Jayanthi1, PS Karthika1, K Nandhakumar2, R Rathy1
1 Departments of Oral Pathology and Microbiology, Azeezia College of Dental Science and Research, Meeyannoor P O, Kollam, Kerala, India
2 Departments of Periodontology andImplantology, Azeezia College of Dental Science and Research, Meeyannoor P O, Kollam, Kerala, India
|Date of Submission||03-Jun-2020|
|Date of Decision||06-Jun-2020|
|Date of Acceptance||08-Jun-2020|
|Date of Web Publication||6-Jan-2021|
Dr. R J Krishnasree
Department of Oral Pathology and Microbiology, Azeezia College of Dental Science and Research, Meeyannoor P O, Kollam, Kerala
Source of Support: None, Conflict of Interest: None
The objective of this article is to review the available literature on the pathogenetic mechanisms involved in the association between oral cancer and periodontitis and its clinical implications. Periodontal diseases are characterized by chronic inflammation as a response to the host tissue invasion by multi-species microbial community. The activation of different inflammatory cascades by chronic periodontitis negatively affects the oral mucosa and has the potential to activate carcinogenesis. An electronic literature search was conducted in the MEDLINE and EMBASE databases. The search terms used were “CHRONIC PERIODONTITIS, ORAL CANCER, and PATHOGENESIS”. Original articles published between January 1990 and March 2018 was identified. Thirty-two potentially relevant articles were selected and included in the review after assessing the title and abstract. Several studies have shown that the inflammatory mediators produced in periodontal diseases may lead to angiogenesis and subsequently promote tumorogenesis. Periodontitis being a polymicrobial disease promotes carcinogenesis by evoking various inflammatory pathways. The rationale behind the association of oral cancer and periodontitis is that inflammation plays a key role in the pathogenesis of both conditions.
Keywords: Chronic periodontitis, inflammation, oral cancer, squamous cell carcinoma
|How to cite this article:|
Krishnasree R J, Jayanthi P, Karthika P S, Nandhakumar K, Rathy R. Association of chronic periodontitis and oral cancer: A review on pathogenetic mechanism and clinical implication. J NTR Univ Health Sci 2020;9:209-12
|How to cite this URL:|
Krishnasree R J, Jayanthi P, Karthika P S, Nandhakumar K, Rathy R. Association of chronic periodontitis and oral cancer: A review on pathogenetic mechanism and clinical implication. J NTR Univ Health Sci [serial online] 2020 [cited 2021 Feb 26];9:209-12. Available from: https://www.jdrntruhs.org/text.asp?2020/9/4/209/306128
| Introduction|| |
Oral cancer (OC) is estimated to be the eleventh most common cancer globally. The incidence of oropharyngeal cancers corresponds to 3.8% of all cancer cases and is reported to be about 5, 29, 500 cases every year. In India itis the third most common malignancy, oral squamous cell carcinoma (OSCC) being the most common type. Major risk factors associated with oral cancer includes tobacco, betelnut chewing, and viral infections (human papilloma virus (HPV) infections). In addition, genetic susceptibility and chronic inflammation may also play a major role in the etiology of oral cancer. Over the past few years, a change in the epidemiology of OSCC has been observed. Several new cases of OSCC lacking the recognized risk factors of smoking, alcohol, and HPV association have been reported. Despite a decline in the prevalence of cigarette smoking and alcohol consumption in the US, the incidence of OC is remaining virtually unchanged. The prevalence of HPV in OSCC is unclear and subjected to great variation with an average of 23%. It is estimated that 15-20% of all death from cancer globally are linked to infection and inflammatory response. Carcinogenesis has been associated with deregulated inflammatory responses. Various studies suggest that chronic inflammation resulting from low-grade persistent chemical, bacterial, and viral agents predispose the formation of preneoplastic foci and promotes tumor growth.
Chronic inflammation produced in response to multispecies sub gingivalmicro flora is the characteristic of periodontitis. Numerous studies have validated that the inflammatory mediators produced during periodontitis disseminate to extra oral-sites. Sufficient studies show a strong association between orodigestive cancers, poor oral health, presence of periodontitis associated bacteria, tooth loss, and clinical signs of periodontitis.Periodontitis being a polymicrobial disease, several species associated with periodontitis promotes carcinogenesis by evoking various inflammatory pathways. The rationale behind the association of malignancy and periodontitis is that inflammation plays a key role in the pathogenesis of both conditions.
| Chronic Inflammation as a Link Between Periodontitis and Oral Cancer|| |
Inflammation is a complex host defense mechanism against physical, chemical, and biological antigens. The polymicrobial sub gingival community in periodontitis condition triggers host defence mechanism leading to infiltration of neutrophils and NK (Natural killer) cells. A CD8, CD4, T cell profile is formed which promotes a proinflammatory medium rich in cytokines namely tumor necrosis factor-alpha (TNFα), interleukin-(IL) 1, IL4, IL10, interferon, and transforming growth factor β (TGFβ). An increased expression of IL8, IL10, CXCL3, CXCL1, IL6, IL1 are also observed in multispecies biofilms. The cytokines that are found to increase the most are the ones that are precisely related to chronic bone damage. In addition to inflammatory mediators produced by immune cells, the gingival epithelium also releases other cytokines such as IL1, IL8, and TNFα which in turn recruits macrophages. A higher expression of IL-1β was observed in gingival fluid from deeper sites of periodontal patients. Studies suggest that an increased IL8 level is associated with periodontitis. Besides IL8, C-X-CL12 (CXC motif chemokine 12) is also reported to provide signals for osteoblast and osteoclast precursors and it enhances the activity of matrix metalloproteinase. CCL17 and CCL22 are also expressed at higher levels in chronic periodontitis.
An overall altered chemokine function progress to enhanced cellular proliferation neovascularization motility and metastasis in oral cancer. The role of chemokine and their receptors in oral squamous cell carcinogenesis has been emphasized by Yeudall et al. (2007). The chemotactic cytokines or chemokines contribute to the tumor microenvironment by establishing a chemokine gradient, which is important for the process of chemoattraction and subsequent cell motility and infiltration for metastasis.An elevated expression of both CXCR1 and CXCR2 in oral cancer has reported by Khurram et al.. A “homing model” which suggests that tumour cells that overexpress a chemokine receptor migrate preferentially to organs that express the cognate ligand via a chemokine gradient has been proposed by Muller et al.
However, there is also a possibility of malignant repressive property of chemokine. Chemokine CXCL14 was shown to be expressed in normal epithelium appeared markedly reduced in OSCC. The dysregulation of any of the converging factors of inflammation like growth factors, transcript factors such as NF-γB, AP-1, and STAT3, and their gene products such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), chemokines, cyclooxygenase-2 (COX-2), 5 lipooxygenase, matrix metalloproteases (MMP), and vascular endothelial growth factor (VEGF), adhesion molecules can lead to the pathogenesis of tumor progression.
| Periodontal Pathogens as a Risk Factor for Oral Squamous Cell Carcinoma|| |
A study was conducted by Gangly et al. (2019) on the role of periodontal pathogens as risk factors for OSCC. The oral microbiome of 18 non-smoker HPV negative OSCC patients and eight PMD (Potentially malignant Diseases) and twelve healthy controls were compared. They reported that the periodontal pathogens Fusobacterium, Prevotella, and Alloprevotella were enriched in oral cancer. The authors suggest a possible association between periodontal pathogens and OSCC patients. Treponema denticola /i>induces the secretion of proinflammatory cytokines such as IL8, IL6, and TNFα. Moffat et al. (2011) has reported Filifactor alocis s an emerging species associated with periodontitis as it infects the gingival epithelium and stimulates the production of cytokines such as IL8, IL6 which are related to osteoclastic stimulation and bone resorption.It has been reported by Bui et al. (2016) that Porphyromansgingivalis and Fusobacterium nucleatum also activates NLRP3 inflammasome inducing the release of damage associated molecular patterns (DAMP) like HIGH MOBILTY GROUP BOX 1 PROTEIN (HMB1) and proteins that recruit and activate caspases F. nucleatum increases MMP13 and IL8 through the MAPK/p38 pathway in epithelial cells. However, limited studies have been done on the effect of subgingival species in carcinogen.
| Discussion|| |
Studies conducted by Bundgard et al. (1990) and has shown a significantly higher risk of oral cancer for patients with fewer teeth than 20.However, the criteria for periodontitis was the number of missing tooth which was determined using a questionnaire based surveyand hence lack scientific validity. Poor oral hygiene was reported as a predictor of oral cancer. Oral hygiene as a risk factor for cancer has been reported by Seymour et al. (2010). However, Guha et al. (2007) noted no association between oral hygiene and cancer.A questionnaire survey was conducted in Cuba by Fernadez et al. (1999) among 200 oral cancer cases and controls and reported a significant higher risk in patients with more than sixteen missing teeth. Another study among 290 OSCC patients and controls was conducted by Marshal et al. and the authors found a significant increased risk of cancer with loss of eleven or more teeth after smoking. A 23 fold increase risk of oral cancer with increase in the number of missing teeth was reported by Zheng et al. However de Rezende et al. (2004) reported no association of risk for oral cancer and DMFT index based on a case control study on 50 OSCC patients and healthy controls in Cuba. Further studies are required to confirm the association between periodontitis and oral cancer as the above-mentioned studies takes missing teeth into account based on questionnaires surveys while emphasize should be on diagnosis with clinical and radiological validation of periodontitis. Kruger et al. (2013) has reported four documented cases of alveolar squamous cell carcinoma directly being associated to teeth showing signs of periodontitis. The authors suggest that, the activation of inflammatory cascade by chronic periodontitis affects the oral mucosa and bone and has the potential to activate carcinogenesis.
A 5.23 fold increase in the risk of tongue cancer with each millimeter bone loss has been reported by Tezal et al. A clinical attachment loss of =1.5mm was associated with an increased risk of oral cancer. Michaud et al. (1983) reported no significant association between periodontitis and oral cancer, however, the parameter accessing periodontitis was relied on patient's reported history of periodontal diseases, verified by radiographic bone loss. Moreover oral cancer was grouped with oropharyngeal cancer and thus risk of oral cancer could not be determined. A possible association between periodontitis and potentially malignant diseases like leukoplakia was reported by Mesel et al. Fitzpatrik (2009) has noted that the available studies linking periodontitis and oral cancer varies wildly between inclusion criteria, and clinical parameters. Using missing teeth as a parameter cannot be reliable as teeth can be lost due to caries, trauma, or periodontitis.
Large number of studies are further required to eliminate the confounding factors like smoking, poor socioeconomic status, diabetes, age, gender, and diet which are all linked carcinogenesis. Arora et al. (2010) has made adjustments for confounding factors like age and gender, while Mai et al. (2014) and Michaud et al. (2008) modified their study for diet and alcohol usage. Momen-Heraviet al. (2017) andMazulet al.(2017) adjusted their study to include familial history and socioeconomic status. Garroteet al. 2001 and Talamaniet al. (2000) conducted their study among non-smokers and did not yield any significant data. Another confounding factor in studies that link oral carcinogenesis to chronic periodontitis was age of the patients involved in the study. Aging retard the human immune system, which in turn leads to cellular and DNA mutations which can be a significant factor in the pathogenesis of cancer. Javed et al. have reported that the periodontal condition is worse in elderly patients (aged 60 years and above) when compared to younger individuals (4045 years). The authors have also hypothesized that periodontitis leads to the upregulation of proinflammatory cytokines level of serum and bacteremia among immunocompromised patients thereby supporting the general hypothesis of periodontal infections inducing tumorgenesis.
| Conclusion|| |
Multi-centric studies are required further, where the periodontal assessment is standardized based upon clinical and radiographical evidences for establishing an association between periodontitis and oral cancer and the role of dysbiotic periodontal flora in inflammation and carcinogenesis has to be deeply studied.
Available literature suggests that inflammatory mediators produced during periodontitis may mediate carcinogenesis but further studies are required to understand the tumorogenic effects of periodontal pathogens.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2013), Released April 2016, based on the November 2015 Submission. Bethesda, MD: National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Surveillance Systems Branch; 2016.
Bektas-Kayhan K.Role of Inflammation in Oral Squamous Cell Carcinoma, Squamous Cell Carcinoma, Xiaoming Li, Intech Open. February 3rd
Ganly I, Yang L, Giese RA, Hao Y, Nossa CW, Morris LGT, et al
.Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus. Int J Cancer 2019;145:775-84.
Hoare A, Soto C, Rojas-Celis V, Bravo D. Chronic inflammation as a link between periodontitis and carcinogenesis. Mediators Inflamm 2019;2019:1029857.
Bakthavatchalu V, Meka A, Mans JJ, Sathishkumar S, Lopez MC, Bhattacharyya I, et al
. Polymicrobial periodontal pathogen transcriptomes in calvarial bone and soft tissue.Mol Oral Microbiol2011;26:303-20.
Gemmell E, Seymour GJ. Immunoregulatory control of Th1/Th2 cytokine profiles in periodontal disease.Periodontology 20002004;35:21-41.
Graves D. Cytokines that promote periodontal tissue destruction.JPeriodontol2008;79 (8 Suppl):1585-91.
Payne JB, Reinhardt RA, Masada MP, DuBois LM, Allison AC. Gingival crevicularfluidIL-8:CorrelationwithlocalIL-1betalevelsandpatientestrogen status.J Periodontal Res 1993;28 (6Pt1):451-3.
Silva TA, Garlet GP, Fukada SY, Silva JS, Cunha FQ. Chemokines in oral inflammatorydiseases: Apicalperiodontitisandperiodontaldisease. J Dent Res 2007;86:306-19.
GravesDT. Thepotential roleofchemokines andinflammatory cytokinesin periodontal disease progression. Clin Infect Dis 1999;28:482-90.
Miyazaki H, Takabe K, Yeudall WA.Chemokines, chemokine receptors and the gastrointestinal tract. World J Gastroenterol 2013;19:2847-63.
Khurram SA, Bingle L, McCabe BM, Farthing PM, Whawell SA. The chemokinereceptorsCXCR1andCXCR2 regulateoralcancercellbehaviour. J Oral Pathol Med 2014;43:667-74.
Muller WA. Mechanisms of leukocyte transendothelial migration.Annu Rev Pathol 2011;6:323-44.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;24:436-44.
Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O. The T cell-directed cc chemokine tarc is a highly specific biological ligand for CC Chemokinereceptor4. J Biol Chem 1997;272:15036-42.
Bui FQ, Johnson L, Roberts JA, Hung S-C, Lee J, Atanasova KR et al
. Fusobacterium Nucleatum Infection of Gingival Epithelial Cells Leads to NLRP3 Inflammasome-Dependent Secretion of IL-1β and the Danger Signals ASC and HMGB1. Cell Microbiol. 2016;18:970-81.
Bundgaard T, Wildt J, Elbrønd O. Oral squamous cell cancer in non-users of tobacco and alcohol. Clin Otolaryngol 1990;19:320-6.
Guha N, Boffetta P, WünschFilho V, ElufNeto J, Shangina O, Zaridze D, et al
.Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: Results of two multicentric case-control studies.Am J Epidemiol 2007;166:1159-73.
Garrote LF, Herrero R, Reyes RM, Vaccarella S, Anta JL, Ferbeye L, et al
.Risk factors for cancer of the oral cavity and oro-pharynx in Cuba.Br J Cancer 1999;85:46-54.
Marshall JR, Graham S, HaugheyBP, Shedd D, O'Shea R, Brasure J, et al
. Smoking, alcohol, dentition, and diet in the epidemiology of oral cancer.Oral Oncol Eur J Cancer 1992;28B: 9-15.
Zheng TZ, Boyle P, Hu HF, Duan J, Jian PJ, Ma DQ, et al
. Dentition, oral hygiene, and risk of oral cancer: Acase control study in Beijing, Peoples Republic of China. Cancer Causes Control 1990;1:234-41.
de Rezende CP, Ramos MB, Daguila CH, Dedivitis RA, Rapport A.Oral health changes in patients with oral and oropharyngeal cancer. Braz J Otolarygeol 2008;74:596-600.
Kruger M, Hansen T, Kasaj A, Maximilian M. The Correlation between Periodontitis and Oral Cancer.Hindawi Publishing Cooperation London, United Kingdom;?2013.
TezalM, SullivanMA, ReidME, MarshallJR, HylandA, LoreeT, etal
. Chronic periodontitisandtheriskoftonguecancer.Arch Otolaryngol Head Neck Surg 2007;133:450-4.
Meyer MS, Joshipura K, Giovannucci E, Michaud DS.A review of the relationship between tooth loss, periodontal disease, and cancer.Cancer Causes Control 2008;19:895-907.
Meisel P, Holtfreter B, Biffar R, Suemnig W, Kocher T.Assosiation of periodontitius with the risk of oral leukoplakia. Oral Oncol 2012;48:859-63.
Fitzpatrick SG, Katz J. The association between periodontal disease and cancer: A review of the literature. J Dent 2010;38:83-95.
Javed F, WarnakulasuryaS. Is there a relation between periodontal disease and oral cancer?A systematic review of currently available evidence. Crit Rev Oncol Hematol 2013;97:197-205.
Javed F, Chotai M, Mehmood A, Almas K. Oral mucosal disorders associated with habitual gutka usage: A review. O?ral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:857-64.