Exploring the Links Between Chronic Periodontitis and Oral Cancer: An Update

INTRODUCTION

Cancer is one of the primary causes of mortality worldwide and oropharyngeal cancer being its most common form.¹ The annual global incidence of oral cancer has been reported to be approximately 500,000 and over 60% of these cases occur in Asian countries like India, Sri Lanka, Pakistan, Taiwan, etc.² Though tobacco and alcohol are the commonly known risk factors of oral cancer, other risk factors include systemic diseases, metabolic syndromes, chronic inflammation and infection.³ Periodontal diseases or gum diseases, more specifically, periodontitis is the sixth-most prevalent disease worldwide. Chronic periodontitis (CP) is an inflammatory disease of the tooth-supporting tissues primarily gets initiated by dysbiotic microbial complex, clinically features through the occurrence of the periodontal pocket and clinical attachment loss, results in loss of periodontal tissue support, ultimately leads to loss of teeth.⁴Even though the inflammatory processes occur locally in the oral cavity, inflammatory mediators produced during periodontal disease process can spread from the oral cavity, contributing to various extra-oral systemic diseases including cancer.⁴ Besides, oral cancer, squamous cell carcinoma (OSCC) in particular, also presents with similar clinical features as advanced periodontal disease. Both these diseases produce bleeding gums, swelling, deep periodontal pockets, tooth mobility and alveolar bone destruction.⁵Herein, we review the possible links between periodontal diseases and oral carcinoma to intensify the importance of maintaining a good oral hygiene for the prevention of oral cancer and reduction of its mortality.

LITERATURE SEARCH METHODOLOGY

PATHWAYS OF LINK BETWEEN PERIODONTAL DISEASE AND ORAL CANCER

Role of microorganisms

Oral microbiome plays an important role in both health and disease, i.e. they are present in normal oral physiological environment as well as in disease condition.⁶ Oral microbiota could also be an important part in the process of carcinogenesis either by initiating inflammatory effects or through metabolism of chemical carcinogens, or both.⁷ Cancers related to various organs such as lung, prostate, gallbladder, colon have been proved to be linked with specific bacterial infections.⁸ Similarly, the oral cavity carries more than 700 microbial species which include commensals, opportunistic bacteria, fungi, and viruses. When this symbiotic relationship, where microorganisms live with an individual's host immune system gets imbalanced, oral cavity becomes prone to various infecto-inflammatory diseases, such as periodontal disease.⁹ Periodontal disease creates the potential for oral microbiota to initiate or promote carcinogenesis. In fact, various studies have shown that periodontopathogens such as Prevotella intermedia, Fusobacterium nucleatum, Porphyromonas gingivalis are associated with oral squamous cell carcinoma (OSCC). A high count of periodontopathogens in saliva could also be diagnostic indicators of oral cancer, as suggested by Mager et al.¹⁰

Porphyromonas gingivalis

Inhibition of apoptosis or programmed cell death is one of the hallmarks for carcinogenesis. Infection originating from Porphyromonas gingivalis modulates several anti-apoptotic pathways.¹¹ Firstly, it activates Jak1/Akt/ Stat3 signalling which controls pathways for mitochondrial apoptosis. This signalling increases the number of anti-apoptotic gene at the mitochondrial membrane and restrains the discharge of Cytochrome-C, an apoptosis effector, which ultimately results in the inhibition of apoptosis.¹² Secondly, P. gingivalis inhibits apoptosis of gingival epithelial cell through the ligation of P2X7 receptors.¹³ These P2X7 receptors secretes inflammatory cytokines, inhibits intracellular infection and helps in apoptosis.Therefore, the ligation of these receptors results in inhibition of apoptosis and an increase in intracellular inflammation.13 In another pathway, P. gingivalis, accelerates the progression of carcinogenesis by reducing the action of tumor suppressor gene, p53, in the S-phase of cell cycle.¹⁴ Furthermore, P. gingivalis also induces the expression of two receptors, B7-H1 and B7-DC in cancer cells and the cells of gingival epithelium.¹⁵ The expression of these receptors results in the release of regulatory T cells (Treg), which suppress effector T cells (Teff). This suppression of Teff contributes to an immune evasion by the cancer cells.¹⁵ P. gingivalis infection also activates pro-matrix metalloproteinase-9 (proMMP-9) expression. P. gingivalis produces Gingipain, a cysteine proteinase which cleaves the MMP-9 pro-enzyme into its active form which causes degradation the basement membrane of the gingival epithelium leading to migration and invasion of carcinoma cell.¹⁵ This way, cancer cells enter the circulatory system for dissemination and metastatic growth.

Fusobacterium nucleatum

F. nucleatum contributes to carcinogenesis by controlling several anti-apoptotic mechanisms. By activating p38 gene, F. nucleatum causes secretion of MMP-9 and MMP-13, which leads to degradation of the basement membrane, promoting carcinoma cell migration. In an animal study, F. nucleatuminduced NF-kB signalling in oral epithelium was demonstrated by Fisherman et al.¹⁶ This NF-kB signalling leads to cell survival and proliferation. Exposure of neoplastic cells of the oral cavity to the periodontopathogens, thus, is implicated as cell survival, proliferation and aggressiveness.

Treponema denticola

T. denticola, an anaerobe considered as one of the periodontopathogens, contains chymotrypsinlike proteinase (CTLP) as major virulence factor. Recent studies could detect CTLP within tumors of oro-digestive region. CTLP converts pro-MMP-8 and pro-MMP-9 to their active forms, which are associated with metastasis of carcinomatous cells in oesophagus, gastrointestinal tract, pancreas, tongue.¹⁶

Candida albicans

Oral candidiasis is a pre-cancerous lesion by itself. Most of the interests in carcinoma and Candidal infection are restricted to orooesophageal region.¹⁷ There are a number of reports available showing development of oral carcinoma in chronic mucocutaneous candidal lesion in immunocompromised patients.¹⁸ Candida albicans produces Nitrosamine compounds. Domingues-Ferreira et al. suggested that these nitrosamine compounds could be a risk factor for oro-oesophageal cancer.¹⁹ Candida albicans is also the most common fungal species present in hyperplastic candidiasis and oral leukoplakia lesions.²⁰ The microbial load of Candida spp. is also found to be significantly higher in patients with OSCC than that of their healthy controls.²¹ These findings suggest a strong association between candidal infection and oral carcinoma.

Virus

A dysbiotic mixed microbial complex is the etiology for chronic periodontitis.²² The role for viruses in the pathogenesis of periodontitis is suggested recently.23 It is now a well-established fact that periodontal pocket act as a reservoir for a number of viruses which are associated with oral neoplastic lesions.²³ Evidence is able to demonstrate viruses to act synergistically with the bacteria to cause periodontitis, or vice-versa.²³ The examples of such viruses which can be found in periodontitis as well as oral carcinomatous lesions include Herpes Simplex virus, Human Cytomegalovirus, Human Papilloma virus, Epstein-Barr virus etc.^24,25

Human Papilloma virus (HPV)

HPV, as the name suggests, is a common pathogen associated with neoplastic papillomatous lesions of oral cavity.²⁶ HPV causes proliferation and migration of the gingival epithelial cells. Interestingly, the hallmark of the periodontal diseases also is the migration and proliferation of junctional epithelium. The common pathogenesis of these two diseases might provide a strong link between them.²⁷

Epstein–Bar virus (EBV)

EBV is commonly associated with Hodgkin’s disease, stomach carcinomas, Burkitt’s lymphoma and nasopharyngeal carcinoma, all of which are known malignancies.²⁸ However, studies were able to demonstrate that the presence of EBV correlates to an increased number of periodontopathogens like Tannerella forsythia, Campylobacter spp, Porphyromonas gingivalis etc.²⁹ Also, a positive correlation between different grades of OSCC and EBV indicates the role of EBV in neoplastic transformation seen in oral cancers.³⁰

Herpes Simplex virus (HSV)

Herpesvirus can cause periodontitis either as a result of direct viral infection or synergistically with the bacteria in an impaired periodontal host defence system.³¹ HSV has ability to act as a mutagen. In vitro studies have shown that a regionof the viral genome, once isolated, raises the mutation frequency in cultured cells, resulting in malignancy.³²

Human cytomegalovirus (HCMV)

An active cytomegalovirus infection has also been associated with all the forms of periodontitis i.e. chronic, aggressive and refractory.³³ The role of HCMV in the pathogenesis of cancer can be best explained by the concept of oncomodulation, which is defined as infecting a tumor cell and increasing its potential to transform to a malignancy.HCMV is proposed to be a therapeutic target for cancer patients because of this property.³⁴

MECHANISMS BY WHICH MICROORGANISMS PROMOTE CANCER

Can a microorganism initiate carcinogenesis just because it is present in the neoplastic lesion? It is always a topic of interest whether the mere presence of the microflora can initiate a malignancy or not.The presence of these species does not, by itself, automatically mean they lead to carcinomas. However, evidence have proved that microorganisms can promote or initiate carcinogenesis in direct or indirect pathways.¹¹ The most important two mechanisms for microorganisms to promote cancer are summarized below.

Production of Nitrosamine

Candida species produces Nitrosamine compounds. These compounds directly, or in conjunction with other carcinogens, trigger specific proto-oncogenes which initiates the development of neoplasia. N-nitroso-benzyl methylamine (NBMA) is an example of such Nitrosamine compound which was capable of inducing carcinoma of the oro-esophageal region in experimental animal models.³⁵ Moreover, studies successfully showed that more advanced precancerous lesions were associated with more production of NBMA, when the nitrosation potential of Candida was assessed.³⁶

Activation of procarcinogens

Activation of procarcinogenic chemicals is the most significant hypothesis for the association of microorganism and the development of oral cancer. Pro-carcinogenic chemicals usually need to be metabolized before they can act together with cellular components to initiate carcinogenesis. This process of metabolism can be performed either by the host cells or local bacterial species.³⁷ For example, Heterocyclic aromatic amines (HAs) found in common foodstuffs like fried foods and cooked meat are procarcinogenic chemicals. Studies have successfully proved these HAs to be an initiator of carcinogenesis.³⁸ However, this effect depends on the microflora present in the individual. The comparative action of Bacteroides fragilis and lactobacilli is an example for this. The former increases mutagenicity in the presence of HAs, whereas the latter decreases.³⁹ Likewise, even though alcohol is considered as a risk factor for carcinoma of gastrointestinal tract, pure ethanol lacks carcinogenic properties.⁴⁰ Therefore, it is legitimate to say that the type of microorganism present plays a very important role in determining the action of pro-carcinogens. Neisseria species, a common periodontopathogen, is a classic example of such bacteria which have been reported to produce carcinogenic effects in the presence of procarcinogens.⁴¹ Therefore, it can be concluded that microflora has a very significant role in activation of various procarcinogens, which creates a link between microorganisms and the pathogenesis of carcinoma.

ROLE OF ORAL HYGIENE

Tobacco, areca nut and alcohol are some of the established etiological factors for oral cancer. Besides, other factors like poor oral hygiene also play a role in oral carcinogenesis.⁴² Poor oral hygiene increases the carcinogenic potential of the known carcinogens. Such factors contributing to poor oral hygiene are described below and shown in Figure 1.

Oral hygiene habits

A study was done to assess the role of oral hygiene in the causation of OSCC and it was found that the individuals who did not brush their tooth regularly had increased risk of oral cancer. It was also observed that use of fingers instead of tooth brush to clean the teeth made the individuals more susceptible for oral malignancy.⁴³ Another study assessing periodontal status in subjects with OSCC also concluded that the majority of oral cancer cases recruited in the study having brushed their teeth less than once daily.⁴⁴ These results indicate a strong association between the maintenance of oral hygiene and development of oral carcinoma.

Frequency of dental visits

A higher frequency of dentist’s consultation on a regular interval certainly help to allow early detection of precancerous and carcinomatous lesions.^45,46 A regular dental check-up also helps maintaining good oral hygiene, which in turn helps prevention and progression of the lesions. A meta- analysis of 13 case-control studies showed the association of poor oral hygiene and cancer of head and neck region. It was concluded that dental visits with regular interval were associated with significant reduction in head and neck cancer for patients with periodontal diseases.⁴⁷

Level of education

A basic knowledge about a disease certainly helps in the prevention as well as progression of it. A survey based on the Brazilian population found a direct influence of level of education on the knowledge of oral diseases.⁴⁸ Another study also found that OSCC was inversely related with the level of education among the study subjects. Even the level of education and awareness of family members has an influence on developing oral cancer, as found in a study.⁴³

Arecanut, tobacco, and alcohol

Though the habits like tobacco, alcohol and arecanut chewing, by themselves, are independent etiological factors for oral cancer,they also promote poor oral hygiene which, in turn, act as a contributory factor for oral cancer.^48,49 Therefore, such habits along with poor oral hygiene can synergistically initiate oral cancer or aggravate the existing condition. Studies have successfully proved chronic alcoholism and tobacco use as causative factors for poor oral hygiene.^50,51

ROLE OF GENETIC SUSCEPTIBILITY

Various studies including a number of large genome-wide association studies have proved the genetic associations for periodontitis.⁵² Several genes have been associated with the aggressive form of periodontitis.⁵³ Genes that have been consistently associated with various types of periodontitis include GLT6D1 gene, the CDKN2B gene, and the COX-2 gene. Variants in the COX2 gene have also been associated with digestive cancers⁵⁴, and polymorphisms in the CDKN2B gene have been associated with nasopharyngeal cancer and glioma.^55,56 Therefore, these findings make it plausible that there may be a shared genetic component between periodontitis and oral cancer.

STUDIES ON ASSOCIATION BETWEEN PERIODONTITIS AND ORAL CANCER5 (Table 1)

CONCLUSION

Our review was able to show a strong degree of positive correlation between periodontal diseases and oral cancer. It would be beneficial to the dentist as well as patients to be aware of the real potential of periodontal disease to transform into malignancy. Thus, it would be of great benefit to the patients with periodontal disease to consider several steps to reduce the risk of developing oral cancer. Steps include maintaining good oral hygiene and a more frequent periodontal checkup to keep the periodontium free of diseases. Moreover, this potential etiological role of periodontal diseases in cancer development may lead to new opportunities for cancer prevention and reduction of its mortality.