The Relationship Between Periodontal Disease and Neoplasms of the Oral Cavity: A Review Article

authors:

avatar Maryam Nourelahi 1 , * , avatar Behnaz Roshannia 2 , avatar Somayeh Kameli 3 , avatar Mohsen Hormozi 4

Department of Periodontics, Dental Faculty, Semnan University of Medical Sciences, Semnan, IR Iran
Student Research Committee, Semnan University of Medical Sciences, Semnan, IR Iran
Department of Pedodontics, Dental Faculty, Semnan University of Medical Sciences, Semnan, IR Iran
Dental Student Research Center, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, IR Iran
Middle East Journal of Rehabilitation and Health: Vol.3, issue 4; e39234
published online: August 20, 2016
article type: Review Article
received: May 27, 2016
revised: July 24, 2016
accepted: August 2, 2016
DOI: https://doi.org/10.17795/mejrh-39234

how to cite: Nourelahi M, Roshannia B, Kameli S, Hormozi M. The Relationship Between Periodontal Disease and Neoplasms of the Oral Cavity: A Review Article. Middle East J Rehabil Health Stud. 2016;3(4):e39234. https://doi.org/10.17795/mejrh-39234.

Abstract

Context:

Oral cavity is one of the most common sites for neoplasms with a multifactorial etiology. Tobacco and alcohol are the main risk factors. Periodontal disease is an inflammatory disease affecting periodontal tissues such as gingiva, periodontal ligament and alveolar bone. Periodontal disease is linked to many systemic diseases. Recently a link between periodontal disease and cancer is suggested. The current review article aimed to evaluate the association between periodontal disease and risk of cancer in the oral cavity and some related factors.

Evidence Acquisition:

Evidence suggests that oral cavity cancer is significantly more prevalent in patients with periodontal disease, poor oral hygiene or more missing teeth. Clinically, gingival squamous cell carcinoma (GSCC) usually appears as an exophytic mass with a granular, papillary or verrucous surface or presents as an ulcerative lesion. Some reported cases of GSCC mimicking periodontal disease include gingival enlargement with no bone invasion, dentoalveolar abscess, erosive erythematosus lesion with keratotic papules, root exposure and tooth mobility, verrucous leukoplakia, verruciform xanthoma and development of hyperplastic granulation tissue after tooth extraction. Greater burden of oral flora that produce carcinogenic metabolites, human papilloma virus (HPV) and other viruses that are residents of periodontal pocket, increased amount of inflammatory mediators and markers and some periodontal pathogens affecting cell cycle leading to mutation and dysplasia are considered as the rational for the relationship between malignant lesions of oral cavity and periodontal disease.

Results:

Cancer of the oral cavity and periodontal disease are related from different aspects. Periodontal disease and tooth loss are considered as independent risk factors for cancer. Gingival squamous cell carcinoma can also mimic periodontal disease leading to misdiagnosis and delayed commencement of appropriate treatment.

Conclusions:

Based on evidence, dentists and dental health care professionals should consider periodontal disease as a risk factor for the development of neoplasms in the oral cavity. It also seems a good idea to provide periodontal therapy for patients with cancer to achieve ideal therapeutic results.

1. Context

Head and neck squamous cell carcinoma (HNSCC) includes cancer of the oral cavity, pharynx and larynx (1). Almost 94% of all cancerous lesions of the oral cavity are within the category of oral squamous cell carcinoma (OSCC) (2). OSCC is one of the most prevalent cancers and assumed to be one of the main reasons of mortality and morbidity worldwide (3, 4). The risk of occurrence is increased with age and is mostly observed in males in their 40s (2, 5). OSCC is multifactorial (6) and the most important risk factors are tobacco and alcohol (2).

OSCC has various clinical manifestations and the most prevalent sites in the oral cavity include lateral and dorsal surfaces of the tongue (2). Human papilloma virus (HPV), Epstein-Barr virus (EBV) and other viruses as well as bacterial and inflammatory factors are considered to have a role in the etiology of OSCC (7, 8).

OSCC is a life threatening issue but the risk can be considerably decreased by avoiding some harmful habits (9, 10). Early detection is helpful to decline mortality and morbidity rate (11). It is observed that five-year survival rate is 78% in cases of early diagnosis compared to advanced cases with only 19% survival rate (12). Although oral cavity is an accessible environment for dental examination, early detection rate of SCC has remained unchanged (2, 13). It is mainly because SCC is usually painless in early stage (2).

Periodontal disease is a chronic inflammatory condition which is associated with bacterial infection causing deterioration of periodontal tissues. Periodontitis is prevalent in adult population and is absolutely preventable (1, 14).

It has different prevalence rate in different nations and racial groups. The age range of occurrence is wide and includes both adolescents and adults (15). Periodontal disease is associated with many systemic factors such as cardiovascular diseases, low birth weight and some side effects of pregnancy (16). Presence of a relationship between periodontal disease and cancer is suggested in some studies. Scientific rational is the presence of inflammatory mediators associated with both cancer and periodontal disease (16-18). These neoplasms sometimes have symptoms compatible with those of periodontal disease such as inflammation, gingival bleeding, tooth mobility, deep probing depth and bone loss (16). There are so many reports of gingival squamous cell carcinoma mimicking periodontal or periodontal-endodontic lesions (16).

Other cases of malignant lesions mimicking periodontal disease include metastatic cancer of pancreas and osteogenic carcinoma (19). There is increasing evidence that the risk of cancer is significantly greater in patients with periodontitis or those with more missing teeth (17, 18, 20). The current review article aimed to discuss the association between periodontal disease and neoplasms of the oral cavity especially SCC of the gingiva.

2. Evidence Acquisition

An electronic search was made in Pubmed, Medline and Cochrane oral health group specialized trial register and also a manual search was conducted from 1990 to 2015 on the association between neoplasms of the oral cavity and periodontal disease. The keywords included: Periodontal disease, periodontitis, tooth loss, oral cancer studies, oral neoplasms, squamous cell carcinoma and all the possible combinations (Table 1).

Table 1.

Inclusion and Exclusion Criteria

Inclusion CriteriaExclusion Criteria
Case control studies on the relationship between bone/attachment loss and head and neck cancer considered independent from smoking and alcoholStudies involving cancer originating from somewhere other than head and neck
Case control studies on the relationship between oral hygiene/number of remaining teeth and head and neck cancer considered independent from smoking and alcoholStudies with unspecified inclusion and exclusion criteria for the samples
Case reports on manifestations of SCC in periodontal tissuesCase control studies with less than 50 samples in each group
Experimental studies and review articles on the relationship between periodontitis and cancerCase control studies with less than five years of follow-up

Some of the studies are mentioned below:

Tezal et al. (21) evaluated the effect of chronic periodontitis on occurrence of HNSCC in 2009. One millimeter increase in radiographic alveolar bone loss was associated with four times increase in HNSCC. The strongest association was observed in neoplasms of the oral cavity (OR 5.23 for the tongue). Tezal et al. conducted another cohort study to investigate the association between oral tumors and precancerous lesions with periodontal attachment loss and concluded that more than 1.5 millimeters of attachment loss is significantly associated with increased risk of developing oral tumors (OR 4.57) and precancerous lesions (OR 1.55) (22). Guha et al. concluded that poor oral hygiene and tooth loss can be considered as independent risk factors for head and neck cancer (OR 2.89 in Europe and 1.89 in Latin America) (23). There was a cohort study by Michaud, commenced by filling out a questionnaire about history of periodontal disease and the number of teeth lost; unexpectedly, no association was observed between cancer of the oral cavity and periodontal disease (20). Bundgaard et al. (24) also observed that patients with less than 15 remaining teeth are significantly at greater risk for developing SCC (OR 2). Another case control study was designated by Caio Perrella de Rezende et al. using community periodontal index of treatment needs (CPITN) and it was observed that 76% of cancer cases had periodontal pocket depth of six millimeters or more compared to 10% in the control group (25). Garrote et al. (OR 2.7), Hiraki et al. (OR 1.68 for no remaining tooth) and Tongzhang Zheng et al. also reported a significant association between more missing teeth and the risk for oral cancer (26-28). In a case control study by James et al. (29) in the USA, eleven or more missing teeth was significantly associated with increased risk of developing oral cancer (OR 2.7). Based on the study by Rosenquist et al. (30), more than twenty missing teeth was independent risk factor for oropharyngeal cancer. Talamini also reported the similar results (OR 3.9 for those with constant gingival bleeding and 4.5 for patients with poor oral hygiene) (31).

2.1. Clinical Manifestations of SCC in Periodontal Tissues

Gingival squamous cell carcinoma (GSCC) is mainly observed as an exophytic mass with a verrucous or papillary surface with red or mixed red and white color (32). GSCC can sometimes mimic severe periodontal disease with symptoms such as swelling, gingival bleeding, tooth mobility, deep pocket depth and bone loss (33). Some manifestations of GSCC which are sometimes similar to periodontal inflammatory lesions are introduced:

1- A single red epulis-like lesion in dental papilla of the tooth #22. It bled with minor provocation and the probing depth reached seven millimeters. There was no bone invasion radiographically. Dental papilla is a rare site for GSCC (34).

2- There were some case reports of GSCC mimicking dento-alveolar abscess. It was reported as an erythematous papule located within the attached gingiva of the teeth #9 and #10 near mucogingival junction. It had a soft spongy texture. Oozing was observed from a little hole on the lesion. No periodontal pocket, no mobility, bone loss, root resorption or the periodontal ligament (PDL) widening was observed around the teeth (35).

3- There was another case report of a lesion with erosive erythematous appearance and keratotic papules located in buccal and lingual gingiva of maxillary molar teeth unilaterally with no sign of bleeding. Roots were exposed to the oral cavity and grade III mobility could be observed. Abundant bone loss could be observed radiographically in posterior maxilla and teeth were floating within the radiolucent area. Lamina dura and PDL could not be detected (36).

4- There was another paper reporting on SCC case as a verrucous leukoplakia in gingiva. There was an overgrowth in palatal gingiva between the teeth #12 and #13 with extension into rugae area. Poor oral hygiene along with general inflammation, gingival recession and generalized periodontal pockets were observed. There was bleeding tendency with light provocation. Lymph nodes were palpable, mobile, tender and firm in consistency (37).

5- SCC was once reported as verruciform xanthoma. There was a verrucouse plaque in anterior maxillary gingiva. No symptom was reported and it grew slowly within four years. There was simultaneous gingival recession (38).

6- SCC in a fourteen-year-old adolescent with gingival bleeding in premolar area was reported. At first it was thought to be pseudoepitheliomatous hyperplasia. It was an exophytic inflammatory lesion in buccal and lingual surface of mandibular first molar and second premolar with ulcerated and firm surface and lingual alveolar bone erosion (39).

7- Sometimes SCC is manifested as a hyperplastic granulation tissue which appears after tooth extraction. The history reported by the patient was occurrence of a swelling two weeks after tooth extraction which was growing. Necrotic bone was found within the extracted socket. It was painful and bled easily (32).

8- An eighteen-year-old female referred to the dentist with the chief complaint of tooth mobility. She was a heavy smoker. In clinical examination there was a multinodular lesion with ulcerative surface in facial and lingual aspect of the teeth #22 - #27. Severe root resorption could be observed about the involved teeth (40).

9- A white eleven-year-old girl referred to the dentist with the chief complaint of growing a white lesion in buccal gingiva of the right mandible. There was no medical or familial history. Primary diagnosis was fibroepithelial hyperplasia. It was recurred after three years and biopsy confirmed SCC (40).

10- There was a report of a growing papillary and nodular mass in facial maxillary gingiva. No history of alcohol or tobacco was reported. Some degree of desquamation could be observed. Well differentiated SCC was confirmed after biopsy (40).

11- In another case report which was finally diagnosed GSCC, patient complained of a growing painful nodule on his gums. It was there for three months as proliferative lesion with purulent exudate. It did not respond to periodontal treatment. Recession and suppuration around the tooth #11 could be observed. Other periodontal tissues except for gingiva were intact (41).

12- There was another report of de novo intraosseous carcinoma. Intraoral examination revealed a non-ulcerative hyperplastic lesion adjacent to mandibular alveolar ridge. It was swollen and tender. There was no evidence of invasion to lymph nodes or nerves (42).

2.2. Rational for the Relationship Between Malignant Lesions of Oral Cavity and Periodontal Disease

Periodontitis is an inflammatory disease related to Gram-negative bacteria. It can cause constant release of bacterial and inflammatory markers in saliva and blood stream leading to tissue destruction (21). Some of the rationales for the association between malignant lesions of oral cavity and periodontal disease are mentioned:

1- Bacterial species in the oral cavity of patients with periodontitis turn nitrate into nitrite or produce acetaldehyde (23). Evidence suggests that carcinogenic metabolites are produced in the presence of periodontal infection. For example, increased nitrosamine in a mouth with poor oral hygiene could act as a carcinogen. Acetaldehyde is a metabolite of ethanol which is assumed to be the risk factor for cancer of the upper esophagus (18, 43). Based on scientific evidence, poor oral hygiene and periodontal disease can cause increased acetaldehyde production twice as much as that of a mouth with good oral hygiene (44). Some viruses such as EBV and cytomegalovirus (CMV) are residents of periodontal pocket considered to be the risk factors for cancer (23).

2- HPV is another virus which is found in periodontal pockets (45). Inflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) stimulate proliferation of HPV and expression of its oncogenes E6 and E7 in gingival epithelial cells. E6 and E7 can bind to tumor suppressors p53 and pRb and deactivate them. This mechanism is responsible for carcinogenic potential of this virus in the oral cavity (1).

3- Increased level of mediators and inflammatory markers: inflammatory cells in the presence of increased level of chemokines, cytokines and prostaglandins are considered to be associated with development of tumors (46). Microorganisms and their products stimulate neutrophils, macrophages, lymphocytes and fibroblasts to produce reactive oxygen species (hydrogen peroxide and free oxygen radicals), reactive nitrogen species (nitric oxide), lipids and matrix metalloproteinase which finally leads to DNA damage in epithelial cells (1, 47, 48). Cytokines, growth factors and some other cellular mediators create an appropriate environment for cell proliferation and migration. They also downregulate cell apoptosis leading to probable mutation (1).

4- Compromised epithelial barrier in periodontal disease causes carcinogenic materials produced by alcohol and tobacco consumption to penetrate the underlying tissues (22).

5- Deficient immune system plays an important role in both periodontal disease and cancer, such as deficiency in neutrophil function. Neutrophils are basic elements of defense system in periodontal attachment apparatus (28, 49).

6- There is increasing evidence that Porphyromonas gingivalis are periodontal pathogens that exist within the specimens of squamous cell carcinoma (40, 48). Porphyromonas gingivalis are important etiologic factors in periodontal disease found in a great number in the oral cavity of patients with poor oral hygiene or severe periodontitis (40). These bacteria affect cell cycle related molecules and can downregulate cell apoptosis which is a protective mechanism in cancer affected cells. It is done through modification of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway which controls intramitochondrial cell death avoiding programmed cell death. Porphyromonas gingivalis also increases longevity and proliferation of host cells (40).

2.3. Differentiating GSCC from Periodontal Disease

Unlike periodontal disease, GSCC lesions are stable and unresponsive to routine therapies. Periodontal disease is usually more generalized in oral cavity than malignant lesions (40).

In periodontitis, horizontal or vertical bone loss, widening of periodontal ligament space and destruction of inter radicular bone are apparent. In GSCC, bone supporting a tooth is invaded; also leading to widening of periodontal ligament space, but with a more invasive appearance. The tooth is sometimes floating within the radiolucent area. Lamina dura is usually absent, so is the periodontal ligament space. Borders of the lesion are often ill defined and non-corticated (36, 45).

Many of the times, severe periodontal disease and malignancy cannot be easily differentiated radiographically because both of them cause severe bone resorption and tooth mobility (45).

3. Results

Cancer of the oral cavity and periodontal disease are related from different aspects. Rate of occurrence of cancer is significantly related to tooth loss and other periodontal parameters such as attachment loss and alveolar bone loss; therefore, periodontal disease and tooth loss are considered as independent risk factors for cancer. Gingival SCC can also mimic periodontal disease leading to misdiagnosis and delayed commencement of appropriate treatment.

4. Conclusions

Based on evidence, dentists and dental health care professionals should consider periodontal disease as a risk factor for development of neoplasms in the oral cavity. It also seems to be a good idea to provide periodontal therapy for patients with cancer to achieve ideal therapeutic results.

Acknowledgements

References

  • 1.

    Gondivkar SM, Gondivkar RS, Gadbail AR, Chole R, Mankar M, Yuwanati M. Chronic periodontitis and the risk of head and neck squamous cell carcinoma: facts and figures. Exp Oncol. 2013;35(3):163-7. [PubMed ID: 24084452].

  • 2.

    Jamshidi MZS, Moghimbeigi A, Delkhah M, Baghaei F. A Comparison between the Knowledge of Dental Students and General Dentists about Oral Squamous Cell Carcinoma (Hamadan-Iran). J Mash Dent Sch. 2011;36(1):23-36.

  • 3.

    Motallebnejad MHM. General dentists knowledge about oral cancers in Babol, in 2005. J Dentistry Mashhad Uni Med Sci. 2006;30:309-18.

  • 4.

    Scully C, Felix DH. Oral medicine--update for the dental practitioner orofacial pain. Br Dent J. 2006;200(2):75-83. [PubMed ID: 16444222]. https://doi.org/10.1038/sj.bdj.4813225.

  • 5.

    Ghapanchi MMJ, Parhiz H, Niknam M. Analytic Evaluation of the Prevalence of Head and Neck Cancers among Patients with Different Kinds of Cancers Visited in Radiotherapy Department of Nemazee Hospital, 2003-2004. J Dentistry shiraz Uni Med Sci. 2004;5(1,2):97-105.

  • 6.

    Shiboski CH, Shiboski SC, Silverman S. Trends in oral cancer rates in the United States, 1973-1996. Community Dent Oral Epidemiol. 2000;28(4):249-56. [PubMed ID: 10901403].

  • 7.

    Gillison ML, Lowy DR. A causal role for human papillomavirus in head and neck cancer. Lancet. 2004;363(9420):1488-9. [PubMed ID: 15135592]. https://doi.org/10.1016/S0140-6736(04)16194-1.

  • 8.

    Kutok JL, Wang F. Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol. 2006;1:375-404. [PubMed ID: 18039120]. https://doi.org/10.1146/annurev.pathol.1.110304.100209.

  • 9.

    Pakfetrat A, Falaki F, Esmaily HO, Shabestari S. Oral cancer knowledge among patients referred to Mashhad Dental School, Iran. Arch Iran Med. 2010;13(6):543-8. [PubMed ID: 21039012].

  • 10.

    Ariyawardana A, Vithanaarachchi N. Awareness of oral cancer and precancer among patients attending a hospital in Sri Lanka. Asian Pac J Cancer Prev. 2005;6(1):58-61. [PubMed ID: 15780034].

  • 11.

    Atena Shiva SJM. Epidemiologic Study of Oral and Paraoral Malignancies in Sari, Iran. J Mash Dent Sch. 2014;38(4):337-46.

  • 12.

    Yellowitz J, Horowitz AM, Goodman HS, Canto MT, Farooq NS. Knowledge, opinions and practices of general dentists regarding oral cancer: a pilot survey. J Am Dent Assoc. 1998;129(5):579-83. [PubMed ID: 9601170].

  • 13.

    Borhan-Mojabi K, Moradi A, Yazdabadi A. Evaluating the degree of knowledge on oral cancer among general practitioners and dentists in Qazvin. J Eval Clin Pract. 2012;18(2):498-501. [PubMed ID: 21210899]. https://doi.org/10.1111/j.1365-2753.2010.01613.x.

  • 14.

    Loesche WJ, Grossman NS. Periodontal disease as a specific, albeit chronic, infection: diagnosis and treatment. Clin Microbiol Rev. 2001;14(4):727-52. [PubMed ID: 11585783]. https://doi.org/10.1128/CMR.14.4.727-752.2001.

  • 15.

    Sadighi Shamami M, Sadighi Shamami M, Amini S. Periodontal Disease and Tooth Loss as Risks for Cancer: A Systematic Review of the Literature. Iran J Cancer Prev. 2011;4(4):189-98. [PubMed ID: 26322197].

  • 16.

    Fitzpatrick SG, Katz J. The association between periodontal disease and cancer: a review of the literature. J Dent. 2010;38(2):83-95. [PubMed ID: 19895866]. https://doi.org/10.1016/j.jdent.2009.10.007.

  • 17.

    Tezal M, Sullivan MA, Reid ME, Marshall JR, Hyland A, Loree T, et al. Chronic periodontitis and the risk of tongue cancer. Arch Otolaryngol Head Neck Surg. 2007;133(5):450-4. [PubMed ID: 17515503]. https://doi.org/10.1001/archotol.133.5.450.

  • 18.

    Abnet CC, Kamangar F, Dawsey SM, Stolzenberg-Solomon RZ, Albanes D, Pietinen P, et al. Tooth loss is associated with increased risk of gastric non-cardia adenocarcinoma in a cohort of Finnish smokers. Scand J Gastroenterol. 2005;40(6):681-7. [PubMed ID: 16036528]. https://doi.org/10.1080/00365520510015430.

  • 19.

    Marshall P, Solomon JB, Michael S, Yale R. Parosteal Osteogenic Sarcoma of the Mandible Existence Masked by Diffuse Periodontal Inflammation. Otolaryngol Head Neck Surg. 1975;101(12):754-60.

  • 20.

    Dominique S, Michaud YL, Mara M, Edward G, Kaumudi J. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 2008;9(6):550-8.

  • 21.

    Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, et al. Chronic periodontitis and the incidence of head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2406-12. [PubMed ID: 19745222]. https://doi.org/10.1158/1055-9965.EPI-09-0334.

  • 22.

    Tezal M, Grossi SG, Genco RJ. Is periodontitis associated with oral neoplasms? J Periodontol. 2005;76(3):406-10. [PubMed ID: 15857075]. https://doi.org/10.1902/jop.2005.76.3.406.

  • 23.

    Guha N, Boffetta P, Wunsch Filho V, Eluf Neto 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(10):1159-73. [PubMed ID: 17761691]. https://doi.org/10.1093/aje/kwm193.

  • 24.

    Bundgaard T, Wildt J, Frydenberg M, Elbrond O, Nielsen JE. Case-control study of squamous cell cancer of the oral cavity in Denmark. Cancer Causes Control. 1995;6(1):57-67. [PubMed ID: 7718736].

  • 25.

    Caio Perrella de Rezende MBR, Carlos HD, Rogerio AD, Abrao R. Oral Health Changes in Patients with Oral and Oropharyngeal Cancer. Rev Bras Otorrinol. 2008;74(4):596-600.

  • 26.

    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. 2001;85(1):46-54. [PubMed ID: 11437401]. https://doi.org/10.1054/bjoc.2000.1825.

  • 27.

    Hiraki A, Matsuo K, Suzuki T, Kawase T, Tajima K. Teeth loss and risk of cancer at 14 common sites in Japanese. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1222-7. [PubMed ID: 18483345]. https://doi.org/10.1158/1055-9965.EPI-07-2761.

  • 28.

    Tongzhang Zheng PB, Huanfang H, Jun D, Peijue J, Daquan M, Liangpeng S, et al. Dentition, oral hygiene, and risk of oral cancer: a case-control study in Beijing, People's Republic of China. Cancer Causes Control. 1990;1(3):235-41.

  • 29.

    James R, Marshall A, Saxon G, Brenda P, Haugheyb DS, Robert O, et al. Smoking, alcohol, dentition and diet in the epidemiology of oral cancer. Eur J Cancer Part B Oral Oncol. 1992;28(1):9-15.

  • 30.

    Rosenquist K, Wennerberg J, Schildt EB, Bladstrom A, Goran Hansson B, Andersson G. Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden. Acta Otolaryngol. 2005;125(12):1327-36. [PubMed ID: 16303683]. https://doi.org/10.1080/00016480510012273.

  • 31.

    Talamini R, Vaccarella S, Barbone F, Tavani A, La Vecchia C, Herrero R, et al. Oral hygiene, dentition, sexual habits and risk of oral cancer. Br J Cancer. 2000;83(9):1238-42. [PubMed ID: 11027440]. https://doi.org/10.1054/bjoc.2000.1398.

  • 32.

    Nagihan Koc BLC, Gokcen A. Squamous cell carcinoma presenting as a hyperplastic granulation tissue. AshEse J Med Med Res. 2015;1(1):1-4.

  • 33.

    Gomez D, Faucher A, Picot V, Siberchicot F, Renaud-Salis JL, Bussieres E, et al. Outcome of squamous cell carcinoma of the gingiva: a follow-up study of 83 cases. J Craniomaxillofac Surg. 2000;28(6):331-5. [PubMed ID: 11465139]. https://doi.org/10.1054/jcms.2000.0177.

  • 34.

    Meleti M, Corcione L, Sesenna E, Vescovi P. Unusual presentation of primary squamous cell carcinoma involving the interdental papilla in a young woman. Br J Oral Maxillofac Surg. 2007;45(5):420-2. [PubMed ID: 16483701]. https://doi.org/10.1016/j.bjoms.2005.12.006.

  • 35.

    Lee JJ, Cheng SJ, Lin SK, Chiang CP, Yu CH, Kok SH. Gingival squamous cell carcinoma mimicking a dentoalveolar abscess: report of a case. J Endod. 2007;33(2):177-80. [PubMed ID: 17258640]. https://doi.org/10.1016/j.joen.2006.08.005.

  • 36.

    Rafael Scaf Molon EDA, Mirian AO, Carlos BN, Elcio M, Gulnara S. Comparison between Periodontal Disease and Gingival Carcinoma with Emphasis on Radiographic Imaging. Int J Dentistry. 2011;10(4):278-81.

  • 37.

    Fettig A, Pogrel MA, Silverman S, Bramanti TE, Da Costa M, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(6):723-30. [PubMed ID: 11113818]. https://doi.org/10.1067/moe.2000.108950.

  • 38.

    Marcia Hatakeyama JMSLA, Marinaldo G, Brandao AAH, Ana Sueli R. Cavalcante Verruciform xanthoma located in anterior gingival. Oral Med Pathol. 2010;2(2):82-4.

  • 39.

    Bill TJ, Reddy VR, Ries KL, Gampper TJ, Hoard MA. Adolescent gingival squamous cell carcinoma: Report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91(6):682-5. [PubMed ID: 11402282]. https://doi.org/10.1067/moe.2001.115029.

  • 40.

    Woo VL, Kelsch RD, Su L, Kim T, Zegarelli DJ. Gingival squamous cell carcinoma in adolescence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107(1):92-9. [PubMed ID: 19101491]. https://doi.org/10.1016/j.tripleo.2008.09.003.

  • 41.

    Luiz AGC, Jose APS, Adriana AHB, Janete DA. Gingival Squamous Cell Carcinoma: a Case Report. J Oral Maxillofacial Res. 2010;1(3):6.

  • 42.

    Gallego L, Junquera L, Villarreal P, Fresno MF. Primary de novo intraosseous carcinoma: report of a new case. Med Oral Patol Oral Cir Bucal. 2010;15(1):48-51. [PubMed ID: 19680174].

  • 43.

    Salaspuro MP. Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci. 2003;40(2):183-208. [PubMed ID: 12755455]. https://doi.org/10.1080/713609333.

  • 44.

    N Homanna NJT, Rintamakib H, Salaspuroa M, Lindqvistb C, Meurman JH. Poor dental status increases acetaldehyde production from ethanol in saliva: a possible link to increased oral cancer risk among heavy drinkers. Oral Oncol. 2001;37(2):153-8.

  • 45.

    Yoon TY, Bhattacharyya I, Katz J, Towle HJ, Islam MN. Squamous cell carcinoma of the gingiva presenting as localized periodontal disease. Quintessence Int. 2007;38(2):97-102. [PubMed ID: 17263148].

  • 46.

    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-44. [PubMed ID: 18650914]. https://doi.org/10.1038/nature07205.

  • 47.

    Catherine ME, Champagne WB, Michael S, Reddy JS, Preisser J, Beck D, et al. Potential for gingival crevice fluid measures as predictors of risk for periodontal diseases. Periodontol. 2000;31(1):167-80.

  • 48.

    Katz J, Onate MD, Pauley KM, Bhattacharyya I, Cha S. Presence of Porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci. 2011;3(4):209-15. [PubMed ID: 22010579]. https://doi.org/10.4248/IJOS11075.

  • 49.

    Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science. 2002;298(5595):1025-9. [PubMed ID: 12411706]. https://doi.org/10.1126/science.1075565.