Periodontitis and Oral Cancer

TO GET C.E. CREDITS FOR THIS ARTICLE
PLEASE LOGIN OR REGISTER

Periodontitis and Oral Cancer: Is There a Linkage?

Interest in associations between periodontal disease and systemic health continues to increase, and strong associations have been found for periodontal disease with diabetes mellitus and cardiovascular disease. Other diseases investigated have included cancers.1Chung SD, Tsai MC, Huang CC, Kao LT, Chen CH. A population-based study on the associations between chronic periodontitis and the risk of cancer. Int J Clin Oncol 2016;21:219-23.,2Michaud DS, Fu Z, Shi J, Chung M. Periodontal disease, tooth loss, and cancer risk. Epidemiol Rev 2017;39:49-58.,3Nwizu NN, Marshall JR, Moysich K, Genco RJ, Hovey KM, Mai X, LaMonte MJ, Freudenheim JL, Wactawski-Wende J. Periodontal disease and incident cancer risk among postmenopausal women: Results from the women's health initiative observational cohort. Cancer Epidemiol Biomarkers Prev 2017;26(8:1255-65. ,4Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, Bilgin E, Hüseyin B, Berker E. Increased cancer risk in patients with periodontitis. Curr Med Res Opin 2017;33(12):2195-200. In a large, five-year cohort study of 80,000 individuals with and without chronic periodontitis (CP), an increased risk for cancer was found for individuals with CP (hazard ratio 1.23; p<0.05). A recent review also examined the relationship between periodontal disease and tooth loss, and the risk for developing all cancers. A linkage between periodontal disease and oral cancer, lung cancer and pancreatic cancer was identified. A number of studies have now examined linkages between periodontal disease and oral/oropharyngeal cancer.

Periodontal disease and oral/oropharyngeal cancer

In a systematic review, an association was found for periodontal disease and oral cancer in 9 of 12 studies.5Javed F, Warnakulasuriyab 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. Findings included a two- to more than five-fold increased risk for oral cancer (OC) for individuals with periodontal disease. However, missing teeth was used to determine the presence of periodontal disease in all studies, and in some studies this was determined by administering a patient questionnaire rather than using findings from the clinical examination/radiographs.5Javed F, Warnakulasuriyab 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 detailed meta-analysis of 11 case-control studies examining the relationship between periodontal disease and oral cancer was recently published.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. Across individual studies, up to a more than five-fold risk of OC was found (odds ratio 1.6 to 5.23). Overall, the increased risk of oral cancer associated with periodontal disease was more than triple (odds ratio 3.21; p<0.05). Publication bias and study heterogeneity were cited as limitations of the meta-analysis.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240.
Findings in a recent systematic review included a two- to more than five-fold increased risk for oral cancer (OC) for individuals with periodontal disease.

Individual studies illustrate the potential importance of this association, as well as confounders that make interpretation of the findings a challenge. A case-control study of 35 patients with OC/oropharyngeal cancer (OPC) and 50 patients without OC/OPC (control group) included full mouth examinations. Patients with OC were found to have more plaque accumulation,similar levels of gingival inflammation, and significantly greater probing depths (PD) and clinical attachment loss (CAL; p<0.05). Severe chronic periodontitis, defined as ≥2 sites with CAL ≥6 mm and PD ≥7 mm at proximal sites of two teeth, was present in 88.6% of cases and in 32.5% of the control group (p<0.05).

Patients with OC were found to have significantly greater probing depths and clinical attachment loss than patients without OC/OPC.
In addition, significant differences between the two groups of patients were found for the median number of teeth present (13.2 vs 18.2) and the level of plaque (34.7 vs 23.1; Figure 1). These differences were
significant after controlling for important confounders (smoking and alcohol consumption).7Moraes RC, Dias FL, Figueredo CM, Fischer RG. Association between chronic periodontitis and oral/oropharyngeal cancer. Braz Dent J 2016;27:261-6.

Figure 1. Percentage patients with generalized /severe CP, and median #teeth

 

Another study examined 350 patients with OC and 471 patients without OC matched by age and sex (control group). Gingival recession (an indirect measure of attachment loss and periodontitis) was associated with an increased risk of OC (odds ratio 1.83; p<0.05). No statistically significant association was found for gingival inflammation.8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9. While confounders were considered, visual assessment of gingival recession and inflammation were used as surrogate markers for periodontitis/bone loss to avoid invasive examinations in frail patients. In addition, oral hygiene status and dental visits were not considered.
The authors also concluded that reverse causality was possible – i.e., that the inflammation and recession were secondary to the patients’ oral cancer.8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9. In a case-control study of 51 males with squamous cell carcinoma of the tongue and 54 controls without cancer, a more than five-fold risk for OC was found per millimeter of radiographically-determined bone loss (p<0.05), after adjusting for smoking status, age and number of teeth.9Tezal M, Sullivan MA, Reid ME, Marshall JR, Hyland A, Loree T, Lillis C, Hauck L, Wactawski-Wende J, Scannapieco FA. Chronic periodontitis and the risk of tongue cancer. Arch Otolaryngol—Head Neck Surg 2007;133:450-4. In an earlier study, >1.5 mm CAL increased risk for precancerous and cancerous oral lesions.10Tezal M, Grossi SG, Genco RJ. Is periodontitis associated with oral neoplasms? J Periodontol 2005;76:406-10.
In a case-control study of 51 males with squamous cell carcinoma of the tongue and 54 controls without cancer, a more than five-fold risk for OC was found per millimeter of radiographically-determined bone loss.
In contrast, other studies have found no association between periodontal disease and OC/OPC. In a large prospective cohort study with almost 66,000 postmenopausal women 54 to 86 years-of-age, and a mean follow-up of more than 8 years, periodontal disease increased risk for total cancer by 14%, and increased risk for specific cancers.3Nwizu NN, Marshall JR, Moysich K, Genco RJ, Hovey KM, Mai X, LaMonte MJ, Freudenheim JL, Wactawski-Wende J. Periodontal disease and incident cancer risk among postmenopausal women: Results from the women's health initiative observational cohort. Cancer Epidemiol Biomarkers Prev 2017;26(8:1255-65.
However, periodontal disease was not found to increase risk for OC/OPC. Determination of a history of periodontal disease was based on a patient questionnaire. In a recent review, 3 of 12 studies also found no association between periodontal disease and OC or other head and neck cancers.11Guha N, Boffetta P, Wunsch F, Ilho V, Eluf N, Eto J, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, Szeszenia-Dabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit R, Brennan P. 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. ,12Divaris K, Olshan A, Smith J, Bell ME, Weissler MC, Funkhouser WK, Bradshaw PT. Oral health and risk for head and neck squamous cell carcinoma: the carolina head and neck cancer study. CCC 2010;21:567-75. ,13Talamini R, Vaccarella S, Barbone F, Tavani A, La Vecchia C, Herrero R, Muñoz N, Franceschi S. Oral hygiene, dentition, sexual habits and risk of oral cancer. Br J Cancer 2000;83:1238-42.

Periodontal disease and human papilloma virus

Human papilloma virus (HPV) is a significant risk factor for OC/OPC, including for persons without traditional risk factors.14Mazul AL, Taylor JM, Divaris K, Weissler MC, Brennan P, Anantharaman D, Abedi-Ardekani B, Olshan AF, Zevallos JP. Oral health and human papillomavirus-associated head and neck squamous cell carcinoma. Cancer 2017;123:71-80. Examining both HPV-negative and HPV-positive individuals with oral/oropharyngeal squamous cell carcinoma (n=145 and n=102, respectively), and controls without cancer (n=1396), having dental visits was associated with a significantly reduced risk of HPV-positive and HPV-negative OC/OPC (OR=0.55 and 0.52, respectively; p<0.05). Tooth mobility was considered a surrogate indicator of periodontal disease, and was associated with a statistically significant increased risk of HPV-negative OC/OPC (OR= 1.70; p<0.05), and to a lesser degree with HPV-positive cases (OR=1.45, not significant).
The authors concluded that there was an association of poor oral health and limited utilization of dental services, for both HPV-positive and HPV-negative OC/OPC. In a study assessing squamous cell carcinoma of the base of the tongue in 21 patients with HPV-positive tumors and 8 patients with HPV-negative tumors, radiographic assessment revealed that mean alveolar bone loss was 3.9 mm and 2.85 mm, respectively (p=0.01).15Tezal M, Sullivan Nasca M, Stoler DL, Melendy T, Hyland A, Smaldino PJ, Rigual NR, Loree TR. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg 2009;135(4):391-6. After adjusting for confounders, a nearly four-fold risk of HPV-positive, base of tongue tumors was associated with each mm of alveolar bone loss. It was concluded that periodontitis may be a significant risk factor.15Tezal M, Sullivan Nasca M, Stoler DL, Melendy T, Hyland A, Smaldino PJ, Rigual NR, Loree TR. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg 2009;135(4):391-6.
Periodontitis may be a significant risk factor for HPV-positive base of tongue tumors.

Biologic Plausability

Periodontal disease and cancers both involve an inflammatory process and inflammatory mediators, including cytokines and prostaglandins. Increased levels of matrix metalloproteinases, tumor necrosis factor-alpha and interleukin1-ß are components of the periodontal inflammatory process and are also found in early tumors.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. ,8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9. ,11Guha N, Boffetta P, Wunsch F, Ilho V, Eluf N, Eto J, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, Szeszenia-Dabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit R, Brennan P. 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. Tumor necrosis factor-alpha is believed to encourage tumorigenesis.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. Inflammatory diseases can also increase risk for some cancers, e.g., ulcerative colitis increases the risk for colorectal cancer.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. ,8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9.,9Tezal M, Sullivan MA, Reid ME, Marshall JR, Hyland A, Loree T, Lillis C, Hauck L, Wactawski-Wende J, Scannapieco FA. Chronic periodontitis and the risk of tongue cancer. Arch Otolaryngol—Head Neck Surg 2007;133:450-4. ,16Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.
Recent research additionally supports a role for bacterial and viral agents and infections in risk for oral cancers.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. ,9Tezal M, Sullivan MA, Reid ME, Marshall JR, Hyland A, Loree T, Lillis C, Hauck L, Wactawski-Wende J, Scannapieco FA. Chronic periodontitis and the risk of tongue cancer. Arch Otolaryngol—Head Neck Surg 2007;133:450-4. Salivary concentrations of periodontal pathogens are significantly higher in patients with OC compared to patients without OC, and periodontal pockets may be reservoirs for viral agents, including HPV associated with OC/OPC (Table 1).6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. ,8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9.
Table 1. Factors in biologic plausibility
CP and OC/OCP both involve an inflammatory process, including metalloproteinases, tumor necrosis factor-alpha, interleukin1-ß
Tumor necrosis factor-alpha may encourage tumorigenesis
Inflammatory disease can increase risk for some cancers
Possible role for bacterial and viral infections in risk for OC
Higher salivary concentrations of periodontal pathogens in patients with OC
Periodontal pockets as reservoirs for viral agents associated with OC/OPC

Implications for Dental Professionals

While causation cannot be implied, there is some evidence to suggest a causal linkage, particularly related to the role of oral microorganisms and periodontal disease and an increased risk for OC/OPC.17Gholizadeh P, Eslami H, Yousefi M, Asgharzadeh M, Aghazadeh M, Kafil HS. Role of oral microbiome on oral cancers, a review. Biomed Pharmacother 2016;84:552-8. However, it is important to remember that periodontal disease and OC also have a number of risk factors in common, including the adverse effect of cigarette smoking, a history of limited utilization/access to dental care, and poor oral hygiene. Further, the prevalence of moderate and severe chronic periodontitis increases with age.18Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ, CDC Periodontal Disease Surveillance workgroup. Prevalence of Periodontitis in Adults in the United States: 2009 and 2010. J Dent Res 2012;91(10):914-20. Therefore, the number of individuals with periodontitis can be expected to increase as the
population ages and the linkages suggest that this may also impact the number of individuals suffering from OC/OPC. From a public health perspective, it is important that dental professionals increase patient education on risk factors for periodontal disease and the linkages found for periodontal disease and OC. Regular dental visits, preventive care and the importance of a healthy lifestyle, including attention to oral hygiene should be emphasized.
It is important that dental professionals increasepatient education on risk factors for periodontal disease and the linkages found for periodontal disease and OC.

Conclusions

Taken together, these findings suggest a linkage between periodontal disease, poor oral hygiene and OC/OPC cancers, which is supported by biologic plausibility. However, several reviews and studies have reported study limitations, including publication bias, study heterogeneity, and varying methods and criteria on how periodontal disease was measured
or reported.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. ,7Moraes RC, Dias FL, Figueredo CM, Fischer RG. Association between chronic periodontitis and oral/oropharyngeal cancer. Braz Dent J 2016;27:261-6. ,8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9. Further research and robust studies are needed to further clarify the relationship between periodontal disease and oral/oropharyngeal cancers, including potential interactions with oral HPV.6Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240. ,7Moraes RC, Dias FL, Figueredo CM, Fischer RG. Association between chronic periodontitis and oral/oropharyngeal cancer. Braz Dent J 2016;27:261-6. ,8Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9. ,15Tezal M, Sullivan Nasca M, Stoler DL, Melendy T, Hyland A, Smaldino PJ, Rigual NR, Loree TR. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg 2009;135(4):391-6.

References

  • 1.Chung SD, Tsai MC, Huang CC, Kao LT, Chen CH. A population-based study on the associations between chronic periodontitis and the risk of cancer. Int J Clin Oncol 2016;21:219-23.
  • 2.Michaud DS, Fu Z, Shi J, Chung M. Periodontal disease, tooth loss, and cancer risk. Epidemiol Rev 2017;39:49-58.
  • 3.Nwizu NN, Marshall JR, Moysich K, Genco RJ, Hovey KM, Mai X, LaMonte MJ, Freudenheim JL, Wactawski-Wende J. Periodontal disease and incident cancer risk among postmenopausal women: Results from the women's health initiative observational cohort. Cancer Epidemiol Biomarkers Prev 2017;26(8:1255-65.
  • 4.Dizdar O, Hayran M, Guven DC, Yılmaz TB, Taheri S, Akman AC, Bilgin E, Hüseyin B, Berker E. Increased cancer risk in patients with periodontitis. Curr Med Res Opin 2017;33(12):2195-200.
  • 5.Javed F, Warnakulasuriyab 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.
  • 6.Ye L, Jiang Y, Liu W, Tao H. Correlation between periodontal disease and oral cancer risk: A meta-analysis. J Cancer Res Ther 2016;12:C237-C240.
  • 7.Moraes RC, Dias FL, Figueredo CM, Fischer RG. Association between chronic periodontitis and oral/oropharyngeal cancer. Braz Dent J 2016;27:261-6.
  • 8.Laprise C, Shahul HP, Madathil SA, Thekkepurakkal AS, Castonguay G, Varghese I, Shiraz S, Allison P, Schlecht NF, Rousseau MC, Franco EL, Nicolau B. Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe life study. Int J Cancer 2016;139:1512-9.
  • 9.Tezal M, Sullivan MA, Reid ME, Marshall JR, Hyland A, Loree T, Lillis C, Hauck L, Wactawski-Wende J, Scannapieco FA. Chronic periodontitis and the risk of tongue cancer. Arch Otolaryngol—Head Neck Surg 2007;133:450-4.
  • 10.Tezal M, Grossi SG, Genco RJ. Is periodontitis associated with oral neoplasms? J Periodontol 2005;76:406-10.
  • 11.Guha N, Boffetta P, Wunsch F, Ilho V, Eluf N, Eto J, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, Szeszenia-Dabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit R, Brennan P. 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.
  • 12.Divaris K, Olshan A, Smith J, Bell ME, Weissler MC, Funkhouser WK, Bradshaw PT. Oral health and risk for head and neck squamous cell carcinoma: the carolina head and neck cancer study. CCC 2010;21:567-75.
  • 13.Talamini R, Vaccarella S, Barbone F, Tavani A, La Vecchia C, Herrero R, Muñoz N, Franceschi S. Oral hygiene, dentition, sexual habits and risk of oral cancer. Br J Cancer 2000;83:1238-42.
  • 14.Mazul AL, Taylor JM, Divaris K, Weissler MC, Brennan P, Anantharaman D, Abedi-Ardekani B, Olshan AF, Zevallos JP. Oral health and human papillomavirus-associated head and neck squamous cell carcinoma. Cancer 2017;123:71-80.
  • 15.Tezal M, Sullivan Nasca M, Stoler DL, Melendy T, Hyland A, Smaldino PJ, Rigual NR, Loree TR. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg 2009;135(4):391-6.
  • 16.Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.
  • 17.Gholizadeh P, Eslami H, Yousefi M, Asgharzadeh M, Aghazadeh M, Kafil HS. Role of oral microbiome on oral cancers, a review. Biomed Pharmacother 2016;84:552-8.
  • 18.Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ, CDC Periodontal Disease Surveillance workgroup. Prevalence of Periodontitis in Adults in the United States: 2009 and 2010. J Dent Res 2012;91(10):914-20.