August 3, 2016

Gum Disease and Risk of Smoking-Related Cancers in Never-Smoker Men

Update on dental health, immune system, and cancer connection
What do periodontal disease, smoking, inflammation, and cancer have in common? Evidence from a recent study elevates the importance of regular dental care for cancer risk reduction.


Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Ann Oncol. 2016;27(5):941-947.


Prospective cohort study spanning a period of 26 years with a goal to examine the association between periodontal disease and the risk of all cancers among male never smokers. 


Mail questionnaires were sent to male participants, ages 40 to 75, who were healthcare professionals (eg, registered dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, podiatrists). The final count consisted of 19,933 men and was restricted to men who never smoked a cigarette, cigar, or pipe.

Outcome Measures

The mail questionnaires were completed by participants at baseline and on a biennial basis thereafter. They were asked about a history of periodontal disease with bone loss and the number of natural teeth present at baseline and on each subsequent questionnaire. Any newly diagnosed cancers self-reported by participants were confirmed by obtaining participants’ medical records. Further differentiation was made by identifying smoking-related and non–smoking related cancers.  

Key Findings

Periodontal disease at baseline was associated with 13% higher risk of all cancers. Men with advanced periodontitis (with fewer than 17 remaining teeth) had a 44% increased cancer risk. The risk for the most common cancers in this cohort (ie, prostate, colorectal cancer, melanoma) was not increased; however, there was a 33% increase in risk for smoking-related cancers [lung, bladder, oropharyngeal, esophageal, kidney, stomach, and liver; HR: 1.33; 95% confidence interval (CI): 1.07-1.65]. Men with advanced periodontal disease had a stronger association (HR: 2.57; 95% CI:1.56-4.21). Advanced periodontitis was especially associated with increased risk of esophageal and head and neck cancers (HR: 6.29; 95% CI: 13-18.6, based on 5 cases) and bladder cancer (HR: 5.06; 95% CI: 2.32-11.0, based on 9 cases).  

Practice Implications

This study, which took place in the United States, demonstrated a 2.5-fold increase in smoking-related cancers among never smokers with periodontal disease. Given the prevalence rate of periodontitis in the United States, this finding is very clinically relevant. According to Centers for Disease Control and Prevention (CDC) survey data, almost half of Americans ages 30 and older have some form of periodontal disease. The prevalence rate is over 60% for smokers, for adults living below the poverty level, and for adults with less than a high school education. Prevalence rates reach 70% in those 65 years of age or older.1
There is a well-established connection between cancer and periodontitis.
Periodontitis is an ongoing infection of the gums, which leads to inflammation and erosion of periodontal ligament, gingiva, and alveolar bone tissue. The presence of the pathogen in the dental biofilm alone is not enough to cause periodontal disease. The proposed mechanisms of periodontal disease include the presence of imbalanced dysbiotic flora in the mouth, genetic predisposition of the host, and actual dysregulation of host immune responses by bacteria, which manipulates the immune system components (such as neutrophils and complement) to its advantage. Through the interaction between the host and mouth bacteria, inflammation continues and destroys the tissue further.2
Periodontitis-produced inflammatory products can reach the bloodstream and travel through the rest of the body. For example, pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) are released and stimulate other inflammatory mediators. This chain reaction of pro-inflammatory processes increases the body’s susceptibility to other infections and, not surprisingly, becomes linked to a host of many systemic inflammatory diseases.3 Periodontitis is associated with cardiovascular and respiratory diseases, mental disorders, and higher rates of cognitive decline in Alzheimer’s, diabetes, kidney disease, obesity, rheumatoid arthritis, osteoporosis, and complications of pregnancy (such as preterm labor and low birth weight). Moreover, systemic diseases, in turn, can exacerbate periodontal disease.4 The relationship between systemic disease and periodontitis is bidirectional, which illustrates the importance of treating the whole person. 
There is a well-established connection between cancer and periodontitis. Additional studies looked at breast cancer in women5 and pancreatic cancer,6 among others. There is a clear connection between cancer and inflammation, which explains why systemic inflammation from periodontitis is implicated in cancer development. Elevated systemic markers of inflammation in patients with chronic periodontitis include the same ones seen in cancers, such as IL-6, TNF-alpha, and fibrinogen.7
This study excluded smoking (which is a well-known risk factor for gum disease) from the data analysis, and noted an increase only in smoking-related cancers in never smokers.  The authors propose that periodontal disease specifically increases the risk of smoking-related cancers because periodontal disease and smoking trigger the same immune pathways. There is also an epigenetic connection. Smoking is associated with altered DNA methylation patterns, which are linked to immune response. Some bacterial metabolites can also cause immune response through regulatory T (Treg) cells, which are involved in carcinogenesis.8
What does this mean for clinical providers? We can improve our patients' chronic disease states by asking them a simple question: When was your last trip to the dentist? Prevention is key; counsel them on risk reduction, such as avoiding excess alcohol and smoking, including second hand smoke,9 and encourage good oral hygiene, including regular brushing and flossing. Dry mouth, which can be caused by medications (including some common over-the-counter ones, like antihistamines and decongestants), can also promote tooth decay. Encourage a plant-based, low-sugar diet for a healthy microbiome.10 Probiotics can be helpful, especially Lactobacillus species.11 Assessment of inflammatory markers is important, because C-reactive protein is also a marker of periodontal disease.12  Numerous anti-inflammatory agents, including antioxidants and traditional botanicals, may be of use in treatment. Options include vitamin C, zinc, vitamin A, coenzyme Q10 (CoQ10), vitamin E, and folate, as well botanicals, such as turmeric preparations,13 aloe vera,14 berberine,15 and tea tree oil.16


The study identified only a small number of participants with advanced periodontal disease. Periodontal disease was self-reported. No data were available on pocket depth, gingival attachment loss, or periodontal treatment. No female participants and few nonwhite participants were included.

Categorized Under


  1. Thornton-Evans G, Eke P, Wei L. Centers for Disease Control and Prevention (CDC). Periodontitis among adults aged ≥30 years—United States, 2009–2010. MMWR Suppl. 2013;62(3):129-135.  
  2. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015; 15(1):30-44. 
  3. Fernandez-Solari J, Barrionuevo P, and Mastronardi C. Periodontal disease and its systemic associated diseases.  Mediators Inflamm. 2015. doi: 10.1155/2015/153074. 
  4. Nagpal R, Yamashiro Y, Izumi Y. The two-way association of periodontal infection with systemic disorders: an overview.  Mediators Inflamm. 2015. doi: 10.1155/2015/793898.
  5. Freudenheim JL, Genco RJ, LaMonte MJ, et al. Periodontal disease and breast cancer: prospective cohort study of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2016;25(1):43-50. 
  6. Michaud D, Joshipura K, Giovannucci E, Fuchs C. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst. 2007;99(2):171-175.  
  7. Kim J, Amar S. Periodontal disease and systemic conditions: a bidirectional relationship. Odontology. 2006;94(1):10-21. 
  8. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral T cell generation. Nature. 2013;504(7480):451-455.
  9. Akinkugbe AA, Slade GD, Divaris K, Poole C. Systematic review and meta-analysis of the association between exposure to environmental tobacco smoke and periodontitis endpoints among nonsmokers. [published online ahead of print April 15, 2016]. Nicotine Tob Res. doi: 10.1093/ntr/ntw105.
  10. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-563. 
  11. Koll-Klais P, Mandar R, Leibur E, Marcotte H, Hammarstrom L, Mikelsaar M. Oral lactobacilli in chronic periodontitis and periodontal health: species composition and antimicrobial activity. Oral Microbiol Immunol. 2005;20(6):354-361.  
  12. Podzimek S, Mysak J, Janatova T, and Duskova J. C-reactive protein in peripheral blood of patients with chronic and aggressive periodontitis, gingivitis, and gingival recessions. Mediators Inflamm. 2015;2015:564858. doi: 10.1155/2015/564858.
  13. Bhatia M, Urolagin SS, Pentyala KB, Urolagin SB, Menaka KB, Bhoi S. Novel therapeutic approach for the treatment of periodontitis by curcumin. J Clin Diagn Res. 2014;8(12):ZC65-ZC69. doi: 10.7860/JCDR/2014/8231.5343.
  14. Namiranian H, Serino G. The effect of a toothpaste containing aloe vera on established gingivitis. Swed Dent J. 2012; 36(4):179-185.
  15. Tu HP, Fu MM, Kuo PJ, et al. Berberine’s effect on periodontal tissue degradation by matrix metalloproteinases: an in vitro and vivo experiment. Phytomedicine. 2013;20(13):1203-1210.  
  16. Elgendy EA, Ali SA, Zineldeen DH. Effect of local application of tea tree (Melaleuca alternifolia) oil gel on long pentraxin level used as an adjunctive treatment of chronic periodontitis: a randomized controlled clinical study. J Indian Soc Periodontol. 2013;17(4):444-448.